Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[S:8][CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13].CC(C)([O-])C.[K+]>CN(C=O)C.CCOCC>[N+:12]([C:11]1[CH:10]=[CH:9][S:8][C:7]=1[N:1]1[CH:5]=[N:4][CH:3]=[N:2]1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ccsc1Cl
Reactant: c1nc[nH]n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccsc1-n1cncn1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
1H-1,2,4-triazole (582 mg, 8.43 mmol), 2-chloro-3-nitrothiophene (1.15 g, 7.03 mmol) and potassium t-butoxide (944 mg, 8.43 mmol) were dissolved in DMF (30 mL). The resulting solution was stirred at 90° C. for 2 h, after which the reaction mixture was cooled to room temperature and diluted with Et2O. The solution was washed with brine and the organic phase was separated, dried (Na2SO4), filtered, concentrated under vacuum to give 1-(3-nitrothiophen-2-yl)-1H-1,2,4-triazole. Retention time (min)=1.073, method [1], MS (ESI) 197.0 (M+H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[C:11]([N:13]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:14](=[O:25])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[O:12])=[CH:2]1>CN(C=O)C.[C].[Pd]>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH:15]([C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[NH:18][CH:17]=3)[C:14](=[O:25])[N:13]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:11]2=[O:12])=[CH:2]1
Reactant: O=C1C(c2c[nH]c3ccccc23)=C(c2c[nH]c3ccccc23)C(=O)N1Cc1ccccc1
Agent: [Pd]
Solvent: CN(C)C=O
Product: O=C1C(c2c[nH]c3ccccc23)C(c2c[nH]c3ccccc23)C(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 91.1 %

Procedure:
To a solution of 2,3-bis(1H-indol-3-yl)-N-benzylmaleimide (35 mg, 0.084 mmol) in DMF (1 mL) was added a small amount of 10% palladium-carbon, and the whole was stirred at room temperature for 6 hours under hydrogen atmosphere. The palladium-carbon was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (ethyl acetate:n-hexane=2:1) to obtain 3,4-bis(1H-indol-3-yl)-1-benzyl-2,5-dioxopyrrolidine (32.1 mg, 91.3%) as pale red solids.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([CH:9]2[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10]2)=[C:4]([F:18])[CH:3]=1.C([Li])CCC.[C:24](=[O:26])=[O:25]>O1CCCC1>[F:8][C:7]1[CH:6]=[C:5]([CH:9]2[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10]2)[C:4]([F:18])=[CH:3][C:2]=1[C:24]([OH:26])=[O:25]
Reactant: Fc1cc(C2CCC3(C2)OCCO3)c(F)cc1Br
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1cc(F)c(C2CCC3(C2)OCCO3)cc1F

Procedure:
A solution of 31.9 g (0.1 mol) of 7-(4-bromo-2,5-difluorophenyl)-1,4-dioxaspiro[4.4]nonane in 300 ml of dry tetrahydrofuran, under an argon atmosphere at -78° C., was treated with 40 ml (0.1 mol) of 2.5 M n-butyl lithium (hexane solution). The solution was warmed to -40° and poured onto 500 g of finely crushed dry ice and the mixture allowed to stand until the dry ice evaporated (18 hours). The solvent was evaporated in vacuo and the residue partitioned between ethyl acetate/1.0 M hydrochloric acid (500 ml ea). The organic layer was washed with water, dried (MgSO4), and evaporated in vacuo to give 18.9 g of the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][OH:23])[CH:17]=1)(C)(C)C>ClCCl>[NH2:14][CH2:15][C:16]1[CH:17]=[C:18]([CH2:22][OH:23])[CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(CO)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1cccc(CO)c1
Reaction time: 0.67 h
Yield: 33.3 %

Procedure:
Trifluoroacetic acid (5 ml) was added to a solution of (3-hydroxymethylbenzyl)carbamic acid tert butylester (1.70 g, 7.17 mmol) in dichloromethane (5 ml). The reaction mixture was stirred for 40 min. The solvent was removed in vacuo. The residue was dissolved in dichloromethane (40 ml). The solvent was removed in vacuo. The latter procedure was repeated twice. The residue was dissolved in water (50 ml) and an 1 N aqueous solution of sodium hydroxide (100 ml). It was washed with tert-butyl methyl ether (3×100 ml). It was saturated with sodium chloride and extracted with dichloromethane (3×75 ml). The combined dichloromethane-phases were dried over magnesium sulphate. The solvent was removed in vacuo to give 328 mg of crude (3-(aminomethyl)phenyl)methanol, which was used for the further steps without purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH:11]2[O:23][CH2:24][C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)=[CH:6][CH:5]=1.[C:35]1([N:41]=[C:42]=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:33]=[CH:34][C:25]=1[CH2:24][O:23][CH:11]1[CH:10]([C:7]2[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][O:1][C:42](=[O:43])[NH:41][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:5][CH:6]=2)[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CCO)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: O=C=Nc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(CCOC(=O)Nc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 24(m), by reacting tert-butyl (3RS,4RS)-4-[4-(2-hydroxy-ethyl)-phenyl]-3-naphthalen-2-ylmethoxy-piperidine-1-carboxylate with phenyl isocyanate there was obtained tert-butyl (3RS,4RS)-3-naphthalen-2-ylmethoxy-4-[4-(2-phenylcarbamoyloxy-ethyl)-phenyl]-piperidine-1-carboxylate as a colourless oil, MS: 481 (M+H)+.
Reaction SMILES: [CH:1]([C:3]([CH3:5])=[O:4])=[CH2:2].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[NH:14][C:15](=[O:20])[C:16]([NH2:19])([CH3:18])[CH3:17]>O1CCCC1>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[NH:14][C:15](=[O:20])[C:16]([NH:19][CH2:2][CH2:1][C:3](=[O:4])[CH3:5])([CH3:17])[CH3:18]
Reactant: C=CC(C)=O
Reactant: CC(C)(N)C(=O)Nc1cc(Cl)ccc1Cl
Solvent: C1CCOC1
Product: CC(=O)CCNC(C)(C)C(=O)Nc1cc(Cl)ccc1Cl
Yield: 97.4 %

Procedure:
Methyl vinyl ketone (1.02 g) was added to a solution of N-(2,5-dichlorophenyl)-2-aminoisobutyramide (2.4 g) in tetrahydrofuran (10 mL) and the mixture was heated at reflux 30 hours. After distilling off the solvent under reduced pressure, 3 g of N-(2,5-dichlorophenyl)-2-(3-oxobutylamino)isobutyramide was obtained.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([CH3:14])[C@H:9]2[CH2:15][N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:26])=[O:7])=[C:4](I)[CH:3]=1.C([Sn](CCCC)(CCCC)[C:35]1[N:40]=[CH:39][CH:38]=[CH:37][N:36]=1)CCC.[F-].[Cs+]>CN(C=O)C.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([CH3:14])[C@H:9]2[CH2:15][N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:26])=[O:7])=[C:4]([C:35]2[N:40]=[CH:39][CH:38]=[CH:37][N:36]=2)[CH:3]=1
Reactant: C[C@@H]1CCCN(C(=O)c2ccc(F)cc2I)[C@@H]1CN1C(=O)c2ccccc2C1=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[C@@H]1CCCN(C(=O)c2ccc(F)cc2-c2ncccn2)[C@@H]1CN1C(=O)c2ccccc2C1=O
Temperature: 100 °C
Yield: 80.7 %

Procedure:
A mixture of 2-(((2S,3R)-1-(4-fluoro-2-iodobenzoyl)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione (0.51 g, 1.0 mmol), 2-(tributylstannyl)pyrimidine (0.406 g, 1.1 mmol), CsF (0.304 g, 2.0 mmol), CuI (0.019 g, 0.1 mmol) and Pd(PPh3)4 (0.116 g, 0.1 mmol) in DMF (5 mL) was degassed and heated at 100° C. for 16 h. The solvent was removed in vacuo to obtain the crude which was purified by silica gel chromatography (0˜100% EtOAc/hexanes) to yield the title compound as a white solid (0.370 g, 81%). MS (ESI) 459 (M+H).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH2:17][NH:16][CH2:15][CH:14]2[CH2:21][CH2:22][NH:23][C:24](=[O:26])[CH3:25].[CH:27]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)=[O:28]>ClCCl>[CH:27]([C:29]1[CH:34]=[C:33]([N:16]2[CH2:15][CH:14]([CH2:21][CH2:22][NH:23][C:24](=[O:26])[CH3:25])[C:13]3[C:18](=[CH:19][CH:20]=[C:11]([O:10][CH3:9])[CH:12]=3)[CH2:17]2)[CH:32]=[CH:31][CH:30]=1)=[O:28]
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: COc1ccc2c(c1)C(CCNC(C)=O)CNC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2c(c1)C(CCNC(C)=O)CN(c1cccc(C=O)c1)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Copper acetate Cu(OAc)2 (960 mg; 5 mmol) and triethylamine (1.5 ml; 10.5 mmol) are suspended in 60 ml of dichloromethane. The compound of Example 4 (1 g; 3.5 mmol), 3-formylphenylboronic acid (1.05 g; 7 mmol) and molecular sieve are then added in succession and progressively to the solution. The reaction mixture is stirred at ambient temperature for 2 hours. The mixture is filtered, washed with water, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue obtained is purified by chromatography on silica gel (eluant: dichloromethane with the progressive addition of methanol until the proportions 9/1 are reached) to yield the title product in the form of a yellow oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](/[CH:14]=[CH:15]/[N:16](C)C)=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=O)C>CN(C=O)C>[CH3:13][S:12][C:9]1[N:10]=[CH:11][C:6]2[C:4](=[O:3])[NH:16][CH:15]=[CH:14][C:7]=2[N:8]=1
Reactant: CCOC(=O)c1cnc(SC)nc1/C=C/N(C)C
Solvent: CN(C)C=O
Product: CSc1ncc2c(=O)[nH]ccc2n1
Yield: 78 %

Procedure:
4-((E)-2-Dimethylamino-vinyl)-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester 5 (13.5 g, 50.5 mmol) and NH4OAc (38.9 g, 505 mmol) were dissolved in DMF (250 mL) and stirred at reflux for about four days. Then mixture was concentrated, residue dissolved in TCM, washed with water, dried, filtered, and concentrated. The product was purified by crystallization from ethanol to obtain a colorless solid (7.60 g, 39.4 mmol, 78%).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:12](=[O:14])[CH3:13])=[CH:8][C:9]=2[Cl:11])[N:4]([CH2:15][CH2:16][CH2:17][O:18][CH3:19])[N:3]=1.[C:20](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1.O>O1CCOCC1.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]>[Cl:11][C:9]1[CH:8]=[C:7]([C:12](=[O:14])[CH3:13])[CH:6]=[C:5]2[C:10]=1[C:2]([CH3:20])=[N:3][N:4]2[CH2:15][CH2:16][CH2:17][O:18][CH3:19]
Reactant: COCCCn1nc(Br)c2c(Cl)cc(C(C)=O)cc21
Reactant: O=C([O-])[O-]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CB1OB(C)OB(C)O1
Solvent: O
Solvent: C1COCCO1
Product: COCCCn1nc(C)c2c(Cl)cc(C(C)=O)cc21
Temperature: 80 °C
Reaction time: 24 h
Yield: 48.3 %

Procedure:
To a solution of 1-[3-bromo-4-chloro-1-(3-methoxypropyl)-1H-indazol-6-yl]ethanone (1.0 g) in 1,4-dioxane (20 mL) were added potassium carbonate (1.2 g), trimethylboroxine (0.41 mL) and 1,1′-bis(diphenylphosphino)ferrocene dichloropalladium (II) (212 mg) under argon, and the mixture was heated to stir at 80° C. for 24 hours. Then, thereto was added water under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by NH-silica gel column chromatography (eluent: n-hexane/ethyl acetate=4/1→3/2) to give 1-[4-chloro-1-(3-methoxypropyl)-3-methyl-1H-indazol-6-yl]ethanone [REx(15-1)] (392 mg) as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][C:39]([CH:42]3[CH2:44][CH2:43]3)=[CH:40][CH:41]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][C:39]([CH:42]3[CH2:43][CH2:44]3)=[CH:40][CH:41]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccc(C3CC3)nc2)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccc(C3CC3)nc2)c1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethoxy-phenyl)-carbamic acid tert-butyl ester (Example J26) (219 mg, 0.75 mmol) and 3-[3-(6-cyclopropyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K21) (253 mg, 0.75 mmol) according to the general procedure M. Obtained as a yellow foam (252 mg, 60%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:28])([F:27])[C:12]3[CH:13]=[CH:14][C:15]4[N:16]([CH:18]=[C:19]([NH:21][C:22]([CH:24]5[CH2:26][CH2:25]5)=[O:23])[N:20]=4)[N:17]=3)=[N:9][N:10]=2)[CH:7]=1.[CH3:29][N:30]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[N:31]1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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]>[F:27][C:11]([F:28])([C:8]1[N:6]2[CH:7]=[C:2]([C:33]3[CH:32]=[N:31][N:30]([CH3:29])[CH:34]=3)[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1)[C:12]1[CH:13]=[CH:14][C:15]2[N:16]([CH:18]=[C:19]([NH:21][C:22]([CH:24]3[CH2:26][CH2:25]3)=[O:23])[N:20]=2)[N:17]=1
Reactant: O=C(Nc1cn2nc(C(F)(F)c3nnc4ccc(Br)cn34)ccc2n1)C1CC1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cn1cc(-c2ccc3nnc(C(F)(F)c4ccc5nc(NC(=O)C6CC6)cn5n4)n3c2)cn1
Yield: 71 %

Procedure:
A mixture of N-(6-((6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)difluoromethyl)imidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (7.2 g, 16.06 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (5.01 g, 24.10 mmol) and PdCl2(dppf):CH2Cl2 (0.655 g, 0.803 mmol) in 1,4-Dioxane:1M Na2CO3 (Ratio: 2.1, Volume: 100 ml) was heated at 95° C. for 4 h. The reaction mixture cooled and concentrated to dryness via rotary evaporation, diluted with EtOAc and water. The resulting solid was collected by filtration, rinsed with H2O followed by EtOAc. The grey color solid dissolved in 20% MeOH in chloroform and treated with activated charcoal for overnight, filtered through a pad of celite and the celite pad rinsed with 20% MeOH in chloroform until no compound detected by HPLC. This solution passed through a silica gel column. The solvent evaporated and the resulting solid rinsed with EtOAc, MeOH, followed by EtOAc and then Et2O, dried under vacuum to provide N-(6-(difluoro(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (5.13 g, 11.41 mmol, 71.1% yield) as white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.35 (s, 1H), 8.71 (s, 1H), 8.41 (s, 1H), 8.19-8.34 (m, 2H), 8.00-8.12 (m, 2H), 7.91 (dd, J=1.64, 9.47 Hz, 1H), 7.71 (d, J=9.35 Hz, 1H), 3.88 (s, 3H), 1.88-2.02 (m, 1H), 0.83 (d, J=6.32 Hz, 4H). ESI-MS:m/z 450.1 (M+H)+. MP: 274.9° C.
Reaction SMILES: [NH2:1][CH:2]1[CH:9]2[CH:10](O)[C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=3[C:3]1([CH3:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]2.[ClH:20].O.Cl.Cl>C(O)C>[OH2:17].[ClH:20].[NH2:1][CH:2]1[C:9]2=[CH:10][C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=3[C:3]1([CH3:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]2.[NH2:1][CH:2]1[C:9]2=[CH:10][C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=3[C:3]1([CH3:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]2.[ClH:20]
Reactant: CC12CCCCCC(C(O)c3ccc(O)cc31)C2N
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC12CCCCCC(=Cc3ccc(O)cc31)C2N
Reaction time: 8 h
Yield: 70 %

Procedure:
13-Amino-5,6,7,8,9,10,11,12-octahydro-5-methyl-5,11-methanobenzocyclodecen-3,12-diol (0.7 g., 0.002 mole) was dissolved in 20 mL of boiling ethanol. To this solution was added 5 mL ethanol saturated with hydrogen chloride and was allowed to stand overnight. The solvent was evaporated under reduced pressure and the resulting residue was recrystallized from acetone-ethanol (5:1) to afford 400 mg (70% yield) of the title compound as a hydrochloride hemihydrate, mp 216°-218° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12](=[CH:15]NC1C=CC=CC=1)[C:13]#[N:14].C[O-].[Na+].Cl.[NH2:27][C:28]([NH2:30])=[NH:29]>C(O)C>[NH2:29][C:28]1[N:30]=[C:13]([NH2:14])[C:12]([CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[CH:15][N:27]=1
Reactant: N#CC(=CNc1ccccc1)Cc1ccc2ccccc2c1
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Nc1ncc(Cc2ccc3ccccc3c2)c(N)n1
Reaction time: 8 h
Yield: 51.2 %

Procedure:
2-(2-Naphthylmethyl)-3-anilinoacrylonitrile (6.65 g, 23.4 mmol) was dissolved in absolute ethanol (225 ml) and heated to reflux. A solution of sodium methylate (4.27 g, 79 mmol) in ethanol (75 ml) was mixed with guanidine hydrochloride (6.87 g, 72 mmol), filtered from salt, and added to the solution of 2-(2-naphthylmethyl)-3-anilinoacrylonitrile. The mixture was then refluxed for 8 hours, and allowed to stand at room temperature overnight. A yellow precipitate formed, which was isolated (2.66 g). An additional 1.33 g was obtained by concentration of the mother liquor. The combined fractions were recrystallized from absolute ethanol, yielding light cream colored 2,4-diamino-5-(2-naphthylmethyl)pyrimidine (3.0 g), m.p. 231°-233° C. Anal. Calcd. for C15H14N4 : C, 71.98; H, 5.64; N, 22.38. Found: C, 71.93; H, 5.68; N, 22.35.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[C:10]([CH3:16])=[N:9][CH2:8][CH2:7]2.[OH-].[Na+].[BH4-].[Na+].Cl>CO>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[CH:10]([CH3:16])[NH:9][CH2:8][CH2:7]2
Reactant: COc1cc2c(cc1OC)C(C)=NCC2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc2c(cc1OC)C(C)NCC2
Reaction time: 2 h
Yield: 100 %

Procedure:
To a stirred solution of 3,4-dihydro-6,7-dimethoxy-1-methylisoquinoline hydrochloride (47.0 g, 0.229 m) and NaOH (5 g) in absolute methanol (500 ml) was added NaBH4 (34.6 g, 0.917 m) and the mixture stirred for 2 hr (TLC complete) and allowed to stand overnight. The mixture was cooled in an ice bath, treated carefully with 20% HCl until pH 1 was achieved and then heated to 50° for 1 hr. The solvent was then removed on the aspirator and the residue dissolved in 1 liter H2O. The solution was basified to pH 11 with NaOH (20%) and extracted with 3×250 ml CHCl3. The extracts were dried over MgSO4 and evaporated to give 1,2,3,4-tetrahydro-6,7-dimethoxy-1-methylisoquinoline as an oil, 47.6 g (100% yield).
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([OH:14])[CH:5]=1.[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24][CH2:25]O)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[CH3:1][S:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([O:14][CH2:25][CH2:24][CH2:23][NH:22][C:20]([O:19][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:21])[CH:5]=1
Reactant: CC(C)(C)OC(=O)NCCCO
Reactant: COC(=O)c1ccc(CSC)cc1O
Product: COC(=O)c1ccc(CSC)cc1OCCCNC(=O)OC(C)(C)C
Yield: 76 %

Procedure:
Using a procedure analogous to Example 1-D, methyl 4-(methylthiomethyl)-2-hydroxybenzoate and 3-(t-butoxy-carbonylamino)propanol gave the title compound as a white solid (2.70 g, 76%).
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][NH:24][CH2:25][C:26]3[NH:27][CH:28]=[CH:29][N:30]=3)=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].[NH:31]1[CH:35]=[CH:34][N:33]=[C:32]1[CH:36]=O.C([BH3-])#N.[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[NH:30]1[CH:29]=[CH:28][N:27]=[C:26]1[CH2:25][N:24]([CH2:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][NH:15][C:12]2[CH:11]=[CH:10][C:9]([CH2:8][N:4]([CH2:5][CH2:6][CH3:7])[CH2:1][CH2:2][CH3:3])=[CH:14][CH:13]=2)=[CH:22][CH:21]=1)[CH2:36][C:32]1[NH:31][CH:35]=[CH:34][N:33]=1
Reactant: O=Cc1ncc[nH]1
Reactant: CCCN(CCC)Cc1ccc(NCc2ccc(CNCc3ncc[nH]3)cc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)Cc1ccc(NCc2ccc(CN(Cc3ncc[nH]3)Cc3ncc[nH]3)cc2)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
The compound (199 mg) obtained in Example 43-1 was dissolved in methanol (6 ml) and then added with 2-imidazole carboxaldehyde (57.1 mg) and sodium cyanoborohydride (65.4 mg). The reaction solution was adjusted to pH 5 with the addition of acetic acid, followed by stirring at room temperature for 14 hours. The reaction solution was added with a 1 mol/l sodium hydroxide aqueous solution and then extracted with chloroform. Then, the organic layer was washed with saturated saline solution and dried with anhydrous sodium sulfate. After the solvent had been distilled off, the residue obtained was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (231 mg) of the subject compound as a yellow solid.
Reaction SMILES: [C:1]1([C:7]2[CH:25]=[C:24]3[C:10]([C:11](=[O:27])[C:12](=[O:26])[C:13]4[S:23][CH2:22][C:16]5([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]5)[O:15][C:14]=43)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:28][C:29]1[CH:39]=[CH:38][C:32]([O:33][CH2:34][C@@H:35]2[CH2:37][O:36]2)=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:39]=[CH:38][C:32]([O:33][CH2:34][C@@H:35]([OH:36])[CH2:37][N:19]2[CH2:20][CH2:21][C:16]3([O:15][C:14]4[C:24]5[C:10]([C:11](=[O:27])[C:12](=[O:26])[C:13]=4[S:23][CH2:22]3)=[CH:9][CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:25]=5)[CH2:17][CH2:18]2)=[CH:31][CH:30]=1
Reactant: Clc1ccc(OC[C@@H]2CO2)cc1
Reactant: O=C1C(=O)c2ccc(-c3ccccc3)cc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccc(-c3ccccc3)cc2C2=C1SCC1(CCN(C[C@H](O)COc3ccc(Cl)cc3)CC1)O2

Procedure:
Compound 226 was synthesized using 9-phenylspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2S)-2-[(4-chlorophenoxy)methyl]oxirane and conditions outlined in procedure Z. M.p.=93-98° C.; 400 MHz 1H NMR (DMSO-d6) δ: 8.01-7.97 (m, 2H), 7.87 (dd, J=1.6, 7.6 Hz, 1H), 7.77 (d, J=7.2 Hz, 2H), 7.59-7.47 (m, 3H), 7.31 (d, J=9.2 Hz, 2H), 6.96 (d, J=9.2 Hz, 2H), 4.90 (d, J=4.0 Hz, 1H), 4.04-3.90 (m, 2H), 3.90-3.84 (m, 1H), 3.11 (s, 2H), 2.88-2.72 (m, 2H), 2.52-2.38 (m, 4H), 2.03 (d, J=14.0 Hz, 2H), 1.88-1.80 (m, 2H); LCMS: 562 [M+H].
Reaction SMILES: [Br:1][C:2]1[C:3]([F:23])=[C:4]([CH:18]=[C:19]([F:22])[C:20]=1[F:21])[C:5]([CH:7](C(OCC)=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:6].C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[Br:1][C:2]1[C:3]([F:23])=[C:4]([CH:18]=[C:19]([F:22])[C:20]=1[F:21])[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:6]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)c1cc(F)c(F)c(Br)c1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC(=O)CC(=O)c1cc(F)c(F)c(Br)c1F
Yield: 56.8 %

Procedure:
To an emulsion of diethyl 3-bromo-2,4,5-trifluorobenzoylmalonate (3.25 g) in water (4 ml) was added p-toluenesulfonic acid (4 mg) and refluxed for 3 hours with vigorous stirring. After cooling, the reaction mixture was extracted with dichloromethane (8 ml×4). The organic layer was washed with water saturated with sodium chloride, dried over anhydrous sodium sulfate and concentrated. The residue was recrystallized from dichloromethane-n-hexane to give the title compound (1.51 g), mp 85°-88° C.