Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:30])=[C:24]([N+:27]([O-])=O)[CH:25]=2)[NH:20][C:19](=[O:31])[C:18]=1[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Br:38])[CH:33]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].NN>O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:30])=[C:24]([NH2:27])[CH:25]=2)[NH:20][C:19](=[O:31])[C:18]=1[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Br:38])[CH:33]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CCOc1c(-c2cccc(Br)c2)c(=O)[nH]c2cc(Cl)c([N+](=O)[O-])cc12
Agent: Cl[Fe](Cl)Cl
Agent: NN
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCCC1CCOc1c(-c2cccc(Br)c2)c(=O)[nH]c2cc(Cl)c(N)cc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 76.9 %

Procedure:
To a solution of 2-{2-[3-(3-bromophenyl)-7-chloro-6-nitro-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester (Example 8, 119 mg in 6 mL methanol) was added 4 mg iron(III)chloride hexahydrate followed by 25 mg activated carbon and the mixture heated to reflux on an oil bath. After 15 minutes, hydrazine (0.037 mL) was added dropwise and the reaction allowed to proceed at reflux for 3 hours. At this time, the mixture was cooled to room temperature, filtered through diatomaceous earth and the solvent removed in vacuo. The concentrate was solvated in 200 mL methylene chloride, washed successively with water (50 mL) and brine (50 mL), dried over sodium sulfate and concentrated in vacuo to give the title compound (crude: 87 mg).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=1)O)C1C=CC=CC=1.Cl.C(=O)([O-])[O-].[K+].[K+]>[OH-].[Pd+2].[OH-].CO>[F:25][C:24]([F:26])([F:27])[O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[OH:8])=[CH:18][CH:19]=1
Reactant: OC(c1ccc(OC(F)(F)F)cc1)c1ccccc1OCc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Product: Oc1ccccc1Cc1ccc(OC(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 97.6 %

Procedure:
A 20% palladium hydroxide catalyst (150 mg) was added to a solution of (2-benzyloxyphenyl)-(4-trifluoromethoxyphenyl)methanol (1.5 g, 4.01 mmol) in methanol (27 mL) and furthermore 36% HCl (0.33 mL) was added thereto. The mixture solution was stirred under a hydrogen atmosphere for 16 hours, and then cooled to 0° C., potassium carbonate (0.54 g) added thereto and the mixture was stirred for 30 minutes, and then the catalyst was removed by filtration. The solvent was distilled under reduced pressure and the obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:10)] to obtain a white solid title compound (1.05 g, 97%).
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[CH:11][C:12]([C:14]3[S:15][C:16]([N:24]([CH3:34])[CH2:25][CH2:26][O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=3)=[CH:13][C:5]1=2)(=O)C.C(O)C.Cl.C(=O)(O)[O-].[Na+]>CCOC(C)=O>[O:7]1[CH2:8][CH2:9][NH:4][C:5]2[CH:13]=[C:12]([C:14]3[S:15][C:16]([N:24]([CH3:34])[CH2:25][CH2:26][O:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=3)[CH:11]=[CH:10][C:6]1=2
Reactant: CCOC(=O)c1nc(-c2ccc3c(c2)N(C(C)=O)CCO3)sc1N(C)CCOc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1nc(-c2ccc3c(c2)NCCO3)sc1N(C)CCOc1ccccc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
To ethyl 2-(4-acetyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-5-(methyl(2-phenoxyethyl)amino)thiazole-4-carboxylate (20A) (0.102 g, 0.212 mmol) was added ethanol (4 mL) and 6N HCl (6 mL). The reaction mixture was allowed to heat to 60° C. and stir for 8 hours. The reaction was allowed to cool to rt. To the reaction mixture was added EtOAc and saturated sodium bicarbonate. The layers were separated and extracted with EtOAc and the combined organic extracts were washed sequentially with water, brine, dried over MgSO4, filtered, and concentrated under reduced pressure to provide 0.079 g (85%) of the desired product ethyl 2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-5-(methyl(2-phenoxyethyl)amino)thiazole-4-carboxylate (20B): LC/MS (APCI): m/z 440.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[C:9][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][CH2:11]2)=[C:6]([Cl:23])[N:5]=[CH:4][N:3]=1.CC(C)([O-])C.[K+].C1OCCOCCOCCOCCOCCOC1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:23][C:6]1[C:7]2[CH:8]=[C:9]([CH:10]3[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:14][CH2:15]3)[NH:1][C:2]=2[N:3]=[CH:4][N:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C#Cc2c(N)ncnc2Cl)CC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2cc3c(Cl)ncnc3[nH]2)CC1
Temperature: 65 °C

Procedure:
To a solution of Example 1B (250 mg, 0.74 mmol), in toluene (5 mL), was added potassium tert-butoxide (249 mg, 2.22 mmol) followed by 18-crown-6 (15 mg, 0.057 mmol) and the mixture was heated under nitrogen at 65° C. for 12 hours. The mixture was cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, filtered, concentrated and purified by column chromatography (silica gel, 40% ethyl acetate in hexane) to afford the title compound. LCMS: 337.1 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:56][C:57]1[CH:62]=[CH:61][C:60]([CH2:63][CH2:64][C:65]([O:67][CH3:68])=[O:66])=[CH:59][CH:58]=1>ClCCl>[Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:56][C:57]2[CH:58]=[CH:59][C:60]([CH2:63][CH2:64][C:65]([O:67][CH3:68])=[O:66])=[CH:61][CH:62]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCc1ccc(N)cc1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)CCc1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1
Reaction time: 2 h
Yield: 96.4 %

Procedure:
To a solution of chiral (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (80.6 mg, 0.172 mmol) in dichloromethane (3 ml) were added DIPEA (89.0 mg, 0.685 mmol) and DIPHENYLPHOSPHINIC CHLORIDE (106 mg, 0.437 mmol). The mixture was stirred for 20 mins under argon before methyl 3-(4-aminophenyl)propanoate (33.4 mg, 0.186 mmol) was added. After 2 hrs, the reaction mixture was diluted with dichloromethane, washed with sat. NaHCO3, water and brine. After drying over Na2SO4 the crude material was purified by silica gel chromatography with ethyl acetate and n-hexanes to give chiral methyl 3-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)phenyl)propanoate (104.2 mg, 96%) as a white solid. MS (ES+) m/z Calcd: [(M+H)+]: 628.19. found: 628.1.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](O)=[CH:7][CH:8]=[N:9]2)=[N:4][CH:3]=1.P(Cl)(Cl)([Cl:15])=O>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[N:9][CH:8]=[CH:7][C:6]=2[Cl:15]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccnc2cc(Br)cnc12
Product: Clc1ccnc2cc(Br)cnc12

Procedure:
7-Bromo-1,5-naphthyridin-4-ol (7.0 g) and phosphoryl chloride (200 mL) were refluxed for 5 h in a RBF fitted with a reflux condenser. Excess POCl3 was distilled off under reduced pressure and the residue poured onto ice. This cold mixture was carefully neutralized with aq. ammonia, which caused an exotherm. The resulting solid was filtered, washed with water and dried. The product was recrystallized from n-heptane to give white needles of 3-bromo-8-chloro-1,5-naphthyridine.
Reaction SMILES: [C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:8]2[CH2:11][CH:10]([C:12](O)=[O:13])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21](N1C=CN=C1)([N:23]1C=CN=C1)=O.C(N(CC)CC)C.Cl.CN>C(#N)C>[C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:8]2[CH2:11][CH:10]([C:12]([NH:23][CH3:21])=[O:13])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CNC(=O)C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 60 °C
Yield: 114.6 %

Procedure:
To a solution of 7.5 g (28 mmole) of 1-(diphenylmethyl)azetidine-3-carboxylic acid in 75 ml of acetonitrile was added 6.0 g (37 mmole) of 1,1'-carbonyldiimidazole. The reaction was heated at 60° C. for two hours and successively treated with 3.11 g (30.8 mmole) of triethylamine and 2.08 g (30.8 mmole) of methylamine hydrochloride. The reaction was stirred at 60° C. for an additional hour, the solvent evaporated in vacuo, and the residue dissolved in chloroform. After washing with water and drying over magnesium sulfate, the chloroform layer was evaporated in vacuo to give 9.0 g of 1-(diphenylmethyl)-N-methyl-3-azetidinecarboxamide, mp 103°-107° C.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=2)[CH:7]=[CH:6][NH:5]1.Br[CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26]>CN(C=O)C>[C:25]([O:24][C:23]([NH:22][CH2:21][CH2:20][CH2:19][N:5]1[CH:6]=[CH:7][C:8]2[C:13](=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)[C:4]1=[O:3])=[O:29])([CH3:28])([CH3:27])[CH3:26]
Reactant: COC(=O)c1ccc2cc[nH]c(=O)c2c1
Reactant: CC(C)(C)OC(=O)NCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2ccn(CCCNC(=O)OC(C)(C)C)c(=O)c2c1
Reaction time: 0.5 h
Yield: 56.1 %

Procedure:
To a stirred suspension of sodium hydride (60% in mineral oil, 0.30 g, 7.4 mmol) in DMF (10 mL) under an atmosphere of nitrogen was added methyl 1-oxo-1,2-dihydroisoquinoline-7-carboxylate (1.0 g, 4.9 mmol) in DMF (10 mL) dropwise. The mixture was stirred for 30 mins, then tert-butyl (3-bromopropyl)carbamate (1.76 g, 7.4 mmol) dissolved in DMF (5 mL) was added dropwise via cannula and the resulting solution was stirred at rt overnight. The reaction was quenched with water and extracted with EtOAc (2×). The combined organic phases were then washed with water, and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (20% to 90% EtOAc/hexanes) to afford methyl 2-{3-[(tert-butoxycarbonyl)amino]propyl}-1-oxo-1,2-dihydroisoquinoline-7-carboxylate (0.99 g, 56%). LC-MS: (FA) ES+ 361.
Reaction SMILES: [Na+:1].[Na+].[N+:3]([C:6]1[CH:32]=[CH:31][C:9]([C:10]([NH:12][C:13]2[C:22]3[C:21]([S:23]([O-:26])(=[O:25])=[O:24])=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]([S:27]([O-:30])(=[O:29])=[O:28])=[CH:15][CH:14]=2)=[O:11])=[CH:8][CH:7]=1)([O-])=O.[H][H]>[Pd].O>[Na+:1].[Na+:1].[NH2:3][C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:12][C:13]2[C:22]3[C:21]([S:23]([O-:26])(=[O:25])=[O:24])=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]([S:27]([O-:30])(=[O:29])=[O:28])=[CH:15][CH:14]=2)=[O:11])=[CH:31][CH:32]=1
Reactant: [H][H]
Reactant: O=C(Nc1ccc(S(=O)(=O)[O-])c2cccc(S(=O)(=O)[O-])c12)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: [Na+]
Solvent: O
Product: Nc1ccc(C(=O)Nc2ccc(S(=O)(=O)[O-])c3cccc(S(=O)(=O)[O-])c23)cc1

Procedure:
A mixture of 10.0 g of 4-p-nitrobenzamido-1,5-naphthalenedisulfonic acid disodium salt (prepared as in Example 3), 200 ml of water and 1.0 g of 10% palladium on charcoal is hydrogenated in a Parr shaker for 11/2 hours at room temperature with an initial pressure of 46 pounds of hydrogen. During this time a total of 4.5 pounds of hydrogen is absorbed. The mixture is heated to dissolve some precipitated product and is filtered hot to remove the catalyst. The filtrate is then evaporated to a small volume in vacuo at about 60° C. and a copious amount of absolute ethyl alcohol is added. The product is collected by filtration and is washed with absolute ethyl alcohol followed by ether. After air drying the material is oven dried at 120° C. overnight.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:24])[N:15]=[C:16]([C:17]3[CH:18]=[C:19](C)[CH:20]=[CH:21][CH:22]=3)[C:3]=12.[F:25]C1C=C(C=CC=1)C=O>>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:24])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:25])[CH:18]=3)[C:3]=12
Reactant: Cc1cccc(-c2nn(C)c3nnc(-c4ccccc4)c(Cl)c23)c1
Reactant: O=Cc1cccc(F)c1
Product: Cn1nc(-c2cccc(F)c2)c2c(Cl)c(-c3ccccc3)nnc21

Procedure:
Compound 32 was synthesised following similar procedures outlined in Example 24 (Compound 19), using 3-fluorobenzaldehyde instead of 3-methylbenzaldehyde in Step 1.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[CH2:5]([NH:8][C:9]1[C:10]2[S:18][CH:17]=[C:16]([CH3:19])[C:11]=2[N:12]=[C:13](Cl)[N:14]=1)[CH:6]=[CH2:7]>O>[CH2:1]([NH:4][C:13]1[N:14]=[C:9]([NH:8][CH2:5][CH:6]=[CH2:7])[C:10]2[S:18][CH:17]=[C:16]([CH3:19])[C:11]=2[N:12]=1)[CH:2]=[CH2:3]
Reactant: C=CCN
Reactant: C=CCNc1nc(Cl)nc2c(C)csc12
Solvent: O
Product: C=CCNc1nc(NCC=C)c2scc(C)c2n1
Temperature: 140 °C
Yield: 81.4 %

Procedure:
In 2.28 g (40.0 mmol) of allylamine was suspended 250 mg (1.1 mmol) of 4-allylamino-2-chloro-7-methylthieno[3,2-d]pyrimidine, and the resulting mixture was heated in a sealed tube at 140° C. for 24 hours. After the reaction mixture was cooled, 50 ml of water was added thereto, followed by extraction with ethyl acetate (50 ml×3). The organic layer was washed with water and dried over anhydrous sodium sulfate, and then the solvent was distilled off. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=4/1) to give 233 mg (yield: 85.7%) of the title compound.
Reaction SMILES: [OH:1][C@@H:2]([C@@H:4]1[C@@H:7]([C@H:8]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[S:11])[CH3:9])[N:6]([CH2:18][C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])[C:5]1=[O:25])[CH3:3].N1C=CC=CC=1.[CH3:32][Si:33]([CH3:36])([CH3:35])Cl.O>C1(C)C=CC=CC=1>[CH3:32][Si:33]([CH3:36])([CH3:35])[O:1][C@@H:2]([C@@H:4]1[C@@H:7]([C@H:8]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[S:11])[CH3:9])[N:6]([CH2:18][C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])[C:5]1=[O:25])[CH3:3]
Reactant: C=CCOC(=O)CN1C(=O)[C@H]([C@@H](C)O)[C@H]1[C@@H](C)C(=S)c1ccccc1
Reactant: C[Si](C)(C)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: Cc1ccccc1
Product: C=CCOC(=O)CN1C(=O)[C@H]([C@@H](C)O[Si](C)(C)C)[C@H]1[C@@H](C)C(=S)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97 %

Procedure:
To a solution of (3S,4S)-3-[(1R)-1-hydroxyethyl]-4-[(1R)-1-phenylthiocarbonylethyl]-1-allyloxycarbonylmethyl-2-azetidinone (5.04 g: 13.35 mmole) in toluene (40 ml) under ice cooling, pyridine (1.51 ml: 18.69 mmole) is added and trimethylchlorosilane (2.26 ml: 17.36 mmole) is added dropwise. The mixture is stirred at room temperature for 1.5 hours. Water (80 ml) is added to the reaction mixture, and aqueous layer is extracted with toluene. The extract and the organic layer are combined, washed with water (2 times) and saturated brine, dried over magnesium sulfate, and concentrated in vacuo to give crude (3S,4S)-3-[(1R)-1-trimethylsilyloxyethyl]-4-[(1R)-1-phenylthiocarbonylethyl]-1-allyloxycarbonylmethyl-2-azetidinone (5.614 g) as oily residue. Yield: 94%.
Reaction SMILES: [C:1]([C:3](=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[C-:17]#[N:18].[Na+].C(Cl)(Cl)Cl.Cl>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[C:1]([CH:3]([CH:9]([C:17]#[N:18])[C:10]1[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: CCOC(=O)C(C#N)=Cc1ccc(O)cc1
Reactant: [C-]#N
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)C(C#N)C(C#N)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 13.3 %

Procedure:
A mixture of-ethyl 2-cyano-3-(4-hydroxyphenyl)-2-propenoate (150 g, 0.69 mole), sodium cyanide (35.8 g, 0.73 mole, 5.8 percent excess), chloroform (500 ml), water (450 ml) and benzyltriethylammonium chloride (3.5 g), is stirred under nitrogen at room temperature for 50 minutes. By this time, all the solid reagents are dissolved. Concentrated hydrochloric acid (115 ml) is added to the mixture and the chloroform layer removed. The residue is extracted with ethyl acetate. Each of the organic layers is washed with water and dried over anhydrous magnesium sulfate. Upon removal of the solvents, 22.4 g (13.4 percent) of ethyl 2,3-dicyano-3-(4-hydroxyphenyl)propionate is isolated from the chloroform layer, and 140 g (83 percent) of the same product is isolated from the ethyl acetate layer. The combined yield is 96.4 percent.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([NH:8][CH2:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][N:11]2[C:16]([C:18]2[C:22]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[CH:21][N:20]([CH3:30])[N:19]=2)=[O:17])=[N:6][CH:7]=1.[Cu][C:32]#[N:33]>CN1CCCC1=O.O>[F:29][C:26]1[CH:27]=[CH:28][C:23]([C:22]2[C:18]([C:16]([N:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C@H:10]3[CH2:9][NH:8][C:5]3[N:4]=[CH:3][C:2]([C:32]#[N:33])=[CH:7][N:6]=3)=[O:17])=[N:19][N:20]([CH3:30])[CH:21]=2)=[CH:24][CH:25]=1
Reactant: N#C[Cu]
Reactant: Cn1cc(-c2ccc(F)cc2)c(C(=O)N2CCCC[C@H]2CNc2ncc(Br)cn2)n1
Solvent: O
Solvent: CN1CCCC1=O
Product: Cn1cc(-c2ccc(F)cc2)c(C(=O)N2CCCC[C@H]2CNc2ncc(C#N)cn2)n1
Yield: 6.1 %

Procedure:
1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-[4-(4-fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanone (0.35 g) in N-methylpyrrolidinone (10 ml) containing copper(I)cyanide (0.13 g) was heated to reflux for 5 h. The reaction mixture was diluted with water, filtered (Kieselguhr) and the filtrate extracted with ethyl acetate. The ethyl acetate phase was washed with water and brine, dried (MgSO4), filtered and solvent removed at reduced pressure. The residue was column chromatographed (silica gel; ethyl acetate:pentane 1:1→ethyl acetate eluant), the appropriate fractions combined and solvent removed at reduced pressure to give the title compound (0.019 g).
Reaction SMILES: C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1.Cl[C:24]1[C:25]2[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:26]=2[S:27][C:28]=1[C:29]([NH2:31])=[O:30].Cl.[N:39]1([CH2:45][CH2:46][SH:47])[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>CN(C=O)C.C(OCC)(=O)C>[CH3:37][O:36][C:34]1[CH:33]=[CH:32][C:26]2[S:27][C:28]([C:29]([NH2:31])=[O:30])=[C:24]([S:47][CH2:46][CH2:45][N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)[C:25]=2[CH:35]=1
Reactant: COc1ccc2sc(C(N)=O)c(Cl)c2c1
Reactant: SCCN1CCOCC1
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc2sc(C(N)=O)c(SCCN3CCOCC3)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
Diazabicycloundecene (DBU) (990 μL, 6.62 mmol) is added to a suspension of 3-chloro-5-methoxybenzo[b]thiophene-2-carboxamide (200 mg, 0.83 mmol) and 4-morpholineethanethiol hydrochloride (608 mg, 3.31 mmol) in 4 mL of DMF. The mixture is stirred at room temperature for 3 hours then diluted with ethyl acetate and washed with water followed by aqueous citric acid. NaHCO3 is added to the acidic extracts and the precipitated solids are collected and washed with water. Recrystallization from methanol:water provides 5-methoxy-3-[[2-(4-morpholinyl)ethyl]thio]benzo[b]thiophene-2-carboxamide in 83% yield; mp=158.5°-159.5° C.
Reaction SMILES: [CH2:1]([N:4]([CH2:30][CH2:31][CH3:32])[C:5]1[CH:6]=[C:7]([C:25](OCC)=[O:26])[C:8](=[O:24])[N:9]2[C:14]=1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]1[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=1[CH3:23])[CH2:2][CH3:3].[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1>[CH2:30]([N:4]([CH2:1][CH2:2][CH3:3])[C:5]1[CH:6]=[C:7]([CH2:25][OH:26])[C:8](=[O:24])[N:9]2[C:14]=1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]1[C:16]([CH3:23])=[CH:17][C:18]([CH3:22])=[CH:19][C:20]=1[CH3:21])[CH2:31][CH3:32]
Reactant: CCCN(CCC)c1cc(C(=O)OCC)c(=O)n2c(-c3c(C)cc(C)cc3C)cccc12
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: CCCN(CCC)c1cc(CO)c(=O)n2c(-c3c(C)cc(C)cc3C)cccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.3 %

Procedure:
Ethyl 1-(dipropylamino)-6-mesityl-4-oxo-4H-quinolizine-3-carboxylate, (0.020 g, 0.046 mmol), in tetrahydrofuran (1 mL) was cooled to −40° C. Diisobutylaluminum hydride (1.5M, 92 mL, 0.14 mmol) was added rapidly and the solution was warmed to room temperature. The reaction was quenched with methanol and stirred with saturated Rochelle's salt for 1 h. The solution was extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated. Flash chromatography (25% ethyl acetate/hexanes) gave 0.0107 g (59% yield) of the title compound as a yellow solid.
Reaction SMILES: [C:1]([O:9][CH2:10][C:11]1[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:26])C=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[C:1]([O:9][CH2:10][C:11]1[CH:12]=[N+:13]([O-:26])[C:14]([CH3:17])=[CH:15][CH:16]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(COC(=O)c2ccccc2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: Cc1ccc(COC(=O)c2ccccc2)c[n+]1[O-]
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 1767 mg of (6-methylpyridin-3-yl)methyl benzoate in 26.5 ml of chloroform was added 2440 mg of m-chloroperbenzoic acid under ice-cooling, followed by stirring for 1 hour. An aqueous potassium carbonate solution was added thereto to carry out a liquid separation operation, and the organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The residue was concentrated under reduced pressure to obtain 1891 mg of (6-methyl-1-oxidopyridin-3-yl)methyl benzoate.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].C(OC([C:11]1[C:12]([CH3:25])=[CH:13][CH2:14][N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[NH+:17]([CH3:24])[C:16]=12)=O)C.Cl>CC(N(C)C)=O>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:25][C:12]1[CH:11]=[C:16]2[N:15]([CH2:14][CH:13]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[NH+:17]2[CH3:24]
Reactant: CCOC(=O)C1=C2N(CC=C1C)c1ccccc1[NH+]2C
Agent: Cl
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC(=O)N(C)C
Product: CC1=CCN2C(=C1)[NH+](C)c1ccccc12

Procedure:
The same material is also prepared from 4-ethoxycarbonyl-3,5-dimethyl-5H-pyrido[1,2-a]benzimidazolium perchlorate by boiling in DMA containing HCl as described for the 1,2-dihydro compound.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1[N:11]=[C:10]([CH2:12][C:13]([OH:15])=[O:14])[O:9][N:8]=1.[CH2:16](O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCCCCC>C1(C)C=CC=CC=1.C(OCC)C.C1(C)C=CC=CC=1.C1(C)C=CC=CC=1.CCCCCC>[CH3:6][C:7]1[N:11]=[C:10]([CH2:12][C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[O:9][N:8]=1
Reactant: Cc1noc(CC(=O)O)n1
Reactant: OCc1ccccc1
Solvent: CCOCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: Cc1noc(CC(=O)OCc2ccccc2)n1
Temperature: 40 °C
Reaction time: 5 h
Yield: 46.7 %

Procedure:
Using the procedure of Example 17, 8 g of phosphorous oxychloride were slowly added to a mixture of 8 g of 3-methyl-1,2,4-oxadiazol-5-yl-acetic acid and 6.2 g of dry benzyl alcohol with the rate of addition adjusted to a reaction temperature of 40°-45° C. The resulting reaction mixture was stirred for 5 hours at 40° C. and then was treated in the usual manner. The obtained yellow oil was submitted to column chromatography over silica employing as eluents n-hexane and 3:1 hexane-toluene-, 1:1-toluene-hexane, 3:1 toluene-hexane mixture, toluene and finally a 3:1 toluene-diethyl ether mixture. The finally obtained colorless oil was 6.1 g (47% yield) of benzyl 3-methyl-1,2,4-oxadiazol-5-yl-acetate with a purity of about 95% (according to TLC and PMR spectrum) and a refractive index nD25 =1.518.