Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@:4]1(C)[CH2:9][C@H:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([Cl:17])[CH:11]=2)[C@@H:7]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[N:6]([C@@H:25]([CH2:33][CH3:34])[CH2:26][NH:27][S:28]([CH2:31][CH3:32])(=[O:30])=[O:29])[C:5]1=[O:35])C=C.CC#N.O.I([O-])(=O)(=O)=O.[Na+].CC[O:49][C:50]([CH3:52])=[O:51]>O.[Ru](Cl)(Cl)Cl>[Cl:17][C:12]1[CH:11]=[C:10]([C@@H:8]2[C@@H:7]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[N:6]([C@@H:25]([CH2:33][CH3:34])[CH2:26][NH:27][S:28]([CH2:31][CH3:32])(=[O:30])=[O:29])[C:5](=[O:35])[C@:4]([CH2:52][C:50]([OH:49])=[O:51])([CH3:1])[CH2:9]2)[CH:15]=[C:14]([F:16])[CH:13]=1
Reactant: CCOC(C)=O
Reactant: C=CC[C@@]1(C)C[C@H](c2cc(F)cc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CNS(=O)(=O)CC)C1=O
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: CC[C@@H](CNS(=O)(=O)CC)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cc(F)cc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N-((S)-2-((3S,5R,6S)-3-allyl-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butyl)ethanesulfonamide (Example 393, Step C, 120 mg, 0.216 mmol) in EtOAc:MeCN:water (1.450 mL) (2/2/3) at rt was added sodium periodate (185 mg, 0.864 mmol) slowly. Then ruthenium chloride hydrate (1.071 mg, 4.75 μmol) was added. The mixture was stirred vigourously at rt for 2 h. Then the mixture was filtered and the solid was washed with EtOAc. The filtrate was extracted with EtOAc 2×. The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase preparatory HPLC (column: Gemini™ Prep C18 5 um column; Phenomenex, Torrance, Calif.; eluent: 0 to 100% MeCN +0.1% TFA in water +0.1% TFA, over 20 minutes) to give the title compound.
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13](=[C:16]2[C:24]3[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=3)[NH:18][C:17]2=[O:26])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>CO.O>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([CH:16]2[C:24]3[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=3)[NH:18][C:17]2=[O:26])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(=C2C(=O)Nc3cc(Cl)ccc32)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C2C(=O)Nc3cc(Cl)ccc32)CC1
Temperature: 40 °C

Procedure:
Sodium borohydride (0.38 g, 10 mmol) (Aldrich) was added in small portions to a solution of 4-(6-chloro-2-oxo-1,2-dihydro-indol-3-ylidene)-piperidine-1-carboxylic acid tert-butyl ester (0.35 g, 1 mmol) (from Example 12a supra) in methanol (25 mL) and water (3 mL) at such a rate that gas evolution was not too vigorous. When addition was complete, mixture was heated at 40° C. for 1 hour. After cooling, mixture was slowly diluted with water. Precipitate formed was collected by filtration and washed with cold aqueous methanol to give rac-4-(6-chloro-2-oxo-2,3-dihydro-1H-indol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester as a white crystalline material. (Yield 0.33 g, 94.0%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][N:18]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.C(N(CC)CC)C.[CH3:32][C:33]([CH3:38])([CH3:37])[C:34](Cl)=[O:35]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:34](=[O:35])[C:33]([CH3:38])([CH3:37])[CH3:32])=[CH:19][N:18]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1
Reactant: COC(=O)CC1CCC(c2ccc(-c3ccc(N)cn3)cc2)CC1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CC1CCC(c2ccc(-c3ccc(NC(=O)C(C)(C)C)cn3)cc2)CC1
Reaction time: 15 h

Procedure:
To a mixture of {4-[4-(5-amino-pyridin-2-yl)-phenyl]-cyclohexyl}-acetic acid methyl ester (100 mg, 0.3 mmol) in methylene chloride (10 ml) was added triethylamine (43 ul, 0.3 mmol) and trimethylacetyl chloride (40 ul, 0.3 mmol). After 15 hours at room temperature, the reaction was diluted with hexanes to afford a precipitate which was collected by filtration: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15 (dd, J=12.69, 1.71 Hz, 2H) 1.26 (s, 10H) 1.42-1.56 (m, 1H) 1.50 (d, J=9.85 Hz, 1H) 1.82 (d, J=11.37 Hz, 5H) 2.26 (d, J=6.69 Hz, 2H) 3.61 (s, 3H) 7.32 (d, J=8.34 Hz, 2H) 7.87 (d, J=8.72 Hz, 1H) 7.95 (d, J=8.34 Hz, 2H) 8.15 (dd, J=8.72, 2.53 Hz, 1H) 8.88 (d, J=2.53 Hz, 1H) 9.53 (s, 1H); (M+H)+409.2.
Reaction SMILES: [F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3].[C:17]1([C:23]2[O:27][CH:26]=[N:25][C:24]=2[C:28](O)=[O:29])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:28]([C:24]3[N:25]=[CH:26][O:27][C:23]=3[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:29])[CH:13]=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3]
Reactant: CC(F)(F)c1csc(Cn2ncc(N)n2)n1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Product: CC(F)(F)c1csc(Cn2ncc(NC(=O)c3ncoc3-c3ccccc3)n2)n1

Procedure:
Following general procedure A, starting from 2-[4-(1,1-Difluoro-ethyl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:7](Cl)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:27]([OH:34])(=[O:33])[CH2:28][CH2:29][C:30]([OH:32])=[O:31]>C1(C)C=CC=CC=1.CO.C1(C)C=CC=CC=1>[C:27]([OH:34])(=[O:33])[CH2:28][CH2:29][C:30]([OH:32])=[O:31].[C:7]([N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C1CNCCN1
Agent: O=C(O)CCC(=O)O
Solvent: CO
Solvent: Cc1ccccc1
Product: c1ccc(C(c2ccccc2)(c2ccccc2)N2CCNCC2)cc1
Reaction time: 1.5 h
Yield: 70 %

Procedure:
To a cooled solution of piperazine (10 eq) in toluene/methanol (5:1 toluene/methanol (v:v); 5 mL/g piperazine) was added slowly a solution of trityl chloride 10 (1.0 eq) in toluene (5 mL/g trityl chloride). Upon reaction completion (1-2 hr), this solution was washed four times with water. To the resulting organic solution was added an aqueous solution of succinic acid (1.1 eq; 13 mL water/g succinic acid). This mixture was stirred for 90 min, and the solid product was collected by filtration. The crude solid was purified by two reslurries in acetone. Yield=70%.
Reaction SMILES: C(N(CC)CC)C.Cl.[Br:9][C:10]1[CH:11]=[C:12]([NH:16][NH2:17])[CH:13]=[CH:14][CH:15]=1.[CH:18]1([C:22](Cl)=[O:23])[CH2:21][CH2:20][CH2:19]1>ClCCl>[Br:9][C:10]1[CH:11]=[C:12]([NH:16][NH:17][C:22]([CH:18]2[CH2:21][CH2:20][CH2:19]2)=[O:23])[CH:13]=[CH:14][CH:15]=1
Reactant: NNc1cccc(Br)c1
Reactant: O=C(Cl)C1CCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NNc1cccc(Br)c1)C1CCC1
Reaction time: 1.5 h
Yield: 59.8 %

Procedure:
Triethylamine (6.90 mL, 49.22 mmol) was added dropwise to a suspension of 3-bromophenylhydrazine hydrochloride (5.00 g, 22.37 mmol) in dichloromethane (60 mL) to give a solution. The mixture was cooled in an ice-salt bath and then cyclobutanecarbonyl chloride (2.68 mL, 23.49 mmol) in dichloromethane (10 mL) was added dropwise at such a rate that the internal temperature did not exceed −10° C. After the addition, the mixture was stirred at −5° C. to −10° C. for 1.5 hours. The cooling bath was removed and the mixture was stirred for a further 2 hours at room temperature. The mixture was evaporated in vacuo and 4% aqueous sodium hydrogen carbonate solution was added. The mixture was filtered and the semi-solid was washed with 4% aqueous sodium hydrogen carbonate solution, water and diethyl ether and dried in vacuo to give the title compound (3.60 g, 60%) as a white solid.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5].Br[C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:20]/[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27])/[C:13](=[O:19])[NH:14]2>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.CN(C=O)C.CCN(CC)CC>[CH3:8][O:7][C:1](=[O:6])[CH2:2][CH2:3][C:4]#[C:5][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:20]/[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27])/[C:13](=[O:19])[NH:14]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Reactant: C#CCCC(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CCC#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method D above, methyl 4-pentynoate (163 mg, 1.45 mmol) (see below) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (300 mg, 1.03 mmol) (Starting Material 1 supra) using (Ph3P)2PdCl2 (30 mg) and Cul (15 mg) as catalyst in DMF (5 mL) and Et3N (5 mL) as solvent at 70° C. for 14 h to yield (Z)-5-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-4-pentynoic acid methyl ester. (Yield 120 mg, 33%).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])=[CH:8][CH:9]=[C:10]([C:15]([NH2:17])=[O:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[CH:25]([S:27]([CH:30]=[CH2:31])(=[O:29])=[O:28])=[CH2:26]>CC(O)C>[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:7]1[C:6]2[C:5]3[C:13](=[CH:14][C:2]([N:1]4[CH2:31][CH2:30][S:27](=[O:29])(=[O:28])[CH2:25][CH2:26]4)=[CH:3][CH:4]=3)[NH:12][C:11]=2[C:10]([C:15]([NH2:17])=[O:16])=[CH:9][CH:8]=1
Reactant: NC(=O)c1ccc(-c2ccccc2F)c2c1[nH]c1cc(N)ccc12
Reactant: C=CS(=O)(=O)C=C
Solvent: CC(C)O
Product: NC(=O)c1ccc(-c2ccccc2F)c2c1[nH]c1cc(N3CCS(=O)(=O)CC3)ccc12
Temperature: 100 °C
Yield: 28.3 %

Procedure:
A suspension of 7-amino-4-(2-fluorophenyl)-9H-carbazole-1-carboxamide (Example 54-1, 36 mg, 0.113 mmol) in 2-propanol (1.0 mL) was treated with vinylsulfonylethene (20 μL, 0.199 mmol) at rt. The reaction mixture was heated at 100° C. for 26 h. The mixture was cooled to rt, concentrated and the residue was purified by preparative HPLC to provide 4-(2-fluorophenyl)-7-(1,1-dioxothiomorpholino)-9H-carbazole-1-carboxamide as a yellow solid (14 mg, 28%). 1H NMR (400 MHz, DMSO-d6) δ 11.26 (1H, s), 8.17 (1H, br. s.), 7.90 (1H, d, J=7.9 Hz), 7.47-7.62 (3H, m), 7.37-7.46 (2H, m), 7.35 (1H, d, J=1.8 Hz), 7.01 (1H, d, J=7.9 Hz), 6.93 (1H, d, J=8.3 Hz), 6.74 (1H, dd, J=9.0, 2.4 Hz), 3.77-3.81 (4H, m), 3.08-3.19 (4H, m). Mass spectrum m/z 438.1 (M+H)+.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[C:31]([C:32]2[S:33][C:34]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([S:43]([CH3:46])(=[O:45])=[O:44])[CH:38]=3)=[CH:35][CH:36]=2)=[CH:30][C:29]([CH2:47]O)=[N:28]1.C1C(=O)N([Br:56])C(=O)C1>C(Cl)Cl>[Br:56][CH2:47][C:29]1[CH:30]=[C:31]([C:32]2[S:33][C:34]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([S:43]([CH3:46])(=[O:45])=[O:44])[CH:38]=3)=[CH:35][CH:36]=2)[N:27]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[Cl:20])[N:28]=1
Reactant: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(CO)nn3-c3ccccc3Cl)s2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(CBr)nn3-c3ccccc3Cl)s2)c1
Reaction time: 0.5 h
Yield: 51.2 %

Procedure:
PPh3 (4.36 g, 16.62 mmol) was added at 0° C. to a stirred solution of [1-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]methanol (6.15 g, 13.85 mmol) in dry DCM. After 30 min, NBS (2.72 g, 15.28 mmol) was added portionwise at 0° C., and the mixture was stirred at it overnight. The solvent was removed in vacuo, and the crude product was purified by flash chromatography (0-50% EtOAc/hexanes) to afford 3-bromomethyl-1-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-thiophen-2-yl]-1H-pyrazole as a pale-yellow solid (3.6 g, 54%).
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2]=[CH2:3].[C:6]([O:10][C:11]([N:13]1[CH2:17][CH2:16][C@H:15]([C:18](=[O:23])N(OC)C)[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[BH4-].[Na+]>C1COCC1.O.[Br-]>[C:6]([O:10][C:11]([N:13]1[CH2:17][CH2:16][C@H:15]([CH:18]([OH:23])[CH2:3][CH:2]=[CH2:1])[CH2:14]1)=[O:12])([CH3:7])([CH3:8])[CH3:9]
Reactant: C=CC[Mg]Br
Reactant: CON(C)C(=O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCC(O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 83.9 %

Procedure:
Add slowly and dropwise a solution of allylmagnesium bromide (2.0 M in THF, 100.3 mL, 200.5 mmol) to a stirred solution of (S)-3-(methoxy(methyl)carbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (37.0 g, 143.2 mmol) in THF (296 mL) kept under nitrogen at 0° C. Allow the reaction to warm to room temperature and continue to stir for 48 hours. Add the mixture over a cold solution (0-5° C.) of sodium borohydride (5.42 g, 143 mmol) and tertabutylammonium bromide (0.74 g, 2.39 mmol) in water (74 mL) and stir for 1 hour. Separate the phases and extract the water phase with t-butylmethylether (2×). Combine the organic phases and wash with water and brine. Concentrate and purify the crude residue by silica gel column chromatography eluting with t-butylmethylether/hexanes (3/7 to 7/3) to obtain (3S)-3-(1-hydroxy-but-3-enyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (S-mix) (29 g, 85%). MS (m/z)=186.1 [M−55].
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.C(N(CC)CC)C.[CH:19]1([C:22]#[CH:23])[CH2:21][CH2:20]1>C1COCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH:19]1([C:22]#[C:23][C:2]2[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=2)[CH2:21][CH2:20]1
Reactant: COC(=O)c1ccc(Br)cn1
Reactant: C#CC1CC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C#CC2CC2)cn1
Temperature: 40 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
To a sealed tube were added methyl 5-bromopyridine-2-carboxylate (450 mg, 2.083 mmol) in THF (4 ml) followed by tetrakis(triphenylphosphine)palladium (193 mg, 0.167 mmol), copper(i) iodide (20 mg, 0.104 mmol), triethylamine (2.3 ml, 16.66 mmol) under N2. Finally cyclopropylacetylene (275 mg, 4.17 mmol) was added. The yellow mixture was stirred at 40° C. for overnight. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine and dried over MgSO4. The solution was filtered and concentrated to give the crude material as an orange oil. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 15% to 30% to 45% EtOAc in Heptane, to provide methyl 5-(cyclopropylethynyl)picolinate (390 mg, 1.938 mmol, 93% yield) as an orange solid. MS m/z=202.2 (M+H).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[NH:11][C:12]([C:14]1[CH:36]=[CH:35][C:17]([O:18][C:19]2[CH:28]=[C:27]3[C:22]([CH:23]([C:29]([O:31]C)=[O:30])[CH2:24][CH2:25][O:26]3)=[CH:21][C:20]=2[C:33]#[N:34])=[CH:16][CH:15]=1)=[O:13].[OH-].[Na+].CO>C1COCC1.C(OCC)(=O)C.Cl>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[NH:11][C:12]([C:14]1[CH:36]=[CH:35][C:17]([O:18][C:19]2[CH:28]=[C:27]3[C:22]([CH:23]([C:29]([OH:31])=[O:30])[CH2:24][CH2:25][O:26]3)=[CH:21][C:20]=2[C:33]#[N:34])=[CH:16][CH:15]=1)=[O:13]
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)NC4CCc5ccccc5C4)cc3)c(C#N)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: N#Cc1cc2c(cc1Oc1ccc(C(=O)NC3CCc4ccccc4C3)cc1)OCCC2C(=O)O
Reaction time: 1 h
Yield: 30.5 %

Procedure:
Methyl 7-(4-((1,2,3,4-tetrahydronaphthalen-2-yl)carbamoyl)phenoxy)-6-cyanochroman-4-carboxylate (10 mg, 0.021 mmol) was diluted with THF (500 μL) followed by the addition of NaOH (0.12 ml, 0.12 mmol) and methanol (100 μL). After stirring for 1 hour, the reaction was diluted with ethyl acetate and 2N HCl. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated to yield 7-(4-((1,2,3,4-tetrahydronaphthalen-2-yl)carbamoyl)phenoxy)-6-cyanochroman-4-carboxylic acid (3.0 mg, 31% yield). MS (ESI)=469.0 (M+H).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([Cl:7])=[C:4]([C:8](O)=[O:9])[CH:3]=1.CSC.B.CO.O>C1COCC1>[Br:1][C:2]1[S:6][C:5]([Cl:7])=[C:4]([CH2:8][OH:9])[CH:3]=1
Reactant: O=C(O)c1cc(Br)sc1Cl
Agent: B
Solvent: C1CCOC1
Solvent: O
Solvent: CSC
Product: OCc1cc(Br)sc1Cl
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 99.3 %

Procedure:
To a solution of acid 1 (3.0 g, 12.4 mmol) in THF (50 mL) were added borane dimethylsulfide complex (10M in THF, 3.2 mL, 31.1 mmol) at 0° C. The mixture was stirred at 0° C. for 15 min, at room temperature for 45 min, and at 65° C. for 2 hours. The reaction mixture was cooled to 0° C. To the mixture were added MeOH (30 mL), H2O (250 mL) dropwise at 0° C. The mixture was extracted with EtOAc (100 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to obtain the title compound 31 (2.8 g, 99%). The crude alcohol 31 was carried on to the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][N:26]=1)[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:23])=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][CH:15]=2)[CH:13]=1)=[O:6].[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH3:23][C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:24]=[CH:25][N:26]=[C:2]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH:3]=2)=[CH:13][C:12]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1ccc(NC(=O)c2ccnc(Cl)c2)cc1-c1ccc(C(=O)O)cc1
Reactant: C1CCNC1
Product: Cc1ccc(NC(=O)c2ccnc(N3CCCC3)c2)cc1-c1ccc(C(=O)O)cc1
Yield: 83 %

Procedure:
5′-[(2-Chloroisonicotinoyl)amino]-2′-methyl-1,1′-biphenyl-4-carboxylic acid (600 mg, 1.64 mmol) and pyrrolidine (0.6 ml) were heated in a sealed tube at 90° C. for 5 h. The excess pyrrolidine was evaporated under vacuum and the residue purified by flash chromatography (silica) eluting with DCM/ethanol/ammonia (20:8:1). The solvents were evaportated under vacuum to give 2′-methyl-5′-[(2-pyrrolidin-1-ylisonicotinoyl)amino]-1,1′-biphenyl-4-carboxylic acid (546 mg, 83%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH:4]([C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[CH:15]=1)[CH2:5][C:6]1[C:7](Cl)=[N:8][C:9](Cl)=[N:10][CH:11]=1.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH3:1][O:2][C:3](=[O:24])[CH:4]([C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[CH:15]=1)[CH2:5][C:6]1[C:7]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:8][C:9]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:10][CH:11]=1
Reactant: COC(=O)C(Cc1cnc(Cl)nc1Cl)c1cc(OC)cc(OC)c1
Reactant: Nc1ccccc1
Product: COC(=O)C(Cc1cnc(Nc2ccccc2)nc1Nc1ccccc1)c1cc(OC)cc(OC)c1
Temperature: 110 °C

Procedure:
A mixture of 3-(2,4-dichloro-pyrimidin-5-yl)-2-(3,5-dimethoxy-phenyl)-propionic acid methyl ester (186 mg, 0.50 mmol) (from Example 3b supra) and aniline (2.0 mL) (Aldrich) was heated at 110° C. for 2 hours. The reaction mixture was washed with hexanes (50 mL×3) and the supernatant was decanted off after each time. The residue was dissolved in ethyl acetate (100 mL) and successively washed with saturated aqueous ammonium chloride solution (30 mL), water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude 3-(2,4-diphenylamino-pyrimidin-5-yl)-2-(3,5-dimethoxy-phenyl)-propionic acid methyl ester as an off-white solid which was used in the next step without further purification. (Yield 241.5 mg, 99.7%).
Reaction SMILES: [C:1]1([C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([CH:9]2[CH2:14][CH2:13][N:12](CC3C=CC=CC=3)[CH2:11][CH2:10]2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd].C(O)C>[C:1]1([C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[OH:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC(c1ccccc1)(c1ccccc1)C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: OC(c1ccccc1)(c1ccccc1)C1CCNCC1
Reaction time: 72 h
Yield: 99.9 %

Procedure:
A mixture of 35.8 g (0.1 mole) of α,α-diphenyl-1-(phenylmethyl)-4-piperidinemethanol and 5% palladium on carbon catalyst in 500 ml of absolute ethanol was hydrogenated at 60° C. in a Parr apparatus for 3 days. The mixture was filtered through Celite® and the filtrate was concentrated to give a solid residue. The solid was triturated with petroleum ether (30°-60° C.), collected by filtration and dried to give 26.7 g of title compound as a white solid. An analytical sample was obtained by recrystallization from 2-propanol-isopropyl ether, mp 160°-161° C.
Reaction SMILES: [CH:1]1([C@H:7]([O:20][CH3:21])[C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=2[CH2:18]O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Br)(Br)(Br)[Br:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:23][CH2:18][C:9]1[CH:10]=[C:11]([C:14]([F:17])([F:16])[F:15])[CH:12]=[CH:13][C:8]=1[C@H:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[O:20][CH3:21]
Reactant: BrC(Br)(Br)Br
Reactant: CO[C@H](c1ccc(C(F)(F)F)cc1CO)C1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CO[C@H](c1ccc(C(F)(F)F)cc1CBr)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.6 %

Procedure:
To a solution of (S)-[2-(cyclohexyl-methoxy-methyl)-5-trifluoromethyl-phenyl]-methanol (340 mg, 1.2 mmol) in methylene chloride (10 mL) at 0° C. was added carbon tetrabromide (485 mg, 1.46 mmol) and stirred for 10 minutes followed by addition of triphenylphosphine (383 mg, 1.46 mmol). Reaction was stirred at 0° C. for 1 hour and allowed to warm to room temperature and stirred for 16 hours. Reaction was concentrated in vacuo and purified on 25+S Biotage column eluting with 0-20% ethyl acetate in heptane (10 CV), 20% (2CV), to yield the title compound (270 mg, 66%) as a colorless oil. This oil solidified upon standing and was recrystalized from hexane to yield crystals (mp=43-45° C.), which were submitted to X-ray crystallography to establish absolute configuration. 1H NMR (400 MHz, CDCl3) δ ppm 1.1 (m, 4H) 1.3 (m, 2H) 1.6 (m, 3H) 1.7 (m, 1H) 2.0 (d, J=12.6, 1H) 3.2 (s, 3H) 4.2 (d, J=7.9, 1H) 4.5 (d, J=10.3 Hz, 1H) 4.6 (d, J=10.3 Hz, 1H) 7.4 (d, J=8.3 Hz, 1H) 7.5 (d, J=8.3 Hz, 1H) 7.6 (s, 1H). [α]D20=−50 deg (c=11.5 mg/mL, acetone)
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][CH2:18][CH2:17]3)=[O:13])[CH:2]=1.C(N(CC)C(C)C)(C)C.[C:32](Cl)(=[O:34])[CH3:33]>ClCCCl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([C:32](=[O:34])[CH3:33])[CH2:18][CH2:17]3)=[O:13])[CH:2]=1
Reactant: O=C(Nc1cnc2ccccc2c1)c1ccc2c(c1)CCN2
Reactant: CC(=O)Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCc2cc(C(=O)Nc3cnc4ccccc4c3)ccc21
Yield: 84 %

Procedure:
A solution of 2,3-dihydro-1H-indole-5-carboxylic acid quinolin-3-ylamide (77 mg, 0.266 mmol) and N,N-diisopropylethylamine (0.060 mL, 0.345 mmol) in 1,2-dichloroethane (2 mL) was treated with acetyl chloride (0.020 mL, 0.292 mmol). The resultant solution was stirred at room temperature overnight. The solvent was evaporated and the residue was triturated in water (1 mL) and saturated aqueous sodium bicarbonate (1 mL). The product was collected by filtration, to give the product 74 mg (84%). MS: m/z 332 (MH+). 1H NMR (DMSO-d6): δ 2.21 (s, 3H), 3.24 (t, 2 H), 4.18 (t, 2 H), 7.59 (t, 1 H), 7.67 (t, 1 H), 7.89-7.98 (m, 4 H), 8.15 (d, 1 H), 8.84 (s, 1 H), 9.14 (s, 1 H) and 10.566 (s, 1 H).