Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:8][C:9]3[N:10]=[CH:11][N:12]=[C:13]([SH:16])[C:14]=3[N:15]=2)=[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:4]=[CH:3]1.[CH3:23]I>[OH-].[Na+]>[CH3:1][N:2]1[C:6]([C:7]2[S:8][C:9]3[N:10]=[CH:11][N:12]=[C:13]([S:16][CH3:23])[C:14]=3[N:15]=2)=[C:5]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:4]=[CH:3]1
Reactant: Cn1cnc(-c2ccccc2)c1-c1nc2c(S)ncnc2s1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Product: CSc1ncnc2sc(-c3c(-c4ccccc4)ncn3C)nc12
Yield: 95 %

Procedure:
2-(1-Methyl-4-phenyl-1H-imidazol-5-yl)[1,3]thiazolo[5,4-d]pyrimidine-7-thiol (Example 31) (2.91 g) was dissolved in 2M NaOH (50 mL) then methyl iodide (0.67 mL) added under an inert atmosphere at ambient temperature. After 2.5 hours the reaction mixture was filtered, washed with water, dried under high-vacuum to give the title compound as a pale brown solid (2.9 g, 95%);
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:17]([NH2:19])=[C:16]([O:20][CH3:21])[C:15]([O:22][CH3:23])=[CH:14][C:13]=3[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].[CH:26](O)=O>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:9]3[C:18]4[C:13]([N:12]=[CH:11][N:10]=3)=[CH:14][C:15]([O:22][CH3:23])=[C:16]([O:20][CH3:21])[C:17]=4[N:19]=[CH:26]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=CO
Reactant: COc1cc2ncnc(Nc3cccc(Br)c3)c2c(N)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: COc1cc2ncnc3c2c(c1OC)N=CN3c1cccc(Br)c1

Procedure:
A solution of N4-(3-bromo-phenyl)-6,7-dimethoxy-quinazoline-4,5-diamine (100 mg, 0.27 mmol) (from Example 6, Step B supra) in formic acid (5 mL) was heated at 110° C. for 2 hours. Aqueous NaOH solution was added to the reaction mixture to a pH 10–12. The solution was diluted with chloroform (100 mL). The organic layer was separated, dried over Na2SO4, and concentrated. This residue was purified by chromatography using EtOAc/Et3N (1:0.04) as eluent to give the desired 3-(3-bromo-phenyl)-8,9-dimethoxy-3H-1,3,4,6-tetraaza-phenalene as a brown solid. (Yield 86 mg, 83%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[C:20]([CH:33]([F:35])[F:34])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.[ClH:37]>C(O)C>[ClH:37].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[C:20]([CH:33]([F:34])[F:35])[CH:19]=1)([CH2:13][OH:12])[CH2:9][OH:10]
Reactant: CCCCCCCCOc1ccc(CCC2(NC(=O)OC(C)(C)C)COC(C)(C)OC2)cc1C(F)F
Agent: Cl
Solvent: CCO
Product: CCCCCCCCOc1ccc(CCC(N)(CO)CO)cc1C(F)F
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Compound 32-1 (230 mg) was dissolved in ethanol (10 ml), concentrated hydrochloric acid (1 ml) was added, and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (105 mg) as a white powder.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH3:22])[C:3]#[C:4]/[CH:5]=[CH:6]/[CH2:7][N:8]([CH2:10][C:11]1C=C(C(OCC)=O)C=CN=1)C.CC(C)(C)C#C/C=C/CN(C[C:35]1[O:39][N:38]=[C:37]([C:40]([O:42]CC)=O)[CH:36]=1)CC.CC1ON=C(C(OCC)=O)C=1.BrN1C(=O)CCC1=O.C(NC/C=C/C#CC(C)(C)C)C>>[CH3:1][C:2]([CH3:22])([CH3:23])[C:3]#[C:4]/[CH:5]=[CH:6]/[CH2:7][N:8]([C:35]1[O:39][N:38]=[C:37]([CH:40]=[O:42])[CH:36]=1)[CH2:10][CH3:11]
Reactant: CCOC(=O)c1cc(CN(CC)C/C=C/C#CC(C)(C)C)on1
Reactant: CCOC(=O)c1ccnc(CN(C)C/C=C/C#CC(C)(C)C)c1
Agent: CCNC/C=C/C#CC(C)(C)C
Agent: CCOC(=O)c1cc(C)on1
Agent: O=C1CCC(=O)N1Br
Product: CCN(C/C=C/C#CC(C)(C)C)c1cc(C=O)no1

Procedure:
The same reaction as in Referential Example 49 is carried out except that instead of the starting (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-4-ethoxycarbonyl-2-pyridylmethylamine, (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-ethyl-3-ethoxycarbonyl-5-isoxazolylmethylamine [synthesized by brominating ethyl 5-methylisoxazole-3-carboxylate with N-bromosuccinimide and condensing the brominated product with (E)-N-ethyl-6,6-dimethyl-2-hepten-4-ynylamine] is used, (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-ethyl-3-formyl-5-isoxazolylamine is obtained.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:6]2[S:14][CH:13]=[C:12]([CH:15]([CH3:17])[CH3:16])[C:7]=2[N:8]=[C:9](Cl)[N:10]=1)[CH:2]=[CH2:3].[CH2:18]([NH2:21])[CH:19]=[CH2:20].C(=O)([O-])O.[Na+]>>[CH2:18]([NH:21][C:9]1[N:10]=[C:5]([NH:4][CH2:1][CH:2]=[CH2:3])[C:6]2[S:14][CH:13]=[C:12]([CH:15]([CH3:17])[CH3:16])[C:7]=2[N:8]=1)[CH:19]=[CH2:20]
Reactant: C=CCN
Reactant: C=CCNc1nc(Cl)nc2c(C(C)C)csc12
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCNc1nc(NCC=C)c2scc(C(C)C)c2n1
Yield: 89.3 %

Procedure:
70 mg (0.26 mmol) of 4-allylamino-2-chloro-7-isopropylthieno[3,2-d]pyrimidine and 239 mg (4.2 mmol) of allylamine were heated in a sealed tube at 140° C. for 16 hours. After completion of the reaction, the reaction mixture was allowed to resume room temperature, followed by adding a saturated aqueous sodium hydrogen carbonate solution thereto and extraction with ethyl acetate (30 ml×2). After the organic layer was washed with brine and dried over anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/4) to give 67 mg (yield: 89.3%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[S:16][N:15]=[C:14]([OH:17])[C:13]=2[C:18]#[N:19])=[CH:7][C:6]=1[F:20].[CH3:26][CH:27]([NH2:30])[CH2:28][OH:29]>C(O)C>[Cl:1][C:2]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[S:16][N:15]=[C:14]([OH:17])[C:13]=2[C:18]([NH:30][CH:27]([CH3:26])[CH2:28][OH:29])=[NH:19])=[CH:7][C:6]=1[F:20]
Reactant: CC(N)CO
Reactant: N#Cc1c(O)nsc1Nc1ccc(Oc2cc(Cl)ccc2Cl)c(F)c1
Solvent: CCO
Product: CC(CO)NC(=N)c1c(O)nsc1Nc1ccc(Oc2cc(Cl)ccc2Cl)c(F)c1
Temperature: 100 °C

Procedure:
A mixture of 5-[4-(2,5-dichloro-phenoxy)-3-fluoro-phenylamino]-3-hydroxy-isothiazole-4-carbonitrile (0.2 g) and DL-2-amino-1-propanol (0.7 g) in 20 ml of ethanol was placed in a high-pressure reaction equipment and heated to 100° C. overnight. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was chromatographed by silica gel column (chloroform/methanol, 25:1) to give the desired product as a light yellow solid. MS: 470; 1H NMR (DMSO-d6, 300 MHz): δ 10.60 (brs, ½H, NH, D2O exchangeable), 9.69 (brs, ½H, NH, D2O exchangeable), 9.22 (brs, ½H, NH, D2O exchangeable), 8.55 (s, 1H, OH, D2O exchangeable), 7.91 (brs, ½H, NH, D2O exchangeable), 7.70 (brs, ½H, NH, D2O exchangeable), 7.61 (d, 1H, J=8.7 Hz, ArH), 7.22 (dd, 1H, J=2.1, 8.7 Hz, ArH), 7.16 (t, 1H, J=8.7 Hz, ArH), 6.99 (dd, 1H, J=2.1, 12.6 Hz, ArH), 6.88 (d, 1H, J=2.1 Hz, ArH), 6.83 (dd, 1H, J=2.1, 8.7 Hz, ArH), 5.09 (brs, 1H, OH), 3.80 (m, 1H, CH), 3.49 (m, 1H, CH). 3.44 (m, 1H, CH), 1.15 (d, 3H, J=6.3 Hz, CH3).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[O:3][CH2:4][CH2:5][OH:6].Cl[C:10]1[N:18]=[C:17]([Cl:19])[C:16]([Cl:20])=[CH:15][C:11]=1[C:12]([NH2:14])=[O:13].C(O[K])(C)(C)C.O>CN(C=O)C.COCCOC.CCOC(C)=O>[Cl:20][C:16]1[C:17]([Cl:19])=[N:18][C:10]([O:6][CH2:5][CH2:4][O:3][C:2]([F:8])([F:7])[F:1])=[C:11]([CH:15]=1)[C:12]([NH2:14])=[O:13]
Reactant: OCCOC(F)(F)F
Reactant: NC(=O)c1cc(Cl)c(Cl)nc1Cl
Agent: CC(C)(C)O[K]
Solvent: CN(C)C=O
Solvent: O
Solvent: COCCOC
Product: NC(=O)c1cc(Cl)c(Cl)nc1OCCOC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.9 %

Procedure:
To a mixture of compound 2-(trifluoromethoxy)ethanol (9.5 mmol) in DMF/DME (20/50 mL) was added 2,5,6-trichloronicotinamide (2.1 g, 9.5 mmol) and tert-BuOK (1.30 g, 11.4 mmol) and the reaction mixture was stirred at room temperature overnight. The mixture was poured into 100 mL of cold water, diluted with 100 mL of EtOAc, the organic layer was separated and the aqueous phase was further extracted twice with EtOAc, the combined organic layers were washed with brine twice, dried over Na2SO4 and concentrated, the residue was purified by silica gel chromatography (Petroleum ether:EtOAc=1:0 to 5:1) to give 5,6-dichloro-2-(2-(trifluoromethoxy)ethoxy)nicotinamide (0.24 g, 8%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm) 8.31 (s, 1H), 7.97 (s, 1H), 7.59 (s, 1H), 4.62 (t, 2H, J=4.0 Hz), 4.51 (t, 2H, J=4.0 Hz).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH2:35][C@@H:34]2[CH2:38][NH:39][CH2:40][C@H:33]12)=[O:31])([CH3:28])([CH3:27])[CH3:26]>C1COCC1>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH2:35][CH:34]2[CH2:38][N:39]([C:10]([C:2]3[NH:1][C:9]4[C:4]([CH:3]=3)=[CH:5][CH:6]=[CH:7][CH:8]=4)=[O:12])[CH2:40][CH:33]12)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]2CNC[C@@H]21
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC2CN(C(=O)c3cc4ccccc4[nH]3)CC21
Reaction time: 72 h
Yield: 32.2 %

Procedure:
To a solution of indole-2-carboxylic acid (67.4 mg, 0.42 mmol) in THF (2.8 mL) was added CDI (68.3 mg, 0.42 mmol) and cis-octahydro-pyrrolo[3,4-b]pyridine-1-carboxylic acid tert-butyl ester (100 mg, 0.44 mmol). After 72 h at rt, the mixture was diluted with satd. aq. NaHCO3 and extracted with CH2Cl2 (3×). The combined organic layers were washed with satd. aq. NaCl, dried (Na2SO4), and concentrated to give a yellow liquid, which was purified by FCC (EtOAc/hexanes) to give a yellow solid (50 mg, 44%). 1H NMR (mixture of rotamers; CDCl3): 7.79-7.72 (m, 1H), 7.72-7.64 (m, 1H), 7.49-7.39 (m, 1H), 7.34-7.29 (m, 1H), 7.25-7.19 (m, 1H), 7.17-7.09 (m, 1H), 6.94-6.89 (m, 1H), 6.89-6.85 (m, 1H), 4.20-3.95 (m, 2H), 3.95-3.86 (m, 0.5H), 3.86-3.69 (m, 2H), 3.69-3.59 (m, 0.5H), 2.91-2.71 (m, 1H), 2.40-2.30 (m, 0.4H), 2.30-2.19 (m, 0.6H), 1.89-1.67 (m, 2H), 1.54-1.42 (m, 9H), 1.41-1.21 (m, 2H).
Reaction SMILES: CCN(CC)CC.[Cl:8][C:9]1[N:14]=[C:13](Cl)[CH:12]=[CH:11][N:10]=1.[NH2:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([CH3:26])=[CH:20]2>CCO>[Cl:8][C:9]1[N:14]=[C:13]([NH:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21]([CH3:26])=[CH:20]3)[CH:12]=[CH:11][N:10]=1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: Clc1ccnc(Cl)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc2cc(Nc3ccnc(Cl)n3)ccc2[nH]1
Yield: 80 %

Procedure:
Et3N (1 mmol) was added to a solution of 2,4-dichloropyrimidine (1 mmol) and 5-amino-2-methylindole (1 mmol) in 5 ml EtOH. The reaction mixture was refluxed for 5 hours. After removal of the solvent in vacuo and addition of H2O, the mixture was extracted with EtOAc. The organic layers were combined, washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated in vacuo. The resulting residue was purified by column chromatography to give N-(2-chloropyrimidin-4-yl)-2-methyl-1H-indol-5-amine in a yield of 80%.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([S:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[CH3:20])=O.[NH2:21][C:22]([NH2:24])=[S:23]>CCO>[CH3:20][C:6]1[CH:7]=[C:8]([S:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH:9]=[C:10]([CH3:11])[C:5]=1[C:3]1[N:21]=[C:22]([NH2:24])[S:23][CH:2]=1
Reactant: NC(N)=S
Reactant: Cc1ccc(Sc2cc(C)c(C(=O)CBr)c(C)c2)cc1
Solvent: CCO
Product: Cc1ccc(Sc2cc(C)c(-c3csc(N)n3)c(C)c2)cc1
Yield: 100 %

Procedure:
A reaction mixture containing 2-bromo-1-(2,6-dimethyl-4-(p-tolylthio)phenyl)ethanone (394.8 mg, 1.1 mmol, 1.0 equiv) and thiourea (86.04 mg, 1.1 mmol, 1.0 equiv) in EtOH (10.0 mL) was heated at reflux for 16 h. The solution was concentrated under reduced pressure, and the residue was re-dissolved in EtOAc (50 mL). The solution was washed with saturated aqueous NaHCO3 (30 mL), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (5.0% EtOAc in hexanes as eluant) to provide 4-(2,6-dimethyl-4-(p-tolylthio)phenyl)thiazol-2-amine (371.9 mg, 1.1 mmol) as yellow solids in >99% yield: 1H NMR (DMSO-d6, 500 MHz) δ 7.27 (d, J=8.0 Hz, 2 H), 7.21 (d, J=8.0 Hz, 2 H), 6.97 (s, 2 H), 6.87 (s, 2 H), 6.36 (s, 1 H), 2.30 (s, 3 H), 2.05 (s, 6 H); ESI-MS: m/z 327.0 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][N:4]=1.[SH:13][C:14]1[NH:15][C:16]2[CH:22]=[C:21]([O:23][CH:24]([F:26])[F:25])[CH:20]=[CH:19][C:17]=2[N:18]=1.ClC1C=CC=C(C(OO)=[O:35])C=1>>[CH3:12][O:11][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([CH2:2][S+:13]([O-:35])[C:14]2[NH:18][C:17]3[CH:19]=[CH:20][C:21]([O:23][CH:24]([F:25])[F:26])=[CH:22][C:16]=3[N:15]=2)[C:8]=1[O:9][CH3:10].[Cl:1][CH2:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][N:4]=1
Reactant: FC(F)Oc1ccc2nc(S)[nH]c2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: COc1ccnc(CCl)c1OC
Product: COc1ccnc(C[S+]([O-])c2nc3cc(OC(F)F)ccc3[nH]2)c1OC

Procedure:
In one of the processes described in this patent application, 2-chloromethyl-3,4-dimethoxy pyridine was reacted with 2-mercapto-5-difluoromethoxy benzimidazole to prepare a precursor sulfide, which was isolated and oxidized by using metachloroperbenzoic acid to yield pantoprazole base in a yield of 102% by weight with respect to 2-chloromethyl-3,4 dimethoxy pyridine.
Reaction SMILES: [C:1]1([C:7]2[N:22]=[C:10]3[CH:11]=[C:12]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[CH:13]=[C:14]([NH2:15])[N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25]>>[C:27]1([O:26][C:24](=[O:25])[NH:15][C:14]2[N:9]3[N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:22]=[C:10]3[CH:11]=[C:12]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH:13]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cc(-c2ccncc2)cc2nc(-c3ccccc3)nn12
Product: O=C(Nc1cc(-c2ccncc2)cc2nc(-c3ccccc3)nn12)Oc1ccccc1

Procedure:
The title compound, MS m/e (%): 408 (M+H+, 100), was prepared in accordance with the general method of example 31 from 2-phenyl-7-pyridin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine and phenyl chloroformate.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[OH-].[Na+].C(O)(=O)C.CN([CH:20]=[N:21][C:22](=O)[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)C>O.O1CCOCC1>[F:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:22]([C:23]3[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=3)=[N:21][CH:20]=[N:10]2)=[CH:5][CH:4]=1
Reactant: NNc1ccc(F)cc1
Reactant: CN(C)C=NC(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(-c2ncnn2-c2ccc(F)cc2)cc1
Temperature: 90 °C

Procedure:
To a solution of 8.80 g. of 4-fluorophenylhydrazine hydrochloride in a mixture of 10.9 ml. of 5 N sodium hydroxide, 100 ml. of 30% aqueous acetic acid and 50 ml. of p-dioxane is added 10.0 g. of N-(dimethylaminomethylene)-p-nitrobenzamide. The reaction mixture is stirred and heated at 90° C. for 1.5 hours, then poured into 200 ml. of water. The solid is collected and recrystallized from ethanol, giving 10.4 g. of the desired product as yellow crystals, mp. 132°-134° C.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[C:12](SC)=[N:13][C:14]([C:16]1[C:20]([CH3:21])=[CH:19][S:18][CH:17]=1)=O>C1(C)C=CC=CC=1>[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[C:12]1[N:13]=[C:14]([C:16]2[C:20]([CH3:21])=[CH:19][S:18][CH:17]=2)[N:2]([CH3:1])[N:3]=1
Reactant: CSC(=NC(=O)c1cscc1C)c1c(F)cccc1Cl
Reactant: CNN
Solvent: Cc1ccccc1
Product: Cc1cscc1-c1nc(-c2c(F)cccc2Cl)nn1C
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 83.1 %

Procedure:
A solution of methylhydrazine (2.02 mL, 1.75 g, 38 mmol) in toluene (5 mL) was added at a rapid dropwise rate to a solution of methyl 2-chloro-6-fluoro-N-[(4-methylthien-3-yl) carbonyl]benzenecarbimidothioate (4.15 g, 12.7 mmol) in dry toluene (100 mL) at 55° C. The reaction was stirred at this temperature for 10 minutes and then left at room temperature for 14 hours. Another identical portion of methylhydrazine in toluene was added at room temperature and the reaction was heated at 80° C. for 3 hours and refluxed for an additional 3 hours. After cooling to room temperature, the reaction mixture was washed with water (100 mL), dilute hydrochloric acid (0.05 N, 2×100 mL) and brine (70 mL), dried over magnesium sulphate and concentrated under reduced pressure. The residue was recrystallised from ethyl acetate/hexane to give white cubes. The mother liquor was chromatographed (eluant, 30:9:1 hexane/methylene chloride/acetonitrile to afford the product (3.25 g, 84%): mp 153-155° C.; 1H NMR (CDCl3) δ 7.54 (d, 1H), 7.26-7.38 (m, 2H), 7.06-7.13 (m, 2H), 3.98 (s, 3H), 2.35 (d, 3H); 19F NMR (external reference)—110 ppm; EI/MS 307 m/e (M−1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([NH:15][CH2:16][CH2:17][CH2:18][CH:19]([N:21]2C(=O)C3=CC=CC=C3C2=O)[CH3:20])=[C:9]2[C:4]=1[C:5]([CH3:33])=[CH:6][C:7]([CH3:32])=[N:8]2.NN.[P:36](=[O:40])([OH:39])([OH:38])[OH:37]>C(O)C>[P:36]([OH:40])([OH:39])([OH:38])=[O:37].[NH2:21][CH:19]([CH3:20])[CH2:18][CH2:17][CH2:16][NH:15][C:10]1[CH:11]=[C:12]([O:13][CH3:14])[C:3]([O:2][CH3:1])=[C:4]2[C:9]=1[N:8]=[C:7]([CH3:32])[CH:6]=[C:5]2[CH3:33]
Reactant: COc1cc(NCCCC(C)N2C(=O)c3ccccc3C2=O)c2nc(C)cc(C)c2c1OC
Agent: NN
Agent: O=P(O)(O)O
Solvent: CCO
Product: COc1cc(NCCCC(C)N)c2nc(C)cc(C)c2c1OC

Procedure:
A solution of 5,6-dimethoxy-2,4-dimethyl-8-[(4-phthalimidopentyl)-amino]quinoline (12.7 g, 28 mmole) in ethanol (270 ml) containing 75% hydrazine (5.6 g, 84 mmole) was refluxed for 18 hr. An additional portion of 75% hydrazine (1.0 g, 15 mmole) was added and the mixture was refluxed for 1 hr more. Following the usual work-up, the base was isolated as a yellow-orange oil. The oil was dissolved in ethanol (30 ml) and treated dropwise with 0.90 equiv (27.8 ml) of 1 M phosphoric acid in ethanol. The phosphate salt separated initially as a gum, but dilution with ether (300 ml), seeding, and thorough trituration for several hours gave a uniform yellow solid, 11.5 g (90%), mp 163°-166°. Crystallization of the crude phosphate from methanol-ethanol-ether (1:1:2) afforded 82% recovery of product; mp 163°-166°.
Reaction SMILES: [C:1](Cl)(=O)C.[CH3:5][C:6]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:7]=1[C:8]([OH:10])=[O:9]>CO>[CH3:1][O:9][C:8](=[O:10])[C:7]1[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=1[CH3:5]
Reactant: CC(=O)Cl
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)O
Solvent: CO
Product: COC(=O)c1cc([N+](=O)[O-])ccc1C
Reaction time: 0.17 h

Procedure:
Acetyl chloride (15 ml) was added to MeOH (500 ml) at room temperature. After 10 min, 2-methyl-5-nitro-benzoic acid (25.00 g, 138.00 mmol) was added. The reaction solution was heated for reflux for 18 h. The solution was then concentrated in vacuo. The residue was dissolved in diethyl ether and washed with H2O and saturated aqueous solution of NaHCO3 respectively. The organic phase was dried over MgSO4 and concentrated in vacuo to provide the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[N:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:25]=3)=[CH:20][CH:19]=2)[CH:11]=[C:12]([C:14](O)([CH3:16])[CH3:15])[N:13]=1.C1(C)C=CC=CC=1>C(O)(=O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[N:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:25]=3)=[CH:20][CH:19]=2)[CH:11]=[C:12]([C:14]([CH3:16])=[CH2:15])[N:13]=1
Reactant: CC(C)(O)c1cn(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2)c(-c2c(Cl)cccc2Cl)n1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: C=C(C)c1cn(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2)c(-c2c(Cl)cccc2Cl)n1
Yield: 78 %

Procedure:
To a 25 mL round bottom flask attached with Vigreux column was added 2-[2-(2,6-Dichloro-phenyl)-1-(3′-methanesulfonyl-biphenyl-4-yl)-1H-imidazol-4-yl]-propan-2-ol (383 mg, 764 μmol), anhydrous toluene (8 mL) and acetic acid (3.5 mL). The reaction solution was allowed to stir at reflux for 1.5 hr. The cooled reaction solution was concentrated in vacuo, and the residue was taken into EtOAc (200 mL) and washed with aq NaHCO3 (100 mL×2) and aq. NaCl (100 mL). The organic phase was partitioned, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was chromatographed through a 25 g SiO2 column using a mobile gradient of 100% Hx to 80% EtOAc to provide 288 mg (78% yield) of title compound. 1H NMR. (400 MHz, DMSO-d6): δ 8.15 (br s, 1H), 8.08-7.97 (m, 2H), 7.92 (d, 1H), 7.89 (d, 2H), 7.75 (t, 1H), 7.64-7.57 (m, 3H), 7.43 (d, 2H), 5.77 (br s, 1H), 5.10 (br s, 1H), 3.29 (s, 3H), 2.11 (s, 3H); MS (ES): 483.1, 485.1 [M+H]+.
Reaction SMILES: CO[C:3](=[O:17])[CH:4]([NH:6][C:7](=O)[C:8]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=1[F:15])O.[I:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[BH4-].[Li+].S(Cl)(Cl)=O>S(=O)(=O)(O)O.C1(C)C=CC=CC=1>[F:14][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([F:15])[C:8]=1[C:7]1[O:17][CH2:3][CH:4]([C:22]2[CH:23]=[CH:24][C:19]([I:18])=[CH:20][CH:21]=2)[N:6]=1
Reactant: Ic1ccccc1
Reactant: COC(=O)C(O)NC(=O)c1c(F)cccc1F
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: Fc1cccc(F)c1C1=NC(c2ccc(I)cc2)CO1
Temperature: 23 °C
Reaction time: 72 h
Yield: 46.1 %

Procedure:
The compound of Step A of Example 1 (31.0 g, 0.13 mol) and iodobenzene (40.2 g, 0.19 mol) were suspended in sulfuric acid (100 mL) and stirred for 3 days at 23° C. The mixture was poured onto ice and extracted with dichloromethane (200 mL). The dichloromethane layer was dried over magnesium sulfate and evaporated under reduced pressure. Methanol (200 mL) and thionyl chloride (6 mL) were added and the mixture and heated at reflux for 30 min. The methanol was removed under reduced pressure and the residue was dissolved in tetrahydrofuran (200 mL). Lithium borohydride (55 mL, 2N in tetrahydrofuran, 0.11 mol) was added slowly and after completion of the addition, the mixture was heated at reflux for 1 h. The mixture was cooled, and quenched by slow addition of aqueous hydrochloric acid (200 mL, 1N). The mixture was extracted with dichloromethane (200 mL), dried over magnesium sulfate and evaporated under reduced pressure. The residue was then treated with toluene (100 mL) and thionyl chloride (23 mL, 0.3 mol). The mixture was heated to reflux for 45 min and then evaporated under reduced pressure. The residue was dissolved in methanol (200 mL) and treated with aqueous sodium hydroxide (30 mL, 50% solution). The mixture was heated to reflux for 30 min and then evaporated under reduced pressure. The residue was partitioned between water (100 mL) and dichloromethane (200 mL). The dichloromethane solution was dried over magnesium sulfate and evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel using hexanes/ethyl acetate (10:1) as eluent to give the title compound (23.1 g) as a white solid: m.p.: 105°-106° C. 1H NMR (CDCl3, 200 MHz) δ 7.7 (m,2H), 7.5 (m, 1H), 7.1 (m, 1H), 7.0 (m,2H), 5.4 (m, 1H), 4.8 (m, 1H), 4.3 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:6]=[CH:5][N:4]=1.Br[C:19]1[CH:20]=[CH:21][C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][CH:24]=1>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:19]2[CH:24]=[N:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[CH:6]=[CH:5][N:4]=1
Reactant: FC(F)(F)c1ccc(Br)cn1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Product: COc1cc(-c2ccc(C(F)(F)F)nc2)ccn1
Yield: 816.4 %

Procedure:
2-Methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.24 g, 0.53 mmol) and 5-bromo-2-(trifluoromethyl)pyridine (2.4 g, 11 mmol) were reacted according to the procedure of Example 5 (step a) to provide the title compound (1.1 g, 81%) as a white solid: ESI MS m/z 255 [M+H].