Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([O:8][C:9](=[O:22])[CH2:10][C:11]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:15][CH2:14][CH2:13][C:12]1=O)[CH3:7].Cl.[CH:24]1([C:29]2[CH:44]=[CH:43][C:32]([CH2:33][O:34][C:35]3[CH:40]=[CH:39][C:38]([NH:41]N)=[CH:37][CH:36]=3)=[CH:31][C:30]=2[C:45]([F:48])([F:47])[F:46])[CH2:28][CH2:27][CH2:26][CH2:25]1>CCO>[CH:24]1([C:29]2[CH:44]=[CH:43][C:32]([CH2:33][O:34][C:35]3[CH:40]=[CH:39][C:38]4[NH:41][C:12]5[C:11]([CH2:10][C:9]([O:8][CH2:6][CH3:7])=[O:22])([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:15][CH2:14][C:13]=5[C:37]=4[CH:36]=3)=[CH:31][C:30]=2[C:45]([F:46])([F:47])[F:48])[CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: NNc1ccc(OCc2ccc(C3CCCC3)c(C(F)(F)F)c2)cc1
Reactant: CCOC(=O)CC1(C(=O)OCC)CCCC1=O
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCOC(=O)CC1(C(=O)OCC)CCc2c1[nH]c1ccc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)cc21
Reaction time: 0.58 h
Yield: 77.2 %

Procedure:
In a 1 L flask was placed EtOH (500 mL). Sulfuric acid (2.4 g, 23.98 mmol) was added at 40° C., followed by ethyl 1-(2-ethoxy-2-oxoethyl)-2-oxocyclopentanecarboxylate (15.2 g, 62.7 mmol). (4-(4-Cyclopentyl-3-(trifluoromethyl)benzyloxy)phenyl)hydrazine hydrochloride (24.0 g, 62.0 mmol) was added and the solution became light yellow and homogenous. The reaction mixture was refluxed overnight with a Dean-Starks condenser attached. The mixture was cooled and extracted in ethyl acetate (3×100 mL). The organics were washed with water (200 mL), sodium bicarbonate solution (2×70 mL), water (100 mL), dried over magnesium sulfate, and concentrated. The residue was dissolved in hexanes/ethyl acetate (80:20, 300 mL), added silica gel (30 g) and stirred for 35 minutes. The slurry was filtered, washed with the same elution solvent (100 mL) and the filtrate was concentrated to give the title compound (26.7 g). LCMS m/z=558.5 [M+H]+.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1>ClCCl>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:2]2[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=2[N+:8]([O-:10])=[O:9])=[CH:16][CH:15]=1
Reactant: COc1ccc(N)cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Solvent: ClCCl
Product: COc1ccc(Nc2cc(O)ccc2[N+](=O)[O-])cc1
Temperature: 150 °C
Reaction time: 1.5 h

Procedure:
0.16 g of 3-fluoro-4-nitrophenol and 0.37 g of p-anisidine were mixed and stirred for 1.5 hours at 150° C. After cooling, it was dissolved in dichloromethane, and extracted twice with 1N aqueous hydrochloric acid and once with saturated sodium chloride solution. The organic phase was dried on sodium sulfate and concentrated by evaporation in a vacuum.
Reaction SMILES: [CH2:1]([C:3]1O[C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[N:4]=1)[CH3:2].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1>CN(C)C=O>[CH2:1]([C:3]1[N:14]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[C:7](=[O:9])[C:6]2[C:5](=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2c(=O)o1
Reactant: Nc1ccc(O)cc1
Solvent: CN(C)C=O
Product: CCc1nc2ccccc2c(=O)n1-c1ccc(O)cc1
Temperature: 140 °C
Reaction time: 10 h
Yield: 66 %

Procedure:
2-ethyl-4H-3,1-benzoxazin-4-one (6.5 g, 37.1 mmol) and 4-aminophenol (4.05 g, 37.1 mmol) were dissolved in dimethylformamide (18 mL) and stirred at 140° C. for 10 hours. After leaving to cool to room temperature, distilled water (94 mL) was added, and the solid precipitate was filtered off. The product was recrystallized (ethanol) and the target compound (6.52 g, 66%) was obtained as light brown crystals.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([OH:13])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.N1C=CN=C1.[Si:23](Cl)([C:36]([CH3:39])([CH3:38])[CH3:37])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[CH2:1]([O:8][CH2:9][C@H:10]([OH:13])[CH2:11][O:12][Si:23]([C:36]([CH3:39])([CH3:38])[CH3:37])([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC[C@@H](O)COCc1ccccc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OC[C@@H](O)COCc1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.03 h
Yield: 90 %

Procedure:
To a solution of (R)-3-benzyloxypropane-1,2-diol (prepared from (S)-4-benzylymethyl-2,2-dimethyl-1,3-dioxolane (commercially available from FLUKA) by acid hydrolysis using 80% aqueous acetic acid), (8.3 g, 47.2 mmol) in dry THF (70 ml) was added imidazole (6.42 g, 94.4 mmol). After 2 minutes, t-butyldiphenylsilyl chloride (12.28 ml, 47.2 mmol) was added. A white precipitate formed immediately. After 2 hours, the reaction mixture was filtered and the filtrate evaporated. The residue was partitioned between ethyl acetate and water, the organic layer separated, washed with saturated brine, dried (MgSO4), filtered and evaporated to give a colourless oil. Chromatography of the oil on silica gel (dichloromethane as eluant) afforded the title compound as a colourless oil (17.72 g, 90%).
Reaction SMILES: [Na].[S:2](Cl)(Cl)=O.[Cl:6][CH2:7][CH2:8][CH:9]1[CH2:15][N:14]([CH3:16])[C:13](=O)[C:12]2[CH:18]=[C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:20]=[N:21][C:11]=2[O:10]1>C1(C)C=CC=CC=1>[Cl:6][CH2:7][CH2:8][CH:9]1[CH2:15][N:14]([CH3:16])[C:13](=[S:2])[C:12]2[CH:18]=[C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:20]=[N:21][C:11]=2[O:10]1
Reactant: CN1CC(CCCl)Oc2ncc(-c3ccccc3)cc2C1=O
Reactant: O=S(Cl)Cl
Agent: [Na]
Solvent: Cc1ccccc1
Product: CN1CC(CCCl)Oc2ncc(-c3ccccc3)cc2C1=S
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64 %

Procedure:
The entire portion of the above sodium salt was added ~400 ml of thionyl chloride slowly (reaction was slightly exothermic) and stirred at room temperature for 10 minutes. The thionyl chloride was removed by rotary evaporation at 70° C. and the residue azeotroped once with toluene. The residue was suspended in 600 ml of methylene chloride and to the suspension was added diisopropylethylamine cautiously until the solution was basic. The reaction solution was washed with 3×200 ml of 1N hydrochloric acid and 3×200 ml of 1N sodium hydroxide, dried over sodium sulfate, filtered, concentrated by rotary evaporation, taken up in toluene, charcoaled twice and concentrated by rotary evaporation. The residue (60 g) was taken up in ethyl acetate and passed through a short bed of silica gel using 25% hexane-75% ethyl acetate as the eluant. Similar fractions were combined to give ~25 g of crude (but 95% (min)) purity oil which is 2-(2-chloroethyl)-2,3-dihydro-4-methyl-7-phenylpyrido[3,2-f]-1,4 -oxazepin-5(4H)-one. To 12.5 g (0.04 mole) of the above amide was added 125 ml of toluene and 16 g (0.04 mole) of 2,4-bis(4-methoxyphenyl)-1,3-dithio-2,4-diphosphotane-2,4-disulfide. The reaction mixture was heated to reflux for 4 hr. After standing overnight, the toluene was decanted off, washed with 3×100 ml of 1N sodium hydroxide, dried over sodium sulfate, filtered, and concentrated by rotary evaporation. The residue was further purified by column chromatography using silica gel as the stationary phase and eluting with ethyl acetate: hexane 1:1, (v/v). Like fractions were combined and concentrated giving 8.5 g (64%) of desired product, m.p. 156°-58° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[S:20]([N:23]3[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][C@H:24]3[CH3:36])(=[O:22])=[O:21])=[CH:10][C:9]=2[F:37])=[CH:4][N:3]=1.C(Cl)Cl.C(O)(C(F)(F)F)=O>>[F:37][C:9]1[CH:10]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][C@H:24]2[CH3:36])(=[O:22])=[O:21])[CH:12]=[CH:13][C:8]=1[C:5]1[CH:6]=[N:7][C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1S(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)nc2)c(F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CNCCN1S(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)nc2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.8 %

Procedure:
The title compound was prepared by dissolving (R)-tert-butyl 4-((4′-(2-aminopyrimidin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)-3-methylpiperazine-1-carboxylate (42 mg, 0.08 mmol) in a 50/50 mixture of DCM/TFA (1 mL) and allowing it to stir at rt for 2 h. The reaction mixture was concentrated to dryness and the residue subjected to HPLC purification to give the title compound (29 mg, 85%). MS (ESI): mass calcd. for C21H22FN5O2S, 427.15; m/z found, 428.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.56 (d, J=1.4, 2H), 8.16 (dd, J=8.0, 1.4, 1H), 7.65-7.58 (m, 1H), 7.56-7.49 (m, 1H), 7.48-7.39 (m, 1H), 7.38-7.31 (m, 3H), 5.18 (s, 2H), 3.64-3.52 (m, 1H), 2.99-2.87 (m, 2H), 2.81-2.69 (m, 1H), 2.61-2.41 (m, 4H), 1.18 (d, J=6.8, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7].[OH-].[Na+].Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]>O>[CH2:14]([O:13][C:11](=[O:12])[NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCCOCCO
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(NCCOCCO)OCc1ccccc1
Yield: 67.5 %

Procedure:
2-(2-Aminoethoxy)ethanol (5.26 g, 50 mmol) and sodium hydroxide (2.1 g, 52.5 mmol) were dissolved in water (200 mL). The resulted solution was cooled in ice bath, followed by the dropwise addition of benzyl chloroformate. After the addition, the reaction mixture was continuously stirred in ice bath for another hour. The desired product was extracted with ethyl acetate (EtOAc, 200 mL). The EtOAc layer was washed with water (3×100 mL) and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo to yield the crude product. The product was further purified by flash column chromatography (SiO2, 1:2 Hexane:EtOAc) to give [2-(2-hydroxy-ethoxy)-ethyl]-carbamic acid benzyl ester as a clear oil (8.07 g, 67.5% yield). 1H-NMR (CDCl3, ppm) 7.35 (m, 5H), 5.34 (b, 1H), 5.10 (s, 2H), 3.71 (m, 2H), 3.56 (m, 4H), 3.41 (m, 2H), 2.20 (b 1H),. ESMS 240.0 (M+1).
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[O:19][CH:18]=[CH:17][C:16]=12)=[O:10].[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[S:31][C:30]([CH3:32])=[N:29][C:28]=2[C:33](O)=[O:34])=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[S:31][C:30]([CH3:32])=[N:29][C:28]=2[C:33]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:6]3)[C@H:2]2[CH2:7][NH:8][C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[O:19][CH:18]=[CH:17][C:16]=23)=[O:10])=[O:34])=[CH:25][CH:26]=1
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Reactant: O=C(NC[C@H]1NC[C@@H]2C[C@@H]21)c1cccc2occc12
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc3occc23)c(-c2ccc(F)cc2)s1

Procedure:
prepared by reaction of benzofuran-4-carboxylic acid[(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid. LC-MS (basic): tR=0.90 min; [M+H]+=476.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[NH:8][C:7]1[N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:14]=[C:15]([CH3:16])[C:6]=1[C:5]2=[O:23].I[CH2:25][CH2:26][CH3:27]>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]1[N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:14]=[C:15]([CH3:16])[C:6]1=[C:5]2[O:23][CH2:25][CH2:26][CH3:27]
Reactant: Cc1nn(-c2ccccn2)c2[nH]c3cc(F)c(F)cc3c(=O)c12
Reactant: CCCI
Product: CCCOc1c2cc(F)c(F)cc2nc2c1c(C)nn2-c1ccccn1
Yield: 27 %

Procedure:
Following the procedure described in Example 2-16, from 6,7-difluoro-3-methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one and 1-iodopropane was prepared the title compound (27% yield).
Reaction SMILES: [OH-].[Na+].[C:3]([N:7]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:10]([C:19]#[N:20])[CH:9]=[N:8]1)([CH3:6])([CH3:5])[CH3:4].N[CH:22]([C:25]([OH:27])=[O:26])[CH2:23][SH:24]>C(O)C>[C:3]([N:7]1[C:11]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)=[C:10]([C:19]2[S:24][CH2:23][CH:22]([C:25]([OH:27])=[O:26])[N:20]=2)[CH:9]=[N:8]1)([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)n1ncc(C#N)c1-c1ccc(F)cc1
Reactant: NC(CS)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)n1ncc(C2=NC(C(=O)O)CS2)c1-c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 14 h
Yield: 62.6 %

Procedure:
A mixed solution of 1N aqueous sodium hydroxide solution (2.65 ml, 2.65 mmol) of the compound (430 mg, 1.77 mmol) obtained in step 1 and DL-cysteine (321 mg, 2.65 mmol), and ethanol (5.3 mL) was stirred at 80° C. for 3 hr. DL-cysteine (200 mg) and 1N aqueous sodium hydroxide solution (1.5 mL) were further added thereto, and the mixture was stirred at 80° C. for 14 hr. DL-cysteine (321 mg) and 1N aqueous sodium hydroxide solution (2.65 mL) were further added thereto, and the mixture was stirred at 80° C. for 5 hr. The reaction mixture was concentrated under reduced pressure, and 1N hydrochloric acid and ethyl acetate were added thereto. The organic layer was washed with saturated brine and dried, and the solvent was evaporated under reduced pressure. The residue was crystallized from ethyl acetate and diethyl ether to give 2-(1-(tert-butyl)-5-(4-fluorophenyl)-1H-pyrazol-4-yl)-4,5-dihydrothiazole-4-carboxylic acid (385 mg, 1.108 mmol, 62.7%) as a pale-yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:24][CH3:25])=[CH:13][C:14]=2[O:16][CH2:17][C@@H:18]2[NH:22][CH2:21][C@@H:20]([OH:23])[CH2:19]2)[N:9]=[CH:8][N:7]=1.[CH3:30][N:31]([CH3:36])[CH2:32][C:33](O)=[O:34]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:24][CH3:25])=[CH:13][C:14]=2[O:16][CH2:17][C@@H:18]2[N:22]([C:33](=[O:34])[CH2:32][N:31]([CH3:36])[CH3:30])[CH2:21][C@@H:20]([OH:23])[CH2:19]2)[N:9]=[CH:8][N:7]=1
Reactant: CN(C)CC(=O)O
Reactant: COc1cc(OC[C@H]2C[C@H](O)CN2)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Product: COc1cc(OC[C@H]2C[C@H](O)CN2C(=O)CN(C)C)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Yield: 73 %

Procedure:
The procedure described in Example 20 was repeated using (3S,5R)-5-[({4-[3-chloro-4-fluoroanilino]-7-methoxyquinazolin-5-yl}oxy)methyl]pyrrolidin-3-ol (185 mg) with N,N-dimethylglycine (50 mg) to give the title compound as a white solid in 73% yield; NMR spectrum (DMSO-d6) 9.93 (s, 1H), 8.45 (s, 1H), 8.15 (dd, 1H), 7.76-7.70 (m, 1H), 7.45 (t, 1H), 6.83 (s, 2H), 5.09-5.08 (m, 1H), 4.70-4.66 (m, 1H), 4.45-4.40 (m, 2H), 4.28-4.23 (m, 1H), 3.93 (s, 3H), 3.62-3.49 (m, 2H), 3.20 (d, 1H), 3.00 (d, 1H), 2.21 (s, 6H), 2.06-2.02 (m, 2H); Mass spectrum MH+ 504.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C@@H:23]([NH:68]C(OC(C)(C)C)=O)[C:24]([O:26][C@H:27]1[C@@H:31]([OH:32])[C@H:30]([N:33]2[CH:41]=[N:40][C:39]3[C:34]2=[N:35][CH:36]=[N:37][C:38]=3[NH2:42])[O:29][C@H:28]1[CH2:43][O:44][P:45]([O:48][C@H:49]1[CH2:53][C@H:52]([N:54]2[CH:59]=[CH:58][C:57]([NH2:60])=[N:56][C:55]2=[O:61])[O:51][C@@H:50]1[CH2:62][O:63][P:64]([OH:67])([OH:66])=[O:65])([OH:47])=[O:46])=[O:25])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClCCl>[NH2:68][C@H:23]([CH2:22][CH2:21][CH2:20][CH2:19][NH:18][C:16]([O:15][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:17])[C:24]([O:26][C@H:27]1[C@@H:31]([OH:32])[C@H:30]([N:33]2[CH:41]=[N:40][C:39]3[C:34]2=[N:35][CH:36]=[N:37][C:38]=3[NH2:42])[O:29][C@H:28]1[CH2:43][O:44][P:45]([O:48][C@H:49]1[CH2:53][C@H:52]([N:54]2[CH:59]=[CH:58][C:57]([NH2:60])=[N:56][C:55]2=[O:61])[O:51][C@@H:50]1[CH2:62][O:63][P:64]([OH:67])([OH:66])=[O:65])([OH:47])=[O:46])=[O:25]
Reactant: CC(C)(C)OC(=O)N[C@H](CCCCNC(=O)OCc1ccccc1)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
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3OC(=O)[C@H](N)CCCCNC(=O)OCc3ccccc3)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 78.5 %

Procedure:
Trifluoroacetic acid (0.075 mL) was added to a solution of (2S)-(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 6-(((benzyloxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)hexanoate (Compound tk46) (18.6 mg, 0.019 mmol) in dichloromethane (1 mL), and the mixture was stirred at room temperature for 40 minutes. Following concentration under reduced pressure, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (2S)-(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-amino-6-(((benzyloxy)carbonyl)amino)hexanoate (Lys(Z)-pdCpA) (Compound tk47) (13.4 mg, 80%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][CH:7]=1.[C:14](OC)(=[O:22])[C:15]1[C:16](=[CH:18][CH:19]=[CH:20][CH:21]=1)[SH:17].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:11]=[C:10]([C:12]2[S:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[C:14](=[O:22])[N:13]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: N#Cc1cccc(-c2ccco2)n1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=c1nc(-c2cccc(-c3ccco3)n2)sc2ccccc12
Yield: 70 %

Procedure:
6-(2-Furyl)-2-pyridinecarbonitrile (0.60 g, 3.5 mmol) and methyl thiosalicylate (1.01 g, 6.0 mmol) were dissolved in toluene (4 ml), and triethylamine (2.0 ml, 14.3 mmol) was added thereto. The reaction mixture was refluxed for 12 hrs. After cooling, the precipitates were collected by filtration and recrystallized from tetrahydrofuran-hexane to give the titled compound (0.75 g, 69%) as pale yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C@@H:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.O1[CH:21]=[CH:20][C:19](=[O:22])[CH:18]=[CH:17]1.Cl>O>[CH3:15][C@@H:9]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:1]3[CH:21]=[CH:20][C:19](=[O:22])[CH:18]=[CH:17]3)=[CH:3][CH:4]=2)=[N:13][NH:12][C:11](=[O:14])[CH2:10]1
Reactant: O=c1ccocc1
Reactant: C[C@H]1CC(=O)NN=C1c1ccc(N)cc1
Agent: Cl
Solvent: O
Product: C[C@H]1CC(=O)NN=C1c1ccc(-n2ccc(=O)cc2)cc1

Procedure:
A mixture of (S)-6-(4-aminophenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone (147 mg), 4H-pyran-4-one (78 mg) and hydrochloric acid (0.1 N, 1.5 ml) in water (2 ml) was stirred under reflux under nitrogen for 3 hours. The reaction mixture was cooled to afford the title compound, which was collected, washed with water and dried, 110 mg, m.p. 256-7° C. (softens 80° C.), [α]25D=+ 354° (1.03% in dimethylformamide).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[NH:15][N:14]=[N:13][N:12]=2)=[O:9])[CH:5]=[N:4][CH:3]=1.[CH3:16][CH:17]1[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]1>C1C=CC=CC=1>[CH3:16][CH:17]1[CH2:22][CH2:21][CH2:20][N:19]([C:2]2[N:7]=[C:6]([C:8]([NH:10][C:11]3[NH:15][N:14]=[N:13][N:12]=3)=[O:9])[CH:5]=[N:4][CH:3]=2)[CH2:18]1
Reactant: CC1CCCNC1
Reactant: O=C(Nc1nnn[nH]1)c1cncc(Cl)n1
Solvent: c1ccccc1
Product: CC1CCCN(c2cncc(C(=O)Nc3nnn[nH]3)n2)C1

Procedure:
To a suspension of 1.13 g of 6-chloro-N-(1H-5-tetrazolyl)pyrazine-2-carboxamide in 20 ml of benzene, 2.94 ml of 3-methylpiperidine was added, and the mixture was refluxed for 6 hours. The reation mixture was evaporated, ethanol was added to the residue, and then the ethanol solution was adjusted with ethanolic hydrogen chloride to pH 3. The precipitate was collected by filtration, and recrystalized from a mixture of dimethylsulfoxide and methanol affording 0.81 g of the desired compound as pale yellow columns, m.p. 236.5°-238.5 ° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[C:14]3[C:24](=[O:25])[NH:23][CH:22]=[CH:21][C:15]=3[N:16]=[C:17]([S:19][CH3:20])[N:18]=2)=[CH:8][CH:7]=1.[Br:29]N1C(=O)CCC1=O>CN(C=O)C>[Br:29][C:21]1[C:15]2[N:16]=[C:17]([S:19][CH3:20])[N:18]=[C:13]([NH:12][C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:26]=[CH:27][CH:28]=[C:2]([F:1])[CH:3]=4)=[CH:11][CH:10]=3)[C:14]=2[C:24](=[O:25])[NH:23][CH:22]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CSc1nc(Nc2ccc(Oc3cccc(F)c3)cc2)c2c(=O)[nH]ccc2n1
Solvent: CN(C)C=O
Product: CSc1nc(Nc2ccc(Oc3cccc(F)c3)cc2)c2c(=O)[nH]cc(Br)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
A 40 mL reaction vial was charged with 238d, (1.00 g, 2.53 mmol) in 15 mL of DMF. The mixture was gently heated until it became a clear solution, and allowed to cool down to room temperature. To the mixture was added N-bromosuccinimide (NBS, 498 mg, 2.80 mmol) and stirred for 1 h at rt. The solvent was removed under reduced pressure yielding the orange solid. The resulting solids were collected by filtration and washed acetonitrile to provide 1.04 g (87%) of the desired product 238e.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([F:10])([F:9])[F:8].C([N-]C(C)C)(C)C.[Li+].[CH2:19]=[O:20].Cl>C(OCC)(=O)C.O1CCCC1>[Br:1][C:2]1[CH:6]=[C:5]([CH2:19][OH:20])[S:4][C:3]=1[C:7]([F:10])([F:9])[F:8]
Reactant: FC(F)(F)c1sccc1Br
Reactant: C=O
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCc1cc(Br)c(C(F)(F)F)s1
Temperature: -10 °C
Reaction time: 1 h
Yield: 19.5 %

Procedure:
To a tetrahydrofuran solution (5.0 mL) of 3-bromo-2-(trifluoromethyl)thiophene (500 μL, 2.08 mmol), lithium diisopropylamide (2.06 mL, 2.29 mmol) was added under nitrogen atmosphere at −40° C., and the resultant mixture was stirred for 30 minutes. To the reaction solution, paraformaldehyde (68.8 mg, 2.29 mmol) was added and the resultant mixture was stirred for 30 minutes, followed by raising the temperature of the mixture to −10° C. The mixture was stirred at −10° C. for 4 hours and at 0° C. for 1 hour. After completion of the reaction, a 1 M hydrochloric acid was added to the reaction solution and extraction from the resultant mixture with ethyl acetate was performed. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (106 mg, yield 20%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.[CH2:14]([O:16][C:17](=[O:23])[C:18](OCC)=[O:19])[CH3:15].CC[O-].[Na+]>CCO>[CH2:14]([O:16][C:17](=[O:23])[C:18](=[O:19])[CH2:12][C:11](=[O:13])[CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH3:15]
Reactant: COc1ccc(CCC(C)=O)cc1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=O)CC(=O)CCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-(4-methoxyphenyl)-2-butanone (14.9908 g, 84.2 mmol) and diethyloxalate (12.3434 g, 84.2 mmol) were mixed together, and then added to a solution of NaOEt (˜3 M, 28.1 mL) stirring in an ice bath under N2. After stirring for 15 minutes, the reaction was warmed to room temperature and stirred. After 10 min, the reaction completely solidified. An additional 100 mL EtOH was added, the reaction was placed on mechanical shaker overnight. The reaction was quenched at 0° C. with 1N HCl and extracted 2× with CH2Cl2. The combined organics were washed with H2O, dried with Na2SO4, filtered, and concentrated to yield crude 22. The crude material was purified with 1:1 Hexanes: CH2Cl2 to obtain 22. 1H (CDCl3, 400 MHz): δ 14.39 (11H, broad s), 7.10 (2H, d, J=7.1 Hz), 6.82 (2H, d, J=6.3 Hz), 6.34 (1H, s), 4.33 (2H, q, J=7.1 Hz), 3.77 (3H, s), 2.91 (2H, t, J=7.3 Hz), 2.78 (2H, t, J=7.3 Hz), 1.36 (3H, t, J=7.1 Hz) ppm. 13C (CDCl3, 100 MHz): δ 202.53, 166.46, 162.29, 158.36, 132.36, 129.44, 114.20, 102.11, 62.75, 55.47, 43.02, 29.94, 14.27 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 55.47, 14.27; CH2 carbons: 62.75, 43.02, 29.94; CH carbons: 129.44, 114.20, 102.11 ppm. HPLC: 10.12 min. (Starting material: HPLC: 9.10 min.)