Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([CH3:18])[C:14](=[O:17])[CH:15]=[CH2:16].P(Br)(Br)[Br:20]>C(OCC)C>[Br:20][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([CH3:18])[C:14](=[O:17])[CH:15]=[CH2:16]
Reactant: C=CC(=O)N(C)CCCCCCCCCCCO
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: C=CC(=O)N(C)CCCCCCCCCCCBr
Temperature: 25 °C
Yield: 53 %

Procedure:
Diethylether (250 ml) was added to N-(11-hydroxy-undecyl)-N-methyl acrylamide (38.31 g, 0.150 mol) and BHT (10 mg). Phosphorus tribromide (13.53 g, 50.0 mmol) was added dropwise. The initially undissolved solid dissolved completely and a yellowish oil precipitated. The reaction mixture was stirred at ambient temperature. After 24 h water (100 ml) and dichloromethane (200 ml) were added and the phases were separated. The aqueous phase was extracted with dichloromethane (2×100 ml). The combined organic phases were dried over Na2SO4, filtered, concentrated on the rotary evaporator and dried on the fine vacuum. The yellowish oil was dissolved in dichloromethane (100 ml) and filtered via a fritted-glass filter filled with diatomaceous earth (n-hexane/ethyl acetate 1:1). The eluent was concentrated on the rotary evaporator and dried under a fine vacuum. 25.25 g (79.3 mmol; 53% yield) of a yellowish oil was obtained.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].[C:9]([O-:12])(=[O:11])[CH3:10].[K+]>C(O)(=O)C>[CH2:6]([CH:7]1[O:12][C:9](=[O:11])[CH2:10][CH2:8]1)[CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: C=CCCCCCC
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: CCCCCCC1CCC(=O)O1
Yield: 48 %

Procedure:
Octene-1 in an amount of 2.2 g. and 23.6 g. of ceric ammonium nitrate, Ce(NH4)2 (NO3)6, were refluxed under nitrogen in 200 ml. glacial acetic acid containing 60 g. potassium acetate for less than 0.5 hour, there being obtained a 48% yield of gamma-n-hexyl-butyrolactone.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH:8]=1)[OH:7].[C:10](=O)(OC)OC>>[CH3:10][O:7][C:6]1[CH:8]=[C:2]([CH3:1])[CH:3]=[C:4]([OH:9])[CH:5]=1
Reactant: Cc1cc(O)cc(O)c1
Reactant: COC(=O)OC
Product: COc1cc(C)cc(O)c1
Yield: 98 %

Procedure:
The reaction is carried out as described in Example 1, with 22.8 parts of 5-methylresorcinol and 9 parts of dimethyl carbonate. 9 parts (98% of theory) of 5-methylresorcinol monomethyl ether of boiling point 63°-65° C./0.4 mbar are obtained. The conversion is 36 percent.
Reaction SMILES: [C:1]([CH:3]=[C:4]([CH:6]1[CH:11]([CH:12]=[C:13]([CH3:15])[CH3:14])[CH:10]2[CH2:16][CH:7]1[CH2:8][CH2:9]2)[CH3:5])#[N:2].[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([CH2:3][CH:4]([CH:6]1[CH:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[CH:10]2[CH2:16][CH:7]1[CH2:8][CH2:9]2)[CH3:5])#[N:2]
Reactant: CC(C)=CC1C2CCC(C2)C1C(C)=CC#N
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)CC1C2CCC(C2)C1C(C)CC#N
Reaction time: 5 h

Procedure:
A solution of 30.6 g (0.14 mole) of 2-(1-cyanoprop-1-en-2-yl)-3-(2-methylprop-1-en-1-yl)-bicyclo[2.2.1]heptane in 100 ml of ethyl acetate was stirred together with 800 mg of 10% palladium on carbon at 90° C. in a hydrogen atmosphere under 90 bar, until the pressure remained constant for 5 hours.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[CH2:11]([O:13][C:14](=[O:24])[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=1)[CH3:12]>>[CH2:11]([O:13][C:14](=[O:24])[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=2)=[O:10])[CH:18]=1)[CH3:12]
Reactant: CCOC(=O)C=Cc1cccc(N)c1
Reactant: O=C(O)c1cccc(Br)n1
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2cccc(Br)n2)c1

Procedure:
6-Bromo-pyridine-2-carboxylic acid (127 mg, 0.63 mmol) was coupled to aniline (60) (120 mg, 0.63 mmol) using Method C to give the title compound.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][C@@H:9]1[CH2:21][CH2:22][CH:23]=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)C1C=CC=CC=1.C(O)=O.N>CCO.[Pd]>[C:25]1([CH2:24][CH2:23][CH2:22][CH2:21][C@H:9]2[CH2:10][NH:11][CH2:12][CH2:13][NH:8]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C(=Cc1ccccc1)CC[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: [Pd]
Agent: N
Solvent: O=CO
Solvent: CCO
Product: c1ccc(CCCC[C@H]2CNCCN2)cc1
Temperature: 25 °C
Yield: 67.4 %

Procedure:
Combine (S)-1,4-dibenzyl-2-(4-phenyl-but-3-enyl)-piperazine (2.12 g, 5.3 mmol), 10% Pd/C (300 mg, 0.027 mmol) and ammonia formate (1.67 g, 26.5 mmol) in EtOH (50 mL), heat to reflux for 3 hours 30 minutes, and cool to room temperature. Remove the catalyst via filtration, and concentrate the filtrate to a residue. Purification by flash chromatography on silica gel using 2N NH3 in MeOH and dichloromethane (5%–15%) to give the title compound (780 mg, yield 67%): mass spectrum (Electrospray): m/z=219.2 (M+1); 1H NMR (CDCl3): δ7.30–7.15 (m, 5H), 2.96–2.55 (m, 8H), 2.37–2.30 (m, 1H), 1.64–1.60 (m, 2H), 1.39–1.29 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[CH:9]=2)[C:4]=1/[CH:21]=[CH:22]/[C:23](O)=[O:24].[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CCOCC>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[CH:9]=2)[C:4]=1/[CH:21]=[CH:22]/[C:23]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]
Reactant: Nc1ccccc1
Reactant: COc1cccc(-c2ccc3c(/C=C/C(=O)O)c(OC)ccc3c2)c1
Solvent: CCOCC
Product: COc1cccc(-c2ccc3c(/C=C/C(=O)Nc4ccccc4)c(OC)ccc3c2)c1

Procedure:
The compound was prepared by reaction of (E)-3-(2-methoxy-6-(3-methoxyphenyl)naphthalene-1-yl)acrylic acid (200 mg, 0.60 mmol, 1 eq) with aniline (1 eq) according to method D. Characterization of this compound was not effected. The raw product was directly employed for ether cleavage.
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[O:14]1[C:19](=[O:20])[CH2:18][O:17][CH2:16][C:15]1=[O:21].Cl>N1C=CC=CC=1>[O:17]([CH2:18][C:19]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:20])[CH2:16][C:15]([OH:21])=[O:14]
Reactant: O=C1COCC(=O)O1
Reactant: CCCCCCCCCCCCO
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCOC(=O)COCC(=O)O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
18.6 g n-dodecanol was dissolved in 25 ml pyridine on a steam bath. When 11.6 g of 1,4-dioxane-2,6-dione was added with stirring, the mixture quickly reached 80° C. After 5 minutes the solution was allowed to cool to room temperature and, after 2 hours, was poured into 200 ml 1 N HCl. The gel which precipitated was extracted with 300 ml ether, washed three times, with 0.1 N HCl and dried over Na2SO4. The ether was evaporated and the resulting clear oil was taken up in petroleum ether. Agitation and cooling under nitrogen precipitated a product which was separated by filtration. The remaining solution was diluted to 250 ml with petroleum ether for precipitation of a second crop. The yield totalled 18.1 g of a white crystalline solid that melted at 57°-59° C. and was soluble in acetone, chloroform, ether and/or methanol. Elemental analysis indicated 56.8% C; 8.5% H (Calc. 56.7% C; 8.5% H).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9]([F:13])([F:12])[CH2:8][CH2:7]1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1>C(OCC)C>[F:12][C:9]1([F:13])[CH2:10][CH2:11][CH:6]([CH2:4][OH:3])[CH2:7][CH2:8]1
Reactant: CCOC(=O)C1CCC(F)(F)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCC1CCC(F)(F)CC1
Reaction time: 0.5 h

Procedure:
To a solution of 4,4-difluorocyclohexanecarboxylic acid ethyl ester (0.50 g, 2.6 mmol) cooled to 0° C. in diethyl ether (20 mL) was added dropwise 1.0 M lithium aluminum hydride in tetrahydrofuran (2.6 mL, 2.6 mmol). The reaction was stirred for 30 min. The reaction was carefully quenched with water (2.0 mL) followed by the addition of 1.0 N NaOH (2 mL). The reaction mixture was stirred for 10 min, filtered through a pad of celite and washed with diethyl ether (20 mL). The organic layer was collected, dried over anhydrous magnesium sulfate, filtered, and concentrated to give the title compound as a crude oil (465 mg) which was used without further purification.
Reaction SMILES: [C:1]([CH2:4][CH2:5][N:6]=[C:7]=[O:8])(=[O:3])[CH3:2].[F:9][C:10]1[C:11](=[O:17])[NH:12][C:13](=[O:16])[NH:14][CH:15]=1>CN(C)C(=O)C.C(OCC)(=O)C>[C:1]([CH2:4][CH2:5][NH:6][C:7]([N:14]1[CH:15]=[C:10]([F:9])[C:11](=[O:17])[NH:12][C:13]1=[O:16])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)CCN=C=O
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(=O)CCNC(=O)n1cc(F)c(=O)[nH]c1=O
Reaction time: 5 h

Procedure:
To the above solution of 2-acetylethyl isocyanate was added a solution of 5-fluorouracil (2.60 g.) in N,N-dimethylacetamide (15 ml.) at 80° C. and stirred for further 5 hours at the same temperature. The resultant mixture was diluted with ethyl acetate (200 ml.), washed with water (each 30 ml., 3 times), dried over magnesium sulfate, treated with activated charcoal, filtered and evaporated in vacuo. The residue was recrystallized from ethyl acetate to give 1-[N-(2-acetylethyl)carbamoyl]-5-fluorouracil (439 mg.).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:22])[C:13]([CH3:21])([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH3:14])=[CH:8][CH:7]=1.N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:47]I>C(Cl)Cl>[I:47][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:22])[C:13]([CH3:21])([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH3:14])=[CH:8][CH:7]=1
Reactant: II
Reactant: CC(C)(C(=O)c1ccc(OCCCO)cc1)N1CCOCC1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C(=O)c1ccc(OCCCI)cc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
16.2 g (53 mmol) of 1-[4-(3-hydroxy-propoxy)-phenyl]-2-methyl-2-morpholin-4-yl-propan-1-one, 8.97 g (132 mmol) of imidazole and 34.5 g (132 mmol) of triphenyl phosphine are dissolved in 150 ml of methylene chloride. To the solution are added 27.0 g (106 mmol) of iodine and stirred at room temperature for 1 hour. 100 ml of methylene chlorideare added to the reaction mixture and washed with sodium sulfite aqueous solution and water, and dried over MgSO4. After methylene chloride is distilled off, the residue is purified by means of column chromatography on silica gel with ethyl acetate-hexane (1:3) as an eluent, and an oily product is obtained. The structure is confirmed by the 1H-NMR spectrum (CDCl3): δ [ppm] 1.31 (s, 6H), 2.30 (m, 2H), 2.57 (m, 4H), 3.38 (t, 2H), 3.69 (m, 4H), 4.11 (t, 2H), 6.91 (d, 2H), 8.60 (d, 2H).
Reaction SMILES: [CH:1]1([C:7]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:8]=2[CH:9]=[C:10]2[C:16]4[CH:17]=[C:18]([C:21]([O:23]C)=[O:22])[CH:19]=[CH:20][C:15]=4[N:14]4[CH2:25][C:26]([CH3:28])=[N:27][C:13]4=[CH:12][N:11]23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>C1COCC1.CO>[CH:1]1([C:7]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:8]=2[CH:9]=[C:10]2[C:16]4[CH:17]=[C:18]([C:21]([OH:23])=[O:22])[CH:19]=[CH:20][C:15]=4[N:14]4[CH2:25][C:26]([CH3:28])=[N:27][C:13]4=[CH:12][N:11]23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(c1)-c1cc3c(C4CCCCC4)cccc3n1C=C1N=C(C)CN12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC1=NC2=Cn3c(cc4c(C5CCCCC5)cccc43)-c3cc(C(=O)O)ccc3N2C1
Temperature: 70 °C
Yield: 88.2 %

Procedure:
To a solution of methyl 10-cyclohexyl-2-methyl-4H-imidazo[1,2-a]indolo[1,2-d][1,4]benzodiazepine-7-carboxylate (74 mg, 0.17 mmol) in THF (3 mL) and MeOH (1.5 mL) was added aq NaOH (1.0N, 0.8 mL, 0.8 mmol). The reaction mixture was heated at 70° C. for 2 h, cooled to rt, neutralized with aq. HCl (1.0N, 0.8 mL, 0.8 mmol) and concentrated to dryness. The solid residue was dissolved into MeOH/DCM, insoluble material was removed by filtration and the filtrate was concentrated and dried under N2 to yield crude 10-cyclohexyl-2-methyl-4H-imidazo[1,2-a]indolo[1,2-d][1,4]benzodiazepine-7-carboxylic acid (60 mg, 0.15 mmol, 86%) as an off-white solid which was used without further purification. 1H NMR (300 MHz, CD3OD) δ 1.16-1.56 (m, 4H), 1.72-2.22 (m, 6H), 2.31 (s, 3H), 2.80-3.01 (m, 1H), 5.12 (d, J=16.1 Hz, 1H), 5.91 (d, J=16.1 Hz, 1H), 7.62 (s, 1H), 7.72-7.86 (m, 5H), 7.97 (d, J=8.8 Hz, 1H), 8.39 (s, 1H). LCMS: m/e 412 (M+H)+, ret time 1.65 min.
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][C:5]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][N:7]=1.[CH3:16][N:17]=[C:18]=[O:19]>C(OCC)(=O)C>[CH3:16][NH:17][C:18]([N:2]([CH3:1])[C:3]1[S:4][C:5]([S:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:6][N:7]=1)=[O:19]
Reactant: CNc1nnc(SCc2ccccc2)s1
Reactant: CN=C=O
Solvent: CCOC(C)=O
Product: CNC(=O)N(C)c1nnc(SCc2ccccc2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-methylamino-5-benzylthio-1,3,4-thiadiazole (4.0 g) in ethyl acetate (100 ml) was added 1.5 g of methyl isocyanate. The reaction was stirred at room temperature for 2 hrs. then heated at reflux for an additional 2 hrs. The product, 1,3-dimethyl-3-(5-benzylthio-1,3,4-thiadiazol-2-yl)urea, crystallized upon the addition of petroleum ether, was collected, washed with ether and dried to give 4.7 g, MP 139°-142° C.
Reaction SMILES: [NH2:1][C@H:2]1[C:9](=[O:10])[N:8]2[C@@H:3]1[CH2:4][CH2:5][O:6][C:7]2([CH3:12])[CH3:11].[CH:13](OC(=O)C)=[O:14]>N1C=CC=CC=1>[CH3:11][C:7]1([CH3:12])[O:6][CH2:5][CH2:4][C@H:3]2[N:8]1[C:9](=[O:10])[C@@H:2]2[NH:1][CH:13]=[O:14]
Reactant: CC1(C)OCC[C@@H]2[C@@H](N)C(=O)N21
Reactant: CC(=O)OC=O
Solvent: c1ccncc1
Product: CC1(C)OCC[C@@H]2[C@@H](NC=O)C(=O)N21
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of (6R,7R)-7-amino-2,2-dimethyl-1-aza-3-oxabicyclo[4.2.0]octan-8-one (300 mg) were added pyridine (0.25 ml) and freshly prepared acetic formic anhydride (0.38 ml) at 0° C. After stirring for 45 minutes at 0° C., the reaction mixture was evaporated in vacuo. The residue was dissolved in xylene and the solution was evaporated in vacuo. The residue was chromatographed on silica gel (6 g) eluting with a mixture of methylene chloride and methanol (25:1-10:1) to give (6R,7R)-2,2-dimethyl-7-formamido-1-aza-3-oxabicyclo[4.2.0]octan-8-one (378 mg) as an oil.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13](S(C)=O)[N:14]=[CH:15][C:10]=3[C:9]([CH3:19])=[CH:8][C:7]2=[O:20])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:35]=[N:36][C:37]([NH2:40])=[CH:38][CH:39]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>C1(C)C=CC=CC=1>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:35]=[N:36][C:37]([NH:40][C:13]3[N:14]=[CH:15][C:10]4[C:9]([CH3:19])=[CH:8][C:7](=[O:20])[N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:11]=4[N:12]=3)=[CH:38][CH:39]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: Cc1cc(=O)n(C2CCCC2)c2nc(S(C)=O)ncc12
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Solvent: Cc1ccccc1
Product: Cc1cc(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)ncc12
Temperature: 25 °C
Yield: 14.4 %

Procedure:
8-Cyclopentyl-2-methanesulfinyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (0.40 g, 1.37 mmol) and 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.497 g, 1.78 mmol) were heated to reflux in toluene (4 mL) for 16 hours. The reaction mixture was cooled to room temperature and the precipitate that formed was collected by filtration and washed on the funnel with toluene (3×10 mL) to give 4-[6-(8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester as a dark brown-gray solid (0.100 g, 16.2%). 1H NMR δ (400 MHz, DMSO-d6) 9.92 (s, 1H), 8.78 (s, 1H), 8.02 (d, J=2.9 Hz, 1H), 7.87 (d, J=9.3 Hz, 1H), 7.50 (dd, J=2.9, 9.0 Hz, 1H), 6.18 (s, 1H), 5.77 (m, 1H), 3.44 (m, 4H), 3.07 (m, 4H), 2.39 (s, 3H), 2.20 (m, 2H), 1.85 (m, 2H), 1.71 (m, 2H), 1.55 (m, 2H), 1.39 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[NH:12][N:11]=[N:10]1.[CH3:15]N(C)C=O.[H-].[Na+].CI>O>[CH3:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[N:12]([CH3:15])[N:11]=[N:10]1
Reactant: Cc1c(Cl)cccc1-n1nn[nH]c1=O
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: Cc1c(Cl)cccc1-n1nnn(C)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of the above-mentioned 1-(2-methyl-3-chlorophenyl)-1,4-dihydrotetrazole-5-one 10.00 g and N,N-dimethylformamide 100 mL was added 55% sodium hydride 2.30 g under ice-cooling. The mixtures were raised to room temperature and were stirred for one hour. To the reaction mixtures was added methyl iodide 3.2 mL under ice-cooling. The mixtures were raised to room temperature and were stirred for fourteen hours. To the reaction mixtures was added water and the mixtures were extracted with ethyl acetate. The organic layers were washed with 10% hydrochloric acid, water and saturated saline, and were dried over anhydrous magnesium sulfate and were then concentrated under reduced pressure. The resulting residues were subjected to a silica gel column chromatography to give 1-(2-methyl-3-chlorophenyl)-4-methyl-1,4-dihydrotetrazole-5-one (hereinafter, referred to as “Intermediate (PRC-P)”) 1.56 g.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32])(OCC)=O>O>[CH:29]1[CH:28]=[C:25]2[C:26]([N:1]([C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([NH2:6])=[O:7])[C:23](=[O:32])[C:24]2=[CH:31][CH:30]=1)=[O:27]
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: NC(=O)CC[C@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: NC(=O)CC[C@@H](C(=O)O)N1C(=O)c2ccccc2C1=O
Reaction time: 1 h
Yield: 59.3 %

Procedure:
To a stirred solution of L-glutamine (43.8 g, 300 mmoL) and sodium carbonate (33.4 g, 315 mmoL) in 750 mL of water is rapidly added N-carbethoxyphthalimide [65.8 (97% pure, 67.8 g), 300 mmoL] as a solid. After 1 hour, the reaction mixture is filtered to remove unreacted N-carbethoxyphthalimide. The pH of the stirred filtrate is adjusted to 3-4 with 4N hydrochloric acid. The mixture is then seeded with N-phthaloyl-L-glutamine and the pH adjusted to 1-2 with 4 N hydrochloric acid. The resulting slurry is stirred for 1 hour. The slurry is filtered and the solid washed with copious amounts of water. The solid is air-dried and then dried in vacuo (60° C., <1 mm) overnight to afford 49.07 g (59%) of N-phthaloyl-L-glutamine, which can be alternatively named as 2-phthalimidoglutaramic acid, as a white powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12](=[S:14])[NH2:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:16][C:17](=O)[CH3:18]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([C:12]2[S:14][CH:16]=[C:17]([CH3:18])[N:13]=2)[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)CCl
Reactant: CC(C)(C)OC(=O)N1CC(C(N)=S)C1
Solvent: CO
Product: Cc1csc(C2CN(C(=O)OC(C)(C)C)C2)n1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To 145 mg (0.67 mmol) 3-thiocarbamoyl-azetidine-1-carboxylic acid tert-butyl ester in 3 mL MeOH in a sealed tube was added 64 μL (0.8 mmol) chloroacetone, and the reaction was stirred at 90° C. for 3 hours. After evaporation of the solvent the product was purified by column chromatography (silica, heptane/EtOAc 8:2 to 6:4).
Reaction SMILES: [NH2:1][C:2]([C:8]1[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][C:9]=1[F:15])([CH:5]([F:7])[F:6])[CH2:3]O.[N+:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26])([O-:18])=[O:17].C(=O)([O-])O.[K+]>C(#N)C>[Br:14][C:12]1[CH:11]=[CH:10][C:9]([F:15])=[C:8]([C:2]2([CH:5]([F:7])[F:6])[CH2:3][N:1]2[S:25]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N+:16]([O-:18])=[O:17])(=[O:26])=[O:27])[CH:13]=1
Reactant: NC(CO)(c1cc(Br)ccc1F)C(F)F
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)N1CC1(c1cc(Br)ccc1F)C(F)F
Temperature: 80 °C
Yield: 37.2 %

Procedure:
2-Amino-2-(5-bromo-2-fluoro-phenyl)-3,3-difluoro-propan-1-ol (13.04 g, 45.9 mmol) [examples 42 step d)] was dissolved in 261 mL acetonitrile, 2-nitrobenzenesulfonyl chloride (22.38 g, 101 mmol) and potassium hydrogencarbonate (13.79 g, 138 mmol) were added. The mixture was heated to 80° C. and stirred over night. After this period, the reaction mixture was cooled down and partitioned between saturated aqueous NaHCO3 solution and TBME. The layers were separated, washed with brine and TBME. The combined organic layers were dried over MgSO4.H2O and evaporated. The crude product was purified on a silica gel column by eluting with hexane/dichloromethane 2/1→1/2 to give 7.71 g of the title compound as white crystals.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([OH:25])[CH:6]=[C:7]([CH2:23][CH3:24])[C:8]=1[O:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH2:15][CH:16]([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])[CH3:2].[Cl:26][C:27]([Cl:31])=[CH:28][CH2:29]Cl.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:23]([C:7]1[CH:6]=[C:5]([O:25][CH2:29][CH:28]=[C:27]([Cl:31])[Cl:26])[CH:4]=[C:3]([CH2:1][CH3:2])[C:8]=1[O:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH2:15][CH:16]([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])[CH3:24]
Reactant: CCOC(COCCCCOc1c(CC)cc(O)cc1CC)OCC
Reactant: ClCC=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(COCCCCOc1c(CC)cc(OCC=C(Cl)Cl)cc1CC)OCC
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.6 %

Procedure:
Then, 19.9 g of 3,5-diethyl-4-(4-(2,2-diethoxyethoxy)butyloxy)phenol, 9.20 g of 1,1,3-trichloro-1-propene, 9.15 g of potassium carbonate, and 200 ml of N,N-dimethylformamide were placed in a reaction vessel. After stirring at room temperature for 24 hours, the reaction mixture was poured into water, and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over anhydrous magnesium, and concentrated to give a residue. This residue was subjected to silica gel chromatography, which afforded 25.4 g (yield, 91%) of 3,5-diethyl-1-(3,3-dichloro-2-propenyloxy)-4-(4-(2,2-diethoxyethoxy)butyloxy)benzene, nD26.0 1.4991.
Reaction SMILES: [OH-].[K+].[NH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH3:8][O:9][CH2:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1>C(O)C>[CH3:8][O:9][CH2:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]([OH:17])[C@@H:4]([C:5]([OH:7])=[O:6])[NH2:3])=[CH:14][CH:13]=1
Reactant: NCC(=O)O
Reactant: COCOc1ccc(C=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COCOc1ccc(C(O)[C@H](N)C(=O)O)cc1
Reaction time: 19 h
Yield: 19.6 %

Procedure:
To a solution of potassium hydroxide (26.8 g) in ethanol (500 ml) was added glycine (14.6 g) and 4-methoxymethoxybenzaldehyde (48.5 g) at room temperature. After stirring for 19 hours, the solvent was removed in vacuo. The residue was dissolved in water and acidified with hydrochloric acid. The solution was washed with ethyl acetate and adjusted to pH 6.0 with sodium bicarbonate. White solid was precipitated and collected to give O-methoxymethyl-β-hydroxytyrosine (9.2 g).