Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:19]1[N:24]=[C:23]([NH2:25])[N:22]=[C:21]([NH:26][CH3:27])[CH:20]=1>CN(C=O)C>[NH2:25][C:23]1[N:24]=[C:19]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([I:1])[CH:10]=3)[C:6]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])=[N:7]2)[CH:20]=[C:21]([NH:26][CH3:27])[N:22]=1
Reactant: CNc1cc(Cl)nc(N)n1
Reactant: CN(C)C(=O)c1n[nH]c2cc(I)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNc1cc(-n2nc(C(=O)N(C)C)c3ccc(I)cc32)nc(N)n1
Temperature: 180 °C

Procedure:
To a suspension of 6-iodo-N,N-dimethyl-1H-indazole-3-carboxamide (100 mg, 0.32 mmol) at 0° C. in DMF (3 mL) was added sodium hydride (19 mg of a 60% dispersion in mineral oil, 0.47 mmol). The reaction mixture was allowed to warm to RT over 15 minutes before the addition of 6-chloro-4-N-methylpyrimidine-2,4-diamine (75 mg, 0.47 mmol). The reaction mixture was then heated at 180° C. for 2 hr. The reaction mixture was allowed to cool to RT. The mixture was cooled to 0° C. and quenched by addition of water (1 mL) and the volatiles evaporated in vacuo. The mixture was diluted with sat ammonium chloride (20 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried (Na2SO4), filtered and evaporated in vacuo. Purification of the residue by column chromatography (Biotage, 55-100% ethyl acetate: heptanes) gave the title compound: 1H NMR (500 MHz, DMSO) delta 2.78 (3H, s), 3.08 (3H, s), 3.42 (3H, s), 6.24 (1H, s), 6.48 (2H, s), 7.08 (1H, s), 7.64 (1H, m), 7.79 (1H, m), 9.40 (1H, s); LC-MS: m/z=+438.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH:14]([NH2:16])=O>CC(C)=O>[O:5]=[C:4]1[C:3]2[C:2](=[CH:10][C:9]([C:11]([OH:13])=[O:12])=[CH:8][CH:7]=2)[N:1]=[CH:14][NH:16]1
Reactant: NC=O
Reactant: Nc1cc(C(=O)O)ccc1C(=O)O
Solvent: CC(C)=O
Product: O=C(O)c1ccc2c(=O)[nH]cnc2c1
Temperature: 180 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
A mixture of 2-amino terephthalic acid (2 g, 11 mmol) and formamide (10 mL) was heated at 180° C. for 5 h. The reaction mixture was cooled to RT and acetone was added. The solid precipitated thus obtained was stirred for 2 h, filtered and dried to give 4-oxo-3,4-dihydroquinazoline-7-carboxylic acid in 80% yield.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]#[N:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(CCN(C)C)C.[Li]CCCC.[C:26]1(=[O:32])[CH2:31][CH2:30][CH2:29][CH:28]=[CH:27]1.Cl>COCCOC>[C:1]1([S:7]([CH:10]([CH:28]2[CH2:29][CH2:30][CH2:31][C:26](=[O:32])[CH2:27]2)[C:11]#[N:12])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1C=CCCC1
Reactant: N#CCS(=O)(=O)c1ccccc1
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: COCCOC
Product: N#CC(C1CCCC(=O)C1)S(=O)(=O)c1ccccc1
Temperature: -10 °C
Reaction time: 0.75 h
Yield: 57.2 %

Procedure:
To 9.4 g (0.052 mol) of benzenesulfonyl-acetonitrile in 200 mL of DME at −50° C., 7.8 mL (0.052 mol, 1 eq) of TMEDA and 32.4 mL (0.052 mL, 1 eq) of nBuLi (1.6M in hexane) were added and stirring was continued for 45 min. To the resulting white suspension, 4.98 g (0.052 mol, 1 eq) of cyclohex-2-enone were added and the temperature was raised to −10° C. within 4 hours. The reaction mixture was poured into 180 mL of 1M HCl, extracted with EtOAc, and the combined organic phases dried over Na2SO4. Evaporation of the solvent and recrystallisation from AcOEt/Et2O yielded 8.25 g (57%) of benzenesulfonyl-(3-oxo-cyclohexyl)-acetonitrile as a racemic mixture of diastereomers, white crystals, MS: 278 (MH+) (in analogy to: E. Hatzigrigoriou, L. Wartski, Synth. Comm., 1983, 14(4), 319-235).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[O:21][C:20](=[O:22])[N:19]([CH3:23])[N:18]=2)[CH2:13][CH2:12]1.O.O.Cl[Sn]Cl>CO>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[O:21][C:20](=[O:22])[N:19]([CH3:23])[N:18]=3)[CH2:13][CH2:12]2)=[C:2]([F:1])[CH:7]=1
Reactant: Cn1nc(C2CCN(c3ccc([N+](=O)[O-])cc3F)CC2)oc1=O
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: Cn1nc(C2CCN(c3ccc(N)cc3F)CC2)oc1=O
Yield: 78.7 %

Procedure:
5-[1-(2-Fluoro-4-nitrophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadazol-2-one (5b, 1.23 g, 4 mmol) on reacting with CH3I (0.68 g, 4.8 mmol) in DMF in the presence of base K2CO3 (1.38 g, 10 mmol) at 0° C. for 10 h, after completion of the reaction, reaction mixture is poured into ice water and extracted into chloroform finally purification by column chromatography to afford pure compound 5-[1-(2-fluoro-4-nitrophenyl)-4-piperidyl]-3-methyl-2,3-dihydro-1,3,4-oxadiazol-2-one (6d, 1.18 g, 92%). Nitro compound (6d, 1.29 g, 4 mmol) on reduction with SnCl2.2H2O (2.71 g, 12 mmol) in methanol and refluxed at 65° C. for 4 h, after completion of reaction methanol is evaporated under vacuum and to this saturated sodium bicarbonate solution is added to quench the excess stannous chloride and filtered through celite bed and purified in silica column (60-120) to afforded pure compound 5[1-(4-amino-2-fluorophenyl)-4-piperidyl]-3-methyl-2,3-dihydro-1,3,4-oxadiazol-2-one (7f, 920 mg, 83%). To a stirred solution of 5-nitro2-furanoic acid in DMF add HOBT (Hydroxybenzotriazole) (0.14 g, 1 mmol), EDCI (1-Ethyl-3-(3-dimethylaminopropyl)carbodi imide)) (0.19 g, 1 mmol) and amine compound (7f, 0.29 g, 1 mmol) and stirred for 2 h at room temperature (27° C.), after completion of the reaction, reaction mixture is poured into ice water and extracted into chloroform finally purification by column chromatography using ethyl acetate-hexane (7:3) as eluant to afford pure compound N2-3-fluoro-4-[4-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidino]phenyl-5-nitro-2-furamide (8f, 375 mg, 87%).
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][C:15]=1[CH3:23].[NH2:24][CH2:25][CH2:26][N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH:24][CH2:25][CH2:26][N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:20])=[CH:16][C:15]=1[CH3:23]
Reactant: NCCN1CCCC1
Reactant: Cc1cc(C(=O)O)ccc1Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C(=O)NCCN2CCCC2)ccc1Br
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1-Ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (2.68 g) was added to a solution of 4-bromo-3-methyl benzoic acid (3.0 g), 1-(2-aminoethyl)pyrrolidine (1.78 ml) and 1-hydroxybenzotriazole hydrate (1.89 g) in dry N,N-dimethylformamide (30 ml). The reaction was stirred at room temperature for 24 hours. The solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with brine. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluting with dichloromethane:methanol (9:1) to give the sub-title compound as an oil. (3.55 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=1)[NH:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])=[S:7].[Cl-].[NH4+].CO>[Zn].O>[CH3:1][O:2][C:3](=[O:26])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1)[NH:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])=[S:7]
Reactant: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=S)c1c(C)cccc1Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Product: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=S)c1c(C)cccc1Cl
Temperature: 55 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
To a mixture of N-[(2-chloro-6-methylphenyl)thioxomethyl]-4-nitro-L-phenylalanine methyl ester (3.86 mmol, 1.52 g), zinc dust (˜325 mesh, 39.0 mmol, 2.55 g, 10 equiv.) and ammonium chloride (58.0 mmol, 3.09 g, 15 equiv.) was added methanol (50 mL) and water (25 mL) at room temperature. After addition of water, an exothermic reaction ensued and the temperature rose to between 45 and 50° C. After the suspension was stirred for 2 h at a bath temperature of 50-60° C., TLC analysis of the mixture indicated the absence of starting material. The reaction mixture was filtered through a pad of celite and the filter cake was washed with methanol (50 mL) and water (40 mL). The filtrate was concentrated under vacuum to remove methanol and the product was extracted into ethyl acetate (2×50 mL). The combined extracts were washed with brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo to give 1.3 g (92%) of 4-amino-N-[(2-chloro-6-methylphenyl)thioxomethyl]-L-phenylalanine methyl ester as an amorphous yellow solid, which was used directly for next step. HRMS: Obs. mass, 363.0932. Calcd. mass, 363.0934 (M+H).
Reaction SMILES: [CH2:1]([N:4]1[C:9]([C:10]([O:12]C)=O)=[C:8]([OH:14])[C:7]2[CH:15]=[CH:16][CH:17]=[CH:18][C:6]=2[S:5]1(=[O:20])=[O:19])[CH2:2][CH3:3].[NH2:21][C:22]1[CH:27]=[N:26][CH:25]=[C:24]([Cl:28])[N:23]=1>C1(C)C(C)=CC=CC=1>[Cl:28][C:24]1[N:23]=[C:22]([NH:21][C:10]([C:9]2[N:4]([CH2:1][CH2:2][CH3:3])[S:5](=[O:20])(=[O:19])[C:6]3[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=3[C:8]=2[OH:14])=[O:12])[CH:27]=[N:26][CH:25]=1
Reactant: Nc1cncc(Cl)n1
Reactant: CCCN1C(C(=O)OC)=C(O)c2ccccc2S1(=O)=O
Solvent: Cc1ccccc1C
Product: CCCN1C(C(=O)Nc2cncc(Cl)n2)=C(O)c2ccccc2S1(=O)=O
Yield: 51.9 %

Procedure:
2.97 g (10 mmols) of methyl 2-n-propyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide and 1.3 g (10 mmols) of 2-amino-6-chloro-pyrazine were reacted in 150 ml of xylene analogous to Example 1, yielding 2.05 g (52% of theory) of N-(6-chloro-pyrazin-2-yl)-4-hydroxy-2-n-propyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][C:15]3([C:25]([O:27][CH3:28])=[O:26])[CH2:17][O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[CH:14]3[NH:13]2)=[O:11])=[CH:5][CH:4]=1.[CH3:31][N:32]=[C:33]=[O:34]>CCOCC.C(N(CC)CC)C>[CH3:31][NH:32][C:33]([N:13]1[CH:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[O:18][CH2:17][C:15]2([C:25]([O:27][CH3:28])=[O:26])[CH2:16][N:12]1[C:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:29])[F:30])=[CH:4][CH:5]=1)=[O:11])=[O:34]
Reactant: COC(=O)C12COc3ccccc3C1NN(C(=O)Nc1ccc(C(F)(F)F)cc1)C2
Reactant: CN=C=O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CNC(=O)N1C2c3ccccc3OCC2(C(=O)OC)CN1C(=O)Nc1ccc(C(F)(F)F)cc1
Reaction time: 0.5 h
Yield: 53 %

Procedure:
The product (0.125 g, 0.000296 mol) of Example 6, Step B was dissolved in 5 mL ether and 0.023 g of methyl isocyanate was added and stirred for 30 min. Three drops of triethylamine was added and the reaction was stirred for 18 hours at room temperature. A white precipitate had formed, was filtered, rinsed with ether and dried to afford 0.075 g of a white solid; mp 208°-209° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.C(O)(=O)CC.[N+:17]([O-])([OH:19])=[O:18]>C(O)C>[N+:17]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=2)([O-:19])=[O:18]
Reactant: Oc1ccnc2ccccc12
Reactant: O=[N+]([O-])O
Solvent: CCC(=O)O
Solvent: CCO
Product: O=[N+]([O-])c1cnc2ccccc2c1O
Temperature: 125 °C
Yield: 86 %

Procedure:
4-Hydroxyquinoline (26.2 g, 0.18 mol) was added to propionic acid (250 mL) and the solution was heated to about 125° C. Nitric acid (16.0 mL of a 70 percent aqueous solution, 0.36 mol) was added dropwise with stirring. When the addition was complete, the mixture was stirred at about 125° C. for 10 minutes, then allowed to cool to room temperature. The mixture was diluted with ethanol. The precipitated solid was filtered, washed sequentially with ethanol, water, and ethanol, and dried to afford 3-nitro-4-hydroxyquinoline (27.7 g, 86%) as a light yellow powder.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[O:7]=[C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:19][CH3:20])=[C:15]([OH:18])[CH:16]=2)[N:11]=[CH:10][NH:9]1.CS(O[C@H:26]1[CH2:31][CH2:30][C@H:29]([N:32]2[CH2:37][CH2:36][N:35]([CH3:38])[C:34](=[O:39])[CH2:33]2)[CH2:28][CH2:27]1)(=O)=O.O>CN1CCCC1=O>[O:7]=[C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:19][CH3:20])=[C:15]([O:18][C@H:26]3[CH2:27][CH2:28][C@H:29]([N:32]4[CH2:37][CH2:36][N:35]([CH3:38])[C:34](=[O:39])[CH2:33]4)[CH2:30][CH2:31]3)[CH:16]=2)[N:11]=[CH:10][NH:9]1
Reactant: CN1CCN([C@H]2CC[C@H](OS(C)(=O)=O)CC2)CC1=O
Reactant: COc1cc2nc[nH]c(=O)c2cc1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1cc2nc[nH]c(=O)c2cc1O[C@H]1CC[C@H](N2CCN(C)C(=O)C2)CC1
Reaction time: 20 h

Procedure:
2.4 g sodium carbonate are added to 2 g of 3,4-dihydro-4-oxo-6-hydroxy-7-methoxy-quinazoline (VII) in 16 ml N-methyl-2-pyrrolidinone at 130° C. Then six times 600 mg (in total: 2.4 g) (trans)-1-methanesulphonyloxy-4-(4-methyl-3-oxo-piperazin-1-yl)-cyclohexane (II) are added stepwise at 130° C. within 4 h and the mixture is kept at 130° C. for 20 h. After 10 days, 25 ml of water are added and the mixture is extracted with 25 ml isopropyl acetate, 50 ml of dichloromethane and 25 ml of dichloromethane. The organic phases are evaporated down and the residue is separated off by preparative HPLC. 500 mg of the product are obtained.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[S:5][C:6]=1[CH:7]([OH:11])[CH2:8][CH:9]=[CH2:10].[OH2:22].[OH-].[Na+].OO>O1CCCC1.C(OCC)(=O)C>[CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][CH:13]=2)[S:5][C:6]=1[CH:7]([OH:11])[CH2:8][CH2:9][CH2:10][OH:22]
Reactant: C=CCC(O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Reactant: O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(O)CCCO
Reaction time: 1 h

Procedure:
To a solution of [rac]-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-but-3-en-1-ol [200 mg, 0.64 mmol; PCT Int. Appl. (2002), WO 02/062774 A1] in tetrahydrofuran (2 ml) was added a 1 M solution of borane-tetrahydrofuran complex in tetrahydrofuran (1.28 ml, 1.28 mmol) at ambient temperature under an argon atmosphere. The yellow solution was stirred for 1 h, water (1 ml), 3 M aqueous NaOH solution (0.2 ml) and 35% aqueous H2O2 solution (0.2 ml) were added and stirring was continued for 1 h. Water and ethyl acetate were added, the layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed two times with brine and dried over sodium sulfate. The solvent was removed under reduced pressure to give 212 mg (0.64 mmol, quant.) of the title compound which was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[C:3]([CH3:23])=[C:4]([C:7]([NH:9][C:10]2[CH:15]=[C:14]([C:16](=[O:21])[NH:17][CH:18]3[CH2:20][CH2:19]3)[CH:13]=[CH:12][C:11]=2[CH3:22])=[O:8])[S:5][CH:6]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26](B(O)O)[CH:25]=1>>[CH:18]1([NH:17][C:16]([C:14]2[CH:13]=[CH:12][C:11]([CH3:22])=[C:10]([NH:9][C:7]([C:4]3[S:5][CH:6]=[C:2]([C:26]4[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=4)[C:3]=3[CH3:23])=[O:8])[CH:15]=2)=[O:21])[CH2:20][CH2:19]1
Reactant: OB(O)c1cccnc1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1scc(Br)c1C
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1scc(-c2cccnc2)c1C

Procedure:
The title compound was prepared by coupling 4-bromo-N-(5-(cyclopropylcarbamoyl)-2-methylphenyl)-3-methylthiophene-2-carboxamide with commercially available 3-pyridylboronic acid using the method described in Step B of Example 136 to afford a white solid (Example 198). HPLC Ret time=1.98 min. LCMS [M+H]+ 392.29.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.O[C:13]1([C:25]2[NH:26][CH:27]=[N:28][CH:29]=2)[CH2:22][CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([C:23]#[N:24])[CH:16]=[CH:15][C:14]1=2.[SH:30][CH2:31][CH2:32][OH:33]>C1(C)C(C)=CC=CC=1.C(=O)(O)[O-].[Na+]>[OH:33][CH2:32][CH2:31][S:30][C:18]1[C:19]2[CH2:20][CH2:21][CH2:22][CH:13]([C:25]3[N:26]=[CH:27][NH:28][CH:29]=3)[C:14]=2[CH:15]=[CH:16][C:17]=1[C:23]#[N:24]
Reactant: OCCS
Reactant: N#Cc1ccc2c(c1)CCCC2(O)c1cnc[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: N#Cc1ccc2c(c1SCCO)CCCC2c1c[nH]cn1
Temperature: 25 °C

Procedure:
5 mol % p-toluenesulphonic acid are added to a solution of 1 mmol of 5-hydroxy-5-(3H-imidazol-4-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile and 2.2 mmol of 2-mercaptoethanol [60-24-2] in 10 ml of xylene, and the mixture is heated to reflux in the presence of molecular sieves (4 Å) overnight. The reaction mixture is cooled to room temperature, diluted with 1M sodium bicarbonate solution and extracted with ethyl acetate (3×). The combined organic phases are dried with sodium sulphate and evaporated. The title compound is identified from the residue on the basis of the Rf by flash chromatography (SiO2 60F).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1)=[O:5])[CH3:2].[CH3:16][Si:17](Cl)([CH3:19])[CH3:18]>>[CH2:1]([NH:3][C:4]([C:6]1[C:15]([Si:17]([CH3:19])([CH3:18])[CH3:16])=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: C[Si](C)(C)Cl
Reactant: CCNC(=O)c1ccc2ccccc2c1
Product: CCNC(=O)c1cc2ccccc2cc1[Si](C)(C)C
Yield: 17 %

Procedure:
N-Ethyl-2-naphthalenecarboxamide was reacted with 2 eq TMSCl according to General Method C. The resulting reaction mixture was worked up in the usual manner, then purified by chromatography with 3:7 ethyl acetate/hexanes to afford 3.3 g of the desired compound as a white solid, a 17% yield. m.p. 132-136° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]4[CH:21]=[CH:20][C:19]([CH2:22][NH2:23])=[CH:18][CH:17]=4)=[CH:13][CH:14]=3)[NH:9][N:8]=2)[CH:4]=[N:3]1.C(N(CC)CC)C.[F:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35](Cl)=[O:36]>O1CCCC1>[F:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35]([NH:23][CH2:22][C:19]1[CH:20]=[CH:21][C:16]([C:12]2[CH:11]=[C:10]3[C:15]([C:7]([C:5]4[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=4)=[N:8][NH:9]3)=[CH:14][CH:13]=2)=[CH:17][CH:18]=1)=[O:36]
Reactant: Cn1cc(-c2n[nH]c3cc(-c4ccc(CN)cc4)ccc23)cn1
Reactant: O=C(Cl)c1cccc(F)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1cc(-c2n[nH]c3cc(-c4ccc(CNC(=O)c5cccc(F)c5)cc4)ccc23)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A 0° C. suspension of Example 31B (70 mg, 0.231 mmol) in tetrahydrofuran (15 ml) was treated with triethylamine (1.00 ml, 7.17 mmol) followed by 3-fluorobenzoyl chloride (0.014 ml, 0.115 mmol) added dropwise. The reaction was allowed to warm to room temperature slowly and after 2 hours was treated with an additional 14 uL acid chloride, stirred for 18 hours, then partitioned between brine and ethyl acetate. The organic extract was dried with MgSO4, concentrated and the residue was purified via by preparative HPLC on a Waters Symmetry C8 column (25 mm×100 mm, 7 μm particle size) using a gradient of 10% to 100% acetonitrile/0.1% aqueous TFA over 8 minutes (10 minute run time) at a flow rate of 40 mL/minute to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.94 (s, 3 H) 4.55 (d, J=5.95 Hz, 2 H) 7.35-7.81 (m, 10 H) 7.99 (s, 1 H) 8.06 (d, J=8.33 Hz, 1 H) 8.37 (s, 1 H) 9.19 (t, J=5.95 Hz, 1 H) 12.98 (s, 1 H). MS (ESI(+)) m/e 426 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:21]=[C:5]2[C:6]([S:10][C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:20])[CH3:19])=[CH:13][CH:12]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([C:35]2[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([C:35]2[CH:40]=[CH:39][C:38]([NH:41][C:2]3[N:21]=[C:5]4[C:6]([S:10][C:11]5[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:20])[CH3:19])=[CH:13][CH:12]=5)=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)=[CH:37][CH:36]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(=O)Nc1ccc(Sc2cccn3nc(Cl)nc23)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CC(=O)Nc1ccc(Sc2cccn3nc(Nc4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)cc4)nc23)cc1

Procedure:
A solution of 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (0.47 g, 2.00 mmol) in dioxane (6.0 mL) was added tris(dibenzylideneacetone)dipalladium(0) (0.256 g, 0.28 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.324 g, 0.56 mmol), N,N-disopropylethylamine (0.52 g, 4.00 mmol), and acetamidothiophenol (0.37 g, 2.20 mmol) under nitrogen. The mixture was degassed with nitrogen for 3 minutes, and then heated to 100° C. for 14 hours. The reaction was cooled to room temperature, filtered through diatomaceous earth, washed with dichloromethane, and concentrated. The residue was diluted with dichloromethane, washed with brine, dried over sodium sulfate, and concentrated. The crude was purified by flash chromatography (silica gel hexane to 5% methanol in dichloromethane) to give N-[4-(2-chloro-[1,2,4]triazolo[1,5-a]pyridine-8-ylsulfanyl)-phenyl]acetamide (0.51 g, 80%). MP=148-150° C. MS=319 (MH)+. 281b) 4-{4-[8-(4-Acetylamino-phenylsulfanyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester was prepared from N-[4-(2-chloro-[1,2,4]triazolo[1,5-a]pyridine-8-ylsulfanyl)-phenyl]acetamide and 4-(4-amino-phenyl)-piperidine-1-carboxylic acid tert-butyl ester with 2,2′-bis-dicyclohexylphosphanyl-biphenyl as the ligand in a manner analogous to Example 2d (0.023 g, 10%). MP=226-228° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 10.2 (s, 1H), 9.69 (s, 1H), 8.62 (d, 1H), 7.72 (m, 2H), 7.55 (m, 2H), 7.49 (m, 2H), 7.12 (m, 2H), 6.91 (m, 1H), 4.18 (bs, 2H), 2.78 (bs, 2H), 2.58 (m, 1H), 2.04 (s, 3H), 1.66 (m, 2H), 1.51 (m, 2H), 1.42 (s, 9H). MS=559 (MH)+.
Reaction SMILES: [NH4+].[N+:2]([C:5]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:6]=1[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:18])([CH3:17])[CH2:15][CH3:16])=[CH:10][C:9]=1[S:19]([O-:22])(=[O:21])=[O:20])([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:2][C:5]1[CH:26]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:24]=[CH:23][C:6]=1[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:18])[CH2:15][CH3:16])=[CH:10][C:9]=1[S:19]([OH:22])(=[O:21])=[O:20]
Reactant: CCC(C)(C)c1ccc(Oc2ccc(C(F)(F)F)cc2[N+](=O)[O-])c(S(=O)(=O)[O-])c1
Agent: [Pd]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: CCC(C)(C)c1ccc(Oc2ccc(C(F)(F)F)cc2N)c(S(=O)(=O)O)c1
Reaction time: 2 h

Procedure:
2-(2-Nitro-4-trifluoromethylphenoxy)-5-(1,1-dimethylpropyl)benzenesulfonic acid, ammonium salt (620 mg) was mixed in ethyl acetate (50 ml) and palladium on carbon (202 mg) was added under argon. The mixture was hydrogenated in a Parr bottle at 55 psi for two hours. The sample was filtered to remove the catalyst, mixed with methanol and degassed for several hours to yield the title compound 1H NMR (250 MHz, CD3OD) ∂7.95 (d, 1H), 7.30 (dd, 1H), 7.05 (dd, 2H), 6.85 (dd, 1H), 6.75 (d, 1H), 1.65 (q, 3H), 1.25 (s, 6H), 0.65 (t, 2H).