Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:3]=1.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([CH2:41][C:42]2[CH:43]=[C:44](B(O)O)[C:45]([F:48])=[N:46][CH:47]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].C([O-])(=O)C.[K+].CC(N)CC1C=CC=CC=1.OP(O)(O)=O.O1CCOCC1.O.ClC1N=C(C)N=C2C=1N=CN2C1CCCCO1>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:4]2[N:5]=[C:6]([CH3:8])[N:7]=[C:2]([C:44]3[CH:43]=[C:42]([CH2:41][N:38]4[CH2:39][CH2:40][N:35]([C:33]([O:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:34])[CH2:36][CH2:37]4)[CH:47]=[N:46][C:45]=3[F:48])[N:3]=2)=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cnc(F)c(B(O)O)c2)CC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(Cl)n2)cc1
Agent: Cl[Pd]Cl
Agent: CC(=O)[O-]
Agent: CC(N)Cc1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(C(=O)OC(C)(C)C)CC4)cnc3F)n2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
A mixture of 4-chloro-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (Example 51) (20 g, 52.0 mmol), 5-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-2-fluoropyridin-3-ylboronic acid (Example 34, Step 3) (21.15 g, 62.4 mmol), potassium acetate (8.12 mL, 130 mmol), and Amphos (bis(di-tert-butyl (4-dimethylaminophenyl)phosphine)dichloropalladium(II) (Aldrich, St. Louis, Mo.) (1.913 g, 2.70 mmol) in p-dioxane (300 mL, 3528 mmol) and water (60 mL, 52.0 mmol) contained in a 1 L 3 neck round-bottomed flask was stirred at 100° C. overnight. The solution was partitioned between water and EtOAc and the organic layer was separated, washed with water, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product which was adsorbed onto silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (Teledyne ISCO, Lincoln, Nebr.) (330 g) eluting with a gradient of 10% to 50% EtOAc in hexane to give tert-butyl 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-fluoropyridin-3-yl)methyl)piperazine-1-carboxylate (25.2 g, 39.1 mmol, 75% yield). m/z (ESI, positive ion) m/z 644 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:6](O)=[O:7].C(Cl)(=O)C([Cl:30])=O>C(Cl)Cl.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:6]([Cl:30])=[O:7]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)cc1OC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)Cl)cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.3 %

Procedure:
To a mixture of 30.0 g of product from Example 47 in 300 ml of methylene chloride and 10 drops of dimethylformamide is added dropwise 15.67 g of oxalyl chloride. The reaction is stirred at room temperature for 18 hours and concentrated in vacuo. The residue is crystallized from diethyl ether to give 31.3 g of the desired product as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[S:17][CH2:16][CH2:15][C:14]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([CH2:27]O)=[CH:23][CH:22]=4)=[O:19])=[CH:13][C:12]=3[CH:29]=2)=[CH:4][CH:3]=1.CN([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1)C.CS(Cl)(=O)=O.N1CCCCC1>O1CCCC1.C(N(CC)CC)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[S:17][CH2:16][CH2:15][C:14]([C:18]([NH:20][C:21]4[CH:22]=[CH:23][C:24]([CH2:27][N:34]5[CH2:35][CH2:36][CH2:37][CH2:38][CH2:33]5)=[CH:25][CH:26]=4)=[O:19])=[CH:13][C:12]=3[CH:29]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CO)cc2)CCS3)cc1
Reactant: CN(C)c1ccccn1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: C1CCNCC1
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN4CCCCC4)cc2)CCS3)cc1
Reaction time: 0.17 h

Procedure:
To a solution of 7-(4-methylphenyl)-N-(4-hydroxymethylphenyl)-2,3-dihydro-1-benzothiepine-4-carboxamide (0.2 g), triethylamine (0.21 ml) and dimethylaminopyridine (catalytic amount) in tetrahydrofuran (10 ml) was dropwise added methane-sulfonylchloride (0.06 ml) under ice-cooling, and the mixture was stirred for 10 minutes. To the mixture was added piperidine (0.15 ml), and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated, and to the residue was added water. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column (methanol/triethylamine/ethyl acetate) to give crude crystals, which were recrystallized from ethyl acetate-hexane to give 7-(4-methylphenyl)-N-(4-piperidinomethylphenyl)-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 93) (0.19 g) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C@@H:6]1[NH2:13])=[O:4].[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(O)(=O)C>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C@@H:6]1[NH:13][CH2:19][C:18]1[CH:21]=[CH:22][C:15]([F:14])=[CH:16][CH:17]=1)=[O:4]
Reactant: COC(=O)[C@@H]1CCCCCC[C@@H]1N
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)[C@@H]1CCCCCC[C@@H]1NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 67.1 %

Procedure:
cis-2-Amino-cyclooctanecarboxylic acid methyl ester (0.66 g, 3.56 mmol) was dissolved in methanol (20 mL). 4-Fluoro-benzaldehyde (0.44 g, 3.56 mmol) was added followed by acetic acid (1 mL). The solution was stirred at 25° C. for 10 min. Sodium cyanoborohydride (0.56 g, 8.9 mmol) was added and the mixture was stirred at 25° C. for 16 h. The mixture was poured into 1/2 saturated aqueous sodium bicarbonate solution (150 mL). The aqueous layer was extracted with ethyl acetate (2×150 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to afford the crude product, cis-2-(4-fluoro-benzylamino)-cyclooctanecarboxylic acid methyl ester (0.7 g, 2.39 mmol, 67%), as a clear oil. LC-MS (ESI) calcd for C17H24FNO2 293.18, found 294.3 [M+H+].
Reaction SMILES: CC(C)([O-])C.[K+].Cl.[Cl:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH2:15][NH:14][CH2:13][CH2:12]2.Br[C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[C:23]([NH:30][C:31](=[O:37])[CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[C:22]([Cl:38])[CH:21]=1>C1(C)C=CC=CC=1>[Cl:38][C:22]1[CH:21]=[C:20]([N:14]2[CH2:13][CH2:12][C:11]3[C:16](=[CH:17][CH:18]=[C:9]([Cl:8])[CH:10]=3)[CH2:15]2)[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[C:23]=1[NH:30][C:31](=[O:37])[CH2:32][C:33]([CH3:35])([CH3:34])[CH3:36]
Reactant: Clc1ccc2c(c1)CCNC2
Reactant: CC(C)(C)CC(=O)Nc1c(Cl)cc(Br)cc1C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)(C)CC(=O)Nc1c(Cl)cc(N2CCc3cc(Cl)ccc3C2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Bis(dibenzylidineacetone)palladium (2 mg, 0.0035 mmol) and (2′-dicyclohexyl phosphanyl-biphenyl-2-yl)-dimethylamine (3.3 mg, 0.0084 mmol) were added to dry toluene (10 mL purged with argon) and stirred for 15 minutes under argon. Potassium tert-butoxide (151 mg, 1.35 mmol), 6-chloro-1,2,3,4-tetrahydroisoquinoline hydrochloride (133 mg, 0.65 mmol) and N-(4-bromo-2-chloro-6-(trifluoromethyl)phenyl)-3,3-dimethylbutanamide (200 mg, 0.54 mmol) were then added and the reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled to room temperature, concentrated and purified by thin layer chromatography (dichloromethane:methanol 5%) to afford the title compound as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH:13]1[CH2:17][CH2:16][O:15][CH2:14]1)[N:8]=[CH:7][C:6]([C:18]#[N:19])=[C:5]2[NH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[C:23]([Cl:35])[CH:22]=1.N1C=CC=CC=1.[CH2:42]1C[O:45][CH2:44][CH2:43]1.C(Cl)(=O)C=C>CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[Cl:35][C:23]1[CH:22]=[C:21]([NH:20][C:5]2[C:4]3[C:9](=[CH:10][C:11]([O:12][CH:13]4[CH2:17][CH2:16][O:15][CH2:14]4)=[C:2]([NH:1][C:44](=[O:45])[CH:43]=[CH2:42])[CH:3]=3)[N:8]=[CH:7][C:6]=2[C:18]#[N:19])[CH:26]=[CH:25][C:24]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1
Reactant: N#Cc1cnc2cc(OC3CCOC3)c(N)cc2c1Nc1ccc(OCc2ccccn2)c(Cl)c1
Reactant: C1CCOC1
Agent: C=CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C=CC(=O)Nc1cc2c(Nc3ccc(OCc4ccccn4)c(Cl)c3)c(C#N)cnc2cc1OC1CCOC1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a reaction flask were added 6-amino-4-(3-chloro-4-(pyridin-2-yl-methoxy)phenylamino)-7-(tetrahydrofuran-3-yl-oxy)quinolin-3-carbonitrile (100 mg, 0.205 mmol), pyridine (0.3 ml), DMAP (20 mg) and THF (10 ml). The mixture was cooled to the temperature of 0° C. To the mixture was added acryloyl chloride (20 mg, 0.22 mmol). The resultant mixture was stirred for 30 min at the temperature of 0° C. Then the mixture was warmed to the room temperature and stirred for 5 hr. After the reaction finished, the resultant mixture was filtered and the filtrate was rotary-evaporated to dryness to give a solid. The solid was dissolved in ethyl acetate. The solution was washed with saturated sodium carbonate once, acetic acid solutioni (10%) once and saturated saline once, successively. The resulting solution was dried over anhydrous magnesium sulfate, filtered and rotary-evaporated to dryness to give a crude prodcut. The product was purified with thin layer chromatography.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([NH:23][C:24](=[O:33])[C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=4[F:32])[CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[CH3:36][N:37]([CH2:39][C:40]1[CH:41]=[C:42]([CH:44]=[CH:45][CH:46]=1)[NH2:43])[CH3:38].Cl>O1CCOCC1.CC(O)C>[CH3:38][N:37]([CH2:39][C:40]1[CH:41]=[C:42]([NH:43][C:2]2[N:7]=[C:6]([C:8]3[C:9]([C:17]4[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([NH:23][C:24](=[O:33])[C:25]5[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=5[F:32])[CH:22]=4)=[N:10][N:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=34)[CH:5]=[CH:4][N:3]=2)[CH:44]=[CH:45][CH:46]=1)[CH3:36]
Reactant: COc1ccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)cc1NC(=O)c1c(F)cccc1F
Reactant: CN(C)Cc1cccc(N)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: COc1ccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(CN(C)C)c3)n2)cc1NC(=O)c1c(F)cccc1F
Temperature: 80 °C
Yield: 35.2 %

Procedure:
To a solution of N-[5-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]-2-(methyloxy)phenyl]-2,6-difluorobenzamide (30 mg, 0.06 mmol) in 1,4-dioxane (6 mL) and 2-propanol (3 mL) was added 3-[(dimethylamino)methyl]aniline (27 mg, 0.18 mmol) followed by 4M HCl in dioxane (0.076 ml, 0.31 mmol). After heating overnight at 80° C., the reaction was quenched with saturated NaHCO3 (25 mL), solvent removed by rotary evaporation, the aqueous layer extracted with DCM (25 mL), organic layer concentrated, and purified by column chromatography (5-50% EtOAc in hexanes) to provide the product (12.8 mg, 35%) as an off-white solid. ESIMS (M+H)+=606. 1H NMR (400 MHz, DMSO-d6) δ 2.12 (s, 6H), 3.33 (bs, 2H), 3.86 (s, 3H), 6.57 (d, 1H, J=5.49 Hz), 6.85 (d, 1H, J=7.14 Hz), 7.07-7.10 (t, J=6.78 Hz, 1H), 7.15-7.19 (m, 4H), 7.35-7.38 (m, 1H), 7.41-7.45 (m, 1H), 7.50-7.54 (m, 1H), 7.63 (d, 1H, J=6.78 Hz), 7.69 (s, 1H), 8.23 (d, 1H, J=5.49 Hz), 8.32 (s, 1H), 8.49-8.50 (m, 1H), 8.80-8.82 (m, 1H), 9.50 (s, 1H), 10.19 (s, 1H).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[O:10][C:11]([C:14]2[N:19]=[C:18](S(C)=O)[C:17]([Cl:23])=[CH:16][N:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:24]1([C:27]2[NH:31][N:30]=[C:29]([NH2:32])[CH:28]=2)[CH2:26][CH2:25]1>C(O)CCC>[C:1]([NH:5][S:6]([C:9]1[O:10][C:11]([C:14]2[N:19]=[C:18]([NH:32][C:29]3[CH:28]=[C:27]([CH:24]4[CH2:26][CH2:25]4)[NH:31][N:30]=3)[C:17]([Cl:23])=[CH:16][N:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)c1nc(-c2ccc(S(=O)(=O)NC(C)(C)C)o2)ncc1Cl
Reactant: Nc1cc(C2CC2)[nH]n1
Solvent: CCCCO
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2ncc(Cl)c(Nc3cc(C4CC4)[nH]n3)n2)o1
Temperature: 90 °C
Reaction time: 2 h
Yield: 28 %

Procedure:
The mixture of the crude N-tert-butyl-5-(5-chloro-4-(methylsulfinyl)pyrimidin-2-yl)furan-2-sulfonamide and 5-cyclopropyl-1H-pyrazol-3-amine (255 mg, 2.08 mmol, 5.0 equiv.) in n-butanol (6 mL) was stirred at 90° C. for 2 h, then, partitioned between brine and ethylacetate. The organic layer was washed over brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to afford N-tert-butyl-5-(5-chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)furan-2-sulfonamide (45 mg, 28% over 2 steps). LC-MS (m/z)=437.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]#[C:21][CH3:22])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH:5]([CH3:7])[CH3:6].Br[CH2:25][CH2:26][CH2:27][Cl:28]>>[CH3:1][O:2][C:3](=[O:23])[CH:4]([N:8]([S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]#[C:21][CH3:22])=[CH:16][CH:17]=1)(=[O:11])=[O:10])[CH2:25][CH2:26][CH2:27][Cl:28])[CH:5]([CH3:7])[CH3:6]
Reactant: ClCCCBr
Reactant: CC#CCOc1ccc(S(=O)(=O)NC(C(=O)OC)C(C)C)cc1
Product: CC#CCOc1ccc(S(=O)(=O)N(CCCCl)C(C(=O)OC)C(C)C)cc1
Yield: 75 %

Procedure:
According to the procedure of Example 5, 1.00 g (2.95 mmol) 2-(4-but-2-ynyloxy-benzenesulfonylamino)-3-methyl-butyric acid methyl ester and 0.88 mL (8.849 mmol) of 1-bromo-3-chloropropane provided 0.92 g of methyl2-[{[4-(2-butynyloxy)penyl]sulfonyl}(3-chloropropyl)amino]-3-methylbutanoate as a white solid. Electrospray Mass Spec 416.2 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.[CH3:13][C:14]1[N:15]=[CH:16][N:17]([C:19]2[S:20][CH:21]=[CH:22][C:23]=2[NH2:24])[CH:18]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([NH:24][C:23]2[CH:22]=[CH:21][S:20][C:19]=2[N:17]2[CH:18]=[C:14]([CH3:13])[N:15]=[CH:16]2)=[O:12])=[CH:7][CH:8]=1
Reactant: Cc1cn(-c2sccc2N)cn1
Reactant: COc1ccc(CC(=O)O)cc1
Product: COc1ccc(CC(=O)Nc2ccsc2-n2cnc(C)c2)cc1
Yield: 6 %

Procedure:
2-(4-methoxyphenyl)-N-(2-(4-methyl-1H-imidazol-1-yl)thiophen-3-yl)acetamide was prepared from 2-(4-methoxyphenyl)acetic acid and 2-(4-methyl-1H-imidazol-1-yl)thiophen-3-amine according to the procedure described in Example 9.7.3., above. Purification by flash column chromatography afforded the final product (silica, 75:25 ethyl acetate/hexane) (77 mg, 6%). Method [7] m/z 328.0 (M+H); retention time=1.001. 1H-NMR (CDCl3) δ 8.00 (broad s, 1H), 7.77 (d, J=6.4 Hz, 1H), 7.16 (s, 1H), 7.13 (d, J=8.7 Hz, 2H), 6.85 (d, J=8.7 Hz, 2H), 6.50 (s, 1H), 3.81 (s, 3H), 3.65 (s, 2H), 2.15 (d, J=0.9 Hz, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:25]=[CH:24][C:13]3[C@:14]4([CH3:23])[C@@H:19]([CH2:20][CH2:21][C:12]=3[CH:11]=2)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]4)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.C[Si](C([Si](C)(C)C)(C(F)(F)F)C(N)=O)(C)C>O1CCOCC1.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:25]=[CH:24][C:13]3[C@:14]4([CH3:23])[C@@H:19]([CH2:20][CH2:21][C:12]=3[CH:11]=2)[NH:18][C:17](=[O:22])[CH:16]=[CH:15]4)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(-c3cccc([N+](=O)[O-])c3)ccc12
Agent: C[Si](C)(C)C(C(N)=O)(C(F)(F)F)[Si](C)(C)C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@]12C=CC(=O)N[C@@H]1CCc1cc(-c3cccc([N+](=O)[O-])c3)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.9 %

Procedure:
To a suspension of (+)-(4aR)-(10bR)-8-(3-nitrophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-quinolin-3-one (264 mg, 0.786 mmol), in 3.0 mL of 1,4-dioxane was added DDQ (196 mg, 1.1 equiv.) followed by bistrimethylsilyltrifluoromethyl acetamide (911 mg, 4.5 equiv.), and the solution was stirred at room temperature for 2 h, then heated at 100° for 20 h. The mixture was cooled to room temperature, diluted with ethyl acetate, and washed with 2M sodium hydroxide. The organic phase was washed with brine, dried over sodium sulfate, concentrated and chromatographed on silica gel (ethyl acetate eluent) to give, after trituration from ether/hexanes, 55 mg (21%) of the title compound as an orange solid. mp 205°-206°. FDMS m/e=334. α[D]589 =+57.23 (c=0.66, chloroform).
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][N:11]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)(=O)=O.[NH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CO>[F:29][C:28]([F:30])([F:31])[C:27]([C:24]1[CH:25]=[CH:26][C:21]([N:8]2[CH2:9][CH2:10][N:11]([S:13]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)(=[O:15])=[O:14])[CH2:12][C@@H:7]2[CH2:6][NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:22][CH:23]=1)([OH:33])[CH3:32]
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2COS(C)(=O)=O)cc1)C(F)(F)F
Reactant: Nc1ccccc1
Solvent: CO
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CNc2ccccc2)cc1)C(F)(F)F
Temperature: 140 °C
Yield: 57.3 %

Procedure:
A 20-mL microwave vial was charged with ((2R)-4-(thiophen-2-ylsulfonyl)-1-(4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)piperazin-2-yl)methyl methanesulfonate (0.500 g, 0.946 mmol, Intermediate B), aniline (0.884 g, 9.46 mmol), and MeOH (8.0 mL). The vial was sealed and heated in an Initiator microwave reactor (Biotage AB, Inc., Uppsala, Sweden) at 140° C. for 30 min. After cooling to room temperature, the reaction mixture was concentrated and the crude product was purified by column chromatography (80 g, 2 to 5% 2M NH3 in MeOH/CH2Cl2) to afford 1,1,1-trifluoro-2-(4-((2S)-2-((phenylamino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (0.285 g) as a mixture of two isomers.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:16]=[C:15]([CH3:17])[C:8]2[N:9]=[C:10]([CH2:12][CH2:13][CH3:14])[NH:11][C:7]=2[CH:6]=1)=[O:4].[H-].[Na+].[C:20]([O:24][C:25]([C:27]1[C:28]([C:33]2[CH:38]=[CH:37][C:36]([CH2:39]Br)=[CH:35][CH:34]=2)=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:16]=[C:15]([CH3:17])[C:8]2[N:9]=[C:10]([CH2:12][CH2:13][CH3:14])[N:11]([CH2:39][C:36]3[CH:37]=[CH:38][C:33]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])=[CH:34][CH:35]=3)[C:7]=2[CH:6]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCCc1nc2c(C)cc(C(=O)OC)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc2c(C)cc(C(=O)OC)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
A solution of 7-methyl-2-propyl-3H-benzoimidazole-5-carboxylic acid methyl ester (10.0 g, 43 mmol; prepared as described in Preparation 1) in DMF (300 mL) was cooled in an ice bath. Sodium hydride (4.5 g, 60 wt % in mineral oil) was slowly added over 5 minutes. 4′-Bromomethylbiphenyl-2-carboxylic acid t-butyl ester (15.7 g, 45.2 mmol; purchased from commercial source or prepared as described in Preparation 2) was then added. The mixture was gradually warmed to room temperature, then stirred at 75° C. overnight. The mixture was then cooled and concentrated in vacuo and the resultant residue was partitioned between saturated aqueous NaCl and EtOAc (1:1, 400 mL). The organic layer was collected, dried over MgSO4 and evaporated to dryness, yielding Intermediate (3a) as a pale yellow oil (16.0 g, 32.1 mmol). MS m/z: [M+H+] calcd for C31H34N2O4, 499.25. found 499.5.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH2:15][C:16]1[N:20]([CH2:21][CH3:22])[N:19]=[CH:18][CH:17]=1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>CC([O-])=O.CC([O-])=O.[Cu+2].C(O)(=O)C.O>[CH2:21]([N:20]1[C:16]([NH:15][C:2]2[C:3](=[CH:7][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:9][CH:10]=2)[C:4]([OH:6])=[O:5])=[CH:17][CH:18]=[N:19]1)[CH3:22]
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reactant: CCn1nccc1N
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: CCn1nccc1Nc1ccc(S(C)(=O)=O)cc1C(=O)O

Procedure:
A mixture of 2-chloro-5-(methylsulfonyl)benzoic acid (5.0 g, 21.4 mmol), 5-amino-1-ethylpyrazole (2.4 g, 21.4 mmol), DMF (50 ml), Cu(OAc)2 (0.5 g) and K2CO3 (2.76 g, 20 mmol) was heated at reflux overnight. The reaction mixture was poured into water, acidified with acetic acid and extracted with CH2Cl2. The CH2Cl2 layer was evaporated to afford N-(1-ethylpyrazol-5-yl)-5-(methylsulfonyl)anthranilic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:15][C:16](=[O:20])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2.[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1)([O-:23])=[O:22]>>[CH3:1][O:2][C:3]1[C:4]([NH:15][C:16]([N:33]2[CH2:34][CH2:35][N:30]([C:27]3[CH:26]=[CH:25][C:24]([N+:21]([O-:23])=[O:22])=[CH:29][CH:28]=3)[CH2:31][CH2:32]2)=[O:20])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)Nc1nc2ccc(OC)cc2nc1OC
Product: COc1ccc2nc(NC(=O)N3CCN(c4ccc([N+](=O)[O-])cc4)CC3)c(OC)nc2c1
Yield: 94 %

Procedure:
Ethyl N-(3,6-dimethoxyquinoxalin-2-yl)carbamate and 1-(4-nitrophenyl)piperazine were reacted by the same way with the example 148 to obtain the titled compound (yield, 94%). 1H NMR (300 MHz, CDCl3): δ 3.57-3.65 (m, 8H), 3.90 (s, 3H), 4.01 (s, 3H), 7.06 (d, J=9.4 Hz, 2H), 7.18-7.22 (m, 2H), 7.69 (d, J=8.6 Hz, 2H), 8.09 (d, J=9.4 Hz, 2H), 9.20 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([NH2:17])([CH3:16])[CH3:15])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[C:24](O)(=[O:28])[CH:25]([CH3:27])[CH3:26]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([NH:17][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])([CH3:16])[CH3:15])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)N)c2c1N
Reactant: CC(C)C(=O)O
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)NC(=O)C(C)C)c2c1N

Procedure:
Prepared as in Example 24a from ethyl 4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate (Example 24b) and isobutyric acid as a white solid (58%). MS 388 (MH+).