Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][CH:6]([F:16])[C:7]1[C:11]([C:12](O)=[O:13])=[CH:10][N:9]([CH3:15])[N:8]=1>ClC1C=CC=CC=1>[F:5][CH:6]([F:16])[C:7]1[C:11]([C:12]([Cl:3])=[O:13])=[CH:10][N:9]([CH3:15])[N:8]=1
Reactant: O=S(Cl)Cl
Reactant: Cn1cc(C(=O)O)c(C(F)F)n1
Solvent: Clc1ccccc1
Product: Cn1cc(C(=O)Cl)c(C(F)F)n1
Temperature: 110 °C
Reaction time: 1 h
Yield: 195.3 %

Procedure:
69.5 g of thionyl chloride (0.58 mol, 1.17 equivalents) are added at 110° C. in the course of 2 hours to a solution of 88 g of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid (0.5 mol) in 440 g of chlorobenzene. The reaction mixture is stirred for 1 hour at 110° C. The reaction mixture is concentrated to a crude product solution. 190 g of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (50% in chlorobenzene, yield: 98%) is obtained. The crude product solution is used without being further purified.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH:7]=[CH:6][C:5]([C:9]([O:11]C)=[O:10])=[CH:4]1.[C:13](Cl)(=[O:15])[CH3:14].C(N(CC)CC)C>ClCCl>[C:13]([NH:2][CH:3]1[CH2:8][CH:7]=[CH:6][C:5]([C:9]([OH:11])=[O:10])=[CH:4]1)(=[O:15])[CH3:14]
Reactant: CC(=O)Cl
Reactant: COC(=O)C1=CC(N)CC=C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC1C=C(C(=O)O)C=CC1

Procedure:
A solution of 190 mg (1 m mole) of methyl 3-amino-1,5-cyclohexadienecarboxylate hydrochloride in 5 ml of dichloromethane is treated with 78 mg (1 m mole) of acetyl chloride and 202 mg (2 m mole) of triethylamine for 1 hour at 25° C. after which the solution is washed with water, dryed and concentrated. The residue is treated at 25° C. with 3 ml of methanol and 100 ml of sodium hydroxide in 200 ml of water for 3 hours then acidified and extracted with dichloromethane. The organic phase is dried and evaporated to afford 3-acetamido-1,5-cyclohexadiene carboxylic acid.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C@@H:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:7][OH:8])=[O:4].[H-].[Na+]>C1COCC1>[C:9]1([C@@H:6]2[NH:5][C:3](=[O:4])[CH2:2][O:8][CH2:7]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(CCl)N[C@H](CO)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1COC[C@H](c2ccccc2)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-2-chloro-N-(2-hydroxy-1-phenylethyl)acetamide (600 mg, 2.8 mmol) in anhydrous THF solution at 0° C. was added NaH mineral oil suspension (247 mg, 6.18 mmol). The resulting mixture was stirred overnight at room temperature. The reaction mixture was concentrated to dryness, and the residue was partitioned between CH2Cl2/brine/H2O (20 mL/18 mL/2 mL). CH2Cl2 layer was dried over anhydrous Na2SO4, filtered off, concentrated in vacuo. The crude product, (S)-5-phenylmorpholin-3-one, was obtained as a white solid (498 mg, 97%). The crude product was used directly in next step without further purification. LCMS (m/z): 178.2 (MH+), 0.47 min.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:26]#[N:27])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[Cl:25])[CH:10]=2)=[O:5])C.C([O:32][C:33](=[O:39])[C:34]([CH3:38])([CH3:37])[CH2:35][NH2:36])(C)(C)C.C(O)(=O)C>CO>[Cl:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[O:17][C:11]1[CH:10]=[C:9]2[C:14]([C:15]([OH:16])=[C:6]([C:4]([NH:36][CH2:35][C:34]([CH3:38])([CH3:37])[C:33]([OH:39])=[O:32])=[O:5])[N:7]=[C:8]2[C:26]#[N:27])=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)CN
Reactant: CCOC(=O)c1nc(C#N)c2cc(Oc3ccc(F)cc3Cl)ccc2c1O
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(CNC(=O)c1nc(C#N)c2cc(Oc3ccc(F)cc3Cl)ccc2c1O)C(=O)O
Yield: 80 %

Procedure:
A mixture of A mixture of 1-cyano-4-hydroxy-7-(4-fluoro-2-chloro-phenoxy)-isoquinoline-3-carboxylic acid ethyl ester (40 mg, 0.10 mmol) and 3-amino-2,2-dimethyl-propionic acid tert-butyl ester (43 mg, 0.25 mmol) in 1 mL of MeOH was microwaved at 130° C. for 1 h. Reaction mixture was quenched with acetic acid (0.3 mmol) and then concentrated. Residue was purified by silica gel chromatography, eluting with 5-60% EtOAc/hexanes, to provide the title compound 41 mg (0.08 mmol) in 80% yield. 1H NMR (200 MHz) in CDCl3, δ ppm: 14.07 (s, 1H), 8.41 (d, J=9.2 Hz, 1H), 8.32 (br t, 1H), 7.50 (dd J=9.1, 2.6 Hz, 1H), 7.38-7.10 (m, 4H), 3.55 (d, J=6.8, 2 H), 1.23 (s, 6H).
Reaction SMILES: CCN=C=NCCCN(C)C.[C:12]([O:16][C:17]([NH:19][CH2:20][CH2:21][C:22]([OH:24])=O)=[O:18])([CH3:15])([CH3:14])[CH3:13].[CH3:25][C:26]1([CH3:34])[O:33][C:31](=[O:32])[CH2:30][C:28](=[O:29])[O:27]1.CO>CN(C1C=CN=CC=1)C.C(Cl)Cl.C(Cl)(Cl)Cl>[CH3:25][C:26]1([CH3:34])[O:33][C:31](=[O:32])[CH:30]([C:22](=[O:24])[CH2:21][CH2:20][NH:19][C:17](=[O:18])[O:16][C:12]([CH3:13])([CH3:14])[CH3:15])[C:28](=[O:29])[O:27]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC(=O)C1C(=O)OC(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.7 %

Procedure:
EDCI (59.39 g, 310.8 mmol) was added at 0° C. to a stirred solution of 3-(tert-butoxycarbonylamino)propanoic acid (I-59a: 49 g, 258.9 mmol), meldrum's acid (41.05 g, 284.8 mmol) and DMAP (47.4 g, 388.5 mmol) in DCM (490 mL) and the resulting reaction mass was allowed to stir at room temperature overnight. The reaction was monitored by TLC (10% methanol in CHCl3). The reaction mass was washed with 5% KHSO4 solution and separated the layers. The organic layer was dried over Na2SO4 and concentrated to afford 70 g of the product (85.8% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.C(N(CC)CC)C.[CH2:16]([S:18](Cl)(=[O:20])=[O:19])[CH3:17].[OH-].[Na+]>ClCCl.CO>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][S:18]([CH2:16][CH3:17])(=[O:20])=[O:19])[CH:5]=[N:6][CH:7]=1
Reactant: CCS(=O)(=O)Cl
Reactant: Nc1cncc(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1cncc(Br)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 5-bromo-3-pyridinamine (0.8 g, 4.62 mmol), triethylamine (2.6 mL, 18.48 mmol) in dichloromethane (20 mL) at 0° C. under inert atmosphere. The reaction mixture was stirred for 15 min and then ethyl sulfonyl chloride (0.88 mL, 9.24 mmol) was added slowly. The reaction mixture was stirred for 2 h at room temperature. Diluted with dichloromethane and then washed with saturated aqueous sodium chloride solution, separated the organic layer, dried over sodium sulphate, concentrated under high vacuum, light yellow solid obtained. The solid was dissolved in methanol (10 mL), cooled to 0° C., added 10N aqueous sodium hydroxide (10 mL) solution. The reaction mixture was stirred for 1 h and then methanol was evaporated completely and extracted with ethyl acetate. The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under vacuum to obtain the title compound. MS (M+1): 266.9.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([CH2:24][OH:25])[CH2:20][CH2:19]1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>ClCCl.C(=O)(O)[O-].[Na+]>[CH3:33][S:34]([O:25][CH2:24][C@H:21]1[CH2:22][CH2:23][C@H:18]([NH:17][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=3)[N:8]=[CH:7][C:6]=2[C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])[CH2:19][CH2:20]1)(=[O:36])=[O:35]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](CO)CC1)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Reaction time: 2 h

Procedure:
To a suspension of (6-bromo-4-((trans-4-(hydroxymethyl)cyclohexyl)amino)quinolin-3-yl) (cyclopropyl)methanone (1.23 g, 3.05 mmol) in dichloromethane (60 mL) was added triethylamine (2.09 mL, 15 mmol) and methanesulfonyl chloride (0.35 mL, 4.5 mmol) was added dropwise. The reaction mixture was stirred for 2 h. The solution was then diluted with saturated sodium bicarbonate solution and extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. Purification by column chromatography (silica, ethyl acteate/hexanes) afforded the desired product (0.98 g, 67%) as a white solid. ESI MS m/z 481 [C21H25BrN2O4S+H]+
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[C@H:3]([OH:20])[CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[CH:7]=[N:6]1.C([Li])CCC.Cl[C:29]([O:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)=[O:30].C(=O)(O)[O-].[Na+]>O1CCCC1>[C:29](=[O:30])([O:31][C:32]1[CH:33]=[CH:34][C:35]([N+:38]([O-:40])=[O:39])=[CH:36][CH:37]=1)[O:20][C@H:3]([CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[CH:7]=[N:6]1)[C:2]([CH3:22])([CH3:21])[CH3:1]
Reactant: CC(C)(C)[C@H](O)Cn1cc(-c2ccc(C(F)(F)F)cc2)cn1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[C@@H](Cn1cc(-c2ccc(C(F)(F)F)cc2)cn1)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 0.17 h
Yield: 77.7 %

Procedure:
To 3.30 g (10.57 mmol) of (2S)-3,3-dimethyl-1-{4-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}-2-butanol in 200 mL of tetrahydrofuran at 0° C. was added 7.26 mL (11.62 mmol) of 1.6 M n-butyllithium in hexanes, and the resulting solution was stirred for 10 min. Then, 3.19 g (15.84 mmol) of 4-nitrophenyl chloroformate in 11 mL of tetrahydrofuran was added, and the solution was stirred at room temperature for 75 min. Saturated aqueous sodium bicarbonate was added, and the resulting mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with an ethyl acetate:hexanes solution (3:7) to give 3.92 g (78%) of (1S)-2,2-dimethyl-1-({4-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl 4-nitrophenyl carbonate. Rf=0.19 (3:7 ethyl acetate:hexanes); 1H-NMR (300 MHz, DMSO-d6): δ 8.44 (s, 1H), 8.14 (d, J=9 Hz, 2H), 8.08 (s, 1H), 7.79 (d, J=8 Hz, 2H), 7.70 (d, J=8 Hz, 2H), 7.27 (d, J=9 Hz, 2H), 4.88 (dd, J=10 Hz, J=2 Hz, 1H), 4.61 (d, J=13 Hz, 1H), 4.32 (dd, J=15 Hz, J=10 Hz, 1H), 1.05 (s, 9H); ES-LCMS m/z 478 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[N:26]=[C:15]3[C:16]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[N:17][CH:18]=[CH:19][N:14]3[N:13]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[S:27]([O-])(=[O:30])(=[O:29])[CH3:28].CS(Cl)(=O)=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[N:26]=[C:15]3[C:16]([N:20]4[CH2:25][CH2:24][N:23]([S:27]([CH3:28])(=[O:30])=[O:29])[CH2:22][CH2:21]4)=[N:17][CH:18]=[CH:19][N:14]3[N:13]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1cc(Nc2nc3c(N4CCNCC4)nccn3n2)cc(OC)c1
Reactant: CS(=O)(=O)[O-]
Agent: CS(=O)(=O)Cl
Product: COc1cc(Nc2nc3c(N4CCN(S(C)(=O)=O)CC4)nccn3n2)cc(OC)c1

Procedure:
N-(3,5-dimethoxyphenyl)-8-piperazin-1-yl-[1,2,4]triazolo[1,5-a]pyrazin-2-amine (synthesized as described earlier) was converted into the mesylate by treatment with Methanesulfonylchloride under standard conditions.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[C:27]3[C:22](=[C:23]([CH2:28][S:29][CH3:30])[CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[CH:9]2C(=O)O[C:12](C)([CH3:16])[O:11][C:10]2=[O:18])=[CH:4][C:3]=1[F:31]>N1C=CC=CC=1.C(O)C.[Cu]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[C:27]3[C:22](=[C:23]([CH2:28][S:29][CH3:30])[CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[CH2:9][C:10]([O:11][CH2:12][CH3:16])=[O:18])=[CH:4][C:3]=1[F:31]
Reactant: CSCc1cccc2c(C(c3ccc(Cl)c(F)c3)C3C(=O)OC(C)(C)OC3=O)c[nH]c12
Agent: [Cu]
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)CC(c1ccc(Cl)c(F)c1)c1c[nH]c2c(CSC)cccc12

Procedure:
17 mg (262 μmol) of copper powder were added to a solution of 2.42 g (5.24 mmol) of the compound from Example 95A in 10 ml of pyridine and 2 ml of ethanol. The reaction mixture was heated under reflux for 4 h. It was concentrated, and the crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient) to result in 1.82 g (85% of theory) of the title compound.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[N:6]2[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1.[C:25]1([C:31]2([C:37](=[O:39])[CH3:38])[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>C(Cl)Cl.C(O)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([N:6]2[C:5]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])=[N:4][C:3]3[C:7]2=[N:8][CH:9]=[N:10][C:2]=3[N:34]2[CH2:35][CH2:36][C:31]([C:37](=[O:39])[CH3:38])([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:32][CH2:33]2)=[CH:12][CH:13]=1
Reactant: Clc1ccc(-n2c(-c3ccccc3Cl)nc3c(Cl)ncnc32)cc1
Reactant: CC(=O)C1(c2ccccc2)CCNCC1
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: ClCCl
Product: CC(=O)C1(c2ccccc2)CCN(c2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Reaction time: 8 h

Procedure:
To a solution of 6-Chloro-9-(4-chlorophenyl)-8-(2-chlorophenyl)-9H-purine I-(4A-7)c (68 mg, 0.18 mmol) in 1:1 methylene chloride/ethanol (2 ml) was added 1-(4-phenylpiperidin-4-yl)-ethanone (48 mg, 0.2 mmol) and triethylamine (70 μl, 0.5 mmol). The mixture was stirred overnight, concentrated under reduced pressure, and then purified on a Biotage™ Flash 12S column using 5–10% methanol in methylene chloride as eluant to give title compound 29A-1 (77 mg, 78%).
Reaction SMILES: [C:1]([Mg]Br)#[CH:2].[OH:5][CH2:6][C:7]1[O:11][N:10]=[C:9]([C:12](=[O:14])[CH3:13])[CH:8]=1>C1COCC1>[OH:5][CH2:6][C:7]1[O:11][N:10]=[C:9]([C:12]([OH:14])([C:1]#[CH:2])[CH3:13])[CH:8]=1
Reactant: C#C[Mg]Br
Reactant: CC(=O)c1cc(CO)on1
Solvent: C1CCOC1
Product: C#CC(C)(O)c1cc(CO)on1
Temperature: 25 °C

Procedure:
To a solution of ethynylmagnesium bromide (0.5M in THF, 99 mL, 49.0 mmol) at 0° C. under N2 was added a solution of 1-[5-(hydroxymethyl)isoxazol-3-yl]ethanone (prepared according to Synthesis 2005, 20, 3541) (4.10 g, 29.0 mmol) in dry THF (25 mL) over 20 minutes. The reaction mixture was warmed to RT for 1.5 hr, quenched by dropwise addition of saturated aqueous ammonium chloride (20 mL) and concentrated in vacuo. After re-dissolving the residue in EtOAc (100 mL), the aqueous phase was removed, diluted with water to dissolve all suspended solids and washed with EtOAc (100 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to furnish the crude title compound as a red-brown syrup: 1H NMR (500 MHz, CDCl3) delta 1.88 (3H, s), 2.67 (1H, s), 4.77 (2H, s), 6.39 (1H, s); LC-MS: m/z=+167.9 (M+H)+. This compound, with LC-MS purity=88% UV, was used in the next step without further purification.
Reaction SMILES: [CH3:1][O-:2].[Na+].C([O:6][C:7]([C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:11]([C:20]2[CH:25]=[CH:24][C:23](Br)=[CH:22][N:21]=2)[N:10]=1)=[O:8])C.O>CO.C1(C)C=CC=CC=1.[Cu]Br>[CH3:1][O:2][C:23]1[CH:24]=[CH:25][C:20]([N:11]2[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[CH:13][C:9]([C:7]([OH:6])=[O:8])=[N:10]2)=[N:21][CH:22]=1
Reactant: C[O-]
Reactant: CCOC(=O)c1cc(-c2ccccn2)n(-c2ccc(Br)cn2)n1
Agent: [Cu]Br
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1ccc(-n2nc(C(=O)O)cc2-c2ccccn2)nc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 70.5 %

Procedure:
In an argon atmosphere at room temperature, sodium methoxide (1.74 g) and copper(I) bromide (0.231 g) were added to the above-obtained 1-(5-bromo-2-pyridyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid ethyl ester (3.00 g) in a mixture of methanol (30 mL) and toluene (30 mL). The resultant mixture was refluxed under heat for 47 hours, and then cooled in air. Water (50 mL) was added to the reaction mixture, followed by stirring at room temperature for 1.5 hours. The reaction mixture was partitioned by use of water, acetic acid (10 mL), and methanol-chloroform (1:10) solvent mixture. The organic layer was dried over sodium sulfate anhydrate, followed by filtration. The solvent was removed under reduced pressure, to thereby give the title compound as a solid (1.68 g, 71%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[C:5]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:25])[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](OCC2C=CC=CC=2)=[CH:9][CH:8]=1)[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:33])[C:5]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:25])[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCc2ccccc2)c2ccccc12)Oc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(Cc1cccc2ccccc12)Oc1ccccc1
Reaction time: 20 h

Procedure:
2-Phenoxy-3-(4-benzyloxynaphthalen-1-yl)-2-methylpropionic acid ethyl ester (1.55 g, 3.5 mmol) was dissolved in ethyl acetate (50 mL) and treated with 5% palladium on carbon (400 mg), and stirred under an atmosphere of hydrogen for 20 h. The suspension was filtered through celite and concentrated in vacuo to a golden oil (1.20 g, 98%) 1H NMR (300 MHz, CDCl3): δ 8.14 (d, 1H, J=8.3), 8.10 (d, 1H, J=8.3), 7.46 (t, 1H, J=8.3), 7.42 (t, 1H, J=8.3), 7.21 (d, 1H, J=7.8), 7.12 (dd, 2H, J=8.8, 7.4), 6.87 (t, 1H, J=7.4), 6.70 (m, 3H), 4.05 (q, 2H, J=6.8), 3.65 (d, 1H, J=14.2), 3.54 (d, 1H, J=14.2), 1.37 (s, 3H), 1.17 (t, 3H, J=6.8). MS [EI+] 373 (M+Na)+, [EI−] 349 (M−H).
Reaction SMILES: O1CCCC1.[CH3:6][CH2:7][CH:8]([OH:11])[CH2:9][CH3:10].[H-].[Na+].[Br:14][C:15]1[N:32]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:18]2[CH:19]=[N:20][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22](=[O:23])[C:17]=2[C:16]=1[CH2:41]Br>O>[Br:14][C:15]1[N:32]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:18]2[CH:19]=[N:20][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22](=[O:23])[C:17]=2[C:16]=1[CH2:41][O:11][CH:8]([CH2:9][CH3:10])[CH2:7][CH3:6]
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(CBr)c(Br)n2COCC[Si](C)(C)C)c1=O
Reactant: CCC(O)CC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCC(CC)OCc1c(Br)n(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
To 15 ml of dehydrated tetrahydrofuran solution containing 1.90 ml of 3-pentanol was added 0.38 g of sodium hydride (55% dispersed material in mineral oil) under cooling in ice-bath, and the mixture was stirred at room temperature for 3 hours. Then, 0.99 g (1.75 mmol) of 2-bromo-3-bromomethyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 25-(a) was added to the mixture, and the mixture was stirred at 45° C. for 2 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and then, concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=7:3 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 0.66 g of the title compound as a slightly yellowish oil. (Yield: 65%)
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH2:14])(=[O:13])=[O:12])=[C:7]([F:15])[CH:6]=1)=O.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([OH:26])=[O:25])=[CH:19][CH:18]=1>>[Br:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[C:24](=[O:26])[O:25][CH2:2][C:3]=2[C:5]2[CH:10]=[CH:9][C:8]([S:11]([NH2:14])(=[O:13])=[O:12])=[C:7]([F:15])[CH:6]=2)=[CH:21][CH:22]=1
Reactant: NS(=O)(=O)c1ccc(C(=O)CBr)cc1F
Reactant: O=C(O)Cc1ccc(Br)cc1
Product: NS(=O)(=O)c1ccc(C2=C(c3ccc(Br)cc3)C(=O)OC2)cc1F

Procedure:
The title compound was prepared according to the procedure of Example 32 using 4-bromoacetyl-2-(fluoro)benzenesulfonamide from step 2 instead of [2-bromo-1-[4-methylsulfonyl)phenyl]ethanone, 4-bromophenylacetic acid instead of 4-(3-thienyl)phenylacetic acid.
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([CH2:12]Cl)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([CH:25]([CH3:29])[C:26]([OH:28])=[O:27])[CH:19]=[CH:18]2>>[CH3:29][CH:25]([C:20]1[CH:19]=[CH:18][C:17]2[C:22](=[CH:23][CH:24]=[C:15]([O:14][CH2:12][C:10]3[N:11]=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[S:8][CH:9]=3)[CH:16]=2)[CH:21]=1)[C:26]([OH:28])=[O:27]
Reactant: ClCc1csc(-c2ccccc2)n1
Reactant: CC(C(=O)O)c1ccc2cc(O)ccc2c1
Product: CC(C(=O)O)c1ccc2cc(OCc3csc(-c4ccccc4)n3)ccc2c1

Procedure:
The title compound is prepared according to the method of Example 7 using 2-phenyl-4-(chloromethyl)thiazole and racemic 6-hydroxy-α-methyl-2-naphthalene acetic acid. White crystals are obtained having a melting point of 163°-164° C.
Reaction SMILES: C1(C(O)=O)CC1.[CH:7]1([C:10]([NH:12][C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:21]=2[C:20](=[O:22])[N:19]([CH:23]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH:35]([F:37])[F:36])=[C:30]([O:38][CH2:39][CH3:40])[CH:29]=2)[CH2:24][C:25](O)=[O:26])[CH2:18]3)=[O:11])[CH2:9][CH2:8]1.C1N=C[N:43](C(N2C=NC=C2)=O)C=1.[NH4+].[OH-]>C1COCC1>[C:25]([CH2:24][CH:23]([N:19]1[C:20](=[O:22])[C:21]2[C:17](=[CH:16][CH:15]=[CH:14][C:13]=2[NH:12][C:10]([CH:7]2[CH2:9][CH2:8]2)=[O:11])[CH2:18]1)[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH:35]([F:36])[F:37])=[C:30]([O:38][CH2:39][CH3:40])[CH:29]=1)(=[O:26])[NH2:43]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOc1cc(C(CC(=O)O)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC(F)F
Agent: O=C(O)C1CC1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(N)=O)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC(F)F
Yield: 69.6 %

Procedure:
Cyclopropanecarboxylic acid {2-[2-carbamoyl-1′-(4-difluoromethoxy-3-ethoxy-phenyl)-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl)}-amide was prepared by the procedure of example 6 from 3-[7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid (0.8 g, 1.7 mmol), CDI (0.41 g, 2.5 mmol) and NH4OH (0.25 ml, 3.4 mmol) in THF (30 ml) to give cyclopropanecarboxylic acid {2-[2-carbamoyl-1-(4-difluoromethoxy-3-ethoxy-phenyl)-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as white solid (0.56 g, 70%): mp, 179-181° C.; 1H NMR (CDCl3): δ 0.92 (m, 2H, c-CH2), 1.44 (t, J=6.8 Hz, 3H, OCH2CH3), 1.68 (m, 1H, c-CH), 2.99 (dd, J=5, 15 Hz, 1H, CH2), 3.44 (dd, J=10, 15 Hz, 1H, CH2), 4.08 (q, J=7.0 Hz, 2H, OCH2CH3), 4.20 (d, J=17.5 Hz, 1H, CH2N), 4.40 (d, J=17.5 Hz, 1H, CH2N), 5.42 (broad, 1H, NH2), 5.58 (m, 1H, CHN), 6.07 (broad, 1H), 6.56 (t, JH-F=75 Hz, 1H, CF2H), 6.98 (m, 3H, Ar), 7.15 (d, J=7.5 Hz, 1H, Ar), 7.46 (t, J=7.5 Hz, 1H, Ar), 8.45 (d, J=8 Hz, 1H, Ar), 10.49 (s, 1H, NHCO). 13C NMR (CDCl3): δ 8.31, 14.6, 16.2, 38.9, 48.6, 53.9, 64.8, 101.57, 102.3, 113.2, 116.7, 117.3, 117.8, 119.2, 122.9, 113.5, 137.3, 138.1, 141.4, 141.2, 150.9, 170.9, 171.4, 172.7; Anal. Calcd. for C24H25F2N3O5: C, 60.88; H, 5.32; N, 8.87; Found: C, 60.82; H, 5.11; N, 8.80.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([CH2:13][CH:14]2[CH2:16][CH2:15]2)(=[O:12])=[O:11])[CH2:7][N:6]1[C:17](=O)[CH2:18][C:19](=[O:21])[CH3:20])=[O:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([CH2:13][CH:14]2[CH2:16][CH2:15]2)(=[O:12])=[O:11])[CH2:7][N:6]1[C:17](=[S:32])[CH2:18][C:19](=[O:21])[CH3:20])=[O:4]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)CC2CC2)CN1C(=O)CC(C)=O
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)CC2CC2)CN1C(=S)CC(C)=O

Procedure:
In analogy to the procedure described in example 192 g, (2S,4R)-4-cyclopropylmethanesulfonyl-1-(3-oxo-butyryl)-pyrrolidine-2-carboxylic acid methyl ester was reacted with Lawesson's reagent to give the title compound as brown solid. MS (ESI): m/z=348.4 [M+H]+.