Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]([CH2:17][OH:18])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[CH3:20][N:21]([CH3:54])[C:22]([C:24]1[CH:25]=[C:26]([CH:32]=[CH:33][C:34]=1[NH:35][C:36]([C:38]1[C:39]([C:44]2[CH:49]=[CH:48][C:47]([C:50]([F:53])([F:52])[F:51])=[CH:46][CH:45]=2)=[CH:40][CH:41]=[CH:42][CH:43]=1)=[O:37])[O:27][CH2:28][C:29](O)=[O:30])=[O:23].CCN=C=NCCCN(C)C>CN(C)C1C=CN=CC=1.CC(C)=O>[CH2:9]([O:8][C:6](=[O:7])[C:5]([CH2:17][O:18][C:29](=[O:30])[CH2:28][O:27][C:26]1[CH:32]=[CH:33][C:34]([NH:35][C:36]([C:38]2[C:39]([C:44]3[CH:49]=[CH:48][C:47]([C:50]([F:53])([F:51])[F:52])=[CH:46][CH:45]=3)=[CH:40][CH:41]=[CH:42][CH:43]=2)=[O:37])=[C:24]([C:22](=[O:23])[N:21]([CH3:20])[CH3:54])[CH:25]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:19])[CH3:10]
Reactant: CCOC(=O)C(CO)(C(=O)OCC)c1ccccc1
Reactant: CN(C)C(=O)c1cc(OCC(=O)O)ccc1NC(=O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CC(C)=O
Product: CCOC(=O)C(COC(=O)COc1ccc(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)c(C(=O)N(C)C)c1)(C(=O)OCC)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
4-Dimethylaminopyridine (53 mg), 2-hydroxymethyl-2-phenylmalonic acid diethyl ester (116 mg) and {3-dimethylcarbamoyl-4-[(4′-trifluoromethylbiphenyl-2-carbonyl)amino]phenoxy}acetic acid (176 mg) were dissolved in acetone (5 mL), and to the solution was added WSC (104 mg). The mixture was stirred at room temperature for 3 hours and then concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:1) to give 2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethylbiphenyl-2-carbonyl)amino]phenoxy}acetoxymethyl)-2-phenylmalonic acid diethyl ester (133 mg) as a colorless solid (m.p. 132-138° C.).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14](I)[CH:13]=2)=[O:10])=[CH:4][C:3]=1[O:19][CH3:20].O[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](NC2C=CC=CC=2I)=O)=[CH:24][C:23]=1OC>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:29]#[C:28][C:25]2[CH:26]=[CH:27][CH:22]=[CH:23][CH:24]=2)=[O:10])=[CH:4][C:3]=1[O:19][CH3:20]
Reactant: COc1cc(CC(=O)Nc2ccccc2I)ccc1O
Reactant: COc1cc(CC(=O)Nc2cccc(I)c2)ccc1O
Product: COc1cc(CC(=O)Nc2ccccc2C#Cc2ccccc2)ccc1O

Procedure:
Instead of Intermediate 1 in Example 36, 4-hydroxy-N-(2-iodophenyl)-3-methoxyphenylacetamide is treated in a similar manner to Example 36 to give the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([N+:16]([O-:18])=[O:17])=[N:11][CH:12]=[C:13](Br)[N:14]=1.[NH2:19][CH2:20][CH2:21][NH:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][N:24]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([NH:19][CH2:20][CH2:21][NH:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][N:24]=2)[CH:12]=[N:11][C:10]=1[N+:16]([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ncc(Br)nc1-c1ccc(Cl)cc1Cl
Reactant: NCCNc1ccc([N+](=O)[O-])cn1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(NCCNc2cnc([N+](=O)[O-])c(-c3ccc(Cl)cc3Cl)n2)nc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a solution of 3-(2,4-dichlorophenyl)-5-bromo-2-nitropyrazine (20 mg, 0.057 mmol) in DMF (1 ml), (2-aminoethyl)(5-nitro(2-pyridyl))amine (11.3 mg, 0.06 mmol) and diisopropylethyl amine (40 μl, 0.228 mmol) were added. The reaction mixture was stirred for 12 hours at 80° C. The crude mixture was concentrated in vacuo and subjected to column chromatography (5% methanol in methylene chloride) to afford the title compound as bright yellow solid.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[C@@H:6]1[CH2:25][N:9]2[C:10](=[O:24])[N:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=3)[CH2:12][C@@H:8]2[CH2:7]1.O>CN(C=O)C>[N:1]([C@H:6]1[CH2:25][N:9]2[C:10](=[O:24])[N:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=3)[CH2:12][C@@H:8]2[CH2:7]1)=[N+:2]=[N-:3]
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)C[C@@H]2C[C@H](Br)CN12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=N[C@@H]1C[C@H]2CN(c3ccc(OC(F)(F)F)cc3)C(=O)N2C1
Temperature: 70 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
Sodium azide (80 mg, 1.2 mmol) was added to a solution of (6S,7aS)-6-Bromo-2-(4-trifluoromethoxy-phenyl)-hexahydro-pyrrolo[1,2-c]imidazol-3-one (350 mg, 1.0 mmol) in anhydrous DMF (10 mL), the mixture was heated to 70° C. and stirred for 2 hours. The mixture was cooled and poured into water (30 mL), extracted with ethyl acetate (3×20 mL), the organic layers was combined and washed with water (2×20 mL), brine (20 mL), dried over anhydrous sodium sulphate, filtered and concentrated. The residue was purified by silica gel column chromatography (eluting with petroleum ether/ethyl acetate=10:1) to give 260 mg (83%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 7.59 (d, 2H, J=9.3 Hz), 7.19 (d, 2H, J=8.4 Hz), 4.33 (t, 1H, J=6.3 Hz), 4.13-3.98 (m, 3H), 3.75-3.72 (m, 1H), 3.15 (dd, 1H, J1=12.6 Hz, J2=2.1 Hz), 2.19 (dd, 1H, J1=13.2 Hz, J2=3.9 Hz), 1.73-1.63 (m, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.CS(O[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][CH3:25])(=O)=O>>[CH3:25][O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: COc1ccccc1COS(C)(=O)=O
Product: COc1ccccc1Cn1cc(C=O)c2ccccc21

Procedure:
The same procedures used in Example 1 were repeated except for using 870 mg of indole-3-carbaldehyde and 2-methoxybenzyl methanesulfonate in place of the benzyl bromide used in Example 1 to give 926 mg of 1-(2-methoxybenzyl)indole-3-carbaldehyde as pale yellow crystals. The yield thereof was found to be 58%.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([O:13][C:14]1[CH:15]=[CH:16][C:17]2[C:18]3[C:19](=[N:25][N:26]([CH2:28][CH3:29])[CH:27]=3)[C:20](=O)[NH:21][C:22]=2[CH:23]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[Na+]>>[CH2:6]([O:13][C:14]1[CH:15]=[CH:16][C:17]2[C:18]3[C:19](=[N:25][N:26]([CH2:28][CH3:29])[CH:27]=3)[C:20]([Cl:3])=[N:21][C:22]=2[CH:23]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCn1cc2c(n1)c(=O)[nH]c1cc(OCc3ccccc3)ccc12
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: CCn1cc2c(n1)c(Cl)nc1cc(OCc3ccccc3)ccc12
Temperature: 100 °C

Procedure:
Phosphorous oxychloride (15 mL) was added to 7-benzyloxy-2-ethyl-2,5-dihydro-pyrazolo[3,4-c]quinolin-4-one (1.20 g, 3.76 mmol) and heated at 100° C. for 1 hour. The reaction mixture was cooled to ambient temperature and the poured onto crushed ice while stirring. 6 N Sodium hydroxide solution was added to the suspension at 4° C. and the solid was harvested by filtration and dried to afford 1.23 g of 7-benzyloxy-4-chloro-2-ethyl-2H-pyrazolo[3,4-c]quinoline as a yellow solid, mp 155-157° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH:6]=[N:5]2.[H-].[Na+].[CH3:23]I>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH3:23])[CH:6]=[N:5]2
Reactant: CI
Reactant: Fc1ccc(CNc2cnc3cc(Br)ccc3n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(Cc1ccc(F)cc1)c1cnc2cc(Br)ccc2n1
Temperature: 7.5 °C
Reaction time: 0.25 h
Yield: 115.5 %

Procedure:
(6-Bromo-quinoxalin-2-yl)-(4-fluoro-benzyl)-amine (0.35 g, 1.0 mmol) was added to a suspension of sodium hydride (0.037 g, 1.5 mmol) in DMF (5 mL) at room temperature and it was stirred for 15 minutes. The reaction mixture was cooled down to 5-10° C. and methyl iodide (0.17 g, 1.2 mmol) was added at 5-10° C. and this was maintained for 30 minutes. After completion of the reaction, the reaction mixture was gradually poured into ice cold water (30 mL) and stirred for a further 30 minutes. The precipitated product was filtered and washed by water and dried under vacuum to afford the title compound (0.4 g) which was used directly for the next step.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][O:20][C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[NH2:23]>>[CH3:19][O:20][C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[NH:23][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][CH:18]=[C:10]([S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:8])=[O:9])[CH:11]=1
Reactant: COc1ccccc1N
Reactant: O=C(O)c1cccc(S(=O)(=O)c2ccccc2)c1
Product: COc1ccccc1NC(=O)c1cccc(S(=O)(=O)c2ccccc2)c1

Procedure:
The entitled compound was produced according to the method of Example 92 but using 3-(phenylsulfonyl)benzoic acid and 2-methoxyaniline as the starting materials.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Br:13][C:14]1[C:19]([F:20])=[CH:18][C:17]([S:21](Cl)(=[O:23])=[O:22])=[C:16]([F:25])[CH:15]=1>>[Br:13][C:14]1[C:19]([F:20])=[CH:18][C:17]([S:21]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:22])=[O:23])=[C:16]([F:25])[CH:15]=1
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: O=S(=O)(Cl)c1cc(F)c(Br)cc1F
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2cc(F)c(Br)cc2F)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 4-bromo-2,5-difluorobenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (21.9 mg) with purity >90%. MS (pos) m/z 441.0, 443.0.
Reaction SMILES: C([O:8][CH2:9][C:10]1[C:11]([O:28][CH3:29])=[N:12][CH:13]=[CH:14][C:15]=1[C:16]([OH:27])([CH2:25][CH3:26])[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])C1C=CC=CC=1>[Pd].C(O)C>[OH:27][C:16]([C:15]1[CH:14]=[CH:13][N:12]=[C:11]([O:28][CH3:29])[C:10]=1[CH2:9][OH:8])([CH2:25][CH3:26])[CH2:17][C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19]
Reactant: CCC(O)(CC(=O)OC(C)(C)C)c1ccnc(OC)c1COCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCC(O)(CC(=O)OC(C)(C)C)c1ccnc(OC)c1CO
Yield: 90.3 %

Procedure:
tert-Butyl 3-{3-[(benzyloxy)methyl]-2-methoxy-4pyridinyl}-3-hydroxypentanoate (1 g, 2.5 numol) is subjected to hydrogenolysis at atmospheric pressure and at ambient temperature using 5% palladium on carbon as catalyst (50 mg) and absolute ethanol as solvent (10 ml). Once the reaction has terminated (6 hours), the catalyst is separated by filtration and the solvent is evaporated off, which leaves 0.7 g (90%) of product (K) of a sufficient purity for a subsequent synthetic use.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH3:14][O:15][C:16]1[CH:31]=[C:30]2[C:19]([C:20]3[CH:21]=[CH:22][C:23]4[O:27][CH2:26][O:25][C:24]=4[C:28]=3[C:29]2=O)=[CH:18][CH:17]=1>C1COCC1>[CH3:14][O:15][C:16]1[CH:31]=[C:30]2[C:19]([C:20]3[CH:21]=[CH:22][C:23]4[O:27][CH2:26][O:25][C:24]=4[C:28]=3[C:29]2=[CH:5][C:3]#[N:4])=[CH:18][CH:17]=1
Reactant: COc1ccc2c(c1)C(=O)c1c-2ccc2c1OCO2
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(=CC#N)c1c-2ccc2c1OCO2
Reaction time: 16 h

Procedure:
Crude 5-(4-methoxyphenyl)-1,3-benzodioxole-4-carboxylic acid was dissolved in thionyl chloride (10 mL) and refluxed for 6 h. The reaction was cooled to ambient temperature and the solvent was removed by rotary evaporation to give the crude acid chloride. The acid chloride was dissolved in methylene chloride (10 mL) and added to a suspension of aluminum chloride (0.67 g, 5.00 mmol) in methylene chloride (10 mL). The reaction was stirred at ambient temperature for 4 h and quenched with a mixture of ice and concentrated HCl. The mixture was extracted with methylene chloride and dried with magnesium sulfate and concentrated by rotary evaporation to afford 89 mg of 8-methoxy-10H-fluoreno[1,2-d]-1,3-dioxol-10-one (0.35 mmol, 45% yield). 1H NMR (300 MHz, CDCl3) δ 7.54 (d, J=8.3 Hz, 1H), 7.10 (d, J=8.3 Hz, 1H), 7.06 (d, J=2.2, 1H), 6.88 (dd, J=8.3, 2.2 Hz, 1H), 6.90 (d, J=8.3 Hz, 1H), 6.15 (s, 2H), 3.86 (s, 3H). Sodium hydride (21 mg, 0.53 mmol) was suspended in THF (5 mL) and diethyl cyanomethylphosphonate (94 mg, 0.53 mmol) was slowly added to the suspension. After 15 min a yellow solution resulted and a solution of 8-methoxy-10H-fluoreno[1,2-d]-1,3-dioxol-10-one (89 mg, 0.35 mmol) in THF (5 mL) was added dropwise. The solution was allowed to stir at ambient for 16 h. The solvent was removed by rotary evaporation and the residue was taken up in methylene chloride, washed with water, and dried with magnesium sulfate. The solvent was removed by rotary evaporation to yield the crude Horner-Emmons product as an orange solid.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:42][CH2:41][C:18]2[C:19]3[C:24]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=4[O:33][CH:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)=[N:23][CH:22]=[N:21][C:20]=3[S:40][C:17]=2[CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[F:32][C:29]1[CH:30]=[CH:31][C:26]([NH:25][C:24]2[C:19]3[C:18]4[CH2:41][CH2:42][NH:15][CH2:16][C:17]=4[S:40][C:20]=3[N:21]=[CH:22][N:23]=2)=[C:27]([O:33][CH:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3ncnc(Nc4ccc(F)cc4OC4CCOCC4)c23)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(Nc2ncnc3sc4c(c23)CCNC4)c(OC2CCOCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.6 %

Procedure:
Trifluoroacetic acid (0.50 mL) was added into a solution of 4-[4-fluoro-2-(tetrahydro-2H-pyran-4-yloxy)-phenylamino]-5,8-dihydro-6H-pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine-7-carboxylic acid tert-butyl ester (0.031 g, 0.06 mmol) in DCM (1 mL) and the reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was diluted with DCM and washed with 2M NaOH. The organic phase was dried (MgSO4), filtered and concentrated in vacuo. The residue was washed with hexane to afford the title compound as a white solid (0.016 g, 65%).
Reaction SMILES: [CH:1]([C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[CH3:17])=[CH:5][CH:4]=1)=[CH2:2].[CH2:20]=[O:21]>N1C=CC=CC=1>[CH:1]([C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[CH2:17][CH2:20][OH:21])=[CH:5][CH:4]=1)=[CH2:2]
Reactant: C=O
Reactant: C=Cc1ccc(Cn2c(C)nc3ccccc32)cc1
Solvent: c1ccncc1
Product: C=Cc1ccc(Cn2c(CCO)nc3ccccc32)cc1
Temperature: 95 °C
Reaction time: 24 h

Procedure:
Next, 1-(4-vinylbenzyl)-2-(2-hydroxyethyl)benzimidazole was prepared. A mixture of 1-(4-vinylbenzyl)-2-methylbenzimidazole (20.0 g, 81 mmol), formaldehyde (320 mmol as 26.1 g of the 37% aqueous solution), and 25 g of pyridine were stirred magnetically and heated to 95° C. The mixture became homogeneous within minutes. After 24 h, the mixture was cooled to ambient and concentrated at reduced pressure to deposit a tan oil. The product was purified by flash chromatography (silica gel, 75% dichloromethane/25% ether), followed by recrystallization from a mixture of 100 mL of methanol plus 40 mL of water. The product was obtained as 9.1 g (41%) of an off-white solid. 1H NMR (CDCl3) δ 2.97 (t, J=5.5, 2H), 4.12 (t, J=5.5, 2H),4.1 (br s, 1H), 5.24 (d, J=10.8, 1H), 5.30 (s, 2H), 5.71 (d, J=17.6, 1H), 6.7 (m, 1H), 7.00 (d, J=8.1, 2H), 7.2 (m,3H) 7.34 (d, J= 8.2, 2H), 7.73 (m, 1H). ES−MS m/e 279+ (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[Mg]Br.[Cl:11][CH2:12][C:13](=[O:23])[C@H:14]([O:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:15].[Cl-].[NH4+].O>C1(C)C=CC=CC=1>[Cl:11][CH2:12][C:13]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])([OH:23])[CH:14]([O:16][C:17](=[O:22])[C:18]([CH3:20])([CH3:19])[CH3:21])[CH3:15]
Reactant: Fc1ccc([Mg]Br)c(F)c1
Reactant: C[C@@H](OC(=O)C(C)(C)C)C(=O)CCl
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(OC(=O)C(C)(C)C)C(O)(CCl)c1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 94 %

Procedure:
First, 8.9 mL (8.0 mmol) of a 0.9 M solution of 2,4-difluorophenylmagnesium bromide prepared by the same method as that in Example 3 was cooled to 0° C., and a solution of 0.83 g (4.0 mmol) of (R)-1-chloro-3-pivaloyloxybutan-2-one in 10 mL of toluene was added dropwise thereto over a period of 5 minutes. After the completion of the dropwise addition, stirring was continued for another 1 hour, and 20 mL of a saturated aqueous solution of ammonium chloride was added to stop the reaction. Furthermore, 10 mL of water was added, and extraction was performed with ethyl acetate (30 mL×2). After drying over anhydrous sodium sulfate, concentration was performed under reduced pressure to obtain 1.57 g of a crude product. A quantitative analysis was performed by HPLC. Thereby, the title compound was obtained in a yield of 94% ((2S,3R)/(2R,3R)=93/7 (the diastereomeric ratio was measured by HPLC under the same HPLC measurement conditions as those in Example 19)).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]([CH:13]=O)[CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:19][CH:18]=1.C([BH3-])#N.[Na+].Cl>CC(O)=O.CO>[C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]([CH2:13][N:27]1[CH2:26][CH2:25][N:24]([CH:23]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[C:20]2[CH:19]=[CH:18][C:17]([F:16])=[CH:22][CH:21]=2)[CH2:29][CH2:28]1)[CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C[C@@H](C=O)NC(=O)OC(C)(C)C
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)C[C@@H](CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1)NC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 41.3 %

Procedure:
(S)-(1-Formyl-3-methyl-butyl)-carbamic acid tert-butyl ester (0.39 mg, 1.8 mmol) and 1-bis(4-fluorophenyl)methyl piperazine (0.50 g, 1.7 mmol) were dissolved in 1% HOAc in methanol (8 mL) under nitrogen atmosphere at ambient temperature. After stirring at that temperature for 1 hour, a solution of sodium cyanoborohydride (250 mg, 3.6 mmol) in methanol was added. The resulting reaction mixture was stirred at ambient temperature for 24 hours at which time TLC showed no starting aldehyde. 3N aqueous HCl was added in 5 mL portions until bubbling subsided; pH was adjusted to 8 with saturated aqueous NaHCO3 solution. The resulting mixture was extracted with EtOAc (3×25 mL), the combined organic solution was washed with brine (50 mL) and dried over MgSO4. The solution was concentrated in vacuo affording an amber oil. The crude product was further purified by flash chromatography (20%-30% EtOAc in hexanes) affording 342 mg (41%) of the pure titled compound as a clear oil. APCI-MS m/z 488.3 (MH+).
Reaction SMILES: Br[C:2]1[C:3]([CH3:12])=[C:4]([C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)[C:5]#[N:6].ClC1C([CH2:22][CH:23]=[O:24])=CC=C(F)C=1C#N>>[CH3:11][O:10][C:7]1[C:4]([C:5]#[N:6])=[C:3]([CH3:12])[C:2]([CH2:22][CH:23]=[O:24])=[CH:9][CH:8]=1
Reactant: N#Cc1c(F)ccc(CC=O)c1Cl
Reactant: COc1ccc(Br)c(C)c1C#N
Product: COc1ccc(CC=O)c(C)c1C#N

Procedure:
6-methoxy-2-methyl-3-(2-oxoethyl)benzonitrile was prepared in two steps starting from 3-bromo-6-methoxy-2-methylbenzonitrile in an analogous fashion to that described for the synthesis of 2-chloro-6-fluoro-3-(2-oxoethyl)benzonitrile (Steps B and C) above.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:8](F)=[CH:7][N:6]=1)=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+].[F:25][C:26]([F:30])([F:29])[CH2:27][OH:28]>CS(C)=O>[CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:8]([O:28][CH2:27][C:26]([F:30])([F:29])[F:25])=[CH:7][N:6]=1)=[O:4]
Reactant: OCC(F)(F)F
Reactant: COC(=O)c1ncc(F)c(-c2ccc(Cl)cc2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: COC(=O)c1ncc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
To a solution of 0.143 g 4-(4-chloro-phenyl)-5-fluoro-pyrimidine-2-carboxylic acid methyl ester in 1.5 ml dried DMSO was added 192 mg of cesium carbonate and 0.059 g of 2,2,2-trifluoroethanol and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was partitioned between water and ethyl acetate, the phases were separated and the organic phase was dried with MgSO4 and purified by chromatography on silica gel with a gradient of heptane:ethyl acetate=9:1 to 1:1 to yield 161 mg (86.60%) of the title compound as white solid, MS 347.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:14]([C:16]1[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=1[O:18][CH2:19][CH:20]1[O:22][CH2:21]1)#[N:15]>C(O)(C)C.CCCCCC>[C:14]([C:16]1[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=1[O:18][CH2:19][CH:20]([OH:22])[CH2:21][N:11]1[CH2:10][CH2:9][N:8]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH2:13][CH2:12]1)#[N:15]
Reactant: N#Cc1ccccc1OCC1CO1
Reactant: Fc1cccnc1N1CCNCC1
Solvent: CC(C)O
Solvent: CCCCCC
Product: N#Cc1ccccc1OCC(O)CN1CCN(c2ncccc2F)CC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 74.1 %

Procedure:
To a solution of 1-(3-fluoro-2-pyridyl)piperazine (453 mg, 2.5 mmol) in 5 ml of isopropanol stirred at 70° C. under nitrogen was added portionwise 2-cyanophenoxy-2,3-epoxypropane (438 mg, 2.5 mmol) and the mixture stirred for 21/2 hours at 70° C. The solvent was removed in vacuo at room temperature and the residual oil was chromatographed on silica gel eluting with 5% methanol-chloroform. The product was obtained as a colorless oil which slowly solidified upon trituration in hexane to yield 0.66 g of 1-[3-(2-cyanophenoxy)-2-hydroxypropyl]-4-(3-fluoro-2-pyridyl)piperazine; m.p. 68°-70° C. Analysis satisfactory for C19H21FN4O2.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[S:22][C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)(O)[CH2:11][CH2:10]1)=O)(C)(C)C.[OH-].[Na+]>C(O)(=O)C>[CH3:29][C:26]1[CH:27]=[CH:28][C:23]([S:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:12]2[CH2:13][CH2:14][NH:9][CH2:10][CH:11]=2)=[CH:24][CH:25]=1
Reactant: Cc1ccc(Sc2ccccc2C2(O)CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1ccc(Sc2ccccc2C2=CCNCC2)cc1
Temperature: 25 °C

Procedure:
Concentrated aq hydrochloric acid (10 ml) was added to a stirred solution of 1-tert-butoxycarbonyl-4-[2-(4-methylphenylsulfanyl)phenyl]piperidin-4-ol (0.84 g, 2.1 mmol) in acetic acid (30 mL). The solution was boiled under reflux overnight, cooled to room temperature and then stirred in an ice bath. An aqueous solution of NaOH (9.1 M, 40 mL) was slowly added and the unclear solution was extracted with ethyl acetate (2×40 ml). The combined organic phases were dried (MgSO4) and the solvents evaporated in vacuo. The crude material (0.48 g) was dissolved in ethyl acetate (3.2 mL) at 50° C. and a solution of oxalic acid (0.11 g) in EtOH (3.2 mL) was slowly added. The target compound was collected as a white oxalic salt. 1H (DMSO-d6) δ 7.3–7.2 (m, 7H); 7.15 (m, 1H); 7.00 (m, 1H); 5.6 (d, 1H); 3.7 (d, 2H); 3.25 (t, 2H); 2.6 (m, 2H); 2.3 (s, 3H). LC/MS (m/z) 282.2 (MH+); RT=2.24; purity (UV, ELSD): 99%, 100%; yield: 0.31 g (40%).