Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].Cl[CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([O:10][CH3:11])[CH2:8][CH3:9].Cl[CH:13]1[CH2:17][CH2:16][CH:15]=[CH:14]1.[Cl-].[NH4+]>O1CCCC1>[CH3:11][O:10][CH:7]([CH2:8][CH3:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH:17]1[CH2:16][CH2:15][CH:14]=[CH:13]1
Reactant: ClC1C=CCC1
Reactant: CCC(CCCCCl)OC
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(CCCCC1C=CCC1)OC
Temperature: -25 °C
Yield: 89.7 %

Procedure:
A three-neck, round-bottomed flask containing magnesium metal turnings (7.2 g, 0.299 moles), is equipped with a Friedrich condenser and kept under a nitrogen atmosphere. Tetrahydrofuran (300 ml) is added and the contents are allowed to stir. A solution of 1-chloro-5-methoxyheptane (48.1 g, 0.292 moles) is added in small portions and refluxed. The mixture is allowed to stir for 3 hours. The resultant dark yellow solution is cooled to -25° C., and the condenser is removed and replaced with a dry ice addition funnel. A solution of 3-chlorocyclopentene (29.9 g, 0.292 moles) is added over a period of one hour. The viscous solution is poured into two liters of saturated ammonium chloride, extracted with ether, and dried over anhydrous sodium sulfate. Distillation yields 3-(5-methoxyheptyl)cyclopentene (51.5 g, 0.262 moles) as a clear, colorless oil boiling at about 90° C. at 0.3 mm and 54° C. at 0.1 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[O:10][CH2:11][C:12]2([CH3:15])[CH2:14][O:13]2)=[CH:4][CH:3]=1.[N+]([C:20]1[NH:21][CH:22]=[C:23]([N+:25]([O-:27])=[O:26])[N:24]=1)([O-])=O.C([O-])(=O)C.[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:16])[O:10][CH2:11][C:12]2([CH3:15])[O:13][C:20]3=[N:24][C:23]([N+:25]([O-:27])=[O:26])=[CH:22][N:21]3[CH2:14]2)=[CH:6][CH:7]=1
Reactant: CC1(COC(=O)Nc2ccc(Cl)cc2)CO1
Reactant: O=[N+]([O-])c1c[nH]c([N+](=O)[O-])n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CC1(COC(=O)Nc2ccc(Cl)cc2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 24 h
Yield: 21.9 %

Procedure:
2-Methyloxiran-2-ylmethyl 4-chlorophenylcarbamate (1.1 g, 4.4 mmol) and 2,4-dinitro-1H-imidazole (0.35 g, 2.2 mmol) were suspended in ethanol (1 ml), and the resulting mixture was stirred at room temperature for 24 hours. Then, sodium acetate (0.36 g, 4.4 mmol) and ethanol (2 ml) were added to the mixture followed by stirring under reflux for 6 hours. The reaction mixture was concentrated under reduced pressure. The residue was added water, and the resulting mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was crystallized from methylene chloride-diethyl ether to afford 2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl 4-chlorophenylcarbamate (0.17 g, yield 22%) as a light yellow solid.
Reaction SMILES: N1C2C(=NC=CC=2)N([N:10]2[C:14](/[CH:15]=[C:16]3\[C:17](=[O:26])[NH:18][C:19]4[C:24]\3=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)=[C:13]([CH3:27])[C:12]([C:28]([O-:30])=O)=[C:11]2[CH3:31])N=1.[NH2:32][C@@H:33]1[CH2:37][O:36][N:35]([CH:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)[C:34]1=[O:44].CCN(C(C)C)C(C)C>CN(C=O)C>[O:44]=[C:34]1[C@H:33]([NH:32][C:28]([C:12]2[C:13]([CH3:27])=[C:14](/[CH:15]=[C:16]3\[C:17](=[O:26])[NH:18][C:19]4[C:24]\3=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[NH:10][C:11]=2[CH3:31])=[O:30])[CH2:37][O:36][N:35]1[CH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1
Reactant: N[C@@H]1CON(C2CCOCC2)C1=O
Reactant: Cc1c(C(=O)[O-])c(C)n(-n2nnc3cccnc32)c1/C=C1\C(=O)Nc2ccc(F)cc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)N[C@@H]1CON(C2CCOCC2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
To a solution of A4 (84 mg, 2 mmol) in 10 mL of DMF, were added the crude 48c from last step and DIEA (2 mL), the reaction mixture was stirred at room temperature overnight. LC/MS was applied to determine completion of the reaction. The reaction mixture was evaporated under reduced pressure and the residue was triturated with 5% diethylamine/methanol (25 mL). The solid was collected by filtration and washed with methanol, dried under vacuum to provide the title compound (58 mg, 62%) as orange solid. 1H NMR (300 MHz, DMSO-d6): δ=13.73 (s, 1H), 10.94 (s, 1H), 8.12-8.15 (d, 1H), 7.73-7.80 (m, 2H), 6.82-6.87 (m, 2H), 5.02-5.05 (q, 1H), 4.58-4.64 (t, 1H), 3.86-4.14 (m, 4H), 3.38-3.44 (m, 2H), 2.42-2.50 (ds, 6H), 1.65-1.88 (m, 4H). LC/MS: 469.0 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.C(N(CC)CC)C.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:26][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: NCc1ccccn1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NCc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 71.2 %

Procedure:
To a 0° C. solution of 15.0 g of 2-(aminomethyl)pyridine, 15.44 g of triethylamine and 150 ml of methylene chloride is added 29.1 g of p-toluenesulfonyl chloride in 100 ml of methylene chloride. The reaction mixture is allowed to warm to room temperature and is stirred for 4.5 hours. The solution is poured into saturated sodium bicarbonate and extracted with methylene chloride. The combined organic layers are washed with saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by column chromatography (silica gel: 50% ethyl acetate/hexane 20% methyl alcohol/ethyl acetate); then recrystallized from ethyl acetate/hexane to give 25.9 g of the desired product as colorless crystals.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27](=[O:35])[C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[C:21]=2[CH3:36])=[C:8]2[C:16]=1[NH:15][C:14]1[CH:13]=[C:12]([C:17](O)=[O:18])[CH:11]=[CH:10][C:9]2=1)(=[O:3])[NH2:2].C1C=[N:41]C2N(O)N=NC=2C=1.[OH-].[NH4+].C(Cl)CCl>C1COCC1>[F:34][C:31]1[CH:30]=[CH:29][C:28]([C:27]([NH:26][C:22]2[C:21]([CH3:36])=[C:20]([C:7]3[C:8]4[C:9]5[C:14](=[CH:13][C:12]([C:17]([NH2:41])=[O:18])=[CH:11][CH:10]=5)[NH:15][C:16]=4[C:4]([C:1]([NH2:2])=[O:3])=[CH:5][CH:6]=3)[CH:25]=[CH:24][CH:23]=2)=[O:35])=[CH:33][CH:32]=1
Reactant: On1nnc2cccnc21
Reactant: Cc1c(NC(=O)c2ccc(F)cc2)cccc1-c1ccc(C(N)=O)c2[nH]c3cc(C(=O)O)ccc3c12
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: C1CCOC1
Product: Cc1c(NC(=O)c2ccc(F)cc2)cccc1-c1ccc(C(N)=O)c2[nH]c3cc(C(N)=O)ccc3c12
Temperature: 25 °C
Reaction time: 22.5 h
Yield: 32.2 %

Procedure:
A mixture of 8-carbamoyl-5-(3-(4-fluorobenzamido)-2-methylphenyl)-9H-carbazole-2-carboxylic acid (Example 23-1, 30 mg, 0.062 mmol) and HOAT (12.72 mg, 0.093 mmol) in THF (0.4 mL) was treated with 28% aqueous ammonium hydroxide (0.052 mL, 0.374 mmol) and EDC (23.89 mg, 0.125 mmol) and the mixture was stirred at rt. After 22.5 h, the mixture was concentrated and purified by preparative HPLC. The appropriate effluent fractions were concentrated and the residue was treated with NaHCO3 (aq) and extracted three times with EtOAc. The combined organic phases were dried and concentrated to provide 4-(3-(4-fluorobenzamido)-2-methylphenyl)-9H-carbazole-1,7-dicarboxamide as an off-white solid (9.6 mg, 29%). 1H NMR (400 MHz, methanol-d4) δ 8.11 (d, J=1.3 Hz, 1H) 8.03-8.08 (m, 2H) 8.01 (d, J=7.9 Hz, 1H) 7.51-7.55 (m, 1H) 7.41-7.48 (m, 2H) 7.29 (dd, J=7.5, 1.3 Hz, 1H) 7.24 (t, J=8.8 Hz, 2H) 7.08-7.12 (m, 2H) 1.98 (s, 3H). Mass spectrum m/z 481.1 (M+H)+.
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][C:9]1[CH:17]=[CH:16][C:15]2[NH:14][CH:13]3[CH2:18][CH2:19][NH:20][CH2:21][CH:12]3[C:11]=2[CH:10]=1.C(Cl)C1C=CC=CC=1>C(N(CC)CC)C>[CH2:7]([N:20]1[CH2:19][CH2:18][CH:13]2[NH:14][C:15]3[CH:16]=[CH:17][C:9]([CH3:8])=[CH:10][C:11]=3[CH:12]2[CH2:21]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc2c(c1)C1CNCCC1N2
Reactant: Cc1ccccc1
Solvent: ClCc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc2c(c1)C1CN(Cc3ccccc3)CCC1N2

Procedure:
To toluene (100 ml) are added 8-methyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (10 g), benzyl chloride (7.4 g) and triethylamine (8.1 g), and the mixture is refluxed for 15 hours. After cooling, the reaction mixture is washed with water, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove toluene. The resulting residue is treated with ethanolic hydrogen chloride in the same manner as described in Example 1 (1) to give the dihydrochloride of the titled compound (11.0 g), m.p. 179° - 182°C (recrystallized from ethanol).
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([C:19]2[C@H:28]3[C@H:23]([CH2:24][CH2:25][CH2:26][CH2:27]3)[C:22](=[O:29])N(CCO)N=2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]>>[CH:9]1([O:10][C:11]2[CH:12]=[C:13]([C:19]3[C@H:28]4[C@H:23]([CH2:24][CH:25]=[CH:26][CH2:27]4)[C:22](=[O:29])[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=3)[CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[CH2:3][CH2:2][CH2:1][CH2:6]1
Reactant: COc1ccc(C2=NN(CCO)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Reactant: NNc1ccccc1
Product: COc1ccc(C2=NN(c3ccccc3)C(=O)[C@H]3CC=CC[C@@H]23)cc1OC1CCCC1

Procedure:
Prepared from compound E (see starting compounds) and phenylhydrazine as described for compound 35. Crystallization from methanol. M.p. 134°-135° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][S:8][CH:9]([CH3:13])[C:10]([O-:12])=[O:11])=[CH:3][CH:2]=1.[Na+].[CH2:15](O)[CH3:16]>>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][S:8][CH:9]([CH3:13])[C:10]([O:12][CH2:15][CH3:16])=[O:11])=[CH:3][CH:2]=1
Reactant: CCO
Reactant: CC(SCc1ccncc1)C(=O)[O-]
Agent: [Na+]
Product: CCOC(=O)C(C)SCc1ccncc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Crude sodium 2-(4-pyridylmethylthio)propionate (approximately 7 g.) was taken up in 100 ml. of absolute ethanol and approximately 5 cc. of 3 A molecular sieves were added. Dry hydrogen chloride was bubbled into the reaction mixture, which was refluxed for 75 minutes, while continuing to saturate with hydrogen chloride during the initial 15 minutes. The mixture was cooled to room temperature and allowed to stir overnight (approximately 16 hours). The mixture was filtered through diatomaceous earth and concentrated to a semi-solid mixture. The esterification step was repeated on this mixture, except saturation with hydrogen chloride was continued during 1 hour of reflux and refluxing was continued overnight. The reaction mixture was cooled to room temperaure, filtered through diatomaceous earth and evaporated to an oil. The oil was extracted with chloroform, leaving filterable salts behind, and the chloroform stripped to yield ethyl 2-(4-picolylthio)propionate (waxy solid; ir (KBr) 3.0, 3.5, 5.75, 6.15, 6.30, 6.70, 8.6, 12.25μ; m.s.: m/e calcd: 225, found: 225, 152, 124, 102, 92, 45).
Reaction SMILES: C([Li])CCC.C1C[O:9][CH2:8]C1.Br[C:12]1[S:13][C:14]([C:18]2[C:19]([CH3:33])=[N:20][N:21]3[C:26]([CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29])=[CH:25][C:24]([CH3:32])=[N:23][C:22]=23)=[C:15]([Br:17])[N:16]=1.C(N1CCOCC1)=O>CCOCC>[Br:17][C:15]1[N:16]=[C:12]([CH:8]=[O:9])[S:13][C:14]=1[C:18]1[C:19]([CH3:33])=[N:20][N:21]2[C:26]([CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29])=[CH:25][C:24]([CH3:32])=[N:23][C:22]=12
Reactant: CCC(CC)c1cc(C)nc2c(-c3sc(Br)nc3Br)c(C)nn12
Reactant: C1CCOC1
Agent: O=CN1CCOCC1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCC(CC)c1cc(C)nc2c(-c3sc(C=O)nc3Br)c(C)nn12
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere, add n-butyl lithium (1.6 M in hexanes, 0.312 mL, 0.50 mmol) to a THF solution (2.5 mL) of 3-(2,4-dibromo-thiazol-5-yl)-7-(1-ethyl-propyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (230 mg, 0.50 mmol) at −78° C. and stir for 30 min. Add a THF (0.5 mL) solution of N-formyl morpholine (58 mg, 0.50 mmol). Stir for one hour, then store the reaction at −20° C. overnight. Warm the reaction to room temperature, dilute with ether, and quench by adding 4 N HCl (4 mL). Separate and extract the organic phase with 4 N HCl (2×4 mL). Combine the aqueous portions, treat with solid sodium bicarbonate to pH=8 to 9 and then extract with diethyl ether. Combine all the organic layers, wash with brine, dry over sodium sulfate, filter, and concentrate to a residue. Purify the crude material by flash chromatography, eluting with hexanes/dichloromethane/ethyl acetate (5/5/1) to give the title compound (154 mg). MS (APCI) m/z (81Br) 409.0 (M+1)+.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH:6]1[O:10][CH2:9][CH2:8][O:7]1)#[N:2].[H][H]>N.C(O)C.[Ru]>[NH2:2][CH2:1][CH2:3][CH2:4][CH2:5][CH:6]1[O:10][CH2:9][CH2:8][O:7]1
Reactant: [H][H]
Reactant: N#CCCCC1OCCO1
Agent: [Ru]
Agent: N
Solvent: CCO
Product: NCCCCC1OCCO1
Yield: 802.4 %

Procedure:
To a solution of 14.5 gm (10.3 mmol) 2-(3-Cyanopropyl)-1,3-dioxolane in anhydrous ammonia and ethanol was added 5% ruthenium on aluminum oxide. The reaction mixture was hydrogenated with an initial hydrogen pressure of 100 psi at ambient temperature for 32 hours. The reaction mixture was filtered and the filtrate concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 12.0 gm (80.5%) of the product.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>O1CCOCC1>[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH:6][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.8 %

Procedure:
To a solution of leucine methyl ester hydrochloride (5.0 g, 27.5 mmol) in 1,4-dioxane (50 mL) was added sodium carbonate (30.3 mL, 2M in water) followed by benzyl chloroformate (4.69 g, 27.5 mmol). The mixture stirred at room temperature for 24 hours when partitioned between ethyl acetate and water. The organic layer was collected, dried (MgSO4), filtered and concentrated to give the title compound as a colorless oil (7.67 g, 100%). 1HNMR (400 MHz, CDCl,) δ7.39 (m, SH), 5.38 (d, 2H), 5.12 (s, 2H), 4.42 (n, 1H), 3.75 (s, 3H), 1.73-1.50 (m, 3H), 0.94 (m, 6H).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:20]=1.[NH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1>C(O)C.O.Cl>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=4)=[N:20][C:6]2=3)[CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCC2)c2nc(Cl)ncc21
Reactant: Nc1ccc(C(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CN1C(=O)C(F)(F)CN(C2CCC2)c2nc(Nc3ccc(C(=O)O)cc3)ncc21
Yield: 60.1 %

Procedure:
A mixture of 2.00 g (6.6 mmole) of 2-chloro-9-cyclobutyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-1), 1.655 g (12.08 mmole) of 4-amino-benzoic acid and 200 mL of ethanol-water-hydrochloric acid (20:80:1) was refluxed for 18 hours, then concentrated under reduced pressure. The solid was washed with water and then purified by silica gel chromatography, eluting with dichloromethane-methanol-ammonium hydroxide (92:8:0.3) to give 1.600 g of 4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-benzoic acid (I-11).
Reaction SMILES: [C:1]1([CH:7]([N:13]2[CH2:18][CH2:17][N:16]([S:19]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH2:15][CH2:14]2)[CH2:8][S:9][C:10](=O)[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O-].[Na+].[F:32][C:33]([F:47])([F:46])[C:34]1[CH:35]=C([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)CBr>CO>[F:32][C:33]([F:46])([F:47])[C:34]1[CH:35]=[C:11]([CH:39]=[C:40]([C:42]([F:43])([F:44])[F:45])[CH:41]=1)[CH2:10][S:9][CH2:8][CH:7]([N:13]1[CH2:18][CH2:17][N:16]([S:19]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH2:15][CH2:14]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: CC(=O)SCC(c1ccccc1)N1CCN(S(=O)(=O)c2ccc(C)cc2)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N2CCN(C(CSCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3ccccc3)CC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 114.1 %

Procedure:
In a round-bottomed flask fitted with a reflux condenser and a thermometer 2.76 g (6.6 mmoles) of thioacetate 83 and 250 ml of degassed methyl alcohol are introduced. The mixture is cooled to 0° C. and 356 mg (6.6 mmoles) of sodium methylate are added. The mixture is stirred under argon for one hour at 0° C., and 1.9 g (7.26 mmoles) of 3,5-bis-trifluoromethyl-benzyl bromide are added. The mixture is stirred for 48 hours, volatile substances are removed under reduced pressure, and 100 ml of water are added. The aqueous phase is extracted three times with methylene chloride, the combined organic phases are washed with brine and dried over magnesium sulfate. Volatile substances are removed under reduced pressure, affording 4.54 g of crude 1-[2-(3,5-bis-trifluoromethyl-benzylsulfanyl)-1-phenyl-ethyl]-4-(toluene-4-sulfonyl)-piperazine (compound 84) as a colorless oil. This oil was purified by chromatography on silica gel (eluent: methylene chloride-hexane 65/35 (v/v)), affording 3.26 g of compound 84 as a colorless oil. Yield: 82%.
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)[CH3:3].[CH3:6][O:7][C:8]1[CH:41]=[CH:40][CH:39]=[CH:38][C:9]=1[CH2:10][N:11]1[C:17]2[CH:18]=[CH:19][C:20]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][CH3:34])=[CH:24][CH:23]=3)=[CH:21][C:16]=2[CH:15]=[C:14]([C:35](O)=[O:36])[CH2:13][CH2:12]1.S(Cl)(Cl)=O>O1CCCC1>[CH3:6][O:7][C:8]1[CH:41]=[CH:40][CH:39]=[CH:38][C:9]=1[CH2:10][N:11]1[C:17]2[CH:18]=[CH:19][C:20]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][CH3:34])=[CH:26][CH:27]=3)=[CH:21][C:16]=2[CH:15]=[C:14]([C:35]([NH:11][C:17]2[CH:18]=[CH:19][C:20]([CH2:4][N:2]([CH3:1])[CH:3]3[CH2:30][CH2:29][O:28][CH2:25][CH2:24]3)=[CH:21][CH:16]=2)=[O:36])[CH2:13][CH2:12]1
Reactant: CN(C)C=O
Reactant: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2ccccc2OC)cc1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3Cc2ccccc2OC)cc1
Reaction time: 1 h

Procedure:
One droplet of DMF was added to a solution of 1-(2-methoxybenzyl)-7-(4-propoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (190 mg) in tetrahydrofuran (10 ml). Then, thionyl chloride (139 mg) was added at 0° C., the temperature was returned to room temperature, and the mixture was stirred under nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were evaporated under reduced pressure, the resulting residue was suspended in tetrahydrofuran (25 ml), and the suspension was added to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (104 mg) and triethylamine (476 mg) in tetrahydrofuran (10 ml) at 0° C. The suspension was stirred under nitrogen atmosphere at room temperature for 3.5 hours, to the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, the resulting residue was separated and purified with silica gel column chromatography (methanol:ethyl acetate=1:8), which was recrystallized from hexane-ethyl acetate to give 1-(2-methoxybenzyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-7-(4-propoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 51) (169 mg) as yellow crystals.
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[O:25])[N:23]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.[N:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[C:34]([CH:42]=O)[CH:33]=1.CC(O)=O>ClCCCl>[CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:26]3[CH2:31][CH2:30][N:29]([CH2:42][C:34]4[CH:33]=[N:32][C:41]5[C:36]([CH:35]=4)=[CH:37][CH:38]=[CH:39][CH:40]=5)[CH2:28][CH2:27]3)=[O:25])[N:23]=2)[S:5]([C:8]2[C:9]([CH3:17])=[CH:10][C:11]([O:15][CH3:16])=[CH:12][C:13]=2[CH3:14])(=[O:6])=[O:7])[CH2:2][CH2:3]1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N3CCNCC3)co2)C2CC2)c(C)c1
Reactant: O=Cc1cnc2ccccc2c1
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N3CCN(Cc4cnc5ccccc5c4)CC3)co2)C2CC2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of N-cyclopropyl-4-methoxy-2,6-dimethyl-N-{[4-(piperazin-1-ylcarbonyl)-1,3-oxazol-2-yl]methyl}benzenesulfonamide (30 mg, 0.07 mmol) in DCE (2 mL) were added quinoline-3-carboxaldehyde (13 mg, 0.08 mmol) and AcOH (3 μL, 0.07 mmol) and the reaction mixture was stirred for 1 h at ambient temperature. STAB (20 mg, 0.09 mmol) was added and the reaction was stirred for 16 h. The reaction mixture was quenched with H2O (2 mL) and extracted with DCM (3×2 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using prep method D to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[NH:26][C:25](=[O:27])[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:39][CH2:40][O:41][CH3:42].C([O-])(O)=O.[Na+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:20][C:21]4[N:26]([CH2:39][CH2:40][O:41][CH3:42])[C:25](=[O:27])[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCBr
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CO4)cc2)CCC1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCN1C(=O)COc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 18.9 %

Procedure:
To a solution of tert-butyl(1-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (48 mg, 0.10 mmol) in dry DMF (1 mL) was added sodium hydride (16 mg, 0.41 mmol) and 1-bromo-2-methoxyethane (28 mg, 0.20 mmol) under nitrogen. The resulting mixture was stirred for 2 hours at 80° C. A saturated solution of NaHCO3 was added and the mixture was extracted with dichloromethane (3×10 ml) using a phase separator (Isolute® SPE). The combined organic phases were concentrated to dryness under reduced pressure. The resulting residue was purified by Biotage silica gel chromatography (gradient 0 to 40% EtOAc in cyclohexane) to give the title compound (10 mg, 18%). 1H NMR (500 MHz, CDCl3): 7.49 (1H, s), 7.23-7.17 (7H, m), 7.12-7.11 (2H, m), 4.95 (1H, s), 4.82 (2H, s), 4.05 (2H, t), 3.61 (2H, t), 3.29 (3H, s), 2.52-2.20 (4H, m), 2.00-1.95 (1H, m), 1.79-1.65 (1H, m), 1.40-1.10 (9H, br).