Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH2:6][NH:7][C:8](=O)[CH3:9])=[CH:4][CH:3]=1.B.CSC.Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][CH2:8][CH3:9])=[CH:11][CH:12]=1
Reactant: CC(=O)NCc1ccc(Cl)cc1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CSC
Product: CCNCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.4 %

Procedure:
N-(4-chlorobenzyl)acetamide (2.337 g, 12.726 mmol) was dissolved in THF (100 ml) and was cooled to zero degrees under argon atmosphere. (Methylthio)methane compound with borane (1:1) (2.417 g, 31.815 mmol) was added and the mixture was refluxed overnight at RT. HCl (15 ml, 10%) was gently added and was stirred overnight. The solvent was removed by evaporation. Diethyl ether (20 ml) was added and the product was extracted to the water phase by K2CO3 (3×15 ml). The aqueous phase was acidified by HCl (10 ml, 10%) and the product was extracted to the organic phase by EtOAc (3×15 ml). The organic phase was dried (MgSO4) and the solvent was removed by evaporation to give 0.938 g of N-(4-chlorobenzyl)-N-ethylamine (yield 43.4%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3([CH2:18][CH2:17][N:16]([CH2:19][CH2:20][NH:21][C:22](=[O:32])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[N+:29]([O-])=O)[CH2:15][CH2:14]3)[C:12](=[O:33])[NH:11][CH2:10]2)=[CH:5][CH:4]=1.[H][H]>[Pd].C(O)(=O)C>[NH2:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:22]([NH:21][CH2:20][CH2:19][N:16]1[CH2:15][CH2:14][C:13]2([N:9]([C:6]3[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=3)[CH2:10][NH:11][C:12]2=[O:33])[CH2:18][CH2:17]1)=[O:32]
Reactant: [H][H]
Reactant: O=C(NCCN1CCC2(CC1)C(=O)NCN2c1ccc(F)cc1)c1ccccc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Product: Nc1ccccc1C(=O)NCCN1CCC2(CC1)C(=O)NCN2c1ccc(F)cc1

Procedure:
A mixture of 9 parts of N-{2-[1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4,5]dec-8-yl]ethyl}-2-nitrobenzamide hydrochloride in 150 parts of acetic acid is hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is taken up in water and the whole is alkalized with ammonium hydroxide. The product is extracted twice with trichloromethane. The combined extracts are washed twice with water, dried, filtered and evaporated. The solid residue is boiled with 2-propanol and filtered. The product is allowed to crystallize from the filtrate. It is filtered off and dried in vacuo, yielding 5 parts of 2-amino-N-{2-[1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4,5]dec-8-yl]ethyl}benzamide; mp. 194.9° C.
Reaction SMILES: Br[CH2:2][CH:3]([OH:8])[C:4]([F:7])([F:6])[F:5].[Br:9][C:10]1[CH:11]=[CH:12][C:13]([OH:33])=[C:14]([CH:32]=1)[CH2:15][N:16]([C:19]1[N:24]=[N:23][C:22]([C:25]([O:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:26])=[CH:21][CH:20]=1)[CH2:17][CH3:18]>>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([O:33][CH2:2][CH:3]([OH:8])[C:4]([F:7])([F:6])[F:5])=[C:14]([CH:32]=1)[CH2:15][N:16]([C:19]1[N:24]=[N:23][C:22]([C:25]([O:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:26])=[CH:21][CH:20]=1)[CH2:17][CH3:18]
Reactant: OC(CBr)C(F)(F)F
Reactant: CCCCOC(=O)c1ccc(N(CC)Cc2cc(Br)ccc2O)nn1
Product: CCCCOC(=O)c1ccc(N(CC)Cc2cc(Br)ccc2OCC(O)C(F)(F)F)nn1

Procedure:
The title compound was prepared by reacting 3-bromo-1,1,1-trifluoropropan-2-ol and butyl 6-[N-(5-bromo-2-hydroxybenzyl)-N-ethylamino]pyridazine-3-carboxylate using a similar method to that of reference example 4.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH3:19][C:20]1([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:23]2[CH2:22][CH2:21][C:20]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:19])[CH2:25][CH2:24]2)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: CC1(NC(=O)OC(C)(C)C)CCNCC1
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Solvent: CO
Product: CC1(NC(=O)OC(C)(C)C)CCN(c2nc(Cl)nc3c2CCC3c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 168 h
Yield: 24.4 %

Procedure:
To a solution of 2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation H) (400 mg, 1.413 mmol) in MeOH (14.100 mL) was added tert-butyl 4-methylpiperidin-4-ylcarbamate (303 mg, 1.413 mmol). The resulting mixture was stirred at RT for 7 days. At that time, the reaction mixture was concentrated in vacuo. Purification by flash chromatography (Silica, EtOAc/Hexanes) gave tert-butyl 1-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-4-methylpiperidin-4-ylcarbamate (159 mg, 0.345 mmol, 24.41% yield) as a yellow foam. LC-MS (M+H)+=461.2. 1H NMR (500 MHz, MeOD) δ ppm 7.12-7.22 (2H, m), 6.98-7.09 (2H, m), 4.19 (3H, d, J=2.14 Hz), 3.38-3.56 (2H, m), 3.13-3.25 (1H, m), 3.02-3.13 (1H, m), 2.53-2.67 (1H, m), 2.11-2.24 (2H, m), 1.96-2.08 (1H, m), 1.53-1.65 (2H, m), 1.47 (9H, s), 1.37 (3H, s).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[NH:16][C:15](=[O:18])[CH:14]([NH:19][C:20](=[O:34])[C@H:21]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:13]2)=[O:6].[H-].[Na+]>CN(C=O)C>[CH3:24][CH:23]([CH3:25])[CH2:22][C@@H:21]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:20](=[O:34])[NH:19][CH:14]1[CH2:13][C:12]2[C:17](=[C:8]([N:7]3[CH2:2][CH2:3][CH2:4][C:5]3=[O:6])[CH:9]=[CH:10][CH:11]=2)[NH:16][C:15]1=[O:18]
Reactant: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)NC1Cc2cccc(NC(=O)CCCCl)c2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)NC1Cc2cccc(N3CCCC3=O)c2NC1=O
Reaction time: 1.5 h

Procedure:
tert-Butyl (2R)-1-[8-(4-chlorobutanamido)-2-oxo-1,2,3,4-tetrahydroquinolin-3-ylamino]-4-methyl-1-oxopentan-2-ylcarbamate (350 mg) was dissolved in N,N-dimethylformaldehyde (4.0 mL), and sodium hydride (34 mg) was added thereto under cooling on ice, followed by stirring for 1.5 hours. The resultant mixture was extracted with water and ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, whereby the title compound (325 mg) was yielded.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:7]=[C:8]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:9]=1.[CH:24]1([S:30](Cl)(=[O:32])=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[CH2:25]1[CH2:26][CH2:27][CH2:28][CH2:29][CH:24]1[S:30]([NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:7]=[C:8]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:9]=1)(=[O:32])=[O:31]
Reactant: CCOC(=O)CCc1cc(CCN)cc(Cc2cccnc2)c1
Reactant: O=S(=O)(Cl)C1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCc1cc(CCNS(=O)(=O)C2CCCCC2)cc(Cc2cccnc2)c1
Yield: 45.5 %

Procedure:
A solution of ethyl 3-[3-(2-aminoethyl)-5-(3-pyridylmethyl)phenyl]propanoate (Preparation 47; 0.60 g), cyclohexylsulphonyl chloride (0.526 g), triethylamine (0.194 g) and 4-dimethylaminopyridine (0.352 g) in dichloromethane (6 ml) was stirred at room temperature for 3 hours and then washed with water and dried (MgSO4). Evaporation under vacuum of the solvent gave a gum which was chromatographed on silica gel. Elution with dichloromethane, followed by a dichloromethane:methanol (97:3) mixture gave the title compound as a gum (401 mg); Rf 0.70 (SS 2); δ (CDCl3): 1.10-1.25(2H,m), 1.21(3H,t,J=7.1 Hz), 1.37-1.50(2H,m), 1.65-1.70(2H,m), 1.83-1.86(2H,m), 2.05-2.09(2H,m), 2.57(2H,t,J=7.7 Hz), 2.79(2H,t,J=6.9 Hz), 2.88 (2H,t,J=7.7 Hz), 3.30-3.37(2H,m), 3.91(2H,s), 3.99-4.02 (1H,m), 4.10(2H,q,J=7.1 Hz), 6.86(1H,s), 6.89(1H,s), 6.91(1H,s), 7.21-7.23(1H,m), 7.44(1H,d,J=7.9 Hz), 8.45-8.47(2H,m).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([N:10]([CH2:42][CH3:43])[C:11]([NH:13][C:14]1[C:15]([C:25]2[NH:29][C:28]3[CH:30]=[C:31]([N:35]4[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]4)[C:32]([F:34])=[CH:33][C:27]=3[N:26]=2)=[N:16][N:17](C2CCCCO2)[CH:18]=1)=[O:12])[CH3:9]>ClCCl>[CH2:42]([N:10]([CH2:8][CH3:9])[C:11]([NH:13][C:14]1[C:15]([C:25]2[NH:29][C:28]3[CH:30]=[C:31]([N:35]4[CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][CH2:40]4)[C:32]([F:34])=[CH:33][C:27]=3[N:26]=2)=[N:16][NH:17][CH:18]=1)=[O:12])[CH3:43]
Reactant: CCN(CC)C(=O)Nc1cn(C2CCCCO2)nc1-c1nc2cc(F)c(N3CCN(C)CC3)cc2[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)C(=O)Nc1c[nH]nc1-c1nc2cc(F)c(N3CCN(C)CC3)cc2[nH]1
Temperature: 22 °C
Reaction time: 72 h
Yield: 48.1 %

Procedure:
0.7 mL of trifluoroacetic acid is added to a solution of 250 mg of 1,1-diethyl-3-[3-[5-fluoro-6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-4-yl]urea in solution in 2 mL of dichloromethane. The reaction medium is stirred at 22° C. for 72 hours. The reaction medium is concentrated under vacuum in a rotary evaporator. After evaporation, the reaction crude is purified by flash chromatography on an Intelliflash apparatus on an Analogix RS-12 cartridge. The elution is carried out in pure dichloromethane for 15 min and then in dichloromethane containing 10% of ammoniacal methanol. 100 mg of 1,1-diethyl-3-{3-[5-fluoro-6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}urea are obtained in the form of a beige solid. 1H NMR (300 MHz, DMSO-d6, δ in ppm): 1.18 (t, J=7.0 Hz, 6H); 2.90 (s, 3H); 3.05 (m, 2H); 3.28 (m, 2H); 3.38 (q, J=7.0 Hz, 4H); 3.54 (m, 4H); 7.24 (d, J=8.0 Hz, 1H); 7.46 (d, J=11.5 Hz, 1H); 8.00 (s, 1H). EI mass spectrum: m/z=414 (M)+.; m/z=341 (M−C4H11N)+; m/z=114 CF3CO2H+. relative to TFA; m/z=72 C4H10N+; m/z=69 CF3+ relative to TFA; m/z=45 CO2H+ relative to TFA, base peak; m/z=43 C2H5N+.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([CH:6]1[CH2:8][CH2:7]1)[OH:5].O.[NH2:11][NH2:12]>CO>[CH:6]1([CH:4]([OH:5])[C:3]([NH:11][NH2:12])=[O:2])[CH2:8][CH2:7]1
Reactant: COC(=O)C(O)C1CC1
Reactant: NN
Solvent: CO
Solvent: O
Product: NNC(=O)C(O)C1CC1
Yield: 69 %

Procedure:
As described for example 112a, (rac.)-2-cyclopropyl-2-hydroxy-acetic acid methyl ester (Newall, Christopher Earle; Foxton, Michael Walter; Hartley, Charles David; Looker, Brian Edgar. Cephalosporin antibiotics. Eur. Pat. Appl. (1985), 57 pp) in methanol was reacted with hydrazine hydrate (1.0 equivalent) at rt for 76 h. All volatiles were evaporated and the residue was triturated with hexane to afford the title compound as a white solid (yield: 69%). MS: m/e=112.2 [M−H2O]+.
Reaction SMILES: C[O:2]C1(F)O[C:6]([C:12]([F:15])([F:14])[F:13])([C:8]([F:11])([F:10])[F:9])[O:5]O1.CSC>[Cl-].[Na+].O>[OH2:2].[OH2:2].[OH2:2].[F:9][C:8]([F:11])([F:10])[C:6]([C:12]([F:15])([F:14])[F:13])=[O:5]
Reactant: COC1(F)OOC(C(F)(F)F)(C(F)(F)F)O1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CSC
Product: O=C(C(F)(F)F)C(F)(F)F
Temperature: 0 °C
Yield: 264.8 %

Procedure:
100 g (0.38 mol) of 1-fluoro-4,4-bis(trifluoromethyl)-2,3,5-trioxolanyl methyl ether (purity: 98%) was charged in a 500-ml five-necked flask. While performing nitrogen bubbling, brine at −20° C. was passed through a Dimroth condenser. While stirring at a reaction temperature of −20° C., 23.4 g (0.38 mol) of dimethyl sulfide was added dropwise using a dropping funnel over 30 minutes. The gas obtained by the reaction was collected by a water trap cooled with ice water to 0° C., and the obtained aqueous layer was analyzed by 19F-NMR. As a result, it was confirmed that 73.8 g (yield: 89%) of hexafluoroacetone trihydrate was obtained.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[F:13][C:14]1[CH:33]=[CH:32][C:17]2[C:18]([CH:21]3[CH2:26][CH2:25][N:24]([CH:27]([CH2:30][CH3:31])[CH2:28]O)[CH2:23][CH2:22]3)=[N:19][O:20][C:16]=2[CH:15]=1.[C:34]1(=[O:44])[NH:38][C:37](=[O:39])[C:36]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:35]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CCOCC>[F:13][C:14]1[CH:33]=[CH:32][C:17]2[C:18]([CH:21]3[CH2:26][CH2:25][N:24]([CH:27]([CH2:30][CH3:31])[CH2:28][N:38]4[C:37](=[O:39])[C:36]5=[CH:40][CH:41]=[CH:42][CH:43]=[C:35]5[C:34]4=[O:44])[CH2:23][CH2:22]3)=[N:19][O:20][C:16]=2[CH:15]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCC(CO)N1CCC(c2noc3cc(F)ccc23)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(CN1C(=O)c2ccccc2C1=O)N1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 7.6 %

Procedure:
A solution of diethyl azodicarboxylate (DEAD, 4.9 g, 28.3 mmol) in THF (50 ml) was added dropwise to a solution of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butanol (6.9 g, 23.6 mmol), phthalimide (4.16 g, 1.2 eq), and triphenylphosphine (7.4 g, 28.3 mmol) in THF (200 ml) at room temperature. The solution was stirred at room temperature for 24 hours. After the reaction, the solvent was stripped to dryness. The residue was stirred in ether (200 ml) and the insolubles were removed by filtration. The oily residue from concentration of the ether solution was purified by two flash chromatography (SiO2, 75 g, eluted with dichloromethane, DCM, and 1-2% CH3OH in DCM) and (100 g of SiO2 ; eluted with DCM, 1 l, and 1% CH3OH in DCM, 1.2 l). Two close compounds were separated and the top compound on TLC (1.6 g) was recrystallized from isopropyl ether to yield 0.76 g of white crystals, m.p. 86-88° C.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Cl:6][C:7]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:8]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10]>>[Cl:6][C:7]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:8]=1[C:9]([C:11]1[CH:16]=[C:15]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:14]=[CH:13][CH:12]=1)=[O:10]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1Cl
Product: O=C(c1cccc(S(=O)(=O)Cl)c1)c1cc(Cl)ccc1Cl
Temperature: 0 °C

Procedure:
Chlorosulfonic acid (233.0 g, 2 mol) was added into a 3 L three-necked flask equipped with a stirrer and cooling pipe, followed by adding 2,5-dichlorobenzophenone (100.4 g, 400 mmol), and the reactant was allowed to react for 8 hours using an oil bath at 100° C. After a predetermined time, the reaction liquid was slowly poured into crushed ice (1000 g) and extracted with ethyl acetate. The organic layer was washed with sodium chloride solution and dried with magnesium sulfate, and then ethyl acetate was removed to obtain a light yellow crude crystal (3-(2,5-dichlorobenzoyl)benzenesulfonic acid chloride. The crude crystal was not purified and directly used in the following step.
Reaction SMILES: [CH:1]([C:4]1[C:5]([CH3:13])=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](O)=[O:8])([CH3:3])[CH3:2].CN(C=O)C.S(Cl)([Cl:21])=O>>[CH:1]([C:4]1[C:5]([CH3:13])=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([Cl:21])=[O:8])([CH3:3])[CH3:2]
Reactant: Cc1c(C(=O)O)cccc1C(C)C
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Cl)cccc1C(C)C

Procedure:
3-Isopropyl-2-methyl-benzoic acid (0.75 g) was refluxed in ca. 3 mL of thionyl chloride with a drop of DMF fro several hours and thionyl chloride was removed in vacuo to yield 3-isoproyl-2-methyl-benzoyl chloride. The acid chloride was dissolved in 5 ML of CH2Cl2 and added slowly and simultaneously but separately with 5 mL of aqueous NaOH (0.265 g, 6.6 mmol) to a solution of 3,5-dimethyl-benzoic acid N-tert-butyl-hydrazide (0.973 g, 4.4 mmol) dissolved in 10 mL of CH2Cl2 prechilled to −5° C. During the addition, the temperature was kept below 5° C. The mixture was allowed to warm slowly to room temperature and was stirred overnight. The organic layer was removed and the aqueous layer was extracted with CH2Cl2. The organic extracts were combined, dried, and solvent was removed in vacuo to give 1.61 g of crude product as a yellow oil. This material was chromatographed on silica gel using 4:1 hexanes: ethyl acetate as eluant, and subsequently triturated from 1:1 hexane: ether, yielding 3,5-dimethyl-benzoic acid N-tert-butyl-N′-(3-isoproyl-2-methyl-benzoyl)-hydrazide, after arduous removal of ether in a vacuum oven at 60° C. (0.35 g, m.p. 182.5° C. 1H NMR (CDCl3, 200 MHz), δ (ppm): 7.6 (s, 1H), 7.25 (d, 1H), 7.1 (s, 2H), 7.05 (s, 1H), 7.0 (m, 1H), 6.3 (d, 1H), 3.1 (m, 1H), 2.3 (s, 6H), 1.95 (s, 3H), 1.6 (s, 9H), 1.18 (m, 6H).
Reaction SMILES: [NH2:1][OH:2].CC1CCCO1.[Na+].[Cl-].[C:11](#[N:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O>[C:11](=[N:1][OH:2])([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N#Cc1ccccc1
Reactant: NO
Agent: [Cl-]
Agent: [Na+]
Solvent: CC1CCCO1
Solvent: O
Product: NC(=NO)c1ccccc1
Temperature: 70 °C

Procedure:
Benzonitrile (50.0 g, 0.485 mol) was added to a 250 mL flask and heated to 70° C. with stirring. Deionized water (1.0 g) was added and the temperature was lined out at 70° C. Aqueous hydroxylamine (50%, 37.50 g, 34.8 ml, assay was 53.3%, 0.605 moles) was added via a syringe pump over 1.5 hours while maintaining the temperature at 70°±2° C. HPLC analysis indicated that the conversion of benzonitrile was >99% after about 2.5 hours of reaction time. The batch was heated for a total of 3.5 hours at 70° C., then was cooled to 60° C. The batch was transferred to a 500 mL flask with 2-methyltetrahydrofuran (208.98 g), followed by 20 wt % aqueous NaCl (40.0 g). The mixture was heated to 60° C., and the phases were separated at 60° C. to give a solution of benzamide oxime in 2-methyltetrahydrofuran (281.80 g) and aqueous waste (44.61 g). The 2-methyltetrahydrofuran solution assayed for 21.73 wt % benzamide oxime.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[N:11]=[C:12]=[S:13].[N-:14]=[N+:15]=[N-:16].[Na+].O.Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[N:11]1[C:12]([SH:13])=[N:16][N:15]=[N:14]1
Reactant: COc1ccc(OC)c(N=C=S)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(OC)c(-n2nnnc2S)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.1 %

Procedure:
2,5-Dimethoxyphenylisothiocyanate (39 g, 0.22 mol) and sodium azide (14.3 g, 0.22 mol) were added to a mixture of water (150 ml) and ethanol (60 ml) and the mixture was heated on a steam bath to about 80° C. to 90° C. with stirring for 3 hours. The reaction mixture was cooled to room temperature and a 2N HCl solution (100 ml) was added. The raw crystals formed were collected by filtration and recrystallized from isopropanol to obtain 1-(2,5-dimethoxyphenyl)-5-mercaptotetrazole (35.7 g, yield 75%). The melting point was 151° to 152° C.
Reaction SMILES: [CH3:1][N:2](S(C1C=CC(C)=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[Cl:24][C:25]1[C:32]([N+:33]([O-:35])=[O:34])=[CH:31][CH:30]=[CH:29][C:26]=1[C:27]#[N:28].[Cl-].[Al+3].[Cl-].[Cl-].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[Cl:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:5]=1[C:4]1[N:28]=[C:27]([C:26]2[CH:29]=[CH:30][CH:31]=[C:32]([N+:33]([O-:35])=[O:34])[C:25]=2[Cl:24])[N:2]([CH3:1])[N:3]=1
Reactant: N#Cc1cccc([N+](=O)[O-])c1Cl
Reactant: Cc1ccc(S(=O)(=O)N(C)N=C(Cl)c2c(F)cccc2Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1cccc([N+](=O)[O-])c1Cl
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
A mixture of N-methyl-N-(p-toluenesulfonyl)-2-chloro-6-fluorobenzohydrazonoyl chloride (1.90 g), 2-chloro-3-nitrobenzonitrile (1.19 g), anhydrous aluminum chloride (0.70 g) and o-dichlorobenzene (20 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, the reaction mixture is dissolved in chloroform (100 ml), washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline in this order, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 1.19 g of desired compound (melting point: 112.0°-114.0° C.).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[CH2:32][C:33]#[N:34])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.N1CCCCC1.[CH3:42][C:43]([N:47]1[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1)([CH3:46])[CH:44]=O>C(O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31]([C:32](=[CH:42][C:43]([CH3:46])([N:47]3[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]3)[CH3:44])[C:33]#[N:34])=[O:35])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: CC(C)(C=O)N1CCCCC1
Reactant: N#CCC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Solvent: C1CCNCC1
Solvent: CCO
Product: CC(C)(C=C(C#N)C(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21)N1CCCCC1
Yield: 7.7 %

Procedure:
A solution of 3-[(2R)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-3-oxo-propanenitrile (150. mg, 0.32 mmol), piperidine (0.03 mL, 0.32 mmol) and 2-methyl-2-(1-piperidyl)propanal (74.08 mg, 0.48 mmol) in ethanol (8 mL) was heated in a sealed tube at 90° C. for 16 hrs. The solution was cooled and concentrated. The residue was dissolved in ethyl acetate and washed with 5% citric acid and brine and then dried (MgSO4), filtered and concentrated. The crude material was purified by Isolera (10 grams column at 0% to 6% MeOH/ethyl acetate) to obtain 15 mg (8%) of the title compound. MS (pos. ion) m/z: 609 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][N:18]2[C:23](=[O:24])[C:22]([CH3:25])=[CH:21][NH:20][C:19]2=[O:26])[CH2:11][CH2:10]1.S(OC)(O[CH3:31])(=O)=O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][N:18]2[C:23](=[O:24])[C:22]([CH3:25])=[CH:21][N:20]([CH3:31])[C:19]2=[O:26])[CH2:13][CH2:14]1
Reactant: COS(=O)(=O)OC
Reactant: COc1ccccc1N1CCN(CCCn2c(=O)[nH]cc(C)c2=O)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: COc1ccccc1N1CCN(CCCn2c(=O)c(C)cn(C)c2=O)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 3-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propyl}-5-methyl-2,4(1H,3H)-pyrimidinedione (550 mg, 1.53 mmol), prepared as in Example 32, dimethyl sulfate (193 mg, 1.53 mmol) and 0.1N tetrabutylammonium fluoride (100 mL, 10 mmol in THF) was stirred 4 hours at 25° C. The reaction mixture then was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with ethyl acetate to give 3-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propyl}-1,5-dimethyl-2,4(1H,3H)-pyrimidinedione, as an oil. The free base was recrystallized from a solution of hydrochloric acid in alcohol to give 3-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propyl}-1,5-dimethyl-2,4(1H,3H)-pyrimidinedione hydrochloride, m.p. 256°-258° C. Anal.: Calcd. for C20H28N4O3.(HCl)2 : C, 53.93; H, 6.79; N, 12.58%; Found: C, 54.05; H, 6.87; N, 12.58%.