Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:33][CH2:32][C:5]2[N:6]([CH2:14][CH2:15][NH:16][C:17]([CH:19]3[CH2:24][CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]3)=[O:18])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][N:2]1[CH2:33][CH2:32][C:5]2[N:6]([CH2:14][CH2:15][NH:16][C:17]([CH:19]3[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]3)=[O:18])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2c(c1)c1c(n2CCNC(=O)C2CCCN(C(=O)OC(C)(C)C)C2)CCN(C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(n2CCNC(=O)C2CCCNC2)CCN(C)C1
Yield: 35.3 %

Procedure:
tert-butyl 3-(2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)ethylcarbamoyl)piperidine-1-carboxylate (40 mg, 0.08 mmol) was stirred with trifluoroacetic acid (0.1 mL) in dichloromethane (2 ml) to obtain 10 mg of N-(2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)ethyl)piperidine-3-carboxamide as di-TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:19]=[C:18]([CH2:20][O:21][C:22]2[C:27]([CH2:28][C:29]#N)=[CH:26][CH:25]=[CH:24][N:23]=2)[O:17][N:16]=1.C(O)C.[OH-:34].[Na+].Cl.[OH2:37]>>[CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:19]=[C:18]([CH2:20][O:21][C:22]2[C:27]([CH2:28][C:29]([OH:37])=[O:34])=[CH:26][CH:25]=[CH:24][N:23]=2)[O:17][N:16]=1
Reactant: O
Reactant: Cc1sc(-c2ccccc2)nc1COc1cc(COc2ncccc2CC#N)on1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1sc(-c2ccccc2)nc1COc1cc(COc2ncccc2CC(=O)O)on1
Yield: 81 %

Procedure:
To a mixture of 2-[2-[[3-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]-5-isoxazolyl]methoxy]-3-pyridyl]acetonitrile (0.35 g) and ethanol (10 mL) was added a 2N aqueous sodium hydroxide solution (10 mL) and the mixture was heated under reflux for 5 hrs. 1N Hydrochloric acid (20 mL) and water were added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give crystals (0.30 g, 81%) of 2-[2-[[3-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]-5-isoxazolyl]methoxy]-3-pyridyl]acetic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 109-110° C.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH2:9][N:10]([CH2:34][C:35]1[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[CH:37][CH:36]=1)[C:11](=[O:33])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[B-](F)(F)(F)F.CN(C(O[N:66]1[C:71](=[O:72])[CH2:70][CH2:69][C:67]1=[O:68])=[N+](C)C)C>C1COCC1>[O:68]=[C:67]1[CH2:69][CH2:70][C:71](=[O:72])[N:66]1[O:40][C:39](=[O:41])[C:38]1[CH:37]=[CH:36][C:35]([CH2:34][N:10]([CH2:9][CH2:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:11](=[O:33])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])=[CH:43][CH:42]=1
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCC(=O)N(CCC(=O)OC(C)(C)C)Cc1ccc(C(=O)O)cc1
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCC(=O)N(CCC(=O)OC(C)(C)C)Cc1ccc(C(=O)ON2C(=O)CCC2=O)cc1
Temperature: 0 °C
Yield: 86.8 %

Procedure:
4-{[(2-tert-Butoxycarbonylethyl)-(15-tert-butoxycarbonyl-pentadecanoyl)amino]methyl}benzoic acid (70 mg, 0.12 mmol) was dissolved in THF (5 mL). The mixture was cooled with an ice bath. Diisopropylethylamin (0.024 mL, 0.14 mmol) and O—(N-succinimidyl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (42 mg, 0.14 mmol) was added. The mixture was stirred under nitrogen at 0° C. After 30 minutes the ice cooling was removed and the mixture was stirred for an additional 3 hours. Solvent removed in vacuo flowed by reevaporation from toluene. The crude product was dissolved in ethyl acetate (25 mL), washed with water (10 mL). The organic phase dried (Na2SO4), solvent removed in vacuo to yield the title compound (73 mg, 87%) which was used in subsequent step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](Cl)([Cl:10])[Cl:9])[CH:5]=[C:4]([Cl:12])[N:3]=1.[Sb](F)(F)[F:14].ClCl>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([Cl:10])([Cl:9])[F:14])[CH:5]=[C:4]([Cl:12])[N:3]=1
Reactant: Clc1cc(C(Cl)(Cl)Cl)cc(Cl)n1
Reactant: F[Sb](F)F
Agent: ClCl
Product: FC(Cl)(Cl)c1cc(Cl)nc(Cl)c1

Procedure:
A mixture containing 138.5 grams (0.522 mole) of 2,6-dichloro-4-(trichloromethyl)pyridine and 34 grams (0.187 mole) of Antimony trifluoride was heated to 80°-84° C. and maintained under agitation for 23 minutes. During this step, a slow stream of chlorine gas was passed over the surface of the reaction mixture. The reaction mixture was steam distilled and the crude 2,6- dichloro-4-(dichlorofluoromethyl)pyridine product was purified by fractionation. The product had a boiling point of 74°-76° C. at 1.0 millimeter of mercury.
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7]([C@H:9]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([N:37]2[CH2:43][CH2:42][C:41]3[CH:44]=[CH:45][CH:46]=[CH:47][C:40]=3[NH:39][C:38]2=[O:48])[CH2:33][CH2:32]1)=[O:30])[CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[C:18]([CH3:20])[CH:19]=1)[N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[N:15]=[CH:14]2)=[O:8])C>O.C1COCC1>[C:7]([C@H:9]([O:28][C:29]([N:31]1[CH2:32][CH2:33][CH:34]([N:37]2[CH2:43][CH2:42][C:41]3[CH:44]=[CH:45][CH:46]=[CH:47][C:40]=3[NH:39][C:38]2=[O:48])[CH2:35][CH2:36]1)=[O:30])[CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[C:18]([CH3:20])[CH:19]=1)[N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[N:15]=[CH:14]2)([OH:8])=[O:6]
Reactant: CCOC(=O)[C@@H](Cc1cc(C)c2c(cnn2C(=O)OC(C)(C)C)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc2cnn(C(=O)OC(C)(C)C)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 19.2 mg (0.8 mmol) lithium hydroxide hydrate in 10 mL water was added at RT to a solution of 330 mg (0.53 mmol) tert.-butyl 5-{(R)-2-ethoxycarbonyl-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyloxy]-ethyl}-7-methyl-indazol-1-carboxylate in 30 mL THF and the reaction mixture was stirred for 30 min at RT. It was evaporated down i.vac., the residue was taken up in 100 mL water, combined with 10% citric acid with stirring, extracted twice with 100 mL DCM and the combined organic phases were dried over Na2SO4. After the desiccant and solvent had been eliminated the residue was reacted further without purification.
Reaction SMILES: C(OC(OCC)C(=O)CC1C=CC(C)=CC=1)C.[CH:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]2[NH:34][C:33]([C:35]3[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=3)=[CH:32][N:31]3[C:26]=2[N:27]=[C:28]([CH2:42][C:43]2[CH:48]=[CH:47][C:46]([OH:49])=[CH:45][CH:44]=2)[C:29]3=[O:30])=[CH:20][CH:19]=1.Cl>O1CCOCC1.O>[CH:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]2[C:26]3[N:31]([CH:32]=[C:33]([C:35]4[CH:36]=[CH:37][C:38]([OH:41])=[CH:39][CH:40]=4)[N:34]=2)[C:29]([OH:30])=[C:28]([CH2:42][C:43]2[CH:48]=[CH:47][C:46]([OH:49])=[CH:45][CH:44]=2)[N:27]=3)=[CH:20][CH:19]=1
Reactant: O=c1c(Cc2ccc(O)cc2)nc2c(Cc3ccccc3)[nH]c(-c3ccc(O)cc3)cn1-2
Agent: CCOC(OCC)C(=O)Cc1ccc(C)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: Oc1ccc(Cc2nc3c(Cc4ccccc4)nc(-c4ccc(O)cc4)cn3c2O)cc1
Temperature: 0 °C
Reaction time: 14 h
Yield: 0.1 %

Procedure:
Under an argon atmosphere, 1,1-diethoxy-3-(4-methylphenyl)propan-2-one (33) (216 mg, 914 μmol) was dissolved in 1,4-dioxane (2 mL) and water (0.4 mL). To this was added coelenteramine (196 mg, 707 mmol) and, after cooling to 0° C., conc. hydrochloric acid (0.20 mL) was further added thereto, and then stirred overnight (14 hours) at 100° C. After cooling to room temperature, the mixture was concentrated under reduced pressure and the residue was purified by silica gel flash chromatography in an argon flow (n-hexane/ethyl acetate=1/2→ethyl acetate→ethyl acetate/methanol=50/1→20/1). The solid obtained was further reprecipitated (n-hexane/acetone) to give me-coelenterazine (34, me-CTZ) as a yellow powder (180 mg, 427 μmol, 60.4%).
Reaction SMILES: N1C=CN=C1.[OH:6][CH2:7][C@@:8]12[C@H:14]([O:15][CH2:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=3)[C@H:11]([O:12][CH2:13]1)[C@H:10]([N:27]1[CH:34]=[CH:33][C:31](=[O:32])[NH:30][C:28]1=[O:29])[O:9]2.[Si:35](Cl)([C:48]([CH3:51])([CH3:50])[CH3:49])([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CN(C=O)C.CCOC(C)=O>[Si:35]([O:6][CH2:7][C@:8]12[C@H:14]([O:15][CH2:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=3)[C@H:11]([O:12][CH2:13]1)[C@H:10]([N:27]1[CH:34]=[CH:33][C:31](=[O:32])[NH:30][C:28]1=[O:29])[O:9]2)([C:48]([CH3:51])([CH3:50])[CH3:49])([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=c1ccn([C@@H]2O[C@@]3(CO)CO[C@H]2[C@H]3OCc2cccc3ccccc23)c(=O)[nH]1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OC[C@]12CO[C@H]([C@H](n3ccc(=O)[nH]c3=O)O1)[C@H]2OCc1cccc2ccccc12)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 78 %

Procedure:
Imidazole (5.5 g) was added to Compound 108 (8.83 g) dissolved in anhydrous DMF (100 mL) followed by addition of t-butyldiphenylsilylchloride (8.5 mL). The reaction mixture was stirred for 15 h at room temperature when it was complete. The reaction mixture was diluted with EtOAc (400 mL) and washed with saturated sodium bicarbonate solution (3×500 mL) followed by water (2×200 mL). The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. Finally the residue was purified on a silica gel column using 30% EtOAc in CH2Cl2 as the eluant. Appropriate fractions were collected and concentrated to give Compound 109 in 78% yield.
Reaction SMILES: [O-:1][Mn](=O)(=O)=O.[K+].[CH3:7][C:8]1[CH:12]=[CH:11][N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]=1.[OH-:19].[Na+]>O>[C:13]1([N:10]2[CH:11]=[CH:12][C:8]([C:7]([OH:1])=[O:19])=[N:9]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1ccn(-c2ccccc2)n1
Reactant: [OH-]
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccn(-c2ccccc2)n1
Temperature: 85 °C
Yield: 44.7 %

Procedure:
KMnO4 (1.2 g, 7.6 mmol) was added portionwise to a stirred solution of 3-Methyl-1-phenyl-1H-pyrazole (100 mg, 0.63 mmol) and NaOH (504 mg, 12.6 mmol) in H2O (4 mL). The resulting mixture was heated to 85° C. for 48 hrs. The reaction mixture was filtered, filtrate was acidified with 30% aqueous HCl solution, extracted the aqueous layer with EtOAc. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by washing with hexane to afford 53 mg (44.53% yield) of 1-phenyl-1H-pyrazole-3-carboxylic acid. 1H NMR (DMSO-d6): δ 8.6 (d, 1H), 7.9 (d, 2H), 7.6-7.5 (t, 2H), 7.4 (t, 1H), 6.96 (d, 1H).
Reaction SMILES: [CH:1]1([CH3:13])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([C:10](Cl)=[O:11])[CH2:2]1.[C:14]([OH:19])(=[O:18])[CH:15]([CH3:17])[OH:16]>O>[CH:1]1([CH3:13])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([C:10]([O:16][CH:15]([CH3:17])[C:14]([OH:19])=[O:18])=[O:11])[CH2:2]1
Reactant: CC(O)C(=O)O
Reactant: CC1CCC(C(C)C)C(C(=O)Cl)C1
Solvent: O
Product: CC1CCC(C(C)C)C(C(=O)OC(C)C(=O)O)C1

Procedure:
p-Menth-3-oyl chloride (2.0 g.) was stirred with lactic acid (20 ml.) at room temperature for 20 hours. The reaction product was then poured into water (600 ml.) and extracted twice with ether. The extracts were dried (CaCl2) and the solvent removed under reduced pressure to leave 2-(p-menth-3-oyloxy)propionic acid as an oily liquid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.C(O)(=O)CC.[N+:17]([O-])([OH:19])=[O:18]>C(O)C>[N+:17]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=2)([O-:19])=[O:18]
Reactant: O=[N+]([O-])O
Reactant: Oc1ccnc2ccccc12
Solvent: CCO
Solvent: CCC(=O)O
Product: O=[N+]([O-])c1cnc2ccccc2c1O
Temperature: 125 °C

Procedure:
4-Hydroxyquinoline (22.2 g) and propionic acid (200 mL) were combined and heated to 125° C. Nitric acid (21.5 mL) was added dropwise over 1.5 h. The reaction mixture was stirred at reflux temperature for a further 15 min and cooled to rt. The mixture was diluted with ethanol and the solid was collected by vacuum filtration. The solid was washed with ethanol, water then ethanol. The residue was refluxed in ethanol and the hot mixture was filtered and dried to give the subtitle compound. Yield: 22 g
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:13]=[C:12]([O:14][CH:15]([CH3:17])[CH3:16])[CH:11]=[C:6]([C:7]([O:9]C)=[O:8])[CH:5]=1.[OH-].[Na+]>CO.O.C(OCC)C>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:13]=[C:12]([O:14][CH:15]([CH3:16])[CH3:17])[CH:11]=[C:6]([C:7]([OH:9])=[O:8])[CH:5]=1
Reactant: COC(=O)c1cc(OC(C)C)cc(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: COC(=O)c1cc(OC(C)C)cc(C(=O)O)c1
Yield: 85.7 %

Procedure:
Stir 5-isopropoxy-isophthalic acid dimethyl ester (3.7 g, 14.7 mmol) and NaOH (0.56 g, 14 mmol) in methanol (100 mL) and water (2 mL) overnight at room temperature. Concentrate methanol and redissolve the residue in diethyl ether (100 mL) and water (100 mL). Separate the layers and wash with diethyl ether. Concentrate the diethyl ether layer and recover 5-isopropoxy-isophthalic acid dimethyl ester (0.45 g). Acidify the aqueous layer with 5 N HCl to about pH=2, extract with ethyl acetate (3×50 mL). Wash the combined organic layers with saturated aqueous sodium chloride, dry (sodium sulfate) and concentrate to give the title compound (3.0 g, 86%).
Reaction SMILES: [CH:1]1([C:7]([CH3:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:10][CH:11]([F:17])[C:12](OCC)=[O:13].C[O-].[Na+].Cl>COCCOC.O.CCOC(C)=O>[F:10][CH:11]([F:17])[C:12](=[O:13])[CH2:9][C:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:8]
Reactant: CCOC(=O)C(F)F
Reactant: CC(=O)C1CCCCC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(CC(=O)C1CCCCC1)C(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of cyclohexylmethylketone (2.52 g, 20 mmol) in DME (50 mL) at −20° C. was added ethyl difluoroacetate (7.44 g, 60 mmol) and sodium methoxide (6.48 g, 120 mmol), and the resulting reaction mixture was then stirred at room temperature for 1 hour. EtOAc (500 ml) and water (50 ml) were added, and the pH of the aqueous layer was adjusted to 6 by addition of 1 N HCl solution. The organic layer was washed with brine (50 ml), dried over Na2SO4, and concentrated in vacuo to give the title (3.8 g, 93%). This was used for the next coupling step without further purification.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[C:29](Cl)(=[O:31])[CH3:30].C(OCC)C>C(Cl)Cl>[CH2:18]([N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][C:29](=[O:31])[CH3:30])[CH2:11][CH2:10]3)[CH2:13][CH2:14]1)[CH2:19][CH2:20][CH3:21]
Reactant: CC(=O)Cl
Reactant: CCCCN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCCCN1CCN(c2cccc3c2C[C@H](NC(C)=O)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86.7 %

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-butylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (100 mg, 0.35 mmol) and triethylamine (53 μL, 0.53 mmol) in methylene chloride (25 mL) was added dropwise acetyl chloride (25 μL, 0.35 mmol) in methylene chloride (10 mL). After the addition the reaction was allowed to stir at ambient temperature for 15 min and was then washed with water. The methylene chloride phase was dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:3) as the eluent. This gave, after crystalization from diethyl ether, 100 mg (89% yield) of the title compound as white crystals: mp 118-120° C.; [α]21D +25° (c 0.54, chloroform); EIMS (70 eV) m/z (relative intensity) 329 (41, M+).
Reaction SMILES: N[C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([C:13]([O:15][CH3:16])=[O:14])=[CH:7][C:8]=2[F:12])[N:3]=1.[I:17]CI.N(OCCC(C)C)=O>C1COCC1.CCOC(C)=O.[Cu]I>[F:12][C:8]1[CH:7]=[C:6]([C:13]([O:15][CH3:16])=[O:14])[CH:5]=[C:4]2[C:9]=1[CH:10]=[N:11][C:2]([I:17])=[N:3]2
Reactant: COC(=O)c1cc(F)c2cnc(N)nc2c1
Reactant: ICI
Agent: [Cu]I
Agent: CC(C)CCON=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cc(F)c2cnc(I)nc2c1
Temperature: 60 °C
Yield: 55.2 %

Procedure:
A suspension of methyl 2-amino-5-fluoro-quinazoline-7-carboxylate (4.28 g, 19.3 mmol, 1.00 equiv), CuI (1.81 g, 9.5 mmol, 0.49 equiv) and diiodomethane (7.80 mL, 96.8 mmol, 5.0 equiv) in THF (80 ml) was treated with isoamyl nitrite (7.80 mL, 58.1 mmol, 3.00 equiv) at ambient temperature, and the mixture heated to 60 ° C. After 18 h the reaction was cooled. The mixture was diluted with EtOAc (100 mL), filtered through a Celite® pad, and the dark green filtrate concentrated in vacuo to an oily residue (23.0 g) which was absorbed onto SiO2 and purified by flash chromatography eluting with an EtOAc/heptane gradient (0 to 30% EtOAc) to afford 3.54 g (55%) of methyl 5-fluoro-2-iodoquinazoline-7-carboxylate as a cream-white solid: 1H NMR (400 MHz, CDCl3) δ 9.39 (s, 1H), 8.49 (s, 1H), 7.90 (d, J=9.5 Hz, 1H), 4.02 (s, 3H); LCMS: MH+333.0
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][NH2:25])=[O:23])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[C:26](O)(=O)C.C(=N)N.CS(C)=O.O(C(C)C)C(C)C>CC(C)CC(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:26]=[N:25][NH:24][C:22]4=[O:23])=[CH:17][CH:16]=3)[CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(N2CCN(c3ccc(NC(=O)NN)cc3)CC2)cc1
Reactant: CC(=O)O
Agent: N=CN
Solvent: CC(=O)CC(C)C
Solvent: CC(C)OC(C)C
Solvent: CS(C)=O
Product: COc1ccc(N2CCN(c3ccc(-n4cn[nH]c4=O)cc3)CC2)cc1
Temperature: 100 °C
Yield: 28 %

Procedure:
A mixture of 3.4 parts of N-{4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl}hydrazinecarboxamide, 3 parts of methanimidamide acetate and 10 parts of dimethyl sulfoxide is stirred and heated for 2 hours at 100° C. The reaction mixture is cooled and poured onto a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane. The precipitated product is filtered off and crystallized from N,N-dimethylformamide (activated charcoal), yielding 1 part (28%) of 2,4-dihydro-4-{4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl}-3H-1,2,4-triazol-3-one; mp.+300° C.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:24]1[C:28]([C:29]2C3C(=CC=CC=3)C=CC=2)=CS[C:25]=1C(OC)=O.C(OCC)(OCC)OCC.[Cl:53]C1C=CC(N)=CC=1>C(O)(=O)C>[Cl:53][C:4]1[CH:5]=[CH:6][C:1]([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[C:18]5[C:19](=[CH:25][CH:24]=[CH:28][CH:29]=5)[CH:20]=[CH:21][CH:22]=4)[C:10]=3[N:9]=[CH:8]2)=[CH:2][CH:3]=1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: COC(=O)c1scc(-c2cccc3ccccc23)c1N
Reactant: Nc1ccc(Cl)cc1
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: O=c1c2scc(-c3cccc4ccccc34)c2ncn1-c1ccc(Cl)cc1
Yield: 46.3 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-(naphthalen-1-yl)thiophene-2-carboxylate (43.8 mg, 0.15 mmol), triethyl orthoformate (0.32 ml), 4-chloroaniline (44.3 mg, 0.4 mmol), and acetic acid (0.04 ml) were used to give 27 mg (0.07 mmol, 46.3% yield) of the title compound.
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].[CH3:6][C:7](=[CH2:9])[CH3:8].[OH2:10]>>[O:10]=[CH:2][C:1](=[CH2:4])[CH3:3].[C:9]([OH:5])(=[O:10])[C:7]([CH3:8])=[CH2:6]
Reactant: C=C(C)C
Reactant: O
Reactant: CC(C)(C)O
Product: C=C(C)C(=O)O
Product: C=C(C)C=O

Procedure:
Subsequently, the resulting mixed gas (a raw material gas) is passed through a dehydration catalyst to decompose part of t-butanol into isobutylene and water by dehydration reaction and then supplied; otherwise the resulting mixed gas is not sent through said dehydration catalyst and directly supplied; to an oxidation catalyst layer maintained at a predetermined temperature to obtain methacrolein and/or methacrylic acid by catalytic gas phase oxidation reaction.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:47])[N:20]([C:39]2[CH:44]=[CH:43][C:42]([CH3:45])=[C:41]([CH3:46])[CH:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>O.C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:47])[N:20]([C:39]2[CH:44]=[CH:43][C:42]([CH3:45])=[C:41]([CH3:46])[CH:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1nc(C)n(-c2ccc(C)c(C)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(-c2ccc(C)c(C)c2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
A mixture of hydroxylammonium chloride (1.50 g), sodium hydrogen carbonate (2.50 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[4-butyl-1-(3,4-dimethylphenyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.27 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.65 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.6 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (1.01 g, 71%).
Reaction SMILES: [N+:1]([C:4]1[S:5][CH:6]=[CH:7][C:8]=1[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])([O-])=O>O1CCOCC1.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Fe+2]>[NH2:1][C:4]1[S:5][CH:6]=[CH:7][C:8]=1[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)Cc1ccsc1[N+](=O)[O-]
Agent: [Fe+2]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)Cc1ccsc1N
Yield: 90 %

Procedure:
Ethyl 2-nitrothiophene-3-acetate (4 g, 18.6 mmol) was dissolved in aqueous dioxan (40 ml, 4:1 dioxan/water) and treated with reduced iron powder (3.5 g, 62.7 mmol) and iron sulfate heptahydrate (400 mg, 1.44 mmol). The reaction mixture was heated at reflux for 2 hours then filtered through celite filter-aid and washed through with diethyl ether. The organic phase was washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. The organic phase was dried over magnesium sulfate and evaporated to a red/black liquid and then chromatographed on silica gel using hexane/ethyl acetate (3:1) as eluent to give 3.1 g of ethyl 2-aminothiophene-3-acetate. MS(ES): m/e 186 [M+H].