Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][CH:23]([N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[C:5]([C:10]([NH2:12])=[O:11])=[N:6][C:7]=1[CH2:8][CH3:9].[NH2:33][CH2:34][CH:35]1[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]1.C(N(C(C)C)CC)(C)C>CN1CCCC1=O>[C:10]([C:5]1[N:6]=[C:7]([CH2:8][CH3:9])[C:2]([NH:33][CH2:34][CH:35]2[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]2)=[N:3][C:4]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)[CH2:22][CH2:21]2)=[CH:16][CH:15]=1)(=[O:11])[NH2:12]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)cc2)nc1Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)cc2)nc1NCC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
A mixture of 5-chloro-6-ethyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (200 mg), tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (300 μL), diisopropylethylamine (240 μL), and N-methylpyrrolidone (0.8 mL) was reacted in a microwave reaction device at 160° C. for 2 hours. The mixture was subjected to liquid separation with ethyl acetate and water, and the organic phase was dried over magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was washed with diisopropyl ether to obtain tert-butyl 4-({[5-carbamoyl-3-ethyl-6-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazin-2-yl]amino}methyl)piperidine-1-carboxylate (195 mg) as a pale yellow solid.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[C:13]([N+:20]([O-:22])=[O:21])[C:6]=1[NH:7][CH2:8][CH2:9][S:10][C:11]#[N:12])([O-:4])=[O:3]>C(O)C>[NH:12]=[C:11]1[N:7]([C:6]2[C:13]([N+:20]([O-:22])=[O:21])=[CH:14][C:15]([N+:17]([O-:19])=[O:18])=[CH:16][C:5]=2[N+:2]([O-:4])=[O:3])[CH2:8][CH2:9][S:10]1
Reactant: N#CSCCNc1c([N+](=O)[O-])cc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Product: N=C1SCCN1c1c([N+](=O)[O-])cc([N+](=O)[O-])cc1[N+](=O)[O-]
Reaction time: 0.17 h
Yield: 7.1 %

Procedure:
Dry gaseous hydrogen chloride is introduced into 1.2 g (0.0038 moles) of 2,4,6-trinitro-N-(2-thiocyanatoethyl)-aniline in 120 ml of anhydrous ethanol for 5 hours, while the mixture is heated under reflux. The solvent is distilled off, the residue is boiled with 30 ml of ethyl acetate for 10 minutes, then the warm mixture is filtered. The insoluble matter is shaken with 30 ml of ethyl acetate and 20 ml of 10 percent aqueous sodium carbonate solution. The phases are separated, and the aqueous solution is extracted twice with 10 ml of ethyl acetate each time. The organic phases are combined, dried over anhydrous magnesium carbonate and evaporated. In this way 0.084 g (7%) of the title compound are obtained. M.p.: 160°-162° C. (ethyl acetate).
Reaction SMILES: C([O:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[C:27]([C:33]([F:36])([F:35])[F:34])[CH:26]=3)=[O:23])=[CH:17][C:16]=2[F:37])=[C:11]([O:38][CH2:39][CH3:40])[CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[C:31]([C:28]1[CH:29]=[CH:30][C:25]([NH:24][C:22](=[O:23])[CH2:21][C:18]2[CH:19]=[CH:20][C:15]([C:12]3[C:11]([O:38][CH2:39][CH3:40])=[CH:10][C:9](=[O:8])[NH:14][CH:13]=3)=[C:16]([F:37])[CH:17]=2)=[CH:26][C:27]=1[C:33]([F:35])([F:36])[F:34])#[N:32]
Reactant: CCOc1cc(OCc2ccccc2)ncc1-c1ccc(CC(=O)Nc2ccc(C#N)c(C(F)(F)F)c2)cc1F
Agent: [Pd]
Solvent: CO
Product: CCOc1cc(=O)[nH]cc1-c1ccc(CC(=O)Nc2ccc(C#N)c(C(F)(F)F)c2)cc1F
Yield: 35.9 %

Procedure:
A solution of 2-(4-(6-(benzyloxy)-4-ethoxypyridin-3-yl)-3-fluorophenyl)-N-(4-cyano-3-(trifluoromethyl)phenyl)acetamide (12 mg, 0.022 mmol) and Pd/C (2.324 mg, 0.022 mmol) in MeOH (10 mL) was stirred at 20° C. under a H2 atmosphere for 16 h. After LCMS analysis showed the starting material had disappeared, the mixture was filtered. The filtrate was concentrated to give the crude product, which was purified by preparative HPLC to yield a white solid of N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-3-fluorophenyl)acetamide (3.63 mg, 7.90 μmol, 36.2% yield): 1H NMR (400 MHz, CD3OD) δ 8.23 (s, 1H), 8.02-7.95 (m, 1H), 7.94-7.88 (m, 1H), 7.59 (s, 1H), 7.35-7.29 (m, 1H), 7.25-7.15 (m, 2H), 6.23 (s, 1H), 4.16 (m, 2H), 3.80 (s, 2H), 1.32 (t, J=7.0 Hz, 3H); ES-LCMS m/z 460.1 (M+H).
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH:10]=2)[CH2:4]1.Cl[CH2:28][C:29]1[CH:34]=[CH:33][N:32]=[C:31]([C:35]2[CH:40]=[C:39]([O:41][CH3:42])[C:38]([O:43][CH3:44])=[C:37]([O:45][CH3:46])[CH:36]=2)[CH:30]=1>>[CH3:1][N:2]([C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=3)[CH:10]=2)[CH2:4]1)[CH2:28][C:29]1[CH:34]=[CH:33][N:32]=[C:31]([C:35]2[CH:40]=[C:39]([O:41][CH3:42])[C:38]([O:43][CH3:44])=[C:37]([O:45][CH3:46])[CH:36]=2)[CH:30]=1
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Reactant: CN[C@H]1CCN(Cc2ccnc(-c3cc(OC)c(OC)c(OC)c3)c2)C1
Product: COc1cc(-c2cc(CN3CC[C@H](N(C)Cc4ccnc(-c5cc(OC)c(OC)c(OC)c5)c4)C3)ccn2)cc(OC)c1OC

Procedure:
(3S)-3-methylamino-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]pyrrolidine (104 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (85 mg) was condensed in the same manner as described in Example 2. Yellow syrup obtained was converted to a tetrahydrochloride by the usual method giving the title compound as yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH2:22][C:23]([CH3:25])=[CH2:24])=[C:6]([CH:20]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17](O)=[O:18])=[CH:13][CH:12]=1)[CH2:9][CH3:10].[F:26][C:27]([F:33])([F:32])[S:28]([NH2:31])(=[O:30])=[O:29]>>[F:26][C:27]([F:33])([F:32])[S:28]([NH:31][C:17]([C:14]1[N:15]=[N:16][C:11]([N:8]([CH2:7][C:6]2[CH:20]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:21][CH2:22][C:23]([CH3:25])=[CH2:24])[CH2:9][CH3:10])=[CH:12][CH:13]=1)=[O:18])(=[O:30])=[O:29]
Reactant: C=C(C)COc1ccc(Cl)cc1CN(CC)c1ccc(C(=O)O)nn1
Reactant: NS(=O)(=O)C(F)(F)F
Product: C=C(C)COc1ccc(Cl)cc1CN(CC)c1ccc(C(=O)NS(=O)(=O)C(F)(F)F)nn1

Procedure:
The title compound was prepared from 6-[N-(5-chloro-2-(2-methylprop-2-en-1-yloxy)-benzyl)-N-ethylamino]pyridazin-3-carboxylic acid (example 19) and trifluoromethanesulphonamide using a similar method to that of example 11 (18%).
Reaction SMILES: CO.C(O)(=O)C.[Br:7][C:8]1[CH:20]=[CH:19][C:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[C:10]([N+:21]([O-])=O)[CH:9]=1.C(=O)([O-])O.[Na+]>[Fe].C(OCC)(=O)C>[NH2:21][C:10]1[CH:9]=[C:8]([Br:7])[CH:20]=[CH:19][C:11]=1[C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13]
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(Br)cc1N
Temperature: 25 °C
Yield: 86.8 %

Procedure:
Iron powder 3.0 g were added to a mixed solution methanol 28 mL and acetic acid 28 mL of tert-butyl 4-bromo-2-nitrobenzoate 5.5 g, it was heated and refluxed for 1 hour. After the reaction mixture was cooled to room temperature, saturated sodium hydrogen carbonate aqueous solution and ethyl acetate were added to it, and insoluble matter was filtrated. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after sequential washing with saturated sodium hydrogen carbonate aqueous solution and saturated sodium chloride aqueous solution, the solvent was removed under reduced pressure to give tert-butyl 2-amino-4-bromobenzoate 4.3 g of pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]#[N:12].N.[H][H]>C(O)C.[Ni]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][NH2:12]
Reactant: N#CCCc1ccc(F)cc1F
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CCO
Product: NCCCc1ccc(F)cc1F

Procedure:
33.4 g (0.20 mol) of 3-(2,4-difluorophenyl)propionitrile are dissolved in 200 ml of ethanol and, after 2.8 g of Raney nickel in ethanol have been added and after 34 g (2.0 mol) of ammonia gas have been injected, are hydrogenated using hydrogen gas in a pressurized reactor at 75°-80° C. The take-up of hydrogen is complete after about 3 hours. The reaction mixture is cooled, decompressed and filtered and then freed from solvent on a vacuum rotary evaporator. The resultant oil is subjected to fractional distillation at 89°-90° C. in vacuo (13 mbar). 26.0 g (76% of theory) of a colourless oil are obtained.
Reaction SMILES: CO[CH:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[NH:6][C:5]1=[O:15].[N:16]1([C:22]2[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>CN(C)C=O>[N:16]1([C:22]2[CH:23]=[CH:24][C:25]([NH:28]/[CH:3]=[C:4]3\[C:5](=[O:15])[NH:6][C:7](=[O:14])[C:8]4[C:13]\3=[CH:12][CH:11]=[CH:10][CH:9]=4)=[CH:26][CH:27]=2)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: COC=C1C(=O)NC(=O)c2ccccc21
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccccc2/C1=C/Nc1ccc(N2CCOCC2)cc1
Temperature: 110 °C
Yield: 79.6 %

Procedure:
A mixture of 4-methoxymethylene-4H-isoquinoline-1,3-dione (101.5 mg, 0.5 mmol), 4-morpholin-4-yl-phenylamine (89.12 mg, 0.5 mmol) in 1 mL of N,N-dimethylformamide is heated at 110° C. for 1 h. After cooling in the refrigerator, the precipitate is collected, and washed with ether to give 139 mg (80%) of greenish yellow solid mp 257-258° C.; MS (ESI) m/z 350.17 (M+1); Analysis for C20H19N3O3: Calcd: C, 68.75; H, 5.48; N, 12.03. Found: C, 68.49; H, 5.57; N, 11.90.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:15]([O:17][CH3:18])=[O:16])=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:24]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[N+:11]([O-:24])[C:10]=1[C:15]([O:17][CH3:18])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1ncccc1OCc1ccccc1
Solvent: ClCCl
Product: COC(=O)c1c(OCc2ccccc2)ccc[n+]1[O-]
Yield: 94.6 %

Procedure:
A solution of methyl 3-benzyloxypicolinate (4.86 g) and 3-chloroperoxybenzoic acid (5.75 g, 60% peracid) in CH2Cl2 (100 mL) was stirred at room temperature for 40 hours. The reaction mixture was then extracted with 5% sodium bisulfite solution (100 mL) then with 0.5N NaOH solution (150 mL). After drying (MgSO4) the solvent was evaporated to give 4.9 g of methyl 3-benzyloxypicolinate-1-oxide as a white solid. Recrystallization from methylcyclohexane/toluene gave a crystalline solid, m.p. 104-106° C.
Reaction SMILES: [Br:1][C:2]1[C:7]2[N:8]([CH3:14])[C:9]([C@@H:11]([NH2:13])[CH3:12])=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH2:15][C:16]1[C:21]([C:22]#[N:23])=[C:20](Cl)[N:19]=[CH:18][N:17]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:15][C:16]1[C:21]([C:22]#[N:23])=[C:20]([NH:13][C@H:11]([C:9]2[N:8]([CH3:14])[C:7]3[C:2]([Br:1])=[CH:3][CH:4]=[CH:5][C:6]=3[N:10]=2)[CH3:12])[N:19]=[CH:18][N:17]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: C[C@H](N)c1nc2cccc(Br)c2n1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2cccc(Br)c2n1C
Temperature: 90 °C
Yield: 72.3 %

Procedure:
A mixture of (S)-1-(7-bromo-1-methyl-1H-benzoimidazol-2-yl)ethylamine (1 g, 3.9 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (0.64 g, 4.1 mmol) and DIPEA (2.1 mL, 4.1 mmol) in IPA (7.8 mL) was heated for 16 h at 90° C. After cooling to RT, the reaction mixture was filtered and the solid washed with MeOH and DCM to afford 421 as a cream solid (1.05 g, 72%). LCMS (Method K): RT 3.27 min [M+H]+ 372 (for 79Br) 1H NMR (DMSO-d6, 400 MHz): δ 8.07 (1H, s), 7.79 (1H, d, J=7.5 Hz), 7.63 (1H, d, J=8.0 Hz), 7.41 (1H, d, J=4.0 Hz), 7.32 (2H, bs), 7.11 (1H, dd, J=8.0, 8.0 Hz), 5.70 (1H, dq, J=7.5, 7.0 Hz), 4.01 (3H, s), 1.60 (3H, d, J=7.0 Hz)
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:28])[CH2:21][CH2:22][CH2:23][S:24][CH2:25][CH2:26][OH:27])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:28])[CH2:21][CH2:22][CH2:23][S:24][CH2:25][CH2:26][O:27][C:29](=[O:31])[CH3:30])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)OC(C)=O
Reactant: O=C(CCCSCCO)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Product: CC(=O)OCCSCCCC(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Yield: 80 %

Procedure:
Following a procedure similar to that described in Example 2, but using N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-4-(2-hydroxyethylthio)butyramide (prepared as described in Example 3) and acetic anhydride as starting materials, in relative proportions similar to those used in that Example, the title compound, melting at 36°-40° C., was obtained in an 80% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-])=O)[CH:22]=3)[CH3:20])[CH2:14][CH2:13]2)[N:3]=1.[Cl-].[NH4+]>CO.O.[Fe]>[CH3:20][CH:19]([C:21]1[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=1)[NH2:27])[CH2:18][N:15]1[CH2:14][CH2:13][N:12]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[CH:10]=[CH:11][C:2]([CH3:1])=[N:3]3)[CH2:17][CH2:16]1
Reactant: Cc1ccc2c(N3CCN(CC(C)c4cccc([N+](=O)[O-])c4)CC3)cccc2n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: Cc1ccc2c(N3CCN(CC(C)c4cccc(N)c4)CC3)cccc2n1
Temperature: 25 °C
Yield: 61.9 %

Procedure:
A solution of 2-methyl-5-{4-[2-(3-nitrophenyl)propyl]-1-piperazinyl}quinoline (70 mg) in methanol (1 mL) was added dropwise to a stirred suspension of iron powder (3.0 equiv., 30 mg) and ammonium chloride (5.0 equiv., 48 mg) in water (1 mL). The reactants were heated at reflux for 18 hours. The reaction mixture was cooled to room temperature then filtered using a Millipore filter. The filtrate was concentrated under reduced pressure and purified using chromatography (SiO2, SPE) eluting with DCM-methanol (95:5) to afford the title compound (40 mg, 60% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH:8]=[CH:9][S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.P(Cl)(Cl)(Cl)=O>C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[CH:9][S:10]([NH:13][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:11])=[O:12])=[CH:14][CH:15]=1)([O-:3])=[O:2]
Reactant: NS(=O)(=O)C=Cc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(NS(=O)(=O)C=Cc1ccc([N+](=O)[O-])cc1)c1ccccc1
Yield: 76 %

Procedure:
A mixture of 4-nitrostyrylsulfonamide (18.2 g., 0.08 mole), benzoyl chloride (12.6 g., 0.09 mole) and phosphorus oxychloride (13.8 g., 0.09 mole) is heated at steam bath temperature for 105 hr. The reaction mixture diluted with 20 ml. of ethyl acetate, cooled and filtered affords 19.0 g. (76% yield) of N-(4-nitrostyrylsulfonyl)benzamide, m.p. 192°-195° C., from ethyl acetate-hexane.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=[CH:10][C:4]=2[N:3]=1.[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.CS(C)=O>O>[N:15]1([C:2]2[NH:6][C:5]3[CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=[CH:10][C:4]=3[N:3]=2)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1
Reactant: C1CNCCN1
Reactant: FC(F)(F)c1ccc2nc(Cl)[nH]c2c1
Solvent: O
Solvent: CS(C)=O
Product: FC(F)(F)c1ccc2nc(N3CCNCC3)[nH]c2c1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A mixture of 2-chloro-6-trifluoromethyl-1H-benzoimidazole (221 mg, 1 mmol, Example 1c), piperazine (172 mg, 2 mmol, Aldrich) and DMSO (2 mL) was stirred at 80° C. for 24 h. The mixture was cooled to room temperature, water (10 mL) was added and the mixture was extracted with EtOAc (2×20 mL). The combined organic phases were washed with water (2×5 mL) and brine (5 mL), dried over Na2SO4, and filtered. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with 10% MeOH/CH2Cl2+1% ammonia (30% in water) to give the title compound. MS (ESI, pos. ion) m/z: 271 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[NH2:10].[Br:11][C:12]1[C:13]([Cl:19])=[N:14][C:15]([Cl:18])=[N:16][CH:17]=1.CC(N(C(C)C)CC)C>O1CCOCC1>[Br:11][C:12]1[C:13]([Cl:19])=[N:14][C:15]([NH:10][C:3]2[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])=[N:16][CH:17]=1.[Br:11][C:12]1[C:13]([NH:10][C:3]2[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])=[N:14][C:15]([Cl:18])=[N:16][CH:17]=1
Reactant: Cc1cc(C)c(N)c(C)c1
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)c(Nc2nc(Cl)ncc2Br)c(C)c1
Product: Cc1cc(C)c(Nc2ncc(Br)c(Cl)n2)c(C)c1
Yield: 65 %
Yield: 24 %

Procedure:
Reaction under argon atmosphere. A solution of 2,4,6-trimethylbenzenamine (0.00461 mol) in 1,4-dioxane (5 ml) was added to a solution of 5-bromo-2,4-dichloropyrimidine (0.00439 mol) in 1,4-dioxane (5 ml). N,N-bis(1-methylethyl)ethanamine (0.00548 mol) was added. The reaction mixture was stirred and refluxed for 20 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate, washed with a saturated aqueous sodium bicarbonate solution, water and brine, dried with sodium sulfate, filtered, and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: 1:5, 1:2 and 1:1 CH2Cl2: hexane). Two pure fraction groups were collected and their solvent was evaporated, yielding 0.35 g (24%) of 5-bromo-4-chloro-N-(2,4,6-trimethylphenyl)-2-pyrimidinamine (interm. 1) and 0.93 g (65%) of 5-bromo-2-chloro-N-(2,4,6-trimethylphenyl)-4-pyrimidinamine (interm. 2).
Reaction SMILES: [CH3:1][CH2:2][C@:3]12[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[N:19]3[C:9]4=[C:10]([C:13]5[C:18]3=[CH:17][CH:16]=[CH:15][CH:14]=5)[CH2:11][CH2:12][N:7]([C@@H:8]14)[CH2:6][CH2:5][CH2:4]2.[OH-].[K+].[CH2:27](Br)[CH3:28]>C(O)C>[CH3:1][CH2:2][C@:3]12[CH:21]=[C:20]([C:22]([O:24][CH2:27][CH3:28])=[O:23])[N:19]3[C:9]4=[C:10]([C:13]5[C:18]3=[CH:17][CH:16]=[CH:15][CH:14]=5)[CH2:11][CH2:12][N:7]([C@@H:8]14)[CH2:6][CH2:5][CH2:4]2
Reactant: CCBr
Reactant: CC[C@@]12C=C(C(=O)O)n3c4c(c5ccccc53)CCN(CCC1)[C@H]42
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C1=C[C@]2(CC)CCCN3CCc4c(n1c1ccccc41)[C@@H]32
Yield: 66 %

Procedure:
1 g. (0.0031 moles) of apovincaminic acid and 0.17 g. (0.003 moles) of potassium hydroxide are dissolved in 80 ml. of anhydrous ethanol, thereafter 0.4 g. (0.0036 moles) of ethyl bromide are added to the solution. The solution is boiled under reflux for 3 hours. The reaction is monitored by layer chromatography. The solution is cooled and evaporated to dryness under reduced pressure. The dry residue is dissolved in 500 ml. of 2% aqueous sulfuric acid, and the solution is filtered. The pH of the filtrate is adjusted to 8 with 5% aqueous sodium hyrodxide solution. A small amount of precipitate separates. The mixture is extracted with 200 ml. portions of methylene chloride until no positive Mayer reaction can be observed in the aqueous phase. The organic phases are separated, combined, dried over anhydrous potassium carbonate, filtered and evaporated to dryness under reduced pressure. The dry residue is dissolved in 10 ml. of anhydrous ethanol, and the solution is left to crystallize at 0° to 2° C for 10 hours. 0.66 g. of apovincaminic acid ethyl ester are obtained (yield: 66%). On the basis of layer chromatography, a uniform product is formed. M.p.: 144° C (Boetius).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13](=[O:19])[CH2:12][CH2:11]3)[CH:5]=[N:6][CH:7]=1.CN1C2C(=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)CCC1=O.BrC1C=NC=C(Br)C=1.[C:49]([O:53][C:54]([N:56]1[CH:61]=[C:60](B2OC(C)(C)C(C)(C)O2)[CH2:59][CH2:58][CH2:57]1)=[O:55])([CH3:52])([CH3:51])[CH3:50]>>[C:49]([O:53][C:54]([N:56]1[CH2:61][CH2:60][CH2:59][C:58]([C:2]2[CH:7]=[N:6][CH:5]=[C:4]([C:8]3[CH:9]=[C:10]4[C:15](=[CH:16][CH:17]=3)[N:14]([CH3:18])[C:13](=[O:19])[CH2:12][CH2:11]4)[CH:3]=2)=[CH:57]1)=[O:55])([CH3:52])([CH3:50])[CH3:51]
Reactant: CN1C(=O)CCc2cc(-c3cncc(Br)c3)ccc21
Reactant: CC(C)(C)OC(=O)N1C=C(B2OC(C)(C)C(C)(C)O2)CCC1
Agent: Brc1cncc(Br)c1
Agent: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Product: CN1C(=O)CCc2cc(-c3cncc(C4=CN(C(=O)OC(C)(C)C)CCC4)c3)ccc21

Procedure:
In analogy to the procedure described for the preparation of example 45, 6-(5-bromo-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-quinolin-2-one (prepared from 1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (intermediate A-1) and 3,5-dibromo pyridine also with a procedure as used for the preparation of example 45) has been coupled to 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester to give the title compound as an amorphous colorless solid. MS: 420.5 (M+H+).
Reaction SMILES: C[N:2]([CH:4]=[C:5]1[C:13]2[C:8](=[CH:9][N:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:14])[CH3:3].[S:15]([NH2:25])(=[O:24])([C:17]1[CH:22]=[CH:21]C(N)=[CH:19][CH:18]=1)=[O:16]>Cl.C(O)C>[O:14]=[C:6]1[NH:7][C:8]2=[CH:9][N:10]=[CH:11][CH:12]=[C:13]2[C:5]1=[CH:4][NH:2][C:3]1[CH:21]=[CH:22][C:17]([S:15]([NH2:25])(=[O:24])=[O:16])=[CH:18][CH:19]=1
Reactant: CN(C)C=C1C(=O)Nc2cnccc21
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Solvent: CCO
Product: NS(=O)(=O)c1ccc(NC=C2C(=O)Nc3cnccc32)cc1
Reaction time: 3 h
Yield: 16.8 %

Procedure:
To a 25-ml round-bottom flask was added 0.12 g (0.47 mmol) of 3-dimethylaminomethylene-1,6-diazainden-2(3H)-one, 0.081 g (0.47 mmol) of sulfanilamide, 10 ml of ethanol and two drops of concentrated hydrochloric acid. The reaction mixture was refluxed using an oil bath with stirring for 3 hours, then cooled and filtered. The collected solid was dissolved in a minimum volume of hot methanol. Upon cooling, a dark material deposited. The methanol solution was decanted and diluted to twice its volume with ethyl acetate. A light brown solid deposited after standing for 48 hours. The solid was isolated by filtration, dried, and redissolved in hot methanol (30 mL). The solution was concentrated to 20 mL and diluted with an equal volume of ethyl acetate. On cooling, a tan solid formed. The solid was isolated by filtration and washed with methanol/ethyl acetate to give 25 mg (17%) of the title compound. 1H NMR (DMSO-d6): δ7.42 (s, 2H), 7.82 (d, J=8.5 Hz, 2H), 7.90 (d, J=8.5 Hz, 2H), 8.28 (s, 1H), 8.11 (d, J=6.0 Hz, 1H), 8.38 (d, J=6.0 Hz, 1H), 9.35 (d, J=13.5 Hz, 1H), 11.53 (s, 1H), 11.60 (d, J=13.5 Hz, 1H), 14.6 (br s, 1H); C14H12N4O3S: APCI−MS m/z 315 (M−H).