Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.C(N(CC)CC)C.[Cl:25][C:26]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29].[OH-].[Na+]>O1CCCC1.CN(C)C=O.C(OCC)(=O)C>[Cl:25][C:26]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:27]=1[C:28]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:29]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(F)cc4Cl)cc23)CC1
Yield: 68.2 %

Procedure:
To a suspension of 0.804 gm (3.5 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole in 10 mL tetrahydrofuran and 5.0 mL dimethylformamide were added 0.586 mL (4.2 mMol) triethylamine followed by a solution of 0.744 gm (3.86 mMol) 2-chloro-4-fluorobenzoyl chloride in 5 mL tetrahydrofuran. After 18 hours the reaction mixture was diluted with ethyl acetate followed by 2N sodium hydroxide. The phases were separated and the aqueous extracted with ethyl acetate. The organic extracts were combined then washed sequentially with 2N sodium hydroxide, water and saturated aqueous sodium chloride. The remaining organics were dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to flash chromatography, eluting with 100:10:1 dichloromethane:methanol:ammonium hydroxide. Fractions shown to contain product were combined and concentrated under reduced pressure. The residue was precipitated from ethyl acetate to give 0.921 gm (68.2%) of the title compound as a light pink powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10]Br)[C:5]=1[N:12]([S:14]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH3:13].[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:30]2[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]2)[C:5]=1[N:12]([S:14]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH3:13]
Reactant: COC(=O)c1cccc(CBr)c1N(C)S(=O)(=O)c1ccc(OC)cc1
Reactant: CN1CCNCC1
Product: COC(=O)c1cccc(CN2CCN(C)CC2)c1N(C)S(=O)(=O)c1ccc(OC)cc1
Yield: 70.4 %

Procedure:
In the same manner as described in Example 189, 0.500 g (1.168 mmol) of the product of Example 188 and 0.143 mL (1.285 mmol) of N-methylpiperazine provided 0.368 g (70%) of the desired product as a tan solid. Electrospray Mass Spec: 448.0 (M+H)+
Reaction SMILES: [C:1]([C:4]1[S:8][CH:7]=[C:6]([C:9]2[C:13]3[C:14](=[O:22])[NH:15][CH:16]=[C:17]([C:18](OC)=[O:19])[C:12]=3[N:11]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:10]=2)[CH:5]=1)(=[O:3])[NH2:2].C1COCC1.CO.[BH4-].[Li+]>O>[CH:23]1([N:11]2[C:12]3[C:17]([CH2:18][OH:19])=[CH:16][NH:15][C:14](=[O:22])[C:13]=3[C:9]([C:6]3[CH:5]=[C:4]([C:1]([NH2:2])=[O:3])[S:8][CH:7]=3)=[CH:10]2)[CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: COC(=O)c1c[nH]c(=O)c2c(-c3csc(C(N)=O)c3)cn(C3CCCC3)c12
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)c1cc(-c2cn(C3CCCC3)c3c(CO)c[nH]c(=O)c23)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.8 %

Procedure:
To a solution of methyl 3-(5-carbamoyl-3-thienyl)-1-cyclopentyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-7-carboxylate (30 mg) obtained in Example 34 in a mixed solvent of THF (0.5 mL) and methanol (0.5 mL) was added lithium borohydride (4.4 mg), and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (8 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)=[CH:5][C:4]=1[F:14].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:10]2[CH2:11][CH2:12][CH2:13][CH:9]2[C:6]2[CH:7]=[CH:8][C:3]([N:2]([CH3:15])[CH3:1])=[C:4]([F:14])[CH:5]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: CN(C)c1ccc(C2CCCN2)cc1F
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: CN(C)c1ccc(C2CCCN2S(=O)(=O)c2ccc(Cl)cc2)cc1F

Procedure:
The title compound, white solid, m.p. 99° C. and MS: m/e=383.2 (M+H+) was prepared in accordance with the general method of example 1e from (RS)-2-(4-dimethylamino-3-fluoro-phenyl)-pyrrolidine and 4-chloro -benzenesulfonyl chloride.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][C:10]([C:12](=O)[CH:13]([CH3:19])[CH2:14][C:15](OC)=[O:16])=[CH:11][C:6]=2[O:5][CH2:4][C:3]1=[O:21].[NH2:22][NH2:23]>>[CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3[CH:13]([CH3:19])[CH2:14][C:15](=[O:16])[NH:22][N:23]=3)=[CH:11][C:6]=2[O:5][CH2:4][C:3]1=[O:21]
Reactant: NN
Reactant: COC(=O)CC(C)C(=O)c1ccc2c(c1)OCC(=O)N2C
Product: CC1CC(=O)NN=C1c1ccc2c(c1)OCC(=O)N2C

Procedure:
Methyl 4-(3,4-dihydro-4-methyl-3-oxo-1,4(2H)-benzoxazin-7-yl)-4-oxo-3-methylbutyrate was treated with hydrazine as in example 1 to give the title compound, mp 188°-190° C.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C[Si]([N:14]=[C:15]=[O:16])(C)C.[OH:17][CH:18]([CH2:34][N:35]1[C:43]2[CH2:42][CH2:41][NH:40][CH2:39][C:38]=2[C:37]([C:44]2[CH:49]=[CH:48][C:47]([I:50])=[CH:46][CH:45]=2)=[N:36]1)[CH2:19][N:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=2[C:28]#[N:29])[CH2:22][CH2:21]1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1.C(Cl)Cl>[C:28]([C:27]1[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=1[N:23]1[CH2:22][CH2:21][N:20]([CH2:19][CH:18]([OH:17])[CH2:34][N:35]2[C:43]3[CH2:42][CH2:41][N:40]([C:15]([NH2:14])=[O:16])[CH2:39][C:38]=3[C:37]([C:44]3[CH:49]=[CH:48][C:47]([I:50])=[CH:46][CH:45]=3)=[N:36]2)[CH2:25][CH2:24]1)#[N:29]
Reactant: N#Cc1ccccc1N1CCN(CC(O)Cn2nc(-c3ccc(I)cc3)c3c2CCNC3)CC1
Reactant: C[Si](C)(C)N=C=O
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1ccccc1N1CCN(CC(O)Cn2nc(-c3ccc(I)cc3)c3c2CCN(C(N)=O)C3)CC1
Reaction time: 20 h
Yield: 78 %

Procedure:
Diisopropylethylamine (0.531 mL, 3.05 mmol), DMAP (5 mg), and trimethylsilyl isocyanate (0.413 mL, 3.05 mmol) were added to a solution of 2-(4-{2-hydroxy-3-[3-(4-iodo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperazin-1-yl)-benzonitrile in pyridine (3 mL) and CH2Cl2 (6 mL). The reaction mixture was stirred for 20 h, then partitioned between aqueous NaHCO3 and CH2Cl2. The CH2Cl2 layer was washed with brine, dried (Na2SO4), and concentrated. The resulting product was dissolved in CH2Cl2 (5 mL) and treated with 21 wt % sodium ethoxide in EtOH (0.5 mL) for 3 h. The reaction mixture was washed with brine, dried (Na2SO4), and concentrated. Purification by column chromatography (silica, 0-10% MeOH/CH2Cl2) afforded 290 mg (78%) of the title compound. HPLC (reverse phase conditions), tR=4.21 min. MS (electrospray): m/z 612.2 (612.5, calculated for C27H30IN7O2, M++H). 1H NMR (400 MHz, CDCl3): 7.73 (d, J=8.6 Hz, 2H), 7.57 (dd, J=7.6, 1.6 Hz, 1H), 7.50 (t, J=7.8 Hz, 1H), 7.36 (d, J=8.6 Hz, 2H), 7.05 (t, J=7.6 Hz, 1H), 7.00 (d, J=8.4 Hz, 1H), 4.64 (br s, 2H), 4.57 (br s, 2H), 4.30 (br s, 1H), 4.20 (dd, J =14.1, 3.3 Hz, 1H), 4.06 (dd, J=14.1, 6.3 Hz, 1H), 3.82-3.65 (m, 2H), 3.29-3.20 (m, 4H), 3.04-2.80 (m, 6H), 2.68 (br s, 2H).
Reaction SMILES: [CH:1]([O:14][NH:15][C:16]([CH:18]1[CH:24]([C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:23][CH:22]=[CH:21][CH2:20][N:19]1[S:33]([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=1)(=[O:35])=[O:34])=[O:17])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.ClCCl>[CH:1]([O:14][NH:15][C:16]([CH:18]1[CH:24]([CH:25]([OH:32])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:23][CH:22]=[CH:21][CH2:20][N:19]1[S:33]([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=1)(=[O:35])=[O:34])=[O:17])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COc1ccc(S(=O)(=O)N2CC=CCC(C(=O)c3ccccc3)C2C(=O)NOC(c2ccccc2)c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(S(=O)(=O)N2CC=CCC(C(O)c3ccccc3)C2C(=O)NOC(c2ccccc2)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
3-Benzoyl-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid benzhydryloxy-amide (32 mg, 0.054 mmoL) was dissolved in a methanol:dichloromethane (3:1, 1.3 mL) mixture and cooled to 0° C. This solution was treated with sodium borohydride and stirred 5 hrs at 0 to 25° C. The solvents were removed in vacuo and the residue was reconstituted in dichloromethane. This solution was washed with 1 M aqueous HCl, and H2O, dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (silica, 1.25% methanol in dichloromethane) to give 3-(hydroxy-phenyl-methyl)-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid benzhydryloxy-amide; MS: (M+H)+ 598.8, (M+NH4)+ 615.7.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH2:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:13][N:14]1[C:23]2[CH2:22][CH2:21][CH2:20][C:19](=O)[C:18]=2[CH:17]=[CH:16][C:15]1=[O:25].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:13][N:14]1[C:23]2[CH2:22][CH2:21][CH2:20][CH:19]([NH:12][CH2:11][CH2:10][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[C:18]=2[CH:17]=[CH:16][C:15]1=[O:25]
Reactant: NCCc1ccc([N+](=O)[O-])cc1
Reactant: Cn1c2c(ccc1=O)C(=O)CCC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cn1c2c(ccc1=O)C(NCCc1ccc([N+](=O)[O-])cc1)CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.6 %

Procedure:
A mixture of 2-(4-nitrophenyl)ethylamine (3.4 g), 5,6,7,8-tetrahydro-1-methyl-5-oxo-2(1H)-quinolinone (3.0 g), and para-toluenesulfonic acid (256 mg) was heated in refluxing toluene (70 ml), was azeotropic removal of water, for a total of 72 hrs. An additional 1.0 g of the amine was added at 24 and 48 hrs. The resulting solution was cooled and concentrated in vacuo. Sodium borohydride (0.6 g) was added to a solution of the residue in ethyl alcohol (70 ml). The resulting mixture was stirred at room temperature for 1 hr, and the mixture was concentrated in vacuo. The residue was quenched with water, and the mixture was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate concentrated. The residue was purified by high performance liquid chromatography (silica gel, eluted with methanol/ethyl acetate) to provide 3.8 g (69%) of product. Recrystallization from ethyl acetate afforded the analytical sample, mp 138°-139° C.,
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11]O)[CH:10]=1)[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[N:6]=[CH:5]2.[CH3:17][O:18][C:19]([C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][N:25]=[CH:24]2)=[O:20]>>[CH3:17][O:18][C:19]([C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[N:26]([CH2:11][C:9]1[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=1[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[N:6]=[CH:5]3)[N:25]=[CH:24]2)=[O:20]
Reactant: COC(=O)c1ccc2[nH]ncc2c1
Reactant: CC(C)Cn1ncc2cc(Cl)cc(CO)c21
Product: COC(=O)c1ccc2c(cnn2Cc2cc(Cl)cc3cnn(CC(C)C)c23)c1
Yield: 40 %

Procedure:
Compound 25 was prepared following general method 3A, using compound 17 as a starting material and 1H-indazole-5-carboxylic acid methyl ester as the heterocycle. Yield: 40%.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:10])[CH2:4]/[CH:5]=[CH:6]/[C:7](O)=[O:8].[NH:11]1[CH2:15][CH2:14][C@H:13]([O:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[C:19]([C:27]3[NH:31][C:30](=[O:32])[NH:29][N:28]=3)[N:18]=2)[CH2:12]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O>[CH3:2][N:3]([CH3:10])[CH2:4]/[CH:5]=[CH:6]/[C:7]([N:11]1[CH2:15][CH2:14][C@H:13]([O:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[C:19]([C:27]3[NH:31][C:30](=[O:32])[NH:29][N:28]=3)[N:18]=2)[CH2:12]1)=[O:8]
Reactant: CN(C)C/C=C/C(=O)O
Reactant: O=c1[nH]nc(-c2cc3ccccc3c(O[C@H]3CCNC3)n2)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C/C=C/C(=O)N1CC[C@H](Oc2nc(-c3n[nH]c(=O)[nH]3)cc3ccccc23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.2 %

Procedure:
To a mixture of (E)-4-(dimethylamino)but-2-enoic acid hydrochloride (23.40 mg, 0.141 mmol), (S)-3-(1-(pyrrolidin-3-yloxy)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one (100 mg, 0.135 mmol) and HATU (61.4 mg, 0.161 mmol) in DCM (3 mL) was added Hünig's Base (0.070 mL, 0.404 mmol). The reaction mixture was stirred at RT overnight and was subsequently diluted with EtOAc and washed with water. The product remained in the aqueous layer, which was concentrated to afford a residue. The crude product was purified by preparative HPLC eluting with a gradient of 25-50% ACN in water (basic mode). The solvent was removed by lyophilization to give the title compound (26 mg, 47%). 1H NMR (400 MHz, CD3OD) δ ppm 2.33-2.44 (m, 1H), 2.44-2.53 (m, 1H), 2.55 (s, 3H), 2.60 (s, 3H), 3.53 (d, J=6.06 Hz, 1H), 3.59 (d, J=6.57 Hz, 1H), 3.72-3.91 (m, 1H), 3.91-4.00 (m, 2H), 4.14-4.18 (m, 1H), 6.15 (d, J=18.44 Hz, 1H), 6.65-6.89 (m, 2H), 7.58-7.69 (m, 1H), 7.73-7.83 (m, 1H), 7.90 (d, J=3.03 Hz, 1H), 7.96 (d, J=5.31 Hz, 1H), 8.21 (d, J=7.33 Hz, 1H); ESI-MS m/z [M+H]+ 409.5.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:20][C@H:21]([CH3:33])[CH2:22][S:23][C:24]2[S:25][C:26]3[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=3[N:28]=2)[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[C:34](O[C@@H]1[C@H](OC(=O)C)[C@@H](COC(=O)C)O[C@H]1N1C=NC2C1=NC(C)=NC=2Cl)(=O)C.CC1N=C(N)C2N=CN(C=2N=1)[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O.C[O-].[Na+]>CO>[S:25]1[C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=[C:24]1[S:23][CH2:22][C@H:21]([NH:20][C:4]1[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=[C:2]([CH3:34])[N:3]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11])[CH3:33]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(C)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: C[C@H](CSc1nc2ccccc2s1)Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: C[O-]
Agent: Cc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Agent: [Na+]
Solvent: CO
Product: Cc1nc(N[C@H](C)CSc2nc3ccccc3s2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Yield: 22.9 %

Procedure:
The title compound was prepared according to general method A as described above in Example 1 by reacting 2-[(R)-2-amino-1-propylthio]benzothiazole hydrochloride (prepared as described in Example 5) (0.89 g, 3.0 mmol) with 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-6-chloro-2-methyl-9H-purine (1.07 g, 2.5 mmol) [prepared from 2-methylinosine (Journal of Organic Chemistry, 1967, 32, 3258-3260) by standard acylation and chlorination steps]. Deacylation of the purified 2',3',5'-tri-O-acetyl-N-[(R)-1-(2-benzothiazolyl)thio° 2-propyl]-2-methyladenosine using sodium methoxide in methanol to provide the desired N-[(R)-1-(2-benzothiazolyl)thio-2-propyl]-2-methyladenosine (0.28 g, 11%) (following column chromatography), 1H NMR (DMSO-d6) δ 1.40 (3H, d, --CHCH3), 2.30 (3H, S, --CH3), 3.50-3.77 (4H, m, H-5'a and H-5'b and --CH2 --), 3.98 (1H, d, H-4'), 4.13 (1H, d, H-3'), 4.63 (1H, q, H-2'), 4.86 (1H, br, --CHCH3), 5.19, 5.42 (2H, 2d, 2'- and 3'-OH), 5.70 (1H, t, 5'-OH), 5.85 (1H, d, H-1'), 7.36, 7.47 (2H, 2t, Ar-H), 7.80-7.96 (2H, m, Ar-H), 8.0 (1H, s, N--H), 8.26 (1H, s, H-8), 8.52 (1H, s, N--H). HPLC retention time 22.4 min [gradient elution, 20-80% acetonitrile/water (containing 0.1% TFA)]. C21H24N6O4S2.H2O requires C, 49.8; H, 4.8; N, 16.6. Found: C, 49.9; H, 5.1; N, 16.4%.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=[N:19][NH2:20])[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2F)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:11]3[C:16](=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[NH:20][N:19]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(C(=NN)c2ccc(F)cc2F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N1CCC(c2n[nH]c3cc(F)ccc23)CC1
Temperature: 120 °C

Procedure:
A mixture of 12.1 g of 1-acetyl-4-(2,4-difluorobenzoyl)-piperidine hydrazone, 11.8 g of potassium carbonate and 120 ml of dimethylformamide was stirred and heated at 120° C. for 16 hrs. The reaction mixture was poured into water and the aqueous solution was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and the solvent concentrated to give a solid. Recrystallization of the solid from ethyl acetate (twice) yielded 4.1 g (42% with concentration of mother liquor) of product, mp 162°-164° C.
Reaction SMILES: [Na].[O:2]=[C:3]1[NH:7][C:6](=[O:8])[CH:5](P(OCC)(=O)OCC)[NH:4]1.[CH3:17][CH:18]([N:20]1[CH2:24][CH:23]([CH2:25][O:26][C:27]2[CH:28]=[CH:29][C:30]([N+:35]([O-:37])=[O:36])=[C:31]([CH:34]=2)[CH:32]=O)[O:22][C:21]1=[O:38])[CH3:19]>C(O)C.O>[CH3:19][CH:18]([N:20]1[CH2:24][CH:23]([CH2:25][O:26][C:27]2[CH:28]=[CH:29][C:30]([N+:35]([O-:37])=[O:36])=[C:31]([CH:32]=[C:5]3[NH:4][C:3](=[O:2])[NH:7][C:6]3=[O:8])[CH:34]=2)[O:22][C:21]1=[O:38])[CH3:17]
Reactant: CC(C)N1CC(COc2ccc([N+](=O)[O-])c(C=O)c2)OC1=O
Reactant: CCOP(=O)(OCC)C1NC(=O)NC1=O
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CC(C)N1CC(COc2ccc([N+](=O)[O-])c(C=C3NC(=O)NC3=O)c2)OC1=O
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
Sodium (0.9 g, 0.04 g atom) was dissolved in ethanol (150 mL) and diethyl 2,4-dioxoimidazolidine-5-phosphonate (9.19 g, 40 mmol) added. After 30 minutes solid 5-[[[3-(1-methylethyl)-2-oxooxazolidin-5-yl]methyl]oxy]-2-nitrobenzaldehyde (10.0 g, 32 mmol) was added and the mixture stirred vigorously. After 30 minutes, the mixture was diluted with water (150 mL) filtered and the solid washed with water and air dried to give 5-[[5-[[[3-(1-methylethyl)-2-oxooxazolidin-5-yl]methyl]oxy]-2-nitrophenyl]methylene]-2,4-imidazolidinedione (9.80 g, 77%). An analytical sample was prepared by crystallization from dimethylformamide and wate and had an m.p. 285°-287° C. (dec.).
Reaction SMILES: [Br:1][C:2]1[C:8]([CH3:9])=[CH:7][C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=1[N:22]=[C:23]=[O:24].CCOCC>C1COCC1>[Br:1][C:2]1[C:8]([CH3:9])=[CH:7][C:5]([NH:6][C:23]([NH:22][C:13]2[CH:14]=[C:15]([C:18]([F:19])([F:21])[F:20])[CH:16]=[CH:17][C:12]=2[F:11])=[O:24])=[C:4]([F:10])[CH:3]=1
Reactant: Cc1cc(N)c(F)cc1Br
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)c(F)cc1Br

Procedure:
To a solution of 4-bromo-2-fluoro-5-methylaniline (500 mg, 2.45 mmoL) in THF (3 mL) was added the 2-fluoro-5-(trifluoromethyl)phenyl isocyanate (625 mg, 3.0 mmol). The reaction generated a white solid within 10 min. An additional portion of THF (3 mL) was added and the mixture dissolved. TLC analysis (1:1 Et2O:Hex) indicated that the reaction was complete. The product was purified by flash column chromatography (Hex:Et2O 2:1 to Et2O). 1H-NMR (DMSO-d6) δ 9.37 (d, J=2.8 Hz, 1H), 9.17 (d, J=2.4 Hz, 1H), 8.61 (dd, J=7.2, 2 Hz, 1H), 8.19 (d, J=8.0 Hz, 1H), 7.55 (d, J=10.8 Hz, 1H), 7.49 (dd, J=10.8, 8.8 Hz, 2H), 7.39 (m, 1H), 2.29 (s, 3H); MS [M+H]+=409.3, LCMS RT=3.91 min.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)=[C:4]([CH2:25][CH3:26])[CH:3]=1.C([Li])CCC.COB([O:37][CH3:38])OC.Cl>O1CCCC1>[CH2:7]([C:6]1[CH:8]=[C:38]([OH:37])[CH:3]=[C:4]([CH2:25][CH3:26])[C:5]=1[O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:22])([F:23])[F:24])=[CH:16][CH:15]=1)[CH3:2]
Reactant: CCc1cc(Br)cc(C)c1OCCCOc1ccc(OC(F)(F)F)cc1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cc(O)cc(CC)c1OCCCOc1ccc(OC(F)(F)F)cc1
Temperature: -70 °C
Reaction time: 2 h
Yield: 69.2 %

Procedure:
Then, 7.0 g of 4-bromo-2-ethyl-6-methyl-1-[3-(4-trifluoromethoxyphenoxy)propyloxy]benzene was dissolved in 200 ml of tetrahydrofuran, followed by stirring at -70° C., to which 10.0 ml of n-butyl lithium solution (in hexane, 1.58 mol/liter) was added dropwise, followed by further stirring at -70° C. for 2 hours. To this reaction mixture was added dropwise a solution of 2.4 g of trimethoxy borane dissolved in 60 ml of tetrahydrofuran. The reaction mixture was stirred for 1 hour, while warming to room temperature, and 13 ml of 10% aqueous hydrochloric acid solution was added in small portions, followed by stirring at room temperature for 20 minutes. The tetrahydrofuran layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated, to which 50 ml of toluene was added, and the mixture was heated at 70° C. under stirring, to which 6 ml of 30% aqueous hydrogen peroxide solution was added dropwise. The mixture was heated under reflux for 1 hours, and washed once with water, and twice with 10% aqueous ammonium ferrous sulfate solution and once with water. The toluene layer was dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 4.3 g of 3,5-diethyl-4-[3-(4-trifluoromethoxyphenoxy)propyloxy]phenol (50% yield), nD25.4 1.5060.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:27])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[C:14]([F:26])[CH:13]=3)[O:11][C:6]=2[C:5]([F:28])=[CH:4][C:3]=1[F:29].[H-].[Na+].I[CH3:33].[Cl-].[NH4+]>CN(C)C=O>[NH2:1][C:2]1[C:7]2[C:8](=[O:27])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20])[CH3:33])=[C:14]([F:26])[CH:13]=3)[O:11][C:6]=2[C:5]([F:28])=[CH:4][C:3]=1[F:29]
Reactant: CI
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.99 g (4.73 mmol) of Compound 51 obtained in Example 51 was dissolved in 80 ml of dimethylformamide under argon atmosphere, 212 mg. of sodium hydride (60% oil disperison) and 0.60 ml of iodomethane were added and the mixture was stirred at room temperature for 1 hour. An aqueous saturated solution of ammonium chloride was added to the reaction solution, the precipitated crystals were collected by filtration and dissolved in ethanol, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform) to give 2.09 g of 5-amino-2-[4-[N-(tert-butoxycarbonyl)-N-methylamino]-3-fluorophenyl]-6,8-difluoro-4H-1-benzopyran-4-one.