Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH2:9])[CH:5]=[C:4]([N:10]2[CH2:15][CH:14]=[CH:13][CH2:12][CH2:11]2)[N:3]=1.C(Cl)Cl.[CH2:19]([O:23][C:24](Cl)=[O:25])[CH2:20][CH2:21][CH3:22]>C(N(CC)CC)C>[N:10]1([C:4]2[N:3]=[C:2]([NH:1][C:24]([O:23][CH2:19][CH2:20][CH2:21][CH3:22])=[O:25])[N+:7]([O-:8])=[C:6]([NH:9][C:24]([O:23][CH2:19][CH2:20][CH2:21][CH3:22])=[O:25])[CH:5]=2)[CH2:11][CH:12]=[CH:13][CH2:14][CH2:15]1
Reactant: Nc1cc(N2CC=CCC2)nc(N)[n+]1[O-]
Reactant: CCCCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCOC(=O)Nc1cc(N2CC=CCC2)nc(NC(=O)OCCCC)[n+]1[O-]
Temperature: 5 °C

Procedure:
20 G. of 2,4-diamino-6-[3,6-dihydro-1(2H)-pyridyl]pyrimidine-3-oxide are mixed with 250 ml. of methylene chloride and 35 ml. of triethylamine, stirred and cooled to 5° C. The mixture is treated with 45 ml. of chloroformic acid butyl ester and stirred at room temperature for 6 hours. The mixture obtained is washed with water, extracted with methylene chloride and evaporated under reduced pressure. The residue is recrystallized from ethanol, there being obtained dibutyl 6-[3,6-dihydro-1(2H)-pyridyl]-2,4-pyrimidine-dicarbamate-3-oxide, having a melting point of 131°-132° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:3]=1.[NH:20]1[C:28]2[C:23](=[C:24]([CH2:29][CH2:30][NH2:31])[CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21]1.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[NH:20]1[C:28]2[C:23](=[C:24]([CH2:29][CH2:30][NH:31][C:2]3[CH:7]=[C:6]([C:8]4[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=4)[N:5]=[C:4]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=4)[N:3]=3)[CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21]1
Reactant: Clc1cc(-c2cccnc2)nc(-c2ccccn2)n1
Reactant: NCCc1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: c1ccc(-c2nc(NCCc3cccc4[nH]ccc34)cc(-c3cccnc3)n2)nc1
Temperature: 25 °C

Procedure:
4-Chloro-6-pyridin-3-yl-2-pyridin-2-yl-pyrimidine (Intermediate A) (1 eq, 50 mg) in NMP (1 ml) is treated with 2-(1H-indol-4-yl)-ethylamine (1.1 eq, 33 mg) followed by K2CO3 (5 eq, 178 mg). The reaction mixture is heated using microwave radiation at 120° C. for 45 minutes. After cooling to room temperature, the mixture is partitioned between EtOAc/water and the organic portion is separated, washed with brine, dried (MgSO4) and concentrated in vacuo. The crude residue is purified by reverse phase column chromatography (Isolute™ C18, 0-100% acetonitrile in water—0.1% TFA) and the appropriate fractions are combined and concentrated in vacuo. The resulting residue is loaded onto a SCX-2 cartridge eluting with MeOH followed by 2M NH3 in MeOH. The methanolic ammonia fractions are concentrated in vacuo and dried under vacuum to afford the title compound [M+H]+=393.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([O:14][C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[C:21]([C:25](Cl)=[O:26])=[CH:20][CH:19]=[CH:18]4)[CH:5]=[CH:4][C:3]1=2.[NH3:29]>>[CH3:1][C:2]1([CH3:28])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([O:14][C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[C:21]([C:25]([NH2:29])=[O:26])=[CH:20][CH:19]=[CH:18]4)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(Oc3ccc4c(C(=O)Cl)cccc4c3)ccc21
Reactant: N
Product: CC1(C)CCC(C)(C)c2cc(Oc3ccc4c(C(N)=O)cccc4c3)ccc21
Yield: 88 %

Procedure:
Utilizing a procedure analogous to that of Example 16(b), 671 mg (1.7 mmol) of 6-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2 -naphthyloxy)naphthoyl chloride were reacted with 10 ml of aqueous ammonia (32%) to provide 560 mg (88%) of the expected amide, having a melting point of 175°-6° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([CH:11]([O:15][CH3:16])[C:12]([OH:14])=[O:13])[CH:9]=[CH:10][C:2]1=2.S(=O)(=O)(O)O.[C:22]([O-])(O)=O.[Na+]>CO>[O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([CH:11]([O:15][CH3:16])[C:12]([O:14][CH3:22])=[O:13])[CH:9]=[CH:10][C:2]1=2
Reactant: O=C([O-])O
Reactant: COC(C(=O)O)c1ccc2c(c1)OCCO2
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(OC)c1ccc2c(c1)OCCO2
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methoxyacetic acid (18.3 mmol) in dry MeOH was added sulfuric acid (2.5 mL) dropwise and heated at 90° C. Stirring was then continued for 3 hours. The reaction mixture was then cooled and poured into saturated aqueous NaHCO3 and extracted with EtOAc. The combined organic fractions were dried over Na2SO4, filtered, and concentrated under reduced pressure to yield an oil (3.7 g) that was not further purified.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[C:13](Br)=[CH:12][O:11][C:10]=1[C:17]([O:19][CH3:20])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:21]1[CH:25]=[CH:24][N:23]=[C:22]1[Sn](CCCC)(CCCC)CCCC>O1CCOCC1.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>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[C:13]([C:22]2[S:21][CH:25]=[CH:24][N:23]=2)=[CH:12][O:11][C:10]=1[C:17]([O:19][CH3:20])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: COC(=O)c1occ(Br)c(=O)c1OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: COC(=O)c1occ(-c2nccs2)c(=O)c1OCc1ccccc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 63.1 %

Procedure:
To a solution of methyl 3-benzyloxy-5-bromo-4-oxo-4H-pyran-2-carboxylate (2.3 g) in dioxane (25 ml) were added tetrakis(triphenylphosphine)palladium(0) (1.57 g) and (2-thiazolyl)tributyltin (5.08 g) under an argon stream, and the mixture was stirred at 100° C. for 1.5 hr. The obtained reaction mixture was concentrated, and subsequently purified by silica gel column chromatography (ethyl acetate:hexane=1:4–1:2) to give methyl 3-benzyloxy-4-oxo-5-(thiazol-2-yl)-4H-pyran-2-carboxylate (1.47 g).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:9]2[C:10]([CH3:22])([CH3:21])[CH:11](CC)[C:12]3[CH:13]=[N:14][C:15](N)=[N:16][C:17]=3[C:8]=2[N:7]([CH3:23])[N:6]=1)=[O:4].[I-:24].II.N(OCCC(C)C)=O>[Cu]I.C(COC)OC>[CH3:1][NH:2][C:3]([C:5]1[C:9]2[C:10]([CH3:22])([CH3:21])[CH2:11][C:12]3[CH:13]=[N:14][C:15]([I:24])=[N:16][C:17]=3[C:8]=2[N:7]([CH3:23])[N:6]=1)=[O:4]
Reactant: [I-]
Reactant: CCC1c2cnc(N)nc2-c2c(c(C(=O)NC)nn2C)C1(C)C
Agent: [Cu]I
Agent: CC(C)CCON=O
Agent: II
Solvent: COCCOC
Product: CNC(=O)c1nn(C)c2c1C(C)(C)Cc1cnc(I)nc1-2
Temperature: 70 °C

Procedure:
In a round bottom flask maintained under argon atmosphere, ethyl 8-amino-1,4,4-trimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid methylamide (13.00 g, 45.400 mmol) was dissolved into anhydrous dimethoxyethane (800 mL); cesiun iodide (11.795 g, 45.400 mmol), bisublimated iodine (5.761 g, 22.698 mmol), copper(I) iodide (2.594 g, 13.621 mmol), and iso-amyl nitrite (9.107 mL, 68.100 mmol) were added in that order and the mixture was heated to 70° C. for 22 hours.
Reaction SMILES: [C:1]1([C:7]2[C:8](=[N:13][NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:9]([NH2:12])=[N:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]1([C:7]2[C:8](=[N:13][NH:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:9]([NH:12][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=3)=[N:10][N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC1=NN=C(c2ccccc2)C1=NNc1ccccc1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1=NN=C(c2ccccc2)C1=NNc1ccccc1)c1cccnc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 36.9 %

Procedure:
5-Phenyl-4-(phenylhydrazono)-4H-pyrazol-3-ylamine (66 mg, 0.25 mmol) was dissolved in 5 mL of anhydrous methylene chloride. Nicotinoylchloride hydrochloride (50 mg, 0.28 mmol) and triethylamine (78 μL, 0.56 mmol) were added to the solution. Slight fuming of the reaction was noted and the solution became red. The reaction was stirred at ambient temperature for 48 hours. The reaction was filtered to remove a small amount of white solid. To the filtrate was added 30 mL of methylene chloride. The solution was washed with 20 mL of a 5% HCl solution. The aqueous layer was washed with methylene chloride and the combined methylene chloride fractions were washed with water and saturated NaHCO3 solution. The methylene chloride solution was dried over MgSO4, filtered, and evaporated to afford a solid. The material was purified by flash chromatography (CH2Cl2:MeOH=15:1) to yield 34 mg (36%) of the title compound as a yellow solid. 1H NMR (ppm, 200 MHz, CDCl3) δ 7.30-7.55 (m, 8H), 7.75 (d, 2H), 8.20-8.30 (m, 2H), 8.55 (d, 1H), 8.81 (d, 1H), 9.45 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH2:14][CH2:15][CH:16]=O)=[CH:12][C:11]([CH2:18][CH2:19][CH3:20])=[N:10]2)=[CH:5][CH:4]=1.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.[BH3-]C#N.[Na+]>>[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][N:31]([CH2:16][CH2:15][CH2:14][C:13]2[N:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:10]=[C:11]([CH2:18][CH2:19][CH3:20])[CH:12]=2)[CH2:30][CH2:29]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: CCCc1cc(CCC=O)n(-c2ccc(OC)cc2)n1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCCc1cc(CCCN2CCN(c3ccccc3F)CC2)n(-c2ccc(OC)cc2)n1

Procedure:
114 mg (66.0%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-(4-methoxyphenyl)-3-propyl-1H-pyrazol-5-yl)propanal (107.73 mg, 0.396 mmol), 1-(2-fluorophenyl)piperazine (82.22 mL, 0.514 mmol), and NaCNBH3 (74.58 mg, 1.187 mmol).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][N:10]=[C:9]([Cl:13])[CH:8]=1)=O.[N+]([O-])(O)=O.[F:19][C:20]([F:32])([F:31])[C:21]1[CH:22]=[C:23]([NH:27][C:28]([NH2:30])=[NH:29])[CH:24]=[CH:25][CH:26]=1.[OH-].[Na+]>CC(O)C>[F:19][C:20]([F:31])([F:32])[C:21]1[CH:22]=[C:23]([NH:27][C:28]2[N:30]=[C:5]([C:7]3[CH:12]=[CH:11][N:10]=[C:9]([Cl:13])[CH:8]=3)[CH:4]=[CH:3][N:29]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: N=C(N)Nc1cccc(C(F)(F)F)c1
Reactant: CN(C)C=CC(=O)c1ccnc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O=[N+]([O-])O
Product: FC(F)(F)c1cccc(Nc2nccc(-c3ccnc(Cl)c3)n2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
150 mg (0.71 mmol) of 3-dimethylamino-1-(2-chloro-4-pyridyl)-2-propen-1-one are suspended in 1.5 ml of 2-propanol. 190 mg (0.712 mmol) of 3-trifluoromethylphenyl-guanidine nitrate and 31 mg (0.783 mmol) of sodium hydroxide are added and the reaction mixture is stirred for 18 h under RF. It is then cooled to RT and filtered, and the material retained on the filter is washed with 2-propanol and water and dried at 50° under HV to give N-(3-trifluoromethyl-phenyl)-4-(2-chloro-4-pyridyl)-2-pyrimidineamine;
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH2:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:20]1[CH:25]=[CH:24][N:23]=[C:22]2[NH:26][CH:27]=[N:28][C:21]=12>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:22]2[C:21]3[N:28]=[CH:27][NH:26][C:20]=3[CH:25]=[CH:24][N:23]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccnc2[nH]cnc12
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Product: O=C(OCc1ccccc1)N1CCC(CNc2nccc3[nH]cnc23)CC1

Procedure:
EXAMPLE 88 was prepared from 4-aminomethyl-piperidine-1-carboxylic acid benzyl ester and 7-chloro-3H-imidazo[4,5-b]pyridine (7-chloro-3H-imidazo[4,5-b]pyridine was prepared according to Y. Mizuno, T. Itoh, K. Saito, Chem. Pharm. Bull., 12:866–872(1964): MS (m+1)=366.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]([CH3:12])[CH3:11])[N:4]=1.C([O:15][C:16](=[O:27])[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([F:26])[CH:20]=1)C>>[F:26][C:21]1[CH:20]=[C:19]([CH2:18][CH2:17][C:16]([OH:27])=[O:15])[CH:24]=[CH:23][C:22]=1[O:25][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]([CH3:12])[CH3:11])[N:4]=1
Reactant: CC(C)Sc1cccc(CCl)n1
Reactant: CCOC(=O)CCc1ccc(O)c(F)c1
Product: CC(C)Sc1cccc(COc2ccc(CCC(=O)O)cc2F)n1
Yield: 83.8 %

Procedure:
2-Chloromethyl-6-isopropylsulfanyl-pyridine (0.028 g, 0.14 mmol) obtained in Step C of Preparation Example 16 and 3-(3-fluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (0.030 g, 0.14 mmol) obtained in Step C of Preparation Example 6 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.041 g, 83%).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([OH:27])[CH2:25][CH3:26])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:30](I)[CH3:31]>CN(C)C=O>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([O:27][CH2:30][CH3:31])[CH2:25][CH3:26])=[CH:4][CH:3]=1
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)nc1C
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(CC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)nc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
To a solution of 1-[9-chloro-1-(6-methoxy-2-methylpyridin-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (138.3 mg, 0.357 mmol) in N,N-dimethylformamide (2.3 mL) was added sodium hydride (21.4 mg, 0.536 mmol) at 0° C. After 30 min, to the mixture was added ethyl iodide (143 μL, 1.785 mmol) at 0° C. The reaction mixture was stirred at room temperature for 17.5 hrs. The mixture was quenched with aqueous saturated ammonium chloride and extracted with ethyl acetate (×3). The combined organic layer was washed with water (×2) and brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-40% ethyl acetate/n-hexane gradient mixture. The resulting solid was recrystallized from ethyl acetate/n-hexane to give the title compound as a colorless powder (112.1 mg, 0.270 mmol, 58%).
Reaction SMILES: [C:1]([NH:8][OH:9])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[K+].[CH2:12]([O:14][C:15](=[O:20])[C:16](Br)([CH3:18])[CH3:17])[CH3:13]>C(O)C>[CH2:12]([O:14][C:15](=[O:20])[C:16]([O:9][NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])([CH3:18])[CH3:17])[CH3:13]
Reactant: CC(C)(C)OC(=O)NO
Reactant: CCOC(=O)C(C)(C)Br
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(C)(C)ONC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 98.4 %

Procedure:
To a solution of N-Boc-hydroxylamine (5.2 g, 39.05 mmol) in ethanol (100 mL) was added potassium hydroxide (2.63 g, 46.86 mmol), the mixture stirred at room temperature until a solution was formed. 2-Bromoisobutyric acid ethyl ester (6.87 mL, 46.9 mmol) was added and the reaction mixture heated at reflux for 18 hours. The reaction mixture was cooled to room temperature then filtered, and the filtrate was concentrated in vacuo. The resultant oily residue was partitioned between water (75 mL) and diethyl ether and the aqueous fraction was extracted with diethyl ether (2×100 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as a clear oil (9.5 g, 99%). LCMS (method C): RT=2.55 min, [M+H]+=248. 1H NMR (CDCl3, 400 MHz) 4.20 (q, 2H), 1.50 (s, 6H), 1.49 (s, 9H), 1.30 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:21]=2[O:28][CH3:29])=[CH:16][CH:15]=1)[NH:5]C(OC(C)(C)C)=O.[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34]>C(Cl)Cl>[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[CH3:1][O:2][C:3](=[O:30])[C@H:4]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:21]=2[O:28][CH3:29])=[CH:18][CH:19]=1)[NH2:5]
Reactant: COC(=O)[C@H](Cc1ccc(-c2c(OC)cccc2OC)cc1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H](N)Cc1ccc(-c2c(OC)cccc2OC)cc1

Procedure:
A methylene chloride solution of N-tert-butoxycarbonyl-4-(2,6-dimethoxyphenyl)-L-phenyalanine methyl ester was treated with trifluoroacetic acid for six hours at room temperature. Concentration of the volatiles yielded the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:35]([F:38])([F:37])[F:36])[C:5]([N:8]2[C:12]3=[N:13][CH:14]=[N:15][C:16]([O:17][C@@H:18]([CH2:29][O:30][CH:31]4[CH2:34][CH2:33][CH2:32]4)[C:19]([NH:21][C:22]4[CH:27]=[N:26][C:25]([CH3:28])=[CH:24][N:23]=4)=[O:20])=[C:11]3[CH:10]=[N:9]2)=[N:6][CH:7]=1>[Pd].C(O)C>[CH:31]1([O:30][CH2:29][C@H:18]([O:17][C:16]2[C:11]3[CH:10]=[N:9][N:8]([C:5]4[C:4]([C:35]([F:37])([F:38])[F:36])=[CH:3][CH:2]=[CH:7][N:6]=4)[C:12]=3[N:13]=[CH:14][N:15]=2)[C:19]([NH:21][C:22]2[CH:27]=[N:26][C:25]([CH3:28])=[CH:24][N:23]=2)=[O:20])[CH2:32][CH2:33][CH2:34]1
Reactant: Cc1cnc(NC(=O)[C@H](COC2CCC2)Oc2ncnc3c2cnn3-c2ncc(Cl)cc2C(F)(F)F)cn1
Agent: [Pd]
Solvent: CCO
Product: Cc1cnc(NC(=O)[C@H](COC2CCC2)Oc2ncnc3c2cnn3-c2ncccc2C(F)(F)F)cn1
Reaction time: 8 h
Yield: 32 %

Procedure:
10% Palladium on carbon (200 mg, 1.88 mmol) and (2S)-2-(1-(5-chloro-3-(trifluoromethyl)pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3-cyclobutoxy-N-(5-methylpyrazin-2-yl)propanamide (Example 138) (501 mg, 0.91 mmol) in ethanol was stirred under an atmosphere of hydrogen at ambient temperature for 20 hours. The mixture was filtered and fresh catalyst (200 mg) added and the mixture stirred under hydrogen atmosphere for 8 hours. The mixture was filtered, triethylamine (1 mL) added, and the mixture evaporated. The residue was purified by flash silica chromatography eluting with ethyl acetate to give the product (150 mg, 32%). 1H NMR (400 MHz, CDCl3) δ 1.46-1.60 (1H, m), 1.64-1.71 (1H, m), 1.92-1.97 (2H, m), 2.18-2.23 (2H, m), 2.54 (3H, s), 3.98-4.07 (3H, m), 6.05 (1H, t), 7.65-7.68 (1H, m), 8.12 (1H, d), 8.29 (1H, dd), 8.44 (1H, s), 8.62-8.67 (1H, m), 8.65 (1H, s), 8.89 (1H, dd), 9.45 (1H, d); m/z (ESI+) (M+H)+=515; HPLC tR=2.25 min.
Reaction SMILES: Cl[CH2:2][N:3]1[CH2:7][CH:6]([CH2:8][CH2:9][CH3:10])[CH2:5][C:4]1=[O:11].[NH3:12]>C1(C)C=CC=CC=1>[NH2:12][CH2:2][N:3]1[CH2:7][CH:6]([CH2:8][CH2:9][CH3:10])[CH2:5][C:4]1=[O:11]
Reactant: N
Reactant: CCCC1CC(=O)N(CCl)C1
Solvent: Cc1ccccc1
Product: CCCC1CC(=O)N(CN)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-(chloromethyl)-4-propylpyrrolidin-2-one x63 (41.34 g, 0.235 mol) in toluene (350 ml) is added dropwise at −78° C. to liquid ammonia (300 ml). At the end of the addition, the temperature is raised slowly to room temperature, and ammonia of the crude mixture is allowed to distille at room temperature overnight. Filtration of the reaction mixture and subsequent evaporation lead to 55 g of the crude 1-(aminomethyl)-4-propylpyrrolidin-2-one x76 which is used without further purification.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:13][C@H:14]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]2)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([F:12])[CH:6]=2.[CH3:26][N:27](C=O)C>[C-]#N.[C-]#N.[Zn+2].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:2]1[N:3]=[C:4]([NH:13][C@H:14]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]2)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([F:12])[CH:6]=2)#[N:27]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(Cl)cc3ccc(F)cc23)C1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(C#N)cc3ccc(F)cc23)C1
Temperature: 160 °C
Yield: 72 %

Procedure:
To a solution of (S)-tert-butyl 3-((3-chloro-7-fluoroisoquinolin-1-yl)amino)pyrrolidine-1-carboxylate (0.5 g, 1.37 mmol) in DMF (15 mL) was added Zn(CN)2 (0.48 g, 4.1 mmol), and Pd(PPh3)4(0.16 g, 0.14 mmol) under a nitrogen atmosphere. The mixture was heated to 160° C. for 30 minutes in a microwave reactor. The mixture was partition between EtOAc (50 mL) and water (50 mL). The aqueous layer was extracted with EtOAc (3×50 mL). The organic layers were combined, washed with saturated aqueous NaCl (3×50 mL) and concentrated in vacuo. The crude product was purified by column chromatography eluting with petroleum ether and ethyl acetate (PE/EtOAc=10:1-5:1 gradient) to give the title compound (0.36 g, 72%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.38-8.35 (d, J=10.8 Hz, 1H), 8.01-7.97 (m, 1H), 7.77-7.72 (m, 3H), 4.66-4.58 (m, 1H), 3.69-3.67 (m, 1H), 3.48-3.46 (m, 1H), 3.39-3.37 (m, 1H), 3.28-3.27 (m, 1H), 2.2 (s, 1H), 1.97-1.91 (m, 1H), 1.40 (s, 9H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([C:16]#[N:17])=[C:9]2[CH:18]1[CH2:20][CH2:19]1)=O)C.[BH4-].[Li+]>>[CH:18]1([CH:9]2[C:8]3[C:13](=[CH:14][CH:15]=[C:6]([CH2:4][OH:3])[CH:7]=3)[NH:12][CH:11]=[C:10]2[C:16]#[N:17])[CH2:19][CH2:20]1
Reactant: CCOC(=O)c1ccc2ncc(C#N)c(C3CC3)c2c1
Agent: [BH4-]
Agent: [Li+]
Product: N#CC1=CNc2ccc(CO)cc2C1C1CC1

Procedure:
Similar procedure as described in example 46e was used, starting from 3-cyano-4-cyclopropyl-quinoline-6-carboxylic acid ethyl ester (example 57a) and lithium borohydride to give 4-cyclopropyl-6-hydroxymethyl-1,4-dihydro-quinoline-3-carbonitrile as a yellow solid. LC-MS m/e 227 (MH+).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.Cl[C:17]([N:19]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[CH:25]=2)[CH2:20]1)=[O:18]>O1CCCC1>[CH:33]1([O:32][C:26]2[CH:25]=[C:24]([CH:21]3[CH2:22][CH2:23][N:19]([C:17]([NH:1][CH2:2][C:3]4[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=4)=[O:18])[CH2:20]3)[CH:29]=[CH:28][C:27]=2[O:30][CH3:31])[CH2:34][CH2:35][CH2:36][CH2:37]1
Reactant: COc1ccc(C2CCN(C(=O)Cl)C2)cc1OC1CCCC1
Reactant: NCc1cccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(C2CCN(C(=O)NCc3cccnc3)C2)cc1OC1CCCC1
Temperature: 0 °C
Reaction time: 6 h
Yield: 64.9 %

Procedure:
216 mg of 3-(aminomethyl) pyridine and 202 mg of triethylamine were dissolved in 5 ml of tetrahydrofuran. During agitation at a cold temperature, a solution obtained by dissolving 545 mg of 1-chloroformyl-3-(3-cyclopentyloxy-4-methoxyphenyl) pyrrolidine in 3 ml of tetrahydrofuran was added in drops. After dropping, agitation was continued for 6 hours at a room temperature. Thereafter, the agitated solution was poured into ice water and then extracted with ethyl acetate. After organic layers were cleaned by water and dried over magnesium sulfate, it was concentrated under a reduced pressure. The residue was purified by means of the silica gel column chromatography to obtain 432 mg of Compound No. 22 in Table 1.