Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([O:24][CH2:25][CH2:26][OH:27])=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2/[CH:15]=[CH:16]/[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:5])C.C(O)C.[OH-].[Na+].Cl>O1CCCC1>[F:23][C:20]1[CH:21]=[CH:22][C:17](/[CH:16]=[CH:15]/[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[C:6]([C:4]([OH:5])=[O:3])[C:7]=3[O:24][CH2:25][CH2:26][OH:27])[NH:11][N:10]=2)=[CH:18][CH:19]=1
Reactant: CCOC(=O)c1ccc2[nH]nc(/C=C/c3ccc(F)cc3)c2c1OCCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2[nH]nc(/C=C/c3ccc(F)cc3)c2c1OCCO
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 86.4 %

Procedure:
To a solution of 31.3 mg of 3-[(E)-2-(4-fluorophenyl)-vinyl]-4-(2-hydroxyethoxy)-1H-indazol-5-carboxylic acid ethyl ester obtained by Example 349 in 0.7 mL of tetrahydrofuran were added 0.3 mL of ethanol and 0.2 mL of 5N sodium hydroxide aqueous solution, and stirred at 70° C. for 1 hour and 20 minutes. After cooling on ice, the solution was neutralized with 2N hydrochloric acid under ice cooling, and the precipitated crystals were collected by filtration, and dried under reduced pressure, to afford 25 mg of the title compound as yellow crude crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][C:6]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7]1.[Cl:19]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[C:3]([Cl:19])=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][C:6]1([C:9]([O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:10])[CH2:8][CH2:7]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)C1(Cc2cccc(N)c2)CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)C1(Cc2cccc(N)c2Cl)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 6.9 %

Procedure:
1.0 g (4.40 mmol) of tert-butyl 1-(3-aminobenzyl)cyclopropanecarboxylate was initially charged in 10.0 ml of acetonitrile, and 540 mg (4.40 mmol) of N-chlorosuccinimide were added a little at a time at 0° C. After 30 min, the mixture was warmed to RT and stirred at this temperature overnight. After concentration under reduced pressure, the residue was taken up in dichloromethane and washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over sodium sulphate and concentrated under reduced pressure. By chromatography on silica gel (mobile phase gradient cyclohexane/ethyl acetate 10:1→6:1), 217 mg of a mixed fraction (about 1:1) consisting of tert-butyl 1-(3-amino-2-chlorobenzyl)cyclo-propanecarboxylate and tert-butyl 1-(3-amino-4-chlorobenzyl)cyclopropanecarboxylate, and also 995.5 mg of tert-butyl 1-(5-amino-2-chlorobenzyl)cyclopropanecarboxylate, slightly contaminated by the starting material tert-butyl 1-(3-aminobenzyl)cyclopropanecarboxylate, were isolated from the crude product obtained in this manner. The mixed fraction (217 mg) was separated further by preparative RP-HPLC [column: Sunfire C18 5 μm, 250 mm×20 mm; injection volume: 0.50 ml; temperature: 25° C.; mobile phase: 55% acetonitrile/40% water/5% (water+1% TFA); flow rate: 35 ml/min; detection: 210 nm]. In this manner, it was possible to isolate 85 mg (7.5% of theory) of tert-butyl 1-(3-amino-2-chlorobenzyl)cyclopropanecarboxylate (Example 22A). Starting with 995.5 mg of the slightly contaminated material, 677.6 mg (59.5% of theory) of pure tert-butyl 1-(5-amino-2-chlorobenzyl)cyclopropanecarboxylate (Example 23A) were isolated by preparative RP-HPLC (mobile phase: acetonitrile/water gradient).
Reaction SMILES: [C:1](OCC(CO)O)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]CC.CCCCCCCCCC(O)=O.CCCCCCCC(O)=O.C(O)C(O)CO>>[CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO
Agent: CCCCCCCCCC(=O)O
Solvent: CCCCCCCC(=O)O
Solvent: OCC(O)CO
Product: CCCCCCCCCCCCCCCCO

Procedure:
Sodium Acrylate Acryloyl Dimethyl Taurate Copolymer (30%); Glyceryl Monostearate (15%); Caprylic/Capric Triglyceride (5%)
Reaction SMILES: C(OC([NH:8][CH:9]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:10]([NH:12][C@@H:13]1[C:38](=[O:39])[N:15]2[C@@H:16]([C:22]([O:24]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:23])[C@@:17]([Cl:21])([CH3:20])[CH2:18][S:19][C@H:14]12)=[O:11])=O)(C)(C)C.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>>[NH2:8][CH:9]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:10]([NH:12][C@@H:13]1[C:38](=[O:39])[N:15]2[C@@H:16]([C:22]([OH:24])=[O:23])[C@@:17]([Cl:21])([CH3:20])[CH2:18][S:19][C@H:14]12)=[O:11]
Reactant: CC(C)(C)OC(=O)NC(C(=O)N[C@@H]1C(=O)N2[C@@H]1SC[C@@](C)(Cl)[C@@H]2C(=O)OC(c1ccccc1)c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: C[C@@]1(Cl)CS[C@@H]2[C@H](NC(=O)C(N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.5 %

Procedure:
A mixture of benzhydryl 7β-(α-tert.-butoxycarbonylamino-α-phenylacetamido)-3β-chloro-3α-methylcepham-4α-carboxylate (150 mg), trifluoroacetic acid (4 ml), and anisole (1 ml) is stirred at room temperature for 30 minutes, then evaporated in vacuo, The residue is treated with ether to remove soluble material. The insoluble material is 7β-(α-aminophenylacetamido)- 3β-chloro-3α-methylcepham-4α-carboxylic acid trifluoroacetate. The material is mixed with water (1.5 ml) and 25% Amberlite LA-1R is methyl isobutyl ketone (1.5 ml), and stirred for 2 hours to give an insoluble material which is collected by filtration. The solid is washed with water, methyl isobutyl ketone, and ethyl acetate, and dried to give 7β-(α-aminophenylacetamido)-3β-chloro-3α-methylcepham-4α-carboxylic acid (35 mg). Yield: 40%. IR: νmaxNujol 5.8, 5.7, 5.7μ.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C:13]2[S:14][C:15]([C:19]([OH:21])=O)=[C:16]([CH3:18])[N:17]=2)[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=CC=1.C1(CCN2CCN(C3SC(C(O)=O)=C(C)N=3)C2=O)CC1.[NH2:43][CH2:44][C:45]1[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=1>>[CH:7]1([CH2:2][CH2:1][N:8]2[CH2:12][CH2:11][N:10]([C:13]3[S:14][C:15]([C:19]([NH:43][CH2:44][C:45]4[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=4)=[O:21])=[C:16]([CH3:18])[N:17]=3)[C:9]2=[O:22])[CH2:6][CH2:5]1
Reactant: NCc1cccnc1
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Agent: Cc1nc(N2CCN(CCC3CC3)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(CCC3CC3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 40 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(2-cyclopropylethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a white powder in 40% yield: mp 146-147° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) d 8.54 (s, 1H), 8.43 (d, J=3.0 Hz, 1H), 7.63 (d, J=7.8 Hz, 1H), 7.23-7.17 (m, 1H), 6.55 (t, J=5.7 Hz, 1H), 4.52 (d, J=5.7 Hz, 2H), 4.06-3.99 (m, 2H), 3.57-3.52 (m, 2H), 3.32 (t, J=7.2 Hz, 2H), 2.54 (s, 3H), 1.44-1.37 (m, 2H), 0.65-0.54 (m, 1H), 0.43-0.35 (m, 2H), 0.06-0.01 (m, 2H); 13C NMR (75 MHz, CDCl3) d 162.7, 157.5, 155.3, 153.5, 149.0, 148.6, 135.7, 134.1, 123.6, 116.7, 44.0, 42.4, 42.0, 41.2, 32.4, 17.2, 8.4, 4.3; MS (ES+) m/z 386.3 (M+1)
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:18])=[N:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:7]=1.C(=O)(O)[O-].[Na+].Cl[CH2:25][CH:26]=O>CCO>[Br:1][C:2]1[C:3]2[N:4]([CH:25]=[CH:26][N:18]=2)[CH:5]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:12][CH:13]=2)[CH:7]=1
Reactant: Nc1ncc(-c2ccc(C(F)(F)F)cc2)cc1Br
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: FC(F)(F)c1ccc(-c2cc(Br)c3nccn3c2)cc1
Temperature: 23 °C
Yield: 62.3 %

Procedure:
To a mixture of 3-bromo-5-(4-trifluoromethyl-phenyl)-pyridin-2-ylamine (example C.25 step 2) (4.96 g, 16 mmol) and sodium bicarbonate (5.256 g, 63 mmol) in EtOH (20 mL) at 50° C. was dropwise added chloroacetaldehyde (50% in water, 3.66 mL, 31 mmol) within 2 h. Cooled to 23° C. and evaporated all volatiles The residue was purified by silica gel column chromatography with dichloromethane/methanol followed by trituration with heptane and very little ether to give the title compound as a white solid (3.4 g, 63%). MS (ISP) 340.9 [(M+H)+], 343.1 [(M+2+H)+].
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:7][NH2:8])[C:4]([OH:6])=[O:5].[C:9]1([C:15]([C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=O)=O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Na+]>CO>[C:9]1([C:15]2[N:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[N:2][C:17]=2[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(C(=O)c1ccccc1)c1ccccc1
Reactant: NCC(N)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cnc(-c2ccccc2)c(-c2ccccc2)n1
Temperature: 25 °C

Procedure:
The monohydrochloride of 2,3-diaminopropionic acid (500 mg, 3.56 mmol) and benzil (890 mg, 4.23 mmol) were added to a solution of sodium hydroxide (677 mg, 16.93 mmol) in methanol (10 ml). An extra portion of methanol was added (5 ml) and the reaction mixture was refluxed for 20 minutes. The mixture was cooled to 25° C. and air was bubbled through for 30 minutes. Hydrochloric acid (aq, 2 M) was added until the reaction mixture reached pH 2. The solution was extracted with diethyl ether. The combined diethyl ether phases were dried (MgSO4), filtrated and evaporated under reduced pressure to give the crude product. MS m/z 277 (M+H)+. The crude product was used in steps described below without further purification.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[C:4]([CH:19]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:20]([OH:22])=[O:21])[C:3]=1[CH3:28].[CH:29]([B-](F)(F)F)=[CH2:30].[K+]>>[C:24]([O:23][CH:19]([C:4]1[C:3]([CH3:28])=[C:2]([CH:29]=[CH2:30])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[C:20]([OH:22])=[O:21])([CH3:26])([CH3:27])[CH3:25]
Reactant: Cc1c(C(OC(C)(C)C)C(=O)O)c(-c2ccc(Cl)cc2)c2ccccc2c1Br
Reactant: C=C[B-](F)(F)F
Agent: [K+]
Product: C=Cc1c(C)c(C(OC(C)(C)C)C(=O)O)c(-c2ccc(Cl)cc2)c2ccccc12

Procedure:
2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-4-vinylnaphthalen-2-yl)acetic acid (128) was prepared in a similar manner as 2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetic acid of Example 125, except using potassium vinyltrifluoroborate in the Suzuki coupling reaction, giving the title compound (parent form). 1H NMR (400 MHz, DMSO-d6) δ 12.78 (s, broad, 1H), 8.13 (d, J=8.2 Hz, 1H), 7.73-7.65 (m, 2H), 7.54-7.48 (m, 2H), 7.41-7.36 (m, 2H), 7.20 (d, J=8.2 Hz, 1H), 7.11 (dd, J=18.0, 11.7 Hz, 1H), 5.87 (d, J=11.4 Hz, 1H), 5.41 (d, J=18.0 Hz, 1H), 5.09 (s, 1H), 2.50 (s, 3H), 0.94 (s, 9H). LCMS-ESI− (m/z): [2M-2H+Na]− calcd for C50H48Cl2NaO6: 839.3; Found: 839.2.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH:13]=[O:14])=O)(C)(C)C.[CH:15]1([Mg]Cl)[CH2:17][CH2:16]1.C(=O)([O-])O.[Na+].ClCCl>O1CCCC1>[CH:15]1([C@H:13]([CH:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)[OH:14])[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C=O
Reactant: Cl[Mg]C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: O[C@H](C1CC1)C1CCCN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.2 %

Procedure:
To a solution of (R)-2-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (200 mg, 1 mmol) in tetrahydrofuran at −78° C. was added a 1 M solution of cyclopropylmagnesium chloride (1.3 ml, 1.3 mmol). After stirring for 1 h at room temperature and addition of aqueous sodium hydrogencarbonate, extraction (3 times with dichloromethane), drying of the combined organic layers over sodium sulfate and evaporation of the solvents the crude product was heated with aqueous sodium hydroxide at 100° C. for 3 days to give 20 mg of crude cyclopropyl-(R)-pyrrolidin-2-yl-methanol which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]([C:31]([OH:33])=O)[C:18]3[C:23]([CH3:24])=[N:22][N:21]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][O:26]4)[C:19]=3[N:20]=2)=[C:11]([F:34])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:44]([O:48][C:49]([N:51]1[CH2:56][CH2:55][NH:54][CH:53]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH2:52]1)=[O:50])([CH3:47])([CH3:46])[CH3:45]>C(Cl)Cl.O>[C:44]([O:48][C:49]([N:51]1[CH2:56][CH2:55][N:54]([C:31]([C:17]2[C:18]3[C:23]([CH3:24])=[N:22][N:21]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][O:26]4)[C:19]=3[N:20]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:10][C:11]=3[F:34])[CH:16]=2)=[O:33])[CH:53]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH2:52]1)=[O:50])([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(C)(C)OC(=O)N1CCNC(c2ccccc2)C1
Reactant: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OCc4ccccc4)cc3F)cc(C(=O)O)c12
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OCc4ccccc4)cc3F)cc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3c3ccccc3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.1 %

Procedure:
To a suspension of 571 mg of 6-(4-benzyloxy-2-fluoro-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid in 14 ml of DCM were added 0.64 ml of Hünig's base, 408 mg of BEP and 390 mg of 3-phenyl-piperazine-1-carboxylic acid tert-butyl ester. The reaction was stirred overnight at r.t. For workup it was diluted with water and DCM and the layers were separated. The organic layer was washed with water twice, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica, heptane/EtOAc gradient) to obtain 900 mg (100%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:12]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]4[NH:22][CH:23]=[C:24]([C:26]([O:28]C)=[O:27])[N:25]=4)=[CH:16][CH:15]=3)[C:10]([CH2:30][CH3:31])=[C:9]([CH3:32])[N:8]=2)=[CH:4][CH:3]=1.[Li+].[OH-].O.C1COCC1.Cl>O.CO>[Cl:1][C:2]1[S:6][C:5]([C:7]2[N:12]=[C:11]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([CH2:20][C:21]4[NH:22][CH:23]=[C:24]([C:26]([OH:28])=[O:27])[N:25]=4)=[CH:18][CH:19]=3)[C:10]([CH2:30][CH3:31])=[C:9]([CH3:32])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Nc1ccc(Cc2nc(C(=O)OC)c[nH]2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Nc1ccc(Cc2nc(C(=O)O)c[nH]2)cc1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
A 8-mL vial was charged with methyl 2-[[4-[[2-(5-chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]amino]phenyl]methyl]-1H-imidazole-4-carboxylate (8 mg, 0.017 mmol, 1 eq.), LiOH/H2O (19 mg, 0.44 mmol, 26 eq.), THF (1 ml), MeOH (0.2 ml) and water (0.2 ml). The resulting mixture was stirred at 55° C. overnight. After cooling to room temperature, the mixture was added 2N HCl aq. to pH 6˜7. The precipitate was collected by filtration and washed with water. After drying, the title compound was obtained as a solid (4.8 mg, 62% yield). MW=453.94. 1H NMR (400 MHz, DMSO-d6) δ 8.52 (brs, 1H), 7.65 (m, 3H), 7.55 (d, J=4.0 Hz, 1H), 7.25 (d, J=8.0 Hz, 2H), 7.16 (d, J=4.0 Hz, 1H), 3.97 (s, 2H), 2.73 (q, J=7.2 Hz, 2H), 2.49 (s, 3H), 1.09 (t, J=7.2 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14]([OH:16])=[O:15])[C:7](=[CH:12][CH:13]=1)[CH2:8][C:9]([OH:11])=[O:10])([O-])=O.[H][H].[K+].[Br-]>[OH-].[Na+].[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:14]([OH:16])=[O:15])[C:7](=[CH:12][CH:13]=1)[CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: [H][H]
Agent: [Pd]
Agent: [Br-]
Agent: [K+]
Product: Nc1ccc(CC(=O)O)c(C(=O)O)c1
Yield: 81 %

Procedure:
Compound 13 (15.75 g/0.07 mol) was then dissolved in 150 ml 1N NaOH, treated with 0.55 g of 5% Pd—C and placed in a 500 ml Parr bottle. The resultant mixture was hydrogenated at 47 psi for 3 hours or until the uptake of hydrogen ceased. The solution was suction filtered through Celite, washed with a minimum amount of DI water and then acidified with c. HCl to pH 4-5. The solution was stored in the refrigerator (scratch to induce crystallization) over night. The product crystallized and was isolated by suction filtration. A second and third crop can be obtained by allowing the filtrate to slowly concentrate at room temperature. The product formed: 11 g (81% yield). 1H NMR (d6-DMSO): δ 7.13 (s, 1H), 6.91 (d, J=8 Hz, 1H), 6.64 (d, J=8 Hz, 1H), 3.69 (s, 2H); IR (KBr): 3320-3640 (br), 1700 (s), 1550 (s) cm−1; EI-MS (m/z) 194.1 (M−); MS/MS 150; Anal. Calcd. for C9H9NO4.(H2O)0.25: C, 54.13; H, 4.80; N, 7.02%. Found: C, 54.09; H, 5.26; N, 7.01; Na, 0.29%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH:10]=[C:11]([C:13]([NH:15][C@@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]2[OH:22])=[O:14])[N:12]=1.[CH:30]1C=CC=CC=1.[OH-].[Na+].CI>[N+](CCCC)(CCCC)(CCCC)CCCC.[O-]S(O)(=O)=O.O.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:23]2[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=2)[CH:10]=[C:11]([C:13]([NH:15][C@@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C@@H:17]2[O:22][CH3:30])=[O:14])[N:12]=1
Reactant: O=C(N[C@@H]1CCCC[C@H]1O)c1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1
Reactant: c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CCCCCC
Product: CO[C@H]1CCCC[C@H]1NC(=O)c1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1
Temperature: 10 °C
Yield: 63 %

Procedure:
A flask was charged with 2-(2-chlorophenyl)-1-(4-chlorophenyl)-N-[trans-2-hydroxycyclohexyl]-1H-imidazole-4-carboxamide (Table entry 336) (35 mg, 0.1 mmol), benzene (3 mL), 50% aqueous NaOH (2.5 mL), and Bu4NHSO4 (17 mg). While the mixture was stirred vigorously at 10° C., CH3I (19 μL, 0.3 mmol) was added dropwise rapidly. The mixture was stirred for another 30 minutes, and diluted with water (5 mL) and hexane (10 mL). The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (75% EtOAc in hexane) to give the product 2-(2-chlorophenyl)-1-(4-chlorophenyl)-N-[(1R,2S)-2-methoxycyclohexyl]-1H-imidazole-4-carboxamide (23 mg, 63% yield): LC-MS m/z 444.2 (MH+), retention time 3.24 min (method 1).
Reaction SMILES: [OH-].[Na+].[CH:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[C:4]31[O:16][O:15][C:14]1([CH2:21][CH2:20][CH:19]([CH2:22][C:23]([O-:25])=[O:24])[CH2:18][CH2:17]1)[O:13]3)[CH2:10]2.Cl>O.C(O)C>[CH:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[C:4]31[O:16][O:15][C:14]1([CH2:21][CH2:20][CH:19]([CH2:22][C:23]([OH:25])=[O:24])[CH2:18][CH2:17]1)[O:13]3)[CH2:10]2
Reactant: O=C([O-])CC1CCC2(CC1)OOC1(O2)C2CC3CC(C2)CC1C3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CC1CCC2(CC1)OOC1(O2)C2CC3CC(C2)CC1C3
Temperature: 50 °C
Reaction time: 4 h

Procedure:
Sodium hydroxide (3.86 g, 96.57 mmol, 3 equiv.) in water (80 mL) was added to a solution of methyl (1 s, 4 s)-dispiro[cyclohexane-1,3′-[1,2,4]trioxolane-5′,2″-tricyclo[3.3.1.13,7]decan]-4-ylacetate (example 3) (10.83 g, 32.19 mmol, 1 equiv.) in 95% ethanol (150 mL). The mixture was stirred at 50° C. for about 4 h, cooled to 0° C., and treated with 1M hydrochloric acid (129 ml, 4 equiv). The precipitate was collected by filtration, washed with 50% aqueous ethanol (150 mL) and dried in vacuum at 40° C. to give the title compound as colorless solid. Yield: 9.952 g, 96%, mp: 146-148° C. (95% ethanol), 1HNMR (500 Hz, CDCl3): δ 1.19-1.41 (m, 2H), 1.60-2.05 (m, 21H), 2.27 (d, J=6.8 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:22][CH3:23])=[C:14]([S:17][CH2:18][CH2:19][O:20][CH3:21])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[C:4]([F:26])[CH:3]=1.[OH:27]OS([O-])=O.[K+].C(Cl)Cl.C(OCC)(=O)C.CO>CO.O>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:22][CH3:23])=[C:14]([S:17]([CH2:18][CH2:19][O:20][CH3:21])=[O:27])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[C:4]([F:26])[CH:3]=1
Reactant: COCCSc1cc2c(Nc3ccc(Cl)cc3F)ccnc2cc1OC
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: CCOC(C)=O
Product: COCCS(=O)c1cc2c(Nc3ccc(Cl)cc3F)ccnc2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.2 %

Procedure:
4-(4-Chloro-2-fluoroanilino)-7-methoxy-6-(2-methoxyethylthio)quinoline (175 mg, 0.45 mmol), (prepared as described in Example 62), was dissolved in methanol (40 ml), OXONE, (trade mark of E.I. du Pont de Nemours & Co.,Inc), (230 mg in 5 ml of water) was added and the mixture was stirred at ambient temperature for 30 minutes. More OXONE, (trade mark of E.I. du Pont de Nemours & Co.,Inc), (60 mg) was added and the mixture was stirred for a further hour. The mixture was diluted with 100 ml of water and extracted with methylene chloride (3×100 ml). The combined extracts were washed with brine, dried by passing through phase separating paper and the volatiles were removed by evaporation. The solid was purified on a Mega Bond Elute (trade mark of Varian Sample Preparation Products) column using first methylene chloride (100%) and gradually increasing the solvent polarity up to methylene chloride/methanol (95/5). The volatiles were removed by evaporation to give 4-(4-chloro-2-fluoroanilino)-7-methoxy-6-(2-methoxyethylsulphinyl)quinoline (120 mg, 66%).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:26][CH:27]2[CH2:29][CH2:28]2)[CH:8]=[C:9]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)=[O:13])[N:10]=1)=[O:5])C.O.[OH-].[Na+]>C(O)C>[F:25][C:22]([F:23])([F:24])[O:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:12]([NH:11][C:9]2[N:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]([CH2:26][CH:27]3[CH2:28][CH2:29]3)[CH:8]=2)=[O:13])=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1nc(NC(=O)Nc2ccc(OC(F)(F)F)cc2)cn1CC1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)Nc1cn(CC2CC2)c(C(=O)O)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10.6 g (28.1 mmol) of 4-[({[4-(trifluoromethoxy)phenyl]amino}-carbonyl)amino]-1-(cyclopropylmethyl)-1H-imidazole-2-carboxylic acid ethyl ester is suspended in 158 ml of ethanol. While being cooled with ice, 16.4 ml of water and 6 ml (112 mmol) of 50% aqueous sodium hydroxide solution are added. The reaction mixture is stirred for 1 hour at room temperature and then concentrated by evaporation in a vacuum. The residue is taken up in 100 ml of isopropanol and mixed with 100 ml of 1N hydrochloric acid while being cooled with ice. The crystals are suctioned off and dried in a vacuum at 40° C.
Reaction SMILES: [CH3:1][C:2]12[O:10][C:3]1([C:11](=[O:15])/[CH:12]=[CH:13]/[CH3:14])[C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][CH2:7]2>O1CCOCC1>[CH3:1][C:2]1[C:3]([OH:10])([C:11](=[O:15])/[CH:12]=[CH:13]/[CH3:14])[C:4]([CH3:8])([CH3:9])[CH2:5][CH2:6][CH:7]=1
Reactant: C/C=C/C(=O)C12OC1(C)CCCC2(C)C
Solvent: C1COCCO1
Product: C/C=C/C(=O)C1(O)C(C)=CCCC1(C)C

Procedure:
A mixture of the cis- and trans-isomers of 2,6,6-trimethyl-1-crotonoyl-1,2-epoxycyclohexane (10 g.) [cf. Example 32] and 2 g. of acid diatomaceous earth in 50 ml. of dioxan was heated under nitrogen at 100°-105°.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CS(C)=O.C(OCC)(=O)C>[CH2:9]([N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1CCCN1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C1CCCN1Cc1ccccc1
Reaction time: 5 h

Procedure:
14.4 g (0.33 mol) of 50% sodium hydride dispersion in oil are added in batches to 25.5 g (0.3 mol) of 2-pyrrolidone in 300 ml of absolute dimethylsulphoxide. The mixture is then stirred for 5 hours at 40° to 50° C. and at 25°-30° C. 56.4 g=39.2 ml (0.33 mol) of benzyl bromide are added dropwize. After stirring for 10 hours at ambient temperature the reaction mixture is dissolved in 500 ml of ethyl acetate and extracted several times with water. The organic phase is separated off, dried over magnesium sulphate and the solvent is eliminated in vacuo. The residue obtained is purified over 900 g of aluminium oxide (neutral, activity II) with methylene chloride and 0.1% ethanol. Yield: 35.6 g (67.7% of theory), Rf value: 0.77 (aluminium oxide, neutral, eluant: 5% ethanol in methylene chloride).