Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:35]=[CH:34][C:12]([NH:13][C:14]2[CH:26]=[C:25](/[CH:27]=[CH:28]/[C:29]3[CH:33]=[CH:32][S:31][CH:30]=3)[CH:24]=[CH:23][C:15]=2[C:16]([O:18]C(C)(C)C)=[O:17])=[CH:11][CH:10]=1>>[F:8][C:9]1[CH:10]=[CH:11][C:12]([NH:13][C:14]2[CH:26]=[C:25](/[CH:27]=[CH:28]/[C:29]3[CH:33]=[CH:32][S:31][CH:30]=3)[CH:24]=[CH:23][C:15]=2[C:16]([OH:18])=[O:17])=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)c1ccc(/C=C/c2ccsc2)cc1Nc1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(/C=C/c2ccsc2)cc1Nc1ccc(F)cc1

Procedure:
Trifluoroacetic acid 15 mL solution of obtained tert-butyl 2-(4-fluoroanilino)-4-((E)-2-(thiophen-3-yl)vinyl)benzoate was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the obtained residue was refined by reversed-phase silica gel column chromatography [eluent; 70-100% acetonitrile/0.1% trifluoroacetic acid aqueous solution] to give 2-(4-fluoroanilino)-4-((E)-2-(thiophen-3-yl)vinyl)benzoic acid 9 mg of pale yellow solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:13][C:14]([F:32])([F:31])[C:15]1[CH:16]=[CH:17][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][OH:30])=[CH:24][CH:23]=2)=[N:19][CH:20]=1.Cl>C1(C)C=CC=CC=1>[F:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][N:3]=[C:2]2[O:30][CH2:29][CH2:28][C:25]1[CH:24]=[CH:23][C:22]([O:21][C:18]2[CH:17]=[CH:16][C:15]([C:14]([F:32])([F:13])[F:31])=[CH:20][N:19]=2)=[CH:27][CH:26]=1
Reactant: OCCc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: Fc1cccc2c(Cl)ncnc12
Agent: Cl
Solvent: Cc1ccccc1
Product: Fc1cccc2c(OCCc3ccc(Oc4ccc(C(F)(F)F)cn4)cc3)ncnc12

Procedure:
A mixture of 4-chloro-8-fluoroquinazoline (2.12 g, 12 mmol) and 2-(4-(5-(trifluoromethyl)-2-pyridinyloxy)phenyl)ethanol (2.83 g, 10 mmol) in 50 mL of toluene containing a catalytic amount of hydrogen chloride was stirred for several days. The title product was isolated by column chromatography. Yield 1.6 g. MP 116°-118° C.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:8]([C:17]([OH:19])=O)=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:4]([O:22][CH3:23])[CH:3]=1.[NH2:24][C:25]1[CH:26]=[C:27]([S:31]([NH2:34])(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:8]([C:17]([NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([S:31](=[O:33])(=[O:32])[NH2:34])[CH:26]=3)=[O:19])=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:4]([O:22][CH3:23])[CH:3]=1
Reactant: COc1cc(F)ccc1Oc1nc2ccccc2nc1C(=O)O
Reactant: Nc1cccc(S(N)(=O)=O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COc1cc(F)ccc1Oc1nc2ccccc2nc1C(=O)Nc1cccc(S(N)(=O)=O)c1
Yield: 37.1 %

Procedure:
A solution of 3-(4-fluoro-2-methoxy-phenoxy)quinoxaline-2-carboxylic acid (47.1 mg, 0.15 mmol), 3-aminobenzenesulfonamide (31.0 mg, 0.18 mmol), HATU (62.7 mg, 0.16 mmol) and N-methylmorpholine (32.98 μL, 0.30 mmol) in DMF (0.5 mL) was stirred at 50° C. for 30 min. Purification was by reverse phase HPLC using a gradient of 1-99% ACN in Water (HCl modifier). The fractions containing the product were evaporated to dryness. The residue was then taken up in ethyl acetate and water and the pH of the solution was adjusted to −8 with a saturated solution of NaHCO3 in water (˜3 drops). The layers separated and the aqueous layer was extracted with ethyl acetate (3×). All organic were combined, evaporated and purification by silica gel column chromatography using a gradient of ethyl acetate in hexanes (5 to 70%) gave 3-(4-fluoro-2-methoxy-phenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide (2) (26.10 mg, 37%) as a white solid. ESI-MS m/z calc. 468.09, found 469.3 (M+1)+; Retention time: 1.49 minutes (3 minutes run). 1H NMR (400 MHz, DMSO) δ 11.27 (s, 1H), 8.42 (s, 1H), 8.18 (d, J=8.0 Hz, 1H), 7.97-7.87 (m, 1H), 7.86-7.71 (m, 3H), 7.68-7.56 (m, 2H), 7.44 (s, 2H), 7.34 (dd, J=8.7, 5.9 Hz, 1H), 7.16 (dd, J=10.8, 2.9 Hz, 1H), 6.88 (ddd, J=8.6, 2.9 Hz, 1H), 3.71 (s, 3H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[C:10](=[O:24])[CH:11]([CH:16](O)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:12][C:13]=2[O:14][CH3:15])=[C:4]([CH3:25])[CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH3:25])[C:5]([C:9]2[C:10](=[O:24])[C:11](=[CH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:12][C:13]=2[O:14][CH3:15])=[C:6]([CH3:8])[CH:7]=1
Reactant: COC1=C(c2c(C)cc(Br)cc2C)C(=O)C(C(O)c2ccccn2)C1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(c2c(C)cc(Br)cc2C)C(=O)C(=Cc2ccccn2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(4-bromo-2,6-dimethylphenyl)-5-(hydroxypyridin-2-ylmethyl)-3-methoxycyclopent-2-enone (7.2 g, 17.9 mmol) in dichloromethane (200 ml) at 0°C. is added triethylamine (7.0 ml, 53.8 mmol) dropwise, then methanesulfonyl chloride (6 ml, 53.8 mmol). The reaction mixture is allowed to warm to room temperature, then is stirred overnight and quenched with ice cold water. The organic phase is separated and the aqueous phase is extracted with ethyl acetate (100 ml×3). The combined organic fractions are concentrated in vacuo and the residue is re-dissolved in methanol (250 ml) and stirred for 10 minutes. To this suspension is then added potassium carbonate (8.1 g, 58.7 mmol), and the reaction mixture is stirred for 4-5 hours at 25-30°C. Volatile solvents are removed under vacuum and the crude product is diluted with distilled water and extracted with ethyl acetate (150 ml×3). The combined organic fractions are washed with distilled water, brine, then dried over sodium sulfate, filtered and the filtrate is concentrated in vacuo. The crude product is purified by flash column chromatography to afford 2-(4-bromo-2,6-dimethylphenyl)-3-methoxy-5-[1-pyridin-2-ylmethylidene]cyclopent-2-enone.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[CH:3]=1.[Br:13]N1C(=O)CCC1=O>OS(O)(=O)=O>[Br:13][C:9]1[CH:10]=[C:2]([C:1]([OH:12])=[O:11])[CH:3]=[C:4]([CH:8]=1)[C:5]([OH:7])=[O:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(O)c1cccc(C(=O)O)c1
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(Br)cc(C(=O)O)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 20.3 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of isophthalic acid (10 g, 60.24 mmol, 1.00 equiv) in 98% H2SO4 (60 mL). This was followed by the addition of N-bromosuccinimide (12.80 g, 72.32 mmol, 1.20 equiv), in portions at 60° C. in 10 min. The resulting solution was stirred overnight at 60° C. in an oil bath. The reaction was cooled to room temperature and then quenched by the addition of water/ice. The solids were collected by filtration, and washed with 2×60 mL of hexane. The solid was dried in an oven under reduced pressure. The crude product was purified by re-crystallization from ethyl acetate to give 3 g (20%) of 5-bromoisophthalic acid as a white solid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[C:10]1([CH:16]2[C:19]3([CH2:21][O:20]3)[O:18][CH2:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl>[N:1]1[N:2]([C:19]2([CH2:21][OH:20])[CH:16]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:17][O:18]2)[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: c1ccc2[nH]nnc2c1
Reactant: c1ccc(C2COC23CO3)cc1
Solvent: ClCCl
Product: OCC1(n2nc3ccccc3n2)OCC1c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 41 %

Procedure:
Benzotriazole (0.15 g, 1.3 mmol) in dry CH2Cl2 (4 mL) at 0° C. was added to a stirred solution under N2 of 3-phenyl-1,5-dioxaspiro[3.2]hexane (0.21 g, 1.3 mmol) in dry CH2Cl2 (4 mL) at 0° C. The reaction mixture was left to stir for 3 hours at 0° C. It was then concentrated to provide a light brown oil. The residue was purified by flash chromatography on silica gel (petroleum ether/EtOAc 80:20) to give 2-(benzotriazol-2-yl)-2-(hydroxymethyl)-3-phenyloxetane as a white solid (0.15 g, 41%): mp 119-123° C.; IR (film) 3437 (br), 3094, 3064, 2941, 1560, 1499 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J=8.1 Hz, 2H), 7.35 (m, 7H), 5.42 (dd, J=8.7, 7.0 Hz, 1H), 5.20 (dd, J=8.7, 6.0 Hz, 1H), 5.09 (dd, J=6.8, 6.0 Hz, 1H), 4.25 (dd, J=13.0, 7.7 Hz, 1H), 4.20 (dd, J=13.0, 7.0 Hz, 1H), 2.6 (dd, J=7.3, 7.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 144.8, 134.3, 129.3, 128.6, 128.5, 127.8, 119.1, 102.2, 69.8, 63.8, 48.8; MS (EI) m/z 281 (M+), 251, 162, 104 (100), 91; HRMS (FAB) calculated for C16H16N3O2 (M++H) m/z 282.1242. Found: 282.1248; Anal. calculated for C16H15N3O2: C, 68.31; H, 5.37; N, 14.94. Found: C, 68.13; H, 5.40; N, 14.97.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][N:3]2[C:7](=[O:10])[CH2:8][CH2:9][CH:2]12.C([O-])([O-])=O.[K+].[K+].Br[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24].C(OCC)(=O)C>CN1CCCC1=O.[Cu]I>[C:19]1([CH3:24])[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[N:1]1[C:5](=[O:6])[CH2:4][N:3]2[C:7](=[O:10])[CH2:8][CH2:9][CH:2]12
Reactant: Cc1ccccc1Br
Reactant: O=C1CN2C(=O)CCC2N1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1ccccc1N1C(=O)CN2C(=O)CCC21
Yield: 15.4 %

Procedure:
To a solution of tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione (1.3 g, 9.28 mmol, prepared as described in J. Med. Chem. 36,4214, 1994) in N-methylpyrrolidone (NMP, 12 cc), CuI (0.5 g, 2.62 mmol), K2CO3 (1.3 g, 9.28 mmol) and 2-bromotoluene (6 g, 35 mmol) were added under stirring. The suspension was heated in a microwave apparatus (250 Watt) for 1 h. Ethyl acetate was added to the suspension and the solid was filtered. The organic phase was washed with water and the aqueous phase was re-extracted with CH2Cl2. The organic phases were gathered and dried over Na2SO4, filtered and concentrated to dryness. The residue was triturated with Et2O. The solid was filtered, and crystallized the first time with iPrOH and then with AcOEt to yield 0.33 g of the title compound, mp=138-139° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:9][C:10](N(OC)C)=[O:11])=[CH:4][CH:3]=1.Br[C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[N:30]=[CH:29][CH:28]=[CH:27]2>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:9][C:10]([C:24]2[CH:25]=[C:26]3[C:31](=[CH:32][CH:33]=2)[N:30]=[CH:29][CH:28]=[CH:27]3)=[O:11])=[CH:6][CH:7]=1
Reactant: Brc1ccc2ncccc2c1
Reactant: CON(C)C(=O)CC(c1ccc(Br)cc1)c1ccccc1C
Product: Cc1ccccc1C(CC(=O)c1ccc2ncccc2c1)c1ccc(Br)cc1

Procedure:
In analogy to example 74, step 5, from 3-(4-bromo-phenyl)-N-methoxy-N-methyl-3-o-tolyl-propionamide (example 74, step 4) and 6-bromoquinoline (CAS RN: [5332-25-2]) was prepared the title compound as a yellow oil, MS (ESI+): m/z=430.0791 ([M+H]+, 1Br).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:13]=[C:12](O)[C:11]2[C:15]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[CH:16][S:17][C:10]=2[C:9]=1[OH:25])=[O:7])[CH2:2][CH2:3][CH3:4].P(Br)(Br)([Br:28])=O>C1(C)C=CC=CC=1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[CH2:1]([O:5][C:6]([C:8]1[N:13]=[C:12]([Br:28])[C:11]2[C:15]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[CH:16][S:17][C:10]=2[C:9]=1[OH:25])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Br)(Br)Br
Reactant: CCCCOC(=O)c1nc(O)c2c(-c3ccc(F)cc3)csc2c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCCOC(=O)c1nc(Br)c2c(-c3ccc(F)cc3)csc2c1O
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 55.9 %

Procedure:
3-(4-Fluoro-phenyl)-4,7-dihydroxy-thieno[3,2-c]pyridine-6-carboxylic acid butyl ester (77.9 mg, 0.216 mmol), example 30-f, was suspended in 1.1 mL of anhydrous toluene. Phosphorous oxybromide (0.155 g, 0.539 mmol) was added, and the reaction mixture was heated at 120° C. for 20 min. using a CEM microwave reactor (CEM, Matthews, N.C.). The reaction mixture was diluted with ethyl acetate, and saturated sodium bicarbonate solution was then added. The biphasic mixture was stirred for 15 min. and separated to isolate the organic fraction. The organic fraction was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography eluting from silica gel with dichloromethane to produce 51.2 mg of the title compound. MS: (−) m/z 422.1, 424.1 (M−1, 79Br/81Br).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6](=O)[CH2:5][C:4](=[O:9])[CH2:3]1.[NH3:10]>C1C=CC=CC=1>[NH2:10][C:6]1[CH2:7][CH:2]([CH3:1])[CH2:3][C:4](=[O:9])[CH:5]=1
Reactant: N
Reactant: CC1CC(=O)CC(=O)C1
Solvent: c1ccccc1
Product: CC1CC(=O)C=C(N)C1
Temperature: 0 °C

Procedure:
5-Methyl-1,3-cyclohexanedione (40 g, 0.32 mol) was dissolved in 500 ml of benzene at 70° C. The solution was heated at reflux for 2 hours, during which NH3 was bubbled through the reaction mixture and formed H2O was collected in a Dean-Stark trap. The mixture was then cooled to 0° C. and title product recovered by filtration, 39.8 g, m.p. 165°-169° C. 1H-NMR(DMSO-d6)delta(ppm): 0.98 (s, 3H), 1.6-1.88 (2H), 2.14-2.38 (2H), 3.14-3.6 (1H), 4.93 (s, 1H), 6.2-7.2 (m, 2H).
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][N:2]=1.[CH2:11](OCC)C>>[CH3:11][C:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][N:2]=1
Reactant: CCOCC
Reactant: c1cc2c(cn1)CCCC2
Product: Cc1nccc2c1CCCC2

Procedure:
2.155 g (16.20 mmol) of 5,6,7,8-tetrahydroisoquinoline, 20 ml of diethylether, and 13 ml (19.50 mmol) of a 1.5 molar solution of methyllithium-lithium bromide complex in diethylether are reacted for approximately 16 hours at 45° C. The excess methyllithium is destroyed by cautious addition of water, and the crude product is obtained by chloroform extraction. Removal of the chloroform in vacuo gives the crude product which is purified by LPLC (methylene chloride-acetone, 4:1) to give 1.00 g of product. The product exhibits NMR peaks (CDCl3, δ) at 8.25, 6.85, 2.65, 2.5, and 1.80.
Reaction SMILES: [CH2:1]1[CH:9]2[CH:4]([CH2:5][NH:6][CH2:7][CH2:8]2)[CH2:3][O:2]1.Br[CH2:11][CH2:12][CH2:13][Cl:14].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:14][CH2:13][CH2:12][CH2:11][N:6]1[CH2:7][CH2:8][CH:9]2[CH2:1][O:2][CH2:3][CH:4]2[CH2:5]1
Reactant: C1CC2COCC2CN1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: ClCCCN1CCC2COCC2C1
Temperature: 25 °C
Yield: 45.6 %

Procedure:
A mixture of octahydrofuro[3,4-c]pyridine (300 mg, 2.40 mmol, 1 eq), 1-bromo-3-chloropropane (760 mg, 4.80 mmol, 2 eq) and K2CO3 (736 mg, 9.60 mmol, 4 eq) in acetone (30 mL) was heated to reflux overnight, cooled to rt and filtered. The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (20:1 (v/v) CH2Cl2/MeOH) to afford the title compound as pale yellow oil (223 mg, 46.5%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 248.05 (M+1).
Reaction SMILES: Br[CH2:2][C:3]#[C:4][CH3:5].[H-].[Na+].[OH:8][C:9]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10]1.O>CN(C)C=O>[CH2:2]([O:8][C:9]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10]1)[C:3]#[C:4][CH3:5]
Reactant: CC#CCBr
Reactant: Cc1ccccc1C1(O)CN(C(=O)OC(C)(C)C)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCOC1(c2ccccc2C)CN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
1 ml (11.4 mmol) of 1-bromo-2-butyne is added to a suspension of 1.4 g (34.2 mmol) of sodium hydride at 60% in 14 ml of dimethylformamide cooled beforehand to 0° C. After stirring for 1 h, 3 g (11.4 mmol) of tert-butyl 3-hydroxy-3-o-tolylazetidine-1-carboxylate in 20 ml of dimethylformamide are added dropwise and the reaction mixture is then stirred for 1 h 30. After hydrolysis with water and with a saturated aqueous solution of ammonium chloride, the reaction medium is extracted with a 1/1 heptane/ethyl acetate mixture. The organic phase is dried over sodium sulphate, filtered and concentrated. The residue obtained is purified by silica gel chromatography, elution being carried out with a 80/20 heptane/ethyl acetate mixture. 2.9 g of tert-butyl 3-but-2-ynyloxy-3-o-tolylazetidine-1-carboxylate are obtained in the form of a yellow oil with a yield of 81%.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6](=[O:16])[C:7]3[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:8]=3[CH:9]=[CH:10][C:4]=2[CH:3]=1.[Br:19]N1C(=O)CCC1=O>C(OCC)(=O)C>[Br:19][CH2:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6](=[O:16])[C:7]3[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:8]=3[CH:9]=[CH:10][C:4]=2[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2c(=O)c3ccc(C)cc3ccc2c1
Solvent: CCOC(C)=O
Product: Cc1ccc2c(=O)c3ccc(CBr)cc3ccc2c1

Procedure:
The product of step (i) (2.0 g) and N-bromosuccinimide (1.52 g) in ethyl acetate (80ml) was irradiated with a 500 W halogen lamp for 4 hours. The reaction mixture was washed with brine, dried (MgSO4) and evaporated under reduced pressure. Purification was by chromatography eluting with toluene. Used directly in the next step.
Reaction SMILES: [N:1]([C@H:4]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C:6](=[CH:7][CH2:8][C@@H:9]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:30])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:5]1)=[N+]=[N-].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[NH2:1][C@H:4]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C:6](=[CH:7][CH2:8][C@@H:9]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:30])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:5]1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](N=[N+]=[N-])CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](N)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 4 °C
Reaction time: 1.5 h
Yield: 93.8 %

Procedure:
To 3β-azido-5-cholestene (14, 3.30 g, 8.02 mmol) in dry diethyl ether (150 mL) at 4° C. was added lithium aluminum hydride (4.60 g, 121.18 mmol) in three equal portions. The reaction was maintained at 4° C. for 30 min, warmed to 23° C., and stirred for an additional 1.5 h. The reaction was quenched by addition of diethyl ether (50 mL) followed by careful dropwise addition of deionized H2O (60 mL). The organic layer was washed with saturated aqueous NaCl (2×100 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to afford 2.90 g (85%) of crude 3β-amino-5-cholestene. This aminosteroid was dissolved in dry THF (150 mL), and diisopropylethylamine (2.61 mL, 15.03 mmol) was added. 2-Nitrobenzenesulfonyl chloride (2.20 g, 9.92 mmol) in dry THF (40 mL) was added by addition funnel over 30 min. After 2 h at 23° C., solvents were removed in vacuo, CH2Cl2 was added (75 mL), and this organic solution was washed with aqueous NaHCO3 (10%, 1×100 mL) and saturated aqueous NaCl (2×100 mL). The organic extracts were dried over anhydrous Na2SO4 and concentrated in vacuo to yield a crude yellow solid. Recrystallization (CH2Cl2/MeOH, 1:5) followed by flash column chromatography (EtOAc/hexanes, 1:5) afforded off-white 15 (3.50 g, 83%), mp 202-203° C.; 1H NMR (300 MHz, CDCl3) δ 8.16-8.12 (m, 1H), 7.86-7.82 (m, 1H), 7.75-7.67 (m, 2H), 5.19 (s, 1H), 5.16 (s, 1H), 3.28-3.18 (m, 1H), 2.18-0.83 (m, 40H), 0.63 (s, 3H); 13C NMR (75.41 MHz, CDCl3) δ 148.1, 139.9, 135.4, 133.6, 133.1, 131.0, 125.6, 122.7, 56.9, 56.3, 55.2, 50.2,42.5, 40.3, 39.9, 39.7, 38.0, 36.6, 36.4, 36.0, 32.0, 31.9, 30.2, 28.4, 28.2, 24.4, 24.0, 23.0, 22.8, 21.1, 19.4, 18.9, 12.0; IR (film) νmax 3331, 2936, 2359, 1541 cm−1; CI m/z 571.3567 (MH+, C33H51N2O4S requires 571.3569).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=O.[NH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:17]=1[NH2:18]>>[CH3:1][C:2]1[CH:3]=[C:4]([C:5]2[NH:18][C:17]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[N:11]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: Nc1ccncc1N
Reactant: Cc1cccc(C(=O)O)c1
Product: Cc1cccc(-c2nc3cnccc3[nH]2)c1
Yield: 70 %

Procedure:
The title compound was prepared in 70% yield according to the procedure in Example 1 using 3-methylbenzoic acid and 3,4-diaminopyridine. Crystallization from methanol/water afforded light tan crystals, m.p. about 202.5°-204° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][N:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:8]=1[S:9]([NH2:12])(=[O:11])=[O:10])([OH:3])=O.CS(O)(=O)=O.[CH2:24](O)[CH:25]=[CH2:26]>>[CH2:26]([C:1]([C:4]1[CH:5]=[N:6][N:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:8]=1[S:9]([NH2:12])(=[O:11])=[O:10])=[O:3])[CH:25]=[CH2:24]
Reactant: NS(=O)(=O)c1c(C(=O)O)cnn1-c1ccccn1
Reactant: C=CCO
Agent: CS(=O)(=O)O
Product: C=CCC(=O)c1cnn(-c2ccccn2)c1S(N)(=O)=O
Temperature: 110 °C
Reaction time: 18 h

Procedure:
To a mixture of 2.2 of 4-carboxy-1-(2-pyridyl)pyrazole-5-sulfonamide and 20 ml of allyl alcohol, 1 ml of methanesulfonic acid was added, followed by stirring at 110° C. for 18 hours. The reaction mixture was concentrated under reduced pressure, and purified by silica gel chromatography to obtain 0.7 g of the title compound. m.p.: 140° to 142° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:11][C:10]=2[C:21]2[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[CH:23][CH:22]=2)=[CH:4][CH:3]=1.[CH3:30][Mg+].[Br-]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:11][C:10]=2[C:21]2[CH:22]=[CH:23][C:24]([C:27]([OH:29])([CH3:30])[CH3:28])=[CH:25][CH:26]=2)=[CH:4][CH:3]=1
Reactant: C[Mg+]
Reactant: CC(=O)c1ccc(-c2nc(-c3ccccc3)n(C)c2Sc2ccc(Cl)cc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: Cn1c(-c2ccccc2)nc(-c2ccc(C(C)(C)O)cc2)c1Sc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To the crude product of Step 1 in 1 mL of THF was added 0.1 mmol of MeMgBr (3M in ether) at −78° C. After stirring at 0° C. for 1 hr, the reaction was quenched with aqueous NH4Cl, and the product was extracted with EtOAc. The combined extracts were concentrated and the crude product was purified by reverse phase HPLC to afford the title compound. 1H NMR (500 MHz, (CDCl3): 8.04 (d, 2H), 7.68 (m, 2H), 7.54 (d, 2H), 7.53 (m, 3H), 7.26 (d, 2H), 7.06 (d, 2H), 3.67 (s, 3H), 1.61 (s, 6H). LCMS: m/z 435 (M+H)+.
Reaction SMILES: [CH2:1]([OH:32])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]#[CH:31].[Si:33](Cl)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]>C(Cl)(Cl)Cl.C(N(CC)CC)C.CN(C)C1C=CN=CC=1>[Si:33]([O:32][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]#[CH:31])([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C#CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C#CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO[Si](C)(C)C(C)(C)C
Reaction time: 8 h

Procedure:
9.6 g (0.0214 mol) of hentriacont-30-yn-1-ol of Example 10 were stirred vigorously in a mixture of 100 ml of chloroform and 4.4 ml of triethylamine for 1 h at room temperature. 3.5 g (0.0235 mol) of t-butyldimethylsilyl chloride were added, followed by a catalytic amount (spatula tipful) of 4-dimethylaminopyridine. The mixture was left to stand overnight at room temperature and half the solvent was stripped off. The remaining solution was chromatographed on a silica gel column (chloroform).