Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH:7]([CH2:14][C:15]2[C:20]([CH2:21]O)=[CH:19][C:18]([Cl:23])=[CH:17][N:16]=2)[C:6]1=[O:24])([CH3:4])([CH3:3])[CH3:2].CN(C=O)C.S(Cl)([Cl:32])=O.[Na+].[Cl-]>ClCCl>[C:1]([N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH:7]([CH2:14][C:15]2[C:20]([CH2:21][Cl:32])=[CH:19][C:18]([Cl:23])=[CH:17][N:16]=2)[C:6]1=[O:24])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)N1C(=O)C(Cc2ncc(Cl)cc2CO)c2cccnc21
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)N1C(=O)C(Cc2ncc(Cl)cc2CCl)c2cccnc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
To a solution of 56 (5.8 g, 16.8 mmol) in dichloromethane (30 mL) was added DMF (60 μL) and thionyl chloride (2.2 g) at 5° C. The mixture was stirred for 30 min at this temperature followed by addition of 5% aqueous NaCl (30 mL). The organic layer was separated and washed with 5% aqueous NaCl (30 mL). The solvent was removed and the residue was dissolved in heptane (20 mL). The solution was stirred for 30 min and the product was precipitated. The suspension was cooled to 0° C. and filtered to give 57 (5.8 g, 93%) as a solid:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][N:8]([CH:24]3[CH2:29][CH2:28][CH:27]([CH2:30][C:31](O)=[O:32])[CH2:26][CH2:25]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:15][CH:16]=3)=[CH:9][N:8]([CH:24]3[CH2:25][CH2:26][CH:27]([CH2:30][CH2:31][OH:32])[CH2:28][CH2:29]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCC(CC(=O)O)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCC(CCO)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
A mixture of 2-{4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexyl}acetic acid (0.23 g, 0.51 mmol) and lithium aluminum hydride (0.30 g, 7.89 mmol) in tetrahydrofuran (25 mL) was stirred at ambient temperature overnight. Water (3 mL) was added followed by 15% aqueous sodium hydroxide (3.5 mL) and water (10.5 mL). Tetrahydrofuran (25 mL) was added and the mixture was stirred for 1 hour. The mixture was filtered through a pad of celite. The filtrate was concentrated and lyophilized to yield 2-{4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexyl}-1-ethanol (0.18 g, 0.42 mmol) as a white solid: 1H NMR (DMSO-d6, 400 MHz) δ 8.13(s, 1H), 7.51(s, 1H), 7.48 (d, 2H), 7.42(t, 2H), 7.16(t, 1H), 7.09(m, 4H), 6.10(br, 2H), 4.57(m, 1H), 4.36 (t, 1H), 3.47(q, 2H), 2.70-1.65(m, 10H); RP-HPLC (Hypersil C18, 5 μm, 100 A, 250×4.6 mm; 25%-100% over 10 min then 100%-25% over 2 min acetonitrile-0.05M ammonium acetate, 1 mL/min) Rt 10.28 min. MS: MH+ 429.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[CH:27]1([CH2:30][OH:31])[CH2:29][CH2:28]1>>[CH:27]1([CH2:30][O:31][C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=2[C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)[CH2:29][CH2:28]1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Reactant: OCC1CC1
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3OCC3CC3)n2)c1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (75 mg; 0.193 mmol), intermediate 42.1, and cyclopropylmethanol (58 mg; 0.773 mmol), example 55 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: CC1C=CC(S([N:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([N:20]4[CH2:25][CH2:24][CH2:23][C@H:22]([CH3:26])[CH2:21]4)[C:14]=3[C:13]([C:27]3[CH:28]=[C:29]([CH2:33][OH:34])[CH:30]=[CH:31][CH:32]=3)=[CH:12]2)(=O)=O)=CC=1.O.[OH-].[Li+].O>CC(O)C>[CH3:26][C@H:22]1[CH2:23][CH2:24][CH2:25][N:20]([C:19]2[C:14]3[C:13]([C:27]4[CH:28]=[C:29]([CH2:33][OH:34])[CH:30]=[CH:31][CH:32]=4)=[CH:12][NH:11][C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:21]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cccc(CO)c3)c3c(N4CCC[C@H](C)C4)ncnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: C[C@H]1CCCN(c2ncnc3[nH]cc(-c4cccc(CO)c4)c23)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (3-{7-[(4-methylphenyl)sulfonyl]-4-[(3S)-3-methylpiperidin-1-yl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)methanol (C16) from the previous step (<0.50 mmol) in 2-propanol (20 mL) was added lithium hydroxide monohydrate (0.42 g, 10 mmol) and water (3 mL) and the reaction mixture was stirred at room temperature for 18 hours. After concentration in vacuo, the residue was purified by preparative HPLC (Column: Waters XBridge; Mobile phase A: 0.1% ammonia in water; Mobile phase B: acetonitrile; Gradient: 44% to 60% B) to provide the product as a white solid. Yield: 130 mg, 0.403 mmol, 80% over two steps. LCMS m/z 323.4 [M+H+]. 1H NMR (400 MHz, CD3OD) δ 8.24 (s, 1H), 7.46 (br s, 1H), 7.35-7.43 (m, 2H), 7.30 (br d, J=6 Hz, 1H), 7.23 (s, 1H), 4.67 (s, 2H), 3.89 (br d, J=13 Hz, 1H), 3.79 (br d, J=12 Hz, 1H), 2.58-2.69 (m, 1H), 2.27 (dd, J=12.0, 11.0 Hz, 1H), 1.62-1.71 (m, 1H), 1.30-1.52 (m, 3H), 0.87-1.01 (m, 1H), 0.60 (d, J=6.5 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:14]=[C:13]([CH2:15][CH2:16][CH:17]=O)[O:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].FC(F)(F)[C:21]1[CH:33]=[CH:32][CH:31]=[CH:30][C:22]=1[CH2:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:14]=[C:13]([CH2:15][CH2:16][CH2:17][N:27]3[CH2:28][CH2:29][N:24]([CH2:23][C:22]4[CH:21]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:25][CH2:26]3)[O:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=CCCc1cc(-c2cccc([N+](=O)[O-])c2)no1
Reactant: FC(F)(F)c1ccccc1CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(-c2cc(CCCN3CCN(Cc4ccccc4)CC3)on2)c1
Yield: 45.5 %

Procedure:
About 2 min after dissolving 3-[3-(3-nitrophenyl)isoxazol-5-yl]propanal (10 mg, 0.04 mmol) and 1-benylpiperazine (7.1, 0.04 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (26 mg, 0.12 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 2 hr and followed the same processes as in Example 1 to obtain 7.4 mg (44.8%) of the target compound.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[C:10]2[C:5](=[CH:6][C:7]([C:24]3[C:29]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:8][CH:9]=2)[N:4]=1.[CH2:34]([O:41][P:42]([O-:52])([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(#N)C>[C:20]([C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:11]2[C:10]3[C:5](=[CH:6][C:7]([C:24]4[C:29]([C:30]([F:32])([F:31])[F:33])=[CH:28][CH:27]=[CH:26][N:25]=4)=[CH:8][CH:9]=3)[N:4]=[C:3]([CH2:2][O:43][P:42](=[O:52])([O:44][CH2:45][C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)[O:41][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:12]=2)=[CH:15][CH:16]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: O=P([O-])(OCc1ccccc1)OCc1ccccc1
Reactant: CC(C)(C)c1ccc(Nc2nc(CCl)nc3cc(-c4ncccc4C(F)(F)F)ccc23)cc1
Solvent: CC#N
Product: CC(C)(C)c1ccc(Nc2nc(COP(=O)(OCc3ccccc3)OCc3ccccc3)nc3cc(-c4ncccc4C(F)(F)F)ccc23)cc1

Procedure:
Heat a solution of [2-chloromethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-t-butyl-phenyl)-amine (417 mg, 0.89 mmol), Ag2O (308 mg, 1.33 mmol), and dibenzylphosphate (370 mg, 1.33 mmol) in acetonitrile at 70° C. for 18 hours. Dilute with additional acetonitrile and filter the hot solution through celite. Concentrate under reduced pressure to give a foam. Crystallize the crude product by dissolving in ether and slowly adding hexanes. Cool the resulting mixture on ice and collect the resulting solid via filtration to afford pure product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH:10]([CH2:15][O:16][CH2:17][O:18][CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:22]([C:26]1[N:27]=[N:28][C:29](Cl)=[CH:30][C:31]=1[C:32]1[CH:37]=[CH:36][C:35]([O:38][CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)=[CH:34][CH:33]=1)[CH2:23][CH2:24][CH3:25]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:29]2[N:28]=[N:27][C:26]([CH2:22][CH2:23][CH2:24][CH3:25])=[C:31]([C:32]3[CH:33]=[CH:34][C:35]([O:38][CH:39]4[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]4)=[CH:36][CH:37]=3)[CH:30]=2)[CH:10]([CH2:15][O:16][CH2:17][O:18][CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCc1nnc(Cl)cc1-c1ccc(OC2CCCCC2)cc1
Reactant: COCOCC1CN(C(=O)OC(C)(C)C)CCC1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCc1nnc(OC2CCN(C(=O)OC(C)(C)C)CC2COCOC)cc1-c1ccc(OC2CCCCC2)cc1
Reaction time: 0.17 h

Procedure:
To a stirred solution of 4-hydroxy-3-methoxymethoxymethyl-piperidine-1-carboxylic acid tert-butyl ester (0.4 mmol, 0.111 g) in 3 mL of THF was added 60% NaH in mineral oil (2.0 mmol, 0.05 g) at room temperature. The mixture was stirred for 10 mins, then a solution of 3-butyl-6-chloro-4-(4-cyclohexyloxy-phenyl)-pyridazine (Example 14, 0.2 mmol, 0.07 g) in THF was added. The mixture was refluxed for 1 h, then, stirred at room temperature overnight. The mixture was quenched with water, extracted with ethyl acetate, the organic layer was washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure, the resulting residue was chromatographed using 10% ethyl acetate in hexane to provide 4-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-3-methoxymethoxymethyl-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([N:6]([CH3:10])[CH2:7][C:8]#[CH:9])=[O:5].[Cl:15][C:16]1[N:21]=[C:20](Cl)[C:19]([Cl:23])=[CH:18][N:17]=1>>[Cl:15][C:16]1[N:21]=[C:20]([NH:1][C:2]2[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=2[C:4]([N:6]([CH3:10])[CH2:7][C:8]#[CH:9])=[O:5])[C:19]([Cl:23])=[CH:18][N:17]=1
Reactant: C#CCN(C)C(=O)c1ccccc1N
Reactant: Clc1ncc(Cl)c(Cl)n1
Product: C#CCN(C)C(=O)c1ccccc1Nc1nc(Cl)ncc1Cl

Procedure:
2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-N-prop-2-ynyl-benzamide was prepared from 2-amino-N-methyl-N-prop-2-ynyl-benzamide and 2,4,5-trichloro-pyrimidine in an analogous manner to Example 1387b. Product isolated as a yellow foam (958 mg, 12%). LCMS (m/e) 335 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 9.45 (s, 1H), 8.35 (d, 1H, J=8.3 Hz), 8.22 (s, 1H), 7.63-7.30 (m, 2H), 7.25-7.17 (m, 1H), 4.53-4.01 (m, 2H), 3.19 (s, 3H), 2.46-2.24 (m, 1H).
Reaction SMILES: [CH2:1]([N:8]1[C@H:12]([C:13]([O:15][CH3:16])=[O:14])[C@H:11]([C:17]([O:19]C)=[O:18])[N:10]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:9]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(Cl)(Cl)Cl.S(=O)(=O)(O)O>P([O-])([O-])([O-])=O.CO>[CH2:1]([N:8]1[C@@H:12]([C:13]([O:15][CH3:16])=[O:14])[C@@H:11]([C:17]([OH:19])=[O:18])[N:10]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:9]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H]1[C@H](C(=O)OC)N(Cc2ccccc2)C(=O)N1Cc1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H]1[C@@H](C(=O)O)N(Cc2ccccc2)C(=O)N1Cc1ccccc1
Temperature: 30 °C
Reaction time: 42 h
Yield: 91.4 %

Procedure:
To a suspension of dimethyl cis-1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylate (10.0 g) in a mixture of 0.1M phosphate buffer (pH 8.0, 900 ml) and methanol (100 ml) was added Pig Liver Esterase (manufactured by Sigma Lab., 32000 units, 200 mg). The mixture was stirred at 30° C. for 42 hours while the pH was adjusted to around 8.0 with 1N aqueous sodium hydroxide solution. Chloroform (500 ml) was added to the mixture. Then, the mixture was adjusted to pH 2 with diluted sulfuric acid. The aqueous and chloroform layers were separated. The chloroform layer was washed with water, dried over anhydrous magnesium sulfate and concentrated to give (4S,5R)-1,3-dibenzyl-5-methoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid (8.80 g). M.P., 145°-147° C. [α]36520 =-25.3° (c=1, DMF).
Reaction SMILES: C([NH:4][C:5]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][CH3:29])=[CH:22][CH:21]=1)([CH2:11][O:12]C(=O)C)[CH2:6][O:7]C(=O)C)(=O)C.[OH-].[Na+]>CO>[NH2:4][C:5]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][CH3:29])=[CH:22][CH:21]=1)([CH2:11][OH:12])[CH2:6][OH:7]
Reactant: CCCCc1ccc(CCCCC(COC(C)=O)(COC(C)=O)NC(C)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCc1ccc(CCCCC(N)(CO)CO)cc1
Yield: 54.6 %

Procedure:
2-Acetamido-1,3-diacetoxy-2-[4-(4-butylphenyl)butyl]propane (66.2 mg) was dissolved in 2 ml of methanol and 2 ml of a 1 N aqueous sodium hydroxide solution was added thereto. The mixture was refluxed under heating for 4 hours. The solvent was distilled away and the residue was purified by silica gel thin layer chromatography (methanol:chloroform=1:4) to give 24.9 mg of 2-amino-2-[4-(4-butylphenyl)butyl]-1,3-propanediol as white crystals.
Reaction SMILES: [OH:1][CH:2]([C:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:6][CH3:7])[C:3]#[N:4].C(=O)([O-])[O-].[K+].[K+].CS([C:30]1[N:35]=[C:34]([O:36][CH3:37])[CH:33]=[C:32]([O:38][CH3:39])[N:31]=1)(=O)=O>CN(C=O)C>[CH3:39][O:38][C:32]1[CH:33]=[C:34]([O:36][CH3:37])[N:35]=[C:30]([O:1][CH:2]([C:5]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:6][CH3:7])[C:3]#[N:4])[N:31]=1
Reactant: CCC(c1ccccc1)(c1ccccc1)C(O)C#N
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(c1ccccc1)(c1ccccc1)C(C#N)Oc1nc(OC)cc(OC)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 81 %

Procedure:
7.0 g (27.9 mmol) of 2-hydroxy-3,3-diphenylvaleronitrile were dissolved in 100 ml of DMF (abs.) and, under nitrogen, 7.57 g (55.7 mmol) of potassium carbonate and 6.1 g (27.9 mmol) of 2-methanesulfonyl-4,6-dimethoxypyrimidine were added, and the mixture was stirred at room temperature for 72 hours. The mixture was concentrated under reduced pressure, and the residue was taken up in water and extracted three times with ethyl acetate. The combined organic phases were dried over MgSO4, and the solvent was evaporated off. The crude product was chromatographed on silica gel with n-heptane/ethyl acetate (20:1). 8.8 g (81%) of product were obtained.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][O:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][S:14]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:16])=[O:15])[C:8]=1[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1.Cl[C:33]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][N:34]=1>C1COCC1>[C:28]1([CH3:31])[CH:29]=[CH:30][C:25]([C:8]2[C:9]([NH:13][S:14]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:15])=[O:16])=[N:10][CH:11]=[N:12][C:7]=2[O:6][CH2:5][CH2:4][O:3][C:33]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][N:34]=2)=[CH:26][CH:27]=1
Reactant: Cc1ccc(-c2c(NS(=O)(=O)CCc3ccccc3)ncnc2OCCO)cc1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(NS(=O)(=O)CCc3ccccc3)ncnc2OCCOc2ccc(C(F)(F)F)cn2)cc1
Reaction time: 17 h
Yield: 88.8 %

Procedure:
To sodium hydride (27 mg, 60% in mineral oil) was added THF (15 ml) followed by 2-phenyl-ethanesulfonic acid [6-(2-hydroxy-ethoxy)-5-p-tolyl-pyrimidin-4-yl]-amide (80 mg, Referential Example 1). The mixture was stirred for 1 h at rt before 2-chloro-5-trifluoromethyl-pyridine (86 mg) was added. Stirring was continued for 17 h at 80° C. The solvent was evaporated, the residue was dissolved in water (20 ml), acidified with citric acid. The suspension was treated with hexane (15 ml). The solid material was collected, washed with hexane:EA 1:1 (20 ml) and dried to yield 2-phenyl-ethanesulfonic acid {5-p-tolyl-6-[2-(5-trifluoromethyl-pyridin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-amide (96 mg) as beige powder. LC-MS: tR=5.86 min, [M+1]+=559.20, [M−1]−=557.37.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[N:14]=[C:13]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C:12]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[S:33]1[CH:37]=[CH:36][N:35]=[C:34]1[CH:38]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C.C(OCC)(=O)C.O>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[N:14]=[C:13]([N:21]3[CH2:22][CH2:23][N:24]([CH2:38][C:34]4[S:33][CH:37]=[CH:36][N:35]=4)[CH2:25][CH2:26]3)[C:12]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: O=Cc1nccs1
Reactant: CS(=O)(=O)c1ccc(-c2nc(C(F)(F)F)nc(N3CCNCC3)c2-c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(-c2nc(C(F)(F)F)nc(N3CCN(Cc4nccs4)CC3)c2-c2ccccc2)cc1
Temperature: 37 °C
Reaction time: 0.08 h
Yield: 45.6 %

Procedure:
To a solution of 6-[4-(methylsulfonyl)phenyl]-5-phenyl-4-piperazin-1-yl-2-(trifluoromethyl)pyrimidine (0.2 g, 0.43 mmol, prepared according to the procedure described in preparation 2) in dichloroethane (25 ml) was added thiazole-2-carboxaldehyde (0.144 g, 1.3 mmol) under stirring at 37° C. After five minutes, sodium triacetoxy borohydride (0.364 g, 1.72 mmol) was added to reaction mixture and then after 10 minutes, acetic acid (0.1 ml) was added to it. The reaction mixture was stirred for 36 hours under the same conditions. Subsequently the reaction mixture was treated with ethyl acetate:water (1:1, 100 ml) and extracted with ethyl acetate (3×50 ml). The organic layer was washed with brine (100 ml) and dried over anhydrous sodium sulphate. The solid obtained upon evaporation was purified by column chromatography using methanol:dichloromethane (0.5:99.5) as an eluent to afford the title compound (0.11 g, yield 45.6%). 1H-NMR (CDCl3) δ: 0.88-0.89 (m, 2H), 1.25-1.28 (t, 2H), 1.33-1.38 (t, 2H), 2.85 (s, 6H), 2.97 (s, 3H), 7.04-7.74 (m, 9H); MS m/z: 544.59 (M++1).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[C:14]([C:16]2[CH2:20][C:19]([C:25]3[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=3)([C:21]([F:24])([F:23])[F:22])[O:18][N:17]=2)[CH:13]=[CH:12][C:3]=1[C:4]([NH:6][CH2:7][C:8]([F:11])([F:10])[F:9])=[O:5].C(N(CC)CC)C.[C:40](OC(=O)C)(=[O:42])[CH3:41]>C(Cl)(Cl)Cl>[C:40]([NH:1][C:2]1[CH:15]=[C:14]([C:16]2[CH2:20][C:19]([C:25]3[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=3)([C:21]([F:24])([F:23])[F:22])[O:18][N:17]=2)[CH:13]=[CH:12][C:3]=1[C:4]([NH:6][CH2:7][C:8]([F:10])([F:9])[F:11])=[O:5])(=[O:42])[CH3:41]
Reactant: Nc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCC(F)(F)F
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCC(F)(F)F

Procedure:
In a solution of 0.05 g of 2-amino-4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-N-(2,2,2-trifluoroethyl) benzoic acid amide (Compound of the present invention No. 5-329) synthesized in Synthetic Example 12 and 0.15 ml of triethylamine in 2 ml of chloroform, 0.10 ml of acetic anhydride was added under cooling with ice with stirring, and stirred at room temperature for 20 hours. After the completion of the reaction, the reaction mixture was subjected to purification with medium-pressure preparative liquid chromatography (Yamazen Corporation, medium pressure preparative system; YFLC-Wprep) that was eluted with ethyl acetate-hexane (1:8 to 1:1 gradient), and 0.045 g of the aimed product was obtained as pale yellow resinous substance.
Reaction SMILES: [BH4-].[Li+].[CH2:3]([O:10][C:11]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH:14]1[C:22](OC)=[O:23])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O1CCCC1>[CH2:3]([O:10][C:11]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH:14]1[CH2:22][OH:23])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)C1Cc2ccccc2N1C(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1c2ccccc2CC1CO
Temperature: 25 °C
Reaction time: 5 h
Yield: 83.2 %

Procedure:
4.6 g (212 mmol) of lithium borohydride were added in three portions to a solution of 33.0 g (106 mmol) of methyl 1-benzyloxycarbonylindoline-2-carboxylate in 450 ml of tetrahydrofuran, and the resulting mixture was stirred for 5 hours at room temperature. At the end of this time, ice was added and the mixture was stirred for a further 1 hour before extracting with ethyl acetate. The organic extract was washed with water, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure. The resulting residue was purified by chromatography on a silica gel column using a 2:5 by volume mixture of ethyl acetate and hexane as the eluant to afford 25.0 g (yield: 83%) of the title compound as a colorless oil.
Reaction SMILES: O=C1C2C(=CC=CC=2)N=C(C(OCC)=O)N1.[O:17]=[C:18]1[NH:23][C:22]([C:24]([O:26]CC)=O)=[N:21][C:20]2[S:29][CH:30]=[C:31]([C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)[C:19]1=2.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)N2C=NC(CCCOC3C=C(CN)C=CN=3)=N2)C=CC=CC=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:81]2[CH:85]=[N:84][C:83]([O:86][CH2:87][CH2:88][O:89][C:90]3[CH:91]=[C:92]([CH2:96][NH2:97])[CH:93]=[CH:94][CH:95]=3)=[N:82]2)C=CC=CC=1>>[O:17]=[C:18]1[NH:23][C:22]([C:24]([NH:97][CH2:96][C:92]2[CH:93]=[CH:94][CH:95]=[C:90]([O:89][CH2:88][CH2:87][O:86][C:83]3[N:84]=[CH:85][NH:81][N:82]=3)[CH:91]=2)=[O:26])=[N:21][C:20]2[S:29][CH:30]=[C:31]([C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)[C:19]1=2
Reactant: NCc1cccc(OCCOc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Reactant: CCOC(=O)c1nc2scc(-c3cccnc3)c2c(=O)[nH]1
Agent: CCOC(=O)c1nc2ccccc2c(=O)[nH]1
Agent: NCc1ccnc(OCCCc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Product: O=C(NCc1cccc(OCCOc2nc[nH]n2)c1)c1nc2scc(-c3cccnc3)c2c(=O)[nH]1

Procedure:
By a method similar to that in Example 22, and using, instead of ethyl 4-oxo-3,4-dihydro-2-quinazolinecarboxylate, ethyl 4-oxo-5-pyridin-3-yl-3,4-dihydrothieno[2,3-d]pyrimidine-2-carboxylate obtained in Reference Example 67 and using, instead of 1-[2-({3-[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]propyl}oxy)pyridin-4-yl]methaneamine, 1-{3-[(2-{[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]oxy}ethyl)oxy]phenyl}methanamine obtained in Reference Example 32, the title compound was obtained as a white powder (41.1 mg, 17%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.C([O-])([O-])=O.[K+].[K+].[CH2:16](OC(OCC)CBr)[CH3:17]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[CH:17]=[CH:16][S:9][C:5]=2[CH:4]=1
Reactant: CCOC(CBr)OCC
Reactant: COc1cccc(S)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc2ccsc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 155.3 %

Procedure:
A mixture of 3-methoxybenzenethiol (10 ml, 11.30 g, 80 mmole), K2CO3 (11.15 g, 80 mmole) and bromoacetaldehyde diethyl acetal (12 ml, 15.72 g, 80 mmole) in acetone (100 ml) was stirred at ambient temperature for 16 hours, then filtered. The filtrate was subsequently concentrated, in vacuo. The residue obtained was partitioned between H2O (150 ml) and Et2O (150 ml). The layers were separated and the aqueous phase was extracted with Et2O (150 ml). The combined organic extracts were washed with 0.5 M KOH (aq), H2O and brine, then dried over Na2SO4 and concentrated, in vacuo, to give 20.4 g of an amber oil which was used directly in the subsequent cyclization without any further purification.