Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)[CH:3]=[CH:4][N+:5]([O-:7])=[O:6].BrBr.[NH2:11][C:12]([NH2:14])=[S:13].[OH-].[NH4+]>C(O)(=O)C.O>[NH2:11][C:12]1[S:13][C:4]([N+:5]([O-:7])=[O:6])=[CH:3][N:14]=1
Reactant: CN(C)C=C[N+](=O)[O-]
Reactant: NC(N)=S
Agent: BrBr
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Nc1ncc([N+](=O)[O-])s1
Temperature: 17 °C
Reaction time: 0.17 h
Yield: 61.7 %

Procedure:
To a stirred mixture of 3.5 g of N,N-dimethyl-2-nitroetheneamine in 25 ml of acetic acid cooled to 17° C. was added 4.8 g bromine at such a rate the reaction temperature did not exceed 25° C. During bromination an orange solid was formed. After stirring the resulting slurry for 10 minutes, 3.0 g thiourea was added and the reaction mixture exothermed to 32° C. A yellow solid formed. The mixture was stirred for 1 hour and then was diluted with 25 ml of water. This mixture and an approximately equal volume of 29% ammonium hydroxide were added simultaneously to 25 ml of acetic acid at such rates that the pH remained between 4 and 5 and the temperature did not exceed 30° C. After all of the reaction mixture had been added the pH was adjusted to 7 with 29% ammonium hydroxide. The product was then filtered off, washed with water and dried to give 2.7 g (62% yield, 92.9% assay) of 2-amino-5-nitrothiazole.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:24]=[CH:23][C:22]([C:25]([OH:27])=O)=[CH:21][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C([Cl:31])=O>C(Cl)(Cl)Cl.CN(C)C=O>[CH:1]1([C:7]2[C:8]3[CH:24]=[CH:23][C:22]([C:25]([Cl:31])=[O:27])=[CH:21][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1ccccc1-3
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=C(Cl)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1ccccc1-3
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
To a solution of 12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid (500 mg, 1.38 mmol) in chloroform (10 ml) were added oxalyl chloride (0.15 ml, 1.66 mmol) and several drops of N,N-dimethylformamide. The mixture was stirred at room temperature for 2 hr and concentrated. Hexane was added to the obtained residue, and the precipitated solid was collected by filtration. The solid was washed with hexane to give 12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl chloride (476 mg, yield 91%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Si:26]([O:33][CH2:34][CH2:35]I)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27].C(OCC)(=O)C>O1CCCC1.CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:16]([CH2:35][CH2:34][O:33][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3[nH]2)CC1
Reactant: CC(C)(C)[Si](C)(C)OCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2CCO[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Combine 2-(t-butyldimethylsilyloxy)ethyl bromide (116.2 g, 486 mmol), and sodium iodide (100 g, 663 mol) in acetone (350 mL) and dimethylformamide (25 mL). Heat to reflux. After 4 hours, cool, filter, and evaporate in vacuo to give a residue. Distill the residue to give 2-(t-butyldimethylsilyloxy)ethyl iodide: bp; 60° C. at 0.5 mm Hg. Combine 1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepane (3.06 g, 9.67 mmol) and sodium hydride (0.43 g, 60% in oil, 10.64 mmol) in tetrahydrofuran (60 mL) and dimethylformamide (6 mL). After 2 hours, add 2-(t-butyldimethylsilyloxy)ethyl iodide (2.78 g, 9.67 mmol). After 20 hours, heat to reflux. After 4 hours, cool to ambient temperature and add ice to quench. Evaporate in vacuo to remove most of the tetrahydrofuran. Partition the evaporated reaction mixture between ethyl acetate (250 mL) and water (200 mL). Separate the layers and extract the organic layer with water. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with ethyl acetate to give 1-(t-butoxycarbonyl)-4-(1-(2-(t-butyldimethylsilyloxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane: Rf =0.58 (silica gel, ethyl acetate).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([C:18]([OH:20])=[O:19])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[CH:1]([N:14]1[CH2:15][CH:16]([C:18]([O:20][CH3:21])=[O:19])[CH2:17]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 20.5 h
Yield: 80.8 %

Procedure:
A solution of 1-benzhydrylazetidine-3-carboxylic acid (4.20 g) in N,N-dimethylformamide (45 ml) were added potassium carbonate (6.53 g) and iodomethane (0.976 ml), followed by stirring at room temperature for 20.5 hr. The reaction mixture was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=5:1, then 3:1). Fractions containing the target compound were concentrated to provide the titled compound as yellow crystals (3.57 g, 80.8%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH:18]1([C:21](Cl)=[O:22])[CH2:20][CH2:19]1.O>N1C=CC=CC=1>[CH:18]1([C:21]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:22])[CH2:20][CH2:19]1
Reactant: O=C(Cl)C1CC1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Solvent: O
Solvent: c1ccncc1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)C4CC4)nc23)CC1
Reaction time: 1.5 h
Yield: 56.7 %

Procedure:
A solution of 0.300 gm (1.30 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine in 40 mL pyridine was heated to 50° C. To this solution was added 0.13 mL (1.43 mMol) cyclopropanecarbonyl chloride and the reaction mixture was stirred for 1.5 hours. An additional 0.10 mL of cyclopropanecarbonyl chloride were added and the reaction mixture was stirred for an additional hour. The reaction mixture was treated with 1.0 mL of water and was then concentrated under reduced pressure. The residue was diluted with 3:1 chloroform: isopropanol and the solution washed sequentially with water, dilute aqueous sodium hydroxide, and saturated aqueous sodium chloride. The organic phase was then dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to radial chromatography (silica gel, 1 mm), eluting with a gradient of dichloromethane (5-10% methanol) containing 1% ammonium hydroxide. Fractions containing product were combined and concentrated under reduced pressure. The residue was recrystallized from ethanol/water to provide 0.22 gm (55.9%) of the title compound as a crystalline solid.
Reaction SMILES: C([Li:5])CCC.[CH:6]([N-:9][CH:10]([CH3:12])[CH3:11])([CH3:8])[CH3:7].[CH2:13]([NH:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH:14]([CH3:16])[CH3:15].CCCC>C1CCCCC1>[CH:6]([N-:9][CH:10]([CH3:12])[CH3:11])([CH3:8])[CH3:7].[Li+:5].[CH2:13]([N-:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH:14]([CH3:16])[CH3:15]
Reactant: [Li]CCCC
Reactant: CC(C)CNCC(C)C
Agent: CC(C)[N-]C(C)C
Solvent: C1CCCCC1
Solvent: CCCC
Product: CC(C)C[N-]CC(C)C
Product: [Li+]

Procedure:
1759 g (7.65 moles) of 24.2% n-butyllithium in cyclohexane is added over a 90- minute period to 3.70 diisopropylamide and 3.70 moles diisobutyl amine containing 0.3 moles tert butyl alcohol in a 5-liter three-necked flask under nitrogen. The mixture was stirred at a temperature of 20°-30° C. Butane gas evolved during the reaction through an oil by bubbler. The reaction was complete upon final addition of the butyllithium solution. The solution was polish filtered. The final product was 2.7M lithium molar mixed lithium diisopropylamide and diisobutylamide with 3% lithium tert butoxide.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[OH:8].C(N(CC)CC)C.[F:16][C:17]1[CH:18]=[N:19][C:20]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([S:33][CH3:34])[CH:28]=2)=[C:21]([CH:25]=1)[C:22](O)=[O:23].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[F:16][C:17]1[CH:18]=[N:19][C:20]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([S:33][CH3:34])[CH:28]=2)=[C:21]([CH:25]=1)[C:22]([NH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[OH:8])=[O:23]
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)O)c1
Reactant: N[C@H]1CCCC[C@H]1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@@H]2CCCC[C@@H]2O)c1
Temperature: 25 °C
Reaction time: 64 h
Yield: 58 %

Procedure:
cis-2-Amino-cyclohexane-1-ol (85 mg, 0.56 mmol) and triethylamine (225 μl, 1.61 mmol) were dissolved in dimethylformamide (225 μl) and a solution of 5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinic acid (150 mg, 0.54 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (113 mg, 0.59 mmol) and 1-hydroxybenzotriazole (80 mg, 0.59 mmol) in dimethylformamide (5 ml) was added. The reaction was stirred under nitrogen at room temperature for 64 h and the solvent was removed under reduced pressure. The residue was partitioned between 0.5N HCl (10 ml) and ethyl acetate (10 ml) and the aqueous phase was extracted with ethyl acetate (2×10 ml). The combined organic phases were washed with brine (10 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with pentane:ethyl acetate (70:30, by volume). The product was triturated with pentane (3 ml) to give 5-fluoro-N-[cis-2-hydroxy-cyclohexyl]-2-(3-methylsulfanyl-phenoxy)-nicotinamide (118 mg) as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:15])[CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][CH:7]=1.[Li+].[OH-].Cl>C1COCC1.O>[C:12]([C:9]1[CH:8]=[CH:7][C:6]([S:5][CH2:4][C:3]([OH:15])=[O:2])=[CH:11][CH:10]=1)(=[O:14])[CH3:13]
Reactant: COC(=O)CSc1ccc(C(C)=O)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1ccc(SCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
(4-Acetyl-phenylsulfanyl)-acetic acid methyl ester (1.48 g, 6.6 mmol) is dissolved in THF (40 ml). To this solution is added LiOH (415 mg, 9.9 mmol) in water (10 ml), and the mixture was stirred at ambient temperature overnight. The mixture was acidified to pH 5 using 1N HCl and then extracted with ethyl acetate (3×25 ml). The combined organic layers were dried over MgSO4 and concentrated in vacuo to yield (4-acetyl-phenylsulfanyl)-acetic acid as a white solid (1.27 g, 91%).
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([NH:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[NH2:24])[CH2:4][CH3:5])[CH3:2].[CH:25](OC)(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([CH:3]([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]2[N:14]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[CH:25]=[N:24][C:8]=12)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Oc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1N
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCC(CC)Oc1cc(C)nc2c1ncn2-c1c(C)cc(C)cc1C

Procedure:
A mixture of 4-(1-ethyl-propoxy)-6-methyl-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,3-diamine, trimethyl orthoformate, p-toluenesulfonic acid monohyrate in toluene was heated at reflux using Dean-Stark apparatus for 24 hours. The mixture was heated at reflux overnight. The mixture was quenched with water, sat. NaHCO3, extracted with ethyl acetate. The organic layer was separated, dried (MgSO4) and concentrated to dryness. After purification, the title compound was isolated. Anal. For C21H29N3O.¼H2O calc. C, 73.76; H, 8.10; N, 12.29; found: C, 73.22; H, 7.96; N, 12.42.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:5]([N:7]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[O:22][CH3:23])[CH3:8])=[O:6].[Br:31]C1C=C(C=C(C(F)(F)F)C=1)C(O)=O>>[Br:31][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:5]([N:7]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[O:22][CH3:23])[CH3:8])=[O:6]
Reactant: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(F)cc(C(F)(F)F)c1
Reactant: O=C(O)c1cc(Br)cc(C(F)(F)F)c1
Product: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(Br)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from 4-(4-fluoro-2-methoxyphenyl)-N-methylpyridin-3-amine (example 129, intermediate) and 3-bromo-5-(trifluoromethyl)benzoic acid after a reaction time of 22 hours. The compound was purified by silica gel chromatography on a 20 g column using an MPLC (ISCO) system eluting with a gradient of n-heptane:EtOAc (100:0 to 20:80). Off-white solid (68%). MS (ESI): m/z=483.03 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].[NH2:28][C:29](=[O:51])[CH2:30][N:31]([C:36]1[CH:37]=[C:38]([CH:46]=[CH:47][C:48]=1[O:49][CH3:50])[C:39]([O:41][CH2:42][C:43](O)=[O:44])=[O:40])[S:32]([CH3:35])(=[O:34])=[O:33].C(Cl)CCl>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[NH2:28][C:29](=[O:51])[CH2:30][N:31]([C:36]1[CH:37]=[C:38]([CH:46]=[CH:47][C:48]=1[O:49][CH3:50])[C:39]([O:41][CH2:42][C:43]([O:10][C@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[CH2:8][C:7]1[C:6]([Cl:26])=[CH:5][N+:4]([O-:27])=[CH:3][C:2]=1[Cl:1])=[O:44])=[O:40])[S:32]([CH3:35])(=[O:34])=[O:33]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: COc1ccc(C(=O)OCC(=O)O)cc1N(CC(N)=O)S(C)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(=O)OCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1N(CC(N)=O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.6 %

Procedure:
(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (30 mg, 0.071 mmol), 2-(3-(N-(2-amino-2-oxoethyl)methylsulfonamido)-4-methoxybenzoyloxy)acetic acid (51.4 mg, 0.143 mmol), DMAP (15 mg, 0.123 mmol), and EDC (100 mg, 0.522 mmol) were dissolved in DMF (2 ml). The reaction was stirred at RT for 3 hours to achieve completion. The reaction mixture was diluted with Water, and the precipitate was washed with water, dissolved in EtOAc and extracted with HCl 1N, Na2CO3 sat. sol. and brine. The organic phase was dried over Na2SO4 and concentrated under vacuum. The crude product was crystallized in EtOH to give (S)-4-(2-(2-(3-(N-(2-amino-2-oxoethyl)methylsulfonamido)-4-methoxybenzoyloxy)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (20 mg, 0.026 mmol, 36.7% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:28][C:12]2=[CH:13][C:14]3[C:15](=[O:27])[N:16]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[C:17](=[O:21])[C:18]=3[C:19]([CH3:20])=[C:11]2[N:10]=1.[F:29][C:30]1[C:35]([F:36])=[CH:34][C:33]([F:37])=[C:32]([F:38])[C:31]=1[CH2:39][CH:40]([NH2:42])[CH3:41].CCN(C(C)C)C(C)C>C(O)CCC>[CH3:25][N:24]([CH3:26])[CH2:23][CH2:22][N:16]1[C:15](=[O:27])[C:14]2[CH:13]=[C:12]3[NH:28][C:9]([C:3]4[C:4](=[O:8])[NH:5][CH:6]=[CH:7][C:2]=4[NH:42][CH:40]([CH3:41])[CH2:39][C:31]4[C:32]([F:38])=[C:33]([F:37])[CH:34]=[C:35]([F:36])[C:30]=4[F:29])=[N:10][C:11]3=[C:19]([CH3:20])[C:18]=2[C:17]1=[O:21]
Reactant: Cc1c2c(cc3[nH]c(-c4c(Cl)cc[nH]c4=O)nc13)C(=O)N(CCN(C)C)C2=O
Reactant: CC(N)Cc1c(F)c(F)cc(F)c1F
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c2c(cc3[nH]c(-c4c(NC(C)Cc5c(F)c(F)cc(F)c5F)cc[nH]c4=O)nc13)C(=O)N(CCN(C)C)C2=O
Yield: 42.8 %

Procedure:
A mixture of 2-(4-chloro-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-(dimethylamino)ethyl)-4-methylimidazo[4,5-f]isoindole-5,7(1H,6H)-dione, (0.54 g, 1.35 mmol), 1-(2,3,5,6-tetrafluorophenyl)propan-2-amine (0.34 g, 1.62 mmol), Hunig's base (0.87 g, 6.75 mmol), and 12 mL of anhydrous 1-butanol was heated at reflux for 13-14 h under an argon atmosphere. Product was purified by a silica gel column using methylene chloride and methanol (9:1 v/v) as eluent to afford 0.33 g of the designed compound as yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 13.33 (s, 1H, NH), 11.29 (br s, 1H, NH), 11.00 (d, J=5.7 Hz, 1H, NH), 7.97 (s, ArH), 7.73-7.70 (m, 1H, ArH), 7.40 (d, J=7.6 Hz, 1H, ArH), 6.21 (d, J=7.6 Hz, 1H, ArH), 4.32-4.28 (m, 1H, CH), 3.65 (t, J=6.3 Hz, 2H, CH2), 3.08 (d, J=5.1 Hz, 2H, CH2), 2.72 (s, 3H, CH3), 2.19 (S, 6H, 2×CH3); 1.36 (d, J=6.3 Hz, 3H, CH3), 1.11 (t, J=6.3 Hz, 2H, CH2); Mass (ESI, negative) m/z 568.8 [M−H]−.
Reaction SMILES: C(O)C.C(=O)([O-])[O-].[K+].[K+].[Br:10][C:11]1[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=1.Br[CH:19]([CH3:21])[CH3:20]>O>[Br:10][C:11]1[CH:12]=[C:13]([O:17][CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=1
Reactant: Oc1cccc(Br)c1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)Oc1cccc(Br)c1
Temperature: 78 °C
Yield: 89.8 %

Procedure:
The following reagents were combined sequentially: anhydrous ethanol (880 ml), potassium carbonate (448.0 g), 3-bromophenol (386.7 g), 2-bromopropane (400.0 g) and finally water (88 ml). The mixture was heated at reflux (78° C.) for 16 hours. Water (880 ml) was added to the reaction mixture and 900 ml of solvent was removed by distillation at atmospheric pressure during a 4 hour period. Heptane (880 ml) was added to the reaction mixture and later separated. The aqueous layer was extracted with heptane (80 ml) and the combined organic fractions were washed sequentially with 1N HCl (300 ml), water (300 ml), 1N NaOH (300 ml) and water (300 ml). Removal of the solvent by rotary evaporation (50° C., 5 mmHg) afforded 453.6 g (97%) of crude product. This was distilled through a short path distillation column (81°-85° C., 2 mmHg) to provide 431.5 g of the product as a colorless liquid.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH2:18]([NH:24][C:25](=[O:37])[NH:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>>[O:4]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][S:33]([C:30]4[CH:29]=[CH:28][C:27]([NH:26][C:25]([NH:24][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:37])=[CH:32][CH:31]=4)(=[O:35])=[O:34])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: CCCCCCNC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(N2CCC3(CC2)OCCO3)cc1
Product: CCCCCCNC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC4(CC3)OCCO4)cc2)cc1

Procedure:
The title compound was prepared from 4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-phenylamine (which was obtained in Example 214) and 4-(3-hexyl-ureido)benzenesulfonyl chloride (U.S. Pat. No. 5,561,142/1996) according to the procedure of Example 215 as a white flake; 1H NMR (300 MHz, DMSO-d6) δ 0.86 (t, J=6.5 Hz, 3 H), 1.20–1.50 (m, 8 H), 1.65 (t, J=5.7 Hz, 4 H), 3.00–3.10 (m, 2 H), 3.14 (t, J=5.7 Hz, 4 H), 3.88 (s, 4 H), 6.28 (t, J=5.6 Hz, 1 H), 6.79 (d, J=9.0 Hz, 2 H), 6.87 (d, J=9.0 Hz, 2 H), 7.45 (d, J=9.1 Hz, 2 H), 7.51 (d, J=9.1 Hz, 2 H), 8.82 (s, 1 H); MS (ES) m/z: 517.2 (MH+); HRMS Calcd. for C26H37N4O5S (MH+): 517.2485. Found: 517.2377. Anal. Calcd. for C26H36N4O5S: C, 60.44; H, 7.02; N, 10.84. Found: C, 60.29; H, 6.95; N, 10.91.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1C=O.[C:11](=O)([O-])[O-].[K+].[K+].CN(C=O)C.[CH2:22]([O:24][C:25](=[O:28])[CH2:26][SH:27])[CH3:23]>O>[CH2:22]([O:24][C:25]([C:26]1[S:27][C:3]2[CH:6]=[C:7]([F:10])[CH:8]=[CH:9][C:2]=2[CH:11]=1)=[O:28])[CH3:23]
Reactant: CCOC(=O)CS
Reactant: O=Cc1cc(F)ccc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2ccc(F)cc2s1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To a mixture of 2,5-difluorobenzaldehyde (280 g, 1.97 mol), potassium carbonate (272 g, 1.97 mol) and anhydrous DMF (1260 ml) was added mercaptoacetic acid ethyl ester (236 g, 1.97 mol). The mixture was stirred at 90° C. for 4 h. After cooling water (4200 ml) was added and the solution was extracted with ethyl acetate (3×1500 ml), the combined extracts dried over sodium sulfate and the solvent was removed to give crude product, which was flash-chromatographed (eluent-ethyl acetate (1):hexane (9). Yield of 6-fluoro-benzo[b]thiophene-2-carboxylic acid ethyl ester 96.49 g (21.8%) as a yellow solid. 1H-NMR (400 MHz, CDCl3); δ (ppm): 1.40 (t, 3H), 4.40 (q, 2H), 7.15 (t, 1H), 7.52 (d, 1H), 7.81 (dd, 1H), 8.00 (s, 1H).
Reaction SMILES: [C@@H:1]1([N:10]2[C:20]3[N:19]=[C:17]([NH2:18])[NH:16][C:14](=[O:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].C[Si](Cl)(C)C.[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](Cl)=[O:35])=[CH:29][CH:28]=1.[NH3:37]>N1C=CC=CC=1.O>[N:37]#[N:10].[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]([C@@:1]2([N:10]3[C:20]4[N:19]=[C:17]([NH2:18])[NH:16][C:14](=[O:15])[C:13]=4[N:12]=[CH:11]3)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]2[OH:3])=[O:35])=[CH:29][CH:28]=1
Reactant: N
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Agent: C[Si](C)(C)Cl
Solvent: c1ccncc1
Solvent: O
Product: N#N
Product: Nc1nc2c(ncn2[C@]2(C(=O)Cc3ccc(F)cc3)O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Guanosine 5 (7.08 g, 25 mmoles) was dried three times by coevaporation with dried pyridine and suspended in 140 ml of dry pyridine. To this was added trimethylsilyl chloride (24 ml, 180 mmoles) at room temperature. After the solution was stirred for 1 hour at room temperature, 4-fluorophenylacetyl chloride (13.9 g, 80 mmoles) was added dropwise and the solution stirred for 15 hours. The reaction mixture was then cooled in an ice bath and 20 ml of cold water was added. After 30 minutes 20 ml of 29% aqueous ammonia was added and the mixture stirred for 30 minutes. The solution was then evaporated to near dryness and the residue dissolved in 300 ml water and 300 ml methylene chloride. The product crystallized out of the solution upon extraction with CH2Cl2 was filtered off, washed with CH2Cl2 (3×70 ml) and ether (5×70 ml) and air dried to yield 6 g (57%) of Ribo GFPA 6b. The product was characterized as following: m.p. 160°-170° C. (dec.); UV (EtOH): λ max 280 nm and 258 nm; IR (KBr): ν 1687 (vs, br, C=O of amides), 3000-3500 (NH, OH) cm-1. 1H-NMR (DMSO-d6): δ 3.36 (m, 2H, C5, CH2), 3.79 (s, 2H, CH2C6H4), 3.91(m, 1H, C4, H), 4.13 (m, 1H, C3, H), 4.42(m, 1H, C2, H), 5.81 (t, 1H, J1',2' =5.64 Hz, C1, H), 7.15-7.37 (m, 4H, C6H4), 8.27 (d, 1H, C8H), 11.91 and 11.97 (2s, 2H, 2×NHCO).