Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[C:17]1[NH:21][C:20]2[CH:22]=[CH:23][C:24]([C:26]#[CH:27])=[CH:25][C:19]=2[N:18]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[C:17]1[NH:21][C:20]2[CH:22]=[CH:23][C:24]([C:26]#[C:27][C:27]#[C:26][C:24]3[CH:23]=[CH:22][C:20]4[NH:21][C:17]([C@@H:12]5[CH2:13][CH2:14][CH2:15][CH2:16][N:11]5[C:9]([O:8][CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[O:10])=[N:18][C:19]=4[CH:25]=3)=[CH:25][C:19]=2[N:18]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#Cc1ccc2[nH]c([C@@H]3CCCCN3C(=O)OCc3ccccc3)nc2c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCCC[C@H]1c1nc2cc(C#CC#Cc3ccc4[nH]c([C@@H]5CCCCN5C(=O)OCc5ccccc5)nc4c3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 12 h
Yield: 38.6 %

Procedure:
To a stirring solution of (S)-2-(5-ethynyl-1H-benzoimidazol-2-yl)-piperidine-1-carboxylic acid benzyl ester (26 mg, 0.0723 mmol), CuI (3 mg) and bis(triphenylphosphine)palladium(II)dichloride (8 mg) in THF (1.5 mL) is added TEA (30 μL, 3.4 mmol). The reaction mixture is stirred at room temperature for 12 hours and filtered through celite and the filtrate is concentrated in vacuum to dryness. The residue is purified by flash column chromatography on silica gel (EtOAc/hexanes 0% to 100%) to give the title compound (S)-2-(5-{4-[2-((S)-1-benzyloxycarbonyl-piperidin-2-yl)-1H-benzoimidazol-5-yl]-buta-1,3-diynyl}-1H-benzoimidazol-2-yl)-piperidine-1-carboxylic acid benzyl ester (10 mg, 39%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH:13]([N:17]1[C:21](=[O:22])[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:27])[C:14](O)=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH2:34]([O:41][C:42]([N:44]1[CH:49]=[CH:48][CH:47]=[C:46]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[NH:45]1)=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(=O)(O)[O-].[Na+].Cl>CCOCC.ClCCl.C(OCC)(=O)C>[CH2:34]([O:41][C:42]([N:44]1[CH:49]=[CH:48][CH:47]=[C:46]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[N:45]1[C:14](=[O:15])[CH:13]([N:17]1[C:21](=[O:22])[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:27])[CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(NCC(C(=O)O)N1C(=O)c2ccccc2C1=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)C1=CC=CN(C(=O)OCc2ccccc2)N1
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)C1=CC=CN(C(=O)OCc2ccccc2)N1C(=O)C(CNC(=O)OCc1ccccc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of the acid 266 (1.32 g, 3.58 mmol) in dry ether (37 ml) was treated with phosphorus pentachloride (1.04 g, 5 mmol) and stirred at room temperature for 2 h. The solution was filtered to remove unreacted phosphorus pentachloride then evaporated to dryness. The residue was treated with dry toluene (25 ml) then evaporated to dryness. This process was repeated several times. The resulting oil was dissolved in dry dichloromethane (25 ml), cooled to 0° C. and treated with a solution of (3S) t-butyl 1-benzyloxycarbonylpyridazine-3-carboxylate (1.15 g, 3.58 mmol) in dry dichloromethane (2 ml) followed by 5% aqueous sodium bicarbonate solution (25 ml). The mixture was stirred rapidly at room temperature for 20 h then diluted with ethyl acetate (100 ml) and acidified to pH2 with 1M HCl. The organic phase was washed twice with dilute HCl solution then brine, dried (MgSO4) and concentrated. The resulting oil was purified by flash chromatography (2-20% ethyl acetate/dichloromethane then 10-20% methanol/dichloromethane) to afford (267), 1.25 g (52%) as a white powder: IR (KBr) 3367, 2955, 1722, 1517, 1455, 1387, 1369, 1251, 1153, 721; 1H NMR (CDCl3) δ 7.81 (2H, m), 7.74 (2H, m), 7.63 (1H, brs), 7.31 (10H, m), 5.46-4.76 (5H, m), 4.07-3.54 (4H, m), 2.4 (1H, m), 2.0-1.6 (3H, m), 1.40 (9H, s); MS (ES+), 671 (M+1), 693 (M+Na).
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1.CCCCCC>O1CCCC1>[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([N:15]2[CH2:16][CH2:17][N:12]([C:10]3[S:9][N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:11]=3)[CH2:13][CH2:14]2)=[O:35])=[CH:29][CH:28]=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: COc1ccc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.1 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 4-methoxyphenyl isocyanate (0.158 ml, 1.22 mmol), and the mixture was stirred at room temperature for 2 hours. To the resulting solution was added hexane (4 ml) and the solid was separated by filtration, which was recrystallized from a mixed solvent of tetrahydrofuran and ethyl acetate to give 180 mg (56.1%) of the desired product as a solid.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH2:7]([O:9][C:10]1[CH:24]=[CH:23][C:13]2[CH:14]3[CH2:20][CH2:19][CH:18]([CH:21]=O)[CH2:17][CH:15]3[O:16][C:12]=2[C:11]=1[F:25])[CH3:8].O.Cl>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:7]([O:9][C:10]1[CH:24]=[CH:23][C:13]2[CH:14]3[CH2:20][CH2:19][CH:18]([CH:21]=[CH2:1])[CH2:17][CH:15]3[O:16][C:12]=2[C:11]=1[F:25])[CH3:8]
Reactant: CCOc1ccc2c(c1F)OC1CC(C=O)CCC21
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: C=CC1CCC2c3ccc(OCC)c(F)c3OC2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5.0 g (14.0 mmol) of methyltriphenylphosphonium bromide are initially introduced in 50 ml of THF, and 1.60 g (14.3 mmol) of potassium tert-butoxide in 20 ml of THF are added at −5° C. After 1 h at this temperature, 3.40 g (12.9 mmol) of (±)-(3R*, 4aR*, 9bS*)-7-ethoxy-6-fluoro-1,2,3,4,4a,9b-hexahydrodibenzofuran-3-carbaldehyde as a solution in 30 ml of THF are added dropwise, and the batch is stirred at room temperature for 16 h. The reaction solution is hydrolysed using water and acidified using 2 N HCl. The mixture is extracted with MTBE, and the combined organic phases are washed with sat. sodium chloride solution and dried using sodium sulfate. The crude product remaining after removal of the solvents is purified by column chromatography (SiO2, toluene). Further purification was carried out by repeated recrystallisation from isopropanol, giving (±)-(3R*, 4aR*, 9bS*)-7-ethoxy-6-fluoro-3-vinyl-1,2,3,4,4a,9b-hexahydrodibenzofuran as colourless solid (melting point 141° C.).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[CH3:11])([O-:3])=[O:2].[Br:12]N1C(C)(C)C(=O)N(Br)C1=O.N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1.C(O)(=O)C>C1(Cl)C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[CH2:11][Br:12])([O-:3])=[O:2]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: Cc1cc(Cl)ccc1[N+](=O)[O-]
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Solvent: Clc1ccccc1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(Cl)cc1CBr
Temperature: 40 °C
Yield: 60 %

Procedure:
2-Nitro-5-chlorotoluene (6.0 g, 35.0 mmol), 1,3-dibromo-5,5-dimethyl hydantoin (10.6 g, 37.1 mmol), and 1,1-azobis-(cyclohexanecarbonitrile) (VAZO 88, 400 mg, 16 μmol) were combined in 275 mL of C6H5Cl and stirred. Glacial acetic acid (200 μL) was added and the reaction was heated to 40° C. for 120 h. The reaction was washed with 150 mL of warm saturated bicarbonate, extracted with warm bicarbonate (4×150 mL) and washed with water (150 mL). The organic layer was dried over MgSO4 and the solvent was removed to yield a pink-red oily solid that consists of 2-nitro-5-chlorotoluene (˜40%) and the desired product (˜60%) and can be carried on to the next reaction without further purification. Flash chromatography on silica gel (25:1 hexanes:EtOAc) yields the pure brominated product as a brown solid (38%). 1H NMR (CDCl3, 300 MHz) δ 8.0 (1H, dd), 7.56 (1H, d), 7.45 (1H, dd), 4.79 (2H, s). 13C NMR (CDCl3, 300 MHz) δ 28.43, 127.02, 129.61, 132.37, 134.64, 139.91, 145.96. FTIR (KBr, cm−1) 1604, 1569, 1522, 1474, 1443, 1338, 1306, 1227, 1202, 1109, 1064, 908, 827, 757, 706.93, 827, 757, 707, 685, 524. HRMS (EI) calcd M+, 248.9187; found, 248.9186.
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:36]1([OH:42])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[C:43]1([CH2:49][N:50]2[CH2:55][CH2:54][N:53]3[N:56]=[C:57]([CH2:59]O)[CH:58]=[C:52]3[CH2:51]2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C1COCC1>[O:42]([CH2:59][C:57]1[CH:58]=[C:52]2[CH2:51][N:50]([CH2:49][C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH2:55][CH2:54][N:53]2[N:56]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: OCc1cc2n(n1)CCN(Cc1ccccc1)C2
Reactant: Oc1ccccc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1ccc(CN2CCn3nc(COc4ccccc4)cc3C2)cc1
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 74 %

Procedure:
Di-tert-butyl azodicarboxylate (0.76 g, 3.3 mmol) was added to a stirred solution of triphenylphosphine (0.87 g, 3.3 mmol), phenol (0.31 g, 3.3 mmol) and 4,5,6,7-tetrahydro-5-(phenylmethyl)-pyrazolo[1,5-a]pyrazine-2-methanol (1.2 mL, 2.75 mmol) in THF (0.6 mL) in a sealed tube and under N2. The mixture was stirred at 120° C. for 20 minutes under microwave irradiation and the solvents were evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 50/50). The desired fractions were collected and the solvents were evaporated in vacuo to yield 4,5,6,7-tetrahydro-2-(phenoxymethyl)-5-(phenylmethyl)-pyrazolo[1,5-a]pyrazine (0.65 g, 74% yield) as a colorless oil that precipitated upon standing. C20H21N3O LCMS: Rt 3.03, m/z 320 [M+H]+ (see LCMS Method 1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:17]#[C:18][Si](C)(C)C)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C@H:12]([CH:14]1[CH2:16][CH2:15]1)[CH3:13])[CH2:7]2.[OH-].[K+]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:17]#[CH:18])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C@H:12]([CH:14]1[CH2:16][CH2:15]1)[CH3:13])[CH2:7]2
Reactant: C[C@@H](C1CC1)N1Cc2cc(C#C[Si](C)(C)C)cc(Cl)c2C1=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C#Cc1cc(Cl)c2c(c1)CN([C@@H](C)C1CC1)C2=O
Temperature: 25 °C
Yield: 64.9 %

Procedure:
7-chloro-2-((S)-1-cyclopropylethyl)-5-(2-(trimethylsilyl)ethynyl)isoindolin-1-one (40.88 g, 123.17 mmol) was dissolved in 250 mL of ethanol and stirred at room temperature. To the reaction mixture was added a solution of potassium hydroxide (0.10 g, 1.85 mmol) in 20 mL of water. The reaction immediately turned black and was allowed to continue stirring for 90 minutes at room temperature. The volatiles were removed under reduced pressure and the product purified by flash chromatography on silica gel eluting with a gradient of 0 to 40% ethyl acetate in hexane. This afforded the desired product as a light tan solid (20.75 g, 69.7%). 1H NMR (300 MHz, CDCl3) δ ppm 0.34-0.50 (m, 3H) 0.58-0.69 (m, 1H) 0.93-1.07 (m, 1H) 1.34 (d, 3H) 3.22 (s, 1H) 3.76 (dq, 1H) 4.31-4.54 (m, 2H) 7.45 (s, 1H) 7.51 (s, 1H). MS ESI m/z=260 (M+H). HPLC Method B: 0.80 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C@@H:15]([CH:16]=O)[CH2:14][C:13]([CH3:19])([CH3:18])[C:12]1=[O:20])[CH3:2].COP([CH2:28][C:29](=[O:39])[C:30]1[O:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=1)(=O)OC.[Cl-].[Li+].C(N(C(C)C)CC)(C)C>C(#N)C>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C@@H:15](/[CH:16]=[CH:28]/[C:29](=[O:39])[C:30]2[O:31][C:32]([C:35]([F:38])([F:36])[F:37])=[CH:33][CH:34]=2)[CH2:14][C:13]([CH3:19])([CH3:18])[C:12]1=[O:20])[CH3:2]
Reactant: CCOC(=O)CCCCCCN1C(=O)C(C)(C)C[C@@H]1C=O
Reactant: COP(=O)(CC(=O)c1ccc(C(F)(F)F)o1)OC
Agent: [Cl-]
Agent: [Li+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCCCCN1C(=O)C(C)(C)C[C@@H]1/C=C/C(=O)c1ccc(C(F)(F)F)o1
Temperature: 25 °C

Procedure:
To a stirred solution of 7-((R)-5-formyl-3,3-dimethyl-2-oxo-pyrrolidin-1-yl)-heptanoic acid ethyl ester. (360 mg, 1.21 mmol) and [2-oxo-2-(5-trifluoromethyl-furan-2-yl)-ethyl]-phosphonic acid dimethyl ester (344 mg, 1.21 mmol)(prepared from 5-trifluoromethyl-furan-2-carboxylic acid as described herein) in acetonitrile (14 mL), were added lithium chloride (62 mg, 1.21 mmol) and diisopropylethyl amine (0.214 mL, 1.21 mmol). The reaction flask was left stirring at room temperature over the weekend. The reaction was then quenched with a saturated solution of ammonium chloride and extracted with ethyl acetate. The organic phase was then washed with brine and dried over magnesium sulfate, and the crude was purified on silicagel column using hexane:ethyl acetate 2:1. Evaporation of the solvent gave 280 mg of 7-{(R)-3,3-dimethyl-2-oxo-5-[(E)-3-oxo-3-(5-trifluoromethyl-furan-2-yl)-propenyl]-pyrrolidin-1-yl}-heptanoic acid ethyl ester.
Reaction SMILES: C1COCC1.Br[C:7]1[C:8]([CH2:18][N:19]2[C@@H:23]([CH3:24])[C@@H:22]([C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=3)[O:21][C:20]2=[O:33])=[N:9][C:10]([N:13]2[CH2:16][CH:15]([F:17])[CH2:14]2)=[N:11][CH:12]=1.[CH:34]([C:37]1[CH:38]=[C:39](B(O)O)[C:40]([O:43][CH3:44])=[N:41][CH:42]=1)([CH3:36])[CH3:35].C([O-])([O-])=O.[K+].[K+]>[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2].O>[F:32][C:27]1[CH:26]=[C:25]([C@H:22]2[O:21][C:20](=[O:33])[N:19]([CH2:18][C:8]3[C:7]([C:39]4[C:40]([O:43][CH3:44])=[N:41][CH:42]=[C:37]([CH:34]([CH3:36])[CH3:35])[CH:38]=4)=[CH:12][N:11]=[C:10]([N:13]4[CH2:16][CH:15]([F:17])[CH2:14]4)[N:9]=3)[C@H:23]2[CH3:24])[CH:30]=[C:29]([F:31])[CH:28]=1
Reactant: COc1ncc(C(C)C)cc1B(O)O
Reactant: C[C@H]1[C@@H](c2cc(F)cc(F)c2)OC(=O)N1Cc1nc(N2CC(F)C2)ncc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: COc1ncc(C(C)C)cc1-c1cnc(N2CC(F)C2)nc1CN1C(=O)O[C@H](c2cc(F)cc(F)c2)[C@@H]1C
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
1,1′-Bis(di-tert-butylphosphino)ferrocene palladium dichloride (25.07 mg, 0.038 mmol) was added to a degassed THF (15 mL)/Water (3 mL) solution of (4S,5R)-3-{[5-bromo-2-(3-fluoroazetidin-1-yl)pyrimidin-4-yl]methyl}-5-(3,5-difluorophenyl)-4-methyl-1,3-oxazolidin-2-one (INTERMEDIATE 15, 200 mg, 0.385 mmol), 5-isopropyl-2-methoxypyridin-3-ylboronic acid (128 mg, 0.462 mmol) and K2CO3 (159 mg, 1.154 mmol). After further de-gassing with N2 and vacuum, the reaction was heated for 1 h at 50° C. LCMS showed complete conversion to product. The reaction was diluted with 50 mL ethyl acetate and poured into 100 mL sat′d NH4Cl soln. The ethyl acetate layer was washed with brine (100 mL) filtered through a 20 g plug of sodium sulfate, eluting with 50 mL ethyl acetate. The filtrate was concentrated prior to purification with an X-Bridge 21.2×150 mm RP column. The sample was loaded in 7:3:1 CH3CN/water/DMSO (5 mL), after which a 10-100% acetonitrile/water (0.1% NH4OH) linear gradient at 15 mL/minutes over 20 minutes was run. The product of interest eluted in 80% portion of above gradient. Pure fractions (rich cut; impure discarded) were concentrated and lyophilized to give product as a white solid. LCMS (M+H)+: 528.5. 1H NMR (500 MHz, CDCl3): δ 8.15 (s, 1H), 8.10 (d, J=2.1 Hz, 1H), 7.35 (d, J=2.1 Hz, 1H), 6.84 (m, 3H), 5.52 (m, 1.5H), 5.42 (m, 0.5H), 4.64 (d, J=17.3 Hz, 1H), 4.51 (m, 2H), 4.33 (m, 2H), 4.02 (d, J=17.4 Hz, 1H), 3.94 (s, 3H), 2.96 (m, 1H), 1.30 (d, J=6.9 Hz, 6H), 0.77 (d, J=6.6 Hz, 3H). RTA IC50: 16 nM.
Reaction SMILES: [CH2:1]([C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C([C@H]1CC[C@H](C(O)=O)CC1)CCC>>[CH2:1]([C@H:7]1[CH2:8][CH2:9][C@H:10]([C:11]([OH:13])=[O:12])[CH2:14][CH2:15]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1ccc(C(=O)O)cc1
Agent: CCCC[C@H]1CC[C@H](C(=O)O)CC1
Product: CCCCCC[C@H]1CC[C@H](C(=O)O)CC1

Procedure:
This compound was prepared from 4n-hexylbenzoic acid (18, 72.34 g, 0.28 mol), in a manner similar to the procedure described for trans-4-n-butylcyclohexanecarboxylic acid (11) in Example I, Preparation 1, in an overall yield of 60% (35.7 g), m.p. 30+C. (pet. ether).
Reaction SMILES: O[CH:2]1[C:11]2[C:6](=[C:7]([O:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1>C1(C)C=CC=CC=1>[SH:27][CH:2]1[C:11]2[C:6](=[C:7]([O:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)COc1cccc2c1CCCC2O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)COc1cccc2c1CCCC2S
Yield: 80.1 %

Procedure:
A solution of 1-hydroxy-1,2,3,4-tetrahydro-5-methoxycarbonylmethoxynaphthalene (0.42 g) and Lawesson's reagent (0.40 g) in toluene (4 ml) was refluxed under N2 atmosphere for 1 hour. The reaction mixture was purified by chromatography on silica gel to give 1-mercapto-1,2,3,4-tetrahydro-5-methoxycarbonylmethoxynaphthalene (0.20 g). A solution of 1-mercapto-1,2,3,4-tetrahydro-5-methoxycarbonylmethoxynaphthalene (0.26 g), (4,5-diphenyloxazol-2-yl)methyl bromide (0.32 g) and potassium carbonate (0.14 g) in DMF (5 ml) was stirred for 6 hours at room temperature. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine. The dried solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel to give 1-[(4,5-diphenyloxazol-2-yl)methylthio]-1,2,3,4-tetrahydro-5-methoxycarbonylmethoxynaphthalene (0.29 g). MS (m/z): 486 (M+ +1) NMR (CDCl3, δ): 1.75-1.92 (1H, m), 2.00-2.22 (3H, m), 2.45-2.72 (1H, m), 2.80-3.02 (1H, m), 3.79 (3H, s), 3.91 (1H, s), 3.94 (1H, s), 4.36 (1H, m), 4.60 (2H, s), 6.50-6.55 (1H, m), 7.04-7.06 (2H, m), 7.33-7.40 (6H, m), 7.59-7.68 (4H, m)
Reaction SMILES: [F:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:7]([N:9]([CH3:11])[CH3:10])=[O:8])[CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[C:23]1([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=2[O:56][CH3:57])[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([Cl:32])[CH:30]=2)[N:25]([S:33]([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][C:37]=2[O:44][C:45]([F:48])([F:47])[F:46])(=[O:35])=[O:34])[C:24]1=[O:49].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C1COCC1.CCOC(C)=O>[Cl:32][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][CH:28]=1)[N:25]([S:33]([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][C:37]=1[O:44][C:45]([F:48])([F:47])[F:46])(=[O:34])=[O:35])[C:24](=[O:49])[C:23]2([N:5]1[CH2:6][C@H:2]([F:1])[CH2:3][C@H:4]1[C:7]([N:9]([CH3:11])[CH3:10])=[O:8])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=1[O:56][CH3:57]
Reactant: COc1ccc(S(=O)(=O)N2C(=O)C(Cl)(c3ccccc3OC)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Reactant: CN(C)C(=O)[C@@H]1C[C@@H](F)CN1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3ccccc3OC)(N3C[C@H](F)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Reaction time: 0.25 h
Yield: 3.7 %

Procedure:
Under nitrogen atmospher, To a solution of 178 mg of compound obtained in Step 7-2-1 in DMF (1.8 ml) was added 170 mg sodium bis-(trimethylsilyl) amide (38% THF solution) under ice cooling, and the reaction mixture was stirred for 15 minutes at the same temperature. Thereafter a solution of 178 mg of compound obtained in Step 7-2-3 in THF (500 μL) was added, and the solution was stirred at the same temperature for one hour, and at room temperature for 15 hours. To the reaction solution was added EtOAc and an aqueous solution of 5% K2CO3, and was stirred for 10 minutes. Liquid separation was performed, and the aqueous layer was extracted with EtOAc. The combined organic layer was washed in water and saturated brine, dried over MgSO4, then, the drying agent was separated by filtration, and the solvent was evaporated under reduced pressure. The obtained residue was subjected to column chromatography (silicagel 60; mobile phase: EtOAc/n-hexane=1/1; v/v) to obtain a brown oil (8 mg). Among the obtained brown oil, 2.0 mg was purified by thin layer chromatography (silicagel 60F254; 1 mm thick; mobile phase: EtOAc/n-hexane=7/3; v/v) to obtain 0.13 mg of the title compound (yellow oil).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[CH:4]=[C:3]1[C:10](Cl)=[O:11].[N:13]1([CH2:19][CH2:20][NH2:21])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.CCN(CC)CC>C(Cl)Cl>[CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[CH:4]=[C:3]1[C:10]([NH:21][CH2:20][CH2:19][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[O:11]
Reactant: NCCN1CCOCC1
Reactant: Cn1cc([N+](=O)[O-])cc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cc([N+](=O)[O-])cc1C(=O)NCCN1CCOCC1
Reaction time: 8 h
Yield: 87.9 %

Procedure:
1-Methyl-4-nitro-1H-pyrrole-2-carbonyl chloride (0.585 g, 4.70 mmol; see step (ii) above) in DCM (10 mL), was added dropwise to a solution of 2-(4-morpholinyl)ethanamine (0.673 g, 5.17 mmol), and NEt3 (0.735 μL, 9.42 mmol), in DCM (10 mL) over 15 min. The resulting solution was allowed to stir overnight and the reaction quenched with a 5% NaOH solution (20 mL). The layers were separated and the DCM fraction collected, dried (MgSO4), filtered and the solvent removed under reduced pressure to yield the sub-title compound as a white/pale yellow solid (1.166 g, 88%).
Reaction SMILES: [F:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH3:12][C:13]1[C:14]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=1>>[CH3:12][C:13]1[C:14]([N:20]2[CH2:21][CH2:22][N:23]([C:6]([C:5]3[CH:4]=[N:3][C:2]([F:1])=[C:10]([CH3:11])[CH:9]=3)=[O:8])[CH2:24][CH2:25]2)=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: Cc1cc(C(=O)O)cnc1F
Product: Cc1cnc(N2CCN(C(=O)c3cnc(F)c(C)c3)CC2)c(C)c1
Yield: 103.9 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 60 and using 6-fluoro-5-methylnicotinic acid (500 mg) and 1-(3,5-dimethylpyridin-2-yl)piperazine (620 mg) described in Preparation Example 47, the title compound (1.1 g) was obtained.
Reaction SMILES: C(OC([N:8]([CH2:54][CH2:55][S:56][S:57][C:58]([CH3:61])([CH3:60])[CH3:59])[CH2:9][C:10]([O:12][C@H:13]1[C@@H:17]([OH:18])[C@H:16]([N:19]2[CH:27]=[N:26][C:25]3[C:20]2=[N:21][CH:22]=[N:23][C:24]=3[NH2:28])[O:15][C@@H:14]1[CH2:29][O:30][P:31]([O:34][C@H:35]1[CH2:39][C@H:38]([N:40]2[CH:45]=[CH:44][C:43]([NH2:46])=[N:42][C:41]2=[O:47])[O:37][C@@H:36]1[CH2:48][O:49][P:50]([OH:53])([OH:52])=[O:51])([OH:33])=[O:32])=[O:11])=O)(C)(C)C>C(O)(C(F)(F)F)=O>[C:58]([S:57][S:56][CH2:55][CH2:54][NH:8][CH2:9][C:10]([O:12][C@H:13]1[C@@H:17]([OH:18])[C@H:16]([N:19]2[CH:27]=[N:26][C:25]3[C:20]2=[N:21][CH:22]=[N:23][C:24]=3[NH2:28])[O:15][C@@H:14]1[CH2:29][O:30][P:31]([O:34][C@H:35]1[CH2:39][C@H:38]([N:40]2[CH:45]=[CH:44][C:43]([NH2:46])=[N:42][C:41]2=[O:47])[O:37][C@@H:36]1[CH2:48][O:49][P:50]([OH:53])([OH:52])=[O:51])([OH:33])=[O:32])=[O:11])([CH3:61])([CH3:59])[CH3:60]
Reactant: CC(C)(C)OC(=O)N(CCSSC(C)(C)C)CC(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)SSCCNCC(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 80.4 %

Procedure:
(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 2-((tert-butoxycarbonyl)(2-(tert-butyldisulfanyl)ethyl)amino)acetate (Compound 6h-A, 56.2 mg, 0.060 mmol) was dissolved in TFA (1.0 ml), and the mixture was stirred at room temperature for 5 minutes. The reaction solution was concentrated under reduced pressure, and the residue was then purified by Column chromatography (0.05% aqueous TFA solution:0.05% TFA-acetonitrile solution=85:15=85:15) to afford the title compound (40.6 mg, 81%).