Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]/[C:2](=[CH:8]\[CH:9]=[CH:10]\[CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH3:25])/[C:3]([O:5]CC)=[O:4].[OH-].[K+].O>CO>[CH3:1]/[C:2](=[CH:8]\[CH:9]=[CH:10]\[CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH3:25])/[C:3]([OH:5])=[O:4]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\CC/C=C/C=C(\C)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC/C=C\C/C=C\C/C=C\C/C=C\CC/C=C/C=C(\C)C(=O)O
Temperature: 65 °C

Procedure:
To a solution of ethyl (2E,4E,8Z,11Z,14Z,17Z)-2-methyl-icosa-2,4,8,11,14,17-hexaenoate (10) in methanol was added an aqueous solution of KOH (8 equiv.) and the mixture was heated to 60-70° C. for 2 hrs. The solution was cooled, water was added and the mixture acidified. The mixture was then extracted with ethyl acetate. The combined organic phases were washed with water and dried (MgSO4). Evaporation of the solvents under reduced pressure followed by flash chromatography on silica gel (8:2 hexane-EtOAc) gave the acid 11. δH(300 MHz): 0.96 (t, J 7.5, 3H, CH3), 1.91 (d, J 0.75, 3H, CH3), 2.08 (m, 2H), 2.2-2.4 (m, 4H), 2.7-2.9 (m, 6H), 5.2-5.5 (m, 8H), 6.11 (dt, J 15.0, J 6.5, 1H), 6.37 (dd, J 15.0, J 11.3, 1H), 7.26 (br d, J 11.3, 1H); δc(75 MHz) 12.16, 14.24, 20.53, 25.52, 25.61, 25.67, 26.57, 33.24, 124.44, 126.34, 126.97, 127.82, 128.04, 128.21, 128.54, 128.70, 128.74, 132.01, 140.79, 143.47, 174.28.
Reaction SMILES: [Cl:1]C1C(CC)=NC=C(CC)N=1.[CH:12]1([CH:15]2[NH:20][C:19](=O)[CH:18]([CH:22]3[CH2:24][CH2:23]3)[NH:17][C:16]2=O)[CH2:14][CH2:13]1>>[Cl:1][C:19]1[C:18]([CH:22]2[CH2:24][CH2:23]2)=[N:17][CH:16]=[C:15]([CH:12]2[CH2:14][CH2:13]2)[N:20]=1
Reactant: CCc1cnc(CC)c(Cl)n1
Reactant: O=C1NC(C2CC2)C(=O)NC1C1CC1
Product: Clc1nc(C2CC2)cnc1C1CC1

Procedure:
Following the procedure for the preparation of 3-chloro-2,5-diethylpyrazine but substituting 3,6-dicyclopropylpiperazine-2,5-dione and making non-critical variations provided the title compound as an oil: 1H NMR (CDCl3) δ 0.99-1.13, 1.94-2.03, 2.38-2.47; MS (ESI+) for C10H11N2 m/z 195 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][C:3]=1[Cl:13].[OH-].[Na+]>CO>[NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[Cl:13]
Reactant: CCOC(=O)c1ccc(N)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1ccc(C(=O)O)cc1Cl

Procedure:
The benzoate ester (2), 45.5 g (0.23 moles), was dissolved in 250 mL of hot MeOH and then 230 mL of 3N NaOH (3 equivalents, 0.69 moles) was added. The mixture was stirred at reflux for 5 hours. The solution was concentrated on a rotary evaporator at 80° C. to remove the MeOH and then the mixture was acidified to pH 2 with 3N HCl. The precipitated solids were filtered on a sintered glass funnel and washed with water. The product was homogeneous by TLC (Hexane: EtOAc, 4:1, Rf=0.1) and therefore was not further purified. The white solid was dried at 70° C. in a vacuum oven to give 38.1 (97%) of 4-amino-3 chlorobenzoic acid (3), mp 225-226° C. 1H NMR (DMSO d6) d 7.70 (d, 1H, J=0.9 Hz, ArH), 7.61-7.56 (dd, 1H, J=0.7 Hz, ArH), 6.78 (d, 1H, J=3.4 Hz, ArH), 6.15 (bs, 2H, NH2). IR (KBr) cm−1, 3515, 3410 (NH2, m), 1675, (C═O, s) 1640. MS(El) m/e 171 (M+), 173 (M+2). Anal. Calc'd for C7H6NO2Cl: C, 49.00; H, 3.62; N, 8.16. Fd. C, 49.22; H, 3.71, N, 7.9. The formula is:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.Cl[C:11]1[C:16]([C:17](OCC)=[O:18])=[CH:15][N:14]=[C:13]2[CH2:22][CH2:23][CH2:24][C:12]=12>C(O)CCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17](=[O:18])[C:16]3[C:11]([C:12]4[CH2:24][CH2:23][CH2:22][C:13]=4[NH:14][CH:15]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnc2c(c1Cl)CCC2
Solvent: CCCCO
Product: O=c1c2c[nH]c3c(c-2nn1-c1ccc(Cl)cc1)CCC3

Procedure:
A mixture of 1.1 g of p-chlorophenylhydrazine and 1.9 g of ethyl 4-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate (Example 2a) in 100 mL of n-butanol is refluxed for 24 hours under nitrogen atmosphere. The precipitate is collected and recrystallized from ethanol to yield 2-p-chlorophenyl-2,3,5,6,7,8-hexahydrocyclopenta[b]pyrazolo[3,4-d]pyridin-3-one, m.p. above 350°, showing IR peaks at 900, 835, 805, 798, 765, and 740 cm-1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:13][C@H:14]([C:16]([OH:18])=O)[CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[CH3:20][O:21][C:22](=[O:29])[C@H:23]([CH2:25][CH:26]([CH3:28])[CH3:27])[NH2:24]>C(Cl)(Cl)Cl.CO>[CH3:20][O:21][C:22](=[O:29])[C@H:23]([CH2:25][CH:26]([CH3:28])[CH3:27])[NH:24][C:16](=[O:18])[C@H:14]([CH3:15])[NH:13][C:11](=[O:12])[CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: C[C@H](NC(=O)Cc1cccc([N+](=O)[O-])c1)C(=O)O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)Cc1cccc([N+](=O)[O-])c1

Procedure:
Following General Procedure C and using N-(3-nitrophenylacetyl)-L-alanine (from Example D11 above) and L-leucine methyl ester hydrochloride (Aldrich), the title compound was prepared as a solid. The reaction was monitored by tlc (Rf=0.75 in 9:1 CHCl3/MeOH) and the product was purified by silica gel chromatography using 97:3 CHCl3/MeOH as the eluent.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18](O)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][NH:24][CH2:25][C@H:26]([OH:29])[CH2:27][OH:28]>>[OH:29][C@@H:26]([CH2:27][OH:28])[CH2:25][N:24]([CH3:23])[C:18]([C:12]1[S:13][C:14]2[CH2:15][CH2:16][O:17][C:8]3[CH:7]=[C:6]([C:4]4[CH:3]=[N:2][NH:1][CH:5]=4)[CH:22]=[CH:21][C:9]=3[C:10]=2[N:11]=1)=[O:19]
Reactant: CNC[C@H](O)CO
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: CN(C[C@@H](O)CO)C(=O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with (S)-3-(methylamino)propane-1,2-diol (1.2 equiv) to give 181 (14.9 mg, M+1 401.1)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[N:20]([CH2:21][CH2:22][O:23][CH2:24][C:25]([F:28])([F:27])[F:26])[C:19]3[CH:29]=[CH:30][CH:31]=[CH:32][C:18]=3[N:17]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[IH:33]>ClCCl>[IH:33].[F:28][C:25]([F:26])([F:27])[CH2:24][O:23][CH2:22][CH2:21][N:20]1[C:19]2[CH:29]=[CH:30][CH:31]=[CH:32][C:18]=2[N:17]=[C:16]1[C:14]([CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2nc3ccccc3n2CCOCC(F)(F)F)CC1
Agent: I
Solvent: ClCCl
Product: O=C(c1nc2ccccc2n1CCOCC(F)(F)F)C1CCNCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Combine 1-(t-butoxycarbonyl)-4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazole-2-carbonyl)piperidine (5.0 mmol) and dichloromethane (150 mL). Cool to 0° C. using an ice bath. Add hydriodic acid (gas) until the solution is saturated and stir. After 30 minutes, again add hydriodic acid (gas) until the solution is saturated. After 2 hours, evaporate in vacuo to give, after drying, the title compound.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.O>C(Cl)Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: CC(=O)c1ccc(OC2CCCCO2)cc1
Yield: 62 %

Procedure:
13.62 g (100 mmol) of 4-hydroxyacetophenone and 10.04 ml (110 mmol) of 3,4-dihydro-2H-pyran were suspended in 100 ml of anhydrous methylene chloride. At 0° C., 190 mg (1 mmol) of p-toluenesulfonic acid were added with stirring and the mixture was stirred at 0° C. for 3 hours. 10.04 ml (110 mmol) of 3,4-dihydro-2H-pyran were added again and the mixture was stirred at room temperature for a further 3 hours. The batch was poured into 150 ml of water, the phases were separated and the organic phase was extracted with saturated NaHCO3 solution, saturated NaCl solution and with water. The organic phase was dried over sodium sulfate, concentrated and, for purification, chromatographed on silica gel (70-200 μm) using methylene chloride as an eluent. 13.65 g (62%) of 10.1 were obtained.
Reaction SMILES: [NH2:1][C:2]1[S:10][C:5]2[CH2:6][NH:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1.CCN(CC)CC.[C:27]1([N:33]=[C:34]=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[NH2:1][C:2]1[S:10][C:5]2[CH2:6][N:7]([C:34]([NH:33][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:35])[CH2:8][CH2:9][C:4]=2[C:3]=1[C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1sc2c(c1C(=O)c1ccc(Cl)cc1)CCNC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Nc1sc2c(c1C(=O)c1ccc(Cl)cc1)CCN(C(=O)Nc1ccccc1)C2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 2-amino-3-(4-chlorobenzoyl)-4,5,6,7-tetrahydrothieno(2,3-c)pyridine) (1.02 mmol) in dry CH2Cl2 (20 mL), Et3N (1.2 eq) and phenylisocyanate (1.2 eq) were added. The mixture was stirred at room temperature for 4 hours, then was concentrated at reduced pressure and the residue purified by flash chromatography (EtOAc/light petroleum 3/7) to afford the desired compound as a solid (mp 216-217 ° C.).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[C:9]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:10][CH2:11][CH:12]=[CH2:13].[Br:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[C:21]([Cl:27])[CH:20]=1>C1COCC1>[Br:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][CH:10]([CH2:11][CH:12]=[CH2:13])[C:9]([O:15][CH2:16][CH3:17])=[O:14])=[C:21]([Cl:27])[CH:20]=1
Reactant: C=CCCC(=O)OCC
Reactant: Clc1cc(Br)ccc1CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC(Cc1ccc(Br)cc1Cl)C(=O)OCC
Yield: 71.1 %

Procedure:
Add LDA (5.27 mL, 10.5 mmol, 2.0 M) into a solution of ethyl pent-4-enoate (0.9 g, 7.0 mmol), in THF (125 mL) at −78° C. and stir for 15 minutes. Add 4-bromo-2-chlorobenzyl bromide (3.3 g, 10.5 mmol) and warm reaction to room temperature. Quench with ammonium chloride solution, extract the reaction mixture with methylene chloride and wash the organic layer with brine. Dry over sodium sulfate, filter and concentrate. Purify the residue with silica gel column (hexanes) to afford the title compound (1.65 g, 73%) as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][C:3]=1[N:17]=[C:18]=S.[NH2:20][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][C:30]=1[NH:31][CH3:32])[C:24]([O:26][CH3:27])=[O:25]>>[C:10]([O:9][C:8]([NH:7][CH2:6][C:5]1[CH:15]=[CH:16][C:2]([Cl:1])=[C:3]([NH:17][C:18]2[N:31]([CH3:32])[C:30]3[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][C:21]=3[N:20]=2)[CH:4]=1)=[O:14])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)c(N=C=S)c1
Reactant: CNc1ccc(C(=O)OC)cc1N
Product: COC(=O)c1ccc2c(c1)nc(Nc1cc(CNC(=O)OC(C)(C)C)ccc1Cl)n2C

Procedure:
The sub-title compound was prepared from tert-butyl 4-chloro-3-isothiocyanatobenzylcarbamate (see Example 2d) and methyl 3-amino-4-methylaminobenzoate according to Example 3, step (g).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([O:16][CH3:17])=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][C:3]=1[CH:4]=O.[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([NH2:31])[C:26]=2[NH2:32])[CH2:21][CH2:20]1>CC(N(C)C)=O>[CH3:17][O:16][C:11]1[C:10]([C:7]2[CH:8]=[CH:9][C:2]([OH:1])=[C:3]([C:4]3[NH:32][C:26]4[C:25]([N:22]5[CH2:21][CH2:20][N:19]([CH3:18])[CH2:24][CH2:23]5)=[CH:30][CH:29]=[CH:28][C:27]=4[N:31]=3)[CH:6]=2)=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: CN1CCN(c2cccc(N)c2N)CC1
Reactant: COc1ncccc1-c1ccc(O)c(C=O)c1
Solvent: CC(=O)N(C)C
Product: COc1ncccc1-c1ccc(O)c(-c2nc3cccc(N4CCN(C)CC4)c3[nH]2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 10.4 %

Procedure:
To mixture of 2-hydroxy-5-(2-methoxy-pyridin-3-yl)-benzaldehyde (57 mg, 0.25 mmol) and 3-(4-methyl-piperazin-1-yl)-benzene-1,2-diamine (51 mg, 0.25 mol) was added DMA (1 mL) and the resulting solution was stirred at the room temperature for 15 min, heated at 110° C. for 15 h open to the air, concentrated under reduced pressure. The residual crude was purified by chromatography (500:10:1 CH2Cl2/MeOH/28% aqueous NH4OH) to afford the title compound (10.8 mg, 10.5%). 1H NMR (MeOH-d4) δ 2.41 (s, 3H), 2.78 (m, 4H), 3.49 (m, 4H), 3.97 (s, 3H), 6.72 (m, 1H) 7.05-7.20 (4H), 7.56 (d, J=9 Hz, 1H), 7.78 (d, J=9 Hz, 1H), 8.10-8.13 (2H). ESI-MS m/z 416.5 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])=[C:5]2[NH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:25]([CH3:27])[CH3:26])=[CH:20][CH:19]=1.[Cl:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([F:44])[C:30]=1[OH:45]>>[Cl:28][C:29]1[CH:34]=[C:33]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])=[C:5]3[NH:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:25]([CH3:26])[CH3:27])=[CH:20][CH:19]=2)[CH:32]=[C:31]([F:44])[C:30]=1[OH:45]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CCCC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(CN(C)C)cc1
Product: CCCC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1Nc1ccc(CN(C)C)cc1
Yield: 62.8 %

Procedure:
Following general procedure D, 1-(6-bromo-4-((4-((dimethylamino)methyl)phenyl)amino)quinolin-3-yl)butan-1-one (43 mg, 0.10 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (41 mg, 0.15 mmol) to afford the desired product (30.9 mg, 63%) as a yellow solid. 1H NMR (500 MHz, MeOD+TFA-d) δ 9.35 (s, 1H), 8.22 (dd, J=8.8, 1.9 Hz, 1H), 8.03 (d, J=8.8 Hz, 1H), 7.85 (d, J=1.9 Hz, 1H), 7.77-7.70 (m, 2H), 7.65-7.58 (m, 2H), 7.08 (dd, J=11.5, 2.1 Hz, 1H), 6.95 (s, J=2.1 Hz, 1H), 4.46 (s, 2H), 3.19 (t, J=7.2 Hz, 2H), 2.88 (s, 6H), 1.81 (h, J=7.4 Hz, 2H), 1.07 (t, J=7.4 Hz, 3H). ESI MS m/z 492 [C28H27ClFN3O2+H]+; HPLC>99% (AUC), tR=10.90 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:31][O:32][C:33]1[CH:34]=[C:35]([NH2:39])[CH:36]=[CH:37][CH:38]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([NH:39][C:35]1[CH:36]=[CH:37][CH:38]=[C:33]([O:32][CH3:31])[CH:34]=1)=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1OCc1ccccc1
Reactant: COc1cccc(N)c1
Agent: O=C(n1ccnc1)n1ccnc1
Product: COc1cccc(NC(=O)c2cc(Br)ccc2OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Solid 5-bromo-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 5, method B; 200 mg, 0.65 mmol) was added to a stirred suspension of CDI (106 mg, 0.65 mmol) in THE (6 ml) under nitrogen at 20° C. The reaction mixture was stirred at room temperature for 10 min and 3-methoxybenzenamine (80 mg, 0.65 mmol) was added dropwise. After refluxing for 14 h, the reaction mixture was concentrated to obtain crude product. The crude product was purified by silica gel chromatography eluting with hexane:ethyl acetate (10:1). The crude product was added to a silica gel column and was eluted with DCM:hexane (2:1). The crude product was then added to a preparative HPLC column and was eluted with 0.05% trifluoroacetic acid, water/acetonitrile to yield the title compound. 110 mg.
Reaction SMILES: [C:1]([C@H:5]([NH:27][CH2:28][C:29]([O:31]CC)=O)[C:6]([N:8]1[CH2:12][C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[CH:10][C@H:9]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:34]([NH2:36])[CH3:35]>C1COCC1>[C:1]([C@H:5]([NH:27][CH2:28][C:29]([NH:36][CH2:34][CH3:35])=[O:31])[C:6]([N:8]1[CH2:12][C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[CH:10][C@H:9]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCN
Reactant: CCOC(=O)CN[C@H](C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1)C(C)(C)C
Solvent: C1CCOC1
Product: CCNC(=O)CN[C@H](C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1)C(C)(C)C

Procedure:
A solution of ethyl ({(1S)-1-tert-butyl-2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-2-oxoethyl}amino)acetate (7-1, 50 mg, 0.11 mmol) in a solution of ethylamine in THF (2 M, 2 mL) was heated in a sealable tube at 100° C. for 16 h. The reaction mixture was concentrated and the residue purified by flash column chromatography (EtOAc) to give 2-({(1S)-1-tert-butyl-2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-2-oxoethyl}amino)-N-ethylacetamide (7-2) as a white solid. 1H NMR (500 MHz, CDCl3) showed a 1:1 mixture of rotamers; one rotamer: δ 7.43-7.22 (m, 5H), 7.11-6.96 (m, 3H), 6.89 (br m, 1H), 6.38 (br s, 1H), 5.94 (m, 1H), 4.92 (ddd, 1H, J=14.9, 4.4, 1.7 Hz), 4.87 (br d, 1H, J=15.3 Hz), 3.42 (d, 1H, J=16.8 Hz), 3.35 (m, 2H), 3.03 (s, 1H), 2.88 (d, 1H, J=16.8 Hz), 2.34 (br s, 1H), 1.18 (t, 3H, J=7.3 Hz), 1.06 (s, 9H). LRMS m/z (M+H) 456.5 found, 456.2 required.
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].FC(F)(F)C(O)=O.[NH2:28][C:29]([CH3:36])([CH3:35])[C:30]([N:32]([CH3:34])[CH3:33])=[O:31]>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([NH:28][C:29]([CH3:36])([CH3:35])[C:30]([N:32]([CH3:34])[CH3:33])=[O:31])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: CN(C)C(=O)C(C)(C)N
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1C1(NC(C)(C)C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 868 mg of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and the compound obtained in Step 255-3 (3.10 mmol, crude form) as starting materials, 1.02 g of the title compound (colorless amorphous) was obtained by a similar method to Step 4-2.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]2[NH:11][C:10](=O)[NH:9][C:6]2=[N:7][CH:8]=1.P(Cl)(Cl)([Cl:17])=O>[Cl-].C[N+](C)(C)C>[Cl:17][C:10]1[NH:9][C:6]2=[N:7][CH:8]=[C:3]([C:2]([F:14])([F:13])[F:1])[CH:4]=[C:5]2[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c2cc(C(F)(F)F)cnc2[nH]1
Agent: C[N+](C)(C)C
Agent: [Cl-]
Product: FC(F)(F)c1cnc2[nH]c(Cl)nc2c1

Procedure:
Heat a solution of 6-trifluoromethyl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one. (0.6 g, 2.95 mmol) and tetramethylammonium chloride (0.3 g) to 110° C. in phosphorus oxychloride (10 mL) for 10 hours. After cooling, remove the excess POCl3 in vacuo, and then neutralize with saturated NaHCO3, extract with EtOAc. Dry over Na2SO4, concentrate under vacuum to obtain 2-chloro-6-trifluoromethyl-3-H-imidazo[4,5-b]pyridine.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[CH2:25][OH:26])=[O:8])[CH2:5][CH2:4]1)#[N:2].O[C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[Cl:24])(=[O:15])=[O:16])[CH2:11][C@H:10]2[CH2:25][O:26][C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: Oc1ccncc1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2CO)CC1
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2COc2ccncc2)CC1

Procedure:
The title compound was prepared in analogy to example 162 using (1R,2R,4S)-4-(2-chloro-4-fluoro-benzenesulfonyl)-2-hydroxymethyl-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (example 155) and 4-hydroxypyridine. Colorless oil (22%). MS (EI): 478.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[N:6]=1.[ClH:19].C(N(C1(C2C=CC=CC=2)CCN([CH2:31][CH2:32][CH2:33][C:34]2([C:49]3[CH:54]=[CH:53][C:52]([Cl:55])=[C:51]([Cl:56])[CH:50]=3)[CH2:40][CH2:39][CH2:38][CH2:37][N:36]([C:41](=[O:48])[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:35]2)CC1)C)(=O)C.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(#N)C>[ClH:55].[ClH:19].[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8][CH2:9][N:10]([CH2:31][CH2:32][CH2:33][C:34]3([C:49]4[CH:54]=[CH:53][C:52]([Cl:55])=[C:51]([Cl:56])[CH:50]=4)[CH2:40][CH2:39][CH2:38][CH2:37][N:36]([C:41](=[O:48])[C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[CH2:35]3)[CH2:11][CH2:12]2)[N:6]=1
Reactant: Nc1nc(C2(c3ccccc3)CCNCC2)cs1
Reactant: CC(=O)N(C)C1(c2ccccc2)CCN(CCCC2(c3ccc(Cl)c(Cl)c3)CCCCN(C(=O)c3ccccc3)C2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: Nc1nc(C2(c3ccccc3)CCN(CCCC3(c4ccc(Cl)c(Cl)c4)CCCCN(C(=O)c4ccccc4)C3)CC2)cs1

Procedure:
This compound is prepared by the procedure described in step D of EXAMPLE 13, starting from 0.77 g of 4-(2-aminothiazol-4-yl)-4-phenylpiperidine (compound of PREPARATION 1.4 in the form of the free base), 1.2 g of the compound obtained in step C of EXAMPLE 13 and 1.2 g of K2CO3 in 20 ml of a DMF/acetonitrile mixture (50/50; v/v). This gives 0.8 g of the expected product after crystallization from AcOEt, m.p.=178° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([CH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]3([CH3:26])OCC[O:22]3)[CH:19]=2)[N:14]([CH2:27][CH3:28])[C:13]1=[O:29])=[O:11].O1CCCC1.Cl>O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([CH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21](=[O:22])[CH3:26])[CH:19]=2)[N:14]([CH2:27][CH3:28])[C:13]1=[O:29])=[O:11]
Reactant: CCN1C(=O)C(C(=O)Nc2ccc(F)cc2F)c2cc(C3(C)OCCO3)ccc21
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CCN1C(=O)C(C(=O)Nc2ccc(F)cc2F)c2cc(C(C)=O)ccc21
Reaction time: 1 h
Yield: 73 %

Procedure:
N-(2,4-Difluorophenyl)-1-ethyl-5-(2-methyl-4,5-dihydro-1,3-dioxol-2-yl)oxindol-3-carboxamide (636 mg., 1.58 mmoles) was dissolved in 15 ml. of tetrahydrofuran to which was added 10 ml. of 1N hydrochloric acid. The solution was stirred for one hour followed by the addition of an equal volume of water. The resulting precipitate was filtered, vacuum dried and recrystallized from diisopropyl ether - methylene chloride, 412 mg. (73% yield), m.p. 160°-161° C.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[F:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[F:15])[C:9](O)=[O:10]>>[CH:1]1([NH:4][C:9](=[O:10])[C:8]2[CH:12]=[CH:13][C:14]([F:15])=[C:6]([F:5])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(F)c(F)c1
Reactant: NC1CC1
Product: O=C(NC1CC1)c1ccc(F)c(F)c1
Yield: 89 %

Procedure:
Using cyclopropylamine and 3,4-difluorobenzoic acid in the general procedure for coupling of amines to carboxylic acids, the title compound was obtained (89% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.52-0.63 (m, 2H) 0.63-0.74 (m, 2H) 2.83 (tq, J=7.42, 3.98 Hz, 1H) 7.52 (dt, J=10.55, 8.37 Hz, 1H) 7.66-7.75 (m, 1H) 7.85 (ddd, J=11.68, 7.89, 2.15 Hz, 1H) 8.42-8.60 (m, 1H). ESI-MS:m/z 198.1 (M+H)+. mp=104.1-108.4° C.