Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[NH:8][C:9](=[O:11])[O:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].[CH3:14][CH:15](O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[N:8]([CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:14])[C:9](=[O:11])[O:10][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=c1[nH]c2ccc([N+](=O)[O-])cc2o1
Reactant: CC(O)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(c1ccccc1)n1c(=O)oc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Into a solution of 6-nitrobenzo[d]oxazol-2(3H)-one (40-1, 5 g, 27.8 mmol) in THF (139 ml) was added α-methylbenzylalcohol (3.7 g, 30.5 mmol), polymer-bound triphenylphosphine (27.7 g, 83 mmol), and DIAD (11.2 g, 55.5 mmol). The reaction was shaken for 1 h at rt, filtered, and concentrated to yield 6-nitro-3-(1-phenylethyl)benzo[d]oxazol-2(3H)-one (7.89 g, 27.8 mmol) which was taken on to the next step without further purification. LRMS C15H14N202 [M−79] calc 205.1, obs 205.4.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]#[N:9].CN(C)[CH:12]=[CH:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]([F:28])=[C:20]([N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=1)=O.C(OCC)(=O)C>C(O)(=O)C>[F:28][C:19]1[CH:18]=[CH:17][C:16]([C:14]2[N:6]3[N:5]=[C:4]([CH3:7])[C:3]([C:8]#[N:9])=[C:2]3[N:1]=[CH:12][CH:13]=2)=[CH:21][C:20]=1[N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24]
Reactant: Cc1n[nH]c(N)c1C#N
Reactant: CN(C)C=CC(=O)c1ccc(F)c(N(C)S(C)(=O)=O)c1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1nn2c(-c3ccc(F)c(N(C)S(C)(=O)=O)c3)ccnc2c1C#N
Yield: 55.7 %

Procedure:
A mixture of 0.041 g (0.33 mmol) of 5-amino-3-methyl-1H-pyrazole-4-carbonitrile and 0.1 g (0.33 mmol) of N-[5-(3-dimethylamino-acryloyl)-2-fluoro-phenyl]-N-methyl-methanesulfonamide in 10 mL of glacial acetic acid was refluxed for 2.5 hours and then the solvent was removed by reduced pressure distillation. To the resulting residue were added 15 mL of dichloromethane and 10 mL of saturated sodium bicarbonate solution. The two layers were separated, and the aqueous layer was washed with 10 mL of dichloromethane. The organic layers were washed with 10 mL of water and dried over magnesium sulfate. The dichloromethane layer was evaporated to dryness to yield an oil which, in the presence of ethyl acetate, gave 66 mg of N-{2-fluoro-5-[3-cyano-2-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methyl-methanesulfonamide as a solid (yield 55%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8](I)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH2:15].[CH3:17][N:18]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[N:19]1.C([O-])([O-])=O.[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:21]2[CH:20]=[N:19][N:18]([CH3:17])[CH:22]=2)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH2:15]
Reactant: COC(=O)c1cc(I)c(C(F)(F)F)cc1N
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2cnn(C)c2)c(C(F)(F)F)cc1N
Temperature: 90 °C
Reaction time: 18 h
Yield: 65.5 %

Procedure:
2-Amino-5-iodo-4-trifluoromethyl-benzoic acid methyl ester (300 mg, 0.87 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-pyrazole (181 mg, 1.0 equiv), K2CO3 (303 mg, 2.5 equiv.) and triphenylphosphine (45 mg. 0.2 equiv) were weighed in air and added in a flame-dried flask. Bis(dibenzylidenacetone)palladium (25 mg, 0.05 equiv) was added and the flask was closed by a septum. Dioxane (6 mL) was added and the mixture was stirred for 18 h (TLC control) at 90° C. The catalyst was filtered off and washed with EtOAc, the filtrate was evaporated to dryness. The crude product was purified by column chromatography (silica gel 60, EtOAc/hexanes 1/3 to 1/2) to give 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-4-trifluoromethyl-benzoic acid methyl ester (0.57 mmol, 66%) as a white solid. ESI-MS: m/z 300 [M+H]+, rt: 4.97 min.
Reaction SMILES: [CH2:1]1[C@@H:3]2[C:4](=[O:23])[CH:5]3O[C:6]43[C@:19]([CH3:20])([CH:2]12)[C@@H:18]1[C@H:9]([C@H:10]2[C@@:14]([CH2:16][CH2:17]1)([CH3:15])[C:13](=[O:21])[CH2:12][CH2:11]2)[CH2:8][CH2:7]4.S(=O)(=O)(O)O.[N-:29]=[N+:30]=[N-:31].[Na+].Cl>CS(C)=O.O>[CH2:1]1[C@@H:3]2[C:4](=[O:23])[C:5]([N:29]=[N+:30]=[N-:31])=[C:6]3[C@:19]([CH3:20])([CH:2]12)[C@@H:18]1[C@H:9]([C@H:10]2[C@@:14]([CH2:16][CH2:17]1)([CH3:15])[C:13](=[O:21])[CH2:12][CH2:11]2)[CH2:8][CH2:7]3
Reactant: C[C@]12CC[C@H]3[C@@H](CCC45OC4C(=O)[C@H]4CC4[C@]35C)[C@@H]1CCC2=O
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C[C@]12CC[C@H]3[C@@H](CCC4=C(N=[N+]=[N-])C(=O)[C@H]5CC5[C@@]43C)[C@@H]1CCC2=O
Temperature: 85 °C
Yield: 70 %

Procedure:
To a stirred solution of 1,2β-methylen-4,5-epoxyandrostane-3,17-dione (0.50 g, 1.59 mmole) in dry dimethylsulfoxide (7.5 ml) is added conc. sulfuric acid (0.11 ml) and sodium azide (1.4 g). The resulting reaction mixture is heated at about 85° C. during 3 hours, cooled, poured into a mixture of water (50 ml) and conc. hydrochloric acid (4 ml), and extracted with ethyl acetate (3×50 ml). The combined organic extracts are dried over sodium sulfate, filtered and evaporated in vacuo to yield a solid which is purified by flash column chromatography eluting with n-hexane-diethyl ether 6:4. There are obtained 0.378 g (70% yield) of 1,2β-methylen-4-azidoandrost-4-ene-3,17-dione [I, R=--N, R1 =R2 =H; (a) and (b)=single bonds]
Reaction SMILES: [CH3:1][N:2]([CH3:34])[C:3]([C:5]1[CH:33]=[CH:32][C:8]([O:9][C:10]2[C:24]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:23][C:13]3[NH:14][C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)=[N:16][C:12]=3[CH:11]=2)=[CH:7][CH:6]=1)=[O:4].[CH3:35][S:36]C1C=CC(O)=CC=1>>[CH3:1][N:2]([CH3:34])[C:3]([C:5]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[C:24]([O:25][C:26]3[CH:27]=[CH:28][C:29]([S:36][CH3:35])=[CH:30][CH:31]=3)=[CH:23][C:13]3[NH:14][C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)=[N:16][C:12]=3[CH:11]=2)=[CH:32][CH:33]=1)=[O:4]
Reactant: CN(C)C(=O)c1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2Oc2ccccc2)cc1
Reactant: CSc1ccc(O)cc1
Product: CSc1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2Oc2ccc(C(=O)N(C)C)cc2)cc1

Procedure:
The entitled compound was obtained in the same method as in Example 1 or in accordance with the method or by combining it with an ordinary method but using 4-fluoro-5-(4-dimethylcarbamoyl-phenoxy)-2-nitro-phenylamine obtained in Example 18 and 4-methylmercapto-phenol.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[F:13][C:14]1[CH:23]=[CH:22][C:17]([CH:18]=[CH:19][CH:20]=O)=[CH:16][CH:15]=1.C1C=CC=CC=1>O>[F:13][C:14]1[CH:23]=[CH:22][C:17](/[CH:18]=[CH:19]/[CH2:20][NH:1][CH2:2][C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=[CH:5][CH:4]=2)=[CH:16][CH:15]=1
Reactant: NCc1cccc2ccccc12
Reactant: O=CC=Cc1ccc(F)cc1
Solvent: c1ccccc1
Solvent: O
Product: Fc1ccc(/C=C/CNCc2cccc3ccccc23)cc1

Procedure:
A mixture of 10 g of 1-aminomethylnaphthalene, 9.55 g of p-fluorocinnamaldehyde and 150 ml of benzene is heated in a reaction vessel equipped with a water separator, at reflux, until the theoretical amount of water has been separated. The mixture is cooled and evaporated to dryness. 5.78 g of the resulting Schiff's base in 60 ml of methanol, after warming to 50°, is mixed, with vigorous stirring, with 1.51 g of solid NaBH4, portionwise, and the mixture is refluxed for 20 minutes. The resulting mixture may be used as such in the next stage. The title compound can be isolated as an oil, however, by evaporation and dividing the residue between aqueous NaHCO3 solution and chloroform, drying the organic phase and evaporation.
Reaction SMILES: [N:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])=[C:2]=[S:3].[CH2:14]([NH:16][CH2:17][CH3:18])[CH3:15].O>C1COCC1>[CH2:14]([N:16]([CH2:17][CH3:18])[C:2](=[S:3])[NH:1][C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])[CH3:15]
Reactant: CCNCC
Reactant: COC(=O)c1ccccc1N=C=S
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC)C(=S)Nc1ccccc1C(=O)OC
Temperature: 25 °C
Yield: 91.5 %

Procedure:
Methyl 2-isothiocyanatobenzoate (3.37 g, 17.4 mmol) was dissolved in THF (75 mL), followed by addition of diethylamine (3.59 mL, 34.9 mmol). The reaction mixture was stirred at RT. After 1 h the mixture was poured into water (400 mL). The formed precipitate was collected by filtration, washed with water and dried in vacuo to give pure title compound (4.24 g, 91%).
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([O:10][CH2:11][CH:12]2[O:14][CH2:13]2)[CH2:4][C:3]1([CH3:16])[CH3:15].[OH-:17].[Na+]>>[OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([O:10][CH2:11][CH:12]([OH:14])[CH2:13][OH:17])[CH2:4][C:3]1([CH3:16])[CH3:15]
Reactant: CC1(C)CC(OCC2CO2)CC(C)(C)N1O
Reactant: [OH-]
Agent: [Na+]
Product: CC1(C)CC(OCC(O)CO)CC(C)(C)N1O

Procedure:
1.0 g of the compound of Example 3 is heated at 110° C. in 50 mL of 5% aqueous sodium hydroxide for six hours. The mixture is extracted with ethyl acetate, and the organic extract is dried and concentrated. The title compound is isolated as a red oil after column chromatography.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:31]=[CH:30][C:11]([O:12][C:13]2[C:22]([Cl:23])=[C:21]3[C:16]([CH:17]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:18][CH2:19][O:20]3)=[CH:15][C:14]=2[Cl:29])=[C:10]([N+:32]([O-])=O)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1.[Cl-].[NH4+].C(OCC)(=O)C.[Zn]>[NH2:32][C:10]1[CH:9]=[C:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH:31]=[CH:30][C:11]=1[O:12][C:13]1[C:22]([Cl:23])=[C:21]2[C:16]([CH:17]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:18][CH2:19][O:20]2)=[CH:15][C:14]=1[Cl:29]
Reactant: CCOC(=O)C1CCOc2c1cc(Cl)c(Oc1ccc(C(=O)OC(C)(C)C)cc1[N+](=O)[O-])c2Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCOc2c1cc(Cl)c(Oc1ccc(C(=O)OC(C)(C)C)cc1N)c2Cl
Reaction time: 1 h
Yield: 86.5 %

Procedure:
To a mixture of ethyl 7-(4-(tert-butoxycarbonyl)-2-nitrophenoxy)-6,8-dichlorochroman-4-carboxylate (2.70 g, 5.27 mmol) in 25 mL of THF and 25 mL of saturated ammonium chloride was added zinc dust (3.45 g, 52.7 mmol) under argon. After 1 hour at ambient temperature, the reaction was diluted with ethyl acetate and filtered. The biphasic filtrate was separated and the organic layer was washed with brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was dissolved in dichloromethane, concentrated onto silica gel and purified by flash column chromatography, eluting with 20% ethyl acetate in hexanes to give ethyl the desired product (2.20 g, 86.5% yield) as a white foam. MS (ESI) m/z=482 (M+H).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:10]=2)=[C:5]([CH3:25])[CH:4]=1)=O.[S:26]1[CH2:30][C:29](=[O:31])[NH:28][C:27]1=[O:32]>>[O:32]=[C:27]1[NH:28][C:29](=[O:31])[C:30](=[CH:1][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:22])[CH3:20])[CH:10]=3)=[C:5]([CH3:25])[CH:4]=2)[S:26]1
Reactant: O=C1CSC(=O)N1
Reactant: Cc1cc(C=O)ccc1-c1cccc(CN(C)C(=O)OC(C)(C)C)c1
Product: Cc1cc(C=C2SC(=O)NC2=O)ccc1-c1cccc(CN(C)C(=O)OC(C)(C)C)c1

Procedure:
In a manner similar to that of Example 1(f), by reacting 3.95 g (11.6 mmol) of tert-butyl (4′-formyl-2′-methylbiphenyl-3-ylmethyl)-N-methylcarbamate with 1.4 g (11.6 mmol) of 2,4-thiazolidine dione, and after purification by chromatography on a column of silica eluted with a heptane/ethyl acetate mixture (8/2), 3 g (59%) of the expected product are obtained in the form of a yellow solid with a melting point of 156° C.
Reaction SMILES: O[CH2:2][CH:3]([NH:5]C(=O)OC(C)(C)C)[CH3:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[Cl:44][C:45]1[C:50]([N+:51]([O-:53])=[O:52])=[CH:49][CH:48]=[CH:47][C:46]=1[OH:54]>C1C=CC=CC=1>[Cl:44][C:45]1[C:50]([N+:51]([O-:53])=[O:52])=[CH:49][CH:48]=[CH:47][C:46]=1[O:54][CH2:2][CH:3]([NH2:5])[CH3:4]
Reactant: CC(CO)NC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1cccc(O)c1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CC(N)COc1cccc([N+](=O)[O-])c1Cl
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 96.3 %

Procedure:
7.2 g (0.0414 mol) of 1,1-dimethylethyl 2-hydroxy-1-methylethylcarbamate and 10.8 g (0.0414 mol) 15 of triphenylphosphine are placed in a 500 ml, three-necked, round-bottomed flask containing 140 ml of benzene. The mixture is cooled in an ice bath and 6.5 ml (0.0414 mol) of diethyl azodicarboxylate are added dropwise. The mixture is left stirring for 15 minutes, 4.8 g (0.027 mol) of 2-chloro-3-nitrophenol are added, the temperature of the reaction mixture is left to return to room temperature and the reaction mixture is left stirring overnight. The precipitate obtained is then filtered and the filtrate evaporated. The residue is taken up in 100 ml of a 3N hydrochloric acid solution and is then heated at 80° C. in an oil bath for 2 hours. The phases are separated, the aqueous phase is recovered, the pH is adjusted to alkaline with a concentrated sodium hydroxide solution and extraction is carried out three times with ether. Washing is carried out with water and drying is carried out. There are obtained 6 g of product which is used as is in the following stage.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([OH:12])[CH2:9][C@H:8]1[CH:13]=[C:14]([CH3:18])[C:15](=[O:17])[CH3:16])=[O:6])[CH:2]=[CH2:3].N1C=CN=C1.[Si:24](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([O:12][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:9][C@H:8]1[CH:13]=[C:14]([CH3:18])[C:15](=[O:17])[CH3:16])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@@H](O)C[C@H]1C=C(C)C(C)=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOC(=O)N1C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=C(C)C(C)=O
Reaction time: 2 h
Yield: 63.2 %

Procedure:
To a solution of (2S,4S)-1-allyloxycarbonyl-4-hydroxy-2-(2-methyl-3-oxo-1-butenyl)pyrrolidine (4.00 g) in N,N-dimethylformamide (40 ml) were added imidazole (2.70 g) and t-butyldimethylsilyl chloride (4.80 g). The resulting mixture was allowed to stand at ambient temperature for 2 hours. The mixture was diluted with ethyl acetate (200 ml), washed in turn with water and brine, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel (100 ml) eluting with a mixture of n-hexane and ethyl acetate (9:1-8:2 V/V) to give (2S,4S)-1-allyloxycarbonyl-4-t-butyldimethylsilyloxy-2-(2-methyl-3-oxo-1-butenyl)-pyrrolidine (3.67 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[CH2:5][C@@H:6]([C:26]1[CH:34]=[CH:33][C:29]2[CH2:30][CH2:31][O:32][C:28]=2[CH:27]=1)[N:7]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[C:8]1=[O:25])[CH3:2].[H][H]>CCO.[Pd].[C]>[CH2:1]([O:3][C:4](=[O:35])[CH2:5][C@@H:6]([C:26]1[CH:34]=[CH:33][C:29]2[CH2:30][CH2:31][O:32][C:28]=2[CH:27]=1)[N:7]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[CH2:21][CH2:20][CH2:19][NH:18][C:17]=3[N:16]=2)[C:8]1=[O:25])[CH3:2]
Reactant: CCOC(=O)C[C@@H](c1ccc2c(c1)OCC2)N1CCC(CCCc2ccc3cccnc3n2)C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C[C@@H](c1ccc2c(c1)OCC2)N1CCC(CCCc2ccc3c(n2)NCCC3)C1=O

Procedure:
A mixture of 4-3 (460 mg, 1.0 mmol) and 10% Pd/carbon (300 mg) in EtOH (20 mL) was stirred under a balloon of hydrogen for 3 h. Following filtration and evaporative removal of the solvent, the residue was chromatographed (silica gel, 70:25:5 chloroform/ethyl acetate/MeOH) to give 4-4 as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[C:13]1[C:14]([C:18]#[N:19])=[CH:15][NH:16][CH:17]=1)=O.[OH-].[NH4+]>[Ni].C(O)(=O)C>[Cl:12][C:10]1[CH:9]=[CH:8][C:7]2[C:13]3[C:14](=[CH:15][NH:16][CH:17]=3)[CH2:18][N:19]=[C:4]([C:3]3[CH:20]=[CH:21][CH:22]=[CH:23][C:2]=3[F:1])[C:6]=2[CH:11]=1
Reactant: N#Cc1c[nH]cc1-c1ccc(Cl)cc1C(=O)c1ccccc1F
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Fc1ccccc1C1=NCc2c[nH]cc2-c2ccc(Cl)cc21
Reaction time: 6 h

Procedure:
A mixture of 3.0 g (9 mmol) of 4-[2-(2-fluorobenzoyl)-4-chlorophenyl]-1H-pyrrole-3-carbonitrile, ca 3 g of Raney nickel and 150 ml of glacial acetic acid was hydrogenated on a Parr apparatus at 50 psi for 6 hours. The Raney nickel was removed by filtration, and the acetic acid was removed at reduced pressure to give a yellow oil. The yellow oil was poured on to ice, basified with ammonium hydroxide solution and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to give tan crystals. Recrystallization from a mixture of ether and methylene chloride gave cream-colored prisms, mp 197°-199° C.
Reaction SMILES: [CH3:1][CH:2]([N:6]1[CH:10]=[C:9]([CH3:11])[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:7]1)[C:3]([OH:5])=O.[CH3:18][NH:19][CH3:20].N>>[CH3:18][N:19]([CH3:20])[C:3](=[O:5])[CH:2]([C:1]1[CH:13]=[CH:12][CH:8]=[CH:9][CH:10]=1)[N:6]1[CH:10]=[C:9]([CH3:11])[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:7]1
Reactant: Cc1cn(C(C)C(=O)O)nc1-c1ccccc1
Reactant: CNC
Agent: N
Product: Cc1cn(C(C(=O)N(C)C)c2ccccc2)nc1-c1ccccc1

Procedure:
Following the procedure of Example 68, but substituting 4-methyl-α,3-diphenylpyrazole-1-acetic acid for α,4-dimethyl-3-phenylpyrazole-1-acetic acid and dimethylamine for aqueous ammonia, there was obtained N,N,4-trimethyl-α,3-diphenylpyrazole-1-acetamide having a melting point of 135.5°-138° C.
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:13]([C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)=[O:15])=[C:12](O)[C:11]2[C:6](=[CH:7][C:8]([C:26]([F:29])([F:28])[F:27])=[CH:9][CH:10]=2)[N:5]=1)[CH3:2].O=P(Cl)(Cl)[Cl:32].C([O-])(O)=O.[Na+]>CCCCCC>[Cl:32][C:12]1[C:11]2[C:6](=[CH:7][C:8]([C:26]([F:29])([F:28])[F:27])=[CH:9][CH:10]=2)[N:5]=[C:4]([S:3][CH2:1][CH3:2])[C:13]=1[C:14]([NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=1)=[O:15]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCSc1nc2cc(C(F)(F)F)ccc2c(O)c1C(=O)NCc1cccc(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Product: CCSc1nc2cc(C(F)(F)F)ccc2c(Cl)c1C(=O)NCc1cccc(F)c1
Temperature: 130 °C
Yield: 48 %

Procedure:
A mixture of 1.0 g (2.36 mmol) 2-(ethylthio)-N-(3-fluorobenzyl)-4-hydroxy-7-(trifluoromethyl)quinoline-3-carboxamide and POCl3 (10 ml) was heated for 2 h at 130° C. After cooling to RT the mixture was adjusted to pH ˜8 with a saturated aqueous NaHCO3 solution and extracted with EE. The organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated to small volume under vacuum. Column chromatography (hexane/EE 22:3) of the residue yielded 0.5 g (1.1 mmol, 48%) 4-chloro-2-ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-7-(trifluoromethyl)-quinoline-3-carboxamide. MS: m/z 443.1 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[C:9]([NH:13][C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.Br[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25].C([O-])([O-])=O.[K+].[K+].C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:14]([NH:13][C:9]1[CH:8]=[C:7]([CH:4]2[CH2:5][CH2:6][N:1]([CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:2][CH2:3]2)[CH:12]=[CH:11][CH:10]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)Nc1cccc(C2CCNCC2)c1
Reactant: CC(C)(C)OC(=O)NCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1cccc(C2CCN(CCCNC(=O)OC(C)(C)C)CC2)c1
Yield: 431.2 %

Procedure:
A solution of N1-[3-(4-piperidyl)phenyl]acetamide (550 mg, 0.210 mmol), tert-butyl N-(3-bromopropyl)carbamate (550 mg, 0.230 mmol), K2CO3 (1.10 g, 0.890 mmol), diisopropylethyl amine (1.50 mL) and a few crystals of KI in dioxane (20 mL) was heated at reflux temperature for 2 days. The precipitated salts were removed by filtration, concentrated in vacuo and the crude product was chromatographed, giving the desired product (340 mg): 1H NMR (CDCl3) δ 8.15 (s, 1H), 7.47-7.44 (m, 2H), 7.22 (t, 1H, J=7.8 Hz), 6.94 (d, 1H, J=7.8 Hz), 5.53 (b, 1H), 3.23 (b, 6H), 2.80-1.60 (m, 9H), 2.20 (s, 3H), 1.45 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]=[C:10]=[O:11].[CH:12]([N:15]1[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]1)([CH3:14])[CH3:13]>C(#N)C>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10]([N:17]1[CH2:18][CH2:19][CH2:20][N:15]([CH:12]([CH3:14])[CH3:13])[CH2:16]1)=[O:11]
Reactant: CC(C)N1CCCNC1
Reactant: Cc1cccc(C)c1N=C=O
Solvent: CC#N
Product: Cc1cccc(C)c1NC(=O)N1CCCN(C(C)C)C1

Procedure:
2,6-Dimethylphenylisocyanate (1.5 g) was added dropwise to a solution of N-isopropylhexahydropyrimidine (1.3 g) in acetonitrile (5 ml) (exothermic). After cooling the title compound was isolated by filtration and recrystallised from acetonitrile (2,5 g, 89%), mp 138°-139° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[C:11]([N:13]1[CH2:20][CH:19]2[CH:15]([CH2:16][NH:17][CH2:18]2)[CH2:14]1)=[O:12].Cl[C:22]1[O:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1>>[O:23]1[C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=[C:22]1[N:17]1[CH2:16][CH:15]2[CH2:14][N:13]([C:11]([C:4]3[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=3[O:9][CH3:10])=[O:12])[CH2:20][CH:19]2[CH2:18]1
Reactant: Clc1nc2ccccc2o1
Reactant: COc1cccc(OC)c1C(=O)N1CC2CNCC2C1
Product: COc1cccc(OC)c1C(=O)N1CC2CN(c3nc4ccccc4o3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 41 and 2-chloro-benzooxazole. MS (ESI): mass calculated for C22H23N3O4, 393.45; m/z found 394.2 [M+H]+.
Reaction SMILES: [CH2:1]([NH:5][C:6](=O)[CH2:7][CH:8]([P:17]([O:22]CC)([O:19]CC)=[O:18])[P:9]([O:14]CC)([O:11]CC)=[O:10])[CH2:2][CH2:3][CH3:4].B.CSC.Cl>C1COCC1>[CH2:1]([NH:5][CH2:6][CH2:7][CH:8]([P:17]([OH:22])(=[O:18])[OH:19])[P:9]([OH:14])(=[O:10])[OH:11])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)CC(P(=O)(OCC)OCC)P(=O)(OCC)OCC
Agent: B
Agent: Cl
Solvent: CSC
Solvent: C1CCOC1
Product: CCCCNCCC(P(=O)(O)O)P(=O)(O)O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 109 %

Procedure:
A solution of N-butyl-3,3-bis(diethoxyphosphinyl)propionamide (1.40 g, 3.5 mmol) in THF (9 mL) was cooled to 0° C., and borane-methyl sulfide (0.90 ml, 9.0 mmol) was added via syringe. The reaction was stirred at 0° C. for 5 minutes, then warmed to 65° C. for 3 hours. The reaction mixture was cooled to 0° C. and 6N HCl (6 ml) was added carefully. The solvent was removed in vacuo, and the residue was repeatedly concentrated from methanol (3×10 mL). The product was dissolved in 12N HCl and heated at reflux for 20 hours. After cooling, the volatile materials were removed under vacuum, the residue was dissolved in water (10 mL) and then concentrated to give 1.05 g of Compound No. 158 as a hygroscopic glass.
Reaction SMILES: [Na].Cl.Cl[CH2:4][C:5]1[N:6]=[CH:7][NH:8][CH:9]=1.[CH2:10]([OH:14])[CH2:11][CH2:12][OH:13]>>[OH:13][CH2:12][CH2:11][CH2:10][O:14][CH2:4][C:5]1[N:6]=[CH:7][NH:8][CH:9]=1
Reactant: OCCCO
Reactant: ClCc1c[nH]cn1
Agent: Cl
Agent: [Na]
Product: OCCCOCc1c[nH]cn1
Reaction time: 8 h

Procedure:
Sodium (13.5 g.) was added over 3 hours to propane-1.3-diol (450 ml.) under nitrogen at 70° with stirring. This solution was added over 20 minutes to a stirred solution of 4-chloromethylimidazole hydrochloride (50.0 g.) under nitrogen at 40°-60 °. Subsequent heating at 60°-65° for 3 hours followed by overnight cooling. filtration and concentraction gave 4-(3-hydroxypropoxy)methylimidazole. Subsequent reaction with thionyl chloride give 4-(3-chloropropoxy)methylimidazole hydrochloride (38.3 g.).