Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]([N:23]1[CH:27]=[C:26]([C:28]([O-:30])=O)[N:25]=[CH:24]1)[CH2:11][CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH3:22])=[CH:14]1)(C(C)(C)C)(C)C.[Cl-].[NH4+].N.[N+:34](CCCC)(CCCC)(CCCC)CCCC.[F-].C([O-])(C)=O.[NH4+]>CN(C=O)C.C1COCC1.O>[OH:8][CH2:9][C@H:10]([N:23]1[CH:27]=[C:26]([C:28]([NH2:34])=[O:30])[N:25]=[CH:24]1)[CH2:11][CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH3:22])=[CH:14]1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: Cc1cn(CC[C@H](CO[Si](C)(C)C(C)(C)C)n2cnc(C(=O)[O-])c2)c2ccccc12
Agent: CC(=O)[O-]
Agent: N
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cn(CC[C@H](CO)n2cnc(C(N)=O)c2)c2ccccc12
Temperature: 100 °C
Reaction time: 1 h
Yield: 103 %

Procedure:
To a solution of 1-[(R)-1-(tert-butyldimethylsilyloxy)-4-(3-methylindol-1-yl)-2-butyl]imidazol-4-carboxylate (200 mg, 0.45 mmol) in DMF (5 ml) were added ammonium chloride (6 mg, 0.11 mmol) and aqueous 28% NH3 solution (10 ml). And the mixture was heated at 100° C. in a sealed steel tube for 8 hours. After cooling, the reaction mixture was poured into water (50 ml) and extracted with ethyl acetate. The organic layer was washed with brine, dried (magnesium sulfate), and concentrated in vacuo. This material was used for the next reaction without further purification. To an ice cooled solution of the carboxamide prepared above (184 mg) in THF (10 ml) was added dropwise 1.0 M Bu4NF in THF (453 ml). After the addition was completed, the reaction mixture was stirred at ice-bath temperature for 1 hour. 25% AcONH4 (5 ml) was added, and the resulting mixture was stirred for several minutes and then extracted with ethyl acetate. The organic layer was washed with brine, dried (sodium sulfate) and concentrated in vacuo. The residue was triturated with a mixed solvent of isopropyl ether and chloroform (20:1). The resulting precipitates were collected by filtration and washed with the same mixed solvent, and dried in vacuo to give 1-[(R)-1-hydroxy-4-(3-methylindol-1-yl)-2-butyl]-imidazole-4-carboxamide (146 mg, 103%) as a white solid.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:19]#[N:20])[C:8]([CH3:18])=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]=2[F:11])[N:6]=1.C([N:24]([CH:27]([CH3:29])C)[CH2:25]C)(C)C.Cl.N1CCC1>ClCCl.C(O)C>[N:24]1([C:2]2[O:3][C:4]3[C:5](=[C:7]([C:19]#[N:20])[C:8]([CH3:18])=[C:9]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:10]=3[F:11])[N:6]=2)[CH2:25][CH2:29][CH2:27]1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cl)nc2c1C#N
Reactant: CCN(C(C)C)C(C)C
Agent: C1CNC1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: Cc1c(-c2ccccc2)c(F)c2oc(N3CCC3)nc2c1C#N
Temperature: 60 °C
Reaction time: 3 h
Yield: 72.8 %

Procedure:
2-Chloro-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-130) (0.11 g, 0.38 mmol) was dissolved in a mixed solvent of dichloromethane (10 ml) and ethanol (7 ml), then diisopropylethylamine (0.21 ml, 1.23 mol) and azetidine hydrochloride (71.5 mg, 0.76 mmol) were added. After stirring at an external temperature of about 60° C. for 3 hours, the reaction liquid was concentrated under reduced pressure and diluted with dichloromethane. After washing with water and drying over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure and the resulting residue was purified by silica gel column chromatography (dichloromethane:methanol=100:1) to obtain a colorless solid (85 mg, 74%).
Reaction SMILES: [Cl:1][C:2]1[S:10][C:9]2[S:8](=[O:12])(=[O:11])[NH:7][CH2:6][C:5]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=3)([OH:13])[C:4]=2[CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH3:34][Si:35]([CH3:42])([CH3:41])[CH2:36][CH2:37][O:38][CH2:39]Cl>C1COCC1>[Cl:1][C:2]1[S:10][C:9]2[S:8](=[O:12])(=[O:11])[N:7]([CH2:39][O:38][CH2:37][CH2:36][Si:35]([CH3:42])([CH3:41])[CH3:34])[CH2:6][C:5]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=3)([OH:13])[C:4]=2[CH:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=S1(=O)NCC(O)(c2ccc3ccccc3c2)c2cc(Cl)sc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCN1CC(O)(c2ccc3ccccc3c2)c2cc(Cl)sc2S1(=O)=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 44 %

Procedure:
To a solution of 6-chloro-4-(2-naphthyl)-3,4-dihydro-2H-thieno[3,2-e][1,2]thiazin-4-ol 1,1-dioxide (0.235 g, 0.642 mmol) in THF (5.2 mL) at −78° C. was added 1.00 M Lithium hexamethyldisilazide in THF (0.771 mL, 0.771 mmol). The reaction mixture was stirred at −78° C. for 30 min, and [β-(trimethylsilyl)ethoxy]methyl chloride (0.341 mL, 1.93 mmol) was added at the same temperature. The mixture was stirred for 1 h at −78° C. and raised to rt. After stirring at rt for 30 min, the mixture was quenched by sat. NH4Cl, extracted with EA, dried and evaporated. The residue was purified by Isco silica gel chromatography (24 g cartridge), EA in hex, 0-30% using solid load to give the title compound (0.140 g, 42%). LCMS (FA) ES−: 494, 496. 1H NMR (400 MHz, DMSO) δ 7.95-7.92 (m, 4H), 7.55-7.52 (m, 2H), 7.32-7.29 (m, 1H), 6.77 (s, 1H), 6.74 (s, 1H), 4.91 (d, 1H), 4.64 (d, 1H), 4.20 (d, 1H), 3.95 (d, 1H), 3.52-3.47 (m, 2H), 0.85-0.76 (m, 2H), −0.05 (s, 9H).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.P(Cl)(Cl)(Cl)=O.[CH:11]1([C:15]2[N:23]3[C:18](C(=O)NC=N3)=[C:17]([I:25])[N:16]=2)[CH2:14][CH2:13][CH2:12]1>N1C=CC=CC=1>[CH:11]1([C:15]2[N:23]3[C:18]([C:5]([NH2:1])=[N:4][CH:3]=[N:2]3)=[C:17]([I:25])[N:16]=2)[CH2:14][CH2:13][CH2:12]1
Reactant: c1nc[nH]n1
Reactant: O=c1[nH]cnn2c(C3CCC3)nc(I)c12
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: Nc1ncnn2c(C3CCC3)nc(I)c12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1,2,4-triazole (1.28 g, 18.59 mmol) in anhydrous pyridine (10 mL) was added phosphorus oxychloride (POCl3) (0.578 mL, 6.20 mmol) and stirred at rt for 15 min. This mixture was dropwise charged (3.5 min) with a solution of 7-cyclobutyl-5-iodo-3H imidazo[5,1-f][1,2,4]triazin-4-one (0.653 mg 2.07 mmol) in anhydrous pyridine (14 mL) and stirred for 1.5 h. The reaction mixture was cooled to 0° C. quenched with 2M NH3 in isopropanol (IPA) until basic then allowed to reach rt and stirred for an additional 2 h. The reaction mixture was filtered through a fritted Buchner funnel and washed with DCM. The filtrate was concentrated in vacuo and purified by chromatography on silica gel [eluting with 30% EtOAc in DCM] resulting in the title compound as an off-white solid; 1H NMR (CDCl3, 400 MHz) δ 1.93-2.04 (m, 1H), 2.05-2.18 (m, 1H), 2.35-2.45 (m, 2H), 2.49-2.62 (m, 2H), 4.00-4.12 (m, 1H), 7.82 (s, 1H); MS (ES+): m/z 316.08 (100) [MH+], HPLC: tR=2.59 min (MicromassZQ, polar—5 min).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([C:15]([NH:17][C@H:18]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:19][C:20](O)=[O:21])=[O:16])[CH:12]=[CH:11][C:10]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])=[CH:5][C:4]=1[O:34][CH2:35][CH2:36][CH2:37][N:38]([CH3:40])[CH3:39]>C1COCC1.CO>[ClH:2].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([C:15]([NH:17][C@@H:18]([CH2:19][CH2:20][OH:21])[C:23]([CH3:24])([CH3:26])[CH3:25])=[O:16])[CH:12]=[CH:11][C:10]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])=[CH:5][C:4]=1[O:34][CH2:35][CH2:36][CH2:37][N:38]([CH3:40])[CH3:39]
Reactant: Cc1ccccc1-c1ccc(C(=O)N[C@@H](CC(=O)O)C(C)(C)C)nc1-c1ccc(Cl)c(OCCCN(C)C)c1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccccc1-c1ccc(C(=O)N[C@@H](CCO)C(C)(C)C)nc1-c1ccc(Cl)c(OCCCN(C)C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.4 %

Procedure:
To a solution of 250 mg (0.42 mmol) of (3S)-3-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}-amino)-4,4-dimethylpentanoic acid hydrochloride (Example 6.1) in 2 mL of THF are added dropwise, under argon, 1.06 mL (2.12 mmol) of a 2N borane/dimethyl sulfide complex solution in THF. The reaction medium is stirred for 16 hours at room temperature and then diluted in 10 mL of anhydrous methanol. The solution obtained is concentrated under reduced pressure and the residue is taken up in 20 mL of methanol and then concentrated again under reduced pressure. The residue obtained is then dissolved in 20 mL of a 1/1 THF/aqueous 1N HCl solution mixture and the solution is refluxed for 4 hours. After cooling and concentrating under reduced pressure, the residue is purified by reverse-phase HPLC (RP18), eluting with a 10−2N HCl/acetonitrile gradient of from 0 to 100% acetonitrile over 120 minutes. After concentrating under reduced pressure and freeze-drying, 50 mg of 6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-N-[(1S)-1-(2-hydroxyethyl)-2,2-dimethylpropyl]-5-(2-methylphenyl)pyridine-2-carboxamide hydrochloride are obtained in the form of a white powder.
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH3:23][C:24]([NH2:27])([CH3:26])[CH3:25]>>[C:24]([NH:27][C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2)([CH3:26])([CH3:25])[CH3:23]
Reactant: CC(C)(C)N
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC(C)(C)C
Temperature: 100 °C
Yield: 32 %

Procedure:
Prepared similarly to that described in Example 131 using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 63 mg, 0.213 mmol) and 2-methylpropan-2-amine (44.9 μl, 0.425 mmol, Aldrich), heating at 100° C. for 3 h. Purification by silica gel (100% DCM to 4% MeOH/DCM) provided 2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (32% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.58 (s, 9H) 2.57 (s, 3H) 2.88 (t, J=6.94 Hz, 2H) 3.45 (td, J=6.80, 2.45 Hz, 2H) 6.03 (s, 1H) 6.95 (br. s., 1H) 7.04 (d, J=2.15 Hz, 1H) 7.35 (t, J=7.82 Hz, 1H) 7.59 (dd, J=8.02, 1.37 Hz, 1H) 7.84 (dd, J=7.53, 1.27 Hz, 1H) 12.01 (br. s., 1H). MS (ESI, pos. ion) m/z: 350.3 (M+1).
Reaction SMILES: [CH2:1]([N:3]([S:30]([C:33]1[S:34][CH:35]=[CH:36][CH:37]=1)(=[O:32])=[O:31])[C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]1[S:14][C:15]([CH2:18][O:19][C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=3)=[CH:16][N:17]=1)=[CH:9]2)[CH3:2].O1CCCC1.[OH-].[Na+].Cl>C(OCC)(=O)C.CO>[CH2:1]([N:3]([S:30]([C:33]1[S:34][CH:35]=[CH:36][CH:37]=1)(=[O:31])=[O:32])[C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]1[S:14][C:15]([CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:28][CH:29]=3)=[CH:16][N:17]=1)=[CH:9]2)[CH3:2]
Reactant: CCN(c1cccc2cc(-c3ncc(COc4ccc(C(=O)OC)cc4)s3)[nH]c12)S(=O)(=O)c1cccs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CCN(c1cccc2cc(-c3ncc(COc4ccc(C(=O)O)cc4)s3)[nH]c12)S(=O)(=O)c1cccs1
Yield: 53.4 %

Procedure:
Methyl 4-[(2-{7-[ethyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-1,3-thiazol-5-yl)methoxy]benzoate (98 mg), tetrahydrofuran (2 mL), methanol (2 mL) and 1N aqueous sodium hydroxide solution (2 mL) was stirred at 50° C. for 16 hr. The reaction mixture was acidified with 1N hydrochloride, diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over magnesium sulfate and filtrated. The filtrate was concentrated, and the residue was subjected to silica gel column chromatography and recrystallized from an ethyl acetate-hexane (4:1) mixture to give the title compound (51 mg, yield 54%) as crystals. melting point 188° C.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]([NH:19][C:20]2[N:25]=[C:24]([N:26]3[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[N:28]=[CH:27]3)[CH:23]=[CH:22][N:21]=2)[CH3:18])=[CH:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]([NH:19][C:20]2[N:25]=[C:24]([N:26]3[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[N:28]=[CH:27]3)[CH:23]=[CH:22][N:21]=2)[CH3:18])=[CH:9]1
Reactant: CC(Nc1nccc(-n2cnc3ccccc32)n1)c1cn(C(=O)OC(C)(C)C)c2ccccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(Nc1nccc(-n2cnc3ccccc32)n1)c1c[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 30.8 %

Procedure:
To a solution of 2-[1-(1-N-tert-butoxycarbonyl-indol-3-yl)ethylamino]-4-[benzimidazol-1-yl]pyrimidine (25 mg, 0.055 mmol) in methylene chloride (0.25 ml) was added TFA (0.25 ml). The reaction mixture was stirred at 0° C. for an hour and room temperature for 30 min. The solvents were concentrated in vacuo. The crude product was purified by preparative thin layer chromatography eluting with 5% 2M NH3 in MeOH/CH2Cl2 to give 6 mg of the title compound. Mass spectrum (ESI) 355.3 (M+1).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([C@@H:19]3[C@@H:22]([CH2:23][CH2:24][C@H:25]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[C:21](=[O:41])[N:20]3[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1)(=O)=O.[P:50]([O-:55])([O:53][CH3:54])[O:51][CH3:52].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Si:34]([O:33][C@H:25]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[CH2:24][CH2:23][C@H:22]1[C:21](=[O:41])[N:20]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C@@H:19]1[C:16]1[CH:15]=[CH:14][C:13]([C:9]2[CH:8]=[CH:7][CH:12]=[C:11]([P:50](=[O:55])([O:53][CH3:54])[O:51][CH3:52])[CH:10]=2)=[CH:18][CH:17]=1)([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CC[C@H]1C(=O)N(c2ccccc2)[C@@H]1c1ccc(-c2cccc(OS(=O)(=O)C(F)(F)F)c2)cc1)c1ccc(F)cc1
Reactant: COP([O-])OC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COP(=O)(OC)c1cccc(-c2ccc([C@@H]3[C@@H](CC[C@H](O[Si](C)(C)C(C)(C)C)c4ccc(F)cc4)C(=O)N3c3ccccc3)cc2)c1
Temperature: 160 °C

Procedure:
This reaction was performed using a PersonalChemistry™ microwave instrument set at normal absorbance, fixed hold time and 30 sec pre-stirring. A 10-mL reaction vial was charged with 4′-{(2S,3R)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl trifluoromethanesulfonate (0.27 g, 0.38 mmol), dimethyl phosphite (0.070 mL, 0.76 mmol) and triethylamine (0.15 mL, 1.08 mmol) in toluene (4 mL). Nitrogen was bubbled through the stirred solution for 5 min, tetrakis(triphenylphosphine)palladium(0) (0.1 g) was added, and the solution was covered with a blanket of nitrogen and sealed. The reaction mixture was heated for 11 min at 160° C., then cooled to room temperature and diluted with ethyl acetate. The yellow solution was washed successively with 0.5 M hydrochloric acid (20 mL) water (3×) and brine. The organic solution was dried over sodium sulfate, filtered and the solvent was removed by rotary evaporation under reduced pressure. Pure dimethyl (4′-{(2S,3R)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)phosphonate was obtained as a white foam (0.26 g, 65%) by chromatography over silica gel using ethyl acetate-hexane (gradient: 5% ethyl acetate to 100%). 1H NMR (300 MHz, CDCl3) δ 8.00 (dt, J=14.2, 1.5 Hz, 1H), 7.60 (d, J=8.5 Hz, 2H), 7.40(d, J=8.5 Hz, 2H), 6.9-7.8 (m, 12H), 4.68 (t, J=5.7 Hz, 1H), 4.64 (d, J=2.4 Hz, 1H), 3.81 (d, J=0.9 Hz, 1H), 3.77 (d, J=0.9 Hz, 1H), 3.0-3.1 (m, 1H), 1.8-2.2 (m, 4H), 0.88 (s, 9H), 0.02 (s, 3H), −0.16 (s, 3H) ppm
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([N:22]1[C:31](=[O:32])[C:30]2[NH:29][C:28]([C:33]3[N:37]([CH3:38])[N:36]=[C:35]([NH2:39])[CH:34]=3)=[N:27][C:26]=2[N:25]([CH2:40][CH2:41][CH3:42])[C:23]1=[O:24])[CH2:20][CH3:21]>>[CH3:42][CH2:41][CH2:40][N:25]1[C:23](=[O:24])[N:22]([CH2:19][CH2:20][CH3:21])[C:31](=[O:32])[C:30]2[C:26]1=[N:27]/[C:28](/[N:29]=2)=[C:33]1/[CH:34]=[C:35]([NH:39][C:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:14][CH:13]=2)=[O:18])[NH:36][N:37]/1[CH3:38]
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1
Reactant: CCCn1c(=O)c2[nH]c(-c3cc(N)nn3C)nc2n(CCC)c1=O
Product: CCCn1c(=O)c2c(n(CCC)c1=O)=N/C(=C1/C=C(NC(=O)Cc3ccc(OCc4ccccc4)cc3)NN1C)N=2

Procedure:
Using 4-(benzyloxy)phenylacetic acid and 1,3-dipropyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine (Example 1, Compound AS3).
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:33])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=3)[N:18]([S:29]([CH3:32])(=[O:31])=[O:30])[N:17]=2)[CH2:9]1.[CH3:34][O:35][C:36]1[N:41]=[CH:40][C:39]([CH:42]2[CH2:47][CH2:46][C:45](=O)[CH2:44][CH2:43]2)=[CH:38][CH:37]=1>>[CH3:32][S:29]([N:18]1[C:19]2[C:24](=[CH:23][C:22]([C:25]([F:27])([F:28])[F:26])=[CH:21][CH:20]=2)[C:16]([NH:15][CH2:14][C:13]([NH:12][CH:10]2[CH2:11][N:8]([CH:45]3[CH2:46][CH2:47][CH:42]([C:39]4[CH:40]=[N:41][C:36]([O:35][CH3:34])=[CH:37][CH:38]=4)[CH2:43][CH2:44]3)[CH2:9]2)=[O:33])=[N:17]1)(=[O:31])=[O:30]
Reactant: CS(=O)(=O)n1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Reactant: COc1ccc(C2CCC(=O)CC2)cn1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C2CCC(N3CC(NC(=O)CNc4nn(S(C)(=O)=O)c5ccc(C(F)(F)F)cc45)C3)CC2)cn1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(1-methanesulfonyl-5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide TFA salt and 4-(6-methoxy-pyridin-3-yl)-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [CH2:1]([N:4]([S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([O:26]CC[Si](C)(C)C)=[O:25])[CH:19]=1)(=[O:17])=[O:16])[C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][N:6]=1)[CH2:2][CH3:3].CCCC[N+](CCCC)(CCCC)CCCC.[F-].Cl>C1COCC1>[CH3:12][O:11][C:9]([C:8]1[CH:13]=[CH:14][C:5]([N:4]([CH2:1][CH2:2][CH3:3])[S:15]([C:18]2[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=2)[C:24]([OH:26])=[O:25])(=[O:16])=[O:17])=[N:6][CH:7]=1)=[O:10]
Reactant: CCCN(c1ccc(C(=O)OC)cn1)S(=O)(=O)c1cccc(C(=O)OCC[Si](C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: CCCN(c1ccc(C(=O)OC)cn1)S(=O)(=O)c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.5 %

Procedure:
To a mixture of 175 mg of methyl 6-{propyl[(3-{[2-(trimethylsilyl)ethoxy]carbonyl}phenyl)sulfonyl]amino}nicotinate and 5 mL of THF was added dropwise a solution of TBAF in THF (1 M, 0.750 mL), followed by stirring at room temperature for 4 hours. To the reaction mixture was added 0.1 M hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure and then dried under reduced pressure to obtain 110 mg of 3-{[5-(methoxycarbonyl)pyridin-2-yl](propyl)sulfamoyl}benzoic acid as a colorless powder.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[F:28])=[C:8]2[C:16]=1[NH:15][C:14]1[CH:13]=[C:12]([C:17](OCC)=[O:18])[CH:11]=[CH:10][C:9]2=1)(=[O:3])[NH2:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].CO.C(O)(C(F)(F)F)=O>C1COCC1.CCOC(C)=O>[F:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:7]1[C:8]2[C:9]3[C:14](=[CH:13][C:12]([CH2:17][OH:18])=[CH:11][CH:10]=3)[NH:15][C:16]=2[C:4]([C:1]([NH2:2])=[O:3])=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)ccc(-c3ccccc3F)c12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1ccc(-c2ccccc2F)c2c1[nH]c1cc(CO)ccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 108.4 %

Procedure:
A solution of ethyl 8-carbamoyl-5-(2-fluorophenyl)-9H-carbazole-2-carboxylate (Example 3-12, 0.81 g, 2.152 mmol) in THF (26.9 mL) at 0° C. was treated with lithium aluminum hydride (1.0 M in THF, 3.01 mL, 3.01 mmol), and the mixture was stirred at rt for 5 h. Additional lithium aluminum hydride (1.3 mL, 1.3 mmol) was added and the mixture was stirred at rt overnight. The mixture was treated with methanol and TFA and diluted with EtOAc, washed with brine, dried and concentrated to provide impure 4-(2-fluorophenyl)-7-(hydroxymethyl)-9H-carbazole-1-carboxamide (0.78 g) contaminated with starting material. A small amount was purified by preparative HPLC to provide 4-(2-fluorophenyl)-7-(hydroxymethyl)-9H-carbazole-1-carboxamide, isolated as the TFA salt. 1H NMR (500 MHz, methanol-d4) δ 7.82 (1H, d, J=7.8 Hz), 7.51 (1H, s), 7.44-7.50 (1H, m), 7.42 (1H, td, J=7.5, 1.9 Hz), 7.25-7.30 (1H, m), 7.22 (1H, t, J=9.2 Hz), 7.05 (1H, d, J=8.3 Hz), 6.99 (1H, d, J=7.8 Hz), 6.85 (1H, dd, J=8.0, 1.4 Hz), 4.62 (2H, s). Mass spectrum m/z 334.9 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([C:18]2[CH:19]=[C:20]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=3)[C:21]([OH:25])=[C:22]([Br:24])[CH:23]=2)=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[S:37]([C:40]1[CH:48]=[CH:47][C:43]([C:44]([OH:46])=[O:45])=[C:42]([OH:49])[CH:41]=1)(=[O:39])=[O:38].[K+].[Br-]>>[Br:24][C:22]1[C:21]([O:25][S:37]([C:40]2[CH:48]=[CH:47][C:43]([C:44]([OH:46])=[O:45])=[C:42]([OH:49])[CH:41]=2)(=[O:39])=[O:38])=[C:20]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=2)[CH:19]=[C:18]([C:16](=[O:17])[NH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:23]=1
Reactant: O=C(NCCCCCCCCc1ccccc1)c1cc(Br)c(O)c(-c2cccc(C(F)(F)F)c2)c1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Agent: [Br-]
Agent: [K+]
Product: O=C(NCCCCCCCCc1ccccc1)c1cc(Br)c(OS(=O)(=O)c2ccc(C(=O)O)c(O)c2)c(-c2cccc(C(F)(F)F)c2)c1

Procedure:
The title compound was prepared as an orange foam (0.455 g, 76%) from 5-bromo-6-hydroxy-3′-trifluoromethyl-biphenyl-3-carboxylic acid (8-phenyl-octyl)-amide and 4-chlorosulfonyl-2-hydroxy-benzoic acid using a procedure similar to step 3 of Example 179. 1H NMR (DMSO-d6) 12.60 (bs, 1H); 11.60 (bs, 1H); 8.68 (t, 1H); 8.21 (d, 1H); 7. 84 (d, 1H); 7.71-7.62 (m, 2H); 7.56-7.44 (m, 3H); 7.26-7.10 (m, 5H); 6.96 (dd, 1H); 6.82 (d, 1H); 3.21 (dd, 2H); 2.62 (t, 4H); 2.53 (t, 2H); 1.52 (m, 4H); 1.25 (m, 8H); IR (KBr) 3370, 2950, 2825, 1690, 1640, 1605, 1560, 1540, 1390, 1325, 1195, 1170, 1125 cm−1; mass spectrum [(−)ESI], m/z 660/662 (M−H)−; Anal. Calcd. for C35H33BrF3NO7S: C, 56.16; H, 4.44; N, 1.87, Found: C, 55.65; H, 4.27; N, 1.90.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][CH2:4][CH:5]([NH:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=1)[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:8][C:7]=1[CH3:22].[NH:35]1[CH2:40][CH2:39][CH2:38][C@@H:37]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:36]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(C(C)C)CC)(C)C>CN(C)C=O.O>[F:34][C:2]([F:1])([F:33])[CH2:3][CH2:4][CH:5]([NH:23][C:24]1[CH:25]=[CH:26][C:27]([C:28]([N:35]2[CH2:40][CH2:39][CH2:38][C@@H:37]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:36]2)=[O:29])=[CH:31][CH:32]=1)[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:14][N:13]=2)=[CH:8][C:7]=1[CH3:22]
Reactant: CCOC(=O)[C@@H]1CCCNC1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cn2)ccc1C(CCC(F)(F)F)Nc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)[C@@H]1CCCN(C(=O)c2ccc(NC(CCC(F)(F)F)c3ccc(-c4ccc(C(F)(F)F)cn4)cc3C)cc2)C1

Procedure:
A solution of 4-((4,4,4-trifluoro-1-(2-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)phenyl)butyl)amino)benzoic acid obtained in step H, ethyl (3R)-piperidine-3-carboxylate (5.05 mL), 1-hydroxybenzotriazole (4.43 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (6.28 g), diisopropylethylamine (5.72 mL) in dimethylformamide (91 mL) was stirred at room temperature overnight. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (15.9 g).