Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])[CH:5]=1.O=C1N(CC(O)=O)N=C(C2C=CC=CN=2)C2C=CC=CC=2N1CC(=O)N1CCCC1.[C:70]([O:74][C:75](=[O:85])[N:76](C1C=CC=C(N)C=1)[CH3:77])([CH3:73])([CH3:72])[CH3:71].C1(C2C3C=CC=CC=3N(CC(=O)C(C)(C)C)C(=O)N(CC(O)=O)N=2)CCCCC1.COC(=O)C1C=CC=C(N)C=1>>[C:70]([O:74][C:75](=[O:85])[N:76]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:17]3[CH2:16][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:34])([CH3:35])[CH3:33])[C:14]2=[O:37])[CH:5]=1)[CH3:77])([CH3:73])([CH3:72])[CH3:71]
Reactant: CN(C(=O)OC(C)(C)C)c1cccc(N)c1
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Agent: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)O)N=C(C2CCCCC2)c2ccccc21
Agent: COC(=O)c1cccc(N)c1
Agent: O=C(O)CN1N=C(c2ccccn2)c2ccccc2N(CC(=O)N2CCCC2)C1=O
Product: CN(C(=O)OC(C)(C)C)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1

Procedure:
The title compound was obtained by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1, step e) except that [2-oxo-1-(2-oxo-2-pyrrolidin-1-yl-ethyl)-5-pyridin-2-yl-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 6, step a) and (3-amino-phenyl)-methyl-carbamic acid tert-butyl ester (Example 3, step c) were used in place of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 1, step d) and 3-amino-benzoic acid methyl ester respectively, followed by reaction of the product obtained, in place of (3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-phenyl)-methyl-carbamic acid tert-butyl ester (Example 3, step d), according to the method of Example 3, step e. 1H NMR (CDCl3) 8.61 (1H, d), 8.07 (2H, m), 7.77 (1H, dt), 7.54 (2H, m), 7.36-7.24 (3H, m), 6.98 (1H, t), 6.88 (1H, s), 6.48 (1H, d), 6.28 (1H, d), 4.53-4.34 (4H, br m), 3.52-3.20 (5H, br m), 2.75 (3H, s), 1.97 (2H, m), 1.87 (2H, m). Found: C, 65.44; H, 6.00; N, 18.79%; C28H29N7O3 requires: C, 65.74; H, 5.71; N, 19.17%.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13](Cl)=[N:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:19][NH2:20]>C(O)C>[CH2:1]([NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([NH:19][NH2:20])=[N:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(NCc1ccccc1)c1ccc(Cl)nc1
Solvent: O
Solvent: CCO
Product: NNc1ccc(C(=O)NCc2ccccc2)cn1
Yield: 78 %

Procedure:
Combined N-benzyl-6-chloronicotinamide (13 g, 52.8 mmol) and ethanol (60 mL) then added hydrazine hydrate (85%, 30 mL) drop wise at room temperature. After the addition, the solution was heated to reflux overnight. The reaction mixture was then concentrated to remove ethanol and a solid was obtained. The solid was collected by filtration, washed with EtOAc (3×20 mL), and dried under reduced pressure to give the title compound (10 g, 78%) as an off-yellow solid.
Reaction SMILES: ClC(Cl)C(O)=O.CO.COC1C=CC(C([O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][N:43]2[C:47](=[O:48])[C:46]3=[CH:49][CH:50]=[CH:51][CH:52]=[C:45]3[C:44]2=[O:53])(C2C=CC=CC=2)C2C=CC(OC)=CC=2)=CC=1>C(Cl)Cl>[C:44]1(=[O:53])[N:43]([O:42][CH2:41][CH2:40][O:39][CH2:38][CH2:37][O:36][CH2:35][CH2:34][O:33][CH2:32][CH2:31][OH:30])[C:47](=[O:48])[C:46]2=[CH:49][CH:50]=[CH:51][CH:52]=[C:45]12
Reactant: COc1ccc(C(OCCOCCOCCOCCON2C(=O)c3ccccc3C2=O)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: O=C(O)C(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: O=C1c2ccccc2C(=O)N1OCCOCCOCCOCCO
Reaction time: 18 h
Yield: 72 %

Procedure:
A solution of dichloroacetic acid in CH2Cl2 (100 mL, 3:97, v/v) and methanol (20 mL) was added to N-[11-(4,4′-dimethoxytrityloxy)-3,6,9-trioxaundecanyloxy]phthalimide (2.3 g, 3.6 mmol), and the reaction mixture was stirred for 18 hours. All volatile material was evaporated in vacuo and the residue was dissolved in CH2Cl2 (10 mL). Silica gel column purification using an eluent system with a stepwise gradient of acetic acid in CH2Cl2 (0-4%) gave 0.88 g (72%) of 11-(phthalimidooxy)-3,6,9-trioxaundecan-1-ol after coevaporation of the pooled fractions with water and pyridine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][OH:15])[O:11][C:10]2=[O:16])[CH:5]=[CH:6][C:7]=1[I:8].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl.C(=O)(O)[O-].[Na+]>[CH3:24][S:25]([O:15][CH2:14][C@@H:12]1[O:11][C:10](=[O:16])[N:9]([C:4]2[CH:5]=[CH:6][C:7]([I:8])=[C:2]([F:1])[CH:3]=2)[CH2:13]1)(=[O:27])=[O:26]
Reactant: O=C1O[C@@H](CO)CN1c1ccc(I)c(F)c1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
(5R)-3-(3-Fluoro-4-iodophenyl)-5-(hydroxymethyl)-1,3-oxazolidin-2-one (Intermediate 3, 25.0 g, 74.2 mmol) was stirred in dichloromethane (250 ml) at 0° C. Triethylamine (10.5 g, 104 mmol) was added followed by methanesulfonyl chloride (11.2 g, 89.0 nmmol) and the reaction was stirred overnight, slowly warming to room temperature. The yellow solution was diluted with sodium bicarbonate and the compound was extracted using dichloromethane (3×250 ml). The organic layer was dried (magnesium sulfate), filtered and concentrated to give the desired product as a light yellow solid (30.3 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]=[C:4]([O:10][CH3:11])[N:3]=1.C1(C)C=CC=CC=1.C(OC([N:24]=[C:25]=S)=O)C.O.[NH2:28]O.S([O-])([O-])=O.[Na+].[Na+]>>[NH2:28][C:25]1[N:1]=[C:2]2[N:3]([C:4]([O:10][CH3:11])=[N:5][CH:6]=[C:7]2[O:8][CH3:9])[N:24]=1
Reactant: COc1ncc(OC)c(N)n1
Reactant: NO
Reactant: CCOC(=O)N=C=S
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cnc(OC)n2nc(N)nc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
To a 700 mL jacketed vessel equipped with a mechanical stirrer, a dual pH/temperature probe, a nitrogen inlet, and a reflux condenser was added sequentially 19.4 g (0.125 mol) of 4-amino-2,5-dimethoxypyrimidine followed by 151 g (1.639 mol) of toluene. The reaction was heated to gentle reflux (˜80° C.) and then 19.24 g (0.144 mol) of 98% ethoxy carbonylisothiocyanate was added, and the reaction mixture was heated at gentle reflux (89° C.) for 7 h. The reaction mixture was cooled to 26° C. and allowed to stand overnight. The mixture was heated to 60° C. and then 100 g (5.500 mol) of deionized water was added to the mixture. After heating to reflux (˜69° C.), 9.6 g (0.145 mol) of a 50 wt % aqueous hydroxylamine solution was continuously added over a 1 h period. During the course of the amine addition, the reaction pH rose from 4.00 to 6.67. After completing addition of hydroxylamine, the reaction mixture was heated to 77° C. and then stirred an additional 3 h during which time the reaction pH naturally raised to 7.42. To this reaction mixture was added a solution of 4.5 g (0.036 mol) of sodium sulfite in 20 g (1.110 mol) of deionized water over a one min period. The reaction pH rose from 7.34 to 7.81 during the sodium sulfite addition. The reaction mixture was stirred an additional 1 h at 77° C. and then cooled to ambient temperature and allowed to stand overnight. The reaction mixture was suction filtered through a medium coarse fritted glass funnel (filtration time was 43 min), and then the reaction vessel was washed with 30 g of deionized water and this rinse was used to wash the isolated product cake. A final displacement wash with 30 g of fresh deionized water was performed and the product was dried to afford 19.62 g of 2-amino-5,8-dimethoxy[1,2,4]triazolo[1,5-c]pyrimidine as a light cream colored solid. NMR analysis (using benzyl acetate as an internal standard) indicated an 83.3% purity of 2-amino-5,8-dimethoxy[1,2,4]triazolo[1,5-c]pyrimidine active which corresponds to a 67.0% yield.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][CH2:6][OH:7].[Si:8](Cl)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]>O1CCCC1.C(OCC)(=O)C>[Si:8]([O:3][CH2:4][CH2:5][CH2:6][OH:7])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCO
Temperature: 0 °C
Reaction time: 6 h

Procedure:
To a suspension of sodium hydride (0.1 mole) in anhydrous tetrahydrofuran (200 ml) cooled to 0° C., with stirring under an atmosphere of nitrogen is added a solution of 1,3-dihydroxypropane (0.1 mole) in tetrahydrofuran (150 ml) slowly over a period of 1 hour. Then a solution of tert-butyldimethylsilyl chloride (0.1 mole) in tetrahydrofuran (150 ml) is added slowly over a period of 1 hour. Stirring is continued for 6 hours. The mixture is then diluted with ethyl acetate (400 ml), washed with water (100 ml), brine (75 ml), dried and concentrated to afford the title compound.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@:10]1([N:35]2[CH:43]=[C:41]([CH3:42])[C:39](=[O:40])[NH:38][C:36]2=[O:37])[O:34][C@H:14]([CH2:15][O:16][Si:17]([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:12]([OH:13])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:44](Cl)([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:45]>C(Cl)Cl.CCN(CC)CC>[CH2:1]([O:8][CH2:9][C@@:10]1([N:35]2[CH:43]=[C:41]([CH3:42])[C:39](=[O:40])[NH:38][C:36]2=[O:37])[O:34][C@H:14]([CH2:15][O:16][Si:17]([C:30]([CH3:33])([CH3:32])[CH3:31])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C@@H:12]([O:13][C:44](=[O:45])[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cn([C@@]2(COCc3ccccc3)C[C@H](O)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O2)c(=O)[nH]c1=O
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cn([C@@]2(COCc3ccccc3)C[C@H](OC(=O)c3ccccc3)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O2)c(=O)[nH]c1=O
Yield: 86.9 %

Procedure:
A stirred solution of 3 (128.0 g, 213.3 mmol) in a 4:1 mixture of CH2Cl2 /Et3N (500 mL) was treated with (48.4 g, 40 mL, 344.6 mmol) of BzCl at 23° C. for 8 h. The resultant precipitate was removed by filtration. The filtrate was concentrated under reduced pressure to leave the crude product as a brownish syrup. Purification of the syrup by silica gel column chromatography (hexanes/AcOEt 10:1 then 1:1) gave 130.7 g (87%) of 4 as a white solid. Rf (Hexanes/AcOEt 1:1) 0.82 1H-NMR (CDCl3): 1.40 (s, 9H, C--Me3), 1.60 (s, 3H, 5-Me), 2.37 (ddd, 1H, J=13.8, 9.3, 7.2 Hz, 2'-Hβ), 2.62 (dd, 1H, J=13.8, 4.3 Hz, 2'-Hβ), 4.09 (m, 2H, 5'-H), 4.26 (m, 1H, 4'-H), 4.74 (s, 2H, O--CH2 --Ph), 5.54 (s, 2H, N--CH2 --O), 5.71 (d, 1H, J=7.2 Hz, 3'-H), 6.57 (dd, 1H, J=9.3, 4.3 Hz, 1'-H), 7.24-7.74 (m, 13H, aromatic-H), 8.05-8.15 (m, 3H, 6-H and aromatic-H). 13C-NMR(CDCl3): 12.82 (-, 5-Me), 19.54 (+, C--Me3), 27.16 (C--Me3), 38.28 (+, 2'-C), 64.41 (+, 5'-C), 70.80 (+, O--C--Ph), 72.29 (+, N--C--O), 75.60 (-, 4'-C), 85.28 (-, 1'-C and 3'-C), 110.95 (+, 5-C), 127.72, 128.23, 128.37, 128.50, 128.63 (-, aromatic-C), 129.43 (+, aromatic-C), 129.84, 130.22 (-, aromatic-C), 132.14, 133.07 (+, aromatic-C), 133.60 (-, 6-C), 133.94, 135.32, 135.65 (-, aromatic-C), 138.15 (+, aromatic-C), 151.19 (+, 2-C), 163.50 (+, 4-C), 166.11 (+, benzoyl C=O).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.[CH3:13][NH:14][O:15][CH3:16].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([N:14]([O:15][CH3:16])[CH3:13])=[O:5]
Reactant: O=C(O)c1cc(F)ccc1Br
Reactant: CNOC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1cc(F)ccc1Br
Reaction time: 1 h
Yield: 73 %

Procedure:
2-Bromo-5-fluorobenzoic acid (4.60 g, 0.02 mol), N,O-Dimethylhydroxylamine hydrochloride (2.05 g, 0.02 mol), carbon tertabromide (6.9 g, 0.02 mol) was added to mixture of methylene chloride (100 mL) and triethylamine (2.9 mL, 0.02 mol). Triphenylphospine (5.53 g, 0.02 mol) was added to the solution over 1 hour and stirred for another 1 hour. The solution was concentrated to an oil. Hexanes (100 mL) and Ethyl Acetate (100 mL) were added to the oil and stirred for 1 hour then filtered. The filtrate was concentrated and the residue was purified by chromatography (Hexanes/Ethyl Acetate) on silica gel to afford 2-bromo-5-fluoro-N-methoxy-N-methylbenzamide as a foamy white solid in 73% yield. 1H NMR (CDCl3, 500 MHz) δ3.00-3.98 (m, 6 H), 6.97-7.08 (m, 2H), 7.51-7.54 (m, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4]([OH:7])(=[O:6])=[O:5].[CH2:8]([O:15][C:16](Cl)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)(O)[O-].[Na+:23]>[OH-].[Na+].O>[Na+:23].[CH2:8]([O:15][C:16]([NH:1][CH2:2][CH2:3][S:4]([O-:7])(=[O:6])=[O:5])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(NCCS(=O)(=O)[O-])OCc1ccccc1
Reaction time: 4 h
Yield: 14 %

Procedure:
Taurine, 1 (about 40 g, 320 mmols), was dissolved in 4N sodium hydroxide solution (80 mL) and water (about 200 mL). To this solution was added benzyloxycarbonyl chloride, (about 48 mL, 330 mmols) dropwise, with vigorous stirring during a period of about 4 hours. The pH of the solution was maintained alkaline by the addition of 10% sodium bicarbonate solution (about 300 mL) and 4N sodium hydroxide solution (about 45 mL). The obtained reaction mixture was then washed with diethyl ether (about 1000 mL) and the aqueous layer was rotary evaporated to dryness, and further dried under high vacuum over phosphorous pentoxide overnight to yield about 12.7 g (14%) of 2. 1H-NMR (D2O): δ 7.50 (5H, s, Ar—H), 5.21 (2H, s, Ar—CH2), 3.62 (2H, t, CH2), 3.14 (2H, t, CH2).
Reaction SMILES: [C:1]([NH:5][S:6]([CH2:9][CH2:10][CH2:11]Cl)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li][CH2:14]CCC.CI>C1COCC1>[C:1]([NH:5][S:6]([C:9]1([CH3:14])[CH2:11][CH2:10]1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NS(=O)(=O)CCCCl
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)C1(C)CC1
Temperature: -78 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
A solution of N-tert-butyl-(3-chloro)propylsulfonamide (4.3 g, 20 mmol) was dissolved in dry THF (100 mL) and cooled to −78° C. To this solution was added n-BuLi (17.6 mL, 44 mmol, 2.5 M in hexane) slowly. The dry ice bath was removed and the reaction mixture was allowed to warm to rt over a period of 1.5 h. This mixture was then cooled to −78° C., and a solution of n-BuLi (20 mmol, 8 mL, 2.5 M in hexane) was added. The reaction mixture was warmed to rt, recooled to −78° C. over a period of 2 h and a neat solution of methyl iodide (5.68 g, 40 mmol) added. The reaction mixture was allowed to warm to rt overnight, quenched with saturated NH4Cl (100 mL) at rt. It was extracted with EtOAc (100 mL). The organic phase was washed with brine (100 mL), dried (MgSO4), and concentrated in vacuo to give a yellow oil which was crystallized from hexane to afford the product as a slightly yellow solid (3.1 g, 81%): 1H NMR (CDCl3) δ 0.79 (m, 2H), 1.36 (s, 9H), 1.52 (m, 2H), 1.62 (s, 3H), 4.10 (bs, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.C(N(CC)CC)C.[C:14]1([C:20]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)Cl)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C=O)C>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:6]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 8 h
Yield: 100.1 %

Procedure:
To a solution of 4-methylimidazole (20.0 g) and triethylamine (53.5 ml) in DMF (300 ml), a solution of triphenylchloromethane (71.3 g) in DMF (200 ml) was added dropwise at 0° C. under nitrogen atmosphere. After finishing the dropping, and the mixture was allowed to be at room temperature and the mixture was stirred overnight. Water was added to the mixture, and the precipitated solid was collected by filtration. The obtained solid was washed with water twice and dried under reduced pressure, to give 4-methyl-1-triphenylmethylimidazole (79.1 g) as colorless solid.
Reaction SMILES: C[O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([Cl:11])[CH:5]=1.[OH-].[Na+]>CCO>[NH2:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:12])=[O:2])=[CH:5][C:6]=1[Cl:11]
Reactant: COC(=O)c1ccc(N)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc(C(=O)O)cc1Cl
Yield: 92 %

Procedure:
4-Amino-3-chloro-benzoic acid methyl ester (21.6 mmol) was saponified in EtOH (25 ml) and NaOH (1M, 25 ml) at reflux for 2 h. The organic solvent was evaporated and pH adjusted to 4. The product was removed by filtration, washed with water and dried in vacuo to give 4-amino-3-chloro-benzoic acid.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]([CH:14]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:15][OH:16])[CH3:13].Cl>N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:16][CH2:15][CH:14]([CH2:12][CH3:13])[CH2:17][CH2:18][CH2:19][CH3:20])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCC(CC)CO
Agent: Cl
Solvent: c1ccncc1
Product: CCCCC(CC)COS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Yield: 87.5 %

Procedure:
In a 1-L round-bottomed flask containing 250 mL of pyridine, added was 75 g of p-toluenesulfonyl chloride. After the reaction solution was cooled to 0° C., 34 g of 2-ethylhexanol was added dropwise over 30 minutes, and the resulting mixture was left at 0° C. while cooled overnight. The reaction solution was poured into cold 1N hydrochloric acid; the product was extracted with ethyl acetate; and the organic layer was washed with 1N hydrochloric acid until the aqueous hydrochloric acid layer became acidic. The organic layer was dried over magnesium sulfate and evaporated, to give 65 g of 2-ethylhexyl p-toluenesulfonate. The fact that the product is the desirable compound was confirmed with NMR, IR, and mass spectrometry spectra.
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: CCOC(=O)C(Br)C#N
Reactant: CC(C)=CC=C(Cl)Cl
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: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(O[CH:12]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])C>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Br)c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)C(=CNc1cccc(Br)c1)C(=O)OCC
Temperature: 80 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
3-Bromoaniline (10.0 g, 47 mmol) was dissolved in abs. ethanol (100 mL). Diethyl ethoxymethylenemalonate (10.2 g, 47 mmol) was added. The solution stirred at 80° C. overnight. The solution was slowly cooled and a precipitant formed. The product was filtered and dried to give 12.6 g (70%) of the title compound.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:8]1[O:12][CH:11]([N:13]2[CH:18]=[CH:17][C:16]([N:19]=[CH:20][N:21]([CH3:23])[CH3:22])=[N:15][C:14]2=[O:24])[C:10]([OH:26])([CH3:25])[CH:9]1[OH:27])([CH3:4])([CH3:3])[CH3:2].[C:40]([NH:47][C@H:48]([C:52](O)=[O:53])[CH:49]([CH3:51])[CH3:50])([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([SiH2:5][O:6][C:7]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH:8]1[CH:9]([O:27][C:52](=[O:53])[CH:48]([NH:47][C:40]([O:42][C:43]([CH3:44])([CH3:46])[CH3:45])=[O:41])[CH:49]([CH3:51])[CH3:50])[C:10]([OH:26])([CH3:25])[CH:11]([N:13]2[CH:18]=[CH:17][C:16]([N:19]=[CH:20][N:21]([CH3:22])[CH3:23])=[N:15][C:14]2=[O:24])[O:12]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)C=Nc1ccn(C2OC(C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)C(O)C2(C)O)c(=O)n1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)C(NC(=O)OC(C)(C)C)C(=O)OC1C(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)OC(n2ccc(N=CN(C)C)nc2=O)C1(C)O

Procedure:
As one nonlimiting example of the invention, if the 3′-valinyl ester is preferred, the esterification process may include the steps depicted in FIG. 4, namely: reacting β-D-2′-C-methyl-cytidine with Me2NCH(OMe)2 in DMF to form (7), N-[1-(3,4-dihydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl)-2-oxo-1,2-dihydro-pyrimidin-4-yl]-N,N-dimethyl-formamidine, which is the amino-protected form of (VI); reacting (7) with TBDPSCl and imidazole in DCM to provide the 5′-silyl-protected form of (7) as N′-{1-[5-(tert-butyl-diphenyl-silanyloxymethyl)-3,4-dihydroxy-3-methyl-tetrahydro-furan-2-yl]-2-oxo-1,2-dihydro-pyrimidin-4-yl}-N,N-dimethyl-formamidine (8); reacting (8) with N—Boc-L-valine, EDC, and DMAP in DCM to form 2-tert-butoxycarbonylamino-3-methyl-butyric acid 2-(tert-butyl-diphenyl-silanyloxymethyl)-5-[4-(dimethylamino-methyleneamino)-2-oxo-2H-pyrimidin-1-yl]-4-hydroxy-4-methyl-tetrahydro-furan-3-yl ester (9); removing the silyl and amino-protecting groups by reacting (9) with NH4F in MeOH with the addition of ethyl acetate (to prevent cleavage of the 3′-O-valinyl ester by liberated ammonia), and refluxing the mixture to provide 2-tert-butoxycarbonylamino-3-methyl-butyric acid 5-(4-amino-2-oxo-2H-pyrimidin-1-yl)-4-hydroxy-2-hydroxymethyl-4-methyl-tetrahydro-furan-3-yl ester (10), which is purified by simple crystallization; and finally, reacting (10) with HCl in EtOH to provide 2-amino-3-methyl-butyric acid 5-(4-amino-2-oxo-2H-pyrimidin-1-yl)-4-hydroxy-2-hydroxymethyl-4-methyl-tetrahydrofuran-3-yl ester, dihydrochloride salt (11) as a final product.