Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].[CH2:5]([Mg]Br)[CH3:6].[CH3:9][C:10]1([CH3:26])[N:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:13]([C:22]([O:24]C)=O)[CH2:12][O:11]1.[CH2:27]1COC[CH2:28]1>>[OH:24][C:22]([C@H:13]1[CH2:12][O:11][C:10]([CH3:9])([CH3:26])[N:14]1[C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])([CH2:5][CH3:6])[CH2:27][CH3:28]
Reactant: COC(=O)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Reactant: CC[Mg]Br
Reactant: C1CCOC1
Agent: [Ce+3]
Agent: [Cl-]
Product: CCC(O)(CC)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
A suspension of cerium (III) chloride (119 g, 482.07 mmol) in THF (350 mL) at room temperature was stirred vigorously for 2 hours. The suspension was cooled to −78° C. and ethylmagnesium bromide (482 mL, 482.07 mmol) was added dropwise. The mixture was stirred at −78° C. for 1.5 hours. (R)-3-tert-butyl 4-methyl 2,2-dimethyloxazolidine-3,4-dicarboxylate (Aldrich, 25 g, 96.41 mmol) in THF (100 mL) was then added dropwise at −78° C. The reaction was stirred at −78° C. for 30 minutes and then warmed to 0° C. for 15 minutes. The reaction was quenched with saturated NH4Cl, diluted further with water and extracted twice with ether. The organics were dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%-20% ethyl acetate/hexanes) afforded the title compound (26.4 g, 95%) as a colorless oil.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[C:4](=[O:34])[CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C(OC([N:52]1[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[C:54]([CH2:61]Br)=[N:53]1)=O)(C)(C)C>CN(C=O)C.C1COCC1>[NH:52]1[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[C:54]([CH2:61][CH:3]2[C:2](=[O:1])[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]3[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)=[O:11])[C:7]3[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=3[N:5]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[C:4]2=[O:34])=[N:53]1
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2ccccc21
Reactant: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3ccccn3)c3ccccc32)C(C)C)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3n[nH]c4ccccc34)C(=O)N(c3ccccn3)c3ccccc32)C(C)C)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 50.7 %

Procedure:
A solution of 0.35 g (0.77 mmol, 1.0 equiv) of 2-(2,4-dioxo-5-pyrid-2-yl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl) acetamide, prepared as in Intermediate 36, in 7 mL of DMF is cooled in an ice/water bath. 0.85 mL (0.84 mmol, 1.1 equiv) of 1M NaN(TMS)2 in THF is added and the solution stirred at 0° C. for 10 min. A solution of 0.26 g (0.84 mmol, 1.1 equiv) of N-tert-butoxycarbonyl-3-bromomethyl-indazole in 3 mL of DMF is added and the resulting yellow solution stirred at RT for 1 h. The reaction is quenched with H2O, extracted with EtOAc (×3), washed with H2O (×2) and brine, dried over MgSO4 and concentrated to a brown oil. Purification by silica gel flash chromatography using EtOAc/hexane 1/1 as eluent followed by Si60 MPLC using EtOAc/hexane 1/1 as eluent gave 0.23 g of a white powder; low resolution MS (FAB) 689 (MH+). A portion of this compound is dissolved in 4N HCl in dioxane and stirred at 0° C. for 30 min, and then concentrated to a white foam. Purification by RP-18 MPLC using MeCN/H2O 3/2 containing 0.1% HCl as eluent gave 33 mg of the title compound HCl salt as an amorphous white powder: 1H NMR (d6 -DMSO, 400 MHz) δ8.47 (d, 1H, J=3.5), 8.0-7.0 (m, 15H), 4.79 (m,1H), 4.20 (m, 2H), 3.79 (s, 3H), 3.51 (dd, 1H, J=7, 15), 3.39 (dd, 1H, J=5, 15), 0.97 (dd, 6H, J=7, 14); low resolution MS (FAB)m/e 589 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:12][CH2:11][CH:10]([CH2:13][O:14][CH3:15])[O:9]2)=[CH:4][CH:3]=1.[Br:16][CH:17]([CH2:21][Br:22])[C:18](Cl)=[O:19].[OH-].[Na+]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:18](=[O:19])[CH:17]([Br:16])[CH2:21][Br:22])[NH:12][CH2:11][CH:10]([CH2:13][O:14][CH3:15])[O:9]2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)C(Br)CBr
Reactant: COCC1CNC(c2ccc(Cl)cc2)O1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: COCC1CNC(C(=O)C(Br)CBr)(c2ccc(Cl)cc2)O1

Procedure:
To 20.8 milliliters of 25 percent w/v, p-chlorophenyl-5-methoxymethyl oxazolidine solution in 50 milliliters of benzene was added 5 grams of 2,3-dibromopropionyl chloride. To this solution was added 1.6 grams of 50% sodium hydroxide. After washing with water, drying and removal of the benzene in vacuo, there was obtained 4.8 grams of the title compound, nD30 1.5478. Analytical data supports the structure.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:20].[Cl:21][C:22]1[C:23]([NH:31][CH2:32][CH2:33][OH:34])=[N:24][CH:25]=[C:26]([CH:30]=1)[C:27](O)=[O:28]>>[Cl:21][C:22]1[C:23]([NH:31][CH2:32][CH2:33][OH:34])=[N:24][CH:25]=[C:26]([CH:30]=1)[C:27]([NH:20][C:3]1[CH:4]=[CH:5][C:6]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[CH2:9]2)=[CH:7][C:2]=1[CH3:1])=[O:28]
Reactant: O=C(O)c1cnc(NCCO)c(Cl)c1
Reactant: Cc1cc(N2CCC(CN3CCCC3C)C2)ccc1N
Product: Cc1cc(N2CCC(CN3CCCC3C)C2)ccc1NC(=O)c1cnc(NCCO)c(Cl)c1

Procedure:
The title compound was prepared in a manner substantially the same as Example 1 by coupling 2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenylamine with 5-chloro-6-(2-hydroxy-ethylamino)-nicotinic acid. MS: 472.3 (M+H).
Reaction SMILES: [CH:1]1[C:6]([CH:7]=O)=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.[N+:12]([CH3:15])([O-:14])=[O:13].[OH-].[Na+]>CO.O>[CH2:10]1[O:11][C:3]2[CH:2]=[CH:1][C:6]([CH:7]=[CH:15][N+:12]([O-:14])=[O:13])=[CH:5][C:4]=2[O:9]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: C[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=[N+]([O-])C=Cc1ccc2c(c1)OCO2
Temperature: 4 °C
Reaction time: 0.5 h

Procedure:
In a 45-L cryogenic reactor with a contoured, anchor stirrer was dissolved 5.537 kg (36.9 moles) piperonal in 9 L methanol and 2.252 kg (36.9 moles) nitromethane at 15°-20° C. The jacket temperature was set to −5° C. and the reaction solution cooled to a temperature of +3.5° C. A 21° C. solution of 3.10 kg (38.8 moles) 50% (w:w) aquous sodium hydroxide diluted with 3.7 L water was pumped in. The reaction temperature was maintained between 10°-15° C. When addition was complete, the jacket temperature was reset to 1° C. and stirring continued for 30 minutes. A mixture of 7 kg ice in 19 L water was added to dissolve most of the solid. The reaction mixture was filtered through canvas and then a 27R10SV Honeycomb filter. The filtered solution was metered into a 21° C. mixture of 7.4 L concentrated hydrochloric acid in 11.1 L deionized water. The final reaction temperature was 26° C. The resulting product was centrifuged and washed until the wash pH rose to at least 6 (by pH indicating paper). The crude product was dissolved in 92 L dichloromethane and the layers separated. The aqueous layer was washed once with 8 L dichloromethane. The combined organics were dried over 1.32 kg magnesium sulfate and filtered through Whatman #1 paper. The volume was reduced to 20% and the solution cooled to 4° C. Filtration through Whatman #1 paper, followed by ambient temperature drying in vacuo with an air leak afforded 1.584 kg (22%) of a first crop Concentration of the MLS to 25% followed by similar cooling, filtration, and drying afforded 0.262 kg (4%) of a second crop. The yellow product darkened on standing in light and air.
Reaction SMILES: C(O[C:4](=[O:32])[CH2:5][N:6]([CH2:17][CH2:18][CH2:19][N:20]([CH2:22][C:23]1[CH:31]=[CH:30][C:26]2[O:27][CH2:28][O:29][C:25]=2[CH:24]=1)[CH3:21])[C:7]1[S:11][N:10]=[C:9]([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)[N:8]=1)C.[NH3:33]>>[O:27]1[C:26]2[CH:30]=[CH:31][C:23]([CH2:22][N:20]([CH3:21])[CH2:19][CH2:18][CH2:17][N:6]([C:7]3[S:11][N:10]=[C:9]([N:12]4[CH:16]=[CH:15][N:14]=[CH:13]4)[N:8]=3)[CH2:5][C:4]([NH2:33])=[O:32])=[CH:24][C:25]=2[O:29][CH2:28]1
Reactant: N
Reactant: CCOC(=O)CN(CCCN(C)Cc1ccc2c(c1)OCO2)c1nc(-n2ccnc2)ns1
Product: CN(CCCN(CC(N)=O)c1nc(-n2ccnc2)ns1)Cc1ccc2c(c1)OCO2

Procedure:
2-[[3-(Benzo[1,3]dioxol-5-ylmethyl-methyl-amino)-propyl]-(3-imidazol-1-yl-[1,2,4]thiadiazol-5-yl)-amino]-acetamide was prepared following the procedures described in the preparation of Example 56 using [[3-(benzo[1,3]dioxol-5-ylmethyl-methyl-amino)-propyl]-(3-imidazol-1-yl-[1,2,4]thiadiazol-5-yl)-amino]-acetic acid ethyl ester and NH3. [M+H]+ 429.87; 1H NMR (400 MHz, d6-DMSO) δ 8.24 (s, 1H), 7.68 (s, 1H), 7.54 (br s, 1H), 7.18 (br s, 1H), 7.06 (s, 1H), 6.86-6.70 (m, 3H), 5.98 (s, 2H), 3.45-3.35 (m, 4H), 3.31 (s, 2H), 2.36 (m, 2H), 2.10 (s, 3H), 1.72 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:23][CH:24]([NH:38][S:39]([C:42]2[C:43]3[CH:44]=[CH:45][N:46]=[CH:47][C:48]=3[CH:49]=[CH:50][CH:51]=2)(=[O:41])=[O:40])[CH2:25][N:26]2[CH2:31][CH2:30][N:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:28][CH2:27]2)[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:54]I.[Cl-].[Na+]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:23][CH:24]([N:38]([CH3:54])[S:39]([C:42]2[C:43]3[CH:44]=[CH:45][N:46]=[CH:47][C:48]=3[CH:49]=[CH:50][CH:51]=2)(=[O:41])=[O:40])[CH2:25][N:26]2[CH2:27][CH2:28][N:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:30][CH2:31]2)[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: O=S(=O)(NC(Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)CN1CCN(c2ccccc2)CC1)c1cccc2cnccc12
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)CN1CCN(c2ccccc2)CC1)S(=O)(=O)c1cccc2cnccc12
Reaction time: 2 h

Procedure:
470 mg of the amorphous compound obtained in Example 5 was dissolved in 8 ml of dimethylformamide, and to the solution were sequentially added 30 mg of 60% sodium hydride and 0.1 ml of methyl iodide with ice cooling, and after stirring for two hours with ice cooling was added saturated sodium chloride, and the mixture was extracted with 50 ml of ethyl acetate. The extract was washed with saturated sodium chloride aqueous solution, dried over magnesium sulfate and concentrated under a reduced pressure to obtain a residue, which was then applied to a silica gel column and eluted with hexane/ethyl acetate (1:1) to obtain 413 mg of the title compound in a colorless amorphous form.
Reaction SMILES: Cl.N([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]3[N:21]=[CH:20][NH:19][C:17]3=2)[N:12]=[C:11]([CH3:22])[CH:10]=1)C1C=CC=CC=1.[Cl:23][C:24]1[C:30]([O:31][CH3:32])=[CH:29][C:27]([NH2:28])=[C:26](OC)[CH:25]=1.[CH2:35]([OH:37])C>>[ClH:23].[Cl:23][C:24]1([O:37][CH3:35])[C:30]([O:31][CH3:32])=[CH:29][C:27]([NH:28][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]4[N:21]=[CH:20][NH:19][C:17]4=3)[N:12]=[C:11]([CH3:22])[CH:10]=2)=[CH:26][CH2:25]1
Reactant: COc1cc(Cl)c(OC)cc1N
Reactant: CCO
Reactant: Cc1cc(Nc2ccccc2)c2c(ccc3nc[nH]c32)n1
Agent: Cl
Product: COC1=CC(Nc2cc(C)nc3ccc4nc[nH]c4c23)=CCC1(Cl)OC
Reaction time: 8 h

Procedure:
A mixture of 18.5 (0.085 m.) of the compound of Example I, C., 16 g. (0.085 m.) of 4-chloro-2,5-dimethoxyaniline and 250 ml. of ethanol was refluxed with stirring overnight. The solution was concentrated to dryness in vacuo. The crude product was recrystallized from 1000 ml. of MeOH to give 21.5 g., m.p. 274°-277°C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][NH2:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:14][C:15]1[C:16]([CH:21]=O)=[N:17][CH:18]=[CH:19][CH:20]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][NH:13][CH2:21][C:16]2[C:15]([CH3:14])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccnc1C=O
Reactant: CC(C)(C)OC(=O)N1CC(CN)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccnc1CNCC1CN(C(=O)OC(C)(C)C)C1

Procedure:
Using General Procedure B: Reaction of 3-aminomethyl-azetidine-1-carboxylic acid tert-butyl ester (Falgueyret, J.-P. et al. J. Med. Chem. 2001, 44, 94-104) in CH2Cl2 with 3-methyl-pyridine-2-carbaldehyde and NaBH(OAc)3 gave 3-{[(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-azetidine-1-carboxylic acid tert-butyl ester as a yellow oil. 1H NMR (CDCl3) δ 1.44 (s, 9H), 2.30 (s, 3H), 2.66-2.75 (m, 1H), 2.92 (d, 2H, J=6.0 Hz), 3.61-3.66 (m, 2H), 3.88 (s, 2H), 4.02 (t, 2H, J=9.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[CH3:12][CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14]1>C(O)CCC>[CH3:12][C:13]1[N:14]([C:4]2[N:3]=[C:2]([Cl:1])[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][NH:8]3)[C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: CC1Cc2ccccc2N1
Solvent: CCCCO
Product: Cc1cc2ccccc2n1-c1nc(Cl)nc2[nH]cnc12
Temperature: 130 °C
Yield: 61.3 %

Procedure:
The same procedure as in stage 1 of Example 1 is carried out, mixing 189 mg of 2,6-dichloropurine, 5 ml of butanol and 0.16 g of 2-methylindoline. The mixture is heated at 130° C. for approximately 1 hour and allowed to return to ambient temperature. Partial drying is carried out, followed by washing with isopropanol. The product is dried and 174 mg of expected product are thus obtained.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:10]#[C:11][C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=2[CH3:21])[C:15]([OH:17])=O)[N:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=12.CN1CCOCC1.C(Cl)(=O)C(Cl)=O.[N:35]1([C:40]2[CH:41]=[C:42]([CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=2)[NH2:43])[CH:39]=[CH:38][N:37]=[CH:36]1.NC1C=CC=CC=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[N:35]1([C:40]2[CH:41]=[C:42]([NH:43][C:15](=[O:17])[C:14]3[CH:18]=[CH:19][C:20]([CH3:21])=[C:12]([C:11]#[C:10][C:3]4[N:4]5[CH:9]=[CH:8][N:7]=[CH:6][C:5]5=[N:1][CH:2]=4)[CH:13]=3)[CH:44]=[C:45]([C:47]([F:49])([F:50])[F:48])[CH:46]=2)[CH:39]=[CH:38][N:37]=[CH:36]1
Reactant: Cc1ccc(C(=O)O)cc1C#Cc1cnc2cnccn12
Reactant: Nc1cc(-n2ccnc2)cc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: Nc1ccccc1
Product: Cc1ccc(C(=O)Nc2cc(-n3ccnc3)cc(C(F)(F)F)c2)cc1C#Cc1cnc2cnccn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-(imidazo[1,2-a]pyrazin-3-ylethynyl)-4-methylbenzoic acid (18 mmol) is dissolved in methylene chloride (100 mL). To this solution is added 3 equivalents of 4-methylmorpholine (NMM) followed by 1.05 equivalents of oxalyl chloride. After stirring at ambient temperature for 30 minutes, 0.8 equivalents of 3-(1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (prepared as above) is added along with 5 mole % of DMAP. After initially stirring at ambient temperature, the mixture is brought to reflux and stirred overnight. After 16 h an additional 0.2 equivalents of the aniline is added, bringing the total charge to 1 equivalent. The mixture can then be stirred for an additional 2 h, quenched with water, and the layers separated. The aqueous layer can be extracted with methylene chloride (2×50 mL) and the combined extracts can be washed with water. The combined methylene chloride layers can then be evaporated and the residue dissolved in 100 mL of ethyl acetate (20 mL). After standing for 1 h, the product is allowed to crystallize. The mixture is cooled, e.g. to 0° C., filtered, and the solid product is washed with cold ethyl acetate.
Reaction SMILES: Cl[Si](Cl)(C)C.[O:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([S:17](Cl)(=O)=O)[CH:15]=2)[CH2:10][CH2:9][NH:8]1.CN1CCN(C)C1=O>ClCCCl.[Zn]>[SH:17][C:14]1[CH:15]=[C:16]2[C:11]([CH2:10][CH2:9][NH:8][C:7]2=[O:6])=[CH:12][CH:13]=1
Reactant: O=C1NCCc2ccc(S(=O)(=O)Cl)cc21
Agent: C[Si](C)(Cl)Cl
Agent: [Zn]
Solvent: ClCCCl
Solvent: CN1CCN(C)C1=O
Product: O=C1NCCc2ccc(S)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a zinc powder (2.79 g, 42.7 mmol) and Dichlorodimethylsilane (5.15 mL, 42.7 mmol) in DCE (45 mL) is added a solution of 1-Oxo-1,2,3,4-tetrahydro-isoquinoline-7-sulfonyl chloride (3 g, 12.2 mmol) and 1,3-dimethylimidazolidin-2-one (3.96 mL, 36.6 mmol) in DCE (5 mL). After stirring at rt during 2 h, the mixture is concentrated.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[CH:13]([C:15]1[NH:19][C:18]([CH3:20])=[C:17]([C:21]([OH:23])=O)[C:16]=1[CH3:24])=[O:14].ON1C2C=CC=CC=2N=N1.[CH2:35]([N:37]1[CH2:41][CH2:40][CH2:39][CH:38]1[CH2:42][NH2:43])[CH3:36]>O.CN(C=O)C.C(N(CC)CC)C>[CH2:35]([N:37]1[CH2:41][CH2:40][CH2:39][CH:38]1[CH2:42][NH:43][C:21]([C:17]1[C:16]([CH3:24])=[C:15]([CH:13]=[O:14])[NH:19][C:18]=1[CH3:20])=[O:23])[CH3:36]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)O
Reactant: CCN1CCCC1CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCN1CCCC1CNC(=O)c1c(C)[nH]c(C=O)c1C
Temperature: 0 °C
Yield: 47.6 %

Procedure:
1-Ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (268.1 g, 1.4 mol), triethylamine (280.0 mL), 5-formyl-2,4-dimethyl-1H-pyrrole-3-formic acid (167.0 g, 1.0 mol) and 1-hydroxybenzotriazole (189.2 g, 1.4 mol) were added to DMF (500 mL) with stirring at about 0° C. and allowed to stir for 1.5 hrs, and then (1-ethylpyrrolidin-2-yl)methylamine (1.2 mol) was added. The reaction was stirred at room temperature until completion was indicated by thin layer chromatography (TLC). 120 mL of water and 100 mL of saturated salt water were added, and the mixture was extracted with 10% methanol/dichloromethane (300 mL×3). The combined organic phase was washed with saturated salt water (300 mL×3), dried over anhydrous Na2SO4, and the solvent was distilled off under reduced pressure. The residue was chromatographed on silica gel (eluted with methanol/ethyl acetate=1/1) to afford 131.86 g (476 mmol) of N-[(1-ethylpyrrolidin-2-yl) methyl]-5-formyl-2,4-dimethyl-1H-pyrrole-3-formamide as an off-white solid. Yield 47.6%, m.p. 166-169° C.
Reaction SMILES: [O:1]([CH2:8][C@H:9]([NH2:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:20][C@@H:21]1[C@H:25]([O:26]C(=O)C2C=CC=CC=2)[C@@H:24]([CH2:35][O:36]C(=O)C2C=CC=CC=2)[O:23][C@H:22]1[N:45]1[CH:53]=[N:52][C:51]2[C:46]1=[N:47][C:48]([Cl:55])=[N:49][C:50]=2Cl)(=O)C1C=CC=CC=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[Cl:55][C:48]1[N:49]=[C:50]([NH:11][C@H:9]([CH3:10])[CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:51]2[N:52]=[CH:53][N:45]([C:46]=2[N:47]=1)[C@@H:22]1[O:23][C@H:24]([CH2:35][OH:36])[C@@H:25]([OH:26])[C@H:21]1[OH:20]
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reactant: C[C@@H](N)COc1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](COc1ccccc1)Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.5 %

Procedure:
(R)-1-phenoxy-2-propylamine (4.3 g, 23 mmol) was reacted with 9-(2,3,5-tri- O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (11.2 g, 18 mmol) in dioxan (150 ml) in the presence of diisopropylethylamine (5.3 g, 41 mmol). The reaction mixture was stirred at room temperature for 18 h, heated at 50° C. for 4 h, and stirred at room temperature for 60 h before being filtered and evaporated. The product (after purification by flash chromatography) was debenzoylated with methanolic ammonia to provide the title 2-chloro- N-[(R)-1-phenoxy-2-propyl]adenosine (after column chromatography) as a foam (4.2 g, 64%), 1H NMR (DMSO-d6)δ 1.31 (3H, d, --CH3), 3.52-3.59 (1H, m, H-5'a), 3.63-3.72 (1H, m, H-5'b), 3.92-3.99 and 4.10-4.21 (4H, 2 m, H-3', H-4' and --CH2 --), 4.52 (1H, dd, H-2'), 4.65 (1H, m, --CH3C H--), 5.07 (1H, t, 5'-OH), 5.22, 5.49 (2H, 2d, 2' and 3'-OH), 5.84 (1H, d, H-1 '), 6.88-7.02 (3H, m, Ar--H), 7.24-7.33 (2H, dd, Ar--H), 8.32-8.45 (2H, s & m, H-8 and N--H).
Reaction SMILES: [CH3:1][C:2]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[N:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:3]=1.[H-].[Na+].I[CH3:25].[OH-].[Na+]>CN(C)C=O.O>[CH3:1][C:2]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]([CH3:25])[C:5]=2[N:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:3]=1
Reactant: CI
Reactant: Cc1nn(-c2ccccn2)c2[nH]c3ccccc3c(=O)c12
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nn(-c2ccccn2)c2c1c(=O)c1ccccc1n2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.5 %

Procedure:
To an ice-cold solution of 3-methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one (1.11 g, 4.0 mmol) in N,N-dimethylformamide (16 mL), sodium hydride (oiliness, content 60%, 0.19 g, 4.8 mmol) was added and the mixture was stirred at room temperature for 1 hour. Subsequently, iodomethane (2.5 mL, 40.2 mmol) was added thereto at 0° C., and the mixture was stirred at room temperature for additional 16 hours. To the mixture was added iced water, and the mixture was made basic by the addition of an aqueous sodium hydroxide solution, and the organic matter was extracted with chloroform. The extract was washed with saturated brine and water, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by basic silica gel column chromatography (hexane:ethyl acetate:chloroform=3:1:1) to give the title compound (0.47 g, 40% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2].C(Cl)(Cl)Cl.[CH3:16][C:17]([CH3:22])([CH3:21])[C:18](O)=O>>[C:17]([C:22]1[NH:11][C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][C:7]=2[N:10]=1)([CH3:21])([CH3:18])[CH3:16]
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Reactant: CC(C)(C)C(=O)O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1nc2ccc([N+](=O)[O-])cc2[nH]1
Yield: 77 %

Procedure:
A solution of 4-nitro-1,2-phenylenediamine (2.0 g, 13 mmol) in 10 ml of trimethylacetic acid was stirred at reflux for 12 h. Reaction mixture was concentrated in vacuo to yield a oil which was subjected to column chromatography (CHCl3, neat) to yield 2.2 g (10 mmol, 77%) of 2-tert-butyl-5-nitrobenzimidazole. The nitrobenzimidazole and 0.5 g of 10% Pd-C were dissolved in 100 ml of MeOH and stirred for 12 h under H2. The reaction mixture was filtered and concentrated in vacuo to provide 1.9 g (10 mmol, >95%) of the desired product.