Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(O[CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])(C1C=CC(C)=CC=1)(=O)=O.[NH2:27][C:28]1[CH:29]=[C:30]([CH2:36][OH:37])[CH:31]=[C:32]([CH2:34][OH:35])[CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:35][CH2:34][C:32]1[CH:33]=[C:28]([NH:27][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:29]=[C:30]([CH2:36][OH:37])[CH:31]=1
Reactant: Nc1cc(CO)cc(CO)c1
Reactant: COC(=O)CCOCCOCCOCCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCOCCOCCOCCNc1cc(CO)cc(CO)c1
Temperature: 80 °C
Reaction time: 18 h
Yield: 25.7 %

Procedure:
To a mixture of methyl 3-(2-(2-(2-(tosyloxy)ethoxy)ethoxy)ethoxy)propanoate (263a) (250 mg, 0.640 mmol) and (5-amino-1,3-phenylene)dimethanol (26) (108 mg, 0.704 mmol) in anhydrous DMF (1.4 ml) was added potassium carbonate (133 mg, 0.960 mmol). The reaction stirred for 18 hours at 80° C. and then was allowed to cool to room temperature. The mixture was quenched with water and extracted two times with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (5% Methanol/methylene chloride) yielded methyl 3-(2-(2-(2-(3,5-bis(hydroxymethyl)phenylamino)ethoxy)ethoxy)ethoxy)propanoate (264a) (61 mg, 25%); 1H NMR (400 Hz, CDCl3): δ 6.58 (s, 1H), 6.47 (s, 2H), 4.49 (s, 4H), 3.67 (t, J=6.4 Hz, 2H), 3.62 (s, 3H), 3.64-3.54 (m, 10H), 3.21 (t, J=5.2 Hz, 2H), 2.51 (t, J=6.4 Hz, 2H); MS (m/z). found 394.3 (M+Na)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([OH:13])=O)[NH:8]2)=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[F:19][C:20]([F:34])([F:33])[CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1)[NH2:22].O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.Cl>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11](=[O:13])[NH:22][CH:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:24]=3)[C:20]([F:34])([F:33])[F:19])[NH:8]2)=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)c1cc2cc(C(=O)O)[nH]c2cc1Cl
Reactant: NC(c1cccc(C(F)(F)F)c1)C(F)(F)F
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)[nH]c2cc1Cl
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A solution of the crude 6-chloro-5-(ethoxycarbonyl)-1H-indole-2-carboxylic acid product (1.9 g) and 2,2,2-trifluoro-1-[3-trifluoromethylphenyl]ethanamine (1.12 g, 4.60 mmol) in N,N-dimethylformamide (15 ml) was admixed with 4-(4,6-dimethoxy[1,3,5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (953 ng, 4.60 mmol) and stirred at room temperature for 4 days. The reaction solution was admixed with hydrochloric acid (1 M) and extracted with ethyl acetate. The organic phase was washed with sat, sodium hydrogencarbonate solution and saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure. Column chromatography purification on silica gel with cyclohexane/ethyl acetate as the eluent (gradient from 10% ethyl acetate to 25% ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:21]([CH:23]=[O:24])[N:22]=3)[CH2:14][C@H:13]2[O:30][CH2:31][CH3:32])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl([O-])=[O:34].[Na+].P([O-])(O)(O)=O.[Na+].CC(=CC)C>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:21]([C:23]([OH:34])=[O:24])[N:22]=3)[CH2:14][C@H:13]2[O:30][CH2:31][CH3:32])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: [O-][Cl+][O-]
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC)C2)nc1C=O
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Product: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC)C2)nc1C(=O)O
Yield: 99.3 %

Procedure:
The same operation as in Example (33c) was performed using ethyl cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl)-4-formyl-1,3-thiazole-5-carboxylate obtained in Example (68b) (about 0.63 mmol), sodium chlorite (113 mg, 1.25 mmol), sodium dihydrogenphosphate (320 mg, 2.05 mmol) and 2-methyl-2-butene (0.33 mL, 3.12 mmol), to obtain 312.7 mg of the title compound as a white solid (99%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:8](=O)[CH2:9][CH2:10][CH3:11].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:8]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][CH2:10][CH3:11]
Reactant: Nc1cccnc1
Reactant: CCCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCCNc1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 941 mg (10 mmol) of 3-aminopyridine and 0.9 mL of butyraldehyde in 30 mL of CH3OH was added 10 mL of glacial acetic acid. The mixture was stirred at room temperature for 1 hour, then the reaction was cooled with an ice bath, and 650 mg (10.3 mmol) of sodium cyanoborohydride was added.
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:9]=1[C:10]#[N:11].[Br:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>O1CCCC1>[Br:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:7][C:8]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:9]=2[C:10]#[N:11])=[O:23])=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: N#Cc1ccc(Cl)cc1N
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: N#Cc1ccc(Cl)cc1NC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Pyridine (0.144 mole) is given to a solution of 2-amino-4-chlorobenzonitrile (0,131 mole) in 100 ml tetrahydrofuran (THF) and a solution of 4-bromobenzoylchloride (31,6 g, 0,144 mole) in 50 ml THF is added under nitrogen. After addition of 100 ml THF, the mixture is stirred for 6 h at room temperature (rt). The crude reaction is then customary worked up for solution reactions affording 4-bromo-N-(5-chloro-2-cyano-phenyl)-benzamide as a solid; m.p. 151-152°.
Reaction SMILES: [Cl:1][C:2]1[S:6][N:5]([CH2:7][CH2:8]C=O)[C:4](=[O:11])[CH:3]=1.[CH:12]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])OCC.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>C(O)C>[CH2:20]([O:19][CH:12]([O:16][CH2:17][CH3:18])[CH2:8][CH2:7][N:5]1[C:4](=[O:11])[CH:3]=[C:2]([Cl:1])[S:6]1)[CH3:21]
Reactant: CCOC(OCC)OCC
Reactant: O=CCCn1sc(Cl)cc1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(CCn1sc(Cl)cc1=O)OCC

Procedure:
A solution of compound 5 (2.5 g, 0.013 mole), triethyl orthoformate (3.87 g, 0.026 mole) in 20 ml ethanol and p-toluenesulfonic acid (35 mg) was refluxed for 18 hours. Upon cooling, the mixture was treated with 0.2 ml of triethylamine and extracted with diethyl ether. The extract was then washed successively with NaHCO3 solution, water and brine. After drying (MgSO4), the solvent was removed in vacuo. The residual brown oil was purified by column chromatography on silica gel, using diethyl ether/hexane (4/1) as eluant. The product was obtained as a light brown oil; 2.2 g; IR (neat) 1625 cm-1 ; NMR (CDCl3) δ6.3 (s, 1H); 4.6 (t, 1H); 3.85 (t, 2H); 3.4-3.8 (m, 4H); 2.0 (q, 2H); 1.2 (t, 6H).
Reaction SMILES: [CH:1]([B-](F)(F)F)=[CH2:2].[K+].C(N(CC)CC)C.Br[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[N:17]=1.C(=O)([O-])O.[Na+]>C(O)CC>[F:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([CH:1]=[CH2:2])[N:17]=1
Reactant: C=C[B-](F)(F)F
Reactant: Fc1cccc(Br)n1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCCO
Product: C=Cc1cccc(F)n1
Temperature: 100 °C
Reaction time: 11 h
Yield: 35.7 %

Procedure:
Potassium vinyltrifluoroborate (2.28 g), triethylamine (2.38 mL) and [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane complex (928 mg) were added in that order to an n-propanol solution (12 mL) of 2-bromo-6-fluoropyridine (2.0 g), and stirred at 100° C. for 11 hours, and then at room temperature for 2 days. Saturated sodium hydrogencarbonate solution was added to the reaction liquid, and extracted with ethyl acetate. The organic layer was washed with saturated saline water, dried, concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (hexane/ethyl acetate=9/1) to obtain the entitled compound (500 mg).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[F:5][C:6]1[CH:7]=[C:8]([S:12]([NH:15][C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][N:20]=[C:19]3[NH2:25])(=[O:14])=[O:13])[CH:9]=[CH:10][CH:11]=1.N1C=CC=CC=1>O>[F:5][C:6]1[CH:7]=[C:8]([S:12]([NH:15][C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][N:20]=[C:19]3[NH:25][C:1](=[O:3])[CH3:2])(=[O:13])=[O:14])[CH:9]=[CH:10][CH:11]=1
Reactant: Nc1n[nH]c2ccc(NS(=O)(=O)c3cccc(F)c3)cc12
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1n[nH]c2ccc(NS(=O)(=O)c3cccc(F)c3)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-[5-(3-Fluorobenzenesulfonylamino)-1H-indazol-3-yl)acetamide can be obtained in the following way: 0.037 ml of acetyl chloride is added dropwise to a solution, cooled to 0° C., of 0.16 g of 3-fluoro-N-(3-amino-1H-indazol-5-yl)benzenesulfonamide and of 3.2 ml of pyridine. The reaction medium is then maintained with stirring at a temperature in the region of 25° C. overnight. After addition of 20 ml of water, the medium is extracted with three times 10 ml of ethyl acetate. The pooled organic phases are dried over magnesium sulfate, filtered and concentrated by evaporation under reduced pressure. The residue thus obtained is purified by chromatography on a silica column with a dichloromethane/methanol (97.5/2.5 by volume) mixture as eluent. The solid obtained is recrystallized from 6 ml of isopropanol. 0.1 g of N-[5-(3-fluorobenzenesulfonylamino)-1H-indazol-3-yl)acetamide is thus obtained, after drying under reduced pressure at 60° C., in the form of a white solid melting at 246° C. (analysis C15H13FN4O3S.0.2H2O % calculated C, 51.73, H, 3.76; F, 5.45; N, 16.08; O, 13.78; S, 9.20. % found C, 51.75; H, 2.82; F, 5.07; N, 16.04; S, 8.13).
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][CH:5]=[C:4]([Cl:9])[N:3]=1.[CH2:10]([O:12]/[CH:13]=[CH:14]/B1OC(C)(C)C(C)(C)O1)[CH3:11]>O1CCOCC1.O.[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[Cl:1][C:2]1[C:7](/[CH:11]=[CH:10]/[O:12][CH2:13][CH3:14])=[CH:6][CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: Clc1ccc(I)c(Cl)n1
Reactant: CCO/C=C/B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: O
Solvent: C1COCCO1
Product: CCO/C=C/c1ccc(Cl)nc1Cl
Temperature: 70 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
To a degassed solution of 2,6-dichloro-3-iodopyridine (3.0 g, 11 mmol) and (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.2 g, 11 mmol) in 1,4-dioxane (20 mL) and water (1.0 mL) was added CS2CO3 (7.1 g, 22 mmol) and 1,1′-bis(di-tert-butylphosphino)ferrocene palladium chloride (357 mg, 0.54 mmol) under N2 protection. The resulting mixture was heated to 70° C. and stirred at this temperature overnight. The reaction was cooled, filtered through a pad of the celite and washed with ethyl acetate. The combined filtrate was evaporated in vacuo. The resulting residue was purified using column chromatography (eluted with 0-20% EtOAc/DCM) to provide (E)-2,6-dichloro-3-(2-ethoxyvinyl)pyridine (1.96 mg, yield: 86%). MS (M+H)+: 218.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[NH2:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[C:13]2[S:18]([NH:21][C:22]1[O:26][N:25]=[C:24]([CH3:27])[C:23]=1[CH3:28])(=[O:20])=[O:19].C(=O)([O-])O.[Na+]>N1C=CC=CC=1.CC(C)=O>[CH3:27][C:24]1[C:23]([CH3:28])=[C:22]([NH:21][S:18]([C:13]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:14]=2[CH:15]=[CH:16][CH:17]=[C:8]3[NH:7][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])(=[O:20])=[O:19])[O:26][N:25]=1
Reactant: Cc1noc(NS(=O)(=O)c2cccc3c(N)cccc23)c1C
Reactant: CC(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: Cc1noc(NS(=O)(=O)c2cccc3c(NC(=O)C(C)C)cccc23)c1C
Reaction time: 2.5 h
Yield: 51 %

Procedure:
Isobutyryl chloride (0.144 mL, 1.38 mmol) was added dropwise to a solution of Example 3 (0.350 g, 1.10 mmol) in pyridine (1 mL) and acetone (7 mL). The mixture was stirred for 2.5 hours and the acetone was removed under vacuum to leave a thick brown residue, which was added dropwise to half-saturated sodium hydrogen carbonate (30 mL). The pH of the resulting mixture was adjusted to 8-8.5 with saturated sodium hydrogen carbonate. The crude product was precipitated by acidifying the solution to pH 1.5 with 6N hydrochloric acid, filtered and dried. Recrystallization from methanol/water afforded 51% of a solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[N:3]1.C([Li])CCC.[CH2:12]([N:19]1[CH2:23][C@H:22]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:21][C@H:20]1[CH:32]=[O:33])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCCC1.CCCCCC>[CH2:12]([N:19]1[CH2:23][C@H:22]([O:24][Si:25]([C:28]([CH3:29])([CH3:30])[CH3:31])([CH3:27])[CH3:26])[CH2:21][C@H:20]1[CH:32]([C:6]1[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=1)[OH:33])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](C=O)N(Cc2ccccc2)C1
Reactant: Cn1cccn1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cn1nccc1C(O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1Cc1ccccc1
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
To a solution of 1-methylpyrazole (30.5 g) in tetrahydrofuran (460 ml) was added dropwise n-butyllithium (1.6N) in hexane (250 ml) keeping the temperature below -60° C. The mixture was warmed to 0°-5° C. over 30 minutes, and stirred for 30 minutes, then cooled to -70°~60° C. To the mixture was added a solution of (2S,4R)-1-benzyl-4-(t-butyldimethylsilyloxy)-2-formylpyrrolidine (91.4 g) in tetrahydrofuran (90 ml) keeping the temperature below -60° C. The reaction mixture was warmed to 0°-5° C. over 40 minutes, and stirred for 2 hours. The mixture was quenched with ice water (300 ml) and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (×2), and the combined organic layer was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was column chromatographed on silica gel (3 kg, eluting with ethyl acetate-n-hexane (1:1 to 5:1)) to give 1-{(2S,4R)-1-benzyl-4-(t-butyldimethylsilyloxy)-pyrrolidin-2-yl }-1-(1-methylpyrazol-5-yl)methanol (101 g) (as a 2:1 mixture of diastereomer).
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C@H:2]([CH3:4])[OH:3].N1C=CN=C1.[CH3:14][C:15]([Si:18](Cl)([CH3:20])[CH3:19])([CH3:17])[CH3:16]>C(Cl)Cl.O>[CH2:7]([O:6][C:1](=[O:5])[C@@H:2]([O:3][Si:18]([C:15]([CH3:17])([CH3:16])[CH3:14])([CH3:20])[CH3:19])[CH3:4])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)[C@H](C)O
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)[C@H](C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of (S)-(−)-ethyl lactate (37.4 g, 0.32 mol) in DCM (200 mL) was added imidazole (25.75 g, 0.38 mol) and TBSCl (50 g, 0.33 mol). The reaction mixture was stirred at room temperature for 2 hours. The reaction was diluted with water and extracted with DCM (2×50 mL), the combined organic extracts washed with brine dried (MgSO4) and concentrated in vacuo to give the title product as a colourless oil (100%). 1H NMR (CDCl3, 400 MHz) 4.21 (1 H, q, J=6.73 Hz), 4.14-4.01 (2H, m), 1.29 (3H, d, J=6.79 Hz), 1.18 (3H, t, J=7.09 Hz), 0.80 (9H, s), −0.01 (6H, s).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[C:14]([C:15](=[O:17])[NH2:16])=[N:13][CH:12]=[C:11]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=3)[N:10]=2)[CH:5]=[CH:4][C:3]=1[N:28]1[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]1.FC(F)(F)C(O)=O>ClCCCl>[Br:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[C:14]([C:15]([NH2:16])=[O:17])=[N:13][CH:12]=[C:11]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=3)[N:10]=2)[CH:5]=[CH:4][C:3]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3nc(Oc4cccc([N+](=O)[O-])c4)cnc3C(N)=O)cc2Br)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: NC(=O)c1ncc(Oc2cccc([N+](=O)[O-])c2)nc1Nc1ccc(N2CCNCC2)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
To a mixture of tert-butyl 4-(2-bromo-4-{[3-carbamoyl-6-(3-nitrophenoxy)pyrazin-2-yl]amino}phenyl)piperazine-1-carboxylate (682 mg) and 1,2-dichloroethane (7 mL) was added trifluoroacetic acid (3 mL) under ice-cooling, and followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, then diluted with chloroform, and neutralized with a 10% aqueous potassium carbonate solution. After extracting with chloroform, the organic phase was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 3-{[3-bromo-4-(piperazin-1-yl)phenyl]amino}-5-(3-nitrophenoxy)pyrazine-2-carboxamide (523 mg) as a yellow amorphous substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]([OH:28])=[O:27])=[CH:21][CH:20]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=O)=[C:4]([CH3:29])[CH:3]=1.Cl.[NH2:31][OH:32].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]([OH:28])=[O:27])=[CH:21][CH:20]=2)[CH2:9]/[C:10](=[N:31]\[OH:32])/[C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[C:4]([CH3:29])[CH:3]=1
Reactant: NO
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(CC(=O)O)cc2)c2ccc(Cl)cc2C)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(C[C@H](c2ccc(CC(=O)O)cc2)c2ccc(Cl)cc2C)=N/O)ccn1

Procedure:
In analogy to example 132, step 6, from (R)-2-(4-(1-(4-chloro-2-methylphenyl)-3-(2-methylpyridin-4-yl)-3-oxopropyl)phenyl)acetic acid and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a white solid, MS (ESI+): m/z=423.2 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](C(C3C(C)=NC(C)=CC=3)O)[CH:10]=2)[N:5]=[C:4]([O:22][CH3:23])[C:3]=1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1.N1(C2C=CC(CC3C(Cl)=NC4C(C=3Cl)=CC(Br)=CC=4C)=CC=2)C=CC=N1.[CH3:61][N:62]1[C:66]([C:67]([CH:69]2[CH2:74][CH2:73][O:72][CH2:71][CH2:70]2)=[O:68])=[CH:65][N:64]=[C:63]1[CH3:75].S1C(CC2C(OC)=NC3C(C=2Cl)=CC(C(C2N(C)C=NC=2)(C2C=NC(C(F)(F)F)=CC=2)O)=CC=3)=CC2C=CC=CC1=2>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:67]([C:66]3[N:62]([CH3:61])[C:63]([CH3:75])=[N:64][CH:65]=3)([CH:69]3[CH2:74][CH2:73][O:72][CH2:71][CH2:70]3)[OH:68])[CH:10]=2)[N:5]=[C:4]([O:22][CH3:23])[C:3]=1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:27][CH:26]=1
Reactant: Cc1ncc(C(=O)C2CCOCC2)n1C
Reactant: COc1nc2ccc(C(O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: COc1nc2ccc(C(O)(c3ccc(C(F)(F)F)nc3)c3cncn3C)cc2c(Cl)c1Cc1cc2ccccc2s1
Agent: Cc1cc(Br)cc2c(Cl)c(Cc3ccc(-n4cccn4)cc3)c(Cl)nc12
Product: COc1nc2ccc(C(O)(c3cnc(C)n3C)C3CCOCC3)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1

Procedure:
The title compound was prepared analogously to the method described in Example 78, using 6-bromo-4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline (Intermediate 12: step d) in place of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-2,4-dichloro-8-methylquinoline (Intermediate 57) and (1,2-dimethyl-1H-imidazol-5-yl)(tetrahydro-2H-pyran-4-yl)methanone (Intermediate 31) in place of 1-(4-(6-(trifluoromethyl)nicotinoyl)piperidin-1-yl)ethanone (Intermediate 56: step d). MS m/e 560.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[C:11](=[O:21])[CH2:12][C:13]1[NH:18][C:17](=[O:19])[CH:16]=[C:15](Cl)[N:14]=1.[OH2:22]>CC1OCCNC1>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[C:11](=[O:21])[CH2:12][C:13]1[NH:18][C:17](=[O:19])[CH:16]=[C:15]([N:6]2[CH2:7][CH2:8][O:22][CH:4]([CH3:3])[CH2:5]2)[N:14]=1
Reactant: O
Reactant: O=C(Cc1nc(Cl)cc(=O)[nH]1)N1CCc2c(F)cccc21
Agent: CC1CNCCO1
Product: CC1CN(c2cc(=O)[nH]c(CC(=O)N3CCc4c(F)cccc43)n2)CCO1

Procedure:
A solution of 200 mg of 2-[2-(4-fluoro-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-chloro-3H-pyrimidin-4-one in 2 ml of 2-methylmorpholine is heated at 100° C. for 15 minutes. The reaction medium is taken up with 10 ml of water. The solid formed is filtered off and washed with water and then dried so as to give 216 mg of 2-[2-(4-fluoro-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-(2-methylmorpholin-4-yl)-3H-pyrimidin-4-one in the form of a beige solid, the characteristics of which are the following:
Reaction SMILES: CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1.C(=O)=O.C[O:21][C:22]([C:24]1[C:25]([CH2:41][CH2:42][O:43][CH3:44])=[N:26][C:27]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)=[N:28][C:29]=1[CH3:30])=O>O1CCCC1>[CH3:44][O:43][CH2:42][CH2:41][C:25]1[C:24]([CH2:22][OH:21])=[C:29]([CH3:30])[N:28]=[C:27]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)[N:26]=1
Reactant: COCCc1nc(-c2ccc(C(F)(F)F)cc2)nc(C)c1C(=O)OC
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COCCc1nc(-c2ccc(C(F)(F)F)cc2)nc(C)c1CO
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 103.6 %

Procedure:
A 1.2 M solution of DIBALH in toluene (34.6 ml, 41.5 mmol) was added dropwise to a dry-ice cooled solution of 4-(2-methoxy-ethyl)-6-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid methyl ester (4.9 g, 13.8 mmol) in tetrahydrofuran (50 ml). The reaction mixture was stirred for 15 min at −70° C., the dry-ice bath was removed and the reaction temperature was allowed to come to RT. The reaction mixture was stirred for 2 h at RT. Under ice-cooling 6 N aqueous HCl (10 ml) was carefully added. After 4 min ether was added, the layers were separated and the organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure to give 4.67 g (14.3 mmol, quant.) of crystalline [4-(2-methoxy-ethyl)-6-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-methanol.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH:9](=[N:16][OH:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>CN(C=O)C>[Cl:1][C:10]1([CH:9]=[N:16][OH:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH2:11]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: ON=Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: ON=CC1(Cl)C=CC=CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N-chlorosuccinimide (4.63 g, 34.7 mmol) was added to a solution of benzaldehyde oxime (3.5 g, 28.9 mmol) in DMF (30 ml) at RT, causing the temperature to rise briefly to 50° C. The reaction mixture was cooled in an ice bath, stirred for 3 h at RT, mixed with water (100 ml) while being pooled with ice and extracted with ether (3×100 ml). The combined organic phases were washed with water (150 ml) and sat. aq. NaCl solution (150 ml), dried and the solvent was removed under vacuum. The desired product 1-chloro-1-hydroxyiminomethylbenzene was obtained as a yellowish solid (4.28 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:15])[C:7]3[N:8]([CH:12]=[CH:13][CH:14]=3)[NH:9][C:10]=2[CH:11]=1.O1CCC[CH2:17]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[N:9][N:8]1[CH:12]=[CH:13][CH:14]=[C:7]1[C:6]=2[O:15][CH3:17]
Reactant: C1CCOC1
Reactant: O=c1c2ccc(Cl)cc2[nH]n2cccc12
Product: COc1c2ccc(Cl)cc2nn2cccc12
Reaction time: 48 h

Procedure:
Diazomethane was prepared by adding Diazald® (21.4 g) in 200 ml of ether to potassium hydroxide (5.0 g) in 20 ml of 50% ethanol/water solution and then distilling. This procedure was followed three times to give a solution of diazomethane (16.25 g) in ether which was then added to a stirred slurry of 7-chloropyrrolo[1,2-b]cinnolin-10(5H)-one (37.0 g) in 250 ml of tetrahydrofuran. The mixture was allowed to stand at room temperature for 48 hours and then the volatiles were removed. The residue was taken up in dichloromethane and washed several times with water. The organic layer was dried (MgSO4), filtered and concentrated to a dark orange powder. The powder was purified by flash chromatography (silica, dichloromethane) to give 18.35 g of an orange powder. A five gram portion of this powder was recrystallized from ether to give 4.3 g of an orange fibrous material, mp 128°-129°.