Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([C@H:8]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[NH:9][C:10]([C:12]2[CH:21]=[C:20]3[C:15]([CH:16]=[CH:17][CH:18]=[N:19]3)=[CH:14][CH:13]=2)=[O:11])=[N:4][CH:5]=[CH:6][CH:7]=1>CO.CCOC(C)=O.[OH-].[Pd+2].[OH-].[Pd]>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:2][C:3]=1[C@H:8]([C:22]1[CH:23]=[CH:24][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:27]=1)[NH:9][C:10]([C:12]1[CH:21]=[C:20]2[C:15]([CH2:16][CH2:17][CH2:18][NH:19]2)=[CH:14][CH:13]=1)=[O:11]
Reactant: O=C(N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1Br)c1ccc2cccnc2c1
Agent: [Pd+2]
Agent: [Pd]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(N[C@@H](c1ccc(C(F)(F)F)cc1)c1ccccn1)c1ccc2c(c1)NCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)—N-((3-bromopyridin-2-yl)(4-(trifluoromethyl)phenyl)-methyl)quinoline-7-carboxamide (Example 195) (0.130 g, 0.267 mmol) in MeOH (0.8 mL) and EtOAc (0.800 mL) was added palladium hydroxide, (20 wt % Pd (dry basis) on carbon, wet) (0.019 g, 0.134 mmol). The resulting mixture was then stirred at rt under H2 (balloon) overnight. The mixture was then filtered through Celite® brand filter agent and the Celite® filter agent was washed with MeOH (2×3 mL). The combined filtrates were concentrated, and the residue was dissolved in MeOH (1 mL). The solution was purified by preparative HPLC (0%-100% MeCN 0.1% TFA/H2O 0.1% TFA) to give the desired product, which was dissolved in MeOH (1 mL). The solution was washed through PL_HCO3 MP-SPE and the resin was washed with MeOH (2×1 mL). The combined filtrates were concentrated and dried in vacuo to give the title compound as a yellow solid. 1H NMR (400 MHz, MeOH) δ ppm 8.59 (d, J=4.7 Hz, 1H), 7.84 (td, J=7.7, 1.6 Hz, 1H), 7.61-7.68 (m, 2H), 7.54-7.60 (m, 2H), 7.49 (d, J=7.8 Hz, 1H), 7.36 (dd, J=7.5, 5.0 Hz, 1H), 6.93-7.07 (m, 3H), 6.44 (s, 1H), 3.25-3.30 (m, 2H), 2.78 (t, J=6.4 Hz, 2H), 1.91 (dt, J=11.6, 6.0 Hz, 2H). MS (ESI pos. ion) m/z: 412.1 (M+H).
Reaction SMILES: C([O:3][C:4](=[O:35])[C@H:5]([CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[NH:6][C:7](=[O:27])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH:16]2[C:24]3[C:23](=[O:25])[NH:22][C:21]([NH2:26])=[N:20][C:19]=3[NH:18][CH2:17]2)=[CH:10][CH:9]=1)C.Cl>[OH-].[Na+]>[NH2:26][C:21]1[NH:22][C:23](=[O:25])[C:24]2[CH:16]([CH2:15][CH2:14][C:11]3[CH:12]=[CH:13][C:8]([C:7]([NH:6][C@H:5]([C:4]([OH:35])=[O:3])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:27])=[CH:9][CH:10]=3)[CH2:17][NH:18][C:19]=2[N:20]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(CCC2CNc3nc(N)[nH]c(=O)c32)cc1)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1nc2c(c(=O)[nH]1)C(CCc1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1)CN2
Yield: 85.2 %

Procedure:
A solution of 1.50 grams (3.09 mmol) of N-[4-[2-(2-amino-4,5,6,7-tetrahydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid diethyl ester in 25 ml 1N NaOH was stirred at room temperature for 3 hours. The solution was carefully acidified to a of pH 2.8 by addition of 6M aqueous HCl and the resulting suspension was then filtered The precipitate was consecutively washed with 20 ml water, 10 ml methanol, 10 ml ether, and dried overnight at 50° C. and 10 torr. 1.13 g (85% of theory) of N-[4-[2-(2-amino-4,5,6,7-tetrahydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid was obtained as an amorphous solid. Selected data: 1H NMR (DMSO-d6) δ 12.20 (bs, 2H), 9.83 (bs, 1H), 8.48 (d, J=7.7 Hz, 1H), 7.74 (d, J=8.1 Hz, 2H), 7.26 (d, J=8.1 Hz, 2H), 6.32 (bs, 2H), 6.28 (bs, 1H), 4.33 (m, 1H), 3.43 (m, 1H), 3.01 (m, 2H), 2.61 (t, J=8.0 Hz, 2H), 2.30 (t, J=7.4 Hz, 2H), 1.96 (m, 3H), 1.54 (m, 1H); 13C NMR (DMSO-d6) δ 173.7, 173.1, 169.4, 166.5, 159.0, 156.7, 146.2, 131.4, 127.9, 127.2, 89.1, 52.1, 49.3, 36.9, 35.5, 32.3, 30.5, 26.2; IR (KBr) 3366, 2931, 1639, 1503, 1451, 1091 cm-1 ; MS(FAB) m/z 430 (MH+); UV (EtOH) 220 nm (ε 27 660), 280 (11 300).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[CH2:11][OH:12])=[CH:4][CH:3]=1.[C:13]([Cu])#[N:14].[C-]#N.[Na+]>CN1CCCC1=O>[C:13]([C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[CH2:11][OH:12])=[CH:4][CH:3]=1)#[N:14]
Reactant: N#C[Cu]
Reactant: OCC1CCc2ccc(Br)cc21
Agent: [C-]#N
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: N#Cc1ccc2c(c1)C(CO)CC2
Temperature: 160 °C
Yield: 57 %

Procedure:
To a solution of 6-bromo-1-indanylmethanol (20 g) in N-methyl-2-pyrrolidone (NMP) (380 ml) was added CuCN (79 g). The mixture was heated at 160° C. for 6 hours. After cooling to 80-90° C. the mixture was poured into an aqueous solution (500 ml) of NaCN (4g). After stirring for 20 minutes excess CuCN was filtered off. Ethyl acetate (300 ml) was added and the organic phase was separated and worked-up. The remaining oil was dissolved in diethyl ether (300 ml) and washed with saturated brine (2×100 ml). The organic phase was separated and worked-up according to the general procedure leaving 14.6 g of crude title compound 2a as a visceous oil. Column chromatography on silica gel (eluent:ethylacetat/heptane 6:4) afforded pure 2a (8.7 g) which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:20][CH2:19][CH:18]([CH:21]4OCCC[O:22]4)[CH2:17][CH2:16]3)=[CH:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)=O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C@H:15]3[CH2:16][CH2:17][C@H:18]([CH:21]=[O:22])[CH2:19][CH2:20]3)=[CH:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(-c2ccc(C3CCC(C4OCCCO4)CC3)cn2)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: Cc1ccccc1
Product: O=C[C@H]1CC[C@H](c2ccc(-c3ccc(F)c(F)c3)nc2)CC1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 1.65 g of 2-(3,4-difluorophenyl)-5-[4-(1,3-dioxan-2-yl)cyclohexyl]pyridine, 15 ml of toluene and 10 ml of formic acid is stirred at room temperature for 10 hours and subsequently carefully neutralized to pH 7 with saturated sodium carbonate solution. The aqueous phase is separated and extracted twice with toluene, the organic phases are combined, washed with water, dried over sodium sulphate and evaporated. The residue is dissolved in 15 ml of methanol and added dropwise to 10 ml of 0.1N methanolic potassium hydroxide solution cooled to 0° C. The mixture is stirred at 0° C. for 1 hour, poured on to 40 ml of ice-water and extracted three times with 25 ml of diethyl ether each time. The organic phases are combined, washed neutral with water, dried over sodium sulphate and, after evaporation, give trans-4[2-(3,4-difluorophenyl)-5-pyridyl]-cyclohexanecarboxaldehyde (cis content about 8%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8](OCC)=[O:9])=[C:4]([NH:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[N:15]=2)[CH:3]=1.[NH3:22]>CO>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:22])=[O:9])=[C:4]([NH:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[N:15]=2)[CH:3]=1
Reactant: N
Reactant: CCOC(=O)c1nnc(Cl)cc1Nc1cc(C)cc(C)n1
Solvent: CO
Product: Cc1cc(C)nc(Nc2cc(Cl)nnc2C(N)=O)c1
Temperature: 50 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
To a solution of ethyl 6-chloro-4-(4,6-dimethylpyridin-2-ylamino)pyridazine-3-carboxylate (165 mg, 538 μmol) in methanol (1 mL) was added ammonia in methanol (4.72 g, 6 mL, 42.0 mmol) and the mixture stirred at 50° C. for 16 h. The mixture was then concentrated in vacuo to give 6-chloro-4-(4,6-dimethylpyridin-2-ylamino)pyridazine-3-carboxamide (140 mg, 504 μmol, 94%) as a white solid. 1H NMR (400 MHz, DMSO-d) δ ppm 11.92 (s, 1H), 9.13 (s, 1H), 8.86 (s, 1H), 8.21 (s, 1H), 6.84 (s, 1H), 6.76 (s, 1H), 2.45 (s, 3H), 2.29 (s, 3H); MS (EI/CI) m/z: 277.9 [M+H].
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.Cl.[NH2:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24][CH2:23]1.CCN(C(C)C)C(C)C>C(O)CCC>[OH:28][C@H:25]1[CH2:26][CH2:27][C@H:22]([NH:21][C:2]2[N:7]3[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=4)[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH2:23][CH2:24]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: O=C(Nc1nc2cccc(Cl)n2n1)c1cccnc1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nc2cccc(N[C@H]3CC[C@H](O)CC3)n2n1)c1cccnc1
Reaction time: 0.67 h

Procedure:
A solution of N-(5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B4), 100 mg; 0.37 mmol; 1.0 eq.), trans-4-aminocyclohexanol hydrochloride (ABCR), 277 mg; 1.83 mmol; 5.0 eq.), DIEA (472 mg; 3.65 mmol; 10.0 eq.) in n-butanol (1.0 mL) was heated at 220° C. for 20 min under microwave irradiation. The reaction mixture was directly purified by reverse phase chromatography (Starting with water then up to 60% ACN in water in 40 min.). The title compound was isolated after lyophilisation as a white powder (31 mg, 24%). HPLC, Rt: 1.77 min. (purity 80.2%). LC/MS, M+(ESI): 353.1, M−(ESI): 351.1.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:9][CH:10]([OH:17])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>C1CCCCC1>[Si:1]([O:17][CH:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH3:9])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCCCCCC(C)O
Solvent: C1CCCCC1
Product: CCCCCCC(C)O[Si](C)(C)C(C)(C)C

Procedure:
Analysis of this material by GC indicated it was 96.9% assay product. addition, the stripped solution contained 1.1% cyclohexane, 0.04% t-butyldimethylsilyl chloride, 0.3% 2-octanol, and 1.7% unknowns.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12]O.[CH3:14][O:15][C:16]([O:20][Si](C)(C)C)=[C:17](C)C.Cl([O-])(=O)(=O)=O.[Mg+2].Cl([O-])(=O)(=O)=O>ClCCl.O>[CH3:14][O:15][C:16](=[O:20])[CH2:17][CH2:12][C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[NH:8][CH:7]=1
Reactant: COc1ccc2[nH]cc(CO)c2c1
Reactant: COC(O[Si](C)(C)C)=C(C)C
Agent: [Mg+2]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: ClCCl
Solvent: O
Product: COC(=O)CCc1c[nH]c2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 100 %

Procedure:
To a solution of 5-methoxy-1H-indol-3yl-methanol 141 (115 mg, 0.643 mmol) dissolved in dichloromethane (3 ml), (1-methoxy-2-methyl-propenyloxy)-trimethylsilane (200 mg, 1 mmol) and magnesium perchlorate (164 mg, 0.74 mmol) were added. The reaction was allowed to stir at ambient temperature for 3-4 hours after after which the mixture was diluted with water (50 ml) and dichloromethane (DCM, 100 mL). The organic layer was separated and washed with water (50 mL; 3×). The organic layer was washed once with brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give an oil and purified with flash chromatography (silica with 80% hexane, 20% ethyl acetate to afford 142 as a light colored oil (150 mg; 88% yield; M+1=262.3).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)=[C:4]([CH3:24])[C:3]=1[F:25].C(O)C.C(=O)(O)[O-].[Na+]>[Pd]>[F:25][C:3]1[C:4]([CH3:24])=[C:5]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19]([CH:21]4[CH2:22][CH2:23]4)=[O:20])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:6]=[N:7][CH:2]=1
Reactant: Cc1c(-c2ccc3cc(NC(=O)C4CC4)ncc3c2)cnc(Cl)c1F
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1c(F)cncc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 40 °C
Reaction time: 12 h
Yield: 47.5 %

Procedure:
To a solution of N-(7-(6-chloro-5-fluoro-4-methylpyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide (180.0 mg, 0.5059 mmol) in ethanol (10 mL, 200 mmol) was added sodium bicarbonate (95.2 mg, 1.13 mmol) and palladium (60.1 mg, 0.0565 mmol) (10 wt % on carbon). The reaction vessel was purged first with nitrogen and then hydrogen, and then stirred under a hydrogen balloon at 40° C. for 12 hours. The reaction mixture was then filtered through celite and evaporated in vacuo. The crude product was purified via reverse phase HPLC and lyophilized to yield 77.3 mg (48%) of N-(7-(5-fluoro-4-methylpyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide. LCMS (ESI): RT (min)=4.130, M+H=322.1, method=E; 1H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.20 (s, 1H), 8.55 (s, 1H), 8.52 (s, 1H), 8.42 (s, 1H), 8.12 (s, 1H), 7.98 (d, J=8.5 Hz, 1H), 7.76 (dd, J=8.5, 1.4 Hz, 1H), 2.26 (d, J=1.8 Hz, 3H), 2.15-2.03 (m, 1H), 0.94-0.75 (m, 4H).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Br:11][CH:12]1[N:16]([CH2:17][C:18]#[C:19][CH3:20])[C:15]([C:21]([O:23][CH3:24])=[O:22])=[C:14]([C:25](OC)=[O:26])[NH:13]1>O1CCCC1>[Br:11][C:12]1[N:16]([CH2:17][C:18]#[C:19][CH3:20])[C:15]([C:21]([O:23][CH3:24])=[O:22])=[C:14]([CH:25]=[O:26])[N:13]=1
Reactant: CC#CCN1C(C(=O)OC)=C(C(=O)OC)NC1Br
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: CC#CCn1c(Br)nc(C=O)c1C(=O)OC
Temperature: -65 °C
Reaction time: 2 h

Procedure:
45 ml diisobutylaluminum hydride solution (1M in toluene) are added dropwise to 12.45 g dimethyl 2-bromo-3-(2-butyn-1-yl)-1H-imidazole-4,5-dicarboxylate in 150 ml of tetrahydrofuran under an argon atmosphere at −65° C. The reaction mixture is stirred for two hours at −65° C., then another 9 ml diisobutylaluminum hydride solution are added. After another hour the reaction mixture is quenched at −65° C. with a mixture of 1 M hydrochloric acid and tetrahydrofuran (1:1) and stirred for ten minutes. Then the cooling bath is removed, the reaction mixture is diluted with water and extracted with ethyl acetate. The combined organic phases are dried over magnesium sulphate and evaporated down. The crude product is purified by chromatography over a silica gel column with cyclohexane/ethyl acetate (2:1 to 1:1).
Reaction SMILES: Cl[CH2:2][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12][C:13]([Cl:16])([Cl:15])[F:14])=[CH:4]1.[F:17][C:18]([F:27])([F:26])[CH2:19][CH2:20][CH:21]([C:24]#[N:25])[C:22]#[N:23].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:15][C:13]([Cl:16])([F:14])[S:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:3]([CH2:2][C:21]([CH2:20][CH2:19][C:18]([F:17])([F:26])[F:27])([C:22]#[N:23])[C:24]#[N:25])[CH:4]=1
Reactant: FC(Cl)(Cl)Sc1cn(CCl)c2ccccc12
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cn1cc(SC(F)(Cl)Cl)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
0.61 g of 1-(chloromethyl)-3-{[dichlorofluoromethyl]thio}-1H-indole and 0.35 g of (3,3,3-trifluoropropyl)malononitrile were dissolved in 2 ml of N,N-dimethylformamide. 0.28g of potassium carbonate was added to the solution under ice cooling, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.65 g of [(3-{[dichlorofluoromethyl]thio}-1H-indole-1-yl) methyl](3,3, 3-trifluoropropyl) malononitrile (referred as the compound of the present invention (44), hereinafter) shown by below formula.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[C:7]=[S:8])=[O:5])[CH3:2].[CH2:9]([NH2:13])[CH:10]([CH3:12])[CH3:11]>>[CH2:1]([O:3][C:4]([NH:6][C:7]([NH:13][CH2:9][CH:10]([CH3:12])[CH3:11])=[S:8])=[O:5])[CH3:2]
Reactant: CC(C)CN
Reactant: CCOC(=O)N=C=S
Product: CCOC(=O)NC(=S)NCC(C)C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of 5.3 grams of ethoxycarbonyl isothiocyanate (Preparation 1) in 100 ml of petroleum ether (b.p. 35°-60° C.) was cooled with stirring in an ice-water bath. To the above solution was added dropwise in 20 minutes a solution of 3.9 grams of isobutylamine in 50 ml of petroleum ether. The reaction flask was cooled in the ice-water bath during the addition. After the addition was complete the reaction flask was removed from the ice-water bath and let stand at an ambient temperature overnight. The solution was concentrated by stripping off most of the solvent. The concentrated solution was cooled in a ice-water bath. The crystals were collected by filtering and washing with hexanes. The product weighed 7.5 grams and melted at 50°-52° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]([O:17][CH3:18])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:22]I.O>CN(C)C=O>[C:1]([O:5][C:6](=[O:19])[N:7]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]([O:17][CH3:18])[CH:11]=1)[CH3:22])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1cc(CCNC(=O)OC(C)(C)C)ccc1F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(CCN(C)C(=O)OC(C)(C)C)ccc1F
Reaction time: 1 h

Procedure:
To a solution of [2-(4-fluoro-3-methoxyphenyl)ethyl]carbamic acid t-butyl ester (795 mg) in N,N-dimethylformamide (6 mL) was added 60% sodium hydride (154 mg) at room temperature. After stirring for 1 hour, methyl iodide (0.55 mL) was added dropwise and the solution was stirred for 14 hours. Water was added cautiously by small amounts, and after extraction with ethyl acetate, the solution was washed with water and saturated sodium chloride water. The residue that was obtained upon removing the solvent by evaporation was purified by silica gel column chromatography (hexane/ethyl acetate), and the title compound (506 mg) was obtained as a colorless oily matter.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[C:10]1([SH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>[Cu]>[Cl:9][C:5]1[CH:6]=[C:7]([F:8])[C:2]([S:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:3][CH:4]=1
Reactant: Fc1cc(Cl)cnc1F
Reactant: Sc1ccccc1
Agent: [Cu]
Product: Fc1cc(Cl)cnc1Sc1ccccc1

Procedure:
Starting from 93 g (0.508 mol) of 2,3-difluoro-5-chloropyridine, 58.8 g (0.5276 mol) of 98.7% pure thiophenol and 3.2 mg (0.01 mol %) of copper powder, 121.5 g (99.9% of theory) of the title compound were obtained as a colorless oil after 1.5 h of stirring in a pressure apparatus at 185° C. and work-up by the method of Example 1. 1H NMR (ppm, d6-DMSO) 8.35 (s/1H), 8.05 (d/1H), 7.4-7.6 (m/5H).
Reaction SMILES: [CH:1]([O:3][CH:4]1[CH2:9][CH:8]2[CH2:10][CH:5]1[CH:6]=[CH:7]2)=[O:2].[CH:11]([CH:13]=[CH2:14])=[O:12]>>[CH:1]([O:3][CH:4]1[CH:5]2[CH2:10][CH:8]([CH:7]3[CH:6]2[O:12][CH:11]=[CH:13][CH2:14]3)[CH2:9]1)=[O:2]
Reactant: C=CC=O
Reactant: O=COC1CC2C=CC1C2
Product: O=COC1CC2CC1C1OC=CCC21
Yield: 49 %

Procedure:
248 g of 5-norbomene-2-yl formate and 33.6 g of acrolein were reacted in the same manner asin Examplel1-1to synthesize adesired product. As aresult, 57 g of 3-oxa-tricyclo[6.2.1.02,7]undec-4-ene-10-yl formate was obtained.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:18]1[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19]1.C(OCC)(=O)C.B(F)(F)F.CCOCC>CCOCC>[C:1]1([C:7]2[N:8]=[CH:9][N:10]([CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23][O:18]3)[C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(-c2nc[nH]c2-c2ccccc2)cc1
Reactant: C1=COCCC1
Agent: FB(F)F
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: c1ccc(-c2ncn(C3CCCCO3)c2-c2ccccc2)cc1

Procedure:
A mixture of 27 g (0.122 mole) 4,5-diphenylimidazole, 21 g (0.25 mole) dihydropyran, 250 ml ethyl acetate and 4.0 g BF3.Et2O was refluxed for five days. The nearly clear solution was diluted with ether and filtered to remove 0.6 g insoluble starting material. The ether filtrate was washed several times with 10% NaHCO3 then dried and evaporated. TLC showed starting material still present, so the crude product was chromatographed on 2 lb. SilicAR CC-7, eluting with toluene containing 20 to 40% ethyl acetate. The pure 4,5-diphenyl-1-(2-tetrahydropyranyl) imidazole thus obtained weighed 30.3 g (82%) and had mp 170°-171°.
Reaction SMILES: [Br:1][C:2]1[CH:26]=[CH:25][C:5]2[C:6]([C:15](C)([CH3:23])[C:16](OC(C)(C)C)=O)=[N:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[C:12](Cl)[N:11]=[CH:10][CH:9]=3.C(O)(C(F)(F)F)=[O:28]>ClCCl>[Br:1][C:2]1[CH:26]=[CH:25][C:5]2[C:6]([CH:15]([CH3:23])[CH3:16])=[N:7][C:8]3[CH:9]=[CH:10][NH:11][C:12](=[O:28])[C:13]=3[C:4]=2[CH:3]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)C(C)(C)c1nc2ccnc(Cl)c2c2cc(Br)ccc12
Solvent: ClCCl
Product: CC(C)c1nc2cc[nH]c(=O)c2c2cc(Br)ccc12
Reaction time: 12 h

Procedure:
To a stirred solution of tert-butyl 2-(9-bromo-1-chlorobenzo[c]-1,6-naphthyridin-6-yl)-2-methylpropanoate (3.32 g, 7.62 mmol) in dichloromethane (30 ml) was added TFA (30 ml). The solution was stirred for 12 hrs, then concentrated to a crude oil. EtOAc was added (20 mL), and the resulting solids were collected by vacuum filtration to afford 9-bromo-6-isopropylbenzo[c]-1,6-naphthyridin-1(2H)-one. The filtrate was concentrated, EtOAc was added, and a second crop of product was obtained by vacuum filtration. 1H NMR (500 MHz, DMSO-D6) δ 11.91 (br d, 1H), 10.28 (d, 1H), 8.41 (d, 1H), 7.89 (dd, 1H), 7.58 (t, 1H), 6.77 (d, 1H), 4.05 (septet, 1H), 1.36 (d, 6H). LRMS (ESI) calc'd for (C15H13BrN2O) [M+H]+, 317.0; found 317.0.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH2:10]([O:12][CH:13]([O:22][CH2:23][CH3:24])[C:14](=[O:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:11]>N1CCCCC1.C1C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[C:15]([C:14]([CH:13]([O:12][CH2:10][CH3:11])[O:22][CH2:23][CH3:24])=[O:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)CC(=O)C(OCC)OCC
Reactant: O=Cc1ccccc1Cl
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: CCOC(=O)C(=Cc1ccccc1Cl)C(=O)C(OCC)OCC
Yield: 106.4 %

Procedure:
A solution of 2-chlorobenzaldehyde (1.0543 g), ethyl 4,4-diethoxyacetoacetate (1.6477 g) and piperidine (1 to 2 drop(s)) in benzene (30 ml) was refluxed under azeotropic dehydration for 4.5 hours. After cooling, the resultant solution was washed with water and dried. The solvent was removed from the solution to give orange oil (2.7196 g) of ethyl 2-(2-chlorobenzylidene)-4,4-diethoxyacetoacetate. The mixture of the compound obtained above and ethyl 3-amino-4,4-diethoxycrotonate (1.6580 g) was heated with stirring at about 100° C. for 1.5 hours and about 120° C. for 8 hours. After cooling, the reaction mixture was dissolved in ethyl acetate. The solution was washed with water and dried, and then the solvent was removed from the solution to give orange oil (4.21 g) of diethyl 2,6-bis(diethoxymethyl)-4-(2-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylate. The product was purified by a column chromatography on silica gel with an eluent (benzene:ethyl acetate=10:1) to give pure product.