Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10](/[CH:14]=[CH:15]/[C:16]([OH:18])=O)[CH:11]=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[CH3:19][N:20]([CH2:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1)[CH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>CN(C=O)C>[CH3:19][N:20]([CH2:27][C:28]1[CH:29]=[CH:30][C:31]([NH:32][C:16](=[O:18])/[CH:15]=[CH:14]/[C:10]2[CH:11]=[N:12][CH:13]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)[CH:9]=2)=[CH:33][CH:34]=1)[CH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Reactant: Cc1ccc(-c2cncc(/C=C/C(=O)O)c2)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cncc(/C=C/C(=O)Nc3ccc(CN(C)C4CCOCC4)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 8.7 %

Procedure:
To a solution of (E)-3-[5-(4-methylphenyl)pyridin-3-yl]acrylic acid (150 mg), 4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]aniline (168 mg) and triethylamine (0.10 ml) in DMF (10 ml) was added diethyl cyanophosphate (0.12 ml) at 0° C., and the mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure. To the residue was added water, the mixture was extracted with chloroform. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethanol/ethyl acetate=1:2) to give (E)-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]-phenyl]-3-[5-(4-methylphenyl)pyridin-3-yl]acrylic amide (Compound 215) (24 mg) as yellow solid.
Reaction SMILES: [C:1]1([NH2:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:20]=[C:21]([S:27]([Cl:30])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=2[O:25][CH3:26])[CH2:15][CH2:14]1>CC(C)=O>[ClH:30].[CH3:26][O:25][C:24]1[CH:23]=[CH:22][C:21]([S:27]([NH:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)(=[O:28])=[O:29])=[CH:20][C:19]=1[N:16]1[CH2:15][CH2:14][N:13]([CH3:12])[CH2:18][CH2:17]1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1N1CCN(C)CC1
Reactant: Nc1cccc2ccccc12
Solvent: CC(C)=O
Product: COc1ccc(S(=O)(=O)Nc2cccc3ccccc23)cc1N1CCN(C)CC1
Product: Cl
Reaction time: 18 h
Yield: 67 %

Procedure:
1-Naphthylamine (29 mg, 0.2 mmol) was added to a stirred solution of 3-(4-methyl-1-piperazinyl)-4-methoxybenzene sulfonyl chloride (D2) (60 mg, 0.2 mmol) in acetone (1 ml) at ambient temperature. After stirring, for 18 h, the precipitate was filtered off and washed with acetone and diethyl ether to afford the title compound (E1) as a cream solid (60 mg, 67%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.ClC(Cl)(O[C:27](=[O:33])[O:28][C:29](Cl)(Cl)Cl)Cl.[CH3:35][O:36][C:37]1[CH:38]=C(O)[CH:40]=[CH:41][CH:42]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:28][C:29]2[CH:40]=[CH:41][CH:42]=[C:37]([O:36][CH3:35])[CH:38]=2)=[CH:18][CH:17]=1
Reactant: COc1cccc(O)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cccc(OC(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)c1
Yield: 71.7 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (100 mg) was added to toluene (10 ml) and triethylamine (1 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (150 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 10 min. Next, 3-methoxyphenol (55 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (108 mg, yield 68%)
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[C:12]([CH3:21])[C:11]([CH:22]2[O:27][CH2:26][CH2:25][NH:24][CH2:23]2)=[N:10]1.C(N(CC)CC)C.[CH:35]([S:38](Cl)(=[O:40])=[O:39])([CH3:37])[CH3:36]>ClCCl>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([C:13]2[N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[Cl:2])[N:10]=[C:11]([CH:22]3[O:27][CH2:26][CH2:25][N:24]([S:38]([CH:35]([CH3:37])[CH3:36])(=[O:40])=[O:39])[CH2:23]3)[C:12]=2[CH3:21])=[CH:19][CH:18]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: Cc1c(C2CNCCO2)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(C2CN(S(=O)(=O)C(C)C)CCO2)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Reaction time: 18 h

Procedure:
To a stirred suspension of 2-[1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-methyl-1H-pyrazol-3-yl]-morpholine hydrochloride 5A-2 (75 mg, 0.18 mmol) and triethylamine (49 μL, 0.36 mmol) in dichloromethane (0.5 ml) was added isopropylsulfonyl chloride (0.22 μL 0.2 mmol) dropwise. After stirring for 18 h, the reaction was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (silica, 40–50% ethyl acetate/hexanes) to give the title compound 6A-1 as a colorless foam (49 mg).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.C(O)(=O)C.[CH2:13]([NH:15][C:16](=[O:18])[O-:17])[CH3:14].[CH3:19][O:20][C:21]1[CH:22]=[CH:23][C:24]2[CH:25]([CH3:33])[CH:26]3[CH2:30][NH:29][CH2:28][CH:27]3[C:31]=2[CH:32]=1>ClCCCl.C(Cl)Cl>[CH2:13]([NH:15][C:16](=[O:17])[O-:18])[CH3:14].[Cl:1][C:32]1[C:31]2[CH:27]3[CH2:28][NH:29][CH2:30][CH:26]3[CH:25]([CH3:33])[C:24]=2[CH:23]=[CH:22][C:21]=1[O:20][CH3:19]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc2c(c1)C1CNCC1C2C
Agent: CCNC(=O)[O-]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc2c(c1Cl)C1CNCC1C2C
Temperature: 60 °C
Reaction time: 3 h
Yield: 5.3 %

Procedure:
N-chlorosuccinimide (0.39 g, 2.9 mmol) and acetic acid (3 mL) were added to a solution of N-ethylcarbamate-5-methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 2, Step A) (0.80 g, 2.9 mmol) in DCE (3 mL). The resulting solution was stirred for 3 hours at 60° C. The reaction mixture was cooled to room temperature, diluted with CH2Cl2 (50 mL), and washed with H2O (50 mL). The organic extract was dried over MgSO4 and concentrated. The crude product was purified by column chromatography (SiO2) using a 0-35% EtOAc-hexanes gradient to afford 50 mg (6%) of the subtitle compound (The major product is N-ethylcarbamate-5-methoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole, 78%). MS calculated for C16H20ClNO3+H: 310, observed: 310.
Reaction SMILES: [CH3:1][CH:2]1[C:10]([CH3:12])([CH3:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[Br-].[CH2:14]([NH3+])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].[OH-].[Na+]>O>[CH3:12][C:10]1([CH3:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14])[C:2]1=[CH2:1]
Reactant: CCCCCCCCCCCCCCCCCC[NH3+]
Reactant: CC1Nc2ccccc2C1(C)C
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=C1N(CCCCCCCCCCCCCCCCCC)c2ccccc2C1(C)C
Yield: 31.9 %

Procedure:
A mixture of 5.2 g (32 mmol) of 2,3,3-trimethylindoline and 15.8 g (48 mmol) of octadecylammonium bromide was heated with stirring followed by treating with a solution of 8 g of sodium hydroxide in 50 ml of water. After usual working-up, there were obtained 4.2 g of the title compound in a 84.1% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:13][CH:12]2[N:14]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:8]([CH2:9][C:10](=[O:25])[CH2:11]2)[CH2:7]1)=[O:5])[CH3:2].[CH:26](OCC)=[O:27].[O-]CC.[Na+]>C1COCC1.C(O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:7][CH:8]2[N:14]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:12]([CH2:11][C:10](=[O:25])[C:9]2=[CH:26][OH:27])[CH2:13]1)=[O:5])[CH3:2]
Reactant: CCOC=O
Reactant: CCOC(=O)C1CC2CC(=O)CC(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C1CC2CC(=O)C(=CO)C(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Temperature: 60 °C
Yield: 94 %

Procedure:
9-(4-Chloro-benzenesulfonyl)-7-oxo-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid ethyl ester (2.49 g, 6.45 mmol) was dissolved in THF/ethanol (14 mL, 1/1, v/v). Ethyl formate (5.19 mL, 64.53 mmol) was added followed by sodium ethoxide (6.2 mL of 21% solution in ethanol). The resulting mixture was heated to 60° C. for 30 minutes after which the solution was cooled to room temperature and quenched by the addition of saturated aqueous NH4Cl (10 mL). The resulting mixture was extracted with EtOAc (2×20 mL) and the combined organic phases were dried (Na2SO4), filtered and concentrated under vacuum to yield 2.51 g (94%) of 9-(4-chloro-benzenesulfonyl)-6-hydroxymethylene-7-oxo-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid ethyl ester as a yellow oil. Retention time (min)=2.017, method [1], MS (ESI) 414.0 (M+H).
Reaction SMILES: C([O:3][C:4](=[O:17])[CH:5]([NH2:16])[CH:6]=[C:7]([CH2:11][P:12]([OH:15])([OH:14])=[O:13])[CH2:8][CH2:9][F:10])C>O>[NH2:16][CH:5]([CH:6]=[C:7]([CH2:11][P:12]([OH:14])([OH:15])=[O:13])[CH2:8][CH2:9][F:10])[C:4]([OH:17])=[O:3]
Reactant: CCOC(=O)C(N)C=C(CCF)CP(=O)(O)O
Solvent: O
Product: NC(C=C(CCF)CP(=O)(O)O)C(=O)O

Procedure:
0.5 g (1.86 mmol) of 2-amino-6-fluoro-4-phosphonomethyl-hex-3-enoic acid ethyl ester are heated under reflux in 4 ml of water for 17 hours. The reaction mixture is concentrated by evaporation and separated with water on a strongly acidic ion-exchanger (Dowex 50W×8; It⊕ form). 2-amino-6-fluoro-4-phosphonomethyl-hex-3-enoic acid having a melting point of 160°-162° C. (decomp.) is obtained.
Reaction SMILES: C1(C)C=CC(S([CH2:10][N+:11]#[C-:12])(=O)=O)=CC=1.[C:14]([O:24][CH3:25])(=[O:23])[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CC(C)([O-])C.[K+]>>[C:17]1([C:16]2[C:15]([C:14]([O:24][CH3:25])=[O:23])=[CH:10][NH:11][CH:12]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: COC(=O)C=Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: COC(=O)c1c[nH]cc1-c1ccccc1
Yield: 52.2 %

Procedure:
Using p-toluenesulfonylmethyl isocyanide (10.1 g), methyl cinnamate (8.33 g) and potassium tert-butoxide (6.97 g), a procedure as in Reference Example 39 was performed to give the title compound as pale-yellow crystals (yield 5.40 g, 52%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]2[C:9]=1[N:10]=[C:11]1[C:16]=2[CH:15]=[CH:14][CH:13]=[CH:12]1.C(N(C(C)C)CC)(C)C.[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O>[CH2:26]([N:5]1[CH2:6][CH2:7][C:8]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[NH:10][C:9]=2[CH:3]([CH2:2][OH:1])[CH2:4]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCc1ccccc1
Reactant: OCc1cnccc2c3ccccc3nc1-2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClC(Cl)Cl
Product: OCC1CN(Cc2ccccc2)CCc2c1[nH]c1ccccc21
Yield: 77.6 %

Procedure:
A solution of 7 g (0.0324 mol) of 5-hydroxymethylazepino[4,5-b]indole, of 5.02 g (0.0388 mol) of diisopropylethylamine, and of 6.67 g (0.0388 mol) of benzyl bromide in 150 ml of chloroform is heated under reflux for 10 hours. The reaction mixture is then drowned in water and alkalified with a saturated aqueous solution of potassium carbonate. The organic phase is separated off and the aqueous phase is again extracted twice with 100 ml portions of chloroform. The organic phases are combined, washed with water, dried over magnesium sulphate, filtered and evaporated to dryness under vacuum. The residue, recrystallized from ether, yields 7.7 g of product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:33])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:21][CH:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].CI.[CH3:37]C(C)([O-])C.[K+].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:34])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([N:25]([C:26](=[O:33])[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH3:37])=[CH:23][CH:24]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(NC(=O)c3ccccc3)cc2)cs1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)c1ccccc1)c1ccc(OCCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.4 %

Procedure:
2-[(4-{2-[4-(Benzoylamino)phenoxy]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (500 mg) synthesized in Example 54-1 and methyl iodide (170 mg) were dissolved in N,N-dimethylformamide (6 mL), potassium tert-butoxide (135 mg) was added, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=3:1) to give the title compound (290 mg) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:30][CH3:31])=[C:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[C:15]([N+:27]([O-])=O)[CH:14]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4].[CH3:32]CO.CC(O)=O>[Fe].C(O)=O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:30][CH3:31])=[C:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]3[N:19]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[CH:32]=[N:27][C:15]=3[CH:14]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4]
Reactant: CCO
Reactant: COC(=O)c1cc(S(=O)(=O)c2ccc(NCc3ccccn3)c([N+](=O)[O-])c2)c(SC)s1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O=CO
Product: COC(=O)c1cc(S(=O)(=O)c2ccc3c(c2)ncn3Cc2ccccn2)c(SC)s1

Procedure:
The procedure in Example 318: part e was followed using 5-methylsulfanyl-4-{3-nitro-4-[(pyridin-2-ylmethyl)-amino]-benzenesulfonyl}-thiophene-2-carboxylic acid methyl ester ((Example 264: step c) 41 mg, 0.08 mmol), iron (110 mg, 2 mmol), and EtOH/aq. AcOH, followed by treatment with formic acid to yield the title compound. 1H-NMR (CD3OD): δ 8.50 (m, 1H), 8.42 (s, 1H), 8.08 (m, 1H), 7.97 (d, 1H, J=2.5 Hz), 7.85 (m, 1H), 7.72 (m, 1H), 7.71 (dt, 1H, J=1.9, 7.7 Hz), 7.57 (m, 1H), 7.29 (m, 1H), 7.22 (d, 1H J=7.8 Hz), 6.95 (d, 1H, J=9.0 Hz), 5.57 (s, 2H), 3.82 (s, 3H), 2.56 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].II.C([C:13]1([N:19]2[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)#N>O1CCCC1.BrCCBr>[C:2]1([C:13]2([N:19]3[CH2:20][CH2:21][CH:22]([OH:25])[CH2:23][CH2:24]3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccc1
Reactant: N#CC1(N2CCC(O)CC2)CCCCC1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: OC1CCN(C2(c3ccccc3)CCCCC2)CC1
Reaction time: 17 h

Procedure:
To bromobenzene (4.1 ml) and magnesium turnings (4 g) in 200 ml dry tetrahydrofuran under nitrogen was added a crystal of iodine and 10 drops of 1,2-dibromoethane. After small bubbles began to form, the reaction was stirred and heated to reflux for 4 hours. After cooling to room temperature 1-(1-cyanocyclohexyl)-4-hydroxypiperidine (2 g) was added. After 17 hours, the reaction was filtered, 120 ml saturated ammonium chloride was added and the mixture was extracted with ethyl ether. The ether layer was dried and the solvent was removed in vacuo. The residue was chromatographed on silica gel eluted with the appropriate mixture of methanol and chloroform to yield pure 1-(1-phenylcyclohexyl)-4-hydroxypiperidine.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[C:6]([OH:8])[CH:7]=1.O=O.[CH:14]1(Br)CCCC[CH2:15]1.Br[CH2:22][CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25]>>[CH3:25][C:24]([CH3:27])([CH3:26])[CH2:23][CH2:22][O:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[C:6]([O:8][CH2:14][CH3:15])[CH:7]=1
Reactant: CC(=O)c1cc(O)cc(O)c1
Reactant: BrC1CCCCC1
Reactant: CC(C)(C)CCBr
Agent: O=O
Product: CCOc1cc(OCCC(C)(C)C)cc(C(C)=O)c1

Procedure:
1-(3,5-Dihydroxyphenyl)ethanone (3.0 g) was converted analogously to O2.031. Instead of cyclohexylbromide, however, 1-bromo-3,3-dimethylbutane was used. After chromatography, 960 mg of the title compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][CH:12]([CH3:14])[CH3:13])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(O[CH:43]1[O:55][C@@H:54]([CH2:56][O:57][C:58](=[O:60])[CH3:59])[C@H:49]([O:50][C:51](=[O:53])[CH3:52])[C@@H:44]1[O:45][C:46](=[O:48])[CH3:47])(=O)C>ClCCCl>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][CH:12]([CH3:14])[CH3:13])[N:7]([C@H:43]3[O:55][C@@H:54]([CH2:56][O:57][C:58](=[O:60])[CH3:59])[C@H:49]([O:50][C:51](=[O:53])[CH3:52])[C@@H:44]3[O:45][C:46](=[O:48])[CH3:47])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC[C@@H]1OC(OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: CC(C)Nc1nc2c(Cl)cccc2[nH]1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCCl
Product: CC(=O)OC[C@@H]1O[C@H](n2c(NC(C)C)nc3c(Cl)cccc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Yield: 46.8 %

Procedure:
4-Chloro-2-(isopropylamino)-1H-benzimidazole (2.24 g, 10.68 mmol), N,O-bis(trimethylsilyl)acetamide (3.00 mL, 2.47g, 12.14 mmol), trimethylsilyl trifluoromethanesulfonate (1.2 mL, 1.42 g, 6.00 mmol), 1,2,3,5-tetra-O-acetyl-L-ribofuranose (4.46 g, 14.01 mmol) and 1,2-dichloroethane (35 mL) were used according to general procedure II. The product was purified by silica gel chromatography using 95:5 dichloromethane/acetonitrile to afford 2.34 g (47%) of an off-white foam MS (EI): m/z 468.2 (M+H).
Reaction SMILES: C[N:2]([CH:4]=[CH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)=O)[CH3:3].[N+]([O-])(O)=O.[N+:19]([O-])(O)=O.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([NH:37]C(N)=N)[CH:28]=[CH:29][C:30]=1[N:31]1[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32]1>>[Cl:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]2[CH:5]=[CH:4][N:2]=[C:3]([C:26]3[C:25]([O:24][CH3:23])=[C:30]([N:31]4[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32]4)[CH:29]=[CH:28][C:27]=3[NH2:37])[N:19]=2)=[CH:13][CH:12]=1
Reactant: CN(C)C=CC(=O)c1ccc(Cl)cc1
Reactant: O=[N+]([O-])O
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Product: COc1c(-n2cnc(C)c2)ccc(N)c1-c1nccc(-c2ccc(Cl)cc2)n1

Procedure:
The title compound was prepared from crude 1-(4-chloro-phenyl)-3-dimethylamino-propenone (87 mg, 0.3 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (83 mg, 0.22 mmol) using in analogous manner the procedure described in example 28b). Obtained as a pale-yellow solid (29 mg, 33%). Mp 202-204° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=2[NH2:19])[CH:7]=1.[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[S:28](Cl)(=[O:30])=[O:29]>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:16])[F:18])=[CH:11][C:10]=2[NH:19][S:28]([C:22]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:21]=2[Cl:20])(=[O:30])=[O:29])[CH:7]=1
Reactant: Nc1cc(C(F)(F)F)ccc1Oc1cncc(Cl)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Product: O=S(=O)(Nc1cc(C(F)(F)F)ccc1Oc1cncc(Cl)c1)c1ccc(Cl)cc1Cl

Procedure:
Using the method of Example 17.4, 4-(3-chloro-5-pyridyloxy)-3-aminobenzotrifluoride (0.4 g) and 2,4-dichlorobenzenesulfonyl chloride ((0.38 g) were combined to provide the title compound (0.26 g), as a crystalline solid following flash chromatography and trituration with ether. mp 150-151.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]2[CH:6]([CH2:27][C:28]([O:30]C)=[O:29])[CH2:7][CH2:8][N:9]([C:11](=[O:26])[NH:12][CH2:13][CH2:14][CH2:15][C:16]3[N:21]=[C:20]4[NH:22][CH2:23][CH2:24][CH2:25][C:19]4=[CH:18][CH:17]=3)[CH2:10][C:4]=2[CH:3]=1.O.[OH-].[Li+].Cl>O1CCCC1.O>[Cl:1][C:2]1[CH:33]=[CH:32][C:5]2[CH:6]([CH2:27][C:28]([OH:30])=[O:29])[CH2:7][CH2:8][N:9]([C:11](=[O:26])[NH:12][CH2:13][CH2:14][CH2:15][C:16]3[N:21]=[C:20]4[NH:22][CH2:23][CH2:24][CH2:25][C:19]4=[CH:18][CH:17]=3)[CH2:10][C:4]=2[CH:3]=1
Reactant: COC(=O)CC1CCN(C(=O)NCCCc2ccc3c(n2)NCCC3)Cc2cc(Cl)ccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CC1CCN(C(=O)NCCCc2ccc3c(n2)NCCC3)Cc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a stirring solution of methyl 2-{8-chloro-2-[N-(3-(1,2,3,4-tetrahydropyridino[2,3-b]pyridin-7-yl)propyl)carbamoyl]-1H,3H,4H,5H-benzo[e]azepin-5-yl}acetate (1 eq) in tetrahydrofuran (0.05 M) and water (0.05 M) was added lithium hydroxide monohydrate (1.5 eq). The reaction mixture was stirred at room temperature for 10 h. 1 M of hydrogen chloride (1.5 eq) was added and the reaction solvent was evaporated in vacuo. The residue was diluted with (5% MeOH/CH2Cl2 and the precipitate was filtered. The filtrate was concentrated and dried under vacuum oven for 24 h to afford product. EI-MS m/z 457 (M+H)+; 1H NMR (CD3OD; 400 MHz): δ7.53 (d, J=7.3 Hz, 1H), 7.39 (s, 1H), 7.18 (s, 2H), 6.51 (d, 7.3 Hz, 1H), 4.56 (s, 2H), 3.80-3.45 (m, 5H), 3.21 (m, 2H), 2.80 (m, 4H), 2.75 (m, 2H), 2.00-1.50 (m, 6H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[S:17][C:18]([C@H:21]([C:29]5[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=5[Cl:36])[NH:22][S@@](C(C)(C)C)=O)=[CH:19][N:20]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.Cl.O1CCOCC1>CO>[NH2:22][C@@H:21]([C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=1[Cl:36])[C:18]1[S:17][C:16]([NH:15][C:13]([C:10]2([C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)[CH2:11][CH2:12]2)=[O:14])=[N:20][CH:19]=1
Reactant: CC(C)(C)[S@@](=O)N[C@H](c1cnc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)s1)c1ccc(F)cc1Cl
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: N[C@H](c1cnc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)s1)c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution, of 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-((S)-(2-chloro-4-fluorophenyl)((R)-1,1-dimethylethylsulfinamido)methyl)thiazol-2-yl)cyclopropanecarboxamide (659 mg, 1.2 mmol) in MeOH (5 mL) was added 4M HCl in dioxane (1.8 mL, 7.2 mmol). The reaction mixture was stirred at room temperature for 1.5 h and evaporated to dryness. The crude product was dissolved in CH2Cl2. The organic layer was washed with aqueous NaHCO3 solution (50 mL×2), brine (50 mL×1), dried over MgSO4 and concentrated to provide (S)-N-(5-(Amino(2-chloro-4-fluorophenyl)methyl)thiazol-2-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide as a colorless solid that was used without further purification. 1H-NMR (400 MHz, CDCl3) δ 8.48 (br s, 1H), 7.63 (dd, J=6.1, 8.7 Hz, 1H), 7.18 (s, 1H), 7.08 (dd, J=2.6, 8.4 Hz, 1H), 6.99 (td, J=8.3, 2.6 Hz, 1H), 6.91-6.86 (m, 2H), 6.81 (d, J=7.9 Hz, 1H), 6.01 (s, 2H), 5.78 (s, 1H), 3.80 (s, 2H), 1.74-1.67 (m, 2H), 1.30-1.22 (m, 2H); HPLC ret. time 2.67 min, 10-99% CH3CN, 5 min run: ESI-MS 446.3 m/z (MH+).