Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][C@@H:21]3[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]3)[CH2:16][CH2:15]2)=[O:13])[CH:7]=[CH:8][C:9]=1[Cl:10].C(N(CC)C(C)C)(C)C.[CH:36](=O)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:36]([N:23]1[CH2:24][CH2:25][CH2:26][C@@H:21]([CH2:20][N:17]2[CH2:18][CH2:19][N:14]([C:12]([NH:11][C:6]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:4]([Cl:3])[CH:5]=3)=[O:13])[CH2:15][CH2:16]2)[CH2:22]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=Cc1ccccc1
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(C[C@@H]2CCCNC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(C[C@@H]2CCCN(Cc3ccccc3)C2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66 %

Procedure:
To a mixture of N-(3,4-dichlorophenyl)-1-[(3R)-piperidin-3-ylmethyl]piperazine-4-carboxamide dihydrochloride (800 mg) in dichloromethane (25 mL) was added N,N-di-iso-propylethylamine (0.94 mL) under argon. The mixture was stirred at room temperature for 5 minutes before benzaldehyde (0.22 mL) and sodium triacetoxyborohydride (573 mg) were added. The reaction mixture was stirred at room temperature under argon for 4 hours. The reaction was quenched with water and then partitioned between dichloromethane and water. The organic extract was washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by silica column chromatography, eluting with a gradient of 0 to 10% MeOH in dichloromethane to give the title compound as a white solid (550 mg, 66%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15](=[O:19])[N:16]([CH3:18])[CH3:17])[C@H:9]2C)[CH:5]=[N:4][C:3]=1[C:21]#[N:22].[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2([CH3:43])[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]2)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:21]([C:3]1[C:2]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3([CH3:43])[CH2:31][CH2:32][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34][CH2:35]3)=[CH:26][CH:25]=2)=[N:7][C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15]([N:16]([CH3:17])[CH3:18])=[O:19])[CH2:9]2)=[CH:5][N:4]=1)#[N:22]
Reactant: CC(C)(C)OC(=O)N1CCC(C)(c2ccc(N)cc2)CC1
Reactant: C[C@@H]1[C@H](NC(=O)N(C)C)CCCN1c1cnc(C#N)c(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CN(C)C(=O)N[C@@H]1CCCN(c2cnc(C#N)c(Nc3ccc(C4(C)CCN(C(=O)OC(C)(C)C)CC4)cc3)n2)C1
Temperature: 115 °C
Reaction time: 2 h

Procedure:
The mixture of 3-((2R,3R)-1-(6-chloro-5-cyanopyrazin-2-yl)-2-methylpiperidin-3-yl)-1,1-dimethylurea (222) (250 mg, 0.81 mmol), tert-butyl 4-(4-aminophenyl)-4-methylpiperidine-1-carboxylate (287) (400 mg, 1.22 mmol), fine-powder cesium carbonate (800 mg, 2.43 mmol), Pd(OAc)2 (55 mg, 0.24 mmol), BINAP (150 mg, 0.24 mmol) in 30 mL dioxane was degassed with nitrogen stream for 3 mM It was then stirred in 115° C. bath in nitrogen atmosphere for 2 hours. The mixture was cooled to RT, diluted with 100 mL EtOAc, and filtered using ChemGlass OP-6602-12 disposable funnel. The filtrate was concentrated in vacuo and subjected to silica flash column using 0 to 8% MeOH in DCM to isolate (R)-tert-butyl 4-(4-(3-cyano-6-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazin-2-ylamino)phenyl)-4-methylpiperidine-1-carboxylate (288). It was dissolved in 10 mL MeOH and 3 mL DMSO. To it were added one NaOH solid bead (about 100 mg) and then 1 mL 30% H2O2. The mixture was stirred at RT for overnight, diluted with 10 mL MeCN, stirred for 5 min, and concentrated on rotavap. The residue was diluted with 150 mL EtOAc, washed with water ×3, dried, and subjected to silica flash column using 0 to 10% MeOH in DCM to isolate (R)-tert-butyl 4-(4-(3-carbamoyl-6-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazin-2-ylamino)phenyl)-4-methylpiperidine-1-carboxylate. It was treated with 20 mL commercial 4N HCl in dioxane at RT for 45 mM, and concentrated to dryness to give crude (R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(4-(4-methylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide (289) as HCl salt. It was subjected to reverse phase prep HPLC using 5 mM HCl (aq) and neat MeCN as mobile phases for purification. MS found for C25H36N8O2 as (M+H)+ 481.3. UV: λ=268, 277, 306, 336, 373 nm.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:25]=[CH:24][C:23]([S:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:22][CH:21]=3)[N:16]=2)[CH:3]=1.[OH:33]O.O>C1COCC1.[Cl-].[Cl-].[Cl-].[V+3]>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=2)[N:5]=[C:4]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:33])=[CH:22][CH:21]=3)[N:16]=2)[CH:3]=1
Reactant: OO
Reactant: Cc1ccc(Cn2nc(-c3nc(-c4ccc(Sc5ccccc5)cc4)no3)cc2C)cc1
Agent: [V+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(Cn2nc(-c3nc(-c4ccc(S(=O)c5ccccc5)cc4)no3)cc2C)cc1

Procedure:
To a mechanically stirred solution of 5-[5-methyl-1-(4-methylbenzyl)-1H-pyrazol-3-yl]-3-[4-(phenylsulfanyl)phenyl]-1,2,4-oxadiazole (Example 114, 350 mg, 0.798 mmol) in THF (3 mL) was added vanadium trichloride (6 mg, 0.04 mmol) and hydrogen peroxide (30% in water, 82 μL, 0.798 mmol). The reaction mixture was stirred at rt for 5 h, before another 40 μL (0.4 mmol) of the hydrogen peroxide solution were added. Stirring was continued at rt over night. Then water (30 mL) was added, and the mixture was extracted with ethyl acetate (3×30 mL). The combined organic extracts were dried over anhydrous sodium sulfate. After filtration and evaporation of the solvent, the crude product was purified by MPLC (silica, cyclohexane/ethyl acetate 3:1), followed by precipitation using acetonitril/water 3:1 affording a first crop of the title compound (29 mg, 8%). A second crop was obtained from the mother liquor after preparative HPLC (26 mg, 7%): 1H NMR (400 MHz, DMSO-d6) 8.39 (s, 1H), 8.18 (d, 1H), 7.96 (d, 1H), 7.81 (d, 2H), 7.78-7.74 (m, 1H), 7.60-7.50 (m, 3H), 7.18 (d, 2H), 7.12 (d, 2H), 6.94 (s, 1H), 5.44 (s, 2H), 2.32 (s, 3H), 2.28 (s, 3H); ES-MS m/z 455, HPLC RT (Method D) 2.78 min.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][CH2:16][CH:17]=[CH2:18])[CH2:11][CH2:10]1)=O)(C)(C)C>CO.[C].[Pd]>[CH2:16]([O:15][C@H:12]1[CH2:13][CH2:14][C@H:9]([NH2:8])[CH2:10][CH2:11]1)[CH2:17][CH3:18]
Reactant: C=CCO[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CO
Product: CCCO[C@H]1CC[C@H](N)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
In 10 ml of methanol was dissolved 204 mg of N-tert-butoxycarbonyl-trans-4-(2-propen-1-yloxy)cyclohexylamine (the compound of Reference Example 9-11). 44 mg of 10% palladium-carbon was added thereto, and the mixture was stirred under hydrogen atmosphere at normal pressure, at room temperature, for 2 days. The catalyst was removed by filtration and the solvent was removed and the residue was stirred in 2 ml of trifluoroacetic acid for 3 hours. The solvent was removed, and the residue was mixed with an aqueous 10% sodium hydroxide solution, extracted with chloroform and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain 102 mg of trans-4-(propoxy)cyclohexylamine (Reference Example 9-13 in Table 10).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[OH:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=2)[CH2:18][CH2:17]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.S(=O)(O)[O-].[Na+]>CN(C)C(=O)C>[OH:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:29]=[CH:28][C:25]([C:26]3[NH:6][C:4](=[O:5])[C:3]4[C:7]([O:13][CH3:14])=[CH:8][C:9]([O:11][CH3:12])=[N:10][C:2]=4[N:1]=3)=[CH:24][CH:23]=2)[CH2:18][CH2:17]1
Reactant: O=Cc1ccc(N2CCC(O)CC2)cc1
Reactant: COc1cc(OC)c(C(N)=O)c(N)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCC(O)CC4)cc3)nc2n1
Temperature: 135 °C
Reaction time: 16 h

Procedure:
A mixture of 2-amino-4,6-dimethoxy-nicotinamide (0.60 g, 3.0 mmol), 4-(4-hydroxy-piperidin-1-yl)-benzaldehyde (0.81 g, 3.9 mmol), p-toluenesulfonic acid monohydrate (1.25 g, 6.6 mmol) and sodium bisulfite (1.06 g, 6.0 mmol) in N,N-dimethylacetamide (8.0 mL) was stirred at 135° C. under N2 for 16 hours and then cooled to room temperature. The mixture was concentrated to dryness under reduced pressure. Water (40 mL) was added to the residue and stirred for 0.5 hours. The precipitate was filtered and the solid was rinsed with water and air-dried. The crude solid was purified by column chromatography (silica gel 230-400 mesh; eluting with 4% methanol in dichloromethane) to afford the title compound, as a yellow solid. Yield: 0.29 g (25.2%). MP 284-286° C. 1H NMR (400 MHz, DMSO-d6): δ 12.09 (s, 1H), 8.12 (d, J=8.8 Hz, 2H), 7.02 (d, J=8.8 Hz, 2H), 6.32 (s, 1H), 4.73 (d, J=4.4 Hz, 1H), 3.94 (s, 3H), 3.89 (s, 3H), 3.72 (m, 3H), 3.05 (m, 2H), 1.80 (m, 2H), 1.43 (m, 2H). MS (ES+) m/z: 383.06 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8](Br)[CH:7]=[CH:6][C:5]=1[NH2:11].[C:13]([Cu])#[N:14].Cl.CCOC(C)=O>CN1C(=O)CCC1.O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([C:13]#[N:14])[CH:7]=[CH:6][C:5]=1[NH2:11]
Reactant: COC(=O)c1cc(Br)ccc1N
Reactant: N#C[Cu]
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cc(C#N)ccc1N
Temperature: 25 °C
Yield: 85 %

Procedure:
A mixture of 2-amino-5-bromo-benzoic acid methyl ester (5.00 g, 21.7 mmol) and CuCN (2.34 g, 26.1 mmol, 2.0 M) in 25 ml of NMP was stirred at reflux for 5 h, then cooled to rt. The mixture was poured into a solution of hydrated FeCl3 (15 g of FeCl3.6H2O) and conc. HCl (2.2 ml) in 15 ml of H2O. The resulting mixture was stirred at 60° C. for 1 h, cooled to rt. Treated with 200 ml of EtOAc, the mixture was washed with H2O (40 ml), 1N NaOH (3×30 ml), brine (30 ml) and dried (Na2SO4). Removal of the solvent under reduced pressure gave a slightly dark solid. Recrystalization of the solid in hexanes/DCM/EtOAc yielded 3.25 g (85%) of product as a yellow solid: 1H-NMR (CDCl3; 400 MHz) δ 8.20 (d, 1H, J=1.9 Hz), 7.45 (dd, 1H, J=8.9, 1.9 Hz), 6.67 (d, 1H, J=8.9 Hz), 6.29 (br s, 2H), 3.90 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C9H8N2O2, 177.1 (M+H), found 177.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@H:9]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([Mg]Br)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33]>C1COCC1>[CH2:17]([O:16][C:14](=[O:15])[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:10][CH2:11][C:12]([C:29]1[CH:28]=[CH:27][C:26]([O:25][CH3:24])=[C:31]([O:32][CH3:33])[CH:30]=1)=[O:13])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)CC[C@H]1C(=O)OCc1ccccc1
Reactant: COc1ccc([Mg]Br)cc1OC
Solvent: C1CCOC1
Product: COc1ccc(C(=O)CCC(NC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)cc1OC
Reaction time: 2 h
Yield: 88 %

Procedure:
A solution of (2S)5-oxo-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (8.20 g, 0.026 mol, 1.0 equivalent) in anhydrous THF was cooled to 0° C. in an ice bath under N2. A chilled 0.5M solution of 3,4-dimethoxyphenylmagnesium bromide in THF (52.1 mL, 0.026 mol, 1.0 equivalent) was slowly added. The reaction mixture was allowed to stir for two hours. The reaction was quenched upon addition of saturated NH4Cl solution (10 ml). The mixture was partitioned between ethyl acetate and brine. The organic extract was washed with brine (3×100 ml). The ethyl acetate layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting crude blue oil was filtered through a layer of silica. The filtrate was concentrated in vacuo to afford 2-tert-butoxycarbonylamino-5-(3,4-dimethoxy-phenyl)-5-oxo-pentanoic acid benzyl ester (10.46 g, 0.023 mol, 88% yield). Analysis H1 NMR (400 MHz, CDCl3): 7.5–7.3 (6H, m), 7.0–6.7 (2H, m), 5.2 (2H, m), 4.0–3.8 (6H, m), 3.0 (1H, m), 2.6–1.9 (4H, m), 1.4 (9H, s). MS (LC-MS): Calculated for C25H31NO7 457.21, found 458.19 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[C:24]([C:26](=[O:40])[NH:27][CH2:28][C:29]4[C:30](=[O:39])[NH:31][C:32]([CH3:38])=[CH:33][C:34]=4[CH2:35][CH2:36][CH3:37])[C:23]([CH3:41])=[C:22]([N:42]([CH2:49][CH3:50])[CH:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)[CH:21]=3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:15]=[CH:16][C:17]([C:20]3[CH:21]=[C:22]([N:42]([CH2:49][CH3:50])[CH:43]4[CH2:44][CH2:45][O:46][CH2:47][CH2:48]4)[C:23]([CH3:41])=[C:24]([CH:25]=3)[C:26]([NH:27][CH2:28][C:29]3[C:30](=[O:39])[NH:31][C:32]([CH3:38])=[CH:33][C:34]=3[CH2:35][CH2:36][CH3:37])=[O:40])=[CH:18][CH:19]=2)[CH2:12][CH2:13]1
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2ccc(N3CCC(NC(=O)OC(C)(C)C)CC3)nc2)cc(N(CC)C2CCOCC2)c1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2ccc(N3CCC(N)CC3)nc2)cc(N(CC)C2CCOCC2)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.8 %

Procedure:
To a stirred solution of tert-butyl(1-(5-(3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-5-(((6-methyl-2-oxo-4-propyl-1,2-dihydropyridin-3-yl)methyl)carbamoyl)phenyl)pyridine-2-yl)piperidin-4-yl)carbamate (0.4 g, 0.00051 mol) in DCM (10 mL) at 0° C., TFA (10 mL) was added and reaction was stirred for 2 h at room temperature. After completion, reaction was concentrated to dryness. The residue was then basified with aqueous sat. bicarbonate solution (80 mL) till pH 8 and aqueous layer extracted with 20% methanol in DCM (60 mL×4). Combined organic phase was dried over Na2SO4 and solvent removed under reduced pressure to afford the title compound (0.315 g, 92.1%) which was used as such for next reaction.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:9]([NH2:11])=[O:10])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Cl[C:31]([O:33][CH3:34])=[O:32]>C(Cl)Cl>[CH3:34][O:33][C:31]([N:15]1[CH2:16][CH2:17][CH:12]([C:8]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]([NH2:11])=[O:10])[CH2:13][CH2:14]1)=[O:32]
Reactant: COC(=O)Cl
Reactant: NC(=O)C(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)N1CCC(C(C(N)=O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.6 %

Procedure:
A mixture of α,α-bis(4-fluorophenyl)-4-piperidineacetamide (7.65 g, 0.023 mol) and sodium bicarbonate (3.36 g, 0.023 mole) in methylene chloride was prepared. To this mixture was added a solution of methyl chloroformate (2.17 g, 0.023 mole) in methylene chloride. The resulting mixture was stirred overnight at room temperature. The mixture was extracted successively with water, 5% sodium hydroxide, and water. The methylene chloride layer was dried (sodium sulfate). The organic layer was filtered, and solvent was removed to provide a fluffy, white residue (5.95 g, 66.6% yield). A 0.5 g sample was crystallized from methylene chloridehexanes. This provided a white solid which was dried in vacuo overnight at 80° C., mp 126°-129° C.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[CH3:19][O:20][C:21]([C:23]1[S:24][C:25]([CH2:28][CH2:29][CH2:30][C@H:31]2[CH2:35][CH2:34][CH:33]=[C:32]2[C:36]2[CH:41]=[CH:40][C:39]([C@@H:42]([O:48][Si](C(C)(C)C)(C)C)[CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[CH:38][CH:37]=2)=[CH:26][CH:27]=1)=[O:22]>[NH4+].[Cl-]>[CH3:19][O:20][C:21]([C:23]1[S:24][C:25]([CH2:28][CH2:29][CH2:30][C@H:31]2[CH2:35][CH2:34][CH:33]=[C:32]2[C:36]2[CH:37]=[CH:38][C:39]([C@@H:42]([OH:48])[CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[CH:40][CH:41]=2)=[CH:26][CH:27]=1)=[O:22]
Reactant: CCCCC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(C2=CCC[C@@H]2CCCc2ccc(C(=O)OC)s2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Product: CCCCC[C@H](O)c1ccc(C2=CCC[C@@H]2CCCc2ccc(C(=O)OC)s2)cc1
Reaction time: 4 h
Yield: 73.5 %

Procedure:
TBAF (0.4 mL, 0.4 mmol, 1 M/THF) was added to 42b (45 mg, 0.083 mmol) and the resulting solution was allowed to stir for 4 h. Saturated NH4Cl (20 mL) solution was added and the mixture was extracted with ethyl acetate (2×20 mL). The combined ethyl acetate solution was dried (Na2SO4), filtered and evaporated. Purification of the residue by flash chromatography using a Combiflash unit by Teledyne Isco (330 g silica gel, 0%→20% ethyl acetate/hexanes) gave the title compound (26 mg, 0.061 mmol, 73%).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[CH2:7][C:8]([CH3:29])([CH3:28])[CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[NH:10][C:11]=2[CH:12]=[CH:13][C:14]=1[Cl:15])=[O:4].[OH-].[Na+].Cl>CO.O1CCCC1.O>[Cl:15][C:14]1[CH:13]=[CH:12][C:11]2[NH:10][CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[CH:17]=3)[C:8]([CH3:29])([CH3:28])[CH2:7][C:6]=2[C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1c(Cl)ccc2c1CC(C)(C)C(c1cccc(N3CCOCC3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC1(C)Cc2c(ccc(Cl)c2C(=O)O)NC1c1cccc(N2CCOCC2)c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 89.8 %

Procedure:
To a stirred mixture solution of 6-chloro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid methyl ester (200 mg, 0.5 mmol) in methanol (5.0 mL) and tetrahydrofuran (5.0 mL) was added 50% sodium hydroxide in water (1.0 mL). The reaction mixture was stirred at 70° C. for 6 hours. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 6-chloro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid (180 mg, 90%) as a light yellow solid: LC/MS m/e calcd for C22H25ClN2O3 (M+H)+: 401.91, observed: 401.1.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.C(O)(=O)C.[N:23]1[CH:28]=[CH:27][C:26]([CH:29]=O)=[CH:25][CH:24]=1>CO>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([N:1]=[CH:29][C:26]4[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=4)[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccncc1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Solvent: CO
Solvent: CC(=O)O
Product: Clc1cccc(Nc2ncnc3[nH]nc(N=Cc4ccncc4)c23)c1

Procedure:
Analogously to Step 32.1, 261 mg (1.00 mmol) of 3-amino-4-(3-chloro-phenyl-amino)-1 H-pyrazolo[3,4-d]pyrimidine (see Step 1.6) and 180 mg of acetic acid are dissolved in 26 ml of methanol and reacted with 161 mg (1.5 mmol) of pyridine-4-carbaldehyde to form 4-(3-chloro-phenylamino)-3-[(pyrid-4-yl)-methyleneamino]-1H-pyrazolo[3,4-d]pyrimidine. Reduction of the above intermediate in 25 ml of DMEU with 8 ml (8 mmol) of DIBAL-H analogously to Example 32 and analogous working-up yield 4-(3-chlorophenylamino)-3-[(pyrid-4-yl)-methylamino]-1H-pyrazolo[3,4-d]pyrimidine; HPLC: tRet(grad20-100/20)7.7; FAB-MS: (M+H)+=352.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]2[O:12][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl[CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1.C[O-].[Na+]>CN(C)C=O.C(OCC)(=O)C.O>[N:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:29]=[CH:30][C:21]=1[CH2:20][O:1][C:2]1[CH:3]=[C:4]([CH:8]2[O:12][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(C2CN=C(c3ccccn3)O2)c1
Reactant: ClCc1ccc2ccccc2n1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: c1ccc(C2=NCC(c3cccc(OCc4ccc5ccccc5n4)c3)O2)nc1
Yield: 21.8 %

Procedure:
A solution of 4,5-dihydro-5-(3-hydroxyphenyl)-2-(2-pyridyl)-1,3-oxazole (7.3 g, 0.03 mol) and 2-(chloromethyl)quinoline (5.4 g, 0.03 mol) in dimethylformamide (200 ml) is heated to 90° for 16 hours in the presence of sodium methoxide (1.6 g, 0.03 mol). The mixture is dissolved in ethyl acetate and water. The aqueous layer is extracted twice with ethyl acetate. The combined ethyl acetate solutions are washed twice with dilute aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated to obtain an oil. This material is chromatographed on a Water Prep Pak 500 silica column with methylene chloride/methanol 99/1 (v/v) as mobile phase to obtain 2.5 g of purified material as a viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:22]#[N:23])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH:18]([CH3:20])[CH3:19])[C:15]([OH:17])=O)[C:10](=[O:21])[CH:9]=2)[CH:7]=1.[NH:24]1[C:28]([C:29]2[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=2)=[N:27][N:26]=[N:25]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:22]#[N:23])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH:18]([CH3:19])[CH3:20])[C:15]([NH:33][C:32]3[CH:34]=[CH:35][C:29]([C:28]4[NH:27][N:26]=[N:25][N:24]=4)=[CH:30][CH:31]=3)=[O:17])[C:10](=[O:21])[CH:9]=2)[CH:7]=1
Reactant: CC(C)C(C(=O)O)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: Nc1ccc(-c2nnn[nH]2)cc1
Product: CC(C)C(C(=O)Nc1ccc(-c2nnn[nH]2)cc1)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
79 mg (purity 86%, 0.21 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-3-methylbutanoic acid (racemate) (Example 4.1C) and 40 mg (0.25 mmol) of 4-(1H-tetrazol-5-yl)aniline were reacted according to General Method 1. Yield: 45 mg (46% of theory)
Reaction SMILES: [CH2:1]([N:8]=[N+:9]=[N-:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11]([C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1)#[CH:12]>C[C-]1C(C)=C(C)C(C)=C1C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Ru+].C1C=CC=CC=1>[CH2:1]([N:8]1[C:11]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)=[CH:12][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#Cc1ccc2ccccc2c1
Reactant: [N-]=[N+]=NCc1ccccc1
Agent: Cl[Ru+]
Agent: Cc1c(C)c(C)[c-](C)c1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: c1ccc(Cn2nncc2-c2ccc3ccccc3c2)cc1

Procedure:
Benzyl azide (0.400 g, 3.00 mmol), 2-ethynylnaphthalene (0.503 g, 3.31 mmol), Cp*RuCl(PPh3)2 (25 mg, 0.031 mmol). Solvent, benzene; reaction temperature, 80° C.; reaction time, 4 hours; yield, 0.80 g (93%). EI-MS: m/z 285 [M+].
Reaction SMILES: [C:1]([O:5][NH:6][C:7](=[O:28])[C@H:8]([NH:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]#[C:26][CH3:27])=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH2:9][CH2:10][CH2:11][NH2:12])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:36]1[CH:40]=[CH:39][CH:38]=[C:37]1[C:41](Cl)=[O:42]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:24]([O:23][C:20]1[CH:21]=[CH:22][C:17]([S:14]([NH:13][C@@H:8]([C:7]([NH:6][O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:28])[CH2:9][CH2:10][CH2:11][NH:12][C:41]([C:37]2[S:36][CH:40]=[CH:39][CH:38]=2)=[O:42])(=[O:16])=[O:15])=[CH:18][CH:19]=1)[C:25]#[C:26][CH3:27]
Reactant: CC#CCOc1ccc(S(=O)(=O)N[C@H](CCCN)C(=O)NOC(C)(C)C)cc1
Reactant: O=C(Cl)c1cccs1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC#CCOc1ccc(S(=O)(=O)N[C@H](CCCNC(=O)c2cccs2)C(=O)NOC(C)(C)C)cc1
Reaction time: 16 h

Procedure:
The residue from Step B (102 mg, 0.25 mmol) was dissolved in DCM (2 mL). Triethylamine (104 uL, 0.75 mmol), DMAP (0.3 mg, 0.025 mmol) and thiophene-2-carbonyl chloride (55 mg, 0.37 mmol) were added. The reaction was shaken on an orbital shaker for 16 hours then concentrated to dryness.