Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][S:9]C1C=CC(O)=CC=1>>[CH3:8][S:9][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[OH:7]
Reactant: Oc1ccccc1
Reactant: CSc1ccc(O)cc1
Product: CSc1ccccc1O
Temperature: 25 °C
Yield: 41 %

Procedure:
The mixture was cooled to room temperature and filtered. The catalyst was washed several times with ether and allowed to dry. The filtrate and ether washings were combined, and volatiles were removed on a rotary flash evaporator. GC analysis indicated the presence of phenol (5.3 g. 42% recovered), ortho(methylthio)phenol (5.2 g. 41% yield), para-(methylthio)phenol (2.0 g, and di-(methylthio)phenols (2.0 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[NH:28][C:29]([CH:31]3[CH2:33][CH2:32]3)=[O:30])[CH2:19]2)[CH2:13][C:14](=[O:17])[NH:15][OH:16])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[C:34](Cl)(=[O:38])[CH:35]([CH3:37])[CH3:36]>C(#N)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[NH:28][C:29]([CH:31]3[CH2:33][CH2:32]3)=[O:30])[CH2:19]2)[CH2:13][C:14](=[O:17])[NH:15][O:16][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CC(C)C(=O)Cl
Reactant: CCOc1cc([C@@H](CC(=O)NO)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Solvent: CC#N
Product: CCOc1cc([C@@H](CC(=O)NOC(=O)C(C)C)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Reaction time: 24 h
Yield: 66 %

Procedure:
To a solution of (1R)-cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-2-hydroxycarbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide (500 mg, 1.1 mmol) in acetonitrile (5 mL) was added isobutyryl chloride (0.15 mL, 1.4 mmol) at room temperature and kept for 24 hrs. The solution was extracted with ethyl acetate (50 mL) and sodium hydrogen carbonate (50 mL, sat). The organic layer was dried over MgSO4. Filtration and removal of solvent gave (1R)-cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-2-isobutyryloxycarbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide (380 mg, 66% yield): mp, 107-109° C.; 1H NMR (DMSO-d6) δ 0.86-0.89 (m, 4H, 2CH2), 1.10 (d, J=7 Hz, 6H, 2CH3), 1.31 (t, J=7 Hz, 3H, CH3), 1.73-1.81 (m, 1H, CH), 2.62-2.73 (m, 1H, CH), 3.02-3.05 (m, 2H, CH2), 3.73 (s, 3H, CH3), 3.96-4.05 (m, 2H, CH2), 4.19 (d, J=18 Hz, 1H, NCHH), 4.59 (d, J=18 Hz, 1H, NCHH), 5.67 (t, J=8 Hz, 1H, NCH), 6.86-6.94 (m, 3H, Ar), 7.19 (d, J=8 Hz, 1H, Ar), 7.50 (d, J=8 Hz, 1H, Ar), 8.23 (d, J=8 Hz, 1H, Ar), 10.54 (s, 1H, NH), 11.86 (s, 1H, NH); 13C NMR (DMSO-d6) δ 7.76, 14.69, 15.46, 18.65, 31.27, 34.64, 46.59, 51.07, 55.47, 63.80, 111.93, 112.09, 116.82, 117.32, 117.50, 119.27, 131.23, 132.77, 136.98, 142.25, 147.95, 148.58, 166.61, 168.04, 171.72, 174.29; Anal Calcd for C28H33N3O7+0.11 H2O: C, 63.99; H, 6.37; N, 8.00; H2O, 0.38. Found: C, 63.64; H, 6.37; N, 7.70; H2O, 0.39.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl[C:8]1[C:9]([CH:14]2[CH2:17][N:16]([C:18]3[N:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)[CH2:15]2)=[N:10][CH:11]=[CH:12][N:13]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>O1CCOCC1.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>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:8]2[C:9]([CH:14]3[CH2:17][N:16]([C:18]4[N:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[CH2:15]3)=[N:10][CH:11]=[CH:12][N:13]=2)=[CH:31][CH:30]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Clc1nccnc1C1CN(c2ncc3ccccc3n2)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Clc1ccc(-c2nccnc2C2CN(c3ncc4ccccc4n3)C2)cc1
Temperature: 80 °C
Reaction time: 17 h
Yield: 63.7 %

Procedure:
2M aqueous sodium carbonate (0.378 mL, 0.756 mmol, J. T. Baker) was added to a stirred mixture of 2-(3-(3-chloropyrazin-2-yl)azetidin-1-yl)quinazoline (0.075 g, 0.252 mmol, Preparation 1), trans-dichlorobis(triphenylphosphine)palladium (ii) (0.009 g, 0.013 mmol, Strem), and 4-chlorophenylboronic acid (0.047 g, 0.302 mmol, ASDI) in 1,4-dioxane (1 mL) in a sealed tube under an argon atmosphere. The reaction mixture was stirred at 80° C. for 17 h. The reaction mixture was concentrated in vacuo and diluted with DCM. The resulting suspension was filtered, and the filtrate was concentrated in vacuo. The resulting crude material was purified via reverse phase HPLC (Column: Xbridge 19×100 mm, 5 μm, 1771302301) eluting with 0.1% NH4OH in acetonitrile/water to give 0.060 g (64%) of a yellow amorphous solid.
Reaction SMILES: CC([O:7][C:8]([C:10]1[N:15]2[C:16]([C@@H:18]([NH:19][C:20](/[C:22](/[C:26]3[O:30][CH:29]=[CH:28][CH:27]=3)=[N:23]\[O:24][CH3:25])=[O:21])[C@H:14]2[S:13][CH2:12][C:11]=1[CH2:31][O:32][C:33]([NH2:35])=[O:34])=[O:17])=[O:9])OC(C)=O.[O-]CC.[Na+].Cl>O1CCCC1.C(O)C>[CH3:25][O:24]/[N:23]=[C:22](\[C:20]([NH:19][C@@H:18]1[C:16](=[O:17])[N:15]2[C:10]([C:8]([OH:9])=[O:7])=[C:11]([CH2:31][O:32][C:33]([NH2:35])=[O:34])[CH2:12][S:13][C@H:14]12)=[O:21])/[C:26]1[O:30][CH:29]=[CH:28][CH:27]=1
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(C)OC(C)=O)=C(COC(N)=O)CS[C@H]12)c1ccco1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1ccco1
Temperature: -60 °C
Reaction time: 1 h

Procedure:
Cefuroxime axetil (20.4 gm, predominantly S-isomer) was dissolved in a mixture of tetrahydrofuran (204 ml) and ethyl alcohol (58 ml). The solution was cooled to −60° C., sodium ethoxide (6.59 gm) was added in portions and the reaction mixture was stirred for 1 hour. Aqueous hydrochloric acid was added and the procedure described in Example 1 was followed to obtain cefuroxime (15.67 gm).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:6][C:7](=[O:21])[C:8]([F:20])([F:19])[CH2:9][N:10]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[H-].[Na+].[CH3:24]I>CC(N(C)C)=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:24])[C:7](=[O:21])[C:8]([F:19])([F:20])[CH2:9][N:10]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1
Reactant: CI
Reactant: O=C1Nc2cnc(Cl)nc2N(C2CCCCC2)CC1(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CN1C(=O)C(F)(F)CN(C2CCCCC2)c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.8 %

Procedure:
To a solution of compound 2-Chloro-9-cyclohexyl-7,7-difluoro-8,9-dihydro-5H-pyrimido[5,4-b][1,4]diazepin-6(7H)-one (6.0 g, 18.98 mmol) in 30 mL of DMA was added sodium hydride (60% dispersion in mineral oil, 1.138 g, 28.47 mmol) at 0° C., followed by the dropwise addition of methyl iodide (1.42 mL, 22.78 mmol). The reaction mixture was warmed up to rt and stirred for 1 h. The whole was poured into ice-water, extracted with ethyl acetate. The organic layer was washed with brine and dried over Na2SO4. The solution was concentrated in vacuo followed by precipitation from ether/EtOA to afford the desired compound (3.0 g, 47.9% yield) as white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.97-1.85 (m, 10H) 3.33 (s, 3H) 4.15 (t, J=12.88 Hz, 2H) 4.44 (m, 1H) 8.31 (s, 1H). [M+H] calc'd for C14H17ClF2N4O, 331. found 331.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][CH3:21])[N:13](C(OC(C)(C)C)=O)[N:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].C(Cl)Cl>CN(C=O)C.O>[Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][CH3:21])[NH:13][N:12]=2)[CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:34])[CH3:35])(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: COc1cccc2c1c(N(COCC[Si](C)(C)C)S(=O)(=O)c1ccc(Cl)s1)nn2C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc2[nH]nc(N(COCC[Si](C)(C)C)S(=O)(=O)c3ccc(Cl)s3)c12
Temperature: 80 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To a solution of 1,1-dimethylethyl 3-[[(5-chloro-2-thienyl)sulfonyl]({[2-(trimethylsilyl)ethyl]oxy}methyl)amino]-4-(methyloxy)-1H-indazole-1-carboxylate (for a preparation see Intermediate 7) (3.12 g, 5.43 mmol) in DMF (20 mL) was added a solution of sodium carbonate (0.864 g, 8.15 mmol) in water (20 mL) at room temperature. A white suspension was obtained and a warming of the medium was noticed. The resulting suspension was stirred overnight at 80° C., the reaction mixture was then cooled to room temperature, and more sodium carbonate (300 mg) was added. The resulting mixture was then stirred at 85° C. After 3 h of stirring, 50 mL of water and 50 mL of DCM were added to the reaction mixture. The organic layer was partitioned and the aqueous layer was further extracted with 30 mL of DCM. The organic solutions were combined, dried with an hydrophobic frit and concentrated under reduced pressure. The crude oil was purified by chromatography on two 100 g Si cartridges on Flashmaster, eluting with a 0 to 25% gradient of EtOAc in cyclohexane, over 25 min. The pure fractions were combined to give the title product as an orange gum (1.62 g, 63%) LCMS (System A) RT=1.41 min, ES+ve m/z 474/476 (M+H)+. Impure fractions were combined and repurified by chromatography on a 70 g silica cartridge on Flashmaster, eluting with a 0 to 25% gradient of EtOAc in cyclohexane over 40 min. Fractions containing pure product were combined to give more of the desired product (277 mg, 11%)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[N:4][C:3]=1Cl.[CH2:11]([NH:15][CH:16](O)[CH3:17])[CH2:12][CH2:13][CH3:14].C(=O)([O-])[O-:20].[K+].[K+].[OH-].[K+]>O1CCOCC1.O>[CH2:11]([N:15]1[CH2:16][CH2:17][O:20][C:3]2[N:4]=[C:5]([Cl:9])[C:6]([Cl:8])=[N:7][C:2]1=2)[CH2:12][CH2:13][CH3:14]
Reactant: Clc1nc(Cl)c(Cl)nc1Cl
Reactant: CCCCNC(C)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCCCN1CCOc2nc(Cl)c(Cl)nc21
Yield: 47.7 %

Procedure:
A mixture of tetrachloropyrazine (21.8 g, 0.1 mol), n-butylaminoethanol (11.7 g, 0.1 mol), and potassium carbonate (28 g, 0.2 mol) were heated to 80° in 225 ml of dioxane and 50 ml of water for 24 hours. After extraction with CH2Cl2 and concentration with rotary evaporation, 30 g of an oil characterized by nmr as the N-substituted product was obtained. An attempt to distill 5 g of this material led to decomposition. The rest of the material was dissolved in 200 ml of benzene and refluxed for 2 hours with crushed KOH (10 g, 85% assay, 0.15 mol). The mixture was partitioned between water and CH2Cl2. The organic layer was dried (MgSO4) and rotary evaporated to give a crude oil. This was distilled two times on a Kugelrohr apparatus (b.p. about 130° at 0.5 mm Hg) to give 12.5 g (48% yield) of the title product.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH3:23])[CH:17]=1.[CH:24]1([NH2:27])[CH2:26][CH2:25]1>>[CH:24]1([NH:27][C:11](=[O:12])[C:10]2[CH:14]=[CH:15][C:7]([N:6]3[C:2]([OH:1])=[C:3]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH3:23])[CH:17]=4)[CH:4]=[N:5]3)=[N:8][CH:9]=2)[CH2:26][CH2:25]1
Reactant: NC1CC1
Reactant: COc1cc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccn1
Product: COc1cc(-c2cnn(-c3ccc(C(=O)NC4CC4)cn3)c2O)ccn1

Procedure:
The title compound was prepared in a manner similar to Example 198 using 6-(5-hydroxy-4-(2-methoxypyridin-4-yl)-1H-pyrazol-1-yl)nicotinic acid and cyclopropanamine. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.49-0.57 (m, 2H) 0.63-0.71 (m, 2H) 2.80 (td, J=7.3, 3.8 Hz, 1H) 3.82 (s, 3H) 7.41 (br. s., 1H) 7.48 (d, J=5.6 Hz, 1H) 8.01 (d, J=5.8 Hz, 1H) 8.27-8.35 (m, 1H) 8.38 (br. s., 1H) 8.51-8.68 (m, 2H) 8.76-8.85 (m, 1H). MS m/z 352 [M+H]+.
Reaction SMILES: C(Cl)(=O)C.[CH3:5][C:6]1([CH3:34])[C:10]([CH3:12])([CH3:11])[O:9][B:8]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][O:23]C3CCCCO3)=[C:15]([C:30]([F:33])([F:32])[F:31])[CH:14]=2)[O:7]1>CO>[CH3:11][C:10]1([CH3:12])[C:6]([CH3:5])([CH3:34])[O:7][B:8]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][OH:23])=[C:15]([C:30]([F:32])([F:33])[F:31])[CH:14]=2)[O:9]1
Reactant: CC1(C)OB(c2ccc(OCCCOC3CCCCO3)c(C(F)(F)F)c2)OC1(C)C
Solvent: CO
Solvent: CC(=O)Cl
Product: CC1(C)OB(c2ccc(OCCCO)c(C(F)(F)F)c2)OC1(C)C
Reaction time: 0.17 h
Yield: 101.2 %

Procedure:
Acetyl chloride (14.26 ml) was added to MeOH (150 ml) at 0° C. and stirred for 10 minutes. The above mixture was added to 4,4,5,5-tetramethyl-2-(4-(3-(tetrahydro-2H-pyran-2-yloxy)propoxy)-3-(trifluoromethyl)phenyl)-1,3,2-dioxaborolane (43 g) in MeOH (300 ml) and stirred at 50° C. for 1.5 hours. The solvent was removed under reduced pressure, DCM was added to the residue and it was basified with sodium bicarbonate, washed with water, and the DCM was removed under reduced pressure to give expected compound (35 g). 1H NMR (CDCl3) δ: 8.00 (s, 1H), 7.92 (d, 1H), 6.98 (d, 1H), 4.21 (t, 2H), 3.86 (t, 2H), 2.07 (quin, 2H), 1.34 (s, 12H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:20]1([NH:23][C:24]([C:26]2[S:39][C:29]3=[N:30][C:31](S(C)=O)=[C:32]([Cl:35])[C:33]([CH3:34])=[C:28]3[C:27]=2[NH2:40])=[O:25])[CH2:22][CH2:21]1>C1COCC1.O>[CH:20]1([NH:23][C:24]([C:26]2[S:39][C:29]3=[N:30][C:31]([O:1][CH2:2][CH2:3][N:4]4[CH2:9][CH2:8][O:7][CH2:6][CH2:5]4)=[C:32]([Cl:35])[C:33]([CH3:34])=[C:28]3[C:27]=2[NH2:40])=[O:25])[CH2:22][CH2:21]1
Reactant: OCCN1CCOCC1
Reactant: Cc1c(Cl)c(S(C)=O)nc2sc(C(=O)NC3CC3)c(N)c12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(Cl)c(OCCN2CCOCC2)nc2sc(C(=O)NC3CC3)c(N)c12
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 58.9 %

Procedure:
To a solution of 4-(2-hydroxyethyl)morpholine (5.72 g, 43.62 mmol) in THF (25 ml) at room temperature is added dropwise a solution of lithium bis(trimethylsilyl)-amide (1.0 M in hexanes) (21.80 ml, 21.80 mmol). The reaction mixture is stirred for 15 minutes, and then is treated with 3-amino-5-chloro-6-methanesulfinyl-4-methyl-thieno[2,3-b]pyridine-2-carboxylic acid cyclopropylamide (30 g, 8.72 mmol). The reaction vessel is sealed and heated at 80° C. for 3 hours. The reaction is cooled to room temperature and quenched by the addition of water (200 ml). A yellow precipitate is formed. The mixture is diluted to 350 ml with water and cooled to 0° C. The yellow precipitate is collected by filtration. The solid is slurried in 100 ml of 3:1 hexane:EtOAc and stirred for 10 minutes. The mixture is filtered, and the collected solid is dried in the vacuum oven overnight to afford the title compound as a yellow solid (2.11 g, 59%). Mass (m/z): 411.1 (M++1), 409.1 (M+−1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:5][CH2:6]Br.C[N+]([O-:25])(C)C.CS(C)=O>>[CH3:1][O:2][C:3](=[O:20])[C:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:5][CH:6]=[O:25]
Reactant: COC(=O)C(CCBr)(c1ccccc1)c1ccccc1
Reactant: C[N+](C)(C)[O-]
Solvent: CS(C)=O
Product: COC(=O)C(CC=O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-bromo-2,2-diphenyl-butyric acid methyl ester (0.10 g, 0.300 mmol) and trimethylamine N-oxide (0.09 g, 1.2 mmol) in dimethyl sulfoxide (0.5 mL, 7 mmol) was stirred overnight at room temperature. The reaction was quenched with cold brine. The crude product was extracted three times with dichloromethane, dried over a bed of Na2SO4, filtered, and concentrated to dryness to provide crude title compound which was used without further purification.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:25])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([CH3:14])[C:7]=1[NH:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1.O.CO>O1CCCC1>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]([NH:15][C:7]2[C:8]([CH3:14])=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:6]=2[C:5]([OH:25])=[O:4])=[O:24])=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccc(OC)c(C)c1NC(=O)c1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=O)O)c(NC(=O)c2ccc(F)cc2)c1C
Temperature: 50 °C
Yield: 101.4 %

Procedure:
LiOH (1M, 4 mL) was added to a solution of 2-(4-fluoro-benzoylamino)-4-methoxy-3-methyl-benzoic acid methyl ester (28) (870 mg, 2.7 mmol), in tetrahydrofuran (15 ml), water (7.5 ml) and methanol (7.5 ml). The mixture was heated to 50° C. for 4 h. Water (30 ml) was then added and the volume reduced to half. Acidification with acetic acid followed by filtration gave pure title compound (830 mg, 100%).
Reaction SMILES: [Li+].[CH3:2][CH:3]([N-]C(C)C)[CH3:4].[CH3:9][CH:10]([CH3:34])[CH2:11][C:12]1([CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]1=[O:25].C(Br)C=C>C1COCC1>[CH3:9][CH:10]([CH3:34])[CH2:11][C:12]1([CH:26]([C:3]([CH3:4])=[CH2:2])[C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]1=[O:25]
Reactant: CC(C)[N-]C(C)C
Reactant: CC(C)CC1(CC(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=C(C)C(C(=O)OC(C)(C)C)C1(CC(C)C)CCN(CCc2ccccc2)C1=O
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 85.9 %

Procedure:
LDA (2.0M, 7.7 mL, 16 mmol) is added to a solution of tert-butyl 3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate (EXAMPLE 1, step 3; 4.62 g, 12.9 mmol) and THF (45 mL) at -78° C. The solution is stirred at -78° C. for 45 minutes and allyl bromide (1.3 mL, 16 mmol) is added. The solution is allowed to warm to 0° C. over 2 hours, and is allowed to stir overnight at room temperature. After quenching with saturated aqueous ammonium chloride, aqueous workup (EtOAc, MgSO4) and purification by column chromatography (2:1:17 v/v EtOAc:CH2Cl2 :hexane) gives 4.43 g (86%) of the title compound as yellow oil which solidified upon standing (mp 54.5°-56° C.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[CH:25]=O)[CH:7]=1)[CH3:2].[CH2:28]([NH2:30])[CH3:29]>>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][C:16]=2[CH2:25][NH:30][CH2:28][CH3:29])[CH:7]=1)[CH3:2]
Reactant: CCN
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(C(F)(F)F)cc2C=O)c1
Product: CCNCc1cc(C(F)(F)F)ccc1Oc1cc(CC(=O)OCC)ccc1OC

Procedure:
Prepared according to the procedure described in Example 3, Step 2, using the following starting materials: [3-(2-formyl-4-trifluoromethyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester and ethylamine (2M in THF).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([C:28]2[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=2)=[C:8]2[C:12](=[CH:13][C:14]=1[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[C@@H:11]1[CH2:24][CH2:25][CH2:26][N:10]1[C:9]2=[O:27])=[O:5])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:49]([NH2:55])[C:50]1[O:54][CH:53]=[CH:52][CH:51]=1>C1COCC1>[F:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][CH2:15][C:14]2[CH:13]=[C:12]3[C:8]([C:9](=[O:27])[N:10]4[CH2:26][CH2:25][CH2:24][C@H:11]43)=[C:7]([C:28]3[CH:29]=[CH:30][C:31]([C:32]([NH:55][CH2:49][C:50]4[O:54][CH:53]=[CH:52][CH:51]=4)=[O:33])=[CH:35][CH:36]=3)[C:6]=2[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:18][CH:19]=1
Reactant: CCOC(=O)c1c(CCc2ccc(F)cc2)cc2c(c1-c1ccc(C(=O)O)cc1)C(=O)N1CCC[C@@H]21
Reactant: NCc1ccco1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOC(=O)c1c(CCc2ccc(F)cc2)cc2c(c1-c1ccc(C(=O)NCc3ccco3)cc1)C(=O)N1CCC[C@@H]21
Temperature: 25 °C
Reaction time: 12 h
Yield: 70000 %

Procedure:
A solution of Example 49 (241 mg, 0.49 mmol) and carbonyldimidazole (0.54 mmol, 88.2 mg) in THF (anhydrous, 15 ml) was stirred for 1 hr at r.t. Then was added dropwise a solution of furfurylamine (96.1 mg, 0.99 mmol) in THF (2 ml) and the mixture stirred at r.t. for 12 hr. Then the reaction mixture concentrated and the yellow oil purified on SiO2 (ethyl acetate:hexanes 1:5) to afford the title compound as a white solid (194 mg, 343 mmol): 1H NMR (400 MHz, d6-DMSO) δ 9.03 (t, 1H), 7.82 (d, J=8.6 Hz, 2H), 7.53 (d, J=8.2 Hz, 2H), 7.26 (d, J=8.2 Hz, 2H), 7.20–7.17 (m, 2H), 7.09–7.04 (m, 2H), 6.36 (d, J=4.0 Hz, 1H), 6.25 (d, J=4.0 Hz, 1H), 4.69–4.65 (m, 1H), 4.46–4.44 (m, 2H), 3.91 (q, 2H), 3.39–3.36 (m, 1H), 3.19–3.13 (m, 1H), 2.90–2.79 (m, 4H), 2.28–2.18 (m, 3H), 1.13–1.08 (m, 1H), 1.08 (t, 3H) ppm. ESI-MS m/z 567 (M+H)+. HPLC (99%). Anal. calcd. for C34H31N2O5F 0.41H2O: C, 71.14; H, 5.59; N, 4.88. Found: C, 71.14; H, 5.66; N, 4.84.
Reaction SMILES: [I:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[CH:8]=2)[N:4]([CH3:18])[C:3]=1[C:19]([OH:21])=O.Cl.Cl.[NH:24]1[CH2:29][CH2:28][CH:27]([N:30]2[CH2:34][CH2:33][CH2:32][C@@H:31]2[CH2:35][OH:36])[CH2:26][CH2:25]1>>[OH:36][CH2:35][C@@H:31]1[CH2:32][CH2:33][CH2:34][N:30]1[CH:27]1[CH2:28][CH2:29][N:24]([C:19]([C:3]2[N:4]([CH3:18])[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:15])([F:17])[F:16])[CH:8]=3)=[N:6][C:2]=2[I:1])=[O:21])[CH2:25][CH2:26]1
Reactant: Cn1c(-c2cccc(OC(F)(F)F)c2)nc(I)c1C(=O)O
Reactant: OC[C@H]1CCCN1C1CCNCC1
Agent: Cl
Product: Cn1c(-c2cccc(OC(F)(F)F)c2)nc(I)c1C(=O)N1CCC(N2CCC[C@H]2CO)CC1

Procedure:
In analogy to the procedure described for example 2, 5-iodo-3-methyl-2-(3-trifluoromethoxy-phenyl)-3H-imidazole-4-carboxylic acid (example 19) and ((S)-1-piperidin-4-yl-pyrrolidin-2-yl)-methanol di-hydrochloride [prepared as described for ((R)-1-piperidin-4-yl-pyrrolidin-2-yl)-methanol di-hydrochloride (intermediate 2), but starting from (S)-(−)-pyrrolidin-2-yl-methanol] gave the title compound as brown amorphous solid. MS: 579.1 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=O)[NH:5][C:6]2=O.B.C1COCC1.CO.Cl>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][NH:5][CH2:6]2
Reactant: O=C1NC(=O)c2c(Cl)cccc21
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: Clc1cccc2c1CNC2
Temperature: 80 °C
Yield: 53.3 %

Procedure:
To solid 4-chloro-1H-isoindole-1,3(2H)-dione (4.0 g, 22.0 mmol) was added borane-THF complex (1 M/THF, 88.1 mL, 88.1 mmol) dropwise with stirring. When the addition was complete, the reaction mixture was heated to reflux (80° C.) and stirred for 6 h. The reaction mixture was then cooled to 0° C., methanol (2.8 mL, 88.1 mmol) was carefully added dropwise and the reaction mixture was warmed to room temperature. HCl (6 N) was added until the mixture was acidic and then the mixture was concentrated. The crude product was dissolved in 1 M HCl and extracted twice with ethyl ether and twice with dichloromethane. The pH of the aqueous layer was adjusted to pH=11 with solid NaOH and extracted three times with ethyl acetate. The combined ethyl acetate extracts were dried over Na2SO4, filtered and concentrated to give 4-chloroisoindoline (1.8 g, 53% yield). LRMS (ESI) m/z 154 [(M+H)+; calcd for C8H9ClN: 154].