Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[C:5]([O:11][CH2:12][O:13][CH3:14])[CH:4]=1.[S:15]([CH2:25][N+:26]#[C-:27])([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)(=[O:17])=[O:16].[C-]#N.[Na+]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([C@H:7]2[O:8][CH:27]=[N:26][C@@H:25]2[S:15]([C:18]2[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=2)(=[O:17])=[O:16])=[C:5]([O:11][CH2:12][O:13][CH3:14])[CH:4]=1
Reactant: COCOc1cc(OC)ccc1C=O
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: [C-]#N
Agent: [Na+]
Product: COCOc1cc(OC)ccc1[C@H]1OC=N[C@@H]1S(=O)(=O)c1ccc(C)cc1

Procedure:
In a manner analogous to Preparation 1, 4-methoxy-2-methoxymethoxybenzaldehyde (0.12 g, 0.63 mmol), tosylmethylisocyanide (0.12 g, 0.60 mmol) and NaCN (3 mg, 0.06 mmol) gave the desired compound as a tan solid. MS(ES+) m/z 392.0 (M+H+).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][N:11]=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][C:13]1=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:22]([O:24][CH:25]([O:28][CH2:29][CH3:30])[CH2:26]Br)[CH3:23]>CN(C)C=O>[CH2:3]([O:10][N:11]=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:26][CH:25]([O:28][CH2:29][CH3:30])[O:24][CH2:22][CH3:23])[C:13]1=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(CBr)OCC
Reactant: O=C1Nc2ccccc2C1=NOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(CN1C(=O)C(=NOCc2ccccc2)c2ccccc21)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To a suspension of 0.35 g of sodium hydride (60%) in 20 ml of N,N-dimethylformamide was added dropwise a solution of 2.00 g of 3-(benzyloxyimino)indolin-2-one in 20 ml of N,N-dimethylformamide at 0° C. in a nitrogen stream. After stirring the mixture at room temperature for 1 hour, 1.40 ml of bromoacetaldehyde diethyl acetal was added thereto, and the mixture was stirred for 12 hours at 70° C. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate and washed with an aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by silica gel column chromatography (chloroform/methanol=100/1) to give 2.20 g (76%) of 3-(benzyloxyimino)-1-(2,2-diethoxyethyl)indolin-2-one.
Reaction SMILES: [N:1]([CH:4]1[CH2:7][C:6]2([CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)=[CH:15][N:14]=3)[CH2:9][CH2:8]2)[CH2:5]1)=[N+]=[N-]>C(O)C.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:16]2[CH:17]=[CH:18][C:13]([N:10]3[CH2:11][CH2:12][C:6]4([CH2:5][CH:4]([NH2:1])[CH2:7]4)[CH2:8][CH2:9]3)=[N:14][CH:15]=2)=[CH:20][CH:21]=1
Reactant: [N-]=[N+]=NC1CC2(CCN(c3ccc(-c4ccc(F)cc4)cn3)CC2)C1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCO
Product: NC1CC2(CCN(c3ccc(-c4ccc(F)cc4)cn3)CC2)C1
Yield: 63.9 %

Procedure:
The process is performed according to the procedure described in Example 6 (step 6.4.). Starting with 6.60 g (19.56 mmol) of 2-azido-7-[5-(4-fluorophenyl)pyridin-2-yl]-7-azaspiro[3.5]nonane, obtained in step 10.4., in 28 mL of ethanol, 0.81 g (3.91 mmol) of Lindlar catalyst (PdCaCO3) is added. 3.89 g of pure product are thus obtained in the form of a yellow powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10][C@@H:9]1[C:18](OC)=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>O1CCCC1.C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][S:14]([CH3:17])(=[O:15])=[O:16])[CH2:10][C@@H:9]1[CH2:18][OH:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@H]1C[C@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](OS(C)(=O)=O)C[C@@H]1CO
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 82.4 %

Procedure:
To a solution of (2R,4S)-1-t-butoxycarbonyl-4-methanesulfonyloxy-2-methoxycarbonylpyrrolidine (3.96 g: 12.2 mmole) in a mixture of tetrahydrofuran (12 ml) and ethanol (18 ml), sodium borohydride (1.85 g: 48.8 mmole) is added in a nitrogen atmosphere under ice cooling. The mixture is stirred for 45 minutes at room temperature to give (2R,4S)-1-t-butoxycarbonyl-4-methanesulfonyloxypyrrolidine-2-methanol (2.97 g). Yield: 83%. Colorless crystals. mp. 95° to 96° C.
Reaction SMILES: [H-].[Na+].C(S)C.[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17]C)[C:13]([CH3:20])([CH3:19])[CH2:12][CH:11]=[C:10]2[CH:21]([CH3:23])[CH3:22].Cl>CN(C=O)C.O>[Br:6][C:7]1[C:16]([OH:17])=[CH:15][C:14]2[C:13]([CH3:19])([CH3:20])[CH2:12][CH:11]=[C:10]([CH:21]([CH3:22])[CH3:23])[C:9]=2[CH:8]=1
Reactant: COc1cc2c(cc1Br)C(C(C)C)=CCC2(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCS
Solvent: O
Product: CC(C)C1=CCC(C)(C)c2cc(O)c(Br)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 101.6 %

Procedure:
To a suspension of sodium hydride 60% w/w (0.30 g, 6.8 mmol) in 20 mL of DMF under argon atmosphere was added slowly ethanethiol 98% (0.5 mL, 6.8 mmol), and the resulting solution was stirred for 15 min. A solution of 6-bromo-4-isopropyl-1,1-dimethyl-7-methoxy-1,2-dihydronaphthalene (Compound 102, 600 mg, 1.9 mmol) in 3 mL of DMF was added, and the reaction mixture was refluxed for 5 h, then cooled to room temperature, acidified with 2 N HCl, diluted with water and extracted with ethyl acetate. The combined extracts were washed with brine, dried over MgSO4, and filtered. The solvent was removed to afford 0.57 g (100%) of the title compound as a dark brown oil.
Reaction SMILES: [CH2:1]([N:8]([CH2:30][C@H:31]([OH:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[C:19]([N+:27]([O-:29])=[O:28])[CH:18]=2)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:39]1[CH:44]=[CH:43][CH2:42][CH2:41][CH2:40]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:1]([N:8]([CH2:30][C@@H:31]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[O:38][CH:40]1[CH2:41][CH2:42][CH2:43][CH2:44][O:39]1)[CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[C:19]([N+:27]([O-:29])=[O:28])[CH:18]=2)=[CH:15][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1=COCCC1
Reactant: COC(=O)c1ccc(-c2ccc(CCN(Cc3ccccc3)C[C@H](O)c3ccccc3)cc2)cc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccc(CCN(Cc3ccccc3)C[C@H](OC3CCCCO3)c3ccccc3)cc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 4′-[2-[benzyl[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-3-nitro-4-biphenylcarboxylate (2.31 g) in methylene chloride (35 ml) were added dihydropyran (1.24 ml) and pyridinium p-toluenesulfonate (1.36 mg) and stirred overnight at room temperature. The mixture was poured into saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate aqueous solution twice and brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=3/1) to give methyl 4′-[2-[benzyl[(2R)-2-phenyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-amino]ethyl]-3-nitro-4-biphenylcarboxylate (1.48 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH:11]=[CH2:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:47][C:48]1[CH:49]=[CH:50][C:51]2[C:55]([CH3:57])([CH3:56])[O:54][B:53]([OH:58])[C:52]=2[CH:59]=1>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]([CH:11]=[CH2:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH:47][C:48]1[CH:49]=[CH:50][C:51]2[C:55]([CH3:56])([CH3:57])[O:54][B:53]([OH:58])[C:52]=2[CH:59]=1)=[O:6]
Reactant: CC1(C)OB(O)c2cc(N)ccc21
Reactant: C=Cc1ccc(C(=O)O)c(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=Cc1ccc(C(=O)Nc2ccc3c(c2)B(O)OC3(C)C)c(Cl)c1

Procedure:
To a solution of 2-chloro-4-vinyl benzoic acid (44 mg, 0.24 mmol) in DMF (2 mL) was added HATU (55 mg, 0.15 mmol) and DIEA (25 mg, 0.21 mmol). After 1 hour 6-amino-3,3-dimethyl-3H-benzo[c][1,2]oxaborol-1-ol hydrochloride salt (30 mg, 0.14 mmol) was added. After 12 hours the reaction was concentrated down under reduced pressure onto celite. The crude material was subjected to flash chromatography (Isco Companion, 4 g SiO2 cartridge, SiO2 solid load, neat DCM to 10% MeOH gradient) to give 2-Chloro-N-(1-hydroxy-3,3-dimethyl-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-vinyl-benzamide as a white powder. Amount obtained: 20.8 mg (48%). Data: LCMS (M/Z): 342 (M+H); 1H NMR (DMSO-d6) δ: 1.36-1.59 (m, 6 H) 5.42 (d, J=11.1 Hz, 1 H) 6.02 (d, J=17.8 Hz, 1 H) 6.79 (dd, J=17.7, 11.0 Hz, 1 H) 7.33-7.46 (m, 1 H) 7.56 (s, 2 H) 7.69 (d, J=1.6 Hz, 2 H) 8.05 (dd, J=1.7, 0.5 Hz, 1 H) 9.00 (br. s, 1 H) 10.35-10.62 (m, 1 H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl.Cl[CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[CH2:19]([O:26][C:27]1[CH:54]=[CH:53][C:52]([OH:55])=[CH:51][C:28]=1[C:29]([NH:31][C:32]1[CH:44]=[C:43]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:42]=[CH:41][C:33]=1[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[O:30])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(OCC)(=O)C.O.CN(C)C(=O)C>[CH2:19]([O:26][C:27]1[CH:54]=[CH:53][C:52]([O:55][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:51][C:28]=1[C:29]([NH:31][C:32]1[CH:44]=[C:43]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:42]=[CH:41][C:33]=1[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[O:30])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(O)ccc1OCc1ccccc1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(OCCN2CCOCC2)ccc1OCc1ccccc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 52.5 %

Procedure:
Potassium carbonate (0.075 g), potassium iodide (0.090 g), and N-(2-chloroethyl)morpholine hydrochloride (0.041 g) were added to an N,N-dimethylacetamide (1.8 mL) solution of tert-butyl 2-(2-(benzyloxy)-5-hydroxybenzamido)-4-phenylbenzoate (0.090 g), followed by stirring at 100° C. for 1 hour. The reaction mixture was cooled to room temperature, and then water and ethyl acetate were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium bicarbonate, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 80-25% hexane/ethyl acetate] to obtain 0.058 g of tert-butyl 2-(2-(benzyloxy)-5-(2-(morpholin-4-yl)ethoxy)benzamido)-4-phenylbenzoate as a light yellow solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7].I[CH2:9][CH3:10].[H-].[Na+]>CN(C=O)C>[CH2:9]([N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7])[CH3:10]
Reactant: CCI
Reactant: O=Cc1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1ccnc1C=O
Temperature: 25 °C
Reaction time: 120 h

Procedure:
In DMF (15 ml), 2-imidazole carboxaldehyde (500 mg) was dissolved. Then, the solution was added with iodoethane (1.25 ml) and sodium hydride (208 mg), followed by stirring at room temperature for 5 days. After completion of the reaction, the solvent was distilled off and the residue was then added with chloroform, followed by washing with water and saturated saline solution. The resultant was dried with anhydrous sodium sulfate, and the solvent was then distilled off. The residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (280 mg) as a yellow oily substance.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([C:12](=[O:16])[N:13]([CH3:15])[CH3:14])[CH2:9]1)=O)(C)(C)C.[C:17]([OH:23])([C:19]([F:22])([F:21])[F:20])=[O:18]>C(Cl)Cl>[F:20][C:19]([F:22])([F:21])[C:17]([OH:23])=[O:18].[CH3:14][N:13]([CH3:15])[C:12]([CH:10]1[CH2:11][NH:8][CH2:9]1)=[O:16].[C:17]([OH:23])([C:19]([F:22])([F:21])[F:20])=[O:18]
Reactant: CN(C)C(=O)C1CN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)C1CNC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 324.3 mg (1.42 mmol) 3-dimethylcarbamoyl-azetidine-1-carboxylic acid tert-butyl ester in 7.5 mL DCM was added 2.5 mL TFA and the reaction was stirred at room temperature for 5 hours. The solvent was evaporated to give the desired product as a TFA salt, which was used for the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[O:10])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH:38]1[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:47]([O:46][C:44]([N:41]1[CH2:42][CH2:43][CH:38]([O:1][C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[O:10])=[CH:4][C:3]=2[N+:15]([O-:17])=[O:16])[CH2:39][CH2:40]1)=[O:45])([CH3:50])([CH3:48])[CH3:49]
Reactant: O=C(Nc1ccc(O)c([N+](=O)[O-])c1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC(=O)C(F)(F)F)cc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 4-hydroxy-3-nitro-N-(trifluoromethylcarbonyl)benzenamine (10.0 g), triphenylphosphine (22.1 g) and 4-hydroxy-N-(t-butoxycarbonyl)piperidine (17.0 g) in THF (30 mL) was added DEAD (13.5 mL) drop-wise. The reaction was stirred at ambient temperature for 1 hour, concentrated and purified on silica gel column (ethyl acetate/hexane, gradient) to afford 4-(N′-(t-butoxycarbonyl)piperidin-4-yl)oxy-3-nitro-N-(trifluoromethylcarbonyl)benzenamine.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][C:12]3[C:17]([N+:18]([O-])=O)=[CH:16][CH:15]=[CH:14][N:13]=3)[C:4]=2[O:3]1>CO.C(OCC)(=O)C.[Pd]>[CH3:1][C:2]1([CH3:21])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][C:12]3[C:17]([NH2:18])=[CH:16][CH:15]=[CH:14][N:13]=3)[C:4]=2[O:3]1
Reactant: CC1(C)Cc2cccc(Oc3ncccc3[N+](=O)[O-])c2O1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC1(C)Cc2cccc(Oc3ncccc3N)c2O1
Reaction time: 1 h
Yield: 97 %

Procedure:
134a (3.27 g, 11.4 mmol) was dissolved in a 1:1 mixture of methanol and ethyl acetate (80 mL). Palladium on charcoal (10%, 1.2 g, 1.1 mmol) was added, and the mixture was stirred 1 h under hydrogen atmosphere (40 psi). The reaction mixture was filtered over Celite® and concentrated to afford 2.78 g (97% yield, 100% pure) of 134b as an off-white solid. [M+H]+=257.17; in NMR (500 MHz, deuterochloroform) δ ppm 7.53 (d, 1H, J=5.0 Hz), 6.97 (d, 2H, J=10.0 Hz), 6.95 (d, 1H, J=5.0 Hz), 6.80 (m, 2H), 3.97 (br, 2H), 3.05 (s, 2H), 1.44 (s, 6H); 13C (125 MHz, deuterochloroform) δ (ppm), 151.60, 150.18, 137.70, 135.60, 131.52, 129.47, 121.77, 121.30, 120.96, 120.27, 119.02, 87.80, 43.19, 28.08.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH:21]2[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[C:15]([CH:21]2[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]2)[CH:16]=1
Reactant: CC1(C)CCC(c2cc(Br)ccc2N2CCN(C(=O)OC(C)(C)C)CC2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CC1(C)CCC(c2cc(Br)ccc2N2CCNCC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 103.7 %

Procedure:
A mixture of 4-[4-bromo-2-(4,4-dimethylcyclohexyl)phenyl]piperazine-1-carboxylic acid t-butyl ester (1.5 g, 3.32 mmol) produced in Example (3e), trifluoroacetic acid (3 mL, 38.7 mmol) and dichloromethane (6 mL) was stirred for 2 hours and 30 minutes at room temperature. Saturated aqueous solution of sodium carbonate was added to the reaction mixture and extraction was performed with ethyl acetate. The separated organic layer was washed with water and brine in that order and then dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The residue was dried under reduced pressure to give 1.21 g of a crude product of the title compound as a brown oil.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5].[CH3:10][Si:11]([CH3:14])([CH3:13])Cl>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C>[CH3:10][Si:11]([CH3:14])([CH3:13])[O:1][CH2:2][C:3]([CH2:8][O:9][Si:11]([CH3:14])([CH3:13])[CH3:10])([CH2:6][O:7][Si:11]([CH3:14])([CH3:13])[CH3:10])[CH2:4][O:5][Si:11]([CH3:14])([CH3:13])[CH3:10]
Reactant: OCC(CO)(CO)CO
Reactant: C[Si](C)(C)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Product: C[Si](C)(C)OCC(CO[Si](C)(C)C)(CO[Si](C)(C)C)CO[Si](C)(C)C

Procedure:
1 mole of pentaerythritol, 6 moles of trimethylchlorosilane and 0.004 moles of triethylbenzyl ammonium chloride were reacted at the reflux temperature (54°-86° C.) as in Example 1 and then worked up by distillation.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:7]2[CH2:8][CH2:9][NH:10][CH2:11][C:6]2=[C:5]([C:12]([NH2:14])=[O:13])[C:4]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1.[N+](C1C=CC([N:31]([CH:35]2[CH2:40][CH2:39][C:38](=[N:41][O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:37][CH2:36]2)[C:32](=O)[O-:33])=CC=1)([O-])=O.C(=O)([O-])[O-].[Na+].[Na+].O>C(#N)C>[Cl:2][C:3]1[N:7]2[CH2:8][CH2:9][N:10]([C:32]([NH:31][CH:35]3[CH2:40][CH2:39][C:38](=[N:41][O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:37][CH2:36]3)=[O:33])[CH2:11][C:6]2=[C:5]([C:12]([NH2:14])=[O:13])[C:4]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1
Reactant: CC(C)(C)ON=C1CCC(N(C(=O)[O-])c2ccc([N+](=O)[O-])cc2)CC1
Reactant: NC(=O)c1c(-c2cccc(F)c2)c(Cl)n2c1CNCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)ON=C1CCC(NC(=O)N2CCn3c(Cl)c(-c4cccc(F)c4)c(C(N)=O)c3C2)CC1
Temperature: 60 °C

Procedure:
A suspension of 0.27 (0.82 mmol) of 6-chloro-7-(3-fluorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxamide hydrochloride, 0.37 g (1.06 mmol) of 4-nitrophenyl[4-[(1,1-dimethylethoxy)imino]cyclohexyl]-carbamate and 0.33 g (2.45 mmol) of sodium carbonate in 30 ml of acetonitrile is heated at 60° C. for 3 hours. After cooling, the mixture is poured into water and the product is extracted with dichloromethane. After drying over sodium sulfate and filtration, the solvent is evaporated off under reduced pressure and the residue is purified by chromatography on a column of 40 g of silica gel, eluting with a mixture of dichloromethane/ethyl acetate (60/40 to 20/80), to give 0.18 g of 6-chloro-7-(3-fluorophenyl)-N2-[4-[(1,1-dimethylethoxy)imino]cyclohexyl]-3,4-dihydropyrrolo-[1,2-a]pyrazine-2,8(1H)-dicarboxamide in the form of a yellowish powder, after evaporating the fractions down to a small volume of solvent, filtering off the crystallized product, washing with ethyl acetate and drying under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][NH:7][C:8]2[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=2)[C:11]([NH:13][CH:14]([CH3:16])[CH3:15])=[O:12])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:31][N:32]1[C:36]([S:37](Cl)(=[O:39])=[O:38])=[CH:35][CH:34]=[N:33]1>ClCCl.O>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]([S:37]([C:36]2[N:32]([CH3:31])[N:33]=[CH:34][CH:35]=2)(=[O:39])=[O:38])[C:8]2[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=2)[C:11]([NH:13][CH:14]([CH3:16])[CH3:15])=[O:12])=[CH:4][CH:3]=1
Reactant: CC(C)NC(=O)c1cccc(NCc2ccc(Cl)cc2)c1
Reactant: Cn1nccc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)c1cccc(N(Cc2ccc(Cl)cc2)S(=O)(=O)c2ccnn2C)c1
Yield: 20.1 %

Procedure:
3-(4-Chloro-benzylamino)-N-isopropyl-benzamide (30 mg, 0.1 mmol), diisopropylethylamine (35 μL, 0.2 mmol) and 1-methyl-1H-pyrazole-5-sulfonyl chloride (36 mg, 0.2 mmol) were stirred in dry dichloromethane (2 ml) at room temperature for 72 hrs. The reaction was diluted with dichloromethane ml) and water (5 ml) with stirring. The organics were collected, dried (PTFE frit) and concentrated in vacuo. The residue was purified by preparative TLC (10% ethyl acetate/dichloromethane) to yield the product as an off-white solid (9 mg). HPLC retention time 8.04 min. Mass spectrum (ES+) m/z 447 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:14]([CH3:16])[CH3:15])[C:5]([O:17]C)=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH:25]([CH3:27])[CH3:26])[CH:3]=1.O.C(OCC)C>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:14]([CH3:16])[CH3:15])[C:5]([OH:17])=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH:25]([CH3:27])[CH3:26])[CH:3]=1
Reactant: COc1c(-c2ccccc2C(C)C)cc(C)cc1-c1ccccc1C(C)C
Solvent: CCOCC
Solvent: ClCCl
Solvent: O
Product: Cc1cc(-c2ccccc2C(C)C)c(O)c(-c2ccccc2C(C)C)c1
Yield: 95 %

Procedure:
A mixed solution of 1 mL of water and 4 mL of dimethoxyethane was added into a flask into which 2,6-dibromo-4-methylanisole (400 mg, 1.43 mmol), 2-isopropylphenylboronic acid (720 mg, 4.39 mmol), palladium acetate (14 mg, 0.062 mmol), triphenylphosphine (60 mg, 0.23 mmol), and potassium phosphate (940 mg, 4.43 mmol) were already added, and then refluxed at normal temperature for 6 hours. After cooling to normal temperature, an ammonium chloride aqueous solution (5 mL) and 10 mL of diethylether were added thereto to separate an organic layer and extract residues using diethylether. The separated organic layer was dried with magnesium sulfate and volatile materials were then removed to produce 670 mg of grey 4-methyl-2,6-bis(2′-isopropylphenyl)anisole solid. The anisole thus produced was dissolved in 5 mL of methylene chloride without separate purification, 3 mL of boron tribromide (1 M methylene chloride solution) was dropped thereon at −78° C., and a reaction was carried out while the temperature was slowly increased to normal temperature. After the reaction, a mixed solution of water (5 mL) and diethylether (10 mL) was added to separate an organic layer and extract an aqueous solution layer using diethylether (5 mL×3), and the separated organic layer was dried. Residues from which volatile components were removed at reduced pressure were purified using a silica gel chromatography tube in a mixed solvent of hexane and methylene chloride to produce 0.47 g of white 4-methyl-2,6-bis(2′-isopropylphenyl)phenol solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.Br[CH2:10][CH2:11][CH2:12][NH2:13]>>[C:2]1([NH:1][CH2:10][CH2:11][CH2:12][NH2:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: NCCCBr
Agent: Br
Product: NCCCNc1ccccc1

Procedure:
Prepared in the manner of Example 1, Step A from aniline and 3-bromopropylamine hydrobromide salt.
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].C(N(CC)CC)C.[CH2:12]([S:14](Cl)(=[O:16])=[O:15])[CH3:13]>ClCCl>[CH:2]([O:4][S:14]([CH2:12][CH3:13])(=[O:16])=[O:15])([CH3:3])[CH3:1]
Reactant: CCS(=O)(=O)Cl
Reactant: CC(C)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)OC(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.2 %

Procedure:
To a solution of 2-propanol (2.4 mL, 32 mmol) in dichloromethane (50 were added triethylamine (3.5 ml, 25 mmol) and ethanesulfonyl chloride (2.0 mL, 21 mmol), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (2.4 g, 16 mmol, 75%).