Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:34]([F:37])([F:36])[F:35])[C:5]([N:8]2[C:12]3=[N:13][CH:14]=[N:15][C:16]([O:17][C@@H:18]([CH2:29][O:30][CH:31]([CH3:33])[CH3:32])[C:19]([NH:21][C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][N:23]=4)=[O:20])=[C:11]3[CH:10]=[N:9]2)=[N:6][CH:7]=1>[Pd].CO>[CH:31]([O:30][CH2:29][C@H:18]([O:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([C:5]3[C:4]([C:34]([F:37])([F:36])[F:35])=[CH:3][CH:2]=[CH:7][N:6]=3)[N:9]=[CH:10][C:11]=12)[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][N:23]=1)=[O:20])([CH3:33])[CH3:32]
Reactant: Cc1ccc(NC(=O)[C@H](COC(C)C)Oc2ncnc3c2cnn3-c2ncc(Cl)cc2C(F)(F)F)nc1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(NC(=O)[C@H](COC(C)C)Oc2ncnc3c2cnn3-c2ncccc2C(F)(F)F)nc1
Reaction time: 16 h
Yield: 47.3 %

Procedure:
(2S)-2-(1-(5-Chloro-3-(trifluoromethyl)pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3-isopropoxy-N-(5-methylpyridin-2-yl)propanamide (Intermediate K6) (1 g, 0.73 mmol), and 10% Palladium on Carbon (100 mg, 0.09 mmol) in MeOH (25 mL) were stirred under an atmosphere of hydrogen for 16 hours. The reaction mixture was filtered through celite. 10% Palladium on Carbon (100 mg, 0.09 mmol) added and stirred under an atmosphere of hydrogen for a further 16 hours. The reaction mixture was filtered through celite and evaporated. The residue was purified by flash silica chromatography, elution gradient 1 to 5% MeOH in DCM to afford (2S)-3-isopropoxy-N-(5-methylpyridin-2-yl)-2-(1-(3-(trifluoromethyl)pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanamide (0.173 g, 47%). 1H NMR (400 MHz, DMSO) δ 1.08-1.14 (6H, m), 2.24 (3H, s), 3.73-3.79 (1H, m), 3.96-4.05 (2H, m), 5.90 (1H, s), 7.57-7.60 (1H, m), 7.86-7.90 (1H, m), 7.94-7.98 (1H, m), 8.17 (1H, s), 8.55 (1H, s), 8.58-8.61 (1H, m), 8.65 (1H, s), 8.97-9.00 (1H, m), 10.82 (1H, s). m/z (ESI+) (M+H)+=502; HPLC tR=2.30 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N+:15]([O-])=O)[C:12]([F:18])=[CH:11][C:10]=1[C:19]([F:22])([F:21])[F:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.Cl[Ni]Cl>[CH2:1]([O:8][C:9]1[C:10]([C:19]([F:22])([F:20])[F:21])=[CH:11][C:12]([F:18])=[C:13]([CH:14]=1)[NH2:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(OCc2ccccc2)c(C(F)(F)F)cc1F
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Nc1cc(OCc2ccccc2)c(C(F)(F)F)cc1F
Reaction time: 0.33 h
Yield: 43.5 %

Procedure:
To a solution of 1-(benzyloxy)-4-fluoro-5-nitro-2-(trifluoromethyl)benzene (382 mg, 1.21 mmol) and NiCl2 (314 mg, 2.42 mmol) in methanol (40 mL) was added NaBH4 (50 mg, 1.32 mmol) portionwise at 0° C. The reaction turned black after 20 minutes. The reaction mixture was quenched with NaHCO3 and diluted with EtOAc. The reaction mixture was then filtered through a plug of celite, the layers separated and the aqueous layer was extracted with EtOAc. The combined organic layer was dried over Na2SO4, filtered and concentrated. The residue was then purified by silica gel column chromatography using 15% EtOAc/hexane gradient to give 5-(benzyloxy)-2-fluoro-4-(trifluoromethyl)aniline (150 mg, 43%). LC/MS: m/z 286.1 (M+H)+ at 1.89 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: CC([N:5]([C:9]1([C:14]([NH:16][N:17]2[CH:21]=[CH:20][CH:19]=[CH:18]2)=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1)C(=O)[O-])(C)C.[ClH:22].CCOC(C)=O.CCCCCC.II>C(OCC)(=O)C.C(O)(C)C>[ClH:22].[NH2:5][C:9]1([C:14]([NH:16][N:17]2[CH:21]=[CH:20][CH:19]=[CH:18]2)=[O:15])[CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: CC(C)(C)N(C(=O)[O-])C1(C(=O)Nn2cccc2)CCCC1
Agent: Cl
Agent: II
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC(C)O
Product: NC1(C(=O)Nn2cccc2)CCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution consisting of 1,1-dimethylethyl-[1-[(1H-pyrrol-1-ylamino)carbonyl]cyclopentyl]carbamate (2.90 g) in ethyl acetate/isopropanol (30 ml, 3:1) was added excess ethereal HCl. After stirring for 18 hours at room temperature, the reaction appeared complete by TLC (silica gel, 30%EtOAc/hexane, I2 stain). The solid was filtered under nitrogen and recrystallized from ether/methanol to afford 1.40 g of the product, m.p. 218°-220° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@:8]([C@@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]2)([OH:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:27][CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]>C1COCC1>[Si:30]([O:29][CH2:28][CH2:27][O:10][C@:8]([C@@H:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]1)([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH3:9])([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@](C)(O)c2cccc(Cl)c2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@](C)(OCCO[Si](C)(C)C(C)(C)C)c2cccc(Cl)c2)C1
Temperature: 80 °C

Procedure:
A mixture of (R)-tert-butyl 3-((R)-1-(3-chlorophenyl)-1-hydroxyethyl)piperidine-1-carboxylate (2.5463 g, 7.49 mmol), 60% NaH (2.120 g, 53 mmol), and (2-bromoethoxy)(tert-butyl)dimethylsilane (7.820 g, 32.7 mmol) in THF was heated at 80° C. for 25 h and then cooled to rt. The reaction mixture was then quenched with water and extracted with ethyl acetate (3×), dried over Na2SO4. After the solvent was evaporated under reduced pressure, crude (R)-tert-butyl 3-((R)-1-(2-(tert-butyldimethylsilyloxy)ethoxy)-1-(3-chlorophenyl)ethyl)piperidine-1-carboxylate was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([S:12]([CH3:14])=[O:13])=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.[CH2:16]([O:18][CH2:19][CH2:20][N:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[C:22]1[NH:30][CH:31]1[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][C:39]2([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH2:43][CH2:42][NH:41][CH2:40]2)[CH2:33][CH2:32]1)[CH3:17]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([S:12]([CH3:14])=[O:13])=[CH:8][C:4]=1[C:5]([N:41]1[CH2:42][CH2:43][C:39]([CH2:38][CH2:37][N:34]2[CH2:35][CH2:36][CH:31]([NH:30][C:22]3[N:21]([CH2:20][CH2:19][O:18][CH2:16][CH3:17])[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=3)[CH2:32][CH2:33]2)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:40]1)=[O:7]
Reactant: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Reactant: COc1ccc(S(C)=O)cc1C(=O)O
Agent: Cl
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(S(C)=O)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 59.1 using 2-methoxy-5-methylsulfinylbenzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][C:11]1[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].Br[CH2:19][C:20]([O:22][CH3:23])=[O:21]>CN(C)C=O>[Si:3]([O:10][C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=1)[O:17][CH2:19][C:20]([O:22][CH3:23])=[O:21])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(O)c1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc(O[Si](C)(C)C(C)(C)C)c1
Temperature: 50 °C
Reaction time: 16 h
Yield: 76.7 %

Procedure:
Sodium hydride (60% mineral oil dispersion, 0.35 g, 8.7 mmol) was added to a solution of 3-((t-butyldimethylsilyl)oxy)phenol (0.49 g, 2.2 mmol), methyl 2-bromoacetate (0.37 g, 2.4 mmol), and dimethylformamide (2 mL) in a 50 mL round bottom flask under a nitrogen atmosphere at room temperature. The solution was heated in a 50° C. oil bath and allowed to stir overnight for approximately 16 hours. The resulting mixture was cooled to room temperature. The reaction was quenched with saturated aqueous ammonium chloride (100 mL) and extracted with ethyl acetate (200 mL). The organic extract was dried (Na2SO4), filtered and concentrated. The resulting crude residue was purified by combiflash (40 g column, hexanes→100% ethyl acetate/hexanes, gradient) to afford 0.5 g (77%) of methyl 2-(3-((t-butyldimethylsilyl)oxy)phenoxy)acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:12]=[CH:11][S:10][C:9]=2[CH:13]=O)[CH:3]=1.O.[CH3:16][NH:17][CH3:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:12]=[CH:11][S:10][C:9]=2[CH2:13][N:17]([CH3:18])[CH3:16])[CH:3]=1
Reactant: CNC
Reactant: O=Cc1sccc1-c1cc(Cl)ccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CN(C)Cc1sccc1-c1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-(4-chloro-pyridin-2-yl)-thiophene-2-carbaldehyde (20 mg, 0.1 mmol) in dichloromethane (3 mL) was added dimethylamine water solution (40%, 0.6 mL) and sodium triacetoxyborohydride (42 mg, 0.2 mmol). The resulting mixture was stirred at room temperature for 16 hours, then washed with NaHCO3 solution and water and concentrated. The resulting residue was purified by preparative TLC to yield [3-(4-Chloro-pyridin-2-yl)-thiophen-2-ylmethyl]-dimethyl-amine.
Reaction SMILES: [NH2:1][C:2]1[C:17]([N+:18]([O-])=O)=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[C:4]([O:21][CH:22]2[CH2:26][CH2:25][O:24][CH2:23]2)[CH:3]=1.C1COCC1>[Pt].CO>[NH2:1][C:2]1[C:17]([NH2:18])=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:7])=[C:4]([O:21][CH:22]2[CH2:26][CH2:25][O:24][CH2:23]2)[CH:3]=1
Reactant: Nc1cc(OC2CCOC2)c(C(=O)OCc2ccccc2)cc1[N+](=O)[O-]
Agent: [Pt]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cc(OC2CCOC2)c(C(=O)OCc2ccccc2)cc1N
Reaction time: 5 h

Procedure:
Platinum on charcoal (100 mg 5%) was added to the product obtained at (659b) (160 mg, 0.45 mmol) in 10 mL methanol with 5 mL THF and the mixture was hydrogenated at 4 bar H2 pressure at ambient temperature for 5 h. The mixture was filtered, washed with methanol and the filtrate concentrated i. vac. The product was reacted without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:14]([NH:15][CH3:16])=[CH:13][C:5]([CH:6](O)CS(C)(=O)=O)=[CH:4][C:3]=1[N:17]([CH3:19])[CH3:18].C[O-].[Na+].[NH:23]([CH2:30][CH2:31][C:32]#[N:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CS(C)=O>[NH:23]([CH:30]=[C:31]([CH2:6][C:5]1[CH:13]=[C:14]([NH:15][CH3:16])[C:2]([Cl:1])=[C:3]([N:17]([CH3:19])[CH3:18])[CH:4]=1)[C:32]#[N:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: N#CCCNc1ccccc1
Reactant: CNc1cc(C(O)CS(C)(=O)=O)cc(N(C)C)c1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CNc1cc(CC(C#N)=CNc2ccccc2)cc(N(C)C)c1Cl

Procedure:
A mixture of 9.48 g. of 4-chloro-3-dimethylamino-5-methylamino-α-[(methylsulfonyl)methyl]benzyl alcohol, 1.8 g. of sodium methylate and 4.8 g. of β-anilinopropionitrile in 20 ml. of dimethylsulfoxide was stirred with the exclusion of moisture for 5 hours at 50° C. The mixture was cooled, poured into 200 ml. of water, the precipitated oil extracted with ethyl acetate, the ethyl acetate solution dried over sodium sulfate and evaporated. By purification of the product over aluminum oxide with benzene and recrystallization from ethanol, there was obtained α-(anilinomethylene)-4-chloro-3-dimethylamino-5-methylaminohydrocinnamonitrile, having a melting point of 173°-174° C.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=[O:16])[CH2:11][CH2:10]1)=O)(C)(C)C.CC(=O)OCC.Cl>CCOC(C)=O>[NH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=[O:16])[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)O)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@H]1CC[C@H](C(=O)O)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of trans-4-((tert-butoxycarbonyl)amino)cyclohexanecarboxylic acid (823 g, 3.38 mol) in EtOAc (4000 mL) was added EA/HCl (2500 mL). The mixture was stirred at 0° C. overnight. The reaction mixture was filtered and dried in vacuo to give a product of hydrochloride salt of trans-4-aminocyclohexanecarboxylic acid as white solid (604 g, 99.42% yield).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[CH2:20]([NH:22][CH2:23][CH3:24])[CH3:21]>>[CH2:20]([N:22]([CH2:23][CH3:24])[C:17]([C:15]1[CH:16]=[C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])[CH:12]=[N:13][CH:14]=1)=[O:19])[CH3:21]
Reactant: CCNCC
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Product: CCc1cc(-c2cncc(C(=O)N(CC)CC)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and diethyl amine to afford the title compound. MS: m/e=314 (M+H).
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][N:7]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8]1.C(N(CC)CC)C.[Na].O[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[C:32]([NH2:34])=[O:33]>C1C=CC=CC=1.O>[CH3:6][N:7]1[CH2:11][CH2:10][CH:9]([O:12][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][C:23]=2[C:32]([NH2:34])=[O:33])[CH2:8]1
Reactant: CN1CCC(O)C1
Reactant: NC(=O)c1ccc2ccccc2c1O
Agent: CS(=O)(=O)Cl
Agent: [Na]
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CN1CCC(Oc2c(C(N)=O)ccc3ccccc23)C1
Temperature: 75 °C
Reaction time: 0.25 h

Procedure:
In another vessel, 79 g (0.69 mole) of methanesulfonylchloride was added dropwise to a solution of 69.7 g (0.69 mole) of 1-methyl-3-pyrrolidinol and 77 g (0.76 mole) of triethylamine in 500 ml of dry benzene while cooling with an ice bath. The mixture was stirred 15 minutes and filtered. The filter cake was washed with 500 ml of benzene and the benzene filtrates were combined and concentrated on the rotary evaporator to about 200 ml. The residue was added dropwise to the above prepared dimethylsulfoxide solution containing the sodium salt of 1-hydroxy-2-naphthalenecarboxamide while stirring at 75° C. The temperature was maintained at 75° C. for 18 hr with external heat. The resulting solution was cooled and an equal volume of water was added. The mixture was extracted with three portions of chloroform. The washes were combined and concentrated. The residue was partitioned between ethyl acetate and dilute hydrochloric acid. The acid layer was made basic with sodium hydroxide and extracted twice with ethyl acetate. The ethyl acetate washes were combined, dried over sodium sulfate and concentrated. The residue was crystallized from ethyl acetate-isooctane. Yield of solid was 55 g (32%). A portion was recrystallized twice from ethyl acetate-isooctane, m.p. 122°-129° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:8]#[N:9])=[N:5][NH:6][CH:7]=1.C1C(=O)N([I:17])C(=O)C1>CN(C)C=O>[I:17][C:7]1[NH:6][N:5]=[C:4]([C:8]#[N:9])[C:3]=1[O:2][CH3:1]
Reactant: COc1c[nH]nc1C#N
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: COc1c(C#N)n[nH]c1I
Temperature: 70 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
To a solution of 4-methoxy-1H-pyrazole-3-carbonitrile (compound 280.7, 200 mg, 1.62 mmol) in N,N-dimethylformamide (15 mL) was added NIS (549 mg, 2.44 mmol). The reaction mixture was stirred for 2 h at 70° C., then quenched with 20 mL of Na2S2O3 (sat.). The aqueous phase was extracted with 2×50 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:6) as the eluent to furnish 330 mg (82%) of the title compound as a white solid.
Reaction SMILES: [NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][N:31]([C:34](=[O:36])[CH3:35])[CH2:30][CH2:29]3)=[CH:24][N:23]=2)=[CH:16][CH:15]=1)=[O:11])[NH:2]C(OC(C)(C)C)=O.O1CCOCC1.[ClH:43]>ClCCl>[ClH:43].[ClH:43].[ClH:43].[NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][N:31]([C:34](=[O:36])[CH3:35])[CH2:30][CH2:29]3)=[CH:24][N:23]=2)=[CH:16][CH:15]=1)=[O:11])[NH2:2]
Reactant: CC(=O)N1CCN(c2ccc(CCc3ccc(COC(=O)NNC(=O)OC(C)(C)C)cc3)nc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(=O)N1CCN(c2ccc(CCc3ccc(COC(=O)NN)cc3)nc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
To a suspension of 4-{2-[5-(4-acetylpiperazin-1-yl)pyridin-2-yl]ethyl}benzyl tert-butyl hydrazine-1,2-dicarboxylate (139.2 mg, 0.2797 mmol) in anhydrous dichloromethane (1.4 ml) was added 4M hydrogen chloride dioxane solution (1.4 ml, 5.6 mmol). After stirring at room temperature for 8 hrs, the mixture was concentrated under reduced pressure. Ethyl acetate was added to the concentrated residue, and the mixture was concentrated again under reduced pressure. The operation was repeated twice to azeotropically remove hydrogen chloride gas. The residue was dissolved in ethanol (6 ml), and ethyl acetate (30 ml) was added. The precipitated solid was filtered and dried under reduced pressure to give the title compound (105.3 mg, yield 74.3%) as a slightly yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](NC(=O)C(C)(C)C)=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].Cl.N([O-])=O.[Na+].[I-:24].[K+]>O>[I:24][C:4]1[C:3]([O:2][CH3:1])=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: [I-]
Reactant: COc1cccc(C(=O)O)c1NC(=O)C(C)(C)C
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: COc1cccc(C(=O)O)c1I
Temperature: 0 °C
Reaction time: 2 h
Yield: 58.4 %

Procedure:
A stirred mixture of 3-methoxy-2-pivalamidobenzoic acid (20 g, 0.08 mol) and 7M hydrochloric acid (280 ml) was heated under reflux for 2 hours then cooled to 0° C. A solution of sodium nitrite (5.8 g, 0.09 mol) in water (46 ml) was added dropwise at <5° C., the mixture was stirred at 0-5° C. for 2 hours, then a solution of potassium iodide (17.8 g, 0.11 mol) in water (39 ml) was added dropwise at 0-5° C. The stirred mixture was heated at 70-80° C. for 2 hours then cooled in ice. The product was extracted into ethyl acetate (3×300 ml), the combined extracts were washed with 20% aqueous sodium thiosulphate solution (3×300 ml), then they were dried (MgSO4) and the solvent was removed in vacuo to leave 2-iodo-3-methoxybenzoic acid (13 g, 58%) as a solid, m.pt. 142-146° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[NH:4][C:5](=[O:8])[NH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=[O:21].O>C(#N)C.C(OCC)(=O)C>[CH:20]([C:19]1[CH:18]=[C:17]([CH:24]=[CH:23][CH:22]=1)[CH2:16][N:4]1[C:3]([O:2][CH3:1])=[N:7][NH:6][C:5]1=[O:8])=[O:21]
Reactant: O=Cc1cccc(CBr)c1
Reactant: COc1n[nH]c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1n[nH]c(=O)n1Cc1cccc(C=O)c1
Reaction time: 6 h
Yield: 18.8 %

Procedure:
To a solution of 0.92 g (8.0 mmol) of 5-methoxy-2,4-dihydro-3H-1,2,4-triazol-3-one in 15 ml of dry acetonitrile was added 1.16 g (8.4 mmol) of potassium carbonate. To the mixture was added dropwise a solution of 1.59 g of crude 3-(bromomethyl)benzaldehyde in 30 ml of dry acetonitrile at 55° C. under an atmosphere of nitrogen. After the mixture was stirred at the same temperature for additional 6 hours, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated. The residue (1.31 g) was subjected to silica gel column chromatography (eluted with n-hexane:ethyl acetate=1:1 and then 1:2) to obtain 0.35 g (1.50 mmol) of 4-(3-formylbenzyl)-5-methoxy-2,4-dihydro-3H-1,2,4-triazol-3-one as white powder.
Reaction SMILES: CO[C:3](=[O:15])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:13]Br.[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([C@H:27]([NH2:33])[CH2:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH3:17].C(N(CC)CC)C>CN(C=O)C.CCOCC>[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([C@H:27]([N:33]2[CH2:13][C:5]3[C:4](=[C:9]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:7][CH:6]=3)[C:3]2=[O:15])[CH2:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH3:17]
Reactant: COC(=O)c1c(CBr)cccc1[N+](=O)[O-]
Reactant: CCOc1cc([C@H](N)CS(C)(=O)=O)ccc1OC
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3cccc([N+](=O)[O-])c3C2=O)ccc1OC
Yield: 54.1 %

Procedure:
A solution of 2-bromomethyl-6-nitro-benzoic acid methyl ester (4.0 g, 14.6 mmol), (1S)-1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine (4.0 g, 14.6 mmol) and triethylamine (4.4 mL, 31.6 mmol) in DMF (40 mL) was heated at 80° C.-90° C. for 1 day. The solvent was removed in vacuo to give an oil. The oil was extracted with ethyl acetate (150 mL) and HCl (2N, 50 mL). The organic layer was washed with HCl (2N, 2×50 mL), water (2×50 mL), brine (2×50 mL) and dried over MgSO4. The solvent was removed in vacuo to give a yellow oil. The oil was slurried in ether (50 mL) to give a suspension. The suspension was filtered and washed with ether to give 2-[(1S)-1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-7-nitro-2,3-dihydro-isoindol-1-one as a yellow solid (3.43 g, 54% yield): 1H NMR (CDCl3) δ 1.5 (t, J=7 Hz, 3H, CH3), 2.99 (s, 3H, CH3), 3.69 (dd, J=5, 15 Hz, 1H, CHH), 3.86 (s, 3H, CH3), 4.07 (q, J=7 Hz, 2H, CH2), 4.27 (dd, J=11, 15 Hz, 1H, CHH), 4.30 (d, J=17 Hz, 1H, NCHH), 4.54 (d, J=17 Hz, 1H, NCHH), 5.70 (dd, J=5, 10 Hz, 1H, NCH), 6.85 (d, J=8 Hz, 1H, Ar), 6.94-7.00 (m, 2H, Ar), 7.58-7.76 (m, 3H, Ar).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][O:21]C3CCCCO3)[C:13](=[O:28])[N:12](COCC[Si](C)(C)C)[C:11]=2[N:10]=[C:9]1[Cl:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(O)C>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][OH:21])[C:13](=[O:28])[NH:12][C:11]=2[N:10]=[C:9]1[Cl:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(Cl)n2Cc1ccccc1
Agent: Cl
Solvent: CCO
Product: O=c1[nH]c2nc(Cl)n(Cc3ccccc3)c2c(=O)n1CCCO
Temperature: 80 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
To a solution of 7-benzyl-8-chloro-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione (500 mg, 0.912 mmol, intermediate 18) in ethyl alcohol (20 mL) was added concentrated HCl (5 mL). The mixture was stirred at 80° C. overnight. Then the mixture was concentrated, neutralized with saturated sodium bicarbonate and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give 7-benzyl-8-chloro-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione (280 mg, 91.9% yield) as yellow oil. LCMS retention time 1.710 min; LCMS MH+ 335.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:29])([F:30])[F:31])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)=[O:23])=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: C1COCCN1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1)N1CCOCC1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with morpholine as in General Procedure 10 to give the title compound. LCMS: m/z=516.96 (M+H+); retention time=0.74 minutes.