Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][C:13](=[CH2:15])[CH2:12][CH:11]3[O:16][C:17](=[O:19])[CH:18]=[C:10]23)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH:13]([CH3:15])[CH2:12][CH:11]3[O:16][C:17](=[O:19])[CH:18]=[C:10]23)=[CH:4][CH:3]=1
Reactant: C=C1CC2OC(=O)C=C2N(Cc2ccc(Cl)nc2)C1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC1CC2OC(=O)C=C2N(Cc2ccc(Cl)nc2)C1
Reaction time: 10 h

Procedure:
150.0 mg (0.54 mmol) of 4-[(6-chloropyridin-3-yl)methyl]-6-methylene-5,6,7,7a-tetrahydrofuro-[3,2-b]pyridin-2(4H)-one (cf. I-5) are dissolved in 75 ml of toluene, 40 mg (0.043 mmol) of tris(triphenylphosphine)rhodium(I) chloride and 15 mg (0.057 mmol) of triphenylphosphine are added and the mixture is hydrogenated under a hydrogen pressure of 3 bar and at 110-120° C. for 10 hours. The mixture is filtered and the filtrate is concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (silica gel 60, Merck, particle size: 0.04 to 0.063 mm) using the mobile phase ethyl acetate/cyclohexane (2:1 to 4:1) gives both possible diastereomers of 4-[(6-chloropyridin-3-yl)methyl]-6-methyl-5,6,7,7a-tetrahydrofuro-[3,2-b]pyridin-2(4H)-one: (a) 85 mg (56% of theory) of diastereomer A and (b) after preparative HPLC 18 mg (12% of theory) of diastereomer B.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[C:4]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:3]=1.C([O-])(O)=O.[Na+].[CH3:30][N:31](C=O)C>[C-]#N.[Zn+2].[C-]#N.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:21]([C:4]1[CH:3]=[C:2]([C:30]#[N:31])[CH:7]=[CH:6][C:5]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)cc2C(C)(C)C)CC1
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: [C-]#N
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C#N)cc2C(C)(C)C)CC1
Temperature: 100 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
A mixture of tert-butyl 4-(4-bromo-2-tert-butylphenyl)piperazine-1-carboxylate (Example 85, 3.0 g, 7.55 mmol), zinc cyanide (1.77 g, 15.1 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.88 g, 0.76 mmol) in DMF (30 mL) was stirred at 100° C. for 4 h under argon atmosphere. The reaction mixture was cooled to room temperature, poured into saturated NaHCO3 solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and the solvent was evaporated under reduced pressure to give the crude product. The product was purified by flash column chromatography (silica gel, n-hexane/ethyl acetate=95:5 to 80:20) to provide tert-butyl 4-(2-tert-butyl-4-cyanophenyl)piperazine-1-carboxylate (2.29 g, 88%) as a white powder.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]1[CH2:7][N:8]=[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:10]2[CH:15]=[C:14]([Cl:16])[S:13][C:11]=2[N:12]=1)(=O)[CH3:2]>O>[Cl:16][C:14]1[S:13][C:11]2[N:12]3[C:1]([CH3:2])=[N:4][N:5]=[C:6]3[CH2:7][N:8]=[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:10]=2[CH:15]=1
Reactant: CC(=O)NNC1=Nc2sc(Cl)cc2C(c2ccccc2Cl)=NC1
Solvent: O
Product: Cc1nnc2n1-c1sc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
2.5 g of 2-(2-acetylhydrazino)-7-chloro-5-(o-chlorophenyl)-3H-thieno[2,3-e]-1,4-diazepine are heated under reduced pressure (water-jet vacuum) for 5-7 minutes in an oil bath (250° C.) until gas evolution is no longer observed. The resulting product is finely triturated in a mortar and boiled out several times with a total of 400 ml of ethyl acetate. After removal of the solvent, the resulting crude product is recrystallised from ethanol containing active carbon to give 2-chloro-4-(o-chlorophenyl)-9-methyl-6H-thieno[3,2-f]-s-triazolo[4,3-a][1,4]diazepine in the form of cream-colored crystals, melting point 205°-206° C.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([Li])(CC)C.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH:24]=[O:25]>C(OCC)C>[OH:25][CH:24]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=1)[CH:12]1[CH2:11][CH2:10][CH2:9][N:8]1[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCCC1
Reactant: O=Cc1ccccn1
Agent: [Li]C(C)CC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCCC1C(O)c1ccccn1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
N-Boc-pyrrolidine (5.0 g) is dissolved in diethyl ether (60 mL) and the solution is cooled to −78° C. N,N,N′,N′-Tetramethylenediamine (TMEDA) (4.4 mL) is added to the mixture followed by sec-butyl lithium (27.0 mL, 1.3 M in cyclohexane) maintaining the temperature below −60° C. After 2 h, 2-pyridine carboxaldehyde (3.3 mL) is added and the mixture is stirred at −70° C. for an additional 30 min. The reaction mixture is allowed to warm to room temperature and is then quenched with water (25 mL) and poured into EtOAc (250 mL). The separated organic layer is washed with water (2×50 mL) followed by brine (50 mL), dried (Na2SO4), and concentrated. The crude product is purified by column chromatography (heptane/EtOAc, 4/1; 2/1, 1/1) to afford 4.79 g of tert-butyl 2-(hydroxy(pyridin-2-yl)methyl)pyrrolidine-1-carboxylate as a mixture of diastereomers. The resulting alcohol is dissolved in dichloromethane (10 mL) and trifluoroacetic acid (80 mL) is added with ice bathe cooling. After 1 h, the reaction mixture is concentrated and added to 1 N sodium hydroxide solution (200 mL). The mixture is extracted with CH2Cl2 (3×100 mL). The combined organic layers are dried (Na2SO4) and concentrated. The resulting oil is distilled in a Kugelrohr apparatus (175-200° C., 0.2 Torr) to afford 2.04 g of the title compound as a mixture of diastereomers. Physical characteristics. 1H NMR (400 MHz, DMSO-d6) δ 8.47, 7.76, 7.46, 7.24, 5.27, 4.50, 4.34, 3.32, 3.22, 2.83, 2.68, 1.62-1.36; MS (ESI+) m/z 179 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[N:12]=[N:13][C:14](Cl)=[CH:15][CH:16]=2)=[CH:6][CH:5]=1.C([O-])(=[O:21])C.[K+]>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14](=[O:21])[NH:13][N:12]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(Oc2ccc(Cl)nn2)cc1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: COC(=O)c1ccc(Oc2ccc(=O)[nH]n2)cc1
Yield: 75.2 %

Procedure:
A mixture of 4-(6-chloro-pyridazin-3-yloxy)-benzoic acid methyl ester (1.0 g, 3.78 mmol) from the previous step and anhydrous potassium acetate (0.526 g, 5.37 mmol) in glacial acetic acid (10 ml) was refluxed for 13 h. The volatiles were evaporated in vacuo and the residue was diluted with dichloromethane (20 ml). The separated solid was collected by filtration, washed with 50% aqueous ethanol (2×5 ml) and water (4×7 ml) and dried to provide 0.7 g (43%) of 4-(6-oxo-1,6-dihydro-pyridazin-3-yloxy)-benzoic acid methyl ester.
Reaction SMILES: [C:1]([N:5]([C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6])([CH3:4])([CH3:3])[CH3:2].[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1.C(OCC)C>[C:1]([N:5]([C:7](=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[NH:6][S:21]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:23])=[O:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)N(N)C(=O)c1ccccc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(C)(C)N(NS(=O)(=O)c1ccccc1)C(=O)c1ccccc1
Reaction time: 2 h

Procedure:
N'-t-butyl-N'-benzoylhydrazine (0.4 g) was stirred in pyridine (3 ml) at room temperature. Benzenesulfonyl chloride (0.5 g) was added slowly, dropwise and stirred for 2 hours, diluted with diethyl ether (20 ml) and washed several times with a 10% HCl solution and then water. The organic layer was dried over magnesium sulfate, filtered and the solvent rotavapped off to afford a white solid in good yield.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([S:11][CH2:12][C:13]([F:18])([F:17])[CH:14]([F:16])[F:15])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-])=O.Cl.[OH-].[NH4+]>>[NH2:6][C:5]1[CH:7]=[CH:8][C:9]([S:11][CH2:12][C:13]([F:18])([F:17])[CH:14]([F:16])[F:15])=[CH:10][C:4]=1[NH2:1]
Reactant: Nc1ccc(SCC(F)(F)C(F)F)cc1[N+](=O)[O-]
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: Nc1ccc(SCC(F)(F)C(F)F)cc1N
Reaction time: 0.5 h

Procedure:
4 G. of 2-nitro-4-(2,2,3,3-tetrafluoropropylthio) aniline is treated with 24 g. of stannous chloride in 25 ml. of concentrated hydrochloric acid. The mixture is stirred for 1/2 hour, basified with ammonium hydroxide and extracted with chloroform. The chloroform solution is filtered, dried over sodium sulfate, and evaporated to give 1,2-diamino-4-(2,2,3,3-tetrafluoropropylthio) benzene.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.CN(C=O)C.[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][C:21]=1[C:22]#[N:23])[NH:18][CH:17]=C2.[OH-].[Na+]>C(Cl)Cl>[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][C:21]=1[C:22]#[N:23])[NH:18][CH:17]=[C:2]2[CH:1]=[O:5]
Reactant: N#Cc1cc2[nH]ccc2cc1F
Reactant: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1cc2[nH]cc(C=O)c2cc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of oxalyl chloride (0.68 mL) in DCM (10 mL) at 0° C. was dropwise added a solution of DMF (0.60 mL) in DCM (2 mL). The mixture was stirred for 0.5 h at 0° C. and then 5-fluoro-1H-indole-6-carbonitrile (D151) (250 mg) in DCM (3 mL) was added in one portion. The reaction mixture was allowed to warm to rt and stirred overnight. Afterwards, the reaction mixture was added with 2 M aqueous NaOH (30 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with water, dried over anhydrous sodium sulfate, and then concentrated under vacuo to give the designed product 5-fluoro-3-formyl-1H-indole-6-carbonitrile (D152) (280 mg), which was used without purification. MS (ES): C10H5FN2O requires 188.0; found 189.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]([CH3:17])([O:4][C:5]([NH:7][C@H:8]1[CH2:14][CH2:13][CH2:12][C@@H:11]([CH3:15])[NH:10][C:9]1=[O:16])=[O:6])[CH3:3].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>O1CCCC1>[CH3:3][C:2]([CH3:1])([O:4][C:5]([NH:7][C@H:8]1[CH2:14][CH2:13][CH2:12][C@@H:11]([CH3:15])[N:10]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:9]1=[O:16])=[O:6])[CH3:17]
Reactant: CCOC(=O)CBr
Reactant: C[C@@H]1CCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CCC[C@H]1C
Reaction time: 0.5 h

Procedure:
A solution of (3S-cis)-hexahydro-3-[[(1,1-dimethylethoxy)carbonyl]amino]-7-methyl-2H-azepin-2-one [prepared as described in Example 64(f), 500 mg., 2.06 mmol.] in tetrahydrofuran (13 ml.) at room temperature under argon was treated dropwise with 1.0M lithium bis(trimethylsilyl)amide in tetrahydrofuran (2.7 ml., 2.7 mmol.) immediately followed by the dropwise addition of ethyl bromoacetate (0.47 ml., 4.21 mmol.). The resulting mixture was stirred for 30 minutes, quenched with aqueous ammonium chloride, diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried (sodium sulfate), filtered and concentrated to a yellow oil. Following flash chromatography (E Merck silica gel) eluting with 2:1 hexane/ethyl acetate, 750 mg. of title product was obtained as a light yellow oil; TLC (1:1 ethyl acetate:hexane) Rf =0.52.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.[C:26]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)#[N:27].COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.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:26]([C:28]1[CH:33]=[C:32]([C:2]2[N:3]=[CH:4][N:5]([C:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:6]=2)[CH:31]=[CH:30][CH:29]=1)#[N:27]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: Brc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
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: ClCCl
Product: N#Cc1cccc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1
Temperature: 120 °C
Yield: 33.4 %

Procedure:
A mixture of 4-bromo-1-trityl-1H-imidazole (0.2g, 0.51 mmol), 3-cyanophenylboronic acid (0.11 g, 0.77 mmol), and Pd(PPh3)4 (0.06g, 0.05 mmol) in a solution of ethylene glycol dimethyl ether (2 mL) and 2M sodium carbonate (2 mL) was heated in a sealed vial overnight at 120° C. After cooling, the reaction mixture was diluted with dichloromethane (30 mL) and washed with water (50 mL) and brine (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography of the crude residue using 2% ethyl acetate in hexanes afforded 0.07 g (34%) 4-(3-cyanophenyl)-1-trityl-1H-imidazole as white foam.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]2[C:14]([F:17])([F:16])[CH2:15][CH:9]1[CH2:10][CH:11]([OH:18])[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl>[CH2:1]([N:8]1[CH:13]2[C:14]([F:17])([F:16])[CH2:15][CH:9]1[CH2:10][C:11](=[O:18])[CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CC2CC(F)(F)C(C1)N2Cc1ccccc1
Solvent: ClCCl
Product: O=C1CC2CC(F)(F)C(C1)N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of compound 116g (1.02 g, 4 mmol, 1.0 eq) in DCM (20 mL) was added DMP (3.4 g, 8 mmol, 2.0 eq) slowly at 0° C., then the mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with water, the solid was filtered off, the filtrate was diluted with DCM (100 mL), washed with NaHCO3 (100 mL) three times and brine (100 mL). The organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel (EA/PE=1:4) to give 8-benzyl-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-one 116h as a colorless oil. 0.5 g. MS: calc'd (MH+) 252, measured (MH+) 2520.
Reaction SMILES: [F-].[K+].Cl[C:4]1[C:9]2[N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[N:12][C:8]=2[CH:7]=[C:6]([Cl:24])[N:5]=1.Cl.[CH:26]1([C@H:30]([NH2:32])[CH3:31])[CH2:29][CH2:28][CH2:27]1.C1CCN2C(=NCCC2)CC1>CC(N(C)C)=O.O.CCOC(C)=O>[Cl:24][C:6]1[N:5]=[C:4]([NH:32][C@@H:30]([CH:26]2[CH2:29][CH2:28][CH2:27]2)[CH3:31])[C:9]2[N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[N:12][C:8]=2[CH:7]=1
Reactant: FC(F)(F)c1ccc(Cn2cnc3cc(Cl)nc(Cl)c32)cc1
Reactant: C[C@@H](N)C1CCC1
Agent: Cl
Agent: [F-]
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@H](Nc1nc(Cl)cc2ncn(Cc3ccc(C(F)(F)F)cc3)c12)C1CCC1
Temperature: 120 °C

Procedure:
Potassium fluoride (0.940 g, 16.18 mmol) was added to a stirred solution of 4,6-dichloro-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-c]pyridine (2.8 g, 8.09 mmol) in DMA (22.40 ml). The solution was stirred at room temperature for 5 min. (R)-1-cyclobutylethanamine hydrochloride (2.194 g, 16.18 mmol) and DBU (3.66 ml, 24.27 mmol) were added and the reaction mixture was heated at 120° C. overnight. The reaction mixture was cooled to room temperature and diluted with water and EtOAc. The aqueous layer was extracted with EtOAc (2×). The organic layers were combined, dried and concentrated. The residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes, linear gradient) to afford (R)-6-chloro-N-(1-cyclobutylethyl)-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-c]pyridin-4-amine. MS ESI calc'd for C20H20ClF3N4 [M+H]+ 409. found 409.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][C:31]=1[F:38]>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:34][C:33]3[CH:36]=[CH:37][C:30]([Cl:29])=[C:31]([F:38])[CH:32]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1ccc(Cl)c(F)c1
Product: Fc1cc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)ccc1Cl

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 4-chloro-3-fluoro benzaldehyde. MS (ESI) m/z 519.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[C:4]=2[N:5]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH:12]=O)[N:7]=1.FC(F)(F)C(O)=O.[F:27][C:28]1[CH:37]=[C:36]2[C:31]([CH:32]=[CH:33][CH:34]=[C:35]2[N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)=[CH:30][CH:29]=1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:27][C:28]1[CH:37]=[C:36]2[C:31]([CH:32]=[CH:33][CH:34]=[C:35]2[N:38]2[CH2:43][CH2:42][N:41]([CH2:12][CH2:11][CH2:10][CH2:9][O:8][C:6]3[N:7]=[C:2]([CH3:1])[C:3]4[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[C:4]=4[N:5]=3)[CH2:40][CH2:39]2)=[CH:30][CH:29]=1
Reactant: Cc1nc(OCCCC=O)nc2c1ccc(=O)n2C
Reactant: Fc1ccc2cccc(N3CCNCC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(OCCCCN2CCN(c3cccc4ccc(F)cc34)CC2)nc2c1ccc(=O)n2C
Reaction time: 0.17 h
Yield: 62.3 %

Procedure:
4-(4,8-dimethyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yloxy)-butyraldehyde (78.4 mg, 0.30 mmol) and 1-(7-fluoro-naphthalen-1-yl)-piperazine trifluoroacetic acid (105 mg, 0.306 mmol) were combined in methylene chloride and triethylamine (63 mg, 0.63 mmol) was added. The mixture was stirred in a vial over sieves for 10 min. Sodium triacetoxyborohydride (89 mg, 0.420 mmol) was added and the reaction was stirred overnight. The reaction was quenched slowly with water and the mixture was filtered. The residue was partitioned between CH2Cl2 and water. The organic layer was washed with water and concentrated. Purification by liquid chromatography (MPLC, gradient of 100% CH2Cl2 to 100% of a 10% MeOH in CH2Cl2 solution) gave the title compound as a white foam (89 mg, 0.187 mmol, 62.4%). MS: APCI: M+1: 476.2 (Exact Mass: 475.24).
Reaction SMILES: [H-].[Na+].CS(C[CH2:8][OH:9])(=O)=O.[Cl:10][C:11]1[C:12]([N:17]2[CH2:26][CH2:25][C:24]3[C:23]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=4)=[N:22]C(S(C)(=O)=O)=[N:20][C:19]=3[CH2:18]2)=[N:13][CH:14]=[CH:15][CH:16]=1>CN(C=O)C>[F:37][C:34]([F:35])([F:36])[C:31]1[CH:32]=[CH:33][C:28]([NH:27][C:23]2[C:24]3[CH2:25][CH2:26][N:17]([C:12]4[C:11]([Cl:10])=[CH:16][CH:15]=[CH:14][N:13]=4)[CH2:18][C:19]=3[N:20]=[C:8]([OH:9])[N:22]=2)=[CH:29][CH:30]=1
Reactant: CS(=O)(=O)c1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCN(c1ncccc1Cl)C2
Reactant: CS(=O)(=O)CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Oc1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCN(c1ncccc1Cl)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 11.9 %

Procedure:
Sodium hydride (40 mg, 1 mmol, 60%) was added to a solution of 2-(methansulphonyl)ethanol (124 mg, 1 mmol) in DMF (5 mL, anhydrous) and stirred at room temperature for 10 min. This mixture (0.6 mL) was added to a solution of 7-(3-chloropyridin-2-yl)-N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-2-(methylsulfonyl)pyrido[3,4-d]pyrimidin-4-amine (50 mg, 0.1 mmol) in DMF (1 mL) and was heated in a sealed tube via microwave at 150° C. for 20 min. Solvent was removed in vacuo and the residue was purified by column chromatography to yield the product as a light brown solid (5 mg).
Reaction SMILES: Cl.Cl.[CH3:3][CH:4]([CH3:18])[CH2:5][N:6]([CH2:11][C@H:12]1[CH2:17][NH:16][CH2:15][CH2:14][NH:13]1)[S:7]([CH3:10])(=[O:9])=[O:8].C(N(CC)CC)C.[N+:26]([C:29]1[S:33][C:32]([S:34](Cl)(=[O:36])=[O:35])=[CH:31][CH:30]=1)([O-:28])=[O:27]>C(Cl)Cl>[N+:26]([C:29]1[S:33][C:32]([S:34]([N:16]2[CH2:15][CH2:14][NH:13][C@@H:12]([CH2:11][N:6]([CH2:5][CH:4]([CH3:18])[CH3:3])[S:7]([CH3:10])(=[O:8])=[O:9])[CH2:17]2)(=[O:36])=[O:35])=[CH:31][CH:30]=1)([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)s1
Reactant: CC(C)CN(C[C@H]1CNCCN1)S(C)(=O)=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CN(C[C@H]1CN(S(=O)(=O)c2ccc([N+](=O)[O-])s2)CCN1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88 %

Procedure:
A 5-mL vial was charged with N-(2-methylpropyl)-N-((2R)-2-piperazinylmethyl)methanesulfonamide dihydrochloride (0.144 g, 0.446 mmol) and CH2Cl2 (2 mL). To this was added triethylamine (0.650 mL, 4.66 mmol) in potions at room temperature followed by drop wise addition of 5-nitrothiophene-2-sulfonyl chloride (0.120 g, 0.525 mmol, Enamine LLC, Monmouth Jct. NJ) in CH2Cl2 (1 mL). The mixture was stirred at room temperature for 15 min and then the reaction mixture was partitioned between water (20 mL) and CH2Cl2 (20 mL). The aqueous phase was extracted with CH2Cl2 (2×20 mL) and the combined organic extracts were washed with saturated aqueous NaCl (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (25 g of silica gel, 0 to 10% (2 M NH3 in MeOH) in CH2Cl2) to afford N-(((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-2-piperazinyl)methyl)-N-(2-methylpropyl)methanesulfonamide (0.173 g) as a light-brown foam.
Reaction SMILES: C([O:5][C:6](=[O:33])[CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[C:19]#[C:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:30]([S:27]([C:23]1[CH:22]=[C:21]([C:20]#[C:19][C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:17]=[CH:18][C:9]=2[O:8][CH2:7][C:6]([OH:33])=[O:5])[CH:26]=[CH:25][CH:24]=1)(=[O:29])=[O:28])[CH2:31][CH3:32]
Reactant: CCCS(=O)(=O)c1cccc(C#Cc2c(OCC(=O)OC(C)(C)C)ccc3ccccc23)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCS(=O)(=O)c1cccc(C#Cc2c(OCC(=O)O)ccc3ccccc23)c1
Reaction time: 1 h

Procedure:
A solution of tert-butyl[(1-{[3-(propylsulfonyl)phenyl]ethynyl}-2-naphthyl)oxy]acetate (Intermediate 218, 60 mg; 0.13 mmol) in DCM (1.2 mL) was treated with trifluoroacetic acid (98 μl; 0.65 mmol). After stirring for 1 hour, the solvents were removed under vacuum to afford a residue, which was purified by preparative HPLC to give the title compound as a beige solid.