Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.[Br:11][C:12]1[CH:17]=[C:16]([CH:18]([CH3:20])[CH3:19])[CH:15]=[CH:14][C:13]=1[N:21]([C:24]1[N:29]=[C:28]([N:30]2[CH2:35][CH2:34][C:33](=[O:36])[CH2:32][CH2:31]2)[CH:27]=[C:26]([CH3:37])[N:25]=1)[CH2:22][CH3:23].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[Br:11][C:12]1[CH:17]=[C:16]([CH:18]([CH3:19])[CH3:20])[CH:15]=[CH:14][C:13]=1[N:21]([C:24]1[N:29]=[C:28]([N:30]2[CH2:35][CH2:34][C:33]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)([OH:36])[CH2:32][CH2:31]2)[CH:27]=[C:26]([CH3:37])[N:25]=1)[CH2:22][CH3:23]
Reactant: c1ccoc1
Reactant: CCN(c1nc(C)cc(N2CCC(=O)CC2)n1)c1ccc(C(C)C)cc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCN(c1nc(C)cc(N2CCC(O)(c3ccco3)CC2)n1)c1ccc(C(C)C)cc1Br
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 55.8 %

Procedure:
To a solution of 136 mg of furan in 1 ml of tetrahydrofuran was added dropwise 0.9 ml of a 1.63M n-hexane solution of n-butyl lithium under cooling at −15° C. over 10 minutes, followed by stirring at 5° C. for 20 minutes. To the reaction mixture was added dropwise a solution of 432 mg of 2-[N-(2-bromo-4-isopropylphenyl)-N-ethylamino]-6-methyl-4-(4-oxopiperidin-1-yl)pyrimidine in 2 ml of tetrahydrofuran over 10 minutes while cooling to −15° C., followed by stirring at −15° to 0° C. for 30 minutes. After stirring at room temperature for 1 hour, a saturated aqueous solution of ammonium chloride was added thereto dropwise under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was washed successively with a saturated ammonium chloride aqueous solution, a saturated sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=3/1) to give 279 mg of 2-[N-(2-bromo-4-isopropylphenyl)-N-ethylamino]-4-[4-(furan-2-yl)-4-hydroxypiperidin-1-yl]-6-methylpyrimidine.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH:5]1[CH:14]=[C:13]2[C:15]([O:17][C:18](=[O:19])[C:11]3=[C:12]2[C:7](=[C:8]([Cl:20])[CH:9]=[CH:10]3)[CH:6]=1)=[O:16]>S(=O)(=O)(O)O>[CH:5]1[CH:14]=[C:13]2[C:15]([O:17][C:18]([C:11]3=[CH:10][C:9]([N+:1]([O-:4])=[O:2])=[C:8]([Cl:20])[C:7](=[C:12]23)[CH:6]=1)=[O:19])=[O:16]
Reactant: O=C1OC(=O)c2ccc(Cl)c3cccc1c23
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C1OC(=O)c2cc([N+](=O)[O-])c(Cl)c3cccc1c23
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Mixture of concentrated sulfuric acid (2.7 mL) and concentrated nitric acid (2.0 mL) was added to a solution of 4-chloro-1,8-naphthalic anhydride (3.0 g, 12.8 mmol) in concentrated sulfuric acid (10.5 mL) at 0° C. The mixture was stirred at room temperature for 2 hours and poured into ice water (50 mL). The separated solid was filtered, washed with water, and dried to give 2.1 g of the title compound (Reference: Tet., 1995;51(33):9127-9138).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH:27]1([C:32]([NH:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=2)=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28]1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[C:39]1[CH:40]=[CH:41][C:36]([CH2:35][NH:34][C:32]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:33])=[CH:37][CH:38]=1
Reactant: O=C(NCc1ccc(B(O)O)cc1)C1CCCC1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NCc1ccc(-c2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1)C1CCCC1
Temperature: 80 °C

Procedure:
Dissolve 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (425 mg, 1 mmol), bis(triphenylphosphine)-palladium(II) chloride (0.1 equiv.), 4-[(cyclopentanecarbonyl-amino)-methyl]-phenyl-boronic acid (490 mg, 2.0 mmol) and sodium carbonate (2 equiv.) in THF/water (2:1, 15 mL) and heat the mixture at 80° C. for 6 h. Cool the reaction mixture to ambient temperature, dilute with EtOAc and wash with water. Dry the organic fraction over MgSO4, filter and concentrate in vacuo to obtain 7-chloro-6-{4-[(cyclopentanecarbonyl-amino)-methyl]-phenyl}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine, suitable for use without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH2:11])[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[N:3]=1.C(N(CC)CC)C.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25].CCOC(C)=O>CC1OCCC1>[CH2:27]([O:26][C:24](=[O:25])[NH:11][C:6]1[CH:5]=[C:4]([C:12]([F:13])([F:14])[F:15])[N:3]=[C:2]([Cl:1])[C:7]=1[N+:8]([O-:10])=[O:9])[CH3:28]
Reactant: CCOC(=O)Cl
Reactant: Nc1cc(C(F)(F)F)nc(Cl)c1[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: CC1CCCO1
Solvent: CCN(CC)CC
Product: CCOC(=O)Nc1cc(C(F)(F)F)nc(Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.6 %

Procedure:
2-Chloro-3-nitro-6-trifluoromethyl-pyridin-4-ylamine (2.2 g, 9.1 mmol) was stirred in 2-MeTHF (20 ml) and triethylamine added (1.52 ml, 10.9 mmol). The solution was cooled in an ice bath to ˜5° C. before the dropwise addition of ethyl chloroformate (1.04 ml, 10.9 mmol), the solution warmed to ambient temperature and left to stir under a nitrogen atmosphere for 16 h. 20 ml EtOAc and 10 ml H20 were added and the phases separated, washed with a additional 2×10 ml sat'd brine solution. The organic extract was dried over MgSO4, concentrated in vacuo and preabsorbed onto a silica column. Elution with Hept:EtOAc, 9:1 gave 2.1 g of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH:10]([NH2:12])=O>>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=[CH:10][N:12]=1
Reactant: N#Cc1ccccc1N
Reactant: NC=O
Product: Nc1ncnc2ccccc12
Temperature: 220 °C

Procedure:
A mixture of o-aminobenzonitrile (22.58 g) and formamide (96 ml) was refluxed for 2 hours at 220° C. After the resultant mixture was cooled to ambient temperature, precipitated crystals were separated by filtration, washed twice with a small volume of water and dried under reduced pressure to give crystalline 4-aminoquinazoline (17.0 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:6]2[C:7]([OH:11])=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][O:3]1.Cl[C:14]1[N:19]=[CH:18][C:17]([N:20]2[C:24](=[O:25])[C@:23]([CH2:27][CH3:28])([CH3:26])[NH:22][C:21]2=[O:29])=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:12])[C:6]2[C:7]([O:11][C:14]3[N:19]=[CH:18][C:17]([N:20]4[C:24](=[O:25])[C@:23]([CH2:27][CH3:28])([CH3:26])[NH:22][C:21]4=[O:29])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][O:3]1
Reactant: CC[C@@]1(C)NC(=O)N(c2ccc(Cl)nc2)C1=O
Reactant: CC1(C)OCc2cccc(O)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC[C@@]1(C)NC(=O)N(c2ccc(Oc3cccc4c3C(C)(C)OC4)nc2)C1=O
Temperature: 130 °C
Yield: 45.9 %

Procedure:
3,3-Dimethyl-1,3-dihydro-2-benzofuran-4-ol (Intermediate 193, 68 mg, 0.4 mmol) and (5R)-3-(6-chloropyridin-3-yl)-5-ethyl-5-methylimidazolidine-2,4-dione (Intermediate 194, 126 mg, 0.48 mmol) were dissolved in DMF (1.0 mL) and K2CO3 (143 mg, 1.03 mmol) was added. The resulting suspension was heated to 130° C. under microwave irradiation for 40 minutes. The reaction mixture was diluted with water (25 mL) and ethyl acetate (25 mL), and then two phases were separated. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography (Biotage system) on silica gel using cyclohexane/ethyl acetate 50:50 as eluent affording the title compound (70 mg) as a white solid.
Reaction SMILES: O.[C:2]([OH:6])(=[O:5])[CH:3]=[O:4].[CH3:7][C:8]([CH3:13])([CH2:11]O)[CH2:9][OH:10]>C1C=CC=CC=1>[C:2]([CH:3]1[O:10][CH2:9][C:8]([CH3:13])([CH3:11])[CH2:7][O:4]1)([OH:6])=[O:5]
Reactant: CC(C)(CO)CO
Reactant: O=CC(=O)O
Solvent: c1ccccc1
Solvent: O
Product: CC1(C)COC(C(=O)O)OC1
Yield: 73.4 %

Procedure:
Following a general procedure,23 a mixture of glyoxylic acid monohydrate (5.0 g, 54 mmol), 2,2-dimethyl 1,3-propanediol (8.5 g, 81 mmol) and Amberlyst-15 ion-exchange resin (100 mg) in benzene (140 mL) was refluxed for 15 h in a flask fitted with a Dean-Stark apparatus. The reaction mixture was filtered. The filtrate was concentrated and then refluxed with 20% aqueous NaOH (50 mL) for 30 min. The resulting alkaline solution was extracted with ether and neutralized in the cold with dilute HCl. At the end the pH was brought to ˜1.0 using H3PO4. The acidified aqueous layer was extracted with ether. The extracts were combined, dried (Na2SO4) and concentrated to afford a white solid (6.349 g, 73%): mp 58-60° C.; 1H NMR δ 0.80 (s, 3H), 1.22 (s, 3H), 3.57 (d, J=12.0 Hz, 2H), 3.79 (d, J=12.0 Hz, 2H), 4.97 (s, 1H); 13C NMR δ 169.1, 124.7, 95.8, 77.5, 30.6, 23.0, 21.9; FAB-MS obsd 161.0806, calcd 161.0814 (C7H12O4).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([NH:11][C:12]([NH2:14])=[S:13])[CH2:6][CH2:5]2.[CH3:15][I:16]>CO>[IH:16].[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([NH:11][C:12](=[NH:14])[S:13][CH3:15])[CH2:6][CH2:5]2
Reactant: NC(=S)NN1CCc2cc(Cl)ccc21
Reactant: CI
Solvent: CO
Product: CSC(=N)NN1CCc2cc(Cl)ccc21
Product: I

Procedure:
1-amino-5-chlorindoline was reacted with benzoyl isothiocyanate in boiling tetrahydrofuran. Saponification of the resulting product with dilute aqueous sodium hydroxide under reflux for 15 minutes gave 1-(5-chloroindolin-1-yl)-thiourea (M.Pt. 199° - 200° from ethyl acetate/petroleum ether). This thiourea was heated in boiling methanol in the presence of methyliodide for 1 hour to give 1-(5-chloroindolin-1-yl)-2-methylisothiourea hydroiodide. The base was liberated with aqueous sodium hydroxide. Reaction of the base with 2N ethanolic hydrogen chloride yielded 1-(5-chlorindolin-1-yl)-2-methylisothiourea hydrochloride (M.Pt. 178° - 179° from ethanol/ether).
Reaction SMILES: [C:1](OC(N1CCCC1C1NC(C2C=CC(C3C=CC(C4NC(C5CCN(C(OC(C)(C)C)=O)C5)=NC=4)=CC=3)=CC=2)=CN=1)=O)(C)(C)C.[CH3:47][O:48][C:49](=[O:84])[NH:50][CH:51]([C:55]([N:57]1[CH:62]([C:63]2[NH:64][C:65]([C:68]3[CH:73]=[CH:72][C:71](B4OC(C)(C)C(C)(C)O4)=[CH:70][CH:69]=3)=[CH:66][N:67]=2)[CH:61]2[CH2:83][CH:58]1[CH2:59][CH2:60]2)=[O:56])[CH:52]([CH3:54])[CH3:53].[CH3:85][O:86][C:87](=[O:109])[NH:88][CH:89]([C:92]([N:94]1[CH2:98][CH2:97][CH2:96][CH:95]1[C:99]1[NH:103][C:102]2[CH:104]=[C:105](Br)[CH:106]=[CH:107][C:101]=2[N:100]=1)=[O:93])[CH2:90][CH3:91].C(OC(N1CCCC1C1NC(C2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)=CN=1)=O)(C)(C)C.C(OC(N1CCC(C2NC(C3C=CC(Br)=CC=3)=CN=2)C1)=O)(C)(C)C>>[CH3:85][O:86][C:87](=[O:109])[NH:88][CH:89]([C:92]([N:94]1[CH2:98][CH2:97][CH2:96][CH:95]1[C:99]1[NH:103][C:102]2[CH:104]=[C:105]([C:71]3[CH:70]=[CH:69][C:68]([C:65]4[NH:64][C:63]([CH:62]5[CH:61]6[CH2:83][CH:58]([CH2:59][CH2:60]6)[N:57]5[C:55](=[O:56])[CH:51]([NH:50][C:49]([O:48][CH3:47])=[O:84])[CH:52]([CH3:54])[CH3:53])=[N:67][CH:66]=4)=[CH:73][CH:72]=3)[CH:106]=[CH:107][C:101]=2[N:100]=1)=[O:93])[CH:90]([CH3:1])[CH3:91]
Reactant: COC(=O)NC(C(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncc(-c3ccc(-c4ccc(-c5cnc(C6CCCN6C(=O)OC(C)(C)C)[nH]5)cc4)cc3)[nH]2)C1
Reactant: CCC(NC(=O)OC)C(=O)N1CCCC1c1nc2ccc(Br)cc2[nH]1
Agent: CC(C)(C)OC(=O)N1CCC(c2ncc(-c3ccc(Br)cc3)[nH]2)C1
Agent: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
Product: COC(=O)NC(C(=O)N1CCCC1c1nc2ccc(-c3ccc(-c4cnc(C5C6CCC(C6)N5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2[nH]1)C(C)C

Procedure:
Following the procedure used to prepare compound 2-(5-{4′-[2-(1-Boc-pyrrolidin-3-yl)-3H-imidazol-4-yl]-biphenyl-4-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester, except that [2-methyl-1-(3-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carbonyl)-propyl]-carbamic acid methyl ester and {1-[2-(6-bromo-1H-benzoimidazol-2-yl)-pyrrolidine-1-carbonyl]-propyl}-carbamic acid methyl ester were used instead of 2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester and 3-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester. 1H-NMR (300 MHz, CD3OD) δ 8.10-7.80 (m, 7H), 5.42-5.30 (m, 1H), 4.65 (s, 1H), 4.40-4.25 (m, 2H), 4.20-3.90 (m, 2H, 3.80-3.60 (m, 6H), 3.00-2.80 (m, 1H), 2.70-2.55 (m, 1H), 2.50-1.60 (m, 12H), 1.10-0.80 (m, 12H); m/z 739.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]([Cl:7])=[O:6])[CH3:2].[NH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[NH:19][CH2:20][C:21]1([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[CH:16][CH:15]=[CH:14][CH:13]=2>C(#N)C>[ClH:7].[CH2:1]([O:3][CH2:4][C:5]([NH:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[NH:19][CH2:20][C:21]1([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:6])[CH3:2]
Reactant: CCOCC(=O)Cl
Reactant: CCOC(=O)C1(CNc2c(N)cnc3ccccc23)CCCCC1
Solvent: CC#N
Product: CCOCC(=O)Nc1cnc2ccccc2c1NCC1(C(=O)OCC)CCCCC1
Product: Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.2 %

Procedure:
A solution of ethoxyacetyl chloride (3.95 g, 32.3 mmol) in acetonitrile (10 mL) was added to a solution of ethyl 1-{[(3-aminoquinolin-4-yl)amino]methyl}cyclohexanecarboxylate (9.60 g, 29.3 mmol) in acetonitrile (200 mL), and the resulting mixture was stirred for five hours at ambient temperature. A precipitate was present and was isolated by filtration, washed with cold acetonitrile, and dried overnight under vacuum to provide 10.18 g of ethyl 1-[({3-[(ethoxyacetyl)amino]quinolin-4-yl}amino)methyl]cyclohexanecarboxylate hydrochloride.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+].C(O)(=O)C.[Cl:17][C:18]1[CH:26]=[C:25]2[C:21]([C:22]([C:33](=O)[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:23]([C:28](OCC)=[O:29])[N:24]2[CH3:27])=[CH:20][CH:19]=1>O>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[C:22]3[C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[N:10][N:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([Cl:2])[CH:4]=4)[C:28](=[O:29])[C:23]=3[N:24]([CH3:27])[C:25]=2[CH:26]=1
Reactant: NNc1cccc(Cl)c1
Reactant: CCOC(=O)C(=O)c1c(C(=O)OCC)n(C)c2cc(Cl)ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1nn(-c2cccc(Cl)c2)c(=O)c2c1c1ccc(Cl)cc1n2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
7.0 g (39.1 mmol) of 3-chlorophenylhydrazine hydrochloride are dissolved in 50 ml of water and 5 ml of a 35% sodium hydroxide solution. Extraction is carried out with diethyl ether. The organic phase is dried over sodium sulphate, filtered and concentrated under reduced pressure. An oil is obtained, to which are added 100 ml of acetic acid and 4.0 g (12.35 mmol) of ethyl 6-chloro-2-(ethoxycarbonyl)-1-methyl-α-oxo-1H-indole-3-acetate. The reaction mixture is stirred for 30 min at room temperature and then for 6 h at reflux. The mixture is cooled, 100 ml of water are added and an insoluble material is collected by filtration, washed with water and purified by chromatography on a silica column (eluant: dichloromethane/ethyl acetate: 98/2). 4.59 g (11 mmol) of compound are isolated in the form of a white solid.
Reaction SMILES: C([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](O)([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(C)=CC2CCC(OC3C=C4C(=CC=3)N(C)C=C4CCO[Si](C(C)(C)C)(C)C)C(OC)C2)[CH:7]([CH3:74])[CH:6](O)[CH2:5][C:4]1=[O:76])C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.CO>[CH3:33][O:32][CH:24]1[CH:23]2[O:34][CH:19]([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][CH2:8][CH:7]([CH3:74])[CH2:6][CH2:5][C:4](=[O:76])[CH2:3][CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25]1
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccc5c(c4)c(CCO[Si](C)(C)C(C)(C)C)cn5C)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: COC1CC(C)CC(C)=CCC(=O)CCC(C)COC(=O)C2CCCCN2C(=O)C(=O)C2OC1C(OC)CC2C
Reaction time: 3 h

Procedure:
To a stirred solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(1-methyl-3-(2-t-butyldimethylsilyloxyethyl)indol-5-yl)oxy-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 (200 mg.) in CH2Cl2 (6 mL.) and CH3OH (6 mL.) was added p-toluenesulfonic acid monohydrate (30 mg.). The reaction mixture was allowed to stir 3 hours. The reaction was quenched with saturated aqueous NaHCO3 and extracted 4× with CH2Cl2. The organic extracts were combined, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The product was purified by preparative TLC on silica gel (1:1 hexanes/acetone) and again (7% CH3OH/CH2Cl2) giving -(4"-(1-methyl-3-(2-hydroxyethyl)indol-5-yl)oxy-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.
Reaction SMILES: [C:1]([OH:12])(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:13][N:14]([CH2:16][CH2:17]O)[CH3:15].Cl.CN(C)CCCN=C=NCC.Cl>ClCCl>[C:1]([O:12][CH2:17][CH2:16][N:14]([CH3:15])[CH3:13])(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: CN(C)CCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCCCCCC/C=C/C(=O)OCCN(C)C
Reaction time: 8 h

Procedure:
trans-2-Decenoic acid (170 mg, 1 mmol) and N,N-dimethylaminoethanol (90 mg, 1 mmol) were dissolved in anhydrous dichloromethane (10 ml) and, under stirring in an ice bath, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (211 mg, 1.1 mmol) (Sigma-Aldrich) was added thereto. After stirring in an ice bath for 1 hour and then at room temperature for 8 hours, the reaction solution was poured over a diluted hydrochloric acid solution followed by extracting with chloroform. The chloroform layer was concentrated to give the aimed compound as a light brown oily product.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:4]=2[S:5](=[O:9])(=[O:8])[C:6]=1[CH3:7].[CH2:15]([NH:17][CH2:18][CH3:19])[CH3:16]>CO>[Cl:14][C:11]1[CH:12]=[CH:13][C:3]2[CH:2]=[C:6]([CH2:7][N:17]([CH2:18][CH3:19])[CH2:15][CH3:16])[S:5](=[O:9])(=[O:8])[C:4]=2[CH:10]=1
Reactant: CCNCC
Reactant: CC1=C(Cl)c2ccc(Cl)cc2S1(=O)=O
Solvent: CO
Product: CCN(CC)CC1=Cc2ccc(Cl)cc2S1(=O)=O

Procedure:
A mixture of 37.3 g (0.15 mol) 3,6-dichloro-2-methylbenzo[b]thiophene-1,1-dioxide, 200 ml methanol and 45 ml diethylamine is heated for 4 hours to reflux. Afterwards it is concentrated by evaporation, taken up in ethyl acetate, washed with water, dried, concentrated and chromatographed on silica gel (eluting agent ethyl acetate/isohexane 1:1). 29.5 g of the title compound (62% of the theoretical yield) having a melting point of 58°-59° C. is isolated.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:27])=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[H-].[Na+:29].[S:30]1([O:36][CH2:35][CH2:34][O:33]1)(=[O:32])=[O:31].CCOCC>O1CCCC1.O>[S:30]([O-:36])([O:33][CH2:34][CH2:35][N:3]1[C:4]([CH3:27])=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:2]1[CH3:1])(=[O:32])=[O:31].[Na+:29]
Reactant: O=S1(=O)OCCO1
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C1=C(C)N(CCOS(=O)(=O)[O-])C(C)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Temperature: -10 °C
Reaction time: 3 h

Procedure:
In 160 ml of tetrahydrofuran was dissolved 40 g of diethyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5 -dicarboxylate and after adding to the solution 5.2 g of 50% oil dispersion of sodium hydride at room temperature, the resultant mixture was stirred for 30 minutes at room temperature. Then, the mixture was cooled to temperatures of from -10° C. to -20° C., and after adding dropwise thereto a solution of 20 g ethylene sulfate in 80 ml of tetrahydrofuran, the mixture was stirred for 1 hr. at -10° C., and the temperature of the system was raised gradually till room temperature. After further adding 4.0 g of 50% oil dispersion of sodium hydride, the mixture was stirred for 3 hrs. at room temperature. The reaction mixture was cooled to -10° C., and after adding dropwise a solution of 5.0 g ethylene sulfate in 10 ml of tetrahydrofuran, the mixture was stirred for 1 hr. at the same temperature. The reaction mixture was cooled and 800 ml of ether was added thereto and further 100 ml of water was added. The separated aqueous layer was subjected to a silica gel column chromatography (12 cm × 5.0 cm). After eluting the small amount of raw material using 50 ml of ethyl acetate as an elute, the product was then developed by using 1:1 ethyl acetate-methanol mixed solvent as an elute. The solvent of the effluent was distilled away under reduced pressure, and to the residue obtained was added 30 ml of water and after cooling, the crystal formed was filtered to provide 35 g of sodium β-[2,6-dimethyl-3,5-bis(ethoxycarbonyl)-4-(3-nitrophenyl)- 1,4-dihydropyridine-1-yl]-ethyl sulfate. By recrystallizing this product from water, scale-shaped yellow crystal was obtained.
Reaction SMILES: CCCCCC.[CH2:7]([N:9]([Al](C)C)[CH2:10][CH3:11])[CH3:8].[CH2:15]([NH:17][C:18](=[O:49])[NH:19][C:20]1[S:24][C:23]2[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=2[C:21]=1[C:29]([N:31]1[CH2:48][CH2:47][C:34]2([N:38]=[C:37]([CH2:39][CH2:40][C:41]([O:43]CC)=O)[NH:36][C:35]2=[O:46])[CH2:33][CH2:32]1)=[O:30])[CH3:16]>C1C=CC=CC=1.C1COCC1>[CH2:7]([N:9]([CH2:10][CH3:11])[C:41](=[O:43])[CH2:40][CH2:39][C:37]1[NH:36][C:35](=[O:46])[C:34]2([CH2:33][CH2:32][N:31]([C:29]([C:21]3[C:22]4[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=4[S:24][C:20]=3[NH:19][C:18]([NH:17][CH2:15][CH3:16])=[O:49])=[O:30])[CH2:48][CH2:47]2)[N:38]=1)[CH3:8]
Reactant: CCN(CC)[Al](C)C
Reactant: CCNC(=O)Nc1sc2ccccc2c1C(=O)N1CCC2(CC1)N=C(CCC(=O)OCC)NC2=O
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CCNC(=O)Nc1sc2ccccc2c1C(=O)N1CCC2(CC1)N=C(CCC(=O)N(CC)CC)NC2=O
Temperature: 80 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
To a 2.0 M hexane solution of (diethylamino)dimethylaluminum (3.2 equivalents) in dry benzene (0.26 M) was cooled to −15° C., a solution of ethyl 3-(8-(2-(3-ethylureido)benzo[b]thiophene-3-carbonyl)-4-oxo-1,3,8-triazaspiro[4.5]dec-1-en-2-yl)propanoate (10 (Example 10), 12 mg, 1.0 equivalent) in THF (0.16M) was added; the mixture was heated to 80° C. for 6 hrs. The mixture was cooled in an ice bath; then a saturated aqueous Rochelle's solution was added and stirred for 1 hr, then partitioned between ethyl acetate and water and the separated organics was washed with brine and dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparatory LCMS to afford N,N-diethyl-3-(8-(2-(3-ethylureido)benzo[b]thiophene-3-carbonyl)-4-oxo-1,3,8-triazaspiro[4.5]dec-1-en-2-yl)propanamide (10, 20%). Two rotamers observed (ratio 1.3:1).