Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[F:8].Br[CH2:22][CH2:23][CH:24]1[CH2:26][O:25]1>>[F:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:22][CH2:23][CH:24]3[CH2:26][O:25]3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1CCN(C(=O)/C=C/c2ccc(F)c(F)c2)CCN1
Reactant: BrCCC1CO1
Product: O=C(/C=C/c1ccc(F)c(F)c1)N1CCC(=O)N(CCC2CO2)CC1

Procedure:
In analogy to the procedure described for example 170A, 1-[(E)-3-(3,4-difluoro-phenyl)-acryloyl]-[1,4]diazepan-5-one (intermediate 55) and (rac)-2-(2-bromo-ethyl)-oxirane (Journal of Organic Chemistry (1969), 34(12), 4060-5) gave the title compound as light yellow viscous oil. MS: 351.3 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][C:16]=2[C:25]([F:28])([F:27])[F:26])[C:6]=1[CH3:29].C1COCC1.[OH-].[Na+]>CO>[CH3:24][S:21]([C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5]([CH2:4][C:3]([OH:30])=[O:2])=[C:6]2[CH3:29])=[C:16]([C:25]([F:28])([F:27])[F:26])[CH:17]=1)(=[O:23])=[O:22]
Reactant: COC(=O)Cc1c(C)n(Cc2ccc(S(C)(=O)=O)cc2C(F)(F)F)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(CC(=O)O)c2ccccc2n1Cc1ccc(S(C)(=O)=O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirring solution of [1-(4-methanesulfonyl-2-trifluoromethyl-benzyl)-2-methyl-1H-indol-3-yl]-acetic acid methyl ester (440 mg, 1.0 mmol) in 1:1 THF:MeOH (20 ml) at room temperature, is added 1N NaOH aq (5 ml). The reaction mixture is stirred at room temperature for 16 h. The reaction mixture is evaporated in vacuo, diluted with water (10 ml) and acidified to acidic pH with 6N HCl aq. The precipitated product is collected by filtration and recrystallised from 1:3 isopropyl alcohol:water. The product is dried under high vacuum at 50° C.; [M+H]+ 426.
Reaction SMILES: CS(O[CH:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH2:7]1)(=O)=O.[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1>>[N+:17]([C:14]1[CH:15]=[CH:16][C:11]([N:8]2[CH2:9][CH2:10][CH:6]([N:20]3[CH:24]=[CH:23][N:22]=[CH:21]3)[CH2:7]2)=[CH:12][CH:13]=1)([O-:19])=[O:18]
Reactant: CS(=O)(=O)OC1CCN(c2ccc([N+](=O)[O-])cc2)C1
Reactant: c1c[nH]cn1
Product: O=[N+]([O-])c1ccc(N2CCC(n3ccnc3)C2)cc1
Temperature: 0 °C
Yield: 73.2 %

Procedure:
22 g (0.0767 mol) of 1-(4-nitrophenyl)pyrrolid-3-yl methanesulphonate (2) were heated at 95° C. for 2 hours in 170 g of imidazole (2.5 mol), This mixture was poured into 1 l of ice-cold water until crystallization takes place. After filtration and drying, the yellow powder obtained was chromatographed, eluting with dichloromethane, and 14.5 g of derivative (3) were recovered (73.2% yield).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=O)[CH2:11][CH3:12])=[CH:9][C:4]=2[CH2:3][CH2:2]1.[Cl:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)=O)=[CH:20][CH:19]=1>C1COCC1.[Zn].Cl[Ti](Cl)(Cl)Cl>[Cl:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)=[C:10]([C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][CH2:3][C:4]=3[CH:9]=2)[CH2:11][CH3:12])=[CH:20][CH:19]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1
Reactant: CCC(=O)c1ccc2c(c1)CCO2
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.3 %

Procedure:
To a suspension of Zn (595 mg, 6 eq) in 20 mL anhydrous THF was added TiCl4 (0.5 mL, 3 eq) dropwise at 0° C. under nitrogen. The mixture was then heated to reflux for 1 h and cooled to rt. Then a solution of 1-(2,3-dihydrobenzofuran-5-yl)propan-1-one (670 mg, 2.5 eq) and (4-(2-chloroethoxy)phenyl)(4-hydroxyphenyl)methanone (420 mg, 1.0 eq) in 10 mL anhydrous THF was added dropwise at 0° C. After the addition, the reaction mixture was heated to reflex for 1 h, cooled and quenched with sat. NaHCO3, filtered and the filtrate was extracted with EtOAc. The extract was dried and evaporated under reduced pressure. The residue was purified by column chromatography to give the desired product (500 mg, 78%, Z/E=1/1).
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[CH:19])[CH:13]=1.N>>[Cl:11][C:12]1[CH:13]=[C:14]([C:18]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[CH:19]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: ON=C(Cl)c1cccnc1
Reactant: C#Cc1cccc(Cl)c1
Agent: N
Product: Clc1cccc(-c2cc(-c3cccnc3)no2)c1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 1A (78 mg, 0.5 mmol) and 1-chloro-3-ethynylbenzene (Apollo, 68 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ 7.46 (s, 1H), 7.49-7.55 (m, 2 H), 7.60 (ddd, J=8.0, 4.9, 1.0 Hz, 1H), 7.82-7.90 (m, 1H), 7.93-8.00 (m, 1H), 8.37 (dt, J=7.9, 2.0 Hz, 1H), 8.67 (dd, J=5.1, 1.7 Hz, 1H), 9.09 (d, J=1.4 Hz, 1H) ppm; MS (DCI/NH3) m/z 259 (M+H)+, 257 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([OH:9])[CH:3]=1.[CH3:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[CH3:20])[C:14](O)=O>>[Br:1][C:2]1[CH:8]=[CH:7][C:5]2[N:6]=[C:14]([C:13]3[CH:17]=[CH:18][C:19]([CH3:20])=[C:11]([CH3:10])[CH:12]=3)[O:9][C:4]=2[CH:3]=1
Reactant: Nc1ccc(Br)cc1O
Reactant: Cc1ccc(C(=O)O)cc1C
Product: Cc1ccc(-c2nc3ccc(Br)cc3o2)cc1C

Procedure:
Preparation is carried out analogously to 4.1.a from 4-bromo-2-hydroxy-aniline and 3,4-dimethyl-benzoic acid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH2:8])=[O:7].[Cl:9][C:10]([Cl:14])([CH3:13])[CH:11]=O.[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[N:16]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N:15]1([CH:11]([NH:8][C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[O:7])[C:10]([Cl:14])([Cl:9])[CH3:13])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[N:16]1
Reactant: CC(Cl)(Cl)C=O
Reactant: c1ccc2[nH]nnc2c1
Reactant: NC(=O)c1cccs1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(Cl)(Cl)C(NC(=O)c1cccs1)n1nnc2ccccc21

Procedure:
A suspension of 2-thiophenecarboxamide, 2,2-dichloropropionaldehyde, benzotriazole, and p-toluenesulfonic acid was processed as described in Example 53A to provide the desired product.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].Cl[C:5]1[N:6]=[N+:7]([O-:21])[C:8]2[CH:17]=[C:16]3[C:12]([CH2:13][CH:14]([N:18]([CH3:20])[CH3:19])[CH2:15]3)=[CH:11][C:9]=2[N:10]=1>COCCOC>[CH2:1]([NH:3][C:5]1[N:6]=[N+:7]([O-:21])[C:8]2[CH:17]=[C:16]3[C:12]([CH2:13][CH:14]([N:18]([CH3:19])[CH3:20])[CH2:15]3)=[CH:11][C:9]=2[N:10]=1)[CH3:2]
Reactant: CCN
Reactant: CN(C)C1Cc2cc3nc(Cl)n[n+]([O-])c3cc2C1
Solvent: COCCOC
Product: CCNc1nc2cc3c(cc2[n+]([O-])n1)CC(N(C)C)C3
Yield: 82.5 %

Procedure:
Aqueous ethylamine (70%, 0.35 mL, 4.4 mmol) was added to a stirred solution of chloride 112 (240 mg, 0.9 mmol) in DME (20 mL) and the solution stirred at reflux temperature for 4 h. The solvent was evaporated and the residue purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 113 (203 mg, 84%) as a yellow solid: mp (MeOH/EtOAc) 187-190° C.; 1H NMR δ 8.05 (s, 1H, H-9), 7.37 (s, 1H, H-5), 5.14 (br s, 1H, NH), 3.54 (dq, J=7.2, 1.3 Hz, 2H, CH2N), 3.06-3.21 (m, 3H, CH, CH2), 2.89-2.99 (m, 2H, CH2), 2.32 [s, 6H, N(CH3)2], 1.28 (t, J=7.2 Hz, 3H, CH3); 13C NMR δ 158.7, 152.1, 148.9, 140.9, 130.0, 120.8, 115.0, 67.7, 43.9 (2), 38.0, 37.1, 36.3, 14.8. Anal. calcd for C14H19N5O: C, 61.5; H, 7.0; N, 25.6. Found: C, 61.3; H, 7.1; N, 25.5%.
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[N:13]([OH:18])[C:12]([CH3:20])([CH3:19])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21](I)([CH3:24])([CH3:23])[CH3:22].C([SnH](CCCC)CCCC)CCC>ClC1C=CC=CC=1>[C:1]([O:9][CH:10]1[CH2:11][C:12]([CH3:20])([CH3:19])[N:13]([O:18][C:21]([CH3:24])([CH3:23])[CH3:22])[C:14]([CH3:16])([CH3:17])[CH2:15]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)I
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Clc1ccccc1
Product: CC(C)(C)ON1C(C)(C)CC(OC(=O)c2ccccc2)CC1(C)C
Yield: 44.5 %

Procedure:
A solution of 56.0 g (203 mmol) of 4-benzoyloxy-1-oxyl-2,2,6,6-tetramethylpiperidine, 125 ml of chlorobenzene, and 58.9 g of t-butyl iodide is cooled to 5° C. Tri-n-butyltin hydride (29 g, 100 mmol) is added dropwise over 110 minutes while the temperature is maintained below 20° C. The reaction mixture is concentrated at reduced pressure and then purified by silica gel chromatography (200:1, then 100:3 heptane:ethyl acetate) to afford 30.1 g of a white solid, m.p. 80°-82.5° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:24]=[C:25]([Cl:27])[CH:26]=1)[O:19][CH2:20][C:21](O)=[O:22].CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.C(Cl)Cl>[C:10]([O:9][C:8](=[O:14])[NH:7][CH:4]1[CH2:3][CH2:2][N:1]([C:21](=[O:22])[CH2:20][O:19][C:18]2[CH:17]=[C:16]([Cl:15])[CH:26]=[C:25]([Cl:27])[CH:24]=2)[CH2:6][CH2:5]1)([CH3:11])([CH3:13])[CH3:12]
Reactant: O=C(O)COc1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)COc2cc(Cl)cc(Cl)c2)CC1
Reaction time: 5 h

Procedure:
To a stirred solution of tert-butyl piperidin-4-ylcarbamate (300 mg, 1.498 mmol) and 2-(3,5-dichlorophenoxy)acetic acid 331 mg, 1.498 mmol) in DMF (5 mL) at RT was added NMM (0.329 mL, 3.00 mmol) and EDC.HCl (287 mg, 1.498 mmol). The reaction mixture was stirred for 5 hours, diluted with DCM and washed with a saturated solution of sodium bicarbonate, brine, dried over MgSO4, filtered and concentrated under reduced pressure. Purification was carried out by chromatography on silica using 0-50% EtOAc in hexanes to afford the title product.
Reaction SMILES: [ClH:1].C([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:25]([NH:27][C:28]1[CH:37]=[C:36]2[C:31]([C:32]([CH3:39])=[CH:33][C:34](=[O:38])[O:35]2)=[CH:30][CH:29]=1)=[O:26])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:24])[NH2:23])=[O:15])(OCC1C=CC=CC=1)=O.[H][H].CCOCC>CO.[C].[Pd]>[ClH:1].[NH2:12][CH2:13][C:14]([NH:16][C@H:17]([C:25]([NH:27][C:28]1[CH:37]=[C:36]2[C:31]([C:32]([CH3:39])=[CH:33][C:34](=[O:38])[O:35]2)=[CH:30][CH:29]=1)=[O:26])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:23])[NH2:24])=[O:15]
Reactant: Cc1cc(=O)oc2cc(NC(=O)[C@H](CCCNC(=N)N)NC(=O)CNC(=O)OCc3ccccc3)ccc12
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: Cc1cc(=O)oc2cc(NC(=O)[C@H](CCCNC(=N)N)NC(=O)CN)ccc12
Yield: 94.1 %

Procedure:
7-(Nα -carbobenzoxyglycyl-L-arginyl)amino-4-methylcoumarin hydrochloric acid salt (559 mg, 1 mM) was dissolved in methyl alcohol (50 ml) and palladium-carbon catalyst (50 mg) was added thereto. This mixture was stirred while being treated with hydrogen gas for 3 hours. The catalyst was removed by filtration and the thus obtained filtrate was concentrated to yield solid material. To the residue ether (50 ml) was added to yield a powder. The powder was separated by filtration and dried to give 7-(glycyl-L-arginyl)amino-4-methylcoumarin hydrochloric acid salt [II] (400 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][OH:9])=[NH:7])=[CH:4][N:3]=1.[F:12][C:13]([F:34])([F:33])[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[N:23]=[C:22]([C:30](O)=O)[N:21]=2)=[CH:16][CH:15]=1>>[F:29][C:26]([F:27])([F:28])[C:24]1[CH:25]=[C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:13]([F:34])([F:33])[F:12])=[CH:15][CH:16]=2)[N:21]=[C:22]([C:30]2[O:9][N:8]=[C:6]([C:5]3[CH:10]=[CH:11][C:2]([NH2:1])=[N:3][CH:4]=3)[N:7]=2)[N:23]=1
Reactant: O=C(O)c1nc(-c2ccc(C(F)(F)F)cc2)cc(C(F)(F)F)n1
Reactant: N=C(NO)c1ccc(N)nc1
Product: Nc1ccc(-c2noc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)n2)cn1

Procedure:
The title compound was prepared from 6-amino-N-hydroxy-nicotinamidine (example C.3) (0.15 g, 1.0 mmol) and 4-(4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine-2-carboxylic acid (example D.2) (0.17 g, 0.5 mmol) according to the general procedure V. Obtained as a light yellow solid (0.13 g, 24%). MS (ISP) 453.1 [(M+H)+]; mp 218.5° C.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Cl.[CH2:13]([NH2:15])[CH3:14].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH2:13]([NH:15][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10])[CH3:14]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCNc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 81447.5 %

Procedure:
A suspension of 2,4-difluoro-1-nitrobenzene (0.50 g, 0.003 mmol), ethylamine hydrochloride (0.49 g, 0.006 mmol), K2CO3 (1.66 g, 0.012 mmol) in acetonitrile (30 mL) was stirred at room temperature for 16 hours and then filtered. The filtrate was concentrated and dissolved in small amount of CHCl3. Purification by column chromatography on silica using pentane/diethyl ether 95:5 as eluent gave 0.45 g of a yellow solid. 1H NMR (CDCl3) δ 8.23-8.18 (m, 1H), 8.08 (br s, 1H), 6.49-6.45 (m, 1H), 6.38-6.32 (m, 1H), 3.34-3.27 (m, 2H), 1.38 (tr, J=7.22 Hz, 3H); 13C NMR (CDCl3) δ 167.55 (d, JCF=255.6 Hz), 147.4 (d, JCF=12.9 Hz), 129.91 (d, JCF=12.9 Hz), 128.71 (br s), 103.73 (d, JCF32 24.8 Hz), 99.14 (d, JCF=27.6 Hz), 37.88, 14.05; MS (posESI) m/z=found 184.0653, calc 184.0648. Anal. (C12H18N4O2) C, H, N.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][CH2:10][O:11][CH3:12])=[N:6][CH:7]=1.C(N(CC)CC)C>C(O)C.[H][H].[Pt]=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][O:11][CH3:12])=[N:6][CH:7]=1
Reactant: [H][H]
Reactant: COCC#Cc1ccc(Br)cn1
Agent: O=[Pt]
Solvent: CCN(CC)CC
Solvent: CCO
Product: COCCCc1ccc(Br)cn1
Yield: 69.4 %

Procedure:
5-Bromo-2-(3-methoxypropynyl)pyridine (5.652 g) was dissolved in ethanol (150 ml), followed by the addition of triethylamine (2.5 ml) and platinum oxide (230 mg), and the resulting mixture was stirred in hydrogen atmosphere at room temperature for 5 hr. After the platinum oxide was filtered off, the resulting mixture was evaporated and partitioned between ethyl acetate and water. The resulting organic layer was washed with water, dried (over MgSO4) and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system), to give the title compound as a yellow oil (3.991 g, yield; 68%).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>C1(C)C=CC=CC=1>[C:15]([O:14][C:12](=[O:13])[CH2:11][NH:9][CH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: NCCc1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CNCCc1ccccc1
Temperature: 95 °C
Yield: 48.9 %

Procedure:
A solution of 12.6 ml (100 mmol) phenethylamine in 50 ml toluene was treated at RT with 7.4 ml (200 mmol) tert-butyl bromoacetate and heated at 95° C. for 4 h. After cooling (0° C.), filtration and evaporation of the filtrate, the residue was suspended in pentane, cooled (0° C.), filtrated and evaporated to give 11.5 g (98%) of phenethylamino-acetic acid tert-butyl ester as an oil, MS: 236 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:24])[CH2:10][O:11][C:12]1[CH:13]=[C:14]([F:23])[C:15]([C:18]([O:20]CC)=[O:19])=[N:16][CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[OH-].[Li+].Cl>C(O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:24])[CH2:10][O:11][C:12]1[CH:13]=[C:14]([F:23])[C:15]([C:18]([OH:20])=[O:19])=[N:16][CH:17]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1ncc(OC[C@H](C)NC(=O)OC(C)(C)C)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: C[C@@H](COc1cnc(C(=O)O)c(F)c1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 96.7 %

Procedure:
A mixture of ethyl 5-({(2S)-2-[(tert-butoxycarbonyl)amino]propyl}oxy)-3-fluoropyridine-2-carboxylate (402 mg), THF (4 mL), ethanol (4 mL) and 1M aqueous lithium hydroxide solution (4 mL) was stirred at 0° C. for 3 hr. The reaction mixture was neutralized with 1M hydrochloric acid at 0° C., and extracted with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (357 mg).
Reaction SMILES: [CH2:1]([Si:4]([CH:11]([CH3:13])[CH3:12])([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])[CH:2]=[CH2:3].[C:14]([OH:20])(=[O:19])[CH2:15][CH2:16]C=C.ClCCl.CCCCCC>CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1.CCOCC>[CH:11]([Si:4]([CH:5]([CH3:6])[CH3:7])([CH:8]([CH3:10])[CH3:9])[CH2:1][CH:2]=[CH:3][CH2:16][CH2:15][C:14]([OH:20])=[O:19])([CH3:13])[CH3:12]
Reactant: C=CC[Si](C(C)C)(C(C)C)C(C)C
Reactant: C=CCCC(=O)O
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(C)[Si](CC=CCCC(=O)O)(C(C)C)C(C)C
Temperature: 40 °C
Yield: 95.4 %

Procedure:
A flame dried round-bottomed flask was charged with allyltriisopropylsilane (0.722 mL, 3 mmol, 3 eq), 4-pentenoic acid (0.102 mL, 1 mmol, 1 eq) and dichloromethane (3 nmL). Hoveyda-Grubbs' catalyst (5 mol %, 31 mg) was subsequently added as a solid and the reaction was heated to reflux (40° C.) and left to stir under an atmosphere of argon. After 3 days the reaction was concentrated under reduced pressure to give a dark brown oil. Column chromatography (100% hexane to remove remaining silane, then hexane:ether, 75:25) gave 6-(triisopropylsilyl)-hex-4-enoic acid as a colourless oil (258 mg, 95% yield). For major isomer E: 1H NMR (400 MHz, CDCl3) δ 1.04-1.06 (m, 21H, Si(i−Pr)3), 1.54-1.56 (d, 2H, CH2Si(i−Pr)3, J=8.0 Hz), 2.29-2.35 (m, 2H, HOOCCH2CH2), 2.37-2.42 (m, 2H, HOOCCH2), 5.28-5.35 (m, 1H, CH2CHCH), 5.52-5.60 (m, 1H, CH2CHCH); 13C NMR (100 MHz, CDCl3) δ 11.0 (Si(CH(CH3)2)3), 15.3 (CH2Si(i−Pr)3), 18.7 (Si(CH(CH3)2)3), 27.8 (HOOCCH2CH2), 34.3 (HOOCCH2CH2), 125.9 (CH2CHCH), 129.0 (CH2CHCH), 179.5 (HOOC). For minor isomer Z: 1H NMR (400 MHz, CDCl3) δ 1.04-1.06 (m, 21H, Si(i−Pr)3), 1.62-1.64 (d, 2H, CH2Si(i−Pr)3, J=8.0 Hz), 2.29-2.35 (m, 2H, HOOCCH2CH2), 2.37-2.42 (m, 2H, HOOCCH2), 5.38-5.50 (m, 1H, CH2CHCH), 5.63-5.75 (m, 1H, CH2CHCH); 13C NMR (100 MHz, CDCl3) δ 10.9 (CH2Si(i−Pr)3), 11.1 (Si(CH(CH3)2)3), 18.7 (Si(CH(CH3)2)3), 24.7 (HOOCCH2CH2), 30.9 (HOOCCH2CH2), 124.6 (CH2CHCH), 128.2 (CH2CHCH), 176.9 (HOOC); IR (v, cm−1) 2867 (COO—H), 1713 (HOC═O), 660 (C—Si); HRMS required for C15H30O2Si [M−H]−: 269.1937, found 269.1937.
Reaction SMILES: [O:1]=[C:2]([NH:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1)[C:3]([O:5]CC)=O.[NH2:19][CH2:20][CH2:21][O:22][CH:23]1[CH2:28][CH2:27][CH:26]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[C:32]([C:39]([F:42])([F:41])[F:40])[CH:31]=2)[CH2:25][CH2:24]1>O1CCCC1>[N+:36]([C:33]1[CH:34]=[CH:35][C:30]([NH:29][CH:26]2[CH2:25][CH2:24][CH:23]([O:22][CH2:21][CH2:20][NH:19][C:3](=[O:5])[C:2]([NH:8][C:9]3[CH:18]=[CH:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)=[O:1])[CH2:28][CH2:27]2)=[CH:31][C:32]=1[C:39]([F:40])([F:41])[F:42])([O-:38])=[O:37]
Reactant: CCOC(=O)C(=O)Nc1ccc2ccccc2n1
Reactant: NCCOC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Solvent: C1CCOC1
Product: O=C(NCCOC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)C(=O)Nc1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.9 %

Procedure:
The mixture of ethyl 2-oxo-2-(quinolin-2-ylamino)acetate (56 mg, 0.23 mmol) and N—(-4-(2-aminoethoxy)cyclohexyl)-4-nitro-3-(trifluoromethyl)benzenamine (80 mg, 0.23 mmol) in tetrahydrofuran (2 mL) was stirred overnight at room temperature and then concentrated under vacuum to give a residue, which was purified by HPLC to afford N1-(2-(-4-(4-nitro-3-(trifluoromethyl)phenylamino) cyclohexyloxy)ethyl)-N2-(quinolin-2-yl)oxalamide as a yellow solid (58.8 mg, 46%). (ES, m/z): [M+H]+ 546.10; 1H NMR (400 MHz, CDCl3): δ 10.11 (br s, 1H), 8.41 (d, J=8.8 Hz, 1H), 8.26 (d, J=8.8 Hz, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.93 (d, J=8.8 Hz, 1H), 7.82 (d, J=7.6 Hz, 2H), 7.73 (t, J=7.2 Hz, 1H), 7.52 (t, J=7.2 Hz, 1H), 6.85 (d, J=2.4 Hz, 1H), 6.65 (dd, J=8.8, 2.4 Hz, 1H), 4.48 (d, J=7.2 Hz, 1H), 3.68-3.58 (m, 4H), 3.42-3.36 (m, 2H), 2.19-2.10 (m, 4H), 1.48-1.38 (m, 2H), 1.34-1.24 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12]([OH:14])[CH3:13])[CH2:11][O:10]1.[CH:15]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH:28]=[CH:27][NH:26][C:25]2=O)=[CH:20][CH:19]=1)([CH3:17])[CH3:16].FC1C=C(F)C=CC=1[C@]1(OC1)[C@H](N1C=CN(C2C=CC(C(C)C)=CC=2)C1=O)C>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@H:12]([O:14][C:25]2[N:24]([C:21]3[CH:22]=[CH:23][C:18]([CH:15]([CH3:17])[CH3:16])=[CH:19][CH:20]=3)[CH:28]=[CH:27][N:26]=2)[CH3:13])[CH2:11][O:10]1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: CC(C)c1ccc(-n2cc[nH]c2=O)cc1
Agent: CC(C)c1ccc(-n2ccn([C@H](C)[C@@]3(c4ccc(F)cc4F)CO3)c2=O)cc1
Product: CC(C)c1ccc(-n2ccnc2O[C@H](C)[C@@]2(c3ccc(F)cc3F)CO2)cc1
Yield: 13.9 %

Procedure:
In the same manner as in Reference Example 5, starting from 0.83 g of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 0.83 g of 1-(4-isopropylphenyl)-2(1H,3H)-imidazolone, 1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-3-(4-isopropylphenyl)-2(1H,3H)-imidazolone (0.25 g) and 0.22 g of (2R)-2-(2,4-difluorophenyl)-2-[(1R)-1-[1-(4-isopropylphenyl)-2-imidazolyloxy]ethyl] oxiran were obtained.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]([CH3:10])([CH3:9])[C:5]([O:7][CH3:8])=[O:6].[I:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=1.C1(C)C=CC=CC=1>CN(C=O)C.O>[I:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][O:3][C:4]([CH3:10])([CH3:9])[C:5]([O:7][CH3:8])=[O:6])=[CH:14][CH:13]=1
Reactant: COC(=O)C(C)(C)O
Reactant: BrCc1ccc(I)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)OCc1ccc(I)cc1
Temperature: 22.5 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (60% in parafin liquid) (2.22 g, 55.5 mmol) in DMF (25 ml) was added dropwise a solution of methyl 2-hydroxy-isobutyrate (6.44 g, 54.5 mmol) in DMF (12 ml) over a period of 20 minutes (the inner temperature: 20° C.). The reaction solution was stirred at 22-23° C. for 30 minutes (the bath temperature: 23° C.). To this reaction solution was added dropwise a solution of 4-iodobenzyl bromide (15.4 g, 51.9 mmol) in DMF (35 ml) over a period of 20 minutes (the inner temperature: 22-26° C.). This reaction solution was stirred at 22-25° C. for 2.5 hours. To the reaction solution were added toluene (80 ml) and water (50 ml), and the mixture was stirred for 5 minutes. The mixture was transferred into a separatory funnel, and separated. The organic layer was washed with water, and concentrated to give a mixture of methyl ester compounds. A part of the mixture was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to give the title compound.