Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:35]=[C:36]([NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH:37]=1)[CH2:12][NH:13][CH2:14][CH2:15][N:16]1[CH:25]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([F:34])[CH:22]=2)[CH2:17]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:53](Cl)([O:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)=[O:54].C(=O)(O)[O-].[Na+]>ClCCl.C(Cl)(Cl)Cl>[CH2:56]([O:55][C:53]([N:13]([CH2:12][C:11]1[CH:35]=[C:36]([NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH:37]=[C:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH:10]=1)[CH2:14][CH2:15][N:16]1[CH:25]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([F:34])[CH:22]=2)[CH2:17]1)=[O:54])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1cc(CNCCN2Cc3ccc(F)cc3CC2Cc2ccc(F)cc2)cc(NC(=O)OC(C)(C)C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)Nc1cc(CN(CCN2Cc3ccc(F)cc3CC2Cc2ccc(F)cc2)C(=O)OCc2ccccc2)cc(NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
31.5 mg of N-[3,5-bis(tert-butyloxycarbonyl)aminobenzyl]-2-[6-fluoro-3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]ethanamine was taken into a 20-mL eggplant flask and dissolved in 1.5 mL of dichloromethane, and 0.01 mL of triethylamine and 0.01 mL of Cbz-chloride were sequentially added thereto under ice-cooling, followed by stirring for 1 hour at room temperature. After completion of the reaction, to the reaction liquid were added a saturated aqueous sodium bicarbonate solution and chloroform under ice-cooling. The organic layer was separated, the aqueous layer was further extracted by addition of chloroform, and the organic layer was combined and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the solvent was removed by evaporation to obtain 120.0 mg of a crude composition. The crude composition was purified by PLC to obtain 35.8 mg (yield 93%) of a title compound as a pale yellow oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13](I)=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:20]=1.[CH3:21][C:22]([OH:39])([CH3:38])[CH2:23][N:24]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[N:25]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([C:27]4[CH:26]=[N:25][N:24]([CH2:23][C:22]([OH:39])([CH3:38])[CH3:21])[CH:28]=4)=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:20]=1
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: NC(=O)c1nc2n(c1I)C1CC(C1)c1ccc(Br)cc1-2
Product: CC(C)(O)Cn1cc(-c2c(C(N)=O)nc3n2C2CC(C2)c2ccc(Br)cc2-3)cn1

Procedure:
10-bromo-3-iodo-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carb oxamide was reacted with 2-methyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]propan-2-ol similarly to as described in Example 4 to produce crude 10-bromo-3-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide.
Reaction SMILES: [CH2:1](N(CC)CC)C.[CH2:8]([O:10][C:11](=[O:37])[C:12]([CH2:14][C:15]1[CH:16]=[N:17][C:18]([N:22]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:19][C:20]=1[CH3:21])=[CH2:13])[CH3:9].C(OCC)(=O)C.[C:44]([OH:47])(=[S:46])[CH3:45]>>[CH2:8]([O:10][C:11](=[O:37])[CH:12]([CH2:13][S:46][C:44](=[O:47])[CH3:45])[CH2:14][C:15]1[CH:16]=[N:17][C:18]([N:22]([C:30]([O:32][C:33]([CH3:36])([CH3:34])[CH3:35])=[O:31])[C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])=[C:19]([CH3:1])[CH:20]=1)[CH3:9].[CH2:8]([O:10][C:11](=[O:37])[CH:12]([CH2:13][S:46][C:44](=[O:47])[CH3:45])[CH2:14][C:15]1[CH:16]=[N:17][C:18]([N:22]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:19][C:20]=1[CH3:21])[CH3:9]
Reactant: CCN(CC)CC
Reactant: CC(O)=S
Reactant: C=C(Cc1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1C)C(=O)OCC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CSC(C)=O)Cc1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(C)c1
Product: CCOC(=O)C(CSC(C)=O)Cc1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 21 %

Procedure:
Triethylamine (0.279 mL, 2.0 mmol) was added to a solution of 2-(6-[N,N-bis(tert-butoxycarbonyl)amino]-4-methyl-pyridin-3-ylmethyl)-acrylic acid ethyl ester (0.8 g, 1.9 mmol) in thioacetic acid (3 mL) at 0° C. The mixture was stirred at room temperature for 16 h. Ethyl acetate was added and the organic phase was washed with water, saturated NaHCO3 and brine and dried. The crude product was purified by flash chromatography (toluene/ethyl acetate, 3:1→1:2) to give pure 2-acetylsulfanylmethyl-3-(6-[N,N-bis(tert-butoxycarbonyl)amino]-5-methyl-pyridin-3-yl)-propionic acid ethyl ester (200 mg, 21%) and slightly impure 2-acetylsulfanylmethyl-3-(6-[N,N-bis(tert-butoxycarbonyl)amino]-4-methyl-pyridin-3-yl)-propionic acid ethyl ester (0.68 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:27]1([CH2:33][S:34][CH:35]([C:39](O)=[O:40])[C:36](O)=[O:37])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[OH:40][C:39]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[O:11][C:36](=[O:37])[C:35]=1[S:34][CH2:33][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(O)C(SCc1ccccc1)C(=O)O
Reactant: COc1ccc(C(C)=O)cc1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(O)c(SCc3ccccc3)c(=O)o2)cc1

Procedure:
The title compound was prepared by Method A using 4'-methoxyacetophenone (0.797 g, 5.31 mmol), lithium bis(trimethylsilyl)amide (0.977 g, 5.84 mmol), chlorotrimethylsilane (0.741 mL, 5.84 mmol), THF (58 mL), and diethyl ester of [(phenylmethyl)thio]propanedioic acid (1.00 g, 3.54 mmol). m.p. dec. 187° C.; 1H NMR (400 MHz, DMSO-d6) δ3.83 (s, 3 H), 3.98 (s, 2 H), 6.62 (s, 1 H), 7.06 (m, 2 H), 7.22 (m, 5 H), 7.73 (m, 2 H), 11.76 (bs, 1 H).
Reaction SMILES: [C:1]([C:4]1[CH:5]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[N:6]([C:11]2[CH:12]=[C:13]([CH3:19])[C:14](=[O:18])[N:15]([CH3:17])[CH:16]=2)[C:7](=[O:10])[C:8]=1O)(=O)[CH3:2].[CH3:27][NH:28][NH2:29]>C1(C)C=CC=CC=1.CCO.CCOCC>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([CH:5]2[C:4]3[C:1]([CH3:2])=[N:29][N:28]([CH3:27])[C:8]=3[C:7](=[O:10])[N:6]2[C:11]2[CH:12]=[C:13]([CH3:19])[C:14](=[O:18])[N:15]([CH3:17])[CH:16]=2)=[CH:21][CH:22]=1
Reactant: CC(=O)C1=C(O)C(=O)N(c2cc(C)c(=O)n(C)c2)C1c1ccc(Cl)cc1
Reactant: CNN
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1nn(C)c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c(=O)n(C)c1)C2=O
Temperature: 110 °C
Reaction time: 18 h
Yield: 37.2 %

Procedure:
To a stirred solution of 5-(3-acetyl-2-(4-chlorophenyl)-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrol-1-yl)-1,3-dimethylpyridin-2(1H)-one (Step 57.1) (500 mg, 1.341 mmol) in toluene (5 mL) and EtOH (5 mL) was added methyl hydrazine (0.353 mL, 6.71 mmol) and the reaction mixture was heated up and stirred at 110° C. for 18 hr. The reaction was concentrated under reduced pressure. The resulting mixture was diluted with AcOH (10 ml), heated up and stirred at 100° C. for 1 hr, concentrated under reduced pressure and quenched with a saturated aqueous NaHCO3 solution. The aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over Na2SO4 and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with EtOAc. Trituration in Et2O afforded the title product (191 mg, 0.499 mmol, 37% yield) as white solid. tR: 3.83 min (HPLC 1); tR: 0.91 min (LC-MS 2); ESI-MS: 383 [M+H]+ (LC-MS 2); Rf=0.09 (EtOAc); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.83-1.97 (m, 6H) 3.33 (s, 3H) 3.89 (s, 3H) 6.04 (s, 1H) 7.24 (d, J=8.2 Hz, 2H) 7.30-7.37 (m, 3H) 7.69 (d, J=2.7, Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[C:20]([C:21](=[O:29])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][N:18]=[C:17](SC)[N:16]=2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:40](Cl)([CH3:43])(=[O:42])=[O:41]>ClCCl>[C:1]([O:5][C:6](=[O:32])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[C:20]([C:21](=[O:29])[NH:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:19][N:18]=[C:17]([S:40]([CH3:43])(=[O:42])=[O:41])[N:16]=2)[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CSc1ncc(C(=O)Nc2ccccc2)c(Oc2cccc(NC(=O)OC(C)(C)C)c2)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1cccc(Oc2nc(S(C)(=O)=O)ncc2C(=O)Nc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 117.9 %

Procedure:
To a stirred solution of 6 (0.35 g, 0.7 mmol) and triethylamine (0.2 mL, 1.4 mmol) in dichloromethane (10 mL) at 0° C. was added mesyl chloride (0.12 g, 1.05 mmol) and then the reaction mixture stirred at room temperature for 1 h. It was quenched with water; the organic layer was separated, dried over anhydrous Na2SO4 and concentrated to obtain 7 as colorless oil (0.4 g, crude).
Reaction SMILES: CO[CH:3]=[CH:4][C:5](=[O:7])[CH3:6].[F:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][NH2:12]>C(Cl)Cl>[F:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][NH:12][CH:3]=[CH:4][C:5](=[O:7])[CH3:6]
Reactant: NCc1ccccc1F
Reactant: COC=CC(C)=O
Solvent: ClCCl
Product: CC(=O)C=CNCc1ccccc1F
Yield: 98.3 %

Procedure:
A solution of 4-methoxy-3-buten-2-one (0.1 g, 1 mmol) and 2-fluorobenzylamine (0.125 g, 1 mmol) in dry CH2Cl2 (5 mL) is stirred under reflux for 2 h. The solvent is evaporated under pressure to afford the title compound 56 as a yellow oil (Yield 0.19 g, 100%).
Reaction SMILES: [CH2:1]([C:3]1[S:23][C:6]2[NH:7][C:8](=[O:22])[N:9]([CH2:12][CH2:13][NH:14]C(=O)OC(C)(C)C)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:38]2[N:42]=[C:41](C(Cl)(Cl)[Cl:44])[O:40][N:39]=2)=[CH:28][CH:27]=1.C(=O)([O-])[O-:48].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[ClH:44].[NH2:14][CH2:13][CH2:12][N:9]1[C:10](=[O:11])[C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[S:23][C:6]=2[N:7]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:38]3[NH:42][C:41](=[O:48])[O:40][N:39]=3)=[CH:28][CH:27]=2)[C:8]1=[O:22]
Reactant: O=C([O-])[O-]
Reactant: CCc1cc2c(=O)n(CCNC(=O)OC(C)(C)C)c(=O)[nH]c2s1
Reactant: ClC(Cl)(Cl)c1nc(-c2ccccc2-c2ccc(CBr)cc2)no1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cc2c(=O)n(CCN)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 15.5 %

Procedure:
A mixture of tert-butyl [2-(6-ethyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)ethyl]carbamate (0.5 g), 3-[4′-(bromomethyl)biphenyl-2-yl]-5-(trichloromethyl)-1,2,4-oxadiazole (0.7 g), potassium carbonate (0.22 g) and N,N-dimethylformamide (20 mL) was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography and dissolved in tetrahydrofuran (5 mL) and methanol (5 mL). 1N Aqueous sodium hydroxide solution (5 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was adjusted to pH 7 with water and 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and dissolved in ethyl acetate (5 mL). 4N Hydrochloric acid (ethyl acetate solution, 4 mL) was added, and the mixture was stirred at room temperature. The precipitated solid was collected by filtration to give the title compound as colorless crystals (0.12 g, 25%).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=2)[C:4](=[O:19])[CH2:3]1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[C:4](=[O:19])[CH2:3][C:2]3([CH3:20])[CH3:1])=[CH:25][CH:24]=1
Reactant: CC1(C)CC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc21
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2ccc3c(c2)C(C)(C)CC3=O)cc1

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester and 4-methoxyphenyl boronic acid according to the procedure described in example 21. MS (ES) m/z 267.1. HRMS: calcd for C18H18O2+H+, 267.13796; found (ESI, [M+H]+), 267.1373.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:16])[C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:17])[C:6]([C:18]([O:20]CC)=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[Cl-].[Li+].[CH3:25][CH:26]1[CH2:31][NH:30][CH2:29][CH2:28][NH:27]1.O>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:16])[C:10]([F:15])=[C:11]([N:30]4[CH2:29][CH2:28][NH:27][CH:26]([CH3:25])[CH2:31]4)[CH:12]=3)[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CC1CNCCN1
Reactant: CCOC(=O)c1cn(C2CC2)c2cc(F)c(F)c(C)c2c1=O
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CC#N
Product: Cc1c(F)c(N2CCNC(C)C2)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 100 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
To a suspension of 1.23 g of ethyl 1-cyclopropyl-6,7-difluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate and 254 mg of lithium chloride in acetonitrile was added 1.00 g of 2-methylpiperazine, followed by heating and refluxing for 4 hours. After adding 24 ml of warm water, the reaction mixture was allowed to cool to precipitate crystals and the resulting crystals were filtered and washed with water. The crystals were suspended in 8 ml of isopropyl alcohol and 8 ml of 1N-NaOH, followed by stirring at a temperature in the range of 50° C. to 60° C. for 1 hour. After evaporating the isopropyl alcohol, to the residue were added 40 ml of water and 1.24 ml of concentrated hydrochloric acid, followed by washing with dichloromethane. The aqueous layer was heated at 100° C. for 1 hour to distill off the residual dichloromethane. After the aqueous layer was allowed to cool, 1.04 g of sodium hydrogencarbonate was added and heated with stirring at 60° C. for 1 hour, thereby neutralizing the aqueous layer. The aqueous layer was allowed to cool again, followed by stirring at 0° C. for 1 hour. The resulting crystals were filtered, washed with water and dried at 80° C. for 16 hours to give 1.40 g of 1-cyclopropyl-6-fluoro-7-(3-methyl-1-piperazinyl)-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.
Reaction SMILES: [O:1]=[C:2]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH2:3][N:4]1[CH2:9][CH2:8][C:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)([OH:10])[CH2:6][CH2:5]1.[BH4-].[Na+].CO>O>[OH:1][CH:2]([CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1)[CH2:3][N:4]1[CH2:9][CH2:8][C:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)([OH:10])[CH2:6][CH2:5]1
Reactant: O=C(COc1ccc(F)cc1)CN1CCC(O)(c2ccc(Cl)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OC(COc1ccc(F)cc1)CN1CCC(O)(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1.9 g of 1-[2-oxo-3-(p-fluorophenoxy)propyl]-4-(p-chlorophenyl)-4-hydroxypiperidine, 0.38 g of sodium borohydride and 20 ml of methanol is stirred at room temperature for 3 hours. The resulting mixture is diluted with water and extracted with chloroform. The organic layer is dried over sodium sulfate and evaporated under reduced pressure to give 1-[2-hydroxy-3-(p-fluorophenoxy)propyl]-4-(p-chlorophenyl)-4-hydroxypiperidine, M.P. 103° to 105°C. Recrystallization from benzene-cyclohexane gives white crystals, M.P. 107° to 108°C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1([CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)[CH2:6][C:5]12[N:20]=[C:19]([NH2:21])[C:18]([CH3:22])=[N:17]1.[Cl:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[F:30]>>[Cl:23][C:24]1[CH:25]=[C:26]([C:2]2[CH:3]=[C:4]3[C:14](=[CH:15][CH:16]=2)[O:13][C:7]2([CH2:12][CH2:11][CH2:10][O:9][CH2:8]2)[CH2:6][C:5]23[N:20]=[C:19]([NH2:21])[C:18]([CH3:22])=[N:17]2)[CH:27]=[CH:28][C:29]=1[F:30]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: CC1=NC2(CC3(CCCOC3)Oc3ccc(Br)cc32)N=C1N
Product: CC1=NC2(CC3(CCCOC3)Oc3ccc(-c4ccc(F)c(Cl)c4)cc32)N=C1N
Yield: 27.6 %

Procedure:
6′-Bromo-5-methyl-5″,6″-dihydro-4″H-dispiro[imidazole-2,4′-chromene-2′,3″-pyran]-4-amine (Example 45 Isomer 2, 77 mg, 0.21 mmol), and 3-chloro-4-fluorophenylboronic acid (47.9 mg, 0.27 mmol) was reacted using the conditions described for Example 46a Isomer 1, to give Isomer 2 of the title compound, (24 mg, 27% yield) with undetermined configuration: 1H NMR (500 MHz, DMSO-d6) δ ppm 1.41-1.54 (m, 1 H), 1.78-1.92 (m, 3 H), 1.99-2.13 (m, 2 H), 2.25 (s, 3 H), 3.40-3.47 (m, 1 H), 3.54 (d, 1 H), 3.68-3.74 (m, 1 H), 3.94 (d, 1 H), 6.53 (br. s, 2 H), 6.58 (d, 1 H), 6.94 (d, 1 H), 7.39-7.46 (m, 3 H), 7.58-7.63 (m, 1 H); MS (ES+) m/z 414 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10].[H-].[Na+].Br[CH2:14][C:15]([OH:17])=[O:16].Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH2:19]([O:17][C:15](=[O:16])[CH2:14][O:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OCCOCCOCCO
Reactant: O=C(O)CBr
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(COCCOCCOCCO)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.7 %

Procedure:
2-[2-(2-Hydroxy-ethoxy)-ethoxy]-ethanol (62.2 g, 414 mmol) was dissolved under argon in 875 mL of abs. DMF and cooled to 0° C. NaH (12.1 g, 277 mmol, 55% in mineral oil) was carefully added, the ice bath removed, and stirring continued for 1 h at 80° C. The reaction mixture was cooled to ambient temperature and treated with bromoacetic acid (18.98 g, 137 mmol) which was added via dropping funnel as a DMF-solution (20 ml). After an additional 30 min. at 75° C., bromomethyl-benzene (23.36 g, 137 mmol) was added neat and esterification allowed to proceed for 30 min. Cooling, careful pouring onto crashed ice, extraction with ethyl acetate, washing with water, drying over Na2SO4, and evaporation of all solvents followed by flash chromatography (SiO2, ethyl acetate/heptane=8/2) yielded 6.41 g of the title compound as a yellow oil. MS (ISP): 299.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]([CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)([OH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O[C@@H:19]1[CH:24]2C[CH2:26][N:21]([CH2:22][CH2:23]2)[CH2:20]1>C1(C)C=CC=CC=1>[N:21]12[CH2:22][CH2:23][CH:24]([CH2:19][CH2:20]1)[C@@H:1]([O:2][C:3](=[O:17])[C:4]([CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)([OH:11])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH2:26]2
Reactant: COC(=O)C(O)(c1ccccc1)C1CCCC1
Reactant: O[C@H]1CN2CCC1CC2
Solvent: Cc1ccccc1
Product: O=C(O[C@H]1CN2CCC1CC2)C(O)(c1ccccc1)C1CCCC1
Yield: 69 %

Procedure:
Prepared using the same method as for Intermediate I-1, but from 13.5 g (0.0576 mol) of 2-Cyclopentyl-2-hydroxy-2-phenylacetic acid methyl ester (commercially available) dissolved in 350 ml of toluene, 8.0 g (0.063 mol) of (3R)-3-hydroxy-1-azabicyclo[2.2.2]octane and 0.91 g (0.023 mol) of HNa (60% dispersion in mineral oil). The yield was 13.1 g (69%) of the title product as an oil mixture of diastereomers, structure confirmed by 1H-NMR; The two diastereomers I-5a and I-5b were separated after several crystallizations.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[C:7]([Br:14])=[C:6]([OH:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4][C:3]1=2.[CH3:20][O:21][CH2:22]Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:14][C:7]1[C:8]2[C:9]([CH3:12])([CH3:13])[CH2:10][CH2:11][C:2]([CH3:19])([CH3:1])[C:3]=2[CH:4]=[C:5]([C:16]([OH:18])=[O:17])[C:6]=1[O:15][CH2:20][O:21][CH3:22]
Reactant: CC1(C)CCC(C)(C)c2c1cc(C(=O)O)c(O)c2Br
Reactant: COCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOc1c(C(=O)O)cc2c(c1Br)C(C)(C)CCC2(C)C
Temperature: 45 °C

Procedure:
To a solution of 4-bromo-3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl acid (Compound M), 233 mg, 0.71 mmol) in 6 ml of CH2Cl2 was added chloromethyl methyl ether (0.162 ml, 2.1 mmol), diisopropylethyl amine (0.764 ml, 4.2 mmol) and a catalytic amount of tetrabutylammonium bromide. The reaction mixture was heated to 45° C. for 2 h. The reaction mixture was concentrated and the residue was purified by column chromatography (ethyl acetate/hexane 1/9) to yield the methoxymethyl ester of the title compound as a white solid (200 mg). This white solid was further dissolved in 20 ml of EtOH. An aqueous solution of NaOH (0.5 ml, 1M) was added. The reaction mixture was stirred at room temperature for over night. The EtOH was removed and the residue was added 2 ml of ethyl acetate and 3 ml of water. This mixture was very slowly acidified with 10% HCl to PH=7. The ethyl acetate layer was separated and washed with brine, dried over Na2SO4. After filtration of the drying agent and removal of solvent, the reaction yielded the title compound as a white solid (155 mg). 1H NMR d 7.99 (s, 1H), 5.20 (s, 2H), 3.66 (s, 3H), 1.74 (m, 2H), 1.67 (m, 2H), 1.60 (s, 6H), 1.32 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:22][C:23]1[CH:24]=[C:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH:26]=[CH:27][CH:28]=1>C(#N)C.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH2:22][C:23]3[CH:24]=[C:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH:26]=[CH:27][CH:28]=3)[CH:10]=2)[O:3]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)Nc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1cccc(Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.4 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.88 g, 4.54 mmol) in acetonitrile (20 mL) was added cesium carbonate (4.43 g, 13.61 mmol) and tert-butyl 3-(bromomethyl)phenylcarbamate (1.298 g, 4.54 mmol). The reaction was stirred at room temperature for 3 h. After this time, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The aqueous phase was extracted with CHCl3. The combined organic layer was dried over anhydrous MgSO4, filtered, and concentrated. The resulting residue was purified by (0-100% ethyl acetate:hexanes) to afford the title compound (1.06 g, 2.65 mmol, 59% yield) as a colorless oil. LCMS, [M+H]+=400.3.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[CH2:9]1)(OC(C)(C)C)=O.[CH2:15](O)[CH2:16][OH:17].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[O:14]1[C:10]2([CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)[O:17][CH2:16][CH2:15]1
Reactant: OCCO
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: C1CNCC2(C1)OCCO2

Procedure:
To a solution of 1-Boc-3-piperidone (700 mg, 3.51 mmol) in toluene (20 mL) was added ethylene glycol (588 μL, 10.54 mmol) followed by p-toluene sulfonic acid hydrate (1.0 g, 5.27 mmol) and the reaction heated to reflux using Dean-Stark apparatus for 7 h. To the mixture was added NaHCO3 solution, and the organic layer was removed. The aqueous phase was evaporated to dryness and the resulting residue dissolved in THF. Filtration through celite and removal of the solvent in vacuo gave the desired product as light brown oil. δH (CD3OD): 3.99 (2H, s), 3.73–3.57 (2H, m), 3.63 (4H, m), 2.77 (1H, m), 2.73 (1H, m), 1.76 (2H, m).