Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:12][CH:11]=2)[CH:3]=1.[Li]CCCC.C[Si](C)(C)[O:32][C@@H:33]1[C@@H:38]([O:39][Si](C)(C)C)[C@H:37]([O:44][Si](C)(C)C)[C@@H:36]([CH2:49][O:50][Si](C)(C)C)[O:35][C:34]1=O>C1(C)C=CC=CC=1.C1COCC1.C1(C)C=CC=CC=1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C@H:34]2[C@H:33]([OH:32])[C@@H:38]([OH:39])[C@H:37]([OH:44])[C@@H:36]([CH2:49][OH:50])[O:35]2)=[CH:3][C:4]=1[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:12][CH:11]=1
Reactant: Clc1ccc(Br)cc1Cc1ccc(OCCOC2CCCC2)cc1
Reactant: C[Si](C)(C)OC[C@H]1OC(=O)[C@H](O[Si](C)(C)C)[C@@H](O[Si](C)(C)C)[C@@H]1O[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(OCCOC4CCCC4)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-1-chloro-2-(4-(2-(cyclopentyloxy)ethoxy)benzyl)benzene (Intermediate AC) (0.41 g) in anhydrous toluene/THF (v/v=2:1, 10 mL), n-BuLi (1.3 eq) was added dropwise at −78° C. and stirred for 1 h. Then the mixture was transferred to a solution of 2,3,4,6-tetra-O-trimethylsilyl-β-D-glucolactone (also called (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)tetrahydro-2H-pyran-2-one) (1.5 eq) in anhydrous toluene (10 mL) at −78° C. The mixture was stirred at −78° C. for 2 h until starting material was consumed. The reaction was quenched with methanesulfonic acid (0.3 g in 10 mL MeOH), and the mixture was allowed to warm to room temperature and stirred overnight. Then 20 mL of water was added. The organic phase was separated, and the water phase was extracted with EtOAc. The organic phases were combined, washed with saturated NaHCO3, water and brine, and then dried with anhydrous Na2SO4, filtered and concentrated. The residue was purified on a flash column (0.8 g, Rf=0.1-0.2, EA:PE=2:1) to collect the crude product. The crude product was dissolved in anhydrous CH3CN (10 mL), Et3SiH (1 mL) was added, the mixture was cooled to −5° C., and BF3.Et2O (0.6 mL) was added dropwise. Then the reaction was allowed to warm to 20° C. and stirred overnight. After the reaction reached completion, it was quenched with saturated aqueous NaHCO3. The solvent was removed under reduced pressure and the residue was extracted with EtOAc and washed with water and brine. The product was dried with anhydrous Na2SO4, filtered, concentrated to a solid, and purified by preparative HPLC to obtain compound AD as a white powder upon freeze-drying. 1H NMR (CD3OD): δ 7.30 (m, 3H), 7.11 (d, J=8.8 Hz, 2H), 6.87 (d, J=8.8 Hz, 2H), 4.07 (m, 5H), 3.87 (s, 1H), 3.71 (m, 3H), 3.15 (m, 1H), 3.10 (m, 2H), 3.07 (m, 6H), 1.72 (m, 6H), 1.55 (m, 2H); MS ESI (m/z): 494 (M+H)+, calc. 493.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](Cl)[CH:3]=1.CCOCC.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[N:14]1([C:4]2[CH:3]=[C:2]([NH2:1])[CH:7]=[CH:6][N:5]=2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: C1COCCN1
Reactant: Nc1ccnc(Cl)c1
Solvent: CCOCC
Product: Nc1ccnc(N2CCOCC2)c1
Temperature: 200 °C
Reaction time: 0.17 h

Procedure:
A stirred mixture of 45.8 g (356 mmol) 4-amino-2-chloropyridine in 124 ml morpholine was heated at 200° C. for 30 min in a microwave oven. The resulting yellow solution was then cooled to room temperature whereupon crystals appeared. 400 ml ether was then added and the suspension stirred for 10 minutes before being filtered. The filter cake was washed with ether and dried to afford 92.9 g of crystalline material (87% yield of desired product) which 1H NMR analysis revealed to comprise 60 wt % 2-morpholin-4-yl-pyridin-4-ylamine and 40 wt % morpholine. This material was used in the next step without any further purification. ES-MS m/e (%): 180 (M+H+, 100).
Reaction SMILES: [C@H:1]12[CH2:17][C@H:4]([N:5]([C:7]3[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=3[F:16])[CH2:6]1)[CH2:3][O:2]2.C1COCC1.O.C([O-])([O-])=O.[K+].[K+].Cl[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32]>[Pd].CC#N.C(Cl)(Cl)Cl.C(O)(=O)C>[C:31]([NH:13][C:10]1[CH:11]=[CH:12][C:7]([N:5]2[CH2:6][C@@H:1]3[CH2:17][C@H:4]2[CH2:3][O:2]3)=[C:8]([F:16])[CH:9]=1)([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32]
Reactant: O=[N+]([O-])c1ccc(N2C[C@@H]3C[C@H]2CO3)c(F)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: O=C(Nc1ccc(N2C[C@@H]3C[C@H]2CO3)c(F)c1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
A solution of 4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-3-fluoronitrobenzene (0.160 g, 0.672 mmol) in 3:1 THF/H2O (4 mL) was treated with acetic acid (0.115 mL) and then 10% palladium/carbon (0.020 g) under a N2 stream. The atmosphere was replaced with H2 (balloon) by repeated evacuation and filling and the mixture stirred at ambient temperature. After 2 h, TLC analysis (6% CH3CN/CHCl3) revealed the reduction to be complete. The reaction mixture was filtered through Celite® and the filtrate immediately placed under an atmosphere of N2 and treated with K2CO3 (0.464 g, 3.36 mmol) followed by benzyl chloroformate (0.117 mL, 0.864 mmol). TLC analysis (6% CH3CN/CHCl3) after 0.5 h revealed the reaction to be complete. The reaction mixture was concentrated under reduced pressure and chromatographed over silica gel (20 g), eluting with a gradient of 1-5% CH3CN/CHCl3. Concentration of appropriate fractions afforded 0.226 g (98%) of the title compound as a white solid with mp 120-121° C. and MS(EI) 342 (M+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([I:10])[C:7]([CH2:11]O)=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19].C(Br)(Br)(Br)[Br:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([I:10])[C:7]([CH2:11][Br:22])=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19]
Reactant: BrC(Br)(Br)Br
Reactant: COC(=O)c1cc(I)c(CO)cc1-c1ccccc1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cc(I)c(CBr)cc1-c1ccccc1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 113.9 %

Procedure:
To a −10° C. solution in dichloromethane of the product of Example 319E (830 mg, 2.17 mmol) and carbon tetrabromide (864 mg, 2.60 mmol) was added triphenylphosphine (626 mg, 2.39 mmol) and the reaction mixture was warmed to 0° C. over 1 hour. The cold bath was then removed and stirring was continued for 2 hours. The reaction mixture was concentrated in vacuo and purified by chromatography on silica gel (5% ethyl acetate-hexanes) to give the desired compound (1.1 g) which also contained some triphenylphosphine.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:18]#[CH:19])([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-])=O)[CH2:4][CH2:3]1.Cl.CO.C(=O)([O-])[O-].[Na+].[Na+]>CCOCC.[Fe].O>[CH3:1][N:2]1[CH2:3][CH2:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:15])([C:18]#[CH:19])[CH2:6][CH2:7]1
Reactant: C#CC1(Oc2ccccc2[N+](=O)[O-])CCN(C)CC1
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CCOCC
Solvent: O
Product: C#CC1(Oc2ccccc2N)CCN(C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
A suspension of 1-methyl-4-ethynyl-4-(2-nitrophenoxy)piperidine (liberated from 10.0 g of the hydrochloride), 140 ml of methanol, 40 ml of water, 10 ml of conc hydrochloric acid and 20 g of iron (reduced electroytic) was stirred for 0.5 hr at 45° under nitrogen. The mixture was allowed to cool to room temperature, poured into saturated sodium carbonate solution, extracted twice with ether; dried over anhydrous potassium carbonate, filtered, and the solvent was evaporated to provide an oil. The oil was dissolved in ether. Precipitation with ethereal hydrogen chloride provided 8.59 g (83%) of product. Recrystallization from ethanol provided the analytical sample.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2.[F:16][C:17]1[C:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O>>[F:16][C:17]1[C:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[CH:21][CH:20]=[CH:19][C:18]=1[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2
Reactant: OB(O)c1cccc(-c2ccccn2)c1F
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2n1
Product: Fc1c(-c2ccccn2)cccc1-c1ccnc2nc(C(F)(F)F)ccc12
Yield: 20.9 %

Procedure:
5-Chloro-2-trifluoromethyl[1,8]naphthyridine (50 mg, 0.22 mmol) was coupled to 2-fluoro-3-(pyridin-2-yl)benzeneboronic acid (61 mg, 0.28 mmol) as described in Example 7 part g), affording 5-(2-fluoro-3-pyridin-2-ylphenyl)-2-trifluoromethyl[1,8]naphthyridine (17 mg, 21%). δH (360 MHz, CDCl3) 7.30-7.36 (1H, m), 7.42-7.55 (2H, m), 7.66 (1H, d, J 4.2), 7.77-7.83 (3H, m), 8.19 (1H, td, J 7.6 and 2.1), 8.38 (1H, dd, J 2.3 and 8.6), 8.78 (1H, dt, J 4.9 and 1.4), 9.33 (1H, d, J 4.2). m/z (ES+) 370 [MH]+.
Reaction SMILES: OC(C(F)(F)F)=O.[F:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1[O:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:19]=[C:20]3[CH2:31][CH2:30][NH:29][CH2:28][C:21]3=[N:22][C:23]=2[NH:24][CH:25]([CH3:27])[CH3:26])[CH2:14][CH2:13]1.C(N(CC)CC)C.[N:44]([CH2:47][CH2:48][O:49][CH3:50])=[C:45]=[O:46]>C(Cl)Cl>[F:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1[O:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[N:19]=[C:20]3[CH2:31][CH2:30][N:29]([C:45]([NH:44][CH2:47][CH2:48][O:49][CH3:50])=[O:46])[CH2:28][C:21]3=[N:22][C:23]=2[NH:24][CH:25]([CH3:27])[CH3:26])[CH2:16][CH2:17]1
Reactant: COCCN=C=O
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCNC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: COCCNC(=O)N1CCc2nc(N3CCC(Oc4ccc(F)cc4F)CC3)c(NC(C)C)nc2C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (39.0 mg, 0.075 mmol) in DCM (754 μL) at 0° C. was added triethylamine (31.5 μL, 0.226 mmol) and 1-isocyanato-2-methoxyethane (11.8 μL, 0.113 mmol). The reaction mixture was stirred for 1 h at 0° C. The reaction mixture was concentrated under reduced pressure and purified by HPLC Method B, with the exception that a Waters SunFire™ C18, 5 μm, ID 30×75 mm column was used, using a 45% to 70% ACN gradient to give the title compound, as a TFA salt, as a yellow oil (24.5 mg, 52.6%). 1H NMR (400 MHz, methanol-d4) δ ppm 1.32 (d, J=6.6 Hz, 6H), 1.97 (m, 2H), 2.14 (m, 2H), 2.77 (t, J=5.8 Hz, 2H), 3.12 (m, 2H), 3.37 (m, 5H), 3.46 (m, 4H), 3.71 (t, J=5.8 Hz, 2H), 4.13 (m, 1H), 4.50 (m, 3H), 6.88 (m, 1H), 6.98 (ddd, J=11.2, 8.5, 3.0 Hz, 1H), 7.17 (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 505.6.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:19]([Cl:20])=[CH:18][C:10]3[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[O:13][C:9]=3[C:8]=2[Cl:21])[N:5]=[C:4]([C:22]#[N:23])[CH:3]=1.[F:24][C:25]([F:30])([F:29])[S:26]([O-])=O.[Na+].S(C1C=CC(C)=CC=1)(O)(=O)=O.CNC.S(Cl)(Cl)=O>C1(C)C=CC=CC=1.O>[NH2:1][C:2]1[N:6]([C:7]2[C:19]([Cl:20])=[CH:18][C:10]3[C:11]([F:16])([F:17])[C:12]([F:14])([F:15])[O:13][C:9]=3[C:8]=2[Cl:21])[N:5]=[C:4]([C:22]#[N:23])[C:3]=1[S:26][C:25]([F:30])([F:29])[F:24]
Reactant: O=S([O-])C(F)(F)F
Reactant: N#Cc1cc(N)n(-c2c(Cl)cc3c(c2Cl)OC(F)(F)C3(F)F)n1
Agent: CNC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: N#Cc1nn(-c2c(Cl)cc3c(c2Cl)OC(F)(F)C3(F)F)c(N)c1SC(F)(F)F
Temperature: 55 °C
Reaction time: 10 h
Yield: 24.6 %

Procedure:
To a suspension wherein 5-amino-3-cyano-1-(5,7-dichloro-2,2,3,3-tetrafluoro-2,3-dihydrobenzofuran-6-yl)pyrazole (734 mg, 2.00 mmol), sodium trifluoromethanesulfinate (624 mg, 4.00 mmol) and dimethylamine tosylate (1.086 g, 5.00 mmol) are in toluene (5 ml), thionyl chloride (476 mg, 2.00 ml) was added dropwise under ice cooling over a period of about 10 minutes and then stirred at 50 to 60° C. for 10 hours. After allowing time to cool, the reaction solution was poured into water, extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was subjected to silica gel column chromatography to give 230 mg of 5-amino-3-cyano-1-(5,7-dichloro-2,2,3,3-tetrafluoro-2,3-dihydrobenzofuran-6-yl)-4-trifluoromethylsulfenylpyrazole.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([O:20][CH2:21][CH3:22])[C:17]([OH:19])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:24][C@H:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:26][OH:27].OS(O)(=O)=O.[OH-].[Na+]>CN(C1C=CN=CC=1)C.CCOC(C)=O.C(Cl)CCl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH:16]([O:20][CH2:21][CH3:22])[C:17]([NH:24][C@H:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:26][OH:27])=[O:19])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Reactant: N[C@@H](CO)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CCOC(Cc1ccc(OCc2ccccc2)cc1)C(=O)N[C@@H](CO)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3-[4-(Benzyloxy)phenyl]-2-ethoxypropanoic acid (30.6 kg, 88 mol) and DMAP (12.9 kg) were dissolved in CH2CI2 (192 L) and cooled to 0° C. To the clear solution EDC×HCl (20.2 kg) was added in 10 minutes. In 18 minutes a solution of (2R)-2-amino-2-phenyl-1-ethanol (14.5 kg, 105.6 mol) in CH2CI2 (60 L) was added, keeping the temperature below 2° C. The reaction mixture was kept at 0° C. for 2 hours and then heated to reflux for ca. 3 hours. The solvent was then distilled off (110 L). EtOAc (110 L) was added and the temperature lowered to 10° C. Over 30 min 1M H2SO4 (110 L, 110 mol) was added, the phases separated and the organic phase extracted with H2SO4 (110 L, 110 mol). To the combined organic phases, 110 L EtOAc and 1 M NaOH (110 L, 110 mol) were added at 10° C. (pH 10). The phases were separated and the organic phase washed with saturated NaCl solution.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-])=O)[C:9]=2[C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>CO.[Pd]>[NH2:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:8]([CH2:7][N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[C:9]=1[C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11]
Reactant: O=C(Nc1ccccc1)c1c(CN2CCOCC2)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(CN2CCOCC2)c1C(=O)Nc1ccccc1

Procedure:
A solution of compound 7 (0.3 g) and 10% Pd/C (30 mg) in methanol (35 mL) was stirred under hydrogen (1 atm) for 1.5 h. The mixture was filtered through a bed of CELITE® and the filtrate was concentrated to provide a yellow solid product, intermediate compound 2. ESI-MS m/z=312 (MH+).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20]([C:23]4[CH:28]=CC=[CH:25][CH:24]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].N1CCC(C2C3C(=C(C(N)=O)C=C(C4C=C[S:49]C=4)C=3)NC=2)CC1.C(N(CC)CC)C.ClCCCS(Cl)(=O)=O>>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20]([C:23]4[CH:24]=[CH:25][S:49][CH:28]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)(=[O:6])=[O:7]
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Reactant: NC(=O)c1cc(-c2ccsc2)cc2c(C3CCNCC3)c[nH]c12
Agent: O=S(=O)(Cl)CCCCl
Solvent: CCN(CC)CC
Product: NC(=O)c1cc(-c2ccsc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Yield: 37 %

Procedure:
The title compound was prepared according to the general procedure for intermediate 11. 3-(4-piperidinyl)-5-(3-thienyl)-1H-indole-7-carboxamide (220 mg, 0.67 mmol) was reacted with triethyl amine (0.4 mL, 2.68 mmol) and 3-chloropropylsulfonyl chloride (0.12 mL, 1.01 mmol) to give the title compound (117 mg, 37%)
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:12][NH2:13])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:14]([C:17](=[CH:23]N(C)C)[C:18]([O:20][CH2:21][CH3:22])=[O:19])(=O)[CH3:15]>C(O)C>[CH2:21]([O:20][C:18]([C:17]1[CH:23]=[N:13][N:12]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:11])([F:9])[F:10])=[CH:5][N:4]=2)[C:14]=1[CH3:15])=[O:19])[CH3:22]
Reactant: NNc1ncc(C(F)(F)F)cc1Cl
Reactant: CCOC(=O)C(=CN(C)C)C(C)=O
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2ncc(C(F)(F)F)cc2Cl)c1C
Temperature: 25 °C
Yield: 69.8 %

Procedure:
A stirred solution of 44.0 grams (0.21 mole) of 3-chloro-5-trifluoromethylpyridin-2-ylhydrazine and 38.6 grams (0.21 mole) of ethyl 2-acetyl-3-dimethylaminoacrylate, prepared by the method of J. R. Beck et al., J. Het. Chem., 24, 693 (1987), in 1000 mL of ethanol was heated at reflux for five hours. After this time, the reaction mixture was cooled to ambient temperature and concentrated under reduced pressure to a residual oil. The oil was taken up in methylene chloride and washed in succession with two 100 mL portions of aqueous 10% hydrochloric acid, an aqueous solution saturated with sodium bicarbonate, and water. The organic layer was dried and filtered. The filtrate was concentrated under reduced pressure, yielding 48.9 grams of 4-ethoxycarbonyl-5-methyl-1-(3-chloro-5-trifluoromethylpyridin-2-yl)-1H-pyrazole. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: C(O[C:9](=[O:32])[CH:10]([N:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](=[O:31])C(Cl)(Cl)Cl)[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])C1C=CC=CC=1.[Cl:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][C:41]=1[Cl:42])[CH2:37][NH2:38].C(N(CC)CC)C.Cl>CN(C)C=O>[CH2:14]([O:13][C:11]([CH:10]1[N:21]2[CH:25]=[CH:24][CH:23]=[C:22]2[C:26](=[O:31])[N:38]([CH2:37][C:36]2[CH:39]=[CH:40][C:41]([Cl:42])=[C:34]([Cl:33])[CH:35]=2)[C:9]1=[O:32])=[O:12])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(OCc1ccccc1)C(C(=O)OCc1ccccc1)n1cccc1C(=O)C(Cl)(Cl)Cl
Reactant: NCc1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)C1C(=O)N(Cc2ccc(Cl)c(Cl)c2)C(=O)c2cccn21
Temperature: 70 °C
Reaction time: 2 h
Yield: 59.5 %

Procedure:
A mixture of 2-(2-trichloroacetylpyrrol-1-yl)malonic acid dibenzyl ester (30.0 g), 3,4 dichlorobenzylamine (11.7 g) and triethylamine (18.4 g, 25.0 ml) in anhydrous dimethylformamide (70 ml) was stirred under the stream of nitrogen at 70° C. for 2 hours. After cooling, the reaction mixture was poured into 5% hydrochloric acid and extracted with ethyl acetate. The extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on silica gel using n-hexane/ethyl acetate (3:1) as the eluent. Fractions containing the title compound were pooled and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to give the title compound (16.0 g, 59.5%) as colorless crystals, mp 104°-106° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:13][C:14]([NH2:16])=[NH:15])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:17]([O:21][C:22](=[O:37])/[C:23](/O)=[C:24](\[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)/[C:25](O)=[O:26])([CH3:20])([CH3:19])[CH3:18].C[O-].[Na+]>CO.ClCCl>[C:17]([O:21][C:22]([C:23]1[C:24]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:25]([OH:26])[N:16]=[C:14]([CH2:13][C:8]2([C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)[CH2:12][CH2:11][CH2:10][CH2:9]2)[N:15]=1)=[O:37])([CH3:20])([CH3:18])[CH3:19]
Reactant: N=C(N)CC1(c2ccc(Br)cc2)CCCC1
Reactant: CC(C)(C)OC(=O)/C(O)=C(\OCc1ccccc1)C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)c1nc(CC2(c3ccc(Br)cc3)CCCC2)nc(O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.5 %

Procedure:
To a mixture of the HCl-salt of 2-[1-(4-bromophenyl)-cyclopentyl]-acetamidine (229) (6.5 g, 20.47 mmol) and (E)-2-benzyloxy-3-hydroxy-but-2-enedioic acid 4-tert-butyl ester 1-methyl ester (4) (9.47 g, 30.71 mmol) in methanol (100 mL) was added sodium methoxide (3.32 g, 23.73 mmol, 25% in methanol) at 0° C. Then the reaction mixture was allowed to warm to room temperature and was stirred for 16 h. After completion of the reaction, solvent was reduced and the crude product was dissolved in dichloromethane (150 mL). The organic part was washed with 1N HCl, separated and dried over Na2SO4. After evaporation, the crude product was purified by 100-200 silica gel column chromatography using 20% ethyl acetate in hexane as the eluent to give 5-benzyloxy-2-[1-(4-bromophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid tert-butyl ester (230) (7.9 g, 71%) as a yellow solid.
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]2[O:20][C:21]([C:24](Cl)=[O:25])=[CH:22][CH:23]=2)=[N:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C1COCC1>[CH2:3]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]2[O:20][C:21]([C:24](=[O:25])[NH:2][CH3:1])=[CH:22][CH:23]=2)=[N:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(Cl)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2.97 ml (5.94 mmol) of a 2 M solution of methylamine in THF were initially charged in 20 ml of THF, and a solution of 0.8 g (2.4 mmol) of 1-benzyl-3-(5-chlorocarbonyl-2-furyl)indazole in 10 ml of THF was added dropwise at RT. After 1 h, the mixture was poured into ice-water and the oil that separated off was extracted with ethyl acetate. The organic phase was washed with 1 N hydrochloric acid, dried and concentrated using a rotary evaporator. The crude product was recrystallized from isopropanol. This gave 0.44 g (55%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](O)=[O:29])=[CH:24][N:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[F:64][C:65]1[CH:72]=[C:71]([C:73]([F:76])([F:75])[F:74])[CH:70]=[CH:69][C:66]=1[CH2:67][NH2:68]>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](=[O:29])[NH:68][CH2:67][C:66]4[CH:69]=[CH:70][C:71]([C:73]([F:74])([F:75])[F:76])=[CH:72][C:65]=4[F:64])=[CH:24][N:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(C(=O)O)cn3)c2CC1
Reactant: NCc1ccc(C(F)(F)F)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(C(=O)NCc4ccc(C(F)(F)F)cc4F)cn3)c2CC1
Temperature: 40 °C
Reaction time: 8 h
Yield: 97814.2 %

Procedure:
Dissolve 3-tert-butoxycarbonyl-6-(5-carboxypyridin-2-ylmethylthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (300 mg, 0.67 mmol) in DMF (5.0 mL). Treat successively with HATU (305 mg, 0.802 mmol), N,N-diisopropylethylamine (140 μL, 0.804 mmol) and 2-fluoro-4-(trifluoromethyl)benzylamine (260 mg, 1.34 mmol). Stir overnight at 40° C. Dilute the mixture with water, extract three times with EtOAc, dry over anhydrous Na2SO4, and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (3:1) to give 3-tert-butoxycarbonyl-7-chloro-6-[5-(2-fluoro-4-trifluoromethyl-benzylcarbamoyl)-pyridin-2-ylmethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a foam (409 g, 98%). Use a method similar to the General Procedure 1-4 to give, after basic work-up and a method similar to the General Procedure 2-1, the title compound as an off-white solid. MS (APCI+) m/z: 524 (M+H)+.