Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH3:10])[CH:7]=1
Reactant: Cc1ccccc1B(O)O
Reactant: COc1ccnc(Br)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1ccnc(-c2ccccc2C)c1
Temperature: 80 °C
Reaction time: 7 h
Yield: 99.4 %

Procedure:
To a suspension of 2-bromo-4-methoxypyridine (1.88 g), 2-methylphenylboronic acid (1.77 g) and tetrakis(triphenylphosphine)-palladium (578 mg) in 1,2-dimethoxyethane (30 ml) was added 2M aqueous solution of sodium carbonate (13 ml). The mixture was stirred at 80° C. for 7 hours under a nitrogen atmosphere, then cooled to room temperature and diluted with ethyl acetate. The organic layer was separated, washed with water and brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 50 g, 25% ethyl acetate in n-hexane) to give 2-(4-methoxypyridin-2-yl)toluene (1.98 g).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[NH:4][CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[H-].[Na+].[CH2:14]([O:16][CH2:17]Cl)[CH3:15].Cl>O1CCCC1.C(OCC)(=O)C.CCCCCC>[CH2:14]([O:16][CH2:17][N:4]1[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:3]1[C:2]([F:1])([F:10])[F:11])[CH3:15]
Reactant: N#Cc1cc[nH]c1C(F)(F)F
Reactant: CCOCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOCn1ccc(C#N)c1C(F)(F)F
Reaction time: 0.33 h

Procedure:
A stirred solution of 2-trifluoromethyl-3-cyanopyrrole (1.0 g, 6.2 mmol) in dry tetrahydrofuran is treated with NaH (0.30 g, 7.5 mmol) as a 60% dispersion in mineral oil, under nitrogen, at room temperature. After 20 minutes, the reaction mixture is treated dropwise with a solution of chloromethyl ethyl ether (0.77 g, 8.1 mmol) in dry tetrahydrofuran, stirred vigorously for 3 hours and treated with a mixture of 1N HCl and ethyl acetate. The phases are separated and the organic phase is washed with brine, dried over Mg SO4 and concentrated in vacuo to afford a residue. Flash chromatography of the residue using silica gel and 3.5:1 hexane: ethyl acetate yields the title compound as a pale yellow oil, 0.83 g (61%).
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH2:5][CH2:6][CH3:7])[CH2:2]1.[NH:8]1[CH:12]=[CH:11][N:10]=[CH:9]1>C(#N)C>[N:8]1([CH2:2][CH:3]([OH:1])[CH2:4][CH2:5][CH2:6][CH3:7])[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: c1c[nH]cn1
Reactant: CCCCC1CO1
Solvent: CC#N
Product: CCCCC(O)Cn1ccnc1
Yield: 63 %

Procedure:
A solution of 1,2-epoxyhexane (2.0 mL, 17 mmol) and imidazole (1.08 g, 16 mmol) in acetonitrile (14 mL) was stirred at reflux for 19 h. The mixture was concentrated, taken up in 2.5 M aqueous hydrochloric acid (15 mL), washed with ethyl acetate (3×6 mL), basified with sodium carbonate and extracted with ethyl acetate (3×6 mL). The combined extracts were dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography (SiO2, CH2Cl2-methanol-ammonium hydroxide 80:20:1) to give 1-(1H-imidazol-1-yl)-2-hexanol as a colorless oil, 1.68 g, 63% yield. NMR spectrum was consistent with structure. MS EI: M+• 168.1259 (M+• 168.1263).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:7]([O:11][CH2:12][CH3:13])(=[O:10])[CH:8]=[CH2:9]>>[C:7]([O:11][CH2:12][CH3:13])(=[O:10])[CH:8]=[CH2:9].[C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)O
Agent: C=CC(=O)OCC
Product: C=C(C)C(=O)OC

Procedure:
141 g of a 30 percent dispersion of a copolymer of equal parts of methacrylic acid and ethyl acrylate (42 g of solids) were mixed with 328 g of a 30 percent dispersion of film forming copolymer of ethyl acrylate and methyl methacrylate in a ratio of 2:1 (98 g of solids). A suspension of 70 g of talc in 514 g of water was then added. The mixture had a pH of 5.7. (The film forming copolymer has a Tλmax of 29° C. The minimum film forming temperature of the aqueous dispersion is 8° C.).
Reaction SMILES: O.C(=O)([O-])[O-].[K+].[K+].S(O[CH2:13][C:14]([NH2:17])([CH3:16])[CH3:15])(O)(=O)=O.[CH2:18]([SH:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C(O)C>[CH3:15][C:14]([NH2:17])([CH3:16])[CH2:13][S:26][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CC(C)(N)COS(=O)(=O)O
Reactant: CCCCCCCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCCCCCCCSCC(C)(C)N
Temperature: 25 °C
Yield: 99.3 %

Procedure:
In a mixed solvent of 10 ml of water and 10 ml of ethanol was suspended 1.38 g (10 mmol) of potassium carbonate. To the suspension were added 0.85 g (5 mmol) of 2-amino-2-methylpropyl hydrogensulfate and 0.73 g (5 mmol) of 1-octanethiol, and the resulting mixture was gently refluxed for 8 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and the desired compound was extracted three times with ethyl acetate. The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then distilled under reduced pressure to remove the solvent, whereby 1.08 g of 2-methyl-1-n-octylthio-2-propylamine was obtained. The purity was measured in terms of area percentage by gas chromatography and found to be 91%.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N+:8]([O-])=[CH:9]2)=[CH:4][C:3]=1[F:13].[C:14]([NH2:18])([CH3:17])([CH3:16])[CH3:15].C1(C)C=CC(S(OS(C2C=CC(C)=CC=2)(=O)=O)(=O)=O)=CC=1>C1(C(F)(F)F)C=CC=CC=1>[C:14]([NH:18][C:9]1[C:10]2[C:5](=[CH:4][C:3]([F:13])=[C:2]([Cl:1])[CH:11]=2)[CH:6]=[CH:7][N:8]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)N
Reactant: [O-][n+]1ccc2cc(F)c(Cl)cc2c1
Agent: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: FC(F)(F)c1ccccc1
Product: CC(C)(C)Nc1nccc2cc(F)c(Cl)cc12
Temperature: 0 °C
Reaction time: 16 h
Yield: 4.3 %

Procedure:
A solution of 5.0 g (25.3 mmol) of 7-chloro-6-fluoro-isoquinoline-2-oxide (9) in 120 mL of benzotrifluoride was treated with 15.9 mL (11.1 g, 152 mmol) of tert-butylamine and cooled to 0° C. Then, 17.3 g (53.1 mmol) of p-toluenesulfonic anhydride were added portionwise with temperature control (<10° C.). The reaction mixture was stirred at room temperature for 16 h, before being cooled to 0° C. and another 8.0 mL (76.1 mmol) of tert-butylamine and 8.26 g (25.3 mmol) of p-toluenesulfonic anhydride were added. The reaction mixture was stirred for 24 h at room temperature, then concentrated and partitioned between 120 mL of water and 150 mL of dichloromethane. The phases were separated and the organic phase was washed eight times with 3N aqueous sodium hydroxide, to extract excess p-toluenesulfonic acid, dried over magnesium sulphate, filtered and evaporated to dryness. The crude product was purified twice by silica gel chromatography (dichloromethane:methanol) to give 277 mg of pure desired product (95) and 714 mg of the product slightly contaminated with p-toluenesulfonic acid. Rt=2.35 min (Method 2). Detected mass: 253.1 (M+H+).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[C:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=O)[CH3:18].[Cl-].[Na+]>O1CCCC1>[C:20]1(/[C:17](/[CH3:18])=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(=O)c1ccccc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)c1ccccc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 128.9 %

Procedure:
A mixture of 10 g (0.25 mol) of sodium hydride and tetrahydrofuran is heated to 50° C., followed by dropwise addition over 30 minutes of a solution of 48 ml (0.19 mol) of ethyl diethylphosphonoacetate in 80 ml of tetrahydrofuran. A solution of 28.4 g (0.24 mol) of acetophenone in 60 ml of tetrahydrofuran is added dropwise at 0° C. and the mixture is stirred for 16 hours at 25° C. 250 ml of saturated sodium chloride solution are added at 0° C. and the resulting mixture is extracted with ether. The organic phase is dried (Na2SO4) and the solvents are evaporated off under reduced pressure. The 46.6 g of product obtained are purified by flash chromatography (90/10 cyclohexane/diisopropyl ether) (29 g; 63%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[Li]CCCC.CN([CH:27]=[O:28])C>C1COCC1>[CH:27]([C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1)=[O:28]
Reactant: O=C(Nc1ccc(Br)cc1)OCc1ccccc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccc(NC(=O)OCc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Benzyl 4-bromophenylcarbamate (20 g, 65.3 mmol) was taken in anhydrous THF (440 mL) and cooled to −78° C. To this solution, n-BuLi (55 mL, 137.2 mmol) was added dropwise and stirred for 0.5 h at −78° C. To this mixture, DMF (7.6 mL) was added dropwise and the reaction was allowed to warm to room temperature over a period of 5 h. The reaction mixture was quenched with 1 N HCl and then concentrated to remove THF, followed by addition of water. The mixture was extracted with three portions of ethyl acetate. The combined organic phases were washed with H2O, brine, and dried (MgSO4) filtered and concentrated. Trituration with hexanes and then with 20% ethyl acetate in hexanes afforded the title compound as a yellow solid.
Reaction SMILES: [N+](C1C=C[C:7]([C:8](Cl)=[O:9])=CC=1)([O-])=O.C(N)CCC.[CH2:18]([NH:22][C:23](=[O:33])[C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=1)[CH2:19][CH2:20][CH3:21]>>[CH2:18]([NH:22][C:23](=[O:33])[C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:8](=[O:9])[CH3:7])=[CH:26][CH:25]=1)[CH2:19][CH2:20][CH3:21]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CCCCNC(=O)c1ccc([N+](=O)[O-])cc1
Solvent: CCCCN
Product: CCCCNC(=O)c1ccc(NC(C)=O)cc1

Procedure:
The method of Example 3 is repeated using 4-nitrobenzoyl chloride and n-butyl amine in the amidation step. This yields N-n-butyl-4-nitrobenzamide (CPI1045).
Reaction SMILES: [I:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH2:16](O)[CH3:17]>>[CH2:16]([O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([I:1])[C:3]=1[CH3:11])[CH3:17]
Reactant: Cc1c(I)cccc1C(=O)O
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cccc(I)c1C
Temperature: 25 °C

Procedure:
To a stirred solution of 3-iodo-2-methyl-benzoic acid (30 g, 0.11 mol) in ethanol (425 mL) was added thionyl chloride (42 mL, 0.57 mol) at 0° C. The mixture was refluxed for 4.5 h before it was cooled to room temperature and concentrated in vacuo. The residue was partitioned between ethyl ether and saturated sodium bicarbonate solution. The organic layer was washed with brine, dried over anhydrous sodium sulfate and was concentrated in vacuo to give the title compound as a pale yellow oil (32.28 g): 1H NMR (CDCl3, 200 MHz): δ=7.94 (d, J=7.8 Hz, 1H), 7.70 (d, J=7.4 Hz, 1H), 6.90 (t, J=7.8 Hz, 1H), 4.35 (q, J=7.2 Hz, 2H), 2.65 (s, 3H), 1.38 (t, J=7.0 Hz, 3H).
Reaction SMILES: [NH2:1][CH:2]1[CH:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([F:31])=[C:7]([O:18][CH2:19][CH2:20][NH:21][S:22]([C:25]3[N:26]=[CH:27][N:28]([CH3:30])[CH:29]=3)(=[O:24])=[O:23])[CH:8]=2)[CH2:3]1.Br[CH2:33][CH2:34][CH2:35]Br.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O.ClCCl>[N:1]1([C@H:2]2[C@@H:10]([CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:9]3[C:4](=[CH:5][C:6]([F:31])=[C:7]([O:18][CH2:19][CH2:20][NH:21][S:22]([C:25]4[N:26]=[CH:27][N:28]([CH3:30])[CH:29]=4)(=[O:24])=[O:23])[CH:8]=3)[CH2:3]2)[CH2:35][CH2:34][CH2:33]1
Reactant: Cn1cnc(S(=O)(=O)NCCOc2cc3c(cc2F)CC(N)C3Cc2ccccc2)c1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: Cn1cnc(S(=O)(=O)NCCOc2cc3c(cc2F)C[C@@H](N2CCC2)[C@H]3Cc2ccccc2)c1
Reaction time: 0.33 h

Procedure:
To N-(2-(2-amino-3-benzyl-6-fluoro-2,3-dihydro-1H-inden-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide (17.9 mg, 0.040 mmol) was added 1,3-dibromopropane (4.90 μL, 0.048 mmol) and potassium carbonate (6.12 mg, 0.044 mmol) in water (1 mL)+1 drop acetonitrile were added. Microwave at 120° C. for 20 min. Evaporated acetonitrile, re-dissolved in dichloromethane and extracted with water and brine, dried over sodium bi-carbonate, filtered and evaporated to obtain the crude product, that was purified by flash silica gel chromatography on 4 g SiO2-cartridge using 10% methanol in dichloromethane to afford cis-N-(2-{[2-(azetidin-1-yl)-3-benzyl-6-fluoro-2,3-dihydro-1H-inden-5-yl]oxy}ethyl)-1-methyl-1H-imidazole-4-sulfonamide as a clear glass. m=4.0 mg (20%)
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([CH3:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=[N:48][C:43]2[CH:44]=C[CH:46]=[N:47][C:42]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CN1CC(N)C1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([CH3:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:48][CH:43]5[CH2:42][N:47]([CH3:46])[CH2:44]5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(F)C(=O)N2C
Agent: CN1CC(N)C1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NC2CN(C)C2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclopentyl-7-fluoro-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-methylazetidin-3-amine hydrochloride. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.44-1.65 (m, 5H) 1.65-1.88 (m, 4H) 1.88-2.01 (m, 1H) 2.92 (dd, J=4.7, 2.4 Hz, 3H) 3.28 (s, 3H) 3.95 (s, 3H) 4.01-4.25 (m, 2H) 4.31-4.55 (m, 2H) 4.64-4.89 (m, 2H) 7.44-7.63 (m, 2H) 8.21 (d, J=8.3 Hz, 1H) 8.18 (s, 1H) 8.97-9.09 (m, 1H) 9.78 (br. s., 1H). [M+H] calc'd for C26H34FN7O3, 512. found 512.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([OH:6])[CH3:5].Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl.CCN(CC)CC>C(Cl)Cl.O>[CH3:5][C:4]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:6][C:14](=[O:16])[NH:1][CH2:2][CH2:3]1
Reactant: CC(O)(CCN)c1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC1(c2ccccc2)CCNC(=O)O1
Reaction time: 1 h
Yield: 59.6 %

Procedure:
A solution of 4-amino-2-phenylbutan-2-ol (5.0 g, 0.03 mol) in CH2Cl2 (50 mL) was added triphosgene (2.97 g, 0.01 mol) and Et3N (9.09 g, 0.09 mol) at 0° C. After stirring for 1 h, the mixture was diluted with water and extracted with CH2Cl2. The organic layer was washed with brine, dried over Na2SO4, concentrated and purified by chromatography to afford 6-methyl-6-phenyl-1,3-oxazinan-2-one (1.14 g, 20%). 1H NMR (CDCl3): 1.60 (s, 3H), 1.80-2.00 (m, 1H), 2.30-2.40 (m, 1H), 3.15-3.21 (m, 1H), 6.00 (s, 1H), 7.30-7.45 (m, 5H), 8.90-9.01 (m, 1H).
Reaction SMILES: [C:1]1([C:7]2([C:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([NH:24][O:25]CC4C=CC=CC=4)=[O:23])=[CH:18][CH:17]=3)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd].CO>[C:1]1([C:7]2([C:13]([O:15][C:16]3[CH:17]=[CH:18][C:19]([C:22]([NH:24][OH:25])=[O:23])=[CH:20][CH:21]=3)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(NOCc1ccccc1)c1ccc(OC(=O)C2(c3ccccc3)CCCCC2)cc1
Agent: [Pd]
Solvent: CO
Product: O=C(NO)c1ccc(OC(=O)C2(c3ccccc3)CCCCC2)cc1
Reaction time: 0.75 h
Yield: 89.6 %

Procedure:
A mixture of 4-{[(benzyloxy)amino]carbonyl}phenyl 1-phenylcyclohexane-carboxylate (E22) (0.054 g, 0.125 mmol) and 5% palladium on activated carbon (0.038 g) in methanol (1 ml) was hydrogenated at room temperature for 45 minutes. The black suspension was filtered, the catalyst was washed with methanol (3×1 ml), and the filtrate was evaporated and dried in vacuum to give the title compound (0.038 g, 89%) as white crystals, m.p. 142-144° C. 1H NMR (DMSO-d6, HMDSO) δ: 1.16-1.94 (8H, m); 2.35-2.64 (2H, m, overlapped with a signal of DMSO); 7.02 (2H, d, J=8.7 Hz); 7.26-7.54 (5H, m); 7.77 (2H, d, J=8.7 Hz); 9.06 (1H, s); 11.24 (1H, br s). HPLC analysis on Symmetry C8 column: impurities 2% (column size 3.9×150 mm; mobile phase acetonitrile−0.1M phosphate buffer (pH 2.5), 50:50; detector UV 230 nm; sample concentration 0.5 mg/ml; flow rate 1.1 ml/min). Anal. Calcd for C20H21NO4*0.4H2O, %: C, 69.31; H, 6.34; N, 4.04. Found, %: C, 69.36; H, 6.24; N, 3.97.
Reaction SMILES: [NH3:1].[CH2:2]([O:4][C:5]([C:7]1[C:8]2[S:16][CH:15]=[C:14]([CH2:17][O:18][C:19]3[CH:24]=[C:23]([C:25]4[O:26][C:27]([C:30]5[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=5)=[N:28][N:29]=4)[CH:22]=[CH:21][C:20]=3[CH3:37])[C:9]=2[C:10](Cl)=[N:11][CH:12]=1)=[O:6])[CH3:3]>CC(O)C>[CH2:2]([O:4][C:5]([C:7]1[C:8]2[S:16][CH:15]=[C:14]([CH2:17][O:18][C:19]3[CH:24]=[C:23]([C:25]4[O:26][C:27]([C:30]5[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=5)=[N:28][N:29]=4)[CH:22]=[CH:21][C:20]=3[CH3:37])[C:9]=2[C:10]([NH2:1])=[N:11][CH:12]=1)=[O:6])[CH3:3]
Reactant: N
Reactant: CCOC(=O)c1cnc(Cl)c2c(COc3cc(-c4nnc(-c5ccc(Cl)cc5)o4)ccc3C)csc12
Solvent: CC(C)O
Product: CCOC(=O)c1cnc(N)c2c(COc3cc(-c4nnc(-c5ccc(Cl)cc5)o4)ccc3C)csc12
Temperature: 140 °C

Procedure:
Ammonia gas was bubbled into a solution of 4-chloro-3-{5-[5-(4-chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-2-methyl-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.30 g, 0.56 mmol) (from Example 46 supra) in 2-propanol (30 mL) for 20 minutes. The mixture was heated in a microwave reactor at 140° C. for 5.5 hours. The reaction mixture was concentrated. The residue washed with hot methanol, filtered and dried to give 4-amino-3-{5-[5-(4-chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-2-methyl-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester. (Yield 0.22 g, 76%).
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:11])([CH3:10])[CH3:9].Br[C:16]1[CH:17]=[CH:18][C:19]([F:31])=[C:20]([C:22]2[C:23]([C:29]#[N:30])=[CH:24][CH:25]=[C:26]([F:28])[CH:27]=2)[CH:21]=1>>[F:28][C:26]1[CH:27]=[C:22]([C:20]2[CH:21]=[C:16]([C:12]3[N:4]4[CH:5]=[CH:6][C:7]([C:8]([OH:11])([CH3:10])[CH3:9])=[C:2]([F:1])[C:3]4=[N:14][CH:13]=3)[CH:17]=[CH:18][C:19]=2[F:31])[C:23]([C:29]#[N:30])=[CH:24][CH:25]=1
Reactant: N#Cc1ccc(F)cc1-c1cc(Br)ccc1F
Reactant: CC(C)(O)c1ccn2ccnc2c1F
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4cc(F)ccc4C#N)c3)cnc2c1F
Yield: 43 %

Procedure:
2-(8-Fluoroimidazo[1,2-α]pyridin-7-yl)propan-2-ol was coupled to 5′-bromo-5,2′-difluorobiphenyl-2-carbonitrile (prepared as described in WO 02/38568) as described in Example 6 to give 5,2′-difluoro-5′-[8-fluoro-7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyridin-3-yl]biphenyl-2-carbonitrile as a white solid (90 mg, 43%): δH (360 MHz, d6-DMSO) 1.58 (6H, s), 7.21 (1H, m), 7.54-7.65 (2H, m), 7.77 (1H, dd, J 10 and 3), 7.84-7.89 (3H, m), 8.15 (1H, dd, J 9 and 6), 8.49 (1H, d, J 7); m/z (ES+) 408 [MH+].
Reaction SMILES: [OH:1][C:2]([CH3:31])([CH3:30])[CH2:3][C@@:4]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]2[CH2:16][CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]2)[CH2:6][CH2:5]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[OH:1][C:2]([CH3:31])([CH3:30])[CH2:3][C@@:4]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]2[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]2)[CH2:6][CH2:5]1
Reactant: CC(C)(O)C[C@]1(c2ccccc2)CCN([C@H]2CCCN(C(=O)OC(C)(C)C)C2)C(=O)O1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(O)C[C@]1(c2ccccc2)CCN([C@H]2CCCNC2)C(=O)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(S)-tert-butyl 3-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)piperidine-1-carboxylate (25 mg, 0.058 mmol) was dissolved in 20% TFA/CH2Cl2 (8 mL) solution and stirred 30 min at rt. The mixture was concentrated, redissolved in CH2Cl2 (25 mL), washed with satd aq NaHCO3 solution (10 mL), brine (8 mL), dried over Na2SO4. After filtration and concentration, the crude (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-piperidin-3-yl)-1,3-oxazinan-2-one as its TFA salt which was used without further purification. LC-MS Method 1 tR=0.86 min., m/z 333 (M+1).
Reaction SMILES: ClC1C(F)=CC(F)=C(C=1)C(NS(C)(=O)=O)=O.[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:32])=[C:22]([CH:31]=1)[C:23]([NH:25][S:26]([CH2:29][CH3:30])(=[O:28])=[O:27])=[O:24].C12(CO)CC3CC(CC(C3)C1)C2.[CH2:46]1[C:48]2([CH2:53][CH2:52][CH:51]([CH2:54][OH:55])[CH2:50][CH2:49]2)[CH2:47]1>>[Cl:17][C:18]1[C:19]([O:55][CH2:54][CH:51]2[CH2:52][CH2:53][C:48]3([CH2:46][CH2:47]3)[CH2:49][CH2:50]2)=[CH:20][C:21]([F:32])=[C:22]([CH:31]=1)[C:23]([NH:25][S:26]([CH2:29][CH3:30])(=[O:28])=[O:27])=[O:24]
Reactant: OCC1CCC2(CC1)CC2
Reactant: CCS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: OCC12CC3CC(CC(C3)C1)C2
Product: CCS(=O)(=O)NC(=O)c1cc(Cl)c(OCC2CCC3(CC2)CC3)cc1F

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with 5-chloro-N-(ethylsulfonyl)-2,4-difluorobenzamide and to replace adamantan-1-ylmethanol with spiro[2.5]octan-6-ylmethanol, the title compound was obtained as a colorless solid (0.378 g, 46%): 1H NMR (300 MHz, CDCl3) δ8.59-8.47 (m, 1H), 8.13-8.05 (m, 1H), 6.75-6.66 (m, 1H), 3.97-3.86 (m, 2H), 3.66-3.55 (m, 2H), 2.02-1.72 (m, 5H), 1.48-1.40 (m, 3H), 1.35-1.22 (m, 2H), 1.01-0.89 (m, 2H), 0.37-0.15 (m, 4H); MS (ES+) m/z 404.1, 406.1 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:18]=[CH:17][C:16]=1[OH:28].Br[CH:30]([Cl:33])[CH2:31][CH3:32].C(=O)([O-])[O-].[K+].[K+]>[Cu].CN(C=O)C>[Cl:33][CH2:30][CH2:31][CH2:32][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:18]=[CH:17][C:16]=1[OH:28]
Reactant: CCC(Cl)Br
Reactant: COC(=O)CCCc1ccc(O)c(-c2cc(CCCC(=O)OC)ccc2O)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCCc1ccc(O)c(-c2cc(CCCC(=O)OC)ccc2OCCCCl)c1

Procedure:
To 5 ml of a DMF solution containing 200 mg (0.5181 mmol) of 2,2'-dihydroxy-5,5'-bis (3-methoxycarbonylpropyl) biphenyl and 0.646 ml (5.181 mmol) of 1-bromo-chloropropane, there were added 85.8 mg (0.6217 mmol) of anhydrous potassium carbonate and a small amount of copper powder and the resulting mixture was agitated for 5 hours at room temperature. The reaction mixture was filtered by suction through Celite to remove the solid matter and the filtrate was washed with ethyl acetate. After the solvent in the filtrate was evaporated off under reduced pressure, the evaporated residue was dissolved in chloroform. This solution was washed with dilute hydrochloric sodium chloride solution in this sequence and was dried by adding anhydrous sodium sulfate. The residue obtained after the solvent had been evaporated off was purified by silica gel column chromatography (with 15 g of WAKO-gel C-200, eluent: toluene and toluene/ethyl acetate of 100/1) to obtain 206 mg (0.4454 mmol, 86%) of 2-(3-chloropropoxy-2' -hydroxy-5,5'-bis (3-methoxycarbonylpropyl) biphenyl as an oily product. 1H-NMR (CDCl3) δ (ppm): 1.8-2.2 (6H, m, 3CH2), 2.36 (4H, t, 2CH2), 2.5-2.8 (4H, m, 2CH2), 3.51 (2H, t, CH2), 3.66 (6H, s, 2CH3), 4.16 (2H, t, CH2), 6.05 (1H, s, OH), 6.8-7.3 (6H, m, arom-H) MS (FAB): 461 (M-H)-