Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16]C3C(=O)[N:13]([CH2:18][C:19]([C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[CH2:26][CH:25]([NH:30][CH3:31])[CH2:24]5)=[O:20])[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[C:32](Cl)(=[O:34])[CH3:33].C(N(CC)CC)C.[O:43]1CC[CH2:45][CH2:44]1>C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:33]3[C:32](=[O:34])[N:13]([CH2:18][C:19]([C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[CH2:26][CH:25]([N:30]([CH3:31])[C:44](=[O:43])[CH3:45])[CH2:24]5)=[O:20])[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: C1CCOC1
Reactant: CNC1Cc2ccc(C(=O)Cn3cnc4cc(-c5ccc(Cl)cc5)sc4c3=O)cc2C1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)N(C)C1Cc2ccc(C(=O)Cn3cnc4cc(-c5ccc(Cl)cc5)sc4c3=O)cc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of the compound (27 mg) obtained in Example 16, acetyl chloride (5.2 mg), triethylamine (9.2 mg) and tetrahydrofuran (1 ml) was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate and water, and the precipitate was collected by filtration to give the title compound (29 mg) as a colorless powder.
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([CH3:11])[C:5]=1[OH:12].[Cl:14]OC(C)(C)C.CCCCCC>C(OCC)(=O)C>[Cl:14][C:8]1[C:7]([OH:10])=[C:6]([CH3:11])[C:5]([OH:12])=[C:4]([CH:9]=1)[C:3]([OH:2])=[O:13]
Reactant: COC(=O)c1ccc(O)c(C)c1O
Reactant: CC(C)(C)OCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(O)c(Cl)cc(C(=O)O)c1O
Reaction time: 2 h
Yield: 37 %

Procedure:
To a solution of 2,4-dihydroxy-3-methylbenzoic acid methyl ester (9.9 g) in ethyl acetate (100 ml) was added tert-butyl hypochlorite (12.3 ml) under ice-cooling. After stirring for 2 hours, hexane (200 ml) was added, and the mixture was cooled with ice to allow precipitation of crystals. The crystals were collected by filtration, and dissolved in a mixed solvent of methanol (20 ml) and tetrahydrofuran (THF, 20 ml). A 1M lithium hydroxide solution (40 ml) was added to the solution, and the mixture was refluxed under heating for 18 hours. The reaction mixture was concentrated, and a 10% aqueous citric acid solution was added to the residue, which was followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure to give the title compound (4.14 g, yield 37%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([C:11]1[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=1[NH2:13])[CH2:9][CH3:10].CN1CCN(C)C1=O.O.C(O[CH:30](OCC)[N:31]1[CH2:35][CH2:34][NH:33][C:32]1=[N:36][N+:37]([O-:39])=[O:38])C>>[CH2:8]([C:11]1[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=1[N:13]=[CH:30][N:31]1[CH2:35][CH2:34][NH:33][C:32]1=[N:36][N+:37]([O-:39])=[O:38])[CH2:9][CH3:10]
Reactant: CCOC(OCC)N1CCNC1=N[N+](=O)[O-]
Reactant: CCCc1ccccc1N
Solvent: CN1CCN(C)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCCc1ccccc1N=CN1CCNC1=N[N+](=O)[O-]
Reaction time: 0.75 h
Yield: 31.7 %

Procedure:
0.05 g of trifluoroacetic acid was dropped in a mixture of 5.0 g of 1-diethoxymethyl-2-nitroiminoimidazolidine, 2.48 g of o-n-propylaniline and 2 ml of 1,3-dimethyl-2-imidazolidinone at 90° C., followed by agitation at the same temperature for 45 minutes. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried and evaporated. Ether was added to the resultant oily residue and the resultant crystals were separated by filtration and dried to give 1.6 g of 1-(2-n-propylphenyliminomethyl)-2-nitroiminoimidazolidine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([OH:14])[CH2:11][CH2:10][N:9]([O:12][CH3:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].CN(C)C1C=CN=CC=1.CN(C1C=CN=CC=1)C.[CH3:33][C:34]1[CH:39]=[C:38]([CH3:40])[CH:37]=[C:36]([CH3:41])[C:35]=1[CH2:42][C:43](Cl)=[O:44]>N1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1([O:14][C:43](=[O:44])[CH2:42][C:35]2[C:34]([CH3:33])=[CH:39][C:38]([CH3:40])=[CH:37][C:36]=2[CH3:41])[CH2:7][CH2:8][N:9]([O:12][CH3:13])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: Cc1cc(C)c(CC(=O)Cl)c(C)c1
Reactant: CCOC(=O)C1(O)CCN(OC)CC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCOC(=O)C1(OC(=O)Cc2c(C)cc(C)cc2C)CCN(OC)CC1
Temperature: 0 °C
Reaction time: 72 h

Procedure:
To a solution of 4-hydroxy-1-methoxy-piperidine-4-carboxylic acid ethyl ester (0.5 g, 2.46 mmol) in 15 ml pyridine under argon was added 4-dimethylaminopyridine DMAP (0.11 g, 0.9 mmol). The solution was cooled down to 0° C., then (2,4,6-trimethylphenyl)-acetyl chloride (0.58 g, 2.95 mmol) was added dropwise. The reaction mixture was warmed up to room temperature and left stirring for 3 days. Then the reaction mixture was concentrated and cold (0° C.) water was added. The aqueous phase was thoroughly extracted three times with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography on silica gel (ethyl acetate/cyclohexane 1:4) to give pure 1-methoxy-4-[2-(2,4,6-trimethyl-phenyl)-acetoxy]-piperidine-4-carboxylic acid ethyl ester (compound P3.6) as light yellow oil. Yield: 610 mg.
Reaction SMILES: [NH2:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]3[C:14]([C:5]2=[N:4][C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])=[CH:13][CH:12]=[CH:11][CH:10]=3.[H-].[Na+].CCCCCC.Br[CH:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH3:32]>CN(C)C=O.O>[CH3:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:3]1[N:4]=[C:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7][N:6]2[C:2]=1[NH:1][CH:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH3:32]
Reactant: CC(Br)c1ccccc1
Reactant: Cc1ccccc1-c1nc2c3ccccc3ccn2c1N
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccccc1-c1nc2c3ccccc3ccn2c1NC(C)c1ccccc1
Reaction time: 1 h
Yield: 76.8 %

Procedure:
A solution of 5.0 g of 3-amino-2-(2-methylphenyl)imidazo[2,1-a]isoquinoline (Compound 3) in 30 ml of dry N,N-dimethylformamide was added dropwise to a solution of 1.2 g of sodium hydride in oil (prewashed with hexane) in 10 ml of dry N,N-dimethylformamide over 30 minutes under dry argon atmosphere at room temperature. After the mixture was stirred for further 1 hour, a solution of 4.1 g of (1-bromoethyl)benzene in 30 ml of dry N,N-dimethylformamide was added dropwise. When addition was complete, the mixture was stirred at room temperature for 1 hour. The solution was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel, and recrystallized from benzene/hexane to give 5.3 g of the title compound as colorless needles.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([N+:18]([O-])=O)=[C:16]([CH3:17])[C:11]=2[N:10]=[CH:9]1)=[O:7])([CH3:4])(C)C.[C:21](OCC)(=O)[CH3:22].C([O-])=O.[NH4+]>CO.[Pd]>[NH2:18][C:15]1[CH:14]=[CH:13][C:12]2[N:8]([C:6]([O:5][CH2:1][CH2:4][CH2:21][CH3:22])=[O:7])[CH:9]=[N:10][C:11]=2[C:16]=1[CH3:17]
Reactant: Cc1c([N+](=O)[O-])ccc2c1ncn2C(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCCCOC(=O)n1cnc2c(C)c(N)ccc21
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of 1-tert-butoxycarbonyl-4-methyl-5-nitrobenzimidazole (8 g) in methanol (40 mL)/ethyl acetate (400 mL) is added palladium-on-carbon (Pd/C) (10%, 0.5 g) and ammonium formate (7.27g). The mixture is stirred at 50° C. for 2 hours, then filtered on Celite, with methanol wash of the solids. The filtrate is rotary evaporated and the residue partitioned between water and ethyl acetate. The organic layer is washed with saturated ammonium chloride, dried over magnesium sulfate, filtered and rotary evaporated to afford pure 5-amino-1-1-butoxycarbonyl-4-methylbenzimidazole as an off-white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH3:42])[C:6]([C:16]#[C:17][CH2:18][C:19]([OH:41])([C:37]([F:40])([F:39])[F:38])[CH2:20][C:21]([C:24]2[C:32]3[O:31][CH2:30][CH2:29][C:28]=3[CH:27]=[C:26]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:25]=2)([CH3:23])[CH3:22])=[C:7]([NH:9]C(=O)C(F)(F)F)[CH:8]=1)#[N:2].CN(C)C(N(C)C)=N.C(OCC)(=O)C>CS(C)=O.ClCCl>[OH:41][C:19]([C:37]([F:39])([F:40])[F:38])([CH2:20][C:21]([C:24]1[C:32]2[O:31][CH2:30][CH2:29][C:28]=2[CH:27]=[C:26]([S:33]([CH3:36])(=[O:34])=[O:35])[CH:25]=1)([CH3:22])[CH3:23])[CH2:18][C:17]1[NH:9][C:7]2[C:6]([CH:16]=1)=[C:5]([CH3:42])[CH:4]=[C:3]([C:1]#[N:2])[CH:8]=2
Reactant: Cc1cc(C#N)cc(NC(=O)C(F)(F)F)c1C#CCC(O)(CC(C)(C)c1cc(S(C)(=O)=O)cc2c1OCC2)C(F)(F)F
Agent: CN(C)C(=N)N(C)C
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc(C#N)cc2[nH]c(CC(O)(CC(C)(C)c3cc(S(C)(=O)=O)cc4c3OCC4)C(F)(F)F)cc12
Yield: 17.7 %

Procedure:
A solution of N-{5-cyano-2-[4-hydroxy-6-(5-methanesulfonyl-2,3-dihydrobenzofuran-7-yl)-6-methyl-4-trifluoromethylhept-1-ynyl]-3-methylphenyl}-2,2,2-trifluoroacetamide (154 mg, 0.25 mmol) in 0.6 mL of anhydrous DMSO was heated in the presence of 1,1,3,3-tetramethylguanidine (0.094 mL, 0.75 mmol) in a microwave at 140° C. for 10 minutes. The reaction was quenched with a mixture of 1 N sulfuric acid and 10 mL of crushed ice. The resulting precipitate was filtered, washed with water, and dried. Preparative TLC chromatography (50% ethyl acetate in hexanes, followed by 15% ethyl acetate in dichloromethane) gave 23 mg of the title product as an off-white solid (18% yield).
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:20])/[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[C:9]([O:21][CH3:22])[C:8]([CH3:23])=[C:7]2[C:3]=1[C:4](=[O:24])[O:5][CH2:6]2.[C:25](N1C=CN=C1)(N1C=CN=C1)=[O:26].O>C(O)=O>[CH:25]([NH:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:20])/[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[C:9]([O:21][CH3:22])[C:8]([CH3:23])=[C:7]2[C:3]=1[C:4](=[O:24])[O:5][CH2:6]2)=[O:26]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)CC/C(C)=C/Cc1c(N)c2c(c(C)c1OC)COC2=O
Solvent: O=CO
Solvent: O
Product: COC(=O)CC/C(C)=C/Cc1c(NC=O)c2c(c(C)c1OC)COC2=O
Yield: 66.4 %

Procedure:
A solution of methyl (E)-6-(1,3-dihydro-4-amino-6-methoxy-7-methyl-3- oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate (0.32g, 1 mmol) in 3ml formic acid was cooled to 0° C. and treated with 0.45g of carbonyldiimidazole. After 1 hour water was added and the precipitate collected by filtration. This material was recrystallized from isopropanol to give 0.24g of methyl (E)-6-[1,3-dihydro-4-formamido-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl]-4-methyl-4-hexenoate, as a white solid, mp 187°-189° C.
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[C:9]([CH:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=3)[C:11]=1[C:12]#[N:13])=[CH:8][CH:7]=[C:6]1[C:25]([NH2:29])=[CH:26][CH:27]=[CH:28][C:5]=21.[C:30](=O)([O-])[O-].[K+].[K+].IC>C(#N)C.O>[NH2:1][C:2]1[O:3][C:4]2[C:9]([CH:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=3)[C:11]=1[C:12]#[N:13])=[CH:8][CH:7]=[C:6]1[C:25]([NH:29][CH3:30])=[CH:26][CH:27]=[CH:28][C:5]=21
Reactant: O=C([O-])[O-]
Reactant: COc1cc(C2C(C#N)=C(N)Oc3c2ccc2c(N)cccc32)cc(Br)c1OC
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CC#N
Product: CNc1cccc2c3c(ccc12)C(c1cc(Br)c(OC)c(OC)c1)C(C#N)=C(N)O3
Reaction time: 1 h
Yield: 90.1 %

Procedure:
2,7-Diamino-4-(3-bromo-4,5-dimethoxy-phenyl)-4H-benzo[h]chromene-3-carbonitrile (10) (45 mg, 0.1 mmol) and potassium carbonate (14 mg, 0.1 mmol) were taken in dry acetonitril (5 ml) at room temperature, stirred for 1 h, charged with iodomethane (15.6 mg, 0.11 mmol) and stirred further at room temperature under LC-MS control. The reaction mixture was diluted with water (10 ml) under stirring, stirred further at room temperature for 2 h, the precipitates were collected by filtration, washed with water and dried to get the title compound (42 mg, 89.9%).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[CH2:16]([C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[CH3:38][N:39]([CH3:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>O1CCOCC1>[CH2:16]([C:28]1[CH:33]=[CH:32][C:31]([S:34]([O-:36])(=[O:7])=[O:35])=[CH:30][CH:29]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N+:39]([CH3:46])([CH3:38])[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:4][CH:3]=1
Reactant: CN(C)c1ccccc1
Reactant: CCCCCCCCCCCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc(CO)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCCCCCCCCCCCc1ccc(S(=O)(=O)[O-])cc1
Product: Cc1ccc(C[N+](C)(C)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 53 %

Procedure:
12.21 g (0.1 mol) of 4-methylbenzylalcohol was dissolved in 60 g of 1,4-dioxane, and was added while cooling to 11.22 g (0.1 mol) of potassium t-butoxide. The solution was added dropwise to a solution of 34.5 g (0.1 mol) of 4-dodecylbenzenesulfonyl chloride in 1,4-dioxane over one hour. Subsequently, 12.12 g (0.1 mol) of N,N-dimethylaniline was added and stirred at room temperature for 16 hours. After the completion of the reaction, the mixture was filtered and concentrated, and the precipitated solid was washed with ether and dried to give the titled compound. Yield: 53%.
Reaction SMILES: C(Cl)(=O)[C:2](Cl)=[O:3].[C:7]([NH2:17])([C:13]([F:16])([F:15])[F:14])([C:9]([F:12])([F:11])[F:10])[Cl:8].[N-]=C=O>N1C=CC=CC=1>[Cl:8][C:7]([N:17]=[C:2]=[O:3])([C:9]([F:12])([F:11])[F:10])[C:13]([F:14])([F:15])[F:16]
Reactant: NC(Cl)(C(F)(F)F)C(F)(F)F
Reactant: O=C(Cl)C(=O)Cl
Agent: [N-]=C=O
Solvent: c1ccncc1
Product: O=C=NC(Cl)(C(F)(F)F)C(F)(F)F
Reaction time: 4 h

Procedure:
A mixture of 127 g (1 mole) of oxalyl chloride, 165 g (1 mole) of perfluoropropyliden-2-imine, and 5 ml of pyridine was heated in a 600 ml Hastelloy tube at 100° for 4 hrs, 105° for 4 hrs, and 200° for 4 hrs. The bomb was cooled and vented, and the contents were filtered to remove suspended solid. Distillation gave 102.3 g of a 25:75 mixture of (CF3)2CClNH2 and the isocyanate, bp 46.0°-46.5°, and 29.3 g of pure isocyanate as a colorless liquid: bp 50.5°-51.0°; 19F nmr (CCl3F) ε 78.0 (s); ir (liquid) 4.40 μ.
Reaction SMILES: [CH2:1]([S:15][CH3:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[Cl:17]Cl.[C:19]1([OH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[Cl-:17].[OH:25][C:19]1[CH:24]=[CH:23][C:22]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][SH+:15][CH3:16])=[CH:21][CH:20]=1
Reactant: ClCl
Reactant: CCCCCCCCCCCCCCSC
Reactant: Oc1ccccc1
Product: C[SH+]CCCCCCCCCCCCCCc1ccc(O)cc1
Product: [Cl-]

Procedure:
(4-hydroxyphenyl)n-tetradecylmethyl sulfonium chloride was prepared using as reactants n-tetradecylmethyl sulfide, chlorine and phenol according to the general procedure described in French patent 1,377,019. The product has a melting point of 136.2° - 137.2° C. and the structure was confirmed by elemental and NMR analyses.
Reaction SMILES: [F:1][C:2]1[C:7]2[NH:8][CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([C:11]([OH:13])=O)[C:3]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=1[CH3:22].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=[CH:53][CH:54]=[CH:55][C:50]2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.Cl.C1([N:69](C)[OH:70])CC1>C1COCC1.C(Cl)Cl>[CH:54]1([CH2:53][O:70][NH:69][C:11]([C:4]2[C:3]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=3[CH3:22])=[C:2]([F:1])[C:7]3[NH:8][CH:9]=[N:10][C:6]=3[CH:5]=2)=[O:13])[CH2:55][CH2:50]1
Reactant: CN(O)C1CC1
Reactant: Cc1cc(Br)ccc1Nc1c(C(=O)O)cc2nc[nH]c2c1F
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(Br)ccc1Nc1c(C(=O)NOCC2CC2)cc2nc[nH]c2c1F
Yield: 43.7 %

Procedure:
7-Fluoro-6-(4-bromo-2-methyl-phenylamino)-1H-benzoimidazole-5-carboxylic acid 10a (48 mg, 0.132 mmol) is dissolved in 1:1 THF: methylene chloride (1 mL) and Hunig's base (0.23 μl, 1.32 mmol) is added followed by PyBOP (82 mg, 0.158 mmol). After a few minutes, cyclopropyl methyl hydroxylamine hydrochloride (20 mg, 0.158 mmol) (WO 0042022) is added. After the reaction is complete, the mixture is partitioned between methylene chloride and saturated NaHCO3 solution. The layers are separated and the organic layer is washed with saturated NaHCO3 and brine. The organic layer is dried (Na2SO4) and concentrated under reduced pressure. After purification by FCC (elute with 20:1 methlene chloride:MeOH), 25 mg (45%) of pure desired product is isolated: MS ESI (+) m/z 435, 433 (M+1 Br pattern) detected; MS ESI (−) m/z 433, 431 (M−1 Br pattern) detected; 1H NMR (400 MHz, CDCl3) δ 8.15 (s, 1H), 8.02 (s, 1H), 7.28 (s, 1H), 7.43 (d, 1H), 7.07 (dd, 1H), 6.36 (m, 1H), 3.70 (d, 2H), 2.38 (s, 3H), 0.86 (m, 1H), 0.41 (m, 2H), 0.13 (m, 2H); 19F NMR (376 MHz, CDCl3) −134.05 (s).
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[F:27][C:28]1([F:34])[CH2:30][CH:29]1[C:31](O)=[O:32]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:31]([CH:29]5[CH2:30][C:28]5([F:34])[F:27])=[O:32])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: O=C(O)C1CC1(F)F
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1)C1CC1(F)F

Procedure:
The title compound, light yellow solid (79 mg, 73%), MS (ISP) m/z=433.4 [(M+H)+], mp 199° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 2,2-difluoro-cyclopropane-carboxylic acid.
Reaction SMILES: [OH:1][B:2]([OH:16])[CH2:3][CH2:4][CH2:5][CH2:6]N1C=C(C)C(=O)NC1=O.[NH2:17][C:18]1[N:26]=[C:25]2[C:21]([NH:22][CH:23]=[N:24]2)=[C:20]([Cl:27])[N:19]=1.BrCCCCB(O)O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:17][C:18]1[N:26]=[C:25]2[C:21]([N:22]=[CH:23][N:24]2[CH2:6][CH2:5][CH2:4][CH2:3][B:2]([OH:16])[OH:1])=[C:20]([Cl:27])[N:19]=1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Reactant: Cc1cn(CCCCB(O)O)c(=O)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: OB(O)CCCCBr
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(Cl)c2ncn(CCCCB(O)O)c2n1
Yield: 56 %

Procedure:
The title compound was synthesized in a similar manner as the compound of Example 1 with 2-amino-6-chloropurine (1.36 g, 8 mmol), 4-bromobutyl boronic acid (1.45 g, 8 mmol), and potassium carbonate (1.66 g, 12 mmol) in dimethylformamide (20 mL). Yield 56%; Wt. 1.2 g; mp 154°-156° C.; 1H NMR (DMSO-d6) 0.55-0.68 (t, B CH2), 1.20-1.32 (m, B CH2 CH2), 1.68-1.77 (m, B CH2 CH2 CH2), 4.00-4.08 (t, CH2 CH2 N), 6.85-6.92 (s, H2N C2 purine), 7.40-7.42 (s, (HO)2 B), 8.10-8.12 (s, H C8 purine). Electrospray Mass Spectrum (MH)+ (low resolution); Calcd. 270.09 (C9H13O2N5BCl); Found 270.10 (37 ppm).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:14])[CH:10]([CH3:13])[CH2:11][CH3:12])=[CH:5][CH:4]=1.[OH-:15].[Na+]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].C(Cl)(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[OH:15][C:10]([CH3:13])([CH2:11][CH3:12])[C:9]([C:6]1[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1)=[O:14]
Reactant: [OH-]
Reactant: CCC(C)C(=O)c1ccc(SC)cc1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCC(C)(O)C(=O)c1ccc(SC)cc1

Procedure:
To a mixture of the ketone from Step 1 (10 g, 48 mmol) and Aliquat® 336 (20 mL) in CCl4 (40 mL) and toluene (80 mL) at r.t. was added NaOH pellets (3.8 g, 96 mmol). While stirring vigourously, the mixture was heated briefly to reflux and was then stirred overnight at r.t. After partitioning between CH2Cl2 and H2O, the whole was filtered through celite. The organic layer was dried (MgSO4), filtered, and evaporated. The residue was purified by flash chromatography (1:10 EtOAc: hexane) to give the title compound as a syrup (5.5 g).
Reaction SMILES: [C:1]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:23][C:24]1[N:25]=[C:26]([C:30]2[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=2)[O:27][C:28]=1[CH3:29]>CN(C)C=O>[C:12]([O:11][C:1](=[O:10])[CH:2]([C:3]([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4])[CH2:23][C:24]1[N:25]=[C:26]([C:30]2[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=2)[O:27][C:28]=1[CH3:29])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(-c2nc(CCl)c(C)o2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2nc(CC(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(C)o2)cc1
Temperature: 65 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
A mixture of di-tert-butyl malonate (4.3 g, 19.91 mmol, 1.99 equiv) and potassium carbonate (2.8 g, 20.29 mmol, 2.03 equiv) in N,N-dimethylformamide (30 mL) was stirred at 65° C. for 30 min A solution of methyl 4-(4-(chloromethyl)-5-methyloxazol-2-yl)benzoate (2.65 g, 10.00 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL) was then added dropwise with stiffing to the reaction mixture. The resulting solution was stirred at 65° C. overnight and then quenched with 60 mL of ice and water. The mixture was extracted with 2×50 mL of ethyl acetate. The combined organic layers was washed with 3×30 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 4.0 g (90%) of methyl 4-(4-(3-tert-butoxy-2-(tert-butoxycarbonyl)-3-oxopropyl)-5-methyloxazol-2-yl)benzoate as a light yellow solid. LC-MS: (ES, m/z): 446 [M+H]+, 390, 334, 272, 230, 115.
Reaction SMILES: Br.[O:2]1[C:8]2[C:9]([OH:13])=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[O:21](C(OC(C)(C)C)=O)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=O>ClCCl>[OH:13][C:9]1[C:8]2[O:2][CH2:3][CH2:4][N:5]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:21])[CH2:6][C:7]=2[CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Oc1cccc2c1OCCNC2
Agent: Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCOc2c(O)cccc2C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 100.9 %

Procedure:
A suspension of 2,3,4,5-tetrahydro-1,4-benzoxazepin-9-ol. hydrobromide (Preparation 85) (55.7 g, 226 mmol) in dichloromethane (DCM) (550 ml) was treated with triethylamine (47.3 ml, 339 mmol) and stirred for 20 minutes. This mixture was cooled in ice/water to ca 5° C. and treated slowly with a solution of BOC2O (59.6 ml, 249 mmol) in dichloromethane (DCM) (200 ml) at such a rate as to keep the internal temperature below 10° C. When the addition was complete, the mixture was allowed to warm to room temperature, stirred for 2 hours and allowed to stand at room temperature overnight. The mixture was washed with 0.5M hydrochloric acid (2×250 ml) and water (250 ml), dried (sodium sulphate) and evaporated to give the title compound as a pale brown solid (60.5 g)