Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:7])[NH:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:14]Br>CN1C(=O)CCC1>[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:14][N:6]1[CH2:5][CH2:4][CH2:3][CH2:2][C:1]1=[O:7]
Reactant: Fc1ccc(CBr)cc1Cl
Reactant: O=C1CCCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: O=C1CCCCN1Cc1ccc(F)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Valerolactam (153.3 g, 1.54 mol) was dissolved in NMP (3.5 L) and cooled to 0° C. NaH (67.7 g, 1.69 mol, 60% dispersion in oil) was added in portions over 5 minutes keeping the temperature at 0° C. The reaction was stirred for 30 minutes, and 3-chloro-4-fluorobenzylbromide (345.5 g, 1.54 mol) dissolved in 200 mL NMP was added over 30 minutes, again keeping the internal temperature at 0° C. The reaction was aged for 1 hour at 0° C., and allowed to warm to room temperature overnight. LCMS showed the reaction complete. The reaction mixture was quenched with 5 L distilled H2O, extracted with 3 portions of CH2Cl2 (2 L, 1 L, 1 L) and the organic layers combined and washed with three 4 L portions of water. The organic layer was concentrated and was found to contain NMP. The residual oil was dissolved in EtOAc (4 L), and extracted with three 2 L portions of water. The organic layer was concentrated to give the product that solidified upon standing.
Reaction SMILES: Br[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:3].[Li]C(C)(C)C.[B:15](OC(C)C)([O:20]C(C)C)[O:16]C(C)C.Cl>C(OCC)C>[CH2:3]=[C:2]([B:15]([OH:20])[OH:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C=C(Br)c1ccccc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: C=C(B(O)O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of α-bromo styrene (5.5 g, 30 mmol) in diethyl ether (30 mL) at −78° C. was treated with a solution of tert-BuLi (1.7 M solution, 21.2 mL, 36 mmol), stirred at −78° C. for 0.5 hours, treated with triisopropyl borate (8.31 mL, 36 mmol) over 48 minutes, stirred for 1 hour, warmed to room temperature over 18 hours, diluted with diethyl ether (100 mL), treated with 1M HCl (100 mL), stirred at room temperature for 5 hours, concentrated to remove the THF, adjusted pH 14 with IN NaOH, washed with hexane, adjusted to pH 1 with 1M HCl, and extracted with ethyl acetate. The extract was dried (Na2SO4), filtered and concentrated to provide the title compound.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:21]=[CH:22][C:23]=1[O:24]C)[O:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([C:15]2[N:16]=[N:17][NH:18][N:19]=2)=[CH:10][C:9]=1[CH3:20])([CH3:3])[CH3:2].B(Br)(Br)Br.O>C(Cl)(Cl)Cl>[CH3:14][C:13]1[CH:12]=[C:11]([C:15]2[N:16]=[N:17][NH:18][N:19]=2)[CH:10]=[C:9]([CH3:20])[C:8]=1[O:7][C:6]1[CH:21]=[CH:22][C:23]([OH:24])=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=1
Reactant: COc1ccc(Oc2c(C)cc(-c3nn[nH]n3)cc2C)cc1C(C)C
Agent: BrB(Br)Br
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1cc(-c2nn[nH]n2)cc(C)c1Oc1ccc(O)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 5-[4-(3-isopropyl-4-methoxy-phenoxy)-3,5-dimethyl-phenyl]-2H-tetrazole (26 mg, 0.077 mmol) in 6 ml of chloroform at RT was added boron tribromide (1M in dichloromethane, 0.12 ml, 0.12 mmol). The reaction was stirred for 20 hours at RT, then additional boron tribromide (1M in dichloromethane, 0.3 ml) was added, and the reaction was stirred at RT for 6 hours. Water (10 ml) was added, and the reaction was stirred for 1 hour at RT, then extracted with ethyl acetate (3×15 ml), dried, and concentrated. The white solid residue was triturated with dichloromethane (2×0.3 ml) and dried in vacuo to afford the title product of Example 1. MS (APCI−) Calc.: 324.4, Found: 323.3 (M−1).
Reaction SMILES: [N:1]1([CH2:5][C:6]2[N:10]([CH3:11])[N:9]=[C:8]([N+:12]([O-])=O)[CH:7]=2)[CH2:4][CH2:3][CH2:2]1>C(O)C>[N:1]1([CH2:5][C:6]2[N:10]([CH3:11])[N:9]=[C:8]([NH2:12])[CH:7]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cn1nc([N+](=O)[O-])cc1CN1CCC1
Solvent: CCO
Product: Cn1nc(N)cc1CN1CCC1
Reaction time: 2 h
Yield: 94.4 %

Procedure:
A 500-mL Parr reactor bottle was purged with nitrogen and charged with 10% palladium on carbon (50% wet, 180 mg dry weight) and a solution of 21 (1.00 g, 5.10 mmol) in ethanol (100 mL). The bottle was attached to a Parr hydrogenator, evacuated, charged with hydrogen gas to a pressure of 50 psi and shaken for 2 h. After this time, the hydrogen was evacuated, and nitrogen was charged into the bottle. Celite 521 (1.0 g) was added, and the mixture was filtered through a pad of Celite 521. The filter cake was washed with ethanol (2×25 mL), and the combined filtrates were concentrated to dryness under reduced pressure to afford a 94% yield of 22 (800 mg) as a yellow oil: 1H NMR (300 MHz, CDCl3) δ 5.47 (s, 1H), 3.64 (s, 3H), 3.57 (br s, 2H), 3.43 (s, 2H), 3.19 (t, 4H, 0.1=7.2 Hz), 2.06 (quintet, 2H, J=7.2 Hz); MS (ESI+) m/z 167.1 (M+H).
Reaction SMILES: O[CH2:2][CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7](=[O:21])[C:6]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(Br)(Br)(Br)[Br:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Br:28][CH2:2][CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7](=[O:21])[C:6]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: BrC(Br)(Br)Br
Reactant: CCOC(=O)c1c(NCCO)c2ccccc2n(-c2ccccc2)c1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1c(NCCBr)c2ccccc2n(-c2ccccc2)c1=O
Yield: 74.6 %

Procedure:
Dissolved in 30 ml of tetrahydrofuran were 0.352 g (1 mmol) of ethyl 4-(2-hydroxyethylamino)-2-oxo-1-phenyl-1,2-dihydroquinoline-3-carboxylate, 0.67 g (2 mmol) of carbon tetrabromide and 0.531 g (2 mmol) of triphenylphosphine, followed by a reaction at room temperature for 5 hours. The insoluble matter was filtered off, and the organic layer was concentrated under reduced pressure. The resulting residue was purified by chromatography on a silica gel column and then recrystallized from ethyl acetate/isopropyl ether, whereby 0.31 g of ethyl 4-(2-bromoethylamino)-2-oxo-1-phenyl-1,2-dihydroquinoline-3-carboxylate was obtained (yield: 74.7%).
Reaction SMILES: C(O[C:4](=[O:26])[C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13](C(F)(F)F)[CH:12]=2)[C:8]([O:21][CH2:22][CH2:23][OH:24])=[C:7]([Br:25])[CH:6]=1)C.[CH3:27][NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[Br:25][C:7]1[CH:6]=[C:5]([C:4]([N:28]([CH3:27])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[O:26])[CH:10]=[C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:8]=1[O:21][CH2:22][CH2:23][OH:24]
Reactant: CNCCCCCCCCc1ccccc1
Reactant: CCOC(=O)c1cc(Br)c(OCCO)c(-c2cccc(C(F)(F)F)c2)c1
Product: CN(CCCCCCCCc1ccccc1)C(=O)c1cc(Br)c(OCCO)c(-c2ccccc2)c1

Procedure:
5-bromo-6-(2-hydroxyethoxy)-N-methyl-N-(8-phenyloctyl)[1,1′-biphenyl]-3-carboxamide was prepared as a colorless oil (0.200 g, 56%) from 3-bromo-5-(m-trifluoromethylphenyl)-4-(2-hydroxyethoxy)-benzoic acid ethyl ester and N-methyl-N-(8-phenyloctyl)amine using a procedure similar to step 2 of Example 175. 1H NMR (CDCl3) δ 7.87–7.54 (m, 5H); 7.38–7.12 (m, 6H); 3.65 (m, 4H); 3.50 and 3.03 (2bt, 2H); 3.03 (2s, 3H); 2.58 (m, 2H); 1.98 (bs, 1H); 1.60 (m, 4H); 1.40–1.22 (m, 8H).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[CH:23])[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.I[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[S:32][C:33]([CH3:36])=[N:34][N:35]=2)[CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C.[Cu]I>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[C:23][C:29]4[CH:30]=[CH:25][CH:26]=[C:27]([C:31]5[S:32][C:33]([CH3:36])=[N:34][N:35]=5)[CH:28]=4)[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1nnc(-c2cccc(I)c2)s1
Reactant: C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CCCC(=O)C1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COc1ccc(C2(C#Cc3cccc(-c4nnc(C)s4)c3)CCCC(=O)C2)cc1OC1CCCC1
Temperature: 25 °C
Yield: 86.7 %

Procedure:
To a solution of the compound from Example 3 (E1) (0.10 g, 0.32 mmol) and 1-iodo-3-(5-methyl-[1,3,4]thiadiazol-2-yl)benzene (0.10 g, 0.32 mmol) in triethylamine (5 mL) under an argon atmosphere was added trace tetrakis(triphenylphosphine)palldium(0), copper(I) iodide and triphenylphosphine. The mixture was refluxed for 0.20 h, was cooled to room temperature and was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, was dried (MgSO4) and was evaporated. Purification by flash chromatography, eluting with 1:1 hexanes/ethyl acetate provided the title compound as a white solid (0.135 g, 87%), m.p. 97-99° C.
Reaction SMILES: [I:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][CH2:8][NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].O=[CH:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>CO.C(OCC)(=O)C>[CH2:10]([N:9]([CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:8][CH2:7][O:6][C:5]1[CH:22]=[CH:23][C:2]([I:1])=[CH:3][CH:4]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCOC(=O)CCC=O
Reactant: CCCCCCCCCCCCNCCOc1ccc(I)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCN(CCCC(=O)OCC)CCOc1ccc(I)cc1
Temperature: 22 °C
Reaction time: 24 h
Yield: 88.7 %

Procedure:
To a mixture of N-2-[4-iodophenoxy]ethyldodecylamine (4.0 g, 9.3 mmol) and sodium cyanoborohydride (1.45 g, 23 mmol) in methanol (80 ml) was added dropwise a solution of ethyl 4-oxobutyrate (Fournet, G.; Balme, G.; Barieux, J. J. and Gore, J.Tetrahedron, 1988, 44, 5821) (2.4 g, 18 mmol) in methanol (20 ml) over a period of 10 min. The resulting mixture was stirred at 22° C. for 24 h, and then diluted with ethyl acetate (600 ml), washed with brine (3×250 ml). The aqueous phase was extracted with ethyl acetate (150 ml), and the combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel (Hexane/ethyl acetate 8:1 to 6:1) to afford the title compound (4.5 g, 89%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH3:11])[C:3]=1[C@H:12]([OH:15])[CH2:13][OH:14].N1C=CC=CC=1.[C:22](Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]>C(Cl)Cl>[C:22]([O:14][CH2:13][C@H:12]([C:3]1[C:4]([CH3:11])=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[Br:1])[OH:15])(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: Cc1cc([N+](=O)[O-])cc(Br)c1[C@H](O)CO
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc([N+](=O)[O-])cc(Br)c1[C@H](O)COC(=O)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a suspension of (S)-1-(2-bromo-6-methyl-4-nitrophenyl)ethane-1,2-diol (65D) (6.96 g, 25.22 mmol) in DCM (100 ml), was added pyridine (5 mL) at 0° C. To the solution was added pivaloyl chloride (PivCl) slowly at 0° C. The reaction mixture was stirred at 0° C. for 5 min, then raised to rt, stirred at rt for 5 h. The reaction mixture was washed by sat. NaHCO3, extracted by DCM, dry over MgSO4, filtered, purified by silica gel column, eluting by 0-40% EtOAc in Hexanes to give 9.13 g of 65E. The product taken on without full characterization.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([OH:17])([CH2:14][NH:15][CH3:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl.[C:21](Cl)(Cl)=[O:22].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH3:16][N:15]1[CH2:14][C:11]2([CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]2)[O:17][C:21]1=[O:22]
Reactant: CNCC1(O)CCN(Cc2ccccc2)CC1
Reactant: O=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CN1CC2(CCN(Cc3ccccc3)CC2)OC1=O

Procedure:
A solution of 23 g 1-benzyl-4-hydroxy-4-methylaminomethylpiperidine and 250 ml dichloromethane is mixed with 100 ml of a 15% solution of phosgene in toluene. Evaporation of solvent gives a residue which is treated with 300 ml dichloromethane and 300 ml aqueous sodium bicarbonate. Separation of the dichloromethane layer followed by evaporation gives 20 g 3-methyl-8-benzyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one, mp 137°-138°.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[C:4]([C:3]1[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)([O:6][CH3:7])=[O:5]
Reactant: C1CNCCN1
Reactant: COC(=O)c1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1ccccc1N1CCNCC1
Temperature: 25 °C
Yield: 25.5 %

Procedure:
To a solution of methyl 2-bromobenzoate (1.63 g, 17.8 mmol) in 1,4-dioxane (100 ml) at room temperature, were added piperazine (15.3 g, 178 mmol) and K2CO3 (4.92 g, 35 mmol). The resulting mixture was heated to reflux for 7 days after which the reaction mixture was cooled to room temperature and the solvent and the excess piperazine were removed in vacuo and heating with a hot water bath. The residue was dissolved in 1N NaOH solution and extracted with CH2Cl2 (6×30 ml), dried over Na2SO4. The solvent was removed in vacuo to obtain 1-(2-carbomethoxyphenyl)-piperazine as a yellow oil (1.0 g, 26%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9].[C:14]([O:18][C:19]([N:21]1[CH:25]=[CH:24][CH:23]=[C:22]1B(O)O)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[CH:11]([S:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:22]1[N:21]([C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])[CH:25]=[CH:24][CH:23]=1)(=[O:10])=[O:9])([CH3:13])[CH3:12]
Reactant: CC(C)S(=O)(=O)c1ccccc1Br
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
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: COCCOC
Product: CC(C)S(=O)(=O)c1ccccc1-c1cccn1C(=O)OC(C)(C)C
Temperature: 95 °C
Yield: 83 %

Procedure:
To 21B (0.53 g, 2.0 mmol), 3A (0.51 g, 2.4 mmol) and sodium carbonate (4.0 mL, 2M, 8.0 mmol) in 1,2-dimethoxyethane (25 mL, flushed and degassed (3×) with nitrogen) was added Pd(PPh3)4 (0.23 g, 0.2 mmol) under nitrogen. The reaction was heated to 95° C. for 3 h. The catalyst was filtered over celite and washed with ethyl acetate. The organic layer was washed with water, brine and then dried over sodium sulfate. The solvent was removed and the crude residue was purified by flash column chromatography to give 0.58 g of product 21C (69% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH:30]1([C:36]([CH3:40])([CH3:39])[CH2:37]O)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.[K+].[Br-].Cl>>[CH:30]1([C:36]([CH3:40])([CH3:39])[CH2:37][O:24][C:23]([C:18]2([C:20]([O:22][CH2:37][C:36]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)([CH3:40])[CH3:39])=[O:21])[O:17][C:16]3[CH:26]=[CH:27][C:13]([CH2:12][C@H:11]([NH:10][CH2:9][C@@H:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[OH:29])[CH3:28])=[CH:14][C:15]=3[O:19]2)=[O:25])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CC(C)(CO)C1CCCCC1
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Product: C[C@H](Cc1ccc2c(c1)OC(C(=O)OCC(C)(C)C1CCCCC1)(C(=O)OCC(C)(C)C1CCCCC1)O2)NC[C@H](O)c1cccc(Cl)c1

Procedure:
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo-[1,3]dioxole-2,2-dicarboxylic acid and 2-cyclohexyl-2-methylpropanol according to the procedure of Example 1 as an off-white solid; 1H NMR (DMSO-d6,400 MHz) δ 1.1 (s, 6H, CH3, CH3), 1.45 (s, 6H, CH3, CH3), 1.5 (s, 6H, CH3, CH3), 2.6 (m, 1H, CH), 3-3.3 (m, 3H, CH, CH2), 3.4 (brs, 1H, CH), 4.04 (s, 4H, OCH2, OCH2), 5.05 (m, 1H, CH), 6.35 (d, J=4.17 Hz, 1H, OH), 6.85 (dd, J=7.9, 1.32 Hz, 1H, Ar--H), 7.07 (m, 2H, Ar--H), 7.38-7.42 (m, 3H, Ar--H), 7.5 (s, 1H, Ar--H), 8.8 (brs, 1H, NH), 9.4 (brs, 1H, NH); IR (KBr, cm-1) 3400 (OH), 2900 (NH), 1760 (CO); MS m/e 698 (M+H)+ ; Analysis for: C40H56ClNO7 ×HCl: Calc'd: C, 65.38; H, 7.82; N, 1.91; Found: C, 65.32; H, 7.96; N, 1.94.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5]2.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>N1C=CC=CC=1>[C:17]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5]2)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1cc2cc(N)ccc2n1C
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2cc(NC(=O)c3ccccc3)ccc2n1C
Temperature: 25 °C
Yield: 52.4 %

Procedure:
In 20 ml of pyridine was dissolved 0.80 g (3.67 mmol) of ethyl 5-amino-1-methyl-2-indolecarboxylate. While stirring at room temperature, 0.57 g (4.03 mmol) of benzoyl chloride was added to the solution. After stirring for 2 hours at 70° C., the reaction mixture was cooled to room temperature and then poured onto ice water. The mixture was then extracted three times with ethyl acetate. The combined extracts were washed with lN hydrochloric acid and then with saturated sodium hydrogencarbonate solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give 0.62 g (52.5%) of ethyl 5-benzamido-1-methyl-2-indolecarboxylate.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12]3[N:17]=[CH:16][N:15]=[C:14]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=4[NH2:28])[CH:13]=3)[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH:29]1([CH:35]=O)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C([O-])(O)=O.[Na+].O>[CH:29]1([CH2:35][NH:28][C:19]2[CH:20]=[C:21]([C:24]([F:25])([F:27])[F:26])[CH:22]=[CH:23][C:18]=2[C:14]2[CH:13]=[C:12]([O:11][C:8]3[CH:9]=[C:10]4[C:5]([CH:4]=[CH:3][CH:2]=[N:1]4)=[CH:6][CH:7]=3)[N:17]=[CH:16][N:15]=2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=CC1CCCCC1
Reactant: Nc1cc(C(F)(F)F)ccc1-c1cc(Oc2ccc3cccnc3c2)ncn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: FC(F)(F)c1ccc(-c2cc(Oc3ccc4cccnc4c3)ncn2)c(NCC2CCCCC2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-[6-(quinolin-7-yloxy)-pyrimidin-4-yl]-5-trifluoromethyl-phenylamine, (Example 163), (0.40 g, 1.1 mmol) in 1,2-dichloroethane (11 mL) was added cyclohexanecarboxaldehyde (0.32 mL, 2.6 mmol, Aldrich) and the mixture was stirred at room temperature for 18 h. NaBH(OAc)3 (0.55 g, 2.6 mmol) was added and stirring was continued for 8 h at 40° C. The reaction was diluted with satd NaHCO3 and H2O, and extracted with EtOAc (2×75 mL). The combined extracts were washed with H2O (75 mL) and brine (75 mL), dried over Na2SO4, filtered and concentrated onto silica gel. Purification by silica gel chromatography (gradient, 10 to 40% EtOAc/hexanes) afforded the title compound as a yellow solid. Mp: 137-138° C. MS (ESI, pos. ion) m/z: 479.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Mg]Br.[CH3:11][C:12]([CH3:20])=[CH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16]>C(OCC)C.[Cu]I>[F:16][C:15]([F:18])([F:17])[C:14](=[O:19])[CH2:13][C:12]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])([CH3:20])[CH3:11]
Reactant: CC(C)=CC(=O)C(F)(F)F
Reactant: COc1ccccc1[Mg]Br
Agent: [Cu]I
Solvent: CCOCC
Product: COc1ccccc1C(C)(C)CC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.9 %

Procedure:
To a solution of 2-methoxyphenylmagnesium bromide (131 mL, 65.7 mmol, 0.5M solution in THF) at 0° C. was added CuI (12.5 g, 65.7 mmol). The reaction mixture was warmed to room temperature and stirred for 1 hour. A solution of 4-methyl-1,1,1-trifluoropent-3-en-2-one (10.0 g, 65.74 mmol) (made via procedure in PCT international application WO03/082280, Example 10), in diethyl ether (200 mL) was added and the reaction mixture was stirred overnight. The reaction was quenched with saturated aqueous ammonium chloride (50 mL) and extracted with three 300 mL portions of ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography using 0%-5% ethyl acetate in hexanes as the eluent. Concentration in vacuo of the product-rich fractions gave 14 g (82%) of 1,1,1-trifluoro-4-(2-methoxyphenyl)-4-methylpentan-2-one.
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][C@H:13]([C@H:15]2[O:24][C@@H:18]3[O:19][C:20]([CH3:23])([CH3:22])[O:21][C@@H:17]3[CH2:16]2)[OH:14])(=O)=O)=CC=1.[C:25]([O-])([O-])=O.[K+].[K+]>CO>[CH3:22][C:20]1([CH3:23])[O:19][C@H:18]2[O:24][C@H:15]([C@@H:13]([OH:14])[CH2:12][O:11][CH3:25])[CH2:16][C@H:17]2[O:21]1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](O)[C@@H]2C[C@H]3OC(C)(C)O[C@H]3O2)cc1
Agent: [K+]
Solvent: CO
Product: COC[C@H](O)[C@@H]1C[C@H]2OC(C)(C)O[C@H]2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.4 %

Procedure:
To a stirred solution of [(2S)-2-[(3aR,5S,6aR)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]-2-hydroxy-ethyl] 4-methylbenzenesulfonate (compound 6a, 3.2 g, 8.9 mmol) in methanol (50 mL) was added K2CO3 (5.4 g, 40 mmol). After being stirred at room temperature for 2 hours, the resulting solution was concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluting with 1:10 EtOAc in petroleum ether) to afford 1.62 g of (1S)-1-[(3aR,5S,6aR)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]-2-methoxy-ethanol (compound 21b) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](Cl)=[O:20]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:19](=[O:20])[C:18]3[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=3[Cl:16])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Reactant: O=C(Cl)c1ccccc1Cl
Product: O=C(NC1CCCc2c1[nH]c1ccc(Br)cc21)c1ccccc1Cl

Procedure:
N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-chlorobenzamide was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and 2-chlorobenzoyl chloride in a similar manner as described above to give a white solid (30% yield). 1H-NMR (DMSO-d6): δ 10.98 (s, 1H), 8.89 (d, 1H), 7.54 (dd, 2H), 7.48-7.44 (m, 1H), 7.42 (dd, 1H), 7.40-7.34 (m, 1H), 7.28 (d, 1H), 7.13 (dd, 1H), 5.26 (m, 1H), 2.60 (m, 2H), 2.08-1.91 (m, 2H), 1.90-1.73 (m, 2H); MS m/z 403 (M−1).