Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].Cl[C:3]1[C:4]2[C:5](=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[N:11]=2)[N:6]=[CH:7][N:8]=1.[CH3:26][CH:27]([OH:29])[CH3:28]>>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:9]2[N:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[N:11]=[C:4]3[C:3]([O:29][CH:27]([CH3:28])[CH3:26])=[N:8][CH:7]=[N:6][C:5]=23)=[CH:20][CH:21]=1
Reactant: CC(C)O
Reactant: Clc1ccc(-c2c3ncnc(Cl)c3nn2-c2ccccc2Cl)cc1
Agent: [Na]
Product: CC(C)Oc1ncnc2c(-c3ccc(Cl)cc3)n(-c3ccccc3Cl)nc12
Temperature: 65 °C
Reaction time: 2 h

Procedure:
Sodium (21 mg, 0.9 mmol) was added to 2-propanol (2 ml), and the resultant mixture was stirred at 65° C. for 16 hours. Next, 7-chloro-3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidine I-2A-1c (75 mg, 0.2 mmol) was added in one portion, and the mixture was stirred at 65° C. for 2 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over anhydrous magnesium sulfate and concentrated. Purification of the residue by flash column chromatography (50% ethyl acetate in hexanes) provided the title compound 3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-isopropoxy-2H-pyrazolo[4,3-d]pyrimidine 8A-1 (41 mg): MS: 399.1 (M+1)+; 1H NMR (400 MHz, CDCl3) δ 8.6 (s, 1H), 7.6 (d, J=6.6 Hz, 1H), 7.5 (m, 5H), 7.3 (d, J=8.7 Hz, 2H), 5.8 (pentuplet, J=6.2 Hz, 1H), 1.5 (d, J=6.2 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:4][CH:3]=1.C([Li])(C)(C)C.CCCCC.[I:25]I.Cl>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12])[C:5]([I:25])=[CH:4][CH:3]=1
Reactant: II
Reactant: CC(C)(C)C(=O)Nc1cccc(Cl)n1
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC(C)(C)C(=O)Nc1nc(Cl)ccc1I
Reaction time: 3 h

Procedure:
To a dry solution of N-(6-chloropyridin-2-yl)-2,2-dimethyl propionamide (Preparation 107, 8.0 g, 37.6 mmol) in THF (120 mL), cooled to −78° C., was added dropwise, a solution of tert-butyllithium in pentane (1.7M, 48.7 mL, 82.8 mmol) over 40 min. The reaction was stirred at —78° C. for 3 h before adding a solution of iodine (11.46 g, 45.1 mmol) in THF (40 mL) dropwise. The mixture was brought up to rt and stirred for 16 h. 2M HCl (3 mL) was added to the reaction, and after 20 min the solvent was removed in vacuo. Crude material was partitioned between ethyl acetate (200 mL) and water (150 mL). Organics were separated and washed with 10% sodium thiosulfate solution (4×100 mL) then NaHCO3 solution (2×100 mL), dried (MgSO4) and the solvent removed in vacuo. The residue was purified by column chromatography (SiO2, CH2Cl2) to give the title compound. m/z (ES+)=338.93 [M+H]+.
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]12[CH2:20][CH2:19][C:16]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)([CH2:17][CH2:18]1)[CH2:15][CH2:14]2)=[S:11])(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.CO.O>[CH3:30][S:27]([C:24]1[CH:23]=[CH:22][C:21]([C:16]23[CH2:17][CH2:18][C:13]([NH:12][C:10]([NH2:9])=[S:11])([CH2:14][CH2:15]2)[CH2:20][CH2:19]3)=[CH:26][CH:25]=1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)c1ccc(C23CCC(NC(=S)NC(=O)c4ccccc4)(CC2)CC3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(C23CCC(NC(N)=S)(CC2)CC3)cc1
Reaction time: 3.5 h

Procedure:
To a 100 mL round-bottomed flask equipped with magnetic stirring was added a solution of 1-benzoyl-3-(4-(4-(methylsulfonyl)phenyl)bicyclo[2.2.2]octan-1-yl)thiourea (185 mg, 418 μmol) suspended in THF (1.5 mL) and methanol (3 mL). A solution of potassium carbonate (289 mg, 2090 μmol) in 1.5 mL of water was added, and the reaction mixture was stirred at ambient temperature. After 3.5 h, 3 mL more of THF was added. Then after 22.5 h, the lower boiling solvents of the reaction mixture were removed in vacuo. Water was added, and the aqueous layer was extracted with EtOAc (1×10 mL), CH2Cl2 (3×10 mL), and EtOAc (1×20 mL). The aqueous layer was the saturated with solid NaCl, and it was extracted with THF (3×10 mL). All organic layers were combined along with 30 mL more THF and dried over K2CO3, filtered, and concentrated in vacuo. The residue was absorbed onto silica gel and purified on a 40 g silica gel column using 1:2 hexanes-EtOAc+2% MeOH as the eluant followed by 1:2 hexanes-EtOAc+4.5% MeOH. Purified 1-(4-(4-(methylsulfonyl)phenyl)bicyclo[2.2.2]octan-1-yl)thiourea was isolated from the chromatography (43 mg, white solid, Mass spec. m/z+ion=339.2).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8]C(=O)C(C)(C)C)[CH:5]=[CH:4][C:3]=1[CH2:15][CH3:16].[OH-].[Na+]>Cl>[Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[CH2:15][CH3:16]
Reactant: CCc1ccc(NC(=O)C(C)(C)C)nc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCc1ccc(N)nc1Cl
Temperature: 25 °C
Yield: 86.1 %

Procedure:
A suspension of N-(6-chloro-5-ethylpyridin-2-yl)pivalamide (1.16 g, 4.82 mmol) in 6N HCl (20 mL) was heated at reflux overnight. The reaction mixture was cooled to room temperature and was treated with aqueous NaOH to pH 8. The aqueous layer was extracted with EtOAc. The organic layer was dried over MgSO4 and the solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel (5% EtOAc in petroleum ether) to afford 6-chloro-5-ethylpyridin-2-amine (650 mg, 86%). 1H NMR (CDCl3, 400 MHz) δ 7.35 (d, J=8.4, 1H), 6.45 (d, J=8.4, 1H), 2.61 (q, J=7.6, 2H), 1.18 (t, J=7.6, 3H).
Reaction SMILES: [Br:1][CH:2]([P:6](=[O:9])([OH:8])[OH:7])[CH:3]([OH:5])[CH3:4].[Na].[C:11](Br)(=[O:13])[CH3:12]>>[Br:1][CH:2]([P:6](=[O:8])([OH:7])[OH:9])[CH:3]([O:5][C:11](=[O:13])[CH3:12])[CH3:4]
Reactant: CC(=O)Br
Reactant: CC(O)C(Br)P(=O)(O)O
Agent: [Na]
Product: CC(=O)OC(C)C(Br)P(=O)(O)O
Temperature: 25 °C

Procedure:
One and one-half grams of (1-bromo-2-hydroxypropyl)phosphonic acid prepared from the sodium salt obtained in Example 22 is heated with 5 ml. of acetyl bromide for one hour. The excess acetyl bromide is distilled off under reduced pressure and ice-cold water is added to the residue. The solution is stirred at room temperature and lyophilized to give (1bromo-2-acetoxypropyl)phosphonic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]([C:15]([NH:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][C:23]=2[C@H:24]2[CH2:29][C@@H:28]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[C@H:27]([OH:38])[C@@H:26]([CH3:39])[CH2:25]2)=[O:16])[CH:12]=[CH:11][C:10]=1[F:40].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]([C:15]([NH:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][C:23]=2[C@H:24]2[CH2:29][C@@H:28]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:36])[CH3:34])[C:27](=[O:38])[C@@H:26]([CH3:39])[CH2:25]2)=[O:16])[CH:12]=[CH:11][C:10]=1[F:40]
Reactant: C[C@H]1C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: C[C@H]1C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](NC(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
To a solution of tert-butyl (1R,2R,3S,5R)-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-2-hydroxy-3-methylcyclohexylcarbamate (1.0 equiv.) in DCM (0.10 M) was added Dess-MartinPeriodinane (1.2 equiv.). The flask was capped and the homogeneous solution was left stirring at rt for 3 hrs. The solution was partitioned between EtOAc and 1:1 10% Na2S2O3/NaHCO3 (sat.). The organic layer was washed with NaCl(sat.), dried over MgSO4, filtered and concentrated, and purified by ISCO SiO2 chromatography to yield tert-butyl (1R,3S,5R)-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-3-methyl-2-oxocyclohexylcarbamate in 83% yield. LC/MS (m/z)=555.4 (MH+), Rt=0.87 min.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH:13]=[C:12]([C:14]([N:16]3[CH2:20][CH2:19][C@H:18]([NH2:21])[CH2:17]3)=[O:15])[N:11]=[CH:10]2)[CH:4]=1.[OH:24][C:25]1([C:32]2[CH:33]=[N:34][C:35]([C:38]3[N:43]=[CH:42][CH:41]=[CH:40][N:39]=3)=[CH:36][CH:37]=2)[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(N(CC)CC)C>C(Cl)Cl.CCOC(C)=O>[N:39]1[CH:40]=[CH:41][CH:42]=[N:43][C:38]=1[C:35]1[N:34]=[CH:33][C:32]([C:25]2([OH:24])[CH2:30][CH2:29][CH:28]([NH:21][C@H:18]3[CH2:19][CH2:20][N:16]([C:14]([C:12]4[N:11]=[CH:10][N:9]([C:5]5[CH:4]=[C:3]([C:2]([F:1])([F:22])[F:23])[CH:8]=[CH:7][N:6]=5)[CH:13]=4)=[O:15])[CH2:17]3)[CH2:27][CH2:26]2)=[CH:37][CH:36]=1
Reactant: N[C@H]1CCN(C(=O)c2cn(-c3cc(C(F)(F)F)ccn3)cn2)C1
Reactant: O=C1CCC(O)(c2ccc(-c3ncccn3)nc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(c1cn(-c2cc(C(F)(F)F)ccn2)cn1)N1CC[C@H](NC2CCC(O)(c3ccc(-c4ncccn4)nc3)CC2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (3S)-1-({1-[4-(trifluoromethyl)pyridin-2-yl]-1H-imidazol-4-yl}carbonyl)pyrrolidin-3-amine (50 mg, 0.15 mmol) and 4-hydroxy-4-(6-pyrimidin-2-ylpyridin-3-yl)cyclohexanone (41 mg, 0.15 mmol) in methylene chloride (3 mL) was added sodium triacetoxyborohydride (36 mg, 0.17 mmol) followed by triethylamine (0.086 mL, 0.61 mmol). After being stirred at room temperature for 2 h, EtOAc (50 mL) was added. The solution was washed with NaHCO3 solution and water, dried (MgSO4) and concentrated. Purification by HPLC provided two isomers. MS (M+H) 579.3 for both isomers.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1[OH:15].N[C:17](N)=[O:18].O.Cl>CN(C=O)C>[O:18]=[C:17]1[NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=2[O:15]1
Reactant: CCOC(=O)C(C)c1ccc(N)c(O)c1
Reactant: NC(N)=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)c1ccc2[nH]c(=O)oc2c1
Temperature: 25 °C

Procedure:
A solution of Ethyl 2-(4-amino-3-hydroxyphenyl)propanoate (205 mg, 0.978 mmol) in DMF (5 mL) was added urea (305 mg, 5.19 mmol) and refluxed for 5 hrs. The reaction mixture was cooled to room temperature and added water (30 mL). The mixture was acidified with conc. HCl (1 ml) and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using EtOAc:hexanes (1:2) as eluant.
Reaction SMILES: [CH:1](=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.[C:11]([O:15][CH3:16])(=[O:14])[CH:12]=[CH2:13].NC1C(C)=CC=CN=1.C(O)(=O)C1C=CC=CC=1>C(OCC)C.[Cl-].[Na+].O.O>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([C:1](=[O:10])[CH2:13][CH2:12][C:11]([O:15][CH3:16])=[O:14])[CH:7]=[CH:6][CH:5]=1
Reactant: COc1cccc(C=O)c1
Reactant: C=CC(=O)OC
Agent: Cc1cccnc1N
Agent: O=C(O)c1ccccc1
Agent: [Cl-]
Solvent: O
Solvent: CCOCC
Product: COC(=O)CCC(=O)c1cccc(OC)c1
Temperature: 130 °C
Reaction time: 72 h
Yield: 90.4 %

Procedure:
A screw-capped tube equipped with a magnetic stir bar is charged with m-anisaldehyde (3.04 mL, 25 mmol), methyl acrylate (4.50 mL, 50 mmol), (PPh3)3RhCl (1.16 g, 1.25 mmol), 2-amino-3-picoline (1.06 mL, 10 mmol), and benzoic acid (702 mg, 5 mmol). The reaction mixture is stirred at 130° C. for 3 days. After cooling to room temperature, the resulting mixture is dissolved in diethyl ether and ished with water and brine. The organic phase is then dried over Na2SO4 and concentrated. The residue is then purified on silica gel (10-30% ethyl acetate in hexane) to give methyl 4-(3-methoxyphenyl)-4-oxobutanoate (5.02 g, 90%) as a clear reddish brown oil. 1H NMR (CDCl3, 400 MHz) δ 7.57 (d, J=9.5 Hz, 1H), 7.51 (dd, J=3.0, 2.0 Hz, 1H), 7.38 (t, J=10.0 Hz, 1H), 7.12 (ddd, J=10.5, 3.5, 1.0 Hz, 1H), 3.85 (s, 3H), 3.71 (s, 3H), 3.32 (t, J=8.5 Hz, 2H), 2.77 (t, J=8.5 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:25])[CH3:24])=[CH:19][CH:18]=1.[Cl:34]N1C(=O)CCC1=O>CN(C=O)C>[Cl:34][C:11]1[C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:25])[CH3:24])=[CH:19][CH:18]=2)=[C:3]([O:2][CH3:1])[CH:12]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)(C)NC(=O)OC(C)(C)C)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: COc1cc(Cl)c2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)(C)NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Yield: 31.2 %

Procedure:
A solution of tert-butyl 2-[4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl]propan-2-ylcarbamate (130 mg, 0.27 mmol) and N-chlorosuccinimide (47 mg, 0.35 mmol) in DMF (3 mL) was heated at 70° C. for 2 h. The reaction mixture was cooled to room temperature, quenched with water and the aqueous layer was extracted with methylene chloride/methanol (9:1). The combined organic layers were dried over sodium sulfate, filtered, concentrated and the residue was purified by column chromatography (silica, methanol/methylene chloride gradient) to afford the desired product (42 mg, 31%) as a brown solid: ESI MS m/z 500 [C26H27ClN2O4S+H]+.
Reaction SMILES: Cl[C:2]1[C:3]([NH:12][S:13]([C:16]2[S:20][C:19]([C:21]([O:23][CH3:24])=[O:22])=[CH:18][C:17]=2[CH3:25])(=[O:15])=[O:14])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:32]=[C:33]([O:35][CH3:36])[CH:34]=1)[NH2:31]>CCO>[CH3:36][O:35][C:33]1[CH:32]=[C:30]([NH:31][C:2]2[C:3]([NH:12][S:13]([C:16]3[S:20][C:19]([C:21]([O:23][CH3:24])=[O:22])=[CH:18][C:17]=3[CH3:25])(=[O:14])=[O:15])=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:29]=[C:28]([O:27][CH3:26])[CH:34]=1
Reactant: COC(=O)c1cc(C)c(S(=O)(=O)Nc2nc3ccccc3nc2Cl)s1
Reactant: COc1cc(N)cc(OC)c1
Solvent: CCO
Product: COC(=O)c1cc(C)c(S(=O)(=O)Nc2nc3ccccc3nc2Nc2cc(OC)cc(OC)c2)s1
Temperature: 170 °C
Yield: 80.5 %

Procedure:
Methyl 5-{[(3-chloroquinoxalin-2-yl)amino]sulfonyl}-4-methylthiophene-2-carboxylate (100 mg; 0.25 mmol; 1 eq) and 3,5-dimethoxyaniline (42.35 mg; 0.28 mmol; 1.1 eq) are taken up in EtOH (2 ml) and the resulting suspension is heated up to 170° C. for 6 min on high absorption in the microwave. The precipitate formed is filtered off and washed with EtOH then dried under vacuum at 40° C. for 1 day. The solid is washed with hot EtOH then THF to afford, after cooling at 4° C., 103.6 mg (80%) of the title compound as a powder. 1H NMR (DMSO-d6) δ 12.64 (brs, 1H), 8.91 (s, 1H), 7.89 (brs, 1H), 7.71 (s, 1H), 7.60 (dd, J=7.7, 1.7 Hz, 1H), 7.46-7.34 (m, 2H), 7.32 (d, J=1.9 Hz, 2H), 6.26 (t, J=1.9 Hz, 1H), 3.83 (s, 3H), 3.77 (s, 6H), 2.48 (s, 3H). HPLC (max plot) 95%; Rt 4.93 min. LC/MS: ES+ 515.2, ES− 512.9.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:15][CH3:16]>CN(C=O)C.O>[CH2:15]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:7]=1)[CH3:16]
Reactant: OCCCc1ccc(O)cc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(CCCO)cc1
Reaction time: 0.25 h
Yield: 81.7 %

Procedure:
To a solution of 3-(4-hydroxyphenyl)-1-propanol (3.00 g, 19.7 mmol, 1 equiv) in DMF (100 ml) was added portion wise NaH (0.45 g, 18.8 mmol, 0.95 equiv) at rt, and the resulting mixture was stirred for 15 min. Iodoethane (1.37 ml, 20.0 mmol, 1 equiv) was added drop wise and the mixture was stirred for 2.5 h. The reaction mixture was diluted with water and extracted with EtOAc. The extract was washed with water, dried over MgSO4, and concentrated under vacuum to give the title compound (2.90 g, 81.7%) that was used as such for the next step.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[C:7]([O:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][N:25]=2)[CH:8]=[C:9]2[C:13]=1[NH:12][C:11]([C:14]1[S:15][CH:16]([CH2:19][C:20]([OH:22])=O)[CH2:17][N:18]=1)=[CH:10]2)[CH3:3].Cl.[CH2:35]([N:37]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.CN>O.CN(C)C=O.C(N(CC)CC)C>[CH3:35][NH:37][C:20](=[O:22])[CH2:19][CH:16]1[S:15][C:14]([C:11]2[NH:12][C:13]3[C:9]([CH:10]=2)=[CH:8][C:7]([O:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:26][N:25]=2)=[CH:6][C:5]=3[O:4][CH:2]([CH3:3])[CH3:1])=[N:18][CH2:17]1
Reactant: CC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)cn2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)cn4)cc(OC(C)C)c3[nH]2)S1
Temperature: 25 °C
Reaction time: 15 h
Yield: 58.4 %

Procedure:
A mixture of {2-[7-(1-methylethoxy)-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetic acid (200 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (120 mg), 1-hydroxybenzotriazole (80 mg), methylamine hydrochloride (60 mg), triethylamine (70 mg) and N,N-dimethylformamide (3 mL) was stirred at room temperature for 15 h. Water was added to the mixture and the resultant was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:methanol=100:0 to 95:5, volume ratio) to give colorless crystals. The crystals were recrystallized from ethyl acetate-hexane to give the title compound (120 mg, 57%) as colorless prisms. MS 503 (MH+). mp 190-192° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12]4.[F:18][C:19]([F:29])([F:28])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]=[CH2:27])[CH:21]=1>>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:27][CH2:26][C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([C:19]([F:18])([F:28])[F:29])[CH:21]=3)[C:6]3[CH:11]4[CH2:12][CH2:13][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:16][CH2:17]4
Reactant: C=Cc1cccc(C(F)(F)F)c1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN1CCC3CC1
Product: Cc1ccc2c(c1)c1c(n2CCc2cccc(C(F)(F)F)c2)C2CCN(CC2)C1

Procedure:
The coupling of 9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (226 mg, 1.0 mmol; Example 2B) and 1-(trifluoromethyl)-3-vinylbenzene (344 mg, 2.0 mmol; Aldrich) was performed according to the procedure described in Example 114B to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 1.45-1.55 (m, 2H), 1.78-1.88 (m, 2H), 2.39 (s, 3H), 2.84-2.93 (m, 3H), 3.04-3.13 (m, 4H), 4.13 (s, 2H), 4.37 (t, J=6 Hz, 2H), 6.91 (d, J=8 Hz, 1H), 7.09 (s, 1H), 7.11-7.16 (m, 3H), 7.33 (t, J=8 Hz, 1H), 7.42 (d, J=8 Hz, 1H); MS (DCI/NH3) m/z 399 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][CH:17]([CH2:21][OH:22])[O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][C@H:17]([CH2:21][O:22][S:24]([CH3:23])(=[O:26])=[O:25])[O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=S(=O)(c1cccc(F)c1)c1ccc2c(c1)OC(CO)CC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@H]1CCc2ccc(S(=O)(=O)c3cccc(F)c3)cc2O1
Temperature: -10 °C
Reaction time: 1 h
Yield: 88.6 %

Procedure:
To a solution of [7-(3-fluoro-benzenesulfonyl)-chroman-2-yl]-methanol (10.0 g, 0.032 mol) in 200 mL of methylene chloride at −10° C. was added methanesulfonyl chloride (2.76 mL, 0.036 mol) and triethylamine (4.95 mL, 0.036 mol). The reaction mixture was stirred for one hour at −10° C. and was then quenched by addition of 10% aqueous NaHCO3. The organic layer was separated, washed with water and brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (hexanes:EtOAc 85:15) to give 11.35 g (92%) of methanesulfonic acid (R)-7-(3-fluoro-benzenesulfonyl)-chroman-2-ylmethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:28])[CH2:22][CH2:23][C:24]([O:26]C)=[O:25])=[CH:17][CH:16]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([C:21](=[O:28])[CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:19][CH:20]=2)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: COC(=O)CCC(=O)c1ccc(N)cc1
Product: O=C(O)CCC(=O)c1ccc(NC(=O)c2ccc(Cl)c([N+](=O)[O-])c2)cc1
Yield: 47.8 %

Procedure:
In a manner similar to that described in Example 3, 4-chloro-3-nitro-benzoyl chloride (0.073 g, 0.00033 mol) was allowed to react with 4-(4-amino-phenyl)-4-oxo-butyric acid, methyl ester (0.052 g, 0.00025 mol), and the resulting intermediate was hydrolyzed to give 0.045 g of 4-[4-(4-chloro-3-nitro-benzoylamino)-phenyl]-4-oxo-butyric acid as a yellow solid; MS-(AP+) MH+377.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:25][C@H:26]([C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=1)[CH3:27]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7]([NH:25][C@H:26]([C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=1)[CH3:27])=[O:9]
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: O=C(O)c1cc(Cl)cnc1N1CCC(Oc2ccc(F)cc2)C1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2N2CCC(Oc3ccc(F)cc3)C2)cc1
Yield: 40.2 %

Procedure:
The title compound (D193) (64 mg) was prepared according to the experimental procedure described in Description 146 starting from 5-chloro-2-(3-(4-fluorophenoxy)pyrrolidin-1-yl)nicotinic acid (D138) (110 mg, 0.320 mmol), and (S)-methyl 4-(1-aminoethyl)benzoate (D3) (68.82 mg, 0.320 mmol) MS: (ES/+) m/z: 499.2 [MH+] C26H25ClFN3O4 requires 497.15
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[C:27]3[C:19]=2[C:20]2[CH:21]=[CH:22][C:23]([C:33]([O:35]CC)=[O:34])=[CH:24][C:25]=2[NH:26]3)[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C(O)C.O>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[C:27]3[C:19]=2[C:20]2[CH:21]=[CH:22][C:23]([C:33]([OH:35])=[O:34])=[CH:24][C:25]=2[NH:26]3)[CH2:13]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc2c(c1)[nH]c1c(C#N)ccc(N3CCC[C@@H](NC(=O)OCc4ccccc4)C3)c12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(N2CCC[C@@H](NC(=O)OCc3ccccc3)C2)c2c1[nH]c1cc(C(=O)O)ccc12
Temperature: 25 °C
Yield: 20.6 %

Procedure:
Step 3 A solution of (R)-ethyl 5-(3-(benzyloxycarbonylamino)piperidin-1-yl)-8-cyano-9H-carbazole-2-carboxylate (0.67 g, 1.349 mmol) and potassium hydroxide (0.379 g, 6.75 mmol) in 10:1 ethanol-water (33 mL) was heated at 85° C. for 2 h. The mixture was cooled to rt and the precipitate was collected by filtration, washed with ethanol and dried to afford (R)-5-(3-(benzyloxycarbonylamino)piperidin-1-yl)-8-cyano-9H-carbazole-2-carboxylic acid as a yellow solid (130 mg, 21%). Mass spectrum m/z 469.1 (M+H)+. (R)-5-(3-aminopiperidin-1-yl)-8-cyano-9H-carbazole-2-carboxylic acid was also isolated from filtrates (150 mg, 33%). Mass spectrum m/z 335.2 (M+H)+.