Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:19][N:18]2[C:10]([C:11]3[NH:12][C:13]([CH:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)=[N:14][C:15]=3[N:16]=[C:17]2[C:20]#[N:21])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:27]=[N+:28]=[N-:29].[Na+].[Cl-].[NH4+].O>CN1CCCC1=O>[CH2:1]([C@@H:8]1[CH2:19][N:18]2[C:10]([C:11]3[NH:12][C:13]([CH:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)=[N:14][C:15]=3[N:16]=[C:17]2[C:20]2[NH:29][N:28]=[N:27][N:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CC1=Nc2nc(C3CCCC3)[nH]c2C2=N[C@H](Cc3ccccc3)CN12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: c1ccc(C[C@@H]2CN3C(c4nnn[nH]4)=Nc4nc(C5CCCC5)[nH]c4C3=N2)cc1
Temperature: 120 °C
Reaction time: 2 h
Yield: 82.6 %

Procedure:
Compound 75 (69 mg, 0.200 mmol) obtained in Example 75 was dissolved in 1-methyl-2-pyrrolidinone (1 mL), to the solution were added sodium azide (52 mg, 0.800 mmol, 4.0 equivalents) and ammonium chloride (42 mg, 0.800 mmol, 4.0 equivalents), and the mixture was stirred at 120° C. for 2 hours. To the reaction mixture was added water, and the deposited crystals were collected by filtration to obtain the title compound (64 mg, 83%) as a white solid.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[N:9]([C:17]1[C:22]([F:23])=[C:21](Cl)[N:20]=[C:19]([Cl:25])[N:18]=1)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])([CH3:4])[CH3:3].C(N(CC)CC)C.Cl.[NH2:41][CH2:42][C:43]1[S:44][CH:45]=[CH:46][N:47]=1>C1COCC1.O>[CH3:4][C:2]([O:5][C:6]([N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[N:9]([C:17]1[C:22]([F:23])=[C:21]([NH:41][CH2:42][C:43]2[S:44][CH:45]=[CH:46][N:47]=2)[N:20]=[C:19]([Cl:25])[N:18]=1)[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])=[O:7])([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(Cl)c1F
Reactant: NCc1nccs1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(NCc2nccs2)c1F

Procedure:
Tris(1,1-dimethylethyl)2-(2,6-dichloro-5-fluoro-4-pyrimidinyl)-1,1,2-hydrazinetricarboxylate (0.988 g, 1.992 mmol) was dissolved in THF (10 mL). To this solution was added triethylamine (0.61 mL, 4.3765 mmol), followed by commercially available 2-aminomethyl thiazole hydrochloride (0.30 g, 1.992 mmol), which was suspended in THF (12 mL). The reaction was left to stir for 2 days during which time an additional 10 mL THF and 2-aminomethyl thiazole hydrochloride (0.061 g, 0.4049 mmol) were added to the reaction mixture. After 3 more days, the reaction mixture was diluted with water and extracted with ethyl acetate. The organics were dried (Na2SO4) and concentrated. The resulting crude material was purified by silica gel chromatography (0-100% ethyl acetate in hexanes) to provide tris(1,1-dimethylethyl)2-{2-chloro-5-fluoro-6-[(1,3-thiazol-2-ylmethyl)amino]-4-pyrimidinyl}-1,1,2-hydrazinetricarboxylate as a yellow oil (0.5826, 51%). LCMS: (M+H−3 Boc)+=375.0.
Reaction SMILES: [CH2:1]([NH:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][NH:27][CH2:28][C@@H:29]([C:31]3[CH:36]=[CH:35][C:34]([O:37]CC4C=CC=CC=4)=[C:33]([NH:45][S:46]([CH3:49])(=[O:48])=[O:47])[CH:32]=3)[OH:30])=[CH:21][CH:20]=2)[CH2:14][CH2:13]1)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[H][H]>C(O)C.[Pd]>[CH2:1]([NH:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][NH:27][CH2:28][C@H:29]([OH:30])[C:31]3[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([NH:45][S:46]([CH3:49])(=[O:48])=[O:47])[CH:32]=3)=[CH:21][CH:20]=2)[CH2:14][CH2:13]1)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)c3ccc(OCc4ccccc4)c(NS(C)(=O)=O)c3)cc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)cc2)CC1
Yield: 62.1 %

Procedure:
4-(4-{2-[(2R)-2-(4-Benzyloxy-3-methanesulfonylamino-phenyl)- 2-hydroxy-ethylamino]-ethyl}-phenylamino)-piperidine-1-carboxylicacid octylamide (0.152 g, 0.219 mmol) was dissolved in ethanol (40 mL) and 10% palladium on carbon (0.05 g) added. The solution was shaken in a Parr apparatus at 50 psi hydrogen atmosphere for 2 hours, filtered through a Celite pad and the solvent removed in vacuo. The residue was purified by flash chromatography on silica gel Merck-60 (eluant: 5:1 chloroform-methanol) to furnish the title compound (0.082 g, 0.136 mmol)
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.FC(F)(F)C(O)=O.[CH3:22][O:23][C@H:24]1[CH2:29][CH2:28][CH2:27][C@@H:26]([NH2:30])[CH2:25]1.CCN(C(C)C)C(C)C>C(O)C>[CH3:22][O:23][C@H:24]1[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=2)[CH2:25]1
Reactant: CO[C@H]1CCC[C@@H](N)C1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cnc(SC)nc1N[C@@H]1CCC[C@H](OC)C1
Temperature: 60 °C
Yield: 94.2 %

Procedure:
To a stirring solution of ethyl 4-chloro-2-(methylthio)-pyrimidine-5-carboxylate (1.084 g, 4.66 mmol) and (1R,3S)-3-methoxycyclohexanamine trifluoroacetate (1.133 g, 4.66 mmol) in ethanol (18.63 mL) was added DIEA (2.434 mL, 13.97 mmol). The reaction mixture was heated to 60° C. for 17 h. The reaction was removed from heat, cooled to room temperature and concentrated. The crude material was purified by silica gel chromatography (0-25% ethyl acetate in hexanes) to afford ethyl 4-((1R,3S)-3-methoxycyclohexylamino)-2-(methylthio)pyrimidine-5-carboxylate (1.4284 g, 4.39 mmol, 94% yield) as a clear oil. MS (ESI) m/z 326.2 [M+1]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([NH:10][C:11]2[CH:26]=[CH:25][C:14]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18](C(N)=O)[CH:17]=3)=[CH:13][C:12]=2[F:27])=[O:9])[C:4](=[O:28])[N:3]1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CC#[N:37].O.C(OI(C1C=CC=CC=1)OC(=O)C)(=O)C>CCOC(C)=O>[NH2:37][C:18]1[CH:17]=[C:16]([O:15][C:14]2[CH:25]=[CH:26][C:11]([NH:10][C:8]([C:5]3[C:4](=[O:28])[N:3]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:2]([CH3:1])[C:6]=3[CH3:7])=[O:9])=[C:12]([F:27])[CH:13]=2)[CH:21]=[CH:20][N:19]=1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(C(N)=O)c3)cc2F)c(=O)n(-c2ccccc2)n1C
Reactant: CC#N
Agent: CC(=O)OI(OC(C)=O)c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(N)c3)cc2F)c(=O)n(-c2ccccc2)n1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 17.3 %

Procedure:
A solution of 4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)-3-fluorophenoxy)picolinamide (370 mg (a little wet), 0.746 mmol) in EtOAc (4.5 mL), CH3CN (4.5 mL) and H2O (2.5 mL) was cooled and stirred at 0° C. for 30 minutes and then PhI(OAc)2 (288 mg, 0.895 mmol) was added. The resulted mixture was stirred at 0° C. for another 30 minutes, then warmed up to rt and stirred for 7 hours. The mixture was filtered and the filter cake was washed with EtOAc (5 mL). The filtrate was concentrated in vacuo and the residue was purified by a silica column gel chromatography (CH2Cl2/MeOH (v/v)=250/9), followed by purifying again by silica gel column chromatography (CH2Cl2/MeOH (v/v)=50/1) to give the title compound as a beige white solid (46 mg, 17.3%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:24]=[CH:25][CH:26]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:14][CH:15]=1)=[O:8])([O-])=O>O.CO.C(O)(=O)C.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:24]=[CH:25][CH:26]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:20])[CH3:21])[CH:13]=[CH:14][CH:15]=1)=[O:8]
Reactant: CC(C)(C)OC(=O)Nc1cccc(NC(=O)c2cccc([N+](=O)[O-])c2)c1
Agent: [Fe]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cccc(NC(=O)c2cccc(N)c2)c1
Yield: 87.3 %

Procedure:
To a solution of tert-butyl {3-[(3-nitrobenzoyl)amino]phenyl}carbamate (2.00 g, 5.6 mmol) in water (4 mL), methanol (22 mL) and acetic acid (8.6 mL) was added iron (0.782 g, 14.0 mmol) powder in small quantities. When the addition was completed, the mixture was stirred in water bath for 3 h. The mixture was filtered, and the cake was washed with MeOH/EtOAc. The brown filtrate was concentrated and diluted with H2O, and the aqueous layer was extracted with EtOAc three times. The combined organic layers were dried, filtered and concentrated to give the desired product as an off-white powder (1.6 g, 87%). LCMS for C18H21N3O3 (M+H)+: m/z=328.1.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C@@H:9]([OH:12])[CH:10]=[CH2:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(O)[O-:22].[Na+].[OH2:26]>N1C=CC=CC=1.[Os](=O)(=O)(=O)=O>[CH:1]1([CH2:7][C@H:8]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C@@H:9]([OH:12])[CH:10]([OH:22])[CH2:11][OH:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C=C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Reactant: O=S([O-])O
Reactant: O
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H](O)C(O)CO
Reaction time: 72 h

Procedure:
A solution of 1.5 g (2.24 mmol) of tert-butyl [(1S,2S)-1-(cyclohexylmethyl)-2-hydroxy-3-butenyl]carbamate, prepared according to the procedure of J. J. Plattner et al. in J. Med. Chem., 30, (10), (1987), 1729, in 10 ml of pyridine is treated with 845 mg (3.36 mmol) of osmium tetroxide and left to stand at room temperature in the dark for 3 days. Subsequently, the reaction mixture is cooled to 0°, treated with 3 ml of 38% sodium bisulphite solution and stirred for 2 hours. Thereafter, the mixture is poured on to ice and water and extracted three times with 250 ml of ethyl acetate. The combined organic extracts are washed in succession with in each case 60 ml of sodium bicarbonate solution, 20% copper sulphate solution and saturated sodium chloride solution, dried over magnesium sulphate and evaporated under reduced pressure. For purification, the residue (1.20 g) is chromatographed on 30 g of silica gel using a 100:10:1 mixture of methylene chloride, methanol and ammonia as the eluent, whereby there are obtained 590 mg of tert-butyl [(1S,2R,3RS)-1-(cyclohexylmethyl)-2,3,4-trihydroxybutyl]carbamate as a foam, MS: 318 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[CH2:13]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[CH3:14]>>[CH2:13]([N:15]1[CH2:20][CH2:19][N:18]([C:2]2[N:7]=[CH:6][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=2)[CH2:17][CH2:16]1)[CH3:14]
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: CCN1CCNCC1
Product: CCOC(=O)c1ccc(N2CCN(CC)CC2)nc1
Temperature: 96 °C
Reaction time: 0.08 h

Procedure:
To 55.69 g of ethyl 6-chloropyridine-3-carboxylate was added 115 ml of 1-ethylpiperazine and the mixture was heated with stirring (55-137° C.) for 5 minutes. After completion of the reaction, the 1-ethylpiperazine was distilled off under reduced pressure, the residue was crystallized from water-metanol. The crystal was washed with water and then dried under reduced pressure to afford 71.89 g of the title compound as a colorless crystal.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[Cl:5][C:6]1[C:7]([CH:15]([S:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[F:23])=[CH:8][C:9](CC#N)=[N:10][CH:11]=1.S(=O)(=O)(O)O>O>[Cl:5][C:6]1[C:7]([CH:15]([S:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[F:23])=[CH:8][C:9]([CH2:2][C:1]([OH:4])=[O:3])=[N:10][CH:11]=1
Reactant: N#CCc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)Cc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Temperature: 100 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
To an acetic acid (2 ml) solution of [5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]acetonitrile (113 mg, 0.25 mmol) was added a mixture of water (2 ml) and concentrated sulfuric acid (2 ml) at room temperature. The resulting mixture was stirred at 100° C. for 2 hours. After the reaction mixture was cooled to room temperature, water was added thereto. The resulting mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was washed with a mixed solvent of diethyl ether/hexane and then, collected by filtration to give the title compound (101 mg, 0.21 mmol, 86%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[CH:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CN([CH:28]=[O:29])C.[NH4+].[Cl-]>C1COCC1>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[CH:28]=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: c1ccc(COCCn2cnc3ccccc32)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=Cc1nc2ccccc2n1CCOCc1ccccc1
Temperature: -75 °C
Reaction time: 1 h

Procedure:
To a stirred, cooled (−75° C.) light orange solution of 3.79 g 1-(2-benzyloxy-ethyl)-1H-benzoimidazole in 80 ml THF under argon atmosphere was added dropwise 9.4 ml n-butyllithium solution (1.6 M in hexanes) for 15 min (temperature of the solution below −71° C. during the addition; reaction mixture turning to orange). When addition was complete, stirring at −75° C. was continued for 1 h 30. The reaction mixture was then treated with 1.44 ml DMF within 5 min and stirring at −75° C. was continued for 4 h. Then 40 ml of saturated NH4Cl-solution was added to the reaction mixture which was subseqently allowed to warm to r.t. The organic phase was washed with brine, dried (MgSO4), filtered and concentrated. The crude product was purified by chromatography on silica gel using a gradient from cyclohexane to cyclohexane/EtOAc 65:35 to give 1.09 g 1-(2-benzyloxy-ethyl)-1H-benzoimidazole-2-carbaldehyde as viscous yellow oil. MS 281.0 ([M+H]+)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]=[C:5]1[CH2:10][CH2:9][C:8]([N:17]([CH3:19])[CH3:18])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[Cl:21][Si](C)(C)C>CC(CC)=O>[ClH:21].[CH3:1][O:2][C:3](=[O:20])[CH:4]=[C:5]1[CH2:6][CH2:7][C:8]([N:17]([CH3:18])[CH3:19])([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:9][CH2:10]1
Reactant: C[Si](C)(C)Cl
Agent: COC(=O)C=C1CCC(c2ccccc2)(N(C)C)CC1
Solvent: CCC(C)=O
Product: Cl

Procedure:
(4-Dimethylamino-4-phenylcyclohexylidene)acetic acid methyl ester (2.4 g, 8.7 mmol) was dissolved in ethyl methyl ketone (70 ml), and chlorotrimethylsilane (1.66 ml, 13.17 mmol) was added, while cooling with ice. After a reaction time of 5 h, it was possible to obtain the hydrochloride of the ester as a colourless solid in a yield of 78% (1.95 g) with an m.p. of 204-208° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([CH2:16][NH:17][C:18]([C:20]2[C:21]3[C:22]([CH3:33])=[CH:23][N:24]([CH:30]([CH3:32])[CH3:31])[C:25]=3[CH:26]=[C:27]([Br:29])[CH:28]=2)=[O:19])=[C:11]([O:34]C)[N:10]=1)(C)(C)C.Cl>O1CCCC1>[NH2:7][CH2:8][C:9]1[NH:10][C:11](=[O:34])[C:12]([CH2:16][NH:17][C:18]([C:20]2[C:21]3[C:22]([CH3:33])=[CH:23][N:24]([CH:30]([CH3:31])[CH3:32])[C:25]=3[CH:26]=[C:27]([Br:29])[CH:28]=2)=[O:19])=[C:13]([CH3:15])[CH:14]=1
Reactant: COc1nc(CNC(=O)OC(C)(C)C)cc(C)c1CNC(=O)c1cc(Br)cc2c1c(C)cn2C(C)C
Agent: Cl
Solvent: C1CCOC1
Product: Cc1cc(CN)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c1c(C)cn2C(C)C
Temperature: 80 °C
Yield: 82.3 %

Procedure:
To a stirred solution of tert-butyl((5-((6-bromo-1-isopropyl-3-methyl-1H-indole-4-carboxamido)methyl)-6-methoxy-4-methylpyridin-2-yl)methyl)carbamate (500 mg, 0.894 mmol) in Tetrahydrofuran (THF) (5 mL) was added 6N HCl (15 mL, 15.00 mmol). The reaction was stirred under N2 with heating at 80° C. for 18 hr. The reaction was cooled to RT and evaporated to dryness under vacuum. The remaining was purified by silica gel chromatography (Analogix, SF25-40 g, 0 to 10% (5% NH4OH in MeOH) in CH2Cl2). The pure fractions were combined and evaporated to dryness under vacuum. Dissolved with a small volume of CH2Cl2, scratched out by slowly adding hexanes, filtered, washed with hexanes and dried under vacuum to give the product N-((6-(aminomethyl)-4-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-bromo-1-isopropyl-3-methyl-1H-indole-4-carboxamide (328 mg, 0.736 mmol, 82% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ=8.26 (t, J=5.1 Hz, 1H), 7.76 (d, J=1.8 Hz, 1H), 7.33 (d, J=1.0 Hz, 1H), 7.01 (d, J=1.5 Hz, 1H), 6.01 (s, 1H), 5.77 (s, 0H), 4.74 (quin, J=6.6 Hz, 1H), 4.32 (d, J=5.1 Hz, 2H), 3.46 (s, 2H), 2.25 (s, 3H), 2.14 (s, 3H), 1.39 (d, J=6.8 Hz, 6H). MS (ES)+m/e 445.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]2[NH:9][N:10]=[CH:11][C:3]=12.C(N(CC)CC)C.[H][H].C(OCC)(=O)C>O1CCOCC1.[OH-].[OH-].[Pd+2]>[CH3:8][C:6]1[N:5]=[C:4]2[NH:9][N:10]=[CH:11][C:3]2=[CH:2][N:7]=1
Reactant: [H][H]
Reactant: Cc1nc(Cl)c2cn[nH]c2n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1ncc2cn[nH]c2n1

Procedure:
4.464 g (approx. 24.28 mmol, purity 92%) of 4-chloro-6-methyl-1H-pyrazolo[3,4-d]pyrimidine were dissolved in 180 ml of dioxane, 2.948 g (29.14 mmol) of triethylamine and 5.629 g of 20% palladium hydroxide on carbon were added, and hydrogenation was effected with hydrogen at 3 bar and RT for 2 d. 100 ml of ethyl acetate, 2.948 g (29.14 mmol) of triethylamine and 2.000 g of 20% palladium hydroxide on carbon were added. The mixture was hydrogenated with hydrogen at 3 bar and RT for 3 h. The mixture was filtered through Celite and washed with a little dioxane/ethyl acetate, and the filtrate was concentrated on a rotary evaporator. 2.180 g (purity 73%, 49% of theory) of the target compound were obtained.
Reaction SMILES: O/[CH:2]=[C:3](\[CH2:8][C:9]1[CH:10]=[N:11][C:12]([O:15][CH3:16])=[N:13][CH:14]=1)/[C:4]([O:6]C)=O.OS(C(F)(F)F)(=O)=O.[C:25](=[NH:48])([O:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[C:39]([C:44]([F:47])([F:46])[F:45])[CH:38]=2)=[CH:32][CH:31]=1)[NH2:26].C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[Cl:43][C:40]1[CH:41]=[CH:42][C:37]([O:36][C:33]2[CH:34]=[CH:35][C:30]([CH2:29][CH2:28][O:27][C:25]3[NH:48][CH:2]=[C:3]([CH2:8][C:9]4[CH:10]=[N:11][C:12]([O:15][CH3:16])=[N:13][CH:14]=4)[C:4](=[O:6])[N:26]=3)=[CH:31][CH:32]=2)=[CH:38][C:39]=1[C:44]([F:45])([F:46])[F:47]
Reactant: N=C(N)OCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: COC(=O)/C(=C/O)Cc1cnc(OC)nc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)C(F)(F)F
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ncc(Cc2c[nH]c(OCCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)cn1
Temperature: 160 °C
Yield: 21.4 %

Procedure:
To the solution of methyl (2E)-3-hydroxy-2-{[2-(methyloxy)-5-pyrimidinyl]methyl}-2-propenoate (177 mg, 0.789 mmol) and 2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-phenyl)ethyl imidocarbamate triflate (267 mg, 0.526 mmol) in NMP (10 mL) was added K2CO3 (218 mg, 1.577 mmol). The mixture was heated with a microwave reactor at 160° C. for 1 h. Purification via MDAP then afforded the title compound (60 mg, 21.41% yield). LCMS: rt=3.58 min, [M+H+]=532.9
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:5][CH:4]=1.Cl[CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[CH:31][C:30]=1[O:38][CH3:39].[C:40](=[O:43])([O-:42])[O-].[K+].[K+].[I-].[K+]>C(O)CCC>[C:23]([OH:22])(=[O:28])[C:40]([OH:42])=[O:43].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[CH:10]2[CH2:15][CH2:14][N:13]([CH2:25][CH2:26][CH2:27][O:28][C:29]3[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[CH:31][C:30]=3[O:38][CH3:39])[CH2:12][CH2:11]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C(c2ccc(OC)cc2)C2CCNCC2)cc1
Reactant: O=C([O-])[O-]
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Product: COc1ccc(C(c2ccc(OC)cc2)C2CCN(CCCOc3ccc(C(C)=O)cc3OC)CC2)cc1
Product: O=C(O)C(=O)O
Yield: 54.8 %

Procedure:
A mixture of 7.78 g (0.025 mole) of 4-[bis(4-methoxyphenyl)methyl]piperidine, 6.05 g (0.025 mole) of 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone, and potassium carbonate (5.53 g, 0.04 mole) in 300 ml of 1-butanol containing potassium iodide (0.3 g) was refluxed overnight. The reaction mixture was stripped to dryness and the residue was partitioned between chloroform and water; removal of chloroform in vacuo gave a dark brown oil. The oil was subjected to column chromatography on silica gel using a gradient elution composed of methanol and ethyl acetate. The corresponding fractions from the column were combined and reacted with oxalic acid. Recrystallization of the salt from methanol-diethyl ether gave 4.16 g (27.4%) of white solid, m.p. 163.5°-165° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=N[CH:7]=1.O.[C:11]([OH:15])(=O)[CH:12]=O.[BH4-].[Na+].[CH3:18]O>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:18][CH:7]=1)[NH:8][C:11](=[O:15])[CH2:12][NH:9]2
Reactant: O=CC(=O)O
Reactant: CO
Reactant: Nc1cc(Br)cnc1N
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: O=C1CNc2cc(Br)ccc2N1
Temperature: 50 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
5-bromo-2,3-diaminopyridine (2.0 g, 10.6 mmol) and glyoxylic acid monohydrate (1.23 g, 13.4 mmol) were combined in water (55 mL), sonicated for 10 minutes and stirred overnight. The product was filtered, washed with water (5×100 mL) and dried under vacuum to afford 2.214 g of crude product. To a suspension of this material in methanol (100 mL) was added NaBH4 (1.0 g, 26.3 mmol) with periodic cooling in an ice water bath to maintain reaction temperature below 35° C. After stirring for 4 hours, the reaction was quenched with 6N HCl (20 mL) and the resulting mixture stirred overnight. The mixture was warmed to 50° C. for 0.5 hour before removing volatile solvents by rotary evaporation. After adjusting the pH of the aqueous reside to 8 by the addition of 10N NaOH, the product was removed by filtration and washed with water (5×50 mL) to give the title compound (1.985 g, 82%). m.p. 265° C. (dec), 1H-NMR (DMSO-d6, 400 MHz) δ 10.47 (s, 1H), 7.65 (d, J=2.1 Hz, 1H), 7.01-6.99 (m, 2H), 3.94 (s, 2H).