Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H](CCC1C=CC(F)=CC=1)CC(SCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)COP(O)(=O)OP(O)(=O)OC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1OP(O)(O)=O)=O.[OH:63][C@H:64]([CH2:116][CH2:117][O:118][C:119]1[CH:124]=[CH:123][CH:122]=[CH:121][CH:120]=1)[CH2:65][C:66](SCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)COP(O)(=O)OP(O)(=O)OC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1OP(O)(O)=O)=[O:67]>>[OH:63][CH:64]([CH2:116][CH2:117][O:118][C:119]1[CH:124]=[CH:123][CH:122]=[CH:121][CH:120]=1)[CH2:65][C:66]([OH:67])=[O:1]
Reactant: CC(C)(COP(=O)(O)OP(=O)(O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OP(=O)(O)O)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C[C@H](O)CCOc1ccccc1
Reactant: CC(C)(COP(=O)(O)OP(=O)(O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OP(=O)(O)O)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C[C@H](O)CCc1ccc(F)cc1
Product: O=C(O)CC(O)CCOc1ccccc1
Reaction time: 0.42 h

Procedure:
Then, (R)-3-hydroxy-5-(4-fluorophenyl) valeryl CoA prepared in Reference Example 3 was added at a final concentration of 5 mM, and was incubated at 37° C. for 25 minutes, followed by adding to this pigment dispersion (R)-3-hydroxy-5-phenoxyvaleryl CoA (prepared by the method described in Eur. J. Biochem., 250, 432-439 (1997) after obtaining 3-hydroxy-5-phenoxyvaleric acid by hydrolyzing 3-hydroxy-5-phenoxyvalerate obtained by Reformatsky reaction with zinc, using as raw materials 3-phenoxypropanal synthesized by the method described in J. Org. Chem., 55, 1490-1492 (1990) and ethyl bromoacetate) so that the final concentration was 1 mM, then incubating the same at 37° C. for 5 minutes. After the reaction, electrophoretic particles were collected and suspended with kerosene as a dispersion medium in a same manner as Example 2.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH3:9])=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[O:17][CH3:18])[CH:3]=1.[CH3:19][S:20]([C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[C:26]([OH:28])=O)(=[O:22])=[O:21]>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:9])[C:26](=[O:28])[C:25]2[CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=[C:23]([S:20]([CH3:19])(=[O:21])=[O:22])[CH:24]=2)=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[O:17][CH3:18])[CH:3]=1
Reactant: CNc1cnc(Cl)cc1-c1ccc(F)cc1OC
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Product: COc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Yield: 61 %

Procedure:
The title compound was prepared in analogy to Example 90, from [6-chloro-4-(4-fluoro-2-methoxy-phenyl)-pyridin-3-yl]-methyl-amine and 3-methanesulfonyl-5-trifluoromethyl-benzoic acid (example 114, intermediate a) after a reaction time of 17 hours. The compound was purified by silica gel chromatography using an MPLC (ISCO) system eluting with a gradient of n-heptane:EtOAc (100:0 to 50:50). The volatiles were evaporated until a precipitate formed. The suspension was filtered and the filter cake was washed three times with a small amount of a mixture of EtOAc:n-heptane (1:4) to give the title compound as a colorless solid (61%). MS (ESI): m/z=517.06 [M+H]+.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[CH2:20]([NH2:25])[CH2:21][CH2:22][CH2:23][CH3:24].CCN(C(C)C)C(C)C>>[CH2:20]([NH:25][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1)[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Reactant: CCCCCN
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCNC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, pentylamine and DIEA to give 2-pentylamino-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 326 (MH+).
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]([OH:32])[CH2:21][C:22](=[O:31])[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(B(CC)OC)C.[BH4-].[Na+].OO.P([O-])([O-])([O-])=O>O1CCCC1.C(Cl)Cl.C(OCC)(=O)C.CO>[Si:1]([O:18][CH2:19][C@@H:20]([OH:32])[CH2:21][C@@H:22]([OH:31])[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CC(=O)C[C@H](O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CCB(CC)OC
Agent: O=P([O-])([O-])[O-]
Agent: OO
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)C[C@H](O)C[C@H](O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: -70 °C
Yield: 76 %

Procedure:
To a solution containing 52.53 g (0.115 mol) of tert-butyl (5S)-6-tert-butyldiphenylsilyloxy-5-hydroxy-3-oxohexanoate, 800 ml of anhydrous tetrahydrofuran and 200 ml of anhydrous methanol was added 126 ml (0.126 mol) of a 1 M solution of diethyl methoxy borane in tetrahydrofuran with stirring at -70° C. After stirring the mixture for 1 hour at -65° C., thereto was added 5.66 g (0.15 mol) of sodium borohydride and the mixture was reacted for 4 hours at the same temperature. The reactant was added dropwise to the mixture of 425 ml of 30% hydrogen peroxide, 850 ml of 0.2 M phosphate buffer solution (pH 7.0 ) and 850 ml of methanol at -20° to -10° C. Further after stirring the mixture for a half hour at room temperature, the mixture was concentrated under reduced pressure. The concentrated solution was extracted with methylene chloride, and the methylene chloride layer was washed with water, then dried and distilled away under reduced pressure. The residue was purified by subjecting to silica gel column chromatography [eluent: methylene chloride-ethyl acetate (10:1)]to give 40.1 g of tert-butyl (3R,5S)-6-tert-butyldiphenylsilyloxy-3,5-dihydroxyhexanoate as syrups (yield: 75%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:27][C:28](=[O:30])[CH3:29])[C:10]2[N:11]([S:21]([N:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])[CH:12]=[C:13]([CH2:15][C:16]([CH3:20])([CH3:19])[CH2:17][CH3:18])[N:14]=2)=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+].[CH3:37][Si:38]([CH3:53])([CH3:52])[CH2:39][CH2:40][O:41][CH2:42][N:43]1[C:47]2[NH:48][CH2:49][CH2:50][CH2:51][C:46]=2[CH:45]=[N:44]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>O1CCOCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:25][N:24]([CH3:26])[S:21]([N:11]1[CH:12]=[C:13]([CH2:15][C:16]([CH3:20])([CH3:19])[CH2:17][CH3:18])[N:14]=[C:10]1[CH:9]([NH:27][C:28](=[O:30])[CH3:29])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([N:48]2[CH2:49][CH2:50][CH2:51][C:46]3[CH:45]=[N:44][N:43]([CH2:42][O:41][CH2:40][CH2:39][Si:38]([CH3:53])([CH3:52])[CH3:37])[C:47]2=3)=[CH:3][CH:4]=1)(=[O:23])=[O:22]
Reactant: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(Cc2ccc(Br)cc2)NC(C)=O)n1
Reactant: C[Si](C)(C)CCOCn1ncc2c1NCCC2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Solvent: O
Product: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(Cc2ccc(N3CCCc4cnn(COCC[Si](C)(C)C)c43)cc2)NC(C)=O)n1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
Palladium (II) acetate (2 mg, 0.01 mmol) was added to a degassed, ambient temperature solution of N-{2-(4-bromophenyl)-1-[1-[(dimethylamino)sulfonyl]-4-(2,2-dimethylbutyl)-1H-imidazol-2-yl]ethyl}acetamide (100 mg, 0.2 mmol), sodium tert-butoxide (77 mg, 0.8 mmol), 1-{[2-(trimethylsilyl)ethoxy]methyl}-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridine (102 mg, 0.4 mmol) and 2-(dicyclohexylphosphino)biphenyl (7 mg, 0.02 mmol) in 1,4-dioxane (5 mL). After stirring at 110° C. overnight, the reaction mixture was cooled, diluted with water and extracted with methylene chloride and ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-60% acetone/methylene chloride afforded N-{1-[1-[(dimethylamino)sulfonyl]-4-(2,2-dimethylbutyl)-1H-imidazol-2-yl]-2-[4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-b]pyridin-7-yl)phenyl]ethyl}acetamide.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([Cl:11])[CH:3]=1.B.C1COCC1.C([O-])([O-])=O.[K+].[K+].O>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[C:4]([Cl:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1Cl
Agent: B
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc(Br)cc1Cl
Temperature: 0 °C
Reaction time: 8 h
Yield: 59.5 %

Procedure:
4-Bromo-2-chlorobenzoic acid (5 g, 21.23 mmol) was dissolved in dry THF (100 mL) and cooled to 0° C. A 1M solution of BH3.THF in THF (31.85 mL, 31.85 mmol) was slowly added. The reaction was stirred overnight, allowing it to gradually reach room temperature. K2CO3 solid (1 g) and H2O (100 mL) were added and the reaction was stirred for 30 minutes. THF was evaporated and residue extracted with EtOAc (30 mL). The organic phase was washed with 1N HCl (3×50 mL), brine (3×50 mL), dried over Na2SO4 and evaporated. The residue was purified by flash column chromatography (30% EtOAc in hexanes) to give the product (2.80 g, 50%) as a color less oil. 1H NMR (400 MHz, CDCl3): δ 4.73 (d, J=5.8 Hz, 2H), 7.37 (d, J=8.1 Hz, 1H), 7.42 (dd, J=8.1 Hz, 1.7), 7.52 (d, J=1.7 Hz, 1H).
Reaction SMILES: [SH:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[CH:4][N:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([NH:28][CH:29]([CH2:34][CH:35]3[O:37][CH2:36]3)[C:30]([O:32]C)=[O:31])(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1>>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:20]=[CH:21][C:22]([S:25]([NH:28][CH:29]([CH2:34][CH:35]([OH:37])[CH2:36][S:1][C:2]3[N:10]=[C:9]4[C:5]([NH:6][CH:7]=[N:8]4)=[CH:4][N:3]=3)[C:30]([OH:32])=[O:31])(=[O:26])=[O:27])=[CH:23][CH:24]=2)=[CH:17][CH:18]=1
Reactant: Sc1ncc2[nH]cnc2n1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(O)CSc3ncc4[nH]cnc4n3)C(=O)O)cc2)cc1

Procedure:
Example 48 is prepared from 2-mercaptopurine and 1d using the procedure described for compound 20.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:17]2[N:18]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH:19]=[N:20][CH:21]=2)=[N:10]S(CC(C)C)=O)=[CH:5][C:4]=1[F:29])#[N:2].[ClH:30].[CH3:31]O>O1CCOCC1>[ClH:30].[ClH:30].[NH2:10][C:9]([C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:29])[CH:5]=1)([C:17]1[N:18]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:19]=[N:20][CH:21]=1)[CH3:31]
Reactant: CC(C)CS(=O)N=C(c1ccc(C#N)c(F)c1)c1cncn1-c1ccc(F)cc1
Reactant: CO
Agent: Cl
Solvent: C1COCCO1
Product: CC(N)(c1ccc(C#N)c(F)c1)c1cncn1-c1ccc(F)cc1

Procedure:
N-[(4-Cyano-3-fluoro-phenyl)-(3-(4-fluorophenyl)-3H-imidazol-4-yl)-methylene]-2-methylpropanesulfinamide (2.217 g, 5.17 mmol) was dissolved in MeOH (20 mL) and 4M HCl in dioxane (10 mL) with stirring at ambient temperature. After 1 h the reaction mixture was concentrated in vacuo, made basic with NaHCO3 solution, extracted with CH2Cl2 (3×20 mL), the organics combined, dried (Na2SO4), filtered, and concentrated to give the title compound as a mixture of enantiomers.
Reaction SMILES: [C:1]1([C@@:7]23[O:15][C:14]4[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=4[C@@H:8]2[CH2:9][NH:10][CH2:11][CH2:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH:27]1([C:30](Cl)=[O:31])[CH2:29][CH2:28]1>C(Cl)(Cl)Cl>[CH:27]1([C:30]([N:10]2[CH2:11][CH2:12][C@:7]3([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:15][C:14]4[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=4[C@@H:8]3[CH2:9]2)=[O:31])[CH2:29][CH2:28]1
Reactant: c1ccc([C@]23CCNC[C@H]2c2ccccc2O3)cc1
Reactant: O=C(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(C1CC1)N1CC[C@]2(c3ccccc3)Oc3ccccc3[C@@H]2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.1 %

Procedure:
To a solution of 3.77 g of cis-1,2,3,4,4a,9b-hexahydro-4a-phenyl-benzofuro[3,2-c]pyridine in 100 ml of chloroform containing 1.67 g of triethylamine was added dropwise with stirring under nitrogen a solution of 1.65 g of cyclopropane carbonyl chloride in 25 ml of chloroform. The reaction mixture was stirred at room temperature for 4 hours, diluted with 100 ml of chloroform and washed with 100 ml of 2N HCl and 100 ml of 10% aqueous NaOH. The organic layer was dried over anhydrous Na2SO4 and evaporated in vacuo to afford 4.70 g (98.1%) of a glass.
Reaction SMILES: C([NH:9][C:10]([NH:29][CH2:30][CH2:31][CH2:32][C:33]1[N:34]=[CH:35][NH:36][CH:37]=1)=[N:11][CH2:12][CH2:13][CH:14]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)(=O)C1C=CC=CC=1>Cl>[Cl:28][C:23]1[CH:22]=[C:21]([CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:13][CH2:12][NH:11][C:10]([NH2:9])=[N:29][CH2:30][CH2:31][CH2:32][C:33]2[N:34]=[CH:35][NH:36][CH:37]=2)[CH:26]=[CH:25][C:24]=1[Cl:27]
Reactant: O=C(NC(=NCCC(c1ccc(Cl)c(Cl)c1)c1ccccn1)NCCCc1c[nH]cn1)c1ccccc1
Agent: Cl
Product: NC(=NCCCc1c[nH]cn1)NCCC(c1ccc(Cl)c(Cl)c1)c1ccccn1

Procedure:
0.8 g (1.5 mmol) of N1 -benzoyl-N2 -[3-(3,4-dichlorophenyl)-3-(pyridin-2-yl)propyl]-N3 -[3-(1H-imidazol-4-yl)propyl]-guanidine are heated under reflux in 40 ml of 20% hydrochloric acid for 10 hours. The hydrochloric acid solution is then extracted three times with ether, evaporated to dryness under vacuum and dried in a high vacuum. 0.74 g (91%) of the trihydrochloride is left behind as a hygroscopic, amorphous solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[Cl:17][C:18]1[CH:19]=[C:20]([N+:26]([O-:28])=[O:27])[CH:21]=[C:22]([Cl:25])[C:23]=1Cl>CN(C)C=O>[Cl:17][C:18]1[CH:19]=[C:20]([N+:26]([O-:28])=[O:27])[CH:21]=[C:22]([Cl:25])[C:23]=1[CH:5]1[C:6](=[O:8])[CH2:7][C:2]([CH3:10])([CH3:1])[CH2:3][C:4]1=[O:9]
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)c(Cl)c1
Reactant: CC1(C)CC(=O)CC(=O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)CC(=O)C(c2c(Cl)cc([N+](=O)[O-])cc2Cl)C(=O)C1
Temperature: 75 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
A solution of 30.98 g (0.221 mol) of 5,5-dimethyl-1,3-cyclohexanedione and 76.36 g (0.553 mol) of anhydrous potassium carbonate in 300 ml of dimethylformamide was heated to 75° C. with stirring under N2 for one hour. The 3,4,5-trichloronitrobenzene (50.0 g, 0.221 mol) was dissolved in 100 ml of dimethylformamide and added to the reaction mixture, while stirring and maintaining the temperature at 75° C. A deep red-colored solution was formed, and when the addition was complete the temperature was raised to 100° C. and the mixture stirred over night at this temperature. Most of the dimethylformamide was removed by vacuum distillation, and 21 of water was added to the residue. The aqueous solution was extracted three times with 500 ml portions of benzene, then N2 was passed through the aqueous solution while warming to remove dissolved benzene. The solution was cooled in an ice bath and acidified with 6 N HCl to give 63.8 g (87%) of 2-(2',6'-dichloro-4'-nitrophenyl)-5,5-dimethyl-1,3-cyclohexanedione as a tan powder, m.p. 288°-290° C.
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:10](=[O:39])[C:11]1[CH:16]=[C:15]([C:17]2[CH:18]=[N:19][C:20]([NH:32][C:33]([NH:35][CH2:36][CH3:37])=[O:34])=[CH:21][C:22]=2[C:23]2[S:24][CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[N:27]=2)[CH:14]=[CH:13][C:12]=1F)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:41][C@@H:42]([CH2:45][CH:46]([CH3:48])[CH3:47])[CH2:43][OH:44].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C1COCC1>[CH2:36]([NH:35][C:33](=[O:34])[NH:32][C:20]1[N:19]=[CH:18][C:17]([C:15]2[CH:16]=[C:11]3[C:12](=[CH:13][CH:14]=2)[N:41]([C@@H:42]([CH2:45][CH:46]([CH3:48])[CH3:47])[CH2:43][OH:44])[CH:3]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:10]3=[O:39])=[C:22]([C:23]2[S:24][CH:25]=[C:26]([C:28]([F:29])([F:31])[F:30])[N:27]=2)[CH:21]=1)[CH3:37]
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc(F)c(C(=O)C(=CN(C)C)C(=O)OCC)c2)cn1
Reactant: CC(C)C[C@H](N)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3[C@H](CO)CC(C)C)cn1
Temperature: 60 °C
Reaction time: 8 h
Yield: 43.8 %

Procedure:
Ethyl 3-(dimethylamino)-2-(5-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-2-fluorobenzoyl)acrylate (0.150 g, 0.26 mmol, Intermediate 125) and (S)-2-amino-4-methylpentan-1-ol (0.033 ml, 0.26 mmol) were taken up in THF (2 ml). The mixture was placed in an oil bath and heated to 60° C. for 2 h. Potassium carbonate (0.107 g, 0.78 mmol) was added followed by DMF (1 ml) and the mixture was stirred at 60° C. overnight. Reaction was cooled to room temperature and concentrated in vacuo. The residue was then diluted with water (0.5 mL) and cooled to 0° C. 1N HCl was added drop wise until pH˜4. A light yellow solid was collected by filtration, washed with water, and dried in vacuum oven overnight at 50° C. to give (S)-ethyl 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-(1-hydroxy-4-methylpentan-2-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (0.072 g, 44%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[C:4]([F:10])[CH:3]=1.[Li+].CC([N-]C(C)C)C.C1CCCCC1.Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27]>C1COCC1>[CH2:29]([O:28][C:26](=[O:27])[C:9]#[C:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[F:10])[CH3:30]
Reactant: CCOC(=O)Cl
Reactant: C#Cc1ccc(Br)cc1F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CCOC(=O)C#Cc1ccc(Br)cc1F
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 165.6 %

Procedure:
In a 100 mL round-bottomed flask, 4-bromo-1-ethynyl-2-fluorobenzene (2.0 g, 10.0 mmol) was combined with THF (28 ml) to give a brown solution. The solution was cooled to −78° C. and 1.5M LDA in cyclohexane (16.4 mL, 24.6 mmol, Eq: 2.45) was added via syringe. The reaction was stirred at −78° C. for 20 mins, ethyl chloroformate (5.42 g, 4.8 mL, 50.0 mmol, Eq: 4.97) was added at −78° C. and the reaction was stirred at room temp for 2 h under argon. The reaction was quenched with saturated NH4Cl and diluted with EtOAc. The aqueous layer was back-extracted with EtOAc. The organic layers were combined, washed with 1 M HCl (2×50 mL), H2O (1×50 mL), saturated NaHCO3 (1×50 mL) and brine (1×25 mL), dried over Na2SO4 and concentrated in vacuo to a dark red oil. The crude material was purified by flash chromatography (silica gel, 220 g, 0% to 20% EtOAc in heptane) to afford a pure fraction (4.49 g, 46%) of the desired product as an off white solid. The less pure fraction was stripped and the residue was recrystallized from EtOAc/hexane to afford an additional 1.64 g (17%) of the desired product as a pink powder. 1H NMR (CDCl3) δ ppm 7.40-7.53 (m, 1H), 7.28-7.39 (m, 2H), 4.28 (q, J=7.0 Hz, 2H), 1.32 (t, J=7.0 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=[O:13])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:15](Cl)(=O)C(Cl)=O>C(Cl)Cl.CN(C=O)C>[OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=C(O)c1cc(O)cc2ccccc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1cc(O)cc2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.9 %

Procedure:
To a stirred solution of 3-hydroxy-1-naphthalenecarboxylic acid (6.67 g, 35.4 mmol) and oxalyl chloride (3.86 mL, 44.2 mmol) in DCM (150 mL) was added 3 drops of DMF. The mixture was stirred at room temperature for 3 h., the solvent was removed under reduced pressure and methanol (150 mL) was added. After stirring at reflux for 15 min the solvent was removed under reduced pressure, the residue was purified by column chromatography (10%, 20% and 30% EtOAc/hexane) to give the title compound as a yellow solid (2.5 g, 35%). 1H NMR (DMSO-d6) δ 10.10 (s, 1H), 8.61 (d, 1H), 7.77 (d, 1H), 7.72 (d, 1H), 7.47 (m, 2H), 7.38 (d, 1H), 3.93 (s, 3H); MS m/z 201.1 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:24][CH3:25])[CH2:22]O)[C:11](=[O:26])[C@:10]([CH2:28][C:29]([O:31][CH3:32])=[O:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:33]([SH:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[CH2:33]([S:40][CH2:22][C@@H:21]([N:12]1[C@H:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C@@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH2:9][C@@:10]([CH2:28][C:29]([O:31][CH3:32])=[O:30])([CH3:27])[C:11]1=[O:26])[CH2:24][CH3:25])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC[C@@H](CO)N1C(=O)[C@@](C)(CC(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: SCc1ccccc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC[C@@H](CSCc1ccccc1)N1C(=O)[C@@](C)(CC(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
To a solution of methyl 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetate (214.4 mg, 0.448 mmol; Example 186, Step A) in toluene (2.0 mL) was added benzyl mercaptan (0.106 mL, 0.90 mmol), followed by cyanomethylenetributylphosphorane (0.235 mL, 0.896 mmol; TCI). The solution was heated at 100° C. for 3.75 hours, then concentrated in vacuo. Purification of the residue by chromatography on silica gel (12 g SiO2, 0% to 50% EtOAc in hexanes) provided the title compound as colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13]C)=[O:12])[CH:10]=1)[N:7](C(OC(C)(C)C)=O)[CH:6]=[C:5]2[CH:22]1[CH2:28][CH2:27][CH2:26][S:25](=[O:30])(=[O:29])[CH2:24][CH2:23]1.C([O-])([O-])=O.[K+].[K+].[C:37]1(B(O)O)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>O1CCOCC1.O.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:30]=[S:25]1(=[O:29])[CH2:26][CH2:27][CH2:28][CH:22]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([OH:13])=[O:12])[CH:10]=[C:2]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:23][CH2:24]1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1cc(Br)cc2c(C3CCCS(=O)(=O)CC3)cn(C(=O)OC(C)(C)C)c12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1cc(-c2ccccc2)cc2c(C3CCCS(=O)(=O)CC3)c[nH]c12
Temperature: 120 °C
Reaction time: 8 h

Procedure:
The intermediate 1-(1,1-dimethylethyl) 7-methyl 5-bromo-3-(1,1-dioxido-4-thiepanyl)-1H-indole-1,7-dicarboxylate (88 mg, 0.18 mmol), PdCl2(dppf) (13 mg, 0.109 mmol), K2CO3 (75 mg, 0.54 mmol), and PhB(OH)2 (33 mg, 0.27 mmol) were mixed together and the taken up in dioxane/H2O (3/1, 2 mL). The reaction was heated in a microwave oven at 120° C. for 10 minutes. The mixture was diluted with AcOEt, washed with 1N HCl, H2O and brine, dried over MgSO4, and concentrated. The residue was dissolved in MeOH (5 mL). 6N NaOH (1 mL) was added and the mixture was stirred at room temperature overnight. The reaction was diluted with AcOEt, washed with 1N HCl, H2O, dried over MgSO4, and then concentrated, giving the title compound.