Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH:9](O)[N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1.C(N(S(F)(F)[F:28])CC)C>C(Cl)Cl>[F:28][CH:9]1[N:8]=[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[C:6]2[CH:21]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[NH:11][C:10]1=[O:12]
Reactant: CCN(CC)S(F)(F)F
Reactant: O=C1Nc2ccc(Br)cc2C(c2ccccc2F)=NC1O
Solvent: ClCCl
Product: O=C1Nc2ccc(Br)cc2C(c2ccccc2F)=NC1F
Temperature: 0 °C
Yield: 74 %

Procedure:
A stirred suspension of 4.2 g (0.012 mole) of 7-bromo-5-(2-fluorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepin-2-one in 200 ml methylene chloride was cooled to -70°, and 5 ml (0.04 mole) of diethylaminosulfur trifluoride was added dropwise. The reaction mixture was allowed to warm to -10°, and held at this temperature until most of the solid had dissolved. The reaction mixture was poured into ice-water and stirred vigorously. The organic layer was separated, washed with water, dried (MgSO4) and evaporated to dryness under reduced pressure. The residue was recrystallized from benzene-hexane to give 3.12 g of 3-fluoro-7-bromo-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one as light yellow crystals: mp 195°-197° (dec.); 19F nmr (DMSO-d6) δ -113.0 ppm (m, 1F) and -162.1 ppm (d, J = 56 Hz, 1F); 1H nmr (DMSO-d6) δ 5.88 ppm (d, J = 56 Hz, 1H), 7.2-7.9 ppm (m, 7H), 11.2 ppm (NH).
Reaction SMILES: [C:1](=O)([O:30]C1C=CC([N+]([O-])=O)=CC=1)[O:2][C@@H:3]1[CH2:19][C@@H:18]2[C@@:6]([CH3:29])([C@@H:7]3[C@@H:15]([CH2:16][CH2:17]2)[C@:14]2([OH:20])[C@@:10]([CH3:28])([C@@H:11]([C:21]4[CH:22]=[CH:23][C:24](=[O:27])[O:25][CH:26]=4)[CH2:12][CH2:13]2)[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.[N:41]1([CH2:46][CH2:47][NH2:48])[CH2:45][CH2:44][CH2:43][CH2:42]1>C(Cl)Cl>[N:41]1([CH2:46][CH2:47][NH:48][C:1](=[O:30])[O:2][C@@H:3]2[CH2:19][C@@H:18]3[C@@:6]([CH3:29])([C@@H:7]4[C@@H:15]([CH2:16][CH2:17]3)[C@:14]3([OH:20])[C@@:10]([CH3:28])([C@@H:11]([C:21]5[CH:22]=[CH:23][C:24](=[O:27])[O:25][CH:26]=5)[CH2:12][CH2:13]3)[CH2:9][CH2:8]4)[CH2:5][CH2:4]2)[CH2:45][CH2:44][CH2:43][CH2:42]1
Reactant: NCCN1CCCC1
Reactant: C[C@]12CC[C@H](OC(=O)Oc3ccc([N+](=O)[O-])cc3)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccc(=O)oc3)CC[C@]12O
Solvent: ClCCl
Product: C[C@]12CC[C@H](OC(=O)NCCN3CCCC3)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccc(=O)oc3)CC[C@]12O
Yield: 73.8 %

Procedure:
To a solution of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl 4-nitrophenyl carbonate (29 mg, 0.054 mmol) in CH2Cl2 was added 2-(pyrrolidin-1-yl)ethanamine (61.6 mg, 0.54 mmol). The resultant mixture was stirred at rt for 16 h and then purified via preparative TLC to afford (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl (2-(pyrrolidin-1-yl)ethyl)carbamate (21 mg, 75%) as a white solid. LRMS (M+H+) m/z 527.5. 1H NMR (CD3OD, 400 MHz) δ 7.89 (dd, J=9.6, 2.4 Hz, 1H), 7.33 (m, 1H), 6.18 (d, J=9.6 Hz, 1H), 4.88 (m, 1H), 3.35 (m, 2H), 3.12 (m, 2H), 2.46 (m, 1H), 1.08-2.15 (m, 29H), 0.87 (s, 3H), 0.62 (s, 3H).
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[C:3](=O)[CH3:4].[NH:7]([C:9]1[CH:14]=[C:13]([S:15]([OH:18])(=[O:17])=[O:16])[CH:12]=[CH:11][C:10]=1[S:19]([OH:22])(=[O:21])=[O:20])N.C([O-])(=O)C.[K+:27]>C(O)(=O)C>[CH3:4][C:3]1[C:2]([CH3:6])([CH3:1])[C:14]2[C:13]([S:15]([O-:18])(=[O:17])=[O:16])=[CH:12][CH:11]=[C:10]([S:19]([O-:22])(=[O:21])=[O:20])[C:9]=2[N:7]=1.[K+:27].[K+:27]
Reactant: CC(=O)C(C)C
Reactant: NNc1cc(S(=O)(=O)O)ccc1S(=O)(=O)O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: CC1=Nc2c(S(=O)(=O)[O-])ccc(S(=O)(=O)[O-])c2C1(C)C
Temperature: 25 °C

Procedure:
To a three-necked flask equipped with mechanical stirrer and a reflux condenser were added 50 ml of acetic acid, 15 ml (140 mmol) of 3-methyl-2-butanone, 16.2 g (60 mmol) of 2-hydrazino-1,4-benzenedisulfonic acid and 13 g (133 mmol) of potassium acetate. The mixture was heated to reflux for 8 h and then cooled to room temperature. The brownish precipitate was filtered off and washed with acetic acid and acetonitrile. Yield: 13.8 g (58%) of the raw product (1k). 1H-NMR (200 MHz, DMSO-d6), δ, ppm: 7.67 (1H, arom., d, 8.1 Hz), 7.59 (1H, arom., d, 8.2 Hz), 2.44 (3H, CH3, s), 1.57 (6H, (CH3)2, s).
Reaction SMILES: [CH3:1][Si:2]([CH3:21])([CH3:20])[CH2:3][CH2:4][O:5][C:6]([NH:8][CH:9]([CH2:13][CH:14]1[CH2:17][C:16]([F:19])([F:18])[CH2:15]1)[C:10](O)=[O:11])=[O:7].CN1CCOCC1.ClC(OCC(C)C)=O.ClC([O-])=O.[BH4-].[Na+]>C1COCC1.O>[F:19][C:16]1([F:18])[CH2:17][CH:14]([CH2:13][CH:9]([NH:8][C:6](=[O:7])[O:5][CH2:4][CH2:3][Si:2]([CH3:20])([CH3:1])[CH3:21])[CH2:10][OH:11])[CH2:15]1
Reactant: C[Si](C)(C)CCOC(=O)NC(CC1CC(F)(F)C1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])Cl
Agent: [BH4-]
Solvent: O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOC(=O)NC(CO)CC1CC(F)(F)C1
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 91.9 %

Procedure:
Crude 2-(2-(trimethylsilyl)ethoxycarbonyl)amino-3-(3,3-difluorocyclobutyl)propanoic acid (273 mg, 0.844 mmol) was dissolved in THF (5 mL) and the solution was cooled to −10° C. N-methylmorpholine (95 mg, 0.929 mmol, 1.1 equiv) was added and the mixture stirred for 15 min. After this time isobutyl chloroformate (127 mg, 0.929 mmol, 1.1 equiv) was added. After stirring for 30 min LC-MS showed remaining starting material. The procedure was repeated with an additional 0.55 equiv of the amine and chloroformate. This consumed all of the starting material. The reaction mixture was quickly filtered through a pad of celite into a solution of NaBH4 (128 mmol, 3.4 mmol, 4.0 equiv) in water (4 mL). The filter cake was washed with an additional dry THF (5 mL). LC-MS analysis showed formation of the desired alcohol. The solvent was removed and the residue partitioned between EtOAc and brine. The layers were separated and the aqueous layer extracted with additional EtOAc. The combined organic layers were dried over Na2SO4. The solvent was removed to yield 2-(trimethylsilyl)ethyl 3-(3,3-difluorocyclobutyl)-1-hydroxypropan-2-ylcarbamate (240 mg, 90%) as an orange oil. 1H and 19F NMR were consistent with the desired product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[CH:15]=1)([CH:11]([F:13])[F:12])[CH:9]=C)([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=[O:23].[Na+].O=[O+][O-].[BH4-].[Na+].Cl>ClCCl.CO>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[CH:15]=1)([CH2:9][OH:23])[CH:11]([F:13])[F:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])O
Reactant: C=CC(NC(=O)OC(C)(C)C)(c1cccc(Br)c1)C(F)F
Agent: Cl
Agent: O=[O+][O-]
Agent: [BH4-]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(CO)(c1cccc(Br)c1)C(F)F
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
[1-(3-Bromo-phenyl)-1-difluoromethyl-allyl]-carbamic acid tert-butyl ester (7.88 g, 21.76 mmol) was dissolved in 218 ml dichloromethane and 73 ml methanol. NaHCO3 (2.74 g, 32.6 mmol) was added and the reaction mixture was cooled to −78° C. The solution was treated with O3 for 30 min. (until the reaction mixture turned blue). Gas was stopped and stirring was continued for 15 minutes. The reaction was flushed with oxygen and nitrogen until color disappeared. NaBH4 (2.47 g, 65.3 mmol) was added in three portions and stirring was continued for 30 min. at −78° C. The reaction was warmed to 0° C. and poured onto 435 ml 1 M HCl solution. The product was extracted with TBME. The organic phases were washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure to yield the title compound as a greenish oil. 1H-NMR (600 MHz, DMSO-d6): 7.49 (m, 2H), 7.38 (br, 1H, NH), 7.32 (m, 2H), 6.37 (t, 1H, CHF2), 5.20 (br, 1H), 3.95 (m, 1H), 3.86 (br, 1H), 1.32 (s, 9H); MS: 366 [(M+H)+].
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3](=[O:28])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[O:13])[CH:6]=1.C(N(CC)C(C)C)(C)C.Cl[C:40]1[C:41]2[C:48]([CH3:49])=[CH:47][NH:46][C:42]=2[N:43]=[CH:44][N:45]=1>C(O)(C)C>[CH3:1][N:2]([CH3:29])[C:3](=[O:28])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2([O:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:19][CH2:18][N:17]([C:40]3[C:41]4[C:48]([CH3:49])=[CH:47][NH:46][C:42]=4[N:43]=[CH:44][N:45]=3)[CH2:16][CH2:15]2)=[O:13])[CH:6]=1
Reactant: CN(C)C(=O)Oc1cccc(NC(=O)C2(OCc3ccccc3)CCNCC2)c1
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c[nH]c2ncnc(N3CCC(OCc4ccccc4)(C(=O)Nc4cccc(OC(=O)N(C)C)c4)CC3)c12
Temperature: 110 °C

Procedure:
To a solution of 3-(4-(benzyloxy)piperidine-4-carboxamido)phenyl dimethylcarbamate, from step E, and N,N-diisopropylethylamine (0.7 mL, 4.02 mmol) in isopropanol (1.6 mL) was added 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (135 mg, 0.804 mmol). The reaction mixture was heated to 110° C. in a sealed high-pressure vial for 17 hours, during which time the mixture became homogenous. The reaction was concentrated under vacuum, and half of the material was purified by prep HPLC (30×100 mm C18 column, 20-100% acetonitrile:water (10 mM ammonium acetate), 15 min, 45 mL/min) to afford the title compound (33.4 mg) as a white solid.
Reaction SMILES: [CH:1](=[N:8][CH2:9][P:10](=[O:21])([O:16][CH2:17][CH2:18][CH2:19][CH3:20])[O:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.Cl[C:28]([O:30][CH2:31][C:32]([C:34]1[CH:39]=[CH:38][C:37]([Br:40])=[CH:36][CH:35]=1)=[O:33])=[O:29]>O1CCCC1.CCCCCC>[CH:1](=[N:8][CH:9]([P:10]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:21])[C:28]([O:30][CH2:31][C:32]([C:34]1[CH:35]=[CH:36][C:37]([Br:40])=[CH:38][CH:39]=1)=[O:33])=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)OCC(=O)c1ccc(Br)cc1
Reactant: CCCCOP(=O)(CN=Cc1ccccc1)OCCCC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCOP(=O)(OCCCC)C(N=Cc1ccccc1)C(=O)OCC(=O)c1ccc(Br)cc1
Reaction time: 0.5 h

Procedure:
Dibutyl N-benzylidene-aminomethylphosphonate (31.1 g) is dissolved in anhydrous tetrahydrofuran (500 ml) and the solution is cooled to -78° under a nitrogen atmosphere. Butyllithium (46 ml of a 2.2 M solution in hexane) is added over a period of 5 minutes. The resulting solution is stirred an additional 30 minutes at -78°, then treated dropwise over a period of 45 minutes with p-bromophenacyl chloroformate (13.9 g) in tetrahydrofuran (100 ml). The reaction mixture is stirred an additiona 2 hours at -78° followed by gradual warming to 3° over a period of 30 minutes. Evaporation of the solvent in vacuo leaves a gum which is partitioned between ether (500 ml) and 0.5 M pH 3 phosphate buffer (100 ml). The ethereal phase is separated, washed with water and saturated brine, dried over magnesium sulfate filtered, and evaporated in vacuo to an oil. Chromatographic purification of this material on silica gel gives p-bromophenacyl N-benzylidene-α-amino-dibutylphosphonoacetate.
Reaction SMILES: [N:1]1[N:5]2[C:6]3[C:11]([C:12]([OH:14])=[CH:13][C:4]2=[N:3][N:2]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3.[N+:15]([O-])([OH:17])=[O:16]>C(O)(=O)C>[N+:15]([C:13]1[C:4]2[N:5]([N:1]=[N:2][N:3]=2)[C:6]2[C:11]([C:12]=1[OH:14])=[CH:10][CH:9]=[CH:8][CH:7]=2)([O-:17])=[O:16]
Reactant: Oc1cc2nnnn2c2ccccc12
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1c(O)c2ccccc2n2nnnc12
Temperature: 52.5 °C
Yield: 76.3 %

Procedure:
Tetrazolo[1,5-a]quinolin-5-ol (63.25 g, 0.34 mol) was added to glacial acetic acid (630 ml) to form a thick off white suspension. The mixture was vigorously stirred while nitric acid (23.6 ml, 0.37 mol, 70% solution) was slowly added. The reaction was then heated from 25 to 80° C. over a period of 15 minutes. A yellow precipitate formed and the reaction was maintained at 80° C. for 5 minutes. The mixture was slowly cooled to 0° C. The solid was collected by filtration and then dried in vacuo to yield 60.0 g of 4-nitro-tetrazolo[1,5-a]quinolin-5-ol as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[NH2:16])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[C:17]([N:20]=[C:21]=[S:22])(=[O:19])[CH3:18]>C(OCC)C>[C:17]([NH:20][C:21](=[S:22])[NH:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[NH2:16])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6])(=[O:19])[CH3:18]
Reactant: CC(=O)N=C=S
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1N
Solvent: CCOCC
Product: CC(=O)NC(=S)Nc1cc(C(=O)c2ccccc2)ccc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a stirred solution of 3,4-diaminobenzophenone (8.48 g.; 0.04 mole) in ethyl ether (1.0 L.) there is added dropwise acetyl isothiocyanate (4.04 g.; 0.04 mole). The solution is stirred at room temperature for two hours and a precipitate collected by filtration and dried to afford 10.7 g. (85% yield) of 3-(3-acetylthioureido)-4-aminobenzophenone, m.p. 211° C., dec.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]([OH:12])=O)[NH:7][C:6]=2[CH:13]=1.C(N(CC)CC)C.[CH2:21]([CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH2:21]([CH:28]1[CH2:33][CH2:32][N:31]([C:10]([C:8]2[NH:7][C:6]3[CH:13]=[C:2]([OH:1])[CH:3]=[CH:4][C:5]=3[N:9]=2)=[O:12])[CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: O=C(O)c1nc2ccc(O)cc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1nc2ccc(O)cc2[nH]1)N1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.7 %

Procedure:
A mixture of 3.0 g (16.75 mmol) of 6-hydroxi-1H-benzoimidazol-2-carboxilic acid, 2.4 ml (17.2 mmol) of triethylamin, 3.0 g (17.1 mmol) of 4-benzyl-piperidine, 7.0 g (18.5 mmol) of HBTU and 100 ml of dimethylformamide is stirred at room temperature for 16 h. The reaction mixture is concentrated and the residue is purified by column chromatography using Kieselgel 60 as adsorbent (Merck) and toluene:methanol=4:1 as eluent, then the product is recrystallized from toluene to yield 3.58 g (63.5%) of the title compound. Mp.: 186° C. (toluene).
Reaction SMILES: C([N:8]1[CH2:16][C@H:15]2[C@H:10]([N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][CH2:13][CH2:14]2)[CH2:9]1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[N:11]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][CH2:13][CH2:14][C@H:15]2[CH2:16][NH:8][CH2:9][C@@H:10]12
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]2CN(Cc3ccccc3)C[C@H]21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@H]2CNC[C@H]21

Procedure:
The product from Example 50A (0.15 g, 0.5 mmol) in methanol (80 mL) was hydrogenated (4 pounds per square inch) in the presence of palladium hydroxide on carbon (0.42 g) for 3 hours at room temperature. The reaction mixture was filtered and concentrated to yield the title compound. MS (DCI) m/z 227 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[C:13]1[CH:14]=[CH:15][C:16]2[O:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[C:18]([C:28](=[O:31])[NH:29][CH3:30])[C:17]=2[CH:32]=1)(=O)=O.[C:35]([C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=1)#[N:36].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:35]([C:37]1[CH:42]=[C:41]([C:13]2[CH:14]=[CH:15][C:16]3[O:20][C:19]([C:21]4[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=4)=[C:18]([C:28]([NH:29][CH3:30])=[O:31])[C:17]=3[CH:32]=2)[CH:40]=[CH:39][CH:38]=1)#[N:36]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(OS(=O)(=O)C(F)(F)F)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C#N)c3)cc12
Temperature: 90 °C

Procedure:
Cesium carbonate (187 mg, 0.575 mmol) was added to Pd(Ph3P)4 (22 mg, 0.019 mmol), 2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl trifluoromethanesulfonate (160 mg, 0.383 mmol), 3-cyanophenylboronic acid (85 mg, 0.575 mmol). Dioxane (3 mL) and water (600 μL) was added at rt. The reaction was degassed 3× and heated to 90° C. overnight. It was allowed to cool. The mixture was diluted with EtOAc and washed with 1M HCl, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated. The crude residue was taken up in DCM. A white precipitate formed which was filtered to give the titled compound. The filtrate was purified on silica gel (Biotage, EtOAc/hexanes gradient, Rf˜0.4:50% EtOAc/Hex, fraction collection at λ=254 nm) to give the titled compound which was combined with the previously collected precipitate (85 mg, 60%). 1H NMR (500 MHz, DMSO-d6) δ ppm 8.46-8.53 (1H, m), 8.24 (1H, s), 8.09 (1H, d, J=7.93 Hz), 7.99-8.05 (2H, m), 7.96 (1H, d, J=1.53 Hz), 7.85 (1H, d, J=7.63 Hz), 7.74-7.82 (2H, m), 7.70 (1H, t, J=7.78 Hz), 7.40 (2H, t, J=8.85 Hz), 2.87 (3H, d, J=4.58 Hz). LC-MS retention time: 2.17 min; m/z (MH+): 371. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 μm, Rt=13.59 min, purity=99%; Column: Waters Xbridge Phenyl column 4.6×150 mm, 3.5 μm, Rt=12.29 min, purity=99%.
Reaction SMILES: C([O:9][C@@H:10]1[C@H:14]([O:15]C(=O)C2C=CC=CC=2)[C@@H:13]([CH2:24][C:25]#[N:26])[O:12][C@H:11]1[N:27]1[C:49]2[N:48]=[C:47]([Cl:50])[N:46]=[C:31]([NH:32][N:33]3[CH2:38][CH2:37][CH:36]([S:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[CH2:35][CH2:34]3)[C:30]=2[N:29]=[CH:28]1)(=O)C1C=CC=CC=1.N.C(OCC)(=O)C>CO>[Cl:50][C:47]1[N:46]=[C:31]([NH:32][N:33]2[CH2:34][CH2:35][CH:36]([S:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:37][CH2:38]2)[C:30]2[N:29]=[CH:28][N:27]([C:49]=2[N:48]=1)[C@@H:11]1[O:12][C@H:13]([CH2:24][C:25]#[N:26])[C@@H:14]([OH:15])[C@H:10]1[OH:9]
Reactant: N#CC[C@H]1O[C@@H](n2cnc3c(NN4CCC(Sc5ccccc5)CC4)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Agent: N
Solvent: CO
Solvent: CCOC(C)=O
Product: N#CC[C@H]1O[C@@H](n2cnc3c(NN4CCC(Sc5ccccc5)CC4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 8.8 %

Procedure:
This compound was prepared by general method A, described in more detail in Example 22. 2',3'-Di-O-benzoyl-2-chloro-5'-cyano-5'-deoxy-N-(4-phenylthio-1-piperidinyl)adenosine [prepared from 1-amino-6-phenylthiopiperidine (Knutsen, L. J. S., Lau, J., Sheardown, M. J., Thomsen, C.; Bioorganic and Medicinal Chemistry Letters, 1993, 3, 2661-2666) and 9-(2',3'-di-O-benzoyl-5'-cyano-5'-deoxy-β-D-ribofuranosyl)-2,6-dichloro-9H-purine as described in Example 24] (1.5 g, 2.5 mmol) in methanol (20 ml) was treated with methanolic ammonia (5 ml). The reaction mixture was stirred at ambient temperature for 0.75 h. Ethyl acetate (5 ml) was added to the residue on evaporation to provide 2-chloro-5'-cyano-5'-deoxy-N-(4-phenylthio-1-piperidinyl)adenosine (0.11 g, 46%) as a solid, m.p. 159°-161° C., 1H-NMR (400 MHz, DMSO-d6) δ1.68 (2H, br q, piperidine C--H), 1.98 (2H, m, piperidine C--H), 2.78 (2H, br, piperidine C--H), 3.04 (2H, br d, H-5'a and H-5'b), 4.11 (2H, m, H-4' and H-3'), 4.63 (1H, m, H-2'), 5.54, 5.68 (2H, 2d, 2'-and 3'-OH), 5.88 (1H, d, H-1'), 7.22-7.45 (5H, 3m, Ar--H), 8.38 (1H, s, H-8), 9.49 (1H, s, N--H). HPLC retention time 20.34 min. (gradient elution over 30 min; 25-45% acetonitrile/0.1% ammonium sulfate in water), purity 96% at 250 nm). C16H20ClN7O3. 0.7 H2O. 0.1 EtOAc requires C, 51.4; H, 5.1; N, 18.7. Found C, 51.4; H, 4.9; N, 18.3%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:23]=[C:24]1[NH:28][C@H:27]([CH2:29][O:30][C:31](=[O:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:26][O:25]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([N:28]3[C@H:27]([CH2:29][O:30][C:31](=[O:38])[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH2:26][O:25][C:24]3=[O:23])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1N[C@H](COC(=O)c2ccccc2)CO1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(I)cc2)CC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3COC(=O)c3ccccc3)cc2)CC1
Yield: 90.3 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 91 and using 4-(4-iodobenzoyl)piperazine-1-carboxylic acid tert-butyl ester (3.75 g) described in Preparation Example 161 and benzoic acid (R)-2-oxooxazolidin-4-ylmethyl ester (1.99 g), the title compound (4.14 g) was obtained.
Reaction SMILES: [OH:1][N:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12].O[C:14]1[C:22]2[CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][C:17]=2[N:16]([CH3:30])[N:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[O:12]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10](=[O:11])[N:2]1[O:1][CH:21]1[CH2:20][N:19]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:18][C:17]2[N:16]([CH3:30])[N:15]=[CH:14][C:22]1=2
Reactant: Cn1nc(O)c2c1CN(C(=O)OC(C)(C)C)CC2
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1ncc2c1CN(C(=O)OC(C)(C)C)CC2ON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.4 %

Procedure:
To a mixture of 2-hydroxy-1H-isoindole-1,3(2H)-dione (2.95 g, 18.1 mmol), tert-butyl hydroxy-1-methyl-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate 135 (US2005/245505 A1, 2.29 g, 9.04 mmol) and triphenylphosphine (4.74 g, 18.1 mmol) in THF (100 mL) was added DIAD (3.85 mL, 19.9 mmol) slowly at room temperature. The resulting mixture was stirred at room temperature overnight and concentrated to provide a residue which was subjected to chromatography to give 136 (2.5 g, 35%) as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][O:9][NH:10][C:11](=[O:28])[C@@H:12]([NH:20]C(OC(C)(C)C)=O)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][O:9][NH:10][C:11](=[O:28])[C@@H:12]([NH2:20])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CONC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CONC(=O)[C@@H](N)Cc1ccccc1
Reaction time: 0.17 h

Procedure:
Trifluoroacetic acid (4.0 ml) is added to N1-methoxy-(2S)-2-(tert-butoxycarbonyl)amino-3-phenylpropionamide (600 mg, Reference compound No. 22-1), and the mixture is stirred for 10 minutes. The reaction mixture is concentrated under reduced pressure, ethyl acetate is added to the resulting residue, and the whole is extracted with 1 N hydrochloric acid. A saturated sodium hydrogencarbonate solution is added to the extract to basify the system, and the whole is extracted with ethyl acetate. The extract is washed with saturated brine and dried over anhydrous magnesium sulfate. The extract is concentrated under reduced pressure to give the titled reference Compound (70.8 mg).