Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)=[N:11][N:12]=2)=[CH:4][CH:3]=1.[CH:21]1[C:33]2[NH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]=2[CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:30]1[C:31]2[N:32]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:9][C:10]([C:13]5[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=5)=[N:11][N:12]=4)=[CH:4][CH:3]=3)[C:33]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:26]=2[CH:27]=[CH:28][CH:29]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: COc1cccc(-c2nnc(-c3ccc(I)cc3)o2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(-c2nnc(-c3ccc(-n4c5ccccc5c5ccccc54)cc3)o2)c1
Reaction time: 4 h

Procedure:
To a solution of 2-(4-iodophenyl)-5-(3-methoxyphenyl)-1,3,4-oxadiazole (3.0 g, 7.93 mmol), carbazole (1.5 g, 8.97 mmol), Cu (2.0 g, 31.47 mmol) in DMF (20.0 ml) was added potassium carbonate (4.0 g, 28.94 mmol) under nitrogen and stirring. Heating was started. The reaction was carried out at 150° C. for 4 h. After cooling, the reaction mixture was filtrated. The solid residues were carefully washed with THF. THF was evaporated from the combined filtration solution, Water (200.0 ml) was added, the yellow solid product was obtained by filtration. The crude product was purified by silica gel column chromatography using dichloromethane/ethyl acetate (9.5:0.5) as eluent. After evaporating solvent, the white solid was recrystallized from acetone/water and finally dried under vacuum. Pure product was obtained as white solid in 3.2 g (96.7%) yield. 1H NMR (400 MHz, CDCl3, δ): 8.38 (m, 2H), 8.16 (d, J=8.0 Hz, 2 Hz), 7.81-7.72 (m, 4H), 7.52-7.43 (m, 5H), 7.33 (m, 2H), 7.12 (m, 1H). 13C NMR (100 MHz, CDCl3, δ): 164.72, 164.02, 159.99, 140.90, 140.21, 130.28, 128.58, 127.21, 126.21, 124.88, 123.76, 122.40, 120.57, 120.48, 119.33, 118.29, 111.61, 109.68, 94.23, 55.55. [M]+ calcd for C27H19N3O2, 417.2. found 417.1.
Reaction SMILES: N.C([S:5][CH2:6][CH2:7][C:8]([N:10]1[CH:14]([C:15]([OH:17])=[O:16])[CH2:13][C:12]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[N:11]1)=[O:9])(=O)C>>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:12]1[CH2:13][CH:14]([C:15]([OH:17])=[O:16])[N:10]([C:8](=[O:9])[CH2:7][CH2:6][SH:5])[N:11]=1
Reactant: CC(=O)SCCC(=O)N1N=C(c2ccccn2)CC1C(=O)O
Agent: N
Product: O=C(O)C1CC(c2ccccn2)=NN1C(=O)CCS
Reaction time: 2 h

Procedure:
Aqueous ammonia (12 ml of 7 N) is stirred at 0°-5° C. under argon and 3.5 g of (±)-1-[3-(acetylthio)-1-oxopropyl]-3-(2-pyridyl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid is added. The resulting solution is stirred for 2 hours under argon and is then extracted with ethyl acetate (discarded). The aqueous layer is acidified with acetic acid and extracted with ethyl acetate (three 50 ml portions). The combined organic layers are washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to yield the title compound.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].CC1(C)C(C)(C)OB([C:19]2[CH2:24][CH2:23][CH2:22][CH:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:20]=2)O1.C([O-])([O-])=O.[Na+].[Na+].C([O-])(=O)C.[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C>[CH3:7][N:6]1[C:2]([C:19]2[CH2:24][CH2:23][CH2:22][CH:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH:20]=2)=[C:3]([N+:8]([O-:10])=[O:9])[CH:4]=[N:5]1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Reactant: CC(C)(C)OC(=O)NC1C=C(B2OC(C)(C)C(C)(C)O2)CCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: Cn1ncc([N+](=O)[O-])c1C1=CC(NC(=O)OC(C)(C)C)CCC1
Temperature: 25 °C
Yield: 49 %

Procedure:
5-Chloro-1-methyl-4-nitropyrazole (100 mg, 0.62 mmol), tert-butyl N-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-2-en-1-yl]carbamate (240 mg, 0.74 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (45 mg, 0.061 mmol), a 1M solution of Na2CO3 (0.93 mL), a 1M solution of potassium acetate (0.93 mL) and acetonitrile (6 mL) were charged in a microwave reaction vial, The mixture was irradiated to 140° C. with a microwave for 30 min and cooled to room temperature. It was filtered through Celite and thoroughly washed with methanol. The filtrate was concentrated and the residue was purified via flash chromatography, 0 to 100% ethyl acetate in heptane to give tert-butyl N-[3-(2-methyl-4-nitro-pyrazol-3-yl)cyclohex-2-en-1-yl]carbamate (98 mg, 49%)
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17](OCC2C=CC=CC=2)=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27](OC(N1CCNCC1)=O)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]([N:11]([CH2:12][CH3:13])[CH2:16][CH2:15][NH:14][CH2:17][CH3:27])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CCN(C(=O)OCc2ccccc2)CC1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Product: CCNCCN(CC)C(=O)OCc1ccccc1

Procedure:
Following substantially the same procedure as described in Examle 32, except that N,N'dibenzyloxycarbonylpiperazine was used as starting material, N-benzyloxycarbonylpiperazine was prepared.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.O=[C:13]([CH2:19][CH3:20])[CH2:14][C:15]([O:17][CH3:18])=[O:16].C1(C)C=CC=CC=1.C(O)(=O)C>O>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:13]([CH2:19][CH3:20])=[CH:14][C:15]([O:17][CH3:18])=[O:16])=[CH:5][CH:4]=1
Reactant: CCC(=O)CC(=O)OC
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCC(=CC(=O)OC)Nc1ccc(C(F)(F)F)cc1
Reaction time: 4.5 h
Yield: 72.8 %

Procedure:
In a IL-flask were placed 4-trifluoromethylaniline (161 g, 1.00 mol), methyl 3-oxopentanoate (130 g, 1.00 mol) and toluene (160 mL). To this solution was added acetic acid (16 g, 0.27 mol), and the resulting mixture was heated in a bath kept at 100° C. under a reduced pressure of 19 kPa for 3.5 hours, while the water generated was taken out of the reaction system by using a Dean-Stark trap under reflux. Acetic acid (16 g, 0.27 mol) was then added, and reflux was continued for 4.5 hours. Acetic acid (8 g, 0.13 mol) was then added again, and reflux was continued for another 2.5 hours. The heating was then discontinued, nitrogen leaked in, and the reaction mixture cooled. After distillation of the solvent and acetic acid under reduced pressure, the residue was distilled under reduced pressure to give 199 g of the title compound. The yield was 72.8%. The 1H-NMR spectrum was identical to that of Example 1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]#[C:12][C:13]1[C:18]([CH3:19])=[CH:17][N:16]=[C:15]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([CH:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]3)=[N:25][CH:26]=2)[N:14]=1>CN(C=O)C.CCN(CC)CC.[Pd]>[CH3:1][O:2][C:3](=[O:40])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][C:13]1[C:18]([CH3:19])=[CH:17][N:16]=[C:15]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([CH:27]3[CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])[CH2:31][CH2:32]3)=[N:25][CH:26]=2)[N:14]=1
Reactant: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)nc2)ncc1C
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)nc2)ncc1C
Temperature: 25 °C
Reaction time: 44 h

Procedure:
A suspension of 10% Pd/C (53% water; 30 mg) and tert-butyl 4-(5-((4-((2-(2-methoxy-2-oxoethyl)phenyl)ethynyl)-5-methylpyrimidin-2-yl)amino)pyridin-2-yl)piperidine-1-carboxylate (A17) (125 mg, 0.231 mmol) in DMF (5 mL) and Et3N (1 mL) was stirred under a hydrogen atmosphere at room temperature for 44 hours. The resulting mixture was filtered through Celite, washing with EtOAc (200 mL). The combined filtrates were evaporated in vacuo and the resulting oil purified by silica gel chromatography (Biotage Isolera, 12 g SiO2 cartridge, 0-100% EtOAc in hexanes) to give the title compound A18 as a yellow foam (115 mg, 91%); 1H NMR (400 MHz, CDCl3) δ 8.62 (d, J=2.5 Hz, 1H), 8.16 (dd, J=8.5, 2.7 Hz, 1H), 8.11 (d, J=0.5 Hz, 1H), 7.25-7.16 (m, 5H), 7.11 (d, J=8.5 Hz, 1H), 4.25 (br. s, 2H), 3.71 (s, 2H), 3.67 (s, 3H), 3.09 (dd, J=9.6, 6.1 Hz, 2H), 2.93 (dd, J=9.4, 6.0 Hz, 2H), 2.88-2.76 (m, 3H), 2.08 (s, 3H), 1.91 (d, J=11.8 Hz, 2H), 1.75-1.61 (m, 2H), 1.47 (s, 9H). LCMS-A: rt 5.401 min; m/z 546 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=1)[O:13][CH2:14][C:15](O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:27][N:28]=[C:29]([C:31]1[CH:47]=[CH:46][C:34]([C:35]([O:37][CH2:38][CH2:39][CH2:40][CH:41]2[O:45][CH2:44][CH2:43][O:42]2)=[O:36])=[CH:33][CH:32]=1)[NH2:30]>C(#N)C.N1C=CC=CC=1.[Cl-].[Na+].O>[C:1]([O:5][C:6]([NH:8][CH:9]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=1)[O:13][CH2:14][C:15]1[O:27][N:28]=[C:29]([C:31]2[CH:32]=[CH:33][C:34]([C:35]([O:37][CH2:38][CH2:39][CH2:40][CH:41]3[O:42][CH2:43][CH2:44][O:45]3)=[O:36])=[CH:46][CH:47]=2)[N:30]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC(c1ccccc1)c1cccc(OCC(=O)O)c1
Reactant: NC(=NO)c1ccc(C(=O)OCCCC2OCCO2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC(c1ccccc1)c1cccc(OCc2nc(-c3ccc(C(=O)OCCCC4OCCO4)cc3)no2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(3-(((tert-butoxycarbonyl)amino)(phenyl)methyl)phenoxy)-acetic acid (0.087 g. 0.34 mmol) and 3-(1,3-dioxolan-2-yl)propyl 4-(N′-hydroxy-carbamimidoyl)benzoate (0.10 g, 0.28 mmol) in acetonitrile (1 mL), was added 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (0.087 g, 0.42 mmol). The reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was diluted with pyridine and heated at 150° C. for 30 minutes in a microwave. The reaction was diluted with saturated brine and extracted with ethyl acetate (×3). The combined organic fractions were dried with magnesium sulfate, and the solvent evaporated at reduced pressure. The material was used directly in the next step without further purification (0.142 g, 87%).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:11]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:12]2)[CH2:10][CH2:9][C:8](=[O:19])[C:7]=3[CH3:20])=[CH:4][C:3]=1[F:21].[Br:22]N1C(=O)CCC1=O.O.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[NH2:1][C:2]1[C:14]([Br:22])=[C:13]2[C:5]([C:6]3[C:11]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:12]2)[CH2:10][CH2:9][C:8](=[O:19])[C:7]=3[CH3:20])=[CH:4][C:3]=1[F:21]
Reactant: CCCCC12CCC(=O)C(C)=C1c1cc(F)c(N)cc1C2
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC12CCC(=O)C(C)=C1c1cc(F)c(N)c(Br)c1C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.5 %

Procedure:
A solution of 7-amino-9a-butyl-6-fluoro4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (0.138 g, 0.481 mmol) in anhydrous N,N-dimethylformamide (4.8 mL) was cooled in an ice bath, placed under a nitrogen atmosphere, treated with N-bromosuccinimide (0.94 g, 0.53 mmol), and stirred at room temperature for 30 minutes. The reaction mixture was poured into a water solution of 10% K2CO3 and extracted with EtOAc. The organic layer was washed with water and evaporated under vacuum. The crude product was purified by preparative layer chromatography on a 0.05×20×20 cm silica gel GF plate, developing with 20% EtOAc in hexanes, to afford 7-amino-8-bromo-9a-butyl-6-fluoro-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (0.089 g, 50%) as a yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:40])[C@@H:4]([O:9][CH2:10][C@@H:11]1[CH2:15][C@@H:14]([S:16][C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][N:12]1[S:36]([CH3:39])(=[O:38])=[O:37])[CH2:5][CH:6]([CH3:8])[CH3:7]>CCO.C1COCC1>[CH3:39][S:36]([N:12]1[CH2:13][C@H:14]([S:16][C:17]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:15][C@H:11]1[CH2:10][O:9][C@@H:4]([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]([OH:40])=[O:2])(=[O:37])=[O:38]
Reactant: COC(=O)[C@H](CC(C)C)OC[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1S(C)(=O)=O
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)C[C@H](OC[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1S(C)(=O)=O)C(=O)O

Procedure:
Hydrolysis in EtOH/THF (see General method for hydrolysis of an ester): (R)- or (S)-2-[(2S,4R)-1-methanesulfonyl-4-tritylsulfanyl-pyrrolidin-2-ylmethoxy]-4-methyl-pentanoic acid methyl ester gave (R)- or (S)-2-[(2S,4R)-1-methanesulfonyl-4-tritylsulfanyl-pyrrolidin-2-ylmethoxy]-4-methyl-pentanoic acid, MS: 568 (MH+); and (S)- or (R)-2-[(2S,4R)-1-methanesulfonyl-4-tritylsulfanyl-pyrrolidin-2-ylmethoxy]-4-methyl-pentanoic acid methyl ester gave (R)- or (S)-2-[(2S,4R)-1-Methanesulfonyl-4-tritylsulfanyl-pyrrolidin-2-ylmethoxy]-4-methyl-pentanoic acid, MS: 568 (MH+).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:19](=O)[NH:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:9][CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(C)(C)C>Cl.O1CCOCC1>[CH2:12]([O:11][CH2:10][CH2:9][C@H:8]([NH2:7])[C:19]1[N:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:22]2[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=2[N:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCOCc1ccccc1)C(=O)Nc1ccc(F)cc1Nc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H](CCOCc1ccccc1)c1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 25 °C
Yield: 68.1 %

Procedure:
A solution of [(S)-3-benzyloxy-1-(4-fluoro-2-phenylaminophenylcarbamoyl)propyl]carbamic acid tert-butyl ester (1.22 g, 2.5 mmol) in 4M HCl in dioxane (10 mL) was heated at 70° C. for 2 h. After cooling to RT, the volatiles were concentrated in vacuo and the residue partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic fraction was washed with brine, dried (MgSO4) and then concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM) to afford the title compound as a colourless oil (639 mg, 68%). LCMS (Method B): RT 2.11 and 2.55 min [M+H]+ 376.2.
Reaction SMILES: [C:1]([O:9]CC)(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[F:12][C:13]1[CH:14]=[C:15]([Mg]Br)[CH:16]=[CH:17][C:18]=1[F:19].[Cl-].[NH4+]>O1CCCC1>[F:12][C:13]1[CH:14]=[C:15]([C:1]([C:16]2[CH:15]=[CH:14][C:13]([F:12])=[C:18]([F:19])[CH:17]=2)([C:2]2[CH:3]=[CH:4][N:5]=[CH:6][CH:7]=2)[OH:9])[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: Fc1ccc([Mg]Br)cc1F
Reactant: CCOC(=O)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(c1ccncc1)(c1ccc(F)c(F)c1)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a magnetically stirred solution of ethyl isonicotinate in dry tetrahydrofuran at 0° C. and under an atmosphere of nitrogen is slowly added a solution 2.2 equivalents of 3,4-difluorophenyl magnesium bromide in tetrahydrofuran. The solution is stirred at ambient temperature of 4 hr and is poured into an icy solution of ammonium chloride. The mixture is extracted with methylene chloride, and the organic phase is dried (sodium sulfate). The solvent is removed in vacuo to give a solid. This solid is recrystallized from methylene chloride/hexane to give the title compound as a white, crystalline solid, mp 147°-149° C.
Reaction SMILES: [CH3:1][C:2]([CH3:24])=[CH:3][CH2:4][CH:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:6]1=[O:23].[OH-].[Na+].O.O.O.O.O.O.O.O.O.O.O.O.P([O-])([O-])(O)=[O:40].[Na+].[Na+]>O>[C:11]1([N:8]([C:9](=[O:10])[CH:5]([CH2:4][CH:3]=[C:2]([CH3:24])[CH3:1])[C:6]([OH:23])=[O:40])[NH:7][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)=CCC1C(=O)N(c2ccccc2)N(c2ccccc2)C1=O
Reactant: O=P([O-])([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)=CCC(C(=O)O)C(=O)N(Nc1ccccc1)c1ccccc1

Procedure:
103.8 gm (0.324 mol) of 4-(3-methyl-2-butenyl)-1,2-diphenyl-3,5-dioxopyrazolidine were dissolved in a solution of 12.96 gm (0.324 mol) of sodium hydroxide pellets and 57.3 gm (0.16 mol) of disodium hydrogen phosphate dodecahydrate in 400 ml of water. The reaction mixture was heated for 30 hours in an atmosphere of nitrogen, then cooled, diluted with 600 ml of water, and filtered. The filtered solution was neutralized (pH 7 to 7.5) with 2 N hydrochloric acid and extracted several times with chloroform. The combined chloroform extracts were evaporated, leaving crude 2-(3-methyl-2-butenyl)propanedioic acid mono(1,2-diphenylhydrazide) which was dissolved in 500 ml of 10% aqueous ammonium hydroxide. To this solution a solution of 17.9 gm (0.162 mol) of calcium chloride in 50 ml of water was added while stirring.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][O:10][CH3:11].[CH3:12][O:13][C:14](=[O:43])[N:15]=[C:16]([S:41][CH3:42])[C:17]([C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([O:38][CH2:39][CH3:40])[CH:32]=1)=[N:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:29]=[C:28]([CH3:30])[O:27][N:26]=2)=[CH:21][CH:20]=1.O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.C(OCC)(=O)C>[CH3:12][O:13][C:14](=[O:43])[N:15]=[C:16]([S:41][CH3:42])[C:17]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:8][CH2:9][O:10][CH3:11])=[C:33]([O:38][CH2:39][CH3:40])[CH:32]=1)=[N:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:29]=[C:28]([CH3:30])[O:27][N:26]=2)=[CH:21][CH:20]=1
Reactant: COCCBr
Reactant: CCOc1cc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)ccc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)ccc1OCCOC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After adding 200 mg of potassium carbonate, 10 mg of tetrabutylammonium iodide and 200 mg of 1-bromo-2-methoxyethane to a solution of {2-(3-ethoxy-4-hydroxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester (Example 126a) in 1 ml of DMF, the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, extraction was performed with ethyl acetate, and the organic layers were combined and washed with 0.5 N hydrochloric acid and saturated brine in that order. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (193 mg) as a yellow solid.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:14][CH2:15][N:16]([CH2:18][CH2:19]Cl)[CH3:17]>CS(C)=O.Cl>[CH3:17][N:16]1[CH2:18][CH2:19][C:8]([C:5]2[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=2)([C:9]#[N:10])[CH2:14][CH2:15]1
Reactant: N#CCc1ccncc1
Reactant: CN(CCCl)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN1CCC(C#N)(c2ccncc2)CC1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 15.4 %

Procedure:
A solution of 4-pyridyl acetonitrile hydrochloride (1.0 g, 6.47 mmol) in DMSO (8 mL) was treated with sodium hydride (0.735 g, 29.11 mmol) portionwise. The resulting suspension was stirred at 23° C. for 30 minutes. 2-Chloro-N-(2-chloroethyl)-N-methylethanamine (1.37 g, 7.11 mmol) was then slowly added over 5 minutes, then the suspension was heated at 65° C. overnight. The reaction was then diluted with 1N hydrochloric acid and washed with ethyl acetate (2×). The aqueous phase was basified with 5N sodium hydroxide and extracted with ethyl acetate (3×). The combined extracts were washed with water (5×), dried over anhydrous magnesium sulfate, filtered and concentrated to give an oil (0.200 g, 15%) which was used as such for the next reaction. 1H NMR (400 MHz, CDCl3) δ ppm: 2.10-2.17 (3H, m), 2.31-2.37 (1H, m), 2.42 (3H, s), 2.47-2.57 (2H, m), 3.01 (2G, d, J=12.6 Hz), 7.45 (2H, dd, J=4.55 and 1.52 Hz), 8.68 (2H, dd, J=4.55 and 1.77 Hz).
Reaction SMILES: [Na+].[NH:2]1[CH:6]=[N:5][C:4]([C:7]([NH-:9])=[O:8])=[N:3]1.[C:10](Cl)(=[O:18])[C:11]1[C:12](=[CH:14][CH:15]=[CH:16][CH:17]=1)[OH:13]>C(#N)C>[C:10]([C:6]1[NH:2][N:3]=[C:4]([C:7]([NH2:9])=[O:8])[N:5]=1)(=[O:18])[C:11]1[C:12](=[CH:14][CH:15]=[CH:16][CH:17]=1)[OH:13]
Reactant: [NH-]C(=O)c1nc[nH]n1
Reactant: O=C(Cl)c1ccccc1O
Agent: [Na+]
Solvent: CC#N
Product: NC(=O)c1n[nH]c(C(=O)c2ccccc2O)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 25 ml. portion of dry acetonitrile is added to a mixture of 1.3 g. of the s-triazole carboxamide sodium salt and 2 g. of salicyloyl chloride followed by a few pellets of 4A molecular sieves. The mixture is stirred at room temperature for 16 hours and then filtered through Celite. The colorless solid is obtained on evaporating the filtrate is washed with diethyl ether; yield, 1 g., m.p. 147°-150° C. (dec.). Its infrared spectrum is essentially the same as that obtained from the product in Example 7.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[CH3:25][S:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)(=[O:28])=[O:27]>>[CH3:25][S:26]([C:29]1[CH:34]=[C:33]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=4)[CH:11]=[C:10]([CH3:24])[N:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:32]=[CH:31][CH:30]=1)(=[O:28])=[O:27]
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(Cl)n2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(S(C)(=O)=O)c3)n2)n1

Procedure:
The title compound was prepared from 2-chloro-4-[6-methyl-4-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-pyrimidine (example E.83) (0.350 g, 1.0 mmol) and commercially available (3-methylsulfonylphenyl)boronic acid (0.220 g, 1.0 mmol) according to the general procedure VI. Obtained as an off-white solid (0.280 g, 59%). MS (ISP) 470.1 [(M+H)+]; mp 208° C.
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:22]([NH:24][CH2:25][C:26]12[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[CH2:27]1)[CH2:33]2)=[O:23].[ClH:36]>CO.O1CCOCC1>[ClH:36].[Cl:36][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:22]([NH:24][CH2:25][C:26]12[CH2:33][CH:32]3[CH2:31][CH:30]([CH2:29][CH:28]([CH2:34]3)[CH2:27]1)[CH2:35]2)=[O:23]
Reactant: Cc1ccc(N2CCCN(C(=O)OC(C)(C)C)CC2)cc1C(=O)NCC12CC3CC(CC(C3)C1)C2
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(N2CCCNCC2)ccc1Cl
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Hexahydro-4-[4-methyl-3-[[(tricyclo[3.3.1.13,7]dec-1-ylmethyl)amino]carbonyl]-phenyl]-1H-1,4-diazepine-1-carboxylic acid, 1,1-dimethylethyl ester (from Example 5c) was dissolved in methanol (5 ml) and hydrochloric acid (0.5 ml of a 4N solution in dioxane) was added. After stirring at room temperature for 14 h, the mixture was evaporated to ⅔ original volume under reduced pressure. Diethyl ether was gradually added to the solution and the resulting precipitate collected by filtration, washed with diethyl ether and dried in vacuo to afford the title compound as a solid (0.027 g)