Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.CC[Mg+].[Br-].[F:16][C:17]1[C:26]([CH:27]=[O:28])=[C:25]([F:29])[CH:24]=[C:23]2[C:18]=1[CH:19]=[CH:20][CH:21]=[N:22]2>C1COCC1>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([CH:27]([C:26]3[C:17]([F:16])=[C:18]4[C:23](=[CH:24][C:25]=3[F:29])[N:22]=[CH:21][CH:20]=[CH:19]4)[OH:28])=[CH:3][N:4]=2)[N:7]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: O=Cc1c(F)cc2ncccc2c1F
Agent: CC[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: OC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(Cl)nn12
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a solution of 3-bromo-6-chloro-imidazo[1,2-b]pyridazine (2.40 g, 10.35 mmol) in 30 mL of THF was added EtMgBr (1 M in THF, 12.43 mL, 12.42 mmol) solution at rt. The solution was stirred for 30 min and a solution of 5,7-difluoroquinoline-6-carbaldehyde (2.0 g, 10.35 mmol) in 10 mL of THF was added. The resulting mixture was stirred at rt for additional 2 h and then quenched with 50 mL of NH4Cl solution. The solution was extracted with EtOAc and the combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated in vacuo to afford 3.48 g (97%) of the title compound. LCMS (method B): [MH]+=347, tR=1.23 min.
Reaction SMILES: C[C:2]1[C:3]([CH3:30])=[C:4]([C:23](=[N:27][O:28][CH3:29])[C:24]([NH2:26])=[O:25])[CH:5]=[C:6]([C:8]2[CH:12]=[CH:11][N:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[N:9]=2)[CH:7]=1.CN.[CH2:33](OCC)C>O1CCCC1>[CH3:29][O:28][N:27]=[C:23]([C:4]1[CH:5]=[C:6]([C:8]2[CH:12]=[CH:11][N:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[N:9]=2)[CH:7]=[CH:2][C:3]=1[CH3:30])[C:24]([NH:26][CH3:33])=[O:25]
Reactant: CON=C(C(N)=O)c1cc(-c2ccn(-c3cccc(C(F)(F)F)c3)n2)cc(C)c1C
Reactant: CCOCC
Agent: CN
Solvent: C1CCOC1
Product: CNC(=O)C(=NOC)c1cc(-c2ccn(-c3cccc(C(F)(F)F)c3)n2)ccc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl α-(methoxyimino)-2-methyl-5-[1-[3-(trifluoromethyl)phenyl]-1H-pyrazol-3-yl]benzeneacetamide (i.e. the product of Example 13) (0.062 g, 0.149 mmol) in tetrahydrofuran (2 mL) under a nitrogen atmosphere was added methylamine (33% by weight in ethanol). The reaction mixture was stirred overnight at room temperature and then concentrated under reduced pressure to leave a solid. Hexanes and diethyl ether were added to the solid, and the mixture was filtered to obtain the tile compound, a compound of the present invention, as a white solid (56 mg).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]([OH:21])([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:9][C:10](OCC)=[O:11]>C(OCC)C>[CH3:7][C:8]([OH:21])([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:9][CH2:10][OH:11]
Reactant: CCCCCCC(C)(O)CC(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCCCCCC(C)(O)CCO
Yield: 97.1 %

Procedure:
To a slurry of lithium aluminium hydride (12.3 g, 0.325 mol) in diethyl ether (300 ml), under nitrogen and cooled in an ice-bath, was added dropwise a solution of ethyl 3-methyl-3-hydroxynonanoate (70.0 g, 0.325 mol) in diethyl ether (300 ml). The resultant mixture was boiled at reflux for 1 hr, then cooled in an ice-bath. Excess lithium aluminium hydride was destroyed by successive dropwise addition of water (12 ml), 10% sodium hydroxide solution (12 ml) and water (36 ml). The reaction mixture was filtered, the filter cake was washed with diethyl ether (2×100 ml) and the filtrate was washed with saturated sodium chloride solution (1×250 ml) and then dried (Na2SO4) and filtered, and the filtrate was concentrated in vacuo to give 3-methyl-3-hydroxynonan-1-ol (55.0 g) as an oil (i.r.(cm-1), OH, 3500). 3-Methyl-3-hydroxy-nonan-1-ol (55.0 g, 0.316 m) was dissolved in pyridine (235 ml) and cooled to 0° C. with stirring. p-Toluenesulphonyl chloride (63.5 g, 0.332 mol) was added portionwise and the resultant mixture stirred for 45 minutes at 0° C. The reaction mixture was stored in a refrigerator for 15 hr and then poured into iced-water (200 ml). The reaction mixture was extracted with diethyl ether (3×200 ml), and the combined extracts were washed with 10% hydrochloric acid (2×200 ml), and saturated sodium chloride solution (3×200 ml) and then dried (Na2SO4). This mixture was filtered, and the filtrate was concentrated at room temperature in vacuo to leave a gum (100 g). This gum was mixed with petrol (b.pt. 60°-80° C., 400 ml) and gradually cooled to -78° C. with stirring, and the petrol was decanted. Residual petrol was removed by evaporation in vacuo at room temperature to give 1-(p-toluenesulphonyloxy)-3-methylnonan-3-ol (90.0 g) as a gum.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][N:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH2:24][CH2:25]Cl)(=[O:22])=[O:21])[CH2:16][CH2:15]1.[CH3:27][O-:28].[Na+]>CO.[I-].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][N:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH2:24][CH2:25][O:28][CH3:27])(=[O:22])=[O:21])[CH2:16][CH2:15]1
Reactant: C[O-]
Reactant: NC(=O)c1cc(Br)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)n[nH]c12
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: COCCCS(=O)(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 5-bromo-3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-1H-indazole-7-carboxamide (Intermediate 7) in MeOH (1.5 mL) were added 3.8 M sodium methoxide in MeOH (1 mL) and sodium iodide (5.0 mg). The reaction mixture was stirred at 80° C. overnight and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (15 mL) and washed with water (5 mL). The organic phase was collected, dried over MgSO4, filtered and concentrated to give the crude title compound (30 mg), which was used in the next step without further purification.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][N:14]([CH3:17])[N:15]=O.[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[C:21]#[N:22]>C1COCC1>[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[C:21]1[N:22]=[N:15][N:14]([CH3:17])[CH:13]=1
Reactant: N#Cc1ccccc1F
Reactant: CN(C)N=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cn1cc(-c2ccccc2F)nn1
Reaction time: 1.5 h
Yield: 44.1 %

Procedure:
To a pre cooled (−78° C., internal temp. −70° C.) solution of diisopropyl amine (193.13 g, 1899.04 mmol) in THF (1500 ml) under nitrogen atmosphere was added n-Butyllithium (759.617 ml, 1899.04 mmol, 2.5 M solution in hexane) and stirred for 90 min. Then N,N-dimethyl nitrous amide 2 (134.57 g, 1816.48 mmol) in THF (500 ml) was cannulated portion wise during a period of 30 min. and stirred for 1 h. Then a solution of 2-Fluorobenzonitrile 1 (100.0 g, 825.671 mmol) in THF (500 ml) was cannulated portion wise during a period of 30 min and stirred at −78° C. (internal temp. −70° C.) for 1 h. Then cooling bath was removed and stirred at room temperature for 2 h. The reaction was monitored by TLC and UPLC. The above reaction mass was slowly quenched with saturated solution of ammonium chloride (2000 ml) at room temperature and the aqueous layer was extracted with dichloromethane (5×2000 ml). The combined organic layer was dried over sodium sulphate, filtered and concentrated to afford crude mass (170.0 g, 116.21% mass balance). It was purified by gravity column using 30% ethyl acetate in pet ether as an eluent to furnish desired product 4-(2-fluorophenyl)-1-methyl-1H-1,2,3-triazole (64.52 g, 44.10% mass balance) as reddish gum. Then it was triturated with methyl tert-butyl ether (1000 ml) and hexane (500 ml), the supernant layer was decanted and the solid was dried to furnish desired product 4-(2-fluorophenyl)-1-methyl-1H-1,2,3-triazole (32.9 g, 22.49%) as yellowish solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([CH:10](O)[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:6][CH:5]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[Br:48][C:49]1[CH:54]=[CH:53][C:52]([SH:55])=[CH:51][CH:50]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([S:55][C:52]2[CH:53]=[CH:54][C:49]([Br:48])=[CH:50][CH:51]=2)[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:6][CH:5]=1
Reactant: Sc1ccc(Br)cc1
Reactant: COC(=O)c1ccc(C(O)CC(C)C)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C(CC(C)C)Sc2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(1-hydroxy-3-methyl-butyl)-benzoic acid methyl ester (1240 mg, 5.59 mmol) in toluene (10 mL) is added 1,1′-(azodicarbonyl)dipiperidine (ADDP, 2114 mg, 8.38 mmol) at 0° C., followed by the additions of tributylphosphine (2.09 mL, 8.38 mmol) and 4-bromo-thiophenol (1267 mg, 6.7 mmol). The reaction mixture is warmed up to room temperature and stirred overnight. The mixture is loaded on silica gel, eluted with hexanes with a gradient from 0% of ethyl acetate to 50% of ethyl acetate giving 4-[1-(4-bromo-phenylsulfanyl)-3-methyl-butyl]-benzoic acid methyl ester. 393 mg of the ester product is taken into ethanol (2 mL), treated with sodium hydroxide (5N aqueous, 1 mL) for 3 h at room temperature. The mixture is concentrated, diluted with ethyl acetate, acidified with 5 N HCl (1.1 mL), extracted with ethyl acetate. The organic layers are dried and concentrated giving 4-[1-(4-bromo-phenylsulfanyl)-3-methyl-butyl]-benzoic acid (379 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[C:7](=[O:12])[N:6]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH:5]2[CH2:19][C:20](OCC)=[O:21].[BH4-].[Na+]>CO>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[C:7](=[O:12])[N:6]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH:5]2[CH2:19][CH2:20][OH:21]
Reactant: CCOC(=O)CC1c2cc(C)c(C)cc2C(=O)N1c1cccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc2c(cc1C)C(CCO)N(c1cccnc1)C2=O
Temperature: 80 °C
Yield: 81.7 %

Procedure:
To a solution of 5,6-dimethyl-3-ethoxycarbonylmethyl-2-(3-pyridyl)isoindolin-1-one [IUPAC name: ethyl 2-[5,6-dimethyl-3-oxo-2-(3-pyridinyl)-2,3-dihydro-1H-isoindol-1-yl]acetate] (8.4 g, 26 mmol) in methanol (250 ml) was added by portions sodium borohydride (11 g, 0.52 mmol), and the reaction mixture was stirred with heating at 80° C. for 3 hrs. To the reaction solution was added ice-cold water, and the precipitated crystals were collected by filtration, washed with water, and dried to give 6.0 g of 5,6-dimethyl-2-(3-pyridyl)-3-(2-hydroxyethyl)isoindolin-1-one.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]([OH:15])=O)[N:3]=1.F[P-](F)(F)(F)(F)F.N1([O+]=C(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:40][O:41][CH2:42][CH2:43][NH2:44].C(N(C(C)C)C(C)C)C>ClCCl>[CH3:40][O:41][CH2:42][CH2:43][NH:44][C:13]([C:4]1[N:3]=[C:2]([Cl:1])[C:11]2[C:6]([C:5]=1[OH:12])=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:15]
Reactant: COCCN
Reactant: O=C(O)c1nc(Cl)c2ccccc2c1O
Agent: CN(C)C(=[O+]n1nnc2ccccc21)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCNC(=O)c1nc(Cl)c2ccccc2c1O
Reaction time: 288 h
Yield: 15.7 %

Procedure:
To a mixture of 45 mg (0.2 mmol) of 1-chloro-4-hydroxy-isoquinoline-3-carboxylic acid (from example A-1 d), 76 mg (0.2 mmol) of benzotriazol-1-yl-(bis-dimethylamino-methylene)-oxonium hexafluoro phosphate (HBTU), 18 μl 2-methoxy-ethylamine (0.2 mmol), and 1 ml of dichloromethane were added 96 μl (0.55 mmol) of ethyl-diisopropyl-amine with stirring. Stirring was continued at ambient temperature for 12 days. The product was isolated from the reaction mixture by flash column chromatography on silica gel using hexanes:ethyl acetate (9:1) as the eluent to give a white solid. 8.8 mg of the title compound were obtained; MS-(+)-ion: M+1=281.0.
Reaction SMILES: C1(C)C=CC=CC=1.[C:8]([O:12][C:13]([NH:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[O:22][CH:21](O)[CH2:20][CH2:19]2)=[O:14])([CH3:11])([CH3:10])[CH3:9].[C:27]([CH:32]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:29][CH2:30][CH3:31])=[O:28].[O-]CC.[Na+]>C1(C)C=CC=CC=1>[C:8]([O:12][C:13]([NH:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[O:22][CH:21]([CH2:32][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:20][CH2:19]2)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)CCC(O)O2
Agent: CC[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1CCc2cc(NC(=O)OC(C)(C)C)ccc2O1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
Into the 6-(tert-butyloxycarbonylamino)chroman-2-ol toluene solution of Example 2 (8 L) was added 1225 g of (carbethoxymethylene)triphenylphosphorane (95%) and 1.1 g of sodium ethoxide. The stirred reaction was heated to 80° C. for 2 h. An additional 3.2 g of sodium ethoxide was added, and the mixture stirred at 80° C. for 18 h. Because the reaction was not complete by TLC, an additional 122 g of (carbethoxymethylene)triphenylphosphorane and 1.0 g of sodium ethoxide was added. The reaction mixture was stirred at 80° C. for 3 h after the addition. The reaction was cooled to room temperature, and 3750 g of silica gel and 7 L of toluene were added. The mixture was stirred for 2 h, filtered, and the filter cake was washed with 2×12 L of toluene. The filtrate and washings were combined, and the volume reduced to about 7 L by distillation under reduced pressure (T≦60° C.) to provide a toluene solution of ethyl 2-(6-(tert-butyloxycarbonylamino)chroman-2-yl)acetate.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10](OCC)=[O:11].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:10][OH:11]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cc2ccccc2[nH]1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 106.2 %

Procedure:
To ethyl 1H-indole-2-carboxylate 16 (6.5 g, 34.35 mmol) in THF at 0° C. was added lithium aluminum hydride solution (1M, in THF 1.43 g, 37.78 mmol) dropwise and the reaction mixture was stirred for 3.5 hours at 0° C. The reaction mixture was quenched with H2O, 15% NaOH, and H2O before it was filtered and rinsed with THF. Reaction mixture was dried (anhydrous Na2SO4) and evaporation of the solvent gave 5.37 g (100% yield) of the crude (1H-indol-2-yl)methanol 17 which was used directly in the next step.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[CH2:3][N:4]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[N:5]1.[N-:24]=[N+:25]=[N-:26].[Na+]>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]([F:23])([F:22])[CH2:3][N:4]1[C:9](=[O:10])[C:8]([N:24]=[N+:25]=[N-:26])=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[N:5]1
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)c1ccc(-c2cnn(CC(F)(F)F)c(=O)c2Cl)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-c2cnn(CC(F)(F)F)c(=O)c2N=[N+]=[N-])cc1
Reaction time: 2 h
Yield: 95 %

Procedure:
2-(2,2,2-Trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone, prepared according to Example 193E, (500 mg, 1.36 mmol) was dissolved in DMF (10 mL) and treated with NaN3 (100 mg, 1.5 mmol). After 2 hours at room temperature, the reaction was diluted with ethyl acetate and washed with water, 4 times, and dried over MgSO4. After filtration of the drying agent and concentration of the filtrate in vacuo, the residue was purified by chromatography on silica gel (Biotage 40S) eluted with 2:1 hexanes-ethyl acetate. The product fractions were combined and evaporated to provide the azido intermediate, 2-(2,2,2-Trifluoroethyl)-4-azido-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 481 mg, 95%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH2:15][CH3:16])[CH2:6][NH:5]2.[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22](Cl)=[O:23].BrC1C=C2C(=CC=1)N(C(=O)C)[C@@H](C)CN2C(C1OC=CC=1)=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH2:15][CH3:16])[CH2:6][N:5]2[C:22]([C:18]1[O:17][CH:21]=[CH:20][CH:19]=1)=[O:23]
Reactant: O=C(Cl)c1ccco1
Reactant: CC[C@H]1CNc2cc(Br)ccc2N1C(C)=O
Agent: CC(=O)N1c2ccc(Br)cc2N(C(=O)c2ccco2)C[C@@H]1C
Product: CC[C@H]1CN(C(=O)c2ccco2)c2cc(Br)ccc2N1C(C)=O

Procedure:
(S)-1-(6-bromo-2-ethyl-4-(furan-2-carbonyl)-3,4-dihydroquinoxalin-1 (2H)-yl)ethan-1-one was synthesized from (S)-1-(6-bromo-2-ethyl-3,4-dihydroquinoxaline-1(2H)-yl)ethan-1-one and furan-2-carbonyl chloride according to the procedure outlined for (S)-1-(6-bromo-4-(furan-2-carbonyl)-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)ethanone. MS (ESI, pos. ion) m/z 335, 337 [M−42 (acyl)]+.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:30])=[C:11]([NH:13][C:14](=[O:29])[C:15]3[CH:20]=[C:19]([O:21][CH2:22][C:23]([CH3:25])=[CH2:24])[CH:18]=[CH:17][C:16]=3[N+:26]([O-])=O)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[BH4-].[Na+].C(OCC)(=O)C>CO.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[NH2:26][C:16]1[CH:17]=[CH:18][C:19]([O:21][CH2:22][C:23]([CH3:25])=[CH2:24])=[CH:20][C:15]=1[C:14]([NH:13][C:11]1[CH:12]=[C:7]([C:5]([NH:4][CH:1]2[CH2:2][CH2:3]2)=[O:6])[CH:8]=[CH:9][C:10]=1[CH3:30])=[O:29]
Reactant: C=C(C)COc1ccc([N+](=O)[O-])c(C(=O)Nc2cc(C(=O)NC3CC3)ccc2C)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [BH4-]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: C=C(C)COc1ccc(N)c(C(=O)Nc2cc(C(=O)NC3CC3)ccc2C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.5 %

Procedure:
To a solution of N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-[(2-methylprop-2-en-1-yl)oxy]-2-nitrobenzamide (8.73 g) in methanol (250 ml) was added a saturated solution of copper acetate in water (80 ml). Sodium borohydride (4.3 g) was added portionwise and the mixture stirred for a further 1 hour at room temperature. Ethyl acetate (300 ml) was added and the mixture washed with aqueous sodium hydrogen carbonate (200 ml). The combined aqueous extracts were extracted with ethyl acetate (2×200 ml), the resulting organics washed with brine (100 ml) and dried (magnesium sulfate) and Concentrated to give the crude 2-amino-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-[(2-methylprop-2-en-1-yl)oxy]benzamide (3.6 g) as an oil which was used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][C:8]([CH3:11])([OH:10])[CH3:9])[N:3]=1.N1C(C)=CC=CC=1C.[Cl:20][C:21]1[CH:22]=[C:23]([CH:31]([CH2:35][C@H:36]2[CH2:40][CH2:39][C:38]([F:42])([F:41])[CH2:37]2)[C:32](Cl)=[O:33])[CH:24]=[CH:25][C:26]=1[S:27]([CH3:30])(=[O:29])=[O:28]>C(Cl)Cl>[Cl:20][C:21]1[CH:22]=[C:23]([CH:31]([CH2:35][C@H:36]2[CH2:40][CH2:39][C:38]([F:42])([F:41])[CH2:37]2)[C:32]([NH:1][C:2]2[CH:6]=[CH:5][N:4]([CH2:7][C:8]([OH:10])([CH3:11])[CH3:9])[N:3]=2)=[O:33])[CH:24]=[CH:25][C:26]=1[S:27]([CH3:30])(=[O:29])=[O:28]
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: CS(=O)(=O)c1ccc(C(C[C@H]2CCC(F)(F)C2)C(=O)Cl)cc1Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(O)Cn1ccc(NC(=O)C(C[C@H]2CCC(F)(F)C2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In a round bottom flask was placed 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared as in Example 80, 56 mg, 0.36 mmol), 2,6-lutidine (54 μL, 0.49 mmol) and methylene chloride (10 mL) which was then cooled to 0° C. in an ice bath. To this solution was then added dropwise a solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-((R)-3,3-difluoro-cyclopentyl)-propionyl chloride (˜0.16 M solution, 2 mL, 0.33 mmol). The reaction was then allowed to warm up to 25° C. and stirred for 16 h. After this time the reaction mixture was quenched with a saturated aqueous sodium bicarbonate solution (10 mL) and then diluted with methylene chloride (10 mL) transferred to a separatory funnel and the layers separated. The aqueous layer was then extracted methylene chloride (3×10 mL). The organics were combined and then washed with a 1 N aqueous hydrochloric acid solution (10 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (12 g column, 55% ethyl acetate/hexanes) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-((R)-3,3-difluoro-cyclopentyl)-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (as a mixture of two diastereomers, 90 mg, 55%) as a white foam: ES-HRMS m/e calcd for C22H28N3O4SClF2 (M+H)+ 504.1530, observed 504.1526; 1H NMR (300 MHz, DMSO-d6) δ 1.03 (s, 3H, CH3), 1.04 (s, 3H, CH3), 1.42 (m, 1H, CH), 1.68-2.33 (m, 8H, 4×CH2), 3.34 (s, 3H, SO2CH3), 3.87 (s, 2H, NCH2), 3.90 (m, 1H, ArCHCO), 4.66 (s, 1H, OH), 6.45 (d, J=2.2 Hz, 1H, Ar), 7.52 (d, J=2.2 Hz, 1H, Ar), 7.60 (d, Jo=8.3 Hz, 1 H, Ar), 7.71 (s, 1H, Ar), 8.02 (d, Jo=8.3 Hz, 1H, Ar), 10.85 (s, 1H, NH).
Reaction SMILES: OI1(=O)C2C=CC=CC=2C(=O)O1.[C:13]1([CH2:23][N:24]2[CH2:29][CH2:28][CH:27]([CH2:30][NH:31][C:32]3[NH:36][C:35]4[CH:37]=[CH:38][C:39]([CH2:41][OH:42])=[CH:40][C:34]=4[N:33]=3)[CH2:26][CH2:25]2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1.C(OCC)(=O)C>CS(C)=O>[C:13]1([CH2:23][N:24]2[CH2:25][CH2:26][CH:27]([CH2:30][NH:31][C:32]3[NH:36][C:35]4[CH:37]=[CH:38][C:39]([CH:41]=[O:42])=[CH:40][C:34]=4[N:33]=3)[CH2:28][CH2:29]2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: OCc1ccc2[nH]c(NCC3CCN(Cc4cccc5ccccc45)CC3)nc2c1
Agent: O=C1OI(=O)(O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=Cc1ccc2[nH]c(NCC3CCN(Cc4cccc5ccccc45)CC3)nc2c1
Temperature: 25 °C
Reaction time: 9 h

Procedure:
A solution of 1-hydroxy-1-oxo-1H-1λ5-benzo[d][1,2]iodoxol-3-one (846 mg, 3.02 mmol) in dimethylsulfoxide (10 ml) was added to a solution of {2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-amino]-1H-benzimidazol-5-yl}-methanol (807 mg, 2.01 mmol) in dimethylsulfoxide (10 ml), and the mixture was stirred at room temperature for 9 hours. The reaction mixture was poured into ice water (200 ml) and stirred at room temperature for 30 minutes, after which ethyl acetate was added and stirring was continued vigorously for 10 minutes for extraction. After washing with saturated aqueous sodium bicarbonate and saturated brine, the mixture was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/methanol=9/1). This was further purified by preparative HPLC to obtain 2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-amino]-1H-benzimidazole-5-carboaldehyde.
Reaction SMILES: Cl[C:2]1[N:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]([OH:16])=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:7]=1)=O.O.[NH2:27][NH2:28]>N1C=CC=CC=1>[C:12]([C:10]1[CH:11]=[C:6]([C:4]2[C:3]3[C:2](=[N:24][C:23]([CH3:25])=[CH:22][CH:21]=3)[NH:28][N:27]=2)[CH:7]=[C:8]([C:17]([CH3:19])([CH3:18])[CH3:20])[C:9]=1[OH:16])([CH3:15])([CH3:13])[CH3:14]
Reactant: Cc1ccc(C(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(Cl)n1
Reactant: NN
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc2c(-c3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)n[nH]c2n1
Yield: 81.2 %

Procedure:
The similar procedures in Example 1 by using 15.5 g of 4-(2-chloro-6-methylnicotinoyl)-2,6-di-tertiary butylphenol, 9.7 g of hydrazine hydrate and 85 ml of pyridine are carried out, and then the obtained crude crystals are recrystallized from ethanol to give 11.8 g of 3-(3,5-di-tertiary butyl-4-hydroxyphenyl)-6-methyl-1H-pyrazolo[3,4-b]pyridine as white crystals, melting at 239°-240° C.