Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:16][CH:17]([CH3:19])[CH3:18])[C@@H:10]([OH:15])[CH2:11][C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:21]1C(=O)C2[CH:24](C3CC2C=C3)[C:22]1=O.C1(N=C=NC2CCCCC2)CCCCC1.Cl.C(N)C.CN1CCOCC1>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:16][CH:17]([CH3:19])[CH3:18])[C@@H:10]([OH:15])[CH2:11][C:12]([NH:21][CH2:22][CH3:24])=[O:14])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1C2C3C=CC(C3)C2C(=O)N1O
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCNC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
275 mg (1 mmole) of 4(S)-t-butoxycarbonylamino-3(S)-hydroxy-6-methylheptanoic acid and 197 mg (1.1 mmole) of N-hydroxy-5-norbornene-2,3-dicarboximide were dissolved in 10 ml of methylene chloride and ice-cooled. To this solution were added 227 mg (1.1 mmole) of dicyclohexylcarbodiimide, and the mixture was stirred for 1 hour whilst ice-cooling and for a further 2 hours at room temperature. 90 mg (1.1 mmole) of ethylamine hydrochloride and 111 mg (1.1 mmole) of N-methylmorpholine were then added and the reaction mixture was stirred overnight at room temperature. The precipitated dicyclohexylurea was removed by filtration, and the filtrate was concentrated by evaporation under reduced pressure. A 10% w/v aqueous solution of citric acid was added to the resulting residue, and the precipitated oily substance was extracted with ethyl acetate. The organic extract was washed with, in turn, a 10% w/v aqueous solution of citric acid, water, a 5% w/v aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. Diethyl ether was added to the oily residue to remove insoluble matter, and the filtrate was concentrated by evaporation under reduced pressure. Hexane was added to the resulting oily residue, to solidify it, and the solid was reprecipitated from a 2:1 by volume mixture of hexane and diethyl ether and filtered to give the title compound as a white powdery solid melting at 103°-107° C., [α]23 -43.6° (C=0.5, methanol).
Reaction SMILES: [O:1]([CH2:8][CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[N+]([C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[C:17]=1[C:18]#[N:19])([O-])=O>CS(C)=O>[N+:24]([C:20]1[CH:21]=[CH:22][CH:23]=[C:16]([O:10][CH2:9][CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:17]=1[C:18]#[N:19])([O-:26])=[O:25]
Reactant: OCCOc1ccccc1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: N#Cc1c(OCCOc2ccccc2)cccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 99.7 %

Procedure:
2-Phenoxyethanol (4.15 ml, 0.033 mole) is added to dimethylsulfoxy sodium prepared from 1.39 g of 57 percent sodium hydride and 40 ml dimethylsulfoxide, giving a mixture of the solid salt of the alcohol after about 20 minutes. This mixture is added to a solution of 5.8 g (0.030 mole) 2,6-dinitrobenzonitrile in 20 ml of dimethylsulfoxide at 30°-40°C., and the resulting purple solution is stirred over night at room temperature. The solvent is removed at 70°C. on a rotary evaporator, and the residue is triturated with water. A solid is filtered off and it is dissolved in ethylacetate. The ethylacetate solution is washed twice with H2O, brine, and dried with calcium sulfate. Evaporation of the ethylacetate, gives 8.5 g of 2-nitro-6(2-phenoxyethyoxy)-benzonitrile, which is crystallized from 200 ml ethyl alcohol, giving 6 g, m.p. 129°-137°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:10])=[N+:7]([O-:9])[CH:8]=1.[N+:11]([O-])([OH:13])=[O:12]>CC(O)=O>[CH3:1][O:2][C:3]1[C:4]([N+:11]([O-:13])=[O:12])=[CH:5][C:6]([CH3:10])=[N+:7]([O-:9])[CH:8]=1
Reactant: COc1ccc(C)[n+]([O-])c1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: COc1c[n+]([O-])c(C)cc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 6 h

Procedure:
5-methoxy-2-methylpyridine-1-oxide (6 g, 43.1 mmol) and nitric acid (18.4 mL, 431 mmol, 1.48 g/mL) was added to AcOH (50 mL) and the reaction was stirred at 90° C. for 6 h. The mixture was concentrated (1/4) and neutralized at 0° C. was addition of ammonium hydroxide. The mixture was extracted with EtOAc, washed with brine and water, dried (Na2SO4), filtered and concentrated. The product crystallised during concentration. tR: 0.50 min (LC-MS 2); ESI-MS: 185.1 [M+H]+ (LC-MS 2).
Reaction SMILES: [BrH:1].[OH:2][C:3]1[CH:4]=[C:5]([CH3:14])[CH:6]=[C:7]2[C:12]=1[NH:11][C:10](=[O:13])[CH:9]=[CH:8]2>C(O)(=O)C.CS(C)=O>[Br:1][C:6]1[C:5]([CH3:14])=[CH:4][C:3]([OH:2])=[C:12]2[C:7]=1[CH:8]=[CH:9][C:10](=[O:13])[NH:11]2
Reactant: Cc1cc(O)c2[nH]c(=O)ccc2c1
Reactant: Br
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: Cc1cc(O)c2[nH]c(=O)ccc2c1Br
Reaction time: 18 h

Procedure:
A 45% solution of hydrobromic acid in acetic acid (324 μL) is added dropwise to a solution of 8-hydroxy-6-methyl-1H-quinolin-2-one (316 mg) in dimethylsulphoxide (9 mL) at room temperature. The reaction mixture is allowed to stand for 18 hours at room temperature and the solvent removed in vacuo.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]([O:17]C(C)(C)C)=[O:16])[CH2:10][CH2:9]1)=[O:7])(C)(C)[CH3:2].[H][H]>[Pd].C(O)C>[CH2:1]([O:5][C:6]([CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([OH:17])=[O:16])[CH2:10][CH2:9]1)=[O:7])[CH3:2]
Reactant: CC(C)(C)OC(=O)C=C1CCC(C(=O)OC(C)(C)C)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1CCC(CC(=O)O)CC1
Yield: 99.8 %

Procedure:
A solution of diester (B) (12.5 g, 46.3 mmol) and 10% palladium on activated carbon (5 g) in absolute ethanol (200 mL) was exposed to a hydrogen atmosphere (at balloon pressure) and stirred vigorously for lh. After removal of catalyst by filtration and concentration, the resultant colorless oil was dissolved in methylene chloride (150 mL) and TEA (75 mL) and stirred for 15 min. All volatiles were removed by rotary evaporation and the resultant colorless oil placed under high vacuum to give (C) 4-carboxymethyl-cyclohexanecarboxylic acid ethyl ester (9.9 g, 99%) as a white solid. Data for cis/trans mixture: 1H NMR (400 MHz, CD3OD) δ 4.13 (2q, 4H), 2.58 (m, 1H), 2.30-2.20 (m, 1H), 2.20 (2d, 4H), 2.05-1.80 (m, 7H), 1.80-1.55 (m, 5H), 1.50-1.38 (m, 3H), 1.32-1.25 (m, 1H), 1.25 (2t, 6H), 1.10-1.00 (m, 2H); mass spectrum m/z 215 [(M+H)+; calcd for C11H19O4: 215].
Reaction SMILES: [O:1]=[S:2]1(=[O:38])[CH2:6][CH2:5][CH:4]=[C:3]1[C:7]1[CH:37]=[CH:36][C:10]2[NH:11][C:12]([C:17]3[C:22](=[O:23])[N:21]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[N:20]4[CH:32]=[CH:33][CH:34]=[C:19]4[C:18]=3[OH:35])=[N:13][S:14](=[O:16])(=[O:15])[C:9]=2[CH:8]=1.[H][H].C(OCC)C>CN(C)C=O.[Pd]>[O:38]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]1[CH:37]=[CH:36][C:10]2[NH:11][C:12]([C:17]3[C:22](=[O:23])[N:21]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[N:20]4[CH:32]=[CH:33][CH:34]=[C:19]4[C:18]=3[OH:35])=[N:13][S:14](=[O:16])(=[O:15])[C:9]=2[CH:8]=1
Reactant: [H][H]
Reactant: O=c1c(C2=NS(=O)(=O)c3cc(C4=CCCS4(=O)=O)ccc3N2)c(O)c2cccn2n1Cc1ccc(F)cc1
Agent: [Pd]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=c1c(C2=NS(=O)(=O)c3cc(C4CCCS4(=O)=O)ccc3N2)c(O)c2cccn2n1Cc1ccc(F)cc1
Reaction time: 1 h
Yield: 27.8 %

Procedure:
3-[7-(1,1-Dioxo-4,5-dihydro-1H-1λ6-thiophen-2-yl)-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl]-1-(4-fluoro-benzyl)-4-hydroxy-pyrrolo[1,2-b]pyridazin-2-one (Example 11b, 0.100 g, 0.180 mmol) was dissolved in N,N-dimethylformamide (15 mL) at 25° C. Palladium on carbon (5%, 0.250 g) was added and the atmosphere in the reaction flask replaced with hydrogen from a balloon. After stirring for 1 h under a hydrogen balloon, the mixture was filtered through Celite. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm, 0→3% methanol in dichloromethane) to afford a yellow solid. Trituration of this material with diethyl ether afforded the desired product, 3-[7-(1,1-dioxo-tetrahydro-1λ6-thiophen-2-yl)-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl]-1-(4-fluoro-benzyl)-4-hydroxy-pyrrolo[1,2-b]pyridazin-2-one (0.028 g, 0.050 mmol, 28% yield). 1H NMR (400 MHz, DMSO-d6) δ: 2.08-2.18 (1H, m), 2.23-2.29 (1H, m), 2.32-2.43 (1H, m), 3.20-3.28 (1H, m), 3.31-3.37 (1H, m), 4.56-4.61 (1H, m), 5.65 (2H, s), 6.60 (2H, d, J=7.0 Hz), 6.59-6.61 (1H, m), 7.02-7.03 (1H, m), 7.14-7.18 (2H, m), 7.42-7.46 (1H, m), 7.67-7.75 (2H, m), 7.87 (1H, bs), 13.73 (1H, s). LC-MS (ESI) calcd for C25H21FN4O6S2 556.09. found 557.15 [M+H+].
Reaction SMILES: [CH:1](=[N:8][C:9]([CH3:24])([CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[C:10](OCC)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[CH2:1]([NH:8][C:9]([CH3:24])([CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[CH2:10][OH:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(CCOC1CCCCO1)N=Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(CO)(CCOC1CCCCO1)NCc1ccccc1
Yield: 92.1 %

Procedure:
A solution of ethyl 2-benzylideneamino-2-methyl-4-((tetrahydro-2H-pyran-2-yl)oxy)butyrate (36C, 100.0 g, 0.3 mol) in THF (100 mL) was added slowly to a suspension of lithium aluminum hydride (Alfa, 22.77 g, 0.6 mol) rapidly stirred in dry THF (1 L) at such a rate to maintain a gentle reflux. After the addition was complete the mixture was refluxed for 4 h. The reaction mixture was cooled and treated successively with H2O (23 mL), 15N NaOH (23 mL) and H2O (45 mL). The solid was removed by filtration and washed with THF (200 mL). The organic layers were combined and concentrated by rotary evaporation to give 2-benzylamino-2-methyl-4-((tetrahydro-2H-pyran-2-yl)oxy)butanol (81.1 g, 92.0%) as a thick oil which was used without further purification.
Reaction SMILES: C([NH:4][C:5]1[N:6]=[C:7]([OH:39])[C:8]2[CH:14]=[C:13]([CH2:15][CH2:16][C:17]3[CH:38]=[CH:37][C:20]([C:21]([NH:23][C@H:24]([C:32]([O:34]CC)=[O:33])[CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])=[O:22])=[CH:19][CH:18]=3)[CH:12]=[N:11][C:9]=2[N:10]=1)(=O)C.[OH-].[Na+].C(O)(=O)C>CO>[NH2:4][C:5]1[N:6]=[C:7]([OH:39])[C:8]2[CH:14]=[C:13]([CH2:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([NH:23][C@H:24]([C:32]([OH:34])=[O:33])[CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[O:22])=[CH:37][CH:38]=3)[CH:12]=[N:11][C:9]=2[N:10]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(CCc2cnc3nc(NC(C)=O)nc(O)c3c2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1nc(O)c2cc(CCc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)cnc2n1

Procedure:
A homogeneous solution of 0.175 of diethyl N-(4-[2-(2-acetamido-4-hydroxypyrido[2,3-d]pyrimidin-6-yl)ethyl]benzoyl)-L-glutamate in 50 mL of methanol containing 3 mL of 1N aqueous sodium hydroxide was stirred at room temperature for 72 hours. Addition of 2 mL of acetic acid followed by centrifugation gave 0.125 g (86) of the title compound, which can be alternatively named as 5,10-dideazafolic acid, as a microcrystalline colorless solid, mp >200° C.; NMR (TFA-d1) delta 2.3-2.7 (m, 2H), 2.7-3.0 (m, 2H), 3.25 (s, 5H), 4.9-5.25 (m, 1H), 7.35, 7.85 (AB q, 4H, J=9 Hz), 8.50 (s, 1H), 8.90 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5](OS(C(F)(F)F)(=O)=O)[CH:4]=1.[NH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29].C(N(C(C)C)CC)(C)C>C(#N)C>[C:28]([O:27][C:26](=[O:32])[NH:25][CH2:24][CH2:23][CH2:22][NH:21][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: COc1cc(OS(=O)(=O)C(F)(F)F)nc2ccccc12
Reactant: CC(C)(C)OC(=O)NCCCN
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1cc(NCCCNC(=O)OC(C)(C)C)nc2ccccc12
Temperature: 25 °C
Yield: 63.6 %

Procedure:
A solution of 1,1,1-trifluoromethanesulfonic acid 4-methoxyquinolin-2-yl ester (4.51 g, 14.7 mmol), tert-butyl N-(3-aminopropyl)carbamate (3.07 g, 17.6 mmol), and diisopropylethylamine (3.84 ml, 22.0 mmol) in anhydrous acetonitrile (35 ml) was heated at reflux for 6 days. The solution was cooled to ambient temperature then evaporated under reduced pressure to an oil. It was taken into water (35 ml) then extracted into ethyl acetate. The extracts were dried (sodium sulfate) then concentrated to an oil. Column chromatography on silica (1:1 ethyl acetate/hexanes) gave [3-(4-methoxyquinolin-2-ylamino)propyl]carbamic acid tert-butyl ester (3.10 g, 64%) as a colorless oil that solidified on standing. [M+H]+ 332.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:2]1.[NH:24]1[CH:31]=[CH:30][C:28]([NH2:29])=[N:27][C:25]1=[O:26].C(=O)([O-])[O-].[K+].[K+].C(Cl)(Cl)Cl>CN(C)C=O>[OH:1][CH:3]([CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:2][N:24]1[CH:31]=[CH:30][C:28]([NH2:29])=[N:27][C:25]1=[O:26]
Reactant: CCCCCCCCCCCCCCCCCCOCC1CO1
Reactant: Nc1cc[nH]c(=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCOCC(O)Cn1ccc(N)nc1=O
Temperature: 25 °C
Yield: 37.3 %

Procedure:
rac-1,2-Epoxy-3-octadecyloxypropane (2.0 g, 6.13 mmol) is added to a mixture of cytosine (1.0 g, 9.0 mmol) and anhydrous potassium carbonate (40 mg) in dimethyl formamide (25 mL) over a 30 minute period under a nitrogen atmosphere. The resultant mixture is stirred at 80°-90° C. (oil bath temperature) for 48 hours. The reaction mixture is cooled to room temperature and concentrated in vacuo to leave a residue. The residue is stirred with chloroform (50 mL). The undissolved material is filtered in vacuo, and the filtrate is concentrated in vacuo, purified by chromatography and dried in vacuo to afford 1.0 g (37%) of 1-[2'-hydroxy-3'-octadecyloxypropyl]-cytosine (CPR 1149): Thin-layer Chromatography (TLC; 4×8 cm silica gel 60, 0.25 mm thickness): 10:2:0.2 (v/v/v) CHCl3 -CH3OH-30% aqueous ammonia (Rf value=0.66); mp 153°-154° C.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[CH:12]=[C:13]([CH:19]([CH3:23])[C:20]([OH:22])=[O:21])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:31](ON1C(=O)CCC1=O)([O:33][CH2:34][CH:35]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:41]2[C:36]1=[CH:37][CH:38]=[CH:39][CH:40]=2)=[O:32]>CN(C=O)C>[C:31]([C:2]([NH2:1])([C:11]1[CH:12]=[C:13]([CH:19]([CH3:23])[C:20]([OH:22])=[O:21])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1)([O:33][CH2:34][CH:35]1[C:36]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:42]2[C:47]1=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:32]
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: COc1ccc(C(N)c2cc(C(C)C(=O)O)ccc2OC)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(C(N)(C(=O)OCC2c3ccccc3-c3ccccc32)c2cc(C(C)C(=O)O)ccc2OC)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The 3-(α-amino-4-methoxybenzyl)-4-methoxyphenylpropionic acid (1.0 g, 3.17 mmol) prepared in Example 4 was dissolved in 5 ml of DMF containing triethylamine (0.88 ml). To the solution, 1.28 g of Fmoc-OSu was added and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated in vacuo and 5% citric acid and ether were added to the residue. The resulting power was recrystallized from methanol and ether.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH:28]=O)=[N:20]1.N1CCCCC1>CO>[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](/[CH:28]=[C:7]2\[O:8][C:4]3[C:3]([CH2:12][N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=3[C:6]\2=[O:9])=[N:20]1
Reactant: O=Cc1n[nH]c2ccccc12
Reactant: O=C1COc2c1ccc(O)c2CN1CCOCC1
Solvent: C1CCNCC1
Solvent: CO
Product: O=C1/C(=C/c2n[nH]c3ccccc23)Oc2c1ccc(O)c2CN1CCOCC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 63.1 %

Procedure:
A solution of 6-hydroxy-7-(morpholinomethyl)benzofuran-3(2H)-one (0.125 g, 0.500 mmol) in methanol (2 mL) was added with 1H-indazole-3-carbaldehyde (0.0731 g, 0.500 mmol), and piperidine (0.00426 g, 0.0500 mmol) at room temperature, and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was cooled to room temperature, and then the precipitated solid was collected by filtration to obtain (Z)-2-[(1H-indazol-3-yl)methylene]-6-hydroxy-7-(morpholinomethyl)benzofuran-3(2H)-one (0.119 g, 63%).
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:4]=1.[C-:19]#[N:20].[Na+]>CN(C=O)C.O>[C:19]([CH2:2][C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:4]=1)#[N:20]
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2cccnc21
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)n1nc(CC#N)c2cccnc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl 3-(bromomethyl)-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (5.18 g, 16.59 mmol) in DMF (30 mL) was added sodium cyanide (1.626 g, 33.2 mmol) and stirred at 25° C. for 4 hours. After this time, the mixture was diluted with water (300 mL) and extracted with ethyl acetate (3×300 mL). The extracts were combined and the resulting solid precipitate was filtered. The filtrate was dried over MgSO4, filtered and the solvent removed in vacuo. This residue was purified by chromatography using 120 g RediSep column and eluting with 0-100% EtOAc/CH2Cl2 gradient. The desired fractions were combined and evaporated in vacuo to provide the title compound. LRMS (M+1): 259.1.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([NH:29][CH2:30][CH3:31])=[O:28])=[CH:23][CH:22]=3)[C:11]=2[CH2:12]P(OCC)(OCC)=O)=[O:6])[CH2:3][CH2:2]1.[H-].[Na+].[C:34]([N:53]1[CH:57]=[CH:56][N:55]=[C:54]1[CH:58]=O)([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.O>C1COCC1>[CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([NH:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:26]=3)[C:11]=2/[CH:12]=[CH:58]/[C:54]2[N:53]([C:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[CH:57]=[CH:56][N:55]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: O=Cc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CP(=O)(OCC)OCC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2/C=C/c2nccn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
To a suspension of N-cyclopropyl-5-(diethylphosphonomethyl)-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazole-4-carboxamide (500 mg) obtained in Example 321b) in THF (20 ml) was added sodium hydride (50% oil dispersion, 80 mg) at 0° C., and the mixture was stirred at room temperature for 1 hr. A solution of 1-trityl-1H-imidazole-2-carbaldehyde (367 mg) in THF (5 ml) was added to the obtained reaction mixture, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure to give a crude product of the title compound as a pale-yellow solid (670 mg).
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH2:13]([C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)[CH3:14]>>[Cl:1][C:2]1[N:3]([C:18]2[CH:19]=[CH:20][C:15]([CH2:13][CH3:14])=[CH:16][CH:17]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: CCc1ccc(B(O)O)cc1
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Product: CCc1ccc(-n2c(Cl)c(C=O)c3ccccc32)cc1
Yield: 73 %

Procedure:
2-Chloro-1H-indole-3-carboxaldehyde is reacted with 4-ethylphenylboronic acid as described in Step 1 of Example 29 to afford 2-chloro-1-(4-ethyl-phenyl)-1H-indole-3-carboxaldehyde (73% yield) as a light yellow solid. ESI/MS 284 (M+H); RT=4.04 min; NMR 10.12 (1H, s); 8.20 (1H, d, J=9 Hz); 7.54 (4H, m); 7.38 (2H, m); 7.28 (1H, d); 2.77 (2H, q); 1.28 (3H, t).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:15])[C:6]1[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][C:7]=1[I:14]>O.CO>[I:14][C:7]1[CH:8]=[CH:9][C:10]([C:12]#[N:13])=[CH:11][C:6]=1[C:5]([OH:15])=[O:4]
Reactant: COC(=O)c1cc(C#N)ccc1I
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N#Cc1ccc(I)c(C(=O)O)c1
Reaction time: 20 h
Yield: 66.2 %

Procedure:
A solution of sodium hydroxide (0.44 g, 11 mmol) in water (10 ml) was added to 2-iodo-5-cyanobenzoic acid methyl ester (2.7 g, 9.4 mmol) in methanol. The mixture was stirred for 20 h, then most of the solvent was evaporated and the residue acidified with 2N hydrochloric acid. The resulting precipitate was filtered off and dried to give a white solid (1.7 g). MS (-CI) m /z 272 [M-H]+.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][N:20]=3)=[O:18])[CH2:13][CH2:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[NH:28]([CH2:32][CH2:33][OH:34])[CH2:29][CH2:30][OH:31]>>[OH:31][CH2:30][CH2:29][N:28]([CH2:32][CH2:33][OH:34])[C:23]([C:22]1[CH:26]=[CH:27][C:19]([C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:6]3[C:5]([NH:4][CH:1]([CH3:2])[CH3:3])=[CH:10][CH:9]=[CH:8][N:7]=3)[CH2:12][CH2:13]2)=[O:18])=[N:20][CH:21]=1)=[O:24]
Reactant: OCCNCCO
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cn2)CC1
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)N(CCO)CCO)cn2)CC1
Yield: 77 %

Procedure:
By the same procedure as described in the example 1, synthesis was carried out starting with 6-[1-[3-(isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]nicotinic acid and using diethanolamine. And then, the product was recrystallized with isopropanol and ether to give a desired compound.
Reaction SMILES: [C:1]1([C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1CCCC1.[CH2:32]([O:34][C:35](=[O:44])[CH2:36][N:37]1[C:41]([CH:42]=O)=[CH:40][N:39]=[CH:38]1)[CH3:33]>C1C=CC=CC=1>[CH2:32]([O:34][C:35]([CH2:36][N:37]1[C:41](/[CH:42]=[C:10]2\[CH2:9][N:8]([C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:13][CH2:12][C:11]\2=[O:14])=[CH:40][N:39]=[CH:38]1)=[O:44])[CH3:33]
Reactant: O=C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Reactant: CCOC(=O)Cn1cncc1C=O
Solvent: C1CCNC1
Solvent: c1ccccc1
Product: CCOC(=O)Cn1cncc1/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1=O
Yield: 18.5 %

Procedure:
To a solution of 1-(triphenylmethyl)piperidin-4-one (3.66 g) in benzene (40 ml) was added pyrrolidine (0.97 ml), and the mixture was heated under reflux for 3.5 hours. To this mixture was added a solution of ethyl(5-formyl-1H-imidazol-1-yl)acetate (1.95 g) in benzene (10 ml) under cooling using an ice bath. Then, the whole was heated further under reflux for 8.5 hours. After cooling, the mixture was partitioned between water and ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The extract was concentrated under reduced pressure and the residue was purified by silica gel chromatography using hexane and ethyl acetate (1:3) as an eluent to afford the title compound (1.0 g, yield: 19%) as a yellow oil.