Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[CH:14][CH:13]=[N:12]2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.C(N(CC)C(C)C)(C)C.[NH2:47][C:48]1[CH:52]=[CH:51][N:50]([CH2:53][C:54]([CH3:57])([OH:56])[CH3:55])[N:49]=1>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[CH:14][CH:13]=[N:12]2)[C:8]([NH:47][C:48]2[CH:52]=[CH:51][N:50]([CH2:53][C:54]([OH:56])([CH3:55])[CH3:57])[N:49]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: O=C(O)C(CC1CCCC1)n1ncccc1=O
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncccc2=O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 7.6 %

Procedure:
A solution of 3-cyclopentyl-2-(6-oxo-6H-pyridazin-1-yl)-propionic acid (183 mg, 0.77 mmol) in methylene chloride (4.30 mL, 0.18M) at 25° C. was treated with N,N,N′,N′-tetramethyl-O—(N-succinimidyl)uronium tetrafluoroborate (0.28 g, 0.92 mmol) and N,N-diisopropylethylamine (0.40 mL, 2.32 mmol). The resulting solution was stirred at 25° C. for 2 h. After this time, the reaction was treated with 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1, 156 mg, 1.0 mmol). The resulting solution was stirred at 25° C. for 2 d. After this time, the reaction was partitioned between water (75 mL) and methylene chloride (3×75 mL). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (ISCO, 40 g, 1-2% methanol/methylene chloride) afforded 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(6-oxo-6H-pyridazin-1-yl)-propionamide as an off-white solid (21.9 mg, 7.6%); ES+-HRMS m/e calcd for C19H27N5O3 [M+H+] 374.2187 found 374.2187. 1H-NMR (300 MHz, DMSO-d6) δ ppm 0.99-1.72 (m, 9H), 1.05 (s, 3H), 1.06 (s, 3H), 1.92 (m, 1H, CH), 2.28 (m, 1H), 3.89 (s, 2H), 4.67 (s, 1H), 5.52 (dd, J=4.2, J=10.6 Hz, 1H), 6.39 (d, J=2.3 Hz, 1H), 6.94 (dd, Jo=9.4 Hz, Jm=1.5 Hz, 1H), 7.42 (dd, Jo=9.4, Jo=3.8 Hz, 1H), 7.52 (d, J=2.3 Hz, 1H), 8.00 (dd, Jo=3.8 Hz, Jm=1.5 Hz, 1H), 10.79 (s, 1H).
Reaction SMILES: N[C@H](C(O)=O)CCCNC(=N)N.[NH:13]1[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][C@H:14]1[C:23]([OH:25])=[O:24].[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>>[N:13]1([S:32]([C:29]2[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=2)(=[O:34])=[O:33])[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][C@H:14]1[C:23]([OH:25])=[O:24]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(O)[C@@H]1Cc2ccccc2CN1
Agent: N=C(N)NCCC[C@H](N)C(=O)O
Product: Cc1ccc(S(=O)(=O)N2Cc3ccccc3C[C@H]2C(=O)O)cc1

Procedure:
To a solution of 100 mg of Tos-L-Tic (0.30 mmol), 122 mg of Arg(NO2)—OMe HCl (0.45 mmol), 61 mg of hydroxybenzotriazole (0.39 mmol), and 184 mg of 4-dimethylaminopyridine (1.51 mmol) in 50 mL of methylene chloride as added 174 mg (0.78 mmol) of 1,3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride. After stirring for 15 hours, 100 mL of additional methylene chloride was added to the reaction, and it was washed three times with 30 mL portions of 10% aqueous hydrochloric acid solution, then twice with 20 mL of 50% saturated sodium bicarbonate solution, and finally once with 20 mL of saturated brine. The product was then dried over anhydrous magnesium sulfate, filtered, and the solvent removed under reduced pressure. The product was next dissolved in 20 mL of methanol, and 230 mg of 10% palladium on carbon was added under nitrogen, followed by addition of 1 mL of formic acid, after which the reaction stirred for 15 hours. The catalyst was filtered off, and the solvent was then removed rapidly under reduced pressure to yield 22 mg of product. This material can also be synthesized by coupling a suitably protected arginine fragment with a suitably protected Tic fragment, deprotecting the Tic amino group, condensing this material with p-toluenesulfonyl chloride, and finally, deprotecting the arginine sidechain.
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[CH:16]3)=[CH:11][C:4]=2[O:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[C:19](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:19][O:1][C:2]1[C:3]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[CH:16]3)=[CH:11][C:4]=2[O:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1oc2cc3ccccc3cc2c1O
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COC(=O)c1oc2cc3ccccc3cc2c1OC
Reaction time: 24 h
Yield: 77 %

Procedure:
A mixture of 25.0 g (0.10 mole) of 3-hydroxynaphtho [2,3-b]furan-2-carboxylic acid, methyl ester, 15.3 g (0.11 mole) of anhydrous potassium carbonate, and 10.6 ml (14.1 g, 11 mole of dimethyl sulfate in 500 ml of acetone is stirred at refux for 24 hours. The mixture is cooled, filtered, and the filter cake is washed several times with fresh acetone. The combined filtrates are evaporated (vacuum), and the residue is recrystallized from methanol to yield 20.3 g (77% yield) of the analytically pure 3-methoxynaphtho[2,3-b]furan-2-carboxylic acid, methyl ester, mp 121°-124 ° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]=[CH:8][C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1.[CH3:14][O:15][C:16](=[O:27])[C:17](=[CH2:26])[NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>>[CH3:14][O:15][C:16](=[O:27])[CH:17]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:26][N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[N:7]=[CH:8][C:9]1=[O:13]
Reactant: C=C(NC(=O)OC(C)(C)C)C(=O)OC
Reactant: COc1ccc2ncc(=O)[nH]c2c1
Product: COC(=O)C(Cn1c(=O)cnc2ccc(OC)cc21)NC(=O)OC(C)(C)C
Yield: 20 %

Procedure:
The compound (yellow solid; 370 mg, 20% yield) was obtained according to procedure H starting from 7-methoxyquinoxalin-2(1H)-one (prepared according to WO 2006/134378) and N-(tert-butoxycarbonyl)dehydroalanine methyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=[O:11])[CH3:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])(=O)C.CCOCC.C([O-])C.[Na+]>C(O)C>[Cl:1][C:2]1[C:3]([C:9](=[O:11])[CH2:10][C:16]([C:17]([F:20])([F:19])[F:18])=[O:15])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(=O)OCC(F)(F)F
Reactant: CC(=O)c1ncc(Cl)cc1Cl
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: O=C(CC(=O)C(F)(F)F)c1ncc(Cl)cc1Cl
Reaction time: 8 h

Procedure:
15.8 g of 3,5-dichloro-2-acetylpyridine are introduced together with 12.0 ml of trifluoroethyl acetate into 125 ml of absolute ether. With stirring, the mixture is cooled using an ice-bath and 46.6 ml of, a 21% sodium ethanolate solution in ethanol are added dropwise. The ice-bath is then removed and the mixture is subsequently stirred overnight at 25° C. After cooling the reaction mixture in an ice-bath and adding dropwise 7.5 ml of glacial acetic acid, the mixture is concentrated in vacuo. 39.0 g of 1-(3,5-dichloro-2-pyridyl)-3-trifluoromethylpropane-1,3-dione are obtained, which can be used directly for the following cyclisation step.
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[CH:12]=[C:13]([C:17]([NH2:24])([C:19]2[CH:23]=[CH:22][NH:21][N:20]=2)[CH3:18])[CH:14]=[CH:15][CH:16]=1.[Cl:25][CH2:26][C:27](Cl)=[O:28]>C(Cl)Cl.[NH4+].[Cl-]>[Br:10][C:11]1[CH:12]=[C:13]([C:17]([NH:24][C:27](=[O:28])[CH2:26][Cl:25])([C:19]2[CH:23]=[CH:22][NH:21][N:20]=2)[CH3:18])[CH:14]=[CH:15][CH:16]=1
Reactant: CC(N)(c1cccc(Br)c1)c1cc[nH]n1
Reactant: O=C(Cl)CCl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)CCl)(c1cccc(Br)c1)c1cc[nH]n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
DIPEA (1.18 mL, 6.77 mmol) was added to a solution of rac-1-(3-bromo-phenyl)-1-(1H-pyrazol-3-yl)-ethylamine (1.2 g, 4.51 mmol) in DCM (20 mL) and the mixture was cooled in an ice bath. Then chloroacetyl chloride (0.40 mL, 4.96 mmol) was added and the mixture was stirred at 0° C. for 3 hours. The mixture was diluted with NH4Cl (aq. sat. solution) and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel; AcOEt in DCM 0/100 to 20/80). The desired fractions were collected and concentrated in vacuo. The residue was dissolved in EtOH (10 mL) and NaHCO3 (aq. sat. solution) (1 mL) and the mixture was stirred at room temperature for 30 minutes. The mixture was diluted with water and the product extracted with DCM. The combined organic layers were concentrated in vacuo to yield rac-N-[1-(3-bromo-phenyl)-1-(1H-pyrazol-3-yl)-ethyl]-2-chloro-acetamide (1.22 g, 79% yield) as a colourless oil, which was used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:30]=[CH:29][CH:28]=[CH:27][C:5]=1[CH2:6][C:7]1[C:11]2[C:12](=[O:26])[N:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:10]=2[NH:9][N:8]=1)([O-])=O>CN(C=O)C.CO.[C].[Pd]>[NH2:1][C:4]1[CH:30]=[CH:29][CH:28]=[CH:27][C:5]=1[CH2:6][C:7]1[C:11]2[C:12](=[O:26])[N:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:10]=2[NH:9][N:8]=1
Reactant: O=c1c2c(Cc3ccccc3[N+](=O)[O-])n[nH]c2c2cccnc2n1-c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Product: Nc1ccccc1Cc1n[nH]c2c1c(=O)n(-c1ccccc1)c1ncccc21
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 3-(2-nitrobenzyl)-5-phenyl-1H-pyrazolo [4,3-c][1,8]naphthyridin-4 (5H)-one (376 mg, 0.95 mmol, prepared in Example 26) in DMF (20 ml) and methanol (20 ml) was added activated carbon-palladium (38 mg), the mixture was stirred under hydrogen atmosphere overnight, and filtered. After methanol was distilled off, the resultant solution was admixed with water, and filtered to give precipitates which were dried to afford 3-(2-aminobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (349 mg, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][C@H:11]2[CH2:17][O:16][C@@H:13]([CH:14]=[O:15])[C@@H:12]2[OH:18])=[CH:5][CH:4]=1.[BH4-].[Na+].O>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][C@@H:11]2[C@@H:12]([OH:18])[C@H:13]([CH2:14][OH:15])[O:16][CH2:17]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CS[C@H]2CO[C@@H](C=O)[C@@H]2O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(CS[C@H]2CO[C@@H](CO)[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
To a room temperature solution, under argon, of 10.9 g of product from Example 322 in 115 ml of absolute ethyl alcohol is added 1.57 g of sodium borohydride. The reaction is stirred at room temperature for 1 hour. Water is added dropwise with stirring and the minute is concentrated in vacuo. The residue is extracted with methylene chloride, washed with water, dried and concentrated in vacuo to give after chromatography (Silica gel: 50-75% ethyl acetate/hexane) 7.68 g of the desired product.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[N:5]=[C:6]([NH:16][C:17](=[NH:21])SCC)[S:7][C:8]=1[C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][N:10]=1.O.[NH2:23][NH2:24]>C(O)C>[CH3:3][C:4]1[N:5]=[C:6]([NH:16][C:17]([NH:23][NH2:24])=[NH:21])[S:7][C:8]=1[C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][N:10]=1
Reactant: CCSC(=N)Nc1nc(C)c(-c2cc(C)ccn2)s1
Reactant: NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccnc(-c2sc(NC(=N)NN)nc2C)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
To a suspension of N-(4-methyl-5-(4-methylpyridin-2-yl)thiazol-2-yl)-S-ethylisothiourea dihydrochloride (36.5 mg) in ethanol (0.5 ml) was added hydrazine hydrate (50 mg). The mixture was stirred at 80° C. for 1 hour and cooled to ambient temperature. The precipitate was collected by filtration, washed with ethanol, water and diisopropyl ether to give N-(4-methyl-5-(4-methylpyridin-2-yl)thiazol-2-yl)-N′-aminoguanidine (11 mg).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([CH3:12])[C:9]([NH:13][C:14](=[O:16])[CH3:15])=[C:8]([CH3:17])[C:3]=1[C:4]([NH:6][NH2:7])=[O:5].[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>[OH-].[Na+]>[NH2:1][C:2]1[N:11]=[C:10]([CH3:12])[C:9]([NH:13][C:14](=[O:16])[CH3:15])=[C:8]([CH3:17])[C:3]=1[C:4]([NH:6][NH:7][S:24]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:26])=[O:25])=[O:5]
Reactant: CC(=O)Nc1c(C)nc(N)c(C(=O)NN)c1C
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Nc1c(C)nc(N)c(C(=O)NNS(=O)(=O)c2ccccc2)c1C

Procedure:
To a solution of 2-amino-5-acetamido-4,6-dimethylnicotinic acid hydrazide (34.4 g., 0.145 mole) in 1N sodium hydroxide solution (348 ml.) is added at ambient temperature and with vigorous stirring, benzenesulfonyl chloride (31.1 g., 0.16 mole) in one portion. After about three-quarters of an hour the acid chloride disappears; the maximum temperature attained by the reaction mixture, 36° C. The product is precipitated by pouring the reaction mixture into a stirred solution of acetic acid (8.3 ml.) in water (250 ml.). It is collected, slurried with water (150 ml.), refiltered and dried affording 49.52 g. (90%) of crude product, m.p. 216°-218° C. with gas evolution. Following purification by dissolving in hot (100° C.) dimethylformamide, filtering, and diluting with methanol (1 part) and water (3 parts) the product melts at 233°-234° C. (dec.).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[O:17][C:18]4[C:23]([C:24](=[O:26])[CH:25]=3)=[CH:22][C:21]([O:27][CH3:28])=[CH:20][C:19]=4[N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N:36]1([C:41](Cl)=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37]1>>[N:36]1([C:41]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]4[O:17][C:18]5[C:23]([C:24](=[O:26])[CH:25]=4)=[CH:22][C:21]([O:27][CH3:28])=[CH:20][C:19]=5[N:29]4[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]4)=[O:15])=[CH:11][CH:12]=3)[CH2:2][CH2:3]2)=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: COc1cc(N2CCN(C)CC2)c2oc(C(=O)Nc3ccc(N4CCNCC4)cc3)cc(=O)c2c1
Reactant: O=C(Cl)N1CCCC1
Product: COc1cc(N2CCN(C)CC2)c2oc(C(=O)Nc3ccc(N4CCN(C(=O)N5CCCC5)CC4)cc3)cc(=O)c2c1

Procedure:
This compound was prepared from 6-methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide (Example 43) and commercially available 1-pyrrolidinecarbonyl chloride (Aldrich) via the parallel synthesis described above. MS—base peak at m/z=575 by positive ion Cl.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:9][CH2:10][CH2:11]Br)=[CH:4][CH:3]=1.[CH2:20]([N:24]1[C:28](=[CH2:29])[C:27]2([CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[O:26][C:25]1=[O:35])[CH2:21][CH2:22][CH3:23].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:9][CH2:10][CH2:11][N:32]2[CH2:33][CH2:34][C:27]3([O:26][C:25](=[O:35])[N:24]([CH2:20][CH2:21][CH2:22][CH3:23])[C:28]3=[CH2:29])[CH2:30][CH2:31]2)=[CH:4][CH:3]=1
Reactant: C=C1N(CCCC)C(=O)OC12CCNCC2
Reactant: Clc1ccc(C(=CCCBr)c2ccc(Cl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=C1N(CCCC)C(=O)OC12CCN(CCC=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1)CC2
Reaction time: 5 h
Yield: 79 %

Procedure:
10.7 g of 4,4-bis(4-chlorophenyl)-3-butenyl bromide are added to the solution of 4.5 g of 3-butyl-4-methylene-2-oxo-1-oxa-3,8-diazaspiro[4,5]decane in 45 ml of acetone containing 4.20 g of anhydrous potassium carbonate and 0.5 g of potassium iodide. The heterogeneous reaction mixture is refluxed under nitrogen while stirring for 5 hours. After evaporating the solvent under reduced pressure, water is added to the residue and extracted with benzene. The benzene phase is washed with water to halide-free, filtered through a silica gel bed and evaporated under reduced pressure. The residue is recrystallized from ethanol to give the title product in 79.0% yield, m.p.: 110°-111° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:3]=1[NH2:16].[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[C:20]([F:27])[CH:19]=1>N1C=CC=CC=1.C(O)C>[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:16][C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=2[NH:8][C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=2)=[O:23])=[C:20]([F:27])[CH:19]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1F
Reactant: Nc1c(Cl)ncnc1Nc1ccc(Cl)cc1
Solvent: CCO
Solvent: c1ccncc1
Product: O=C(Nc1c(Cl)ncnc1Nc1ccc(Cl)cc1)c1ccc(Cl)cc1F
Temperature: 25 °C

Procedure:
6-Chloro-N4-(4-chlorophenyl)-pyrimidine-4,5-diamine I-(1A-1)a (6.6 g, 26 mmol) in pyridine (30 ml) was cooled to 0° C. and to it was added 4-chloro-2-fluorobenzoyl chloride (5 g, 26 mmol). The reaction was then allowed to warm to ambient temperature overnight. The heterogeneous reaction was diluted with ethanol (50 ml) and the resulting solid collected by filtration. The solids were slurried in toluene, which was then removed under reduced pressure to remove residual ethanol. The solid was slurried in diethyl ether and then collected by filtration to give I-(7A-91)a (8.3 g, 78%): +ACPI MS (M+1) 409.0; 1H NMR (400 MHz, CD3OD) δ 10.60 (s, 1H), 10.10 (s, 1H), 9.19 (s, 1H), 8.74 (t, J=8.1 Hz, 1H), 8.46–8.40 (m, 3H), 8.28 (dd, J=8.7, 2.1 Hz, 1H), 8.20 (d, J=8.7 Hz, 2H).
Reaction SMILES: Cl[CH:2]([C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[C:9]([CH3:14])[C:8]=1[O:15][CH3:16])[C:3]([O:5]C)=[O:4].S1CC(=[O:22])NC1=O>>[OH:22][CH:2]([C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[C:9]([CH3:14])[C:8]=1[O:15][CH3:16])[C:3]([OH:5])=[O:4]
Reactant: O=C1CSC(=O)N1
Reactant: COC(=O)C(Cl)c1cc(Cl)cc(C)c1OC
Product: COc1c(C)cc(Cl)cc1C(O)C(=O)O

Procedure:
It was converted to methyl alpha-chloro-alpha-(5-chloro-2-methoxy-3-methylphenyl)acetate by the chlorination/esterification procedure of Preparation A. The product was used directly to prepare the thiazolidine-2,4-dione of Example 4.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[F:12].BrC1C=C(S(CC)(=O)=O)C=CC=1OCCC.FC1C=CC(S(C)(=O)=O)=CC=1B1OC(C)(C)C(C)(C)O1.Br[C:50]1[C:55]2[N:56]=[CH:57][N:58]=[CH:59][C:54]=2[C:53](=[O:60])[N:52]([CH3:61])[CH:51]=1>>[F:12][C:3]1[CH:4]=[CH:5][C:6]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:7][C:2]=1[C:50]1[C:55]2[N:56]=[CH:57][N:58]=[CH:59][C:54]=2[C:53](=[O:60])[N:52]([CH3:61])[CH:51]=1
Reactant: CS(=O)(=O)c1ccc(F)c(Br)c1
Reactant: Cn1cc(Br)c2ncncc2c1=O
Agent: CC1(C)OB(c2cc(S(C)(=O)=O)ccc2F)OC1(C)C
Agent: CCCOc1ccc(S(=O)(=O)CC)cc1Br
Product: Cn1cc(-c2cc(S(C)(=O)=O)ccc2F)c2ncncc2c1=O

Procedure:
2-bromo-1-fluoro-4-methylsulfonylbenzene was substituted for the title compound of Example 225, step 1 and was converted to 2-(2-fluoro-5-methylsulfonylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in a manner similar to Example 225, step 2 and then reacted with the title compound of Example 231, step 3 in a manner similar to Example 231, step 4. LCMS: 333.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([C:23]([O:25]CC)=O)[N:12]([CH3:22])[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21].[NH2:28][N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>>[N:29]1([NH:28][C:23]([C:11]2[N:12]([CH3:22])[C:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[Cl:21])=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[N:10]=2)=[O:25])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: CCOC(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2Cl)n1C
Reactant: NN1CCCCC1
Product: Cn1c(C(=O)NN2CCCCC2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1Cl
Temperature: 90 °C

Procedure:
A mixture of ethyl 4,5-di-(2,4-dichlorophenyl)-1-methylimidazole-2-carboxylate (20 mg, 0.045 mmol) from Step D in neat 1-aminopiperidine (1 mL) was heated at 90° C. for 72 hr. Most of the amine was evaporated under a stream of nitrogen and the residue was purified by Prep TLC (1 mm, silica) (25% ethyl acetate in hexanes to afford the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[O:5][N:4]=1.[Li+].[Br-:16].CC(=O)OCC>C1COCC1>[Br:16][CH2:2][C:3]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[O:5][N:4]=1
Reactant: ClCc1noc(-c2cccc(Cl)c2)n1
Reactant: [Br-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Clc1cccc(-c2nc(CBr)no2)c1
Temperature: 25 °C
Yield: 85.3 %

Procedure:
3-(chloromethyl)-5-(3-chlorophenyl)-1,2,4-oxadiazole (1.38 g, 6.0 mmol) and LiBr (0.90 g, 10.3 mmol) in THF (50 ml) was heated to reflux under a nitrogen atmosphere o.n. After cooling to r.t. EA was added and the organic phase was washed with H2O and brine, dried and evaporated to give the title compound (1.40 g, 85%). MS (M++1) 275
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]2[CH2:18][C@H:17]3[N:13]([CH2:14][CH2:15][CH2:16]3)[C:12]3[N:19]=[C:20]([S:23][CH3:24])[N:21]=[CH:22][C:11]=3[C:10]2=[O:25])[CH:6]=[CH:7][CH:8]=1)#[N:2].C(N(C(C)C)CC)(C)C.Cl.[NH2:36][OH:37]>C(O)C>[OH:37][N:36]=[C:1]([NH2:2])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N:9]2[CH2:18][C@H:17]3[N:13]([CH2:14][CH2:15][CH2:16]3)[C:12]3[N:19]=[C:20]([S:23][CH3:24])[N:21]=[CH:22][C:11]=3[C:10]2=[O:25])[CH:4]=1
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(C#N)c1)C2=O
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(C(N)=NO)c1)C2=O
Yield: 96 %

Procedure:
(S)-5-(3-Cyanophenyl)-9-methylthio-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (2.00 g, 5.69 mmol) obtained in Step 1 of Example 71 was suspended in ethanol (30 mL), and the mixture was refluxed for 5 hours after adding diisopropylethylamine (1.90 mL, 10.9 mmol) and hydroxylamine hydrochloride (761 mg, 10.9 mmol). After concentrating the mixture under reduced pressure, water was added to the resulting residue, and the precipitated white solid was filtered off to give (S)—N′-hydroxy-3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)benzamidine (2.10 g, 96%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=O>CCO.CN(C=O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of tert-butyl 4-(4-nitrophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (I43) (0.570 g, 1.87 mmol) in EtOH (5 mL) and DMF (5 mL) was added to a solution of 10% Pd/C (200 mg) in DMF (10 mL). The reaction was stirred at room temperature for 24 hours under an atmosphere of hydrogen. The reaction was filtered through a pad of celite and washed through with EtOAc (130 mL). The solvent was removed in vacuo to yield a brown oil which was purified by column chromatography on silica gel (0-50% EtOAc in petroleum benzine 40-60° C.) to afford the title compound (I44) (0.46 g, 89%) as a crystalline solid; 1H NMR (400 MHz, CDCl3) δ 7.02-6.96 (m, 2H), 6.67-6.61 (m, 2H), 4.21 (bs, 2H), 3.57 (s, 2H), 2.77 (t, J=12.2 Hz, 2H), 2.53 (tt, J12.1, 3.5 Hz, 1H), 1.77 (d, J=13.3 Hz, 2H), 1.64-1.50 (m, peak obscured by solvent), 1.48 (s, 9H). LCMS Method C: rt 4.77 min; m/z 221 [M−tButyl+2H]+, 177 [M-Boc+2H]+.