Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([Br:13])[CH:12]=1)[C:5]([O:7][CH2:8]C)=[O:6].[C:14]1(=O)[CH2:18][CH2:17][CH2:16][CH2:15]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Br:13][C:11]1[CH:10]=[C:4]([CH:3]=[C:2]([NH:1][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:12]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C1CCCC1
Reactant: CCOC(=O)c1cc(N)cc(Br)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)cc(NC2CCCC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.5 %

Procedure:
To a stirred solution of ethyl 3-amino-5-bromobenzoate (2 g, 8.73 mmol) and cyclopentanone (2.2 g, 26.1 mmol) in methanol (20 mL), acetic acid (1.04 g, 17.4 mmol) was added and reaction stirred at room temperature for 3 h. Then sodium cyanoborohydride (1.37 g, 21.83 mmol) was added and reaction stirred overnight. On completion, solvent was removed under reduced pressure and crude material was purified by column chromatography to afford desired compound (1.6 g, 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[O:5][CH:6]1[CH2:12][CH:11]2[N:13]([CH2:14][C:15]([NH2:17])=[S:16])[CH:8]([CH2:9][CH2:10]2)[CH2:7]1.Cl[CH2:23][CH:24]=O>C(O)(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[O:5][CH:6]1[CH2:12][CH:11]2[N:13]([CH2:14][C:15]3[S:16][CH:23]=[CH:24][N:17]=3)[CH:8]([CH2:9][CH2:10]2)[CH2:7]1
Reactant: NC(=S)CN1C2CCC1CC(Oc1ccc(Cl)c(Cl)c1)C2
Reactant: O=CCCl
Solvent: CC(=O)O
Solvent: O
Product: Clc1ccc(OC2CC3CCC(C2)N3Cc2nccs2)cc1Cl
Temperature: 25 °C

Procedure:
to 2-[3-(3,4-Dichloro-phenoxy)-8-aza-bicyclo[3.2.1]oct-8-yl]-thioacetamide (0.5 g) in 5 ml of acetic acid was added 0.13 g of 50% chloroacetaldehyde in water. The reaction mixture was stirred at reflux overnight and cooled to room temperature and poured into 50 ml of water. The mixture was extracted twice with dichloromethane. The organic phase was dried with magnesium sulphate and evaporated to and oil. The product was isolated by column chromatography with dichloromethane/methanol (9:1) with 1% ammonia as eluent, the product fractions was evaporated to dryness. Yield 0.1 g (19%). Mp. 123-124° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]([NH:13][C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([OH:25])=O)=[C:16]3[N:15]=2)[CH2:11][OH:12])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C.Cl.[Cl:55][CH2:56][CH2:57][CH2:58][NH2:59]>C(Cl)Cl.CN(C=O)C>[Cl:55][CH2:56][CH2:57][CH2:58][NH:59][C:23]([C:22]1[CH:21]=[N:20][N:17]2[CH:18]=[CH:19][C:14]([NH:13][C@@H:10]([C:4]3[C:5]([O:8][CH3:9])=[N:6][CH:7]=[C:2]([F:1])[CH:3]=3)[CH2:11][OH:12])=[N:15][C:16]=12)=[O:25]
Reactant: NCCCCl
Reactant: COc1ncc(F)cc1[C@@H](CO)Nc1ccn2ncc(C(=O)O)c2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ncc(F)cc1[C@@H](CO)Nc1ccn2ncc(C(=O)NCCCCl)c2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 101.4 %

Procedure:
To a suspension of (S)-5-(1-(5-fluoro-2-methoxypyridin-3-yl)-2-hydroxyethylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (50 mg, 0.14 mmol) in DCM (2 mL) was added HOBt (44 mg, 0.29 mmol) followed by EDCI (83 mg, 0.43 mmol). The heterogeneous mixture was stirred at ambient temperature for 10 minutes then treated with triethylamine (100 μL, 0.72 mmol) followed by 3-chloro-propylamine hydrochloride (56 mg, 0.43 mmol). The mixture was stirred for 2 hours, then DMF (2 mL) was added and stirring was continued for 48 hours. The mixture was partitioned between saturated NH4Cl solution (20 mL) and EtOAc (20 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (2×10 mL) and the combined organic phases were washed with water (5×10 mL) and brine (10 mL), then dried over Na2SO4, filtered and concentrated to afford (S)-N-(3-chloropropyl)-5-(1-(5-fluoro-2-methoxypyridin-3-yl)-2-hydroxyethylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (60 mg, 99% yield) as a pale yellow foam which was used without further purification. MS (apci) m/z=423.0 (M+H).
Reaction SMILES: C(OC([N:8]1[C:13](=[O:14])[CH2:12][CH2:11][CH2:10][C@H:9]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=O)(C)(C)C.Cl>C(OCC)(=O)C>[C:18]([O:17][C:15]([C@@H:9]1[CH2:10][CH2:11][CH2:12][C:13](=[O:14])[NH:8]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCC(=O)N1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@@H]1CCCC(=O)N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-6-oxo-piperidine-1,2-dicarboxylic acid di-tert-butyl ester (6.30 g, 21.0 mmol) in ethyl acetate (50 mL) was added 1.1-M HCl in ethyl acetate (28.7 mL, 31.5 mmol). The reaction was stirred at room temperature for 1 h, then washed with water, saturated aq.NaHCO3 and brine. The organic phase was dried (MgSO4), filtered and evaporated to afford the title compound as a yellow oil which crystallized upon standing (3.11 g, 74%): 1H NMR (400 MHz, CDCl3) δ 1.49 (9H, s), 1.74-1.94 (3H, m), 2.18 (1H, m), 2.29-2.44 (2H, m), 3.95-3.98 (1H, m), 6.32 (1H, br s); 13C NMR (100 MHz, CDCl3) δ 19.9 (CH2), 25.9 (CH2), 28.4 (CH3), 31.4 (CH2), 55.7 (CH), 83.0 (C), 170.4 (C), 171.9 (C).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][CH3:12])[N:9]=[CH:10][C:5]2=[C:4]([N:13]2[CH2:19][CH:18]3[O:20][CH:15]([CH2:16][CH2:17]3)[CH2:14]2)[N:3]=1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][CH:23]=1>C1(C)C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:15]12[O:20][CH:18]([CH2:17][CH2:16]1)[CH2:19][N:13]([C:4]1[N:3]=[C:2]([C:25]3[CH:26]=[CH:27][C:22]([NH2:21])=[CH:23][CH:24]=3)[N:7]=[C:6]3[N:8]([CH2:11][CH3:12])[N:9]=[CH:10][C:5]=13)[CH2:14]2
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: CCn1ncc2c(N3CC4CCC(C3)O4)nc(Cl)nc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(N)cc3)nc21
Temperature: 120 °C

Procedure:
A mixture of 3-(6-chloro-1-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (0.55 g, 1.9 mmol), 4-aminophenylboronic acid pinacol ester (0.62 g, 2.8 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.22 g, 10 mol %) in toluene/ethanol (1:1, 12 mL) and 2 M aqueous sodium carbonate solution (2 mL) was heated in a 10-20 mL Smith process vial in the microwave reactor for one hour at 120° C. The cooled mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted three times with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude residue was purified via automated flash chromatography (methanol/chloroform) to provide 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-ethyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)aniline. MS (ES+): 351.0 (M+H)+
Reaction SMILES: [CH:1](=[C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N+:18]([O-:20])=[O:19])[CH:14]=2)[NH:9]1)C1C=CC=CC=1.[O-:21][Mn](=O)(=O)=O.[K+].[OH2:27]>N1C=CC=CC=1>[C:1]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N+:18]([O-:20])=[O:19])[CH:14]=2)[N:9]=1)([OH:21])=[O:27]
Reactant: O=[N+]([O-])c1ccc2c(c1)C=CC(=Cc1ccccc1)N2
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O
Agent: [K+]
Solvent: c1ccncc1
Product: O=C(O)c1ccc2cc([N+](=O)[O-])ccc2n1
Yield: 39 %

Procedure:
To a solution of 2-benzylidene-6-nitroquinoline (4.9 g; 17.7 mM) in pyridine (36.6 ml) and water (8 ml) was added portion wise KMnO4 (7.5 g; 47.8 mM) keeping the temperature between 18 and 20° C. After filtration on celite, the solution was acidified (pH3), at 0° C., with H2SO4 (65%). The resulting precipitate was filtered, washed with water and ether and then dried to give 2-carboxy-6-nitroquinoline (1.5 g; 39%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][NH:11][CH:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Ca+2].[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[C@@:26]1([CH2:30][N:31]2[CH:35]=[N:34][CH:33]=[N:32]2)[C@H:28]([CH3:29])[O:27]1>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[N:11][N:10]([C@H:28]([CH3:29])[C@:26]([C:20]3[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:19]=3[F:18])([OH:27])[CH2:30][N:31]3[CH:35]=[N:34][CH:33]=[N:32]3)[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2cn[nH]c2)cc1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CN(C)C=O
Product: C[C@@H](n1cc(-c2ccc(F)cc2)cn1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 0.33 h
Yield: 56 %

Procedure:
To a suspension of 4-(4-fluorophenyl)-1H-pyrazole (0.12 g) in N,N-dimethylformamide (5 ml) were added calcium carbonate (0.15 g) and 1-(((2R,3S)-2-(2,4-difluorophenyl)-3-methyloxiran-2-yl)methyl)-1H-1,2,4-triazole (0.204 g). While argon gas was provided, stirring was conducted at room temperature for 20 min prior to the irradiation of microwaves thereto at 180° C. for 15 min for reaction. After the reaction was terminated, the solution was diluted in ethyl acetate (10 ml) and washed with a saturated ammonium chloride solution (10 ml) and then with brine (10 ml). The washed organic layer thus formed was dried over anhydrous magnesium sulfate and concentrated by evaporation in a vacuum. The residue was separated through silica gel chromatography to give the title compound (Yield 56%).
Reaction SMILES: [CH3:1][S:2]([C:5]1([C:9]([O:11]C)=[O:10])[CH2:8][CH2:7][CH2:6]1)(=[O:4])=[O:3].O.[OH-].[Li+:15]>O1CCOCC1.O>[CH3:1][S:2]([C:5]1([C:9]([O-:11])=[O:10])[CH2:8][CH2:7][CH2:6]1)(=[O:3])=[O:4].[Li+:15]
Reactant: COC(=O)C1(S(C)(=O)=O)CCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CS(=O)(=O)C1(C(=O)[O-])CCC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 1-methylsulfonylcyclobutanecarboxlate (0.10 g, 0.52 mmol) in 2 mL of dioxane and 2 mL of water was added lithium hydroxide monohydrate (44 mg, 1.0 mmol). After stirring at 100° C. for 1 h, the reaction mixture was concentrated to dryness, and the residue was azeotroped with toluene to give the crude lithium 1-methylsulfonylcyclobutanecarboxylate, which was used without further purification. Thus, the crude lithium salt was suspended in 2 mL of anhydrous dimethylformamide, and was added N-(2S,3S)-[3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-amine hydrochloride (0.15 g, 0.52 mmol), tris(pyrrolindinyl)phosphonium hexafluorophosphate (0.41 g, 0.78 mmol) and N-methylmorpholine (0.23 mL, 2.1 mmol). After stirring at room temperature overnight, the reaction mixture was partitioned between water (20 mL) and ether (20 mL). The organic layer was separated, and the aqueous layer was extracted with ether (20 mL). The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to dryness, and the residue was purified by flash chromatography on silica gel eluting with 20 to 40% ethyl acetate in hexane to give the title compound. 1H NMR (500 MHz, CD3OD): δ 7.57 (m, 1H), 7.49 (s, 1H), 7.43 (m, 2H), 7.10 (d, 2H), 6.92 (d, 2H), 4.38 (m, 1H), 3.35-2.63 (m, 7H), 2.93 (s, 3H), 2.14 (m, 1H), 1.98 (m, 1H), 0.98 (d, 3H). LC-MS: m/e 445 (M+H)+ (3.5 min).
Reaction SMILES: CO[C:3](=[O:34])[N:4]=[C:5](SC)[C:6]([C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([CH2:30][OH:31])[CH:21]=1)=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1.[NH:35]([C:37]1[N:42]=[CH:41][CH:40]=[CH:39][N:38]=1)[NH2:36].C(N(CC)CC)C>CN(C=O)C>[OH:31][CH2:30][C:22]1[C:23]([O:28][CH3:29])=[C:24]([O:26][CH3:27])[CH:25]=[C:20]([CH:6]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:18]=[C:17]([CH3:19])[O:16][N:15]=3)=[CH:10][CH:9]=2)[C:5]2[NH:4][C:3](=[O:34])[N:35]([C:37]3[N:42]=[CH:41][CH:40]=[CH:39][N:38]=3)[N:36]=2)[CH:21]=1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(CO)c(OC)c(OC)c1
Reactant: NNc1ncccn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)cc(CO)c1OC
Temperature: 85 °C
Reaction time: 8 h
Yield: 43.5 %

Procedure:
To a solution of 114 mg of [2-(3-hydroxymethyl-4,5-dimethoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester (Example (22b)) in 2 ml of DMF there were added 25 mg of 2-hydrazinopyrimidine and 35 μl of triethylamine, and the mixture was stirred overnight at 85° C. under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 3 ml of methanol and 0.3 ml of acetic acid. After adding 200 mg of sodium cyanotrihydroborate to the solution, the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give 5-{(5-hydroxymethyl-3,4-dimethoxyphenyl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[1,2,4]triazol-3-one (51 mg) as a light brown solid.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2([C:17](=[N:19][OH:20])[CH3:18])[CH2:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1.[CH3:21][CH2:22][C:23](=[O:26])[CH2:24][CH3:25].O>CCCCCC.O1CCCC1>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2([C:17](=[N:19][OH:20])[CH2:18][C:23]([CH2:24][CH3:25])([OH:26])[CH2:22][CH3:21])[CH2:14][CH2:15][CH2:16]2)=[CH:11][CH:12]=1
Reactant: CCC(=O)CC
Reactant: CC(=NO)C1(c2ccc(Cl)cc2)CCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CCC(O)(CC)CC(=NO)C1(c2ccc(Cl)cc2)CCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 2.7M solution of butyllithium in hexane (24 ml) was added under nitrogen to a stirred solution of 1-[1-(4-chlorophenyl)cyclobutyl]ethanone oxime [prepared as described in Example 84 (7.2 g)] in dry tetrahydrofuran (100 ml) over a period of 45 minutes whilst maintaining the temperature in the range -3° to 0° C. The mixture was stirred at 0° C. for 1 hour and then cooled to -5° C. A solution of dry pentan-3-one (3.4 ml) in dry tetrahydrofuran (10 ml) was added, the temperature of the mixture was allowed to rise to ambient and the mixture was stirred under nitrogen for 16 hours. The mixture was cooled to below 10° C. and water (100 ml) was added dropwise under nitrogen. The mixture was extracted with ether, the extracts dried and evaporated and the residue triturated with ice-cold petroleum ether (b.p. 40°-60° C.) to give 1-[1-(4-chlorophenyl)cyclobutyl]-3-ethyl-3-hydroxypentan-1-one oxime (m.p. 113°-115° C.).
Reaction SMILES: O1CCCC1.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[C:14]=2/[CH:21]=[CH:22]/[CH:23]([OH:32])[CH2:24][C:25](=[O:31])[CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:9][C:8]=1[CH3:33].C(B(CC)CC)C.[BH4-].[Na+]>CO>[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[C:14]=2/[CH:21]=[CH:22]/[CH:23]([OH:32])[CH2:24][CH:25]([OH:31])[CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:9][C:8]=1[CH3:33]
Reactant: COC(=O)CC(=O)CC(O)/C=C/c1c(C)cc(C)cc1-c1ccc(F)c(C)c1
Agent: CCB(CC)CC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)CC(O)CC(O)/C=C/c1c(C)cc(C)cc1-c1ccc(F)c(C)c1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
Into a glass vessel under nitrogen was charged tetrahydrofuran (22 ml), methyl E-7-(4'-fluoro-3,3',5-trimethyl[1,1'-biphenyl]-2-yl)-5-hydroxy-3-oxo-6-heptenoate (3.0 g, 7.8 mmole) and triethylborane (0.92 g, 9.4 mmole) at ambient temperature and air was bubbled through the solution. After a 5 minute age, the solution was cooled to -78° C. Sodium borohydride (350 mg, 9.25 mmole) was added followed by the addition over 15 minutes of methanol (5 ml) maintaining a temperature below -65° C. After a 30 minute age at -78° C. the mixture is carefully quenched into a rapidly stirred solution of 30% hydrogen peroxide (15 ml) and water (30 ml) at 20° C., aged 30 min then extracted with 50 ml of ethyl acetate. The organic extract was washed successively with 1N aqueous hydrochloric acid (25 ml), water (25 ml) and pH 7 buffer (25 ml), then dried over sodium sulfate (25 g). After filtration, the solution was concentrated to an oil in vacuo. Crystallization was induced by flushing with hexane, and reconcentrating in vacuo to yield the title compound in 90% assay yield (2.71 g). The product was triturated with hexanes to yield a white solid, mp. 78°-80° C. (dec). HPLC assay indicated a purity of 99%.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].[F:23][CH:24]([F:36])[O:25][C:26]1[CH:35]=[CH:34][C:29]([C:30](=O)[CH2:31]Br)=[CH:28][CH:27]=1>>[F:23][CH:24]([F:36])[O:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]2[N:12]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=3)[S:13][CH:31]=2)=[CH:28][CH:27]=1
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Reactant: O=C(CBr)c1ccc(OC(F)F)cc1
Product: O=C(O)c1cc(-c2nc(-c3ccc(OC(F)F)cc3)cs2)ccc1-c1ccccc1[N+](=O)[O-]
Yield: 61 %

Procedure:
4-[4-(4-Difluoromethoxy-phenyl)-thiazol-2-yl]-2′-nitro-biphenyl-2-carboxylic acid (180 mg, 61%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 4-(difluoromethoxy)phenacyl bromide (available from Oakwood Products, Inc.) using the procedure described for the preparation of Example 1. 1H NMR (300 MHz, DMSO-d6) δ 13.15 (s, 1H), 8.57 (d, J=1.9 Hz, 1H), 8.11-8.27 (m, 5H), 7.63-7.81 (m, 2H), 7.41-7.48 (m, 2H), 7.30 (d, J=9.2 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=3)[N:7]=2)[CH:3]=1.[O:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:34]=[CH:33][C:29]([C:30]([O-])=[O:31])=[CH:28][CH:27]=2)[CH2:22][CH2:21]1>>[O:20]1[CH2:21][CH2:22][N:23]([C:26]2[CH:27]=[CH:28][C:29]([C:30]([NH:1][C:2]3[CH:10]=[CH:9][C:8]4[C:4](=[CH:5][N:6]([C:11]5[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=5)[N:7]=4)[CH:3]=3)=[O:31])=[CH:33][CH:34]=2)[CH2:24][CH2:25]1
Reactant: O=C([O-])c1ccc(N2CCOCC2)cc1
Reactant: Nc1ccc2nn(-c3ccc([N+](=O)[O-])cc3)cc2c1
Product: O=C(Nc1ccc2nn(-c3ccc([N+](=O)[O-])cc3)cc2c1)c1ccc(N2CCOCC2)cc1

Procedure:
Compound 540 was prepared according to the procedure described in Scheme IV from 5-amino-2-(4-nitrophenyl)indazole and 4-morpholinobenzoate. [M+H]+ calcd for C24H21N5O4: 444.16; found: 444.27.
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]=[C:7]([S:9][C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)[S:8][C:4]=2[CH:3]=1.[Br:19][CH2:20][CH2:21][CH2:22][CH2:23]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][O:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]=[C:7]([S:9][C:10]3[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=3)[S:8][C:4]=2[CH:3]=1
Reactant: BrCCCCBr
Reactant: Oc1ccc2nc(Sc3ccc(Cl)cc3)sc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc(Sc2nc3ccc(OCCCCBr)cc3s2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
0.74 g (2.5 mmol) of 6-hydroxy-2-(4-chlorophenylmercapto)-benzothiazole are dissolved in 20 ml of dimethylformamide and after the addition of 2.16 g (10 mmol) of 1.4-dibromobutane and 2.07 g (15 mmol) of potassium carbonate the resulting mixture is stirred for 20 hours at ambient temperature. The mixture is then added to water and extracted with ethyl acetate. The extracts are dried and evaporated down. The evaporation residue is purified by column chromatography on silica gel (eluant: petroleum ether/ethyl acetate=4:1). Yield: 0.85 g (79.3% of theory), oil.
Reaction SMILES: N1CCC[C@H:2]1[C:3](O)=[O:4].Br[CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]2[O:19][C:18]([N+:20]([O-:22])=[O:21])=[C:17]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:16]=2[CH:29]=1>C(O)C>[CH2:3]([O:4][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]2[O:19][C:18]([N+:20]([O-:22])=[O:21])=[C:17]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:16]=2[CH:29]=1)[CH3:2]
Reactant: O=[N+]([O-])c1oc2ccc(CCBr)cc2c1-c1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CCOCCc1ccc2oc([N+](=O)[O-])c(-c3ccccc3)c2c1

Procedure:
A mixture of 1.04 g. (0.009 mole) of proline and 3 g. (0.009 mole) of 5-(2-bromoethyl)-2-nitro-3-phenylbenzofuran (prepared by reaction of 5-(2-hydroxyethyl)-2-nitro-3-phenylbenzofuran with phosphorus tribromide) in 50 ml. of ethanol is heated to its reflux temperature and maintained at reflux temperature for about 14 hours. The mixture is evaporated to provide a solid residue which is recrystallized from ethanol to provide 5-ethoxyethyl-2-nitro-3-phenylbenzofuran, m.p. 108°-109° C.
Reaction SMILES: CC(=[N:4][OH:5])C.CC(C)([O-])C.[K+].[C:12]([C:14]1[CH:15]=[C:16]([CH:37]=[CH:38][C:39]=1F)[C:17]([NH:19][C:20]1[C:21]([NH:26][C:27](=[O:36])[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:18])#[N:13]>CN(C=O)C.C1COCC1>[NH2:13][C:12]1[C:14]2[CH:15]=[C:16]([C:17]([NH:19][C:20]3[C:21]([NH:26][C:27](=[O:36])[C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:18])[CH:37]=[CH:38][C:39]=2[O:5][N:4]=1
Reactant: CC(C)=NO
Reactant: COc1ccc(C(=O)Nc2ccccc2NC(=O)c2ccc(F)c(C#N)c2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)c2ccc3onc(N)c3c2)cc1
Reaction time: 0.5 h
Yield: 45.9 %

Procedure:
To a stirring solution of acetone oxime (94 mg, 1.28 mmol) in DMF (2 mL) was added a 1 M solution of potassium t-butoxide (1.28 mL, 1.28 mmol) in THF. After 30 min, N1-(3-cyano-4-fluorobenzoyl)-N2-(4-methoxybenzoyl)-1,2-benzenediamine (100 mg, 0.26 mmol) was added and stirring continued for 72 h. The solvents were removed in vacuo and the residue was dissolved in methanol (20 mL). To this stirring solution was added water (15 mL) and conc HCl (3 mL), and the solution was heated to reflux. After 2 h, the solvents were removed in vacuo and the residue was dissolved in methanol. Silica gel was added and then the solvents were removed in vacuo. This dry pack was loaded onto a silica gel column and eluted with 1:1 ethyl acetate/dichloromethane. The product containing fractions were combined and concentrated to give 48 mg (46%) of white solid.