Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:26])([CH3:25])[CH2:3][CH2:4][CH2:5]/[C:6](/[CH2:19][N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1)=[CH:7]\[C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14]CC)=[O:13])=[CH:10][CH:9]=1.[OH-].[Na+]>C(O)C>[CH3:1][C:2]([CH3:26])([CH3:25])[CH2:3][CH2:4][CH2:5]/[C:6](/[CH2:19][N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1)=[CH:7]\[C:8]1[CH:18]=[CH:17][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1ccc(/C=C(\CCCC(C)(C)C)Cn2ccnc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)CCC/C(=C\c1ccc(C(=O)O)cc1)Cn1ccnc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution containing ethyl 4-[6,6-dimethyl-2-(1H-imidazol-1-ylmethyl)-1-heptenyl]benzoate (prepared as in Example 14; 0.7 g, 0.0017 mol) in ethanol (10 ml ) was treated with aqueous sodium hydroxide (3.5 ml of 1M). The resulting mixture was stirred at room temperature for 5 hours after which time the solvent was evaporated off under reduced pressure and the resulting residue was dissolved in water (100 ml) and washed with ethyl acetate. The aqueous solution was acidified to pH 6.5 with hydrochloric acid and extracted with ethyl acetate (3×150 ml). The extracts were combined, dried over sodium sulfate, and the solvent was evaporated off under reduced pressure to yield a crude product. The crude product was recrystallised from dichloromethane-pentane to yield 4-[6,6-dimethyl-2-(1H-imidazol-1-ylmethyl)-1E-heptenyl]benzoic acid as a colorless, crystalline solid, having a melting point of 190°-192° C. and the following structural characteristics:
Reaction SMILES: [CH3:1][C:2]([CH3:26])([CH3:25])[C:3]([NH:5][C:6]1[CH:24]=[CH:23][C:9]2[N:10]([CH2:18][C:19]([F:22])([F:21])[F:20])[CH:11]([C:14]([F:17])([F:16])[F:15])[CH2:12][O:13][C:8]=2[CH:7]=1)=[O:4].C([Li])(C)(C)C.C([O:35][CH2:36][C:37]([F:40])([F:39])[F:38])(=O)C>C(OCC)C>[F:38][C:37]([F:40])([F:39])[C:36]([C:7]1[C:8]2[O:13][CH2:12][CH:11]([C:14]([F:17])([F:15])[F:16])[N:10]([CH2:18][C:19]([F:22])([F:21])[F:20])[C:9]=2[CH:23]=[CH:24][C:6]=1[NH:5][C:3](=[O:4])[C:2]([CH3:26])([CH3:25])[CH3:1])=[O:35]
Reactant: CC(=O)OCC(F)(F)F
Reactant: CC(C)(C)C(=O)Nc1ccc2c(c1)OCC(C(F)(F)F)N2CC(F)(F)F
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: CC(C)(C)C(=O)Nc1ccc2c(c1C(=O)C(F)(F)F)OCC(C(F)(F)F)N2CC(F)(F)F
Temperature: -10 °C
Yield: 16 %

Procedure:
To a solution of (±)-7-(2,2-dimethylpropionamido)-3,4-dihydro-4-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)-2H-1,4-benzoxazine (200 mg, 0.52 mmol) in 3 mL of dry diethyl ether at −30° C. was added t-butyllithium (1.7M/pentane, 0.80 mL, 1.35 mmol) was added dropwise over of 30 min and then stirred at −10° C. The deep yellow solution was allowed to stir at −10° C. for 5–6 hours and then recooled to −30° C. and trifluoroethyl acetate (0.186 mL, 1.56 mmol) was slowly added. The reaction was allowed to gradually warm to room temperature over the course of 12 hours. The reaction was quenched with saturated ammonium chloride (2 mL) and extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to give a brown oil. The substrate was purified via flash chromatography (4:1 hexanes:EtOAc) to afford 40 mg (15%) of (±)-3,4-dihydro-8-(trifluoroacetyl)-4-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)-7-(trimethylacetamido)-2H-1,4-benzoxazine. 1H NMR (400 MHz, CDCl3) d 8.92 (s, 1H), 7.81 (d, 1H), 7.06 (d, 1H), 4.68 (d, 1H, J=12), 4.22–4.38 (m, 1H), 4.05–4.12 (m, 1H), 3.93–4.20 (m, 1H), 3.78–3.91 (m, 1H), 1.28 (s, 9H).
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:17][C:18]2[CH:19]=[CH:20][C:21]3[N:25]=[C:24]([CH2:26][O:27][C:28]4[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=4)[C:31]([OH:33])=[O:32])[N:23]([CH3:37])[C:22]=3[CH:38]=2)=[N:13][C:14]=1[O:15][CH3:16]>C1(C)C=CC=CC=1.CO>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:17][C:18]2[CH:19]=[CH:20][C:21]3[N:25]=[C:24]([CH2:26][O:27][C:28]4[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=4)[C:31]([O:33][CH3:1])=[O:32])[N:23]([CH3:37])[C:22]=3[CH:38]=2)=[N:13][C:14]=1[O:15][CH3:16]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COc1nc(Oc2ccc3nc(COc4cccc(C(=O)O)c4)n(C)c3c2)ccc1Br
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(OCc2nc3ccc(Oc4ccc(Br)c(OC)n4)cc3n2C)c1
Yield: 49 %

Procedure:
Methyl 3-({6-[(5-bromo-6-chloropyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoate produced in Example (3a) (0.74 g, 1.47 mmol), sodium methoxide (5.0 M solution in methanol, 2.94 mL, 14.7 mmol), water (10 mL) and 1,4-dioxane (20 mL) were stirred with heating under reflux for three days. After leaving to cool, the reaction mixture was concentrated and water (50 mL) was added. This aqueous solution was neutralized by adding 1 M hydrochloric acid and the precipitated solid was collected by filtration to obtain crude 3-({6-[(5-bromo-6-methoxypyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid. Trimethylsilyldiazomethane (2.0 M solution in hexane) was added to a solution of the crude 3-({6-[(5-bromo-6-methoxypyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid in toluene (20 mL) and methanol (10 mL) until the raw material disappeared. The reaction mixture was concentrated under reduced pressure. Then, the residue was purified by silica gel chromatography (hexane/ethyl acetate, 1:1) to obtain the title compound (0.36 g, 49%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[C:13]([CH3:18])[CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][N:9]=2)=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4].C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[C:13]([CH3:18])[CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1cccc2c1CCN=C2c1ccc(Br)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: c1ccccc1
Product: Cc1cccc2c(-c3ccc(Br)cc3)nccc12

Procedure:
Thirty-four (34) grams of 1-(4-bromophenyl)-5-methyl-3,4-dihydroisoquinoline was reacted for 8 hours together with 200 g of active manganese dioxide and 1000 ml of benzene. After the reaction, the manganese dioxide was removed by filtration, and the benzene was distilled off. Recrystallization of the resulting colorless crystals (29 g) from cyclohexane afforded 1-(4-bromophenyl)-5-methylisoquinoline as colorless needles having a melting point of 126.5° to 127.5° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([NH:23][C@H:24]1[C@@H:28]([N:29]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:27][C@@H:26]([C:40]([O:42][CH3:43])=[O:41])[CH2:25]1)[N:17]=[CH:16]2.O.NN>CCO>[NH2:29][C@@H:28]1[C@H:24]([NH:23][C:18]2[N:17]=[CH:16][C:15]3[C:20](=[CH:21][CH:22]=[C:13]([C:3]4[C:4]([Cl:12])=[C:5]([O:10][CH3:11])[CH:6]=[C:7]([O:8][CH3:9])[C:2]=4[Cl:1])[CH:14]=3)[N:19]=2)[CH2:25][CH:26]([C:40]([O:42][CH3:43])=[O:41])[CH2:27]1
Reactant: COC(=O)[C@H]1C[C@@H](Nc2ncc3cc(-c4c(Cl)c(OC)cc(OC)c4Cl)ccc3n2)[C@@H](N2C(=O)c3ccccc3C2=O)C1
Agent: NN
Solvent: O
Solvent: CCO
Product: COC(=O)C1C[C@H](N)[C@H](Nc2ncc3cc(-c4c(Cl)c(OC)cc(OC)c4Cl)ccc3n2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
(1S,3R,4S)-methyl 3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)-4-(1,3-dioxoisoindolin-2-yl)cyclopentanecarboxylate (0.500 g, 0.805 mmol) was taken up in EtOH (20 ml) and hydrazine monohydrate (0.079 ml, 1.61 mmol) was added. The reaction was stirred overnight at room temperature. A white precipitate was filtered off and solvent was removed under reduced pressure. The precipitate was triturated with ether, followed by removal of the solvent under reduced pressure to give methyl (3S,4R)-3-amino-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)cyclopentane-1-carboxylate (0.395 g, 0.805 mmol) in quantative yield, which was carried on without further purification. MS (ES+) C23H24Cl2N4O4 requires: 491, found: 492 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20](OC)=[O:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([SiH2]CC)C.Cl>ClCCl.C1CCCC=CCC1.C1CCCC=CCC1.C1CCCC=CCC1.C1CCCC=CCC1.[Cl-].[Cl-].[Ir].[Ir]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[CH:16][C:17]([CH:20]=[O:21])=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [Ir]
Agent: C1=CCCCCCC1
Agent: C1=C\CCCCCC/1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(C=O)cc2)CC1

Procedure:
To a solution of 4-(4-methoxycarbonyl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (776 mg, 2.43 mmol) in dichloromethane (10 ml) are added diethylsilane (470 μl, 3.64 mmol) and chlorobis(cyclooctene)iridium(I) dimer (22 mg, 0.025 mmol) and the mixture is irradiated in a microwave reactor for 1.5 hours at 50° C. The reaction mixture is stirred vigorously with 2 N hydrochloric acid (0.6 ml) for 30 minutes. The organic layer is separated, dried over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to afford 4-(4-formyl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester as yellow resin; HPLC/MS 2.10 min (A), [M-tBu] 234.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][C@H:4]([CH2:7][C@H:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:9]([OH:11])=O)[CH2:3]1.C(Cl)(=O)C(Cl)=O.[C:28]([Si:32]([CH3:43])([CH3:42])[O:33][CH2:34][CH2:35][N:36]1[CH:40]=[CH:39][C:38]([NH2:41])=[N:37]1)([CH3:31])([CH3:30])[CH3:29].N1C(C)=CC=CC=1C>C(Cl)Cl>[C:28]([Si:32]([CH3:43])([CH3:42])[O:33][CH2:34][CH2:35][N:36]1[CH:40]=[CH:39][C:38]([NH:41][C:9](=[O:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[CH2:7][C@H:4]2[CH2:5][CH2:6][C:2](=[O:1])[CH2:3]2)=[N:37]1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(N)n1
Reactant: O=C1CC[C@H](C[C@@H](C(=O)O)c2cccc(C(F)(F)F)c2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCn1ccc(NC(=O)[C@H](C[C@H]2CCC(=O)C2)c2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
(R)-3-((R)-3-Oxo-cyclopentyl)-2-(3-trifluoromethyl-phenyl)-propionic acid (85 mg, 0.28 mmol) was dissolved in methylene chloride (2 mL) and N,N-dimethylfomamide (three drops) at 25° C. under argon. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 150 μL, 0.29 mmol) which produced gas evolution and it was then stirred at 25° C. for 30 minutes after which time it was concentrated in vacuo. The residue was then dissolved in methylene chloride (2 mL) and added dropwise into a solution of 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-ylamine (prepared in Example 67, 68 mg, 0.28 mmol), 2,6-lutidine (66 μL, 0.56 mmol) and methylene chloride (2 mL) at 0° C. It was then allowed to warm to 25° C. and stirred for 1.5 h. After this time, the reaction was quenched with a small amount of methanol and then concentrated with silica gel (2 g) in vacuo and purified on Biotage Flash chromatography system (40S column, silica gel, 50% ethyl acetate/hexanes) to afford (R)—N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-3-((R)-3-oxo-cyclopentyl)-2-(3-trifluoromethyl-phenyl)-propionamide (85 mg, 57%) as a yellow oil: [α]25589=−9.4° (c=0.16, methanol); ES-HRMS m/e calcd for C26H36N3O3SiF3 (M+Na)+ 546.2370, observed 546.2367; 1H NMR (300 MHz, CDCl3) δ-0.06 (s, 6H, 2×SiCH3), 0.83 (s, 9H, 3×CH3), 1.57 (m, 1H, CH), 1.82-2.47 (m, 8H, 4×CH2), 3.57 (m, 1H, ArCHCO), 3.85 (t, J=5.3 Hz, 2H, OCH2), 4.05 (t, J=5.3 Hz, 2H, NCH2), 6.64 (d, J=2.2 Hz, 1H, Ar), 7.32 (d, J=2.2 Hz, 1H, Ar), 7.46-7.62 (m, 4H, Ar), 7.67 (brs, 1H, NH).
Reaction SMILES: C(N1C[C@@H]2[C@@H](CCCN2)C1)C1C=CC=CC=1.[C:17]([OH:26])(=[O:25])[C@@H:18]([C@H:20]([C:22]([OH:24])=[O:23])[OH:21])[OH:19].C([C@@H]([C@H](C(O)=O)O)O)(O)=O.C(N1C[C@H]2[C@H](CCCN2)C1)C1C=CC=CC=1>CN(C)C=O>[C:17]([OH:26])(=[O:25])[C@H:18]([C@@H:20]([C:22]([OH:24])=[O:23])[OH:21])[OH:19]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: c1ccc(CN2C[C@@H]3CCCN[C@@H]3C2)cc1
Agent: c1ccc(CN2C[C@H]3CCCN[C@H]3C2)cc1
Solvent: CN(C)C=O
Product: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Temperature: 18 °C

Procedure:
73.6 g (0.34 mol) of cis-8-benzyl-2,8-diazabicyclo[4.3.0]nonane, as a solution in 111 ml of dimethylformamide, are added dropwise, at 80° to 90° C., to a solution of 102.9 g (0.685 mol) of L(+)-tartaric acid in 343 ml of dimethylformamide. Seeding with [R,R]-8-benzyl-2,8-diazabicyclo[4.3.0]nonane L-tartrate takes place, and the mixture is cooled slowly down to an internal temperature of 18° C. The crystals are filtered off with suction, and the filtrate is seeded with [S,S]-8-benzyl-2,8-diazabicyclo[4.3.0]nonane L-tartrate and stirred until crystallisation is complete. (After concentrating and liberating the base as described under method I, [S,S]-8-benzyl-2,8-diazabicyclo[4.3.0]nonane D-tartrate can be obtained from the mother liquor by purification with D(-)-tartaric acid.) Subsequently, filtration takes place with suction, and the sediment is washed with dimethylformamide and isopropanol and air-dried. The crystals are recrystallised from 88% strength ethanol. 52 g of [S,S] -8-benzyl-2,8-diazabicyclo[4.3.0]nonane L-tartrate trihydrate are obtained.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:26][CH2:25][C:11]2[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:10]=2[CH2:9]1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.[CH3:34][O:35][C:36]1[CH:44]=[N:43][C:42]([O:45][CH3:46])=[C:41]2[C:37]=1[C:38]([C:47](=[O:51])C(O)=O)=[CH:39][NH:40]2.CCN(C(C)C)C(C)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>C(Cl)Cl>[C:19]1([N:12]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:10]3[CH2:9][N:8]([C:6](=[O:7])[C:47]([C:38]4[C:37]5[C:41](=[C:42]([O:45][CH3:46])[N:43]=[CH:44][C:36]=5[O:35][CH3:34])[NH:40][CH:39]=4)=[O:51])[CH2:26][CH2:25][C:11]2=3)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(c3ccccc3n2-c2ccccc2)C1
Reactant: COc1ncc(OC)c2c(C(=O)C(=O)O)c[nH]c12
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc(OC)c2c(C(=O)C(=O)N3CCc4c(c5ccccc5n4-c4ccccc4)C3)c[nH]c12
Reaction time: 1 h
Yield: 33.6 %

Procedure:
General Method: A solution of 5-phenyl-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester (0.054 g, 0.155 mmol) in dry CH2Cl2 (2 mL) was treated with TFA (0.20 mL). After stirring the mixture for 1 h, the solvent was evaporated in vacuo and the residue was dissolved in CHCl3 (5 mL). To this mixture was added 4,7-dimethoxy-6-azaindol-3-yl-oxoacetic acid (0.042 g, 0.155 mmol), i-Pr2NEt (0.27 mL, 1.55 mmol) and then BOP-Cl (0.039 g, 0.153 mmol). The mixture was allowed to stir at room temperature for 2 h and then the solvent was removed in vacuo. The residue was partitioned with EtOAc-H2O, the organic phase was separated and the aqueous phase was re-extracted with EtOAc (2×). The combined organic layers were washed (H2O, brine), dried (Na2SO4) and evaporated. The residue was purified by preparative HPLC to give the title compound (0.025 g, 33%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 9.27 (s, 0.67H), 9.22 (s, 0.33H), 8.06 (d, J=3.0 Hz, 0.67H), 8.00 (d, J=3.0 Hz, 0.33H), 7.59-7.07 (m, 10H), 4.11 (m, 1H), 4.05 (s, 3H), 3.88 (s, 1H), 3.85 (m, 2H), 3.72 (s, 2H), 2.88 (m, 1H), 2.78 (m, 2H); LCMS: m/e 481 (M+H)+.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2C(=O)N(CC(C)C)N=C(C3C=CC(C)=C(F)C=3)C=2C)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:34][C:35]1[CH:36]=[C:37]([C:43]2[C:44](C)=[C:45](OS(C)(=O)=O)[C:46](=[O:53])[N:47]([CH2:49][CH:50]([CH3:52])[CH3:51])[N:48]=2)[CH:38]=[CH:39][C:40]=1[O:41][CH3:42].CN1CCNCC1>>[Cl:34][C:35]1[CH:36]=[C:37]([C:43]2[CH:44]=[C:45]([CH2:6][N:8]3[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]3)[C:46](=[O:53])[N:47]([CH2:49][CH:50]([CH3:51])[CH3:52])[N:48]=2)[CH:38]=[CH:39][C:40]=1[O:41][CH3:42]
Reactant: COc1ccc(-c2nn(CC(C)C)c(=O)c(OS(C)(=O)=O)c2C)cc1Cl
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Agent: CN1CCNCC1
Product: COc1ccc(-c2cc(CN3CCN(C)CC3)c(=O)n(CC(C)C)n2)cc1Cl
Yield: 76.1 %

Procedure:
Following the procedure of Example 1 (10), 6-(3-chloro-4-methoxyphenyl)-2-isobutyl-4-methanesulfonyloxy-methyl-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 76.1%).
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4]([C:6]1[CH:11]=[CH:10][C:9](I)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1OB(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C1(C)C=CC=CC=1.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>[CH2:1]([N:3]([CH2:13][CH3:14])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[O:16][CH3:15])=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCN(CC)C(=O)c1ccc(I)cc1
Reactant: COc1ccccc1OB(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: COCCOC
Solvent: O
Product: CCN(CC)C(=O)c1ccc(-c2ccccc2OC)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.6 %

Procedure:
4-Diethylcarbamoyl-1-iodobenzene (100 mg) was dissolved in dimethoxyethane (1 ml), added with tetrakis(triphenylphosphine)palladium (19.1 mg) under argon atmosphere, and stirred at room temperature for 10 minutes. The reaction mixture was added with the solution of (2-methoxyphenyl)boric acid (100 mg) dissolved in toluene (0.5 ml) prepared above and a solution of sodium carbonate (105 mg) dissolved in water (0.5 ml) and stirred at 90° C. for 5.5 hours. The reaction mixture was added with water (2 ml) and extracted twice with dichloromethane (4 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate=3:1) to obtain 81.9 mg of the title compound. Yield: 88%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:7][NH:6][C:5](=[O:8])[CH:4]=1.[Na].[CH2:10](O)C>>[CH2:1]([O:2][C:3]1[CH2:7][NH:6][C:5](=[O:8])[CH:4]=1)[CH3:10]
Reactant: COC1=CC(=O)NC1
Reactant: CCO
Agent: [Na]
Product: CCOC1=CC(=O)NC1
Yield: 65 %

Procedure:
A solution of 4-methoxy-3-pyrrolin-2-one (3 g; 26.52 mmols) in absolute ethanol (60 ml) is treated with sodium ethoxyde (2.17 g; 31.82 mmols) under nitrogen atmosphere. The solution is refluxed for 2 hours and then poured into a 30% NaH2PO4 solution (200 ml) The resulting mixture is extracted with ethyl acetate (3×150 ml) and the organic phase is shacked with brine, dried over sodium sulphate and evaporated to dryness to obtain 4-ethoxy-3-pyrrolin-2-one (2.19 g; 17.24 mmols). Yield: 65%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][CH2:8][C:9]1[N:10]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:11](=[O:34])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=[CH:16][C:15](OS(C(F)(F)F)(=O)=O)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].[C:40]([O:44][CH2:45][CH2:46][CH2:47][CH3:48])(=[O:43])[CH:41]=[CH2:42].C(=O)([O-])O.[Na+].O>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([NH:7][CH2:8][C:9]1[N:10]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:11](=[O:34])[C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)=[CH:16][C:15](/[CH:42]=[CH:41]/[C:40]([O:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:43])=[CH:14][CH:13]=2)=[O:39])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CC(=O)OCCCC
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccc(F)cc2)c2cc(OS(=O)(=O)C(F)(F)F)ccc2c1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOC(=O)/C=C/c1ccc2c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccc(F)cc3)c2c1
Temperature: 100 °C

Procedure:
A suspension of tert-butyl[4-(4-fluorophenyl)-2-isobutyl-1-oxo-6-trifluoromethanesulfonyloxy-1,2-dihydro-3-isoquinolinyl]methylcarbamate (2.00 g, 3.5 mmol), butyl acrylate (0.76 ml, 5.3 mmol), sodium hydrogencarbonate (0.45 g, 5.5 mmol), tetrabutylammonium chloride (0.11 g, 0.4 mmol) and palladium acetate (90 mg, 0.4 mmol) in N,N-dimethylformamide (30 ml) was stirred with heating at 100° C. under an argon atmosphere for 24 h. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the extract with water, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give butyl (E)-3-[3-[[(tert-butoxycarbonyl)amino]methyl]-4-(4-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenate as an amorphous.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[C:9]([CH:10]=O)=[C:8]([O:12][Si:13]([CH3:21])([CH3:20])[C:14]([CH3:19])([CH3:18])[CH:15]([CH3:17])[CH3:16])[CH:7]=[C:6]([O:22][CH3:23])[C:5]=1[F:24].C([SiH](CC)CC)C>FC(F)(F)C(O)=O.ClCCl>[CH3:1][O:2][C:3](=[O:25])[C:4]1[C:9]([CH3:10])=[C:8]([O:12][Si:13]([CH3:20])([CH3:21])[C:14]([CH3:19])([CH3:18])[CH:15]([CH3:16])[CH3:17])[CH:7]=[C:6]([O:22][CH3:23])[C:5]=1[F:24]
Reactant: COC(=O)c1c(F)c(OC)cc(O[Si](C)(C)C(C)(C)C(C)C)c1C=O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1c(C)c(O[Si](C)(C)C(C)(C)C(C)C)cc(OC)c1F
Reaction time: 18 h
Yield: 87.9 %

Procedure:
1H-NMR (250 MHz, CDCl3): δ 0.18 (s, 6H); 0.80 (d, 6H); 0.85 (s, 6H); 1.60 (m, 1H); 3.78 (s, 3H); 3.83 (s, 3H); 6.29 (d, 1H); 10.07 (d, 1H) ppm. (b) To a solution of 1.3 g of 2-fluoro-6-formyl-3-methoxy-5-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-benzoic acid methyl ester in 4 ml of trifluoroacetic acid, cooled to 0° C., was added over 10 min a solution of 0.6 g of triethylsilane in 4 ml of dichloromethane. The solution was kept at 0° C. for 18 h and then evaporated in vacuo. The residue was taken up in ethyl acetate and the solution was successively washed with water, saturated sodium carbonate solution and brine, and dried over sodium sulfate. The solvent was evaporated in vacuo and the residue was chromatographed on silica gel using ethyl acetate/hexane (1:3, v/v) as eluent to yield 1.1 g of 2-fluoro-3-methoxy-6-methyl-5-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-benzoic acid methyl ester as colorless oil.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH2:3][O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[C:15](O)=[O:16].S(Cl)([Cl:22])=O>CN(C)C=O>[F:1][C:2]([F:19])([F:18])[CH2:3][O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[C:15]([Cl:22])=[O:16]
Reactant: O=C(O)c1ccc2ccccc2c1OCC(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc2ccccc2c1OCC(F)(F)F

Procedure:
A mixture of 10 g. (37 mmoles) of 1-(2,2,2-trifluoroethoxy)-2-naphthoic acid, 21.8 ml. (35.7 g., 300 mmoles) of purified thionyl chloride and 3 drops of dimethylformamide is refluxed for one hour. Excess thionyl chloride is removed in vacuo at water aspirator pressure while heating on a steam bath. Last traces of thionyl chloride are removed by vacuum distillation with added benzene. The product is 1-(2,2,2-trifluoroethoxy)-2-naphthoyl chloride according to infrared spectral measurement.