Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N.[N+]([O-])(O)=O.[N+:22]([O:25][CH2:26][CH2:27][NH2:28])([O-:24])=[O:23].[CH3:29][N:30]1[CH:34]([C:35](O)=[O:36])[CH2:33][S:32][C:31]1=[O:38]>O1CCCC1>[N+:22]([O:25][CH2:26][CH2:27][NH:28][C:35]([CH:34]1[CH2:33][S:32][C:31](=[O:38])[N:30]1[CH3:29])=[O:36])([O-:24])=[O:23]
Reactant: NCCO[N+](=O)[O-]
Reactant: CN1C(=O)SCC1C(=O)O
Agent: CCOP(=O)(C#N)OCC
Solvent: O=[N+]([O-])O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1C(=O)SCC1C(=O)NCCO[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 49 %

Procedure:
1.33 ml of triethylamine and 0.36 ml of diethyl cyanophosphonate were added, whilst ice-cooling and stirring, to a suspension of 402 mg of N-(2-nitrooxyethyl)amine nitrate and 326 mg of 3-methyl-2-oxothiazolidine-4-carboxylic acid in 35 ml of dry tetrahydrofuran, and the resulting mixture was stirred at room temperature for 3.5 hours, after which the solvent was removed by distillation under reduced pressure. The residue was mixed with ethyl acetate, and the resulting mixture was washed with a saturated aqueous solution of sodium chloride. It was then dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The crystalline residue was recrystallized from ethanol, to give 247 mg of the title compound as colorless crystals, melting at 105°-106° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH2:15](Br)[CH:16]=[CH2:17].[Cl-].[NH4+]>C1COCC1.[Zn]>[CH2:17]([C:2]1([OH:1])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)[CH:16]=[CH2:15]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C=CCBr
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Product: C=CCC1(O)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (10 g, 50.2 mmol), allyl bromide (10.8 mL, 124 mmol) in THF (10 mL), and saturated ammonium chloride solution (50 mL) was added Zn dust (6.5 g, 100 mmol) portionwise below 10° C. After addition was complete, the reaction mixture was stirred overnight, when TLC indicated consumption of s.m. The reaction mixture was diluted with water (50 mL) and acidified with several drops of 10% H2SO4 to pH=6. The reaction mixture was extracted with EtOAc (3×200 mL). The organic layers were combined and washed with a saturated solution of NaHCO3, brine and evaporated, to give the crude product which was purified by chromatography to give title compound 11B as colorless oil.
Reaction SMILES: [Cl:1][CH2:2][CH:3]=O.[Br:5][C:6]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([Cl:18])[N:9]=[N:8][C:7]=1[NH2:19]>CCO>[ClH:1].[Br:5][C:6]1[C:7]2[N:8]([CH:2]=[CH:3][N:19]=2)[N:9]=[C:10]([Cl:18])[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1nnc(Cl)c(-c2ccccc2)c1Br
Reactant: O=CCCl
Solvent: CCO
Product: Cl
Product: Clc1nn2ccnc2c(Br)c1-c1ccccc1
Temperature: 118 °C
Yield: 63 %

Procedure:
Chloroacetaldehyde (2.0 mL, 31.5 mmol) was added to a solution of crude 4-bromo-6-chloro-5-phenylpyridazin-3-amine (0.193 g, 0.676 mmol) from 1b in EtOH (5.0 mL). The mixture was heated in a sealed tube at 118° C. for 5 h. After cooling to room temperature, the reaction mixture was concentrated in vacuo, and suspended in acetone/Et2O (1:1, 3 mL), filtered, and washed with Et2O to give 8-bromo-6-chloro-7-phenylimidazo[1,2-b]pyridazine HCl salt (0.147 g, >94% purity).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:12]=2)=[CH:7][C:6]=1[C:22]1[CH:27]=[CH:26][C:25]([N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[C:24]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH:23]=1.[C:37]1(=[O:47])[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39](=[O:46])[NH:38]1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.O>[C:33]([C:24]1[CH:23]=[C:22]([C:6]2[CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:12]=3)[CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][CH2:2][N:38]2[C:39](=[O:46])[C:40]3[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:37]2=[O:47])[CH:27]=[CH:26][C:25]=1[N:28]([CH2:29][CH3:30])[CH2:31][CH3:32])([CH3:36])([CH3:35])[CH3:34]
Reactant: CCOC(=O)c1ccc(-c2ccc(CCCBr)c(-c3ccc(N(CC)CC)c(C(C)(C)C)c3)c2)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2ccc(CCCN3C(=O)c4ccccc4C3=O)c(-c3ccc(N(CC)CC)c(C(C)(C)C)c3)c2)cc1
Temperature: 100 °C
Yield: 84.6 %

Procedure:
In a 50 mL three-necked flask under a nitrogen atmosphere, equipped with a magnetic stirrer, 1.0 g (1.82 mmol) of ethyl 4′-(3-bromopropyl)-3″-tert-butyl-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylate, 294 mg (2 mmol) of isoindole-1,3-dione and 276 mg of potassium carbonate (2 mmol) are placed in 20 mL of dimethylformamide. The reaction medium is heated at 100° C. for 3 hours and is then poured into water beforehand and acidified slightly with a 1 mol/L solution of hydrochloric acid, and extracted twice with ethyl acetate. The organic phases obtained are combined and washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated to give a brownish oil. This oil is purified by chromatography on silica (eluent: 80/20 heptane/ethyl acetate) to give 950 mg of ethyl 3″-tert-butyl-4″-diethylamino-4′-[3-(1,3-dioxo-1,3-dihydroisoindol-2-yl)propyl]-[1,1′;3′,1″]terphenyl-4-carboxylate (yield=86%) in the form of a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH:11][NH2:12])=O)=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.Cl.Cl.[NH2:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](N)=[NH:20].CC[O-].[Na+].O>CN(C=O)C>[NH2:15][C:16]1[CH:17]=[C:18]([C:19]2[NH:20][C:9]([C:3]3[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([Br:8])[N:4]=3)=[N:11][N:12]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: NNC(=O)c1nc(Br)cnc1N
Reactant: N=C(N)c1cccc(N)c1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cccc(-c2nnc(-c3nc(Br)cnc3N)[nH]2)c1
Temperature: 100 °C
Yield: 100 %

Procedure:
A mixture of 3-amino-6-bromo-pyrazine-2-carbohydrazide (5 g, 21.55 mmol), 3-aminobenzamidine dihydrochloride (4.484 g, 21.55 mmol) and NaOEt (4.399 g, 64.65 mmol) were combined in DMF (50.00 mL) and heated to 100° C. in the microwave for 20 min. Water was added and the precipitate collected. Used without further purification. Assumed 100% Yield.
Reaction SMILES: Cl[C:2]1[C:11]([O:12][CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:14])[CH:8]=2)[N:3]=1.O.[NH2:16][NH2:17]>C(O)C>[F:14][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:16][NH2:17])[C:11]([O:12][CH3:13])=[N:10]2
Reactant: NN
Reactant: COc1nc2cc(F)ccc2nc1Cl
Solvent: CCO
Solvent: O
Product: COc1nc2cc(F)ccc2nc1NN
Temperature: 20 °C
Reaction time: 16 h

Procedure:
To a solution consisting of 47 g. (0.22 mole) of 2-chloro-6-fluoro-3-methoxyquinoxaline dissolved in 1000 ml. of ethanol, there were added 27.6 g. (0.55 mole) of hydrazine hydrate (26.8 ml.). The resulting mixture was stirred at room temperature overnight (i.e., at ca. 20° C. for approximately 16 hours). An additional amount of hydrazine hydrate (9.0 ml.) was then added and the final reaction mixture was allowed to stir at room temperature for a period of four hours. At this point, the precipitate was filtered and washed with ethanol to ultimately afford 43.3 g. (94%) of pure 6-fluoro-2-hydrazino-3-methoxyquinoxaline, m.p. 170°-174° C. (decomp.).
Reaction SMILES: [NH2:1][C:2]1[C:12]2[C:11](=[O:13])[NH:10][CH2:9][CH2:8][N:7](C(=O)C(F)(F)F)[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[S:34]([NH:37][CH3:38])(=[O:36])=[O:35])[C:24]([Cl:39])=[CH:23][N:22]=1.Cl>C(O)(C)C.O1CCOCC1>[Cl:39][C:24]1[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[S:34]([NH:37][CH3:38])(=[O:36])=[O:35])=[N:26][C:21]([NH:1][C:2]2[C:12]3[C:11](=[O:13])[NH:10][CH2:9][CH2:8][NH:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)=[N:22][CH:23]=1
Reactant: CNS(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: Nc1cccc2c1C(=O)NCCN2C(=O)C(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: CNS(=O)(=O)c1ccccc1Nc1nc(Nc2cccc3c2C(=O)NCCN3)ncc1Cl
Reaction time: 0.17 h
Yield: 15.4 %

Procedure:
Into a microwave vial was placed 6-amino-1-(2,2,2-trifluoro-acetyl)-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one (25 mg, 0.092 mmol) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzenesulfonamide (27 mg, 0.082 mmol) in isopropyl alcohol (3 mL) with 4 M HCl in dioxane (˜2 drops). The mixture was subjected to microwaves at 120° C. for 10 minutes. Trace starting materials were present so the reaction mixture was resubjected to the same microwave conditions. The resulting solid was collected by filtration and washed with cold methylene chloride and dried in a vacuum oven at 50° C. overnight to give product as an off-white solid 2-[5-Chloro-2-(5-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-6-ylamino)pyrimidin-4-ylamino]-N-methylbenzene-sulfonamide (6 mg, 16% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.60 (s, 1H), 9.62 (s, 1H), 9.04 (d, 1H, J=8 Hz), 8.95-8.86 (m, 3H), 8.55 (s, 1H), 7.88-7.25 (m, 4H), 6.71 (d, 1H, J=7.8 Hz), 6.52 (s, 1H), 3.46 (m, 2H), 2.84 (d, 3H), 2.5 (m, 2H); MS (m/e) 474 (M+1)
Reaction SMILES: C(C1C=CC(S([N:14]2[C:18]3=[N:19][CH:20]=[C:21]([NH:23][NH2:24])[N:22]=[C:17]3[CH:16]=[CH:15]2)(=O)=O)=CC=1)(C)(C)C.CCN(C(C)C)C(C)C.[CH:34]1([C:40](Cl)=O)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.O=S(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[CH:34]1([C:40]2[N:22]3[C:17]4[CH:16]=[CH:15][NH:14][C:18]=4[N:19]=[CH:20][C:21]3=[N:23][N:24]=2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)n2ccc3nc(NN)cnc32)cc1
Reactant: O=C(Cl)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: c1cc2c(ncc3nnc(C4CCCCC4)n32)[nH]1
Temperature: 25 °C
Yield: 41.1 %

Procedure:
To a solution of 5-(4-tert-butylphenylsulfonyl)-2-hydrazinyl-5H-pyrrolo[2,3-b]pyrazine (0.39 g, 1.1 mmol; Preparation #3) and DIEA (0.20 mL, 1.1 mmol) in 1,4-dioxane (12 mL) at about 0° C. was added cyclohexanecarbonyl chloride (0.17 g, 1.1 mmol). The reaction was then warmed to ambient temperature for about 1 h. SOCl2 (0.41 mL, 5.6 mmol) was added and the reaction was heated to about 90° C. for about 1 h. The reaction was cooled to ambient temperature and aqueous Na2CO3 (2 M, 12 mL, 24 mmol) was added slowly followed by 1,4-dioxane (5 mL). The reaction was heated at about 60° C. for about 72 h. The reaction was cooled to ambient temperature and concentrated under reduced pressure. The crude product was diluted with EtOAc (40 mL) and washed with saturated aqueous NaHCO3 (40 mL) and brine (40 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluting with a gradient of 0-100% heptane/EtOAc (12 g column) and dried in a vacuum oven at about 55° C. for about 18 h to give 1-cyclohexyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0.109 g, 40%): LC/MS (Table 2, Method a) Rt=1.66 min; MS m/z: 242 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[CH:15][C:16]3[N:25]([CH3:26])[C:24](=[O:27])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][C:22]=4[CH3:28])[N:17]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1>C1COCC1.C(OCC)(=O)C.CO.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][C:16]3[N:25]([CH3:26])[C:24](=[O:27])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][C:22]=4[CH3:28])[N:17]=3)=[CH:12][CH:13]=2)=[O:7])=[CH:29][CH:30]=1
Reactant: Cc1cccc2nc(C=Cc3ccc(C(=O)c4ccc(Cl)cc4)cc3)n(C)c(=O)c12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cccc2nc(CCc3ccc(C(=O)c4ccc(Cl)cc4)cc3)n(C)c(=O)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.7 %

Procedure:
To a solution of 2-[2-[4-(4-chlorobenzoyl)phenyl]-vinyl]-3,5-dimethyl-4(3H)-quinazolinone (104 mg) in THF-ethyl acetate-methanol (2:1:1) (20 ml) was added 10% Pd/C (50% hydrous) (10 mg) and the mixture was stirred under hydrogen at room temperature for 2 hours. The catalyst was then filtered off and the filtrate was concentrated. The residue was washed with ethyl acetate-methanol and dried to provide 53 mg of white powder.
Reaction SMILES: [CH3:1][N:2]1[CH2:24][C:7]2=[C:8]3[C:12](=[CH:13][CH:14]=[C:6]2[O:5][CH2:4][CH2:3]1)[N:11]([S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:17])=[O:16])[CH:10]=[CH:9]3.[Li]CCCC.[CH:30]1([C:33](OC)=[O:34])[CH2:32][CH2:31]1>C1COCC1>[CH:30]1([CH:33]([C:10]2[N:11]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:17])=[O:16])[C:12]3[C:8]([CH:9]=2)=[C:7]2[CH2:24][N:2]([CH3:1])[CH2:3][CH2:4][O:5][C:6]2=[CH:14][CH:13]=3)[OH:34])[CH2:32][CH2:31]1
Reactant: CN1CCOc2ccc3c(ccn3S(=O)(=O)c3ccccc3)c2C1
Reactant: COC(=O)C1CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN1CCOc2ccc3c(cc(C(O)C4CC4)n3S(=O)(=O)c3ccccc3)c2C1
Reaction time: 8 h
Yield: 4.1 %

Procedure:
2-Methyl-8-(phenylsulfonyl)-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole (Example 5, 0.030 g, 0.088 mmol) was dissolved in dry THF (1 mL) at −78° C. under an atmosphere of nitrogen gas. BuLi (2.5 M in hexanes, 0.053 mL, 0.13 mmol) was added. The solution was stirred for 15 minutes before methyl cyclopropane carboxylate (0.013 mL, 0.13 mmol) was added. The temperature of the reaction mixture was allowed to rise to room temperature overnight. The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound (1.5 mg). MS m/z 413 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][CH2:10][CH2:11][CH2:12][NH2:13])=[CH:4][N:3]=1.[N+:14]([NH:17][C:18](N)=N)([O-:16])=[O:15]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:10][CH2:11][CH2:12][NH:13][C:18]2=[N:17][N+:14]([O-:16])=[O:15])=[CH:4][N:3]=1
Reactant: NCCCNCc1ccc(Cl)nc1
Reactant: N=C(N)N[N+](=O)[O-]
Solvent: O
Product: O=[N+]([O-])N=C1NCCCN1Cc1ccc(Cl)nc1
Temperature: 80 °C
Yield: 45.2 %

Procedure:
A solution composed of N-(2-chloro-5-pyridylmethyl)trimethylenediamine (10 g), nitroguanidine (5.7 g) and water (80 ml) was heated at 80° C. for 3 hours The reaction mixture was cooled to room temperature, and extracted twice with 50 ml of dichloromethane. Dichloromethane was distilled off from the extracts, and the tarry residue was purified by silica gel column chromatography to give almost colorless 1-(2-chloro-5-pyridylmethyl)-2-(nitroimino)tetrahydropyrimidine (6.1 g).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:11]=[CH:10][N:9]2[N:12]=[CH:13][C:14]([CH:15]=O)=[C:8]2[N:7]=1)[CH:2]([CH3:4])[CH3:3].[NH:17]1[CH2:23][C:21](=[O:22])[NH:20][C:18]1=[O:19].N1CCCCC1>C(#N)C>[CH2:1]([NH:5][C:6]1[CH:11]=[CH:10][N:9]2[N:12]=[CH:13][C:14]([CH:15]=[C:23]3[NH:17][C:18](=[O:19])[NH:20][C:21]3=[O:22])=[C:8]2[N:7]=1)[CH:2]([CH3:3])[CH3:4]
Reactant: O=C1CNC(=O)N1
Reactant: CC(C)CNc1ccn2ncc(C=O)c2n1
Solvent: CC#N
Solvent: C1CCNCC1
Product: CC(C)CNc1ccn2ncc(C=C3NC(=O)NC3=O)c2n1
Temperature: 70 °C

Procedure:
To 5-(isobutylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (24 mg, 0.110 mmol) in acetonitrile was added hydantoin (11 mg, 0.110 mmol) and piperidine (11 μL, 0.110 mmol). The reaction was heated at 70° C. for 48 hr. The reaction was cooled to room temperature and the solid formed was isolated by filtration to yield 5-((5-(isobutylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=301)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[OH:10].F[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][C:13]=1[N+:20]([O-:22])=[O:21].C(C1C=CC(OC2C(OC)=CC=CC=2F)=C(C=1)N)=O.NC1SC=CN=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[O:10][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][C:13]=1[N+:20]([O-:22])=[O:21]
Reactant: COc1cccc(F)c1O
Reactant: O=Cc1ccc(F)c([N+](=O)[O-])c1
Agent: COc1cccc(F)c1Oc1ccc(C=O)cc1N
Agent: Nc1nccs1
Product: COc1cccc(F)c1Oc1ccc(C=O)cc1[N+](=O)[O-]
Yield: 68.7 %

Procedure:
4-(2-Fluoro-6-methoxy-phenoxy)-3-nitrobenzaldehyde (1.0 g, 70%) was prepared from 2-fluoro-6-methoxyphenol (0.78 g, 5.5 mmol) and 4-fluoro-3-nitrobenzaldehyde (0.84 g, 5.0 mmol) following the general procedure A. This was reduced to 5-formyl-2-(2-fluoro-6-methoxy-phenoxy)-aniline (0.57 g, 62%) following general procedure B. 1-[2-(2-Fluoro-6-methoxy-phenoxy)-5-fonnyl-phenyl]-3-thiazol-2-yl-urea (265 mg, 69%) was prepared from 5-formyl-2-(2-fluoro-6-methoxy-phenoxy)-aniline (261 mg, 1.0 mmol) and 2-aminothiazole (100 mg, 1.0 mmol) following the general procedure D.
Reaction SMILES: Cl([O-])=O.[Na+].[OH:5]P([O-])(O)=O.[Na+].[F:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:22]([CH:23]=[O:24])=[CH:21][N:20]=[C:19]2[C:25]2[C:30]([F:31])=[CH:29][CH:28]=[C:27]([F:32])[C:26]=2[F:33])=[CH:14][CH:13]=1.CC(=CC)C>O.C(O)(C)(C)C.C(OCC)(=O)C>[F:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[C:22]([C:23]([OH:5])=[O:24])=[CH:21][N:20]=[C:19]2[C:25]2[C:30]([F:31])=[CH:29][CH:28]=[C:27]([F:32])[C:26]=2[F:33])=[CH:16][CH:17]=1
Reactant: O=Cc1cnc(-c2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)(C)O
Product: O=C(O)c1cnc(-c2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Reaction time: 0.25 h

Procedure:
A solution of sodium chlorite (80%, 2.53 g, 22.5 mmol), sodium phosphate mono-basic (210.6 mg, 1.76 mmol) in water was added to a solution of 1-(4-fluorophenyl)-2-(2,3,6-trifluorophenyl)-1H-imidazole-5-carb aldehyde (26) (720 mg, 2.25 mmol) and 2-methyl-2-butene (2M in THF, 7.53 mL, 15.1 mmol) in tert-butanol and the reaction was stirred for 15 minutes. Water and ethyl acetate were added and the layers were separated. The organic layer was washed with saturated sodium bicarbonate. The aqueous layer was acidified to pH 6 with 2N HCl and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give 1-(4-fluorophenyl)-2-(2,3,6-trifluorophenyl)-1H-imidazole-5-carboxylic acid (27).
Reaction SMILES: Br[C:2]1[C:7]2[S:8][C:9]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:10][C:6]=2[CH:5]=[C:4](Br)[N:3]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20](B(O)O)[CH:19]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>CN(C=O)C.O.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>[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:2]2[C:7]3[S:8][C:9]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:10][C:6]=3[CH:5]=[C:4]([C:7]3[CH:2]=[N:3][CH:4]=[CH:5][CH:6]=3)[N:3]=2)[CH:19]=1
Reactant: OB(O)c1cccnc1
Reactant: CCNC(=O)Nc1nc2cc(Br)nc(Br)c2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)nc(-c3cccnc3)c2s1
Temperature: 90 °C
Yield: 46.9 %

Procedure:
To a solution of 1-(4,6-dibromo-thiazolo[5,4-c]pyridin-2-yl)-3-ethyl-urea (0.07 g, 0.17 mmol) in DMF:H2O (3:1, 4 mL) was added pyridine-3-boronic acid (0.08 g, 0.68 mmol) and potassium phosphate tribasic (0.09 g, 0.43 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was degassed by bubbling nitrogen for 15-20 min followed by addition of Pd(PPh3)4 (0.04 g, 0.07 mmol). The resulting solution was again degassed for 15-20 min followed by heating up to 90° C. overnight. After completion of reaction (TLC monitoring), the reaction mixture was cooled, water was added and extracted with ethyl acetate, dried over Na2SO4 and evaporated to dryness under high vacuum. The crude residue was purified by Prep HPLC to get the desired product (0.015 g, 23%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([O:27]C)=[O:26])[CH:20]=3)[C:15]([F:29])=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4].[OH-].[Na+]>C1COCC1.O.C(OCC)(=O)C>[C:3]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([OH:27])=[O:26])[CH:20]=3)[C:15]([F:29])=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1cccc(Nc2ncc(F)c(Nc3cccc(C(=O)OC)c3)n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1cccc(Nc2ncc(F)c(Nc3cccc(C(=O)O)c3)n2)c1
Yield: 58.6 %

Procedure:
A solution of N2,N4-bis(3-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine (100 mg, 0.25 mmol) and NaOH (140 mg, 3.5 mmol) in THF:H2O (5 mL, each) was stirred at room temperature overnight. The reaction mixture was diluted with water (60 mL) and ethyl acetate (60 mL). The aqueous layer was separated, acidified with 1N HCl solution to pH 3. The formed precipitate was collected by filtration and recrystallized from methanol to give N2,N4-bis(3-carboxyphenyl)-5-fluoro-2,4-pyrimidinediamine (54 mg, 58%) as a white solid. 1H NMR (CD3OD): δ 7.31 (t, J=8.1 Hz, 1H), 7.42 (t, J=8.1 Hz, 1H), 7.61 (dm, J=7.8 Hz, 1H), 7.76 (dm, J=8.4 Hz, 1H), 7.89 (dm, J=7.2 Hz, 1H), 7.98 (d, J=3.6 Hz, 1H), 8.01 (m, 1H), 8.20 (m, 1H), 8.37 (m, 1H); LCMS: ret. time: 15.77 min.; purity: 98.84%; MS (m/e): 369.03 (MH+).
Reaction SMILES: C(OC(=O)[C@@H]1CCCN1CCCSC(=O)[C@H](CC1C=CC=CC=1C(=O)C1C=CC=CC=1)N)(C)(C)C.C([O:40][C:41](=[O:71])[C@@H:42]1[CH2:46][CH2:45][CH2:44][N:43]1[C:47](=[O:70])[CH2:48][CH2:49][S:50][C:51](=[O:69])[C@H:52]([CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[C:61](=[O:68])[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)[NH2:53])(C)(C)C.FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1>[C:61]([C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][C:55]=1[CH2:54][C@@H:52]([C:51]([S:50][CH2:49][CH2:48][C:47]([N:43]1[CH2:44][CH2:45][CH2:46][C@H:42]1[C:41]([OH:71])=[O:40])=[O:70])=[O:69])[NH2:53])(=[O:68])[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)CCSC(=O)[C@@H](N)Cc1ccccc1C(=O)c1ccccc1
Agent: CC(C)(C)OC(=O)[C@@H]1CCCN1CCCSC(=O)[C@@H](N)Cc1ccccc1C(=O)c1ccccc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](Cc1ccccc1C(=O)c1ccccc1)C(=O)SCCC(=O)N1CCC[C@H]1C(=O)O
Reaction time: 3 h

Procedure:
The product of step (b), N-(2-benzoylphenylalanylthiopropanoyl)-L-proline-t-butyl ester, 1.25 g, was suspended in 4 ml anisole and reacted with 8 ml trifluoroacetic acid for 1 hour at room temperature with stirring. In view of the fact that some starting material was later recovered, the reaction time should be increased. Trifluoroacetic acid was removed with a rotary evaporator under high vacuum. The residue was dissolved in 1 ml THF and chromatographed on a 2.2 cm×99 cm column of Sephadex LH-20 eluted with THF. Fractions of about 5.3 ml were collected. The product was eluted in fractions 41-43. The combined fractions41-43 were evaporated to dryness, dissolved in a small amount of isopropanol and rechromatographed on a 1.2 cm×95 cm LH-20 column, eluted with isopropanol. Fractions of about 2.05 ml were collected. Fractions 48-50 contained 78 mg of the desired compound as an oil. Side fractions 46-47 and 51-53 were saved for rechromatography. The oil was dissolved in a small volume of THF in a vial, then the THF was evaporated under a stream of N2. The vial was then placed in a round bottom flask connected to a rotary evaporator. After 3 hours under high vacuum, a stable, dry foam was obtained.
Reaction SMILES: [C:1]1([C:7]2[C:8](=O)[NH:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:16])=O.[OH-].[NH4+]>>[Cl:16][C:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: O=c1[nH]cccc1-c1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Product: Clc1ncccc1-c1ccccc1
Temperature: 0 °C
Yield: 31 %

Procedure:
A solution of 3-phenyl-2-(1H)-pyridone (VIII; 20.0 g, 0.12 mole) and phosphorus oxychloride (300 mL) was refluxed for 6 hr and then slowly poured over crushed ice (300 mL). The resulting solution was made basic with ammonium hydroxide which led to formation of a precipitate. The mixture was extracted with ethyl ether (3×500 mL) and the combined organic extracts were dried (Na2SO4). Concentration in vacuo gave a solid which was recrystallized from ethyl acetate to yield 7.0 g (31%) of 2-chloro-3-phenylpyridine (VI), m.p. 52°-56°.