Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]([CH3:23])[CH2:3][C:4]1[C:5](=[O:22])[N:6]([CH3:21])[CH2:7][CH2:8][CH:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=3)[C:10]=12.[CH:24]([NH2:27])([CH3:26])[CH3:25].Cl.C([BH3-])#N.[Na+]>CO>[CH:24]([NH:27][CH:2]([CH3:23])[CH2:3][C:4]1[C:5](=[O:22])[N:6]([CH3:21])[CH2:7][CH2:8][CH:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=3)[C:10]=12)([CH3:26])[CH3:25]
Reactant: COc1ccc2c(c1)CCC1CCN(C)C(=O)C(CC(C)=O)=C21
Reactant: CC(C)N
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(c1)CCC1CCN(C)C(=O)C(CC(C)NC(C)C)=C21

Procedure:
The mixture of 4.7 g of 1-(2-oxopropyl)-9-methoxy-3-methyl-3,4,5,5a,6,7-hexahydro-2H-naphth[1,2-d]azepin-2-one, 8.88 ml of isopropylamine, 3.45 ml of 5 N methanolic hydrochloric acid, 1.02 g of sodium cyanoborohydride and 75 ml of methanol is stirred and refluxed overnight. An additional 1.02 g of sodium cyanoborohydride is added and refluxing is continued for another day. The mixture is cooled, acidified to pH=1 with concentrated hydrochloric acid, the methanol is evaporated and the solution washed with diethyl ether. It is rendered basic to pH=10-11 with 3 N aqueous sodium hydroxide, extracted with diethyl ether, the extract dried and evaporated. The residue is recrystallized from hexane, to yield the 1-(2-isopropylaminopropyl)-9-methoxy-3-methyl-3,4,5,5a,6,7-hexahydro-2H-naphth[1,2-d]azepin-2-one melting at 118°-120°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[N+:23]([C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30])([O-:25])=[O:24].C([O-])([O-])=O.[Na+].[Na+]>O1CCCC1>[N+:23]([C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29]([NH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH:5]=[CH:6][CH:7]=1)=[O:30])([O-:25])=[O:24]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)Nc1cccc(N)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccc(NC(=O)c2cccc([N+](=O)[O-])c2)c1
Temperature: 25 °C
Yield: 99.1 %

Procedure:
To a stirring solution of tert-butyl (3-aminophenyl)carbamate (2.00 g, 9.6 mmol) and triethylamine (1.40 mL, 10 mol) in dry tetrahydrofuran (27.3 mL) at 0° C. was slowly added a solution of 3-nitrobenzoyl chloride (1.87 g, 10.1 mmol) in tetrahydrofuran (7.8 mL). The resulting mixture was slowly warmed up to rt and stirred for one additional hour at rt. The reaction mixture was treated with Na2CO3 (aq). The aqueous layer was extracted with EtOAc three times. The combined organic layers were dried, filtered and concentrated to give the desired product as a white powder (3.4 g, 99%). LCMS for C18H19N3O5 (M-tBu+H)+: m/z=302.0. 1H NMR (400 MHz, CD3OD): δ 8.79 (t, J=2.0 Hz, 1H), 8.43 (ddd, J=8.0, 2.0, 1.2 Hz, 1H), 8.31 (ddd, J=6.4, 2.4, 1.2 Hz, 1H), 7.87 (t, J=2.1 Hz, 1H), 7.77 (t, J=8.0 Hz, 1H), 7.60 (ddd, J=8.0, 4.0, 2.4, 1H), 7.25 (t, J=8.0 Hz, 1H), 7.19 (d, J=1.2 Hz, 1H), 1.52 (s, 9H).
Reaction SMILES: [Li+].[OH-].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:35]=[CH:34][C:17]2[CH2:18][CH:19]([CH2:29][C:30]([O:32]C)=[O:31])[C:20](=[O:28])[N:21]([CH2:23][C:24]([F:27])([F:26])[F:25])[CH2:22][C:16]=2[CH:15]=1>C1COCC1.O>[O:28]=[C:20]1[CH:19]([CH2:29][C:30]([OH:32])=[O:31])[CH2:18][C:17]2[CH:34]=[CH:35][C:14]([O:13][CH2:12][CH2:11][CH2:10][NH:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=3)=[CH:15][C:16]=2[CH2:22][N:21]1[CH2:23][C:24]([F:27])([F:25])[F:26]
Reactant: COC(=O)CC1Cc2ccc(OCCCNc3ccccn3)cc2CN(CC(F)(F)F)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CC1Cc2ccc(OCCCNc3ccccn3)cc2CN(CC(F)(F)F)C1=O
Reaction time: 0.17 h
Yield: 84.7 %

Procedure:
1.0 N LiOH (0.44 mL, 0.44 mmole) was added to a solution of methyl (±)-8-[3-(2-pyridylamino)-1-propyloxy]-3-oxo-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate (159.5 mg, 0.34 mmole) in THF (1.7 mL) and H2O (1.3 mL) at RT. The yellow, cloudy reaction became homogeneous within 10 min. After 24 hr, the reaction was concentrated to dryness and the yellow residue was dissolved in H2O (4 mL). The solution was filtered, then was carefully neutralized (pH≈7) with 1.0 N HCl. The precipitate was collected, washed with plenty of H2O, and dried in high vacuum at 40-45° C. to afford the title compound (130.0 mg, 83%) as an off-white solid: HPLC (PRP-1®, 25% CH3CN/H2O containing 0.1% TFA) k′=3.1; 1H NMR (400 MHz, DMSO-d6) δ 7.91-8.00 (m, 1 H), 7.28-7.40 (m, 1 H), 7.02 (d, J=9.2 Hz, 1 H), 6.76-6.87 (m, 2 H), 6.51-6.02 (m, 1 H), 6.39-6.50 (m, 2 H), 5.30 (d, J=16.6 Hz, 1 H), 4.10-4.30 (m, 3 H), 4.02(t, J=6.3 Hz, 1 H), 3.70-3.82 (m, 1 H), 3.20-3.45 (m, 2 H, partially obscured by residual solvent signal), 2.99 (dd, 1 H), 2.59-2.74 (m, 2 H), 2.39 (dd, J=16.9, 4.8 Hz, 1 H), 1.90-2.03 (m, 2 H); MS (ES) m/e 452 (M+H)+. Anal. Calcd for C22H24F3N3O4.0.5 H2O: C, 57.39; H. 5.47; N, 9.13. Found: C, 57.39; H, 5.18; N, 9.00.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]1[CH:13]=[N:14][N:15]3[C:20]([N:21]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])=[CH:19][C:18]([CH:38]=C)=[N:17][C:16]=13)=[CH:5]2.CC([OH:44])(C)C.N1C(C)=CC=CC=1C.[O-]S([O-])(=S)=O.[Na+].[Na+]>O=[Os](=O)(=O)=O.O.C(Cl)Cl>[CH3:27][Si:26]([CH3:29])([CH3:28])[CH2:25][CH2:24][O:23][CH2:22][N:21]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:35])([CH3:36])[CH3:37])[C:20]1[N:15]2[N:14]=[CH:13][C:12]([C:6]3[CH:7]=[N:8][C:9]4[C:4]([CH:5]=3)=[CH:3][C:2]([F:1])=[CH:11][CH:10]=4)=[C:16]2[N:17]=[C:18]([CH:38]=[O:44])[CH:19]=1
Reactant: CC(C)(C)O
Reactant: C=Cc1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n2ncc(-c3cnc4ccc(F)cc4c3)c2n1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Solvent: O
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C=O)nc2c(-c3cnc4ccc(F)cc4c3)cnn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 2200 %

Procedure:
To 3-(6-fluoroquinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)-5-vinylpyrazolo[1,5-a]pyrimidin-7-amine (1.3 g, 2.2 mmol) in 1,4-doixane (20 mL) was added 2.5 wt % OsO4 in t-BuOH (4.9 g, 0.1 mmol), 2,6-lutidine (1.1 mL, 9.0 mmol) and H2O (3 mL) and the resulting mixture was stirred at room temperature for 1 hour. NaIO4 (1.9 g, 8.9 mmol) was then added and stirring at room temperature was continued for 16 hours. LC/MS analysis at this time showed no starting material or diol intermediate present and confirmed full conversion to product. Saturated Na2S2O3 solution (30 mL) was added and the mixture stirred for 10 minutes. The reaction was transferred to a separatory funnel with CH2Cl2 (30 mL) and H2O (30 mL) and organics were extracted with CH2Cl2 (4×40 mL), dried (Na2SO4) and concentrated in vacuo to give 7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-fluoroquinolin-3-yl)pyrazolo[1,5-a]pyrimidine-5-carbaldehyde as a brown solid (1.3 g, 2.2 mmol, 100%). LC/MS: 2.92 mins, m/z=568.3 (MH+).
Reaction SMILES: O.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[CH2:28][C:29]([NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:30].O>CN(C)C=O>[NH:31]([C:29]([CH2:28][NH:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH2:5][CH2:4]1)=[O:30])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: NC1CCN(CCc2c[nH]c3ccccc23)CC1
Reactant: O=C(CCl)Nc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(CNC1CCN(CCc2c[nH]c3ccccc23)CC1)Nc1ccccc1
Reaction time: 24 h
Yield: 109.2 %

Procedure:
3-[2-(4-Amino-1-piperidyl) ethyl]indole hydrate (1.31g.) was dissolved in dimethylformamide (15 ml) containing triethylamine (2 ml) and chloroacetanilide (0.85g) added. The mixture was stirred for 24 hours, poured into water (100 ml) and extracted with chloroform (2 × 50 ml). The combined chloroform layers were washed with water, dried (MgSO4), filtered and evaporated to give the title compound as an amber oil (2.06 g). This was converted to the hydrochloride (1.29 g), m.p. 240.7°, on addition of EtOH-HC1 and Et2O.
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[OH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:32]2[CH2:31][CH2:30][N:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[OH:22])[CH2:34][CH2:33]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: Oc1ccccc1N1CCNCC1
Product: CCc1cc(NC(=O)N2CCN(c3ccccc3O)CC2)c(OC)nc1C
Yield: 59 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2-hydroxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[C:7]1(B(O)O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.I[C:17]1[CH:39]=[CH:38][C:20]([CH2:21][N:22]([S:34]([CH3:37])(=[O:36])=[O:35])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:19][CH:18]=1>C1(C)C=CC=CC=1.CCO.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:17]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:39]=[CH:38][C:20]([CH2:21][N:22]([S:34]([CH3:37])(=[O:36])=[O:35])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:19][CH:18]=1
Reactant: CCOC(=O)CCCCCCN(Cc1ccc(I)cc1)S(C)(=O)=O
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)CCCCCCN(Cc1ccc(-c2ccccc2)cc1)S(C)(=O)=O
Yield: 80.2 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (102 mg, 0.09 mmol), aqueous Na2CO3 (0.9 mL, 1M), and phenyl boronic acid (216 mg, 1.77 mmol) were added to a solution of ethyl 7-{[4-iodobenzyl]-methanesulfonyl-amino}-heptanoate (415 mg, 0.89 mmol) in toluene (37 mL) and EtOH (7 mL). The reaction mixture was heated at reflux for 3 h. The solution was diluted with EtOAc and was washed with water (2×) followed by brine (1×). The organic solution was dried over MgSO4, filtered, and concentrated in vacuo. Purification by radial chromatography (10% EtOAc/hexanes to 30% EtOAC/hexanes) provided the title compound of Step A (298 mg). 1H NMR (400 MHz, CDCl3) δ7.62-7.30 (m, 4H), 4.41 (s, 2H), 4.12 (q, 2H), 3.20 (t, 2H), 2.82 (s, 3H), 2.23 (t, 3H), 1.58 (m, 4H), 1.35 (m, 7H); MS 418.3 (M+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([OH:11])[CH:3]=1.IC.[C:14](=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([O:11][CH3:14])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1ccc(F)cc1O
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: COc1cc(F)ccc1C(C)=O
Temperature: 75 °C
Yield: 103.1 %

Procedure:
1-(4-fluoro-2-hydroxyphenyl)ethanone (12.0 g, 77.9 mmol), iodomethane (6.38 ml, 101 mmol), potassiumcarbonate (14.0 g, 101 mmol) were heated at 75° C. in ACN (200 ml) for 8 h. The reaction mixture was brought to ambient temperature, filtered and then evaporated under reduced pressure to dryness. New ACN (150 ml), iodomethane (2 ml, 32 mmol) and potassiumcarbonate (4 g, 29 mmol) was added. The reaction mixture was heated at 75° C. for 3 h. The reaction mixture was concentrated, EtOAc (100 ml) was added and the mixture was filtered and evaporated to give the title product (13.5 g, 100%). MS m/z (rel. intensity, 70 eV) 168 (M+, 11), 153 (bp), 110 (23), 95 (21), 82 (12).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[C:16]1([C:22]2[CH:23]=[CH:24][C:25]([NH2:28])=[N:26][CH:27]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:28][C:25]2[CH:24]=[CH:23][C:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:27][N:26]=2)=[O:11])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13]
Reactant: Nc1ccc(-c2ccccc2)cn1
Reactant: O=C(O)Cc1ccc(Br)c(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Cc1ccc(Br)c(C(F)(F)F)c1)Nc1ccc(-c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 2-(4-bromo-3-(trifluoromethyl)phenyl)acetic acid 46-6 (71 mg, 0.25 mmol), 5-phenylpyridin-2-amine (64 mg, 0.38 mmol) and HATU (148 mg, 0.38 mmol) in DMF (1 mL) was added DIEA (125 μL, 0.75 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate (50 mL), washed with saturated NaHCO3 aqueous solution, water and brine, dried over Na2SO4, and concentrated by rotary evaporation. The crude product was purified by silica gel flash chromatography, eluted with 40% ethyl acetate in hexane to give 2-(4-bromo-3-(trifluoromethyl)phenyl)-N-(5-phenylpyridin-2-yl)acetamide 46-7 as pale yellow solid. MS m/z 435.2 (M+1)
Reaction SMILES: [H-].[Na+].[CH3:3][OH:4].F[C:6]1[C:14]2[O:13][C:12]([C:15]3[C:16]([NH2:21])=[N:17][CH:18]=[CH:19][CH:20]=3)=[N:11][C:10]=2[CH:9]=[CH:8][CH:7]=1>CN1C(=O)CCC1>[CH3:3][O:4][C:6]1[C:14]2[O:13][C:12]([C:15]3[C:16]([NH2:21])=[N:17][CH:18]=[CH:19][CH:20]=3)=[N:11][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: CO
Reactant: Nc1ncccc1-c1nc2cccc(F)c2o1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COc1cccc2nc(-c3cccnc3N)oc12
Temperature: 70 °C
Reaction time: 16 h

Procedure:
Sodium hydride (3.76 g) was added portionwise to a stirred solution of methanol (3.82 ml) dissolved in NMP (100 ml) under nitrogen. 3-(7-fluoro-1,3-benzoxazol-2-yl)pyridin-2-amine (5.39 g) was added to the stirred mixture. The resulting suspension was stirred at 70° C. for 16 hours. After dilution with water (220 ml) the mixture was extracted with ethyl acetate (3×150 ml. The organic phases were washed with brine, dried over magnesium sulphate and concentrated. The crude product was purified by flash chromatography on silica gel eluting with 10 to 50% ethyl acetate in dichloromethane. The solvent was evaporated to dryness to afford 3-(7-methoxy-1,3-benzoxazol-2-yl)pyridin-2-amine (2.13 g) as a solid. NMR Spectrum: (DMSOd6) 4.01 (s, 3H), 6.77 (dd, 1H), 7.08 (d, 1H), 7.34 (dd, 1H), 7.40 (dd, 1H), 7.64 (bs, 1H), 8.23 (dd, 1H), 8.27 (dd, 1H); Mass spectrum: M+H+ 242.
Reaction SMILES: F.N1C=CC=CC=1.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH:16]1[CH2:26][CH2:25][CH:24]([O:27][Si](C(C)C)(C(C)C)C(C)C)[C:19]2=[N:20][CH:21]=[CH:22][CH:23]=[C:18]2[CH:17]1[F:38]>O1CCCC1>[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH:16]1[CH2:26][CH2:25][CH:24]([OH:27])[C:19]2=[N:20][CH:21]=[CH:22][CH:23]=[C:18]2[CH:17]1[F:38]
Reactant: CC(C)[Si](OC1CCC(c2cccc(F)c2F)C(F)c2cccnc21)(C(C)C)C(C)C
Agent: F
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: OC1CCC(c2cccc(F)c2F)C(F)c2cccnc21
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Pyridine hydrofluoride (0.037 g, 0.38 mmol) was added dropwise to a solution of (5R,6S,9R and 5S,6R,9S)-6-(2,3-difluorophenyl)-5-fluoro-9-((triisopropylsilyl)oxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine (0.155 g, 0.345 mmol) in tetrahydrofuran (3 mL) cooled to 0° C., and the mixture was stirred for 3 h. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate (3×). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash chromatography on silica gel, eluting with 55% dichloromethane in petroleum ether to give the title compound as a racemic mixture. MS: m/z=294.2 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:10][C:9](=[CH2:11])[CH2:8][C@@H:7]1[C:12]([O:14]CC)=[O:13])=[O:5])[CH3:2].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Na+].[Cl-].[OH-].[Na+]>>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:10][C:9](=[CH2:11])[CH2:8][C@@H:7]1[C:12]([OH:14])=[O:13])=[O:5])[CH3:2]
Reactant: C=C1C[C@H](C(=O)OCC)[C@@H](C(=O)OCC)C1
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Product: C=C1C[C@H](C(=O)O)[C@@H](C(=O)OCC)C1
Temperature: 25 °C
Yield: 86 %

Procedure:
An emulsion of 1.7 g 41a in an aqueous buffer (potassium phosphate 3 mM, NaCl 0.1 M) was adjusted to pH 7.5. Under stirring at room temperature the hydrolysis was performed with 15 mg lipase OF from Candida rugosa under pH control (pH-static, 1M NaOH). After consumption of 6.5 ml 1M NaOH solution and 7 h the reaction mixture was washed with 50 ml t-butyl methyl ether. The aqueous layer was adjusted to pH 2.0 (conc. HCl) and was extracted with 85 ml ethyl acetate. Drying over sodium sulfate, evaporation and drying overnight on a high vacuum yielded 1.28 g of the title compound 41b. MS: 197.2 (M−H)−; chiral GC: ee 99.4%.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][OH:4].[H][H]>>[CH:8]1([CH2:7][CH2:6][CH2:5][CH:2]([CH3:1])[CH2:3][OH:4])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CC(CO)CCCc1ccccc1
Reactant: [H][H]
Product: CC(CO)CCCC1CCCCC1
Reaction time: 15.5 h
Yield: 97.3 %

Procedure:
3415 g of 2-Methyl-5-phenyl-pentanol (Rosaphen™, supplier: Symrise) combined with 33 g Ru on activated carbon (Ru content: 5 wt. %) were hydrogenated at a hydrogen pressure of 20 bar and at a temperature of 100° C. After 14-17 hours the reaction was finished. The catalyst was removed and the product distilled. 3437 g (content: 99.9%) of 5-cyclohexyl-2-methyl-pentanol were obtained. Yield: 97% of theoretical.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9]([Mg]Cl)([CH3:12])([CH3:11])[CH3:10].C(OCC)C.[Cl-].[Na+]>C1COCC1.[Cu](I)I>[C:9]([C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: Clc1cccnc1Cl
Reactant: CC(C)(C)[Mg]Cl
Agent: I[Cu]I
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)c1ncccc1Cl
Temperature: 0 °C
Yield: 9 %

Procedure:
2,3-Dichloropyridine (1.0 g, 0.0068 mol) and copper iodide (0.065 g, 0.341 mmol) were dissolved in THF (6 mL). The mixture was degassed three times then cooled to 0° C. with an ice bath. Then tert-butyl(chloro)magnesium in diethylether (5.10 mL, 0.0102 mol) was added drop wise to the reaction mixture under nitrogen keeping the temperature at 0° C. with an ice bath. When the addition was complete, it was left to warm up to room temperature for 16 hours. A saturated aqueous solution of sodium chloride was slowly added to the reaction mixture (20 mL). The product was then extracted with tert-butyl methyl ether (20 mL). The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting crude was purified by silica gel chromatography eluting with 0 to 5% EtOAc in heptanes to yield the title compound as a yellow oil (0.108 g, 9% yield).
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:4]=2[N:3]=1.[F:18][C:19]([F:33])([F:32])[C:20]1[C:21]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:22][CH:23]=[CH:24][CH:25]=1>>[N+:11]([C:10]1[C:4]2[NH:3][C:2]([N:29]3[CH2:30][CH2:31][N:26]([C:21]4[C:20]([C:19]([F:33])([F:18])[F:32])=[CH:25][CH:24]=[CH:23][N:22]=4)[CH2:27][CH2:28]3)=[N:6][C:5]=2[CH:7]=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)([O-:13])=[O:12]
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc2[nH]c(Cl)nc12
Product: O=[N+]([O-])c1cc(C(F)(F)F)cc2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c12

Procedure:
The benzoimidazole from step (c) above (1.5 g, 5.7 mmol) and 1-(3-trifluoromethylpyridin-2-yl)piperazine (1.8 g, 7.8 mmol, Matrix) reacted under the conditions of Example 3c to give the title compound as a orange solid. M.p. 192° C. MS (ESI, pos. ion) m/z: 461 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH:9]([C:15](=O)[CH2:16][CH2:17][CH3:18])[C:10](OCC)=[O:11])[CH:5]=[CH:4][C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]#[N:27].Cl.[C:29](=[NH:32])([NH2:31])[CH3:30].C[O-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[C:10](=[O:11])[NH:32][C:29]([CH3:30])=[N:31][C:15]=2[CH2:16][CH2:17][CH3:18])[CH:5]=[CH:4][C:3]=1[C:20]1[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)c(Cl)c1)C(=O)OCC
Reactant: CC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)c(Cl)c1
Yield: 73 %

Procedure:
To a suspension of 60% sodium hydride (0.50 g) in tetrahydrofuran (20 mL) was added dropwise a solution of ethyl butyrylacetate (2.40 g) in tetrahydrofuran (10 mL). After stirring for 30 min, 4′-(bromomethyl)-2′-chlorobiphenyl-2-carbonitrile (2.30 g) was added. The mixture was stirred at room temperature for 15 hr, and 1 M hydrochloric acid was added. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography to give ethyl 2-[(2-chloro-2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate. Then, a solution of the obtained ethyl 2-[(2-chloro-2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate, ethanimidamide hydrochloride (1.35 g) and 28% sodium methoxide (4.09 g) in methanol (30 mL) was stirred overnight. The solvent was evaporated under reduced pressure, and saturated aqueous ammonium chloride solution was added to the residue. The precipitated solid was collected by filtration, and washed with water and diethyl ether to give the title compound (1.95 g, 73%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]2[C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[C:21]([CH3:28])=[C:20]([CH3:29])[C:19]=2[OH:30])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:33]I.O>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]2[C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[C:21]([CH3:28])=[C:20]([CH3:29])[C:19]=2[O:30][CH3:33])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=1
Reactant: COC(=O)CCCCCC(c1ccc(F)cc1)c1c(O)c(C)c(C)c2c1CCCC2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCCCCC(c1ccc(F)cc1)c1c2c(c(C)c(C)c1OC)CCCC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of methyl 7-(4-fluorophenyl)-7-(2-hydroxy-3,4-dimethyl-5,6,7,8-tetrahydronaphthyl)heptanoate (0.5 g) in dimethylformamide (1 ml) was added to a mixture of 60% sodium hydride (51 mg) and dimethylformamide (2 ml) at 0° C. The reaction mixture was stirred at room temperature for 30 minutes. Methyl iodide (82 ml) was added dropwise and the mixture was stirred at the same temperature for 2 hours. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was subjected to silica gel column chromatography to obtain methyl 7-(4-fluorophenyl)-7-(2-methoxy-3,4-dimethyl-5,6,7,8-tetrahydronaphthyl)heptanoate (0.4 g) (Compound 58). The physical properties and spectrum data thereof are shown in Tables 3 and 4.