Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S([O-])([O-])=O.[Na+].[Na+].[OH-].[Na+].[Cl:9][C:10]1[CH:11]=[C:12]([S:17]([O-:19])=[O:18])[CH:13]=[C:14]([Cl:16])[CH:15]=1.Br[C:21]1[S:22][C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][N:25]=1>O.CN(C)C=O>[Cl:16][C:14]1[CH:13]=[C:12]([S:17]([C:21]2[S:22][C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][N:25]=2)(=[O:19])=[O:18])[CH:11]=[C:10]([Cl:9])[CH:15]=1
Reactant: FC(F)(F)c1nnc(Br)s1
Reactant: O=S([O-])c1cc(Cl)cc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=S(=O)(c1cc(Cl)cc(Cl)c1)c1nnc(C(F)(F)F)s1
Yield: 70 %

Procedure:
A solution of 75.6 g (0.6 mole) of analytically pure sodium sulfite in 300 ml of water was pre-warmed to 60°-70° C in a beaker. 122.8 g (0.5 mole) of 3,5-dichlorobenzenesulfochloride, and a solution of 40 g (1 mole) of sodium hydroxide in 200 ml of water were synchronously added dropwise from two dropping funnels in such a way that the pH value (measured with an electrode in the reaction solution) was always between 7 and 9; during the addition the mixture was stirred magnetically. The saline solution of the 3,5-dichlorobenzenesulfinate (about 600 ml) was then diluted with 1.8 liters of dimethylformamide and after adding 116.5 g (0.5 mole) of 2-bromo-5-trifluoromethyl-1,3,4-thiadiazole the whole was stirred for 15 hours at 50° C. The sulfone was precipitated completely by adding ice water and was recrystallized from ethanol. 121 g (70% of theory) of 2-(3',5'-dichlorophenylsulfonyl)-5-trifluoromethyl-1,3,4-thiadiazole of melting point 123° C were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[NH:15][NH2:16].C(O[CH:20](O)[C:21]([F:24])([F:23])[F:22])C>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:13])([F:14])[F:12])=[CH:4][C:3]=1[NH:15][N:16]=[CH:20][C:21]([F:24])([F:23])[F:22]
Reactant: Cc1cc(Cl)c(NN)cc1SCC(F)(F)F
Reactant: CCOC(O)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: Cc1cc(Cl)c(NN=CC(F)(F)F)cc1SCC(F)(F)F
Yield: 67.8 %

Procedure:
A mixture of 4.1 g of 2-chloro-4-methyl-5-(2,2,2-trifluoroethylthio)phenylhydrazine, 2.3 g of trifluoroacetaldehyde ethyl hemiacetal, 0.1 g of p-toluenesulfonic acid monohydrate and 50 ml of ethanol was refluxed with heating for 6 hours. The obtained reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with toluene. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 3.6 g of trifluoroacetaldehyde {2-chloro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}hydrazone.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2.[SH:18][C:19]1[NH:28][C:27](=[O:29])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1>>[N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27](=[O:29])[NH:28][C:19]=1[S:18][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2
Reactant: O=c1[nH]c(S)nc2ccccc12
Reactant: O=C1CCc2cc(OCCCCBr)ccc2N1
Product: O=C1CCc2cc(OCCCCSc3nc4ccccc4c(=O)[nH]3)ccc2N1

Procedure:
Prepared analogous to Example 1 from 6-(4-bromobutoxy)-3,4-dihydro-carbostyril m.p. 142°-147° C.) and 2-mercaptoquinazoline-4-one.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][N:8](C(OCC2C=CC=CC=2)=O)[CH:7]2[CH2:20][CH2:21][N:22]([C:23](=[O:39])[CH:24]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:6]12)=[O:4]>CO.[Pd]>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][NH:8][CH:7]2[CH2:20][CH2:21][N:22]([C:23](=[O:39])[CH:24]([NH:31][C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:6]12)=[O:4]
Reactant: COC(=O)C1CN(C(=O)OCc2ccccc2)C2CCN(C(=O)C(NC(=O)OC(C)(C)C)C3CCCCC3)C12
Agent: [Pd]
Solvent: CO
Product: COC(=O)C1CNC2CCN(C(=O)C(NC(=O)OC(C)(C)C)C3CCCCC3)C21
Reaction time: 1.5 h
Yield: 99.9 %

Procedure:
A solution of 16 (1.2 g, 2.2 mmol) in MeOH (30 mL) was treated with Pd/C (10% wet, 354 mg) and placed under H2 (50 psi) using a Parr apparatus. After 1.5 h, the reaction mixture was filtered through syringe filter disc (Acrodisc-PSF-0.45 μM) and rinsed with MeOH. The filtrate was concentrated to afford crude 27 (0.9 g) as a glassy solid which was used without further purification. 1H NMR (CDCl3, 300 MHz): δ5.23 (d, J=9.0 Hz, 1H), 4.83 (dd, J=2.1, 6.0 Hz, 1H), 4.32-4.21 (m, 2H), 4.03 (app t, J=9.9 Hz, 1H), 3.77 (s, 3H), 3.86-3.32 (m, 1H), 3.25-3.23 (m, 1H), 2.49-2.42 (m, 1H), 2.27-2.13 (m, 1H), 1.72-1.59 (m, 6H), 1.42 (s, 9H), 1.31-0.99 (m, 6H) ppm; 13C NMR (CDCl3, 75 MHz): δ172.1, 171.5, 156.1, 79.9, 65.4, 61.8, 56.8, 52.9, 50.2, 49.3, 46.4, 41.0, 30.4, 29.9, 28.5, 28.3, 26.2, 26.1, 26.0 ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([CH:10]1[O:12][CH2:11]1)[Cl:9]>C(O)C>[Cl:9][CH2:8][CH:10]([OH:12])[CH2:11][N:1]([CH2:11][CH:10]([OH:12])[CH2:8][Cl:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCC1CO1
Reactant: Nc1ccccc1
Solvent: CCO
Product: OC(CCl)CN(CC(O)CCl)c1ccccc1
Yield: 75 %

Procedure:
1.0 mol of aniline and 2.4 mol of epichlorohydrin are heated in 375 ml of ethanol for 16 h under reflux. The solvent is then removed in vacuum and the residue introduced drop by drop into n-hexane. The crystals obtained are filtered off and dried (yield: 75%); MP: 60° C.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:12]=[C:11]([C:13](OC)=[O:14])[CH:10]=[CH:9][C:8]=2[C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=2[F:25])[CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>C1COCC1>[O:1]1[CH2:2][CH:3]=[C:4]([C:7]2[CH:12]=[C:11]([CH2:13][OH:14])[CH:10]=[CH:9][C:8]=2[C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=2[F:25])[CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C2=CCOCC2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(CO)cc2C2=CCOCC2)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 80.9 %

Procedure:
To a cooled solution of 66.46F (452.7 mg, 1.3 mmol) in dry THF (10 mL) at 0° C. was added LAH (1.0 M in THF) (2.7 mL, 2.7 mmol) dropwise. Upon complete addition, the reaction was maintained at 0° C. and was monitored by TLC and LCMS. After 45 minutes, 1N NaOH was added to quench the reaction. The resulting solution was extracted three times with EtOAc. After drying over anhydrous magnesium sulfate, filtration, and concentration, the residue was purified by flash chromatography (silica gel 60, eluted with 0%-50% EtOAc in hexanes). Fractions containing the desired product were combined and concentrated to provide 66.46G as a colorless oil (330.4 mg, 80%). 1H NMR (400 MHz, CDCl3) δ ppm 7.33 (3H, m), 7.03 (1H, m), 6.84 (2H, m), 5.51 (1H, s), 4.69 (2H, s), 4.08 (2H, q, J=2.5 Hz), 3.77 (3H, s), 3.67 (2H, t, J=5.3 Hz), 3.00 (1H, s), 2.13 (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH2:11][C:7]=2[N:6]=[C:5]([NH:12][C:13](=[N:17][S:18]([C:21]2[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=2[C:23]([O:25][CH3:26])=[O:24])(=[O:20])=[O:19])SCC)[N:4]=1.CC(C)=[O:33]>>[CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH2:11][C:7]=2[N:6]=[C:5]([NH:12][C:13]([NH:17][S:18]([C:21]2[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=2[C:23]([O:25][CH3:26])=[O:24])(=[O:20])=[O:19])=[O:33])[N:4]=1
Reactant: CCSC(=NS(=O)(=O)c1ccccc1C(=O)OC)Nc1nc2c(c(OC)n1)CCC2
Reactant: CC(C)=O
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc2c(c(OC)n1)CCC2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 3.2 g of methyl 2-[[1-(6,7-dihydro-4-methoxy-5H-cyclopentapyrimidin-2-ylamino)-1-(ethylthio)methylene]aminosulfonyl]benzoate in 75 ml of acetone is treated with 3.0 g of mercuric oxide and stirred at room temperature for 3 days. The mercury salts are removed by filtration and the solvent is evaporated to yield the solid product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@:10]2([CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)[CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[C:28]([CH3:35])[CH:27]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@:10]2([CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:30](=[O:31])[C:29]4[CH:33]=[CH:34][C:26]([O:25][CH3:24])=[CH:27][C:28]=4[CH3:35])=[CH:19][CH:18]=3)[CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(C(=O)O)c(C)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@]2(CCN(c3ccc(N)cc3)C2)C1
Product: COc1ccc(C(=O)Nc2ccc(N3CC[C@]4(CCN(C(=O)OC(C)(C)C)C4)C3)cc2)c(C)c1

Procedure:
According to Method P, (S)-7-(4-amino-phenyl)-2,7-diaza-spiro[4.4]nonane-2-carboxylic acid tert-butyl ester was reacted with 4-methoxy-2-methyl-benzoic acid. In this way the product was obtained with molecular weight 465.60 (C27H35N3O4); MS (ESI): 466 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[C:5](Cl)=[O:6])[CH3:2].[C:9]([SiH2:13][O:14][C:15]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:16]1[N:17]=[CH:18][C:19]2[N:20]([CH:22]=[C:23]([CH3:25])[N:24]=2)[CH:21]=1)([CH3:12])([CH3:11])[CH3:10].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1>[CH2:1]([O:3][C:4](=[O:8])[C:5]([C:22]1[N:20]2[CH:21]=[C:16]([C:15]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[O:14][SiH2:13][C:9]([CH3:12])([CH3:11])[CH3:10])[N:17]=[CH:18][C:19]2=[N:24][C:23]=1[CH3:25])=[O:6])[CH3:2]
Reactant: Cc1cn2cc(C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)ncc2n1
Reactant: CCOC(=O)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1c(C)nc2cnc(C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)cn12
Temperature: 120 °C
Yield: 64.3 %

Procedure:
In a reaction tube, chloro-oxo-acetic acid ethyl ester (0.51 ml, 4.5 mmol, 7.2 equiv) is added to a solution of 6-(tert-butyl-diphenyl-silanyloxymethyl)-2-methyl-imidazo[1,2-a]pyrazine (250 mg, 0.62 mmol) in anhydrous THF (5 ml) under an atmosphere of argon. The tube is sealed under argon, and the reaction mixture is heated under microwave irradiation for 30 minutes at 120° C. After cooling, the reaction mixture is carefully poured into an aqueous solution of sodium carbonate. After three extractions with EtOAc, the combined organic layers are dried over Na2SO4, filtered and concentrated in vacuo. Purification via flash chromatography (hexane/EtOAc 4:1) affords the title compound (200 mg, 64%). 1H NMR (400 MHz, d6-DMSO): δ=9.49 (d, J=1.4 Hz, 1H), 9.25 (d, J=1.4 Hz, 1H), 7.70-7.67 (m, 4H), 7.48-7.42 (m, 6H), 4.95 (s, 2H), 4.47 (q, J=7.4 Hz, 2H), 2.57 (s, 3H), 1.38 (t, J=7.4 Hz, 3H), 1.11 (s, 9H). MS (ES+): 502 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:14]3[CH:22]=[CH:21][C:20]4[C:16](=[CH:17][N:18]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[N:19]=4)[CH:15]=3)([OH:13])[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[CH3:31][N:32]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[N:33]1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>COCCOC.[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:31][N:32]1[CH:36]=[C:35]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C:11]([C:14]4[CH:22]=[CH:21][C:20]5[C:16](=[CH:17][N:18]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[N:19]=5)[CH:15]=4)([OH:13])[CH3:12])=[CH:9][N:10]=3)[N:7]=2)[CH:34]=[N:33]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(O)(c1ccc2nn(COCC[Si](C)(C)C)cc2c1)c1cnc2ccc(Cl)nn12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1cc(-c2ccc3ncc(C(C)(O)c4ccc5nn(COCC[Si](C)(C)C)cc5c4)n3n2)cn1
Temperature: 80 °C

Procedure:
To a solution of (rac)-1-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-1-[2-(2-trimethylsilanyl-ethoxymethyl)-2H-indazol-5-yl]-ethanol (Stage 195.2, 400 mg, 0.901 mmol) in DME (4 mL) degassed with argon was added 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (281 mg, 1.351 mmol), followed by 2 M K2CO3 (1.216 mL) and PdCl2(PPh3)2 (19 mg). The RM was heated at 80° C. for 5 h. It was then taken into EtOAc and brine and extracted. Combined organic layers were dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (CombiFlash® Companion System®, with RediSep® silica gel column, EtOAc/MeOH=100:0->80:20) to afford the title compound (tR 4.56 min (conditions 3), MH+=490).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][OH:10])=[CH:7][CH:6]=1.C1OCCOCCOCCOCCOC1.[Cl:28][C:29]1[CH:38]=[C:37](Cl)[C:36]2[C:31](=[C:32]([Cl:42])[C:33]([O:40][CH3:41])=[CH:34][CH:35]=2)[N:30]=1>CN(C=O)C.O>[Cl:28][C:29]1[CH:38]=[C:37]([O:10][CH2:9][C:8]2[CH:11]=[CH:12][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)[C:36]2[C:31](=[C:32]([Cl:42])[C:33]([O:40][CH3:41])=[CH:34][CH:35]=2)[N:30]=1
Reactant: COc1ccc2c(Cl)cc(Cl)nc2c1Cl
Reactant: COc1ccc(CO)cc1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(COc2cc(Cl)nc3c(Cl)c(OC)ccc23)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
NaH (60% in oil) (670 mg, 1.2 eq.) was added portionwise to a stirred solution of p-methoxybenzylalcohol (2.31 g, 1.2 eq.) and 15-crown-5 (3.32 mL, 1.2 eq.) in anhydrous DMF (10 mL). The mixture was stirred at room temperature for 30 min. Compound 220d (3.66 g, 1 eq.) in anhydrous DMF (25 mL) was then added and the reaction mixture was stirred at room temperature for 16 hrs. The reaction mixture was then poured into water (300 mL), extracted with EtOAC, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by chromatography on silica gel (petroleum ether/DCM, 50/50) to give compound 221d as a yellow solid in 38% yield. 1H NMR (CDCl3, 376 MHz) δ (ppm) 3.86 (s, 3H), 4.05 (s, 3H). 5.20 (s, 2H), 6.77 (s, 1H), 6.98 (d, J=8.53 Hz, 2H), 7.23 (d, J=9.41, 1H), 7.42 (d, J=8.53 Hz, 2H), 8.08 (d, J=9.41 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][CH:33]=1)[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[C:16]([NH:18][C@H:19]([C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=2)[CH3:20])=[O:17])[CH:9]=[CH:8]1.[OH-].[Na+]>C1COCC1.CO>[F:34][C:2]([F:1])([F:35])[C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][CH:33]=1)[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[C:16]([NH:18][C@H:19]([C:21]2[CH:30]=[CH:29][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=2)[CH3:20])=[O:17])[CH:9]=[CH:8]1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cccc3ccn(Cc4cccc(C(F)(F)F)c4)c23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](NC(=O)c1cccc2ccn(Cc3cccc(C(F)(F)F)c3)c12)c1ccc(C(=O)O)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Methyl 4-{(1S)-1-[({1-[3-(trifluoromethyl)benzyl]-1H-indol-7-yl}carbonyl)amino]ethyl}benzoate (220 mg, 0.458 mmol) was dissolved in THF (2 ml) and MeOH (1.14 ml). 2M NaOH (1.14 ml, 2.29 mmol) was added and the mixture stirred at 50° C. for 1 hour. The mixture was cooled, the organic solvents removed and poured into 1N HCl. The resulting solid was filtered and washed with water. 1H NMR (500 MHz, DMSO-d6): δ 12.90 (bs, 1H), 8.90 (d, 1H), 7.85 (d, 2H), 7.75 (d, 1H), 7.65-7.55 (m, 2H), 7.50-7.40 (m, 3H), 7.25 (m, 2H), 7.15-7.00 (m, 4H), 7.00 (d, 1H), 6.65 (s, 1H), 5.60 (dd, 2H), 5.00 (m, 1H), 1.20 (d, 3H). MS-ESI (464.9).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][C:18]2[N:22]3[CH:23]=[CH:24][N:25]=[C:26]([NH2:27])[C:21]3=[C:20]([C:28]3[CH:37]=[C:36]4[C:31]([CH:32]=[CH:33][C:34]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)=[N:35]4)=[CH:30][CH:29]=3)[N:19]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.Cl>>[C:38]1([C:34]2[CH:33]=[CH:32][C:31]3[C:36](=[CH:37][C:28]([C:20]4[N:19]=[C:18]([CH2:17][CH:14]5[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]5)[N:22]5[CH:23]=[CH:24][N:25]=[C:26]([NH2:27])[C:21]=45)=[CH:29][CH:30]=3)[N:35]=2)[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: Nc1nccn2c(CC3CCN(C(=O)OCc4ccccc4)CC3)nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c12
Agent: Cl
Product: Nc1nccn2c(CC3CCNCC3)nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c12
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
4-[8-Amino-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-ylmethyl]-piperidine-1-carboxylic acid benzyl ester (1.94 g, 3.41 mmol) was mixed with 37% HCl (90.00 mL, 3.96 mol), heated to 60° C. and continued to stir for 5 mins. It was then cooled to rt, washed with ether (2×90 mL) and then with CH2Cl2 (2×90 mL). The aqueous layer was gradually basified with 5N NaOH and extracted with CH2Cl2 (3×50 mL). The combined organic layer was dried with Na2SO4, filtered and concentrated in vacuo. The crude product was purified by a 25 g Jones silica gel (eluted with 10% (7N NH3) in MeOH/EtOAc), affording the desired product; 1H NMR (400 MHz, METHANOL-d) δ 8.38 (1H, d, J=8.68), 8.24 (1H, d, J=0.74 Hz), 8.08 (2H, dd, J=1.55 Hz, J=1.19), 8.00 (2H, m), 7.80 (1H, dd, J=1.68, J=1.70), 7.51 (1H, d, J=5.14), 7.44 (3H, m), 6.99 (1H, d, J=5.10), 2.99 (2H, d, J=12.60), 2.94 (2H, d, J=7.20), 2.55 (2H, t), 2.01 (1H, m), 1.66 (2H, d, J=12.72), 1.29 (2H, m); MS (ES+): m/z 435.12/436.10 (15/5) [MH+]; HPLC: tR=1.71 min (OpenLynx, polar—5 min).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH3:17])[CH:10]=[C:11]([C:13](OC)=[O:14])[N:12]=2)=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].CCOC(C)=O.[OH-].[Na+]>C1(C)C=CC=CC=1>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([CH3:17])[CH:10]=[C:11]([CH2:13][OH:14])[N:12]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1cn(C)c(-c2ccc(I)cc2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cn1cc(CO)nc1-c1ccc(I)cc1
Temperature: 110 °C

Procedure:
To a suspension of methyl 2-(4-iodophenyl)-1-methyl-1H-imidazole-4-carboxylate prepared above (72 mg, 0.21 mmol) in toluene (4 mL), LiAlH4 (61 mg, 1.6 mmol) was added. The mixture was heated at 110° C. overnight. After being cooled to room temperature, EtOAc (15 mL) and 1N aq. NaOH (15 mL) were added. The mixture was filtered through celite. The organic layer was separated, dried over Na2SO4, concentrated in vacuo to give (2-(4-iodophenyl)-1-methyl-1H-imidazol-4-yl)methanol (46 mg). MS 315.0 (M+H).
Reaction SMILES: Br[C:2]1[C:3]([OH:11])=[C:4]([CH:7]=[C:8]([CH3:10])[CH:9]=1)[CH:5]=[O:6].[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].CCOCC.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>[OH:11][C:3]1[C:4]([CH:5]=[O:6])=[CH:7][C:8]([CH3:10])=[CH:9][C:2]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1cc(Br)c(O)c(C=O)c1
Reactant: OB(O)c1ccccc1
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: CCOCC
Solvent: Cc1ccccc1
Product: Cc1cc(C=O)c(O)c(-c2ccccc2)c1
Temperature: 80 °C
Yield: 50.5 %

Procedure:
A mixture of 3-bromo-2-hydroxy-5-methylbenzaldehyde (0.30 g, 1.40 mmoles), phenyl boronic acid (0.20 g, 1.67 mmoles) and tetrakis(triphenylphosphine)palladium(0) (81 mg, 0.07 mmoles) in toluene (10 ml) and 2M K2CO3 (3 ml) was heated to 80° C. for 2 hr. The reaction mixture was cooled to ambient temperature, diluted with ether (100 ml) and washed with NaHCO3. The organic layer was dried (MgSO4), filtered and concentrated to yield a residue which was purified using flash chromatography (10% ethyl acetate/hexanes) to yield 0.15 g (49%) of the title compound as a yellow oil.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][C:5]([CH2:7]Cl)=[CH2:6].[OH:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].CC(O)=O>CN(C)C=O.C1COCC1>[CH2:6]=[C:5]1[CH2:7][O:9][CH2:10][CH2:11][N:12]([C:13]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:19])[CH2:4]1
Reactant: C=C(CCl)CCl
Reactant: CC(C)(C)OC(=O)NCCO
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C=C1COCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
60% Sodium hydride in oil (26 g, 0.65 mol, 2.17 eq) was added in one portion in a stream of argon at 5° C. to a solution of 3-chloro-2-(chloromethyl)prop-1-ene (35 mL, 0.3 mol, 1 eq) in dimethylformamide (500 mL). Then a solution of tert-butyl (2-hydroxyethyl)carbamate (48.3 g, 0.3 mol, 1 eq) in THF (500 mL) was added, and the reaction mixture was heated to 25° C. and stirred at this temperature for 2 h. The reaction mixture was then neutralized with glacial AcOH (4.5 mL) and evaporated in a water aspirator in vacuo at 45-55° C. using a 15-cm reflux condenser. The residue was poured with water (300 mL) and extracted with a mixture of ethylacetate (200 mL), hexane (100 mL) and chloroform (50 mL). The organic layer was separated and washed with water (2×100 mL) and brine. The combined aqueous layer was extracted with a mixture of ethylacetate (150 mL) and hexane (50 mL). The organic layer was separated and washed with water (2×100 mL) and brine. The extracts were filtered sequentially through silica gel (25 g) and sodium sulphate (50 mL), eluting with chloroform (100 mL). The filtrate was evaporated, and the residue was distilled in vacuo to give title compound as a colorless oil (bp 76-79° C. at 0.7 mm Hg) (35.8 g, 0.168 mol, 53%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][CH2:11][CH3:12])=[CH:5][CH:4]=1.[Cl-].[OH:15][NH3+:16].C([O-])(=O)C.[Na+]>C(O)C.O>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[N:16][OH:15])[CH2:10][CH2:11][CH3:12])=[CH:5][CH:4]=1
Reactant: [NH3+]O
Reactant: CCCC(=O)c1ccc(SC)cc1
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCC(=NO)c1ccc(SC)cc1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
9.72 g (50 mmol) of 1-(4-Methylsulfanyl-phenyl)-butane-1-one is dissolved in hot ethanol. Then a solution of hydroxylammonium chloride (3.58 g, 51.5 mmol) and sodium acetate (7.0 g, 85 mmol) in 20 ml of water is added, and the reaction solution is stirred at 100° C. for 4 hrs. After cooling and concentrating, water is added. The crude product is extracted with ethyl acetate, washed with brine, dried over MgSO4, and concentrated. The residue is purified by column chromatography on silica gel with ethyl acetate-hexane (20:80) as an eluent. The structure is confirmed by the 1H-NMR spectrum (CDCl3). δ[ppm]: 0.98 (t, 3H), 1.54-1.64 (m, 2H), 2.50 (s, 3H), 2.76 (t, 2H), 7.24 (d, 2H), 7.54 (d, 2H), 7.98 (s, 1H).
Reaction SMILES: ClC1C=CC=C(Cl)C=1C(NC1C(C2NC3C=CC(CN4CCOCC4)=CC=3N=2)=NNC=1)=O.[F:33][C:34]1[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[C:35]=1[C:36]([NH:38][C:39]1[C:40]([C:44](O)=O)=[N:41][NH:42][CH:43]=1)=[O:37].[Cl:52][C:53]1[C:58]([Cl:59])=[CH:57][C:56]([NH2:60])=[C:55]([NH2:61])[CH:54]=1>>[Cl:52][C:53]1[C:58]([Cl:59])=[CH:57][C:56]2[NH:60][C:44]([C:40]3[C:39]([NH:38][C:36](=[O:37])[C:35]4[C:34]([F:33])=[CH:50][CH:49]=[CH:48][C:47]=4[F:51])=[CH:43][NH:42][N:41]=3)=[N:61][C:55]=2[CH:54]=1
Reactant: O=C(O)c1n[nH]cc1NC(=O)c1c(F)cccc1F
Reactant: Nc1cc(Cl)c(Cl)cc1N
Agent: O=C(Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1)c1c(Cl)cccc1Cl
Product: O=C(Nc1c[nH]nc1-c1nc2cc(Cl)c(Cl)cc2[nH]1)c1c(F)cccc1F

Procedure:
The compound was prepared in a manner analogous to 2,6-dichloro-N-[3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-benzamide (Example 94E), however using 4-(2,6-difluoro-benzoylamino)-1H-pyrazole-3-carboxylic acid (Example 16D) and 4,5-dichloro-1,2-phenylene diamine to give N-[3-(5,6-dichloro-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-2,6-difluoro-benzamide (29 mg) as a beige solid. (LC/MS: Rt 3.53, [M+H]+ 408.02).