Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+:2].C[O:4][C:5]([C:7]1[CH:8]=[C:9]([C:17]#[C:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:10]=[C:11]([C:13]([O:15]C)=[O:14])[CH:12]=1)=[O:6]>C(O)CCC>[C:19]1([C:18]#[C:17][C:9]2[CH:10]=[C:11]([C:13]([O-:15])=[O:14])[CH:12]=[C:7]([CH:8]=2)[C:5]([O-:6])=[O:4])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[K+:2].[K+:2]
Reactant: COC(=O)c1cc(C#Cc2ccccc2)cc(C(=O)OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Product: O=C([O-])c1cc(C#Cc2ccccc2)cc(C(=O)[O-])c1
Yield: 97 %

Procedure:
Into a 5 liter four-necked flask equipped with a thermometer, a Dimroth condenser and a stirrer, 3 liters of n-butanol and 180 g (2.72 moles) of potassium hydroxide (85%) were placed and dissolved by heating under the refluxing condition. To the obtained solution, 80 g (0.272 moles) of (3,5-bis(methoxycarbonyl)phenyl)-2-phenylethyne synthesized above was added and the resultant mixture was heated for 30 minutes under the refluxing condition. The reaction mixture was then cooled in an ice bath and the formed crystals were separated by filtration. The crystals were washed twice with 1 liter of ethanol and dried at 60° C. under a reduced pressure and 90.35 g of dipotassium 5-(2-phenylethynyl)-isophthalate was obtained (the yield: 97%).
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[K+].[C:11]1([C:21]([N:23]2[CH2:27][CH:26]([CH:28]=O)[CH:25]([CH2:30][N:31]3[CH2:36][CH2:35][CH:34]([C:37]4[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=4)[CH2:33][CH2:32]3)[CH2:24]2)=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:11]1([C:21]([N:23]2[CH2:27][CH:26]([CH:28]=[CH2:1])[CH:25]([CH2:30][N:31]3[CH2:32][CH2:33][CH:34]([C:37]4[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=4)[CH2:35][CH2:36]3)[CH2:24]2)=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: O=CC1CN(C(=O)c2cccc3ccccc23)CC1CN1CCC(c2ccc(F)cc2)CC1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CC1CN(C(=O)c2cccc3ccccc23)CC1CN1CCC(c2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 0.08 g (0.22 mmol) of methyltriphenyl phosphonium bromide (Ph3PCH3Br) in 4 mL of THF at rt was added 0.36 mL of potassium bis(trimethylsilyl)amide and the reaction mixture was stirred for 30 min. The reaction mixture was cooled to 0° C. and to it was added a solution of 0.04 g (0.089 mmol) of 1-(1-naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-formylpyrrolidine in 2 mL of THF. The reaction mixture was warmed to rt and stirred for 1.2 h. The reaction mixture was filtered through a thin pad of silica eluting with acetone:hexanes, 1:2, then concentrated. The residue was purified by chromatography (silica, acetone:hexanes, 1:2) to give the title compound. Mass Spectrum (ESI) m/e=444 (M+1).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:12]3[CH3:25])=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[CH3:18][N:14]1[C:15]2[C:11](=[CH:10][C:9]([C:6]3[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=3)=[CH:17][CH:16]=2)[C:12]([CH3:25])=[C:13]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1ccc(-c2ccc3c(c2)c(C)c(-c2ccccc2)n3C)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1c(-c2ccccc2)n(C)c2ccc(-c3ccc(O)cc3)cc12
Yield: 90.3 %

Procedure:
The desired product was prepared using a procedure similar to step 4 of example 3. Thus, 5-(4-methoxy-phenyl)-1,3-dimethyl-2-phenyl-1H-indole (0.560 g, 1.710 mmol) was reacted with BBr3 (2.1 ml of a 1M solution in CH2Cl2) to give the desired product (0.484 g, 1.544 mmol, 90%) as a white solid, mp 148-150° C. 1H NMR (DMSO-d6) δ 2.24 (s, 3H), 3.60 (s, 3H), 6.84 (d, J=8.6 Hz, 2H), 7.40 (dd, J=1.4, 8.4 Hz, 1H), 7.44-7.47 (m, 4H), 7.50-7.56 (m, 4H), 7.68 (s, 1H), 9.37 (s, 1H); IR (solid) 3350, 3050, 1590, 1520, 1460, and 1230 cm−1; [ESI(+)], m/z 314 (M+H)+; Anal. Calcd. for C22H19NO: C, 84.31; H, 6.11; N, 4.47; Found: C, 84.21; H, 6.37; N, 4.38.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.C[N:33]1CCOCC1.N.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:29])([F:30])[F:31])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH2:33])=[O:5]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: CN1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Product: NC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 8 h
Yield: 30 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 30 mg, 0.070 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (0.076 mL, 0.696 mmol), ammonia (0.5M in dioxane, 0.278 mL, 0.139 mmol), and HATU (39.7 mg, 0.104 mmol). This was stirred overnight and was then purified by preparative HPLC (PHENOMENEX® Luna 5u C18 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention time=11.4 min) to give (R/S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (10 mg, 0.021 mmol, 30.4% yield): LCMS=431.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.18 (2 H, d, J=8.36 Hz), 7.65-7.80 (4 H, m), 7.52-7.65 (3 H, m), 5.11 (1 H, s). HPLC Peak RT=7.9 min (Analytical Method C).
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br:13]Br>C(O)(=O)C>[Br:13][CH2:2][C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C(O)c1ccc(C(=O)CBr)cc1
Reaction time: 8 h
Yield: 36.8 %

Procedure:
4-Acetylbenzoic acid (186 mg, 1.14 mmol) was dissolved in warm acetic acid (5 mL) and treated with bromine (58 mL, 1.14 mmol). The solution was stirred overnight before being cooled on ice. The resulting solid was filtered, washed with 1:1 methanol/water (3×10 mL) and dried in vacuo to provide 4-(2-bromoacetyl)benzoic acid as a white solid (102 mg). 1H NMR (200 MHz, DMSO-d6) δ 8.07 (s, 4H), 4.98 (s, 2H).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[C:11]([CH3:12])=[CH:10][C:9]([SH:13])=[C:8]([CH3:14])[CH:7]=1)([O-:5])=[O:4].Br[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH:23]([F:25])[F:24])[CH:17]=1>CN(C)C=O.Cl[Cu]>[N+:3]([C:6]1[CH:7]=[C:8]([CH3:14])[C:9]([S:13][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH:23]([F:25])[F:24])[CH:17]=2)=[CH:10][C:11]=1[CH3:12])([O-:5])=[O:4]
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1S
Reactant: FC(F)Oc1cccc(Br)c1
Agent: Cl[Cu]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])c(C)cc1Sc1cccc(OC(F)F)c1
Reaction time: 1 h

Procedure:
4.36 g (0.109 moles) of sodium hydride are suspended in 80 ml of N,N-dimethylformamide at 0° C. 20 g of 4-nitro-2,5-dimethylthiophenol (0.109 moles) dissolved in 67 ml of N,N-dimethylformamide are added dropwise under stirring. 24.4 g of 1-bromo-3-(difluoromethoxy)benzene (0.109 moles) dissolved in 20 ml of N,N-dimethylformamide are then added dropwise; catalytic Cu° and CuCl are subsequently added and the reaction temperature is brought to 150° C. for 1 h.
Reaction SMILES: C(O)C.[O-]CC.[Na+].C(O)C.[F:11][C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([S:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:14][C:13]=1[NH:25][NH2:26].[C:27](OCC)(=[O:35])/[CH:28]=[CH:29]\[C:30]([O:32][CH2:33][CH3:34])=[O:31]>C(O)(=O)C>[F:11][C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([S:19][CH2:20][C:21]([F:23])([F:24])[F:22])=[CH:14][C:13]=1[N:25]1[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][C:27]([OH:35])=[N:26]1
Reactant: CCOC(=O)/C=C\C(=O)OCC
Reactant: Cc1cc(F)c(NN)cc1SCC(F)(F)F
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1cc(O)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Reaction time: 0.01 h
Yield: 25.5 %

Procedure:
14 g of a 20 mass % sodium ethoxide ethanol solution was added to 20 mL of ethanol, and 10 g of 2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenylhydrazine was rapidly added under reflux with heating. After stirring for 30 seconds, 7.8 g of diethyl maleate was dropwise added, followed by stirring under reflux with heating for 10minutes. The reaction solution was cooled to 50° C. or below, and 4.5 g of acetic acid was added. Then, the solvent was distilled off under reduced pressure, extraction with ethyl acetate was carried out, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in 80 mL of toluene, 0.68 g of tetra n-butyl ammonium bromide was added, and 3.5 g of a 10 mass % aqueous solution of potassium permanganate was gradually added. After completion of the reaction, ethyl acetate and 20 mL of a saturated aqueous solution of citric acid were added, and the solution was washed with an aqueous sodium thiosulfate solution and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:1) to obtain 3.80 g of ethyl 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-hydroxypyrazole-5-carboxylate.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[OH-].[Na+].S(OC)(O[CH3:19])(=O)=O.CC1C=CC(COC(NNC(C2C=NC=CN=2)=O)=O)=CC=1>O>[CH3:19][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2
Reactant: COS(=O)(=O)OC
Reactant: O=C1CCc2cc(O)ccc2N1
Agent: Cc1ccc(COC(=O)NNC(=O)c2cnccn2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc2c(c1)CCC(=O)N2

Procedure:
To a solution, prepared by mixing 8.2 g. 6-hydroxy-3,4-dihydrocarbostyril with 50 ml. water containing 2 g. sodium hydroxide, was added dropwise with stirring 8.5 ml. dimethyl sulfate (sp. gr. 1.332). During the course of the addition the resulting mixture was maintained at about pH10 by periodic additions of 10% sodium hydroxide solution. The mixture was stirred for 21/2 hours at room temperature, filtered and the collected solids were washed thoroughly with water to give after recrystallization from methyl alcohol 6.3 g. 6-methoxy-3,4-dihydrocarbostyril; m.p. 142.5°-143.5° C.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:17]=[CH:16][C:10]3[CH2:11][CH2:12][NH:13][CH2:14][CH2:15][C:9]=3[CH:8]=2)[CH2:5][CH:4]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:3]1.[CH:23]1([N:26]2[C:35]3[C:30](=[CH:31][C:32]([F:38])=[C:33](F)[C:34]=3[F:36])[C:29](=[O:39])[C:28]([C:40]([OH:42])=[O:41])=[CH:27]2)[CH2:25][CH2:24]1>>[C:20]([NH:19][CH2:18][CH:4]1[O:3][C:2](=[O:1])[N:6]([C:7]2[CH:17]=[CH:16][C:10]3[CH2:11][CH2:12][N:13]([C:33]4[C:34]([F:36])=[C:35]5[C:30]([C:29](=[O:39])[C:28]([C:40]([OH:42])=[O:41])=[CH:27][N:26]5[CH:23]5[CH2:25][CH2:24]5)=[CH:31][C:32]=4[F:38])[CH2:14][CH2:15][C:9]=3[CH:8]=2)[CH2:5]1)(=[O:22])[CH3:21]
Reactant: CC(=O)NCC1CN(c2ccc3c(c2)CCNCC3)C(=O)O1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Product: CC(=O)NCC1CN(c2ccc3c(c2)CCN(c2c(F)cc4c(=O)c(C(=O)O)cn(C5CC5)c4c2F)CC3)C(=O)O1

Procedure:
The title compound was prepared in a procedure analogous to that used in Example 6, using N-[2-Oxo-3-(2,3,4,5-tetrahydro-1 H-benzo[d]azepin-7-yl)-oxazolidin-5-ylmethyl]-acetamide (0.25 g) and 1-Cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (0.23 g). The product was triturated with EtOH to purify. MS (APCI) AP+, 567. NMR (DMSO6)1. 1-1.22 (m, 4H), 1.78 (s, 3H), 3.0 (m, 4H), 3.35 (m, 6H), 3.65 (m, 1H), 4.05 (m, 2H), 4.65 (m, 1H), 7.13 (d, 1H), 7.26 (dd, 1H), 7.35 (d, 1H), 7.78 (d, 1H), 8.17 (t, 1H), 8.62 (s, 1H).
Reaction SMILES: N(C(C)C)C(C)C.[Li]CCCC.[CH3:13][O:14][C:15](=[O:17])[CH3:16].[C:18]1([CH:24]=[N:25][S:26]([C:28]([CH3:31])([CH3:30])[CH3:29])=[O:27])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[NH4+].[Cl-]>C1COCC1.O>[CH3:13][O:14][C:15](=[O:17])[CH2:16][CH:24]([NH:25][S:26]([C:28]([CH3:31])([CH3:30])[CH3:29])=[O:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)S(=O)N=Cc1ccccc1
Reactant: COC(C)=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: O
Product: COC(=O)CC(NS(=O)C(C)(C)C)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Under anhydrous conditions a solution of i-Pr2NH (2.2 eq) in 60 mL THF is cooled to 0° C. (J. Org. Chem. 2003, 68, 9948-9957). n-BuLi (2.1 eq, 1.6 M solution in hexane) is added via syringe and the solution is stirred for 30 min. The solution is then cooled to −78° C. A solution of acetic acid methyl ester (2 eq) in 1 mL of THF is added via syringe and the reaction solution is stirred for 30 min. To this solution is added ClTi(Oi-Pr)3 (4.2 eq) in 20 mL THF and the solution is stirred for 30 min. A solution of the tert.-butane-sulfinic acid 1-phenyl-methylidene amide (5.4 mmol, 1 eq) in 5 mL THF is slowly added via syringe and the solution is stirred for 3 h at −78° C. Upon reaction completion as determined by TLC, a saturated aqueous solution of NH4Cl (5 mL) is added and the suspension is warmed to room temperature. The mixture is diluted with H2O and vigorously stirred to dissolve the precipitate. The mixture is then decanted into a separatory funnel, and the remaining solid is diluted with equal parts of H2O and ethyl acetate and vigorously stirred for 15 min. The mixture is then added to the separatory funnel and the organic layer is collected. The aqueous layer is then extracted 3× with ethyl acetate. The combined organic layers are washed with brine, dried with Na2SO4, and concentrated in vacuo. 3-(2-Methyl-propane-2-sulfinylamino)-3-phenyl-propionic acid methyl ester is obtained as a clear colourless solid (102% yield); ES-MS (MH+)=284.1; 1H-NMR (DMSO-d6, 400 MHz): δ [ppm] 7.35-7.23 (m, 5H), 5.59 (d, 1H, 6.1 Hz), 4.63 (m, 1H), 3.54 (s, 3H), 3.04-2.99 (m, 1H), 2.80-2.74 (m, 1H), 1.06 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[N:9]2[CH2:12][CH:11]([CH:13]([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=3)[C:14]([CH3:16])=[O:15])[CH2:10]2)=[CH:4][CH:3]=1.[CH3:32][Mg]Cl.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]2[CH2:12][CH:11]([CH:13]([C:17]3[CH:18]=[C:19]([F:24])[CH:20]=[C:21]([F:23])[CH:22]=3)[C:14]([CH3:32])([OH:15])[CH3:16])[CH2:10]2)=[CH:30][CH:29]=1
Reactant: CC(=O)C(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Reactant: C[Mg]Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(O)C(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 230 mg (0.5 mmol) of 1-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-1-(3,5-difluorophenyl)acetone in 10 mL of THF was added slowly a solution of 0.42 mL (1.25 mmol) of methylmagnesium chloride (3.0M solution in THF) at −78° C. and stirred for 1 h. The reaction mixture was warmed to 0° C. for 1 h, followed by adding 1 g of sodium sulfate decahydrate to quench the reaction, and stirring for 1 h at rt. The quenched reaction mixture was filtered and the organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography with hexanes/acetone=8:1 to afford racemic 1-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-1-(3,5-difluorophenyl)-2-methylpropan-2-ol as a white solid. The enantiomers were separated by a chiral column (OJ Column with hexanes/ethyl alcohol); 1H NMR(CDCl3) δ 1.06 (s, 3H), 1.15 (S, 3H), 2.29 (t, 1H, J=7.5 Hz), 6.73 (m, 3H), 7.21-7.33 (m, 8H); Mass Spectrum: m/e=476 (M+1 35Cl, 35Cl) and 478 (M+1 35Cl, 37Cl).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4][CH2:3]1.[NH2:14][CH2:15][CH2:16][NH:17][S:18]([CH3:21])(=[O:20])=[O:19].FC(F)(F)C(O)=O.C(N(CC)CC)C.[BH4-].[Na+].C([O-])([O-])=O.[Na+].[Na+]>ClCCl.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[CH3:21][S:18]([NH:17][CH2:16][CH2:15][NH:14][CH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4][CH2:3]1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)NCCN
Reactant: CCOC(=O)CC1CCC(=O)CC1
Agent: [Ti+4]
Agent: CC[O-]
Agent: O=C([O-])[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC1CCC(NCCNS(C)(=O)=O)CC1
Temperature: -78 °C
Reaction time: 4 h

Procedure:
To a mixture of ethyl 2-(4-oxocyclohexyl)acetate (736 mg, 4 mmol) and N-(2-aminoethyl)methanesulfonamide; 2,2,2-trifluoroacetic acid salt (1.26 g, 5 mmol) in dichloromethane (6 mL) was added triethylamine (690 μL, 5 mmol) followed by Titanium (IV) ethoxide (420 μL, 2 mmol, technical grade). The resulting cloudy mixture was stirred for 4 hours then concentrated under reduced pressure. The residue was taken up in methanol (6 mL). This mixture was cooled to −78° C. To the resulting mixture was added sodium borohydride (187 mg, 4.8 mmol). On complete addition, the cold bath was allowed to expire and stirring continued for 15.5 hours. The resulting mixture was concentrated under reduced pressure to give a thick paste. This residue was taken up in dichloromethane (40 mL). To this mixture was added Na2CO3 (5.5 mL, saturated aqueous solution). The resulting mixture was stirred for 5 minutes. To this mixture was added celite (1.8 g). This mixture was stirred for 5 minutes then filtered through a pad of celite. The filtrate is washed with saturated aqueous Na2CO3, dried over magnesium sulfate and concentrated to give the title compound as a 6:1 mixture of trans:cis isomers. This material was used without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[S:14][CH2:13][CH2:12][CH2:11]2.[NH2:16][CH:17]1[CH2:22][O:21][C:20]2[CH:23]=[CH:24][CH:25]=[C:26]([O:27][CH3:28])[C:19]=2[CH2:18]1.C(N(CC)CC)C>CN(C)C=O>[CH3:28][O:27][C:26]1[C:19]2[CH2:18][CH:17]([NH:16][CH2:2][CH2:3][CH2:4][O:5][C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:15]=3[S:14][CH2:13][CH2:12][CH2:11]4)[CH2:22][O:21][C:20]=2[CH:23]=[CH:24][CH:25]=1
Reactant: COc1cccc2c1CC(N)CO2
Reactant: BrCCCOc1cccc2c1SCCC2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cccc2c1CC(NCCCOc1cccc3c1SCCC3)CO2
Reaction time: 24 h

Procedure:
Under argon, 1.6 g (5.58 mmol) of 8-[(3-bromopropyl) oxy]thiochroman, 1 g (5.58 mmol) of 3-amino-5-methoxy-dihydro-[2H]-benzo[b]pyran and 1.69 g (16.74 mmol) of triethylamine are dissolved in 20 cm3 of dimethylformamide. The mixture is kept at room temperature for 24 hours. The solvent is evaporated off. The residue is taken up in H2O and extracted with methylene chloride. The product is dried over MgSO4. After evaporation, the product is purified over a flash silica column. Eluant: methanol/CH2Cl2 5:95. The title compound is obtained (yellow oil).
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH2:5])[CH2:3][CH2:2]1.C(S(O)(=O)=O)(F)(F)F>>[CH:1]1([CH:4]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH3:5])[CH2:3][CH2:2]1
Reactant: C=C(c1ccccc1)C1CC1
Agent: O=S(=O)(O)C(F)(F)F
Product: CC(c1ccccc1)C1CC1
Reaction time: 0.08 h
Yield: 58 %

Procedure:
A solution of α-cyclopropylstyrene (5 microliters, 0.033 mmol) and (C5H5)(CO)3MoH (24 mg, 0.097 mmole) in dichloromethane-d2 was treated at room temperature with CF3SO3H (3 microliters, 0.034 mmol). A color change indicated an immediate reaction and an 1H NMR after 5 minutes showed that α-cyclopropyl-ethylbenzene (58% yield) was the major product. This indicates that hydrogenation of the carbon-carbon double bond is favored over cleavage of the cyclopropyl group. Additional CF3SO3H (5 microliters, 0.056 mmol) was added. NMR after one hour showed the major product to be 2-phenylpentane (Ca 57%). Two other products, 3-phenylpentane and β-methyl-butylbenzene, were observed in approximate yields of 14% and 7% respectively. These two products are formed due to rearrangement of the intermediate carbocation which is formed from the reaction of CF3SO3H with α-cyclopropyl-ethylbenzene.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[N:16][C:5]2[NH:6][C:7]3[CH2:15][CH:14]4[N:10]([CH2:11][CH2:12][CH2:13]4)[CH2:9][C:8]=3[C:4]=2[CH:3]=1.[H-].[Na+].Cl[CH2:21][C:22]([N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:23]>CN(C=O)C.O>[CH3:1][C:2]1[CH:17]=[N:16][C:5]2[N:6]([CH2:21][C:22]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:23])[C:7]3[CH2:15][CH:14]4[N:10]([CH2:11][CH2:12][CH2:13]4)[CH2:9][C:8]=3[C:4]=2[CH:3]=1
Reactant: Cc1cnc2[nH]c3c(c2c1)CN1CCCC1C3
Reactant: O=C(CCl)N1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cnc2c(c1)c1c(n2CC(=O)N2CCCCC2)CC2CCCN2C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 3-methyl-7,8,9,9a,10,11-hexahydro-5H-pyrido[3′,2′:4,5]pyrrolo[3,2-f]indolizine (100 mg, 0.440 mmol) in DMF (1 mL) was added a suspension of sodium hydride (52 mg, 1.32 mmol) in DMF (1 mL). After stirring for 5 min at RT, a solution of 2-chloro-1-(piperidin-1-yl)ethanone (142 mg, 0.881 mmol) in DMF (1 mL) was added to the reaction mixture, and stirring continued for 2 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by silica gel flash chromatography to yield 2-(3-methyl-8,9,9a,10-tetrahydro-5H-pyrido[3′,2′:4,5]pyrrolo[3,2-f]indolizin-11(7H)-yl)-1-(piperidin-1-yl)ethanone;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[N:20]([CH3:21])[CH2:19][CH2:18][C@@:14]4([C:15]=2[C:16]=1[OH:17])[C:9]3=[CH:10][C@@H:11]([CH3:24])[C:12]([O:22][CH3:23])=[CH:13]4.Br[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.[Cu]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[N:20]([CH3:21])[CH2:19][CH2:18][C@@:14]4([C:15]=2[C:16]=1[O:17][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:9]3=[CH:10][C@@H:11]([CH3:24])[C:12]([O:22][CH3:23])=[CH:13]4
Reactant: COC1=C[C@]23CCN(C)[C@H](Cc4ccc(OC)c(O)c42)C3=C[C@H]1C
Reactant: Brc1ccccc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: COC1=C[C@]23CCN(C)[C@H](Cc4ccc(OC)c(Oc5ccccc5)c42)C3=C[C@H]1C
Yield: 84.6 %

Procedure:
Compound 2 (18.80 g, 42 mmol) was dried by azeotropic distillation several times with pyridine and then dissolved in pyridine (100 ml). To this solution was added bromobenzene (4.90 ml, 46 mmol), powdered potassium carbonate (6.40 g, 46 mmol) and 40μ copper powder (1.34 g, 21 mmol) and the resulting mixture refluxed under argon for 48 hours. The solution was filtered while hot, the insoluble material washed with warm pyridine and the filtrate evaporated to dryness. The residue was dissolved in benzene, treated with charcoal and evaporated to a crystalline residue. Crystallization from ethyl acetate gave 14.33 g (85%) of 3 as tan needles, mp 177°-178°. Recrystallization from ethyl acetate gave analytically pure 3, mp. 177°-178°. NMR (CDCl3): δ7.43-6.67, m(7), aromatic; 5.57, m(2), H5α and H8; 3.60, 3--OCH3 ; 3.03; 6--OCH3 ; 2.42, N--CH3 ; 1.17, d(3), 7--CH3, J=7 Hz.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Br>>[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Reactant: Clc1cccc(CBr)c1
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1cccc(Cl)c1

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 3-chlorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.