Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([C@@:8]1([OH:42])[C@@H:12]([CH2:13][O:14][Si](C(C)(C)C)(C)C)[O:11][C@@H:10]([N:22]2[CH:29]=[C:28]([CH2:30][O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[N+:39]([O-:41])=[O:40])[C:26]([NH2:27])=[N:25][C:23]2=[O:24])[CH2:9]1)(C(C)(C)C)(C)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>C1COCC1>[N+:39]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[CH2:32][O:31][CH2:30][C:28]1[C:26]([NH2:27])=[N:25][C:23](=[O:24])[N:22]([CH:29]=1)[C@@H:10]1[O:11][C@H:12]([CH2:13][OH:14])[C@@H:8]([OH:42])[CH2:9]1)([O-:41])=[O:40]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(COCc3ccccc3[N+](=O)[O-])c(N)nc2=O)C[C@@]1(O)[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Nc1nc(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1COCc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.3 %

Procedure:
To a solution of compound 42 (55 mg, 0.09 mmol) in THF (10 mL), n-Bu4NF (63 mg, 0.20 mmol) was added. The mixture was stirred at room temperature for four hours and concentrated in vacuo, and the residue was purified by silica gel column chromatography to yield 5-(2-nitrobenzyloxy)methyl-2′-deoxycytidine 43 (34 mg, 96%). 1H NMR (400 MHz, DMSO-d6): δ 8.05 (d, J=8.0 Hz, 1H, Ph-H), 7.89 (s, 1H, H-6), 7.74 (m, 2H, Ph-H), 7.55 (m, 1H, Ph-H), 7.39 (br s, 1H, D2O exchangeable, NH2), 6.74 (br s, 1H, D2O exchangeable, NH2), 6.12 (t, 1H, J=6.4 Hz, H-1′), 5.21 (br s, 1H, D2O exchangeable, 3′-OH), 4.99 (br s, 1H, D2O exchangeable, 5′-OH), 4.81 (s, 2H, Ph-CH2), 4.30 (dd, 2H, J=11.6 Hz, 5-CH2), 4.20 (m, 1H, H-3′), 3.76 (m, 1H, H-4′), 3.55 (m, 2H, H-5′), 2.11 (m, 1H, H-2′a), 1.95 (m, 1H, H-2′b).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)=[O:24])[CH2:19][CH2:18]2)[C:5]2[N:10]=[C:9]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[S:8][C:6]=2[N:7]=1.[H-].[Na+].[CH3:35]I>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([N:25]([CH3:35])[C:26]3[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=3)=[O:24])[CH2:19][CH2:18]2)[C:5]2[N:10]=[C:9]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[S:8][C:6]=2[N:7]=1
Reactant: Cc1ccc(NC(=O)N2CCN(c3nc(N)nc4sc(-c5cccnc5)nc34)CC2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(N(C)C(=O)N2CCN(c3nc(N)nc4sc(-c5cccnc5)nc34)CC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 43.4 %

Procedure:
To a suspension of 4-(5-amino-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin-7-yl)-N-p-tolylpiperazine-1-carboxamide (90 mg, 0.2 mmol) in DMF (5 ml) was added NaH (60%, 12 mg, 0.31 mmol). The resulting mixture was stirred at room temperature for 10 minutes. Then, methyl iodide (0.3 mmol) was added to the mixture. After stirring at room temperature for 30 minutes, the solvents were evaporated in vacuo and the crude residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio of 1/30), yielding the pure title compound as yellowish solid (40 mg, 43%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[C:5]([C:7]1[C:8]([NH:14][CH2:15][CH3:16])=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=1)=[O:6].[H-].[Na+].Cl[CH:23]([CH2:29][CH2:30][C:31]([O-:33])=O)[C:24]([O:26][CH2:27][CH3:28])=[O:25]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[C:5]([C:7]1[C:8]([N:14]([CH2:15][CH3:16])[C:31]([CH2:30][CH2:29][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:33])=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=1)=[O:6]
Reactant: CCOC(=O)C(Cl)CCC(=O)[O-]
Reactant: CCNc1nc(C)ccc1C(=O)c1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCC(=O)N(CC)c1nc(C)ccc1C(=O)c1cccc(Cl)c1

Procedure:
A DMF solution of 3-(3-chlorobenzoyl)-2-ethylamino-6-methylpyridine was treated with 60% sodium hydride and then reacted with monoethyl chloroglutarate under heating. Thereafter, the whole was worked up and purified in a usual manner to obtain ethyl 4-{N-[3-(3-chlorobenzoyl)-6-methylpyridin-2-yl]-N-ethylcarbamoyl}butanoate. The resulting compound was reacted with sodium methoxide in ethanol under heating, then concentrated sulfuric acid was added to the reaction mixture, followed by reaction under heating for 2 days. Thereafter, the reaction mixture was worked up and purified in a usual manner to obtain ethyl 3-[4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl]propanoate. MS: 399.
Reaction SMILES: C(OC(=O)[N:7]([C@H:12]1[CH2:16][C@@H:15]([N:17]2[CH:25]=[N:24][C:23]3[C:18]2=[N:19][C:20]([Cl:32])=[N:21][C:22]=3[NH:26][CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29])[C@H:14]([OH:33])[C@@H:13]1[OH:34])[C:8](=[O:11])[CH2:9][CH3:10])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:32][C:20]1[N:19]=[C:18]2[C:23]([N:24]=[CH:25][N:17]2[C@@H:15]2[CH2:16][C@H:12]([NH:7][C:8](=[O:11])[CH2:9][CH3:10])[C@@H:13]([OH:34])[C@H:14]2[OH:33])=[C:22]([NH:26][CH:27]([CH2:28][CH3:29])[CH2:30][CH3:31])[N:21]=1
Reactant: CCC(=O)N(C(=O)OC(C)(C)C)[C@H]1C[C@@H](n2cnc3c(NC(CC)CC)nc(Cl)nc32)[C@H](O)[C@@H]1O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NC(CC)CC)nc(Cl)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
{(1S,2R,3S,4R)-4-[2-Chloro-6-(1-ethyl-propylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionyl-carbamic acid tert-butyl ester (300 mg, 0.59 mmol) is dissolved in dichloromethane (5 ml). TFA (2 ml) is added and the reaction mixture is stirred at room temperature. The reaction is shown to be complete by LCMS after 1 hour. The solvent is removed in vacuo and the residue is partitioned between dichloromethane (50 ml) and saturated NaHCO3 (50 ml). The organic layer is washed with water (20 ml) and brine (20 ml), dried over MgSO4, filtered and the solvent is removed in vacuo to give the title compound. 1H nmr (MeOD, 400 MHz); 8.05(s, 1H), 4.75(m, 1H), 4.60(m, 1H), 4.20(m, 2H), 4.00(m, 1H), 2.90(m, 1H), 2.40(q, 2H), 2.10(m, 1H), 1.70(m, 2H), 1.60(m, 2H), 1.20(t, 3H), 0.95(t, 6H), MS (ES+) mine 411 (MH+).
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:21][NH2:22])=[N:5][CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)#[N:2].[CH2:23](OC(OCC)OCC)C>C1(C)C(C)=CC=CC=1>[C:1]([C:3]1[C:4]2[N:5]([CH:23]=[N:22][N:21]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:10][CH2:11][CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:14]1)#[N:2]
Reactant: N#Cc1c(N2CCC(c3ccccc3)CC2)ccnc1NN
Reactant: CCOC(OCC)OCC
Solvent: Cc1ccccc1C
Product: N#Cc1c(N2CCC(c3ccccc3)CC2)ccn2cnnc12
Yield: 90.1 %

Procedure:
D7 (1 g, 3.409 mmol) and triethylorthoformate (7.577 g, 51.13 mmol) in xylene (25 ml) were heated in a sealed tube at 180° C. for 1 h. After cooling, the resulting mixture was concentrated in vacuo. The residue thus obtained was triturated with Et2O to yield compound D8 (0.932 g, 90%).
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=3)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:23][CH2:22]2)[CH2:10]1)=[O:7])(C)(C)C.[F:44][C:45]1[CH:53]=[CH:52][C:48](C(Cl)=O)=[CH:47][CH:46]=1>>[F:44][C:45]1[CH:53]=[CH:52][C:48]([C:6]([NH:8][C@H:9]2[CH2:13][C@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C@@H:11]([CH2:20][N:21]3[CH2:22][CH2:23][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]4[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=4)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:25][CH2:26]3)[CH2:10]2)=[O:7])=[CH:47][CH:46]=1
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](NC(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Reactant: O=C(Cl)c1ccc(F)cc1
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](NC(=O)c3ccc(F)cc3)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(S)-((t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 33 in Step A and 4-fluorobenzoyl chloride in Step B, the title compound was prepared.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]([NH2:17])[CH2:14][CH2:15][CH3:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29](O)=[O:30])[CH:24]=[CH:25][C:26]=1[CH3:27])[CH3:19]>>[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29]([NH:17][CH:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:14][CH2:15][CH3:16])=[O:30])[CH:24]=[CH:25][C:26]=1[CH3:27])[CH3:19]
Reactant: CCOc1cc(CC(=O)O)ccc1C
Reactant: CCCC(N)c1ccccc1N1CCCCC1
Product: CCCC(NC(=O)Cc1ccc(C)c(OCC)c1)c1ccccc1N1CCCCC1

Procedure:
Prepared from 1-(2-piperidino-phenyl)-1-butylamine and 3-ethoxy-4-methyl-phenylacetic acid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5](P(OC)(OC)=O)[NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])=[O:4].CN(C)C(N(C)C)=N.[CH3:31][C:32]1[CH:33]=[C:34]([CH:37]=[C:38]([N+:43]([O-:45])=[O:44])[C:39]=1[N+:40]([O-:42])=[O:41])[CH:35]=O>O1CCCC1>[CH3:1][O:2][C:3](/[C:5](/[NH:6][C:7](=[O:8])[O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[CH:35]/[C:34]1[CH:37]=[C:38]([N+:43]([O-:45])=[O:44])[C:39]([N+:40]([O-:42])=[O:41])=[C:32]([CH3:31])[CH:33]=1)=[O:4]
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Reactant: Cc1cc(C=O)cc([N+](=O)[O-])c1[N+](=O)[O-]
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Product: COC(=O)/C(=C/c1cc(C)c([N+](=O)[O-])c([N+](=O)[O-])c1)NC(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 61.1 %

Procedure:
To a solution of N-(benzyloxycarbonyl)-α-phophonoglycine trimethyl ester (2.4 g, 7.3 mmol) in tetrahydrofuran (40 mL) at −78° C. was added 1,1,3,3-tetramethylguanidine (729 mg, 6.33 mmol) and the mixture was stirred for 1 h at −78° C. To this mixture was added a solution of 3-methyl-4,5-dinitrobenzaldehyde (1.4 g, 6.7 mmol) in tetrahydrofuran (15 mL). The reaction mixture was allowed to slowly warm to room temperature and was then stirred for 16 h at room temperature. The solvent was evaporated and the residue subjected to flash column chromatography (gradient, 1:2 to 1:1 ethyl acetate/hexanes). The product was then recrystallized from ethyl acetate/hexanes (1:1) to give the title compound (1.7 g, 62% yield). 1H-NMR (CDCl3, 300 MHz) δ 8.01 (s, 1H), 7.55 (s, 1H), 7.33-7.22 (m, 6H), 6.94 (bs, 1H), 5.06 (s, 2H), 3.89 (s, 3H), 2.29 (s, 3H). 13C-NMR (CDCl3, 75 MHz) δ 164.7, 152.5, 143.1, 140.6, 137.7, 137.0, 135.3, 132.5, 128.8, 128.7, 128.6, 127.1, 123.5, 123.2, 68.3, 53.5, 17.4. Mass spec.: 414.20 (MH)−.
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[C:8]([NH2:9])=[C:7]([Cl:10])[CH:6]=[CH:5][C:4]=1[OH:11].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[ClH:2].[Cl:1][CH:5]1[C:6](=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]([Cl:10])=[C:8]([NH2:9])[CH:3]=[C:4]1[OH:11]
Reactant: O=Cc1ccccc1
Reactant: Nc1c(Cl)ccc(O)c1Cl
Agent: Cl
Product: NC1=C(Cl)C(=Cc2ccccc2)C(Cl)C(O)=C1

Procedure:
Analogously to the procedure and data in Examples 1 and 2, 2,4-dichloro-3-aminophenol hydrochloride was reacted with benzaldehyde. The reaction product of this example of this invention had the following characteristic data: IR-spectrum (Kbr) cm-1 : 1692, 1620, 1598, 1582, 1515, 1480, 1450, 1430, 1310, 1205, 1160, 1075, 1030, 930, 905, 890, 872, 830, 805, 745, 700, 685, 650.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:25])[C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[N:6][CH:7]=1.[CH:26]1([C:29]([CH3:31])=O)[CH2:28][CH2:27]1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:25])[C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([CH:29]([CH:26]3[CH2:28][CH2:27]3)[CH3:31])[CH2:21][CH2:20]2)=[N:6][CH:7]=1
Reactant: Cc1ccc(NCC2CCNCC2)c(C(=O)Nc2ccc(Cl)cn2)c1
Reactant: CC(=O)C1CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc(NCC2CCN(C(C)C3CC3)CC2)c(C(=O)Nc2ccc(Cl)cn2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 64 %

Procedure:
A solution of N-(5-chloropyridin-2-yl)-2-[(4-piperidinylmethyl)amino]-5-methylbenzamide from Example 204 (1.0 g, 2.78 mmol) in 6 mL of 95:5 methanol-acetic acid was treated with excess cyclopropylmethyl ketone (5.52 mL, 55.6 mmol), followed by sodium cyanoborohydride (0.65 g, 10.3 mmol). After stirring at room temperature for 24 hr, the reaction mixture was concentrated in vacuo; and the residue was subjected to silica gel chromatography. Elution with 9:1 dichloromethane-methanol afforded 0.76 g (64%) of the title compound as a yellow solid.
Reaction SMILES: [CH:1]1([O:7][N:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][CH:11]([OH:16])[CH2:10][C:9]2([CH3:18])[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19](OC)(=[O:22])[CH2:20][SH:21].[NH2-].[Li+]>C1(C)C=CC=CC=1>[C:19]([O:16][CH:11]1[CH2:10][C:9]([CH3:18])([CH3:17])[N:8]([O:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:13]([CH3:14])([CH3:15])[CH2:12]1)(=[O:22])[CH2:20][SH:21]
Reactant: CC1(C)CC(O)CC(C)(C)N1OC1CCCCC1
Reactant: COC(=O)CS
Agent: [Li+]
Agent: [NH2-]
Solvent: Cc1ccccc1
Product: CC1(C)CC(OC(=O)CS)CC(C)(C)N1OC1CCCCC1

Procedure:
1-Cyclohexyloxy-2,2,6,6-tetramethylpiperidin-4-ol a (25.5 grams, 0.1 mol) and methyl thioglycolate (10.6 grams, 0.11 mol) are dissolved in toluene. Lithium amide (0.09 mol) is added and the reaction mixture is heated under reflux and the distillate collected in a Dean-Stark trap. After heating under reflux overnight, the toluene is removed under reduced pressure. Acetic acid is added to neutralize the basic catalyst. The crude reaction product is purified by liquid chromatography to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([O:8][CH2:9][N:10]2[C:15](=[O:16])[NH:14][C:13](=[O:17])[CH2:12][NH:11]2)=[O:7])=[CH:4][CH:3]=1.C[O-].[Na+:22]>CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][N:10]2[C:15](=[O:16])[N:14]([Na:22])[C:13](=[O:17])[CH2:12][NH:11]2)=[O:7])=[CH:18][CH:19]=1
Reactant: [Na+]
Reactant: Cc1ccc(C(=O)OCN2NCC(=O)NC2=O)cc1
Agent: C[O-]
Solvent: CO
Product: Cc1ccc(C(=O)OCN2NCC(=O)N([Na])C2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-(4-Methylbenzoyloxymethyl)-3,5-dioxo-hexahydro-1,2,4-triazine (1.0 g) is dissolved in methanol (60 ml), and the mixture is added with sodium methoxide (0.21 g) and stirred at room temperature for 30 minutes. The methanol is removed in vacuo, and the resulting white crystals are thoroughly washed with ethanol to give 2-(4-methylbenzoyloxymethyl)-3,5-dioxo-4-sodio-hexahydro-1,2,4-triazine (Compound No. 74). Yield, 0.84 g (77.8%). M.P., 225°-235° C. (decomp.).
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl.[NH:7]1[C:11]([CH2:12][OH:13])=[CH:10][N:9]=[CH:8]1.[S:14](Cl)([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15]>O.C(OCC)(=O)C>[S:14]([N:7]1[C:11]([CH2:12][OH:13])=[CH:10][N:9]=[CH:8]1)([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15]
Reactant: OCc1cnc[nH]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cncc2CO)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To an ice cold solution of 0.08 mole of sodium bicarbonate in 40 ml of water is added 0.02 mole of imidazol-5-ylmethanol hydrochloride followed by a solution of 0.025 mole of tosylchloride in 30 ml of ethyl acetate. The reaction mixture is stirred at room temperature for 5 hours. The organic phase is separated, washed with sodium bicarbonate, and dried over magnesium sulfate and concentrated under reduced pressure. The residue is crystallized from ethyl acetate to afford 1-tosylimidazol-5-ylmethanol.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][O:21]C(=O)C)[C@@H:13]([O:14]C(=O)C)[C@H:8]2[O:9]C(=O)C)[C:5]2[CH:25]=[CH:26][CH:27]=[CH:28][C:4]=2[N:3]=1.[CH2:29]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][O:41][C:42]1[CH:43]=[C:44]([CH:47]=[CH:48][C:49]=1[C:50]1[CH:55]=[CH:54][CH:53]=[C:52]([S:56]([CH3:59])(=[O:58])=[O:57])[CH:51]=1)[CH:45]=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>O1CCCC1>[CH2:29]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][O:41][C:42]1[CH:43]=[C:44]([CH:47]=[CH:48][C:49]=1[C:50]1[CH:55]=[CH:54][CH:53]=[C:52]([S:56]([CH3:59])(=[O:58])=[O:57])[CH:51]=1)[CH2:45][NH:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][OH:21])[C@@H:13]([OH:14])[C@H:8]2[OH:9])[C:5]2[CH:25]=[CH:26][CH:27]=[CH:28][C:4]=2[N:3]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CS(=O)(=O)c1cccc(-c2ccc(C=O)cc2OCCCCOCc2ccccc2)c1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(N)nc3ccccc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cccc(-c2ccc(CNc3nc4ccccc4n3[C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)cc2OCCCCOCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.8 %

Procedure:
2-Amino-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-1H-benzimidazole (0.11 g) and 3-(4-benzyloxybutoxy)-4-(3-methanesulfonylphenyl)benzaldehyde (0.24 g) were suspended in tetrahydrofuran (5 mL). To the reaction mixture was added sodium triacetoxyborohydride (0.12 g), and the mixture was stirred at room temperature for 24 hours. After adding water to the reaction mixture, the mixture was concentrated under reduced pressure. The obtained residue was dissolved in methanol (2 mL). To the mixture was added 5 mol/L aqueous sodium hydroxide solution (0.5 mL), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added acetic acid (1 mL), and the mixture was concentrated under reduced pressure. The obtained residue was purified by preparative reverse phase column chromatography (Shiseido CAPSELL PAC C18UG80, 5 μm, 20×50 mm, flow rate 30 mL/minutes linear gradient, water/methanol=70/30-10/90) to give 2-[3-(4-benzyloxybutoxy)-4-(3-methanesulfonylphenyl)benzylamino]-1-(β-D-ribofuranosyl)-1H-benzimidazole (0.16 g). The obtained compound was dissolved in methanol (2 mL). To the solution was added a catalytic amount of 10% palladium-carbon powder, and the mixture was stirred at 40° C. under a hydrogen atmosphere for 24 hour. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (0.04 g).
Reaction SMILES: C(OP([CH2:9]/[C:10](/[CH3:17])=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[F:18]/[C:19](=[C:22](/[C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][C:33]=1[O:34][CH2:35][CH2:36][CH3:37])[O:30][C:29]([CH3:39])([CH3:38])[CH:28]=[C:27]2[CH:40]([CH3:42])[CH3:41])\[CH3:23])/[CH:20]=O>>[F:18]/[C:19](=[C:22](/[C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][C:33]=1[O:34][CH2:35][CH2:36][CH3:37])[O:30][C:29]([CH3:39])([CH3:38])[CH:28]=[C:27]2[CH:40]([CH3:41])[CH3:42])\[CH3:23])/[CH:20]=[CH:9]/[C:10](/[CH3:17])=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCCOc1cc2c(cc1/C(C)=C(/F)C=O)C(C(C)C)=CC(C)(C)O2
Reactant: CCOC(=O)/C=C(\C)CP(=O)(OCC)OCC
Product: CCCOc1cc2c(cc1/C(C)=C(F)\C=C\C(C)=C\C(=O)OCC)C(C(C)C)=CC(C)(C)O2

Procedure:
Following General Procedure O, ethyl 4-(diethoxyphosphoryl)-3-methyl-but-2E-enoate (159 mg, 0.60 mmol) and (2E)-2-fluoro-3-(4-isopropyl-2,2-dimethyl-7-propoxy-2H-chromen-6-yl)but-2-enal (Compound 99, 72 mg, 0.21 mmol) were reacted to give the title compound as a yellow oil after purification by flash chromatography (silica gel, 5% ethyl acetate in hexane).
Reaction SMILES: [C:1]12([NH:11][C:12]#[N:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[ClH:14].[I:15][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18]>>[ClH:14].[C:1]12([NH:11][C:12]([NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[I:15])=[NH:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: N#CNC12CC3CC(CC(C3)C1)C2
Reactant: Nc1ccccc1I
Agent: Cl
Product: N=C(Nc1ccccc1I)NC12CC3CC(CC(C3)C1)C2
Yield: 4.2 %

Procedure:
Adamantan-1-ylcyanamide (299 mg, 1.70 mmol) and o-iodoaniline hydrochloride (433 mg 1.70 mmol) were finely ground together and heated at 200° for 10 min. The resultant black glassy solid was pulverized, and recrystallized 5 times from EtOH/Et2O. The resultant faintly blue needles (80 mg) were dissolved in 4 ml EtOH, and passed through a short (<1 cm) column packed from bottom to top with Celite, charcoal, activated alumina, and sand. The colorless eluate was then diluted with 5ml Et2O, and allowed to stand in an Et2O diffusion chamber overnight. The white needles were collected by suction filtration, 40 mg, mp 274°-275° C. Addition of another 5 ml Et2O yielded a second crop (31 mg) of identical material. Combined yield: 21%. 1H (CD3OD) 1.779 (s, 6H), 2.090 (s, 6H), 2.164 (s, 3H), 7.168 (t, 1 H, J=8.1 Hz), 7.388 (d, 1H, J=9.1 Hz), 7.503 (t, 1H, J=7.8 Hz), 8.004 (d, 1H, J=7.8 Hz).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[CH:9]=[N:10][NH:11][C:3]=12.[C:12](O)([C:14](F)(F)F)=O>N1CCCCC1>[CH3:8][C:6]1[N:5]=[C:4]2[CH:9]=[N:10][NH:11][C:3]2=[C:2]([N:5]2[CH2:14][CH2:12][CH2:2][CH2:3][CH2:4]2)[CH:7]=1
Reactant: Cc1cc(Cl)c2[nH]ncc2n1
Reactant: O=C(O)C(F)(F)F
Solvent: C1CCNCC1
Product: Cc1cc(N2CCCCC2)c2[nH]ncc2n1

Procedure:
7-Chloro-5-methyl-1H-pyrazolo(4,3-b)pyridine (1 g) and piperidine (10 ml) were heated under reflux for 24 h. The piperidine was removed in vacuo to yield a pale yellow solid which was washed with water to yield the piperidino-compound (1 g, 78%), Crystallisation from ethanol-water gave pale yellow crystals, m.p. 244°. Found: C, 66.5; H, 7.55.; N, 25.7. C12H16N4 requires C, 66.6; H, 7.5; N, 25.9%), νmax 2660-2200 (broad), 2000-1800 (broad), 1540, 1430, 1355, 1290, 1210, 1020, 980, 810 and 760 cm-1, δ (CF3COOH) 1.97 (6H, s, --CH2 --), 2.70 (3H, s, 5 --CH3), 4.13 (4H, s, --N--CH2 --), 6.59 (1H, s, 6-H), 8.32 (1H, s, 3-H), total proton count 15.
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[N:5]=[C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15](=[O:27])[CH2:16][N:17]3[C:21]([CH3:22])=[CH:20][C:19]([C:23]([F:26])([F:25])[F:24])=[N:18]3)[CH2:11][CH2:10]2)[S:7][CH:8]=1.[C:28]1([C:34]#[CH:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl[O-].[Na+]>O1CCCC1>[CH3:22][C:21]1[N:17]([CH2:16][C:15]([N:12]2[CH2:13][CH2:14][CH:9]([C:6]3[S:7][CH:8]=[C:4]([C:3]4[CH:35]=[C:34]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[O:1][N:2]=4)[N:5]=3)[CH2:10][CH2:11]2)=[O:27])[N:18]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:20]=1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C=NO)cs2)CC1
Reactant: C#Cc1ccccc1
Agent: [Na+]
Agent: [O-]Cl
Solvent: C1CCOC1
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(-c3cc(-c4ccccc4)on3)cs2)CC1

Procedure:
4-[4-[(Hydroxyimino)methyl]-2-thiazolyl]-1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]piperidine (i.e. the product of Example 2, Step C) (0.2 g, 0.5 mmol) was suspended in tetrahydrofuran (20 mL), and phenylacetylene (1.1 mL, 1 mmol) was added, followed by a slow dropwise addition of Clorox® bleach solution (6.15 wt. % sodium hypochlorite, 10 mL) over 1 h. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine, dried (MgSO4) and concentrated under reduced pressure to give an oil, which was purified by flash column chromatography on silica gel using 10% methanol in ethyl acetate as eluant to give 70 mg of the title product, a compound of present invention, as a clear yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.COC1C=CC=CC=1N[C:19](=[O:24])[CH2:20][C:21]([OH:23])=[O:22]>>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:19](=[O:24])[CH2:20][C:21]([OH:23])=[O:22])=[CH:5][CH:4]=1
Reactant: COc1ccccc1NC(=O)CC(=O)O
Reactant: COc1ccc(N)cc1
Product: COc1ccc(NC(=O)CC(=O)O)cc1
Yield: 56 %

Procedure:
Starting from 4-methoxyaniline and following the procedure described above for the synthesis of compound 27 (example 8, scheme 8), title compound 157 was obtained in 56% yield. MS (m/z): 210.0 (M+H).