Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:4]([F:17])=[CH:5][N:6]=[C:7]2[C:12]=1[N:11]=[C:10]([O:13]CC=C)[CH:9]=[CH:8]2)[CH3:2].[C:18]1(C)[C:19](C)=CC=C[CH:23]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([C:3]1[C:4]([F:17])=[CH:5][N:6]=[C:7]2[C:12]=1[N:11]([CH2:19][CH:18]=[CH2:23])[C:10](=[O:13])[CH:9]=[CH:8]2)[CH3:2]
Reactant: C=CCOc1ccc2ncc(F)c(CC)c2n1
Reactant: Cc1ccccc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: C=CCn1c(=O)ccc2ncc(F)c(CC)c21
Temperature: 150 °C
Yield: 27 %

Procedure:
8-Ethyl-7-fluoro-2-(2-propen-1-yloxy)-1,5-naphthyridine (0.660 g, 2.84 mmol) was dissolved in xylene (14 ml) at rt under argon, whereupon tetrakis(triphenylphosphine)palladium (0.329 g, 0.284 mmol) was added. The reaction was then heated to 150° C. for 30 mins. Reaction was then cooled, a solid then precipitated out which was filtered. The filtrate was then purified by column chromatography on silica gel eluting with 0-100% EtOAc in hexane then 0-20% MeOH in EtOAc gradient to give title compound as a white solid (0.181 g, 27%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][C@H:2]1[C:7]([OH:9])=O.Cl[C:11]1[C:20]([N+:21]([O-])=O)=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][N:12]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.C(Cl)Cl.[Pt].[NH4+].[O-][V](=O)=O.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>[O:9]=[C:7]1[NH:21][C:20]2[CH:19]=[C:14]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=[N:12][C:11]=2[N:1]2[CH2:6][CH2:5][S:4][CH2:3][C@@H:2]12
Reactant: O=C(O)[C@@H]1CSCCN1
Reactant: COC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Agent: O=[V](=O)[O-]
Agent: [Pt]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)c1cnc2c(c1)NC(=O)[C@@H]1CSCCN21
Temperature: 25 °C
Reaction time: 24 h
Yield: 51 %

Procedure:
To a suspension of (R)-thiomorpholine-3-carboxylic acid (1.009 g, 6.86 mmol) in THF was added methyl 6-chloro-5-nitronicotinate (1.35 g, 6.23 mmol) and potassium carbonate (2.58 g, 18.70 mmol). The suspension was heated to reflux for 3 hours. The crude orange solution was allowed to cool to RT and filtered through a pad of celite which was washed with DCM (50 mL), and transferred to a bomb hydroginator. To the solution was added triphenyl phosphite (0.019 ml, 0.061 mmol), platinum (0.238 g, 0.061 mmol), and ammonium metavanadate. The vessel was sealed and pressurized to 140 psi with stirring for 24 h at room temperature. The vessel was depressurized and the mixture was diluted with DCM (100 mL) and refluxed for 30 minutes. The hot mixture was filtered through celite and concentrated to yield 887 mg (52%) of the product as a white solid. [M+H] calc'd for C12H13N3O3S, 280; found, 280.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[N+:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([O-:11])=[O:10].Cl>C(Cl)Cl>[C:5]([C:21]1[CH:20]=[CH:19][C:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N+:9]([O-:11])=[O:10])=[CH:23][CH:22]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)Cl
Reactant: O=[N+]([O-])c1ccccc1-c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc(-c2ccccc2[N+](=O)[O-])cc1

Procedure:
A suspension of 96.0 g. of aluminum chloride and 135 ml. of methylene chloride is stirred and treated with a mixture of 60 ml. of methylene chloride, 63 ml. of acetyl chloride, and 77.4 g. of 2-nitrobiphenyl. The mixture is heated at reflux for three hours and cautiously poured into 1200 g. of ice and 900 ml. of concentrated hydrochloric acid. The mixture is extracted with methylene chloride. The extract is washed with water and aqueous sodium bicarbonate, dried (Na2SO4), and the solvent removed to give a dark oil. This is stirred with 200 ml. of ether and the resulting solid recovered and washed with 1:1 ether:Skellysolve B; yield 53.50 g., m.p. 106°-109°. For analysis a sample is recrystallized from ether; m.p. 108°-111°.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][CH2:28][CH:27]([CH2:31][OH:32])[CH2:26]2)=[CH:21][C:5]=1[C:6]([NH:8][C:9]1[C:10]([CH3:20])=[C:11]([CH:16]=[CH:17][C:18]=1[CH3:19])[C:12]([O:14]C)=[O:13])=[O:7].CCO>O.C1COCC1>[F:3][C:4]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][CH2:28][CH:27]([CH2:31][OH:32])[CH2:26]2)=[CH:21][C:5]=1[C:6]([NH:8][C:9]1[C:10]([CH3:20])=[C:11]([CH:16]=[CH:17][C:18]=1[CH3:19])[C:12]([OH:14])=[O:13])=[O:7]
Reactant: COC(=O)c1ccc(C)c(NC(=O)c2cc(N3CCCC(CO)C3)ccc2F)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)O)c(C)c1NC(=O)c1cc(N2CCCC(CO)C2)ccc1F
Reaction time: 4 h
Yield: 23.2 %

Procedure:
A solution of NaOH (0.146 mg, 0.00366 mol) in 1.5 ml of H2O is added to a stirred solution of methyl 3-[[2-fluoro-5-[3-(hydroxymethyl)-1-piperidyl]benzoyl]amino]-2,4-dimethyl-benzoate (0.38 g, 0.000916 mol) in THF:EtOH (3 ml:2 ml). After 4 hours at ambient temperature, the organic solvent is removed under reduced pressure and the residue is diluted with water, acidified to pH 4 with 1N HCl, and extracted with ethyl acetate. The organic layer are combined and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure to afford the title compound as a light yellow solid (85 mg g, 36.8%). Mass spectrum (m/z): 401.2 (M+1).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:17])([F:16])[F:15])[CH2:5][CH2:4][N:3]1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[CH:23][CH:22]=1)(=[O:20])=[O:19].[Si]([C:34]([F:37])([F:36])[F:35])(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C([O-])(O)=O.[Na+]>[F:35][C:34]([F:37])([F:36])[C:27]([C:24]1[CH:23]=[CH:22][C:21]([S:18]([N:3]2[CH2:4][CH2:5][N:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:14]([F:16])([F:17])[F:15])[CH2:7][C@H:2]2[CH3:1])(=[O:20])=[O:19])=[CH:26][CH:25]=1)([OH:29])[CH3:28]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC(=O)c1ccc(S(=O)(=O)N2CCN(c3ccccc3C(F)(F)F)C[C@H]2C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@@H]1CN(c2ccccc2C(F)(F)F)CCN1S(=O)(=O)c1ccc(C(C)(O)C(F)(F)F)cc1
Reaction time: 4 h
Yield: 31.8 %

Procedure:
To a 50 mL flask containing (R)-1-{4-[2-methyl-4-(2-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-phenyl}-ethanone (200 mg, 0.47 mmol) and 2.34 mL of 0.5 M TMS-CF3, was added 0.47 mL of 1.0 M tetrabutylammonium fluoride in THF at 0° C. After stirring for 4 h, the solution was diluted with saturated NaHCO3, extracted (2×CH2Cl2), washed with brine and dried over Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography to yield 1,1,1-trifluoro-2-[4-({(2R)-2-methyl-4-[2-(trifluoromethyl)phenyl]piperazin-1-yl}sulfonyl)phenyl]propan-2-ol in 31.8% yield (74.1 mg) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](=[O:8])[NH:4][C:3]=1[C:9]#[N:10].[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].N1C=CN=C1>CN(C=O)C.O>[Br:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([O:8][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: N#Cc1[nH]c(=O)ccc1Br
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Br)c(C#N)n1
Reaction time: 8 h

Procedure:
A solution of 3-bromo-6-oxo-1,6-dihydropyridine-2-carbonitrile (from step 2) (1.0 eq.), tert-butyldimethylsilylchloride (TBSCl) (1.8 eq.), and imidazole (2.5 eq.) in DMF (0.2 M) was heated to 60° C. and stirred overnight. The reaction mixture was diluted with water and extracted with ether. The combined organic layers were dried over anhydrous MgSO4 and concentrated en vacuo. The residue was purified by a COMBIFLASH® system (ISCO) using 0-20% ethyl acetate in hexane to give 3-bromo-6-(tert-butyldimethylsilyloxy)picolinonitrile.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].CS(O)(=O)=O.[H][H]>C(O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH:5]2[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)Cc1c[nH]c2ccc(F)cc12
Reactant: [H][H]
Agent: [Pd]
Agent: CS(=O)(=O)O
Solvent: CCO
Product: CCOC(=O)CC1CNc2ccc(F)cc21

Procedure:
A mixture of ethyl (5-fluoro-1H-indol-3-yl)acetate (Bullock et al. J. Am. Chem. Soc. 1951, 73, 5155-5157) (72.5 g, 0.33 mol), 70% methane sulfonic acid (aq) (50 mL) and palladium (5 wt %, dry basis) on activated carbon (20 g) in ethanol (700 mL) was treated with hydrogen at 3 bar and 50° C. for 48 h. The mixture was filtered and concentrated in vacuo. The residue was dissolved in ethyl acetate, and aqueous ammonia was added. The phases were separated, and the aqueous phase was extracted twice with ethyl acetate. The combined organic phase was washed with brine, dried (MgSO4) and concentrated in vacuo (55 g, 75%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:38]=[CH:39][CH:40]=1)[CH2:6][N:7]([CH:17]1[CH2:22][CH2:21][N:20]([CH:23]([CH3:37])[CH2:24][CH2:25][NH:26][C:27]([C:29]2[C:30]([CH3:36])=[N:31][CH:32]=[N:33][C:34]=2[CH3:35])=[O:28])[CH2:19][CH2:18]1)[C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=1)#[N:2].Cl.[CH3:42][O:43][C:44](=[O:47])[CH2:45][NH2:46]>>[CH3:42][O:43][C:44](=[O:47])[CH2:45][NH:46][C:12](=[O:13])[C:11]1[CH:15]=[CH:16][C:8]([N:7]([CH2:6][C:5]2[CH:38]=[CH:39][CH:40]=[C:3]([C:1]#[N:2])[CH:4]=2)[CH:17]2[CH2:22][CH2:21][N:20]([CH:23]([CH3:37])[CH2:24][CH2:25][NH:26][C:27]([C:29]3[C:34]([CH3:35])=[N:33][CH:32]=[N:31][C:30]=3[CH3:36])=[O:28])[CH2:19][CH2:18]2)=[CH:9][CH:10]=1
Reactant: Cc1ncnc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(C(=O)O)cc2)CC1
Reactant: COC(=O)CN
Agent: Cl
Product: COC(=O)CNC(=O)c1ccc(N(Cc2cccc(C#N)c2)C2CCN(C(C)CCNC(=O)c3c(C)ncnc3C)CC2)cc1
Yield: 40.9 %

Procedure:
Using general procedure E, 4-[(3-cyano-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-benzoic acid (see EXAMPLE 129) (100 mg, 0.26 mmol) and glycine methyl ester hydrochloride (46 mg, 0.37 mmol) afforded COMPOUND 175 as a white solid (65 mg, 57%). 1H NMR (CDCl3) δ 1.04 (d, 3H, J=6.3 Hz), 1.04-1.26 (m, 2H), 1.46-1.62 (m, 1H), 1.67-1.86 (m, 3H), 2.14-2.27 (m, 1H), 2.51 (s, 6H), 2.56-2.65 (m, 1H), 2.70-2.93 (m, 3H), 3.28-3.38 (m, 2H), 3.47-3.53 (m, 1H), 3.67-3.89 (m, 2H), 3.96-4.07 (m, 3H), 4.20, 4.21 (s, 2H), 6.43-6.59 (m, 3H), 7.42-7.58 (m, 4H), 7.64 (d, 3H, J=8.1 Hz), 8.49 (br s, 1H), 8.90 (s, 1H). 13C NMR (CDCl3) δ 13.50, 14.75, 21.97, 25.65, 28.42, 29.32, 30.43, 30.82, 36.04, 36.33, 39.99, 41.65, 43.55, 44.41, 48.02, 51.89, 52.40, 53.80, 55.71, 56.68, 60.17, 111.77, 112.07, 112.78, 118.78, 122.09, 128.89, 129.50, 129.65, 130.72, 130.84, 131.65, 140.87, 150.78, 157.58, 158.34, 163.12, 166.28, 166.90, 170.80, 181.11. ES-MS m/z 612 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:15](Cl)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].O>CN(C)C=O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH3:15])=[CH:4][CH:3]=1
Reactant: CCCCCCCCCCCCCCCCCCCl
Reactant: Oc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCCCCCCCSc1ccc(O)cc1
Temperature: 80 °C
Yield: 69 %

Procedure:
Under a nitrogen atmosphere, p-hydroxythiophenol (126 g) was dissolved in N,N-dimethylformamide (600 ml) and thereto was added potassium carbonate (152 g). Thereto was added octadecyl chloride (318 g), followed by heating at 80° C. for 2 hours. After completion of the reaction, the reaction mixture was poured into water to precipitate a white solid. Thereto was added 5% hydrochloric acid to adjust the pH to acidic state and then, the white solid was filtered off under reduced pressure and then recrystallized from methyl ethyl ketone to obtain the desired product (261 g). Yield 70%; m.p. 95° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:40])[C:7]=1[CH:8]([OH:39])[CH2:9][N:10]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:11]([C:13]1[CH:14]=[N:15][N:16]([C@H:22]2[CH2:27][CH2:26][C@H:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C@@H:24]([CH3:33])[CH2:23]2)[C:17]=1[C:18]([F:21])([F:20])[F:19])=[O:12].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:40])[C:7]=1[C:8](=[O:39])[CH2:9][N:10]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:11]([C:13]1[CH:14]=[N:15][N:16]([C@H:22]2[CH2:27][CH2:26][C@H:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C@@H:24]([CH3:33])[CH2:23]2)[C:17]=1[C:18]([F:20])([F:21])[F:19])=[O:12]
Reactant: CCOC(=O)[C@H]1CC[C@H](n2ncc(C(=O)N(CC(O)c3c(Cl)cncc3Cl)CC(C)(C)C)c2C(F)(F)F)C[C@@H]1C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCOC(=O)[C@H]1CC[C@H](n2ncc(C(=O)N(CC(=O)c3c(Cl)cncc3Cl)CC(C)(C)C)c2C(F)(F)F)C[C@@H]1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a light-yellow clear solution of (1S,2S,4S)-ethyl 4-(4-((2-(3,5-dichloropyridin-4-yl)-2-hydroxyethyl)(neopentyl)carbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylcyclohexanecarboxylate with its (1R,2R,4R)-isomer (0.4702 g, 0.774 mmol) in DCM (12.90 ml) was added Dess-Martin periodinane (0.492 g, 1.161 mmol). The white cloudy mixture was stirred at room temperature. After 2 h, the mixture was quenched with saturated aqueous NaHCO3 (30 mL) and saturated aqueous Na2S2O3 (30 mL). The reaction mixture was extracted with DCM (2×50 mL). The organic extract was dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a colorless syrup. The crude material was absorbed onto a plug of silica gel and purified by silica gel column chromatography eluting with a gradient of 0% to 50% EtOAc in hexane to give (1S,2S,4S)-ethyl 4-(4-((2-(3,5-dichloropyridin-4-yl)-2-oxoethyl)(neopentyl)carbamoyl)-5-(trifluoro methyl)-1H-pyrazol-1-yl)-2-methylcyclohexanecarboxylate with its (1R,2R,4R)-isomer (0.437 g, 0.722 mmol, 93% yield): 1H NMR (400 MHz, CDCl3) δ 8.46-8.61 (2H, m), 7.51-7.74 (1H, m), 4.49-4.92 (2H, m), 4.25-4.39 (1H, m), 4.18 (2H, q, J=7.1 Hz), 3.29-3.61 (2H, m), 1.63-2.18 (8H, m), 1.29 (3H, t, J=7.1 Hz), 0.81-1.06 (12H, m), rotamers present; LCMS (ESI) m/z 605.0 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][O:18][C:19]3[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=3[C:21]([O:23]C)=[O:22])[CH2:12][CH2:11]2)=[CH:2]1.[H-].[Na+].[CH3:31][CH:32]([CH3:36])[CH2:33][CH2:34]I>>[CH3:31][CH:32]([CH3:36])[CH2:33][CH2:34][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][O:18][C:19]3[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=3[C:21]([OH:23])=[O:22])[CH2:12][CH2:11]2)=[CH:2]1
Reactant: CC(C)CCI
Reactant: COC(=O)c1ccccc1OCCN1CCC(c2c[nH]c3ccccc23)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)CCn1cc(C2CCN(CCOc3ccccc3C(=O)O)CC2)c2ccccc21

Procedure:
This compound was prepared following the procedure described in Example 138 (part B) starting with 3 g (7.9 mmol) of methyl 2-{2-[4-(1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-benzoate, 0.54 g (13.5 mmol) of NaH in 60% of mineral oil and 1.67 g (11.08 mmol) of 3-methylbutyl iodide. The crude mixture was hydrolised following the procedure described in Example 138 (part C) and purified by chromatography over silica gel affording 2.7 g (77% of yield) of the desired product. Melting point=150-151° C.
Reaction SMILES: OC(C(F)(F)F)=O.[N:8]1([CH2:14][C:15]2[N:16]=[N:17][C:18]3[C:19](=[C:21]([NH2:26])[N:22]=[C:23]([NH2:25])[N:24]=3)[N:20]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Br[CH2:28][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=1.C(=O)([O-])[O-].[K+].[K+].CC#N.O>CN(C=O)C>[CH:30]1[C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:37]=[CH:38][C:29]=1[CH2:28][N:11]1[CH2:12][CH2:13][N:8]([CH2:14][C:15]2[N:16]=[N:17][C:18]3[C:19](=[C:21]([NH2:26])[N:22]=[C:23]([NH2:25])[N:24]=3)[N:20]=2)[CH2:9][CH2:10]1
Reactant: Nc1nc(N)c2nc(CN3CCNCC3)nnc2n1
Reactant: BrCc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CC#N
Product: Nc1nc(N)c2nc(CN3CCN(Cc4ccc5ccccc5c4)CC3)nnc2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.7 %

Procedure:
To a stirred solution of 3-Piperazin-1-ylmethyl-pyrimido[5,4-e][1,2,4]triazine-5,7-diamine TFA salt 5 (30 mg; 0.05 mmol; prepared in EXAMPLE 4) in dry DMF (1.0 mL) was added 2-bromomethylnaphthalene (17 mg; 0.075 mmol) followed by potassium carbonate (28 mg; 0.20 mmol). The mixture was allowed to stir for 24 h at room temperature then taken up into CH3CN/H2O/0.1% TFA. The mixture was purified by reverse phase HPLC (Rainin C18, 0% CH3CN to 30% CH3CN gradient, CH3CN/H2O, 0.1% TFA) and the bright yellow fractions containing the product were lyophilized after removal of CH3CN in vacuo to give 19 mg of yellow colored 3-(4-Naphthalen-2-ylmethyl-piperazin-1-ylmethyl)-pyrimido[5,4-e][1,2,4]triazine-5,7-diamine as the trifluoroacetate salt.
Reaction SMILES: [OH-].[K+].CO.O.C(O[C:11]([N:13]1[CH2:18][CH2:17][CH:16]([N:19]2[CH:23]=[C:22]([C:24]([O:26]CC)=[O:25])[CH:21]=[N:20]2)[CH2:15][CH2:14]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+].C=O.O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:11][N:13]1[CH2:14][CH2:15][CH:16]([N:19]2[CH:23]=[C:22]([C:24]([OH:26])=[O:25])[CH:21]=[N:20]2)[CH2:17][CH2:18]1
Reactant: CCOC(=O)c1cnn(C2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CN1CCC(n2cc(C(=O)O)cn2)CC1
Reaction time: 1 h

Procedure:
According to the previously reported procedure, before the basic hydrolysis (KOH/MeOH/water), 4-(4-ethoxycarbonyl-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (776 mg, 2.4 mmol) was dissolved in DCM (24 mL) and treated with TFA (1.85 mL, 24 mmol) for 3 hours. The reaction was poured into saturated NaHCO3 solution (100 mL), extracted with DCM (2×200 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated to dryness to afford 550 mg of crude product that was dissolved in DCM (20 mL) and treated first with TEA (1.058 mL, 7.595 mmol), then with 37 wt. % in water formaldehyde solution (0.22 mL, 2.95 mmol) and finally with sodium triacetoxyborohydride (782 mg, 3.69 mmol) at room temperature, with stirring, under a nitrogen atmosphere. After 1 hour, DCM was added (20 mL) and the organic layer was washed with saturated NaHCO3 solution (25 mL), dried over anhydrous sodium sulfate and evaporated to leave an oil that was employed in the basic hydrolysis step with no further purification affording title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[NH2:20][CH2:21][C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23].C(N(C(C)C)CC)(C)C>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([NH:20][CH2:21][C:22](=[O:23])[NH:24][CH:25]([CH3:27])[CH3:26])=[O:9]
Reactant: O=C(O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: CC(C)NC(=O)CN
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)CNC(=O)c1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 365.4 %

Procedure:
To a solution of 5-fluoro-2-nitrobenzoic acid (2.3 g, 12.4 mmol) in dichloromethane (20 mL) was added oxalyl chloride (3.2 g, 2.2 mL, 24.8 mmol) dropwise. After 1 h the solution was concentrated to dryness. 2-Amino-N-isopropylacetamide (INTERMEDIATE I.1) (0.30 g, 2.6 mmol) was dissolved in dichloromethane (20 mL) and diisopropylethylamine (DIEA) (6.8 mL, 38.9 mmol) added. The acid chloride in dichloromethane (10 mL) was added dropwise and the reaction mixture stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo, the residue dissolved in dichloromethane and washed with 1 N NaOH (aq.), 1 N HCl (aq.) and brine. The organic layers were dried (MgSO4) and concentrated in vacuo to yield 5-fluoro-N-(isopropylcarbamoylmethyl)-2-nitrobenzamide (2.7 g, 9.5 mmol, 81%) as a yellow solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][C:24]([F:27])([F:26])[F:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5])C.[OH-].[K+]>C(O)C>[F:27][C:24]([F:25])([F:26])[O:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=[CH:8]2)[CH:12]=1
Reactant: CCOC(=O)c1cn(-c2cccc(-c3ccccc3OC(F)(F)F)c2)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cn(-c2cccc(-c3ccccc3OC(F)(F)F)c2)cn1

Procedure:
This compound is prepared by hydrolysis of 9f using a 1:1 mixture of aqueous potassium hydroxide (2M) and ethanol.
Reaction SMILES: CO[C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.COC(=O)C1C=CC(OC[C:37]2[C:38]([C:43]3[CH:48]=CC=CC=3F)=[N:39][O:40][C:41]=2C)=NC=1.NC1CCOCC1>>[CH3:17][C:16]1[O:15][N:14]=[C:13]([C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)[C:12]=1[CH2:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([NH:39][CH:38]2[CH2:43][CH2:48][O:40][CH2:41][CH2:37]2)=[O:25])=[CH:5][N:6]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3cccc(C)c3)noc2C)nc1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccc3F)noc2C)nc1
Agent: NC1CCOCC1
Product: Cc1cccc(-c2noc(C)c2COc2ccc(C(=O)NC3CCOCC3)cn2)c1
Yield: 79 %

Procedure:
As described for example 84f, 6-(5-methyl-3-m-tolyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (200 mg, 0.6 mmol) was converted, instead of [6-[3-(2-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester, using 4-aminotetrahydropyran instead of 2,2,2-trifluoroethylamine, to the title compound (190 mg, 79%) which was obtained as a white solid. MS: m/e=408.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].CC([O-])(C)C.[K+].C1(S([C:25]2[CH:30]=[CH:29][C:28]([S:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)(=[O:33])=[O:32])=[CH:27][N:26]=2)(=O)=O)C=CC=CC=1.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[O:9][C:25]1[CH:30]=[CH:29][C:28]([S:31]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)(=[O:33])=[O:32])=[CH:27][N:26]=1
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: O=S(=O)(c1ccccc1)c1ccc(S(=O)(=O)c2ccccc2)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=S(=O)(c1ccccc1)c1ccc(Oc2ccc(Cl)c(Cl)c2)nc1
Temperature: 25 °C
Yield: 68 %

Procedure:
To 4.08 g of 3,4-dichlorophenol dissolved in a 25 ml THF/25 ml DMSO mixture was added 2.9 g of t-BuOK and then 8.99 g of 2,5-bis(phenylsulfonyl)pyridine, and the resulting mixture heated at 58° C. for 11/2 hrs. The reaction mixture was cooled to room temperature, then added to 3 to 4 volumes of water and stirred. The brown precipitate which formed was removed by filtration. Recrystallization from CH2Cl2 /ethanol gave the purified product, 2-(3,4-dichlorophenoxy)-5-(phenylsulfonyl)pyridine, (68% yield), as white shiny needles, m.p. 113°-114° C.