Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]([CH2:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1)[C:5]2=[O:22].C(N(C(C)C)CC)(C)C.[C:32]1([CH2:38][C:39]#[CH:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C.CCOC(C)=O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:22]=[C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:40]#[C:39][CH2:38][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:3]=2)[N:8]=[CH:7][N:6]1[CH2:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1
Reactant: O=C(O)c1ccc(Cn2cnc3ccc(I)cc3c2=O)cc1
Reactant: C#CCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(Cn2cnc3ccc(C#CCc4ccccc4)cc3c2=O)cc1
Temperature: 50 °C
Yield: 77.2 %

Procedure:
To a solution of the compound obtained in Step 1 (0.3 g, 0.739 mmol) in 6.5 ml of DMF, is added diisopropylethylamine (0.381 g, 2.96 mmol), CuI (catalytic amount), 3-phenyl-1-propyne (0.120 g, 1.03 mmol), and Pd(PPh3)2Cl2 (catalytic amount). The reaction mixture is heated to 50° C. for 4 hours. The mixture is then diluted with 150 ml of EtOAc, and washed with 3×100 ml of water, 1×100 ml of brine. The organic layer is then dried over MgSO4, and filtered. The filtrate is concentrated in vacuo. The crude product is triturated with a mixture of hexane/ethyl acetate: 8/1 to yield 225 mg of the pure desired product as a light yellow solid.
Reaction SMILES: [H-].[Na+].[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]1[N:13]=[C:12]([NH2:14])[CH:11]=[N:10][C:9]=1[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][N:16]=1.[C:21](Cl)(=[O:23])[CH3:22]>CN(C=O)C.C(OCC)(=O)C>[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]1[N:13]=[C:12]([NH:14][C:21](=[O:23])[CH3:22])[CH:11]=[N:10][C:9]=1[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][N:16]=1
Reactant: Nc1cnc(-c2ccncn2)c(-c2ccco2)n1
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)Nc1cnc(-c2ccncn2)c(-c2ccco2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 6.8 %

Procedure:
Sodium hydride (42 mg, 1.05 mmol) was added to a stirred solution of 6-(2-furyl)-5-pyrimidin-4-ylpyrazin-2-amine (Example 8, 100 mg, 0.42 mmol) in DMF (4 mL) at 0° C. under nitrogen. The solution was allowed to stir for 30 min. at 0° C. Acetyl chloride (60.0 μL, 0.84 mmol) was then added and the reaction mixture was warmed up to room temperature and stirred for 3 days. The reaction was diluted with ethyl acetate and washed with water. The organic layer was washed with brine, dried (Na2SO4) and evaporated. The residue was purified by silica gel flash chromatography (50% ethyl acetate in hexanes to 75% ethyl acetate in hexanes). Concentration in vacuo of the product-rich fractions provided the titled compound as a pale-yellow solid (8 mg, 7%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH2:13]([N:15](CC)CC)C.CN>CO>[Cl:1][C:2]1[N:7]=[C:6]([NH:15][CH3:13])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: CCN(CC)CC
Agent: CN
Solvent: CO
Product: CNc1nc(Cl)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.7 %

Procedure:
To a cooled (−10° C.) solution of 2,4-dichloro-5-trifluoromethylpyrimidine (20 g, 0.089 mol) in methanol (100 mL) was added triethylamine (12.5 mL, 0.089 mol) and a 2 M solution of methylamine in methanol (45 mL). The reaction was allowed to warm to room temperature and stirred overnight. The reaction was then concentrated and re-dissolved in ethyl acetate. The solution was washed with sat. NaHCO3, brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (5-25% EtOAc in heptane) to give 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (8.6 g, 45%). 1H-NMR (DMSO): δ 8.37 (s, 1H), 7.90 (s, 1H), 2.90 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH:3]1[CH2:8][CH2:7][C:6](=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:5][CH2:4]1.[H][H]>C(OCC)(=O)C.[Pd]>[F:1][C:2]([F:15])([F:16])[CH:3]1[CH2:4][CH2:5][CH:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:7][CH2:8]1
Reactant: [H][H]
Reactant: CCOC(=O)C=C1CCC(C(F)(F)F)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1CCC(C(F)(F)F)CC1
Yield: 79.3 %

Procedure:
To a stirred solution of [4-(trifluoromethyl)cyclohexylidene]-acetic acid, ethyl ester (Example 8 (a)) (1 g) in ethyl acetate (20 mL) was added 5% palladium on carbon (450 mg). The mixture was stirred at room temperature under a 2 bar atmosphere of hydrogen. The reaction mixture was then filtered through diatomaceous earth and concentrated. Purification (SiO2, ethyl acetate:isohexane 1:19 as eluant) gave 4-(trifluoromethyl)-cyclohexaneacetic acid, ethyl ester (800 mg), which was dissolved in methanol (3 mL). Potassium hydroxide (1 g) in water (3 mL) was added and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated and subsequently acidified to pH1 with aqueous 2M hydrochloric acid. The resulting solution was extracted with dichloromethane (3×10 mL) and the combined organic extracts dried, filtered and evaporated to give the sub-title compound as an oil (660 mg).
Reaction SMILES: O.[NH2:2][C:3]1[CH:8]=[C:7]([OH:9])[N:6]=[C:5]([SH:10])[N:4]=1.[CH3:11][CH:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[NH2:2][C:3]1[N:4]=[C:5]([S:10][CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:11])[N:6]=[C:7]([OH:9])[CH:8]=1
Reactant: Nc1cc(O)nc(S)n1
Reactant: CC(Br)c1ccccc1
Solvent: O
Product: CC(Sc1nc(N)cc(O)n1)c1ccccc1

Procedure:
The subtitle compound was prepared according to the procedure of Example 1 step i) treating 4-amino-6-hydroxy-2-mercaptopyrimidine monohydrate (5.0 g) with □-methylbenzyl bromide (5.74 g) to afford the subtitle compound which was used directly in the subsequent step.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([CH3:19])=[N:8][S:9][C:10]=1[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:5].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([Mg]Br)=[CH:24][CH:23]=1>C1COCC1>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:4]([C:6]2[C:7]([CH3:19])=[N:8][S:9][C:10]=2[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:5])=[CH:24][CH:23]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: CON(C)C(=O)c1c(C)nsc1NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: Cc1nsc(NC(=O)OC(C)(C)C)c1C(=O)c1ccc(Cl)cc1
Reaction time: 0.25 h
Yield: 78.3 %

Procedure:
To a solution of tert-butyl 4-(methoxy(methyl)carbamoyl)-3-methylisothiazol-5-ylcarbamate (1.20 g, 3.98 mmol) in THF (30 mL) at −10° C. was added a solution of (4-chlorophenyl)magnesium bromide (1 M in diethylether) (11.95 mL, 11.95 mmol). After a period of 15 min, additional Grignard reagent was added (11.95 mL). After a period of 30 min, the reaction mixture was quenched with saturated ammonium chloride and EtOAc. The organic phase was separated, dried over Na2SO4, filtered and evaporated under reduced pressure. The resulting mixture was purified by flash chromatography (EtOAc/hexane 0:10 to 4:6) to give tert-butyl 4-(4-chlorobenzoyl)-3-methylisothiazol-5-ylcarbamate as an oil (1.1 g). LRMS (M+H)+: 353 m/z.
Reaction SMILES: C([O:3][C:4](=[O:20])[C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][CH2:8]1)=[O:6])C.[OH-].[K+]>CO>[CH2:13]([CH:10]1[CH2:9][CH2:8][N:7]([C:5](=[O:6])[C:4]([OH:20])=[O:3])[CH2:12][CH2:11]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)C(=O)N1CCC(Cc2ccccc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(=O)N1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 86.3 %

Procedure:
A mixture of 15.5 g (56 mmol) of (4-benzylpiperidin-1-yl)oxoacetic acid ethyl ester, 5 g (79.4 mmol) of potassium hydroxide and 250 ml of methanol is stirred at room temperature for 6 h. Then reaction mixture is concentrated, the residue is taken up in water, acidified with 1N hydrochloric acid, the precipitated product is filtered off, washed with water and dried to yield 11.95 g (85%) of the title compound. Mp.: 115° C. (water).
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:4]3[N:14]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:12]=[C:11]([C:21]([O:23]C)=O)[C:5]=3[NH:6][C:7]=2[CH:8]=[CH:9][CH:10]=1.[NH3:25]>CO>[OH:1][C:2]1[C:3]2[C:4]3[N:14]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:12]=[C:11]([C:21]([NH2:25])=[O:23])[C:5]=3[NH:6][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)c1cc(-c2ccccc2)nc2c1[nH]c1cccc(O)c12
Reactant: N
Solvent: CO
Product: NC(=O)c1cc(-c2ccccc2)nc2c1[nH]c1cccc(O)c12
Temperature: 80 °C
Yield: 58 %

Procedure:
A mixture of methyl 9-(benzyloxy)-2-phenyl-5H-pyrido[3,2-b]indole-4-carboxylate (1.28 g, 3.13 mmol), 10% Pd on carbon (0.567 g, 0.533 mmol) and ammonium formate (0.988 g, 15.7 mmol) in EtOH (8 mL) was heated at reflux for 1 hr. This was filtered and the solvent was removed from the filtrate to leave methyl 9-hydroxy-2-phenyl-5H-pyrido[3,2-b]indole-4-carboxylate (1.10 g) which was carried on. A suspension of methyl 9-hydroxy-2-phenyl-5H-pyrido[3,2-b]indole-4-carboxylate (1.1 g, 3.11 mmol) in 7 N NH3 in MeOH (40 mL) in a sealed microwave vial was heated at 80° C. for 48 h. Filtration afford 9-hydroxy-2-phenyl-5H-pyrido[3,2-b]indole-4-carboxamide (675 mg, 1.78 mmol, 58% yield) as a solid. MS (ESI) m/z 304.12 (M+H). 1H NMR (500 MHz, MeOD) δ ppm 8.36 (1H, s), 8.07-8.11 (2H, m), 7.52-7.66 (4H, m), 7.24 (1H, d, J=7.93 Hz), 6.79 (1H, d, J=7.93 Hz).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=1)=[O:4].[F:14][C:15]([F:21])([F:20])[CH2:16][CH2:17][CH2:18][NH2:19]>>[F:14][C:15]([F:21])([F:20])[CH2:16][CH2:17][CH2:18][NH:19][C:11]([C:8]1[CH:7]=[CH:6][C:5]([C:3]([OH:2])=[O:4])=[CH:10][N:9]=1)=[O:13]
Reactant: COC(=O)c1ccc(C(=O)O)nc1
Reactant: NCCCC(F)(F)F
Product: O=C(O)c1ccc(C(=O)NCCCC(F)(F)F)nc1

Procedure:
The title compound was synthesized in two steps. The first as described for Intermediate example I-97, starting from 5-(methoxycarbonyl)pyridine-2-carboxylic acid and 4,4,4-trifluorobutan-1-amine, and the second as described for Intermediate example I-98 at 55° C., starting from the product received in the first step which was first purified by column chromatography using a gradient of ethyl acetate in heptane. Total yield (two steps) 34%; 1H NMR (400 MHz, DMSO-d6) δ ppm 9.16 (t, 1 H), 9.09 (dd, 1 H), 8.44 (dd, 1 H), 8.14 (dd, 1 H), 3.38 (q, 2 H), 2.20-2.36 (m, 2 H), 1.71-1.81 (m, 2 H); MS (ESI) m/z 277[M+H+], m/z 275[M−H+];
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([NH2:8])=[N:3]1.Br[C:10]1[C:11](=[O:18])[N:12]([CH3:17])[N:13]=[C:14]([Cl:16])[CH:15]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:16][C:14]1[CH:15]=[C:10]([NH:8][C:4]2[CH:5]=[C:6]([CH3:7])[N:2]([CH3:1])[N:3]=2)[C:11](=[O:18])[N:12]([CH3:17])[N:13]=1
Reactant: Cn1nc(Cl)cc(Br)c1=O
Reactant: Cc1cc(N)nn1C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(Nc2cc(Cl)nn(C)c2=O)nn1C
Temperature: 100 °C
Yield: 44.7 %

Procedure:
1,5-Dimethyl-1H-pyrazol-3-amine (400 mg, 3.6 mmol, Eq: 1.00) and 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (965 mg, 4.32 mmol, Eq: 1.20) were combined with 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (312 mg, 540 μmol, Eq: 0.15), cesium carbonate (3.52 g, 10.8 mmol, Eq: 3) and tris(dibenzylideneacetone)dipalladium(0) (165 mg, 180 μmol, Eq: 0.05) in dioxane (10.0 ml). The solution was degassed with Ar. The reaction mixture heated at 100° C. for 18 h. The mixture was cooled to room temperature. The solution was diluted with 100 ml DCM. The organic layer was washed with water. The organic layer was dried over MgSO4. Concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 10% to 50% (60:10:1 DCM:MeOH:NH4OH)/DCM gradient) to give 6-chloro-4-(1,5-dimethyl-1H-pyrazol-3-ylamino)-2-methylpyridazin-3(2H)-one (408 mg, 45%). LC/MS-ESI observed [M+H]+ 235.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[C:30]([NH2:37])[CH:29]=3.[CH3:39][C:40]1[N:41]=[CH:42][O:43][C:44]=1[C:45](Cl)=[O:46]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[C:30]([NH:37][C:45]([C:44]1[O:43][CH:42]=[N:41][C:40]=1[CH3:39])=[O:46])[CH:29]=3
Reactant: Cc1ncoc1C(=O)Cl
Reactant: Nc1cc2cc(c1)Nc1nc(ncc1Cl)Nc1cccc(c1)CC2
Solvent: O=C(O)C(F)(F)F
Product: Cc1ncoc1C(=O)Nc1cc2cc(c1)Nc1nc(ncc1Cl)Nc1cccc(c1)CC2
Yield: 55 %

Procedure:
The desired compound was prepared according to the procedure of Example B26, using 6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-11-amine bis(trifluoroacetate) and 4-methyl-1,3-oxazole-5-carbonyl chloride as the starting materials in 55% yield. LCMS for C23H20ClN6O2(M+H)+: m/z=447.2. 1H NMR (400 MHz, DMSO-d6): δ 10.20 (s, 1H), 9.69 (s, 1H), 9.63 (s, 1H), 8.48 (d, 1H), 8.15 (s, 1H), 7.82 (m, 1H), 7.55 (m, 1H), 7.43 (m, 1H), 7.29 (m, 1H), 7.07 (dd, 1H), 6.84 (m, 2H), 2.84 (m, 4H), 2.36 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].Cl>[Cu]Cl.C(O)CCC>[CH2:5]([O:6][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6])[CH2:4][CH2:3][CH3:2]
Reactant: O=Cc1ccc(O)c(Br)c1
Agent: Cl[Cu]
Agent: Cl
Solvent: CCCCO
Product: CCCCOc1cc(C=O)ccc1O
Temperature: 120 °C
Reaction time: 2 h
Yield: 161.1 %

Procedure:
4.3 g (188 mmol) of sodium is put at the bottom of a flask under nitrogen and 40 ml of 1-butanol is poured on top. The reaction mixture is stirred and heated progressively up to 120° C.; as the butanolate formed is sparingly soluble, 20 ml of 1-butanol is added. When all the sodium has been consumed, the reaction mixture is brought back to room temperature and 40 ml of dimethylformamide is added. Under nitrogen, 6.8 g (68.2 mmol) of copper(I) chloride is added and then 12.4 g (62 mmol) of 3-bromo-4-hydroxy-benzaldehyde. The reaction mixture is heated progressively to 120° C. and stirred for 2 hours. After cooling to room temperature and then acidifying to pH5 with aqueous hydrochloric acid of concentration 2M, the reaction mixture is extracted with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered, and evaporated. After trituration and then recrystallization of the residue from pentane, 9.7 g (81%) of 3-butoxy-4-hydroxy-benzaldehyde is obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Sn](C)(C)C)([CH3:4])([CH3:3])[CH3:2].Cl[C:20]1[CH:25]=[N:24][CH:23]=[CH:22][N:21]=1>O1CCOCC1.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.[Cu+]>[N:21]1[CH:22]=[CH:23][N:24]=[CH:25][C:20]=1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[NH:7][C:6](=[O:18])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1[Sn](C)(C)C
Reactant: Clc1cnccn1
Agent: [Cu+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1ccccc1-c1cnccn1
Temperature: 25 °C
Yield: 61 %

Procedure:
(2-Trimethylstannyl-phenyl)-carbamic acid tert-butyl ester (Bioorganic & Medicinal Chemistry,1998, 6,811-823) (1.4 g, 3.93 mmol), 2-chloropyrazine (0.5 g, 4.33 mmol, 1,1 eq), tetrakis(triphenylphosphine)palladium (0.18 g, 0.156 mmol), and copper (I) b (0.022 g, 0.156 mmol), in 1,4-dioxane (10 mL) were heated at 110° C. for 75 min. The reaction mixture was allowed to cool at room temperature. The crude product was adsorbed onto silica gel and purified by column chromatography to give 0.65 g of tert-butyl 2-(2-pyrazinyl)phenylcarbamate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[N:9][C:10]([O:12][Si](C)(C)C)=[CH2:11])[CH:5]=[CH:6][CH:7]=1.[CH2:17]([O:19][C:20]([N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([Cl:31])[CH:29]=2)/[C:24](=[CH:32]/[C:33]2[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=2[CH3:40])/[C:23]1=[O:41])=[O:21])[CH3:18].CO>C1(C)C=CC=CC=1>[CH2:17]([O:19][C:20]([N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([Cl:31])[CH:29]=2)[C:24]2([CH:32]([C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[CH2:12][C:10](=[O:11])[NH:9][CH:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:23]1=[O:41])=[O:21])[CH3:18]
Reactant: CCOC(=O)N1C(=O)/C(=C\c2cc(F)ccc2C)c2ccc(Cl)cc21
Reactant: C=C(N=Cc1cccc(Cl)c1)O[Si](C)(C)C
Solvent: CO
Solvent: Cc1ccccc1
Product: CCOC(=O)N1C(=O)C2(c3ccc(Cl)cc31)C(c1cc(F)ccc1C)CC(=O)NC2c1cccc(Cl)c1
Temperature: 135 °C
Yield: 82 %

Procedure:
To a toluene (15 ml) solution of 1-(3-chlorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 1b in toluene (30 ml) was added E/Z-6-chloro-3-(5-fluoro-2-methyl-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester (0.16 g, 0.45 mmol) prepared in example 145b. The reaction tube was sealed and heated by microwave irradiation at 135° C. for 35 min. After the solution was cooled to room temperature, methanol (25 mL) was added, and then the mixture was concentrated. The residue was purified by chromatography (EtOAc:CH2Cl2=1:3) to give racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester as a yellow oil (Yield 200 mg, 82%).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[O:24]1[CH2:28][CH2:27][CH:26]([NH:29][C:30]2[CH2:34][S:33][C:32](=[O:35])[N:31]=2)[CH2:25]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:34]2/[C:30]([NH:29][CH:26]3[CH2:27][CH2:28][O:24][CH2:25]3)=[N:31][C:32](=[O:35])[S:33]/2)[CH2:8][CH2:7]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: O=C1N=C(NC2CCOC2)CS1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: O=C1N=C(NC2CCOC2)/C(=C/C2CCN(Cc3ccc(C(F)(F)F)cc3C(F)(F)F)CC2)S1
Temperature: 80 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (2.5 g) in 2-propanol (20 mL) were added 4-(tetrahydrofuran-3-ylamino)-1,3-thiazol-2(5H)-one (2.06 g) and piperidinium acetate (1.07 g). The reaction mixture was stirred at 80° C. for 1 hr, and the solvent was evaporated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.67 g).
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([C:14]#[N:15])=[CH:12][N:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].S(=O)(=O)(O)[OH:23].C(O)C>O>[N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([C:14]([NH2:15])=[O:23])=[CH:12][N:11]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: N#Cc1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Reactant: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: NC(=O)c1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Yield: 93 %

Procedure:
Add 10 g of 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carbonitrile to a mixture of 20 ml of concentrated sulfuric acid and 20 ml of ethanol. Heat the resulting reaction mixture for 1.5 hours in a water bath at 90° to 100° C. Pour the solution onto ice and water to obtain a 93% yield of 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxamide [m.p. 236° to 238° C (from dimethylformamide/methanol)].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[Cl-].[Al+3].[Cl-].[Cl-].COCCOC.CCO.[CH:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:5]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:6])[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(Cl)c1cccc(Br)c1
Reactant: c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: COCCOC
Solvent: CCO
Product: O=C(c1ccccc1)c1cccc(Br)c1
Yield: 92.4 %

Procedure:
1.65 ml (12.50 mmol) 3-Bromobenzoyl chloride was dissolved in 10 ml of dry benzene. This solution was then added cautiously under stirring to a suspension of 2.00 g (15.00 mmol, 1.20 eq.) aluminum chloride in 20 ml dry benzene at 10° C. After the complete addition the resulting mixture was refluxed for 5 h. After quenching the mixture by adding water and conc. hydrochloric acid the aq. layer was extracted with ethyl acetate. The comb. org. fractions were dried over Na2SO4 and evaporated. Column chromatography (hexanes/ether (9+1)) yielded 3.02 g (11.55 mmol, 92.40%) (3-Bromo-phenyl)-phenyl-methanone as a white solid. Rf.(hexanes/ether (9+1))=0.40. 1H-NMR (500 MHz, CDCl3): δ=7.37 (t, 1H, J=7.88 Hz), 7.51 (m, 2H), 7.62 (tt, 1H, J1=7.41 Hz, J2=1.42 Hz), 7.72 (m, 2H), 7.79 (m, 2H), 7.94 (t, 1H, J=1.80 Hz).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:17]=[C:16]([CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[C:15]([C:25]([F:28])([F:27])[F:26])=[CH:14][C:10]=2[C:11]([OH:13])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[N:38]1[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][N:39]=1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CN(C)C=O>[C:1]1([CH2:7][O:8][C:9]2[CH:17]=[C:16]([CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[C:15]([C:25]([F:28])([F:27])[F:26])=[CH:14][C:10]=2[C:11]([NH:44][C:41]2[CH:42]=[CH:43][N:38]=[N:39][CH:40]=2)=[O:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccnnc1
Reactant: O=C(O)c1cc(C(F)(F)F)c(CN2CCCCC2)cc1OCc1ccccc1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccnnc1)c1cc(C(F)(F)F)c(CN2CCCCC2)cc1OCc1ccccc1
Reaction time: 18 h

Procedure:
To a solution of 2-[(phenylmethyl)oxy]-4-(1-piperidinylmethyl)-5-(trifluoromethyl)benzoic acid (may be prepared as described in Description 53; 112 mg, 0.29 mmol) in N,N-dimethylformamide (5 ml) was added diisopropylethylamine (0.10 ml, 0.57 mmol), 4-pyridazinamine (40.6 mg, 0.43 mmol), 1-hydroxy-7-azabenzotriazole (50.4 mg, 0.37 mmol) and EDC (109 mg, 0.57 mmol). The reaction was stirred for 18 hours, then the solvent removed in vacuo to give a yellow oil. Purification by MDAP gave the title compound as a white solid. 66 mg.