Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:3].[N+:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26](Cl)(=[O:28])=[O:27])([O-:19])=[O:18]>C(Cl)Cl>[C:5]([O:4][C:2](=[O:3])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][S:26]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[N+:17]([O-:19])=[O:18])(=[O:27])=[O:28])([CH3:6])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)NCCCCCCN
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCCCCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.2 %

Procedure:
To a stirred solution of N-Boc 1,6-diaminohexane hydrochloride (1.51 g, 6 mmol) and triethyle amine (1.31 g, 13 mmol) in 50 mL methylene chloride was added 2-Nitrobenzenesulfonyl chloride (1.326 g, 6 mmol). The reaction mixture was stirred for 6 h at room temperature, quenched with brine, and extracted with methylene chloride (2×50 mL). The organic layer was washed with brine (a saturated solution of sodium chloride in water, unless otherwise specified), dried over anhydrous sodium sulfate, and concentrated in vacuo to yield the titled compound as yellow oil (2.1 g, 87%).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:32])=[C:5]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[C:6]=1[C:7]([NH:9][C@H:10]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)[CH3:11])=[O:8].[CH3:33][S:34]([NH2:37])(=[O:36])=[O:35].Cl.CN(C)CCCN=C=NCC>C1COCC1.CN(C=O)C.CN(C)C1C=CN=CC=1>[CH3:1][C:2]1[S:3][C:4]([CH3:32])=[C:5]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:26][CH:27]=2)[C:6]=1[C:7]([NH:9][C@H:10]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH:37][S:34]([CH3:33])(=[O:36])=[O:35])=[O:18])=[CH:14][CH:13]=1)[CH3:11])=[O:8]
Reactant: CS(N)(=O)=O
Reactant: Cc1sc(C)c(C(=O)N[C@@H](C)c2ccc(C(=O)O)cc2)c1Cc1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1sc(C)c(C(=O)N[C@@H](C)c2ccc(C(=O)NS(C)(=O)=O)cc2)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-{(1S)-1-[({2,5-dimethyl-4-[4-(trifluoromethyl)benzyl]-3-thienyl}carbonyl)amino]ethyl}benzoic acid from Example 12 (200 mg, 0.433 mmol) in a mixture of THF (5 mL) and DMF (2.5 mL), were successively added methanesulfonamide (52.0 mg, 0.542 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (166 mg, 0.866 mmol) and 4-dimethylaminopyridine (66.0 mg, 0.542 mmol). The mixture was stirred overnight at r.t. and quenched with acetic acid. After 10 min., the mixture was diluted with water and partitioned between 1N HCl and EtOAc. The organic layer was washed with 1N HCl (2×) and brine, dried and concentrated. The residue was purified by Combi Flash chromatography system (50% THF/CHCl3 in 13 min.) to afford the desired product as a white solid. MS (−APCI): m/z 537 (M−1)−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:6]([CH:14]=1)[CH2:7]NC(C)(C)CO.ClN1C(=[O:29])CCC1=O>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:6]([CH:14]=1)[CH:7]=[O:29]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(CO)NCc1cc(Br)ccc1CCc1ccccc1
Solvent: ClCCl
Product: O=Cc1cc(Br)ccc1CCc1ccccc1
Reaction time: 4 h
Yield: 48.6 %

Procedure:
A mixture of 2-(N-(5-bromo-2-(phenethyl)benzyl)amino)-2-methylpropan-1-ol (9.13 g), N-chlorosuccinimide (3.38 g) and dichloromethane (50mi) was stirred for 4 hours. Alumina (10 g) was added and the mixture stirred for 6 days, filtered and the solvent evaporated. The residue was dissolved in dichloromethane (200 ml) and alumina (60 g) added in 6 portions over 8 hours. The mixture was filtered, the filtrate evaporated and the residue purified by MPLC eluting with dichloromethane/hexane (1: 1) to give 5-bromo-2-(phenethyl)benzaldehyde (3.54 g).
Reaction SMILES: OO.[CH3:3][N:4]([CH3:21])[CH:5]1[CH2:20][C:19]2[C:7](=[CH:8][C:9]3[N+:14]([O-:15])=[N:13][C:12]([CH2:16][CH3:17])=[N:11][C:10]=3[CH:18]=2)[CH2:6]1.C(O)(C(F)(F)F)=[O:23].N>C(Cl)Cl.C(Cl)(Cl)Cl>[CH3:21][N:4]([CH3:3])[CH:5]1[CH2:20][C:19]2[C:7](=[CH:8][C:9]3[N+:14]([O-:15])=[N:13][C:12]([CH2:16][CH3:17])=[N+:11]([O-:23])[C:10]=3[CH:18]=2)[CH2:6]1
Reactant: CCc1nc2cc3c(cc2[n+]([O-])n1)CC(N(C)C)C3
Reactant: O=C(O)C(F)(F)F
Agent: N
Agent: OO
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCc1n[n+]([O-])c2cc3c(cc2[n+]1[O-])CC(N(C)C)C3
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 20.7 %

Procedure:
H2O2 (70%, 0.47 mL, ca. 9.7 mmol) was added dropwise to a stirred solution of TFM (1.35 mL, 9.7 mmol) in DCM (15 mL) at 0° C. The solution was stirred at 20° C. for 10 min, then cooled to 0° C. and added to a solution of 1-oxide 115 (250 mg, 0.97 mmol) and TFA (0.16 mL, 2.07 mmol) in CHCl3 (15 mL) at 0° C. The solution was stirred at 20° C. for 5 h. The solution was made basic with dilute aqueous NH3 solution and extracted with CHCl3 (3×30 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by column chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 116 (55 mg, 21%) as an unstable brown solid: 1H NMR δ 8.30 (s, 1H, H-9), 8.25 (s, 1H, H-5), 3.07-3.37 (m, 7H, H-6, H-7, H-8, CH2), 2.36 [s, 6H, N(CH3)2], 1.43 (t, J=7.5 Hz, 3H, CH3); HRMS calcd for C14H18N4O2 (M+) m/z 274.1430, found 274.1428.
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[CH3:11][C:12]1[C:16]([CH3:17])=[CH:15][NH:14][CH:13]=1>ClCCCl>[CH3:11][C:12]1[C:16]([CH3:17])=[CH:15][NH:14][C:13]=1[CH:3]=[O:4]
Reactant: Cc1c[nH]cc1C
Reactant: CN(C)C=O
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1c[nH]c(C=O)c1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49.5 %

Procedure:
To a solution of 0.92 mL (12 mmoles) of N,N-dimethylformamide in 10 mL of 1,2-dichloroethane was added dropwise 1.0 mL (12 mmoles) of phosphorus oxychloride at 0° C. The ice-bath was removed and the reaction mixture was further stirred for 30 min. 3,4-Dimethylpyrrole (960.0 mg, 10 mmoles) was added to the above solution portionwise and the reaction mixture was stirred at 50° C. for 5 h. The reaction mixture was poured into ice-cold 1N sodium hydroxide solution (pH=9 after mixing) and the resulting mixture was stirred at room temperature for 1 h. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine until pH=7, dried over anhydrous sodium sulfate and evaporated. The residue was chromatographed on a silica gel column eluting with a solvent mixture of ethyl acetate and hexane to afford 610 mg (50%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([F:26])[C:24]=1F)[C:20]#[N:21].C(N(C(C)C)CC)(C)C>C1(C)C(C)=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][NH:15][C:24]1[C:17]([F:16])=[CH:18][C:19]([C:20]#[N:21])=[CH:22][C:23]=1[F:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1cc(F)c(F)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1CN
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1C
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1CNc1c(F)cc(C#N)cc1F
Yield: 7.2 %

Procedure:
(S)-2-Aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (1.36 g) and 3,4,5-trifluorobenzonitrile (1.00 g) were heated under argon in xylene (10 ml) containing diisopropylethylamine (3.3 ml) for 16 h. The reaction mixture was cooled and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried and evaporated to give a solid which was triturated with pentane-ether to afford the title product (0.16 g) as an off white powder. Chromatography of the mother liquors on silica gel eluting with ethyl acetate-pentane mixtures afforded further title product (0.92 g). Mass Spectrum (API+): Found 252 (MH+-tBoc). C18H23F2N3O2 requires 351.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].ClC1[C:25](Cl)=[N:26][CH:27]=[C:28](C=1)[C:29]([OH:31])=O.N1CC[C@@H](O)C1.CCN(C(C)C)C(C)C>CC(O)C>[Cl:1][C:2]1[C:3]([N:26]2[CH2:27][CH2:28][C@@H:29]([OH:31])[CH2:25]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Cl)c1
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Agent: O[C@@H]1CCNC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Cl)c1

Procedure:
A mixture of 5,6-dichloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (prepared from 5,6-dichloronicotinic acid in an analogous fashion to that described in Stage 12.2, 1.5 g, 4.27 mmol), (R)-pyrrolidin-3-ol (447 mg, 5.13 mmol), iPrOH (10 mL) and DIPEA (1.104 g, 8.54 mmol) were subjected to MW irradiation at 140° C. for 60 min. The RM was quenched with water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic extracts were washed with brine (100 mL), dried over MgSO4, filtered and the filtrate was evaporated off under reduced pressure to afford the title compound as a beige powder. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.85-1.97 (m, 2H) 3.59 (d, J=12 Hz, 1H) 3.7-3.8 (m, 1H) 3.8-3.95 (m, 2H) 4.35-4.40 (m, 1H) 5.00 (s, 1H) 7.35 (d, J=2 Hz, 2H) 7.86 (d, J=2 Hz, 2H) 8.17 (s, 1H) 8.66 (s, 1H) 10.22 (s, 1H).
Reaction SMILES: Cl.O1CCOCC1.[CH2:8]([O:15][C:16]([NH:18][C@H:19]1[C@@H:24]([F:25])[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[CH2:8]([O:15][C:16](=[O:17])[NH:18][C@H:19]1[C@@H:24]([F:25])[CH2:23][CH2:22][NH:21][CH2:20]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](F)[C@H](NC(=O)OCc2ccccc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(N[C@@H]1CNCC[C@@H]1F)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
4N HCl in dioxane (3.29 mL, 13.2 mmol) was added to a solution of cis-tert-butyl 3-(benzyloxycarbonylamino)-4-fluoropiperidine-1-carboxylate (0.58 g, 1.65 mmol) in DCM (3 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo. The resulting solid was dissolved in water (5 mL) and extracted with ether (10 mL). The resulting aqueous layer was basified with 30% potassium carbonate to a pH of about 10 and extracted with DCM (2×30 mL). The combined organic layer was dried (sodium sulfate) and concentrated in vacuo to give benzyl-cis-4-fluoropiperidin-3-ylcarbamate (0.39 g, 94%) as a solid.
Reaction SMILES: [C:1]1([C:7]2[NH:12][C:11](=[O:13])[CH:10]=[C:9]([C:14]([F:17])([F:16])[F:15])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:18]N1C(=O)CCC1=O>CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>[Br:18][C:10]1[C:11](=[O:13])[NH:12][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][C:9]=1[C:14]([F:16])([F:17])[F:15]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=c1cc(C(F)(F)F)nc(-c2ccccc2)[nH]1
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Product: O=c1[nH]c(-c2ccccc2)nc(C(F)(F)F)c1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.5 %

Procedure:
To a solution of 1.0 g (3.94 mmol) of 2-phenyl-6-trifluoromethyl-4(3H)-pyrimidinone and 20 mL of glacial acetic add was added 1.0 g (5.6 mmol) N-bromosuccinimide and the mixture was left to stir at room temperature for 16 h. The reaction was poured onto ice water and vacuum filtered, washing well with water. The crude product was recrystallized from ethyl acetate to yield 1.05 g (83.5%) of 5-bromo-2-phenyl-6-trifluoromethyl-4(3H)-pyrimidinone, as a white solid. 1H-NMR (d6DMSO) δ 7.6(3H,m); 8.15(2H,m).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](Cl)=[O:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([NH:19][C:20](=[O:34])[C:21]2[CH:26]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:24]=[C:23]([F:33])[CH:22]=2)[CH:15]=[CH:16][C:17]=1[Cl:18]>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:11][C:12]2[CH:13]=[C:14]([NH:19][C:20](=[O:34])[C:21]3[CH:26]=[C:25]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[CH:24]=[C:23]([F:33])[CH:22]=3)[CH:15]=[CH:16][C:17]=2[Cl:18])=[O:9])=[CH:4][CH:3]=1
Reactant: Nc1cc(NC(=O)c2cc(F)cc(N3CCOCC3)c2)ccc1Cl
Reactant: O=C(Cl)c1ccc(Cl)nc1
Product: O=C(Nc1ccc(Cl)c(NC(=O)c2ccc(Cl)nc2)c1)c1cc(F)cc(N2CCOCC2)c1
Yield: 48 %

Procedure:
Using an analogous procedure to that described in Example 2, 6-chloropyridine-3-carbonyl chloride was reacted with N-(3-amino-4-chlorophenyl)-3-fluoro-5-morpholinobenzamide to give the title compound in 48% yield; NMR Spectrum: (DMSOd6) 3.23 (m, 4H), 3.74 (m, 4H), 6.97 (d, 1H), 7.12 (d, 1H), 7.26 (s, 1H), 7.54 (d, 1H), 7.71 (d, 2H), 8.07 (s, 1H), 8.35 (d, 1H), 8.95 (s, 1H), 10.37 (m, 2H); Mass Spectrum: M+H+ 487.
Reaction SMILES: C1(O[C:8](=[O:27])[NH:9][C:10]2[S:11][C:12]3[C:13]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:14][CH:15]=[C:16]([O:19][CH3:20])[C:17]=3[N:18]=2)C=CC=CC=1.[CH3:28][NH:29][C@@H:30]1[CH2:35][CH2:34][C@H:33]([OH:36])[CH2:32][CH2:31]1>ClC(Cl)C.O1CCCC1>[OH:36][C@@H:33]1[CH2:34][CH2:35][C@H:30]([N:29]([CH3:28])[C:8]([NH:9][C:10]2[S:11][C:12]3[C:13]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:14][CH:15]=[C:16]([O:19][CH3:20])[C:17]=3[N:18]=2)=[O:27])[CH2:31][CH2:32]1
Reactant: CN[C@H]1CC[C@@H](O)CC1
Reactant: COc1cnc(N2CCOCC2)c2sc(NC(=O)Oc3ccccc3)nc12
Solvent: CC(Cl)Cl
Solvent: C1CCOC1
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)N(C)[C@H]3CC[C@@H](O)CC3)nc12

Procedure:
From (7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-yl)-carbamic acid phenyl ester with cis-4-Methylamino-cyclohexanol in dichloroethane and tetrahydrofuran. ES-MS m/e (%): 422 (M+H+, 100).
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([NH2:23])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:24]1([S:27](Cl)(=[O:29])=[O:28])[CH2:26][CH2:25]1.C(O)(C(F)(F)F)=O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([NH:23][S:27]([CH:24]3[CH2:26][CH2:25]3)(=[O:29])=[O:28])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CC(C)(C)c1nc2cc(N)ccc2n1CC1CCC(F)(F)CC1
Agent: CN(C)c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)c1nc2cc(NS(=O)(=O)C3CC3)ccc2n1CC1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-amine (300 mg, 0.934 mmol) and DMAP (115 mg, 0.934 mmol) were dissolved in 10 mL of DCM. Cyclopropanesulfonyl chloride (170 mg, 1.21 mmol) was added and the solution was stirred at rt for 2 h. The solution was washed with saturated aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. The product was purified by silica gel flash chromatography using EtOAc as eluent. The fractions were concentrated and the residue was dissolved in 25 mL of MeOH. TFA (0.143 mL, 1.86 mmol) was added dropwise and the solution was stirred at rt for 30 min. The solvent was evaporated and the product was precipitated in ether affording the title compound as its corresponding TFA salt. Yield: 390 mg (77%). 1H NMR (400 MHz, METHANOL-D4) δ 0.91-0.97 (m, 2 H), 1.02-1.08 (m, 2 H), 1.48-1.60 (m, 2 H), 1.65 (s, 9 H), 1.67-1.75 (m, 3 H), 1.75-1.82 (m, 1 H), 2.00-2.10 (m, 2 H), 2.18-2.28 (m, 1 H), 2.53-2.61 (m, 1 H), 4.50 (d, J=7.42 Hz, 2 H), 7.42 (dd, J=8.98, 2.15 Hz, 1 H), 7.74 (d, J=1.56 Hz, 1 H), 7.85 (d, J=8.79 Hz, 1 H); MS (ESI) (M+H)+ 426.0; Anal. Calcd (%) for C21H29N3O2SF2+1.0 TFA; C, 51.20; H, 5.60; N, 7.79. Found: C, 51.38; H, 5.66; N, 7.56.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([O:9][CH3:10])=[O:8].[Cl-].[Al+3].[Cl-].[Cl-].Cl[CH:16]([O:18]C)Cl>ClCCCl.[N+](C)([O-])=O>[CH:16]([C:5]1[CH:4]=[C:3]([C:7]([O:9][CH3:10])=[O:8])[N:2]([CH3:1])[CH:6]=1)=[O:18]
Reactant: COC(Cl)Cl
Reactant: COC(=O)c1cccn1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: ClCCCl
Product: COC(=O)c1cc(C=O)cn1C

Procedure:
To a mixture of methyl 1-methylpyrrole-2-carboxylate (5.0 g, 0.036 m) and 11.4 g anhydrous aluminum chloride in 150 ml of 1:1 1,2-dichloroethane and nitromethane at -20° C. was added over two minutes a solution of dichloromethyl methylether (3.9 ml, 0.043 m) in 1,2-dichloroethane (20 ml). The resultant mixture was stirred at -10° to -30° C. for 3 hours, quenched with excess ice-water, the resultant mixture extracted well with ether, and the combined ether extracts washed two times with water, passed through a small layer of sodium sulfate-silica gel, and concentrated in vacuo to 5.4 g (90%) of methyl 4-formyl-1-methylpyrrole-2-carboxylate, m.p. 95°-97° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[F:18][C:19]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:20]=1[CH2:21][C:22]1[O:26][N:25]=[C:24]([C:27](O)=[O:28])[CH:23]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:12]1[CH2:17][CH2:16][N:15]([C:27]([C:24]2[CH:23]=[C:22]([CH2:21][C:20]3[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:19]=3[F:18])[O:26][N:25]=2)=[O:28])[CH2:14][CH2:13]1
Reactant: O=C(O)c1cc(Cc2cc(F)ccc2F)on1
Reactant: Clc1ccc2[nH]cc(C3CCNCC3)c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cc(Cc2cc(F)ccc2F)on1)N1CCC(c2c[nH]c3ccc(Cl)cc23)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 36.4 %

Procedure:
The mixture of 5-chloro-3-(piperidin-4-yl)-1H-indole hydrochloride (0.070 g; 0.258 mmol), 5-(2,5-difluorobenzyl)isoxazole-3-carboxylic acid (0.062 g; 0.258 mmol), HART (N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate) (0.098 g: 0.258 mmol) and N,N-diisopropylethylamine (0.113 mL; 0.634 mmol) in DMF (3 mL) was stirred for 72 hours at room temperature and was concentrated under reduced pressure. The residue was dissolved in dichloromethane and the organic layer was washed with water and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluent: 0 to 10% of ethyl acetate in dichloromethane) to give 0.0428 g (36%) of (4-(5-chloro-1H-indol-3-yl)piperidin-1-yl)(5-(2,5-difluorobenzyl)isoxazol-3-yl)methanone as a white solid.
Reaction SMILES: CC([O-])(C)C.[K+].[Br:7][C:8]1[CH:9]=[CH:10][C:11]([F:26])=[C:12]([C:14]([NH:21][C:22](=[O:25])[CH2:23]Cl)([CH:18]([F:20])[F:19])[CH2:15][CH2:16][OH:17])[CH:13]=1>CC(O)(C)C.C1COCC1>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([F:26])=[C:12]([C:14]2([CH:18]([F:20])[F:19])[CH2:15][CH2:16][O:17][CH2:23][C:22](=[O:25])[NH:21]2)[CH:13]=1
Reactant: O=C(CCl)NC(CCO)(c1cc(Br)ccc1F)C(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: O=C1COCCC(c2cc(Br)ccc2F)(C(F)F)N1

Procedure:
To a refluxing solution of potassium tert-butylate (1.63 g, 14.52 mmol) in 555 ml t-BuOH was added dropwise a solution of) N-[1-(5-bromo-2-fluoro-phenyl)-1-difluoromethyl-3-hydroxy-propyl]-2-chloro-acetamide (2.72 g, 7.26 mmol) in 45 ml THF over a period of 40 minutes. The reaction mixture was cooled down and quenched with 1N HCl. EtOAc was added and the organic layer was washed with brine, dried with Na2SO4 and evaporated. The crude product was crystallized from DCM/TBME to provide the title compound as white crystals.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:18]=[CH:17][C:13]([CH:14]=[N:15][OH:16])=[CH:12][CH:11]=1>CN(C=O)C>[F:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([Cl:1])=[N:15][OH:16])=[CH:12][CH:11]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: ON=Cc1ccc(F)cc1
Solvent: CN(C)C=O
Product: ON=C(Cl)c1ccc(F)cc1
Temperature: 40 °C
Yield: 68.7 %

Procedure:
N-Chlorosuccinimide (85.5 g, 438 mmol) was added to a solution of 4-fluorobenzaldehyde oxime (61.0 g, 438 mmol) in DMF (100 mL) at room temperature; an exotherm occurred. After the addition, the solution was heated at 40° C. for 30 minutes under nitrogen. The solution was poured onto ice and extracted with chloroform. The combined extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure, and further dried under high vacuum for 16 hours to provide 52.23 g of 4-fluoro-N-hydroxybenzenecarboximidoyl chloride as an amber oil.
Reaction SMILES: [Br:1][C:2]1[N:3]([CH3:19])[C:4]2[C:9]([C:10]=1[CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:16]([O-:18])=[O:17])[CH:5]=2.[CH:20]1(C2C3C(=CC(C([O-])=O)=CC=3)N(C)C=2)[CH2:24]CC[CH2:21]1.BrBr>>[Br:1][C:2]1[N:3]([CH3:19])[C:4]2[C:9]([C:10]=1[CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:16]([O:18][CH:20]([CH3:24])[CH3:21])=[O:17])[CH:5]=2
Reactant: Cn1cc(C2CCCC2)c2ccc(C(=O)[O-])cc21
Reactant: Cn1c(Br)c(C2CCCC2)c2ccc(C(=O)[O-])cc21
Agent: BrBr
Product: CC(C)OC(=O)c1ccc2c(C3CCCC3)c(Br)n(C)c2c1

Procedure:
This process identified the optimal conditions for the synthesis of 2-bromo-3-cyclopentyl-1-methyl-1H-indole-6-carboxylate via bromination of the corresponding 3-cyclopentyl-1-methyl-1H-indole-6-carboxylate with bromine. It's very important to control the reaction temperature and to quench the reaction mixture with a mixture of aqueous sodium thiosulfate and 4-methylmorpholine to minimize the formation of the dibromo- and 2-indolone impurities. Further neutralization of the crude product with NaOH in isopropanol greatly increases the stability of the isolated product.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[F:6][C:7]([F:24])([F:23])[CH:8]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][C:11]2[CH:19]=[CH:20][CH:21]=[CH:22][C:10]=2[O:9]1>>[Cl:1][S:2]([C:20]1[CH:21]=[CH:22][C:10]2[O:9][CH:8]([C:7]([F:24])([F:23])[F:6])[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][C:11]=2[CH:19]=1)(=[O:5])=[O:3]
Reactant: O=S(=O)(O)Cl
Reactant: CCOC(=O)C1=Cc2ccccc2OC1C(F)(F)F
Product: CCOC(=O)C1=Cc2cc(S(=O)(=O)Cl)ccc2OC1C(F)(F)F
Temperature: -15 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
Chlorosulfonic acid (50.0 mL) was cooled to 15° C. and ethyl 2-trifluoromethyl-2H-1-benzopyran-3-carboxylate (Example 10, Step 2) (6.21 g, 22.83 mmol) was added. After stirring at −15° C. for 1 hour, the solution was warmed to room temperature and stirred for 16 hours. The solution was added dropwise onto ice (500 mL) with vigorous stirring and extracted with diethyl ether (2×250 mL). The ether layers were combined, washed with water (2×250 mL), saturated sodium bicarbonate (2×250 mL), and brine (2×250 mL). Hexanes (50 mL) were added and the solution was dried over sodium sulfate. The solvent was removed in vacuo to afford the ester as a yellow solid (7.41 g, 87%): mp 97.2–98.4° C. 1H NMR (CDCl3, 300 MHz) 7.97 (dd, 1H, J=8.6, 2.2. Hz), 7.92 (d, 1H, J=2.2 Hz), 7.73 (s, 1H), 7.17 (d, 1H, J=2.2 Hz), 5.82 (qH-F, 1H, J=7.2 Hz), 4.28–4.39 (m, 2H), 1.35 (t, 3H, J=7.0 Hz). FABLRMS m/z 376 (M+Li+).