Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].O[CH2:13][CH2:14][CH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](=[O:24])[NH:16]1>C(Cl)Cl>[S:1]([CH2:13][CH2:14][CH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](=[O:24])[NH:16]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: O=C1NC(CCO)c2ccccc21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)CCC2NC(=O)c3ccccc32)cc1
Reaction time: 12 h
Yield: 78.8 %

Procedure:
Tosyl chloride (3.4 g, 17.7 mmol) is added to a solution of TEA (5.1 g, 50.8 mmol) and 1,3-dihydro-3-(2-hydroxyethyl)-2H-isoindol-1-one (3.0 g, 16.9 mmol) in 50 mL of CH2Cl2 at room temperature under argon. After 12 hours, the reaction mixture is extracted with H2O (2×100 mL) and dried over Na2SO4. Evaporation of the solvent gives 4.2 g (75% yield) of 1,3-dihydro-3-(2-tosylethyl)-2H-isoindol-1-one; mp=146-149° C. (dec) after recrystallization from ethyl acetate.
Reaction SMILES: [CH:1]1([C:4]([CH:6]([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([S:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]=2[S:29]([CH3:32])(=[O:31])=[O:30])=[O:15])C(OC(C)(C)C)=O)=[O:5])[CH2:3][CH2:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH:1]1([C:4](=[O:5])[CH2:6][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([S:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]=2[S:29]([CH3:32])(=[O:31])=[O:30])=[O:15])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)C(C(=O)c1cccc(Sc2ccccc2)c1S(C)(=O)=O)C(=O)C1CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1c(Sc2ccccc2)cccc1C(=O)CC(=O)C1CC1
Yield: 92.4 %

Procedure:
A mixture of t-butyl 2-cyclopropylcarbonyl-3-(2-methylsulphonyl-3-phenylsulphenylphenyl)-3-oxopropionoate (8.5 g) and para-toluene sulphonic acid (0.25 g) in toluene was heated at reflux for six hours. Water and ethyl acetate were then added and the organic phase was dried over anhydrous sodium sulphate, filtered and evaporated. The residue was crystallised from ether to give 1-cyclopropyl-3-(2-methylsulphonyl-3-phenylsulphenylphenyl)propan-1,3-dione (6.2 g) as a beige powder,
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[S:13][C:12]([CH3:14])=[N:11][C:10]=2[CH:15]=1.[N:16]1([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.[Yb]>C(Cl)Cl>[CH3:14][C:12]1[S:13][C:9]2[CH:8]=[CH:7][C:6]([O:5][CH2:4][C@H:2]([OH:1])[CH2:3][CH3:17])=[CH:15][C:10]=2[N:11]=1.[N:16]1([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1
Reactant: Cc1nc2cc(OC[C@H]3CO3)ccc2s1
Agent: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Yb]
Solvent: ClCCl
Product: CC[C@@H](O)COc1ccc2sc(C)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-[((2R)oxiran-2-yl)methoxy]-2-methylbenzothiazole, a compound of formula (3) (6.2 g, 28 mmol), and tert-butyl 1-piperazinecarboxylate, a compound of formula (4) (5.7 g, 31 mmol), in methylene chloride (200 ml), was added ytterbium (111) trifluoromethanesulfonate (1.73 g, 28 mmol). The resulting solution was allowed to stir at room temperature overnight. The solvent was evaporated (in vacuo), to yield a semi-solid, which was chromatographed on silica gel, eluting with 5% methanol/methylene chloride, to yield (2R)-1-(2-methylbenzothiazol-5-yloxy)butan-2-ol, tert butyl piperazinecarboxylate as a clear oil (9.5 g, 23 mmol).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:20]I.N1C=CN=C1.[CH2:27]([O:34][C:35](=[O:48])[CH2:36][C@H:37]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:38]O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)Cl>[CH2:27]([O:34][C:35](=[O:48])[CH2:36][C@H:37]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:38][I:20])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CC(=O)OCc1ccccc1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](CI)CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A suspension of polymer bound triphenyl phosphine (18.25 g, 54.76 mmol) in DCM (100 ml) is treated with iodine (12.2 g, 48.1 mmol) and the reaction mixture stirred at ambient temperature for 15 minutes. Imidazole (3.72 g, 54.7 mmol) is added and the reaction mixture stirred for a further 15 minutes. A solution of (S)-3-tert-butoxycarbonylamino-4-hydroxy-butyric acid benzyl ester (6.76 g, 21.9 mmol) in DCM (100 ml) is added. The suspension is stirred at reflux for 1.5 hours, then filtered through Celite™ filter material, washing through with DCM. The combined organic phase is washed with an aqueous solution of 10% sodium thiosulphate, water and brine, then dried over magnesium sulphate and evaporated. The crude product is chromatographed over flash silica using 8% ethylacetate in iso-hexane as eluent to afford (S)-3-tert-butoxycarbonylamino-4-iodo-butyric acid benzyl ester. [M-BOC] 320.12
Reaction SMILES: [H-].[Na+].[CH:3]1([CH:6]([OH:33])[C:7]2[N:11]([CH3:12])[C:10]3[CH:13]=[C:14]([N:17]4[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]5[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=5)=[CH:19][C:18]4=[O:32])[CH:15]=[CH:16][C:9]=3[N:8]=2)[CH2:5][CH2:4]1.IC.[CH3:36]N(C=O)C>C1COCC1>[CH:3]1([CH:6]([O:33][CH3:36])[C:7]2[N:11]([CH3:12])[C:10]3[CH:13]=[C:14]([N:17]4[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]5[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=5)=[CH:19][C:18]4=[O:32])[CH:15]=[CH:16][C:9]=3[N:8]=2)[CH2:5][CH2:4]1
Reactant: CN(C)C=O
Reactant: Cn1c(C(O)C2CC2)nc2ccc(-n3ccc(OCc4ccc(F)cc4)cc3=O)cc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(c1nc2ccc(-n3ccc(OCc4ccc(F)cc4)cc3=O)cc2n1C)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
NaH (40% oil dispersion, 5.2 mg) was added to a solution of 1-(2-(cyclopropyl(hydroxy)methyl)-1-methyl-1H-benzimidazol-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one (30 mg) and iodomethane (0.013 ml) in THF (2 ml)-DMF (1 ml) at room temperature. The mixture was stirred at room temperature for 30 min. The mixture was quenched with water and extracted with EtOAc twice. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The resulting solid was washed with Et2O to give the title compound (23.6 mg) as a white solid.
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:28](=[CH:29][CH:30]=2)[O:27][C:14]2([CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)[CH2:13][C:12]3=[O:31])=[CH:5][CH:4]=1.[ClH:32]>>[ClH:32].[O:2]=[C:3]1[NH:8][CH:7]=[C:6]([C:9]2[CH:10]=[C:11]3[C:28](=[CH:29][CH:30]=2)[O:27][C:14]2([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH2:13][C:12]3=[O:31])[CH:5]=[CH:4]1
Reactant: COc1ccc(-c2ccc3c(c2)C(=O)CC2(CCN(C(=O)OC(C)(C)C)CC2)O3)cn1
Agent: Cl
Product: O=C1CC2(CCNCC2)Oc2ccc(-c3ccc(=O)[nH]c3)cc21
Reaction time: 20 h

Procedure:
Tert-Butyl 6-[6-(methoxy)pyridin-3-yl]-4-oxo-spiro[chroman-2,4′-piperidine]-1′-carboxylate (550 mg) was suspended in conc. HCl aq. (10 ml) and stirred at 100 deg. for 20 h. After removal of the solvent, the resulted solid was washed with MeOH and Et2O to obtain the intended compound as a colorless solid.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[S:10][CH:9]=[C:8]([C:11]([OH:13])=O)[CH:7]=2)[CH:3]=[N:2]1.[C:14]1([C:20]2([OH:26])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(#N)C>[OH:26][C:20]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:25][CH2:24][N:23]([C:11]([C:8]2[CH:7]=[C:6]([C:4]3[CH:5]=[N:1][NH:2][CH:3]=3)[S:10][CH:9]=2)=[O:13])[CH2:22][CH2:21]1
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: O=C(O)c1csc(-c2cn[nH]c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1csc(-c2cn[nH]c2)c1)N1CCC(O)(c2ccccc2)CC1
Yield: 58 %

Procedure:
5-(1H-Pyrazol-4-yl)-thiophene-3-carboxylic acid (0.04 g, 0.2 mmol) and 4-phenyl-piperidin-4-ol (0.041 g, 0.23 mmol) were dissolved in acetonitrile (3 mL). HATU (0.24 mmol) and diisopropylethylamine (0.077 mL, 0.45 mmol) were added and the reaction mixture was stirred. After 1 hour the solvent was evaporated under vacuum and the residue stirred with aqueous sodium hydroxide (1 N, 3 mL) for 0.5 hours. The mixture was diluted with ethyl acetate and washed with brine, dried over magnesium sulphate, filtered and the solvent evaporated under vacuum. The residue was purified by flash chromatography on silica eluting with ethyl acetate. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.041 g) as a white solid.
Reaction SMILES: [NH2:1][CH:2]([OH:24])[C@H:3]([CH3:23])[CH2:4][CH2:5][C:6]1[S:7][C:8]([C:11](=[O:22])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:9][CH:10]=1.[BH4-].[Na+].O.[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30]>CO>[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].[NH2:1][CH:2]([OH:24])[C@H:3]([CH3:23])[CH2:4][CH2:5][C:6]1[S:7][C:8]([CH:11]([OH:22])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:9][CH:10]=1
Reactant: C[C@H](CCc1ccc(C(=O)CCCCc2ccccc2)s1)C(N)O
Agent: O=C(O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C[C@H](CCc1ccc(C(O)CCCCc2ccccc2)s1)C(N)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.1 %

Procedure:
(2R)-Amino-2-methyl-4-[5-(5-phenylpentanoyl)thiophen-2-yl]butan-1-ol (130 mg, 0.38 mmol) obtained in Example 50 was dissolved in methanol (3 ml), and sodium borohydride (17 mg, 0.45 mmol) was added thereto in an ice bath followed by stirring for 1 hour at room temperature. To the reaction solution was added water in the ice bath, and the resulting solution was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol, and oxalic acid (34 mg, 0.38 mmol) was added thereto, and the solvent was evaporated in vacuo. To the residue was added ethanol (3 ml), and the resulting precipitate was filtered off to give the title compound (95 mg, 58% yield) as a white crystalline solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH2:12][C@@H:13]([OH:41])[C@@H:14]([NH:22][C:23](=[O:40])[C@H:24]([CH2:36][C:37](=[O:39])[NH2:38])[NH:25]C(OCC1C=CC=CC=1)=O)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:42])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH2:12][C@@H:13]([OH:41])[C@@H:14]([NH:22][C:23](=[O:40])[C@H:24]([CH2:36][C:37](=[O:39])[NH2:38])[NH2:25])[CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(N)=O
Yield: 84.6 %

Procedure:
A solution of 1.75 g of N-[3(S)-[[N-(benzyloxycarbonyl)-L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-L-proline tert.butyl ester in 100 ml of ethanol was hydrogenated over 10% palladium-on-carbon for 64 hours. The catalyst was removed by filtration and the filtrate was evaporated. The residual gum was partitioned between ethyl acetate and 2M hydrochloric acid. The aqueous phase was made basic with dilute sodium hydroxide solution and extracted with ethyl acetate. The ethyl acetate extract was evaporated to give 1.14 g of N-[3(S)-[[L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-L-proline tert.butyl ester as a white, solid foam; MS: m/e 449 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]1[C:7](=[O:8])[CH2:6][CH2:5][CH2:4][C:3]1=[O:9].[I-].[Li+].C1CCN2C(=NCCC2)CC1.Cl.Cl[CH2:25][N:26]1[CH:30]=[C:29]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[N:28]=[CH:27]1>C(OCC)(=O)C.CCCCCCC.O.C1COCC1>[F:37][C:34]1[CH:35]=[CH:36][C:31]([C:29]2[N:28]=[CH:27][N:26]([CH2:25][C:2]3([CH3:1])[C:7](=[O:8])[CH2:6][CH2:5][CH2:4][C:3]3=[O:9])[CH:30]=2)=[CH:32][CH:33]=1
Reactant: Fc1ccc(-c2cn(CCl)cn2)cc1
Reactant: CC1C(=O)CCCC1=O
Agent: Cl
Agent: [I-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(Cn2cnc(-c3ccc(F)cc3)c2)C(=O)CCCC1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
To a stirred solution of 2-methylcyclohexane-1,3-dione (10 g, 79 mmol), lithium iodide (26 g, 194 mmol), and anhydrous THF (300 mL) cooled in a water bath was added 1,8-diazabicyclo[5.4.0]-7-undecene (14 mL, 94 mmol) dropwise under nitrogen. The mixture was stirred at RT for 40 min before 1-(chloromethyl)-4-(4-fluorophenyl)-1H-imidazole hydrochloride (9.8 g, 40 mmol) was added in one portion. The reaction mixture was stirred at RT for 3 hr and at 60° C. for 2 hr. After the mixture was cooled, water (250 mL) and heptane (250 mL) were added. The aqueous layer was separated and extracted with ethyl acetate (2×250 mL). The combined organic solutions were washed with 16% aqueous potassium carbonate solution (3×50 mL), dried (Na2SO4), and concentrated. Silica gel flash chromatography (20-100% ethyl acetate in hexanes) gave 2((4-(4-fluorophenyl)-1H-imidazol-1-yl)methyl)-2-methylcyclohexane-1,3-dione (7.1 g, 24 mmol, 60% yield) as a solid. MS found: (M+H)+=301.4.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([N:14]([C:24](=[O:34])[C:25]2[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[C:26]=2I)[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-].CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:32][C:27]1[CH:26]=[C:25]2[C:30](=[C:29]([Cl:31])[CH:28]=1)[C:11]1([CH:12]=[CH:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]1)[N:14]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[C:24]2=[O:34]
Reactant: COc1ccc(CN(C(=O)c2cc(Cl)cc(Cl)c2I)C2=CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: COc1ccc(CN2C(=O)c3cc(Cl)cc(Cl)c3C23C=CN(C(=O)OC(C)(C)C)CC3)cc1
Temperature: 25 °C
Yield: 47.7 %

Procedure:
4-[(3,5-Dichloro-2-iodo-benzoyl)-(4-methoxy-benzyl)-amino]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (9.0 g, 15 mmol) was dissolved in 100 mL of acetonitrile in a three flask fitted with a condenser and the mixture was sparged with N2 for 1 h. The flask was quickly opened and Pd(OAc)2 (336 mg, 1.5 mmol), PPh3 (786 mg, 3.0 mmol), K2CO3 (4.14 g, 30 mmol) and nBu4NBr (4.82 g, 15 mmol) was added. The mixture was heated to reflux overnight. After this time, the iodide was consumed and the mixture was cooled to rt and evaporated. The residue was taken up with EtOAc/H2O and the layers were separated. The organic layer was washed with brine, dried and concentrated to give the crude product. It was purified by column chromatography (PE:EtOAc=10:1) to give tert-butyl 5,7-dichloro-2-(4-methoxybenzyl)-3-oxo-2′,3′-dihydro-1′H-spiro[isoindoline-1,4′-pyridine]-1′-carboxylate (3.5 g, 48%). 1H NMR (CDCl3): 1.52 (s, 9H), 1.63 (s, 1H), 1.78 (m, 1H), 2.71 (m, 1H), 3.04 (m, 1H), 3.78 (s, 3H), 3.97 (m, 1H), 4.25 (m, 1H), 4.46 (m, 1H), 5.02 (m, 1H), 6.82 (m, 2H), 7.18 (m, 2H), 7.52 (s, 1H), 7.81 (s, 1H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([O:9]C)[C:5]([F:11])=[C:4]([F:12])[C:3]=1[C:13]1[C:14]([NH:16][C:17](=[O:19])[CH:18]=1)=[O:15].B(Br)(Br)Br>C(Cl)Cl>[F:1][C:2]1[C:7]([F:8])=[C:6]([OH:9])[C:5]([F:11])=[C:4]([F:12])[C:3]=1[C:13]1[C:14]([NH:16][C:17](=[O:19])[CH:18]=1)=[O:15]
Reactant: COc1c(F)c(F)c(C2=CC(=O)NC2=O)c(F)c1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1C=C(c2c(F)c(F)c(O)c(F)c2F)C(=O)N1
Temperature: 25 °C
Reaction time: 72 h
Yield: 52.7 %

Procedure:
2 g of the 2,3,5,6-tetrafluoro-4-methoxyphenylmaleimide obtained in Example 1 was dissolved in 10 ml of dry methylene chloride. Thereto was added 15 ml of a methylene chloride solution containing 1 M of boron tribromide. The mixture was stirred at room temperature for 3 days in an argon atmosphere. The reaction mixture was poured into 200 ml of ice water. The organic layer was extracted with ether. The ether layer was washed with an aqueous sodium chloride solution and dried over magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove ether. The residue was recrystallized from ligroin/toluene to obtain 1 g of an intended compound (yield: 53%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([NH:12][C:13]([C:15]1[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=1)[C:21](=[O:25])[N:20]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:19]([CH2:33][CH2:34][CH2:35][CH2:36][C:37](O)=[O:38])=[CH:18]3)=[O:14])[CH2:7][CH2:6][CH2:5]2.[CH:40]1([S:43]([NH2:46])(=[O:45])=[O:44])[CH2:42][CH2:41]1.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH:40]1([S:43]([NH:46][C:37](=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33][C:19]2[N:20]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[C:21](=[O:25])[C:22]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:13]([NH:12][C@H:8]2[C:9]4[C:4](=[CH:3][C:2]([F:1])=[CH:11][CH:10]=4)[CH2:5][CH2:6][CH2:7]2)=[O:14])=[CH:24][CH:23]=3)(=[O:45])=[O:44])[CH2:42][CH2:41]1
Reactant: NS(=O)(=O)C1CC1
Reactant: O=C(O)CCCCc1cc2cc(C(=O)N[C@@H]3CCCc4cc(F)ccc43)ccc2c(=O)n1-c1ccc(F)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(CCCCc1cc2cc(C(=O)N[C@@H]3CCCc4cc(F)ccc43)ccc2c(=O)n1-c1ccc(F)cc1)NS(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.8 %

Procedure:
A mixture of (R)-5-(6-((6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-2-(4-fluorophenyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoic acid (10 mg, 0.019 mmol), cyclopropanesulfonamide (3.43 mg, 0.028 mmol, 1.50 equiv.), DMAP (4.61 mg, 0.038 mmol, 2.0 equiv.) and EDC (7.23 mg, 0.038 mmol, 2.0 equiv.) in DCM (1 mL) was stirred at room temperature overnight. The residue was purified by column chromatography on silica gel eluting with 0-3% CH2Cl2/MeOH to give 7.8 mg of (R)-3-(5-(cyclopropanesulfonamido)-5-oxopentyl)-N-(6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-2-(4-fluorophenyl)-1-oxo-1,2-dihydroisoquinoline-6-carboxamide as a white solid. LCMS [M+H]+=634. 1H NMR (DMSO, 500 MHz) δ ppm: 8.18 (dd, J=8.0, 3.5 Hz, 2H), 7.91 (d, J=8.0 Hz, 1H), 7.43-7.36 (m, 4H), 7.26 (t, J=7.0 Hz, 1H), 7.00 (t, J=8.5 Hz, 2H), 6.66 (s, 1H), 5.26-5.22 (m, 1H), 2.85-2.74 (m, 3H), 2.30-2.15 (m, 4H), 2.09 (t, J=7.0 Hz, 2H), 2.00-1.96 (m, 2H), 1.91-1.76 (m, 2H), 1.45-1.39 (m, 4H), 1.10-1.00 (m, 4H).
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][CH2:5][NH:6][CH3:7].C1(=O)CCCC1.[C-]#N.[K+].CN(C)[C:19]1([C:24]#[N:25])[CH2:23][CH2:22][CH2:21][CH2:20]1>O>[CH3:7][N:6]([CH2:5][CH2:4][O:3][CH3:2])[C:19]1([C:24]#[N:25])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CN(C)C1(C#N)CCCC1
Reactant: CNCCOC
Agent: Cl
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: O=C1CCCC1
Product: COCCN(C)C1(C#N)CCCC1
Yield: 82 %

Procedure:
The title compound (3.39 g; 82%) was prepared from N-(2-methoxyethyl)methylamine hydrochloride (2.84 g; 22.6 mmol), cyclopentanone (1.90 g, 22.6 mmol) and potassium cyanide (1.47 g; 22.6 mmol) in water (15 ml) in a similar manner to that described in D1. 1H NMR (CDCl3) δ: 1.83 (6H, m). 2.20 (2H, m), 2.48 (3H, s), 2.68 (2H, t), 3.46 (3H, s), 3.5 (2H, t).
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[ClH:7].[N:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:23]=[C:22]([C:24](O)=[O:25])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)=[CH:10][CH:9]=1>ClCl>[ClH:4].[N:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:23]=[C:22]([C:24]([Cl:7])=[O:25])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)=[CH:10][CH:9]=1
Reactant: O=C(O)c1cc(-c2ccncc2)nc2ccccc12
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Agent: ClCl
Product: O=C(Cl)c1cc(-c2ccncc2)nc2ccccc12
Temperature: -10 °C
Reaction time: 72 h
Yield: 126 %

Procedure:
1.3 ml (10.4 mmol) of oxalyl chloride were dissolved in 60 ml of CH2 Cl2. The solution was cooled at -10° C. and 3.0 g (14.4 mmol) of 2-(4-pyridyl)quinoline-4-carboxylic acid hydrochloride were added portionwise. The reaction mixture was left 72 hours at room temperature and then evaporated to dryness to yield 4.0 g of the title compound, used without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([O:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:10][N:9]1[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])=O)(C)(C)C.S(Cl)(Cl)=O.Cl>CO>[CH2:23]([O:22][C:20]([N:9]1[CH2:10][CH:11]([O:13][C:14](=[O:19])[C:15]([CH3:17])([CH3:16])[CH3:18])[CH2:12][NH:8]1)=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CC(OC(=O)C(C)(C)C)CN1C(=O)OCc1ccccc1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CO
Product: CC(C)(C)C(=O)OC1CNN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 12 h
Yield: 98 %

Procedure:
4-(2,2-Dimethylpropionyloxy)pyrazolidine-1,2-dicarboxylic acid 1-benzyl ester 2-tert-butyl ester, 29, (1.76 g, 4.33 mmol) is dissolved in methanol (40 mL) and the solution cooled to 0° C. Thionyl chloride (3.16 mL, 43.3 mmol) is added dropwise and the reaction allowed to warm to room temperature and continue stirring 12 hours. The reaction solution is concentrated in vacuo to give afford 1.45 g (98% yield) of the desired product as the HCl salt as an off-white solid.
Reaction SMILES: Cl[CH:2]([F:4])[F:3].[CH:5]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:12].[OH-].[Na+].O1CCOCC1>O>[F:3][CH:2]([O:11][C:10]1[CH:5]=[C:6]([CH3:12])[CH:7]=[CH:8][CH:9]=1)[F:4]
Reactant: Cc1cccc(O)c1
Reactant: FC(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc(OC(F)F)c1
Temperature: 68 °C
Reaction time: 0.75 h
Yield: 64.5 %

Procedure:
260 parts by weight of chlorodifluoromethane are passed over 10 hours, whilst stirring, into a mixture of 221 parts by weight of m-cresol, 412 parts by weight of sodium hydroxide, 600 parts by volume of 1,4-dioxane and 500 parts by volume of water, at 67°-70° C. After stirring for 45 minutes at 68° C., the reaction mixture is cooled, diluted with 1,000 parts by volume of water and extracted four times with 200 parts by volume of diethyl ether. After drying, concentrating under reduced pressure and distilling, 209 parts by weight (yield: 64.5% of theory) of 3-tolyl difluoromethyl ether of boiling point 64°-67° C./24.7 mbar are obtained.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13](/[CH:15]=[CH:16]/[N+]([O-])=O)[C:12]([N+:20]([O-])=O)=[CH:11][C:10]=1[O:23][CH3:24])C1C=CC=CC=1>CO.[C].[Pd]>[CH3:24][O:23][C:10]1[CH:11]=[C:12]2[C:13]([CH:15]=[CH:16][NH:20]2)=[CH:14][C:9]=1[OH:8]
Reactant: COc1cc([N+](=O)[O-])c(/C=C/[N+](=O)[O-])cc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COc1cc2[nH]ccc2cc1O
Reaction time: 3 h
Yield: 46 %

Procedure:
(E)-1-(Benzyloxy)-2-methoxy-4-nitro-5-(2-nitrovinyl)benzene described in Production Example 1-2 (9.4 g, 28.5 mmol) was suspended in methanol (300 mL), then 10% palladium-carbon (water content, 50%) (3.09 g) was added, and the mixture was stirred under hydrogen atmosphere for 3 hours. The catalyst was filtered off with celite and washed with methanol. The filtrate was concentrated under vacuum and the resultant was purified with silica gel column chromatography (n-heptane:ethyl acetate=3:1-3:7). The target fraction was concentrated under vacuum to obtain the title compound (2.12 g, 46%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][CH2:14][NH2:15])=[CH:5][CH:4]=1.[CH:16](O)=[O:17]>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][CH2:14][NH:15][CH:16]=[O:17])=[CH:5][CH:4]=1
Reactant: O=CO
Reactant: COc1ccc2cccc(CCN)c2c1
Product: COc1ccc2cccc(CCNC=O)c2c1
Temperature: 120 °C

Procedure:
0.01 mol of 2-(7-methoxynaphth-1-yl)ethylamine and 0.02 mol of formic acid are placed in a porcelain crucible, and heated at 120° C. until a dry residue is obtained. This is recrystallized.