Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[CH:8]=[CH:7][N:6]=1)=[O:4].O.O.[OH-].[Li+]>C1COCC1.CO>[CH3:16][O:15][CH2:14][CH2:13][CH2:12][CH2:11][C:9]1[CH:8]=[CH:7][N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:10]=1
Reactant: COCCCCc1ccnc(C(=O)OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COCCCCc1ccnc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 63 %

Procedure:
To a mixture of 4-(4-Methoxy-butyl)-pyridine-2-carboxylic acid methyl ester ((107 mg, 0.48 mmol, 1 equiv) in THF (1.5 mL) and water (0.5 mL) was added lithium hydroxide monohydrate (30.2 mg, 0.72 mmol, 1.5 equiv). The mixture was stirred at rt for 4 h and diluted with methanol (20 mL). Then H+ resin (0.4 g) was added and the mixture was shaken for 10 minutes. The resin was washed with methanol (1×), 1:1 acetonitrile/water (1×), and acetonitrile (1×). The product was eluted with 5% TEA in methanol (4×) and acetonitrile (1×). The combined organic solvents were evaporated and co-evaporated with toluene to give 4-(4-Methoxy-butyl)-pyridine-2-carboxylic acid (63.4 mg, 63%): 1H NMR (300 MHz, CD3OD) δ 8.47–8.43 (m, 1), 7.98–7.94 (m, 1), 7.43–7.37 (m, 1), 3.41 (t, J=6.3, 2), 3.30 (s, 3), 2.75 (t, J=7.5, 2), 1.80–1.55 (m, 4).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[OH:13][C@H:14]([CH2:23][CH2:24][OH:25])[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20]>ClCCl>[CH3:8][S:9]([O:13][C@H:14]([CH2:23][CH2:24][O:25][S:9]([CH3:8])(=[O:11])=[O:10])[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)CCCC[C@H](O)CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCCC[C@@H](CCOS(C)(=O)=O)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
Under an argon atmosphere, triethylamine (324 ml, 2.32 mmol) and methanesulfonyl chloride (132 ml, 1.70 mmol) were added to a solution of (6S)-(-)-methyl 6,8dihydroxyoctanoate (147 mg, 0.77 mmol) in dichloromethane (3.9 ml) at 0° C. The mixture was stirred at 0° C. for 30 min, then quenched with ice water (10 ml) and extracted with dichloromethane (10 ml). The extract was washed with 2 M hydrochloric acid (10 ml), saturated sodium bicarbonate solution (10 ml) and brine (10 ml). The organic phase was dried over magnesium sulphate and the solvent was evaporated under reduced pressure to give the crude product which was purified using flash column chromatography with hexane-ethyl acetate (2:3) to give (6S)-(+)-methyl 6,8-bis(methylsulfonyloxy)octanoate (247 mg, 92% yield) as a clear yellow oil. Rf 0.30 (hexane-ethyl acetate, 3:2).
Reaction SMILES: CO[C:3]([C:5]1[C:10](=[O:11])[N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[N:8]2[C:20]([Cl:24])=[C:21]([Cl:23])[CH:22]=[C:7]2[C:6]=1[OH:25])=[O:4].[NH2:26][CH2:27][C:28]([O-:30])=[O:29].[Na+]>>[Cl:23][C:21]1[CH:22]=[C:7]2[C:6]([OH:25])=[C:5]([C:3]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:4])[C:10](=[O:11])[N:9]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=3)[N:8]2[C:20]=1[Cl:24]
Reactant: NCC(=O)[O-]
Reactant: COC(=O)c1c(O)c2cc(Cl)c(Cl)n2n(Cc2ccc(F)cc2)c1=O
Agent: [Na+]
Product: O=C(O)CNC(=O)c1c(O)c2cc(Cl)c(Cl)n2n(Cc2ccc(F)cc2)c1=O

Procedure:
Prepared according to the glycinolysis condition used in Example 1 step d) from 6,7-Dichloro-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid methyl ester (1.0 eq.) and sodium glycinate (5 eq.). ESI (m/z): 428 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH:5]([N:7]1[CH2:12][CH2:11][CH2:10][CH:9]([NH:13][C:14]([O:16][CH3:17])=[O:15])[C:8]1=[O:18])[CH3:6])C.COC(N1CC(=O)N2C(C(OCC)=O)CCC2C1)=O>>[CH3:17][O:16][C:14]([NH:13][CH:9]1[CH2:10][CH2:11][CH2:12][N:7]([CH:5]([CH3:6])[C:4]([OH:19])=[O:3])[C:8]1=[O:18])=[O:15]
Reactant: CCOC(=O)C(C)N1CCCC(NC(=O)OC)C1=O
Agent: CCOC(=O)C1CCC2CN(C(=O)OC)CC(=O)N21
Product: COC(=O)NC1CCCN(C(C)C(=O)O)C1=O

Procedure:
2-(3-Methoxycarbonylamino-2-oxo-piperidin-1-yl)-propionic acid was prepared by method 801 substituting 2-(3-methoxycarbonylamino-2-oxo-piperidin-1-yl)-propionic acid ethyl ester for 4-oxo-hexahydro-pyrrolo[1,2-a]pyrazine-2,6-dicarboxylic acid 6-ethyl ester 2-methyl ester. C10H16N2O5 calculated 244.1 observed [M+1]+245.1; rt=1.53 min.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[CH:12]=1.[Na].[CH2:22]([SH:24])[CH3:23].CN(C=O)C>O>[CH2:22]([S:24][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[CH:12]=1)[CH3:23]
Reactant: CCS
Reactant: Fc1cnccc1-c1cc2cc(C(F)(F)F)ccc2o1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CCSc1cnccc1-c1cc2cc(C(F)(F)F)ccc2o1
Yield: 90.4 %

Procedure:
A mixture of 0.25 g of 3-fluoro-4-[5-(trifluoromethyl)benzofuran-2-yl]pyridine, 0.11 g of ethyl mercaptan sodium salt and 3.5 ml of DMF was stirred under ice-cooling for 2 hours. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layers were combined and washed with water and saturated brine and dried over magnesium sulfate, then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.26 g of 3-ethylthio-4-[5-(trifluoromethyl)benzofuran-2-yl]pyridine (hereinafter, referred to as “Present Active Compound 12”).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.C(N(C(C)C)C(C)C)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C1COCC1>[Cl:10][C:7]1[CH:6]=[CH:5][C:4]([CH:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[CH2:2][NH:1][S:29]([CH3:28])(=[O:31])=[O:30])=[CH:9][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NC(CN)c1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC(CNS(C)(=O)=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl 2-amino-1-(4-chlorophenyl)ethylcarbamate (Intermediate 73) (220 mg, 0.81 mmol) and N-ethyldiisopropylamine (0.281 mL, 1.63 mmol) in THF (5 mL) was treated with methanesulfonyl chloride (0.075 mL, 0.98 mmol). The resulting solution was stirred at ambient temperature for 2 hours. The mixture was partitioned between DCM and sodium bicarbonate solution. The organic layer was concentrated and the residue was purified by flash column chromatography on silica using gradient elution (10% ethyl acetate/DCM to 30% ethyl acetate/DCM). The desired product, tert-butyl 1-(4-chlorophenyl)-2-(methylsulfonamido)ethylcarbamate, was thus isolated as a colourless solid (154 mg, 54.3%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:22]=[CH:21][C:9]([O:10][CH2:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:13])=[CH:8][CH:7]=1.C(N(CC)CC)C.I.[NH2:31][C:32]1[C:33]([C:40]([NH:42][C:43](=[NH:46])SC)=[O:41])=[N:34][C:35]([Cl:39])=[C:36]([NH2:38])[N:37]=1>C(O)C>[NH2:31][C:32]1[C:33]([C:40]([N:42]=[C:43]([NH2:46])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]2[CH:22]=[CH:21][C:9]([O:10][CH2:11][C:12]([NH:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:13])=[CH:8][CH:7]=2)=[O:41])=[N:34][C:35]([Cl:39])=[C:36]([NH2:38])[N:37]=1
Reactant: NCCCCc1ccc(OCC(=O)Nc2ccccc2)cc1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Agent: I
Solvent: CCO
Solvent: CCN(CC)CC
Product: NC(=NC(=O)c1nc(Cl)c(N)nc1N)NCCCCc1ccc(OCC(=O)Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.1 %

Procedure:
A solution of 2-[4-(4-aminobutyl)phenoxy]-N-phenylacetamide 19 (100 mg, 0.35 mmol) and triethylamine (0.14 mL, 1.00 mmol) in absolute ethanol (2 mL) was stirred at 60° C. for 30 min, after which 1-(3,5-diamino-6-chloropyrazine-2-carbonyl)-2-methyl-isothiourea hydriodide (140 mg, 0.37 mmol) was added in one portion. The reaction mixture was stirred at that temperature for 4 h, cooled to room temperature, and concentrated by rotary evaporation. The crude residue was triturated with water and filtered. The filter cake was purified by flash silica gel column chromatography eluting with dichloromethane/methanol/concentrated ammonium hydroxide (500:10:0, 500:10:1, 200:10:1, v/v) to give 2-(4-{4-[N′-(3,5-diamino-6-chloro-pyrazine-2-carbonyl)guanidino]butyl}phenoxy)-N-phenylacetamide (20, PSA 17482) as a yellow solid (120 mg, 67% yield). mp 168-170° C. 1H NMR (300 MHz, DMSO-d6) δ 1.55 (m, 4H), 2.55 (m, 2H), 3.16 (m, 2H), 4.65 (s, 2H), 6.60 (br s, 2H), 6.90 (d, 2H), 7.08 (m, 2H), 7.15 (d, 2H), 7.30 (m, 5H), 7.60 (d, 2H), 9.00 (br s, 1H), 10.00 (br s, 1H). m/z (ESI): 511 [C24H27ClN8O3+H]+.
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[I:16]I>C(Cl)Cl>[I:16][C:13]1[CH:14]=[C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH:10]=[CH:11][C:12]=1[OH:15]
Reactant: CCCCCCCCc1ccc(O)cc1
Reactant: II
Solvent: ClCCl
Product: CCCCCCCCc1ccc(O)c(I)c1
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
A mixture of 4-octyl phenol (0.15 g, 0.73 mmol), CF3CO2Ag (0.25 g, 1 mmol) and I2 (0.185 g, 0.73 mmol) in CH2Cl2 (10 ml) was stirred for 0.5 h at 0, then for 0.5 h at room temperature. The solution was filtered through Celite bead and washed with CH2Cl2 (30 ml). The filtrates were evaporated to dryness to give the title compound (0.21 g, 87%) as fawn oil. 1H NMR (CDCl3) 7.32 (d, 1H, J=8.34 Hz); 7.28 (d, 1H, J=1.26 Hz); 6.98 (dd, 1H, 8.37, 1.71 Hz); 6.62 (s, 1H); 4.69 (t, 2H, J=5.88 Hz); 3.62-3.38 (m, 4H); 2.59 (t, 2H, J=7.29 Hz); 1.56-1.51 (m, 2H); 1.34-1.2 (m, 10H); 0.81 (t, 3H, J=6.48 Hz).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH:5]1(Cl)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>C1C=CC=CC=1>[CH:5]1([C:5]2[C:6]([CH:5]3[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]3)=[C:7]([CH:5]3[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]3)[CH:8]=[CH:9][CH:10]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: ClC1CCCCC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: c1cc(C2CCCCC2)c(C2CCCCC2)c(C2CCCCC2)c1
Temperature: 3 °C
Yield: 50.7 %

Procedure:
First, 6.83 g of aluminum chloride was added to 20.0 g of benzene, and agitated while cooling at 3° C. Then, 40.4 g of cyclohexyl chloride was slowly dropped thereinto. After the completion of the dropping, the mixture was agitated at room temperature for five hours and poured into ice water. The organic phase was extracted with ethyl acetate, and the obtained organic phase was subjected to vacuum distillation at 40° C. Further, vacuum distillation was performed at 170° C., and the product was cooled to room temperature. Thereafter, 50 ml of acetone was placed thereinto, and recrystallization was carried out. The resultant crystal was collected by filtration. Thus, 14 g of tricyclohexylbenzene was obtained.
Reaction SMILES: ClCCCC([O:11]C(=O)C)CCCCC.BrCC#CC(OC(=O)C)CCCCC.C([O:32][CH:33]([CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[C:34]#[C:35][CH2:36][N:37]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][C:46]([O:48]CC)=[O:47])[C:38]#[N:39])(=O)C>>[OH:32][CH:33]([CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[C:34]#[C:35][CH2:36][N:37]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][C:46]([OH:48])=[O:47])[C:38]([NH2:39])=[O:11]
Reactant: CCCCCC(C#CCN(C#N)CCCCCCC(=O)OCC)OC(C)=O
Reactant: CCCCCC(CCCCl)OC(C)=O
Agent: CCCCCC(C#CCBr)OC(C)=O
Product: CCCCCC(O)C#CCN(CCCCCCC(=O)O)C(N)=O

Procedure:
The synthesis of this compound is carried out as described in Example 1 except that, in Step A, the 1-chloro-4-acetoxynonane is replaced by an equimolar amount of 1-bromo-4-acetoxy-2-nonyne (Example I, Step 3). The product of Step A is thus ethyl 7-[N-(4-acetoxy-2-nonynyl)cyanamido]heptanoate. The subsequent steps yield 7-[N-(4-hydroxy-2-nonynyl)cynamido]heptanoic acid (B), and 7-[1-(4-hydroxy-2-nonynyl)ureido]heptanoic acid (C).
Reaction SMILES: [H][H].[CH3:3][O:4][C:5]1[C:10]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:9][CH:8]=[CH:7][C:6]=1[CH:19]=[CH:20][C:21]([OH:23])=[O:22].C(O)(=O)C>[Pd].O1CCOCC1>[CH3:3][O:4][C:5]1[C:10]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:19][CH2:20][C:21]([OH:23])=[O:22]
Reactant: COc1c(C=CC(=O)O)cccc1Oc1ccccc1C
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: COc1c(CCC(=O)O)cccc1Oc1ccccc1C
Yield: 90 %

Procedure:
Hydrogen gas was introduced to a mixture of 3-[2-methoxy-3-(o-tolyloxy)phenyl]acrylic acid (17 g), palladium on carbon (5%, 3.4 g) and a small amount of glacial acetic acid in dioxane (200 ml) with stirring. The reaction mixture was filtered, and the filtrate was evaporated. The residue was pulverized with n-hexane to give 3-[2-methoxy-3-(o-tolyloxy)phenyl]propionic acid (15.4 g). mp 71°-75° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5](N)[CH2:4][CH:3]=1.C([O:11][C:12]1[CH:22]=[CH:21][C:20]([C:23]#[C:24][C:25]2[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:19][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])(=O)C.[OH-].[K+].C(O)C.[N:40]1C=CC=CC=1>O.C(O)=O>[OH:11][C:12]1[CH:22]=[CH:21][C:20]([C:23]#[C:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([NH:40][C:4]3[CH:3]=[C:2]([CH3:1])[O:6][N:5]=3)(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:19][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CC1=CCN(N)O1
Reactant: CCOC(=O)c1cc(C#Cc2ccc(S(=O)(=O)Cl)cc2)ccc1OC(C)=O
Reactant: c1ccncc1
Agent: [K+]
Agent: [OH-]
Solvent: O=CO
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(C#Cc2ccc(S(=O)(=O)Nc3cc(C)on3)cc2)ccc1O
Reaction time: 72 h

Procedure:
5-methyl-2-isoxazolamine (1.2 g, 12 mmol) was dissolved in dry pyridine (20 ml) and ethyl 2-acetyloxy-5-[(4-chlorosulfonylphenyl)ethynyl]-benzoate (4.1 g, 10 mmol) was added. The solution was kept at ambient temperature for 72 h. The solvent was evaporated and the residue dissolved in a small amount of tetrahydrofuran. The solution was added to a refluxing solution of potassium hydroxide (2.5 g, 38 mmol) in water (100 ml). After 5 min, ethanol (50 ml) was added and the solution acidified with formic acid to produce a precipitate. The solid was collected by filtration, washed with water and dried. It was recrystallize three times from ethanol. Yield 1.5 g, 35%.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[CH3:7][C:8]([CH2:10][CH3:11])=O.C(O)C>O.[Pd]>[CH:8]([NH:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3])([CH2:10][CH3:11])[CH3:7]
Reactant: C[C@H](N)C(=O)O
Reactant: CCC(C)=O
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: CCC(C)N[C@@H](C)C(=O)O

Procedure:
356 g of alanine (4 mols) is dissolved in 1.5 liters of deionized water and put into a 1-gallon autoclave. 25 g of 10% Pd on carbon, wet with water, 423 g of methylethylketone (5.85 mols) and 250 ml of ethanol are added. The autoclave is closed and hydrogenation is carried out at 90°-105° C. and 63.3-77.3 kg/cm2. A pressure drop corresponding to 83.3 kg/cm2 is observed in the course of 4 hours. The autoclave is allowed to cool overnight.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](Cl)=[N:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[OH:18][C:19]1[CH:20]=[C:21]([O:33][CH:34]([CH3:36])[CH3:35])[CH:22]=[C:23]([CH:32]=1)[C:24]([NH:26][C:27]1[S:28][CH:29]=[CH:30][N:31]=1)=[O:25].O>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([O:18][C:19]2[CH:32]=[C:23]([C:24](=[O:25])[NH:26][C:27]3[S:28][CH:29]=[CH:30][N:31]=3)[CH:22]=[C:21]([O:33][CH:34]([CH3:36])[CH3:35])[CH:20]=2)=[N:6][CH:5]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: CC(C)Oc1cc(O)cc(C(=O)Nc2nccs2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(Oc2cc(OC(C)C)cc(C(=O)Nc3nccs3)c2)nc1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
After adding 123 mg (0.72 mmol) of 6-chloronicotinic acid methyl ester and 199 mg (1.44 mmol) of potassium carbonate to a solution of 100 mg (0.36 mmol) of the obtained amide compound in N,N-dimethylformamide (10.0 ml), the mixture was stirred at 80° C. for 18 hours under a nitrogen atmosphere. Water was added to the reaction mixture, extraction was performed with ethyl acetate, and the organic layer was dried and then concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane:ethyl acetate=3:1) to obtain the title compound as a white solid. The analysis data for the compound obtained in Production Example 65 are shown below.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([C:8]([NH:10][C:11](=[O:13])[CH3:12])=[CH2:9])=[N:6][CH:7]=1>CO>[F:1][C:2]1[CH:7]=[N:6][C:5]([C@@H:8]([NH:10][C:11](=[O:13])[CH3:12])[CH3:9])=[N:4][CH:3]=1
Reactant: C=C(NC(C)=O)c1ncc(F)cn1
Solvent: CO
Product: CC(=O)N[C@@H](C)c1ncc(F)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.3 %

Procedure:
N-(1-(5-Fluoropyrimidin-2-yl)vinyl)acetamide (Intermediate 12, 0.10 g, 0.55 mmol) in MeOH (5 ml) under N2 was added (+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene (cyclooctadiene)rhodium(I)trifluoromethanesulfonate (0.04 g, 0.0055 mmol). The solution was transferred to a high-pressure bomb and charged 150 psi H2. The reaction was stirred at room temperature for 4 hours. The solvent was removed and the resulted residue was purified by column chromatography (EtOAc) to give the title compound as a white solid (0.096 g, 95%). 1H NMR (400 MHz) 8.84 (d, J=0.8 Hz, 2H), 8.34 (d, J=7.6 Hz, 1H), 5.00 (m, 1H), 1.84 (s, 3H), 1.37 (d, J=6.8 Hz, 3H). MS: Calculated: 183. Found: [M+H]+ 184. Enantiomeric excess determined by HPLC (Chiralpak IA; 95:5 CO2/MeOH), >99% ee.
Reaction SMILES: Cl.[F:2][C:3]([F:7])([F:6])[CH2:4][NH2:5].Cl.[NH:9]1[CH:13]=[CH:12][C:11](C=O)=[N:10]1.[CH2:16](N(CC)CC)C>C(#N)C>[NH:9]1[CH:13]=[C:12]([CH:16]=[N:5][CH2:4][C:3]([F:7])([F:6])[F:2])[CH:11]=[N:10]1
Reactant: CCN(CC)CC
Reactant: NCC(F)(F)F
Reactant: O=Cc1cc[nH]n1
Agent: Cl
Solvent: CC#N
Product: FC(F)(F)CN=Cc1cn[nH]c1

Procedure:
To a solution of 2,2,2-Trifluoroethylamine hydrochloride (Sigma-Aldrich) (15.2 g, 113.2 mmol) in acetonitrile (36 mL) was added 3-pyrazole carboxaldehyde hydrochloride (which could be prepared as described in Traydakov, et. al., Synthetic Communications, 2011, 41, 2430-2434) (10 g, 75.75 mmol) followed by triethylamine (31.5 ml, 226.4 mmol) at 0° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH2:11])[CH:10]=1)[NH:7][C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:5]2.C([N:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1)(OC(C)(C)C)=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:28]3[CH2:29][CH2:30][NH:25][CH2:26][CH2:27]3)[CH:10]=1)[NH:7][C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:5]2
Reactant: Nc1cc(Cl)cc2cc(-c3ccccc3)[nH]c12
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: Clc1cc(NC2CCNCC2)c2[nH]c(-c3ccccc3)cc2c1

Procedure:
7-Amino-5-chloro-2-phenyl-1H-indole prepared in Example 3 and 1-BOC-4-piperidinone were reacted according to the same procedure as Step B of Example 1 to give the title compound.
Reaction SMILES: [C:1]1(=[N:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O[Cl:14])(C)(C)C.C1CCC=CC=1>C(Cl)Cl.C(O)C>[ClH:14].[CH:4]12[CH2:5][CH2:6][CH:1]([CH:2]=[CH:3]1)[NH:7][O:8]2
Reactant: ON=C1CCCCC1
Reactant: CC(C)(C)OCl
Solvent: ClCCl
Solvent: CCO
Solvent: C1=CCCC=C1
Product: C1=CC2CCC1NO2
Product: Cl
Temperature: -20 °C
Reaction time: 48 h
Yield: 74.1 %

Procedure:
To a solution of 30.0 g (0.265 mol) of cyclohexanone oxime in 300 ml of methylene chloride and 38 ml of ethanol was slowly added at 0° C. 34.5 g (0.318 mol) of tert.-butyl-hypochlorite. The resulting dark blue solution was cooled to −20° C. and then 31.9 g (0.398 mol) of 1,3-cyclohexadiene were added and the mixture was stored in a freezer at 5° C. for 2 days until the blue color had disappeared. The reaction mixture was concentrated to 50% of its volume and then 600 ml of diethyl ether were slowly added. After stirring overnight the resulting precipitate was isolated by suction to yield 29.0 g of 2-oxa-3-aza-bicyclo[2.2.2]oct-5-ene hydrochloride. 5.0 g (0.045 mol) of this material were hydrogenated with 3.0 g (0.013 mol) platinum oxide at 2 bar hydrogen pressure. After 7 h the catalyst was filtered off and a solution of 20 ml 4 M hydrochloric acid in dioxane was added. After evaporation the residue was recrystallized from 30 ml isopropanol giving 3.1 g of cis-4-aminocyclohexanol hydrochloride.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([N:10]1[C:14]2=[N:15][CH:16]=[C:17]([C:31]3[CH2:38][C:34]4([CH2:37][CH2:36][CH2:35]4)[O:33][N:32]=3)[C:18]([NH:19][CH:20]3[CH2:23][CH:22]([C:24]([O:26]C(C)(C)C)=[O:25])[CH2:21]3)=[C:13]2[CH:12]=[N:11]1)[CH3:9]>ClC(Cl)C.C(OCC)(=O)C>[CH2:8]([N:10]1[C:14]2=[N:15][CH:16]=[C:17]([C:31]3[CH2:38][C:34]4([CH2:35][CH2:36][CH2:37]4)[O:33][N:32]=3)[C:18]([NH:19][CH:20]3[CH2:21][CH:22]([C:24]([OH:26])=[O:25])[CH2:23]3)=[C:13]2[CH:12]=[N:11]1)[CH3:9]
Reactant: CCn1ncc2c(NC3CC(C(=O)OC(C)(C)C)C3)c(C3=NOC4(CCC4)C3)cnc21
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCn1ncc2c(NC3CC(C(=O)O)C3)c(C3=NOC4(CCC4)C3)cnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (4 equivalent) is added to the solution of tert-butyl 3-{[1-ethyl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl]amino}cyclobutanecarboxylate (1 equivalent) (example 9) in dichloroethane and the reaction mixture is stirred at room temperature for about 2 hours under inert atmosphere. It is cooled and diluted with ethyl acetate. The organic layer is washed with saturated sodium bicarbonate, water and brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to get the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:12]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:22]=2)([CH3:20])[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].OC1[CH2:38][C:37](C)([CH3:39])[NH:36][C:35]([CH3:42])([CH3:41])[CH2:34]1.C([Sn](=O)CCCC)CCC.C(O)C>C1(C)C(C)=CC=CC=1>[C:28]([C:23]1[CH:22]=[C:21]([C:12]([C:7]2[CH:8]=[CH:9][C:10]([OH:11])=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:6]=2)([CH3:20])[CH2:13][CH2:14][C:15]([O:17][CH:18]2[CH2:34][C:35]([CH3:42])([CH3:41])[NH:36][C:37]([CH3:39])([CH3:38])[CH2:19]2)=[O:16])[CH:26]=[CH:25][C:24]=1[OH:27])([CH3:30])([CH3:29])[CH3:31]
Reactant: CC1(C)CC(O)CC(C)(C)N1
Reactant: CCOC(=O)CCC(C)(c1ccc(O)c(C(C)(C)C)c1)c1ccc(O)c(C(C)(C)C)c1
Agent: CCCC[Sn](=O)CCCC
Solvent: CCO
Solvent: Cc1ccccc1C
Product: CC1(C)CC(OC(=O)CCC(C)(c2ccc(O)c(C(C)(C)C)c2)c2ccc(O)c(C(C)(C)C)c2)CC(C)(C)N1
Temperature: 25 °C

Procedure:
8.5 g (0.02 mol) of ethyl 4,4-bis-(3-tert.-butyl-4-hydroxyphenyl)-valerate and 3.1 g (0.02 mol) of 4-hydroxy-2,2,6,6-tetramethylpiperidine are dissolved in 200 ml of xylene. 0.1 g of dibutyltin oxide is added, and the mixture is heated at the boil under nitrogen for about 6 hours, during which the resulting ethanol is distilled off continuously. When no more ethanol distils off, the reaction solution is cooled down to room temperature, is admixed with 200 ml of water and is efficiently mixed. The organic phase is separated off, is dried over magnesium sulfate and is evaporated. The resulting oil is purified by column chromatography to give 2,2,6,6-tetramethylpiperidin-4-yl 4,4-bis-(3-tert.-butyl-4-hydroxyphenyl)-valerate in the form of a colourless solid having a melting point of 100°.
Reaction SMILES: [Na].[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9]C(=O)C(F)(F)F.Br[CH2:17][CH:18]=[CH:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(O)C>[O:2]1[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[NH:9][CH:18]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:17]1
Reactant: O=C(Nc1ccccc1O)C(F)(F)F
Reactant: CCOC(=O)C=CCBr
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CC1COc2ccccc2N1
Temperature: 0 °C

Procedure:
650 ml of ethanol are introduced into a 3 l reactor, with magnetic stirring, cooled to 0° C., 5.9 g (0.259 mol) of sodium are added slowly, in small portions, followed by successive dropwise addition of 53 g (0.259 mol) of N-(2-hydroxyphenyl)trifluoroacetamide and 50 g (0.259 mol) of 75% pure ethyl 4-bromo-2-butenoate, and the mixture is heated at 80° C. for 1.5 h.