Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].CN(P(N(C)C)(N(C)C)=O)C.[CH2:21]=[O:22]>C1(C)C=CC=CC=1.C([Mg]Br)C>[OH:22][C:21]1[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][C:4]=1[CH:3]=[O:9]
Reactant: C=O
Reactant: Cc1ccc(O)c(C)c1
Agent: CC[Mg]Br
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(O)c(C=O)c1
Yield: 58.4 %

Procedure:
To a solution of 2,4-dimethylphenol (24.9 g, 204 mmole) in anhydrous toluene (75 mL) at 0° C. was added HMPA (35 mL) and then a solution of ethylmagnesium bromide (61 mL-3 M in ethyl ether, 0.183 mmole), keeping the temperature <10° C. Then paraformaldehyde (13 g, 0.43 mole) was added and the cooling was removed. The ethyl ether was removed by distillation and the mixture was refluxed. The mixture was quenched with 10% HCl and EtOAc was added. The EtOAc solution was washed twice with H2O, twice with aqueous NH4Cl, dried over Na2SO4 and concentrated in vacuo. Purification by silica chromatography (98:2 hexanes:EtOAc) gave 17.9 g (59% yield) of the product as a yellow oil: ESHRMS m/z 147.0619 (M−H, C9H9O2, Calc'd 147.0603).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.[C:25]([NH2:29])(=[O:28])[CH:26]=[CH2:27]>CN(C)C=O>[C:25]([CH2:26][CH2:27][N:17]1[CH2:18][CH2:19][N:14]([C:11]2[CH:12]=[C:13]3[C:8]([C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[CH:9][C:10]=2[F:20])[CH2:15][CH2:16]1)(=[O:28])[NH2:29]
Reactant: C=CC(N)=O
Reactant: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Solvent: CN(C)C=O
Product: NC(=O)CCN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1
Temperature: 140 °C
Yield: 49.7 %

Procedure:
A mixture of 3.31 g (0.01 mole) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid and 4.2 g (0.058 mole) of acrylamide in 50 ml of dimethylformamide is heated at 140° C. for 6 hours. The suspension is concentrated under a high vacuum and the residue is stirred with water and recrystallised from glycol monomethyl ether. 2 g (50% of theory) of 7-[4-(2-carbamoylethyl)-1-piperazinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of decomposition point 283° to 286° C. are obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C@H:3]([C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)[CH3:4].C=O.[CH:15]([OH:17])=O>>[CH3:4][CH2:3][N:2]([C:15]([O:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([C@@H:3]([N:2]([CH3:1])[CH3:12])[CH3:4])[CH:6]=1)=[O:17])[CH3:1]
Reactant: C[C@@H](c1cccc(O)c1)N(C)C
Reactant: O=CO
Agent: C=O
Product: CCN(C)C(=O)Oc1cccc([C@H](C)N(C)C)c1

Procedure:
Patent publication WO2006/068386 describes a process for preparation of 3-(1-dimethylamino)phenol by subjecting (S)-3-(1-dimethylaminoethyl)phenol to N-methylation using formaldehyde/formic acid. The 3-(1-dimethylamino)phenol it is subjected to O-carbamoylation to form rivastigmine.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:11][C:12](=[O:22])[C:13]2[CH:18]=[C:17]([F:19])[C:16](F)=[CH:15][C:14]=2[F:21])=[C:4]([C:7]([O:9]C)=[O:8])[S:5][CH:6]=1.[CH3:23][OH:24].[OH-].[Na+].Cl>C1COCC1>[F:21][C:14]1[CH:15]=[C:16]([O:24][CH3:23])[C:17]([F:19])=[CH:18][C:13]=1[C:12]([NH:11][C:3]1[C:2]([CH3:1])=[CH:6][S:5][C:4]=1[C:7]([OH:9])=[O:8])=[O:22]
Reactant: COC(=O)c1scc(C)c1NC(=O)c1cc(F)c(F)cc1F
Reactant: CO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(F)c(C(=O)Nc2c(C)csc2C(=O)O)cc1F
Temperature: 70 °C

Procedure:
After a mixture of methyl 4-methyl-3-[(2,4,5-trifluorobenzoyl)amino]thiophene-2-carboxylate, MeOH, THF and 1M NaOH aq was stirred at 70° C., 1M of hydrochloric acid aq was added and the extracted solid was filtered to give 3-[(2,5-difluoro-4-methoxybenzoyl)amino]-4-methythiophene-2-carboxylic acid.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[C:8]([CH:10]=1)[OH:9])([CH3:3])[CH3:2].[CH:12]([N:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1)([CH3:14])[CH3:13].[ClH:22]>C(O)(=O)C>[ClH:22].[CH:12]([N:15]1[CH2:16][CH:17]=[C:18]([C:7]2[C:8]([OH:9])=[CH:10][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][C:6]=2[OH:11])[CH2:19][CH2:20]1)([CH3:14])[CH3:13]
Reactant: CC(C)c1cc(O)cc(O)c1
Reactant: CC(C)N1CCC(=O)CC1
Agent: Cl
Solvent: CC(=O)O
Product: CC(C)c1cc(O)c(C2=CCN(C(C)C)CC2)c(O)c1
Yield: 50 %

Procedure:
5-Isopropyl resorcinol (5.40 g), N-isopropyl-4-piperidone (5.00 g) and 12 ml acetic acid was treated with HCl as described in Example I to give 5.48 g product (50% yield); m.p. 247°-248°.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:16][C:15](=[O:17])[C:14]([C:18]2[NH:22][N:21]=[N:20][N:19]=2)=[CH:13][N:12]=1)[CH2:2][CH3:3].[N+:23]([O-])([OH:25])=[O:24].S(=O)(=O)(O)O>>[N+:23]([C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:1][CH2:2][CH3:3])=[C:6]([C:11]2[NH:16][C:15](=[O:17])[C:14]([C:18]3[NH:22][N:21]=[N:20][N:19]=3)=[CH:13][N:12]=2)[CH:7]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])O
Reactant: CCCOc1ccccc1-c1ncc(-c2nnn[nH]2)c(=O)[nH]1
Agent: O=S(=O)(O)O
Product: CCCOc1ccc([N+](=O)[O-])cc1-c1ncc(-c2nnn[nH]2)c(=O)[nH]1
Reaction time: 2 h
Yield: 61.5 %

Procedure:
2-(2-n-Propoxyphenyl)-5-(5-1H-tetrazolyl)pyrimidin-4(3H)-one (1.03 g., 3.46 mmoles) was added over a period of 20 minutes to a cooled (5°) mixture of 70% nitric acid (1.7 ml., 26.9 mmoles) and concentrated sulfuric acid (2 ml.). The mixture was allowed to stand at room temperature for 2 hours. The mixture was poured onto ice-water (200 ml.). The precipitate was recrystallized from 2-methoxyethanol to give the title compound (0.73 g., 61.3%), m.p. 251°-252° (decomp).
Reaction SMILES: [CH3:1][NH:2][N:3]=[CH:4][C:5](=[O:7])[CH3:6].[F:8][C:9]([F:21])([F:20])[C:10]1[CH:15]=[CH:14][C:13]([C:16](=O)[CH:17]=[O:18])=[CH:12][CH:11]=1>C(O)(=O)C>[F:8][C:9]([F:21])([F:20])[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:2]([CH3:1])[N:3]=[C:4]([C:5](=[O:7])[CH3:6])[C:17]=2[OH:18])=[CH:12][CH:11]=1
Reactant: O=CC(=O)c1ccc(C(F)(F)F)cc1
Reactant: CNN=CC(C)=O
Solvent: CC(=O)O
Product: CC(=O)c1nn(C)c(-c2ccc(C(F)(F)F)cc2)c1O
Temperature: 100 °C
Reaction time: 5 h
Yield: 8.6 %

Procedure:
2-Oxopropanal methylhydrazone (8.540 mmol, 855 mg) synthesized in Reference Synthetic Example 1 and (4-trifluoromethylphenyl)(oxo)acetaldehyde (6.432 mmol, 1.3 g) synthesized in Reference Synthetic Example 7 were dissolved in acetic acid (30 mL) and stirred at 100° C. for about 5 hours. Then, the solvent was evaporated, and the residue was dried by means of a vacuum pump and purified by silica gel column chromatography (n-hexane/AcOEt=2/1, and 4/1) to give the desired product as an orange solid (157.3 mg, yield 8.6%).
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:20])[CH:7](OC(=O)C)[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:2][CH2:3][CH3:4].[NH:21]1[CH:25]=[CH:24][CH:23]=[CH:22]1>>[CH2:1]([O:5][C:6](=[O:20])[CH:7]([NH:8][C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[C:22]1[NH:21][CH:25]=[CH:24][CH:23]=1)[CH2:2][CH2:3][CH3:4]
Reactant: c1cc[nH]c1
Reactant: CCCCOC(=O)C(NC(=O)OC(C)(C)C)OC(C)=O
Product: CCCCOC(=O)C(NC(=O)OC(C)(C)C)c1ccc[nH]1

Procedure:
A solution of 14.5 g. (0.05 mol.) of N-t-butoxycarbonyl-2-acetoxyglycine n-butyl ester and 10 ml. of redistilled pyrrole in 75 ml. of toluene was slowly distilled with replacement of fresh toluene to maintain the volume at 50-75 ml. After 30 minutes the reaction mixture was cooled and concentrated in vacuo. The residue was dissolved in hexane and chromatographed on alumina (Woelm, activity II) with hexane-benzene followed by benzene to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][CH:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:15](O)=[O:16])=[O:12])=[CH:5]2.Cl.CN(C)CCCN=C=NCC.[CH3:37][O:38][C:39]1[CH:50]=[C:49]2[C:42]([NH:43][CH:44]=[C:45]2[CH2:46][CH2:47][NH2:48])=[CH:41][CH:40]=1>CN(C)C=O>[CH3:37][O:38][C:39]1[CH:50]=[C:49]2[C:42](=[CH:41][CH:40]=1)[NH:43][CH:44]=[C:45]2[CH2:46][CH2:47][NH:48][C:15]([CH:14]([NH:13][C:11]([C:6]1[NH:7][C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2)=[O:12])[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16]
Reactant: O=C(NC(Cc1ccccc1)C(=O)O)c1cc2cc(F)ccc2[nH]1
Reactant: COc1ccc2[nH]cc(CCN)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: COc1ccc2[nH]cc(CCNC(=O)C(Cc3ccccc3)NC(=O)c3cc4cc(F)ccc4[nH]3)c2c1
Reaction time: 72 h

Procedure:
To 5.0 μmol of 2-[(5-fluoro-1H-indole-2-carbonyl)-amino]-3-phenyl-propionic acid (50 μL of a 0.1 mM solution in dimethylformamide) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (50 μL of a 0.11 mM solution in DMF, 5.5 μmol) followed by 5-methoxytryptamine (50 μL of a 0.11 mM solution in DMF, 5.5 μmol). The reaction was agitated for 3 days and then concentrated to dryness. The crude product was partitioned between chloroform (0.5 mL) and water (0.25 mL) and the organic layer was then concentrated to give the title compound. TSPMS ion (expected) 499 (499); HPLC RT 6.78 (25%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:11])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH:11]=[CH:17][N:18]([CH3:20])[CH3:19])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: Cc1c([N+](=O)[O-])cc(F)cc1[N+](=O)[O-]
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)C=Cc1c([N+](=O)[O-])cc(F)cc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 94 %

Procedure:
To a solution of 5-fluoro-2-methyl-1,3-dinitrobenzene (15 g, 0.075 mol) in N,N-dimethylformamide (300 mL) was added dimethylformamide dimethylacetal (89 g, 0.75 mol). The bright red reaction mixture was heated at 120° C. for 5 h, then concentrated in vacuo to provide 18 g crude product, which was used in the next step without further purification. LC/MS m/z=256.2 [M+H]+.
Reaction SMILES: CO[CH:3](OC)[CH:4]([C:18]#[N:19])[CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[C:8]([O:16][CH3:17])[CH:7]=1.S(O)(O)(=O)=O.[OH:27][CH2:28][CH2:29][NH:30][C:31]([NH2:33])=[NH:32].C[O-].[Na+]>C(O)C>[OH:27][CH2:28][CH2:29][NH:30][C:31]1[N:33]=[C:18]([NH2:19])[C:4]([CH2:5][C:6]2[CH:7]=[C:8]([O:16][CH3:17])[C:9]([O:14][CH3:15])=[C:10]([O:12][CH3:13])[CH:11]=2)=[CH:3][N:32]=1
Reactant: COc1cc(CC(C#N)C(OC)OC)cc(OC)c1OC
Reactant: N=C(N)NCCO
Agent: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: COc1cc(Cc2cnc(NCCO)nc2N)cc(OC)c1OC
Yield: 68.2 %

Procedure:
6.4 g of α-cyano-β-(3,4,5-trimethoxyphenyl)-propionaldehyde dimethylacetal, 3 g of β-hydroxyethylguanidine sulfate and 1.1 g of sodium methylate in 100 ml of ethanol were refluxed for 5 hours. The ethanol was then distilled off and the residue was dissolved in 100 ml of water. On extracting the solution with chloroform, 3.4 g (50% of theory) of 2-(β-hydroxyethylamino)-4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidine were obtained, melting at 146° C. after recrystallization from isopropanol.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:6]([NH2:7])=[CH:5][C:4]=1F)#N.[CH2:14]([N:16]1[CH2:21][CH2:20][NH:19][CH:18]([CH3:22])[CH2:17]1)[CH3:15]>>[CH2:14]([N:16]1[CH2:21][CH2:20][N:19]([C:4]2[C:3]([CH3:1])=[CH:9][C:8]([N+:10]([O-:12])=[O:11])=[C:6]([CH:5]=2)[NH2:7])[CH:18]([CH3:22])[CH2:17]1)[CH3:15]
Reactant: CCN1CCNC(C)C1
Reactant: N#Cc1cc([N+](=O)[O-])c(N)cc1F
Product: CCN1CCN(c2cc(N)c([N+](=O)[O-])cc2C)C(C)C1

Procedure:
A reaction was conducted by the method similar to Example 143-1) except that the compound of 1) above was used in place of 4-cyano-3-fluoro-6-nitroaniline and 1-ethyl-3-methylpiperazine was used in place of 1-tert-butoxycarbonyl-3-methylpiperazine, to provide the title compound as an orange-yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([F:10])[C:3]=1[CH:11]([O:15][CH2:16][CH3:17])[C:12]([OH:14])=O.[NH2:18][CH2:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][C:21]=1[Cl:28]>>[Cl:28][C:21]1[CH:22]=[C:23]([C:24]#[N:25])[CH:26]=[CH:27][C:20]=1[CH2:19][NH:18][C:12](=[O:14])[CH:11]([C:3]1[C:4]([F:10])=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=1[F:1])[O:15][CH2:16][CH3:17]
Reactant: CCOC(C(=O)O)c1c(F)cc(OC)cc1F
Reactant: N#Cc1ccc(CN)c(Cl)c1
Product: CCOC(C(=O)NCc1ccc(C#N)cc1Cl)c1c(F)cc(OC)cc1F

Procedure:
(RS)-(2,6-Difluoro-4-methoxy-phenyl)-ethoxy-acetic acid was coupled with 4-aminomethyl-3-chlorobenzonitrile (CAS 202521-97-9) according to general procedure C to give (RS)-N-(2-chloro-4-cyano-benzyl)-2-(2,6-difluoro-4-methoxy-phenyl)-2-ethoxy-acetamide. Colorless oil. MS 395.0 ([M+H]+)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[N:10][N:11]([CH3:13])[N:12]=2)=[N:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:22])C=1>ClCCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[N:10][N:11]([CH3:13])[N:12]=2)=[N+:6]([O-:22])[CH:7]=1
Reactant: Cn1nnc(-c2ccc(Br)cn2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCCl
Product: Cn1nnc(-c2ccc(Br)c[n+]2[O-])n1
Temperature: 80 °C

Procedure:
5-Bromo-2-(2-methyl-2H-tetrazol-5-yl)pyridine (175 mg, 0.73 mM) and 3-chloroperbenzoic acid (wet, 70%: 0.50 g, 2.05 mM) were dissolved in 1,2-dichloroethane (5 ml) and heated at 80° C. for 1.5 hours. The mixture was submitted directly to silica gel chromatography, eluting with 25% acetonitrile in dichloromethane. 5-Bromo-2-(2-methyl-2H-tetrazol-5-yl)pyridine 1-oxide was thus obtained as a white solid (165 mg). This material was homogeneous by tlc analysis and was used in the subsequent step without further characterization or purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C@H:5]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])[NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH3:2].O[N:24]1[C:28](=[O:29])[CH2:27][CH2:26][C:25]1=[O:30].C1(N=C=NC2CCCCC2)CCCCC1>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:22])[C@H:5]([CH2:17][CH2:18][C:19]([O:21][N:24]1[C:28](=[O:29])[CH2:27][CH2:26][C:25]1=[O:30])=[O:20])[NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH3:2]
Reactant: CCOC(=O)[C@H](CCC(=O)O)NC(=O)OCc1ccccc1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1COCCO1
Product: CCOC(=O)[C@H](CCC(=O)ON1C(=O)CCC1=O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of N-CBZ-L-glutamic acid-α-ethyl ester (0.096 mole, 29.6 g.) and N-hydroxysuccinimide (0.1 mole, 11.5 g.) in 200 ml. of dioxane was added with stirring at room temperature (0.1 mole, 21 g.) of dicyclohexylcarbodimide. After stirring 24 hours at room temperature, the mixture was filtered to remove dicyclohexylurea. The filtrate was concentrated in vacuo to give an oil. This oil failed to crystallize and was used in the next step without further purification.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@@H:9]([C:10]#[C:11]C)[CH2:8][CH2:7][C@H:6]1[C:13]#[N:14])=[O:4].[NH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[O:23])[CH2:18][CH2:17]1>C(#N)C>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([C:22]([N:19]2[CH2:18][CH2:17][CH:16]([NH:15][CH2:2][C:3]([N:5]3[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]3[C:13]#[N:14])=[O:4])[CH2:21][CH2:20]2)=[O:23])=[CH:25][CH:26]=1
Reactant: CC#C[C@H]1CC[C@@H](C#N)N1C(=O)CCl
Reactant: NC1CCN(C(=O)c2ccc(Cl)cc2)CC1
Solvent: CC#N
Product: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CNC1CCN(C(=O)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (2S,5R)-1-(chloroacetyl)-5-propynylpyrrolidine-2-carbonitrile (0.023 g, 0.118 mmol, Example 8D) in acetonitrile (1 mL) at room temperature was added (4-amino-piperidin-1-yl)-(4-chloro-phenyl)methanone (56 mg, 0.235 mmol). The reaction mixture was stirred at room temperature for 18 hours, concentrated under reduced pressure and purified by flash chromatography with 3% methanol:dichloromethane to provide the titled compound. MS (ESI) m/z 399 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[C@H:15]([OH:24])[CH2:16][C@H:17]([OH:23])[CH2:18][C:19]([O:21]C)=[O:20])=[C:11]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:3].C(#N)C.[OH-].[Na+:36]>CO>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:24])[CH2:16][CH:17]([OH:23])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:1].[Na+:36]
Reactant: COC(=O)C[C@@H](O)C[C@@H](O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CO
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 40 °C
Yield: 81.1 %

Procedure:
Fluvastatin methyl ester (3.0 g) was added to acetonitrile (60 ml) and dissolved by heating the mixture to reflux. The solution was then cooled to about 40° C. and NaOH (1 eq.) dissolved in MeOH (7.5 ml) was added. Turbidity appeared immediately. After 30 minutes an oil residue separated from the mixture. The mixture was heated again to about 55° C. for 3 h to dissolve the oil. The product was isolated by filtration under nitrogen, washed with acetonitrile (40 ml) and dried at 50° C. in a vacuum oven for 24 h to obtain 2.48 g (81.1%) of fluvastatin sodium Form LV.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([NH:12][C:13](OC)=[O:14])[N+:9]([O-:17])=[C:8]([NH:18][C:19]([O:21][CH3:22])=[O:20])[CH:7]=2)[CH2:5][CH:4]=[CH:3][CH2:2]1.C(Cl)Cl.[OH-].[Na+]>O>[N:1]1([C:6]2[CH:7]=[C:8]([NH:18][C:19]([O:21][CH3:22])=[O:20])[N:9]3[O:17][C:13](=[O:14])[N:12]=[C:10]3[N:11]=2)[CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: COC(=O)Nc1cc(N2CC=CC2)nc(NC(=O)OC)[n+]1[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COC(=O)Nc1cc(N2CC=CC2)nc2nc(=O)on12
Reaction time: 3 h

Procedure:
4.5 G. of dimethyl 6-(3-pyrrolin-1-yl)-2,4-pyrimidine-dicarbamate-3-oxide are suspended in a mixture of 200 ml. of methylene chloride and 200 ml. of water. The suspension is adjusted with concentrated sodium hydroxide to pH 12.5 and stirred at this pH for 3 hours. The two phases are then separated and the aqueous phase is adjusted to pH 3 with concentrated hydrochloric acid. The separated white precipitate is filtered off, pre-dried and recrystallized from a mixture of methylene chloride and methanol, there being obtained pure methyl 5-(3-pyrrolin-1-yl)-2-oxo-2H-[1,2,4]-oxadiazolo[2,3-a]pyrimidine-7-carbamate, having a melting point of 230°-234° C. (decomposition).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[S:9](Cl)(=[O:11])=[O:10].[CH3:13][N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([OH:29])[CH:27]=3)[NH:22][CH:21]=2)[CH2:16][CH2:15]1.[OH-].[Na+]>>[CH3:13][N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([O:29][S:9]([C:3]4[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])(=[O:11])=[O:10])[CH:27]=3)[NH:22][CH:21]=2)[CH2:16][CH2:15]1
Reactant: CN1CCC(c2c[nH]c3ccc(O)cc23)CC1
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Agent: [Na+]
Agent: [OH-]
Product: CN1CCC(c2c[nH]c3ccc(OS(=O)(=O)c4c(F)cccc4F)cc23)CC1
Yield: 98.4 %

Procedure:
By a method similar to Example 31, using 2,6-difluorobenzenesulfonyl chloride (256 mg, 1.2 mmol) and 3-(1-methylpiperidin-4-yl)-5-hydroxy-1H-indole (231 mg, 1.0 mmol), and 0.2 N sodium hydroxide (5.5 mL, 1.1 mmol) gave 400 mg (98%) of the title compound as an off white powder were obtained. The product was recrystallized from ethyl acetate/methanol/hexanes: mp=214-215° C.; MS(m/e): 407 (M+1); Calculated for C20H20F2N2O3S: C, 59.10; H, 4.96; N, 6.89. Found: C, 59.07; H, 5.16; N, 6.73.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH:5]([C:13]([NH:15][S:16](/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:18])=[O:17])=[O:14])[C:6](N(CC)CC)=[O:7])#[N:2].[F:27][C:28]1[CH:37]=[CH:36][C:31]([NH:32][CH:33]([CH3:35])[CH3:34])=[CH:30][CH:29]=1>>[C:1]([CH2:3][CH2:4][CH:5]([C:13]([NH:15][S:16](/[CH:19]=[CH:20]/[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)(=[O:17])=[O:18])=[O:14])[C:6]([N:32]([C:31]1[CH:36]=[CH:37][C:28]([F:27])=[CH:29][CH:30]=1)[CH:33]([CH3:35])[CH3:34])=[O:7])#[N:2]
Reactant: CCN(CC)C(=O)C(CCC#N)C(=O)NS(=O)(=O)/C=C/c1ccccc1
Reactant: CC(C)Nc1ccc(F)cc1
Product: CC(C)N(C(=O)C(CCC#N)C(=O)NS(=O)(=O)/C=C/c1ccccc1)c1ccc(F)cc1
Yield: 41.9 %

Procedure:
In the same manner as in Example 1 (4), a crude product was obtained using the compound (657 mg) obtained in Example 216 (2) and 4-fluoro-N-isopropylaniline (306 mg). This was purified by silica gel column chromatography to give the title compound (334 mg) as a white powder.
Reaction SMILES: [NH:1]1[C:5]2[CH2:6][CH2:7][CH2:8][C:4]=2[C:3]([C:9]#[N:10])=[N:2]1.[N-:11]=[N+:12]=[N-:13].[Na+]>CN(C=O)C>[N:10]1[NH:11][N:12]=[N:13][C:9]=1[C:3]1[C:4]2[CH2:8][CH2:7][CH2:6][C:5]=2[NH:1][N:2]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1n[nH]c2c1CCC2
Agent: [Na+]
Solvent: CN(C)C=O
Product: C1Cc2[nH]nc(-c3nn[nH]n3)c2C1
Temperature: 175 °C
Yield: 41.2 %

Procedure:
1,4,5,6-Tetrahydro-cyclopentapyrazole-3-carbonitrile (0.022 g, 0.165 mmol) and sodium azide (0.086 g, 1.30 mmol) were taken up in DMF (3 cm3) at heated under microwave irradiation to 175° C. for 20 minutes. The solution was cooled to room temperature, filtered and the filtered solid washed with ethyl acetate. The combined solutions was added to saturated aqueous sodium bicarbonate (20 cm3) and washed with ethyl acetate. The aqueous layer was acidified to pH 1 with the addition of 1M aqueous hydrochloric acid and extracted into ethyl acetate. The ethyl acetate washes were combined and solvent removed under reduced pressure, the resulting solid purified by preparative HPLC to give 3-(2H-tetrazol-5-yl)-1,4,5,6-tetrahydro-cyclopentapyrazole as a white solid (0.012 g, 0.068 mmol, 41%). 1H NMR δ (CD3OD): 2.88 (t-like, 2H, J=7.0), 2.82 (t-like, 2H, J=7.3), 2.64 (quintet-like, 2H, J=7.1); m/z (ES+): 177 [M+H]+.
Reaction SMILES: [OH-].[Na+].O.[CH:4]([O:7][C:8](Cl)=[O:9])([CH3:6])[CH3:5].[CH2:11]([N:18]1[CH2:25][CH:24]2[CH2:26][CH:20]([CH2:21][NH:22][CH2:23]2)[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl>[CH2:11]([N:18]1[CH2:19][CH:20]2[CH2:26][CH:24]([CH2:23][N:22]([C:8]([O:7][CH:4]([CH3:6])[CH3:5])=[O:9])[CH2:21]2)[CH2:25]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)OC(=O)Cl
Reactant: c1ccc(CN2CC3CNCC(C3)C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(C)OC(=O)N1CC2CC(CN(Cc3ccccc3)C2)C1
Reaction time: 3 h
Yield: 95 %

Procedure:
NaOH (6.0 mL; 10M), H2O (10 mL) and iso-propylchloroformate (55 mmol) were added to a solution of 3-benzyl-3,7-diazabicyclo[3.3.1]nonane (10.8 g; 50 mmol; see Example E above)-in DCM (50 mL) The reaction mixture was stirred for 3 h and the phases were then separated. The organic phase -was washed with H2O and brine, dried and concentrated to give the sub-title compound in a 95% yield.
Reaction SMILES: C1C=CN=CC=1.[FH:7].[N:8]1[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10](N)[CH:9]=1.N([O-])=O.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[F:7][C:10]1[CH:9]=[N:8][C:17]2[C:12]([CH:11]=1)=[N:13][CH:14]=[CH:15][CH:16]=2
Reactant: F
Reactant: Nc1cnc2cccnc2c1
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Fc1cnc2cccnc2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To 2 mL of hydrogen fluoride/pyridine, 145 mg of 1,5-naphthyridin-3-amine was added at 0° C., 76 mg of sodium nitrite was added to the reaction mixture, and stirred at 0° C. for 1 hour. The reaction mixture was stirred at 60° C. for 1 hour, and neutralized with a saturated aqueous sodium hydrogen carbonate solution at 0° C., chloroform was then added thereto, and the organic layer was separated. The organic layer was washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using silica gel; Silica Gel 60N made by KANTO CHEMICAL CO., INC., and an eluent of chloroform:methanol=20:1 to obtain 77 mg of 3-fluoro-1,5-naphthyridine as a light yellow solid.