Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C@@H:2]1[CH2:6][N:5]([C:7](=[O:10])[CH2:8][OH:9])[C@H:4]([C:11]#[N:12])[CH2:3]1.[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22](Cl)(=[O:24])=[O:23])([O-:15])=[O:14]>>[F:1][C@@H:2]1[CH2:6][N:5]([C:7](=[O:10])[CH2:8][O:9][S:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N+:13]([O-:15])=[O:14])(=[O:23])=[O:24])[C@H:4]([C:11]#[N:12])[CH2:3]1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CO
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)COS(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 15.1 %

Procedure:
Using (2S,4S)-4-fluoro-1-(2-hydroxyacetyl)pyrrolidine-2-carbonitrile (259 mg) and 2-nitrobenzenesulfonyl chloride (366 mg), the same procedure was followed as in Reference Example 3 to give (2S,4S)-4-fluoro-1-[2-[(2-nitrophenyl)sulfonyloxy]acetyl]pyrro lidine-2-carbonitrile as a pale yellow solid (81.2 mg, 15% yield).
Reaction SMILES: [Al](OS(C(F)(F)F)(=O)=O)(OS(C(F)(F)F)(=O)=O)OS(C(F)(F)F)(=O)=O.[NH2:26][CH2:27][C:28]1[CH:29]=[C:30]([CH:36]=[CH:37][CH:38]=1)[N:31]([CH2:34][CH3:35])[CH2:32][CH3:33].[O:39]1[CH2:41][C@@H:40]1[C@@H:42]([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])[CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>CCOC(C)=O.O>[CH2:34]([N:31]([CH2:32][CH3:33])[C:30]1[CH:29]=[C:28]([CH:38]=[CH:37][CH:36]=1)[CH2:27][NH:26][CH2:41][C@@H:40]([OH:39])[C@@H:42]([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:55])([CH3:54])[CH3:56])[CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH3:35]
Reactant: CCN(CC)c1cccc(CN)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H]1CO1
Agent: O=S(=O)(O[Al](OS(=O)(=O)C(F)(F)F)OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Product: CCN(CC)c1cccc(CNC[C@@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)c1
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 21.7 %

Procedure:
Al(OTf)3 (0.0168 g, 0.036 mmol, 5 mol %) was added to a flask charged with 3-(aminomethyl)-N,N-diethylaniline (0.19 g, 1.07 mmol, 1.5 eq) under Ar. After stirring for 10 min tert-butyl (S)-1-((S)-oxiran-2-yl)-2-phenylethylcarbamate (0.187 g, 0.71 mmol, 1 eq) was added and the mixture was heated to 70° C. for 1 h. After cooling to room temperature the residue was dissolved in EtOAc with a few drops of water. After 20 min of vigorous stirring the mixture was filtered through cotton and dried over Na2SO4. The inorganics were filtered off, and the solvent was removed in vacuo. Purification via flash chromatography yielded 0.0682 g (0.154 mmol, 22% yield) of the product.
Reaction SMILES: [CH3:1][S:2]([C:5](C(OC)=O)([CH2:16][CH2:17][CH2:18][CH:19]([O:29]CC1C=CC=CC=1)[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]C)=[O:13])(=[O:4])=[O:3].[Cl-].[Na+].CN(C)C=O>O>[CH3:1][S:2]([CH:5]([CH2:16][CH2:17][CH2:18][CH:19]([OH:29])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])(=[O:4])=[O:3]
Reactant: COC(=O)CCCCCCC(CCCC(COc1ccc(F)cc1)OCc1ccccc1)(C(=O)OC)S(C)(=O)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)C(CCCCCCC(=O)O)CCCC(O)COc1ccc(F)cc1
Temperature: 160 °C

Procedure:
A mixture of methyl 8-methylsulfonyl-8-methoxycarbonyl-12-benzyloxy-13-(4-fluorophenoxy)tridecanoate (2.60 g., 4.5 mmoles), sodium chloride (0.5 g., 8.5 mmoles), dimethylformamide (8 ml.) and water (0.2 ml.) is heated with an oil bath at 160° C. overnight (ca. 15 hours). The reaction mixture is allowed to cool to room temperature, quenched with cold water, and then extracted with chloroform three times. The combined extracts are washed with brine and dried over anhydrous magnesium sulfate. The solvent is removed by evaporation in vacuo leaving the desired product as a viscous oil residue (2.30 g., 4.4 mmoles, 98%). ir (neat) 3.40, 5.72, 6.20, 6.62, 6.87, 7.71, 8.00, 8.28, 8.90, 12.04, 13.17, 14.37μ; pmr (CCl4) δ 1.0-2.9 (22H, m, containing a methyl singlet at 2.60 δ), 3.54 (3H, s); 3.5-4.1 (3H, m), 4.47 (1H, d, J=12Hz), 4.70 (1H, d, J= 12Hz), 6.6-7.1 (4H, m), 7.20 (5H, s).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])[CH3:2].[I:10]I>ClC1C=CC=CC=1.[Cu](Cl)Cl>[CH2:1]([C:3]1[CH:8]=[C:7]([I:10])[CH:6]=[CH:5][C:4]=1[OH:9])[CH3:2]
Reactant: CCc1ccccc1O
Reactant: II
Agent: Cl[Cu]Cl
Solvent: Clc1ccccc1
Product: CCc1cc(I)ccc1O

Procedure:
A solution of 119.9 ml of 2-ethylphenol in 500 ml of chlorobenzene was treated with 126.9 g of iodine and 134.5 g of copper(II) chloride and stirred under reflux for 5.5 hours. After cooling the reaction mixture was filtered and the residue was washed with methylene chloride. The combined filtrates were washed with aqueous sodium thiosulphate solution and ice-water. The organic phases were dried over sodium sulphate and concentrated. The residue was crystallized from hexane and gave 79.3 g of 2-ethyl-4-iodo-phenol. The mother liquor was chromatographed over silica gel and gave a further 41 g of 2-ethyl-4-iodo-phenol; MS (EI) m/z 248 (M).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[N:11]([CH2:22][C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][CH:24]=3)[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.O[N:33]1[C:37]2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC.[C:63]([OH:69])([C:65](F)(F)F)=[O:64].C(Cl)Cl>C(Cl)Cl.CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[N:11]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([C:27]([NH:33][CH2:37][CH2:65][C:63]([OH:69])=[O:64])=[O:29])=[CH:30][CH:31]=3)[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(O)C(F)(F)F
Reactant: On1nnc2cccnc21
Reactant: COc1ccc(-c2cc(-c3cc(Cl)cc(Cl)c3)nn2Cc2ccc(C(=O)O)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cc(-c3cc(Cl)cc(Cl)c3)nn2Cc2ccc(C(=O)NCCC(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of the intermediate from example 73 step D (100 mg, 0.22 mmol) in 1:1 DMF/DCM (0.54 mL) was added 1-hydroxy-7-azabenzo-triazole (35 mg, 0.264 mmol), N,N-diisopropylethyl amine (92 μL, 0.53 mmol) β-alanine-t-butyl ester hydrochloride (48 mg, 0.26 mmol) and 1-(3-(Dimethylamino)propyl-3-ethyl carbodiimide hydrochloride (51 mg, 0.26 mmol). The reaction was left stirring at room temperature for 18 hours. The reaction was diluted with DCM, washed with 1N HCl, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography using 2:5 ethyl acetate-hexanes to give a colorless oil. LC-MS: 4.5 min; (M+H)=580.2. This material was dissolved in 1:1 TFA/DCM (4 mL) and stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and azeotroped with toluene (1×). The residue was purified by reverse phase HPLC (Gilson) to give the title compound. 1H NMR (DMSO, 500 MHz): δ 8.49 (t, J=5.5 Hz, 1H), 7.88 (d, J=2.1 Hz, 2H), 7.76 (d, J=8.3 Hz, 2H), 7.55 (t, J=1.8 Hz, 1H), 7.39 (d, J=8.7 Hz, 2H), 7.1 (s, 1H), 7.09 (d, J=8.9 Hz, 2H), 7.04 (d, J=9.0 Hz, 2H), 5.47 (s, 2H), 3.79 (s, 3H), 3.45 (q, J=7.1 Hz, 2H), 2.49 (t, J=7.1 Hz, 2H). LC-MS: 3.85 min; (M+H)=524.1.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[N:14]=[CH:13][C:12]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])=[CH:11][CH:10]=2)[CH:3]=1.[C:23]([O:26][CH2:27][C:28]1[C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=[CH:30][C:29]=1[N:43]1[N:52]=[CH:51][C:50]2[C:45](=[C:46]([F:57])[CH:47]=[C:48]([C:53]([CH3:56])([CH3:55])[CH3:54])[CH:49]=2)[C:44]1=[O:58])(=[O:25])[CH3:24].C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.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>[C:53]([C:48]1[CH:49]=[C:50]2[C:45](=[C:46]([F:57])[CH:47]=1)[C:44](=[O:58])[N:43]([C:29]1[CH:30]=[CH:31][CH:32]=[C:33]([C:2]3[CH:3]=[C:4]([NH:8][C:9]4[CH:10]=[CH:11][C:12]([C:15]([N:17]5[CH2:22][CH2:21][O:20][CH2:19][CH2:18]5)=[O:16])=[CH:13][N:14]=4)[N:5]=[CH:6][N:7]=3)[C:28]=1[CH2:27][O:26][C:23](=[O:25])[CH3:24])[N:52]=[CH:51]2)([CH3:54])([CH3:55])[CH3:56]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Reactant: O=C(c1ccc(Nc2cc(Cl)ncn2)nc1)N1CCOCC1
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+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(C(=O)N4CCOCC4)cn3)ncn2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Temperature: 80 °C
Reaction time: 13 h
Yield: 30.7 %

Procedure:
To a stirred solution of (6-(6-chloropyrimidin-4-ylamino)pyridin-3-yl)(morpholino)methanone (0.15 g, 0.45 mmol) in 1,4-dioxane (5 mL) was added 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate (0.250 g, 0.5 mmol), Pd(PPh3)4 (30 mg, 0.08 mmol), Na2CO3(212 mg, 2 mmol) and H2O (2 mL). The mixture was stirred at 80° C. for 13 hrs under N2. The mixture was evaporated and ethyl acetate (50 mL) and H2O (20 mL) were added to the resulting residue. The organic phase was washed with H2O (2×20 mL), brine (2×20 mL) and dried over Na2SO4. After filtration and concentration, the final product (90 mg, 30%) was obtained as yellow solid. LC-MS: 652.2 [M+H]+, tR=1.499 min.
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[C:53]([O:54][CH2:55][CH2:56][CH2:57][O:58][C:59]2[C:60]([O:84][CH3:85])=[CH:61][C:62]3[C:68](=[O:69])[N:67]4[CH:70]=[C:71]([CH3:73])[CH2:72][C@H:66]4[C:65](=[O:74])[N:64]([CH2:75][O:76][CH2:77][CH2:78][Si:79]([CH3:82])([CH3:81])[CH3:80])[C:63]=3[CH:83]=2)=[CH:52][C:12]2[N:13]([CH2:44][O:45][CH2:46][CH2:47][Si:48]([CH3:51])([CH3:50])[CH3:49])[C:14](=[O:43])[C@@H:15]3[CH2:21][C:20](/[CH:22]=[CH:23]/[CH2:24][NH:25]C(=O)OCC4C5C=CC=CC=5C5C4=CC=CC=5)=[CH:19][N:16]3[C:17](=[O:18])[C:11]=2[CH:10]=1>CN(C=O)C>[NH2:25][CH2:24]/[CH:23]=[CH:22]/[C:20]1[CH2:21][C@H:15]2[C:14](=[O:43])[N:13]([CH2:44][O:45][CH2:46][CH2:47][Si:48]([CH3:50])([CH3:49])[CH3:51])[C:12]3[CH:52]=[C:53]([O:54][CH2:55][CH2:56][CH2:57][O:58][C:59]4[C:60]([O:84][CH3:85])=[CH:61][C:62]5[C:68](=[O:69])[N:67]6[CH:70]=[C:71]([CH3:73])[CH2:72][C@H:66]6[C:65](=[O:74])[N:64]([CH2:75][O:76][CH2:77][CH2:78][Si:79]([CH3:80])([CH3:82])[CH3:81])[C:63]=5[CH:83]=4)[C:9]([O:8][CH3:7])=[CH:10][C:11]=3[C:17](=[O:18])[N:16]2[CH:19]=1
Reactant: COc1cc2c(cc1OCCCOc1cc3c(cc1OC)C(=O)N1C=C(/C=C/CNC(=O)OCC4c5ccccc5-c5ccccc54)C[C@H]1C(=O)N3COCC[Si](C)(C)C)N(COCC[Si](C)(C)C)C(=O)[C@@H]1CC(C)=CN1C2=O
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: COc1cc2c(cc1OCCCOc1cc3c(cc1OC)C(=O)N1C=C(/C=C/CN)C[C@H]1C(=O)N3COCC[Si](C)(C)C)N(COCC[Si](C)(C)C)C(=O)[C@@H]1CC(C)=CN1C2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
Piperidine (0.133 mL, 1.35 mmol, 12 eq.) was added to a stirred solution of Fmoc amine 14a (0.125 g, 0.112 mmol, 1.0 eq.) in DMF (1.8 ml). After stirring at room temperature for 30 minutes, LCMS analysis indicated consumption of starting material and the reaction mixture was diluted with DCM (200 mL) and washed with water (3×200 mL). The organic layer was dried over MgSO4, filtered and concentrated to dryness to afford the crude product which did not undergo further purification (0.100 g, assumed 100% yield). This material was used without further characterisation.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH:9]([O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH2:8][CH2:7][N:6]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=O.[Li+].[BH4-]>C1COCC1.CO>[C:21]([O:20][C:18]([N:6]1[CH2:7][CH2:8][CH:9]([O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH:5]1[CH2:3][OH:2])=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: COC(=O)C1C(O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O[Si](C)(C)C(C)(C)C)C1CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
A solution containing 3-(tert-Butyldimethylsilanyloxy)pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (3, 12 g, 33 mmol) in THF (50 mL) was cooled to 0° C. LiBH4 in THF (2M, 20 mL) was added in a dropwise fashion. After 1 h, the solution was warmed to ambient temperature. After 2 h, the solution was diluted with MeOH, then H2O, and concentrated. The residue was extracted with EtOAc, washed with 1M HCl, saturated aqueous NaHCO3, brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 9.5 g (87%) of 3-(tert-Butyldimethylsilanyloxy)-2-hydroxymethylpyrrolidine-1-carboxylic acid tert-butyl ester (4) as a colorless oil (See: Herdeis, C.; Hubmann, H. P.; Lotter, H. Tetrahedron: Asymmetry, 1994, 5, 119).
Reaction SMILES: [OH2:1].C1C=CC(P([C:15]2[CH:20]=CC=CC=2)C2C=CC=CC=2)=CC=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[OH:24][CH2:25][CH2:26][N:21]1[CH2:15][CH2:20][O:1][CH2:23][CH2:22]1.[O:24]1[CH2:25][CH2:26][N:21]([CH:22]([N:21]2[CH2:15][CH2:20][O:1][CH2:25][CH2:26]2)[CH3:23])[CH2:22][CH2:23]1
Reactant: O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: C1COCCN1
Product: CC(N1CCOCC1)N1CCOCC1
Product: OCCN1CCOCC1
Temperature: 25 °C
Yield: 87 %

Procedure:
The procedure of Example 1 was repeated using a catalyst system consisting of 39 mg RuCl3 ×H2O (43.1% Ru, 1.7×10-4 mol Ru) and 226 mg PPh3 (8.6×10-4 mol). In this run, the maximum reaction pressure was 71 psig which, on cooling to room temperature. dropped to 27 psig. Analysis of reaction products showed 100% conversion of morpholine with yields of hydroxyethylmorpholine and bismorpholinoethane being 87% and 7%, respectively.
Reaction SMILES: [N+:1]([C:4]([N+:8]([O-:10])=[O:9])(O)[CH2:5]C)([O-:3])=[O:2].[CH2:11]([CH:13]([CH2:17][CH2:18][CH2:19][CH3:20])[C:14]([OH:16])=[O:15])[CH3:12].Cl[CH:22](Cl)C>>[CH2:11]([CH:13]([CH2:17][CH2:18][CH2:19][CH3:20])[C:14]([O:16][CH2:22][C:4]([N+:8]([O-:10])=[O:9])([N+:1]([O-:3])=[O:2])[CH3:5])=[O:15])[CH3:12]
Reactant: CCCCC(CC)C(=O)O
Reactant: CC(Cl)Cl
Reactant: CCC(O)([N+](=O)[O-])[N+](=O)[O-]
Product: CCCCC(CC)C(=O)OCC(C)([N+](=O)[O-])[N+](=O)[O-]
Temperature: 70 °C
Yield: 87 %

Procedure:
Dinitropropanol (25.5 g, 0.17 mol), 2-ethylhexanoic acid (27.4 g, 0.19 mol) and 50 g of polyphosphoric acid were added to 50 mL of dichloroethane and the resulting mixture was slowly stirred using a stirrer. The solution thus obtained was slowly heated to 70° C. and then reacted for 15 hr (overnight). After the reaction, the temperature of the reactor was lowered to room temperature, and the stirrer was powered off. When the temperature of the reactor was room temperature, the dichloroethane layer was decanted, followed by extraction with a 1 N sodium hydroxide aqueous solution and then distillation under reduced pressure, affording 2,2-dinitropropyl 2-ethylhexanoate (41.0 g, yield: 87%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].S(=O)(=O)(O)O.[CH:22]1([CH2:28][CH2:29]O)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.S1(CCCC1)(=O)=O>CO>[Cl:1][C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[CH:4][C:5]([C:6]([O:8][CH2:29][CH2:28][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:7])=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Reactant: OCCC1CCCCC1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O=S1(=O)CCCC1
Product: O=C(OCCC1CCCCC1)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Temperature: 105 °C
Reaction time: 0.5 h

Procedure:
After charging 50 parts of 4-chloro-3,5-dinitrobenzoic acid, 0.3 part of 98% sulfuric acid, 78 parts of cyclohexaneethanol and 50 parts of sulfolane into a flask, the mixture was heated to 100 to 110° C., and was maintained at the same temperature for 8 to 10 hours. After checking the disapearance of 4-chloro-3,5-dinitrobenzoic acid by HPLC, the reaction mass was cooled to room temperature under atmospheric pressure, and to the mass was 240 parts of methanol, and was stirred for 30 minutes. The resulting mixture was filtrated to obtain crystals, and the crystals were washed with 40 parts of methanol and then dried to obtain 58 parts of 2-cyclohexylethyl 4-chloro-3,5-dinitrobenzoate.
Reaction SMILES: [N+]([O-])(O)=O.[NH2:5][C:6]([NH2:8])=[NH:7].CC[O-].[Na+].[CH3:13][S:14][C:15](SC)=[C:16]1[C:25](=O)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][O:17]1.O>CCO>[CH3:13][S:14][C:15]1[C:16]2[O:17][CH2:18][C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:25]=2[N:5]=[C:6]([NH2:8])[N:7]=1
Reactant: CSC(SC)=C1OCc2ccccc2C1=O
Reactant: N=C(N)N
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: O=[N+]([O-])O
Product: CSc1nc(N)nc2c1OCc1ccccc1-2

Procedure:
A solution of guanidine nitrate (1.5 g, 12 mmol) in EtOH (9 mL) was treated with 3 mL of 1 M EtONa in EtOH, refluxed for 15 minutes, cooled, treated with a solution of Example 41A in EtOH (5 mL), heated at reflux overnight, cooled, treated with water (25 mL) and extracted with CH2Cl2 (3×25 mL). The combined CH2Cl2 layers were dried (MgSO4), filtered, concentrated under reduced pressure and chromatographed on silica gel eluting with a gradient of CH2Cl2:EtOAc (1:0 and 20:1) to provide the title compound. 1H NMR (DMSO-d6) δ 2.46 (s, 3H), 5.18 (s, 2H), 6.31 (s, 2H), 7.29 (m, 1H), 7.42-7.51 (m, 2H), 7.96 (m, 1H). MS (M+H)+ m/z 246.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:5]=2[N:6]=1.[OH-:12].[Na+].[CH3:14]O>O>[CH3:14][O:12][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:5]=2[N:6]=1
Reactant: [OH-]
Reactant: CO
Reactant: Clc1cccc2sc(Br)nc12
Agent: [Na+]
Solvent: O
Product: COc1nc2c(Cl)cccc2s1
Yield: 93.8 %

Procedure:
2-Bromo-4-chlorobenzothiazole (6.21 g, 0.025 mole) and 94% sodium hydroxide (1.57 g, 0.037 mole) were added to methanol (100 c.c.), and the mixture was heated under reflux for 30 minutes. After cooling, water (100 c.c.) was added to the reaction solution, followed by ice-cooling. The deposited crystals were filtered and washed with water to obtain 4.68 g of 2-methoxy-4-chlorobenzothiazole. Yield 93.8%, purity 99.3%, m.p. 55°-57° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:3]=1.[N+:22]([O-])([O-:24])=[O:23].[K+].C([O-])([O-])=O.[K+].[K+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:7]=[C:6]([N+:22]([O-:24])=[O:23])[C:5]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:11])[F:12])=[C:4]([CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:3]=1
Reactant: O=[N+]([O-])[O-]
Reactant: O=C(Nc1ccc(Cl)cc1CN1CCOCC1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C(Nc1c(CN2CCOCC2)cc(Cl)cc1[N+](=O)[O-])C(F)(F)F
Temperature: 0 °C
Yield: 83 %

Procedure:
To a mixture of N-[4-chloro-2-(morpholin-4-ylmethyl)phenyl]-2,2,2-trifluoroacetamide (3.8 g, 11.8 mmol) in concentrated sulfuric acid (35 mL) cooled to 0° C. is added potassium nitrate (1.4 g, 14.1 mmol). The reaction is slowly warmed to room temperature over a period of 2 h and is then poured into ice water. The mixture is neutralized with saturated aqueous K2CO3 and the resulting solid is isolated by filtration to afford the title compound (3.6 g, 82%).
Reaction SMILES: [CH3:1][NH:2][N:3]1[C:8](=[O:9])[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][N:5]=[C:4]1SC.[CH3:18][NH2:19]>C(O)(C)C>[CH3:18][NH:19][C:4]1[N:3]([NH:2][CH3:1])[C:8](=[O:9])[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][N:5]=1
Reactant: CN
Reactant: CNn1c(SC)nnc(-c2ccccc2)c1=O
Solvent: CC(C)O
Product: CNc1nnc(-c2ccccc2)c(=O)n1NC
Yield: 87.6 %

Procedure:
10.0 g (0.04 mole) of 4-methylamino-3-methylthio-6-phenyl-4H-1,2,4-triazin-5-one, 1.6 g (0.05 mole) of methylamine and 50 ml of isopropanol are heated for 4 hours in a bomb tube to 155° C. The resultant clear orange solution is concentrated by evaporation and the residue is chromatographed through silica gel eluted with a 95:5 mixture of methylene chloride/ether. The eluate is concentrated by evaporation and the residue is washed with petroleum ether, affording 8.1 g (88% of theory) of 3,4-bis(methylamino)-6-phenyl-4H-1,2,4-triazin-5-one with a melting point of 150°-151° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[C:4]([S:10][CH3:11])[CH:3]=1.Cl.[NH2:13][OH:14].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[NH3:1].[NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:13][OH:14])=[NH:9])[CH:5]=[C:4]([S:10][CH3:11])[CH:3]=1
Reactant: CSc1cc(N)nc(C#N)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CSc1cc(N)nc(C(=N)NO)c1
Product: N
Temperature: 85 °C
Reaction time: 1 h
Yield: 111.7 %

Procedure:
To a solution of 0.179 g 6-amino-4-methylsulfanyl-pyridine-2-carbonitrile in 2.7 ml ethanol and 1.3 ml water was added 0.151 g hydroxylamine hydrochloride and 0.344 g sodium carbonate and the mixture was stirred at 85° C. for 1 h. The mixture was charged onto a 10 g kartusche (Varian Chem Elut 12198007) and the product was eluted with ethyl acetate and purified by chromatography on silica gel with dichloromethane:methanol:ammonia=8:2:0.2 to yield 0.120 g of the title compound as white solid. MS (ISP) M+H+=199.0
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([CH2:9]Br)=[CH:7][N:6]=[C:5]([C:11]#[N:12])[CH:4]=1.[NH:13]1[C:17]2=[N:18][CH:19]=[CH:20][CH:21]=[C:16]2[CH2:15][C:14]1=[O:22].O.[OH-].[Li+]>C1COCC1.O>[NH4+:6].[OH-:22].[O:22]=[C:14]1[NH:13][C:17]2=[N:18][CH:19]=[CH:20][CH:21]=[C:16]2[C:15]21[CH2:9][C:8]1[CH:7]=[N:6][C:5]([C:11]#[N:12])=[CH:4][C:3]=1[CH2:2]2
Reactant: N#Cc1cc(CBr)c(CBr)cn1
Reactant: O=C1Cc2cccnc2N1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cc2c(cn1)CC1(C2)C(=O)Nc2ncccc21
Product: [NH4+]
Reaction time: 0.33 h

Procedure:
To a solution of 4,5-bis(bromomethyl)pyridine-2-carbonitrile from Step B (2.56 g, 8.83 mmol) and 1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one [Marfat & Carta (1987) Tetrahedron Lett. 28, 4027] (1.18 g, 8.83 mmol) in THF (120 mL) and H2O (60 mL) was added lithium hydroxide monohydrate (1.11 g, 26.5 mmol). After 20 min, the reaction mixture was poured onto water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH:NH4OH—100:0:0 to 95:5:1, to give the title compound. MS: m/z=263 (M+1).
Reaction SMILES: Br[CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH:16]([C:19]2[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:17][OH:18])=[CH:10][CH:9]=1)[C:3](OC)=[O:4].[NH2:26][C:27]([NH2:29])=[S:28].C([O-])(=O)C.[Na+].C(=O)([O-])O.[Na+]>O.C(O)C>[OH:18][CH2:17][CH:16]([C:19]1[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=1)[CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][CH:2]2[S:28][C:27](=[NH:26])[NH:29][C:3]2=[O:4])=[CH:9][CH:10]=1
Reactant: NC(N)=S
Reactant: COC(=O)C(Br)Cc1ccc(OCC(CO)c2ncccc2C)cc1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cccnc1C(CO)COc1ccc(CC2SC(=N)NC2=O)cc1

Procedure:
A mixture of methyl 2-bromo-3-{4-[3-hydroxy-2-(3-methyl-2-pyridyl)propoxy]phenyl}propionate (4.7 g), thiourea (875 mg), sodium acetate (943 mg) and ethanol (50 ml) was heated under reflux for 3 hours. The mixture was diluted with water, neutralized with aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and freed of the solvent to give 5-{4-[3-hydroxy-2-(3-methyl-2-pyridyl)propoxy]-benzyl}-2-imino-4-thiazolidinone in the form of crystals. Yield of 25 g. Recrystallization from chloroform-methanol produced colorless prisms. m.p. 213°-214° C.