Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:18][C@H:19]([C:23]([OH:25])=[O:24])[CH2:20][CH2:21][CH3:22])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].S(Cl)(Cl)=O.[CH3:30]O>C(OC(=O)C)C>[NH:18]([C:1]([O:3][CH2:4][CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12]2[C:17]1=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:2])[C@H:19]([C:23]([O:25][CH3:30])=[O:24])[CH2:20][CH2:21][CH3:22]
Reactant: CCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: CCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC

Procedure:
To a chilled solution of the commercially available Fmoc-norvaline (25 g, 73.75 mmol) in anhydrous methanol (469 ml) was added thionyl chloride (53.76 ml, 737.5 mmol) over one hour. TLC in ethylacetate taken an hour later confirmed the completion of the reaction (Rf=0.85). The reaction mixture was concentrated and the remaining residue was dissolved in ethylacetate. The organic layer was washed with several 200 ml portions of saturated sodium bicarbonate followed by brine. The organic layer was dried, filtered and concentrated to afford Fmoc-norVal-OMe) as a white solid (26.03 g) in quantitative yield. NMR δ ppm (CD3OD): 7.7 (m, 2H), 7.6 (m, 2H), 7.4 (m, 2H), 7.3 (m, 2H), 4.3 (m, 2H), 4.1 (m, 2H), 3.7 (s, 3H), 1.7 (m, 1H), 1.6 (m, 1H), 1.4 (m, 2H), 0.95 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:25])=[C:6]([CH:24]=1)[CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[O:16][CH2:15][CH2:14][N:13](C(=O)C(F)(F)F)[C:12]=2[CH:23]=1.[BH4-].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:25])=[C:6]([CH:24]=1)[CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[O:16][CH2:15][CH2:14][NH:13][C:12]=2[CH:23]=1
Reactant: O=C(N1CCOc2ccc(Cc3cc(Br)ccc3Cl)cc21)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Clc1ccc(Br)cc1Cc1ccc2c(c1)NCCO2
Reaction time: 8 h
Yield: 91 %

Procedure:
To a stirred solution of 1-[6-(5-bromo-2-chloro-benzyl)-2,3-dihydro-benzo[1,4]oxazin-4-yl]-2,2,2-trifluoro-ethanone (8.6 g, 19.8 mmol) in ethanol (40 mL) was added NaBH4 (1.5 g, 39.0 mmol) portion wise and the reaction mixture was stirred overnight. Excess of NaBH4 was quenched by adding aq. NH4Cl, and ethanol was evaporated. The residue was partitioned between ethyl acetate and water, and the organic layer was separated, washed with brine (40 mL) and dried over sodium sulphate. Crude product obtained after evaporation of solvent was purified by silica gel column chromatography to furnish 6-(5-bromo-2-chloro-benzyl)-3,4-dihydro-2H-benzo[1,4]oxazine (6.1 g).
Reaction SMILES: [C:1]([NH:4][C:5](=[O:26])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:15])=[O:14])=[CH:9][C:8]=1[N+:23]([O-])=O)(=[O:3])[CH3:2].[H][H]>CO.COCCO.[Ni]>[C:1]([NH:4][C:5](=[O:26])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:15])=[O:14])=[CH:9][C:8]=1[NH2:23])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)NC(=O)Nc1ccc(S(=O)(=O)Oc2ccccc2)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: COCCO
Solvent: CO
Product: CC(=O)NC(=O)Nc1ccc(S(=O)(=O)Oc2ccccc2)cc1N

Procedure:
48 g of 2-(3-acetylureido)-5-phenoxysulfonylnitrobenzene in 300 ml of methanol and 300 ml of 2-methoxyethanol are hydrogenated under normal pressure with a catalytic amount of Raney nickel. After hydrogen uptake is complete, the catalyst is filtered off with suction, washed with dimethylformamide and the solution is evaporated under reduced pressure. The residue is stirred with hot methanol, and the solid is filtered off cold under suction and washed with methanol and diisopropyl ether, melting point 202° C., decomposition.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:11](Cl)(=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].Cl>N1C=CC=CC=1>[C:11]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)(=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCC(=O)Cl
Reactant: O=C(O)c1ccc(O)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCC(=O)Oc1ccc(C(=O)O)cc1
Temperature: 0 °C
Yield: 86.5 %

Procedure:
10 g 4-hydroxybenzoic acid was dissolved in 50 ml dry pyridine. The solution was then externally cooled with ice water while 10.5 g hexanoyl chloride was added dropwise. After the resultant mixture had been further stirred overnight at room temperature, it was poured in 300 ml 3-N dilute hydrochloric acid. White precipitate was taken up by filtration. By recrystallizing the white precipitate in a mixed solvent of methanol/water (3:2), 14.8 g 4-hexanoyloxybenzoic acid was obtained in 87% yield based upon the amount of the hydroxybenzoic acid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:13])=[CH:6][CH:5]=1)([OH:3])=[O:2].C(=O)(O)[O-].[Na+].CN(C)C=O.I[CH2:32][CH3:33]>O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]#[C:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:13])=[CH:8][CH:9]=1)([O:3][CH2:32][CH3:33])=[O:2]
Reactant: CCI
Reactant: O=C(C#Cc1ccc(C(=O)O)cc1)Nc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(C#CC(=O)Nc2ccccc2)cc1
Temperature: 25 °C
Yield: 89.4 %

Procedure:
A mixture of 1.00 g (3.77 mmol)3 -(4-carboxyphenyl)-N-phenylpropiolamide, 1.00 g (excess) anhydrous sodium bicarbonate and 25 mL dry N,N-dimethylformamide was stirred at room temperature. Added was 1.95 g (excess) iodoethane and the mixture heated at 70°-80° C. for 3 hrs. The mixture was allowed to cool to room temperature and poured into 75 mL water. The resulting solid was filtered and recrystallized from ethanol/water to provide 0.99 g (3.37 mmol, 90%)3-(4-carbethoxyphenyl)-N-phenylpropiolamide as a pale, yellow powder, mp=114°-115° C. NMR (CDCl3 /TMS): 1.40 (t, 3H), 4.39 (q, 2H), 7.16 (t, 1H), 7.36 (t, 2H), 7.60 (d, 4H), 7.90 (s, 1H), 8.03 (d, 2H)). IR (KBr): 3292, 2210, 1692, 1660. High resolution mass spectrum: Calculated; 294.113019. Measured; 294.112376.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH3:14])[C@H:9]1[CH2:15][CH3:16])C1C=CC=CC=1.[ClH:17]>CO.[OH-].[OH-].[Pd+2]>[ClH:17].[CH2:15]([C@@H:9]1[C@@H:10]([CH3:14])[O:11][CH2:12][CH2:13][NH:8]1)[CH3:16]
Reactant: CC[C@@H]1[C@@H](C)OCCN1Cc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: CC[C@H]1NCCO[C@@H]1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Pd(OH)2 (15.0 mg, 10% on carbon) was added to a solution of (2R,3R)-4-benzyl-3-ethyl-2-methylmorpholine (110 mg, 0.50 mmol) in MeOH (10 mL) under N2. Hydrogen was bubbled through the reaction mixture for one minute and then the reaction was stirred at rt under hydrogen (1 atm) for 2 hours. Then, N2 was bubbled through the reaction for 1 minute. A solution of HCl (3M, 3 mL, 9 mmol) in methanol was added. The reaction mixture was stirred at room temperature for 30 minutes and concentrated in vacuo to afford (2R,3R)-3-ethyl-2-methylmorpholine hydrochloride. 1H NMR (300 MHz, DMSO-d6) δ 9.45-9.34 (br s, 1H), 3.84-3.91 (m, 1H), 3.68-3.78 (m, 1H), 3.53-3.61 (m, 1H), 3.08-3.21 (m, 1H), 2.93-3.01 (m, 1H), 2.70-2.85 (m, 1H), 1.45-1.81 (m, 2H), 1.13 (d, J=6.3 Hz, 3H), 0.90-1.05 (m, 3H). MS APCl calc'd for C7H15NO [M+H]+ 130. found 130.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([O:21][CH3:22])[CH:20]=1)[NH2:17]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:17][C:16]1[CH:18]=[C:19]([O:21][CH3:22])[CH:20]=[C:14]([O:13][CH3:12])[CH:15]=1)=[O:9]
Reactant: COc1cc(N)cc(OC)c1
Reactant: O=C(O)c1cc(Br)ccc1O
Product: COc1cc(NC(=O)c2cc(Br)ccc2O)cc(OC)c1
Yield: 40.3 %

Procedure:
Using 5-bromosalicylic acid and 3,5-dimethoxyaniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:9]([O:11][C:12](=[O:18])[C:13](=O)[CH:14](Br)[CH3:15])[CH3:10].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[NH2:8][C:7]1[C:2]2[N:3]([C:14]([CH3:15])=[C:13]([C:12]([O:11][CH2:9][CH3:10])=[O:18])[N:1]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(=O)C(C)Br
Reactant: Nc1cccnc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)c1nc2c(N)cccn2c1C
Yield: 33.8 %

Procedure:
A solution of 2,3-diaminopyridine (6.8 g, 62 mmol) and 3-bromo-2-oxo-butyric acid ethyl ester (13 g, 62 mmol) in 1,2-dimethoxyethane (150 ml) was refluxed for 2 h. Sodium carbonate (6.5 g, 62 mmol) was added and the mixture was refluxed for 2 h. The solids were isolated by filtration and washed with dichloromethane:methanol (10:1). The filtrate and washings were combined and the solvents were removed under reduced pressure. The oily residue was washed with petroleum ether and was purified twice by column chromatography on silica gel using 1) dichloromethane:methanol (10:1) 2) ethyl acetate as eluent to give 4.6 g (34%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][C:10]#[N:11].Cl[CH2:13][CH2:14][N:15]([CH2:23][CH2:24]Cl)[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].C(=O)([O-])[O-].CS(C)=O>C(OCC)(=O)C>[C:10]([C:9]1([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=2[Cl:1])[CH2:24][CH2:23][N:15]([C:16]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:22])[CH2:14][CH2:13]1)#[N:11]
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Reactant: N#CCc1cccc(Cl)c1Cl
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2cccc(Cl)c2Cl)CC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 58.9 %

Procedure:
2-(2,3-dichlorophenyl)acetonitrile (2.49 g crude, est. 83% purity, 11 mmol), 2.70 g tert-butyl bis(2-chloroethyl)carbamate (J. Med. Chem. 1992, 35, 11, 2033-2039) (11 mmol), 19.5 g aesium carbonate (60 mmol) and 200 ml DMSO were combined in a round bottom flask and stirred at room temperature for 4 days. The reaction mixture was diluted with ethyl acetate and the organic layer washed with 1M aq. KHSO4 solution, and then saturated aq. NaHCO3 solution, then brine. The organic layer was dried over magnesium sulfate, filtered and concentrated. The product was purified by column chromatography on silica, using a gradient from 5% to 35% ethyl acetate in hexanes as eluent. 2.3 g of the title compound were isolated as an oil (59% yield)
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[CH2:17][C:16]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[C:7]=3[NH:8][C:9](=[O:10])[C:4]2=[N:3][CH:2]=1.[N+:18]([C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=O)([O-:20])=[O:19].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[N+:18]([C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=[C:17]1[C:6]2[N:5]3[CH:1]=[CH:2][N:3]=[C:4]3[C:9](=[O:10])[NH:8][C:7]=2[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:16]1=2)([O-:20])=[O:19]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: O=c1[nH]c2c(n3ccnc13)Cc1ccccc1-2
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=c1[nH]c2c3ccccc3c(=Cc3cccc([N+](=O)[O-])c3)c2n2ccnc12
Yield: 62.6 %

Procedure:
10 g of 5H,10H-imidazo[1,2-a]indeno[1,2-e]-pyrazin-4-one and 27.1 g of 3-nitrobenzaldehyde are refluxed for 15 hours in the presence of 13.79 g of ammonium acetate in 600 ml of acetic acid. The precipitate formed is filtered off, washed with water and dried under reduced pressure (1 mmHg; 0.13 kPa) at 45° C. 10 g of 10-(3-nitrobenzylidene)-5H-imidazo-[1,2-a]indeno[1,2-e]pyrazin-4-one are obtained in the form of a yellowish powder, the melting point of which is greater than 260° C. (Analysis, C20H12N4O3 ; % calculated C: 67.42; H: 3.39; N: 15.57; O: 13.47; % found C: 67.4; H: 3.2; N: 15.6; O: 13.5).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[C:20]([C:24]#[N:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[F:28][C:29]1[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31]Br>>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:31][C:30]5[CH:33]=[CH:34][CH:35]=[C:36]([F:37])[C:29]=5[F:28])[C:20]([C:24]#[N:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Fc1cccc(CBr)c1F
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C#N)c4Br)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C#N)c4Cc3cccc(F)c3F)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-cyano-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2,3-difluoro-benzyl bromide following a procedure analogous to that described for Intermediate 7. LC (method 4): tR=1.25 min; Mass spectrum (ESI+): m/z=476 [M+H]+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:15][N:16]([CH3:20])[CH2:17][CH2:18][NH2:19]>ClCCl>[CH3:15][N:16]([CH3:20])[CH2:17][CH2:18][NH:19][S:11]([C:8]1[CH:9]=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=1)(=[O:13])=[O:12]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN(C)CCN
Solvent: ClCCl
Product: CC(=O)Nc1ccc(S(=O)(=O)NCCN(C)C)cc1
Temperature: 25 °C

Procedure:
4-Acetylaminobenzenesulfonyl chloride is introduced into dichloromethane and treated at room temperature with two equivalents of N,N-dimethylethylenediamine and stirred at room temperature until complete conversion can be determined (LCMS). For work-up, the solvent is distilled off, the oily residue is taken up in dichloromethane or ethyl acetate and the mixture is washed with NaHCO3 solution. The phases are separated and the aqueous phase is extracted once more with dichloromethane or ethyl acetate. The organic phases are dried using Na2SO4 and concentrated. The crude product thus obtained is reacted further without further purification. (MS-CI+: 286.0; LCMS Rt=2.542 min)
Reaction SMILES: [N:1]1([CH2:10][CH2:11][CH2:12][CH2:13]O)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.S(Cl)([Cl:17])=O>ClC(Cl)Cl>[Cl:17][CH2:13][CH2:12][CH2:11][CH2:10][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=S(Cl)Cl
Reactant: OCCCCn1cnc2ccccc21
Solvent: ClC(Cl)Cl
Product: ClCCCCn1cnc2ccccc21
Reaction time: 3 h
Yield: 45 %

Procedure:
To a stirred mixture of 50 parts of 1H-benzimidazol-1-butanol and 375 parts of trichloromethane are added dropwise 35.2 parts of sulfinyl chloride. Upon completion, stirring is continued for 3 hours at reflux temperature. The reaction mixture is evaporated. The residue is taken up in trichloromethane. The whole is washed with ammonium hydroxide and the solvent is evaporated. The residue is purified by column-chromatography over silica gel using trichloromethane as eluent. The pure fractions are collected and the eluent is evaporated, yielding 22 parts (45%) of 1-(4-chlorobutyl)-1H-benzimidazole as an oily residue.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[CH:7]=[CH:6][C:5]=1[O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]([F:36])([F:35])[F:34])=[CH:23][C:22]=1[N+:37]([O-])=O)([O-])=O.[H][H]>C(O)C.[Pt]=O>[NH2:37][C:22]1[CH:23]=[C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]([F:35])([F:36])[F:34])[CH:25]=[CH:26][C:21]=1[O:20][C:5]1[CH:6]=[CH:7][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:17])([F:18])[F:19])=[CH:9][C:4]=1[NH2:1]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(-c2ccccc2C(F)(F)F)ccc1Oc1ccc(-c2ccccc2C(F)(F)F)cc1[N+](=O)[O-]
Agent: O=[Pt]
Solvent: CCO
Product: Nc1cc(-c2ccccc2C(F)(F)F)ccc1Oc1ccc(-c2ccccc2C(F)(F)F)cc1N
Yield: 49.3 %

Procedure:
2-Nitro-α,α,α-trifluoro-p-tolylphenyl ether (57.0 g., 0.209 mole) is dissolved in ethanol (200 ml.) and shaken in an atmosphere of hydrogen in a Parr apparatus in the presence of platinum oxide (100 mg.) until uptake is complete. The catalyst is removed by filtration and the solvent stripped off to give 2-amino-α,α,α-trifluoro-p- tolyl phenylether (50.3 g. 99%) which is used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=1)[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C)C=O>[C:1]([O:5][C:6]([N:8]([C@@H:9]([CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=1)[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc2ccccc2c1)C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(Cc1ccccc1)[C@@H](Cc1ccc2ccccc2c1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of benzyl (2S)-2-[N-(tert-butoxycarbonyl)amino]-3-(2-naphthyl)propionate (5.0 g) in dimethylformamide (50 ml) was added dropwise to a stirred mixture of 60% sodium hydride (0.6 g) and dimethylformamide (50 ml) at ice-bath temperature. After the addition was completed, the reaction mixture was stirred at the same temperature for 30 minutes. Benzyl bromide (1.76 ml) was added and then the whole mixture was stirred for 3.5 hours. Additional benzyl bromide (0.4 ml) was added and then stirred for 2.5 hours. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed successively with 1N hydrochloric acid, aqueous sodium bicarbonate solution and brine and dried over magnesium sulfate. After evaporation of the solvent in vacuo, the residue was purified by column chromatography on silica gel eluting with a mixture of n-hexane and ethyl acetate (4:1) to give benzyl (2S)-2-[N-(tert-butoxycarbonyl)-N-benzylamino]-3-(2-naphthyl)propionate (3.53 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:22]=[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20]([Br:31])=[CH:19][C:10]=1[C:11]([NH:13][CH2:14][CH2:15][CH2:16][O:17][CH3:18])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[Si]([N:42]=[N+:43]=[N-:44])(C)(C)C>ClCCl>[CH2:1]([O:8][C:9]1[CH:22]=[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20]([Br:31])=[CH:19][C:10]=1[C:11]1[N:13]([CH2:14][CH2:15][CH2:16][O:17][CH3:18])[N:44]=[N:43][N:42]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCCNC(=O)c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: COCCCn1nnnc1-c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
2,4-Bis-benzyloxy-5-bromo-N-(3-methoxy-propyl)-benzamide (3.3 g, 6.8 mmole) was dissolved in anhydrous dichloromethane (20 ml), then PCl5 (1.77 g, 8.2 mmol) was added and the resulting solution was stirred at r.t. for 3 h under nitrogen. The reaction mixture was then cooled to 0° C., and TMSN3 (6 ml, neat) was added at 0° C. and the resulting mixture was stirred at r.t. for 3 hr. After quenching the reaction with NaHCO3 solution, and the reaction mixture was extracted with dichloromethane (30 ml×3). The combined organic was dried over Na2SO4. After filtration and concentration, the residue was purified by flash chromatography on silica gel to give 5-(2,4-bis-benzyloxy-5-bromo-phenyl)-1-(3-methoxy-propyl)-1H-tetrazole (2.8 g, 82%). M.p.: 92-93° C.; 400 MHz 1H NMR (CDCl3) δ: 7.68 (s, 1H), 7.44-7.31 (m, 8H), 7.19-7.15 (m, 2H), 6.64 (s, 1H), 5.17 (s, 2H), 4.99 (s, 2H), 4.28 (t, J=7.2 Hz, 2H), 3.22 (t, J=6.0 Hz, 2H), 3.16 (s, 3H), 2.03 (pent, J=6.4 Hz, 2H); LCMS: 509, 511 [M+H].
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(N(CC)CC)C.[Cl:19][CH2:20][C:21](Cl)=[O:22]>C1COCC1>[Cl:19][CH2:20][C:21]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)=[O:22]
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)CCl)cc1[N+](=O)[O-]
Yield: 89.7 %

Procedure:
A solution of 4-methyl-3-nitroaniline (1.0 g, 6.58 mmol, Lancaster), triethylamine (2.00 g, 19.7 mmol, Aldrich), and chloroacetyl chloride (0.96 g, 8.55 mmol) in THF (50 mL) was stirred overnight at rt. The reaction was washed with 1M HCl (50 mL), concentrated by rotary evaporation, and placed under high vacuum to give 2-chloro-N-(4-methyl-3-nitrophenyl)acetamide (1.35 g, 90%). ESIMS (M+H)+=229.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH3:14])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Br:22]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH3:14])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:22])[N:6]2[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCCNc1nc(N)c2ncn(Cc3ccccc3)c2n1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCNc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
6-Amino-9-benzyl-2-propylaminopurine (87 mg, 0.31 mmol) and bromine (0.5 ml) were dissolved in 50 ml of methylene chloride and the solution was stirred at room temperature for 1 hour. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, dried on sodium sulfate and filtered. The solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (95 mg, yield 85%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][NH:22][C:23](=[O:34])[O:24][C:25]4[CH:30]=CC([N+]([O-])=O)=CC=4)[CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:44]([C:47]1[N:48]=C(CO)[O:50][CH:51]=1)(=[O:46])[NH2:45]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][NH:22][C:23](=[O:34])[O:24][CH2:25][C:30]4[O:50][CH:51]=[C:47]([C:44](=[O:46])[NH2:45])[N:48]=4)[CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: NC(=O)c1coc(CO)n1
Reactant: O=C(NCCC1CCN(c2ccc(-c3ccc(F)cc3)cn2)CC1)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1coc(COC(=O)NCCC2CCN(c3ccc(-c4ccc(F)cc4)cn3)CC2)n1
Yield: 64.2 %

Procedure:
The process is performed according to the procedure described in Example 4. Starting with 0.25 g (0.54 mmol) of 4-nitrophenyl 2-[5′-(4-fluorophenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]ethylcarbamate, described in Example 1 (step 1.5.), 0.139 g (1.08 mmol) of N,N-diisopropylethylamine, 0.033 g (0.27 mmol) of N,N-dimethylaminopyridine and 0.084 g (0.59 mmol) of 4-carbamoyloxazol-2-ylmethanol, prepared in step 5.2., 0.162 g of pure product is obtained in the form of a white powder.