Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]2[CH:14]=[C:15]([CH:28]=[CH:29][CH:30]=2)[C:16]([NH:18][C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)=[O:17])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:32]1C=C(S(Cl)(=O)=O)C=C[C:37]=1Cl>>[CH2:32]([O:24][C:23](=[O:25])[C:22]1[CH:26]=[CH:27][C:19]([NH:18][C:16](=[O:17])[C:15]2[CH:28]=[CH:29][CH:30]=[C:13]([NH:12][S:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)(=[O:10])=[O:11])[CH:14]=2)=[CH:20][CH:21]=1)[CH3:37]
Reactant: O=C(O)c1ccc(NC(=O)c2cccc(NS(=O)(=O)c3ccc(Cl)c(Cl)c3)c2)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Product: CCOC(=O)c1ccc(NC(=O)c2cccc(NS(=O)(=O)c3ccc(Cl)c(Cl)c3)c2)cc1

Procedure:
4-[3-(3,4-Dichloro-benzenesulfonylamino)-benzoylamino]-benzoic acid, MS (ISP): m/e=462.9 (M−H), was prepared in analogy to example 1, steps A to D. Step C was performed using 3,4-dichloro-benzenesulfonyl chloride and yielded 4-[3-(3,4-dichloro-benzenesulfonylamino)-benzoylamino]-benzoic acid ethyl ester, which was hydrolyzed in step D.
Reaction SMILES: N[C@H](C(NN)=O)CC1N=CNC=1.Cl.N(OCCC(C)C)=O.[C:22]1([CH2:32][CH:33]([CH2:49][C:50]([N:52]2[CH2:57][CH2:56][O:55][CH2:54][CH2:53]2)=[O:51])[C:34]([NH:36][C@H:37]([C:44]([N:46]=[N+]=[N-])=[O:45])[CH2:38][C:39]2[N:43]=[CH:42][NH:41][CH:40]=2)=[O:35])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1.[N-]=[N+]=[N-].Cl.N[C@@H:63]([CH2:72][CH:73]([CH3:75])[CH3:74])[CH:64]([OH:71])[C:65]([O:67][CH:68]([CH3:70])[CH3:69])=[O:66].C(=O)(O)[O-].[Na+]>CN(C)C=O.C(N(CC)CC)C>[C:22]1([CH2:32][CH:33]([CH2:49][C:50]([N:52]2[CH2:57][CH2:56][O:55][CH2:54][CH2:53]2)=[O:51])[C:34]([NH:36][C@H:37]([C:44]([NH:46][C@@H:63]([CH2:72][CH:73]([CH3:75])[CH3:74])[CH:64]([OH:71])[C:65]([O:67][CH:68]([CH3:69])[CH3:70])=[O:66])=[O:45])[CH2:38][C:39]2[N:43]=[CH:42][NH:41][CH:40]=2)=[O:35])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: [N-]=[N+]=NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)C(CC(=O)N1CCOCC1)Cc1cccc2ccccc12
Reactant: CC(C)C[C@H](N)C(O)C(=O)OC(C)C
Agent: CC(C)CCON=O
Agent: Cl
Agent: NNC(=O)[C@@H](N)Cc1c[nH]cn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)C(CC(=O)N1CCOCC1)Cc1cccc2ccccc12)C(O)C(=O)OC(C)C
Reaction time: 16 h

Procedure:
To a solution of 50 mg of N-[2-(1-naphthylmethyl)-3-morpholinocarbonyl)propionyl]-L-histidine hydrazide in 1 ml of N,N-dimethylformamide were added successively 0.068 ml of a dry 5.1N-hydrogen chloride in N,N-dimethylformamide solution and 0.017 ml of isoamyl nitrite at -20° C. with stirring. After disappearance of hydrazide compound, the reaction mixture was cooled to -30° C., and the reaction mixture was neutralized by adding 0.048 ml of triethylamine to prepare a solution of N-[2-(1-naphthylmethyl)-3-(morpholinocarbonyl)propionyl]-L-histidine azide. The cold azide solution was added dropwise to a solution of 25 mg of isopropyl (2RS, 3S)-3-amino-2-hydroxy-5-methylhexanoate hydrochloride and 0.032 ml of triethylamine in 2 ml of N,N-dimethylformamide under ice-cooling, and the mixture was stirred for 16 hours. A 5% aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with a saturated sodium chloride, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by preparative silica gel thin layer chromatography (developing solvent: chloroform/methanol=5/1 by volume Rf2 =0.53 to obtain 4 mg of isopropyl (2RS, 3S)-3-{N-[2-(1-naphthylmethyl)-3-(morpholinocarbonyl)propionyl]-L-histidyl}amino-2-hydroxy-5-methylhexanoate as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[C:10](Cl)(Cl)=[S:11]>O.C(OCC)C>[F:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[C:10]([SH:11])[O:9][C:3]=2[CH:4]=1
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc(F)cc1O
Solvent: CCOCC
Solvent: O
Product: Fc1ccc2nc(S)oc2c1

Procedure:
2-Amino-5-fluorophenol [CAS:53981-24-1] (18.4 g) in 100 ml of water was stirred at room temperature while thiophosgene (16.8 g) was added dropwise as a solution in 100 ml of diethyl ether at such a rate that the resultant exotherm was controlled.
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][C:5]2[NH:6][C:7]([C:9](=O)[C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.[CH2:18]([NH2:21])[CH2:19][NH2:20].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][C:5]2[NH:6][C:7]([C:9]3([C:10]([F:13])([F:12])[F:11])[NH:21][CH2:18][CH2:19][NH:20]3)=[N:8][C:4]=2[CH:3]=1
Reactant: NCCN
Reactant: O=C(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: FC(F)(F)C1(c2nc3cc(Cl)c(Cl)cc3[nH]2)NCCN1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-(5,6-DiChloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (1.02 g; 3.61 mmol), ethylene diamine (0.74 mL; 11.04 mmol) and para-toluenesulphonic acid monohydrate (0.12 g; 0.603 mmol) were suspended in toluene (80 mL), then heated to reflux with a Dean-Stark trap for 3 hrs. After 3 hrs, ethylene diamine (0.74 mL; 11.04 mmol) was added to the reaction mixture and the reaction mixture was allowed to reflux with the Dean-Stark trap for 18 hrs. The reaction was cooled to room temperature and concentrated in vacuo to a crude brown residue. The crude brown residue was dissolved in ethyl acetate (60 mL), washed with water (3×50 mL) and brine (50 mL), then dried over Na2SO4. The drying agent was removed by filtration and the filtrate was concentrated in vacuo to a crude brown oil, which was purified by column chromatography (SiO2, 50% ethyl acetate/hexanes) to yield the title compound as a light orange solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[C:5]([C:7]1[CH:8]=[C:9]([NH:27][CH2:28][CH2:29][C:30]([F:33])([F:32])[F:31])[C:10]2[N:14]=[CH:13][N:12]([C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[C:17]([CH3:25])[CH:16]=3)[C:11]=2[CH:26]=1)=[O:6].CO.[OH-].[Li+].Cl>O1CCCC1.O>[F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[C:5]([C:7]1[CH:8]=[C:9]([NH:27][CH2:28][CH2:29][C:30]([F:33])([F:32])[F:31])[C:10]2[N:14]=[CH:13][N:12]([C:15]3[CH:24]=[CH:23][C:18]([C:19]([OH:21])=[O:20])=[C:17]([CH3:25])[CH:16]=3)[C:11]=2[CH:26]=1)=[O:6]
Reactant: COC(=O)c1ccc(-n2cnc3c(NCCC(F)(F)F)cc(C(=O)c4ccc(OC)c(F)c4)cc32)cc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc(C(=O)c2cc(NCCC(F)(F)F)c3ncn(-c4ccc(C(=O)O)c(C)c4)c3c2)cc1F
Temperature: 23 °C
Reaction time: 8 h
Yield: 98.1 %

Procedure:
To a solution of 660 mg (1.25 mmol) methyl 4-{6-(3-fluoro-4-methoxybenzoyl)-4-[(3,3,3-trifluoropropyl)amino]-1H-benzimidazol-1-yl}-2-methylbenzoate which was prepared according to intermediate example 101b in 25 mL tetrahydrofurane and 8 mL methanol were added 6.2 mL of a 1M aqueous lithium hydroxide solution and the mixture was stirred at 23° C. overnight. Water was added, the mixture was acidified by the addition of a 1M hydrochloric acid and extracted with dichloromethane and methanol. The organic layer was washed with brine and dried over sodium sulfate. After filtration and removal of solvent the residue was purified by chromatography to give 632 mg (98%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1.C([Li])CCC.[O:18]1[CH2:22][CH2:21]OS1(=O)=O.Cl.O.[OH-].[Na+]>O1CCCC1.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:21][CH2:22][OH:18])[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1
Reactant: O=S1(=O)OCCO1
Reactant: FC(F)(F)c1cc(I)cc(Cl)n1
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: OCCc1cc(Cl)nc(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
2-Chloro-4-iodo-6-(trifluoromethyl)pyridine (0.50 g, 1.6 mmol, European Journal of Organic Chemistry, (18), 3793-3798, 2004) was dissolved in tetrahydrofuran (9.0 mL) and cooled to −78° C. 2.5 M n-Butyllithium in hexanes (0.98 mL, 2.4 mmol) was added dropwise. The reaction was stirred at −78° C. for 45 minutes, at which time 1,3,2-dioxathiolane 2,2-dioxide (0.24 g, 2.0 mmol, Aldrich) in Tetrahydrofuran (2.2 mL) was added. The mixture was then allowed to warm to ambient temperature and stir over 1.5 hours. 12.0 M hydrogen chloride in water (0.81 mL, 9.8 mmol) was added to the mixture and the reaction was stirred overnight. 1N NaOH was then added to achieve a pH between 8 and 9, and brine was also added. The product was extracted with EtOAc, and the organic layer was dried over sodium sulfate, filtered and concentrated. Flash chromatography using a 40 g silica gel cartridge, eluting with a gradient from 0-40% EtOAc in hexanes afforded product as a mixture of isomers, which contained about 50% of the desired isomer (0.09 g, 24%). LCMS (M+H)+: 226.0/228.1.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]([OH:13])=O)[CH:6]=[CH:7][CH:8]=1.[C:16]([O:20][C:21](=[O:33])[NH:22][C:23]1[CH:28]=[C:27]([C:29]([NH:31][NH2:32])=[O:30])[CH:26]=[CH:25][N:24]=1)([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21](=[O:33])[NH:22][C:23]1[CH:28]=[C:27]([C:29]([NH:31][NH:32][C:11](=[O:13])[CH2:10][CH2:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:15])[F:14])[CH:4]=2)=[O:30])[CH:26]=[CH:25][N:24]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: O=C(O)CCc1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(C(=O)NN)ccn1
Product: CC(C)(C)OC(=O)Nc1cc(C(=O)NNC(=O)CCc2cccc(C(F)(F)F)c2)ccn1
Yield: 80 %

Procedure:
In the same manner as in Reference Example 1 and using 3-[3-(trifluoromethyl)phenyl]propionic acid instead of benzothiazole-6-carboxylic acid and tert-butyl[4-(hydrazinocarbonyl)-2-pyridyl]carbamate instead of tert-butyl carbazate, the title compound (yield 80%) was obtained as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[CH3:19]N(CN(C)C)C.C(OC(=O)C)(=O)C.O>CS(C)=O>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11](=[CH2:19])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: CN(C)CN(C)C
Reactant: CC(C)(C)OC(=O)Cc1ccc([N+](=O)[O-])cc1F
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: C=C(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])cc1F
Reaction time: 0.5 h

Procedure:
To a solution of t-butyl 2-fluoro-4-nitrophenylacetate (11.3 g) in dimethyl sulfoxide (70 mL) was added bis(dimethylamino)methane (6.80 g) and acetic anhydride (14.9 g) at room temperature, and the mixture was stirred at the same temperature for 30 min. The mixture was poured to water, and the mixture was extracted with toluene. The organic extracts were washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. Flash chromatography (silica, hexane:ethyl acetate=9:1) of the residue gave t-butyl 2-(2-fluoro-4-nitrophenyl)acrylate. To a solution of the above t-butyl 2-(2-fluoro-4-nitrophenyl)acrylate and trimethylsulfoxonium iodide (11.7 g) in dimethyl sulfoxide (70 mL) was added potassium t-butoxide (5.96 g) at room temperature, and the mixture was stirred at the same temperature for 1 hour. After quenching the reaction by the addition of 5% hydrochloric acid, the mixture was extracted with ethyl acetate. The organic extracts were washed with 3% sodium thiosulfate solution and brine, dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. Flash chromatography (silica, hexane:ethyl acetate=9:1) of the residue gave t-butyl 1-(2-fluoro-4-nitrophenyl)cyclopropane-1-carboxylate. MS (EI+) m/z: 281 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:42])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH2:31][CH3:32])([C:27]([O:29]C)=[O:28])[CH2:25][CH3:26])[CH2:14][C:13](=[O:33])[NH:12][CH:11]3[C:34]3[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=3[CH3:41])[C:5]2=[CH:4][CH:3]=1.O[Li].O.O>CO>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:42])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH2:31][CH3:32])([C:27]([OH:29])=[O:28])[CH2:25][CH3:26])[CH2:14][C:13](=[O:33])[NH:12][CH:11]3[C:34]3[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=3[CH3:41])[C:5]2=[CH:4][CH:3]=1
Reactant: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)OC
Agent: [Li]O
Solvent: O
Solvent: CO
Product: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)O
Temperature: 25 °C
Yield: 28.8 %

Procedure:
A mixture of racemic (2′S, 3S, 4′R)-6-chloro-4′-[5-chloro-2-(1-ethyl-1-methoxycarbonyl-propoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (200 mg, 0.33 mmol), LiOH.H2O (69 mg, 1.16 mmol), H2O (2 mL) and methanol (20 mL) was refluxed for 2 h. After cooled to room temperature, the solution was concentrated and the residue was acidified to “pH” 2-3 by addition of concentrated HCl solution. The precipitate was collected by filtration to give the title compound as a white solid (57 mg).
Reaction SMILES: [C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][C:4]([C:7]2[O:8][C:9]([CH3:25])=[C:10]([CH2:12][CH2:13][O:14]S(C3C=CC(C)=CC=3)(=O)=O)[N:11]=2)=[CH:3][CH:2]=1.C([O:34][C:35](=[O:55])[C:36]([CH3:54])([O:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH2:37][C:38]1[CH:43]=[CH:42][C:41](O)=[C:40]([O:45][CH3:46])[CH:39]=1)C>C(O)C>[C:1]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:2]=[CH:3][C:4]([C:7]2[O:8][C:9]([CH3:25])=[C:10]([CH2:12][CH2:13][O:14][C:41]3[CH:42]=[CH:43][C:38]([CH2:37][C:36]([CH3:54])([O:47][C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)[C:35]([OH:55])=[O:34])=[CH:39][C:40]=3[O:45][CH3:46])[N:11]=2)=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)c(OC)c1)Oc1ccccc1
Solvent: CCO
Product: COc1cc(CC(C)(Oc2ccccc2)C(=O)O)ccc1OCCc1nc(-c2ccc(-c3ccccc3)cc2)oc1C
Temperature: 55 °C

Procedure:
Toluene-4-sulfonic acid 2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethyl ester (0.132 mmol) (see Ex. 1, Part I) was added to a one dram, screw-cap vial and diluted with ethanol (0.5 mL). To this solution are added 3-(4-hydroxy-3-methoxyphenyl)-2-methyl-2-phenoxypropionic acid ethyl ester (0.5 mL of a 0.264 M solution in ethanol, 0.132 mmol) and polystyrene bound 1,5,7-triazabicyclo[4.4.0]dec-5-ene (100–125 mg, 2.6 mmol/g) and the vial was tightly closed. The reaction vessel was heated in a block heater for 24–48 h at 55° C., or until TLC or MS analysis indicates the disappearance of starting materials. The suspension was filtered while warm and the residue washed with ethanol (1 mL). The solution was treated with aqueous NaOH (5N solution, 100 μl) and the vial resealed tightly. The solution was heated in a block heater at 55° C. for 3–16 h, or until MS analysis indicates the completion of the hydrolysis. The solvents are removed with a stream of nitrogen or under reduced pressure and the residue redissolved in 1 mL water. The solution was acidified with aqueous HCl (5N solution, 150 μl), often causing precipitation of product. The suspension was diluted with dichloromethane (3 mL) and the resultant biphasic solution was filtered through a Chrom-Elut column to remove water. The filtrate was concentrated in vacuo and the resultant residue was purified by mass directed HPLC to provide analytically pure material. MS (EI) 564.4 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:33][CH2:34][CH3:35])[CH:27]=4)[CH2:23][CH2:22][C:21]([C:36]([O:38]C)=[O:37])=[CH:20][C:19]=3[CH:40]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O.Cl>O1CCCC1.CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:33][CH2:34][CH3:35])[CH:27]=4)[CH2:23][CH2:22][C:21]([C:36]([OH:38])=[O:37])=[CH:20][C:19]=3[CH:40]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2cccc(OCCC)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2cccc(OCCC)c2)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 76.7 %

Procedure:
To a solution of methyl 7-(4-butoxyethoxyphenyl)-1-(3-propoxybenzyl)-2,3-dihydro-1-benzazepine-4-carboxylate (412 mg) in a mixture of tetrahydrofuran (24 ml) and methanol (24 ml) was added 1N sodium hydroxide solution (8 ml), and the mixture was stirred at room temperature for 4 days. Then, to the mixture was added water at 0° C., and 1N hydrochloric acid was further added to make acidic (pH=4), and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, which was recrystallized from hexane-ethyl acetate to give 7-(4-butoxyethoxyphenyl)-1-(3-propoxybenzyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (308 mg) as yellow crystals.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([OH:15])[C:6]=1[C:16]1[C:17]([OH:30])=[CH:18][C:19]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:20][C:21]=1[C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:4])([CH3:3])[CH3:2].C1(O)C=CC(C2C=CC([OH:43])=CC=2)=CC=1>>[C:1]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:10]=1[OH:43])([CH3:4])([CH3:3])[CH3:2].[C:22]([C:21]1[CH:20]=[C:19]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:18]=[C:17]([OH:30])[C:16]=1[C:6]1[C:7]([OH:15])=[CH:8][C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:10][C:5]=1[C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:23])([CH3:24])[CH3:25]
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Agent: CC(C)(C)c1cc(O)c(-c2c(O)cc(C(C)(C)C)cc2C(C)(C)C)c(C(C)(C)C)c1
Product: CC(C)(C)c1cccc(C(C)(C)C)c1O

Procedure:
In the production of 3,3',5,5'-tetra-t-butylbiphenol, which is an intermediate of 4,4'biphenol, from 2,6-di-t-butylphenol as a starting material, the second process for producing 3,3',5,5'-tetra-t-butylbiphenol according to the present invention enables obtaining 3,3',5,5'-tetra-t-butylbiphenol in high yield with the full utilization of 2,6-di-t-butylphenol charged in the reaction vessel without detriment to the selectivity of 3,3',5,5'-tetra-t-butylbiphenol. Although the average degree of oxidation of 2,6-di-t-butylphenol is in the range of about 70 to 80 mol % in the conventional process for producing 3,3',5,5'-tetra-t-butylbiphenol, the degree of oxidation of 2,6-di-t-butylphenol can be as high as, for example, 95 mol % in the second process for producing 3,3',5,5'-tetra-t-butylbiphenol according to the present invention.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7](=[N:14][O:15][CH2:16][C:17]1[N:22]=[C:21]([NH2:23])[CH:20]=[CH:19][N:18]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[CH:31]1([C:34](Cl)=[O:35])[CH2:33][CH2:32]1>ClCCl>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7](=[N:14][O:15][CH2:16][C:17]1[N:22]=[C:21]([NH:23][C:34]([CH:31]2[CH2:33][CH2:32]2)=[O:35])[CH:20]=[CH:19][N:18]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Cn1ccnc1C(=NOCc1nccc(N)n1)c1ccccc1
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1ccnc1C(=NOCc1nccc(NC(=O)C2CC2)n1)c1ccccc1
Yield: 7 %

Procedure:
A solution of 2-[({[(1-methyl-1H-imidazol-2-yl)(phenyl)methylene]amino}oxy)methyl]pyrimidin-4-amine (200 mg, 0.64 mmol), triethylamine (0.18 mL, 1.29 mmol), cyclopropanecarboxylic acid chloride (136 mg, 1.29 mmol) in dichloromethane (10 mL) was stirred 6 h30 at room temperature. After dilution with water (50 mL), the layers were separated and the aqueous layer further extracted with dichloromethane (30 mL). The combined organic layers were dried over MgSO4 and the solvents removed in vacuo. Purification on silica gel afforded N-{2-[({[(1-methyl-1 H-imidazol-2-yl)(phenyl)methylene]amino}oxy)methyl]pyrimidin-4-yl}cyclopropanecarboxamide as an oil [19 mg, yield 7%; HPLC/MS: m/z=377 (M+H); log P(HCOOH)=1.50].
Reaction SMILES: [CH:1](=[C:8]1/[N:9]=[C:10]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])[NH:11][C:12]/1=[O:13])/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27](/[CH:30]=[CH:31]/[CH:32]=[O:33])=[CH:26][CH:25]=1>>[F:21][C:15]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=1[C:10]1[NH:11][C:12]2[O:13][C:32](=[O:33])[CH:31]([CH2:30][C:27]3[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)[CH:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:8]=2[N:9]=1
Reactant: O=C1NC(c2cc(F)ccc2F)=N/C1=C\c1ccccc1
Reactant: COc1ccc(/C=C/C=O)cc1
Product: COc1ccc(CC2C(=O)Oc3[nH]c(-c4cc(F)ccc4F)nc3C2c2ccccc2)cc1
Yield: 76 %

Procedure:
Prepared according to the general procedure using (Z)-4-benzylidene-2-(2,5-difluorophenyl)-1H-imidazol-5(4H)-one and (E)-3-(4-methoxyphenyl)acrylaldehyde. The unpurified residue was purified by flash chromatography using 15% EtOAc/hexanes to afford 9 as an off-white solid (102 mg, 76%). Analytical data for 9: 1H NMR (500 MHz, CDCl3) δ 9.38 (d, J=8.1 Hz, 1H), 7.89 (ddd, J=9.2, 6.1, 3.2 Hz, 1H), 7.39-7.29 (m, 3H), 7.10-6.93 (m, 6H), 6.88-6.83 (m, 2H), 4.09 (d, J=6.8 Hz, 1H), 3.81 (s, 3H), 3.55 (ddd, J=10.1, 6.8, 4.6 Hz, 1H), 3.29 (dd, J=14.9, 4.6 Hz, 1H), 2.38 (dd, J=14.9, 10.1 Hz, 1H); 13C NMR (CDCl3, 126 MHz) δ 169.0, 159.1 (d, JCF=243.6 Hz), 158.4, 155.4 (d, JCF=241.1 Hz), 148.9, 137.1, 136.3, 130.0, 129.7, 129.2, 128.3, 128.0, 118.4 (dd, JCF=12.3, 9.5 Hz), 117.1 (dd, JCF=25.7, 8.7 Hz), 116.5 (dd, JCF=24.7, 9.5 Hz), 114.0, 114.5 (dd, JCF=26.8, 3.7 Hz), 111.0 (d, JCF=3.8 Hz), 55.3, 47.5, 38.3, 31.8; IR (film) cm−1 1772, 1617, 1528, 1513, 1481, 1464 1249, 1176, 1118, 1100, 1033, 766, 735, 700; LRMS (ESI): Mass calcd for [M+H]+ C26H21F2N2O3: 447.1. found 447.4; Enantiomeric ratio was measured by chiral phase HPLC (Chiralcel OD-H; 5% IPA/3% MeOH/hexanes 0.5 mL/min, 280 nm), Rt1 (major)=48.1, Rt2 (minor)=56.9 min; er=99:1.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:11][C@@H:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:19](=[O:21])[CH3:20].[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27](Cl)=[O:28].N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:19]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C@H:10]([N:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:27]([C:23]2[O:22][CH:26]=[CH:25][CH:24]=2)=[O:28])[CH2:11][C@@H:2]1[CH3:1])(=[O:21])[CH3:20]
Reactant: O=C(Cl)c1ccco1
Reactant: CC(=O)N1c2ccccc2[C@H](Nc2ccccc2)C[C@@H]1C
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(=O)N1c2ccccc2[C@H](N(C(=O)c2ccco2)c2ccccc2)C[C@@H]1C
Temperature: 90 °C
Yield: 40 %

Procedure:
A round bottom flask under nitrogen atmosphere was charged with cis-1-(2-methyl-4-phenylamino-3,4-dihydro-2H-quinolin-1-yl)-ethanone (0.163 g, 0.58 mmol, 1.0 equiv) and 2-furoyl chloride (0.285 mL, 2.9 mmol, 5.0 equ), pyridine (1.0 equiv.) and dry toluene (3 mL). The solution was heated to 90° C. for 15 h. The reaction mixture was evaporated in vacuo. The residue was purified by Biotage flash system (50% hexane/50% ethyl acetate) to yield the cis isomer 40% yield.