Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:28])[CH2:9][CH2:10][C:11]1[N:12]=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH:25]([CH3:27])[CH3:26])[CH:17]=2)[O:14][CH:15]=1.[CH2:29](Br)[CH:30]=[CH2:31].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[CH2:31]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:28])[CH2:9][CH2:10][C:11]1[N:12]=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH:25]([CH3:26])[CH3:27])[CH:17]=2)[O:14][CH:15]=1)[CH:30]=[CH2:29]
Reactant: C=CCBr
Reactant: COc1ccc(-c2nc(CCC(=O)c3ccccc3O)co2)cc1OC(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOc1ccccc1C(=O)CCc1coc(-c2ccc(OC)c(OC(C)C)c2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 67 mg quantity of 1-(2-hydroxyphenyl)-3-[2-(3-isopropoxy-4-methoxyphenyl)oxazol-4-yl]propan-1-one obtained in Example 223 was dissolved in 5 ml of dimethylformamide. A 31 μl quantity of allyl bromide and 73 mg of potassium carbonate were added thereto, and the mixture was stirred at room temperature overnight. A 50 μl quantity of allyl bromide was further added thereto, and the mixture was stirred at 50° C. for 8 hours, and at room temperature overnight. The reaction mixture was added to water, and extraction was then performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate 3:1), and crystallized from n-hexane to give 33 mg of colorless powdery 1-(2-allyloxyphenyl)-3-[2-(3-isopropoxy-4-methoxyphenyl)oxazol-4-yl]propan-1-one.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C([O-])=O.[Na+].S([O-])([O-])(=O)=O.O[NH3+:21].O[NH3+]>C(O)=O>[OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:21]
Reactant: [NH3+]O
Reactant: O=Cc1ccc(O)cc1O
Agent: O=C[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O=CO
Product: N#Cc1ccc(O)cc1O
Temperature: 33 °C
Reaction time: 0.17 h
Yield: 117.7 %

Procedure:
In a double walled reactor 50.0 g (0.362 mol, 1.0 meq) 2,4-dihydroxybenzaldehyde were added to 180 mL formic acid, which resulted in a brown suspension at room temperature. Then 45.8 g (0.673 mol, 1.8 meq) sodium formate were added over 2 min, and the temperature increased to 33° C. After the temperature decreased to 30° C., 35.6 g (0.217 mol, 1.2 meq) hydroxyl ammonium sulfate were added during 3 min to give a thick brown suspension which became a brown solution after stirring 10 min at 30-32° C. While heating the mixture to 100° C., crystallization occurred at 38° C. and stirring was interrupted. At 70° C. the reaction mixture became a thin suspension, which was easy to stir. This reaction mixture was stirred for 2 hours at 100° C. The color turned dark brown. TLC (silica gel 60 F254, acetone:n-hexane:water 20:20:1) showed an almost complete reaction. Formic acid (170 mL) was evaporated under reduced pressure (60° C., 10 mbar). The solid dark brown residue was stirred with 400 mL MTBE at 40° C. for 1 hour (incomplete dissolution). The insoluble residue (62.5 g) was filtered and washed two times each with 50 mL MTBE. To the mother liquor 10 g activated carbon (Norit CA 5) were added and this mixture was refluxed for 1 hour and filtered at 40° C. by Celite Super Hyflow (washing with 2×50 mL portions of MTBE). The MTBE-mother liquor was washed three times each with 100 mL water. After removing the water from this MTBE solution with azeotropic distillation (water separator) it was concentrated under reduced pressure to 20% of the starting volume and 500 mL toluene were added. Then the MTBE was distilled off under reduced pressure. During this process a brown residue began to precipitate, which was filtered. The toluene mother liquor was concentrated to 150 mL and 2,4-dihydroxybenzonitrile precipitated, which was filtered and washed two times each with 30 mL toluene. The pale tan product was dried under reduced pressure (45° C., 20 mbar). The reaction yielded 34.5 g of 2,4-dihydroxybenzonitrile (70.5%, purity 97% (HPLC)).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[CH:11][CH:10]=[N:9]1.C([Li])CCC.[S:18](Cl)([Cl:21])(=[O:20])=[O:19]>C(OCC)C.CCCCCC>[N:8]1([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[S:18]([Cl:21])(=[O:20])=[O:19])[CH:12]=[CH:11][CH:10]=[N:9]1
Reactant: Brc1ccccc1-n1cccn1
Reactant: O=S(=O)(Cl)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: O=S(=O)(Cl)c1ccccc1-n1cccn1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 52 g of 1-(2-bromophenyl)pyrazole in 230 ml of diethyl ether under a nitrogen atmosphere and cooled at -70° C. was added dropwise 175 ml of a 1.6M solution of n-butyl lithium in hexane. The suspension was allowed to warm from -70° C. to -25° C. on its own, then a solution of 37 ml of sulfuryl chloride in 69 ml of hexane was added dropwise at -25° to -20° C. After allowing the suspension to warm to room temperature, the suspension was stirred for 5 hours, then filtered to yield 38 g of crude 2-(1H-pyrazol-1-yl)benzenesulfonyl chloride which was contaminated with inorganic salts.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:11]([F:12])=[C:10](Cl)[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:21][CH:22]1[CH:26]([CH3:27])[CH2:25][NH:24][CH2:23]1.[Cl-].[NH4+]>C(#N)C>[CH2:1]([O:5][C:6]1[C:11]([F:12])=[C:10]([N:24]2[CH2:25][CH:26]([CH3:27])[CH:22]([CH3:21])[CH2:23]2)[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ncnc(Cl)c1F
Reactant: CC1CNCC1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC#N
Product: CC#CCOc1ncnc(N2CC(C)C(C)C2)c1F
Temperature: 80 °C
Reaction time: 7 h
Yield: 76.2 %

Procedure:
Into 3 ml of acetonitrile were added 0.20 g of 4-(2-butynyloxy)-6-chloro-5-fluoropyrimidine, 0.41 g of potassium carbonate and 0.20 g of 3,4-dimethylpyrrolidine hydrochloride (cis and trans diastereomer mixture), and the mixture was stirred for 7 hours at 80° C. The reaction mixture was cooled to near room temperature, a saturated ammonium chloride aqueous solution was added therein, and the mixture was extracted with tert-butyl methyl ether three times. The organic layers were washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.20 g of 4-(2-butynyloxy)-6-(3,4-dimethylpyrrolidin-1-yl)-5-fluoropyrimidine (hereinafter, referred to as Compound (36)).
Reaction SMILES: N1CCCC1.[CH2:6]([N:13]1[CH2:17][CH:16]([N+:18]([O-])=O)[CH:15]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[CH3:28])[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[CH2:6]([N:13]1[CH2:14][CH:15]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[CH3:28])[CH:16]([NH2:18])[CH2:17]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Cc1cc(Cl)ccc1C1CN(Cc2ccccc2)CC1[N+](=O)[O-]
Solvent: C1CCNC1
Product: Cc1cc(Cl)ccc1C1CN(Cc2ccccc2)CC1N

Procedure:
In analogy to the procedure described for the synthesis of pyrrolidine intermediate VIII-1 (step b), the title compound (3RS,4SR)-1-benzyl-4-(4-chloro-2-methyl-phenyl)-pyrrolidin-3-ylamine was prepared from (3SR,4RS)-1-benzyl-3-(4-chloro-2-methyl-phenyl)-4-nitro-pyrrolidine instead of (3SR,4RS)-1-benzyl-3-(3,4-dichloro-phenyl)-4-nitro-pyrrolidine and was obtained as a light brown foam. MS m/e: 301.2 [M+H]+.
Reaction SMILES: CS([C:4]1[N:9]=[C:8]([C:10]2[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=3)=[N:12][N:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=23)[CH:7]=[CH:6][N:5]=1)=O.[O:28]1[C:33]2[CH:34]=[CH:35][C:36]([NH2:38])=[CH:37][C:32]=2[O:31][CH2:30][CH2:29]1>C(O)C.Cl.C(Cl)Cl>[O:28]1[C:33]2[CH:34]=[CH:35][C:36]([NH:38][C:4]3[N:9]=[C:8]([C:10]4[C:11]([C:19]5[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=5)=[N:12][N:13]5[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=45)[CH:7]=[CH:6][N:5]=3)=[CH:37][C:32]=2[O:31][CH2:30][CH2:29]1
Reactant: CS(=O)c1nccc(-c2c(-c3cccc([N+](=O)[O-])c3)nn3ccccc23)n1
Reactant: Nc1ccc2c(c1)OCCO2
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: O=[N+]([O-])c1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)OCCO4)n2)c1
Temperature: 160 °C
Yield: 67 %

Procedure:
To a solution of 3-[2-(methylsulfinyl)-4-pyrimidinyl]-2-(3-nitrophenyl)pyrazolo[1,5-a]pyridine (1.32 g, 3.49 mmol) in ethanol (4.0 mL) is added 1,4-benzodioxan-6-amine (0.56 mL, 4.54 mmol) and conc. HCl (3 drops). The dark mixture is heated in a microwave apparatus at 160° C. for 20 min. The mixture is monitored, and heated for an additional 10 min. The mixture is diluted with DCM and concentrated to a brown foam. The crude material is purified by silica gel chromatography (30-50% EtOAc/hexanes) to give the desired product (1.09 g). 1H NMR (400 MHz, d6-DMSO) δ 9.36 (s, 1H), 8.88 (d, 1H, J=6.8), 8.45 (s, 1H), 8.28-8.31 (m, 3H), 8.01-8.03 (m, 1H), 7.72 (t, 1H, J=8.0), 7.47-7.51 (m, 1H), 7.13-7.18 (m, 2H), 6.97-6.95 (m, 1H), 6.63-6.65 (m, 2H), 4.14 (m, 1H), 7.13-7.18 (m, 2H), 6.95-6.97 (m, 1H), 6.63-6.65 (m, 2H), 4.14 (s, 4H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][C:6]1[C:11]([Cl:12])=[CH:10][N:9]=[C:8]([N:13](C(OC(C)(C)C)=O)[CH2:14][C:15]([F:24])([F:23])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N+:17]=2[O-:22])[C:7]=1[F:32])[CH3:2].Cl.N#N>CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:33])[CH2:5][C:6]1[C:11]([Cl:12])=[CH:10][N:9]=[C:8]([NH:13][CH2:14][C:15]([F:23])([F:24])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N+:17]=2[O-:22])[C:7]=1[F:32])[CH3:2]
Reactant: CCOC(=O)Cc1c(Cl)cnc(N(CC(F)(F)c2cccc[n+]2[O-])C(=O)OC(C)(C)C)c1F
Agent: Cl
Agent: N#N
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1c(Cl)cnc(NCC(F)(F)c2cccc[n+]2[O-])c1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 0° C. solution of 0.6 g (1.25 mmol) ethyl(2-{(tert-butoxycarbonyl)[2,2-difluoro-2-(1-oxido-2-pyridinyl)ethyl]amino}-5-chloro-3-fluoro-4-pyridinyl)acetate 1-7 in 20 mL EtOAc was passed a steady stream of HCl gas for 10 min, then the reaction mixture was allowed to stir at 0° C. for 1 hr. A stream of N2 gas was then passed through the mixture for 5 min, and the mixture poured into 200 mL EtOAc/50 mL 2M NaOH/7 mL conc NaOH and the layers mixed and separated. The aqueous, layer was back extracted with 50 mL EtOAc and the combined organic layers washed with 150 mL water, and brine, then dried over Na2SO4, filtered, concentrated, to give ethyl(5-chloro-2-{[2,2-difluoro-2-(1-oxido-2-pyridinyl)ethyl]amino}-3-fluoro-4-pyridinyl)acetate 1-8 which was used without further purification. 1H NMR (400 mHz, CDCl3) δ8.28 (br d, 1H, J=6.41 Hz); 7.81 (s, 1H); 7.62 (dd, 1H, J=8.06 and 2.20 Hz); 7.33 (m, 2H); 5.21 (br m, 1H); 4.68 (dt, 2H, J=13.9 and 6.59 Hz); 4.18 (q, 2H, J=6.96 Hz); 3.72 (d, 2H, J=1.47 Hz); 1.26 (t, 3H, J=7.14 Hz). Mass spectrum (electrospray) M+H=390.1
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11]([OH:13])=[O:12])[CH:6]=[C:7]([CH3:9])[CH:8]=1.OS(O)(=O)=O.[CH3:19][CH2:20]O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11]([O:13][CH2:19][CH3:20])=[O:12])[CH:6]=[C:7]([CH3:9])[CH:8]=1
Reactant: CCO
Reactant: COc1cc(C)cc(CC(=O)O)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cc(C)cc(OC)c1
Reaction time: 40 h
Yield: 85 %

Procedure:
To a solution 3-methoxy-5-methylphenylacetic acid of (8.1 g; 0.045 mol; from step (iii) above) in EtOH (100 mL) was added H2SO4 (conc.), and the solution was left to stand for 40 hours. The reaction mixture was concentrated, and the crude product was partitioned between water and ether. The organic layer was washed with NaHCO3/aq and water, dried (Na2SO4), and evaporated to yield 8.0 g (85%) of the sub-title compound as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:24]([N:27]2[CH:31]=[N:30][N:29]=[N:28]2)=[CH:23][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C@@:9]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)([CH2:12][CH2:13][OH:14])[CH2:8]1)=[O:6].C(N(CC)C(C)C)(C)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>ClCCl>[CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:24]([N:27]2[CH:31]=[N:30][N:29]=[N:28]2)=[CH:23][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C@@:9]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)([CH2:12][CH2:13][O:14][S:42]([CH3:41])(=[O:44])=[O:43])[CH2:8]1)=[O:6]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N1CC[C@](CCO)(c2ccc(Cl)c(Cl)c2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(-n2cnnn2)cc1C(=O)N1CC[C@](CCOS(C)(=O)=O)(c2ccc(Cl)c(Cl)c2)C1
Reaction time: 0.5 h

Procedure:
Combine (S)-1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine (600 mg, 1.3 mmol) and N,N-diisopropylethylamine (0.5 mL, 2.87 mmol) in dichloromethane (13 mL). Cool in a ice-bath. Add dropwise, methanesulfonyl chloride (0.12 mL, 1.55 mmol). After 15 minutes add more methanesulfonyl chloride (0.03 mL, 0.39 mmol). After 30 minutes, extract with 5% sodium bicarbonate solution and water. Dry the organic layer over MgSO4, filter, and concentrate invacuo to give the title compound: Rf= 0.15 (silica gel, ethyl acetate).
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)[CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[Cl:28][C:29]1[C:30]([Cl:44])=[CH:31][C:32]2[O:37][CH2:36][C:35](=[O:38])[N:34]([CH2:39][C:40]([OH:42])=O)[C:33]=2[CH:43]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[Cl:28][C:29]1[C:30]([Cl:44])=[CH:31][C:32]2[O:37][CH2:36][C:35](=[O:38])[N:34]([CH2:39][C:40]([N:2]([CH3:1])[C@H:3]([C:11]3[CH:12]=[CH:13][C:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:19][CH:18]=4)=[CH:15][CH:16]=3)[CH2:4][N:5]3[CH2:10][CH2:9][O:8][CH2:7][CH2:6]3)=[O:42])[C:33]=2[CH:43]=1
Reactant: CCOC(=O)c1ccc(-c2ccc([C@H](CN3CCOCC3)NC)cc2)cc1
Reactant: O=C(O)CN1C(=O)COc2cc(Cl)c(Cl)cc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(-c2ccc([C@H](CN3CCOCC3)N(C)C(=O)CN3C(=O)COc4cc(Cl)c(Cl)cc43)cc2)cc1
Temperature: 0 °C
Yield: 69.5 %

Procedure:
Ethyl 4′-[(1R)-1-(methylamino)-2-(4-morpholinyl)ethyl]-4-biphenylcarboxylate (crude, 26.5 g) was dissolved in 500 mL of DMF at room temperature with magnetic stirring. The resulting solution was treated with (6,7-dichloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)acetic acid (28.8 g, 80.4 mmol, with 23 wt % LiCl) and cooled to 0° C. To this solution was added triethylamine (20.5 mL, 147.4 mmol) and BOP (35.5 g, 80.4 mmol). The reaction mixture was maintained at room temperature overnight. The reaction mixture was filtered. The filtrate was slowly added to 2500 mL of H2O with vigorous stirring. The resulting precipitate was collected by filtration and partitioned between 300 mL of brine solution and 1000 mL of DCM. The organic layer was dried over MgSO4, filtered, and concentrated. The brown residue was purified by column chromatography (250 g silica gel 60, 230-400 mesh, 2% MeOH and 0.5% NEt3 in CH2Cl2 as eluent) to give the title compound as a brown solid (31.3 g, 75% yield). MS (ES) m/e 626 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:19]([CH:20]=[O:21])[CH2:18][CH2:17][C:16]([C:22]([O:24]C)=[O:23])=[CH:15][C:14]=3[CH:26]=2)=[CH:6][C:5]=1[F:27])[CH3:2].[OH-].[Na+].Cl>C1COCC1.C(O)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:19]([CH:20]=[O:21])[CH2:18][CH2:17][C:16]([C:22]([OH:24])=[O:23])=[CH:15][C:14]=3[CH:26]=2)=[CH:6][C:5]=1[F:27])[CH3:2]
Reactant: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3C=O)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3C=O)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 102.5 %

Procedure:
In a mixture of THF and ethanol (1:1, v/v, 20.0 ml) was dissolved methyl 7-(4-ethoxy-3-fluorophenyl)-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (441 mg). To the solution was added 1N sodium hydroxide solution (12.0 ml), and the mixture was stirred at room temperature for 16 hours. The mixture was a little concentrated, and to the residue was added 1N hydrochloric acid to convert weakly acidic solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give crystals, which were washed with ethyl acetate/hexane to give 7-(4-ethoxy-3-fluorophenyl)-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (435 mg) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Cl.[CH2:10]([N:12]([CH2:16][CH3:17])[CH2:13][CH2:14]Cl)[CH3:11].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:10]([N:12]([CH2:16][CH3:17])[CH2:13][CH2:14][S:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=1)[CH3:11]
Reactant: Nc1ccc(S)cc1
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCN(CC)CCSc1ccc(N)cc1
Temperature: 60 °C
Yield: 48.8 %

Procedure:
To a solution of 4-aminothiophenol (23.0 mmol, 2.88 g) in DMF (23 mL) was added 2-(diethylamino)ethyl chloride hydrochloride (11.5 mmol, 1.98 g) and cesium carbonate (34.5 mmol, 11.2 g). The resulting mixture was heated to 60° C. for 3 hours. The solvent was removed by rotary evaporation. The residue was partitioned between dichloromethane and water. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography eluting with 5% methanol in dichloromethane with 1% triethylamine, giving the title compound (1.26 g, 49%). 1H NMR (CDCl3): δ 0.98 (6H, t, J=7.0 Hz), 2.51 (4H, q, J=7.1 Hz), 2.65 (2H, t, J=8.1 Hz), 2.85 (2H, t, J=8.3 Hz), 6.61 (2H, d, J=8.6 Hz), 7.25 (2H, d, J=8.6 Hz). LCMS m/z=225 (m+H+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.[CH3:19][O:20][NH:21][CH3:22].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.O>[F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[CH:7][C:3]=1[C:4]([N:21]([O:20][CH3:19])[CH3:22])=[O:5]
Reactant: O=C(O)c1cc(-c2cccc(F)c2)ccc1F
Reactant: CNOC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: CON(C)C(=O)c1cc(-c2cccc(F)c2)ccc1F
Reaction time: 48 h
Yield: 86.1 %

Procedure:
To a solution of 2-fluoro-5-(3-fluorophenyl)benzoic acid (intermediate III(a)) (2 g, 8.5 mmol, 1.0 eq) and N-methoxymethanamine hydrochloride (916 mg, 9.4 mmol, 1.1 eq) in DMF (20 mL) was added triethylamine (3.6 mL, 25.6 mmol, 3.0 eq) at 0° C. HOBt (1.51 g, 11.1 mmol, 1.3 eq) and EDC (2.13 g, 11.1 mmol, 1.3 eq) were added and the solution was stirred for 2 days. Water was added and the aqueous layer was extracted with EtOAc. The organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum ether: EtOAc, 20:1 to 10:1 then CH2Cl2) to give the title compound as a colorless oil (2.03 g, 85%).
Reaction SMILES: Br[C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:30])[C:8]4[CH:20]=[CH:19][C:18]([O:21][CH2:22][C@H:23]5[CH2:27][O:26]C(C)(C)[O:24]5)=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C1CCN2C(=NCCC2)CC1.Cl[C:65](OCC)=[O:66].[BH4-].[Na+]>C1COCC1.C(O)C.CC#N.CC#N.Cl[Pd]Cl.C(=[Mo](=C=O)(=C=O)(=C=O)(=C=O)=C=O)=O>[OH:24][C@H:23]([CH2:27][OH:26])[CH2:22][O:21][C:18]1[CH:19]=[CH:20][C:8]2[C:7](=[O:30])[C:6]3[C:5]4[C:13](=[CH:14][C:2]([CH2:65][OH:66])=[CH:3][CH:4]=4)[NH:12][C:11]=3[C:10]([CH3:15])([CH3:16])[C:9]=2[CH:17]=1
Reactant: CC1(C)OC[C@H](COc2ccc3c(c2)C(C)(C)c2[nH]c4cc(Br)ccc4c2C3=O)O1
Reactant: CCOC(=O)Cl
Agent: Cl[Pd]Cl
Agent: O=C=[Mo](=C=O)(=C=O)(=C=O)(=C=O)=C=O
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCO
Solvent: C1CCOC1
Solvent: CC#N
Product: CC1(C)c2cc(OC[C@H](O)CO)ccc2C(=O)c2c1[nH]c1cc(CO)ccc21
Temperature: 70 °C
Reaction time: 2 h
Yield: 8.3 %

Procedure:
3-Bromo-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimethyl-5,6-dihydrobenzo[b]carbazol-11-one (200.2 mg, 0.426 mmol), palladium acetate (II) (19 mg, 0.0848 mmol), hexacarbonyl molybdenum (115.5 mg, 0.438 mmol) and tris(o-tolyl)phosphine (52.5 mg, 0.172 mmol) were dissolved in THF (1.3 ml) and ethanol (0.075 ml), added with DBU (0.195 ml), and subjected to microwave irradiation at 160° C. for 15 min under nitrogen atmosphere. The resulting reaction solution was partitioned between aqueous solution of potassium dihydrophosphoric acid and ethyl acetate. The organic layer was washed with saturated brine, and then concentrated under reduced pressure. The resulting residues were dissolved in ethanol (10 ml) and THF (3 ml), added with 2 N KOH (2 ml), and stirred at room temperature for 2 hrs, at 50° C. overnight and at 70° C. for 2 hrs. The reaction solution was partitioned between aqueous solution of potassium dihydrophosphoric acid and ethyl acetate. The organic layer was washed with saturated brine, and then concentrated under reduced pressure. The resulting residues were suspended and purified with MTBE/hexane (1/1) (155.4 mg). The THF solution (1.5 ml) of the product (109 mg) was added with TEA (0.052 ml, 0.373 mmol) and ethyl chloroformate (0.029 ml, 0.303 mmol) under ice cooling, and the mixture was stirred at 0° C. for 2 hrs. Subsequently, ethanol (1 ml) and sodium borohydride (75.7 mg, 2.0 mmol) were added to the mixture, which was then stirred at room temperature for 2 hrs. The reaction solution was partitioned between aqueous solution of potassium dihydrophosphoric acid and ethyl acetate. The organic layer was washed with saturated brine, and then concentrated under reduced pressure. The resulting residues were purified by silica gel column (MeOH/DCM) (35.2 mg). Thus-obtained solid (9.6 mg) was dissolved in MeOH (1 ml), added with 1 N HCl (3 drops), and the mixture was stirred at 60° C. for 90 min. After cooling and concentration under reduced pressure, the resultant was purified by TLC (MeOH/DCM) to obtain Compound GT20-8 (6.2 mg, white solid) and Compound GT20-9 (4.3 mg, white solid).
Reaction SMILES: [C:1]([C:3]1[CH:33]=[CH:32][C:6]([CH2:7][CH:8]([C:16]([NH:18][S:19]([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)(=[O:21])=[O:20])=[O:17])[C:9]([N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)#[N:2].[N:34]1[CH:39]=[CH:38][C:37]([N:40]2CCNCC2)=[CH:36][CH:35]=1>>[C:1]([C:3]1[CH:33]=[CH:32][C:6]([CH2:7][CH:8]([C:9](=[O:10])[N:11]2[CH2:12][CH2:13][N:40]([C:37]3[CH:38]=[CH:39][N:34]=[CH:35][CH:36]=3)[CH2:15][CH2:14]2)[C:16]([NH:18][S:19]([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)(=[O:20])=[O:21])=[O:17])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCN(CC)C(=O)C(Cc1ccc(C#N)cc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1
Reactant: c1cc(N2CCNCC2)ccn1
Product: N#Cc1ccc(CC(C(=O)NS(=O)(=O)c2ccc3ccccc3c2)C(=O)N2CCN(c3ccncc3)CC2)cc1
Yield: 30.4 %

Procedure:
In the same manner as in Example 1 (4), a crude product was obtained using the compound (300 mg) obtained in Example 111 (4) and 1-(4-pyridyl)piperazine (144 mg). This was purified by silica gel column chromatography to give the title compound (109 mg) as a white powder.