Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.CS(O[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[N:26]=[C:27](/[CH:30]=[CH:31]/[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:28][CH:29]=2)=[CH:19][CH:18]=1)(=O)=O>>[N:1]1([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27](/[CH:30]=[CH:31]/[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[O:28][CH:29]=3)=[CH:19][CH:18]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CS(=O)(=O)OCCCCCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Reactant: c1c[nH]cn1
Product: C(=C/c1nc(COc2ccc(CCCCCCn3ccnc3)cc2)co1)\c1ccccc1
Yield: 66 %

Procedure:
In substantially the same manner as in Working Example 8, imidazole was allowed to react with 6-[4-[2-[(E) -2-phenylethenyl]-4-oxazolylmethoxy]phenyl]hexyl methanesulfonate to give 4-[4-[6-(1-imidazolyl)hexyl]phenoxymethyl]-2-[(E)-2-phenylethenyl]oxazole. The yield was 66%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 108-109° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:21][C:22]#[N:23]>>[CH3:16][O:17][C:18]1[CH:19]=[C:20](/[C:21](=[CH:12]/[C:11]2[CH:14]=[CH:15][C:8]([O:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:9][CH:10]=2)/[C:22]#[N:23])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: COCCOCOc1ccc(C=O)cc1
Product: COCCOCOc1ccc(/C=C(\C#N)c2ccc(OC)c(OC)c2)cc1
Yield: 78.9 %

Procedure:
The hydroxyl group of 4-hydroxybenzaldehyde (24.9 g) was protected by use of 2-methoxyethoxymethyl chloride (24.4 g) in accordance with (production process 1), to thereby produce 4-methoxyethoxymethoxybenzaldehyde (33.5 g, yield: 80%). The thus-produced 4-methoxyethoxymethoxybenzaldehyde (21.0 g) and 3,4-dimethoxybenzyl cyanide (17.7 g) were subjected to condensation in accordance with process A of (production process 2), to thereby produce (Z)-2-(3,4-dimethoxyphenyl)-3-[4-(2-methoxy-ethoxymethoxy)-phenyl]acrylonitrile (29.1 g, yield: 86%). Separately, 2-methoxyethoxymethyl chloride (4.1 g), which had been prepared in a manner similar to that described above, and 3,4-dimethoxybenzyl cyanide (3.4 g) were subjected to condensation in accordance with process B of (production process 2), to thereby produce (Z)-2-(3,4-dimethoxy-phenyl)-3-[4-(2-methoxy-ethoxymethoxy)-phenyl]acrylonitrile (5.2 g, yield: 73%). The thus-produced (Z)-2-(3,4-dimethoxy-phenyl)-3-[4-(2-methoxy-ethoxymethoxy)-phenyl]-acrylonitrile (10.2 g) was subjected to deprotection in accordance with (production process 3), to thereby produce the target product (6.22 g, yield: 74%).
Reaction SMILES: [F:1][C:2]1([F:16])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][C:12]([OH:14])=O)[C:3]1=[O:15].[Br:17][C:18]1[C:19]([C:24]2[NH:28][CH:27]=[N:26][N:25]=2)=[C:20]([NH2:23])[S:21][CH:22]=1>>[Br:17][C:18]1[C:19]([C:24]2[NH:28][CH:27]=[N:26][N:25]=2)=[C:20]([NH:23][C:12](=[O:14])[CH2:11][N:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]([F:1])([F:16])[C:3]2=[O:15])[S:21][CH:22]=1
Reactant: Nc1scc(Br)c1-c1nnc[nH]1
Reactant: O=C(O)CN1C(=O)C(F)(F)c2ccccc21
Product: O=C(CN1C(=O)C(F)(F)c2ccccc21)Nc1scc(Br)c1-c1nnc[nH]1
Yield: 14.7 %

Procedure:
The title compound was prepared from 2-(3,3-difluoro-2-oxoindolin-1-yl)acetic acid (50 mg, 0.22 mmol), 4-bromo-3-(4H-1,2,4-triazol-3-yl)thiophen-2-amine (45 mg, 0.18 mmol) using protocol A. HPLC purification gave N-(4-bromo-3-(4H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(3,3-difluoro-2-oxoindolin-1-yl)acetamide (12 mg) as a white solid (m/z 454.0, retention of 5.696 min in [7]). 1H-NMR (300MHz, CDCl3) δ 13.1 (s, 1H), 7.82 (s, 1H), 7.70 (dd, J=7.5, 1.5Hz, 1H), 7.50 (td, J=7.9, 1.2Hz, 1H), 6.99 (s, 1H), 6.92 (d, J=7.9Hz, 1H), 4.71 (s, 2H).
Reaction SMILES: ClC1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([O:10]O)=O)C=1.[C:12]([O:16][C:17]([N:19]1CCC(=C)[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>C(Cl)(Cl)Cl>[C:12]([O:16][C:17]([N:19]1[CH2:7][CH2:6][CH:5]([CH:4]2[O:10][CH2:8]2)[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C1CCN(C(=O)OC(C)(C)C)C1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(C2CO2)C1
Reaction time: 6 h
Yield: 56.8 %

Procedure:
3.54 g (0.0175 mole) of 85% m-chloroperbenzoic acid were added to a solution of 2.67 g (0.0146 mole) of 1-t-butoxycarbonyl-3-methylenepyrrolidine [prepared as described in Step (4) above] in 20 ml of chloroform, whilst ice-cooling, and the mixture was stirred at the same temperature for 6 hours and then stirred at room temperature overnight. At the end of this time, 1.8 g (0.073 mole) of 70% m-chloroperbenzoic acid were added, and the mixture was stirred at room temperature for 12 hours. At the end of this time, the mixture was extracted with toluene. The toluene extract was washed, in turn, with an aqueous solution of sodium bicarbonate, with an aqueous solution of sodium thiosulfate and with water, in that order, after which it was dried and concentrated by evaporation under reduced pressure. The residue was subjected to column chromatography through silica gel eluted with a 1:9 by volume mixture of ethyl acetate and toluene, to give 1.77 g of 1-t-butoxycarbonyl-3 -(1,2-epoxyethyl)pyrrolidine as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:38])[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]([CH3:28])([CH3:27])[CH2:25][OH:26])[CH2:14][C:13](=[O:29])[NH:12][CH:11]3[C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[CH3:37])[C:5]2=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[N:70]1([CH2:76][CH2:77][NH2:78])[CH2:75][CH2:74][CH2:73][CH2:72][CH2:71]1>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:38])[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]([CH3:28])([C:25](=[O:26])[NH:78][CH2:77][CH2:76][N:70]4[CH2:75][CH2:74][CH2:73][CH2:72][CH2:71]4)[CH3:27])[CH2:14][C:13](=[O:29])[NH:12][CH:11]3[C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[CH3:37])[C:5]2=[CH:4][CH:3]=1
Reactant: NCCN1CCCCC1
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC(C)(C)CO)C12C(=O)Nc1cc(Cl)ccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC(C)(C)C(=O)NCCN2CCCCC2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.1 %

Procedure:
To a mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(2-hydroxy-1,1-dimethyl-ethoxy)-phenyl]-2′-[5-fluoro-2-methylphenyl]-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (35 mg, 0.06 mmol), EDCl (18 mg, 0.094 mmol), HOBt (14 mg, 0.094 mmol) and DIPEA (23 mg, 0.2 mmol) in THF (2 mL) was added 2-piperidin-1-yl-ethylamine (24 mg, 0.18 mmol). The mixture was stirred at room temperature overnight, purified by prep-HPLC to give the title compound as a white solid (7 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: OB(O)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=[N+]([O-])c1ccc(-c2ccccc2)nc1
Yield: 85.2 %

Procedure:
To a solution of 2-bromo-5-nitropyridine (DM) (302 mg, 1.49 mmol) in a mixture of dioxane (14 mL) and water (3 mL) was added phenylboronic acid (LXXII) (199 mg, 1.64 mmol), Pd(PPh3)4 (86 mg, 0.74 mmol) and K3PO4 (473 mg, 2.23 mmol). The reaction was microwaved at 95° C. for 1 h. The reaction was cooled and the organic phase was separated, dried over MgSO4 and evaporated under vacuum. The residue was purified by silica gel column chromatography (100% hexane→5:95 EtOAc:hexane) to give 5-nitro-2-phenylpyridine (LXXIII) as off-white needles (254 mg, 1.27 mmol, 85% yield). ESIMS found for C11H8N2O2 m/z 200.9 (M+H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)=[O:4].[CH3:12][O-:13].[Na+].Cl>CO>[OH:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][O:13][CH3:12])=[CH:6][CH:7]=1
Reactant: C[O-]
Reactant: O=C(CBr)c1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COCC(=O)c1ccc(O)cc1
Reaction time: 0.75 h

Procedure:
3.0 g of 2-bromo-1-(4-hydroxy-phenyl)-ethanone in 25 ml of methanol are added dropwise in the course of 10 minutes to a solution of 7.5 g of sodium methanolate in 80 ml of methanol. Stirring is then carried out at 60° C. for 45 minutes. The reaction mixture is cooled, poured into dilute hydrochloric acid and extracted with ethyl acetate. After concentration of the organic phases and crystallisation from diethyl ether, 1-(4-hydroxy-phenyl)-2-methoxyethanone is obtained. 1H-NMR (CDCl3) 300 MHz: 3.50 (s, 3H), 4.70 (s, 2H), 6.62 (s, 1H), 6.91 (d, 2H), 7.89 (d, 2H)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[O:14][C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:12][C:11]=2[CH2:21][O:22][CH2:23][O:24][CH3:25])=[CH:4][CH:3]=1.Cl[CH2:27][C:28]1[N:29]=[C:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:31][C:32]=1[CH3:33].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:33][C:32]1[O:31][C:30]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[N:29][C:28]=1[CH2:27][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[O:14][C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:12][C:11]=2[CH2:21][O:22][CH2:23][O:24][CH3:25])=[CH:4][CH:3]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Reactant: COCOCc1nc(-c2ccccc2)oc1CCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOCc1nc(-c2ccccc2)oc1CCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Temperature: 90 °C
Reaction time: 15 h
Yield: 100.1 %

Procedure:
A mixture of 5-[2-(4-hydroxyphenyl)ethyl]-4-methoxymethoxymethyl-2-phenyloxazole (3.12 g), 4-chloromethyl-5-methyl-2-phenyloxazole (2.28 g), potassium carbonate (1.27 g) and N,N-dimethylformamide (50 ml) was stirred at 90° C. for 15 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was washed successively with dilute hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography, and 5-[2-[4-(5-methyl-2-phenyl-4-oxazolyl)methoxyphenyl]ethyl]-4-methoxymethoxymethyl-2-phenyloxazole (4.70 g, yield 85%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 124–125° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:49]1[CH:53]=[C:52]([C:54]2[CH:55]=[C:56]([NH2:60])[CH:57]=[CH:58][CH:59]=2)[CH:51]=[N:50]1>CN(C=O)C>[NH:49]1[CH:53]=[C:52]([C:54]2[CH:55]=[C:56]([NH:60][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:57]=[CH:58][CH:59]=2)[CH:51]=[N:50]1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: Nc1cccc(-c2cn[nH]c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(-c2cn[nH]c2)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Yield: 8.9 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(1H-pyrazol-4-yl)-phenylamine (0.011 g, 0.065 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.002 g of product in 11% yield: LCMS (ESI) m/z 348 (MH+).
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[F:9][C:10]([F:20])([F:19])[C:11](=O)[CH2:12][C:13](OCC)=[O:14].[OH-].[Na+]>>[I:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:3]=1[NH:4][C:11]([C:10]([F:20])([F:19])[F:9])=[CH:12][C:13]2=[O:14]
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: Nc1ccccc1I
Agent: [Na+]
Agent: [OH-]
Product: O=c1cc(C(F)(F)F)[nH]c2c(I)cccc12
Temperature: 180 °C
Reaction time: 1 h
Yield: 42.3 %

Procedure:
A mixture of 2-iodoaniline (25.0 g), ethyl 4,4,4-trifluoro-3-oxobutanoate (20.8 g), and PPA (78.0 g) was stirred at 180° C. for 1 hour. After cooling, the reaction solution was neutralized with an aqueous sodium hydroxide solution, and the deposit was filtered and washed with water. The filtrate was rendered acidic with hydrochloric acid, and the deposit was filtered and washed with water. The filtration residues were dried under reduced pressure to obtain compound (3a) (16.2 g, 42%) as a white solid.
Reaction SMILES: Cl.[OH:2][N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.[N:16]1([C:22](Cl)=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([C:4]2[N:3]([O:2][C:22]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[O:23])[CH:7]=[CH:6][N:5]=2)=[CH:13][CH:12]=1
Reactant: COc1ccc(-c2nccn2O)cc1
Reactant: O=C(Cl)N1CCOCC1
Agent: Cl
Product: COc1ccc(-c2nccn2OC(=O)N2CCOCC2)cc1

Procedure:
The title compound was prepared from 1-hydroxy-2-(4-methoxyphenyl)imidazole, hydrochloride and 4-morpholine carbonyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc) (49%, crystals).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[N:7]2[CH2:8][CH2:9][NH:10][CH2:11][C:6]2=[C:5]([C:12](=[O:14])[CH3:13])[N:4]=1.[C:17]([O:21][C:22]([NH:24][C@H:25]([CH2:30][C:31]1[CH:36]=[C:35]([F:37])[C:34]([F:38])=[CH:33][C:32]=1[F:39])[CH2:26][C:27](O)=[O:28])=[O:23])([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl>[C:17]([O:21][C:22](=[O:23])[NH:24][C@H:25]([CH2:30][C:31]1[CH:36]=[C:35]([F:37])[C:34]([F:38])=[CH:33][C:32]=1[F:39])[CH2:26][C:27]([N:10]1[CH2:9][CH2:8][N:7]2[C:3]([C:2]([F:1])([F:15])[F:16])=[N:4][C:5]([C:12](=[O:14])[CH3:13])=[C:6]2[CH2:11]1)=[O:28])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(=O)c1nc(C(F)(F)F)n2c1CNCC2
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C)CC2
Yield: 76 %

Procedure:
1-(3-Trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-1-yl)-ethanone 27g (192 mg, 0.72 mmol) and (R)-3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyric acid 1f (0.24 g, 0.72 mmol) were dissolved in 20 mL of dichloromethane under stirring, and triethylamine (0.4 mL, 2.88 mmol) was then added to the solution. After stirring to mix well, bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.275 g, 1.08 mmol) was then added. The reaction mixture was reacted overnight at room temperature and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-(1-acetyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 27h (0.3 g) as a white solid.
Reaction SMILES: C([O:3][C:4](=[S:17])[CH2:5][CH2:6][CH2:7][CH2:8][CH:9]([S:13]C(=O)C)[CH2:10][CH2:11][CH3:12])C.[OH-].[K+].CO>O>[SH:13][CH:9]([CH2:10][CH2:11][CH3:12])[CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:3])=[S:17]
Reactant: CCCC(CCCCC(=S)OCC)SC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCC(S)CCCCC(O)=S
Yield: 84.5 %

Procedure:
11.9 grams (40.7 mmoles) of 6-acetylthio-8-methylthiooctanoic acid ethyl ester (XI) were added to a solution of 7.5 grams (133.7 mmoles) of potassium hydroxide in l00ml of methanol and 5 ml of water and the mixture heated at reflux for 10 hours under a cover of nitrogen. After a further 10 hours at room temperature the solvent was removed in a vacuum, the residue taken up in 100 ml of 3N hydrochloric acid and extracted three times, each time with 100 ml of ethyl acetate. After drying the combined extracts with magnesium sulfate the solvent was removed in a vacuum. The short path distillation of the residue gave 7.1 grams (78% of theory) of 6-mercapto-8-methylthiooctanoic acid as a pale yellow oil having a boiling point of 150° C. to 170° C. at 0.5 mbar.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7](I)[CH:6]=1)[CH3:2].[C:14]([Cu])#[N:15]>CS(C)=O>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([C:14]#[N:15])[CH:6]=1)[CH3:2]
Reactant: N#C[Cu]
Reactant: CCOC(=O)c1ccc(O)c(I)c1
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(O)c(C#N)c1
Temperature: 105 °C
Reaction time: 2.5 h

Procedure:
Charge a 10 L double jacket reactor, equipped with a mechanical stirrer, a reflux condenser and set under N2 with 4-hydroxy-3-iodo-benzoic acid ethyl ester (1312 g, 4.49 mol), dimethylsulfoxide (3277 mL) and CuCN (442.3 g). Heat the mixture to 105° C. and hold at this temperature for 2.5 h. Cool the brown solution down to 20° C. Add water at 48° C. water (6.5 L) Filter the mixture at 20° C., then wash the cake with water (2 L). Suspend the cake in EtOAc (5 L) and stir during 1 h at 20° C. Filter the suspension on Hyflo Super Cel® (250 g) and rinse with EtOAc (3 L). Decant the filtrates, then evaporate the organic layer to dryness. Take the residue up in n-heptane (10 L). Distill off 2 L of n-heptane, then add CH2Cl2 (400 mL). Cool the mixture cooled to 27° C., filter and rinse the cake with n-heptane (2 L). Dry 48 h at 55° C. under pressure to give 4-hydroxy-3-cyano-benzoic acid ethyl ester. (777.7 g, 4.067 mol). 1H NMR (250 MHz, DMSOd): 1.32 (t, j=7.1 Hz, 3H), 4.3 (q, j=7.1 Hz, 2H), 7.13(d, j=8.8 Hz, 1H), 8.07(dxd, j=8.8 Hz, 2.2 Hz, 1H), 8.16 (d, j=2.2 Hz), 12.11(s (broad), 1H).
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH2:8][CH:9]1[O:11][CH2:10]1)(=[O:3])[NH2:2].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>C(O)C>[C:1]([CH2:4][C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH2:8][CH:9]([OH:11])[CH2:10][N:27]1[CH2:26][CH2:25][N:24]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[O:17][CH3:16])[CH2:29][CH2:28]1)(=[O:3])[NH2:2]
Reactant: COc1ccccc1N1CCNCC1
Reactant: NC(=O)Cc1ccccc1OCC1CO1
Solvent: CCO
Product: COc1ccccc1N1CCN(CC(O)COc2ccccc2CC(N)=O)CC1

Procedure:
A solution consisting of 5.0 g. of 1-(2-carbamoylmethylphenoxy)-2,3-epoxypropane and 4.6 g. of 1-(2-methoxyphenyl)piperazine dissolved in 50 ml. of ethanol was allowed to stand at room temperature (~25°C.) for a period of approximately 16 hours. At the end of this time, the resultant precipitate was removed from the reaction mixture by means of suction filtration and subsequently recrystallized from ethyl acetate to give 1-(2-carbamoylmethylphenoxy)-3-[4-(2-methoxyphenyl)piperazin-1-yl]propan-2-ol as the pure free base compound, m.p. 120°-122°C.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[CH:13]2[O:14][C:15]([CH3:18])([CH3:17])[O:16][CH:12]2[C:11](=[O:19])[CH:10]=1.[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([CH:29]3[CH2:31][NH:30]3)=[CH:28][C:23]=2[O:22][CH2:21]1>O1CCCC1>[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([CH:29]3[CH2:31][N:30]3[C:9]3[CH:13]4[O:14][C:15]([CH3:18])([CH3:17])[O:16][CH:12]4[C:11](=[O:19])[CH:10]=3)=[CH:28][C:23]=2[O:22][CH2:21]1
Reactant: c1cc2c(cc1C1CN1)OCO2
Reactant: CC1(C)OC2C(=O)C=C(Cl)C2O1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(C)OC2C(=O)C=C(N3CC3c3ccc4c(c3)OCO4)C2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.6 %

Procedure:
Triethylamine (0.4 mL, 3.0 mmol, 2.0 equiv) and β-chloroenone 53 (280 mg, 1.5 mmol, 1.0 equiv) were sequentially added to a stirred solution of aziridine 15 (360 mg, 2.2 mmol, 1.5 equiv) in tetrahydrofuran (10 mL) at 25° C. The resulting white mixture was stirred at 25° C. for 3 h. The crude reaction mixture was loaded directly onto a column and purified by silica gel column chromatography (1% triethylamine and 49% benzene in ethyl acetate) to afford 54 (400 mg, 85% yield) as a yellow foam. Rf=0.68 (1% triethylamine and 49% benzene in ethyl acetate); 1H NMR (500 MHz, C6D6) δ 6.55-6.70 (m, 3H, ArH), 5.24-5.28 (m, 2H, OCH2O), 5.14-5.18 (m, 1H, NCCH), 4.50-4.56 (m, 1H, CH(OR)), 4.19-4.27 (m, 1H, CH(OR)), 2.46-3.18 (m, 1H, ArCHN), 1.84-2.17 (m, 1H, CH2N), 1.63-1.78 (m, 1H, CH2N), 1.28-1.32 (m, 3H, CH3), 1.10-1.12 (m, 3H, CH3); IR (neat film) 2989 (w), 1703 (m), 1586 (s) cm−1; HRMS (ESI) m/z: Calcd for C17H18NO5 (MO 316.1185; observed 316.1186.
Reaction SMILES: [CH:1]([S:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](O)=[O:8])([CH3:3])[CH3:2].CO.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C1COCC1>[CH:1]([S:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[CH:7]=[O:8])([CH3:3])[CH3:2]
Reactant: CC(C)Sc1ccccc1C(=O)O
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)Sc1ccccc1C=O
Reaction time: 0.5 h

Procedure:
To a solution of 2-(isopropylthio)benzoic acid (0.98 g, 5 mmol) in THF (10 ml) was added dropwise borane-dimethyl sulphide complex (0.8 ml, 8 mmol) at 3° C. under argon with vigorous stirring. After continuing to stir in an ice bath for 30 min, the reaction was left to stand at RT for a further 24 h. Methanol (1.5 ml) was added cautiously and the reaction solution was concentrated under reduced pressure. The residue was taken up in diethyl ether (50 ml), and washed with saturated K2CO3 solution and NaCl solution. Aqueous solutions were additionally extracted with ether, the combined organic phases were dried over MgSO4 and filtered, and the solvent was removed under reduced pressure. The residue was taken up in dichloromethane (30 ml), admixed cautiously with PCC (1.20 g, 5.6 mmol) and stirred at room temperature for 36 h. After solvent removal, the residue was purified by column chromatography on silica gel (10:1 hexane:ethyl acetate). Yield 0.69 g (76%).
Reaction SMILES: [Cl:1][CH2:2][O:3][C:4](Cl)=[O:5].[NH:7]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]>>[Cl:1][CH2:2][O:3][C:4]([N:7]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5]
Reactant: CCOC(=O)CNCC(=O)OCC
Reactant: O=C(Cl)OCCl
Product: CCOC(=O)CN(CC(=O)OCC)C(=O)OCCl

Procedure:
Using chloroformic acid chloromethyl ester and diethyl iminodiacetate as the raw materials, the same operation as the Example 101(1) gave the title compound as a crude product, and the crude product was used for the next reaction without further purification.