Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C=O.O.[C:17](=O)(O)[O-:18].[Na+]>C1COCC1>[C:1]1([CH2:17][OH:18])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C([O-])O
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: C=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cccc2c1Cc1ccccc1-2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Fluorene 60 g (0.36 mol) was dissolved in dehydrated THF 1500 ml. Subsequently, butyl lithium-hexane solution 225 ml (1.6 M) was slowly dropped in at 0° C. under argon gas atmosphere. Next, paraformaldehyde 12 g was added and the mixture was agitated at a room temperature for 5 hours. After agitation, saturated sodium bicarbonate water 600 ml was added, and extracted with diethyl ether. An organic layer was washed twice with an aqueous saturated NaCl solution, and then the solvent was evaporated off after drying using anhydrous magnesium sulfate. The obtained pasty solid matter was refined by recrystallization with a mixed solvent of hexane and ethanol to obtain a white needle crystal 50 g of fluorenyl methanol. It was determined by measurement of 1H-NMR that the obtained compound had a structure illustrated in the above-described formula (6). The melting point and the measurement result of 1H-NMR will be shown in the following paragraph.
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[P:18]([O:22][CH2:23][C@@H:24]1[C@@H:28]([O:29][P:30]([O:33][CH2:34][C@@H:35]2[C@@H:39]([OH:40])[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36]2)([OH:32])=[O:31])[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25]1)([OH:21])([OH:20])=[O:19].[C:60]([O:64][C:65]([NH:67][C@H:68]([C:88](OCC#N)=[O:89])[CH2:69][CH2:70][CH2:71][CH2:72][NH:73][C:74]([C@@H:76]1[CH2:80][S:79][CH2:78][N:77]1[C:81]([O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:82])=[O:75])=[O:66])([CH3:63])([CH3:62])[CH3:61]>O.O1CCCC1>[NH2:58][C:55]1[CH:56]=[CH:57][N:52]([C@@H:26]2[O:25][C@H:24]([CH2:23][O:22][P:18]([OH:21])([OH:20])=[O:19])[C@@H:28]([O:29][P:30]([O:33][CH2:34][C@@H:35]3[C@@H:39]([O:40][C:88](=[O:89])[C@@H:68]([NH:67][C:65]([O:64][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:66])[CH2:69][CH2:70][CH2:71][CH2:72][NH:73][C:74]([C@@H:76]4[CH2:80][S:79][CH2:78][N:77]4[C:81]([O:83][C:84]([CH3:86])([CH3:87])[CH3:85])=[O:82])=[O:75])[C@@H:38]([OH:41])[C@H:37]([N:42]4[CH:50]=[N:49][C:48]5[C:43]4=[N:44][CH:45]=[N:46][C:47]=5[NH2:51])[O:36]3)([OH:32])=[O:31])[CH2:27]2)[C:53](=[O:59])[N:54]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)[C@@H]1CSCN1C(=O)OC(C)(C)C)C(=O)OCC#N
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)[C@@H]1CSCN1C(=O)OC(C)(C)C)C(=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: 2 h

Procedure:
A solution of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate (Compound 1h) (50 mg, 0.079 mmol) in water (0.5 mL) and a solution of (R)-tert-butyl 4-(((S)-5-((tert-butoxycarbonyl)amino)-6-(cyanomethoxy)-6-oxohexyl)carbamoyl)thiazolidine-3-carboxylate (Compound tk83) (118 mg, 0.236 mmol) in tetrahydrofuran (0.5 mL) were added to buffer A (40 mL), and the mixture was stirred at room temperature for 2 hours. Following lyophilization, the resulting residue was purified by reverse-phase silica gel column chromatography (water/acetonitrile solution) to afford a crude purified product of (4R)-tert-butyl 4-(((5S)-6-(((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)oxy)-5-((tert-butoxycarbonyl)amino)-6-oxohexyl)carbamoyl)thiazolidine-3-carboxylate (Compound tk84) (80 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]1[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C[Li].[Cl-].N>C1COCC1>[C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([OH:14])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCCC(=O)C1
Agent: N
Agent: [Cl-]
Agent: [Li]C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCCC(O)C1
Temperature: -75 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
To a degassed suspension of tert-butyl(3-oxocyclohexyl)carbamate (4.0 g, 18.78 mmol) in dry THF 200 mL) was added a solution of methyllithium in THF (3M, 25.0 mL, 75 mmol) at −75° C. The resulting reaction mixture was stirred at −75° C. for 1 h. A solution of methyllithium in THF (3M, 25.0 mL, 75 mmol) was added at −75° C. and the mixture was stirred for 1 h. Aqueous ammonia chloride solution was added dropwise to quench the reaction. The resulting reaction mixture was continued to stir at room temperature for 2 h. The reaction mixture was extracted with ethyl acetate (150 mL×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum to afford the crude product (4.0 g, crude), which was used directly in the next step without purification. MS (ESI) m/z 230.1 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([C@H:10]1[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:12]([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([N:28]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=3)=[O:33])[CH2:29][CH:30]=[CH2:31])[CH2:24][CH2:23]2)[CH2:11]1)[C:3]([O:5]C(C)(C)C)=O.[C:45]1([CH2:51]C(Cl)=O)[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>>[CH3:1][N:2]([C@H:10]1[CH2:14][C@H:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@@H:12]([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([N:28]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=3)=[O:33])[CH2:29][CH:30]=[CH2:31])[CH2:24][CH2:23]2)[CH2:11]1)[C:3]([CH2:51][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:5]
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](N(C)C(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Reactant: O=C(Cl)Cc1ccccc1
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](N(C)C(=O)Cc3ccccc3)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(S)-(N-(methyl)-N-(t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 31 in Step A and phenylacetyl chloride in Step B, the title compound was prepared.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:9][CH2:10][CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:8][O:7]1)=[O:5])C.[OH-].[Na+:19]>O1CCCC1>[CH:12]1([CH2:11][CH2:10][CH2:9][C:6]2([C:4]([O-:5])=[O:3])[CH2:8][O:7]2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1.[Na+:19]
Reactant: CCOC(=O)C1(CCCC2CCCCC2)CO1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C([O-])C1(CCCC2CCCCC2)CO1

Procedure:
1.1 g of 2-(3-cyclohexylpropyl)-oxirane-2-carboxylic acid ethyl ester are stirred for 2 hours at room temperature with 4.58 ml of 1 N sodium hydroxide solution and 5 ml of tetrahydrofuran. The mixture is concentrated to half its volume and the crystals of the title compound which have been precipitated are filtered off. Mp 105°-110° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11](Cl)=[C:12]([F:17])[CH:13]=2)[N:8]([CH:19]2[CH2:21][CH2:20]2)[CH:7]=1)=[O:5])C.[OH:22][CH2:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[CH2:29][NH:28][CH2:27]2.C(N(CC)CC)C>C(Cl)(Cl)Cl>[OH:22][CH2:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[CH2:29][N:28]([C:11]1[N:10]=[C:9]3[C:14]([C:15](=[O:16])[C:6]([C:4]([OH:3])=[O:5])=[CH:7][N:8]3[CH:19]3[CH2:20][CH2:21]3)=[CH:13][C:12]=1[F:17])[CH2:27]2
Reactant: CCOC(=O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Reactant: OCc1ccc2c(c1)CNC2
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(O)c1cn(C2CC2)c2nc(N3Cc4ccc(CO)cc4C3)c(F)cc2c1=O
Yield: 22.3 %

Procedure:
310 mg of 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4- oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester, 298 mg of 5-hydroxymethylisoindoline, 0.42 ml of triethylamine, and 5 ml of anhydrous chloroform were processed in a similar manner as in Example 107 to produce 88 mg of 7-(5- hydroxymethyl-2-isoindolinyl)-1-cyclopropyl-6-fluoro-1,4- dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid.
Reaction SMILES: C(OC(=O)[NH:10][C@@H:11]([C:17]1([OH:20])[CH2:19][CH2:18]1)[C:12]([N:14]([CH3:16])[CH3:15])=[O:13])C1C=CC=CC=1>C(O)C.[C].[Pd]>[NH2:10][C@@H:11]([C:17]1([OH:20])[CH2:19][CH2:18]1)[C:12]([N:14]([CH3:16])[CH3:15])=[O:13]
Reactant: CN(C)C(=O)[C@@H](NC(=O)OCc1ccccc1)C1(O)CC1
Agent: [Pd]
Solvent: CCO
Product: CN(C)C(=O)[C@@H](N)C1(O)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 58.4 %

Procedure:
To a solution of benzyl[(1S)-2-(dimethylamino)-1-(1-hydroxycyclopropyl)-2-oxoethyl]carbamate (190 mg) in ethanol (5 mL) was added 10% palladium carbon (69 mg) at room temperature. The reaction mixture was stirred at room temperature for 5 hr under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (60 mg).
Reaction SMILES: [CH3:1][OH:2].[Cl:3][S:4]([N:7]=[C:8]=[O:9])(=[O:6])=[O:5]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:8](=[O:9])[NH:7][S:4]([Cl:3])(=[O:6])=[O:5]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CO
Solvent: Cc1ccccc1
Product: COC(=O)NS(=O)(=O)Cl
Temperature: 25 °C
Yield: 75.4 %

Procedure:
A solution of methanol (10.2 mL, 252 mmoles) in 15 mL toluene was added dropwise to a solution of chlorosulfonyl isocyanate (22.0 mL, 252 mmoles) in 75 mL toluene at 0° C. The mixture was removed from the cooling bath and stirred for one-half hour at room temperature, then cooled to 0° C. and 65 mL ice cold hexanes was added. The white precipitate was collected by filtration and washed two times with a small amount of cold hexanes and dried in vacuo to give 33.0 g of a white solid, mp 72°-74° C.
Reaction SMILES: [CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16](OS(C(F)(F)F)(=O)=O)[CH:17]=[CH:18][C:4]1=2)[CH3:2].[C:27]([O:31][CH2:32][CH3:33])(=[O:30])[CH:28]=[CH2:29].[Cl-].[Li+].C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[CH2:32]([O:31][C:27](=[O:30])/[CH:28]=[CH:29]/[C:16]1[CH:17]=[CH:18][C:4]2[N:3]([CH2:1][CH3:2])[C:9](=[O:10])[C:8]([CH3:11])([CH3:12])[C:7](=[O:13])[N:6]([CH3:14])[C:5]=2[CH:15]=1)[CH3:33]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc21
Reactant: C=CC(=O)OCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1ccc2c(c1)N(C)C(=O)C(C)(C)C(=O)N2CC
Temperature: 180 °C
Yield: 103.1 %

Procedure:
Trifluoromethane sulfonic acid 1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl ester (0.40 g), ethyl acrylate (0.13 g), dichlorobis(triphenylphosphine)palladium (II) (35 mg), lithium chloride (64 mg), and triethylamine (0.19 ml) were added to DMF (4 ml). The mixture was heated at 180° C. (microwave reactor) for 20 minutes. The reaction liquid was cooled to room temperature, and subjected to celite filtration. The filtrate was condensed under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=70:30→30:70). The purified product was condensed under reduced pressure to give the title compound (0.36 g) as a pale yellow solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:25](=[O:26])[C:24]3[N:23]([C:27]4[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=4)[C:30]#[N:31])[CH:22]=[N:21][C:20]=3[N:19]([CH2:35][CH2:36][CH3:37])[C:18]2=[O:38])=[CH:13][CH:12]=1)(=[O:4])=[O:3].Cl>[Pd].CO>[NH2:31][CH2:30][C:29]1[CH:28]=[C:27]([N:23]2[C:24]3[C:25](=[O:26])[N:17]([C:14]4[CH:13]=[CH:12][C:11]([C:6]5[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=5[S:2]([CH3:1])(=[O:4])=[O:3])=[CH:16][CH:15]=4)[C:18](=[O:38])[N:19]([CH2:35][CH2:36][CH3:37])[C:20]=3[N:21]=[CH:22]2)[CH:34]=[CH:33][CH:32]=1
Reactant: CCCn1c(=O)n(-c2ccc(-c3ccccc3S(C)(=O)=O)cc2)c(=O)c2c1ncn2-c1cccc(C#N)c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCCn1c(=O)n(-c2ccc(-c3ccccc3S(C)(=O)=O)cc2)c(=O)c2c1ncn2-c1cccc(CN)c1
Reaction time: 12 h
Yield: 34.8 %

Procedure:
A Parr bomb was charged with 9 (100 mg, 0.19 mmol), MeOH (10 mL), 1 N HCl (0.2 mL), and catalytic amount of 10% Pd/C. The reaction mixture was exposed to H2 at 38 psi. After 12 h, the reaction was filtered through a pad of Celite® and concentrated in vacuo. The residue was dissolved in CH2Cl2 (10 mL), washed with NaOH (5.0 mL, 30% aqueous), dried (Na2SO4), filtered, and concentrated in vacuo. Chromatography of the residue on silica (8% MeOH/CH2Cl2) provided free base 10 (35 mg, 35%) as a pale yellow solid: ESI-MS m/z: [C28H27N5O4S+H]+ 530; 1H NMR (300 MHz, DMSO-d6) δ 8.42 (s, 1H), 8.12 (d, J=7.5 Hz, 1H), 7.82-7.35 (m, 10H), 4.06 (br t, 2H), 3.80 (s, 2H), 2.79 (s, 3H), 1.83-1.75 (m, 2H), 0.97 (t, J=7.4 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[N:4]=[CH:5][NH:6][CH:7]=1.S(O)(=O)(=O)C.[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[C:23]1([CH2:26][N:27]2[CH:31]=[N:30][CH:29]=[N:28]2)[CH2:25][O:24]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[C:23]([OH:24])([CH2:25][N:4]1[C:3]([C:2]([F:9])([F:8])[F:1])=[CH:7][N:6]=[CH:5]1)[CH2:26][N:27]1[CH:31]=[N:30][CH:29]=[N:28]1
Reactant: Clc1ccc(C2(Cn3cncn3)CO2)c(Cl)c1
Reactant: FC(F)(F)c1c[nH]cn1
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC(Cn1cncn1)(Cn1cncc1C(F)(F)F)c1ccc(Cl)cc1Cl
Yield: 1 %

Procedure:
A mixture of 4-trifluoromethylimidazole (0.7 g, 5 mmole), 2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-oxirane mesylate salt (1.88 g, 5 mmole) and anhydrous potassium carbonate (2.0 g, 14 mmole) in dry N,N-dimethylformamide (20 ml) was heated at 75°-80° C. for 18 hours. The solvent was evaporated under vacuum and the residue was partitioned between water (20 ml) and methylene chloride (50 ml). The aqueous layer was separated and extracted twice with methylene chloride (30 ml). The organic layers were combined, dried over magnesium sulphate and evaporated to yield the crude product containing the 4- and 5-trifluoromethyl-imidazolyl isomers. The residue was chromatographed on silica eluting with a mixture of hexane, isopropyl alcohol and concentrated ammonium hydroxide (80:20:1.5); fractions containing the minor component were evaporated and the product recrystallised from a mixture of acetone and water to give the desired title compound (0.02 g, 1%), m.p. 190°-192° C.
Reaction SMILES: Br[CH:2]=[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[CH3:4].P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O.[Cl:28][C:29]1[CH:37]=[CH:36][C:35]2[NH:34][C:33]3[CH2:38][CH2:39][N:40]([CH3:42])[CH2:41][C:32]=3[C:31]=2[CH:30]=1>CN(C=O)C.[Cu]I>[Cl:28][C:29]1[CH:37]=[CH:36][C:35]2[N:34](/[CH:2]=[C:3](\[C:5]3[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=3)/[CH3:4])[C:33]3[CH2:38][CH2:39][N:40]([CH3:42])[CH2:41][C:32]=3[C:31]=2[CH:30]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: CC(=CBr)c1ccc(F)cc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C/n1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1ccc(F)cc1
Temperature: 85 °C

Procedure:
1-(1-Bromoprop-1-en-2-yl)-4-fluorobenzene (511.2 mg, 2.4 mmol) was dissolved in DMF. Potassium phosphate (848 mg, 4 mmol) was added followed by the addition of copper (I)iodide (38 mg, 0.2 mmol) and L-proline (46 mg, 0.4 mmol). 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (440 mg, 2 mmol) was added to the reaction mixture and nitrogen gas purged for 2 min. The reaction mixture was heated at 85° C. overnight. The reaction mixture was cooled to RT and ice water was added. Solid mass was filtered under vacuum and crude purified by silica gel chromatography using 0-3% MeOH:DCM as eluent. Two isomers were further purified through reverse phase HPLC and peak 1 was submitted as the final compound. Yield: 120 mg. 1H NMR (DMSO, HCl salt) δ (ppm): 7.50 (s, 1H), 7.10-6.95 (m, 6H), 6.82 (s, 1H), 4.50 (m, 1H), 4.20 (m, 1H), 3.60 (m, 2H), 2.85 (s, 3H), 2.80 (m, 2H), 2.25 (s, 3H).
Reaction SMILES: [C:1]([C:11]1[CH:19]=[CH:18][C:14]2[S:15][CH:16]=[CH:17][C:13]=2[CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C([Li])CCC.CN(C)[CH:27]=[O:28]>CCOCC>[C:1]([C:11]1[CH:19]=[CH:18][C:14]2[S:15][C:16]([CH:27]=[O:28])=[CH:17][C:13]=2[CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCC#Cc1ccc2sccc2c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCCCCCCC#Cc1ccc2sc(C=O)cc2c1
Temperature: 25 °C
Yield: 52.1 %

Procedure:
To a solution of 5-(1-decynyl)benzo[b]thiophene (20.0 g) in dry ether (150 ml), under nitrogen, was added n-butyllithium (2.5M in hexanes) (32.6 ml) dropwise, with stirring at room temperature. The solution was stirred at room temperature, under nitrogen, for 2.5 hrs and then cooled to -60° C. A solution of dry dimethylformamide (5.95 g) in dry ether (15 ml) was added dropwise, and the reaction mixture was allow to warm to room temperature. The reaction mixture was quenched with ammonium chloride solution and the layers separated. The aqueous phase was extracted with ether, the organic extracts combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. The residue was flash chromatographed (silica: 3-4%, ethyl acetate:heptane). The appropriate fractions were collected and evaporated. The residue was recrystallized from heptane to give 11.5 g (52.0%) of product, mp 45°-47° C.
Reaction SMILES: [OH:1][C:2]1[C:9]([Br:10])=[C:8]([O:11][CH3:12])[CH:7]=[C:6]([O:13][CH3:14])[C:3]=1[CH:4]=[O:5].[Br:15]N1C(=O)CCC1=O>C(O)(=O)C.O>[OH:1][C:2]1[C:9]([Br:10])=[C:8]([O:11][CH3:12])[C:7]([Br:15])=[C:6]([O:13][CH3:14])[C:3]=1[CH:4]=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(OC)c(C=O)c(O)c1Br
Solvent: CC(=O)O
Solvent: O
Product: COc1c(Br)c(O)c(C=O)c(OC)c1Br
Temperature: 60 °C
Yield: 84.6 %

Procedure:
A solution of 1.0 g (3.83 mmol) of 2-hydroxy-3-bromo-4,6-dimethoxybenzaldehyde (see R. Royer, et al, Eur. J. Med. Chem., 12:455 (1977) as an example of how to obtain this material) in 50 ml of glacial acetic acid was warmed to 60° C. N-Bromosuccinimide (0.68 g, 3.83 mmol) was added in one portion and the solution was cooled to ambient temperature. The reaction mixture was diluted with 200 ml of water and the solids were filtered and air dried. The solid was crystallized from ethanol. There was obtained 1.1 g (3.24 mmol, 84%) of 2-hydroxy-3,5-dibromo-4,6-dimethoxybenzaldehyde as a white solid; mp 103°-104° C.
Reaction SMILES: Cl.C([O:4][C:5]([C@H:7]([NH:16][C@@H:17]1[C:23](=[O:24])[N:22]([CH2:25][C:26]([OH:28])=[O:27])[C:21]2[CH:29]=[CH:30][CH:31]=[CH:32][C:20]=2[O:19][CH2:18]1)[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6])C.Cl>C(O)C.[OH-].[Na+]>[C:5]([C@H:7]([NH:16][C@@H:17]1[C:23](=[O:24])[N:22]([CH2:25][C:26]([OH:28])=[O:27])[C:21]2[CH:29]=[CH:30][CH:31]=[CH:32][C:20]=2[O:19][CH2:18]1)[CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([OH:6])=[O:4]
Reactant: CCOC(=O)[C@@H](CCc1ccccc1)N[C@H]1COc2ccccc2N(CC(=O)O)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CN1C(=O)[C@@H](N[C@H](CCc2ccccc2)C(=O)O)COc2ccccc21
Reaction time: 2 h
Yield: 23.2 %

Procedure:
In a mixture of 1 ml of ethanol and 4 ml of sodium hydroxide solution (1N) is dissolved 0.15 g of 3(S)-[1(R)-ethoxycarbonyl-3-phenylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid hydrochloride obtained in Example 17, and the resulting mixture is allowed to stand for 2 hours and acidified slightly with 1N hydrochloric acid. The deposited powder is collected by filtration, dried and dissolved in 10 ml of ethanol. The insoluble substance is filtered off and filtrate is dried under reduced pressure to give 0.03 g of 3(S)-[1(R)-carboxy-3-phenylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid as a colorless powder.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]1[OH:13].[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][NH2:24].CN(C)C=O.C(O)(C)C>C(N(CC)CC)C>[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][NH:24][C:2]1[C:3]2[N:4]=[CH:5][N:6]([C:7]=2[N:8]=[CH:9][N:10]=1)[C@@H:11]1[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]1[OH:13]
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Reactant: NCc1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: OC[C@H]1O[C@@H](n2cnc3c(NCc4ccccc4Cl)ncnc32)[C@H](O)[C@@H]1O
Reaction time: 96 h

Procedure:
A mixture of 28.6 g of 6-chloro-9(β-D-ribofuranosyl)-purine, 14.2 g of o-chlorobenzyl amine, 400 ml of dimethylformamide, 400 ml of isopropanol and 50 ml of triethylamine is left to stand at 20° for 4 days. The mixture is evaporated, the residue is dissolved in chloroform, the chloroform solution is washed with 1% aqueous acetic acid and evaporated again and the residue is triturated with ether to give N6 -o-chlorobenzyl-adenosine (Ia). M.p.: 182°-183°.
Reaction SMILES: C([C:8]1[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=1)C1C=CC=CC=1.[CH3:21][CH2:22][OH:23]>[Pd]>[O:23]([C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][CH:13]=1)[C:22]1[CH:10]=[CH:9][CH:8]=[CH:13][CH:21]=1
Reactant: CCOC(=O)/C=C/c1ccc(Cc2ccccc2)cc1
Reactant: CCO
Agent: [Pd]
Product: CCOC(=O)CCc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of ethyl (E)-3-(4-benzylphenyl)acrylate (S28, 500 mg, 1.97 mmol) in EtOH (20 mL) was treated with 10% Pd/C (45 mg) and purged with H2. The reaction mixture was stirred overnight at 25° C., filtered through Celite and concentrated to afford S29 (502 mg, 1.96 mmol, 99%) as a yellow oil: 1H NMR (CDCl3, 500 MHz) 7.34 (dd, 2H, J=8.4, 7.4 Hz), 7.17 (d, 2H, J=8.4 Hz), 7.09 (dt, 1H, J=7.7, 1.1 Hz), 7.00 (dd, 2H, J=8.8, 1.1 Hz), 6.95 (d, 2H, J=8.8 Hz), 4.14 (q, 2H, J=7.0 Hz), 2.94 (t, 2H, J=7.7 Hz), 2.63 (t, 2H, J=7.7 Hz), 1.25 (t, 3H, J=7.0 Hz).
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][C:4](O)=[O:5].C(Cl)(=O)C>>[CH3:1][C:2]1([CH3:11])[CH2:7][C:8](=[O:10])[O:9][C:4](=[O:5])[CH2:3]1
Reactant: CC(C)(CC(=O)O)CC(=O)O
Solvent: CC(=O)Cl
Product: CC1(C)CC(=O)OC(=O)C1
Temperature: 0 °C

Procedure:
3,3-Dimethylglutaric acid (18.70 g, 116.8 mmol) was dissolved in acetyl chloride (25 mL, 352 mmol), and refluxed for 2 hours. The reaction mixture was evaporated to dryness, and the residue was dissolved in diethyl ether. The ether solution was concentrated on a steam bath, and then cooled to 0° C. for 1 hour. The precipitate was filtered to give the title compound.