Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:22])[CH2:9][CH2:10][C:11]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[NH:13][C:12]=2[CH:20]=O)[CH2:4][CH2:3]1.[CH3:23][NH:24][S:25]([C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32](=[O:37])[CH2:31]2)(=[O:27])=[O:26]>>[CH3:23][NH:24][S:25]([C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32](=[O:37])/[C:31]/2=[CH:20]\[C:12]1[NH:13][C:14]2[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=2[C:11]=1[CH2:10][CH2:9][C:8]([N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)=[O:22])(=[O:27])=[O:26]
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: CN1CCN(C(=O)CCc2c(C=O)[nH]c3c2CCCC3)CC1
Product: CNS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c3c(c1CCC(=O)N1CCN(C)CC1)CCCC3)C(=O)N2
Yield: 56 %

Procedure:
3-[3-(4-Methylpiperazin-1-yl)-3-oxo-propyl]-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde (121 mg, 0.3 mmol) was condensed with 5-methylaminosulfonyl-oxindole (68 mg, 0.3 mmol) following the same procedure used in Example 1 to give the desired product (86 mg, 56% yield).
Reaction SMILES: CN(C)C=O.C(Cl)(=O)C(Cl)=O.[C:12]1([C:18]2[N:23]=[CH:22][C:21]([C:24]([OH:26])=O)=[CH:20][CH:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[NH2:27][C:28]1[CH:40]=[C:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:38]=[CH:37][C:29]=1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>C(Cl)Cl.C(N(CC)CC)C>[C:41]1([C:39]2[CH:38]=[CH:37][C:29]([C:30]([O:32][C:33]([CH3:36])([CH3:34])[CH3:35])=[O:31])=[C:28]([NH:27][C:24]([C:21]3[CH:22]=[N:23][C:18]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[CH:19][CH:20]=3)=[O:26])[CH:40]=2)[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: O=C(O)c1ccc(-c2ccccc2)nc1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(-c2ccccc2)nc1
Reaction time: 1 h

Procedure:
N,N-Dimethylformamide (0.9 μl) and oxalyl chloride (0.023 mL) were added to a methylene chloride (0.5 mL) suspension of 6-phenylpyridine-3-carboxylic acid (44 mg) at room temperature, followed by stirring at the same temperature for 1 hour. The reaction mixture was added to a solution mixture of tert-butyl 2-amino-4-phenylbenzoate (40 mg) in methylene chloride (1 mL) and triethylamine (0.17 mL) at room temperature, followed by stirring at same temperature for 1 hour. The solvent was evaporated under reduced pressure, and ethyl acetate and a 10% aqueous solution of citric acid were added to the residue. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Trikonex AB, FlashTube 2008, eluent: hexane/ethyl acetate=2:1] to obtain tert-butyl 4-phenyl-2-(6-phenylpyridine-3-carboxamido)benzoate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][C@@H:18]1[C:23](O)=[O:24])=[O:16])([CH3:13])([CH3:12])[CH3:11].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.O>C(Cl)Cl>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][C@@H:18]1[C:23]([NH:9][NH:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=1)=[O:24])=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCOC[C@@H]1C(=O)O
Reactant: NNc1ccc(F)cn1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCOC[C@@H]1C(=O)NNc1ccc(F)cn1
Reaction time: 8 h
Yield: 97.5 %

Procedure:
To a solution of (5-fluoro-pyridin-2-yl)-hydrazine (143 mg, 1.13 mmol) in DCM (10.0 mL) was added (R)-morpholine-3,4-dicarboxylic acid 4-tert-butyl ester (260 mg, 1.13 mmol), EDC (238 mg, 1.24 mmol) and HOBt.H2O (15.0 mg, 0.11 mmol). The reaction was stirred overnight then partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM, to give the title compound (375 mg, 98%). LCMS (Method 1): Rt 2.69, m/z 341.2 [MH+].
Reaction SMILES: O=[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][O:3]1.[F:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1>CN(C=O)C>[F:12][C:13]1[CH:19]=[CH:18][C:16]([N:17]2[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:2]2=[O:3])=[CH:15][CH:14]=1
Reactant: Nc1ccc(F)cc1
Reactant: COC(=O)c1cccoc1=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccn(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of methyl 2-oxo-2H-pyran-3-carboxylate (10.0 g, 65 mmol, Aldrich) in DMF (80 mL) at ice bath temperature was added a solid of 4-fluoroaniline (7.21 g, 65 mmol), stirred for 15 min. and the reaction mixture was warmed to rt, stirred for 3 h at rt. To the 4-fluoroaniline adduct intermediate formed via Michael addition was added in situ solids of EDCI.HCl (14.8 g, 77 mmol) and DMAP (1.80 g) at rt. The reaction mixture was stirred at rt overnight. Most of DMF was removed in vacuo, and to the residue were added 1N aq HCl (150 mL) and EtOAc (400 mL), the EtOAc layer was separated, and the aqueous layer was washed with EtOAc (2×200 mL), the combined EtOAc layer was washed with brine (150 mL), dried over MgSO4 and concentrated in vacuo. The residue was triturated with iPrOH (180 mL) to obtain the 1st crop of product (8.5 g) as a yellow solid. The mother liquor was concentrated, and the residue was triturated with a small amount of ether to obtain the 2nd crop of product (2.5 g, total 11 g, 68%). 1H NMR (CDCl3) δ 8.23 (dd, 1H, J=7.2, 2.2 Hz), 7.57 (dd, 1H, J=6.6, 1.7 Hz), 7.32-7.34 (m, 2H), 7.17 (t, 2H, J=8.8 Hz), 6.32 (t, 1H, J=7.1 Hz), 3.89 (s, 3H); MS(ESI+) m/z 248.2 (M+H)+.
Reaction SMILES: [C:1]1([S:7]([CH2:10][CH2:11][CH:12]([CH:16]([S:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=2)[CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13](O)=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C=O)C.C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[O:51][NH2:52]>C(Cl)Cl>[OH:51][NH:52][C:13](=[O:14])[CH:12]([CH2:11][CH2:10][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8])[CH:16]([S:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=1)[CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C[Si](C)(C)ON
Reactant: COc1ccc(SC(CCCCc2ccccc2)C(CCS(=O)(=O)c2ccccc2)C(=O)O)cc1OC
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(SC(CCCCc2ccccc2)C(CCS(=O)(=O)c2ccccc2)C(=O)NO)cc1OC
Reaction time: 0.5 h
Yield: 189.5 %

Procedure:
To a solution containing (-)-2-(2-benzenesulfonylethyl)-3-(3,4-dimethoxyphenylsulfanyl)-7-phenylheptanoic acid (285 mg, 0.53 mmol) in anhydrous CH2Cl2 (10 mL) under nitrogen atmosphere is added anhydrous DMF (41 μL, 0.53 mmol) followed by oxalyl chloride (2 M in CH2Cl2, 0.66 mL, 1.31 mmol). The yellow solution is stirred for 30 minutes then O-(trimethylsilyl)hydroxylamine (0.32 mL, 2.65 mmol) is added dropwise. The resulting white precipitate is stirred for 10 minutes then partitioned between 1 N HCl (50 mL) and ethyl acetate (50 mL). The aqueous layer is extracted with ethyl acetate (2×20 mL) and the combined organic extracts are washed with water (30 mL), brine (30 mL), dried over anhydrous MgSO4, filtered and concentrated to afford a pale yellow oil. The crude product is combined with the product of a reaction performed on identical scale and chromatographed on silica gel (CH2Cl2 →CH2Cl2 :MeOH, 19:1) to afford (-)-N-hydroxy-2-(2-benzenesulfonylethyl)-3-(3,4-dimethoxyphenylsulfanyl)-7-phenylheptanamide (560 mg, 95%) as a cream-colored foam. TLC analysis [pet-ether/EtOAc, 1:2, Rf (carboxylic acid)=0.45, Rf (hydroxamate)=0.40]. [α]23D -28° (c 1.1, CHCl3); 1H NMR (300 MHz, CDCl3) δ 1.40-1.80 (m, 6H), 2.10 (m, 1H), 2.22 (m, 1H), 2.60 (m, 2H), 2.68 (m, 1H), 3.05 (broad s, 3H), 3.83 (s, 3H), 3.84 (s, 3H), 6.76 (d, J=8.7 Hz, 1H), 6.98 (m, 2H), 7.12 (m, 3H), 7.28 (m, 2H), 7.52 (m, 2H), 7.64 (t, J=7.3 Hz, 1H), 7.84 (d, J=7.4 Hz, 2H), 8.85 (broad s, 1H) ppm. Mass spectrum (FAB) m/z 557 (M)+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[F:32][C:33]([F:73])([F:72])[C:34]1[CH:35]=[C:36]([C:44]([CH3:71])([CH3:70])[C:45]([N:47]([C:49]2[C:50]([C:62]3[CH:67]=[CH:66][C:65]([F:68])=[CH:64][C:63]=3[CH3:69])=[CH:51][C:52]([N:55]3[CH2:60][CH2:59][CH:58]([OH:61])[CH2:57][CH2:56]3)=[N:53][CH:54]=2)[CH3:48])=[O:46])[CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1.[C:74](O)(=[S:76])[CH3:75]>C1COCC1>[F:73][C:33]([F:32])([F:72])[C:34]1[CH:35]=[C:36]([C:44]([CH3:70])([CH3:71])[C:45]([N:47]([CH3:48])[C:49]2[C:50]([C:62]3[CH:67]=[CH:66][C:65]([F:68])=[CH:64][C:63]=3[CH3:69])=[CH:51][C:52]([N:55]3[CH2:60][CH2:59][CH:58]([O:61][C:74](=[S:76])[CH3:75])[CH2:57][CH2:56]3)=[N:53][CH:54]=2)=[O:46])[CH:37]=[C:38]([C:40]([F:41])([F:42])[F:43])[CH:39]=1
Reactant: Cc1cc(F)ccc1-c1cc(N2CCC(O)CC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(O)=S
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=S)OC1CCN(c2cc(-c3ccc(F)cc3C)c(N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)CC1
Yield: 58.1 %

Procedure:
A solution of 0.22 g (0.84 mmol) triphenylphosphine and 0.15 g (0.84 mmol) diethyl azodicarboxylate in 3.33 ml THF was stirred for 15 min at 0° C. This solution was added to a solution of 0.25 g (0.42 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-hydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide and 64 mg (0.84 mmol) thioacetic acid in 10 ml THF at 0° C. Conversion was monitored by thin layer chromatography. After complete consumption of the starting material a 2 N aqueous solution of sodium carbonate was added. The mixture was extracted with three portions of tert-butyl methyl ether. The combined organic extracts were dried over sodium sulphate and concentrated. Flash column chromatography gave 0.16 g (59%) of the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][CH:6]([C:10]1[N:15]([CH3:16])[C:14](=[O:17])[C:13]2[NH:18][CH:19]=[CH:20][C:12]=2[C:11]=1[C:21]1[C:22]([CH3:31])=[C:23]2[C:28](=[CH:29][CH:30]=1)[O:27][CH2:26][CH2:25][CH2:24]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].Br[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1.CCN(C(C)C)C(C)C>CC#N.O>[C:1]([O:5][CH:6]([C:10]1[N:15]([CH3:16])[C:14](=[O:17])[C:13]2[N:18]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)[CH:19]=[CH:20][C:12]=2[C:11]=1[C:21]1[C:22]([CH3:31])=[C:23]2[C:28](=[CH:29][CH:30]=1)[O:27][CH2:26][CH2:25][CH2:24]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3[nH]ccc23)ccc2c1CCCO2
Reactant: BrCc1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC#N
Product: Cc1c(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3c2ccn3Cc2ccccn2)ccc2c1CCCO2

Procedure:
The title compound was prepared in a manner similar to that described in Example 41 from 2-(tert-butoxy)-2-(6-methyl-4-(5-methylchroman-6-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetic acid and 2-(bromomethyl)pyridine, except that Hunig's base (10 eq.) was used instead of cesium carbonate and was isolated by reverse phase chromatography (10-90% MeCN/H2O-0.1% TFA, 12 min) on an achiral column. 1H NMR (400 MHz, CHLOROFORM-d) ppm 8.75-8.91 (m, 1H) 8.14-8.27 (m, 1H) 7.85-8.01 (m, 1H) 7.62-7.75 (m, 1H) 7.30-7.42 (m, 1H) 6.68-6.80 (m, 1H) 6.38-6.47 (m, 2H) 5.80-6.03 (m, 2H) 5.25-5.54 (m, 1H) 4.15-4.28 (m, 2H) 3.68 (s, 3H) 2.61-2.74 (m, 2H) 2.06-2.16 (m, 2H) 1.89-2.02 (m, 3H) 1.04 (s, 9H); LCMS (m/z) ES+=516 (M+1).
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]2=[C:3]([C:10]([OH:12])=O)[CH:2]=1.[OH-].[K+].C1(C)C=CC=CC=1.C(Cl)(=O)C([Cl:25])=O>CO.N1C=CC=CC=1>[N:1]1[N:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]2=[C:3]([C:10]([Cl:25])=[O:12])[CH:2]=1
Reactant: O=C(O)c1cnn2ccccc12
Reactant: O=C(Cl)C(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C(Cl)c1cnn2ccccc12
Reaction time: 8 h

Procedure:
Pyrazolo[1,5-a]pyridine-3-carboxylic acid (9.72 g) was dissolved in hot anhydrous methanol (225 ml) and treated with a solution of potassium hydroxide (3.73 g) in dry methanol (45 ml) with stirring. The resulting orange solution was evaporated to dryness under reduced pressure, to give a colourless solid. This solid was treated with dry toluene (300 ml) and the mixture was stirred and treated with oxalyl chloride (10.2 ml), with stirring, at room temperature. After further stirring for a period of 15 minutes the mixture was treated with pyridine (45 drops), and the mixture was vigorously stirred overnight. The mixture was then filtered and the filtrate was evaporated under reduced pressure, to give pyrazolo[1,5-a]pyridine-3-carbonyl chloride (10.6 g), m.p. 119°-120° C. (in a sealed tube).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])[CH:5]=[CH:6][C:7]=1I.[Si:20]([O:27][CH2:28][C@@H:29]1[O:33][C:32](=[O:34])[N:31]([C:35]2[CH:40]=[CH:39][C:38]([Sn](C)(C)C)=[C:37]([F:45])[CH:36]=2)[CH2:30]1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>>[Si:20]([O:27][CH2:28][C@@H:29]1[O:33][C:32](=[O:34])[N:31]([C:35]2[CH:40]=[CH:39][C:38]([C:7]3[CH:6]=[CH:5][C:4]([N:9]4[CH2:13][C@H:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]4=[O:19])=[CH:3][C:2]=3[F:1])=[C:37]([F:45])[CH:36]=2)[CH2:30]1)([C:23]([CH3:26])([CH3:24])[CH3:25])([CH3:22])[CH3:21]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CN(c2ccc([Sn](C)(C)C)c(F)c2)C(=O)O1
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3ccc(N4C[C@H](CO[Si](C)(C)C(C)(C)C)OC4=O)cc3F)c(F)c2)C(=O)O1
Yield: 57.7 %

Procedure:
Using essentially the same procedure as Example 28, but starting from N-{[(5S)-3-(3-fluoro-4-iodophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide (0.38 g, 1.00 mM) and adding (5R)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-[3-fluoro-4-(trimethylstannyl)phenyl]-1,3-oxazolidin-2-one (0.73 g, 1.50 mM) gave the title compound as a light yellow solid (0.334 g).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH2:11](O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(C)C(C)=CC=CC=1>CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4].O>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: OCc1ccccc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: Cc1ccccc1C
Solvent: O
Product: O=C(OCc1ccccc1)c1ccc(O)cc1
Temperature: 85 °C
Yield: 98.7 %

Procedure:
69.1 g (0.5 mole) of p-hydroxybenzoic acid, 216.2 g (2 moles) of benzyl alcohol, 0.7 g of tetraisopropyl titanate and 30 g of xylene were fed into a fournecked glass flask, and refluxed for 3 hours with stirring in an atmosphere of nitrogen. During this time, the temperature of the reaction mixture was maintained at 85° C. Water formed by the reaction was removed out of the reaction system by the Dien-Stark's device. The presence of xylene simplified temperature control and promoted removal of water. Benzyl p-hydroxybenzoate was obtained in a yield of 98.7%.
Reaction SMILES: [CH2:1]1[C:5]2=[C:6]3[C:11](=[CH:12][CH:13]=[C:4]2[NH:3][C:2]1=[O:14])[N:10]=[CH:9][CH:8]=[CH:7]3.C(O[CH:20](OC(C)(C)C)[N:21]([CH3:23])[CH3:22])(C)(C)C.C(OCC)(=O)C>CN(C=O)C>[CH3:20][N:21]([CH:23]=[C:1]1[C:5]2=[C:6]3[C:11](=[CH:12][CH:13]=[C:4]2[NH:3][C:2]1=[O:14])[N:10]=[CH:9][CH:8]=[CH:7]3)[CH3:22]
Reactant: O=C1Cc2c(ccc3ncccc23)N1
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)C=C1C(=O)Nc2ccc3ncccc3c21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 3-H-pyrrolo[3,2-f]quinoline-2-one (13 mmol) and dimethylformamide di-t-butyl acetal (15 mmol) in DMF was stirred at room temperature for 3 h. Ethyl acetate (25 mL) was added and the resulting solid was collected by filtration and allowed to air dry. The desired compound was obtained (70%) and used directly in the next step.
Reaction SMILES: C(O[C:4](=[O:14])[CH2:5][C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.[CH2:15]([O:17][C:18]([C:20]1[NH:21][N:22]=[C:23]([NH2:25])[CH:24]=1)=[O:19])[CH3:16]>C(O)(=O)C>[CH2:15]([O:17][C:18]([C:20]1[CH:24]=[C:23]2[NH:25][C:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[CH:5][C:4](=[O:14])[N:22]2[N:21]=1)=[O:19])[CH3:16]
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: CCOC(=O)c1cc(N)n[nH]1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2[nH]c(-c3ccccc3)cc(=O)n2n1
Yield: 55.9 %

Procedure:
A solution of 0.56 mL (3.22 mmol) of 3-oxo-3-phenyl-propionic acid ethyl ester and 0.50 g (3.22 mmol) 5-amino-2H-pyrazole-3-carboxylic acid ethyl ester in 4 mL of acetic acid (HOAc) was heated at reflux for 4 h, during which time a precipitate formed. The precipitate was filtered off, washed with ethyl acetate and dried to give 0.51 g (56% yield) of 7-oxo-5-phenyl-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid ethyl ester as a solid as indicated by 1H NMR; LC-MS—calcd for C15H13N3O3 [M++H]+: 284.1, found: 284.1.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[C:9]([C:11]([OH:13])=O)[N:10]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.CS(C)=O.[NH2:30][C:31]1[NH:35][N:34]=[N:33][N:32]=1>CN(C=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[C:9]([C:11]([NH:30][C:31]2[NH:35][N:34]=[N:33][N:32]=2)=[O:13])[N:10]=1
Reactant: O=C(O)c1csc(-c2ccco2)n1
Reactant: Nc1nnn[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: O=C(Nc1nnn[nH]1)c1csc(-c2ccco2)n1
Reaction time: 3 h
Yield: 43.2 %

Procedure:
A solution of 2-(2-furyl)-4-thiazolecarboxylic acid (300 mg) and CDI (373.8 mg) in a mixed solvent of dry DMF (10 mg) and dry DMSO (2 ml) was prepared at 100° C. and allowed to react under the same condition for 1 hour. Then a solution of 5-aminotetrazole (156.9 mg) in dry DMF (2 ml) was added dropwise thereto and the reaction was continued for additional 3 hours. The solvent was removed from the reaction mixture. The residue was treated with water and acidified with 2N-HCl. The produced solids were filtered, washed sufficiently with water and then with ether, and dried to give yellow ocher solids of 2-(2-furyl)-N-(1H-tetrazole-5-yl)-4-thiazolecarboxamide (174 mg, 43%), m.p. 275°-277° C.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:14]([NH:16][CH2:17][C@@H:18]4[CH2:22][CH2:21][CH2:20][O:19]4)=[N:13][CH:12]=[N:11][C:10]=3[NH:9][C:8]=2[Si](CC)(CC)CC)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:30]N1C(=O)CCC1=O>CN(C=O)C>[I:30][C:8]1[NH:9][C:10]2[N:11]=[CH:12][N:13]=[C:14]([NH:16][CH2:17][C@@H:18]3[CH2:22][CH2:21][CH2:20][O:19]3)[C:15]=2[C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC[Si](CC)(CC)c1[nH]c2ncnc(NC[C@@H]3CCCO3)c2c1-c1ccccc1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: Ic1[nH]c2ncnc(NC[C@@H]3CCCO3)c2c1-c1ccccc1

Procedure:
A solution of 1.00 g (2.5 mmol) of (S)-[5-phenyl-6-(triethylsilanyl)-7-H-pyrrolo[2,3-d]pyrimidine-4-yl]-(tetrahydrofuran-2-ylmethyl)-amine and 830 mg (3.7 mmol) of N-iodosuccinimide in 10 ml DMF was stirred at 45° C. for 1 h. The reaction mixture was partitioned between dichloromethane (120 ml) and a 4:1 mixture of brine and saturated aqueous sodium thiosulfate (35 ml). The organic layer was washed with saturated aqueous sodium bicarbonate (1×) and brine (1×), dried over Na2SO4, filtered and concentrated. The residue was dissolved in dichloromethane (10 ml), and hexanes (200 ml) was added slowly. A solid precipitate formed. The solid was filtered off and dried under high vacuum to give the title compound. 1H-NMR (400 MHz, CDCl3) δ 1.51 (m, 1 H), 1.69-1.91 (m, 3 H), 3.19-3.69 (m, 4 H), 3.99 (m, 1 H), 5.27 (t, J=4.4 Hz, 1 H), 7.37-7.56 (m, 5 H), 8.42 (s, 1 H), 13.21 (s, 1 H). Mass Spectrum (ESI) m/e=421.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:16]4[CH:17]=[N:18][C:19]([O:23]C)=[CH:20][C:21]=4[CH3:22])[CH2:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:4][CH:3]=1.[I-].[Na+].C(#N)C.Cl[Si](C)(C)C>C(=O)([O-])O.[Na+]>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:16]4[C:21]([CH3:22])=[CH:20][C:19](=[O:23])[NH:18][CH:17]=4)[CH2:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([CH:25]([CH2:26][CH3:27])[CH2:28][CH3:29])=[CH:4][CH:3]=1
Reactant: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1cnc(OC)cc1C
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CC#N
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1c[nH]c(=O)cc1C
Yield: 71.9 %

Procedure:
To a mixture of 10-chloro-7-(1-ethylpropyl)-1-(6-methoxy-4-methylpyridin-3-yl)-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]benzimidazole (Example 30; 410 mg, 0.993 mmol), sodium iodide (447 mg, 2.98 mmol) and acetonitrile (10 mL) was added chlorotrimethylsilane (0.381 mL, 2.99 mmol) at 0° C. After the resultant mixture was stirred at room temperature for 24 hr, the mixture was diluted with aqueous saturated sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with ethyl acetate to give the title compound as a solid (285 mg, 0.714 mmol, 72%).
Reaction SMILES: O.Cl.Cl.[NH2:4][C:5]1[N:13]=[CH:12][N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[C@@H:14]1[O:19][C@H:18]([C:20]([OH:22])=[O:21])[C@@H:17]([NH:23]C(=O)[C@H](CC2C=CC(OC)=CC=2)N)[C@H:15]1[OH:16]>[OH-].[Na+]>[OH2:16].[NH2:4][C:5]1[N:13]=[CH:12][N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[C@@H:14]1[O:19][C@H:18]([C:20]([OH:22])=[O:21])[C@@H:17]([NH2:23])[C@H:15]1[OH:16]
Reactant: COc1ccc(C[C@H](N)C(=O)N[C@H]2[C@@H](O)[C@H](n3cnc4c(N)ncnc43)O[C@@H]2C(=O)O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](C(=O)O)[C@@H](N)[C@H]1O
Reaction time: 8 h
Yield: 165.7 %

Procedure:
A mixture of 1-(6-amino-9H-purin-9-yl)-1,3-dideoxy-3-(O-methyl-L-tyrosylamino)-β-D-ribofuranuronic acid dihydrochloride monohydrate (5.48 g) prepared in Example 98 in 1N methanolic sodium hydroxide solution (1000 ml) was heated under reflux for 20 hours. The reaction mixture was evaporated and the residue was neutralized with concentrated hydrochloric acid. The aqueous solution was subjected to column chromatography on a non-ionic adsorption resin "HP-20" (trade mark, Mitsubishi Chemical Industries Ltd.) (500 ml). The elution was carried out with water, and the eluate was concentrated, stood overnight. The resulting precipitates were collected, washed with water, and dried to give 1-(6-amino-9H-purin-9-yl)-1,3-dideoxy-3-amino-β-D-ribofuranuronic acid monohydrate (2.47 g).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].C([O-])(=O)C.[K+].[C-:17]#[N:18].[Na+]>C(O)C.O>[O:5]=[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][CH2:2][C:17]#[N:18]
Reactant: O=C(CCCl)c1ccccc1
Reactant: [C-]#N
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CCCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.3 %

Procedure:
To a solution of 3-chloro-1-phenylpropan-1-one (5.0 g, 29.7 mmol) in hot ethanol (7 mL) was added potassium acetate (2.91 g, 29.77 mmol). After cooling to room temperature, the precipitated salt was removed via filtration. To the filtrate in a septum-sealed flask under a nitrogen bubbler was slowly added sodium cyanide (2.91 g, 59.3 mmol) as a solution in water (10 mL). After stirring at room temperature for 24 hours, ethanol (30 mL) was added, and the mixture was cooled in an ice bath. The precipitate was filtered and rinsed with ethanol to provide the product (3.42 g, 73%) as fluffy white solid.