Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C@H:9]([C:17]1[NH:21][C:20]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:19]=2[N:18]=1)[CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:26][C:24]1[CH:23]=[CH:22][C:20]2[NH:21][C:17]([C@@H:9]([NH2:8])[CH2:10][C:11]3[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=3)=[N:18][C:19]=2[CH:25]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccncc1)c1nc2cc(Cl)ccc2[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](Cc1ccncc1)c1nc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.88 g (5.04 mmol) of (S)—N-tert-butoxycarbonyl-1-(5-chloro-1H-benzimidazol-2-yl)-2-(pyridin-4-yl)ethylamine is dissolved in 35 mL of dichloromethane and combined with 5 mL of trifluoroacetic acid. The mixture is stirred for 16 hours at ambient temperature and then the volatile constituents are distilled off. The residue is made alkaline with 2 molar sodium hydroxide solution, evaporated down and then digested with a little water and ethyl acetate. The crystals thus obtained are dried. Yield: 1.38 g (quantitative); Rf value: 0.09 (silica gel; dichloromethane/methanol=9:1); C14H13ClN4 (272.74); mass spectrum: (M+H)+=273/275 (chlorine isotope).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][N:13](C(OC(C)(C)C)=O)[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[F:30])[NH2:26].O1CCOCC1>CC(O)C.Cl.O1CCOCC1>[Cl:22][C:23]1[CH:24]=[C:25]([NH:26][C:2]2[C:3]3[C:10]4[CH2:11][CH2:12][NH:13][CH2:14][C:9]=4[S:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:27]=[CH:28][C:29]=1[F:30]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3ncnc(Cl)c23)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: Fc1ccc(Nc2ncnc3sc4c(c23)CCNC4)cc1Cl
Temperature: 80 °C
Yield: 94.8 %

Procedure:
tert-Butyl 4-chloro-5,8-dihydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine-7(6H)-carboxylate from Example 11A (407.5 g, 1.251 mol) was dissolved in 2-propanol (5.7 L). 3-Chloro-4-fluoroaniline (191.2 g, 1.313 mol) and a 4 M solution of gaseous hydrogen chloride in dioxane (17.4 mL, 63 mmol) were added. The mixture was heated to 80° C. for 3 days. The thick suspension was then diluted with additional 2-propanol (1 L), and further 4 M hydrogen chloride in dioxane (695 mL, 2.5 mol) was added. The mixture was again heated to 80° C. for 3 h. The solvent was then removed in vacuo, and the residue was treated with 1 M aqueous sodium hydroxide solution (12 L). The precipitate was collected by suction filtration and washed with water. The product was dried for 2 days at 50° C., then triturated with tert-butyl methyl ether and collected by suction filtration to yield 397 g (95%) of the title compound.
Reaction SMILES: Cl.N=[C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:4]1[C:5](OCC)=O.[NH2:14][CH:15]([C:19]([NH2:21])=[O:20])[C:16]([NH2:18])=[O:17]>CO>[C:4]1([C:5]2[NH:18][C:16]([OH:17])=[C:15]([C:19]([NH2:21])=[O:20])[N:14]=2)[CH:3]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NC(=O)C(N)C(N)=O
Reactant: CCOC(=O)C1C=CC=CC1=N
Agent: Cl
Solvent: CO
Product: NC(=O)c1nc(-c2ccccc2)[nH]c1O
Yield: 63.1 %

Procedure:
To a chilled solution of ethyl iminobenzoate hydrochloride (18.57 g) in anhydrous methanol (250 ml) was added aminomalonamide (11.71 g). The mixture was stirred for a half hour at 0°-5° C. and then 1 hour under reflux. After cooling to 0°-5° C. again, the precipitated product was filtered and washed with ethanol, isopropylether to give 2-phenyl-5-hydroxy-1H-imidazole-4-carboxamide (11.81 g).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[C:8]([OH:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Cs+:19].[Cs+].CC(C)=O>O>[OH:1][C:2]1[CH:10]=[C:9]([C:11]([O-:13])=[O:12])[C:8]([OH:14])=[CH:7][C:3]=1[C:4]([O-:6])=[O:5].[Cs+:19].[Cs+:19]
Reactant: O=C(O)c1cc(O)c(C(=O)O)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: O
Product: O=C([O-])c1cc(O)c(C(=O)[O-])cc1O
Yield: 200 %

Procedure:
0.5 mol of 2,5-dihydroxyterephthalic acid and 0.5 mol of cesium carbonate were added to 200 ml of acetone and 200 ml of water and dissolved therein by stirring. After completely dissolving, the resultant solution was concentrated to dryness to give 0.5 mol of cesium 2,5-dihydroxyterephthalate. 46.2 g (0.1 mol) of cesium 2,5-dihydroxyterephthalate, 38.62 g (0.2 mol) of bromooctane and 400 ml of DMF were introduced into a reactor and reacted under a nitrogen gas stream at 100° C. for 3 hours. The reaction solution was concentrated, washed with water and dried to give 40.1 g (0.95 mol) of 2,5-dihydroxybenzene-1,6-dicarboxylic octane.
Reaction SMILES: [NH2:1][C:2]([CH2:7][CH3:8])([CH2:5][OH:6])[CH2:3][OH:4].[C:9](=O)(OCC)[O:10]CC>C[O-].[Na+].CCO>[CH2:7]([C:2]1([CH2:5][OH:6])[CH2:3][O:4][C:9](=[O:10])[NH:1]1)[CH3:8]
Reactant: CCC(N)(CO)CO
Reactant: CCOC(=O)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CCC1(CO)COC(=O)N1
Yield: 66.5 %

Procedure:
Sodium methoxide (2.2 g, Aldrich) was added to a solution of 2-amino-2-ethyl-1,3-propanediol(100.0 g, Aldrich) and diethyl carbonate (169.0 g, Aldrich) This solution was refluxed in a Dean Stark apparatus until no more EtOH was collected. The reaction mixture was cooled, added acetone(200 ml) and allowed to stand overnite at room temperature. The resulting suspension was filtered to give 81.0 g of the desired product as a beige solid. 1H NMR consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[CH2:13]([NH2:17])[CH2:14][CH2:15][CH3:16]>CN(C=O)C>[CH2:13]([NH:17][C:4]1[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=[C:2]([Cl:1])[N:3]=1)[CH2:14][CH2:15][CH3:16]
Reactant: Cc1csc2c(Cl)nc(Cl)nc12
Reactant: CCCCN
Solvent: CN(C)C=O
Product: CCCCNc1nc(Cl)nc2c(C)csc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
In DMF was dissolved 700 mg (3.2 mmol) of 2,4-dichloro-7-methylthieno[3,2-d]pyrimidine, and then an aqueous solution of 548 mg (7.5 mmol) of butylamine was added dropwise to the resulting solution under ice cooling over 5 minutes. The reaction mixture was stirred at 0° C. for one hour and then allowed to resume room temperature, followed by stirring for one hour. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/10) to give 698 mg (yield: 85.4%) of the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[N:11]=[C:10]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([CH:19]4[CH2:22][O:21][CH2:20]4)[CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[Si]([N:36]1[C:44]2[C:39](=[C:40](B3OC(C)(C)C(C)(C)O3)[C:41]([F:45])=[CH:42][CH:43]=2)[CH:38]=[CH:37]1)(C(C)(C)C)(C)C>>[F:45][C:41]1[C:40]([C:2]2[N:3]=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:5]3[N:11]=[C:10]([CH2:12][N:13]4[CH2:18][CH2:17][CH:16]([CH:19]5[CH2:22][O:21][CH2:20]5)[CH2:15][CH2:14]4)[CH:9]=[CH:8][C:6]=3[N:7]=2)=[C:39]2[C:44](=[CH:43][CH:42]=1)[NH:36][CH:37]=[CH:38]2
Reactant: Clc1nc(N2CCOCC2)c2nc(CN3CCC(C4COC4)CC3)ccc2n1
Reactant: CC1(C)OB(c2c(F)ccc3c2ccn3[Si](C)(C)C(C)(C)C)OC1(C)C
Product: Fc1ccc2[nH]ccc2c1-c1nc(N2CCOCC2)c2nc(CN3CCC(C4COC4)CC3)ccc2n1

Procedure:
4-(2-chloro-6-((4-(oxetan-3-yl)piperidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)morpholine (0.11 g) was reacted with 1-(tert-butyldimethylsilyl)-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole via General Procedure A to produce 59.8 mg of 130 following reverse phase HPLC purification.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:12])=[CH:7][CH:8]=[N:9]2)=[N:4][CH:3]=1.[OH-].[Na+].[N+:15]([O-])([OH:17])=[O:16]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:12])=[C:7]([N+:15]([O-:17])=[O:16])[CH:8]=[N:9]2)=[N:4][CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: Oc1ccnc2cc(Br)cnc12
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1cnc2cc(Br)cnc2c1O
Temperature: 90 °C

Procedure:
A mixture of 7-bromo[1,5]naphthyridin-4-ol (33 g, 0.147 mol) and fuming nitric acid (350 mL) was heated at reflux (90° C. internal reaction vessel temperature) for 3 hours. The reaction mixture was cooled to 50° C., poured over 1 L of ice and neutralized to pH 2-3 with a solution of 50% aqueous sodium hydroxide. The resulting precipitate was filtered, washed with water, and dried over vacuum for 3 days to yield 25.1 g of 7-bromo-3-nitro[1,5]naphthyridin-4-ol as a yellow crystalline solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([Cl:9])[CH:3]=1.[Mg].[CH2:11](Br)[CH:12]=[CH2:13].Cl>O1CCCC1>[Cl:9][C:4]1[CH:3]=[C:2]([CH2:13][CH:12]=[CH2:11])[CH:7]=[CH:6][C:5]=1[F:8]
Reactant: C=CCBr
Reactant: Fc1ccc(Br)cc1Cl
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CCc1ccc(F)c(Cl)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 71 %

Procedure:
The corresponding arylmagnesium bromide was prepared from 406 g (1.94 mol) of 4-bromo-2-chlorofluorobenzene and 48.6 g (2.00 mol) of magnesium turnings in 1,300 ml of anhydrous tetrahydrofuran by the customary process. The solution thus obtained was added dropwise to a solution of 278.3 g (2.3 mol) of allyl bromide in 200 ml of anhydrous tetrahydrofuran at 30°-45° C. The mixture was then heated under reflux for 0.5 h, allowed to stand at room temperature for 16 h and poured onto 1.5 liters of ice-water. After acidification using a little 2N hydrochloric acid, the mixture was extracted twice using 1 liter of hexane each time. The extracts were washed three times with water, dried over Na2SO4 and evaporated. The residue yielded 235 g (71%) of 3-(3-chloro-4-fluorophenyl)propene of b.p.10 =72° C. with a purity of 98.7% (determined by gas chromatography) on subsequent distillation.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH2:25]([NH2:29])[CH:26]([CH3:28])[CH3:27]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:29][CH2:25][CH:26]([CH3:28])[CH3:27])=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: CC(C)CN
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NCC(C)C)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and isobutylamine. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.92 (d, J=6.57 Hz, 6H) 1.87 (dt, J=13.52, 6.63 Hz, 1H) 2.44 (s, 3H) 3.13 (t, J=6.32 Hz, 2H) 7.67 (d, J=8.08 Hz, 1H) 7.74 (s, 1H) 7.78 (br. s., 1H) 8.18 (br. s., 1H) 8.43 (d, J=6.82 Hz, 2H) 8.70 (t, J=5.31 Hz, 1H) 8.92 (s, 1H) 13.18 (br. s., 1H). MS m/z [M+H]+ 376.2.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=[O:11].[CH2:13](O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: OCc1ccccc1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)c1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 7.2 %

Procedure:
A solution of 19.9 g (124 mmol) of indole-2-carboxylic acid, 16 ml (155 mmol) of benzyl alcohol, and 3.0 g (25 mmol) of 4-dimethylaminopyridine in 800 ml of dichloromethane was treated with 25.6 g (124 mmol) of N,N'-dicyclohexylcarbodiimide and stirred at ambient temperature for 2.5 h. The resulting mixture was filtered, concentrated in vacuo, taken up in 1 l of ethyl acetate, and filtered. The solution was subsequently washed sequentially with 1N NCl, H2O, saturated NaHCO3, and saturated brine, dried over MgSO4, and concentrated. Recrystallization of the residue from ethyl acetate/hexane gave three crops of crystalline material containing 15.79 g, 11.13 g, and 2.25 g of the desired compound (94%). 1H NMR (CDCl3) δ 5.40 (s,2H), 7.26 (br t,1H), 7.3-7.5 (m,8H), 7.69 (br d,1H), 8.9 (br s,1H). Mass spectrum: (M+H)+ =252.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]([NH:12][C:13]([O:15][CH3:16])=[O:14])=[CH:5][CH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1>CO.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:17])[CH:4]([NH:12][C:13]([O:15][CH3:16])=[O:14])[CH2:5][CH:6]1[CH2:7][CH2:8][O:9][CH2:10][CH2:11]1
Reactant: COC(=O)NC(=CC1CCOCC1)C(=O)OC
Solvent: CO
Solvent: ClCCl
Product: COC(=O)NC(CC1CCOCC1)C(=O)OC
Reaction time: 72 h
Yield: 78.7 %

Procedure:
A solution of 2-Methoxycarbonylamino-3-(tetrahydro-pyran-4-yl)-acrylic acid methyl ester (0.14 g, 0.57 mmol) in MeOH (2.1 mL) and CH2Cl2 (0.21 mL) was degassed with argon for 2 min. (S,S)-Me-BPE-Rh (0.02 g, 0.03 mmol) was added and the solution was degassed with argon for an additional 2 min. The solution was shaken on a Parr apparatus under an H2 atmosphere (65 psi) for 3 days. The reaction was concentrated and the crude oil was purified by column chromatography (SiO2, 20→100% EtOAc in Hexanes) to provide 2-Methoxycarbonylamino-3-(tetrahydro-pyran-4-yl)-propionic acid methyl ester (0.11 g, 77%). LCMS-ESI+: calc'd for C11H19NO5: 245.13 (M+); Found: 246.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8](SC)=[N:7][C:6]=2[CH:18]=1.C(OC(N[NH:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)=O)(C)(C)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]([N:31]3[CH2:32][CH2:33][CH:28]([NH2:27])[CH2:29][CH2:30]3)=[N:7][C:6]=2[CH:18]=1
Reactant: CC(C)(C)OC(=O)NNC1CCNCC1
Reactant: CSC1=Nc2cc(Cl)ccc2Nc2ccccc21
Product: NC1CCN(C2=Nc3cc(Cl)ccc3Nc3ccccc32)CC1
Yield: 18.1 %

Procedure:
8-Chloro-11-methylsulfanyl-5H-dibenzo[b,e][1,4]diazepine (166JO50) (50 mg, 0.11 mmol) and 4-(tert-butoxycarbonylamino)aminopiperidine (39 mg, 0.2 mmol) were reacted according to GP8 to give 6.5 mg of the title compound (166JO55). MS (ESI) 327 (MH+). Purity for MH+ (UV/MS) 100/99.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[CH3:17][N:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19](Cl)=[O:20]>>[C:8]1([NH:7][C:5]([C:4]2[CH:3]=[C:2]([O:1][C:19](=[O:20])[N:18]([CH3:17])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:16]=[CH:15][CH:14]=2)=[O:6])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: O=C(Nc1ccccc1)c1cccc(O)c1
Product: CN(C(=O)Oc1cccc(C(=O)Nc2ccccc2)c1)c1ccccc1

Procedure:
The title product was prepared from 3-hydroxy-N-phenyl-benzamide and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (54%, white solid). HPLC-MS: m/z=347.2 (M+1); Rt: 4.01 min.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:4]2[CH:3]=1.[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][NH2:20].C(N(CC)C(C)C)(C)C>C(O)C>[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][NH:20][C:2]1[CH:3]=[CH:4][N:5]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:6]2[N:7]=1
Reactant: COC(=O)c1cnn2cnc(Cl)cc12
Reactant: NCc1cccc(F)c1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cnn2ccc(NCc3cccc(F)c3)nc12
Yield: 80 %

Procedure:
A solution of methyl 5-chloropyrazolo[1,5-c]pyrimidine-3-carboxylate (240 mg, 1.1 mM, 1.0 equiv), 3-fluorobenzylamine (200 uL, 2.0 mM, 2.0 equiv), 30 mL of ethanol and 400 uL of N,N-diisopropylethylamine (2.0 mM, 2 equiv) were combined and heated under reflux for 4 hours. The mixture was concentrated and the product collected by filtration and washed with cold ethanol to give 271 mg (80%) of methyl 5-(3-fluorobenzylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylate LCMS (ESI) m+H=301.2, 1H NMR (400 MHz, DMSO-d6) δ: 8.56 (d, 1H), 8.41 (m 1H), 8.17 (s, 1H), 7.35 (m, 3H), 7.08 (td, 1H), 6.44 (d, 1H), 4.61 (d, 2H), 3.74 (s, 3H).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][C:9](=[N:28][OH:29])[C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[O:24][C:25](=[O:27])[CH3:26])[CH2:6]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:37][CH2:38][CH2:39][Cl:40].O>CC(CC)=O>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][C:9](=[N:28][O:29][CH2:37][CH2:38][CH2:39][Cl:40])[C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[O:24][C:25](=[O:27])[CH3:26])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: ClCCCBr
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC(=NO)[C@H]3[C@@H]4CC[C@H](OC(C)=O)[C@@]4(C)CC[C@@H]32)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC(=NOCCCCl)[C@H]3[C@@H]4CC[C@H](OC(C)=O)[C@@]4(C)CC[C@@H]32)C1
Reaction time: 8 h
Yield: 58.8 %

Procedure:
A mixture of 7-oximino-5-androstene-3β,17β-diol diacetate (1 g, 2.48 mmol) and anhydrous potassium carbonate (2 g) was stirred and refluxed in ethyl methyl ketone (100 Ml) at 110° C. for 3 h. 1-Bromo-3-chloropropane (0.25 Ml, 2.48 mmol) was added to the reaction mixture and further refluxed for 20 h with continuous stirring. The completion of the reaction was monitored by TLC. The slurry was cooled, filtered and excess of solvent was removed under reduced pressure to obtain an oily residue. Iced water was added to the oily residue and it was allowed to stand overnight. The precipitate obtained was filtered, washed with water, dried and crystallized from pet-ether (60-80° C.) to afford 7-[O-(3-chloropropyl)oximino]-5-androstene-3β,17β-diol diacetate (23) (0.7 g, 58.82%), mp 155° C. (Decomp).
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:5]1([NH:39][CH2:40][CH2:41][NH:42]S(C)(=O)=O)[CH2:4][CH2:3]2.[CH3:47][CH:48]([S:50](Cl)(=[O:52])=[O:51])[CH3:49]>>[CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:21])([CH3:22])[C:14]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:5]1([NH:39][CH2:40][CH2:41][NH:42][S:50]([CH:48]([CH3:49])[CH3:47])(=[O:52])=[O:51])[CH2:4][CH2:3]2
Reactant: CC(C)S(=O)(=O)Cl
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCNS(C)(=O)=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NCCNS(=O)(=O)C(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(methylsulfonamido)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid using propane-2-sulfonyl chloride as the reagent in Step 1. The product was isolated as a colorless oil (3.5 mg, 34%). LCMS: m/e 679.55 (M+H)+, 2.36 min (method 11). 1H NMR (400 MHz, CHLOROFORM-d) δ 9.56 (br. s., 1H), 7.98 (d, J=8.5 Hz, 2H), 7.23 (d, J=8.3 Hz, 2H), 6.91 (t, J=6.3 Hz, 1H), 5.94 (br. s., 1H), 5.18 (d, J=4.5 Hz, 1H), 4.87 (s, 1H), 4.71 (s, 1H), 3.88-3.69 (m, 1H), 3.63-3.49 (m, 1H), 3.37-3.16 (m, 3H), 2.90-2.68 (m, 1H), 2.26-1.07 (m, 22H), 1.70 (s, 3H), 1.44 (dd, J=8.8, 6.8 Hz, 6H), 1.20 (s, 3H), 1.02 (s, 3H), 0.96 (s, 3H), 0.96 (s, 3H), 0.92 (s, 3H).
Reaction SMILES: C([Li])CCC.[NH2:6][C:7]1[O:11][N:10]=[C:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=1.O1CCCC1.[C:24](=[O:26])=[O:25]>CCCCCC>[NH2:6][C:7]1[O:11][N:10]=[C:9]([CH:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:24]([OH:26])=[O:25])[N:8]=1
Reactant: O=C=O
Reactant: Nc1nc(Cc2ccccc2)no1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Nc1nc(C(C(=O)O)c2ccccc2)no1
Reaction time: 2 h

Procedure:
260 g. (0.507 mole + 20%) of a 15% solution of butyl lithium in n-hexane is cooled to -60° under nitrogen. At this temperature a solution of 27.6 g. of 5-amino-3-(phenylmethyl)-1,2,4-oxadiazole in 300 ml. of absolute tetrahydrofuran is added dropwise with stirring over a period of about 21/2 hours. The reaction mixture is stirred for an additional 30 minutes. Then over a period of 2 hours a proportionate stream of carbon dioxide is passed through the mixture. The cold bath is removed and the reaction mixture is permitted to come to room temperature. This mixture is concentrated in a rotary evaporator, the residue is treated with water and adjusted to pH 8. The aqueous solution is extracted with ether and the aqueous phase is acidified with 2N hydrochloric acid. The precipitate is filtered under suction and reprecipitated twice by dissolving in dilute sodium hydroxide solution and acidifying with dilute hydrochloric acid. 7.4 g. of 5-amino-α-phenyl-1,2,4-oxadiazole-3-acetic acid are obtained, m.p. 163°-164° (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][C:12](=[O:15])[CH2:13]Cl)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH:16]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)C(C)C)(C)C.[I-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][C:12](=[O:15])[CH2:13][N:32]2[CH2:33][CH2:34][N:29]([CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:30][CH2:31]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=C(CCl)Nc1ccc(Cl)cc1C(=O)O
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CN1CCN(C(c2ccccc2)c2ccccc2)CC1)Nc1ccc(Cl)cc1C(=O)O
Yield: 11 %

Procedure:
1.0 g (4.0 mmol) of 5-chloro-2-[(chloroacetyl)amino]benzoic acid obtained in Example 72-(i), 1.0 g (4.0 mmol) of 1-benzhydrylpiperazine, 1.1 g (8.8 mmol) of N,N-diisopropylethylamine, and 60 mg (0.4 mmol) of sodium iodide were stirred in 5 mL of DMF solution at 80° C. for 3 hours. Thereafter, the solvent was distilled off under reduced pressure, H2O was added to the residue, and solids were collected by filtration and dried. The obtained crude product was separated and purified by silica gel column chromatography, and the resultant was then recrystallized using ethyl acetate/n-hexane, thereby giving 198 mg of the target 5-chloro-2-({[4-(diphenylmethyl)piperazine-1-yl]acetyl}amino)benzoic acid (yield: 11%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH3:2].[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([F:22])[CH:21]=1)[CH:17]=O>C(O)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:17][C:16]2[CH:15]=[C:14]([F:13])[CH:21]=[C:20]([F:22])[CH:19]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=Cc1cc(F)cc(F)c1
Solvent: CCO
Product: CCOC(=O)c1ccc(N=Cc2cc(F)cc(F)c2)cc1
Temperature: 25 °C
Yield: 73.8 %

Procedure:
A mixture of 4-amino-benzoic acid ethyl ester (3.3 g, 20 mmol) and 3,5-difluoro-benzaldehyde (2.84 g, 20 mmol) in ethanol (50 mL) was heated to reflux for 2 h. Then the reaction mixture cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 4-{[1-(3,5-difluoro-phenyl)-methylidene]-amino}-benzoic acid ethyl ester (4.27 g, 74%) as a white solid: LC/MS m/e calcd for C16H13F2NO2 (M+H)+: 290.3, observed: 290.2.