Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([NH:14][C:15](=[O:18])[CH:16]=[CH2:17])[CH:11]=[CH:12][CH:13]=2)[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:22]=[CH:23][C:24]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[C:25]([OH:27])[CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CC(O)(C)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[Cl:19][C:5]1[C:6]([C:8]2[CH:9]=[C:10]([NH:14][C:15](=[O:18])[CH:16]=[CH2:17])[CH:11]=[CH:12][CH:13]=2)=[N:7][C:2]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([N:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)=[C:25]([OH:27])[CH:26]=2)=[N:3][CH:4]=1
Reactant: Nc1ccc(N2CCOCC2)c(O)c1
Reactant: C=CC(=O)Nc1cccc(-c2nc(Cl)ncc2Cl)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(C)(C)O
Product: C=CC(=O)Nc1cccc(-c2nc(Nc3ccc(N4CCOCC4)c(O)c3)ncc2Cl)c1
Temperature: 140 °C
Yield: 51.6 %

Procedure:
N-(3-(2,5-dichloropyrimidin-4-yl)phenyl)acrylamide (151 mg, 0.515 mmol), 5-amino-2-morpholinophenol (100 mg, 0.515 mmol) and potassium carbonate (178 mg, 1.287 mmol) were dissolved in t-BuOH (5 mL) and Pd2dba3 (9.43 mg, 10.30 μmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (11.92 mg, 0.021 mmol) were added and then the reaction mixture was heated via microwave irradiation to 140° C. for 1 h. Reaction was monitored by TLC. After completion of the reaction, it was allowed to cool to about room temperature, and then reaction mixture was extracted with ethyl acetate (2×50 mL). The organic phase was concentrated and the residue was purified by flash column chromatography (4% MeOH/DCM) to provide the title compound (120 mg, 50.0% yield) as an off white solid. 1HNMR (400 MHz, CD3OD): δ 8.43 (s, 1H), 8.36 (s, 1H), 7.68 (m, 2H), 7.53 (d, 1H, J=2.0 Hz), 7.46 (t, 1H, J=8.4 Hz), 7.02 (dd, 1H, J=2.4 & 8.8 Hz), 6.97 (d, 1H, J=8.4 Hz), 6.50-6.38 (m, 2H), 5.80 (dd, 1H, J=2.4 & 9.6 Hz), 3.83 (m, 4H), 2.93 (m, 4H). Mass: 452.1 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][O:12][CH3:13])[CH:6]=[CH:5][C:4]=1[Cl:14].C[N+]1([O-])CC[O:19]CC1>O1CCOCC1.[Cl-].[Na+].O>[Cl:14][C:4]1[CH:5]=[CH:6][C:7]([O:9][CH2:10][CH2:11][O:12][CH3:13])=[CH:8][C:3]=1[CH:2]=[O:19]
Reactant: C[N+]1([O-])CCOCC1
Reactant: COCCOc1ccc(Cl)c(CBr)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COCCOc1ccc(Cl)c(C=O)c1
Temperature: 80 °C

Procedure:
To a solution of 2-(bromomethyl)-1-chloro-4-(2-methoxyethoxy)benzene from the previous step (1 eq.) in dioxane (0.2 M) was added 4-methylmorpholine N-oxide (3 eq.). The reaction mixture was heated at 80° C. The resulting solution was allowed to cool to RT, poured into brine and then extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, Hex→2:1 (v/v) Hex:EtOAc) afforded the title compound as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH:21]=O)[CH:19]=2)[CH:14]=[N:13]1.N1CCCCC1>CO>[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18](/[CH:21]=[C:5]3/[C:6](=[O:11])[NH:7][C:8]4[C:4]/3=[CH:3][C:2]([F:1])=[CH:10][CH:9]=4)[CH:19]=2)[CH:14]=[N:13]1
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: O=Cc1ccc2cn[nH]c2c1
Solvent: CO
Solvent: C1CCNCC1
Product: O=C1Nc2ccc(F)cc2/C1=C\c1ccc2cn[nH]c2c1
Temperature: 60 °C

Procedure:
A scintillation vial was charged with 5-fluoroindolin-2-one (40 mg, 0.265 mmol), 1H-indazole-6-carbaldehyde (43 mg, 0.292 mmol), piperidine (3 uL, 0.027 mmol) and MeOH (2 mL). The reaction was then heated to 60° C. for 2 hrs. LC-MS analysis of the filtered yellow solid indicated a 9:1 mixture of geometric isomers. The mixture was resolved through prep-HPLC purification to give 11 mg, 15% of the major isomer (E) as the title compound. The minor fraction was also isolated; see Example A32. 1H NMR (400 MHz, d6-DMSO) δ 13.31 (s, 1H), 10.66 (s, 1H), 8.18 (s, 1H), 7.92 (d, J=8.7 Hz, 1H), 7.91 (s, 1H), 7.86 (s, 1H), 7.42 (d, J=8.5 Hz, 1H), 7.29 (d, J=9.5 Hz, 1H), 7.10 (t, J=6.8 Hz, 1H), 6.88 (dd, J1=8.8 Hz, J2=4.7, 1H); MS ESI 280.0 [M+H]+, calcd for [C16H10FN3O+H]+ 280.09.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:31](=[O:32])[N:12]2[C:13]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)=[O:19])=[C:14]([OH:17])[CH2:15][S:16][C@H:11]12)=[O:8].CC(N(C)C)=O.C1OC1C.[CH2:43]([S:45](Cl)(=[O:47])=[O:46])[CH3:44]>C(OCC)(=O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:31](=[O:32])[N:12]2[C:13]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)=[O:19])=[C:14]([O:17][S:45]([CH2:43][CH3:44])(=[O:47])=[O:46])[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Reactant: CCS(=O)(=O)Cl
Agent: CC1CO1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCS(=O)(=O)OC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1

Procedure:
By following the procedure described by Example 4, 4.7 g. (10 mmole) of p-nitrobenzyl 7-[2-(2-thienyl)acetamido]-3-hydroxy-3-cephem-4-carboxylate was reacted for about 3 hours in 50 ml. of dimethylacetamide containing about 2 ml. of propylene oxide with a stoichiometric amount of ethanesulfonyl chloride. The reaction mixture was dissolved in ethyl acetate and the solution washed with a saturated solution of sodium chloride. The organic phase was dried and evaporated to dryness to provide the reaction product. The product was purified by preparative thin layer chromatography on silica gel by employing 65 percent ethyl acetate/hexane for development. The purified product, p-nitrobenzyl 7-[2-(2-thienyl)acetamido]-3-ethylsulfonyloxy-3-cephem-4-carboxylate, gave the following percent elemental composition on microanalysis for the formula C22H21N3O9S3 :
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29](O)=[O:30])=[CH:23][CH:22]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:24]3[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: COc1ccc(/C=C/C(=O)O)cc1
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Product: COc1ccc(/C=C/C(=O)Nc2ccn(Cc3ccc(C(C)=O)o3)n2)cc1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(4-methoxy-phenyl)-acrylic acid.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C@H:9]([C:12]1[C:21]([C:22]([NH:24][C:25]2[S:26][CH:27]=[CH:28][N:29]=2)=[O:23])=[C:20]([OH:30])[C:19]2[C:14](=[C:15]([C:31]([F:34])([F:33])[F:32])[CH:16]=[CH:17][CH:18]=2)[N:13]=1)[CH2:10][CH3:11].N1C=CC=CC=1.Cl>O>[C:1]([NH:8][C@H:9]([C:12]1[C:21]([C:22]([NH:24][C:25]2[S:26][CH:27]=[CH:28][N:29]=2)=[O:23])=[C:20]([OH:30])[C:19]2[C:14](=[C:15]([C:31]([F:33])([F:32])[F:34])[CH:16]=[CH:17][CH:18]=2)[N:13]=1)[CH2:10][CH3:11])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC[C@H](N)c1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC[C@H](NC(C)=O)c1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1
Temperature: 25 °C

Procedure:
10 ml of acetic anhydride and 6 g of 2-[(1S) 1-aminopropyl]-4-hydroxy-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline carboxamide of Example 8 were added dropwise with stirring to 60 ml of pyridine and stirring was maintained for 90 minutes at ambient temperature. The solution was poured into 150 ml of iced water and concentrated hydrochloric acid was added until a pH of 1. The precipitate was filtered, washed with water and then dissolved in tetrahydrofuran. The organic phase was dried, and concentrated to dryness under reduced pressure. The residue was taken up in ether, filtered and dried under reduced pressure at 80° to obtain 5.3 g of 2-[(1S) 1-(acetylamino)-propyl]-4-hydroxy-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline carboxamide melting at 275° C. and having a specific rotation of [α]D =+43.5°±4° (c=0.3% in DMF).
Reaction SMILES: C([O:8][C@H:9]([C@H:11]([N:25]1[CH:29]=[C:28]([C:30]([NH2:32])=[O:31])[N:27]=[CH:26]1)[CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2)[CH3:10])C1C=CC=CC=1>C1CCCCC=1.C(O)C.[OH-].[OH-].[Pd+2]>[OH:8][C@H:9]([C@H:11]([N:25]1[CH:29]=[C:28]([C:30]([NH2:32])=[O:31])[N:27]=[CH:26]1)[CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2)[CH3:10]
Reactant: C[C@H](OCc1ccccc1)[C@@H](CCOc1ccc2ncccc2c1)n1cnc(C(N)=O)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1=CCCCC1
Solvent: CCO
Product: C[C@H](O)[C@@H](CCOc1ccc2ncccc2c1)n1cnc(C(N)=O)c1
Temperature: 25 °C
Yield: 86.6 %

Procedure:
To a solution of 1-[(2S,3R)-2-benzyloxy-5-(6-quinolyloxy)-3-pentyl]imidazole-4-carboxamide (58 mg, 0.135 mmol) in cyclohexene (2.5 ml) and ethanol (5 ml) was added 20% palladium hydroxide on carbon (50 mg). The resulting mixture was stirred at reflux for 8 h. After cooling to room temperature, the mixture was filtered through Celite and washed with ethanol. The filtrate was concentrated in vacuo and then the residue was purified by silica gel (1.5 g) chromatography eluted with chloroform/methanol (50:1 to 10:1) to give 1-[(2S,3R)-2-hydroxy-5-(6-quinolyloxy)-3-pentyl]imidazole-4-carboxamide (2) (39.8 mg, 86.8%).
Reaction SMILES: O1CCCC1.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([Mg]Br)[CH:11]=[CH:12][CH:13]=1.Br[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1.[Cl-].[NH4+]>[Ni](Cl)Cl.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)C>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: COc1cccc([Mg]Br)c1
Reactant: Brc1ccccn1
Agent: Cl[Ni]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cccc(-c2ccccn2)c1
Yield: 96.9 %

Procedure:
A tetrahydrofuran solution of 3-methoxyphenyl magnesium bromide (52.4 ml, 1.0 M, 52.4 mmol) was dropwise added to a mixture of 2-bromopyridine (5.0 ml, 52.4 mmol), 1,3-bis(diphenylphosphino)propane nickel (II) chloride (284 mg) and diethyl ether (100 ml) at room temperature while 1 hour. Thereafter, this reaction mixture was poured into an aqueous ammonium chloride solution, the mixture was extracted with toluene, the solvent was distilled off, and the residue was purified by silica gel column chromatography, thereby obtaining 9.4 g of 2-(3-methoxyphenyl)pyridine as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH:13]([CH3:16])[CH2:14][NH2:15].[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH:22]=O>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH:13]([CH3:16])[CH2:14][NH:15][CH2:22][C:18]1[O:17][CH:21]=[CH:20][CH:19]=1
Reactant: CC(CN)Oc1ccc2ccccc2c1Cl
Reactant: O=Cc1ccco1
Product: CC(CNCc1ccco1)Oc1ccc2ccccc2c1Cl
Yield: 56 %

Procedure:
Prepared from 2-[(1-chloronaphthalen-2-yl)oxy]propan-1-amine and furan-2-carbaldehyde in 56% yield as a red oil.
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[N:10][C:9]2[C:4](=[CH:5][C:6]([N+:17]([O-])=O)=[C:7]3[N:15]=[N:14][N:13]([CH3:16])[C:8]3=2)[N:3]=1>Cl>[NH2:17][C:6]1[CH:5]=[C:4]2[C:9]([N:10]=[C:11]([OH:12])[C:2]([OH:1])=[N:3]2)=[C:8]2[N:13]([CH3:16])[N:14]=[N:15][C:7]=12
Reactant: Cn1nnc2c([N+](=O)[O-])cc3nc(O)c(O)nc3c21
Agent: Cl
Product: Cn1nnc2c(N)cc3nc(O)c(O)nc3c21
Reaction time: 1.5 h

Procedure:
A solution of stannous chloride dihydrate (2.26 g, 10 mmol) in 10 ml of conc. hydrochloric acid was added dropwise to a suspension of 7,8-dihydroxy-1-methyl-4-nitro-lH-1,2,3-triazolo[4,5-f]quinoxaline (0.79 g, 3 mmol) in 5 ml of conc. hydrochloric acid with stirring on an oil bath at 60°-70° C. Stirring was continued at this temperature for 90 min. Then the mixture was cooled on an ice bath, and filtered. The precipitate was washed with 1 ml of conc. hydrochIoric acid, suspended in 150 ml of hot water, and adjusted to pH 6-7 with solid sodium hydrogen carbonate. After reflux for 1 h the mixture was cooled on ice and the crude product was isolated by filtration, dissolved in 4? ml of hot 2N sodium hydroxide and reprecipitated with 4M acetic acid giving 0.16 g (23%) of the pure amino compound; m.p. >300° C.; IR (KBr): 3435, 3350, 3240, 3100-2400, 1690, 1640 cm-1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[C:10]([C:18]([OH:20])=O)[CH:9]=2)=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[F:44][C:45]([F:55])([F:54])[C:46]1[N:51]=[CH:50][C:49]([CH2:52][NH2:53])=[CH:48][CH:47]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([S:14]([CH3:17])(=[O:15])=[O:16])[CH:11]=[C:10]([C:18]([NH:53][CH2:52][C:49]3[CH:50]=[N:51][C:46]([C:45]([F:55])([F:44])[F:54])=[CH:47][CH:48]=3)=[O:20])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(S(C)(=O)=O)c2)cc1
Reactant: NCc1ccc(C(F)(F)F)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc(C(F)(F)F)nc3)cc(S(C)(=O)=O)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4′-methyl-5-(methylsulfonyl)biphenyl-3-carboxylic acid (40 mg, 0.14 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (53 mg, 0.28 mmol), 1-hydroxybenzotriazole hydrate (21 mg, 0.14 mmol), and CH2Cl2 (3 mL) were added C-(6-trifluoromethyl-pyridin-3-yl)-methylamine (36 mg, 0.21 mmol) and N,N-diisopropylethylamine (48 μL, 0.28 mmol). The mixture was stirred at room temperature overnight and then concentrated. The residue was purified by preparative HPLC (100×20.2 mm, C18 column; 40-80% MeCN-water[10 mM Et2NH]) to afford a white solid.
Reaction SMILES: [F:1][C:2]([CH2:5][CH2:6][CH2:7][C@H:8]([C@@H:10]1[C@:27]2([CH3:28])[C@H:13]([C@H:14]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:17](=[CH:18][C@@H:19](O)[CH2:20][C@@H:21]2[OH:29])[CH:16]=[CH:15]3)[CH2:12][CH2:11]1)[CH3:9])([CH3:4])[CH3:3].N.[Li]>O1CCCC1>[F:1][C:2]([CH2:5][CH2:6][CH2:7][C@H:8]([C@@H:10]1[C@:27]2([CH3:28])[C@H:13]([C@H:14]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:17]([CH2:18][CH2:19][CH2:20][C@@H:21]2[OH:29])=[CH:16][CH2:15]3)[CH2:12][CH2:11]1)[CH3:9])([CH3:3])[CH3:4]
Reactant: C[C@H](CCCC(C)(C)F)[C@H]1CC[C@H]2[C@@H]3C=CC4=C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Agent: N
Agent: [Li]
Solvent: C1CCOC1
Product: C[C@H](CCCC(C)(C)F)[C@H]1CC[C@H]2[C@@H]3CC=C4CCC[C@H](O)[C@]4(C)[C@H]3CC[C@]12C

Procedure:
25-Fluoro-4,6-cholestadiene-1α,3β-diol (0.005 mole) prepared according to 3B above is dissolved in 100 ml. of a 1:1 solvent mixture of tetrahydrofuran and liquid ammonia and stirred at reflux using a dry-ice condenser with 0.4 gm. of finely divided lithium for 1.0 hour. The liquid ammonia is allowed to evaporate and 10 ml. of water is added. The tetrahydrofuran is evaporated at room temperature under high vacuum. The organics are extracted from the water three times with 50 ml. of chloroform. The chloroform extracts are combined, dried (magnesium sulfate) and the solvent is removed to give crude 25-fluoro-1α-hydroxycholest-5-ene. 25-Fluoro-1α-hydroxycholest-5-ene can be purified by chromatographing the crude product on a silica gel column using a solvent of petroleum ether and diethyl ether.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.[N:12]([S:15]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[O:26][CH:27]=[N:28][N:29]=1)(=[O:17])=[O:16])=[C:13]=[O:14]>O1CCCC1>[CH3:9][O:8][C:6]1[CH:5]=[C:4]([O:10][CH3:11])[N:3]=[C:2]([NH:1][C:13]([NH:12][S:15](=[O:17])(=[O:16])[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]2[O:26][CH:27]=[N:28][N:29]=2)=[O:14])[N:7]=1
Reactant: O=C=NS(=O)(=O)Oc1ccccc1-c1nnco1
Reactant: COc1cc(OC)nc(N)n1
Solvent: C1CCOC1
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)Oc2ccccc2-c2nnco2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 11.9 %

Procedure:
To a suspension of 6 g of 2-amino-4,6-dimethoxypyrimidine in 25 ml of tetrahydrofuran was added a solution of 8 g of the isocyanate prepared in Example 3 dissolved in 25 ml of tetrahydrofuran. After an initial exotherm, the solution was stirred at 25° C. for 16 hours, to yield a precipitate. The mixture was filtered, and the solid was recrystallized from acetonitrile to yield 1.5 g of the title compound; m.p. 161°-164° C.
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([CH2:6][NH:7][C:8]2[C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]([S:17]([NH2:20])(=[O:19])=[O:18])=[C:10]([Cl:21])[CH:9]=2)[O:4][CH:5]=1.Br[CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].C1CN2C(=NCCC2)C1.C(#N)C>ClCCl>[NH2:20][S:17]([C:11]1[C:10]([Cl:21])=[CH:9][C:8]([NH:7][CH2:6][C:3]2[O:4][CH:5]=[CH:1][CH:2]=2)=[C:13]([CH:12]=1)[C:14]([O:16][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:15])(=[O:19])=[O:18]
Reactant: NS(=O)(=O)c1cc(C(=O)O)c(NCc2ccco2)cc1Cl
Reactant: CCOC(=O)CCCBr
Agent: C1CN=C2CCCN2C1
Solvent: ClCCl
Solvent: CC#N
Product: CCOC(=O)CCCOC(=O)c1cc(S(N)(=O)=O)c(Cl)cc1NCc1ccco1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of furosemide (5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoic acid (10), (Aldrich) (0.060 mole), ethyl 4-bromobutyrate (Aldrich) (0.055 mole), DBN (1,5-diazabicyclo[4.3.0]non-5-ene, Aldrich) (0.060 mole) and dry acetonitrile (100 mL) is stirred at ambient temperature for 10 hours. The reaction mixture is diluted with dichloromethane (200 mL) and extracted with sodium bicarbonate solution, washed with water, and then with a saturated sodium chloride solution. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo to give crude product, which may be purified by column chromatography on silica gel with hexanes/ethyl acetate as eluent. The fractions that contain pure product may be combined and spin evaporated in vacuo to give ethyl 4-(5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyloxy)butanoate (300). See eg., T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, p. 228 (1991).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](Cl)=[O:7])(=[O:3])[CH3:2].[CH3:9][O:10][C:11]1[CH:55]=[C:54]([O:56][CH3:57])[CH:53]=[C:52]([O:58][CH3:59])[C:12]=1/[CH:13]=[CH:14]/[CH:15]([S:25]([CH:28](/[CH:38]=[CH:39]/[C:40]1[C:45]([O:46][CH3:47])=[CH:44][C:43]([O:48][CH3:49])=[CH:42][C:41]=1[O:50][CH3:51])[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([NH2:37])[CH:30]=1)(=[O:27])=[O:26])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([NH2:24])[CH:17]=1>>[CH3:59][O:58][C:52]1[CH:53]=[C:54]([O:56][CH3:57])[CH:55]=[C:11]([O:10][CH3:9])[C:12]=1/[CH:13]=[CH:14]/[CH:15]([S:25]([CH:28](/[CH:38]=[CH:39]/[C:40]1[C:41]([O:50][CH3:51])=[CH:42][C:43]([O:48][CH3:49])=[CH:44][C:45]=1[O:46][CH3:47])[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([NH:37][C:6](=[O:7])[CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH:30]=1)(=[O:27])=[O:26])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([NH:24][C:6](=[O:7])[CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH:17]=1
Reactant: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(N)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(N)c2)c(OC)c1
Reactant: CC(=O)OCC(=O)Cl
Product: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(NC(=O)COC(C)=O)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(NC(=O)COC(C)=O)c2)c(OC)c1
Yield: 90 %

Procedure:
A solution of acetoxyacetyl chloride (10 mmol) and (E)-2,4,6-trimethoxystyryl-3-amino-4-methoxy benzylsulfone (10 mmol) was reacted according to General Method A. The product obtained was purified column chromatography to give a 90% yield of the desired product. (m.p. 192-194° C.)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[CH:22]=O)[CH:7]=1)[CH3:2].[CH2:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@@H:27]([NH2:34])[C@H:26]1[OH:35]>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[CH2:22][NH:34][C@@H:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:25][C@@H:26]2[OH:35])[CH:7]=1)[CH3:2]
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2C=O)c1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CN[C@@H]2c3ccccc3C[C@@H]2O)c1

Procedure:
Prepared according to the procedure described in Example 45, Step 3, using the following starting materials: [3-(4-bromo-2-formyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester and (1R,2S)-(+)-cis-1-amino-2-indanol.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:15]=[CH:14][C:13]3[N:12]=[C:11]([NH:16]C(=O)C(C)(C)C)[NH:10][C:9](=[O:23])[C:8]=3[C:7]=2[CH:24]=1.[F:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[NH2:16][C:11]1[NH:10][C:9](=[O:23])[C:8]2[C:7]3[CH:24]=[C:3]([CH2:2][NH:30][C:29]4[CH:31]=[CH:32][C:26]([F:25])=[CH:27][CH:28]=4)[CH:4]=[CH:5][C:6]=3[CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: Nc1ccc(F)cc1
Reactant: CC(C)(C)C(=O)Nc1nc2ccc3ccc(CBr)cc3c2c(=O)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1nc2ccc3ccc(CNc4ccc(F)cc4)cc3c2c(=O)[nH]1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 36.5 %

Procedure:
N-(9-Bromomethyl-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide (0.97 g, 2.5 mmole) and 4-fluoroaniline (0.56 g, 5 mmole) (Aldrich) were dissolved in dimethylformamide (15 ml). The reaction was stirred for 30 minutes at 100° C., sodium bicarbonate (0.42 g, 5 mmole) added and the suspension stirred for a further 30 minutes. The dimethylformamide was removed in vacuo, the residue washed with methylene chloride and filtered. The filtrate was evaporated, and the residue was subjected to chromatography on a Waters Prep 500 instrument (silica cartridge, elution with ethyl acetate/methylene chloride (1:19)). Fractions containing product were concentrated in vacuo, the residue dissolved in a minimum amount of ethyl acetate, and the solution diluted with hexane until precipitate formed. The solid was collected by filtration and dried under high vacuum to give the title compound as a beige solid (0.305 g,29%). 1H NMR (DMSO-d6, 200 MHz) δ: 1.25 (s, 9H, t-butyl); 4.42 (d, J=6 Hz,2H, CH2); 6.33 (t,J=6 Hz, 1H, NH); 6.53-6.60 (m, 2H, Ar); 6.85 (t, J=8 Hz, 2H, Ar); 7.50 (d, J=10 Hz, 1H, Ar); 7.60 (dd, J=8, 2 Hz, 1H, Ar); 7.96 (d, J=8 Hz, 1H, Ar); 8.19 (d, J=8 Hz, 1H, Ar); 9.72 (s, 1H, Ar); 11.23 (s, 1H, NH); 12.28 (s, 1H, NH).