Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7]([C:9]12[CH2:26][CH:25]1[CH:24]=[CH:23][CH2:22][CH2:21][CH2:20][CH2:19][N:18]([CH3:27])[C:17](=[O:28])[CH:16]1[CH:12]([CH2:13][CH:14]([O:29][C:30]3[C:39]4[C:34](=[C:35]([CH3:42])[C:36]([O:40][CH3:41])=[CH:37][CH:38]=4)[N:33]=[C:32]([N:43]4[CH:47]=[CH:46][C:45]([CH:48]([CH3:50])[CH3:49])=[N:44]4)[N:31]=3)[CH2:15]1)[C:11](=[O:51])[NH:10]2)=[O:8])C>O.C1COCC1>[CH:48]([C:45]1[CH:46]=[CH:47][N:43]([C:32]2[N:31]=[C:30]([O:29][CH:14]3[CH2:13][CH:12]4[CH:16]([C:17](=[O:28])[N:18]([CH3:27])[CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[CH:24][CH:25]5[C:9]([C:7]([OH:8])=[O:6])([NH:10][C:11]4=[O:51])[CH2:26]5)[CH2:15]3)[C:39]3[C:34](=[C:35]([CH3:42])[C:36]([O:40][CH3:41])=[CH:37][CH:38]=3)[N:33]=2)[N:44]=1)([CH3:50])[CH3:49]
Reactant: CCOC(=O)C12CC1C=CCCCCN(C)C(=O)C1CC(Oc3nc(-n4ccc(C(C)C)n4)nc4c(C)c(OC)ccc34)CC1C(=O)N2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)nc(-n3ccc(C(C)C)n3)nc2c1C
Reaction time: 120 h

Procedure:
A solution of lithium hydroxide hydrate (796 mg, 18.6 mmol) in water (10 mL) was added to a stirred solution of the ester (145) (346 mg, 0.526 mmol) in THF (30 mL). After 5 days at room temperature, the reaction mixture was concentrated under vacuum. The pH was adjusted to 4 with 1N HCl and the resulting solution was successively extracted with AcOEt, washed with brine, dried (Na2SO4) and evaporated.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4](=O)[C:5]([CH3:8])([CH3:7])[CH3:6].[S-:10][C:11]#[N:12].[K+]>O>[C:5]([C:4]1[N:12]=[C:11]([SH:10])[NH:2][CH:3]=1)([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)C(=O)CN
Reactant: N#C[S-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: CC(C)(C)c1c[nH]c(S)n1

Procedure:
35.2 g. 1-Amino-3,3-dimethylbutan-2-one hydrochloride and 30 g. potassium thiocyanate in 50 ml. water was warmed on the steam bath for two hours. After cooling, the solid formed was collected, washed with water, dried and recrystallised from industrial methylated spirit to give 4-tert.butylimidazole-2-thiol, melting point 232°-234°C. A solution/suspension of this in industrial methylated spirit was added to a solution of 4.5 g. sodium hydroxide in 100 ml. water. 17.6 g. Ethyl iodide was added forming a lower layer and the mixture was shaken for two minutes whilst the ethyl iodide reacted and dispersed. After 20 minutes the alkali was neutralised by passing in carbon dioxide and the methylated spirit removed by evaporation. The solid was collected, washed with water, dried and on recrystallisation from toluene gave 2-ethylthio-4-tert.butylimidazole, melting point 116.5°-120°C.
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[OH2:7].[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[C:30]([O:31][C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)=[CH:29][C:19]3[NH:20][C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)=[N:22][C:18]=3[CH:17]=2)=[CH:11][N:10]=1>O1CCCC1>[CH3:14][C:13]1[CH:8]=[CH:9][N:10]=[CH:11][C:12]=1[S:15]([C:16]1[C:30]([O:31][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)=[CH:29][C:19]2[NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[N:22][C:18]=2[CH:17]=1)(=[O:1])=[O:7]
Reactant: Cc1ccc(Sc2cc3nc(-c4ccccn4)[nH]c3cc2Oc2cccnc2)cn1
Reactant: O=S([O-])OO
Reactant: O
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccncc1S(=O)(=O)c1cc2nc(-c3ccccn3)[nH]c2cc1Oc1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
92 mg of OXONE and 0.1 ml of water were added to a tetrahydrofuran (1.5 ml) solution of 42 mg of 5-(2-methyl-pyridin-5-ylsulfanyl)-2-pyridin-2-yl-6-(pyridin-3-yloxy)-1H-benzimidazole obtained in Example 13, and the reaction liquid was stirred overnight at room temperature. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through reversed-phase middle-pressure liquid chromatography [ODS-AS-360-CC (by YMC), mobile phase: water-acetonitrile-0.1% trifluoroacetic acid]. An aqueous solution of saturated sodium hydrogencarbonate was added to the resulting fraction, and this was extracted with chloroform, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure to obtain the entitled compound.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[C:4]([Cl:19])[N:3]=1.[N:20]1[C:29]2[C:24](=[CH:25][C:26]([CH2:30][NH2:31])=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1>CC#N.CCN(CC)CC>[Cl:19][C:4]1[N:3]=[C:2]([NH:31][CH2:30][C:26]2[CH:25]=[C:24]3[C:29](=[CH:28][CH:27]=2)[N:20]=[CH:21][CH:22]=[CH:23]3)[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)nc(Cl)c1[N+](=O)[O-]
Reactant: NCc1ccc2ncccc2c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1cc(Cl)nc(NCc2ccc3ncccc3c2)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 95.4 %

Procedure:
A solution of tert-butyl 2,6-dichloro-3-nitropyridin-4-ylcarbamate (1.2 g, 3.9 mmol) and quinolin-6-ylmethanamine (616 mg, 3.9 mmol) in CH3CN (15 mL) and Et3N (1 mL) was stirred at 80° C. for 1 h. After cooled to room temperature, the mixture was concentrated. The residue was purified by chromatography to afford the title compound (1.60 g). MS (m/z): 430 (M+1)+.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])=[CH:6][CH:5]=1.[C:21]([O:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@@H:29]1[CH2:33]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:27])([CH3:24])([CH3:23])[CH3:22]>CN(C=O)C>[C:21]([O:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@@H:29]1[CH2:33][O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])=[CH:8][CH:9]=1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: O=C1c2ccccc2C(=O)N1c1ccc(O)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(N2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.8 %

Procedure:
To a 25 mL vial which contained a suspension of NaH (60% in mineral oil, 30 mg, 0.75 mmol) in DMF (3 mL) was added 2-(4-Hydroxy-phenyl)-isoindole-1,3-dione (105 mg, 0.5 mmol) at 0° C. The mixture was allowed to warm to rt and stir at rt for 30 min then cooled to 0° C. To this reaction mixture was added (R)-2-(toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (173 mg, 0.5 mmol) at 0° C. The resulting mixture was allowed to warm to rt and stir at rt for 30 min and then was heated to 90° C. and stirred at 90° C. for 16 h. After cooled to it, the mixture was poured into 150 mL ice-water solution and then was extracted with EtOAc (3×50 mL). The combined organic layers were washed with water (3×50 mL), brine (30 mL) and dried over Na2SO4. After concentrated in vacuo, the residue was purified by a column chromatography on silica gel to yield the title product, (120 mg, 55%)
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([OH:15])[C@@H:11]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][CH:17]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CCCCCC.C(O)(C)C>[Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@@H:12]([OH:15])[C@H:11]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][CH:17]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: Cn1nccc1[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]1O
Solvent: CC(C)O
Solvent: CCCCCC
Product: Cn1nccc1[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@H]1O

Procedure:
The (1S*,2R*,4R*)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol prepared in Example 161a was optically resolved with CHIRALFLASH IC (Daicel Corp.; hexane/isopropanol=6:4) to yield the title compound as a colorless oil.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].[N:9]([CH2:12][C:13](OCC)=[O:14])=[C:10]=[S:11].C(N(CC)CC)C>C(#N)C>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][N:7]1[C:13](=[O:14])[CH2:12][NH:9][C:10]1=[S:11])[CH3:3]
Reactant: CCOC(=O)CN=C=S
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)CN1C(=O)CNC1=S
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.2 %

Procedure:
Glycine ethyl ester hydrochloride (140 mg, 1 mmol) and ethyl isothiocyanatoacetate (145 mg, 1 mmol) were dissolved in acetonitrile (6 mL), triethylamine (0.6 mL) was added thereto, and the mixture was stirred at room temperature (25° C.) for 10 minutes. After the reaction was completed the solvent was removed by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography using ethyl acetate/hexane (1/1 (volume ratio)) as an eluent, to give ethyl-2-(5-oxo-2-thioxoimidazolidin-1-yl)acetate in a yield of 170 mg (yield 84.2%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14](Br)[C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:27])[N:22]([CH2:24][CH2:25][OH:26])[CH3:23])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][C:37]=2B(O)O)[CH:32]=[CH:31][CH:30]=1.C([O-])([O-])=O.[K+].[K+]>CC(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:27])[N:22]([CH2:24][CH2:25][OH:26])[CH3:23])=[CH:17][CH:16]=2)[C:37]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:38]=2[N:29]=[CH:30][CH:31]=[CH:32]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cccc2cccnc12
Reactant: CN(CCO)C(=O)c1ccc(C(Br)=C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CN(CCO)C(=O)c1ccc(C(=C2CCN(C(=O)OC(C)(C)C)CC2)c2cccc3cccnc23)cc1
Yield: 74.1 %

Procedure:
Compound 1A (4.0 g, 8.8 mmol), 8-quinolineboronic acid (3.0 g, 17.6 mmol), POPd (0.088 g, 0.18 mmol), and K2CO3 (3.6 g, 26.4 mmol) in iPrOH (90 mL) were stirred in a preheated 100° C. oil bath under nitrogen for 20 h. The reaction was filtered through celite and concentrated. The material was purified by chromatography on silica gel (gradient 2-5% MeOH in CH2Cl2) to give a yellow solid 1B (3.27 g, 74%). 1H NMR (500.333 MHz, CDCl3) δ 8.91 (dd, J=4.0, 1.6 Hz, 1H), 8.13 (dd, J=8.2, 1.5 Hz, 1H), 7.74 (dt, J=9.5, 3.5 Hz, 1H), 7.50 (d, J=2.5 Hz, 2H), 7.37-7.33 (m, 5H), 3.86 (br s, 2H), 3.68 (br s, 2H), 3.59 (br s, 2H), 3.52-3.43 (m, 3H), 3.34-3.23 (m, 2H), 3.03 (s, 3H), 2.57-2.52 (m, 2H), 2.01 (dd, J=19.3, 7.6 Hz, 2H), 1.44 (s, 9H). MS ES+502.2.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:7]2[N:12]3[N:13]=[C:14]([NH2:16])[N:15]=[C:11]3[CH:10]=[C:9]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:8]=2)=[CH:5][N:6]=1.[CH2:23]([N:25]=[C:26]=[O:27])[CH3:24]>C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC.C1COCC1.C1(C)C=CC=CC=1>[CH2:23]([NH:25][C:26]([NH:16][C:14]1[N:15]=[C:11]2[CH:10]=[C:9]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:8]=[C:7]([C:4]3[O:3][C:2]([CH3:1])=[N:6][CH:5]=3)[N:12]2[N:13]=1)=[O:27])[CH3:24]
Reactant: CCN=C=O
Reactant: Cc1ncc(-c2cc(-c3cccnc3)cc3nc(N)nn23)o1
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(-c3cnc(C)o3)n2n1
Temperature: 0 °C

Procedure:
A mixture of the product of Step 1 (0.23 g, 0.787 mmol), ethyl isocyanate (0.28 g, 3.93 mmol) and a catalytic quantity of dibutyltin diacetate (3 drops) in THF/toluene (1:1, 10 mL) was heated in a sealed tube at 100° C. for 15 h. This mixture was cooled to 0° C., the solid obtained was filtered and washed with 10% CHCl3/hexanes to provide the target compound, N-ethyl-N′-[5-(2-methyl-1,3-oxazol-5-yl)-7-pyridin-3-yl[1,2,4]triazolo[1,5-a]pyridin-2-yl]urea as a solid. LCMS (APCI+) 364.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6](=[O:17])[NH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[F:18][C:19]([F:42])([F:41])[C:20]([C:26]1[CH:31]=[CH:30][C:29]([CH2:32][N:33]2[CH2:38][CH2:37][NH:36][CH2:35][C@@H:34]2[CH2:39][OH:40])=[CH:28][CH:27]=1)([OH:25])[C:21]([F:24])([F:23])[F:22].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl>[CH:1]1([CH2:4][NH:5][C:6]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]([N:36]3[CH2:37][CH2:38][N:33]([CH2:32][C:29]4[CH:30]=[CH:31][C:26]([C:20]([OH:25])([C:19]([F:18])([F:41])[F:42])[C:21]([F:24])([F:22])[F:23])=[CH:27][CH:28]=4)[C@@H:34]([CH2:39][OH:40])[CH2:35]3)=[O:14])=[CH:15][CH:16]=2)=[O:17])[CH2:2][CH2:3]1
Reactant: OC[C@H]1CNCCN1Cc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reactant: O=C(NCC1CC1)Nc1ccc(C(=O)O)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCC1CC1)Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)[C@@H](CO)C2)cc1
Reaction time: 3 h
Yield: 35.3 %

Procedure:
To a solution of 4-(3-(cyclopropylmethyl)ureido)benzoic acid (0.487 mmol, 114 mg), (R)-1,1,1,3,3,3-hexafluoro-2-(4-((2-(hydroxymethyl)piperazin-1-yl)methyl)phenyl)propan-2-ol (0.443 mmol, 165 mg) and triethylamine (1.330 mmol, 0.185 mL, 135 mg) in dichloromethane (4 mL) was added 1-propanephosphonic acid cyclic anhydride (0.665 mmol, 0.395 mL, 423 mg, 50% solution in ethyl acetate). The reaction was stirred for 3 hours and then was diluted with dichloromethane/saturated sodium hydrogen carbonate (aqueous). The organic layer was separated, dried (magnesium sulfate) and concentrated under reduced pressure. The residue was purified by silica column chromatography (eluting with ethyl acetate to 5% methanol/ethyl acetate and basic reverse phase HPLC to afford the title compound (92 mg).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22](O)[CH3:23])=[CH:18][CH:17]=1>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)[CH3:23])=[CH:18][CH:17]=1
Reactant: CC(O)c1ccc(F)cc1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: CC(Oc1ccnn1-c1cc(C#N)ccn1)c1ccc(F)cc1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and 1-(4-fluorophenyl)ethanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 1.65 (3H, d, J=6.4 Hz), 5.24 (1H, q, J=6.4 Hz), 5.44 (1H, d, J=2.0 Hz), 6.95-7.00 (2H, m), 7.27-7.30 (2H, m), 7.35 (1H, dd, J=0.8 Hz, J=5.2 Hz), 7.41 (1H, d, J=2.0 Hz), 7.97 (1H, s), 8.66 (1H, d, J=4.8 Hz). [M+H] Calc'd for C17H13FN4O, 309. Found, 309.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C([Cl:15])=O>C(Cl)Cl.CN(C=O)C>[N:1]1([CH2:7][CH2:8][C:9]([Cl:15])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CCN1CCCCC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)CCN1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-piperidin-1-yl-propionic acid (472 mg, 3 mmol) in DCM (15 mL) at 0° C. was added oxalyl chloride (4.5 mmol) followed by one drop of DMF. After stirring for 2 hours at rt, the solvent was removed to give 3-piperidin-1-yl-propionyl chloride as a white solid. To a solution of 1,4,5,6,7,8-hexahydro-pyrrolo[3,2-b]azepine (347 mg, 2.55 mmol) in DCM (10 mL) was added TEA (1 eq.) and 1-piperidinepropionic acid chloride. The mixture was stirred at rt for overnight. The reaction was diluted with DCM, washed with NaHCO3, brine, dried and concentrated. The residue was purified on a silica gel column to give 230 mg of 3-piperidin-1-yl-1-(5,6,7,8-tetrahydro-1H-pyrrolo[3,2-b]azepin-4-yl)-propan-1-one as a light brown gel.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[N+](=[CH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N-]>[Cu].CC1CCCCC1>[CH:10]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:2]2([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[CH2:1]1
Reactant: C=C1CCCCC1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Cu]
Solvent: CC1CCCCC1
Product: CCOC(=O)C1CC12CCCCC2
Temperature: 102.5 °C
Reaction time: 12 h

Procedure:
A 250 mL round-bottom flask was charged with methylenecyclohexane (20.0 g, 0.21 mol, commercially available from Aldrich), copper powder (2.8 g), methyl cyclohexane (50 mL) and heated to 105° C. Ethyl diazoacetate (26 g, 0.23 mol, commercially available from Aldrich) was added dropwise over an 8-hour period while maintaining the temperature between 100-105° C. Upon complete addition, the mixture was heated an additional 2 hours, allowed to cool to ambient temperature and stirred for an additional 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to afford the title compound which was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:12]([CH2:17][CH:18]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:14][CH2:15][CH3:16])=[O:13].CCCCC>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:11]=[CH:10][C:7](/[CH:8]=[C:17](\[CH3:18])/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCCCC
Product: CCOC(=O)/C(C)=C/c1ccc([N+](=O)[O-])cc1
Reaction time: 8 h

Procedure:
4-Nitrobenzaldehyde (4.20 g) and (carbetoxyethylidene)triphenylphosphorane (10 g) were dissolved in toluene (36 ml), and the obtained mixture was stirred overnight under reflux conditions. After the obtained reaction mixture was allowed to cool, N-pentane (50 ml) was added thereto, and the produced white precipitate was filtered off. The filtrate was concentrated, and N-pentane (70 ml) was added to the residue. Then, ultrasonic waves were applied to the mixture. The produced precipitate was filtered off and dried under reduced pressure to obtain crude (E)-ethyl 3-(4-nitrophenyl)-2-methylacrylate as a yellow powder.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH2:13][C:12]([NH:25][C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])([C:16]([F:24])([F:23])[CH2:17]OS(C)(=O)=O)[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].O>CN(C)C=O>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH2:13][C:12]2([N:25]([C:26]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[O:27])[CH2:17][C:16]2([F:24])[F:23])[CH2:11]1)=[O:9])([CH3:4])([CH3:5])[CH3:6]
Reactant: CC(C)(C)OC(=O)N1CCCC(NC(=O)OCc2ccccc2)(C(F)(F)COS(C)(=O)=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC2(C1)N(C(=O)OCc1ccccc1)CC2(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 91.5 %

Procedure:
To a suspension of sodium hydride (1.7 g, with 40% mineral oil) in N,N-dimethylformamide (428 ml) cooled to 0° C. was added a solution of an optically-active compound of 3-benzyloxycarbonylamino-3-(1,1-difluoro-2-methanesulfonyloxy-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (17.1 g) in N,N-dimethylformamide (86 ml), and the mixture was stirred at the same temperature for 15 minutes. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The separated organic layer was sequentially washed with water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=5/1) to give the titled compound (12.6 g).
Reaction SMILES: [CH3:1][O:2][C:3]1([O:13][CH3:14])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[N:11][OH:12].[Cl:15]Cl>C(Cl)Cl>[Cl:15][CH:10]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4](=[N:11][OH:12])[C:3]1([O:2][CH3:1])[O:13][CH3:14]
Reactant: ClCl
Reactant: COC1(OC)CCCCCCC1=NO
Solvent: ClCCl
Product: COC1(OC)C(=NO)CCCCCC1Cl
Reaction time: 2 h

Procedure:
Following the general procedure of Example 1, to a solution of 5.025 parts of 2,2-dimethoxycyclooctanone oxime in 40 parts dry methylene chloride at about 35° C., was added 1.78 parts elemental chlorine over about 3/4 of an hour. The contents were stirred at 25° to 30° C. for about 21/2 hours after the addition. The contents were then treated according to the procedure of Example 1 to yield 5.3 parts of product 3-chloro-2,2-dimethoxycyclooctanone oxime as determined by elemental analysis and nuclear magnetic resonance spectroscopy.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:15]1[CH:16]=[CH:17][C:18]([N+:22]([O-:24])=[O:23])=[C:19]([CH:21]=1)[NH2:20].N12CCN(CC1)CC2>CS(C)=O.O>[C:10]([O:9][C:7]([N:1]1[CH2:6][CH2:5][N:4]([C:15]2[CH:16]=[CH:17][C:18]([N+:22]([O-:24])=[O:23])=[C:19]([CH:21]=2)[NH2:20])[CH2:3][CH2:2]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: C1CN2CCN1CC2
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Temperature: 25 °C

Procedure:
A solution of t-butyl 1-piperazine carboxylate 38 (1.0 g., 5.4 mmole), 5-chloro-2-nitroaniline 54 (0.93 g., 5.4 mmole) and 1,4-diazabicyclo[2.2.2]octane (0.61 g., 54 mmole) in DMSO (10 mL.) was heated 16 hours under argon, cooled to r.t. and diluted with water (150 mL.) and extracted with ethyl acetate (3×50 mL.). The combined organic layers were washed with water (3×30 mL.) and dried over Na2SO4. Solvent was removed and the residue chromatographed (40% EtOAc/Hexane, silica) to give the title compound as a yellow solid, (0.5 g., 30%). MS (M+H)+ 323.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1I.[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].CCOCC>C(COC)OC.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.O>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:23]1[O:22][CH:26]=[CH:25][CH:24]=1
Reactant: OB(O)c1ccco1
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
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: COCCOC
Solvent: CCOCC
Solvent: O
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1-c1ccco1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (0.45 g) in dimethoxyethane (4 ml) containing tetrakis(triphenylphosphine)palladium(0) (0.035 g) was stirred at room temperature for 30 minutes and then heated to 80° C. Furan-2-boronic acid (0.125 g) and aqueous sodium carbonate solution (2 ml, 1M) were added and the mixture heated under reflux for 3 hours. The cooled reaction was poured into ether and water. The organic layer was separated, dried (MgSO4) and evaporated. The residue was taken up the minimum amount of dichloromethane and silica gel (10 g) added. The solvent was removed and the residue applied to a column of silica gel (75 g) which was eluted with hexane containing increasing proportions of dichloromethane. Combination and evaporation of suitable fractions gave the title compound as an very light pink crystalline solid 195-6° C.