Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].[C:9]([C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10].C(N(CC)CC)C>O1CCCC1>[CH3:12][C:9]([C:13]1[CH:14]=[CH:15][C:16]([S:19][CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]2=[O:8])=[CH:17][CH:18]=1)([CH3:10])[CH3:11]
Reactant: O=C1CCCCC1Cl
Reactant: CC(C)(C)c1ccc(S)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(SC2CCCCC2=O)cc1
Reaction time: 0.25 h

Procedure:
To a solution of 2-chlorocyclohexanone (6.1 g, 0.046 moles) in tetrahydrofuran (250 ml) cooled to +5° C. by an ice bath was added 4-t-butyl-thiophenol (6.6 g, 0.040 moles). After stirring for 15 minutes, triethylamine (13 ml) was added. The ice bath was removed and the mixture was stirred at room temperature for 60 hours. The mixture was filtered to remove a white solid. The filtrate was concentrated to an oil, and the product was purified by silica gel chromatography to give a white solid which was recrystallized from hexane (DSC 64.25° C.). The structure was supported by NMR and Ir.
Reaction SMILES: C1([C@@H]([N:9]2[CH2:15][CH2:14][C@@H:13]3[CH2:16][C@H:10]2[C:11](=[O:17])[O:12]3)C)C=CC=CC=1.[CH3:18][OH:19]>[Pd]>[CH3:18][O:19][C:11](=[O:17])[C@H:10]1[CH2:16][C@@H:13]([OH:12])[CH2:14][CH2:15][NH:9]1
Reactant: CO
Reactant: C[C@@H](c1ccccc1)N1CC[C@@H]2C[C@H]1C(=O)O2
Agent: [Pd]
Product: COC(=O)[C@H]1C[C@@H](O)CCN1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of (1S,5R)-2-((S)-1-phenylethyl)-6-oxa-2-azabicyclo[3.2.1]octan-7-one (2.95 g) and 10% palladium on activated carbon (570 mg) in methanol (75 mL) was stirred at room temperature for 6 hr under hydrogen (3.5 kgf/cm2). The catalysts were removed by filtration and washed with methanol. The combined organic layers were evaporated in vacuo. A mixture of the residue and 10% palladium on activated carbon (500 mg) in methanol (75 mL) was stirred at room temperature for 8 hr under hydrogen (3.5 kgf/cm2). The catalysts were removed by filtration and washed with methanol. The combined organic layers were evaporated in vacuo. The mixture of the residue and 10% palladium on activated carbon (504 mg) in methanol (75 mL) was stirred at room temperature for 8 hr under hydrogen (4.0 kgf/cm2). The catalysts were removed by filtration and washed with methanol. The combined organic layers were evaporated in vacuo to give the title compound (2.11 g): 1H NMR (400 MHz, CDCl3) δ 1.32-1.49 (m, 2H), 1.83 (br s, 2H), 1.93-1.95 (m, 1H), 2.27-2.32 (m, 1H), 2.61-2.69 (m, 1H), 3.22 (dt, J=12.7, 3.9 Hz, 1H), 3.39 (dd, J=2.9, 10.7 Hz, 1H), 3.71-3.78 (m, 1H), and 3.75 (m, 3H).
Reaction SMILES: C([O:3][C:4]([C:6]1([C:29]([O:31]CC)=[O:30])[O:10][C:9]2[CH:11]=[CH:12][C:13]([CH2:15][CH:16]([NH:18][CH2:19][CH:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[OH:21])[CH3:17])=[CH:14][C:8]=2[O:7]1)=O)C.[CH2:34]([NH2:38])[CH2:35][CH2:36][CH3:37]>C(O)C>[CH2:34]([N:38]([CH2:14][CH2:8][CH2:9][CH3:11])[C:4]([C:6]1([C:29]([OH:31])=[O:30])[O:10][C:9]2[CH:11]=[CH:12][C:13]([CH2:15][CH:16]([NH:18][CH2:19][CH:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[OH:21])[CH3:17])=[CH:14][C:8]=2[O:7]1)=[O:3])[CH2:35][CH2:36][CH3:37]
Reactant: CCCCN
Reactant: CCOC(=O)C1(C(=O)OCC)Oc2ccc(CC(C)NCC(O)c3cccc(Cl)c3)cc2O1
Solvent: CCO
Product: CCCCN(CCCC)C(=O)C1(C(=O)O)Oc2ccc(CC(C)NCC(O)c3cccc(Cl)c3)cc2O1

Procedure:
A mixture of 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl)-benzo-[1,3]dioxole-2,2-dicarboxylic acid bis-ethyl ester (2.4 g, 5 mmol) and n-butylamine (10 mL, excess) was refluxed in ethanol for 48 h. The reaction mixture was concentrated and the residue obtained was extracted with chloroform:methanol (3:1). It was washed with water and dried over anhydrous MgSO4. The organic layer was filtered and concentrated. The residue obtained was chromatographed over silica gel eluted with 9:1 chloroform:methanol to yield a brown semi solid; yield 1.6 g; 61%; M+H 532.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH:13]1[CH:17]=[CH:16][CH:15]=[N:14]1>CN(C)C=O>[N:13]1([C:2]2[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:17]=[CH:16][CH:15]=[N:14]1
Reactant: CCOC(=O)c1ccccc1F
Reactant: c1cn[nH]c1
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccccc1-n1cccn1

Procedure:
As described for the general reaction of ethyl 2-fluorobenzoate with amines set forth in Tetrahedron, 53, 7557-7576 (1997), ethyl 2-fluorobenzoate was reacted with pyrazole by refluxing N, N-dimethylformamide to give ethyl 2-(1-pyrazolyl)benzoate, as a thick yellow oil. Anal. Calc'd: for C12H12N2O2 : C, 66.7; H, 5.6; N 13.0: Found: C, 66.5: H, 5.4: N, 12.9; Mass spectrum (ES) 217.2 (M+H). A sample (7.02 g) of this compound and 8.42 ml of 5N NaOH in 40 ml of ethanol-tetrahydrofuran (2:1) was refluxed for 2 hrs and the solvent removed. The residue was made acidic (pH6) with 2N citric acid and the precipated solid was filtered to obtain 3.7g of product. The pH of the filtrate was adjusted to 4:5 and extracted with ethyl acetate The extract was concentrated to dryness to give 1.5 g of product. The two crops were combined to give 5.2 g of 2-(1-pyrazolyl)benzoic acid, mp 140-142° C. To the preceding compound (2.07 g) in 5 ml CH2Cl2 (chilled in an ice bath )was added 11.1 ml of a 2 Molar solution of oxalyl chloride in CH2Cl2 and 0.085 ml of N,N-dimethylformamide. The mixture was allowed to warm to room temperature and stirred for 4 hours. The solvent was removed and 25 ml of toluene added (twice) and removed under vacuum to give 2-(1-pyrazolyl)benzoyl chloride as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[NH:31][C:32]([CH:35]5[CH2:39][CH2:38][CH2:37][N:36]5[C:40](=[O:53])[CH:41]([NH:48][C:49]([O:51][CH3:52])=[O:50])[CH2:42][CH2:43]C(F)(F)F)=[N:33][CH:34]=4)=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC(=O)C(NC(OC)=O)CC[O:60][CH2:61][C:62]([F:65])([F:64])[F:63]>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[NH:31][C:32]([CH:35]5[CH2:39][CH2:38][CH2:37][N:36]5[C:40](=[O:53])[CH:41]([NH:48][C:49]([O:51][CH3:52])=[O:50])[CH2:42][CH2:43][O:60][CH2:61][C:62]([F:65])([F:64])[F:63])=[N:33][CH:34]=4)=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)NC(CCOCC(F)(F)F)C(=O)OC
Reactant: COC(=O)NC(CCC(F)(F)F)C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CCCN5C(=O)OC(C)(C)C)[nH]4)cc3)cc2)[nH]1
Product: COC(=O)NC(CCOCC(F)(F)F)C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CCCN5C(=O)OC(C)(C)C)[nH]4)cc3)cc2)[nH]1
Yield: 74 %

Procedure:
This compound was made in 74% yield by the same procedure as 2-[5-(4′-{2-[1-(5,5,5-Trifluoro-2-methoxycarbonylamino-pentanoyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl]-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester, using 2-Methoxycarbonylamino-4-(2,2,2-trifluoro-ethoxy)-butyric acid methyl ester as the starting material. LCMS-ESI+: calculated for C39H46F3N7O6: 765.35; observed [M+1]+: 766.12.
Reaction SMILES: [Cl:1][C:2]([Cl:8])=[CH:3][CH:4]=[C:5]([CH3:7])[CH3:6].[CH2:9]([O:11][C:12](=[O:17])[CH:13](Br)[C:14]#[N:15])[CH3:10]>[Cu]>[CH2:9]([O:11][C:12]([C:13]1([C:14]#[N:15])[CH:4]([CH:3]=[C:2]([Cl:8])[Cl:1])[C:5]1([CH3:7])[CH3:6])=[O:17])[CH3:10]
Reactant: CC(C)=CC=C(Cl)Cl
Reactant: CCOC(=O)C(Br)C#N
Agent: [Cu]
Product: CCOC(=O)C1(C#N)C(C=C(Cl)Cl)C1(C)C
Reaction time: 6 h

Procedure:
A mixture of 1,1-dichloro-4-methylpenta-1,3-diene (15.1 parts) ethylbromocyanoacetate (19.2 parts), copper-containing catalyst (as indicated in the table below), acid binder (as indicated in the table below) in solvent (as indicated in the table below; 100 parts by volume) is heated to the reflux temperature of the mixture if below 90° C., otherwise at a temperature not exceeding 90° C., and held at the reaction temperature for 6 hours. After removal of the solvent by distillation under reduced pressure the residue is extracted with a mixture of toluene (100 parts by volume), water (150 parts) and concentrated hydrochloric acid (100 parts by volume). The extract is filtered, the toluene layer is separated, washed with water (4×50 parts) and the crude ethyl-1-cyano-3-(2',2'-dichlorovinyl)-2,2-dimethylcyclopropane-1-carboxylate is isolated by distilling off the toluene under reduced pressure. The yield, strength and composition of the product obtained is given in the table below together with other reaction details.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][N:21]4[C:30]([Br:33])=[CH:31][N:32]=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.Cl.CO>CO>[Br:33][C:30]1[N:21]2[CH:22]=[C:23]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:18]([C:15]3[CH:14]=[CH:13][C:12]([C:8]4([NH2:7])[CH2:9][CH2:10][CH2:11]4)=[CH:17][CH:16]=3)=[N:19][C:20]2=[N:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ncc(Br)n4cc3-c3ccccc3)cc2)CCC1
Agent: Cl
Solvent: CO
Product: NC1(c2ccc(-c3nc4ncc(Br)n4cc3-c3ccccc3)cc2)CCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-3 (52 mg, 0.1 mmol) in 1 mL of MeOH was added 4M HCl/MeOH (2 mL) and the mixture was stirred at room temperature for 3 h. The mixture was concentrated by evaporation and the residue was purified by prep.HPLC to give the product 4-4. MS (ESI) m/e (M+H+): 420.3
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:38])[C@@H:10]([NH:20][C:21]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[N:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[C:39](Cl)([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[C:16]([O:15][C:13]([NH:12][CH2:11][C@H:10]([NH:20]/[C:21](/[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[N:22]/[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:26])[CH3:27])[C:9]([NH:8][C:3]1[CH:4]=[N:5][N:6]([CH3:7])[C:2]=1[NH:1][C:39]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)=[O:38])=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1ncc(NC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cn1ncc(NC(=O)[C@H](CNC(=O)OC(C)(C)C)N/C(=N/C(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
To a solution of di-tert-butyl {[((1S)-2-[(5-amino-1-methyl-1H-pyrazol-4-yl)amino]-1-{[(tert-butoxycarbonyl)amino]methyl}-2-oxoethyl)amino]methylylidene}biscarbamate (1.72 g) in dichloromethane (17 ml) was added trityl chloride (931 mg). To the mixture was added triethylamine (0.53 ml) dropwise. The mixture was stirred at room temperature for 1 hour. The reaction mixture was dissolved in ethyl acetate. The solution was washed with water and brine. The extract was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give di-tert-butyl {(Z)-[((1S)-{[(tert-butoxycarbonyl)amino]methyl}-2-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}-2-oxoethyl)amino]methylylidene}biscarbamate (2.25 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][C:3]=1[Cl:14].[Li]CCCC.CN([CH:23]=[O:24])C>C1COCC1.CCCCCC>[Cl:14][C:3]1[CH:4]=[C:5]([CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][C:2]=1[CH:23]=[O:24]
Reactant: Clc1cc(CN2CCCC2)ccc1Br
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1ccc(CN2CCCC2)cc1Cl
Reaction time: 0.5 h

Procedure:
Reaction under N2 atmosphere. A solution of 1-[(4-bromo-3-chlorophenyl)methyl]-pyrrolidine (25.8 g, 93.96 mmol) in THF (200 ml) was stirred at −78° C. for 15 min A 2.5 M n-BuLi solution in hexane was added to the mixture over a period of 15 min. After 30 min, a solution of DMF (7.3 ml, 93.96 mmol) in THF (50 ml) was added dropwise to the mixture. The reaction temperature was allowed to rise to r.t. slowly, and the mixture was stirred overnight. The reaction was quenched by the addition of water at 0° C. The mixture was extracted with EtOAc (3×150 ml). The combined organic layer was washed with brine, dried (MgSO4), filtered and the solvent was evaporated in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8](=[O:30])[N:9]2[CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][C:17](=O)[CH:16]([CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:15]2)=[CH:4][CH:3]=1.[O:31]1[C:40]2[CH:39]=[C:38]([CH2:41][NH2:42])[N:37]=[CH:36][C:35]=2[O:34][CH2:33][CH2:32]1.O1C2C=C(CO)N=CC=2OCC1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2.[N-]=[N+]=[N-].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[BH4-].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.ClCCl.[Pd].CO.C(O)C.C(O)(=O)C>[O:31]1[C:40]2[CH:39]=[C:38]([CH2:41][NH:42][CH:17]3[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][N:9]4[C:10]5[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:11]=5)[N:6]=[CH:7][C:8]4=[O:30])[CH2:15][CH:16]3[CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])[N:37]=[CH:36][C:35]=2[O:34][CH2:33][CH2:32]1
Reactant: NCc1cc2c(cn1)OCCO2
Reactant: CC(C)(C)OC(=O)NCC1CN(CCn2c(=O)cnc3ccc(F)cc32)CCC1=O
Agent: [Pd]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Solvent: CCO
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)NCC1CN(CCn2c(=O)cnc3ccc(F)cc32)CCC1NCc1cc2c(cn1)OCCO2

Procedure:
A mixture of racemic 1,1-dimethylethyl ({1-[2-(7-fluoro-2-oxo-1(2H)-quinoxalinyl)ethyl]-4-oxo-3-piperidinyl}methyl)carbamate (1.35 g, 3.23 mmol) and (2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amine (0.54 g, 3.23 mmol, prepared from 2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethanol (for a synthesis see WO2004002490, Example 6(b)) by reaction with diphenylphosphoryl azide and 1,8 diazabicyclo[5.4.0]undec-7-ene in toluene, 0° C.-room temperature, followed by hydrogenation of the resulting azide over 5% palladium/carbon paste in 200:1 ethanol/acetic acid) in dichloromethane (30 mL) and methanol (3 mL) was stirred with 3A molecular sieves for 1 h. Sodium triacetoxyborohydride (2.05 g, 9.69 mmol) was added and stirring continued at room temperature. More borohydride was added after 6 h (0.20 g), and after an overnight period more amine (0.20 g) and borohydride (0.80 g) were added. After stirring for a further 6 h, aqueous sodium bicarbonate was added and the phases were separated. The aqueous phase was extracted twice with 10% methanol/dichloromethane and the organic fractions were dried and evaporated. Chromatography on silica, eluting with 0-20% methanol/dichloromethane, gave firstly a major product (Isomer1, 1.12 g, 61%), followed by a minor product (Isomer 2, 0.10 g, 5% of good purity, plus 0.17 g less pure).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:15][P:16]([CH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])([CH3:18])=[O:17])[CH3:14].[F:26][C:27]1[CH:37]=[CH:36][C:30]([CH:31]=[CH:32][N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[F:26][C:27]1[CH:28]=[CH:29][C:30]([CH:31]([CH2:32][N+:33]([O-:35])=[O:34])[CH2:18][P:16]([CH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])(=[O:17])[O:15][CH2:13][CH3:14])=[CH:36][CH:37]=1
Reactant: CCOC(OCC)P(C)(=O)OCC
Reactant: O=[N+]([O-])C=Cc1ccc(F)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(OCC)P(=O)(CC(C[N+](=O)[O-])c1ccc(F)cc1)OCC
Reaction time: 0.17 h

Procedure:
To a solution of 5.8 g of diisopropylamine in 40 ml of tetrahydrofuran at -78° C. under an atmosphere of nitrogen are added 35.7 ml of a 1.6M solution of n-butyllithium in hexane. This solution is then stirred for a period of 10 minutes at this temperature, after which time a solution of 10.0 g of ethyl(diethoxymethyl)methylphosphinate in 20 ml of tetrahydrofuran is added. This mixture is then stirred for a period of 1 hour at -78° C. after which time a solution of 7.96 g of 4-fluoro-β-nitrostyrene in 20 ml of tetrahydrofuran is introduced. This mixture is then allowed to warm to room temperature when 40 ml of a saturated ammonium chloride solution is added. The aqueous layer is then extracted with 2×25 ml of diethyl ether and the organic extracts are combined and dried over magnesium sulphate. The solvent is then evaporated under reduced pressure and the crude product chromatographed on silica gel using ethyl acetate as an eluent to give ethyl 2-(4-fluorophenyl)-3-nitropropyl(diethoxymethyl)phosphinate as a viscous oil, 31P=+42.3 and +41.9 ppm (CDCl3).
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][O:8][NH:9][C:10]([C:12]2[N:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=3[F:29])[C:15]3=[CH:16][N:17]=[CH:18][CH:19]=[C:14]3[CH:13]=2)=[O:11])[CH2:4][O:3]1.Cl>>[OH:6][C@H:5]([CH2:4][OH:3])[CH2:7][O:8][NH:9][C:10]([C:12]1[N:20]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=2[F:29])[C:15]2=[CH:16][N:17]=[CH:18][CH:19]=[C:14]2[CH:13]=1)=[O:11]
Reactant: CC1(C)OC[C@H](CONC(=O)c2cc3ccncc3n2Cc2ccc(I)cc2F)O1
Agent: Cl
Product: O=C(NOC[C@H](O)CO)c1cc2ccncc2n1Cc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 44.7 %

Procedure:
1-(2-Fluoro-4-iodo-benzyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-amide (29 mg, 0.06 mmol) was dissolved in 0.067 M methanolic HCl solution (2.3 ml, 0.15 mmol) and stirred at room temperature for 1.5 hours. The reaction mixture was concentrated in vacuo then azeotroped with toluene (2×15 ml). Purification by flash chromatography (NH2-SPE, dichloromethane, ethyl acetate, 20:80 methanol:dichloromethane, 5:35:60 triethylamine:methanol:dichloromethane) followed by trituration in acetonitrile afforded the product as a cream solid (13 mg, 49%). LCMS (Method A): RT=4.53 min, (M−H)−=484, M+H+=486. 1H NMR (CD3OD): 3.60 (2H, m), 3.85 (1H, m), 3.91 (1H, dd, J=10.2, 6.8 Hz), 4.02 (1H, dd, J=10.2, 3.8 Hz), 5.93 (2H, s), 6.66 (1H, t, J=8.0 Hz), 7.13 (1H, s), 7.43 (1H, dd, J=8.0, 1.6 Hz), 7.52 (1H, dd, J=9.7, 1.6 Hz), 7.80 (1H, d, J=5.5 Hz), 8.22 (1H, d, br, J=5.5 Hz), 8.97 (1H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:26][C:27]=3[CH3:28])=[CH:17][CH:16]=2)=[C:6]([CH2:8][C:9]([O:11]C)=[O:10])[CH:7]=1.O1CCCC1.[OH-].[Na+].Cl>O.CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[O:26][C:27]=3[CH3:28])=[CH:17][CH:16]=2)=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:7]=1
Reactant: COC(=O)Cc1cc(C)ccc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1ccc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)c(CC(=O)O)c1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 75 %

Procedure:
To a mixture of methyl 2-[5-methyl-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate (0.22 g), tetrahydrofuran (1 mL) and methanol (1 mL) was added a 1N aqueous sodium hydroxide solution (1 mL) and the mixture was stirred at 50° C. for 1.5 hrs. 1N Hydrochloric acid (1 mL) and water were added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give crystals (0.16 g, 76%) of 2-[5-methyl-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 115-116° C.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=S)=[N:8][CH:9]=[CH:10][CH:11]=1.[NH3:27]>>[Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[NH:27])=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: S=C(Nc1ccccc1)Nc1ncccc1OCc1c(Cl)cccc1Cl
Reactant: N
Product: N=C(Nc1ccccc1)Nc1ncccc1OCc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of yellow mercuric oxide (0.62 g, 0.0029 mol), N-[3-(2-,6-dichlorobenzyloxy)pyrid-2-yl]-N'-phenylthiourea (1.0 g, 0.0025 mol) and methanolic ammonia solution (30 ml) was stirred for 15 hours at room temperature. The solvent was removed in vacuo and the black residue was boiled with chloroform and filtered hot. Evaporation of the solvent followed by recrystallisation from ethanol gave the desired product. Yield 0.33 g (55%), m.p. 163°-165 ° C.
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Si+4]>C(O)(=O)C>[C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@@H:2]1[OH:3]
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1
Agent: CC(=O)[O-]
Agent: [Si+4]
Solvent: CC(=O)O
Product: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)n1
Temperature: 120 °C
Reaction time: 0.08 h
Yield: 50 %

Procedure:
1.0 G of cytidine is dissolved in 20 ml of acetic acid under heating. After cooling, 2.17 g of silicon tetraacetate are added to the solution. The mixture is stirred at 120°C for 5 minutes. The mixture is cooled to room temperature, and 0.6 ml of boron trifluoride-ether complex is added thereto. Then, the mixture is stirred at room temperature for 4 days. After the reaction, the mixture is concentrated under reduced pressure, and the residue is treated in the same manner as described in Example 3. 0.5 g of 1-β-D-arabinofuranosyl cytosine is thereby obtained. Yield: 50 % M.p. 213°-214°C (decomp.) (recrystallized from 50 % ethanol)
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:18]=[C:17]([C:19]#[N:20])[S:16][CH:15]=2)[C:9]1=[O:21])(C)(C)C.[ClH:23]>CCOC(C)=O>[ClH:23].[NH2:7][C@H:8]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:18]=[C:17]([C:19]#[N:20])[S:16][CH:15]=2)[C:9]1=[O:21]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(Cc2csc(C#N)c2)C1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: N#Cc1cc(CN2CC[C@H](N)C2=O)cs1
Reaction time: 3 h

Procedure:
[1-(5-Cyanothiophene3-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-carbamic acid tert-butyl ester (4.0 g, 13.8 mmol) is added to a solution of 100 mL of EtOAc saturated with HCl gas at 0° C. After 3 h, the solution is concentrated. The title compound (3.3 g, 13.5 mmol) is obtained as a white solid.