Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].O1CCC[CH2:23]1.Cl>O.CO>[CH3:23][C:17]1[CH:18]=[C:9]([CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=[CH:11][C:12]=1[C:13]([OH:15])=[O:14]
Reactant: C1CCOC1
Reactant: COC(=O)c1ccc(COc2ccccc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(COc2ccccc2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 81 %

Procedure:
A mixture of methyl 4-(phenoxymethyl)benzoate (1.1 g, 4.55 mmol), lithium hydroxide monohydrate (955 mg, 22.8 mmol), tetrahydrofuran (20 mL), methanol (7 mL) and water (7 mL) were stirred at room temperature for 5 hours. The mixture was neutralized to pH to 1 with concentrated hydrochloric acid and then extracted with ethyl acetate (15 mL×3). The combined organic phase was separated, dried over sodium sulfate, and then filtered. The filtrate was concentrated in vacuo to give methyl 4-(phenoxymethyl)benzoic acid as a white solid (840 mg, 81%). LRMS (M+H)− m/z: calcd 228.08. found 228.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([CH2:19][CH3:20])[C:8]1[S:12][C:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:22]N1C(=O)CCC1=O>C(#N)C>[C:1]([O:5][C:6](=[O:21])[N:7]([C:8]1[S:12][C:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:10][C:9]=1[Cl:22])[CH2:19][CH3:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(C(=O)OC(C)(C)C)c1cnc(-c2cccnc2)s1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: CCN(C(=O)OC(C)(C)C)c1sc(-c2cccnc2)nc1Cl
Temperature: 45 °C
Reaction time: 16 h
Yield: 67.1 %

Procedure:
To a solution of ethyl-(2-pyridin-3-yl-thiazol-5-yl)-carbamic acid tert-butyl ester (3.0 g, 9.82 mmol) in acetonitrile (58 mL) was added N-chlorosuccinimide (2.62 g, 19.64 mmol) in one portion and the reaction mixture was stirred at 45° C. for 16 h. The reaction mixture was concentrated and the crude product was purified by silica gel chromatography (0 to 100% ethyl acetate/hexanes) to afford a red oil (2.24 g, 67%): 1H NMR (300 MHz, CDCl3) δ 9.09 (d, J=1.9 Hz, 1H), 8.68 (dd, J=4.8, 1.6 Hz, 1H), 8.19 (dd, J=5.9, 4.2 Hz, 1H), 7.39 (dd, J=7.6, 5.2 Hz, 1H), 3.68 (q, J=7.2 Hz, 2H), 1.45 (s, 9H), 1.22 (t, J=7.0 Hz, 3H); ESIMS m/z 340 (M+1).
Reaction SMILES: Br[C:2]1[C:11]([C@H:12]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:23])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:24])=[N:7]2.[Cl:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.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>[C:19]([O:18][C@@H:12]([C:11]1[C:2]([C:29]2[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][CH:28]=2)=[C:3]2[C:8](=[CH:9][C:10]=1[CH3:23])[N:7]=[C:6]([CH3:24])[CH:5]=[CH:4]2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])([CH3:22])([CH3:21])[CH3:20]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(C)ccc2c1Br
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: [K+]
Solvent: COCCOC
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(C)ccc2c1-c1ccc(Cl)cc1
Temperature: 110 °C
Yield: 79.6 %

Procedure:
Pd(PPh3)4 (68 mg, 0.06 mmol) was added to a mixture of (S)-ethyl 2-(5-bromo-2,7-dimethylquinolin-6-yl)-2-tert-butoxyacetate (5H) (230 mg, 0.59 mmol) and 4-chlorophenylboronic acid (183 mg, 1.17 mmol), K2CO3 (1.0 mL 2 M in water, 2.06 mmol) in 1,2-dimethoxyethane (8 mL). The reaction mixture was flushed with nitrogen, heated at 110° C. for 30 min under microwave, and then the volatile component was removed in vacuo. The residue was dissolved in ethyl acetate (100 mL), washed with NaHCO3 solution, water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The obtained residue was purified by HPLC to provide the desired product (200 mg, 80%). LCMS-ESI+ (m/z): 426.2, 428.2 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([CH2:14][CH:15]([CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>ClCCl>[C:27]([CH2:26][CH:15]([CH2:14][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])([OH:29])=[O:28]
Reactant: CC(C)(C)OC(=O)CC(Cc1ccccc1)C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CC(Cc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 7 h
Yield: 62.8 %

Procedure:
8 ml of trifluoroacetic acid are added, at 0° C., to a solution of 2 g (5.6 mmol) of phenylmethyl 1,1-dimethylethyl 2-(phenylmethyl)-1,4-butanedioate in 16 ml of dichloromethane. After 7 h at room temperature, the mixture is evaporated to dryness and the residue is recrystallized from cyclohexane. 1.05 g of a white product are obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:19]([N:22]([CH3:24])[CH3:23])[C:20]#[CH:21]>CN(C=O)C.CC#N.CC#N.Cl[Pd]Cl>[CH3:9][O:8][C:5]1[N:6]=[CH:7][C:2]([C:21]#[C:20][CH2:19][N:22]([CH3:24])[CH3:23])=[CH:3][C:4]=1[N+:10]([O-:12])=[O:11]
Reactant: COc1ncc(Br)cc1[N+](=O)[O-]
Reactant: C#CCN(C)C
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: COc1ncc(C#CCN(C)C)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 4 h
Yield: 27.1 %

Procedure:
To a solution of 5-bromo-2-methoxy-3-nitropyridine (1.50 g, 6.44 mmol) in DMF (30 mL) were added bis(acetonitrile)palladium(II)chloride (83.5 mg, 0.322 mmol), 2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1-1′-biphenyl (399 mg, 0.837 mmol), cesium carbonate (4.19 g, 12.9 mmol) and propargyl(dimethylamine) (0.832 mL, 7.72 mmol). The reaction mixture was flushed with nitrogen gas and allowed to stir for 4 h at 50° C. The reaction mixture was diluted with EtOAc and washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give 3-(6-methoxy-5-nitropyridin-3-yl)-N,N-dimethylprop-2-yn-1-amine (0.41 g, 27%) as a white solid. LCMS (FA): Rt=0.85 min, m/z=236.2 (M+H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:39])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[N:33]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:16][N:14]([CH3:15])[C:12]1[C:11]([C:17]([F:18])([F:20])[F:19])=[CH:10][C:9]2[NH:21][C:22](=[O:39])[CH2:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[N:33]=4)[CH:27]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N(C)C)cc3NC(=O)OC(C)(C)C)c2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccc(-c2cccc(C3=Nc4cc(N(C)C)c(C(F)(F)F)cc4NC(=O)C3)c2)n1

Procedure:
The title compound was prepared from (5-dimethylamino-2-{3-[3-(6-methyl-pyridin-2-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M142) (244 mg, 0.44 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (168 mg, 87%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[N:11]=[CH:12][S:13][CH:14]=2)[C:5]([C:15]#[N:16])=[C:4]([SH:17])[N:3]=1.Cl[CH2:19][C:20]1[N:21]=[C:22]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[O:23][CH:24]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[N:11]=[CH:12][S:13][CH:14]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17][CH2:19][C:20]2[N:21]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[O:23][CH:24]=2)[N:3]=1
Reactant: N#Cc1c(N)nc(S)c(C#N)c1-c1cscn1
Reactant: ClCc1coc(-c2ccc(Cl)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(N)nc(SCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1cscn1

Procedure:
90 mg (about 0.298 mmol) of 2-amino-6-sulfanyl-4-(1,3-thiazol-4-yl)pyridine-3,5-dicarbonitrile, together with 87 mg (0.382 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-oxazole and 88 mg (1.041 mmol) of sodium bicarbonate, were stirred in 20 ml DMF at room temperature overnight. The reaction mixture was purified by preparative HPLC (acetonitrile/water: 10:90→95:5, 0.1% TFA added). This gave 37 mg (24% of theory) of the target compound.
Reaction SMILES: [CH3:1][C:2]([N:6]1[CH2:11][CH2:10][CH:9]([S:12]([C:14]2[CH:15]=[CH:16][C:17]3[O:23][CH2:22][CH2:21][N:20]4[CH:24]=[C:25]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=5)[N:26]=[C:19]4[C:18]=3[CH:33]=2)=[O:13])[CH2:8][CH2:7]1)([CH3:5])[CH2:3][OH:4].C(O)(C(F)(F)F)=[O:35].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl>[CH3:5][C:2]([N:6]1[CH2:7][CH2:8][CH:9]([S:12]([C:14]2[CH:15]=[CH:16][C:17]3[O:23][CH2:22][CH2:21][N:20]4[CH:24]=[C:25]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=5)[N:26]=[C:19]4[C:18]=3[CH:33]=2)(=[O:35])=[O:13])[CH2:10][CH2:11]1)([CH3:1])[CH2:3][OH:4]
Reactant: CC(C)(CO)N1CCC(S(=O)c2ccc3c(c2)-c2nc(-c4ccccn4)cn2CCO3)CC1
Reactant: O=C(O)C(F)(F)F
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(CO)N1CCC(S(=O)(=O)c2ccc3c(c2)-c2nc(-c4ccccn4)cn2CCO3)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.3 %

Procedure:
To an ice-cooled solution of 2-methyl-2-[4-(2-pyridin-2-yl-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene-9-sulfinyl)piperidin-1-yl]propan-1-ol 197 (30 mg, 0.064 mmol) in DCM (2 mL) was added TFA (25 μL, 0.318 mmol) followed by a slow addition of a solution of m-CPBA (13 mg, 0.076 mmol) in DCM (0.5 mL) and the resulting mixture was stirred for 1 h at RT. Volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (C18, gradient 5-30% MeOH in 0.5% TFA/H2O). To an ice-cooled solution in DCM (10 mL) of the product thus obtained was added TFA (12 μA) followed by a solution of m-CPBA (13 mg, 0.076 mmol) in DCM (0.5 mL). The mixture was stirred at RT for 1.5 h and then volatiles were removed under reduced pressure. The resulting residue was purified by column chromatography (C18, gradient 5-30% MeOH in 0.5% TFA/H2O) and then loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 0.5M NH3 in MeOH. Further purification by column chromatography (Si-PCC, gradient 2-8% 2M NH3/MeOH in DCM) afforded 199 as a white solid (14 mg, 47%). LCMS: RT 2.03 min [M+H]+ 483.1. 1H NMR (DMSO, 400 MHz): δ 8.95 (1H, d, J=2.41 Hz), 8.53 (1H, ddd, J=4.81, 1.80, 0.93 Hz), 8.00-7.94 (2H, m), 7.85 (1H, td, J=7.69, 1.84 Hz), 7.68 (1H, dd, J=8.62, 2.43 Hz), 7.29-7.22 (2H, m), 4.65-4.55 (4H, m), 4.21 (1H, t, J=5.42 Hz), 3.22-3.10 (3H, m), 3.07-2.99 (2H, m), 2.09 (2H, bt, J=11.55 Hz), 1.86 (2H, bd, J=12.02 Hz), 1.50-1.37 (2H, m), 0.87 (6H, s)
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:9]([C:10]2[CH:14]=[CH:13][O:12][N:11]=2)=[CH:8][C:7]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=2)=[N:6]1.OO.NC(N)=O.F[C:33](F)(F)[C:34]([O:36]C(=O)C(F)(F)F)=[O:35]>C(Cl)Cl.C(OC(=O)C)(=O)C>[C:34]([O:36][C:17]1[C:18]([F:21])=[CH:19][CH:20]=[C:15]([C:7]2[CH:8]=[C:9]([C:10]3[CH:14]=[CH:13][O:12][N:11]=3)[N:5]([CH2:4][C:3]3[CH:22]=[CH:23][CH:24]=[CH:25][C:2]=3[F:1])[N:6]=2)[N:16]=1)(=[O:35])[CH3:33]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: Fc1ccc(-c2cc(-c3ccon3)n(Cc3ccccc3F)n2)nc1
Agent: NC(N)=O
Agent: OO
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)Oc1nc(-c2cc(-c3ccon3)n(Cc3ccccc3F)n2)ccc1F
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a cold mixture of 3-(1-(2-fluorobenzyl)-3-(5-fluoropyridin-2-yl)-1H-pyrazol-5-yl)isoxazole (1 equiv.) and urea compound with hydrogen peroxide (1:1) (3 equiv.) in DCM (1.7 ml) at 0° C., was added trifluoroacetic anhydride (3 equiv.). The mixture was allowed to warm to 25° C. and stirred for 3 days. The mixture was quenched with saturated solution of sodium bisulfate and extracted with dichloromethane (50 ml×3). The organic layers were combined, filtered and evaporated to give solid. The solid was dissolved in acetic anhydride (1.4 ml) and heated to 145° C. for 4 h. The mixture was cooled to 25° C., diluted with dichloromethane (100 ml) and washed with saturated solution of sodium bicarbonate (50 ml). The organic layer was dried (MgSO4), filtered and evaporated to give an oil. Purification of the oil by column chromatography (0 to 30% ethyl acetate in hexanes) gave 3-fluoro-6-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyridin-2-yl acetate as an yellow oil. The yellow oil was combined with methanol (1.7 ml) and potassium carbonate (1 equiv.). The mixture was heated to 65° C. for 30 min. The mixture was concentrated under vacuum. The resulting residue was diluted with dichloromethane (100 ml) and washed with 1N HCl (30 ml). The organic layer was dried (MgSO4), filtered and evaporated to give a solid. Purification of the solid by column chromatography (0 to 5% methanol in dichloromethane) gave 3-fluoro-6-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyridin-2(1H)-one as a yellow solid (7% overall yield).
Reaction SMILES: C([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:19]([OH:21])=O)[N:13]2[CH3:18])C1C=CC=CC=1.[CH3:22][NH:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH3:22][N:23]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:19]([C:12]1[N:13]([CH3:18])[C:14]2[C:10]([CH:11]=1)=[C:9]([OH:8])[CH:17]=[CH:16][CH:15]=2)=[O:21]
Reactant: CNCCc1ccccc1
Reactant: Cn1c(C(=O)O)cc2c(OCc3ccccc3)cccc21
Product: CN(CCc1ccccc1)C(=O)c1cc2c(O)cccc2n1C

Procedure:
From 4-benzyloxy-1-methyl-1H-indole-2-carboxylic acid and N-methylphenethylamine the title compound was prepared by a method analogous to that described in Example 11. MS ES (M++H)=309.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH3:28])[CH2:10][O:11][C:12]1[CH:27]=[CH:26][C:15]([C:16]([O:18]CC2C=CC=CC=2)=[O:17])=[CH:14][CH:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>[Pd].C(O)C>[C:1]([NH:8][C@@H:9]([CH3:28])[CH2:10][O:11][C:12]1[CH:27]=[CH:26][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: C[C@@H](COc1ccc(C(=O)OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: C[C@@H](COc1ccc(C(=O)O)cc1)NC(=O)OC(C)(C)C
Reaction time: 20 h

Procedure:
A mixture of 22-3 (1.6 g, 4.3 mmol), 10% Pd/C (0.33 g) and ethanol (25 mL) was stirred under a hydrogen atmosphere (1 atm) for 20 h. Filtration through a celite pad followed by concentration of the filtrate gave 22-4 as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.C1C(=O)N([Br:18])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CCOCC.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:18][CH2:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2sccc2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc2sccc2c1
Yield: 99.8 %

Procedure:
A mixture of 5-methylbenzo[b]thiophene (3.8 g, 25.6 mmol), NBS (4.7 g, 27 mmol), and benzoyl peroxide (310 mg, 1.3 mmol) were refluxed one hour in CCl4 (100 mL) while being irradiated with a sunlamp. Upon completion, the reaction was cooled, diluted with Et2O, filtered and concentrated to yield 5.8 g of 5-bromomethylbenzo[b]thiophene. The crude 5-bromomethylbenzo[b]thiophene was refluxed for 36 hours in 1:1 dioxane/2N aq. NaOH (128 mL). After cooling, extraction with EtOAc and concentration of the extracts, the residue was chromatographed on silica gel eluting 2.6 g of 5-hydroxymethylbenzo[b]thiophene with 35% EtOAc/hexane. The title compound (1.96 g) was obtained after filtration and concentration of the reaction product produced by refluxing 5-hydroxymethylbenzo[b]thiophene (2.08 g, 12.7 mmol) and 50% MnO2 /C (17.6 g, 101 mmol) for five hours in toluene while H2O was continually removed using a Dean-Stark trap.
Reaction SMILES: C[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N:11]([S:13]([C:16]2[CH:21]=[CH:20][C:19](F)=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH3:12])[C:3]=1[CH3:23].[OH:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]([C:31]1[CH:39]=[CH:38][C:34]2[O:35][CH2:36][O:37][C:33]=2[CH:32]=1)=[O:30]>>[O:35]1[C:34]2[CH:38]=[CH:39][C:31]([C:29]([NH:28][CH2:27][CH2:26][CH2:25][O:24][C:19]3[CH:18]=[CH:17][C:16]([S:13]([N:11]([CH3:12])[C:4]4[C:3]([CH3:23])=[CH:2][CH:10]=[CH:9][C:5]=4[C:6]([OH:8])=[O:7])(=[O:14])=[O:15])=[CH:21][CH:20]=3)=[O:30])=[CH:32][C:33]=2[O:37][CH2:36]1
Reactant: Cc1ccc(C(=O)O)c(N(C)S(=O)(=O)c2ccc(F)cc2)c1C
Reactant: O=C(NCCCO)c1ccc2c(c1)OCO2
Product: Cc1cccc(C(=O)O)c1N(C)S(=O)(=O)c1ccc(OCCCNC(=O)c2ccc3c(c2)OCO3)cc1
Yield: 49 %

Procedure:
The product of Example 2 (0.30 g, 0.92 mmol) was coupled to N-(3-hydroxypropyl)-1,3-benzodioxole-5-carboxamide, prepared according to Example 20, (0.205 g, 0.92 mmol) using the procedure of Example 3 to provide 0.23 g (49% yield) of yellow solid. MP 120° C.; 1H NMR (DMSO-d6): δ 1.63 (m, CH2) 1.9 (s, CH3), 3.20 (s, CH3), 3.6 (m, CH2), 4.1 (m, CH2), 6.07 (s, CH2), 6.9-7.1 (m, 5 Ar H), 7.3-7.5 (m, 3 Ar H), 7.88-7.94 (m, 2 Ar H), 8.52 (br s, NH). Electrospray Mass Spec: m/z 527.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][C:4]1[CH:8]=[C:7]([NH2:9])[NH:6][N:5]=1.O.[N+:13]([CH:16]([CH:19]=O)[CH:17]=O)([O-:15])=[O:14].[Na]>O>[N+:13]([C:16]1[CH:17]=[C:8]2[C:4]([CH2:3][C:2]([F:1])([F:10])[F:11])=[N:5][NH:6][C:7]2=[N:9][CH:19]=1)([O-:15])=[O:14]
Reactant: O=CC(C=O)[N+](=O)[O-]
Reactant: Nc1cc(CC(F)(F)F)n[nH]1
Agent: [Na]
Solvent: O
Product: O=[N+]([O-])c1cnc2[nH]nc(CC(F)(F)F)c2c1
Temperature: 85 °C
Yield: 36.1 %

Procedure:
A round-bottom flask was charged with 3-(2,2,2-trifluoroethyl)-1H-pyrazol-5-amine (0.145 g, 0.878 mmol, WO 2008/005956), sodium nitromalonaldehyde monohydrate (0.150 g, 0.966 mmol) and water (3.5 mL). The reaction mixture was heated at 85° C. for 16 hours. The reaction mixture was poured into water and subsequently extracted with ethyl acetate (2×). The combined organic layers were dried with sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography to afford 5-nitro-3-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-b]pyridine (0.078 g, 36%).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[NH:7][C:8](=O)[O:9][C:10](=[O:11])[C:5]=2[S:4][CH:3]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:23]=[CH:22][C:18](C(Cl)=O)=[CH:17][CH:16]=1.Cl>CN(C)C1C=CN=CC=1.O1CCOCC1>[CH3:1][C:2]1[C:6]2[N:7]=[C:8]([C:18]3[CH:22]=[CH:23][C:15]([C:14]([F:25])([F:24])[F:13])=[CH:16][CH:17]=3)[O:9][C:10](=[O:11])[C:5]=2[S:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: Cc1csc2c(=O)oc(=O)[nH]c12
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1csc2c(=O)oc(-c3ccc(C(F)(F)F)cc3)nc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.7 %

Procedure:
4-(Dimethylamino)pyridine (0.66 g, 5.41 mmol) was added to the product from Step A in dioxane (10 mL). 4-(Trifluoromethyl)benzoyl chloride (1.13 g, 5.42 mmol) was added to the mixture and the mixture was boiled for approximately 3 hours. The mixture was allowed to cool to room temperature and was poured into hydrochloric acid (100 mL, 1 N). The mixture was extracted with ethyl acetate (3×50 mL) and the combined extracts were dried and evaporated. Chromatography on silicon gel (eluted with ethyl acetate/hexanes) gave the product as a white solid 1.56 g, (91.7%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2=[N:13][C:14]([O:18][CH2:19][C:20]3[N:21]([CH3:25])[N:22]=[CH:23][N:24]=3)=[C:15](Br)[CH:16]=[C:11]2[N:10]=[N:9]1.C([Sn](CCCC)(CCCC)[C:31]1[O:32][CH:33]=[CH:34][CH:35]=1)CCC>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2=[N:13][C:14]([O:18][CH2:19][C:20]3[N:21]([CH3:25])[N:22]=[CH:23][N:24]=3)=[C:15]([C:31]3[O:32][CH:33]=[CH:34][CH:35]=3)[CH:16]=[C:11]2[N:10]=[N:9]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: Cn1ncnc1COc1nc2c(cc1Br)nnn2-c1ccccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ncnc1COc1nc2c(cc1-c1ccco1)nnn2-c1ccccc1F
Temperature: 100 °C
Yield: 36.6 %

Procedure:
A mixture of 3-(2-fluorophenyl)-5-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-6-bromo-1,2,3-triazolo[4,5-b]pyridine (0.12 g, 0.29 7 mmol) (Example 3, step c), 2-tributylstannylfuran (0.19 ml, 0.60 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.02 g, 5 mol %) in DMF (3 ml) was heated in a sealed tube at 100° C. for 7 h. The solution was cooled, diluted with water (40 ml) and extracted with 10% methanol-dichloromethane (2×20 ml). The extracts were dried (Na2SO4), filtered and concentrated. The residue was dissolved in ethyl acetate-dichloromethane and decolourised with charcoal (50 mg). The filtrate was concentrated to give 3-(2-fluorophenyl)-6-(2-furyl)-5-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,3-triazolo[4,5-b]pyridine (0.086 g, 74%) as an off-white solid, m.p. 170-173° C. Found: C, 57.28; H, 3.67. C19H14FN7O2.0.5(H2O) requires C, 57.00; H, 3.78. δH (400 MHz; CDCl3) 3.84 (3H, s), 5.66 (2H, s), 6.51 (1H, dd, J=3 and 2), 6.93 (1H, d, J=3), 7.37-7.43 (2H, m), 7.56-7.60 (2H, m), 7.71 (1H, dd, J=8 and 8), 7.90 (1H, s) and 8.80 (1H, s); m/z (ES+) 392 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1.[CH:20]1([NH2:23])[CH2:22][CH2:21]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[CH:20]1([NH:23][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([B:11]3[O:12][C:13]([CH3:18])([CH3:19])[C:14]([CH3:16])([CH3:17])[O:15]3)[CH:4]=2)[CH2:22][CH2:21]1
Reactant: Cc1ccc(C(=O)O)cc1B1OC(C)(C)C(C)(C)O1
Reactant: NC1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (WO200700565, 5.47 g, 20.87 mmol) in N,N′-dimethylformamide (55 mL) were added cyclopropylamine (1.76 mL, 25.08 mmol), diisopropylethylamine (8.00 mL, 45.93 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (7.62 g, 20.04 mmol). The clear solution was stirred at room temperature overnight. The mixture was then concentrated in vacuo and the residue was taken up with ethyl acetate and the organic phase was washed with 4% aqueous sodium bicarbonate solution, water, brine, dried (MgSO4) and concentrated to afford an oily residue. The oil was triturated with a mixture of hexanes and diethyl ether to give the title compound (5.78 g, 96%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[NH:3][N:4]=[C:5]2[C:10]=1[CH:9]=[CH:8][CH:7]=[CH:6]2.[CH2:11]=[O:12]>O>[Cl:1][C:2]1[N:3]([CH2:11][OH:12])[N:4]=[C:5]2[C:10]=1[CH:9]=[CH:8][CH:7]=[CH:6]2
Reactant: C=O
Reactant: Clc1[nH]nc2ccccc12
Solvent: O
Product: OCn1nc2ccccc2c1Cl
Temperature: 25 °C
Yield: 99.7 %

Procedure:
In a 250 mL round bottom flask, 3-chloro-2H-indazole (1.95 g, 10 mmol), 30% HCHO (2 mL, 20 mmol) were mixed in water (10 mL). The reaction mixture was refluxed for 2 hours. After cooling down to room temperature, the solid was filtered, washed with water, and dried under vacuum to provide (3-chloro-2H-indazol-2-yl)methanol (1.82 g, 99% yield).