Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([C:19](=[O:29])[C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[CH2:11][CH2:10][C:9]1=[O:30].C([O:34][CH2:35][CH3:36])(=O)C>CN(C)C=O>[N+:26]([C:23]1[CH:24]=[CH:25][C:20]([C:19]([N:12]2[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:12]3[C:19](=[O:29])[C:20]4=[CH:21][CH:22]=[CH:23][CH:24]=[C:36]4[C:35]3=[O:34])[C:9](=[O:30])[CH2:10][CH2:11]2)=[O:29])=[CH:21][CH:22]=1)([O-:28])=[O:27]
Reactant: CCOC(C)=O
Reactant: O=C1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ccccc2N1CCCCCCCl
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCCCN1C(=O)CCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(6-chlorohexyl)-5-(4-nitrobenzoyl) -1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (675 mg) and potassium phthalimido (291 mg) in N,N-dimethylformamide (15 ml) was stirred at ambient temperature for 8 hours. The mixture was diluted with ethyl acetate and washed successively with 1N hydrochloric acid, aqueous sodium hydrogen carbonate and brine, and dried over magnesium sulfate. The solvent was evaporated in vacuo to give 5-(4-nitrobenzoyl)-1-(6-phthalimidohexyl) -1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (758 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[CH2:9][C:10]1[CH:11]=[C:12]([CH:38]=[CH:39][CH:40]=1)[C:13]([NH:15][C:16]1[CH:17]=[C:18]([CH:34]=[CH:35][C:36]=1[CH3:37])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH:23]=1)=[O:20])=[O:14].C(=O)([O-])[O-].[K+].[K+].CC(C)=O>C(OCC)(=O)C>[CH3:37][C:36]1[CH:35]=[CH:34][C:18]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)[CH:23]=2)=[O:20])=[CH:17][C:16]=1[NH:15][C:13](=[O:14])[C:12]1[CH:38]=[CH:39][CH:40]=[C:10]([CH2:9][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH:11]=1
Reactant: CN1CCNCC1
Reactant: Cc1ccc(C(=O)Nc2cccc(N3CCOCC3)c2)cc1NC(=O)c1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)Nc2cccc(N3CCOCC3)c2)cc1NC(=O)c1cccc(CN2CCN(C)CC2)c1
Temperature: 60 °C
Yield: 41.6 %

Procedure:
N-Methylpiperazine (0.036 g) was added to a mixture of 3-(3-chloromethylbenzamido)-4-methyl-N-(3-morpholinophenyl)benzamide (0.15 g), potassium carbonate (0.09 g) and acetone (5 ml) and the resultant mixture was stirred and heated to 60° C. for 16 hours. The mixture was evaporated and the residue was partitioned between methylene chloride and a saturated aqueous sodium bicarbonate solution. The organic phase was dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica gel using methanol as eluent. The product so obtained was dissolved in ethyl acetate and precipitated by the addition of isohexane. There was thus obtained the title compound (0.071 g); NMR Spectrum: (DMSOd6) 2.1 (s, 3H), 2.3 (s, 3H), 2.2-2.4 (m, 8H), 3.1 (t, 4H), 3.55 (s, 2H), 3.75 (t, 4H), 6.65-6.7 (m, 1H), 7.18 (t, 1H), 7.3-7.35 (m, 1H), 7.38-7.55 (m, 4H), 7.78-7.8 (m, 1H), 7.85-7.9 (m, 2H), 7.95 (s, 1H); Mass Spectrum: M+H+ 528.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]3[C:21](=[O:32])[N:20]([CH2:33][CH2:34][CH3:35])[C:19](Cl)=[N:18][C:17]=3[N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:37][C:38]([F:49])([F:48])[C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[CH:43][CH:44]=1.C([O-])(O)=O.[Na+]>C1COCC1.O.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>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]3[C:21](=[O:32])[N:20]([CH2:33][CH2:34][CH3:35])[C:19]([C:43]4[CH:42]=[CH:41][CH:40]=[C:39]([C:38]([F:49])([F:48])[F:37])[CH:44]=4)=[N:18][C:17]=3[N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CCCn1c(Cl)nc2nc(-c3ccc(OCc4ccccc4)cc3)n(COCC[Si](C)(C)C)c2c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCn1c(-c2cccc(C(F)(F)F)c2)nc2nc(-c3ccc(OCc4ccccc4)cc3)n(COCC[Si](C)(C)C)c2c1=O
Temperature: 85 °C
Reaction time: 28 h
Yield: 11.2 %

Procedure:
A mixture of 8-(4-benzyloxy-phenyl)-2-chloro-1-propyl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (50.0 mg, 0.96 mmol), 3-Trifluoromethyl phenyl boronic acid (31.0 mg, 1.4 mmol) were taken in THF (5 ml) and degassed for 10 minutes. To above degassed solution NaHCO3 (20.0 mg, 0.24 mmol) in water (1 ml) and Pd(PPh3)4 were added and degassed for another 20 minutes. The reaction mixture was stirred for 28 hours at 80-90° C. The mixture was cooled to 25-27° C. and diluted with water (5 ml). The aqueous layer was extracted with DCM (3×5 ml). The organic layer was washed with brine (2×10 ml), dried over Na2SO4, and the solvent was evaporated. The residue obtained was purified by preparative TLC (35% Ethyl acetate in hexane) to obtain pure 8-(4-Benzyloxy-phenyl)-1-propyl-2-(3-trifluoromethyl-phenyl)-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (68 mg, quantitative) as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([I:10])=[CH:8][N:7]=[C:6]([OH:11])[CH:5]=1)[CH3:2].Br[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1.C(=O)([O-])[O-].[Ag+2]>[CH2:13]([O:11][C:6]1[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[C:9]([I:10])=[CH:8][N:7]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOc1cc(O)ncc1I
Reactant: BrCc1ccccc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CCOc1cc(OCc2ccccc2)ncc1I
Temperature: 70 °C
Reaction time: 16 h
Yield: 63.4 %

Procedure:
To a mixture of 4-ethoxy-5-iodopyridin-2-ol (800 mg, 3.02 mmol) in THF (10 mL) was added (bromomethyl)benzene (619 mg, 3.62 mmol) and silver carbonate (1665 mg, 6.04 mmol). The mixture was stirred at 70° C. for 16 h. The reaction residue was filtered and the filtrate was concentrated. The mixture was diluted with H2O and extracted with DCM. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The resulting 2-(benzyloxy)-4-ethoxy-5-iodopyridine (800 mg, 1.915 mmol, 63.4% yield) was used to next step without further purification: 1H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 7.45-7.43 (m, 2H), 7.38-7.36 (m, 3H), 6.22 (s, 1H), 5.33 (s, 2H), 4.12-4.07 (m, 2H), 1.48 (t, J=6.8 Hz, 3H); ES-LCMS m/z 355.9 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:12][CH2:11][N:10]([CH:13]=[CH2:14])[C:9]1=[O:15])=[O:7])([CH3:4])(C)C.[H-].[Na+].Cl[CH:19]1[CH2:23]CC[O:20]1>O1CCCC1.C(OCC)C>[O:20]1[CH2:19][CH2:23][CH2:4][CH:1]1[O:5][C:6]([CH:8]1[CH2:12][CH2:11][N:10]([CH:13]=[CH2:14])[C:9]1=[O:15])=[O:7]
Reactant: C=CN1CCC(C(=O)OC(C)(C)C)C1=O
Reactant: ClC1CCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CN1CCC(C(=O)OC2CCCO2)C1=O

Procedure:
8.9 g or 3-(t-butoxycarbonyl)-1-vinyl-2-pyrrolidinone (BCVP) was dissolved in 50 ml of tetrahydrofuran free of moisture. To this solution 1.0 g of sodium hydride and 4.4 g of 2-chlorotetrahydrofuran were added and allowed to react at room temperature for 1 hour. This solution was diluted with diethylether and washed many times with pure water. The organic solvent of the organic phase was evaporated and the residue was subjected to silica gel column chromatography, to obtain 9.3 g of pure 3-(tetrahydrofuranyloxycarbonyl)-1-vinyl-2-pyrrolidinone (hereinafter referred to as “TFVP”). Its chemical structure was determined by IR spectra and NMR.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[N:14][N:13]([CH:16]([F:18])[F:17])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:19]([O:22][CH2:23][C:24]1[C:25]([N:39]2[N:48]=[CH:47][C:46]3[C:41](=[C:42]([F:53])[CH:43]=[C:44]([C:49]([CH3:52])([CH3:51])[CH3:50])[CH:45]=3)[C:40]2=[O:54])=[N:26][CH:27]=[CH:28][C:29]=1B1OC(C)(C)C(C)(C)O1)(=[O:21])[CH3:20]>>[C:19]([O:22][CH2:23][C:24]1[C:25]([N:39]2[N:48]=[CH:47][C:46]3[C:41](=[C:42]([F:53])[CH:43]=[C:44]([C:49]([CH3:51])([CH3:50])[CH3:52])[CH:45]=3)[C:40]2=[O:54])=[N:26][CH:27]=[CH:28][C:29]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[N:14][N:13]([CH:16]([F:18])[F:17])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:21])[CH3:20]
Reactant: Cn1cc(Br)cc(Nc2cnn(C(F)F)n2)c1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Product: CC(=O)OCc1c(-c2cc(Nc3cnn(C(F)F)n3)c(=O)n(C)c2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Yield: 32.1 %

Procedure:
Following the procedure of Example 152c, and starting with 159c (150 mg, 0.46 mmol, 1.0 eq.) and 3-(acetoxymethyl)-2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)pyridin-4-ylboronic acid (116c) (285 mg, 0.69 mmol, 1.5 eq.) afforded 159d as a yellow solid (90 mg, 32%). MS-ESI: [M+H]+ 609.3
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=[O:4].[CH:14]1([C:17]2[CH:22]=[N+:21]([O-])[C:20]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:19][CH:18]=2)[CH2:16][CH2:15]1.O>CN(C)C=O>[CH:14]1([C:17]2[CH:18]=[CH:19][C:20]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N:21][C:22]=2[OH:4])[CH2:16][CH2:15]1
Reactant: CCOC(=O)c1ccc(C2CC2)c[n+]1[O-]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(C2CC2)c(O)n1
Temperature: 50 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
Trifluoroacetic anhydride (23 mL) was added to a solution of ethyl 5-cyclopropylpyridine-2-carboxylate 1-oxide (15.4 g) in N,N-dimethylformamide (45 mL), and the mixture was stirred at 50° C. for two hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=10:0→9:1) to give ethyl 5-cyclopropyl-6-hydroxypyridine-2-carboxylate (12.4 g, 78%) as a colorless powder.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[C:13]([Cl:20])=[N:14][CH:15]=[C:16]([CH2:18][CH3:19])[CH:17]=2)[C:10]=1[CH3:11])=[O:5])C.[OH-].[Na+].C(O)C.Cl>O>[Cl:20][C:13]1[C:12]([N:9]2[C:10]([CH3:11])=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]2)=[CH:17][C:16]([CH2:18][CH3:19])=[CH:15][N:14]=1
Reactant: CCOC(=O)c1cnn(-c2cc(CC)cnc2Cl)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCc1cnc(Cl)c(-n2ncc(C(=O)O)c2C)c1
Temperature: 25 °C
Yield: 84.4 %

Procedure:
1-(2-Chloro-5-ethylpyridin-3-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (0.639 g) and 4N aqueous solution of sodium hydroxide (5 ml) were added to a mixed solvent of ethanol (10 ml) and water (5 ml) and stirred at room temperature for an hour. The reaction solution was cooled to 0° C., 1N hydrochloric acid aqueous solution (30 ml) was added dropwise and the precipitated solid was filtered to give the titled compound (0.488 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1.[NH:24]1[CH2:29][CH2:28][CH:27]([NH:30][C:31](=[O:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:26][CH2:25]1.C(N(CC)CC)C>O1CCCC1.C(=O)([O-])O.[Na+]>[C:31]([NH:30][CH:27]1[CH2:28][CH2:29][N:24]([C:2]2[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[N:3]=2)[CH2:25][CH2:26]1)(=[O:38])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Reactant: O=C(NC1CCNCC1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCC(NC(=O)c3ccccc3)CC2)nc1-c1ccc(C)cc1
Temperature: 110 °C
Yield: 31.4 %

Procedure:
A mixture of methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (0.104 g; 0.312 mmol), N-(piperidin-4-yl)benzamide (0.191 g; 0.937 mmol) and triethyl amine (0.220 mL; 1.56 mmol) in tetrahydrofuran (2 mL) was heated at 110° C. in a sealed tube for 5 h. The reaction mixture was diluted with a saturated solution of sodium hydrogen carbonate, extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (15-80%) in heptane furnished 0.049 g (34%) of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH2:13][CH2:14][CH:15]=O)=[CH:11][C:10]([CH2:17][CH2:18][CH2:19][CH3:20])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][N:31]([CH2:15][CH2:14][CH2:13][C:12]2[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[N:9]=[C:10]([CH2:17][CH2:18][CH2:19][CH3:20])[CH:11]=2)[CH2:30][CH2:29]1
Reactant: CCCCc1cc(CCC=O)n(Cc2ccccc2)n1
Reactant: Fc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCCCc1cc(CCCN2CCN(c3ccccc3F)CC2)n(Cc2ccccc2)n1

Procedure:
180 mg (84.2%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-benzyl-3-butyl-1H-pyrazol-5-yl)propanal (133 mg, 0.492 mmol), 1-(2-fluorophenyl)piperazine (155 mL, 0.984 mmol), and NaBH(OAc)3 (198 mg, 0.936 mmol).
Reaction SMILES: [OH:1][C@H:2]([CH2:8][C:9](=[O:11])[O-:10])[CH2:3][N+:4]([CH3:7])([CH3:6])[CH3:5].[C:12]([OH:17])(=[O:16])[CH2:13][CH2:14][CH3:15].O.[OH-].[Ca+2:20].[OH-]>CO>[C:9]([O-:11])(=[O:10])[CH2:8][CH2:2][CH3:3].[Ca+2:20].[OH:1][C@H:2]([CH2:8][C:9](=[O:10])[O-:11])[CH2:3][N+:4]([CH3:7])([CH3:5])[CH3:6].[C:12]([O-:17])(=[O:16])[CH2:13][CH2:14][CH3:15]
Reactant: CCCC(=O)O
Agent: C[N+](C)(C)C[C@H](O)CC(=O)[O-]
Agent: [Ca+2]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCC(=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
L-Carnitine (0.5 g, 0.003 mol) and butyric acid (0.54 g, 0.006 mol) were added to 5 mL of water and 1 mL of methanol. To the resulting solution was added calcium hydroxide (0.22 g, 0.003 mol). The resulting slurry clarified during 15 minutes of stirring at room temperature. After continued stirring at room temperature for four hr, the solution was filtered, and the filtrate was concentrated to dryness under vacuum at bath temperatures that were less than about 70° C. The solid, L-carnitine calcium butyrate, was obtained in greater than 90% yield and had a melting point of 97.6° C., with decomposition and evolution of trimethylamine. (The melting point of L-carnitine was 186-190° C. Butyric acid is a liquid.) The solid was not hygroscopic. The solid had no objectionable taste but had a somewhat bitter aftertaste. The 1H-NMR spectrum (FIG. 2) is consistent with the structure of the salt and shows the presence of L-carnitine and butyrate in a molar ratio of approximately 1:2. (Calcium is not detected by 1H-NMR.)
Reaction SMILES: C(N(CC)CC)C.[C:8]([OH:16])(=O)[C:9]1[CH:14]=[CH:13][CH:12]=[N:11][CH:10]=1.Cl.[CH3:18][NH:19][O:20][CH3:21].ON1C2C=CC=CC=2N=N1.Cl.CNC(N=C=NCC)CCNC>C(#N)C>[CH3:21][O:20][N:19]([CH3:18])[C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[N:11][CH:10]=1
Reactant: O=C(O)c1cccnc1
Reactant: CNOC
Agent: CCN=C=NC(CCNC)NC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cccnc1
Reaction time: 2 h
Yield: 97.8 %

Procedure:
Add triethylamine (11.9 mL, 84.5 mmol) dropwise to a suspension of nicotinic acid (10 g, 81.2 mmol), N,O-dimethylhydroxylamine hydrochloride (8.3 g, 85.3 mmol, 1.05 eq), 1-hydroxybenzotriazole (3.29 g, 24.36 mmol, 0.3 eq) and 1,3-dimethylamino propyl-3-ethylcarbodiimide hydrochloride (18.68 g, 97.44 mmol, 1.2 eq) in acetonitrile (100 mL) at room temperature under nitrogen. After 2 h a white precipitate forms. Add water (100 mL) and acetonitrile and evaporate under vacuum. Extract with ethyl acetate (3×100 mL), dry the organic phase over anhydrous sodium sulfate and concentrate to afford 13.19 g (98%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[O:16])[C:5]2[C:10]([C:11]=1[OH:12])=[C:9]([CH2:13][CH3:14])[CH:8]=[CH:7][CH:6]=2.[CH3:17][O:18][CH2:19]Cl.C(N(CC)C(C)C)(C)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[O:16])[C:5]2[C:10]([C:11]=1[O:12][CH2:17][O:18][CH3:19])=[C:9]([CH2:13][CH3:14])[CH:8]=[CH:7][CH:6]=2
Reactant: CCc1cccc2c(C=O)cc(Cl)c(O)c12
Reactant: COCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cccc2c(C=O)cc(Cl)c(OCOC)c12

Procedure:
1.0 g of 3-chloro-5-ethyl-4-hydroxy-1-naphthalenecarbaldehyde, 0.91 ml of chloromethyl methyl ether and 3.5 ml of N,N-diisopropylethylamine were dissolved in 10 ml of dichloromethane, and reacted at room temperature for 4 hours.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[S:20][C:19]([C:21]4[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=4[C:23]#[N:24])=[CH:18][CH:17]=3)=[C:11]([CH2:29][CH2:30][CH3:31])[N:10]3[N:32]=[CH:33][N:34]=[C:9]23)[CH2:4][CH2:3]1.[N+](=[CH:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[N-]>C([O-])(=O)C.[Rh+].C1(C)C=CC=CC=1>[C:23]([C:22]1[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=1[C:19]1[S:20][C:16]([CH2:15][C:12]2[C:13](=[O:14])[N:8]([C@H:5]3[CH2:6][CH2:7][C@H:2]([O:1][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:3][CH2:4]3)[C:9]3[N:10]([N:32]=[CH:33][N:34]=3)[C:11]=2[CH2:29][CH2:30][CH3:31])=[CH:17][CH:18]=1)#[N:24]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)s2)c(=O)n([C@H]2CC[C@H](O)CC2)c2ncnn12
Agent: [Rh+]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)s2)c(=O)n([C@H]2CC[C@H](OCC(=O)OCC)CC2)c2ncnn12
Reaction time: 1 h

Procedure:
To a mixture of 2-(5-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}thiophen-2-yl)benzonitrile (0.4 g), rhodium(I) acetate (0.0019 g) and toluene (10 mL) was added dropwise ethyl diazoacetate (0.46 mL) at 80° C., and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was concentrated, and the obtained residue was subjected to silica gel column chromatography to give the title compound as a colorless solid (0.25 g, 53%).
Reaction SMILES: CN(C)CCNC.[Li]CCCC.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][N:16]=1.[I:23]I>C1COCC1.CCOCC>[I:23][C:21]1[C:18]([CH:19]=[O:20])=[CH:17][N:16]=[C:15]([O:14][CH3:13])[CH:22]=1
Reactant: II
Reactant: COc1ccc(C=O)cn1
Agent: CNCCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc(I)c(C=O)cn1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 15.9 %

Procedure:
To a stirred solution of N,N,N′-trimethylethylenediamine (1.9 mL, 15 mmol) in anhydrous THF (65 mL) under argon at −70° C. was slowly added 1.6M n-BuLi in hexanes (9.0 mL, 14 mmol). After stirring at −70° C. for 15 minutes, 6-methoxy-nicotinaldehyde (1.3 g, 9.8 mmol) was added dropwise. After the addition was complete, stirring was continued at −70° C. for another 15 minutes. Then 1.6M n-BuLi in hexanes (10 mL, 16 mmol) was added dropwise and stirring continued at −45° C. for 4 h. The solution was cooled to −70° C. and then a solution of iodine (3.0 g, 12 mmol) and anhydrous THF (25 mL) was added dropwise. When the addition was complete, stirring was continued at −70° C. for 30 minutes and then at RT for 3 h. The crude product was taken up in ether (40 mL) and washed successively with saturated ammonium chloride (2×40 mL) and 5% sodium thiosulfate (2×20 mL). The organic phase was dried, filtered and concentrated. Purification by column chromatography with EtOAc-heptanes (1:1) as eluent gave 0.41 g (15% yield) of 4-iodo-6-methoxynicotinaldehyde.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](OC(=O)C)(=[O:7])[CH3:6].[CH2:12]([O:14][C:15]([C:17]1[NH:18][C:19]([CH3:23])=[C:20]([CH3:22])[CH:21]=1)=[O:16])[CH3:13]>ClC(Cl)C>[CH2:12]([O:14][C:15]([C:17]1[NH:18][C:19]([CH3:23])=[C:20]([CH3:22])[C:21]=1[C:5](=[O:7])[CH3:6])=[O:16])[CH3:13]
Reactant: CCOC(=O)c1cc(C)c(C)[nH]1
Reactant: CC(=O)OC(C)=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1[nH]c(C)c(C)c1C(C)=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 57.2 %

Procedure:
To a solution of aluminum chloride (50.19 g, 0.376 mol) in dry dichloroethane (580 mL) at 25° C. was added slowly acetic anhydride (17.75 mL, 0.188 mol). The resulting mixture was stirred at room temp. for 10 minutes, then a solution of pyrrole 3b (10.49 g, 0.0627 mol) in dichloroethane (30 mL) was added and the reaction mixture was stirred at room temp. for 2 hours. After an additional 3 hours at 80° C., the mixture was poured into ice water and extracted with dichloromethane. The organic layer was dried with anhydrous sodium sulfate and concentrated in vacuo to an orange residue. Short plug filtration over silica gel (30% ethyl acetate/70% hexanes) gave 7.5 g (60%) of ethyl-3-acetyl-4,5-dimethyl-2-pyrrole carboxylate 4b. 1H NMR (CDCl3) δ 9.0 (bs, 1H), 4.3 (q, 2H), 2.7 (s, 3H), 2.1 (s, 3H), 1.9 (s, 3H), 1.3 (t, 3H) ppm.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]1[C:9]([OH:10])=[C:8]([C:11]([CH3:13])=[O:12])[CH:7]=[CH:6][C:5]=1[OH:14].[Br:15][CH2:16][CH2:17][CH2:18]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:11]([C:8]1[CH:7]=[CH:6][C:5]([O:14][CH2:18][CH2:17][CH2:16][Br:15])=[C:4]([CH2:3][CH2:2][CH3:1])[C:9]=1[OH:10])(=[O:12])[CH3:13]
Reactant: BrCCCBr
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(OCCCBr)ccc(C(C)=O)c1O

Procedure:
A mixture of 2,4-dihydroxy-3-propylacetophenone (2.7 g), 1,3-dibromopropane (2.8 ml) and potassium carbonate (1.9 g) in acetone (50 ml) was refluxed for 3 hours. Insoluble materials were filtered off, and the filtrate was concentrated. The resulting syrup was purified by means of a silica gel flash chromatography (chloroform-hexane=1:1) to give 3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl bromide (2.9 g) as colorless and transparent syrup.
Reaction SMILES: O1CCCC1.[NH2:6][C:7]1[C:12]([C:13]2[O:17][N:16]=[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:11][CH:10]=[C:9]([NH2:26])[N:8]=1.[OH-].[Na+].[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([CH2:36]Cl)=[N:34][CH:35]=1>CN(C)C=O>[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([CH2:36][O:25][C:22]2[CH:23]=[CH:24][C:19]([CH2:18][C:15]3[CH:14]=[C:13]([C:12]4[C:7]([NH2:6])=[N:8][C:9]([NH2:26])=[CH:10][CH:11]=4)[O:17][N:16]=3)=[CH:20][CH:21]=2)=[N:34][CH:35]=1
Reactant: Nc1ccc(-c2cc(Cc3ccc(O)cc3)no2)c(N)n1
Reactant: ClCc1ccc(Cl)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Nc1ccc(-c2cc(Cc3ccc(OCc4ccc(Cl)cn4)cc3)no2)c(N)n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
To a tetrahydrofuran (3 mL) solution of 4-(5-(2,6-diamino-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (30 mg, 0.11 mmol) described in Manufacturing Example 18-1-1 was added a 5 N sodium hydroxide aqueous solution (21.2 μL, 0.11 mmol), which was dissolved by irradiating ultrasonic wave for 1 minute. The reaction solution was concentrated under a reduced pressure, which gave a white solid. An N,N-dimethylformamide (1 mL) solution of 5-chloro-2-chloromethyl-pyridine (18.9 mg, 0.12 mmol) described in manufacturing Example 63-1-2 was added to a suspension of this solid in N,N-dimethylformamide (1 mL), which was stirred for 1 hour at 60° C. The reaction mixture was cooled to room temperature and then partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (38.4 mg, 89%).