Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:13]2[C:12]3[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH2:4][CH2:3]1.N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Cl[CH2:34][C:35]([N:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1)=[O:36]>[Cu]I.CN(C=O)C>[CH3:1][N:2]1[CH2:15][CH2:14][C:13]2[C:12]3[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][C:7]=3[N:6]([CH2:34][C:35]([N:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)=[O:36])[C:5]=2[CH2:4][CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)CC3
Reactant: O=C(CCl)N1CCCCC1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(=O)N2CCCCC2)CCN(C)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 8.8 %

Procedure:
The title compound was prepared by following general procedure 7. 3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.47 mmol), was taken into DMF. CuI (9 mg, 0.046 mmol), L-proline (11 mg, 0.093 mmol), K3PO4 (198 mg, 0.93 mmol) were added to the solution and stirred for 10 min. at RT. 2-Chloro-1-(piperidin-1-yl)ethanone (91 mg, 0.56 mmol) was added dropwise. The reaction mixture was heated at 90° C. for 12 h. After completion of reaction, the reaction mixture was filtered through Celite. DMF was evaporated under reduced pressure and then extracted with ethyl acetate. The organic layer was dried over Na2SO4, and concentrated under reduced pressure to obtain 14 mg of 2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(piperidin-1-yl)ethanone as the TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min., injection vol. 5 mL).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[NH:10]1[CH2:18][CH2:17][CH:13]([C:14]([NH2:16])=[O:15])[CH2:12][CH2:11]1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C=O)C>[Br:1][C:2]1[C:3]([N:10]2[CH2:18][CH2:17][CH:13]([C:14]([NH2:16])=[O:15])[CH2:12][CH2:11]2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: NC(=O)C1CCNCC1
Reactant: Clc1ncc(Br)c(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)C1CCN(c2nc(Cl)ncc2Br)CC1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 108.9 %

Procedure:
To a solution of 5-bromo-2,4-dichloropyrimidine (0.11 g, 0.50 mmol) and isonipecotamide (77 mg, 0.60 mmol) in DMF (2 mL) was added triethylamine (77 μL, 0.55 mmol) and the mixture was stirred at r.t. for 4.5 h. The mixture was poured into a saturated solution of sodium hydrogen carbonate (10 mL) and extracted with EtOAc (2×10 mL). The combined organic extracts were washed with water (10 mL), brine (10 mL), dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (CH2Cl2, MeOH, 98:2) to furnish the title compound as a white solid (174 mg, 95%), m/z (ESI) C10H12BrClN4NaO requires 340.9775 found [M+Na]+ 340.9776.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([C:11]([C:13]1[CH:18]=[C:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:16]=[CH:15][C:14]=1[O:23][C@@H:24]([CH3:29])[C:25]([F:28])([F:27])[F:26])=[O:12])[CH2:5]2.[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:22][S:19]([C:17]1[CH:16]=[CH:15][C:14]([O:23][C@@H:24]([CH3:29])[C:25]([F:26])([F:28])[F:27])=[C:13]([C:11]([N:6]2[CH2:5][C:4]3[C:8](=[CH:9][CH:10]=[C:2]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:3]=3)[CH2:7]2)=[O:12])[CH:18]=1)(=[O:20])=[O:21]
Reactant: OB(O)c1ccccc1
Reactant: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1Cc2ccc(I)cc2C1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1Cc2ccc(-c3ccccc3)cc2C1)C(F)(F)F
Temperature: 120 °C
Yield: 50 %

Procedure:
To a solution of 0.19 mmol (5-Iodo-1,3-dihydro-isoindol-2-yl)-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone (Example C3) in 1 ml DMF under argon was added successively 0.018 mmol tetrakistriphenylphosphine, 0.28 mmol phenyl boronic acid and 0.56 mmol potassium carbonate. The reaction mixture was heated at 120° C. for 2 hours then cooled to room temperature and filtered. The filtrate was evaporated to dryness and the residue was treated with sat. NaCl. The resulting mixture was extracted 3 times with dichloromethane. The organics phases were dried over sodium sulfate and evaporated. The crude compound was purified on a 10 g of Si-Amine cartridge: n-Heptane/Ethylacetate to provide the title compound (50%). Off-white solid. MS (m/e): 490.0 [M+H]+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:42]2[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=2)[O:10][CH:11]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:12]2[CH:16]([OH:17])[CH2:15][N:14]([C:18](=[O:35])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]3[C:32](=[O:33])[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:25]3=[O:34])[CH2:13]2)=[CH:5][CH:4]=1.[C:50]1(=[O:56])[O:55][C:53](=[O:54])[CH2:52][CH2:51]1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[CH3:49][O:48][C:45]1[CH:46]=[CH:47][C:42]([CH:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[O:10][CH:11]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:12]2[CH2:13][N:14]([C:18](=[O:35])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]3[C:32](=[O:33])[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:25]3=[O:34])[CH2:15][CH:16]2[O:17][C:50](=[O:56])[CH2:51][CH2:52][C:53]([OH:55])=[O:54])=[CH:43][CH:44]=1
Reactant: COc1ccc(C(OC(c2ccccc2)C2CN(C(=O)CCCCCN3C(=O)c4ccccc4C3=O)CC2O)c2ccc(OC)cc2)cc1
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(OC(c2ccccc2)C2CN(C(=O)CCCCCN3C(=O)c4ccccc4C3=O)CC2OC(=O)CCC(=O)O)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.6 %

Procedure:
Referring to scheme 19, Compound 77 (2 g, 3 mmol) was mixed with succinic anhydride (0.600 g, 6 mmol) and DMAP (0.366 g, 3 mmol) and dried in a vacuum at 40° C. overnight. The mixture was dissolved in anhydrous dichloromethane (5 mL), triethylamine (0.913 g, 1.25 mL, 9 mmol) was added and the solution was stirred at room temperature under argon atmosphere for 4 h. It was then diluted with dichloromethane (50 mL) and washed with ice cold aqueous citric acid (5% wt., 50 mL) and water (2×50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness. The crude product was purified by column chromatography using 6% MeOH/DCM to afford compound 79 as white solid (2.05 g, 89% yield; Rf=0.4 in 10% MeOH/CHCl3).
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]([CH:11]([F:13])[F:12])=[CH:9][CH:10]=1)=[O:5])C.[OH-].[Na+]>C(O)C>[F:13][CH:11]([F:12])[C:8]1[O:7][C:6]([C:4]([OH:5])=[O:3])=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1ccc(C(F)F)o1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(C(F)F)o1
Temperature: 25 °C
Yield: 61.2 %

Procedure:
5-Formyl-2-furancarboxylic acid (2.9 g) was dissolved in N,N-dimethylformamide (30 ml), and potassium carbonate (2.9 g) and iodoethane (3.6 g) were added. The mixture was stirred at room temperature for 12 hours, poured into ice water and extracted with diethyl ether. The extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 5-formyl- 2-furancarboxylic acid ethyl ester (1.3 g). 5-Formyl-2-furancarboxylic acid ethyl ester (1.3 g) in methylene chloride (5 ml) was slowly added dropwise to diethylaminosulfur trifluoride (DAST) (1.3 g) in methylene chloride (5 ml) at room temperature. The mixture was stirred at room temprature for 30 minutes, and water was added to the mixture. The resulting mixture was extracted with diethyl ether, and the extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 5-difluoromethyl-2-furancarboxylic acid ethyl ester (0.7 g). 5-Difluoromethyl-2-furancarboxylic acid ethyl ester (2.3 g) synthesized in this manner was dissolved in ethanol (20 ml), and 1N aqueous sodium hydroxide (15 ml) was added. The mixture was stirred at room temperature and concentrated under reduced paressure. The residue was dissolved in water and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Precipitated crystals were collected by filtration and washed with hexane-isopropyl ether to give 5-difluoromethyl-2-furancarboxylic acid (1.2 g) as crystals.
Reaction SMILES: [Br:1][C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[C:5]([Cl:11])=[C:4]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH3:22])=[CH:16][CH:15]=2)=O)[CH:3]=1.[SiH](CC)(CC)CC.B(F)(F)F.CCOCC>C(Cl)Cl.CC#N>[Br:1][C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[C:5]([Cl:11])=[C:4]([CH2:12][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH3:22])=[CH:16][CH:15]=2)[CH:3]=1
Reactant: CCOc1ccc(C(=O)c2cc(Br)c3sccc3c2Cl)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CC#N
Solvent: CCOCC
Product: CCOc1ccc(Cc2cc(Br)c3sccc3c2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
To a solution of (7-bromo-4-chlorobenzo[b]thiophen-5-yl)(4-ethoxyphenyl)methanone 98 (917 mg, 2.32 mmol) in a mixture of CH2Cl2 (9 mL) and CH3CN (30 mL) at 0° C. was added Et3SiH (1.6 mL, 9.27 mmol) and BF3.Et2O (0.47 mL, 3.48 mmol). The reaction mixture was warmed to room temperature, and then stirred overnight. The resulting solution was quenched with aqueous sat. NH4Cl solution (40 mL) and normal work-up with EtOAc was accomplished. After evaporating volatile solvents, the residue was purified by silica gel chromatography to afford the title compound (761 mg, 84%) as an off-white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C.O>[CH2:19]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:5]=[O:6])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=Cc1ccc([N+](=O)[O-])c(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Hydroxy-4-nitro-benzaldehyde (4.68 g, 28 mmol) is dissolved in DMF (27 mL) and to the solution is added with stirring powdered potassium carbonate (4.27 g, 30.1 mmol) and benzyl bromide (3.34 mL, 28.1 mmol). The mixture is stirred at RT overnight, diluted with water (200 mL) and extracted three times with EtOAc. The organic extracts are washed with 10% potassium carbonate and brine, dried over anhydrous MgSO4, decolorized with charcoal, filtered and evaporated to give 3-benzyloxy-4-nitro-benzaldehyde as an oil which is used in the next step without purification.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH:17]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:12][N:11]=1)=O)(C)(C)C.Cl>CO>[NH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)=[CH:12][N:11]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(OC2CCCCCC2)cn1
Agent: Cl
Solvent: CO
Product: NCc1ccc(OC2CCCCCC2)cn1
Temperature: 0 °C
Yield: 71.8 %

Procedure:
Dissolve 2-(tert-butoxycarbonylamino-methyl)-5-cycloheptyloxy-pyridine (1.9 g, 5.95 mmol) in methanol (25 mL) and cool to 0° C. Bubble hydrogen chloride through the vigorously stirred solution for 30 min. Evaporate in vacuo and partition the residue between 3N aqueous NaOH (10 mL) and DCM (20 mL). Separate the two layers and extract the aqueous layer with DCM (2×20 mL). Wash the combined organic extracts with brine (20 mL), dry over Na2SO4, filter, and concentrate in vacuo to obtain the title compound as a colorless oil (941 mg, 72%). MS (APCI+) m/z: 221 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:18]=[CH:17][C:6]2[N:7]=[C:8]([C:10]3[CH:11]=[CH:12][C:13]([NH2:16])=[N:14][CH:15]=3)[O:9][C:5]=2[CH:4]=1.B(Br)(Br)Br.CCOC(C)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[NH2:16][C:13]1[N:14]=[CH:15][C:10]([C:8]2[O:9][C:5]3[CH:4]=[C:3]([OH:2])[CH:18]=[CH:17][C:6]=3[N:7]=2)=[CH:11][CH:12]=1
Reactant: COc1ccc2nc(-c3ccc(N)nc3)oc2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Nc1ccc(-c2nc3ccc(O)cc3o2)cn1
Temperature: 0 °C
Yield: 116.9 %

Procedure:
To a stirred and cooled (ice bath) solution of 5-(6-methoxy-1,3-benzoxazol-2-yl)pyridin-2-amine (2.07 mmol) in CH2Cl2 (50 mL) was slowly added boron tribromide 1M in CH2Cl2 (4.15 mL) from a pressure equalized dropping funnel. After full addition the reaction mixture was stirred 5 mins in the ice bath, before it was allowed to reach room temperature and then stirred at room temperature overnight. The reaction mixture was cooled (ice bath) and diluted with CH2Cl2 (100 mL), followed by EtOAc (100 mL), water (100 mL) and sat aq NaHCO3 (100 mL) and the resulting mixture allowed to reach room temperature and stirred vigorously for 10 mins. The organic layer was separated and the aqueous layer extracted with CH2Cl2 (3×100 mL), the combined organic layers were dried (Na2SO4), filtered and evaporated to give 0.55 g of 2-(6-aminopyridin-3-yl)-1,3-benzoxazol-6-ol, as a pale yellow foamy solid. MS m/z 228 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([C:15]([F:18])([F:17])[F:16])=[N:13][N:12]=[N:11]2)=[CH:6][C:3]=1[CH:4]=[O:5].[C:19](=O)([O-])[O-].[K+].[K+].CI.O>CC(C)=O>[CH3:19][O:1][C:2]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([C:15]([F:18])([F:17])[F:16])=[N:13][N:12]=[N:11]2)=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cc(-n2nnnc2C(F)(F)F)ccc1O
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: CI
Product: COc1ccc(-n2nnnc2C(F)(F)F)cc1C=O
Yield: 113 %

Procedure:
A mixture of 2-hydroxy-5-(5-trifluoromethyl-tetrazol-1-yl)benzaldehyde (1.56 mmol), potassium carbonate (7.8 mmol) and methyl iodide (7.8 mmol), in acetone (25 ml) was stirred for 18 h at 23° under nitrogen. Water (150 ml) was added and the mixture extracted with diethyl ether (3×50 ml). The combined organic extracts were washed with saturated brine, dried (Na2SO4) and evaporated to give the title compound as a yellow solid (0.48 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[C:18](=[O:19])[NH:17][C:12]3=[N:13][CH:14]=[CH:15][N:16]=[C:11]3[C:10]=2[O:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:32](I)[CH3:33]>C(#N)C>[Cl:1][C:2]1[C:3]([C:9]2[C:18](=[O:19])[N:17]([CH2:32][CH3:33])[C:12]3=[N:13][CH:14]=[CH:15][N:16]=[C:11]3[C:10]=2[O:20][C:21](=[O:25])[CH:22]([CH3:23])[CH3:24])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCI
Reactant: CC(C)C(=O)Oc1c(-c2ncc(Cl)cc2Cl)c(=O)[nH]c2nccnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCn1c(=O)c(-c2ncc(Cl)cc2Cl)c(OC(=O)C(C)C)c2nccnc21
Temperature: 100 °C

Procedure:
Isobutyric acid 7-(3,5-dichloro-pyrid-2-yl)-6-oxo-5,6-dihydro-pyrido[2,3-b]pyrazin-8-yl ester (Example 1.3) (0.250 g) was dissolved in acetonitrile (2 ml) and potassium carbonate (0.138 g) and ethyl iodide (0.1 ml) were added successively. The reaction mixture was heated in a microwave at 100° C. for 11 minutes, cooled to ambient temperature and concentrated. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate 1:1) to give Compound No. A6 of Table A as a yellow gum which solidified on standing (0.101 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:39])[C:9]([C:11]1[S:38][C:14]2[C:15]3[CH:23]=[CH:22][C:21]([N:24]=C(C4C=CC=CC=4)C4C=CC=CC=4)=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10].CC(Cl)=O>CO>[NH2:24][C:21]1[CH:22]=[CH:23][C:15]2[C:14]3[S:38][C:11]([C:9]([N:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[CH3:39])=[O:10])=[CH:12][C:13]=3[CH2:19][CH2:18][O:17][C:16]=2[CH:20]=1
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(N=C(c3ccccc3)c3ccccc3)cc1OCC2)c1ccccc1Cl
Solvent: CC(=O)Cl
Solvent: CO
Product: CN(C(=O)c1cc2c(s1)-c1ccc(N)cc1OCC2)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 104.9 %

Procedure:
Solid Pd2(dba)3 (101 mg, 0.11 mmol) and BINAP (205 mg, 0.33 mmol) was added to a 10 mL flask and the whole purged with nitrogen. To the flask was added 8-bromo-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide (500 mg, 1.11 mmol), benzophenone imine (303 mg, 1.67 mmol), NaOtBu (213 mg, 2.22 mmol) and toluene (30 mL). The mixture was heated to 80° C. with stirring until the starting material had been consumed (determined by TLC analysis). The mixture was cooled to room temperature, diluted with EtOAc, filtered and concentrated. The crude product was purified by column chromatography (5:1 hexanes:ethyl acetate) to give N-(2-chlorophenyl)-8-(diphenylmethyleneamino)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide as a yellow solid (400 mg, yield 65%). N-(2-chlorophenyl)-8-(diphenylmethyleneamino)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide (4.9 g, 8.92 mmol) was dissolved in 10 mL of MeOH. To the solution was added 6 mL of CH3COCl in MeOH (1:10). The mixture was stirred at room temperature for 15 min before concentrated under vacuum. The residue was washed with EtOAc to give 8-amino-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide as a white solid (3.6 g, yield 95%). 1H NMR (MeOD, 400 MHz): δ 7.59-6.60 (m, 8H), 4.21 (t, J=5.2 Hz, 2H), 3.31 (s, 3H), 2.96 (t, J=4.8 Hz, 2H).
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5][CH2:4]1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[CH:2]([C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5][CH2:4]1)=[O:1]
Reactant: CCOC(=O)C1(CO)CCC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(=O)C1(C=O)CCC1
Reaction time: 17.5 h
Yield: 86.1 %

Procedure:
To a dichloromethane (250 mL) solution of ethyl 1-(hydroxymethyl)cyclobutanecarboxylate (12 g) at room temperature, was added a mixture of pyridinium chlorochromate (PCC) (24.5 g) and 20 g SiO2. After 17.5 h, the organic solvent was decanted, and more dichloromethane and ethylacetate were added to wash the SiO2. The combined organic phases were concentrated, the residue and the SiO2 used in the reaction were loaded onto a column and eluted with EtOAc/DCM, 0-17%, to afford ethyl 1-formylcyclobutanecarboxylate (10.2 g) as a clear oil 1H-NMR (300 MHz, CDCl3): δ=9.76 (s, 1H); 4.32-4.0751 (d, 2H); 2.7145-2.2827 (t, 4H); 2.1954-1.6632 (m, 2H); 1.4254-1.0664(t, 3H) ppm. 13C-NMR (75 MHz, CDCl3) δ=196.96, 171.7, 61.54, 57.2, 25.95, 15.64, 14.17 ppm.
Reaction SMILES: O=[C:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:13][NH:14][NH2:15]>CCO>[CH3:13][NH:14][N:15]=[C:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CNN
Reactant: CCOC(=O)C(=O)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)C(=NNC)C(=O)OCC
Temperature: 60 °C
Reaction time: 6 h
Yield: 73.4 %

Procedure:
To a solution of diethyl ketomalonate (95 g, 546 mmol) in EtOH (600 mL) (2 L 3-neck flask equipped with thermocouple, N2 line, condenser and mechanical stirrer) was added MeNHNH2 (32 mL, 600 mmol) in one portion at room temperature. The reaction mixture was warmed to 60° C. (internal temperature, heated by a heating mantle) and stirred for 6 hours. The reaction mixture was cooled to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure to give the crude material along with solid precipitates that was purified by a silica gel plug (3:2 hexanes:EtOAc) to afford 81 g (74%) of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[Br-].BrC1C=CC(C[P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=O)C1C=CC=CC=1.CC(C)([O-])C.[K+]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:7]=1
Reactant: Brc1ccc(C=Cc2ccccc2)cc1
Agent: Brc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Solvent: O=Cc1ccccc1
Solvent: C1CCOC1
Product: Brc1ccc(/C=C/c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 29.2 %

Procedure:
First, a synthesis method of 4-bromostilbene is described. 25.3 g (49.5 mmol) of (4-bromobenzyl)triphenylphosphoniumbromide and 5.25 g (49.5 mmol) of benzaldehyde were put into a 500 mL three-necked flask and the air in the flask was replaced with nitrogen. 250 mL of tetrahydrofuran (THF) was added to the mixture. Then, a suspension in which 6.10 g (54.4 mmol) of potassium tert-butoxide was dissolved in 60 mL of THF was dropped to this mixture. After the dropping, the reaction mixture was stirred for 24 hours at room temperature. After the reaction, the reaction mixture was washed with water and the product was extracted with ethyl acetate from the water which was used for the washing. The obtained extraction solution and the organic layer, which was washed with water, were mixed and dried with magnesium sulfate. After the drying, the mixture was suction filtrated, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (developing solution: toluene). The obtained compound was washed with methanol and the solid was collected by suction filtration to give 3.75 g or a white powdered solid of (E)-4-bromostilbene (yield: 29.2%). A synthesis scheme (h-1) of 4-bromostilbene is shown below. Note that (Z)-4-bromostilbene was also observed in this reaction, but only (E)-4-bromostilbene was isolated and purified.
Reaction SMILES: [C:1]([CH2:3][CH:4]([CH2:7][O:8][C:9](=[O:29])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:5][OH:6])#[N:2].[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(N(CC)CC)C.N(CC(NC(OC)=O)CSCCCCCCCCCCCCCCCC)=[N+]=[N-]>ClCCl>[CH3:30][S:31]([O:6][CH2:5][CH:4]([CH2:3][C:1]#[N:2])[CH2:7][O:8][C:9](=[O:29])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])(=[O:33])=[O:32]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CO)CC#N
Reactant: CS(=O)(=O)Cl
Agent: CCCCCCCCCCCCCCCCSCC(CN=[N+]=[N-])NC(=O)OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CC#N)COS(C)(=O)=O

Procedure:
A mixture of 940 mg (2.29 mM) of 2-cyanomethyl-3-octadecylcarbamoyloxypropanol V n2, 0.231 ml (2.98 mM) of methanesulfonyl chloride and 0.483 ml (3.44 mM) of triethylamine in 10 ml of dichloromethane is allowed to react by the same procedure as described in (52) and crude product of the titled compound V n2a is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([NH2:11])[CH:6]=[CH:5][N:4]=1.[CH3:12][C:13]([CH:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1)([CH3:19])[CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16]>>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([NH:11][C@H:23]2[CH2:22][CH2:21][C@@H:20]([C:13]([CH3:19])([CH3:12])[CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:25][CH2:24]2)[CH:6]=[CH:5][N:4]=1
Reactant: COc1nccc(N)c1OC
Reactant: CC(C)(C)CC(C)(C)C1CCC(=O)CC1
Product: COc1nccc(N[C@H]2CC[C@@H](C(C)(C)CC(C)(C)C)CC2)c1OC

Procedure:
As Example 75, but using 1.54 g (10 mmol) of 2,3-dimethoxy-4-aminopyridine instead of 2-ethyl-3-bromo-4-amino-pyridine and 4.2 g (20 mmol) of 4-(1,1,3,3-tetramethylbutyl)cyclohexanone instead of 4-phenylcyclohexanone.