Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][CH2:16][CH:17]([NH2:25])[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:26][C:27]1[C:35]2[C:30](=[CH:31][C:32]([C:36](O)=[O:37])=[CH:33][CH:34]=2)[NH:29][CH:28]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][O:15][CH2:16][CH:17]([NH:25][C:36]([C:32]2[CH:31]=[C:30]3[C:35]([C:27]([Cl:26])=[CH:28][NH:29]3)=[CH:34][CH:33]=2)=[O:37])[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(COCC(N)c2ccc(F)cc2)CC1
Reactant: O=C(O)c1ccc2c(Cl)c[nH]c2c1
Product: CC(C)(C)OC(=O)N1CCC(COCC(NC(=O)c2ccc3c(Cl)c[nH]c3c2)c2ccc(F)cc2)CC1
Yield: 100.6 %

Procedure:
Using coupling method A, 4-[2-amino-2-(4-fluorophenyl)-ethoxymethyl]piperidine-1-carboxylic acid tert-butyl ester (1.1 g, 3.0 mmol) and 3-chloroindole-6-carboxylic acid (653 mg, 3.3 mmol) afforded 1.6 g (100%) of the title compound as a crude residue, which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[C:13]([NH:17][C@H:18]([C:22]([NH:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[O:23])[CH:19]([CH3:21])[CH3:20])[CH:14]=[N:15][CH:16]=3)=[CH:9][N:8]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:5]2=[N:6][CH:7]=1.[C:38](OC(=O)C)(=[O:40])[CH3:39]>C(Cl)Cl.N1C=CC=CC=1>[C:38]([NH:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[C:13]([NH:17][C@H:18]([C:22]([NH:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[O:23])[CH:19]([CH3:21])[CH3:20])[CH:14]=[N:15][CH:16]=3)=[CH:9][N:8]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:5]2=[N:6][CH:7]=1)(=[O:40])[CH3:39]
Reactant: CC(C)[C@H](Nc1cncc(-c2cn(COCC[Si](C)(C)C)c3ncc(N)cc23)c1)C(=O)NCC(F)(F)F
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1cnc2c(c1)c(-c1cncc(N[C@H](C(=O)NCC(F)(F)F)C(C)C)c1)cn2COCC[Si](C)(C)C
Reaction time: 2 h

Procedure:
To a solution of N2-[5-(5-amino-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl]-N-(2,2,2-trifluoroethyl)valinamide 5-1b (50 mg, 0.093 mmol) in DCM (1.5 mL) and pyridine (0.2 mL) was added acetic anhydride (9.23 μL, 0.098 mmol) and the mixture was stirred for 2 h. The reaction was concentrated and the residue 5-2a was carried on without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11]([NH:13][C:14]1[C:15]([CH3:35])=[N:16][O:17][C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([CH2:31][C:32]([OH:34])=[O:33])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)=[O:12])[CH3:9].[CH3:36][Si](C=[N+]=[N-])(C)C>C1C=CC=CC=1.CO>[CH3:36][O:33][C:32](=[O:34])[CH2:31][C:28]1[CH:27]=[CH:26][C:25]([C:22]2[CH:23]=[CH:24][C:19]([C:18]3[O:17][N:16]=[C:15]([CH3:35])[C:14]=3[NH:13][C:11]([O:10][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH3:9])=[O:12])=[CH:20][CH:21]=2)=[CH:30][CH:29]=1
Reactant: Cc1noc(-c2ccc(-c3ccc(CC(=O)O)cc3)cc2)c1NC(=O)OC(C)c1ccccc1Cl
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3NC(=O)OC(C)c3ccccc3Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To (4′-{4-[1-(2-chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-acetic acid (0.050 g, 0.1 mmol) in benzene (17 mL) and methanol (2 mL) was added (trimethylsilyl)diazomethane (2M in hexanes; 0.1 mL, 0.2 mmol), and the reaction was stirred at room temperature for 5 minutes. Additional (trimethylsilyl)diazomethane (2M in hexanes; 0.25 mL, 0.5 mmol) was added, and the reaction was stirred until no starting material was seen by analytical LCMS. The mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed twice with water and once with brine, and then dried and concentrated. The residue was purified by silica gel chromatography (0-80% EtOAc in hexanes) to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:14]([CH3:15])[CH:13]=[N:12][CH:11]=2)=[O:9])=[CH:4][N:3]=1.Cl.[CH3:17][NH:18][CH3:19].CCN(CC)CC>CO>[CH3:17][N:18]([CH3:19])[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:14]([CH3:15])[CH:13]=[N:12][CH:11]=2)=[O:9])=[CH:4][N:3]=1
Reactant: Cn1cncc1C(=O)c1ccc(Cl)nc1
Reactant: CNC
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CN(C)c1ccc(C(=O)c2cncn2C)cn1
Temperature: 75 °C

Procedure:
In a 50-mL round-bottom flask was placed a solution of 2-chloro-5-[(1-methyl-1H-imidazol-5-yl)carbonyl]pyridine (250 mg, 1.13 mmol, Intermediate 22, step c), dimethylamine hydrochloride (96 mg, 1.2 mmol), and Et3N (342 mg, 3.39 mmol) in methanol (15 mL). The resulting mixture was heated at 75° C. overnight and concentrated under vacuum. The residue was purified by flash column chromatography (silica gel column, 100:0-20:1 CH2Cl2/MeOH) to give the title compound as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:20]2[O:24][C:23]([NH:25][C:26]([C@@H:28]3[CH2:33][CH2:32][CH2:31][CH2:30][N:29]3C(OCC3C=CC=CC=3)=O)=[O:27])=[N:22][N:21]=2)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.CCOC(C)=O>CO.[Pd]>[NH2:1][C:2]1[C:3]([C:20]2[O:24][C:23]([NH:25][C:26]([C@@H:28]3[CH2:33][CH2:32][CH2:31][CH2:30][NH:29]3)=[O:27])=[N:22][N:21]=2)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]([CH3:18])[CH3:19])(=[O:15])=[O:16])=[CH:10][CH:9]=2)=[CH:6][N:7]=1
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3nnc(NC(=O)[C@@H]4CCCCN4C(=O)OCc4ccccc4)o3)n2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3nnc(NC(=O)[C@@H]4CCCCN4)o3)n2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 47.8 %

Procedure:
Pd on C, wet, degussa (50 mg,) was added to a stirred solution of (S)-benzyl 2-(5-(3-amino-6-(4-(isopropylsulfonyl)phenyl)pyrazin-2-yl)-1,3,4-oxadiazol-2-ylcarbamoyl)piperidine-1-carboxylate (251 mg, 0.25 mmol) in MeOH (5 mL)/ EtOAc (5 mL) and the reaction mixture was placed under an atmosphere of H2. The reaction was stirred at ambient temperature for 17 hours. Once the reaction had gone to completion, the Pd was removed by filtration and the solvent was removed in vacuo. The material was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected and freeze-dried to give the product as a yellow solid (56.4 mg, 39%); 1H NMR (400.0 MHz, DMSO) d 1.19 (d, 6H), 1.38-1.49 (m, 2H), 1.51-1.61 (m, 1H), 1.80-1.83 (m, 1H), 1.89-1.92 (m, 1H), 2.09-2.11 (m, 1H), 3.01 (br s, 2H), 3.19-3.23 (m, 1H), 3.47-3.51 (m, 1H), 4.13 (d, 1H), 4.31 (br s, 1H), 7.81 (s, 2H), 7.91 (d, 2H), 8.52 (d, 2H), 9.06 (s, 1H) and 11.04 (br s, 1H) ppm; MS (ES+) 472.3
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:15])[C:5]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:6][C:7]=1[CH3:8].Cl[C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][CH:18]=1>CN(C1C=CN=CC=1)C.ClC1C=CC=CC=1Cl>[CH3:28][O:27][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][C:23]=1[O:29][CH3:30])[N:20]=[CH:19][CH:18]=[C:17]2[O:15][C:4]1[C:5]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Cc1cc(O)c(-c2cccnc2)nc1C
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cc(C)c(C)nc3-c3cccnc3)c2cc1OC
Temperature: 140 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
5,6-Dimethyl-[2,3′]-bipyridin-3-ol (50 mg), 4-chloro-6,7-dimethoxyquinoline (168 mg), and 4-(N,N-dimethylamino)pyridine (92 mg) were dissolved in 1,2-dichlorobenzene (2.5 ml), and the mixture was stirred at 140° C. overnight. The reaction solution was cooled to room temperature, and the solvent was then removed by distillation under the reduced pressure. The residue was purified by thin layer chromatography using hexane-acetone to give the title compound (81 mg, yield 84%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[N+:13]([O-])=O.[H-].[Na+].[CH3:18]I.O>CN(C)C=O>[NH2:13][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[CH3:1])[N:9]([CH3:18])[C:8](=[O:12])[CH2:7][CH2:6]2
Reactant: Cc1cc2c(cc1[N+](=O)[O-])CCC(=O)N2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc2c(cc1N)CCC(=O)N2C
Yield: 60.9 %

Procedure:
The compound (3.14 g, 15.2 mmol) obtained in step A was dissolved in N,N-dimethylformamide (30 ml), 60% sodium hydride (730 mg, 18.2 mmol) was added under ice-cooling with stirring, and thereafter the mixture was stirred at room temperature for 30 min. The reaction mixture was ice-cooled again, methyl iodide (1.9 ml, 30.4 mmol) was added with stirring, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added water, and the precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to give a bistered solid. Using this solid and according to the method of Reference Example 116, step B, the title compound (1.76 g, yield 61%) was obtained as a pale-bistered solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[C:14]([N:22]=[C:23]=[S:24])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O>[C:14]([NH:22][C:23](=[S:24])[NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1csc(NC(=S)NC(=O)c2ccccc2)n1

Procedure:
The reaction described in Preparation 1 was repeated, but using 20 g of ethyl 2-aminothiazol-4-ylglyoxylate, 16.5 g of benzoyl isothiocyanate, and 100 ml of dimethylformamide, giving the title compound as a pale yellow powder.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[O:19]1[C:24]2[C:25]([NH2:29])=[CH:26][CH:27]=[CH:28][C:23]=2[NH:22][CH2:21][CH2:20]1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[O:19]1[C:24]2[C:25]([NH:29][C:15](=[O:17])[CH2:14][C:9]3[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[N:8]=3)=[CH:26][CH:27]=[CH:28][C:23]=2[NH:22][CH2:21][CH2:20]1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1cccc2c1OCCN2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cccc2c1OCCN2
Yield: 26.9 %

Procedure:
The product is prepared according to the procedure described in example 5, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 166 mg of 3,4-dihydro-2H-1,4-benzoxazin-8-ylamine and 249 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 162 μl of pyridine and 4.0 ml of N,N-dimethylformamide. 100 mg of N-(3,4-dihydro-2H-1,4-benzoxazin-8-yl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white powder, the characteristics of which are the following:
Reaction SMILES: [CH3:1][S:2][C:3]1(C(O)=O)[CH:8]=[CH:7][CH:6]=[CH:5][NH:4]1.B.C1C[O:16][CH2:15]C1>CO>[CH3:1][S:2][C:3]1[C:8]([CH2:15][OH:16])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CSC1(C(=O)O)C=CC=CN1
Reactant: C1CCOC1
Agent: B
Solvent: CO
Product: CSc1ncccc1CO
Temperature: 80 °C
Yield: 30.3 %

Procedure:
To 2-(methylthio)picolinic acid (1.00 g, 5.91 mmol) was added BH3.THF (1.0 M/THF, 15 mL, 15 mmol) and the mixture heated at 80° C. for 24 h. Methanol (30 mL) was carefully added at room temperature and the solution was concentrated in vacuo. Purification of the crude material on silica gel (20% EtOAc/hexanes) gave the title compound as colourless crystals (278 mg, 30%). 1H NMR (CDCl3) □ 1.99 (t, 1H, J=6.0 Hz), 2.61 (s, 3H), 4.70 (d, 2H, J=6.0 Hz), 7.04 (dd, 1H, J=6, 3 Hz), 7.62 (d, 1H, J=6 Hz), 8.40 (d, 1H, J=3 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:12]=[CH:11][C:10]([S:13]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH3:23])[CH2:18][CH2:17]2)(=[O:15])=[O:14])=[CH:9][C:5]=1[C:6]([OH:8])=O)[CH3:2].[NH2:24][C:25]1[C:26]([C:36]([NH2:38])=[O:37])=[N:27][N:28]([CH2:32][CH2:33][O:34][CH3:35])[C:29]=1[CH2:30][CH3:31].O>C(OCC)(=O)C>[C:36]([C:26]1[C:25]([NH:24][C:6](=[O:8])[C:5]2[CH:9]=[C:10]([S:13]([N:16]3[CH2:17][CH2:18][N:19]([CH2:22][CH3:23])[CH2:20][CH2:21]3)(=[O:14])=[O:15])[CH:11]=[N:12][C:4]=2[O:3][CH2:1][CH3:2])=[C:29]([CH2:30][CH3:31])[N:28]([CH2:32][CH2:33][O:34][CH3:35])[N:27]=1)(=[O:37])[NH2:38]
Reactant: CCc1c(N)c(C(N)=O)nn1CCOC
Reactant: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1C(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1C(=O)Nc1c(C(N)=O)nn(CCOC)c1CC
Temperature: 45 °C
Reaction time: 1 h

Procedure:
2-ethoxy-5-(4-ethyl-1-piperazinylsulfonyl)nicotinic acid (27.5 g, 0.08 Mol) was suspended in ethyl acetate (0.193 L) and 1,1-carbonyidimidazole (13.3 g, 0.082 Mol) was added at room temperature. The reaction mixture was heated at 45° C. for 15 minutes and then the reaction was stirred for a further 60 minutes at reflux. After cooling to ambient temperature 4-amino-5-ethyl-1-(2-methoxyethyl)-1H-pyrazole-3-carboxamide (16.5 g, 0.078 Mol) was added to the cooled mixture, and the reaction stirred for a further 17 hours under reflux. The solution was cooled and water (0.07 L) and ethyl acetate (0.17 L) added. The slurry was warmed to 40° C. and the organic separated. The organic was concentrated to by evaporating 0.23 L solvent. The slurry was cooled, granulated at 0-−10° C. filtered and the filter cake was washed with 90% water/10% ethyl acetate, (2 mL/g) to afford N-[3-carbamoyl-5-ethyl-1-(2-methoxyethyl)-1H-pyrazol-4-yl}-2-ethoxy-5-(4-ethyl-1-piperazinyl sulfonyl)nicotinamide as an off white crystalline solid, 38.7 g, 89%. m.p.=159-161° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:12])[C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH2:13](OS(C1C=CC(C)=CC=1)(=O)=O)[C@@H:14]1[O:16][CH2:15]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([F:12])[C:5]([O:11][CH2:13][C@H:14]2[CH2:15][O:16]2)=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: CC(=O)c1cc(Br)cc(F)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1cc(Br)cc(F)c1OC[C@H]1CO1
Yield: 39.9 %

Procedure:
Preparation according to Preparation 1 using 1-(5-bromo-3-fluoro-2-hydroxyphenyl)ethanone (16.8 g, 72 mmol), (R)-glycidyltosylate (18.1 g, 79 mmol), K2CO3 (15.0 g, 108 mmol) and DMF (60 ml). The combined organic phases were washed with LiCl (5%), HCl (1 N). Flash column chromatography (isooctane/EtOAc) yielded the title compound (8.3 g). MS m/z (rel. intensity, 70 eV) 290 (M+, 9), 288 (M+, 9), 217 (bp), 81 (47), 57 (46).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:10]([C:13]1([CH3:30])[C:17](=[O:18])[NH:16][C:15]([C:19]2[N:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:20]=2[C:21]([O:23][CH3:24])=[O:22])=[N:14]1)([CH3:12])[CH3:11].C(Cl)Cl>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:1]([N:16]1[C:17](=[O:18])[C:13]([CH:10]([CH3:12])[CH3:11])([CH3:30])[N:14]=[C:15]1[C:19]1[N:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(C)cnc1C1=NC(C)(C(C)C)C(=O)N1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cc(C)cnc1C1=NC(C)(C(C)C)C(=O)N1C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 67.9 %

Procedure:
Benzoyl chloride (42.1 mL, 0.363 mol) is added dropwise to a 0° C. solution of 2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)-5-methylnicotinic acid, methyl ester (50 g, 0.173 mol) and 4-dimethylaminopyridine (4.2 g, 0.0344 mol) in pyridine. The reaction mixture is stirred for 1 hour at 0° C. and 4 hours at room temperature. Concentration in vacuo gives a liquid that is dissolved into methylene chloride and washed sequentially with 2 normal hydrochloric acid and saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate and concentrated in vacuo to yield a solid that upon trituration with ether gives the title compound as a white solid (46.2 g, 68%), mp 104°-106° C., identified by IR and NMR spectral analyses.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:31])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25](F)=[O:26])[CH:11]3[C:28]([CH3:30])=[CH2:29])[C:5]2=[CH:4][CH:3]=1.[NH2:32][CH2:33][CH2:34][OH:35].CN1CCOCC1>CN(C)C1C=CN=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:31])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25]([NH:32][CH2:33][CH2:34][OH:35])=[O:26])[CH:11]3[C:28]([CH3:30])=[CH2:29])[C:5]2=[CH:4][CH:3]=1
Reactant: NCCO
Reactant: C=C(C)C1N(CC(=O)F)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: CN(C)c1ccncc1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: C=C(C)C1N(CC(=O)NCCO)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 36.8 %

Procedure:
In a manner similar to the method described in example 34b, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-fluorocarbonylmethyl-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.2 g, 0.433 mmol) prepared in example 116d was reacted with 2-amino-ethanol (61 mg, 0.86 mmol), N-methylmorpholine (90 mg, 0.86 mmol) and 4-dimethylaminopyridine (5 mg) in tetrahydrofuran to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-[(2-hydroxy-ethyl)aminocarbonyl-methyl]-2′-isopropenyl-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as an off-white solid (Yield: 80 mg, 36.8%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[CH:12]3[CH2:13][CH2:14][CH:9]([CH:10]=[CH:11]3)[N:8]2[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:2]=1>C(O)(=O)C.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[CH:12]3[CH2:11][CH2:10][CH:9]([CH2:14][CH2:13]3)[N:8]2[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:2]=1
Reactant: CCOC(=O)N1C2C=CC(CC2)C1c1cccnc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)N1C2CCC(CC2)C1c1cccnc1
Yield: 98 %

Procedure:
A solution of the (+/-)-endo and (+/-)-exo isomers of 3-(3-pyridyl)-2-carboethoxy-2-azabicyclo[2.2.2]oct-5-ene, compound (II), (750 mg, 2.90 mmol) in glacial acetic acid (0.5 mL) and Pd/C (10%) was shaken under a H2 atmosphere in a Parr apparatus for 2 hours. The catalyst was removed by filtration over a bed of Celite and the filtrate was basified by addition of a solution of 40% of NaOH in water. The aqueous basic solution was extracted with dichloromethane (4×20 mL) to give 740 mg (98%) of compound (XII). 1H NMR (CDCl3): δ 8.48 (m, 2H), 7.60 (m, 2H), 4.78 and 4.67 (m, 1H), 4.30 (m, 1H), 4.13 and 4.10 (q, 2H), 2.19 (m, 2H), 1.90 (m, 3H), 1.63 (m, 4H), 1.28 and 0.90 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:9]2[C:10]([Cl:15])=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[S:7][CH:6]=1.CN(C=O)C.Cl[CH2:23][C:24]1[N:28]([CH3:29])[N:27]=[C:26]([CH3:30])[CH:25]=1.C([O-])([O-])=O.[K+].[K+]>O>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:9]2[C:10]([Cl:15])=[CH:11][C:12]([O:14][CH2:23][C:24]3[N:28]([CH3:29])[N:27]=[C:26]([CH3:30])[CH:25]=3)=[CH:13][C:8]=2[S:7][CH:6]=1
Reactant: COC(=O)Cc1csc2cc(O)cc(Cl)c12
Reactant: Cc1cc(CCl)n(C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1csc2cc(OCc3cc(C)nn3C)cc(Cl)c12
Temperature: 60 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
To a mixture of methyl(4-chloro-6-hydroxy-1-benzothiophen-3-yl)acetate (125 mg) and DMF (dry) (2 mL) were added 5-(chloromethyl)-1,3-dimethyl-1H-pyrazole (84 mg) and K2CO3 (101 mg) at room temperature, and the mixture was stirred at 60° C. for 1 h. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed successively with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (172 mg).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:8]2[C:9]([O:13][CH3:14])=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][N:5]=1)[CH3:2].ClC1C=CC=C(C(OO)=[O:23])C=1>ClCCl>[CH2:1]([NH:3][C:4]1[C:8]2[C:9]([O:13][CH3:14])=[CH:10][CH:11]=[CH:12][C:7]=2[S:6](=[O:23])[N:5]=1)[CH3:2]
Reactant: CCNc1nsc2cccc(OC)c12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCNC1=NS(=O)c2cccc(OC)c21
Reaction time: 0.5 h

Procedure:
90 mg (0.43 mmol) Ethyl-(4-Methoxy-benzo[d]isothiazol-3-yl)-amine, prepared in analogy to compound example 32, was dissolved in 10 ml dichloromethane. The solution was cooled to 0 C and 100 mg of a 70% m-chlor-perbenzoic acid was added portion wise. The cooling bath was removed and stirring was continued for 30 min at room temperature. The solution was poured into Na2CO3-solution. The layers were separated and the organic layer was washed with Na2CO3-solution and water. The organic layer was dried over NaSO4 and concentrated. The crude product was purified by reverse-phase HPLC (eluent acetonitrile/water) to yield 40 mg (0.18 mmol) of the title product.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([C:20]2[C:39]([CH:40]3[CH2:42][CH2:41]3)=[CH:38][C:23]3[C:24]([C:34]([NH:36][CH3:37])=[O:35])=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[O:26][C:22]=3[CH:21]=2)[S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][C:10]=1[Cl:43])C1C=CC=CC=1.B(Cl)(Cl)Cl.C(Cl)Cl>C(Cl)Cl.CCOC(C)=O>[Cl:43][C:10]1[CH:11]=[C:12]([N:15]([C:20]2[C:39]([CH:40]3[CH2:42][CH2:41]3)=[CH:38][C:23]3[C:24]([C:34]([NH:36][CH3:37])=[O:35])=[C:25]([C:27]4[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=4)[O:26][C:22]=3[CH:21]=2)[S:16]([CH3:19])(=[O:18])=[O:17])[CH:13]=[CH:14][C:9]=1[OH:8]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(OCc4ccccc4)c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: ClB(Cl)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(O)c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 25 °C
Yield: 42.9 %

Procedure:
A solution of 6-(N-(4-(benzyloxy)-3-chlorophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (0.300 g, 0.485.mmol) in anhydrous DCM (12 mL) was cooled in an ice water bath and treated with 1M BCl3/DCM (2.00 mL, 2.00 mmol). After stirring in the ice bath for 10 minutes the solution was allowed to warm to RT. This solution was then combined with the solution from an analogous 50 mg scale reaction and poured into 50 mL of stirred ice water. The mixture was diluted with 50 mL of EtOAc, stirred vigorously for several minutes and the phases separated. The EtOAc solution was washed with water (2×), brine (1×), dried over sodium sulfate and concentrated to dryness at reduced pressure. The crude material was subjected to flash chromatography (silica gel, gradient from DCM to 1:1 DCM/EtOAc) followed by recrystallization from hexane/EtOAc to afford the title compound (0.110 g, 37%) as a white powder. Impure fractions from the above chromatography were combined, concentrated, and subjected to RP-HPLC purification (C18, MeCN/water/0.1% formic acid) to afford an additional portion of the title compound (0.107 g, 36%) for a total yield of 73%. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.45 (s, 1H) 8.40-8.48 (m, 1H) 8.18 (s, 1H) 7.90-8.01 (m, 2H) 7.61 (d, J=2.6 Hz, 1H) 7.34-7.45 (m, 3H) 7.14 (s, 1H) 6.96 (d, J=8.8 Hz, 1H) 3.30 (s, 3H) 2.82 (d, J=4.6 Hz, 3H) 2.20-2.34 (m, 1H) 0.77-1.09 (m, 3H) 0.43 (br. s., 1H). LCMS (m/z, ES+)=529 (M+H+).