Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([O:11][CH2:12][C:13]1[S:17][C:16]([CH2:18][NH:19][C:20](OC(C)(C)C)=[O:21])=[N:15][CH:14]=1)(=[O:10])[CH3:9]>>[C:8]([O:11][CH2:12][C:13]1[S:17][C:16]([CH2:18][NH:19][CH:20]=[O:21])=[N:15][CH:14]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)OCc1cnc(CNC(=O)OC(C)(C)C)s1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OCc1cnc(CNC=O)s1
Reaction time: 1 h
Yield: 94.5 %

Procedure:
A 8 ml potion of trifluoroacetic acid was dissolved in 2.46 g of 5-acetoxymethyl-2-(N-t-butoxycarbonylamino)methylthiazole under ice-cooling, and the mixture was then allowed to stand at room temperature for 1 hour. Then, the solvent was evaporated under reduced pressure, and the resulting residue was dissolved in 24.6 ml of dichloromethane under ice-cooling. Furthermore, 40 ml of an aqueous saturated sodium bicarbonate solution was added thereto, followed by stirring. To this solution, a 10% aqueous sodium carbonate solution and a mixed acid anhydride solution comprising a mixed solution of 3.7 ml of formic acid and 2.0 ml of acetic anhydride which had been beforehand reacted with each other at 50° C. for 30 minutes were added dropwise under ice-cooling so that the pH of the reaction solution might be within the range of 3.0 to 6.5. Afterward, the organic layer was separated, and the remaining aqueous layer was concentrated under reduced pressure until its amount became half, followed by extraction with chloroform (15 ml×4). The combined organic layer was dried over anhydrous sodium sulfate and then filtered, and the solvent was evaporated under reduced pressure to obtain 1.74 g of 5-acetoxymethyl-2-(formylamino)methylthiazole.
Reaction SMILES: [CH2:1]([S:8][CH:9]([CH:42]=O)[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([O:23][CH2:24][CH2:25][CH2:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:18][C:17]=2[N:31]([CH3:41])[S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1)(=[O:34])=[O:33])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:44][S:45]([N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)(=[O:47])=[O:46].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(=O)([O-])O.[Na+]>ClCCCl>[CH2:1]([S:8][CH:9]([CH2:42][N:51]1[CH2:52][CH2:53][N:48]([S:45]([CH3:44])(=[O:47])=[O:46])[CH2:49][CH2:50]1)[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([O:23][CH2:24][CH2:25][CH2:26][S:27]([CH3:30])(=[O:28])=[O:29])=[CH:18][C:17]=2[N:31]([CH3:41])[S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1)(=[O:33])=[O:34])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(c1cc(OCCCS(C)(=O)=O)cc2cc(C(=O)NCC(C=O)SCc3ccccc3)[nH]c12)S(=O)(=O)c1ccccn1
Reactant: CS(=O)(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])O
Solvent: ClCCCl
Product: CN(c1cc(OCCCS(C)(=O)=O)cc2cc(C(=O)NCC(CN3CCN(S(C)(=O)=O)CC3)SCc3ccccc3)[nH]c12)S(=O)(=O)c1ccccn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79.2 %

Procedure:
A mixture of N-[2-(benzylthio)-3-oxopropyl]-7-[methyl(pyridin-2-ylsulfonyl)amino]-5-[3-(methylsulfonyl)propoxy]-1H-indole-2-carboxamide (0.35 g), N-methylsulfonylpiperazine (0.18 g) and 1,2-dichloroethane (8 mL) was stirred at room temperature for 20 min. Sodium triacetoxyborohydride (345 mg) was added to the reaction solution, and the mixture was stirred at room temperature for 16 hr. The reaction solution was acidified with aqueous citric acid solution, and basified with aqueous sodium hydrogencarbonate solution. The precipitated crystals were collected by filtration, washed with water and ethyl acetate, and dried to give the title compound (341 mg, yield: 43%) as colorless crystals. MS: 794 (MH+). melting point: 195-196° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7](=[O:12])[C:8]([Cl:11])([Cl:10])[Cl:9])[NH:5][CH:6]=1.Cl[C:14](Cl)(Cl)C(C1N(C)C=CC=1)=O>>[Br:1][C:2]1[CH:3]=[C:4]([C:7](=[O:12])[C:8]([Cl:9])([Cl:10])[Cl:11])[N:5]([CH3:14])[CH:6]=1
Reactant: Cn1cccc1C(=O)C(Cl)(Cl)Cl
Reactant: O=C(c1cc(Br)c[nH]1)C(Cl)(Cl)Cl
Product: Cn1cc(Br)cc1C(=O)C(Cl)(Cl)Cl
Yield: 81 %

Procedure:
Using the same general procedure as used for the synthesis of 1-(4-bromo-1H-pyrrol-2 -yl)-2,2,2-trichloro-ethanone 7, 5.00 g of 2-trichloroacetyl-1-methyl pyrrole afforded 5.46 g (81%) of the title compound 13 as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 7.66 (d, 1H, J=1.2 Hz), 7.42 (d, 1H, J=1.8 Hz), 3.91 (s, 3 H); 13C NMR (100 MHz, DMSO-d6) δ 171.48, 134.40, 123.62, 121.19, 95.36, 95.12; HRMS (FAB) calcd for C7H6BrCl3NO (MH+) 303.8698, found 303.8678.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N+:5]=1[O-:10].[N+:11]([O-])([OH:13])=[O:12].N>S(=O)(=O)(O)O>[CH3:2][O:3][C:4]1[CH:9]=[C:8]([N+:11]([O-:13])=[O:12])[CH:7]=[CH:6][N+:5]=1[O-:10]
Reactant: COc1cccc[n+]1[O-]
Reactant: O=[N+]([O-])O
Agent: Cl
Agent: N
Agent: O=S(=O)(O)O
Product: COc1cc([N+](=O)[O-])cc[n+]1[O-]
Temperature: 0 °C

Procedure:
30 ml of concentrated sulfuric acid, cooled to 0° C., are added to 15.5 g of 2-methoxypyridine N-oxide hydrochloride, after which 42 ml of fuming nitric acid and 14 ml of concentrated sulfuric acid are added dropwise at 0° C. After the temperature has been allowed to rise, the reaction mixture is heated for 3 hours at 90°-100° C. and is then cooled and poured onto 50 g of ice. It is neutralized to pH 7 by the addition of concentrated aqueous ammonia at a temperature below 10° C. The aqueous phase is extracted 6 times with methylene chloride, the organic phase is then dried over sodium sulfate and concentrated and 11 g of a yellow solid corresponding to a mixture of 2-methoxy-4-nitropyridine N-oxide and 2-methoxy-5-nitropyridine N-oxide are recovered. The 2 products are separated by chromatography on silica using a methylene chloride/methanol mixture (95/5) as the eluent. 6.3 g of 2-methoxy-4-nitropyridine N-oxide are collected.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([OH:20])[C:3]=1/[C:4](=[N:12]\[OH:13])/[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[F:11].[C:21](OC(=O)C)(=[O:23])[CH3:22]>>[C:21]([O:13]/[N:12]=[C:4](\[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[F:11])/[C:3]1[C:14]([OH:20])=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:2]=1[Cl:1])(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(O)c(/C(=N\O)c2ccccc2F)c(Cl)c1
Product: COc1cc(O)c(/C(=N/OC(C)=O)c2ccccc2F)c(Cl)c1

Procedure:
The Z-2-chloro-2'-fluoro-6-hydroxy-4-methoxybenzophenone oxime may be reacted with acetic anhydride as described in Example 30c to form E-2-chloro-2'-fluoro-6-hydroxy-4-methoxybenzophenone O-acetyl oxime.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][O:13][CH:12]([CH2:17][NH2:18])[C:11]=2[S:10][C:9]=1[NH2:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][O:21][CH2:22][O:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[C:26](=O)[O:27][C:28]2=[O:33].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C(#N)C>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][O:13][CH:12]([CH2:17][N:18]3[C:26](=[O:27])[C:25]4[C:29](=[CH:30][CH:31]=[CH:32][C:24]=4[O:23][CH2:22][O:21][CH3:20])[C:28]3=[O:33])[C:11]=2[S:10][C:9]=1[NH2:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCOc1cccc2c1C(=O)OC2=O
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CCOC2CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COCOc1cccc2c1C(=O)N(CC1OCCc3c1sc(N)c3C(=O)OC(C)(C)C)C2=O
Temperature: 25 °C
Yield: 71.6 %

Procedure:
A mixture of 2-amino-7-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (0.15 g, 0.53 mmol) and 4-methoxymethoxy-isobenzofuran-1,3-dione (135 mg, 0.64 mmol) was dissolved in distilled acetonitrile (7 ml) under nitrogen. The flask was cooled in an ice bath with stirring and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.12 g, 0.64 mmol), and triethylamine (0.22 ml, 1.59 mmol) were added. The reaction was warmed to ambient temperature and stirred for 18 h. The solution was concentrated in vacuo and the residue dissolved in ethyl acetate (40 ml). The organic layer was washed with 1% hydrochloric acid (2×10 ml), saturated sodium bicarbonate (10 ml), and brine (10 ml). The resulting solution was dried (Na2SO4), filtered, and the solvent evaporated in vacuo which afforded 0.18 g of a crude 2-amino-7-(4-methoxymethoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11](OS(C(F)(F)F)(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O)#[N:23].C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[C:22]#[N:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1ccccc1B(O)O
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccccc2C#N)CC1
Temperature: 120 °C
Yield: 51.6 %

Procedure:
4-Trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.5 g, 1.5 mmol), 2-cyanophenylboronic acid (0.23 g, 1.6 mmol), tetrakis-triphenylphosphine (0.17 g, 0.15 mmol) and cesium carbonate (0.73 g, 2.26 mmol) were dissolved in a mixture of DME (3 mL), IMS (1.0 mL) and water (0.4 mL) under argon. The mixture was heated by microwave irradiation to 120° C. for 0.3 hours then diluted with water. The products were extracted into DCM, dried over magnesium sulphate, filtered and the solvent removed by evaporation under vacuum. The residue was purified by flash chromatography on silica eluting with 0-20% ethyl acetate/hexane. The fractions containing the desired product were concentrated under vacuum to give the title compound as a yellow oil (0.22 g). LCMS m/z 261.2 [M+H]+. R.T.=4.59 min (Analytical Method 4).
Reaction SMILES: [C:1](Cl)(=[O:5])[O:2][CH2:3][CH3:4].[C:7]([O:11][C:12]([N:14]1[CH2:21][C:20]2[C:19]([NH2:22])=[N:18][NH:17][C:16]=2[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].CCN(C(C)C)C(C)C>C1COCC1>[CH2:3]([O:2][C:1]([N:17]1[C:16]2[CH2:15][N:14]([C:12]([O:11][C:7]([CH3:9])([CH3:8])[CH3:10])=[O:13])[CH2:21][C:20]=2[C:19]([NH2:22])=[N:18]1)=[O:5])[CH3:4]
Reactant: CCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1Cc2[nH]nc(N)c2C1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)n1nc(N)c2c1CN(C(=O)OC(C)(C)C)C2
Reaction time: 2 h
Yield: 72 %

Procedure:
A solution of ethyl chlorocarbonate (8.9 ml, 93 mmol) in THF (250 ml) was added slowly to a mixture of 3-amino-4,6-dihydro-1H-pyrrolo[3,4-c]pyrazole-5-carboxylic acid tert-butyl ester (20 g, 89 mmol) and DIEA (92 ml, 528 mmol) in THF (500 ml) at 0-5° C. The reaction was kept at the same temperature for two hours then allowed to reach r.t. and stirred overnight. The obtained mixture was evaporated to dryness under vacuum. The resulting residue was extracted with AcOEt and water. The organic phase was separated, dried over sodium sulfate and evaporated to dryness. The mixture was purified by flash-chromatography (eluent: ethyl acetate/cyclohexane 4/6 to 7/3) to give 19 g (72% yield) of the title compound as a white solid.
Reaction SMILES: CN(C)C(=CC=C(C1C=CC=CC=1)C(OCC)=O)C(OCC)=S.F[B-](F)(F)F.[CH3:29][N:30]([CH3:42])[C:31]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:32][CH:33]=[N+](C)C.CC[O-].[Na+].[CH2:47]([S:50][CH2:51][C:52]([O:54][CH2:55][CH3:56])=[O:53])[CH:48]=[CH2:49]>C(O)C>[CH2:47]([S:50][C:51]([C:52]([O:54][CH2:55][CH3:56])=[O:53])=[CH:33][CH:32]=[C:31]([N:30]([CH3:42])[CH3:29])[C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH:48]=[CH2:49]
Reactant: CCOC(=O)C(=CC=[N+](C)C)N(C)C
Reactant: C=CCSCC(=O)OCC
Agent: CCOC(=O)C(=CC=C(C(=S)OCC)N(C)C)c1ccccc1
Agent: CC[O-]
Agent: F[B-](F)(F)F
Solvent: CCO
Product: C=CCSC(=CC=C(C(=O)OCC)N(C)C)C(=O)OCC
Yield: 84.6 %

Procedure:
The procedure is as in Example 2 for the preparation of diethyl 2-dimethylamino-5-phenylthio-2,4-hexadienedioate, starting with N-(3-dimethylamino-3-ethoxycarbonylpropenylidene)-N-methylmethanaminium tetrafluoroborate (5.5 g), a 2M ethanolic solution of sodium ethylate (9.7 cc) and ethyl (allylthio)acetate (3.1 g) in ethanol (31 cc). Diethyl 5-allylthio-2-dimethylamino-2,4-hexadienedioate (5.1 g) is thereby obtained, and is used in the crude state in the subsequent phases.
Reaction SMILES: C([O:4][C:5]1[CH:18]=[C:17]2[C:8]([NH:9][C:10]3[C:15]([S:16]2(=[O:20])=[O:19])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:7]2[CH:21]=[CH:22][CH:23]=[CH:24][C:6]=12)(=O)C.[OH-].[Na+].C(O)(=O)C>CO>[OH:4][C:5]1[CH:18]=[C:17]2[C:8]([NH:9][C:10]3[C:15]([S:16]2(=[O:20])=[O:19])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:7]2[CH:21]=[CH:22][CH:23]=[CH:24][C:6]=12
Reactant: CC(=O)Oc1cc2c(c3ccccc13)Nc1ccccc1S2(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: O=S1(=O)c2ccccc2Nc2c1cc(O)c1ccccc21
Temperature: 25 °C
Reaction time: 0.12 h

Procedure:
To a suspension of 5-acetoxy-12H-benzo[a]phenothiazine-7,7-dioxide (6.6 g) in methanol (200 ml) there was added 2N aqueous sodium hydroxide solution (132 ml) and the mixture was stirred in the absence of air at room temperature for 7 minutes; at that point an amber solution had resulted. There was rapidly added 10% aqueous acetic acid solution (200 ml) causing precipitation of the title compound which was collected by filtration (5.68 g). A sample (500 mg) was crystallized from THF affording purified product (250 mg), m.p. 334° C. (dec).
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][C@@H:8]1[C@@H:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@H:12]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@@H:11]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@:10]([C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[C:42]([CH2:47][C:48]3[CH:53]=[CH:52][C:51]([O:54][C:55]([F:58])([F:57])[F:56])=[CH:50][CH:49]=3)[CH:41]=2)([O:38][CH3:39])[O:9]1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:15]([O:14][C@H:13]1[C@H:12]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@@H:11]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@:10]([C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[C:42]([CH2:47][C:48]3[CH:49]=[CH:50][C:51]([O:54][C:55]([F:57])([F:58])[F:56])=[CH:52][CH:53]=3)[CH:41]=2)([O:38][CH3:39])[O:9][C@@H:8]1[CH2:7][OH:6])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OC(F)(F)F)cc3)c2)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OC(F)(F)F)cc3)c2)O[C@H](CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 45 °C
Reaction time: 48 h
Yield: 35.3 %

Procedure:
To a solution of tert-butyl-dimethyl-[[(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(trifluoromethoxy)phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methoxy]silane 15j (5.27 g, 6.43 mmol) in tetrahydrofuran (35 mL) was added tetrabutylammonium fluoride (9.64 mL, 9.64 mmol, 1 M in tetrahydrofuran) at room temperature. The mixture was stirred at 45° C. for 48 hours. The reaction mixture was quenched with water (10 mL) and partitioned. The aqueous layer was extracted with ethyl acetate (20 mL×2). The combined organic layers were washed with saturated aqueous sodium chloride (20 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=8/1 to give the title compound 15k as yellow oil (1.70 g, 35.3%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3) δ (ppm): 7.45-7.30 (m, 13H), 7.26-7.17 (m, 3H), 7.14 (d, 2H), 7.08 (d, 2H), 7.01 (d, 2H), 4.99-4.87 (m, 3H), 4.71 (d, 1H), 4.56 (d 1H), 4.25-4.11 (m, 2H), 3.95 (m, 3H), 3.75 (m, 3H), 3.33 (d, 1H), 3.09 (s, 3H).
Reaction SMILES: C(OC([NH:11][C@H:12]([C:16]([NH:18][C@H:19]([C:21]([O:23][CH3:24])=[O:22])[CH3:20])=[O:17])[CH:13]([CH3:15])[CH3:14])=O)C1C=CC=CC=1.[C:25]([OH:30])(=[O:29])[C:26]([OH:28])=[O:27]>CO.[Pd]>[C:25]([OH:30])(=[O:29])[C:26]([OH:28])=[O:27].[NH2:11][C@H:12]([C:16]([NH:18][C@H:19]([C:21]([O:23][CH3:24])=[O:22])[CH3:20])=[O:17])[CH:13]([CH3:15])[CH3:14]
Reactant: COC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Agent: [Pd]
Agent: O=C(O)C(=O)O
Solvent: CO
Product: COC(=O)[C@H](C)NC(=O)[C@@H](N)C(C)C

Procedure:
2.69 g (8.0 mmol) of methyl benzyloxycarbonyl-L-valyl-L-alaninate [E. Klieger and E. Schr{overscore (o)}der: Ann. Chem. 661, 193 (1963)] are dissolved in 25 ml of methanol, 0.72 9 (8.0 mmol) of anhydrous oxalic acid and 0.1 g of Pd/C catalyst are added, then the mixture is submitted to hydrogenation at about 20° C. The catalyst is filtered off and the filtrate is evaporated at a pressure of 2.0-2.5 kPa. The crystalline residue is rubbed with diethyl ether, filtered, washed with diethyl ether and dried in a vacuum desiccator.
Reaction SMILES: [C:1](#[N:4])[CH2:2][OH:3].[C:5]1([CH3:15])[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1.COCCOC.[OH-].[Na+]>O>[C:5]1([CH3:15])[CH:10]=[CH:9][C:8]([S:11]([O:3][CH2:2][C:1]#[N:4])(=[O:13])=[O:12])=[CH:7][CH:6]=1
Reactant: N#CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC#N)cc1
Reaction time: 6.5 h

Procedure:
Method of preparation: 8.1 g (0.1 mole of glycolonitrile (70% aqueous solution) is added to a cooled (15° -20° C.) mixture of 9.5 g (0.05 mole) of p-toluenesulfonyl chloride in 20 ml. of 1,2-dimethoxyethane and 50 ml. distilled water. A solution of 2.1 g (0.05 mole) of NaOH in 50 ml. distilled water is added slowly with stirring at 20°-25° C. over a period of 6.5 hours, maintaining the pH of the reaction mixture at about 8. The insoluble material is filtered off, washed with cold water, and dried at 40° C. under vacuum to yield 6.8 g (64% conversion) of the product, a light brown solid, m.p. 48°-50.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11](Br)[CH:10]=2)=[O:5])[CH3:2].[C:18]1([NH:24][C:25]([NH2:27])=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([NH:27][C:25]([NH:24][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:26])[CH:10]=2)=[O:5])[CH3:2]
Reactant: NC(=O)Nc1ccccc1
Reactant: CCOC(=O)c1ncc2cc(Br)ccc2c1O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCOC(=O)c1ncc2cc(NC(=O)Nc3ccccc3)ccc2c1O
Reaction time: 44 h
Yield: 84 %

Procedure:
7-Bromo-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester (250 mg, 0.8443 mmol) was combined in an oven-dried flask with phenyl urea (138 mg, 1.013 mmol), cesium carbonate (550 mg, 1.69 mmol), XantPhos (49 mg, 0.0844 mmol) and tris(dibenzylideneacetone)dipalladium(0) (25 mg, 0.0422 mmol). The flask was flushed with dry nitrogen and charged with dioxane (5 mL) and the solution brought to reflux. After 44 h, the reaction was cooled and the solution partitioned between equal volumes of ethyl acetate and brine resulting in precipitation. Filtration of the solid followed by vacuum drying provided the desired urea product in 84% yield. MS ESI(+) m/e: 352.0330 (M+1).
Reaction SMILES: [C:1]([S-:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+]>O.[Fe-3](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+]>[C:1]([S:9][S:9][C:1](=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: S=C([S-])c1ccccc1
Agent: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: S=C(SSC(=S)c1ccccc1)c1ccccc1

Procedure:
Potassium ferricyanide (III) (32.93 g) was dissolved in deionized water (500.0 mL). Sodium dithiobenzoate solution (350.0 mL) was transferred to a 1 L conical flask equipped with a magnetic stir bar. Potassium ferricyanide solution was added dropwise to the sodium dithiobenzoate via an addition funnel over a period of one hour under vigorous stirring. The red precipitate was filtered and washed with deionized water until the washings become colorless. The solid was dried in vacuo at room temperature overnight; the product was recrystallized from ethanol.
Reaction SMILES: [OH-].[Na+].[I:3][C:4]1[C:9]([O:10][CH3:11])=[C:8]([OH:12])[CH:7]=[C:6]([I:13])[N:5]=1.I[CH2:15][CH2:16][CH2:17][O:18][CH3:19].O>CN(C)C=O.C(OCC)(=O)C>[I:3][C:4]1[C:9]([O:10][CH3:11])=[C:8]([O:12][CH2:15][CH2:16][CH2:17][O:18][CH3:19])[CH:7]=[C:6]([I:13])[N:5]=1
Reactant: COc1c(O)cc(I)nc1I
Reactant: COCCCI
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COCCCOc1cc(I)nc(I)c1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 60 mmol NaOH in 50 ml N,N-dimethyl formamide is progressively added 50 mmol 2,6-diiodo-3-methoxy-pyridin-4-ol [437709-87-0]. The reaction mixture is stirred for 30 minutes and then cooled to 0° C. 60 mmol 1-iodo-3-methoxy-propane [61542-10-7] are added and the mixture is stirred for 15 minutes at room temperature. Water and ethyl acetate are added to the mixture, the layers are separated and the aqueous layer is extracted with ethyl acetate (3×). The combined organic layers are dried over sodium sulphate, filtered and concentrated. The title compound is obtained from the residue by means of flash chromatography (SiO2 60 F) and identified based on its Rf value,
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=1.C(=O)(O)[O-].[Na+]>C1COCC1.C(OCC)(=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cn2)CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 75.3 %

Procedure:
Add a suspension of pre-washed NaH (0.1 g, 2.48 mmol, 60% dispersion in mineral oil) in THF (2 mL) to an ice cold solution of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.5 g, 2.48 mmol) in dry THF (3 mL). Allow mixture to stir for 20 minutes, then add 2-chloro-5-nitro-pyridine (0.36 g, 2.26 mmol) in portions. After addition is completed, remove cooling bath and stir the reaction mixture at 22° C. overnight. Cool reaction mixture with ice bath and add a saturated aq. sodium bicarbonate solution (5 mL). Distribute the reaction mixture between ethyl acetate (25 mL) and distilled water (25 mL). Isolate the aqueous phase and extract with ethyl acetate (3×35 mL). Dry the combined organic phases over sodium sulfate and concentrate under reduced pressure. Subject residue to silica gel chromatography eluting with hexanes and ethyl acetate to give 4-(5-Nitro-pyridin-2-yloxy)-piperidine-1-carboxylic acid tert-butyl ester as a white solid (0.55 g, 75% yield). MS(ES): m/z=324.2 [M+H].