Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][C:5]=1[NH:10][C:11](=[O:24])[CH2:12][C:13]1[C:18]([CH2:19][CH3:20])=[CH:17][C:16]([CH3:21])=[CH:15][C:14]=1[CH2:22][CH3:23].I[CH3:27].[H-].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][C:5]=1[N:10]([C:11](=[O:24])[CH2:12][C:13]1[C:18]([CH2:19][CH3:20])=[CH:17][C:16]([CH3:21])=[CH:15][C:14]=1[CH2:22][CH3:23])[CH3:27]
Reactant: CI
Reactant: CCc1cc(C)cc(CC)c1CC(=O)Nc1ncccc1C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1cc(C)cc(CC)c1CC(=O)N(C)c1ncccc1C(=O)OC
Reaction time: 1 h

Procedure:
To a solution of 2-[2-(2,6-diethyl-4-methyl-phenyl)-acetylamino]-nicotinic acid methyl ester (Example 1.2) (460 mg) in N,N-dimethylformamide (5 ml) was added iodomethane (0.42 ml) at between −5° C. and 0° C. under a nitrogen atmosphere. The reaction mixture was stirred for 2 minutes before the addition of sodium hydride (60 mg) (60% by weight dispersion in mineral oil) in one portion at between −5° C. and 0° C. The reaction mixture was stirred at between −5° C. and 0° C. for 1 hour, and then at ambient temperature for 2 hours. The reaction mixture was partitioned between diethylether and aqueous hydrochloric acid (2M). The phases were separated and the organic phase was washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: 10% ethyl acetate/dichloromethane) to give 2-{[2-(2,6-diethyl-4-methyl-phenyl)-acetyl]-methyl-amino}-nicotinic acid methyl ester as a light orange oil (370 mg). 1H-NMR (400 MHz, CDCl3): 8.76 (m, 1H), 8.36-8.38 (m, 1H), 7.44-7.47 (m, 1H), 6.83 (s, 2H), 3.97 (s, 3H), 3.33 (bs, 2H), 3.27 (bs, 3H), 2.47-2.57 (m, 4H), 2.26 (bs, 3H), 1.09-1.12 (m, 6H) ppm.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([C:5]1[CH:9]=[C:8]([CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[N:7]([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([O:21][C:20]([F:19])([F:31])[F:32])[CH:23]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1cc(C(C)(C)C)n[nH]1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCc1cc(C(C)(C)C)nn1-c1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 35.9 %

Procedure:
To a mixture tert-butyl (3-tert-butyl-1H-pyrazol-5-yl)methylcarbamate (501 mg, 1.98 mmol, 1 equiv.), 3-(trifluoromethoxy)-phenylboronic acid (814 mg, 3.96 mmol, 2 equiv.) and copper acetate (541 mg, 2.97 mmol, 1.5 equiv.) in dichloromethane (30 mL) was added pyridine (315 mg, 0.315 mL, 3.96 mmol, 2 equiv.) and the mixture was stirred in the presence of air for 2 d at room temperature. The reaction mixture was filtered over silica gel, the filter cake was washed with dichloromethane (250 mL) and the solvent of the filtrate was evaporated to give tert-butyl (3-tert-butyl-1-(3-(trifluoromethoxy)phenyl)-1H-pyrazol-5-yl)methylcarbamate (294 mg, 36%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:15]=C)[CH:12]=[C:11]([Cl:17])[C:10]=1[F:18])([CH3:4])([CH3:3])[CH3:2].O.C[N+]1([O-])CC[O:25]CC1.[O-]S([O-])(=S)=O.[Na+].[Na+]>CC(C)=O.[Os](=O)(=O)(=O)=O>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:15]=[O:25])[CH:12]=[C:11]([Cl:17])[C:10]=1[F:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=Cc1cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c1
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NCc1cc(C=O)cc(Cl)c1F
Reaction time: 1 h

Procedure:
To a solution of (3-chloro-2-fluoro-5-vinyl-benzyl)-carbamic acid tert-butyl ester (2.7 g, 9.5 mmol) in acetone (20 mL) was added N-methylmorpholine-N-oxide monohydrate (1.5 g, 11 mmol) and a solution of 4% aq. osmiumtetraoxide (3.7 mL, 0.5 mmol). The reaction was stirred for 1 h, saturated aqueous Na2S2O3-solution was added and stirring was continued for one hour. After extraction with EtOAc and removal of the solvent in vacuo, the residue was dissolved in acetone/water (3:1, 40 mL) and NalO4 (4.0 g, 19 mmol) was added. After stirring for 2 h at ambient temperature, the reaction mixture was filtered, washed with EtOAc, extracted with EtOAc, dried (Na2SO4) and the solvent was removed in vacuo to give the title compound which was used without further purification. tR (HPLC conditions c): 5.22 min.
Reaction SMILES: [CH2:1]([CH:6]([CH2:9][OH:10])[CH2:7][OH:8])[CH2:2][CH2:3][CH:4]=[CH2:5].[CH2:11]([O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)[CH2:12][CH:13]=[CH2:14]>S(=O)(=O)(O)O.C1(C)C=CC=CC=1>[CH2:11]([O:15][C:16]1[CH:17]=[CH:18][C:19]([C@H:20]2[O:10][CH2:9][C@H:6]([CH2:1][CH2:2][CH2:3][CH:4]=[CH2:5])[CH2:7][O:8]2)=[CH:22][CH:23]=1)[CH2:12][CH:13]=[CH2:14]
Reactant: C=CCCOc1ccc(C=O)cc1
Reactant: C=CCCCC(CO)CO
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: C=CCCC[C@H]1CO[C@H](c2ccc(OCCC=C)cc2)OC1
Reaction time: 2.5 h

Procedure:
A mixture of 3.6 g of 2-(4-pentenyl)-1,3-propanediol, 4,4 of p-(3-butenyl)oxybenzaldehyde, 75 ml of toluene and 3 drops of 10 percent sulphuric acid is heated to boiling for 2.5 hours, whereby about 50 ml of wet solvent are distilled off and are replaced by the dropwise addition of 50 ml of fresh toluene. Thereafter, the mixture is neutralized with 4 drops of triethylamine and, after cooling, is washed with 5 percent sodium hydrogen carbonate solution and water. The organic phase is dried over sodium sulphate and concentrated. Chromatographic separation of the residue on silica gel with hexane/ethyl acetate and recrystallization from hexane gives trans-2-[p-(3-butenyl)oxyphenyl]-5-(4-pentenyl)-m-dioxane with m.p. (C-I) 17.8° C. and cl.p. (N-I) 7.3° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:24])=[CH:5][C:6]([Cl:23])=[C:7]([C:9]2[NH:10][C:11](=[O:22])[N:12]([CH:14]3[CH2:19][CH2:18][C:17]([CH3:21])([CH3:20])[CH2:16][CH2:15]3)[N:13]=2)[CH:8]=1.[C:25](Cl)(=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27]>C1COCC1>[Cl:23][C:6]1[C:7]([C:9]2[NH:10][C:11](=[O:22])[N:12]([CH:14]3[CH2:19][CH2:18][C:17]([CH3:20])([CH3:21])[CH2:16][CH2:15]3)[N:13]=2)=[CH:8][C:3]([CH2:2][NH:1][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[C:4]([F:24])[CH:5]=1
Reactant: CC1(C)CCC(n2nc(-c3cc(CN)c(F)cc3Cl)[nH]c2=O)CC1
Reactant: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Product: CC1(C)CCC(n2nc(-c3cc(CNC(=O)C(C)(C)C)c(F)cc3Cl)[nH]c2=O)CC1

Procedure:
The title compound was prepared according to the procedure described in Example-108 by using 5-(5-(aminomethyl)-2-chloro-4-fluorophenyl)-2-(4,4-dimethylcyclohexyl)-2H-1,2,4-triazol-3(4H)-one (Intermediate-77, 0.200 g), pivaloyl chloride (0.5 mL), TEA (2.0 mL), dry THF (5 mL) to afford 0.033 g of the desired product. 1H NMR (300 MHz, CDCl3): δ 1.36 (s, 6H), 1.37 (s, 9H), 1.62 (m, 2H), 1.79 (m, 1H), 1.82 (m, 2H), 1.89 (m, 2H), 3.46-3.94 (m, 1H), 4.28 (s, 2H), 7.47 (d, J=7.9 Hz, 1H), 7.59 (d, J=9.72 Hz, 1H), 8.15 (m, 1H), 11.95 (s, 1H); MS (m/z): 436.55 (M+H)+.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[CH2:7]([O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[CH2:7]([O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([Cl:2])=[O:23])=[CH:20][CH:19]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCOc1ccc(C(=O)O)cc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Product: CCCCCCCCCCOc1ccc(C(=O)Cl)cc1
Temperature: 80 °C

Procedure:
Phosphorus pentachloride (0.80g, 0.0038 mol) was added to 4-n-decyloxybenzoic acid (1.0g, 0.0036 mol) and the mixture was allowed to react by heating at about 80° C. POCl3 and excess phosphorus pentachloride were completely removed by evaporation in vacuo to obtain 4-n-decyloxybenzoyl chloride. This chloride was dissolved in toluene (10 ml) and to the mixture were added R-(+)-α-(4-n-octylphenyl)ethyl alcohol (0.84g, 0.0036 mol) and pyridine (1 ml, a dehydrochlorination agent). The mixture was allowed to stand for 10 hours at room temperature, warmed at 60° C. and maintained as such for 3 hours, and then cooled. The resulting mixture was added to diluted hydrochloric acid and the resultant was extracted with ether. The ether layer was washed with an aqueous solution of NaHCO3 and then with water, and dried over Na2SO4. The ether was distilled off and the residue was purified by means of a column chromatography (solvent : chloroform) to obtain the objective compound of α-(4-n-octylphenyl)ethyl 4-n-decyloxybenzoate. The infrared spectrum of said compound is shown in FIG. 2. This compound did not show any liquid crystalline phase and it was a liquid at room temperature. The angle of rotation [α]25D of the compound was -26.0° C. (solvent : chloroform).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH:20]1[C:32]2[CH:31]([CH2:33][O:34][C:35](Cl)=[O:36])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[CH:23]=[CH:22][CH:21]=1.O1CCOCC1>O>[CH:20]1[C:32]2[CH:31]([CH2:33][O:34][C:35]([NH:1][C:2]3[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=3)=[O:36])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[CH:23]=[CH:22][CH:21]=1
Reactant: Nc1ccc(C(=O)O)c([N+](=O)[O-])c1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(Nc1ccc(C(=O)O)c([N+](=O)[O-])c1)OCC1c2ccccc2-c2ccccc21
Reaction time: 20 h
Yield: 67.2 %

Procedure:
To a solution of 11.4 g 4-amino-2-nitro-benzoic acid in 228 ml of water containing 6.63 g of sodium carbonate were added 17.0 g of 9-fluorenylmethyl-chloroformate and dropwise 20 ml of dioxane. After stirring for 20 hours under nitrogen, the mixture was filtered and the filtrate was washed five times with methyl-tert.-butylether. Residual methyl-tert.-butylether was removed from the aqueous phase by evaporation under vacuum. To the aqueous phase were added 456 g of 0° C. cold water. The mixture was adjusted to pH=3 by addition of 31 ml of 2M aqueous hydrochloric acid. The precipitate was sucked off, washed with 513 ml of water, dried at 40° C. in vacuum to give 17.0 g of 4-(((9H-fluorene-9-yl)methoxy)carbonylamino)-2-nitrobenzoic acid as off-white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:16][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CC(C)(C)N
Solvent: ClCCl
Product: CC(C)(C)NS(=O)(=O)c1ccc(Br)cc1
Yield: 26.3 %

Procedure:
According to general procedure C, 4-Bromobenzene sulfonyl chloride (0.40 g, 1.56 mmol) and tert-butylamine (0.41 mL, 3.90 mmol) were stirred together in dry dichloromethane (5 mL) for 16 hours. 4-bromo-N-(tert-butyl)benzenesulfonamide (0.12 g) was provided after purification. MS (ESI) m/z 292. HPLC purity 100.0% at 210-370 nm, 9.2 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)=[O:13])=[CH:7][C:3]=1[C:4](O)=O.[NH2:19][C:20]1[C:25]([NH2:26])=[CH:24][C:23]([CH3:27])=[CH:22][N:21]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)=[O:13])=[CH:7][C:3]=1[C:4]1[NH:26][C:25]2[C:20]([N:19]=1)=[N:21][CH:22]=[C:23]([CH3:27])[CH:24]=2
Reactant: Cc1cnc(N)c(N)c1
Reactant: O=C(Nc1ccc(Cl)c(C(=O)O)c1)c1ccco1
Product: Cc1cnc2nc(-c3cc(NC(=O)c4ccco4)ccc3Cl)[nH]c2c1
Temperature: 150 °C
Yield: 5.9 %

Procedure:
In a 40 mL vial was transferred 2-chloro-5-(furan-2-carboxamido)benzoic acid (I-1) (1 g, 3.75 mmol) in polyphosphoric acid (10 mL), and the 2,3-diamino-5-methyl-pyridine (578 mg, 4.69 mmols, 1.25 eq) was added. The dark brown reaction mixture was heated at 150° C. for 4 hrs. The reaction mixture was then quenched with solid sodium carbonate and extracted with ethyl acetate (3×50 mL). The organic phases were combined, dried over sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (0-100 EtOAC/Hex), afforded 80 mg (0.22 mmols, 6%) of the title compound (Example 1). 1H NMR (400 MHz, MeOD) δ 8.36-8.25 (m, 1H), 8.20 (s, 1H), 8.04-7.94 (m, 1H), 7.93-7.83 (m, 1H), 7.77 (s, 1H), 7.61 (d, J=8.8 Hz, 1H), 7.31 (d, J=3.5 Hz, 1H), 6.67 (dd, J=1.7, 3.5 Hz, 1H), 2.53 (s, 3H). LCMS M/Z=353.0 (M+1). RT=1.39: Method B.
Reaction SMILES: O=O.[CH:3]1([OH:11])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1>[Pt].O>[C:3]1(=[O:11])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: OC1CCCCCCC1
Agent: [Pt]
Agent: O=O
Solvent: O
Product: O=C1CCCCCCC1
Yield: 92.7 %

Procedure:
In an ambient pressure oxygen atmosphere, 25 mg of cyclooctanol and 137 mg of the platinum catalyst obtained in Example 1 were agitated for sixty hours at 60° C. in 2 ml of water. The reaction mixture was subsequently extracted using ethyl acetate, and the organic layer was dried using magnesium sulfate, filtered and concentrated to obtain 22.8 mg (93% yield) of cyclooctanone.
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:13](O)=[O:14])=[CH:12][C:7]=2[N:6]=[C:5]1[NH:16][C:17]1[S:18][C:19]2[CH:25]=[C:24]([O:26][C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:22][C:20]=2[N:21]=1)([CH3:3])[CH3:2].[CH2:31]([NH2:33])[CH3:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:31]([NH:33][C:13]([C:11]1[CH:10]=[CH:9][C:8]2[N:4]([CH:1]([CH3:2])[CH3:3])[C:5]([NH:16][C:17]3[S:18][C:19]4[CH:25]=[C:24]([O:26][C:27]([F:28])([F:30])[F:29])[CH:23]=[CH:22][C:20]=4[N:21]=3)=[N:6][C:7]=2[CH:12]=1)=[O:14])[CH3:32]
Reactant: CCN
Reactant: CC(C)n1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C(C)C

Procedure:
1-Isopropyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid ethylamide (50.0 mg) was prepared by following General Procedure F starting from 1-isopropyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzo-imidazole-5-carboxylic acid (100.0 mg), ethylamine (2.0 M solution in THF, 0.5 mL), HBTU (130.0 mg) and DIEA (0.1 mL) in DMF (1.0 mL). LCMS: m/z 465; and 1H NMR (DMSO-d6, 400 MHz): δ 8.43 (1H, m), 8.11 (1H, m), 7.92 (1H, m), 7.71-7.67 (2H, m), 7.36-7.35 (1H, m), 5.15-5.12 (1H, m), 3.32 (2H, m), 1.58-1.57 (6H, d), 1.16-1.13 (3H, t), 2 —NH proton signals were not observed.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[N:12]1([S:18](Cl)(=[O:20])=[O:19])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([S:18]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)(=[O:20])=[O:19])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=S(=O)(Cl)N1CCOCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C1CCN(S(=O)(=O)N2CCOCC2)CC1
Yield: 103.4 %

Procedure:
Piperidine-4-carboxylic acid ethyl ester (0.943 g) dissolved in methylene chloride (60 ml) under an argon atmosphere was treated at RT, first with 4-dimethylaminopyridine (1.465 g) then dropwise with morpholine-4-sulfonyl chloride (1.136 g) and the reaction mixture was stirred for 12 h at RT to complete the reaction. The reaction mixture was then partitioned between methylene chloride and aqueous 1N HCL, the layers were separated and the organic layer washed with 2M aqueous KHCO3 then dried over Na2SO4. The solvent was evaporated off, to give 1-(morpholine-4-sulfonyl)-piperidine-4-carboxylic acid ethyl ester (1.9 g) as a light yellow solid which was directly used in the next step.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:25][C:26](O)=[O:27])[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.CC(C)(C)C(Cl)=O.[CH2:43]([C@@H:50]1[CH2:54][O:53][C:52](=[O:55])[NH:51]1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.[Li]CCCC>C1COCC1>[CH2:43]([CH:50]1[CH2:54][O:53][C:52](=[O:55])[N:51]1[C:26](=[O:27])[CH2:25][C:11]1[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:17][CH:16]=2)[CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=1)[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: O=C(O)Cc1cc(OCc2ccccc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Agent: CC(C)(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: O=C(Cc1cc(OCc2ccccc2)cc(-c2ccc(C(F)(F)F)cc2)c1)N1C(=O)OCC1Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a mechanically stirred solution of (5-benzyloxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid from the previous step (20 g, 52 mmol) in THF (104 mL) at −78° C. was added N-methyl morpholine (NMM) (6.3 mL, 57 mmol) and trimethylacetyl chloride (7.0 mL, 57 mmol) maintaining the internal temperature below −70° C. This mixture was stirred at −78° C. for 15 minutes and at 0° C. for 1 h. The white solid was filtered off and the filtrate containing the mixed anhydride cooled back to −78° C. for the subsequent reaction. In a separate flask, to a solution of (R)-(+)-4-benzyl-2-oxazolidinone (9.6 g, 54.4 mmol) in THF (109 mL) at −78° C. was added nBuLi (1.6M in hexanes, 34 mL, 54.4 mol), drop-wise, maintaining the internal temperature below −70° C. and stirred for 45 min. This metalated chiral auxiliary was cannulated to add to a reaction flask containing the anhydride solution at −78° C. The reaction was stirred and allowed to warm to 0° C. over 1.5 h. The resulting mixture was stirred further at 0° C. for 30 minute and quenched by adding excess saturated aqueous NH4Cl solution. The solution was diluted with EtOAc (200 mL) and the organic phase was washed with saturated aqueous NaHCO3 solution (3×100 mL) and brine (2×100 mL). The solution was dried over MgSO4 and the solvent was removed in vacuo. The crude material was purified by ISCO silica gel column chromatography to yield 20.3 g (72%) of 4-benzyl-3-[2-(5-benzyloxy-4′-trifluoromethyl-biphenyl-3-yl)-acetyl]-oxazolidin-2-one as a white solid.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:2][CH:3]([CH3:5])[CH3:4].[P:13]12(SP3(SP(SP(S3)(S1)=S)(=S)[S:15]2)=S)=[S:14]>CCCCCC>[CH2:1]([O:6][C:7]1[CH:8]=[CH:9][C:10]([P:13](=[S:15])=[S:14])=[CH:11][CH:12]=1)[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)CCOc1ccccc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: CCCCCC
Product: CC(C)CCOc1ccc(P(=S)=S)cc1
Reaction time: 48 h

Procedure:
iso-Pentyloxybenzene (Ib) and P4S10 (in a molar ratio of 10:1) were stirred for six hours at 150° C. under anhydrous conditions. The mixture was cooled, hexane was added, and the reaction flask was left for two days at 5° C. The resulting precipitate was recovered by filtration, washed with anhydrous hexane and dried. The yield of product was 27% of theory; after recrystallization from chloroform/petroleum ether it melted at 150°-2° C. Its solubility in tetrahydrofuran was found to be 5 gms/100 ml at room temperature.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=4)[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH:29]1[CH2:34][CH2:33][CH2:32][C@@H:31]([NH:35]C(=O)OC(C)(C)C)[CH2:30]1>>[CH3:22][N:20]1[CH:21]=[C:17]([C:14]2[CH:15]=[C:16]3[C:8]([C:6]4[N:7]=[C:2]([N:29]5[CH2:34][CH2:33][CH2:32][C@@H:31]([NH2:35])[CH2:30]5)[CH:3]=[CH:4][CH:5]=4)=[N:9][NH:10][C:11]3=[CH:12][N:13]=2)[CH:18]=[N:19]1
Reactant: Cn1cc(-c2cc3c(-c4cccc(F)n4)nn(C4CCCCO4)c3cn2)cn1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Product: Cn1cc(-c2cc3c(-c4cccc(N5CCC[C@@H](N)C5)n4)n[nH]c3cn2)cn1
Yield: 59.5 %

Procedure:
Following the procedures as described in Example 189, 3-(6-fluoropyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine and (R)-tert-butyl piperidin-3-ylcarbamate were reacted and the product was deprotected to give 177 as a white solid (59.5% over two steps). 1H NMR (400 MHz, DMSO) δ 9.03 (d, J=1.1 Hz, 1H), 8.60 (s, 1H), 8.34 (s, 1H), 7.95 (s, 1H), 7.69-7.56 (m, 1H), 7.42 (d, J=7.3 Hz, 1H), 6.83 (d, J=8.6 Hz, 1H), 4.47 (d, J=9.0 Hz, 1H), 4.22 (d, J=12.8 Hz, 1H), 3.89 (s, 3H), 3.04-2.90 (m, 1H), 2.81-2.66 (m, 2H), 2.01-1.92 (m, 2H), 1.88-1.74 (m, 2H), 1.56-1.52 (m, 2H), 1.37-1.27 (m, 1H). LC/MS: m/z 375.1 [M+1].
Reaction SMILES: [C:1]([CH:4]1[C:9](=[O:10])[CH2:8][CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[CH2:6][C:5]1=O)(=O)[CH3:2].[NH2:19][C:20]1[N:29]=C(C)C2C(=O)CC(C3C=CC(F)=CC=3)CC=2[N:21]=1>>[NH2:29][C:20]1[N:21]=[C:1]([CH3:2])[C:4]2[C:9](=[O:10])[CH2:8][CH:7]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=3)[CH2:6][C:5]=2[N:19]=1
Reactant: Cc1nc(N)nc2c1C(=O)CC(c1ccc(F)cc1)C2
Reactant: CC(=O)C1C(=O)CC(c2cccc(F)c2)CC1=O
Product: Cc1nc(N)nc2c1C(=O)CC(c1cccc(F)c1)C2

Procedure:
The title compound was prepared from 2-acetyl-5-(3-fluoro-phenyl)-cyclohexane-1,3-dione (100 mg, 0.42 mmol), from stage 1, following the procedure describing the synthesis of 2-amino-7-(4-fluoro-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one (example 3/a stage 2/3) except that the title compound was further purified by recrystallisation in methanol.
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:11]1[NH:15][CH:14]=[N:13][CH:12]=1.[H-].[Na+].[CH3:18][Si:19]([CH2:22][CH2:23][O:24][CH2:25]Cl)([CH3:21])[CH3:20]>>[CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:11]1[N:15]([CH2:25][O:24][CH2:23][CH2:22][Si:19]([CH3:21])([CH3:20])[CH3:18])[CH:14]=[N:13][CH:12]=1
Reactant: c1ncc(-c2ccc3c(c2)CCCC3)[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Product: C[Si](C)(C)CCOCn1cncc1-c1ccc2c(c1)CCCC2
Yield: 50.1 %

Procedure:
Reaction of 5-(5,6,7,8-tetrahydro-naphthalen-2-yl)-1H-imidazole (387 mg, 1.95 mmol), NaH (60%, 76 mg, 1.89 mmol), and SEMCl (474 uL, 2.28 mmol) followed by column chromatography on silica gel (hexane/EtOAC 3:2) gave the title compound (321 mg, 52%) as a brown oil. 1H NMR (300 MHz, CDCl3) δ 0.00 (s, 9H), 0.92 (t, 2H, J=9.0 Hz), 1.80–1.83 (m, 4H), 2.77–2.81 (m, 4H), 3.51 (t, 2H, J=9.0 Hz), 5.28 (s, 2H), 7.08 (d, 1H, J=9.0 Hz), 7.29 (s, 1H), 7.48 (d, 1H, J=6.0 Hz), 7.54 (s, 1H), 7.61 (s, 1H).