Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:15]([CH3:17])=[CH2:16])([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5][CH2:4][N:3]1[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Li+].CC([N-]C(C)C)C.Br[CH2:35][CH2:36][Cl:37]>C1COCC1>[Cl:37][CH2:36][CH2:35][CH:7]([C:6]1([C:15]([CH3:17])=[CH2:16])[CH2:5][CH2:4][N:3]([CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:2]1=[O:1])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: ClCCBr
Reactant: C=C(C)C1(CC(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(C)C1(C(CCCl)C(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A cold (-78° C.) solution of tert-butyl 2-oxo-1-(2-phenylethyl)-3-(propen-2-yl)-3-pyrrolidineacetate (prepared similarly to that described in EXAMPLE 1, step 3; 5.52 g, 16.1 mmol) in dry THF (100 mL) is treated with the dropwise addition of LDA (9.66 mL, 19.3 mmol, 2.0N). The solution is stirred for 30 min, and then treated with the dropwise addition of 1-bromo-2-chloroethane (1.61 mL, 19.3 mmol). The solution is maintained at -78° C. for 5 hours and then allowed to slowly warm to room temperature under N2 overnight. The solution is quenched with saturated NH4Cl (10 mL) and diluted with H2O (25 mL). The product is extracted with EtOAc (3×100 mL), dried over anhydrous MgSO4, filtered, and concentrated to give 6.6 g of a brown oil. The oil is purified by silica gel chromatography (275 g SG; 10% EtOAc/hexane) to provide 5.07 g (78%) of the title compound as a clear, yellow oil:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([NH:19][C@H:20]1[CH2:24][CH2:23][O:22][CH:21]1[OH:25])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[C:27](OC(=O)C)(=[O:29])[CH3:28]>CN(C)C1C=CN=CC=1>[C:27]([O:25][CH:21]1[C@@H:20]([NH:19][C:17](=[O:18])[C@H:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:24][CH2:23][O:22]1)(=[O:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@H]1CCOC1O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: O
Product: CC(=O)OC1OCC[C@@H]1NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 29 %

Procedure:
(3S)-3-[[N-tert-Butoxycarbonyl-(L)-phenylalanyl]amino]-2-hydroxytetrahydrofuran (0.1 g) was dissolved in acetic anhydride (3 ml) followed by addition of 4-dimethylaminopyridine (DMAP) (0,012 g) and the mixture was stirred at room temperature for 12 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with 10% aqueous citric acid, water, saturated aqueous sodium hydrogen carbonate, and saturated aqueous sodium chloride in the order mentioned and dried (MgSO4) and the solvent was distilled off to give (3S)-2-acetoxy-3-[[N-tert-butoxycarbonyl-(L)-phenylalanyl]amino]tetrahydrofuran (chemical formula below) (0,035 g, 29%). This product was recrystallized from ethyl acetate-hexane. Colorless crystals, m.p. 156°-157° C. Optical rotation [α]D -49.9° (C=0.15, CHCl3). ##STR45##
Reaction SMILES: [H-].[Na+].F[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11].[O:13]=[C:14]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>CN(C=O)C>[N+:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH:15]([C:14](=[O:13])[CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: COC(=O)CCC(=O)CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCC(=O)C(C(=O)OC(C)(C)C)c1ccccc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 59.5 %

Procedure:
To the suspension of NaH (2.3 g, 57.5 mmol) in DMF (50 mL) was added 2-fluoro-1-nitrobenzene (4.04 g, 28.7 mmol) and 1-(1,1-dimethylethyl) 6-methyl 3-oxohexanedioate (6.6 g, 28.7 mmol). The mixture was heated at 60° C. for 12 h. After cooling to room temperature, the mixture was quenched with NH4Cl aqueous solution, and extracted with ethyl acetate. The combined organic phase was dried over sodium sulfate, filtered, and concentrated. Purification via flash chromatography then afforded the title compound (6.0 g, 45.3% yield). LCMS: rt=4.15 min, [M+H+]=350
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][C:21](=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.BrC[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[N:30]=1>>[ClH:19].[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[S:20][CH2:21][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[N:30]=1
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Reactant: Clc1cccc(CBr)n1
Agent: Cl
Product: Clc1cccc(CSc2c(Cl)ccc3c2CCNCC3)n1

Procedure:
Use a method similar to the Preparation 177, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine and 2-bromomethyl-6-chloropyridine hydrochloride to give, after deprotection by a method similar to the General Procedure 1-4, the title compound as an off-white solid. MS (APCI+) m/z: 339 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH2:5][S:6][CH3:7].C(N(CC)CC)C.[F:19][C:20]1[CH:30]=[CH:29][CH:28]=[CH:27][C:21]=1[CH:22]=[CH:23][C:24](O)=[O:25].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:19][C:20]1[CH:30]=[CH:29][CH:28]=[CH:27][C:21]=1[CH:22]=[CH:23][C:24]([NH:2][C@H:3]([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH2:5][S:6][CH3:7])=[O:25]
Reactant: COC(=O)[C@@H](N)CCSC
Reactant: O=C(O)C=Cc1ccccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](CCSC)NC(=O)C=Cc1ccccc1F
Yield: 94.9 %

Procedure:
The same procedures as in Example 2 were carried out from methyl L-methioninate hydrochloride (2.5 g), triethylamine (2.1 mL), 2-fluorocinnamic acid (2.5 g), WSC.HCl (2.9 g, 15.0 mmol), and methylene chloride (80 mL), to give the captioned compound (3.7 g, 95%) as an oily product.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:4]=2[N:3]=1.[CH3:12][NH2:13]>>[F:11][C:8]1[CH:9]=[CH:10][C:4]2[N:3]=[C:2]([NH:13][CH3:12])[NH:6][C:5]=2[CH:7]=1
Reactant: Fc1ccc2nc(Cl)[nH]c2c1
Reactant: CN
Product: CNc1nc2ccc(F)cc2[nH]1
Temperature: 160 °C
Yield: 63.7 %

Procedure:
4-Fluorobenzene-1,2-diamine (2 g, 15.86 mmol) was dissolved in THF (49.4 ml) and 1,1′-Carbonyldiimidazole (2.83 g, 17.44 mmol) was added at RT. The reaction mixture was stirred overnight at RT. To this was added concentrated ammonia solution (1.5 ml) and the mixture stirred for 30 minutes and then diluted with water (100 ml). The resultant solid was collected by filtration, washed with water, followed by Et2O and then dried in vacuo to afford 5-fluoro-1H-benzo[d]imidazol-2(3H)-one (1.250 g, 52%); 1H NMR (400 MHz, DMSO-d6) 6.66-6.79 (2H, m), 6.81-6.94 (1H, m), 10.64 (1H, s), 10.76 (1H, s); m/z: (ES+) MH+, 151.19. b) A solution of 5-fluoro-1H-benzo[d]imidazol-2(3H)-one (1.25 g, 8.22 mmol) in phosphorus oxychloride (25.2 ml, 270.34 mmol) was heated for 18 hours at 100° C. The reaction mixture was cooled to RT and excess of POCl3 was evaporated in vacuo. The residue was neutralized with saturated NaHCO3 solution (10 ml) and extracted with EtOAc (3×20 ml). The organic phase was washed with brine and then dried over MgSO4, filtered and concentrated under reduced pressure to afford 2-chloro-6-fluoro-1H-benzo[d]imidazole (1.146 g, 82%); 1H NMR (400 MHz, DMSO-d6) 7.09 (1H, ddd), 7.36 (1H, dd), 7.53 (1H, dd); m/z: (ES+) MH+, 171.34. c) 2-Chloro-6-fluoro-1H-benzo[d]imidazole (1.146 g, 6.72 mmol) was charged to high pressure autoclave PV10832 (Parr 160 ml) with methylamine 40% EtOH solution (50 ml, 6.72 mmol) and sealed on its trolley and the resulting solution heated to 160° C. in high pressure blast cell 60 for 16 hours. The pressure in the autoclave reached 13 bar. The reaction mixture was evaporated and the residue dissolved in MeOH and added to an SCX column. The desired product was eluted from the column using 7M NH3/MeOH. Fractions containing product were evaporated and the residue was purified by flash chromatography on silica, eluting with a gradient of 0 to 10% MeOH in DCM. Pure fractions were evaporated to afford 6-fluoro-N-methyl-1H-benzo[d]imidazol-2-amine (0.707 g, 64%); 1H NMR (400 MHz, DMSO-d6) 2.27 (3H, d), 6.38-6.44 (2H, m), 6.67 (1H, dd), 6.79-6.84 (1H, m); m/z: (ES+) MH+, 166.31.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:21]=[CH:20][C:12]([C:13]([O:15]C(C)(C)C)=[O:14])=[C:11]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2]>FC(F)(F)C(O)=O>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:21]=[CH:20][C:12]([C:13]([OH:15])=[O:14])=[C:11]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cccc(C#N)c2)cc1Nc1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(-c2ccc(C(=O)O)c(Nc3ccc(F)cc3)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid 10 mL was added to the obtained tert-butyl 4-(3-cyanophenyl)-2-(4-fluoroanilino)benzoate, and it was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, methanol was added to the obtained residue, and solid matter was filtrated to give 4-(3-cyanophenyl)-2-(4-fluoroanilino)benzoic acid 13 mg of pale yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.[Br:16][C:17]1[CH:22]=[C:21](Cl)[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][N:18]=1.C(N(CC)CC)C>C(#N)C>[Br:16][C:17]1[CH:22]=[C:21]([NH:1][CH2:2][CH:3]2[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]2)[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][N:18]=1
Reactant: O=[N+]([O-])c1cnc(Br)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCCC(CN)C1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC(CNc2cc(Br)ncc2[N+](=O)[O-])C1
Reaction time: 1 h
Yield: 95 %

Procedure:
A solution of 3-(aminomethyl)-1-boc-piperidine (409 mg, 1.91 mmol) in acetonitrile (2.5 mL) was added dropwise to a solution of 2-bromo-4-chloro-5-nitropyridine (431 mg, 1.82 mmol) and triethylamine (0.28 mL, 2.0 mmol) in acetonitrile (10 mL). The solution was stirred for 1 hr then partitioned between dichloromethane and water. The aqueous phase was extracted with dichloromethane (×3) and the combined organic phases were dried (Na2SO4) and concentrated to give tert-butyl 3-((2-bromo-5-nitropyridin-4-ylamino)methyl)piperidine-1-carboxylate as a yellow-brown solid (718 mg, 95%) which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=3)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[N+:21]([O-])=O>C(O)(=O)C.[Fe]>[NH2:21][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[Cl:1])[N:9]=[CH:8][N:7]=[C:6]2[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1
Reactant: O=[N+]([O-])c1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1Cl
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1Cl
Yield: 20 %

Procedure:
Using an analogous procedure to that described in Example 9, 7-chloro-4-(3',4'-dichloroanilino)-6-nitroquinazoline was reduced with iron in acetic acid to give 6-amino-7-chloro-4-(3',4'-dichloroanilino)quinazoline in 20% yield;
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:9]([O:11]CC)=[O:10])[S:7][CH:8]=1)([CH3:3])[CH3:2].[OH-].[Li+].Cl>C1COCC1.CO>[CH:1]([C:4]1[N:5]=[C:6]([C:9]([OH:11])=[O:10])[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1nc(C(C)C)cs1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1csc(C(=O)O)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of ethyl 4-isopropylthiazole-2-carboxylate (9.1 g, 46 mmol) in THF (100 ml) and MeOH (30 ml) was added a solution of lithium hydroxide (1.16 g, 48.5 mmol) and the mixture was stirred for two days at room temperature. The mixture was acidified with 2M hydrochloric acid and extracted four times with diethyl ether. The organic phase was dried with sodium sulfate and evaporated under reduced pressure. Yield: 7.1 g, 90%.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[C:8]([O:11][CH2:12][CH2:13][CH2:14][O:15][NH2:16])=[CH:9][CH:10]=1)=[O:4].[CH2:27]([N:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[C:35]1[CH:43]=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([N:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[C:35]1/[CH:43]=[N:16]/[O:15][CH2:14][CH2:13][CH2:12][O:11][C:8]1[C:7]([C:17]2[CH:18]=[CH:19][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:21][CH:22]=2)=[CH:6][C:5]([C:3]([OH:2])=[O:4])=[CH:10][CH:9]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=Cc1cc2ccccc2n1Cc1ccccc1
Reactant: COC(=O)c1ccc(OCCCON)c(-c2ccc(C(F)(F)F)cc2)c1
Product: O=C(O)c1ccc(OCCCO/N=C/c2cc3ccccc3n2Cc2ccccc2)c(-c2ccc(C(F)(F)F)cc2)c1
Yield: 53.9 %

Procedure:
This compound was produced using similar methods as those used in Step 6, example 4, starting with 6-(3-aminooxy-propoxy)-4′-trifluoromethyl-biphenyl-3-carboxylic acid methyl ester (0.25 g, 0.68 mmol) and 1-benzyl-1H-indole-2-carbaldehyde (0.16 g, 0.68 mmol). The crude material was purified by recrystallizing two times from ethyl acetate/hexanes followed by HPLC (82% acetonitrile in 0.1% trifluoroacetic acid solution) and one final recrystallization from ethyl acetate/hexanes to give 6-[3-({[(1E)-(1-benzyl-1H-indol-2-yl)methylidene]amino}oxy)propoxy]-4′-(trifluoromethyl)-1,1 ′-biphenyl-3-carboxylic acid (0.21 g, 54%) as a white solid. mp=196-197° C. 1H NMR (400 MHz, DMSO-d6); δ 12.80 (bs, 1H), (s, 1H), 7.96 (dd, 1H), 7.88 (d, 1H), 7.74 (AA′BB′, 4H), 7.60 (d, 1H), 7.46 (d, 1H), 7.22-7.16 (m, 4H), 7.12 (t, 1H), 7.06 (t, 1H), 6.94 (d, 2H), 6.89 (s, 1H), 5.72 (s, 2H), 4.13 (t, 2H), 4.11 (t, 2H), 2.49 (m, 2H). Mass spec; (ES−) m/z 571.2. Elemental analysis; Calculated for C33H27F3N2O4: C, 69.22; H, 4.75; N, 4.89. Found: C, 69.04; H, 4.55; N, 4.82.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:24])[NH:4][C:5](=[O:23])[N:6]([CH:8]2[CH2:13][S:12][CH:11]([CH2:14][O:15]CC3C=CC=CC=3)[CH2:10][O:9]2)[CH:7]=1.B(Cl)(Cl)Cl.CO.C(Cl)Cl.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[C:3](=[O:24])[NH:4][C:5](=[O:23])[N:6]([CH:8]2[CH2:13][S:12][CH:11]([CH2:14][OH:15])[CH2:10][O:9]2)[CH:7]=1
Reactant: O=c1[nH]c(=O)n(C2CSC(COCc3ccccc3)CO2)cc1Cl
Agent: ClB(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O=c1[nH]c(=O)n(C2CSC(CO)CO2)cc1Cl
Temperature: -78 °C
Reaction time: 4 h
Yield: 18.9 %

Procedure:
5-Chloro-1-(5-benzyloxymethyl-1,4-oxathian-2-yl) uracil (0.42 g) was dissolved in methylene chloride (40 ml), and the solution cooled to -78° C. To the solution, 3M boron trichloride (11.5 ml) was added dropwise, and the mixture stirred at the same temperature for 4 hours. After adding a mixed solution of methanol-methylene chloride (1/1, 14 ml) at room temperature, sodium bicarbonate was added thereto. Upon stirring and filtering the mixture, the filtrate was concentrated under reduced pressure, and the residue was purified on a silica gel column (eluent: chloroform/methanol=10/1) to obtain the desired product (0.06 g) as white solid.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([CH2:11][CH2:12][NH:13][NH2:14])#[N:10]>>[C:9]([CH2:11][CH2:12][NH:13][N:14]=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)#[N:10]
Reactant: O=Cc1ccccc1
Reactant: N#CCCNN
Product: N#CCCNN=Cc1ccccc1
Yield: 81 %

Procedure:
Benzaldehyde (2-cyanoethyl)hydrazone is prepared by condensation of benzaldehyde with (2-cyanoethyl)hydrazine according to the following procedure:
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[OH:22])=[C:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2].[C:23]([O:30][CH2:31][C:32](Cl)=[O:33])(=[O:29])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C(OCC)(=O)C.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:32](=[O:33])[CH2:31][O:30][C:23](=[O:29])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[C:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2]
Reactant: CCCCCC(=O)OCC(=O)Cl
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3CC[C@]2(C)[C@H]1O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCCCC(=O)OCC(=O)O[C@H]1[C@@H](CC)C[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3CC[C@@]21C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In 20 ml of toluene are dissolved 1.5 g of 16β-ethyl-17β-hydroxy-4,9(10)-estradien-3-one and 1.92 g of 4-dimethylaminopyridine, and 1.6 ml of n-hexanoyloxyacetyl chloride is added. The mixture is stirred at 50°-60° C. for 3 hours. After cooling to 25° C., the mixture is poured into a mixture of ethyl acetate (200 ml) and saturated aqueous sodium hydrogen carbonate (50 ml). The organic layer is separated and the aqueous layer is extracted with ethyl acetate. These organic layers are combined, washed with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure and the residue is chromatographed on a silica gel column. Following passage of diisopropyl ether-n-hexane (1:1), elution is carried out with 1000 ml of a 3:2 mixture of the same solvents. The eluate is evaporated under reduced pressure to remove the solvent, giving 1.69 g of the above-identified compound as a light-yellow viscous oil.
Reaction SMILES: [H-].[Na+].[C:3]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][CH2:17][CH2:16]2)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:20]I>CN(C)C=O>[CH3:20][N:18]1[C:19]2[C:15](=[CH:14][CH:13]=[CH:12][C:11]=2[C:3](=[O:10])[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:16][CH2:17]1
Reactant: O=C(c1ccccc1)c1cccc2c1NCC2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCc2cccc(C(=O)c3ccccc3)c21
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a stirred slurry of 4.8 grams (0.1 mole) of 50% sodium hydride/oil in 100 ml. of dimethylformamide is added dropwise a solution of 22.3 grams (0.1 mole) of 7-benzoylindoline in 50 ml of dimethylformamide. After addition is complete, the mixture is warmed at 50° C. until all solids dissolve. While maintaining the mixture at 50° C., 9.5 grams (0.1 mole) of methyl iodide is added dropwise to the mixture. The mixture is stirred for 4 hours. The mixture is poured into 2 liters of ice water and extracted with 3 portions of 300 ml of benzene. The benzene extracts are combined, washed with water, dried over sodium sulfate and concentrated to give 1-methyl-7-benzoylindoline as a residue.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4](C(OCC)=O)[C:3]=1[C:17](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=1.C([O-])([O-])=O.[K+].[K+].CCO>O>[NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:17](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=1
Reactant: CCOC(=O)n1c(C(=O)c2cccc(C)c2)c(N)c2ccc(Cl)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cc1cccc(C(=O)c2[nH]c3cc(Cl)ccc3c2N)c1
Yield: 83.9 %

Procedure:
A mixture of ethyl 3-amino-6-chloro2-(3-methylbenzoyl)-1H-indole-1-caboxylate (step 1, 6.4 g, 18 mmol), K2CO3 (6.3 g, 45 mnmol) , EtOH (50 ml) and water (30 ml) was heated at reflux temperature for 20 h. The mixture was concentrated, and then water (30 ml) was added to the residue. The resulting mixture was extracted with dichloromethane (80 ml×2) and the combined extracts were dried (MgSO4). Removal of solvent gave 4.3 g (84%) of brown amorphous solids.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=O.[C:14]1(=[O:19])[CH2:18][CH2:17][CH2:16][CH2:15]1>>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=[C:15]1[CH2:16][CH2:17][C:18](=[CH:5][C:4]2[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]([OH:10])=[C:2]([OH:1])[CH:3]=2)[C:14]1=[O:19]
Reactant: O=C1CCCC1
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Product: O=C1C(=Cc2cc(O)c(O)c([N+](=O)[O-])c2)CCC1=Cc1cc(O)c(O)c([N+](=O)[O-])c1

Procedure:
The procedure described in Example 8 was repeated using 5.0 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 2.0 g of cyclopentanone. Yield 4.4 g(78%), m.p. 300° C. (decomp.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Br[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Fc1cccc(CBr)c1
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Product: O=[N+]([O-])c1cc(OCc2cccc(F)c2)ccc1Cl

Procedure:
A solution of 4-chloro-3-nitro-phenol was reacted with 1-bromomethyl-3-fluoro-benzene using the conditions described in Example 237C to provide 1-Chloro-4-(3-fluoro-benzyloxy)-2-nitro-benzene which was treated sequentially using the procedures from Examples 237D and 237E to provide 4-[2-amino-4-(3-fluoro-benzyloxy)-phenylsulfanyl]-phenol.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[NH:12][C:11]2[C:10](=[O:13])[N:9]([CH2:14][CH:15]3[CH2:17][CH2:16]3)[C:8](=[O:18])[N:7]([CH2:19][CH:20]3[CH2:22][CH2:21]3)[C:6]=2[N:5]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1.Cl>O1CCCC1.O>[CH:15]1([CH2:14][N:9]2[C:10](=[O:13])[C:11]3[NH:12][C:4]([NH:3][S:31]([C:28]4[CH:27]=[CH:26][C:25]([O:24][CH3:23])=[CH:30][CH:29]=4)(=[O:33])=[O:32])=[N:5][C:6]=3[N:7]([CH2:19][CH:20]3[CH2:22][CH2:21]3)[C:8]2=[O:18])[CH2:16][CH2:17]1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nc2c([nH]1)c(=O)n(CC1CC1)c(=O)n2CC1CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)Nc2nc3c([nH]2)c(=O)n(CC2CC2)c(=O)n3CC2CC2)cc1
Reaction time: 0.5 h
Yield: 30.8 %

Procedure:
Sodium hydride (0.31 g of a 60% suspension in oil, 2.1 eq) was added to a suspension of 8-amino-1,3-di(cyclopropylmethyl)xanthine (1 g, 3.64 mmol) in tetrahydrofuran (25 ml). After 30 minutes, 4-methoxybenzenesulphonyl chloride (0.82 g, 1.1 eq) was added and stirring continued for 48 hours. The reaction mixture was poured into water, acidified with dilute hydrochloric acid and extracted into ethyl acetate. The combined organic solutions were dried (MgSO4), filtered and concentrated. The crude residue was purified by column chromatography over silica in 2-5% methanol/dichloromethane to afford 1,3-di(cyclopropylmethyl)-8-(4-methoxybenzenesulphonylamino )xanthine (0.50 g, 31%) as a white solid m.pt>200° C. (decomp.)
Reaction SMILES: Cl[CH2:2][CH2:3][S:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12].[NH3:13].Cl>>[CH3:12][O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[S:4][CH2:3][CH2:2][NH2:13]
Reactant: COc1ccccc1SCCCl
Reactant: N
Agent: Cl
Product: COc1ccccc1SCCN

Procedure:
by the reaction of o-(2-chloroethylthio)-anisole in liquid ammonia for 8 hours at 120° C.; oil; b.p. 118°-122° C./0.05 mm.Hg.; hydrochloride m.p. 163°-167° C.;