Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:11]([CH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19](Cl)=[O:20])=[CH:14][CH:13]=1)(OCC1C=CC=CC=1)=O.C(N(CC)CC)C.[C:37]([OH:45])(=[O:44])[CH:38]([CH2:40][C:41]([OH:43])=[O:42])[OH:39].[H][H]>O1CCCC1.[Pd].CCOCC>[CH:24]1([CH2:23][CH2:22][NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:44][C:37](=[O:45])[CH:38]([CH2:40][C:41]([OH:43])=[O:42])[OH:39])=[O:20])=[CH:14][CH:13]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: [H][H]
Reactant: O=C(O)CC(O)C(=O)O
Reactant: O=C(Cl)Cc1ccc(N(CCC2CCCCC2)C(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C(O)CC(O)C(=O)OC(=O)Cc1ccc(NCCC2CCCCC2)cc1

Procedure:
A warm solution of 4-[N-carbobenzyloxy-(2-cyclohexylethylamino)]phenylacetyl chloride and 1.3 g. triethylamine in 100 ml. ether is treated with 2 g. malic acid. An immediate precipitate forms, but the mixture is refluxed for one hour and filtered while hot. The solid is washed several times with hot ether, then the ether is evaporated to yield a white solid. The product is dissolved in tetrahydrofuran (100 ml.) and hydrogenated over 600 mg. 10% palladium-on-carbon at 50 psi until hydrogen uptake stops. The catalyst is filtered, and the solution is evaporated. The residue is crystallized from acetic acid to yield O-[4-(2-cyclohexylethylamino)phenylacetyl]malic acid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH2:35][CH2:36][NH:37][CH2:38][CH:39]=2)=[CH:30][CH:29]=1>CN(C)C=O>[CH3:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]2[CH2:39][CH2:38][N:37]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:36][CH:35]=2)=[CH:32][CH:33]=1
Reactant: COc1ccc(C2=CCNCC2)cc1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(C2=CCN(CCCN3c4cccc5cccc(c45)S3(=O)=O)CC2)cc1
Temperature: 20 °C
Reaction time: 12 h
Yield: 19.4 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1 -dioxide (6.74 g), triethylamine (3.4 cc) and 4-(4-methoxyphenyl)-1,2,3,6-tetrahydropyridine (4.5 g ) in dimethylformamide (70 cc). The mixture is heated for 8 hours at boiling point, then cooled to a temperature of about 20° C. Stirring is continued for 12 hours at this temperature. After purification by flash-chromatography on silica gel, under a current of argon at medium pressure (0.5-1.5 bar) with ethyl acetate as eluant, and recrystallization from boiling acetonitrile (60 cc), 2{3-[4-(4-methoxyphenyl)-1,2,3,6-tetrahydro -1-pyridyl]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (2 g) is obtained, m.p. 178° C.
Reaction SMILES: Cl.[OH2:2].[O:3]([C:10]1[CH:11]=[C:12]([CH:19]=[CH:20][CH:21]=1)[CH:13]=NCC(C)C)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C1(C)C=CC=CC=1>[O:3]([C:10]1[CH:11]=[C:12]([CH:19]=[CH:20][CH:21]=1)[CH:13]=[O:2])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O
Reactant: CC(C)CN=Cc1cccc(Oc2ccccc2)c1
Agent: Cl
Solvent: Cc1ccccc1
Product: O=Cc1cccc(Oc2ccccc2)c1
Yield: 94.9 %

Procedure:
20 g of 37% hydrochloric acid (about 0.2 mol) and 20 ml of water are added, with stirring, to a solution of 40 g (0.158 mol) of 3-phenoxybenzylidene-isobutylamine in 40 ml of toluene, and the whole is refluxed for 15 minutes. The organic phase is separated; it is then washed neutral with 10% sodium hydrogen carbonate solution, and the toluene is removed by rotation in a slight water-jet vacuum. Distillation of the residue yields 29.7 g (0.15 mol) of 3-phenoxybenzaldehyde, corresponding to a yield of 94.9% of theory; b.p. 94° C./6 Pa; nD20 =1.5976.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[C:4](Cl)[N:3]=1.[Na].[CH3:19][SH:20].COCCOCCN(CCOCCOC)CCOCCOC>[Cu].C1COCC1>[NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[C:4]([S:20][CH3:19])[N:3]=1
Reactant: CS
Reactant: Nc1nc(Cl)c(-c2ccc(Cl)cc2Cl)c(Cl)n1
Agent: [Cu]
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: [Na]
Solvent: C1CCOC1
Product: CSc1nc(N)nc(Cl)c1-c1ccc(Cl)cc1Cl
Temperature: 180 °C
Yield: 51.4 %

Procedure:
A mixture of 2-amino-5-(2,4-dichlorophenyl)-4,6-dichloropyrimidine (0.5 g) (Example 32) THF (15 ml), methanethiol sodium salt (0.113 g), copper powder (0.05 g) and tris[2-(2-methoxyethoxy)ethyl]amine (0.1 g) was heated in an autoclave at 180° C. for 18 hours. The cooled reaction mixture was filtered, evaporated and the residue purified by flash column chromatography to give the title compound (0.262 g, 52%), mp. 201°-202° C. (softens at 196° C.). Microanalysis:
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([C:9]([NH2:11])=[O:10])[C:6]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)=[CH:15][CH:14]=2)=[N:5][C:4]=1[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N+:34]([O-])=O)[CH:29]=1)[CH3:2].O.NN>C(O)C.O.[Fe](Cl)Cl>[NH2:34][C:30]1[CH:29]=[C:28]([CH:33]=[CH:32][CH:31]=1)[O:27][C:4]1[N:5]=[C:6]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][N:20]3[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]3)=[CH:17][CH:18]=2)[C:7]([C:9]([NH2:11])=[O:10])=[N:8][C:3]=1[CH2:1][CH3:2]
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(CN3CCN(C)CC3)cc2)nc1Oc1cccc([N+](=O)[O-])c1
Agent: Cl[Fe]Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: CCc1nc(C(N)=O)c(Nc2ccc(CN3CCN(C)CC3)cc2)nc1Oc1cccc(N)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 43.7 %

Procedure:
To a mixture of 6-ethyl-3-({4-[(4-methylpiperazin-1-yl)methyl]phenyl}amino)-5-(3-nitrophenoxy)pyrazine-2-carboxamide (112 mg) in ethanol (3 mL) and water (1 mL) were added iron chloride (III) hexahydrate (31 mg), activated carbon (60 mg), and hydrazine monohydrate (221 μL), followed by stirring at 80° C. for 2 hours. The reaction mixture was left to be cooled, and then water was added thereto. The insoluble matter was collected by filtration. To the obtained solid was added a solution in chloroform-methanol (10:1), and the insoluble matter was separated by filtration. The obtained filtrate was concentrated under reduced pressure to obtain 5-(3-aminophenoxy)-6-ethyl-3-({4-[(4-methylpiperazin-1-yl)methyl]phenyl}amino)pyrazine-2-carboxamide (46 mg) as a pale yellow solid.
Reaction SMILES: [PH2:1]([OH:3])=[O:2].[C:4]([O:23][CH3:24])(=[O:22])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>C(OOC(CC)(C)C)(CC)(C)C>[CH3:24][O:23][C:4](=[O:22])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]([P:1]([OH:3])([CH:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([O:23][CH3:24])=[O:22])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:2])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OC
Reactant: O=[PH2]O
Agent: CCC(C)(C)OOC(C)(C)CC
Product: CCCCCCCCCC(CCCCCCCC(=O)OC)P(=O)(O)C(CCCCCCCCC)CCCCCCCC(=O)OC
Temperature: 140 °C
Yield: 95.6 %

Procedure:
3.1 mL (0.03 moles) of 50% aqueous hypophosphorous acid and 16.92 g (0.06 moles) of methyl oleate (CE-1897 from P&G Chemical; iodine value=90) are mixed in a 100 mL single neck flask equipped with a distillation head. The mixture is purged with argon to remove oxygen and is heated under argon at 140° C. to remove water. After water is removed the mixture is cooled and 0.5 mL (0.0023 moles) of di-tert-amylperoxide are added and the mixture is purged with argon to remove oxygen and is heated under argon for 5 hours at 140° C. Tert-amyl alcohol is removed by distillation and 18.9 g (quantitative yield) of 9-{hydroxy-[1-(7-methoxycarbonyl-heptyl)-decyl]-phosphinoyl}-octadecanoic acid methyl ester (mixture of isomers) is obtained as a colorless wax melting near ambient temperature.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH2:6][CH3:7])[CH:3]=[CH2:4].[N+:8]([O-])([OH:10])=[O:9]>>[CH3:1][C:2]([CH2:5][CH2:6][CH3:7])=[CH:3][CH2:4][N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])O
Reactant: C=CC(C)CCC
Product: CCCC(C)=CC[N+](=O)[O-]
Temperature: 65 °C

Procedure:
3-Methyl-1-hexene (22.2 mL, 0.15 moles) was mixed with concentrated nitric acid (18 mL, 0.28 moles) at room temperature. With rapid stirring the solution was heated to 65° C. for 3 hours. The heat was removed and the solution stirred an additional 30 min. The organic layer was separated and washed with a saturated sodium chloride solution (3×15 mL) then dried over magnesium sulfate. Vacuum distillation (20 Torr, 28° C.) removed unreacted 3-methyl-1-hexene. A yellow oil remained. Gas chromatography and IR spectroscopy indicate both cis- and trans-3-methyl-1-nitro-2-hexene are present along with a small amount of 1-nitro-2-hexanol. These structures were confirmed by IR and GC analysis.
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5](=[O:15])[CH:4]=1)[NH2:2].[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH:26]=O.[CH:28]([C:30]1[N:34]([CH3:35])[CH:33]=[C:32]([C:36]([O:38][CH3:39])=[O:37])[CH:31]=1)=O>>[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH2:26][N:2]1[C:28]([C:30]2[N:34]([CH3:35])[CH:33]=[C:32]([C:36]([O:38][CH3:39])=[O:37])[CH:31]=2)=[C:4]2[C:3]([N:8]([CH2:9][CH:10]([CH3:11])[CH3:12])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2=[O:15])=[N:1]1
Reactant: COC(=O)c1cc(C=O)n(C)c1
Reactant: CC(C)Cn1c(NN)cc(=O)n(C)c1=O
Reactant: O=Cc1c[nH]c2ccc(F)cc12
Product: COC(=O)c1cc(-c2c3c(=O)n(C)c(=O)n(CC(C)C)c3nn2Cc2c[nH]c3ccc(F)cc23)n(C)c1

Procedure:
This compound was made following the procedure described above, starting with 6-hydrazino-1-isobutyl-3-methylpyrimidine-2,4(1H,3H)-dione, and condensing first with 5-fluoro-1H-indole-3-carbaldehyde, followed by methyl 5-formyl-1-methyl-1H-pyrrole-3-carboxylate. Mass: 507.05 (M+H).
Reaction SMILES: CN(C)C=O.[F:6][C:7]1[C:15]([OH:16])=[C:14]([F:17])[C:13]([F:18])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[OH-].[Na+].Cl[CH:22]([F:24])[F:23]>O>[F:23][CH:22]([F:24])[O:16][C:15]1[C:7]([F:6])=[C:8]([CH:12]=[C:13]([F:18])[C:14]=1[F:17])[C:9]([OH:11])=[O:10]
Reactant: O=C(O)c1cc(F)c(F)c(O)c1F
Reactant: FC(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cc(F)c(F)c(OC(F)F)c1F
Reaction time: 0.5 h

Procedure:
20 ml of dimethylformamide, followed by 4.97 g (0.026 mole) of 2,4,5-trifluoro-3-hydroxybenzoic acid [(XXIII), X=X'=F], were added in portions, whilst ice-cooling, to a solution of 2.18 g (0.052 mole) of sodium hydroxide in 5 ml of water. Thereafter the solution was stirred for 30 minutes, whilst ice-cooling. The reaction mixture was then transferred to a 200 ml stainless steel autoclave, and 100 ml of dimethylformamide containing 24.0 g (0.277 mole) of chlorodifluoromethane were added to it. The mixture was then stirred at between 100° and 110° C. for 5 hours under pressure. At the end of this time, the reaction mixture was poured into water and extracted with chloroform. The chloroform extracts were washed with water and dried over anhydrous sodium sulfate; the solvent was then removed by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel using a 9:1 by volume mixture of ethyl acetate and ethanol as the eluent, to afford 2.00 g of 3-difluoromethoxy-2,4,5-trifluorobenzoic acid as a colorless powder.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:40])[N:20]([CH3:39])[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>O.C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:40])[N:20]([CH3:39])[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1nc(C)n(C)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(C)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 58.1 %

Procedure:
A mixture of hydroxylammonium chloride (1.40 g), sodium hydrogen carbonate (2.10 g) and dimethyl sulfoxide (13 mL) was stirred at 40° C. for 30 min, 4′-[(4-butyl-1,2-dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (0.95 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.32 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.30 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.64 g, 59%).
Reaction SMILES: O[CH:2]([CH3:24])[CH:3]([C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)[CH2:4][C:5]1[O:9][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][CH:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(P([N:70]=[N+:71]=[N-:72])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCCC1>[N:70]([CH:2]([CH3:24])[CH:3]([C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)[CH2:4][C:5]1[O:9][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][CH:6]=1)=[N+:71]=[N-:72]
Reactant: CCOC(=O)c1ccc(CC(c2ccc([N+](=O)[O-])cc2)C(C)O)o1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(CC(c2ccc([N+](=O)[O-])cc2)C(C)N=[N+]=[N-])o1
Yield: 82.3 %

Procedure:
3.66 g of ethyl 5-{(2RS,3SR)-3-hydroxy-2-(4-nitrophenyl)butyl}-2-furancarboxylate was dissolved in 40 ml of tetrahydrofuran, and 4.32 g of triphenylphosphine, 2.60 ml of diethyl azodicarboxylate and 4.53 g of diphenylphosphoryl azide were added under cooling with ice with stirring, followed by stirring at room temperature for 18 hours. The reaction solution was evaporated to dryness under reduced pressure. Then, the residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/1) to obtain 3.24 g of the above-identified compound.
Reaction SMILES: [CH:1]1([C:8]2[CH:17]=[CH:16][C:11]3[NH:12][C:13](=[O:15])[O:14][C:10]=3[CH:9]=2)[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[F:18][C:19]1[CH:20]=[C:21]([CH2:25][CH2:26][CH2:27][NH2:28])[CH:22]=[CH:23][CH:24]=1.Cl>>[F:18][C:19]1[CH:20]=[C:21]([CH2:25][CH2:26][CH2:27][NH:28][C@H:4]2[CH2:5][CH2:6][C@H:1]([C:8]3[CH:17]=[CH:16][C:11]4[NH:12][C:13](=[O:15])[O:14][C:10]=4[CH:9]=3)[CH2:2][CH2:3]2)[CH:22]=[CH:23][CH:24]=1
Reactant: O=C1CCC(c2ccc3[nH]c(=O)oc3c2)CC1
Reactant: NCCCc1cccc(F)c1
Agent: Cl
Product: O=c1[nH]c2ccc([C@H]3CC[C@H](NCCCc4cccc(F)c4)CC3)cc2o1

Procedure:
Coupling of ketone 5 and 3-(3-fluorophenyl)-1-propylamine, using the method given in Example 1, gave 6-{trans-4-[3-(3-fluorophenyl)propylamino]-cyclohexyl}-3H-benzoxazol-2-one (1.4 g, 37%) as the HCl salt: 1H NMR (500 MHz, DMSO-d6): δ 11.48 (s, 1H), 8.79 (s, 2H), 7.38-7.33 (m, 1H), 7.17 (s, 1H), 7.12-7.08 (m, 2H), 7.06-6.97 (m, 3H), 3.10-3.03 (m, 1H), 2.97-2.89 (m, 2H), 2.71 (dd, J=8, 8 Hz, 2H), 2.57-2.50 (m, 1H), 2.18-2.11 (m, 2H), 1.98-1.92 (m, 2H), 1.89-1.85 (m, 2H), 1.57-1.46 (m, 4H).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C:12]([OH:14])=O)=[O:6])[CH:2]=[CH2:3].[CH:15]1(N=C=NC2CCCCC2)CCCCC1.CC1(C)OC(=O)CC(=O)O1.C(OCC)(=O)C>ClCCl.CN(C)C1C=CN=CC=1>[C:12]([C@@H:8]1[CH2:9][CH2:10][CH2:11][N:7]1[C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])(=[O:14])[CH3:15]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: C=CCOC(=O)N1CCC[C@H]1C(=O)O
Agent: CC1(C)OC(=O)CC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=CCOC(=O)N1CCC[C@H]1C(C)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 43.8 %

Procedure:
To a solution of (2S)-1-allyloxycarbonyl-2-carboxypyrrolidine (10 g) in dichloromethane (100 ml) were added dicyclohexylcarbodiimide (9.8 g), Meldrum's acid (6.8 g) and 4-dimethylaminopyridine (5.8 g) at 0° C. After stirring for 24 hours at ambient temperature, the resulting precipitate was removed by filtration. The filtrate was washed with 1N hydrochloric acid solution, evaporated in vacuo. The residue was dissolved in a mixture of acetic acid (80 ml) and water (60 ml), and refluxed for 1 hour. Evaporation of the solvent gave a residue, which was taken up into ethyl acetate. The solution was washed in turn with saturated sodium bicarbonate and brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel eluting with a mixture of n-hexane and ethyl acetate (2:1, V/V) to give (2S)-2-acetyl-1-allyloxycarbonylpyrrolidine (4.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([C@@H:23]3[CH2:27][CH2:26][NH:25][CH2:24]3)[C:7]([CH2:9][N:10]3[C:14]4=[CH:15][N:16]=[CH:17][CH:18]=[C:13]4[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])=[N:11]3)=[N:8][C:4]=2[CH:3]=1.[C:30](OC(=O)C)(=[O:32])[CH3:31].O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([C@@H:23]3[CH2:27][CH2:26][N:25]([C:30](=[O:32])[CH3:31])[CH2:24]3)[C:7]([CH2:9][N:10]3[C:14]4=[CH:15][N:16]=[CH:17][CH:18]=[C:13]4[C:12]([S:19]([CH3:22])(=[O:20])=[O:21])=[N:11]3)=[N:8][C:4]=2[CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2[C@@H]2CCNC2)c2cnccc12
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1CC[C@@H](n2c(Cn3nc(S(C)(=O)=O)c4ccncc43)nc3cc(Cl)ccc32)C1
Reaction time: 1 h

Procedure:
To a solution of 1-({5-chloro-1-[(3R)-(pyrrolidin-3-yl)]-1H-benzo[d]imidazol-2-yl}methyl)-3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine (30 mg), acetic anhydride (0.1 mL) in 8 mL of DCM was added DMAP (3 mg, 0.025 mmol). The mixture was stirred for 1 hour. Then 20 mL of DCM and 10 mL of water was added. The organic phase was washed with water and NaHCO3 and then dried over anhydrous Na2SO4. The solvent was evaporated. The residue was purified by preparative-HPLC to afford the title compound (15 mg) as a pale solid.
Reaction SMILES: [CH2:1]([O:5]/[N:6]=[N+:7](/[N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[CH2:14][OH:15])\[O-:8])[CH2:2][CH2:3][CH3:4].I([O-])(=O)(=O)=[O:17].[Na+]>CC#N.C(Cl)(Cl)(Cl)Cl.O.O.[Ru](Cl)(Cl)Cl>[CH2:1]([O:5]/[N:6]=[N+:7](/[N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([OH:17])=[O:15])\[O-:8])[CH2:2][CH2:3][CH3:4]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCCCO/N=[N+](\[O-])N1CCC[C@H]1CO
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Solvent: O
Product: CCCCO/N=[N+](\[O-])N1CCC[C@H]1C(=O)O
Temperature: 25 °C

Procedure:
To a solution of {(2S)-1-[(Z)-1-butoxy-NNO-azoxy]pyrrolidin-2-yl}methanol (360 mg, 1.66 mmol) and sodium periodate (1.06 g, 4.97 mmol) in 17.5 mL of CH3CN/CCl4/H2O (2:2:3) was added ruthenium(III) chloride hydrate (34 mg, 1.66 mmol). After stirring at rt over night, the mixture was extracted with CH2Cl2 (3×50 mL), dried over MgSO4 and concentrated to give the title product, which was used directly.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[OH:12].[C:13](O)(=[O:20])[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.CCN=C=NCCCN(C)C.N1C=CC=CC=1>O>[OH:12][C:3]1[CH:4]=[C:5]([C:8]([F:9])([F:10])[F:11])[CH:6]=[CH:7][C:2]=1[NH:1][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1
Reactant: O=C(O)c1ccncc1
Reactant: Nc1ccc(C(F)(F)F)cc1O
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1ccc(C(F)(F)F)cc1O)c1ccncc1
Temperature: 80 °C
Yield: 72.7 %

Procedure:
A mixture of 1.30 g of 2-amino-5-trifluoromethylphenol, 0.9 g of isonicotinic acid, 1.83 g of WSC and 15 ml of pyridine was stirred while heating at 80° C. for three hours. The mixture was cooled to room temperature, and then water was poured. Precipitated solid was filtered and washed with water, and then dried under reduced pressure to give 1.5 g of N-(2-hydroxy-4-trifluoromethylphenyl)isonicotinamide.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]3[C:10](=[CH:11][CH:12]=2)[CH:9]=[CH:8][CH:7]=[N:6]3)[N:3]=1.[S:16]([O:21]C)([O:19][CH3:20])(=[O:18])=[O:17]>C(OCC)C>[S:16]([O-:21])([OH:19])(=[O:18])=[O:17].[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4]([N:3]=1)=[C:5]1[C:10]([CH:9]=[CH:8][CH:7]=[N+:6]1[CH3:20])=[CH:11][CH:12]=2
Reactant: COS(=O)(=O)OC
Reactant: Clc1ccc2ccc3cccnc3c2n1
Solvent: CCOCC
Product: C[n+]1cccc2ccc3ccc(Cl)nc3c21
Product: O=S(=O)([O-])O
Temperature: 120 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
Under a stream of argon, to compound (3) (5.2 g; 24.2 mmol), dimethyl sulfate (22.1 g; 175 mmol) was added at room temperature over 10 minutes. The reaction temperature was raised to 120° C. and the resulting reaction mixture was stirred for 1 hour and then cooled to room temperature. Diethyl ether was added thereto and light brown crude crystals which precipitated out were separated by filtration. The obtained crude crystals were washed with a solution of diethyl ether/ethanol=1/1 to 1/2 and dried under reduced pressure to give 6.17 g of the title compound (4).
Reaction SMILES: CCN(C(C)C)C(C)C.[Li]CCCC.[CH2:15]([O:17][C:18](=[O:36])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1)[CH3:16].[CH:37]1([CH2:42]I)[CH2:41][CH2:40][CH2:39][CH2:38]1.[NH4+].[Cl-]>C1COCC1.C1COCC1.CN1C(=O)N(C)CCC1>[CH2:15]([O:17][C:18](=[O:36])[CH:19]([C:20]1[CH:21]=[CH:22][C:23]([S:26]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)(=[O:27])=[O:28])=[CH:24][CH:25]=1)[CH2:42][CH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1)[CH3:16]
Reactant: CCOC(=O)Cc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1
Reactant: ICC1CCCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CCOC(=O)C(CC1CCCC1)c1ccc(S(=O)(=O)N2CCN(C)CC2)cc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
DIEA (0.742 g, 7.32 mmol) is dissolved in THF (10 mL) and cooled to −78° C., under an atmosphere of N2. n-BuLi (2.5M in hexanes, 2.25 mL, 5.63 mmol) is added to this slowly. The resulting solution is stirred at −78° C. for 15 min. A solution of the title B compound, [4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-acetic acid ethyl ester (1.84 g, 5.63 mmol) in THF/DMPU (10 mL/5 mL) is then added dropwise. The reaction is then stirred at −78° C. for one hour. A solution of cyclopentylmethyl iodide (1.18 g, 5.63 mmol) in THF/DMPU (10 mL/5 mL) is then added dropwise and the reaction is allowed to warm to RT overnight. The reaction is then poured into saturated NH4Cl solution and extracted with EtOAc. The organic layer is dried over MgSO4, filtered and concentrated to afford a brown oil. This is purified by flash chromatography (0→2% EtOAc in MeOH) to afford 3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid ethyl ester as a brown oil: 1H NMR (CDCl3) δ 1.12 (m, 2H) 1.24 (m, 3H) 1.50 (m, 2H) 1.60 (m, 3H) 1.76 (m, 2H) 2.08 (m, 2H) 2.27 (s, 3H) 2.47 (s, 4H) 3.04 (s, 4H) 3.65 (m, 1H) 4.13 (m, 2H) 7.48 (m, 2H) 7.69 (m, 2H); LC/MS 409.3 (M+1).