Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=O)=[CH:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:5][CH:4]=1.Cl.[NH2:27][OH:28].[Na]>CO.O>[OH:28][N:27]=[C:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[C:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[CH:10][CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: NO
Reactant: COC(=O)CC=C(C(=O)c1ccc(OC)cc1)c1ccc(OC)cc1
Agent: Cl
Agent: [Na]
Solvent: CO
Solvent: O
Product: COC(=O)CC=C(C(=NO)c1ccc(OC)cc1)c1ccc(OC)cc1
Yield: 90 %

Procedure:
A 24.5 g quantity of methyl 4,5-bis(4-methoxyphenyl)-5-oxo-3-pentenoate obtained in Example 1 and 51.5 g of hydroxylamine hydrochloride was refluxed with heating in a mixture of 650 ml of methanol and 72 ml of water for 23 hours. With the progress of reaction at this time, 0.9 equivalent weight of sodium hydrogentarbonate was added in divided portions to the reaction system. On completion of the reaction, the methanol was distilled off at a reduced pressure. The residue was dissolved with water and ethyl acetate, and the organic layer was collected, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium suliate. The organic layer was concentrated at a reduced pressure, and the residue was subjected to silica gel column chromatography (eluants: ethyl acetate-n-hexane) for separation and purification, affording 23 g (yield 90%) of the above-identified compound as an oily product.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.O=[C:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH2:14][CH2:13]1>Cl>[F:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][C:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19](=[O:23])[CH:20]([CH3:21])[CH3:22])[CH2:14][C:13]2=1
Reactant: CC(C)C(=O)NC1CCC(=O)CC1
Reactant: NNc1ccc(F)cc1
Agent: Cl
Product: CC(C)C(=O)NC1CCc2[nH]c3ccc(F)cc3c2C1
Yield: 84.3 %

Procedure:
Combine p-fluorophenylhydrazine hydrochloride (5.00 g, 30.7 mmol) and N-(4-oxo-cyclohexyl)isobutyramide (5.64 g, 30.7 mmol) in ethanolic HCl (125 mL) and heat at reflux under nitrogen for 18 h. Concentrate the reaction in vacuo to remove most of the EtOH, dilute with water and extract with EtOAc. Wash the EtOAc extracts with water and brine, dry over Na2SO4, and evaporate to give 7.1 g (56%) of a beige solid. MS (ES): m/z 275 (M+1); 1H NMR(DMSO-d6): δ 10.79 (s, 1H, NH), 7.81 (d, 1H, J=7.5 Hz), 7.19 (dd, 1H, J=8.6, 4.6 Hz), 7.07 (d, 1H, J=10.1 Hz), 6.79 (dt, 1H, J=8.9, 1.8 Hz), 4.00 (m, 1H), 2.85 (dd, 1H, J=15.0, 5.3 Hz), 2.76 (m, 2H), 2.39 (m, 2H), 1.93 (m, 1H), 1.75 (m, 1H), 0.99 (d, 6H, J=6.6 Hz).
Reaction SMILES: [Cl-].[Cl:2][C:3]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][Zn+].I[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1.[Cl-].[NH4+]>C1COCC1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>[Cl:11][C:10]1[CH:9]=[CH:8][CH:7]=[C:4]([CH2:5][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[C:3]=1[Cl:2]
Reactant: Clc1cccc(C[Zn+])c1Cl
Reactant: O=[N+]([O-])c1ccc(I)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(Cc2cccc(Cl)c2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.9 %

Procedure:
Under an argon stream, bis(dibenzylidenacetone)palladium(0) (3.2 g, 5.6 mmol) and tri(2-furyl)phosphine (2.6 g, 11.2 mmol) were dissolved in THF (310 ml), the reaction mixture of 2,3-dichlorobenzylzinc chloride (421.7 mmol) in THF obtained in Reference Example 1 was added dropwise under ice-cooling through a cannula, and then a solution of 4-iodonitrobenzene (70.0 g, 281 mmol) in THF (700 ml) was added dropwise, after which the mixture was stirred at room temperature for 2 hr, saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was filtered through celite. The filtrate was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the precipitated solid was collected by filtration on the way. The filtrate was again concentrated under reduced pressure, and the precipitated solid was collected by filtration on the way. The collected solids were combined washed with n-hexane and vacuum dried to give the object product (60.2 g, yield 76%) as a pale-brown solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:24][C:25]2[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][N:19](C)[CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:23])=[N:6][CH:7]=1.NC1C(F)=CC(C2CCN(C(OC(C)(C)C)=O)CC2)=C(C)C=1>CC(O)C.Cl>[Cl:1][C:2]1[C:3]([NH:24][C:25]2[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]3)=[CH:11][C:10]=2[F:23])=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(C)CC4)cc3F)ncc2Cl)n[nH]1
Agent: Cc1cc(N)c(F)cc1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CC(C)O
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Temperature: 130 °C

Procedure:
A mixture of 2,5-dichloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Intermediate 1, 132 mg, 0.54 mmol) and tert-butyl 4-(4-amino-5-fluoro-2-methylphenyl)piperidine-1-carboxylate (Intermediate 19, 166 mg, 0.54 mmol) in 2-propanol (15 mL) was treated with conc. aqueous HCl (14 drops). The mixture was sealed and heated in a microwave at 130° C. for 60 min. The mixture was concentrated to afford 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine as a yellow solid. A portion of the crude product was purified with preparative RP-HPLC to afford 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine as a white solid; ESMS m/z 416.1 (M+H+). The remainder of the crude product was used directly for the next step without further purification.
Reaction SMILES: [F:1][CH:2]([F:21])[O:3][C:4]1[CH:9]=[C:8]([C@@H:10]2[CH2:15][CH:14]=[CH:13][CH2:12][C@@H:11]2[N+:16]([O-])=O)[CH:7]=[CH:6][C:5]=1[O:19][CH3:20].[H][H]>C(O)C.[Ni]>[F:1][CH:2]([F:21])[O:3][C:4]1[CH:9]=[C:8]([C@@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]2[NH2:16])[CH:7]=[CH:6][C:5]=1[O:19][CH3:20]
Reactant: COc1ccc([C@@H]2CC=CC[C@@H]2[N+](=O)[O-])cc1OC(F)F
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: COc1ccc([C@@H]2CCCC[C@@H]2N)cc1OC(F)F

Procedure:
14.6 g of (+/−)-cis-2-difluoromethoxy-1-methoxy-4-(2-nitrocyclohex-4-enyl)benzene are dissovled in 170 ml of ethanol, admixed with 3.0 g of Raney nickel and hydrogenated in an autoclave at a hydrogen pressure of 50 bar for 9 days. The suspension is filtered, the solvent is removed under reduced pressure and the residue is chromatographed over silica gel using a mixture of toluene/dioxane/triethylamine 3/1/0.5. Concentration of the appropriate fractions gives 3.4 g (25.7% of Th.) of the title compound as an oil.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17](O)=[O:18])=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.C(O[C:44]([C@H:46]1[C@@H:51]([NH:52][CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[C@H:50]2[CH2:60][C@@H:47]1[CH2:48][CH2:49]2)=[O:45])C.[O-]CC.[Na+].C(O)C>CN(C)C=O>[CH2:53]([N:52]1[C:17](=[O:18])[C:16]([C:11]2[NH:10][C:9]3[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:7][C:8]=3[S:13](=[O:15])(=[O:14])[N:12]=2)=[C:44]([OH:45])[C@H:46]2[C@@H:51]1[C@H:50]1[CH2:60][C@@H:47]2[CH2:48][CH2:49]1)[C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCc1ccccc1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Agent: CCN=C=NCCCN(C)C
Agent: CC[O-]
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CCO
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@@H]3[C@H]4CC[C@H](C4)[C@@H]3N(Cc3ccccc3)C1=O)N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 37 %

Procedure:
(7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1g, 0.200 g, 0.600 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.121 g, 0.631 mmol) and N-methylmorpholine (0.139 mL, 1.26 mmol) were added sequentially to a solution of (1S,2R,3S,4R)-3-benzylamino-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (0.164 g, 0.600 mmol) in N,N-dimethylformamide (5 mL) at 25° C. The reaction mixture was stirred at 25° C. for 2 h, and then was partitioned between 1.0 M aqueous hydrochloric acid solution (100 mL) and ethyl acetate (2×100 mL). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in ethanol (15 mL) at 25° C. A 21 wt. % solution of sodium ethoxide in ethanol (0.972 mL, 3.00 mmol) was added and the reaction mixture was heated at 60° C. for 1 h. After cooling to 25° C., the reaction mixture was partitioned between a 1.0 M aqueous hydrochloric acid solution (100 mL) and ethyl acetate (2×100 mL). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (Teledyne Isco RediSep column; 40 to 100% ethyl acetate in hexanes) to afford the desired product, (1R,2S,7R,8S)-N-[3-(3-benzyl-6-hydroxy-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl)-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl]-methanesulfonamide (0.120 g, 0.222 mmol, 37%), as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.15-1.21 (2H, m), 1.39-1.61 (4H, m), 2.52 (1H, bs), 2.64 (1H, bs), 3.05 (3H, s), 3.30 (2H, bs), 3.54 (1H, d, J=9.5 Hz), 4.43 (1H, d, J=16.4 Hz), 4.99 (1H, d, J=15.5 Hz), 7.23-7.28 (2H, m), 7.33 (2H, m), 7.48-7.51 (2H, m), 7.55-7.57 (2H, m), 10.17 (1H, s). LC-MS (ESI) calcd for C25H26N4O6S2 542.13. found 543.2 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:23])=[C:4]([CH:20]=[CH:21][CH:22]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([CH:16]=O)[CH:14]=2)[N:9]=[CH:8][N:7]=1.[NH2:24][C:25]1([C:38]([OH:40])=[O:39])[CH2:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]1>>[C:34]([O:33][C:31]([N:27]1[CH2:28][CH2:29][CH2:30][C:25]([NH:24][CH2:16][C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][C:12]=2[O:18][CH3:19])[N:9]=[CH:8][N:7]=[C:6]3[NH:5][C:4]2[CH:20]=[CH:21][CH:22]=[C:2]([Cl:1])[C:3]=2[F:23])([C:38]([OH:40])=[O:39])[CH2:26]1)=[O:32])([CH3:35])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)N1CCCC(N)(C(=O)O)C1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1C=O
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CNC1(C(=O)O)CCCN(C(=O)OC(C)(C)C)C1

Procedure:
4-(3-Chloro-2-fluoroanilino)-7-methoxyquinazoline-6-carbaldehyde was coupled with 3-amino-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (Isomer 1) using an analogous method to that described for the equivalent step in Example 1 to give 1-(tert-butoxycarbonyl)-3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)amino]piperidine-3-carboxylic acid (Isomer 1); 1H NMR Spectrum: (DMSO d6+d4 AcOH) 1.27 (s, 9H); 1.46 (m, 1H); 1.92 (m, 3H); 3.08 (m, 1H); 3.52 (m, 2H); 3.72 (m, 2H); 3.86 (d, 1H); 3.96 (s, 3H); 7.19 (s, 1H); 7.28 (dt, 1H); 7.48 (t, 1H); 7.56 (m, 1H); 8.31 (s, 1H); 8.43 (s, 1H). Mass Spectrum: (M+H)+ 560.5.
Reaction SMILES: C([O-])(=O)C.[C:5]([O:8][C@H:9]1[CH2:33][CH2:32][C@@:31]2([CH3:34])[C:11](=[CH:12][C@@H:13](Br)[C@@H:14]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:35])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[C@H:19]([CH3:26])[CH2:20][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:10]1)(=[O:7])[CH3:6].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[CH3:26][C@@H:19]([C@@H:18]1[C@@:27]2([CH3:35])[CH2:28][CH2:29][C@@H:30]3[C@@:31]4([CH3:34])[CH2:32][CH2:33][C@H:9]([O:8][C:5]([CH3:6])=[O:7])[CH2:10][C:11]4=[CH:12][CH:13]=[C:14]3[C@@H:15]2[CH2:16][CH2:17]1)[CH2:20][CH2:21][CH2:22][CH:23]([CH3:24])[CH3:25]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=C[C@@H](Br)[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]32)C1
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC=C3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]32)C1
Reaction time: 1 h

Procedure:
507.6 mg of the pure 7α-bromocholester acetate obtained sub (a) were dissolved in 5 ml of anhydrous tetrahydrofuran. To this solution was added at 25° C. a solution of 1.0 g of tetrabutyl ammonium fluoride which contained per mol 1 mol of crystal water, in 5 ml of anhydrous tetrahydrofuran, and then, after stirring at 20°-25° C. for 60 minutes, 10 ml of petroleum ether (40°-60° C.). The 1 mole crystal water-containing tetrabutyl ammonium fluoride was obtained by freeze-drying a 10% solution in water. After washing the reaction mixture three times with 10 ml of water, the organic layer was evaporated to dryness. 426 mg (100%) of dry substance were obtained with a content of 7-dehydrocholesterol acetate of 100% (UV). The final product could be recrystallized from ethanol in which 400 mg of white crystalline material were obtained with a melting-point of 128°-129° C. The crystalline final product was 100% pure Δ5,7-cholestadienol acetate both according to the UV-absorption spectrum and according to the NMR spectrum.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[C:24]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:29]=[CH:28][C:27]([C:30](Cl)=[O:31])=[CH:26][CH:25]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:30](=[O:31])[C:27]3[CH:28]=[CH:29][C:24]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:25][CH:26]=3)=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)N1c2ccc(NC(=O)c3ccc(-c4ccccc4)cc3)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Acylation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (11 mg) with 4-biphenylcarbonyl chloride (16 mg) and N,N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 ml) was performed according to the method described in example 6.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11]S)=[CH:2]1.[N+](C([N+]([O-])=O)=O)([O-])=O.[N+:21]([CH2:24][C:25](=[O:27])[CH3:26])([O-:23])=[O:22]>C1C=CC=CC=1.B(F)(F)F.CCOCC.FC(F)(F)C(O)=O>[CH3:26][C:25]1([CH2:24][N+:21]([O-:23])=[O:22])[C:2]2[NH:1][C:9]3[C:4]([C:3]=2[CH2:10][CH2:11][O:27]1)=[CH:5][CH:6]=[CH:7][CH:8]=3
Reactant: SCCc1c[nH]c2ccccc12
Reactant: CC(=O)C[N+](=O)[O-]
Agent: FB(F)F
Agent: O=C([N+](=O)[O-])[N+](=O)[O-]
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccccc1
Product: CC1(C[N+](=O)[O-])OCCc2c1[nH]c1ccccc21

Procedure:
To a solution of 322 mg of tryptophol (II, R2, R3, R4, R5, R6 = H and X1 =OH) and 248 mg of the nitroketone, nitro-2-propanone, in 100 ml of benzene is added five drops of boron trifluoride etherate and three drops of trifluoroacetic acid. The reaction mixture is stirred and heated at reflux under water-separator for 18 hr. The benzene solution is cooled, washed with 10% sodium bicarbonate solution, water, saturated brine solution, and dried over magnesium sulfate. The solvent is removed and the residue is subjected to chromatography on silica gel. Elution with chloroform gives the title compound, νmaxCHCl3 3450, 1550cm-1, nmr (CHCl3) δ1.68 (s, 3H), 2.84 (t, 2H), 4.10 (t, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:48]([CH2:49][O:50][CH3:51])=[CH:47][C:39]([O:40][CH2:41][C:42]2([CH3:46])[CH2:45][O:44][CH2:43]2)=[CH:38][C:37]=1[CH2:52][O:53][CH3:54].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:54][O:53][CH2:52][C:37]1[CH:38]=[C:39]([O:40][CH2:41][C:42]2([CH3:46])[CH2:45][O:44][CH2:43]2)[CH:47]=[C:48]([CH2:49][O:50][CH3:51])[C:36]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:10]2[C:6]=1[CH2:7][CH2:8][C@H:9]2[O:11][C:12]1[CH:25]=[CH:24][C:15]2[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=2[CH:13]=1
Reactant: COCc1cc(OCC2(C)COC2)cc(COC)c1Br
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COCc1cc(OCC2(C)COC2)cc(COC)c1-c1ccc(F)c2c1CC[C@H]2Oc1ccc2c(c1)OC[C@H]2CC(=O)OC

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydro-benzofuran-3-yl)acetate and 3-((4-bromo-3,5-bis(methoxymethyl)phenoxy)methyl)-3-methyloxetane following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 8): tR=0.72 min; Mass spectrum (ESI+): m/z=607 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]12[CH2:16][CH2:15][C:14]([F:18])([F:17])[C@@H:13]1[CH2:12][N:11]([C:19]1[C:28]([CH3:29])=[C:27]3[C:22]([C:23](=[O:39])[C:24]([C:34]([O:36]CC)=[O:35])=[CH:25][N:26]3[C@@H:30]3[CH2:32][C@@H:31]3[F:33])=[CH:21][C:20]=1[F:40])[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C>[C:1]([O:5][C:6]([NH:8][C@@:9]12[CH2:16][CH2:15][C:14]([F:17])([F:18])[C@@H:13]1[CH2:12][N:11]([C:19]1[C:28]([CH3:29])=[C:27]3[C:22]([C:23](=[O:39])[C:24]([C:34]([OH:36])=[O:35])=[CH:25][N:26]3[C@@H:30]3[CH2:32][C@@H:31]3[F:33])=[CH:21][C:20]=1[F:40])[CH2:10]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cn([C@@H]2C[C@@H]2F)c2c(C)c(N3C[C@H]4C(F)(F)CC[C@@]4(NC(=O)OC(C)(C)C)C3)c(F)cc2c1=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(N2C[C@H]3C(F)(F)CC[C@@]3(NC(=O)OC(C)(C)C)C2)c(F)cc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Temperature: 25 °C
Reaction time: 13 h
Yield: 82.4 %

Procedure:
To a solution of ethyl 7-[(1S,5R)-1-tert-butoxycarbonylamino-6,6-difluoro-3-azabicyclo[3.3.0]octan-3-yl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylate (436 mg, 0.769 mmol) in ethanol (5 mL) was added 1 mol/L aqueous solution of sodium hydroxide (0.845 mL) at 0° C., and the mixture was stirred at room temperature for 13 hours. To the mixture was further added 1 mol/L aqueous solution of sodium hydroxide (0.845 mL) at 0° C., and the mixture was stirred at room temperature for 4 hours. To the mixture was added 10% aqueous solution of citric acid, and ethanol was distilled off under reduced pressure. The residue was diluted with water and extracted with dichloromethane (3×). The combined organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel flush column chromatography (ethyl acetate/hexane=1:3→1:1→2:1→ethyl acetate) to afford 342 mg of the title compound as a colorless foam.
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][CH2:26][NH2:27])[CH:20]=1>>[CH:15]([N:4]1[C:3](=[O:18])[C:2]([NH:27][CH2:26][CH2:25][C:21]2[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=2)=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:5]1(=[O:14])=[O:13])([CH3:17])[CH3:16]
Reactant: CC(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: NCCc1cccnc1
Product: CC(C)N1C(=O)C(NCCc2cccnc2)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 4-chloro-2-isopropyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide and (2-pyridin-3-ylethyl)amine in a similar manner as described for Example 118. 1H NMR (500 MHz CDCl3): δ 1.59 (d, 6H), 2.59 (t, 2H), 3.17 (q, 2H), 4.37-4.45 (m, 1H), 5.47 (t, 1H), 7.06-7.09 (m, 1H), 7.14-7.17 (m, 1H), 7.46-7.55 (m, 5H), 8.07 (s, 1H), 8.44-8.46 (m, 1H); 13C NMR (125 MHz CDCl3): δ 20.38, 33.39, 44.78, 47.88, 107.76, 123.70, 125.15, 129.13, 130.20, 131.84, 133.02, 135.16, 136.13, 148.57, 150.06, 158.61; Mass Spectrum: M+H+ 372.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:4]=1[CH2:5][N:6]([C:29]1[S:33][N:32]=[CH:31][N:30]=1)[S:7]([C:10]1[CH:18]=[C:17]2[C:13]([C:14](B3OC(C)(C)C(C)(C)O3)=[CH:15][N:16]2[CH3:19])=[CH:12][CH:11]=1)(=[O:9])=[O:8].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Cl:48][C:49]1[CH:54]=[C:53]([C:55]([F:58])([F:57])[F:56])[CH:52]=[CH:51][C:50]=1I>C(OCC)(=O)C.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:48][C:49]1[CH:54]=[C:53]([C:55]([F:56])([F:57])[F:58])[CH:52]=[CH:51][C:50]=1[C:14]1[C:13]2[C:17](=[CH:18][C:10]([S:7]([N:6]([CH2:5][C:4]3[CH:34]=[CH:35][C:36]([O:38][CH3:39])=[CH:37][C:3]=3[O:2][CH3:1])[C:29]3[S:33][N:32]=[CH:31][N:30]=3)(=[O:8])=[O:9])=[CH:11][CH:12]=2)[N:16]([CH3:19])[CH:15]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(B4OC(C)(C)C(C)(C)O4)cn(C)c3c2)c(OC)c1
Reactant: FC(F)(F)c1ccc(I)c(Cl)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4Cl)cn(C)c3c2)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.2 %

Procedure:
A vial was charged with N-(2,4-dimethoxybenzyl)-1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide (0.500 g, 0.876 mmol), potassium phosphate (0.651 g, 3.07 mmol), and bis(tri-t-butylphosphine)palladium(0) (0.045 g, 0.088 mmol). The vial was flushed with Ar, then 1,4-dioxane (6.57 ml) and water (2.191 ml) were added in sequence, followed by 2-chloro-1-iodo-4-(trifluoromethyl)benzene (0.426 ml, 2.63 mmol). The vial was sealed and stirred at room temperature for two hours. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried with sodium sulfate, filtered and concentrated. The material was purified via column chromatography (RediSep Gold (Teledyne Isco, Lincoln, Nebr.) 40 g, gradient elution 0-100% EtOAc/Heptane) to afford 3-(2-chloro-4-(trifluoromethyl)phenyl)-N-(2,4-dimethoxybenzyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide (0.405 g, 0.650 mmol, 74.2% yield) as a light yellow solid. m/z (ESI) 624.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]3[CH:12]=[N:13][N:14]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[C:15]=3[CH:16]=[CH:17][CH:18]=2)=[O:9])=[C:4]([Cl:28])[CH:3]=1.[H-].[Na+].[CH3:31][O:32][CH2:33]Cl>CN(C=O)C.O.C(OCC)C>[Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]([CH2:31][O:32][CH3:33])[C:8]([C:10]2[C:11]3[CH:12]=[N:13][N:14]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[C:15]=3[CH:16]=[CH:17][CH:18]=2)=[O:9])=[C:4]([Cl:28])[CH:3]=1
Reactant: COCCl
Reactant: O=C(NCc1ccc(Br)cc1Cl)c1cccc2c1cnn2-c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: COCN(Cc1ccc(Br)cc1Cl)C(=O)c1cccc2c1cnn2-c1ccc(F)cc1
Reaction time: 0.17 h

Procedure:
To a room temperature solution of 1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid 4-bromo-2-chloro-benzylamide (1.5 g, 3.3 mmol) in DMF (30 mL) was added a 60% dispersion of sodium hydride in mineral oil (145 mg, 3.60 mmol). After stirring for 10 minutes, chloromethyl methyl ether (0.28 mL, 3.6 mmol) was added. After 16 hours, the mixture was then diluted with water (30 mL) and extracted with ethyl acetate (3×20 mL). The extract was washed with saturated aqueous ammonium chloride (30 mL) followed by brine (30 mL) and dried over sodium sulfate. The residue was purified by silica gel chromatography eluting with a gradient of 0-70% ethyl acetate in hexanes. The fractions containing product were condensed in vacuo to provide a colorless oil. The oil was dissolved in diethyl ether (25 mL), causing the starting material to solidify from solution. Filtration gave the title compound as a white solid.