Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH2:13][O:14][CH2:15][P:16]([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])=[O:17])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:31]1([CH3:41])[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH:10]([CH2:13][O:14][CH2:15][P:16]([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])=[O:17])[CH2:11][O:12][S:37]([C:34]1[CH:35]=[CH:36][C:31]([CH3:41])=[CH:32][CH:33]=1)(=[O:39])=[O:38])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOP(=O)(COCC(CO)COCc1ccccc1)OCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOP(=O)(COCC(COCc1ccccc1)COS(=O)(=O)c1ccc(C)cc1)OCC
Temperature: 25 °C
Reaction time: 14 h
Yield: 81.9 %

Procedure:
A solution of 2-benzyloxymethyl-3-diethylphosphonomethoxy-1-propanol (0.25 g, 0.72 mmol) in 5 mL of CH2Cl2 was cooled to 0° C. and treated with triethylamine (0.22 g, 2.16 mmol). A solution of p-toluenesulfonyl chloride (0.151 g, 0.79 mmol) in 2 mL of CH2Cl2 was added next and the reaction mixture allowed to warm gradually to room temperature. After 14 hours at room temperature, the mixture was diluted with CH2Cl2 and washed with two portions of 10% aqueous HCl and saturated sodium chloride solution, dried over MgSO4, filtered, and concentrated to give an orange oil. Purification by column chromatography on silica gel (1-3% ethanol in ethyl acetate) provided 0.295 g of 2-benzyloxymethyl-3-diethylphosphonomethoxy-1-(p-toluenesulfonyloxy)propane as a pale yellow oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH:14][C@@H:15]1[CH2:19][NH:18][CH2:17][C@H:16]1[NH:20][C:21]([C:23]1[S:24][C:25]3[CH2:26][N:27]([CH3:32])[CH2:28][CH2:29][C:30]=3[N:31]=1)=[O:22])=[O:13])=[CH:6]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:40][C:41]([O:43][CH3:44])=[O:42]>CN(C)C=O.C(OCC)(=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH:14][C@H:15]1[C@H:16]([NH:20][C:21]([C:23]3[S:24][C:25]4[CH2:26][N:27]([CH3:32])[CH2:28][CH2:29][C:30]=4[N:31]=3)=[O:22])[CH2:17][N:18]([CH2:40][C:41]([O:43][CH3:44])=[O:42])[CH2:19]1)=[O:13])=[CH:6]2
Reactant: COC(=O)CBr
Reactant: CN1CCc2nc(C(=O)N[C@@H]3CNC[C@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CN1C[C@@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)[C@H](NC(=O)c2nc3c(s2)CN(C)CC3)C1

Procedure:
The compound (230 mg) obtained in Example 95 and potassium carbonate (90 mg) were dissolved in N,N-dimethylformamide (4.6 ml), and the mixture was cooled with ice. Methyl bromoacetate (0.062 ml) was added, and the resultant mixture was stirred for 45 minutes. The reaction mixture was diluted with ethyl acetate, washed with water and saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by preparative thin-layer chromatography on silica gel (chloroform:methanol=10:1) and solidifier with methanol-water to obtain the title compound (190 mg).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:78])[C@H:10]([CH2:74][CH:75]([CH3:77])[CH3:76])[NH:11][C:12](=[O:73])[C@H:13]([C:69]([CH3:72])([CH3:71])[CH3:70])[NH:14][C:15](=[O:68])[C@H:16]([CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=1[CH3:67])[NH:17][C:18](=[O:59])[C@H:19]([CH2:50][CH2:51][C:52](=[O:58])[O:53][C:54]([CH3:57])([CH3:56])[CH3:55])[NH:20][C:21](=[O:49])[C@H:22]([CH2:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[NH:23]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>N1CCCCC1.ClCCl>[CH2:1]([O:8][C:9](=[O:78])[C@H:10]([CH2:74][CH:75]([CH3:76])[CH3:77])[NH:11][C:12](=[O:73])[C@H:13]([C:69]([CH3:72])([CH3:71])[CH3:70])[NH:14][C:15](=[O:68])[C@H:16]([CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=1[CH3:67])[NH:17][C:18](=[O:59])[C@H:19]([CH2:50][CH2:51][C:52](=[O:58])[O:53][C:54]([CH3:55])([CH3:56])[CH3:57])[NH:20][C:21](=[O:49])[C@H:22]([CH2:41][C:42](=[O:48])[O:43][C:44]([CH3:45])([CH3:46])[CH3:47])[NH2:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1C[C@H](NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1)C(C)(C)C
Solvent: C1CCNCC1
Solvent: ClCCl
Product: Cc1ccccc1C[C@H](NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@@H](N)CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1)C(C)(C)C

Procedure:
A solution of 10.088 g (9.4 mmol) of N-[N-[N-[N-[N-[(9-fluorenyl)methoxycarbonyl] O-tert-butyl-L-α-aspartyl]-O-tert-butyl-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucine benzyl ester in 30 ml of piperidine and 120 ml of dichloromethane was stirred for 30 minutes at room temperature. The solvent was removed by evaporation and the residue was chromatographed on silica gel using firstly 20% ethyl acetate in hexane and then 10% methanol in dichloromethane for the elution. Evaporation gave N-[N-[N-[N-[O-tert-butyl-L-α-aspartyl]-O-tert-butyl-L-α-glutamyl-2-methyl-L-phenylalanyl]-3-methyl-L-valyl-L-leucine benzyl ester in the form of an oil which was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.[Na]>>[C:12]1([CH:4]2[CH2:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:2][NH:3]2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Clc1nc(-c2ccccc2)cc2ccccc12
Agent: [Na]
Product: c1ccc(C2Cc3ccccc3CN2)cc1
Reaction time: 6 h
Yield: 106.4 %

Procedure:
1-Chloro-3-phenylisoquinoline (2.8 g) was dissolved in absolute alcohol (200 ml) and the solution was heated at reflux while sodium metal (2.4 g) was added in portions. It was maintained at reflux for a further 2 hr., when tlc indicated incomplete reaction. Further sodium metal (2.4 g) was added then, and again (2.4 g)after another 6 hr., the heating being continued for 12 hr. in tote. The ethanol was evaporated in vacuo to give an oil which was partitioned between ether and 2M hydrochloric acid. The aqueous layer was separated, basified with 2M sodium hydroxide solution and extracted with ether (2×150 ml). The ether layer was dried (magnesium sulphate) and evaporated in vacuo to give an oil (2.6 g). This was purified by column chromatography on silica gel and 3-phenyl-1,2,3,4-tetrahydroisoquinoline was eluted with dichloromethane/methanol characterised by its nmr spectrum.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([N:18]([CH3:20])[CH3:19])=[C:16]([S:21]([C:23]([F:26])([F:25])[F:24])=[O:22])[C:15]([C:27](=[N:29][OH:30])[NH2:28])=[N:14]1.O.[C:32]1(C)C=CC(S(O)(=O)=O)=CC=1>C(OC)(OC)OC>[Cl:12][C:4]1[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:13]1[C:17]([N:18]([CH3:20])[CH3:19])=[C:16]([S:21]([C:23]([F:25])([F:26])[F:24])=[O:22])[C:15]([C:27]2[N:28]=[CH:32][O:30][N:29]=2)=[N:14]1
Reactant: CN(C)c1c(S(=O)C(F)(F)F)c(C(N)=NO)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(OC)OC
Solvent: O
Product: CN(C)c1c(S(=O)C(F)(F)F)c(-c2ncon2)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 4375 %

Procedure:
1-(2,6-dichloro-4-trifluoromethylphenyl)-5-dimethylamino-4-trifluoromethylsulfinyl-3-pyrazolecarboxamide oxime 0.59 g (1.18 mmol) was dissolved in 5 ml of trimethyl orthoformate, and then 5 mg of p-toluenesulfonic acid monohydrate was added. After the mixture was was stirred at room temperature for 3 hrs, trimethyl orthoformate was distilled off in vacuo, and then added 40 ml of ethyl acetate. The ethyl acetate solution was washed twice with 15 ml of aqueous saturated sodium hydrogencarbonate solution, and then once with 15 ml of aqueous saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain 583 mg (1.15 mmol) of the title compound as a colorless crystal. Yield 97%.
Reaction SMILES: Br[C@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].C(N(CC)CC)C>C(OCC)(=O)C>[C:3]([OH:5])(=[O:4])[CH:2]=[CH:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(O)[C@H](Br)Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(O)C=Cc1ccccc1

Procedure:
5 g of crude (2R)-2-bromo-3-phenylpropionic acid (HPLC: 92.5%) were dissolved in 20 ml of ethyl acetate and treated at room temperature with 2.7 ml of triethylamine. After a stirring time of about 150 minutes, no precipitation of the product was to be observed. An HPLC analysis of the solution showed that the (2R)-2-bromo-3-phenyl-propionic acid had reacted completely to give cinnamic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([F:17])[CH:16]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]C)=[CH:8][CH:7]=1.Br>C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([F:17])[CH:16]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]([OH:12])=[CH:10][CH:11]=1
Reactant: COc1ccc(Oc2cc(F)cc(F)c2)cc1
Agent: Br
Solvent: CC(=O)O
Product: Oc1ccc(Oc2cc(F)cc(F)c2)cc1
Temperature: 0 °C
Yield: 98.1 %

Procedure:
A mixture of 4-(3,5-difluorophenoxy)anisole (22.0 g, 0.093 mol), acetic acid (200 ml) and a 47% aqueous hydrogen bromide solution (200 ml) was heated with stirring under reflux for 8 hours. After allowed to cool, the reaction mixture was poured into ice-water and extracted with a mixture of ether and n-hexane (1 : 2). The organic layer was washed with water three times and dried over anhydrous magnesium sulfate. Removal of the solvent gave 4-(3,5-difluorophenoxy)phenol (20.27 g).
Reaction SMILES: [O-]CC.[Na+].[CH:5]1([C:11](=[O:13])[CH3:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1>C(O)C.CCOCC>[CH:5]1([C:11](=[O:13])[CH:12]=[CH:19][C:18]2[CH:21]=[CH:22][C:15]([F:14])=[CH:16][CH:17]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: CC(=O)C1CCCCC1
Reactant: O=Cc1ccc(F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: O=C(C=Cc1ccc(F)cc1)C1CCCCC1
Yield: 69.6 %

Procedure:
A sodium ethoxide solution (21% by weight in ethanol, 6.805 gm, 21 mmol) was added to a mixture of 1-cyclohexyl-1-ethanone (18.749g, 140 mmol, from Aldrich) and 4-fluorobenzaldehyde (17.37g, 140 mmol, from Aldrich) in ethanol (100 ml), stirring under argon. The solution was allowed to stir 1.5 hours. The reaction mixture was then concentrated to afford an orange oil. The oil was dissolved in ether, washed with saturated NH4Cl and brine, then dried over Na2SO4, filtered and concentrated to an orange oil. The oil was purified by distillation (bp=143° C. at 1.3 mm Hg). The resultant yellowish oil slowly solidified to afford the title compound as hard yellow crystals (22.640 gm, 65%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](O)=O)[CH:5]=[CH:4][CH:3]=1.C1(P(=[CH:30][CH:31]=[O:32])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:1][C:2]1[N:7]=[C:6](/[CH:8]=[CH:30]/[CH:31]=[O:32])[CH:5]=[CH:4][CH:3]=1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1cccc(Br)n1
Solvent: ClCCl
Product: O=C/C=C/c1cccc(Br)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.4 %

Procedure:
Solution of 6-bromo-2-carboxypyridine (3 g, 16.1 mmol) was dissolved in dichloromethane (100 mL). (Triphenylphosphoranylidene) acetaldehyde (4.9 g, 16.1 mmol) was added and obtained mixture was stirred at room temperature for 5 hrs. Dichloromethane was partially evaporated (to the volume about 50 mL) and reaction mixture was applied on chromatography column (SilicaGel 60) Products were eluted with dichloromethane. Fractions containing product were combined and evaporated to give 2.3 g of white powder (Yield 67%).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[CH3:32][O:33][C:34]([CH:36]1[CH2:40][CH:39]([NH:41][CH3:42])[CH2:38][N:37]1[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[O:35]>>[CH3:32][O:33][C:34]([CH:36]1[CH2:40][CH:39]([N:41]([C:20]2[S:21][C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][C:4]=3[C:28]([F:31])([F:29])[F:30])[N:8]=[CH:9]4)[C:18](=[O:25])[N:19]=2)[CH3:42])[CH2:38][N:37]1[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[O:35]
Reactant: CNC1CC(C(=O)OC)N(C(=O)OC(C)(C)C)C1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: COC(=O)C1CC(N(C)C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CN1C(=O)OC(C)(C)C

Procedure:
4-({5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-methyl-amino)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 4-Methylamino-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester following General Procedure C.
Reaction SMILES: [CH3:1][Si:2]([CH3:14])([CH3:13])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[C:10]([OH:12])[CH:9]=[N:8]1.[C:15]([O-])([O-])=O.[Cs+].[Cs+].CI>O1CCCC1>[CH3:15][O:12][C:10]1[CH:9]=[N:8][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:14])([CH3:13])[CH3:1])[CH:11]=1
Reactant: C[Si](C)(C)CCOCn1cc(O)cn1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: C1CCOC1
Product: COc1cnn(COCC[Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
To a solution of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-ol (compound 280.2, 2.14 g, 10.0 mmol) in tetrahydrofuran (50 mL) was added Cs2CO3 (6.5 g, 20.0 mmol) in portions. To this was added CH3I (1.25 mL, 20.0 mmol) dropwise. The reaction mixture was stirred for 3 h at room temperature, then concentrated under reduced pressure. The resulting residue was dissolved in 100 mL of EtOAc. The solids were filtered off and the filtrate was concentrated under reduced pressure. This resulted in 2.1 g (92%) of the title compound as a colorless oil.
Reaction SMILES: C1COCC1.[Cl:6][C:7]1[CH:8]=[C:9]([C:13]2[C:22]3[C:17](=[N:18][C:19]([CH3:23])=[CH:20][CH:21]=3)[N:16]([CH2:24][CH3:25])[C:15](=[O:26])[C:14]=2[CH2:27][CH2:28][CH2:29][OH:30])[CH:10]=[CH:11][CH:12]=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(N(CC)CC)C>[Cl:6][C:7]1[CH:8]=[C:9]([C:13]2[C:22]3[C:17](=[N:18][C:19]([CH3:23])=[CH:20][CH:21]=3)[N:16]([CH2:24][CH3:25])[C:15](=[O:26])[C:14]=2[CH2:27][CH2:28][CH2:29][O:30][S:32]([CH3:31])(=[O:34])=[O:33])[CH:10]=[CH:11][CH:12]=1
Reactant: CCn1c(=O)c(CCCO)c(-c2cccc(Cl)c2)c2ccc(C)nc21
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCn1c(=O)c(CCCOS(C)(=O)=O)c(-c2cccc(Cl)c2)c2ccc(C)nc21

Procedure:
To a THF solution of 4-(3-chlorophenyl)-1-ethyl-3-(3-hydroxypropyl)-7-methyl-1,8-naphthyridin-2(1H)-one were added triethylamine and methanesulfonyl chloride, followed by reaction under heating. Thereafter, the reaction mixture was worked up and purified in a usual manner to obtain 4-(3-chlorophenyl)-1-ethyl-3(3-methanesulfonyloxypropyl)-7-methyl-1,8-naphthyridin-2(1H)-one. NMR1: 4.67 (2H, q, J=7.1 Hz), 4.18 (2H, t, J=6.3 Hz), 2.93 (3H, s).
Reaction SMILES: O.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH2:5][CH2:4]1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]=1>CO>[F:30][C:29]([F:32])([F:31])[C:25]1[N:26]=[C:27]([N:3]2[CH2:4][CH2:5][CH:6]([CH2:9][N:10]3[CH2:14][CH2:13][CH2:12][C:11]3=[O:15])[CH2:7][CH2:8]2)[CH:28]=[CH:23][N:24]=1
Reactant: FC(F)(F)c1nccc(Cl)n1
Reactant: O=C1CCCN1CC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C1CCCN1CC1CCN(c2ccnc(C(F)(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.5 %

Procedure:
Using the procedure described above in Examples 2 and 3, a mixture of 1-[(4-piperidinyl)methyl]-2-pyrrolidinone hydrochloride (II, 21.85 g, 0.1 mole) and sodium carbonate (26.5 g, 0.25 mole) in methanol (150 mL) was refluxed for one hour. The methanol was then removed in vacuo, and acetonitrile (150 mL) was added to the residue. The mixture was cooled and stirred as 4-chloro-2-(trifluoromethyl)pyrimidine (18.28 g, 0.2 mole) was added. The mixture was stirred at room temperature for 18 hours and then filtered and the filtrate concentrated in vacuo to give a thick residue which solidified upon being washed with hexane (100 mL). The light tan powder (23.8 g, 73%) which resulted was chromatographed (5% methanol/ethyl acetate on silica) to give 19.8 g as white crystals, m.p. 118.5°-120.5°.
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]2[NH:15][CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1B(O)O>>[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[N:15]1[C:13]2=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]2[N:17]=[CH:16]1
Reactant: c1ccc(COc2ccc3nc[nH]c3n2)cc1
Reactant: Cc1ccc(C)c(B(O)O)c1
Product: Cc1ccc(C)c(-n2cnc3ccc(O)nc32)c1

Procedure:
From 5-(benzyloxy)-3H-imidazo[4,5-b]pyridine and 2,5-dimethylphenylboronic acid, prepared in a similar manner as the one described in Example 1.26, the title compound was obtained. LCMS m/z=239.9 [M+H]+.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.Cl[CH:9]([CH3:17])[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]>>[SH:7][C:4]1[S:3][C:2]([S:1][CH:9]([CH3:17])[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:6][N:5]=1
Reactant: Sc1nnc(S)s1
Reactant: CCOC(=O)CCC(C)Cl
Product: CCOC(=O)CCC(C)Sc1nnc(S)s1
Yield: 15.3 %

Procedure:
By following the same procedure as Reference Example 6 using 6.9 g of 2,5-dimercapto-1,3,4-thiadiazole and 5.8 g of ethyl 4-chlorovalerate as the starting materials, 1.5 g of ethyl 4-[(5-mercapto-1,3,4-thiadiazol-2-yl)thio]valerate was obtained as an oily product.
Reaction SMILES: [CH:1]1[N:6]=[C:5](Cl)[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:3]=2[N:2]=1.[CH:20]1([CH2:29][NH2:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1.C(N(CC)CC)C>C(O)C>[CH:20]1([CH2:29][NH:30][C:5]2[C:4]3[N:8]=[CH:9][N:10]([C:3]=3[N:2]=[CH:1][N:6]=2)[C@@H:11]2[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]2[OH:19])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1
Reactant: NCC1CCc2ccccc21
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Solvent: CCN(CC)CC
Solvent: CCO
Product: OC[C@H]1O[C@@H](n2cnc3c(NCC4CCc5ccccc54)ncnc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Yield: 66.8 %

Procedure:
A mixture of 3.0 g of 6-chloropurine riboside, 2.0 g of 1-indanylmethylamine as prepared in Example A hereinafter and 3.18 g of triethylamine are refluxed in 75 ml of absolute ethanol under nitrogen for 24 hours. The reaction is cooled to room temperature, precipitated nucleoside is filtered, washed with ethanol and dried affording 2.78 g (67%) of N6 -[2,3-dihydro-1H-inden-1-yl]methyl-adenosine having a melting point of 137°-139° C. Anals. calcd. for C20H23N5O4 ; Found: C=60.44; H=5.83; N=17.62 C=60.81; H=5.70; N=17.35.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][CH:8]([OH:17])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([S:15][CH3:16])[N:10]=1)([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.O.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:18])[CH2:7][C:8]([C:9]1[CH:14]=[CH:13][N:12]=[C:11]([S:15][CH3:16])[N:10]=1)=[O:17])([CH3:3])([CH3:4])[CH3:2]
Reactant: CSc1nccc(C(O)CC(=O)OC(C)(C)C)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CSc1nccc(C(=O)CC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a solution of 3-hydroxy-3-(2-methylsulfanyl-pyrimidin-4-yl)-propionic acid tert-butyl ester, 18, (5.6 g, 20.9 mmol) in CH2Cl2 is added Dess-Martin periodinane (10.7 g, 25.1 mmol) followed by H2O (0.5 mL, 25.1 mmol). After stirring 1 h at room temperature, the solution is poured into aqueous saturated Na2S2O4. The aqueous phase is extracted with CH2Cl2, then EtOAc. The combined organic phases are dried (MgSO4), filtered and concentrated in vacuo. The crude residue is purified over silica (10% EtOAc/hexanes) to afford 5.6 g (95% yield) of the desired product. 1H NMR (300 MHz, CDCl3) (observed 3:1 mixture of enol:keto tautomers) enol tautomer: δ 12.34 (s, OH), 8.67 (d, J=5.1 Hz, 1H), 7.48 (d, J=5.1 Hz, 1H), 6.35 (s, 1H), 2.62 (s, 3H), 1.57 (s, 9H); ESI+ MS: m/z (rel intensity) 269.1 (30, M++H).
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:27])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][CH3:26])[N:14]=2)=[CH:6][C:5]=1[OH:28].Br[CH2:31][CH2:32][CH3:33]>>[F:29][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:27])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][CH3:26])[N:14]=2)=[CH:6][C:5]=1[O:28][CH2:31][CH2:32][CH3:33]
Reactant: CCOc1ccccc1C(=O)NCc1coc(-c2ccc(OC(F)F)c(O)c2)n1
Reactant: CCCBr
Product: CCCOc1cc(-c2nc(CNC(=O)c3ccccc3OCC)co2)ccc1OC(F)F

Procedure:
Using the compound obtained in Example 347 and 1-bromopropane, white powdery N-[2-(4-difluoromethoxy-3-propoxy phenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide was obtained following the procedure of Example 348.
Reaction SMILES: [CH:1]([Si:4]([CH:13]([CH3:15])[CH3:14])([CH:10]([CH3:12])[CH3:11])[N:5]1[CH:9]=[CH:8][CH:7]=[CH:6]1)([CH3:3])[CH3:2].[Br:16][C:17]1[CH:18]=[C:19]([C:23]#[CH:24])[CH:20]=[CH:21][CH:22]=1>CC#N.C(N(CC)CC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[Br:16][C:17]1[CH:18]=[C:19]([C:23]#[C:24][C:7]2[CH:8]=[CH:9][N:5]([Si:4]([CH:1]([CH3:3])[CH3:2])([CH:10]([CH3:12])[CH3:11])[CH:13]([CH3:15])[CH3:14])[CH:6]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cccc1
Reactant: C#Cc1cccc(Br)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc(C#Cc2cccc(Br)c2)c1
Temperature: 25 °C
Yield: 670.9 %

Procedure:
A solution of N-triisopropylsilylpyrrole (3.49 g, 1 mmol), 3-bromo-1-ethynylbenzene (1.81 g, 1 mmol), Pd(PPh3)4 (800 mg) and CuI (185 mg) in CH3CN (15 ml) and triethylamine (35 ml) is refluxed for 5 h. The reaction mixture is cooled to room temperature and the solvent is evaporated on a rotary evaporator. The crude material is purified by flash chromatographied (silica gel, 100% hexane) to afford 3-[(3-bromophenyl)ethynyl]-1-(triisopropylsilyl)-1H-pyrrole (2.7 g, 85%) as a clear oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[O:20](C(C(F)(F)F)=O)[C:21]([C:23]([F:26])([F:25])[F:24])=O.Cl>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:21](=[O:20])[C:23]([F:26])([F:25])[F:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)C(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of piperazine-1-carboxylic acid tert-butyl ester (10 g, 53.69 mmol) and pyridine (8.7 mL, 107.57 mmol) in CH2Cl2 (100 mL) was added dropwise (CF3CO)2O (10.5 mL, 75.54 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 2 h. 2N HCl (60 mL) was then added. The organic layer was dried over MgSO4, filtered, and then concentrated. The resulting residue, the title compound, was used in the next reaction without further purification. MS m/z (MH+-Boc) 183.1, (MH+—C4H9) 227.1; 1H NMR (300 MHz, CDCl3): δ 3.45-3.7 (m, 8H), 1.5 (s, 9H).