Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[C:11](=[O:12])[C:10]([CH3:13])=[N:9][N:8]=[C:7]1[N:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]([NH:20]C(=O)OC(C)(C)C)[CH2:15]1)#[N:2].Cl.C([O-])(O)=O.[Na+]>ClCCl.CO>[NH2:20][C@@H:16]1[CH2:17][CH2:18][CH2:19][N:14]([C:7]2[N:6]([CH2:5][C:4]3[CH:28]=[CH:29][CH:30]=[CH:31][C:3]=3[C:1]#[N:2])[C:11](=[O:12])[C:10]([CH3:13])=[N:9][N:8]=2)[CH2:15]1
Reactant: Cc1nnc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)n(Cc2ccccc2C#N)c1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1nnc(N2CCC[C@@H](N)C2)n(Cc2ccccc2C#N)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-tert-butyl 1-(4-(2-cyanobenzyl)-6-methyl-5-oxo-4,5-dihydro-1,2,4-triazin-3-yl)piperidin-3-ylcarbamate (7, 13 mg) in dichloromethane (0.5 mL) was added HCl in methanol (20%) (1 mL) and the mixture was stirred at RT for 2 h. The mixture was carefully neutralized with NaHCO3 (aq, saturated), and extracted with CH2Cl2 (50 mL×3). The combined extracts were dried over Na2SO4 and concentrated to give the crude product. This was purified by column chromatography on silica gel, eluted with 92:6:2 dichloromethane-methanol-ammonia to provide (R)-2-((3-(3-aminopiperidin-1-yl)-6-methyl-5-oxo-1,2,4-triazin-4(5H)-yl)methyl)benzonitrile (8). MS: m/z, 325 (100%, M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1.[Cl-].C[NH3+].C([BH3-])#N.[Na+].[O:29]=[CH:30][CH:31]([CH2:33]O)[OH:32].C#N>CO>[OH:32][CH:31]([CH2:30][OH:29])[CH2:33][NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1
Reactant: Nc1ccc2c(c1)C(=Cc1c[nH]c3ncccc13)C(=O)N2
Reactant: O=CC(O)CO
Agent: C#N
Agent: C[NH3+]
Agent: [BH3-]C#N
Solvent: CO
Product: O=C1Nc2ccc(NCC(O)CO)cc2C1=Cc1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 50 h
Yield: 60 %

Procedure:
To a stirred solution of 5-amino-3-[(7-azaindol-3-yl) methylen]-2-oxindole (2.773 g, 10 mmol) in methanol (30 ml) was added anhydrous methylammonium chloride (0.60 g, 10 mmol). Then sodium cyanoborohydride (0.378 g, 6 mmol) was added in portions. Finally, glyceraldehyde (0.901 g, 10 mmol) was added portionwise over 30 min and the solution stirred at room temperature for 50 h. Ice cold 6N HCl was added until gas evolution (HCN) stopped and the pH of the solution was 2. The methanol was evaporated in vacuo and the remaining aqueous solution was washed with CHCl3. Solid KOH was added until the pH was 12. Solid NaCl was added to saturation and the solution extracted twice with CHCl3. The CHCl3 extracts were washed with saturated NaCl solution, dried over K2CO3 and evaporated. The residue was chromatographed on silica gel using CHCl3 --MeOH mixtures as eluant. Thus pure title compound was obtained in about 60% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][O:7][C:8]([C:15]([F:18])([F:17])[F:16])([C:11]([F:14])([F:13])[F:12])[C:9]#[N:10])=[CH:4][CH:3]=1.[OH-].[K+].C([OH:25])C>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]([C:11]([F:12])([F:13])[F:14])([C:15]([F:16])([F:17])[F:18])[C:9]([NH2:10])=[O:25])=[CH:19][CH:20]=1
Reactant: CCO
Reactant: N#CC(OCc1ccc(Cl)cc1)(C(F)(F)F)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: NC(=O)C(OCc1ccc(Cl)cc1)(C(F)(F)F)C(F)(F)F

Procedure:
A mixture of 2-(4-chlorobenzyloxy)-3,3,3-trifluoro-2-trifluoromethylpropionitrile (20 g.), potassium hydroxide (25 g.), ethanol (250 ml.) and water (250 ml.) is heated under reflux for 15 minutes. Most of the ethanol is evaporated in vacuo, and the residue is cooled until the precipitated oil solidifies. The solid is filtered off, and is recrystallised from a mixture of ether and light petroleum (b.p. 40°-60° C.) (charcoal) to give 2-(4-chlorobenzyloxy)-3,3,3-trifluoro-2-trifluoromethylpropionamide, m.p. 94°-95° C. (13.9 g.).
Reaction SMILES: C(OCC)(=O)C.[ClH:7].[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:23][C:24]3[CH:43]=[CH:42][C:27]([CH2:28][CH:29]4[CH2:34][CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30]4)=[CH:26][CH:25]=3)=[O:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1>>[ClH:7].[F:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([NH:23][C:24]3[CH:43]=[CH:42][C:27]([CH2:28][CH:29]4[CH2:34][CH2:33][CH2:32][NH:31][CH2:30]4)=[CH:26][CH:25]=3)=[O:22])=[CH:19][CH:20]=2)=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(Cc2ccc(NC(=O)c3ccc(-c4ccc(F)cc4)cc3)cc2)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(CC2CCCNC2)cc1)c1ccc(-c2ccc(F)cc2)cc1

Procedure:
4N Hydrogen chloride-ethyl acetate (3 ml) was added to tert-butyl 3-[4-[[(4′-fluoro[1,1′-biphenyl]-4-yl)carbonyl]amino]benzyl]-1-piperidinecarboxylate (150 mg, 0.307 mmol) obtained in Reference Example 81. Two hours later, the solvent was distilled out under reduced pressure. Diisopropyl ether was added to the residue, to give the titled compound (115 mg) as a colorless powder.
Reaction SMILES: C([N:3]([CH2:7][P:8](=[O:11])([OH:10])[OH:9])[CH2:4][CH2:5][OH:6])C.[OH2:12]>Cl>[P:8]([CH2:7][NH:3][CH2:4][C:5]([OH:6])=[O:12])([OH:9])([OH:10])=[O:11]
Reactant: O
Reactant: CCN(CCO)CP(=O)(O)O
Agent: Cl
Product: O=C(O)CNCP(=O)(O)O
Temperature: 315 °C
Yield: 20 %

Procedure:
To a 100 ml Monel autoclave were charged 2.08 g (11.4 mmol) of N-ethyl-N-(2-hydroxyethyl)-aminomethylphosphonic acid and 3.63 g (91 mmol) of dry, powdered NaOH. The two powders were intimately mixed. To this mixture 1 ml of water was added and mixed until the dampness was evenly distributed through the mass. The reaction vessel was then flushed with N2, sealed and heated to 315° C. for two and a half hours. When the vessel had reached 315° C. an internal pressure of 2.2×106N/M2 had been established. By the end of the heating period the pressure had risen to 3.5×106N/M2. The excess pressure generated to this point was released and an additional 9 ml of H2O were introduced. The reaction temperature was adjusted to 300° C. which produced an internal pressure of 4.3×106N/M2. After five hours of heating at 300° C., the internal pressure had reached 4.6× 106N/M2. The reaction was allowed to cool to room temperature at which point the residual pressure was released. The reaction mixture was diluted with water and neutralized with 91 mmol of HCl. The solution was stripped to dryness. The residue was taken up in conc. HCl and the precipitated NaCl was filtered off. The filtrate was concentrated and purified by ion exchange chromatography to yield 0.38 g (20%) of N-phosphonomethylglycine based on the original substrate.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][CH2:10][CH2:11][CH2:12][N:13]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[C:22]([O-:24])=O)[CH:15]=[CH:14]1)[CH2:2]2.[Li+].C(N(CC)C(C)C)(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>CN(C=O)C>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([N:9]1[CH2:10][CH2:11][CH2:12][N:13]3[C:21]4[C:16]([CH:15]=[CH:14]3)=[CH:17][CH:18]=[CH:19][C:20]=4[C:22]1=[O:24])[CH2:2]2
Reactant: O=C([O-])c1cccc2ccn(CCCN[C@H]3CN4CCC3CC4)c12
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1c2cccc3ccn(c23)CCCN1[C@H]1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 5 h
Yield: 24.1 %

Procedure:
A solution of lithium (R)-1-(3-(quinuclidin-3-ylamino)propyl)-1H-indole-7-carboxylate (574 mg, 1.7 mmol) from Step D above in DMF (8 mL) was cooled in an ice bath while N,N-diisopropylethylamine (1.3 g, 10.3 mmol) was added, followed by 1-propanephosphonic acid cyclic anhydride (T3P) (3.3 g, 10.3 mmol). The reaction mixture was stirred at room temperature for 5 h. The reaction was quenched with water and the aqueous phase was extracted with methylene chloride (3×) and the combined extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 80:18:2 methylene chloride/methanol/concentrated ammonium hydroxide) to give (R)-2-(quinuclidin-3-yl)-2,3,4,5-tetrahydro-1H-[1,5]diazocino[3,2,1-hi]indol-1-one (127 mg, 24%) as an off-white solid: 1H NMR (300 MHz, CD3OD) δ 7.67 (d, J=6.6 Hz, 1H), 7.33 (d, J=7.5 Hz, 1H), 7.20 (d; J=3.3 Hz, 1H), 7.11 (t, J=7.8 Hz, 1H), 6.50 (d, J=3.0 Hz, 1H), 4.40-4.20 (m, 2H), 3.80-3.45 (m, 3H), 3.25-2.80 (m, 5H), 2.30-1.50 (m, 6H), 1.40-1.20 (m, 2H); MS (ESI+) m/z 310 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([O:19][CH2:20][CH3:21])[C:13]=1[C:14]1[CH:15]=[N:16][O:17][CH:18]=1)[C:7]([O:9]C)=[O:8])[CH3:2].Cl>CO.C1COCC1.[OH-].[Na+]>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([O:19][CH2:20][CH3:21])[C:13]=1[C:14]1[CH:15]=[N:16][O:17][CH:18]=1)[C:7]([OH:9])=[O:8])[CH3:2]
Reactant: CCOc1cc(C(=O)OC)cc(OCC)c1-c1cnoc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1cc(C(=O)O)cc(OCC)c1-c1cnoc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Methyl 3,5-diethoxy-4-(isoxazol-4-yl)benzoate (91 mg) was dissolved in a mixed solvent of methanol/THF (8 mL, 3/5), aqueous 1 M NaOH solution (1.2 mL) was added to it, and stirred at room temperature for 5 hours. Aqueous 1 M HCl solution (1.2 mL) was added to it, and the solvent was concentrated under reduced pressure. The formed solid was taken out through filtration, washed with water, and dried under reduced pressure to obtain the title compound as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[C:5]([N+:12]([O-])=O)[CH:6]=[CH:7][CH:8]=2)[N:3]=1>CO.[Cl-].[Cl-].[Cl-].[Ti+3]>[CH3:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[C:5]([NH2:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cnc2cccc([N+](=O)[O-])c2n1
Agent: [Ti+3]
Agent: [Cl-]
Solvent: CO
Product: Cc1cnc2cccc(N)c2n1
Temperature: 25 °C
Yield: 77.1 %

Procedure:
To a solution of 2-methyl-8-nitroquinoxaline (3.50 g) in MeOH (350 mL) was added dropwise a 20% aqueous solution of titanium trichloride (88.64 g) at 0° C. After the addition, the reaction solution was warmed to room temperature, and the mixture was stirred for another hour, and then concentrated under reduced pressure. The resultant was neutralized by addition of an aqueous sodium carbonate solution, and the mixture was extracted five times with ethyl acetate (200 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform) to give 2-methyl-8-aminoquinoxaline (2.27 g, 77%) as red oil.
Reaction SMILES: Br.[N:2]1([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[C:25]([C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)#[N:26]>ClCCl.C(OCC)(=O)C>[C:25]([C:27]1[CH:35]=[CH:34][C:30]([C:31]([N:5]2[CH2:4][CH2:3][N:2]([NH:8][C:9](=[O:17])[C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[CH2:7][CH2:6]2)=[O:32])=[CH:29][CH:28]=1)#[N:26]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: O=C(NN1CCNCC1)c1ccc(F)cc1
Agent: Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: N#Cc1ccc(C(=O)N2CCN(NC(=O)c3ccc(F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.3 %

Procedure:
To a stirred solution of N-piperazinyl-p-fluorobenzamide hydrobromide (300 mg) and triethylamine (0.41 ml) in dichloromethane (6 ml) was added 4-cyanobenzoyl chloride (196 mg) at 0° C. The mixture was stirred at ambient temperature for 3 hours, diluted with ethyl acetate and washed with water (×2). The organic layer was separated, dried over magnesium sulfate, and concentrated. The crystal residue was recrystallized from methanol, ethyl acetate and n-hexane to give N-[4-(4-cyanobenzoyl)-1-piperazinyl]-4-fluorobenzamide (199 mg).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:32]=[CH:31][C:30](Br)=[C:29]4[C:25]=3[C:26](=[O:35])[N:27]([CH3:34])[CH2:28]4)[C:20]([C:36]([F:39])([F:38])[F:37])=[CH:19][N:18]=2)=[CH:12][CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].CC1(C)C(C)(C)OB([C:48]2[CH:49]=[N:50][N:51]([CH2:53][CH2:54][CH2:55][OH:56])[CH:52]=2)O1>>[OH:56][CH2:55][CH2:54][CH2:53][N:51]1[CH:52]=[C:48]([C:30]2[CH:31]=[CH:32][C:24]([NH:23][C:21]3[C:20]([C:36]([F:39])([F:38])[F:37])=[CH:19][N:18]=[C:17]([NH:16][C:13]4[CH:14]=[CH:15][C:10]([CH2:9][P:4](=[O:8])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])=[CH:11][CH:12]=4)[N:22]=3)=[C:25]3[C:29]=2[CH2:28][N:27]([CH3:34])[C:26]3=[O:35])[CH:49]=[N:50]1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)c4c3C(=O)N(C)C4)n2)cc1)OCC
Reactant: CC1(C)OB(c2cnn(CCCO)c2)OC1(C)C
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)cc1)OCC

Procedure:
The title compound was prepared according to the procedure for Example 97 using diethyl[4-({4-[(7-bromo-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzyl]phosphonate and 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propan-1-ol (WO2008/001076). 1H NMR (400 MHz, DMSO-d6) δ ppm: 10.74 (br s, 1H), 9.93 (s, 1H), 8.47 (s, 1H), 8.40-9.11 (m, 1H), 8.24 (s, 1H), 7.96 (s, 1H), 7.77 (d, J=8.6 Hz, 1H), 7.46-7.62 (m, 2H), 7.30 (d, J=6.8 Hz, 2H), 4.64 (s, 2H), 4.22 (t, J=7.1 Hz, 2H), 3.97 (quin, J=7.2 Hz, 4H), 3.43 (q, J=6.1 Hz, 2H), 3.26 (d, J=22.0 Hz, 2H), 3.12 (s, 3H), 1.97 (qd, J=6.7, 6.6 Hz, 2H), 1.16 (t, J=6.9 Hz, 6H). MS (ES+): m/z 674.22 [MH+]. HPLC: tR=1.39 min (UPLC TOF, polar—3 min).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.Cl.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:21](=[O:28])[C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)c1ccncc1

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and isonicotinoyl chloride hydrochloride were combined to provide N4-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]isonicotinamide as a white crystalline solid, m.p. 213.0-213.7° C. 1H NMR (300 MHz, DMSO-d6) δ 8.76 (m, 1H), 8.69 (d, J=5.6 Hz, 2H), 8.22 (s, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.67 (d, J=5.7 Hz, 2H), 7.62 (d, J=8.2 Hz, 1H), 7.43 (t, J=7.5 Hz, 1H), 7.21 (t, J=7.5 Hz, 1H), 6.62 (broad s, 2H), 4.64 (t, J=6.8 Hz, 2H), 3.30 (m, 2H), 1.92 (m, 2H), 1.58 (m, 2H); MS (EI) m/e 360.1699 (360.1699 calcd for C20H20N6O).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[N:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[OH-].[Na+].[CH2:15]([SH:17])[CH3:16]>CC(C)=O.O>[Cl:1][C:2]1[N:3]=[C:4]([S:17][CH2:15][CH3:16])[C:5]2[N:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CCS
Reactant: Clc1nc(Cl)c2ncccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CCSc1nc(Cl)nc2cccnc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
A suspension of 15 gm (0.075 mol) of 2,4-dichloropyrido[3,2-d]pyrimidine in 100 ml of acetone at -40°C was admixed with a solution of 3.2 gm (0.08 mol) of sodium hydroxide and 4.9 gm (5.8 ml) of ethylmercaptan in 25 ml of water, and the mixture was stirred for two hours at room temperature. Thereafter, 200 ml of water were added to the reaction mixture, and the precipitate formed thereby was collected and recrystallized from petroleum ether, yielding 11.0 gm (65% of theory) of 2-chloro-4-ethylmercapto-pyrido[3,2-d]pyrimidine, m.p. 101°-103°C.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[N:6]=1.[Br:14][C:15]1[C:16](Cl)=[C:17]([N+:22]([O-:24])=[O:23])[C:18]([NH2:21])=[N:19][CH:20]=1>CC(O)C.CCN(C(C)C)C(C)C>[Br:14][C:15]1[C:16]([N:11]2[CH2:10][CH2:9][N:8]([CH2:7][C:5]3[N:6]=[C:2]([CH3:1])[S:3][CH:4]=3)[CH2:13][CH2:12]2)=[C:17]([N+:22]([O-:24])=[O:23])[C:18]([NH2:21])=[N:19][CH:20]=1
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Reactant: Cc1nc(CN2CCNCC2)cs1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(CN2CCN(c3c(Br)cnc(N)c3[N+](=O)[O-])CC2)cs1
Temperature: 60 °C
Reaction time: 17 h
Yield: 55 %

Procedure:
LC (Method B)-MS (ESI, m/z): Rt=0.50 min—198 [(M+H)+, 100%]. Half of this material (i.e. 2-methyl-4-(piperazin-1-ylmethyl)thiazole; supposedly 0.331 g, 1.68 mmol, 0.55 eq) was suspended in iPrOH (3.3 mL) and DIPEA (1.3 mL). To this solution, 5-bromo-4-chloro-3-nitropyridin-2-amine (0.390 g, 1.53 mmol, 0.45 eq) was added and the mixture heated and stirred for 17 h at 60° C. The mixture was filtered, washed with iPrOH (3×3 mL), cold H2O (3×3 mL), Et2O (2×3 mL), and dried to give the title compound (0.380 g, 55%); 1H-NMR (500 MHz, DMSO-d6): δ 2.50-2.70 (m, 7H, piperazine N(CH2)2 and Me), 3.07 (br s, 4H, piperazine N(CH2)2), 3.60 (s, 2H, NCH2), 6.98 (br s, 2H, NH2), 7.29 (s, 1H. thiazole 5-H), 8.17 (s, 1H, pyridine 6-H); LC (Method B)-MS (ESI, m/z): Rt-2.00 min—413/415 [(M+H+), Br isotopic pattern, 100%].
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:7](Cl)=[O:8])=[CH:3][CH:2]=1.Cl.[CH3:17][NH:18][O:19][CH3:20].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:20][O:19][N:18]([CH3:17])[C:7]([C:4]1[CH:5]=[CH:6][C:1]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:2][CH:3]=1)=[O:8]
Reactant: CNOC
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CON(C)C(=O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Biphenylcarbonyl chloride (8 g) was suspended in chloroform (30 mL). This was added dropwise to a stirred solution of N,O-dimethyl hydroxylamine hydrochloride (5.2 g) and triethylamine (13.5 mL) in chloroform (80 mL) at 0° C. After addition was complete, the mixture was allowed to warm to room temperature and was stirred for a further 30 minutes. The organic phase was separated, washed with water and dried over MgSO4. Evaporation gave an oil, purified by flash column chromatography (ethyl acetate:light petroleum, 1:1) to give the title compound as a white solid. δC (CDCl3, 62.9 MHz): 33.8, 61.1, 126.7, 127.2, 127.9, 128.9, 132.8, 140.2, 143.4 and 169.7. δH (CDCl3, 250 MHz): 3.38 (3H, s), 3.59 (3H, s), 7.37-7.48 (3H, m), 7.61 (4H, m) and 7.77 (2H, d, J 8.5).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:25])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[C:12]([NH:21][CH2:22]CC)=[N:11][N:10]=1.[C:26]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:25])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[C:12]([N:21]([CH3:26])[CH3:22])=[N:11][N:10]=1
Reactant: CCCNc1nnc(Cc2c(Cl)cncc2Cl)c2ccc(OC)cc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(N(C)C)c2c1
Temperature: 50 °C
Yield: 48.8 %

Procedure:
At room temperature a solution of [4-(3,5-dichloro-pyridin-4-ylmethyl)-7-methoxy-phthalazin-1-yl]-propyl-amine (3.5 g, 5.64 mmoles), prepared as described in example 78, in DMF (35 ml) was stirred under N2, then added with K2CO3 (0.78 g, 5.64 mmoles) and methyl iodide (0.35 ml, 5.64 mmoles). The mixture was heated at 50° C. and after 20 hours was dried and partitioned between water and CH2Cl2. The organic phase was washed with water, anhydrified and concentrated to give an oil which was flash chromatographed (eluent: hexane/ethyl acetate 4:6) to give 1 g of the title compound (yield: 50%). m.p.: 170-173° C.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:5])[CH3:4].[Cl:6][CH2:7][CH:8]([OH:11])[CH2:9]O.O>CC1C=CC(S(O)(=O)=O)=CC=1.C1CCCCC1>[Cl:1][CH2:2][C:3]1([CH3:4])[O:11][CH:8]([CH2:7][Cl:6])[CH2:9][O:5]1
Reactant: CC(=O)CCl
Reactant: OCC(O)CCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCCCC1
Solvent: O
Product: CC1(CCl)OCC(CCl)O1
Yield: 87.5 %

Procedure:
In a similar manner to the preceding Examples, 92.5 g (1 mol) of chloroacetone and 110.5 g (1 mol) of 3-chloro-1,2-propanediol are boiled together in a water separator with 0.5 g of p-TSA and 150 ml of cyclohexane. Once the equivalent quantity of water has separated, the cyclohexane is removed and the residue fractionated. 162 g (87%) of 2,4-bis(chloromethyl)-2-methyl-1,3-dioxolane are obtained. Bp.: 98° C. to 102° C. (1500 Pa); IR: acetal bands at 1120 cm−1, 1098 cm−1, 1053 cm−1, MS: m/e=169 (M−15), 135, 106, 93, 75, 57, 49, 43.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[N:12][C:11]([SH:22])=[N:10]2)=[CH:5][CH:4]=1.IC.Cl[CH2:26]Cl.O>[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[N:12][C:11]([S:22][CH3:26])=[N:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nc(S)nn2-c2ccc(OC)cc2)cc1
Reactant: ClCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Solvent: O
Product: COc1ccc(-c2nc(SC)nn2-c2ccc(OC)cc2)cc1
Reaction time: 8 h
Yield: 47.9 %

Procedure:
To a mixture of 1,5-bis(4-methoxyphenyl)-1H-1,2,4-triazole-3-thiol (470 mg, 1.5 mmol) in 1N sodium hydroxide solution (5 mL), was added iodomethane (0.934 mL, 15 mmol). The mixture was shaken overnight. Dichloromethane and water were added to the mixture and the organic layer was separated, washed with 0.1 N hydrochloric acid and sat sodium bicarbonate, and brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure.The generated precipitate was isolated by filtration, washed with diisopropyl ether, and dried in vacuo to give 1,5-bis(4-methoxyphenyl)-3-(methylthio)-1H-1,2,4-triazole (235 mg, 47.9% yield).
Reaction SMILES: [CH:1]1(Br)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][N:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:10][N:9]=1
Reactant: Oc1ccc(Cl)nc1
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Clc1ccc(OC2CCCC2)cn1
Reaction time: 2 h

Procedure:
Cyclopentyl bromide (690.3 mg, 4.63 mmol), 2-chloro-5-hydroxypyridine (500 mg, 3.86 mmol) and cesium carbonate (1.51 g, 4.63 mmol) were stirred in 30 ml of DMF at room temperature for 3 h. The reactants had not yet completely reacted. 50% of each of cyclopentyl bromide and cesium carbonate were added, and stirring was continued for 2 h. The reaction mixture was concentrated in vacuo, and the residue was taken up in ethyl acetate and water. The organic phase was separated off and concentrated. Yield: 737 mg (97%), M+H+: 198.08.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:26])/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][C:21]([CH2:24]Cl)=[CH:20][CH:19]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(O)(=O)C.C(O)(=O)C(O)=O.[CH:37]1([CH2:42][NH2:43])[CH2:41][CH2:40][CH2:39][CH2:38]1.C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:26])/[CH:16]=[CH:17]/[C:18]3[CH:19]=[CH:20][C:21]([CH2:24][NH:43][CH2:42][CH:37]4[CH2:41][CH2:40][CH2:39][CH2:38]4)=[CH:22][CH:23]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(/C=C/c1ccc(CCl)cc1)Nc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: NCC1CCCC1
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(/C=C/c1ccc(CNCC2CCCC2)cc1)Nc1ccc(-c2ccc(Cl)cc2)cc1

Procedure:
A reaction mixture of 200 mg (0.523 mmol) of (E)-N-(4′-chlorobiphenyl-4-yl)-3-(4-chloromethylphenyl)acrylamide, 295 mg (1.56 mmol) of cyclopentylmethylamine oxalic acid acetate and 0.44 mL (3.12 mmol) of triethylamine in 5 mL of THF is refluxed for 18 hours. Then the reaction mixture is poured onto water and the precipitate formed is suction filtered. Further purification is carried out by column chromatography on silica gel (eluant: dichloromethane/methanol (10:1)). Yield: 10 mg (4% of theory); C28H29ClN2O (M=445.0); melting point: 209° C.-210° C.; calc.: molecular ion peak (M+H)+: 445/447 (Cl); found: molecular ion peak (M+H)+: 445/447 (Cl).