Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[C:6]1([CH2:12][CH2:13][C@H:14]([OH:17])[C:15]#[CH:16])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:18][Si:19](Cl)([CH3:21])[CH3:20].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO.[Cl-].[Na+].O.CCOCC>[C:6]1([CH2:12][CH2:13][C@H:14]([OH:17])[C:15]#[C:16][Si:19]([CH3:21])([CH3:20])[CH3:18])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C[Si](C)(C)Cl
Reactant: C#C[C@@H](O)CCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)C#C[C@@H](O)CCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Following a procedure of Trost (Trost, B. M. et al., J. Am. Chem. Soc. 128, 6745-6754 (2006)); n-butyllithium (2.5 M in hexanes, 474 μL, 1.18 mmol, 3 eq.) was added dropwise to a solution of (S)-5-phenylpent-1-yn-3-ol 86 (63.3 mg, 0.39 mmol, 1 eq.) in THF (1 ml) at −78° C. The mixture was allowed to warm to 0° C. and stirred 30 min before being cooled to −78° C. TMSCl (148.2 μL, 1.18 mmol, 3 eq.) was added dropwise and the mixture was allowed to warm to r.t. and stirred for 2 h. Citric acid (65 mg) in methanol (0.7 ml) was added and the mixture stirred for 1 h. The mixture was poured into a mixture of brine (3 ml) and Et2O (5 ml). The aqueous layer was extracted with Et2O (3×10 ml) and the combined organic phases were washed with brine (10 ml) before being dried (MgSO4), filtered and concentrated to give the crude product. This was purified by column chromatography on silica, eluting with petrol/Et2O (9:1), giving the title product 87 as a clear, colourless oil (18.5 mg, 15.5%). Analytical data consistent with the literature (Trost, B. M. et al., J. Am. Chem. Soc. 128, 6745-6754 (2006)).
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[OH:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH:9]=[O:10].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:1][CH2:2][CH2:3][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH:9]=[O:10]
Reactant: COc1ccc(C=O)cc1O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C=O)cc1OCCBr
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.3 %

Procedure:
1,2-Dibromoethane (56 mL, 0.66 moles) was added to a mixture of 3-hydroxy-4-methoxybenzaldehyde (10 g, 66 mmoles) and potassium carbonate (45 g, 328 mmoles) in DMF (170 ml) and the resulting mixture was stirred vigorously at room temperature for 16 hours. The mixture was poured into water (0.5 L) and extracted with ethyl acetate (3×200 mL). The combined organic phases were washed with saturated sodium chloride (500 mL), dried over MgSO4 and evaporated in vacuo. The residue was purified by column chromatography on silica gel (800 mL) eluting with a mixture of ethyl acetate and heptane (1:1) to afford 9.8 g (58%) of 3-(2-bromoethoxy)-4-methoxybenzaldehyde.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][C:17]([CH:24]=[O:25])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:19]([C:20]([F:23])([F:21])[F:22])=[CH:18][C:17]([CH2:24][OH:25])=[CH:16][N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(C=O)cc2C(F)(F)F)CC1
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(CO)cc2C(F)(F)F)CC1

Procedure:
4-(5-Formyl-3-trifluoromethyl-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester from step (c) above (1.44 g, 4.0 mmol) reacted with NaBH4 (180 mg, 4.8 mmol, Aldrich) under the conditions of Example 183f to give the title compound as a gum. MS (ESI, pos. ion) m/e: 262 (M-Bu+1).
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:13]([N:15]1[CH2:20][CH:19]=[CH:18][CH:17]([OH:21])[CH2:16]1)=[O:14])[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:22][S:23](Cl)(=[O:25])=[O:24].Cl>C(Cl)Cl.CN(C)C1C=CN=CC=1>[S:23]([O:21][CH:17]1[CH:18]=[CH:19][CH2:20][N:15]([C:13](=[O:14])[C@@H:9]([CH:10]([CH3:12])[CH3:11])[NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:16]1)([CH3:22])(=[O:25])=[O:24]
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CC=CC(O)C1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CC=CC(OS(C)(=O)=O)C1
Reaction time: 24 h

Procedure:
0.894 g of N—(N-BOC-(R)-valyl)-1,2,3,6-tetrahydropyridin-3-ol dissolved in 10 ml of CH2Cl2 are treated with 0.844 g of 4-dimethylaminopyridine and 0.31 g of methanesulfonic acid chlorid (mesylchloride) and stirred for ca. 24 hours, the mixture obtained is treated with 0.1 N HCl and CH2Cl2, the organic phase obtained is washed with H2O and aqueous NaHCO3-solution, the solvent is evaporated and the evaporation residue is dried. 3-Mesyloxy-N—(N-BOC-(R)-valyl)-1,2,3,6-tetrahydropyridine is obtained. 1H-NMR (CDCl3): 6.1-5.85(m,2H,HIV,HV), 4.5(m,1H,NHCHCO), 3.7(s,3H,CH3SO2), 1.2-0.9(m,6H,(CH3)2.
Reaction SMILES: [C:1]1([C:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[OH:19]O>C(Cl)Cl>[C:1]1([C:7]23[O:19][CH:8]2[CH2:9][CH2:10][CH2:11][CH2:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OO
Reactant: C1=C(c2ccccc2)CCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: c1ccc(C23CCCCC2O3)cc1
Reaction time: 6 h
Yield: 90.7 %

Procedure:
In a 50 mL flask equipped with a magnetic stirrer, 7.9 g (50 mmol) of 1-phenylcyclohexene and 63 mg (0.25 mmol, 0.5 mol %) of MTO are dissolved in 1.5 Molar CH2Cl2 and to this solution is added 0.48 mL (6 mmol, 12 mol %) of pyridine followed by 7.6 mL (75 mmol; 1.5 equivalents) of 30% aqueous H2O2 added dropwise from a syringe (circa 5-10 minutes). During the H2O2 -addition the temperature is kept at 20-25° C. by applying an external cooling bath. The reaction is complete after 6 h and the aqueous phase is seperated and discarded. The remaining H2O2 in the yellow organic phase is decomposed to O2 and H2O by stirring with a catalytic amount of MnO2 (circa 10 mg). After the yellow color has completely disappeared the mixture is dried over Na2SO4, concentrated, and purified by filtration through a short column of silica gel which has been deactivated with NEt3. The column is washed with hexane/CH2Cl2 and concentration of the eluate affords 7.9 g (91%) of 1-phenyl-1,2-epoxycyclohexane as a colorless oil.
Reaction SMILES: C(OC(N1CCC(C2C3SC=C(C)C=3ON=2)CC1)=O)(C)(C)C.C([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([C:36]([C:39]2[S:40][C:41]([CH3:45])=[CH:42][C:43]=2Br)=[N:37][OH:38])[CH2:32][CH2:31]1)=[O:29])(C)(C)C>[Cu](I)I>[CH3:45][C:41]1[S:40][C:39]2[C:36]([CH:33]3[CH2:34][CH2:35][N:30]([C:28]([OH:27])=[O:29])[CH2:31][CH2:32]3)=[N:37][O:38][C:43]=2[CH:42]=1
Reactant: Cc1cc(Br)c(C(=NO)C2CCN(C(=O)OC(C)(C)C)CC2)s1
Agent: I[Cu]I
Agent: Cc1csc2c(C3CCN(C(=O)OC(C)(C)C)CC3)noc12
Product: Cc1cc2onc(C3CCN(C(=O)O)CC3)c2s1

Procedure:
Prepared essentially as in 29c except that 4-[1-(3-bromo-5-methyl-thiophen-2-yl)-1-hydroxyimino-methyl]-piperidine-1-carboxylic acid tert-butyl ester is used as the starting material. Two other differences are: 1) 0.05 equivalents of copper iodide is used, and 2) no partition between ethyl acetate and water accompanied by subsequent extraction with ethyl acetate is required. Purification of the residue via flash column chromatography uses a mixture of ethyl acetate: n-heptane (1:4) to yield a white solid. LC/MS (ESI), m/e 345 (MNa+), retention time 2.12 minutes. Condition II.
Reaction SMILES: C([Li])CCC.CCCCCC.[S:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[CH:13]1.[Cl:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26](=[O:31])[C:25]2=[O:32].[Cl-].[NH4+]>C1COCC1>[S:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[C:25]1([OH:32])[C:24]2[C:28](=[CH:29][CH:30]=[C:22]([Cl:21])[CH:23]=2)[NH:27][C:26]1=[O:31]
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: c1ccc2scnc2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1Nc2ccc(Cl)cc2C1(O)c1nc2ccccc2s1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 70.6 %

Procedure:
A 1.6 M solution of n-butyllithium in hexane (35 ml, 56 mmol) was added dropwise to a solution of benzothiazole (6.2 ml, 56 mmol) in THF (100 ml) at −78° C. After stirring at −78° C. for 1.5 h, the solution of the lithiated benzothiazole was transferred via a needle into an ice-cold suspension of 5-chloroisatin (3.63 g, 20 mmol) in THF (70 ml). The reaction mixture was stirred at 0° C. for 1 h and then saturated ammonium chloride solution was added. The mixture was extracted three times with ethyl acetate and the combined organic layers were washed with saturated brine. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure, during which the intermediate starts to crystallize. Filtration and drying yielded 4.47 g of the intermediate as yellow crystalline solid.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[N+:10]([C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:6]=1)([O-:12])=[O:11]
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(CCN2CCOCC2)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
1-(2-Bromo-ethyl)-4-nitro-benzene (1 g, 4.3 mmol) was added to a mixture of morpholine (435 μL, 5 mmol) and potassium carbonate (690 mg, 5.0 mmol) in 5 mL of DMSO. The mixture was stirred at 100° C. for 1 hour. After cooling to room temperature, the mixture was extracted into ethyl acetate (EtOAc), washed with water, brine and then dried with sodium sulfate (Na2SO4). Removal of the solvent and chromatography on silica, eluting with EtOAc/CH3OH/NH4OH (10:1:0.1, v/v), gave 950 mg of 4-[2-(4-nitro-phenyl)-ethyl]-morpholine, which was converted to the title compound under normal hydrogenation conditions. The title compound was obtained as a yellow solid (880 mg, 99%). 1H NMR (400 MHz, CDCl3) δ (ppm): 6.98 (d, J=8.2 Hz, 2H), 6.61 (d, J=8.2 Hz, 2H), 3.73 (t, J=4.5 Hz, 4H), 3.57 (br, 2H), 2.64-2.71 (m, 2H), 2.45-2.56 (m, 6H).
Reaction SMILES: C(NC(C)C)(C)C.[CH2:8]([Li])[CH2:9][CH2:10][CH3:11].[C:13]([C:15]1[C:16](=[O:22])[NH:17][C:18](C)=[CH:19][CH:20]=1)#[N:14].BrCCC>C1COCC1>[CH2:8]([C:18]1[NH:17][C:16](=[O:22])[C:15]([C:13]#[N:14])=[CH:20][CH:19]=1)[CH2:9][CH2:10][CH3:11]
Reactant: Cc1ccc(C#N)c(=O)[nH]1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCBr
Product: CCCCc1ccc(C#N)c(=O)[nH]1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
A solution of diisopropylamine (20.5 mL, 2 eq) in THF (200 mL) was cooled to −5° C. n-Butyllithium (53.5 mL, 2.9 M in hexanes, 2 eq) was added over 10 minutes. The solution was allowed to rise to 0° C., stirred for 0.5 hours, then cooled again to −30° C. 3-Cyano-6-methyl-2(1H)pyridinone (10 g, 75 mmol) was added portionwise, and the mixture was allowed to warm to room temperature and stirred for 2 hours. The solution was then cooled to −50° C., and 1-bromopropane (6.8 mL, 1 eq) was added. The solution was allowed to warm to room temperature, stirred for 1 hour, and then quenched with a saturated ammonium chloride solution. The THF was evaporated and the aqueous phase extracted with DCM (2×100 mL). The organics were washed with saturated aqueous NaCl, dried over Na2SO4, and evaporated to yield intermediate (24a) as an orange solid (10.8 g, 61 mmol), which was used without further purification. MS m/z: [M+H+] calcd for C10H12N2O, 177.2. found 177.0. 1H-NMR (DMSO) 7.87 (1H, d), 6.05 (1H, d), 2.38 (2H, t), 1.41 (2H, m), 1.15 (2H, m), 0.93 (1H, d), 0.73 (3H, t).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Br:16][C:17]1[CH:18]=[C:19](/[CH:23]=[C:24](/[C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[F:34])\[C:25]#[N:26])[CH:20]=[CH:21][CH:22]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([Br:16])[CH:18]=2)[C:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[F:34])([C:25]#[N:26])[CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[NH:8]1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#C/C(=C\c1cccc(Br)c1)c1ccc(Cl)cc1F
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Br)c2)C1(C#N)c1ccc(Cl)cc1F
Yield: 40.1 %

Procedure:
In a manner similar to the method described in Example 1c, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 1a (2.1 g, 10 mmol) was reacted with (Z)-3-(3-bromo-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (2 g, 5.9 mmol) prepared in Example 66a, AgF (1.5 g, 12 mmol), and triethylamine (2.7 mL, 20 mmol) in dichloromethane (120 mL) at room temperature for 18 h to give rac-(2R,3R,4R,5S)-3-(3-bromo-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.3 g, 40%).
Reaction SMILES: [NH2:1][C:2]1[C:20]([N+:21]([O-])=O)=[CH:19][C:5]2[O:6][C:7]([CH3:18])([CH3:17])[C@@H:8]([OH:16])[C@H:9]([N:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[C:4]=2[CH:3]=1.[H][H]>C(O)C.[Pd]>[NH2:1][C:2]1[C:20]([NH2:21])=[CH:19][C:5]2[O:6][C:7]([CH3:17])([CH3:18])[C@@H:8]([OH:16])[C@H:9]([N:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[C:4]=2[CH:3]=1
Reactant: CC1(C)Oc2cc([N+](=O)[O-])c(N)cc2[C@@H](N2CCCCC2)[C@@H]1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC1(C)Oc2cc(N)c(N)cc2[C@@H](N2CCCCC2)[C@@H]1O
Yield: 94.5 %

Procedure:
A solution of 6-amino-3,4-dihydro-2,2-dimethyl-7-nitro-trans-4-piperidino-2H-benzo[b]pyran-3-ol (140 mg) in ethanol (30 ml) was hydrogenated over 5% palladium-charcoal (0.1 g) until uptake of hydrogen ceased. The solution was filtered (Kieselguhr) and evaporated to dryness in vacuo to give unstable 6,7-diamino-3,4-dihydro-2,2-dimethyl-trans-4-piperidino-2H-benzo[b]pyran-3-ol (0.12 g) which was used immediately in the following reactions. Rf (0.3) in ethyl acetate-hexane 1:2 (colourless spot) compared with starting material with Rf (0.6) as an orange spot.
Reaction SMILES: [CH:1]1[CH2:5][CH2:4][CH2:3][CH:2]=1.[CH2:6](Cl)Cl>[Pd]>[CH:1]1[CH2:5][CH2:4][CH2:3][CH:2]=1.[CH3:6][CH:1]1[CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: ClCCl
Agent: [Pd]
Agent: C1=CCCC1
Product: CC1C=CCC1
Reaction time: 96 h

Procedure:
Inside a nitrogen purged drybox, the palladium catalyst, {[ (2,6-iPr2Ph)2DABMe2]Pd(CH2CH2CH2CO2Me)}BAF (77 mg, 0.053 mmol) was dissolved in CH2Cl2 (2 ml) and cyclopentene (2 ml) and 3-MeCyp (1 ml) added. The solution was stirred for 4 days after which the volatiles were removed. MeOH was added and the polymer filtered, washed well with MeOH and finally with 2% Irganox® 1010/acetone solution and dried. Yield=1.06 g. Tm (DSC)=210.5° C., Tg (DSC)=73° C. 13C-NMR (TCB, 120° C.) indicated 5% 3-MeCyp incorporation.
Reaction SMILES: [CH:1](NC(C)C)(C)[CH3:2].[F:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1.C(I)C>O1CCCC1.O>[CH2:1]([C:14]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[F:8])[CH3:2]
Reactant: Fc1cccnc1
Reactant: CC(C)NC(C)C
Solvent: O
Solvent: C1CCOC1
Solvent: CCI
Product: CCc1ccncc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
nButyllithium (1.6M in tetrahydrofuran, 62.4 ml, 100 mmol) was added dropwise to a solution of diisopropylamine (10 g, 100 mmol) in tetrahydrofuran (110 mL), cooled to −78° C. 3-Fluoropyridine (10 g, 100 mmol) was added dropwise and the reaction mixture was stirred for 1 hour with the temperature maintained below −60° C. Ethyl iodide (31.2 g, 200 mmol) was then added dropwise and the mixture was allowed to stir at room temperature for 30 minutes. The reaction mixture was slowly diluted with water, the solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was separated, dried over magnesium sulfate and concentrated in vacuo to give a crude residue. The residue was distilled and title product was obtained during a temperature range of 152-156° C., in 35% yield, 4.46 g.
Reaction SMILES: [OH:1]O.[CH:3]([P:7]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])([CH2:5][CH3:6])[CH3:4]>O>[CH:3]([P:7](=[O:1])([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])([CH2:5][CH3:6])[CH3:4]
Reactant: OO
Reactant: CCCCCCCCP(CCCCCCCC)C(C)CC
Solvent: O
Product: CCCCCCCCP(=O)(CCCCCCCC)C(C)CC
Temperature: 70 °C

Procedure:
40 g H2O2 (0.35 mol, 30% solution) was added dropwise while cooling with water and with intense agitation to 80 g (0.25 mol) sec.-butyl-di-n-octyl phosphine in a 500 ml-double-walled vessel. After all had been added, the reaction solution was heated to 70° C. over a period of 30 minutes, while stirring was interrupted. An aqueous phase which deposited on the bottom of the vessel was separated. It was admixed with 4.5 ml sodium carbonate solution (30 g/l) and the pH increased from 5.6 to 9.2. The whole was stirred over a period of 1 hour at 80° C. and allowed to deposit. The aqueous phase was separated and the crude product was distilled in vacuum.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[NH:20][C:19](=[O:21])[C@H:18]([CH:22]([CH3:24])[CH3:23])[NH:17][C:16](=[O:25])[C@@H:15]([NH:26]C(OC(C)(C)C)=O)[CH2:14][C:13]2=[CH:34][CH:35]=[C:10]([CH:11]=[CH:12]2)[O:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[ClH:36]>O1CCOCC1>[ClH:36].[CH3:1][O:2][C:3]([C@H:5]1[NH:20][C:19](=[O:21])[C@H:18]([CH:22]([CH3:24])[CH3:23])[NH:17][C:16](=[O:25])[C@@H:15]([NH2:26])[CH2:14][C:13]2=[CH:34][CH:35]=[C:10]([CH:11]=[CH:12]2)[O:9][CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1CCCOc2ccc(cc2)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@@H]1CCCOc2ccc(cc2)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl ester 66 (0.2 g) was dissolved in 4M HCl in 1,4-dioxane (10 mL). The solution was stirred at rt for 16 h before being concentrated in vacuo to yield a brown solid, 0.17 g, 100%.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:14][CH2:15][C:16]3(C(F)(F)F)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:6][C:7]([F:13])=[C:8]([CH:12]=2)[C:9](O)=[O:10])[CH2:3][CH2:2]1.C1(COC2C(C3CC3)=CC(C(O)=O)=C(F)C=2)CCCCC1.CS(N)(=O)=O.[CH3:52][NH:53][S:54]([NH2:57])(=[O:56])=[O:55]>>[CH:16]1([CH2:15][O:14][C:5]2[C:4]([CH:1]3[CH2:3][CH2:2]3)=[CH:12][C:8]([C:9]([NH:57][S:54](=[O:56])(=[O:55])[NH:53][CH3:52])=[O:10])=[C:7]([F:13])[CH:6]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CNS(N)(=O)=O
Reactant: O=C(O)c1cc(C2CC2)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Agent: CS(N)(=O)=O
Agent: O=C(O)c1cc(C2CC2)c(OCC2CCCCC2)cc1F
Product: CNS(=O)(=O)NC(=O)c1cc(C2CC2)c(OCC2CCCCC2)cc1F

Procedure:
Following the procedure as described in Example 158 step 5, and making variations as required to replace 5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)benzoic acid with 4-(cyclohexylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid and to replace methanesulfonamide with (methylsulfamoyl)amine, the title compound was obtained (0.13 g, 25%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ8.76-8.65 (m, 1H), 7.57-7.50 (m, 1H), 6.62-6.52 (m, 1H), 5.31-5.22 (m, 1H), 3.86-3.78 (m, 2H), 2.79-2.74 (m, 3H), 2.11-1.99 (m, 1H), 1.95-1.65 (m, 6H), 1.41-1.03 (m, 5H), 0.98-0.89 (m, 2H), 0.69-0.61 (m, 2H); MS (ES−) m/z 383.3 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][CH3:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl[CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[CH3:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=[N+]([O-])c1ccc(OCCCCl)cc1
Reactant: CNCCc1ccc(OC)c(OC)c1
Solvent: CC#N
Product: COc1ccc(CCN(C)CCCOc2ccc([N+](=O)[O-])cc2)cc1OC

Procedure:
In a manner similar to Preparation 56 react 3,4-dimethoxy-N-methylbenzeneethanamine with 1-(3-chloropropoxy)-4-nitrobenzene in acetonitrile to obtain the title compound.
Reaction SMILES: Br[C:2]1[C:3]([CH3:14])=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[F:15][C:16]([F:21])([F:20])C([O-])=O.[K+].C1(C)C=CC=CC=1>CN(C)C=O.[Cu]I>[CH3:14][C:3]1[C:2]([C:16]([F:21])([F:20])[F:15])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([O:12][CH3:13])[CH:4]=1
Reactant: COC(=O)c1cc(Br)c(C)cc1OC
Reactant: O=C([O-])C(F)(F)F
Agent: [Cu]I
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(C(F)(F)F)c(C)cc1OC
Temperature: 170 °C

Procedure:
To a mixture of methyl 5-bromo-4-methyl-2-(methyloxy)benzoate (may be prepared as described in Description 43; 2.5 g, 9.65 mmol) in N,N-dimethylformamide (40 ml) was added copper (I) iodide (4.04 g, 21.23 mmol) and potassium trifluoroacetate (2.94 g, 19.30 mmol). Toluene (10 ml) was added and the mixture heated in Dean Stark apparatus at 170° C. for 45 minutes. The toluene was removed via the Dean Stark trap and the resulting mixture was heated for 18 hours at 170° C. The mixture was diluted with water (10 ml) and ethyl acetate (20 ml) and the solid was removed using Celite. The filtrate was taken and the organic layer separated, dried (MgSO4) and the solvent removed in vacuo. The residue was purified by column chromatography (SiO2, 50% Cyclohexane/diethyl ether) to yield the title compound as a white solid. 1.76 g.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[CH:9][C:10]2[N:14]=[C:13]([C@@H:15]3[CH2:21][C:18]4([CH2:20][CH2:19]4)[CH2:17][N:16]3[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[NH:12][C:11]=2[CH:29]=1)(C)C.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CO>[C:6]([C:7]1[CH:8]=[CH:9][C:10]2[N:14]=[C:13]([C@@H:15]3[CH2:21][C:18]4([CH2:19][CH2:20]4)[CH2:17][N:16]3[C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[NH:12][C:11]=2[CH:29]=1)#[CH:5]
Reactant: CC(C)(C)OC(=O)N1CC2(CC2)C[C@H]1c1nc2ccc(C#C[Si](C)(C)C)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: C#Cc1ccc2nc([C@@H]3CC4(CC4)CN3C(=O)OC(C)(C)C)[nH]c2c1
Yield: 104 %

Procedure:
A brown opaque mixture of (S)-tert-butyl 6-(6-((trimethylsilyl)ethynyl)-1H-benzo[d]imidazol-2-yl)-5-azaspiro[2.4]heptane-5-carboxylate (0.99 kg, 2.41 mol, 1 equiv.) in methanol (5.5 L) is treated with solid potassium carbonate (340 g, 2.46 mol, 1.02 equiv.) for about 1.5 hours and the reaction was complete as indicated by TLC/MS. The mixture was rotavapped and solvent swapped to EtOAc (6 L), and then washed with 10% NaCl solution (5 L). Upon drying over Na2SO4 it was rotavapped and vacuum dried at about 25˜30° C. overnight to afford 0.845 kg (104% yield, 98% HPLC purity) of the title compound as a light brown foam. ESI MS m/z (M+H)+ 338.19.
Reaction SMILES: C([O:8][CH2:9][CH:10]1[CH2:15][N:14]([S:16]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)(=[O:18])=[O:17])[CH2:13][CH2:12][N:11]1[C:24]1[CH:29]=[CH:28][C:27]([C:30]([OH:36])([CH3:35])[C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=1)C1C=CC=CC=1.C(=O)(O)[O-].[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[S:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[S:16]([N:14]1[CH2:13][CH2:12][N:11]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([OH:36])([CH3:35])[C:31]([F:33])([F:32])[F:34])=[CH:28][CH:29]=2)[CH:10]([CH:9]=[O:8])[CH2:15]1)(=[O:17])=[O:18]
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)CC2COCc2ccccc2)cc1)C(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)CC2C=O)cc1)C(F)(F)F
Reaction time: 0.5 h

Procedure:
To a suspension of 1,1,1-trifluoro-2-(4-(2-(hydroxymethyl)-4-(thiophen-3-ylsulfonyl)piperazin-1-yl)phenyl)-2-propanol hydrochloride (50 mg, 0.103 mmol, Example 44) in CH2Cl2 (2.0 mL) at room temperature was added solid sodium bicarbonate (17.25 mg, 0.205 mmol) followed by Dess-Martin periodinane (47.9 mg, 0.113 mmol, Sigma-Aldrich, St. Louis, Mo.). The reaction was stirred at this temperature for 30 min and then filtered through a pad of Celite® (diatomaceous earth) eluting with CH2Cl2. The filtrate was concentrated to yield 4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinecarbaldehyde which was used without purification.