Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[C:5]([F:9])=[CH:6][C:7]=1[NH2:8].O.O.[C:16](O)(=[O:20])[C:17](O)=[O:18]>Cl.[OH-].[Na+]>[F:9][C:5]1[CH:6]=[C:7]2[C:2](=[CH:3][C:4]=1[C:10]([F:13])([F:11])[F:12])[NH:1][C:17](=[O:18])[C:16](=[O:20])[NH:8]2
Reactant: Nc1cc(F)c(C(F)(F)F)cc1N
Reactant: O=C(O)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1[nH]c2cc(F)c(C(F)(F)F)cc2[nH]c1=O
Temperature: 25 °C
Yield: 40.3 %

Procedure:
A mixture of 3,4-diamino-6-fluorobenzotrifluoride (270 mg, 1.38 mmol) and oxalic acid dihydrate (200 mg, 1.60 mmol, used as received) in 4N HCl (5 mL) was refluxed at 120°-5° C. for 3 h, then cooled to room temperature. The mixture was centrifuged and the liquid layer was removed. The yellow solid was washed twice with cold water (2×2 mL), collected by filtration, and dried at 60° C. under reduced pressure for 2 h, affording 152 mg of crude title compound (40%) as a light yellow powder. The crude compound was dissolved in 1N NaOH (4 mL) and filtered. The filtrate was acidified to pH=5, affording 138 mg of title compound as a yellow powder. Mp: 330°-333° C. IR (KBr, cm-1) 3398, 3170, 2959, 1701, 1641, 1515; 1398. 1H NMR (DMSO-d6): δ7.079 (d, 1H, J=11.4 Hz); 7.376 (d, 1H, J=5.1 Hz); 12.022 (s, 1H); 12.225 (s, 1H). HRMS: calcd for C9H4F4N2O2 (M+) m/z: 248.0208; found: 248.0220.
Reaction SMILES: [O:1]=[C:2]1[CH:19]=[CH:18][O:17][C:4]2([CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]2)[CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:9]1[C:4]2([O:17][CH:18]=[CH:19][C:2](=[O:1])[CH2:3]2)[CH2:5][CH2:6][NH:7][CH2:8]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)C=CO2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1C=COC2(CCNCC2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 239.9 %

Procedure:
To a solution of tert-butyl 8-oxo-11-oxa-3-azaspiro[5.5]undec-9-ene-3-carboxylate (200 mg, 0.748 mmol) in CH2Cl2 (2.4 mL) was added TFA (0.6 mL, 7.8 mmol). The mixture was stirred at room temperature for 15 min. Solvent was removed. The crude material was evaporated again from toluene (2×) and dried under high vacuum overnight to provide 11-oxa-3-azaspiro[5.5]undec-9-en-8-one (300 mg). 1H NMR (400 MHz, CDCl3) δ 7.34 (d, J=6.1 Hz, 1H), 5.57 (d, J=6.1 Hz, 1H), 3.45 (d, J=11.7 Hz, 2H), 3.34 (dd, J=24.1, 12.7 Hz, 2H), 2.67 (s, 2H), 2.38 (d, J=14.6 Hz, 2H), 1.98 (td, J=14.8, 4.8 Hz, 2H). ESI-MS m/z calc. 167.09, found 168.2 (M+1)+; Retention time: 0.17 minutes (3 minute run).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][N:14]=2)[CH:9]=[CH:8]1.[C:19](Cl)(=[O:23])[C:20]([Cl:22])=[O:21]>COC(C)(C)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][N:14]=2)[C:9]([C:19](=[O:23])[C:20]([Cl:22])=[O:21])=[CH:8]1
Reactant: COc1cccc(Cn2ccc3cccnc32)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: COC(C)(C)C
Product: COc1cccc(Cn2cc(C(=O)C(=O)Cl)c3cccnc32)c1

Procedure:
1-(3-Methoxybenzyl)-7-azaindole (3.57 g, 15 mmoles) is dissolved in 50 mL of t-butyl methyl ether. A solution of 1.54 mL of oxalyl chloride (18 mmoles) in 10 mL of t-butyl methyl ether is added dropwise at 0° C. with stirring. Subsequently, the mixture is refluxed for 2 hours, after which the solvent is distilled off under vacuum. The resulting 1-(3-methoxybenzyl)-7-azaindole-3-yl-glyoxylic acid chloride is obtained as a solid residue, which is suspended in 50 mL of tetrahydrofuran (THF).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH2:10]([NH:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH3:13].CC(C)([O-])C.[Na+]>>[CH2:10]([N:14]([CH2:15][CH2:16][CH2:17][CH3:18])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCNCCCC
Reactant: COc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: CCCCN(CCCC)c1ccc(OC)cc1
Yield: 93.1 %

Procedure:
According to the general procedure B, 4-chloroanisole (150 mg, 1.05 mmol) reacted with N,N-di-n-butylamine (160 mg, 1.24 mmol) using 1 mol % of catalyst and sodium tert-butoxide (120 mg, 1.25 mmol) at 100° C. for 20 h to give the title compound (230 mg, 93%) as an colorless oil: 1H-NMR (400 MHz, CDCl3): δ 6.74 (d, 2H, J=9.2 Hz), 6.58 (d, 2H, J=9.2 Hz), 3.68 (s, 3H), 3.11 (t, 4H, J=8.0 and 7.2 Hz), 1.45 (m, 4H), 1.26 (m, 4H), 0.86 (t, 6H, J=7.6 and 7.2 Hz). 13C{1H}-NMR (100 MHz, CDCl3): δ 150.96, 143.33, 114.79, 114.33, 55.82, 51.65, 29.46, 20.40, 14.02. GC/MS (EI): m/z 235 (M+), 235, 192, 150.
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]3[O:16][CH2:15]3)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[NH2:19][CH2:20][CH2:21][N:22]1[C:26]2[CH:27]=[CH:28][C:29]([C:31]3[CH:32]=[CH:33][C:34](=[O:37])[NH:35][N:36]=3)=[CH:30][C:25]=2[N:24]=[CH:23]1>>[CH:1]1([CH2:4][O:5][CH2:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:19][CH2:20][CH2:21][N:22]3[C:26]4[CH:27]=[CH:28][C:29]([C:31]5[CH:32]=[CH:33][C:34](=[O:37])[NH:35][N:36]=5)=[CH:30][C:25]=4[N:24]=[CH:23]3)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1
Reactant: c1cc(OCC2CO2)ccc1CCOCC1CC1
Reactant: NCCn1cnc2cc(-c3ccc(=O)[nH]n3)ccc21
Product: O=c1ccc(-c2ccc3c(c2)ncn3CCNCC(O)COc2ccc(CCOCC3CC3)cc2)n[nH]1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2cyclopropylmethoxyethyl)phenoxy]-2,3-epoxypropane and 6-[1-(2-aminoethyl)benzimidazol-5-yl]-3(2H)-pyridazinone.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:19][C:20]2[CH:24]=[C:23]([O:25][CH3:26])[NH:22][N:21]=2)=[N:4][C:5]([NH:9][C@H:10]([C:12]2[N:17]=[CH:16][C:15]([F:18])=[CH:14][N:13]=2)[CH3:11])=[N:6][C:7]=1Cl.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.CCN(C(C)C)C(C)C>CCCCO>[Cl:1][C:2]1[C:3]([NH:19][C:20]2[CH:24]=[C:23]([O:25][CH3:26])[NH:22][N:21]=2)=[N:4][C:5]([NH:9][C@H:10]([C:12]2[N:17]=[CH:16][C:15]([F:18])=[CH:14][N:13]=2)[CH3:11])=[N:6][C:7]=1[N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: C1COCCN1
Reactant: COc1cc(Nc2nc(N[C@@H](C)c3ncc(F)cn3)nc(Cl)c2Cl)n[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COc1cc(Nc2nc(N[C@@H](C)c3ncc(F)cn3)nc(N3CCOCC3)c2Cl)n[nH]1
Temperature: 150 °C

Procedure:
A mixture of 5,6-dichloro-N2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N4-(5-methoxy-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (Example 30, 100 mg), morpholine (0.026 mL) and DIPEA (0.066 ml) in n-BuOH (2.0 ml) was charged into a microwave reaction vessel. The vessel was sealed and heated at 150° C. for 24 hours. The solvent was removed under reduced pressure and the residue was purified by Gilson 2%-40% MeCN/H2O, 15 minutes) to give the titled compound as solid (21.8 mg). 1H NMR δ 11.99 (s, 1H) 9.30 (s, 1H) 8.82 (s, 2H) 7.89 (d, 1H) 5.49 (s, 1H) 4.93-5.14 (m, 1H) 3.75 (s, 3H) 3.44-3.62 (m, 4H) 3.09-3.27 (m, 4H) 1.47 (d, 3H) m/z 450.
Reaction SMILES: [NH:1]=[C:2]1[N:6]([C:7]2[S:8][CH:9]=[C:10]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)[N:11]=2)[C:5]([CH3:21])([CH3:20])[CH2:4][O:3]1.C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>O1CCCC1>[C:16]([C:15]1[CH:14]=[CH:13][C:12]([C:10]2[N:11]=[C:7]([N:6]3[C:5]([CH3:21])([CH3:20])[CH2:4][O:3]/[C:2]/3=[N:1]\[S:30]([CH3:29])(=[O:32])=[O:31])[S:8][CH:9]=2)=[CH:19][CH:18]=1)#[N:17]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)COC(=N)N1c1nc(-c2ccc(C#N)cc2)cs1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(C)CO/C(=N\S(C)(=O)=O)N1c1nc(-c2ccc(C#N)cc2)cs1
Reaction time: 8 h
Yield: 6.4 %

Procedure:
4-[2-(2-Imino-4,4-dimethyl-1,3-oxazolidin-3-yl)-1,3-thiazol-4-yl]benzonitrile (0.250 g, 0.83 mmol), prepared in Example 63, was dissolved in tetrahydrofuran (2 mL), followed by triethylamine (0.139 mL, 1 mmol) and methanesulfonyl chloride (0.154 mL, 2 mmol). The mixture was stirred overnight, filtered and the tetrahydrofuran was removed in vacuo. Purification by normal phase HPLC on a phenomenex cyano column and eluting with hexane/1,2-dimethoxyethane (9:1 to 1:9) gave the title compound (0.020 g, 6%). HRMS: calcd for C16H16N4O3S2+H+, 377.07366; found (ESI, [M+H]+), 377.0722. HPLC purity 97.0% at 210-370 nm, 8.5 min; 97.1% at 244 nm, 8.5 min; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:13]([C:14]3[N:18]([CH3:19])[N:17]=[N:16][N:15]=3)=[CH:12][N:11]=[C:10]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:35])(=[N:29]C(OCC)=O)=[O:28])=[CH:23][CH:22]=3)[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])C.[Na+].[Na+].[Cl-]>C(O)C>[CH:1]1([NH:7][C:8]2[C:13]([C:14]3[N:18]([CH3:19])[N:17]=[N:16][N:15]=3)=[CH:12][N:11]=[C:10]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([S:27]([CH3:35])(=[NH:29])=[O:28])=[CH:25][CH:26]=3)[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)N=S(C)(=O)c1ccc(Nc2ncc(-c3nnnn3C)c(NC3CCCCC3)n2)cc1
Agent: CC[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: Cn1nnnc1-c1cnc(Nc2ccc(S(C)(=N)=O)cc2)nc1NC1CCCCC1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
12 mg (0.024 mmol) (RS)—S-(4-{[4-(cyclohexylamino)-5-(1-methyl-1H-tetrazol-5-yl)pyrimidine-2-yl]amino}phenyl)-N-(ethoxycarbonyl)-S-methylsulfoximide (Ex. 3.2) in 1.2 ml ethanol are treated with 0.12 mL (0.18 mmol) of a freshly prepared 1.53 molar sodium ethanolate solution and stirred for 18 hrs at 70° C. The mixture is treated with saturated NaCl solution and extracted with THF. The combined organic phases are dried (Na2SO4), filtered and concentrated. The resulting residue is digested with MTB ether. 9 mg (0.021 mmol, corresponding to 86% of theor.) of the product is obtained.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:4][CH:3]=1.[F:14][C:15]([F:29])([F:28])[C:16]1[CH:17]=[C:18]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[CH3:13][C:10]1[N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:25]3[CH2:24][CH2:23][N:22]([C:18]4[CH:19]=[CH:20][CH:21]=[C:16]([C:15]([F:28])([F:29])[F:14])[CH:17]=4)[CH2:27][CH2:26]3)=[CH:3][CH:4]=2)[S:12][N:11]=1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: Cc1nsc(-c2ccc(F)cc2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nsc(-c2ccc(N3CCN(c4cccc(C(F)(F)F)c4)CC3)cc2)n1
Temperature: 140 °C
Reaction time: 24 h
Yield: 51.5 %

Procedure:
A mixture of 5-(4-fluorophenyl)-3-methyl-1,2,4-thiadiazole (0.012 mol), 1-[3-(trifluoromethyl)phenyl]-piperazine (0.014 mol) and sodium carbonate (0.024 mol) in DMF (10 ml) was stirred at 140° C. for 24 hours, then at 150° C. for 24 hours, cooled, poured out into ice water (200 ml) and stirred. The precipitate was filtered off, taken up in DCM, dried, filtered and the solvent was evaporated. The residue was crystallized from DIPE. The precipitate was filtered off and dried, yielding 2.5 g (52%) of 1-[4-(3-methyl-1,2,4-thiadiazol-5-yl)phenyl]-4-[3-(trifluoromethyl)phenyl]piperazine (compound 2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[CH2:10][C:11]([F:14])([F:13])[F:12])=[C:4]([F:16])[CH:3]=1.[N+:17]([O-])([OH:19])=[O:18]>OS(O)(=O)=O>[Cl:1][C:2]1[CH:7]=[C:6]([N+:17]([O-:19])=[O:18])[C:5]([NH:8][C:9](=[O:15])[CH2:10][C:11]([F:13])([F:14])[F:12])=[C:4]([F:16])[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: O=C(CC(F)(F)F)Nc1ccc(Cl)cc1F
Agent: O=S(=O)(O)O
Product: O=C(CC(F)(F)F)Nc1c(F)cc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 17 %

Procedure:
A solution of N-(4-chloro-2-fluorophenyl)-3,3,3-trifluoropropanamide (2 g, 7.8 mmol) in 15 mL of concentrated H2SO4 was added 1 mL of concentrated nitric acid and stirred at room temperature overnight. The reaction was monitored by LC-MS. The reaction mixture was poured into 20 mL of ice-water. The mixture was filtered to give the solid crude N-(4-chloro-2-fluoro-6-nitrophenyl)-3,3,3-trifluoropropanamide (600 mg, yield: 17%) which was further purified by column chromatography (PE/EtOAc=6/1). MS obsd. (ESI+) [(M+H)+] 301.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([F:9])[C:3]=1[CH2:10][C:11]([OH:13])=O.[NH:14]1[CH2:17][CH2:16][CH2:15]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:14]1([C:11](=[O:13])[CH2:10][C:3]2[C:4]([F:9])=[CH:5][C:6]([OH:8])=[CH:7][C:2]=2[F:1])[CH2:17][CH2:16][CH2:15]1
Reactant: C1CNC1
Reactant: O=C(O)Cc1c(F)cc(O)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Cc1c(F)cc(O)cc1F)N1CCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (2,6-difluoro-4-hydroxyphenyl)acetic acid (0.98 g, 4.95 mmol) in 8 ml anhydrous DMF at RT was added azetidine (0.565 g, 9.89 mmol) and N,N-diisopropylethylamine (2.15 ml, 12.3 mmol). o-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (3.76 g, 9.89 mmol) was added to the solution and the reaction mixture was stirred at RT for 4 hrs. The solution was purified by preparative biotage Reverse phase (C-18) (50 g column), eluting with Acetonitrile/Water+0.1% formic acid (35% to 100%), to afford the title compound. LC/MS (m/z) 242.3 (M+15)+.
Reaction SMILES: [OH-].[Na+].[CH3:3][SH:4].[Na].CS.[Na].[C:9]1([NH:15][C:16](=[O:24])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2Cl)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O>[C:9]1([NH:15][C:16](=[O:24])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[S:4][CH3:3])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Nc1ccccc1)c1ccccc1Cl
Reactant: CS
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Product: CSc1ccccc1C(=O)Nc1ccccc1
Temperature: 25 °C

Procedure:
To a 500 ml four-necked flask equipped with a stirrer, a thermometer, and a condenser, 46.3 g (0.2 mol) of N-phenyl-2-chlorobenzamide obtained in Production Example 1, 100 g of toluene, and 9.3 g of an aqueous solution of 50% by weight tetra-n-butylammonium bromide are placed. Separately, 12.0 g (0.30 mol) of sodium hydroxide and 113.7 g of water are placed into another container under a nitrogen gas atmosphere, and 14.5 g (0.30 mol) of methanethiol are added to the above mixture at room temperature over about 1 hour to prepare 140.2 g of sodium salt solution of methanethiol. 140.2 g (0.3 mol) of the aqueous solution of sodium methyl mercaptan thus prepared is added to the mixture containing N-phenyl-2-chlorobenzamide described above at 80° C. while stirring, to be allowed to react with each other under reflux for 1 hour. After completion of the reaction, the reaction mixture is cooled to room temperature to precipitate white crystals, which are washed with water and then with toluene and dried, to give 46.2 g of N-phenyl-2-(methylthio)benzamide (melting point 148 to 149° C.). The yield of the product against N-phenyl-2-chlorobenzamide is 95%.
Reaction SMILES: [Br:1]Br.[NH:3]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:12]([O:14][CH3:15])=[O:13])[N:5]=[CH:4]1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.C(#N)C>[Br:1][C:4]1[NH:3][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:12]([O:14][CH3:15])=[O:13])[N:5]=1
Reactant: BrBr
Reactant: COC(=O)c1nc[nH]c1C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: COC(=O)c1nc(Br)[nH]c1C(=O)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At ambient temperature 9.50 g (59.45 mmol) bromine were added dropwise to a solution of 9.90 g (53.76 mmol) dimethyl imidazole-4,5-dicarboxylate in 300 ml dichloromethane and 80 ml acetonitrile. 7.46 g (54.00 mmol) potassium carbonate was added, and the reaction mixture was stirred for 2 hours at ambient temperature. Then the dichloromethane was eliminated using the rotary evaporator and the residue was combined with a saturated solution of sodium chloride and sodium thiosulphate. It was extracted ten times with ethyl acetate, the organic extracts were dried over sodium sulphate and then the solvent was eliminated.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]=[C:7]([CH3:10])[CH2:8]Cl)(=[O:3])[CH3:2].C1N2CN3CN(C2)CN1C3.S(=O)(=O)(O)[OH:22]>O>[C:1]([O:4][CH2:5][CH:6]=[C:7]([CH3:10])[CH:8]=[O:22])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC=C(C)CCl
Reactant: O=S(=O)(O)O
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Product: CC(=O)OCC=C(C)C=O
Temperature: 35 °C
Reaction time: 4 h
Yield: 69 %

Procedure:
Crude 4-acetoxy-2-methyl-1-chloro-2-butene (194 g, Purity: 83.8%, 1 mol) was added to hexamethylenetetramine (168 g, 1.2 mol)/water (1 liter), and the mixture was stirred at 35° C. for 4 hours and then separated into aqueous and organic layers. 1,2-Dichloroethane (1 liter) was added to the aqueous layer, the mixture was subjected to reaction at 72° C. for 6 hours while adjusting the pH with 1N sulfuric acid. The 1,2-dichloroethane layer was separated, 1,2-dichloroethane (1 liter) was added, and the reaction was carried out again. The 1,2-dichloroethane layers were combined and concentrated. The residue was distilled under reduced pressure to give 4-acetoxy-2-methyl-2-buten-1-al (98 g, 69%). bp.0.2-0.3 : 58°-66° C.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]([NH2:14])[NH:12][N:13]=2)[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([N+:29]([O-:31])=[O:30])=[C:24]([CH:28]=1)[C:25](Cl)=[O:26]>O1CCCC1.C(OCC)(=O)C>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([N+:29]([O-:31])=[O:30])=[C:24]([CH:28]=1)[C:25]([NH:14][C:11]1[NH:12][N:13]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:15])([F:1])[F:16])[CH:4]=2)[N:10]=1)=[O:26]
Reactant: Nc1nc(-c2cccc(C(F)(F)F)c2)n[nH]1
Reactant: O=C(Cl)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Nc1nc(-c2cccc(C(F)(F)F)c2)n[nH]1)c1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.2 %

Procedure:
To a solution of 5-(3-(trifluoromethyl)phenyl)-2H-1,2,4-triazol-3-amine (100 mg, 0.44 mmol, 1.00 equiv) in tetrahydrofuran (1 mL) was added sodium hydride (35 mg, 0.88 mmol, 2.00 equiv, 60%) followed by the dropwise addition of a solution of 5-chloro-2-nitrobenzoyl chloride (96.49 mg, 0.44 mmol, 1.00 equiv) in tetrahydrofuran (1 mL) and the resulting solution was stirred for 2 h at room temperature. The mixture was diluted with 50 mL of ethyl acetate, washed with 2×20 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to afford 120 mg (67%) of a yellow solid.
Reaction SMILES: [C:1]([O:4][CH:5]1[C@@H:22]2[CH2:23][C@@H:21]2[C@@:20]2([CH3:24])[C@@H:7]([CH2:8][CH2:9][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[OH:25])[CH2:6]1)(=[O:3])[CH3:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl.C(OCC)C>[C:1]([O:4][CH:5]1[C@@H:22]2[CH2:23][C@@H:21]2[C@@:20]2([CH3:24])[C@@H:7]([CH2:8][CH2:9][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:14]2=[O:25])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1C[C@@H]2CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@H]2C[C@@H]12
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)OC1C[C@@H]2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)[C@H]2C[C@@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.5 %

Procedure:
A solution of 6.8 g of 3-acetoxy-1α,2α-methylene-5α-androstan -17β-ol in 68 ml of dichloromethane is combined with 10.2 g of pyridinium chlorochromate and stirred for one hour at room temperature, then diluted with diethyl ether, washed with water, and dried. Evaporation yields 7.0 g of 3-acetoxy-1α, 2α-methylene -5α-androstan-17-one.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:12]=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:15]=1)=[O:10].Br[CH2:23][C:24]([O:26]CC)=[O:25]>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:23][C:24]([OH:26])=[O:25])=[C:3]([C:9]([C:11]2[CH:12]=[N:13][N:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:15]=2)=[O:10])[CH:4]=1
Reactant: CCOC(=O)CBr
Reactant: O=C(c1cnn(-c2ccccc2)c1)c1cc(Cl)ccc1O
Product: O=C(O)COc1ccc(Cl)cc1C(=O)c1cnn(-c2ccccc2)c1

Procedure:
Prepared from (2-hydroxy-5-chlorophenyl)-(1-phenyl-1H-pyrazol-4-yl)-methanone and ethyl bromoacetate according to GP2 and GP3: LC/MS (an10p8): Rt 3.08 min, m/z 356.6 [M+1]+; 1H NMR (CDCl3): δ 4.75 (s, 2H), 6.95 (d, J=8.9 Hz, 1H), 7.33-7.41 (m, 1H), 7.44-7.52 (m, 3H), 7.55 (d, J=2.6 Hz, 1H), 7.69-7.75 (m, 2H), 8.18 (s, 1H), 8.52 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]3[CH3:21])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1>>[CH3:21][C@H:16]1[CH2:17][CH2:18][CH2:19][CH2:20][N:15]1[CH2:14][C:10]1[CH:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=3)[N:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: NCCc1ccc(O)cc1
Reactant: CC1CCCCN1Cc1cccc(-c2ccnc(Cl)n2)c1
Product: C[C@H]1CCCCN1Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 108 was coupled with tyramine following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 404. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.26 (d, 1H), 7.93 (s, 1H), 7.86 (d, 1H), 7.36 (m, 2H), 6.99 (d, 2H), 6.92 (d, 1H), 6.63 (d, 2H), 5.26 (t, 1H), 4.05 (d, 1H), 3.70 (d, 2H), 3.28 (d, 1H), 2.75 (m, 4H), 2.37 (s, 1H), 1.63 (m, 2H), 1.39 (m, 3H), 1.20 (m, 4H).
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)=[O:3].I[C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[O:24][CH2:23][CH2:22][O:21]2)=[C:16]([C:25]([F:28])([F:27])[F:26])[CH:15]=1>C1(C)C=CC=CC=1.CCO>[O:21]1[CH2:22][CH2:23][O:24][CH:20]1[C:17]1[CH:18]=[CH:19][C:14]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([C:2]([NH2:1])=[O:3])[CH:5]=2)=[CH:15][C:16]=1[C:25]([F:26])([F:27])[F:28]
Reactant: FC(F)(F)c1cc(I)ccc1C1OCCO1
Reactant: NC(=O)c1cccc(B(O)O)c1
Solvent: CCO
Solvent: Cc1ccccc1
Product: NC(=O)c1cccc(-c2ccc(C3OCCO3)c(C(F)(F)F)c2)c1

Procedure:
The title compound was prepared from 3-(aminocarbonyl)phenyl boronic acid and 2-[4-iodo-2-(trifluoromethyl)phenyl]-1,3-dioxolane (I-IX-7) according to the procedure described for IX-10, using PhMe/EtOH (4:1) as organic cosolvents. Colorless solid. LC/MS (method A) 2.38 min; m/z 338 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Br)=[C:6]([N+:12]([O-:14])=[O:13])[CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:35]([O:39][C:40](=[O:53])[CH2:41][CH2:42][C:43]1[CH:48]=[C:47]([Cl:49])[C:46]([CH:50]=O)=[C:45]([Cl:52])[CH:44]=1)([CH3:38])([CH3:37])[CH3:36].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:50]/[C:46]2[C:45]([Cl:52])=[CH:44][C:43]([CH2:42][CH2:41][C:40]([O:39][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:53])=[CH:48][C:47]=2[Cl:49])=[C:6]([N+:12]([O-:14])=[O:13])[CH:5]=1
Reactant: CC(C)(C)OC(=O)CCc1cc(Cl)c(C=O)c(Cl)c1
Reactant: COC(=O)c1ccc(CBr)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(/C=C/c2c(Cl)cc(CCC(=O)OC(C)(C)C)cc2Cl)c([N+](=O)[O-])c1
Temperature: 100 °C

Procedure:
To a solution of 4-bromomethyl-3-nitrobenzoic acid methyl ester (1.64 g, 6.0 mmol) in DMF (15 mL) was added triphenylphosphine (1.57 g, 6.0 mmol) and the mixture was heated at 100° C. for 30 min. To this solution was added a solution of 3-(3,5-dichloro-4-formylphenyl)-propionic acid tert-butyl ester (1.50 g, 4.95 mmol) (from Example 6-25) in DMF (5 mL) in one portion, followed by pulverized potassium carbonate (1.37 g, 9.9 mmol) and the mixture was heated at 100° C. for 18 h. The reaction mixture was partitioned between ethyl acetate and water, washed with brine, dried with MgSO4, filtered, and concentrated. The crude residue was purified by flash chromatography on silica gel, eluting with a gradient of 0-50% ethyl acetate/heptane to obtain 4-{(E)-2-[4-(2-tert-butoxycarbonylethyl)-2,6-dichlorophenyl]-vinyl}-3-nitrobenzoic acid methyl ester as a yellow solid. MS (m/z) 497.1 (M+18); 1H NMR (DMSO-d6, 400 MHz) δ 8.49 (d, J=1.64 Hz, 1H), 8.28 (dd. J=8.15, 1.58 Hz, 1H), 8.14 (d, J=8.21 Hz, 1H), 7.47 (s, 2H), 7.47 (d, J=16.7 Hz, 1H), 7.33 (d, J=16.4 Hz, 1H), 3.93 (s, 3H), 2.83 (t, J=7.33 Hz, 2H), 2.58 (t, J=7.33 Hz, 2H), 1.37 (s, 9H).