Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH3:18])[CH2:15][CH2:16][NH2:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:25](Cl)(=[O:27])[CH3:26]>O>[C:25]([NH:17][CH2:16][CH2:15][CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:9][CH:10]=1)[CH3:18])(=[O:27])[CH3:26]
Reactant: CC(=O)Cl
Reactant: CC(CCN)c1ccc(-c2ccc(Cl)cc2)cc1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)NCCC(C)c1ccc(-c2ccc(Cl)cc2)cc1
Reaction time: 2 h

Procedure:
A mixture of 2.6 g of of 3-(4'-chloro-4-biphenylyl)butylamine, 12 ml of pyridine and 1 ml of acetyl chloride is allowed to stand for 2 hours, decomposed with water and worked up in the customary manner to give 1-acetamido-3-(4'-chloro-4-biphenylyl)-butane, m.p. 118°-120°.
Reaction SMILES: N#N.[Cl:3][CH2:4][C:5]1[N:6]=[C:7]([C:10](=[O:12])[CH3:11])[S:8][CH:9]=1.[CH2:13](O)[CH2:14][OH:15].COC(OC)OC>C([O-])(O)=O.[Na+]>[Cl:3][CH2:4][C:5]1[N:6]=[C:7]([C:10]2([CH3:11])[O:15][CH2:14][CH2:13][O:12]2)[S:8][CH:9]=1
Reactant: OCCO
Reactant: CC(=O)c1nc(CCl)cs1
Agent: N#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COC(OC)OC
Product: CC1(c2nc(CCl)cs2)OCCO1
Temperature: 95 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and a Dean-Stark apparatus under inert atmosphere (N2), a solution of 1-(4-chloromethyl-thiazol-2-yl)-ethanone (992 mg, 5.65 mmol) in ethylene glycol (6.30 mL, 112.96 mmol) was treated with trimethylorthoformate (1.24 mL, 11.30 mmol) followed by LiBF4 (106 mg, 1.13 mmol). The reaction mixture was heated at 95° C. for 2 h. Sat. aq. NaHCO3 (50 mL) was added and the mixture was extracted with EA (50 mL). The org. extracts were washed with brine (2×50 mL), dried over MgSO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (4:1 hept-EA) gave the title compound as a yellow oil: TLC:rf (4:1 hept-EA)=0.30. LC-MS-conditions 02: tR=0.84 min, [M+H]+=220.36.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:14])([CH3:13])[C:7](=[O:12])[N:8]2C)=[CH:4][CH:3]=1.[CH3:15][O:16][C:17](=[O:31])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29]Br)[CH:24]=1.[C:32](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:15][O:16][C:17](=[O:31])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]([O:1][C:2]2[CH:10]=[C:9]3[C:5]([C:6]([CH3:13])([CH3:14])[C:7](=[O:12])[NH:8]3)=[CH:4][CH:3]=2)[CH3:32])[CH:24]=1
Reactant: COC(=O)CCCCCc1cccc(CBr)c1
Reactant: O=C([O-])[O-]
Reactant: CN1C(=O)C(C)(C)c2ccc(O)cc21
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CCCCCc1cccc(C(C)Oc2ccc3c(c2)NC(=O)C3(C)C)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 41.5 %

Procedure:
To a solution of 6-hydroxy-1,3,3-trimethyl-1,3-dihydro-indol-2-one (396 mg, 2.07 mmol) in DMF (7.6 mL) is added 6-(3-Bromomethyl-phenyl)-hexanoic acid methyl ester (682 mg, 2.28 mmol) and potassium carbonate (315 mg, 2.28 mmol). The resulting mixture is heated to 60° C., stirred for 2 hrs. then cooled to room temp and diluted with EtOAc. The organic layer is washed with water, brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (eluting with 30% ethyl acetate/hexanes) to give 352 mg of title compound. MS (ESI) 410 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N+:5]([O-])=[CH:6][CH:7]=1.P(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:3]=1
Reactant: [O-][n+]1ccc(Br)cc1-c1ccccn1
Solvent: ClP(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Brc1ccnc(-c2ccccn2)c1
Temperature: 25 °C
Yield: 85 %

Procedure:
To a stirred suspension of 4-bromo-2,2′-bipyridyl-N-oxide in 60 mL CHCl3, was added 12 mL PCl3, at room temperature. The mixture was refluxed for 2 h under N2 and then cooled to room temperature. The reaction mixture was poured into 100 mL ice/water. The aqueous layer was separated and saved. The CHCl3, layer was extracted three times with H2O (3×60 mL) and then discarded. The combined aqueous solution was neutralized with NaHCO3 powder to about pH 7-8. The resulting white precipitate was collected by suction filtration, washed with H2O (30 mL) and then dried under vacuum at 50° C. for 24 h. Yield: 85%.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][NH:9][C:10](=[O:14])[O:11][CH2:12][CH3:13].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][S:2]([O:6][CH2:7][CH2:8][NH:9][C:10](=[O:14])[O:11][CH2:12][CH3:13])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)NCCO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)NCCOS(C)(=O)=O
Reaction time: 16 h

Procedure:
60 g of methanesulfonyl chloride are metered over approximately 30 minutes at 0° to +5° C. to a solution of 66.5 g of ethyl 2-hydroxyethylcarbamate, 43.5 g of pyridine and 1.9 g of 4-dimethylaminopyridine in 150 ml of methylene chloride, with stirring, and the mixture is stirred for 2 more hours at +5° C. and then for 16 hours at room temperature. The reaction mixture is filtered, the residue is washed with a small quantity of ethyl acetate, and the combined filtrates are washed with dilute hydrochloric acid and water. After the mixture has been dried over magnesium sulfate, the solvent mixture is removed completely by distillation in vacuo, which gives ethyl 2-methylsulfonyloxyethylcarbamate, nD20 1.4450.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([CH3:15])([CH3:14])[C:10]([O:12]C)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C1COCC1.O.O.[OH-].[Li+].Cl>C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([CH3:15])([CH3:14])[C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)C(C)(C)c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CC(C)(C(=O)O)c1ccc(Cl)c(Cl)c1
Temperature: 50 °C
Reaction time: 72 h

Procedure:
To methyl 2-(3,4-dichlorophenyl)-2-methylpropanoate (22.03 g, 89.1 mmol) was added THF/water (4:1) (178 mL) and lithium hydroxide hydrate (22.4 g, 535 mmol). The reaction was then stirred at 50° C. for 3 days. The reaction mixture was acidified with 3N HCl, diluted with 200 mL of diethyl ether, added to a separatory funnel, partitioned with water, washed 2 times with 100 mL of water, separated, dried over Na2SO4, and concentrated in vacuo to give the title compound which was used without further purification. MS (m/z)=233 (M+H)+.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH:9]=[CH:10][C:11]=2[NH2:12])=[N:4][N:3]=[N:2]1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][C:25]=1[C:33]([F:36])([F:35])[F:34]>C1(C)C=CC=CC=1>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:12][C:11]2[CH:10]=[CH:9][C:8]([C:13]3[CH:14]=[CH:15][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:17][CH:18]=3)=[CH:7][C:6]=2[C:5]2[NH:1][N:2]=[N:3][N:4]=2)=[O:32])=[CH:26][C:25]=1[C:33]([F:34])([F:35])[F:36]
Reactant: Nc1ccc(-c2ccc(C(F)(F)F)cc2)cc1-c1nnn[nH]1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)Nc1ccc(-c2ccc(C(F)(F)F)cc2)cc1-c1nnn[nH]1

Procedure:
3-(1H-Tetrazol-5-yl)-4′-trifluoromethyl-biphenyl-4-ylamine (0.5 g) and 4-choro-3-trifluoromethyl-phenyl isocyanate (0.4 g) in toluene (15 mL) was stirred at room temperature for two days. The reaction mixture was evaporated to an oil, the oil was dissolved in acetone and filtrated through Celite, the filtrate was added water, the product precipitated and was isolated by filtration. Yield 0.6 g Mp. 226-228° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:27])=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][O:6][C:7]1[C:8]([NH:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=S)=[N:9][CH:10]=[CH:11][CH:12]=1.[NH3:28]>>[Cl:1][C:2]1[C:3]([F:27])=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][O:6][C:7]1[C:8]([NH:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[NH:28])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: Fc1c(Cl)cccc1COc1cccnc1NC(=S)Nc1ccc(Cl)cc1
Reactant: N
Product: N=C(Nc1ccc(Cl)cc1)Nc1ncccc1OCc1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of yellow mercuric oxide (1.23 g, 0.0047 mol), N-[3-(3-chloro-2-fluorobenzyloxy)pyrid-2-yl]-N'-4-chlorophenylthiourea (2.0 g, 0.0047 mol) and methanolic ammonia solution (40 ml) was stirred for 2 days at room temperature. The solvent was removed in vacuo and the black residue was boiled with chloroform and filtered hot. Evaporation of the solvent followed by trituration with ether and recrystallisation from acetonitrile gave the desired product. Yield 0.38 g (20%), m.p. 204°-207 ° C.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:18])[C:4]([CH2:11][CH2:12][C:13](OCC)=[O:14])=[C:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([OH:9])[C:5]([CH3:10])=[C:4]([CH2:11][CH2:12][CH2:13][OH:14])[C:3]=1[OH:18]
Reactant: CCOC(=O)CCC1=C(C)C(=O)C(C)=C(C)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: Cc1c(C)c(O)c(CCCO)c(C)c1O

Procedure:
A solution of 2,3,5-trimethyl-6-(2'-ethoxycarbonylethyl)-1,4-benzoquinone (formula I-2 wherein R=H3C, n=1, in the form of ethyl ester) (0.39 part) in diethyl ether (50 volume parts) was treated with lithium aluminum hydride in the same manner as Example 53 to give 2,3,5-trimethyl-6-(3'-hydroxypropyl)-hydroquinone (formula III-2 wherein R=H3C, X=Y=OH, n=1 in the free form). The product was treated with ferric chloride in the same manner as Example 53 and then subjected to column chromatography on silica gel and eluted with chloroform. The procedure provided 2,3,5-trimethyl-6-(3'-hyydroxypropyl)-1,4-benzoquinone (formula IV-2 wherein R=H3C, n=1, in the free form) (0.25 part) as a yellow oil.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:9]=[CH:10][C:11]=2[OH:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:28]([O:30][CH3:31])=[O:29]>ClCCl>[CH:1]1([C:6]2[CH:7]=[C:8]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:9]=[CH:10][C:11]=2[O:12][C:28]([O:30][CH3:31])=[O:29])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)CCc1ccc(O)c(C2CCCC2)c1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCc1ccc(OC(=O)OC)c(C2CCCC2)c1
Reaction time: 1 h
Yield: 87.8 %

Procedure:
To a solution of ethyl 3-(3-cyclopentyl-4-hydroxy-phenyl)propanoate (857 mg, 3.27 mmol) and triethylamine (911 μL, 6.53 mmol) in dichloromethane (5 mL) under a N2 atmosphere at 0° C. was added methyl chloroformate (463 mg, 377 μL, 4.90 mmol) dropwise. After 1 h, the reaction mixture was partitioned between dichloromethane/water, separated and the aqueous layer was extracted once more with dichloromethane. The combined organics were dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (0-30% ethyl acetate/hexanes) provided ethyl 3-(3-cyclopentyl-4-methoxycarbonyloxy-phenyl)propanoate (920 mg, 88% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 7.20 (d, J=1.7 Hz, 1H), 7.09-7.03 (m, 2H), 4.04 (q, J=7.1 Hz, 2H), 3.82 (s, 3H), 3.03-2.96 (m, 1H), 2.83 (t, J=7.6 Hz, 2H), 2.61 (t, J=7.6 Hz, 2H), 1.93-1.86 (m, 2H), 1.77-1.72 (m, 2H), 1.66-1.58 (m, 2H), 1.54-1.47 (m, 2H), 1.15 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]([CH:4]([CH2:15][C:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6])(=O)[CH3:2].C([O-])(=O)C.[NH4+:28]>C(O)(=O)C.O>[CH3:2][C:1]1[NH:28][C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:15][C:4]=1[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6]
Reactant: [NH4+]
Reactant: CC(=O)C(CC(=O)c1ccccc1)C(=O)OCc1ccccc1
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1[nH]c(-c2ccccc2)cc1C(=O)OCc1ccccc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A 6.00 g portion of benzyl 2-acetyl-4-oxo-4-phenylbutanoate was dissolved in a mixture of 54 ml acetic acid and 5.4 ml water, and 14.9 g of ammonium acetate was added, followed by stirring at 100° C. for 1 hour. After evaporation of the solvent under a reduced pressure and subsequent addition of ethyl acetate-water, the ethyl acetate layer was washed with a 1 M sodium hydroxide aqueous solution and saturated brine, followed by drying with anhydrous sodium sulfate. Then, the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:5-1:4) to obtain 3.84 g of benzyl 2-methyl-5-phenyl-1H-pyrrole-3-carboxylate as a light purple solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH2:13][C@H:12]1[C:15](O)=O)=[O:10])[C:2]1[CH:7]=CC=C[CH:3]=1.N1CC[C@H:19]1C(O)=O.C(Cl)[Cl:26]>>[CH2:1]([O:8][C:9]([Cl:26])=[O:10])[CH:2]([CH3:7])[CH3:3].[CH3:19][CH:12]1[CH2:15][CH2:9][NH:11][CH2:14][CH2:13]1
Reactant: ClCCl
Reactant: O=C(O)[C@@H]1CCN1C(=O)OCc1ccccc1
Reactant: O=C(O)[C@@H]1CCN1
Product: CC(C)COC(=O)Cl
Product: CC1CCNCC1

Procedure:
A suspension of 1,200 g (5.10 mmoles) of N-benzyloxycarbonyl-(S)-(-)-2-azetidine-carboxylic acid (abbreviation Z-(S)-AzeOH, prepared from (S)-(-)-2-azetidine-carboxylic acid (Aldrich) according to the method of Wunsch) in 60 ml of dry methylene chloride (CH2Cl2) was brought in an argon atmosphere to a temperature of approximately -20° C. On stabilization of the temperature, the following were added in quick succession: 0.690 ml (5.27 mmoles) of isobutylchloroformate (IBCF) and 0.650 ml (5.34 mmoles) of 4-methylpiperidine (NMP), leaving the system under stirring for approximately 2 minutes. A solution, pre-cooled to approximately -15° C. for 30 minutes, of 1.850 g (5.03 mmoles) of (L)-Leu-(L)-TrpOMe. HCl (Novabiochem) and 0.620 ml (5.10 mmoles) of NMP in 25 ml of anhydrous N,N-dimethylformamide (DMF) was then added, leaving, under stirring and static argon, the temperature free to rise to room temperature. After approximately 3.5 hours of reaction, the white precipitate was filtered away and washed with a little CH2Cl2. The latter was put back into the pale yellow coloured organic solution, which was extracted in succession using 5% NaHCO3 (3×30 ml); saturated aqueous NaCl (2×30 ml); 4% KHSO4 (3×30 ml) and finally saturated aqueous NaCl (3×30 ml), discarding the aqueous phases. The organic phase extracted, of a pale yellow colour, was left in a cold chamber under argon and on anhydrous Na2SO4 for 12 hours. The desiccant was then filtered away and the organic solution, concentrated to a small volume, leaves a dense residual oil which, when taken up with a minimum amount of CH2Cl2, was purified using flash-chromatography in a normal phase (SiO2, eluant CH2Cl2 /n-hexane: 2/1). The chromatographic fractions of interest were concentrated to a small volume and ground with anhydrous ethyl ether. The whitish solid thus obtained was filteres and left for 24 hours under vacuum on P2O5 2.040 g (75.0%) of an analytically pure rubbery white solid were recovered.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH2:41][C:42](=[O:68])/[CH:43]=[CH:44]/[C:45]2[CH:50]=[CH:49][C:48]([O:51][C:52](=[O:67])[C:53]3[CH:58]=[CH:57][C:56]([O:59][CH2:60][CH2:61][CH2:62][C:63]([F:66])([F:65])[F:64])=[CH:55][CH:54]=3)=[CH:47][CH:46]=2)[C:11]([C:14](=[O:40])/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24](=[O:39])[C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][C:35]([F:38])([F:37])[F:36])=[CH:27][CH:26]=3)=[CH:19][CH:18]=2)([OH:13])[OH:12])=[CH:6][CH:5]=1)([O-])=O.CCCCCC.C[N:76](C)C=O>O.[Zn]>[NH2:76][C:8]1[CH:9]=[C:4]([NH2:1])[CH:5]=[CH:6][C:7]=1[CH:10]([CH2:41][C:42](=[O:68])/[CH:43]=[CH:44]/[C:45]1[CH:50]=[CH:49][C:48]([O:51][C:52](=[O:67])[C:53]2[CH:58]=[CH:57][C:56]([O:59][CH2:60][CH2:61][CH2:62][C:63]([F:66])([F:65])[F:64])=[CH:55][CH:54]=2)=[CH:47][CH:46]=1)[C:11]([C:14](=[O:40])/[CH:15]=[CH:16]/[C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24](=[O:39])[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][C:35]([F:38])([F:37])[F:36])=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)([OH:13])[OH:12]
Reactant: CN(C)C=O
Reactant: O=C(/C=C/c1ccc(OC(=O)c2ccc(OCCCC(F)(F)F)cc2)cc1)CC(c1ccc([N+](=O)[O-])cc1)C(O)(O)C(=O)/C=C/c1ccc(OC(=O)c2ccc(OCCCC(F)(F)F)cc2)cc1
Agent: [Zn]
Solvent: O
Solvent: CCCCCC
Product: Nc1ccc(C(CC(=O)/C=C/c2ccc(OC(=O)c3ccc(OCCCC(F)(F)F)cc3)cc2)C(O)(O)C(=O)/C=C/c2ccc(OC(=O)c3ccc(OCCCC(F)(F)F)cc3)cc2)c(N)c1

Procedure:
7.60 g (7.64 mmol) of 2-(4-nitrophenyl)-1,3 di[(2E)-3-{4-[(4-(4,4,4-trifluorobutoxy)benzoyl)oxy]phenyl}prop-2-enoyl]propanediol are dissolved in a mixture of 45 ml of N,N-dimethylformamide and 5 ml water. 12.39 g (45.84 mmol) ferric chloride hexahydrate are added. 4.99 g (76.4 mmol) Zinc powder are added portionwise within 40 min. The mixture is allowed to react for 2 hours. The reaction mixture is then partitioned between ethyl acetate and water and filtered. The organic phase is washed repeatedly with water, dried over sodium sulfate, filtered and concentrated by rotary evaporation. Chromatography of the residue on 1000 g silica gel using toluene:ethyl acetate 1:1 as eluant and crystallization form ethylacetate:hexane mixture to yield 4.30 g of 2-(2,4-Diaminophenyl)-1,3 di[(2E)-3-{4-[(4-(4,4,4-trifluorobutoxy)benzoyl)oxy]phenyl}prop-2-enoyl]propanediol.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16](OC)=[O:17])[CH:15]=[C:10]3[CH:9]=[N:8]2)=[CH:4][CH:3]=1.[NH2:22][OH:23].[OH-].[Na+].Cl>CO.O>[F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16]([NH:22][OH:23])=[O:17])[CH:15]=[C:10]3[CH:9]=[N:8]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc2cnn(Cc3ccc(F)cc3)c2cn1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(NO)c1cc2cnn(Cc3ccc(F)cc3)c2cn1
Reaction time: 2 h
Yield: 52 %

Procedure:
To a stirring solution of methyl 1-(4-fluorobenzyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylate (96 mg, 0.33 mmol) in methanol (4 mL) was added a 50% v/v solution of hydroxylamine in water (2 mL) followed by 10% sodium hydroxide solution in water (1 mL). The mixture was stirred for 2 hours, then 10% hydrochloric acid solution in water (1 mL) was added until a neutral pH was obtained, and the mixture was concentrated under reduced pressure. Methanol was added and the mixture was purified by reverse phase preparative HPLC (Dionex, 0-40% acetonitrile:water v/v, 40 minutes) to provide a white solid (50 mg, 52% yield). 1H NMR (DMSO-d6): δ ppm 9.22 (s, 1H), 8.39 (s, 1H), 8.37 (s, 1H), 7.37 (m, 2H), 7.15 (m, 2H), 5.83 (s, 2H). Anal. HPLC: >95% (@ 254, 222 nM). HRMS calcd for C14H11FN4O2 (M+H) 287.0939, found 287.0936.
Reaction SMILES: C([O:3][C:4](=[O:18])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[C:14](=O)[CH2:15]Br)C.[CH3:19][O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[O:26])=[CH:23][CH:22]=1>>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:3])=[O:18])=[C:8]([C:14]2[N:27]=[C:25]([C:24]3[CH:28]=[CH:29][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)[O:26][CH:15]=2)[CH:9]=1
Reactant: COc1ccc(C(N)=O)cc1
Reactant: CCOC(=O)COc1ccc(Br)cc1C(=O)CBr
Product: COc1ccc(-c2nc(-c3cc(Br)ccc3OCC(=O)O)co2)cc1

Procedure:
Title compound was prepared from [4-bromo-2-(2-bromoacetyl)phenoxy]acetic acid ethyl ester and 4-methoxybenzamide according to GP5 and GP3: LC/MS (an10p8) Rt 2.61 min, m/z 404 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH:11]([F:13])[F:12])=[CH:9][C:5]([C:6](N)=[O:7])=[C:4]([OH:14])[N:3]=1.S(=O)(=O)(O)[OH:16]>>[Cl:1][C:2]1[C:10]([CH:11]([F:13])[F:12])=[CH:9][C:5]([C:6]([OH:16])=[O:7])=[C:4]([OH:14])[N:3]=1
Reactant: NC(=O)c1cc(C(F)F)c(Cl)nc1O
Reactant: O=S(=O)(O)O
Product: O=C(O)c1cc(C(F)F)c(Cl)nc1O
Yield: 98 %

Procedure:
6-Chlorodifluoromethyl-2-hydroxynicotinamide (48.5 g) was heated in dilute sulphuric acid (36 ml in 250 ml water) for 12 hours. The reaction was concentrated to about half the volume and cooled in ice. The precipitate was filtered, washed with water and air dried to give 6-chlorodifluoromethyl-2-hydroxynicotinic acid (48.1 g, 98% yield) as a pale brown solid mp.131-3° C.; 1H NMR (270 MHz): δ 7.36(1H,d), 8.33(1H,d) ppm.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[S:13][CH:14]=[C:15]([C:17](=[C:21](Cl)[CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[C:18]([OH:20])=[O:19])[N:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(S)C=CC=CC=1.C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][C:12]1[S:13][CH:14]=[C:15]([C:17](=[CH:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[O:26])[C:18]([OH:20])=[O:19])[N:16]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCCC(Cl)=C(C(=O)O)c1csc(NC(=O)OCc2ccccc2)n1)OCc1ccccc1
Agent: Sc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CCCC=C(C(=O)O)c1csc(NC(=O)OCc2ccccc2)n1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 118.8 %

Procedure:
To a solution of diester (4) (3.03 g) in tetrahydrofuran (30 ml) are added benzenethiol (0.70 ml) and triethylamine (0.79 ml). The mixture is stirred at room temperature for 3.5 hours, concentrated, and purified by silica gel chromatography (eluting with benzene-ethyl acetate (9:1 to 8:2) mixture) to give phenylthiopropionate (5) (3.36 g). Yield: 92%.
Reaction SMILES: Cl.[OH:2][CH2:3][C:4]1[N:5]=[CH:6][NH:7][CH:8]=1.C(N(CC)CC)C.[C:16]([Si:20]([CH3:23])([CH3:22])Cl)([CH3:19])([CH3:18])[CH3:17]>ClCCl.CN(C=O)C>[Si:20]([O:2][CH2:3][C:4]1[N:5]=[CH:6][NH:7][CH:8]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:23])[CH3:22]
Reactant: OCc1c[nH]cn1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCc1c[nH]cn1

Procedure:
4-Hydroxymethylimidazole hydrochloride (5.03 g) was dissolved in a mixed solvent of dichloromethane (90 mL) and DMF (20 mL), and to the solution triethylamine (8.25 g) was added at 0° C. tert-Butyldimethylchlorosilane (6.14 g) was then added to the mixture, and the resultant mixture was stirred at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was then purified by column chromatography on silica gel (chloroform:methanol=20:1) to obtain the title compound.
Reaction SMILES: [I:1][C:2]1[C:3](=[O:10])[N:4]=[C:5]([O:8][CH3:9])[NH:6][CH:7]=1.N12CCCN=C1CCCCC2.[CH3:22][C:23]1[CH:24]=[CH:25][C:26]([NH:29][C:30]2[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=2)=[N:27][CH:28]=1>C(#N)C.CCOC(C)=O>[I:1][C:2]1[C:3]([O:10][C:33]2[CH:32]=[CH:31][C:30]([NH:29][C:26]3[CH:25]=[CH:24][C:23]([CH3:22])=[CH:28][N:27]=3)=[CH:35][CH:34]=2)=[N:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1nc(=O)c(I)c[nH]1
Reactant: Cc1ccc(Nc2ccc(O)cc2)nc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1ncc(I)c(Oc2ccc(Nc3ccc(C)cn3)cc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 5-iodo-2-methoxypyrimidin-4(1H)-one (0.12 g, 0.46 mmol) and (1H-benzo[d][1,2,3]triazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate(V) (0.24 g, 0.55 mmol) in acetonitrile (4 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.14 mL, 0.91 mmol). The reaction mixture was stirred at room temperature for 30 min before 4-(5-methylpyridin-2-ylamino)phenol (0.27 g, 1.37 mmol) was added. The reaction mixture was stirred at room temperature for an additional 1 h. The reaction mixture was diluted with EtOAc and washed with water. The organic layer was separated, washed with sat. sodium chloride, dried over magnesium sulfate, filtered, and concentrated. The resulting crude product was purified by silica gel chromatography to give N-(4-(5-iodo-2-methoxypyrimidin-4-yloxy)phenyl)-5-methylpyridin-2-amine. MS (ESI, pos. ion) m/z: 435.1 (M+1).