Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH3:8][C:9]1([CH3:23])[CH:14]=[C:13]([CH3:15])[CH2:12][C:11]([CH3:17])([CH3:16])[CH:10]1[C:18](=C)[CH2:19]CO.C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[C:5]([O:4][CH2:1][CH2:2][C:18](=[CH2:19])[CH:10]1[C:11]([CH3:17])([CH3:16])[CH2:12][C:13]([CH3:15])=[CH:14][C:9]1([CH3:23])[CH3:8])(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: C=C(CCO)C1C(C)(C)C=C(C)CC1(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(CCOC(C)=O)C1C(C)(C)C=C(C)CC1(C)C

Procedure:
A solution of acetic anhydride (0.23 mL) in dichloromethane (2 mL) was reacted with a mixture of 2,2,4,6,6-pentamethyl-γ-methylene-3-cyclohexene-1-propanol (0.56 g, 0.0025 mol), triethylamine (0.41 mL), 4-dimethylaminopyridine (0.031 g) and dichloromethane at 25° C. Work-up, chromatography and distillation gave 0.60 g of 2,2,4,6,6-pentamethyl-γ-methylene-3-cyclohexene-1-propanol acetate bp (kugelrohr bath 110°-120° C.), 0.5 mm (GLC purity: 88%). 1H-NMR (60 MHz, CDCl3) δ0.93 (6H, s), 1.00 and 1.02 (6H, 2s), 1.60 (3H, s), 2.00 (3H, s), 0.9-2.6 (5H, m), 4.20 (1H, t, J=7 Hz), 4.86-5.07 (3H, m); IR (film) vmax 2960, 1735, 1635, 1440, 1370, 1350 cm-1 ; MS (m/e) 264, 249, 221, 204, 189, 108, 96.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:13])[C:6](=[CH:11][CH:12]=1)[C:7]([O:9][CH3:10])=[O:8].Br[CH2:15][CH2:16][CH3:17].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(OCC)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([O:13][CH2:15][CH2:16][CH3:17])[CH:4]=1
Reactant: COC(=O)c1ccc(OC)cc1O
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOCC
Product: CCCOc1cc(OC)ccc1C(=O)OC

Procedure:
A stirred mixture of methyl 4-methoxysalicylate (25 g), bromopropane (15.6 ml), potassium iodide (2.82 g) and anhydrous potassium carbonate (27.53 g) was heated under reflux for 48 hours. The cooled reaction mixture was filtered and the filtrate was evaporated under reduced pressure to yield an oil which was dissolved in diethyl ether (200 ml). The ethereal solution was extracted with aqueous sodium hydroxide to remove unreacted starting material and the organic phase was then washed with water and brine, dried (magnesium sulphate) and evaporated under reduced pressure to yield methyl 4-methoxy-2-propoxybenzoate, 22.45 g.
Reaction SMILES: C(O[C:4]([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)=[O:5])C.[CH2:11]([Mg]Br)[CH3:12].S(=O)(=O)(O)O>C(OCC)C>[S:8]1[CH:9]=[CH:10][C:6]([C:4]2([OH:5])[CH2:12][CH2:11]2)=[CH:7]1
Reactant: CCOC(=O)c1ccsc1
Reactant: CC[Mg]Br
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: OC1(c2ccsc2)CC1
Reaction time: 1.5 h

Procedure:
1.37 ml (10.00 mmol) ethylthiophene-3-carboxylate and 0.29 ml (1.00 mmol)titanium tetra-isopropyloxide are placed in 5 ml diethyl ether, 21.20 ml (21.20 mmol) ethylmagnesium bromide (Grignard reagent in tetrahydrofuran) in 15 ml diethyl ether are added dropwise within 1 hour, while the temperature should not rise above 20° C. The reaction mixture is stirred for 1.5 hours, then hydrolysed with 10% sulphuric acid. The aqueous phase is extracted with diethyl ether, the combined organic phases are dried and evaporated to dryness. The residue is purified by chromatography. Yield: 0.330 g (24% of theoretical)
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][NH:49][CH2:48]1.[F:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[N:61]=[C:62]=[O:63]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][N:49]([C:62]([NH:61][C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][C:55]=2[F:54])=[O:63])[CH2:48]1
Reactant: O=C(C[C@@H]1CCNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=C=Nc1ccccc1F
Solvent: O=C(O)C(F)(F)F
Product: O=C(C[C@@H]1CCN(C(=O)Nc2ccccc2F)C1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 87 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) and 1-fluoro-2-isocyanatobenzene as the starting materials in 87% yield. LCMS for C30H29ClFN8O2 (M+H)+: m/z=587.0.
Reaction SMILES: C([O:8][C:9](=[O:72])[C@H:10]([CH2:68][CH:69]([CH3:71])[CH3:70])[NH:11][C:12](=[O:67])[C@H:13]([C:63]([CH3:66])([CH3:65])[CH3:64])[NH:14][C:15](=[O:62])[C@H:16]([CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[CH3:61])[NH:17][C:18](=[O:53])[C@H:19]([CH2:44][CH2:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])[NH:20][C:21](=[O:43])[C@H:22]([CH2:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[NH:23][C:24](=[O:34])[CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])C1C=CC=CC=1>CN(C)C=O.[Pd]>[C:30]([O:29][C:27]([CH2:26][CH2:25][C:24]([NH:23][C@H:22]([C:21]([NH:20][C@H:19]([C:18]([NH:17][C@H:16]([C:15]([NH:14][C@H:13]([C:12]([NH:11][C@H:10]([C:9]([OH:72])=[O:8])[CH2:68][CH:69]([CH3:70])[CH3:71])=[O:67])[C:63]([CH3:66])([CH3:65])[CH3:64])=[O:62])[CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[CH3:61])=[O:53])[CH2:44][CH2:45][C:46](=[O:52])[O:47][C:48]([CH3:49])([CH3:50])[CH3:51])=[O:43])[CH2:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:34])=[O:28])([CH3:31])([CH3:33])[CH3:32]
Reactant: Cc1ccccc1C[C@H](NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)CCC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1)C(C)(C)C
Agent: [Pd]
Solvent: CN(C)C=O
Product: Cc1ccccc1C[C@H](NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)CCC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)O)C(C)(C)C
Yield: 96.8 %

Procedure:
A solution of 6.8 g (6.75 mmol) of N-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-α-aspartyl]-O-tert-butyl-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucine benzyl ester in 200 ml of dimethylformamide was hydrogenated over 600 mg of 10% palladium/carbon for 1 hour. The catalyst was removed by filtration and the filtrate was evaporated to give 15 g of crude product which was chromatographed on silica gel using 10-15% methanol in dichloromethane for the elution to give 6 g of N-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-α-aspartyl]-O-tert-butyl-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucine as a white solid of melting point 235-236° C.; MS: m/e 918.4 [M+H]+, m/e 940.3 [M+Na]+.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:9][CH2:10][NH2:11])[CH:5]=[C:6]([I:8])[N:7]=1)[CH3:2].[F:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[C:16]([F:23])=[CH:15][C:14]=1[CH2:24][CH2:25][CH:26]=O>>[F:12][C:13]1[CH:18]=[C:17]([C:19]([F:20])([F:21])[F:22])[C:16]([F:23])=[CH:15][C:14]=1[CH2:24][CH2:25][CH:26]1[NH:11][CH2:10][CH2:9][N:4]2[C:3]([CH2:1][CH3:2])=[N:7][C:6]([I:8])=[C:5]12
Reactant: O=CCCc1cc(F)c(C(F)(F)F)cc1F
Reactant: CCc1nc(I)cn1CCN
Product: CCc1nc(I)c2n1CCNC2CCc1cc(F)c(C(F)(F)F)cc1F

Procedure:
According to the general procedure (GP10), microwave-assisted Pictet-Spengler reaction (60 W; 140° C.; 6.5 bars; 10 min.) between 2-(2-ethyl-4-iodo-imidazol-1-yl)-ethylamine (6.340 mmol) and 3-(2,5-difluoro-4-trifluoromethyl-phenyl)-propionaldehyde (1.509 g; 6.340 mmol) afforded 8-[2-(2,5-difluoro-4-trifluoromethyl-phenyl)-ethyl]-3-ethyl-1-iodo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine. LC-MS: tR=0.79 min.; [M+H]+=485.87 g/mol. Subsequent protection of the secondary amine, and purification by FC (DCM/MeOH=50/1) allowed the isolation of the pure product 8-[2-(2,5-difluoro-4-trifluoromethyl-phenyl)-ethyl]-3-ethyl-1-iodo-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as a slightly beige solid (1.890 g; 51%). LC-MS: tR=0.99 min.; [M+H]+=585.78 g/mol.
Reaction SMILES: Br[C:2]1[C:3]([C:8]2[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[N:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[Na].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][SH:23])=[CH:20][CH:19]=1>>[CH3:13][C:11]1([CH3:14])[CH2:10][O:9][C:8]([C:3]2[C:2]([S:23][CH2:22][C:21]3[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=3)=[CH:7][CH:6]=[CH:5][N:4]=2)=[N:12]1
Reactant: COc1ccc(CS)cc1
Reactant: CC1(C)COC(c2ncccc2Br)=N1
Agent: [Na]
Product: COc1ccc(CSc2cccnc2C2=NC(C)(C)CO2)cc1

Procedure:
The above prepared 3-bromo-2-(4,4-dimethyl-2-oxazolinyl)pyridine is reacted with the sodium salt of p-methoxybenzyl mercaptan by the procedure of Example 1 to give 2-(4,4-dimethyl-2-oxazolinyl)-3-(p-methoxybenzylthio)pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[C:10]([Cl:14])=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[NH2:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][N:24]=1)[C:19]([NH2:21])=[O:20].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CO>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[C:10]([Cl:14])=[CH:9][C:3]=1[O:4][CH2:5][C:6]([NH:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][N:24]=1)[C:19]([NH2:21])=[O:20])=[O:8]
Reactant: O=C(O)COc1cc(Cl)c(Cl)cc1Cl
Reactant: NC(=O)c1ccnc(N)c1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CO
Product: NC(=O)c1ccnc(NC(=O)COc2cc(Cl)c(Cl)cc2Cl)c1
Temperature: 25 °C
Yield: 41.1 %

Procedure:
To solution of (2,4,5-trichloro-phenoxyacetic acid (100 mg, 0.39 mmol), 2-amino isonicotinamide (107 mg, 0.78 mmol) and DMAP (96.22 mg, 0.78 mmol) in DMF 12 ml was added PyBOP (409.7 mg, 0.78 mmol), and stirred room temperature. Reaction mixture was poured onto ice cold water, diluted by methanol/MC mixture (10%). The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSO4, and concentrated. The residue was purified by PLC (EtoAC:Hexane:MeOH=3:6:1-2:4:1) to afford 2-[2-(2,4,5-trichloro-phenoxy)-acetylamino]-isonicotinamide as a colorless solid (0.06 g, 41% yield).
Reaction SMILES: Cl.CN.[C:4]([N:9]1[CH2:14][CH2:13][C:12](=O)[CH:11]([CH3:16])[CH2:10]1)([O:6][CH2:7][CH3:8])=[O:5].[OH-].[K+].[C:19]([BH3-])#[N:20].[Na+]>CO>[C:4]([N:9]1[CH2:14][CH2:13][CH:12]([NH:20][CH3:19])[CH:11]([CH3:16])[CH2:10]1)([O:6][CH2:7][CH3:8])=[O:5]
Reactant: [BH3-]C#N
Reactant: CCOC(=O)N1CCC(=O)C(C)C1
Agent: CN
Agent: Cl
Agent: [K+]
Solvent: CO
Product: CCOC(=O)N1CCC(NC)C(C)C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Methylamine hydrochloride (10 g, 148 mmol) was added to the stirred solution of 1-carbethoxy-3-methyl-4-piperidone (7 g, 37.83 mmol) obtained as described in Preparation 1, in methanol (50 ml) followed by 8.3 g (148 mmol) KOH. Stirring was continued for 3 hr at ambient temperature. The resulting mixture was cooled at 0° C. and sodium cyanoborohydride (3.0 g, 46.0 mmol) was added to it. Cooling was removed after 10 min. and resulting mixture was stirred for 12 hr at ambient temperature. The reaction mixture was concentrated to dryness, triturated with water, acidified with conc. HCl (pH 3˜4) and extracted with ethyl acetate to remove impurities. The aqueous layer was basified with 1 M sodium hydroxide solution (pH˜10) and extracted with ethyl acetate. Ethyl acetate extract was dried (Na2SO4) and concentrated to dryness to give 1-carbethoxy-4-methylamino-3-methylpiperidine. Yield 4.0 g (50%), C10H20N2O2, m/z 201 (M+1), PMR (CDCl3): 0.92 (dd, 3H), 1.26 (t, 3H), 1.54 (m, 1H), 2.1 (m, 2H), 2.34 (s, 3H), 2.62 (m, 1H) 2.86 (m, 1H), 3.06 (m, 1H), 3.46 (m, 1H), 3.72 (m, 1H), 4.1 (q, 2H).
Reaction SMILES: [F:1][C:2]([F:34])([CH2:29][C@@H:30]([CH3:33])[CH2:31][CH3:32])[CH:3]([OH:28])[CH2:4][CH2:5][C@H:6]1[C@H:10]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH2:9][C@H:8]([OH:18])[C@@H:7]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26].C(N(C(C)C)CC)(C)C.[CH2:44](Br)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C(#N)C>[F:34][C:2]([F:1])([CH2:29][C@@H:30]([CH3:33])[CH2:31][CH3:32])[CH:3]([OH:28])[CH2:4][CH2:5][C@H:6]1[C@H:10]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH2:9][C@H:8]([OH:18])[C@@H:7]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:26]
Reactant: BrCc1ccccc1
Reactant: CC[C@H](C)CC(F)(F)C(O)CC[C@@H]1[C@@H](CCCCCCC(=O)O)[C@@H](O)C[C@H]1OC1CCCCO1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)CC(F)(F)C(O)CC[C@@H]1[C@@H](CCCCCCC(=O)OCc2ccccc2)[C@@H](O)C[C@H]1OC1CCCCO1
Temperature: 25 °C
Reaction time: 13.5 h
Yield: 98.7 %

Procedure:
To the crude 7-[(1R,2R,3R,5S)-2-((6S)-4,4-difluoro-6-methyl-3-hydroxyoctyl)-5-hydroxy-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanoic acid (F) in acetonitrile (319 ml), diisopropyl ethylamine (68.9 ml, 368 mmol) and benzyl bromide (46.7 ml, 366 mmol) were added and the mixture was stirred for about 13.5 hours at room temperature. The reaction mixture was concentrated under reduced pressure, ethyl acetate (369 ml) and water (283 ml) were added to the residue and the mixture was stirred, let to stand and then separated into two layers. The aqueous layer was extracted twice with ethyl acetate (226 ml). The organic layers were combined and washed with 1M-hydrochloric acid (339 ml), saturated sodium bicarbonate water (339 ml) and saturated aqueous sodium chloride (339 ml). After drying with anhydrous magnesium sulfate (50 g), the solution was concentrated under reduced pressure. The concentration residue was purified by silica gel column chromatography (Fuji Silysia BW-300: 2400 g; ethyl acetate:hexane=1:2) to give benzyl 7-[(1R,2R,3R,5S)-2-((6S)-4,4-difluoro-3-hydroxy-6-methyloctyl)-5-hydroxy-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]heptanoate (3) (76.16 g; 130.7 mmol; yield: 98.7%) as a colorless oil.
Reaction SMILES: [CH:1]([C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[H][H]>C(O)C.[Pd]>[CH2:1]([C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: [H][H]
Reactant: CCCCCCC=Cc1cc2ccccc2[nH]1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCCc1cc2ccccc2[nH]1

Procedure:
2-Oct-1-enyl-1H-indole was dissolved in ethanol and 10% palladium on carbon was added to the solution. The reaction flask was sealed and exposed to hydrogen gas under pressure and was stirred until the hydrogen gas consumption was completely stopped. The reaction mixture was filtered through celite. The solvent was evaporated to afford the desired product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].O.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>O1CCCC1.C(OCC)(=O)C>[CH2:20]([O:19][C:17](=[O:18])[NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1cccc(F)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Nc1cccc(F)c1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
A solution of the 3-fluoro-phenylamine (1015, 18.7 g, 168.3 mmol) in tetrahydrofuran (THF, 150 mL) was treated with potassium carbonate (K2CO3, 46.45 g, 336.6 mmol, 2.0 equiv) and H2O (150 mL) before a solution of benzyl chloroformate (CBZCl, 31.58 g, 185.1 mmol, 26.1 mL, 1.1 equiv) in THF (50 mL) was dropwise added into the reaction mixture at room temperature under N2. The resulting reaction mixture was stirred at room temperature for 2 h. When TLC showed that the reaction was complete, the reaction mixture was treated with H2O (100 mL) and ethyl acetate (EtOAc, 100 mL). The two layers were separated, and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic extracts were washed with H2O (2×100 mL) and saturated NaCl aqueous solution (100 mL), dried over MgSO4, and concentrated in vacuo. The residue was further dried in vacuo to afford the crude, desired (3-fluoro-phenyl)-carbamic acid benzyl ester (1016, 39.2 g, 41.23 g theoretical, 95%) as pale-yellow oil, which was found to be essentially pure and was directly used in the subsequent reactions without further purifications. For 1016: 1H NMR (300 MHz, CDCl3) δ 5.23 (s, 2H, OCH2Ph), 6.75-6.82 (m, 2H), 7.05 (dd, 1H, J=1.4, 8.2 Hz), 7.22-7.45 (m, 6H); C14H12FNO2, LCMS (EI) nm/e 246 (M++H).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:18][C:19]2[C:24]([CH3:25])=[CH:23][C:22]([C:26]#[N:27])=[CH:21][C:20]=2[CH3:28])=[N:4][C:5]([NH:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)=[N:6][C:7]=1Cl.[CH3:29][O:30][NH2:31].[OH-].[Na+]>O1CCCC1>[Br:1][C:2]1[C:3]([O:18][C:19]2[C:24]([CH3:25])=[CH:23][C:22]([C:26]#[N:27])=[CH:21][C:20]=2[CH3:28])=[N:4][C:5]([NH:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)=[N:6][C:7]=1[NH:31][O:30][CH3:29]
Reactant: CON
Reactant: Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc(Cl)c1Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CONc1nc(Nc2ccc(C#N)cc2)nc(Oc2c(C)cc(C#N)cc2C)c1Br
Temperature: 25 °C
Reaction time: 72 h
Yield: 50.4 %

Procedure:
To a pressure vessel was added 4-[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-6-chloro-2-pyrimidinyl]amino]benzonitrile (0.00064 mol), tetrahydrofuran (3 ml), O-methylhydroxylamine (0.06 g), tetrahydrofuran and NaOH 1N (0.00067 mol). The reaction mixture was stirred for 3 days at room temperature, then for 1 day at 75° C., for 1 day at 90° C. and for 2 days at 110° C. To O-methylhydroxylamine (0.60 g) was added tetrahydrofuran (4 ml) and NaOH 50% (0.00719 mol). The liquid was decanted into the reaction flask and the reaction mixture was heated at 110° C. for 3 days. The solvent was evaporated. The residue was dissolved in CH2Cl2, washed with a saturated NaHCO3 solution and water, dried (Na2SO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 98/2). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from CH3CN, filtered off and dried, yielding 0.15 g of 4-[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-6-(methoxyamino)-2-pyrimidinyl]amino]benzonitrile (51%); mp. 185–186° C. The sample was dried (0.2 mm Hg, 80° C., 16 hours) (interm. 33).
Reaction SMILES: OO.[CH3:3][C:4]1[CH2:10][C:8](=[O:9])[CH2:7][C:6]([CH3:12])([CH3:11])[CH:5]=1.C(O)=[O:14].OO.C(=O)([O-])[O-].C(=O)(O)[O-].C(=O)(O)[O-].[Na+]>C(O)=O>[CH3:3][C:4]1[CH:5]([OH:14])[C:6]([CH3:12])([CH3:11])[CH2:7][C:8](=[O:9])[CH:10]=1
Reactant: CC1=CC(C)(C)CC(=O)C1
Reactant: O=CO
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: OO
Product: CC1=CC(=O)CC(C)(C)C1O

Procedure:
The process of the present invention is relatively simple technically. Inexpensive commercial chemicals are used as reagents. For example, formic acid and 30% hydrogen peroxide solution are placed in a stirred apparatus in a molar ratio of from about 1:1 to about 5:1 in a temperature range between 0° C. and 100° C., and about 0.5 to 2.5 moles, preferably 1 mole of beta-isophorone is added slowly. The formic acid/hydrogen peroxide mixture may also be added to the beta-isophorone. Gentle cooling may be used to remove the heat of reaction, depending on the selected temperature conditions and batch size. After completing the reaction and allowing the reaction to stand, the batch, which has become homogeneous, is neutralized with a suitable base, such as for example an alkali or alkaline earth metal hydroxide, oxide, carbonate or bicarbonate. A preferred base is sodium bicarbonate. The upper phase that forms is separated, dried, and distilled under vacuum. After the separation of back-isomerized alpha-isophorone, 4-hydroxyisophorone is obtained as a distillate. The alpha-isophorone distilled off in the forerun can be recycled to the process after reisomerization according to DE-OS 37 35 211.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH:8]=O)[CH:5]=[C:4]([CH3:10])[N:3]=1.[NH2:11][C:12]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[C:13]=1[C:14]([NH2:16])=[O:15].S([O-])(O)=O.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[NH:16][C:14](=[O:15])[C:13]3[C:12](=[CH:20][C:19]([O:21][CH3:22])=[CH:18][C:17]=3[O:23][CH3:24])[N:11]=2)[CH:5]=[C:4]([CH3:10])[N:3]=1
Reactant: Cc1cc(C=O)cc(C)n1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)nc(C)c3)nc2c1
Temperature: 110 °C
Reaction time: 16 h

Procedure:
To a solution of 2,6-dimethylpyridine-4-carbaldehyde (0.14 g, 1.00 mmol) in N,N-dimethyl acetamide (10 mL) were added 2-amino-4,6-dimethoxybenzamide (0.20 g, 1.00 mmol), sodium hydrogen sulfite (0.21 g, 2.00 mmol), and p-toluenesulfonic acid (0.28 g, 1.50 mmol). The reaction mixture was stirred at 110° C. for 16 hours under nitrogen. After cooling to room temperature, solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated NaHCO3 solution (30 mL), water (30 mL), and brine (30 mL), and dried over anhydrous sodium sulfate. Solvent was evaporated, and the residue was purified by column chromatography (silica gel 230-400 mesh; 2-5% methanol in dichloromethane as eluent) to give the title compound as a yellow solid. Yield: 0.030 g (10%). MP 291-292° C. 1H NMR (400 MHz, CDCl3): δ 9.86 (br s, 1H), 7.60 (s, 2H), 6.87 (d, J=2.2 Hz, 1H), 6.53 (d, J=2.2 Hz, 1H), 3.99 (s, 3H), 3.95 (s, 3H), 2.66 (s, 6H). MS (ES) m/z: 312.50 (M+1) (100%).
Reaction SMILES: [N:1]1([C:7]2[CH:25]=[CH:24][C:10]([C:11]([NH:13][C:14]3[CH:15]=[N:16][C:17]4[C:22]([CH:23]=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:26]1([CH2:32][C:33](O)=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(#N)C>[C:26]1([CH2:32][C:33]([N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]([C:11]([NH:13][C:14]4[CH:15]=[N:16][C:17]5[C:22]([CH:23]=4)=[CH:21][CH:20]=[CH:19][CH:18]=5)=[O:12])=[CH:24][CH:25]=3)[CH2:6][CH2:5]2)=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: O=C(Nc1cnc2ccccc2c1)c1ccc(N2CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Product: O=C(Nc1cnc2ccccc2c1)c1ccc(N2CCN(C(=O)Cc3ccccc3)CC2)cc1
Temperature: 25 °C

Procedure:
A solution of 4-piperazin-1-yl-N-quinolin-3-yl-benzamide (75 mg, 0.284 mmol), phenylacetic acid (51 mg, 0.375 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU)(118 mg, 0.30 mmol) and N,N—N,N-diisopropylethylamine (0.110 mL, 0.626 mmol) in acetonitrile (2 mL) was heated to 80° C. The solution was cooled to room temperature and the product crystallized. The product was collected by filtration washed with acetonitrile to give 63 mg (49%). MS: m/z 451 (MH+). 1H NMR (DMSO-d6): δ 3.24-3.34 (m, 4 H), 3.63-3.69 (m, 4 H), 3.79 (s, 2 H), 7.05 (d, 2 H), 7.22-7.46 (m, 5 H), 7.54-7.67 (m, 2 H), 7.92-7.99 (m, 4 H), 8.82 (d, 1 H), 9.15 (d, 1 H) and 10.40 (s, 1 H).