Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)CO.COC>[C:12]1([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[CH:4][N:3]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Clc1nccc2ccccc12
Reactant: OB(O)c1ccccc1
Agent: COC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCO
Product: c1ccc(-c2nccc3ccccc23)cc1
Temperature: 90 °C
Yield: 88.2 %

Procedure:
3.0 g of 1-chloro-isoquinoline (18 mmmol), 2.7 g of Phenyl boronic acid (21 mmol), 1.6 g of tetrakis-triphenylphosphine palladium (0.8 mmol %), and 2.9 g of potassium carbonate (21 mmol) were added into 100 ml of reaction bowl, and 50 ml of ethylene glycol-dimethyl ether as distilled solvent was added thereto under the flow of nitrogen, and then the reaction was performed in reflux at 90° C. for 12 hr. The mixture was cooled to room temperature, extracted by chloroform and distilled water, and then, separated by silica gel column chromatography (chloroform:hexane=1:3), to obtain 3.32 g of 1-phenyl-isoquinoline (yield: 90%).
Reaction SMILES: [Mg].II.[Cl:4][C:5]1[CH:6]=[C:7](Br)[CH:8]=[CH:9][C:10]=1[Cl:11].[CH3:13][N:14]1[CH2:19][C:18]([C:20]([O:22][CH3:23])=[O:21])=[CH:17][CH2:16][CH2:15]1.Cl>CCOCC>[CH3:13][N:14]1[CH2:15][CH2:16][CH:17]([C:7]2[CH:8]=[CH:9][C:10]([Cl:11])=[C:5]([Cl:4])[CH:6]=2)[CH:18]([C:20]([O:22][CH3:23])=[O:21])[CH2:19]1
Reactant: Clc1ccc(Br)cc1Cl
Reactant: COC(=O)C1=CCCN(C)C1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: COC(=O)C1CN(C)CCC1c1ccc(Cl)c(Cl)c1
Temperature: -20 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To magnesium (5.5 g, 229 mmol) and a few crystals of iodine in anhydrous ether (20 mL) was added 3,4-dichlorobromobenzene (46.4 g, 206 mmol) in anhydrous ether (200 mL) at a rate sufficient to keep the reaction at reflux. After the addition was completed the reaction was heated at reflux for another 15 min. The reaction was cooled to −20° C. and arecoline (16 g, 103 mmol) in anhydrous ether (200 mL) was added over 20 min while keeping the temperature at −20° C. The reaction was stirred for another 2 hour at −20° C. and then heated to 0° C. Hydrochloric acid (4 N, 80 mL) was added and the pH adjusted to 1 using concentrated hydrochloric acid. The organic phase was separated off and the pH adjusted to 9 with concentrated ammonia. Extraction with ether (2×200 mL)afforded 24.6 g of the title compound as a brownish oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl.O1[CH2:14][CH2:13][NH:12]C1=O>C(OCC)C.O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][CH2:14][CH2:13][NH2:12])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Br)c1
Reactant: O=C1NCCO1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: NCCNc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16 %

Procedure:
To a solution of 3-bromoaniline (0.50 g, 2.9 mmol) in diethyl ether (Et2O, 5 mL) was added 4 M HCl in dioxane (1 mL), and the mixture was stirred at 25° C. for 1 h. Solvent was removed under reduced pressure, and the resulting HCl salt was dissolved in 2-(2-methoxyethoxy)ethanol (2 mL). 2-Oxazolidinone (0.429 g, 4.93 mmol) was added, and the reaction mixture was heated to 180° C. for 24 h. The collected crude solid was purified by column chromatography (0-10% (1% NH4OH in MeOH)/CH2Cl2) to provide N1-(3-bromo-phenyl)-ethane-1,2-diamine (0.10 g, 16%). 3-(Piperidine-1-carbonyl)-benzaldehyde (Example 1, step D; 0.091 g, 0.42 mmol) was added to a solution of the phenyl-diamine in 1,2-dichloroethane (10 mL), and the reaction mixture was stirred at 25° C. for 15 min. The mixture was treated with NaBH(OAc)3 (0.128 g, 0.604 mmol), and the resulting suspension was stirred at 25° C. for 18 h. The suspension was partitioned with satd NH4Cl (20 mL) and CH2Cl2 (20 mL), and the aqueous layer was extracted with CH2Cl2 (3×20 mL). The combined organic layers were washed with brine (50 mL), dried (MgSO4), filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (2-10% CH3OH/CH2Cl2), and then by preparative TLC (10% CH3OH/CH2Cl2) to provide the desired product (0.060 g, 34%). MS (ESI): mass calculated for C21H26BrN3O, 415.13; m/z found, 416.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.28-7.26 (m, 3H), 7.21-7.16 (m, 1H), 6.93 (t, J=8.0 Hz, 1H), 6.74-6.71 (m, 1H), 6.67 (t, J=2.0 Hz, 1H), 6.47-6.44 (m, 1H), 4.23 (br s, 1H), 3.75 (s, 2H), 3.64 (br s, 2H), 3.25 (br s, 2H), 3.10 (t, J=5.6 Hz, 2H), 2.83-2.80 (m, 2H), 1.60-1.43 (m, 6H).
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][OH:19])[CH:12]=1)[C:5]([O:7]CC)=[O:6])[CH3:2].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>>[CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][O:19][C:29]([NH:28][C:25]2[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)=[O:30])[CH:12]=1)[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCOC(=O)C(Cc1cccc(CCO)c1)OCC
Reactant: COc1ccc(N=C=O)cc1
Product: CCOC(Cc1cccc(CCOC(=O)Nc2ccc(OC)cc2)c1)C(=O)O

Procedure:
Using ethyl 2-ethoxy-3-[3-(2-hydroxyethyl)phenyl]propanoate and 4-methoxyphenylisocyanate, the title compound was obtained in the same manner as described in Example 160b).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C@@:9]23[O:18][C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[C@@H:10]2[CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]3)[CH:6]=[CH:7][CH:8]=1.C[S-].[Li+].Cl>CN(C)P(N(C)C)(N(C)C)=O.O>[OH:2][C:3]1[CH:4]=[C:5]([C@@:9]23[O:18][C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[C@@H:10]2[CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]3)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc([C@]23CCN(C)C[C@H]2c2ccccc2O3)c1
Agent: C[S-]
Agent: Cl
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CN1CC[C@]2(c3cccc(O)c3)Oc3ccccc3[C@@H]2C1
Yield: 94.8 %

Procedure:
A mixture of 3.50 g of cis-1,2,3,4,4a,9b-hexahydro-4a-(3-methyoxyphenyl)-2-methyl-benzofuro[3,2-c]pyridine and 3.62 g of lithium thiomethoxide in 30 ml of dry hexamethylphosphoramide was heated at 140° under a drying tube for 41/2 hours. The cooled reaction mixture was diluted with 350 ml of water and the pH adjusted to 7 by slow addition of 2N HCl with stirring. The mixture was extracted with ether (2×300), and the combined extracts were washed with water (3×300 ml), dried over anhydrous Na2SO4, and evaporated in vacuo to provide 3.16 g (94.8%) a solid foam. This material was boiled and triturated with a small amount of ether. After cooling to 0°, the resulting solid was filtered off, washed with cold ether, and dried to afford 2.58 g (77.4%) of crystalline solid, m.p. s 157°, 158°-160°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[N:7]([CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)[CH2:8][CH2:9][NH:10]C(=O)C(F)(F)F)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].CO>O>[C:1]([O:5][C:6](=[O:29])[N:7]([CH2:8][CH2:9][NH2:10])[CH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(CCCc1ccc([N+](=O)[O-])cc1)CCNC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCN)CCCc1ccc([N+](=O)[O-])cc1
Temperature: 50 °C

Procedure:
Add [3-(4-Nitro-phenyl)-propyl]-[2-(2,2,2-trifluoro-acetylamino)-ethyl]carbamic acid tert-butyl ester (16 g, 33 mmol), potassium carbonate (23 g, 170 mmol), methanol (100 mL) and water (45 mL) to a 500 mL flask. Heat to 50° C. for 1 hr. Cool the reaction and filter off any solids. Add dichloromethane and water, stir and separated the layers. Extract the aqueous layer with dichloromethane. Combine the organic layers, wash with brine, dry over MgSO4 and concentrate under reduced pressure to obtain the title compound as an oily residue. The title compound was used without purification. 1H NMR (CDCl3, 500.0 MHz): δ 8.13 (d, 2H, J=9 Hz), 7.32 (d, 2H, J=8.5 Hz), 3.24 (br m, 4H), 2.82 (br m, 2H), 2.69 (t, 2H, J=7.5 Hz), 1.87 (p, J=7.5 Hz), 1.48 (br s, 2H), 1.43 (s, 9H).
Reaction SMILES: [CH:1]1([C:4]2[C:19]([O:20][CH2:21][C@@H:22]([NH:27]C(=O)OC(C)(C)C)[CH2:23][CH:24]([CH3:26])[CH3:25])=[CH:18][C:7]3[N:8]([CH3:17])[C:9](=[O:16])[C:10]4[C:15]([C:6]=3[CH:5]=2)=[CH:14][CH:13]=[N:12][CH:11]=4)[CH2:3][CH2:2]1.Cl.O1CCOCC1>CO>[NH2:27][C@@H:22]([CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:21][O:20][C:19]1[C:4]([CH:1]2[CH2:3][CH2:2]2)=[CH:5][C:6]2[C:15]3[C:10](=[CH:11][N:12]=[CH:13][CH:14]=3)[C:9](=[O:16])[N:8]([CH3:17])[C:7]=2[CH:18]=1
Reactant: CC(C)C[C@@H](COc1cc2c(cc1C1CC1)c1ccncc1c(=O)n2C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)C[C@H](N)COc1cc2c(cc1C1CC1)c1ccncc1c(=O)n2C
Yield: 17.1 %

Procedure:
To a solution of (S)-tert-butyl (1-((9-cyclopropyl-6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (60 mg, 0.129 mmol) in MeOH (4 mL), at 0° C. was added a 4M solution of HCl in 1,4-dioxane (2 mL, 8 mmol). The resultant solution was stirred for 2 h at RT. The methanol was removed under reduced pressure and the residue was extracted with ethyl acetate (2×5 mL). The organic phase was washed with saturated aqueous NaHCO3 (2×5 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica-gel column (MeOH—CHCl3) to afford (S)-8-((2-amino-4-methylpentyl)oxy)-9-cyclopropyl-6-methylbenzo[c][2,7]naphthyridin-5(6H)-one (8 mg, 0.022 mmol, 17% yield) as an off-white solid. LC/MS (ESI) m/z 366.2 [(M+H)+, calcd for C22H28N3O2 366.2]; LC/MS retention time (method B): tR=1.34 min. HPLC retention time (method B): tR=4.87 min and HPLC retention time (method A): tR=9.18 min. 1H NMR (400 MHz, CDCl3) δ ppm 9.47 (s, 1H), 8.75 (d, J=5.7 Hz, 1H), 8.28 (d, J=5.7 Hz, 1H), 7.96 (s, 1H), 7.06 (s, 1H), 4.27 (m, 1H), 4.06-4.15 (m, 1H), 3.84 (s, 3H), 3.38-3.48 (m, 1H), 2.23-2.38 (m, 1H), 1.83-1.94 (m, 1H), 1.56-1.67 (m, 1H), 1.46-1.55 (m, 1H), 1.00-1.08 (m, 6H), 0.79-0.94 (m, 4H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:24]=[CH:23][C:12]([CH2:13][C@@H:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[NH2:15])=[CH:11][CH:10]=1)[CH3:2].F[C:27]1[N:31]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:30]=[N:29][N:28]=1>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][C@@H:14]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[NH:15][C:27]2[N:31]([CH2:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[N:30]=[N:29][N:28]=2)=[CH:23][CH:24]=1)[CH3:2]
Reactant: Fc1nnnn1Cc1ccccc1
Reactant: CCOC(=O)CCCOc1ccc(C[C@H](N)C(=O)OC(C)(C)C)cc1
Solvent: c1ccncc1
Product: CCOC(=O)CCCOc1ccc(C[C@H](Nc2nnnn2Cc2ccccc2)C(=O)OC(C)(C)C)cc1
Yield: 57.6 %

Procedure:
A solution of aminoester 4-2 (325 mg, 0.92 mmole) and 5-fluoro-1-(phenylmethyl)-1H-tetrazole (170 mg, 0.95 mmole) in 15 ml of pyridine is heated at 100° C. for 2 hours. Evaporation is then carried out under reduced pressure until a dry extract is obtained which is purified by chromatography eluting with a heptane/AcOEt mixture 50/50. 270 mg of the expected product 5-1 is obtained.
Reaction SMILES: C([O:4][C:5]1[CH:33]=[CH:32][C:8]([C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[C:14]([Cl:31])[CH:13]=2)=[O:10])=[CH:7][CH:6]=1)(=O)C.[Li+].[OH-]>C1COCC1.CO>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[C:14]([Cl:31])[CH:13]=2)=[O:10])=[CH:32][CH:33]=1
Reactant: CCCCCCCCCCCCOc1ccc(OC(=O)c2ccc(OC(C)=O)cc2)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCCCCCCOc1ccc(OC(=O)c2ccc(O)cc2)cc1Cl

Procedure:
In ethanol, chlorohydroquinone was reacted with dodecylbromide in ethanol by using 1 equivalent of potassium hydroxide to obtain 3-chloro-4-dodecyloxyphenol. Then, 3.1 g of this 3-chloro-4-dodecyloxyphenol was reacted with 2.0 g of 2,4-acetoxybenzoic acid chloride in pyridine and the reaction mixture was treated by customary procedures to obtain 4 g of 3-chloro-4-dodecyloxyphenyl 4-acetoxybenzoate. This ester was dissolved in a THF/methanol liquid mixture and 1 equivalent of 1N LiOH was added to selectively isolate the acetoxy group, whereby 3-chloro-4-dodecyloxyphenyl 4-hydroxybenzoate was obtained.
Reaction SMILES: [C:1](=O)([O:43]C1C=CC([N+]([O-])=O)=CC=1)[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@H:10]([NH:31][C:32]([O:34][C@@H:35]2[C@H:42]3[C@H:38]([O:39][CH2:40][CH2:41]3)[O:37][CH2:36]2)=[O:33])[C@H:11]([OH:30])[CH2:12][N:13]([S:18]([C:21]2[CH:29]=[CH:28][C:24]3[O:25][CH2:26][O:27][C:23]=3[CH:22]=2)(=[O:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:5][CH:4]=1.[OH-].[NH4+:55]>>[NH2:55][C:1]([O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@H:10]([NH:31][C:32](=[O:33])[O:34][C@@H:35]2[C@H:42]3[C@H:38]([O:39][CH2:40][CH2:41]3)[O:37][CH2:36]2)[C@H:11]([OH:30])[CH2:12][N:13]([S:18]([C:21]2[CH:29]=[CH:28][C:24]3[O:25][CH2:26][O:27][C:23]=3[CH:22]=2)(=[O:19])=[O:20])[CH2:14][CH:15]([CH3:16])[CH3:17])=[CH:5][CH:4]=1)=[O:43]
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Reactant: [NH4+]
Agent: [OH-]
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OC(N)=O)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2

Procedure:
4-{(2S,3R)-2-({[(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl}amino)-4-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-3-hydroxybutyl}phenyl 4-nitrophenyl carbonate was treated with concentrated ammonium hydroxide as described in Example 311 to afford the title compound as a white solid. 1H NMR (DMSO-d6): δ 0.78 (3H, d), 0.86 (3H, d), 1.2 (1H, dd), 1.4 (1H, br quintuplet), 1.85-1.95 (1H, m), 2.2 (1H, t), 2.65-2.80 (3H, m), 2.9-3.0 (2H, m), 3.25-3.30 (1H, m), 3.5-3.6 (4H, m), 3.7 (1H, t), 3.8 (1H, dd), 4.8 (1H, dt), 5.0 (1H, d), 5.4 (1H, d), 6.18 (2H, d), 6.8 (2H, br d), 6.9 (2H, d), 7.0 (1H, d), 7.15 (2H, d), 7.2 (1H, s), 7.25-7.30 (2H, m); MS: 636 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+:13].Br[CH2:15][CH2:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>O.C(O)(C)C>[CH:17]1([CH2:16][CH2:15][O:1][C:2]2[CH:7]=[CH:6][C:5]([S:8]([O-:11])(=[O:9])=[O:10])=[CH:4][CH:3]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1.[Na+:13]
Reactant: BrCCC1CCCC1
Reactant: O=S(=O)(O)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: O=S(=O)([O-])c1ccc(OCCC2CCCC2)cc1

Procedure:
A solution of 4-hydroxybenzenesulfonic acid (6.5 grams, 28.2 mmole) and sodium hydroxide (2.2 grams, 55 mmole) in water (15 mL) was mixed with a solution of 2-(bromoethyl)cyclopentane (15.0 grams, 84.7 mmole) in isopropanol (40 mL) and the resulting mixture was heated at reflux for 2 days. The isopropanol was removed by evaporation under vaccuum. The titled compound, 4.7 grams (57%), was collected by filtration washing with isopropanol.
Reaction SMILES: Cl[C:2]1[C:7]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][S:15][CH2:14][CH2:13]1>CN(C)C=O>[N:12]1([C:2]2[C:7]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:17][CH2:16][S:15][CH2:14][CH2:13]1
Reactant: C1CSCCN1
Reactant: NS(=O)(=O)c1cccnc1Cl
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1cccnc1N1CCSCC1

Procedure:
In a dry flask under an inert nitrogen atmosphere was mixed 2.5 g of 2-chloro-3-pyridinesulfonamide, 100 mL of dry N,N-dimethylformamide (DMF), and 2.7 mL of thiomorpholine. The mixture was heated at 80° C. overnight at which time an additional 0.3 mL of thiomorpholine was added and the heating was continued. After 24 hours the mixture was concentrated and the residue was taken up in THF. The solids were filtered and the filtrate was concentrated and chromatographed on silica gel using 1:1 ethyl acetate/hexane as eluent. The pure subject compound was isolated as a solid, which melted at 176°-177° C.; NMR (200 MHz, CDCl3): δ 2.89 (m, CH2S, 4H), 3.45 (m, CH2N, 4H), 5.52 (s, NH2, 2H), 7.26 (t, ArH, 1H), 8.2-8.6 (m, ArH, 2H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=O)[CH:2]=1.CN.CO.CC(O)=O.[BH3-][C:22]#[N:23].[Na+]>CO>[CH3:22][NH:23][CH2:11][C:3]1[CH:2]=[N:1][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: [BH3-]C#N
Reactant: O=Cc1cnc2ccccc2c1
Agent: CN
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNCc1cnc2ccccc2c1
Yield: 48.2 %

Procedure:
A solution of 3-quinolinecarboxaldehyde (1.5 g,10 mmole), 2.0 M CH3NH2/MeOH (10 mL, 20 mmole), glacial AcOH (0.6 mL, 10 mmole), and NaBH3CN (0.35 g, 11 mmole) in MeOH (20 mL) was stirred at RT overnight, then was concentrated in vacuo. The residue was diluted with 5% NaOH and extracted with CH2Cl2. The combined organic extracts were washed with brine, dried over MgSO4, and concentrated. Flash chromatography on silica gel (10% MeOH/CH2Cl2) gave the title compound (0.83 g, 24%) as a slightly yellow viscous oil: MS (ES) m/e 173 (M+H)+.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[C:9](=[O:22])[NH:10][C:11]2[C:16]([N:17]=1)=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=2.N1C=CC=CC=1.[O:29](S(C(F)(F)F)(=O)=O)[S:30]([C:33]([F:36])([F:35])[F:34])(=O)=[O:31]>ClCCl>[CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[C:9]([O:22][S:30]([C:33]([F:36])([F:35])[F:34])(=[O:31])=[O:29])=[N:10][C:11]2[C:16]([N:17]=1)=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=2
Reactant: COC(=O)c1ccc2[nH]c(=O)c(N3CCCC[C@@H]3C)nc2c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCCC[C@@H]3C)nc2c1
Temperature: 0 °C

Procedure:
To a solution of (S)-methyl 3-(2-methylpiperidin-1-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (165 mg, 0.55 mmol) in dichloromethane (40 mL) was added pyridine (231 mg, 2.92 mmol) followed by the addition of Tf2O (412 mg, 1.46 mmol) dropwise with stirring at 0° C. The resulting solution was stirred overnight at room temperature and then washed with water (3×50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to afford (S)-methyl 3-(2-methylpiperidin-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate as red oil (240 mg, crude).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[CH:16]=[CH:15][C:14]=1[S:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][O:19][C:17]2[CH:16]=[CH:15][C:14]([S:28][C:29]3[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=3)=[C:13]([NH:12][C:2]3[C:11]4[C:6](=[N:7][CH:8]=[CH:9][CH:10]=4)[N:5]=[CH:4][CH:3]=3)[CH:18]=2)=[CH:22][CH:23]=1
Reactant: Clc1ccnc2ncccc12
Reactant: Nc1cc(OCc2ccc(Cl)cc2)ccc1Sc1ccc(O)cc1
Product: Oc1ccc(Sc2ccc(OCc3ccc(Cl)cc3)cc2Nc2ccnc3ncccc23)cc1

Procedure:
The product from Example 16c (50 mg, 0.30 mmol) was reacted with the product from Example 143a (107 mg, 0.30 mmol) for 24 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (50 mg, 27%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 5.14 (s, 2 H) 6.31 (d, J=7.36 Hz, 1 H) 6.64 (d, J=8.82 Hz, 2 H) 7.05-7.40 (m, J=8.46 Hz, 4 H) 7.46 (m, J=5.52 Hz, 3 H) 7.93 (m, J=4.41 Hz, 1 H) 8.48 (d, J=6.98 Hz, 1 H) 9.17 (m, J=1.47 Hz, J=5.88 Hz, 3 H) 9.79 (s,1 H) 11.15 (br s, 1 H) 14.54 (br s, 1 H); MS (ESI+) m/z,486 (M+H−TFA)+; (ESI−) m/z,484 (M−H−TFA)−.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][CH:10]([S:13]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][C:20](=[O:25])[CH2:19]3)(=[O:15])=[O:14])[CH2:9]1.[C:26]1([CH2:32][CH2:33][CH2:34][CH:35]=O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:26]1([CH2:32][CH2:33][CH2:34][CH2:35][N:8]2[CH2:12][CH2:11][CH:10]([S:13]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][C:20](=[O:25])[CH2:19]4)(=[O:15])=[O:14])[CH2:9]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=CCCCc1ccccc1
Reactant: O=C1Cc2cc(S(=O)(=O)C3CCNC3)ccc2N1
Solvent: O=C(O)C(F)(F)F
Product: O=C1Cc2cc(S(=O)(=O)C3CCN(CCCCc4ccccc4)C3)ccc2N1

Procedure:
The title compound, MS: m/e=399.4 (M+H+) was prepared from (RS)-5-(pyrrolidine-3-sulfonyl)-1,3-dihydro-indol-2-one trifluoroacetic acid and 4-phenyl-butyraldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:10])[C:6]=1[C:7](O)=[O:8].ClC(N(C)C)=C(C)C.[NH:19]1[C:27]2[C:22](=[C:23]([C:28]3[CH:29]=[C:30]([NH2:37])[C:31]4[CH:32]=[N:33][NH:34][C:35]=4[CH:36]=3)[CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20]1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:10])[C:6]=1[C:7]([NH:37][C:30]1[CH:29]=[C:28]([C:23]2[CH:24]=[CH:25][CH:26]=[C:27]3[C:22]=2[CH:21]=[CH:20][NH:19]3)[CH:36]=[C:35]2[C:31]=1[CH:32]=[N:33][NH:34]2)=[O:8]
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reactant: Cn1ncc(Cl)c1C(=O)O
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1ncc(Cl)c1C(=O)Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Temperature: 20 °C
Reaction time: 18 h
Yield: 12.4 %

Procedure:
A solution of 4-chloro-1-methyl-1H-pyrazole-5-carboxylic acid (available from Fluorochem) (50 mg) in dry DCM (10 ml) was treated with 1-chloro-N,N,2-trimethyl-1-propen-1-amine (0.041 ml) (available from Acros) and allowed to stir at 20° C. for 10 min when a solution of 6-(1H-indol-4-yl)-1H-indazol-4-amine (77 mg) and triethylamine (0.043 ml) in DCM (5 ml) was added and the mixture stirred at 20° C. for 18 h. The mixture was poured onto an aminopropyl SPE cartridge (1 g) and allowed to stand for 2 h, then the mixture was eluted with methanol (5 ml) and blown to dryness under a stream of nitrogen. The crude product was purified by mass directed preparative HPLC (Method A) to give the title compound as a white solid (15 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH2:13][C:14]([O:16]C)=[O:15])=[CH:10][C:9]=2[CH3:18])=[CH:4][CH:3]=1.Br[CH2:20][C:21]1[C:26]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[C:25]([O:34]C(OC(C)(C)C)=O)[C:24]([C:42]([F:45])([F:44])[F:43])=[CH:23][CH:22]=1>>[C:30]([O:29][C:27]([C:26]1[C:25]([OH:34])=[C:24]([C:42]([F:43])([F:44])[F:45])[CH:23]=[CH:22][C:21]=1[CH2:20][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH2:13][C:14]([OH:16])=[O:15])=[CH:10][C:9]=2[CH3:18])=[CH:4][CH:3]=1)=[O:28])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)Oc1c(C(F)(F)F)ccc(CBr)c1C(=O)OC(C)(C)C
Reactant: COC(=O)Cc1cc(C)c(-c2ccc(O)cc2)s1
Product: Cc1cc(CC(=O)O)sc1-c1ccc(OCc2ccc(C(F)(F)F)c(O)c2C(=O)OC(C)(C)C)cc1
Yield: 13 %

Procedure:
According to a method similar to Example (2-3), Example (33-5) and Example (17-4), from methyl [5-(4-hydroxyphenyl)-4-methyl-2-thienyl]acetate (133 mg, 0.51 mmol) obtained in Example (96-4) and tert-butyl 6-(bromomethyl)-2-[(tert-butoxycarbonyl)oxy]-3-(trifluoromethyl)benzoate (254 mg, 0.56 mmol) obtained in Example (28-5), the title compound was obtained as a pale yellow crystal (35 mg, three-step total yield: 13%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]2[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]2)[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[H][H]>C(O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][CH:12]2[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]2)[CH:5]=[C:6]([F:9])[C:7]=1[F:8]
Reactant: [H][H]
Reactant: O=C1CCC(C=Cc2cc(F)c(F)c(F)c2)CC1
Agent: [Pd]
Solvent: CCO
Product: O=C1CCC(CCc2cc(F)c(F)c(F)c2)CC1
Yield: 97.8 %

Procedure:
4-(2'-(3",4",5"-Trifluorophenyl)ethenyl)cyclohexanone (71 g) was dissolved in ethanol (500 ml), followed by adding Pd/C (5%) (2.0 g), hydrogenating the compound in a hydrogen gas atmosphere with stirring till the hydrogen absorption was completed, filtering off the catalyst after completion of the reaction, and concentrating the solvent under reduced pressure, to obtain 4-(2'-(3",4",5"-trifluorophenyl)ethyl)cyclohexanone (70 g).