Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([S:4]([C:7]1[C:8]([C@H:13]2[C@H:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][CH2:15][N:14]2C(OC(C)(C)C)=O)=[N:9][CH:10]=[CH:11][CH:12]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].Cl.O1CCOCC1>CCOC(C)=O>[CH:1]([S:4]([C:7]1[C:8]([C@H:13]2[C@H:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][CH2:15][NH:14]2)=[N:9][CH:10]=[CH:11][CH:12]=1)(=[O:5])=[O:6])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CCN(C(=O)OC(C)(C)C)[C@H]1c1ncccc1S(=O)(=O)C(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H]1CCN[C@H]1c1ncccc1S(=O)(=O)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.5 %

Procedure:
To 65F (1.51 g, 3.53 mmol) in EtOAc (15 mL) at rt was added 4.0 N HCl in dioxane (15 mL, 60 mmol). The mixture was stirred at rt for 8.0 h. After removal of the solvent, the crude was diluted in methylene chloride and washed with sat. NaHCO3. The aqueous was extracted with methylene chloride (3×80 mL). The combined organic layer was dried over Na2SO4. After removal of solvent 65G (1.1 g, 95% yield) was obtained as viscous oil. 1H NMR (400 MHz, Methanol-d4) δ ppm 1.15 (t, J=7.03 Hz, 3H) 1.25 (d, J=7.03 Hz, 3H) 1.30 (d, J=7.03 Hz, 3H) 2.11-2.38 (m, 2H) 3.00-3.12 (m, 1H) 3.24-3.29 (m, 1H) 3.36-3.47 (m, 1H) 3.53-3.64 (m, 1H) 4.02-4.14 (m, 2H) 7.58 (dd, J=7.91, 4.83 Hz, 1H) 8.32 (dd, J=8.35, 1.76 Hz, 1H) 8.83-8.93 (m, 1H); LC-MS 327 (M+H).
Reaction SMILES: C[O:2][C:3](=[O:36])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[C:17]([C:18]3[N:22]([CH2:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[C:21]4[CH:30]=[C:31]([F:35])[C:32]([F:34])=[CH:33][C:20]=4[N:19]=3)=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:6][CH:5]=1.O.[OH-].[Li+]>O1CCCC1.O>[CH:24]1([CH2:23][N:22]2[C:21]3[CH:30]=[C:31]([F:35])[C:32]([F:34])=[CH:33][C:20]=3[N:19]=[C:18]2[C:17]2[C:12]([O:11][CH2:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:36])=[O:2])=[CH:5][CH:6]=3)=[N:13][CH:14]=[CH:15][CH:16]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: COC(=O)c1ccc(COc2ncccc2-c2nc3cc(F)c(F)cc3n2CC2CCCCC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(COc2ncccc2-c2nc3cc(F)c(F)cc3n2CC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26 %

Procedure:
A solution of 4-[3-(1-cyclohexylmethyl-5,6-difluoro-1H-benzoimidazol-2-yl)-pyridin-2-yloxymethyl]-benzoic acid methyl ester (84 mg, 0.17 mmol) in tetrahydrofuran (20 ml) and water (10 ml) was treated with an aqueous solution of lithium hydroxide monohydrate (36 mg, 0.86 mmol) and stirred at 25° C. for 2 h. The solvent removed in vacuo, the resulting crude material diluted with water (5 ml) and acidified with 2M aqueous hydrochloric acid solution. The aqueous layer was extracted with ethyl acetate, washed with water, brine, dried over sodium sulfate, filtered and evaporated under reduced pressure. The crude product was purified by column chromatography over silica gel (50% ethyl acetate/n-hexane) to afford the final compound as an off-white powder (26%). MS (Turbo Spray): m/z=478.4 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[C:10](=[NH:14])OCC.[NH2:15][NH:16][C:17]([NH2:19])=[S:18]>OS(O)(=O)=O.CO>[CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[C:10]([NH:15][NH:16][C:17]([NH2:19])=[S:18])=[NH:14]
Reactant: NNC(N)=S
Reactant: CCOC(=N)c1ncc([N+](=O)[O-])n1C
Agent: O=S(=O)(O)O
Solvent: CO
Product: Cn1c([N+](=O)[O-])cnc1C(=N)NNC(N)=S
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a stirred mixture of ethyl 1-methyl-5-nitro-2-imidazolecarboximidate (0.198 g., 0.001 mole) and thiosemicarbazide (0.091 g., 0.001 mole) in 5 ml. of methanol is added 1 drop of conc. H2SO4 and the mixture is stirred at room temperature for 50 minutes. The solid is filtered and washed with methanol, yielding 0.149 g. of the title compound, melting point 200°-201° C. dec.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:24](O)=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:27]([O:29][C:30](=[O:40])[CH2:31][NH:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:28]>>[CH2:27]([O:29][C:30](=[O:40])[CH2:31][N:32]([C:24](=[O:25])[C@H:19]([CH2:20][CH:21]([CH3:22])[CH3:23])[NH:18][C:16]([O:15][CH2:14][CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)=[O:17])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:28]
Reactant: CCOC(=O)CNCc1ccccc1
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Product: CCOC(=O)CN(Cc1ccccc1)C(=O)[C@H](CC(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21

Procedure:
N-(9-Fluorenylmethoxycarbonyl)-L-leucine (1.31 g) and N-(benzyl)glycine ethyl ester (738 mg) were reacted in the same manner as in Preparation Example 52 to obtain the title compound.
Reaction SMILES: O.Cl(O)(=O)(=O)=O.[CH2:7]([N:14]1[CH2:22][CH2:21][C:17]2([C:19](=[O:20])C2)[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-:24].[Na+].[Na+]>O1CCCC1>[CH2:7]([N:14]1[CH2:22][CH2:21][C:17]([CH2:19][OH:20])([OH:24])[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1CC12CCN(Cc1ccccc1)CC2
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: C1CCOC1
Solvent: O
Product: OCC1(O)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
100 ml water and 10 ml perchloric acid were added to 100 ml solution of 6.8 g of this 6-benzyl-1-oxo-6-azaspiro[2.5]octane in tetrahydrofuran, and the mixture was stirred at room temperature for 7 hr. The mixture was ice-cooled, and aqueous sodium carbonate was added thereto to adjust the pH thereof to 7, and then the mixture was evaporated. Ethyl acetate was added to the residue, and the insoluble mattters were removed by filtration. The filtrate was evaporated, and then purified by silica gel column chromatography to give 4 g of 1-benzyl-4-(hydroxymethyl)-4-piperidinol.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[N:23]=[CH:22][CH:21]=[CH:20][C:8]=2[C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[O:10])=[CH:4][CH:3]=1.[CH3:26][C:27]([CH3:32])([CH3:31])[C:28](Cl)=[O:29].C(N(CC)CC)C>C(Cl)Cl.[OH-].[Na+]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[C:8]([C:9]([NH:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][C:28](=[O:29])[C:27]([CH3:32])([CH3:31])[CH3:26])=[CH:15][CH:14]=3)=[O:10])=[CH:20][CH:21]=[CH:22][N:23]=2)=[CH:24][CH:25]=1
Reactant: O=C(NCc1ccc(O)cc1)c1cccnc1Oc1ccc(F)cc1
Reactant: CC(C)(C)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)Oc1ccc(CNC(=O)c2cccnc2Oc2ccc(F)cc2)cc1
Yield: 68.8 %

Procedure:
A solution 2-(4-Fluoro-phenoxy)-N-(4-hydroxy-benzyl)-nicotinamide (0.050 grams, 0.148 mmole), trimethylacetyl chloride (0.019 grams, 0.163 mmole) and triethyl amine (0.022 grams, 0.222 mmole) in methylene chloride (5 ml) was stirred for 30 minutes. The mixture was diluted with 50 ml 1N sodium hydroxide and extracted with ethyl acetate. The combined organics were washed with water and brine, dried over Na2SO4, filtered and concentrated to give an oil that was purified by chromatography on silica gel eluting with 40% ethyl acetate/hexane. Recrystalization from ethyl acetate/hexane gave a solid (0.043 g). M.P. 91-93° C.; Anal. calcd. for C24H23N2O4F: C, 68.24; H, 5.49; N, 6.63. Found: C, 66.07; H, 5.24; N, 6.42.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:6][C:5](=[O:7])[NH:4][C@H:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Br[C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22](=[O:26])[NH:21][CH2:20][CH2:19]2>>[CH3:1][C:2]1([CH3:14])[O:6][C:5](=[O:7])[N:4]([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[C:22](=[O:26])[NH:21][CH2:20][CH2:19]3)[C@H:3]1[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C1NCCc2cc(Br)ccc21
Reactant: CC1(C)OC(=O)N[C@H]1c1ccccc1
Product: CC1(C)OC(=O)N(c2ccc3c(c2)CCNC3=O)[C@H]1c1ccccc1
Yield: 53.6 %

Procedure:
The title compound was prepared as described in General Scheme A substituting (S)-5,5-dimethyl-4-phenyloxazolidin-2-one (commercially available from Sigma-Aldrich, Milwaukee, Wis.) and 6-bromo-3,4-dihydroisoquinolin-1(2H)-one (commercially available from Astatech Inc., Bristol, Pa.). The final reaction mixture was filtered through Celite® brand filter aid with MeOH and DCM, concentrated, and purified (ISCO: 5 g cartridge, 12 g column, 0 to 35 to 100%, 90/10 DCM-MeOH in DCM). Fractions with product were repurified (ISCO: 5 g cartridge, 12 g column, 0 to 100% EtOAc-heptanes) giving (S)-5,5-dimethyl-3-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-phenyloxazolidin-2-one (79.7 mg, 0.237 mmol, 53.6% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.76-7.80 (m, 1H), 7.70 (d, J=8.51 Hz, 1H), 7.53-7.56 (m, 1H), 7.36 (m, 6H), 5.49 (s, 1H), 3.30 (s, 2H), 2.73-2.88 (m, 2H), 1.62 (s, 3H), 0.90 (s, 3H). m/z (ESI) 337.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([C:11]1[S:19][C:18]2[C:13](=[N:14][CH:15]=[CH:16][C:17]=2[O:20][C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[NH:26][C:25]([CH3:30])=[CH:24]3)[CH:12]=1)=[O:10].[CH3:31]I>>[CH3:31][N:26]1[C:27]2[C:23](=[CH:22][C:21]([O:20][C:17]3[CH:16]=[CH:15][N:14]=[C:13]4[CH:12]=[C:11]([C:9]([N:5]5[CH2:6][CH2:7][CH2:8][C@@H:4]5[CH2:3][O:2][CH3:1])=[O:10])[S:19][C:18]=34)=[CH:29][CH:28]=2)[CH:24]=[C:25]1[CH3:30]
Reactant: CI
Reactant: COC[C@H]1CCCN1C(=O)c1cc2nccc(Oc3ccc4[nH]c(C)cc4c3)c2s1
Product: COC[C@H]1CCCN1C(=O)c1cc2nccc(Oc3ccc4c(c3)cc(C)n4C)c2s1

Procedure:
The title compound was prepared by the method described for Example 10, using (2R)-(2-methoxymethyl-pyrrolidin-1-yl)-[7-(2-methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridin-2-yl]-methanone and methyl iodide. MS: 436 (MH+); HPLC Rf: 6.33 min; HPLC purity: 96%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[C:24]([O:28][C:29](=[O:34])[C@@H:30]([NH2:33])[CH2:31][CH3:32])([CH3:27])([CH3:26])[CH3:25]>N1C=CC=CC=1.O>[C:24]([O:28][C:29](=[O:34])[C@@H:30]([NH:33][C:8]([C:3]1[C:2]([NH2:1])=[CH:7][CH:6]=[CH:5][N:4]=1)=[O:10])[CH2:31][CH3:32])([CH3:26])([CH3:25])[CH3:27]
Reactant: Nc1cccnc1C(=O)O
Reactant: CC[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Solvent: O
Product: CC[C@H](NC(=O)c1ncccc1N)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.1 %

Procedure:
To a solution of 276 mg of 3-aminopyridine-2-carboxylic acid in pyridine (3.0 mL) is added 324 mg of 1,1′-carbonyldiimidazole. The mixture is stirred at room temperature for 2 h. Then 391 mg of (S)-2-amino-butyric acid tert-butyl ester hydrochloride is added and the mixture is stirred for 16 h at room temperature. Then the reaction mixture is diluted with water (1 mL) and concentrated. The residue is diluted with additional 5 mL water and the product is extracted with ethyl acetate (3×5 mL). The combined organic layers are washed with brine, dried (sodium sulfate) and concentrated. The residue is purified by flash chromatography on silica gel to give 218 mg (39%) of (S)-2-[(3-amino-pyridine-2-carbonyl)-amino]-butyric acid tert-butyl ester.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:43][CH2:42][CH:41]([CH2:44][OH:45])[CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:38]3[CH2:43][CH2:42][CH:41]([CH2:44][OH:45])[CH2:40][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: OCC1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CO)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with piperidin-4-yl-methanol (Lancaster) to give the title compound. HR-MS (ES, m/z) calculated for C35H43Cl2N4O3 [(M+H)+] 637.2707, observed 637.2708.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[CH3:9].[C:10]1(=[O:20])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][NH:11]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(Cl)Cl.[Cu]I>[Br:8][C:4]1[C:3]([CH3:9])=[C:2]([N:11]2[CH2:12][CH2:13][C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]2=[O:20])[CH:7]=[CH:6][CH:5]=1
Reactant: Cc1c(Br)cccc1Br
Reactant: O=C1NCCc2ccccc21
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: Cc1c(Br)cccc1N1CCc2ccccc2C1=O
Temperature: 150 °C
Yield: 66.1 %

Procedure:
Step 2 A mixture of 1,3-dibromo-2-methylbenzene (340 mg, 1.359 mmol), 3,4-dihydroisoquinolin-1(2H)-one (100 mg, 0.679 mmol) and potassium carbonate (94 mg, 0.679 mmol) in DMSO (2 mL) was purged with nitrogen, treated with copper (I) iodide (25.9 mg, 0.136 mmol) and heated at 150° C. for 3.5 h. The mixture was combined with that from a second reaction using 1,3-dibromo-2-methylbenzene (2.59 g, 10.36 mmol) and 3,4-dihydroisoquinolin-1(2H)-one (508 mg, 3.45 mmol), diluted with DCM and filtered through Celite. The filtrate was washed with 5% aqueous ammonium hydroxide, dried and concentrated. The residue was purified by column chromatography (eluting with hexane-EtOAc) to provide 2-(3-bromo-2-methylphenyl)-3,4-dihydroisoquinolin-1(2H)-one as a yellow solid (142 mg, 11%). 1H NMR (400 MHz, chloroform-d) δ 8.15 (1H, dd, J=7.70, 1.10 Hz), 7.55 (1H, dd, J=7.92, 1.10 Hz), 7.46-7.51 (1H, m), 7.37-7.42 (1H, m), 7.24-7.28 (1H, m), 7.17-7.21 (1H, m), 7.09-7.16 (1H, m), 3.95 (1H, ddd, J=12.21, 10.12, 4.73 Hz), 3.73 (1 H, ddd, J=11.94, 6.33, 5.28 Hz), 3.26 (1H, ddd, J=15.74, 10.23, 5.28 Hz), 3.06-3.14 (1H, m), 2.36 (3H, s). Mass spectrum m/z 316, 318 (M+H)+.
Reaction SMILES: [OH:1]N1C(=O)CCC1=O.[CH2:9]1[CH2:14][CH2:13][CH:12]([N:15]=[C:16]=[N:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:11][CH2:10]1>CN(C1C=CN=CC=1)C.C(#N)C>[C:16]([NH:15][CH:12]1[CH2:11][CH2:10][CH2:9][CH2:14][CH2:13]1)([NH:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:1]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C1CCC(=O)N1O
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 5 h

Procedure:
To a cooled (0 to 5° C.) solution of DPGS-ω-carboxy-PEG (200 mg) from Step B, N-hydroxysuccinimide (6 mg), DMAP (2 mg) and acetonitrile (40 mL) in a 250 mL round bottom flask was added dropwise a solution of DCC (12 mg) in acetonitrile (10 mL). The resulting mixture was stirred for 5 hours and the white solid which formed (dicyclohexylurea) was removed by filtration. The filtrate was concentrated in vacuo to afford 200 mg of DPGS-ω-carboxy-PEG-succinimide as a white solid.
Reaction SMILES: C([Si](C)(C)O[C@@H]1CC[C@H]([N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])CC1)(C)(C)C.[F:21][C:22]([F:32])([F:31])[C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1.[Li+].CC([N-]C(C)C)C>>[F:21][C:22]([F:31])([F:32])[C:23]1[CH:30]=[CH:29][C:26]([CH2:27][CH:15]2[CH2:16][CH2:17][NH:13][C:14]2=[O:18])=[CH:25][CH:24]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](N2CCCC2=O)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: O=C1NCCC1Cc1ccc(C(F)(F)F)cc1
Yield: 39 %

Procedure:
Using the procedure to synthesize Example 202 and using cis-1-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-pyrrolidin-2-one (Preparation 17), 4-trifluoromethyl benzylbromide and 1.5 equivalents of LDA affords an oil. Chromatography (silica, 4:1 hexanes/EtoAc) yields 4-[4-tert-butyl dimethyl-silanyloxy)-cyclohexyl]-3-(4-trifluoromethyl-benzyl)-pyrrolidin-2-one in 39% yield. The silylether is dissolved in THF, treated with 5.0 equivalents of TBAF and allowed to stir at room temperature overnight. Quench reaction with water, dilute with methylene chloride, separate, dry over sodium sulfate, filter and evaporate. Chromatography (silica, 4:6 hexanes/EtoAc) provides the titled compound in 21% yield: Mass spectrum (API-ES positive) m/z=342.3 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:8]([C:9]([CH3:12])=[CH:10][CH:11]=1)=[N:7][C:6](=[O:13])[C:5]([CH3:15])([CH3:14])[CH:4]=2.[CH2:16](I)[CH:17]=[CH2:18].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.CCCCCC>[CH2:18]([O:1][C:2]1[C:3]2[C:8]([C:9]([CH3:12])=[CH:10][CH:11]=1)=[N:7][C:6](=[O:13])[C:5]([CH3:15])([CH3:14])[CH:4]=2)[CH:17]=[CH2:16]
Reactant: C=CCI
Reactant: Cc1ccc(O)c2c1=NC(=O)C(C)(C)C=2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: C=CCOc1ccc(C)c2c1=CC(C)(C)C(=O)N=2
Yield: 92.6 %

Procedure:
Using 5-hydroxy-3,3,8-trimethylcarbostyril (2.0 g, 9.77 mmol), allyl iodide (1.72 g, 10.2 mmol), and potassium carbonate (3 g, 21.7 mmol), the procedure of Reference Example 41 was followed (reaction, post-treatment, and recrystallization from chloroform-n-hexane). 2.2 g of the title compound was obtained as colorless flakes (92.0%).
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:9][CH:8]=1.[CH3:18]O>>[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:12]=1
Reactant: COc1ccc(CCC(=O)O)cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CCc1ccc(OC)cc1
Temperature: 25 °C

Procedure:
Thionyl chloride (3.1 ml, 42.5 mmol) was added slowly to methanol (30 ml) with stirring under cooling with a Dry Ice/methanol bath. After allowing the reaction to warm to room temperature, 3-(4-methoxyphenyl) propionic acid (5 g, 27.7 mmol) was added and stirred for an additional 1 hour. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The solution was washed twice with a saturated aqueous solution of sodium bicarbonate, then once with a saturated aqueous solution of sodium chloride. After drying over unhydrous sodium sulfate, the solvent was evaporated in vacuo to produce a pale yellow crystal in an amount of 5.29 g (yield, 98%).
Reaction SMILES: Cl[CH2:2][C:3]([O:5][C:6]1[CH:11]=[CH:10][C:9](/[C:12](/[C:22]2[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31])=[CH:24][CH:23]=2)=[C:13](\[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)/[CH2:14][CH3:15])=[CH:8][CH:7]=1)=[O:4].[NH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>>[C:16]1(/[C:13](/[CH2:14][CH3:15])=[C:12](/[C:22]2[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31])=[CH:24][CH:23]=2)\[C:9]2[CH:10]=[CH:11][C:6]([O:5][C:3](=[O:4])[CH2:2][N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:7][CH:8]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC/C(=C(\c1ccc(/C=C/C(=O)O)cc1)c1ccc(OC(=O)CCl)cc1)c1ccccc1
Reactant: C1CCNCC1
Product: CC/C(=C(\c1ccc(/C=C/C(=O)O)cc1)c1ccc(OC(=O)CN2CCCCC2)cc1)c1ccccc1

Procedure:
Treatment of compound 32 with piperidine as described in Example 19 (Step 2) afforded the title compound, 33, as a light yellow solid (85 mg, 77%). 1HNMR (400 MHz, DMSO-d6): δ 0.85 (t, 3H), 1.35 (br, 2H), 1.74 (br, 4H), 2.40 (q, 2H), 3.00 (br, 2H), 3.44 (br, 2H), 4.36 (br, 2H), 6.51 (d, J=16.1 Hz, 1H), 6.87-6.90 (m, 4H), 7.09-7.19 (m, 5H), 7.25 (d, J=8.1 Hz, 2H), 7.58 (d, J=16.1 Hz, 1H), 7.70 (d, J=8.2 Hz, 2H), 10.17 (br, 1H), 12.39 (br, 1H); MS m/z 496 (M+H)+; Anal. calculated for C32H33N1O4.HCl.1.5H2O: C, 68.74; H, 6.67; N, 2.50; Found: C, 68.31; H, 6.34; N, 2.37.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:9]=[C:8]([S:10][CH3:11])[N:7]=[C:6]([NH2:12])[N:5]=1.[CH3:13][O:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([N:26]=[C:27]=[O:28])(=[O:25])=[O:24])=[O:16]>C(Cl)Cl>[CH3:1][O:2][CH2:3][C:4]1[N:9]=[C:8]([S:10][CH3:11])[N:7]=[C:6]([NH:12][C:27]([NH:26][S:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:15]([O:14][CH3:13])=[O:16])(=[O:25])=[O:24])=[O:28])[N:5]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: COCc1nc(N)nc(SC)n1
Solvent: ClCCl
Product: COCc1nc(NC(=O)NS(=O)(=O)c2ccccc2C(=O)OC)nc(SC)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.6 %

Procedure:
To a solution of 0.8 g of 4-methoxymethyl-6-methylthio-2-amino-1,3,5-triazine in 15 ml of anhydrous methylene chloride was added 1.5 g of 2-methoxycarbonylbenzenesulfonylisocyanate. The mixture was heated for one hour and then stirred at ambient temperature for 18 hours. Solvent was removed in vacuo and the residue was triturated with 1-chlorobutane (50 ml) and filtered to give 1.7 g of the desired product, m.p. 147°-149° C. mmr: 2.6 ppm δ, 3H; 3.4 ppm δ, 3H; 3.85 ppm δ, 3H; 4.45 δ, 2H; 7.65-8.5 broad, 4H.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH:14]=[CH:13][C:3]=1[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][CH:7]=1.C(N(CC)CC)C.[C:31]1([CH3:43])[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33]([CH3:38])[C:32]=1[S:39](Cl)(=[O:41])=[O:40].C(=O)(O)[O-].[Na+]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:16]=[C:15]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH:14]=[CH:13][C:3]=1[CH2:4][N:5]([C:6]1[CH:7]=[CH:8][C:9]([I:12])=[CH:10][CH:11]=1)[S:39]([C:32]1[C:33]([CH3:38])=[CH:34][C:35]([CH3:37])=[CH:36][C:31]=1[CH3:43])(=[O:41])=[O:40]
Reactant: Clc1cc(OC2CCCCO2)ccc1CNc1ccc(I)cc1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(S(=O)(=O)N(Cc2ccc(OC3CCCCO3)cc2Cl)c2ccc(I)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.4 %

Procedure:
To a solution of [2-chloro-4-(tetrahydro-pyran-2-yloxy)-benzyl]-(4-iodophenyl)-amine (3.00 g, 6.76 mmol) in 4 mL methylene chloride was added triethylamine (2.84 mL, 20.3 mmol) and 2-mesitylenesulfonyl chloride (2.96 g, 13.5 mmol). The reaction mixture was stirred at room temperature overnight. Additional triethylamine (1 mL, 7.15 mmol) was added and the reaction mixture was allowed to stir at room temperature overnight. DMAP was added and the reaction mixture was allowed to stir at room temperature for three days. Additional methylene chloride (2 mL), triethylamine (1 mL, 7.15 mmol) and 2-mesitylenesulfonyl chloride (1.00 g, 4.57 mmol) were added. The reaction mixture was stirred at 30° C. overnight. Additional triethylamine (2.84 mL, 20.3 mmol) and DMAP were added and the reaction was stirred at 30° C. overnight. Additional 2-mesitylenesulfonyl chloride (0.54 g, 2.47 mmol) was added and the reaction mixture was stirred at 30° C. overnight. Saturated aqueous sodium bicarbonate was added and the mixture was extracted with methylene chloride. The organic layer was dried (magnesium sulfate) and concentrated. Medium pressure silica gel chromatography of the residue afforded 2.30 g (54%) of the title compound of Step B.
Reaction SMILES: BrB(Br)Br.[F:5][C:6]1[CH:7]=[C:8]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])[CH:9]=[C:10]([F:14])[C:11]=1[O:12]C.[CH3:20]O>ClCCl>[F:5][C:6]1[CH:7]=[C:8]([CH:15]([CH3:19])[C:16]([O:18][CH3:20])=[O:17])[CH:9]=[C:10]([F:14])[C:11]=1[OH:12]
Reactant: COc1c(F)cc(C(C)C(=O)O)cc1F
Reactant: CO
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)C(C)c1cc(F)c(O)c(F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.6 %

Procedure:
tribromoborane (7.37 mL, 77.99 mmol) was added dropwise to 2-(3,5-difluoro-4-methoxyphenyl)propanoic acid (Intermediate 21-4; 2.81 g, 13.00 mmol) in dichloromethane (96 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 1 hour. The reaction mixture was added dropwise to methanol (26.3 mL, 649.92 mmol) (—care reaction is vigorous and exothermic—MeOH kept in ice bath) and the mixture was stirred for a further 20 minutes. The reaction mixture was evaporated to dryness and redissolved in DCM (50 mL), and washed sequentially with saturated NaHCO3 (50 mL) and water (50 mL). The organic layer was dried with MgSO4 and evaporated to afford desired product methyl 2-(3,5-difluoro-4-hydroxyphenyl)propanoate (2.490 g, 89%).