Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:6]1[C:14]2[S:13][CH:12]=[CH:11][C:10]=2[C:9]([OH:15])=[CH:8][CH:7]=1)C(O)=O.C(O)C.S(=O)(=O)(O)O.C(OC(C)C)(=O)C>O>[OH:15][C:9]1[C:10]2[CH:11]=[CH:12][S:13][C:14]=2[C:6]([CH:2]=[O:1])=[CH:7][CH:8]=1
Reactant: O=C(O)C(O)c1ccc(O)c2ccsc12
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)C
Solvent: O
Solvent: CCO
Product: O=Cc1ccc(O)c2ccsc12
Temperature: 57.5 °C
Reaction time: 5 h

Procedure:
Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-hydroxy-2-(4-hydroxy-1-benzothiophen-7-yl)acetic acid (500 mg, 2.01 mmol, 1.00 equiv, 90%), Fe2(SO4)3 (750 mg, 1.88 mmol, 1.15 equiv), ethanol (0.75 mL), sulfuric acid(0.4N) (3.75 mL). The resulting solution was stirred for 5 h at 55-60° C. in an oil bath. After cooling to 25° C., 15 mL of isopropyl acetate and 5 ml of water were added under stirring, then the organic phase was separated and organic phase was diluted by 10 ml of water (pH was 3), then used NaOH (2N) solution were added dropwise at 20 degree C. until a pH of 12-12.5 was reached. The organic phase was removed and to the aqueous phase were added H2SO4 (2N) solution until a pH was 4-4.5. The product precipitated during the addition. The suspension was stirred overnight at 25° C., then for 1.2 h in an ice bath and then filtered. This resulted in 200 mg (53%) of 4-hydroxy-1-benzothiophene-7-carbaldehyde as a gray solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]2[O:15][CH:16]=[CH:17][N:18]=2)[CH:13]=1)[C:8](O)=O)=[O:4].[BH4-].[Li+].C[Si](C=[N+]=[N-])(C)C.CCCCCC.CS(Cl)(=O)=O.C(N(CC)CC)C.[CH3:46][NH:47][CH2:48][CH2:49][CH2:50][CH3:51]>O1CCCC1.C(O)C>[CH2:48]([N:47]([CH2:8][C:7]1[CH:6]=[C:5]([CH:13]=[C:12]([C:14]2[O:15][CH:16]=[CH:17][N:18]=2)[CH:11]=1)[C:3]([O:2][CH3:1])=[O:4])[CH3:46])[CH2:49][CH2:50][CH3:51]
Reactant: COC(=O)c1cc(C(=O)O)cc(-c2ncco2)c1
Reactant: CCCCNC
Agent: CS(=O)(=O)Cl
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCCCCC
Product: CCCCN(C)Cc1cc(C(=O)OC)cc(-c2ncco2)c1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
To an ice-cold solution of 3-(methoxycarbonyl)-5-(1,3-oxazol-2-yl)benzoic acid (340 mg, 1.4 mmol) in anhydrous tetrahydrofuran (10 mL) is added lithium borohydride (250 mg, 11 mmol) slowly. The reaction is stirred 30 min, then absolute ethanol (4 mL) is added, and the reaction is stirred 1 h. The solution is poured onto ice containing excess hydrochloric acid and extracted with ethyl acetate. The organic layer is washed with water, brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. The residue is redissolved in 20% methanol/benzene (50 mL), and 2M trimethylsilyldiazomethane in hexane (0.9 mL, 1.8 mmol) is added. The reaction is stirred 2 h at room temperature, then concentrated under reduced pressure. The residue is redissolved in anhydrous methylene chloride (10 mL), cooled to −30° C., then methanesulfonyl chloride (150 μL, 1.9 mmol) and triethylamine (380 μL, 2.7 mmol) are added. The reaction is stirred at 0° C. 15 min, then N-methylbutylamine (480 μL, 4 mmol) is added, and the reaction is stirred 16 h at room temperature. The solution is concentrated under reduced pressure. Purification by flash column chromatography (silica gel, 40-100% ethyl acetate/hexane gradient) provides the title compound in pure form. ESI MS m/z 303.3 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[NH:6][CH:5]=1.Cl.[C:16]1([CH3:28])[CH:21]=[CH:20][C:19]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:14][O:13][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[NH:6][CH:5]=[C:4]2[CH2:3][CH2:2][N:25]1[CH2:26][CH2:27][CH:22]([C:19]2[CH:18]=[CH:17][C:16]([CH3:28])=[CH:21][CH:20]=2)[CH2:23][CH2:24]1
Reactant: COc1ccc2[nH]cc(CCBr)c2c1
Reactant: Cc1ccc(C2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2[nH]cc(CCN3CCC(c4ccc(C)cc4)CC3)c2c1
Temperature: 25 °C
Reaction time: 80 h

Procedure:
A solution of 8.8 g of 3-(2-bromoethyl)-5-methoxy indole in 100 ml of dimethylformamide is added to a stirring mixture of 4-(4-toluyl)piperidine hydrochloride [Example 5(a)] and 10.1 g of potassium carbonate in 400 ml of dimethylformamide and the reaction mixture is stirred at ambient temperature for 80 hours and then at 50° C. for 10 additional hours. It is cooled to ambient temperature, filtered, and 2 liters of water are added dropwise to produce a precipitate. The precipitate is triturated with ether and eluted with a 5% methanol in benzene solution through a silica gel column. The precipitate is recrystallized from an ethanol-water mixture to give off-white crystals, mp 131°-133° C., 5-methoxy-3-{2-[4-(4-toluyl)piperidyl]ethyl}indole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][NH:11][CH:12]=2)=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O>O1CCCC1>[Br:18][C:12]1[NH:11][CH:10]=[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: CCOC(=O)c1c[nH]cc1-c1ccc(Cl)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: CCOC(=O)c1c[nH]c(Br)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90348.4 %

Procedure:
Ethyl 4-(p-chlorophenyl)pyrrole-3-carboxylate (1.6 g., 0.0064 mmol) is dissolved in tetrahydrofuran (40 mL). N-bromosuccinimide (1.14 g., 0.0064 mmol) is added in small portions at 25°-28° C. After the addition is complete, the solution is stirred overnight at room temperature. The solution is concentrated in vacuo and the solid residue partioned between water and ether. The ether layer is separated and dried over magnesium sulfate. Work-up of the ether extract leaves 1.9 g (90%) Of a white solid which is purified by stirring with a mixture of 80/20 hexane/ethyl acetate. The insoluble solid (1.3 g, 62%) is collected and has m.p. 161°-164° C.
Reaction SMILES: [OH:1][C:2]1([C:15]2[CH:24]=[CH:23][C:18]([O:19][CH2:20][C:21]#[N:22])=[CH:17][CH:16]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH:8][S:9]([CH:12]([CH3:14])[CH3:13])(=[O:11])=[O:10].COCCO[AlH2-]OCCOC.[Na+].O>C1COCC1.C1(C)C=CC=CC=1.C1(C)C=CC=CC=1>[NH2:22][CH2:21][CH2:20][O:19][C:18]1[CH:23]=[CH:24][C:15]([C:2]2([OH:1])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]2[NH:8][S:9]([CH:12]([CH3:13])[CH3:14])(=[O:11])=[O:10])=[CH:16][CH:17]=1
Reactant: CC(C)S(=O)(=O)NC1CCCCC1(O)c1ccc(OCC#N)cc1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)NC1CCCCC1(O)c1ccc(OCCN)cc1
Temperature: 25 °C
Yield: 118.1 %

Procedure:
Into a 100 mL, 3 neck flask with stirrer, 2-[4-(1-hydroxy-2-{[(methylethyl)sulfonyl]amino}cyclohexyl)phenoxy]ethanenitrile (400 mg) in THF-toluene 1:1 (30 mL) was added dropwise to Red-Al® (3 mL, 65% solution in toluene) while stirring at room temperature under a nitrogen atmosphere. The reaction mixture was then stirred for two hours at this temperature. The mixture was poured into water and the desired material was extracted with ethyl acetate. The organic layer was washed once with water, dried over potassium carbonate, filtered, and concentrated under reduced vacuum to yield the intermediate title compound (478 mg, 89%) as a white foam. This material was used without further purification. Ion spray M.S. 355.2 (M*−1). Calculated for C17H28N2O4S-H2O: Theory: C 54.51, H 8.07. Found: C 54.20, H 8.29.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]2=[O:22])[N:3]=1.[Br:23]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:23][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[N:3][C:4]=1[CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:11][C:10]1=[O:22]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(O)n2)C(=O)C1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCN(Cc2nc(O)ccc2Br)C(=O)C1
Reaction time: 0.5 h

Procedure:
To a solution of the product from Step A (511 mg, 1.66 mmol) in 10 mL of chloroform at 0° C. was added N-bromosuccinimide (296 mg, 1.66 mmol). After 30 minutes, the solution was concentrated in vacuo. The resulting product was purified by silica gel chromatography (3-4% MeOH/CH2Cl2) to provide the desired product.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[N:6][C:5]([CH3:9])=[CH:4][N:3]=1.[CH:10]([B-](F)(F)F)=[CH2:11].[K+]>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].CCO>[CH3:8][C:7]1[C:2]([CH:10]=[CH2:11])=[N:3][CH:4]=[C:5]([CH3:9])[N:6]=1
Reactant: Cc1cnc(Cl)c(C)n1
Reactant: C=C[B-](F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: CCO
Product: C=Cc1ncc(C)nc1C

Procedure:
To a mixture of 2-chloro-3,5-dimethylpyrazine (2 g) and EtOH (20 mL) were added potassium vinyltrifluoroborate (2.067 g) and TEA (2.93 mL) at room temperature, and the mixture was stirred under nitrogen atmosphere. To the mixture was added PdCl2(dppf) (1.026 g), and the mixture was refluxed for 2 h.
Reaction SMILES: [CH2:1]([N:8]1[CH2:11][C:10]2([CH2:20][C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](/[CH:22]=[CH:23]/[C:24](O)=[O:25])[CH:17]=3)[O:12]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:41][O:42][CH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][O:44]1>C(Cl)Cl>[CH2:1]([N:8]1[CH2:11][C:10]2([CH2:20][C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](/[CH:22]=[CH:23]/[C:24]([NH:41][O:42][CH:43]4[CH2:48][CH2:47][CH2:46][CH2:45][O:44]4)=[O:25])[CH:17]=3)[O:12]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NOC1CCCCO1
Reactant: O=C(O)/C=C/c1ccc2c(c1)C(=O)CC1(CN(Cc3ccccc3)C1)O2
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CN(Cc3ccccc3)C1)O2)NOC1CCCCO1
Yield: 117673.3 %

Procedure:
A suspension of (E)-3-[1′-benzyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-acrylic acid (490 g, 1.30 mmol) in DCM (6.5 ml) was treated with TEA (0.12 ml, 0.90 mmol) and then with EDC (172 mg, 0.900 mmol), HOBt (122 mg, 0.904 mmol) and NH2OTHP (82 mg, 0.72 mmol) following the procedure described in Example 30, Step B, giving (E)-3-[1′-benzyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (380 g) as a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@:9]1([C:14]([NH:16][S:17]([C:20]2([CH3:23])[CH2:22][CH2:21]2)(=[O:19])=[O:18])=[O:15])[CH2:11][C@H:10]1[CH:12]=[CH2:13].[C:24]([O:28][C:29]([NH:31][C@@H:32]([C@H:44]([CH3:52])[CH2:45][C@H:46]([CH3:51])[CH2:47][CH2:48][CH:49]=[CH2:50])[C:33]([N:35]1[CH2:39][C@H:38]([OH:40])[CH2:37][C@H:36]1[C:41](O)=[O:42])=[O:34])=[O:30])([CH3:27])([CH3:26])[CH3:25].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C>[OH:40][C@H:38]1[CH2:39][N:35]([C:33](=[O:34])[C@@H:32]([NH:31][C:29](=[O:30])[O:28][C:24]([CH3:26])([CH3:25])[CH3:27])[C@H:44]([CH3:52])[CH2:45][CH:46]([CH3:51])[CH2:47][CH2:48][CH:49]=[CH2:50])[C@H:36]([C:41](=[O:42])[NH:8][C@:9]2([C:14](=[O:15])[NH:16][S:17]([C:20]3([CH3:23])[CH2:22][CH2:21]3)(=[O:19])=[O:18])[CH2:11][C@H:10]2[CH:12]=[CH2:13])[CH2:37]1
Reactant: C=CCC[C@@H](C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)NS(=O)(=O)C1(C)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@]1(C(=O)NS(=O)(=O)C2(C)CC2)C[C@H]1C=C
Temperature: 25 °C
Reaction time: 20 h
Yield: 41.4 %

Procedure:
To a 500 mL round-bottom flask charged with (1R,2S)-1-amino-N-((1-methylcyclopropyl)sulfonyl)-2-vinylcyclopropanecarboxamide trifluoroacetic acid salt (7.53 g, 21.0 mmol) was added a solution of (2S,4R)-1-((2S,3R,5R)-2-((tert-butoxycarbonyl)amino)-3,5-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylic acid (8.82 g, 21.38 mmol) in CH2Cl2 (100 mL). To the solution was added N,N-diisopropylethylamine (15 mL, 86 mmol) and DMF (15 mL) to afford a homogeneous orange solution. The flask was placed in a room temperature water bath. To the stirred solution was added HATU (9.59 g, 25.2 mmol). The solution was stirred at room temperature for 20 h. The reaction mixture was concentrated in vacuo and the resulting residue was dissolved in EtOAc (300 mL) and transfered to a 1 L separatory funnel. The solution was washed with aq. 1M HCl (4×225 mL). The combined aqueous phases were extracted with EtOAc (150 mL). The combined organics were dried over MgSO4; filtered, then concentrated in vacuo. The resulting residue was dissolved in MeOH and concentrated onto Celite in vacuo; the resulting powder was subjected to silica gel chromatography (hexanes:acetone, 90:10 to 60:40) to afford tert-butyl ((2S,3R)-1-((2S,4R)-4-hydroxy-2-(((1R,2S)-1-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamoyl)pyrrolidin-1-yl)-3,5-dimethyl-1-oxonon-8-en-2-yl)carbamate as a colorless solid (5.56 g, 41%). MS: MS m/z 639.5 (M++1).
Reaction SMILES: C(OC(=O)[O:7][CH2:8][CH2:9][N:10](C(OC(C)(C)C)=O)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[S:26][C:25]3[C:20](=[N:21][CH:22]=[CH:23][C:24]=3[O:27][C:28]3[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH:37][C:38](=[O:46])[CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[S:36])=[CH:30][C:29]=3[F:47])[CH:19]=2)=[CH:14][CH:13]=1)(C)(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O>>[F:47][C:29]1[CH:30]=[C:31]([NH:34][C:35]([NH:37][C:38](=[O:46])[CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[S:36])[CH:32]=[CH:33][C:28]=1[O:27][C:24]1[CH:23]=[CH:22][N:21]=[C:20]2[CH:19]=[C:18]([C:15]3[CH:14]=[CH:13][C:12]([CH2:11][NH:10][CH2:9][CH2:8][OH:7])=[CH:17][CH:16]=3)[S:26][C:25]=12
Reactant: CC(C)(C)OC(=O)OCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4F)c3s2)cc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3cc(-c4ccc(CNCCO)cc4)sc23)c(F)c1
Reaction time: 3 h

Procedure:
To a solution of 62 in DCM (190 mg, 0.24 mmol) was added TFA (excess) at room temperature and the reaction mixture was stirred for 3 hrs, evaporated under reduced pressure and the residual solid was triturated with Et2O to afford the title compound 63 as the di-TFA salt (100 mg, 51% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 12.49 (s, 1H), 11.84 (s, 1H), 8.89 (s, 1H), 8.53 (d, J=5.1 Hz, 1H), 8.14 (s, 1H), 8.01 (m, 1H), 7.62 (dd, J=2.5 and 7.7 Hz, 2H), 7.54 (d, J=2.7 Hz, 2H), 7.33 (m, 4H), 7.28 (m, 1H), 6.67 (d, J=5.5 Hz, 1H), 4.64 (m, 1H), 4.30 (m, 1H), 4.22 (t, J=5.3 Hz, 2H), 3.82 (s, 2H), 3.63 (t, J=5.3 Hz, 2H), 2.98 (m, 1H). MS (m/z) 587.0 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:20])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:20][C:29]([NH:28][C:25]2[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=2)=[O:30])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]([CH3:18])[CH3:19]
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CN(C)CCOc1ccc(N)cc1-c1c(Br)cnn1C
Solvent: ClCCl
Product: CN(C)CCOc1ccc(NC(=O)Nc2ccc(Cl)cc2)cc1-c1c(Br)cnn1C
Yield: 85 %

Procedure:
To a stirred solution of 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-dimethylamino-ethoxy)-phenylamine (0.033 g, 0.10 mmol) in CH2Cl2 (2.0 mL) was added 4-chlorophenyl isocyanate (0.017 g, 0.11 mmol, 1.1 equiv.). The solvent was removed after the completion of the reaction and it was purified by the HPLC. The pure fractions were collected and CH3CN was evaporated under vacuum. The residue was diluted with EtOAc and neutralized with saturated NaHCO3, the EtOAc phase was washed with brine, dried over MgSO4, filtered and evaporated. Compound 69 was obtained in 85% yield. LCMS m/z (%)=492 (M+H79Br35Cl, 28), 494 (M+H81Br35Cl, 100), 496 (M+H81Br37Cl, 28). 1H NMR (400 MHz, acetone-d6) δ: 8.27 (s, 1H), 8.20 (1H), 7.66 (dd, J=2.7, 9.0 Hz, 1H), 7.56 (d, J=8.9 Hz, 2H), 7.48 (s, 1H), 7.43 (d, J=2.7 Hz, 1H), 7.29 (d, J=8.9 Hz, 2H), 7.14 (d, J=9.0 Hz, 1H), 3.98-4.20 (m, 2H), 3.73 (s, 1H), 2.48-2.68 (m, 2H), 2.16 (s, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Br[CH:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[CH:3][CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(O)cc1
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1ccc(C=O)cc1
Yield: 71.5 %

Procedure:
By the method of Example 1, Step F, 10.0 g (0.0819 mole) of 4-hydroxy-benzaldehyde and 16.4 g (0.0983 mole) of methyl 2-bromopropionate were reacted in the presence of 13.6 g (0.0983 mole) of anhydrous potassium carbonate in N,N-dimethylformamide, yielding 12.2 g of methyl 2-(4-formyl-phenoxy)propionate as a yellow liquid. The NMR and IR spectra were consistent with the proposed structure.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[I:11])[C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:18](I)[CH3:19].O1CCCC1>CC(=O)CC>[CH2:18]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[I:11])[C:5]([OH:7])=[O:6])[CH3:19]
Reactant: CCI
Reactant: O=C(O)c1ccc(I)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: C1CCOC1
Product: CCOc1cc(C(=O)O)ccc1I
Temperature: 25 °C
Yield: 62 %

Procedure:
To a solution of 3-hydroxy-4-iodo-benzoic acid (4 g, 15.15 mmol) in 2-butanone (100 mL) were added potassium carbonate (20 g, finely ground) and ethyl iodide (4.85 mL). The mixture was stirred at reflux overnight. Upon cooling to room temperature, the solids were filtered off, and the filtrate was concentrated. The residue was partitioned between ethyl acetate and water, and the organic layer was washed with 10% sodium carbonate solution, brine, and concentrated. The residue reconstituted in methanol. 1.0 M sodium hydroxide was added giving a cloudy solution. Tetrahydrofuran was added to clarity and the mixture stirred at room temperature for one hour. The volatiles were evaporated and the residue was dissolved in water. It was washed once with diethyl ether and then acidified with 37% hydrochloric acid to precipitate a white solid. The solid was filtered, washed with water and dried in a vacuum oven to give 3-ethoxy-4-iodo-benzoic acid (2.73 g, 62%). LC-MS: 293 [(M+H)+].
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][C:4](=[O:20])[CH:3]=1.CCN(CC)CC.[CH3:28][C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31](Cl)=O.CC(C)(O)C#N.C([BH3-])#N.[Na+]>C(O)(=O)C.C(#N)C.C(Cl)Cl>[OH:1][C:2]1[CH2:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:5][C:4](=[O:20])[C:3]=1[CH2:28][C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[CH3:31]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: O=C1C=C(O)CC(c2ccccc2)(c2ccccc2)O1
Agent: CC(C)(O)C#N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1CC1=C(O)CC(c2ccccc2)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared as described in General Method 8 using the following: 5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (0.300 g, 1.13 mmol), Et3N (0.16 mL, 1.15 mmol), 2-methylbenzoyl chloride (0.15 mL, 1.13 mmol), CH2Cl2 (4.0 mL), acetonitrile (4.0 mL), acetone cyanohydrin (0.05 mL, 0.58 mmol), Et3N (0.32 mL, 2.3 mmol), glacial acetic acid (4.0 mL), sodium cyanoborohydride (0.28 g, 4.5 mmol). Purification was achieved by submitting the final residue to column chromatograpy (SiO2, 100% CH2Cl2 to 1% MEOH in CH2Cl2) to provide a solid (0.135 g, m.p. 169-171° C.). 1H NMR (400 MHz, DMSO-d6) δ 11.102 (bs, 1 H), 7.444-7.260 (m, 10 H), 6.981 (d, 1 H, J=7.5 Hz), 6.900 (t, 1 H, J=7.5 Hz), 6.577 (t, 1 H, J=7 Hz), 5.897 (d, 1 H, J=7.5 Hz), 3.557 (s, 2 H), 3.341 (s, 2 H), 2.115 (s, 3 H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:18])[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1.[Li]C(C)(C)C.[CH3:24][O:25][CH2:26][CH2:27][N:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[CH:33]=[O:34]>C1COCC1.CCCCC>[OH:34][CH:33]([C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:18])[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1)[C:29]1[N:28]([CH2:27][CH2:26][O:25][CH3:24])[CH:32]=[CH:31][CH:30]=1
Reactant: CN(c1ccc(Br)cc1)S(=O)(=O)c1ccccc1
Reactant: COCCn1cccc1C=O
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: COCCn1cccc1C(O)c1ccc(N(C)S(=O)(=O)c2ccccc2)cc1
Temperature: -30 °C

Procedure:
To a solution of 1.49 g (4.59 mmol) of N-(4-bromophenyl)-N-methyl benzenesulfonamide (Example 78, Step C) in 37.5 mL THF at −78° C. was added dropwise 5.94 mL (10.10 mmol) of a 1.7 M solution of tert-BuLi in pentane and the resultant mixture was stirred at −78° C. for 15 min. To this mixture was then added a solution of 1.01 g (6.59 mmol) of N-methoxyethylpyrrole-2-carboxaldehyde in 6 mL THF and the mixture was allowed to gradually warm to −30° C. over a 4 h period. After this time, the reaction mixture was quenched by the addition of a saturated aqueous solution of ammonium chloride and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by chromatography on silica gel (hexanes:EtOAc, 13:7) to give the title compound.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([CH3:11])[CH2:9][C@@H:8]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[NH2:18])[CH2:7][C@H:6]1[NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])(=O)C.[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:29]=1[C:35]1[N:40]=[C:39]([C:41](O)=[O:42])[CH:38]=[CH:37][C:36]=1[F:44].C(Cl)CCl.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(O)C.CCOC(C)=O.CCO>[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:29]=1[C:35]1[N:40]=[C:39]([C:41]([NH:18][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][C:12]=2[C@H:8]2[CH2:7][C@@H:6]([NH:19][C:20](=[O:21])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C@H:5]([OH:4])[C@@H:10]([CH3:11])[CH2:9]2)=[O:42])[CH:38]=[CH:37][C:36]=1[F:44]
Reactant: CC(=O)O[C@@H]1[C@@H](C)C[C@@H](c2ccncc2N)C[C@H]1NC(=O)OC(C)(C)C
Reactant: O=C(O)c1ccc(F)c(-c2c(F)cccc2F)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: C[C@H]1C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 99 %

Procedure:
To a solution of (1R,2R,4R,6S)-4-(3-aminopyridin-4-yl)-2-(tert-butoxycarbonylamino)-6-methylcyclohexyl acetate (1.0 equiv.) in DMF/Ethanol (1/5, 0.05 M) was added 6-(2,6-difluorophenyl)-5-fluoropicolinic acid (1.3 equiv.), aza-HOBt (1.3 equiv.) and EDC (1.3 equiv.). The mixture was stirred at rt for 6 hrs. The solution was diluted with EtOAc, washed with H2O, 1N NaOH, NaCl (sat.), dried over MgSO4, filtered and concentrated to yield crude protected amide. The material was dissolved in EtOH (0.45 M), Cs2CO3 (1.0 equiv.) was added and the solution was submerged in a 60° C. oil bath and stirred for 90 mins. The volatiles were removed in vacuo; the residue was partitioned between with EtOAc and H2O. The organic layer was washed with NaCl(sat.), dried over MgSO4, filtered, concentrated and pumped on to yield tert-butyl (1R,2R,3S,5R)-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-2-hydroxy-3-methylcyclohexylcarbamate in 99% yield. LC/MS (m/z)=557.3 (MH+), Rt=0.80 min.