Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:32]=[CH:31][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[C:21]([C:22]4[CH:27]=[CH:26][N:25]=[C:24]([NH:28][CH3:29])[N:23]=4)=[CH:20][CH:19]=[CH:18][N:17]=3)=[C:11]([CH3:30])[CH:10]=2)=[O:7])=[CH:4][C:3]=1[C:33]([F:36])([F:35])[F:34].[CH3:37][N:38]([CH3:43])[CH2:39][CH2:40][NH:41][CH3:42]>CN(C=O)C.C(OCC)(=O)C>[CH3:37][N:38]([CH3:43])[CH2:39][CH2:40][N:41]([CH3:42])[C:2]1[CH:32]=[CH:31][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[C:21]([C:22]4[CH:27]=[CH:26][N:25]=[C:24]([NH:28][CH3:29])[N:23]=4)=[CH:20][CH:19]=[CH:18][N:17]=3)=[C:11]([CH3:30])[CH:10]=2)=[O:7])=[CH:4][C:3]=1[C:33]([F:34])([F:36])[F:35]
Reactant: CNc1nccc(-c2cccnc2Oc2ccc(NC(=O)c3ccc(F)c(C(F)(F)F)c3)cc2C)n1
Reactant: CNCCN(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNc1nccc(-c2cccnc2Oc2ccc(NC(=O)c3ccc(N(C)CCN(C)C)c(C(F)(F)F)c3)cc2C)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 4-fluoro-N-(3-methyl-4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-3-(trifluoromethyl)benzamide (0.10 g, 0.22 mmol) and N1,N1,N2-trimethylethane-1,2-diamine (0.045 g, 0.44 mmol) in DMF (2 mL) was heated to 100 deg. C. for 48 h. Additional N1,N1,N2-trimethylethane-1,2-diamine (0.045 g, 0.44 mmol) was added, and the reaction heated for 6 h. Additional N1,N1,N2-trimethylethane-1,2-diamine (0.045 g, 0.44 mmol) was added, and the reaction heated for 48 h. The reaction was cooled to ambient temperature, was diluted with ethyl acetate, and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a solid. Purification by reverse-phase HPLC using acetonitrile/water/TFA as eluent gave 4-((2-(dimethylamino)ethyl)(methyl)amino)-N-(3-methyl-4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-3-(trifluoromethyl)benzamide as a white solid. MS m/z=580 [M+1]+. Calc'd for C30H32F3N7O2: 579.62.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[NH:10][C:11]([N:13]1[CH:17]=[CH:16]N=C1)=[S:12].[CH3:18][O:19][C:20]1[CH:21]=[C:22](CCN)[CH:23]=[CH:24][CH:25]=1.C(OCC)(=O)C>CN(C)C=O>[CH3:18][O:19][C:20]1[CH:25]=[C:24]([CH2:16][CH2:17][NH:13][C:11]([NH:10][C:2]2[NH:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[S:12])[CH:23]=[CH:22][CH:21]=1
Reactant: S=C(Nc1nc2ccccc2[nH]1)n1ccnc1
Reactant: COc1cccc(CCN)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cccc(CCNC(=S)Nc2nc3ccccc3[nH]2)c1
Temperature: 25 °C
Yield: 73.5 %

Procedure:
A solution of 1-[(2-benzimidazolyl)thiocarbamoyl]imidazole (1.22 g, 5.0 mmol) and 2-(3-methoxyphenyl)ethylamine (0.78 g, 5.0 mmol) in N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, 1N aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was purified by chromatography on silica gel to provide 1.2 g (73%) of the titled product as a white solid:
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[K+].[Br-].[F:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=1[C:22](=O)[CH3:23]>C1(C)C=CC=CC=1.C1COCC1>[F:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=1[C:22]([CH3:23])=[CH2:1]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(=O)c1cc([N+](=O)[O-])ccc1F
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=C(C)c1cc([N+](=O)[O-])ccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
KHMDS(1 eq) in toluene is added dropwise over 5 minutes to a stirred suspension of triphenylphosphinemethyl bromide(1.2 eq) in THF at −78° C. under nitrogen. After complete addition solution is allowed to warm to room temperature for 5 minutes then cooled a second time to −78° C. 1-(2-fluoro-5-nitrophenyl)ethanone(1 eq) in THF is then added via cannulla into the cold suspension over 10 minutes. Resulting mixture is then allowed to warm to room temperature and stirred for 1 h. Solvent is then removed under reduced pressure, cyclohexane is then added and mixture heated briefly to reflux, cooled to room temperature, filtered and filtrate concentrated. Crude product is purified using flash chromatography(85% Hex:15% EtoAc) on silica to afford 1-fluoro-4-nitro-2-(prop-1-en-2-yl)benzene.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.CO[CH:21]=[C:22]([C:27]([O:29][CH3:30])=[O:28])[C:23]([O:25][CH3:26])=[O:24].O>CN(C)C=O>[C:13]([NH:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:1][CH:21]=[C:22]([C:27]([O:29][CH3:30])=[O:28])[C:23]([O:25][CH3:26])=[O:24])=[N:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1)(=[O:18])[C:14]([CH3:15])([CH3:17])[CH3:16]
Reactant: CC(C)(C)C(=O)Nc1ccc2c(N)ncnc2c1
Reactant: COC=C(C(=O)OC)C(=O)OC
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(=CNc1ncnc2cc(NC(=O)C(C)(C)C)ccc12)C(=O)OC
Temperature: 100 °C
Reaction time: 0.42 h
Yield: 82.5 %

Procedure:
A mixture of 4-amino-7-pivalamidoquinazoline (10.5 g) and dimethyl methoxymethylenepropanedioate (10.9 g) in N,N-dimethylformamide (32 ml) was stirred at 100° C. for 1 hour and 25 minutes. After the reaction mixture was cooled to ambient temperature, water was added. The resulting solid was separated by filtration, washed with water and dried. The crustals were recrystallized from a mixture of ethyl acetate and ethanol to give crystalline dimethyl [[7-pivalamido-4-quinazolinylamino]methylene]propanedioate (13.7 g).
Reaction SMILES: N[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11](=[O:13])[CH3:12])[C:3]=1[C:4]([OH:6])=[O:5].Cl.N([O-])=O.[Na+].[S-:19][S-].[Na+].[Na+]>O>[SH:19][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11](=[O:13])[CH3:12])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CC(=O)c1cccc(N)c1C(=O)O
Reactant: [S-][S-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)c1cccc(S)c1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.4 %

Procedure:
10.2 g of 2-amino-6-acetylbenzoic acid was converted into a diazonium salt with a mixture of 14.2 ml of concentrated hydrochloric acid, 40 ml of water and 4.3 g of sodium nitrite, and the diazonium salt was gradually added dropwise at a temperature of 0 to 5° C. to a sodium disulfide aqueous solution (prepared from 14.3 g of sodium sulfide.9H2O, 1.9 g of sulfur, 4.6 g of sodium hydroxide and 30 ml of water). After adding dropwise, the reaction liquor was stirred for 2 hours at room temperature to complete the reaction. The reaction liquor was poured into a large amount of water, and after adding concentrated hydrochloric acid thereto, the product was extracted with ethyl acetate. To the ethyl acetate layer, was added sodium hydrogencarbonate aqueous solution, and the content soluble in sodium hydrogencarbonate was extracted. To the resultant aqueous solution, was added 14.8 g of sodium pyrosulfate, and the mixture was refluxed for 30 minutes to complete the reaction. To the reaction liquor, was added concentrated hydrochloric acid, and the product was extracted with ethyl acetate. The extracted liquor was dried, and the solvent was distilled off under reduced pressure to obtain 10.1 g of 2-mercapto-6-acetylbenzoic acid at a yield of 90%.
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]([F:12])[C:3]=1[C:4]([NH2:6])=[O:5].S([O-])([O-])(=O)=O.[NH4+].[NH4+].[CH2:20](OC(OCC)OCC)C.C(OC(=O)C)(=O)C>>[F:12][C:7]1[CH:8]=[CH:9][C:10]([F:11])=[C:2]2[C:3]=1[C:4]([OH:5])=[N:6][CH:20]=[N:1]2
Reactant: CCOC(OCC)OCC
Reactant: NC(=O)c1c(F)ccc(F)c1N
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: CC(=O)OC(C)=O
Product: Oc1ncnc2c(F)ccc(F)c12
Temperature: 145 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
2-Amino-3,6-difluorobenzamide (2.0 g, 11.6 mmol), ammonium sulfate (0.15 g, 1.16 mmol), triethylorthoformate (4.3 g, 4.8 mL, 29.1 mmol) and acetic anhydride (3.0 g, 2.8 mL, 29.1 mmol) were combined in a 100 mL round bottomed flask and the mixture heated to 145° C. on a heating mantle, becoming nearly homogeneous around 90° C., then precipitating additional solid. After 1 h, the mixture was cooled to room temperature and diluted with water and stirred. The precipitated solids were collected by filtration, washed with water and dried to give 1.95 g of 5,8-difluoroquinazolin-4-ol as a white solid. A second crop of 0.13 g was collected from the cold concentrated filtrate, 98% overall. M.P. 257-258° C., LC/MS (ESI) m/z 182, 1H NMR (300 MHz, d6-DMSO) δ 12.48 (bs, 1H), 8.13 (s, 1H), 7.70 (m, 1H), 7.27 (m, 1H).
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][CH:37]3[CH2:41][CH2:40][NH:39][CH2:38]3)[CH:30]=2)=[CH:24][CH:23]=1)[C:9]1[C:10]([CH3:20])=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:44]([BH3-])#N.[Na+]>CC#N.CO>[CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][CH:37]3[CH2:41][CH2:40][N:39]([CH3:44])[CH2:38]3)[CH:30]=2)=[CH:24][CH:23]=1)[C:9]1[C:10]([CH3:20])=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCC3CCNC3)c2)cc1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCC3CCN(C)C3)c2)cc1

Procedure:
The product from Example 93D (0.030 g, 0.0525 mmoles) in 1:1 CH3CN/MeOH (2 mL) was treated with 37% aqueous formaldehyde (0.020 mL, 0.263 mmoles) and sodium cyanoborohydride (0.008 g, 0.131 mmoles). Reaction mixed overnight at room temperature. Reaction quenched with two drops acetic acid and concentrated under reduced pressure. The residue was purified by preparative HPLC (CH3CN:0.1% TRIFLUOROACETIC ACID in H2O) on a YMC ODS Guardpak column to provide the title compound. 1H NMR (500 MHz, DMSO) δ8.96 (s, 1 H), 7.25 (m, 7 H), 7.20 (m, 1 H), 7.05 (m, 1 H), 6.97 (d, 2 H), 6.92 (d, 2 H), 6.70 (m, 1 H), 6.56 (dd, 1 H), 6.53 (dd, 1 H), 4.06 (s, 2 H), 4.03 (s, 2 H), 3.95 (m, 1 H), 3.50-3.80 (m, 1 H), 3.30-3.50 (m, 1 H), 3.00-3.20 (m, 2 H), 2.92 (s, 3 H), 2.80 (m, 5 H), 2.40 (s, 3 H), 2.00-2.30 (m, 1 H), 1.80 (m, 1 H); MS (ESI+) m/z 586 (M+H)+.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:22])[NH:5][C:6]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]([C:10]([OH:12])=O)=[CH:8][N:7]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Cl:56][C:57]1[CH:63]=[CH:62][CH:61]=[CH:60][C:58]=1[NH2:59]>CN(C=O)C>[Cl:56][C:57]1[CH:63]=[CH:62][CH:61]=[CH:60][C:58]=1[NH:59][C:10](=[O:12])[C:9]1[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][C:6]([NH:5][C:4]([NH:3][CH2:1][CH3:2])=[O:22])=[N:7][CH:8]=1
Reactant: Nc1ccccc1Cl
Reactant: CCNC(=O)Nc1cc(Nc2ccccc2)c(C(=O)O)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1cc(Nc2ccccc2)c(C(=O)Nc2ccccc2Cl)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.2 %

Procedure:
To an ice-cold solution of 6-(3-ethylureido)-4-(phenylamino)nicotinic acid (50 mg, 0.16 mmol, 1.0 eq) in DMF (2.0 mL) was added HBTU (91 mg, 0.24 mmol, 1.50 eq) followed by DIPEA (62 mg, 0.48 mmol, 3.0 eq) and finally 2-chloroaniline (24 mg, 0.19 mmol, 1.20 eq). The resulting reaction mixture was stirred overnight at room temperature. The reaction mass was then poured onto ice-cold water followed by extraction with EtOAc (3×20 mL). The organics were combined, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified over silica gel (60-120 M, 1-2.5% MeOH-DCM) to obtain Compound 9 (10 mg, 15%). NMR (300 MHz, DMSO-d6): δ 10.17 (br s, 1H), 10.08 (br s, 1H), 9.12 (s, 1H), 8.67 (s, 1H), 7.87 (m, 1H), 7.56 (m, 1H), 7.24-7.40 (m, 8H), 7.15 (m, 1H), 3.14 (m, 2H), 1.06 (t, J=7.20 Hz, 3H). [M+H]+ m/z=410.15.
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]([OH:13])[CH:7]=1)[C:3]([OH:5])=[O:4].[N+:14]([O-])([OH:16])=[O:15].[OH-].[Na+]>O>[NH2:1][CH:2]([C:6]1[CH:7]=[C:8]([OH:13])[CH:9]=[C:10]([OH:12])[C:11]=1[N+:14]([O-:16])=[O:15])[C:3]([OH:5])=[O:4]
Reactant: O=[N+]([O-])O
Reactant: NC(C(=O)O)c1cc(O)cc(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(C(=O)O)c1cc(O)cc(O)c1[N+](=O)[O-]
Temperature: -10 °C

Procedure:
2-Amino-2-(3,5-dihydroxyphenyl)-acetic acid (183 mg, 1 mmol) was added portionwise to stirred 5.5M nitric acid (2.5 ml, 15 mmol), which has been cooled to -10° C. in an ice/salt bath. The resulting brown solution was diluted with water (2 ml), neutralised with 2M sodium hydroxide, and purified by cationic exchange chromatography (as in Example 14) to give the title compound as a fluffy yellow solid, m.p. >280° C.
Reaction SMILES: C(N(CC)CC)C.S(O/[N:19]=[C:20](\[C:27]#[N:28])/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(C1C=CC(C)=CC=1)(=O)=O.[SH:29][CH2:30][C:31]([O:33][CH3:34])=[O:32]>CO>[NH2:28][C:27]1[C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[N:19][S:29][C:30]=1[C:31]([O:33][CH3:34])=[O:32]
Reactant: Cc1ccc(S(=O)(=O)O/N=C(\C#N)c2ccccc2)cc1
Reactant: COC(=O)CS
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1snc(-c2ccccc2)c1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.3 %

Procedure:
Triethylamine (5.39 g, 53.3 mmol) was added dropwise to a stirred solution of (Z)—N-(tosyloxy)benzimidoyl cyanide (Preparation 103B, 8 g, 26.6 mmol) and methyl 2-mercaptoacetate (2.86 mL, 32.0 mmol) in MeOH (70 mL) at room temperature. After stirring at room temperature for 3 h, the reaction was cooled and treated with 100 mL ice/water. The resultant solid was filtered and washed with water. The solid was vacuum dried to yield 6 g brown colored solid. Recrystallization from hexane/ethyl acetate yielded the titled compound (3 g) as a beige colored needles. The compound had an LC/MS M+1=235.2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[C:4]([F:12])[CH:3]=1.[F:13][C:14]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:15]=1[NH2:16].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:16][C:15]2[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:14]=2[F:13])=[O:11])=[C:4]([F:12])[CH:3]=1
Reactant: Nc1cc(F)ccc1F
Reactant: O=C(O)Cc1ccc(Br)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccc(Br)cc1F)Nc1cc(F)ccc1F
Temperature: 20 °C
Reaction time: 3 h
Yield: 35.6 %

Procedure:
To a solution of 2-(4-bromo-2-fluorophenyl)acetic acid (180 mg, 0.775 mmol) and 2,5-difluoroaniline (100 mg, 0.775 mmol) in DCM (20 mL) was added Et3N (0.324 mL, 2.324 mmol) and HATU (884 mg, 2.324 mmol) in portions. Then the mixture was stirred at 20° C. for 3 h. After LCMS analysis showed the starting material had disappeared, the solvent was removed in vacuo. Then the crude product was dissolved in DCM and washed with H2O and brine. The organic layer was evaporated to dryness. The crude product which was purified by silica column chromatography (PE/EA 100/1 to 10/1) to afford 2-(4-bromo-2-fluorophenyl)-N-(2,5-difluorophenyl)acetamide (103 mg, 0.276 mmol, 35.6% yield). 1H NMR: (400 MHz, CD3OD) δ 7.87-7.82 (m, 1H), 7.39-7.26 (m, 3H), 7.20-7.13 (m, 1H), 6.90-6.82 (m, 1H), 3.83 (s, 2H); ES-LCMS: m/z 343.9 (M+H).
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][C:18]([CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])=[CH:19][CH2:20]Br>CN(C)C=O.O>[N+:7]([C:6]1[CH:5]=[CH:4][C:3]([O:10][CH2:20][CH:19]=[C:18]([CH3:17])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])=[CH:2][CH:1]=1)([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(C)=CCCC(C)=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)=CCCC(C)=CCOc1ccc([N+](=O)[O-])cc1
Reaction time: 12 h

Procedure:
To a solution of p-nitrophenol (2 g.) in dimethylformamide (10 ml.) is added anhydrous potassium carbonate (2 g.) and 3,7-dimethylocta-2,6-dienyl bromide (3.1 g.). The reaction is kept at 50° for 12 hours, diluted with water and extracted with ether. The ethereal extract is washed with 5% aqueous sodium hydroxide and dried over sodium sulfate. The crude product is purified by distillation to yield 3,7-dimethylocta-2,6-dienyl p-nitrophenyl ether.
Reaction SMILES: [F:1][C:2]1[C:11]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:10][C:9]2[NH:8][CH:7]=[C:6]3[C:18](=[O:27])[N:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:20]=[C:5]3[C:4]=2[CH:3]=1.F[C:29]1C(F)=CC2C3C(C(=O)N(C4C=CC=CC=4)N=3)=CNC=2C=1.N1CCCNCC1>>[F:1][C:2]1[C:11]([N:12]2[CH2:13][CH2:14][CH2:29][NH:15][CH2:16][CH2:17]2)=[CH:10][C:9]2[NH:8][CH:7]=[C:6]3[C:18](=[O:27])[N:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:20]=[C:5]3[C:4]=2[CH:3]=1
Reactant: O=c1c2c[nH]c3cc(F)c(F)cc3c-2nn1-c1ccccc1
Reactant: O=c1c2c[nH]c3cc(N4CCNCC4)c(F)cc3c-2nn1-c1ccccc1
Agent: C1CNCCNC1
Product: O=c1c2c[nH]c3cc(N4CCCNCC4)c(F)cc3c-2nn1-c1ccccc1

Procedure:
The title compound was prepared following the procedure described in the synthesis of 28a using 27a and homopiperazine. 1H-NMR (DMSO-d6) δ (ppm): 1.98 (2H, brm), 2.48 (2H, brm), 2.67 (2H, brm), 3.45 (4H, brm), 7.15 (2H, m), 7.40 (2H, m), 7.76 (1H, d, J=2.91 Hz), 8.20 (2H, m), 8.64 (1H, s). m/z 378.2 (MH+).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O.O>CC(C)=O>[F:19][C:20]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=1[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:6][CH:7]=1
Reactant: CCCCCc1ccc(I)cc1
Reactant: OB(O)c1cccc(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCCCCc1ccc(-c2cccc(F)c2F)cc1
Temperature: 40 °C

Procedure:
1-Iodo-4-pentylbenzene (82 g, 0.3 mol), potassium carbonate (100 g, 0.72 mol), 2,3-difluorophenyl boronic acid (47 g, 0.3 mol), water (100 ml) and acetone (300 ml) were placed in a round-bottom three necked flask equipped with condenser, thermometer, mechanical stirrer, nitrogen inlet and outlet. The reaction flask was flushed with nitrogen and minor flow was held during whole reaction time. The mixture was heated up to the boiling point to degas the reaction system and then cooled down to 40° C. and the catalyst palladium acetate (0.1 g) was added. The temperature has increased by a few degrees and the solution turned brown. The mixture was refluxed for three days, then it was cooled down, poured on cold water and extracted with dichlorometane and the organic phase separated, dried over MgSO4 and dichlorometane was distilled off. The residue was distilled under reduced pressure at 0.2 mmHg collecting the fraction at 133° C. The colorless liquid fraction 41.5 g of was obtained, 53% of theor. yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][Si](C=[N+]=[N-])(C)C>CO.C1(C)C=CC=CC=1>[CH3:17][O:15][C:14]([CH:10]1[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]1)=[O:16]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Yield: 83.7 %

Procedure:
To a room temperature solution of piperidine-1,3-dicarboxylic acid-1-tert-butyl ester (5.00 g, 21.81 mmol) in 20% MeOH/toluene (100 ml) was added 14.18 ml of (trimethylsilyl)diazomethane (2.0 M, 28.35 mmol) dropwise and the reaction was monitored by TLC until completion and then concentrated under reduced pressure to yield 4.44 g (83.7%) of piperidine-1,3-dicarboxylic acid 1-tert-butyl ester-3-methyl ester (Intermediate 53). 1H NMR (400 MHz, CDCl3) δ ppm 1.4 (s, 9 H), 1.6 (d, J=3.4 Hz, 1 H), 1.6 (m, 1 H), 1.7 (m, 1 H), 2.0 (m, 1 H), 2.4 (m, 1 H), 2.8 (m, 1 H), 3.0 (s, 1 H), 3.7 (s, 3 H), 3.9 (d, J13.2 Hz, 1 H), 4.1 (s, 1 H).
Reaction SMILES: C(OC(=O)COC1C=CC(SC2C=CC(C=O)=CC=2)=CC=1C)C.[CH2:24]([O:26][C:27](=[O:39])[CH2:28][O:29][C:30]1[CH:35]=[C:34]([CH3:36])[C:33]([SH:37])=[CH:32][C:31]=1[CH3:38])[CH3:25].Cl[C:41]1[CH:48]=[CH:47][C:44]([CH:45]=[O:46])=[CH:43][C:42]=1[CH3:49]>>[CH2:24]([O:26][C:27](=[O:39])[CH2:28][O:29][C:30]1[CH:35]=[C:34]([CH3:36])[C:33]([S:37][C:41]2[CH:48]=[CH:47][C:44]([CH:45]=[O:46])=[CH:43][C:42]=2[CH3:49])=[CH:32][C:31]=1[CH3:38])[CH3:25]
Reactant: Cc1cc(C=O)ccc1Cl
Reactant: CCOC(=O)COc1cc(C)c(S)cc1C
Agent: CCOC(=O)COc1ccc(Sc2ccc(C=O)cc2)cc1C
Product: CCOC(=O)COc1cc(C)c(Sc2ccc(C=O)cc2C)cc1C

Procedure:
The title compound was prepared according to the method described for preparing compound 7.1, using compound 21.3 and 4-chloro-3-methylbenzaldehyde as the starting materials. 1H NMR (400 MHz) (CDCl3) δ 9.86 (1H, s); 7.62 (1H, s); 7.44 (1H, d, J=8.1 Hz); 7.33 (1H, s); 6.70 (1H, s); 6.62 (1H, d, J=8.1 Hz); 4.68 (2H, s); 4.29 (2H, q, J=7.1 Hz); 2.46 (3H, s); 2.29 (3H, s); 2.26 (3H, s); 1.32 (3H, t, J=7.1 Hz).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:17]=[CH:16][C:15]=1[S:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1>>[CH3:12][C:6]1[N:7]=[C:8]2[C:3]([C:2]([NH:13][C:14]3[CH:19]=[C:18]([CH2:20][O:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:17]=[CH:16][C:15]=3[S:28][C:29]3[CH:30]=[CH:31][C:32]([OH:35])=[CH:33][CH:34]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:5]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: Nc1cc(COc2ccccc2)ccc1Sc1ccc(O)cc1
Product: Cc1ccc2c(Nc3cc(COc4ccccc4)ccc3Sc3ccc(O)cc3)ccnc2n1

Procedure:
The product from Example 1d (0.037 g, 0.205 mmol) was reacted with the product from Example 221d (0.066 g, 0.205 mmol) for 16.5 hours following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (0.041 g, 34%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.77 (s, 3H) 5.13 (s, 2H) 6.31 (d, J=6.99 Hz, 1H) 6.79 (d, J=8.46 Hz, 2H) 6.88-7.12 (m, 4H) 7.20-7.36 (m, 4H) 7.46-7.56 (m, 2H) 7.81 (d, J=8.82 Hz, 1H) 8.48 (d, J=6.99 Hz, 1H) 9.02 (d, J=8.46 Hz, 1H) 10.01 (s, 1H); MS (ESI+) m/z 466.3 (M+H)+; (ESI−) m/z 464.2 (M−H)−.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@:25]2([CH3:26])[C:9](=[CH:10][CH:11]=[C:12]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:27])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[CH:17]([CH:19]=[O:20])[CH3:18])[CH2:8][C@@H:7]([O:28][C:29](=[O:31])[CH3:30])[CH2:6]1)(=[O:3])[CH3:2].C[O:33]C(O[C@@H]1[C@@]2(C)C(=CC=C3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2C(C=O)C)C[C@@H](OC(OC)=O)C1)=O>>[C:1]([O:4][C@@H:5]1[C@@:25]2([CH3:26])[C:9](=[CH:10][CH:11]=[C:12]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:27])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[CH:17]([C:19]([OH:33])=[O:20])[CH3:18])[CH2:8][C@@H:7]([O:28][C:29](=[O:31])[CH3:30])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Reactant: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Product: CC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C(=O)O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Yield: 81.7 %

Procedure:
The procedure of Example 6 was repeated except that 105 mg of 1α,3β-diacetoxypregna-5,7-diene-20-carbaldehyde was used in lieu of 120 mg of 1α,3β-bis(methoxycarbonyloxy)pregna-5,7-diene-20-carbaldehyde to give 89 mg of 1α,3β-diacetoxypregna-5,7-diene-20-carboxylic acid.
Reaction SMILES: Cl[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=2[Cl:14])[N:5]=[N:4][N:3]=1.[C:15]1([CH:21]2[CH2:25][CH2:24][CH2:23][NH:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[Cl:14][C:8]1[C:9]([Cl:13])=[CH:10][CH:11]=[CH:12][C:7]=1[N:6]1[C:2]([N:22]2[CH2:23][CH2:24][CH2:25][CH:21]2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:3][N:4]=[N:5]1
Reactant: c1ccc(C2CCCN2)cc1
Reactant: Clc1cccc(-n2nnnc2Cl)c1Cl
Product: Clc1cccc(-n2nnnc2N2CCCC2c2ccccc2)c1Cl
Yield: 20.1 %

Procedure:
The product of Example 75B (0.1 g) was reacted with 2-phenylpyrrolidine (0.1 g) according to the method of Example 75C to provide 0.029 g of the title compound as a white solid. MS (ESI/NH3) m/z 359 (M+H)+. 1H NMR (DMSO-d6) δ 1.78-1.9 (m, 4H), 3.3-3.6 (m, 2H), 4.8-5.0 (m, 1H) 6.8-6.9 (m, 1H), 7.0-7.2 (m, 5H), 7.59-7.65 (t, 1H), 7.79-7.85 (d, 1H), 7.95-7.99 (d, 1H).