Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11](Cl)(=[O:13])=[O:12].[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(N(C(C)C)CC)(C)C>ClCCl>[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[N:23]1[CH2:24][CH2:25][N:26]([S:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)(=[O:13])=[O:12])[CH2:27][CH2:28]1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: Fc1ccc(N2CCNCC2)c(F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1ccc2ccccc2c1)N1CCN(c2ccc(F)cc2F)CC1
Reaction time: 0.5 h
Yield: 55 %

Procedure:
To a stirred solution of naphthalene-2-sulfonyl chloride (350 mg, 1.54 mmol) and 1-(2,4-difluorophenyl)piperazine (305.0 mg, 1.54 mmol) in anhydrous dichloromethane (5 mL) was added diisopropylethylamine (0.670 mL, 3.85 mmol). The mixture was stirred for 30 minutes. Reaction was complete as determined by TLC. The reaction mixture was purified via flash column chromatography to afford 1-(2,4-difluorophenyl)-4-(2-naphthylsulfonyl)piperazine in 55% yield (327 mg) as white solid.
Reaction SMILES: [CH2:1]([C:3]([C:16]1[CH:29]=[CH:28][C:19]([O:20][CH2:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])=[C:18]([CH3:30])[CH:17]=1)([C:6]1[O:7][C:8]2[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:9]=2[CH:10]=1)[CH2:4][CH3:5])[CH3:2].CCN(CC)CC.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[CH3:26][C:23]([CH3:25])([CH3:24])[C:22](=[O:27])[CH2:21][O:20][C:19]1[CH:28]=[CH:29][C:16]([C:3]([C:6]2[O:7][C:8]3[CH:14]=[C:13]([O:15][S:39]([CH3:38])(=[O:41])=[O:40])[CH:12]=[CH:11][C:9]=3[CH:10]=2)([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:17][C:18]=1[CH3:30]
Reactant: CS(=O)(=O)Cl
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2ccc(O)cc2o1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2ccc(OS(C)(=O)=O)cc2o1
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
A solution of 1-{4-[1-ethyl-1-(6-hydroxy-benzofuran-2-yl)-propyl]-2-methyl-phenoxy}-3,3-dimethyl-butan-2-one (116 mg, 0.407 mmol) and Et3N (0.20 mL) in CH2Cl2 (5.0 mL) at 0° C. is added methanesulfonic chloride (70 mg, 0.610 mmol). The resulting mixture is stirred for 30 min and quenched with MeOH (1.0 mL). The mixture is purified on column chromatography (25% EtOAc/Hex) to afford the title compound (185 mg, 93%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@:6]1([NH:21]C(OC(C)(C)C)=O)[CH2:11][C@H:10]([O:12][C:13](=[O:15])[CH3:14])[C@@H:9]2[C@H:7]1[C@H:8]2[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:5])[CH3:2]>C(O)(C(F)(F)F)=O.ClCCl>[CH2:1]([O:3][C:4]([C@:6]1([NH2:21])[CH2:11][C@H:10]([O:12][C:13](=[O:15])[CH3:14])[C@@H:9]2[C@H:7]1[C@H:8]2[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1[C@H]2[C@@H]1[C@](NC(=O)OC(C)(C)C)(C(=O)OCC)C[C@@H]2OC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@H]1[C@H]2[C@@H]1[C@](N)(C(=O)OCC)C[C@@H]2OC(C)=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 97.8 %

Procedure:
Dissolve (1S,2S,4S,5R,6R)-4-acetyloxy-2-(tert-butoxycarbonyl)aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester (1.25 g, 3.13 mmol, Preparation 19) in a solution of 95% TFA in dichloromethane (60 mL) and stir under nitrogen at room temperature for 5 minutes. After this time remove the TFA/dichloromethane in vacuo. Dissolve the crude product in a suspension of NaHCO3 (1.00 g) in dichloromethane (50 mL) and stir for 30 minutes. Filter the suspension, wash with dichloromethane (3×25 mL), and concentrate in vacuo to afford 916 mg (98%) of the product as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].F[C:19]1[CH:24]=[C:23]([N:25]2[C:30](=[O:31])[CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[N:27]([CH3:36])[C:26]2=[O:37])[C:22]([F:38])=[CH:21][C:20]=1[N+:39]([O-:41])=[O:40]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][C:19]1[CH:24]=[C:23]([N:25]2[C:30](=[O:31])[CH:29]=[C:28]([C:32]([F:34])([F:35])[F:33])[N:27]([CH3:36])[C:26]2=[O:37])[C:22]([F:38])=[CH:21][C:20]=1[N+:39]([O-:41])=[O:40])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(F)c([N+](=O)[O-])cc2F)c1=O
Reactant: Oc1ccccc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccccc3OCc3ccccc3)c([N+](=O)[O-])cc2F)c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
A mixture of 4.05 g of 2-benzyloxyphenol and 9.5 ml of N,N-dimethylformamide was added dropwise to a mixture of 0.80 g of sodium hydride and 20 ml of N,N-dimethylformamide under ice cooling, and the mixture was stirred for 30 minutes. A mixture of 7.1 g of 2,5-difluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyri midin-1-yl]nitrobenzene and 17 ml of N,N-dimethylformamide was added dropwise at the same temperature, and the mixture was stirred for 1 hour. The reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The organic layer was washed once with 1N hydrochloric acid and once with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 8.6 g of 2-(2-benzyloxyphenoxy)-5-fluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzene.
Reaction SMILES: [H-].[Na+].[CH:3]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[NH:19][CH:18]=[C:17]([CH:20]=[O:21])[CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([S:28](Cl)(=[O:30])=[O:29])[CH:23]=1>O1CCCC1>[CH:3]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:19]([S:28]([C:24]4[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=4)(=[O:30])=[O:29])[CH:18]=[C:17]([CH:20]=[O:21])[CH:16]=3)=[CH:11][CH:10]=2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: O=Cc1c[nH]c(-c2ccc(C3CCCCC3)cc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1cc(-c2ccc(C3CCCCC3)cc2)n(S(=O)(=O)c2cccnc2)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 98.2 %

Procedure:
Sodium hydride (60% in oil, 68 mg) was added to a solution of 5-(4-cyclohexylphenyl)-1H-pyrrole-3-carbaldehyde (0.17 g) in tetrahydrofuran (12 mL) at room temperature. The mixture was stirred for 20 min, 3-pyridinesulfonyl chloride (0.19 g) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=3:2→2:1) to give the title compound as crystals (yield 0.26 g, 97%).
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:5]=[C:6]([C:9]#[N:10])[S:7][CH:8]=1)[NH2:3].[F:11][C:12]([F:24])([F:23])[C:13](=O)[CH2:14][C:15]([C:17]1[O:18][CH:19]=[CH:20][CH:21]=1)=O.C1(C)C=CC=CC=1>CC(O)=O>[O:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:15]1[N:2]([C:4]2[CH:5]=[C:6]([C:9]#[N:10])[S:7][CH:8]=2)[N:3]=[C:13]([C:12]([F:11])([F:23])[F:24])[CH:14]=1
Reactant: N#Cc1cc(NN)cs1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccco1
Agent: Cl
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: N#Cc1cc(-n2nc(C(F)(F)F)cc2-c2ccco2)cs1
Reaction time: 0.37 h
Yield: 73.7 %

Procedure:
To a solution of compound 13 (0.701 g, 3.99 mmol) in AcOH (10 mL) was added 4,4,4-trifluoro-1-(2-furyl)-1,3-butanedione (0.591 mL, 3.99 mmol). The solution was stirred at 80 degrees for a total of 22 minutes. After the addition of toluene to the brown solution it was concentrated under reduced pressure to a brown-green sludge. The sludge was dry loaded onto a 40M Biotage column and then eluted with a gradient of 5 to 20% ethyl acetate in hexanes to furnish compound 14 (0.909 g, 74%) as a light brown oil which solidified upon standing. LRMS (ESI): calc. 309.2; found 310.1 (MH)+.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8]Br)[CH:5]=[CH:4][CH:3]=1.[C-:10]#[N:11].[Na+]>O1CCOCC1.O>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][C:10]#[N:11])[CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1cccc(Br)n1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N#CCc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.8 %

Procedure:
To a stirred solution of the above crude 6-bromo-2-bromomethylpyridine (70 g, 0.28 mol) in dioxane (500 mL) and water (250 mL), was added NaCN (28 g, 0.74 mol) at 0° C. and then stirred at RT for 16 h. The reaction mixture was quenched with 3 Lit of water and extracted with ethylacetate (4×500 mL). The organic layer was washed with water (400 L), brine (250 mL), dried over Na2SO4 and concentrated to give crude product. The crude was purified by column chromatography over silica gel (pet. ether/ethylacetate, 8:2) to give 6-bromopyridine-2-yl-acetonitrile (22.5 g, 40%). [TLC: Pet. ether/ethylacetate, 7:3, Rf=0.35]
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]([NH2:15])[C:12]([NH2:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17](OC)(OC)OC>C1COCC1.C(O)(C(F)(F)F)=O>[CH2:1]([O:8][C:9]1[N:14]=[C:13]2[NH:15][CH:17]=[N:16][C:12]2=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(OCc2ccccc2)nc1N
Reactant: COC(OC)OC
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(COc2ccc3nc[nH]c3n2)cc1
Reaction time: 24 h
Yield: 81.1 %

Procedure:
To a solution of 6-(benzyloxy)pyridine-2,3-diamine (19.31 g, 89.71 mmol) in THF (300 mL) was added trimethyl orthoformate 99% (99.16 ml, 897.1 mmol) and TFA (345 μL, 4.49 mmol) at room temperature. After stirring for 24 h the solvent was removed under reduced pressure. The residue was taken up in 2 M HCl and EtOAc. The two layers were separated. The organic layer was washed with 2 M HCl and the combined aqueous layers were then made basic by the careful addition of 2 N NaOH. The precipitate was collected by vacuum filtration to give the title compound as a white solid (16.39 g). LCMS m/z=226.3, [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 5.40 (s, 2H), 6.91 (d, J=9.1 Hz, 1H), 7.32 (m, 1H), 7.38 (m, 2H), 7.48 (m, 2H), 8.09 (d, J=9.1 Hz, 1H), 8.79 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[O:13][CH3:14].CN(C)C=O.C(Cl)(=O)C([Cl:23])=O>C(Cl)Cl>[Br:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6]([Cl:23])=[O:7])=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc(C(=O)O)cc(OC)c1Br
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(C(=O)Cl)cc(OC)c1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-bromo-3,5-dimethoxybenzoic acid (Acta Chem. Scand., 2, 34–41, (1948)) (22.6 g, 86.6 mmol) in methylene chloride (400 mL) was added dimethylformamide (1.5 mL, 19.4 mmol). Oxalyl chloride (13.0 g, 102.0 mmol) was gradually added to the ice-cold solution, and the mixture was stirred at room temperature for 1 hour and 30 minutes. The reaction mixture was concentrated under reduced pressure to yield crude crystals of 4-bromo-3,5-dimethoxybenzoyl chloride. To an ice-cold solution of 2-amino-2-methylpropanol (8.40 g, 94.2 mmol) in methylene chloride (100 mL) were added N,N-diisopropylethylamine (16.6 mL, 95.3 mmol) and a solution of the crude 4-bromo-3,5-dimethoxybenzoyl chloride in methylene chloride (200 mL). After the mixture was stirred at room temperature for 10 minutes, the mixture was washed successively with water, 8.0 M hydrochloric acid, a saturated aqueous sodium hydrogencarbonate and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Thionyl chloride (47.5 mL, 651.0 mmol) was added to the residue, and the mixture was stirred at room temperature for 10 minutes. To the reaction mixture were added ice water and a 2.5 M aqueous sodium hydroxide (600 mL, 1500 mmol), and the mixture was extracted with diethyl ether. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized form diethyl ether-hexane to yield 2-(4-bromo-3,5-dimethoxyphenyl)-4,4-dimethyl-2-oxazoline as colorless fine needles (melting point: 172.5–174.5° C.) (20.9 g, yield: 77%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH:11]C(=O)OC(C)(C)C)[CH:6]=[CH:7][CH:8]=1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:11][CH2:10][CH2:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[C:1]#[N:2]
Reactant: CC(C)(C)OC(=O)NCCc1cccc(C#N)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(CCN)c1
Yield: 71 %

Procedure:
tert-Butyl [2-(3-cyanophenyl)ethyl]carbamate (0.949 g, 3.853 mmol) was dissolved in DCM (5 mL) and TFA (4 mL) and stirred at rt for 2 h. The mixture was concentrated and redissolved in EtOAc. The mixture was washed with saturated aqueous K2CO3, dried over Na2SO4, filtered and evaporated affording the title compound (0.40 g, 71.7%). 1H NMR (500 MHz, CDCl3): δ 1.18 (bs, 2H), 2.79 (t, 2H), 3.00 (t, 2H), 7.39-7.47 (m, 2H), 7.50-7.53 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 39.81, 43.42, 112.74, 119.17, 129.47, 130.24, 132.57, 133.66, 141.67.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1([NH2:12])[CH2:11][CH2:10]1.CCN(C(C)C)C(C)C.C[CH2:23][O:24]C(C)=O>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:8][C:5]1[CH:4]=[C:3]2[C:2]([C:23](=[O:24])[NH:12][C:9]32[CH2:11][CH2:10]3)=[CH:7][CH:6]=1
Reactant: CCOC(C)=O
Reactant: NC1(c2cc(F)ccc2Br)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1NC2(CC2)c2cc(F)ccc21
Temperature: 25 °C
Yield: 65.2 %

Procedure:
A solution of 1-(2-bromo-5-fluoro-phenyl)-cyclopropylamine (4.2 g, 18.3 mmol), Pd(dppf)Cl2 (0.42 g), DIPEA (7 g, 54.8 mmol) in 40 mL of DMF was heated at 130° C. under 2 MPa of CO for 12 hours. After it was cooled to room temperature, EtOAc was added it was washed with brine. The organic layer was dried over anhy. Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography to give title compound (0.3 g, yield 65.2%) as a solid; meanwhile, 3.3 g of starting material was recovered.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>N1C=CC=CC=1>[CH3:17][S:18]([NH:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)Cn1c(=O)oc2cc(N)ccc21
Solvent: c1ccncc1
Product: COC(=O)Cn1c(=O)oc2cc(NS(C)(=O)=O)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.9 %

Procedure:
A solution of methyl 2-(6-amino-2-oxobenzo[d]oxazol-3(2H)-yl)acetate (0.497 g, 2.237 mmol) in pyridine (15 ml) was cooled to 0° C., and methanesulfonyl chloride (0.209 ml, 2.68 mmol) was added. The mixture was warmed to room temperature and stirred for 1 hour. The solvent was removed and the residue was portioned between ethyl acetate and 1N HCl. The organic phase was washed with brine and dried over sodium sulfate; the solvent was removed and the crude was purified by trituration with diethyl ether affording methyl 2-(6-(methylsulfonamido)-2-oxobenzo[d]oxazol-3(2H)-yl)acetate (0.523 g, 1.742 mmol, 78% yield). MS/ESI+ 300.9 [MH]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:45])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:35]=[C:34]([CH2:36][O:37]C3CCCCO3)[N:33]=[C:32]([CH3:44])[CH:31]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:14][C:12]1[C:11]([C:15]([F:16])([F:17])[F:18])=[CH:10][C:9]2[NH:19][C:20](=[O:45])[CH2:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[CH:31]=[C:32]([CH3:44])[N:33]=[C:34]([CH2:36][OH:37])[CH:35]=4)[CH:25]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(Cl)cc3NC(=O)OC(C)(C)C)c2)cc(COC2CCCCO2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4cc(Cl)c(C(F)(F)F)cc4NC(=O)C3)c2)cc(CO)n1

Procedure:
The title compound was prepared from (RS)-[5-chloro-2-(3-{3-[2-methyl-6-(tetrahydro-pyran-2-yloxymethyl)-pyridin-4-yl]-phenyl}-3-oxo-propionylamino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M299) (0.41 g, 0.62 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (150 mg, 53%).
Reaction SMILES: [CH3:1][C:2]1(C)[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@@H:12]([OH:36])[CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]3[CH:27]=[C:28]([S:32]([NH2:35])(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=3)=[CH:11][C:5]=2[CH2:4][O:3]1.C(O)(=O)C>O>[C:2]([OH:7])(=[O:3])[CH3:1].[OH:36][C@H:12]([C:10]1[CH:9]=[CH:8][C:6]([OH:7])=[C:5]([CH2:4][OH:3])[CH:11]=1)[CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]1[CH:27]=[C:28]([S:32]([NH2:35])(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1
Reactant: CC1(C)OCc2cc([C@@H](O)CNCCCCCCOCCCCc3cccc(S(N)(=O)=O)c3)ccc2O1
Solvent: O
Solvent: CC(=O)O
Product: NS(=O)(=O)c1cccc(CCCCOCCCCCCNC[C@H](O)c2ccc(O)c(CO)c2)c1
Yield: 216.6 %

Procedure:
3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}benzenesulfonamide (0.283 g) was stirred with acetic acid (8 ml) and water (4 ml) at 70° for 35 min before evaporating to dryness. The residue was re-evaporated twice with toluene to give the title compound (0.318 g) LCMS RT=2.34 min, ES+ve 495 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[CH3:10][O:11][CH:12]([O:15][CH3:16])[CH:13]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][CH2:13][CH:12]([O:15][CH3:16])[O:11][CH3:10])=[CH:4][CH:3]=1
Reactant: COC(C=O)OC
Reactant: NCc1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(CNCc1ccc(F)cc1)OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 71.9 %

Procedure:
To a solution of 4-fluorobenzylamine (2.00 mL, 17.6 mmol) and dimethoxyacetaldehyde (60% solution in water, 3.00 mL, 19.9 mmol) in tetrahydrofuran (100 mL) was added sodium triacetoxyborohydride (5.90 g, 26.4 mmol) at ambient temperature. The resulting reaction mixture was stirred at ambient temperature for 5 hours, followed by the addition of saturated sodium bicarbonate (50 mL) and extraction with ethyl acetate (3×100 mL). The combined organic solution was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and the residue was purified by column chromatography to afford N-(4-fluorobenzyl)-2,2-dimethoxyethanamine (2.70 g, 71%): 1H NMR (300 MHz, CDCl3) δ 7.24-7.19 (m, 2H), 6.97-6.89 (m, 2H), 4.43-4.39 (m, 1H), 3.70 (s, 2H), 3.30 (s, 6H), 2.67 (dd, J=5.4, 1.5 Hz, 2H); MS (ES+) m/z 214.3 (M+1).
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:12][C:13]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[C:14]=1[C:15](O)=[O:16]>>[Cl:12][C:13]1[CH:21]=[C:20]([C:22]([F:24])([F:25])[F:23])[CH:19]=[C:18]([C:26]([F:27])([F:28])[F:29])[C:14]=1[C:15]([NH:11][CH:7]1[CH2:8][CH2:9][CH2:10][CH:6]1[N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:16]
Reactant: O=C(O)c1c(Cl)cc(C(F)(F)F)cc1C(F)(F)F
Reactant: N[C@@H]1CCC[C@@H]1N1CCCC1
Product: O=C(NC1CCCC1N1CCCC1)c1c(Cl)cc(C(F)(F)F)cc1C(F)(F)F

Procedure:
The title compound, white solid, MS: m/e=429.1 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclopentylamine (intermediate Q) and 2-chloro-4,6-bis-trifluoromethyl-benzoic acid
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]([OH:10])=O)[N:3]=1.S(Cl)([Cl:13])=O>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]([C:8]([Cl:13])=[O:10])[CH:5]=[N:6][CH:7]=1
Reactant: O=C(O)c1cncc(Cl)n1
Reactant: O=S(Cl)Cl
Solvent: CC#N
Product: O=C(Cl)c1cncc(Cl)n1

Procedure:
A mixture of 2-chloro-6-carboxy-pyrazine (1000 mg, 6.3 mmol) in ACN (20 mL) was treated with thionyl chloride (800 uL). The resulting mixture, which became homogeneous upon heating, was refluxed for 2 h. The solvent was removed under reduced pressure which gave an oil. The crude product was used in the next step.
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH3:4].[Br:7][CH2:8][CH:9](Br)[O:10][CH2:11][CH3:12].O.Cl>CCOCC>[Br:7][CH2:8][CH:9]([O:10][CH2:11][CH3:12])[CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: CCCC[Mg]Br
Reactant: CCOC(Br)CBr
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: CCCCC(CBr)OCC
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1.68 moles of n-butylmagnesium bromide, as a 1.7M solution in ether, is added dropwise a solution of 300 g. of 1,2-dibromo-2-ethoxyethane in 750 ml. of ether during a period of 2 hours at -15° C. The resulting mixture is stirred for one hour while warming to 20° C., then cooled to 0° C., and treated while stirring with 500 ml. of water, followed by 100 ml. of 4N hydrochloric acid. The organic layer is washed with brine, dried over magnesium sulfate and concentrated. The residue is distilled to provide a colorless liquid, b.p. 83°-84° C., 18 mm.
Reaction SMILES: [H-].[Na+].C([C:6]1[S:10][C:9]2[C:11]([C:15]3[CH:20]=[C:19]([CH:21]([CH3:23])[CH3:22])[CH:18]=[C:17]([CH:24]([CH3:26])[CH3:25])[C:16]=3[O:27][CH2:28][CH3:29])=[CH:12][CH:13]=[CH:14][C:8]=2[CH:7]=1)(=O)C.CN([CH:33]=[O:34])C>>[CH2:16]([O:27][C:33](=[O:34])[CH:6]=[C:7]([C:6]1[S:10][C:9]2[C:11]([C:15]3[CH:20]=[C:19]([CH:21]([CH3:22])[CH3:23])[CH:18]=[C:17]([CH:24]([CH3:26])[CH3:25])[C:16]=3[O:27][CH2:28][CH3:29])=[CH:12][CH:13]=[CH:14][C:8]=2[CH:7]=1)[CH3:8])[CH3:15]
Reactant: CCOc1c(-c2cccc3cc(C(C)=O)sc23)cc(C(C)C)cc1C(C)C
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C=C(C)c1cc2cccc(-c3cc(C(C)C)cc(C(C)C)c3OCC)c2s1
Temperature: 40 °C
Reaction time: 0.17 h
Yield: 59 %

Procedure:
To a mixture of 38 mg (0.79 mmol) of NaH in 1 mL of dry DMF was added dropwise a solution of 148 mg (0.66 mmol, 0.13 mL) of triethylphosphonoacetate at 0° C. After 10 minutes, 125 mg of 2-acetyl-7-(2-ethoxy-3,5-diisopropylphenyl)-benzo[b]thiophene (diluted in 2 mL of dry DMF) was added slowly and the mixture is warmed-up to 40° C. After complexion of the reaction (TLC), and work-up, the crude ester was purified over a short pad of silica gel (eluent: ethyl acetate/hexane: 95/5) to afford 87 mg (0.193 mmol, yield=59%) of 3-[7-(2-ethoxy-3,5-diisopropylphenyl)-benzo[b]thien-2-yl]-but-2-enoic acid ethyl ester (ratio E/Z=85/15)1. 1H-NMR (CDCl3), δ: 7.73 (d, J=7.8 Hz, 1H), 7.60 (s, 1H), 7.45 (d, J=1.0 Hz, 1H), 7.43 (t, J=7.9 Hz, 1H), 7.17 (m, 2H), 6.29 (s, 1H), 4.19 (dd, J=14.5, 7.3 z, 2H), 3.44 (dt, J=13.7, 6.9 Hz, 1H), 3.36 (dd, J=14.0, 7.0 Hz, 2H), 2.92 (dt, J=13.7, 6.8 Hz, 1H), 2.66 (s, 3H), 1.28 (m, 12H), 0.90 (t, J=7.0 Hz, 3H).
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:16]([NH2:22])[C:17]1[O:21][CH:20]=[CH:19][CH:18]=1>Cl>[CH2:16]([NH:22][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])[C:17]1[O:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCc1ccco1
Reactant: CS(=O)(=O)c1cc(C(=O)O)c(Cl)cc1Cl
Agent: Cl
Product: CS(=O)(=O)c1cc(C(=O)O)c(NCc2ccco2)cc1Cl
Temperature: 125 °C

Procedure:
A mixture of 2,4-dichloro-5-methylsulfonylbenzoic acid (15 g.; 0.055 mole) and furfurylamine (30 ml.) is heated in an oil bath at 125° C. under an atmosphere of nitrogen for 3 hours then poured into cold, dilute hydrochloric acid (200 ml.) to precipitate 17.6 g., (98%) of 2-furfurylamino-4-chloro-5-methylsulfonylbenzoic acid, m.p. 204° C. (dec.) after recrystallization from nitromethane (200 ml.).