Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:30]([O:34][C:35]([N:37]1[CH2:42][C@@H:41]2[CH2:43][C@H:38]1[CH2:39][NH:40]2)=[O:36])([CH3:33])([CH3:32])[CH3:31]>>[C:30]([O:34][C:35]([N:37]1[CH2:42][C@@H:41]2[CH2:43][C@H:38]1[CH2:39][N:40]2[C:20]([C:19]1[CH:18]=[N:17][C:16]([NH:15][C:12]2[N:13]=[CH:14][C:9]3[CH:8]=[C:7]([C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[N:6]([CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[C:10]=3[N:11]=2)=[CH:24][CH:23]=1)=[O:22])=[O:36])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4C[C@@H]5C[C@H]4CN5C(=O)OC(C)(C)C)cn3)nc2n1C1CCCC1

Procedure:
Following general amide formation method 1, 6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinic acid (0.150 g, 0.380 mmol) was combined with (S,S)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (100 mg, 0.504 mmol, 1.3 eq), which gave 5-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-(S,S)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester and used directly in the next step. MS m/z 575.7 (M+H)+.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1.Cl.[NH2:21][OH:22].O.O.O.C([O-])(=O)C.[Na+].O>C(O)C>[OH:22][N:21]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1
Reactant: CC(C(=O)O)c1ccc(CC2CCCCC2=O)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C(=O)O)c1ccc(CC2CCCCC2=NO)cc1
Reaction time: 2 h
Yield: 107.1 %

Procedure:
A solution of 1.3 g of 2-[4-(2-oxocyclohexan-1-ylmethyl)phenyl]propionic acid, 0.33 g of hydroxylamine hydrochloride and 1.6 g of sodium acetate trihydrate in 85% ethanol was heated with stirring at 70°-75° C. for 2 hours, and the mixture was poured into 100 ml of water and extracted with ether. The extract was washed with water, dried over anhydrous sodium sulfate, and the solvent removed by distillation to give 1.4 g of the desired compound, which by recrystallization from a mixture of ethyl acetate and n-hexane afforded colorless prisms, m.p. 143°-150.5° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH:22]4[CH2:24][CH2:23]4)=[CH:20][C:19]([CH:25]4[CH2:27][CH2:26]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:3]=1.[CH3:32][C:33]1([CH3:39])[CH2:37][O:36][C:35](=[O:38])[NH:34]1>>[CH:22]1([C:21]2[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:34]5[C:33]([CH3:39])([CH3:32])[CH2:37][O:36][C:35]5=[O:38])=[CH:3][C:4]=4[S:28]([CH3:31])(=[O:30])=[O:29])=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=[C:19]([CH:25]3[CH2:27][CH2:26]3)[CH:20]=2)[CH2:24][CH2:23]1
Reactant: CC1(C)COC(=O)N1
Reactant: CS(=O)(=O)c1cc(Br)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Product: CC1(C)COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C4CC4)cc3C3CC3)CC2)c(S(C)(=O)=O)c1
Yield: 17.3 %

Procedure:
By reaction and treatment in the same manner as in Example 111 and using (4-bromo-2-methanesulfonylphenyl)[4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl]methanone (463 mg) described in Preparation Example 89 and 4,4-dimethyloxazolidin-2-one (106 mg), the title compound (85.6 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].CO[CH:13]1[CH2:17][CH2:16][CH:15](OC)O1>C(O)(=O)C>[N:1]1([C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7]([O:9][CH3:10])=[O:8])[CH:13]=[CH:17][CH:16]=[CH:15]1
Reactant: COC1CCC(OC)O1
Reactant: COC(=O)c1sccc1N
Solvent: CC(=O)O
Product: COC(=O)c1sccc1-n1cccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
At room temperature, add 20 g (0.127 mol) of methyl 3-aminothiophene-2-carboxylate in small portions to a solution of 16.80 g (0.127 mol) of 2,5-dimethoxytetrahydrofuran in 100 ml of acetic acid. After 30 minutes' stirring at room temperature, then 90 minutes at 90° C., the acetic acid is removed under reduced pressure and the residue is taken up in 100 ml of 2N sodium hydroxide solution and extracted with diethyl ether. After washing with water and rendering colourless with animal charcoal, the ethereal phase is concentrated to dryness to yield the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([C:10]1[CH:14]=[CH:13][S:12][C:11]=1[CH:15]=O)(=[O:9])=[O:8].[CH3:17][O:18][C:19](=[O:32])[CH2:20][N:21]1[C:29]2[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=2)[CH:23]=[C:22]1[CH3:31]>>[CH3:17][O:18][C:19](=[O:32])[CH2:20][N:21]1[C:29]2[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=2)[C:23]([CH2:15][C:11]2[S:12][CH:13]=[CH:14][C:10]=2[S:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)(=[O:8])=[O:9])=[C:22]1[CH3:31]
Reactant: O=Cc1sccc1S(=O)(=O)c1ccccn1
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Product: COC(=O)Cn1c(C)c(Cc2sccc2S(=O)(=O)c2ccccn2)c2cc(F)ccc21

Procedure:
The title compound was prepared by the method of Preparation 1c using 3-(pyridine-2-sulfonyl)thiophene-2-carbaldehyde and (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester.
Reaction SMILES: CC(C)([O-])C.[K+].O.Cl.[OH:9][CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C:17]([NH:19][CH3:20])=[O:18])[CH:12]=1.[NH2:21][C:22]1[C:27]([C:28]#[N:29])=[C:26]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[C:25]([C:37]#[N:38])=[C:24](SC2C=CC=CC=2)[N:23]=1.O>COCCOC>[NH2:21][C:22]1[N:23]=[C:24]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([C:17]([NH:19][CH3:20])=[O:18])[CH:12]=2)[C:25]([C:37]#[N:38])=[C:26]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[C:27]=1[C:28]#[N:29]
Reactant: CNC(=O)c1cc(CO)ccn1
Reactant: N#Cc1c(N)nc(Sc2ccccc2)c(C#N)c1-c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CNC(=O)c1cc(COc2nc(N)c(C#N)c(-c3ccc(F)cc3)c2C#N)ccn1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
1.62 g (14.44 mmol) of potassium tert-butoxide were suspended in 10 ml of 1,2-dimethoxyethane. After addition of 1.44 g (8.66 mmol) of 4-(hydroxymethyl)-N-methylpyridine-2-carboxamide hydrochloride monohydrate (Example 40A) and 1.00 g (2.89 mmol) of 2-amino-4-[4-fluorophenyl]-6-(phenylsulfanyl)pyridine-3,5-dicarbonitrile (Example 38A), the mixture was stirred at 60° C. for 2 h and at RT overnight. 30 ml of water were added to the reaction mixture. The precipitate was filtered off and washed with water.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([N:20]=C=O)=[CH:16][CH:15]=1)([O-:13])=[O:12]>[O-]CC.[Na+].O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Reactant: O=C(O)c1ccc(O)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Product: O=C(Nc1ccc([N+](=O)[O-])cc1)c1ccc(O)cc1
Temperature: 30 °C
Reaction time: 0.4 h

Procedure:
p-Hydroxybenzoic acid (59.05 grams, 0.4275 mole), sodium ethoxide catalyst (0.133 gram, 0.225% wt. of the p-hydroxybenzoic acid used) and N,N'-dimethylacetamide solvent (404 grams) are added to a reactor equipped with a reflux condenser and stirred under a nitrogen atmosphere at 80° C. p-Nitrophenylisocyanate (73.85 grams, 0.450 mole) is initially added in an aliquot of 25.00 grams, followed by 25.00 and 23-85 gram aliquots eleven then nine minutes later, respectively, and so as to maintain a 80° to 82° C. reaction temperature. After the last aliquot of p-nitrophenylisocyanate is added, heating of the reactor commenced and a 160° C. reaction temperature is achieved 24 minutes later. After three hours at the 160° C. reaction temperature, the reactor is cooled to 30° C. then the contents poured into one gallon of deionized water. A precipitated yellow powder is recovered via filtration of the aqueous slurry then dissolved into 1900 milliliters of boiling methanol and refluxed therein (65° C.). After cooling the methanol solution to 5° C. and maintaining therein for twelve hours, a first crop of pale yellow colored crystalline product is filtered off and dried at 110° C. under vacuum to a constant weight of 92.5 grams (79.6% isolated yield). No attempt was made to recover a second crop of crystalline product from the mother liquor. Fourier transform infrared spectrophotometric analysis of a nujol mull of a portion of the product on a sodium chloride plate revealed the presence of the expected secondary amide N--H stretching (solid state) at 3385 cm-1 (sharp), the secondary amide carbonyl stretching (solid state) at 1655 cm-1 (sharp), the hydroxyl group O--H stretching centered at 3232 cm-1 (broad) and the conjugated nitro group absorbances at 1537 and 1339 cm-1 (sharp). Proton magnetic resonance spectroscopy (250 MHz) further confirmed the product structure as -hydroxy-4'-nitrobenzanilide.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:20]([NH:22][NH:23][C:24]([C:26]2[CH:40]=[CH:39][C:29]([CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:28][CH:27]=2)=[O:25])=O)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.CCN(C(C)C)C(C)C.BrP(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(#N)C>[NH2:1][C:2]1[C:3]([C:20]2[O:25][C:24]([C:26]3[CH:27]=[CH:28][C:29]([CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[CH:39][CH:40]=3)=[N:23][N:22]=2)=[N:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:12][CH:13]=2)=[CH:6][N:7]=1
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(C(=O)NNC(=O)c3ccc(CNC(=O)OC(C)(C)C)cc3)n2)cc1
Agent: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4ccc(CNC(=O)OC(C)(C)C)cc4)o3)n2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 35.4 %

Procedure:
A mixture of tert-butyl 4-(2-(3-amino-6-(4-(isopropylsulfonyl)phenyl)pyrazine-2-carbonyl)hydrazinecarbonyl)benzylcarbamate (136 mg, 0.24 mmol) and DIPEA (109.8 mg, 148.0 μL, 0.8499 mmol) in acetonitrile (3.000 mL) at 0° C. was treated portionwise with dibromo(triphenyl)phosphorane (143.5 mg, 0.3400 mmol) and the resulting mixture stirred at room temperature for 48 h. The mixture was concentrated in vacuo and pre-absorbed onto silica gel and purified by column chromatography on silica gel eluting with 50% EtOAc/CH2Cl2 to give the product (46.8 mg, 30% yield); MS (ES+) 551.31
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[NH2:12][C:13]1[CH:34]=[CH:33][C:16]([C:17]([N:19]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[CH2:23][N:22]3[CH:30]=[CH:31][CH:32]=[C:21]3[CH2:20]2)=[O:18])=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:12][C:13]1[CH:34]=[CH:33][C:16]([C:17]([N:19]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[CH2:23][N:22]3[CH:30]=[CH:31][CH:32]=[C:21]3[CH2:20]2)=[O:18])=[CH:15][CH:14]=1)(=[O:10])=[O:9]
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(NS(=O)(=O)c2ccccc2Cl)cc1)N1Cc2cccn2Cc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.9 %

Procedure:
To a solution of 0.418 g of 2-chlorobenzenesulfonyl chloride in 5 ml of dichloromethane, cooled to 0° C. is added 0.50 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine and 0.346 μl of triethylamine. The mixture is stirred at room temperature overnight and diluted with 50 ml of dichloromethane. The mixture is washed with 20 ml each of H2O, 2N citric acid, 1M NaHCO3, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the filtrate concentrated to dryness. The residue is chromatographed on thick layer silica gel plates (4) with the solvent ethyl acetate-hexane (1:1) to give a solid. Crystallization from ethyl acetate gives 0.165 g of white crystals, m.p. 206°-210° C.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[O:12][CH2:11][CH2:10][O:9][C:8]=2[CH:7]=[CH:6][C:5]=1[NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])([O-:3])=[O:2].[H-].[Na+].S(OC)(O[CH3:28])(=O)=O.O>CN(C=O)C>[CH3:28][N:14]([C:5]1[CH:6]=[CH:7][C:8]2[O:9][CH2:10][CH2:11][O:12][C:13]=2[C:4]=1[N+:1]([O-:3])=[O:2])[C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19]
Reactant: COS(=O)(=O)OC
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1[N+](=O)[O-])OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)OC(C)(C)C)c1ccc2c(c1[N+](=O)[O-])OCCO2
Temperature: 0 °C
Yield: 90.9 %

Procedure:
A mixture of tert-butyl 5-nitro-2,3-dihydrobenzo[b][1,4]dioxin-6-ylcarbamate (2.3 g, 7.8 mmol) in DMF (25 mL) was stirred at 0° C. Sodium hydride (373 mg, 9.3 mmol) was added slowly. Dimethyl sulfate (1.017 g, 9.3 mmol) was added dropwise and the mixture was stirred at 0° C. for 0.5 h. To the reaction mixture was slowly added water (40 mL). The mixture was extracted with toluene (40 mL), the organic phase was washed with water (40 mL) and dried, and the solvent removed. The product was purified by silica gel column (5% v/v EtOAc in PE) to give tert-butyl methyl(5-nitro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)carbamate (2.2 g, 92% yield). ESI MS: m/z 311 [M+H]+,
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[C:9]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:26][CH2:27][CH2:28][Br:29]>CN(C)C=O>[Br:29][CH2:28][CH2:27][CH2:26][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:18])[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:26][CH2:27][CH2:28][Br:29])=[CH:13][CH:12]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(C(=O)c1ccc(O)cc1)c1ccc(O)cc1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(C(=O)c1ccc(OCCCBr)cc1)c1ccc(OCCCBr)cc1
Temperature: 80 °C
Reaction time: 72 h

Procedure:
1,2-bis(4-hydroxyphenyl)ethane-1,2-dione (2.6 g, 10.74 mmol) was dissolved in DMF and K2CO3 (5.9 g, 42.7 mmol) was added, 100 mmol of 1,3-dibromopropane and a catalytic amount of KI were then added. The mixture was heated to 80° C. and stirred for 3 days. TLC check showed 1,2-bis(4-hydroxyphenyl)ethane-1,2-dione disappeared. Dimethylformamide (DMF) was removed, and water was added, extracted by EtOAc, washed with brine, dried over MgSO4. The solvent was removed and the residue was purified by column chromatography to give 1,2-bis(4-(3-bromopropoxy)phenyl)ethane-1,2-dione 6 as a pale yellow solid, as confirmed by the following nuclear magnetic resonance (NMR) data obtained therefrom: 1H NMR (500 MHz, CDCl3): δ 7.94 (d, J=8.8 MHz, 4H), 6.99 (d, J=8.8 MHz, 4H), 4.20 (t, J=6.2 MHz, 4H), 3.61 (t, J=6.2 MHz, 4H), 2.34 (m, 4H) ppm.
Reaction SMILES: [CH2:1]([N:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:16]=[CH:15][C:14](=[O:17])[NH:13][CH:12]=2)=[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[N:6]=[C:5]1[NH2:25])[CH:2]=[CH2:3].[C:26](=O)([O-])[O-].[K+].[K+].IC>CS(C)=O>[CH2:1]([N:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:16]=[CH:15][C:14](=[O:17])[N:13]([CH3:26])[CH:12]=2)=[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[N:6]=[C:5]1[NH2:25])[CH:2]=[CH2:3]
Reactant: C=CCn1c(N)nc(-c2cccc(F)c2)c(-c2ccc(=O)[nH]c2)c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CI
Product: C=CCn1c(N)nc(-c2cccc(F)c2)c(-c2ccc(=O)n(C)c2)c1=O
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a solution of 3-allyl-2-amino-6-(3-fluorophenyl)-5-(6-oxo-1,6-dihydro-3-pyridinyl)-3,4-dihydro-4-pyrimidinone in dimethyl sulfoxide were added potassium carbonate (2 equivalents) and iodomethane (4 equivalents), followed by stirring at 50° C. for 16 hours. After filtering off the insoluble matters, the filtrate was purified by HPLC, to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([C:8]([N:10]2[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[C:12]3[CH:18]=[CH:19][CH:20]=[N:21][C:11]2=3)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(O[CH:29](N(C)C)[N:30]([CH3:32])[CH3:31])(C)(C)C>O1CCCC1>[CH3:29][N:30]([CH:32]=[C:14]1[CH2:15][CH2:16][N:10]([CH2:8][C:7]2[CH:22]=[CH:23][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[C:11]2[N:21]=[CH:20][CH:19]=[CH:18][C:12]=2[C:13]1=[O:17])[CH3:31]
Reactant: O=C1CCCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ncccc21
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: C1CCOC1
Product: CN(C)C=C1CCN(Cc2ccc([N+](=O)[O-])cc2)c2ncccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
To a slurry of 0.50 g of 6,7,8,9-tetrahydro-9-(4-nitrobenzoyl)-5H-pyrido[2,3-b]azepin-5-one in 10 ml of tetrahydrofuran under argon is added 0.70 g of tert-butoxy-bis(dimethylamino)methane and the mixture is stirred at room temperature overnight. The volatiles are removed under vacuum and the residue in ethyl acetate--CH2Cl2 (2:8) filtered through a short column of silica gel. The silica gel is washed with ethyl acetate (discard) and then with chloroform containing 3% methanol to give 0.51 g of the product as a yellow solid.
Reaction SMILES: C([Mg]Br)(C)C.[F:6][C:7]([F:18])([F:17])[O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1Br.[B:19](OC(C)C)([O:24]C(C)C)[O:20]C(C)C.Cl>O1CCCC1.C(OCC)(=O)C>[F:6][C:7]([F:18])([F:17])[O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[B:19]([OH:24])[OH:20]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Fc1ccc(OC(F)(F)F)c(Br)c1
Agent: CC(C)[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OB(O)c1cc(F)ccc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of isopropylmagnesium bromide (2M solution in tetrahydrofuran) (83 ml, 0.166 mol) was added drop-wise to a stirred solution of 2-(trifluoromethoxy)-5-fluoro-1-bromobenzene (Preparation 49, 27.6 g, 0.107 mol) in anhydrous tetrahydrofuran (125 ml) at −10° C. under an atmosphere of nitrogen. The resulting mixture was stirred at room temperature for 2 hours. Triisopropyl borate (26.1 g, 0.139 mol) was then added drop-wise at −10° C. and the resulting mixture was stirred at room temperature for 16 hours. Hydrochloric acid (1N aqueous solution) (100 ml) was added drop-wise at 0° C. and the mixture stirred at room temperature for 30 minutes. Ethyl acetate (150 ml) was added and the layers were separated, the aqueous layer was further extracted with ethyl acetate (2×150 ml). The organic extracts were combined and concentrated in vacuo. The residue was dissolved in potassium hydroxide (10% aqueous solution) (50 ml) and extracted with diethyl ether (2×150 ml). The separated aqueous layer was acidified to pH˜4 by addition of hydrochloric acid (1N aqueous solution) (100 ml) and extracted with ethyl acetate (3×150 ml). The combined organic extracts were dried over anhydrous Na2SO4, filtered and evaporated in vacuo to give an off white solid. Purification by preparative HPLC gave the title compound as an off white solid (5.82 g, 24%).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([N:15]3[CH2:20][CH2:19][CH:18]([NH2:21])[CH2:17][CH2:16]3)=[O:14])[N:10]=[C:9]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[CH:8]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:37]1([C:41](Cl)=[O:42])[CH2:40][CH2:39][CH2:38]1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([N:15]3[CH2:16][CH2:17][CH:18]([NH:21][C:41]([CH:37]4[CH2:40][CH2:39][CH2:38]4)=[O:42])[CH2:19][CH2:20]3)=[O:14])[N:10]=[C:9]([C:22]3[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=3)[CH:8]=2)=[CH:28][CH:29]=1
Reactant: NC1CCN(C(=O)Cn2nc(-c3ccncc3)cc2Cc2ccc(F)cc2)CC1
Reactant: O=C(Cl)C1CCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CCN(C(=O)Cn2nc(-c3ccncc3)cc2Cc2ccc(F)cc2)CC1)C1CCC1
Reaction time: 0.17 h

Procedure:
To a solution of 1-{[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetyl}piperidin-4-amine (150 mg, 0.38 mmol) in DCM (4 mL) at room temperature was added triethylamine (56 μL, 0.40 mmol) followed by cyclobutanecarbonyl chloride (43 μL, 0.38 mmol) and the solution stirred for 10 minutes. The solution was then loaded directly onto a pre-wetted Biotage 25M column for flash chromatography and eluted with 2-8% MeOH/DCM to yield the title compound as a white solid, 138 mg, 76%. 1H NMR (400 MHz, DMSO-D6) δ ppm 8.43-8.56 (2 H, m), 7.60-7.70 (3 H, m), 7.24-7.35 (2 H, m), 7.09-7.21 (2 H, m), 6.51 (1 H, s), 5.09-5.31 (2 H, m), 4.13 (1 H, d, J=13.39 Hz), 3.93 (2 H, s), 3.70-3.88 (2 H, m), 3.15 (1 H, t, J=11.37 Hz), 2.89-3.04 (1 H, m), 2.69-2.82 (1 H, m), 2.03-2.17 (2 H, m), 1.93-2.03 (2 H, m), 1.81-1.92 (1 H, m), 1.66-1.80 (3 H, m,) 1.29-1.48 (1 H, m), 1.13-1.27 (1 H, m); m/z (APCI+) for C27H30N5O2F 476.2 (M+H)+.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CS(O[C@H:10]1[CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])[C@H:12]([C:28]([C:30]2[N:31]=[CH:32][N:33]3[CH:37]=[CH:36][S:35][C:34]=23)=[O:29])[CH2:11]1)(=O)=O.O>CN(C=O)C>[N:1]([C@@H:10]1[CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])[C@H:12]([C:28]([C:30]2[N:31]=[CH:32][N:33]3[CH:37]=[CH:36][S:35][C:34]=23)=[O:29])[CH2:11]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)c2ncn3ccsc23)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@H]1C[C@@H](C(=O)c2ncn3ccsc23)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 100 °C
Reaction time: 13 h
Yield: 96.2 %

Procedure:
Sodium azide (87 mg) was added to a solution of 552 mg of 7-[(2S,4R)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-2-yl]carbonylimidazo[5,1-b]thiazole in 5 ml of DMF, and the mixture was stirred at 100° C. for 13 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate, followed by washing three times with brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was then removed by distillation to give 474 mg of a crude product of 7-[(2S,4S)-4-azido-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-2-yl]carbonylimidazo[5,1-b]thiazole.
Reaction SMILES: CO[CH:3](OC)[C:4]1[CH:15]=[CH:14][C:7](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=1.[CH:18]1([CH2:24][N:25]2[C:32]([NH2:33])=[C:31]([NH2:34])[C:29](=[O:30])[N:28]([CH2:35][CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)[C:26]2=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)(=O)C>[CH:36]1([CH2:35][N:28]2[C:29](=[O:30])[C:31]3[N:34]=[C:3]([C:4]4[CH:5]=[CH:6][C:7](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[CH:14][CH:15]=4)[NH:33][C:32]=3[N:25]([CH2:24][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:26]2=[O:27])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]1
Reactant: Nc1c(N)n(CC2CCCCC2)c(=O)n(CC2CCCCC2)c1=O
Reactant: COC(=O)/C=C/c1ccc(C(OC)OC)cc1
Solvent: CC(=O)O
Product: COC(=O)/C=C/c1ccc(-c2nc3c(=O)n(CC4CCCCC4)c(=O)n(CC4CCCCC4)c3[nH]2)cc1

Procedure:
(E)-Methyl 4-(dimethoxymethyl)cinnamate (from step (a)) was used in place of 4-formylcinnamic acid in the procedure described in step (d) of Example 1, except that a drop of acetic acid was added during the formation of the Schiff base with 1,3-bis(cyclohexylmethyl)-5,6-diaminouracil. Title compound was formed as a white powder, m.p. >270° C.; 1H-NMR (DMSO-d6) consistent with structure.
Reaction SMILES: C([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[C:30](OC)=[CH:31][CH:32]=[C:33](C)[C:7]=2[N:6]=1)CCC>C(Cl)Cl.C(O)C>[N:9]1([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[CH:31][CH:32]=[CH:33][C:7]=2[N:6]=[CH:5]1
Reactant: CCCCc1nc2c(C)ccc(OC)c2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)OC(=O)c1ccccc1-c1ccc(Cn2cnc3ccccc32)cc1

Procedure:
tert.butyl 4'-[(2-n-butyl-7-methoxy-4-methyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate oil, Rf value: 0.50 (Silica gel: methylene chloride/ethanol=19:1)