Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[O-:11][S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13].[C:19]1([I+]C2C=CC=CC=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(OCC)C>O.C([O-])(=O)C1C=CC=CC=1.[Cu+2].C([O-])(=O)C1C=CC=CC=1>[O-:14][S:12]([C:15]([F:18])([F:17])[F:16])(=[O:13])=[O:11].[C:19]1([S+:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[CH:3]=[C:2]2[CH3:1])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: c1ccc([I+]c2ccccc2)cc1
Reactant: Cc1cc2ccccc2s1
Agent: [Cu+2]
Agent: O=C([O-])c1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: O
Solvent: CCOCC
Product: Cc1cc2ccccc2[s+]1-c1ccccc1
Reaction time: 1 h
Yield: 73.3 %

Procedure:
2-Methylthianaphthene (5 g, 0.0327 mole), diphenyliodonium triflate (18.28 g, 0.0425 mole) and copper benzoate (0.1 g, 0.000327 mole) were heated without solvent for 0.5 hours at 140° C. under a nitrogen atmosphere. After cooling down, 150 ethyl ether was added to solidify the product. Filtration and washing with ethyl ether yielded a brownish-grey solid, which was dissolved in 500 ml hot water, and the solution filtered and the water removed in vacuo. The resulting off-white solid was stirred in 50 ml ethyl ether for 1 hour, the mixture filtered and the residue washed with ethyl ether. The product was recrystallized from dichloromethane/t-butyl methyl ether to yield 8.97 g (76%) of 1-phenyl-2-methylbenzothiophenium triflate. The structure was confirmed by 1H/13C NMR spectroscopy.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:21])[C:7](=[O:20])[C:8]([CH3:19])([CH3:18])[CH2:9][N:10]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[C:22]1([C@@H:28]([NH2:30])[CH3:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C>C(O)CCC>[CH:13]1([N:10]2[CH2:9][C:8]([CH3:19])([CH3:18])[C:7](=[O:20])[N:6]([CH3:21])[C:5]3[CH:4]=[N:3][C:2]([NH:30][C@H:28]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH3:29])=[N:12][C:11]2=3)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C[C@H](N)c1ccccc1
Reactant: CN1C(=O)C(C)(C)CN(C2CCCC2)c2nc(Cl)ncc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2C)c1ccccc1
Temperature: 140 °C
Yield: 26.3 %

Procedure:
2-Chloro-9-cyclopentyl-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[5,4-b][1,4]diazepin-6(7H)-one (100 mg, 0.3238 mmol, prepared as described in WO 2007/095188) was dissolved in n-butyl alcohol (1 mL). To the butyl alcohol solution thus obtained were then added (1S)-1-phenylethanamine (750 μL, 5.830 mmol) and DIPEA (167.4 mg, 225.6 μL, 1.295 mmol). The resulting solution was heated at 140° C. in microwave for 90 minutes. Additional (1S)-1-phenylethanamine (500 μL, 3.887 mmol) was added and the reaction mixture heated for 90 minutes in microwave at 140° C. The solvent was removed in vacuo and the residue dissolved in dichloromethane and washed sequentially with 0.5M HCl (three times, 5 mL each), saturated aqueous sodium hydrogen carbonate solution (three times, 5 mL each), and brine (once, 5 mL). The washed solution was dried over MgSO4, filtered, and concentrated in vacuo to give yellow oil. The oil was purified by mass directed HPLC and the product fractions passed through a bicarbonate cartridge and lypholized to afford the title compound as a white solid (33.5 mg, 26% yield).
Reaction SMILES: [C:1]([CH:4]([NH:12][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])(=[O:3])[CH3:2].S(=O)(=O)(O)O.[CH3:26]O>>[C:1]([CH:4]([NH:12][C:13](=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:26])=[O:10])(=[O:3])[CH3:2]
Reactant: CC(=O)C(CCCCC(=O)O)NC(=O)c1ccccc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCCCC(NC(=O)c1ccccc1)C(C)=O

Procedure:
6-Acetyl-6-benzoylaminohexanoic acid (4.35 g) was dissolved in 100 ml of methanol, and 0.5 ml of conc. sulfuric acid was added. The mixture was heated to reflux for 2.5 hours. The reaction solution was cooled, poured into ice-cold water, extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and concentrated to provide 4.4 g of the objective compound as yellowish crystals. M.p. 59-60° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[C:5]([O:7][CH:8]([CH3:10])[CH3:9])=[O:6])[CH3:2].P([O-])([O-])([O-])=O>>[CH2:1]([O:3][C@H:4]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=1)[C:5]([OH:7])=[O:6])[CH3:2].[CH2:1]([O:3][C@@H:4]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[C:5]([O:7][CH:8]([CH3:10])[CH3:9])=[O:6])[CH3:2]
Reactant: CCOC(Cc1ccc(O)cc1)C(=O)OC(C)C
Agent: O=P([O-])([O-])[O-]
Product: CCO[C@@H](Cc1ccc(O)cc1)C(=O)OC(C)C
Product: CCO[C@H](Cc1ccc(O)cc1)C(=O)O
Temperature: 25 °C

Procedure:
Isopropyl (2RS) (+/−) 2-ethoxy-3-(4-hydroxyphenyl)propanoate (0.5 ml of a solution containing 2 mg/ml in a phosphate buffer, 0.1 M, pH 7) was added followed by α-chymotrypsin type II from bovine pancreas (SIGMA) (2.5 mg in a phosphate buffer. 0.1M, pH 7, 0.5 ml). The reaction mixture was shaken at room temperature and analysed at different times (maximum 28 h). The reaction mixtures were analysed by the gradient HPLC method 1 and by the chiral HPLC method.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]([O:12][C:13]([N:15]1[C@@H:20]([C@@H:21]([OH:33])[C@@H:22]([NH2:32])[CH2:23][C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=2)[CH2:19][O:18][C@@H:17]([CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C>O1CCCC1>[C:8]([O:12][C:13]([N:15]1[C@H:20]([C@H:21]([OH:33])[C@H:22]([NH:32][C:1](=[O:3])[CH3:2])[CH2:23][C:24]2[CH:25]=[C:26]([F:31])[CH:27]=[C:28]([F:30])[CH:29]=2)[CH2:19][O:18][C@@H:17]([CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)CC[C@H]1CN(C(=O)OC(C)(C)C)[C@@H]([C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)CO1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N[C@H](Cc1cc(F)cc(F)c1)[C@@H](O)[C@@H]1CO[C@@H](CCC(C)C)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Add acetic anhydride (25 μL, 0.264 mmol) to a solution of 5-(R)-[2-(S)-amino-3-(3,5-difluorophenyl)-1-(S)-hydroxypropyl]-2-(S)-(3-methylbutyl)-morpholine-4-carboxylic acid tert-butyl ester (107 mg, 0.240 mmol) and triethylamine (37 μL, 0.267 mmol) in tetrahydrofuran (5 mL) and stir at room temperature for 18 hours. Concentrate and purify (silica gel chromatography, eluting with 80:20 ethyl acetate:dichloromethane), to separate the two title compounds 5-(R)-[2-(S)-acetylamino-3-(3,5-difluorophenyl)-1-(S)-hydroxypropyl]-2-(S)-(3-methylbutyl)-morpholine-4-carboxylic acid tert-butyl ester (0.141 g, 59%) and 5-(S)-[2-(R)-acetylamino-3-(3,5-difluorophenyl)-1-(R)-hydroxypropyl]-2-(S)-(3-methylbutyl)-morpholine-4-carboxylic acid tert-butyl ester (25.1 mg, 22%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].[CH3:12][S:13](Cl)(=[O:15])=[O:14]>C(Cl)Cl>[Cl:1][CH2:2][CH2:3][CH:4]([O:5][S:13]([CH3:12])(=[O:15])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: OC(CCCl)c1ccccc1
Solvent: ClCCl
Product: CS(=O)(=O)OC(CCCl)c1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of the 3-chloro-1-phenyl-propan-1-ol (1.5 g, 8.79 mmol) in DCM at 0° C. (50 mL) was added TEA (1.6 mL, 11.4 mmol) followed by MsCl (0.75 mL, 9.7 mmol). The reaction mixture was stirred 1.5 hours at 0° C., quenched with ice, and partitioned between a saturated solution of NaHCO3 and DCM. The organic layer was separated, washed with brine, dried over MgSO4, filtered, and concentrated at 0° C. The methanesulfonic acid 3-chloro-1-phenyl-propyl ester (95% crude yield, 2.08 g) thus prepared was used in the next step without purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[N:7]=[C:8]([CH2:11][OH:12])[S:9][CH:10]=1>C(Cl)Cl.CO.O=[Mn]=O>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[N:7]=[C:8]([CH:11]=[O:12])[S:9][CH:10]=1
Reactant: OCc1nc(-c2nccs2)cs1
Agent: O=[Mn]=O
Solvent: CO
Solvent: ClCCl
Product: O=Cc1nc(-c2nccs2)cs1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
A mixture of [2,4′]bithiazol-2′-ylmethanol (1.53 g; 7.72 mmol), obtained as described in the above step, and MnO2 (13.93 g; 160.2 mmol) in CH2Cl2 (76.5 ml) and methanol (7.65 ml) was stirred at room temperature for about 23 hours.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#N)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[OH-:16].[K+].[OH2:18]>C(O)CO>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]([OH:18])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: [OH-]
Reactant: CC1CCN(c2ccc(C#N)cc2)CC1
Reactant: O
Agent: [K+]
Solvent: OCCO
Product: CC1CCN(c2ccc(C(=O)O)cc2)CC1

Procedure:
4-(4-Methylpiperidin1-yl)benzonitrile (1.2 g) was heated to reflux with potassium hydroxide (0.7 g) in water (2 ml) and ethylene glycol (8 ml) for 3 hours. The mixture was diluted with water, washed with ethyl acetate and acidified with 2N hydrochloric acid. The precipitated product was filtered off with suction, dissolved in dichloromethane, dried over sodium sulfate, concentrated and crystallized from diethyl ether. This resulted in the product with the molecular weight of 219.29 (C13H17NO2); MS(ESI): 220 (M+H+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4][S:5][CH2:6][C:7]([NH:9][CH:10]([CH2:14][C:15]([OH:17])=O)[C:11]([OH:13])=O)=[O:8].[NH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH3:39])[CH2:23][CH2:24][CH2:25][NH:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[N+:34]=[N-:35])=[CH:29][C:28]=1[N+:36]([O-:38])=[O:37].C([N:42](CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C.C(Cl)Cl>[N:33]([C:30]1[CH:31]=[CH:32][C:27]([NH:26][CH2:25][CH2:24][CH2:23][N:22]([CH2:21][CH2:20][CH2:19][NH:18][N:42]2[C:15](=[O:17])[CH2:14][CH:10]([NH:9][C:7](=[O:8])[CH2:6][S:5][S:4][CH2:3][CH2:2][OH:1])[C:11]2=[O:13])[CH3:39])=[C:28]([N+:36]([O-:38])=[O:37])[CH:29]=1)=[N+:34]=[N-:35]
Reactant: CCN(CC)CC
Reactant: O=C(O)CC(NC(=O)CSSCCO)C(=O)O
Reactant: CN(CCCN)CCCNc1ccc(N=[N+]=[N-])cc1[N+](=O)[O-]
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(CCCNc1ccc(N=[N+]=[N-])cc1[N+](=O)[O-])CCCNN1C(=O)CC(NC(=O)CSSCCO)C1=O
Reaction time: 0.25 h

Procedure:
The reaction was carried out in the dark. A one necked flask was charged with 95.0 mg (1 eq., 0.375 mmole) (2-hydroxyethyldithio)ethylamidosuccinic acid in 1.5 ml DMF and this solution was then sequentially treated with 0.1154 g (1 eq., 0.375 mmole) N-(3-aminopropyl)-N'-(4-azido-2-nitrophenyl)-N-methyl-1,3-propanediamine in 2 ml methylene chloride, 57.5 μl, (1.1 eq., 41.74 mg, 0.4125 mmole) triethylamine (neat), and then 156.4 mg (1.1 eq., 0.4175 mmole) O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate in 1 ml DMF. The reaction was monitored by TLC and found to be complete after 15 min at which time the solvents were removed via vacuum transfer (bath temp. 40° C.). The residue was purified by flash chromatography. 1H NMR (CD3CN/TMS) δ: 1.17 (2H, t, J=7.29 Hz, CH2), 1.71 (2H, m, J=6.88 Hz, CH2), 1.89 (2H, t, J=6.99 Hz, CH2), 2.37 (2H, t, J=3.10 Hz, CH2), 2.40 (3H, s, CH3), 2.64 (2H, t, J=7.45 Hz, CH2), 2.69 (2H, t, J=7.27 Hz, CH2), 2.76 (2H, t, J=6.69 Hz, CH2), 2.80 (2H, t, J=5.33 Hz, CH2), 3.01 (2H, q, J=7.31 Hz, CH2), 3.16 (2H, q, J=6.42 Hz, CH2), 3.40 (4H, m, J=6.48 Hz, 2×CH2), 3.70 (2H, t, J=6.30 Hz, CH2), 6.97 (2H, d, ArH), 7.18 (2H, dd, ArH), 7.77 (2H, d, NH), 13C NMR (CD3CN/TMS) δ: 27.2 (CH2), 27.8 (CH2), 32.25 (CH2), 32.28 (CH2), 38.60 (CH2), 38.80 (CH2), 39.7 (CH2), 42.2 (CH3), 42.4 (CH2), 42.5 (CH2), 56.3 (CH2), 56.4 (CH2), 61.4 (CH2), 116.6 (ArH), 117.3 (Ar), 128.9 (Q), 129.3 (Ar), 132.7 (Q), 144.6 (Q), 174.6 (C=O), 174.8 (C=O).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[N+:27]([C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37]O)=[CH:32][CH:31]=1)([O-:29])=[O:28]>C(Cl)Cl>[I:25][CH2:37][CH2:36][C:33]1[CH:34]=[CH:35][C:30]([N+:27]([O-:29])=[O:28])=[CH:31][CH:32]=1
Reactant: O=[N+]([O-])c1ccc(CCO)cc1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(CCI)cc1

Procedure:
To a 0° C. solution of triphenylphosphine (1.9 g, 7.2 mmol) and imidazole (489 mg, 7.18 mmol) in DCM (20 ml) was added iodine (1822 mg, 7.18 mmol) to form a solution. Small portions of 2-(4-nitrophenyl)ethanol (1.0 g, 6.0 mmol) was added to the suspension. TLC showed conversion to the desired product quickly. Hexane was added to the reaction to precipitate side products which were filtered off. The filtrate was concentrated in vacuo to obtain crude 1-(2-iodoethyl)-4-nitrobenzene, which was purified by silica gel flash chromatography using Hexane and EtOAc system. 1H-NMR (500 MHz, CD3Cl) δ 8.22 (d, J=8.5 Hz, 2H), 7.40 (d, J=8.5 Hz, 2H), 3.41 (t, J=7.0 Hz, 2H), 3.32 (t, J=7.0 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][NH:20]C(OC(C)(C)C)=O)[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][NH2:20])[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cccc(-c2cccc(OCCNC(=O)OC(C)(C)C)c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cccc(-c2cccc(OCCN)c2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 98.5 %

Procedure:
The methyl-3′-[2-[[(tert-butoxy)carbonyl]amino]ethoxy]-[1,1′-biphenyl]-3-carboxylate (659 mg) was dissolved in methylene chloride (25 mL) and trifluoroacetic acid (2.5 mL) was added. The mixture was stirred at room temperature for 6 h, additional trifluoroacetic acid (1.0 mL) was added and the mixture was stirred overnight. The mixture was concentrated and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer was separated, dried over sodium sulfate, filtered and concentrated to give the crude product. This residue was partitioned between 1:1 hexane: ethyl acetate and 1 N aqueous HCl. The aqueous layer was separated, washed with 1:1 hexane: ethyl acetate and made basic by addition of solid sodium bicarbonate. The mixture was extracted twice with ethyl acetate, and the combined organic extracts were dried over sodium sulfate, filtered and concentrated to afford the title compound (474 mg) as a colorless oil. Electrospray MS (positive ion): (M+H) 272.0.
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10].[SH2:14]>CCCCC>[SH:14][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:12][CH3:13])=[O:11]
Reactant: S
Reactant: C=CCCCCCCCC(=O)OC
Solvent: CCCCC
Product: COC(=O)CCCCCCCCCS

Procedure:
The resulting methyl 9-decenoate (156 g) is placed in a photochemical reactor comprising a reaction loop, with 100 g of pentane and 60 molar equivalents of liquefied hydrogen sulfide (1806 g condensed at 20° C. under a pressure of 17.5 bar).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([O:8][CH:9]([CH2:14][CH2:15]OS(C)(=O)=O)[C:10]([O:12][CH3:13])=[O:11])(=[O:7])[CH3:6]>CN(C)C=O>[C:5]([O:8][CH:9]([CH2:14][CH2:15][N:1]=[N+:2]=[N-:3])[C:10]([O:12][CH3:13])=[O:11])(=[O:7])[CH3:6]
Reactant: COC(=O)C(CCOS(C)(=O)=O)OC(C)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(CCN=[N+]=[N-])OC(C)=O
Temperature: 70 °C
Yield: 134.3 %

Procedure:
1.91 g of sodium azide was added to a dimethylformamide (10 ml) solution of 2.54 g of methyl 2-(acetyloxy)-4-[(methylsulfonyl)oxy]butanoate, and stirred under heat at 70° C. for 8 hours. The reaction liquid was restored to room temperature and extracted with ethyl acetate. The organic layer was washed with saturated saline water and dried, and the solvent was evaporated away under reduced pressure to obtain 2.70 g of methyl 2-(acetyloxy)-4-azidobutanoate as a brown oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:8](N)=[CH:7][C:6]=1[C:16]([F:19])([F:18])[F:17])(=[O:3])[CH3:2].Cl.[N+:21]([O-])([O-])=O.[Na+].[S:26](=[O:28])=[O:27]>C(O)(=O)C.O>[C:1]([NH:4][C:5]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:8]([S:26]([NH2:21])(=[O:28])=[O:27])=[CH:7][C:6]=1[C:16]([F:19])([F:18])[F:17])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1c(C(F)(F)F)cc(N)cc1C(F)(F)F
Reactant: O=[N+]([O-])[O-]
Reactant: O=S=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1c(C(F)(F)F)cc(S(N)(=O)=O)cc1C(F)(F)F

Procedure:
5.7 G. of 4-acetylamino-3,5-bis-trifluoromethylaniline is dissolved in 16 ml. of acetic acid and cooled to 10° C., 3.2 ml. of concentrated hydrochloric acid is added, and the mixture cooled to 0°-5° C. with stirring. A solution of 1.4 g. of sodium nitrate in 4 ml. of water is added dropwise, with vigorous stirring and the resultant mixture stirred for 1/2 hour. The aqueous diazonium salt solution is then added to a solution of 0.4 g. of cupric chloride in 50 ml. of acetic acid which has been previously saturated at 20° C. with sulfur dioxide. The reaction mixture is stirred for 10 minutes, while sulfur dioxide is bubbled through this mixture and for 20 minutes further. The reaction mixture is poured into ice, extracted with methylene chloride, washed with water, dried and evaporated in vacuo. The residual 4-acetylamino-3,5-bis-trifluoromethylbenzenesulfonylchloride is again dissolved in methylene chloride and added to an excess of liquid ammonia. The contents of the flask is allowed to evaporate at room temperature overnight, affording 4 -acetylamino-3,5-bis-trifluoromethylbenzenesulfonamide. This is taken up with 25 ml. of 6N hydrochloric acid and treated on a steam bath for 3 hours. It is cooled in ice and allowed to crystallize. The residue is collected by filtration, washed with water, and crystallized from aqueous ethanol to afford pure 4-amino-3,5-trifluoromethylbenzenesulfonamide.
Reaction SMILES: [OH:1][CH2:2][C:3]1([NH:7][CH:8]=[C:9]([C:15](=[O:26])[C:16]2[CH:21]=[C:20]([F:22])[C:19]([F:23])=[C:18](F)[C:17]=2F)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5][CH2:4]1.[H-].[Na+]>CN(C=O)C>[F:22][C:20]1[C:19]([F:23])=[C:18]2[O:1][CH2:2][C:3]3([CH2:6][CH2:5][CH2:4]3)[N:7]3[CH:8]=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:15](=[O:26])[C:16]([CH:21]=1)=[C:17]23
Reactant: CCOC(=O)C(=CNC1(CO)CCC1)C(=O)c1cc(F)c(F)c(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2c3c(c(F)c(F)cc3c1=O)OCC21CCC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 44.5 %

Procedure:
A solution of ethyl 3-[1-(hydroxymethyl)cyclobutylamino]-2-(2,3,4,5-tetrafluorobenzoyl)acrylate (1.52 g, 4.05 mmol) in DMF (10 mL) was added to an ice-cooled suspension of 60% NaH in oil (356 mg, 8.91 mmol) in DMF (10 mL), under argon atmosphere. The reaction mixture was stirred for 4 hours and poured into ice-water. The product was extracted with AcOEt, dried over MgSO4 and the crude product was purified by column chromatography (Hexane:EtOAc 2:1→AcOEt) to yield the title compound (604 mg, 44%) as a white solid. Mp 255-256° C. 1H-NMR (400 MHz, DMSO-d6) δ 1.29 (3H, t, J=7.3 Hz), 1.91-2.07 (2H, m), 2.16-2.22 (2H, m), 2.65-2.76 (2H, m), 4.24 (2H, q, J=7.3 Hz), 4.62 (2H, s), 7.62 (1H, dd, J=10.4, 7.9 Hz), 8.80 (1H, s). ESIMS (+): 336 [M+H]+.
Reaction SMILES: [H-].[Na+].[OH:3][C@H:4]1[C@H:9]([CH2:10][O:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:8][CH2:7][N:6]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:5]1.[CH3:29]I.O>C1COCC1>[CH3:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([O:11][CH2:10][C@@H:9]2[CH2:8][CH2:7][N:6]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:5][C@H:4]2[O:3][CH3:29])(=[O:13])=[O:14])=[CH:16][CH:17]=1
Reactant: CI
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1COS(=O)(=O)c1ccc(C)cc1
Reaction time: 0.5 h

Procedure:
Reaction under nitrogen atmosphere. Sodiumhydride (0.3 mol) was added to a solution of 1,1-dimethylethyl trans-3-hydroxy4-[[[(4-methylphenyl)sulfonyl]oxy]methyl]-1-piperidinecarboxylate [described in WO-00/37461 as intermediate (1-c)] (0.27 mol) in THF (1300 ml). The mixture was stirred for 30 minutes. Methyliodide (0.54 mol) was added and the resulting reaction mixture was stirred for 90 minutes. A small amount of water was added. The solvent was evaporated and the residue was partitioned between water and DCM. The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 1,1-dimethylethyl trans4-[[[(4-methylphenyl)sulfonyl]oxy]-methyl]-3-methoxy-1-piperidinecarboxylate (intermediate 49).
Reaction SMILES: [P:1]([O:5][CH2:6][C@H:7]1[O:11][C@@H:10]([N:12]2[CH:19]=[C:18]([I:20])[C:16](=[O:17])[NH:15][C:13]2=[O:14])[C@H:9]([OH:21])[C@@H:8]1[OH:22])([OH:4])([OH:3])=O.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.N1C=CC=CC=1SSC1C=CC=CN=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CS(C)=O.CN(C=O)C>[CH2:24]1[N:23]([P:1]([O:5][CH2:6][C@H:7]2[O:11][C@@H:10]([N:12]3[C:13](=[O:14])[NH:15][C:16](=[O:17])[C:18]([I:20])=[CH:19]3)[C@H:9]([OH:21])[C@@H:8]2[OH:22])([OH:3])=[O:4])[CH2:28][CH2:27][O:26][CH2:25]1
Reactant: C1COCCN1
Reactant: O=c1[nH]c(=O)n([C@@H]2O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]2O)cc1I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(SSc2ccccn2)nc1
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: O=c1[nH]c(=O)n([C@@H]2O[C@H](COP(=O)(O)N3CCOCC3)[C@@H](O)[C@H]2O)cc1I
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 104.9 %

Procedure:
5-Iodouridine-5′-monophosphate 1 (292 mg, 0.65 mmol) was dissolved in dry DMSO, co-evaporated (3×) with dry DMF, and finally dissolved in 0.5 mL of dry DMSO. Morpholine (400 μL, 4.6 mmol) was added and the reaction mixture was stirred at room temperature for 5 min. Dipyridyl disulfide (500 mg, 2.3 mmol) and triphenylphosphine (600 mg, 2.3 mmol) were added in 5 min intervals, and the reaction mixture was stirred for another 60 minutes at room temperature. Upon quenching of the reaction with 0.1 M NaI in acetone a precipitate formed. The supernatant was removed, and the precipitate was washed repeatedly with cold acetone, to give 354 mg (99% yield) of 5-Iodouridine-5′-phosphoromorpholidate as a white powder. This material was used in the next step without further purification. δH (400 MHz, D2O) 3.04-3.16 (4H, m, H-Morpholine), 3.65-3.73 (4H, m, H-Morpholine), 4.00-4.15 (2H, m, H-5′), 4.24-4.26 (1H, m, H-4′), 4.27-4.32 (1H, m, H-3′), 4.36 (1H, t, J=5.4 Hz, H-2′), 5.94 (1H, d, J=5.8 Hz, H-1′), 8.17 (1H, s, H-6). δC (75.5 MHz, D2O) 64.3 (morpholine), 63.3 (d, J=5.4 Hz, C-5′), 66.3 (morpholine), 67.8 (C-5), 68.6 (C-3′), 73.2 (C-2′), 83.0 (d, J=8.4 Hz, C-4′), 88.2 (C-1′), 145.0 (C-6), 153.3 (C-2), 161.9 (C-4); OP (121.5 MHz, D2O) 11.0 ppm. m/z (ESI) 519.9968 [M+H]+, C13H19IN3O9P requires 519.9976.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:8])[N:5]=[CH:4][C:3]=1[C:15]([O:17]C)=[O:16].O.[OH-].[Li+].O1CCCC1.Cl>O.CO>[CH3:1][C:2]1[N:6]([CH:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH3:8])[N:5]=[CH:4][C:3]=1[C:15]([OH:17])=[O:16]
Reactant: COC(=O)c1cnn(C(C)c2ccccc2)c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)cnn1C(C)c1ccccc1
Temperature: 20 °C
Reaction time: 4 h
Yield: 66.5 %

Procedure:
A mixture of methyl 5-methyl-1-(1-phenylethyl)-1H-pyrazole-4-carboxylate (80 mg, 0.32 mmol), lithium hydroxide monohydrate (57.1 mg, 1.36 mmol), tetrahydrofuran (5 mL), methanol (1 mL) and water (1 mL) was stirred at 20° C. for 4 hours. The mixture was acidified to pH=1 with concentrated hydrochloric acid and then extracted with ethyl acetate (15 mL×3). The combined organic phase was dried by sodium sulfate, and then filtered. The filtrate was concentrated in vacuo to give 5-methyl-1-(1-phenylethyl)-1H-pyrazole-4-carboxylic acid as a white solid (49 mg, 62%). 1H NMR (300 MHz, d6-DMSO): δ 12.16 (s, 1H), 8.26 (s, 1H), 7.37-7.25 (m, 5H), 5.55 (q, J=7.2 Hz, 1H), 2.30 (s, 3H), 1.78 (d, J=6.9 Hz, 3H).