Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:4]=1O)[CH3:2].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH2:21][C:22]([OH:24])=O)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20].P(Cl)(Cl)(Cl)(Cl)Cl.CN([CH:34]=[O:35])C>>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:21]2[C:22](=[O:24])[C:6]3[C:7](=[CH:8][C:9]([OH:10])=[C:3]([CH2:1][CH3:2])[CH:4]=3)[O:35][CH:34]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]
Reactant: CCc1c(O)cccc1O
Reactant: COc1ccc(CC(=O)O)cc1OC
Reactant: CN(C)C=O
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: CCc1cc2c(=O)c(-c3ccc(OC)c(OC)c3)coc2cc1O
Yield: 92 %

Procedure:
This compounds was synthesised in the same manner as described above. Ethyl resorcinol (0.83 g, 6 mmol), 3,4-dimethoxyphenylacetic acid (0.83 g, 6 mmol), BF3Et2O (4 ml), PCl5 (1.9 g, 9.1 mmol), DMF (5 ml and 10 ml). The precipitate formed was filtered and re-crystallized from methanol to give 3-(3,4-dimethoxy-phenyl)-6-ethyl-7-hydroxy-chromen-4-one as a pale brown solid (1.8 g, 92%); Rf 0.4 cf SM 0.5 ether/petroleum ether [40–60° C.] (50/50).
Reaction SMILES: O=P(Cl)(Cl)Cl.[Cl:6][C:7]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:8]=1[O:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH:14]=[CH:13][O:12]1.[Cl:22][CH2:23][CH:24]([OH:35])[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=1[Cl:34]>C(OCC)C.C(N(CC)CC)C>[Cl:6][C:7]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:8]=1[O:9][CH2:10][C@@H:11]1[O:12][C@@H:13]([O:35][CH:24]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[Cl:34])[CH2:23][Cl:22])[CH2:14][CH2:15][CH2:16]1
Reactant: Clc1ccc(OCC2CCC=CO2)c(Cl)c1
Reactant: OC(CCl)CCc1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: O=P(Cl)(Cl)Cl
Product: ClCC(CCc1ccc(Cl)cc1Cl)O[C@H]1CCC[C@H](COc2ccc(Cl)cc2Cl)O1

Procedure:
2 Drops of phosphorus oxytrichloride were added to a solution of 388 mg of 2-(2,4-dichlorophenoxymethyl)-3,4-dihydro-2H-pyran and 418 mg of 1-chloro-4-(2,4-dichlorophenyl)-2-butanol in 8 ml of diethyl ether, and the mixture was allowed to react at room temperature for 2 days. At the the end of this time, 3 drops of triethylamine were added and the solvent was evaporated off. The residue was purified by column chromatography through silica gel eluted with a 50:5:1 by volume mixture of hexane, benzene and ethyl acetate, to give 185 mg of the isomer of lesser polarity of trans-6-(2,4-dichlorphenoxymethyl)-2-[1-chloro-4-(2,4-dichlorophenyl)-2-butoxy]tetrahydropyran and 153 mg of the isomer of greater polarity.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH2:16][C:17]3[CH:18]=[C:19]([C:23]4[N:28]=[CH:27][C:26]([N:29]5[CH2:34][CH2:33][N:32](NC(OC(C)(C)C)=O)[CH2:31][CH2:30]5)=[CH:25][N:24]=4)[CH:20]=[CH:21][CH:22]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].Cl>C(#N)C.O1CCOCC1>[O:15]=[C:12]1[N:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[N:28]=[CH:27][C:26]([N:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[CH:25][N:24]=3)[CH:18]=2)[N:10]=[C:9]([C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[C:1]#[N:2])[CH:14]=[CH:13]1
Reactant: CC(C)(C)OC(=O)NN1CCN(c2cnc(-c3cccc(Cn4nc(-c5cccc(C#N)c5)ccc4=O)c3)nc2)CC1
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: N#Cc1cccc(-c2ccc(=O)n(Cc3cccc(-c4ncc(N5CCNCC5)cn4)c3)n2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
143 mg (0.26 mmol of tert-butyl 4-(2-{3-[3-(3-cyanophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-yl)piperazine-1-carbamate are dissolved in 6 ml of acetonitrile, and 6 ml of 4 M HCl in dioxane are added. The reaction mixture is stirred at room temperature for 1 h and evaporated. The residue is taken up in water and ethyl acetate, and the water phase is adjusted to pH 12 using NaOH and extracted with ethyl acetate and dichloromethane. The organic phases are combined, dried over sodium sulfate and purified by means of column chromatography.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH:20]=[O:21])=[C:12]2Cl)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH:20]=[O:21])=[C:12]2[N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCNCC1
Reactant: CC(C)(C)c1ccc(-n2c(Cl)c(C=O)c3ccccc32)cc1
Product: CC(C)(C)c1ccc(-n2c(N3CCCCC3)c(C=O)c3ccccc32)cc1
Yield: 87 %

Procedure:
1-(4-tert-Butylphenyl)-2-chloro-1H-indole-3-carboxaldehyde is reacted with piperidine as described in Step 2 of Example 29 to afford 1-(4-tert-butylphenyl)-2-piperidin-1-yl-1H-indole-3-carboxaldehyde (87% yield) as an off-white solid. TLC (silica gel, heptane-30% ethyl acetate); Rf 0.23; ESI/MS 361 (M+H); RT 4.48 min; NMR 10.14 (1H, s); 8.11 (1H, d, J=6 Hz); 7.66 (2H, d); 7.46 (2H, d); 7.16 (2H, m); 6.91 (1H, d, J=9 Hz); 3.27 (4H, m); 1.46 (6H, m); 1.36 (9H, s).
Reaction SMILES: [S:1]=[C:2]1[CH2:6][O:5][C:4](=[O:7])[NH:3]1.[OH:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[C:16]=1[OH:17])[CH:12]=O.N1CCCCC1>C(O)(=O)C>[OH:8][C:9]1[CH:10]=[C:11]([CH:12]=[C:6]2[O:5][C:4](=[O:7])[NH:3][C:2]2=[S:1])[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[C:16]=1[OH:17]
Reactant: O=C1NC(=S)CO1
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: O=C1NC(=S)C(=Cc2cc(O)c(O)c([N+](=O)[O-])c2)O1
Temperature: 100 °C

Procedure:
A solution containing 0.25 g of 4-thioxo-2-oxazolone 0.38 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 0.1 ml of piperidine in 5 ml of acetic acid was heated overnight at 100° C. The product was filtered and washed with actic acid. Yield 0.05 g, mp 245° C.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([N:12]2[CH:16]=[C:15]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][C:23]([S:27][C:28]3[N:32]5[N:33]=[C:34]([CH3:37])[CH:35]=[CH:36][C:31]5=[N:30][N:29]=3)=[CH:22][CH:21]=4)[CH:14]=[N:13]2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH:8]1[CH2:9][CH:10]([N:12]2[CH:16]=[C:15]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][C:23]([S:27][C:28]3[N:32]5[N:33]=[C:34]([CH3:37])[CH:35]=[CH:36][C:31]5=[N:30][N:29]=3)=[CH:22][CH:21]=4)[CH:14]=[N:13]2)[CH2:11]1
Reactant: Cc1ccc2nnc(Sc3ccc4ncc(-c5cnn(C6CN(C(=O)OC(C)(C)C)C6)c5)cc4c3)n2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2nnc(Sc3ccc4ncc(-c5cnn(C6CNC6)c5)cc4c3)n2n1
Reaction time: 2 h

Procedure:
To 3-{4-[6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-quinolin-3-yl]-pyrazol-1-yl}-azetidine-1-carboxylic acid tert-butyl ester (65 mg, 0.126 mmol) was added 6 mL of (1:1) TFA:dichloromethane. The mixture was allowed to sit for 2 hours. The volatiles were removed by rotary evaporation and then methanol (6 mL) and MP-carbonate (500 mg, 3.18 mmol/g) were added. The resin was filtered and the volatiles were removed in vacuo to provide 3-(1-azetidin-3-yl-1H-pyrazol-4-yl)-6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-quinoline as a yellow solid (quantitative yield).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(O)[CH3:10])[CH2:3][CH2:2]1.C1(S(O)(=O)=O)C=CC=CC=1>C1C=CC=CC=1>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH:8]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:10])[CH2:3][CH2:2]1
Reactant: CC(O)(CCN1CCOCC1)c1ccccc1-c1ccccc1
Agent: O=S(=O)(O)c1ccccc1
Solvent: c1ccccc1
Product: CC(=CCN1CCOCC1)c1ccccc1-c1ccccc1
Reaction time: 24 h

Procedure:
A mixture of 3.1 g of 1-morpholino-3-biphenylyl-butan-3-ol, 0.1 g of benzenesulfonic acid and 80 ml of benzene is boiled for 24 hours under a water separator. After working up in the customary manner, 1-morpholino-3-p-biphenylyl-2-butene is obtained.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>N1C=CC=CC=1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:10]1([N:1]2[C:9]3[CH:8]=[CH:7][N:6]=[CH:5][C:4]=3[N:3]=[CH:2]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:10]1([N:3]2[C:4]3[CH:5]=[N:6][CH:7]=[CH:8][C:9]=3[N:1]=[CH:2]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: c1cc2[nH]cnc2cn1
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: c1ccc(-n2cnc3ccncc32)cc1
Product: c1ccc(-n2cnc3cnccc32)cc1
Temperature: 25 °C

Procedure:
1H-Imidazo[4,5-c]pyridine (2.01 g, 0.0169 mol), copper acetate (7.66 g, 42.2 mmol) and phenyl boronic acid (5.14 g, 042.2 mmol) in pyridine (60 mL) were stirred vigorously at 37° C. in a flask open to the atmosphere for 3 days. The mixture was allowed to cool to RT then partitioned between water and DCM (3×50 mL). The combined DCM extracts were washed with water, dried (Na2SO4) and concentrated in vacuo. The residue was purified by chromatography (SiO2 0-6% (2M ammonia in methanol) in DCM) to give 1-phenyl-1H-imidazo[4,5-c]pyridine (1.60 g) and 3-phenyl-3H-imidazo[4,5-c]pyridine (1.06 g) as white solids (combined 81%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][C:3]=1[NH2:9].[CH:10]1([CH2:13][O:14][C:15]2[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=2)[CH2:12][CH2:11]1.C(OCC)(=O)C>N1C=CC=CC=1.C1COCC1>[CH:10]1([CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]([C:19]([NH:9][C:3]3[CH:4]=[N:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])=[O:20])=[CH:22][CH:23]=2)[CH2:12][CH2:11]1
Reactant: O=C(Cl)c1ccc(OCC2CC2)cc1
Reactant: Nc1cnc(Cl)cc1Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Nc1cnc(Cl)cc1Cl)c1ccc(OCC2CC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 36.3 %

Procedure:
To a solution of 4,6-dichloropyridin-3-amine (2.00 g) in pyridine (30 mL) was added a solution of 4-(cyclopropylmethoxy)benzoyl chloride (3.88 g) in THF (5 mL), and the mixture was stirred at room temperature for 10 min. The reaction mixture was subjected to silica gel column chromatography (NH, ethyl acetate), and the solvent was evaporated, and the obtained solid was washed with diethyl ether/hexane to give the title compound (1.50 g).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3](=[N:5][NH:6][C:7]1[CH:8]=[N:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)[NH2:4].[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=O)=[CH:21][CH:20]=1.N1C=CC=CC=1>CN(C)C1C=CN=CC=1.O1CCOCC1>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([N:6]2[C:23]([C:22]3[CH:26]=[CH:27][C:19]([O:18][CH3:17])=[CH:20][CH:21]=3)=[N:4][C:3]([C:2]([F:1])([F:15])[F:16])=[N:5]2)=[CH:8][N:9]=1
Reactant: COc1ccc(NN=C(N)C(F)(F)F)cn1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: COc1ccc(-c2nc(C(F)(F)F)nn2-c2ccc(OC)nc2)cc1
Reaction time: 8 h
Yield: 19.1 %

Procedure:
A mixture of 2,2,2-trifluoro-N′-(6-methoxypyridin-3-yl)ethanehydrazonamide (0.2 g, 0.854 mmol), 4-methoxybenzoyl chloride (175 mg, 1.02 mmol), pyridine (0.083 mL, 1.02 mmol), and 4-dimethylaminopyridine (125 mg, 1.02 mmol) in dioxane (2 mL) was refluxed with stirring overnight. After cooling, the solvent was removed under reduced pressure. ethyl acetate-tetrahydrofuran (9:1) and water was poured into the residue and the organic layer was separated, washed with 0.1 N hydrochloric acid, water, and brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography to give 2-methoxy-5-[5-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]pyridine (57 mg, 19.1% yield).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[F:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[F:15])[C:9](O)=[O:10]>>[CH:1]1([NH:4][C:9](=[O:10])[C:8]2[CH:12]=[CH:13][C:14]([F:15])=[C:6]([F:5])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: O=C(O)c1ccc(F)c(F)c1
Product: O=C(NC1CC1)c1ccc(F)c(F)c1
Yield: 89 %

Procedure:
Using cyclopropylamine and 3,4-difluorobenzoic acid in the general procedure for coupling of amines to carboxylic acids, the title compound was obtained (89% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.52-0.63 (m, 2H) 0.63-0.74 (m, 2H) 2.83 (tq, J=7.42, 3.98 Hz, 1H) 7.52 (dt, J=10.55, 8.37 Hz, 1H) 7.66-7.75 (m, 1H) 7.85 (ddd, J=11.68, 7.89, 2.15 Hz, 1H) 8.42-8.60 (m, 1H). ESI-MS:m/z 198.1 (M+H)+. mp=104.1-108.4° C.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][NH2:21])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl.CCOCC>[C:1]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][NH:21][S:30]([CH3:29])(=[O:32])=[O:31])[CH2:12][CH2:13]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2CN)CC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2CNS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
1-Boc-4-(2-aminomethyl-phenyl)-piperazine (2.09 g, 7.18 mmol) was dissolved in methylene chloride (50 mL), cooled to 0° C. and treated with triethylamine (1.5 mL, 10.8 mmol) followed by methanesulfonyl chloride (0.67 mL, 8.61 mmol). The resulting mixture was stirred for about 3 hours at r.t., and then diluted with ether (200 mL) and washed with water (50 mL), saturated aqueous sodium bicarbonate (50 mL) and brine (50 mL), which is then dried over anhydrous magnesium sulfate. Concentration under reduced pressure followed by silica gel chromatography (30% ethyl acetate in hexanes) afforded the title compound (2.07 g, 78%) as a clear oil.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]([O:10]C(C)(C)C)=[O:9])[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.Cl>CCOC(C)=O>[O:1]=[C:2]1[N:6]([CH2:7][C:8]([OH:10])=[O:9])[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: CC(C)(C)OC(=O)Cn1c(=O)n(-c2ccccn2)c2ccccc21
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(O)Cn1c(=O)n(-c2ccccn2)c2ccccc21

Procedure:
A solution of tert-butyl (2-oxo-3-pyridin-2-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetate from Step B (2.27 g, 6.98 mmol) in EtOAc (100 mL) at 0° C. was saturated with HCl (g). The mixture was stood at 0° C. for a total of 3 h, and was re-saturated with HCl every 30 min. The mixture was concentrated in vacuo to give the title compound as a white solid. MS: m/z=270 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:15][C:16]1[NH:17][CH:18]=[C:19]([CH3:21])[CH:20]=1>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([C:4]([C:18]2[NH:17][C:16]([CH3:15])=[CH:20][C:19]=2[CH3:21])=[O:5])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: Cc1c[nH]c(C)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc(C)c(C(=O)c2cccnc2Cl)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.8 %

Procedure:
2-Chloronicotinoyl chloride (3.4 g, 20 mmol) (Aldrich, Milwaukee, Wis.) was added to a solution of aluminum chloride (2.7 g, 20 mmol) (Aldrich, Milwaukee, Wis.) in dichloromethane (100 mL) at 0° C., followed by a solution of 2,4-dimethylpyrrole (2.9 g, 30 mmol) in dichloromethane (20 mL). The mixture was then stirred at room temperature for one hour. The reaction was diluted with ethyl acetate, washed with brine, dried and concentrated. The residue was purified on a silica gel column to give 2.9 g (62%) of (2-chloro-pyridin-3-yl)-(3,5-dimethyl-1H-pyrrol-2-yl)-methanone.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].CN1CCOCC1.Cl.[NH2:40][CH2:41][C:42]([NH:44][CH3:45])=[O:43].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:31])([F:29])[F:30])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:40][CH2:41][C:42]([NH:44][CH3:45])=[O:43])=[O:4]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: CNC(=O)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CNC(=O)CNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 8 h
Yield: 46 %

Procedure:
2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-Vb, 60 mg, 0.139 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (0.092 mL, 0.835 mmol), 2-amino-N-methylacetamide-HCl (31.2 mg, 0.250 mmol), and HATU (95 mg, 0.250 mmol). This was stirred overnight and was then purified by preparative HPLC (PHENOMENEX® Luna 5u C18 21.2×250 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 30 min, 15 mL/min, 220 nM, product retention=33.0 min) to give single enantiomer 2-hydroxy-N-(2-(methylamino)-2-oxoethyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (33 mg, 0.064 mmol, 46.4% yield): LCMS=502.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.14-8.23 (2 H, m), 7.66-7.79 (4 H, m), 7.52-7.66 (3 H, m), 5.20 (1 H, s), 3.88-4.00 (2 H, m), 3.78-3.88 (2 H, m), 2.75 (3 H, s); HPLC Peak RT=9.1 min (Analytical Method B).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15]([CH3:17])=O)[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8].O.[NH2:19][NH2:20]>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15](=[N:19][NH2:20])[CH3:17])[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NN
Reactant: CC(=O)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Solvent: O
Solvent: CC(C)O
Product: CC(=NN)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Temperature: 25 °C
Yield: 70.3 %

Procedure:
2-(3,4-Dichlorophenyl)-3-hydroxy-4-(methylcarbonyl)thiophene (50 mg, 0.17 mmol) (prepared by the method disclosed in WO2004/108683) in isopropanol was stirred with hydrazine monohydrate (95 μL/0.19 mmol) at 90° C. for 1 hour, then allowed to cool to room temperature and stirred at 0° C. The precipitated solid was collected by filtration and dried to give 36 mg of the desired product (yield 69%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH:25]1[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([CH2:13][O:14][C:15]3[N:16]=[CH:17][C:18]([C:19]([N:25]4[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[CH2:27][CH2:26]4)=[O:21])=[CH:22][CH:23]=3)=[C:11]([CH3:24])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1onc(-c2cccc(Cl)c2)c1COc1ccc(C(=O)O)cn1
Reactant: O=S1(=O)CCNCC1
Product: Cc1onc(-c2cccc(Cl)c2)c1COc1ccc(C(=O)N2CCS(=O)(=O)CC2)cn1
Yield: 87 %

Procedure:
As described for example 98b, 6-[3-(3-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (69 mg, 0.2 mmol) was converted, using thiomorpholine-S,S-dioxide instead of 2,2,2-trifluoroethylamine, to the title compound (80 mg, 87%) which was obtained as a white solid. MS: m/e=462.1 [M+H]+.
Reaction SMILES: O1CCOCC1.CN(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.C(O)=O.C(=O)([O-])OC[CH2:29]/[CH:30]=[C:31](/[CH2:33][CH2:34][CH:35]=[C:36]([CH3:38])[CH3:37])\[CH3:32]>CCCCC>[CH3:32][C@@H:31]([CH2:33][CH2:34][CH:35]=[C:36]([CH3:38])[CH3:37])[CH:30]=[CH2:29]
Reactant: CC(C)=CCC/C(C)=C/CCOC(=O)[O-]
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: CCCCC
Solvent: C1COCCO1
Solvent: O=CO
Product: C=C[C@@H](C)CCC=C(C)C
Temperature: 20 °C
Reaction time: 17 h
Yield: 100.4 %

Procedure:
In a Schlenk's tube, (R)-(+)-3-diphenylphosphino-3'-methoxy-4,4'-biphenanthryl prepared in Example 1 (6.24 mg, 0.011 mmol) and tris(dibenzylideneacetone)(chloroform)dipalladium (0) (2.6 mg, 0.0025 mmol) were charged, and dioxane was added under a nitrogen atmosphere. To the mixture cooled on an ice bath, 1,8-bis(dimethylamino)naphthalene (128.6 mg, 0.60 mmol) and formic acid (52.5 mg, 1.14 mmol) were added in this order. At the same temperature, geranylmethyl carbonate (104.5 mg, 0.49 mmol) was added, and the mixture was stirred at 20° C. for 17 hours. The reaction mixture was diluted with pentane and washed with water, and the organic layer was dried over anhydrous magnesium sulfate and filtrated through a mass of silica gel. From the filtrate, the solvent was evaporated off under reduced pressure to obtain (S)-3,7-dimethyl-1,6-octadiene as a colorless oil (68.0 mg). Yield, >99%. Rotatory power: :[α]D20 =+8.1 (C=1.6, CHCl3). 1 H-NMR (CDCl3): δ(ppm)=0.98 (d, J=7.0 Hz, 3H), 1.27-1.36 (m, 2H), 1.60 (s, 3H), 1.67 (s, 3H), 1.96 (q, J=7.0 Hz, 2H), 2.12 (heptet, J=7 Hz, 1H), 4.88-4.99 (m, 2H), 5.05-5.15 (m, 1H), 5.70 (ddd, J=17.1, 10.1 and 7.0 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([NH:12][C:13]([NH:15][C:16]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:17]=2[CH:18]=[N:19][N:20]3C(OC)=O)=[O:14])[CH2:4][CH2:3]1.O>[OH-].[Na+].CO>[NH:20]1[C:21]2[C:17](=[C:16]([NH:15][C:13]([NH:12][CH:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[N:2]([CH3:1])[CH2:3][CH2:4]3)=[O:14])[CH:24]=[CH:23][CH:22]=2)[CH:18]=[N:19]1
Reactant: COC(=O)n1ncc2c(NC(=O)NC3CCN(C)c4ccccc43)cccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN1CCC(NC(=O)Nc2cccc3[nH]ncc23)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound obtained in example 95B was dissolved in 2 mls of 5N NaOH in methanol and stirred for 2 hours at ambient temperature. Water was added to the reaction mixture and the precipitate was collected. The precipitated compound was redissolved in 10% methanol in dichloromethane and purified by flash chromatography on silica using a gradient from dichloromethane to 20% methanol in dichloromethane with a few drops of NH4OH as the solvents to provide the titled compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.99 (s, 1 H) 8.53 (s, 1 H) 8.01 (s, 1 H) 7.70 (d, J=7.46 Hz, 1 H) 7.21 (t, J=7.97 Hz, 1 H) 7.11-7.17 (m, 2 H) 7.07 (t, J=8.48 Hz, 1 H) 6.58-6.72 (m, 3 H) 4.76-4.85 (m, 1H) 3.15-3.29 (m, 2 H) 2.89 (s, 3 H) 1.99 (s, 2 H). MS (DCI/NH3) m/z 322.0 (M+H)+.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@@H:29]4[CH2:33][CH2:32][NH:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@@H:29]4[CH2:33][CH2:32][N:31]([C:34](=[O:37])[CH2:35][CH3:36])[CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: CCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)N[C@@H]1CCNC1
Agent: Cl
Product: CCC(=O)N1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-6-methyl-N-[(3R)-pyrrolidin-3-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f4) and commercially available propionyl chloride the title compound is obtained as colorless solid.