Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.[CH:12](O)=O.C=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:8]([O:7][C:5]([CH:4]1[CH2:3][CH2:2][N:1]([CH3:12])[CH2:11][CH2:10]1)=[O:6])[CH3:9]
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=CO
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C1CCN(C)CC1
Reaction time: 1 h
Yield: 61 %

Procedure:
Ethyl isonipecotate (3.0 g, 19.1 mmol) was added to a mixture of 90% formic acid (10 mL) and 30% aqueous formaldehyde (10 mL, 100 mmol) then the mixture was heated at reflux for 24 h. After cooling, the mixture was concentrated in vacuo to give an oil which was dissolved in dichloromethane. Solid sodium bicarbonate (1 g) was added and the mixture stirred for 1 h then filtered. The filtrate was concentrated in vacuo to afford 1-methyl-piperidine-4-carboxylic acid ethyl ester (2.0 g, 61%) as a liquid, which was used as such for the next step.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][CH2:10][C:6]2[S:7][CH:8]=[CH:9][C:5]=2[CH2:4]1.C(N(CC)CC)C.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26]([NH:2][CH:3]1[CH2:11][CH2:10][C:6]2[S:7][CH:8]=[CH:9][C:5]=2[CH2:4]1)(=[O:28])=[O:27]
Reactant: NC1CCc2sccc2C1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1S(=O)(=O)NC1CCc2sccc2C1
Reaction time: 1 h
Yield: 79.6 %

Procedure:
To 2.00 g of 5-amino-4,5,6,7-tetrahydrobenzo[b]thiophene.hydrochloride and 2.40 g of triethylamine dissolved in 15 ml of methylene chloride was added dropwise 2.11 g of 2-methylbenzenesulfonyl chloride dissolved in 5 ml of methylene chloride under ice cooling, and the mixture was stirred for 1 hour. The reaction mixture was washed and dried, and then the solvent was removed. The resulting crystals were recrystallized from ethyl acetate-hexane to obtain 2.58 g of 5-[(2-methylphenyl)sulfonylamino]-4,5,6,7-tetrahydrobenzo[b]thiophene.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[C:9]2[C:5]([CH:6]=[C:7]([C:16]([NH2:18])=O)[NH:8]2)=[CH:4][C:3]=1[O:19][C:20]1[CH:21]=[N:22][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:24][CH:25]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:39])=CC=1>O1CCCC1>[F:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[C:9]2[C:5]([CH:6]=[C:7]([C:16](=[S:39])[NH2:18])[NH:8]2)=[CH:4][C:3]=1[O:19][C:20]1[CH:21]=[N:22][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:24][CH:25]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COCCOc1c(F)c(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(N)=O)[nH]c12
Solvent: C1CCOC1
Product: COCCOc1c(F)c(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(N)=S)[nH]c12
Temperature: 55 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
A mixture of 6-fluoro-7-(2-methoxyethoxy)-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxamide (0.61 g) and Lawesson's reagent (0.61 g) in tetrahydrofuran (25 mL) was stirred at 55° C. for 2 h. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:hexane=40:60 to 70:30, volume ratio) to give light yellow crystals, which were washed with ethyl acetate-hexane to give the title compound (585 mg, 92%) as light yellow crystals. MS 440 (MH+).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1.[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:8][CH:7]=1
Reactant: C1CCNCC1
Reactant: O=Cc1ccc(OCCCCl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCCl
Product: ClCCCOc1ccc(CN2CCCCC2)cc1
Reaction time: 16 h

Procedure:
A solution of the product of Example 11 (5.0 g), piperidine (3.1 mL), and acetic acid (2.0 mL) in DCE (100 mL) was treated with sodium triacetoxyborohydride (9.3 g). After 16 h, the resulting mixture was diluted with water (100 mL) and extracted with DCM (3×50 mL). The combined organic phases were dried (magnesium sulfate) and evaporated, giving the title compound as an amber oil (5.3 g).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:28](=[O:29])[N:13]3[C:14]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[C:15]([CH2:19]Br)[CH2:16][S:17](=[O:18])[C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C([O-])=[O:33].[NH4+].[I-].[Na+].C(OCC)(=O)C>CN(C)C=O.O>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:28](=[O:29])[N:13]3[C:14]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[C:15]([CH2:19][OH:33])[CH2:16][S:17](=[O:18])[C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C([O-])C(F)(F)F
Reactant: CC(C)(C)OC(=O)C1=C(CBr)CS(=O)[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N12
Agent: [I-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C1=C(CO)CS(=O)[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N12
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a solution of tert-butyl 7-phenylacetamido-3-bromomethyl-3-cephem-4-carboxylate-1-oxide (76.1 g; 0.158 mol) in N,N-dimethylformamide (350 ml), ammonium trifluoroacetate (41.3 g; 0.316 mol) and sodium iodide (23.6 g; 0.158 mol) were added, followed by stirring at room temperature. The reaction mixture was added with ammonium trifluoroacetate (10.3 g; 0.079 mol) upon an elapsed time of 4 hours and 35 minutes from the initiation of the stirring and then with sodium iodide (11.8 g, 0.079 mol) upon an elapsed time of 8 hours and 5 minutes after the initiation of the stirring. Stirring was continued at room temperature for 24 hours and 25 minutes in total. The reaction mixture was poured into a mixture of ethyl acetate, and water and the ethyl acetate layer was collected. The water layer was extracted twice with ethyl acetate. Ethyl acetate layers were combined together, successively washed with water and saturated aqueous sodium chloride solution, and then dried over magnesium sulfate. The solvent was then distilled off under reduced pressure, whereby tert-butyl 7-phenylacetamido-3-hydroxymethyl-3-cephem-4-carboxylate-1-oxide was obtained (yield: 63.5 g; 96.1%). NMR (CDCl3, δ): 1.58(9 H,s), 3.00(1 H,br.s), 3.17,3.94(2 H,ABq, J=18.7 Hz), 3.62(2 H,s), 4.13,4.47 (2 H,ABq,J=13.2 Hz), 4.42(1 H,d,J=4.8 Hz), 6.02(1 H,dd,J=4.8 Hz,9.7 Hz), 6.90(1 H,d,J=9.7 Hz), 7.24-7.30(5 H,m)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1/[CH:23]=[CH:24]/[C:25]1[S:29][C:28]([C:30]([O:32][CH3:33])=[O:31])=[CH:27][C:26]=1[N+:34]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(OCC)(OCC)OCC.C(OCC)(=O)C>C1(C)C=C(C)C=C(C)C=1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[C:23]1[NH:34][C:26]2[CH:27]=[C:28]([C:30]([O:32][CH3:33])=[O:31])[S:29][C:25]=2[CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(/C=C/c2ccc(OCc3ccccc3)cc2OCc2ccccc2)s1
Agent: CCOP(OCC)OCC
Solvent: CCOC(C)=O
Solvent: Cc1cc(C)cc(C)c1
Product: COC(=O)c1cc2[nH]c(-c3ccc(OCc4ccccc4)cc3OCc3ccccc3)cc2s1
Temperature: 160 °C
Reaction time: 43 h
Yield: 47.2 %

Procedure:
To a solution of methyl (E)-5-[2-(2,4-bisbenzyloxyphenyl)vinyl]-4-nitrothiophene-2-carboxylate (3.08 g, 6.13 mmol) in mesitylene (15 ml) was added triethyl phosphite (3.15 ml, 18.4 mmol), and the mixture was stirred at 160° C. for 43 hr. The reaction mixture was allowed to cool to room temperature, and ethyl acetate (50 ml) was added. The organic layer was washed successively with 1N hydrochloric acid (30 ml), water (30 ml×2) and saturated brine (20 ml), and dried over sodium sulfate. After filtration and concentration, isopropyl alcohol (20 ml) was added to the obtained residue and the precipitated solid was collected by filtration. The solid was washed with isopropyl alcohol (10 ml×3) to give methyl 5-(2,4-bisbenzyloxyphenyl)-4H-thieno[3,2-b]pyrrole-2-carboxylate (1.36 g, yield 47%).
Reaction SMILES: CC1(C)O[CH2:8][CH2:7][C@H:6]2N1[C:4](=[O:12])[C@@H:5]2[N+]#[C-].[CH2:14]([SnH](CCCC)CCCC)[CH2:15][CH2:16]C.N(C(C)(C)C#N)=NC(C)(C)C#N>C1C=CC=CC=1>[CH3:14][CH2:15][CH2:16][CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=[O:12]
Reactant: [C-]#[N+][C@H]1C(=O)N2[C@@H]1CCOC2(C)C
Reactant: CCCC[SnH](CCCC)CCCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: CCCCCCCC=O

Procedure:
A mixture of (6R,7R)-2,2-dimethyl-7-isocyano-1-aza-3-oxabicyclo[4.2.0]octan-8-one (150 mg), tributyltinhydride (0.263 ml), and azobisisobutyronitrile (14 mg) in benzene (4.5 ml) was refluxed for 15 minutes. The resulting solution was chromatographed on silica gel (4.5 g) eluting with a mixture of benzene and acetone (15:1-16:1) to give the crude product (140 mg) as an oil, which was purified by silica gel (5 g) chromatography (eluate: a mixture of methylene chloride and ethyl acetate 30:1-5:1) to give (6R)-2,2-dimethyl-1-aza-3-oxabicycle[4.2.0]-octan-8-one (98 mg) as an oil.
Reaction SMILES: [O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[N:4][C:3]1=2.C1(N=C=NC2CCCCC2)CCCCC1.CN(C)C(=O)C.[CH3:37][N:38]([CH3:43])[CH2:39][CH:40](O)[CH3:41]>CCOCC.CC(C)=O>[O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([O:15][CH:40]([CH3:41])[CH2:39][N:38]([CH3:43])[CH3:37])=[O:14])[CH:5]=[N:4][C:3]1=2
Reactant: O=C(O)CCn1cnc2c(=O)[nH]cnc21
Reactant: CC(O)CN(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC(C)=O
Solvent: CC(=O)N(C)C
Solvent: CCOCC
Product: CC(CN(C)C)OC(=O)CCn1cnc2c(=O)[nH]cnc21
Yield: 96.5 %

Procedure:
0.300 g (1.441 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propanoic acid (AIT-0080) and 0.305 g (1.478 mmol) of dicyclohexylcarbodiimide were placed into a 10 ml round bottom flask equipped with magnetic stirring bar and thermometer. 4 ml of N,N-dimethylacetamide and 0.168 g (1.628 mmol) of 1-dimethyamino-2-propanol were added and the solution was heated to 75° (closed flask) for two hours. The solution was allowed to come to room temperature and a large amount of precipitate formed. The contents were transferred to a larger flask with 20 ml of acetone. 20 ml of ether was added and the solution was allowed to cool down in the refrigerator. Crystals formed within a short period of time. A solid was obtained by filtration and washed with ether. 408 mg of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propanoic acid, 1-(dimethylamino)-2-propyl ester (AIT-0106) as a white crystalline solid was obtained. Yield: 97%. m.p.: 280° -284°.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:10]=[CH:9][C:8](=[O:11])[CH:7]=[CH:6]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[Cl:30][C:31]1[CH:50]=[CH:49][C:34]([NH:35][C:36]2[C:45]3[C:40](=[CH:41][C:42](O)=[C:43]([O:46][CH3:47])[CH:44]=3)[N:39]=[CH:38][N:37]=2)=[C:33]([F:51])[CH:32]=1.C(P(CCCC)CCCC)CCC>C(Cl)Cl>[Cl:30][C:31]1[CH:50]=[CH:49][C:34]([NH:35][C:36]2[C:45]3[C:40](=[CH:41][C:42]([O:1][CH2:2][CH2:3][CH2:4][N:5]4[CH:6]=[CH:7][C:8](=[O:11])[CH:9]=[CH:10]4)=[C:43]([O:46][CH3:47])[CH:44]=3)[N:39]=[CH:38][N:37]=2)=[C:33]([F:51])[CH:32]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: O=c1ccn(CCCO)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCCn1ccc(=O)cc1
Temperature: 5 °C
Reaction time: 3 h
Yield: 11.2 %

Procedure:
1-(3-Hydroxypropyl)-1,4-dihydro-4-pyridone (2 20 mg, 1.44 mmol) in methylene chloride (4 ml) followed by 1,1'-(Azodicarbonyl)dipiperidine (720 mg, 2.86 mmol) were added to a stirred solution of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (300 mg, 0.94 mmol), (prepared as described for the starting material in Example 15), and tributylphosphine (0.69 ml, 2.8 mmol) in methylene chloride (20 ml) under nitrogen at 5° C. The mixture was stirred at 5° C. for 3 hours, allowed to warm to ambient temperature and stirred for a further 18 hours. The solvent was removed by evaporation and the residue partitioned between ethyl acetate and water. The organic phase was separated, dried (MgSO4), and solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol/triethylamine mixtures (100/0/0 increasing to 70/30/0.5) to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-[3-(4-oxo-1,4-dihydro-1-pyridyl)propoxy]quinazoline (48 mg, 11%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8](=[O:10])[CH3:9])[CH2:4][CH2:3]1.[CH3:11][C:12]([CH2:16]O)([CH2:14][OH:15])[CH3:13]>CC1C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH3:9][C:8]1([CH:5]2[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)[O:15][CH2:14][C:12]([CH3:16])([CH3:13])[CH2:11][O:10]1
Reactant: CC(=O)C1CCC(O)CC1
Reactant: CC(C)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1(C)COC(C)(C2CCC(O)CC2)OC1
Temperature: 25 °C
Yield: 62 %

Procedure:
A mixture of 1-(4-hydroxy-cyclohexyl)-ethanone (2.24 g, 1 eq.), toluene (160 mL), neopentylglycol (1.96 g, 1.2 eq.) and pTsOH (150 mg, 0.05 eq.) in a flask equipped with Dean-Stark apparatus was heated to reflux overnight. The mixture was cooled down to room temperature and concentrated. The crude product was purified by silica gel column chromatography (25% to 50% EtOAc/hexanes) to give 4-(2,5,5-trimethyl-[1,3]dioxan-2-yl)-cyclohexanol (2.23 g, 62%).
Reaction SMILES: [CH3:1][Si:2]([CH3:30])([CH3:29])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([Si:25]([CH3:28])([CH3:27])[CH3:26])[CH:24]=1)[C:6]([NH:8][C:9]1[N:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1.C[Si](C)(C)C1C=C(C(NC2C=CC(C=CC(OCC)=O)=CC=2)=S)C=C([Si](C)(C)C)C=1>>[CH3:1][Si:2]([CH3:30])([CH3:29])[C:3]1[CH:4]=[C:5]([C:6]([NH:8][C:9]2[N:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=2)=[S:40])[CH:22]=[C:23]([Si:25]([CH3:28])([CH3:27])[CH3:26])[CH:24]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)/C=C/c1ccc(NC(=O)c2cc([Si](C)(C)C)cc([Si](C)(C)C)c2)nc1
Agent: CCOC(=O)C=Cc1ccc(NC(=S)c2cc([Si](C)(C)C)cc([Si](C)(C)C)c2)cc1
Product: CCOC(=O)/C=C/c1ccc(NC(=S)c2cc([Si](C)(C)C)cc([Si](C)(C)C)c2)nc1
Yield: 92.6 %

Procedure:
Using Compound 18a (135 mg) and Lawesson's reagent (86.7 mg), Compound 18b (90.7 mg, 65%) was obtained as a yellow solid in the same manner as Compound 17b was synthesized.
Reaction SMILES: C[O:2][C:3]1[CH2:8][CH:7]=[C:6]([CH2:9][CH2:10][CH2:11][NH:12][CH2:13][CH2:14][CH3:15])[CH2:5][CH:4]=1.S(=O)(=O)(O)O.[OH-].[Na+]>>[CH2:13]([N:12]1[C@@H:7]2[C@@H:6]([CH2:5][CH2:4][C:3](=[O:2])[CH2:8]2)[CH2:9][CH2:10][CH2:11]1)[CH2:14][CH3:15]
Reactant: CCCNCCCC1=CCC(OC)=CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CCCN1CCC[C@@H]2CCC(=O)C[C@@H]21
Yield: 22.7 %

Procedure:
One hundred twenty-one grams of 1-methoxy-4-(3-n-propylamino)propyl-1,4-cyclohexadiene were dissolved in 1 l. of 15% aqueous sulfuric acid. The acidic solution was refluxed for about 6 hours and was then poured over ice. The dilute acidic solution was made basic with 50% aqueous sodium hydroxide. The now-basic aqueous solution was extracted with methylene dichloride. The methylene dichloride extract was dried and the solvent removed therefrom to yield 25.6 g of cis-(±)-1-n-propyl-7-oxodecahydroquinoline.
Reaction SMILES: [C:1]([C:3]([C:13](=[O:16])[CH2:14][CH3:15])=[CH:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)#[N:2].CO.[H][H]>[Pd].CC#N>[C:1]([CH:3]([C:13](=[O:16])[CH2:14][CH3:15])[CH2:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)#[N:2]
Reactant: CCC(=O)C(C#N)=Cc1ccc(C#N)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC#N
Solvent: CO
Product: CCC(=O)C(C#N)Cc1ccc(C#N)cc1
Yield: 99.1 %

Procedure:
To a hydrogenation reactor was charged with 4-(2-cyano-3-oxopent-1-enyl)benzonitrile (24) (20 g, 95.1 mmol), Pd/C (2 g, 10%, wet), MeOH (100 ml) and MeCN (100 ml). The mixture was stirred at 25° C. under 50 psi hydrogen for 2 h until absorption of hydrogen was stopped. The mixture was filtered through a celite pad to remove catalyst. It was concentrated under reduced pressure to give product 25 (20 g, 99%) as an oil. The product was directly used for the next step reaction without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH:19]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]3[CH2:27][CH2:28][NH:29][CH2:30][CH:31]=3)[CH:21]=2)[CH2:18][C:17]([C:32]([F:38])([F:37])[C:33]([F:36])([F:35])[F:34])=[N:16]1.C(N(CC)CC)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48]>ClCCl>[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH:19]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]3[CH2:27][CH2:28][N:29]([S:47]([CH3:46])(=[O:49])=[O:48])[CH2:30][CH:31]=3)[CH:21]=2)[CH2:18][C:17]([C:32]([F:38])([F:37])[C:33]([F:34])([F:35])[F:36])=[N:16]1
Reactant: CS(=O)(=O)Cl
Reactant: FC(F)(F)C(F)(F)C1=NN(c2ccccc2Cl)C(c2cccc(C3=CCNCC3)c2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CC=C(c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccccc3Cl)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.1 %

Procedure:
1-(2-Chloro-phenyl)-5-[3-(1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole trifluoroacetate (100.0 mg, 0.18 mmol) prepared in Example 117, triethylamine (74.0 uL, 0.53 mmol) and methanesulfonyl chloride (20.0 uL, 0.26 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 1 hour, washed with distilled water, 1N hydrochloride, a saturated solution of sodium hydrogen carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3) to give 51.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [CH:1](=[C:8]1[NH:12][C:11](=[O:13])[C:10]([N:14]=[O:15])=[C:9]1OC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CO>[CH:1](=[C:8]1[NH:12][C:11](=[O:13])[C:10]([N:14]=[O:15])=[C:9]1[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: COC1=C(N=O)C(=O)NC1=Cc1ccccc1
Solvent: CO
Product: O=NC1=C(Nc2ccccc2)C(=Cc2ccccc2)NC1=O
Yield: 30 %

Procedure:
A solution of 0.11 g (0.5 mmol) 5-benzylidene-4-methoxy-3-nitroso-1,5-dihydropyrrol-2-one (prepared by the method of H. Poschenrieder et al (Arch. Pharm. Pharm. Med. Chem. 1998, vol. 331, pp. 389-394) and Stachel et al (J. Heterocycl. Chem. 1980, vol. 17, pp. 1195-1199 and Liebigs Ann. Chem. 1985, pp. 1692-1696)) in methanol was boiled under reflux with 0.25 mol (0.25 mmol) aniline for two minutes. The compound 5-benzylidene-3-nitroso-4-phenylamino-1,5-dihydropyrrol-2-one was obtained in a yield of 30% after recrystallization from methanol. The compound decomposes at 230° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[C:6]([NH2:11])[CH:7]=[CH:8][CH:9]=2)[C@H:4]([CH3:12])[CH2:3]1.C(N(CC)CC)C.[CH3:21][N:22]1[C:26]([CH3:27])=[C:25]([C:28](Cl)=[O:29])[C:24]([CH3:31])=[N:23]1>CN(C)C1C=CN=CC=1.C1COCC1>[CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[C:6]([NH:11][C:28]([C:25]3[C:24]([CH3:31])=[N:23][N:22]([CH3:21])[C:26]=3[CH3:27])=[O:29])[CH:7]=[CH:8][CH:9]=2)[C@H:4]([CH3:12])[CH2:3]1
Reactant: C[C@@H]1CC(C)(C)c2cccc(N)c21
Reactant: Cc1nn(C)c(C)c1C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nn(C)c(C)c1C(=O)Nc1cccc2c1[C@H](C)CC2(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.8 %

Procedure:
Into a solution composed of 0.15 g of (R)-1,1,3-trimethyl-4-aminoindane (optical purity: 99% ee), 0.13 g of triethylamine, 5 mg of 4-dimethylaminopyridine and 1 mL of THF, a solution of 0.15 g of 1,3,5-trimethylpyrazole-4-carbonyl chloride in THF was dropped under ice cool. The mixture was stirred at room temperature for 15 minutes, then, to the reaction mixture was added ice water, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium hydrogen carbonate aqueous solution and saturated saline sequentially, then, dried over magnesium sulfate and concentrated under reduced pressure. The resultant residue was subjected to silica gel column chromatography to obtain 0.17 g of (R)-(−)-N-(1,1,3-trimethylindan-4-yl)-1,3,5-trimethylpyrazole-4-carboxamide (hereinafter, referred to as present carboxamide compound (3)) (optical purity: 99% ee).
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]1([CH3:11])[CH3:10].N(OC(C)(C)C)=O.N1C=CC=CC=1.N[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(#N)C.[Cu](F)F>[O:1]([N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]1([CH3:11])[CH3:10])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1ccccc1
Reactant: CC1(C)CCCC(C)(C)N1O
Agent: F[Cu]F
Agent: CC(C)(C)ON=O
Solvent: CC#N
Solvent: c1ccncc1
Product: CC1(C)CCCC(C)(C)N1Oc1ccccc1
Yield: 84 %

Procedure:
The process of Example 1 is repeated using 3.9 g (25 mmol) of 1-oxyl-2,2,6,6-tetramethylpiperidine, 7.84 g (76 mmol) of tert-butyl nitrite, 25 mg (0.25 mmol) of copper(II) fluoride in a mixture of 100 mL of acetonitrile/20 mL of pyridine and 4.65 g (50 mmol) of aniline in 10 mL of acetonitrile at 70° C. The crude product obtained is purified by vacuum flash chromatography (heptane) to give 4.9 g of the title compound as a colorless oil in 84.5% yield.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[CH:33]1([CH2:38][CH2:39][C:40](Cl)=[O:41])[CH2:37][CH2:36][CH2:35][CH2:34]1>>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:21][CH2:22][N:23]([C:40](=[O:41])[CH2:39][CH2:38][CH:33]5[CH2:37][CH2:36][CH2:35][CH2:34]5)[CH2:24][CH2:25]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Reactant: O=C(Cl)CCC1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCN(C(=O)CCC5CCCC5)CC4)cn3)nc2n1C1CCCC1
Yield: 44.4 %

Procedure:
Following General Procedure G, 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.230 mmol) and 3-cyclopentyl propionyl chloride (39 mL, 0.690 mmol) gave 7-cyclopentyl-2-{5-[4-(3-cyclopentyl-propionyl)-piperazin-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (57 mg, 44%). MS(ESI) m/z 559.4 (M+H)+
Reaction SMILES: CC([O-])(C)C.[K+].Cl[CH:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10].[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N+:27]([O-:29])=[O:28].Cl>CN(C=O)C.O>[F:20][C:21]1[CH:26]=[C:25]([CH:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:24]=[CH:23][C:22]=1[N+:27]([O-:29])=[O:28]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CCOC(=O)C(Cl)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(c1ccccc1)c1ccc([N+](=O)[O-])c(F)c1
Temperature: -45 °C
Reaction time: 0.33 h
Yield: 44.4 %

Procedure:
9.8 g of potassium tert-butylate were dissolved in 90 mL of DMF and cooled to −45° C. To this, a mixture of ethyl 2-chloro-2-phenylacetate (43.8 mmol, 8.7 g) and 1-fluoro-2-nitrobenzene (43.8 mmol, 4.6 mL) was gently added dropwise and stirring was continued for a further 20 minutes. The reaction mixture was set to pH 4 with aq. 16% strength. HCl, diluted with 25 mL of water, and extracted with EA (3×50 mL). Following combination of the organic phases, they were washed with water and sat. aq. NaCl solution, dried over MgSO4 and concentrated in vacuo. The resulting residue was purified by column chromatography (silica gel: mesh 100-200, eluent: 10% EA in cyclohexane) and yielded 5.9 g (44.9%) of the desired product.