Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:4][C:3](=[CH:5][C:6]#[N:7])[CH2:2]1.[C:8]1([CH2:14][NH2:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH2:14]([NH:15][C:3]1([CH2:5][C:6]#[N:7])[CH2:4][O:1][CH2:2]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NCc1ccccc1
Reactant: N#CC=C1COC1
Product: N#CCC1(NCc2ccccc2)COC1
Temperature: 60 °C
Reaction time: 5 h
Yield: 81.6 %

Procedure:
A mixture of oxetan-3-ylidene-acetonitrile (950 mg, 10 mmol) and phenylmethanamine (1.31 ml, 12 mmol) was heated with stirring at 60° C. for 5 hours under nitrogen. The mixture was concentrated in vacuo. The residue was purified by flash column (eluting with 0-50% ethyl acetate in hexane) to afford 1.65 g of 3-(benzylamino)oxetan-3-acetonitrile as a colorless oil (yield was 81.7%).
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH2:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]([CH2:14][C:15](O)=[O:16])#[N:13].CC(OC(C)=O)=O>CCOCC>[CH2:1]([N:8]1[C:12]([NH2:13])=[CH:14][C:15](=[O:16])[NH:11][C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)NCc1ccccc1
Reactant: N#CCC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Product: Nc1cc(=O)[nH]c(=O)n1Cc1ccccc1
Temperature: 77.5 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
A mixture of benzylurea (33.3 mmol), 2-cyanoacetic acid (36.63 mmol) and Ac2O (20 mL) was heated at 75-80° C. for 2 hours. After cooling to room temperature, 30 mL of Et2O was added and the resultant suspension was stirred for 1 h. The solid intermediate was filtered, suspended in a mixture of water (30 mL) and ethanol (15 mL) and heated at 80-85° C. 5 mL of 10% NaOH were slowly added. After 30 minutes, the reaction mixture was concentrated, acidified with 10% HCl and the precipitate collected by filtration (Yellow solid. Yield 70-80%).
Reaction SMILES: Cl[CH:2]([C:8](=O)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:18]([NH2:26])(=[S:25])[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1>CC(O)C>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][C:8]2[N:26]=[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[S:25][C:2]=2[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:11][CH:12]=1
Reactant: CCOC(=O)C(Cl)C(=O)Cc1ccc(Cl)cc1
Reactant: NC(=S)c1ccncc1
Solvent: CC(C)O
Product: CCOC(=O)c1sc(-c2ccncc2)nc1Cc1ccc(Cl)cc1
Yield: 35.8 %

Procedure:
To a solution of ethyl 2-chloro-4-(4-chlorophenyl)-3-oxobutanoate (70.8 g, 257 mmol) in IPA (2.96 L) was added thioisonicotinamide (71.1 g, 515 mmol) and the resulting mixture was refluxed for 3 days. The reaction was cooled and concentrated in vacuo and the residue was partitioned between DCM (300 ml) and saturated sodium bicarbonate solution (200 mL). The layers were separated and the aqueous layer was extracted with DCM (100 mL). The combined DCM layers were washed with brine (100 mL), dried over MgSO4, filtered, and concentrated in vacuo to give crude product which was purified by silica gel chromatography (ethyl acetate/DCM=0/100→40/60) followed by recrystallization from ethyl acetate/hexanes to give 33 g of the title compound as yellow crystals. (36% yield). LC/MS (FA) ES+ 359. 1H NMR (400 MHz, CDCl3) δ: 8.74-8.72 (m, 2H), 7.81-7.80 (m, 2H), 7.36-7.32 (m, 2H), 7.27-7.23 (m, 2H), 4.54 (s, 2H), 4.38 (q, 2H, J=7.2 Hz), 1.40 (t, 3H, J=7.2 Hz).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:13]([NH:15][C@H:16]([C:19]([NH:21][C@H:22]([C:38]([NH:40][C@H:41]([C:47]([OH:49])=[O:48])[CH2:42][CH2:43][C:44](=[O:46])[OH:45])=[O:39])[CH2:23][CH2:24][CH2:25][CH2:26][NH:27][S:28]([C:31]1[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=1)(=[O:30])=[O:29])=[O:20])[CH2:17][OH:18])=[O:14])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:12])[NH:8][N+]([O-])=O.C(O)(=O)C>CO.O.[Pd]>[NH2:1][C@H:2]([C:13]([NH:15][C@H:16]([C:19]([NH:21][C@H:22]([C:38]([NH:40][C@H:41]([C:47]([OH:49])=[O:48])[CH2:42][CH2:43][C:44](=[O:45])[OH:46])=[O:39])[CH2:23][CH2:24][CH2:25][CH2:26][NH:27][S:28]([C:31]1[CH:32]=[CH:33][C:34]([CH3:35])=[CH:36][CH:37]=1)(=[O:30])=[O:29])=[O:20])[CH2:17][OH:18])=[O:14])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:12]
Reactant: Cc1ccc(S(=O)(=O)NCCCC[C@H](NC(=O)[C@H](CO)NC(=O)[C@H](CCCNC(=N)N[N+](=O)[O-])NC(=O)OCc2ccccc2)C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1
Agent: [Pd]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)NCCCC[C@H](NC(=O)[C@H](CO)NC(=O)[C@@H](N)CCCNC(=N)N)C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1
Reaction time: 36 h

Procedure:
2.00 Grams of Z-Arg(NO2)-Ser-Lys(Tos)-Glu-OH was suspended in a mixture of 30 ml of methanol with 30 ml of 50%-acetic acid and a small amount of palladium black was added thereto and the mixture was stirred for 36 hours under introducing hydrogen gas. After the reaction was completed, the catalyst was removed by filtration in vacuo, and the filtrate was distilled under a reduced pressure to obtain residue, then the residue was poured into water and was lyophilized. In 18 hours after the lyophilization, the lyophilized product was dissolved in water, then again the solution was lyophilized to obtain the desired product.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][C:8]([NH:12][C:13]1[N:14]=[CH:15][C:16]([C:19]#[N:20])=[N:17][CH:18]=1)=[CH:7]2.[NH:21]1[CH:25]=[CH:24][C:23](B(O)O)=[N:22]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:21]1[CH:25]=[CH:24][C:23]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[CH:10]=[N:9][C:8]([NH:12][C:13]2[N:14]=[CH:15][C:16]([C:19]#[N:20])=[N:17][CH:18]=2)=[CH:7]3)=[N:22]1
Reactant: OB(O)c1cc[nH]n1
Reactant: N#Cc1cnc(Nc2cc3cccc(Br)c3cn2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cnc(Nc2cc3cccc(-c4cc[nH]n4)c3cn2)cn1
Temperature: 140 °C
Yield: 30 %

Procedure:
A mixture of 5-(8-bromoisoquinolin-3-ylamino)pyrazine-2-carbonitrile (65 mg, 0.20 mmol), 1H-pyrazol-3-yl boronic acid (33 mg, 0.30 mmol) and aqueous sodium carbonate (0.5M, 0.60 mL, 0.30 mmol) in DMF (2 mL) was degassed for 15 minutes before the addition of tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.10 mmol). The mixture was further degassed for 5 minutes and then heated to 140° C. for 20 minutes in a microwave reactor. The cooled mixture was partitioned between ethyl acetate and water. The aqueous layer was further extracted with ethyl acetate and the combined organics were washed with water and brine, dried (Na2SO4), and passed sequentially through two PS-Thiol cartridges. The eluent was concentrated to a yellow solid which was dissolved in methanol and purified by SPE on a MP-TsOH cartridge, eluting with 2 M ammonia in methanol. Concentration of the eluent gave the required product as a light yellow solid (18 mg, 0.06 mmol, 29%). 1H NMR (DMSO, 400 MHz) δ 13.25 (br s, 1H), 11.10 (br s, 1H), 10.00 (s, 1H), 8.84 (s, 1H), 8.72 (s, 1H), 8.55 (s, 1H), 7.80-8.00 (m, 2H), 7.70-7.80 (m, 2H), 6.80 (s, 1H). LCMS (2) Rt=2.46 min, m/z (ESI+) 314 (MH+).
Reaction SMILES: C([O:3][C:4](=O)/[CH:5]=[CH:6]/[CH2:7][CH2:8][C:9]([F:12])([F:11])[F:10])C.[H-].C([Al+]CC(C)C)C(C)C.Cl>C(OCC)C.CCCCCC>[F:10][C:9]([F:12])([F:11])[CH2:8][CH2:7][CH2:6]/[CH:5]=[CH:4]/[OH:3]
Reactant: CCOC(=O)/C=C/CCC(F)(F)F
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCOCC
Solvent: CCCCCC
Product: O/C=C/CCCC(F)(F)F

Procedure:
A solution of 10 g of 6,6,6-trifluoro-2-transhexenoic acid ethyl ester (see above) in 70 ml of diethyl ether is cooled to 0°-5° and at this temperature 102 ml of 1M diisobutylaluminium hydride solution in hexane are added. The reaction mixture is then stirred for 5 minutes at 0°-5° and carefully hydrolysed with approx. 200 ml of 6N hydrochloric acid. The organic phase is separated off and the aqueous phase is extracted a further 3 times with ether. The combined organic phases are dried over MgSO4, and concentrated by evaporation. Chromatography of the residue on silica gel with hexane/ethyl acetate (7:3) yields the title compound in the form of a colourless liquid.
Reaction SMILES: C([O:4][C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11](Cl)=[O:12])=[CH:7][C:6]=1[O:16][CH3:17])(=O)C.[NH:18]1[CH2:23][CH2:22][CH:21]([C:24]([OH:26])=[O:25])[CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+].Cl>C(OCC)(=O)C>[OH:4][C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]([OH:26])=[O:25])[CH2:20][CH2:19]2)=[O:12])=[CH:7][C:6]=1[O:16][CH3:17]
Reactant: COc1cc(C=CC(=O)Cl)ccc1OC(C)=O
Reactant: O=C(O)C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COc1cc(C=CC(=O)N2CCC(C(=O)O)CC2)ccc1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.6 %

Procedure:
8.1 g of 4-acetoxy-3-methoxycinnamoyl chloride and 15 g of 4-piperidinecarboxylic acid were added to 200 ml of saturated aqueous potassium carbonate. The solution was stirred for 4 hours at room temperature. After reaction, 2N hydrochloric acid was added to the reaction solution, acidifying the solution. 50 ml of ethyl acetate was added to the solution, and the solution was stirred for 1 hour. The crystal precipitated was filtered out and recrystallized from ethyl acetate/hexane, yielding 5.4 g of 1-(4-hydroxy-3-methoxycinnamoyl)piperidine-4-carboxylic acid (a compound of the present invention) as white crystal, which had the following physiochemical properties:
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].Cl[C:12]1[N:17]=[N:16][C:15]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>[Br-].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[Pd+]>[CH3:10][C:8]1[N:9]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[S:6][C:7]=1[C:12]1[N:17]=[N:16][C:15]([NH:18][S:19]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)(=[O:20])=[O:21])=[CH:14][CH:13]=1
Reactant: O=S(=O)(Nc1ccc(Cl)nn1)c1ccccc1
Reactant: CC(=O)Nc1nc(C)cs1
Agent: [Pd+]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Product: CC(=O)Nc1nc(C)c(-c2ccc(NS(=O)(=O)c3ccccc3)nn2)s1
Temperature: 150 °C
Yield: 19.9 %

Procedure:
A mixture of 2-acetamido-4-methylthiazole (78 mg), N-(6-chloropyridazin-3-yl)benzenesulfonamide (80 mg), potassium carbonate (374 mg), palladium (I) tri-tert-butylphosphine bromide dimer (commercially available from Alfa Aesar (Johnson-Matthey company); 241 mg) and DMSO (5 mL) was purged with nitrogen. The resultant mixture was heated to 150° C. for 30 minutes. The mixture was cooled to room temperature, filtered and purified directly by preparative HPLC. There was thus obtained the title compound as a solid (23 mg); 1H NMR Spectrum: (DMSOd6) 2.15 (s, 3H), 2.46 (s, 3H), 7.53-7.60 (m, 3H), 7.78 (m, 1H), 7.86-7.88 (m, 2H), 7.95-7.97 (br d, 1H); Mass Spectrum: M+H+ 390.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.[F:23][C:24](=[C:34]1[CH2:37][N:36]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:35]1)[S:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:27])=[O:26].N12CCCN=C1CCCCC2.C(#N)C>>[F:23][CH:24]([S:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:26])=[O:27])[C:34]1([N:1]2[CH:5]=[C:4]([C:6]3[C:7]4[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=4[N:9]=[CH:10][N:11]=3)[CH:3]=[N:2]2)[CH2:35][N:36]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:37]1
Reactant: CC(C)(C)OC(=O)N1CC(=C(F)S(=O)(=O)c2ccccc2)C1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC(C(F)S(=O)(=O)c2ccccc2)(n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.1 %

Procedure:
A mixture of 4-(1H-pyrazol-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (0.40 g, 1.3 mmol), tert-butyl 3-[fluoro(phenylsulfonyl)methylene]azetidine-1-carboxylate (0.56 g, 1.7 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.182 mL, 1.22 mmol) in acetonitrile (6 mL, 100 mmol) was stirred at rt for 3 h. After evaporation to dryness, the residue was purified on silica gel, eluting with 0 to 100% EtOAc in hexane, to give the desired product (820 mg, 100%). LCMS calculated for C30H40FN6O5SSi(M+H)+: m/z=643.3; Found: 643.4. 1H NMR (CDCl3, 300 MHz) δ 8.92 (1H, s), 8.55 (1H, s), 8.32 (1H, s), 7.87 (2H, m), 7.68 (1H, m), 7.55 (2H, m), 7.47 (1H, d, J=3.6 Hz), 6.84 (1H, d, J=3.6 Hz), 5.77 (1H, d, J=45.6 Hz), 5.74 (2H, s), 4.93 (1H, d, J=10.2 Hz), 4.73˜4.58 (3H, m), 3.60 (2H, t, J=8.1 Hz), 1.51 (9H, s), 0.98 (3H, t, J=8.1 Hz), 0.07 (9H, s) ppm. 19F NMR (CDCl3, 300 MHz) δ −181.84 (1F, d, J=48.6 Hz) ppm.
Reaction SMILES: C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]2[N:26]([CH3:27])[C:25](=[O:28])[O:24][CH2:23][CH2:22][C:21]=2[CH:29]=1.[CH2:30]([O:33][C:34]1[CH:39]=[C:38]([N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)[CH:37]=[C:36]([F:46])[C:35]=1[NH:47][C:48]1[C:53]([Cl:54])=[CH:52][N:51]=[C:50](Cl)[N:49]=1)[CH:31]=[CH2:32].C(=O)([O-])[O-].C(=O)(O)[O-].[Na+].ClC(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O.NC1C=CC=CC=1>C(O)(C)C.O1CCOCC1.CCOC(C)=O.O>[CH2:30]([O:33][C:34]1[CH:39]=[C:38]([N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)[CH:37]=[C:36]([F:46])[C:35]=1[NH:47][C:48]1[C:53]([Cl:54])=[CH:52][N:51]=[C:50]([NH:16][C:17]2[CH:18]=[CH:19][C:20]3[N:26]([CH3:27])[C:25](=[O:28])[O:24][CH2:23][CH2:22][C:21]=3[CH:29]=2)[N:49]=1)[CH:31]=[CH2:32]
Reactant: C=CCOc1cc(N2CCOCC2)cc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CN1C(=O)OCCc2cc(N)ccc21
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])O
Solvent: Nc1ccccc1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: C=CCOc1cc(N2CCOCC2)cc(F)c1Nc1nc(Nc2ccc3c(c2)CCOC(=O)N3C)ncc1Cl

Procedure:
10-Camphorsulfonic acid (3.4 mg, 0.015 mmol), 2-Amino-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one (28 mg, 0.15 mmol), and (2-Allyloxy-6-fluoro-4-morpholin-4-yl-phenyl)-(2,5-dichloro-pyrimidin-4-yl)-amine (59 mg, 0.15 mmol) in Isopropyl alcohol (3 mL) was irradiated in a CEM microwave (120° C., 30 min). The solution was neutralized by the addition of MP-Carbonate (2.69 mmol/g loading; 0.10 g, 0.269 mmol), filtered and conc. in vacuo. The resultant oil was chromatographed (ISCO, 12 g SiO2, 0-100% EtOAc:Hex) to afford the product as the second eluting peak. The isolated product was contaminated in a 1:1 ratio with remaining 2-Amino-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one as determined by 1H-NMR. The mixture of product and 2-Amino-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one (32 mg) was dissolved in dioxane (5 mL) and aq. satd. sodium bicarbonate (1 mL) was added. 9-Fluorenylmethyl chloroformate (21 mg, 0.081 mmol) was added, and the mixture was stirred under an atmosphere of Nitrogen. HPLC/LCMS showed FMOC-incorporation onto the impurity aniline. A second aliquot of 9-Fluorenylmethyl chloroformate (42 mg, 0.16 mmol) was added and stirred for an additional 48 h. The solution was diluted with EtOAc (10 mL) and water (5 mL). The layers were separated, the aq. extracted with 5 mL DCM, and the combined organics dried over sodium sulfate, then conc. onto 1.5 g SiO2. Chromatography (ISCO, 12 g, 0-85% EtOAc:Hex) afforded 4 major peaks, the last eluting at 80% being 2-[4-(2-Allyloxy-6-fluoro-4-morpholin-4-yl-phenylamino)-5-chloro-pyrimidin-2-ylamino]-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one as a beige foam (14 mg, 17%). LCMS: 555 (M+H); 1H-NMR (CDCl3): 8.01 (s, 1H), 7.50 (s, 1H), 7.15 (d, 1H, J=8.9 Hz), 6.93 (d, 1H, J=8.1 Hz), 6.86 (s, 1H), 5.92 (m, 1H), 5.30 (d, 1H, J=17.0 Hz), 5.21 (d, 1H, J=10.6 Hz), 4.52 (m, 2H), 4.41 (t, 2H, J=6.3 Hz), 3.86 (m, 4H), 3.34 (s, 3H), 3.16 (m, 4H), 2.78 (t, 2H, J=6.3 Hz).
Reaction SMILES: [NH2:1][C:2]12[CH2:8][C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.Br[CH2:15][C:16]([N:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[C:23]#[N:24])=[O:17]>>[CH2:12]([O:11][C:9]([C:5]12[CH2:8][C:2]([NH:1][CH2:15][C:16]([N:18]3[CH2:22][CH2:21][CH2:20][C@H:19]3[C:23]#[N:24])=[O:17])([CH2:3][CH2:4]1)[CH2:7][CH2:6]2)=[O:10])[CH3:13]
Reactant: CCOC(=O)C12CCC(N)(CC1)C2
Reactant: N#C[C@@H]1CCCN1C(=O)CBr
Product: CCOC(=O)C12CCC(NCC(=O)N3CCC[C@H]3C#N)(CC1)C2
Yield: 91.1 %

Procedure:
In a similar manner to Example 6, ethyl 4-aminobicyclo[2.2.1]heptane-1-carboxylate (50.0 mg) and (2S)-1-(2-bromoacetyl)pyrrolidine-2-carbonitrile (59.3 mg) were used to obtain (2S)-1-[[N-(4-ethoxycarbonylbicyclo[2.2.1]hept-1-yl)amino]acetyl]pyrrolidine-2-carbonitrile (79.4 mg).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[C@H:19]([CH2:24][C:25]4[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=4)[C:28]([O:30]C)=[O:29])[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C.O1CCCC1>[C:1]1([C:7]2[N:8]=[C:9]([C:18]3[C@H:19]([CH2:24][C:25]4[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=4)[C:28]([OH:30])=[O:29])[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cccc(C[C@@H]2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1cccc(C[C@@H]2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reaction time: 24 h
Yield: 96.3 %

Procedure:
To a solution of methyl (S)-3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}benzoate (0.3 g) in a mixture of ethanol (8 ml) and tetrahydrofuran (5 ml) was added 1N-sodium hydroxide solution (3.5 ml). After stirring the mixture for 24 hours at the same temperature, the solvent was removed. The residue was partitioned between EtOAc and 1N-hydrochloric acid, and the organic layer was washed with brine. The dried solvent was evaporated in vacuo and the obtained solid was washed with a mixture hexane and ether to afford (S)-3-{[2-(4,5-diphenyl-oxazol-2-yl)-2-cyclohexen-1-yl]methyl}benzoic acid (0.28 g).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:17][N:16]=[CH:15][C:14]=3[CH2:18][CH2:19][C:20](OC)=[O:21])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[C:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:17][N:16]=[CH:15][C:14]=3[CH2:18][CH2:19][CH2:20][OH:21])=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CCc1cnoc1-c1ccc(-c2ccccc2)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: OCCCc1cnoc1-c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.2 %

Procedure:
To a solution of methyl 3-[5-(4-phenylphenyl)-4-isoxazolyl]propionate (1.00 g) in tetrahydrofuran (25 ml) was gently added diisobutylaluminum hydride (1.0 M hexane solution, 8.0 ml) at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and 3-[5-(4-phenylphenyl)-4-isoxazolyl]propan-1-ol (0.656 g, yield 72%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 94–95° C.
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[C:12]([C:13](Cl)=[O:14])=[C:11]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]>O1CCOCC1>[NH2:1][C:13]([C:12]1[C:3]([Cl:2])=[C:4]([CH:9]=[CH:10][C:11]=1[S:16]([CH3:19])(=[O:18])=[O:17])[C:5]([O:7][CH3:8])=[O:6])=[O:14]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C(=O)Cl)c1Cl
Reactant: N
Solvent: C1COCCO1
Product: COC(=O)c1ccc(S(C)(=O)=O)c(C(N)=O)c1Cl

Procedure:
Ammonia was passed for 2 hours into a solution of 15.0 g (48 mmol) of methyl 2-chloro-3-chlorocarbonyl-4-methylsulfonylbenzoate and 300 ml of dry dioxane. The precipitate formed was filtered off with suction and the filtrate was concentrated. This gave 15.2 g of methyl 3-aminocarbonyl-2-chloro-4-methylsulfonylbenzoate in quantitative yield.
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].C=CCC.S(=O)(=O)(O)O.O.[C:15](O)([CH3:18])([CH3:17])[CH3:16]>>[CH3:4][C:2]([CH2:3][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH2:1].[CH3:3][C:2](=[CH2:1])[CH3:4]
Reactant: CC(C)(C)O
Agent: C=C(C)C
Agent: C=CCC
Agent: O=S(=O)(O)O
Solvent: O
Product: C=C(C)CC(C)(C)C
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Into a 300 ml pressure-resistant glass autoclave were charged 10 g of isobutylene, 10 g of 1-butene, 50 g of sulfuric acid and 50 g of water, and the mixture was stirred at 60° C. at a pressure of 8.5 atms for one hour. As a result, isobutylene was hydrated to form tert-butanol with the conversion of 90% and the selectivity to tert-butanol of 92%. At the same time, diisobutylene and the trimer of isobutylene were produced at a yield of 2% and 6%, respectively, and 1-butene was hydrated to form sec-butanol at a yield of 4%.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:6][C:7]([NH:15][C:16]([C:18]1[S:41][C:21]2[N:22](C(OCC)=O)[N:23]=[C:24]([NH:25][C:26](=[O:35])[C:27]3[CH:32]=[CH:31][C:30]([CH2:33]Cl)=[CH:29][CH:28]=3)[C:20]=2[CH:19]=1)=[O:17])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8]>C(O)C>[CH3:8][C:7]([NH:15][C:16]([C:18]1[S:41][C:21]2[NH:22][N:23]=[C:24]([NH:25][C:26](=[O:35])[C:27]3[CH:32]=[CH:31][C:30]([CH2:33][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:29][CH:28]=3)[C:20]=2[CH:19]=1)=[O:17])([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH3:6]
Reactant: CCOC(=O)n1nc(NC(=O)c2ccc(CCl)cc2)c2cc(C(=O)NC(C)(C)c3ccccc3)sc21
Reactant: C1CCNC1
Solvent: CCO
Product: CC(C)(NC(=O)c1cc2c(NC(=O)c3ccc(CN4CCCC4)cc3)n[nH]c2s1)c1ccccc1
Temperature: 79 °C
Reaction time: 1 h
Yield: 33.9 %

Procedure:
Pirrolidine (1.81 mL, 21.8 mmol), was added to a suspension of ethyl 5-{[(1-methyl-1-phenylethyl)amino]carbonyl}-3-[(4-chloromethyl-benzoyl)amino]-1H-thieno[2,3-c]pyrazole-1-carboxylate (3.80 mg, 7.25 mmol) in 100 mL of dry ethanol. And the resulting mixture was stirred at 79° C. for 1 hour. Afterward the volatiles were removed by evaporation under reduced pressure and the residue was purified by chromatography over silica gel (eluant dichloromethane/methyl alcohol/aqueous ammonia 92:8:01) to give 1.2 g of the title compound.