Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CN=C1.[OH:6][C@H:7]([CH2:14][I:15])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[Na+].[I-].[C:18]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])([CH3:20])[CH3:19].[O-]S([O-])(=S)=O.[Na+].[Na+]>CN(C=O)C.O>[Si:22]([O:6][C@H:7]([CH2:14][I:15])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)C[C@H](O)CI
Agent: O=S([O-])([O-])=S
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C[C@@H](CI)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 87.1 %

Procedure:
To a solution of imidazole (252.3 g, 7.36 mol) in dry DMF (7.6 L) are added ethyl 3(S)-hydroxy-4-iodobutyrate (2) (949.6 g, 3.68 mol, GC purity 85.9%) and anhydrous NaI (1106 g, 7.36 mol) under argon atmosphere at ambient temperature. The suspension is cooled to 0° C. and tert-butyl(chloro)dimethylsilane (838 g, 5.56 mol) is added portionwise. The reaction mixture is stirred at 0° C. for 1.5 hours followed by stirring for 15.5 hours from 0° C. to ambient temperature. Then the mixture is cooled to 0° C. and H2O (4.2 L) is added. After 2 hours of stirring additional amount of H2O (6.2 L) and saturated Na2S2O3 solution (0.5 L) are added. The product is extracted with t-BuMeO. The combined organic layers are washed with water and dried (MgSO4). Ether is removed completely under the reduced pressure (20 mbar) at 60° C. to produce a yellow oily residue. This residue is purified further by vacuum distillation (80-89° C. at 0.150-0.310 mbar) to give 1193.5 g (97%) of ethyl 3(S)-(tert-butyldimethylsilyloxy)-4-iodobutyrate (3) as a pale yellow oil (GC purity 96.1%). 1H NMR (300 MHz, CDCl3): δ 4.13 (qd, J=7.2 and 2.1 Hz, 2H), 4.01 (m, 1H), 3.28 (dd, J=10.2 and 4.2 Hz, 1H), 3.24 (dd, J=10.2 and 6.0 Hz, 1H), 2.66 (dd, J=15.3 and 4.8 Hz, 1H), 2.51 (dd, J=15.3 and 7.2 Hz, 1H), 1.26 (t, J=7.2 Hz, 3H), 0.87 (s, 9H), 0.10 (s, 3H), 0.05 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 170.8, 68.3, 60.5, 42.5, 25.6, 17.9, 14.1, 12.9, −4.6, −5.0.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17](O)=[O:18])[N:14]=[N:13]2)=[C:8]([O:20][CH2:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=1)=[O:5])[CH3:2].[CH3:30][O:31][CH2:32][CH2:33][NH2:34].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.O.C(N(CC)CC)C>[CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]([NH:34][CH2:33][CH2:32][O:31][CH3:30])=[O:18])[N:14]=[N:13]2)=[C:8]([O:20][CH2:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)c1ccc(-n2cc(C(=O)O)nn2)c(OCCCc2ccccc2)c1
Reactant: COCCN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(-n2cc(C(=O)NCCOC)nn2)c(OCCCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of 1-{4-[(ethylamino)carbonyl]-2-(3-phenylpropoxy)phenyl}-1H-1,2,3-triazole-4-carboxylic acid (0.14 g) obtained in Example 133e) in DMF (4 ml) were successively added 2-methoxyethylamine (0.04 ml), triethylamine (0.06 ml), HOBt (0.07 g) and WSC (0.08 g), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture and the deposited precipitate was collected by filtration, washed with water, and recrystallized from ethanol-water to give the title compound as a white powder (0.14 g, 86%).
Reaction SMILES: C(N(CC)CC)C.N1C2C(=NC=CC=2)N(O)N=1.C(Cl)CCl.Cl.[NH2:23][C@H:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[OH:29].[N:30]1[N:31]([C:35]2[CH:43]=[CH:42][CH:41]=[CH:40][C:36]=2[C:37](O)=[O:38])[N:32]=[CH:33][CH:34]=1>C(Cl)Cl>[OH:29][C@@H:25]1[CH2:26][CH2:27][CH2:28][C@@H:24]1[NH:23][C:37](=[O:38])[C:36]1[CH:40]=[CH:41][CH:42]=[CH:43][C:35]=1[N:31]1[N:32]=[CH:33][CH:34]=[N:30]1
Reactant: N[C@H]1CCC[C@H]1O
Reactant: O=C(O)c1ccccc1-n1nccn1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(N[C@H]1CCC[C@H]1O)c1ccccc1-n1nccn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Triethylamine (1.52 ml, 10.90 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (0.59 g, 4.36 mmol) and EDC (0.84 g, 4.36 mmol) were added to a solution of (1R,2S)-2-aminocyclopentan-1-ol hydrochloride (CAS number 137254-03-6; 0.50 g, 3.63 mmol) and 2-(2H-1,2,3-triazol-2-yl)benzoic acid (CAS number 1001401-62-2; 0.76 g, 4.00 mmol) in DCM (10 ml). The reaction was stirred at room temperature for 18 hours and then diluted with DCM (50 ml) and washed with a saturated solution of sodium bicarbonate (2×20 ml). The crude product was purified by column chromatography (silica, 0-100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][N:7]([C@@H:52]([CH3:60])[CH:53]([O:57][CH2:58][CH3:59])[O:54][CH2:55][CH3:56])[C:8](=[O:51])[C@@H:9]([NH:33]C(=O)OCC2C3C=CC=CC=3C3C2=CC=CC=3)[CH2:10][C:11](=[O:32])[NH:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:3]2[CH:61]=[CH:62][CH:63]=[CH:64][C:2]1=2.N1CCCCC1.CC(=O)OCC.CO>C(Cl)Cl>[NH2:33][C@@H:9]([CH2:10][C:11]([NH:12][C:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:32])[C:8]([N:7]([CH2:6][C:4]1[C:3]2[CH:61]=[CH:62][CH:63]=[CH:64][C:2]=2[S:1][CH:5]=1)[C@@H:52]([CH3:60])[CH:53]([O:54][CH2:55][CH3:56])[O:57][CH2:58][CH3:59])=[O:51]
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@@H](N)CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 86.1 %

Procedure:
(9H-Fluoren-9-yl)methyl (S)-1-((benzo[b]thiophen-3-ylmethyl)((S)-1,1-diethoxypropan-2-yl)amino)-1,4-dioxo-4-(tritylamino)butan-2-ylcarbamate (Compound III-21) 23.5 g (27 mmol) and piperidine 22.7 g (270 mmol) were added in DCM (90 ml). The mixture was stirred for 1.5 h at room temperature. The mixture was diluted with DCM (200 ml) and washed with water (150 ml×3). The solution was concentrated in vacuo. The residue was purified by column chromatography on silica gel with PE:EA=50:1 to DCM:MeOH=10:1 to give the title compound 15.1 g, (yield 86%).
Reaction SMILES: I[C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:6]3[C:11]([C:12]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1.[CH:28]1[C:36]2[C:35]3[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=3[S:33][C:32]=2[C:31]([C:41]2[CH:42]=[CH:43][C:44]3[NH:45][C:46]4[C:51]([C:52]=3[CH:53]=2)=[CH:50][CH:49]=[CH:48][CH:47]=4)=[CH:30][CH:29]=1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].CCCCCC.C1(C)C=CC=CC=1>[CH:28]1[C:36]2[C:35]3[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=3[S:33][C:32]=2[C:31]([C:41]2[CH:42]=[CH:43][C:44]3[N:45]([C:15]4[CH:2]=[CH:3][C:4]5[C:13](=[C:12]([C:16]6[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=6)[C:11]6[C:6]([C:5]=5[C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)=[CH:7][CH:8]=[CH:9][CH:10]=6)[CH:14]=4)[C:46]4[C:51]([C:52]=3[CH:53]=2)=[CH:50][CH:49]=[CH:48][CH:47]=4)=[CH:30][CH:29]=1
Reactant: c1ccc2c(c1)[nH]c1ccc(-c3cccc4c3sc3ccccc34)cc12
Reactant: Ic1ccc2c(-c3ccccc3)c3ccccc3c(-c3ccccc3)c2c1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: c1ccc(-c2c3ccccc3c(-c3ccccc3)c3cc(-n4c5ccccc5c5cc(-c6cccc7c6sc6ccccc67)ccc54)ccc23)cc1
Yield: 76 %

Procedure:
To a 100-mL three-neck flask were added 1.4 g (3.0 mmol) of 2-iodo-9,10-diphenylanthracene, 1.1 g (3.0 mmol) of 3-(dibenzothiophen-4-yl)-9H-carbazole, and 0.86 g (9.0 mmol) of sodium tert-butoxide. After the air in the flask was replaced with nitrogen, to this mixture were added 20 mL of toluene and 0.2 mL of tri(tert-butyl)phosphine (a 10 wt % hexane solution). This mixture was degassed by being stirred while the pressure was reduced. After the degassing, 86 mg (0.15 mmol) of bis(dibenzylideneacetone)palladium(0) was added to the mixture. This mixture was stirred at 110° C. for 4 hours under a nitrogen stream. After the stirring, the obtained mixture was suction-filtered through Celite (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855), alumina, and Florisil (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 540-00135). The filtrate was concentrated to give a yellow solid. The obtained solid was purified by silica gel column chromatography (developing solvent, hexane:toluene=5:1). The obtained fraction was concentrated to give a yellow solid. The obtained yellow solid was recrystallized from toluene/hexane, so that 1.5 g of a yellow solid was obtained in 76% yield. The synthesis scheme of Step 2 is illustrated in (b-7).
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:5]=[C:6]([C:9]([O:11][CH3:12])=[O:10])[NH:7][CH:8]=1.I[CH3:14].O>CN(C=O)C>[CH3:14][N:7]1[CH:8]=[C:4]([I:3])[CH:5]=[C:6]1[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1cc(I)c[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(I)cn1C
Reaction time: 2 h

Procedure:
780 mg (25.9 mmol) of sodium hydride (80% in oil) and 20 ml of DMF were introduced into a three-necked flask, a solution of 6.5 g (25.9 mmol) of methyl 4-iodo-2-pyrrolecarboxylate in 50 ml of DMF was added dropwise and stirring was carried out until gas evolution has ceased. 2.1 ml (33.6 mmol) of iodomethane were then added and stirring was carried out at room temperature for two hours. The reaction mixture was poured into water and extracted with ethyl ether. The organic phase was separated by settling, dried over magnesium sulfate and was evaporated. The residue obtained was purified by chromatography on a silica column eluted with a mixture of dichloromethane and hexane (40/60). 4.5 g (65%) of methyl N-methyl-4-iodo-2-pyrrolecarboxylate, with a melting point of 64°-65° C., were recovered.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[NH:12][C:13]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[C:14]([CH3:16])[N:15]=1.[BrH:23].[OH-].[Na+]>C(O)(=O)C.Br.[NH+]1C=CC=CC=1>[Br:23][C:6]1[C:7]([O:9][CH3:10])=[CH:8][C:3]([O:2][CH3:1])=[C:4]([C:11]2[NH:12][C:13]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[C:14]([CH3:16])[N:15]=2)[CH:5]=1
Reactant: Br
Reactant: COc1ccc(-c2nc(C)c(-c3cccnc3)[nH]2)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Product: COc1cc(OC)c(-c2nc(C)c(-c3cccnc3)[nH]2)cc1Br
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a solution of 2-(2,4-dimethoxyphenyl)-4-methyl-5-(3-pyridyl)imidazole (1.0 g) in acetic acid (10 ml) were added a solution of hydrogen bromide in acetic acid (28%, 0.2 ml) and pyridinium hydrobromide perbromide (1.49 g), and was stirred at ambient temperature for 19 hours. Then the mixture was poured into ice-water (100 ml), adjusted to pH 4.8 with 8N sodium hydroxide, and extracted with chloroform. The organic layer was washed by aqueous sodium bicarbonate and evaporated, and the residue was triturated in diisopropyl ether to give 2-(5-bromo-2,4-dimethoxyphenyl)-4-methyl-5-(3-pyridyl)imidazole (0.92 g).
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH:4]=[CH:3][CH2:2]1.N1C=CC=CC=1.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>C(Cl)Cl>[CH3:13][S:14]([O:6][CH:1]1[CH2:5][CH:4]=[CH:3][CH2:2]1)(=[O:16])=[O:15]
Reactant: OC1CC=CC1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)OC1CC=CC1
Temperature: 35 °C
Reaction time: 4 h
Yield: 68.5 %

Procedure:
3-Cyclopentene-1-ol (0.500 g, 5.94 mmol) was stirred in DCM (95 mL). Pyridine (2.40 mL), N,N-dimethylaminopyridine (0.10 g, 1.00 mmol) and methanesulfonyl chloride (0.690 mL, 8.92 mmol) were added, and the reaction mixture was stirred at 35° C. for 4 h. N,N-Dimethylaminopyridine (0.14 g, 1.2 mmol) and methanesulfonyl chloride (0.69 mL, 8.92 mmol) were added, and the reaction was stirred overnight. TLC indicated complete conversion. The reaction mixture was cooled and concentrated. The residue was purified by silica gel chromatography, eluting with DCM, to afford the title compound as a clear oil (0.660 g, 68%).
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([OH:3])=O.CN(C)C=O.S(Cl)(Cl)=O.[CH2:21]([NH:23][CH2:24][CH3:25])[CH3:22]>ClCCl.C(O)C>[CH:8]([C:7]1[CH:10]=[CH:11][C:4]([C:1]([N:23]([CH2:24][CH3:25])[CH2:21][CH3:22])=[O:3])=[CH:5][CH:6]=1)=[O:9]
Reactant: CCNCC
Reactant: O=Cc1ccc(C(=O)O)cc1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc(C=O)cc1
Reaction time: 18 h
Yield: 32.6 %

Procedure:
A mixture of 4-carboxybenzaldehyde (100 g, 0.66 mol), 1 L of dimethylformamide and 2 L of dichloromethane was cooled in an ice bath. Thionyl chloride (53 mL, 0.73 mol) was added dropwise while stirring. After 18 hours at room temperature, the mixture was cooled again and diethylamine (275 mL, 2.6 mol) was added dropwise. After stirring at room temperature for one hour the solvent was evaporated, and the residue was dissolved in aqueous 0.1 M sodium hydroxide and extracted with ethyl acetate. The organic layers were washed with water and brine, dried over sodium sulfate and evaporated to give a yellow oil. Chromatography on silica gel with ethanol (0-2%) in dichloromethane gave 44.2 g (32%) of 4-formyl-N,N-diethylbenzamide as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:16][CH2:17][CH3:18])[CH2:5][CH2:6][C:7]1[C:12](=[O:13])[NH:11][C:10]([NH2:14])=[N:9][C:8]=1[NH2:15])[CH3:2].C(O[C:23](=[O:25])[CH3:24])(=O)C>N1C=CC=CC=1>[CH2:1]([O:3][CH:4]([O:16][CH2:17][CH3:18])[CH2:5][CH2:6][C:7]1[C:12](=[O:13])[NH:11][C:10]([NH:14][C:1](=[O:3])[CH3:2])=[N:9][C:8]=1[N:15]([C:23](=[O:25])[CH3:24])[C:12](=[O:13])[CH3:7])[CH3:2]
Reactant: CCOC(CCc1c(N)nc(N)[nH]c1=O)OCC
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCOC(CCc1c(N(C(C)=O)C(C)=O)nc(NC(C)=O)[nH]c1=O)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred mixture of 7.20 g (28.1 mmol) of 3-(2,4-diamino-1,6-dihydro-6-oxo-5-pyrimidinyl)propionaldehyde diethyl acetal, 30 ml of dry pyridine and 30 ml of freshly distilled acetic anhydride was heated on an oil bath at 90° for 6 hours and then stirred at ambient temperature overnight. Solution occurred within 15 minutes as a mixture of diacetyl and triacetyl pyrimidinone formed; extended reaction was required to obtain only the title compound. The solution was spin evaporated in vacuo to give an oil. Ethyl acetate was added and spin evaporated several times until a solid was obtained. The solid was dispersed in cyclohexane and collected; yield, 8.88 g (82%), mp 126°-137° (one spot on TLC). Recrystallization of a portion from cyclohexane-ethylacetate gave the analytical sample, mp 138°-139°; TLC (C6H6 :EtOH/5:1); NMR (DMSO-d6) δ1.08 (t, 6H, 2CH2CH3), 1.63 (m, 2H, CH2CH2CH), 2.13 (s, 3H, Ac), 2.27 (s, 6H, 2Ac), 2.2 (2H, CH2CH2CH, superimposed on the acetyl singlets), 3.2-3.7 (m, 4H, 2×OCH2), 4.42 (t, 1H, CH), 11.87 (br s, 2H, AcNH and HNC(O)).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([NH2:11])=S)=[N:6][CH:7]=1.CI.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:17]=1[CH2:18][NH2:19]>CO>[CH3:25][O:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:16]([O:15][CH3:14])[C:17]=1[CH2:18][NH:19][C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([I:1])=[CH:7][N:6]=1)=[NH:11]
Reactant: COc1cccc(OC)c1CN
Reactant: NC(=S)Nc1ccc(I)cn1
Solvent: CI
Solvent: CO
Product: COc1cccc(OC)c1CNC(=N)Nc1ccc(I)cn1
Temperature: 75 °C
Yield: 835.9 %

Procedure:
2.019 g (7.233 mmol) N-(5-iodopyridin-2-yl)thiourea was dissolved in 50 mL methanol, 0.60 mL (9.553 mmol) methyl iodide in 2 mL methanol was added dropwise, and the mixture was heated for 2.7 hr at 75° C. (oil bath temperature). The solvent was removed under vacuum, and the intermediate product was redissolved in 50 mL ethanol. 1.870 g (0.736 mmol) 2,6-dimethoxybenzylamine was added to the reaction mixture and heated for 2.25 hr at 90° C. (oil bath temperature). The solvent was then evaporated under vacuum. The crude product was dissolved in acetonitrile, and the product crystallized out with addition of water. The solid was suctioned off and washed with water. 2.698 g (6.152 mmol, 85%) N-(2,6-dimethoxybenzyl)-N′-(5-iodopyridin-2-yl)guanidine was isolated and used for further reaction.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([Br:20])=[CH:7][CH:8]=2)[C:3]1=[O:21].[F:22][C:23]1[CH:24]=[C:25]([CH2:30][C:31](Cl)=[O:32])[CH:26]=[C:27]([F:29])[CH:28]=1>>[Br:20][C:6]1[CH:5]=[C:4]2[C:9]([C:10]([C:12]3[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=3)=[N:11][N:2]([NH:1][C:31](=[O:32])[CH2:30][C:25]3[CH:24]=[C:23]([F:22])[CH:28]=[C:27]([F:29])[CH:26]=3)[C:3]2=[O:21])=[CH:8][CH:7]=1
Reactant: COc1ccc(-c2nn(N)c(=O)c3cc(Br)ccc23)cc1
Reactant: O=C(Cl)Cc1cc(F)cc(F)c1
Product: COc1ccc(-c2nn(NC(=O)Cc3cc(F)cc(F)c3)c(=O)c3cc(Br)ccc23)cc1

Procedure:
The product from Example 174A and 2-(3,5-difluorophenyl)acetyl chloride were treated using a method similar to that described in Example 53 to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.77-11.80 (bs, 1H), 8.49 (d, J=2.1 Hz, 1H), 8.15 (dd, J=8.6, 2.2 Hz, 1H), 7.70 (d, J=8.7 Hz, 1H), 7.51-7.55 (m, 2H), 7.06-7.22 (m, 5H), 3.85 (s, 3H), 3.76-3.77 (bs, 2H); MS (ESI+) M/Z 503 (M+H)+.
Reaction SMILES: C1C=CC(C(NC2C3NC=NC=3N=CN=2)=[O:8])=CC=1.C(N[C:23]1[CH:44]=[CH:43][N:26]([C@@H:27]2[O:42][C@H:36]([CH2:37][O:38]C(=O)C)[C@@H:31]([O:32]C(=O)C)[C@H:28]2[O:29]C)[C:25](=[O:45])[N:24]=1)(=O)C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>C(#N)C.ClCCl>[C@@H:27]1([N:26]2[CH:43]=[CH:44][C:23](=[O:8])[NH:24][C:25]2=[O:45])[O:42][C@H:36]([CH2:37][OH:38])[C@@H:31]([OH:32])[C@H:28]1[OH:29]
Reactant: O=C(Nc1ncnc2nc[nH]c12)c1ccccc1
Reactant: CO[C@@H]1[C@H](OC(C)=O)[C@@H](COC(C)=O)O[C@H]1n1ccc(NC(C)=O)nc1=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Solvent: ClCCl
Product: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Temperature: 75 °C
Yield: 50 %

Procedure:
A solution of N6 -benzoylaminopurine (Lancaster) (1.23 g, 5.16 mmol) stirring in anhydrous acetonitrile under an argon atmosphere was treated with BSA (3.82 ml, 15.48 mmol) at reflux for 3 hours. Upon cooling, a solution of N4 -acetyl-5',3'-di-O-acetyl-2'-O-methyl cytidine (2) (see above) (0.66 g, 1.72 mmol) in 20 ml anh. acetonitrile was added to the reaction mixture followed by TMStriflate (1.03 ml, 5.16 mmol). The reaction mixture was then heated to 75° C. for 16 hours while stirring under positive pressure argon. Upon cooling, an additional 1.03 ml (5.16 mmol) of TMStriflate was added, and the reaction heated to 75° C. for an additional 20 hours. Once cool, the reaction mixture was diluted with two volumes of dichloromethane and washed with sat. NaHCO3. The organic layer was then dried over Na2SO4 and evaporated in vacuo. Flash chromatography employing a gradient of 10 to 80% ethyl acetgate/hexanes afforded (1) as a white foam; 0.403 g, 50% yield. 1H NMR (CDCl3): 8.88 (br s, 1H, NH), 8.81 (s, 1H, H8), 8.31 (s, 1H, H2), 8.11-7.53 (m, 5H, benzoyl), 6.18 (d, J1'2,' =4.8, 1H, H1'), 5.41 (t, J3',2' =4.8, J3',4' =4.8, 1H, H3'), 4.75 (t, J2',1' =4.8, J2',3' =4.8, 1H, H2'), 4.50-4.34 (m, 3H, H4', H5', H5"), 3.44 (s, 3H, OCH3), 2.19 (s, 3H, OAc), 2.14 (s, 3H, OAc).
Reaction SMILES: C(OC[N:10]1[C:14]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[CH:13][N:12]=[C:11]1[CH2:23][O:24][Si](C(C)(C)C)(C)C)C1C=CC=CC=1.C1(OC)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[Cl:22][C:18]1[CH:17]=[C:16]([S:15][C:14]2[NH:10][C:11]([CH2:23][OH:24])=[N:12][CH:13]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1ncc(Sc2cccc(Cl)c2)n1COCc1ccccc1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COc1ccccc1
Product: OCc1ncc(Sc2cccc(Cl)c2)[nH]1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87 %

Procedure:
To a solution of 1-benzyloxymethyl-2-t-butyldimethylsilyloxymethyl-5-(3-chlorophenylthio)imidazole (45)in nitromethane (108 ml)was added 14.7 g of (137 mmol)of anisole, and then, 18.1 g (136 mmol)of anhydrous aluminium chloride was gradually added at lower than 30° C. After completion of the addition, the mixture was stirred at room temperature for 15 minutes. The reaction mixture was cooled, and there were added water and a saturated aqueous sodium hydrogen carbonate solution to be alkaline. Ethyl acetate was added to the mixture, and the mixture was filtered on Hiflow Super Cell to separate. The organic layer was washed with water, dried over sodium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified by silica gel chromatography (7% methanol-methylene chloride) to give 9.5 g of [5-(3-chlorophenylthio)-1H-imidazol-2-yl]methanol as oil (yield 87%).
Reaction SMILES: ClC(Cl)(Cl)COC(=O)C1C=CC=CC=1CSC1C=CC=C(CC(O[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=O)C=1.[Cl:38][C:39]([Cl:63])([Cl:62])[CH2:40][O:41][C:42](=[O:61])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[CH2:49][S:50][C:51]1[CH:56]=[CH:55][C:54]([CH2:57][C:58]([OH:60])=[O:59])=[CH:53][CH:52]=1.FC(F)(F)C1C=CC(CO)=CC=1.Cl>CN(C1C=CN=CC=1)C.CCCCCCC.CCOC(C)=O.C(Cl)Cl.C(Cl)CCl>[Cl:63][C:39]([Cl:38])([Cl:62])[CH2:40][O:41][C:42](=[O:61])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[CH2:49][S:50][C:51]1[CH:52]=[CH:53][C:54]([CH2:57][C:58]([O:60][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:29][CH:30]=2)=[O:59])=[CH:55][CH:56]=1
Reactant: O=C(O)Cc1ccc(SCc2ccccc2C(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: O=C(Cc1cccc(SCc2ccccc2C(=O)OCC(Cl)(Cl)Cl)c1)OCc1ccc(C(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: OCc1ccc(C(F)(F)F)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: ClCCCl
Product: O=C(Cc1ccc(SCc2ccccc2C(=O)OCC(Cl)(Cl)Cl)cc1)OCc1ccc(C(F)(F)F)cc1
Yield: 35 %

Procedure:
The titled compound was prepared according to the method described for 2-[3-(4-trifluoromethyl-benzyloxycarbonylmethyl)-phenylsulfanylmethyl]-benzoic acid 2,2,2-trichloro-ethyl ester above from 2-(4-carboxymethyl-phenylsulfanylmethyl)-benzoic acid 2,2,2-trichloro-ethyl ester (155 mg, 0.357 mmol), (4-trifluoromethyl-phenyl)-methanol (157 mg, 0.893 mmol), EDC×HCl (206 mg, 1.072 mmol), DMAP (4.4 mg, 0.036 mmol) and DCM (3 mL). The crude was submitted to flash chromatography using heptane and EtOAc (90/10) as eluent to yield the titled compound (74 mg, 35%) as an oil; 1H NMR (400 MHz, CDCl3): δ 3.64 (dd, 2H), 4.54 (s, 2H), 4.96 (s, 2H), 5.17 (s, 2H), 7.16 (d, 2H), 7.18-7.28 (m, 3H), 7.31-7.44 (m, 4H), 7.60 (d, 2H), 8.08 (d, 1H)); Mass spectrum: M−H+ 590.
Reaction SMILES: [NH2:1][CH:2]([CH:6]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)[C:3]([OH:5])=[O:4].[CH3:23][O:24][C:25]1[CH:30]=[C:29]([O:31][CH3:32])[N:28]=[C:27](S(C)(=O)=O)[N:26]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>C(OCC)(=O)C.O.CN(C=O)C>[CH3:22][O:21][C:17]1[CH:16]=[C:15]([CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=2)[CH:2]([NH:1][C:27]2[N:28]=[C:29]([O:31][CH3:32])[CH:30]=[C:25]([O:24][CH3:23])[N:26]=2)[C:3]([OH:5])=[O:4])[CH:20]=[CH:19][CH:18]=1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: COc1cccc(C(c2cccc(OC)c2)C(N)C(=O)O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cccc(C(c2cccc(OC)c2)C(Nc2nc(OC)cc(OC)n2)C(=O)O)c1
Temperature: 80 °C
Reaction time: 10 h
Yield: 34.1 %

Procedure:
2.20 g (7.3 mmol) of 2-amino-3,3-di(3-methoxyphenyl)propionic acid, 0.66 g (3.04 mmol) of 4,6-dimethoxy-2-methylsulfonylpyrimidine and 0.39 g (3.65 mmol) of sodium carbonate were introduced into a mixture of 16 ml of DMF and 16 ml of water and stirred at 80° C. for 10 hours. Water and ethyl acetate were then added to the reaction mixture. The aqueous phase was acidified with 6 normal hydrochloric acid and extracted three times with ethyl acetate. Drying with MgSO4 and concentration resulted in the crude product, which was chromatographed on silica gel with dichloromethane/methanol (50:1). 0.455 g (34.1%) of a white powder of melting point 58-66° C. was obtained.