Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>ClCCl>[C:16]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1cccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cccnc1)OCc1ccccc1
Reaction time: 8 h
Yield: 39.3 %

Procedure:
To a solution of 3-aminopyridine (10 g, 0.106 mol) and triethyl amine (16.3 mL, 0.117 mol) in dichloromethane (100 mL) at 0° C., was added benzyl chloroformate (15.2 mL, 0.106 mol) slowly. The reaction mixture was stirred overnight and was washed with water, saturated NaHCO3, dried over MgSO4, and evaporated. The residue was purified on a silica gel column to give the product (9.51 g)
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C[O:12][C:13](=O)[C:14]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:15]=1[NH2:21].CO.C(OCC)(=O)C>C1COCC1>[NH2:21][C:15]1[CH:16]=[CH:17][C:18]([I:20])=[CH:19][C:14]=1[CH2:13][OH:12]
Reactant: COC(=O)c1cc(I)ccc1N
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ccc(I)cc1CO
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of diisobutylaluminium hydride (210 cm3 of a 1.5M solution in THF) was added at -30° to a stirred solution of methyl-2-amino-5-iodobenzoate (28.0 g) in THF (100 cm3) under nitrogen. The mixture was warmed to room temperature, stirred for 16 hours and treated with methanol (35 cm3). Ethyl acetate (500 cm3) was added and the mixture filtered to remove inorganic material. The filtrate was concentrated in vacuo to afford a solid which was chromatographed on silica (Merck "MK 60.9385") eluting wiht chloroform:methanol, 49:1 (by volume), and the requisite fractions were combined and evaporated in vacuo to give 2-amino-5-iodobenzyl alcohol, m.p. 125°, (19.0 g).
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH3:4][OH:5].Br[CH2:7][C:8](=[CH2:13])[C:9]([O:11][CH3:12])=[O:10]>CO>[CH3:1][O:2][CH2:7][CH:8]([CH2:13][O:5][CH3:4])[C:9]([O:11][CH3:12])=[O:10]
Reactant: C=C(CBr)C(=O)OC
Reactant: C[O-]
Reactant: CO
Agent: [Na+]
Product: COCC(COC)C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a 28% sodium methoxide/methanol solution (4.24 g) in methanol (35 mL) was added methyl 2-(bromomethyl)acrylate (1.79 g) in methanol (10 mL). The mixture was stirred at room temperature for 2 hours and was heated to reflux for 3 hours. The reaction mixture was poured into 2N hydrochloric acid-ice, then extracted with ethyl acetate. The obtained organic layer was washed with brine, dried and concentrated to give the title compound (1.33 g) having the following physical data.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([C:20]1[CH:25]=[C:24]([CH3:26])[N:23]=[C:22]([N:27]2[CH:31]=[CH:30][N:29]=[CH:28]2)[N:21]=1)[CH2:6][C:7]([NH:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=[O:8].O.[O-:33][C:34]#[N:35].[K+]>N1C=CC=CC=1>[NH:1]([CH2:2][CH2:3][CH2:4][N:5]([C:20]1[CH:25]=[C:24]([CH3:26])[N:23]=[C:22]([N:27]2[CH:31]=[CH:30][N:29]=[CH:28]2)[N:21]=1)[CH2:6][C:7]([NH:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=[O:8])[C:34]([NH2:35])=[O:33]
Reactant: COc1ccc(CCNC(=O)CN(CCCN)c2cc(C)nc(-n3ccnc3)n2)cc1
Reactant: N#C[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(CCNC(=O)CN(CCCNC(N)=O)c2cc(C)nc(-n3ccnc3)n2)cc1
Temperature: 80 °C

Procedure:
To 2-[(3-aminopropyl)[2-(1H-imidazol-1-yl)-6-methyl-4-pyrimidinyl]amino]-N-[2-(4-methoxyphenyl)ethyl]acetamide (135 mg, 0.32 mmol) (a compound of formula (Yc6)) in pyridine (1.5 mL) was added water (1.5 mL) solution of potassium cyanate (64 mg, 0.76 mmol). The mixture was stirred and heated in an oil bath at 80° C. overnight. The mixture was poured into water and extracted with ethyl acetate (3×20 mL). The combined ethyl acetate fractions were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (9:1 CH3CN/NH4OH) to afford 2-[[3-(ureido)propyl][2-(1H-imidazol-1-yl)-6-methyl-4-pyrimidinyl]amino]-N-[2-(4-methoxyphenyl)ethyl]acetamide, a compound of formula (Yc9); as a white solid; NMR (DMSO-d6, 90 C) 8.4 (s, 1), 7.8 (s, 1), 7.05 (d, 2), 7.0 (s, 1), 6.75 (d, 2), 6.4 (s, 1), 4.1 (s, 2), 3.7 (s, 3), 3.5 (m, 2), 3.25 (m, 2), 3.05 (m, 2), 2.65 (t, 2), 2.3 (s, 3), 1.7 (m, 2) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[C:12]([C:14]([OH:16])=[O:15])[N:11]=[CH:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].S(=O)(=O)(O)O.[CH3:22]O>>[CH3:22][O:15][C:14]([C:12]1[N:11]=[CH:10][N:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH:13]=1)=[O:16]
Reactant: O=C(O)c1cn(-c2ccc(Cl)c(Cl)c2)cn1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cn(-c2ccc(Cl)c(Cl)c2)cn1
Yield: 81 %

Procedure:
A mixture of 1-(3,4-dichloro-phenyl)-1H-imidazole-4-carboxylic acid (7.0 g, 27 mmol), methanol (150 ml) and conc. sulfuric acid (25 ml) was refluxed for 3 h. The solution was then concentrated to 80 ml and a solution of sodium carbonate (60 g) in H2O at 0° C. (500 ml) was added. Extraction with CH2Cl2, drying of the organic phase and evaporation of the solvent gave a brown residue, which upon triturating with ether gave the title compound (6.0 g, 81%) as a light brown solid. MS: m/e=269.9 (M+).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]1[C:18]([OH:20])=[O:19])=O)(C)(C)C.[OH:21][NH:22][C:23](=[NH:25])[CH3:24].[ClH:26].[CH3:27]N(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.Cl.O1CCOCC1>>[ClH:26].[CH3:24][C:23]1[N:25]=[C:27]([C:9]2([C:18]([OH:20])=[O:19])[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:16][CH2:17][NH:8]2)[O:21][N:22]=1
Reactant: CC(=N)NO
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)N1CCc2ccccc2C1C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Product: Cc1noc(C2(C(=O)O)NCCc3ccccc32)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2-(tert-butyoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (2.00 g, 7.21 mmol), N-hydroxyacetamidine (1.39 g, 18.8 mmol), [3-(dimethylamino)propyl]ethyl carbodiimide hydrochloride (3.04 g, 15.9 mmol), and 1-hydroxybenzotriazole (1.55 g, 1.01 mmol) was heated to 100° C. for 18 hours, then cooled to rt and concentrated in vacuo. The resultant residue was redissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered, concentrated in vacuo, and subjected to silica gel chromatography from 0 to 20% ethyl actate in hexanes. To a solution of the resultant compound (0.600 g, 1.90 mmol) was added 4 N HCl in dioxane (1.42 mL, 4.26 mmol). After 2 hours, the reaction was concentrated in vacuo to provide the title compound as a beige solid that gave a proton NMR spectrum consistent with theory and a mass ion (ES+) of 216.2. This crude intermediate was used to prepare Example 21, by the procedure described for Example 1.
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][CH2:15][OH:16].C(N(CC)CC)C.[N+:25]([C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1)([O-:27])=[O:26]>O1CCCC1>[O:17]=[S:2]1(=[O:1])[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][CH2:15][O:16][S:34]([C:31]1[CH:30]=[CH:29][C:28]([N+:25]([O-:27])=[O:26])=[CH:33][CH:32]=1)(=[O:35])=[O:36]
Reactant: O=C1c2cccnc2S(=O)(=O)N1CCCCO
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1c2cccnc2S(=O)(=O)N1CCCCOS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 4 h

Procedure:
To a stirred solution of 0.73 g of 1,1-dioxido-2-(4-hydroxybutyl)-isothiazolo[5,4-b]pyridin-3(2H)-one and 0.8 mL of triethylamine in 50 mL of dry tetrahydrofuran at 0° C. was added 0.63 g of technical grade 4-nitrobenzenesulfonyl chloride. After 4 h, the solution was filtered and concentrated to dryness under reduced pressure. The residue was dissolved in 100 mL of ethyl acetate, washed with 10 mL of saturated sodium carbonate and dried over MgSO4. Concentration under reduced pressure gave 1.4 g of crude 1,1-dioxido-2-(4-(4-nitrobenzenesulfonyloxy)butyl)-isothiazolo[5,4-b]pyridin-3(2H)-one as an oil. The crude product was a mixture of 4-nitrobenzenesulfonate contaminated with a small amount of chloride by NMR, and was used in the next step without further purification.
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[CH:12]=[C:11]([CH3:13])[O:10][N:9]=1.[C:14](Cl)(=O)[O:15]C1C=CC=CC=1.[NH2:24][C:25]1[CH:26]=[C:27]([CH:44]=[CH:45][C:46]=1[F:47])[O:28][C:29]1[CH:30]=[CH:31][C:32]2[N:33]([CH:35]=[C:36]([NH:38][C:39]([CH:41]3[CH2:43][CH2:42]3)=[O:40])[N:37]=2)[N:34]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[F:47][C:46]1[CH:45]=[CH:44][C:27]([O:28][C:29]2[CH:30]=[CH:31][C:32]3[N:33]([CH:35]=[C:36]([NH:38][C:39]([CH:41]4[CH2:43][CH2:42]4)=[O:40])[N:37]=3)[N:34]=2)=[CH:26][C:25]=1[NH:24][C:14]([NH:7][C:8]1[CH:12]=[C:11]([CH3:13])[O:10][N:9]=1)=[O:15]
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Reactant: Cc1cc(N)no1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1cc(NC(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2F)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.4 %

Procedure:
To a solution of pyridine (475 mg, 6 mmol) and 3-amino-5-methylisoxazole (147 mg, 1.5 mmol) in N,N-dimethylformamide (2.0 mL) was added dropwise a solution of phenyl chlorocarbonate (235 mg, 1.5 mmol) in N,N-dimethylformamide (2.0 mL) under ice-cooling. After the mixture was stirred at room temperature for 2 hr, N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (327 mg, 1.0 mmol) was added to the mixture, and the mixture was stirred at 80° C. for 15 hr and at 100° C. for 2 hr. Under ice-cooling, aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by basic silica gel column chromatography (ethyl acetate/hexane=80/20→100/0) and recrystallized from tetrahydrofuran/ethanol to give the title compound (101 mg, 22%) as colorless crystals.
Reaction SMILES: [NH:1]([CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[CH2:9][CH2:10][CH2:11][C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH:8]2[N:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:12](=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:16][CH:17]=1
Reactant: O=C(O)CCCC(Nc1ccccc1)c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: O=C1CCCC(c2ccc(Cl)cc2)N1c1ccccc1
Reaction time: 1.5 h
Yield: 80.3 %

Procedure:
(2)-(b) To a suspended solution of 2.0 g of 5-anilino-5-(4-chlorophenyl)pentanoic acid in 10 ml of toluene and 520 mg of pyridine was added 1.21 g of acetic anhydride at 25° C., and the solution was stirred at same temperature for 1.5 hours. Then, the reaction solution was treated in the same manner as in Example 1-(2)-(a) to give 1.51 g of 6-(4-chlorophenyl)-1-phenyl-2-piperidone.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2([CH3:14])[CH2:13][CH2:12]2)=[C:5]([CH:15]([CH3:17])[CH3:16])[CH:4]=1)#[CH:2].[CH3:18][O:19][C:20](=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=1>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:18][O:19][C:20](=[O:29])[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][O:10][C:11]3([CH3:14])[CH2:12][CH2:13]3)=[C:5]([CH:15]([CH3:17])[CH3:16])[CH:4]=2)=[CH:26][CH:27]=1
Reactant: C#Cc1ccc(COC2(C)CC2)c(C(C)C)c1
Reactant: COC(=O)Cc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(C#Cc2ccc(COC3(C)CC3)c(C(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 60.2 %

Procedure:
Using General Procedure F; 4-ethynyl-2-isopropyl-1-(1-methyl-cyclopropoxymethyl)-benzene (Intermediate 166, 78.0 mg, 0.34 mmol) and methyl-(4-iodophenyl)-acetate (Reagent B, 94.0 mg, 0.34 mmol) in triethylamine (8 mL) was treated with copper(I)iodide (22.0 mg, 0.11 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (79 mg, 0.11 mmol) was added and the reaction mixture was stirred at room temperature for 3.5 hours. Column chromatography (2-5% EtOAc-hexanes) afforded 77.0 mg (60%) of the title compound as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:13][CH:12]([OH:14])[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:15][S:16](Cl)(=[O:18])=[O:17].O>N1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:11][CH:12]([O:14][S:16]([CH3:15])(=[O:18])=[O:17])[CH2:13]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1ccc(N2CC(O)C2)cc1
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)OC1CN(c2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
1-(4-Nitro-phenyl)-azetidin-3-ol (which was obtained in Example 396) (5.0 g, 25.8 mmol) was added to a solution of methanesulfonyl chloride (2.2 mL, 28.3 mmol) in dry pyridine (35 mL) and stirred at room temperature overnight. Water was added and the resultant precipitate was captured on a filter, washed with water, methanol, and hexanes to give 3.72 g of the desired product as an orange solid; 1H NMR (DMSO-d6) δ3.35 (s, 3H), 4.15 (m, 3H), 4.45 (m, 2H), 5.48 (m, 1H), 6.53 (d, 2H, J=9.12 Hz), 8.09 (d, 2H, J=9.12 Hz); MS (ES) m/z: 273.5 (MH+); Anal. Calcd. for C10H12N2O5S: C, 44.1 1; H, 4.44; N, 10.29. Found: C, 44.50; H, 4.48; N, 10.64.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:27]=[C:28]([NH:37][C:38]([C@H:40]2[C:49]3[C:44](=[CH:45][C:46]([O:50][CH3:51])=[CH:47][CH:48]=3)[CH2:43][CH2:42][NH:41]2)=[O:39])[CH:29]=[C:30]([F:36])[C:31]=1[Si:32]([CH3:35])([CH3:34])[CH3:33].[C:52]([O:56][C:57](=[O:66])[CH2:58][C@H:59]1[CH2:62][C@H:61]([C:63](O)=[O:64])[CH2:60]1)([CH3:55])([CH3:54])[CH3:53].CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:25][C:26]1[CH:27]=[C:28]([NH:37][C:38]([C@H:40]2[C:49]3[C:44](=[CH:45][C:46]([O:50][CH3:51])=[CH:47][CH:48]=3)[CH2:43][CH2:42][N:41]2[C:63]([C@H:61]2[CH2:60][C@H:59]([CH2:58][C:57]([O:56][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:66])[CH2:62]2)=[O:64])=[O:39])[CH:29]=[C:30]([F:36])[C:31]=1[Si:32]([CH3:33])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@H](C(=O)O)C1
Reactant: COc1ccc2c(c1)CCN[C@H]2C(=O)Nc1cc(F)c([Si](C)(C)C)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ccc2c(c1)CCN(C(=O)[C@H]1C[C@H](CC(=O)OC(C)(C)C)C1)[C@H]2C(=O)Nc1cc(F)c([Si](C)(C)C)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
HATU (55.7 mg, 0.15 mmol) was added to a solution of (R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide (52 mg, 0.13 mmol), trans-3-(2-(tert-butoxy)-2-oxoethyl)cyclobutanecarboxylic acid (30.0 mg, 0.14 mmol) and DIEA (0.026 mL, 0.15 mmol) in DMF (2 mL) at room temperature, and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the precipitate was collected by filtration, and washed with water to give tert-butyl 2-(trans-3-((R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclobutyl)acetate (64.0 mg, 0.109 mmol, 82%) as a white solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1.[Br:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([Br:23])[C:15]=1OC.Cl>CN(C=O)C.O>[Br:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([Br:23])[C:15]=1[CH:10]([C:7]1[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][CH:6]=1)[C:11]#[N:12]
Reactant: N#CCc1ccc(Cl)cc1
Reactant: COc1c(Br)cc([N+](=O)[O-])cc1Br
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC(c1ccc(Cl)cc1)c1c(Br)cc([N+](=O)[O-])cc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 46.2 %

Procedure:
NaH (0.0772 mol) was added portionwise at 0° C. under N2 flow to a mixture of 4-chloro-benzeneacetonitrile (0.0643 mol) in DMF (50 ml). The mixture was stirred at 0° C. under N2 flow for 1 hour. A mixture of 1,3-dibromo-2-methoxy-5-nitro-benzene (0.0643 mol) in DMF (50 ml) was added at 0° C. under N2 flow. The mixture was stirred at RT for 3 hours, hydrolized with H2O and HCl 3N and extracted with EtOAc. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/cyclohexane 60/40). The pure fractions were collected and the solvent was evaporated, yielding 12.8 g (46%) of (±)-2,6-dibromo-α-(4-chlorophenyl)-4-nitrobenzeneacetonitrile (interm. 76).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([CH2:23][C@@H:24]5[CH2:28][C@@H:27]([OH:29])[CH2:26][NH:25]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1.[CH3:37][O:38][CH2:39][CH2:40]Br>>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([CH2:23][C@@H:24]5[CH2:28][C@@H:27]([OH:29])[CH2:26][N:25]5[CH2:40][CH2:39][O:38][CH3:37])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1
Reactant: COCCBr
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C[C@@H]1C[C@@H](O)CN1
Product: COCCN1C[C@H](O)C[C@H]1CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-{[(2S,4R)-4-hydroxy-1-(2-methoxyethyl)pyrrolidin-2-yl]methyl}-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-{[(2S,4R)-4-hydroxypyrrolidin-2-yl]methyl}-1,3-thiazolidine-2,4-dione (Example 182) and 2-bromoethyl methyl ether following General Procedure S.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](=[CH2:21])[CH:19]=[O:20])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([O:24][C:25](=[O:29])[CH2:26][N+:27]#[C-:28])[CH3:23]>C1(C)C=CC=CC=1.[Cu-]=O>[CH2:22]([O:24][C:25]([CH:26]1[CH:19]([C:18]([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])=[CH2:21])[O:20][CH:28]=[N:27]1)=[O:29])[CH3:23]
Reactant: C=C(C=O)CCCCCCNC(=O)OCc1ccccc1
Reactant: [C-]#[N+]CC(=O)OCC
Agent: O=[Cu-]
Solvent: Cc1ccccc1
Product: C=C(CCCCCCNC(=O)OCc1ccccc1)C1OC=NC1C(=O)OCC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 38.3 %

Procedure:
15.30 g (52.9 mmol) of 8-(N-benzyloxycarbonylamino)-2-methyleneoctanal and 7.37 ml (67.4 mmol) of isocyanoacetic acid ethyl ester are dissolved in 78 ml of toluene and added dropwise under argon, within a period of 75 minutes, to a suspension of 0.30 g of copper(I) oxide in 76 ml of toluene. The mixture is then stirred for 90 minutes at 30°, cooled to room temperature and filtered, and the clear, bright red filtrate is introduced into a column filled with 250 g of silica gel (particle size 0.04-0.063 mm) and eluted with hexane/ethyl acetate (2:1). Concentration of the suitable fractions by evaporation yields 8.15 g of 5-[8-(N-benzyloxycarbonylamino)oct-1-en-2-yl]-oxazoline-4-carboxylic acid ethyl ester in the form of a colourless honey.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[H][H].[C:11]([OH:14])(=[O:13])[CH3:12]>[Rh]>[C:11]([OH:14])(=[O:13])[CH3:12].[NH:1]=[C:2]1[CH2:7][CH:6]([CH3:8])[CH2:5][CH2:4][NH:3]1
Reactant: Cc1ccnc(N)c1
Reactant: [H][H]
Agent: [Rh]
Solvent: CC(=O)O
Product: CC1CCNC(=N)C1

Procedure:
2-Amino-4-methylpyridine (1.56 g; 15 mmoles) and 5% rhodium on carbon (0.51 g, wet, Degussa type G10) in glacial acetic acid (30 mL) were shaken on a Parr hydrogenation apparatus at 55 psi of hydrogen overnight. The catalyst was removed by filtration and the filtrate was diluted with water to 250 mL, and lyophilized to yield a light tan powder. The powder was recrystallized from warm ethanol/ether to give 0.3 g of white solid. mp 181°-182° C. A second crop of white solid was obtained (0.85 g; mp 180°-182° C.). MH+=113; 1H NMR (D2O): δ3.32-3.16 (m, 2H); 2.54-2.46 (m, 1H); 2.10-2.00 (m, 1H); 1.80-1.70 (m, 2H); 1.74 (s, 3H); 1.32-1.25 (m, 1H); 0.87 (d, J=6.6 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]([CH2:7][NH:8][C:9](=[O:20])[CH:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[O:11][CH3:12])=[CH:5][CH:4]=1)#[N:2].Br[CH:24]([OH:26])[CH3:25].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9](=[O:20])[CH:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:25][CH2:24][OH:26])=[CH:15][CH:14]=2)[O:11][CH3:12])=[CH:21][CH:22]=1)#[N:2]
Reactant: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(O)cc1
Reactant: CC(O)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(OCCO)cc1

Procedure:
In analogy to example 16.4, (RS)-N-(4-cyano-benzyl)-2-(4-hydroxy-phenyl)-2-methoxy-acetamide (example 21.2) was alkylated with bromoethanol/cesium carbonate in DMF to give (RS)-N-(4-cyano-benzyl)-2-[4-(2-hydroxy-ethoxy)-phenyl]-2-methoxy-acetamide as a colorless oil. MS 363.1 ([M+Na]+)
Reaction SMILES: C[Mg]Cl.O1CCC[CH2:5]1.[C:9]([N:12]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH:33]=[O:34])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:11])[CH3:10].[Cl-].[NH4+]>O1CCCC1>[C:9]([N:12]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH:33]([OH:34])[CH3:5])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:11])[CH3:10]
Reactant: C1CCOC1
Reactant: CC(=O)N(Cc1ccccc1C=O)c1ccccc1Oc1ccccc1
Agent: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Product: CC(=O)N(Cc1ccccc1C(C)O)c1ccccc1Oc1ccccc1
Temperature: 25 °C

Procedure:
To an ice-cooled solution of 5.25 ml of 1M methylmagnesium chloride/tetrahydrofuran diluted with 15 ml of tetrahydrofuran was added dropwise a solution of 1.20 g of N-acetyl-N-(2-formylbenzyl)-2-phenoxyaniline in 7 ml of tetrahydrofuran, followed by stirring at room temperature for an hour. The reaction solution was again cooled on ice, and after addition of a saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate-hexane=1:1) to give 1.19 g of N-acetyl-N-[2-(1-hydroxyethyl)benzyl]-2-phenoxyaniline as an oil.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:14]=[S:15]>CC(C)=O>[C:1]1([N:7]2[CH2:12][CH2:11][N:10]([C:14]([NH:13][C:16](=[O:17])[O:18][CH2:19][CH3:20])=[S:15])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)N=C=S
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CC(C)=O
Product: CCOC(=O)NC(=S)N1CCN(c2ccccc2)CC1
Yield: 71.5 %

Procedure:
1-Phenylpiperazine (10 g, 62 mmol) was added to a solution of ethyl isothiocyanatoformate (8.1 g, 62 mmol) in acetone (30 mL) and the mixture was refluxed under heating for 1 h. The reaction mixture was concentrated and the crude crystals were recrystallized from ethyl acetate to give the title compound (13 g, yield 73%).