Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:40])[CH2:7][C@H:8]([NH:23][C:24](=[O:39])[C@@H:25]([N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([NH:34][C:35](=[O:37])[CH3:36])[C:29]1=[O:38])[CH2:26][CH3:27])[C:9](=[O:22])[CH2:10][O:11][C:12]1[C:17]([F:18])=[C:16]([F:19])[CH:15]=[C:14]([F:20])[C:13]=1[F:21])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:35]([NH:34][C:30]1[C:29](=[O:38])[N:28]([C@@H:25]([CH2:26][CH3:27])[C:24]([NH:23][C@H:8]([C:9](=[O:22])[CH2:10][O:11][C:12]2[C:17]([F:18])=[C:16]([F:19])[CH:15]=[C:14]([F:20])[C:13]=2[F:21])[CH2:7][C:6]([OH:40])=[O:5])=[O:39])[CH:33]=[CH:32][CH:31]=1)(=[O:37])[CH3:36]
Reactant: CC[C@@H](C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)COc1c(F)c(F)cc(F)c1F)n1cccc(NC(C)=O)c1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)COc1c(F)c(F)cc(F)c1F)n1cccc(NC(C)=O)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
A solution of (S,S)-3-[2-(3-Acetylamino-2-oxo-2H-pyridin-1-yl)-butyrylamino]-4-oxo-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid tert-butyl ester (187 mg, 0.327 mmol) in dichloromethane (5 mL) was cooled to 0° C. Trifluoroacetic acid (5 ml) was added and the resulting mixture allowed to warm to room temperature and stir for 2 hours. The mixture was then concentrated under reduced pressure and the residue redissolved in dichloromethane. This process was repeated several times in order to remove excess trifluoroacetic acid. The resulting solid was slurried in diethyl ether, filtered and washed with more diethyl ether. The solid was then dried to constant weight under vacuum. This gave the title product as a white solid (138 mg, 82%); 1H NMR (400 MHz, d6-DMSO) δ 0.78 (3H, t), 1.87-2.13 (5H, m), 2.56-2.78 (2H, m), 4.62 (1H, m), 5.18-5.29 (2H, m), 5.40 (1H, m), 6.28 (1H, t), 7.37 (1H, d), 7.53-7.66 (1H, m), 8.17-8.21 (1H, m), 8.92 (1H, d), 9.21 (1H, s), 12.51 (1H, br s); 19F NMR (376 MHz, d6-DMSO, proton-decoupled) δ−156.9, −141.1; M+H 516.2, M−H 514.2.
Reaction SMILES: S(Cl)([Cl:3])=O.[N:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1>C(Cl)Cl>[N:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]([Cl:3])=[O:19])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1
Reactant: O=C(O)C1CCN(c2ccncc2)CC1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)C1CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (1.6 ml) was added dropwise to a stirred suspension of 1-(4-pyridyl)piperidine-4-carboxylic acid (2.17 g) in methylene chloride (30 ml) and the mixture was stirred at ambient temperature for 1 hour. The mixture was evaporated to give 1-(4-pyridyl)piperidine-4-carbonyl chloride which was used without further purification.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[C:10]3=[O:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:18](O)[CH2:19][OH:20].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[C:10]23[O:20][CH2:19][CH2:18][O:17]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: OCCO
Reactant: O=C1Nc2ccc(C3CCCCC3)cc2C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1Nc2ccc(C3CCCCC3)cc2C12OCCO2

Procedure:
5-Cyclohexyl-1H-indole-2,3-dione (1 equivalent), ethane-1,2-diol (5 equivalents) and p-toluenesulphonic acid (0.02 equivalents) in dry toluene were heated under reflux overnight with azeotropic removal of water. The reaction mixture was cooled, washed with saturated sodium bicarbonate solution, and then worked up in the usual manner to afford the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH3:16][NH:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]=[CH2:25])=[CH:20][N:19]=1.[OH-].[K+]>CN1C(=O)CCC1>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:25][CH2:24][C:21]3[CH:22]=[CH:23][C:18]([NH:17][CH3:16])=[N:19][CH:20]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=Cc1ccc(NC)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CNc1ccc(CCn2c3c(c4cc(C)ccc42)CN(C)CC3)cn1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole, N-methyl-5-vinylpyridin-2-amine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[C:11]([O:14][CH3:15])=[CH:10][N:9]([C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[CH:25][CH:24]=[N:23]3)=[CH:18][C:17]=2[F:27])[N:8]=1)=O.Cl.[F:30][C:31]([F:42])([F:41])[O:32][C:33]1[CH:34]=[C:35]([NH:39][NH2:40])[CH:36]=[CH:37][CH:38]=1.C(O)(C(F)(F)F)=O>C(O)C>[F:27][C:17]1[CH:18]=[C:19]([N:22]2[CH:26]=[CH:25][CH:24]=[N:23]2)[CH:20]=[CH:21][C:16]=1[N:9]1[CH:10]=[C:11]([O:14][CH3:15])[C:12](=[O:13])[C:7]([C:5]2[N:39]([C:35]3[CH:36]=[CH:37][CH:38]=[C:33]([O:32][C:31]([F:41])([F:42])[F:30])[CH:34]=3)[N:40]=[CH:3][CH:4]=2)=[N:8]1
Reactant: COc1cn(-c2ccc(-n3cccn3)cc2F)nc(C(=O)C=CN(C)C)c1=O
Reactant: NNc1cccc(OC(F)(F)F)c1
Agent: Cl
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(-c2ccc(-n3cccn3)cc2F)nc(-c2ccnn2-c2cccc(OC(F)(F)F)c2)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 35.9 %

Procedure:
To a suspension of 3-[3-(dimethylamino)prop-2-enoyl]-5-methoxy-1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]pyridazin-4(1H)-one (200 mg) in ethanol (2.0 mL) was added dropwise a solution of [3-(trifluoromethoxy)phenyl]hydrazine hydrochloride (139 mg) and TFA (0.2 mL) in ethanol (2.0 mL), and the mixture was so stirred at room temperature for 24 hr. To the reaction mixture was added an ethanol solution (0.3 ml) of [3-(trifluoromethoxy)phenyl]hydrazine hydrochloride (16.7 mg), and the mixture was stirred at room temperature for 24 hr. The precipitated solid was collected by filtration. The mother liquor was concentrated, and the precipitated solid was collected by filtration. The solid was combined with the previously obtained solid, and recrystallized from acetone/water to give the title compound (96.1 mg).
Reaction SMILES: [N+:1]([C:4]1[C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[C:15](OC(=O)C)(=[O:17])[CH3:16]>[Ni].C(O)(=O)C>[C:15]([NH:1][C:4]1[C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1cccc2c1CCCCC2
Agent: [Ni]
Solvent: CC(=O)O
Product: CC(=O)Nc1cccc2c1CCCCC2

Procedure:
8.7 gm of 1-nitro-6,7,8,9-tetrahydro-5H-benzocycloheptene [J. Am. Chem. Soc., 5820 (9169)] was dissolved into a mixed solvent of 150 ml of acetic anhydride and 50 ml of acetic acid. The mixture was catalytically hydrogenated with the addition of 10 ml of raney nickel. After removing the catalyst by filtration, the reaction mixture was concentrated, the residue was washed with saturated aqueous solution of sodium bicarbonate and saturated brine, and dried over anhydrous sodium sulfate. The product was concentrated to produce 6.17.gm of the title compound.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([C:8]([F:11])([F:10])[F:9])[CH2:5][N:4]([C:12]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:13]=2[CH:14]=O)[CH2:3]1.[NH:23]1[C:30](=[O:31])[CH2:29][C:27](=[O:28])[NH:26][C:24]1=[O:25]>CO>[CH3:1][C@@H:2]1[C@H:3]2[C:29]3([CH2:14][C:13]4[C:12]([N:4]2[CH2:5][C@H:6]([C:8]([F:10])([F:9])[F:11])[O:7]1)=[CH:19][CH:18]=[C:17]([N+:20]([O-:22])=[O:21])[CH:16]=4)[C:27](=[O:28])[NH:26][C:24](=[O:25])[NH:23][C:30]3=[O:31]
Reactant: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2C=O)C[C@H](C(F)(F)F)O1
Reactant: O=C1CC(=O)NC(=O)N1
Solvent: CO
Product: C[C@H]1O[C@@H](C(F)(F)F)CN2c3ccc([N+](=O)[O-])cc3CC3(C(=O)NC(=O)NC3=O)[C@H]12
Temperature: 80 °C
Reaction time: 0.43 h

Procedure:
2-[cis-2-methyl-6-(trifluoromethyl)morpholin-4-yl]-5-nitrobenzaldehyde (212 mg, 0.67 mol) is combined with barbituric acid (95 mg, 0.67 mmol, Aldrich) in a vial with MeOH (3 mL). The sealed reaction is heated to 80° C. on a shaker block for 21 hours and then the solvent is removed by rotary evaporation. The product is purified on a Biotage Flash 25M+ using a 26 minute linear gradient of 2.5%–10% MTBE in CH2Cl2 eluent. The product is dried under vacuum yielding a yellow-orange solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.01, 2.93, 3.46, 3.66, 3.73, 4.04, 4.40, 4.48, 7.10, 7.88, 8.01, 11.63, 11.94.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27]([OH:29])=O)[CH:5]=[CH:6][CH:7]=1.[C:30]([C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1)([CH3:33])([CH3:32])[CH3:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:30]([C:34]1[CH:35]=[CH:36][C:37]([CH2:38][NH:39][C:27]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:12]([C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:25])([CH3:24])[CH3:26])[NH:10]2)=[O:29])=[CH:40][CH:41]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)c1ccc(CN)cc1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)NCc2ccc(C(C)(C)C)cc2)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Yield: 36.2 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example 1d was reacted with 4-tert-butylbenzylamine (48.98 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2Cl2 (2 mL) at rt overnight to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid 4-tert-butyl-benzylamide (41.8 mg, 36.25%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[O:24][CH:23]=[CH:22][C:5]=2[C:6](S(C(F)(F)F)(=O)=O)=[C:7]2[C:12]=1[O:11][C:10]([CH3:13])=[CH:9][C:8]2=[O:14].[Li][CH3:26]>[Zn](Br)Br.O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]2[O:24][CH:23]=[CH:22][C:5]=2[C:6]([CH3:26])=[C:7]2[C:12]=1[O:11][C:10]([CH3:13])=[CH:9][C:8]2=[O:14]
Reactant: [Li]C
Reactant: COc1c2occc2c(S(=O)(=O)C(F)(F)F)c2c(=O)cc(C)oc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Br[Zn]Br
Solvent: O
Product: COc1c2occc2c(C)c2c(=O)cc(C)oc12
Yield: 70 %

Procedure:
9-Methoxy-7-methyl-4-trifluoromethanesulfonyl-5H-furo[3,2-g]chromen-5-one (324 mg, 1.0 mmol), ZnBr2.H2O (1.04 g, 4.0 mmol), CuI (28 mg, 0.15 mmol), PdCl2(PPh3)2 (84 mg, 0.12 mmol) and MeLi (2.5 mL of 1.6 M in diethylether, 4.0 mmol) were treated as described under General Procedure D (Step 2) to afford the title compound (Yield 70%). 1H NMR (300 MHz, CDCl3): δ 2.38 (s, 3H, Me), 2.94 (s, 3H, Me), 4.21 (s, 3H, OMe), 6.05 (s, 1H), 6.91 (d, J=2.4, 1H), 7.65 (d, J=2.4, 1H). MS (ES) m/z: 244.9 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[CH2:12][CH2:11]1)[CH3:8])([CH3:4])([CH3:3])C.Cl.ClC(OC1C=[CH:32][C:31]([Cl:34])=[CH:30]C=1)=O>CO.O>[Cl:34][C:31]1[CH:32]=[CH:3][C:1]([O:5][C:6](=[O:22])[N:7]([CH2:9][C@H:10]2[CH2:11][CH2:12][C@H:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[CH2:14][CH2:15]2)[CH3:8])=[CH:4][CH:30]=1
Reactant: CN(C[C@H]1CC[C@H](OCCCCO)CC1)C(=O)OC(C)(C)C
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Agent: Cl
Solvent: O
Solvent: CO
Product: CN(C[C@H]1CC[C@H](OCCCCO)CC1)C(=O)Oc1ccc(Cl)cc1

Procedure:
In analogy to the sequence described in examples 1.5 and 1.7, trans-[4-(4-hydroxy-butoxy)-cyclohexylmethyl]-methyl-carbamic acid tert-butyl ester was treated with hydrogen chloride solution in methanol/water followed by acylation with 4-chlorophenyl chloroformate giving trans-[4-(4-hydroxy-butoxy)-cyclohexylmethyl]-methyl-carbamic acid 4-chloro-phenyl ester as colorless viscous oil, MS: 370 (MH+, 1Cl).
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3].C([O:12][CH2:13][CH2:14]CC)(=O)C=C.C=CC1C=CC=CC=1.C(OO)(C)(C)C>O>[C:1]([O:6][CH2:7][CH:13]1[O:12][CH2:14]1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=CC(=O)OCCCC
Reactant: C=C(C)C(=O)OC
Agent: CC(C)(C)OO
Solvent: O
Solvent: C=Cc1ccccc1
Product: C=C(C)C(=O)OCC1CO1
Temperature: 70 °C

Procedure:
An amount of 1300 g of an aqueous latex of a core polymer mainly comprising a styrene-butadiene rubber (containing 420 g of styrene-butadiene rubber particles) as obtained using the procedure described in Example 2 was charged into a 3 L glass vessel followed by addition of 440 g of pure water and stirring at 70° C. while replacing the atmosphere inside the vessel with nitrogen. A monomer mixture composed of 60 g of methyl methacrylate, 10 g of butyl acrylate, 35 g of styrene and 0.4 g of t-butyl hydroperoxide as a monomer mixture that is not the shell forming monomers (A) was added thereto over the course of 120 minutes to carry out graft polymerization. Following completion of the addition of the monomer mixture, stirring was further continued for 2 hours to complete the reaction and obtain minute polymer particles (CS-2C) in the form of an aqueous latex. The polymerization conversion rate was 99%. As a result of measuring the particle size in the same manner as in Example 2 after diluting the minute polymer particles in the form of an aqueous latex with water, the measured particle size was 0.1 μm, and a sharp, monodisperse particle size distribution nearly similar to that of Example 2 was shown.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.CC1(C)[O:17][C:16](=O)[CH:15]=[C:14]([CH2:19][CH2:20][C@H:21]2[NH:24][C:23](=[O:25])[C@H:22]2[NH:26][C:27](=[O:35])[CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:13]1>C1(C)C=CC=CC=1>[O:13]=[C:14]([CH2:19][CH2:20][C@H:21]1[NH:24][C:23](=[O:25])[C@H:22]1[NH:26][C:27](=[O:35])[CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:15][C:16]([O:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:17]
Reactant: COc1ccc(CO)cc1
Reactant: CC1(C)OC(=O)C=C(CC[C@H]2NC(=O)[C@H]2NC(=O)Cc2ccccc2)O1
Solvent: Cc1ccccc1
Product: COc1ccc(COC(=O)CC(=O)CC[C@H]2NC(=O)[C@H]2NC(=O)Cc2ccccc2)cc1
Yield: 74 %

Procedure:
A solution of 4-methoxybenzyl alcohol (1.50 g, 10.87 mmol) in toluene (6 ml) was added to a solution of (3S,4R)-4-[(2,2-dimethyl-4H-1,3-dioxin-4-on-6-yl)ethyl]-3-phenylacetamidoazetidin-2-one (3.86 g, 10.78 mmol) and heated to reflux for 1.5 h. The reaction mixture was concentrated in vacuo and the residue triturated with toluene to give the title compound (3.50 g, 75%) as a crude product; νmax (CH2Cl2) 3412, 1772, 1747, 1717, 1684 and 1514 cm-1 ; δH (CDCl3) 1.63 (2H, m), 2.39 (2H, t, J7.0 Hz), 3.37 (2H, s), 3.58 (2H, s), 3.68 (1H, m), 3.81 (3H, s), 5.09 (2H, s), 5.18 (1H, m), 6.26 (1H, br.s, exch.), 6.63 (1H, d, J 7.9 Hz), 6.89 (2H, d, J 8.6 Hz) and 7.21-7.38 (7H, m); m/z (FAB, -ve ion, thioglycerol) 437 (M-H)-.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([O:9]C)=O.[CH2:11]([CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[CH2:11]([CH:18]1[CH2:23][CH2:22][N:21]([C:7]([CH:2]2[NH:1][C:5](=[O:6])[CH2:4][CH2:3]2)=[O:9])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: COC(=O)[C@@H]1CCC(=O)N1
Solvent: Cc1ccccc1
Product: O=C1CCC(C(=O)N2CCC(Cc3ccccc3)CC2)N1
Reaction time: 24 h
Yield: 83.7 %

Procedure:
Methyl pyroglutamate (4.3 g) and 7.9 g of 4-benzylpiperidine were dissolved in 20 ml of toluene and the mixture was heated to reflux with stirring for 24 hours. The reaction solution was treated with a silica gel column chromatography to give 7.2 g of the product which was recrystallized from diethyl ether to afford 6.5 g of desired product, m.p. 160°-161° C.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:17][O:18][C:19]1[CH:29]=[CH:28][C:22]([O:23][CH2:24][CH2:25][CH2:26][NH2:27])=[CH:21][CH:20]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>ClCCCl>[CH3:17][O:18][C:19]1[CH:29]=[CH:28][C:22]([O:23][CH2:24][CH2:25][CH2:26][NH:27][CH2:12][C:11]2[CH:14]=[CH:15][CH:16]=[C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:10]=2)=[CH:21][CH:20]=1
Reactant: COc1ccc(OCCCN)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1ccc(OCCCNCc2cccc(O[Si](C)(C)C(C)(C)C)c2)cc1
Reaction time: 8 h

Procedure:
3-tert-Butyldimethylsilyloxybenzaldehyde (1.5 g, 6.34 mmol) was dissolved in 1,2-dichloroethane (10.0 mL). Subsequently, 3-(4-methoxyphenoxy)propylamine (1.5 g, 8.25 mmol) was added thereto, and the resultant mixture was stirred for 20 minutes. At room temperature, sodium triacetoxyborohydride (1.75 g, 8.25 mmol) and acetic acid (495 mg, 8.25 mmol) were added thereto, and the mixture was stirred overnight. A saturated aqueous sodium hydrogencarbonate solution was added thereto. The reaction mixture was extracted with chloroform, and the organic layer was washed with brine. The resultant mixture was subjected to drying over anhydrous sodium sulfate, concentration under reduced pressure, and purification by silica gel chromatography (chloroform/methanol=50/1), whereby the target compound was obtained (1.9 g, 78%).
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH2:19][C:20]([F:23])([F:22])[F:21])[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.Br[C:27]1C=CC2C3N=C(C(N)=O)SC=3CCOC=2C=1.FC(F)(F)C(NN)C>>[Br:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH:19]([CH3:27])[C:20]([F:23])([F:21])[F:22])[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1
Reactant: NC(=O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: FC(F)(F)Cn1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Agent: CC(NN)C(F)(F)F
Product: CC(n1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2)C(F)(F)F

Procedure:
Following the procedure for 8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene, 8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide 25 was reacted with (2,2,2-Trifluoro-1-methyl-ethyl)-hydrazine to give 8-Bromo-2-[2-(2,2,2-trifluoro-1-methyl-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene. MS(ESI+) 445.0/447.0.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.I[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][C:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37](=[O:44])[C:36](=[O:45])[CH:35]=1>CN(C=O)C>[C:1]1([O:7][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:37](=[O:44])[C:36](=[O:45])[CH:35]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: O=C1C=C(OCCCCCCI)c2ccccc2C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C1C=C(OCCCCCCOc2ccccc2)c2ccccc2C1=O
Reaction time: 48 h
Yield: 42.8 %

Procedure:
Phenol (28 mg, 0.3 mmol) was treated with tetrabutylammonium hydroxide (0.3 mL of 1.0 M solution in methanol) and the reaction mixture was concentrated to dryness in vacuo. Iodonaphtoquinone 5 (115 mg, 0.3 mmol) in DMF (3 mL) was added to the tetrabutylammonium salt, stirred for 48 h and quenched with H2O (10 mL). The product was extracted with CHCl3, the extract was washed with H2O, then brine, dried (Na2SO4), and purified by chromatography (5% EtOAc in benzene) to give 12 as a yellow solid (45 mg, 43%) 1H NMR (CDCl3) 8.13 (d, J=7.4 Hz, 1H), 7.86 (d, J=7.4 Hz, 1H), 7.67 (t, J=7.6 Hz, 1H), 7.61 (t, J=7.5 Hz, 1H), 7.15-7.40 (m, 2H), 6.85-7.10 (m, 3H), 5.96 (s, 1H), 4.17 (t, J=6.5 Hz, 2H), 3.99 (t, J=6.2 Hz), 1.70-2.10 (m, 4H), 1.35-1.70 (m, 4H).
Reaction SMILES: C[C:2](C)(C)[C@H:3]([NH:8][C:9]([N:11]1[C:19]2[CH2:18][CH2:17][N:16]([CH3:20])[CH2:15][C:14]=2[C:13]([C:21]2[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:22]=2F)=[N:12]1)=[O:10])[C:4](NC)=O.F[C:33]1C=C(C2C3CN(C(OC(C)(C)C)=O)CCC=3NN=2)C=CC=1F.C(N)(C)(C)C>>[C:3]([NH:8][C:9]([N:11]1[C:19]2[CH2:18][CH2:17][N:16]([CH3:20])[CH2:15][C:14]=2[C:13]([C:21]2[CH:22]=[CH:23][C:24]([F:28])=[C:25]([F:27])[CH:26]=2)=[N:12]1)=[O:10])([CH3:33])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(F)c(F)c3)c2C1
Reactant: CNC(=O)[C@@H](NC(=O)n1nc(-c2cc(F)c(F)cc2F)c2c1CCN(C)C2)C(C)(C)C
Solvent: CC(C)(C)N
Product: CN1CCc2c(c(-c3ccc(F)c(F)c3)nn2C(=O)NC(C)(C)C)C1

Procedure:
Compound 46 was prepared according to the procedure described for the synthesis of compound 37 by replacing intermediate 19 with intermediate 15, and replacing tert-leucine methylamide with tert-butylamine. 1H NMR (CDCl3) δ 7.47-7.52 (m, 1H), 7.21-7.31 (m, 2H), 4.06 (s, 2H), 3.43 (t, J=6.1 Hz, 2H), 3.20 (t, J=6.1 Hz, 2H0, 2.75 (3H), 1.48 (s, 9H). LCMS (+ESI) m/z=349.2 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:14][C:15]([F:18])([F:17])[F:16])[C:5](=O)[O:6]C1C=CC=CC=1.[NH2:19][NH2:20].O>C(O)C>[NH2:19][N:20]1[CH2:2][CH2:3][N:4]([CH2:14][C:15]([F:18])([F:17])[F:16])[C:5]1=[O:6]
Reactant: O=C(Oc1ccccc1)N(CCCl)CC(F)(F)F
Reactant: NN
Solvent: O
Solvent: CCO
Product: NN1CCN(CC(F)(F)F)C1=O

Procedure:
Into a 250-mL round-bottom flask, was placed a solution of phenyl N-(2-chloroethyl)-N-(2,2,2-trifluoroethyl)carbamate (5.6 g, 19.88 mmol, 1.00 equiv) in ethanol (100 mL), NH2NH2.H2O (10 mL, 80%). The resulting solution was heated to reflux overnight in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate (1:1). This resulted in 0.8 g (22%) of 1-amino-3-(2,2,2-trifluoroethyl)imidazolidin-2-one as colorless oil. (ES, m/z): 184 [M+H]+
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([NH:16][C@H:17]([C:25](O)=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>>[C:9]([NH:16][C@H:17]([C:25]([NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:26])[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10]
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NCc1ccccc1
Yield: 87.5 %

Procedure:
In substantially the same manner as Working Example 2, benzylamine (3.53 g) was condensed with Boc-L-phenylalanine (7.96 g) to give N-(Boc-L-phenylalanyl)benzylamine (9.30 g) (yield 87%). The compound thus obtained (7.08 g) was dissolved in ethyl acetate (100 ml), to which was added 4N hydrochloric acid/ethyl acetate solution (80 ml, manufactured by Kokusan Chemical Works, Ltd.), and the mixture was left standing for a half hour at room temperature. The reaction mixture was treated with ethylether to give N-(L-phenylalanyl)benzylamine hydrochloride (3.51 g) (yield 60%). The compound thus obtained (0.96 g) was condensed, in substantially the same manner as Working Example 8, with monoethyl ester of (2S,3S)-N-methylaziridine-2,3-dicarboxylic acid (0.52 g) obtained in Working Example 42 to give the above-titled compound (Compound 91; 0.86 g) as white crystals (yield 71%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][C:14]([OH:16])=O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].S(Cl)([Cl:19])=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][C:14]([Cl:19])=[O:16])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: O=S(Cl)Cl
Reactant: COc1cc(CC(=O)O)cc(OC)c1OC
Product: COc1cc(CC(=O)Cl)cc(OC)c1OC

Procedure:
In a manner similar to Preparation 15, react 3,4,5-trimethoxybenzeneacetic acid with thionyl chloride to obtain the title compound.