Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.FC(F)(F)C(O)=O.[NH2:53][C@H:54]([C:59]([O:61][CH2:62][CH2:63][O:64][C:65]1[CH:70]=[CH:69][C:68]([C:71]2[C:76]([C:77]#[N:78])=[C:75]([N:79]3[CH2:83][CH2:82][CH2:81][CH2:80]3)[N:74]=[C:73]([S:84][CH2:85][C:86]3[N:87]=[C:88]([C:91]4[CH:96]=[CH:95][C:94]([Cl:97])=[CH:93][CH:92]=4)[S:89][CH:90]=3)[C:72]=2[C:98]#[N:99])=[CH:67][CH:66]=1)=[O:60])[CH2:55][CH:56]([CH3:58])[CH3:57]>CN(C=O)C.O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([NH:53][C@H:54]([C:59]([O:61][CH2:62][CH2:63][O:64][C:65]1[CH:66]=[CH:67][C:68]([C:71]2[C:76]([C:77]#[N:78])=[C:75]([N:79]3[CH2:83][CH2:82][CH2:81][CH2:80]3)[N:74]=[C:73]([S:84][CH2:85][C:86]3[N:87]=[C:88]([C:91]4[CH:96]=[CH:95][C:94]([Cl:97])=[CH:93][CH:92]=4)[S:89][CH:90]=3)[C:72]=2[C:98]#[N:99])=[CH:69][CH:70]=1)=[O:60])[CH2:55][CH:56]([CH3:57])[CH3:58])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: CC(C)C[C@H](N)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCCC3)c2C#N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@H](NC(=O)CCNC(=O)OC(C)(C)C)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCCC3)c2C#N)cc1

Procedure:
86 mg (0.45 mmol) of N-(tert-butoxycarbonyl)-beta-alanine were initially charged in 5.0 ml of DMF, and 95 mg (0.49 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 95 mg (0.62 mmol) of 1-hydroxy-1H-benzotriazole hydrate and 266.13 g (2.06 mmol) of N,N-diisopropylethylamine were added. The mixture was stirred until a clear solution had been obtained. 330 mg (0.41 mmol) of 2-{4-(2-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-3,5-dicyano-6-(pyrrolidin-1-yl)pyridin-4-yl)phenoxy}ethyl L-leucinate trifluoroacetate were then added, and the mixture was stirred at room temperature for 18 h. The reaction mixture was added to 300 ml of water. The residue formed was filtered off with suction and washed with 20 ml of water. The crude product was suspended in 15 ml of methanol and sonicated in an ultrasonic bath for 5 min. The residue was filtered off with suction and washed with 10 ml of diethyl ether. This gave 0.13 g (37% of theory) of the desired target compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].Cl[CH2:17][C:18]1[C:19]([CH:34]2[CH2:36][CH2:35]2)=[N:20][C:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)=[N:22][CH:23]=1>>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:17][C:18]2[C:19]([CH:34]3[CH2:36][CH2:35]3)=[N:20][C:21]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:28][CH:29]=3)=[N:22][CH:23]=2)=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: FC(F)(F)c1ccc(-c2ncc(CCl)c(C3CC3)n2)cc1
Reactant: CCOC(=O)CCc1ccc(O)cc1C
Product: CCOC(=O)CCc1ccc(OCc2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)cc1C

Procedure:
In analogy to the procedures described in examples 8A] and 31B], 3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester was reacted with 5-chloromethyl-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 27F]) to give 3-{4-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-2-methyl-phenyl}-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
Reaction SMILES: [C:1]1([CH:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:8]([O:10][CH2:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH2:41]=[O:42]>C1COCC1>[OH:42][CH2:41][C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:8]([O:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)=[O:9]
Reactant: CC(C)(C)OC(=O)N1CCC(COC(=O)C(c2ccccc2)c2ccccc2)CC1
Reactant: C=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COC(=O)C(CO)(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 23.2 %

Procedure:
tert-Butyl 4-((2,2-diphenylacetyloxy)methyl)piperidine-1-carboxylate (prepared as in Preparation intermediate 12 with 2,2-diphenylacetic acid replacing cyclohexylmandelic acid) (0.40 g, 0.98 mmol) in THF (5 mL) was treated with lithium hexamethyldisilazide (1.17 mL, 1.17 mmol, 1.0 M solution in THF) followed by formaldehyde (0.20 g, 50% w/w). The reaction mixture was stirred at RT for 16 hours then quenched with saturated aqueous ammonium chloride solution. The aqueous layer was extracted with dichloromethane. The combined organic extracts were dried (magnesium sulfate), filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 30-60% ethyl acetate in petroleum ether (40:60) to afford the title compound (0.10 g, 23%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([NH:13][C:14](=[O:17])[CH2:15]Cl)([CH2:11][OH:12])[CH2:9][OH:10])[CH:5]=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].[I-].[Na+].O>CC(O)(C)C.C(OCC)C.CCCCC>[Br:1][C:2]1[N:7]=[C:6]([C:8]2([CH2:11][OH:12])[NH:13][C:14](=[O:17])[CH2:15][O:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCl)NC(CO)(CO)c1cccc(Br)n1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CCCCC
Solvent: CCOCC
Product: O=C1COCC(CO)(c2cccc(Br)n2)N1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To the solution of N-[1-(6-bromo-pyridin-2-yl)-2-hydroxy-1-hydroxymethyl-ethyl]-2-chloro-acetamide (5.4 g, 16.69 mmol) in t-BuOH (80 ml) was added t-BuOK (2.06 g, 18.38 mmol) at rt followed by sodium iodide (0.25 g, 1.669 mmol) and allowed the reaction mixture to stir at 90° C. for 1 h. The reaction mixture was concentrated under reduced pressure and the residue obtained was treated with water. Compound present in the residue was extracted with ethyl acetate (2×100 ml). Organic portion was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to obtain gummy compound. Further trituration of the formed product with n-pentane (5.0 ml) and diethyl ether (5.0 ml) furnished title compound as a pale yellow gummy compound. Yield=3.3 g (68.8%). TLC (50% ethyl acetate in hexane) Rf=0.21; LCMS: RtH8=0.155, [M+1]=286.9 and 288.8; HPLC RtH9=3.03 min (69.8%); 1H NMR (400 MHz, CDCl3): δ 8.40 (s, 1H), 7.79 (t, 1H), 7.57 (d, 2H), 5.11 (s, 1H), 4.15 (d, 1H), 3.99 (d, 2H), 3.88 (d, 1H), 3.71-3.60 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][CH2:19][CH3:20])=[O:17])=[C:11]([Cl:21])[CH:10]=2)[C:3]=1[CH:22]=O.Cl.[OH:25][NH2:26]>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][CH2:19][CH3:20])=[O:17])=[C:11]([Cl:21])[CH:10]=2)[C:3]=1[CH:22]=[N:26][OH:25]
Reactant: NO
Reactant: CCNC(=O)Nc1ccc(Oc2ncnc(N)c2C=O)cc1Cl
Agent: Cl
Product: CCNC(=O)Nc1ccc(Oc2ncnc(N)c2C=NO)cc1Cl

Procedure:
Using the procedure for Example 1, 1-[4-(6-amino-5-formyl-pyrimidin-4-yloxy)-2-chloro-phenyl]-3-ethyl-urea Compound 26b was reacted with hydroxy-amine hydrochloride to provide 1-{4-[6-amino-5-(hydroxyimino-methyl)-pyrimidin-4-yloxy]-2-chloro-phenyl}-3-ethyl-urea Compound 27a.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5](Cl)=O.[NH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:16][CH:15]=[CH:14][CH:13]=2.C(N(CC)CC)C.C(O)C>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:8]=1
Reactant: COCCC(=O)Cl
Reactant: CCOC(=O)CCCCCNc1c(N)cnc2ccccc12
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CCCCCn1c(CCOC)nc2cnc3ccccc3c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methoxypropionyl chloride (4.85 g, 39.8 mmol) was added dropwise over a period of ten minutes to a solution of ethyl 6-(3-aminoquinolin-4-ylamino)hexanoate (10.0 g, 33.2 mmol, prepared as described in Part A of Example 8) in dichloromethane (200 mL). The reaction was stirred for one hour at ambient temperature and then concentrated under reduced pressure. Triethylamine (18.49 g, 132.7 mmol) and ethanol (200 mL) were added, and the resulting solution was heated at reflux for three hours. The solvent was removed under reduced pressure. Dichloromethane (75 mL) was added, and the resulting solution was washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 12.05 g of ethyl 6-[2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]hexanoate as a dark oil.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH3:5].C(=O)([O-])[O-].[K+].[K+].[OH:13][C:14]1[CH:15]=[C:16]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH:17]=[CH:18][C:19]1[S:20][C:21]2[NH:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]=2[N:28]=1>CN(C)C=O>[CH3:33][O:32][C:31]1[CH:30]=[CH:29][C:16]([CH:17]=[CH:18][C:19]2[S:20][C:21]3[NH:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]=3[N:28]=2)=[CH:15][C:14]=1[O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: COc1ccc(C=Cc2nc3c(s2)NCCCC3)cc1O
Reactant: CCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCOc1cc(C=Cc2nc3c(s2)NCCCC3)ccc1OC
Reaction time: 1 h
Yield: 15.4 %

Procedure:
Amyl bromide (0.49 ml) and potassium carbonate (0.46 g) were added to a solution (20 ml) of 2-(3-hydroxy-4-methoxy-styryl)-5,6,7,8-tetrahydro-4H-thiazolo[5,4-b]azepine (1.00 g) in dimethylformamide, and the whole was stirred for 1 hr. at 100°. After cooling, the reaction mixture was washed with water, dried and concentrated under reduced pressure. The residue was purified by a column chromatography on silica gel, and recrystallized from isopropyl ether to give the title compound (0.19 g, 15.4%). m.p. 124-125°.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[C:2]=[O:3].[CH3:17][CH:18]([CH3:41])[CH:19]([NH:24][C:25]([C:27]1[S:28][C:29]([C:32]2[CH:37]=[CH:36][C:35]([N+:38]([O-])=O)=[CH:34][CH:33]=2)=[CH:30][N:31]=1)=[O:26])[C:20]([O:22][CH3:23])=[O:21]>>[CH3:17][CH:18]([CH3:41])[CH:19]([NH:24][C:25]([C:27]1[S:28][C:29]([C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:2]([NH:1][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:3])=[CH:34][CH:33]=2)=[CH:30][N:31]=1)=[O:26])[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)C(NC(=O)c1ncc(-c2ccc([N+](=O)[O-])cc2)s1)C(C)C
Reactant: O=C=Nc1ccccc1Oc1ccccc1
Product: COC(=O)C(NC(=O)c1ncc(-c2ccc(NC(=O)Nc3ccccc3Oc3ccccc3)cc2)s1)C(C)C
Yield: 84 %

Procedure:
The title compound was synthesized analogous to Example 9, using 1-isocyanato-2-phenoxybenzene and intermediate 2. Yield: 84%; 1H NMR (DMSO-d6, 300 MHz): δ 9.53 (s, 1H), 8.73 (d, 1H), 8.54 (s, 1H), 8.35 (s, 1H), 8.27 (dd, 1H), 7.73 (d, 2H), 7.57 (d, 2H), 7.43 (dd, 2H), 7.17 (m, 1H), 7.1 (d, 1H), 7.07 (dd, 2H), 6.98 (d, 1H), 6.86 (d, 1H), 4.32 (m, 1H), 3.68 (s, 3H), 2.28 (m, 1H), 0.94 (d, 6H); MS (ES+) m/z 545 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([CH3:12])=[N:5][C:6]([NH2:11])=[N:7][C:8]=1[S:9][CH3:10])[CH3:2].Br[CH2:14][C:15](=O)[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17]>CCOCC>[CH2:1]([C:3]1[C:8]([S:9][CH3:10])=[N:7][C:6]2[N:5]([CH:14]=[C:15]([C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:17])[N:11]=2)[C:4]=1[CH3:12])[CH3:2]
Reactant: O=C(CBr)C(=O)c1ccccc1
Reactant: CCc1c(C)nc(N)nc1SC
Solvent: CCOCC
Product: CCc1c(SC)nc2nc(C(=O)c3ccccc3)cn2c1C
Reaction time: 48 h
Yield: 54.4 %

Procedure:
A stirred suspension of 4.5 g of 5-ethyl-4-methyl-6-methylthio-2-pyrimidinamine in 28 ml of ether was treated with 5.5 g of 3-bromo-1-phenylpropane-1,2-dione to obtain a yellow solution. After standing two days at room temperature, the crystallized pyrimidinium salt was filtered off, washed with ether and heated for one hour in refluxing ethanol. The solution was evaporated to dryness under reduced pressure and the residue was shaken with a mixture of chloroform and aqueous potassium carbonate. The organic layer was washed, dried over MgSO4 and evaporated to dryness under reduced pressure. Trituration of the residue with ethanol and filtration yielded 4.1 g (53% yield) of [6-ethyl-5-methyl-7-(methylthio)imidazo[1,2-a]pyrimidin-2-yl]phenylmethanone after recrystallization from methanol in the form of a buff solid.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:18])[N:9]2[CH2:12][CH:13]2[O:17][CH2:16][CH2:15][O:14]2)=[CH:4][CH:3]=1.[CH3:19][O-:20].[Na+].CO.O>CO>[O:14]1[CH2:15][CH2:16][O:17][CH:13]1[CH2:12][N:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([O:20][CH3:19])[N:11]=2)[CH:6]=[CH:7][C:8]1=[O:18]
Reactant: O=c1ccc2ccc(Cl)nc2n1CC1OCCO1
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc2ccc(=O)n(CC3OCCO3)c2n1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 2.5 g of 7-chloro-1-(1,3-dioxolan-2-ylmethyl)-1,8-naphthyridin-2(1H)-one in 30 mL of methanol, 5.4 g of a 28% sodium methoxide/methanol solution was added, and the mixture was heated under reflux while stirring for 3 hours 40 minutes. The reaction mixture was cooled to room temperature, then water was added thereto, and the solvent was then distilled off under reduced pressure. To the resultant residue, water, a saturated aqueous ammonium chloride solution and chloroform were added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, and the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 2.9 g of 1-(1,3-dioxolan-2-ylmethyl)-7-methoxy-1,8-naphthyridin-2(1H)-one as a yellow oily substance.
Reaction SMILES: [C:1]1([C:16]2[NH:15][C:14]3[C:7](=[CH:8][CH:9]=[C:10]([CH:13]=3)[O:11][CH3:12])[C:6]=2[CH:5]=[CH:4][N:3]=1)[CH3:2].CN(C=O)C.[H-].[Na+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[CH2:24]([N:15]1[C:16]2[C:1]([CH3:2])=[N:3][CH:4]=[CH:5][C:6]=2[C:7]2[C:14]1=[CH:13][C:10]([O:11][CH3:12])=[CH:9][CH:8]=2)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COc1ccc2c(c1)[nH]c1c(C)nccc12
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc2c3ccnc(C)c3n(Cc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 67 %

Procedure:
Harmine 1 (2.1 g, 10 mmol), DMF (50 ml) and THF (50 ml) were respectively added in a 250 ml round-bottom flask, and were stirred at room temperature for 10 minutes followed by the addition of 60% NaH (1.2 g, 30 mmol). The mixture was stirred until there were no bubbles formed. Benzyl bromide (3 ml) was added dropwise. The mixture was then refluxed by heating for 8 h. THF was evaporated in reduced pressure, and the residues were poured into cold water. The mixture was adjusted to pH 3.0 with concentrated HCl, and extracted with ethyl ether. The aqueous phase was neutralized (pH8) with saturated NaHCO3 solution and extracted with ethyl acetate. The organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, filtered, evaporated in reduced pressure and then recrystallized with ethyl acetate to afford gray crystals (2.2 g, 67%). mp 131-133° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([O-:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].[Na+].[OH-].[Na+]>C1(C)C(C)=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([OH:10])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C(=O)[O-])cc(C(C)(C)C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O

Procedure:
In a 200 ml four-necked flask were placed 49.53 g (0.240 mol) of 2,6-di-tert-butylphenol (hereinafter abbreviated to “2,6-DBP”), 2.05 g (0.018 mol) of DMi and 40 g of xylene, and the solution was heated until reflux begun. Afterward, azeotropic dehydration was carried out, while 4.41 g (0.054 mol) of a 49 wt % aqueous NaOH solution was added dropwise over 5 hours. Next, 20 g of xylene was added dropwise, and the solution was allowed to mature under the reflux for 2 hours. It was confirmed that a stoichiometric amount of water was distilled. The reaction solution was put in a 300 ml autoclave, heated up to 160° C., and then allowed to absorb a carbon dioxide gas at 6 kg/cm2G, followed by maturation at the same temperature for 5 hours. In this case, a conversion was 90.0%/NaOH. The reaction solution was slowly cooled to 70° C., and then crystallized at 70° C. for 2 hours. The reaction solution was filtered at the same temperature, and then washed three times with 20 g of xylene to obtain wet sodium 3,5-ditert-butyl-4-hydroxybenzoate. According to analysis, the recovery yield of sodium 3,5-di-tert-butyl-4-hydroxybenzoate was 88.4%/NaOH, and any DMi was not detected. It was confirmed that DMi was completely recovered in a filtrate and a wash liquid in the steps of the heating, the filtration and the washing. The wet product was dissolved in 54 g of water at 60° C., and an extraction operation was carried out twice with 18 g of xylene to obtain an aqueous layer. Xylene dissolved in this aqueous layer was distilled off under reduced pressure, and the aqueous layer was added dropwise to 49 g of a 6% sulfuric acid solution over 2 hours to crystallize. The resulting precipitate was filtered, and then washed three times with 12 g of water. Next, wet 3,5-di-tert-butyl-4-hydroxybenzoic acid was taken out, and then dried to obtain 12.0 g of 3,5-di-tert-butyl-4-hydroxybenzoic acid, and a purity was 99.9% or more and a total recovery yield in terms of pure product from the raw material was 88.0%/NaOH.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]#[N:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:19][C:20]1[N:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)[O:22][N:21]=1>CN(C=O)C>[F:33][C:31]([F:32])([F:34])[C:27]1[CH:26]=[C:25]([C:23]2[O:22][N:21]=[C:20]([CH2:19][N:1]3[C:9]4[C:4](=[CH:5][C:6]([C:10]#[N:11])=[CH:7][CH:8]=4)[CH:3]=[CH:2]3)[N:24]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: N#Cc1ccc2[nH]ccc2c1
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)no2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3cccc(C(F)(F)F)c3)n2)c1
Temperature: 90 °C
Yield: 77.6 %

Procedure:
To a solution of 1H-indole-5-carbonitrile (0.05 g, 0.35 mmol) in anhydrous DMF (2 mL) was added Cs2CO3 (0.18 g, 0.55 mmol) and 3-(chloromethyl)-5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole (0.14 g, 0.55 mmol). The mixture was heated at 90° C., under N2, for 30 min. Upon cooling, the mixture was partitioned between Et2O and H2O. The aqueous phase was extracted with Et2O (×2). The combined organic phases were washed with sat'd brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (2-20% EtOAc-hexanes gradient) and the product crystallized from CH2Cl2-hexanes to afford the title compound as a white solid (0.1 g, 78% yield): MS (ES) m/z 369 (M+1).
Reaction SMILES: [C:1]([O:14][C@H:15]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:16][C:17]([OH:19])=O)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CN1CCOCC1.ClC(OCC(C)C)=O.[C:46]1([O:52][P:53]([O:62][CH2:63][CH2:64][CH:65]([C:67]([O:69][CH2:70][C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)=[O:68])[NH2:66])([O:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[O:54])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>O1CCCC1.C1COCC1.O.C1COCC1.CCN(CC)CC>[C:1]([O:14][C@H:15]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:16][C:17]([NH:66][CH:65]([CH2:64][CH2:63][O:62][P:53]([O:55][C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1)([O:52][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)=[O:54])[C:67]([O:69][CH2:70][C:71]1[CH:72]=[CH:73][CH:74]=[CH:75][CH:76]=1)=[O:68])=[O:19])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: NC(CCOP(=O)(Oc1ccccc1)Oc1ccccc1)C(=O)OCc1ccccc1
Reactant: CCCCCCCCCCCC(=O)O[C@H](CCCCCCCCCCC)CC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CN1CCOCC1
Product: CCCCCCCCCCCC(=O)O[C@H](CCCCCCCCCCC)CC(=O)NC(CCOP(=O)(Oc1ccccc1)Oc1ccccc1)C(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
(R)-3-dodecanoyloxytetradecanoic acid (4.284 g; 10.07 mmol, 1 eq.) prepared according to the method disclosed in [Bull. Chem. Soc. Jpn., 60 (1987), 2205-2214], was dissolved in tetrahydrofurane THF (30 ml) and the solution was cooled down to −15° C. N-methylmorpholin (1.108 ml; 10.07 mmol, 1 eq.) and isobutyl chloroformate (1.31 ml; 10.07 mmol; 1 eq.) were then added. The reaction mixture was kept under stirring for 30 minutes at 15° C. To the reaction mixture, there was next added benzyl O-(diphenyloxyphosphoryl)-DL-homoserinate (5.724 g; 10.07 mmol 1 eq.) in a THF/Et3N mixture (30 ml/5 ml). After stirring for 18 hours at room temperature, the solvent was driven away under vacuum. The residue was diluted with H2O (20 ml) and then extracted with ethyl acetate (2×30 ml). The organic layers were pooled, washed in succession with water (20 ml) and brine (20 ml) and dried over MgSO4 before evaporating the solvent. By running flash chromatography purification on a silica gel (2/1 hexane/ethyl acetate eluent), the required benzyl ester was recovered (7.455 g 87%) as a crystalline solid. m.p.=31.0°-32.1° C., 1H-NMR (CDCl3, 250 MHz), δ in ppm: 7.4-7.1 (m, 15H), 6.90 (2d, 1H, 3J=7.6 Hz, NH), 5.3-5.1 (m, 3H), 4.7 (m, 1H), 4.35 (m, 2H), 2.45 (m, 2H), 2.4-2.1 (m, 4H), 1.6 (m, 4H), 1.4-1.1 (m, 34H), 0.9 (t, 6H). 13C-NMR (CDCl3, 63 MHz), δ in ppm: 173.01, 171.08, 169.66, 150.18, (d, 2JP,C=7.1 Hz), 135.01, 129.60, 128.33, 128.14, 127.96, 125.21, 119.80 (d, 3JP,C=5.0 Hz), 70.69, 67.05, 65.19 (d, 2JP,C=5.6 Hz), 49.13, 40.97, 40.77 (2 diast.), 34.20, 33.98, 33.82, 31.70, 29.42, 29.34, 29.14, 28.94, 25.01, 24.77, 22.47, 13.91.
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].[OH:15][NH3+:16]>N1C=CC=CC=1>[C:1]1([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:16][OH:15])[CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: O=C(c1ccccc1)C1CCCC1
Reactant: [NH3+]O
Agent: [Cl-]
Solvent: c1ccncc1
Product: ON=C(C1=CCCC1)c1ccccc1
Temperature: 25 °C
Yield: 36 %

Procedure:
A mixture of cyclopentylphenylmethanone (15.0 g, 86 mmol), hydroxyl ammonium chloride (12.0 g, 172 mmol) and anhydrous pyridine (90 ml) was heated at reflux for 16 h. The reaction mixture was allowed to cool to room temperature and the solvent evaporated in vacuo. To the residue was added 10% aqueous citric acid (100 ml) and the mixture was extracted with ethyl acetate (100 ml). The organic phase was washed with 10 % aqueous citric acid (50 ml), brine (25 ml) and dried (Na2SO4). The solvent was evaporated in vacuo. The residue was dissolved in cyclohexane (100 ml) and left for crystallisation. The precipitate was collected and washed with cyclohexane to give 5.8 g of the crude cyclopenten-1-ylphenylmethanone oxime as an amorphous solid.