Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][OH:3].N1C=CC=CC=1.C[Si](Cl)(C)C.[CH2:15]([O:17][C:18](=[O:47])[CH2:19][CH2:20][N:21]([C:39]1([C:44](Cl)=[O:45])[CH2:43][CH2:42][CH2:41][CH2:40]1)[S:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[CH:27][CH:26]=1)(=[O:24])=[O:23])[CH3:16]>Cl>[CH2:15]([O:17][C:18](=[O:47])[CH2:19][CH2:20][N:21]([S:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[CH:27][CH:26]=1)(=[O:24])=[O:23])[C:39]1([C:44](=[O:45])[NH:2][OH:3])[CH2:43][CH2:42][CH2:41][CH2:40]1)[CH3:16]
Reactant: CCOC(=O)CCN(C1(C(=O)Cl)CCCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Reactant: NO
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)CCN(C1(C(=O)NO)CCCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1.37 g (19.7 mmol, 1.3 equivalents) of hydroxylamine hydrochloride in 9.2 mL (114 mmol, 7.5 equivalents) of dry pyridine at 0° C. was treated with 5.8 mL (45 mmol, 3.0 equivalents) of trimethylsilyl chloride, causing white solids to precipitate, and allowedc to warm to ambient temperature overnight. This mixture was cooled to 0° C. and treated with a solution of 7.54 g (15.1 mmol) of 3-{(1-chlorocarbonylcyclopentyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino}propionic acid ethyl ester in 73 mL of dichloromethene, prepared as described above without isolation, causing an exotherm to 8° C. This mixture was stirred at 0° C. for 30 minutes and at ambient temperature for one hour before treating with 50 mL of 2N aqueous hydrochloric acid and stirring at ambient temperature for one hour. The aqueous phase was extracted with dichloromethane and the combined organic phases were washed with 2N aqueous hydrochloric acid (2×50 mL) and water (50 mL). This solution of 3-[[4-(4-fluorophenoxy)benzenesufonyl]-(1-hydroxycarbamoylcyclopentyl)amino]propionic acid ethyl ester in dichloromethane was used for the preparation of 3-[[4-(4-fluoro-phenoxy)benzenesulfonyl]-1-hydroxycarbamoylcyclopentyl)amino]propionic acid without isolation. An aliquot was concentrated to a foam.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4](C2C=CC=CC=2S(C)(=O)=O)[C:3]=1[CH3:24].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:3]=1[CH3:24]
Reactant: Cc1c(-c2ccccc2S(C)(=O)=O)nc2cc(F)cc(F)c2c1Cl
Reactant: C1COCCN1
Product: Cc1c(N2CCOCC2)nc2cc(F)cc(F)c2c1Cl

Procedure:
Essentially prepared according to Procedure G using 4-chloro-5,7-difluoro-3-methyl-2-(2-(methylsulfonyl)phenyl)quinoline (380.0 mg, 1.50 mmol) and morpholine to give 4-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)morpholine. Mass Spectrum (ESI) m/e=299.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:21]([O-:23])=[O:22])=[C:6]([CH:20]=1)[O:7][C:8]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:9]=1[C:10]([O:12]C)=O>O>[Cl:1][C:2]1[C:20]2[C:10](=[O:12])[C:9]3[C:8](=[CH:17][C:16]([O:18][CH3:19])=[CH:15][CH:14]=3)[O:7][C:6]=2[C:5]([N+:21]([O-:23])=[O:22])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(OC)cc1Oc1cc(Cl)ccc1[N+](=O)[O-]
Solvent: O
Product: COc1ccc2c(=O)c3c(Cl)ccc([N+](=O)[O-])c3oc2c1
Reaction time: 18 h
Yield: 101.7 %

Procedure:
To 500 g of polyphosphoric acid stirred at 110° C. was added 62.9 g of 2-(5-chloro-2-nitrophenoxy)-4-methoxybenzoic acid, methyl ester. After 18 hours, the hot solution was poured into water, and the resulting precipitate collected. The solid was washed with water and isopropyl alcohol to give 57.9 g of the title compound, mp 211°-213° C. after recrystallization from DMF.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](Br)=[C:7]([O:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)[N:6]=1)=[O:4].[O:17]1[CH2:21][CH:20]=[CH:19][CH2:18]1.C([O-])(=O)C.[Na+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[CH3:40][O:41][C:42]([C:44]1[CH:49]=[CH:48][C:47]([C:50]2[CH2:51][O:52][CH2:53][CH:54]=2)=[C:46]([O:55][CH2:56][CH:57]2[CH2:59][CH2:58]2)[N:45]=1)=[O:43]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:40][O:41][C:42]([C:44]1[CH:49]=[CH:48][C:47]([C:50]2[CH2:51][O:52][CH2:53][CH:54]=2)=[C:46]([O:55][CH2:56][CH:57]2[CH2:59][CH2:58]2)[N:45]=1)=[O:43].[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:18]2[O:17][CH2:21][CH2:20][CH:19]=2)=[C:7]([O:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)[N:6]=1)=[O:4]
Reactant: C1=CCOC1
Reactant: COC(=O)c1ccc(Br)c(OCC2CC2)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C2=CCCO2)c(OCC2CC2)n1
Temperature: 120 °C
Reaction time: 2.5 h
Yield: 79 %

Procedure:
A mixture of 5-bromo-6-(cyclopropylmethoxy)-pyridine-2-carboxylic acid methyl ester (0.5 g, 1.7 mmol), 2,5-dihydrofuran (CAN 1708-29-8, 1.2 g, 17 mmol), palladium(II) acetate (CAN 3375-31-3, 0.02 g, 0.09 mmol), sodium acetate (0.17 g, 2 mmol) and tri-tert-butylphosphine (CAN 13716-12-6, 0.037 g, 0.2 mmol) in DMF (10 mL) was stirred at 120° C. for 2.5 h under a nitrogen atmosphere. Water was poured into the reaction mixture and the resulting mixture was extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography (silica gel, 10 g, eluting with 5% ethyl acetate in petroleum ether) to yield 6-(cyclopropylmethoxy)-5-(2,5-dihydrofuran-3-yl)-pyridine-2-carboxylic acid methyl ester (b1) and 6-(cyclopropylmethoxy)-5-(4,5-dihydrofuran-2-yl)-pyridine-2-carboxylic acid methyl ester (b2) (mixture b1:b2=3:2, 0.38 g, 1.4 mmol, 79%) as yellow oil; MS (EI): m/e=376.1 [M+H]+.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[C:11]4[CH2:20][CH2:19][CH2:18][C:12]=4[C:13](=[O:17])[NH:14][C:15]=3[CH:16]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Mg]>>[N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[CH:11]4[CH2:20][CH2:19][CH2:18][CH:12]4[C:13](=[O:17])[NH:14][C:15]=3[CH:16]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=c1[nH]c2cc(N3CCOCC3)ccc2c2c1CCC2
Agent: [Mg]
Product: O=C1Nc2cc(N3CCOCC3)ccc2C2CCCC12

Procedure:
Analogously to Example 7, 7-(4-morpholinyl)-1,2,3,5-tetrahydrocyclopenta[c]quinolin-4-one (1.17 g, 4.3 mmol) is converted with magnesium (2.16 g, 86.6 mmol) into 660 mg (56%) of product.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:36]([CH3:37])=[CH:35][C:14]2[N:15]=[C:16]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[N:23]([CH3:27])[N:22]=[C:21]4C3C(C)=NC=CC=3)[S:17][C:13]=2[C:12]=1[C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[CH3:47][CH2:48]O>C1COCC1>[C:1]([O:5][C@@H:6]([C:11]1[C:36]([CH3:37])=[CH:35][C:14]2[N:15]=[C:16]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[N:23]([CH3:27])[N:22]=[C:21]4[C:48]3[CH:47]=[CH:16][N:15]=[CH:14][CH:13]=3)[S:17][C:13]=2[C:12]=1[C:38]1[CH:39]=[CH:40][C:41]([Cl:44])=[CH:42][CH:43]=1)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCO
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(c3)c(-c3cccnc3C)nn4C)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc2nc(-c3ccc4c(c3)c(-c3ccncc3)nn4C)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 50 °C

Procedure:
In a vial was dissolved (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(1-methyl-3-(2-methylpyridin-3-yl)-1H-indazol-5-yl)benzo[d]thiazol-6-yl)acetate (100 mg, 0.16 mmol) in THF (3 mL) and EtOH (1.5 mL). 1M NaOH (1.5 mL) was added, and the mixture was heated to 50° C. overnight. The reaction was cooled to 23° C., and filtered (0.45 micron teflon syringe filter). The filtrate was purified by reverse phase HPLC, eluting with 5-100% acetonitrile in H2O with 0.1% TFA to give the desired product. LCMS-ESI+: calc'd for C33H30ClN4O3S: 597.2 (M+H+); Found: 597.2 (M+H+). 1H NMR (400 MHz, CD3OD) δ 8.77 (d, J=6.1 Hz, 2H), 8.73 (s, 1H), 8.47 (d, J=6.3 Hz, 2H), 8.06 (d, J=8.9 Hz, 1H), 7.78-7.70 (m, 3H), 7.60 (dt, J=11.1, 7.5 Hz, 3H), 5.26 (s, 1H), 4.18 (s, 3H), 2.61 (s, 3H), 0.98 (s, 9H).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][C:7]=1[N+:16]([O-])=O)[CH:2]([CH3:4])[CH3:3]>C(O)C.[Pt]>[NH2:16][C:7]1[CH:8]=[N:9][C:10]2[C:15]([C:6]=1[NH:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:14][CH:13]=[CH:12][CH:11]=2
Reactant: CC(C)CNc1c([N+](=O)[O-])cnc2ccccc12
Agent: [Pt]
Solvent: CCO
Product: CC(C)CNc1c(N)cnc2ccccc12

Procedure:
To a solution of 15.0 g (0.0612 mole) of 4-isobutylamino-3-nitroquinoline (from Example 1) in ethanol was added about 0.5 g of 5% platinum on charcoal, and the mixture was hydrogenated on a Parr apparatus at about 20° C. The mixture was filtered to provide a solution of 3-amino-4-(isobutylamino)quinoline.
Reaction SMILES: N1CCCC1.C(O)(=O)C.[C:10]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:11][CH2:12][C:13]([CH3:15])=[O:14].[CH3:20][C:21]1[O:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1>C(O)C>[CH3:25][C:24]1[O:27][C:21]([CH:20]=[CH:15][C:13](=[O:14])[CH2:12][CH2:11][C:10]([O:17][CH2:18][CH3:19])=[O:16])=[CH:22][CH:23]=1
Reactant: CCOC(=O)CCC(C)=O
Reactant: Cc1ccc(C=O)o1
Solvent: CC(=O)O
Solvent: C1CCNC1
Solvent: CCO
Product: CCOC(=O)CCC(=O)C=Cc1ccc(C)o1
Temperature: 25 °C
Yield: 69.4 %

Procedure:
To make a starting compound of Formula I, 11.5 mL of pyrrolidine (0.139 mol, 0.2 eq) and 8.0 mL of acetic acid (0.139 mol, 0.2 eq) were added to a solution of 100 g of ethyl levulinate (0.694 mol, 1.0 eq) in 400 mL of ethanol. To this solution, 76.4 g of 5-methyl-furfural (0.694 mol, 1.0 eq) was added over 30 minutes. The reaction was stirred at ambient temperature until complete, as analyzed by gas chromatography-mass spectrometry (GCMS). The reaction mixture was evaporated to dryness and dissolved in a mixture of 400 mL of hexane and 100 mL of ethyl acetate. Activated charcoal (Darco® G-60, Sigma-Aldrich) was added and stirred for 15 minutes. The reaction mixture was filtered over a six inch sintered glass funnel containing a six inch bed of silica and washed with 4:1 hexane/ethyl acetate to collect 7 fractions. Fractions 3 and 4 were combined and evaporated to an oil to give ethyl 6-(5-methylfuran-2-yl)-4-oxohex-5-enoate as an orange oil (114.6 g, 69.4% yield, proton nuclear magnetic resonance (HNMR), GCMS molecular weight=236).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:7]=[CH:6][C:5]=1[OH:14].[F:16][C:17]([F:29])([F:28])[CH:18](OS(C(F)(F)F)(=O)=O)[CH3:19].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:7]=[CH:6][C:5]=1[O:14][CH:18]([CH3:19])[C:17]([F:29])([F:28])[F:16]
Reactant: CC(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1cc(S(C)(=O)=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(S(C)(=O)=O)ccc1OC(C)C(F)(F)F
Temperature: 80 °C
Reaction time: 48 h

Procedure:
A mixture of 21.7 mmol 2-hydroxy-5-methanesulfonyl-benzoic acid methyl ester (WO 2002074774), 32.5 mmol rac-trifluoro-methanesulfonic acid 2,2,2-trifluoro-1-methyl-ethyl ester [212556-43-9] and 43.4 mmol potassium carbonate in 87 ml DMF was stirred at 80° C. for 48 hours. After cooling to room temperature, the mixture was concentrated in vacuo, resuspended in water and stirred for 1 hour. Filtration yielded the title compound.
Reaction SMILES: Cl[CH2:2][C:3]([CH3:5])=O.[NH2:6][C:7]([N:9]1[CH2:14][CH2:13][CH:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH2:11][CH2:10]1)=[S:8]>C(O)C>[CH3:5][C:3]1[N:6]=[C:7]([N:9]2[CH2:10][CH2:11][CH:12]([CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[CH2:13][CH2:14]2)[S:8][CH:2]=1
Reactant: CC(=O)CCl
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCN(C(N)=S)CC2)CC1
Solvent: CCO
Product: Cc1csc(N2CCC(C3CCN(C(=O)OC(C)(C)C)CC3)CC2)n1
Temperature: 75 °C

Procedure:
The 1-chloroacetone (57 mg, 0.61 mmol) and tert-butyl 1′-(aminocarbonothioyl)-4,4′-bipiperidine-1-carboxylate (prepared as for Example 175, step 1) (200 mg, 0.61 mmol) were dissolved in ethanol (1.2 ml) and heated at 75° C. overnight. The solution was cooled to RT, and the solvent removed in vac. The residue was used in the subsequent procedure without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:23](=[O:24])[N:22]2[CH2:25][C@H:26]([OH:28])[CH2:27][C@H:21]2[C:20](=[O:29])[NH:19][C@:18]2([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:30][C@H:17]2[CH2:16][C:15]([F:37])([F:36])[CH2:14][CH2:13][CH:12]=[CH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:23](=[O:24])[N:22]2[CH2:25][C@H:26]([OH:28])[CH2:27][C@H:21]2[C:20](=[O:29])[NH:19][C@:18]2([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:30][C@H:17]2[CH2:16][C:15]([F:36])([F:37])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: [H][H]
Reactant: CCOC(=O)[C@@]12C[C@H]1CC(F)(F)CCC=CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)N2
Agent: [Pd]
Agent: CCOC(=O)[C@@]12C[C@H]1CC(F)(F)CC/C=C/C[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)N2
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@]12C[C@H]1CC(F)(F)CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)N2
Yield: 94.9 %

Procedure:
A solution of (2R,6S,13aS,14aR,16aS,E)-ethyl 6-(tert-butoxycarbonylamino)-12,12-difluoro-2-hydroxy-5,16-dioxo-1,2,3,5,6,7,10,11,12,13,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxylate (Example 7h, 1.06 g, 2.002 mmol) in ethyl acetate (50 ml) at 25° C. was added 10% palladium/carbon (0.170 g, 0.160 mmol). The reaction mixture was stirred under a balloon of hydrogen for 2 days. The reaction mixture was filtered through a small plug of silica gel and eluted with ethyl acetate then methanol. The solvent was evaporated under reduced pressure and the resulting solid was purified by flash chromatography on silica gel (40% ethyl acetate/dichloromethane, then ethyl acetate) to provide (2R,6S,13aS,14aR,16aS)-ethyl 6-(tert-butoxycarbonylamino)-12,12-difluoro-2-hydroxy-5,16-dioxooctadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylate (1.01 g, 1.900 mmol, 95% yield) as a white solid. MS (ESI): m/z=532.3 [M+H].
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:35])[C@H:5]([CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[NH:6][C:7](=[O:19])[C@H:8]([CH2:10][S:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[NH2:9].[CH3:36][C:37]([CH3:52])([CH2:41][S:42][CH2:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=1)[C:38](O)=[O:39]>>[CH3:2][O:3][C:4](=[O:35])[C@H:5]([CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[NH:6][C:7](=[O:19])[C@H:8]([CH2:10][S:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[NH:9][C:38](=[O:39])[C:37]([CH3:36])([CH3:52])[CH2:41][S:42][CH2:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=1
Reactant: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)[C@@H](N)CSCc1ccccc1
Reactant: COc1ccc(CSCC(C)(C)C(=O)O)cc1
Agent: Cl
Product: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)[C@H](CSCc1ccccc1)NC(=O)C(C)(C)CSCc1ccc(OC)cc1

Procedure:
Nα -(S-benzyl-L-cysteinyl)-Nε -benzyloxycarbonyl-L-lysine methyl ester hydrochloride and 2,2-dimethyl-3-(4-methoxybenzylthio)propionic acid were used as starting materials.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:30])[C:4](=[O:29])[C@@:5]([C:17]2[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH2:25][O:26][CH3:27])[CH:20]=[CH:21][CH:22]=2)([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:16])[F:15])=[CH:9][CH:8]=2)[N:6]=1>CO>[NH2:1][C:2]1[N:3]([CH3:30])[C:4](=[O:29])[C@:5]([C:17]2[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH2:25][O:26][CH3:27])[CH:20]=[CH:21][CH:22]=2)([C:7]2[CH:8]=[CH:9][C:10]([O:13][CH:14]([F:16])[F:15])=[CH:11][CH:12]=2)[N:6]=1
Reactant: COCC(=O)Nc1cccc([C@]2(c3ccc(OC(F)F)cc3)N=C(N)N(C)C2=O)c1
Solvent: CO
Product: COCC(=O)Nc1cccc([C@@]2(c3ccc(OC(F)F)cc3)N=C(N)N(C)C2=O)c1

Procedure:
[B] N-(3-{(4S)-2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)-2-methoxyacetamide, MS m/e (M+H)+ 419; 1H NMR (400 MHz, DMSO-d6) 2.93 (s, 3H), 3.30 (s, 3H), 3.90 (s, 2H), 6.61 (brs, 2H), 7.08 (m, 3H), 7.2 (m, 2H), 7.44 (d, J=8.78 Hz, 2H), 7.55 (d, J=7.93 Hz, 1H), 7.62 (s, 1H), 9.71 (s, 1H); [a]25=−16 (C=1% in MeOH).
Reaction SMILES: [CH2:1]([O:3][N:4]=[CH:5][C:6]1[CH:11]=[C:10]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[NH:14][C:13]2=[O:23])[C:9]([Cl:24])=[CH:8][C:7]=1[Cl:25])[CH3:2].[C:26](=O)([O-])[O-].[K+].[K+].CI>>[CH2:1]([O:3][N:4]=[CH:5][C:6]1[CH:11]=[C:10]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[N:14]([CH3:26])[C:13]2=[O:23])[C:9]([Cl:24])=[CH:8][C:7]=1[Cl:25])[CH3:2]
Reactant: CCON=Cc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(Cl)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: CCON=Cc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(Cl)cc1Cl

Procedure:
69.3 g (0.175 mol) of 2,4-dichloro-5-(6-trifluoromethyl-2,4(1H,3H)-pyrimidinedion-3-yl)benzaldehyde (O-ethyl)oxime, 26.6 g (0.19 mol) of potassium carbonate and 27.3 g (0.19 mol) of methyl iodide were reacted in the manner described for precursor 3.3. Yield: 69.0 g; m.p.: 140-143° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C@H:4]([CH:5]=C(C)C)[C@H:3]1[C:9]([O:11][CH2:12][C:13]1[C:18]([F:19])=[C:17]([F:20])[C:16]([CH3:21])=[C:15]([F:22])[C:14]=1[F:23])=[O:10].CO.O=O.[O:29]=[O+][O-]>CCCCCC.C(OCC)(=O)C.C(OCC)(=O)C>[CH:5]([C@@H:4]1[C@@H:3]([C:9]([O:11][CH2:12][C:13]2[C:18]([F:19])=[C:17]([F:20])[C:16]([CH3:21])=[C:15]([F:22])[C:14]=2[F:23])=[O:10])[C:2]1([CH3:24])[CH3:1])=[O:29]
Reactant: CC(C)=C[C@@H]1[C@@H](C(=O)OCc2c(F)c(F)c(C)c(F)c2F)C1(C)C
Reactant: O=[O+][O-]
Agent: O=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CO
Product: Cc1c(F)c(F)c(COC(=O)[C@@H]2[C@@H](C=O)C2(C)C)c(F)c1F
Reaction time: 24 h
Yield: 82 %

Procedure:
Into a mixture solution of 1.27 g of (2,3,5,6-tetrafluoro-4-methylphenyl)methyl(1R)-trans-2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropanecarboxylate, 20 ml of methanol and 20 ml of ethyl acetate, oxygen containing ozone was blown at −78° C. until the color of the solution was changed to blue. Then nitrogen gas was blown into the solution for removing excess ozone, 5 ml of dimethylsulfide was added to the solution and the solution was brought to room temperature. After one day, the reaction solution was concentrated under reduced pressure. To the residue, 20 ml of acetone, 2 ml of water and 0.2 g of p-toluenesulfonic acid monohydrate were added and allowed to stand at room temperature for 2 hours. The reaction solution was poured into water and extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue, which was subjected to silica gel column chromatography (eluent: hexane/ethyl acetate=10/1) to give 0.98 g of (2,3,5,6-tetrafluoro-4-methylphenyl)methyl(1R)-trans-3-formyl-2,2-dimethylcyclopropanecarboxylate (yield 82%). m.p. 43.2° C.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:21])=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH3:13])([CH3:12])[C:9](=[O:14])[C:8]([C:15](OCC)=[O:16])=[C:7]2[OH:20].Cl.[NH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C(N(C(C)C)C(C)C)C>O1CCOCC1>[F:1][C:2]1[C:3]([OH:21])=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH3:13])([CH3:12])[C:9](=[O:14])[C:8]([C:15]([NH:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:16])=[C:7]2[OH:20]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCOC(=O)C1=C(O)c2ccc(O)c(F)c2C(C)(C)C1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccc(O)c(F)c2C(C)(C)C1=O
Temperature: 85 °C
Reaction time: 4 h
Yield: 105.4 %

Procedure:
A mixture of ethyl 8-fluoro-4,7-dihydroxy-1,1-dimethyl-2-oxo-naphthalene-3-carboxylate (0.4 g, 1 mmol) and tert-butyl 2-aminoacetate hydrochloride (0.3 g, 2 mmol) in 2 mL dioxane, was treated with N-ethyl-N-isopropylpropan-2-amine (0.5 g, 4 mmol). The resulting mixture was warmed to 85° C. and stirred for 4 hours, M+Na=402, M+1=380. The mixture was then cooled to room temperature and concentrated in vacuo. The crude product was purified by column chromatography eluting with 10-30% EtOAc/hexane to give 0.4 g of the title compound as a pale white solid. MS (m/z)=378 (M−1)−.
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[CH:10]([CH3:16])[CH2:9]2)([OH:5])=[O:4]>C(O)(=O)C>[Br:1][C:10]1([CH3:16])[CH2:9][C:8]2[C:12](=[CH:13][CH:14]=[C:6]([C:3]([OH:5])=[O:4])[CH:7]=2)[C:11]1=[O:15]
Reactant: CC1Cc2cc(C(=O)O)ccc2C1=O
Reactant: BrBr
Solvent: CC(=O)O
Product: CC1(Br)Cc2cc(C(=O)O)ccc2C1=O
Reaction time: 0.5 h

Procedure:
Bromine (0.57 ml) was added dropwise during 15 minutes to a stirred solution of 5-carboxy-2-methylindan-1-one (2 g) in acetic acid (75 ml) at 35° C. The solution was stirred for a further 30 minutes then evaporated to low volume under reduced pressure and the residue was diluted with water to give 2-bromo-5-carboxy-2-methylindan-1-one, m.p. 203°-205° C. (from acetic acid).
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]([CH3:10])([CH2:8][F:9])[C:5](=[O:7])[CH3:6].CCOCC>O>[Br:1][CH2:6][C:5](=[O:7])[C:4]([CH3:10])([CH3:3])[CH2:8][F:9]
Reactant: CC(=O)C(C)(C)CF
Reactant: BrBr
Solvent: CCOCC
Solvent: O
Product: CC(C)(CF)C(=O)CBr
Yield: 79.8 %

Procedure:
480 g of bromine were slowly added dropwise to a mixture of 354 g (3 mols) of 3,3-dimethyl-4-fluoro-2-butanone and 2,000 ml of ether at 20° to 30° C., while cooling and stirring. The yellowish solution was subsequently stirred for a further hour at 20° C. and 500 ml of water were then carefully added. The ether phase was separated off, washed several times with water and dried over sodium sulphate. After distilling off the solvent, the residue was distilled under a waterpump vacuum. 472 g (80% of theory) of 1-bromo-3,3-dimethyl-4-fluoro-2-butanone of boiling point 80°-90° C./11 mm Hg were obtained. ##STR81##
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=[O:13])[C:5](=[CH:9][C:10]=1[F:11])C(O)=O.CCCCCCCCCCCCC>CN1CCCC1=O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:9][C:10]=1[F:11])[C:12]([OH:14])=[O:13]
Reactant: O=C(O)c1cc(F)c(F)cc1C(=O)O
Agent: CCCCCCCCCCCCC
Solvent: CN1CCCC1=O
Product: O=C(O)c1ccc(F)c(F)c1
Temperature: 190 °C
Yield: 87 %

Procedure:
4,5-difluorophthalic acid (0.55 grams, 2.7 mmole) was added to a slurry of cupric oxide (10% by weight of starting material) in 5 ml. of N-methyl-2-pyrrolidone solvent. n-tridecane (0.25 grams) was added as an internal standard. The mixture was heated to 190° C. for 3 hours, at which time GC analysis indicated complete consumption of the starting material and conversion to 3,4-difluorobenzoic acid in an 87% yield, based upon the internal standard, corrected for response factors.