Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[C:32]([C:36]1[CH:41]=[CH:40][C:39]([S:42]([NH:45][C:46]2[N:51]=[C:50]([C:52](O)=[O:53])[N:49]=[C:48]([O:55][CH2:56][CH2:57][OH:58])[C:47]=2[O:59][C:60]2[CH:65]=[CH:64][CH:63]=[C:62]([O:66][CH3:67])[CH:61]=2)(=[O:44])=[O:43])=[CH:38][CH:37]=1)([CH3:35])([CH3:34])[CH3:33]>C(#N)C>[C:26]1([NH:25][C:52]([C:50]2[N:49]=[C:48]([O:55][CH2:56][CH2:57][OH:58])[C:47]([O:59][C:60]3[CH:65]=[CH:64][CH:63]=[C:62]([O:66][CH3:67])[CH:61]=3)=[C:46]([NH:45][S:42]([C:39]3[CH:40]=[CH:41][C:36]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:37][CH:38]=3)(=[O:43])=[O:44])[N:51]=2)=[O:53])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1ccccc1
Reactant: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)nc(C(=O)O)nc2OCCO)c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)nc(C(=O)Nc3ccccc3)nc2OCCO)c1

Procedure:
0.2 ml of Hunig base, 0.052 g of bis-(2-oxo-3-oxazolidinyl)-phosphinic acid chloride and 0.01 ml of aniline were added to a solution of 0.053 g of 6-(4-tert.butyl-phenylsulphonylamino)-4-(2-hydroxy-ethoxy)-5-(3-methoxy-phenoxy)-pyrimidine-2-carboxylic acid in 5 ml of acetonitrile. After 3 hours the reaction mixture was evaporated and partitioned between ethyl acetate and water. The organic phase was dried and evaporated, and the residue purified over silica gel with chloroform. There was obtained 0.032 g of 6-(4-tert.butyl-phenylsulphonylamino)-4-(2-hydroxy-ethoxy)-5-(3-methoxy-phenoxy)-pyrimidine-2-carboxylic acid phenylamide, m.p. 143° C., MS: (M-H)- 591.
Reaction SMILES: S(Cl)(Cl)=O.[F:5][CH:6]([F:26])[O:7][C:8]1[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=1)[C:11]([NH:13][C:14]1[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:16]([OH:18])=[O:17])=O>ClCCCl>[F:5][CH:6]([F:26])[O:7][C:8]1[CH:9]=[C:10]([C:11]2[O:17][C:16](=[O:18])[C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[N:13]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: O=C(Nc1ccccc1C(=O)O)c1cccc(OC(F)F)c1
Solvent: O=S(Cl)Cl
Solvent: ClCCCl
Product: O=c1oc(-c2cccc(OC(F)F)c2)nc2ccccc12
Reaction time: 4 h

Procedure:
25 parts by weight of 3-difluoromethoxybenzoyl chloride and 12.2 parts by weight of triethylamine are added over 15 minutes, from 2 separate feeds, to a stirred mixture of 16.6 parts by weight of anthranilic acid in 360 parts by weight of 1,2-dichloroethane at 25°-30° C. After stirring for 2 hours at 25° C., the reaction mixture is extracted with 0.5 N hydrochloric acid and with water. The organic phase is then extracted with four times 100 parts of 0.5 N sodium hydroxide solution, and the extracts are stirred into dilute hydrochloric acid. After filtration and drying, 30.4 parts by weight, corresponding to 82% of theory, of N-(3-difluoromethoxybenzoyl)-anthranilic acid of melting point 186°-191° C. are obtained. 8.33 Parts by weight of thionyl chloride are introduced into a stirred mixture of 18 parts by weight of N-(3-difluoromethoxybenzoyl)-anthranilic acid in 250 parts by weight of 1,2-dichloroethane at 25° C.; the mixture is then stirred for 4 hours under reflux. When it has cooled, the reaction mixture is extracted with 100 parts by volume of ice-water and 100 parts by volume of 0.5 N sodium hydroxide solution and is chromatographed over neutral aluminum oxide. 12 parts by weight, corresponding to 71% of theory, of 2-(3'-difluoromethoxy-phenyl)-3,1-benzoxazin-4-one, of melting point 84°-87° C., are obtained.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3.[C:18]([NH:28][CH2:29][CH2:30][C:31](O)=[O:32])([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[C:18]([NH:28][CH2:29][CH2:30][C:31]([NH:1][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3)=[O:32])([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CN)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CNC(=O)CCNC(=O)OCc1ccccc1)C2
Temperature: 25 °C
Reaction time: 48 h
Yield: 46.1 %

Procedure:
2-Aminomethyl-5-methyl-2,3,6,7-tetrahydrofuro-[2,3-f]quinoline-7-one (3.00 g, 13.0 mmol) was dissolved in dimethylformamide (200 ml). To this solution, N-carbobenzyloxy-β-alanine (4.40 g, 19.5 mmol), WSC-HCl (3.50 g, 19.5 mmol), and HOBT (1.00 g, 7.2 mmol) were added, and the mixture was stirred at room temperature for 48 hours. The reaction mixture was condensed under reduced pressure, and the residue was subjected to extraction using a solvent mixture (chloroform--methanol =4:1) combined with 1N-HCl. The organic phase was washed with saturated aqueous NaCl solution, followed by drying and condensing under reduced pressure. The resultant residue was recrystallized from chloroform--methanol--ether. As a result, 2.61 g of the title compound was obtained as colorless powdery crystals (46.2%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]3[CH2:15][NH:14][CH2:13][CH2:12][NH:11]3)=[CH:7][C:6]=2[CH:16]=1.Cl[C:18]1[CH:27]=[C:26]2[C:21]([C:22](=[O:33])[C:23]([C:30]([OH:32])=[O:31])=[CH:24][N:25]2[CH2:28][CH3:29])=[CH:20][C:19]=1[F:34]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]3[NH:11][CH2:12][CH2:13][N:14]([C:18]4[CH:27]=[C:26]5[C:21]([C:22](=[O:33])[C:23]([C:30]([OH:32])=[O:31])=[CH:24][N:25]5[CH2:28][CH3:29])=[CH:20][C:19]=4[F:34])[CH2:15]3)=[CH:7][C:6]=2[CH:16]=1
Reactant: Clc1ccc2oc(C3CNCCN3)cc2c1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(c4cc5cc(Cl)ccc5o4)C3)cc21

Procedure:
A 1.45 g portion of 2-(5-chloro-2-benzofuranyl)piperazine was added to 5 ml of pyridine. A 540 mg portion of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was added and the mixture was heated in a sealed bottle, under argon, at 130°-135° C. for 18 hours, then cooled in an ice bath. The solid was collected, triturated with cold pyridine, dichloromethane, ether and dimethylformamide, giving 180 mg of the desired product, mp 262°-263° C.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]3[C:21](=[O:22])[C:20]4=[CH:23][S:24][CH:25]=[C:19]4[NH:18][C:17]3=[O:26])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[C:29](Cl)(=[O:31])[CH3:30].C(N(CC)CC)C>C(Cl)Cl>[C:29]([N:18]1[C:19]2=[CH:25][S:24][CH:23]=[C:20]2[C:21](=[O:22])[N:16]([CH2:15][CH2:14][N:11]2[CH2:12][CH2:13][CH:8]([C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:28][CH:27]=3)[CH2:9][CH2:10]2)[C:17]1=[O:26])(=[O:31])[CH3:30]
Reactant: O=C(c1ccc(F)cc1)C1CCN(CCn2c(=O)[nH]c3cscc3c2=O)CC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)n1c(=O)n(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c(=O)c2cscc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The title compound was prepared by suspending the 3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]thieno[3,4-d]pyrimidine-2,4-dione (2.0 g, 5 mmol) of Example 10 in CH2Cl2 and treating it with acetyl chloride (469 mg, 6 mmol) and triethylamine (1 equivalent). After stirring at room temperature for 24 hours, the organic phase was washed with water and brine and dried over MgSO4. Solvent removal produced a crude product which was purified by flash silica gel chromatography using EtOAc/hexane (1/1). The title compound was crystallized from CH2Cl2 /hexane to give a white solid (337 mg, 15% yield), mp 150°-151° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[CH3:13][NH:14][S:15]([C:18]1[CH:23]=[CH:22][C:21](F)=[CH:20][CH:19]=1)(=[O:17])=[O:16].C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[CH3:13][NH:14][S:15]([C:18]1[CH:19]=[CH:20][C:21]([N:10]2[CH2:9][CH2:8][N:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:12][CH2:11]2)=[CH:22][CH:23]=1)(=[O:16])=[O:17]
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: CNS(=O)(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CNS(=O)(=O)c1ccc(N2CCN(c3ccncc3)CC2)cc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 6.9 %

Procedure:
A mixture of 1-(4-pyridyl)piperazine (0.86 g), N-methyl-4-fluorobenzenesulphonamide (1.00 g) and potassium carbonate (2.00 g) in N-methylpyrrolidone was stirred at 100° C. for 24 hours and then evaporated. The residue was partitioned between dichloromethane and 2N hydrochloric acid. The acid layer was washed with dichloromethane, filtered and made basic with sodium bicarbonate solution. The mixture was extracted several times with chloroform, and the combined extracts were washed with water, dried over magnesium sulphate and evaporated. The residue was crystallised from ethanol/ethyl acetate to give the title compound (0.12 g), m.p. 204°-206° C. Found: C,57.55; H,6.13; N,16.62. C16H20N4O2S requires: C,57.81; H,6.06; N,16.85%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]([C:28]1[NH:29][CH:30]=[CH:31][N:32]=1)[CH2:9][C:10]1[CH:18]=[C:17]([CH3:19])[C:16]2[C:12](=[CH:13][N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:15]=2)[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[F:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39]Br)=[CH:37][CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][N:32]2[CH:31]=[CH:30][N:29]=[C:28]2[CH:8]([NH:7][C:6](=[O:33])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:9][C:10]2[CH:18]=[C:17]([CH3:19])[C:16]3[C:12](=[CH:13][N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:27])[CH3:26])[N:15]=3)[CH:11]=2)=[CH:37][CH:36]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: Cc1cc(CC(NC(=O)OC(C)(C)C)c2ncc[nH]2)cc2cn(COCC[Si](C)(C)C)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(CC(NC(=O)OC(C)(C)C)c2nccn2Cc2ccc(F)cc2)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
tert-Butyl-1-(1H-imidazol-2-yl)-2-(7-methyl-2-[{2-[trimethylsilyl]ethoxy}methyl]-2H-indazol-5-yl)ethylcarbamate (34.4 mg, 0.073 mmol), 4-fluorobenzyl bromide (10.5 μL, 0.084 mmol, 1.05 equiv), and potassium carbonate (25.0 mg, 0.18 mmol) were combined in dimethylformamide (1.0 mL). After stirring at room temperature for 16 h, the solvents were removed and the residue purified by column chromatography to afford 28.8 mg (68%). Mass spec.: 580.42 (MH)+.
Reaction SMILES: [Na].[CH3:2][NH:3][C:4](=[O:6])[CH3:5].[CH3:7][CH:8]=[CH:9][SiH:10](Cl)Cl>C1(C)C=CC=CC=1>[CH3:7][CH:8]=[CH:9][SiH:10]([N:3]([CH3:2])[C:4](=[O:6])[CH3:5])[N:3]([CH3:2])[C:4](=[O:6])[CH3:5]
Reactant: CNC(C)=O
Reactant: CC=C[SiH](Cl)Cl
Agent: [Na]
Solvent: Cc1ccccc1
Product: CC=C[SiH](N(C)C(C)=O)N(C)C(C)=O

Procedure:
The amidosilanes can be prepared, by the following illustration: mixing a sodium salt of N-methylacetamide with methylvinyldichlorosilane in an inert organic solvent such as toluene, filtering the by-produced sodium chloride from the toluene-product solution and thereafter removing the toluene by vacuum distillation to obtain the product, methylvinyldi-(N-methylacetamido)silane.
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH3:11])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=1)[NH2:16]>CN1CCCC1=O.C(=O)([O-])O.[Na+]>[Cl:12][C:13]1[CH:14]=[C:15]([NH:16][C:2]2[C:3]3[N:10]([CH3:11])[CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=1
Reactant: Cn1ccc2ncnc(Cl)c21
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cn1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c21
Temperature: 140 °C
Reaction time: 1.5 h
Yield: 53 %

Procedure:
To a solution of 4-chloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidine (100 mg) in 1-methyl-2-pyrrolidone (1.0 mL) was added 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (225 mg), and the mixture was heated to 140° C. and stirred for 1.5 hrs. The reaction mixture was allowed to cool to room temperature, diluted with 5% aqueous sodium hydrogen carbonate solution (25 mL), and extracted with ethyl acetate (30 mL×3). The organic layer washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent:hexane/ethyl acetate=95/5→0/100). The object fraction was concentrated under reduced pressure. The residue was recrystallized from a mixed solvent of diisopropyl ether and chloroform, collected by filtration and dried under reduced pressure to give the title compound (121 mg) as a pale-purple powder crystals.
Reaction SMILES: [F:1][C:2]1([F:23])[CH2:4][CH:3]1[CH2:5][N:6]1[CH2:10][CH2:9][N:8]([C:11]2[S:12][C:13]([C:17]([O:19]CC)=[O:18])=[C:14]([CH3:16])[N:15]=2)[C:7]1=[O:22].O.[OH-].[Li+].Cl>O1CCCC1.O>[F:23][C:2]1([F:1])[CH2:4][CH:3]1[CH2:5][N:6]1[CH2:10][CH2:9][N:8]([C:11]2[S:12][C:13]([C:17]([OH:19])=[O:18])=[C:14]([CH3:16])[N:15]=2)[C:7]1=[O:22]
Reactant: CCOC(=O)c1sc(N2CCN(CC3CC3(F)F)C2=O)nc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(N2CCN(CC3CC3(F)F)C2=O)sc1C(=O)O
Temperature: 25 °C
Yield: 68.9 %

Procedure:
To a solution of ethyl 2-(3-((2,2-difluorocyclopropyl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylate (0.77 g, 2.24 mmol) in tetrahydrofuran (40.0 mL) was added lithium hydroxide monohydrate (0.27 g, 11.2 mmol) in water (2.0 mL). The reaction mixture was heated at reflux for 16 h, cooled to an ambient temperature, then acidified with a solution of hydrochloric acid (3.0 N, 10.0 mL). The solvent was removed in vacuo to dryness and the precipitate was filtered, dried to afford the title compound as a colourless solid (0.49 g, 68%): mp 210-215° C.; 1H NMR (300 MHz, DMSO-d6) δ 12.79 (br, 1H), 3.99 (t, J=9.0 Hz, 2H), 3.64-3.48 (m, 3H), 3.19-3.12 (m, 1H), 2.46 (s, 3H), 2.02-1.88 (m, 1H), 1.67-1.55 (m, 1H), 1.37-1.26 (m, 1H); 13C NMR (75 MHz, DMSO-d6) δ 164.0, 159.8, 156.0, 155.2, 115.2, 114.9 (t), 42.4, 42.1, 41.1 (d), 20.3 (t, 2JC-F=43 Hz), 17.4, 14.9 (t, 2JC-F=43 Hz); MS (ES+) m/z 318.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[C:14]2[CH2:15][CH:16]([CH2:18][NH2:19])[O:17][C:13]=2[CH:12]=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[C:14]2[CH2:15][CH:16]([CH2:18][NH:19][C:30](=[O:31])[O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[O:17][C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: Cc1cccc(C)c1-c1cccc2c1CC(CN)O2
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(C)c1-c1cccc2c1CC(CNC(=O)OCc1ccccc1)O2
Yield: 94.8 %

Procedure:
Treatment of (±)-1-[4-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (1.2 g, 4.14 mmol) with diisopropylethylamine (0.803 g, 6.21 mmol) followed by benzyl chloroformate (0.848 g, 4.97 mmol) generally according to the procedure described for Intermediate 12 provided 1.52 g (95%) of (±)-benzyl {[4-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate as a colorless oil. Anal. calcd. for C25H25NO3: C, 77.49; H, 6.5; N, 3.61. Found: C, 76.66; H, 6.31; N, 3.44. Chiral HPLC separation of (±)-benzyl {[4-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (Chiralcel OD, ethanol) provided two fractions. Fraction 1 (Rt=4.818 min, Chiralcel OD, ethanol); Fraction 2 (Rt=6.985 min, Chiralcel OD, ethanol).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4](O)=[O:5].C[N:18](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH2:18])=[O:5]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)S(=O)(=O)c1ccc(Br)c(C(=O)O)c1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)c1ccc(Br)c(C(N)=O)c1
Reaction time: 1 h
Yield: 58.2 %

Procedure:
2-Bromo-5-(isopropylsulfonyl)benzoic acid (Preparation 23, 623 mg, 2.03 mmol) and HATU (925 mg, 2.44 mmol) were dissolved in DMF (10 mL) and diisopropylethylamine (1.74 mL, 10.0 mmol) was added dropwise to the mixture. The mixture was stirred for 1 hour and then partitioned between water (50 mL) and EtOAc (25 mL). The aqueous layer was extracted with EtOAc (2×10 mL) and the combined organic extracts were washed with saturated brine (20 mL) and dried (MgSO4). The solvent was removed under reduced pressure to leave a pale yellow solid. This material was purified by silica gel column chromatography eluting with MeOH/CH2Cl2 3:97 to give the title compound as a white solid 59% yield, 362 mg.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5](Cl)(=[O:8])[CH2:6][CH3:7].[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=1>CCCCCC>[C:5]([CH:10]1[CH2:15][CH2:14][CH:13]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:12][CH2:11]1)(=[O:8])[CH2:6][CH3:7]
Reactant: CCC(=O)Cl
Reactant: C1=CCCCC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCC
Product: CCC(=O)C1CCC(c2ccccc2)CC1
Temperature: -60 °C
Reaction time: 3.5 h
Yield: 120.1 %

Procedure:
In a 2,000 mL (inside volume) three-necked flask equipped with a reflux condenser, 600 mL of hexane and 160 g of anhydrous AlCl3 were mixed and cooled to −60° C., to which were then added 110 g of propionyl chloride and 82.2 g of cyclohexene. The temperature of the mixture was raised to −40° C. while stirring the mixture for 3.5 h. The solvent was then removed by decantation and the residues were washed with cold hexane. The thus obtained 1-propionyl-2-chlorocyclohexane was added with 500 mL of benzene and an additional amount (60 g) of AlCl3. The mixture was then stirred at 45° C. for 3.5 h. The reaction liquid was cooled to room temperature and then poured onto ice. An oil layer was separated and concentrated to obtain 130 g of (4-propionylcyclohexyl)benzene. This was mixed with 1,200 mL of diethylene glycol, 225 g of potassium hydroxide and 310 g of 80% by mass hydrazine hydrate. After refluxing the resulting mixture for 1 h, the contents in the flask were heated to 220° C. to distil off volatile matters therefrom. The mixture was further refluxed for 1 h, cooled to room temperature and then poured in water. An oil layer was then extracted with hexane, washed with water, 5% by mass sulfuric acid and 80% by mass sulfuric acid and then dried. The obtained oil layer was purified by distillation to obtain 85 g of (4-n-propylcyclohexyl)-benzene. As a result of gas chromatography, it was confirmed that the (4-n-propylcyclohexyl)benzene purity was 98.0% and the cis/trans molar ratio was 1.36.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([O:49][CH3:50])=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44].C(=O)([O-])[O-].[K+].[K+].Cl.[N:58]1[CH:63]=[CH:62][CH:61]=[C:60]([CH2:64][Cl:65])[CH:59]=1>>[ClH:65].[OH:24][C@H:22]1[C@:21]2([O:25][CH3:26])[C@@:8]([OH:45])([C:9](=[O:44])[C:10]3[C:19]([C:20]2=[O:27])=[C:18]([OH:28])[C:17]2[C:16](=[O:29])[CH:15]=[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)[C:13](=[O:43])[C:12]=2[CH:11]=3)[C:7]2[C:2]([O:1][CH2:64][C:60]3[CH:59]=[N:58][CH:63]=[CH:62][CH:61]=3)=[C:3]([C:47]([O:49][CH3:50])=[O:48])[C:4]([CH3:46])=[CH:5][C:6]=2[CH2:23]1
Reactant: ClCc1cccnc1
Reactant: COC(=O)c1c(C)cc2c(c1O)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=O)C=C(N[C@H]1O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]1OC)C4=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1c(C)cc2c(c1OCc1cccnc1)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=O)C=C(N[C@H]1O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]1OC)C4=O
Yield: 31.5 %

Procedure:
Following General Procedure: Method B using (6R,6aS,14aR)-methyl 1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (35 mg, 0.050 mmol), potassium carbonate (21 mg, 0.15 mmol) and 3-picolyl chloride hydrochloride (25 mg, 0.15 mmol), the product was purified by preparative TLC (silica gel, 95:5 dichloromethane/methanol) and converted to hydrochloride to afford (6R,6aS,14aR)-methyl 6,8,14a-trihydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-1-(pyridin-3-ylmethoxy)-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate hydrochloride (13 mg, 31%) as an orange-red solid: 1H NMR (500 MHz, CDCl3) δ 14.21 (s, 1H), 8.79 (br s, 2H), 8.26 (d, J=4.1 Hz, 1H), 7.87 (br s, 1H), 7.41 (s, 1H), 6.92 (s, 1H), 6.89 (br s, 1H), 5.85 (s, 1H), 5.12 (d, J=11.2 Hz, 1H), 5.05 (d, J=11.3 Hz, 1H), 4.98 (br s, 1H), 4.66 (br s, 1H), 4.39 (br s, 1H), 3.85 (s, 3H), 3.81-3.74 (m, 1H), 3.72 (s, 3H), 3.65 (dd, J=19.3, 7.3 Hz, 1H), 3.60 (s, 3H), 3.43 (s, 1H), 3.40 (s, 3H), 3.36-3.31 (m, 1H), 3.14 (t, J=9.0 Hz, 1H), 2.51 (br s, 1H), 2.24 (s, 3H), 1.36 (d, J=6.1 Hz, 3H); MS (ESI+) m/z 789 (M+H); HPLC >99% (AUC), tR 12.34 min.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7](OC)=[O:8])=[CH:5][CH:4]=1.O.[NH2:14][NH2:15]>C(O)C>[OH:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([NH:14][NH2:15])=[O:8])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(CO)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)c1ccc(CO)cc1
Reaction time: 2 h

Procedure:
To a solution of 1.66 g (10.0 mmol) of methyl 4-hydroxymethylbenzoate (19) in 20 ml of ethanol was added 3.0 g (60 mmol) of hydrazine hydrate. The mixture was stirred for 2 h, an additional 3.0 g hydrazine hydrate was added and the mixture was allowed to stand overnight. The precipitate was filtered, washed twice with ethanol and dried in vacuo to yield 20 as a white powder. (Literature references for compound: Yaroshenko, V. V.; Grekov, A. P.; Tkach, V. P.; Yakovenko, A. G. Inst. Khim. Vysokomol. Soedin. Sint. Fiz.-Khim. Polim. 1975, 17 97; and Galiano, R.; Joaquin, A.; Soria, A. (Instituto de Investigacion y Desarrollo Quimico Biologico, S. A., Spain). Span. (1993), 24 pp. CODEN: SPXXAD ES 2039161 A1 19930816)
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:4]=2[CH:3]=1.O.[NH2:15][NH2:16]>>[NH:15]([C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:4]=2[CH:3]=1)[NH2:16]
Reactant: Clc1cc2c(nn1)CCCCCC2
Reactant: NN
Solvent: O
Product: NNc1cc2c(nn1)CCCCCC2

Procedure:
11.7 g of 3-chloro-5,6,7,8,9,10-hexahydrocycloocta[c]pyridazine and 60 cc of hydrazine hydrate are reacted in accordance with the process described in Example 1. The orange-coloured solution is completely concentrated, and the remaining crystalline crude title compound is washed with water. M.P. 145°-148° (decomp., from absolute ethanol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.[S:12]1[CH:16]=[CH:15][C:14]2[CH:17]=[CH:18][CH:19]=[CH:20][C:13]1=2>>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5][C:16]1[S:12][C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=2[CH:15]=1
Reactant: COc1ccc(C=O)cc1Br
Reactant: c1ccc2sccc2c1
Product: COc1ccc(Cc2cc3ccccc3s2)cc1Br

Procedure:
Preparation was performed in a similar manner as in Preparation Example 4 using 3-bromo-4-methoxybenzaldehyde and benzo[b]thiophene.