Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].O1CCOCC1.[O:8]([C:15]1[C:16]([NH:31][C:32]2[S:33][CH:34]=[C:35]([CH2:37][CH:38]3[CH2:43][CH2:42][N:41](C(OC(C)(C)C)=O)[CH2:40][CH2:39]3)[N:36]=2)=[N:17][CH:18]=[C:19]([S:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[CH:28]=[CH:29][S:30][C:23]=23)[CH:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClCCl.CO>[ClH:1].[ClH:1].[O:8]([C:15]1[C:16]([NH:31][C:32]2[S:33][CH:34]=[C:35]([CH2:37][CH:38]3[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]3)[N:36]=2)=[N:17][CH:18]=[C:19]([S:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[CH:28]=[CH:29][S:30][C:23]=23)[CH:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2csc(Nc3ncc(Sc4ccnc5ccsc45)cc3Oc3ccccc3)n2)CC1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: C1COCCO1
Product: c1ccc(Oc2cc(Sc3ccnc4ccsc34)cnc2Nc2nc(CC3CCNCC3)cs2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.5 %

Procedure:
Added 4N HCl in dioxane (3.0 mL, 12.0 mmol) to a solution of tert-butyl 4-((2-(3-phenoxy-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-ylamino)thiazol-4-yl)methyl)piperidine-1-carboxylate (0.790 g, 1.25 mmol) in dichloromethane (4 mL) and methanol (4 mL). The reaction was stirred at ambient temperature for 3 hours. Concentrated, triturated with hexanes, filtered to afford the title compound (0.745 g, 98.5% yield) as a light yellow powder: 1H NMR (d6-DMSO) δ 9.13 (m, 1H), 8.89 (m, 1H), 8.67 (d, 1H), 8.51 (d, 1H), 8.47 (s, 1H), 7.80 (d, 1H), 7.57 (s, 1H), 7.42 (t, 2H), 7.16-7.23 (m, 4H), 6.91 (s, 1H), 3.21 (m, 2H), 2.80 (m, 2H), 2.60 (d, 2H), 1.95 (m, 1H), 1.76 (m, 2H), 1.45 (m, 2H).
Reaction SMILES: Cl([O-])(=O)(=O)=O.[CH2:6]([C:8]1[C:12]2[C:13]([F:17])=[CH:14][CH:15]=[CH:16][C:11]=2[S:10][C:9]=1[C:18]1[C:30]2[C:22](=[CH:23][C:24]3[NH:25][C:26](=[O:31])[O:27][C:28]=3[CH:29]=2)[CH:21]=[C:20]([CH3:32])[O+]=1)[CH3:7].C(C1C2C(F)=CC=CC=2SC=1C=O)C.O.[NH2:48][NH2:49]>CC(O)C>[CH2:6]([C:8]1[C:12]2[C:13]([F:17])=[CH:14][CH:15]=[CH:16][C:11]=2[S:10][C:9]=1[C:18]1[C:30]2[CH:29]=[C:28]3[O:27][C:26](=[O:31])[NH:25][C:24]3=[CH:23][C:22]=2[CH2:21][C:20]([CH3:32])=[N:49][N:48]=1)[CH3:7]
Reactant: CCc1c(-c2[o+]c(C)cc3cc4[nH]c(=O)oc4cc23)sc2cccc(F)c12
Reactant: NN
Agent: CCc1c(C=O)sc2cccc(F)c12
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC(C)O
Product: CCc1c(C2=NN=C(C)Cc3cc4[nH]c(=O)oc4cc32)sc2cccc(F)c12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a suspension of 5-(3-ethyl-4-fluoro-1-benzothien-2-yl)-7-methyl-2-oxo-1H,2H-isochromeno[6,7-d][1,3]oxazol-6-ium perchlorate (51 mmol) (obtained according to Steps A and B described in Example 1 using 3-ethyl-4-fluoro-1-benzothiophene-2-carbaldehyde instead of 2-naphthaldehyde) in 2-propanol (468 mL) there is added hydrazine hydrate (6.68 mL; 133 mmol), with vigorous stirring, at ambient temperature. The reaction mixture is stirred for 20 hours at ambient temperature. The crystals obtained are then filtered off and then stirred in warm water (1900 mL) for 30 minutes. After filtration and drying, the solid is purified by chromatography over a silica gel column (eluant: dichloromethane/acetonitrile) to yield the title product.
Reaction SMILES: [CH2:1]([O:3][C:4]([P:6](=[O:21])([O:14]C1C=CC=CC=1)[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5])[CH3:2].C(=O)([O-])O.[Na+:26]>O>[CH2:1]([O:3][C:4]([P:6](=[O:14])([O-:21])[O:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:5])[CH3:2].[Na+:26]
Reactant: CCOC(=O)P(=O)(Oc1ccccc1)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)P(=O)([O-])Oc1ccccc1
Yield: 26.6 %

Procedure:
Diphenyl ethoxycarbonylphosphonate (3.06 g) and sodium hydrogencarbonate (0.84 g) were stirred in water (10 ml) at room temperature for about 24 hours. The solvent was evaporated and the residue extracted with ethanol. The ethanol was evaporated and the residue was washed with ether. The residue was recrystallized twice from isopropanol. Colourless crystals (0.67 g, 27%) were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([CH3:10])[CH:3]=1.[C:11]1(O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([CH3:10])[CH:3]=1
Reactant: Oc1ccccc1
Reactant: Cc1cc(Br)ccc1CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Br)ccc1COc1ccccc1
Temperature: 20 °C
Reaction time: 12 h
Yield: 46.2 %

Procedure:
To a solution of (4-bromo-2-methylphenyl)methanol (1 g, 5 mmol), phenol (525 mg, 5.6 mmol) and triphenylphosphine (2.2 g, 8.4 mmol) in tetrahydrofuran (30 mL) was added diisopropyl azodicarboxylate (1.7 g, 8.4 mmol) at 0° C. The mixture was stirred at 20° C. for 12 hours. Water (15 mL) was added to the mixture and then extracted with ethyl acetate (35 mL×3). The combined organic phase was dried by sodium sulfate, and then filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1) to give 4-bromo-2-methyl-1-(phenoxymethyl)benzene (640 mg, 46%).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[CH2:10][CH2:11][CH2:12][NH:13][C:14]([NH:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])=[N:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])=[O:4].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:47]1([CH3:57])[CH:52]=[CH:51][C:50]([S:53](Cl)(=[O:55])=[O:54])=[CH:49][CH:48]=1>C1COCC1>[CH3:1][O:2][C:3]([C@@H:5]1[N:8]([S:53]([C:50]2[CH:51]=[CH:52][C:47]([CH3:57])=[CH:48][CH:49]=2)(=[O:55])=[O:54])[C:7](=[O:9])[C@H:6]1[CH2:10][CH2:11][CH2:12][NH:13][C:14]([NH:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])=[N:15][C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])=[O:4]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)[C@@H]1NC(=O)[C@H]1CCCNC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)[C@H]1[C@H](CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)C(=O)N1S(=O)(=O)c1ccc(C)cc1
Temperature: -20 °C
Reaction time: 48 h
Yield: 48.2 %

Procedure:
To a -78° C. THF (5 mL) solution of compound 7 (436 mg, 0.67 mmol) was added IN THF solution of sodium bis(trimethylsilyl)amide (0.67 mL, 0.67 mmol), and the resultant solution was stirred for 15 min. p-Toluenesulfonyl chloride (134 mg, 0.70 mmol) was added, and the mixture was stirred at -78° C. for 4 h and at -20° C. for 21/2 days. The reaction mixture was partitioned between EtOAc and H2O. The organic layer was dried (Na2SO4) and concentrated. The residue was purified by silica gel chromatography (Et2O:hexane/3:2) to afford 210 mg (48%) of the title product.
Reaction SMILES: [N+:1]([C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]([CH3:11])[N:5]=1)([O-:3])=[O:2].Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][CH:14]=1>CN(C1C=CN=CC=1)C.ClC1C=CC=CC=1Cl>[CH3:24][O:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][C:19]=1[O:25][CH3:26])[N:16]=[CH:15][CH:14]=[C:13]2[O:10][C:9]1[C:4]([N+:1]([O-:3])=[O:2])=[N:5][C:6]([CH3:11])=[CH:7][CH:8]=1
Reactant: Cc1ccc(O)c([N+](=O)[O-])n1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccc(C)nc3[N+](=O)[O-])c2cc1OC
Temperature: 130 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
2-Nitro-6-methylpyridin-3-ol (4.1 g), 4-chloro-6,7-dimethoxyquinoline (2 g), and 4-(N,N-dimethylamino)-pyridine (3.3 g) were dissolved in 1,2-dichlorobenzene (90 ml) to prepare a solution which was then stirred at 130° C. overnight. The reaction solution was cooled to room temperature, and the solvent was then removed by distillation under the reduced pressure. A 1 N aqueous sodium hydroxide solution was added to the residue, the mixture was extracted with ethyl acetate, and the ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using hexane-acetone to give the title compound (732 mg, yield 24%).
Reaction SMILES: CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].I[C:13]1[C:18]([O:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][CH:21]=2)=[CH:17][CH:16]=[C:15]([CH3:34])[N:14]=1.[N:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1>O.C(O)C>[CH3:31][O:30][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][C:26]=1[O:32][CH3:33])[N:23]=[CH:22][CH:21]=[C:20]2[O:19][C:18]1[C:13]([C:38]2[CH:39]=[CH:40][N:35]=[CH:36][CH:37]=2)=[N:14][C:15]([CH3:34])=[CH:16][CH:17]=1
Reactant: OB(O)c1ccncc1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3ccncc3)c2cc1OC
Temperature: 70 °C
Reaction time: 3 h
Yield: 65.6 %

Procedure:
N,N-Dimethylformamide (1 ml), ethanol (0.5 ml), and a 2 M aqueous potassium carbonate solution (1 ml) were added to 4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound 116) (50 mg), tetrakistriphenylphosphine palladium (14 mg) and 4-pyridylboronic acid (44 mg) under an argon atmosphere, and the mixture was stirred at 70° C. for 3 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (29 mg, yield 66%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(C(Cl)=O)=O.[NH2:24][C:25]1[C:26]([CH3:33])=[C:27]([OH:32])[CH:28]=[CH:29][C:30]=1[F:31].O>C(Cl)Cl.CN(C=O)C.C1COCC1>[F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[CH:7][C:3]=1[C:4]([NH:24][C:25]1[C:30]([F:31])=[CH:29][CH:28]=[C:27]([OH:32])[C:26]=1[CH3:33])=[O:6]
Reactant: Cc1c(O)ccc(F)c1N
Reactant: O=C(O)c1cc(-c2cccc(F)c2)ccc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(O)ccc(F)c1NC(=O)c1cc(-c2cccc(F)c2)ccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
To a mixture of 2-fluoro-5-(3-fluorophenyl)benzoic acid (intermediate III(a)) (365 mg, 1.56 mmol, 1.1 eq) and (COCl)2 (541 mg, 4.26 mmol, 3.0 eq) in DCM (10 mL) was added DMF (3 drops). The reaction mixture was stirred at room temperature for 2 h, then concentrated in vacuo. The residue obtained was dissolved in THF (5 mL) and added dropwise to a solution of 3-amino-4-fluoro-2-methyl-phenol (200 mg, 1.42 mmol, 1.0 eq) in THF (15 mL) at 0° C. After the addition was completed, the reaction mixture was allowed to warm to room temperature and stirred for 2 h. The resulting mixture was poured into water and extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4), filtered, evaporated in vacuo and purified by column chromatography (EtOAc:petroleum ether, 0:1 to 1:3) to give the title compound as a yellow solid (300 mg, 59%).
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH:3]=[CH:2]1.[CH:7](=[O:12])[CH2:8][CH2:9][CH2:10][CH3:11].C(P(CCCC)CCCC)CCC>C1COCC1>[OH:12][CH:7]([C:2]1[C:1](=[O:6])[CH2:5][CH2:4][CH:3]=1)[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCC=O
Reactant: O=C1C=CCC1
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: CCCCC(O)C1=CCCC1=O
Yield: 92 %

Procedure:
A solution of cyclopentenone (1.23 g, 15 mmol), pentanal (1.94 g, 22.5 mmol), rac-1,1′-bi-2-naphthol (429 mg, 1.5 mmol) and tributyl phosphine (606 mg, 3 mmol) in dry THF (12 ml) was stirred at 20° C. under Argon for 3 hours. The solution was then passed through a short column of SiO2 (cyclohexane/Et2O 6:4) to obtain the pure title compound in 92% yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[C:14]3[CH:20]=[CH:19][C:18](I)=[CH:17][C:15]=3[O:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1C=CC2C=CC3C=CC(C)=NC=3C=2N=1.[F:38][C:39]1[CH:40]=[C:41]([SH:46])[CH:42]=[C:43]([F:45])[CH:44]=1.CC(C)([O-])C.[Na+]>CN(C=O)C.[Cu]I>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[C:14]3[CH:20]=[CH:19][C:18]([S:46][C:41]4[CH:42]=[C:43]([F:45])[CH:44]=[C:39]([F:38])[CH:40]=4)=[CH:17][C:15]=3[O:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1cc(F)cc(S)c1
Reactant: CC(C)(C)OC(=O)N1CCc2c(oc3cc(I)ccc23)C1
Agent: [Cu]I
Agent: CC(C)(C)[O-]
Agent: Cc1ccc2ccc3ccc(C)nc3c2n1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2c(oc3cc(Sc4cc(F)cc(F)c4)ccc23)C1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
Anhydrous DMF was sparged with argon gas for 1 h before being used. 560 μL of a 0.625 M stock solution of 7-iodo-3,4-dihydro-1H-benzo[4,5]furo[2,3-c]pyridine-2-carboxylic acid tert-butyl ester P08 (120 mg, 0.300 mmol) in DMF, 300 μL of a 0.10 M stock solution of neocuproine (6.2 mg, 0.030 mmol) in DMF and 580 μL of a 0.310 M stock solution of copper (I) iodide (34 mg, 0.180 mmol) in DMF were added sequentially into a reaction vial. 3,5-Difluorobenzenethiol (96.5 μL, 0.660 mmol, 2.2 eq) was added neat followed by 630 μL of a 1.0 M stock solution of sodium tert-butoxide (60.5 mg, 0.630 mmol) in DMF. The reaction mixture was shaken at 100° C. for 16 h and the solvent was evaporated. The residue was suspended into DCE:MeOH 95:5 (2.0 mL), passed through a silica gel column (1 g) and eluted with DCE:MeOH 95:5 (3×2.0 mL). The eluent was concentrated to yield crude 7-(3,5-difluoro-phenylsulfanyl)-3,4-dihydro-1H-benzo[4,5]furo[2,3-c]pyridine-2-carboxylic acid tert-butyl ester which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:4][CH:5]([CH2:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15](COCC[Si](C)(C)C)[CH:14]=[CH:13]2)[C:6]([OH:8])=[O:7])[CH2:2][CH3:3].C(N)CN.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C)C=O>[NH:15]1[C:16]2[C:12](=[CH:11][C:10]([CH2:9][CH:5]([O:4][CH2:1][CH2:2][CH3:3])[C:6]([OH:8])=[O:7])=[CH:18][CH:17]=2)[CH:13]=[CH:14]1
Reactant: CCCOC(Cc1ccc2c(ccn2COCC[Si](C)(C)C)c1)C(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CN(C)C=O
Solvent: NCCN
Product: CCCOC(Cc1ccc2[nH]ccc2c1)C(=O)O
Temperature: 80 °C
Reaction time: 6 h

Procedure:
0.96 g rac-2-propoxy-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-indol-5-yl]-propionic acid were dissolved in 40 ml N,N-dimethylformamide. 0.94 ml Ethylene diamine were added, followed by 7.63 ml of a tetra-butylammonium fluoride solution (1 molar in tetrahydrofuran); a small amount of molecular sieves was then added to the reaction mixture and it was heated to 80° C. After 6 hours, the mixture was cooled to r.t., filtered and the filtrate was poured into ice water and extracted 3 times with dichloromethane. The organic phases were washed with water, dried over MgSO4, filtered again and evaporated. The crude rac-3-(1H-indol-5-yl)-2-propoxy-propionic acid was used for the next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([CH:8]([C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=2)[CH2:9]/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:7])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Br[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]([P:47](=[O:58])([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])([F:46])[F:45])=[CH:40][CH:39]=1.C([O-])(=O)C.[NH4+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>[C:54]([O:53][P:47]([C:44]([F:46])([F:45])[C:41]1[CH:42]=[CH:43][C:38]([CH2:37][C:8]([C:18]2[CH:19]=[CH:20][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:26][CH:27]=2)([C:6](=[O:7])[C:5]2[CH:28]=[CH:29][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:9]/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:39][CH:40]=1)([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:58])([CH3:55])([CH3:56])[CH3:57]
Reactant: CC(C)(C)OP(=O)(OC(C)(C)C)C(F)(F)c1ccc(CBr)cc1
Reactant: COC(=O)c1ccc(C(C/C=C/c2ccccc2)C(=O)c2ccc(F)cc2)cc1
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(C/C=C/c2ccccc2)(Cc2ccc(C(F)(F)P(=O)(OC(C)(C)C)OC(C)(C)C)cc2)C(=O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 4-[(E)-1-(4-fluorobenzoyl)-4-phenyl-3-butenyl]benzoate (racemate) (0.430 g, 1.10 mmol), 18 crown 6 (0.236 g) and a catalytic amount of tetrabutylammonium iodide in THF (5 ml) degassed at −78° C. was added potassium tert-butoxide 1 M in THF (1.1 ml, 1.10 mmol). After a period of 0.5 h, a solution of di(tert-butyl) [4-(bromomethyl)phenyl](difluoro)methylphosphonate (0.46 g, 1.11 mmol) in THF (5 ml) was added to the reaction mixture, and the reaction mixture was then stirred at room temperature for 1 hour. Saturated ammonium acetate solution (20 ml) was added and the mixture was extracted with ethyl acetate (20 ml). The organic phase was washed with brine and dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by flash chromatography using hexane/ethyl acetate 15% containing 1% triethylamine giving 0.39 g of the title compound.
Reaction SMILES: [CH2:1]([C:5]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:28](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:27]=[N:26][N:25]=3)=[CH:14][CH:13]=2)[C:9](=[O:48])[C:8]([CH2:49][CH3:50])=[C:7]([CH3:51])[N:6]=1)[CH2:2][CH2:3][CH3:4]>C(O)(=O)C.O.[Cl-].[Na+].O>[CH2:1]([C:5]1[N:10]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[NH:28][N:27]=[N:26][N:25]=3)=[CH:16][CH:17]=2)[C:9](=[O:48])[C:8]([CH2:49][CH3:50])=[C:7]([CH3:51])[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)c(CC)c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCCc1nc(C)c(CC)c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
A solution of 2-n-butyl-3-[(2'-(N-triphenylmethyl-tetrazol-5-yl)-biphen-4-yl)-methyl]-5-ethyl-6-methylpyrimidin-4(3H)-one (from Example 5) in 4 mL acetic acid and 2 mL water was stirred at room temperature for 6 hours. The reaction mixture was diluted with brine and extracted three times with ether. The combined organic material was washed with brine, was dried over MgSO4, was stripped of solvent in vacuo, and then was MPLC'd in 1 acetic acid/39 hexane/60 ethyl acetate to give the title compound as a white foam. 1H NMR (300 MHz, CDCl3) δ7.87 (m, 1H), 7.58 (m, 1H), 7.49 (m, 1H), 7.40 (m, 1H), 7.02 (4 line m, 4H), 5.19 (br s, 2H), 2.57 (3 line m, 2H), 2.42 (4 line m, 2H), 2.24 (s, 3H), 1.63 (m, 2H), 1.34 (m, 2H), 0.96 (3 line m, 3H), 0.88 (3 line m, 3H); IR (CHCl3) 3420 (br), 3020, 1645, 1530, 1120 cm-1 ; FABMS: 429 (M+1).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[C:17]([CH:29]=O)=[N:18][CH:19]=[C:20]([N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]2[CH3:28])[N:21]=1.[CH2:31]([NH:38][CH2:39][CH2:40][OH:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(=O)([O-])O.[Na+]>C(#N)C.C(O)(=O)C>[CH2:31]([N:38]([CH2:29][C:17]1[C:16]([Cl:15])=[N:21][C:20]([N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]2[CH3:28])=[CH:19][N:18]=1)[CH2:39][CH2:40][OH:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: OCCNCc1ccccc1
Reactant: CC1CCCCN1c1cnc(C=O)c(Cl)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CC1CCCCN1c1cnc(CN(CCO)Cc2ccccc2)c(Cl)n1
Temperature: 25 °C
Reaction time: 21 h
Yield: 88.3 %

Procedure:
Sodium triacetoxyborohydride (1.56 g) was added to a solution of 3-chloro-5-(2-methylpiperidin-1-yl)pyrazine-2-carbaldehyde (1.18 g), N-benzylethanolamine (0.83 g) and acetic acid (0.84 mL) in acetonitrile (8 mL), and the mixture was stirred at room temperature for 21 hr. The reaction mixture was basified with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient: 10→50% ethyl acetate/hexane) to give the title compound (1.63 g, 89%) as a pale-yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:21][OH:22].[OH-].[Na+].CO>O>[F:1][C:2]1[CH:3]=[C:4]([C:8](=[N:21][OH:22])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cc1ccc(C(F)(F)F)cn1)c1cccc(F)c1
Reactant: NO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: ON=C(Cc1ccc(C(F)(F)F)cn1)c1cccc(F)c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
A reaction vessel was charged with 1-(3-fluorophenyl)-2-(5-trifluoromethyl-2-pyridinyl)ethanone (2 g, 7 mmol), hydroxylamine (2.2 g, 32 mmol), 10% NaOH aqueous solution (11 ml, 27 mmol) and methanol (24 ml). The reaction mixture was heated to 70° C. and stirred at 70° C. for 3 hrs. It was then cooled to room temperature and water (12 ml) was added. The mixture was stirred at 0° C. for 1 hr. The solids were collected on a filter, washed with water, and dried under vacuum at 50° C. overnight to provide 1.9 g (91%) of the title compound as a solid with purity 99% AUC by HPLC (Phenomenex Luna 3μ cyano, 100 mm×4.6 mm. Flow rate: 1 ml/min. UV detection: 220 nm. Eluent: 75% A, 25% B. A: 80/20/0.05 water/acetonitrile/TFA. B: 20/80/0.05 water/acetonitrile/TFA).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)(=O)=O)[N:3]=1.[C:19]1([CH2:25][CH2:26][CH2:27][OH:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:28][CH2:27][CH2:26][CH2:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:3]=1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: OCCCc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(OCCCc2ccccc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile, 3-phenyl-1-propanol and DBU in DME. ES-MS m/e (%): 359 (M+K+, 20), 343 (M+Na+, 21), 321 (M+H+, 100).
Reaction SMILES: CC(C)(C)C([NH:5][C:6]1[C:11]([C:12]2[O:16][N:15]=[C:14]([C:17](OCC)=[O:18])[CH:13]=2)=[CH:10][CH:9]=[CH:8][N:7]=1)=O.[BH4-].[Na+].[OH-].[Na+].[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30]>COC(C)(C)C.O1CCCC1.O.C(O)C>[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].[NH2:5][C:6]1[C:11]([C:12]2[O:16][N:15]=[C:14]([CH2:17][OH:18])[CH:13]=2)=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: CCOC(=O)c1cc(-c2cccnc2NC(=O)C(C)(C)C)on1
Agent: O=C(O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O
Solvent: CCO
Product: Nc1ncccc1-c1cc(CO)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
To a mixture of ethyl 5-{2-[(2,2-dimethylpropanoyl)amino]pyridin-3-yl}isoxazol-3-carboxylate (3.17 g, 10 mmol), ethanol (3 mL) and tetrahydrofuran (10 mL) was added sodium borohydride (0.38 g, 10 mmol) at room temperature, which was stirred overnight under a ice cooling to room temperature. The reaction mixture was divided equally into five, among which one was added to 5N aqueous sodium hydroxide (2 mL), which was stirred overnight at 55° C. To the reaction mixture was added water, which was extracted with a mixture of methyl-tert-butylether and tetrahydrofuran, and oxalic acid (0.18 g, 2 mmol) was added to the organic layer. The precipitated solid was filtered, so as to obtain the title compound (0.39 g) as a white solid.