Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:8][CH:9]2[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][CH:10]2[CH:21]=1)(=O)=O.C([O-])(=O)C.[K+].Cl[C:30]1[N:35]=[C:34]2[N:36]([CH3:46])[C:37](=[O:45])[N:38]([CH2:39][CH:40]3[CH2:42][C:41]3([F:44])[F:43])[C:33]2=[CH:32][CH:31]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.O.O1CCOCC1>[F:44][C:41]1([F:43])[CH2:42][CH:40]1[CH2:39][N:38]1[C:33]2[C:34](=[N:35][C:30]([C:7]3[CH2:8][CH:9]4[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:11][CH:10]4[CH:21]=3)=[CH:31][CH:32]=2)[N:36]([CH3:46])[C:37]1=[O:45]
Reactant: Cn1c(=O)n(CC2CC2(F)F)c2ccc(Cl)nc21
Reactant: CC(C)(C)OC(=O)N1CC2C=C(OS(=O)(=O)C(F)(F)F)CC2C1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Solvent: C1COCCO1
Solvent: O
Product: Cn1c(=O)n(CC2CC2(F)F)c2ccc(C3=CC4CN(C(=O)OC(C)(C)C)CC4C3)nc21
Temperature: 60 °C
Reaction time: 18 h

Procedure:
tert-Butyl 5-{[(trifluoromethyl)sulfonyl]oxy}-3,3a,4,6a-tetrahydrocyclopenta-[c]pyrrole-2(1H)-carboxylate (8-2, 1 g, 2.7 mmol, 1.0 equiv), bis(pinocolato)diboron (0.75 g, 3.0 mmol, 1.1 equiv), potassium acetate (0.8 g, 8.4 mmol, 3.0 equiv) and PdCl2(dppf) (0.144 g, 0.196 mmol, 0.07 equiv) were added to anhydrous 1,4-dioxane (4 mL) and heated to 60° C. After 18 h, the reaction contents were cooled to RT, followed by the subsequent addition of water (1.4 mL), 5-Chloro-1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (6-1, 766 mg, 2.8 mmol, 1.0 equiv), Cs2CO3 (1.8 g, 5.5 mmol, 2.00 equiv) and Bis(tri-tert-butylphosphine)palladium(0) (0.186 g, 0.364 mmol, 0.13 equiv). The resulting mixture was heated to 60° C. for 4.5 h. Following this duration, LCMS showed consumption of starting material. The contents were then cooled to room temperature, diluted with ethyl acetate (50 mL), filtered through Celite and rinsed with ethyl acetate (3×50 mL) and water (1×30 mL). The filtrate layers were separated and the combined organics were washed with saturated NaHCO3 (100 mL). The combined aqueous layers were then back-extracted with ethyl acetate (2×50 mL). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to give a dark orange oil. Purification by normal-phase chromatography (0-50% EtOAc:Hex) afforded 14-1 as an off-white solid. MS m/z (M+H): calculated=447.2; observed=447.2.
Reaction SMILES: SC1C=C2C(=CC=1)NC(=O)C2.[CH3:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH2:15][C:16](=[O:22])[NH:17]2.[Cl:23][S:24](O)(=[O:26])=[O:25]>>[Cl:23][S:24]([C:21]1[C:13]([CH3:12])=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:22])[CH2:15]2)(=[O:26])=[O:25]
Reactant: Cc1cccc2c1CC(=O)N2
Reactant: O=S(=O)(O)Cl
Agent: O=C1Cc2cc(S)ccc2N1
Product: Cc1c(S(=O)(=O)Cl)ccc2c1CC(=O)N2

Procedure:
Under reaction conditions analogous to preparation of 5-mercaptooxindole, chlorosulfonylation of 4-methyloxindole 3.15 g (21.40 mmol) with neat chlorosulfonic acid 25 mL provided 4.55 g of 5-chlorosulfonyl-4-methyloxindole (86.5% Y, 95% isomeric purity by 1H-NMR, in d6-acetone) which was reduced with triphenyl phosphine 17.0 g (65 mmol) in anhydrous dichloromethane, to provide a crude thiol 2.573 g (75% Y) which was then methylated with excess of methyl iodide (1.50 mL; 24 mmol) to provide a crude methylthio intermediate 2.722 g (98% Y, 90% pure), by using conditions analogous to preparation of 5-methylsulfoxyoxindole.
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:11][C:12]([NH:14][C:15]1[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=1[CH3:23])=S>C(#N)C.C(OCC)(=O)C.[Hg](Cl)Cl>[C:16]1([CH3:23])[CH:17]=[C:18]([CH3:22])[CH:19]=[C:20]([CH3:21])[C:15]=1[NH:14][C:12]1[O:1][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=2[N:11]=1
Reactant: Cc1cc(C)c(NC(=S)Nc2cccc([N+](=O)[O-])c2O)c(C)c1
Agent: Cl[Hg]Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1cc(C)c(Nc2nc3cccc([N+](=O)[O-])c3o2)c(C)c1
Reaction time: 1 h
Yield: 87.8 %

Procedure:
To a solution containing 0.06 g (0.18 mmol) of 1-(2-hydroxy-3-nitrophenyl)-3-mesitylthiourea in acetonitrile was added 0.10 g (0.36 mmol) of mercury (II) chloride, and the mixture was then stirred for 1 h. The reaction mixture was diluted with ethyl acetate (2 ml) and filtered through a prepacked celite column. The filtrate was concentrated under reduced pressure and the residue was purified via Biotage chromatography eluting with 20% ethyl acetate/dichloromethane to afford 0.047 g (90%) of product.
Reaction SMILES: S(=O)(=O)(O)O.[N+]([O-])(O)=[O:7].[C:10]12([CH2:20][NH2:21])[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][CH:12]([CH2:13]3)[CH2:11]1)[CH2:17]2>>[NH2:21][CH2:20][C:10]12[CH2:17][CH:16]3[CH2:15][CH:14]([CH2:13][C:12]([OH:7])([CH2:18]3)[CH2:11]1)[CH2:19]2
Reactant: NCC12CC3CC(CC(C3)C1)C2
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: NCC12CC3CC(CC(O)(C3)C1)C2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a vigorously stirred mixture of concentrated sulfuric acid (22.7 mL) and 65% nitric acid (2.3 mL) at 0° C. was added C-adamantan-1-yl-methylamine (2.0 g, 12.12 mmol) dropwise. The reaction mixture was stirred for 2 h at 0° C., warmed to room temperature and stirred at that temperature for 24 h, cooled to 0° C. and slowly quenched with ice (10.8 g). The mixture was allowed to warm to ambient as ice melts overnight, cooled to 0° C. again and treated with sodium hydroxide (50 g) in small portions. The resulting brownish paste was filtered, and the filter cake was rinsed with DCM (200 mL). After separation, the organic layer was washed with brine (2×20 mL), dried over sodium sulfate, filtered and concentrated to give a white solid (1.09 g). (m/z): [M+H]+ calcd for C11H19N 182.2; found 182.2.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([F:25])([F:24])[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.I[Si](C)(C)C.C(=O)(O)[O-].[Na+].[OH-].[Na+]>C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[F:25][C:16]([F:24])([C:17]1[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=1)[CH2:15][CH2:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(F)(F)c2ccc(F)cc2)CC1
Agent: C[Si](C)(C)I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: Fc1ccc(C(F)(F)CCC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-(t-Butoxycarbonyl)-4-(3,3-difluoro-3-(4-fluorophenyl)prop-1-yl)piperidine from Step G (122 mg, 0.34 mmol) was dried by evaporation of a toluene solution at reduced pressure. The residue was dissolved in chloroform (7.6 mL) and iodotrimethylsilane (0.100 mL, 141 mg, 0.70 mmol) was added. After stirring 30 min at rt, the solution was poured into a mixture of saturated aqueous sodium bicarbonate (15 mL) and 2.5 N aq. NaOH (5 mL), and extracted with ether (50 mL). The organic layer was washed with saturated aq. brine (15 mL), dried (sodium sulfate), decanted, and evaporated to give the title compound as 88 mg of colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[CH:11]1([NH2:14])[CH2:13][CH2:12]1>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:14][CH:11]2[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(Br)cc1
Reactant: NC1CC1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Br)cc1)NC1CC1

Procedure:
Under a nitrogen atmosphere, tetrahydrofuran (80 ml) was added to 4-bromophenyl isocyanate 30 (10.0 g), and a solution of cyclopropylamine 1 (3.17 g) in tetrahydrofuran (20 ml) was added dropwise with stirring under ice-cooling. After the completion of the dropwise addition, the mixture was stirred at room temperature for 3 hrs, and the reaction mixture was concentrated under reduced pressure. Diethyl ether-hexane [1:1 (volume ratio), 100 ml] was added to the residue and, after stirring, the crystals were collected by filtration and dried to give 1-(4-bromo-phenyl)-3-cyclopropyl-urea 31 (12.9 ġ, over weight) as colorless crystals, which were used for the next step without purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5]O[CH2:3][CH2:2]1.Cl[C:8]1[C:13]([Br:14])=[CH:12][N:11]=[C:10]([CH2:15][OH:16])[CH:9]=1.ClC1C(O)=NC=CC=1Cl>>[N:1]1([C:8]2[C:13]([Br:14])=[CH:12][N:11]=[C:10]([CH2:15][OH:16])[CH:9]=2)[CH2:6][CH2:5][CH2:3][CH2:2]1
Reactant: OCc1cc(Cl)c(Br)cn1
Reactant: C1COCCN1
Agent: Oc1nccc(Cl)c1Cl
Product: OCc1cc(N2CCCC2)c(Br)cn1

Procedure:
Substituting pyrrolidine (7.4 ml) for morpholine and 4-chloro-5-bromo-2-hydroxymethylpyridine (4 g) for 3,4-dichloro-2-hydroxypyridine and using corresponding molar proportions of the other reagents in the method of Example 3D gave 4-pyrrolidino-5-bromo-2-hydroxymethylpyridine. 2.28 g, m.p. 108°-10° C., from ether.
Reaction SMILES: CN(C=O)C.[CH3:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1F)=[O:8].[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.O>C(OCC)(=O)C>[F:15][C:12]1[CH:13]=[CH:14][C:9]([C:7](=[O:8])[CH3:6])=[C:10]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH:11]=1
Reactant: C1COCCN1
Reactant: CC(=O)c1ccc(F)cc1F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)c1ccc(F)cc1N1CCOCC1
Yield: 44.9 %

Procedure:
A DMF (5.0 mL) solution of 2,4-difluoroacetophenone (1.0 g) and morpholine (558 mg) was agitated at 110° C. for 6 hours and 30 minutes. Water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: heptane-ethyl acetate system), and 642 mg of the title compound was obtained. The physical properties of the compound are as follows.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=3[F:17])=[C:7]([C:18](O)=[O:19])[C:6]=2[CH:21]=1.C1C=CC2N(O)N=[N:33][C:31]=2C=1.CCN=C=NCCCN(C)C.CCN(CC)CC.CN>CN(C=O)C>[Br:1][C:2]1[C:3]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=3[F:17])=[C:7]([C:18]([NH:33][CH3:31])=[O:19])[C:6]=2[CH:21]=1
Reactant: On1nnc2ccccc21
Reactant: CS(=O)(=O)Nc1cc2oc(-c3ccc(F)cc3F)c(C(=O)O)c2cc1Br
Agent: CCN=C=NCCCN(C)C
Agent: CN
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(-c2ccc(F)cc2F)oc2cc(NS(C)(=O)=O)c(Br)cc12
Reaction time: 2 h
Yield: 88 %

Procedure:
A solution of 5-bromo-2-(2,4-difluorophenyl)-6-(methylsulfonamido)benzofuran-3-carboxylic acid (440 mg, 0.99 mmol), HOBT (199 mg, 1.48 mmol) and EDCI (283 mg, 1.48 mmol) in dry DMF (10 mL) was stirred at 25° C. After 2 hours, Et3N (299 mg, 2.96 mmol) and MeNH2 (200 mg, 2.96 mmol) was added to the mixture and then stirred overnight. The solvent was removed by vacuum, the mixture was washed with H2O (20 mL) and extract with EtOAc (40 mL*3), dried over Na2SO4, After concentrated, the resulting residue was purified using column chromatography (dichloromethane:EtOAc=2:1) to provide 5-bromo-2-(2,4-difluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (400 mg, yield: 88%). 1H-NMR (DMSO-d6, 400 MHz) δ 9.61 (s, 1H), 8.19 (d, J=3.6 Hz, 1H), 7.97 (s, 1H), 7.80˜7.86 (m, 1H), 7.73 (s, 1H), 7.44˜7.50 (m, 1H), 7.27˜7.31 (m, 1H), 3.02 (s, 3H), 2.75 (d, J=4.8 Hz, 3H). MS (M+H)+: 459/461.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH2:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][N:12]1[C:21]1[N:22]=[C:23]([C:32]#N)[CH:24]=[C:25]2[C:29]([CH3:30])=[C:28]([CH3:31])[NH:27][C:26]=12.[OH2:34].[OH-].[Na+]>O1CCCC1.C(OCC)C>[CH2:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][N:12]1[C:21]1[N:22]=[C:23]([CH:32]=[O:34])[CH:24]=[C:25]2[C:29]([CH3:30])=[C:28]([CH3:31])[NH:27][C:26]=12
Reactant: Cc1[nH]c2c(N3CCc4ccccc4C3)nc(C#N)cc2c1C
Reactant: O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1[nH]c2c(N3CCc4ccccc4C3)nc(C=O)cc2c1C
Reaction time: 5 h
Yield: 16 %

Procedure:
Diisobutyl aluminum hydride (1.0M in toluene solution; 1.98 ml, 1.98 mmol) was added at −78° C. to a solution of 7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carbonitrile (300 mg, 099 mmol) prepared in Example 682 in anhydrous tetrahydrofuran (2 ml). The reaction mixture was stirred for 5 hours and then diluted with diethyl ether. Water (2 ml) and 15% sodium hydroxide solution (2 ml) were added to the reaction mixture, which was then stirred for 30 minutes. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/3, v/v) to give 50.6 mg of the titled compound as a white solid. (Yield: 16%).
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][S:6]([O:9][C:10]1[CH:15]=[CH:14][C:13](O)=[C:12]([C:17]([CH3:21])([CH3:20])[CH2:18][OH:19])[CH:11]=1)(=[O:8])=[O:7].O>CN(C)C=O>[CH3:5][S:6]([O:9][C:10]1[CH:15]=[CH:14][C:13]2[O:19][CH2:18][C:17]([CH3:21])([CH3:20])[C:12]=2[CH:11]=1)(=[O:8])=[O:7]
Reactant: CC(C)(CO)c1cc(OS(C)(=O)=O)ccc1O
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: O
Product: CC1(C)COc2ccc(OS(C)(=O)=O)cc21
Temperature: 15 °C

Procedure:
Thionyl chloride (83 parts) was added dropwise with cooling to dimethyl formamide (260 parts). To this mixture was then added dropwise a solution of 4-hydroxy-3-(2-hydroxy-1,1-dimethylethyl)phenyl methanesulphonate (180 parts) (from Example 1) in dimethyl formamide (190 parts) with stirring at about 15° C. The mixture was then stirred for one hour at room temperature and for five hours at 100° C. Addition to water (2000 parts) caused precipitation of an off-white solid which was filtered off and recrystallised from aqueous ethanol to give 2,3-dihydro-3,3-dimethylbenzofuran-5-yl methanesulphonate (65.2 parts) identical with the product of Example 37(a) above.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].[O:11](C(OC(C)(C)C)=O)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=O.CCCCCC.C(OCC)(=O)C.O>C1COCC1.CN(C1C=CN=CC=1)C>[N+:1]([C:4]1[CH:5]=[C:6]([NH:7][C:12](=[O:11])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:8]=[CH:9][CH:10]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Nc1cccc([N+](=O)[O-])c1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 82.4 %

Procedure:
In a 50 mL 3-neck RBF, 3-nitroaniline 5 (5.0 g) in THF (40 mL) and (BOC)2O (7.89 g) was charged and cooled to 0° C. DMAP (6.09 g) was added portion-wise into the reaction mixture and reaction mixture was warmed to room temperature and stirred at room temperature for 5 hr. The reaction was monitored on TLC using hexane:ethyl acetate (5:5) as mobile phase. After completion of the reaction, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with 50 mL brine solution, dried over sodium sulfate and concentrated completely under reduced pressure at 40° C. Crude material was purified by using column chromatography. Product was eluted with 4% ethyl acetate in hexane and concentrated to give 7.1 g of tert-butyl (3-nitrophenyl)carbamate.
Reaction SMILES: Cl[C:2]1[C:3]([O:14][CH3:15])=[CH:4][C:5]2[CH2:11][CH2:10][NH:9][CH2:8][CH:7]([CH3:12])[C:6]=2[CH:13]=1.IC1C(OC)=CC2CCNCC(C)C=2C=1.CN1CC(C)C2C=C([Br:46])C(OC)=CC=2CC1.BrC1C(OC)=CC2CCNCC(CC)C=2C=1.ClC1C(OC)=CC2CCNCC(CC)C=2C=1.IC1C(OC)=CC2CCNCC(CC)C=2C=1.COC1C(C(F)(F)F)=CC2C(C)CNCCC=2C=1.COC1C(C(F)(F)C(F)(F)F)=CC2C(C)CNCCC=2C=1>>[Br:46][C:2]1[C:3]([O:14][CH3:15])=[CH:4][C:5]2[CH2:11][CH2:10][NH:9][CH2:8][CH:7]([CH3:12])[C:6]=2[CH:13]=1
Reactant: COc1cc2c(cc1Br)C(C)CN(C)CC2
Reactant: COc1cc2c(cc1Cl)C(C)CNCC2
Agent: CCC1CNCCc2cc(OC)c(Br)cc21
Agent: CCC1CNCCc2cc(OC)c(Cl)cc21
Agent: CCC1CNCCc2cc(OC)c(I)cc21
Product: COc1cc2c(cc1Br)C(C)CNCC2

Procedure:
8-Chloro-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-Iodo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; N-Methyl-8-bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-Bromo-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-Chloro-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-Iodo-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine; 7-Methoxy-1-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-3-benzazepine; and 7-Methoxy-1-methyl-8-pentafluoroethyl-2,3,4,5-tetrahydro-1H-3-benzazepine; or a pharmaceutically acceptable salt, solvate or hydrate thereof.
Reaction SMILES: [CH3:1][S:2][C:3](=[CH:8]OS(C1C=CC(C)=CC=1)(=O)=O)[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.C(Cl)(Cl)Cl.[C:31]1([SH:37])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>COC(C)(C)C>[CH3:1][S:2][C:3](=[CH:8][S:37][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(=COS(=O)(=O)c1ccc(C)cc1)SC
Reactant: Sc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: COC(=O)C(=CSc1ccccc1)SC
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
To a mixture of methyl 2-methylthio-3-(p-toluenesulfonyloxy)acrylate (3.05 g), triethylamine (2 mL) and chloroform (20 mL) was added slowly thiophenol (1.28 g) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture were added tert-butyl methyl ether, and then a 1N aqueous sodium hydroxide solution, thereby layers were separated. The organic layer was washed with a saturated aqueous sodium chloride solution, dried, and then concentrated. The residue was subjected to silica gel column chromatography (hexane/ethyl acetate=10/1) to obtain methyl 2-methylthio-3-(phenylthio)acrylate (1.64 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([OH:9])=O.ClC(OCC(C)C)=O.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[N:20]=1.C(=O)(O)[O-].[Na+]>O1CCCC1.C(N(CC)CC)C>[NH2:18][C:19]1[N:20]=[C:21]([NH:25][C:7](=[O:9])[CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:22]=[CH:23][CH:24]=1
Reactant: COCCOCC(=O)O
Reactant: Nc1cccc(N)n1
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCOCC(=O)Nc1cccc(N)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4.9 ml of (2-methoxyethoxy)-acetic acid is dissolved in 500 ml of tetrahydrofuran. 9.7 ml of triethylamine and 5.6 ml of isobutyl chloroformate are added at 0° C., and it is stirred for 30 minutes at 0° C. 3.96 g of 2,6-diaminopyridine is added, and it is stirred for another 4 hours at room temperature. The reaction mixture is mixed with semi-saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic solution is washed with saturated sodium chloride solution, dried on sodium sulfate, concentrated by evaporation, and after purification by chromatography on silica gel, 5.04 g of the title compound is obtained.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].[Li]CCCC.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28](/[CH:29]=[CH:30]/[CH:31]=[O:32])=[C:27]([CH:33]([CH3:35])[CH3:34])[CH:26]=[C:25]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:24]=2)=[CH:19][CH:18]=1.Cl.C([O-])(O)=O.[Na+]>C1COCC1.CCOCC.O>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28](/[CH:29]=[CH:30]/[CH:31]([OH:32])[CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH3:8])=[O:6])=[C:27]([CH:33]([CH3:35])[CH3:34])[CH:26]=[C:25]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:24]=2)=[CH:19][CH:18]=1
Reactant: COC(=O)CC(C)=O
Reactant: CC(C)c1cc(-c2ccccc2)nc(-c2ccc(F)cc2)c1/C=C/C=O
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)CC(=O)CC(O)/C=C/c1c(C(C)C)cc(-c2ccccc2)nc1-c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 44 %

Procedure:
Methyl acetoacetate (160 mg, 1.38 mmol) was dropwise to a slurry of NaH (60% in mineral oil, 55.1 mg, 1.38 mmol) in dry THF (3.5 ml) at 0° C. After 15 minutes, n-BuLi (1.5M in hexane, 830 ul, 1.25 mmol) was added and the mixture was stirred an additional 15 minutes. The bright yellow solution was cooled to -78° C. and treated with a solution of (E)-3-[2-(4-fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinyl]-2-propenal (317 mg, 0.92 mmol) in THF (2 ml). Stirring continued for 20 minutes, after which time the reaction was warmed to 0° C. and stirred for an additional 20 minutes. The yellow-orange solution was then added to a biphasic mixture of 1N HCl (3 ml), H2O (15 ml), and Et2O (30 ml). The aqueous layer was made slightly basic with saturated NaHCO3 and the phases were separated. The aqueous layer was diluted with saturated NH4Cl and was extracted with Et2O once again. The combined organic layers were washed with brine and dried (Na2SO4). Filtration and removal of the solvent afforded an oil which was chromatographed (flash, Merck SiO2, 35% EtOAc in hexane) to give (E)-7-[2-(4-fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinyl]-5-hydroxy-3-oxo-6-heptenoic acid, methyl ester as an oily solid (187 mg, 44%).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N)CN.C1COCC1.[Li]>O>[CH2:10]1[C:11]2[CH2:12][C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH2:7][CH2:8][CH2:9]1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: [Li]
Solvent: C1CCOC1
Solvent: O
Solvent: NCCN
Product: c1ccc2c(c1)CC1=C2CCCC1
Yield: 90.1 %

Procedure:
30 g (0.18 mol) of fluorene was placed in a 1 L glass vessel, to which a mixed solution of 175 mL of ethylenediamine and 175 mL of THF was added under a nitrogen atmosphere, and dissolved by stirring. 5.6 g (0.812 mol) of metallic lithium was added to the resulting solution at 0° C. over 50 minutes. After completing the reaction, water was added thereto, and the target compound was extracted with diethyl ether and rinsed with a sodium chloride aqueous solution. Magnesium sulfate was added to the diethyl ether layer, which was dried in a refrigerator overnight. Magnesium sulfate was filtered off, and diethyl ether was removed to provide 27.6 g of 1,2,3,4-tetrahydrofluorene (4HFluH) as an orange solid matter (yield: 90%).
Reaction SMILES: Br[C:2]1[C:28]([F:29])=[CH:27][C:5]2[O:6][C:7]3[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:8]=3[C@H:9]3[C@H:14]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:13][CH2:12][CH2:11][N:10]3[C:4]=2[CH:3]=1.[C:30]([Cu])#[N:31].CN1C(=O)CCC1.O>C(OCC)(=O)C.[Cu]I>[C:30]([C:2]1[C:28]([F:29])=[CH:27][C:5]2[O:6][C:7]3[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:8]=3[C@H:9]3[C@H:14]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:18])[F:19])[CH2:13][CH2:12][CH2:11][N:10]3[C:4]=2[CH:3]=1)#[N:31]
Reactant: O=C(N[C@@H]1CCCN2c3cc(Br)c(F)cc3Oc3cc(F)ccc3[C@@H]12)C(F)(F)F
Reactant: N#C[Cu]
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: N#Cc1cc2c(cc1F)Oc1cc(F)ccc1[C@H]1[C@H](NC(=O)C(F)(F)F)CCCN21
Temperature: 180 °C
Reaction time: 0.33 h
Yield: 59.7 %

Procedure:
A mixture of 2.74 g (5.74 mmol) of (−)-(cis)-N-(7-bromo-8,12-difluoro-1,3,4,14b-tetrahydro-2H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide, CuCN (1.3 g, 14.3 mmol), CuI (0.123 g, 0.57 mmol) and NMP (25 mL) was stirred in a microwave for 20 min. at 180° C., 300 Watt with cooling. After cooling down, the reaction mixture was poured into water (500 mL). The precipitate, containing product and salts, was redissolved in ethyl acetate and the salts were filtered off. The organic layer was washed with NH4OH-solution, water, and brine, dried, and concentrated to give the crude compound which was crystallized to give the title compound (1.45 g, 59%). 1H-NMR (400 MHz, DMSO) 1.60-1.86 (m, 3H), 2.01 (m, 1H), 3.15 (m, 1H), 3.86 (m, 1H), 4.133 (d, J=10.0, 1H), 4.35 (m, 1H), 7.00 (m, 1H), 7.03 (m, 1H), 7.44 (d, J=7.7, 1H), 7.6 (d, J=6.3, 1H), 9.23 (br-d, J=7.8, 1H). (m/z)=424 (M+H)+.