Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Br:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1>O1CCCC1.C(OCC)C>[Br:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:2]([CH3:3])[CH3:1])(=[O:13])=[O:12])=[CH:7][CH:6]=1
Reactant: CNC
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN(C)S(=O)(=O)c1ccc(Br)cc1
Yield: 94.8 %

Procedure:
A 25% aqueous solution of dimethylamine (420 mL, 2.3 mol) was diluted with 1000 mL of tetrahydrofuran and added dropwise to a solution of p-bromobenzenesulfonyl chloride (200 g, 0.78 mol) in 700 mL of tetrahydrofuran. The mixture was diluted with diethyl ether and the organic layer was washed with water and saturated aqueous sodium chloride and dried over sodium sulfate. Evaporation of the solvent gave 195.4 g (95%) of 4-bromo-N,N-dimethylbenzenesulfonamide as white crystals, mp 90°-92° C. (lit. 94° C., J. Am. Chem. Soc. 45, 2696 (1923)).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])O.[Na+].[C:15]([C:17]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24])([CH3:19])[CH3:18])#[N:16]>O1CCCC1.O>[C:15]([C:17]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([OH:8])[CH:7]=1)=[O:24])([CH3:19])[CH3:18])#[N:16]
Reactant: CC(C)(C#N)c1cccc(C(=O)Cl)c1
Reactant: Cc1ccc(N)cc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1O
Temperature: 25 °C
Yield: 94 %

Procedure:
To a solution of 5-amino-2-methylphenol (3.00 g, 24.3 mmol) in tetrahydrofuran (20 mL) was added a suspension of sodium hydrogencarbonate (3.00 g, 36.5 mmol) in water (30 mL), and the mixture was vigorously stirred at room temperature. To this mixture was added dropwise a solution of 3-(1-cyano-1-methylethyl)benzoyl chloride produced above in tetrahydrofuran (30 mL) under ice-cooling, and the mixture was stirred at room temperature for 5 hr. The aqueous layer was separated from the reaction mixture, and the organic layer was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and decolorized with activated carbon. The insoluble material was passed through a pad filled with two layers of silica gel and celite for filtration. The solvent was evaporated under reduced pressure, and the obtained solid was washed with ethyl acetate-hexane mixture to give the title compound (6.75 g, 94%) as a white powder.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]([C@@H:5]1[CH2:9][C@@H:8](O)[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].[F-].[Na+].[F:21]C(F)(N(CC)CC)C(F)C(F)(F)F.C([O-])([O-])=O.[K+].[K+]>ClCCl>[CH3:1][N:2]([CH3:18])[C:3]([C@@H:5]1[CH2:9][C@@H:8]([F:21])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: CN(C)C(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: CCN(CC)C(F)(F)C(F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [F-]
Agent: [K+]
Solvent: ClCCl
Product: CN(C)C(=O)[C@@H]1C[C@@H](F)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of 25.7 g of the compound obtained in Step 6-1a and 5.00 g of sodium fluoride in dichloromethane (260 ml) was added dropwise under ice cooling a mixture (approximately 3:1) of 1,1,2,3,3,3-hexafluoro-1-(diethylamino)propane and 26.6 g 1,2,3,3,3-pentafluoro-1-(diethylamino)-2-propene over 10 minutes, then, the solution was stirred at room temperature for 16 hours. To the reaction solution was added an aqueous solution of 5% K2CO3 under ice cooling, and the resulting mixture was stirred for 30 minutes at the same temperature. After liquid separation, obtained aqueous layer was extracted with CHCl3, the combined organic layer was washed with saturated brine, dried over MgSO4, then, the drying agent was separated by filtration, and the solvent was evaporated under reduced pressure. The obtained residue was subjected to column chromatography (silicagel 60; mobile phase: EtOAc/n-hexane=1/1 to 10/0; v/v) to obtain 12.2 g of the title compound (pale yellow solid).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.Cl[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][C:23]([OH:25])=[O:24])=[C:14]([CH3:26])[N:13]=1.O1CCOCC1.Cl>CCOCC>[ClH:10].[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][N:2]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([CH2:22][C:23]([OH:25])=[O:24])=[C:14]([CH3:26])[N:13]=2)[CH3:1])=[CH:5][CH:6]=1
Reactant: CNCc1ccc(Cl)cc1
Reactant: Cc1nc(Cl)c2ccccc2c1CC(=O)O
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cc1nc(N(C)Cc2ccc(Cl)cc2)c2ccccc2c1CC(=O)O

Procedure:
N-Methyl-4-chlorobenzylamine (1.40 g., 9.0 mmol) and 1-chloro-3-methyl-4-isoquinoline acetic acid (770 mg., 3.0 mmol), prepared as in Example 8, were refluxed in 20 ml. p-dioxane for 16 hr. The cooled reaction mixture was partitioned between 200 ml ether and 50 ml 1 N sodium hydroxide. The ether rafinate was extracted with 2×30 ml 1 N sodium hydroxide. The combined basic phases were acidified to pH 6.5 with 6 N hydrochloric acid and extracted with 3×75 ml ethyl acetate. This organic phase was dried over magnesium sulfate, filtered, and vacuum evaporated to an oily residue. Chromatography of this on silica gel eluted with ethyl acetate gave an oil. The title compound was prepared from this oil by treatment with hydrochloric acid gas in ether, filtrate, and drying in vacuo; 52 mg. (4%), m/e 354.
Reaction SMILES: [CH2:1]([CH:6]1[CH2:11][CH2:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=2[F:19])=[CH:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[H][H]>C1(C)C=CC=CC=1.[Pd]>[CH2:1]([CH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=2[F:19])[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCC1CC=C(c2cccc(F)c2F)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CCCCCC1CCC(c2cccc(F)c2F)CC1
Yield: 93.3 %

Procedure:
The compound (9) (50.0 g) was dissolved in a mixed solvent of toluene (150 ml) and Solmix A-11 (150 ml), Pd/C (0.5 g) was added thereto, and the mixture was stirred at room temperature under a hydrogen atmosphere until hydrogen absorption had ceased. After the reaction had been completed, Pd/C was removed and then the solvent was distilled off. The residue obtained was purified with a fractional operation by means of column chromatography using heptane as the eluent and silica gel as the stationary phase powder, and further purified by means of recrystallization from Solmix A-11 and dried, giving 47.0 g of 4-pentyl-(2,3-difluorophenyl)cyclohexane (10). The yield based on the compound (9) was 94.0%.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH:11]2[CH2:13][CH2:12]2)=[N:8][O:9][CH:10]=1)=[O:5])C.[OH-].[K+].Cl>C(O)C.O.O>[CH:11]1([C:7]2[C:6]([C:4]([OH:5])=[O:3])=[CH:10][O:9][N:8]=2)[CH2:12][CH2:13]1
Reactant: CCOC(=O)c1conc1C1CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1conc1C1CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5.6 g (31 mmol) of 3-Cyclopropyl-isoxazole-4-carboxylic acid ethyl ester were slowly added to a solution of 6.1 g (93 mmol, 85% purity) of potassium hydroxide in ethanol/water (1:3, 100 ml) at 0° C. The reaction mixture was stirred at room temperature for 16 h, diluted with water, acidified (pH=2) with 20% aqueous HCl and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and the solvent was removed to yield 4.7 g (94%, 95% purity) of the title compound which did not need further purification.
Reaction SMILES: B(OC(C)C)(OC(C)C)OC(C)C.Br[C:15]1[CH:20]=[CH:19][C:18]([S:21]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1.C([Li])CCC.[ClH:36].C(=O)([O-])[O-].[Na+].[Na+].[NH2:43][C:44]1[C:45]([C:51]([NH:53][CH2:54][CH2:55][C:56]2[S:57][CH:58]=[CH:59][CH:60]=2)=[O:52])=[N:46][C:47](Br)=[CH:48][N:49]=1>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[ClH:36].[NH2:43][C:44]1[C:45]([C:51]([NH:53][CH2:54][CH2:55][C:56]2[S:57][CH:58]=[CH:59][CH:60]=2)=[O:52])=[N:46][C:47]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:48][N:49]=1
Reactant: CN1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Reactant: Nc1ncc(Br)nc1C(=O)NCCc1cccs1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)OB(OC(C)C)OC(C)C
Solvent: C1CCOC1
Product: CN1CCN(S(=O)(=O)c2ccc(-c3cnc(N)c(C(=O)NCCc4cccs4)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 5.8 %

Procedure:
Triisopropyl borate (0.82 mL, 3.6 mmol) was added to a stirred solution of 1-[(4-bromophenyl)sulfonyl]-4-methylpiperazine (0.38 g, 1.2 mmol; described: in Keasling, H. H. et el. J. Med. Chem. 1965, 8, 549-550) in anhydrous tetrahydrofuran (115 mL) at −78° C. under an atmosphere of nitrogen, followed by dropwise addition of n-butyllithium (2.4 mL, 3.6 mmol) over 10 min. The resulting mixture was allowed to warm up to room temperature and was stirred for another 10 min at ambient temperature. Aqueous HCl (3 M, 1.9 mL, 6.0 mmol) was added and the mixture was stirred for 10 min, followed by an addition of sodium carbonate (1.26 g, 11.9 mmol). 3-Amino-6-bromo-N-(2-thien-2-ylethyl)pyrazine-2-carboxamide (0.272 g, 0.83 mmol) and Pd(dppf)Cl2 (39 mg, 0.05 mmol) were added and the resulting mixture was heated at 65° C. for 1 h. The solvent was evaporated, the resulting residue dissolved in methylene chloride/water, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were evaporated, methanol was added, and the insoluble material was filtered off. The solvent was evaporated and the residue was purified on a silica gel column using methylene chloride/methanol/triethyl amine, (98:2:0.1), as the eluent. The crude product was purified by re-crystallization from methanol to give the free base that was treated with HCl (1.0 M in diethyl ether, 0.6 mmol). The formed precipitate was filtered off and dried under vacuo to give 25 mg (6% yield) of the title compound as a yellow solid: 1H NMR (DMSO-d6, 400 MHz) δ 10.55 (br s, 1H), 9.05 (m, 1H), 8.99 (s, 1H), 8.46 (d, J=8 Hz, 2H), 7.82 (d, J=8 Hz, 2H), 7.37 (d, J=5 Hz, 1H), 6.98 (m, 2H), 3.83 (m, 2H), 3.58 (m, 2H), 3.46 (m, 2H), 3.13 (m, 4H), 2.75 (s, 3H), 2.67 (m, 2H); MS (S) m/z 487 (M++1).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([C:31]([F:34])([F:33])[F:32])(=[O:30])=[O:29])=[CH:24][C:23]=1[CH3:35])=[N:17][N:16]=[CH:15]2.[OH-].[Na+].Cl>C1COCC1.CO>[CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([C:31]([F:33])([F:32])[F:34])(=[O:30])=[O:29])=[CH:24][C:23]=1[CH3:35])=[N:17][N:16]=[CH:15]2
Reactant: COC(=O)c1ccc(C)c(-c2ccc3c(-c4ccc(S(=O)(=O)C(F)(F)F)cc4C)nncc3c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)O)cc1-c1ccc2c(-c3ccc(S(=O)(=O)C(F)(F)F)cc3C)nncc2c1
Reaction time: 8 h
Yield: 70.2 %

Procedure:
To a solution of methyl 4-methyl-3-(1-(2-methyl-4-(trifluoromethylsulfonyl)phenyl)phthalazin-6-yl)benzoate (120 mg, 0.24 mmol) in 3 mL of 2/1 THF/MeOH was added NaOH (30 mg, 0.72 mmol) at RT. After 8 h, the mixture was acidified with 2M HCl and extracted with DCM (3×). The combined DCM layers were washed with brine, dried and concentrated to afford the 4-methyl-3-(1-(2-methyl-4-(trifluoromethylsulfonyl)phenyl)phthalazin-6-yl)benzoic acid (82 mg) as a tan solid. The crude acid was used in the next step. MS (ESI, pos. ion) m/z: 486.9 (M+1).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([NH:22][C@@H:23]1[C:29](=[O:30])[N:28]([CH2:31][C:32]([O:34]C(C)(C)C)=[O:33])[C:27]2[CH:39]=[CH:40][CH:41]=[CH:42][C:26]=2[O:25][CH2:24]1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=O)(C)(C)C.C(OCC)(=O)C.[ClH:49]>>[ClH:49].[ClH:49].[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([NH:22][C@@H:23]1[C:29](=[O:30])[N:28]([CH2:31][C:32]([OH:34])=[O:33])[C:27]2[CH:39]=[CH:40][CH:41]=[CH:42][C:26]=2[O:25][CH2:24]1)[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)[C@H](CCCCCCCNC(=O)OC(C)(C)C)N[C@H]1COc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](CCCCCCCN)N[C@H]1COc2ccccc2N(CC(=O)O)C1=O
Reaction time: 3.5 h

Procedure:
A mixture of tert-butyl 3(S)-[8-tert-butoxycarbonylamino-1(S)-ethoxycarbonyloctyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.45 g) and 5N hydrogen chloride-ethyl acetate solution (10 ml) is allowed to stand for 3.5 hours at room temperature. The mixture is diluted with petroleum ether (80 ml) to precipitate colorless powder, which is collected and dried in vacuo to give 3(S)-[8-amino-1(S)-ethoxycarbonyloctyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid.dihydrochloride (0.37 g).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:23][CH2:22][C:13]2[NH:14][C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][C:20]=3[C:12]=2[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].I[CH3:25]>C1COCC1>[C:3]([O:7][C:8]([N:10]1[CH2:23][CH2:22][C:13]2[N:14]([CH3:25])[C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][C:20]=3[C:12]=2[CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3ccc(F)cc3c2C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c2c(c3cc(F)ccc31)CN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 91.1 %

Procedure:
To a suspension of NaH (80% in oil, 0.0190 g, 0.633 mmol) in dry THF (1 mL), was added a solution of 8-fluoro-1,3,4,5-tetrahydropyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester (0.114 g, 0.393 mmol) in THF (4 mL) via cannula. The reaction mixture was allowed to stir at room temperature for 5 min and then iodomethane (0.098 mL, 1.57 mmol) was added. The resulting mixture was stirred for 2 h and then it was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic phase was separated, dried (MgSO4), filtered and concentrated to dryness to give the title compound (0.109 g, 91%) as a yellow oil which was used without further purification. LCMS: m/e 305 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].Br.C(OC(=O)C)(=O)C>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: COc1ccc(Cl)c([N+](=O)[O-])c1
Agent: Br
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])c1cc(O)ccc1Cl
Yield: 83.8 %

Procedure:
There were mixed 20 g of 4-chloro-3-nitroanisole, 67 ml of acetic acid and 83 ml of 47% (w/w) hydrobromic acid. Thereto was added 50 ml of acetic anhydride. The mixture was refluxed for 8.5 hours. After the completion of the reaction, the solvent was removed by distillation under reduced pressure. The residue was mixed with 300 ml of ethyl acetate and 500 ml of water. The resulting organic layer was separated, washed with a saturated aqueous sodium hydrogencarbonate solution, water and a saturated aqueous sodium chloride solution in this order, and then dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The resulting crystal was recrystallized from toluene to obtain 15.5 g (yield: 83.6%) of 4-chloro-3-nitrophenol having a melting point of 123.5°-125.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:26][CH2:27][CH2:28]S([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:25])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:34]1([C:40]2([C:46]([NH2:48])=[O:47])[CH2:45]C[NH:43][CH2:42][CH2:41]2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:26][CH2:27][CH:28]3[CH2:45][C:40]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:46]([NH2:48])=[O:47])[CH2:41][CH2:42][NH:43]3)[CH2:13][CH2:12][N:11]([C:14](=[O:25])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Reactant: COc1cc(OC)cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)c1
Agent: Cl
Product: COc1cc(OC)cc(C(=O)N2CCC(CCC3CC(C(N)=O)(c4ccccc4)CCN3)(c3ccc(Cl)c(Cl)c3)C2)c1

Procedure:
The method of example 3.3 was used with 2-[3-(3,4-dichloro-phenyl)-1-(3,5-dimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (0.96 mmol) and 4-phenylpiperidine-4-carboxylic acid amide hydrochloride (1.06 mmol) to prepare the title compound. Chromatography on silica gel eluting sequentially with ethyl acetate, 6% methanol in dichloromethane, and then 10% methanol in dichloromethane gave the title compound:
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].CS(O[CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([Br:21])[CH:20]=1)(=O)=O>C1COCC1.CN(C=O)C>[Br:21][C:19]1[CH:18]=[N:17][CH:16]=[C:15]([CH2:14][O:4][CH2:3][C:2]([F:6])([F:5])[F:1])[CH:20]=1
Reactant: OCC(F)(F)F
Reactant: CS(=O)(=O)OCc1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: FC(F)(F)COCc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.4 %

Procedure:
2,2,2-Trifluoroethanol (0.434 g, 4.34 mmol) was added to a suspension of NaH (0.198 g, 4.96 mmol) in THF (10 mL). When gas evolution had ceased, a solution of (5-bromopyridin-3-yl)methyl methanesulfonate (see WO2007/076247; 1.10 g, 4.13 mmol) in DMF was added. The resulting mixture was stirred for 2 h at r.t. and then the volatile solvent was evaporated. The remaining solution was diluted with water and extracted with EtOAc (3×30 mL). The combined extracts were dried over MgSO4 and concentrated. The residue was purified by flash chromatography on silica using gradient elution with EtOAc in heptane to give 227 mg of the title compound (20% yield). 1H NMR (500 MHz, CDCl3) δ ppm 3.92 (q, 2 H), 4.70 (s, 2 H), 7.87 (m, 1 H), 8.50 (m, 1 H), 8.66 (d, 1 H); MS (EI) m/z 269 M+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]#[N:27])=[CH:16][CH:15]=2)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Cl[C:29]([O:31][CH3:32])=[O:30]>N1C=CC=CC=1>[C:26]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:17]1[CH:18]=[CH:19][C:14]([CH2:13][NH:12][C:3]2[C:2]([NH:1][C:29]([O:31][CH3:32])=[O:30])=[CH:11][CH:10]=[CH:9][C:4]=2[C:5]([O:7][CH3:8])=[O:6])=[CH:15][CH:16]=1)#[N:27]
Reactant: COC(=O)Cl
Reactant: COC(=O)c1cccc(N)c1NCc1ccc(-c2ccccc2C#N)cc1
Solvent: c1ccncc1
Product: COC(=O)Nc1cccc(C(=O)OC)c1NCc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
To a stirred solution of methyl 3-amino-2-[(2'-cyanobiphenyl-4-yl)methylamino]benzoate (10 g) in pyridine (50 ml) was added dropwise methyl chloroformate (9.0 ml) under ice-cooling. The mixture was stirred at room temperature for 3 hours and concentrated. The residue was extracted with ethyl acetate. The extract was washed with water, dried and evaporated. The residue was recrystallized from ethyl acetate-hexane to afford pale yellow needles (10.5 g, 90%), m.p. 113-115° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([OH:30])([C:24]3[N:28]([CH3:29])[N:27]=[N:26][CH:25]=3)[CH:13]3[CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]3)[CH:10]=2)[N:5]=[C:4]([CH3:31])[C:3]=1[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=1.F[C:44](F)(F)[C:45](O)=[O:46].C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([OH:30])([C:24]3[N:28]([CH3:29])[N:27]=[N:26][CH:25]=3)[CH:13]3[CH2:16][N:15]([C:45](=[O:46])[CH3:44])[CH2:14]3)[CH:10]=2)[N:5]=[C:4]([CH3:31])[C:3]=1[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([F:40])([F:41])[F:42])=[CH:35][CH:34]=1
Reactant: Cc1nc2ccc(C(O)(c3cnnn3C)C3CN(C(=O)OC(C)(C)C)C3)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)N1CC(C(O)(c2ccc3nc(C)c(Cc4ccc(C(F)(F)F)cc4)c(Cl)c3c2)c2cnnn2C)C1
Temperature: 23 °C
Reaction time: 18 h

Procedure:
A mixture containing tert-butyl 3-((4-chloro-2-methyl-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(hydroxy)(1-methyl-1H-1,2,3-triazol-5-yl)methyl)azetidine-1-carboxylate (250 mg, 0.42 mmol, Example 31) and trifluoroacetic acid (0.32 mL, 0.32 mmol) in dichloromethane (2 mL) was stirred at 23° C. After 18 hours, dichloromethane (50 mL) and saturated aqueous sodium bicarbonate solution (25 mL) were added. The biphasic mixture was stirred for 5 minutes. The layers were separated. The organic layer was dried with sodium sulfate and the dried solution was filtered. The filtrate was concentrated to provide a residue. This residue was used in the next step without further purification. A mixture of the residue (174 mg), triethylamine (0.25 mL), and acetic anhydride (0.14 mL) in dichloromethane (3.5 mL) was stirred at 46° C. After 2 hours, the flask was cooled to 23° C. Dichloromethane (40 mL) and saturated aqueous sodium bicarbonate solution (25 mL) were added. The biphasic mixture was stirred for 10 minutes at 23° C. The layers were separated. The organic layer was dried with sodium sulfate and the dried solution was filtered. Celite® (3 g) was added to the filtrate and the mixture was concentrated in vacuo. The dry solid was loaded onto a silica gel column for flash-column chromatography. Elution with 100% dichloromethane initially, grading to 5% methanol-dichloromethane provided the title compound as an off-white solid. 1H NMR (500 MHz, CDCl3, 3:1 mixture of amide rotamers, asterisk denotes minor rotamer) δ ppm 8.44 (d, J=2.0 Hz, 1H), 8.38* (d, J=2.1 Hz, 1H), 8.00-7.94 (m, 1H), 7.60-7.51 (m, 3H), 7.48-7.42 (m, 1H), 7.25-7.20 (m, 2H), 6.23 (s, 1H), 5.09* (s, 1H), 4.54-4.45 (m, 2H), 4.43-4.36* (m, 1H), 4.34-4.28* (m, 1H), 4.27-4.19 (m, 1H), 4.19-4.13 (m, 1H), 4.08-3.96 (m, 1H), 3.80-3.65 (m, 4H), 3.63-3.54* (m, 1H), 3.54-3.46 (m, 1H), 2.69-2.63 (m, 3H), 1.82* (s, 3H), 1.65-1.54 (m, overlap with water, 3H); MS (ESI): mass calcd. for C27H25ClF3N5O2, 543.2. m/z found, 544.1 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13](=O)([O-])[O-].[K+].[K+].CN(C)C=O.C(=O)(OC)OC>CCCCCCC.O.C(OCC)(=O)C>[CH3:13][N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=2)[CH:8]=[CH:9]1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Agent: [K+]
Solvent: COC(=O)OC
Solvent: CCCCCCC
Solvent: O
Product: Cn1ccc2ccc([N+](=O)[O-])cc21
Temperature: 126 °C
Yield: 408.4 %

Procedure:
A 1L, three-necked flask equipped with a thermocouple, condenser, and addition funnel was charged with 6-nitroindole (60.0 g, 0.37 mol), potassium carbonate (12.0 g, 87 mmol), N,N-dimethylformamide (240 mL) and dimethyl carbonate (66 mL, 0.784 mol) and the resulting stirred mixture was heated to 126±3° C. The progress of the reaction was monitored by HPLC or TLC (solvent system: 30% ethyl acetate in heptane). After 1 h at this temperature, residual 6-nitroindole could not be detected. Then, the reaction mixture was cooled to 10±5° C. and slowly diluted with water (480 mL). As the water was added, a yellow precipitate formed. The resulting mixture was stirred at room temperature for 2 h, then the solid was recovered by filtration, washed with water (250 mL) and dried under high vacuum at 60-65° C. for 24 h to give 62.6 g of 1-methyl6-nitroindole (96.1% yield) as a yellow solid.