Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(=O)C1C=CC=C(N[C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])C=1.CC(C)(C)C(=O)CN1C2C=CC=CC=2C(C2C=CC=CC=2)=NN([CH2:61][C:62](O)=[O:63])C1=O.C(OC(=O)CSC1C=CC=C(N)C=1)C.C1(C2C3C=CC=CC=3N(CC(=O)C(C)(C)C)C(=O)N(CC(O)=O)N=2)CCCCC1.COC(=O)C1C=CC=C(N)C=1>>[CH2:62]([O:63][C:11](=[O:38])[CH2:12][N:13]1[N:19]=[C:18]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:34])([CH3:33])[CH3:35])[C:14]1=[O:37])[CH3:61]
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Reactant: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)O)N=C(c2ccccc2)c2ccccc21
Agent: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)O)N=C(C2CCCCC2)c2ccccc21
Agent: CCOC(=O)CSc1cccc(N)c1
Agent: COC(=O)c1cccc(N)c1
Product: CCOC(=O)CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C(C)(C)C)C1=O

Procedure:
The title compound was obtained by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1) except that [1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-5-phenyl-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 4, step a) and (3-amino-phenylsulfanyl)-acetic acid ethyl ester were used instead of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 1, step d) and 3-amino-benzoic acid methyl ester respectively in step e, followed by reaction of the product obtained, in place of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid ethyl ester (Example 1, step c), according to the method of Example 1, step d. 1H NMR (CDCl3) 8.60 (1H, br s), 8.40 (1H, s), 7.63-7.40 (7H, m), 7.25-7.14 (6H, m), 4.76 (2H, m), 4.43 (2H, s), 3.58 (2H, s), 1.25 (9H, s). The compound was further characterised as the N-methyl-D-glucamine salt. Found: C, 50.02; H, 6.04; N, 7.59%; C30H30N5O5S.C7H17NO5.1.8C4H8O2.2.2CH2Cl2 requires: C, 50.06; H, 5.96; N, 7.55%.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:3]=1[NH2:4].[C:10](Cl)(=[O:14])[CH:11]([CH3:13])[CH3:12]>>[Br:1][C:2]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:3]=1[NH:4][C:10](=[O:14])[CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)C(=O)Cl
Reactant: Cc1ccc(Br)c(N)c1
Product: Cc1ccc(Br)c(NC(=O)C(C)C)c1

Procedure:
Analogously to Example 18e, 12.20 g of 2-bromo-5-methylaniline are reacted with 7.77 ml of isobutyryl chloride. The title compound is obtained as a white solid. Rt=4.29.
Reaction SMILES: [C:1]([OH:16])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:17](O)(=O)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].P(=O)(O)(O)O.C(O)CCCCCCCCCCCCCCC>CCCCCC>[C:1]([O:16][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCC(=O)O
Reactant: CCCCCCCCCCCCCCCC(=O)O
Agent: CCCCCCCCCCCCCCCCO
Agent: O=P(O)(O)O
Solvent: CCCCCC
Product: CCCCCCCCCCCCCCCCOC(=O)CCCCCCCCCCCCC

Procedure:
Myristic acid/palmitic acid, 200 cc. of 85% phosphoric acid and 1800 ml. of hexane were mixed, heated to reflux and then 251 grams of cetyl alcohol added in 30 min. The mixture was refluxed further for 8 hours. Then the hot mixture consisted of a muddy acid layer and a opaque solvent layer which could not be separated by decantation or filtration. The mixture was further diluted with three volumes of hexane causing the slushy hexane layer to further soften enough to be separated from aqueous layer. The hexane layer was then cooled to bring about crystallization of fatty ester. The weight of cetyl myristate isolated was 294 grams which had a melting point of 54-59° C. The conversion, based on the cetyl alcohol used, was 63.71%.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][NH:9][C:10](=[O:50])[C@H:11]([CH:47]([CH3:49])[CH3:48])[CH2:12][C@H:13]([OH:46])[C@@H:14]([NH:38]C(OC(C)(C)C)=O)[CH2:15][C@@H:16]([CH:35]([CH3:37])[CH3:36])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][OH:28])=[C:20]([O:29][CH2:30][CH2:31][CH2:32][O:33][CH3:34])[CH:19]=2)[CH2:3][CH2:2]1.[ClH:51]>O1CCOCC1>[ClH:51].[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][NH:9][C:10](=[O:50])[C@H:11]([CH:47]([CH3:49])[CH3:48])[CH2:12][C@H:13]([OH:46])[C@@H:14]([NH2:38])[CH2:15][C@@H:16]([CH:35]([CH3:37])[CH3:36])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][OH:28])=[C:20]([O:29][CH2:30][CH2:31][CH2:32][O:33][CH3:34])[CH:19]=2)[CH2:3][CH2:2]1
Reactant: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@H](C(=O)NCCN2CCOCC2)C(C)C)C(C)C)ccc1OCCCO
Agent: Cl
Solvent: C1COCCO1
Product: COCCCOc1cc(C[C@@H](C[C@H](N)[C@@H](O)C[C@H](C(=O)NCCN2CCOCC2)C(C)C)C(C)C)ccc1OCCCO
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
30 mg of 5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(S),7(S)-diisopropyl-8-[4-(3-hydroxypropyloxy)-3-(3-methoxypropyloxy)-phenyl]-octanoic acid (N-2-morpholinoethyl)amide are dissolved in 1.5 ml of a 4N solution, cooled to 0° C., of hydrochloric acid in dioxane, and the mixture is then stirred for 10 minutes at 0° C. The reaction mixture is concentrated to dryness by evaporation under reduced pressure and at room temperature. Purification of the residue by means of FC (5 g of silica gel, dichloromethane/methanol=98:2) yields the title compound: Rf (dichloromethane/methanol=8:2)=0.20; Rt =10.43 minutes; FAB-MS (M+H)+ =610.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([CH3:15])[CH:13]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.O>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([CH3:15])=[CH:13][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C=O)Cc1ccc(C(C)(C)C)cc1
Reactant: C1CCNCC1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=CN1CCCCC1)Cc1ccc(C(C)(C)C)cc1

Procedure:
6.54 kg of 3-(p-tert.butyl-phenyl)-2-methyl-propionaldehyde and 3 kg of piperidine are heated at reflux overnight in 4.54 liters of toluene in a water-separator under nitrogen gasification and the toluene is distilled in vacuo. The residue is distilled in vacuo. There is obtained pure 1-[3-(p-tert.butyl-phenyl)-2-methyl-1-propenyl]-piperidine of boiling point 118°-120° C./0.026 Torr.
Reaction SMILES: Cl[C:2]1[C:3](=[O:11])[N:4]([CH3:10])[N:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH2:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O)[CH3:13].C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:2]1[C:3](=[O:11])[N:4]([CH3:10])[N:5]=[CH:6][C:7]=1[O:8][CH3:9])[CH3:13]
Reactant: COc1cnn(C)c(=O)c1Cl
Reactant: CCc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CCc1ccccc1-c1c(OC)cnn(C)c1=O
Yield: 92 %

Procedure:
To a mixture of 2.516 g of 4-chloro-5-methoxy-2-methyl-3 (2H)-pyridazinone, 2.575 g of 2-ethylphenylboronic acid and 3.333 g of sodium carbonate were added 30 mL of 1,4-dioxane and 20 mL of water. To the mixture were added 2.417 g of tetrabutylammonium bromide and 0.657 g of tetrakis(triphenylphosphine)palladium, and then under a nitrogen atmosphere, the resulting mixture was stirred and heated under reflux for 17 hours. After cooling, 50 mL of water was added to the reaction mixture, which was extracted with 100 mL of ethyl acetate and then 30 mL of ethyl acetate. The extracts were combined, washed with a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The solid obtained was washed with a mixed solvent of ethyl acetate and hexane (1:2) to yield 3.238 g of the title compound as yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[NH:5][C:4]([CH3:11])([CH3:10])N=1.CC(C)=[O:14].CS(O)(=O)=O>CO>[CH3:10][C:4]1([CH3:11])[NH:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2](=[O:14])[CH2:1]1
Reactant: CC(C)=O
Reactant: CC1=NC(C)(C)NC(C)(C)C1
Agent: CS(=O)(=O)O
Solvent: CO
Product: CC1(C)CC(=O)CC(C)(C)N1
Temperature: 25 °C
Yield: 95.3 %

Procedure:
A solution of 6.3 g. of acetonine in a mixed solvent comprising 30 g. of acetone and 30 g. of methanol was added with 1.6 g. of methanesulfonic acid. The mixture was maintained at room temperature for 24 hours in a sealed equipment to effect the reaction. After completion of the reaction, the reaction mixture was purified in the same manner as in Example 1 to obtain triacetonamine in a yield of 95.3%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])/[CH:5]=[C:6](\[CH3:30])/[CH:7]=[CH:8]/[CH:9]=[C:10](/[C:15]1[C:24]([OH:25])=[CH:23][C:22]2[C:21]([CH3:27])([CH3:26])[CH2:20][CH2:19][C:18]([CH3:29])([CH3:28])[C:17]=2[CH:16]=1)\[C:11]([F:14])([F:13])[F:12])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:38](I)[CH3:39].CC(C)=O>CCOC(C)=O.CCCCCC>[CH2:1]([O:3][C:4](=[O:31])/[CH:5]=[C:6](\[CH3:30])/[CH:7]=[CH:8]/[CH:9]=[C:10](/[C:15]1[C:24]([O:25][CH2:38][CH3:39])=[CH:23][C:22]2[C:21]([CH3:27])([CH3:26])[CH2:20][CH2:19][C:18]([CH3:29])([CH3:28])[C:17]=2[CH:16]=1)\[C:11]([F:13])([F:12])[F:14])[CH3:2]
Reactant: CCOC(=O)/C=C(C)/C=C/C=C(/c1cc2c(cc1O)C(C)(C)CCC2(C)C)C(F)(F)F
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC(C)=O
Product: CCOC(=O)/C=C(C)/C=C/C=C(/c1cc2c(cc1OCC)C(C)(C)CCC2(C)C)C(F)(F)F

Procedure:
Following General Procedure A and using (2E,4E,6Z)-8,8,8-trifluoro-7-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-3-methyl-octa-2,4,6-trienoic acid ethyl ester (Intermediate 5, 160 mg, 0.37 mmol), K2CO3 (253 mg, 1.83 mmol), EtI (0.15 mL, 1.83 mmol), and acetone (2 mL) followed by HPLC (2.5% EtOAc-hexane), the title compound was obtained as a clear syrup (81 mg, 48%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[O:29][CH2:30][C:31]1[N:32]=[C:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:34][C:35]=1[CH3:36])[CH2:6][O:7][C:8]1[C:12](/[CH:13]=[CH:14]/[C:15]([O:17]CC)=[O:16])=[CH:11][N:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:9]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[O:29][CH2:30][C:31]1[N:32]=[C:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:34][C:35]=1[CH3:36])[CH2:6][O:7][C:8]1[C:12](/[CH:13]=[CH:14]/[C:15]([OH:17])=[O:16])=[CH:11][N:10]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:9]=1
Reactant: CCOC(=O)/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/C(=O)O)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 60 °C
Reaction time: 5 h
Yield: 94.7 %

Procedure:
A mixture of ethyl (E)-3-(3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-phenyl-1H-pyrazol-4-yl)-2-propenoate (800 mg), 1N aqueous sodium hydroxide solution (3 mL), tetrahydrofuran (10 mL) and ethanol (10 mL) was stirred at 60° C. for 5 hrs. 1N Hydrochloric acid (3 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained colorless crystals were collected by filtration to give (E)-3-(3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-phenyl-1H-pyrazol-4-yl)-2-propenoic acid (720 mg, yield 95%). The crystals were recrystallized from ethyl acetate-hexane. melting point: 188-189° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=1)[NH:7][C:8]1[CH:19]=[CH:18][CH:17]=[CH:16][C:9]=1[C:10]([NH:12][CH2:13][CH:14]=[CH2:15])=[O:11])([O-:3])=[O:2].[H-].[Na+].ClC1C=C(N=[C:33]=[O:34])C=CC=1>O1CCCC1>[N+:1]([C:4]1[CH:5]=[C:6]([N:7]2[C:8]3[C:9](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:10](=[O:11])[N:12]([CH2:13][CH:14]=[CH2:15])[C:33]2=[O:34])[CH:20]=[CH:21][CH:22]=1)([O-:3])=[O:2]
Reactant: C=CCNC(=O)c1ccccc1Nc1cccc([N+](=O)[O-])c1
Reactant: O=C=Nc1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCn1c(=O)c2ccccc2n(-c2cccc([N+](=O)[O-])c2)c1=O
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
3.0 g of 2-(m-nitroanilino)-N-allylbenzamide was dissolved in 20 ml of tetrahydrofuran. To the solution was added 1.0 g of approximately 50 % sodium hydride and stirring was performed for 30 minutes. To this was added dropwise under cooling 4.6 g of m-chlorophenyl isocyanate, and the mixture was stirred for one hour, and then refluxed for 5 hours. After the reaction was complete, the solvent was distilled off from the resulting mixture. The residue thus obtained was recrystallized from methanol to give 2.3 g of 1-(m-nitrophenyl)-3-allylquinazoline-2,4(1H, 3H)-dione as colorless needles, melting at 165°-166° C.
Reaction SMILES: C(OC(=O)[N:7]([CH2:11][C:12](=[O:14])[NH2:13])[CH:8]([CH3:10])[CH3:9])(C)(C)C.[ClH:16].C(OCC)C>O1CCOCC1>[ClH:16].[CH:8]([NH:7][CH2:11][C:12]([NH2:13])=[O:14])([CH3:10])[CH3:9]
Reactant: CC(C)N(CC(N)=O)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(C)NCC(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
To a solution of N-carbamoylmethyl-N-isopropyl-carbamic acid t-butyl ester (2.67 g, 12.3 mmol) (obtained as described in Reference Example 49(1)) in 1,4-dioxane (30 ml) was added a solution of 4N hydrogen chloride in 1,4-dioxane (30 ml) in an ice bath, and then the mixture was stirred at room temperature overnight. After checking the completion of the reaction, diethyl ether was added thereto and the reaction mixture was stirred for 30 minutes. The resulting mixture was filtered, and the residue was washed with diethyl ether and then dried under reduced pressure to give 2-isopropylaminoacetamide hydrochloride (1.82 g, yield 97%) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:11]=[C:10]([O:12][CH:13]([F:15])[F:14])[N:9]([CH3:16])[N:8]=2)[N:5]=[CH:4][C:3]=1[C:17]#[N:18].S(Cl)([Cl:22])(=O)=O>C(#N)C>[NH2:1][C:2]1[N:6]([C:7]2[C:11]([Cl:22])=[C:10]([O:12][CH:13]([F:14])[F:15])[N:9]([CH3:16])[N:8]=2)[N:5]=[CH:4][C:3]=1[C:17]#[N:18]
Reactant: O=S(=O)(Cl)Cl
Reactant: Cn1nc(-n2ncc(C#N)c2N)cc1OC(F)F
Solvent: CC#N
Product: Cn1nc(-n2ncc(C#N)c2N)c(Cl)c1OC(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5.0 g (19.7 mmol) 5-Amino-1-(5-difluoromethoxy-1-methyl-3-pyrazolyl)-4-pyrazolecarbonitrile was dissolved in 180 ml acetonitrile and 2.65 g (19.7 mmol) sulfuryl chloride added dropwise. The mixture was stirred for one hour at room temperature and concentrated.
Reaction SMILES: C[O:2][C:3]([CH:5]([N:7]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9](OCC2C=CC=CC=2)[C:8]1=[O:25])[CH3:6])=[O:4].C([OH:28])C>[Pd]>[OH:28][C@@:5]([C:3]([OH:2])=[O:4])([CH3:6])[NH:7][C:8](=[O:25])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCO
Reactant: COC(=O)C(C)N1C(=O)C(OCc2ccccc2)C1c1ccccc1
Agent: [Pd]
Product: C[C@](O)(NC(=O)CCc1ccccc1)C(=O)O
Reaction time: 12 h
Yield: 90.5 %

Procedure:
According to the same procedure as in Example 1, Diastereomer A (700 mg.) of 1-(1-methoxycarbonylethyl)-3-benzyloxy-4-phenylazetidin-2-one, which had been obtained in Example 5, was subjected to hydrogenolysis at room temperature in ethanol (40 ml.) under a hydrogen pressure of one atmosphere in the presence of a 10% Pd-C (220 mg.). The reaction was completed in 12 hours. The same after-treatment as in Example 1 was followed to give methyl ester of α-hydroxy-β-phenylpropionylalanine (468 mg., yield: 90.5%), which was an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](OC(=O)C)(=O)C>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16](=[O:18])[CH3:19])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Cc1ccc(OCc2ccccc2)cc1
Reaction time: 6 h

Procedure:
To 10.0 g (41.3 mmol) of 4-benzyloxyphenylacetic acid (31) was added, 20 mL of acetic anhydride and 20 mL of pyridine, which was heated to reflux with stirring under argon atmosphere for 6 hours. Solvents were evaporated and residue dissolved in CHCl3 (50 mL) and washed with 1N NaOH (2×50 mL). Dried organic layer (MgSO4), filtered, and evaporated to 11.8 g of an amber oil. Vacuum distillation at 0.1 mm Hg in an oil-bath set to 170° C. followed by silica gel chromatography eluting with 8/2 CH2Cl2-hexanes gave 2.68 g (27%). 1H NMR (CDCl3) □δ□ 2.14 (s, 3H), 3.63 (s, 2H), 5.05 (s, 2H), 6.94 (d, 2H, J=8.7 Hz), 7.10 (d, 2H, J=8.7 Hz), 7.26-7.47 (m, 5H).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3I)[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH:34]([C:36]1[CH:37]=[CH:38][C:39]([O:45][CH3:46])=[C:40](B(O)O)[CH:41]=1)=[O:35].C(=O)([O-])[O-].[Na+].[Na+].C(Cl)Cl>O.CCO.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCCCCC>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:38]3[C:39]([O:45][CH3:46])=[CH:40][CH:41]=[C:36]([CH:34]=[O:35])[CH:37]=3)[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1I
Reactant: COc1ccc(C=O)cc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCCCCC
Solvent: O
Product: COc1ccc(C=O)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
A mixture of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)-benzyl]-4-methyl-1,3-oxazolidin-2-one (0.50 g, 0.84 mmol), 5-formyl 2-methoxy phenyl boronic acid (0.22 g, 1.25 mmol), tetrakis(triphenylphosphine)palladium (48 mg, 5% mol) and sodium carbonate (0.19 g, 1.84 mmol) in 20 ml of water/EtOH/toluene (1:2:4) was heated to reflux for 4 h. TLC (CH2Cl2:hexane/1:1) showed that the reaction was over. The solvents were removed. Water (30 ml) was added. The organic was extracted with methylene chloride (3×40 ml). The combined methylene chloride layers were washed with brine, and dried over sodium sulfate. The title compound was obtained after flash column using EtOAc:hexane/3:7 as the eluant. 1H NMR (CDCl3, 500 MHz): δ 1:1 mixture of atropisomers 9.95 (s, 1H), 7.62-7.98 (m, 6H), 7.42 (m, 1H), 7.17 (m, 2H), 5.65 (d, J=8 Hz, 0.5H), 5.20 (d, J=8 Hz, 0.5H), 4.96 (d, J=15.5 Hz, 0.5H), 4.92 (d, J=16.5 Hz, 0.5H), 3.85-4.10 (m, 2H), 3.98 (s, 1.5H), 3.92 (s, 1.5H), 0.59 (d, J=6.5 Hz, 1.5H), 0.42 (d, J=6 Hz, 1.5H).
Reaction SMILES: C1[O:14][C:4]([CH3:13])([CH2:5][C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)OC1.[OH-].[Na+].Br[CH2:18][CH2:19][CH2:20][OH:21]>O>[OH:21][CH2:20][CH2:19][CH2:18][O:12][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][C:4](=[O:14])[CH3:13])=[CH:11][CH:10]=1
Reactant: OCCCBr
Reactant: CC1(Cc2ccc(O)cc2)OCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Cc1ccc(OCCCO)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.7 %

Procedure:
1-(4-Hydroxyphenyl)propan-2-one ethylene ketal (3.88 g) was added to a solution of sodium hydroxide (1.5 g) in water (30 ml) and the mixture was stirred at room temperature for 30 minutes. 1-Bromo-3-hydroxypropane (2.98 g) was added and the mixture was boiled under reflux with stirring for 11/2 hours. After cooling water (50 ml) was added, the mixture was extracted with ether, the extracts dried (MgSO4) and evaporated to give the title compound (3.94 g) as its ethylene ketal.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([OH:25])=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[C:9]2[CH2:14][CH2:13][CH2:12][N:10]2[N:11]=1.[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36](Br)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([O:25][C:21]2[CH:20]=[C:19]3[C:24]([C:15]([C:8]4[C:7]([C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=5)=[N:11][N:10]5[CH2:12][CH2:13][CH2:14][C:9]=45)=[CH:16][CH:17]=[N:18]3)=[CH:23][CH:22]=2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCC(Br)CC1
Reactant: Oc1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(-c4c(-c5ccccn5)nn5c4CCC5)ccnc3c2)CC1
Temperature: 80 °C

Procedure:
To a suspension of 4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-ol (0.27 g, 0.84 mmol) in N,N-dimethylformamide (15 mL) is added 4-bromo-piperidine-1-carboxylic acid tert-butyl ester (0.29 mL, 2.28 mmol) and cesium carbonate (1.5 g, 4.57 mmol). The mixture is heated at 80° C. for 48 h and concentrated in vacuo. The residue is taken up in dichloromethane, washed with water and saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated in vacuo. The residue is chromatographed on SiO2 (7% methanol in dichloromethane) to yield the title compound, 262 mg (61%), as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:16])=[C:4]([C:13]([OH:15])=[O:14])[C:5]([I:12])=[C:6]([C:9]([OH:11])=[O:10])[C:7]=1[I:8].[OH2:17]>CC(N(C)C)=O>[C:13]([CH2:4][CH2:5][CH2:6][C:9]([NH:1][C:2]1[C:7]([I:8])=[C:6]([C:9]([OH:11])=[O:10])[C:5]([I:12])=[C:4]([C:13]([OH:15])=[O:14])[C:3]=1[I:16])=[O:10])([OH:14])=[O:17]
Reactant: Nc1c(I)c(C(=O)O)c(I)c(C(=O)O)c1I
Reactant: O
Solvent: CC(=O)N(C)C
Product: O=C(O)CCCC(=O)Nc1c(I)c(C(=O)O)c(I)c(C(=O)O)c1I
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To an ice cool stirred solution of 5-amino-2,4,6-triiodo-1,3-benzenedicarboxylic acid, diacid chloride (2.7 g, 4.6 mmol) in 3 mL of dimethylacetamide was added methyl (4-chloroformyl)butyrate (1.5 g, 9.0 mmol). The solution was stirred for 18 hours at room temperature. The reaction mixture ws poured into 25 mL of water and extracted with 3×15 mL of ethyl acetate. The combined organic phase was extracted with 2×10 mL of water, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the desired product as a residue. The crude product was crystallized from CH3CN to yield 1.35 g of the title A compound, i.e., the isophthalyl chloride. The product was used without further purification.