Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]=[C:24]2[CH3:48])=[CH:19][CH:18]=1)[CH:14]([CH3:16])[CH3:15]>O.C(OCC)(=O)C>[CH2:13]([C:17]1[CH:18]=[CH:19][C:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[C:43]4[NH:3][C:4](=[O:7])[O:5][N:44]=4)=[CH:35][CH:36]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]=[C:24]2[CH3:48])=[CH:21][CH:22]=1)[CH:14]([CH3:16])[CH3:15]
Reactant: CCCc1nc(C)n(-c2ccc(CC(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc(CC(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 39.8 %

Procedure:
A mixture of hydroxylammonium chloride (1.9 g), sodium hydrogen carbonate (2.7 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[1-(4-isobutylphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.34 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.55 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.51 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.60 g, 40%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=O.[C:12](#[N:15])[CH:13]=C.C(N(C(C)C)C(C)C)C>[Pd](Cl)Cl.C1(=O)CCCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH:6]=[CH:13][C:12]#[N:15]
Reactant: C=CC#N
Reactant: COc1cccc(C(=O)Cl)c1
Agent: Cl[Pd]Cl
Solvent: O=C1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(C=CC#N)c1
Yield: 6.3 %

Procedure:
The procedure described in Example 1 is repeated, except that 17.05 g (0.1 mol) of 3-methoxybenzoyl chloride, 6.63 g (0.125 mol) of acrylonitrile, 12.96 g (0.1 mol) of ethyldiisopropylamine, 0.1773 g (0.001 mol) of palladium chloride and 50 ml of cyclohexanone, as the solvent, are used. After a reaction time of 13 hours at 120° C, 1 g (0.0063 mol) of 3-methoxycinnamonitrile are obtained, corresponding to a yield of 6.3% of theory; boiling point 159°-166° C./19×102Pa.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].[Br:13][CH2:14][CH2:15][CH2:16]Br.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C.C(Cl)(Cl)Cl>[Br:13][CH2:14][CH2:15][CH2:16][O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12]
Reactant: BrCCCBr
Reactant: O=C1CCCc2c(O)cccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: O=C1CCCc2c(OCCCBr)cccc21
Yield: 57 %

Procedure:
32.43 g (0.2 mol) 5-hydroxy-1-oxotetraline and 120.14 g (0.6 mol) 1,3-dibromopropane were, while stirring, heated to the boil in 200 ml anhydrous isopropanol and thereafter 41.46 g (0.3 mol) pulverized anhydrous potassium carbonate were added thereto over the course of about three hours. Subsequently, the reaction mixture was vigorously stirred for six hours at reflux temperature, then filtered with suction and the filter cake washed out with isopropanol. The filtrate was evaporated in a vacuum and excess 1,3-dibromopropane was substantially stripped off. The oily evaporation residue obtained was taken up in chloroform, the chloroform solution was extracted several times with a dilute aqueous solution of sodium hydroxide, then shaken with water until neutral and dried. After distilling off the chloroform, the oily residue was distilled at oil pump vacuum. Between 145°-155°C/0.05 mm Hg, there were obtained 32.3 g (57.1% of theory) 5-(3-bromopropoxy)-1-oxotetraline, which was then further worked up.
Reaction SMILES: [CH2:1](O)[CH3:2].Cl.[OH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][NH:14][CH:15]1[CH2:24][CH2:23][CH2:22][C:21]2[N:20]=[C:19]([C:25]([OH:27])=[O:26])[CH:18]=[CH:17][C:16]1=2.C(=O)(O)[O-].[Na+]>O1CCOCC1.C(OCC)(=O)C>[OH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][NH:14][CH:15]1[CH2:24][CH2:23][CH2:22][C:21]2[N:20]=[C:19]([C:25]([O:27][CH2:1][CH3:2])=[O:26])[CH:18]=[CH:17][C:16]1=2
Reactant: O=C(O)c1ccc2c(n1)CCCC2NCCc1ccccc1O
Reactant: CCO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2c(n1)CCCC2NCCc1ccccc1O
Temperature: 25 °C

Procedure:
645 ml of anhydrous ethanol and 52 ml of a 4 N solution of hydrogen chloride in dioxane were added to 25.8 g (82.59 mmol) of 5-{[2-(2-hydroxyphenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid, and the mixture was stirred under reflux overnight. The reaction solution was then cooled to room temperature, and first ethyl acetate and then, slowly, saturated aqueous sodium bicarbonate solution were added. Subsequently, the organic phase was separated off, dried over sodium sulphate, filtered and concentrated to dryness. This gave 23.9 g (70.21 mmol, 85% of theory) of the target compound.
Reaction SMILES: CC(N)COCC(OCC(OCC([NH2:16])C)C)C.[C:18]([C:21]1[CH:22]=[C:23]([CH:30]=[CH:31][CH:32]=1)C([N:27]=[C:28]=[O:29])(C)C)([CH3:20])=[CH2:19]>CC(CCC)=O>[NH2:27][C:28]([NH2:16])=[O:29].[CH3:20][C:18]([C:21]1[CH:22]=[CH:23][CH:30]=[CH:31][CH:32]=1)=[CH2:19]
Reactant: C=C(C)c1cccc(C(C)(C)N=C=O)c1
Reactant: CC(N)COCC(C)OCC(C)OCC(C)N
Solvent: CCCC(C)=O
Product: C=C(C)c1ccccc1
Product: NC(N)=O
Temperature: 25 °C

Procedure:
59.95 g (0.010 m) of α,ω-Di-(1-methyl-aminoethyl)-poly-(ethylene oxide) of MW 5995 (Jeffamine-ED 6000) and 59.95 g of anhydrous methyl propyl ketone are charged into a 3-necked round bottomed flask which has been equipped with a stirrer, nitrogen inlet, condenser, thermometer and dropping funnel. The solution is stirred at room temperature under dry nitrogen, then 4.02 g (0.020 mole) of m-isopropenyl-alpha,alpha-dimethylbenzyl isocyanate (MW 201) dissolved in 3.1 g of anhydrous methylpropyl ketone are added slowly from the dropping funnel. The mildly exothermic reaction is maintained at 35° C. and below by water bath cooling for 1 hour, at which time an IR analysis shows the reaction to be complete.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.N>O.S(C1C=CC(C)=CC=1)(O)(=O)=O.C(OCC)(=O)C>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][O:11]1
Reactant: C1=COCCC1
Reactant: Clc1ncnc2nc[nH]c12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: O
Solvent: CCOC(C)=O
Product: Clc1ncnc2c1ncn2C1CCCCO1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
Ethyl acetate (300 ml) was added to 6-chloropurine (25 g, 162 mmol) and tosylic acid monohydrate (460 mg, 2.43 mmol) and the resulting mixture was heated at 60° C. Dihydropyrane (16 ml, 178 mmol) was added and the resulting mixture was stirred at the same temperature for 30 minutes. The reaction mixture was cooled to room temperature followed by the addition of 28% aqueous ammonia solution (15 ml) and the organic layer was fractionated, washed with water, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (35 g, 91%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([S:3]([C:5]1[N:9]=[CH:8][NH:7][N:6]=1)=[O:4])[CH3:2].[CH2:10]([N:13]([CH2:17][CH3:18])[C:14](Cl)=[O:15])[CH:11]=[CH2:12].C(N(CC)CC)C>O1CCCC1>[CH2:10]([N:13]([CH2:17][CH3:18])[C:14]([N:7]1[CH:8]=[N:9][C:5]([S:3]([CH2:1][CH3:2])=[O:4])=[N:6]1)=[O:15])[CH:11]=[CH2:12]
Reactant: CCS(=O)c1nc[nH]n1
Reactant: C=CCN(CC)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCN(CC)C(=O)n1cnc(S(=O)CC)n1

Procedure:
A mixture of 7.25 g. 3-ethylsulphinyl-1,2,4-triazole, 7.8 g. N-allyl-N-ethylcarbamoyl chloride, 7.5 ml. dry triethylamine and 100 ml. dry tetrahydrofuran was refluxed under anhydrous conditions for 4 hours. The cooled reaction mixture was filtered and the filtrate distilled under reduced pressure to give 1-(N-allyl-N-ethylcarbamoyl)-3-ethylsulphinyl-1,2,4-triazole as a residual oil, nD25 1.5328.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([CH2:13][C@H:14]([CH3:15])[N:8]3[CH:7]=[C:6]([C:16]([OH:18])=[O:17])[C:5]2=[O:19])[C:11]=1Cl.[CH3:20][CH:21]1[CH2:26][NH:25][CH2:24][CH2:23][NH:22]1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([CH2:13][C@H:14]([CH3:15])[N:8]3[CH:7]=[C:6]([C:16]([OH:18])=[O:17])[C:5]2=[O:19])[C:11]=1[N:25]1[CH2:24][CH2:23][NH:22][CH:21]([CH3:20])[CH2:26]1
Reactant: CC1CNCCN1
Reactant: C[C@H]1Cc2c(Cl)c(Cl)cc3c(=O)c(C(=O)O)cn1c23
Product: CC1CN(c2c(Cl)cc3c(=O)c(C(=O)O)cn4c3c2C[C@@H]4C)CCN1
Product: Cl

Procedure:
(+)-8,9-dichloro-2-(S)-methyl-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid obtained in Example 6 and 2-methylpiperazine were used as the starting substances, and treated in a manner analogous to Example 8, to give the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)=[CH:6][N:5]=[C:4]([NH2:14])[CH:3]=1.C1C(=O)N([Br:22])C(=O)C1>C(#N)C>[Br:22][C:3]1[C:4]([NH2:14])=[N:5][CH:6]=[C:7]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)[C:2]=1[F:1]
Reactant: Cn1cc(-c2cnc(N)cc2F)cn1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Cn1cc(-c2cnc(N)c(Br)c2F)cn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 14.2 %

Procedure:
To a solution of 4-fluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (150 mg, 0.780 mmol) in acetonitrile (7. 805 mL) was added NBS (142 mg, 0.796 mmol) in three portions at 0° C. The reaction mixture was stirred at 0° C. for 20 min. LCMS showed the reaction complete. After quenched with sat Na2SO3 and NaHCO3, stirred for 30 min. The reaction mixture was extracted with EtOAc 3 times. Filtered out solid. The solid was not the desired product. The EtOAc layers were washed by sat NaHCO3, water and brine. Dried and concentrated. The crude material was purified with flash chromatography eluting with 0-100% EtOAc (containing 10% MeOH/heptane to provide 30 mg of desired product. LCMS (m/z): 273.1 (MH+), 0.46 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[N:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](OC)=[O:31])=[CH:21][CH:20]=1.[Li+].CC([N-]C(C)C)C>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:11]3[C:12](=[CH:15][CH:16]=[CH:17][N:18]=3)[CH:13]=[C:29]([CH2:28][CH2:27][CH2:26][CH2:25][C:22]3[CH:21]=[CH:20][N:19]=[CH:24][CH:23]=3)[C:30]2=[O:31])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COC(=O)CCCCCc1ccncc1
Reactant: O=Cc1cccnc1Nc1cccc([N+](=O)[O-])c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=c1c(CCCCc2ccncc2)cc2cccnc2n1-c1cccc([N+](=O)[O-])c1

Procedure:
The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), methyl 6-(pyridin-4-yl)hexanoate (2.0 eq., prepared in Synthetic Example 13) and LDA (2.0 eq.) to obtain 1-(3-nitrophenyl)-3-[4-(pyridin-4-yl)butyl]-1,8-naphthyridin-2(1H)-one, mp 168.8 to 169.6° C./DMF, wherein the product was purified through silica gel column chromatography and recrystallization.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][C@H:6]([C:8]([O:10][CH3:11])=[O:9])[CH2:5][N:4]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[C@H:3]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:35]([O:38][C:39]([F:42])([F:41])[F:40])=[CH:34][C:31]=1[CH:32]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH2:15]([O:14][C:12]([N:4]1[CH2:5][C@@H:6]([C:8]([O:10][CH3:11])=[O:9])[CH2:7][C@H:2]([NH:1][CH2:32][C:31]2[CH:34]=[C:35]([O:38][C:39]([F:40])([F:41])[F:42])[CH:36]=[CH:37][C:30]=2[O:29][CH3:28])[C@@H:3]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:13])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)[C@H]1C[C@H](N)[C@H](c2ccccc2)N(C(=O)OCc2ccccc2)C1
Reactant: COc1ccc(OC(F)(F)F)cc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@H]1C[C@H](NCc2cc(OC(F)(F)F)ccc2OC)[C@H](c2ccccc2)N(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 125.3 %

Procedure:
To a stirred solution of (2S*,3S*,5S*)-3-amino-1-benzyloxycarbonyl-5-methoxycarbonyl-2-phenylpiperidine (0.79 g, 2.16 mmol) and 2-methoxy-5-trifluoromethoxybenzaldehyde (0.59 g, 2.70 mmol) in CH2Cl2 (25.0 ml) was added NaB(OAc)3H (0.69 g, 3.24 mmol) potionwise at room temperature. The turbid reaction mixture was stirred at room temperature for 3 hours; the NaB(OAc)3H added dissolved gradually with stirring, and the turbidity of the reaction mixture decreased. sat. Na2CO3 aq. solution was added, and from the mixture was separated the CH2C2 layer. The aqueous layer was extracted with CH2Cl2. The combined CH2Cl2 layer and extracts were dried (Na2SO4), and concentrated in vacuo to give a pale yellow oil (1.55 g). This was flash chromatographed over SiO2 (Merck Kieselgel 60, 32.0 g). Elution with CH2Cl2 --MeOH (300:1/200:1) gave title compound (1.15 g, 93.1%) as a colorless syrup, which crystallized spontaneously on standing in a refrigerator. This was recrystallized from (i-Pr)2O to give analytically pure title compound (1.058 g, 85.3%). mp 93.5-95.0 C. (fine colorless needles); IRmax (nujol): 1730(s), 1700(s), 1610(w), 1498(s), 1220(s), 1147(s), 1110(s), 1080(s), 1055(s), 1028(s), 742(s), 730(s), 703(s), 695(s) cm-1 ; 1H-NMR δ: 7.43-7.23(m, 9H), 7.21(br.s, 1H), 7.09-7.00(m, 2H), 6.73(d, J=9.2 Hz, 1H), 5.39(br.d, J=5.3 Hz, 1H), 5.16(d, J=12.5 Hz, 1H), 5.02(d, J=12.5 Hz, 1H), 4.50(dd, J=13.7, 1.8 Hz, 1H), 3.79(d, J=13.9 Hz, 1H), 3.68(d, J=13.9 Hz, 1H), 3.63(s, 3H), 3.54(dd, J=13.7, 5.5 Hz, 1H), 3.28(ddd, J=10.2, 5.5 4.8 Hz, 1H), 2.89-2.28(m, 1H), 2.24-2.01(m, 1H), 1.54(br.s, 2H) ppm.
Reaction SMILES: [N:1]([C@H:4]1[C@@H:8]([CH2:9][CH3:10])[CH2:7][N:6]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:5]1)=[N+]=[N-].O>C(#N)C>[NH2:1][C@H:4]1[C@@H:8]([CH2:9][CH3:10])[CH2:7][N:6]([C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])[CH2:5]1
Reactant: CC[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1N=[N+]=[N-]
Solvent: O
Solvent: CC#N
Product: CC[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1N
Temperature: 60 °C
Yield: 86.9 %

Procedure:
(3S,4S)-Benzyl 3-azido-4-ethylpyrrolidine-1-carboxylate (14.0 g, 51.0 mmol) was dissolved in acetonitrile (200 mL). Added water (20 mL) and stirred at RT to a clear solution. This soln. was warmed to 60° C. for 6.5 hrs. Acetonitrile was removed in vacuo and residual aqueous portion was diluted with 1N HCl (100 mL) which was washed with ethyl acetate (5×50 mL) until all Ph3P and Ph3P oxide was removed from the aqueous portion. The aqueous portion which contains HCl salt of the amine was cooled to ˜5 deg. This acidic soln was made basic (pH 12) with 1N NaOH. Extracted this basic milky suspension with DCM (5×, 50 mL), dried (Na2SO4) and concentrated. On vacuum overnight gave (3S,4S)-benzyl 3-amino-4-ethylpyrrolidine-1-carboxylate (11.01 g, 44.3 mmol, 87% yield). LCMS: M+1=249, t=1.39 min. This material was resolved using the following chiral SFC conditions [column: CHIRALPAK® AD-H 5×25 cm, 5 μm, Column Temp. 48° C., Flow rate: 290 mL/min, Mobile Phase: CO2/MeOH=77/23 with 0.3% triethylamine, injection volume: 3 mL (Conc. 68.8 mg/mL), detector wavelength: 215 nm, 100 bars]. The isolated isomers were named “Pk1” and “Pk2” in the elution order. Fractions containing Pk1 were concentrated to afford 5.1 g of the desired (3S,4S)-benzyl 3-amino-4-ethylpyrrolidine-1-carboxylate (Intermediate 9). Chiral purity: >99% ee (chiral HPLC conditions: column: CHIRALPAK® AD-H (25×0.46 cm, 5 μm), 30% MeOH in CO2 with 0.3% triethylamine, 3 mL/min, 40° C., 200-400 nm, 100 bars). 1H NMR (400 MHz, chloroform-d) δ ppm 7.33-7.42 (5H, m), 5.12-5.17 (2H, m), 3.51-3.67 (3H, m), 3.32-3.40 (1H, m), 3.14-3.21 (1H, m), 2.0-2.15 (1H, m), 1.44-1.55 (2H, m), 0.97-1.02 (5H, m). LCMS: (M+1)=249, t=1.39 min.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].ON1C2C=CC=CC=2N=N1.[CH3:33][NH:34][C:35]([C:37]1[N:38]=[C:39]([C:46]([F:49])([F:48])[F:47])[N:40]2[CH2:45][CH2:44][NH:43][CH2:42][C:41]=12)=[O:36].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([N:43]1[CH2:44][CH2:45][N:40]2[C:39]([C:46]([F:49])([F:47])[F:48])=[N:38][C:37]([C:35]([NH:34][CH3:33])=[O:36])=[C:41]2[CH2:42]1)=[O:5]
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: CNC(=O)c1nc(C(F)(F)F)n2c1CNCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)c1cc(Cc3n[nH]c(=O)c4ccccc34)ccc1F)CC2
Reaction time: 12 h
Yield: 61.5 %

Procedure:
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (598 mg, 2 mmol) was dissolved in 10 mL of N,N-dimethylformamide, followed by addition of 1-hydroxybenzotriazole (135 mg, 1 mmol), crude N-methyl-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide 13a (498 mg, 2 mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (573 mg, 3 mmol) and N, N-diisopropylethylamine (774 mg, 6 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure, added with 30 mL of H2O, extracted with ethyl acetate (50 mL×3). The organic phase was combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 7-[2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]-N-methyl-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1-carboxamide 13 (650 mg, yield 61.0%) as a white solid.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:35])=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH:22]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)[N:17]=[CH:16]4)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[ClH:36].CO>O1CCOCC1>[ClH:36].[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:8]=[CH:9][C:10]([CH3:35])=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:17]=[CH:16]4)[CH:12]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(cnn2C2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(cnn2C2CCNCC2)c1
Reaction time: 18 h

Procedure:
A suspension of 1,1-dimethylethyl 4-(5-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-1H-indazol-1-yl)-1-piperidinecarboxylate Example 115) (0.01 g) in a solution of hydrogen chloride in dioxan (4M, 1 ml) was treated with methanol (0.25 ml) to give a solution which was stirred at room temp. for 18 h. The solvent was evaporated and the residue was dried under vacuum to give the title compound (0.009 g).
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:32])[C:17]2[CH:22]=[CH:21][C:20]([CH2:23][NH:24][CH2:25][C:26]3[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=3)=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].[NH:33]1[CH:37]=[N:36][C:35]([CH:38]=O)=[N:34]1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:1]([N:4]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:32])[C:17]2[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH2:25][C:26]3[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=3)[CH2:38][C:35]3[N:36]=[CH:37][NH:33][N:34]=3)=[CH:19][CH:18]=2)=[CH:13][CH:14]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3]
Reactant: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CNCc3nccn3C)cc2)cc1
Reactant: O=Cc1nc[nH]n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CN(Cc3nc[nH]n3)Cc3nccn3C)cc2)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
The compound (256.8 mg) obtained in Example 122-4 was dissolved in methanol (7.7 ml) and added with 1H-[1,2,4]-triazol-3-carboxaldehyde (115.0 mg) and sodium cyanoborohydride (74.4 mg). Then, the solution was adjusted to pH 5 with acetic acid and stirred at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure. Subsequently, the residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (337.9 mg) of the subject compound as a white solid.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[CH2:17]([O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=O)[CH2:18][CH3:19].Cl>C1COCC1.O>[CH2:17]([O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:18][CH3:19]
Reactant: CCCOc1cccc(C=O)c1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCOc1cccc(C=CC(=O)OCC)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 104.5 %

Procedure:
To ethyl diethylphosphonoacetate (24.7 g) was added THF (200 ml), and sodium hydride (60%, 4.4 g) was added at 0° C. to the resulting mixture, to which was then added dropwise a solution of 3-propoxybenzaldehyde (16.1 g) in THF (100 ml). The resulting mixture was stirred at room temperature for 1.5 hours. The reaction mixture was poured into water, was neutralized with hydrochloric acid and was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with anhydrous magnesium sulfate. After concentration under reduced pressure to remove the solvent, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=6:1) to obtain ethyl 3-propoxycinnamate (24.0 g) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[C:10]([NH:17][CH2:18][CH2:19][CH2:20]O)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH2:20][CH2:19][CH2:18][NH:17][C:10](=[O:11])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)NCCCO
Reactant: Oc1cc(F)ccc1F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCOc1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The solution of 2.50 g of 2,5-difluorophenol, 3-(Boc-amino)-1-propanol, 7.26 g of triphenylphosphine and tetrahydrofuran (30 ml) is cooled to 0° C. and admixed dropwise with 5.65 ml of diisopropyl azodicarboxylate. The reaction mixture is stirred at room temperature for a further 2 hours and subsequently concentrated by evaporation. The title compound is obtained as a yellowish solid from the residue by means of flash chromatography (SiO2 60F). Rf=0.34 (1:2 EtOAc-heptane); Rt=4.69.