Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH2:15][O:16][C@@H:17]2[CH2:22][CH2:21][CH2:20][C@H:19]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[CH:32]=[C:33]([CH3:37])[CH:34]=[CH:35][CH:36]=4)[O:28][C:29]=3[CH3:30])[CH2:18]2)[C:3]=1[C:4]([O:6]CC)=[O:5].[OH-].[Na+]>CO.Cl.C(OCC)(=O)C>[CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH2:15][O:16][C@@H:17]2[CH2:22][CH2:21][CH2:20][C@H:19]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[CH:32]=[C:33]([CH3:37])[CH:34]=[CH:35][CH:36]=4)[O:28][C:29]=3[CH3:30])[CH2:18]2)[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)c1c(C)cccc1OCCO[C@@H]1CCC[C@H](OCc2nc(-c3cccc(C)c3)oc2C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cccc(-c2nc(CO[C@H]3CCC[C@@H](OCCOc4cccc(C)c4C(=O)O)C3)c(C)o2)c1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
Unpurified ethyl (1R,3S)-2-methyl-6-{2-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]ethoxy}benzoate are dissolved in 3 ml of methanol, and 0.25 ml of a 5 N sodium hydroxide solution are added. The mixture is stirred at 60° C. for 8 h and at 80° C. for 12 h. After cooling, the mixture is taken up in 2N HCl/ethyl acetate, the organic phase is dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is purified by RP-HPLC. This gives (1R,3S)-2-methyl-6-{2-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]ethoxy)benzoic acid as a colorless oil. C28H33NO6 (479.58), MS (ESI). 480 (M+H+).
Reaction SMILES: O[CH2:2][CH2:3][CH:4]1[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[O:6][CH2:5]1.C(Br)(Br)(Br)[Br:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO>CN(C)C=O>[Br:13][CH2:2][CH2:3][CH:4]1[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[O:6][CH2:5]1
Reactant: BrC(Br)(Br)Br
Reactant: CC1(C)OCC(CCO)CO1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CO
Product: CC1(C)OCC(CCBr)CO1
Temperature: 0 °C
Reaction time: 8 h
Yield: 33.2 %

Procedure:
To an ice-cooled solution of 5-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxan (1.92 g, 12 mmol) and carbon tetrabromide (7.96 g, 24 mmol) in dimethylformamide (100 ml), triphenylphosphine (6.30 g, 24 mmol) was added and the solution was left at 4° C. overnight. To this solution methanol (20 ml) was added and the solvent was then evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with hexane-acetone (12:1) to afford 5-(2-bromoethyl)-2,2-dimethyl-1,3-dioxan as a clear colourless liquid (0.89 g, 40%); νmax (film) 2940, 1370, 1270, 1260, 1200, and 1070 cm-1 ; δH (CDCl3) 1.42 (6 H, s, C(CH3)2), 1.94 (3 H, m, CHCH2CH2Br), 3.43 (2 H, t, J 7 Hz, CH2Br), and 3.5-4.1 (4 H, m, 2×CH2O); (Found: C, 42.84; H, 6.93%. C8H15BrO2 requires: C, 43.07; H, 6.78%. [M-CH3 ]+ found 207.0024; C7H12BrO2 requires 207.0021).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH3:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[C:14]2=[O:21]>>[OH:21][C:14]1([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)[C:13]2[C:17](=[CH:18][CH:19]=[C:11]([CH3:10])[CH:12]=2)[NH:16][C:15]1=[O:20]
Reactant: COc1ccc(Br)cc1
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2
Product: COc1ccc(C2(O)C(=O)Nc3ccc(C)cc32)cc1
Yield: 81.2 %

Procedure:
With 5.61 g of 4-bromoanisole and 3.23 g of 5-methyl isatin as starting materials, 4.38 g of the title compound (light brown solid) was obtained by a similar method to Step 21-1.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:11]=2)[C@:7]([C:25](=O)[CH3:26])([CH3:24])[CH2:6]1)=[O:4].C(O)(=O)C.[CH3:32][NH:33][NH2:34]>CO>[CH3:1][O:2][C:3]([N:5]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:11]=2)[C@@:7]([CH3:24])([C:25](=[N:34][NH:33][CH3:32])[CH3:26])[CH2:6]1)=[O:4]
Reactant: COC(=O)N1CC(c2ccc(OC)c(OC3CCCC3)c2)[C@@](C)(C(C)=O)C1
Reactant: CNN
Solvent: CC(=O)O
Solvent: CO
Product: CNN=C(C)[C@@]1(C)CN(C(=O)OC)CC1c1ccc(OC)c(OC2CCCC2)c1

Procedure:
To a stirred solution of (R)-3-acetyl-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methyl-pyrrolidine-1-carboxylic acid methyl ester (see Example 12 of Feldman et al. U.S. Pat. No. 5,665,654, incorporated herein by reference) (or (R)-3-acetyl-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methyl-pyrrolidine-1-carboxylic acid methyl ester) (0.133 mmol, 50 mg) in methanol (2 mL) with catalytic amount of acetic acid (20 μL) was added methyl hydrazine (0.147 mmol, 7.8 μL). The reaction was heated gently for 36 hours, and three more portions of methl hydrazine were added. The resulting hydrazone was purified by HPLC. The named product was confirmed by HNMR.
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.[CH3:17][S:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[CH3:17][S:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH2:6][CH2:5][CH2:4][C:3]=2[C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[CH:21][CH:20]=1
Reactant: CS(=O)(=O)c1ccc(C2=C(Br)CCC2)cc1
Reactant: CSc1ccc(B(O)O)cc1
Product: CSc1ccc(C2=C(c3ccc(S(C)(=O)=O)cc3)CCC2)cc1
Yield: 85.5 %

Procedure:
Following a synthetic procedure which was similar to the one outlined in Step 3 of Example 1, 270 mg (0.9 mmol) of 1-(2-bromocyclopenten-1-yl)-4-(methylsulfonyl)benzene (Step 1) was reached with 300 mg (1.8 mmol) of 4-methylthiophenylboronic acid (Example 1, Step 1). Purification by silica gel chromatography (MPLC) with hexane/ethyl acetate (4:1) gave 265 mg (86%) of 1-[2-(4-methylthiophenyl)cyclopenten-1-yl)-4-(methylsulfonyl)benzene as a colorless solid: mp 138°-139° C.; NMR (CDCl3) d 2.08 (m, J=7 Hz, 2H), 2.47 (s, 3H), 2.90 (t, J=7 Hz, 4H), 3.04 (s, 3H), 7.06 (d, J=8 Hz, 2H), 7.11 (d, J=8 Hz, 2H), 7.34 (d, J=8 Hz, 2H), 7.75 (d, J=8 Hz, 2H); ME (EI) m/e (rel intensity) 344 (100), 297 (4), 218 (33); HRMS. Calc'd for C19H20O2S2 : 344.0905. Found: 344.0907. Anal, Calc'd for C19H20O2S2 : C, 66.24; H, 5.85; S, 18.16. Found: C, 66.28; H, 5.81; S, 18.95.
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:6])([OH:5])[CH3:4].[CH2:7]([N:9]=[C:10]=[O:11])[CH3:8]>C(Cl)Cl>[CH3:4][C:3]([OH:5])([CH3:6])[CH2:2][NH:1][C:10]([NH:9][CH2:7][CH3:8])=[O:11]
Reactant: CCN=C=O
Reactant: CC(C)(O)CN
Solvent: ClCCl
Product: CCNC(=O)NCC(C)(C)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-amino-2-methyl-2-propanol (4.0 g, 45 mmol) in CH2Cl2 (25 mL) at 0° C. was added a solution of ethyl isocyanate (3.2 g, 45 mmol) in CH2Cl2 (5 mL) dropwise. The mixture was stirred at ambient temperature for 18 hours, then concentrated of all volatiles in vacuo to afford a quantitative yield of N-(2-methyl-2-hydroxypropyl)-N'-ethylurea as a yellow solid; NMR (DMSO-d6 /TFA) 5.9 (m. 1), 5.7 (m, 1), 3.0 (m, 2), 2.9 (d, 2), 1.0 (s, 6), 0.9 (t, 3) ppm.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][CH:18]=2)[O:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:19](OC)=[O:20].[H-].[Na+]>CN(C=O)C>[OH:20][CH:19]=[C:11]([O:10][C:9]1[CH:16]=[CH:17][CH:18]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC=O
Reactant: COC(=O)COc1cccc(-c2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=CO)Oc1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 90 %

Procedure:
Methyl (3-phenylphenoxy)acetate (6.0 g) and methyl formate (30.2 ml) were dissolved in DMF and added dropwise with stirring to a suspension of sodium hydride (1.44 g, 50% dispersion in oil) in DMF at 0° C. (ice-bath). After 45 minutes, the ice-bath was removed and the reaction mixture was stirred for 2 hours at room temperature. Aqueous sodium carbonate was then added. The aqueous layer was washed with ether, acidified to pH 4-5 with concentrated hydrochloric acid and then re-extracted with ether. The combined organic layers were washed with brine, dried, filtered and evaporated to give methyl 3-hydroxy-2-(3'-phenylphenoxy)propenoate as a pale yellow oil (6.05 g, 90% yield).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])(C)(C)C.[NH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[C:35]([O:40][CH3:41])[CH:34]=1>>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([OH:39])=[C:35]([O:40][CH3:41])[CH:34]=3)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1cccc(-c2ccnc(Cl)n2)c1)S(C)(=O)=O
Reactant: COc1cc(CN)ccc1O
Product: COc1cc(CNc2nccc(-c3cccc(CN(CCCN)S(C)(=O)=O)c3)n2)ccc1O

Procedure:
Intermediate 4 was coupled with 4-Aminomethyl-2-methoxy-phenol following procedure F and the resulting product deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 472. 1H NMR (Varian 300 MHz, CDCl3—CD3OD, shifts relative to the solvent peak at 7.24 ppm) δ 8.2 (m, 3H) 7.6 (m, 2H) 7.3 (m, 2H) 6.8 (m, 2H) 4.4 (s, 2H) 3.8 (s, 2H) 3.7 (m, 2H) 3.4 (s, 3H) 2.9 (s, 3H) 2.8 (m, 2H) 1.7 (m, 2H).
Reaction SMILES: O[CH2:2][C:3]1[C:12]([CH3:13])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.P(Br)(Br)[Br:15]>CCOCC>[Br:15][CH2:2][C:3]1[C:12]([CH3:13])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1
Reactant: Cc1cc2ccccc2cc1CO
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: Cc1cc2ccccc2cc1CBr
Temperature: 0 °C
Reaction time: 1.25 h
Yield: 86.8 %

Procedure:
To a stirred solution of 2-hydroxymethyl-3-methylnaphthalene (2.47 g, 14.4 mmol) in dry Et2O (50 mL) cooled to 0° C. was added phosphorus tribromide (4.88 g, 18 mmol) dropwise over 20 minutes. The resulting heterogeneous mixture was stirred at 0° C. for 1.25 hours and then quenched with H2O (50 mL). The reaction mixture was diluted further with H2O (50 mL) and extracted with Et1O (2×150 mL). The combined organic layers were washed with H2O (1×100 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by filtration through silica gel using CH2Cl2 as eluent to give the product as an off-white solid (2.94 g, 87%).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[CH:13]1([C:19](Cl)=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.Cl>[OH-].[Na+]>[CH:13]1([C:19]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: N=C(N)NCCC[C@H](NC(=O)C1CCCCC1)C(=O)O
Temperature: 50 °C
Yield: 37.6 %

Procedure:
(L)-Arginine (103.2 g., 0.6 mole) was dissolved in 600 mL of 2 N sodium hydroxide. Cyclohexanoyl chloride (87 mL, 0.6 mole) was added dropwise to the mixture. The reaction mixture was maintained at 50° C. for 2 hours. The mixture was then cooled to room temperature and acidified to pH 2.3 with aqueous (4:1) hydrochloric acid. The precipitate which formed was separated by decantation. The solids were dissolved in 2 N sodium hydroxide and dried by lyophilization to furnish 64.1 g of crude N-cyclohexanoyl-(L)-arginine. The product was purified by column chromatography on silica gel/using butanol/acetic acid/water as the eluent system. The products isolated were N-cyclohexanoyl-(L)-arginine and Nα,Nγ -dicyclohexanoyl-(L)-arginine.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:6][C:5]=1[C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:3])=[CH2:2]>C(OC(=O)C)C.C(Cl)Cl.[Pd]>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[O:11])=[O:12])=[CH:6][C:5]=1[C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:27]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:3])[CH3:2]
Reactant: C=C(C)c1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)c1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Reaction time: 1 h
Yield: 70 %

Procedure:
To a solution of (2-Isopropenyl-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone, (Example 44, 20 mg, 0.0442 mmol) in Ethylacetate (1 ml) was added Pd/C 10% (1 mg). The mixture was hydrogenated at rt for 1 hour. Then, Pd/C 10% (10 mg) and Ethylacetate (5mL) were added and the mixture was hydrogenated at reflux temperature for 1 hour. The mixture was diluted with MeCl2 ,filtered and the filtrate was concentrated in vacuo. The crude mixture was purified on SiO2 Eluent: Heptane/AcOEt 0% to 40% (20 minutes) to provide the title compound (14 mg, 70%, yellow solid); M+H=455.2
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21]#[N:22])[CH:17]=[CH:18][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:42]([N:49]1[CH2:55][CH2:54][CH2:53][C@@H:50]1[CH2:51]O)([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43]>O1CCCC1>[C:21]([CH2:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[O:13][CH2:51][C@H:50]1[CH2:53][CH2:54][CH2:55][N:49]1[C:42]([O:44][C:45]([CH3:46])([CH3:48])[CH3:47])=[O:43])#[N:22]
Reactant: N#CCc1cccc(O)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cccc(CC#N)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.8 %

Procedure:
Diethyl azodicarboxylate (3.92 g, 22.5 mmol) was added dropwise to a solution of 3-hydroxyphenyl acetonitrile (3.0 g, 22.5 mmol), triphenylphosphine (5.90 g, 22.5 mmol) and Boc-(R)-prolinol (4.53 g, 22.5 mmol) in tetrahydrofuran (30 ml), and the reaction stirred at room temperature for 18 hrs. The mixture was evaporated under reduced pressure and the residue partitioned between dichloromethane and water. The layers were separated, the organic phase washed with water, dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane:pentane:methanol (80:20 to 100:0:0 to 95:0:5) to give the title compound, (2.69 g, 38%).
Reaction SMILES: [O:1]1[CH2:15][CH:2]1[CH2:3][N:4]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:14].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[N:25][C:26]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[N:27][CH:28]=2)=[CH:19][CH:18]=1>C(O)(C)C>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[N:25][C:26]([N:29]3[CH2:34][CH2:33][N:32]([CH2:15][CH:2]([OH:1])[CH2:3][N:4]4[C:12](=[O:13])[C:11]5[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=5)[C:5]4=[O:14])[CH2:31][CH2:30]3)=[N:27][CH:28]=2)=[CH:19][CH:18]=1
Reactant: Clc1ccc(-c2cnc(N3CCNCC3)nc2)cc1
Reactant: O=C1c2ccccc2C(=O)N1CC1CO1
Solvent: CC(C)O
Product: O=C1c2ccccc2C(=O)N1CC(O)CN1CCN(c2ncc(-c3ccc(Cl)cc3)cn2)CC1
Reaction time: 2 h

Procedure:
0.022 of 2-(2,3-epoxypropyl)isoindole-1,3(2H)dione, 0.02 mol of 1-(5-(4-chlorophenyl)-2-pyrimidinyl)piperazine and 70 ml of isopropanol are heated to boiling for 2 hours. The mixture is evaporated and the residue is purified by column chromatography on silica gel 60. After elution with methylene chloride/alcohol (96:4), the compound is stirred with alcohol and filtered off with suction.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[C:11]([O:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[N:10]([CH2:24][CH2:25][OH:26])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.N1C(C)=CC=CC=1C.O([Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])S(C(F)(F)F)(=O)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[C:11]([O:13][C:14]3[CH:15]=[CH:16][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:18][CH:19]=3)[N:10]([CH2:24][CH2:25][O:26][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OCCn1nc(-c2cccc(Br)c2)cc1Oc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)[Si](C)(C)OCCn1nc(-c2cccc(Br)c2)cc1Oc1ccc(C(F)(F)F)cc1
Reaction time: 0.5 h

Procedure:
A stirred solution of 2-{3-(3-bromophenyl)-5-[4-(trifluoromethyl)phenoxy]-1H-pyrazol-1-yl}ethanol (7.6 g, 18 mmol) and 2,6-lutidine (6.2 mL, 53 mmol) in 40 mL of CH2Cl2 under an argon atmosphere was cooled in an ice bath. TBDMS triflate (7.1 g, 27 mmol) was added dropwise and the mixture was stirred for 30 min. The mixture was diluted with CH2Cl2 and washed with saturated aqueous NaHCO3, water, brine, then dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. The residue was chromatographed on a 120 g silica gel column using 0-70% CHCl3:hexanes over 40 min at 85 mL/min. The product-containing fractions were combined and the solvent was removed under reduced pressure to give 2-{3-(3-bromophenyl)-5-[4-(trifluoromethyl)phenoxy]-1H-pyrazol-1-yl}-1-(tert-butyldimethylsilyloxy)ethane as an oil. Calcd (M+1)+: 542.5. Found: 542.8
Reaction SMILES: C([O:3][C:4](=[O:18])[C:5]([C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:6]N(C)C)C.Cl.[OH:20][CH2:21][C:22]([NH2:24])=[NH:23]>>[OH:20][CH2:21][C:22]1[N:24]=[C:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:5]([C:4]([OH:18])=[O:3])=[CH:6][N:23]=1
Reactant: N=C(N)CO
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccccc1
Agent: Cl
Product: O=C(O)c1cnc(CO)nc1-c1ccccc1

Procedure:
In an analogous manner to that described in example 3b) starting from 2-benzoyl-3-dimethylamino-acrylic acid ethyl ester and 2-hydroxy-acetamidine hydrochloride followed by saponification as described in Example 3c), there was obtained 2-hydroxymethyl-4-phenyl-pyrimidine-5-carboxylic acid.
Reaction SMILES: [CH:1]([C:3]1[N:4]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][C:9]=2[CH3:16])[CH:5]=[CH:6][CH:7]=1)=O.[C:17]([CH:22]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:19][CH2:20][CH3:21])=[O:18]>C1(C)C=CC=CC=1>[C:12]([C:11]1[CH:14]=[CH:15][C:8]([N:4]2[CH:5]=[CH:6][CH:7]=[C:3]2[CH:1]=[CH:22][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:9]([CH3:16])[CH:10]=1)#[N:13]
Reactant: Cc1cc(C#N)ccc1-n1cccc1C=O
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C=Cc1cccn1-c1ccc(C#N)cc1C
Temperature: 100 °C
Yield: 98.9 %

Procedure:
The mixture of 4-(2-formyl-1H-pyrrol-1-yl)-3-methylbenzonitrile (15 g, 71.4 mmol) and (carbethoxymethylene)-triphenylphosphorane (27.5 g, 78.6 mmol) in toluene was heated to 100° C. overnight. Then it was cooled to room temperature, concentrated and purified by silica gel column chromatography (PE:EA=5:1) to afford ethyl 3-(1-(4-cyano-2-methylphenyl)-1H-pyrrol-2-yl)acrylate as a yellow oil (19.8 g, 98%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[O:11]1[CH2:16][CH:15]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH2:13][CH2:12]1.C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC>[O:11]1[CH2:12][CH:13]=[C:14]([C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=2[OH:10])[CH2:15][CH2:16]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: Cc1cc(C)c(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(C)c(O)c(C2=CCOCC2)c1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 36.6 %

Procedure:
2-Bromo-4,6-dimethylphenol (430 mg, 2.14 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (494 mg, 2.35 mmol), Pd(dbpf)Cl2 (69.7 mg, 0.11 mmol) and sodium carbonate (680 mg, 6.45 mmol) were dissolved in dimethoxyethane:water=3 mL:1 mL, followed by stirring in microwave at 120° C. for 30 minutes. The reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure, and purified by column chromatography (silica gel; hexane/ethyl acetate, 9/1) to obtain 2-(3,6-dihydro-2H-pyran-4-yl)-4,6-dimethylphenol (160 mg, 37%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH3:6].O.Br[C:9]1[N:13]([C:14]2[C:22]3[C:18](=[N:19][O:20][N:21]=3)[CH:17]=[CH:16][CH:15]=2)[C:12]([C:23]2[CH:24]=[N:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:27][CH:28]=2)=[N:11][N:10]=1>C(Cl)(Cl)Cl>[N:19]1[O:20][N:21]=[C:22]2[C:14]([N:13]3[C:12]([C:23]4[CH:24]=[N:25][C:26]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[CH:27][CH:28]=4)=[N:11][N:10]=[C:9]3[N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH3:6])=[CH:15][CH:16]=[CH:17][C:18]=12
Reactant: Brc1nnc(-c2ccc(-c3ccccc3)nc2)n1-c1cccc2nonc12
Reactant: CNCCOC
Solvent: O
Solvent: ClC(Cl)Cl
Product: COCCN(C)c1nnc(-c2ccc(-c3ccccc3)nc2)n1-c1cccc2nonc12
Temperature: 160 °C
Reaction time: 6 h
Yield: 19 %

Procedure:
In a sealed tube, N-(2-methoxyethyl)methylamine (3 ml) and water (3 ml) were added to 4-[3-bromo-5-(6-phenylpyridin-3-yl)-4H-1,2,4-triazol-4-yl]-2,1,3-benzooxadiazol (336 mg) prepared in the Production Example 5, and stirred at 160° C. for 6 hours. After the reaction solution was cooled to ambient temperature, chloroform was added to the solution, which was then washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the resulting solid was recrystallized from ethyl acetate, to afford the entitled compound as white crystal (66 mg, 19%). The physico-chemical values are as follows.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8].[N:9]1([C:14](N2C=CN=C2)=[O:15])[CH:13]=[CH:12][N:11]=[CH:10]1>C(Cl)Cl>[N:9]1([C:14]([O:8][CH2:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)=[O:15])[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: OCC1CCCCO1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C(OCC1CCCCO1)n1ccnc1

Procedure:
A solution of (tetrahydro-2H-pyran-2-yl)methanol (1 g, 8.60 mmol) and di(1H-imidazol-1-yl)methanone (2.8 g, 17.2 mmol) in 17 mL CH2Cl2 was heated overnight at 50° C. The reaction was quenched with water, extracted with CH2Cl2, dried over MgSO4, filtered, and concentrated.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:12]=[C:11](O)[C:10]2[C:5](=[CH:6][C:7]([O:14][CH3:15])=[CH:8][CH:9]=2)[N:4]=1.O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:11]1[C:10]2[C:5](=[CH:6][C:7]([O:14][CH3:15])=[CH:8][CH:9]=2)[N:4]=[C:3]([O:2][CH3:1])[N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(O)nc(OC)nc2c1
Product: COc1ccc2c(Cl)nc(OC)nc2c1
Yield: 36.1 %

Procedure:
A solution of 2,7-dimethoxyquinazolin-4-ol (155 mg, 0.752 mmol) in POCl3 (2 ml, 21.46 mmol) was refluxed for 4 h. The reaction mixture was concentrated. The residue was dissolved in DCM and the pH was adjusted to 7 with 4N NaOH. The organic phase was collected and dried over sodium sulfate, filtered, then concentrated under vacuum. The crude material was purified by silica gel chromatography using 50% DCM in hexanes. The product fractions were collected and the solvent removed under vacuum to give 4-chloro-2,7-dimethoxyquinazoline (61 mg, 36% yield). MS: MS m/z 225.1 (M++1).
Reaction SMILES: COC1C=CC(C[NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[NH:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[NH:26][CH:27]=[CH:28][C:21]=23)=[O:13])=CC=1.[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][C:33]=1[C:40]([F:43])([F:42])[F:41]>>[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[NH:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[NH:26][CH:27]=[CH:28][C:21]=23)=[O:13])=[CH:34][C:33]=1[C:40]([F:43])([F:42])[F:41]
Reactant: O=Cc1ccc(Cl)c(C(F)(F)F)c1
Reactant: COc1ccc(CNCCNC(=O)c2sccc2Nc2ccnc3[nH]ccc23)cc1
Product: O=C(NCCNCc1ccc(Cl)c(C(F)(F)F)c1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid [2-(4-methoxy-benzylamino)-ethyl]-amide using 4-chloro-3-(trifluoromethyl)benzaldehyde instead of 4-methoxy benzaldehyde. LCMS (ESI) 494 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.52 (1H, br. s.) 10.28 (1H, s) 7.95-8.09 (2H, m) 7.81 (1H, s) 7.77 (1H, d, J=5.42 Hz) 7.56-7.64 (2H, m) 7.47 (1H, d, J=5.42 Hz) 7.29 (1H, dd, J=3.27, 2.64 Hz) 6.80 (1H, d, J=5.47 Hz) 6.42 (1H, dd, J=3.51, 1.90 Hz) 3.75 (2H, s) 3.34 (2H, d, J=5.95 Hz) 2.62 (2H, t, J=6.56 Hz)