Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1>C(O)C>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:2]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:20][CH:19]=1
Reactant: FC(F)(F)c1ccc2c(Cl)ncnc2c1
Reactant: COc1ccc(N)cc1
Solvent: CCO
Product: COc1ccc(Nc2ncnc3cc(C(F)(F)F)ccc23)cc1
Yield: 79.2 %

Procedure:
5 ml of ethanol were added to a mixture of 2.3 g of 4-chloro-7-trifluoromethylquinazoline and 1.4 g of p-anisidine. The resulting mixture was heated to dissolve the solids, whereupon the solution solidified immediately. After cooling, the resulting crystals were collected by filtration and washed with, in turn, ethanol, dilute aqueous sodium hydroxide and water. The resulting crystals were recrystallized from ethanol, to give 2.5 g (yield 78%) of the desired Compound No. 51 in the form of colourless needles melting at 190°-194° C.
Reaction SMILES: Cl(O)(=O)(=O)=O.[CH2:6]([N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH2:21][CH2:22][CH:23]3[O:25][CH2:24]3)[CH:16]=[N:15][C:14]=2[N:13]([CH2:26][CH2:27][CH2:28][CH3:29])[C:11]1=[O:12])[CH2:7][CH2:8][CH3:9].C(=O)(O)[O-:31].[Na+]>COCCOC.O>[CH2:6]([N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH2:21][CH2:22][CH:23]([OH:31])[CH2:24][OH:25])[CH:16]=[N:15][C:14]=2[N:13]([CH2:26][CH2:27][CH2:28][CH3:29])[C:11]1=[O:12])[CH2:7][CH2:8][CH3:9]
Reactant: CCCCn1c(=O)c2c(ncn2CCC2CO2)n(CCCC)c1=O
Reactant: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Solvent: COCCOC
Product: CCCCn1c(=O)c2c(ncn2CCC(O)CO)n(CCCC)c1=O
Temperature: 25 °C
Reaction time: 45 h

Procedure:
0.4 ml of perchloric acid (70% strength) was added dropwise with stirring in 5 minutes to a solution of 7 g of 1,3-dibutyl-7-(3,4-epoxybutyl)xanthine in 300 ml of a mixture of ethylene glycol dimethyl ether/water (volume ratio 3:2) at room temperature. After stirring at room temperature for 45 hours, the mixture was neutralized with sodium bicarbonate and the solution was evaporated. The residue was taken up with methylene chloride and purified by column chromatography on silica gel with a mixture of chloroform and ethanol (volume ratio 8:2) as the mobile phase and by recrystallization from methylene chloride/petroleum ether.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[C:6]([C:11](Cl)=[N:12][OH:13])[C:5]=1[F:15].[F:17][C:18]([F:27])([F:26])[C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].NC1C=CC=CC=1>C1COCC1>[Cl:10][C:9]1[C:4]([C:3]([O:2][CH3:1])=[O:16])=[C:5]([F:15])[C:6]([C:11](=[N:12][OH:13])[NH:22][C:21]2[CH:23]=[CH:24][CH:25]=[C:19]([C:18]([F:17])([F:26])[F:27])[CH:20]=2)=[CH:7][CH:8]=1
Reactant: COC(=O)c1c(Cl)ccc(C(Cl)=NO)c1F
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: Nc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1c(Cl)ccc(C(=NO)Nc2cccc(C(F)(F)F)c2)c1F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of methyl-6-chloro-3-(chloro(hydroxyimino)methyl)-2-fluorobenzoate (1.2 g, 4.3 mmol) in THF (10 ml) at 0° C. was added 3-(trifluoromethyl)aniline (2.7 ml, 22 mmol). After stirring at 0° C. for 10 min, the reaction was allowed to warm to RT and stir for 3 h, then heat at 50° C. in an oil bath overnight. Added more of the aniline (5 mL) and heated at 50° C. for another 5 h. After cooling to RT, the solvent was evaporated and solid formed was filtered off. The filtrate was dissolved in DCM and purified by chromatography through a Redi-Sep® pre-packed silica gel column (120 g), eluting with a gradient of 5% to 25% EtOAc in hexane, to provide methyl 6-chloro-2-fluoro-3-(N′-hydroxy-N-(3-(trifluoromethyl)phenyl)carbamimidoyl)benzoate as off-white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]([O:12][CH3:13])=[O:11])[S:7][C:8]=1[CH3:9])([O-:3])=[O:2].[CH2:14]([O:21][C:22]1[CH:29]=[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:27]=[CH:26][C:23]=1[CH:24]=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.N1CCCC1>C(O)C>[CH2:14]([O:21][C:22]1[CH:29]=[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:27]=[CH:26][C:23]=1/[CH:24]=[CH:9]/[C:8]1[S:7][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(C)s1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Solvent: C1CCNC1
Solvent: CCO
Product: COC(=O)c1cc([N+](=O)[O-])c(/C=C/c2ccc(OCc3ccccc3)cc2OCc2ccccc2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
To a solution of methyl 4-nitro-5-methylthiophene-2-carboxylate (1.50 g, 7.46 mmol) in ethanol (7.5 ml) were added 2,4-bisbenzyloxybenzaldehyde (2.49 g, 7.83 mmol) and pyrrolidine (0.65 ml, 7.83 mmol). After stirring for 1 hr with heating under reflux, the reaction mixture was allowed to cool to room temperature. The precipitated solid was collected by filtration. The solid was washed with ethanol (3 ml×3), and dried under reduced pressure to give methyl (E)-5-[2-(2,4-bisbenzyloxyphenyl)vinyl]-4-nitrothiophene-2-carboxylate (3.08 g, yield 82%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:14](=[O:15])[C:13](=[C:16]([CH3:18])[CH3:17])[O:12][C:11]1=[O:19].C(=O)([O-])[O-].[Na+].[Na+].[CH2:26](Br)[C:27]#[CH:28]>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:28][C:27]#[CH:26])=[CH:4][C:3]=1[N:10]1[C:14](=[O:15])[C:13](=[C:16]([CH3:17])[CH3:18])[O:12][C:11]1=[O:19]
Reactant: CC(C)=C1OC(=O)N(c2cc(O)c(Cl)cc2F)C1=O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: C#CCOc1cc(N2C(=O)OC(=C(C)C)C2=O)c(F)cc1Cl
Yield: 65 %

Procedure:
To an acetonitrile solution (30 ml) of 3-(2'-fluoro-4'-chloro-5'-hydroxyphenyl)-5-isopropylidene-1,3-oxazolidine-2,4-dione (0.72 g, 2.5 mmol) was added sodium carbonate (0.16 g), and the mixture was heated at reflux for 1 hour. After the addition of propargyl bromide (0.36 g, 3.0 mmol), the reaction mixture was further refluxed for 1 hour. After the solution was quenched with 0.1N hydrochloric acid, the product was extracted with chloroform. The extracts combined were dried and evaporated as small a volume as possible. The resulting pale yellow oil was purified by silica gel column chromatography to give pure 3-(2'-fluoro-4'-chloro-5'-propargyloxyphenyl)-5-isopropylidene-1,3-oxazolidine-2,4-dione. (0.53 g, 65% yield)
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([CH:14]2[CH2:16][CH2:15]2)[CH2:10][C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1.[CH3:17]O>>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]([CH:14]2[CH2:15][CH2:16]2)[CH2:10][C:11]([O:13][CH3:17])=[O:12])=[CH:7][CH:8]=1
Reactant: O=C(O)C[C@@H](c1ccc(Cl)cc1)C1CC1
Reactant: CO
Agent: Cl
Product: COC(=O)C[C@@H](c1ccc(Cl)cc1)C1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84 %

Procedure:
Hydrogen chloride gas is bubbled into a solution of (3R)-3-(4-chlorophenyl)-3-cyclopropylpropanoic acid (5.79 g, 25.85 mmol) in methanol (100 ml) at 0° C. for 30 seconds. The solution is allowed to warm to room temperature and stirred for 18 hours. The solution is concentrated in vacuo, diluted with chloroform (100 ml) and washed with 5% aqueous sodium bicarbonate (100 ml). The organic layer is dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel eluting with ether:hexane (10:90) to yield the title compound as a colorless liquid (5.15 g, 84% from (3R)-3-(4-chlorophenyl)-3-cyclopropylpropanenitrile) which is characterized by 1HNMR, IR and mass spectral analyses.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:8][O:9][CH2:10][CH3:11])[CH:7]=1.B([C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:26])([CH3:25])[C:22]([OH:24])=[O:23])=[CH:17][CH:16]=1)(O)O>>[CH2:10]([O:9][CH2:8][C:6]1[CH:7]=[C:2]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:26])([CH3:25])[C:22]([OH:24])=[O:23])=[CH:17][CH:16]=2)[CH:3]=[N:4][CH:5]=1)[CH3:11]
Reactant: CC(C)(C(=O)O)c1ccc(B(O)O)cc1
Reactant: CCOCc1cncc(Br)c1
Product: CCOCc1cncc(-c2ccc(C(C)(C)C(=O)O)cc2)c1
Yield: 90 %

Procedure:
Prepared in a similar manner as example 21a starting from 3-Bromo-5-(ethoxymethyl)pyridine (example 26b) and 2-(4-boronophenyl)-2-methylpropanoic acid (example 21b). Yield: 90%. MS (M+H, 300).
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:12]([N:1]1[CH2:2][CH2:3][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10][CH2:11]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 75.5 %

Procedure:
A mixture of ethyl isonipecotate (212 g, 1.35 mol), benzyl chloride (170 g, 1.35 mol) and potassium carbonate (322 g, 2.33 mol) in absolute ethanol (1.8 L) was stirred mechanically at room temperature for 72 h. Solvent was removed in vacuo and the residue was dissolved in water and then extracted with ether three times. The combined organic layers were dried over magnesium sulfate, filtered and solvent was removed in vacuo to give a pale yellow oil. Vacuum distillation (b.p. 134°-136° C., 1.0 Torr) gave a colorless liquid (252 g, 76% yield): 'H-NMR: 7.30-7.22 (m, 5H), 4.12 (q, 2H, J=7), 3.48 (s, 2H), 2.88-2.82 (m, 2H), 2.33-2.19 (m, 1H), 2.08-1.67 (m, 6H), 1.24 (t, 3H, J=7); Anal.: Calcd. for C15H21NO2 : C,72.84, H,8.56, N,5.66; Found: C,72.91, H,8.38, N,5.88.
Reaction SMILES: CC([N:5]([CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[C:19]([C:21]3[CH:29]=[C:28]4[C:24]([C:25]([NH2:30])=[N:26][NH:27]4)=[CH:23][CH:22]=3)[N:18]=[C:17]([NH2:31])[N:16]=2)[CH2:10]1)C(=O)[O-])(C)C.[ClH:32]>>[ClH:32].[NH2:31][C:17]1[N:18]=[C:19]([C:21]2[CH:29]=[C:28]3[C:24]([C:25]([NH2:30])=[N:26][NH:27]3)=[CH:23][CH:22]=2)[CH:20]=[C:15]([N:11]2[CH2:12][CH2:13][CH2:14][CH:9]([NH2:5])[CH2:10]2)[N:16]=1
Reactant: CC(C)(C)N(C(=O)[O-])C1CCCN(c2cc(-c3ccc4c(N)n[nH]c4c3)nc(N)n2)C1
Agent: Cl
Product: Nc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2CCCC(N)C2)n1
Temperature: 25 °C
Yield: 115 %

Procedure:
1,1-Dimethylethyl{1-[2-amino-6-(3-amino-1H-indazol-6-yl)-4-pyrimidinyl]-3-piperidinyl}carbamate (865 mg, 2.04 mmol) was added portionwise to ice-cooled hydrochloric acid (concentrated aqueous) (8 mL, 96 mmol) with stirring. A solid yellow mass formed. The ice bath was removed and the reaction was allowed to warm to room temperature with stirring. HPLC indicated complete conversion. The mixture was diluted with ice-water (20 mL) and the solution was concentrated under reduced pressure. The residue was dissolve in ethanol (15 mL) and evaporated, followed by suspending in CH3CN (15 mL) and evaporating. The residue was then triturated with isopropanol (10 mL) and filtered, washed with isopropanol, followed by hexanes and dried under vacuum to afford an HCl salt of the title compound (761 mg) as a yellow powder. A 140 mg portion was suspended in CH3OH (2 mL) and water (1 mL) and was neutralized to pH 10 with 1 N NaOH. The solution was filtered and purified by Gilson automated reverse phase HPLC (Gemini Phenomenex C18 5u, 100×300 mm), eluting with 5-90% CH3CN-water+0.1% NH4OH). Pure fractions were combined, evaporated and dried to afford the title compound (72 mg) as a white solid. LC-MS (ES) m/z=325 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.15-1.29 (m, 1H), 1.31-1.46 (m, 1H), 1.51 (bs, 2H), 1.62-1.75 (m, 1H), 1.87 (d, J=10.6 Hz, 1H), 2.53-2.68 (m, 2H), 2.83 (t, J=12.1 Hz, 1H), 4.30 (m, 2H), 5.38 (s, 2H), 6.03 (bs, 2H), 6.58 (s, 1H), 7.56 (d, J=8.6 Hz, 1H), 7.70 (d, J=8.3 Hz, 1H), 7.94 (s, 1H), 11.52 (s, 1H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].[O-]S([O-])(=O)=O.[Mg+2].[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:17]=1[CH:18]=O>C(Cl)(Cl)Cl>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:17]=1[CH:18]=[N:5][CH2:4][CH:3]([O:6][CH3:7])[O:2][CH3:1]
Reactant: COC(CN)OC
Reactant: COc1ccc(OC)c(C=O)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClC(Cl)Cl
Product: COc1ccc(OC)c(C=NCC(OC)OC)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
Aminoacetaldehyde dimethylacetal (20.0 mL, 19.5 g, 0.185 mol) was dissolved in chloroform (100 mL) and MgSO4 (10 g) was added. Then 2,5-dimethoxybenzaldehyde (10d, 7.00 g, 0.042 mol) was also added and the mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with chloroform (100 mL), washed with water (2×200 mL), brine (200 mL), dried (Na2SO4), and concentrated to provide the pure imine as a yellow oil (10.64 g, 100%). 1H NMR (300 MHz CDCl3) 8.66 (s, 1H), 7.47 (d, J=3.0 Hz, 1H), 6.91 (dd, J1=9.0 Hz, J2=3.0 Hz, 1H), 6.81 (d, J=9.0 Hz, 1H), 4.65 (t, J=5.1 Hz, 1H), 3.78 (s, 3H), 3.77 (s, 3H), 3.76 (dd, J1=5.4 Hz, J2=1.2 Hz, 2H), 3.38 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12]([C:25]3[CH:30]=[CH:29][C:28](Cl)=[CH:27][CH:26]=3)[N:13]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:14]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:13]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:14]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2nn(Cc3ccccc3)c(-c3ccc(Cl)cc3)c2CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2nn(Cc3ccccc3)c(-c3ccccc3)c2CC1

Procedure:
To a solution of 2-benzyl-3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (0.1 mmol) (Example 59, Step D) in THF (25 mL) was added lithium aluminum hydride (100 mg). The mixture was heated at reflux for 4 h. Water (1 mL) was added, the mixture was filtered, and the filtrate was concentrated. After purification (SiO2, EtOAc/hexanes), 2-benzyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester was obtained. The intermediate was diluted with CH2Cl2 (5 mL) and TFA (1 mL) was added. The reaction mixture was stirred at RT for 4 h. The reaction mixture was concentrated to obtain the title compound (0.018 g). MS (ESI): exact mass calculated for C20H21N3, 303.17; found, m/z 304.3 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.38-7.35 (m, 3H), 7.19-7.18 (m, 3H), 7.12-7.10 (m, 2H), 5.13 (s, 2H), 3.35-3.21 (br m, 6H), 3.34-3.30 (br m, 2H), 2.81-2.79 (br m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH:9]2[CH2:11][CH2:10]2)[N:3]=1.O.[NH2:13][NH2:14]>C(O)C>[NH:13]([C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH:9]2[CH2:11][CH2:10]2)[N:3]=1)[NH2:14]
Reactant: Cc1cc(C2CC2)nc(Cl)n1
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1cc(C2CC2)nc(NN)n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
3.0 g of 2-chloro-4-methyl-6-cyclopropylpyrimidine are dissolved in 30 ml of ethanol; 3.8 ml of hydrazine hydrate are added and the mixture is stirred for 20 hours at room temperature. The solvent is then evaporated off in vacuo and the residue is recrystallised with ethyl acetate. M.p. 98°-99° C.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([C:7](Cl)=[O:8])=[CH:3][CH:2]=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][C@@H:23]([NH2:27])[CH:24]([CH3:26])[CH3:25])[CH2:18][CH2:17]1>N1C=CC=CC=1>[Cl:11][C:12]1[CH:13]=[C:14]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:15][CH:16]1[CH2:17][CH2:18][N:19]([CH2:22][C@@H:23]([NH:27][C:7](=[O:8])[C:4]2[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=2)[CH:24]([CH3:26])[CH3:25])[CH2:20][CH2:21]1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CC(C)[C@H](N)CN1CCC(Cc2ccc(Cl)c(Cl)c2)CC1
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)N[C@H](CN2CCC(Cc3ccc(Cl)c(Cl)c3)CC2)C(C)C)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.9 %

Procedure:
p-Toluoyl chloride (0.14 ml, 1 mmol) was added to a solution of 1-(S)-[4-(3,4-dichlorobenzyl)piperidin-1-ylmethyl]-2-methylpropylamine (0.33 g, 1 mmol) in dry pyridine (7 ml) at 0° C. under argon atmosphere. The solution was stirred for 30 min., at 0° C. and then allowed to warm to room temperature. After 3 h, the reaction mixture was concentrated under reduced pressure and water (10 ml) was added. The product was extracted with ethyl acetate and the organic layer was dried with magnesium sulfate and then concentrated in vacuo. The crude product (0.5 g) was chromatographed by eluting with a gradient of from 1% to 4% methanol/methylene chloride to give N-{1-(S)-[4-(3,4-dichlorobenzyl)piperidin-1-ylmethyl]-2-methylpropyl}-4-methylbenzamide (0.25 g) as partially solidified gum.
Reaction SMILES: [CH3:1]C(C[AlH]CC(C)C)C.[CH3:10][C:11]1([CH3:24])[CH2:15][CH2:14][C:13](=[O:16])[N:12]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>CCOCC.CO>[CH3:1][O:16][CH:13]1[N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:11]([CH3:24])([CH3:10])[CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1C(=O)CCC1(C)C
Reactant: CC(C)C[AlH]CC(C)C
Solvent: CO
Solvent: CCOCC
Product: COC1CCC(C)(C)N1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
DIBAL-H (73.65 mL, 110.5 mmol, 1.5M in toluene) was added portionwise to a solution of tert-butyl 2,2-dimethyl-5-oxopyrrolidine-1-carboxylate (23.10 g, 108.3 mmol) in dry Et2O (200 mL) cooled to −78° C. The reaction was stirred for 1 hour at −78° C. and then allowed to warm to room temperature and stirred overnight. The reaction was quenched with NH4OH (50 mL) and stirred for 20 minutes. The reaction was then diluted with EtOAc (200 mL), 0.5M Rochelle's Salt (100 mL) was added, and the layers were separated. The organic fraction was washed with 0.5M Rochelle's Salt (2×100 mL), brine (100 mL), dried (MgSO4) and concentrated to an oil. The oil was taken up in a solution of p-TsOH monohydrate (2.06 g, 10.8 mmol) in MeOH (200 mL) and stirred overnight at room temperature. The reaction was then concentrated, taken up in EtOAc (200 mL), washed with saturated Na2CO3 (2×100 mL), brine (50 mL), dried (MgSO4) and concentrated to give tert-butyl 5-methoxy-2,2-dimethylpyrrolidine-1-carboxylate (24.07 g, 96.9% yield) as an oil.
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=1.CC1(C)C(C)(C)OB([C:17]2[CH:18]=[N:19][NH:20][CH:21]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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:19]1[CH:18]=[C:17]([C:2]2[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=2)[CH:21]=[N:20]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: O=Cc1cnc(Br)s1
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: CCO
Solvent: Cc1ccccc1
Product: O=Cc1cnc(-c2cn[nH]c2)s1
Temperature: 70 °C
Yield: 53.7 %

Procedure:
To a solution of 2-bromothiazole-5-carbaldehyde (500 mg, 2.6 mmol) in toluene (15 mL) and ethanol (7 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (606 mg, 3.1 mmol), 2M sodium carbonate solution (7.3 mL) and Pd(PPh3)4 (30 mg, 0.02 mmol). The reaction mixture was purged with argon for 15 min and the resulting mixture was heated at 70° C. for 4 h. The reaction mixture was concentrated, diluted with water (100 mL), and extracted with ethyl acetate (2×200 mL). The combined extracts were washed with brine solution (20 mL), dried over Na2SO4, filtered and concentrated to under vacuum to obtain crude product. The crude product was purified by flash chromatography (60-120μ; 50% ethyl acetate in hexane) to afford 2-(1H-pyrazol-4-yl)thiazole-5-carbaldehyde as yellow solid (250 mg, 54% yield). 1H NMR (400 MHz, DMSO-d6): δ 13.49 (br s, 1H), 10.00 (s, 1H), 8.61 (s, 1H), 8.55 (s, 1H), 8.09 (s, 1H); LC-MS m/z calculated for [M+H]+180.02. found 180.1.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[CH2:42]([C:44]1[CH:49]=[CH:48][C:47]([S:50](Cl)(=[O:52])=[O:51])=[CH:46][CH:45]=1)[CH3:43]>C(#N)C>[CH2:42]([C:44]1[CH:45]=[CH:46][C:47]([S:50]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:52])=[O:51])=[CH:48][CH:49]=1)[CH3:43]
Reactant: CCc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCc1ccc(S(=O)(=O)Oc2ccc(-c3cc4cc(CN5CCCCC5)ccc4n3C(=O)OC(C)(C)C)c3c2CNC3=O)cc1
Yield: 51 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0322 g, 0.0698 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0580 mL, 0.419 mmol) and 4-ethylbenzene-1-sulfonyl chloride (0.0430 g, 0.209 mmol) to obtain 4-(4-ethylbenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0224 g, yield 51%).
Reaction SMILES: [C:1]([C:3]1([C:13]2[N:18]=[CH:17][C:16]([NH:19][C:20]([C:22]3[CH:23]=[N:24][N:25]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)[C:26]=3[CH3:27])=[O:21])=[CH:15][CH:14]=2)[CH2:12][CH2:11][C:6]2(OCC[O:7]2)[CH2:5][CH2:4]1)#[N:2].C(O)(=O)C.Cl.C(=O)([O-])[O-].[K+].[K+]>O>[C:1]([C:3]1([C:13]2[N:18]=[CH:17][C:16]([NH:19][C:20]([C:22]3[CH:23]=[N:24][N:25]([C:28]4[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=4)[C:26]=3[CH3:27])=[O:21])=[CH:15][CH:14]=2)[CH2:12][CH2:11][C:6](=[O:7])[CH2:5][CH2:4]1)#[N:2]
Reactant: Cc1ccc(-n2ncc(C(=O)Nc3ccc(C4(C#N)CCC5(CC4)OCCO5)nc3)c2C)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(-n2ncc(C(=O)Nc3ccc(C4(C#N)CCC(=O)CC4)nc3)c2C)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 58.7 %

Procedure:
A solution of N-[6-(8-cyano-1,4-dioxaspiro[4.5]dec-8-yl)pyridin-3-yl]-5-methyl-1-(4-methylphenyl)-1H-pyrazole-4-carboxamide (181 mg) described in Example E3 in a mixed solvent of acetic acid (2 ml), water (0.5 ml) and 1N hydrochloric acid aqueous solution (0.5 ml) was stirred at 100° C. for two hours. After the reaction, a saturated aqueous solution of potassium carbonate was added and extracted with ethyl acetate. The organic solution was dried over anhydrous magnesium sulfate and concentrated. The residue was purified with a column chromatography to give the titled compound (96 mg).
Reaction SMILES: C(O[C:6]([N:8](C)[NH:9][C:10]([C@@H:12]1[CH2:18][CH2:17][C@@H:16]2[CH2:19][N:13]1[C:14](=[O:25])[N:15]2[O:20][S:21]([O-:24])(=[O:23])=[O:22])=[O:11])=O)(C)(C)C.C([N+](CCCC)(CCCC)CCCC)CCC.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:6][NH:8][NH:9][C:10]([C@@H:12]1[CH2:18][CH2:17][C@@H:16]2[CH2:19][N:13]1[C:14](=[O:25])[N:15]2[O:20][S:21]([OH:24])(=[O:23])=[O:22])=[O:11]
Reactant: CN(NC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OS(=O)(=O)[O-])C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OS(=O)(=O)O
Reaction time: 2 h

Procedure:
To a solution of N,N,N-tributylbutan-1-aminium({[(2S,5R)-2-{[2-(tert-butoxycarbonyl)-2-methylhydrazinyl]carbonyl}-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl]oxy}sulfonyl)oxidanide 180 (0.31 g, 0.49 mmol) in DCM (20 mL) was added trifluoroacetic acid (1.2 mL, 15.55 mmol) dropwise at 0° C. The reaction mixture was stirred for 2 h, than evaporated. Ether was added to the residue and the resulting white precipitate was collected by centrifugation. The solid was triturated with acetonitrile (2×) and the white solid was collected by centrifugation. The white solid was purified by HPLC and freeze-dried to give (2S,5R)—N′-methyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide Compound 1 (Table 2) (0.01 g, 6.9%) as a white solid.