Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].[Cl:5][C:6]1(Cl)[N:10]([CH3:11])[CH2:9][CH2:8][N:7]1[CH3:12]>>[N+:1]([O-:4])([O-:3])=[O:2].[CH3:12][NH+:7]1[CH2:8][CH2:9][N:10]([CH3:11])[CH:6]1[Cl:5]
Reactant: O=[N+]([O-])O
Reactant: CN1CCN(C)C1(Cl)Cl
Product: CN1CC[NH+](C)C1Cl
Product: O=[N+]([O-])[O-]
Yield: 85.1 %

Procedure:
2.34 g (24.1 mmol) of a 65% nitric acid are added with vigorous stirring to 3.77 g (22.3 mmol) of 2,2-dichloro-1,3-dimethylimidazolidine. This reaction mixture is evacuated firstly at room temperature for one hour at 4 kPa and for 20 min at 7 Pa. After cooling using an ice bath, the mixture is evacuated again for 6 hours at 7 Pa, giving 3.7 g of 1,3-dimethyl-2-chloroimidazolidinium nitrate as an oil, corresponding to a yield of 85.1%.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:10][C:11]1[CH:15]=[CH:14][NH:13][N:12]=1.[CH3:16][O:17][C:18]1[CH:31]=[CH:30][C:21]([C:22]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=O)=[CH:20][CH:19]=1>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:22]([C:21]2[CH:20]=[CH:19][C:18]([O:17][CH3:16])=[CH:31][CH:30]=2)[NH:10][C:11]2=[N:12][NH:13][CH:14]=[C:15]12
Reactant: O=Cc1ccccc1Cl
Reactant: CCOC(=O)CC(=O)c1ccc(OC)cc1
Reactant: Nc1cc[nH]n1
Product: CCOC(=O)C1=C(c2ccc(OC)cc2)Nc2n[nH]cc2C1c1ccccc1Cl

Procedure:
The title compound was prepared from 2-chlorobenzaldehyde, 3-aminopyrazole and ethyl (4-methoxybenzoyl)acetate in the same manner as in Example 1.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1.[Li]CCCC.CN(OC)[C:30](=[O:32])[CH3:31].Cl>C1COCC1.O>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:30](=[O:32])[CH3:31])[N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1
Reactant: Clc1nc(N2CCOCC2)c2ncn(C3CCCCO3)c2n1
Reactant: CON(C)C(C)=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1nc2c(N3CCOCC3)nc(Cl)nc2n1C1CCCCO1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 82.9 %

Procedure:
A solution of 2-Chloro-6-morpholin-4-yl-9-(tetrahydro-pyran-2-yl)-9H-purine (0.50 g, 1.55 mmol) and N,N,N′,N-tetramethylethylenediamine (0.35 mL, 2.33 mmol) in dry THF (14 mL) was cooled to −78° C. n-BuLi (2.5M in hexanes, 1.22 mL, 3.05 mmol) was added dropwise and the mixture was stirred at −78° C. for 40 min. N-methyl-N-methoxyacetamide (0.25 mL, 2.33 mmol) was added dropwise and the mixture was stirred at −78° C. for 1.5 h, then allowed to warm to −30° C. Water was added followed by 1M aqueous HCl and the mixture was extracted seven times with ethyl acetate. The combined organic extracts were dried (Na2 SO4), filtered and concentrated in vacuo. The resulting residue was subjected to flash chromatography (SiO2), gradient 0-50% ethyl acetate in cyclohexane to give 1-[2-Chloro-6-morpholin-4-yl-9-(tetrahydro-pyran-2-yl)-9H-purin-8-yl]-ethanone (0.47 g, 83%). LCMS RT=3.57 min, [M+H]+=366/368
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][S:6](=[O:19])(=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:15](=[O:17])[CH3:16])[CH:9]=1)[CH3:2].[OH:21][C:22]1[CH:29]=C(O)C=C[C:23]=1[CH:24]=O.N1CCC[CH2:33][CH2:32]1>C(O)C>[CH3:32][C:33]1[C:2]2[CH:24]=[CH:23][C:22]([OH:21])=[CH:29][C:1]=2[O:3][C:4](=[O:20])[C:5]=1[S:6]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:15](=[O:17])[CH3:16])[CH:9]=1)(=[O:19])=[O:18]
Reactant: C1CCNCC1
Reactant: CCOC(=O)CS(=O)(=O)Nc1cccc(NC(C)=O)c1
Reactant: O=Cc1ccc(O)cc1O
Solvent: CCO
Product: CC(=O)Nc1cccc(NS(=O)(=O)c2c(C)c3ccc(O)cc3oc2=O)c1
Yield: 666.5 %

Procedure:
(3-Acetylaminophenylsulfamoyl)acetic acid ethyl ester (280 mg, 0.93 mmol), 2,4-dihydroxybenzaldehyde (516 mg) and piperidine (10 mg) were added to 9 mL of ethanol, and the mixture was heated under reflux overnight. It was then purified by silica gel chromatography (methylene chloride:methanol=30:1) to yield the title compound (304 mg, 87%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[CH:22]=[C:21]([F:23])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH2:6]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:31][C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[C:34](Cl)=[O:35]>O1CCOCC1>[C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[CH:22]=[C:21]([F:23])[C:19](=[O:20])[N:18]([C:34](=[O:35])[C:33]3[CH:37]=[CH:38][CH:39]=[CH:40][C:32]=3[CH3:31])[C:16]2=[O:17])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OC(C)=O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)n(C(=O)c3ccccc3C)c2=O)C[C@@H]1OC(C)=O
Reaction time: 0.5 h

Procedure:
10.0 g of 2'-deoxy-3',5'-di-O-acetyl-5-fluorouridine and 10 ml of triethylamine were dissolved in 50 ml of dioxane, and the resulting mixture was cooled with ice. To the mixture was added 7.0 g of 2-methylbenzoyl chloride, and the resulting mixture was allowed to stand at room temperature for 30 minutes and then at 45° C. for 60 minutes. The crystals formed were filtered off, and the filtrate was concentrated under reduced pressure. The thus obtained oily residue was dissolved in 50 ml of ethanol by application of heat. After being cooled, the solution was inoculated, and there was obtained 2'-deoxy-3',5'-di-O-acetyl-5-fluoro-3-(2-methylbenzoyl)-uridine) as crystals. Recrystallization of the product from ethanol afforded 11.3% (yield: 84.0%) of colorless prismatic crystals having a melting point of 108° to 109° C. The structure of the product was supported by the absorption spectra and elemental analysis.
Reaction SMILES: [CH2:1]1[S:5][C@H:4]([CH2:6][OH:7])[O:3][C@@H:2]1[N:8]1[C:13](=[O:14])[N:12]=[C:11]([NH2:15])[C:10]([F:16])=[CH:9]1.Cl>CO.O1CCOCC1>[NH2:15][C:11]1[C:10]([F:16])=[CH:9][N:8]([CH:2]2[O:3][CH:4]([CH2:6][OH:7])[S:5][CH2:1]2)[C:13](=[O:14])[N:12]=1
Reactant: Nc1nc(=O)n([C@@H]2CS[C@H](CO)O2)cc1F
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Nc1nc(=O)n(C2CSC(CO)O2)cc1F
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A mixture of (−)-FTC [32(2R, β/α)](60:40 of a β:α anomer mixture, 3.0 g) was dissolved in methanol (30 ml), cooled to 0° C., and treated with a 4.0 M solution of HCl in 1,4-dioxane (3.3 ml [1.1x]). The solution was stirred for 20 minutes, and subsequently concentrated to dryness affording an off-white solid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[N:7]1[CH:12]=[C:11]([Cl:13])[CH2:10][N:9](Cl)[NH:8]1>>[Cl:13][C:11]1[C:12]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:7][N:8]=[N:9][C:10]=1[N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: ClC1=CN(Cl)NN(Cl)C1
Reactant: C1CCNC1
Product: Clc1c(N2CCCC2)nnnc1N1CCCC1
Reaction time: 1.25 h

Procedure:
Pyrrolidine (28.5 g) is cooled on an ice bath. 1,3,5-Trichlorotriazine (18.4 g) is added with vigorous stirring. After 1-1.5 h the mixture is permitted to warm to 20°-25°. The solid is filtered and rinsed several times with water and dried under reduced pressure to give the monochloro-bis(1-pyrrolidinyl)triazine.
Reaction SMILES: [OH:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[N:11]([CH3:12])[N:10]=[C:9]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[N:8]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:30]1[C:35]([Cl:36])=[CH:34][C:33]([C:37]([F:40])([F:39])[F:38])=[CH:32][N:31]=1.O>CN(C=O)C>[Cl:36][C:35]1[C:30]([O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][C:7]3[N:11]([CH3:12])[N:10]=[C:9]([C:13]4[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=4[F:20])[N:8]=3)=[CH:21][CH:22]=2)=[N:31][CH:32]=[C:33]([C:37]([F:39])([F:38])[F:40])[CH:34]=1
Reactant: Cn1nc(-c2c(F)cccc2F)nc1Cc1ccc(O)cc1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(-c2c(F)cccc2F)nc1Cc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1
Temperature: 70 °C
Yield: 43.1 %

Procedure:
To a solution of 0.8 g of 5-(4-hydroxybenzyl)-3-(2,6-difluorophenyl)-1-methyl 1H-1,2,4-triazole in 10 ml of DMF at room temperature were added 0.4 g of anhydrous potassium carbonate and 0.63 g of 2,3-dichioro-5-trifluoromethylpyridine and then the suspension solution was heated to 70° C. or 1 hour. After cooling, the reaction mixture was poured into iced water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to afford 0.55 g of 5-(4-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-benzyl)-3-(2,6-difluorophenyl)-1-methyl-1H-1,2,4-triazole.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]([CH3:16])([CH2:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[C:5]([O:7][CH3:8])=[O:6].[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[N:27]=[C:26](Cl)[C:25]3=[CH:29][C:30]([CH3:32])=[CH:31][N:24]3[CH2:23][C:22]=2[CH:33]=1.C(#N)C.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[N:27]=[C:26]([N:13]3[CH2:14][CH2:15][N:10]([CH2:9][C:4]([CH3:16])([CH3:3])[C:5]([O:7][CH3:8])=[O:6])[CH2:11][CH2:12]3)[C:25]3=[CH:29][C:30]([CH3:32])=[CH:31][N:24]3[CH2:23][C:22]=2[CH:33]=1
Reactant: Cc1cc2n(c1)Cc1cc(Cl)ccc1N=C2Cl
Reactant: COC(=O)C(C)(C)CN1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)C(C)(C)CN1CCN(C2=Nc3ccc(Cl)cc3Cn3cc(C)cc32)CC1
Temperature: 140 °C
Reaction time: 3.5 h
Yield: 58.3 %

Procedure:
Dissolve methyl 2,2-dimethyl-3-(piperazin-1-yl)propanoate dihydrochloride (1.61 g, 5.89 mmoles) in water and load on to two SCX-2 (10 g) cartridges. Wash the cartridges with methanol and elute with 2M ammonia in methanol. Concentrate in vacuo, then dissolve the resultant oil in acetonitrile (40 mL). Add 7,11-dichloro-2-methyl-5H-pyrrolo[2,1-c][1,4]benzodiazepine (1.167 g, 4.4 mmoles) to the acetonitrile solution. Divide the acetonitrile solution and place in to 2 microwave tubes, add potassium carbonate (0.89 g, 6.79 mmoles) to each microwave tube and heat and stir at 140° C. in the microwave for 3.5 hr. Allow the reaction mixture to cool, filter, wash the solid collected on the sinter with acetonitrile then concentrate the filtrate in vacuo, add methanol and then evaporate to dryness. Treat with more methanol and collect the resultant precipitate, wash the precipitate with methanol to give methyl 3-[4-(7-chloro-2-methyl-5H-pyrrolo[2,1-c][1,4]benzodiazepin-11-yl)piperazin-1-yl]-2,2-dimethylpropanoate as a crystalline solid (1.1 g). MS (m/z): 429.18 (M+1).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH2:8]([O:10][CH:11]([O:16][CH2:17][CH3:18])[CH2:12][CH2:13][CH2:14][NH2:15])[CH3:9]>C(Cl)Cl>[CH2:17]([O:16][CH:11]([O:10][CH2:8][CH3:9])[CH2:12][CH2:13][CH2:14][NH:15][C:4](=[O:5])/[CH:3]=[CH:2]\[C:1]([OH:6])=[O:7])[CH3:18]
Reactant: O=C1C=CC(=O)O1
Reactant: CCOC(CCCN)OCC
Solvent: ClCCl
Product: CCOC(CCCNC(=O)/C=C\C(=O)O)OCC

Procedure:
Maleic anhydride (85 g) of 1300 mL of CH2Cl2 was cooled to 15° C. and treated with 155 g of 4-aminobutyraldehyde diethyl acetal (AmBDA). (Other preparations used the reverse mode of addition with similar results.) Fifteen min after the addition was complete no further AmBDA was detected by glpc. The solvent was removed under reduced pressure (maintained at 0.2 torr for 2 h to assure completion) to give 230 g of slightly orange colored thick oil. On standing for several months at 0° C., this material solidified to an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([CH3:11])=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[O:12]([C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CC(O)C>[ClH:1].[CH3:11][C:10]1[C:3]2[C:2]([NH:23][C:22]3[CH:21]=[CH:20][C:19]([O:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[CH:25][CH:24]=3)=[N:7][CH:6]=[N:5][C:4]=2[S:8][CH:9]=1
Reactant: Cc1csc2ncnc(Cl)c12
Reactant: Nc1ccc(Oc2ccccc2)cc1
Solvent: CC(C)O
Product: Cc1csc2ncnc(Nc3ccc(Oc4ccccc4)cc3)c12
Product: Cl
Yield: 80.3 %

Procedure:
4-Chloro-5-methylthieno[2,3-d]pyrimidine (0.185 g, 1.00 mmol) and 4-phenoxyaniline (0.210 g, 1.1 mmol) were reacted in 2-propanol (6 ml) for 17 hours according to Procedure A. The product was obtained as a pale grey solid (0.297 g, 80%), m.p. 218-221° C.; (Found: C, 61.61; H, 4.33, N, 11.25. C19H15N3OS.HCl requires: C, 61.70; H, 4.36; N, 11.36%); δH [2H6]-DMSO 8.60 (1H, br s, NH), 8.49 (1H, s, 2-H), 7.68 (2H, d, J 9, 2′-H, 6′-H), 7.33-7.48 (3H, m, 6-H, 3″-H, 5″-H), 7.17 (1H, t, J 9, 4″-H), 7.00-7.10 (4H, m, 3′-H, 5′-H, 2″-H, 6″-H), 2.75 (3H, s, 5-CH3); m/z 333 (M+).
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1.[CH3:17][Sn:18](Cl)([CH3:20])[CH3:19].O1CCOCC1.[NH4+].[OH-]>C(OCC)C>[C:8]1([Sn:18]([CH3:20])([CH3:19])[CH3:17])[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[CH:16][CH:7]=1
Reactant: C[Sn](C)(C)Cl
Reactant: Brc1ccc2ccccc2c1
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1COCCO1
Product: C[Sn](C)(C)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95.6 %

Procedure:
tert-Butyllithium (12.5 ml, 21.25 mmol, 1.7M in pentane) is added dropwise to a stirred solution of 2-bromonaphthalene (2 g, 9.66 mmol) in anhydrous diethyl ether (40 ml) under argon at -78° C. The solution is stirred for 15 min and then treated with a 2.71M solution of trimethyltin chloride in dioxane (4.63 ml, 12.55 mmol). The heterogeneous mixture is warmed to room temperature, diluted with diethyl ether (150 ml) and treated with 10% NH4OH solution (90 ml) for 5 minutes. The two phases are separated and the organic phase is washed with water followed by brine, dried over MgSO4 and concentrated to dryness. The oil is purified by flash silica chromatography (hexane) to give napthyltrimethyl stannane (2.69 g, 95.6%).
Reaction SMILES: COP([CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Br:16])[CH:14]=2)[C:9](=[O:17])[O:8]1)(=O)OC.[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.O>O1CCCC1>[CH:18](=[C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Br:16])[CH:14]=2)[C:9](=[O:17])[O:8]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COP(=O)(OC)C1OC(=O)c2ccc(Br)cc21
Reactant: O=Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C1OC(=Cc2ccccc2)c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 1C (4.6 g, 14.08 mmol) in anhydrous tetrahydrofuran (30 mL) was added benzaldehyde (0.71 mL, 7.4 mmol) and triethylamine (1.00 mL, 7.39 mmol). The reaction mixture was stirred at ambient temperature overnight. Water was added and the mixture stirred for 10 minutes. The precipitated solid was filtered and dried under vacuum to yield the title compound. MS (ESI) m/z 302 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[C:6]([C:13]([OH:15])=[O:14])[CH:7]=[CH:8][CH:9]=2)[O:4][C:3]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[O:22]1[CH2:26][CH:23]1[CH2:24]O.C(N(CC)CC)C.O>C1C=CC=CC=1>[CH3:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[C:6]([C:13]([O:15][CH2:24][CH:23]3[O:22][CH2:26]3)=[O:14])[CH:7]=[CH:8][CH:9]=2)[O:4][C:3]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1c(-c2ccccc2)oc2c(C(=O)O)cccc2c1=O
Reactant: OCC1CO1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Solvent: O
Product: Cc1c(-c2ccccc2)oc2c(C(=O)OCC3CO3)cccc2c1=O
Reaction time: 20 h
Yield: 75.2 %

Procedure:
21.3 g of 3-methylflavone-8-carboxylic acid were slowly added, over a period of 4 hours at 20° C., to a stirred solution of 5.55 g of 2,3-epoxy-1-propanol and 8.34 g of triethylamine in 165 ml of anhydrous benzene. The mixture was permitted to stand at 20°-25° C. for 20 hours, and then 60 ml of water were added. The entire reaction mass was stirred for 15 minutes and the layers were separated. The organic layer was washed and dried, the solvent was evaporated off and 18.95 g of 2,3-epoxypropyl 3-methylflavone-8-carboxylate, m.p. 103°-105° C., were obtained.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH:7]([C:10]1[NH:14][N:13]=[C:12]([C:15](O)=[O:16])[C:11]=1[N+:18]([O-:20])=[O:19])([CH3:9])[CH3:8].C[N:22](C)C=O>ClCCl>[CH:7]([C:10]1[NH:14][N:13]=[C:12]([C:15]([NH2:22])=[O:16])[C:11]=1[N+:18]([O-:20])=[O:19])([CH3:9])[CH3:8]
Reactant: CN(C)C=O
Reactant: CC(C)c1[nH]nc(C(=O)O)c1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC(C)c1[nH]nc(C(N)=O)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Oxalyl chloride (6.8 ml, 77.6 mmol) was added dropwise to a suspension of 5-isopropyl-4-nitro-1H-pyrazol-3-carboxylic acid (5.15 g, 25.9 mmol) in dichloromethane (80 ml) containing dimethylformamide (0.1 ml) under nitrogen at 0° C. The reaction was stirred at 0° C. for 1 hours, allowed to warm to room temperature and stirred for a further 2 hours. The solvent was removed under reduced pressure, the residue was dissolved in toluene (100 ml) and ammonia gas was bubbled into the solution for 2 hours. The reaction was stirred under nitrogen at room temperature for 18 hours, concentrated under reduced pressure and the residue was dissolved in hot methanol (300 ml). The resultant precipitate was filtered and the filtrate was concentrated under reduced pressure. The residue was azeotroped with water (300 ml), concentrated to approximately 80 ml under reduced pressure and the precipitate was isolated by filtration. This was washed with water and dried under to give 5-isopropyl-4-nitro-1H-pyrazol-3-carboxylic acid amide (3.1 g) as an orange solid. 1H NMR (400 MHz, DMSO-D6): δ=7.94-7.99 (1H, brs), 7.68-7.72 (1H, brs), 3.45-3.55 (1H, m), 1.24-1.30 (6H, d) ppm. LRMS (electrospray): m/z [M+Na]+ 221, [M−H]+ 197.
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])[C:5]2=O>O.NN>[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
Reactant: O=C1Nc2ccc(F)cc2C1=O
Agent: NN
Solvent: O
Product: O=C1Cc2cc(F)ccc2N1
Temperature: 0 °C

Procedure:
5-Fluoroisatin (8.2 g) was dissolved in 50 mL of hydrazine hydrate and refluxed for 1.0 hr. The reaction mixtures were then poured in ice water. The precipitate was then filtered, washed with water and dried under vacuum oven afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:16][C:17](=[O:19])[CH3:18])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[F:15])[CH:7]=1.F[C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=1[N+:31]([O-:33])=[O:32].[F-].[K+]>CN(C=O)C>[C:17]([NH:16][C:4]1[CH:3]=[C:2]([NH:1][C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=2[N+:31]([O-:33])=[O:32])[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[F:15])[CH:5]=1)(=[O:19])[CH3:18]
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CC(=O)Nc1cc(N)cc(-c2ccc(F)cc2F)c1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Nc2cc(NC(C)=O)cc(-c3ccc(F)cc3F)c2)c([N+](=O)[O-])c1
Yield: 48.78 %

Procedure:
A solution of N-(5-amino-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamide (1.0 g, 3.813 mmol), methyl 4-fluoro-3-nitrobenzoate (0.835 g, 4.194 mmol, 1.1 eq.) and potassium fluoride (0.265 g, 4.457 mmol, 1.2 eq.) in DMF was heated at 130° C. for 16 h. The mixture was quenched and extracted as in Example 1(d). The solvent was distilled off to give the crude residue which was purified by column chromatography (60-120 silica gel, 40% ethyl acetate in hexane) to give the product in 48.78% yield (0.82 g).
Reaction SMILES: CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH3:23][C:24]([CH3:53])([CH3:52])[C@H:25]([NH:37][C:38]([C@H:40]([CH2:49][CH:50]=[CH2:51])[C@H:41]([O:46][CH2:47][CH3:48])[C:42]([O:44][CH3:45])=[O:43])=[O:39])[C:26]([NH:28][C@@H:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:30])=[O:27].[F:54][C:55]1[CH:56]=[C:57](Br)[CH:58]=[CH:59][C:60]=1[O:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:53][C:24]([CH3:23])([CH3:52])[C@H:25]([NH:37][C:38]([C@H:40]([CH2:49]/[CH:50]=[CH:51]/[C:57]1[CH:58]=[CH:59][C:60]([O:61][C:62]2[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=2)=[C:55]([F:54])[CH:56]=1)[C@H:41]([O:46][CH2:47][CH3:48])[C:42]([O:44][CH3:45])=[O:43])=[O:39])[C:26]([NH:28][C@@H:29]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH3:30])=[O:27]
Reactant: C=CC[C@@H](C(=O)N[C@H](C(=O)N[C@H](C)c1ccccc1)C(C)(C)C)[C@H](OCC)C(=O)OC
Reactant: Fc1cc(Br)ccc1Oc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCO[C@H](C(=O)OC)[C@@H](C/C=C/c1ccc(Oc2ccccc2)c(F)c1)C(=O)N[C@H](C(=O)N[C@H](C)c1ccccc1)C(C)(C)C
Yield: 60.4 %

Procedure:
A mixture of palladium acetate (12 mg, 0.05 mmol) and tri-(2-methylphenyl)phosphine (30 mg, 0.10 mmol) in anhydrous acetonitrile (1 mL) was sonicated at room temperature for 1 min until a creamy-coloured suspension formed. This suspension was added via Pasteur pipette to a stirred solution of methyl (2S,3R)-3-({[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]amino}carbonyl)-2-ethoxy-hex-5-enoate (415 mg, 0.96 mmol), 3-fluoro-4-phenoxy-bromobenzene (Preparation 10)(400 mg, 1.50 mmol), and triethylamine (280 μL, 2.0 mmol) in anhydrous acetonitrile (1 mL) under nitrogen. The mixture was purged with nitrogen, then heated at reflux for 16 h. After being cooled, the mixture was poured into ethyl acetate (70 mL) and washed with 5% aqueous citric acid (20 mL), saturated aqueous sodium chloride (50 mL), dried (MgSO4), and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution with dichloromethane:ethyl acetate) to give mainly methyl (2S,3R,5E)-3-({[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]amino}carbonyl)-2-ethoxy-6-(3-fluoro-4-phenoxyphenyl)hex-5-enoate as a pale yellow foam (359 mg, 69%). 1H nmr suggested that two alkene isomers, the (5Z) and (4E) were also present. The mixture of alkenes was taken onto the next step (see c, below).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18]([C:22]([OH:24])=O)=[CH:17][CH:16]=[CH:15]3)=[CH:3][CH:2]=1.[C:25]1([NH2:32])[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH2:31]>>[NH2:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[NH:32][C:22]([C:18]1[C:19]2[C:14](=[CH:13][C:12]([O:11][C:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=[CH:2][CH:3]=3)=[CH:21][CH:20]=2)[CH:15]=[CH:16][CH:17]=1)=[O:24]
Reactant: O=C(O)c1cccc2cc(Oc3ccnc4ccccc34)ccc12
Reactant: Nc1ccccc1N
Product: Nc1ccccc1NC(=O)c1cccc2cc(Oc3ccnc4ccccc34)ccc12
Yield: 87.8 %

Procedure:
The title compound (35.6 mg, 88% yield) was prepared as a brown solid from 6-(quinolin-4-yloxy)-1-naphthoic acid (31.5 mg, 0.1 mmol) and o-phenylenediamine (43.2 mg, 0.4 mmol) by an analogous procedure to that described in example 16. 1H NMR (DMSO-d6) δ 4.97 (s, 2H, benzene-NH2), 6.65 (t, J=7.3 Hz, 1H, Ar—H), 6.75 (d, J=5.1 Hz, 1H, Ar—H), 6.82 (d, J=7.8 Hz, 1H, Ar—H), 7.00 (t, J=7.1 Hz, 1H, Ar—H), 7.38 (d, J=7.5 Hz, 1H, Ar—H), 7.59 (dd, J=2.3 and 9.2 Hz, 1H, Ar—H), 7.64-7.71 (m, 2H, Ar—H), 7.83-7.92 (m, 3H, Ar—H), 8.08 (d, J=8.4 Hz, 2H, Ar—H), 8.37 (d, J=7.9 Hz, 1H, Ar—H), 8.45 (d, J=9.2 Hz, 1H, Ar—H), 8.73 (d, J=5.1 Hz, 1H, Ar—H), 9.85 (s, 1H, benzene-NH). LC-MS (m/z) 406 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([NH:14][C:15](=[O:23])[CH2:16][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:3]=1.[C:24]([NH:27][CH2:28][CH2:29][NH2:30])(=[O:26])[CH3:25]>CS(C)=O>[C:24]([NH:27][CH2:28][CH2:29][NH:30][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([NH:14][C:15](=[O:23])[CH2:16][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:3]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)NCCN
Reactant: O=C(CN1CCCCC1)Nc1cc(Cl)nc(-c2ccccc2)n1
Solvent: CS(C)=O
Product: CC(=O)NCCNc1cc(NC(=O)CN2CCCCC2)nc(-c2ccccc2)n1
Temperature: 130 °C
Reaction time: 16 h
Yield: 60.1 %

Procedure:
N-(6-Chloro-2-phenylpyrimidin-4-yl)-2-piperidin-1-ylacetamide (25 mg) was dissolved in DMSO (1 ml) and N-acetylethylenediamine (78 mg) added. A reflux condenser was fitted and the mixture heated to 130° C. with stirring for 16 hrs. The reaction was cooled to room temperature and the solvent removed in vacuo. Purification via flash chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (95:5, then 93:7 v/v) yielded the title compound (18 mg).