Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:9][CH2:10][OH:11])[CH:8]=1)([O-:3])=[O:2].[H-].[Na+].Cl[C:15]1[N:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[N:16]=1>C1COCC1>[CH3:24][O:23][C:17]1[CH:18]=[C:19]([O:21][CH3:22])[N:20]=[C:15]([O:11][CH2:10][CH2:9][N:7]2[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[N:6]2)[N:16]=1
Reactant: O=[N+]([O-])c1cnn(CCO)c1
Reactant: COc1cc(OC)nc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(OC)nc(OCCn2cc([N+](=O)[O-])cn2)n1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To an ice-cooled solution of 2-(4-nitro-1H-pyrazol-1-yl)ethanol (1.90 g, 12.02 mmol) in THF (60 mL), NaH (673 mg, 16.82 mmol, 60%) was added and the solution was stirred for 5 min at 0° C., then the ice bath was removed and the reaction mixture was stirred at rt for 30 min, before 2-chloro-4,6-dimethoxypyrimidine (2.31 g, 13.22 mmol) was added. After 40 min at rt, the reaction mixture was quenched with water and the org. solvent was removed in vacuo. The aq. layer was extracted with DCM (1×), then acidified with 1 N HCl-solution to pH 2, and extracted with DCM (2×). The combined org. layers were washed with brine, dried (MgSO4), filtered and the solvent removed under reduced pressure. Purification by crystallization (DCM-hept-mixture) yielded 4,6-dimethoxy-2-(2-(4-nitro-1H-pyrazol-1-yl)ethoxy)pyrimidine as a beige solid. LC-MS conditions A: tR=0.88 min, [M+H]+=295.98.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][CH:4]=1.[CH3:13][CH:14](O)[CH:15]=[CH2:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:13]([CH:8]1[CH2:7][C:6]2[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]1=[O:12])[CH:14]=[CH:15][CH3:16]
Reactant: C=CC(C)O
Reactant: COc1ccc2c(c1)C(=O)CC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: COC(C)(C)OC
Product: CC=CCC1Cc2ccc(OC)cc2C1=O
Yield: 74 %

Procedure:
A solution of 9.3 g of 6-methoxy-1-indanone, 11.8 ml of 3-buten-2-ol and 100 mg of p-toluenesulfonic acid in 100 ml of 2,2-dimethoxypropane was boiled under reflux for 64 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 4:1). 9.2 g (74%) of (RS)-2-(2-buten-1-yl)-6-methoxy-1-indanone were obtained as a yellow oil.
Reaction SMILES: [OH:1][CH:2]([C:25]([O:27][CH3:28])=[O:26])[C:3]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[O:4][CH2:5][C:6]([CH3:12])([CH3:11])[C:7]([O:9][CH3:10])=[O:8].C([O-])([O-])=O.[K+].[K+].CS([C:39]1[N:44]=[C:43]([O:45][CH3:46])[CH:42]=[C:41]([CH3:47])[N:40]=1)(=O)=O>CN(C=O)C.O>[CH3:28][O:27][C:25]([CH:2]([O:1][C:39]1[N:44]=[C:43]([O:45][CH3:46])[CH:42]=[C:41]([CH3:47])[N:40]=1)[C:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[O:4][CH2:5][C:6]([CH3:12])([CH3:11])[C:7]([O:9][CH3:10])=[O:8])=[O:26]
Reactant: COc1cc(C)nc(S(C)(=O)=O)n1
Reactant: COC(=O)C(O)C(OCC(C)(C)C(=O)OC)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(Oc1nc(C)cc(OC)n1)C(OCC(C)(C)C(=O)OC)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
10 g (25.9 mmol) of methyl 3-(2-hydroxy-2-methoxycarbonyl-1,1-di-phenylethoxy)-2,2-dimethylpropionate were dissolved in 40 ml of DMF under N2, 1.78 g (13 mmol) of K2CO3 and 5.2 g (25.9 mmol) of 2-methanesulfonyl-4-methoxy-6-methylpyrimidine were added, and the mixture was stirred at 80° C. for 2 h. It was subsequently diluted with 40 ml of H2O and extracted twice with 30 ml of diethyl ether, the organic phase was dried over MgSO4 and concentrated, and the residue was purified by chromatography on silica gel with ethyl acetate/cyclohexane mixtures. Crystallization from diethyl ether/hexane resulted in 11.8 g (90%) of the product as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([CH:34]=1)[CH2:7][CH:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][CH:19]([CH2:31][CH3:32])[C:20]([NH:22][CH2:23][C:24](OC(C)(C)C)=O)=[O:21])=[O:17])[CH2:12][C:11](=[O:33])[NH:10][CH2:9]1.Cl.C(OC(=O)CN)(C)(C)C.N[C:48]1[CH:49]=[C:50]([S:54]([NH2:57])(=[O:56])=[O:55])[CH:51]=CC=1>>[NH2:57][S:54]([C:50]1[CH:51]=[C:23]([CH:24]=[CH:48][CH:49]=1)[NH:22][C:20]([C@H:19]([NH:18][C:16]([N:13]1[C:14](=[O:15])[CH:8]([CH2:7][C:6]2[CH:34]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:35][CH3:36])[CH2:9][NH:10][C:11](=[O:33])[CH2:12]1)=[O:17])[CH2:31][CH3:32])=[O:21])(=[O:56])=[O:55]
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: CCC(NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)NCC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)CN
Agent: Cl
Product: CC[C@@H](NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)Nc1cccc(S(N)(=O)=O)c1

Procedure:
Instead of the starting material compound of Example 220, that is, glycine tert-butyl ester hydrochloride, 3-aminobenzenesulfonamide was used for the similar procedure as in Example 220 to obtain the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]([CH2:22][C:23]([OH:25])=[O:24])[CH2:14]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]([CH2:22][C:23]([OH:25])=[O:24])[CH2:14]2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(CC(=O)O)c1ccccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CC1CC2(CCNCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 112.5 %

Procedure:
2-(1′-(Tert-butoxycarbonyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic acid (200 mg, 0.58 mmol) was added to a solution of 20% trifluoroacetic acid in anhydrous CH2Cl2 (3 mL) at 0° C. The reaction solution was stirred at rt for 2 h until the starting material had been consumed. The solution was concentrated to give crude 2-(2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic acid (160 mg) which was used in the next step without further purification.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]12[CH2:17][CH2:16][CH2:15][C:13]3[C:14]1=[C:9]([CH:10]=[CH:11][CH:12]=3)[NH:8][C:7]2=[O:18].ClC1C=CC=[C:22]([C:26]([O:28]O)=[O:27])C=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:26]([O:28][C:12]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:18])[C:6]3([CH2:5][CH2:4][CH2:3][CH2:2][Br:1])[CH2:17][CH2:16][CH2:15][C:13]=1[C:14]=23)(=[O:27])[CH3:22]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C1Nc2cccc3c2C1(CCCCBr)CCC3
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Oc1ccc2c3c1CCCC3(CCCCBr)C(=O)N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
A 2 ml portion of methylene chloride solution of 2a-(4-bromobutyl)-2a,3,4,5-tetrahydrobenz[cd]indole-2(1H)-one (94 mg, 0.26 mmol) was cooled to 0° C. and then mixed with 93 mg (0.52 mmol) of m-chloroperbenzoic acid and 21 μl (0.26 mmol) of trifluoroacetic acid. After 2 hours of stirring in the dark at a room temperature, the reaction solution was extracted with chloroform and washed with sodium sulfite and sodium bicarbonate in that order. After drying (Na2SO4), the solvent was evaporated under a reduced pressure, and the thus obtained oily substance was purified by a silica gel column chromatography (20 cc; elution with ethyl acetate-hexane=1:2) to obtain 88 mg of the title compound (89% in yield).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([NH2:11])=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=2)[N:3]=1.[CH3:20][N:21]([CH3:39])[CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][N:28]2[C:31]([C:34](OCC)=[O:35])=[CH:32][N:33]=[C:27]2[CH:26]=1>O1CCCCC1.O1CCCC1>[CH3:20][N:21]([CH3:39])[CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][N:28]2[C:31]([C:34]([NH:11][C:9]3[CH:8]=[CH:7][CH:6]=[C:5]4[C:10]=3[C:2]([CH3:1])=[N:3][N:4]4[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=3)=[O:35])=[CH:32][N:33]=[C:27]2[CH:26]=1
Reactant: Cc1cccc(Cn2nc(C)c3c(N)cccc32)n1
Reactant: CCOC(=O)c1cnc2cc(OCCN(C)C)ccn12
Solvent: C1CCOCC1
Solvent: C1CCOC1
Product: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(OCCN(C)C)ccn45)cccc32)n1
Temperature: 0 °C
Yield: 51.7 %

Procedure:
3-Methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine (59 mg, 0.24 mmol) was dissolved in tetrahydropyran (DriSolve; 1.2 mL) and degassed before back-filling with nitrogen. The solution was cooled in an ice water bath for 15 minutes before dropwise addition of lithium bis(trimethylsilyl)amide (0.25 mL, 1 M in tetrahydrofuran). The reaction stirred for 10 minutes before dropwise addition into a solution of ethyl 7-(2-(dimethylamino)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (31 mg, 0.12 mmol) in tetrahydrofuran (DriSolve; 1.2 mL) cooled in an ice-water bath. The reaction was then stirred while being cooled in the ice-water bath for 1.5 hours. The reaction was quenched with water and concentrated. Purification using reverse phase chromatography, eluting with a gradient from 10% to 60% ACN/water, gave 7-(2-(dimethylamino)ethoxy)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (30 mg). MS m/z 484.1 (M+1, APCI+).
Reaction SMILES: C([O:3][C:4](=[O:27])[C:5]([C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:26])[CH2:13][CH2:14][C:15](=[O:25])[N:16]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:17])=[O:6])C.C(=O)([O-])[O-].[K+].[K+].CO>O>[OH2:3].[CH2:18]([N:16]([CH3:17])[C:15]([CH2:14][CH2:13][C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C@H:7]1[C:5](=[O:6])[C:4]([OH:27])=[O:3])=[O:26])=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(=O)[C@@H]1CCCN1C(=O)CCC(=O)N(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CN(Cc1ccccc1)C(=O)CCC(=O)N1CCC[C@H]1C(=O)C(=O)O
Reaction time: 1 h
Yield: 150.4 %

Procedure:
A mixture of 2-[(2S)-1-[3-(N-benzyl-N-methylcarbamoyl) propanoyl]pyrrolidin-2-yl]-2-oxoacetic acid ethyl ester (626 mg), potassium carbonate (277 mg), methanol (7 ml) and water (4 ml) was stirred for 1 hr. at room temperature. Water was added to the reaction solution. The mixture was extracted with EtOAc. The extract was washed, dried and evaporated to give the title compound (458 mg) having the following physical data:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:30][CH2:29][CH2:28][NH:27]3)=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[CH3:31][O:32][CH2:33][C:34]#[C:35][C:36](O)=[O:37]>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:36](=[O:37])[C:35]#[C:34][CH2:33][O:32][CH3:31])=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccn2c([C@@H]3CCCN3)nc(-c3ccc(C(=O)Nc4ccccn4)cc3)c12
Reactant: COCC#CC(=O)O
Product: COCC#CC(=O)N1CCC[C@H]1c1nc(-c2ccc(C(=O)Nc3ccccn3)cc2)c2c(N)nccn12
Yield: 24.7 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 2, from the compound described in intermediate 2b and 4-methoxybut-2-ynoic acid (Intermediate 50), to afford the title compound (9.1 mg, 24.7%). Data: UPLC (C) Rt: 1.44 min; m/z 496.2 (M+H)+.
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])/[CH:9]=[C:10](\[CH3:14])/[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1>C(O)C.CC1C=CC(C(C)C)=CC=1.CC1C=CC(C(C)C)=CC=1.[Ru](I)I.[Ru](I)I>[C:1]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:9][C@@H:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:5][CH:6]=1
Reactant: C/C(=C\[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Agent: I[Ru]I
Solvent: Cc1ccc(C(C)C)cc1
Solvent: CCO
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Temperature: 40 °C
Reaction time: 6 h

Procedure:
To a suspension of (E)-(R)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpent-2-enoic acid [2(ii-a)] (200 g, 524.3 mmol) in degassed ethanol (900 ml) at 40° C. a solution of diiodo(p-cymene)ruthenium(II) dimer (0.052 g, 0.0524 mmol) and (αR,αR)-2,2′-bis(α-N,N-dimethylaminophenylmethyl)-(S,S)-1,1′-bis[di(3,5-dimethyl-4-methoxyphenyl)phosphine]ferrocene (=Mandyphos SL-M004-1) (0.116 g, 0.110 mmol) is added in degassed ethanol (100 ml). The solution is degassed using vacuum and a pressure of 20 bar hydrogen applied. The mixture is stirred at 40° C. for 6 h. Vessel is then purged with nitrogen. Ethanol (700 ml) is removed by distillation. Isopropyl acetate (600 ml) is added. Solvent (600 ml) is removed by distillation. Isopropyl acetate (600 ml) is added. Solvent (600 ml) is removed by distillation. Isopropyl acetate (300 ml) is added and the solution is heated to reflux. Heptane fraction (1200 ml) is added and the mixture is cooled to room temperature. The solid is collected by filtration and washed with heptane fraction-isopropyl acetate 2:1 mixture (360 ml). The solid is dried overnight at 50° C. under 1-50 mbar vacuum to afford the title compound as a white/off-white solid [Ratio 2(i-a): 2(i-b) 99:1, as determined by HPLC analysis]. Mpt 146-147° C.; δH (500 MHz; DMSO) 1.07 (3H, d, J 7.0, 1-CH3), 1.34 (9H, s, (CH3)3), 1.38 (1H, m, 3-HA), 1.77 (1H, m, 3-HB), 2.43 (1H, m, 2-H), 2.70 (2H, d, J 7.0, 5-H), 3.69 (1H, m, 4-H), 6.74 (1H, d, J 9.0, NH), 7.27 (2H, d, J 8.0, Ar-ortho-H(Ph)), 7.36 (1H, t, J 7.0, Ar-(Ph)-para-H), 7.46 (2H, t, J 7.5, Ar-(Ph)-meta-H), 7.57 (2H, d, J 8.0, Ar-meta-H(Ph), 7.64 (2H, d, J 7.5, Ar-(Ph)-ortho-H), 12.01 (1H, s, CO2H); δC (500 MHz, DMSO) 18.1 (1-CH3), 28.3 [(CH3)3], 35.9 (2-C), 37.9 (3-C), 40.7 (5-C), 50.0 (4-C), 77.4 [(C(CH3)3], 126.3, 126.5, 127.2, 128.9, 129.8 (Ar—CH), 137.7 (Ar-ipso-C(Ph)), 138.3 (Ar-para-C(Ph)), 140.1 (Ar-(Ph)-ipso-C), 155.2 (NCO), 177.2 (CO2H); m/z (+ESI) 406 ([MNa]+, 6%), 384 ([MH]+, 31), 328 (100), 284 (19); Found: [MH]+, 384.21691. C23H30NO4 requires MH 384.21693.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][O:14][CH3:15])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH2:30][CH2:31][CH2:32]Cl)=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1.[NH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>COCCO.ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][O:14][CH3:15])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH2:30][CH2:31][CH2:32][N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1
Reactant: COCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCCl)c(OC)cc23)c2c1OCO2
Reactant: C1CNCCN1
Solvent: COCCO
Solvent: ClCCl
Product: COCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCN4CCNCC4)c(OC)cc23)c2c1OCO2
Temperature: 110 °C
Yield: 69.3 %

Procedure:
N-[5-chloro-7-(3-methoxyprop-1-yn-1-yl)-1,3-benzodioxol-4-yl]-7-(3-chloropropoxy)-6-methoxyquinazolin-4-amine (0.165 g) was dissolved in 2-methoxyethanol (5 ml) and piperazine (0.586 g) was then added and the mixture heated to 110° C. for 45 minutes. The reaction mixture was cooled to room temperature, diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate and then evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of dichloromethane and methanol with methanolic ammonia as eluent. There was thus obtained the title compound (0.126 g) as a clear gum; NMR Spectrum: (CDCl3) 2.09 (quin, 2H), 2.46 (s(broad), 4H), 2.54 (t, 2H), 2.91 (t, 4H), 3.45 (s, 3H), 3.47 (s, 1H), 3.96 (s, 3H), 4.23 (t, 2H), 4.35 (s, 2H), 6.06 (s, 2H), 7.06 (s, 1H), 7.13 (s, 1H), 7.28 (s, 2H), 8.62 (s, 1H); Mass Spectrum: M+H+ 540/542.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[CH2:9][N:8](CC2C=CC=CC=2)[CH2:7][CH2:6][N:5]1CC1C=CC=CC=1.[H][H]>[Pd].CO>[CH3:1][O:2][CH2:3][CH:4]1[CH2:9][NH:8][CH2:7][CH2:6][NH:5]1
Reactant: COCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COCC1CNCCN1
Yield: 78.8 %

Procedure:
A mixture of 117 parts of 2-(methoxymethyl)-1,4-bis(phenylmethyl)piperazine and 400 parts of methanol was hydrogenated at normal pressure and at room temperature with 5 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was distilled, yielding 38.6 parts (78.8%) of 2-(methoxymethyl)piperazine; bp. 75°-80° C. (intermediate 31).
Reaction SMILES: CC(=O)CC.[OH:6][C:7]1[C:16]([CH2:17][CH2:18][CH3:19])=[C:15]2[C:10]([C:11]([C:21]([F:24])([F:23])[F:22])=[CH:12][C:13](=[O:20])[O:14]2)=[CH:9][CH:8]=1.Br[CH2:26][CH2:27][CH2:28][CH2:29][N:30]1[C:34](=[O:35])[C:33]([CH3:37])([CH3:36])[N:32]([CH3:38])[C:31]1=[O:39].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:38][N:32]1[C:33]([CH3:37])([CH3:36])[C:34](=[O:35])[N:30]([CH2:29][CH2:28][CH2:27][CH2:26][O:6][C:7]2[C:16]([CH2:17][CH2:18][CH3:19])=[C:15]3[C:10]([C:11]([C:21]([F:24])([F:22])[F:23])=[CH:12][C:13](=[O:20])[O:14]3)=[CH:9][CH:8]=2)[C:31]1=[O:39]
Reactant: CCCc1c(O)ccc2c(C(F)(F)F)cc(=O)oc12
Reactant: CN1C(=O)N(CCCCBr)C(=O)C1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CCCc1c(OCCCCN2C(=O)N(C)C(C)(C)C2=O)ccc2c(C(F)(F)F)cc(=O)oc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 103.8 %

Procedure:
A 2-butanone (2 mL) solution of 7-hydroxy-8-propyl-4-(trifluoromethyl)-2H-chromen-2-one (30 mg, 0.11 mmol), 3-(4-bromobutyl)-1,5,5-trimethylimidazolidine-2,4-dione (30.5 mg, 0.11 mmol), and potassium carbonate (22.8 mg, 0.165 mmol) was heated and stirred overnight at 80° C. The reaction solution was added with water and extracted with ethyl acetate. Subsequently, the organic layer was washed with saturated saline, dried using anhydrous sodium sulfate, and concentrated under vacuum. The obtained residue was purified using thin-layer silica-gel chromatography (hexane:ethyl acetate=1:1), and 53.5 mg of the title compound (yield 100%) was obtained as colorless oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[C:17]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(CCCCCO)OCc1ccccc1
Solvent: ClCCl
Product: O=C(CCCCCOC(=O)c1ccccc1)OCc1ccccc1

Procedure:
To a solution of benzyl 6-hydroxyhexanoate (b) (27.37 g) in methylene chloride were added 4-dimethyl amino pyridine (19.5 g) and benzoyl chloride (19.53 g), and the resultant mixture was stirred for 2 hours. The reaction mixture was treated in the conventional manner and was distilled under reduced pressure (1 mmHg, 190°-215° C.) to give the title compound (c). Yield: 38.09 g (95%)
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][N:5]=1)[CH3:2].Cl[SiH:12]([CH3:14])[CH3:13].[Mg].O>O1CCCC1>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([SiH:12]([CH3:14])[CH3:13])=[CH:6][N:5]=1)[CH3:2]
Reactant: C[SiH](C)Cl
Reactant: CCOc1ccc(Br)cn1
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1ccc([SiH](C)C)cn1
Yield: 42.9 %

Procedure:
A mixture of 18.2 g (0.09 mol) of 2-ethoxy-5-bromopyridine (can be obtained from 2,5-dibromopyridine and sodium methanolate in DMSO), 11.4 g (0.12 mol) of chlorodimethylsilane and 50 ml of anhydrous tetrahydrofuran (THF) is added dropwise to 2.4 g (0.10 mol) of magnesium turnings in 10 ml of anhydrous THF, a strongly exothermic reaction occurring. The reaction is completed by refluxing for two hours. The mixture is then poured into water and extracted repeatedly with n-hexane, The extracts are washed with water and saturated sodium chloride solution, dried and evaporated, and the residue is distilled. 7 g (43%) of 2-ethoxy-5-dimethylsilylpyridine are obtained as a colorless oil of boiling point 7=140°-150° C.
Reaction SMILES: [F:1][C:2]1[C:6]([F:7])=[CH:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17](=[O:22])[C:16]([C:23]4[N:27]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[N:26]=[CH:25][CH:24]=4)=[N:15]3)=[C:10]([OH:34])[CH:9]=2)[CH:3]=1.FC(F)(F)S(O[CH2:41][C:42]([F:45])([F:44])[F:43])(=O)=O.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[C:6]([F:7])=[CH:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17](=[O:22])[C:16]([C:23]4[N:27]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[N:26]=[CH:25][CH:24]=4)=[N:15]3)=[C:10]([O:34][CH2:41][C:42]([F:45])([F:44])[F:43])[CH:9]=2)[CH:3]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: COc1cn(-c2ccc(-n3cc(F)c(F)c3)cc2O)nc(-c2ccnn2-c2ccccc2)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cn(-c2ccc(-n3cc(F)c(F)c3)cc2OCC(F)(F)F)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.6 %

Procedure:
A suspension of 1-[4-(3,4-difluoro-1H-pyrrol-1-yl)-2-hydroxyphenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (138 mg), 2,2,2-trifluoroethyl trifluoromethanesulfonate (104 mg) and potassium carbonate (82 mg) in DMF (1.5 mL) was stirred at room temperature for 30 min. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, THF), and crystallized from methanol to give the title compound (131 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.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>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:2]1[CH:12]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:5]=[N:4][CH:3]=1
Reactant: CCOC(=O)c1cncc(Br)c1
Reactant: COc1ccccc1B(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: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cncc(-c2ccccc2OC)c1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
A solution of ethyl 5-bromonicotinate (2.29 g, 10 mmol), prepared as reported in the Journal of Medicinal Chemistry 1995, 38, 1608-28, 2-methoxy phenyl boronic acid (1.22 g, 10 mmol), Pd(PPh3)4 (5% mol), K2CO3 (5 g) in DMF/water (3/1) is stirred at 50° C. for 12 hours. The reaction mixture is then pored on water (150 mL). The aqueous phase is extracted with ethyl acetate (3×100 mL). The combined organic layers are washed with water (3×200 mL). The organic phase is dried over magnesium sulfate and evaporated under vacuum to afford the title compound.