Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:11][CH2:12]O>OS(O)(=O)=O>[CH2:11]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][N:9]=[CH:10][C:2]=1[Cl:1])[CH3:12]
Reactant: CCO
Reactant: O=C(O)c1ccncc1Cl
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccncc1Cl

Procedure:
A solution of 3-chloroisonicotinic acid (18.6 mmol) in 120 mL EtOH and 3 mL conc. H2SO4 was heated to reflux overnight. The mixture was concentrated in vacuo, redissolved in aq. NaHCO3 solution and extracted with EtOAc (2×). The combined organic layers were dried over MgSO4 and concentrated in vacuo to give the desired product as yellow oil;
Reaction SMILES: [F:1][C:2]1[C:3]([F:45])=[CH:4][C:5]2[C:10]3[C:11]4[C:42](=[O:43])[NH:41][C:40](=[O:44])[C:12]=4[C:13]4[C:14]5[C:19]([N:20]([C@@H:22]6[O:35][C@@H:34]7[CH2:36][O:37][C@@H:32]([CH2:33]7)[C@H:23]6[O:24]CC6C=CC=CC=6)[C:21]=4[C:9]=3[NH:8][C:6]=2[CH:7]=1)=[CH:18][C:17]([F:38])=[C:16]([F:39])[CH:15]=5>[OH-].[OH-].[Pd+2].C1COCC1>[F:1][C:2]1[C:3]([F:45])=[CH:4][C:5]2[C:10]3[C:11]4[C:42](=[O:43])[NH:41][C:40](=[O:44])[C:12]=4[C:13]4[C:14]5[C:19]([N:20]([C@@H:22]6[O:35][C@@H:34]7[CH2:36][O:37][C@@H:32]([CH2:33]7)[C@H:23]6[OH:24])[C:21]=4[C:9]=3[NH:8][C:6]=2[CH:7]=1)=[CH:18][C:17]([F:38])=[C:16]([F:39])[CH:15]=5
Reactant: O=C1NC(=O)c2c1c1c3cc(F)c(F)cc3[nH]c1c1c2c2cc(F)c(F)cc2n1[C@@H]1O[C@@H]2CO[C@@H](C2)[C@H]1OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C1NC(=O)c2c1c1c3cc(F)c(F)cc3[nH]c1c1c2c2cc(F)c(F)cc2n1[C@@H]1O[C@@H]2CO[C@@H](C2)[C@H]1O
Yield: 58.8 %

Procedure:
A mixture of 2,3,9,10-tetrafluoro-12-(2—O-benzyl-3, 6-anhydro-4-deoxy-β-D-glucopyranosyl)-6, 7, 12, 13-tetrahydro(5H)indolo[2, 3-a]pyrrolo[3, 4-c]carbazole-5, 7-dione (0.034 g, 0.055 mmol) and 20% Pd(OH)2/C (0.048 g) in 5 mL of freshly distilled THF was hydrogenated (balloon pressure) at room temperature for 5 days. The resulting mixture was filtered through a bed of Celite and the cake was washed with THF and then with methanol. The filtrate was evaporated and the residue was chromatographed (Sephadex LH-20/ methanol) to give the title compound (0.017 g, 59%) as a yellow solid: 1H NMR (THF-d8, 400 MHz) δ 11.15 (br s, 1H), 10.17 (br s, 1H), 9.19 (dd, J=11.1, 8.5 Hz, 1H), 9.09 (dd, J=11.2, 8.3 Hz, 1H), 7.81 (dd, J=11.6, 6.7 Hz, 1H), 7.51 (dd, 10.5, 6.7 Hz, 1H), 6.21 (d, J=7.3 Hz, 1H), 5.37 (br s, 1H), 4.89 (s, 1H), 4.57 (m, 2H), 4.27 (d, J=9.7 Hz, 1H), 3.85 (d, J=9.1 Hz, 1H), 3.09 (d, J=13.4 Hz, 1H), 2.09 (dd, J=13.1, 6.0 Hz, 1H); MS (ESI−) m/e 524 (M−H)−; HPLC: 99.0% (270 nm).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:34])[NH:6][C:7]([C:15]1[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]([CH:31]([CH3:33])[CH3:32])C(=O)C)[CH2:23][CH2:22]3)=[CH:17][CH:16]=1)=[N:8]2.[OH-].[Na+]>Cl>[CH:31]([NH:27][CH:24]1[CH2:25][CH2:26][N:21]([C:18]2[CH:19]=[CH:20][C:15]([C:7]3[NH:6][C:5](=[O:34])[C:4]4[C:9](=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:3]=4[O:2][CH3:1])[N:8]=3)=[CH:16][CH:17]=2)[CH2:22][CH2:23]1)([CH3:33])[CH3:32]
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCC(N(C(C)=O)C(C)C)CC4)cc3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCC(NC(C)C)CC4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.6 %

Procedure:
A solution of N-(1-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperidin-4-yl)-N-isopropylacetamide (0.130 g, 0.27 mmol) in 2 N HCl (8 mL) was heated to reflux and stirred overnight. The resulting solution was cooled to room temperature, basified with 2 N NaOH (pH 14), and extracted with CH2Cl2. The solution was concentrated in vacuo and the residue was purified by flash chromatography on silica gel, eluting with 30% to 100% of 92:7:1 CHCl3/MeOH/concentrated NH4OH in CH2Cl2, to afford the title compound (0.060 g, 52%). 1H NMR (300 MHz, DMSO-d6): δ 8.07 (d, J=9.0 Hz, 2H), 6.99 (d, J=9.1 Hz, 2H), 6.67 (s, 1H), 6.46 (s, 1H), 3.75-3.95 (m, 8H), 2.81-2.99 (m, 3H), 2.69-2.79 (m, 1H), 1.79-1.92 (m, 2H), 1.14-1.37 (m, 3H), 0.97 (d, J=6.1 Hz, 6H). ESI MS m/z 423 [M+H]+.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]([O:21][Si](C)(C)C)C#N.[Br:26][C:27]1[S:31][C:30]([CH:32]=[O:33])=[CH:29][CH:28]=1>O1CCCC1>[Br:26][C:27]1[S:31][C:30]([CH:32]([OH:33])[C:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[Cl:11])=[O:21])=[CH:29][CH:28]=1
Reactant: O=Cc1ccc(Br)s1
Reactant: C[Si](C)(C)OC(C#N)c1ccccc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(c1ccccc1Cl)C(O)c1ccc(Br)s1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 14 %

Procedure:
Under an atmosphere of nitrogen, to a clod (−78° C.) solution of lithium bis(trimethylsilyl)amide (8.05 mL, 1.0M solution in THF, 8.05 mmol) was added a solution of (2-chloro-phenyl)-trimethylsilanyloxy-acetonitrile (1.69 g, 7 mmol) in tetrahydrofuran (10 mL) dropwise over 10 min. After stirring for another 30 min, a solution of 5-bromothiophen-2-carboxaldehyde in tetrahydrofuran (10 mL) was added dropwise. The reaction was stirred overnight from −78° C. to reach room temperature, then was quenched by adding 3N HCl (20 mL) and warming at 40° C. for 5 hrs. After cooling, the mixture was partitioned between ethyl ether and water. The organic layer was stirred with 1M NaOH (30 mL) for 2 hrs; and the layers were separated. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (Hexane/EtOAc, 8/2) to give a brown oil (320 mg, 14% yield). 1H-NMR (400 MHz, CDCl3): δ 4.35 (d, 1H), 6.12 (d, 1H), 7.02 (d, 1H), 7.26 (m, 2H), 7.41 (d, 1H), 7.44 (dd, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:39])[C@@H:12]([N:24]2[C:28](=[O:29])[CH:27]([C:30]3[CH:35]=[CH:34][C:33]([S:36][CH3:37])=[CH:32][CH:31]=3)[NH:26][C:25]2=[O:38])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:22])[F:21])[S:8][CH:9]=1)=[O:4].ClC1C=CC=C(C(OO)=[O:48])C=1>ClCCl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:39])[C@@H:12]([N:24]2[C:28](=[O:29])[CH:27]([C:30]3[CH:31]=[CH:32][C:33]([S:36]([CH3:37])=[O:48])=[CH:34][CH:35]=3)[NH:26][C:25]2=[O:38])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:22])[F:21])[S:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1csc(NC(=O)[C@H](Cc2ccccc2C(F)(F)F)N2C(=O)NC(c3ccc(SC)cc3)C2=O)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC(=O)c1csc(NC(=O)[C@H](Cc2ccccc2C(F)(F)F)N2C(=O)NC(c3ccc(S(C)=O)cc3)C2=O)n1
Reaction time: 0.17 h
Yield: 52.6 %

Procedure:
To a solution of 2-[(S)-2-[4-(4-methylsulfanyl-phenyl)-2,5-dioxo-imidazolidin-1-yl]-3-(2-trifluoromethyl-phenyl)-propionylamino]-thiazole-4-carboxylic acid methyl ester (95 mg, 0.16 mmol) in dichloromethane (15 mL) was added 3-chloroperbenzoic acid (75% purity) (45 mg, 0.19 mmol) at 0° C. After stirring for 10 minute the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium carbonate. The organic layer was dried over sodium sulfate, filtered, concentrated and the residue was purified by chromatography over silica gel eluted with acetone. The isolated material was precipitated from acetone with an excess of hexanes to afford 2-[(S)-2-[4-(4-methanesulfinyl-phenyl)-2,5-dioxo-imidazolidin-1-yl]-3-(2-trifluoromethyl-phenyl)-propionylamino]-thiazole-4-carboxylic acid methyl ester as an amorphous white solid (50 mg, 52%).
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl[CH2:12][C:13]([NH:15][C:16]1[CH:34]=[CH:33][C:19]([C:20]([N:22]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:21])=[CH:18][CH:17]=1)=[O:14]>CS(C)=O>[CH3:8][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=1[O:7][CH2:12][C:13]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([N:22]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:21])=[CH:33][CH:34]=1)=[O:14]
Reactant: Cc1ccccc1O
Reactant: O=C(CCl)Nc1ccc(C(=O)N2CCCCc3ccccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cc1ccccc1OCC(=O)Nc1ccc(C(=O)N2CCCCc3ccccc32)cc1
Temperature: 90 °C
Reaction time: 7.5 h
Yield: 43.8 %

Procedure:
o-Cresol (0.36 g) is dissolved in dimethylsulfoxide (4 ml) containing sodium hydroxide powder (0.18 g) and thereto is added 1-[4-(2-chloroacetylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1.03 g). The mixture is stirred at 90° C. for 7.5 hours. The reaction mixture is poured into ice-water (300 ml) and the precipitated crystal is collected by filtration, washed with water, and purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=2:1), and recrystallized from ethyl acetate to give 1-{4-[2-(2-methylphenoxy)acetylamino]benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine (546 mg) as colorless scales, m.p. 172.5°-175° C.
Reaction SMILES: [C:1]12([C:11]3[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:12]=3[OH:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.CN(C=O)C.C(N(CC)CC)C.[Si:31](Cl)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]>CN(C1C=CN=CC=1)C.O>[C:1]12([C:11]3[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:12]=3[O:18][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc(Br)cc1C12CC3CC(CC(C3)C1)C2
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Br)cc1C12CC3CC(CC(C3)C1)C2
Yield: 64152.2 %

Procedure:
A 2.0 L three-neck flask attached with a power-stirrer was charged with 2-adamantan-1-yl-4-bromophenol (102.8 g, 0.334 mol, 1.0 eq), DMAP (3.67 g, 0.0301 mol), anhydrous DMF (1.0 L) and triethylamine (76.1 g, 0.753 mol, 1.25 eq). Stirring was initiated and to the resulting solution at room temperature was added t-butyl-dimethylsilyl chloride (99.8 g, 0.662 mmol, 1.10 eq). The resulting mixture was allowed to stir overnight, poured into water, and extracted with diethyl ether (2×). The combined organics were washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered, and evaporated. The residue was purified on silica gel (hexane) to give 179 g (70%) of 3-adamantan-1-yl-4-t-butyldimethylsilanyloxybromobenzene as a white powder. 1H NMR (300 MHz; CDCl3): δ 0.33 (s, 6H), 1.03 (s, 9H), 1.75 (brs, 6H), 2.06 (s, 9H), 6.65 (d, J=8.4 Hz, 1H), 7.14 (dd, J1=8.4 Hz, J2=2.1 Hz, 1H), 7.29 (d, J=2.1 Hz, 1H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[I:13][C:14]1[CH:25]=[CH:24][C:17]([O:18][CH2:19][C:20]([NH:22][NH2:23])=[O:21])=[CH:16][CH:15]=1>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:23][NH:22][C:20](=[O:21])[CH2:19][O:18][C:17]1[CH:24]=[CH:25][C:14]([I:13])=[CH:15][CH:16]=1
Reactant: NNC(=O)COc1ccc(I)cc1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Product: O=C(COc1ccc(I)cc1)NN=C1C(=O)Nc2ccc(I)cc21
Temperature: 100 °C
Yield: 79 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 2-(4-iodophenoxy)acetohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 173 mg of the title compound (79%) as a yellow solid in 96.4% purity by HPLC (Rt: 6.41, gradient of 10 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][NH:8][C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][CH:21]=2)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:5][CH:4]=1.[Cl:24][C:25]1[CH:26]=[C:27](N(C2CC2)CC2C=CC(OC)=CC=2)[C:28]2[N:29]([C:31]([C:34]#[N:35])=[CH:32][N:33]=2)[N:30]=1>CO>[Cl:24][C:25]1[CH:26]=[C:27]([N:8]([CH2:7][C:6]2[CH:22]=[CH:23][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][CH:21]=2)[C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[C:28]2[N:29]([C:31]([C:34]#[N:35])=[CH:32][N:33]=2)[N:30]=1
Reactant: COc1ccc(CN(c2cc(Cl)nn3c(C#N)cnc23)C2CC2)cc1
Reactant: COc1ccc(CNc2cccc(C(=O)OC(C)(C)C)c2)cc1
Solvent: CO
Product: COc1ccc(CN(c2cccc(C(=O)OC(C)(C)C)c2)c2cc(Cl)nn3c(C#N)cnc23)cc1

Procedure:
253B was prepared from 253A and a mixture of 1F following the procedure as described in 1G. HPLC: Rt=4.99 min. (PHENOMENEX® Luna C18 4.6×30 mm 3 u, A10-90% aqueous methanol containing 0.1% TFA in 2 min; 4 mL/min flow). MS (ES): m/z=490.1 [M+H]+.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:13]([NH2:15])=O)[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].F[P-](F)(F)(F)(F)F.C([O+](CC)CC)C.[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CCO>C(Cl)Cl>[C:4]([O:3][C:1](=[O:2])[NH:8][C@@H:9]([C:13](=[NH:15])[NH:37][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH:10]([CH3:12])[CH3:11])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(N)=O
Reactant: NCc1ccccc1
Agent: CC[O+](CC)CC
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCO
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=N)NCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 201.6 %

Procedure:
To a stirred solution of Boc-D-Valine amide (10 g, 46 mMol) in CH2Cl2 (200 mL) was added Triethyloxonium hexafluorophosphate (13.0 g, 48 mMol). (The reaction started out as a suspension which gradually cleared.) The reaction was stirred for 48 h at RT, poured into a separatory funnel, washed with 1 N Na2CO3, dried (Na2SO4), filtered and concentrated under vacuum. To the remaining oil was added Benzylamine (5.0 mL, 23 mMol) and EtOH (20 mL). The reaction was stirred at 60° C. for 24 h. After cooling to RT the reaction was evaporated under vacuum. The title compound (14.16 g, >95% pure by LCMS) was obtained without purification as a pale yellow oil which eventually solidified to a waxy solid: MS (ES) m/e 306.4 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:34])([CH3:33])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:32])=[C:9]([CH3:31])[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18](/[C:21](/[CH3:28])=[CH:22]/[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:17][CH:16]=3)[C:11]=2[C:29]=1[CH3:30])=[O:5]>C(OCC)(=O)C.CCCCCC>[CH3:34][C:2]([CH3:1])([CH3:33])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:32])=[C:9]([CH3:31])[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:28])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:17][CH:16]=3)[C:11]=2[C:29]=1[CH3:30])=[O:5]
Reactant: CCOC(=O)/C=C(\C)c1ccc(C2COc3c(C)c(C)c(NC(=O)CC(C)(C)C)c(C)c32)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)CC(C)c1ccc(C2COc3c(C)c(C)c(NC(=O)CC(C)(C)C)c(C)c32)cc1
Yield: 76 %

Procedure:
Using ethyl(2E)-3-(4-(5-((3,3-dimethylbutanoyl)amino)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-3-yl)phenyl)but-2-enoate obtained in Example 179, the title compound was synthesized in the same manner as in Example 180. Yield: 76%. Melting point: 100-101° C. (ethyl acetate-hexane).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[C@H:9]([CH3:10])[CH2:8][C:7](=[O:11])[CH2:6]1)=[O:4].Cl>>[C:3]([C@@H:5]1[C@H:9]([CH3:10])[CH2:8][C:7](=[O:11])[CH2:6]1)([OH:4])=[O:2]
Reactant: COC(=O)[C@H]1CC(=O)C[C@H]1C
Agent: Cl
Product: C[C@@H]1CC(=O)C[C@@H]1C(=O)O
Yield: 79.9 %

Procedure:
1.18 g of (3S, 4R)-3-methoxycarbonyl-4-methylcyclopentanone was added to 20 ml of 3N-hydrochloric acid, and the mixture was refluxed for 2 hours. The resultant mixture was cooled down to room temperature, and concentrated to dryness. The residue was purified by distillation under a reduced pressure, and thus 0.858 g of the titled compound was obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10]([NH:17][C:18]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:19])=[N:9]1.C(N(CC)CC)C.Cl[C:34]([O:36][CH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1)=[O:35].O>O1CCCC1>[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10]([NH:17][C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:34]([O:36][CH:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)=[O:35])[CH2:22][CH2:21]2)=[O:19])=[N:9]1
Reactant: O=C(Cl)OC1CCCC1
Reactant: O=C(Nc1noc2ccccc12)N1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1noc2ccccc12)N1CCN(C(=O)OC2CCCC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
To a solution of N-1,2-benzisoxazol-3-ylpiperazine-1-carboxamide trifluoroacetate (200 mg, 0.555 mmol) and triethylamine (0.309 ml, 2.22 mmol) in tetrahydrofuran (4 ml) was added cyclopentyl chloroformate (124 mg, 0.833 mmol) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured to water and extracted with ethyl acetate. The extract was washed with water, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and ethyl acetate to give 135 mg (67.8%) of the desired product as a solid.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C@H:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl[CH2:36][C:37]([NH:39][C:40]1[C:45]([CH3:46])=[CH:44][CH:43]=[CH:42][C:41]=1[CH3:47])=[O:38]>>[F:34][C:2]([F:33])([F:1])[C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1)[C:13]([N:15]1[CH2:20][CH2:19][C@H:18]([N:21]2[CH2:26][CH2:25][N:24]([CH2:36][C:37]([NH:39][C:40]3[C:45]([CH3:46])=[CH:44][CH:43]=[CH:42][C:41]=3[CH3:47])=[O:38])[CH2:23][CH2:22]2)[C@H:17]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:16]1)=[O:14]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCNCC2)[C@H](c2ccccc2)C1
Reactant: Cc1cccc(C)c1NC(=O)CCl
Product: Cc1cccc(C)c1NC(=O)CN1CCN([C@H]2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)C[C@H]2c2ccccc2)CC1

Procedure:
The title compound, MS: m/e=647.2 (M+H+), was prepared in accordance with the general method of example 35 from rac-cis-(3,5-bis-trifluoromethyl-phenyl)-(3-phenyl-4-piperazin-1-yl-piperidin-1-yl)-methanone and N-chloroacetyl-2,6-dimethylaniline.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:2][CH3:3].[Br:10]Br>[Fe]>[Br:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:1][CH2:2][CH3:3]
Reactant: BrBr
Reactant: CCCc1ccccc1
Agent: [Fe]
Product: CCCc1ccccc1Br
Yield: 88.7 %

Procedure:
Into a 250-mL round-bottom flask was placed propylbenzene (20 g, 166.40 mmol, 1.00 equiv) and Fe (10 g, 178.57 mmol, 1.07 equiv). This was followed by the addition of Br2 (26.6 g, 166.45 mmol, 1.00 equiv) dropwise with stirring. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 100 mL of NaHSO3 (aq.). The mixture was extracted with 3×100 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. Purification afforded 29.4 g (crude) of 1-bromo-2-propylbenzene as a yellow oil.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].C(=O)CCCCCCCCC=C.C(Cl)(=O)C(Cl)=O.Br[C:32](Br)([F:34])[F:33].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl.CC(N(C)C)=O.[Zn].C(N(CC)CC)C.CS(C)=O>[F:33][C:32]([F:34])=[CH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=[CH2:1]
Reactant: FC(F)(Br)Br
Reactant: C=CCCCCCCCCCO
Agent: C=CCCCCCCCCC=O
Agent: O=C(Cl)C(=O)Cl
Agent: [Zn]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: C=CCCCCCCCCC=C(F)F

Procedure:
Other primary and secondary alcohols of the present invention were also prepared from commercially available omega unsaturated alcohols by a second route. An unsaturated alcohol (I), e.g., 10-undecen-1-ol, was first oxidized to 10-undecen-1-al (V) by the Swern oxidation using oxalyl chloride, dimethyl sulfoxide, and triethylamine in methylene chloride. This aldehyde was then reacted with dibromodifluoromethane, triphenylphosphine, and powdered zinc in dimethylacetamide, producing 1,1-difluoro-1,11-dodecadiene (VI). In order to prepare a secondary alcohol from (VI), the latter was reacted with mercuric acetate in tetrahydrofuran and water and then with sodium borohydride and aqueous sodium hydroxide, producing 12,12-difluoro-11-dodecen-2-ol (VII). Oxidation of (VII) with Jones reagent in acetone yielded methyl 10,10-difluoro-9-decenyl ketone (VIII) which could in turn be reacted with a Grignard reagent, e.g., methylmagnesium bromide, to produce 2-methyl-12,12-difluoro-11-dodecen-2-ol (IX), a tertiary alcohol. Synthesis of primary alcohols was accomplished by reacting (VI) with borane tetrahydrofuran complex and then with sodium hydroxide and hydrogen peroxide, yielding 12,12-difluoro-11-dodecen-1-ol (X). Examples 3, 4, and 5 detail the methods employing this route.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)[C:8](=[O:22])[CH2:7]2.C(Cl)Cl.CCN(CC)CC.CC[O:35][C:36](C)=[O:37]>CS(C)=O.CO.O>[O:22]=[C:8]1[CH2:7][C:6]2[C:10](=[C:2]([C:36]([OH:37])=[O:35])[CH:3]=[CH:4][CH:5]=2)[N:9]1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1
Reactant: CCOC(C)=O
Reactant: O=C1Cc2cccc(Br)c2N1Cc1ccc(C(F)(F)F)cc1
Solvent: CO
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C(O)c1cccc2c1N(Cc1ccc(C(F)(F)F)cc1)C(=O)C2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture 2.8 g of 7-bromo-1-(4-trifluoromethylbenzyl)-1,3-dihydro-indol-2-one, 0.70 g of PdCl2dppf.CH2Cl2, and 2.34 ml of Et3N in 75 ml of 2:1 DMSO/MeOH was heated under CO (balloon pressure) at 75° C. for 24 h. The reaction mixture was poured into 400 ml of 1:1 heaxan/EtOAc and stirred with 200 ml of water for 4 h. The organic layer was washed with 150 ml of brine and dried over Na2SO4, filtered through a pad of silica gel, and concentrated. The residue was dissolved in 60 ml THF, 20 ml of MeOH and 20 ml of water, followed by 30 ml of 1N aqueous LiOH solution. After stirring for 5 h at room temperature, 5 ml of AcOH was added and the mixture was extracted with 250 ml of EtOAc. The organic layer was washed with 50 ml of brine and dried over Na2SO4, filtered, and concentrated. The residue was swished from 50 ml of 1:1 hexane/EtOAc to give 1.2 g of the title compound as a light brown solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]1=[O:11].[Br:13]Br>C(O)(=O)C>[Br:13][C:8]1[CH:9]=[CH:10][C:5]2[O:4][C:3](=[O:11])[C:2]([CH3:12])([CH3:1])[C:6]=2[CH:7]=1
Reactant: BrBr
Reactant: CC1(C)C(=O)Oc2ccccc21
Solvent: CC(=O)O
Product: CC1(C)C(=O)Oc2ccc(Br)cc21
Reaction time: 8 h

Procedure:
3,3-Dimethyl-3H-benzofuran-2-one (2.81 g, 17.3 mmol) was added to a solution of Bromine (1.51 mL, 29.5 mmoL) and Acetic acid (35 mL) at room temperature, then stirred overnight. The resulting mixture was stripped of solvent, then distilled under high vacuum. The product fraction (2.08 g, 50%) was collected between 65° C. and 79° C.