Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][CH:32]=1)[C:6]([NH:8][CH2:9][C:10]1[C:11]([NH:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[C:12]2[CH:20]=[N:19][N:18]([CH2:21][CH3:22])[C:13]2=[N:14][C:15]=1[CH2:16][CH3:17])=[O:7].[Br:33][C:34]1[CH:35]=[C:36]([CH2:41][NH:42][CH3:43])[CH:37]=[CH:38][C:39]=1[F:40].CCOC(C)=O>CN(C=O)C>[Br:33][C:34]1[CH:35]=[C:36]([CH2:41][N:42]([CH2:2][C:3]2[CH:4]=[C:5]([CH:30]=[CH:31][CH:32]=2)[C:6]([NH:8][CH2:9][C:10]2[C:11]([NH:23][CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[C:12]3[CH:20]=[N:19][N:18]([CH2:21][CH3:22])[C:13]3=[N:14][C:15]=2[CH2:16][CH3:17])=[O:7])[CH3:43])[CH:37]=[CH:38][C:39]=1[F:40]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(CCl)c1
Reactant: CNCc1ccc(F)c(Br)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(CN(C)Cc2ccc(F)c(Br)c2)c1
Temperature: 25 °C
Reaction time: 66 h
Yield: 93.4 %

Procedure:
To a solution of 3-(chloromethyl)-N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}benzamide (0.284 g, 0.623 mmol) in DMF (2.5 mL) was added [(3-bromo-4-fluorophenyl)methyl]methylamine (0.436 g, 2.0 mmol). This mixture was stirred at room temperature for 66 h. Then EtOAc (50 mL) was added and that solution washed with H2O (7.5+2×5 mL), brine (5 mL), dried over Na2SO4. The dried organic solution was filtered, concentrated and purified by CombiFlash chromatograph to afford the title compound 0.371 g (93%). LC-MS m/z 637 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:9](=[O:20])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([O:18][CH3:19])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][O:28][C:29](=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([N:8]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:9](=[O:20])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:36][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[C:29]([O:28][CH3:27])=[O:38])=[C:13]([O:18][CH3:19])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccccc1CBr
Reactant: CCCCCCN(Cc1ccccc1)C(=O)Cc1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCCN(Cc1ccccc1)C(=O)Cc1ccc(OCc2ccccc2C(=O)OC)c(OC)c1
Yield: 85.8 %

Procedure:
N-Benzyl-N-hexyl-2-(4-hydroxy-3-methoxyphenyl)acetamide (84 mg, 0.236 mmol), 2-bromomethylbenzoic acid methyl ester (57 mg, 0.248 mmol) and potassium carbonate anhydrous (49 mg, 0.355 mmol) were mixed in acetonitrile (5 ml). The mixture was heated to reflux overnight and then evaporated to dry. Ethyl acetate and water were added and the two phases were separated. The organic phase was washed with brine and dried (magnesium sulphate) and evaporated. Chromatography of the residue on a column (ISOLUTE® SI, 2 g/6 ml) using DCM, MeOH/DCM (0.5:99.5) as eluant gave 102 mg the desired product yield 86%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[OH:11].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:20][CH2:21]Br>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:4]1[C:5]2[O:11][CH2:21][CH2:20][O:10][C:6]=2[CH:7]=[CH:8][CH:9]=1)=[O:12]
Reactant: BrCCBr
Reactant: COC(=O)c1cccc(O)c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1OCCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.4 %

Procedure:
A suspension of 2,3-Dihydroxy-benzoic acid methyl ester (336 mg, 2 mmol) and cesium carbonate (1.56 g, 4.8 mmol) in DMF was stirred at room temperature for 0.5 h. 1,2-Dibromoethane (0.224 ml, 2.6 mmol) was added to the DMF solution. The mixture was stirred at 80 C for 4 h, and then diluted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to give the crude product. It was chromatographed on silica gel with EtOAc/hexane (20%-40%) as eluent to afford 2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid methyl ester as a white solid. (223 mg, 1.14 mmol, 57.4% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:30]=[CH:29][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@H:15]([O:17]C(=O)C3C=CC=CC=3)[CH2:14][C@H:13]2CC#N)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:31]([OH:34])(=[O:33])[CH3:32]>Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]2[CH2:32][C:31]([OH:34])=[O:33])=[O:11])=[CH:29][CH:30]=1)([O-:3])=[O:2]
Reactant: N#CC[C@@H]1C[C@@H](OC(=O)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)O
Agent: Cl
Product: O=C(O)C[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(2R,4R)-1-(p-Nitrobenzyloxycarbonyl)-2-cyanomethyl-4-benzoyloxypyrrolidine (3.0 g) was dissolved in 10 ml of acetic acid and 10 ml of conc. hydrochloric acid. After refluxing for 3 hours, the reaction mixture was cooled down to room temperature and distilled to remove the solvent. The residue was diluted with 4 ml of water and 25 ml of 1N sodium hydroxide solution. A solution of 1.53 g of p-nitrobenzyl chloroformate in 6 ml of diethyl ether and 2 ml of tetrahydrofuran was added to the above mixture at 0° C., followed by stirring at the same temperature for 30 minutes. The reaction mixture was separated. The aqueous layer was acidified with 6N hydrochloric acid to pH 1.0 and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was removed by distillation to give (2S,4R)-1-(p-nitrobenzyloxycarbonyl)-2-carboxymethyl-4-hydroxypyrrolidine.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[O:7]1[CH:12]=[CH:11][CH2:10][CH2:9][CH2:8]1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.P(Cl)(Cl)(Cl)=O>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][O:7]1
Reactant: OCCCCBr
Reactant: C1=COCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: BrCCCCOC1CCCCO1
Reaction time: 24 h

Procedure:
To a solution of commercially available 4-bromobutan-1-ol (16) (1 equi.) and 3,4-dihydropyran (17) (1.5 equi.) in dichloromethane (3 mL/mmole), phosphorus oxychloride (0.01 equi.) was added at room temperature. The reaction mixture was stirred at that temperature for 24 h. Then potassium carbonate (1 equi.) was added to the reaction mixture and the reaction mixture was stirred at room temperature for 1 h, quenched with water, extracted with dichloromethane, washed with brine, dried over MgSO4, and concentrated in vacuo. Purification by chromatography on silica gel (5% EtOAc (ethylacetate)/hexanes) afforded 2-(4-bromobutoxy) -tetrahydropyran (18), as a colorless oil (88%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.F[C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=1.CS(C)=O>O>[OH:6][CH:3]1[CH2:4][CH2:5][N:1]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)[CH2:2]1
Reactant: OC1CCNC1
Reactant: CCOC(=O)c1ccc(F)cc1
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1ccc(N2CCC(O)C2)cc1
Temperature: 110 °C
Reaction time: 20 h
Yield: 56.3 %

Procedure:
To a seal tube was added pyrrolidin-3-ol (1 gm, 11.48 mmol), ethyl 4-fluorobenzoate (2.90 gm, 17.22 mmol) and DMSO (20 ml). The reaction was stirred at 110° C. for 20 hrs. After this time, the reaction was diluted with water (50 ml). The resulting solution was extracted with EtOAc (2×50 ml). The combined organics were washed with saturated NaHCO3 (50 ml), water (50 ml) and saturated aqueous NaCl (50 ml). The organic layer was separated, dried over MgSO4, filtered and concentrated. The resulting residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 50-100% EtOAc/Hex) to give the product ethyl 4-(3-hydroxypyrrolidin-1-yl)benzoate (1.52 g, 6.46 mmol, 56.3% yield) as white solid. Anal. Calcd. for C13H12NO3 m/z 235.3, found: 236.4 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.97-7.87 (m, 2H), 6.61-6.44 (m, 2H), 4.77-4.57 (m, 1H), 4.32 (q, J=7.1 Hz, 2H), 3.63-3.51 (m, 2H), 3.49-3.40 (m, 1H), 3.34 (d, J=10.8 Hz, 1H), 2.27-2.03 (m, 2H), 1.73 (d, J=4.4 Hz, 1H), 1.37 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH:1]1([O:7][CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[C:9](O)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[NH:28][Si](C)(C)C>ClCCl.CN(C)C=O>[CH:1]1([O:7][CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[C:9]([NH2:28])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: O=C(O)C(OC1CCCCC1)c1ccc(Cl)c(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NC(=O)C(OC1CCCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
A solution of rac-cyclohexyloxy-(3,4-dichloro-phenyl)-acetic acid (Example 2; 364 mg, 1.20 mmol) in dichloromethane (10 mL) and N,N-dimethylformamide (one drop) cooled to 0° C. was treated with oxalyl chloride (2.OM solution in dichloromethane, 0.84 mL, 1.68 mmol). The reaction was stirred at 0° C. for 1 h, then 1,1,1,3,3,3-hexamethyldisilazane (0.90 mL, 4.20 mmol) was added and the cloudy mixture was stirred at 25° C. for 16 h. At this time, the reaction was quenched with methanol (10 mL), washed with an aqueous solution of 5% sulfuric acid (2×15 mL) and extracted with dichloromethane (3×10 mL). The combined organic extracts were washed with brine (1×10 mL), then were dried over magnesium sulfate, filtered and evaporated under reduced pressure. The product was purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 hexanes/ethyl acetate) to afford rac-2-cyclohexyloxy-2-(3,4-dichloro-phenyl)-acetamide (311 mg, 76% yield) as a colorless oil: FAB-HRMS m/e calcd for C14H17NCl2O2 (M+H)+302.0714, found 302.0728.
Reaction SMILES: [NH2:1]C1N=C(C2CCN(C(=O)CN3C(C)=CC(C(F)(F)F)=N3)CC2)SC=1.C(N(C(C)C)CC)(C)C.[C:35]1([O:41][C:42](Cl)=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>ClCCl>[C:35]1([O:41][C:42](=[O:43])[NH2:1])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(N)cs2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: NC(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-[4-(4-amino-thiazol-2-yl)-piperidin-1-yl]-2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone (80 mg, 0.21 mmol) in dichloromethane (5 mL) is added diisopropylethylamine (0.053 mL, 0.25 mmol), and subsequently phenylchloroformate (0.033 mL, 0.21 mmol) at 0° C. After stirring overnight at RT, solvents are evaporated under reduced pressure and the residue is purified by column chromatography on silica gel (ethyl acetate/heptane 7:3) to give 2-{1-[2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperidin-4-yl}-thiazol-4-yl)-carbamic acid phenyl ester (Compound No. I.g.023, 71 mg, 67%). 1H-NMR (400 MHz, CDCl3): δ=1.57-1.78 (m, 2H), 2.08-2.19 (m, 2H), 2.22 (s, 3H), 2.75-2.81 (m, 1H), 3.05-3.20 (m, 2H), 3.95-3.99 (m, 1H), 4.44-4.52 (m, 1H), 4.83-4.98 (2d, 2H, diastereotopic protons), 6.25 (s, 1H), 7.05-7.20 (m, 3H), 7.29-7.38 (m, 2H), 7.95 (br, 1H). MS: m/z=494 (M+1).
Reaction SMILES: [Li]CCCC.[CH2:6]([C:13]1[CH:18]=[C:17](Br)[CH:16]=[CH:15][C:14]=1[O:20][CH3:21])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[B:22](OC)([O:25]C)[O:23]C.[OH-].[Na+]>C1COCC1.O>[CH2:6]([C:13]1[CH:18]=[C:17]([B:22]([OH:25])[OH:23])[CH:16]=[CH:15][C:14]=1[O:20][CH3:21])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COc1ccc(Br)cc1Cc1ccccc1
Reactant: COB(OC)OC
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(B(O)O)cc1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
8.61 ml (13.8 mmol, 1 eqv) of a 1.6 M solution of n-BuLi in hexanes was added to a solution of 3.82 g (13.8 mmol) 2-Benzyl-4-bromo-anisol (21) in 100 ml dry THF at −78° C. After stirring this mixture for 30 min at −78° C., 4.70 ml (41.4 mmol, 3 eqv) B(OMe)3 was added and the solution was stirred for 24 h at rt. Now 10 ml water and 25 ml of a 10% aq. NaOH-solution were added and stirring was continued for further 60 min. Then the pH was adjusted to 4-5 with 1-N-HCl-solution and most of the solvent was evaporated. The residue was extracted with EtOAc and the comb. org. fractions were dried over MgSO4 and evaporated, which led after drying in high vacuum to 3.33 g (13.8 mmol, 100%) of an orange solid. This crude boronic acid 22 was used without further purification: 1H NMR (500 MHz, CDCl3) δ 3.81 (s, 3H), 3.98 (s, 2H), 6.89 (d, 1H, J=8.20 Hz), 7.10-7.23 (m, 5H), 7.79 (d, 1H, J=1.58 Hz), 7.96 (dd, 1H, J1=8.20 Hz, J2=1.73 Hz).
Reaction SMILES: [N:1]1[C:9]2[CH:8]([NH2:10])[CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:11][CH2:12][O:13]C(C)=O.[NH4+].[OH-]>C(Cl)Cl.CO>[N:1]1[C:9]2[C@H:8]([NH:10][C:12](=[O:13])[CH3:11])[CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(C)=O
Reactant: NC1CCc2cccnc21
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CC(=O)N[C@@H]1CCc2cccnc21
Reaction time: 7 h

Procedure:
Following the general procedure, 6,7-dihydro-5H-[1]pyrindin-7-ylamine (271 mg, 2.02 mmol), CALB (81 mg) and EtOAc (6.5 mL) were stirred for 7 hours. The conversion determined from 1H NMR by integration of the peaks at 5.17 ppm (CHNHAc) and 4.21 ppm (CHNH2) was 55%. Flash chromatography of the material on silica gel using 1:10 MeOH:CH2Cl2 followed by 1:1:4 NH4OH:MeOH:CH2Cl2 furnished (R)—N-(6,7-dihydro-5H-[1]pyrindin-7-yl)acetamide ((194 mg, 41%). The two enantiomers of the acetamide could not be resolved by GC nor HPLC, and hence the % ee had to be determined indirectly. A small sample of the acetamide was treated with 1N HCl to convert it to the amine, and the resulting amine was resolved by chiral GC (chiral GC method: 85° C. for 120 min, ramp rate 5° C./min to 210° C., final time 5 min; (S)-enantiomerrt=124.3 min, (R)-enantiomerrt=126.1 min) to give % ee of 79%; [α]D=−41° (c 1.49, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 1.75–1.89 (m, 1H), 2.07 (s, 3H), 2.80–2.98 (m, 3H), 5.19–5.27 (m, 1H), 6.32 (br s, 1H), 7.14 (dd, 1H, J=7.5, 5.0 Hz), 7.55 (d, 1H), J=7.5 Hz), 8.39 (d, 1H, J=4.5 Hz); 13C NMR (CDCl3) δ 23.6, 28.3, 33.9, 55.7, 123.0, 133.3, 137.2, 148.2, 148.4, 162.7, 171.0. The unreacted (S)-6,7-dihydro-5H[1]pyrindin-7-ylamine (was isolated in 42% yield (113 mg) and 99% ee (chiral GC, (S)-enantiomerrt=124.3 min, (R)-enantiomerrt=126.1 min) and displayed spectra identical to the starting material: 1H NMR (CDCl3, 300 MHz) δ 1.68–1.88 (m, 1H), 2.50–2.61 (m, 3H), 2.75–2.86 (m, 1H), 2.92 (ddd, 1H, J=13.2, 9.0, 3.0 Hz), 4.32 (dd, 1H, J=7.8, 7.8 Hz), 7.08 (dd, 1H, J=7.8, 4.8 Hz), 7.51 (d, 1H, J=7.8 Hz), 8.40 (d, 1H, J=4.8 Hz). The dark color of the amine after purification by column chromatography prevented determination of its optical rotation.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([O:17]CC)=[O:16])=[CH:10][C:9]=2[CH2:20][CH3:21])=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][C:9]=2[CH2:20][CH3:21])=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1cc(CC)c(C(=O)c2ccc(Cl)cc2)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1cc(CC(=O)O)n(C)c1C(=O)c1ccc(Cl)cc1

Procedure:
A suspension of 4.5 g. (0.0136 mole) of ethyl 5-(p-chlorobenzoyl)-4-ethyl-1-methylpyrrole-2-acetate in 28 ml. 0.5 N sodium hydroxide and 1 ml. of ethanol is heated under reflux for 30 minutes. The mixture is then poured into ice-dilute hydrochloric acid. The precipitated solid is filtered, air dried and recrystallized from 2-propanol to give 5-(p-chlorobenzoyl)-4-ethyl-1-methylpyrrole-2-acetic acid as a white solid, m.p. 129-131° C. Anal. Calcd. for C16H16ClNO3 : C, 62.85; H, 5.29; N, 4.5%. Found: C, 62.58; H, 5.40; N, 4.83%.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:27]=[CH:28][CH:29]=1)[C:16]([CH2:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1)=[O:17].[N-:30]=[N+:31]=[N-:32].[Na+].Cl.[NH+]1C=CC=CC=1.O>CN(C=O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:27]=[CH:28][CH:29]=1)[C:16]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]2[NH:32][N:31]=[N:30][N:24]=2)=[CH:25][CH:26]=1)=[O:17]
Reactant: N#Cc1ccc(CC(=O)c2cccc(OCc3ccc4ccccc4n3)c2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(-c2nnn[nH]2)cc1)c1cccc(OCc2ccc3ccccc3n2)c1

Procedure:
A heterogenous mixture of 4-(3-(2-quinolinylmethyloxy)benzoylmethyl)benzonitrile (1.35 mmol). NaN3 (6.77 mmol), pyridinium hydrochloride (6.77 mmol) in DMF (3 ml) is heated at 100° C. for 3 hours under nitrogen. The reaction mixture is poured into water and the product is collected on a filter. Recrystallization from EtOAc-DMF gives 5-(4-(3-(2-quinolinylmethyloxy)benzoylmethyl)phenyl)tetrazole.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:10]2[C:13]3[C:3]=1[CH2:4][CH:5]([N:14]1[CH2:19][CH2:18][CH:17]([N:20]4[C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[NH:22][C:21]4=[O:29])[CH2:16][CH2:15]1)[C:6]=3[CH:7]=[CH:8][CH:9]=2.O.C(OCC)(=O)C.[CH3:37][N:38](C)C=O>[C-]#N.[Zn+2].[C-]#N.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:37]([C:2]1[CH:12]=[CH:11][C:10]2[C:13]3[C:3]=1[CH2:4][CH:5]([N:14]1[CH2:15][CH2:16][CH:17]([N:20]4[C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[NH:22][C:21]4=[O:29])[CH2:18][CH2:19]1)[C:6]=3[CH:7]=[CH:8][CH:9]=2)#[N:38]
Reactant: O=c1[nH]c2ccccc2n1C1CCN(C2Cc3c(Br)ccc4cccc2c34)CC1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1ccc2cccc3c2c1CC3N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
1-[1-(3-Bromoacenaphthen-1-yl)piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one (1.25 g) was dissolved in N,N-dimethylformamide (16 ml), zinc cyanide (380 mg) and tetrakistriphenylphosphinepalladium (1.6 g) were added, and the mixture was stirred at 110° C. for 1 hr. After allowing to cool, water and ethyl acetate were poured into the reaction mixture, and the mixture was subjected to celite filtration. The filtrate was extracted with ethyl acetate, and the extract was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography, and recrystallized from acetone to give the title compound (1.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([O:19]C)[CH:13]=[C:12]([O:21]C)[C:11]=2[C@@H:23]1[CH2:27][CH2:26][N:25]([CH3:28])[C@H:24]1[CH2:29][C:30]#[N:31].Cl.N1C=CC=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([OH:19])[CH:13]=[C:12]([OH:21])[C:11]=2[C@@H:23]1[CH2:27][CH2:26][N:25]([CH3:28])[C@H:24]1[CH2:29][C:30]#[N:31]
Reactant: COc1cc(OC)c2c(=O)cc(-c3ccccc3Cl)oc2c1[C@@H]1CCN(C)[C@H]1CC#N
Agent: Cl
Solvent: c1ccncc1
Product: CN1CC[C@@H](c2c(O)cc(O)c3c(=O)cc(-c4ccccc4Cl)oc23)[C@@H]1CC#N

Procedure:
Compound of example 110 (0.45 g, 1.0 mmol) was demethylated using pyridine hydrochloride (4.5 g, 39.0 mmol) as described in example 17 to obtain the title compound.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][OH:8])(=[O:4])[CH:2]=[CH2:3].C(N(CC)CC)C.Cl[P:17]1(=[O:22])[O:21][CH2:20][CH2:19][O:18]1>C(OCC)C>[C:1]([O:5][CH2:6][CH2:7][O:8][P:17]1(=[O:22])[O:21][CH2:20][CH2:19][O:18]1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)OCCO
Reactant: O=P1(Cl)OCCO1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=CC(=O)OCCOP1(=O)OCCO1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
2-Hydroxyethyl acrylate (11.5 ml, 0.1M) and triethylamine (14.6 ml) in dry diethyl ether (250 ml) were cooled to -25° C. under nitrogen as a solution of 2-chloro-2-oxo-1,3,2-dioxaphospholane (14.3 g) in dry diethyl ether was added over 20 minutes. The mixture was stirred for a further 1 hour at -20° C. and then allowed to warm to 10° C. over a further hour. The precipitate was filtered, washed with ethyl acetate (100 ml) and the combined filtrate and washings evaporated under reduced pressure to give a pale yellow oil (21 g).
Reaction SMILES: [Li:1][CH2:2][CH2:3][CH2:4][CH3:5].Br[C:7]1[CH:14]=CC=C[C:8]=1[CH:9]=C.C1COCC1>C(OCC)C>[Li:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:14][C:3]=1[CH:4]=[CH2:5]
Reactant: [Li]CCCC
Reactant: C=Cc1ccccc1Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: [Li]c1ccccc1C=C

Procedure:
A 0.35M solution of 2-lithiostyrene was prepared dropwise addition of nBuLi to a -78° C. solution of 2-bromostyrene in 5:1 THF:diethyl ether.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][N:24]=2)[N:21]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:9][CH2:10][N:11]([C:16]3[CH:17]=[CH:18][C:19]4[N:20]([C:22]([C:25]([F:26])([F:28])[F:27])=[N:23][N:24]=4)[N:21]=3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: OC1(c2ccc(F)cc2)CCNCC1
Product: OC1(c2ccc(F)cc2)CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Yield: 74 %

Procedure:
A mixture of 4-(4-fluorophenyl)piperidin-4-ol and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by the method of Example 306 to give 4-(4-fluorophenyl)-1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-ol in 74% yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([O:30]C)=[O:29])=[C:24]([F:32])[CH:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].Cl>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([OH:30])=[O:29])=[C:24]([F:32])[CH:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(CSc2c(Cl)ccc3c2CCN(C(=O)OC(C)(C)C)CC3)cc1F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(C(=O)O)c(F)c3)c2CC1
Temperature: 0 °C
Yield: 101 %

Procedure:
Heat a stirred solution of 3-tert-butoxycarbonyl-7-chloro-6-(3-fluoro-4-methoxycarbonylbenzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (3.56 g, 7.44 mmol) in THF (50 mL) and water (40 mL) overnight at 65° C. in the presence of potassium hydroxide (8.30 g, 148.77 mmol). Cool the mixture to 0° C., add slowly a 1N solution of hydrochloric acid until pH 5. Extract three times with EtOAc, dry over anhydrous Na2SO4 and concentrate in vacuo to provide the desired intermediate as a white solid (3.5 g, 99%).
Reaction SMILES: C([O:3][C:4](=[O:21])[CH:5]([O:19][CH3:20])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15][CH2:16][CH2:17]Br)=[CH:9][CH:8]=1)C.[C:22]([C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH3:24])[CH3:23]>>[CH3:20][O:19][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]#[C:14][CH2:15][CH2:16][CH2:17][O:37][C:34]2[CH:33]=[CH:32][C:31]([C:22]([CH3:24])([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH3:23])=[CH:36][CH:35]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:21]
Reactant: CC(C)(c1ccccc1)c1ccc(O)cc1
Reactant: CCOC(=O)C(Cc1ccc(C#CCCCBr)cc1)OC
Product: CO[C@@H](Cc1ccc(C#CCCCOc2ccc(C(C)(C)c3ccccc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from 3-[4-(5-Bromo-pent-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 24, Step A and 4-cumylphenol in a manner analogous to that described for Example 24, Step B. MS(ES) for C30H32O4 [M+NH4]+: 474.3