Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].[OH-].[K+].Cl>CO>[CH2:1]([O:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:20][CH:21]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4]
Reactant: COC(=O)c1ccc(OC/C=C(\C)CCC=C(C)C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
To a solution of methyl 4-geranyloxybenzoate(13.00 g) in methanol(50 ml) was added aqueous solution(10 ml) of potassium hydroxide (3.90 g). After being stirred overnight at room temperature, the mixture was refluxed with heating for 1 hour. After being acidified with concentrated hydrochloric acid, the reaction mixture was extracted with chloroform. The organic layer was dried over sodium sulfate anhydride and then the solvent was evaporated out under a vacuum. The resulting solid was recrystallized from hexane/ethyl acetate mixed solution, thereby yielding 9.77 g(71%) of the aimed compound.
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22]([OH:24])=O)=O)(C)(C)C.[NH2:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][C:31]=1[N:32]1[CH2:37][CH2:36][CH2:35][C@H:34]([OH:38])[CH2:33]1>>[NH2:8][C:9]1[S:13][C:12]([C:14]2[C:15]([F:21])=[CH:16][CH:17]=[CH:18][C:19]=2[F:20])=[N:11][C:10]=1[C:22]([NH:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][C:31]=1[N:32]1[CH2:37][CH2:36][CH2:35][C@H:34]([OH:38])[CH2:33]1)=[O:24]
Reactant: Nc1cnccc1N1CCC[C@H](O)C1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Product: Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnccc1N1CCC[C@H](O)C1
Yield: 100 %

Procedure:
Followed the procedure as described in EXAMPLE 1, starting with 5-(tert-butoxycarbonylamino)-2-(2,6-bisfluorophenyl)thiazole-4-carboxylic acid and (S)-1-(3-aminopyridin-4-yl)piperidin-3-ol. Obtained the desired product as a white solid (111 mg, 100%). 1H NMR (400 MHz, DMSO) δ 9.37 (s, 1H), 9.30 (s, 1H), 8.21 (d, J=5.3 Hz, 1H), 7.67 (s, 2H), 7.59-7.47 (m, 1H), 7.29 (t, J=8.9 Hz, 2H), 7.14 (d, J=5.3 Hz, 1H), 4.81 (d, J=4.7 Hz, 2H), 3.81-3.63 (m, 3H), 3.19-3.07 (m, 1H), 2.99 (d, J=11.2 Hz, 1H), 2.61-2.33 (m, 2H), 1.90 (d, J=12.1 Hz, 1H), 1.71 (m, 3H), 1.30-1.09 (m, 2H). ESIMS m/z=432.2 (M+1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[Br:8][C:9]1[C:10]([OH:20])=[C:11]([NH2:19])[C:12](=[C:16]([Br:18])[CH:17]=1)[C:13]([OH:15])=[O:14].[O-]S([O-])(=O)=O.[Na+].[Na+].C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[Br:8][C:9]1[C:10]([OH:20])=[C:11]([NH:19][CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[C:12](=[C:16]([Br:18])[CH:17]=1)[C:13]([OH:15])=[O:14]
Reactant: Nc1c(O)c(Br)cc(Br)c1C(=O)O
Reactant: O=Cc1cccs1
Agent: O=S(=O)([O-])[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(O)c1c(Br)cc(Br)c(O)c1NCc1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.3 %

Procedure:
A solution of 2-thiophenecarboxaldehyde (38 mg, 0.34 mmol) in dry methanol (0.8 mL) was added to a mixture of 4,6-dibromo-3-hydroxyanthranilic acid (105 mg, 0.34 mmol) and Na2SO4 (240 mg, 1.7 mmol) in methanol (2 mL ). The reaction mixture was stirred overnight at room temperature. Sodium cyanoborohydride (32 mg, 0.51 mmol) was added, and the mixture was stirred for 2 days at room temperature. Conc. acetic acid (1 mL) was added, and the solvent was removed in vacuo. The residue was partitioned between brine and EtOAc (20 mL). The layers were separated and the aqueous layer was extracted with EtOAc (20 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The obtained material was purified by column chromatography (SiO2, CH2Cl2 -hexane-EtOAc-conc. HOAc 30:30:20:3). Preparative HPLC (H2O-acetonitrile-conc. HOAc 50:50:1) yielded the title compound as a yellowish solid (17 mg): 1H NMR (CD3OD-d4) 7.26 (dd, J=5 Hz, 1 Hz), 7.20 (s 1 H), 6.99 (m, 1 H), 6.92 (dd, J=5 Hz, J=5 Hz, 1 H), 4.54 (s, 2 H); MS (TSP): m/z (rel.int.) 410/408/406 (M+1, 5/12/7), 234/232 (31/28), 154 (100).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([N:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=4)[CH:19]=[N:18]3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([N:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=4)[CH:19]=[N:18]3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc2cnn(-c3cnc4c(n3)c(C(=O)NC(C)(C)C)cn4COCC[Si](C)(C)C)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2cnn(-c3cnc4[nH]cc(C(=O)NC(C)(C)C)c4n3)c2c1
Reaction time: 15 h
Yield: 65.7 %

Procedure:
To a stirred solution of N-tert-butyl-2-(6-methoxy-1H-indazol-1-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (130 mg, 263 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL). After 15 h, the mixture was concentrated in vacuo, add 25 mL Jan. 10, 1960 mixture of ammonium hydroxide/methanol/dichloromethane, stir for 1 hour. concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-4% methanol containing 10% ammonium hydroxide in dichloromethane) gave 2-(6-methoxy-indazol-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (63 mg, 66%). MS (M+H)+=365; 1H NMR (DMSO-d6) δ: 8.92 (s, 1H), 8.40 (d, J=5.1 Hz, 2H), 8.01 (s, 1H), 7.85 (d, J=8.9 Hz, 1H), 7.67 (s, 1H), 7.07 (dd, J=8.9, 2.0 Hz, 1H), 3.91 (s, 3H), 1.46 (s, 9H).
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[N:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][N:8]=1.F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1>CN(C)C=O>[N+:22]([C:19]1[CH:20]=[CH:21][C:16]([S:3][C:4]2[N:5]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:7][N:8]=2)=[CH:17][CH:18]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Sc1nccn1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Sc2nccn2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 26.6 %

Procedure:
To a mixture of 0.6 g (13.6 mmoles) of 50% sodium hydride in mineral oil and 8 ml of N,N-dimethylformamide was added 2.0 g (11.4 mmoles) of 2-mercapto-1-phenylimidazole. After stirring for 10 minutes the mixture was cooled in an icebath and 2.1 g (14.8 mmoles) of 1-fluoro-4-nitrobenzene was added. After stirring for 20 minutes, the mixture was warmed to room temperature and stirred for 3 hours. Ice was added and the mixture partitioned between dichloromethane and water. The aqueous phase was separated and extracted with dichloromethane. The organics were dried and concentrated. The residue was recrystallized from dichloromethane/petroleum ether (bp 30°-60° C.) to give 0.9 g (27%) of the product as off-white prisms, mp 123°-125° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([C:7]([C:9]2[NH:10][C:11](=[O:15])[NH:12][C:13]=2[CH3:14])=[O:8])=[CH:5][CH:4]=1>C(OC(=O)C)(=O)C>[C:3]([N:12]1[C:13]([CH3:14])=[C:9]([C:7](=[O:8])[C:6]2[CH:16]=[CH:17][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]([C:7](=[O:8])[CH3:6])[C:11]1=[O:15])(=[O:2])[CH3:4]
Reactant: COc1ccc(C(=O)c2[nH]c(=O)[nH]c2C)cc1
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(C(=O)c2c(C)n(C(C)=O)c(=O)n2C(C)=O)cc1

Procedure:
A mixture of 46.4 g of 1,3-dihydro-4-(4-methoxybenzoyl)-5-methyl-2H-imidazol-2-one and 200 ml of acetic anhydride is refluxed for 2 hours. The mixture is distilled to remove 100 ml of acetic anhydride and acetic acid; this is replaced by fresh acetic anhydride and refluxing is resumed. After a total of 4 hours of reflux, excess acetic anhydride is evaporated under reduced pressure and the resulting residue is crystallized from ethanol to give 1,3-diacetyl-1,3-dihydro-4-(4-methoxybenzoyl)-5-methyl-2H-imidazol-2-one melting at about 123°-125° C.
Reaction SMILES: [C:1]([O:10][CH2:11][CH2:12][OH:13])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:14]([OH:23])(=[O:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C(O)CO>>[C:1]([O:10][CH2:11][CH2:12][O:13][C:14](=[O:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:14]([OH:23])(=[O:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCC(=O)OCCO
Solvent: OCCO
Solvent: CCCCCCCC(=O)O
Product: CCCCCCCC(=O)OCCOC(=O)CCCCCCC

Procedure:
Three fractions containing 68.6 to 97.8% of 2-hydroxyethyl caprylate were obtained by heating caprylic acid (1.25 mol; 180 g) with ethylene glycol (8.27 mol; 513.5 g) to boiling temperature for 5 hours and gradual distillation; the overall yield of 2-hydroxyethyl caprylate was 61.3%. In addition to 2-hydroxyethyl caprylate, ethylene dicaprylate was formed from 21% of caprylic acid. In a similar experiment, the reaction mixture after 7 hours of heating was first extracted with benzene and the benzene extract with water, instead of direct distillation. Caprylic acid was consumed in 60.6% for 2-hydroxyethyl caprylate, whereas ethylene dicaprylate resulted from 21.5% of acid; distillation gave fractions of raw product containing 97.6 to 98.5% of 2-hydroxyethyl caprylate. Further procedure was carried out according to example 1.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:13]#[C:14][C:15]2[CH2:20][CH2:19][CH:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17][CH:16]=2)=[C:4]([F:31])[CH:3]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40]([N:42]=[C:43]=[O:44])=[O:41])=[CH:35][CH:34]=1.COC1C=CC(CNC2N=CN=C(OC3C=CC(NC(NC(=O)CC4C=CC(F)=CC=4)=O)=CC=3F)C=2)=CC=1>C(Cl)Cl>[F:31][C:4]1[CH:3]=[C:2]([NH:1][C:43]([NH:42][C:40](=[O:41])[CH2:39][C:36]2[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=2)=[O:44])[CH:30]=[CH:29][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[C:13]#[C:14][C:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH2:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)NC1CC=C(C#Cc2cnccc2Oc2ccc(N)cc2F)CC1
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Agent: COc1ccc(CNc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)ncn2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CC=C(C#Cc2cnccc2Oc2ccc(NC(=O)NC(=O)Cc3ccc(F)cc3)cc2F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
A solution of tert-butyl 4-(2-(4-(4-amino-2-fluorophenoxy)pyridin-3-yl)ethynyl)cyclohex-3-enylcarbamate (50 mg, 0.12 mmol) in dry CH2Cl2 (2 mL) was treated with a 0.3 M solution of 2-(4-fluorophenyl)acetyl isocyanate in toluene (Compound D of Example 11, 0.8 mL, 0.24 mmol) and the mixture stirred at rt for 1 h. The solvents were evaporated under vacuum and the residue purified by flash chromatography on silica gel eluting with 10-60% EtOAc/hexanes to give the title compound (50 mg, 69%) as a white solid. 1H NMR (DMSO-d6) δ 11.03 (s, 1H), 10.57 (s, 1H), 8.57 (s, 1H), 8.36 (d, 1H, J=5.7 Hz), 7.78 (dd, 1H, J=1.8, 13.1 Hz), 7.41-7.29 (m, 3H), 7.16 (dd, 3H, J=8.6, 8.6 Hz), 6.85 (d, 1H, J=8.3 Hz), 6.70 (d, 1H, J=5.7 Hz), 6.13-6.08 (m, 1H), 3.73 (s, 2H), 3.51-3.41 (m, 1H), 2.38-2.27 (m, 1H), 2.27-2.20 (m, 2H), 1.82-1.72 (m, 1H), 1.54-1.28 (m, 2H), 1.37 (s, 9H); ESI MS): m/z 603.24 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[N:9]([CH3:11])[CH3:10].CN(CCN(C)C)C.[Li]CCCC.CN([CH:32]=[O:33])C>C1COCC1.O>[CH3:11][N:9]([CH3:10])[C:8]1[CH:12]=[CH:13][CH:14]=[C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:15])[CH3:1])[C:7]=1[CH:32]=[O:33]
Reactant: CN(C)C=O
Reactant: CN(C)CCOc1cccc(N(C)C)c1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CN(C)CCOc1cccc(N(C)C)c1C=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of Compound 71 (2.8 g, 13.5 mmol) in THF (10 mL) was added TMEDA (1.88 g, 16.2 mmol) followed by n-BuLi (2.5 M solution in hexane, 6.5 mL, 16.2 mmol). The mixture was stirred for 30 min at room temperature then DMF (1.48 g, 20.25 mmol) was added and the solution stirred for 3 h at room temperature. The reaction was then diluted with water (20 mL), and the product was extracted with EtOAc (3×50 mL). The organic layers were combined and washed with brine, and dried (MgSO4), and filtered, and the solvent was removed under reduced pressure. After silica gel chromatography, the product (Compound 72) was obtained as an oil.
Reaction SMILES: [C:1]([C:5]1[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=1[O:7][C:8]1[C:13](I)=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.CCCCC.[B:29](OC(C)C)([O:34]C(C)C)[O:30]C(C)C.[Li+].[OH-]>C1COCC1.O>[C:1]([C:5]1[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=1[O:7][C:8]1[C:13]([B:29]([OH:34])[OH:30])=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccccc1Oc1ncccc1I
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li+]
Agent: [Li]CCCC
Agent: [OH-]
Solvent: O
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccccc1Oc1ncccc1B(O)O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 92.5 %

Procedure:
To a solution of 141a (3.35 g, 9.49 mmol) in THF (60 ml) under nitrogen at −78° C. was added 2.0 M nBuLi in pentane (14.2 mL, 28.47 mmol, 3 eq) over ˜3 min. The reaction was stirred at −78° C. for 10 min & then B(OiPr)3 (6.54 mL, 28.47 mmol, 3 eq) was added in a single aliquot. The reaction was stirred at −78° C. for 40 min and then the reaction was poured into water (˜60 mL) followed by the addition of LiOH (˜3.5 g). The reaction was stirred for 2 h at rt. Partition the reaction mixture between water (˜200 mL additional) and EtOAc (˜200 mL). Separate layers and wash the aqueous once more with EtOAc. Pour aqueous into a large erlenmyer flask & add EtOAc (˜200 mL). With vigorous stirring add conc. HCl dropwise until pH ˜2. Separate layers in sep. funnel & extract aqueous once more with EtOAc (˜200 mL). Combine these last two EtOAc extracts, dry over sodium sulfate, filter and concentrate. Azeotrope twice with toluene to give 234b (2.38 g) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.31 (s, 9H); 4.1 (bs, 1H); 5.61 (bs, 1H); 6.91 (d, J=7.47 Hz, 1H); 7.05 (dd, J=6.37, 3.74 Hz, 1H); 7.15-7.3 (m, 2H); 7.48 (dd J=7.47, 1.32 Hz, 1H); 8.23 (bs, 1H); 8.27 (dd, J=7.03 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12](=[O:17])[CH2:13][C:14](=[O:16])[CH3:15])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].B(OB=O)=O.[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[OH:32])[CH:27]=O.B(OCCCC)(OCCCC)OCCCC.C(N)CCC.Cl.C([O-])(O)=O.[Na+]>C(OCC)(=O)C.[Cl-].[Na+].O>[F:23][C:24]1[CH:25]=[C:26](/[CH:27]=[CH:15]/[C:14](=[O:16])[CH2:13][C:12](=[O:17])/[CH:11]=[CH:10]/[C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([OH:1])[CH:3]=2)[CH:29]=[CH:30][C:31]=1[OH:32]
Reactant: COc1ccc(C=CC(=O)CC(C)=O)cc1O
Reactant: O=Cc1ccc(O)c(F)c1
Agent: CCCCOB(OCCCC)OCCCC
Agent: Cl
Agent: O=BOB=O
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCN
Product: COc1ccc(/C=C/C(=O)CC(=O)/C=C/c2ccc(O)c(F)c2)cc1O
Reaction time: 1 h
Yield: 47.5 %

Procedure:
6-(3-Hydroxy-4-methoxyphenyl)hex-5-ene-2,4-dione (20 mg, 85 μmol) and boron trioxide (11 mg, 0.16 mmol) was placed in a 20 mL reaction vessel, and dissolved in 0.4 mL of ethyl acetate. To the stirring solution at 80° C. was added a solution of 3-fluoro-4-hydroxybenzaldehyde (15 mg, 0.11 mmol) and tri-n-butyl borate (25 μL, 93 μmol) in 0.7 mL of ethyl acetate. After being stirred for 2 h at the same temperature, n-butylamine (10 μL, 0.10 mmol) was added with additional stirring for 1 h. The reaction mixture was treated with a 1:1 solution (1 mL) of 1N HCl and brine, and was stirred at 50° C. for 5 min to 1 h (if necessary, the reaction mixture was neutralized by saturated NaHCO3 aqueous solution). The organic layer was purified directly by silica gel column chromatography (eluting with hexane/ethyl acetate or chloroform/methanol) to obtain the title compound as a solid (14.4 mg, 47%).
Reaction SMILES: [C:1]([S:5]([CH2:8][C:9]#[N:10])(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].CS(O[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)(=O)=O>CN(C)C=O>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][CH2:16][CH:8]([S:5]([C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:7])=[O:6])[C:9]#[N:10])=[CH:19][CH:20]=1
Reactant: CC(C)(C)S(=O)(=O)CC#N
Reactant: CS(=O)(=O)OCCc1ccc(Cl)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)S(=O)(=O)C(C#N)CCc1ccc(Cl)cc1
Yield: 80 %

Procedure:
Into a 3-neck, 200 milliliter (mL) round bottom flask was charged 2.4 grams (g), 0.06 mole, of 60% sodium hydride (NaH), which had been previously washed two times with successive 30 mL portions of hexane, in 30 mL of dimethylformamide (DMF). While stirring under nitrogen, 7.6 g (0.05 mole) of t-butylsulfonylacetonitrile in 25 mL of DMF was added. The mixture was stirred for 0.5 hour (hr) and 12.8 g (0.055 mole) of 2-(4-chlorophenyl)ethyl methanesulfonate in 25 mL of DMF was added dropwise. The mixture was stirred at room temperature for 3 hrs. and then an additional 96 hrs by which time the mixture had changed to an orange slurry. The mixture was stirred yet an additional 96 hrs at room temperature after which analysis by gas liquid phase chromatography (GLC) indicated the absence of starting material. The reaction was quenched by the addition of 100 mL of diethyl ether and 50 mL of water. The ether was washed with water and the combined aqueous phases were extracted with 50 mL of ethyl acetate. The organic phases were combined, dried with sodium sulfate, filtered and concentrated to give 12.0 g of an orange oil (80.3% yield) which was used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[CH:13])[CH:10]=2)[S:5][CH2:4][CH2:3]1.Br[C:16]1[O:20][C:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:18][CH:17]=1>>[CH2:24]([O:23][C:21]([C:19]1[O:20][C:16]([C:13]#[C:12][C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[S:5][CH2:4][CH2:3][C:2]3([CH3:14])[CH3:1])=[CH:17][CH:18]=1)=[O:22])[CH3:25]
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCS2
Reactant: CCOC(=O)c1ccc(Br)o1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCS3)o1

Procedure:
Again using the general procedure of Example 11, but using instead 4,4-dimethyl-6-ethynylthiochroman and ethyl 5-bromo-2-furate, the title compound was synthesized.
Reaction SMILES: [C:1]([NH:4][C@H:5]1[C@H:13]([C@@H:14]([C@@H:16]([CH2:18][OH:19])[OH:17])[OH:15])[O:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C@@H:6]1[NH2:20])(=[O:3])[CH3:2].C([O-])(=O)C.[Na+].[N:26]#[C:27]Br>CO>[C:1]([NH:4][C@H:5]1[C@H:13]([C@@H:14]([C@@H:16]([CH2:18][OH:19])[OH:17])[OH:15])[O:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C@@H:6]1[NH:20][C:27]#[N:26])(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)CO)OC(C(=O)O)=C[C@@H]1N
Reactant: N#CBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)CO)OC(C(=O)O)=C[C@@H]1NC#N
Reaction time: 3.5 h
Yield: 106.6 %

Procedure:
5-(Acetylamino)-4-amino-2,6-anhydro-3,4,5-trideoxy-D-glycero-D-galacto-non-2-enonic acid (3 g, 10.35 mmol) was suspended in methanol (37.5 ml) and sodium acetate (1.89 g, 23.1 mmol) was added, causing a "caking" of the suspension and making stirring difficult. To this at 21° C. with exclusion of moisture was added a solution of cyanogen bromide (1.14 g, 10.8 mmol) in methanol (150 ml), in a dropwise manner. Stirring gradually became easier, until a readily stirrable suspension was obtained. Addition was complete in 3.5 hr. The mixture was then stirred at 21° C. with exclusion of moisture for 44 hr. The small amount of remaining solid was filtered off and solvent evaporated in vacuo to an orange-brown foam. The foam was taken up in methanol (125 ml) and with rapid stirring at 21° C. was treated dropwise with propan-2-ol (130 ml). The precipitate was filtered off, washed with iPrOH:MeOH 3:2, and combined filtrate and washings evaporated to give the title compound as a pale yellow foam (3.48 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH:8]([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1.[CH2:26]([O:28][C:29](=[O:43])[CH2:30][CH2:31][NH:32][C:33](=[O:42])[C:34]1[CH:39]=[CH:38][C:37](O)=[C:36]([F:41])[CH:35]=1)[CH3:27].C(P(CCCC)CCCC)CCC.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH2:26]([O:28][C:29](=[O:43])[CH2:30][CH2:31][NH:32][C:33](=[O:42])[C:34]1[CH:39]=[CH:38][C:37]([O:15][CH:8]([C:6]2[CH:5]=[CH:4][C:3]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:20][CH:21]=3)=[C:2]([CH3:1])[CH:7]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[C:36]([F:41])[CH:35]=1)[CH3:27]
Reactant: CCCCCCC(O)c1ccc(-c2ccc(C(F)(F)F)cc2)c(C)c1
Reactant: CCOC(=O)CCNC(=O)c1ccc(O)c(F)c1
Agent: CCCCP(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCCCCC(Oc1ccc(C(=O)NCCC(=O)OCC)cc1F)c1ccc(-c2ccc(C(F)(F)F)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.3 %

Procedure:
Combine 1-(2-methyl-4′-trifluoromethyl-biphenyl-4-yl)-heptan-1-ol (0.090 g, 0.25 mmol) and 3-(3-fluoro-4-hydroxy-benzoylamino)-propionic acid ethyl ester (0.050 g, 0.20 mmol) in toluene (1.0 mL). Add 1,1′(diazocarbonyl)dipiperidine (0.076 g, 0.3 mmol) followed by tributyl-phosphane (0.074 mL, 0.3 mmol) under inert atmosphere. Stir at room temperature for 16 hours. Dilute reaction with ethyl acetate filter and remove solvent under reduced pressure. Purify on silica gel chromatography (0-50% Ethyl acetate/hexanes gradient) to provide 0.105 g of title compound (90%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH:13](I)([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH:13]([O:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5])([CH3:15])[CH3:14]
Reactant: CC(C)I
Reactant: O=Cc1cc([N+](=O)[O-])ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc([N+](=O)[O-])cc1C=O
Temperature: 95 °C
Yield: 89.2 %

Procedure:
To commercially available 2-hydroxy-5-nitrobenzaldehyde (500 mg, 3.0 mmol) in DMF (10 mL) in a sealable tube was added isopropyl iodide (1.02 g, 6.0 mmol) and potassium carbonate (1.7 g, 12 mmol). The tube was sealed and heated to 95° C. overnight. After cooling to rt, the reaction was diluted with ethyl acetate. The layers were separated, and the organic layer was washed with brine, then concentrated and purified via silica gel chromatography (10-20% ethyl acetate/hexane) to provide 8A (560 mg, 89%). 1H NMR (400 MHz, CDCl3) δ ppm 1.48 (d, J=6.15 Hz, 6H) 4.69-4.96 (m, 1H) 7.10 (d, J=9.23 Hz, 1H) 8.40 (dd, J=9.23, 3.08 Hz, 1H) 8.70 (d, J=3.08 Hz, 1H) 10.46 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH3:40])[CH2:9][O:10][C:11]([NH:13][C:14]2[CH:15]=[C:16]([F:39])[C:17]([O:33][C@@H:34]3[CH2:38][CH2:37][O:36][CH2:35]3)=[C:18]([CH:32]=2)[CH2:19][N:20]([CH3:31])[C:21](=[O:30])[O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:12])=[C:4]([CH3:41])[CH:3]=1.CC1(C)C[O:47][B:46](B2OCC(C)(C)CO2)[O:45]C1.CC([O-])=O.[K+]>CS(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]>[CH2:23]([O:22][C:21]([N:20]([CH2:19][C:18]1[CH:32]=[C:14]([NH:13][C:11]([O:10][CH2:9][C@@H:8]([C:5]2[CH:6]=[CH:7][C:2]([B:46]([OH:47])[OH:45])=[CH:3][C:4]=2[CH3:41])[CH3:40])=[O:12])[CH:15]=[C:16]([F:39])[C:17]=1[O:33][C@@H:34]1[CH2:38][CH2:37][O:36][CH2:35]1)[CH3:31])=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC1(C)COB(B2OCC(C)(C)CO2)OC1
Reactant: Cc1cc(Br)ccc1[C@@H](C)COC(=O)Nc1cc(F)c(O[C@@H]2CCOC2)c(CN(C)C(=O)OCc2ccccc2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CS(C)=O
Product: Cc1cc(B(O)O)ccc1[C@@H](C)COC(=O)Nc1cc(F)c(O[C@@H]2CCOC2)c(CN(C)C(=O)OCc2ccccc2)c1
Temperature: 85 °C
Reaction time: 2 h
Yield: 70.2 %

Procedure:
To a reaction tube was added 38D (258 mg, 0.410 mmol), 5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane) (111 mg, 0.492 mmol), KOAc (101 mg, 1.025 mmol) and Pd(dppf)Cl2 (67.4 mg, 0.082 mmol) in DMSO (1.5 ml). The tube was filled with Ar, sealed and stirred at 85° C. for 2 h. The mixture was quenched with H2O, and extracted with EtOAc (3×). The combined organic layers was filtered though silica gel and concentrated. The residue was purified by prep HPLC to give 38E (171 mg, 0.288 mmol, 70.2% yield) as a tan solid. MS (ESI) m/z: 595.4 (M+H)+.