Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH3:8])[C:6]2[CH:9]=[C:10]([N:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]3=[O:20])[CH:11]=[CH:12][C:5]=2[N:4]=1)[CH3:2].[F:21][C:22]1[S:26][C:25]([CH2:27]O)=[CH:24][CH:23]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH2:1]([C:3]1[N:7]([CH3:8])[C:6]2[CH:9]=[C:10]([N:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:27][C:25]4[S:26][C:22]([F:21])=[CH:23][CH:24]=4)=[CH:15][C:14]3=[O:20])[CH:11]=[CH:12][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccc(-n3ccc(O)cc3=O)cc2n1C
Reactant: OCc1ccc(F)s1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCc1nc2ccc(-n3ccc(OCc4ccc(F)s4)cc3=O)cc2n1C
Temperature: 60 °C
Reaction time: 4 h
Yield: 6.9 %

Procedure:
To a solution of 1-(2-ethyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (224 mg), (5-fluorothiophen-2-yl)methanol (100 mg) and tributylphosphine (750 mg) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (956 mg), and the mixture was stirred at 60° C. for 4 h. The reaction mixture was concentrated in vacuo, and diluted with DCM. The mixture was washed with water and brine successively, dried over Na2SO4, concentrated in vacuo and purified by silica gel column chromatography (MeOH/DCM) followed by preparative HPLC to afford the title compound (20 mg) as a white solid.
Reaction SMILES: C([O:4][CH2:5][CH2:6][C@@H:7]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.C(Cl)(Cl)Cl>[OH:4][CH2:5][CH2:6][C@@H:7]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]1
Reactant: CC(=O)OCC[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CC[C@@H](CCO)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 101.9 %

Procedure:
To a solution of 34 mg of t-butyl (3S)-3-(2-acetyloxyethyl)-pyrrolidine-1-carboxylate in 1 ml of methanol, 54 mg of potassium carbonate was added, and stirred for 2.5 hours at room temperature. The reaction liquid was diluted with chloroform, washed successively with water and saturated brine and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, 29 mg of the title compound was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH2:9][C:10]1[C:18]([CH3:19])=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][C:11]=1[CH2:20][CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=[N:28]C=2C=1.CCN=C=NCCCN(C)C.Cl.N>C(O)(C)C.C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[CH2:8][CH2:9][C:10]1[C:18]([CH3:19])=[CH:17][C:13]([C:14](=[O:15])[NH2:28])=[CH:12][C:11]=1[CH2:20][CH3:21])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1cc(C(=O)O)cc(C)c1CCC(=O)OC(C)(C)C
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CC(C)O
Solvent: ClCCl
Product: CCc1cc(C(N)=O)cc(C)c1CCC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a solution of 4-(2-tert-butoxycarbonyl-ethyl)-3-ethyl-5-methyl-benzoic acid (36.0 g, 123 mmol) in isopropanol (400 mL), HOBT (18.3 g, 135 mmol) followed by EDC HCl (27.1 g, 142 mmol) is added. The mixture is stirred at rt for 1 h before aq. ammonia (69 mL of 25% solution) is added. Stirring is continued for 1 h before the mixture is diluted with DCM (500 mL) and washed with half sat. aq. NaHCO3 solution (3×400 mL), followed by water (400 mL). The org. extract is dried over MgSO4, filtered and concentrated. The crude product is trituated with TBME 8250 mL). The solid material is collected, washed with additional TBME (50 mL) and dried under high vacuum to give 3-(4-carbamoyl-2-ethyl-6-methyl-phenyl)-propionic acid tert-butyl ester (31.91 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22](F)=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1.[N:31]1([CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH2:35][CH2:34][CH2:33][CH2:32]1>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([N:39]4[CH2:40][CH2:41][CH:36]([N:31]5[CH2:35][CH2:34][CH2:33][CH2:32]5)[CH2:37][CH2:38]4)=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: COc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1F
Solvent: CN1CCCC1=O
Product: COc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1N1CCC(N2CCCC2)CC1
Temperature: 105 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
A mixture of 150 mg (0.34 mmol) of 4-[3-chloro-4-(1-methyl-1H-imidazole-2-ylsulfanyl)-phenylamino]-7-fluoro-6-methoxyquinoline-3-carbonitrile and 316 mg (2.05 mmol) of 4-pyrrolidin-1-yl-piperidine in 1 mL of 1-methyl-2-pyrrolidinone is heated at 105° C. for 16 hours. The solvents are removed in vacuo. A 10 mL portion of water is added to the residue, from which a tan solid is precipitated out. The solid is filtered off and washed with water. After drying in vacuo, the solid is suspended in ethyl acetate and stirred for 1 hour. The solid is filtered off, washed with ethyl acetate and dried in vacuo to provide 140 mg of 4-[3-chloro-4-(1-methyl-1H-imidazole-2-ylsulfanyl)-phenylamino]-6-methoxy-7-(4-pyrrolidin-1-yl-piperidin-1-yl)quinoline-3-carbonitrile as a yellow solid, mp 225-229° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([C@@H:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[C:21]([O:23]C)=[O:22])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[F:25][C:26]1[CH:27]=[CH:28][C:29]2[O:33][C:32](S(C)(=O)=O)=[N:31][C:30]=2[CH:38]=1.[OH-].[Na+].Cl>ClC(Cl)C.CO>[F:25][C:26]1[CH:27]=[CH:28][C:29]2[O:33][C:32]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:8]4[CH:13]=[CH:12][C:11]([C:14]([CH:16]5[CH2:20][CH2:19][CH2:18][CH:17]5[C:21]([OH:23])=[O:22])=[O:15])=[CH:10][CH:9]=4)=[CH:6][CH:7]=3)=[N:31][C:30]=2[CH:38]=1
Reactant: COC(=O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(N)cc2)cc1
Reactant: CS(=O)(=O)c1nc2cc(F)ccc2o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: CO
Product: O=C(O)C1CCCC1C(=O)c1ccc(-c2ccc(Nc3nc4cc(F)ccc4o3)cc2)cc1
Temperature: 85 °C
Yield: 31.7 %

Procedure:
To a solution of methyl trans-2-[(4′-amino-1,1′-biphenyl-4-yl)carbonyl]cyclopentane-carboxylate (100 mg, 0.31 mmol) in dichloroethane (3 mL), 5-fluoro-2-(methylsulfonyl)-1,3-benzoxazole (80 mg, 0.37 mmol) was added and the mixture was heated at 85° C. overnight. The solvent was removed by rotary evaporation, and the residue was redissolved in DMF (5 mL). A solution of 1 N aqueous NaOH (0.93 mL, 0.93 mmol) was added and the mixture was heated at 65° C. overnight. A solution of 1 N aqueous HCl (0.31 mL, 0.31 mmol) and methanol (5 mL) were added to the reaction mixture, and the crude product was purified by preparative reverse-phase HPLC (water/acetonitrile gradient, containing 0.1% TFA) to afford 2-({4′-[(5-fluoro-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentanecarboxylic acid as a white solid (43.7 mg, 31.4%). 1H NMR (300 MHz, DMSO-d6) δ 8.05 (d, 2H), 7.90-7.80 (m, 6H), 7.50 (m, 1H), 7.30 (m, 1H), 6.95 (m, 1H), 4.05 (m, 1H), 3.20 (m, 1H), 2.20 (m, 1H), 1.95 (m, 1H), 1.80-1.60 (m, 4H); LC-MS ret. time 3.66 min (method 2), m/z 445.1 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:16](O)=[O:17]>O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:6]=[CH:5][C:4]=1[O:9][CH3:10])[C:16]([C:15]1[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:13]([O:12][CH3:11])[CH:14]=1)=[O:17]
Reactant: COc1ccc(C(=O)O)cc1OC
Reactant: COc1ccccc1OC
Solvent: O
Product: COc1ccc(C(=O)c2ccc(OC)c(OC)c2)cc1OC

Procedure:
Surprisingly, it has been found that when polyphosphoric acid is used as the catalyst, 1,2-dimethoxybenzene (veratrole) can be acylated directly using 3,4-dimethoxybenzoic acid (veratric acid). The advantages of this reaction are the ready availability of the starting materials coupled with a high yield and very simple product isolation. After water has been added, the 3,3',4,4'-tetramethoxybenzophenone can be isolated by simple filtration.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:30]=[CH:29][C:18]([CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[CH2:33](Br)[CH:34]=[CH2:35]>>[CH2:35]([N:21]([CH2:20][CH2:19][C:18]1[CH:29]=[CH:30][C:15]([C:12]2[N:13]=[CH:14][N:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:31])[F:32])=[CH:9][CH:8]=3)[N:11]=2)=[CH:16][CH:17]=1)[C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH:34]=[CH2:33]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)NCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Product: C=CCN(CCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)C(=O)OC(C)(C)C

Procedure:
The title compound was prepared as described in Example 102 using tert-butyl 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethylcarbamate (C50) and allyl bromide and isolated as a yellow oil (0.144 g, 99%): 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.15-8.08 (m, 2H), 7.85-7.76 (m, 2H), 7.39 (dq, J=7.8, 1.0 Hz, 2H), 7.30 (s, 2H), 5.76 (s, 1H), 5.12 (s, 2H), 3.76 (d, J=45.8 Hz, 2H), 3.42 (s, 2H), 2.89 (d, J=0.7 Hz, 2H), 1.47 (s, 9H); 19F NMR (376 MHz, CDCl3) δ −58.03; ESIMS m/z 489 ([M+H]+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:9]=[CH:10][C:3]=12.[CH2:17]([Mg]Cl)[CH2:18][CH3:19]>>[C:11]1([N:8]2[C:4]3=[N:5][CH:6]=[CH:7][C:2]([CH2:17][CH2:18][CH3:19])=[C:3]3[CH:10]=[CH:9]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Clc1ccnc2c1ccn2-c1ccccc1
Reactant: CCC[Mg]Cl
Product: CCCc1ccnc2c1ccn2-c1ccccc1

Procedure:
The title compound was prepared from the compound of step 1 (4.69 g, 20.5 mmol) and propylmagnesium chloride analogously as described in example 42, step 1. Yield: 3.57 g.
Reaction SMILES: [C:1]1([S:7]([C:10]#[N:11])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]1([CH3:18])[CH:17]=CC=[CH:14][CH:13]=1.B(OCCCC)(OCCCC)OCCCC>C(O)CCC>[C:1]1([S:7]([C:10]2[CH:14]=[CH:13][C:12]([CH3:18])=[CH:17][N:11]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CS(=O)(=O)c1ccccc1
Reactant: Cc1ccccc1
Agent: CCCCOB(OCCCC)OCCCC
Solvent: CCCCO
Product: Cc1ccc(S(=O)(=O)c2ccccc2)nc1
Temperature: 119 °C
Yield: 72 %

Procedure:
First, 9.00 g (107 mmol) of tiglic aldehyde and 8.35 g (50.0 mmol) of benzenesulfonyl cyanide were introduced to the same reaction vessel as in Example 1. Toluene (15 ml) as the solvent and butanol (1.5 ml) were added, and 0.57 g (2.48 mmoles) of tributyl borate were added. Then the mixture was heated under reflux for 7 hours while agitating at an internal temperature of 119° C. in a nitrogen atmosphere, separating and removing water that was produced. After this solution was cooled to room temperature, the low-boiling components, such as solvent, etc., were removed under reduced pressure and the resulting concentrate was cooled in an ice bath to precipitate crystals. The crystals were filtered with a glass filter and washed with 10 ml of toluene that had been cooled to 5° C. or lower. Then the crystals were dried for 2 hours in vacuo to give 8.50 g of 2-benzenesulfonyl-5-methylpyridine as colorless crystals (purity of 99%, yield of 72% based on benzenesulfonyl cyanide).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[C@@:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)([CH3:15])[C@@:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)([CH3:23])[N:12]=[C:11]2[C:31]2[CH:32]=[N:33][C:34]([C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:35][C:36]=2[O:37][CH2:38][CH3:39])=[O:9])[CH2:4][CH2:3]1.[CH:44]([N:47]=[C:48]=[O:49])([CH3:46])[CH3:45]>>[C:40]([C:34]1[N:33]=[CH:32][C:31]([C:11]2[N:10]([C:8]([N:5]3[CH2:4][CH2:3][CH:2]([NH:1][C:48]([NH:47][CH:44]([CH3:46])[CH3:45])=[O:49])[CH2:7][CH2:6]3)=[O:9])[C@@:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)([CH3:15])[C@@:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)([CH3:23])[N:12]=2)=[C:36]([O:37][CH2:38][CH3:39])[CH:35]=1)([CH3:42])([CH3:41])[CH3:43]
Reactant: CC(C)N=C=O
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(NC(=O)NC(C)C)CC1

Procedure:
In a manner similar to the method described in example 160, (4-Amino-piperidin-1-yl)-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazol-1-yl]-methanone (example 204) was reacted with isopropyl isocyanate (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C38H49Cl2N6O3 [(M+H)+] 707.3238, observed 707.3236
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C:13]2[S:14][C:15]([C:19]([OH:21])=O)=[C:16]([CH3:18])[N:17]=2)[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=CC=1.C1(CCN2CCN(C3SC(C(O)=O)=C(C)N=3)C2=O)CC1.[F:43][C:44]1[CH:51]=[CH:50][C:47]([CH2:48][NH2:49])=[CH:46][CH:45]=1>>[CH:7]1([CH2:2][CH2:1][N:8]2[CH2:12][CH2:11][N:10]([C:13]3[S:14][C:15]([C:19]([NH:49][CH2:48][C:47]4[CH:50]=[CH:51][C:44]([F:43])=[CH:45][CH:46]=4)=[O:21])=[C:16]([CH3:18])[N:17]=3)[C:9]2=[O:22])[CH2:6][CH2:5]1
Reactant: NCc1ccc(F)cc1
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Agent: Cc1nc(N2CCN(CCC3CC3)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(CCC3CC3)C2=O)sc1C(=O)NCc1ccc(F)cc1
Yield: 34 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(2-cyclopropylethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with 4-fluorobenzylamine in place of benzylamine, the title compound was obtained as a white powder in 34% yield: mp 122-123° C.; 1H NMR (300 MHz, CDCl3) δ 7.27-7.23 (m, 2H), 7.00-6.94 (m, 2H), 5.98 (s, 1H), 4.48 (d, J=5.7 Hz, 2H), 4.05 (t, J=7.8 Hz, 2H), 3.56 (t, J=8.7 Hz, 2H), 3.35 (t, J=7.8 Hz, 2H), 2.57 (s, 3H), 1.47-1.40 (m, 2H), 0.67-0.56 (m, 1H), 0.46-0.37 (m, 2H), 0.06-0.01 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 163.8, 162.5, 157.4, 155.3, 153.2, 133.9, 129.5, 116.8, 115.6, 44.0, 43.2, 42.7, 42.0, 32.4, 17.2, 8.4, 4.3; MS (ES+) m/z 403.2 (M+1).
Reaction SMILES: [N:1]1[N:2]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH2:17]Cl)[C:11]=2[OH:19])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH2:20]([CH:22]([CH2:26][CH2:27][CH2:28][CH3:29])[C:23]([OH:25])=[O:24])[CH3:21].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[N:1]1[N:2]([C:10]2[C:11]([OH:19])=[C:12]([CH:13]=[C:14]([CH3:16])[CH:15]=2)[CH2:17][O:25][C:23](=[O:24])[CH:22]([CH2:20][CH3:21])[CH2:26][CH2:27][CH2:28][CH3:29])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CCCCC(CC)C(=O)O
Reactant: Cc1cc(CCl)c(O)c(-n2nc3ccccc3n2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCC(CC)C(=O)OCc1cc(C)cc(-n2nc3ccccc3n2)c1O
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
2-(2H-Benzotriazol-2-yl)-6-chloromethyl-4-methyl-phenol (10.0 g, 33 mmol) is suspended in a mixture of 2-ethylhexanoic acid (11.9 g, 82 mmol) and tetrahydrofuran (75 g) and stirred at 70° C. for 30 minutes. Sodium carbonate (10.5 g, 99 mmol) is added. The reaction mixture is stirred at 60° C. for 15 minutes and evaporated to dryness. The residue is dissolved in ethyl acetate and extracted with an aqueous potassium carbonate solution (10%) and brine. The organic layer is dried over sodium sulphate, filtered and evaporated to dryness. The crude product is purified by column chromatography (ethyl acetate/heptane 1:12) to yield 11.2 g of 2-Ethyl-hexanoic acid 3-(2H-benzotriazol-2-yl)-2-hydroxy-5-methyl-benzyl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:24])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=3)[S:17][C:10]=12.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][C:33]([N:35]=[C:36]=[S:37])=[O:34].[ClH:38]>C1COCC1.CO>[ClH:38].[ClH:38].[F:1][C:2]1[CH:3]=[C:4]([NH:24][C:36]([NH:35][C:33](=[O:34])[CH2:32][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[F:25])=[S:37])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=3)[S:17][C:10]=12
Reactant: O=C(Cc1ccccc1F)N=C=S
Reactant: Cn1ccnc1-c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: Cn1ccnc1-c1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4F)cc3F)c2s1
Reaction time: 1 h
Yield: 45 %

Procedure:
A mixture of aniline 219 (100 mg, 0.29 mmol, scheme 47) and 2-(2-fluorophenyl)acetyl isothiocyanate (115 mg, 0.58 mmol) in THF (3 mL) was stirred for 1 hour, loaded directly onto a column containing silica gel and eluted sequentially with EtOAc and EtOAc/MeOH (100:1), to produce a white solid. This material was suspended in MeOH (5 mL) and HCl (1.0M in ether, 1 mL) was added to form a clear solution that was evaporated to dryness. The residue was washed with ether, suspended in H2O, and lyophilized to afford the title compound (80 mg, 45% yield) as a yellowish solid. 1H-NMR (DMSO-d6) δ (ppm): 12.42(s, 1H), 11.88(s, 1H), 8.65(d. 1H, J=5.5 Hz), 8.20(s, 1H), 8.05(d, 1H, J=1.7 Hz), 7.74(s, 1H), 7.58-7.55(m, 3H) 7.39-7.32(m, 2H), 7.21-7.16(m, 2H), 6.82(d, 1H, J=5.5 Hz), 4.02(s, 3H), 3.93(s, 2H), MS (m/z): 536.2(M+H) (found).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([OH:21])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([O:29][C:30]1[CH:31]=[C:32]([CH2:44][NH:45][C:46]2[CH:51]=[CH:50][C:49]([CH:52]([CH3:54])[CH3:53])=[CH:48][CH:47]=2)[CH:33]=[CH:34][C:35]=1[O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:45]([CH2:44][C:32]1[CH:33]=[CH:34][C:35]([O:36][CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)=[C:30]([O:29][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:31]=1)[C:46]1[CH:47]=[CH:48][C:49]([CH:52]([CH3:53])[CH3:54])=[CH:50][CH:51]=1)=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1ccc(NCc2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)cc1
Reactant: O=C(O)C1CCCc2c(OCc3ccccc3)cccc21
Product: CC(C)c1ccc(N(Cc2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Yield: 65.8 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.94 g) and [(3,4-dibenzyloxyphenyl)methyl](4-isopropylphenyl)amine (2.5 g) as starting materials, 5-benzyloxy-N-[(3,4-dibenzyloxyphenyl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (2.64 g) was obtained. By the reaction and treatment in the same manner as in Example 17 using this compound, N-[(3,4-dihydroxyphenyl)methyl]-5-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.35 g) was obtained.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:20])=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Br:21]N1C(=O)CCC1=O>C(#N)C>[Br:21][C:16]1[C:17]([CH3:19])=[CH:18][C:13]2[O:12][CH2:11][CH:10]([C:7]3[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=3)[C:14]=2[C:15]=1[CH3:20]
Reactant: Cc1cc(C)c2c(c1)OCC2c1ccc(C(C)C)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Cc1cc2c(c(C)c1Br)C(c1ccc(C(C)C)cc1)CO2
Reaction time: 1 h
Yield: 82 %

Procedure:
To a solution of 3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran synthesized in Reference Example 15 (5.62 g, 21.1 mmol) in acetonitrile (60 mL) was added N-bromosuccinimide (3.76 g, 21.1 mmol) at 0° C., and the mixture was stirred at the same temperature for 1 hour. The solvent was distilled off under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain 5.95 g (yield 82%) of the title compound. Melting point: 90-91° C. (methanol).
Reaction SMILES: [C:1]1([C:7]2([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:11][C:10]3[CH:12]=[CH:13][C:14]([C:16](ON4C5C=CC=CC=5N=N4)=[O:17])=[CH:15][C:9]=3[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>C(#N)C>[C:1]1([C:7]2([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[O:11][C:10]3[CH:12]=[CH:13][C:14]([C:16]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)=[O:17])=[CH:15][C:9]=3[O:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(On1nnc2ccccc21)c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2
Reactant: C1COCCN1
Solvent: CC#N
Product: O=C(c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2)N1CCOCC1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a mixture of 1H-benzotriazol-1-yl 2,2-diphenyl-1,3-benzodioxole-5-carboxylate (300 mg, 0.689 mmol) in acetonitrile ( 2.0 mL) was added morpholine (100 mg, 1.15 mmol, 1.67 eq.) at 0° C. After 10 min, the cooling bath was removed and the reaction was stirred 3 h at 20° C. The reaction was partitioned between water and dichloromethane. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine and water and then dried in vacuo, affording the title compound (267 mg, quant.) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[CH2:6].C(O)(=[O:12])C.BrN1C(=O)CCC1=O.[OH-].[Na+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]2[CH2:6][O:12]2)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)O
Reactant: C=Cc1cccc(Cl)c1
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Clc1cccc(C2CO2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of m-chlorostyrene (5.70 g, 41.0 mmol) and acetic acid (2.33 mL, 40.9 mmol) in dioxane (33 ml) and H2O (78 ml) at 0° C. was added N-bromosuccinimide (8.02 g, 45.0 mmol) in three portions. The reaction was allowed to warm to R.T. After 4 hours, 2N NaOH (60 ml) was added and the reaction was allowed to stir at RT overnight. The reaction mixture was partitioned between water and EtOAc, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo to give 6.20 g of a slightly tinted oil which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][OH:25])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[CH3:34][S:35]([O:25][CH2:24][CH2:23][CH2:22][C@@:13]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[O:12][C:11](=[O:26])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1)(=[O:37])=[O:36]
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCOS(C)(=O)=O)(c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
To a solution of (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one (200 mg, 0.48 mmol) in CH2Cl2 (5 mL) was added Et3N (240 mg, 2.4 mmol) and methanesulfonyl chloride (164 mg, 1.4 mmol) at 0° C. The reaction solution was stirred at rt for 1 h. The reaction was quenched with H2O and the mixture was extracted with CH2Cl2. The organic phase was concentrated to give 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propyl methanesulfonate (234 mg, 98%), which was used for the next step without further purification.