Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:18][N:19]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:20]3[CH:21]=[C:22]([CH:29]=[CH:30][CH:31]=3)[O:23][CH2:24][C:25]([O:27]C)=[O:26])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[Li].O>CCO>[C:1]1([C:7]2[N:8]=[C:9]([CH2:18][N:19]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:20]3[CH:21]=[C:22]([CH:29]=[CH:30][CH:31]=3)[O:23][CH2:24][C:25]([OH:27])=[O:26])[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)N(Cc1nc(-c2ccccc2)c(-c2ccccc2)o1)c1cccc(OCC(=O)OC)c1
Agent: [Li]O
Solvent: CCO
Solvent: O
Product: CCOC(=O)N(Cc1nc(-c2ccccc2)c(-c2ccccc2)o1)c1cccc(OCC(=O)O)c1
Temperature: 25 °C
Reaction time: 25 h
Yield: 78 %

Procedure:
A mixture of methyl [3-[[(4,5-diphenyl-2-oxazolyl) methyl](ethoxycarbonyl)amino]phenoxy]acetate (0.90 g, 1.9 mmol), LiOH.H2O (82 mg, 2 mmol) and 95% EtOH (25 mL) was stirred at room temperature for about 25 hours. The EtOH was evaporated, the residue diluted with H2O and acidified with 2N HCl solution. Extraction with CH2Cl2 afforded an oil which was chromatographed first on a column of silica gel using CH2Cl2 /MeOH (9:1) as eluent and subsequently on a column of silica gel using hexanes/EtOAc/AcOH (12:7:1) as eluent to give [3-[[(4,5-diphenyl-2-oxazolyl) methyl](ethoxycarbonyl)amino]phenoxy]acetic acid (0.70 g, 80%). IR (film) 3000, 1710 cm-1 ; 1H NMR (CDCl3) δ1.22 (3H, t, J=8 Hz, OCH2CH3), 4.21 (2H, q, J=8 Hz, OCH2CH 3), 4.55 (2H, s, OCH2CO2CH3), 5.03 (2H, s, CH2 -oxazole), 6.79 (1H, dd, J=9 Hz, J'=2 Hz, aromatic H), 7.00 (2H, m, aromatic H), 7.20 to 7.40 (7H, m, aromatic H), 7.50 to 7.70 (4H, m, aromatic H), 10.49 (1H, bs, CO2H); MS m/z 473 (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:16]([C:22]([NH:24][NH2:25])=O)=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:26](OC)(OC)OC.C(OC)(=O)NN.[C:39]([N:46]1[CH2:50][CH2:49][CH:48]([NH2:51])[CH2:47]1)([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40]>O1CCOCC1.CC(O)=O>[C:42]([O:41][C:39]([N:46]1[CH2:50][CH2:49][CH:48]([N:51]2[CH:26]=[N:25][N:24]=[C:22]2[C:16]2[C:15]([NH:14][S:11]([C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=3)(=[O:13])=[O:12])=[CH:20][C:19]([Cl:21])=[CH:18][N:17]=2)[CH2:47]1)=[O:40])([CH3:45])([CH3:44])[CH3:43]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(Cl)cnc2C(=O)NN)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Reactant: COC(OC)OC
Agent: COC(=O)NN
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(n2cnnc2-c2ncc(Cl)cc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)C1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A 25 mL scintillation vial was charged with 4-tert-butyl-N-(5-chloro-2-hydrazinocarbonyl-pyridin-3-yl)-benzenesulfonamide (191 mg, 0.50 mmol), trimethyl orthoformate (0.072 mL, 0.65 mmol), AcOH (0.60 mL), and dioxane (1.5 mL). The vial was sealed, heated to 110° C., and stirred overnight. The following day, the intermediate methyl carbazate was observed at m/z 425 (via LCMS). 1-Boc-3-aminopyrrolidine (187 mg, 1.0 mmol) was subsequently added and the reaction continued at 110° C. until LCMS analysis indicated consumption of the oxadiazole intermediate. The volatiles were subsequently evacuated in vacuo and the residue was purified via reverse-phase HPLC to provide 3-{3-[3-(4-tert-butyl-benzenesulfonylamino)-5-chloro-pyridin-2-yl]-[1,2,4]triazol-4-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester as a white solid: MS (ES) M+H expected 561.1, found 561.1.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].Br[C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1/[C:8](=[CH:16]/[C:17]1[NH:18][CH:19]=[CH:20][C:21]=1[O:22][CH3:23])/[C:9](=[O:15])[NH:10]2>CN(C=O)C.CCN(CC)CC>[OH:4][CH2:1][C:2]#[C:3][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1/[C:8](=[CH:16]/[C:17]1[NH:18][CH:19]=[CH:20][C:21]=1[O:22][CH3:23])/[C:9](=[O:15])[NH:10]2
Reactant: C#CCO
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CCO)c21

Procedure:
Using Method D above, propargyl alcohol (43.9 mg, 0.78 mmol) (Aldrich) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (100 mg, 0.31 mmol) (Starting Material 1 supra) using DPPFPdCl2 (12.8 mg) and Cul (3 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 85° C. for 18 h to yield (Z)-1,3-dihydro-4-(3-hydroxy-1-propynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 42 mg, 46%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][OH:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13](N1C=CN=C1)(N1C=CN=C1)=[O:14].[C:25]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:28])[NH:26][NH2:27].Cl>O1CCCC1.C(OCC)(=O)C>[NH:26]([C:25]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[NH:27][C:13]([O:12][CH2:11][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)=[O:14]
Reactant: O=[N+]([O-])c1ccc(CCO)cc1
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NNC(=O)OCCc1ccc([N+](=O)[O-])cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
To a solution of 2-(4-nitrophenyl)ethanol (5.015 g, 30.00 mmol) in anhydrous tetrahydrofuran (50 ml) was added 1,1′-carbonyldiimidazole (5.839 g, 36.01 mmol), and the mixture was stirred at room temperature for 30 min. tert-Butyl carbazate (5.956 g, 45.06 mmol) was added, and the mixture was stirred at room temperature for 16 hr and further at 50° C. for 8 hr. 0.5M Hydrochloric acid (100 ml) and ethyl acetate (100 ml) were added to the reaction mixture, and the mixture was stirred, stood still and then partitioned. The organic layer was washed with 0.5M hydrochloric acid, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (FUJI SILYSIA CHEMICAL LTD. BW-300SP 200 g, ethyl acetate:hexane=4:6→5:5) to give tert-butyl 2-(4-nitrophenyl)ethyl hydrazine-1,2-dicarboxylate (9.780 g, quantitative) as a slightly yellow solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[CH:8]=[C:7]2[CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=1[O:25][CH3:26])([OH:3])=O.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.Cl.[F:47][C:48]([F:55])([F:54])[CH2:49][CH:50]([CH3:53])[CH2:51][NH2:52]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:26][O:25][C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][C:15]=1[CH2:14][C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([C:1](=[O:3])[NH:52][CH2:51][CH:50]([CH3:53])[CH2:49][C:48]([F:55])([F:54])[F:47])[CH:5]=2)[N:9]([CH3:13])[CH:8]=1)[C:19]([O:21][CH3:22])=[O:20]
Reactant: CC(CN)CC(F)(F)F
Reactant: COC(=O)c1ccc(Cc2cn(C)c3ccc(C(=O)O)cc23)c(OC)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(Cc2cn(C)c3ccc(C(=O)NCC(C)CC(F)(F)F)cc23)c(OC)c1
Yield: 81.6 %

Procedure:
A solution of methyl 4-(5-carboxy-1-methylindol-3-ylmethyl)-3-methoxybenzoate (2.0 g), 4-dimethylaminopyridine (0.71 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.3 g), triethylamine (1.0 mL) and 4,4,4-trifluoro-2-methylbutylamine hydrochloride (1.2 g) in methylene chloride (28 mL) was stirred under a nitrogen atmosphere for 18 hours. The mixture was diluted with methylene chloride, washed (10% (w/v) hydrochloric acid, water and brine), dried (MgSO4), and evaporated. The resulting ivory foam was purified by flash chromatography, eluting with 1:1 ethyl acetate:hexane to afford methyl 3-methoxy-4-[1-methyl-5-(2-methyl-4,4,4-trifluorobutylcarbamoyl)indol-3-ylmethyl]benzoate as a white powder (2.2g, 82%); mp 168°-170° C.; partial NMR (300 MHz, CDCl3): 1.12 (d, 3H, CHCH3), 2.00 (m, 1H), 2.22 (m, 2H), 3.34-3.52 (m, 2H, NCH2), 3.75 (s, 3H, NCH3), 3.90 (s, 3H, CO2CH3), 3.93 (s, 3H, OCH3), 4.13 (s, 2H, CH2), 6.21 (t, 1H, NH), 6.82 (s, 1H, indole-H(2)), 8.02 (s, 1H, indole-H(4)).
Reaction SMILES: [C:1]([NH:5][NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22](Cl)=[O:23]>C1(C)C=CC=CC=1>[C:1]([N:5]([C:22]([C:18]1[S:17][CH:21]=[CH:20][CH:19]=1)=[O:23])[NH:6][C:7](=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1cccs1
Reactant: CC(C)(C)NNC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)(C)N(NC(=O)c1ccccc1)C(=O)c1cccs1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
N'-t-butyl-N-benzoylhydrazine (1.0 g) was dissolved in 20 ml toluene. 50% aqueous sodium hydroxide (1.25 g) was added followed by 2-thiophene-carbonylchloride (0.76 g). The mixture was stirred at room temperature for 14 hours. The solid product, N'-t-butyl-N-benzoyl-N'-(2-thiophenecarbonyl)hydrazine, was removed by filtration and washed with water. m.p. >200° C.
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]([C:12]([N:14]2[CH:18]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH3:29])[N:23]=3)=[O:20])[CH2:17][CH:16]=[N:15]2)=[O:13])[CH2:8][C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:30]1([CH2:36][O:37][NH2:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CN1CCOCC1.N1C2C(=NC=CC=2)N(O)N=1.C(Cl)CCl>ClCCl>[CH:1]1([CH2:6][C@H:7]([CH2:8][C:9](=[O:11])[NH:38][O:37][CH2:36][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:12]([N:14]2[C@H:18]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH3:29])[N:23]=3)=[O:20])[CH2:17][CH:16]=[N:15]2)=[O:13])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1cccc(NC(=O)C2CC=NN2C(=O)[C@@H](CC(=O)O)CC2CCCC2)n1
Reactant: NOCc1ccccc1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCc1cccc(NC(=O)[C@@H]2CC=NN2C(=O)[C@@H](CC(=O)NOCc2ccccc2)CC2CCCC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.1 %

Procedure:
To a solution of (3R)-3-(cyclopentylmethyl)-4-(5-{[(6-ethyl-2-pyridinyl)amino]carbonyl}-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (323 mg, 0.81 mmol) in dichloromethane (DCM) (10 ml) was added O-(phenylmethyl)hydroxylamine (129 mg, 1.05 mmol), 4-methylmorpholine (0.23 ml, 2.1 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (110 mg, 0.81 mmol), and EDC (186 mg, 0.97 mmol) at 0° C. The reaction was left to warm to room temperature and stirred overnight. The reaction was then washed with water (15 mL) and NaHCO3 solution (15 mL×3), then concentrated to provide the crude product as a mixture of diastereomers, which was purified by Gilson HPLC (Sunfire Column 19×50 mm, flowrate 25 mL/min, 10 min, 5-65% MeCN: H2O) to afford (5S)-1-((2R)-2-(cyclopentylmethyl)-4-oxo-4-{[(phenylmethyl)oxy]amino}butanoyl)-N-(6-ethyl-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxamide (119 mg, 29% yield). MS: 506 ([M+H]+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([CH3:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].[I:24][C:25]1[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=1>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([CH3:22])[CH:16]=1)[C:9]([C:28]1[CH:29]=[CH:30][C:25]([I:24])=[CH:26][CH:27]=1)=[O:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(C)c1
Reactant: Ic1ccc(I)cc1
Product: Cc1cc(C(NC(=O)OC(C)(C)C)C(=O)c2ccc(I)cc2)ccc1Cl

Procedure:
The title compound was prepared from rac-[(4-chloro-3-methyl-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 2) and 1,4-di-iodobenzene in analogy to Example 1a): MS (ISN): 484.1 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:30][CH3:31])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[CH:16][C:9]=23)[CH:7]=1.[Br:32]N1C(=O)CCC1=O>CN(C)C=O.O.C(OCC)(=O)C>[Br:32][C:16]1[C:9]2[C:10](=[N:11][CH:12]=[CH:13][C:8]=2[C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:30][CH3:31])[NH:14][C:15]=1[CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:19][CH2:18]1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(F)cc1-c1ccnc2[nH]c(C3CCN(C(=O)OC(C)(C)C)CC3)cc12
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(F)cc1-c1ccnc2[nH]c(C3CCN(C(=O)OC(C)(C)C)CC3)c(Br)c12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of Example 17F (300 mg, 0.705 mmol) in N,N-dimethylformamide (3 mL) at 0° C. was added N-bromosuccinimide (188 mg, 1.058 mmol) and the mixture was stirred at room temperature for 3 hours. The mixture was diluted with water and ethyl acetate and the ethyl acetate layer was washed with water and brine, dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography (silica gel, 15% ethyl acetate in hexane) afforded the title compound. LCMS: 506 (M+3)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:15]([OH:17])=O)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:22][CH:23]([CH3:26])[CH2:24][OH:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:15]([NH:22][CH:23]([CH3:26])[CH2:24][OH:25])=[O:17])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2ccc(-c3cc(F)cc(C(=O)O)c3)nc12
Reactant: CC(N)CO
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
Product: CC(CO)NC(=O)c1cc(F)cc(-c2ccc3ncnc(N)c3n2)c1

Procedure:
Following the same reaction and purification procedure as above, the acid 3 (60 mg, 0.21 mmol) was reacted with 2-aminopropan-1-ol (CAS 78-91-1) (0.03 mL, 0.42 mmol), HATU (166 mg, 0.42 mmol) and DIPEA (0.18 mL, 1.1 mmol) in DMF (1 mL) at room temperature to provide 3-(4-aminopyrido[3,2-d]pyrimidin-6-yl)-5-fluoro-N-(1-hydroxypropan-2-yl)benzamide 9. LC/MS (ESI+): m/z 342 (M+H). 1H NMR (400 MHz, DMSO) δ 8.64 (d, J=10.3 Hz, 1H), 8.56 (d, J=8.7 Hz, 2H), 8.43 (d, J=5.5 Hz, 1H), 8.38 (d, J=7.9 Hz, 1H), 8.30 (s, 1H), 8.21 (d, J=8.8 Hz, 1H), 8.03 (s, 1H), 7.75 (d, J=9.4 Hz, 1H), 4.77 (t, J=5.8 Hz, 1H), 4.17-3.99 (m, 1H), 3.52 (dt, J=11.2, 5.7 Hz, 1H), 3.46-3.36 (m, 1H), 1.19 (d, J=6.7 Hz, 3H).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:14][O:15][CH:16]([CH2:19][NH2:20])[CH2:17][NH2:18].CCN(C(C)C)C(C)C>CO>[NH3:3].[NH2:18][CH2:17][CH:16]([O:15][CH3:14])[CH2:19][NH:20][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COC(CN)CN
Reactant: COc1cc(Cl)nc2ccccc12
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(NCC(CN)OC)nc2ccccc12
Product: N
Temperature: 110 °C
Reaction time: 18 h
Yield: 36 %

Procedure:
A mixture of 2-chloro-4-methoxyquinoline (1.75 g, 0.00903 mol), 2-methoxy-1,3-propanediamine, bis(trifluoroacetate) (6.00 g, 0.0181 mol) and N,N′-diisopropylethylamine (20 ml) was stirred for 18 h at 110° C. in a sealed reaction tube. After cooling the two phase mixture was diluted in methanol, concentrated onto silica, and then purified by silica gel chromatography (100% dichloromethane, 5%, 10% then 20% (10% 880 aqueous ammonia in methanol) in dichloromethane) to give the title compound as a yellow oil (0.86g, 36%). δH (CD3OD) 3.26-3.56 (4H, m, 2CH2), 3.46 (3H, s, CHOCH3), 3.40-3.60 (1H, m, CHOCH3), 4.02 (3H, s, COCH3), 6.10 (1H, s, 3-H), 7.00-7.81 (4H, m, ArH). MS (ES+) 262 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[C:4]2[N:5]([CH:10]=[C:11]([CH3:13])[N:12]=2)[N:6]=[C:7]([CH3:9])[CH:8]=1)[CH3:2].[CH2:14]([CH:16]([C:19]1[C:20]2[N:21]([C:26](I)=[C:27]([CH3:29])[N:28]=2)[N:22]=[C:23]([CH3:25])[CH:24]=1)[CH2:17][CH3:18])[CH3:15]>>[CH2:14]([CH:16]([C:19]1[C:20]2[N:21]([C:26]([C:10]3[N:5]4[N:6]=[C:7]([CH3:9])[CH:8]=[C:3]([CH2:1][CH3:2])[C:4]4=[N:12][C:11]=3[CH3:13])=[C:27]([CH3:29])[N:28]=2)[N:22]=[C:23]([CH3:25])[CH:24]=1)[CH2:17][CH3:18])[CH3:15]
Reactant: CCc1cc(C)nn2cc(C)nc12
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Product: CCc1cc(C)nn2c(-c3c(C)nc4c(C(CC)CC)cc(C)nn34)c(C)nc12
Yield: 37.4 %

Procedure:
Using a procedure analogous to Example 16B, 8-ethyl-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.30 g, 1.71 mmol) and 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.59 g, 1.71 mmol) give the title compound (0.25 g, 0.64 mmol, 38%). 1H NMR (CDCl3): δ 0.90 (t, J=7.5 Hz, 6H), 1.43 (d, J=1.4 Hz, 3H), 1.78-1.92 (m, 4H), 2.42 (s, 3H), 2.43 (s, 3H), 2.44 (s, 3H), 2.45 (s, 3H), 3.11 (q, J=7.5 Hz, 2H), 3.34-3.42 (m, 1H), 6.67 (s, 1H), 6.74 (s, 1H) ppm. ES-MS (m/z): calcd for C23H30N6 (M+H)+: 391.5. found: 391.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([SH:17])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[OH-].[Na+].Cl[CH2:21][C:22]([NH2:24])=[O:23].[CH2:25](O)C>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:16]([CH3:25])=[N:15][C:14]([S:17][CH2:21][C:22](=[O:23])[NH2:24])=[N:13][CH:12]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: CCO
Reactant: O=C(Nc1ccc(F)cc1)c1cnc(S)nc1
Reactant: NC(=O)CCl
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc(SCC(N)=O)ncc1C(=O)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 70 %

Procedure:
A solution of 2-mercaptopyrimidine-5-carboxylic acid (4-fluorophenyl)amide (100 mg, 0.38 mmol) in 3 mL of ethanol was treated with aqueous NaOH (3 M, 0.28 mL, 0.84 mmol). A yellow slurry formed, which dissolved over the course of 5 min. An addition of 2-chloroacetamide (53 mg, 0.57 mmol) resulted in the formation of a white slurry. After stirring at ambient temperature for 2.5 h, the reaction was quenched with 50 mL of water and titrated to acidity with 1 M HCl. The slurry was filtered over sintered glass and washed with copious water. Drying in vacuo yielded 85 mg (70%) of 2-carbamoylmethylsulfanyl-4-methylpyrimidine-5-carboxylic acid (4-fluorophenyl)amide. ESI-MS m/z 321 (MH+), 319 (M−H−).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([CH:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)=[C:4]([N+:32]([O-])=O)[CH:3]=1.[H][H]>[Ni].CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:32])[C:5]([NH:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][N:16]([CH:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:17][CH2:18]2)=[CH:6][C:7]=1[Cl:8]
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1NCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: Nc1cc(Cl)c(Cl)cc1NCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
A mixture of 8 parts of N-(4,5-dichloro-2-nitrophenyl)-4-(diphenylmethyl)-1-piperazinepropanamine and 200 parts of methanol is hydrogenated at normal pressure and at room temperature with 2 parts of Raney-nickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst if filtered off and the filtrate is evaporated, yielding 4,5-dichloro-N1 -{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,2-benzenediamine as an oily residue.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:13]1[CH2:19][CH2:18][CH2:17][C@H:14]1[CH2:15][OH:16]>>[OH:16][CH2:15][C@@H:14]1[CH2:17][CH2:18][CH2:19][N:13]1[C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cc(Cl)nc2ccccc12
Reactant: OC[C@@H]1CCCN1
Product: Cc1cc(N2CCC[C@H]2CO)nc2ccccc12
Yield: 93.2 %

Procedure:
The title compound (22 g, 94%) was prepared as thick liquid from 2-chlorolepidine (17.3 g) and L-prolinol (59 g) by an analogous procedure to that described in preparation 1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]([CH2:17]OS(C)(=O)=O)=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[F:29][C:30]([F:41])([F:40])[C:31]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[NH:33][N:32]=1>C(#N)C>[F:39][C:36]([F:37])([F:38])[C:34]1[CH:35]=[C:31]([C:30]([F:29])([F:40])[F:41])[N:32]([CH2:17][C:10]2[CH:11]=[C:12]([C:13]([O:15][CH3:16])=[O:14])[N:8]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[N:9]=2)[N:33]=1
Reactant: FC(F)(F)c1cc(C(F)(F)F)[nH]n1
Reactant: COC(=O)c1cc(COS(C)(=O)=O)nn1-c1ncccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(Cn2nc(C(F)(F)F)cc2C(F)(F)F)nn1-c1ncccc1Cl
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A solution of 700 mg (2.03 mmol) of methyl 2-(3-chloropyridin-2-yl)-5-methane-sulphonyloxymethyl-2H-pyrazole-3-carboxylate in 15 ml of acetonitrile is admixed in succession with 336 mg (2.43 mmol) of potassium carbonate and 413 mg (2.03 mmol) of 3,5-bis(trifluoromethyl)pyrazole and the mixture is subsequently stirred at 60° C. for 1 h. After the mixture has cooled to room temperature, the solvent is concentrated on a rotary evaporator, water is added and extraction is carried out with three times 50 ml of ethyl acetate. The combined organic phases are dried over magnesium sulphate and then the solvent is removed on a rotary evaporator.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([OH:7])=[O:6].[C:12](Cl)(C)=O>CO.CC(=O)OCC>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([O:7][CH3:12])=[O:6]
Reactant: CC(=O)Cl
Reactant: O=C(O)c1cc(O)cc(Br)c1
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1cc(O)cc(Br)c1
Temperature: 25 °C
Yield: 98.8 %

Procedure:
To a flask containing 3-bromo-5-hydroxybenzoic acid (2.0 g, 9.2 mmol) in anhydrous MeOH (10 mL) at 0° C. under N2 was added AcCl (912 μL, 12.9 mmol). The reaction mixture was allowed to warm to room temperature overnight. The mixture was diluted with EA and washed with NaHCO3. The organic layers were dried and concentrated to provide 2.1 g (97%) of methyl 3-bromo-5-hydroxybenzoate as a white solid. LCMS-ESI (m/z) calculated for C8H7BrO3: 231.04. found 232.9 [M+H]+, tR=3.06 min.
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[CH3:9][CH2:10][CH3:11].C(OC)(OC)OC.O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C1(C)C=CC=CC=1>[CH2:9]([O:7][C:3]1[CH2:4][CH2:5][CH2:6][C:1](=[O:8])[CH:2]=1)[CH2:10][CH3:11]
Reactant: CCC
Reactant: O=C1CCCC(=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: COC(OC)OC
Solvent: Cc1ccccc1
Product: CCCOC1=CC(=O)CCC1

Procedure:
In a 21 three-necked flask, 100 g (0.89 mol) of cyclohexane-1,3-dione are initially charged and dissolved in 166.6 ml (2.23 mol) of n-propane and 600 ml of toluene and 97.6 ml (892 mmol) of trimethyl orthoformate, 5 g of p-toluenesulphonic acid dihydrate are added and the mixture is stirred under reflux on a water separator for 5 h until no more water separates off. The solution is then concentrated under reduced pressure on a rotary evaporator and the residue is taken up in 400 ml of MTBE and washed three times with 100 ml of 10% strength NaOH and saturated NaCl solution. The organic phase is dried over sodium sulphate and concentrated using a rotary evaporator. This gives 124.8 g yield of a yellow oil which is used for the next step without further purification.