Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1I)([F:4])[F:3].[CH:13]1([C:16]#[CH:17])[CH2:15][CH2:14]1>C(N(CC)CC)C.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.[Cu]I>[CH:13]1([C:16]#[C:17][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:2]([F:4])([F:3])[F:1])[CH2:15][CH2:14]1
Reactant: FC(F)(F)Sc1ccccc1I
Reactant: C#CC1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: FC(F)(F)Sc1ccccc1C#CC1CC1
Temperature: 25 °C
Yield: 76.8 %

Procedure:
Bis(triphenylphosphine)palladium(II) dichloride ([(C6H5)3P]2PdCl2, 0.0518 g, 5 mol %), copper(I) iodide (0.0086 g, 3 mol %), and triethylamine (3 ml) were charged into a 25-ml round-bottomed flask equipped with a stirrer, and were suspended by stirring at room temperature. To the suspension, a solution obtained by dissolving 2-trifluoromethylsulfanyliodobenzene (1.08 g, 3.6 mmol) prepared in Reference Example 1 and cyclopropylacetylene (0.35 g, 5.3 mmol) in triethylamine (2 ml) was added dropwise, and the solution was stirred at room temperature overnight. After completion of the reaction, a solvent was removed under reduced pressure, and water was added to the obtained residue. The solution was extracted with ether, and the organic layers were combined together, washed with water, dried over magnesium sulfate, filtered, and concentrated to obtain a crude product. The obtained crude product was purified by silica gel column chromatography (hexane) to give target 1-cyclopropylethynyl-2-trifluoromethylsulfanylbenzene (0.67 g, yield: 78%) as an oil.
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:9]([C:12]1[CH:37]=[CH:36][C:15]([O:16][C:17]2[CH:18]=[C:19]([CH:23]=[C:24]([O:26][C:27]3[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=3)[CH:25]=2)[C:20](Cl)=[O:21])=[CH:14][CH:13]=1)([O-:11])=[O:10].N1C=CC=CC=1>C1C=CC=CC=1>[N+:9]([C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17]2[CH:18]=[C:19]([CH:23]=[C:24]([O:26][C:27]3[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=3)[CH:25]=2)[C:20]([CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:1]2=[O:8])=[O:21])=[CH:36][CH:37]=1)([O-:11])=[O:10]
Reactant: O=C1CCCCCN1
Reactant: O=C(Cl)c1cc(Oc2ccc([N+](=O)[O-])cc2)cc(Oc2ccc([N+](=O)[O-])cc2)c1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: O=C1NCCCCC1C(=O)c1cc(Oc2ccc([N+](=O)[O-])cc2)cc(Oc2ccc([N+](=O)[O-])cc2)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
A solution of ε-caprolactam (14.82 g, 0.131 mol) in 400 ml of benzene is added to the above reactor containing 0.131 mol of 3,5-bis(4-nitrophenoxy)benzoyl chloride. The mixture is heated to 80°-90° C., and after all the reactants are dissolved, 150 ml of pyridine is added. The solution is stirred at 90° C. for 3 hours and the pyridine/acid chloride salt removed by filtration, the filtrate being kept in a freezer. White crystals formed from the filtrate are collected by filtration and dried. In order to remove traces of the 3,5-bis(4-nitrophenoxy)benzoic acid, the product is further purified by chromatography using silica gel as filler and ethyl acetate as eluate to yield 65 percent of white crystals: mp 157°-158° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[C:5]2[CH:12]([CH3:24])[N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:15][O:16][C:4]=12.[H-].[Na+].[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:30]=1[S:36](Cl)(=[O:38])=[O:37]>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[S:36]([C:30]2[CH:31]=[C:32]([CH3:35])[CH:33]=[CH:34][C:29]=2[O:28][CH3:27])(=[O:38])=[O:37])=[C:5]2[CH:12]([CH3:24])[N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:15][O:16][C:4]=12
Reactant: COc1cc2[nH]ccc2c2c1OCCN(C(=O)OC(C)(C)C)C2C
Reactant: COc1ccc(C)cc1S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C)cc1S(=O)(=O)n1ccc2c3c(c(OC)cc21)OCCN(C(=O)OC(C)(C)C)C3C
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.4 %

Procedure:
tert-Butyl 6-methoxy-1-methyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 36, 25 mg, 0.059 mmol) was dissolved in DMF (1 mL) and sodium hydride (60% in mineral oil, 4.0 mg, 0.15 mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes before 2-methoxy-5-methylbenzenesulfonyl chloride (24.0 mg, 0.113 mmol) was added. The reaction mixture was allowed to stir at room temperature overnight and a few drops of water were added. The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give tert-butyl 6-methoxy-8-[(2-methoxy-5-methylphenyl)sulfonyl]-1-methyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (4.4 mg) which was dissolved in DCM (1 mL) and TFA (1 mL) was added. The reaction mixture was stirred at room temperature for 3 hours and evaporated to give the title compound (4.6 mg). MS m/z 417 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[CH:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][C:10]=12)=[O:5])C.O.[OH-].[Na+]>CO>[CH2:11]1[C:10]2=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[CH:8][N:9]2[CH2:14][CH2:13][O:12]1
Reactant: CCOC(=O)c1ccn2c1COCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccn2c1COCC2
Yield: 100 %

Procedure:
To a solution of 3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid ethyl ester (Comp. No. 2a) (3.2 g, 16.4 mmol) in methanol (64 ml) was added water (64 ml) and sodium hydroxide (3.3 g, 82 mmol) and the mixture was stirred at reflux until complete conversion according to LC/MC (about 4 h). Approximately half of the solvents were evaporated in vacuo and the mixture was acidified with excess hydrochloric acid. The forming precipitate was filtered off, washed once with water and dried in vacuo to give 2.7 g (100%) of 3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid as white solid. LC/MS (method 4): Rt=0.77 min; m/z=168.02 (M+H+).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([NH2:10])OCC)C.[N+:12]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[CH2:18][NH:19][NH2:20])([O-:14])=[O:13]>>[NH2:10][C:6]1[NH:20][N:19]([CH2:18][C:17]2[CH:21]=[CH:22][CH:23]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=2)[C:4](=[O:3])[CH:5]=1
Reactant: NNCc1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)C=C(N)OCC
Product: Nc1cc(=O)n(Cc2cccc([N+](=O)[O-])c2)[nH]1

Procedure:
17.5 g of β-amino-β-ethoxyacrylic acid ethyl ester and 16.7 g of 3-nitrobenzylhydrazine, analogously to the procedure described in Example 1 yield 12.3 g of the compound identified above as yellow crystals of melting point 163°, corresponding to 52% of theory.
Reaction SMILES: [OH-].[Na+].C([NH:11][C:12]([NH:14][C:15]1[CH:20]=[C:19]([N:21]2[CH:25]=[CH:24][CH:23]=[N:22]2)[CH:18]=[C:17]([Br:26])[CH:16]=1)=[S:13])(=O)C1C=CC=CC=1>O.C1COCC1>[Br:26][C:17]1[CH:16]=[C:15]([NH:14][C:12]([NH2:11])=[S:13])[CH:20]=[C:19]([N:21]2[CH:25]=[CH:24][CH:23]=[N:22]2)[CH:18]=1
Reactant: O=C(NC(=S)Nc1cc(Br)cc(-n2cccn2)c1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NC(=S)Nc1cc(Br)cc(-n2cccn2)c1
Temperature: 70 °C
Reaction time: 12 h
Yield: 85.4 %

Procedure:
A solution of NaOH (0.13 g, 3.35 mmol) dissolved in 1.0 mL of H2O was added to a solution of 1-Benzoyl-3-(3-bromo-5-pyrazol-1-yl-phenyl)-thiourea 3 (0.27 g, 0.67 mmol) in 5.0 mL of THF. The resulting reaction mixture was stirred at 70° C. for 12 hours. THF was distilled off and extracted with ethyl acetate (×3). The combined organic layer was dried over Na2SO4, filtered and distilled off to get the crude residue that was washed with 2% Ethyl acetate-hexane to obtain the desired compound (0.17 g, 85%).
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3].O[C:24]1[CH:76]=[CH:75][C:27]([CH2:28][NH:29][C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33](/[N:40]=[N:41]/[C:42]3[C:51]4[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=4)[C:45](/[N:52]=[N:53]/[C:54]4[CH:73]=[CH:72][C:57]([C:58]([O:60][C:61]5[CH:66]=[CH:65][C:64]([CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])=[CH:63][CH:62]=5)=[O:59])=[CH:56][C:55]=4[CH3:74])=[CH:44][CH:43]=3)=[CH:32][CH:31]=2)=[CH:26][CH:25]=1>C1COCC1.C(N(CC)CC)C.CN(C1C=CN=CC=1)C>[C:1]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([O:20][C:24]2[CH:76]=[CH:75][C:27]([CH2:28][NH:29][C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:33](/[N:40]=[N:41]/[C:42]4[C:51]5[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=5)[C:45](/[N:52]=[N:53]/[C:54]5[CH:73]=[CH:72][C:57]([C:58]([O:60][C:61]6[CH:62]=[CH:63][C:64]([CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])=[CH:65][CH:66]=6)=[O:59])=[CH:56][C:55]=5[CH3:74])=[CH:44][CH:43]=4)=[CH:32][CH:31]=3)=[CH:26][CH:25]=2)=[O:19])=[CH:21][CH:22]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OCCCCCCOc1ccc(C(=O)O)cc1
Reactant: CCCCCc1ccc(OC(=O)c2ccc(/N=N/c3ccc(/N=N/c4ccc(NCc5ccc(O)cc5)c5ccccc45)c4ccccc34)c(C)c2)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCCCCCCOc1ccc(C(=O)Oc2ccc(CNc3ccc(/N=N/c4ccc(/N=N/c5ccc(C(=O)Oc6ccc(CCCCC)cc6)cc5C)c5ccccc45)c4ccccc34)cc2)cc1
Temperature: -30 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
0.68 g of 4-{[6-(methacryloyloxy)hexyl]oxy}benzoic acid (2.20 mM) were dissolved in 20 ml of THF and 2.22 g of triethylamine (22.00 mM). The solution was cooled to −30° C. and 0.25 ml of methansulfochloride (2.20 mM) were added. The mixture was stirred for 1 h at this temperature, then 1.42 g of 4-pentylphenyl 4-{(E)-[4-((E)-{4-[(4-hydroxybenzyl)-amino]1-naphthyl}-diazenyl)-1-naphthyl]diazenyl}-3-methylbenzoate (2.00 mM) were added at once, followed by 50 mg of DMAP. The reaction mixture was stirred for 1 h at −30° C. and was allowed to warm to room temperature while stirred overnight. The next day, 10 g of celite filter aid were added and the resulting suspension was stirred for 15 min., filtered, the cake was washed with THF and the filtrate was evaporated to dryness. The residue was dissolved in 10 ml of dichloromethane and to this solution was then added approx. 30 ml of methanol dropwise at 0° C. The precipitated crystals were filtered off, washed with cooled methanol and dried to give 1.60 g (1.60 mM, 80%) of 4-pentylphenyl 4-[(E)-(4-{(E)-[4-({4-[(4-{[6-(methacryloyloxy)hexyl]oxy}benzoyl)oxy]benzyl}amino)-1-naphthyl]-diazenyl}-1-naphthyl)diazenyl]-3-methylbenzoate as dark crystals; λmax=571 nm, ε=35000 (THF). For total purification, the dye might be flash chromatographed on silica gel.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][OH:6])[CH3:2].[H-].[Na+].Br[CH2:10][C:11]1[N:16]=[C:15]([CH2:17][N:18]2[C:22]3[N:23]=[C:24]([NH2:33])[N:25]=[C:26]([C:27]4[O:28][C:29]([CH3:32])=[CH:30][CH:31]=4)[C:21]=3[N:20]=[N:19]2)[CH:14]=[CH:13][CH:12]=1>C1COCC1>[CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:10][C:11]1[N:16]=[C:15]([CH2:17][N:18]2[C:22]3[N:23]=[C:24]([NH2:33])[N:25]=[C:26]([C:27]4[O:28][C:29]([CH3:32])=[CH:30][CH:31]=4)[C:21]=3[N:20]=[N:19]2)[CH:14]=[CH:13][CH:12]=1)[CH3:2]
Reactant: Cc1ccc(-c2nc(N)nc3c2nnn3Cc2cccc(CBr)n2)o1
Reactant: CCOCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOCCOCc1cccc(Cn2nnc3c(-c4ccc(C)o4)nc(N)nc32)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 33.2 %

Procedure:
A solution of 2-ethoxyethanol (242 μl, 2.5 mmol) in anhydrous THF (15 mL) was cooled to 0° C. and treated with NaH (100 mg, 2.5 mmol). The reaction was stirred at 0° C. for 10 mins, then treated with 3-(6-bromomethylpyridin-2-ylmethyl)-7-(5-methyl-2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine (100 mg, 0.25 mmol), stirred at room temperature for 30 mins. The reaction was quenched with aqueous NH4Cl and extracted with EtOAc. The combined organic phases were dried (MgSO4) and concentrated in vacuo. The resulting solid was suspended in MeOH (10 mL) and treated with 4M HCl in dioxane (2 mL), the reaction mixture was then diluted with diethyl ether (40 mL) and the resulting solid isolated by filtration to give the product (34 mg, 31%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[O:23][CH:22]=[CH:21][C:4]=2[C:5]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH3:1][C:2]1[C:3]2[O:23][CH:22]=[CH:21][C:4]=2[C:5]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: Cc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c2ccoc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc(N2CCNCC2)c2ccoc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
A stirred solution of tert-butyl 4-(7-methyl-furo[3,2-c]pyridin-4-yl)-piperazine-1-carboxylate (step A) (2.34 g, 7.37 mmol) in dichloromethane (4.1 ml) was cooled to 0° C., trifluoroacetic acid (8.41 g, 5.68 ml, 73.7 mmol) was added drop wise and the reaction mixture was allowed to stir for 10 min at 0° C. and for 30 min at room temperature. The solution was poured onto ice and 2N sodium carbonate solution (50 ml) and extracted with dichloromethane (2×25 ml). The combined organic layers were washed with brine (30 mL), dried (MgSO4) and evaporated. The crude product (1.59 g) was further purified by flash chromatography on silica gel (100% dichloromethane/MeOH/NH4OH 80:10:1) to yield 7-methyl-4-(piperazin-1-yl)-furo[3,2-c]pyridine as a yellow solid (1.27 g, 79%), MS (ISP) m/z=218.4 [(M+H)+], mp 111.5° C.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]1[C:12]1[CH:17]=[C:16]([C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:31][CH2:32][CH3:33])=[C:25]([O:28][CH2:29][CH3:30])[CH:26]=3)[CH:21]=[C:20]([CH2:34][O:35]C(=O)C)[C:19]=2[CH2:39][O:40]C(=O)C)[CH:15]=[CH:14][N:13]=1.C[O-].[Na+].C(O)(=O)C>CO>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]1[C:12]1[CH:17]=[C:16]([C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:31][CH2:32][CH3:33])=[C:25]([O:28][CH2:29][CH3:30])[CH:26]=3)[CH:21]=[C:20]([CH2:34][OH:35])[C:19]=2[CH2:39][OH:40])[CH:15]=[CH:14][N:13]=1
Reactant: CCOc1cc2cc(COC(C)=O)c(COC(C)=O)c(-c3ccnc(-n4ccc5ccccc5c4=O)c3)c2cc1OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOc1cc2cc(CO)c(CO)c(-c3ccnc(-n4ccc5ccccc5c4=O)c3)c2cc1OCC
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 60.4 %

Procedure:
To a solution of 1-[2-(1-oxo-1,2-dihydroisoquinolin-2-yl)-4-pyridyl]-2,3-bis(acetoxymethyl)-6,7-diethoxynaphthalene (1.84 g) in methanol (50 ml) is added sodium methoxide (0.52 g) under ice-cooling. The mixture is stirred at room temperature for 2.5 hours. To the mixture is added sodium methoxide (0.17 g) under ice-cooling, and the mixture is stirred at room temperature for one hour. Acetic acid (0.74 ml) is added to the reaction mixture under ice-cooling, and the mixture is Concentrated under reduced pressure to remove the solvent. To the residue are added methylene chloride and an aqueous sodium hydrogen carbonate solution, and the methylene chloride layer is separated, washed, dried and concentrated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform:ethanol=25:1) to give 1-[2-(1-oxo-1,2-dihydroisoquinolin-2-yl)4-pyridyl]-2,3-bis(hydroxymethyl)-6,7-diethoxynaphthalene (0.95 g) which is listed in Table 1.
Reaction SMILES: [F:1][C:2]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:36]=[CH:35][C:20]([O:21][C:22]2[CH:23]=[CH:24][C:25]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[C:26]([OH:28])[CH:27]=2)=[CH:19][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH3:15].[C:42]([O:46][CH2:47][CH3:48])(=[O:45])[CH2:43]O>>[F:1][C:2]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:36]=[CH:35][C:20]([O:21][C:22]2[CH:23]=[CH:24][C:25]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[C:26]([CH:27]=2)[O:28][CH2:43][C:42]([O:46][CH2:47][CH3:48])=[O:45])=[CH:19][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH3:15]
Reactant: CCCCCCc1ccc(Oc2ccc(CN(Cc3ccc(F)cc3F)c3cccc([N+](=O)[O-])c3C)cc2)cc1O
Reactant: CCOC(=O)CO
Product: CCCCCCc1ccc(Oc2ccc(CN(Cc3ccc(F)cc3F)c3cccc([N+](=O)[O-])c3C)cc2)cc1OCC(=O)OCC

Procedure:
The product from Example 238F and ethyl glycolate were processed as described in Example 62A to provide the titled compound. MS (ESI+) m/z 597 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH2:20]([Sn:24](Cl)([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH3:23]>C(COC)OC>[CH2:1]([N:8]1[CH2:13][CH:12]=[C:11]([Sn:24]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: COCCOC
Product: CCCC[Sn](CCCC)(CCCC)C1=CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 15.85 g (0.0837 mole) of 1-benzyl-4-piperidone in 140 ml of anhydrous dimethoxyethane and 25 g (0.0837 mole) of trisilidrazine in 140 ml of anhydrous dimethoxyethane is stirred at room temperature for 3 hours. The solvent is evaporated off under reduced pressure. The residue is taken up into 420 ml of anhydrous hexane and 420 ml of anhydrous tetramethylethylenediamine are added thereto. The mixture is cooled to −78° C. and 156 ml of n-butyllithium (0.25 mole) (1.6 M solution in hexane) are added dropwise thereto. After about 30 minutes the temperature is allowed to attain 0° C. and stirring is effected for 15 minutes. 45 ml (0.167 mole) of tributylstannyl chloride are then added to the reaction mixture. After 1 hour, a water/ice mixture is added with extreme caution. Extraction is carried out with ethyl ether, the organic phase is washed with water, drying is effected over sodium sulphate and the solvent is evaporated off under reduced pressure. 70 g of crude product are obtained which are purified by silica gel column chromatography in eluting with a cyclohexane/ethyl acetate mixture=95/5. The title compound is obtained as an oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[C:3]([CH:10]=O)=[CH:2]1.[O:12]=[C:13]1[CH2:17][O:16][C:15]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:14]1[C:25]([O:27][CH2:28][CH3:29])=[O:26].N1CCCCC1>C(O)C>[NH:1]1[C:9]2=[N:8][CH:7]=[CH:6][CH:5]=[C:4]2[C:3]([CH:10]=[C:17]2[O:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:14]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:13]2=[O:12])=[CH:2]1
Reactant: CCOC(=O)C1=C(Nc2ccccc2)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)C1=C(Nc2ccccc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 49.5 %

Procedure:
To a solution of 7-azaindole-3-carboxaldehyde (0.10 g, 0.70 mmol) and ethyl 4-oxo-2-(phenylamino)-4,5-dihydrofuran-3-carboxylate (0.18 g, 0.70 mmol) in ethanol (3.0 mL), piperidine (0.083 mL, 0.84 mmol) was added at ambient temperature. The mixture was refluxed for 12 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with cold ethanol and isopropyl ether then dried to afford the titled compound (0.13 g, y. 48%).
Reaction SMILES: [OH:1][CH:2]([C:27]1[S:28][CH:29]=[C:30]([C:32](=[O:35])[NH:33][CH3:34])[N:31]=1)[CH2:3][CH:4]([N:8]([CH3:26])[C:9]([CH:11]([NH:16][C:17]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]1[CH3:25])=[O:18])[CH:12]([CH3:15])[CH2:13][CH3:14])=[O:10])[CH:5]([CH3:7])[CH3:6].[C:36](OC(=O)C)(=[O:38])[CH3:37]>N1C=CC=CC=1>[CH3:7][CH:5]([CH3:6])[CH:4]([N:8]([CH3:26])[C:9](=[O:10])[CH:11]([NH:16][C:17]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]1[CH3:25])=[O:18])[CH:12]([CH3:15])[CH2:13][CH3:14])[CH2:3][CH:2]([O:1][C:36](=[O:38])[CH3:37])[C:27]1[S:28][CH:29]=[C:30]([C:32](=[O:35])[NH:33][CH3:34])[N:31]=1
Reactant: CCC(C)C(NC(=O)C1CCCCN1C)C(=O)N(C)C(CC(O)c1nc(C(=O)NC)cs1)C(C)C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCC(C)C(NC(=O)C1CCCCN1C)C(=O)N(C)C(CC(OC(C)=O)c1nc(C(=O)NC)cs1)C(C)C
Temperature: 25 °C
Reaction time: 21 h
Yield: 71.7 %

Procedure:
A 0.050 M solution of 25 (12.0 mg, 0.0235 mmol) in pyridine (0.500 mL) was cooled to 0° C., and acetic anhydride (18.0 μL, 0.188 mmol) was added. The reaction mixture was allowed to warm to rt over 2 h and was stirred at rt for 21 h. The solvent was removed under reduced pressure. Reverse-phase HPFC (20:80 to 100:0 MeCN:H2O) followed by lyophilization afforded 9.3 mg (72%) of 11 as an amorphous solid. The 1H NMR corresponds to a 23:1 mixture of rotamers, with the major isomer reported. [α]D23=−2.2 (c=0.6, MeOH). IR: 1221, 1498, 1549, 1643, 1755, 2937 cm−1. 1H NMR (500 MHz, MeOD): δ 0.80 (d, 3H, J=7.0 Hz), 0.92 (t, 3H, J=7.5 Hz), 0.98 (d, 3H, J=7.0 Hz), 1.02 (d, 3H, J=6.5 Hz), 1.13-1.22 (m, 1H), 1.24-1.34 (m, 1H), 1.49-1.67 (m, 4H), 1.72-1.78 (m, 2H), 1.79-1.91 (m, 2H), 2.07 (dt, 1, J=3.0, 11.5 Hz), 2.15 (s, 3H), 2.18 (s, 3H), 2.22-2.31 (m, 1H), 2.34-2.41 (m, 1H), 2.56 (dd, 1H, J=2.5, 11.0 Hz), 2.90-2.95 (m, 1H), 2.94 (s, 3H), 3.11 (s, 3H), 4.40-4.51 (br s, 1H), 4.74 (d, 1H, J=8.0 Hz), 5.70 (dd, 1H, J=2.5, 11.5 Hz), 8.14 (s, 1H). 13C NMR (125 MHz, MeOD) δ 11.2, 16.4, 20.4, 20.6, 20.9, 24.4, 25.6, 26.3, 26.4, 31.1, 31.7, 35.7, 37.7, 44.9, 54.9, 56.7, 70.6, 71.2, 125.0, 150.9, 163.9, 171.82, 171.83, 175.3, 175.6. HRMS (FAB) calcd for C27H46N5O5S (M+H): 552.3220. Found: 552.3218.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH:4]([CH2:7][CH:8]=O)[CH2:3]1.[Br-].[C:11]1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)CCC)[CH:16]=CC=C[CH:12]=1>>[CH2:7]([CH:4]1[CH2:5][CH2:6][CH:2]([OH:1])[CH2:3]1)[CH:8]=[CH:12][CH2:11][CH3:16]
Reactant: CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CCC1CCC(O)C1
Agent: [Br-]
Product: CCC=CCC1CCC(O)C1
Yield: 24.9 %

Procedure:
Using the procedure of Example 3, 5 g of 3-hydroxy cyclopentyl-acetaldehyde and 20 g of triphenyl propyl phosphonium bromide were reacted and the product was chromatographed over silica gel. Elution with a 7-3 cyclohexane-ethyl acetate mixture yielded 1.5 g of 3-(2-pentenyl)-cyclopentanol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:8][S:9](O)(=[O:11])=[O:10]>S1(CCCC1)(=O)=O>[S:9]([OH:11])(=[O:10])([C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=1)=[O:8]
Reactant: O=S(=O)(O)O
Reactant: Nc1ccccc1
Solvent: O=S1(=O)CCCC1
Product: Nc1ccc(S(=O)(=O)O)cc1

Procedure:
247.7 g (2.525 mols) of aniline are reacted in 500 ml of sulpholane with 245.3 g (2.50 mols) of 100% strength H2SO4, as described in Example 1. A yield of p-sulphanilic acid of 95.9% is obtained.
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].O.[CH3:18]S(C)=O>>[C:3]([O:7][C:8]([N:10]1[CH2:11][CH2:12][C:13]2([O:16][CH2:18]2)[CH2:14][CH2:15]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CS(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.5 %

Procedure:
A stirred solution of 60% aqueous sodium hydroxide solution (117 mg, 2.92 mmol) in dimethyl sulfoxide (2 ml) was added with trimethyl sulfoxinium iodide (627 mg, 2.79 mmol) under a nitrogen atmosphere. The mixture was stirred for 45 minutes in ice-water bath, added slowly with 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (500 mg, 2.5 mmol) while maintaining the temperature below 10° C. Upon completion of the addition, the mixture was stirred for 5 minutes in the ice-water bath and stirred for another 2 hours at 25° C. in an oil bath. The resulting mixture was added with cold water (20 ml) and extracted with ethyl ether (20 ml×3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1-oxa-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester (479 mg, 85.5%) as a white solid.