Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH:14]CC2C=CC=CC=2)[C@H:10]([F:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH2:14])[C@H:10]([F:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NCc2ccccc2)[C@H](F)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H](N)[C@H](F)C1
Temperature: 25 °C
Yield: 100 %

Procedure:
Cis(±)tert-butyl-4-(benzylamino)-3-fluoropiperidine-1-carboxylate (Intermediate 82; 711 mg), ammonium formate (582 mg), and 10% Pd/C (200 mg) in MeOH (10 ml) was heated to 50° C. for 1 h. The reaction mixture was cooled to room temperature, filtered through diatomaceous earth and concentrated under reduced pressure to give the title compound (503 mg, quantitative). NMR (CDCl3): 1.40 (s, 9H), 1.88 (m, 2H), 3.01 (m, 2H), 3.55 (m, 2H), 3.77 (m, 1H), 4.66 (d, 1H).
Reaction SMILES: [CH:1]1([CH:7]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([N:32]([CH3:40])[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:31])=[CH:26][CH:25]=2)[C:8]2[C:9]([CH2:21][CH3:22])=[N:10][N:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:43]I>CN(C)C(=O)C>[CH:1]1([CH:7]([N:23]([CH3:43])[C:24]2[CH:29]=[CH:28][C:27]([C:30]([N:32]([CH3:40])[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:31])=[CH:26][CH:25]=2)[C:8]2[C:9]([CH2:21][CH3:22])=[N:10][N:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CI
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2cn(-c3cccc(OC)c3)nc2CC)C2CCCCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)CCN(C)C(=O)c1ccc(N(C)C(c2cn(-c3cccc(OC)c3)nc2CC)C2CCCCC2)cc1
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a solution of ethyl 3-[{[4-({cyclohexyl[3-ethyl-1-(3-methoxyphenyl)-1H-pyrazol-4-yl]methyl}amino)phenyl]carbonyl}(methyl)amino]propanoate (1.1 g) synthesized in Example 78(4) in N,N-dimethylacetamide (5 mL) was added sodium hydride (0.16 g) under ice-cooling and, after stirring for 30 min, methyl iodide (0.37 mL) was added. The ice bath was removed, the reaction mixture was stirred at room temperature overnight, saturated aqueous ammonium chloride solution was added and the mixture was extracted with diethyl ether. The extract was washed with brine to give ethyl 3-[({4-[{cyclohexyl[3-ethyl-1-(3-methoxyphenyl)-1H-pyrazol-4-yl]methyl}(methyl)amino]phenyl}carbonyl)(methyl)amino]propanoate (0.23 g, 75%) as a pale-yellow oil. This was dissolved in ethanol (3.0 mL), 1N aqueous sodium hydroxide solution (1.5 mL) was added at room temperature, and the mixture was stirred at room temperature for 0.5 hr. Ethanol was evaporated under reduced pressure, 1N hydrochloric acid (1.5 mL) was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=10:1, volume ratio) to give the title object compound (0.10 g, 10%) as a pale-yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:20]([C:21]#[C:22][Si](C)(C)C)=[CH:19][C:5]([O:6][C:7]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:8]=2[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([Cl:27])[CH:3]=1.[F-].[Cs+]>CO>[NH2:1][C:2]1[C:20]([C:21]#[CH:22])=[CH:19][C:5]([O:6][C:7]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:8]=2[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([Cl:27])[CH:3]=1
Reactant: CCOC(=O)c1ccc(F)cc1Oc1cc(C#C[Si](C)(C)C)c(N)cc1Cl
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Product: C#Cc1cc(Oc2cc(F)ccc2C(=O)OCC)c(Cl)cc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 242C (2.69 g) in methanol (20 mL) was added CsF (5 g). The mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was dissolved in ethyl acetate (200 mL) and washed with water, brine and dried over Na2SO4. The mixture was filtered, and the solvent was evaporated.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:16]([Cl:19])[CH2:17][CH3:18]>CC(=O)CC>[Cl:19][CH2:16][CH2:17][CH2:18][O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: Oc1ccc(I)cc1
Reactant: CCC(Cl)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: ClCCCOc1ccc(I)cc1
Temperature: 82.5 °C
Reaction time: 0.29 h

Procedure:
A mixture of 4-iodophenol (250 g), potassium carbonate (313.6 g) and 2-butanone (1500 ml) is stirred for 15-20 min. 1-bromochloropropane (357.71 g) is added over about 10 minutes at 25-30° C. After stirring for a further 10 min, the reaction mass is heated to reflux (about 80-85° C.) for 22-24 h. After cooling to 25-30° C., the mixture is filtered, washing the cake with 2-butanone (750 ml). The filtrate is concentrated under reduced pressure at 50-60° C. Ethyl acetate (3750 ml) is added and stirred for 10-20 min to get a clear solution. This is washed with 2N sodium hydroxide solution (1250 ml), water (2500 ml) and aqueous sodium chloride (2500 ml) and then dried with sodium sulfate. The solvent is concentrated under reduced pressure at 50-60° C. n-heptane (250 ml) is added and stirred for about 20 min at 25-30° C. The solution is then cooled to −5 to −10° C. and stirred for about 30 min. The solid is filtered, washed with chilled n-heptane (125 ml, 0-5° C.) and the solid is allowed to dry.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](/[CH:12]=[C:13](/[C:16](=O)[CH3:17])\[C:14]#[N:15])[CH:10]=2)[NH:5][N:4]=1)[CH3:2].[NH2:19][C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][C:22]#[N:23]>C(O)C.CC(O)C>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]3[C:21]([C:22]#[N:23])=[C:20]([C:24]([F:27])([F:26])[F:25])[NH:19][C:16]([CH3:17])=[C:13]3[C:14]#[N:15])[CH:10]=2)[NH:5][N:4]=1)[CH3:2]
Reactant: CCc1n[nH]c2ccc(/C=C(\C#N)C(C)=O)cc12
Reactant: N#CC=C(N)C(F)(F)F
Solvent: CC(C)O
Solvent: CCO
Product: CCc1n[nH]c2ccc(C3C(C#N)=C(C)NC(C(F)(F)F)=C3C#N)cc12

Procedure:
A suspension of 300 mg (1.25 mmol) (2E)-2-[(3-ethyl-1H-indazol-5-yl)methylidene]-3-oxobutanenitrile (Example 11A) and 853 mg (6.27 mmol) 3-amino-4,4,4-trifluorobut-2-enenitrile [preparation: A. W. Lutz, U.S. Pat. No. 3,635,977; C. G. Krespan, J. Org. Chem. 34, 42 (1969)] in ethanol/2-propanol (8:1 v/v, 1.0 ml) was stirred at reflux temperature for 24 h. After cooling, the reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative RP-HPLC (acetonitrile/water+0.1% TFA gradient) to yield 59 mg (13% of th.) of the racemic title compound.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH3:9])=[O:7].[H-].[Na+].[CH2:12](Br)[C:13]#[CH:14].O>O1CCCC1>[CH2:14]([N:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH3:9])=[O:7])[C:13]#[CH:12]
Reactant: C#CCBr
Reactant: COC(=O)c1ccc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C#CCn1cccc1C(=O)OC
Temperature: 20 °C
Reaction time: 1 h

Procedure:
3.302 g of methyl 1H-pyrrole-2-carboxylate were dissolved in 40 ml of tetrahydrofuran and then, at 0° C., 1.422 g of sodium hydride in suspension at 50% in vaseline oil were added. The mixture stirred for 1 hour at 20° C. and a solution of 2 ml of propargyl bromide in 10 ml of tetrahydrofuran was introduced dropwise. The mixture was stirred for 1 hour at 50° C. and after having added 5 ml of propargyl bromide, the reaction mixture was poured into water. The mixture was extracted with methylene chloride and the extracts were concentrated to dryness by distilling under reduced pressure. The residue was chromatographed over silica and eluted with a mixture of hexane and ethyl acetate (9-1) to obtain 2.993 g of methyl 1-(2-propynyl)-1H-pyrrol-2-carboxylate.
Reaction SMILES: [C:1]1(=[O:12])[O:11][C@H:8]([CH2:9][OH:10])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].CCCCCCCCCCCCCC[N:27](CCC)CCC>CO>[O:12]=[C:1]([NH2:27])[C@@H:2]([C@H:4]([C@@H:6]([C@@H:8]([CH2:9][OH:10])[OH:11])[OH:7])[OH:5])[OH:3]
Reactant: O=C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: CCCCCCCCCCCCCCN(CCC)CCC
Solvent: CO
Product: NC(=O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 40 °C
Reaction time: 8 h
Yield: 215.2 %

Procedure:
A 1 liter round bottom flask equipped with a condenser, addition funnel, thermometer and mechanical stirrer was charged with D-glucono-1,5-lactone (20.0 g, 0.11 mole) and methanol (56 g). The suspension was heated to 40° C. over 15 minutes and the heating mantle removed. Hydrogenated tallowaminopropylamine (36.0 g, 0.11 mole) was added dropwise over 15 minutes with rapid stirring. The reaction mixture was cooled and placed in a refrigerator at 0° C. overnight. The white product was filtered, washed with cold isopropanol (3×100 ml) and dried under vacuum at 35° C. giving 46.2 g (83% yield) of hydrogenated tallowaminopropyl D-gluconamide with a melting point of 112°-115° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:10])[CH2:7][C:8]#[N:9].C(N(CC)CC)C.C(O)=O>CC1C=CC(C(C)C)=CC=1.CC1C=CC(S([N-][C@H]([C@@H](N)C2C=CC=CC=2)C2C=CC=CC=2)(=O)=O)=CC=1.[Cl-].[Ru+2].O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([OH:10])[CH2:7][C:8]#[N:9]
Reactant: N#CCC(=O)c1cccs1
Agent: [Ru+2]
Agent: Cc1ccc(S(=O)(=O)[N-][C@@H](c2ccccc2)[C@@H](N)c2ccccc2)cc1
Agent: [Cl-]
Solvent: O
Solvent: O=CO
Solvent: Cc1ccc(C(C)C)cc1
Product: N#CCC(O)c1cccs1
Reaction time: 24 h
Yield: 92 %

Procedure:
A 50 ml Schlenk flask was charged with 4.54 g (30.0 mmol) of 3-(2-thienyl)-3-oxopropanenitrile, 10.88 ml (78 mmol) of triethylamine, 3.51 ml (93 mmol) of formic acid, and 19.1 mg (0.03 mmol, S/C=1000) of RuCl[(S,S)-Tsdpen](p-cymene) under an atmosphere of argon, and stirring was carried out at 30° C. for 24 hours. The reaction solution was poured into water and extracted with ether, and the organic layer was washed with saturated brine and then dried with anhydrous sodium sulfate. After removing the drying agent, the solvent was distilled off, and the oil so obtained was purified by silica gel column chromatography (eluant; n-hexane:ethyl acetate=4:1) to give 4.23 g of optically active 3-(2-thienyl)-3-hydroxypropanenitrile. 1H-NMR supported it was the target product and the yield was 92%.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]3[N:13]([CH2:16][C@H:17]4[O:22][CH2:21][CH2:20][N:19]([C:23](OC(C)(C)C)=O)[CH2:18]4)[N:14]=[N:15][C:10]3=[N:9][CH:8]=2)[CH:4]=[N:3]1.[Br:30][C:31]1[CH:32]=[N:33]C(Cl)=[N:35][CH:36]=1.CCN(C(C)C)C(C)C>CCO>[Br:30][C:31]1[CH:36]=[N:35][C:23]([N:19]2[CH2:20][CH2:21][O:22][C@H:17]([CH2:16][N:13]3[C:11]4=[N:12][C:7]([C:5]5[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=5)=[CH:8][N:9]=[C:10]4[N:15]=[N:14]3)[CH2:18]2)=[N:33][CH:32]=1
Reactant: Cn1cc(-c2cnc3nnn(C[C@@H]4CN(C(=O)OC(C)(C)C)CCO4)c3n2)cn1
Reactant: Clc1ncc(Br)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cn1cc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(Br)cn5)CCO4)c3n2)cn1
Reaction time: 9 h
Yield: 74.8 %

Procedure:
(S)-tert-butyl 2-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholine-4-carboxylate (16.4 g, 54.69 mmol) was dissolved in EtOH (500 ml), and 5-bromo-2-chloropyrimidine (12.7 g, 65.62 mmol) and DIPEA (47.6 g, 273.45 mmol) were added, followed by 50° C. for 9 hours. After the completion of the reaction, the reaction mixture was recrystallized with EtOH to give (S)-4-(5-bromopyrimidin-2-yl)-2-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholine (18.7 g, 75%).
Reaction SMILES: C(O[C:4]([C:6]1([CH2:22][CH2:23]OC)[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])(=[O:14])=[O:13])[CH2:8][CH2:7]1)=[O:5])C.[Cl-].C[Al+]C.[F:30][C:31]1[CH:32]=[C:33]([CH2:37][CH2:38][NH2:39])[CH:34]=[CH:35][CH:36]=1>C1(C)C=CC=CC=1>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:12]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:39]([CH2:38][CH2:37][C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([F:30])[CH:32]=3)[CH2:23][CH2:22]2)[CH2:11][CH2:10]1)(=[O:13])=[O:14]
Reactant: CCOC(=O)C1(CCOC)CCN(S(=O)(=O)c2ccccc2Cl)CC1
Reactant: NCCc1cccc(F)c1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=C1N(CCc2cccc(F)c2)CCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2

Procedure:
This material was prepared in analogy to example 1 step D) from 1-(2-chloro-benzenesulfonyl)-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester, dimethylaluminium chloride in toluene and 2-(3-Fluoro-phenyl)-ethylamine. MS (ESI): 451.4 (MH+).
Reaction SMILES: [CH3:1][CH:2]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.P(=O)(O)(O)O.[CH2:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)(=O)C>[CH3:21][CH:22]([C:13]1[CH:14]=[C:9]([CH:2]([CH3:1])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:10]=[CH:11][C:12]=1[OH:15])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C=Cc1ccccc1
Reactant: CC(c1ccccc1)c1ccc(O)cc1
Agent: O=P(O)(O)O
Solvent: CC(=O)O
Product: CC(c1ccccc1)c1ccc(O)c(C(C)c2ccccc2)c1

Procedure:
The reaction was similarly carried out as Example 10 except that into a mixture of 59.5 g of p-(α-methylbenzyl)phenol, 25 g of phosphoric acid and 20 g of acetic acid was poured 31 g of styrene to give only 2,4-di-(α-methylbenzyl)phenol, but scarcely to detect other tert-butylated compounds.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([C:17]3[C:18]([CH2:26][CH3:27])=[C:19]([CH2:23][CH:24]=O)[CH:20]=[CH:21][CH:22]=3)=[N:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[NH:28]1[CH2:33][CH2:32][CH:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:30][CH2:29]1.C([O-])(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)C.ClCCl.O.CC(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([C:17]3[C:18]([CH2:26][CH3:27])=[C:19]([CH2:23][CH2:24][N:28]4[CH2:33][CH2:32][CH:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:30][CH2:29]4)[CH:20]=[CH:21][CH:22]=3)=[N:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCc1c(CC=O)cccc1-c1nnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Reactant: CCOC(=O)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C1CCN(CCc2cccc(-c3nnc(-c4ccc(OC(C)C)c(Cl)c4)s3)c2CC)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.1 %

Procedure:
To a solution of [3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-thiadiazol-2-yl)-2-ethylphenyl]acetaldehyde (D15) (97 mg) and ethyl 4-piperidinecarboxylate (234 mg) in ethanol (10.00 mL) stirred at room temperature was added sodium acetate (99 mg) and AcOH (0.069 mL). The reaction mixture was stirred at room temperature for 10 min. The residue was dissolved in dichloromethane (DCM) (10 mL), and sodium triacetoxyborohydride (154 mg) was added. Stirring continued for overnight. Water was added to quench the reaction, and DCM was removed by evaporation. The mixture was extracted by EA for 3 times. The combined organic solution was washed by brine, dried over anhydrous Na2SO4. The dried solution was filtered and concentrated to give ethyl 1-{2-[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-thiadiazol-2-yl)-2-ethylphenyl]ethyl}-4-piperidinecarboxylate (D16) (92 mg), which was used for the next without further purification. MS (ES): C29H35ClN3O3S requires 541. found 542.3 (M+H+).
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.Br[CH2:11][C:12]#[N:13]>>[CH3:1][N:2]([CH3:9])[CH:3]1[CH2:8][CH2:7][N:6]([CH2:11][C:12]#[N:13])[CH2:5][CH2:4]1
Reactant: N#CCBr
Reactant: CN(C)C1CCNCC1
Product: CN(C)C1CCN(CC#N)CC1

Procedure:
The title compound is synthesized by coupling of Dimethyl-piperidin-4-yl-amine and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless oil; ES-MS: M+=168.1: 1HNMR(DMSO-d6) 3.65 (s, 2H), 2.80-2.75 (m, 2H), 2.15-2.05 (m, 8H, including a singlet at 2.10), 2.00-1.95 (m, 1H), 1.75-1.65 (m, 2H), 1.40-1.30 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4([C:26]([F:29])([F:28])[F:27])[CH2:25][CH2:24]4)=[CH:19][CH:18]=3)[N:13]=2)=[N:7]1.[OH:33][CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[CH3:11][C:10]1[N:6]([CH2:5][C:4]2[CH:3]=[C:2]([N:37]3[CH2:38][CH2:39][CH:34]([OH:33])[CH2:35][CH2:36]3)[CH:32]=[CH:31][CH:30]=2)[N:7]=[C:8]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4([C:26]([F:29])([F:28])[F:27])[CH2:25][CH2:24]4)=[CH:19][CH:18]=3)[N:13]=2)[CH:9]=1
Reactant: Cc1cc(-c2nc(-c3ccc(C4(C(F)(F)F)CC4)cc3)no2)nn1Cc1cccc(Br)c1
Reactant: OC1CCNCC1
Product: Cc1cc(-c2nc(-c3ccc(C4(C(F)(F)F)CC4)cc3)no2)nn1Cc1cccc(N2CCC(O)CC2)c1

Procedure:
Analogously to the process described in Example 3, 125 mg (0.248 mmol) of the compound from Example 2A and 50 mg (0.497 mmol) of 4-hydroxypiperidine were used to obtain 20 mg (16% of theory) of the title compound. The first component step of the process was effected here at a reaction temperature of 130° C. The preparative HPLC purification was performed by method 11
Reaction SMILES: C([O:3][C:4](=[O:20])[C:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]([CH3:17])[CH3:16])=[C:10]([O:18][CH3:19])[CH:9]=1)([CH3:7])[CH3:6])C.[OH-].[Na+].O>C1COCC1.CCO>[CH:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]([CH3:7])([CH3:6])[C:4]([OH:20])=[O:3])=[CH:9][C:10]=1[O:18][CH3:19])([CH3:16])[CH3:17]
Reactant: CCOC(=O)C(C)(C)c1ccc(OC(C)C)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(C)(C)C(=O)O)ccc1OC(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
2-(4-Isopropoxy-3-methoxy-phenyl)-2-methyl-propionic acid ethyl ester (Compound L3-1, 1.45 g, 5.17 mmol) was dissolved in THF (13 mL) and EtOH (13 mL), added with 1 N aqueous solution of sodium hydroxide (10.3 mL, 2.0 eq.), and stirred at 80° C. overnight. The reaction solution was added to water and extracted with ethyl acetate. The aqueous layer was acidified by using 1 N aqueous solution of hydrochloric acid, extracted with ethyl acetate, washed with saturated brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the target compound (white solid, 1.10 g, 84%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[O:5][C:6]1[C:7](C(O)=O)=[N:8][CH:9]=[CH:10][C:11]=1[CH3:12].C([N:22](CC)CC)C.N1C=CC=CC=1.C(O)(C)(C)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[O:5][C:6]1[C:7]([NH2:22])=[N:8][CH:9]=[CH:10][C:11]=1[CH3:12]
Reactant: CCN(CC)CC
Reactant: Cc1ccnc(C(=O)O)c1Oc1cc(Cl)cc(Br)c1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CC(C)(C)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccnc(N)c1Oc1cc(Cl)cc(Br)c1
Temperature: 65 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 3-(3-bromo-5-chlorophenoxy)-4-methylpyridine-2-carboxylic acid (11-3; 2 g, 5.84 mmol) in THF (12 mL) was added triethylamine (1.627 mL, 11.68 mmol), pyridine (944 μL, 11.68 mmol), t-butanol (2.79 mL, 29.2 mmol) and diphenylphosphoryl azide (1.89 mL, 8.76 mmol) and the mixture heated to 65° C. for 35 minutes. After this time, the reaction mixture was diluted with CH2Cl2 (2×100 mL) and washed with water (100 mL). The combined organic extracts were concentrated to an oil on a rotary evaporator. This residue was dissolved in trifluoroacetic acid (20 mL) and allowed to stand for 15 minutes. After this time, the solvent was removed in vacuo and the residue was partitioned between CH2Cl2 (2×100 mL) and saturated aqueous NaHCO3 (50 mL). The combined extracts were concentrated on the rotary evaporator and the residue was purified using a RediSep column (330 g) eluting with a gradient of 0-30% EtOAc/CH2Cl2 to give the title compound. LRMS (M+1)=314.9.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](O)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccccc1C1(O)CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccccc1C1=CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 69.1 %

Procedure:
1-t-Butoxycarbonyl-4-hydroxy-4-(2-methoxyphenyl)piperidine (230 mg, 0.75 mmol) was dissolved in methylene chloride (10 ml). Thereto was added trifluoroacetic acid (0.20 ml, 2.6 mmol) and the resulting solution was stirred at a room temperature for 2.5 hours. The reaction solution was washed with saturated sodium bicarbonate aqueous solution and saturated brine in that order and dried with anhydrous sodium sulfate. Then the compound obtained by the evaporation of the solvent under a reduced pressure was separated and purified by a silica gel column chromatography to obtain 150 mg of the aforementioned compound of interest (0.53 mmol, 71% in yield).
Reaction SMILES: [N:1]1([C:6]2[CH:31]=[CH:30][C:9]([CH2:10][N:11]3[C:19]([S:20][CH3:21])=[C:18]4[C:13]([N:14]([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:15](=[O:24])[N:16]([CH3:23])[C:17]4=[O:22])=[N:12]3)=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[OH:32]OS([O-])=O.[K+]>C(Cl)Cl.CO>[N:1]1([C:6]2[CH:31]=[CH:30][C:9]([CH2:10][N:11]3[C:19]([S:20]([CH3:21])=[O:32])=[C:18]4[C:13]([N:14]([CH2:25][C:26]([CH3:28])([CH3:27])[CH3:29])[C:15](=[O:24])[N:16]([CH3:23])[C:17]4=[O:22])=[N:12]3)=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=S([O-])OO
Reactant: CSc1c2c(=O)n(C)c(=O)n(CC(C)(C)C)c2nn1Cc1ccc(-n2cncn2)cc1
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: Cn1c(=O)c2c(S(C)=O)n(Cc3ccc(-n4cncn4)cc3)nc2n(CC(C)(C)C)c1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 48.8 %

Procedure:
2-(4-(1H-1,2,4-triazol-1-yl)benzyl)-5-methyl-3-(methylthio)-7-neopentyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (16 mg, 0.036 mmol) is dissolved in CH2Cl2 (500 μL) and MeOH (500 μL), and then an aqueous solution of Oxone (22.4 mg, 0.036 mmol) is added. The reaction mixture is stirred at room temperature for 2 days, and then purified by a semi-preparative HPLC to give 8 mg of product as off-white solids. MS (ESI) m/z 456.2 [M+H]+.
Reaction SMILES: [ClH:1].[C:2]1([N:8]([CH2:32][CH2:33][CH2:34][O:35]CC2C=CC=CC=2)[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd].CO>[ClH:1].[C:2]1([N:8]([CH2:32][CH2:33][CH2:34][OH:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH2:28])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CCCOCc3ccccc3)c3ccccc3)ccc21
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CCCO)c3ccccc3)ccc21
Yield: 61 %

Procedure:
Prepared from 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-benzyloxy-n-propyl)amide hydrochloride by hydrogenation over palladium/charcoal (10%) at 5 bar hydrogen pressure and at ambient temperature. Yield: 61% of theory, C26H28N6O2 (456.6); Rf value: 0.70 (Reversed Phase silica gel RP-18; methanol/5% aqueous saline solution=9:1); EKA mass spectrum: (M+H)+=457; (M+H+Na)++=240.