Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:6]([N+:19]([O-:21])=[O:20])[C:5]=1[NH2:22])([O-])=O.[Cl-].[NH4+].CCN(C(C)C)C(C)C.Cl[C:35]([O:37][CH2:38][CH3:39])=[O:36]>CO.[Zn]>[NH2:22][C:5]1[C:6]([N+:19]([O-:21])=[O:20])=[C:7]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH:8]=[CH:9][C:4]=1[NH:1][C:35](=[O:36])[O:37][CH2:38][CH3:39]
Reactant: CCOC(=O)Cl
Reactant: Nc1c([N+](=O)[O-])ccc(NCc2ccc(F)cc2)c1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CCOC(=O)Nc1ccc(NCc2ccc(F)cc2)c([N+](=O)[O-])c1N
Reaction time: 5 h

Procedure:
To a stirred solution of compound 9 (1.5 g, 5 mmol, 1.00 equiv) in methanol (7 mL) is added zinc powder (1.64 g, 25 mmol, 5.00 equiv) followed by ammonium chloride solution (1.33 g, 25 mmol, 5.00 equiv) dropwise. After 5 h, DIPEA (0.806 g, 6.25 mmol, 1.25 equiv) and ethyl chloroformate (0.54 g, 5 mmol, 1.00 equiv) are added to reaction mixture at 10° C. and the stirring continued till consumption of starting material (by TLC). The reaction mixture is diluted with water (30 mL) and extracted in ethyl acetate (75 mL), dried using brine and over MgSO4. After concentration the crude material obtained is purified to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH:35]([F:37])[F:36])=[C:6]([C:8]2[N:12]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:11]=[CH:10][C:9]=2[NH:21][C:22]([C:24]2[CH:25]=[N:26][N:27]3[CH:32]=[CH:31][C:30](Cl)=[N:29][C:28]=23)=[O:23])[CH:7]=1.[NH3:38]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH:35]([F:36])[F:37])=[C:6]([C:8]2[N:12]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:18])([CH3:20])[CH3:19])[N:11]=[CH:10][C:9]=2[NH:21][C:22]([C:24]2[CH:25]=[N:26][N:27]3[CH:32]=[CH:31][C:30]([NH2:38])=[N:29][C:28]=23)=[O:23])[CH:7]=1
Reactant: N
Reactant: C[Si](C)(C)CCOCn1ncc(NC(=O)c2cnn3ccc(Cl)nc23)c1-c1cc(Cl)ccc1OC(F)F
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ncc(NC(=O)c2cnn3ccc(N)nc23)c1-c1cc(Cl)ccc1OC(F)F
Temperature: 50 °C
Yield: 99 %

Procedure:
5-chloro-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [5-(5-chloro-2-difluoromethoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-4-yl]-amide (756 mg, 1.32 mmol) was dissolved in THF (10 mL) and concentrated aqueous ammonia (10 mL) added. The mixture was heated at 50° C. for 3 hours then allowed to cool to ambient temperature. The solvent was evaporated and the residue azeotroped with methanol (×2) to afford 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [5-(5-chloro-2-difluoromethoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-4-yl]-amide as a white solid (724 mg, 99%). LCMS (Method 4) [M+H]+=549.9, RT=4.11 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([OH:12])=[N:7][CH:6]=[CH:5]2.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.CC(OC)(C)C>[CH2:13]([N:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[C:8]1=[O:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: Oc1nccc2cc(Br)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: COC(C)(C)C
Product: O=c1c2ccc(Br)cc2ccn1Cc1ccccc1
Temperature: 90 °C
Reaction time: 1.33 h
Yield: 100 %

Procedure:
6-Bromo-1-hydroxyisoquinoline (150 mg, 0.67 mmol, 1.0 equiv), tetrabutylammonium bromide (25 mg, 0.07 mmol, 0.1 equiv), and benzyl bromide (95 uL, 0.8 mmol, 1.2 equiv) were combined in toluene (7 mL), and treated with 50% aq. NaOH (2 mL) after which point the resulting mixture was stirred rapidly at 90° C. After 80 min, the mixture was diluted with MTBE and washed with water and brine. The organic phase was dried over Na2SO4. Addition of silica gel, concentration, and purification of the residue by flash silica gel chromatography (gradient of 2-12% ethyl acetate/hexanes) provided 2-benzyl-6-bromo-isoquinolin-1-one (221 mg, 0.67 mmol, quantitative) which was then converted, via Methods 1 and 2, to compound 2 (91 mg, 49%) and isolated as a light-brown solid. [M-H]-=278.1 m/z. Activity: B
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:25])[CH2:15][N:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23]O)[CH2:18][CH2:17]1)([CH3:3])[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O.[SH:38][C:39]1[O:40][C:41]2[CH:47]=[CH:46][CH:45]=[CH:44][C:42]=2[N:43]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>C1COCC1.CN(C)C1C=CN=CC=1.O>[O:40]1[C:41]2[CH:47]=[CH:46][CH:45]=[CH:44][C:42]=2[N:43]=[C:39]1[S:38][CH2:23][CH2:22][N:19]1[CH2:18][CH2:17][N:16]([CH2:15][C:14]([NH:13][C:5]2[C:6]([CH:10]([CH3:12])[CH3:11])=[CH:7][CH:8]=[CH:9][C:4]=2[CH:1]([CH3:2])[CH3:3])=[O:25])[CH2:21][CH2:20]1
Reactant: Sc1nc2ccccc2o1
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CN1CCN(CCO)CC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CN1CCN(CCSc2nc3ccccc3o2)CC1
Yield: 78.9 %

Procedure:
To a solution of this alcohol (300 mg, 0.86 mmol) in THF (5 ml) were added triethylamine (172 mg, 1.7 mmol) and 4-dimethylaminopyridine (10 mg, 0.09 mmol), then methanesulfonyl chloride (115 mg, 1.0 mmol) was dropped there into with ice-cooling and stirring, and the mixture was stirred for 40 minutes. After that, triethylamine (172 mg, 1.7 mmol) was further added thereto, then methanesulfonyl chloride (115 mg, 1.0 mmol) was dropped thereinto with ice-cooling and stirring, and the mixture was stirred for 20 minutes. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, an aqueous solution of sodium bicarbonate and a saturated sodium chloride solution successively and dried over anhydrous sodium sulfate, and the solvent was evaporated therefrom. The resulting residue was dissolved in DMF (7 ml), then 2-mercaptobenzooxazole (130 mg, 0.86 mmol), potassium carbonate (180 mg, 1.3 mmol) and 18-crown-6 (21 mg, 0.08 mmol) were added thereto, and the mixture was stirred at 80° C. for 1 hour. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution successively and dried over anhydrous sodium sulfate and the solvent was evaporated therefrom. The residue was purified by a silica gel column chromatography (40 g of silica gel; developing solvent, hexane:acetone=5:1˜10:3) and the resulting crystals were recrystallized from acetone-hexane to provide 326 mg (yield 79%) of the desired compound as colorless needles.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:9]([NH:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)=[N:10][CH:11]=[C:12]([C:15]#[N:16])[C:13]=3[S:14][C:4]=2[CH:3]=1.[F:27][C:28]([F:39])([F:38])[C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Na+].[Na+]>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][NH:17][C:9]2[C:8]3[C:5]4[CH:6]=[CH:7][C:2]([C:32]5[CH:33]=[CH:34][C:29]([C:28]([F:39])([F:38])[F:27])=[CH:30][CH:31]=5)=[CH:3][C:4]=4[S:14][C:13]=3[C:12]([C:15]#[N:16])=[CH:11][N:10]=2)=[CH:20][CH:21]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COc1ccc(CNc2ncc(C#N)c3sc4cc(Br)ccc4c23)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Product: COc1ccc(CNc2ncc(C#N)c3sc4cc(-c5ccc(C(F)(F)F)cc5)ccc4c23)cc1
Temperature: 100 °C

Procedure:
A mixture containing 7-bromo-1-[(4-methoxybenzyl)amino][1]benzothieno[3,2-c]pyridine-4-carbonitrile (Example 12, Step 9), 4-trifluoromethylphenylboronic acid (1.7 equiv), Pd(OAc)2 (0.14 equiv), Ph3P (0.42 equiv), Na2CO3 2 M (2.9 equiv) in 1-PrOH/DMF (3/1) (0.09 M) was degassed and heated at 100° C. for 3 h. The resulting mixture was concentrated to dryness, and the crude solid was washed successively with H2O and MeOH to provide the title compound as a brown solid.
Reaction SMILES: C([CH:6]1[CH:11]([CH2:12][CH:13]([S:15][CH2:16][CH3:17])[CH3:14])[CH2:10][C:9](=[O:18])[CH2:8][C:7]1=[O:19])(OCC)=O.[OH-].[Na+]>CO>[CH2:16]([S:15][CH:13]([CH3:14])[CH2:12][CH:11]1[CH2:6][C:7](=[O:19])[CH2:8][C:9](=[O:18])[CH2:10]1)[CH3:17]
Reactant: CCOC(=O)C1C(=O)CC(=O)CC1CC(C)SCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCSC(C)CC1CC(=O)CC(=O)C1
Temperature: 25 °C
Yield: 68 %

Procedure:
The ester product of Example 1 (0.70 g, 2.4 mmole) was dissolved in 15 ml of methanol and 1 ml of 2N NaOH and heated to reflux for 21/2 hours. The mixture was maintained at room temperature overnight. Methanol was evaporated, and the residue partitioned between about 30 ml of toluene and about 30 ml of aqueous HCl. The toluene extract was dried over sodium sulfate and evaporated to give 0.35 g (66.8%) of product as a yellow solid which was identical with an authentic sample. This target product was further identified by NMR.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:7][O:8][C:9]=1[CH3:10])=O.[NH2:17][C:18]1[CH:23]=[C:22]([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20][N:19]=1>>[CH3:27][O:26][C:24]([C:22]1[CH:21]=[CH:20][N:19]2[CH:2]=[C:3]([C:5]3[C:6]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:7][O:8][C:9]=3[CH3:10])[N:17]=[C:18]2[CH:23]=1)=[O:25]
Reactant: Cc1onc(-c2ccccc2)c1C(=O)CBr
Reactant: COC(=O)c1ccnc(N)c1
Product: COC(=O)c1ccn2cc(-c3c(-c4ccccc4)noc3C)nc2c1
Yield: 58 %

Procedure:
As described for Example 1, 4-(bromoacetyl)-5-methyl-3-phenylisoxazole (commercially available) (280 mg, 1.0 mmol) was converted, using methyl 2-aminopyridine-4-carboxylate instead of 2-aminopyridine, to the title compound (194 mg, 58%) which was obtained as a yellow foam. MS: m/e=334.1 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[N:4][C:5]([C:18]([F:21])([F:20])[F:19])=[C:6]([CH:17]=1)[C:7]([NH:9][CH2:10][C:11]([CH:14]1[CH2:16][CH2:15]1)([OH:13])[CH3:12])=[O:8].[Cl:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1.CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:2]2[C:3]([O:22][CH2:23][C:24]([F:25])([F:26])[F:27])=[N:4][C:5]([C:18]([F:21])([F:20])[F:19])=[C:6]([CH:17]=2)[C:7]([NH:9][CH2:10][C:11]([CH:14]2[CH2:16][CH2:15]2)([OH:13])[CH3:12])=[O:8])=[CH:31][CH:30]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC(O)(CNC(=O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F)C1CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(O)(CNC(=O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)nc1C(F)(F)F)C1CC1
Temperature: 90 °C
Yield: 56.1 %

Procedure:
5-Bromo-N-(2-cyclopropyl-2-hydroxy-propyl)-6-(2,2,2-trifluoro-ethoxy)-2-trifluoromethyl-nicotinamide (0.09 g, 0.19 mmol) was dissolved in toluene (4 mL) and dimethylformamide (0.3 mL). To this solution was added with stirring [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) CH2Cl2 (8 mg, 0.010 mmol), 4-chlorophenylboronic acid (32 mg, 0.20 mmol) and sodium carbonate solution (2M, 0.20 mL). This mixture was heated to 90° C. for 15 h and cooled to room temperature. Water (10 mL) was added, the phases were separated and the water mixture was extracted with ethylacetate. Organic phases were pooled, dried with MgSO4 and the volatiles removed in vacuo. The residue was purified by flash chromatography (SiO2, dichloromethane/ethyl acetate) to give the title compound (53 mg) as a brown gum; MS (ISP) 497.2 (M)+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][CH:16]([CH2:20][CH2:21][S:22][CH2:23][CH2:24][OH:25])[C:17]([OH:19])=[O:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[CH3:26][Si](C=[N+]=[N-])(C)C>CCOCC.CO>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][CH:16]([CH2:20][CH2:21][S:22][CH2:23][CH2:24][OH:25])[C:17]([O:19][CH3:26])=[O:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC#CCOc1ccc(S(=O)(=O)NC(CCSCCO)C(=O)O)cc1
Solvent: CO
Solvent: CCOCC
Product: CC#CCOc1ccc(S(=O)(=O)NC(CCSCCO)C(=O)OC)cc1

Procedure:
To a solution of 2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-4-[(2-hydroxyethyl)sulfanyl]butanoic acid (20.8 g) in ether and methanol was dropwise added trimethylsilyidiazomethane (25 mL. 2.0 M in hexanes). The reaction mixture was concentrated in vacuo and the resulting oil was chromatographed on silica gel eluting with hexane/ethyl acetate to give methyl 2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-4-[(2-hydroxyethyl)sulfanyl]butanoate as a light yellow oil (6.68 g). Electrospray Mass Spec 401.9 (M+H)+.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10](Cl)=[N:9][C:8]=2[N:7]=[C:6]1[N:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1)[C:2]#[C:3][CH3:4].[OH:30][C:31]1([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:33][CH2:32]1.[H-].[Na+].Cl>CN1CCCC1=O>[CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10]([O:30][C:31]3([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:33][CH2:32]3)=[N:9][C:8]=2[N:7]=[C:6]1[N:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2nc(Cl)n(C)c(=O)c21
Reactant: CCOC(=O)C1(O)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2nc(OC3(C(=O)OCC)CC3)n(C)c(=O)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 257.7 %

Procedure:
20 mg of t-butyl 4-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl]piperazine-1-carboxylate and 20 mg of ethyl 1-hydroxycyclopropanecarboxylate were dissolved in 0.2 ml of N-methylpyrrolidone, and 10 mg of sodium hydride was added thereto. The mixture was stirred at room temperature overnight. 1N hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated to give 63 mg of t-butyl 4-[7-(2-butynyl)-2-(1-ethoxycarbonylcyclopropyloxy)-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl]piperazine-1-carboxylate. This compound was dissolved in a solution consisting of 0.4 ml of ethanol and 0.1 ml of a 5N aqueous sodium hydroxide solution, and the mixture was stirred at 50° C. overnight. 1N hydrochloric acid solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated to give 22 mg of t-butyl 4-[7-(2-butynyl)-2-(1-carboxycyclopropyloxy)-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl]piperazine-1-carboxylate. 11 mg of this compound was dissolved in trifluoroacetic acid, and the mixture was concentrated. The residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 1.64 mg of the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.[C:13]([O:17][C:18]([NH:20][CH2:21][CH2:22][CH2:23][NH2:24])=[O:19])([CH3:16])([CH3:15])[CH3:14].C([O-])([O-])=O.[K+].[K+]>CC#N.CN(C=O)C>[C:13]([O:17][C:18](=[O:19])[NH:20][CH2:21][CH2:22][CH2:23][NH:24][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Reactant: CC(C)(C)OC(=O)NCCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])c(NCCCNC(=O)OC(C)(C)C)n1
Temperature: 40 °C
Yield: 96.5 %

Procedure:
A mixture of 2-chloro-6-methoxy-3-nitropyridine (5.9 g; commercial), N-(tert-butoxycarbonyl)-1,3-propanediamine (4.48 g; commercial) and K2CO3 (3.55 g) in MeCN (90 mL) and DMF (25 mL) was heated at 40° C. for 30 min. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was taken up in EA, sequentially washed with water and brine and evaporated under reduced pressure, affording 8.1 g (96% yield) of a crude yellow solid which was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][C:3]=1[F:26].[CH3:27][NH:28][C:29]([C:31]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][N:32]=1)=[O:30].C(=O)([O-])[O-].[K+].[K+].ClCCl>O1CCOCC1.O>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:2]([C:34]4[CH:35]=[CH:36][C:31]([C:29]([NH:28][CH3:27])=[O:30])=[N:32][CH:33]=4)=[C:3]([F:26])[CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)[N:15]=1
Reactant: CN1CCN(c2cc(N3CCc4cc(F)c(Br)cc4C3)nc(N)n2)CC1
Reactant: CNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CNC(=O)c1ccc(-c2cc3c(cc2F)CCN(c2cc(N4CCN(C)CC4)nc(N)n2)C3)cn1
Temperature: 120 °C

Procedure:
A mixture of 4-(7-bromo-6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (0.025 g, 0.060 mmol), N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxamide (0.0140 g, Frontier, Cat. No. M10074) in 1,4-dioxane (0.36 mL) was stirred at r.t. for 10 min. Potassium carbonate (37.8 mg, 0.274 mmol) in water (0.18 mL) was added. The mixture was degassed and refilled with nitrogen three times [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (3.0 mg, 0.0036 mmol) was added and the mixture was degassed and refilled with nitrogen three times and then heated at 120° C.) (oil bath temperature) for 3 h. After cooling, the mixture was diluted with methanol, and filtered. The filtrate was purified on RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=477.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[C:30]([F:42])=[CH:31][C:32]([F:41])=[C:33]([NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:34]=2)[CH2:25][CH2:24]1>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][CH:26]([C:29]3[C:30]([F:42])=[CH:31][C:32]([F:41])=[C:33]([NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:34]=3)[CH2:27][CH2:28]2)=[O:11])=[CH:13][CH:14]=1
Reactant: CC(C)C(=O)Nc1cc(C2CCN(CCCN)CC2)c(F)cc1F
Reactant: O=C(O)C(c1ccc(F)cc1)c1ccc(F)cc1
Product: CC(C)C(=O)Nc1cc(C2CCN(CCCNC(=O)C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c(F)cc1F

Procedure:
Example 165 was prepared from bis(4-fluorophenyl)acetic acid and N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2,4-difluorophenyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 8.25 (t, 1 H, J=8.4 Hz), 7.67–7.57 (m, 1 H), 7.51 (s, 1 H), 7.36–7.25 (m, 4 H), 7.03–6.91 (m, 4 H), 6.81 (t, 1 H, J=9.6 Hz), 4.81 (s, 1 H), 3.45–3.31 (m, 2 H), 2.92 (m, 2 H), 2.83–2.67 (m, 1 H), 2.63–2.47 (m, 1 H), 2.47–2.33 (m, 2 H), 2.05–1.90 (m, 2 H), 1.82–1.72 (m, 2 H), 1.72–1.56 (m, 4 H), 1.22 (d, 6 H, J=6.8 Hz); ESMS m/e: 570.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[O:5].[F:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[CH2:23][CH2:24][NH2:25].C([O-])([O-])=O.[K+].[K+].CN(C=O)C>C(OCC)(=O)C>[Cl:18][C:16]1[CH:15]=[CH:14][C:3]([C:4]([NH:6][CH2:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[O:5])=[C:2]([NH:25][CH2:24][CH2:23][C:22]2[CH:26]=[CH:27][CH:28]=[C:20]([F:19])[CH:21]=2)[N:17]=1
Reactant: O=C(NCc1cccnc1)c1ccc(Cl)nc1Cl
Reactant: NCCc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NCc1cccnc1)c1ccc(Cl)nc1NCCc1cccc(F)c1
Temperature: 100 °C
Reaction time: 10 h
Yield: 45.3 %

Procedure:
A mixture of 2,6-dichloro-N-(pyridin-3-ylmethyl)nicotinamide (20.4 g, 72.3 mmol), 3-fluorophenethyl amine (11.1 g, 79.5 mmol), K2CO3 (20 g 145 mmol) and DMF (200 mL) was stirred at 100° C. for 10 hours. The mixture was diluted with ethyl acetate (2×300 mL) and washed with saturated ammonium chloride, sodium bicarbonate and brine. The organic layers were combined, dried (MgSO4) and concentrated. The residue was purified by silica gel chromatography to give 6-chloro-2-(3-fluorophenethylamino)-N-(pyridin-3-ylmethyl)nicotinamide (12.6 g, 46%). LRMS (M+H+) m/z 385.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]([F:16])([F:15])[C:10]([O:12]CC)=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[OH-].[Li+]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([C:9]([F:16])([F:15])[C:10]([OH:12])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCOC(=O)C(F)(F)c1cc(F)cc(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C(F)(F)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of ethyl 3,5-difluorophenyl-α,α-difluoroacetate (from Example D24 below; 1 molar eq.) in 50% aqueous ethanol was treated with lithium hydroxide (1.5 molar eq.). The solution was stirred for 3 hours at ambient temperature then concentrated via rotary evaporation. The residue was taken up in water; a small amount of 1 N NaOH was added to make basic. The aqueous mixture was extracted with ether. The aqueous layer was acidified to pH 3 with 1 N HCl. The acid was extracted thrice with methylene chloride. The combined methylene chloride extracts were dried over Na2SO4, filtered, and concentrated.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[CH3:18][N:19]([CH2:21][C:22]1[N:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1)[CH3:20]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:28][C:25]1[CH:26]=[N:27][C:22]([CH2:21][N:19]([CH3:20])[CH3:18])=[CH:23][CH:24]=1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Reactant: CN(C)Cc1ccc(N)cn1
Product: CN(C)Cc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)cn1
Yield: 8.2 %

Procedure:
Following general procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (330 mg, 1.06 mmol) was reacted with 6-[(dimethylamino)methyl]pyridin-3-amine (200 mg, 1.32 mmol) to afford the desired product (37 mg, 8%) as an orange oil: ESI MS m/z 425 [C21H21BrN4O+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:35])[C@H:10]([CH3:34])[CH2:11][C@H:12]([NH:26]C(OC(C)(C)C)=O)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:36]>C1COCC1.O1CCOCC1>[ClH:36].[CH2:1]([O:8][C:9](=[O:35])[C@H:10]([CH3:34])[CH2:11][C@H:12]([NH2:26])[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: C[C@H](C[C@H](N)Cc1ccc(-c2ccccc2)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methyl-pentanoic acid (prepared using the procedure described in WO 2008083967)(1.0 g, 2.61 mmol) and benzyl bromide (468 mg, 2.74 mmol) in DMF (15 mL) is added potassium carbonate (541 mg, 3.91 mmol) and the mixture is stirred at room temperature for 2 hours. Water is added and the mixture is extracted with ethyl acetate. The combined organic layers are washed with water and dried over magnesium sulfate. The solvent is removed under reduced pressure and the residual oil is purified by column chromatography using heptane/EtOAc (4:1) to furnish (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methyl-pentanoic acid benzyl ester. Next, to a solution of (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methyl-pentanoic acid benzyl ester in THF (5 mL) is added 4M HCl in dioxane (3 mL) and the solution is stirred at room temperature for 1 hour. The solvent is removed under reduced pressure to give the title compound. MS 374.4 (M+1).