Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([O:10][N:11]=[C:12]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH2:15][CH3:16])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.CS([C:25]1[N:30]=[C:29]([O:31][CH3:32])[CH:28]=[C:27]([O:33][CH3:34])[N:26]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:34][O:33][C:27]1[CH:28]=[C:29]([O:31][CH3:32])[N:30]=[C:25]([O:1][C:2]2[C:3]([C:8]([O:10][N:11]=[C:12]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH2:15][CH3:16])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=2)[N:26]=1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: CCCCC(CCCC)=NOC(=O)c1ncccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC(CCCC)=NOC(=O)c1ncccc1Oc1nc(OC)cc(OC)n1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a mixture of 6.3 g of 5-nonanylidenamino 3-hydroxypicolinate, 2.5 g of 2-methylsulfonyl-4,6-dimethoxypyrimidine and 3.9 g of anhydrous potassium carbonate, 50 ml of N,N-dimethylformamide was added, and the mixture was stirred at 100° C. for 2 hours. After cooling, the reaction solution was poured into water and extracted with ethyl ether. The organic layer was further washed with water and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue thereby obtained was purified by silica gel column chromatography by using as a developing solvent a mixture of hexane/ethyl ether to obtain 5.2 g of the above identified compound as slightly yellow transparent viscous liquid.
Reaction SMILES: I[CH:2]([CH3:4])[CH3:3].CN(C)C=O.[NH2:10][C:11](=[N:17][OH:18])[C:12](=[N:15][OH:16])[C:13]#[N:14].C(=O)([O-])[O-].[K+].[K+]>O>[NH2:10][C:11](=[N:17][OH:18])[C:12](=[N:15][O:16][CH:2]([CH3:4])[CH3:3])[C:13]#[N:14]
Reactant: N#CC(=NO)C(N)=NO
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)ON=C(C#N)C(N)=NO
Temperature: 0 °C
Reaction time: 16 h
Yield: 53.9 %

Procedure:
2.52 g (14.8 mM) of 2-iodopropane was added to an N,N-dimethylformamide solution (30 ml) of 2.00 g (15.6 mM) of 3-amino-2,3-bis(hydroxyimino)propionitrile. The mixture was cooled to 0° C. 2.05 g (14.8 mM) of potassium carbonate was added, followed by stirring at room temperature for 16 hours. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer obtained was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered to remove inorganic matter. The solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetete:hexane=1:2) to obtain 1.36 g (yield: 51%) of 3-amino-3-hydroxyimino-2-isopropoxyiminopropionitrile (compound No. 1-004).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([CH:18]1[CH2:20][CH:19]1[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:12]2)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([CH:18]1[CH2:20][CH:19]1[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:12]2
Reactant: CCOC(=O)C1CC1c1cc2cc(OCc3ccccc3)ccc2[nH]1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)C1CC1c1cc2cc(O)ccc2[nH]1
Reaction time: 6 h
Yield: 99.6 %

Procedure:
Ethyl 2-(5-benzyloxyindolyl)cyclopropanecarboxylate(1.75 g, 0.0052 mol), as prepared in the preceding step, was added under argon to a suspension of 10% of palladium(0) on carbon (0.50 g) in methanol (50 mL). The reaction was carried out under H2 atmosphere for a period of 6 h. Filtration of the reaction over Celite and evaporation of the filtrate yielded the title compound (1.27 g, 99%). 1H NMR (400 MHz, CDCl3) δ 1.32 (t, 3H, J=7.1 Hz), 1.60 (m, 1H), 1.72 (m, 1H), 2.13 (m, 1H), 3.77 (m, 1H), 4.25 (q, 2H, J=7.1 Hz), 6.29 (d, 1H, J=3.0 Hz), 6.81 (d, 1H, J=8.3 Hz), 7.00 (m, 2H), 7.27 (m, 1H)
Reaction SMILES: Cl.[CH2:2]([NH:4][CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][O:21][N:22]=[C:23]([C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)=[CH:27][CH:26]=2)[CH3:24])=[CH:14][CH:13]=1)[C:6]([O:8]CC)=[O:7])[CH3:3].[OH-].[Na+].Cl>>[CH2:2]([NH:4][CH:5]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][O:21][N:22]=[C:23]([C:25]2[CH:26]=[CH:27][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)=[CH:29][CH:30]=2)[CH3:24])=[CH:16][CH:17]=1)[C:6]([OH:8])=[O:7])[CH3:3]
Reactant: CCNC(Cc1ccc(OCCON=C(C)c2ccc(-c3ccccn3)cc2)cc1)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCNC(Cc1ccc(OCCON=C(C)c2ccc(-c3ccccn3)cc2)cc1)C(=O)O

Procedure:
Reaction was carried out according to Example 2 using 273 mg of ethyl 2-ethylamino-3-[4-[2-[[1-[4-(2-pyridyl)phenyl]ethylidene]aminoxy]ethoxy]phenyl]propionate obtained in Example 15 and 2.4 ml of a 1N aqueous sodium hydroxide solution. When the pH of the reaction mixture thus obtained was adjusted to a value of 4 with 1N hydrochloric acid, the desired compound was obtained as a precipitate. The precipitate was collected by filtration and washed with water to obtain 186 mg of the desired compound.
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[S:19]([O:22][CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])(=[O:21])=[O:20])(OCC)=O)C.[H-].[Na+].[N+:30]([C:33]1[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=1)([O-:32])=[O:31]>O1CCCC1.C(OCC)(=O)C>[CH3:27][C:24]([CH3:25])([CH3:26])[CH2:23][O:22][S:19]([C:11]1[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:10]=1[CH:9]=[CH:37][C:36]1[CH:39]=[CH:40][C:33]([N+:30]([O-:32])=[O:31])=[CH:34][CH:35]=1)(=[O:20])=[O:21]
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])cc1S(=O)(=O)OCC(C)(C)C)OCC
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)COS(=O)(=O)c1cc([N+](=O)[O-])ccc1C=Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 91 %

Procedure:
2-(Diethoxyphosphorylmethyl)-5-nitro-benzenesulfonic acid, 2,2-dimethylpropyl ester Example 55, 1.15 g, 2.72 mmol) was dissolved in 55 mL of anhydrous tetrahydrofuran. Sodium hydride (0.12 g, 2.99 mmol) was added in one portion and the reaction mixture was stirred for twenty minutes. The solution turned a deep red color. After attaching a reflux condenser, 4-nitrobenzaldehyde (0.821 g, 5.43 mmol) was added and the mixture was heated to reflux in an oil bath. After six hours the solution was cooled to room temperature, diluted with ethyl acetate (300 mL), washed with brine (2×), washed with conc. sodium bisulfite (2×), and the organic layer was dried (MgSO4). After concentration on a rotovap the crude material was purified by a gradient flash column using 30 to 60% ethyl acetate in hexanes as the eluant to afford 1.13 g of the title compound as a yellow solid (91%): 1HNMR (CDCl3) δ8.91 (d, J=2 Hz, 1H), 8.51 (dd, J=9 Hz, 2 Hz, 1H), 8.29 (d, J=9 Hz, 2H), 8.09 (d, J=16 Hz, 1H), 8.06 (d, J=9Hz, 1H), 7.74 (d, J=9Hz, 2H), 7.31 (d, J=16 Hz, 1H), 3.75 (s, 2H), 0.88 (s, 9H); MS (ES-NEG): [M−H]− 419; Anal. Calc. for C19H20N2O7S: C, 54.28; H, 4.79; N, 6.66. Found: C, 54.13; H, 4.68; N, 6.54.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[CH:14](OC)[C:15]1[C:23]2[C:18](=[N:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1.C(#N)C.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>>[Cl:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[CH2:14][C:15]1[C:23]2[C:18](=[N:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1
Reactant: COC(c1c(C)nn(-c2ccccc2)c1Cl)c1c[nH]c2ncccc12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Cc1nn(-c2ccccc2)c(Cl)c1Cc1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 3-((5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)(methoxy)methyl)-1H-pyrrolo [2,3-b]pyridine (P-0079, 0.030 g, 0.085 mmol) was added acetonitrile (10 mL, 0.2 mol). Trifluoroacetic acid (500 uL, 0.006 mol) and triethylsilane (500 uL, 0.003 mol) were added and the reaction allowed to stir at room temperature for 16 hours. The reaction was extracted with ethyl acetate and water. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with dichloromethane followed 5% methanol in dichloromethane to give the compound as a yellowish foam (P-0080, 29 mg, 98%). MS (ESI) [M+H+]+=323.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH3:18])=[N:10][C:9]=2[C:19]([O:21]C)=[O:20])[CH:5]=[CH:6][CH:7]=1.[OH-].[Li+].O.Cl>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH3:18])=[N:10][C:9]=2[C:19]([OH:21])=[O:20])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1nc(C)c2ccccc2c1-c1cccc(F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(C(=O)O)c(-c2cccc(F)c2)c2ccccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of methyl 4-(3-fluorophenyl)-1-methylisoquinoline-3-carboxylate (0.423 g, 1.43 mmol) and 3.0 M lithium hydroxide in water (2.39 mL, 7.16 mmol) in tetrahydrofuran (2.4 mL) was stirred at room temperature for 3 hours. After neutralized with 1 N HCl, the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The resulting crude acid was used directly in the next step (0.40 g, 99%). LCMS calculated for C17H13FNO2 (M+H)+: m/z=282.1; Found: 282.0.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([N:8]([CH2:17][C:18](O)=[O:19])[C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])=[O:7])=[CH:4][CH:3]=1.[NH:23]1[CH2:32][CH2:31][CH2:30][C@H:24]1[C:25]([O:27][CH2:28][CH3:29])=[O:26]>>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([N:8]([CH2:17][C:18]([N:23]2[CH2:32][CH2:31][CH2:30][C@H:24]2[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:19])[C:9]2[C:10]([CH3:16])=[CH:11][CH:12]=[CH:13][C:14]=2[CH3:15])=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1cccc(C)c1N(CC(=O)O)C(=O)c1ccc(Cl)cc1
Reactant: CCOC(=O)[C@@H]1CCCN1
Product: CCOC(=O)[C@@H]1CCCN1C(=O)CN(C(=O)c1ccc(Cl)cc1)c1c(C)cccc1C

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(p-chlorobenzoyl)-2-(2,6-dimethylanilino)acetic acid and ethyl L-prolinate and suitable processing produces ethyl N-[N-(p-chlorobenzoyl)-2-(2,6-dimethylanilino)acetyl]-L-prolinate (oil), saponification of which and processing of the reaction product yields N-[N-(p-chlorobenzoyl)-2-(2,6-dimethylanilino)acetyl]-L-proline (M.P. 199°).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([CH2:15][CH2:16][CH2:17][O:18][N:19]4C(=O)C5C(=CC=CC=5)C4=O)[C:13]([CH2:30][CH2:31][CH3:32])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[NH4+:45].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[NH2:19][O:18][CH2:17][CH2:16][CH2:15][N:14]1[C:6]2[C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:11][C:10]=3[N:9]=[C:8]([NH2:45])[C:7]=2[N:12]=[C:13]1[CH2:30][CH2:31][CH3:32]
Reactant: CCCc1nc2cnc3cc(Br)ccc3c2n1CCCON1C(=O)c2ccccc2C1=O
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCON
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 2-[3-(7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propoxy]-1H-isoindole-1,3(2H)-dione (1.00 g, 2.03 mmol) in chloroform (20 mL) at room temperature and under an atmosphere of nitrogen was added mCPBA (1.00 g, 4.06 mmol). The reaction was stirred for 2 hours, then was cooled to 0° C. Concentrated ammonium hydroxide (1 mL) was added followed by p-toluenesulfonyl chloride (111 mg, 0.58 mmol) in portions. The mixture was stirred for 1.5 hours at 0° C. and then filtered to remove a solid, which was washed with chloroform. The filtrate was washed with brine (2×10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 0-35% CMA in chloroform) to afford 300 mg of 1-[3-(aminooxy)propyl]-7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine.
Reaction SMILES: C(O)(=O)[CH2:2][C:3]([CH3:5])=[O:4].[OH-].[Na+].Cl.C([O-])(=O)C.[Na+].[F:16][C:17]([F:30])([F:29])[C:18]1[CH:23]=[CH:22][C:21]([S:24][CH2:25][CH2:26][CH:27]=[O:28])=[CH:20][CH:19]=1>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[OH:28][CH:27]([CH2:26][CH2:25][S:24][C:21]1[CH:22]=[CH:23][C:18]([C:17]([F:29])([F:16])[F:30])=[CH:19][CH:20]=1)[CH2:2][C:3](=[O:4])[CH3:5]
Reactant: O=CCCSc1ccc(C(F)(F)F)cc1
Reactant: CC(=O)CC(=O)O
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)CC(O)CCSc1ccc(C(F)(F)F)cc1
Reaction time: 6 h
Yield: 85.6 %

Procedure:
1.51 Grams of acetoacetic acid were dissolved in 2 ml of water, and 1.82 g of a 30% aqueous sodium hydroxide solution were added thereto by drops while cooling the mixture to 35° C. or less. After having been stirred at 30°-35° C. for 6 hours, the mixture was adjusted to pH 7.5 with a concentrated aqueous hydrochloric acid solution. Thereafter, 0.08 g of sodium acetate and 0.32 g of tetrabutylammonium bromide were added thereto and then 5.82 g of a toluene solution containing 40.2% of 3-(4-trifluoromethylphenylthio)propanal were added thereto. The mixture was stirred at 45°-50° C. for 6 hours and then at room temperature for 12 hours. After the mixture had been neutralized with a concentrated aqueous hydrochloric acid solution, the organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. Removing the solvent from the layer under reduced pressure gave 3.02 g of crude 4-hydroxy-6-(4-trifluoromethylphenylthio)-2-hexanone (purity: 82.8%, yield: 85.6%).
Reaction SMILES: [Br:1]Br.[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:13]1([C:17](=[O:19])[CH3:18])[CH2:16][CH2:15][CH2:14]1>CCOCC>[Br:1][CH2:18][C:17]([C:13]1([C:4]2[CH:5]=[CH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:3]=2)[CH2:16][CH2:15][CH2:14]1)=[O:19]
Reactant: CC(=O)C1(c2ccc3ccccc3c2)CCC1
Reactant: BrBr
Solvent: CCOCC
Product: O=C(CBr)C1(c2ccc3ccccc3c2)CCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Bromine (2.6 ml) was added dropwise over 1 hour at ambient temperature to a stirred solution of 1-[1-(2-naphthyl)cyclobutyl]ethanone (11.25 g) in ether (300 ml). After the addition was complete and the bromine colour had dissipated, the mixture was stirred at ambient temperature for a further 0.5 hour then it was washed with water (100 ml), saturated aqueous sodium hydrogen carbonate solution (2×100 ml) and water (100 ml), dried (MgSO4), and the solvent removed in vacuo to give 2-bromo-1-[1-(2-naphthyl)cyclobutyl]ethanone as an oil which was used without purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[C:5]([N+:15]([O-:17])=[O:16])=[C:4]([NH2:18])[CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[F:27][C:28]([F:39])([F:38])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O>O1CCOCC1.O.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2].CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:14][N:11]1[CH2:12][CH2:13][N:8]([C:6]2[C:5]([N+:15]([O-:17])=[O:16])=[C:4]([NH2:18])[CH:3]=[C:2]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[C:28]([F:39])([F:38])[F:27])[N:7]=2)[CH2:9][CH2:10]1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: CN1CCN(c2nc(Cl)cc(N)c2[N+](=O)[O-])CC1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: C1COCCO1
Product: CN1CCN(c2nc(-c3ccccc3C(F)(F)F)cc(N)c2[N+](=O)[O-])CC1
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
A solution of 6-chloro-2-(4-methyl-piperazin-1-yl)-3-nitro-pyridin-4-ylamine (578 mg, 2.13 mmol, prepared as described in the previous step) in 1,4-dioxane (20 mL) was treated with K3PO4 (2.03 g, 9.58 mmol), 1,1′-bis(di-tert-butylphosphino)ferrocene (101 mg, 0.213 mmol), and 2-trifluoromethylphenylboronic acid (910 mg, 4.79 mmol). The resulting mixture was degassed via sonication, Pd(OAc)2 (47.8 mg, 0.213 mmol) was added, and the mixture was heated to 80° C. for 18 h. The cooled mixture was diluted with water (50 mL) and extracted twice with EtOAc (60 mL). The combined extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 40-g SEPRA Si 50 SPE column (Isco system: Flow rate=20 mL/min; Eluent=EtOAc-hexanes, 3:1 v/v for 5 min, then 3:1 to 1:0 v/v over 40 min) to yield 2-(4-methyl-piperazin-1-yl)-3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-4-ylamine as an orange solid. 1H-NMR (400 MHz, CDCl3) δ: 7.74 (d, J=7.6 Hz, 1H), 7.55-7.61 (m, 1H), 7.45-7.54 (m, 2H), 6.13 (s, 1H), 6.02 (br. s., 2H), 3.46-3.52 (m, 4H), 2.44-2.50 (m, 4H), 2.32 (s, 3H). Mass Spectrum (LCMS, APCI pos.): Calculated for C17H18F3N5O2: 382.1 (M+H); Measured: 382.1.
Reaction SMILES: [C:1](OC(=O)C)(=O)C.[OH-].[Na+].O.[CH3:11][S:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:29])[CH3:28])=[CH:22][CH:21]=2)=[CH:15][C:14]=1C>C(O)C>[CH3:11][S:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]2[CH:21]=[CH:22][C:23]([NH:26][C:27](=[O:29])[CH3:28])=[CH:24][CH:25]=2)=[C:17]([CH3:1])[CH:18]=1
Reactant: CC(=O)OC(C)=O
Reactant: CSc1ccc(Oc2ccc(NC(C)=O)cc2)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CSc1ccc(Oc2ccc(NC(C)=O)cc2)c(C)c1
Reaction time: 0.17 h

Procedure:
This solid was dissolved in ethanol and treated with first excess of acetic anhydride, and then, with stirring, with dilute aqueous sodium hydroxide solution until strongly alkaline. After about 10 minutes, the reaction was treated with water to faint turbidity and left to stand. Platelets of the product 4-(4-acetamidophenoxy)-2-methylphenyl methyl sulphide, come out of solution slowly, melting point 99.6° to 101° C. On recrystallisation from ethanol-water, analytical samples were obtained melting between 101.4° and 102.1° C.
Reaction SMILES: [OH:1][CH2:2][C:3](=[O:17])[CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:9]=[CH:10][CH:11]=1.N1C=CN=C1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>CN(C=O)C>[Si:23]([O:1][CH2:2][C:3](=[O:17])[CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:9]=[CH:10][CH:11]=1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)Cc1cccc(CCC(=O)CO)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)Cc1cccc(CCC(=O)CO[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.7 %

Procedure:
To an ice cooled solution of methyl 3-(4-hydroxy-3-oxo-butyl)phenylacetate (472 mg, 2.00 mmol) in DMF (10 ml) was added imidazole (264 mg, 3.88 mmol) followed by tert-butyldimethylsilyl chloride (408 mg, 5.99 mmol). After 30 minutes the ice-bath was removed and then the mixture was stirred overnight at room temperature. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate. The organic layer was washed with brine, dried (magnesium sulfate), and concentrated in vacuo. The residue was purified by silica gel (20 g) column chromatography eluting with hexane/ethyl acetate (10:1) to give methyl 3-[4-(tert-butyldimethylsilyloxy)-3-oxobutyl]phenylacetate (664 mg, 94.9%) as a colorless oil.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([C@@H:13]([CH2:19][N:20](C(OCC2C=CC=CC=2)=O)[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=2[CH3:29])[C@@H:14]([OH:18])[C:15]#[C:16][CH3:17])[C:9]1=[O:40])(C)(C)C.C(O)(C(F)(F)F)=O.C(N(CC)C(C)C)(C)C.[F:58][C:59]([F:70])([F:69])[C:60]1[CH:61]=[C:62]([N:66]=[C:67]=[O:68])[CH:63]=[CH:64][CH:65]=1>C(Cl)Cl>[CH3:29][C:23]1[CH:24]=[C:25]([CH3:28])[CH:26]=[CH:27][C:22]=1[CH2:21][NH:20][CH2:19][C@H:13]([N:10]1[CH2:11][CH2:12][C@H:8]([NH:7][C:67]([NH:66][C:62]2[CH:63]=[CH:64][CH:65]=[C:60]([C:59]([F:69])([F:70])[F:58])[CH:61]=2)=[O:68])[C:9]1=[O:40])[C@@H:14]([OH:18])[CH2:15][CH2:16][CH3:17]
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: CC#C[C@H](O)[C@H](CN(Cc1ccc(C)cc1C)C(=O)OCc1ccccc1)N1CC[C@H](NC(=O)OC(C)(C)C)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCC[C@H](O)[C@H](CNCc1ccc(C)cc1C)N1CC[C@H](NC(=O)Nc2cccc(C(F)(F)F)c2)C1=O
Reaction time: 3 h

Procedure:
A solution of {(3S)-1-[(1S,2S)-(1-{[benzyloxycarbonyl-(2,4-dimethyl-benzyl)-amino]-methyl}-2-hydroxy-pent-3-ynyl)]-2-oxo-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (1.16 g, 1.74 mmol, see procedure 1c above) was dissolved in CH2Cl2 (16 mL) and treated with TFA (8 mL). The solution was stirred for 3 h and then concentrated in vacuo. The residue was dissolved in CH2Cl2 and concentrated in vacuo; this procedure was repeated. A portion (0.22 mmol) of the product amine was dissolved in CH2Cl2 (4 mL). The resultant solution was charged sequentially with N, N-diisopropylethylamine (0.16 mL, 0.88 mmol) and (meta-trifluoromethyl-phenyl)isocyanate (0.033 mL, 0.22 mmol). The reaction was stirred for 12 h and partitioned between EtOAc and sat. NH4Cl. The organic phase was washed with sat. NaHCO3 and brine, and then dried (Na2SO4), filtered, and concentrated in vacuo. The residue was dissolved in MeOH (6 mL). The resultant solution was charged with 5% Pd/C, Degussa style (50 mg), stirred under H2 (1 atm) for 12 h at RT, filtered, and concentrated in vacuo. The residue was purified by reverse-phase HPLC to afford the title compound as a white powder after lyopholization. MS found: (M+H)+=521.5.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[CH2:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>ClC1CCCOC1C1C=CC=CC=1>[C:1]1(/[CH:7]=[CH:8]/[CH2:9][CH2:10][CH:11]=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCC/C=C/c1ccccc1
Agent: ClC1CCCOC1c1ccccc1
Product: O=CCC/C=C/c1ccccc1
Reaction time: 0.25 h
Yield: 93.8 %

Procedure:
To a dry 3 liter 3-necked flask equipped with mechanical stirrer, thermometer and nitrogen inlet was added 1.5 liter of dry dichloromethane (a) and 95 g of dry pyridine (b). The stirred solution was cooled ot an internal temperature of 5° and 60 g of chromium trioxide (c) was added in one portion. The mixture was stirred an additional 5 minutes and then allowed to warm to 20° over 60 minutes, giving a solution of Collins reagent. A solution of 16.2 g of trans-5-phenyl-4-penten-1-ol (d) in 100 ml of dry dichloromethane (e) was then added rapidly. The mixture was stirred an additional 15 minutes and then decanted from the residue. The residue, a black tar, was washed with ether (3×500 ml) and the combined organic solution was worked up in the usual manner. Evaporation of the solvent gave the aldehyde (15 g) as a pale yellow liquid. TLC; silica gel HF254 ; ethyl acetate/benzene 1:9 Rf 0.50.