Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:15](O)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH2:69]([O:71][C:72](=[O:82])[CH2:73][CH2:74][CH2:75][NH:76][CH:77]1[CH2:81][CH2:80][CH2:79][CH2:78]1)[CH3:70]>CN(C=O)C>[CH2:69]([O:71][C:72](=[O:82])[CH2:73][CH2:74][CH2:75][N:76]([C:15](=[O:16])[C:14]1[CH:18]=[C:19]([Cl:21])[CH:20]=[C:12]([O:11][CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH:13]=1)[CH:77]1[CH2:81][CH2:80][CH2:79][CH2:78]1)[CH3:70]
Reactant: CCOC(=O)CCCNC1CCCC1
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CCCN(C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1)C1CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.1 %

Procedure:
To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid (0.300 g), TBTU (0.482 g) and HOBt (0.150 g) in DMF (5 ml) was added DIPEA (0.260 ml) followed by 4-cyclopentylamino-butyric acid ethyl ester (0.316 g) after 10 min. The reaction mixture was stirred at room temperature for 16 h and then further 4-cyclopentylamino-butyric acid ethyl ester (0.316 g) was added. After 24 h, the reaction mixture was concentrated under reduced pressure to give a viscous gum which was partitioned between ethyl acetate and water. The aqueous layer was removed and the organic phase washed with further water, aqueous saturated sodium bicarbonate solution, water and dried with brine and over sodium sulphate. The organic phase was concentrated under reduced pressure to give crude product as a black gum (0.420 g) which was purified by preparative hplc and the title compound (0.189 g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1.[CH2:15]([NH:22][C:23]([C:25]1[S:29][C:28]([NH2:30])=[N:27][C:26]=1[CH3:31])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([NH:22][C:23]([C:25]1[S:29][C:28]([NH:30][C:8](=[O:9])[C:7]2[CH:11]=[CH:12][C:4]([O:3][C:2]([F:14])([F:13])[F:1])=[CH:5][CH:6]=2)=[N:27][C:26]=1[CH3:31])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Product: Cc1nc(NC(=O)c2ccc(OC(F)(F)F)cc2)sc1C(=O)NCc1ccccc1
Yield: 20 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 4-trifluoromethoxybenzoyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 20% yield; m.p. 168-170° C.; 1H NMR (CDCl3, 300 MHz) δ 7.98 (d, J=8.8 Hz, 2H), 7.41-7.23 (m, 7H), 5.97 (t, J=5.6 Hz, 1H), 4.58 (d, J=5.6 Hz, 2H), 2.49 (s, 3H); MS (ES+) m/z 436.1 (M+1).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:25]3[N:24]4[C:20](=[CH:21][CH:22]=[CH:23]4)[C:19](=[O:26])[C:18]=3[S:17][CH:16]=2)=[CH:11][C:10]=1[O:27][CH3:28])C1C=CC=CC=1.Br.O>C(O)(=O)C>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:25]3[N:24]4[C:20](=[CH:21][CH:22]=[CH:23]4)[C:19](=[O:26])[C:18]=3[S:17][CH:16]=2)=[CH:11][C:10]=1[O:27][CH3:28]
Reactant: COc1cc(-c2csc3c2-n2cccc2C3=O)ccc1OCc1ccccc1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(-c2csc3c2-n2cccc2C3=O)ccc1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1mmol of the compound of Example 23 dissolved in an excess of hydrobromic acid in 33% acetic acid is stirred for 30 minutes at ambient temperature. After adding 100 ml of water, a precipitate is formed, which is filtered off and then dried. Chromatography on silica gel (ethyl acetate/hexane:1/2) allows the expected product to be isolated.
Reaction SMILES: [Si](O[CH2:19][C@H:20]1[O:27][C@@H:24]([O:25][CH3:26])[C@H:23]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@@H:22]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@@H:21]1[O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C.[S:67]([O:74]S(C(F)(F)F)(=O)=O)([C:70]([F:73])([F:72])[F:71])(=[O:69])=[O:68].C([O-])(O)=O.[Na+]>ClCCl>[CH2:29]([O:28][C@@H:23]1[C@@H:22]([O:36][CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C@H:21]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C@@H:20]([CH2:19][O:74][S:67]([C:70]([F:73])([F:72])[F:71])(=[O:69])=[O:68])[O:27][C@H:24]1[O:25][CH3:26])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CO[C@@H]1O[C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CO[C@@H]1O[C@H](COS(=O)(=O)C(F)(F)F)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of methyl 6-O-tert-butyldiphenylsilyl-2,3,4-tri-O-benzyl-β-D-glucopyranoside (800 mg, 1.71 mmol) in 8.55 mL of dry dichloromethane at -78° C. was added 2,6-di-tert-butyl-4-methyl pyridine (632 mg, 3.08 mmol) followed by triflic anhydride (345 μl, 2.05 mmol). After stirring 15 minutes at -78° C., the mixture was warmed to room temperature over 20 minutes, and then poured into a solution of saturated aqueous NaHCO3 (20 mL) and extracted with ethyl acetate (50 mL) . The organic layer was washed with saturated NaHCO3 (3×20 mL), saturated aqueous NaCl (1×20 mL), and dried over magnesium sulfate. Concentration provided crude target compound, which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:21]([CH2:23][N:24]3C(=O)C4C(=CC=CC=4)C3=O)[N:22]=2)[CH2:14][CH2:13]1)=[O:10].O.NN>CCO>[NH2:24][CH2:23][C:21]1[N:22]=[C:18]([N:15]2[CH2:14][CH2:13][CH:12]([NH:11][C:9]([C:3]3[NH:4][C:5]([CH3:8])=[C:6]([Cl:7])[C:2]=3[Cl:1])=[O:10])[CH2:17][CH2:16]2)[S:19][C:20]=1[C:35]([O:37][CH2:38][CH3:39])=[O:36]
Reactant: CCOC(=O)c1sc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1sc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc1CN
Temperature: 25 °C
Yield: 53.9 %

Procedure:
Ethyl 2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-4-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-1,3-thiazole-5-carboxylate (Example 277; 1.43 g, 2.42 mmol) in EtOH (10 ml) was added hydrazine hydrate (0.174 ml; 3.63 mmol) and refluxed for 14 h. The reaction mixture cooled to room temperature and concentrated in vacuo, diluted with DCM and acidified with 10% HCl, washed with H2O. The precipitate was filtered and dried in vacuo to give the title compound (600 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].[H-].[Na+].Cl[CH2:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([C:9]([CH2:23][O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(F)c(F)c1
Reactant: COc1ccc(COCCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(COCc1ccc(OC)cc1)(C(=O)OCC)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of diethyl 3,4-difluorophenylmalonate (13 g, 48 mmol) in dry tetrahydrofuran (100 ml) at 0° C. under a nitrogen atmosphere was added sodium hydride (1.5 g, 50 mmol) of 80% oil dispersion). The mixture was allowed to warm to room temperature and then heated to reflux for 1hour. To the cooled mixture was added 4-methoxybenzyl chloromethyl ether (9.5 g, 51 mmol ref. Synthesis, 1983, 762) and reflux was continued overnight. The cooled mixture was partitioned between water and diethyl ether, the organic layer was separated, dried over anhydrous magnesium sulphate and evaporated to leave diethyl 2-(3,4-difluorophenyl)-2(4-methoxybenzyloxymethyl)malonate as a yellow oil Nmr δ7.35 (1H,m), 7.2 (2H,d), 7.15-7.00 (2H,m), 6.85 (2H,d), 4.45 (2H,s), 4.20 (4H,q), 4.10 (2H,s), 3.80 (3H,s), 1.25 (6H,t).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH2:9][C:10](OCC)=O)[CH:3]=1.Cl.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([NH2:25])[CH:19]=1.N>Cl>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]2[N:24]=[C:10]([CH2:9][S:8][C:4]3[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=3)[NH:25][C:20]=2[CH:19]=1
Reactant: CCOC(=O)CSc1cc(C)ccn1
Reactant: COc1ccc(N)c(N)c1
Agent: Cl
Agent: N
Product: COc1ccc2nc(CSc3cc(C)ccn3)[nH]c2c1

Procedure:
10.6 g of ethyl 2-(4-methyl-2-pyridylthio)acetate (0.05 mole) and 8.8 g of 4-methoxy-1,2-phenylenediamine hydrochloride (0.05 mole) in 400 ml of 6N hydrochloric acid are heated under reflux for 2 days. The mixture is allowed to cool and is neutralized with ammonia solution. It is extracted with ethyl acetate (3×100 ml), and the extract is dried (Na2SO4), filtered and concentrated to a volume of 75 ml. From this solution, 8.4 g (59%) of 5-methoxy-2-(4-methyl-2-pyridylthiomethyl)benzimidazole, melting point 138°-140° C., crystallize. The data for the identification of the product appear in Tables 1 and 2.
Reaction SMILES: CCC([O-])(C)C.[K+].[N:8]1[CH:13]=[CH:12][C:11]([C:14]([O:16]CC)=O)=[N:10][CH:9]=1.Cl.[C:20]([O:23][CH2:24][CH3:25])(=[O:22])[CH3:21]>C1(C)C=CC=CC=1.O>[O:16]=[C:14]([C:11]1[CH:12]=[CH:13][N:8]=[CH:9][N:10]=1)[CH2:21][C:20]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)c1ccncn1
Agent: CCC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(=O)c1ccncn1
Yield: 76 %

Procedure:
To a 25% solution (5.31 g, 10.52 mmol) of potassium tert-amylate in toluene was added dropwise a solution of ethyl pyrimidine-4-carboxylate (1.00 g, 6.57 mmol) and ethyl acetate (1.09 mL, 11.1 mmol) in toluene (2.4 ml) at room temperature. Disappearance of the ethyl ester was confirmed by HPLC analysis, water (5 mL), ethyl acetate (5 mL) and concentrated hydrochloric acid (0.45 mL) were added, and the mixture was extracted with ethyl acetate (4 mL). The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give ethyl 3-oxo-3-(pyrimidin-4-yl)propionate (0.97 g, 76%).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([CH2:10][C:11](=[O:16])[CH2:12][CH2:13][CH2:14][CH3:15])[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(=O)([O-])[O-].[K+].[K+].[Br:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[C:26]([F:32])[CH:25]=1>CN(C=O)C>[Br:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][CH:10]([C:11](=[O:16])[CH2:12][CH2:13][CH2:14][CH3:15])[C:4](=[N:3][O:2][CH3:1])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:26]([F:32])[CH:25]=1
Reactant: CCCCC(=O)CC(=NOC)C(=O)OCC
Reactant: Fc1cc(Br)ccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCC(=O)C(Cc1ccc(Br)cc1F)C(=NOC)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.7 %

Procedure:
A mixture of 5.0 g (21.8 mmol) of ethyl 2-methoxyimino-4-oxooctanoate (from Example 1, Step A), 3.6 g (26 mmol) of anhydrous potassium carbonate, and 70 mL of dry DMF was stirred under N2 at room temperature for 1 hour. The mixture was then cooled to 0° C. and treated dropwise with a solution of 5.9 g (21.8 mmol) of 4-bromo-2-fluorobenzyl bromide in 20 mL of dry DMF. The mixture was allowed to warm slowly to room temperature and was stirred under N2 for 48 hours. The mixture was partitioned between 400 mL of ethyl acetate and 400 mL of 0.2N HCl. The organic layer was washed twice with H2O and then dried over Na2SO4. The filtered solution was concentrated, and the residual oil was flash chromatographed on silica gel. Gradient elution with 5-20% ethyl acetate in hexane afforded 3.51 g (39%) of the title compound as an oil; homogeneous by TLC in 3:1 hexane-EtOAc; mass spectrum (FAB) m/e 416, 418 (M+1)+. 200 MHz 1H NMR (CDCl3) δ0.87 (t, J=7.1 Hz, 3H), 1.2-1.4 (m, 5H) including 1.25 (t, J=7.1 Hz, 3H), 1.55 (m, 2H), 2.31 (t, J=7.1 Hz, 2H), 2.97 (dd, J=14, 10 Hz, 1H), 3.36 (dd, J=14, 5 Hz, 1H), 3.95 (s, 3H), 4.15-4.35 (m, 3H), 6.98 (dd, J≈8, 8 Hz, 1H), 7.15 (apparent d, J=8.2 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[C:4]([CH3:10])[C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1.[CH2:21]([Mg]Br)[CH:22]([CH3:24])[CH3:23]>C1COCC1>[CH3:1][C:2]1[CH:7]=[C:6]([CH:8]([OH:9])[CH2:21][CH:22]([CH3:24])[CH3:23])[CH:5]=[C:4]([CH3:10])[C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:18])[F:20])=[CH:13][CH:12]=1
Reactant: Cc1cc(C=O)cc(C)c1-c1ccc(C(F)(F)F)cc1
Reactant: CC(C)C[Mg]Br
Solvent: C1CCOC1
Product: Cc1cc(C(O)CC(C)C)cc(C)c1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2,6-Dimethyl-4′-trifluoromethyl-biphenyl-4-carbaldehyde (1.0 g, 3.6 mmol) in THF (10 mL) at 0° C. is added isobutyl magnesium bromide (2M, 2.2 mL). After stirring at room temperature for 2 hours, it is quenched with saturated ammonium chloride, extracted with EtOAc. The organic is concentrated to give the titled compound as colorless oil: 0.47 g (39%).
Reaction SMILES: CS([O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:8][CH2:7]1)(=O)=O.O[C:23]1[CH:28]=[CH:27][NH:26][C:25](=[O:29])[CH:24]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[O:29]=[C:25]1[CH:24]=[C:23]([O:5][CH:6]2[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[CH2:8][CH2:7]2)[CH:28]=[CH:27][NH:26]1
Reactant: O=c1cc(O)cc[nH]1
Reactant: CS(=O)(=O)OC1CCN(C(=O)OCc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CCC(Oc2cc[nH]c(=O)c2)CC1
Temperature: 140 °C
Yield: 33.5 %

Procedure:
A stirring suspension of benzyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (1.97 g, 6.30 mmol), 4-hydroxypyridin-2(1H)-one (0.50 g, 4 5 mmol, Aldrich), potassium carbonate (1.43 g, 10 6 mmol, EMD) and DMF (25 mL) was heated at 140° C. for 2.5 h and then cooled to room temperature. The resulting mixture was diluted with H2O and extracted with EtOAc (2×). The organic layers were combined and washed with brine, dried over Na2SO4 and concentrated in vacuo to a light yellow oil. The oil was purified by flash chromatography (SiO2, 0 to 10% MeOH in CH2Cl2) to yield 550 mg of desired product as a white solid. MS (ESI) 329 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@@:11]([OH:15])([CH3:14])[CH2:12][OH:13])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[N:3]([CH2:10][C@@:11]([OH:15])([CH3:14])[CH2:12][O:13][S:17]([CH3:16])(=[O:19])=[O:18])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@](O)(CO)Cn1cc([N+](=O)[O-])nc1Cl
Agent: Cl
Solvent: c1ccncc1
Product: C[C@@](O)(COS(C)(=O)=O)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 4 °C
Reaction time: 1 h
Yield: 57.3 %

Procedure:
(S)-2-Chloro-1-(2,3-dihydroxy-2-methylpropyl)-4-nitroimidazole prepared in Example 16 (4.05 g, 16.9 mmol) was dissolved in pyridine (8 ml), and this solution was cooled to 4° C. Methanesulfonyl chloride (1.6 ml, 20.28 mmol) was added dropwise to the solution below 15° C. followed by stirring at the same temperature for 1 hour. 6N hydrochloric acid (33 ml) was added to the mixture below 30° C. The reaction mixture was extracted with methylene chloride (20 ml) three times. The organic phases were combined, washed with water (20 ml) and a saturated saline solution (20 ml), dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. Toluene (10 ml) was added to the residue, and the resulting precipitates were filtered off to afford (S)-2-chloro-1-(2-hydroxy-2-methyl-3-methanesulfonyloxypropyl)-4-nitroimidazole (3.04 g, yield 57%) as a white powder.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=1.[C:15]1([OH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[N+:8]([C:7]1[C:2]([O:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:3][CH:4]=[C:5]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)([O-:10])=[O:9]
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(C(F)(F)F)cnc1Oc1ccccc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 23 %

Procedure:
To a solution of 2-chloro-3-nitro-5-(trifluoromethyl)pyridine (1280 mg) in dimethylformamide (18 mL) were added phenol (800 mg) and cesium carbonate (5530 mg). The reaction mixture was stirred at 60° C. for 3 hours. The reaction mixture was diluted with ethyl acetate and washed with water and a saturated sodium chloride aqueous solution. The obtained organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified on silica gel column chromatography (hexane:ethyl acetate=1:19) to give the titled compound (370 mg) having the following physical data.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:38]=[CH:37][C:6]([CH2:7][NH:8][C:9]2[N:14]=[C:13]([O:15]C3C=CC(NC(=O)CC(NC4C=CC(F)=CC=4)=O)=CC=3F)[CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.FC1C=CC(CC(N=C=O)=O)=CC=1.COC1C=CC(CNC2N=CN=C(O[C:67]3[CH:72]=[CH:71][C:70]([NH:73][C:74]([NH:76][C:77](=[O:86])[CH2:78][C:79]4[CH:84]=[CH:83][C:82]([F:85])=[CH:81][CH:80]=4)=[O:75])=[CH:69][C:68]=3[F:87])C=2)=CC=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9]2[N:14]=[C:13]([O:15][C:67]3[CH:72]=[CH:71][C:70]([NH:73][C:74]([NH:76][C:77](=[O:86])[CH2:78][C:79]4[CH:84]=[CH:83][C:82]([F:85])=[CH:81][CH:80]=4)=[O:75])=[CH:69][C:68]=3[F:87])[CH:12]=[CH:11][N:10]=2)=[CH:37][CH:38]=1
Reactant: COc1ccc(CNc2nccc(Oc3ccc(NC(=O)CC(=O)Nc4ccc(F)cc4)cc3F)n2)cc1
Reactant: COc1ccc(CNc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)ncn2)cc1
Agent: O=C=NC(=O)Cc1ccc(F)cc1
Solvent: C1CCOC1
Product: COc1ccc(CNc2nccc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.6 %

Procedure:
A solution of N-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)pyrimidin-2-amine (Compound C of Example 14, 34 mg, 0.10 mmol) in THF (1 ml) was treated with 0.36 M 2-(4-fluorophenyl)acetyl isocyanate in toluene (Compound D of Example 11, 0.31 mL, 0.11 mmol) and the mixture stirred at RT for 1 h. The mixture was concentrated in vacuo and the solid obtained was triturated first with 3:1 isopropyl ether/EtOAc and then CH2Cl2 to give the title compound (32 mg, 62%) as an off-white solid. 1H NMR (DMSO-d6) δ 10.47 (s, 1H), 10.26 (s, 1H), 8.15 (s, 1H), 7.76 (d, 1H, J=12.6 Hz), 7.61 (dd, 3H, J=9.1, 5.0 Hz), 7.29 (s, 2H), 7.31-7.21 (m, 3H), 6.81 (s, 3H), 6.24 (s, 1H), 4.32 (s, 1H), 3.96 (s, 1H), 3.68 (s, 3H), 3.48 (s, 2H); MS(ESI+) m/z 520.14 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[CH3:20])[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C(O)(C(F)(F)F)=O.[NH2:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=1>C(OCC)(=O)C>[C:13]1([CH3:20])[CH:14]=[C:15]([CH3:19])[CH:16]=[C:17]([CH3:18])[C:12]=1[NH:11][C:4]1[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=[C:2]([NH:28][C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=2)[N:3]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: Cc1cc(C)c(Nc2nc(Cl)nc3ccsc23)c(C)c1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)c(Nc2nc(Nc3ccc(C#N)cc3)nc3ccsc23)c(C)c1
Temperature: 90 °C
Reaction time: 15 h
Yield: 19.8 %

Procedure:
To a solution of 2-Chloro-N-mesitylthieno[3,2-d]pyrimidin-4-amine (51.4mg, 0.17 mmol), TFA (0.11 mL, 1.36 mmol) in TFE (1 mL) was added 4-aminobenzonitrile (80.2 mg, 0.68 mmol) in a sealed tube. The reaction was stirred at 90° C. for 15 h. Reaction mixture was diluted with ethyl acetate and washed with saturated NaHCO3 (3×10 mL). The combined organic layers were washed with brine dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by prep HPLC to afford the product as a white solid (13 mg, 20%):
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[CH:9][C:10]3[N:14]=[N:13][N:12]([OH:15])[C:11]=3[CH:16]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[Na+].[CH2:19](O)C>>[N:1]1([CH2:6][C:7]2[CH:8]=[CH:9][C:10]3[N:14]=[N:13][N:12]([O:15][CH3:19])[C:11]=3[CH:16]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCO
Reactant: On1nnc2ccc(Cn3ccnc3)cc21
Agent: [Na+]
Agent: [OH-]
Product: COn1nnc2ccc(Cn3ccnc3)cc21
Yield: 65.4 %

Procedure:
To a stirred suspension of 4.7 parts of 6-(1H-imidazol-1-ylmethyl)-1H-benzotriazol-1-ol in 60 parts of ethanol were added 22.5 parts of a sodium hydroxide solution 1N. The whole was stirred till a clear solution was obtained. The mixture was evaporated to dry. The residue was dissolved in 18 parts of N,N-dimethylformamide. To the thus obtained solution was added at once a solution of 3.2 parts of iodomethane in 9 parts of N,N-dimethylformamide. After stirring for 30 minutes at room temperature, the whole was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was recrystallized from 8 parts of 4-methyl-2-pentanone. The product was filtered off and dried, yielding 3.3 parts (65.4%) of 6-(1H-imidazol-1-ylmethyl)-1-methoxy-1H-benzotriazole; mp. 132.4° C. (compound 229).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH2:12]([C:14]1[CH:15]=[C:16]([CH3:26])[C:17]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:18][CH:19]=1)[CH3:13]>>[CH2:12]([C:14]1[CH:15]=[C:16]([CH3:26])[C:17]([N:20]2[CH2:21][CH2:22][N:23]([C:6]([C:5]3[CH:4]=[N:3][C:2]([F:1])=[CH:10][C:9]=3[CH3:11])=[O:8])[CH2:24][CH2:25]2)=[N:18][CH:19]=1)[CH3:13]
Reactant: Cc1cc(F)ncc1C(=O)O
Reactant: CCc1cnc(N2CCNCC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3cnc(F)cc3C)CC2)c(C)c1
Yield: 52.4 %

Procedure:
Using 6-fluoro-4-methylnicotinic acid (300 mg) and 1-(5-ethyl-3-methylpyridin-2-yl)piperazine (389 mg) described in Preparation Example 81 and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (340 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]2[C:15]3[CH2:16][NH:17][CH2:18][CH2:19][C:14]=3[NH:13][C:12](=[O:20])[N:11]2[CH:21]=1.[CH:22](=O)[CH2:23][CH2:24][CH3:25].C([BH3-])#N.[Na+].Cl>O.CO>[CH2:22]([N:17]1[CH2:18][CH2:19][C:14]2[NH:13][C:12](=[O:20])[N:11]3[CH:21]=[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[N:9]=[C:10]3[C:15]=2[CH2:16]1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCC=O
Reactant: O=c1[nH]c2c(c3nc(-c4ccccc4F)cn13)CNCC2
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCN1CCc2[nH]c(=O)n3cc(-c4ccccc4F)nc3c2C1
Reaction time: 6 h

Procedure:
To 2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e] pyrimidin-5(6H)-one (171 mg, 0.6 mmol) in pH4-5 HCL-methanol (6 mL) at room temperature was added n-butyraldehyde (53 uL, 0.6 mmol) and sodium cyanoborohydride (38 mg, 0.6 mmol). After the reaction mixture was stirred for 6 hours, concentrated HCl was added until the mixture became homogenous. The mixture was then diluted with water (5 mL) and extracted twice with ether. The aqueous layer was made alkaline with aqueous ammonium hydroxide, saturated with sodium chloride, and extracted twice with 10% methanol/ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated to give 9-n-Butyl-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e] pyrimidin-5(6H)-one (Compound 48). Recrystallization from aqueous ethanol gave a white fluffy solid, m.p. 251°-253° C. (d).