Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][C:19]([F:29])([F:28])[CH:20]([OH:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(N(CC)CC)C.CN(C1C=CC=CN=1)C>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([O:27][CH:20]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:19]([F:18])([F:28])[F:29])=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Reactant: CCCCCCC(O)C(F)(F)F
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCC(OC(=O)c1ccc(OCc2ccccc2)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
In 20 ml of methylene chloride was dissolved 1.0 g of 4-benzyloxybenzoic acid chloride, and a solution of 0.67 g of optically active 1,1,1-trifluoro-2-octanol, 0.36 g of triethylamine, and a catalytic amount of dimethylaminopyridine in 10 ml of methylene chloride was slowly added thereto under ice-cooling. The reaction mixture was allowed to warm to room temperature, stirred at that temperature for 12 hours, poured into ice-water and extracted with methylene chloride. The methylene chloride phase was washed successively with diluted hydrochloric acid, water, an aqueous 1N sodium carbonate solution, and water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain a crude product. The crude product was purified by column chromatography using silica gel to obtain 0.65 g of 1,1,1-trifluoro-2-octyl 4-benzyloxybenzoate.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9](B2OC(C)(C)C(C)(C)O2)[C:8]2[N:7]3[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:6]3=[C:5]([CH3:25])[C:4]=2[CH:3]=1.Br[C:27]1[S:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][N:31]=1>>[F:1][C:2]1[CH:10]=[C:9]([C:27]2[S:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][N:31]=2)[C:8]2[N:7]3[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:6]3=[C:5]([CH3:25])[C:4]=2[CH:3]=1
Reactant: Cc1c2n(c3c(B4OC(C)(C)C(C)(C)O4)cc(F)cc13)CCNC2=O
Reactant: FC(F)(F)c1cnc(Br)s1
Product: Cc1c2n(c3c(-c4ncc(C(F)(F)F)s4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, off-white solid (16 mg, 22%), MS (ISP) m/z=370.4 [(M+H)+], mp 263° C., was prepared in accordance with the general method of example 171, step B from 8-fluoro-10-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (Example 171, step A) (68.8 mg, 0.2 mmol) and commercially available 2-bromo-5-trifluoromethyl-thiazole (69.6 mg, 0.3 mmol).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:26]=[CH:25][C:13]([O:14][CH:15]([CH3:24])[CH2:16][NH:17][S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[F:34][C:35]([F:41])([F:40])[S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[CH3:23][CH:21]([S:18]([NH:17][CH2:16][CH:15]([O:14][C:13]1[CH:25]=[CH:26][C:10]([C:7]2[CH:6]=[CH:5][C:4]([CH2:3][NH:2][S:36]([C:35]([F:41])([F:40])[F:34])(=[O:38])=[O:37])=[CH:9][CH:8]=2)=[CH:11][CH:12]=1)[CH3:24])(=[O:20])=[O:19])[CH3:22]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2ccc(CN)cc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2ccc(CNS(=O)(=O)C(F)(F)F)cc2)cc1
Yield: 10.8 %

Procedure:
The final title compound (23 mg, 11%) was prepared from (2-{4-[4-(aminomethyl)phenyl]phenoxy}propyl)[(methylethyl)sulfonyl]amine hydrochloride (150 mg, 0.430 mmol, prepared in example 32) methylene chloride 2.5 mL, anhydrous) triethylamine (0.07 mL, 0.471 mmol) and trifluoromethylsulfonyl chloride (9.06 mL, 0.565 mmol), in a manner analogous to Example 29.
Reaction SMILES: [C:1]1([CH:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:17](OC(=O)C)(=[O:19])[CH3:18]>ClCCl>[C:1]1([CH:7]([NH:9][C:17](=[O:19])[CH3:18])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(N)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC(C)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 1-phenylethylamine (10.45 g) and triethylamine (14.4 ml) in dichloromethane (100 ml) was added dropwise acetic anhydride (9.0 ml) at room temperature. The mixture was stirred at room temperature for 5 hr. The reaction mixture was poured into ice water (200 ml) and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The obtained residue was left standing at room temperature for 3 hr. The obtained crude crystals were washed several times with hexane to give the title compound (14.0 g) as white crystals.
Reaction SMILES: [C:1]1([Si:7](Cl)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:21]=[N+:22]=[N-:23].[Li+]>O1CCCC1>[C:1]1([Si:7]([N:21]=[N+:22]=[N-:23])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cl[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Li+]
Solvent: C1CCOC1
Product: [N-]=[N+]=N[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 86.3 %

Procedure:
Following the method of Wiberg et al [Wiberg et al, Angew. Chem. Internat'l Ed. Engl., 1, 335 (1962)] in an inert atmosphere enclosure a solution of triphenylsilylchloride (73.9 g, 0.251 mol) in tetrahydrofuran (400 ml) was stirred with lithium azide (15.3 g, 0.312 mol) at room temperature over a period of 115 hr. After filtration, the solvent was removed in vacuo. The resulting white solid was boiled with heptane (350 ml), filtered hot and allowed to crystalline. Triphenylsilyl azide, 65.5 g (86.3% yield), mp 82°-84° C was obtained. The melting point and infrared spectrum were identical with that of an authentic sample.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([C:14]([N+:19]([O-:21])=[O:20])=[C:15]([CH3:18])[C:16]=2[F:17])[NH:10][CH:11]2[CH2:13][CH2:12]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(O[CH:25]=[C:26]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28])C>>[CH:11]1([N:10]([CH:25]=[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:9]2[C:14]([N+:19]([O-:21])=[O:20])=[C:15]([CH3:18])[C:16]([F:17])=[C:7]([N:1]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)[CH:8]=2)[CH2:12][CH2:13]1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Cc1c(F)c(N2CCNCC2)cc(NC2CC2)c1[N+](=O)[O-]
Product: CCOC(=O)C(=CN(c1cc(N2CCNCC2)c(F)c(C)c1[N+](=O)[O-])C1CC1)C(=O)OCC
Temperature: 150 °C

Procedure:
To 3-(1-piperazinyl)-4-fluoro-5-methyl-6-nitro-N-cyclopropylaniline (1.57 g) is added diethyl ethoxymethylenemalonate (1.45 ml) and the mixture is heated at 150° C. for 25 hours. After cooling, the reaction product is purified by silica-gel column-chromatography (dichloromethane:methanol=100:1) to give diethyl [N-cyclopropyl-N-[3-(1-piperazinyl)-4-fluoro-5-methyl-6-nitrophenyl]aminomethylene]malonate (1.50 g). The product is dissolved in acetic anhydride (7.9 ml) and thereto conc. sulfuric acid (3.16 ml) is added dropwise at 50°-60° C., followed by stirring for 30 minutes. The resultant mixture is poured into ice-water, neutralized, extracted with dichloromethane and the extract is dried. The solvent is distilled off under reduced pressure. Purification by silica-gel column-chromatography (dichloromethane:methanol=10:1) to give ethyl 7-(1-piperazinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (26 mg).
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][O:6][C:7]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:8]=1[CH2:9]O.O>C(Cl)Cl>[Br:2][CH2:9][C:8]1[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:7]=1[O:6][CH3:5]
Reactant: BrP(Br)Br
Reactant: COc1ccc(OC)c(CO)c1
Solvent: O
Solvent: ClCCl
Product: COc1ccc(OC)c(CBr)c1
Yield: 173.4 %

Procedure:
A solution of phosphorous tribromide (5.74 ml, 60.4 mmol) in anhydrous DCM (90 ml) was added over 20 min to a cooled, stirred solution of 2,5-dimethoxybenzyl alcohol (25.0 g, 148.8 mmol) in DCM (180 ml), maintaining the temperature between −5° C. and 0° C. Following the addition, the reaction was stirred at this temperature for a further 20 min. when water (200 ml) was added. After separation of the layers, the organic was washed with water (3×200 ml), dried with magnesium sulfate and evaporated to dryness under reduced pressure. The resulting crude product was crystallised from diethyl ether/heptane to afford 2-bromomethyl-1,4-dimethoxy-benzene (24.2 g, 72%).
Reaction SMILES: [CH3:1]N(C)C=O.[H-].[Na+].[Cl:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:12]=[CH:11][C:10]=1[NH:30][C:31](=[O:40])[O:32][CH:33]([CH2:37][CH2:38][CH3:39])[CH2:34][CH2:35][CH3:36].CI>O>[Cl:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:12]=[CH:11][C:10]=1[N:30]([CH3:1])[C:31](=[O:40])[O:32][CH:33]([CH2:37][CH2:38][CH3:39])[CH2:34][CH2:35][CH3:36]
Reactant: CCCC(CCC)OC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CCCC(CCC)OC(=O)N(C)c1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68 %

Procedure:
Dimethylformamide (5 ml) was added to sodium hydride (11 mg), and 1-propylbutyl N-{2-chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl}carbamate (62 mg) was added to the mixture. Subsequently, a dimethylformamide solution (2 ml) of methyl iodide (77 mg) was added thereto, and the mixture was stirred at room temperature for 10 min. Water was added to stop the reaction, and the reaction solution was then extracted with ethyl acetate, followed by washing with 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 (43 mg, yield 68%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:5]([I:13])=[C:6]2[CH:12]=[CH:11][NH:10][C:7]2=[N:8][CH:9]=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>CN(C)C=O>[F:3][C:4]1[C:5]([I:13])=[C:6]2[CH:12]=[CH:11][N:10]([S:20]([C:17]3[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=3)(=[O:22])=[O:21])[C:7]2=[N:8][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Fc1cnc2[nH]ccc2c1I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(I)c(F)cnc32)cc1
Reaction time: 0.5 h

Procedure:
To a stirring suspension of sodium hydride (0.595 g, 24.81 mmol) in N,N-dimethylformamide (74.2 ml) was added a solution of 5-fluoro-4-iodo-1H-pyrrolo[2,3-b]pyridine (5 g, 19.08 mmol, Adesis) in N,N-dimethylformamide (10.60 mL). The mixture was stirred under nitrogen for about 30 minutes. para-Toluenesulfonyl chloride (4.00 g, 20.99 mmol) in N,N-dimethylformamide (10.60 ml) was added, and the reaction stirred at room temperature for about an hour. The reaction was quenched by the slow addition of the reaction mixture to a stirring ice-water solution (about 100 mL). The resulting mixture was filtered, and the solid was collected and dried under vacuum overnight to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 8.28 (s, 1H), 8.09 (d, 1H), 7.98 (d, 2H), 7.43 (d, 2H), 6.67 (d, 1H), 2.35 (s, 3H). MS ESI(+) m/z 416.31 [M+H]+.
Reaction SMILES: [F:1][CH:2]([F:18])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)=O.[NH2:19][C:20]1[C:24]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([CH3:31])[CH:26]=2)=[CH:23][NH:22][N:21]=1>>[F:1][CH:2]([F:18])[C:3]1[N:21]2[N:22]=[CH:23][C:24]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([CH3:31])[CH:26]=3)=[C:20]2[N:19]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[CH:4]=1
Reactant: Cc1cc(-c2c[nH]nc2N)ccn1
Reactant: O=C(CC(=O)C(F)F)c1ccc(C(F)(F)F)cc1
Product: Cc1cc(-c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)ccn1
Yield: 78.6 %

Procedure:
Reaction of 4,4-difluoro-1-(4-trifluoromethyl-phenyl)-butane-1,3-dione (133 mg, 0.5 mmol), prepared from commercially available 4-trifluoromethyl-acetophenone according to general procedure A, and 3-amino-4-(2-methyl-4-pyridinyl)-pyrazole [prepared from 4-cyanomethyl-2-methyl-pyridine, as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (87 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (159 mg, 79%). MS (ISP) 405.4 [(M+H)+]; mp 213° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][S+:12]([O-:24])[C:13]2[NH:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH3:23])=[CH:19][C:20]=3[N:21]=2)=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].[OH-].[Na+:26]>C(O)C>[CH3:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][S+:12]([O-:24])[C:13]2[N-:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH3:23])=[CH:19][C:20]=3[N:21]=2)=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].[Na+:26]
Reactant: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2[n-]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Temperature: 25 °C

Procedure:
According to the present invention omeprazole sodium ethanol solvate is prepared by dissolving omeprazole (base) in a solution of NaOH in absolute ethanol. Mechanical particles are removed from the resulting solution, e.g. by filtration, and further seeded with crystals of omeprazole sodium form A to induce crystallisation. The slurry is then agitated for several hours at ambient temperature and additionally for several hours at low temperatures, e.g. from 0° to 5° C., in order to improve the yield. The precipitated omeprazole sodium form A is separated, e.g. by filtration or centrifugation, and washed with cooled absolute ethanol. Omeprazole sodium ethanol wet thus derived is dried under reduced pressure from 40° to 50° C., preferably at about 45° C. to yield stable anhydrous omeprazole sodium in ethanol solvate form. By the term “omeprazole sodium ethanol wet” is meant the product obtained before the step of drying under reduced pressure. The term “reduced pressure” generally refers to a pressure of about 10 mbar to about 50 mbar.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=[C:5]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[N+:22]([O-:24])=[O:23])[CH2:4][CH:3]1[CH3:25].[CH3:26][C:27](OC(C)=O)=[O:28]>N1C=CC=CC=1>[C:27]([O:1][CH:2]1[CH:3]([CH3:25])[CH2:4][C:5]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[N+:22]([O-:24])=[O:23])=[CH:6][CH:7]1[NH:8][C:9]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:15])(=[O:28])[CH3:26]
Reactant: CC1CC(c2ccncc2[N+](=O)[O-])=CC(NC(=O)OC(C)(C)C)C1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC1C(C)CC(c2ccncc2[N+](=O)[O-])=CC1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a solution of (+/−)-tert-butyl 6-hydroxy-5-methyl-3-(3-nitropyridin-4-yl)cyclohex-2-enylcarbamate (1.0 equiv.) in pyridine (0.1M) was added Ac2O (2.0 equiv.) and the reaction was stirred at room temperature overnight. Upon completion, the reaction was concentrated to dryness, then worked-up with ethyl acetate and water. The organic phase was dried with brine, then sodium sulfate, filtered, and concentrated to give (+/−)-2-(tert-butoxycarbonylamino)-6-methyl-4-(3-nitropyridin-4-yl)cyclohex-3-enyl acetate in 94% yield. LC/MS=392.2 (M+H), Rt=0.94 min.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH2:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2]>C(Cl)Cl.FC(F)(F)C(O)=O>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH:50][C:10](=[O:9])[CH2:11][NH2:16])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(NC(=O)CN)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-amino-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone in (100 mg) in dry methylene chloride (4 ml) was added 100 mg of freshly prepared BOC-L-glycine anhydride under nitrogen. After stirring at room temperature for 1.5 hours, the reaction mixture was subjected to work-up and the residue was purified on silica gel (5% MeOH/CH2Cl2) to give the 65 mg of BOC protected compound. This material (48 mg) was dissolved in 1 ml of trifluoroacetic acid at -10° and stirred at this temperature. After 30 minutes, the reaction mixture was cooled to -78° and freeze-dried to give the yellow solid. Purification of the crude material by preparative tlc on silica gel (1% NH4OH in 5% MeOH/CH2Cl2) gave 28 mg of the title compound.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1(/[CH:34]=[C:35](\[C:39]2[CH:44]=[CH:43][C:42]([S:45]([CH3:48])(=[O:47])=[O:46])=[C:41]([C:49]([F:52])([F:51])[F:50])[CH:40]=2)/[C:36]([OH:38])=O)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:53][C:54]1[CH:59]=[CH:58][C:57]([Br:60])=[CH:56][N:55]=1>C(Cl)Cl>[Br:60][C:57]1[CH:58]=[CH:59][C:54]([NH:53][C:36](=[O:38])/[C:35](/[C:39]2[CH:44]=[CH:43][C:42]([S:45]([CH3:48])(=[O:47])=[O:46])=[C:41]([C:49]([F:51])([F:50])[F:52])[CH:40]=2)=[CH:34]/[CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[N:55][CH:56]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CS(=O)(=O)c1ccc(/C(=C\C2CCCCC2)C(=O)O)cc1C(F)(F)F
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(/C(=C\C2CCCCC2)C(=O)Nc2ccc(Br)cn2)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 8.3 %

Procedure:
A solution of triphenylphosphine (525 mg, 2 mmol) in methylene chloride (12 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (356 mg, 2 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with (E)-3-cyclohexyl-2-(4-(methanesulfonyl)-3-(trifluoromethyl)-phenyl)-acrylic acid (prepared in Example 12, 376 mg, 1 mmol). The reaction mixture was stirred at 25° C. for 15 min and then allowed to warm to 25° C. where it was stirred for 1.5 h. The reaction mixture was then treated with 2-amino-5-bromopyridine (519 mg, 3 mmol), and the resulting suspension was stirred for 3 d at 25° C. The reaction mixture was concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (50 mL) and a 1N aqueous hydrochloric acid solution (50 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×30 mL). The combined organic extracts were successively washed with a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL). The organic layer was then dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 4/1 to 2/1 hexanes/ethyl acetate) afforded the (E)-N-(5-bromo-pyridin-2-yl)-3-cyclohexyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-acrylamide (44 mg, 8.3%) as an amorphous solid: EI-HRMS m/e calcd for C22H22BrF3N2O3S (M+) 530.0487, found 530.0484.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([CH:6](SC)[C:7](=[O:12])[NH:8]2)=[CH:4][C:3]=1[O:15][CH3:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.O>ClCCl>[CH3:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([CH2:6][C:7](=[O:12])[NH:8]2)=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: COc1cc2c(c(C)c1C)NC(=O)C2SC
Agent: Cc1ccccc1S(=O)(=O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: COc1cc2c(c(C)c1C)NC(=O)C2
Reaction time: 3 h
Yield: 72.6 %

Procedure:
To a solution of 6,7-dimethyl-5-methoxy-3(methylthio)-1,3-dihydro-2H-indole-2-one (30 g, 126 mmol) in dichloromethane (600 mL) were added triphenylphosphine (40 g, 153 mmol) and toluenesulfonic acid monohydrate (29 g, 153 mmol) at room temperature, and the mixture was stirred for 3 hours. The reaction solution was poured into cool water, and the precipitated crystals were filtered. The crystals were washed with dichloromethane and water to obtain 17.5 g of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[C:12](Br)[C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>C(O)C>[CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[C:12]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1nccc2c1ccn2Cc1ccccc1
Reactant: C1CNCCN1
Solvent: CCO
Product: c1ccc(Cn2ccc3c(N4CCNCC4)nccc32)cc1

Procedure:
A solution of 4.5 g of 1-benzyl-4-bromo-1H-pyrrolo[3,2-c]pyridine in 25 ml of anhydrous ethanol and 8 g of piperazine are stirred at 120° C. for 15 hours under an inert atmosphere, then brought to ambient temperature and concentrated under reduced pressure. The residue is taken up in 200 ml of dichloromethane and washed with water. The organic phase is treated in conventional manner and then concentrated, enabling the expected product to be isolated.
Reaction SMILES: [CH:1]12[O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[CH3:8][NH:9][CH3:10].Cl>C1C=CC=CC=1>[CH3:8][N:9]([CH3:10])[C@@H:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[OH:7]
Reactant: C1CCC2OC2C1
Reactant: CNC
Agent: Cl
Solvent: c1ccccc1
Product: CN(C)[C@@H]1CCCC[C@H]1O

Procedure:
This compound was previously prepared from cyclohexene oxide and dimethylamine in benzene at room temperature for 14 days in 95% yield, b.p. 90° (20 mm): J. Chem. Soc., 4835 (1965); or in autoclave: C. A. 67, 63899 d, Rocz. Chem. 41, 541 (1967) b.p. 88° (14 mm); also Bull. Soc. Chim. France, 850 (1947): hydrochloride and resolution reported.
Reaction SMILES: COC1C=C(OC)C=CC=1C[O:6][N:7](CC1C(OC)=CC(OC)=CC=1OC)[C:8](=[O:27])[CH2:9][CH2:10][S:11]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)(=[O:13])=[O:12].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[OH:6][NH:7][C:8](=[O:27])[CH2:9][CH2:10][S:11]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)(=[O:12])=[O:13]
Reactant: COc1ccc(CON(Cc2c(OC)cc(OC)cc2OC)C(=O)CCS(=O)(=O)N2CCN(c3ccc(F)cc3)CC2)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CCS(=O)(=O)N1CCN(c2ccc(F)cc2)CC1)NO
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.6 %

Procedure:
To a solution of N-(2,4-dimethoxybenzyloxy)-N-(2,4,6-trimethoxybenzyl)-3-[4-(4-fluorophenyl)piperazine-1-sulfonyl]propionamide (125 mg, 0.19 mmol) in dichloromethane (2 ml) was added triethylsilane (66 μl, 0.42 mmol) and trifluoroacetic acid (150 μl). The mixture was stirred at room temperature for 4 hours. The solvents were evaporated in vacuo. The residue was purified by chromatography on silica (eluant:dichloromethane, then ethyl acetate then dichloromethane −10% MeOH) to give 35 mg of the title compound.