Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH:12]([CH2:28]O)[CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:16][CH2:15]1)=[N:9][C:8]([O:30]C)=[CH:7][CH:6]=2.CO.C(N(CC)CC)C.CS(OS(C)(=O)=O)(=O)=O>ClCCl>[F:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]=[CH:7][C:8](=[O:30])[N:9]3[CH2:28][CH:12]([CH2:13][N:14]4[CH2:19][CH2:18][CH:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])[CH2:16][CH2:15]4)[C:11]=1[C:10]=23
Reactant: COc1ccc2ncc(F)c(C(CO)CN3CCC(NC(=O)OC(C)(C)C)CC3)c2n1
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCN(CC2Cn3c(=O)ccc4ncc(F)c2c43)CC1
Temperature: 55 °C

Procedure:
A solution of 1,1-dimethylethyl (1-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]-3-hydroxypropyl}-4-piperidinyl)carbamate (18.28 g, containing some non-alcohol impurity and a little MeOH, judged to contain 40 mmol alcohol-containing compounds) in dichloromethane (180 ml) was stirred under argon, ice-cooled and treated with triethylamine (11.1 ml, 80 mmol) and methanesulfonic anhydride (8.7 g, 50 mmol). After 1 hour the solution was heated to reflux for 2 days, evaporated and redissolved in chloroform (180 ml). This solution was heated under argon at 55° C. for 3 days, cooled, washed with aqueous sodium bicarbonate and the aqueous twice re-extracted with chloroform. The combined organic phases were dried and evaporated. Chromatography of the residue (methanol/dichloromethane gradient) and rechromatography of some impure fractions gave the product (13.35 g, containing 12.5% dichloromethane by weight).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:13][CH2:14][O:15][CH3:16])/[C:9](/[F:12])=[CH:10]\[F:11])=[CH:4][CH:3]=1.C([Li])CCC.Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:25]=1>O1CCCC1.CCCCCC.[Cl-].[Zn+2].[Cl-]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:13][CH2:14][O:15][CH3:16])/[C:9](/[F:12])=[C:10](\[F:11])/[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:25]=2)=[CH:6][CH:7]=1
Reactant: COCCC(/C(F)=C\F)c1ccc(Cl)cc1
Reactant: BrCc1cccc(Oc2ccccc2)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCCC(/C(F)=C(\F)Cc1cccc(Oc2ccccc2)c1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.5 %

Procedure:
To a stirred solution of 1-chloro-4-[(2E)-2,3-difluoro-1-(2-methoxyethyl)-2-propenyl]benzene (0.87 g, 3.52 mmol) in tetrahydrofuran (10 ml) under nitrogen at −65° C. was added n-butyllithium (1.1 ml of a 2.5 M solution in hexane, 2.75 mmol). To this mixture was added zinc chloride (5.3 ml of 0.5 M in tetrahydrofuran, 2.65 mmol) and the resulting mixture was stirred for one hour. Tetrakis(triphenyl-phosphine)palladium (0.066 g, 0.057 mmol) in tetrahydrofuran (1 ml) was added, followed by α-bromo-3-phenoxytoluene (0.70 g, 2.66 mmol) in tetrahydrofuran (2 ml), and the resulting mixture was stirred and allowed to warm to room temperature over four hours and was then stirred for another sixteen hours. The reaction mixture was then quenched with water, diluted with 10% hydrochloric acid and thoroughly extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo to a brown oil (1.378 g). Chromatography of this oil on silica gel eluting with ethyl acetate:hexane (5:95) afforded the title compound as a yellow syrup (0.359 g) which was characterized by IR, 1HNMR, 19FNMR and mass spectral analysis.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1.[CH2:16](O)[CH2:17][OH:18].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:11]([CH:12]2[O:18][CH2:17][CH2:16][O:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1
Reactant: OCCO
Reactant: COc1ccc2nc(Cl)c(C=O)cc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc2nc(Cl)c(C3OCCO3)cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
To a solution of 2-chloro-6-methoxyquinoline-3-carbaldehyde (4.01 g, 18.10 mmol) in toluene (200 mL) in a 500 mL round-bottomed flask equipped with a magnetic stirrer under N2 was added ethylene glycol (1.20 mL, 21.52 mmol) followed by p-toluenesulfonic acid monohydrate (348 mg, 1.83 mmol). The mixture was stirred overnight under reflux using a Dean-Stark apparatus. After cooling to RT, the mixture was concentrated at 40° C. under vacuum, then the residue was diluted with saturated aqueous NaHCO3 solution (40 mL) before extraction with CH2Cl2 (100 mL). The organic phase was isolated, washed with brine (20 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent cyclohexane:EtOAc=100:0 to 92:8 to 75:25) gave 2-chloro-3-(1,3-dioxolan-2-yl)-6-methoxyquinoline SMA 44002 as a white solid (4.39 g, 91% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH2:15]([N:17](CC)CC)C.Cl.CN>C1COCC1.O.O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:17][CH3:15])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1F
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Temperature: -35 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
To a solution of 4-fluoro-3-nitrobenzenesulfonyl chloride (43 g, 179.5 mmol) in THF (500 mL), was added triethylamine (150 mL, 1.08 mol). The mixture was cooled to −35° C. and methylamine hydrochloride (14.5 g, 215.4 mmol) in water was added dropwise. After 1 h, the mixture was warmed to room temperature and diluted with 1:1 water/ethyl acetate. The organic layer was separated and washed with saturated aqueous sodium bicarbonate, then brine, dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified via column chromatography (20% ethyl acetate/petroleum ether) to give 4-fluoro-N-methyl-3-nitrobenzenesulfonamide (38 g, 90% yield) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][CH2:9][C:10]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[O:11])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH:9]([C:10]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[O:11])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:7])=[CH:17][CH:18]=1
Reactant: Cc1ccc(C(=O)NCC(=O)c2ccco2)cc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC(NC(=O)c1ccc(C)cc1)C(=O)c1ccco1
Yield: 85.6 %

Procedure:
12.0 g of N-(4-methylbenzoyl)-(2-furylcarbonyl)methylamine, 2.3 g of 61% sodium hydride and 9.1 g of ethyl bromoacetate are treated in the same manner as described in Preparation 1-(2). 13.9 g of ethyl 3-(4-methylbenzoylamino)-3-(2-furylcarbonyl)propionate are thereby obtained. Yield: 85.5%
Reaction SMILES: Br[C:2]1([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:12].[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].CCN(C(C)C)C(C)C>C(#N)C>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:2]2([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)[C:10]3[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=3)[NH:4][C:3]2=[O:12])[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: O=C1Nc2cc(Cl)ccc2C1(Br)Cc1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
The mixture of rac-3-bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (1 g, 2.703 mmol), piperazine-1-carboxylic acid tert-butyl ester (0.604 g, 3.24 mmol) and DIPEA (0.419 g, 3.24 mmol) in acetonitrile (20 mL) was stirred at room temperature for overnight. The reaction mixture was concentrated and extracted with dichloromethane. The organic layer was dried over Na2SO4, filtered and concentrated to give 1.1 g of rac-4-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperazine-1-carboxylic acid tert-butyl ester. MS m/z 476 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][C:5]2[O:6][CH:7]([C:17]([OH:19])=[O:18])[O:8][C:9]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:10]=3[CH2:11][C:4]=2[CH:3]=1.S(=O)(=O)(O)O.[CH3:27]O>>[CH3:1][C:2]1[CH:21]=[CH:20][C:5]2[O:6][CH:7]([C:17]([O:19][CH3:27])=[O:18])[O:8][C:9]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:10]=3[CH2:11][C:4]=2[CH:3]=1
Reactant: Cc1ccc2c(c1)Cc1cc(C)ccc1OC(C(=O)O)O2
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C1Oc2ccc(C)cc2Cc2cc(C)ccc2O1

Procedure:
The carboxylic acid was dissolved in 300 ml of methanol and 2 ml of concentrated sulfuric acid was added. The mixture was refluxed for 1 hour, cooled, the resulting crystals collected and recrystallized from methanol-acetone to give methyl 2,10-dimethyl-12H-dibenzo[d,g][1,3]dioxocin-6-carboxylate, m.p. 158°-160°C. The methyl ester and excess diethylamine are refluxed for 16 hours. The remaining diethylamine is removed, and N,N-diethyl-2,10-dimethyl-12H-dibenzo[d,g][1,3]dioxocin-6-carboxamide is obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C@@H:11]2[CH2:13][O:12]2)=[CH:7][CH:6]=1.[NH2:16][CH2:17][C@H:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:28]3[CH:37]=[CH:36][C:31]([C:32]([O:34]C)=[O:33])=[CH:30][CH:29]=3)[CH:24]=2)[O:19]1.[OH-].[Na+]>O1CCOCC1>[OH:12][C@H:11]([CH2:10][O:9][C:8]1[CH:14]=[CH:15][C:5]([CH2:4][CH2:3][O:2][CH3:1])=[CH:6][CH:7]=1)[CH2:13][NH:16][CH2:17][C@H:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:28]3[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:36][CH:37]=3)[CH:24]=2)[O:19]1
Reactant: COCCc1ccc(OC[C@@H]2CO2)cc1
Reactant: COC(=O)c1ccc(-c2ccc3c(c2)CC[C@H](CN)O3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COCCc1ccc(OC[C@@H](O)CNC[C@H]2CCc3cc(-c4ccc(C(=O)O)cc4)ccc3O2)cc1
Temperature: 80 °C
Reaction time: 72 h
Yield: 10.5 %

Procedure:
To a solution of epoxide (Example 16, 0.25 mmol) in 2 mL of aqueous 1,4-dioxane (10% water) was added methyl 4-[(2R)-2-(aminomethyl)-3,4-dihydro-2H-chromen-6-yl]benzoate (40 mg, 0.13 mmol). The mixture was stirred at 80° C. for 72 hours and allowed to cool to room temperature. When ambient temperature was achieved, 1N aqueous sodium hydroxide (1 mL) was added to the solution at room temperature, and stirring continued for another 0.5 hour. The product was then purified by preparative HPLC (Gradient 0-70% Acetonitrile/0.1% aq. TFA) to obtain 6.7 mg of product (as a TFA salt). MH+492.4 (free base).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[F:11]OC(F)(F)F.CC(NC1C=CC(F)=CC=1)=O.CC(NC1C=CC(F)=CC=1F)=O.CC(NC1C(F)=CC=CC=1F)=O>C(Cl)(Cl)Cl>[F:11][CH2:2][C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3]
Reactant: FOC(F)(F)F
Reactant: CC(=O)Nc1ccccc1
Agent: CC(=O)Nc1c(F)cccc1F
Agent: CC(=O)Nc1ccc(F)cc1
Agent: CC(=O)Nc1ccc(F)cc1F
Solvent: ClC(Cl)Cl
Product: O=C(CF)Nc1ccccc1
Yield: 37 %

Procedure:
A solution of 67.5 parts of acetanilide in 22,200 parts of chloroform was cooled to 0° C. and maintained at that temperature for 2.5 hours while fluoroxytrifluoromethane was bubbled into the solution at a rate of 46 parts per hour. Analysis of the reaction product by gas chromatographic technique indicated a 91 percent conversion with a yield of 37% 2-fluoroacetanilide, 16% 4-fluoroacetanilide, 10% 2,4-difluoroacetanilide, 3% 2,6-difluoroacetanilide and about 25% higher molecular weight material.
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][CH:20]([NH:23][C:24](=[O:27])[CH2:25]Br)[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:28]1([OH:33])[CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][CH:20]([NH:23][C:24](=[O:27])[CH2:25][O:33][CH:28]5[CH2:32][CH2:31][CH2:30][CH2:29]5)[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CBr)NC1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Reactant: OC1CCCC1
Product: O=C(COC1CCCC1)NC1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1

Procedure:
Using a procedure similar to that described in Example 21 except starting with N-(1-[9,10-dihydro-9,10-methanoanthracen-9-ylmethyl]-4-piperidyl)-2-bromoacetamide (described in Example 38a) and cyclopentanol, the title compound was obtained as a white solid (63%), mp 127.0°-8.0° C.; MS(CI): 431 (M+H); NMR (300 MHz,DMSO-d6): 1.48(br m, 4H), 1.62(br m, 8H), 2.28(br m, 2H), 2.45(s, 2H), 2.94(br m, 2H), 3.34(s, submerged, 2H), 3.60(br m, 1H), 3.74(2, 2H), 3.89(sextet, 1H, J=3.9 Hz), 4.30(s, 1H), 6.91(br m, 4H), 7.18(d, 2H, J=6.2 Hz), 7.26(d, 2H, J=6.2 Hz), 7.33(d, 1H, J=8.3 Hz).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[NH2:9][C:10]([NH:12][C:13]1[NH:14][C:15]([C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=2)=[CH:16][C:17]=1[C:18]([NH2:20])=[O:19])=[O:11].O>CN(C)C=O>[NH2:9][C:10]([NH:12][C:13]1[NH:14][C:15]([C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=2)=[C:16]([Cl:1])[C:17]=1[C:18]([NH2:20])=[O:19])=[O:11]
Reactant: O=C1CCC(=O)N1Cl
Reactant: NC(=O)Nc1[nH]c(-c2ccc(Br)cc2)cc1C(N)=O
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)Nc1[nH]c(-c2ccc(Br)cc2)c(Cl)c1C(N)=O
Yield: 51 %

Procedure:
N-Chlorosuccinimide (48 mg, 0.36 mmol) was added to a solution of 2-aminocarbonylamino-5-(4-bromophenyl)pyrrole-3-carboxamide (Compound No. 1-1, 97 mg, 0.30 mmol) in anhydrous N,N-dimethylformamide (2 mL), and the mixture was stirred overnight at 50° C. After cooling, water (4 mL) was added thereto, the precipitated solid was filtered off, and washed with water (5 mL). The obtained solid was dried under reduced pressure to give the target compound (54 mg) as a pale brown solid (Yield 51%).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:25]1([C:31]2[O:35][N:34]=[C:33]([CH:36]=O)[C:32]=2[C:38]([F:41])([F:40])[F:39])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>ClCCl>[Br:2][C:1]([Br:5])=[CH:36][C:33]1[C:32]([C:38]([F:39])([F:40])[F:41])=[C:31]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:35][N:34]=1
Reactant: BrC(Br)(Br)Br
Reactant: O=Cc1noc(-c2ccccc2)c1C(F)(F)F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)(F)c1c(C=C(Br)Br)noc1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 66 %

Procedure:
To a solution of carbon tetrabromide (12.24 g, 36.9 mmol) in dichloromethane (10 mL) at 0° C. was added a solution of triphenylphosphine (4.84 g, 18.5 mmol) in dichloromethane (10 mL), and the resulting mixture was stirred at 0° C. for 5 min. A solution of 5-phenyl-4-(trifluoromethyl)isoxazole-3-carbaldehyde (Intermediate I-13B, 1.59 g, 4.62 mmol) in dichloromethane (10 mL) was added via syringe, and the reaction mixture was stirred at 0° C. for 20 min. The reaction mixture was diluted with dichloromethane and washed with water. A white precipitate formed in the organic and was removed by vacuum filtrating. The filtrate was washed with a saturated aqueous solution of sodium bicarbonate, washed with a saturated aqueous solution of ammonium chloride, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash silica gel chromatography using a mixture of ethyl acetate in hexane (1%-3%) to give 3-(2,2-dibromovinyl)-5-phenyl-4-(trifluoromethyl)isoxazole (1.21 g, 3.05 mmol, 66.0% yield) as a white solid. The product had an HPLC ret. time=3.10 min.−Column: Chromolith SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=397.9. 1H NMR (500 MHz, CDCl3) δ ppm 7.43 (s, 1H), 7.52-7.56 (m, 2H), 7.56-7.61 (m, 1H), and 7.74 (d, J=7.49 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[N:5]=[CH:4][C:3]=1[C:12]([NH2:14])=[O:13].[CH2:15]([N:22]1[CH2:26][CH2:25][CH:24]([C:27](OC)=O)[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([N:22]1[CH2:26][CH2:25][CH:24]([C:27]2[NH:14][C:12](=[O:13])[C:3]3[CH:4]=[N:5][N:6]([CH:7]4[CH2:11][CH2:10][CH2:9][CH2:8]4)[C:2]=3[N:1]=2)[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NC(=O)c1cnn(C2CCCC2)c1N
Reactant: COC(=O)C1CCN(Cc2ccccc2)C1
Product: O=c1[nH]c(C2CCN(Cc3ccccc3)C2)nc2c1cnn2C1CCCC1

Procedure:
Following the procedure for the preparation of 6-[(3,4-trans)-1-benzyl-4-methylpyrrolidin-3-yl]-1-(2-methoxyphenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting 5-amino-1-cyclopentyl-1H-pyrazole-4-carboxamide and methyl 1-benzylpyrrolidine-3-carboxylate provided the title compound. 400 MHz 1H NMR (CDCl3) δ 8.01 (s, 1H), 7.39-7.32 (m, 4H), 7.27-7.23 (m, 1H), 5.12-5.09 (m, 1H), 3.84 (d, J=12.4 Hz, 1H), 3.61 (d, J=12.4 Hz, 1H), 3.30-3.26 (m, 1H), 3.18-3.14 (m, 1H), 3.01 (d, J=9.9 Hz, 1H), 2.45-2.32 (m, 3H), 2.11-1.90 (m, 7H), 1.71-1.65 (m, 2H). MS: (M+H m/z=364.1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9](O)=[O:10])=[CH:4][CH:3]=1.C(OCC)(=O)CC(O)=O.CN.BrC1C=CC([C@H:32]([NH2:34])C)=CC=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([NH:34][CH3:32])=[O:10])=[CH:4][CH:3]=1
Reactant: C[C@@H](N)c1ccc(Br)cc1
Reactant: CC(C)(C(=O)O)c1ccc(Br)cc1
Agent: CCOC(=O)CC(=O)O
Agent: CN
Product: CNC(=O)C(C)(C)c1ccc(Br)cc1
Yield: 84 %

Procedure:
The title compound was prepared as described in Step 1 of Example A(39), where 2-(4-bromophenyl)-2-methyl propionic acid was substituted for ethyl hydrogen malonate and methyl amine was substituted instead of (R)-(+)-1-(4-bromophenyl)ethylamine on that example. Yield 84%. 1H NMR (CDCl3) δ: 1.55 (s, 6H), 2.72 (d, J=4.6 Hz, 3H), 5.15 (brs, 1H), 7.22-7.26 (m, 2H), 7.46-7.50 (m, 2H).
Reaction SMILES: C(OC([N:11]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:12]1[CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])=O)C1C=CC=CC=1.C(Cl)(Cl)Cl.C(OC(N1C[C@H](O)C[C@H]1C(OC)=O)=O)C=C>C(OCC)(=O)C.C(O)C.[Pd]>[Si:19]([O:18][CH2:17][C@@H:12]1[CH2:13][C@@H:14]([OH:16])[CH2:15][NH:11]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Agent: [Pd]
Agent: C=CCOC(=O)N1C[C@H](O)C[C@H]1C(=O)OC
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](O)CN1

Procedure:
A slurry of 10% Pd/C (190 mg) in ethyl acetate (20 mL) was added to a solution of TBDMS ether (48) (1.90 g, 5.19 mmol) in ethanol (100 mL). The reaction mixture was hydrogenated (Parr apparatus) for 16 h. The catalyst was removed by vacuum filtration through Celite and excess solvent was evaporated under reduced pressure to give a yellow oil in quantitative yield (1.20 g, 100%). [α]22D=+35.6° (c 0.042, CHCl3). 1H NMR (CDCl3): δ-(0.07-0.08) (m, 6H, H1′, H2′), 0.82 (s, 9H, H3′, H4′, H5′), 1.68-1.73 (m, 2H, H1,), 2.99-3.11 (m, 2H, H11), 3.47-3.50 (m, 3H, H11a, H3), 4.09 (bs, 1H, NH or OH), 4.32 (bs, 1H, NH or OH). 13C NMR (CDCl3): δ−5.4 (C3′, C5′, C6′), 18.1 (C4′), 25.8 (C1′, C2′), 37.4 (C1), 54.6 (C11), 58.1 (C2), 64.6 (C3), 72.2 (C11a). IR (thin film): ν=3330 (OH), 2928, 2857, 1557, 1421, 1331 (C—CH3), 1249 (CH3—Si), 1204 (t-Bu), 1191 (t-Bu), 1100 (Si—O), 1073, 993, 713 cm−1. MS (CI) m/e (relative intensity): 232 (M+., 100), 230 (13), 174 (5), 133 (6), 86 (6).
Reaction SMILES: Br[CH2:2][C:3]#[N:4].[OH:5][CH:6]1[CH2:11][CH2:10][CH2:9][NH:8][CH2:7]1>C1COCC1>[OH:5][CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:2][C:3]#[N:4])[CH2:7]1
Reactant: N#CCBr
Reactant: OC1CCCNC1
Solvent: C1CCOC1
Product: N#CCN1CCCC(O)C1
Temperature: 47.5 °C

Procedure:
BrCH2CN (3.19 g, 25.82 mmol) was added dropwise to a solution of 3-hydroxypiperidine (6.53 g, 64.55 mmol) in dry THF (25 mL) under N2, maintaining the temperature between 45-50° C. Following addition of BrCH2CN, the solution was refluxed for 30 min., before allowing the solution to cool down to room temperature. The solvent was removed in vacuo and the residual oil was purified by flash chromatography using CH2Cl2:CH3OH (9:1) as eluent. The title compound was obtained as a straw-coloured oil (3.04 g, 83%). δh (250 MHz; CDCl3); 1.9-2.15 (m, 3H, CH2CH2CH2, 1×CH2CH2CHOH), 2.25 (m, 1H, 1×CH2CH2CHOH), 2.55 (d, OH), 2.85-3 (m, 3H, NCH2CH2, 1×NCH2CH), 3.1 (2×d, 1H, 1×NCH2CH), 3.9 (s, 2H, NCH2CN) and 4.3 (m, 1H, CH2CHOH); FAB MS, m/z (M+H)+141.
Reaction SMILES: C(O)(=O)C.[Cl:5][C:6]1[CH:11]=[CH:10][C:9](/[C:12](/[C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:27]=[N:28][NH:29][CH:30]=3)=[C:22]([O:31][CH3:32])[N:21]=2)=[CH:13]\[C@@H:14]2[NH:18][C:17](=[O:19])[CH2:16][CH2:15]2)=[CH:8][CH:7]=1.[H][H]>CO.[Pd]>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:30]=[N:29][NH:28][CH:27]=3)=[C:22]([O:31][CH3:32])[N:21]=2)[CH2:13][C@@H:14]2[NH:18][C:17](=[O:19])[CH2:16][CH2:15]2)=[CH:8][CH:7]=1
Reactant: COc1nc(/C(=C/[C@H]2CCC(=O)N2)c2ccc(Cl)cc2)ccc1-c1cn[nH]c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: COc1nc(C(C[C@H]2CCC(=O)N2)c2ccc(Cl)cc2)ccc1-c1cn[nH]c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 62.8 %

Procedure:
10% palladium-activated carbon (60 mg) and acetic acid (2 mL) were added to a solution of (5R)-5-{(E)-2-(4-chlorophenyl)-2-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]ethenyl}pyrrolidin-2-one (122 mg) in methanol (3 mL) in a hydrogen gas stream, and the mixture was stirred at room temperature for 20 hours. The reaction solution was filtered through celite, and then the solvent was evaporated under reduced pressure. Saturated aqueous sodium bicarbonate was added to the residue, followed by extraction with chloroform. The solvent was evaporated from the organic layer under reduced pressure to give a crude product of (5R)-5-{2-(4-chlorophenyl)-2-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]ethyl}pyrrolidin-2-one as a yellow oil (77 mg).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[CH:12]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C>[CH:12]([N:15]1[CH2:20][CH2:19][N:18]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:7])[CH:8]=2)[CH2:17][CH2:16]1)([CH3:14])[CH3:13]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CC(C)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)N1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Temperature: 130 °C
Reaction time: 24 h
Yield: 53.4 %

Procedure:
A mixture of 5-chloro-2-nitroaniline (1.35 g, 7.8 mmol), 1-isopropyl-piperazine (2.0 g, 15.6 mmol) and anhydrous potassium carbonate (1.18 g, 8.6 mmol) in N,N-dimethylacetamide (2.5 ml) was stirred at 130° C. under nitrogen for 1 day. Sample NMR analysis showed complete conversion of the starting material. The resultant mixture was then cooled to room temperature, poured onto cold water and stirred vigorously for 3 h. The resulting brown precipitate was collected by filtration, washed well with water then dried on the filter funnel. The resulting brown solid was slurried in diethyl ether, filtered, washed with additional diethyl ether, dried to afford 5-(4-Isopropyl-piperazin-1-yl)-2-nitro-phenylamine (1.1 g, 53%) and used in the next step without further purification.