Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C@@H:16]([CH2:41][C@H:42]3[CH2:46][CH2:45][C:44](=[O:47])[CH2:43]3)[C:17]([NH:19][C:20]3[CH:25]=[N:24][C:23]([O:26][CH2:27][C:28]([O:31]CC4C=CC(OC)=CC=4)([CH3:30])[CH3:29])=[CH:22][N:21]=3)=[O:18])[CH:7]=[CH:8][C:9]=2[S:10]([CH:13]2[CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH2:3][CH2:2]1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.ClCCl>O>[CH:1]1([C:4]2[CH:5]=[C:6]([C@@H:16]([CH2:41][C@H:42]3[CH2:46][CH2:45][C:44](=[O:47])[CH2:43]3)[C:17]([NH:19][C:20]3[CH:25]=[N:24][C:23]([O:26][CH2:27][C:28]([OH:31])([CH3:29])[CH3:30])=[CH:22][N:21]=3)=[O:18])[CH:7]=[CH:8][C:9]=2[S:10]([CH:13]2[CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH2:3][CH2:2]1
Reactant: COc1ccc(COC(C)(C)COc2cnc(NC(=O)[C@H](C[C@H]3CCC(=O)C3)c3ccc(S(=O)(=O)C4CC4)c(C4CC4)c3)cn2)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: ClCCl
Product: CC(C)(O)COc1cnc(NC(=O)[C@H](C[C@H]2CCC(=O)C2)c2ccc(S(=O)(=O)C3CC3)c(C3CC3)c2)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77.5 %

Procedure:
To a solution of (2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(1R)-3-oxocyclopentyl]propanoic acid (99 mg) in dichloromethane (2.0 mL) were added oxalyl chloride (27 μL) and DMF (3 μL) under ice-cooling, followed by stirring for 10 minutes. Thereafter, pyridine (28 μL) and 5-{2-[(4-methoxybenzyl)oxy]-2-methylpropoxy}pyrazin-2-amide (53 mg) were added thereto under ice-cooling, followed by stirring for 20 minutes. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1-1:1) to obtain (2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-N-(5-{2-[(4-methoxybenzyl)oxy]-2-methylpropoxy}pyrazin-2-yl)-3-[(1R)-3-oxocyclopentyl]propanamide (82 mg) as a white amorphous substance. A mixture of (2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-N-(5-{2-[(4-methoxybenzyl)oxy]-2-methylpropoxy}pyrazin-2-yl)-3-[(1R)-3-oxocyclopentyl]propanamide (82 mg), 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (56 mg), dichloromethane (7.5 mL), and water (0.38 mL) was stirred at room temperature for 10 minutes. To the reaction mixture was added water, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=80:20). The obtained residue was sonicated with diethyl ether and the resulting precipitate was collected by filtration to obtain (2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-N-[5-(2-hydroxy-2-methylpropoxy)pyrazin-2-yl]-3-[(1R)-3-oxocyclopentyl]propanamide (52 mg) as a white solid.
Reaction SMILES: C(O[CH:6](N(C)C)[N:7]([CH3:9])[CH3:8])(C)(C)C.[CH:13]([O:26][C:27]([C:29]1[N:30]2[CH:33]([S:34][CH2:35][C:36]=1[CH3:37])[CH:32]([NH:38][C:39](=[O:78])[C:40](=[N:66][O:67][C:68]([C:71]([O:73][C:74]([CH3:77])([CH3:76])[CH3:75])=[O:72])([CH3:70])[CH3:69])[C:41]1[N:42]=[C:43]([NH:46][C:47]([C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[S:44][CH:45]=1)[C:31]2=[O:79])=[O:28])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(OCC)(=O)C.O>CN(C)C=O>[CH:13]([O:26][C:27]([C:29]1[N:30]2[CH:33]([S:34][CH2:35][C:36]=1[CH:37]=[CH:6][N:7]([CH3:9])[CH3:8])[CH:32]([NH:38][C:39](=[O:78])[C:40](=[N:66][O:67][C:68]([C:71]([O:73][C:74]([CH3:77])([CH3:76])[CH3:75])=[O:72])([CH3:70])[CH3:69])[C:41]1[N:42]=[C:43]([NH:46][C:47]([C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)([C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=3)[C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)[S:44][CH:45]=1)[C:31]2=[O:79])=[O:28])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC(C)(C)C(=O)OC(C)(C)C)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)C2SC1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CN(C)C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC(C)(C)C(=O)OC(C)(C)C)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)C2SC1
Reaction time: 0.25 h

Procedure:
t-Butoxy-bis-dimethylaminomethane (1.9 cc) is added, whilst stirring, to a solution, at 80° C., under nitrogen, of the syn isomer of 2-benzhydryloxycarbonyl-7-{2-[(2-t-butoxycarbonylprop-2-yl)-oxyimino]-2-(2-tritylaminothiazol-4-yl)-acetamido}-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (product 5g) (6 g) in dimethylformamide (64 cc), and the reaction is continued for 15 minutes. The mixture is then poured into a mixture of ethyl acetate (200 cc) and water (200 cc), the organic phase is decanted, washed with water (3×100 cc) and a saturated aqueous solution of sodium chloride (100 cc), dried over sodium sulphate and filtered and the filtrate is concentrated to dryness at 20° C. under 20 mm Hg (2.7 kPa). This yields a crude product (5f) (6.5 g) in the form of a hard brown foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:13])CSC.[O-][S:15]([C:18]([F:21])(F)[F:19])(=O)=O.F[N+]1C=CC=C[CH:24]=1.CCCCCC.C(Cl)(Cl)Cl>ClC(Cl)CCl>[CH3:24][S:15][C:18]([F:21])([F:19])[C:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])=[O:13]
Reactant: O=S(=O)([O-])C(F)(F)F
Reactant: F[n+]1ccccc1
Reactant: CSCC(=O)c1ccc(F)cc1F
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Solvent: ClCC(Cl)Cl
Product: CSC(F)(F)C(=O)c1ccc(F)cc1F
Temperature: 100 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
To a 20 ml solution of 0.5 g (2.5 mmol) of 2',4'-difluoro-2-(methylthio)acetophenone [Compound (2a-1)] in 1,1,2-trichloroethane, 3.0 g (12.1 mmol) of N-fluoropyridinium triflate ("Onoda Fluorinate FP-T500", trade name; product of Chichibu Onoda Co., Ltd.) were added at an internal temperature of 80° C., followed by stirring at an internal temperature of 100° C. for one hour. After cooling, the reaction mixture was added to n-hexane. The insoluble matter precipitated was filtered off. The insoluble matter was then washed with ethyl ether, followed by combination with the hexane layer. The layers so combined were washed successively with water and saturated saline, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue so obtained was subjected to chromatography on a silica gel column using chloroform, whereby 0.28 g of the title Compound (2c-1) was obtained in the form of a light yellow oil (yield: 47.5%).
Reaction SMILES: Cl.[NH:2]1[CH:6]=[C:5]([CH2:7][CH2:8][C:9]([OH:11])=O)[N:4]=[CH:3]1.[P:12]([OH:15])([OH:14])[OH:13].P(Cl)(Cl)Cl>ClC1C=CC=CC=1>[OH:11][C:9]([P:12]([OH:15])(=[O:13])[OH:14])([P:12]([OH:15])(=[O:14])[OH:13])[CH2:8][CH2:7][C:5]1[N:4]=[CH:3][NH:2][CH:6]=1
Reactant: O=C(O)CCc1c[nH]cn1
Reactant: OP(O)O
Agent: Cl
Solvent: ClP(Cl)Cl
Solvent: Clc1ccccc1
Product: O=P(O)(O)C(O)(CCc1c[nH]cn1)P(=O)(O)O
Reaction time: 4 h

Procedure:
3.53 g (20 mMol) 3-(4-imidazolyl)-propionic acid hydrochloride are heated with 2.26 g phosphorous acid in 10 ml chlorobenzene to 110° C., while stirring. 4.12 g (30 mMol) phosphorus trichloride are slowly added dropwise thereto and heating continued for 4 hours at 110° C. After cooling, the chlorobenzene is decanted off and the residue boiled under reflux for 5 hours with 15 ml. 6N hydrochloric aci. The reaction mixture is allowed to cool, mixed with active charcoal, filtered and the filtrate evaporated. The residue is taken up in 10 ml. water, the solution is adjusted with an aqueous solution of sodium bicarbonate to a pH value of 5.5 and mixed with methanol until no further precipitate is formed. The precipitate is filtered off with suction, washed with methanol and dried. There are obtained 3.23 g. (48% of theory) of the title compound. The product is obtained as the monosodium salt with 1 mole of water of crystallisation.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([B:10]([OH:12])[OH:11])=[CH:6][CH:5]=1)=[C:2]=[O:3].[CH2:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][NH:14]1.O>ClCCl>[CH3:15][C:16]1([CH3:17])[C:21]([CH3:13])([CH3:20])[O:12][B:10]([C:7]2[CH:6]=[CH:5][C:4]([NH:1][C:2]([N:14]3[CH2:15][C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:13]3)=[O:3])=[CH:9][CH:8]=2)[O:11]1
Reactant: O=C=Nc1ccc(B(O)O)cc1
Reactant: c1ccc2c(c1)CNC2
Solvent: O
Solvent: ClCCl
Product: CC1(C)OB(c2ccc(NC(=O)N3Cc4ccccc4C3)cc2)OC1(C)C

Procedure:
500 mg (4-Isocyanatophenyl)boronic acid pinacolester (1.979 mmol) and 365 mg isoindoline (2.97 mmol) were dissolved in 10 ml dichloromethane and the resultant mixture was stirred over night at room temperature. After adding water, the mixture was extracted several times with dichloromethane, the combined organic phases were washed with dried over magnesium sulfate and filtered. The solvent was evaporated under reduced pressure. Column chromatography of the residue with dichloromethane resulted in the title compound.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH2:16]>CN(C=O)C>[C:8]([NH:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)([NH:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:16]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 4 °C
Reaction time: 8 h

Procedure:
To N-Teoct4 (0.017 g, 17 μmol) in 1 mL dry DMF was added dicyclohexylcarbodiimide (0.004 g, 18 μmol). After stirring for 30 minutes N-dimethyl-4-aminopyridine (0.004 g, 36 μmol) and Gly18 (SEQ ID NO: 6) (0.017 g,17 μmol) were added and the reaction stirred overnight. The cloudy solution was poured into 20 mL H2O and extracted twice with 10 mL CH2Cl2. The aqueous component was acidified to pH 3 with 1 N HCl and chilled to 4° C. The material was isolated by centrifugation and the pellet washed 3 times with 8 mL H2O. The pellet was dried in vacuum to yield dicyclohexylurea and N-TeocT4-Gly18 (SEQ ID NO:6).
Reaction SMILES: C(O[C:9]([NH:11][CH:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=O)C1C=CC=CC=1.[Na].[CH:24](=O)[CH:25]=[CH:26][CH2:27]C.C(O)(=O)C>C(O)C.[Pd]>[CH2:25]([CH:26]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])([C:18]([O:20][CH2:21][CH3:22])=[O:19])[NH:11][CH:9]=[CH:27]1)[CH3:24]
Reactant: CCC=CC=O
Reactant: CCOC(=O)C(NC(=O)OCc1ccccc1)C(=O)OCC
Agent: [Pd]
Agent: [Na]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C1(C(=O)OCC)NC=CC1CC
Reaction time: 1 h
Yield: 63 %

Procedure:
Diethyl benzyloxycarbonylaminomalonate (11.5 g, 38 mM) was dissolved in dry ethanol (50 ml) and added to a solution of sodium (150 mg) in dry ethanol (10 ml). Pent-2-enal (3.2 g 38 mM) in ethanol (10 ml) was added dropwise to the stirred mixture and the solution stirred for 1 hr. A solution of acetic acid (0.29 ml) in ethanol (1 ml) was then added and the solution hydrogenated for 2 hrs at atmospheric pressure using palladium on carbon (5%) as catalyst. The catalyst was removed by filtration and the filtrate evaporated. The residue was dissolved in chloroform and the solution washed with brine containing a little sodium bicarbonate, dried (Na2SO4) and evaporated. Distillation of the residue at 15 mm Hg gave 4-ethyl-5,5-dicarboethoxy-2-pyrroline (5.65 g) as a colourless oil b.p. 115°-120° (15 mm Hg) I.R. 1715, 1610 cm-1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7]C(C)(C)C)=[O:6].FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([OH:7])=[O:6]
Reactant: Cc1cc(C(=O)OC(C)(C)C)ccc1Oc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C(=O)O)ccc1Oc1ccccc1
Temperature: 20 °C
Reaction time: 4 h
Yield: 38.1 %

Procedure:
A mixture of tert-butyl 3-methyl-4-phenoxybenzoate (654 mg, 2.3 mmol), 2,2,2-trifluoroacetic acid (1 mL) and dichloromethane (4 mL) were stirred at 20° C. for 4 hours. The mixture was washed with water (10 mL×2). The organic phase was separated, dried over sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=2:1) to give 3-methyl-4-phenoxybenzoic acid as a white solid (200 mg, 38%). LRMS (M+H)− m/z: calcd 228.08. found 228.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][C:4](=[O:6])[OH:5].[NH:12]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C@H:13]([C:24](ON1C(=O)CCC1=O)=[O:25])[C@@H:14]([CH3:23])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C.Cl>C1COCC1.CN(C=O)C>[NH:12]([C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35])[C@H:13]([C:24]([NH:1][C@H:2]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][C:4](=[O:5])[OH:6])=[O:25])[C@@H:14]([CH3:23])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)[C@@H](N)CC(=O)O
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](CC(=O)O)NC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)OCc1ccccc1
Reaction time: 1 h
Yield: 86.6 %

Procedure:
To a suspension consisting of 2.3 g of H-Asp-OEt, 5.8 g of Boc-Thr(Bzl)-OSu in 20 ml of THF and 20 ml of DMF, was added 2 ml of triethylamine under an ice-cooling condition and the mixture was stirred for 1 hour so as to the pH of the reaction mixture was adjusting to about pH 7, and the reaction was continued for 36 hours. The reaction mixture was concentrated under reduced pressure and the residue thus obtained was acidified by adding 1N-hydrochloric acid, and extracted with ethyl acetate (80 ml×3 times). The organic layer was washed with water, then with a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate, The ethyl acetate extract was concentrated under reduced pressure and the residue thus obtained was crystallized and recrystallized from diethyl ether-petroleum ether. 5.59 Grams (yield: 86.6%) of the above-mentioned objective product was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH3:9].S(=O)(=O)(O)O.[N+:15]([O-])([O-:17])=[O:16].[K+]>ClCCCl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1ccc(F)cc1Cl
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: ClCCCl
Product: Cc1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 0 °C
Yield: 49.7 %

Procedure:
To a mixture of 20.0 g (0.138 mole) of 2-chloro-4fluorotoluene in 50 ml of 1,2-dichloroethane which had been cooled to 0° C. was added 50 ml of concentrated sulfuric acid. While maintaining the temperature below 10° C., 14.0 g (0.138 mole) of potassium nitrate was added slowly to the mixture. After three hours the reaction mixture was poured into ice, and the resulting mixture was extracted with methylene chloride. The extract was dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was passed through a silica gel column, eluting with heptane. Appropriate fractions were combined, and the solvent was evaporated under reduced pressure, yielding 13.0 g of 2-chloro-4-fluoro-5-nitrotoluene as a yellow solid. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]([F:29])([F:28])[F:27])[NH:15][C:16]3=[O:19])=[CH:11][CH:10]=2)[CH2:4]1.N1C=CC=CC=1.[CH3:36][S:37](Cl)(=[O:39])=[O:38].O>C(Cl)Cl>[O:8]=[C:6]1[N:5]([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]([F:28])([F:27])[F:29])[NH:15][C:16]3=[O:19])=[CH:11][CH:10]=2)[CH2:4][C@H:3]([CH2:2][NH:1][S:37]([CH3:36])(=[O:39])=[O:38])[O:7]1
Reactant: NC[C@H]1CN(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C(=O)O1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)NC[C@H]1CN(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C(=O)O1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 37.4 %

Procedure:
The 7-((S)-5-aminomethyl-2-oxooxazolidin-3-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (30 mg, 0.07 mmol) obtained in step B was dissolved in methylene chloride (0.3 ml). Thereafter, pyridine (30 μl, 0.37 mmol) and methanesulfonyl chloride (5.8 μl, 0.07 mmol) were added to the solution, and the obtained mixture was stirred at 0° C. for 30 minutes. Thereafter, water was added to the reaction solution, and the mixture was then extracted with methylene chloride. The extract was washed with water and a saturated saline solution, and was then dried over magnesium sulfate. Thereafter, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (methylene chloride:methanol=20:1), so as to obtain N-{(R)-2-oxo-3-[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]oxazolidin-5-ylmethyl}methanesulfonamide (12.6 mg, 36%) in the form of a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[CH2:11][C:12]#[N:13]>CCO.Cl.CCOC(C)=O.C([O-])([O-])=O.[K+].[K+]>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH2:11][C:12]#[N:13])[CH:4]=1
Reactant: N#CCc1cc([N+](=O)[O-])ccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: N#CCc1cc(N)ccc1Cl
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
To a suspended solution of (2-Chloro-5-nitro-phenyl)-acetonitrile (4.0 g, 20.0 mmol) in EtOH (10 mL) is added a solution of Sn(II)Cl2 (15.36 g, 81.0 mmol) in concentrated HCl (14 mL) at 75° C. After the mixture is stirred for 30 minutes at 75° C., the mixture is diluted with EtOAc and neutralized with K2CO3 until a pH of 8 is achieved. The organic layer is washed with saturated K2CO3, brine and dried, filtered and concentrated to give crude product, which is purified by recrystallization with CH2Cl2/EtOAc/Hexane to give the title intermediate as a solid (3.04 g, 89.7%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:22])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[F-].[Cs+].CS(O[CH:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]1)(=O)=O>CC(N(C)C)=O>[Cl:1][C:2]1[C:3]([F:22])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH:30]4[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: COc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1O
Agent: [Cs+]
Agent: [F-]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 60 °C
Reaction time: 18 h
Yield: 96 %

Procedure:
4-[(3-chloro-2-fluorophenyl)amino]-6-methoxyquinazolin-7-ol (3, 500 mg, 1.565 mmol) was dissolved in DMA (20 ml). tert-Butyl(4-methanesulfonyloxy)piperidine-1-carboxylate (436.6 mg, 1.565 mmol) and cesium fluoride (236.3 mg, 1.565 mmol) were added, and the mixture was heated to 60° C. with stirring. After 18 hours, tert-butyl 4-methanesulfonyloxypiperidine-1-carboxylate and cesium fluoride were again added in the same quantities to the reaction mixture and heating was continued at 60° C. for a further 18 hours. The solvent was evaporated, and the residue was partitioned between saturated aqueous sodium bicarbonate solution (50 mL) and EtOAc (2×50 mL). The organics were combined, dried over MgSO4 and evaporated. The crudes were then purified by column chromatography eluting with increasingly polar mixtures of methylene chloride/EtOAc (100/0 to 0/100). The fractions containing the desired product were combined and evaporated under vacuum to give tert-butyl 4-({4-[(3-chloro-2-fluorophenyl)amino]-6-methoxyquinazolin-7-yl}oxy)piperidine-1-carboxylate as a colourless foam (757 mg, 96%); 1H NMR Spectrum: (DMSO-d6): 1.52 (s, 9H), 1.60-1.80 (m, 2H), 2.02-2.20 (m, 2H), 3.20-3.45 (m, 2H), 3.75-3.92 (m, 2H), 4.05 (s, 3H), 4.95 (m, 1H), 7.32-7.45 (m, 2H), 7.55-7.70 (m, 2H), 7.92 (s, 1H), 8.50 (s, 1H), 9.73 (s, 1H); Mass Spectrum: (M+H)+ 503.08.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:16](=[O:18])[CH2:15][CH2:14][CH2:13][C:12]=3[N:11]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:10](=[O:29])[NH:9]2)=[C:4]([O:30][CH3:31])[CH:3]=1.[Cu][C:33]#[N:34]>CN(C)C=O.CO.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[O:29]=[C:10]1[NH:9][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:33]#[N:34])=[CH:3][C:4]=2[O:30][CH3:31])[C:17]2[C:16](=[O:18])[CH2:15][CH2:14][CH2:13][C:12]=2[N:11]1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:26])[F:27])[CH:20]=1
Reactant: COc1cc(Br)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CCC2
Reactant: N#C[Cu]
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CCC2
Temperature: 140 °C

Procedure:
Under an atmosphere of argon, a mixture of 4-(4-bromo-2-methoxyphenyl)-1-(3-(trifluoromethyl)phenyl)-3,4,7,8-tetrahydroquinazoline-2,5(1H,6H)-dione (intermediate 50, 21 mg, 42 μmol), copper(I) cyanide (10 mg, 0.11 mmol) and tetrakis(triphenylphosphine)-palladium(O) (5 mg, 4 μmol) in N,N-dimethylformamide (1 mL) is heated at 140° C. over it) night. The mixture is cooled at room temperature, diluted with methanol and purified by reversed phase HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 4 mg; ESI mass spectrum [M+H]+=442; Retention time HPLC: 0.87 min (Z011_S03).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[CH3:37][C:38]1[CH:43]=[CH:42][C:41](CO)=[CH:40][CH:39]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][CH2:26][C:41]2[CH:42]=[CH:43][C:38]([CH3:37])=[CH:39][CH:40]=2)=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: Cc1ccc(CO)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCc4ccc(C)cc4)c(C)c3C)c2cc1OC
Yield: 27.5 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (100 mg) was added to toluene (10 ml) and triethylamine (1 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (140 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, (4-methylphenyl)methanol (57 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (40 mg, yield 25%).