Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8]([O:21][CH2:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:10][C:11]2=[O:14])=[CH:6][CH:5]=1)([O-])=O.C1CCCCC=1>O1CCOCC1.[Pd]>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([O:21][CH2:22][CH2:23][CH2:24][N:25]3[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]3)=[C:9]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:10][C:11]2=[O:14])=[CH:6][CH:5]=1
Reactant: O=c1[nH]c(-c2ccccc2)c(OCCCN2CCCCC2)c2ccc([N+](=O)[O-])cc12
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: C1COCCO1
Product: Nc1ccc2c(OCCCN3CCCCC3)c(-c3ccccc3)[nH]c(=O)c2c1
Temperature: 100 °C
Yield: 39.5 %

Procedure:
To a suspension of 575 mg (1.41 mmol) of 7-nitro-3-phenyl-4-(3-piperidin-1-yl-propoxy)-2H-isoquinolin-1-one (cmpd. 35) in dioxane (15 mL), cyclohexene (5 mL, 49.4 mmol) and 250 mg of palladium on carbon (10 wt. % loading) were added and the mixture was heated at 100° C. under argon atmosphere for 3 hours. The mixture was cooled to room temperature and filtered through a celite pad, which was then washed with dioxane. The solvent was concentrated under reduced pressure and the resulting crude was purified by flash chromatography (eluant: dichloromethane/methanol/acetone/7N ammonia in methanol: 90/5/5/1) to afford 210 mg of the title compound (39%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]#[C:9][C:10]1[S:23][C:13]2[C:14]3[CH:22]=[N:21][CH:20]=[CH:19][C:15]=3[O:16][CH2:17][CH2:18][C:12]=2[CH:11]=1.[N-:24]=[N+:25]=[N-:26].[Na+].O>CS(C)=O>[S:23]1[C:13]2[C:14]3[CH:22]=[N:21][CH:20]=[CH:19][C:15]=3[O:16][CH2:17][CH2:18][C:12]=2[CH:11]=[C:10]1[C:9]1[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[N:26][NH:25][N:24]=1
Reactant: Clc1ccccc1C#Cc1cc2c(s1)-c1cnccc1OCC2
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Clc1ccccc1-c1n[nH]nc1-c1cc2c(s1)-c1cnccc1OCC2
Temperature: 90 °C
Yield: 18.4 %

Procedure:
A mixture of 68 mg (0.2 mmol) of 2-((2-chlorophenyl)ethynyl)-4,5-dihydropyrido[4,3-b]thieno[2,3-d]oxepine and 52 mg (0.8 mmol) of sodium azide in 4 ml of dimethylsulfoxide was heated at 90° C. for 36 hours. Water (20 ml) was added to the mixture and extracted 6 times with 10 ml of ethyl acetate. The combined organic extracts were washed with water, brine and dried over sodium sulfate. The solvent was removed in vacuum and the crude product was recrystallized from ethyl acetate to give 324 (14 mg, 18%). 1H NMR (400 MHz, DMSO) δ 8.68 (s, 1H), 8.24 (d, J=5.5, 1H), 7.73-7.46 (m, 4H), 6.98 (d, J=5.5, 1H), 6.77 (s, 1H), 4.31 (t, J=4.7, 2H), 3.08 (t, J=4.7, 2H). MS: (ESI+) 381.1
Reaction SMILES: S(C)C.[CH3:4][Li].[CH2:6]([N:13]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C@@H:14]([CH2:17][CH3:18])[CH:15]=[O:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CCOCC>[CH2:19]([N:13]([CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[C@@H:14]([CH2:17][CH3:18])[C@H:15]([OH:16])[CH3:4])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC[C@@H](C=O)N(Cc1ccccc1)Cc1ccccc1
Reactant: [Li]C
Solvent: CCOCC
Solvent: CSC
Product: CC[C@@H]([C@@H](C)O)N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.4 %

Procedure:
To a stirred suspension of CuBr.SMe2 (1.54 g, 7.5 mmol) in anhydrous ether under an argon atmosphere at −78° C., was added methyllithium (1.6M in ether, 9.4 ml, 15 mmol) dropwise. After the addition was complete, the reaction was allowed to warm to room temperature. The reaction was recooled to −78° C. and a solution of (S)-2-(dibenzylamino)butanal (1 g, 3.75 mmol) in ether (20 ml) was added dropwise. After the addition, continued stirring for 2 h The reaction was then quenched with a saturated aqueous solution of NH4Cl (10 ml). The reaction mixture was extracted with ether (2×30 ml) and the combined organic phase washed with brine (20 ml), dried (MgSO4) and evaporated in vacuo. The residue was purified by flash silica gel gradient column chromatography, eluted with hexane:ethyl acetate (100:0→80:20) to afford the product as a light yellow oil (0.95 g, 89%) as the only isomer. δH (250 MHz, CDCl3) 1.05 (3 H, t, J 7.5, CHCH2CH3), 1.25 [3 H, d, J 7.5, CH(CH3)OH], 1.6-1.49 (1 H, m, CHHCH3), 1.88-1.73 (1 H, m, CHHCH3), 2.41 (1 H, s, br, OH), 2.66-2.59 (1 H, m, CHCH2CH3), 3.85-3.65 (4 H, m, 2×CH2Ph), 4.05-3.9 (1 H, m, CHOH), 7.41-7.25 (10 H, m, ArH) δC (250 MHz, CDCl3) 140.05 (2×C), 128.98 (4×CH), 128.37 (4×CH), 127.3 (2×CH), 66.81 (CH), 63.65 (CH), 55.41 (CH2), 20.63 (CH3) 18.44 (CH2), 12.5 (CH3)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][C:7](=O)[CH2:8]Br.[C:12]([NH:19][C:20]([NH2:22])=[NH:21])([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[Na+].[I-]>CN(C=O)C>[C:15]([O:14][C:12]([N:19]1[CH:8]=[C:7]([CH2:6][CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:11])[N:21]=[C:20]1[NH2:22])=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: COC(=O)CCCC(=O)CBr
Reactant: CC(C)(C)OC(=O)NC(=N)N
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Temperature: 25 °C
Yield: 64.8 %

Procedure:
6-bromo-5-oxo-hexanoic acid methyl ester (2.30 g, 10.3 mmol), Boc-guanidine (4.92 g, 30.9 mmol),32 and NaI (3.07 g, 20.6 mmol) were dissolved in DMF (30 mL) and allowed to stir at room temperature. After 24 h the DMF was removed under reduced pressure and the residue was taken up in ethyl acetate (100 mL) and washed with water (3×50 mL) and brine (50 mL) before being dried (Na2SO4), filtered and evaporated to dryness. The resulting oil was purified by flash column chromatography (50-100% EtOAc/Hexanes) to obtain a yellow oil. Trituration of the viscous oil with cold hexanes (20 mL) produced a precipitate, which upon filtration yielded 18 (1.89 g, 65%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 6.53 (s, 1H), 5.6 (br s, 2H), 2.41 (t, 2H, J=7.2 Hz), 2.37 (t, 2H, J=7.2 Hz), 1.93 (quint., 2H, J=7.2 Hz), 1.58 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 174.09, 150.11, 149.61, 138.39, 107.15, 84.81, 51.56, 33.65, 28.18, 27.68, 23.82; HRMS (ESI) calcd for C13H22N3O4(MH)+ 284.1604. found 284.1606.
Reaction SMILES: O[NH:2][C:3]1[N:4]=[CH:5][C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:7][CH:8]=1>CO.[OH-].[OH-].[Pd+2]>[NH2:2][C:3]1[N:4]=[CH:5][C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:7][CH:8]=1
Reactant: CCOC(=O)Cc1cnc(NO)cn1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)Cc1cnc(N)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of ethyl [5-(hydroxyamino)pyrazin-2-yl]acetate (2.8 g, 14.2 mmol) and Pd(OH)2 (3 g, 10%) in 150 mL of methanol was stirred at room temperature under 50 psi of H2 for 2 hours before filtration. The filtrate was concentrated to afford ethyl (5-aminopyrazin-2-yl)acetate. 1H-NMR (400 MHz, CDCl3) δ ppm 7.96 (s, 1H), 7.94 (s, 1H), 4.59 (brs, 2H), 4.18 (q, J=7.2 Hz, 2H), 3.71 (s, 2H), 1.25 (t, J=7.2 Hz, 3H).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:13]([N:15]1[CH2:19][CH2:18][CH:17]2[N:20]([C:36](=[O:49])[CH2:37][NH:38][C:39]([O:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[O:40])[CH2:21][CH:22]([C:23](=[O:35])[NH:24][C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][CH:26]=3)[CH:16]12)=[O:14])[C:9]([CH3:12])([CH3:11])[CH3:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:42]([O:41][C:39](=[O:40])[NH:38][CH2:37][C:36]([N:20]1[CH2:21][CH:22]([C:23](=[O:35])[NH:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=[CH:27][CH:26]=2)[CH:16]2[N:15]([C:13](=[O:14])[CH:8]([NH2:7])[C:9]([CH3:10])([CH3:11])[CH3:12])[CH2:19][CH2:18][CH:17]12)=[O:49])[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: CC(C)(C)OC(=O)NC(C(=O)N1CCC2C1C(C(=O)Nc1cccc3ccccc13)CN2C(=O)CNC(=O)OCc1ccccc1)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C(N)C(=O)N1CCC2C1C(C(=O)Nc1cccc3ccccc13)CN2C(=O)CNC(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 92.4 %

Procedure:
A solution of 57 (570 mg) in DCM (10 mL) was treated with TFA (3 mL) at ambient temperature. After 2 h, the solution was concentrated, diluted with EtOAc, and washed with saturated NaHCO3. The aqueous phase was back extracted with DCM and the combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to afford 58 (450 mg) which was used without further purification. Mass spectrum, m/z [586.4] (M+H)+.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:4]([NH:6][C@H:7]([C:17]([NH:19][C@H:20]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:21][CH:22]([CH3:24])[CH3:23])=[O:18])[CH2:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:5])[CH3:3].[NH:37]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][C:39]([OH:41])=O>>[NH:37]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][C:39]([NH:1][C@H:2]([C:4]([NH:6][C@H:7]([C:17]([NH:19][C@H:20]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:21][CH:22]([CH3:24])[CH3:23])=[O:18])[CH2:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:5])[CH3:3])=[O:41]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CCOC(=O)[C@H](CC(C)C)NC(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Product: CCOC(=O)[C@H](CC(C)C)NC(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](C)NC(=O)CNC(=O)OC(C)(C)C
Yield: 77.8 %

Procedure:
By using 3.50 g of Boc-Ala-Ser(Bzl)-Leu-OEt and 1.30 g of Boc-Gly-OH, and the same procedure as in Reference Example 15 was repeated to obtain 3.03 g (yield: 77.8%) of the above-mentioned objective product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([C:11](C1C=C(C(C)C)C(OC)=CC=1OC)=[O:12])[CH2:5]2.C([O-])([O-])=O.[Na+].[Na+].[C:32]1(C)C=CC=C[CH:33]=1>CO.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>[CH:32]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([CH:11]=[O:12])[CH2:5]2)=[CH2:33]
Reactant: Cc1ccccc1
Reactant: COc1cc(OC)c(C(C)C)cc1C(=O)N1Cc2ccc(Br)cc2C1
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: CO
Solvent: O
Product: C=Cc1ccc2c(c1)CN(C=O)C2
Temperature: 80 °C

Procedure:
To (5-bromo-1,3-dihydro-isoindol-2-yl)-(5-isopropyl-2,4-dimethoxyphenyl)methanone (2.2 g, 5.44 mmol), and 2-vinyl-4,4,5,5-tetramethyl-1,3,2-dioxaboralane (1.2 ml, 6.53 mmol) in MeOH (25 ml) and toluene (25 ml) was added Na2CO3 in water (25 ml). The reaction was degassed, Pd(PPh3)4 (0.38 g, 0.05 mmol) added then heated at 80° C. overnight. The reaction was worked up by adding water and extracting with EtOAc (×3). The combined organic layers were washed with brine and dried over MgSO4. The product was filtered and evaporated to dryness then purified by flash column chromatography, gradient elution (ether:petrol) to yield 5-isopropyl-2,4-dimethoxy-phenyl)-(5-vinyl-1,3-dihydro-isoindol-2-yl)-methanone as a yellow oil (1.6 g). 1H NMR (Me-d3-OD) 7.47-7.15 (3H, m), 7.15 (1H, s), 6.82-6.72 (1H, m), 6.71 (1H, s), 5.79 (1H, dd), 5.24 (1H, dd), 4.90 (2H, d), 4.64 (2H, d), 3.93 (3H, s), 3.91 (3H, s), 3.27 (1H, sept), 1.23 (6H, d). MS: [M+H]+ 352.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[O:19])[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([Cl:28])=[CH:7][CH:8]=2)[N:3]=1.[C:29]1([N:35]=[C:36]=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CC#N.ClCCCl>[Cl:28][C:6]1[CH:5]=[C:4]2[C:9]([C:10]([N:12]3[CH2:13][CH2:14][N:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)=[O:19])[CH2:16][CH2:17]3)=[CH:11][C:2]([NH:1][C:36]([NH:35][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:37])=[N:3]2)=[CH:8][CH:7]=1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1cc(N2CCN(C(=O)Nc3ccc(F)cc3)CC2)c2ccc(Cl)cc2n1
Solvent: CC#N
Solvent: ClCCCl
Product: O=C(Nc1ccccc1)Nc1cc(N2CCN(C(=O)Nc3ccc(F)cc3)CC2)c2ccc(Cl)cc2n1

Procedure:
To a solution of 2-amino-7-chloro-4-[4-(4-fluorophenylaminocarbonyl)piperazin-1-yl]quinoline (20 mg, 0.05 mmol) in MeCN-1,2-dichloroethane 1:1 (12 mL) is added phenyl isocyanate (17 μL, 0.11 mmol). The reaction mixture is heated at reflux for 1 h. Upon cooling the title product precipitates and is collected by filtration.
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][C:7]1[CH:8]=[C:9]([O:13][B:14]([OH:16])[OH:15])[CH:10]=[CH:11][CH:12]=1.NC1[CH:19]=[C:20]([O:24]B(O)O)C=CC=1.[OH-].[Na+].C([CH:32]([C:36](Cl)=[O:37])[C:33](Cl)=[O:34])C>O.O1CCCC1>[CH2:20]([O:24][C:36]([CH2:32][C:33]([NH:6][C:7]1[CH:8]=[C:9]([O:13][B:14]([OH:16])[OH:15])[CH:10]=[CH:11][CH:12]=1)=[O:34])=[O:37])[CH3:19]
Reactant: CCC(C(=O)Cl)C(=O)Cl
Reactant: Nc1cccc(OB(O)O)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CC(=O)Nc1cccc(OB(O)O)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 45 %

Procedure:
1.86 g of 3-aminophenyl-boric acid hemisulphate are suspended are suspended in 20 ml of water and treated with 5 ml of a 2N sodium hydroxide solution. The clear, yellowish solution is treated dropwise while cooling with ice with a solution of monoethyl malonyl chloride in 7 ml of tetrahydrofuran. The mixture is stirred at room temperature for a further 15 min. and the precipitate is filtered off under suction. It is recrystallized in 50 ml of water. 1.12 g (45%) of 3-(2-ethoxycarbonylacetylamino)-phenylboric acid are isolated. M.p. 247°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[N:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][N:22]=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2ccncc21
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: CC1c2cnccc2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-methyl-1,2,3,4-tetrahydro-[2,7]naphthyridine to provide the title compound in moderate yield.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:15])=[O:5])[CH3:2].O1CCCC1.C(=O)([O-])[O-].[K+].[K+].Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>O>[C:32]1([CH2:31][O:30][C:28]([NH:15][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:8]=2[NH:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:14]3)=[O:29])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCOC(=O)c1cc2cccc(N)c2[nH]1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cc2cccc(NC(=O)OCc3ccccc3)c2[nH]1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
0.8 g (3.925 mmol) of 7-amino-1H-indole-2-carboxylic acid ethyl ester are mixed with 16 ml of tetrahydrofurane and 1.08 g (7.83 mmol) of potassium carbonate. The reaction medium is cooled to 0° C. and 0.615 ml (4.30 mmol) of benzyl chloroformate are added. Agitation is performed for 1 hour 30 minutes at 0° C., and then the temperature of the mixture is allowed to rise again to ambient temperature over one hour. Then 30 ml of water are added and the product is extracted using ethyl acetate. The combined organic phases are dried on magnesium sulfate, filtered and concentrated under reduced pressure. The evaporation residue is purified by silica column chromatography eluting with the help of a methylcyclohexane/ethyl acetate mixture (90/1; v/v). The expected product is obtained in the form of white crystals with a yield of 61%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21]C=CC=4)N=3)=[CH:12][CH:11]=2)=[O:9])=[CH:3][CH:2]=1.C(OC1C=CC(C(N(OC)C)=O)=C([F:48])C=1)C1C=CC=CC=1>>[CH2:17]([O:16][C:13]1[CH:12]=[CH:11][C:10]([C:8](=[O:9])[CH2:7][C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[C:15]([F:48])[CH:14]=1)[C:18]1[CH:27]=[CH:26][CH:25]=[CH:20][CH:21]=1
Reactant: CON(C)C(=O)c1ccc(OCc2ccccc2)cc1F
Reactant: O=C(Cc1ccncc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Product: O=C(Cc1ccncc1)c1ccc(OCc2ccccc2)cc1F

Procedure:
Following the procedure for the preparation of 2-pyridin-4-yl-1-[4-(quinolin-2-ylmethoxy)-phenyl]-ethanone but substituting 4-Benzyloxy-2-fluoro-N-methoxy-N-methyl-benzamide provided the title compound. MS: (M+H m/z=322.1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([F:10])[CH:3]=1.[CH3:11][CH:12](O)[CH3:13].OS(O)(=O)=O>>[Br:1][C:2]1[CH:3]=[C:4]([F:10])[C:5]([O:8][CH3:9])=[C:6]([CH:12]([CH3:13])[CH3:11])[CH:7]=1
Reactant: CC(C)O
Reactant: COc1ccc(Br)cc1F
Agent: O=S(=O)(O)O
Product: COc1c(F)cc(Br)cc1C(C)C
Temperature: 80 °C
Yield: 38.4 %

Procedure:
To a mixture of 4-bromo-2-fluoroanisole (2.0 g, 9.70 mmol) and 2-propanol (1.2 g, 19.4 mmol) at room temperature was added 80% H2SO4 (10.0 mL). The reaction mixture was heated at 80° C. for 12 h, cooled to room temperature, quenched with ice (50 g) and extracted with ether (20 mL×2). The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with 5% ethyl acetate in hexanes to afford 4-bromo-6-fluoro-2-iso-propylanisole (0.92 g, 38%): 1H NMR (300 MHz, CD3OD): δ 7.36 (d, J=10.5 Hz, 1 H), 7.22 (d, J=10.5 Hz, 1 H), 3.91 (s, 3 H), 3.24 (m, 1 H), 1.26 (d, J=6.6 Hz, 6 H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=ethyl acetate-hexanes (5:95); Rf=0.50.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16](Br)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1.[CH:21]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)([CH3:23])[CH3:22]>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16]([C:27]3[CH:28]=[CH:29][C:24]([CH:21]([CH3:23])[CH3:22])=[CH:25][CH:26]=3)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1
Reactant: COC(=O)Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Reactant: CC(C)c1ccc(B(O)O)cc1
Product: COC(=O)Cc1cccc(NC(=O)c2ccc(-c3ccc(C(C)C)cc3)o2)c1

Procedure:
Methyl ester (16) (100 mg, 0.30 mmol) was coupled to 4-isopropyl-phenylboronic acid (53 mg, 0.33 mmol) using Method E. The crude compound was purified by column chromatography, eluting in 17% EtOAc in heptane to give the title compound.
Reaction SMILES: C1(N2C=C(Cl)C(Cl)[C:9](=[O:15])N2)C=CC=CC=1.[C:16]1([N:22]2[C:27](=[O:28])[C:26]([Cl:29])=[C:25](Cl)[CH:24]=[N:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CO>[C:16]1([N:22]2[C:27](=[O:28])[C:26]([Cl:29])=[C:25]([O:15][CH3:9])[CH:24]=[N:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=c1c(Cl)c(Cl)cnn1-c1ccccc1
Reactant: O=C1NN(c2ccccc2)C=C(Cl)C1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1cnn(-c2ccccc2)c(=O)c1Cl
Yield: 95 %

Procedure:
The title compound was prepared according to the method of (S. Cho et al. described in J. Het. Chem., (1996), 33, 1579-1582), starting with the N-phenyl-dichloropyridazinone. A mixture of 2-phenyl-4,5-dichloro-3(2H)-pyridazinone (1 g, 4.1 mmol) and finely powdered, anhydrous K2CO3 (580 mg, 4.2 mmol) in 50 mL of methanol was heated at reflux for 5 hours and concentrated in vacuo. The residue was partitioned between water and ethyl acetate. The acetate layer was washed with water, and brine to provide 2-phenyl-4-chloro-5-methoxy-3(2H)-pyridazinone (yield: 920 mg, 95%). 1H NMR (300 MHz, DMSO-d6) δ 4.15 (s, 3H), 7.50 (m, 5H), 8.43 (s, 1H). MS (DCI/NH3) m/z 237 (M+H)+, 254 (M+NH4)+.
Reaction SMILES: [CH2:1]([CH:8]1[C:12](=[O:13])[N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:9]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:27]O>C(O)(=O)C>[CH2:1]([C:8]1([OH:27])[C:9](=[O:26])[N:10]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:12]1=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C(Cc2ccccc2)C(=O)N(c2ccccc2)N1c1ccccc1
Reactant: OO
Solvent: CC(=O)O
Product: O=C1N(c2ccccc2)N(c2ccccc2)C(=O)C1(O)Cc1ccccc1

Procedure:
Prepared from 4-benzyl-1,2-diphenyl-3,5-pyrazolidinedione (3.3 g; 9.6 mmol), 35% H2O2 (1.4 ml; 16.3 mmol), and acetic acid (50 ml) using the procedure of Example 10 to give 1.0 g (30%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:32]=[CH:31][C:8]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:12][CH2:11]2)=[C:7]([N+:33]([O-])=O)[CH:6]=1)(=[O:4])=[O:3].Cl>CO>[NH2:33][C:7]1[CH:6]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:32]=[CH:31][C:8]=1[NH:9][CH:10]1[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:14][CH2:15]1
Reactant: CS(=O)(=O)c1ccc(NC2CCN(CCC(c3ccccc3)c3ccccc3)CC2)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CO
Product: CS(=O)(=O)c1ccc(NC2CCN(CCC(c3ccccc3)c3ccccc3)CC2)c(N)c1
Temperature: 95 °C
Yield: 27.5 %

Procedure:
To a stirred solution of 4-methanesulphonyl-2-nitro-1-N-[1-(3,3-diphenylpropyl)-piperidin-4-yl]aniline (200 mg, 0.4 mmol) in methanol (4 ml) was added concentrated HCl (1 ml) followed by stannous chloride dihydrate (620 mg) and the mixture was heated to 95° C. After 3 h the reaction mixture was concentrated and suspended in water (100 ml) and potassium carbonate was added to basify the solution. The solution was extracted with EtOAc (150 ml) and the emulsion left to separate. The mixture was then filtered through Celite™, separated, dried (MgSO4), concentrated and purified by Bond Elut™ chromatography (using 1% to 7.5% EtOH in DCM) to give the title compound as an oil (50 mg, 0.11 mmol); MS: 464.
Reaction SMILES: C1(C)C=CC=CC=1.[Cl:8][C:9]1[CH:10]=[C:11]([CH:27]=[CH:28][CH:29]=1)[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH2:21][CH:22]([OH:26])[CH:23]([OH:25])[CH3:24])=[CH:16][CH:15]=1.[C:30](=O)([O-])[O:31]CC.CC[O-].[Na+]>CCO>[Cl:8][C:9]1[CH:10]=[C:11]([CH:27]=[CH:28][CH:29]=1)[CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([N:20]2[CH2:21][CH:22]([CH:23]([OH:25])[CH3:24])[O:26][C:30]2=[O:31])=[CH:18][CH:19]=1
Reactant: CCOC(=O)[O-]
Reactant: CC(O)C(O)CNc1ccc(OCc2cccc(Cl)c2)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(O)C1CN(c2ccc(OCc3cccc(Cl)c3)cc2)C(=O)O1

Procedure:
From a solution of 600 ml of toluene containing 33.4 g (0.10 mol) of the mixture obtained in Example 2, 150 ml of solvent is distilled in an argon atmosphere. Then, successively, 15 g (15.5 ml; 0.127 mol) of ethyl carbonate and 3.4 ml of a solution of EtONa in 1M anhydrous EtOH are added. After 4 hrs 30 mins of reflux, the cyclization reaction is complete. The reaction medium is concentrated, then taken up by 300 ml of methyl ethyl ketone. After washing with 2N HCl, then with a saturated NaCl solution, 35 g of brown solid is recovered corresponding to the product expected.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH2:12]([N:16]1[C:25](=[O:26])[CH2:24][C:19]2([CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:18][C:17]1=[O:27])[CH2:13][CH:14]=[CH2:15]>C(Cl)Cl>[O:9]1[CH2:15][CH:14]1[CH2:13][CH2:12][N:16]1[C:17](=[O:27])[CH2:18][C:19]2([CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:24][C:25]1=[O:26]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCCN1C(=O)CC2(CCCC2)CC1=O
Solvent: ClCCl
Product: O=C1CC2(CCCC2)CC(=O)N1CCC1CO1
Yield: 75 %

Procedure:
A solution of MCPBA (80%, 5.01 g, 1.13 equiv) in 50 mL of CH2Cl2 was added to a stirring solution of 8-(3-butenyl) -8-azaspiro[4.5]decane-7,9-dione (4.54 g, 1.00 equiv) in 0 mL of CH2Cl2. The resulting solution was stirred until TLC inspection indicated the absence of limiting reagent (δ15 h). The reaction was quenched with 40 mL of 2% Na2CO3 solution and transferred to a separatory funnel. The layers were separated and the organic phase was washed with 2% Na solution (3×20 mL). The combined aqueous layers were back-extracted with CH2Cl2 (40 mL). The combined organic layers were dried on anhydrous Na2SO4, filtered and the solvent removed in vacuo. Flash chromatography of the resulting residue in 25% EtOAc/hexane afforded the title compound (3.65 g, 75%) as a clear, viscous liquid.