Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH:11]([C:13]1[CH:14]=[CH:15][C:16]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:17]([CH:27]=1)[C:18]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)=[O:19])=O.[C:36]([O:39][CH2:40][CH3:41])(=[O:38])[CH3:37].CCCCCC>O1CCCC1>[C:30]1([CH2:29][O:28][C:16]2[CH:15]=[CH:14][C:13](/[CH:11]=[CH:37]\[C:36]([O:39][CH2:40][CH3:41])=[O:38])=[CH:27][C:17]=2[C:18]([NH:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[O:19])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCOC(C)=O
Reactant: O=Cc1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)/C=C\c1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
0.5N KHMDS (1.81 ml, 0.90 mmol) was added to a solution of triethyl phosphonoacetate (0.20 g, 0.90 mmol) in tetrahydrofuran (5 ml) at −78° C. The solution was stirred at −78° C. for 15 minutes, then a suspension of 5-formyl-2-[(phenylmethyl)oxy]-N-3-pyridinylbenzamide (may be prepared as described in Example 66; 200 mg, 0.60 mmol) in tetrahydrofuran (10 ml) was added dropwise over 3 minutes. The mixture was stirred at −78° C. for 15 minutes. It was then allowed to warm to room temperature and stirred for a further hour. The reaction was quenched with saturated NH4Cl (10 ml) and extracted with ethyl acetate (2×10 ml). The combined organic layers were dried (MgSO4) and the solvent removed in vacuo to give a brown solid. Trituration with 2:1 ethyl acetate/hexane yielded the title compound as a brown solid. 160 mg.
Reaction SMILES: C([S:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([O:15]C)=[O:14])=[CH:9][C:8]=1[C:17]([O:19]C)=[O:18])(=O)C.[OH-].[Na+]>C1COCC1.O>[SH:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([OH:15])=[O:14])=[CH:9][C:8]=1[C:17]([OH:19])=[O:18]
Reactant: COC(=O)c1ccc(CCSC(C)=O)c(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(CCS)c(C(=O)O)c1
Reaction time: 8 h
Yield: 45.2 %

Procedure:
To a degassed solution of dimethyl 4-[2-(acetylthio) ethyl]-1,3-benzenedicarboxylate (0.130 g, 0.44 mmol) in THF (5 mL) was added a degassed solution of 5 N NaOH (5 mL). The reaction mixture was stirred under nitrogen overnight. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAC (10 mL). The organic layer was dried over MgSO4 and concentrated to give 0.045 g of white solid (45% yield): 1H NMR (DMSO) δ 2.67 (t, 2H) 3.21 (t, 2H), 7.37 (d, 1H), 7.98 (d, 1H), 8.46 (s, 1H). 13C NMR (DMSO) δ 26.64, 40.60, 130.87, 132.05, 133.46, 133.81, 134.13, 148.53, 169.22, 170.20. Elemental analysis calculated for C10H10SO4: C, 53.09; H, 4.45; S, 14.47. Found: C, 53.37; H, 4.87; S, 12.84. MS(FAB): 225.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][C:10]([NH2:13])([CH3:12])[CH3:11].[CH2:14]([O:21][C:22]1[CH:31]=[C:30]2[C:25]([C:26](Cl)=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=[N:29]2)=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl>[NH2:13][C:10]([CH3:12])([CH3:11])[CH2:9][NH:8][C:26]1[C:25]2[C:30](=[CH:31][C:22]([O:21][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:23][CH:24]=2)[N:29]=[CH:28][C:27]=1[N+:32]([O-:34])=[O:33]
Reactant: CC(C)(N)CN
Reactant: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(N)CNc1c([N+](=O)[O-])cnc2cc(OCc3ccccc3)ccc12
Reaction time: 8 h
Yield: 73.6 %

Procedure:
Triethylamine (12.8 mL, 92.0 mmol) and 1,2-diamino-2-methylpropane (5.29 mL, 50.6 mmol) were added sequentially to a solution of 7-benzyloxy-4-chloro-3-nitroquinoline (14.5 g, 46.0 mmol) in dichloromethane (400 mL). The reaction mixture was stirred overnight and then concentrated under reduced pressure. The residue was partitioned between water (200 mL) and dichloromethane (300 mL). The organic layer was washed with brine, dried over sodium sulfate, and then concentrated under reduced pressure to provide crude product as a brown solid. The crude product was passed through a layer of silica gel (eluting sequentially with chloroform and 96:4 chloroform:methanol) to provide 12.4 g of (2-amino-2-methylpropyl)(7-benzyloxy-3-nitroquinolin-4-yl)amine as a yellow solid.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:26])([CH3:25])[O:6][CH2:7][C@H:8]([CH3:24])[C@@H:9]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[C@@H:10]([CH3:13])[CH:11]=O)([CH3:4])[CH3:3].Br[CH:28]([Si](C)(C)C)[CH:29]=[CH2:30].CO.[OH-].[K+]>C1COCC1>[CH3:1][C:2]([Si:5]([O:6][CH2:7][C@H:8]([CH3:24])[C@@H:9]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)[C@@H:10]([CH3:13])/[CH:11]=[CH:30]\[CH:29]=[CH2:28])([CH3:26])[CH3:25])([CH3:4])[CH3:3]
Reactant: COc1ccc(CO[C@@H]([C@@H](C)C=O)[C@@H](C)CO[Si](C)(C)C(C)(C)C)cc1
Reactant: C=CC(Br)[Si](C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=C/C=C\[C@H](C)[C@H](OCc1ccc(OC)cc1)[C@@H](C)CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 71.1 %

Procedure:
A suspension consisting of CrCl2 (12.93 g, 105.38 mmol) and 700 mL anhydrous THF is cooled to 0° C. 2,4-dideoxy-5-O-[(1,1-dimethylethyl)dimethylsilyl]-3-O-[(4-methoxyphenyl)methyl]-2,4-dimethyl-L-lyxose (8.9 g, 23.42 mmol) in 40 mL THF is added dropwise. (1-Bromoallyl) trimethylsilane (22.61, 117.1 mmol) is added neat. After 3 h at room temperature, the reaction mixture is cooled to 10° C. Methanol (270 mL) and 6 N aqueous KOH (550 mL) are added in sequence, keeping the reaction temperature less than 20° C. during the addition. The mixture is stirred overnight at room temperature. The organic layer is separated. The aqueous layer is extracted with ether (3×400 mL). The combined organic phase is washed with brine, dried over NaSO4, and concentrated. Flash chromatography gives the desired compound (6.74 g, 71.2%) as a clear oil.
Reaction SMILES: [NH:1]1[C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][C:3]([C:11]2[NH:12][N:13]=[CH:14][CH:15]=2)=[N:2]1.[OH-].[Na+]>C(O)C>[NH:1]1[C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]([C:11]2[NH:12][N:13]=[CH:14][CH:15]=2)=[N:2]1
Reactant: CCOC(=O)c1cc(-c2ccn[nH]2)n[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc(-c2ccn[nH]2)n[nH]1
Temperature: 60 °C
Reaction time: 8 h
Yield: 157.9 %

Procedure:
Ethyl 1H,2′H-3,3′-bipyrazole-5-carboxylate (1.959 mmol, 0.404 g) was dissolved in ethanol (5 ml) and cooled in an ice bath. NaOH 1 M solution (1.959 mmol, 4 ml) was slowly added. The solution was heated to 60° C. for 1 h. Ethanol was removed under vacuum and the residue was diluted with tert-butyl methyl ether. The solution was again cooled with an ice bath and acidified with 2 N HCl solution. The solution was allowed to warm to ambient temperature and stirred overnight. Water and DCM was added and the phases were separated. Both phases were evaporated and combined. 0.551 g of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 6.70 (d, 1H), 7.04 (s, 1H), 7.77 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[C:27]([O:31][C:32](=[O:35])[CH2:33]Br)([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32](=[O:35])[CH2:33][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[C:6]([C:11]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])[CH2:15][CH2:14]2)=[O:12])=[CH:7]1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COc1ccccc1C1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Product: COc1ccccc1C1CCN(C(=O)c2cn(CC(=O)OC(C)(C)C)c3cc(Cl)ccc23)CC1

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperidin-1-yl]-methanone (preparation described herein), with (commercially available) bromo-acetic acid tert-butyl ester gave the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[CH3:12][O:13][CH2:14]Br.O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH2:12][O:13][CH3:14])[CH:4]=1
Reactant: COc1cccc(O)c1
Reactant: COCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCOc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
To a solution of 3-(methyloxy)phenol (10.38 g, 84 mmol) in tetrahydrofurane (100 ml, SCRC) was added NaH (60% wt., 1.824 g, 76 mmol, Aldrich) portionwise under ice-cooling. The reaction mixture was stirred at room temperature for 1 hour and bromomethyl methyl ether (9.5 g, 76 mmol, SCRC) was then added. The resulting mixture was stirred at room temperature for 2 hours and water (50 ml) was added. The reaction mixture was extracted with ethyl acetate (2 times 50 ml, SCRC) and the combined organic layers were dried over sodium sulphate, evaporated. The residue was purified by column chromatography on silica gel (EtOAc: PE=1:100) to afford the title compound (10.2 g) as a colorless liquid.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH:9](=O)/[CH:10]=[CH:11]/[CH3:12]>Cl>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:3]=1[N:4]=[C:11]([CH3:12])[CH:10]=[CH:9]2
Reactant: Nc1ccccc1Br
Reactant: C/C=C/C=O
Agent: Cl
Product: Cc1ccc2cccc(Br)c2n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a refluxed solution of 2-bromoaniline (5.0 g, 29.1 mmol) in 6 N hydrochloric acid (15 mL) was added crotonaldehyde (2.2409 g, 32.0 mmol) drop wise. After heated under reflux for 8 h, the reaction mixture was cooled down and washed with 20 ml of ether, followed by addition of zinc chloride (3.95 g). The reaction mixture was stirred for 30 min at room temperature and another 15 min at 0° C. to give yellow solid. The solid was collected and washed with 3 N cold hydrochloric acid, and then suspended in 2-propanol (20 mL) and stirred for 5 min at room temperature. The solid was filtered and washed with 2-propanol until the washing becomes colorless, then washed with 20 mL of ether and dried with air. The solid was suspended in 15 mL of cold water and 5 mL of concentrated ammonium hydroxide was added. Shake it and then extract with 3×20 mL of ether. Dried over magnesium sulfate and concentrated to give a dark solid. Purification by chromatography (EtOAC/Hexanes 10:90) yielded a white solid product. (3.62 g, 56%) 1H NMR(400 MHz CDCl3) δ8.02 (2H, t, J=8.4 Hz), 7.73 (1H, d, J=8 Hz), 7.33 (2H, t, J=8), 2.82 (3H, s); 13C NMR (300 MHz CDCl3) δ160.2, 144.7, 136.4, 132.8, 127.6, 127.3, 125.9, 124.0, 122.7, 25.6; EIMS, m/z 221/223 (M/(M+2)); Anal. Calcd for C10H8BrN: C, 54.08; H, 3.63; N, 6.31. Found: C, 54.25; H, 3.41; N, 5.89.
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:16]1([CH2:21][NH2:22])[CH2:20][CH2:19][CH2:18][CH2:17]1.C([BH3-])#N.[Na+]>CO>[CH:16]1([CH2:21][NH:22][CH2:12][C:11]2[CH:14]=[CH:15][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:9][CH:10]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Reactant: NCC1CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: c1ccc(Oc2ccc(CNCC3CCCC3)cc2)cc1
Reaction time: 48 h
Yield: 80 %

Procedure:
4-Phenoxybenzaldehyde (3.0 g, 15.1 mmol) and cyclopentylmethylamine (1.49 g, 15.1 mmol) were dissolved in methanol (85 mL) under nitrogen at room temperature. Sodium cyanoborohydride (0.95 g, 15.1 mmol) was added, and stirring was continued for 48 hours. The solvent was evaporated, and the residue was suspended in ether, washed with brine, and dried over Na2SO4. The ether was evaporated, and the crude product was chromatographed on silica gel eluting with 3% methanol in methylene chloride to provide 3.4 g (80%) of the title compound as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ 1.10-1.24 (m, 2H), 1.45-1.67 (m, 2H), 1.71-1.90 (m, 3H), 2.06 (p, J=7.5 Hz, 1H), 2.58 (d, J=7.5 Hz, 2H), 3.79 (s, 2H), 6.95-7.05 (m, 4H) 7.09 (tt, J=7.5, 1.5 Hz, 1H), 7.28-7.38 (m, 4H). MS (DCl/NH3) m/e 282 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[CH:16][CH:17]=[C:18](I)[C:9]=2[C:8]1=[O:20].[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B(O)O>>[F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[CH:16][CH:17]=[C:18]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[F:30])[C:9]=2[C:8]1=[O:20]
Reactant: O=C1c2c(I)ccnc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: OB(O)c1ccccc1F
Product: O=C1c2c(-c3ccccc3F)ccnc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 77.3 %

Procedure:
In a similar manner to Reference Example 4, 5-[3,5-bis(trifluoromethyl)benzyl]-7-iodo-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (300 mg) was reacted with 2-fluorophenylboronic acid (143 mg) to obtain 5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-fluorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (218 mg, 77%).
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].[Li+].[OH-].Cl>O1CCOCC1.O>[C:1]([C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: COC(=O)c1ccc(-c2ccc(C#N)nc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2ccc(C(=O)O)cc2)cn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 74.4 %

Procedure:
Methyl 4-(6-cyano-3-pyridinyl)benzoate (D8) (0.5 g) in dioxane (30 ml) was treated with 1.1 eq aqueous LiOH solution (2.3 ml), 1N) and stirred at rt for 2 days. Solvent was removed by evaporation to give a white solid which was dissolved in water (10 ml) and acidified with 2N HCl to give a white solid which was filtered and dried to give the title compound (D9) (0.35 g). LCMS electrospray (+ve) 224 (MH+).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH:12]2[C:14]([CH3:16])([CH3:15])[C:13]2([Cl:18])[Cl:17])(=O)=O)=CC=1.[C-:20]#[N:21].[K+].O>CN(C)C=O>[Cl:18][C:13]1([Cl:17])[C:14]([CH3:15])([CH3:16])[CH:12]1[CH2:11][C:20]#[N:21]
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)OCC2C(C)(C)C2(Cl)Cl)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)C(CC#N)C1(Cl)Cl
Temperature: 100 °C
Yield: 106.5 %

Procedure:
6.48 g of 2,2-dichloro-3,3-dimethylcyclopropylmethyl p-toluenesulfonate and 2.0 g of potassium cyanide were suspended in 20 ml of dimethyl formamide, and the mixture was heated at 100° C. for 24 hours with stirring. After cooling, 50 ml of water was added to the reaction mixture. The mixture was extracted with hexane. The hexane layer was washed with water, and dried over sodium sulfate. After drying, the hexane was evaporated under reduced pressure to give 3.8 g of 2,2-dichloro-3,3-dimethylcyclopropylacetonitrile, the desired compound shown above. The boiling point of the product was 96° to 98° C. at 14 mmHg.
Reaction SMILES: [O:1]=[C:2]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH:3]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[H-].[Na+].[CH3:29][O:30][CH2:31]Cl.O>CN(C)C=O>[CH3:29][O:30][CH2:31][O:1][C:2]([C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18])=[C:3]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:4][C:5]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:6]
Reactant: COCCl
Reactant: CCOC(=O)C(CC(=O)OC(C)(C)C)C(=O)C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(CC(=O)OC(C)(C)C)=C(OCOC)C(=O)OCc1ccccc1
Reaction time: 0.75 h
Yield: 86.5 %

Procedure:
992 mg of 1-benzyl 3-tert-butyl 2-ethyl 1-oxo-1,2,3-propanetricarboxylate in 10 ml of dimethylformamide was stirred together with 131 mg of 60% oily sodium hydride at room temperature for 1 hour. After addition of 273 mg of chloromethyl methyl ether, the reaction solution was stirred for another 45 minutes, then poured into water and extracted with ethyl ether. The organic layer was dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [hexane/ethyl acetate=5/1] to give 962 mg of the title compound as a colorless oily substance.
Reaction SMILES: [CH2:1]([CH:3]([C:9]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)O)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([C:3](=[C:9]([C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: CCOC(=O)C(CC)C(O)(c1ccc(F)cc1)c1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(CC)=C(c1ccc(F)cc1)c1ccc(F)cc1
Yield: 89.6 %

Procedure:
A mixture of ethyl 2-ethyl-3,3-bis(4-fluorophenyl)-3-hydroxypropionate (1.0 g, 3.0 mmol) and p-toluenesulfonic acid (0.2 g) in 100 mL toluene was heated at reflux for 1.25 hours. The mixture was cooled and washed with saturated sodium bicarbonate solution and water. The solution was dried with magnesium sulfate and concentrated in vacuo. The residue was crystallized from petroleum ether to give 0.85 g of the title compound; m.p. =57°-59° C.
Reaction SMILES: O[C:2]([CH3:13])([CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:3]>CS(O)(=O)=O>[CH3:3][C:2]1([CH3:13])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1
Reactant: CC(C)(O)CCCc1ccccc1
Agent: CS(=O)(=O)O
Product: CC1(C)CCCc2ccccc21
Temperature: 105 °C
Yield: 89.9 %

Procedure:
A mixture of P2O, (55.3 g, 0.390 mol) in 400 ml of methanesulfonic acid was heated to 105° C. under argon until all of the solid had dissolved. The resulting solution was cooled to room temperature and 2-hydroxy-2-methyl-5-phenylpentane (63.0 g, 0.354 mol) added slowly with stirring. After 4 hours the reaction was quenched by carefully pouring the solution onto 1 L of ice. The resulting mixture was extracted with Et2O (4×125 ml)and the combined organic layers washed with water, saturated aqueous NaHCO3, water, and saturated aqueous NaCl before being dried over MgSO4. Concentration of the solution under reduced pressure, followed by distillation afforded 51.0 g (90%) of the product as a clear colorless oil, bp. 65-67° C./1.1 mmHg. 1H NMR (CDCl3): δ 7.32 (1H, d, J=7.4 Hz), 7.16-7.05 (3H, m), 2.77 (2H, t, J=6.3 Hz), 1.80 (2H, m), 1.66 (2H, m), 1.28 (6H, s).
Reaction SMILES: [CH2:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[C:6]([CH3:13])[C:5]=1[OH:14])[CH:2]=[CH2:3].[OH-].[Na+].[C:17](OC(=O)C)(=[O:19])[CH3:18].Cl>O>[C:17]([O:14][C:5]1[C:6]([CH3:13])=[C:7]([CH:11]=[CH:12][C:4]=1[CH2:1][CH:2]=[CH2:3])[C:8]([OH:10])=[O:9])(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: C=CCc1ccc(C(=O)O)c(C)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CCc1ccc(C(=O)O)c(C)c1OC(C)=O

Procedure:
4-Allyl-3-hydroxy-2-methylbenzoic acid (2.0 g, 10.4 mmol) was slurried in 6 ml water in a 500 ml round bottom flask, cooled in an ice bath, and stirred. Aqueous NaOH solution (4.2 g of 50% NaOH in 6 ml water) was added slowly. The mixture was stirred for few minutes until the solution was clear. Acetic anhydride was added drop wise until pH 6 was obtained, by that time the reaction mixture become a thick slurry with an off white color. The mixture was stirred overnight at room temperature. The reaction mixture became a thick white slurry. The pH was adjusted to 2 with conc. HCl. A precipitate formed, and was filtered under vacuum and dried. The combined dried product was dissolved in DCM and purified on an ISCO system using 40 g silica column and hexane/EtOAc solvent gradient. The product eluted ˜30% EtOAc in hexane, and the fractions were collected and dried under vacuum to give (2.4 g, 98%) SKC-01-116. 1H NMR (400 MHz, CDCl3) δ 12.0 (br s, 1H), 7.92 (d, J=8.1 Hz, 1H), 7.18 (d, J=8.1 Hz, 1H), 6.03-5.67 (m, 1H), 5.26-4.89 (m, 2H), 3.31 (d, J=6.6 Hz, 2H), 2.44 (s, 3H), 2.37 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([F:11])[N:3]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:11])[N:3]=1
Reactant: O=[N+]([O-])c1ccc(F)nc1F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(F)nc1F
Temperature: 80 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
2,6-Difluoro-3-nitropyridine (3.84 g) was dissolved in ethanol (42 ml). A solution of iron powder (4.03 g) and ammonium chloride (2.57 g) in water (14 ml) was added, and the reaction solution was heated and stirred at 80° C. for one hour. After leaving to cool, the reaction solution was filtered through celite. Ethyl acetate and water were added and the organic layer was separated. The resulting organic layer was washed with brine and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration, and then the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (2.06 g). The property values of the compound are as follows.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([I:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:12]1[C@H:19]2[C@H:15]([O:16][C:17]([CH3:21])([CH3:20])[O:18]2)[C@@H:14]([CH2:22][OH:23])[O:13]1.[OH-].[K+].[O-:26][Mn](=O)(=O)=O.[K+].OO>O>[NH2:1][C:2]1[N:10]=[C:9]([I:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:12]1[C@H:19]2[C@@H:15]([O:16][C:17]([CH3:20])([CH3:21])[O:18]2)[C@H:14]([C:22]([OH:26])=[O:23])[O:13]1
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CO)O[C@H]2n1cnc2c(N)nc(I)nc21
Reactant: O=[Mn](=O)(=O)[O-]
Agent: OO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC1(C)O[C@@H]2[C@@H](O1)[C@H](C(=O)O)O[C@H]2n1cnc2c(N)nc(I)nc21
Temperature: 7.5 °C
Yield: 70 %

Procedure:
To a stirred solution of 1.6 g (3.7 mmol) of [(1R,2R,4R,5R)-4-(6-amino-2-iodopurin-9-yl)-7,7-dimethyl-3,6,8-trioxabicyclo[3.3.0]oct-2-yl]methan-1-ol (6.6) in 200 mL of H2O was added 0.60 g of KOH and, dropwise, a solution of 1.70 g (10.8 mml) of KMnO4 in 50 mL of H2O. The mixture was set aside in the dark at room temperature for 225 hours. The reaction mixture was then cooled to 5-10° C. and decolorized by a solution of 4 mL of 30% H2O2 in 16 mL of water, while the temperature was maintained under 10° C. using an ice-salt bath. The mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to about 10 mL and then acidified to pH 4 with 2N HCl. The resulting precipitate was filtered off and washed with ether to yield 6.7 (70%) after drying as a white solid, m.p. 187-190° C. 1H NMR (300 MHz, DMSO-d6) δ 8.11 (s, 1H, H-8), 7.62 (s, 2H, NH2), 7.46 (s, 1H, COOH), 6.22 (s, 1H, H-1′), 5.42 (d, J=5.71 Hz, 1H, H-2′), 5.34 (d, J=6.16 Hz, 1H, H-3′), 4.63 (s, 1H, H-4′), 1.46 and 1.30 (s, 3H, C(CH3)2).
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:26])[CH2:7][C@H:8]([OH:25])[C@@H:9]([NH:17]C(=O)OC(C)(C)C)[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[CH2:2][CH2:3][CH3:4]>Cl.O1CCOCC1>[NH2:17][C@@H:9]([CH2:10][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)[C@@H:8]([OH:25])[CH2:7][C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:26]
Reactant: CCCCNC(=O)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCCCNC(=O)C[C@H](O)[C@@H](N)CC1CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.8 %

Procedure:
tert-butyl (2S,3S)-5-(butylamino)-1-cyclohexyl-3-hydroxy-5-oxopentan-2-ylcarbamate (394 mg, 1.1 mmol) was dissolved in 4M HCl in dioxane (5 mL, 200 mmol and stirred at rt for 4 h. Removal of the solvent left a sticky solid (344 mg). This material was taken up in 10% aq K2CO3 (20 mL) and extracted with CH2Cl2 (4×30 mL). The combined CH2Cl2 extracts were dried over MgSO4 and concentrated to afford (3S,4S)-4-Amino-N-butyl-5-cyclohexyl-3-hydroxypentanamide (279 mg, 97%).