Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:13]=2)=[N:5][C:4]([NH2:25])=[N:3]1.[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31](Cl)=[O:32]>N1C=CC=CC=1>[CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:13]=2)=[N:5][C:4]([NH:25][C:31]([C:27]2[O:26][CH:30]=[CH:29][CH:28]=2)=[O:32])=[N:3]1
Reactant: Cn1nc(N)nc1NCCCOc1cccc(CN2CCCCC2)c1
Reactant: O=C(Cl)c1ccco1
Solvent: c1ccncc1
Product: Cn1nc(NC(=O)c2ccco2)nc1NCCCOc1cccc(CN2CCCCC2)c1
Yield: 23.6 %

Procedure:
A solution of 1-methyl-N5 -[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-1H-1,2,4-triazole-3,5-diamine (A) (1.0 g) and 2-furancarboxylic acid, chloride (0.42 g) in pyridine (25 ml) was kept at ambient temperature for 1 h. The pyridine was evaporated in vacuo and the residue was azeotropically distilled with toluene to give an oil which was partitioned between ethyl acetate and 2 M hydrochloric acid. The pH of the aqueous extract was adjusted to pH 9 and it was extracted with ethyl acetate. The organic extracts were evaporated to a gum which was chromatographed on silica using ethyl acetate: methanol (9:1) to give the title compound (0.30 g) as a glassy solid. tlc System B, Rf 0.57. Nmr (CDCl3) 1.5,brs, (1H); 2.53,m, (1H); 2.75,t+m, (2H); 3.0-3.3,m, (3H); 3.5,dd (1H); 5.31,t, (1H); 5.92,t, (2H); 6.42,q, (2H); 6.50,s, (3H); 6.59,s, (3H); 7.6,brs; (4H); 7.9,m, (2H); 8.5,m, (6H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=2[F:42])=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].O>C(COC)OC.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>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:33]=[CH:32][C:31]([S:34][C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=3[F:42])=[CH:30][CH:29]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1
Reactant: Fc1ccc(Sc2ccc(Br)cc2)c(F)c1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(Sc3ccc(F)cc3F)cc2)c1C
Yield: 32.9 %

Procedure:
A stirred solution of [6-fluoro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.2 g, 0.55 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.032 g, 0.028 mmol), impure 1-(4-bromo-phenylsulfanyl)-2,4-difluorobenzene (0.184 g) and 1.0 M aqueous sodium bicarbonate (5 mL, 5 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then brought to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (0-3% ethyl acetate in hexanes) to give {4-[4-(2,4-difluoro-phenylsulfanyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.082 g, 33%) as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](OS(C)(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19]([O-:22])(=[S:21])[CH3:20].[K+]>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([S:21][C:19](=[O:22])[CH3:20])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC([O-])=S
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)SC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 4 h
Yield: 68.7 %

Procedure:
Amine preparation: A mixture of 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (2.82 g) and potassium thioacetate (2.31 g) was heated to 60° C. in DMF (10 mL). After 4 h, the reaction mixture was diluted with water, extracted with ethyl acetate, dried (MgSO4), filtered and concentrated in vacuo and then purified by flash chromatography to give 4-acetylsulfanyl-piperidine-1-carboxylic acid tert-butyl ester (1.80 g). To a solution of 4-acetylsulfanyl-piperidine-1-carboxylic acid tert-butyl ester (607 mg) in dry MeOH (5 mL) was added a solution of sodium methoxide in MeOH (25% wt, 0.59 mL). After stirring for 15 min, toluene-4-sulfonic acid 3-methoxy-propyl ester (described elsewhere, 571 mg) was added in MeOH. After 24 h, the reaction mixture was diluted with water, extracted with ethyl acetate, dried (MgSO4), filtered and concentrated in vacuo to yield 4-(3-methoxy-propylsulfanyl)-piperidine-1-carboxylic acid tert-butyl ester. Treatment with mCPBA (as described above) yielded 4-(3-methoxy-propane-1-sulfonyl)-piperidine-1-carboxylic acid tert-butyl ester. Treatment of this compound with HCl in DCM/MeOH yielded the desired amine, isolated as the hydrochloride salt.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]3[CH:19]([CH:20]4[CH2:22][CH2:21]4)[CH2:18][NH:17][CH2:16]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:29]1([C:39](Cl)=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[C:29]1([C:39]([N:17]2[CH2:18][CH:19]([CH:20]3[CH2:21][CH2:22]3)[CH:15]([CH2:14][N:11]3[CH2:12][CH2:13][CH:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[CH2:9][CH2:10]3)[CH2:16]2)=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: Fc1ccc(C2CCN(CC3CNCC3C3CC3)CC2)cc1
Reactant: O=C(Cl)c1cccc2ccccc12
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1cccc2ccccc12)N1CC(CN2CCC(c3ccc(F)cc3)CC2)C(C2CC2)C1
Reaction time: 1 h

Procedure:
To a solution of 0.02 g (0.067 mmol) of 3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(cyclopropyl)pyrrolidine and 0.12 mL of pyridine in 2 mL of CH2Cl2 at rt was added 0.19 g (1 mmol) of 1-naphthoyl chloride and the reaction mixture was stirred for 1 h. The reaction mixture was partitioned between ethyl acetate and sat'd NaHCO3 solution. The organic fraction was dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chomatography (HPLC Waters Nova-Pak 8×10 RCM 25-40% MeOH in H2O 0.5%TFA) to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.O[N:12]1C(=O)CCC1=O.Cl.CN(C)CCCN=C=NCC.[Cl-].[NH4+]>C1COCC1.CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH2:12])=[O:10])=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(F)cn1
Reactant: O=C1CCC(=O)N1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(F)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.6 %

Procedure:
Take up 5-Fluoropyridine-2-carboxylic acid (3.82 g, 27.1 mmol) in THF (67.7 mL). Add N-hydroxysuccinimide (3.43 g, 29.8 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.71 g, 29.8 mmol). Add DMF (15 mL) to dissolve the gum formed. Stir for 3 hours at room temperature before adding ammonium chloride (2.17 g, 40.6 mmol). Bubble in ammonia gas for five minutes. Seal the reaction vessel and stir the reaction mixture overnight before concentrating. Take the solid up in water (150 mL) and extract with ethyl acetate (4×225 mL). Dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography, eluting with 25% ethyl acetate, 1% (2.0 M NH3 in methanol) and 74% dichloromethane to give the title compound (3.06 g, 80.7%): TOF MS EI+ 140.0 (M)+, TOF MS EI+ 97.0 (M+B—CONH2), HRMS calcd for C6H5N2OF 140.0386, found 140.0394, time 3.4 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-95% over 19 min], tR=7.1 min, 100% purity.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8]Br)[CH:5]=[CH:4][C:3]=1[O:10][CH3:11].CC1(C)C(C)(C)OB([C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH2:29])=[O:28])=[CH:22][CH:21]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(COC)OC>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:10][CH3:11])[CH2:8][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH2:29])=[O:28])=[CH:22][CH:21]=1
Reactant: COc1ccc(CBr)cc1Br
Reactant: CC1(C)OB(c2ccc(NC(N)=O)cc2)OC1(C)C
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: COc1ccc(Cc2ccc(NC(N)=O)cc2)cc1Br
Temperature: 65 °C
Reaction time: 12.5 h
Yield: 36.9 %

Procedure:
To a 40 mL vial equipped with a teflon screw cap and a magnetic stir bar was added 2-bromo-4-bromomethyl-1-methoxybenzene (649 mg, 2.32 mmol), [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-urea (577 mg, 2.20 mmol) and potassium phosphate (933 mg, 4.40 mmol). To the vial was then added dimethoxyethane (15 mL), ethanol (3.7 mL) and water (3.7 mL). To this stirring solution was added tetrakis(triphenylphosphine) palladium (127 mg, 0.11 mmol) and the solution was degassed by bubbling N2 gas through the solution for 20 min. The vial was capped and placed in an oil bath with stirring at 65° C. for 12.5 h. The cooled reaction mixture was concentrated under a stream of N2 gas to a total volume of ˜5 mL and then diluted with ethyl acetate (20 mL) and water (10 mL). Upon shaking a white solid precipitates. The solid is filtered and dried to afford 272 mg (34%) of [4-(3-bromo-4-methoxy-benzyl)-phenyl]-urea (I-44) as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH:4]=[C:5]([C:22]([O:24]C)=[O:23])[CH:6]=[N:7][C:8]=2[N:9]([CH3:21])[C:10](=[O:20])[C:11]=1[C:12](=[O:19])[CH2:13][CH2:14][C:15]([O:17]C)=[O:16].OC1C2C(=NC=C(I)C=2)N(C)C(=O)C=1C(=O)CCC(O)=O.[C]=O>CO.[Pd]>[C:15]([CH2:14][CH2:13][C:12]([C:11]1[C:10](=[O:20])[N:9]([CH3:21])[C:8]2[N:7]=[CH:6][C:5]([C:22]([OH:24])=[O:23])=[CH:4][C:3]=2[C:2]=1[OH:1])=[O:19])([OH:17])=[O:16]
Reactant: COC(=O)CCC(=O)c1c(O)c2cc(C(=O)OC)cnc2n(C)c1=O
Agent: [Pd]
Agent: Cn1c(=O)c(C(=O)CCC(=O)O)c(O)c2cc(I)cnc21
Agent: [C]=O
Solvent: CO
Product: Cn1c(=O)c(C(=O)CCC(=O)O)c(O)c2cc(C(=O)O)cnc21

Procedure:
Methyl 5-hydroxy-6-(4-methoxy-4-oxobutanoyl)-8-methyl-7-oxo-7,8-dihydro-1,8-naphthyridine-3-carboxylate. The title compound is prepared by metal mediated carbonylation of methyl 4-(4-hydroxy-6-iodo-1-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl)-4-oxobutanoate (Method 4) with carbon monoxide in MeOH according to the procedure set forth in Tsuji, J. Palladium Reagents and catalysts: Innovations in Organic Synthesis Publisher: (Wiley, Chichester, UK), 340-45 (1995).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Br:9])=[CH:4][N:3]=1.BrN1C(=O)CCC1=O.[C:18]([O-:21])(=[O:20])[CH3:19].[K+].C1OCCOCCOCCOCCOCCOC1>C(Cl)(Cl)(Cl)Cl.C(#N)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][O:21][C:18](=[O:20])[CH3:19])[C:5]([Br:9])=[CH:4][N:3]=1
Reactant: Cc1cc(Br)ncc1Br
Reactant: CC(=O)[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C1CCC(=O)N1Br
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Product: CC(=O)OCc1cc(Br)ncc1Br
Temperature: 5 °C
Yield: 20.5 %

Procedure:
2.5-Dibromo-4-methylpyridine(26.06 g, 103.8 mmol) and N-bromosuccinimide (27.72 g, 155.7 mmol) in carbon tetrachloride (500 ml) were heated to reflux over a 150 W light bulb for 2 h. Cooling to 5° C., filtration and evaporation to dryness under reduced pressure gave the crude brominated products which were treated with potassium acetate (66.0 g, 673 mmol) and 18-crown-6 (3.00 g, 11.4 mmol) in acetonitrile (500 ml) at room temperature for 40 h. Filtration and evaporation of the filtrate to dryness gave the crude products which were dissolved in ethyl acetate, washed with saturated aqueous potassium bromide solution, the organic phase dried (Na2SO4) and evaporated to dryness under reduced pressure with purification by flash chromatography using hexane/ethyl acetate (6:1) as eluent giving the title compound (6.56 g. 19%) as a white solid: δH (CDCl3), 2.22 (3H, s, CH3), 5.12 (2H, s, CH2OAc), 17.50 (1H, s, 3-H), 18.45 (1H, s, 6-H); m/z (E.I.) 308 (MH+, 3%), 230 (100%): (Found: M+, 307.8926. C8H8NO2Br requires M. 307.89221.
Reaction SMILES: [N:1]1([CH2:6]/[CH:7]=[CH:8]/[C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])[CH:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[Na+]>CO>[N:1]1([CH2:6]/[CH:7]=[CH:8]/[C:9]2[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])[CH:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COC(=O)c1ccc(/C=C/Cn2ccnc2)cc1-c1ccc(F)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(/C=C/Cn2ccnc2)cc1-c1ccc(F)cc1F
Yield: 49 %

Procedure:
A solution of methyl 4-[(E)-3-(imidazol-1-yl)prop-1-en-1-yl]-2-(2,4-difluorophenyl)benzoate (0.9 g; 2.54 mmol) and 2N sodium hydroxide solution (3.8 ml) in methanol was heated at reflux for 7 hours. After evaporation of the solvent and neutralisation to pH 6.5 with 6N HCl, the residue was purified on reverse phase silica eluting with methanol/ammonium carbonate buffer (2 g/l, pH 7) (50/50) to give 4-[(E)-3-(imidazol-1-yl)prop-1-en-1-yl]-2-(2,4-difluorophenyl)benzoic acid after freeze-drying. Yield: 49%.
Reaction SMILES: [N:1]1(/[C:10](/[C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH3:24])=[CH:19][CH:18]=2)=[CH:11]\[C:12]([O:14]CC)=[O:13])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1>Cl>[N:1]1(/[C:10](/[C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH3:24])=[CH:19][CH:18]=2)=[CH:11]\[C:12]([OH:14])=[O:13])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CCOC(=O)/C=C(/c1ccc(CC)cc1)n1cnc2ccccc21
Agent: Cl
Product: CCc1ccc(/C(=C/C(=O)O)n2cnc3ccccc32)cc1
Temperature: 25 °C

Procedure:
A solution of ethyl (2Z)-3-(1H-benzimidazol-1-yl)-3-(4-ethylphenyl)-2-propenoate (60 mg, 187 μmol) in hydrochloric acid (10 mL of a 5N solution) was stirred at room temperature for 72 hours, and then heated at reflux for 6 hours. The solution was cooled to room temperature, and evaporated in vacuo to afford the title compound, [LCMS (Method A, Mobile Phase I) RT=6.63 min, MH+ 294].
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[O:4][C:3]=1[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1.[Cl:17][C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1[N:25]=[C:26]=[O:27].CN(C)CCN>C(Cl)Cl.CCOC(C)=O>[N:14]1[CH:13]=[CH:12][C:11]([C:3]2[O:4][C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])=[CH:6][C:2]=2[NH:1][C:26]([NH:25][C:19]2[CH:20]=[CH:21][CH:22]=[C:23]([Cl:24])[C:18]=2[Cl:17])=[O:27])=[CH:16][CH:15]=1
Reactant: O=C=Nc1cccc(Cl)c1Cl
Reactant: CC(C)(C)c1cc(N)c(-c2ccncc2)o1
Agent: CN(C)CCN
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(Cl)c2Cl)c(-c2ccncc2)o1
Reaction time: 0.5 h
Yield: 64.5 %

Procedure:
A solution of 3-amino-2-(4-pyridinyl)-5-tert-butylfuran (Method A2; 0.10 g, 0.46 mmol) and 2,3-dichlorophenyl isocyanate (0.13 g, 0.69 mmol) in CH2Cl2 was stirred at room temp. for 2 h, then was treated with 2-(dimethylamino)ethylamine (0.081 g, 0.92 mmol) and stirred for an additional 30 min. The resulting mixture was diluted with EtOAc (50 mL), then was sequentially washed with a 1 N HCl solution (50 mL), a saturated NaHCO3 solution (50 mL) and a saturated NaCl solution (50 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified using column chromatography (gradient from 10% EtOAc/90% hexane to 40% EtOAc/60% hexane) to give the desired compound as a white solid (0.12 g, 63%): mp 195-198° C.; TLC (60% EtOAc/40% hexane) Rf 0.47; 1H NMR (DMSO-d6) δ1.30 (s, 9H); 6.63 (s, 1H); 7.30-7.32 (m, 2H), 7.58 (dm, J=6.62 Hz, 2H), 8.16 (dd, J=2.57, 6.99 Hz, 1H), 8.60 (dm, J=6.25 Hz, 2H), 8.83 (s, 1H), 9.17 (s, 1H); 13C NMR (DMSO-d6) δ 28.5 (3C), 32.5, 103.7, 117.3 (2C), 119.8, 120.4, 123.7, 125.6, 128.1, 131.6, 135.7, 136.5, 137.9, 150.0 (2C), 152.2, 163.5; CI-MS m/z (rel abundance) 404 ((M+H)+, 15%), 406 ((M+H+2)+, 8%).
Reaction SMILES: [CH2:1]([N:6]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7]1[C:14]([O:16]CC)=[O:15])[CH2:2][CH:3]([CH3:5])[CH3:4].[OH-].[Na+]>C(O)C>[CH2:1]([N:6]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7]1[C:14]([OH:16])=[O:15])[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])cn1CCC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)CCn1cc([N+](=O)[O-])cc1C(=O)O
Temperature: 0 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
Ethyl 1-isopentyl-4-nitro-1H-pyrrole-2-carboxylate (2.377 g, 9.329 mmol; see step (i) above) was suspended in ethanol (5 mL), then a solution of NaOH (955 mg dissolved in 20 mL of water) was added. The reaction mixture was reduced by half under reduced pressure at 50° C., and then the cooled solution was extracted with ether. The water layer was cooled to 0° C. then conc. HCl was added dropwise with vigorous stirring until pH 2. The white solid material was filtered off, washed with water, dried at 60° C. under reduced pressure for 2 h then left at room temperature overnight. The product was obtained as white solid (2.008 g, 95% yield), m.p. 154-157° C. [Lit.m.p. 154-156° C.].
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[C:5]2[N:6](C(=O)C)[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:4]2[N:3]=1.Cl.C(=O)(O)[O-].[Na+]>C(O)C.O>[CH3:1][C:2]1[CH:16]=[C:5]2[NH:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:4]2[N:3]=1
Reactant: CC(=O)n1c2ccccc2n2nc(C)cc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc2[nH]c3ccccc3n2n1
Temperature: 25 °C

Procedure:
2-Methyl-4-acetylpyrazolo[1,5-a]benzimidazole (11), (0.25 g, 1.17 mmol), was added to a mixture of concentrated hydrochloric acid (0.5 ml) in ethanol (5 ml) and heated to reflux for 20 minutes. The solution was cooled to room temperature and poured into a solution of sodium bicarbonate in water (30 ml) to afford a light tan solid which was filtered off, washed and dried, mp. 248°-252° C., 0.20 g, 99%. This was shown by comparative thin layer chromatography and infra-red analysis to be identical to an authentic sample of 2-methylpyrazolo-[1,5-a]benzimidazole (6).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12]([C:14]2[N:19]=[C:18]([NH:20][CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:17]([N+:26]([O-])=O)=[CH:16][CH:15]=2)=[C:11]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:10]=1.O.O.[Sn](Cl)Cl.[N:40]#[C:41]Br.C(OCC)(=O)C>C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12]([C:14]2[N:19]=[C:18]3[N:20]([CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:41]([NH2:40])=[N:26][C:17]3=[CH:16][CH:15]=2)=[C:11]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:10]=1
Reactant: CC(C)(C)CNc1nc(-c2[nH]c(-c3c(F)cccc3Cl)nc2-c2ccccc2)ccc1[N+](=O)[O-]
Reactant: N#CBr
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CC(C)(C)Cn1c(N)nc2ccc(-c3[nH]c(-c4c(F)cccc4Cl)nc3-c3ccccc3)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
Dissolve {6-[2-(2-chloro-6-fluoro-phenyl)-5-phenyl-3H-imidazol-4-yl]-3-nitro-pyridin-2-yl}-(2,2-dimethylpropyl)-amine (240 mg, 0.50 mmol) in 100% ethanol (10 mL) and add tin(II) dichloride dihydrate (564 mg, 2.50 mmol, 5.0 equiv). Heat the reaction mixture until starting material is consumed. Cool the reaction solution to room temperature, quench slowly with saturated aqueous NaHCO3. Add Celite® to the quenched reaction and filter the suspension on a Celite® pad with water and ethyl acetate washes. Separate the layers and wash the organic layer with saturated aqueous NaCl. Dry the organic layer with Na2SO4, filter, and concentrate under reduced pressure. Add 10% aqueous ethanol and cyanogen bromide (106 mg, 1.00 mmol, 2.0 equiv) to the resulting solid and stir overnight. Quench the reaction with saturated aqueous NaHCO3 (20 mL). Add ethyl acetate and water to dissolve all solids. Wash the organic layer three times with saturated aqueous NaCl, dry with Na2SO4, filter, and concentrate under reduced pressure. Subject the residue to medium pressure silica gel chromatography eluting with a gradient of 1.5-3% (2M ammonia in MeOH)/CH2Cl2 to provide 5-[2-(2-Chloro-6-fluoro-phenyl)-5-phenyl-3H-imidazol-4-yl]-3-(2,2-dimethylpropyl)-3H-imidazo[4,5-b]pyridin-2-ylamine as a yellow-green solid (196 mg, 60% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]O)=[CH:20][C:19]=2[CH3:26])=[O:17])[C:11](=[O:27])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)[Br:29]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][Br:29])=[CH:20][C:19]=2[CH3:26])=[O:17])[C:11](=[O:27])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrP(Br)Br
Reactant: Cc1cc(CO)ccc1C(=O)Cn1ccc(OCc2ccccc2)cc1=O
Solvent: ClCCl
Product: Cc1cc(CBr)ccc1C(=O)Cn1ccc(OCc2ccccc2)cc1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-benzyloxy-1-[2-(4-hydroxymethyl-2-methyl-phenyl)-2-oxo-ethyl]-1H-pyridin-2-one (preparation 1c, 1.10 g, 3.03 mmol) in CH2Cl2 (20 mL) is added slowly phosphorus tribromide (199 μL, 2.12 mmol) at 0° C. The cooling bath is removed and the mixture is stirred for 1 h at room temperature. After cooling, the reaction mixture is quenched with aqueous NaHCO3 solution and extracted with CH2Cl2. The organic layer is washed with water, dried over MgSO4, and concentrated under reduced pressure.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:4]=1[C:10]1[N:15]=[C:14]([C:16]([NH:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][C:24]=2[C@H:25]2[CH2:30][C@@H:29]([NH:31]C(=O)OC(C)(C)C)[C@H:28]([S:39][CH3:40])[C@@H:27]([CH3:41])[CH2:26]2)=[O:17])[CH:13]=[CH:12][C:11]=1[F:42]>O1CCOCC1>[NH2:31][C@H:29]1[C@H:28]([S:39][CH3:40])[C@@H:27]([CH3:41])[CH2:26][C@@H:25]([C:24]2[CH:23]=[CH:22][N:21]=[CH:20][C:19]=2[NH:18][C:16](=[O:17])[C:14]2[CH:13]=[CH:12][C:11]([F:42])=[C:10]([C:4]3[C:3]([F:2])=[CH:8][CH:7]=[CH:6][C:5]=3[F:9])[N:15]=2)[CH2:30]1
Reactant: CS[C@@H]1[C@@H](C)C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@H]1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CS[C@H]1[C@H](N)C[C@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H]1C
Reaction time: 1 h
Yield: 43 %

Procedure:
To a solution of HCl (30.0 equiv.) in dioxane was added to tert-butyl (1R,2R,3S,5R)-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-3-methyl-2-(methylthio)cyclohexylcarbamate (1.0 equiv.). The solution was capped and left standing at rt for 1 hr. The volatiles were removed in vacuo, dissolved in DMSO and purified by reverse phase HPLC to yield N-(4-((1R,3R,4R,5S)-3-amino-5-methyl-4-(methylthio)cyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide in 43% yield. LC/MS (m/z)=487.2 (MH+), Rt=0.65 min.