Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].[C:15]1([Mg]Br)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1.C(Cl)Cl>[NH2:1][C:2]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:3]=1[C:4]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:5]
Reactant: CON(C)C(=O)c1cc(F)ccc1N
Reactant: Br[Mg]c1ccccc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: Nc1ccc(F)cc1C(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 3.5 h

Procedure:
To a −78° C. solution of 2-amino-5-fluoro-N-methoxy-N-methylbenzamide in THF (100 mL) was added 1M phenylmagnesium bromide in THF (124.12 mL, 124.12 mmol). The reaction was stirred from −78° C. to ambient temperature over 3.5 h and then cooled again to −78° C. Additional 1M phenylmagnesium bromide in THF (62.06 mL, 62.06 mmol) was added and the reaction stirred at −78° C. for another hour. The reaction was then diluted with CH2Cl2 (500 mL) and quenched with saturated ammonium chloride solution (300 mL). The layers were separated and the organic one washed with brine (300 mL), dried over Na2SO4, filtered and concentrated in vacuo. Purification by normal phase chromatography (3-8% MeOH/CH2Cl2) yielded (2-amino-5-fluorophenyl)(phenyl)methanone as a yellow solid. 1H NMR (CDCl3, 400 MHz) 7.63 (m, 2H, ArH); 7.55 (m, 1H, ArH); 7.47 (m, 2H, ArH); 7.15 (m, 1H, ArH); 7.08 (m, 1H, ArH); 6.70 (m, 1H, ArH); 5.91 (s, NH2); MS (Electrospray): m/z 216.1 (M+H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[OH:11])=[O:3].[C:12]1([CH:18]2[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1CCCC1>CO>[Br:10][C:8]1[CH:9]=[C:4]2[C:5](=[CH:6][CH:7]=1)[O:11][C:21]1([CH2:20][CH2:19][CH:18]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:23][CH2:22]1)[CH2:1][C:2]2=[O:3]
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: O=C1CCC(c2ccccc2)CC1
Solvent: C1CCNC1
Solvent: CO
Product: O=C1CC2(CCC(c3ccccc3)CC2)Oc2ccc(Br)cc21
Yield: 65.2 %

Procedure:
In a 50 mL round bottom flask was placed 5-bromo-2-hydroxyacetophenone (1 g, 4.65 mmol) and 4-phenylcyclo-hexanone (810 mg, 4.65 mmol). They were dissolved in MeOH (9.3 mL). To this solution was added pyrrolidine (764 μL, 9.30 mmol) dropwise. To the flask was attached a condenser and the reaction mixture was heated at reflux overnight (˜14 hours). The next morning the volatiles were remove under reduced pressure and the crude material was purified by flash chromatography (ISCO, 40 g SiO2 cartridge, Ethyl Acetate/Hexanes as the eluents). The corresponding fractions were combined and concentrated yielding 6-bromo-4′-phenylspiro[chroman-2,1′-cyclohexan]-4-one (1.12 g, 3.03 mmol, 65%).
Reaction SMILES: [Na].[NH2:2][C:3]([NH2:5])=[O:4].[CH2:6]([CH:11]([C:17](OCC)=[O:18])[C:12](OCC)=[O:13])[CH:7]=[C:8]([CH3:10])[CH3:9]>C(O)C>[CH3:9][C:8]([CH3:10])=[CH:7][CH2:6][CH:11]1[C:12](=[O:13])[NH:5][C:3](=[O:4])[NH:2][C:17]1=[O:18]
Reactant: NC(N)=O
Reactant: CCOC(=O)C(CC=C(C)C)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CC(C)=CCC1C(=O)NC(=O)NC1=O

Procedure:
To a solution of 70 mg sodium (3.03 mmol) in 1.0 mL absolute ethanol was added 61 mg urea (1.01 mmol), followed by 200 mg of the diethyl prenylmalonate (0.88 mmol) prepared in the previous experiment. The solution was refluxed gently for 12 hours. Most of the ethanol was removed by rotary evaporation, and the residue was diluted in water. The solution was acidified to pH 3 and extracted 2×10 mL with ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate and concentrated to 214 mg of an off-white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[N+:9]([O-:11])=[O:10].Cl.[CH:13]1([CH:16]([NH2:19])[CH2:17][CH3:18])[CH2:15][CH2:14]1.C(N(CC)C(C)C)(C)C>CC#N>[CH:13]1([CH:16]([NH:19][C:2]2[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=2[N+:9]([O-:11])=[O:10])[CH2:17][CH3:18])[CH2:15][CH2:14]1
Reactant: O=c1[nH]ccc(Cl)c1[N+](=O)[O-]
Reactant: CCC(N)C1CC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCC(Nc1cc[nH]c(=O)c1[N+](=O)[O-])C1CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.3 %

Procedure:
Part A. A mixture of 4-chloro-3-nitro-2-pyridone (2.0 g, 11.4 mmol), 1-cyclopropylpropyl amine hydrochloride (1.5 g, 11.4 mmol) and N,N-diisopropylethylamine (4.8 ml, 27.4 mmol) in CH3CN (50 ml) were stirred at 25° C. for 16 h and at reflux for 4 h. After cooling it was stripped in vacuo, and the residue was partitioned between EtOAc (100 mL) and H2O (50 mL). The insolubles were separated, washed with H2O and EtOAc and vacuum dried 1.51 g. The filtrate layers were separated and the aqueous layer was extracted with EtOAc (2×50 mL). The Combined extracts were washed with brine, dried over MgSO4, filtered and concd. in vacuo. The residue was washed with EtOAc (2×) and vacuum dried, to give 0.69 g, yellow solid. Combined wt. of 4-(1-cyclopropylpropyl)amino-3-nitro-2-pyridone 2.20 g, 81% yield. 1H NMR(300 MHz, dmso d6): 11.19 (1H, br), 8.94 (1H, d J=8.8 Hz), 7.33 (1H, t J=6.9 Hz), 6.03 (1H, d J=7.7 Hz), 3.18-3.24 (1H, m), 1.60-1.74 (2H, m), 1.03-1.11(1H, m), 0.91 (3H, t), 0.40-0.60 (1H, m), 0.20-0.39 (1H, m).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([OH:20])[C@@H:10]([NH:12]C(=O)OC(C)(C)C)[CH3:11])=[CH:5][CH:4]=1)[CH3:2].Cl>C(#N)C.O>[NH2:12][C@@H:10]([CH3:11])[C@@H:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=1)[OH:20]
Reactant: CCc1ccc([C@@H](O)[C@H](C)NC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: O
Solvent: CC#N
Product: CCc1ccc([C@@H](O)[C@H](C)N)cc1
Reaction time: 3.5 h

Procedure:
To a stirred solution of tert-butyl [(1S,2R)-2-(4-ethylphenyl)-2-hydroxy-1-methylethyl]carbamate (450 mg, 1.51 mmol) in acetonitrile (10 ml) was added aq. HCl (6 N, 3 ml), and stirring was continued for 3.5 h. Then the mixture was diluted with water (10 ml), and acetonitrile was removed in vacuo. The mixture was washed with dichloromethane (20 ml). The aqueous layer was then made alkaline (pH≈10) by addition of aq. NaOH (10 N), and extracted with dichloromethane (3×20 ml). The combined organic extracts were dried with Na2SO4, the solvent was removed in vacuo to afford white solid, 280 mg (97%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].[CH2:5]([S:7](Cl)(=[O:9])=[O:8])[CH3:6].CCOCC>C(N(CC)CC)C>[CH2:5]([S:7]([O:4][CH2:3][CH2:2][Br:1])(=[O:9])=[O:8])[CH3:6]
Reactant: OCCBr
Reactant: CCS(=O)(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)OCCBr
Reaction time: 1 h

Procedure:
A mixture containing 12.5 ml. of 2-bromoethanol, 12.9 ml. of ethane sulfonyl chloride and 100 ml. of ether was formed. Then, 14 ml. of triethylamine was added dropwise over a 55 minute period at 5°-10°C. and stirred for 1 hour. The mixture was allowed to come to room temperature and stirred for an additional 15 minutes. To the mixture was added 100 ml. of water, the ether layer was separated, dried over magnesium sulfate and evaporated to yield 17.6 grams of a yellow oil. nD30 1.4760.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH2:15]([N:22]1[CH2:28][CH:27]([CH2:29][OH:30])[CH2:26][O:25][CH2:24][CH:23]1[CH3:31])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36](O)=[CH:35][C:34]=1[CH3:40]>ClCCl>[CH2:15]([N:22]1[CH2:28][CH:27]([CH2:29][O:30][C:36]2[CH:37]=[CH:38][C:33]([F:32])=[C:34]([CH3:40])[CH:35]=2)[CH2:26][O:25][CH2:24][CH:23]1[CH3:31])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC1COCC(CO)CN1Cc1ccccc1
Reactant: Cc1cc(O)ccc1F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: ClCCl
Product: Cc1cc(OCC2COCC(C)N(Cc3ccccc3)C2)ccc1F
Reaction time: 20 h

Procedure:
Diisopropyl azodicarboxylate (40 uL, 0.20 mmol, 1.2 equiv) was added to a suspension of (4-benzyl-3-methyl-1,4-oxazepan-6-yl)methanol (4-5, 40 mg, 0.17 mmol, 1 equiv), 4-fluoro-3-methylphenol (26 mg, 0.20 mmol, 1.2 equiv), and polystyrene-supported triphenylphosphine resin (250 mg, 0.51 mmol, 3.0 equiv) in anhydrous dichloromethane (30 mL) at 23° C. The mixture was stirred for 20 h, then filtered. The filtrate was concentrated and the residue was purified by flash column chromatography (20% EtOAc in hexanes) to provide 4-benzyl-6-[(4-fluoro-3-methylphenoxy)methyl]-3-methyl-1,4-oxazepane (4-6) as a ˜1:1 mixture of diastereomers (colorless oil). 1H NMR (300 MHz, CDCl3, reported for a single diasteromer) δ 7.38-7.19 (m, 5H), 6.85 (ddd, 1H,J=12.5, 9.2, 3.7 Hz), 6.53 (m, 2H), 3.97-3.50 (m, 6H), 3.08 (m, 1H), 3.00 (dd, 1H,J=14.0, 4.0 Hz), 2.90 (d, 1H,J=13.7 Hz), 2.82 (dd, 1H,J=14.0, 3.0 Hz), 2.60 (d, 1H,J=13.7 Hz), 2.44 (m, 1H), 2.21 (s w/small splittings, 3H), 1.08 (d, 3H,J=6.7 Hz). LRMS m/z (M+H) 344.4 found, 344.2 required.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[S:22][C:13]=2[N:14]=[C:15]([C:17]2[O:21][N:20]=[CH:19][CH:18]=2)[N:16]=1>>[O:21]1[C:17]([C:15]2[N:16]=[C:11]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[C:12]3[CH:24]=[C:23]([C:25]([F:27])([F:28])[F:26])[S:22][C:13]=3[N:14]=2)=[CH:18][CH:19]=[N:20]1
Reactant: NCc1ccc(F)cc1
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3ccno3)nc2s1
Product: Fc1ccc(CNc2nc(-c3ccno3)nc3sc(C(F)(F)F)cc23)cc1

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(isoxazol-5-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(4-fluorobenzylamino)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.C(OCC)(=O)C.[CH3:18][N:19](C)C=O>>[O:11]=[C:7]1[C:8]2[C:4](=[CH:3][C:2]([C:18]#[N:19])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: CN(C)C=O
Reactant: O=C1CCc2cc(Br)ccc21
Solvent: CCOC(C)=O
Product: N#Cc1ccc2c(c1)CCC2=O
Temperature: 140 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
5-Bromo-2,3-dihydro-1H-inden-1-one (21.1 g, 100 mmol) and cupric cyanide (17.9 g, 200 mmol) were mixed in 200 ml of dimethylformamide and stirred overnight at 140° C. After the solution was cooled down to room temperature, 500 ml of ethyl acetate was added and the precipitate was removed by filteration using kieselguhr. The solid was rinsed with ethyl acetate for several times. The pooled filtrates were washed with 1 N hydrochloric acid twice and then with brine for 3 times, dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude product was purified on silica gel, eluting with ethyl acetate/hexanes (1:2), to obtain 7.9 g of the desired compound (50% yield). MS (M+1)=158.05.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:24])[S:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:25]([O:27]CC)=[O:26])=[CH:9]2.[OH-].[Na+].O1CCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:24])[S:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)(=[O:17])=[O:18])[CH:14]=1)[NH:11][C:10]([C:25]([OH:27])=[O:26])=[CH:9]2
Reactant: CCOC(=O)c1cc2cc(OCCOC)cc(N(C)S(=O)(=O)c3cccs3)c2[nH]1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COCCOc1cc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C(=O)O)cc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 94.5 %

Procedure:
A mixture of ethyl 5-(2-methoxyethoxy)-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxylate (1.30 g), 1N aqueous sodium hydroxide solution (10 mL), tetrahydrofuran (10 mL) and ethanol (10 mL) was stirred at room temperature for 15 hr. The reaction mixture was acidified with aqueous citric acid solution, and extracted with ethyl acetate. The ethyl acetate layer was washed successively with water and saturated brine, dried (MgSO4), and concentrated to give the title compound (1.15 g, yield 93%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane to give colorless prism crystals. melting point 198-199° C.
Reaction SMILES: CN(C)C=O.[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:11][C:10]=1[CH:20]=[C:21]1[NH:25][C:24](=[O:26])[NH:23][C:22]1=O)([O-])=O>CO.CN(C)C=O>[N:15]1([C:12]2[CH:13]=[CH:14][C:9]3[N:6]=[C:22]4[NH:23][C:24](=[O:26])[NH:25][C:21]4=[CH:20][C:10]=3[CH:11]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C1NC(=O)C(=Cc2cc(N3CCCC3)ccc2[N+](=O)[O-])N1
Solvent: CN(C)C=O
Solvent: CO
Product: O=c1[nH]c2cc3cc(N4CCCC4)ccc3nc2[nH]1

Procedure:
This compound, m.p. >300° C. (obtained as a dimethylformamide solvate by crystallization from methanol-dimethylformamide), was prepared analogous to Example 4 from 5-[[2-nitro-5-(1-pyrrolidinyl)phenyl]methylene]-2,4-imidazolidinedione.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][CH3:16])[C:9]=2[F:17])[N:5]=[C:4]([C:18]([O:20][CH3:21])=[O:19])[C:3]=1[Cl:22].[CH2:23](O)C>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][CH3:16])[C:9]=2[F:17])[N:5]=[C:4]([C:18]([O:20][CH2:21][CH3:23])=[O:19])[C:3]=1[Cl:22]
Reactant: CCO
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)cc(N)c1Cl
Agent: [Ti+4]
Agent: CC(C)[O-]
Product: CCOC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)cc(N)c1Cl

Procedure:
To a solution of 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylic acid, methyl ester (200 mg, 0.9 mmol) in ethanol (5 mL) was added a catalytic amount of titanium tetraisopropoxide and the solution heated under reflux for 2 hours. The solution was cooled and partitioned between ethyl acetate (10 mL) and water (10 mL) and the organic phase was dried (sodium sulfate) and concentrated. The residue was passed over a plug of silica gel (1:1 ethyl acetate: hexanes) to give 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylic acid, ethyl ester (150 mg. 0.6 mmol): mp 74-75° C.
Reaction SMILES: [Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]4([OH:18])[CH2:17][CH2:16]4)=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][CH:3]=1.[C:22]([Si:26](Cl)([CH3:28])[CH3:27])([CH3:25])([CH3:24])[CH3:23].N1C=CN=C1>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]4([O:18][Si:26]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:28])[CH3:27])[CH2:17][CH2:16]4)=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(Br)c2c1[nH]c1cc(C3(O)CC3)ccc12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OC1(c2ccc3c(c2)[nH]c2c(C(N)=O)ccc(Br)c23)CC1
Reaction time: 1 h
Yield: 71.9 %

Procedure:
Step 2 A solution of 4-bromo-7-(1-hydroxycyclopropyl)-9H-carbazole-1-carboxamide (0.151 g, 0.436 mmol), tert-butylchlorodimethylsilane (0.079 g, 0.524 mmol) and imidazole (0.074 g, 1.091 mmol) in DMF (2.2 mL) was stirred at rt for 18 h. Additional tert-butylchlorodimethylsilane (0.079 g, 0.524 mmol) and imidazole (0.074 g, 1.091 mmol) were added and stirring was continued for 1 h. The mixture was diluted with EtOAc (75 mL) and washed seven times with brine. The organic layer was dried and concentrated and the residue was purified by column chromatography (eluting with a gradient from 90:10 to 50:50 hexane-EtOAc) to give 4-bromo-7-(1-(tert-butyldimethylsilyloxy)cyclopropyl)-9H-carbazole-1-carboxamide (0.144 g, 67%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([CH2:11][CH2:12][C@H:13]([OH:27])[CH2:14]OS(CC2C=CC(C)=CC=2)(=O)=O)=[CH:9][CH:10]=1)=[O:5])[CH3:2].[N-:28]=[N+:29]=[N-:30].[Na+].[Na+].[Cl-]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([CH2:11][CH2:12][C@H:13]([OH:27])[CH2:14][N:28]=[N+:29]=[N-:30])=[CH:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)c1ccc(CC[C@H](O)COS(=O)(=O)Cc2ccc(C)cc2)s1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(CC[C@H](O)CN=[N+]=[N-])s1
Temperature: 80 °C
Yield: 113.5 %

Procedure:
To a stirred solution of 42.94 g (108 mmol) of the tosylate (4) in 250 ml of DMF (N,N-dimethylformamide) was added 31.52 g (485 mmol) of sodium azide. The solution was heated under argon for 4 hours at 80° C. The reaction mixture was cooled and poured into 600 ml of saturated NaCl, and the resulting oil was separated. The aqueous solution was extracted three times with Et2O. The Et2O extracts were combined with the oil and washed once with saturated NaCl, dried (MgSO4), and concentrated, yielding 33.0 g of the azide (5) as a crude product that was sufficiently pure to use in the next step (f). An analytical sample of the azide (5) was obtained by flash chromatography on silica gel, eluting CH2Cl2 -EtOAc (20:1) to produce a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4]P(OCC(F)(F)F)(OCC(F)(F)F)=O.[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1>C1COCC1.[NH4+].[Cl-].C(Cl)Cl>[CH3:1][O:2][C:3](=[O:19])/[CH:4]=[CH:25]\[C:24]1[CH:27]=[CH:28][C:21]([Br:20])=[CH:22][CH:23]=1
Reactant: COC(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Reactant: O=Cc1ccc(Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)/C=C\c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of [Bis-(2,2,2-trifluoro-ethoxy)-phosphoryl]-acetic acid methyl ester (1.0 eq.) and 18—C-6 (5.0 eq.) in THF (0.05M) at −78° C. was added dropwise KN(TMS)2 (1.0 eq.). The mixture was stirred at −78° C. for 15 min then 4-bromobenzaldehyde (1.0 eq.) was added. The final mixture stirred for 1 h at −78° C., poured in saturated aqueous NH4Cl and extracted with Et2O (3×). The combined organic extracts were washed with, brine, dried over Na2SO4, filtered and concentrated. Flash chromatography (Hex:EtOAc 10 to 25%) afforded a mixture of desired material and the starting aldehyde. Upon treatment in CH2Cl2 of the mixture with Amino-Merrifield resin for 10 min, the aldehyde was removed. Filtration and concentration afforded the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[C:4](=[O:18])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.I[CH2:31][CH3:32]>C(OCC)(=O)C>[C:12]1([S:9]([N:5]2[CH:6]=[C:7]([F:8])[C:2](=[NH:1])[N:3]([CH2:31][CH3:32])[C:4]2=[O:18])(=[O:10])=[O:11])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCI
Reactant: Nc1nc(=O)n(S(=O)(=O)c2ccccc2)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCn1c(=N)c(F)cn(S(=O)(=O)c2ccccc2)c1=O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a 25 mL sealed tube were added 4-amino-1-benzenesulfonyl-5-fluoro-1H-pyrimidine-2-one (1.0 g, 3.71 mmol), anhydrous potassium carbonate (K2CO3; 2.05 g, 14.9 mmol), and N,N-dimethylformamide (DMF; 10 mL), followed by iodoethane (EtI; 3.45 g, 22.3 mmol). The reaction vessel was sealed, and the reaction mixture was warmed to 60° C. and stirred for 1 hour. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (EtOAc; 250 mL), and washed with water (H2O; 3×100 mL). The organic phase was dried over magnesium sulfate (MgSO4), filtered, and the solvent evaporated under reduced pressure. Purification by flash chromatography (SiO2, EtOAc/Hexanes gradient) afforded benzenesulfonyl-5-fluoro-4-imino-3-ethyl-3,4-dihydro-1H-pyrimidin-2-one as a pale yellow solid (200 mg; 18%): mp 163-166° C.; 1H NMR (400 MHz, DMSO-d6) δ 8.82 (m, 1H), 8.29 (d, J=6.8 Hz, 1H), 8.02 (dd, J=8.4, 1.1 Hz, 2H), 7.79 (ddd, J=6.9, 2.3, 1.1 Hz, 1H), 7.66 (dd, J=10.7, 4.9 Hz, 2H), 3.31 (q, J=7.2 Hz, 2H), 1.09 (t, J=7.2 Hz, 3H); ESIMS m/z 298 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:20])[C:11]([CH3:19])([S:17][CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl[O-:22].[Na+]>O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:20])[C:11]([CH3:19])([S:17]([CH3:18])=[O:22])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCOC(=O)C(C)(SC)C(=O)Nc1cc(Cl)cc(Cl)c1
Reactant: [O-]Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(C)(C(=O)Nc1cc(Cl)cc(Cl)c1)S(C)=O

Procedure:
Ethyl 3-[(3,5-dichlorophenyl)amino]-2-methyl-2-methylthio-3-oxopropanoate, prepared in Example XC (Compound 261), was reacted with aqueous sodium hypochlorite in a water-methylene chloride mixture in a manner similar to that described in Example XCIII to give ethyl 3-[(3,5-dichlorophenyl)amino]-2-methyl-2-methylsulfinyl-3-oxopropanoate having a melting point of 124° C.-127° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:22][C:23]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:24]=1[C:25]([NH2:27])=[O:26]>>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][C:23]2[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:24]=2[C:25]([NH2:27])=[O:26])[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1
Reactant: COc1ccc(C(N)=O)c(N)c1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Product: COc1ccc(C(N)=O)c(Nc2nc(Cl)nc3c2ccn3S(=O)(=O)c2ccc(C)cc2)c1
Yield: 29 %

Procedure:
Using General Protocol II and starting with 2,4-dichloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (4.0 g, 11.7 mmol) and 2-amino-4-(methyloxy)benzamide (4.5 g, 26.8 mmol), 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-4-(methyloxy)benzamide was isolated as a yellow solid (0.1.58 g, 29% yield); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.33 (s, 3 H), 4.28 (s, 3 H), 6.62 (t, J=3.48 Hz, 1 H), 6.68 (ddd, J=6.00, 2.88, 2.66 Hz, 1 H), 7.41-7.46 (m, 2 H), 7.64 (s, 1 H), 7.74 (t, J=3.48 Hz, 1 H), 7.81-7.87 (m, 1 H), 7.92-7.98 (m, 2 H), 8.22 (s, 1 H), 8.32 (t, J=2.66 Hz, 1 H), 13.13 (s, 1 H).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([CH2:19][O:20][C:21]3[CH:22]=[C:23]([NH:27][C:28](=[O:38])[CH2:29][C:30]([CH2:36][CH3:37])([CH2:34][CH3:35])[C:31]([OH:33])=[O:32])[CH:24]=[CH:25][CH:26]=3)=[N:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C(N(CC)CC)C>[Pd].O1CCCC1>[OH:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([CH2:19][O:20][C:21]3[CH:22]=[C:23]([NH:27][C:28](=[O:38])[CH2:29][C:30]([CH2:36][CH3:37])([CH2:34][CH3:35])[C:31]([OH:33])=[O:32])[CH:24]=[CH:25][CH:26]=3)=[N:16]2)=[CH:11][CH:10]=1
Reactant: CCC(CC)(CC(=O)Nc1cccc(OCc2ccc3ccc(OCc4ccccc4)cc3n2)c1)C(=O)O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(CC)(CC(=O)Nc1cccc(OCc2ccc3ccc(O)cc3n2)c1)C(=O)O
Reaction time: 3 h

Procedure:
A mixture consisting of 0.37 g of 4-[3-(7-benzyloxy-2-quinolinylmethoxy)phenylamino]-2,2-diethyl-4-oxobutanoic acid (Example 18), 2 ml of triethylamine, 0.0185 g of palladium/activated carbon catalayst and 10 ml of tetrahydrofuran is hydrogenated for 3 hours under normal pressure. The reaction mixture is then filtered and concentrated by evaporation. The residue is chromatographed on silica gel using methylene chloride/methanol 95:5 and 9:1. The title compound is obtained in the form of a slightly yellowish amorphous solid; 1H-NMR, 400 MHz, DMSO, delta (ppm)=10.3 (s, 1H), 8.20 (d, 1H), 7.28 (m, 2H), 7.25 (d, 1H), 7.1-7.18 (m, 3H), 6.65 (dd, 1H), 5.22 (s, 2H), 2.47 (s, 2H), 1.49 (m, 4H), 0.78 (t, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10][CH2:11][CH2:12][NH:13][C:14]([NH:18][C:19]#[N:20])=[N:15][CH2:16][CH3:17])=[N:7][C:6]=2[CH:21]=1.ClC1C=CC=C(C(OO)=[O:30])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([CH2:11][CH2:12][NH:13][C:14]([NH:18][C:19]#[N:20])=[N:15][CH2:16][CH3:17])=[O:30])=[N:7][C:6]=2[CH:21]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCN=C(NC#N)NCCSc1nc2cc(Cl)ccc2s1
Solvent: ClCCl
Product: CCN=C(NC#N)NCCS(=O)c1nc2cc(Cl)ccc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
Dissolved in 8 ml of methylene chloride were 0.20 g (0.59 mmol) of the compound obtained in Example 27, and 0.15 g (0.59 mmol) of m-chloroperbenzoic acid with a 70% purity were added to the solution, which was stirred at room temperature for 2 hours. The solvent was removed in vacuo and the residue was purified by silica gel chromatography to obtain 0.20 g of white crystalline powders (95% yield).