Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:27]=[CH:26][C:7]([CH2:8][O:9][C:10]([C:12]2[N:13]=[C:14]([N:17]3[CH2:20][CH:19](OS(C)(=O)=O)[CH2:18]3)[S:15][CH:16]=2)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:28]([O-:31])(=[S:30])[CH3:29].[K+]>CN(C)C=O>[C:28]([S:30][CH:19]1[CH2:20][N:17]([C:14]2[S:15][CH:16]=[C:12]([C:10]([O:9][CH2:8][C:7]3[CH:26]=[CH:27][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)=[O:11])[N:13]=2)[CH2:18]1)(=[O:31])[CH3:29]
Reactant: CC([O-])=S
Reactant: CS(=O)(=O)OC1CN(c2nc(C(=O)OCc3ccc([N+](=O)[O-])cc3)cs2)C1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(C(=O)OCc3ccc([N+](=O)[O-])cc3)cs2)C1
Temperature: 90 °C
Reaction time: 4 h
Yield: 10 %

Procedure:
To a solution of 1-(4-p-nitrobenzyloxycarbonyl-1,3-thiazol-2-yl)-3-methanesulfonyloxyazetidine (776 mg, 1.88 mmol) (obtained as described in Reference Example 2(7)) in dimethylformamide (35 ml) was added potassium thioacetate (860 mg, 7.53 mmol) at room temperature. The mixture was stirred in an oil bath (90° C.) for 4 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (1:1) as the eluant to afford 3-acetylthio-1-(4-p-nitrobenzyloxycarbonyl-1,3-thiazol-2-yl)azetidine (73.8 mg, yield 11%) as a pale brown solid.
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([N:34]2[CH:38]=[C:37]([NH2:39])[CH:36]=[N:35]2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C1(P(C2CCCCC2)C2(P(C3CCCCC3)C3CCCCC3)CC=CC=C2C2C=CC=CC=2)CCCCC1>>[C:21]([O:25][C:26]([N:28]1[CH2:29][CH2:30][CH:31]([N:34]2[CH:38]=[C:37]([NH:39][C:2]3[N:20]=[C:5]4[C:6]([C:10]5[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=5)=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)[CH:36]=[N:35]2)[CH2:32][CH2:33]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(Cl)nc23)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(N)cn2)CC1
Agent: C1=CCC(P(C2CCCCC2)C2CCCCC2)(P(C2CCCCC2)C2CCCCC2)C(c2ccccc2)=C1
Product: CC(C)(C)OC(=O)N1CCC(n2cc(Nc3nc4c(-c5ccc(S(C)(=O)=O)cc5)cccn4n3)cn2)CC1

Procedure:
4-{4-[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino]-pyrazol-1-yl}-piperidin-1-carboxylic acid tert-butyl ester was prepared from 2-chloro-8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1.5-a]pyridine (0.150 g, 0.48 mmol) and 4-(4-amino-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.168 g, 0.63 mmol) with 2,2-bis-dicyclohexylphosphanyl-biphenyl (0.048 g, 0.088 mmol) as the ligand in a manner analogous to Example 2d. Product was isolated as a tan solid (0.134 g, 51%). MP=Softened at 161-166° C. then melted at 207-209° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.37 (s, 1H), 8.78 (d, J=6.52 Hz, 1H), 8.42 (d, J=8.00 Hz, 2H), 8.06 (d, J=7.89 Hz, 2H), 7.94 (d, J=7.45 Hz, 1H), 7.85 (s, 1H), 7.52 (s, 1H), 7.12 (t, J=6.89 Hz, 1H), 4.32 (s, 1H), 4.04 (d, J=11.40 Hz, 2H), 3.28 (s, 3H), 2.91 (s, 2H), 2.005 (d, J=11.77 Hz, 2H), 1.76 (q, J=12.21 Hz, 2H), 1.42 (s, 9H). MS=538 (MH)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].[OH-].[Na+].[CH3:18][C:19]([C:21](Cl)=[O:22])=[CH2:20].Cl>O.C(OCC)(=O)C>[C:21]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])(=[O:22])[C:19]([CH3:20])=[CH2:18]
Reactant: C=C(C)C(=O)Cl
Reactant: NCCCCCCCCCCCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: C=C(C)C(=O)NCCCCCCCCCCCC(=O)O
Temperature: 10 °C
Reaction time: 1 h

Procedure:
In 9 l of water at 30° C. were dissolved 218 g of 12-aminododecanoic acid and 100 g of sodium hydroxide (purity: 93%), and 102 ml of methacryl chloride was added thereto over 1 hour while stirring. The reaction mixture was stirred for 2 hours and then heated to 60° C., at which 3 l of ethyl acetate and 300 ml of concentrated hydrochloric acid were added thereto successively. The mixture was filtered while hot (60° C.) to remove any insoluble matter, followed by liquid-liquid separation. The organic layer was dried over 30 g of magnesium sulfate and, after removal of the magnesium sulfate, cooled to 10° C., at which 6 l of n-hexane was added, whereupon a precipitate was formed. The precipitate was collected by filtration and thoroughly washed with 1 l of n-hexane. Recrystallization of the precipitate from 500 ml of ethyl acetate yielded 128 g of 12-methacryloylaminododecanoic acid.
Reaction SMILES: [C:1]1([CH:7]2[C:11](=[O:12])[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)=[C:9]([NH2:23])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:24]1(N)[CH2:26][CH2:25]1>C(O)C>[C:1]1([CH:7]2[C:11](=[O:12])[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[CH:14]=3)=[C:9]([NH:23][CH:24]3[CH2:26][CH2:25]3)[O:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC1=C(c2cccc(C(F)(F)F)c2)C(=O)C(c2ccccc2)O1
Reactant: NC1CC1
Solvent: CCO
Product: O=C1C(c2cccc(C(F)(F)F)c2)=C(NC2CC2)OC1c1ccccc1
Yield: 36.8 %

Procedure:
In this example, a mixture containing 5.0 g (0.0157 g mole) of 2-phenyl-3-oxo-4-(3-trifluoromethylphenyl)-5-amino-2,3-dihydrofuran and 8.96 g of cyclopropylamine in 50 ml of ethanol containing 5% water was refluxed for six days. At the end of this time, a sample of the reaction mixture was checked by thin layer chromatography and then an additional 8.96 g of cyclopropylamine was added. The mixture was refluxed for an additional 24 hours and then allowed to stand at room temperature over night. The mixture was then concentrated by evaporation under vacuum, affording a crude product oil. The crude product was chromatographed over silica gel eluting with 80:20 (V/V) petroleum ether and ethyl acetate. The product fractions were combined and evaporated in vacuo affording 2.07 g of the title compound Elemental Analysis Carbon calc.: 66.8%, found 67.4%; hydrogen calc.: 4.5%, found 4.7%; nitrogen calc.: 3.9%, found 4.6%; melting point 160°-164° C.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH:9]([CH3:11])[CH2:8][CH2:7][CH:6]1[OH:12])([CH3:4])([CH3:3])[CH3:2].[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[C:13]([O:12][CH:6]1[CH2:7][CH2:8][CH:9]([CH3:11])[CH2:10][CH:5]1[C:1]([CH3:4])([CH3:2])[CH3:3])(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: CC1CCC(O)C(C(C)(C)C)C1
Product: CC(=O)OC1CCC(C)CC1C(C)(C)C
Yield: 95 %

Procedure:
A mixture of 680 g (4 moles) of 2-tert-butyl-4-methylcyclohexanol and 612 g (6 moles) of acetic anhydride was heated to 145°-160° C. and the resulting acetic acid was distilled off slowly in the course of 3 hours. When the reaction was complete, the mixture was cooled, the excess acetic anhydride was distilled off under 20 mbar, the residue was cooled and then taken up in 500 ml of diethyl ether, the ether solution was washed acid-free with aqueous sodium bicarbonate solution, the solvent was removed and the residue was then fractionated. After a small initial fraction (13 g of boiling point 30°-45° C./0.005 mbar), 806 g of 2-tert-butyl-4-methylcyclohexyl acetate distilled over at 54°-56° C./0.005 mbar. The refractive index nD25 was 1.4505 and the yield was 95% of theory.
Reaction SMILES: [C:1]([O:9][C:10]12[O:16][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.CCOCC.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[C:1]([O:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=[O:16])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OC12CCCCC1O2)c1ccccc1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(O[C@@H]1CCCCC1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 7.5 h
Yield: 78 %

Procedure:
To a solution of (R)-(+)-binaphthol (7.9 mg, 0.0275 mmol) in CH2Cl2 (0.5 mL) was added a solution of Ti(OiPr)4 (3.8 uL, 3.6 mg, 0.0125 mmol) in CH2Cl2 (0.5 mL). Upon stirring at room temperature for 5-10 h, the reaction mixture was concentrated and dried using a vacuum pump (ca. 0.5 h). The catalyst was then dissolved in Et2O (1 mL) and cooled in an ice bath. To this solution was added a solution of racemic 1-benzoyloxy-1,2-epoxycyclohexane (0.109 g, 0.5 mmol) in Et2O (1 mL). After stirring at 0° C. for 1 h, the reaction mixture was quenched with saturated NaHCO3 solution (4 mL) and poured into a mixture of ether (20 mL) and saturated NaHCO3 solution (10 mL). The organic layer was washed with water and brine, dried (Na2SO4), and rapidly filtered through a plug of silica gel (ca. 10 g) (pre-treated with 5% Et3N in hexane and washed thoroughly with hexane to remove Et3N before use). The silica gel was further washed with Et2O (10 mL). The combined ether solutions were concentrated to give a residue. Upon drying under vacuum for 1 h, the mixture was dissolved in CH2Cl2 (4 mL) followed by addition of anhydrous p-TsOH (8.6 mg, 0.05 mmol). After stirring at room temperature for 20 min, the mixture was rapidly filtered through a plug of silica gel (ca. 10 g) (without Et3N treatment) followed by washing with ether (2×10 mL). The combined solutions were concentrated to give (R)-2-benzoyloxycyclohexanone as a white solid (0.0845 g, 78% yield, 93% ee).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COCCOC[N:16]1[C:20]2[CH:21]=[CH:22][C:23]([NH2:33])=[C:24]3[C:25](=[O:32])[C:26]4[C:31]([C:18]([C:19]=23)=[N:17]1)=[CH:30][CH:29]=[CH:28][CH:27]=4.C(N(CC)CC)C.Cl>C(Cl)Cl>[C:1]([NH:33][C:23]1[CH:22]=[CH:21][C:20]2[NH:16][N:17]=[C:18]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:25](=[O:32])[C:24]=1[C:19]=23)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCOCn1nc2c3c(c(N)ccc31)C(=O)c1ccccc1-2
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc2[nH]nc3c2c1C(=O)c1ccccc1-3)c1ccccc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Benzoyl chloride is added to a solution of 2-(methoxyethoxymethyl)-5-aminoanthra[1,9cd]pyrazol-6-(2H)one and triethylamine in methylene chloride at 0° C. The mixture is stirred for 16 hours, quenched with water, and extracted with ethyl acetate (×2). The combined organic layer is washed with sodium bicarbonate solution, and brine, dried and evaporated. The crude reaction mixture is then taken in aqueous 6N hydrochloric acid, and heated at 80° C. for 4 hours. After cooling, the mixture is extracted with ethyl acetate (×2), washed with brine, dried, and evaporated. The residue is chromatographed on silica gel to furnish the desired amide as a yellow solid.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[S:16][C:15]3[C:10](=[N:11][CH:12]=[CH:13][C:14]=3[O:17][C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=3[F:25])[CH:9]=2)[N:5]=[CH:4]1)[CH3:2].[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][C:34]([N:36]=[C:37]=[S:38])=[O:35]>C1COCC1>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[S:16][C:15]3[C:10](=[N:11][CH:12]=[CH:13][C:14]=3[O:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:37]([NH:36][C:34](=[O:35])[CH2:33][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[F:26])=[S:38])=[CH:20][C:19]=3[F:25])[CH:9]=2)[N:5]=[CH:4]1)[CH3:2]
Reactant: O=C(Cc1ccccc1F)N=C=S
Reactant: CCn1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Solvent: C1CCOC1
Product: CCn1cnc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5F)cc4F)c3s2)c1
Reaction time: 1 h
Yield: 67.4 %

Procedure:
To a suspension of the 308 (385 mg, 0.99 mmol) in THF (10 mL) was added 2-(2-fluorophenyl)acetyl isothiocyanate (263 mg, 1.49 mmol) and the reaction mixture was stirred for 1 hr, transferred onto a flash chromatography column and eluted with EtOAc/MeOH 19:1, to afford title compound 310a (366.9 mg, 67% yield) as a creamy solid. 1HNMR: (DMSO-d6) δ (ppm): 12.42 (s, 1H), 11.87 (s, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.02 (d, J=11.5 Hz, 1H), 7.95 (s, 1H), 7.78 (s, 1H), 7.67 (s, 1H), 7.52 (m, 2H), 7.42 (m, 2H), 7.25 (m, 2H), 7.06 (d, J=5.5 Hz, 1H), 4.04 (q, J=7.3 Hz, 2H), 3.92 (s, 2H), 7.4 (t, J=7.3 Hz, 3H). MS (m/z): 550.0 (M+1).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10]>[Si]=[Mo]=[Si]>[C:9](=[O:10])([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Oc1ccccc1
Agent: [Si]=[Mo]=[Si]
Product: O=C(Oc1ccccc1)Oc1ccccc1

Procedure:
Example 1 was repeated with 14.1 g of a powdered molybdenum disilicide from H. C. Starck at 140° C. After 2 hours' reaction time, phenol conversion was 8.7%, wherein 4.2 g of phenyl chloroformate and 10.3 g of diphenyl carbonate were formed. Selectivity for carbonates was approximately 95%.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[C:31]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)#[N:32].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:30][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:37]3[CH:38]=[C:33]([CH:34]=[CH:35][CH:36]=3)[C:31]#[N:32])[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]([CH3:28])[CH3:29])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CN(C)C1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C)C1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2cccc(C#N)c2)CC1
Yield: 26 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-dimethylamino-piperidine-1-carbonyl)-1H-indol-2-yl]-methanone (example 140, intermediate a)), 3-cyanophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as an off-white foam (26%).
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]2[NH:15][CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1)C1C=CC=CC=1.[H-].[Na+].Br[CH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>C1COCC1.CCOCC>[CH:21]1([N:15]2[C:13]3=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]3[N:17]=[CH:16]2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: c1ccc(COc2ccc3nc[nH]c3n2)cc1
Reactant: BrC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Oc1ccc2ncn(C3CCCC3)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10.5 %

Procedure:
5-(Benzyloxy)-3H-imidazo[4,5-b]pyridine (0.300 g, 1.33 mmol) was dissolved in THF and NaH (0.050 g, 2.0 mmol) was added portionwise. The resulting mixture was heated in a sealed tube for 1 h and then cooled to room temperature. Bromocyclopentane (0.20 g, 17.8 mmol) was added and the reaction was heated to 70° C. overnight. The solution was then diluted with ether and washed with water. The aqueous layer was back extracted with additional ether and the combined organic portions were washed with brine, dried over MgSO4 and purified by preparative HPLC. The resulting 5-(benzyloxy)-3-cycloheptyl-3H-imidazo[4,5-b]pyridine was then dissolved in DCM and diluted with excess sulfuric acid. The resulting solution was stirred for 30 minutes at room temperature then acidified with the addition of 1 M aqueous hydrochloric acid. The solvent was removed from the organic layer and the residue was purified via preparative HPLC to give the title compound (0.0284 g). LCMS m/z=204.31 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.65-1.80 (m, 2H), 1.80-1.95 (m, 2H), 2.0-2.1 (m, 2H), 2.15-2.30 (m, 2H), 4.95-5.05 (m, 1H), 6.88 (d, J=8.8 Hz, 1H), 8.13 (d, J=8.8 Hz, 1H), 9.35 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10](Cl)[C:5]2=[N:4][CH:3]=1.Cl.[NH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1.CCN(C(C)C)C(C)C>C(O)C(C)C>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10]([NH:13][CH2:14][C:15]3[CH:16]=[CH:17][C:18]([S:21]([NH2:24])(=[O:22])=[O:23])=[CH:19][CH:20]=3)[C:5]2=[N:4][CH:3]=1
Reactant: NCc1ccc(S(N)(=O)=O)cc1
Reactant: Clc1nccn2c(Br)cnc12
Agent: Cl
Solvent: CC(C)CO
Solvent: CCN(C(C)C)C(C)C
Product: NS(=O)(=O)c1ccc(CNc2nccn3c(Br)cnc23)cc1
Temperature: 108 °C
Reaction time: 16 h
Yield: 37.7 %

Procedure:
To a solution of 3-bromo-8-chloro-imidazo[1,2-a]pyrazine (2 g, 8.6 mmol) in iBuOH (5 ml) is added 4-aminomethyl-benzenesulfonamide hydrochloride (2.1 g, 9.5 mmol) and DIPEA (3.7 ml, 21.5 mmol). The reaction is heated to 108° C. and stirred for 16 h. After this time the solution is allowed to cool, resulting in a thick white precipitate. The precipitate is filtered and washed with diethyl ether to give 4-[(3-Bromo-imidazo[1,2-a]pyrazin-8-ylamino)-methyl]-benzenesulfonamide as a white solid (1.24 g, 38%)
Reaction SMILES: [CH3:1][Si:2]([CH3:30])([CH3:29])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([Si:25]([CH3:28])([CH3:27])[CH3:26])[CH:24]=1)[C:6]([NH:8][C:9]1[CH:21]=[CH:20][C:12]([CH:13]=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=1)=[O:7].[H][H]>CO.C(OCC)(=O)C>[CH3:28][Si:25]([CH3:26])([CH3:27])[C:23]1[CH:22]=[C:5]([CH:4]=[C:3]([Si:2]([CH3:1])([CH3:30])[CH3:29])[CH:24]=1)[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:20][CH:21]=1)=[O:7]
Reactant: CCOC(=O)C=Cc1ccc(NC(=O)c2cc([Si](C)(C)C)cc([Si](C)(C)C)c2)cc1
Reactant: [H][H]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1ccc(NC(=O)c2cc([Si](C)(C)C)cc([Si](C)(C)C)c2)cc1
Yield: 99.5 %

Procedure:
Compound 17a (150 mg) was dissolved in methanol (35 ml) and ethyl acetate (35 ml). The obtained mixture was stirred for 30 minutes in a hydrogen atmosphere. After the reaction was over, the obtained reaction mixture was filtered through Cerite, and then washed with methanol. The solvent was distilled off from the filtrate, and the obtained residue was dried. Thus, Compound 20a (150 mg, quant.) was obtained as a white solid.
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][C:8]1[S:12][C:11]2[CH2:13][CH2:14][CH2:15][CH2:16][C:10]=2[C:9]=1[C:17]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)=O.[C:26](OCC)(=[O:34])[CH2:27][CH2:28][C:29]([O:31]CC)=[O:30].Cl>C(O)(C)(C)C.O>[OH:34][C:26]1[N:7]=[C:8]2[S:12][C:11]3[CH2:13][CH2:14][CH2:15][CH2:16][C:10]=3[C:9]2=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[C:27]=1[CH2:28][C:29]([OH:31])=[O:30]
Reactant: CCOC(=O)CCC(=O)OCC
Reactant: Cc1ccc(C(=O)c2c(N)sc3c2CCCC3)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1ccc(-c2c(CC(=O)O)c(O)nc3sc4c(c23)CCCC4)cc1
Temperature: 25 °C
Yield: 14.3 %

Procedure:
To a solution of potassium tert-butoxide (0.269 g; 2.4 mmol) in dry tert-butanol (10 mL) under a nitrogen atmosphere at 50° C. were added (2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(p-tolyl)methanone (0.542 g; 2 mmol) and diethyl succinate (0.464 mL; 2.8 mmol). The mixture was heated at reflux for 24 h and then cooled down to room temperature. Water (8 ml) was added and then the reaction mixture was acidified with a solution of hydrochloric acid 1N until pH 1. The aqueous layer was extracted with diisopropylether (3×10 ml) and ethyl acetate (3×10 mL). The organics were combined and the volatiles were removed under reduced pressure. The remaining crude was crystallized from acetic acid to furnish 0.101 g (14%) of the title compound.
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:20])([CH:17]([CH3:19])[CH3:18])[C:4]([NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8])=[O:5].C(N(CC)CC)C.[C:28](Cl)(=[O:31])[CH2:29][CH3:30]>C1(C)C=CC=CC=1>[CH3:20][C:3]([NH:2][C:28](=[O:31])[CH2:29][CH3:30])([CH:17]([CH3:18])[CH3:19])[C:4]([NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8])=[O:5]
Reactant: Cc1ccc(S(=O)(=O)NC(=O)C(C)(N)C(C)C)cc1
Reactant: CCC(=O)Cl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCC(=O)NC(C)(C(=O)NS(=O)(=O)c1ccc(C)cc1)C(C)C

Procedure:
2-Amino-2,3-dimethyl-N-(p-tolylsulfonyl)-butyramide hydrochloride (1.2 g, 5.3 mol) is dissolved in 25 mL of toluene under N2. Then triethylamine (1.9 mL, 2.5 equivalents) is added, followed by immediate addition of propionyl chloride (0.55 mL, 6.36 mol). The reaction mixture is heated for one hour, and then solvents are removed under reduced pressure. The yellowish residue is recrystallized from EtOH/water, to yield the title product as a white solid having mp 166°-168° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([O:16]CC2C=CC=CC=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:24])[CH:11]=2)[CH:6]=1.[H][H]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([OH:16])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:24])[CH:11]=2)[CH:6]=1
Reactant: [H][H]
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(OCc2ccccc2)c1C
Agent: [Pd]
Solvent: CO
Product: COC(=O)Cc1cc2ccc(F)cc2c(O)c1C
Yield: 81.9 %

Procedure:
To a stirred solution of (4-benzyloxy-6-fluoro-3-methyl-naphthalen-2-yl)-acetic acid methyl ester (15.8 g, 46.7 mmol) in MeOH (150 mL) was added 10% palladium on carbon (2.4 g). The resulting mixture was vigorously stirred under a balloon of hydrogen overnight. The reaction mixture was filtered through celite. The filtrate was concentrated to give the crude product, which was purified by silica gel chromatography (10% ethyl acetate in hexanes) to yield (6-fluoro-4-hydroxy-3-methyl-naphthalen-2-yl)-acetic acid methyl ester (9.5 g, 82%) as a white solid. MS cald. for C1H13FO3 [(M+H)+] 249, obsd. 249.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:27])[CH2:9][N:10]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[CH:6][CH:7]=1.O[CH2:29][C:30]1[CH:31]=[C:32]([CH:40]=[CH:41][CH:42]=1)[O:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:13]([O:12][C:11]([N:10]([CH2:9][C@@H:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[OH:27])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:29][C:30]2[CH:31]=[C:32]([CH:40]=[CH:41][CH:42]=2)[O:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:22][CH:21]=1)=[O:17])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(O)cc1)C[C@H](O)c1cccc(Cl)c1
Reactant: CCOC(=O)COc1cccc(CO)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)COc1cccc(COc2ccc(CCN(C[C@H](O)c3cccc(Cl)c3)C(=O)OC(C)(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 46.5 %

Procedure:
Under nitrogen at 5° C., to a solution of tert-butyl [(2R)-2-(3-chlorophenyl)-2-hydroxyethyl][2-(4-hydroxyphenyl)ethyl]carbamate (1.5 g), ethyl [3-(hydroxymethyl)phenoxy]acetate (885 mg) and triphenyl phosphine (1.1 g) in tetrahydrofuran (30 ml) was added diethyl azodicarboxylate (0.66 ml). The mixture was stirred at room temperature for 12 hours and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=2/1) to give ethyl [3-[[4-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]phenoxy]methyl]-phenoxy]acetate (1.04 g).