Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:6][NH:5][C:4](=[O:7])[C:3]=1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1.[CH3:16][C:17]1[NH:21][N:20]=[C:19]([O:22][C@@H:23]2[O:40][C@H:39]([CH2:41][O:42][C:43](=[O:45])[CH3:44])[C@@H:34]([O:35][C:36](=[O:38])[CH3:37])[C@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@H:24]2[O:25][C:26](=[O:28])[CH3:27])[C:18]=1[CH2:46][C:47]1[CH:52]=[CH:51][C:50]([CH3:53])=[CH:49][CH:48]=1>>[CH3:16][C:17]1[NH:21][N:20]=[C:19]([O:22][C@@H:23]2[O:40][C@H:39]([CH2:41][O:42][C:43](=[O:45])[CH3:44])[C@@H:34]([O:35][C:36](=[O:38])[CH3:37])[C@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@H:24]2[O:25][C:26](=[O:28])[CH3:27])[C:18]=1[CH2:46][C:47]1[CH:48]=[CH:49][C:50]([CH3:53])=[CH:51][CH:52]=1.[C@@H:23]1([O:7][C:4]2[C:3]([CH2:8][C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=3)=[C:2]([CH3:1])[NH:6][N:5]=2)[O:40][C@H:39]([CH2:41][OH:42])[C@@H:34]([OH:35])[C@H:29]([OH:30])[C@H:24]1[OH:25]
Reactant: Cc1ccc(Cc2c(C)[nH][nH]c2=O)cc1
Agent: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C)c2Cc2ccc(C)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: Cc1ccc(Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)n[nH]c2C)cc1

Procedure:
5-Methyl-4-[(4-methylphenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole was prepared in a similar manner to that described in Example 15 using 1,2-dihydro-5-methyl-4-[(4-methylphenyl)methyl]-3H-pyrazol-3-one instead of 1,2-dihydro-4-[(4-isopropoxyphenyl)methyl]-5-methyl-3H-pyrazol-3-one. Then, the title compound was prepared in a similar manner to that described in Example 35 using 5-methyl-4-[(4-methylphenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole instead of 4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole.
Reaction SMILES: ClCCl.Cl.[CH3:5][C:6]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][C:7]=1[NH2:8].[C:20](OC(=O)C)(=[O:22])[CH3:21]>N1C=CC=CC=1>[CH3:5][C:6]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:9][C:7]=1[NH:8][C:20](=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(Oc2ccccc2)cc1N
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(Oc2ccccc2)ccc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To dichloromethane 5.0 mL solution of 2-methyl-5-phenoxyaniline hydrochloride 0.50 g were added pyridine 0.34 mL and acetic anhydride 0.24 mL under ice cooling, and it was stirred at room temperature for 6 hours and 30 minutes. The solvent was removed under reduced pressure,1.0 mol/L hydrochloric acid and ethyl acetate were added to the obtained residue. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after sequential washing with saturated sodium hydrogen carbonate aqueous solution and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Fuji SILYSIA Chemical Ltd., PSQ100B(spherical type), eluent; hexane:ethyl acetate=2:1] to give N-(2-methyl-5-phenoxyphenyl)acetamide 0.44 g of white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:16][CH:17]=O)=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:8].O.[NH2:20][NH2:21]>CO>[NH2:20][N:21]1[C:7]([OH:8])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:15]=2)[N:16]=[CH:17]1
Reactant: NN
Reactant: O=CNc1ccc(Br)cc1C(=O)c1ccccn1
Solvent: O
Solvent: CO
Product: NN1C=Nc2ccc(Br)cc2C1(O)c1ccccn1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
To a solution of 11.2 g. of the 2-(5-bromo-2-formamidobenzoyl)pyridine prepared in the experiment (a) in 50 ml. of methanol is added 10 ml. of hydrazine hydrate (100 %). The resulting mixture is heated at 60° C for several minutes and thereafter left to stand at room temperature for 5 hours. The resulting precipitate is collected by filtration and washed with methanol and ether and dried to give 3-amino-6-bromo-4-hydroxy-4-(2-pyridyl)-3,4-dihydroquinazoline as colorless granules melting at 185° to 187° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([CH:6]=[C:7]([CH3:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[Br:19]Br.CC1C(C)=NC2C(C=1)=CC=CC=2>ClC1C=CC=CC=1Cl.O>[Br:19][CH2:12][C:11]1[C:2]([Cl:1])=[CH:3][CH:4]=[C:5]2[C:10]=1[N:9]=[CH:8][C:7]([CH3:13])=[CH:6]2
Reactant: Cc1cnc2c(C)c(Cl)ccc2c1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: Cc1cc2ccccc2nc1C
Agent: [Na+]
Solvent: O
Solvent: Clc1ccccc1Cl
Product: Cc1cnc2c(CBr)c(Cl)ccc2c1

Procedure:
9.6 g of 7-chloro-3,8-dimethylquinoline are dissolved in 850 g of 1,2-dichlorobenzene, 6.2 g of sodium acetate, dissolved in 150 ml of water, and then 8 g of bromine are added, and the mixture is exposed to a 150 watt low pressure mercury lamp for from 5 to 6 hours at 15° C. The yield, determined chromatographically, is 80% of theory, based on converted dimethylquinoline. The selectivity of the reaction is 88% at a conversion of 91%. Table 1 sumarizes the result of varying the reaction conditions.
Reaction SMILES: BrC1C=CC=C2C=1C(O)(C1C(O)=CC3OCOC=3C=1)C(=O)N2CCCCC.[CH2:28]([O:35][CH2:36][CH2:37][CH2:38][N:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:41](O)([C:48]2[C:56]([OH:57])=[CH:55][C:51]3[O:52][CH2:53][O:54][C:50]=3[CH:49]=2)[C:40]1=[O:59])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([O:35][CH2:36][CH2:37][CH2:38][N:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]([C:48]2[C:56]([OH:57])=[CH:55][C:51]3[O:52][CH2:53][O:54][C:50]=3[CH:49]=2)[C:40]1=[O:59])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C1N(CCCOCc2ccccc2)c2ccccc2C1(O)c1cc2c(cc1O)OCO2
Agent: CCCCCN1C(=O)C(O)(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Product: O=C1C(c2cc3c(cc2O)OCO3)c2ccccc2N1CCCOCc1ccccc1

Procedure:
Following the procedure as described in PREPARATION 1D, and making non-critical variations to replace 4-bromo-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with 1-[3-(benzyloxy)propyl]-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained (92%): 1H NMR (300 MHz, CDCl3) δ 7.42-6.95 (m, 9H), 6.56 (s, 1H), 6.24 (s, 1H), 5.86 (ABq, 1H), 5.81(ABq, 1H), 4.99 (s, 1H), 4.42 (s, 2H), 3.91-3.76 (m, 2H), 3.46 (t, 2H), 2.03-1.93 (m, 2H); MS (ES+) m/z 418.3 (M+1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Cl:6][CH:7]([C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1)[CH3:8].Cl>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:13]([C:12]1[CH:16]=[CH:17][C:9]([CH:7]([Cl:6])[CH3:8])=[CH:10][CH:11]=1)=[O:14]
Reactant: c1ccsc1
Reactant: CC(Cl)c1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Product: CC(Cl)c1ccc(C(=O)c2cccs2)cc1

Procedure:
To a stirred and cooled (0° C) mixture of 4.2 parts of thiophene, 13 parts of stannic chloride and 40 parts of methylene chloride is added dropwise a solution of 10.2 parts of p-(1-chloroethyl)benzoyl chloride in 20 parts of methylene chloride (exothermic reaction with gaseous hydrogen chloride evolution). After stirring for 2h. 30 the reaction mixture is poured onto a mixture of crushed ice and hydrochloric acid solution. The product is extracted with methylene chloride. The organic layer is separated, washed with alkaline water, dried and evaporated. The solid residue is triturated with hot petroleum-ether. The product is filtered off and crystallized from ethanol, yielding p-(1-chloroethyl)phenyl 2-thienyl ketone.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C@H:7]2[CH2:11][CH2:10][CH2:9][NH:8]2)[S:5][CH:6]=1.[OH:12][CH2:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:22]=1)[C:17](O)=[O:18].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl.C(Cl)(Cl)Cl>[OH:18][CH2:17][C:16]1[CH:20]=[C:21]([CH:22]=[C:14]([C:13]([N:8]2[CH2:9][CH2:10][CH2:11][C@@H:7]2[C:4]2[S:5][CH:6]=[C:2]([CH3:1])[N:3]=2)=[O:12])[CH:15]=1)[C:23]([O:25][CH3:26])=[O:24]
Reactant: Cc1csc([C@H]2CCCN2)n1
Reactant: COC(=O)c1cc(CO)cc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1cc(CO)cc(C(=O)N2CCC[C@@H]2c2nc(C)cs2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.7 %

Procedure:
A solution of (R)-4-methyl-2-(pyrrolidin-2-yl)thiazole (511 mg, 3.037 mmol) and 3-(hydroxymethyl)-5-(methoxycarbonyl)benzoic acid (702.5 mg, 3.34 mmol) in DCM (50 mL) were added diisopropylthylamine (3 mL, excess), HOBt (410 mg, 3.34 mmol) and EDCI (754.1 mg, 3.948 mmol). The resulting solution was stirred at room temperature for overnight. The reaction mixture was diluted with chloroform, washed with sodium bicarbonate saturated aqueous solution and separated. The aqueous layer was extracted one more time with chloroform. The combined organic layers were concentrated to give a residue, which was purified with flash chromatography to produce the desired compound (840 mg). 1H NMR (300 MHz, CDCl3), d: 8.011 (m, 1.5H), 7.876 (br, 0.5H), 7.683 (m, 1H), 6.749 (m, 1H), 5.579 (m, 0.7H), 5.061 (br, 0.3H), 4.641 (br, 1.2H), 4.525 (br, 0.8H), 3.875 (m, 3H), 3.692 (m, 1H), 3.457 (m, 1H), 2.345 (m, 5H), 2.034 (m, 2H).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][C:35]([NH2:42])([CH2:38][C:39]([OH:41])=[O:40])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C[O-].[Na+].Cl>O.CC(N(C)C)=O>[C:25]([O:29][C:30]([N:32]1[CH2:33][CH2:34][C:35]([CH2:38][C:39]([OH:41])=[O:40])([NH:42][C:3]([C:5]2[N:6]=[C:7]([C:23]#[N:24])[C:8]3[C:13]([C:14]=2[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:9]=3)=[O:4])[CH2:36][CH2:37]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCC(N)(CC(=O)O)CC1
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CC(=O)O)(NC(=O)c2nc(C#N)c3cc(Oc4ccccc4)ccc3c2O)CC1
Temperature: 150 °C
Yield: 51.6 %

Procedure:
A 20-mL scintillation vial was charged with 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (100 mg, 0.31 mmol), 4-amino-4-carboxymethyl-piperidine-1-carboxylic acid tert-butyl ester (322 mg, 1.25 mmol), NaOMe (59 mg, 1.09 mmol) and dimethylacetamide (3 mL). It was close-capped and heated in a 150° C. oil bath for 4 h. Reaction mixture was diluted with water (70 mL) and acidified by 1 N HCl to pH=4-5. Precipitate was collected, rinsed with water and dried. Crude product was purified by silica gel chromatography, eluting with 10-100% EtOAc/hexanes, to provide the title compound 92 mg (0.16 mmol) in 54% yield. LC-MS ESI−: 545.08 (M−1)−.
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:40]=[CH:39][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([N:28]4[CH2:33][CH2:32][CH:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:30][CH2:29]4)[S:25][C:26]=3[CH3:27])=[C:18]([O:41][CH3:42])[CH:17]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1)=O.[CH2:43](P(=O)(OCC)OCC)[P:44](=[O:51])([O:48][CH2:49][CH3:50])[O:45][CH2:46][CH3:47].CN(C)C=O.[H-].[Na+]>O>[CH2:46]([O:45][P:44](/[CH:43]=[CH:1]/[C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:40]=[CH:39][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([N:28]4[CH2:29][CH2:30][CH:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:32][CH2:33]4)[S:25][C:26]=3[CH3:27])=[C:18]([O:41][CH3:42])[CH:17]=2)=[N:5][N:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=1)([O:48][CH2:49][CH3:50])=[O:51])[CH3:47]
Reactant: CCOC(=O)C1CCN(c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4C=O)cc3OC)c(C)s2)CC1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/P(=O)(OCC)OCC)cc3OC)c(C)s2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.8 %

Procedure:
To a mixture of ethyl 1-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-thiazol-2-yl}piperidine-4-carboxylate (0.30 g), tetraethyl methylenediphosphonate (0.16 g) and N,N-dimethylformamide (10 mL) was added sodium hydride (60% in oil, 25 mg) at room temperature. The mixture was stirred at room temperature for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give ethyl 1-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-thiazol-2-yl]piperidine-4-carboxylate as a colorless oil (0.29 g, yield 78%) from a fraction eluted with ethyl acetate-hexane (9:1, v/v).
Reaction SMILES: O[C:2]1([CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([I:11])[CH:9]=2)[NH:4][C:3]1=O.B(F)(F)F.CCOCC>COCCOC>[I:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][CH:3]=[C:2]2[CH2:13][C:14]([N:16]([CH3:17])[CH3:18])=[O:15]
Reactant: CN(C)C(=O)CC1(O)C(=O)Nc2ccc(I)cc21
Agent: FB(F)F
Solvent: COCCOC
Solvent: CCOCC
Product: CN(C)C(=O)Cc1c[nH]c2ccc(I)cc12
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
To a suspension of 2-(5-iodo-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl)-N,N-dimethyl-acetamide (Example 6) (36.0 g, 0.1 mol) in DME (250 mL), at 20° C. boron trifluoride etherate (28.3 g, 0.2 mol) is added. Under cooling with an ice bath, borane dimethyl sulfide complex (12.0 g, 0.15 mol) is added during 10 minutes, and then the cooling bath is removed. The temperature rises slowly to 55° C., and a suspension forms at about 50° C. When the exothermic reaction has subsided, the mixture is stirred at 75° C. for another 30 minutes, and then quenched by adding 4 N NaOH (100 mL). The mixture is heated under reflux for another 30 minutes, and then filtered while still hot. Removal of the solvent on the rotavapor leads to crystallization of the product, which goes to completion on standing in the refrigerator for 12 hours. The product is filtered off, washed with cold acetone (50 mL, −20° C.) and pentane, and dried to give the title product (24.8 g, 75%) as crystals, mp.=195-200° C. 1H-NMR (DMSO-D6, 300 MHz) δ 2.80, 2.99 (2 s, 3H each, N(CH3)2); 3.69 (s, 2H, CH2); 7.19 (d, 1H, 3J=2.4 Hz, H-2); 7.21 (d, 1H, 3J=8.5 Hz, H-7); 7.32 (dd, 1H, 4J=1.7 Hz, H-6); 7.92 (d, 1H, H-4); 11.04 (br s, 1H, NH). 13C-NMR (DMSO-D6, 75 MHz) δ 31.11 (CH2); 35.70, 37.91 (N(CH3)3); 82.82 (C-5); 108.54 (C-3); 114.51 (C-7); 125.46 (C-2); 128.16 (C-4); 129.54 (C-6); 130.85 (C-9); 135.91 (C-8).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[C@H:22]([C:23]([OH:25])=[O:24])[CH2:21][C@@H:20]4[CH2:26][CH2:27][CH2:28][C@H:19]34)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:29][CH2:30][CH2:31][CH2:32][CH2:33]O.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[N:18]1([C:16]([O:15][CH2:14][CH:12]2[C:13]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6]3[C:11]2=[CH:10][CH:9]=[CH:8][CH:7]=3)=[O:17])[C@H:22]([C:23]([O:25][CH2:33][CH2:32][CH2:31][CH2:30][Cl:29])=[O:24])[CH2:21][C@@H:20]2[CH2:26][CH2:27][CH2:28][C@H:19]12
Reactant: OCCCCCl
Reactant: O=C(O)[C@@H]1C[C@@H]2CCC[C@@H]2N1C(=O)OCC1c2ccccc2-c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(OCCCCCl)[C@@H]1C[C@@H]2CCC[C@@H]2N1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 4 h
Yield: 45.3 %

Procedure:
(2S,3aS,6aS)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)octahydrocyclopenta[b]pyrrole-2-carboxylic acid (0.250 g, 0.66 mmol) and 4-chloro-1-butanol (0.1 ml, 0.99 mmol) were dissolved under nitrogen in CH2Cl2 (5 ml) and the mixture was cooled to 0° C. N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) (0.190 g, 0.99 mmol) and N,N-dimethylaminopyridine (DMAP) (0.016 g, 0.13 mmol) were added and the reaction was slowly warmed to room temperature and stirred for 4 h. Then the mixture was diluted with CH2Cl2 (10 ml) and washed with 5% aqueous NaHCO3, 5% aqueous Na2HPO4 and brine. The organic layer was dried over sodium sulphate, concentrated under reduced pressure and purified by flash chromatography (n-hexane/EtOAc 80:20 as eluent) affording the title compound as an oil (0.14 g, 45%)
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24].[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][NH2:39])[CH:33]=1>>[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:39][CH2:38][C:34]3[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=3)=[O:19])=[CH:20][CH:21]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)(=[O:25])=[O:24]
Reactant: NCc1cccnc1
Reactant: Cc1oc(-c2ccc(C(=O)O)cc2)nc1CS(=O)(=O)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Product: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)c1ccccc1
Yield: 48.4 %

Procedure:
Method E. Reaction of oxalyl chloride (102 λL, 1.17 mmol) and benzoic acid 17 (280 mg, 0.78 mmol) with subsequent coupling to 3-pyridinylmethylamine (87 λL, 0.86 mmol) gave benzamide 18 (169 mg, 48%) as a white powder: mp (EtOAc) 196-198° C.; 1H NMR δ 9.20 (t, J=5.9 Hz, 1 H, CONH), 8.57 (br s, 1 H, H-2′), 8.46 (br s, 1 H, H-6′), 8.00 (br dd, J=8.6, 1.8Hz, 2 H, H-2, H-6), 7.89 (br dd, J=8.6, 1.8Hz, 2 H, H-3, H-5), 7.80 (br d, J=8.5Hz, 2 H, H-2″, H-6″), 7.71-7.76 (m, 2 H, H-4′, H-4″), 7.62 (br dd, J=8.2, 7.5 Hz, 2 H, H-3″, H-5″), 7.36 (dd, J=7.8, 4.8Hz, 1 H, H-5′), 4.68 (s, 2 H, CH2SO2), 4.50 (d, J=5.8Hz, 2 H, CH2N), 2.13 (s, 3 H, CH3); 13C NMR δ 165.4, 157.9, 149.9, 148.8, 148.0, 138.3, 135.3, 135.0, 134.8, 133.8, 129.1 (2), 128.7, 128.1 (2), 128.0 (2), 125.8, 125.3 (2), 123.4, 52.7, 40.4, 9.5; MS m/z 448.5 (MH+, 100%). Anal. calcd for C24H21N3O4S: C, 64.41; H, 4.73; N, 9.39. Found: C, 64.23; H, 4.71; N, 9.37%.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=O.C(=O)(O)O.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH2:29])=[NH:28])=[CH:22][CH:21]=1>C(O)(C)C>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([NH:26][C:27]2[N:29]=[C:5]([C:7]3[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][N:28]=2)=[CH:24][CH:25]=1
Reactant: CN(C)C=CC(=O)c1ccncc1
Reactant: COc1ccc(NC(=N)N)cc1
Agent: O=C(O)O
Solvent: CC(C)O
Product: COc1ccc(Nc2nccc(-c3ccncc3)n2)cc1

Procedure:
A 14.4 g amount of 3-dimethylamino-1-(4-pyridinyl)-2-propen-1-one (U.S. Pat. No. 4,281,000) and 16.1 g of 4-methoxyphenylguanidine carbonate in 200 ml of isopropanol was heated at reflux for 24 hours. The solvent was evaporated to 1/3 volume, then the mixture was cooled in an ice-bath to crystallize the crude product. The product was collected by filtration and washed with water, then with isopropanol. The material was recrystallized from isopropanol/ethylene glycol monomethyl ether to give 16.7 g of the desired product as yellow crystals, mp 174°-175° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([OH:28])[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1.[OH-].[Na+]>>[CH3:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([O:28][S:8]([C:5]4[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=4)(=[O:10])=[O:9])[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1
Reactant: CN1CCC(c2c[nH]c3ccc(O)cc23)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(S(=O)(=O)Oc2ccc3[nH]cc(C4CCN(C)CC4)c3c2)cc1
Yield: 79.3 %

Procedure:
By a method similar to Example 31, using 4-methylbenzenesulfonyl chloride (228 mg, 1.2 mmol) and 3-(1-methylpiperidin-4-yl)-5-hydroxy-1H-indole (230 mg, 1.0 mmol), 0.2 N sodium hydroxide (5.5 mL, 1.1 mmol) gave 400 mg of crude product. The crude product was recrystallized from ethyl acetate to give 305 mg (79%) of a white powder: mp=186-187° C. MS(m/e): 384 (M+); Calculated for C21H24N2O3S: Calcd: C, 65.60; H, 6.29; N, 7.29. Found: C, 65.50; H, 6.35; N, 7.23.
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][C:8]2[C:11]([C:15]([OH:17])=[O:16])=[CH:12][CH:13]=[CH:14][C:7]1=2.[Br:18][C:19]1[CH:20]=[N:21][C:22]([Cl:25])=[N:23][CH:24]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.Cl>C1COCC1.C(O)(=O)C>[Br:18][C:19]1[C:20]([C:10]2[S:6][C:7]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([OH:17])=[O:16])[C:8]=3[CH:9]=2)=[N:21][C:22]([Cl:25])=[N:23][CH:24]=1
Reactant: Clc1ncc(Br)cn1
Reactant: O=C(O)c1cccc2sccc12
Agent: Cl
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(O)c1cccc2sc(-c3nc(Cl)ncc3Br)cc12
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 42 %

Procedure:
Butyllithium (2.5 M in hexane, 14.1 mL) is added dropwise to a stirred solution of benzo[b]thiophene-4-carboxylic acid (3.00 g, 16.8 mmol) in anhydrous THF (50 mL) at −78° C. under nitrogen. The resultant mixture is allowed to stir for 45 minutes at −78° C. before it is added, via cannula, to a stirred cold solution of 5-bromo-2-chloropyrimidine (3.26 g, 16.8 mmol) in anhydrous THF (50 mL) at −30° C. Upon the completion of the addition, the reaction mixture is stirred for 30 minutes at −30° C., then at ambient temperature for another 1.5 hours. Acetic acid (2.4 mL) is added to the reaction mixture, after 5 minutes, followed by the addition of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (4.01 g, 17.7 mmol) dissolved in THF (10 mL). The mixture is allowed to stir for 10 minutes before it is treated dropwise with HCl (37%, 30 mL), then the mixture is stirred for another 1 hour. THF is evaporated off and the mixture becomes a suspension. The solid is filtered off, washed with water (100 mL×2), and then dried under vacuum. The dry solid is suspended in dichloromethane (45 mL) and ethanol (5 mL) and stirred for 30 minutes. After filtration, the solid is resuspended in ether (50 mL) and the suspension is stirred for another 30 minutes. After filtration and vacuum drying, the title compound is obtained as a yellow solid. (2.64 g, 42% yield).
Reaction SMILES: [CH2:1]1[CH2:29][O:28][C:3]2([CH:8]=[CH:7][C@H:6]3[C@H:9]4[C@H:18]([CH2:19][CH2:20][C@:4]23[CH3:5])[C:17]2[CH:16]=[CH:15][C:14]([OH:21])=[CH:13][C:12]=2[CH2:11][C@H:10]4[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27])[O:2]1.[OH-].[Li+].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C)C=O.C(OCC)(=O)C>[CH2:32]([O:21][C:14]1[CH:15]=[CH:16][C:17]2[C@@H:18]3[C@H:9]([C@H:6]4[C@@:4]([CH2:20][CH2:19]3)([CH3:5])[C:3]3([O:2][CH2:1][CH2:29][O:28]3)[CH:8]=[CH:7]4)[C@H:10]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27])[CH2:11][C:12]=2[CH:13]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCO)[C@H]3[C@@H]1C=CC21OCCO1
Reactant: BrCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4C[C@@H](CCCCCO)[C@H]3[C@@H]1C=CC21OCCO1

Procedure:
A solution of 32.7 g of 17,17-ethylenedioxy-7α-(5-hydroxypentyl)-estra-1,3,5(10),15-tetraen-3-ol (see Example 1h) in 327 ml of dimethylformamide is mixed at room temperature with 5.73 g of lithium hydroxide and stirred with 15.1 ml of benzyl bromide for 2 hours at 60° C. Then, it is diluted with ethyl acetate, washed with water, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with dichloromethane/methanol. 32.8 g of 3-benzyloxy-17,17-ethylenedioxy-7α-(5-hydroxypentyl)-estra-1,3,5(10),15-tetraene is obtained.