Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([OH:10])(=[O:9])=[O:8])[CH:2]=1.P(Cl)(Cl)(Cl)(Cl)Cl.Cl.[Br:18]Br>O.C(Cl)(Cl)Cl>[Br:18][C:5]1[CH:4]=[C:3]([S:7]([OH:10])(=[O:9])=[O:8])[CH:2]=[N:1][CH:6]=1
Reactant: BrBr
Reactant: O=S(=O)(O)c1cccnc1
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=S(=O)(O)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3g. of 3-pyridinesulfonic acid and 8.5g. of phosphorous pentachloride was heated at 120° C for 1.5 hours. Upon cooling to room temperature, the mixture solidified. Chloroform was added thereto and dry hydrogen chloride gas was introduced. The resulting precipitate was collected by filtration and dried. The crystalline substance obtained was heated with bromine (4g.) at 120° C. for 8 hours and water (60 ml.) was added to the mixture. After stirring at 80° C. for 2 hours, the solution was concentrated. On addition of acetone, 2g. of 5-bromo- 3-pyridinesulfonic acid was obtained.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([NH2:9])=[O:8].[C:10]([O:14][C:15]([NH:17][CH2:18][C:19](O)=[O:20])=[O:16])([CH3:13])([CH3:12])[CH3:11].C(Cl)CCl>C1COCC1>[C:7]([C:3]1[N:2]([NH:1][C:19](=[O:20])[CH2:18][NH:17][C:15](=[O:16])[O:14][C:10]([CH3:11])([CH3:12])[CH3:13])[CH:6]=[CH:5][CH:4]=1)(=[O:8])[NH2:9]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: NC(=O)c1cccn1N
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(=O)Nn1cccc1C(N)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.3 %

Procedure:
1-Amino-1H-pyrrole-2-carboxamide (5.00 g, 40.0 mmol) and 2-(tert-butoxycarbonylamino)acetic acid (7.70 g, 44.0 mmol) were combined and dissolved in THF (250 mL). To this solution was added EDC (8.43 g, 44.0 mmol). The reaction was stirred at room temperature for 16 h, after which the reaction was concentrated in vacuo. The residue was partitioned between EtOAc (250 mL) and water (200 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (150 mL). The combined organics were dried (MgSO4) and filtered. The filtrate was treated with activated charcoal and filtered over Celite. The filtrate was concentrated in vacuo to remove most of the solvent, then diluted with hexanes to ˜1 L. A solid was filtered off and dried to give 21A (8.73 g). The aqueous layer was extracted again with EtOAc (2×100 mL). A second crop was obtained similarly to above to give 465 mg, for a total yield of 9.20 g (82%). 21A had an analytical HPLC retention time=1.75 min (Phenomonex-Luna (4.6×50 mm S10); 10-90% MeOH/H2O (0.1% TFA) over 4 min; flow=4 mL/min) and a LC/MS M+-Boc+1=183.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1.S1C=CC=C1C(Cl)=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:18](=[O:19])[C:17]2[CH:21]=[CH:22][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Agent: O=C(Cl)c1cccs1
Product: COc1ccc(C(=O)Nc2ccc(F)c([N+](=O)[O-])c2)cc1

Procedure:
4-Fluoro-3-nitro-phenylamine was reacted with 4-methoxybenzoyl chloride according to the procedure of Example 256a substituting 4-methoxybenzoyl chloride for thiophene-2-carbonyl chloride to provide N-(4-Fluoro-3-nitro-phenyl)-4-methoxy-benzamide which was then reacted according to the procedures of Examples 256b and 256c to provide the title product.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][N:10]([CH2:14][CH:15]=[CH2:16])[C:9]=2[C:8](=[O:17])[NH:7][C:6]1=[O:18])[CH2:2][CH2:3][CH3:4].[C:19]([O-])([O-])=O.[Na+].[Na+].CI.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][N:10]([CH2:14][CH:15]=[CH2:16])[C:9]=2[C:8](=[O:17])[N:7]([CH3:19])[C:6]1=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: C=CCn1cnc2c1c(=O)[nH]c(=O)n2CCCC
Reactant: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: C=CCn1cnc2c1c(=O)n(C)c(=O)n2CCCC
Temperature: 35 °C
Reaction time: 18 h
Yield: 117.3 %

Procedure:
A stirred solution of 3-butyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (1.0 g, 4.03 mmol) in anhydrous DMF (10 ml) was treated with Na2CO3 (470 mg, 4.43 mmol) followed by Methyliodide (275 ul, 4.43 mmol). The mixture was heated at 35° C. for 17 hours. K2CO3 (500 mg, 3.6 mmol) and Methyliodide (275 ul, 4.43 mmol) were added and then stirred at 50° C. for a further 18 hours. The reaction mixture was allowed to cool then partitioned between 2M HCl(aq) and EtOAc. The organic layer was separated and the aqueous extracted once more with EtOAc. The combined extracts were washed with brine, dried (MgSO4) and concentrated giving a yellow/brown oil (1.24 g). The product was purified by silica SPE (10 g), eluting with EtOAc/cyclohexane mixtures. The product fractions were combined and concentrated to afford the title compound as a pale yellow solid (1.11 g, quant.); m/z 263.3[MH+].
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=1.[F:26][C:27]1[C:32]([CH:33]=[O:34])=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>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>[F:26][C:27]1[C:32]([CH:33]=[O:34])=[CH:31][CH:30]=[CH:29][C:28]=1[C:2]1[N:6]([S:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=1
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Reactant: O=Cc1cccc(B(O)O)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CN(Cc1cc(-c2cccc(C=O)c2F)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C

Procedure:
By a similar operation as in Reference Example 79 and using tert-butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (430 mg), (2-fluoro-3-formylphenyl)boronic acid (252 mg), sodium carbonate (254 mg) and tetrakis(triphenylphosphine)palladium (173 mg), the title compound was obtained as a pale-yellow oil (yield 250 mg, 53%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][C:8](=O)[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:6]2[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1.P(Cl)(Cl)([Cl:33])=O>>[Cl:33][C:8]1[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:6]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=2)[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=1
Reactant: CCOC(=O)c1c(-c2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc2[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1c(Cl)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Reaction time: 1.33 h
Yield: 73 %

Procedure:
A mixture of ethyl 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2(1H)-quinolone-3-carboxylate (5.0 g) and phosphorus oxychloride (POCl3)(6.3 ml) was stirred at 100° to 110° C. for 80 minutes. The reaction mixture was concentrated under reduced pressure. The residue was poured into water, neutralized with an aqueous saturated sodium bicarbonate solution and extracted with chloroform. The chloroform layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated. The residual oil was subjected to column chromatography on silica gel. The fractions eluted with chloroform gave ethyl 2-chloro-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylate (3.8 g, 73%) which was then recrystallized from ethyl acetate-hexane. mp. 168°-169° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]([N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[C:9]2[CH:10]=[C:11]([NH2:16])[C:12]([NH2:15])=[CH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH:22](=O)[CH:23]=O>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:8]([N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[C:9]2[CH:10]=[C:11]3[C:12](=[CH:13][CH:14]=2)[N:15]=[CH:23][CH:22]=[N:16]3)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(C(c2cccc(F)c2)n2ccnc2)cc1N
Reactant: O=CC=O
Solvent: CO
Product: Fc1cccc(C(c2ccc3nccnc3c2)n2ccnc2)c1
Yield: 74.5 %

Procedure:
A mixture of 8.1 parts of 4-[(3-fluorophenyl)(1H-imidazol-1-yl)methyl]-1,2-benzenediamine, 5 parts of ethanedial and 80 parts of methanol was stirred at reflux temperature. Upon complete reaction, the mixture was evaporated to dry and the residue was taken up in water. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (98:2 by volume) was eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 6.35 parts (74.5%) of 6-[(3-fluorophenyl)(1H-imidazol-1-yl)methyl]quinoxaline; mp. 109.7° C. (comp. 15).
Reaction SMILES: [S:1]1[CH2:6]CSCC1.C[O:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10].O1[CH2:20][CH2:19][CH2:18][CH2:17]1>>[OH:11][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:10])=[O:8].[CH3:17][CH:18]1[CH2:19][CH2:20][CH2:6][S:1][S:9]1
Reactant: COS(=O)(=O)C(F)(F)F
Reactant: C1CCOC1
Reactant: C1CSCCS1
Product: CC1CCCSS1
Product: O=S(=O)(O)C(F)(F)F

Procedure:
2 mmol of 1,4-dithiane was dissolved in 8 ml of tetrahydrofuran at 0° C., and about 2 mmol of methyltrifluoromethane sulfonate was slowly dripped to the mixture. After 20 minutes a white solid product was obtained in a salt form. The solid product was filtered and dried for 1 hour in an oven at 50° C. to obtain the following product:
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[CH:14]([OH:17])[CH2:15][CH3:16].[B:18](OC(C)C)([O:23]C(C)C)[O:19]C(C)C.Cl>CCCCC.C1COCC1>[F:13][C:9]1[C:8]([CH:14]([OH:17])[CH2:15][CH3:16])=[C:7]([B:18]([OH:23])[OH:19])[CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCC(O)c1c(F)cccc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCC(O)c1c(F)cccc1B(O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of n-BuLi (2.15 mL, 4.3 mmol) in pentane (2 M) is added dropwise to a solution of 1-(2-bromo-6-fluoro-phenyl)-propan-1-ol (500 mg, 2.15 mmol) in THF at −78° C. The mixture is stirred for 2 hours at −78° C. (i-PrO)3B (41 mL, 4.3 mmol) is added in one portion and the mixture is warmed slowly to room temperature and stirred for 12 hours. 1N HCl (10 mL) is added and the mixture is stirred for 2 hours at room temperature. The organic layer is separated and the aqueous layer is extracted with DCM (3×30 mL). The combined organic layers are dried and solvents are removed in vacuo. The crude product is purified by PTLC eluting with 5% MeOH in DCM to give 3-fluoro-2-(1-hydroxypropyl)phenylboronic acid.
Reaction SMILES: [Na].Cl[C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:6]([CH3:12])=[CH:5][N:4]=1.[CH3:13][OH:14]>>[CH3:13][O:14][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:6]([CH3:12])=[CH:5][N:4]=1
Reactant: CO
Reactant: Cc1cnc(Cl)c([N+](=O)[O-])c1
Agent: [Na]
Product: COc1ncc(C)cc1[N+](=O)[O-]
Yield: 92 %

Procedure:
To a solution of sodium (2.31 g, 0.1 mol) dissolved in methanol (100 mL) at room temperature, 2-chloro-5-methyl-3-nitro-pyridine (17.2 g, 0.1 map was added. The reaction mixture was refluxed for 4 h under N2 atmosphere. After evaporated to dryness, the residue was diluted with water (100 mL) and extracted (2×50 mL CH2Cl2). The combined extracts were washed with brine, dried on MgSO4, and filtered. The solvent was evaporated and the residue was crystallized from a mixture of water (300 mL) and ethanol (20 mL) to yield 2-methoxy-5-methyl-3-nitro-pyridine as a light orange solid (15.4 g, 92%). 1H-NMR (DMSO-d6): δ 2.31 (s, 3H, CH3), 3.98 (s, 3H, OCH3), 8.30 (d, 1H, J=2.0 Hz, Py-H), 8.35 (d, 1H, J=2.0 Hz, Py-H); 13C-NMR (DMSO-d6): δ 16.80, 54.86, 127.36, 133.7, 135.91, 152.03, 154.27; HR-MS (ESI+) m/z 169.0570 [M+H]+; C7H8N2O3 requires 168.0535.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([C@:8]1([OH:30])[CH2:25][C:24]2[C:23]([OH:26])=[C:22]3[C:13]([C:14](=[O:28])[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:21]3=[O:27])=[C:12]([OH:29])[C:11]=2[CH2:10][CH2:9]1)=[O:7])(=[O:3])[CH3:2].[Br:31]Br.C12OC1CCCC2.Br>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[Br:31][CH:10]1[CH2:9][C@@:8]([C:6](=[O:7])[CH2:5][O:4][C:1](=[O:3])[CH3:2])([OH:30])[CH2:25][C:24]2[C:23]([OH:26])=[C:22]3[C:13]([C:14](=[O:28])[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:21]3=[O:27])=[C:12]([OH:29])[C:11]1=2
Reactant: BrBr
Reactant: CC(=O)OCC(=O)[C@@]1(O)CCc2c(O)c3c(c(O)c2C1)C(=O)c1ccccc1C3=O
Agent: Br
Agent: C1CCC2OC2C1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC(=O)OCC(=O)[C@]1(O)Cc2c(O)c3c(c(O)c2C(Br)C1)C(=O)c1ccccc1C3=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Treatment of 9(R)-acetoxyacetyl-6,9,11-trihydroxy-5,7,8,9,10,12-hexahydronaphthacene-5,12-dione (3.5 g) with bromine (3.41 g) was effected in a refluxing mixture of chloroform (875 ml) and carbon tetrachloride (1750 ml) with heating for 3 hours, while the reaction mixture was irradiated with 500 W lamp as radical reaction initiator in the presence of cyclohexene oxide (2.51 g) as a scavenger of the generated HBr. The solvent was removed under reduced pressure and ether (52.5 ml) was added to the residue. The resultant mixture was stirred at room temperature for 1.5 hours and precipitated crystals were filtered to give reddish orange powders of 7-bromo-9(S)-acetoxyacetyl-6,9,11-trihydroxy-5,7,8,9,10,12-hexahydronaphthacene-5,12-dione. M.P., 173°-175° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:18]([CH2:19][CH3:20])[N:17]=[C:16]([CH2:21][OH:22])[C:15]=2[CH3:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24](OC(N1CCC(C2NNC(=O)C=2C)CC1)=O)(C)(C)C.CI.C(I)C>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:18]([CH2:19][CH3:20])[N:17]=[C:16]([CH2:21][O:22][CH3:24])[C:15]=2[CH3:23])[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCn1nc(CO)c(C)c1C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cc1c(C2CCN(C(=O)OC(C)(C)C)CC2)[nH][nH]c1=O
Solvent: CI
Solvent: CCI
Product: CCn1nc(COC)c(C)c1C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
The title compound was prepared from 1-(tert-butoxycarbonyl)-4-(1-ethyl-3-hydroxymethyl-4-methyl-(1H)-pyrazol-5-yl)piperidine (from Piperidine 19, Step C) using a procedure analogous to that described for Piperidine 15, Step E, except methyliodide was substutited for ethyliodide. RF: 0.47 (3:2 v/v hexanes/acetone); 1H-NMR (500 MHz) δ 1.39 (t, J=7.2, 3H), 1.49 (s, 9H), 1.69–1.71 (m, 2H), 1.85–1.94 (m, 2H), 2.08 (s, 3H), 2.75–2.81 (m, 3H), 3.39 (s, 3H), 4.12 (q, J=7.2, 2H), 4.14–4.27 (m, 2H), 4.38 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][C@H:6]([CH3:13])[CH2:5]2.[CH2:14](N(CC)CC)[CH3:15].C([B-](F)(F)F)=C.[K+]>CCO.C(Cl)(Cl)Cl>[CH:14]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][CH:6]([CH3:13])[CH2:5]2)=[CH2:15]
Reactant: CCN(CC)CC
Reactant: C[C@@H]1Cc2cc(Br)ccc2C(=O)O1
Agent: C=C[B-](F)(F)F
Agent: [K+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: C=Cc1ccc2c(c1)CC(C)OC2=O
Temperature: 100 °C

Procedure:
A solution of (3R)-6-bromo-3-methyl-3,4-dihydro-1H-isochromen-1-one (2.4 g, 9.96 mmol) and triethylamine (2.78 ml, 19.91 mmol) in EtOH (39.8 ml) was added to a microwave vial containing Cl2Pd(dppf)2-DCM (0.406 g, 0.498 mmol) and potassium vinyltrifluoroborate (2,000 g, 14.93 mmol). The contents of the vial were heated to 100° C. for 1 hour after which the mixture was cooled, diluted with chloroform (50 mL) and washed with aqueous ammonium chloride (25 mL). The organic layer was then dried over magnesium sulfate, filtered and the solvent was evaporated under reduced pressure. MPLC purification (15-60% EtOAc/Hex) gave 6-ethenyl-3-methyl-3,4-dihydro-1H-isochromen-1-one. 1H NMR (500 MHz; CDCl3): 8.07 (d, J=8.0 Hz, 1H), 7.44 (dd, J=1.2, 7.1 Hz, 1H), 7.26 (s, 1H), 6.75 (dd, J=10.8, 17.6 Hz, 1H), 5.90 (d, J=17.6 Hz, 1H), 5.44 (d, J=11 Hz, 1H), 4.75 (m, 1H), 2.96 (m, 2H), 1.54 (d, J=6.1 Hz, 3H); LC/MS (M+H)+189;
Reaction SMILES: [CH2:1]([N:15]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])S(C1C=CC(C)=CC=1)(=O)=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C-]1C2C(=CC=CC=2)C=CC=1.[Li+].CO.O>O1CCCC1>[CH2:26]([NH:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCCCCCCCCCN(CCCCCCCCCCCCCC)S(=O)(=O)c1ccc(C)cc1
Agent: [Li+]
Agent: [c-]1cccc2ccccc12
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCCCCCCCCNCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.6 %

Procedure:
A solution of N,N-ditetradecyl-p-toluenesulfonamide (4.16 g; 7.38 mmol) in tetrahydrofuran (2 ml) is added at 0° C. to a solution of lithium naphthalenide [prepared from naphthalene (4.73 g; 36.88 mmol) and lithium metal (0.38 g; 55.35 mmol) in tetrahydrofuran (40 ml) at room temperature for 1 h] and the reaction mixture is stirred for 1 h at room temperature. Methanol (2 ml) is added, followed by water (25 ml) and the mixture is extracted with ether (2×25 ml). The organic phase is dried over sodium sulfate, filtered and concentrated under reduced pressure to give a white solid which is purified by chromatography on a column of silica gel (eluent: ether) to give ditetradecylamine (2.68 g; 89%).
Reaction SMILES: [H-].[Na+].[CH:3]1([NH:6][C:7](=[O:15])[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.[CH2:16](Br)[C:17]#[CH:18].C1(C)C=CC=CC=1>CCOCC.C1COCC1>[CH:3]1([N:6]([CH2:18][C:17]#[CH:16])[C:7](=[O:15])[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:5]1
Reactant: C#CCBr
Reactant: O=C(Cc1ccccc1)NC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: C#CCN(C(=O)Cc1ccccc1)C1CC1
Temperature: 5 °C
Reaction time: 0.33 h
Yield: 58.8 %

Procedure:
Sodium hydride (60% in mineral oil, 706 mg, 17.65 mmol) was washed with dry ether (2×20 mL) and then suspended in dry THF (30 mL) and cooled with ice-water. Crude N-cyclopropyl-2-phenylacetamide from the last step in THF (5 mL) was added dropwise at 5° C. to the sodium hydride suspension. The reaction mixture was stirred at 5° C. for 20 min. A solution of propargyl bromide in toluene (80% wt., 2.68 mL, 24.06 mmol) was added dropwise with a syringe. The ice bath was removed and the mixture was stirred at room temperature overnight. The mixture was poured into ice-water (100 mL) and extracted with DCM (3×100 mL). The organic phases were combined and washed with brine (2×50 mL), dried with anhydrous MgSO4, filtered and evaporated to dryness, then purified by silica gel column chromatography, eluting with MeOH/DCM (0-2%) to give the title compound (2.05 g, 58.8% yield), LRMS ESI (M+H+) 214.
Reaction SMILES: C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O.[NH2:14][C:15]1[N:23]=[C:22]2[C:18]([NH:19][CH:20]=[N:21]2)=[C:17]([O:24][CH:25]([CH3:27])[CH3:26])[N:16]=1.[N:28]([C@@H:31]1[C@@H:35]([CH2:36][OH:37])[O:34][C@@H:33](N2C=C(C)C(=O)NC2=O)[CH2:32]1)=[N+:29]=[N-:30]>>[NH2:14][C:15]1[N:23]=[C:22]2[C:18]([N:19]=[CH:20][N:21]2[C@@H:33]2[O:34][C@H:35]([CH2:36][OH:37])[C@@H:31]([N:28]=[N+:29]=[N-:30])[CH2:32]2)=[C:17]([O:24][CH:25]([CH3:27])[CH3:26])[N:16]=1
Reactant: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: CC(C)Oc1nc(N)nc2nc[nH]c12
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Product: CC(C)Oc1nc(N)nc2c1ncn2[C@H]1C[C@H](N=[N+]=[N-])[C@@H](CO)O1
Temperature: 50 °C
Yield: 28 %

Procedure:
To 800 mL of an aqueous pH 6.0, 50 mM citrate buffer, prepared as described in Example 2c. was added 2-amino-6-isopropoxypurine (0.159 g, 0.8 mmol) and 3'-azido-3'-deoxythymidine (1.069 g, 4.0 mmol). Solution was achieved by heating the mixture at 50° C. with sonication. A sample was removed as a control. A 40 mL solution of trans-N-deoxyribosylase (Example 2b) with an activity of 1500 units/mL was added. The reaction was heated at 50° C. Six days later, 0.159 g, 0.8 mmol, of 2-amino-6-isopropoxypurine was added to the reaction. Fifteen days after the reaction was started, another 0.159 g, 0.8 mmol, of 2-amino-6-isopropoxypurine and 0.428 g, 1.6 mmol, of 3'-azido-3'-deoxythymidine were added to the reaction. Twenty-seven days after the reaction was started, 0.159 g, 0.58 mmoles, of 2-amino-6-isopropoxypurine was added to the reaction. The reaction was stopped after thirty-three days. The reaction was heated at 80° C. to precipitate the enzyme and filtered. The aqueous solution was extracted with ethyl acetate to remove the product. The combined ethyl acetate fractions were dried with magnesium sulfate, filtered, and the solvent was removed in vacuo to give a foam. The foam was chromatographed on basic alumina grade 1 eluted with chloroform/methanol (95:5, v/v). The product containing fractions were combined and the solvent removed in vacuo to give the product as a foam (28% yield). mp=195°-197° C.
Reaction SMILES: [Br:1]Br.[F:3][CH:4]([F:16])[O:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=1.O.O.O.C([O-])(=O)C.[Na+].ClCCl>C(Cl)(Cl)(Cl)Cl>[Br:1][C:11]1[C:9]([NH2:10])=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=[C:6]([O:5][CH:4]([F:16])[F:3])[CH:12]=1
Reactant: BrBr
Reactant: Nc1ccc(OC(F)F)cc1[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: Nc1c(Br)cc(OC(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Bromine (10 cm3) was added to a stirred suspension of 4-difluoromethoxy-2-nitroaniline (available as described for example in Example B5(b) of U.S. Pat. No. 4,686,230.) (26.6 g) and sodium acetate trihydrate (19.5 g) in carbon tetrachloride (250 mls). After stirring at ambient temperature for a period of 30 minutes, the reaction mixture was added to dichloromethane (350 mls) and washed with aqueous sodium metabisulphite solution, followed by aqueous sodium bicarbonate solution, and finally brine. The organic layer was the dried over anhydrous magnesium sulphate, and removal of the solvent by evaporation under reduced pressure, gave 6-bromo-4-difluoromethoxy-2-nitroaniline as an orange-brown solid. Melting Point: 60.5°-61.5° C. (cyclohexane).
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][C@H:9]([C:11]([OH:13])=[O:12])[NH2:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[Na+].C(=O)(O)[O-].[Na+].Cl[S:24]([C:27]1[CH:36]=[CH:35][CH:34]=[CH:33][C:28]=1[C:29]([O:31][CH3:32])=[O:30])(=[O:26])=[O:25]>O1CCOCC1>[CH3:32][O:31][C:29]([C:28]1[CH:33]=[CH:34][CH:35]=[CH:36][C:27]=1[S:24]([NH:10][C@@H:9]([C:11]([OH:13])=[O:12])[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:15][CH:14]=1)(=[O:26])=[O:25])=[O:30]
Reactant: N[C@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: COC(=O)c1ccccc1S(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COC(=O)c1ccccc1S(=O)(=O)N[C@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Temperature: 25 °C
Reaction time: 9 h
Yield: 71.6 %

Procedure:
2.3 g of p-nitro-D-phenylalanine are suspended in 25 ml of dioxan and treated with 10 ml of 1N sodium hydroxide solution and 1.7 g of sodium bicarbonate. A solution of 2.6 g of methyl 2-chlorosulfonylbenzoate in 22 ml of dioxanl is added dropwise thereto and the mixture is stirred at room temperature for 9 hours. The reaction mixture is poured into ice-cold 2N hydrochloric acid and extracted with ethyl acetate. The organic phase is washed with water, dried and evaporated. There are obtained 3.2 g of N-[[o-(methoxycarbonyl)phenyl]sulfonyl]-3-(p-nitrophenyl)-D-alanine.