Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])/[C:7](=[CH:12]\[C:13]([O:15][CH2:16][CH3:17])=[O:14])/O[C:5]2=[O:18].[F:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1>C(O)(=O)C>[CH3:11][C:10]1[CH:9]=[C:8]2[C:4](=[CH:3][C:2]=1[CH3:1])[C:5](=[O:18])[N:24]([C:23]1[CH:25]=[CH:26][C:20]([F:19])=[CH:21][CH:22]=1)/[C:7]/2=[CH:12]/[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: Nc1ccc(F)cc1
Reactant: CCOC(=O)/C=C1/OC(=O)c2cc(C)c(C)cc21
Solvent: CC(=O)O
Product: CCOC(=O)/C=C1\c2cc(C)c(C)cc2C(=O)N1c1ccc(F)cc1
Yield: 87.3 %

Procedure:
Ethyl (E)-5,6-dimethyl-3-oxo-1,3-dihydroisobenzofuran-1-ylideneacetate (0.20 g, 0.81 mmol) and 4-fluoroaniline (0.10 g, 0.89 mmol) were stirred with heating in acetic acid at 110° C. for 7 hrs. The reaction solution was concentrated under reduced pressure, and methanol was added to the residue. The resulting crystals were collected by filtration, and dried to give 0.24 g of 5,6-dimethyl-3-[(E)-2-ethoxy-2-oxoethylidene]-2-(4-fluoro-phenyl)isoindolin-1-one [IUPAC name: ethyl 2-[2-(4-fluorophenyl)-5,6-dimethyl-3-oxo-2,3-dihydro-1H-isoindol-1-ylidene]acetate].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[C:10]([C:12]3[N:17]=[C:16]([C:18](=[O:20])[CH3:19])[CH:15]=[CH:14][CH:13]=3)[CH:9]=[N:8]2)[CH:2]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:32](O)[CH2:33][OH:34]>>[CH3:19][C:18]1([C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([C:10]3[CH:9]=[N:8][N:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[CH:11]=3)[N:17]=2)[O:34][CH2:33][CH2:32][O:20]1
Reactant: OCCO
Reactant: CC(=O)c1cccc(-c2cnn(-c3cccnc3)c2)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC1(c2cccc(-c3cnn(-c4cccnc4)c3)n2)OCCO1

Procedure:
In 100 ml of 1,1-benzotrifluoride, 0.13 g (0.49 mmol) of 1-[6-(1-pyridin-3-yl-1H-pyrazol-4-yl)pyridin-2-yl]ethanone, 0.1 g (0.58 mmol) of 4-toluenesulphonic acid and 1.8 ml (32 mmol) of 1,2-ethanediol were heated under reflux in a reflux apparatus with Soxleth extractor which had been charged with 4 Å molecular sieve for 2 h. The reaction mixture concentrated by evaporation, ethyl acetate, dil. aqueous sodium hydroxide solution, citrate buffer to pH=9 and also aq. NaCl were added to the residue, the aqueous phase was extracted twice with ethyl acetate, the combined organic phases were dried with MgSO4 and concentrated by evaporation. The residue was purified by chromatography on silica gel (petroleum ether/acetone).
Reaction SMILES: [CH:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:10](=[O:18])[CH:9]([NH:19][C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].I[CH2:33][CH:34]([CH3:36])[CH3:35]>CN(C)C=O>[CH:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:10](=[O:18])[CH:9]([NH:19][C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)CI
Reactant: O=C(NC1N=C(C2CCCCC2)c2ccccc2NC1=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)CN1C(=O)C(NC(=O)OCc2ccccc2)N=C(C2CCCCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.9 %

Procedure:
A solution of 5-cyclohexyl-1,3-dihydro-3(R,S)-[ (benzyloxycarbonyl)amino]-2H-1,4-benzodiazepin-2-one(7.0 g, 18 mmol)in dimethylformamide (84 ml), under an atmosphere of nitrogen, was treated with sodium hydride (0.77 g of a 55-60% dispersion in mineral oil, 18 mmol) in one portion, at -10° C. After 30 min at -10° C., 1-iodo-2-methylpropane (2.3 ml, 19.8 mmol) was added in one portion and the solution allowed to reach 0° C. over 2 h, then stirred at ambient temperature overnight. After this time the solvent was removed under reduced pressure, and the crude residue partitioned between water (500 ml) and dichloromethane (500 ml). The organic phase was separated and the aqueous phase extracted with dichloromethane (2×500 ml). The combined organic layers were washed with brine (500 ml), dried (MgSO4) and evaporated in vacuo. The residue was chromatographed on silica gel, using 2:1 petrol:ethyl acetate as the eluant, to afford the title compound (4.5 g, 56%) as a white solid. mp 148°-150° C. 1H NMR (360 MHz, CDCl3) δ 0.73 (3H, d, J=7 Hz), 0.79 (3H, d, J=7 Hz), 1.14-2.09 (11H, m), 2.80 (1H, m), 3.42 (1H, dd, J=14 and 5 Hz), 4.27 (1H, dd, J=14 and 9 Hz), 5.10 (3H, m), 6.55 (1H, d, J=8 Hz), 7.23-7.34 (8H, m), 7.45 (1H, t, J=8 Hz), 7.56 (1H, d, J=8 Hz).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:12][C:13]3[CH:14]=[C:15]([C:19]4[N:24]=[CH:23][C:22]([N:25]5[CH2:30][CH2:29][N:28](C(OCCCC)=O)[CH2:27][CH2:26]5)=[CH:21][N:20]=4)[CH:16]=[CH:17][CH:18]=3)[C:9](=[O:11])[O:10][C:5]2=[CH:4][CH:3]=1.Cl>C(#N)C.O1CCOCC1>[CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]4[N:24]=[CH:23][C:22]([N:25]5[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]5)=[CH:21][N:20]=4)[CH:14]=3)[C:9](=[O:11])[O:10][C:5]2=[CH:4][CH:3]=1
Reactant: CCCCOC(=O)N1CCN(c2cnc(-c3cccc(Cn4c(=O)oc5ccc(C)nc54)c3)nc2)CC1
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: Cc1ccc2oc(=O)n(Cc3cccc(-c4ncc(N5CCNCC5)cn4)c3)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
80 mg (0.16 mmol) of tart-butyl 4-{2-[3-(5-methyl-2-oxooxazolo[4,5-b]pyridin-3-ylmethyl)phenyl]pyrimidin-5-yl}piperazine-1-carboxylate are dissolved in 6 ml of acetonitrile, and 6 ml of 4 M HCl in dioxane are added. The reaction mixture is stirred at room temperature for 1 h and evaporated. The residue is taken up in water and ethyl acetate, and the water phase is adjusted to pH 12 using NaOH and extracted with ethyl acetate and dichloromethane. The organic phases are combined, dried over sodium sulfate and purified by column chromatography.
Reaction SMILES: [O:1]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[CH:4](O)[CH2:3][CH2:2]1.C1C=CC(P([N:26]=[N+:27]=[N-:28])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[N:26]([CH:4]1[C:5]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[O:1][CH2:2][CH2:3]1)=[N+:27]=[N-:28]
Reactant: OC1CCOc2ncccc21
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: [N-]=[N+]=NC1CCOc2ncccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ol (3.31 mmol) in 16.5 mL toluene were added DPPA (4.96 mmol) followed by DBU (4.96 mmol) at 0° C. The cooling bath was removed after 2 h and the mixture was stirred at RT overnight. The reaction was quenched by adding sat. aq. NaHCO3 solution and extracted with EtOAc. The combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification by CC (KP-SIL™ from Biotage) using Hept/EtOAc (4/1) to EtOAc gives the desired product as colorless oil;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:13][CH2:12][NH:11][C:10]1=[S:14].[H-].[Na+].[CH3:17]I>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]=[CH:12][N:11]=[C:10]1[S:14][CH3:17]
Reactant: COc1ccccc1N1CCNC1=S
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1-n1ccnc1SC
Temperature: 0 °C
Yield: 100.1 %

Procedure:
A solution of 8.1 g (0.039 mol) of this 1-(2-methoxyphenyl)imidazoline-2-thione in 88 ml of dimethylformamide is added dropwise, under nitrogen at 0° C., to a suspension of 1.19 g (0.047 mol) of sodium hydride (95%) in 88 ml of anhydrous dimethylformamide. The reaction mixture is stirred for ¾ h at 0° C. 2.7 ml (0.043 mol) of methyl iodide previously diluted in 24 ml of dimethylformamide are added and the mixture is stirred for 1 hour at 0° C. The reaction mixture is poured over ice, extracted three times with ethyl acetate and washed twice with water and then with brine. The product is dried over magnesium sulphate, filtered and concentrated. 8.6 g of oil are obtained.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[C:10]([C:19]2[CH:24]=[CH:23][C:22]([C:25](=[O:46])[NH:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][N:34]4[CH2:39][CH2:38][N:37]([S:40]([CH2:43][CH2:44][CH3:45])(=[O:42])=[O:41])[CH2:36][CH2:35]4)=[CH:29][CH:28]=3)=[CH:21][CH:20]=2)[C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:12][CH:13]=1)(C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[CH2:43]([S:40]([N:37]1[CH2:38][CH2:39][N:34]([CH2:33][C:30]2[CH:31]=[CH:32][C:27]([NH:26][C:25]([C:22]3[CH:23]=[CH:24][C:19]([C:10]4[CH:9]=[C:8]([NH2:7])[CH:13]=[CH:12][C:11]=4[O:14][C:15]([F:17])([F:18])[F:16])=[CH:20][CH:21]=3)=[O:46])=[CH:28][CH:29]=2)[CH2:35][CH2:36]1)(=[O:41])=[O:42])[CH2:44][CH3:45]
Reactant: CCCS(=O)(=O)N1CCN(Cc2ccc(NC(=O)c3ccc(-c4cc(NC(=O)OC(C)(C)C)ccc4OC(F)(F)F)cc3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCS(=O)(=O)N1CCN(Cc2ccc(NC(=O)c3ccc(-c4cc(N)ccc4OC(F)(F)F)cc3)cc2)CC1
Yield: 95.6 %

Procedure:
(4′-{4-[4-(propane-1-sulfonyl)-piperazin-1-ylmethyl]-phenylcarbamoyl}-6-trifluoromethoxy-biphenyl-3-yl)-carbamic acid tert-butyl ester (459 mg) in DCM (4 ml) and Trifluoroacetic Acid (4 ml) was stirred for 2 hrs. The mixture was evaporated and the residue partitioned between EtOAc and saturated potassium carbonate. The dried extracts were then evaporated giving the title compound as a tan foam (374 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]([OH:14])=[O:13])=[N:6][C:7]=1[S:8]([OH:11])(=[O:10])=[O:9].Cl.[CH3:16]O>O1CCOCC1>[CH3:16][O:13][C:12]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[C:7]([S:8]([OH:11])(=[O:9])=[O:10])[N:6]=1)=[O:14]
Reactant: CO
Reactant: Cc1ccc(C(=O)O)nc1S(=O)(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C)c(S(=O)(=O)O)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-methyl-6-sulfo-pyridine-2-carboxylic acid (0.8 g, 3.69 mmol) in methanol (20 mL) was added 4 N hydrogen chloride in dioxane (8 mL). The mixture was stirred overnight at room temperature. Undissolved solid was filtered off, and the filtrate was concentrated to give the product as yellow solid 0.5 g; MS (EI): m/e=232.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]#[C:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].[OH:13][CH2:14][C:15]1([CH2:19][CH2:20][CH3:21])[CH2:18]O[CH2:16]1>>[CH3:1][O:2][CH2:3][C:4]#[C:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]12[O:13][CH2:14][C:15]([CH2:19][CH2:20][CH3:21])([CH2:18][O:12]1)[CH2:16][O:11]2
Reactant: CCCC1(CO)COC1
Reactant: COCC#CCCCCC(=O)O
Product: CCCC12COC(CCCCC#CCOC)(OC1)OC2

Procedure:
1-(7-Methoxyhept-5-ynyl)-4-n-propyl-2,6,7-trioxabicyclo[2.2.2]octane was prepared from 8-methoxyoct-6-ynoic acid and 3-hydroxymethyl-3-n-propyloxetane using the methodology described in Example 1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][O:8][CH2:9][C:10](OCC)=O)[CH:2]=1.[Cl:15][C:16]1[CH:17]=[C:18]([NH:22][C:23]2[N:24]=[N:25][C:26]([NH:29][NH2:30])=[CH:27][CH:28]=2)[CH:19]=[CH:20][CH:21]=1>CS(C)=O.Cl.CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][O:8][CH2:9][C:10]2[N:25]3[N:24]=[C:23]([NH:22][C:18]4[CH:19]=[CH:20][CH:21]=[C:16]([Cl:15])[CH:17]=4)[CH:28]=[CH:27][C:26]3=[N:29][N:30]=2)[CH:2]=1
Reactant: CCOC(=O)COCc1cccnc1
Reactant: NNc1ccc(Nc2cccc(Cl)c2)nn1
Agent: Cl
Solvent: CO
Solvent: CS(C)=O
Product: Clc1cccc(Nc2ccc3nnc(COCc4cccnc4)n3n2)c1

Procedure:
(Step 4-ii) Ethyl 2-((pyridin-3-yl)methoxy)acetate (65 mg, 0.33 mmol) and N-(3-chlorophenyl)-6-hydrazinylpyridazin-3-amine (60 mg, 0.25 mmol) were combined in a 16×100 mm test tube and placed into a 160° C. oil bath for 15 min. The residue was dissolved in 1 mL DMSO and purified by reversed-phase HPLC. Fractions containing pure product were concentrated in vacuo to yield a solid, dissolved in HCl/methanol, and concentrated in vacuo to give the yellow solid product, 3-(((pyridin-3-yl)methoxy)methyl)-N-(3-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-amine, as an HCl salt (22 mg, 0.055 mmol, 22% yield). 1H-NMR (500 MHz, DMSO-d6) 10.25 (s, 1H), 8.80 (s, 1H), 8.77 (d, J=5.2 Hz, 1H), 8.40 (d, J=8.1 Hz, 1H), 8.16 (d, J=9.9 Hz, 1H), 8.07 (t, J=2.0 Hz, 1H), 7.90 (dd, J=5.6, 7.9 Hz, 1H), 7.61 (dd, J=2.0, 8.2 Hz, 1H), 7.36 (t, J=8.1 Hz, 1H), 7.20 (d, J=9.9 Hz, 1H), 7.08-7.06 (m, 1H), 5.11 (s, 2H), 4.89 (s, 2H); MH+367.3.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)[CH2:4][CH2:5]Cl.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17].C(N(C(C)C)CC)(C)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCOCC1>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([CH:3]([O:2][CH3:1])[CH2:4][CH2:5][N:28]2[CH2:29][CH2:30][CH:25]([C:21]3[CH:20]=[C:19]([NH:18][C:16](=[O:17])[CH:15]([CH3:14])[CH3:31])[CH:24]=[CH:23][CH:22]=3)[CH2:26][CH2:27]2)=[CH:8][CH:9]=1
Reactant: COC(CCCl)c1ccc(Cl)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(CCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 72 h
Yield: 73.7 %

Procedure:
A mixture of 3-methoxy-3-(p-chlorophenyl)-1-chloropropane (27.4 mg, 0.125 mmol), 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide (28.3 mg, 0.125 mmol), diisopropylethylamine (0.50 mL) and catalytic amount of tetrabutylammonium iodide in dioxane (2.0 mL) was stirred at 90° C. for 72 hrs. The reaction mixture was concentrated to a small volume and chromatographed using preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave N-(3-{1-[3-(4-chlorophenyl)-3-methoxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (39.5 mg, 73.8% yield) as a thick oil: 1H NMR δ 7.48 (s, 1H), 7.34-7.3 (m, 2H), 7.25 (m, 4H), 6.96 (d, 1H, J=7.4 Hz), 4.20 (apparent dd, 1H, J=5.9, 7.6 Hz), 3.2 (s, 3H), 3.04 (d, 1H, J=10.1 Hz), 2.99 (d, 1H, J=10.1 Hz), 2.49 (h, 4H, J=6.6 Hz), 2.20-2.10 (m, 4H), 1.82 (m, 4H), 1.25 (d, 6H, J=7.1 Hz); ESMS m/e: 429.4 (M+H)+.
Reaction SMILES: [CH2:1]1[C@@H:10]2[C@H:5]([CH2:6][CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)[CH2:4][NH:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[C:21]([C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22]>CN(C=O)C>[C:21]([C:25]1[CH:26]=[CH:27][C:28]([CH2:29][N:3]2[CH2:2][CH2:1][C@@H:10]3[C@H:5]([CH2:6][CH2:7][C:8]4[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=43)[CH2:4]2)=[CH:31][CH:32]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: c1ccc2c(c1)CC[C@@H]1CNCC[C@@H]21
Reactant: CC(C)(C)c1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CN2CC[C@H]3c4ccccc4CC[C@@H]3C2)cc1
Yield: 26.6 %

Procedure:
Following the procedure of Example 3, step 4, 0.300 g (1.60 mmol) of crude trans-1,2,3,4,4a,5,6,10b-octahydrobenz[f]isoquinoline in 10 ml of anhydrous DMF was reacted with 0.243 g (1.76 mmol) of anhydrous potassium carbonate and 0.310 ml (1.60 mmol) of 4-(tert-butyl)benzyl chloride. Chromatography on flash silica, eluting with 10-30% ethyl acetate/petroleum ether and 30-90% ether/petroleum ether, gave 0.142 g (27%) of the title product as a white solid. The hydrochloride salt was made using ethereal hydrogen chloride. Upon evaporation of the solvent the title product hydrochloride was obtained as a white solid, m.p. 229°-230° C. (dec). NMR δ(D2O) 1.33 (9H, s), 1.52 (1H, m), 1.65 (1H, m), 1.72-1.84 (2H, m), 2.60-2.72 (2H, m), 2.88-2.94 (2H, m), 3.20 (1H, t of d), 3.51 (1H, m), 3.70 (1H, m), 4.33 (2H, m), 7.21-7.25 (3H, m), 7.30-7.32 (1H, m), 7.47 (2H, d, J=8.4 Hz), 7.61 (2H, d, J=8.3 Hz). m/z (CI+, NH3) 334 (M+H)+, 233, 186 (M-CH2C6H4CMe3)+, 113.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[N:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][CH:28]([CH2:31][NH2:32])[CH2:27][CH2:26]2)=[CH:21][CH:20]=1>C(O)C>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:8]([C:7]2[C:2]([NH:32][CH2:31][CH:28]3[CH2:27][CH2:26][N:25]([C:22]4[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=4)[CH2:30][CH2:29]3)=[N:3][CH:4]=[CH:5][CH:6]=2)=[O:9])=[CH:12][CH:13]=1
Reactant: NCC1CCN(c2ccncc2)CC1
Reactant: COc1ccc(NC(=O)c2cccnc2Cl)cc1
Solvent: CCO
Product: COc1ccc(NC(=O)c2cccnc2NCC2CCN(c3ccncc3)CC2)cc1
Yield: 23.8 %

Procedure:
A pressure tube (Aldrich) was charged with 2-chloro-N-(4-methoxyphenyl)pyridine-3-carboxamide (139 mg, 0.524 mmol), 1-(4-pyridyl)piperidine-4-methylamine (100 mg, 0.524 mmol), triethylanine (0.22 mL), and ethanol (3 mL). The mixture was placed in a 110° C. bath for 5 days. The mixture was concentrated and the residue purified by RPHPLC, yielding 52 mg (24%) of the title compound as a hydrochloride salt.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9](=[O:18])[N:10]([CH3:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:6][CH:7]=1.[CH3:19][C:20]1([CH3:28])[CH2:26][C:25](=[O:27])[O:24][C:22](=[O:23])[CH2:21]1>ClCCl>[CH3:19][C:20]([CH3:28])([CH2:26][C:25](=[O:27])[NH:1][C:2]1[CH:7]=[N:6][C:5]([O:8][C:9](=[O:18])[N:10]([CH3:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1)[CH2:21][C:22]([OH:24])=[O:23]
Reactant: CC1(C)CC(=O)OC(=O)C1
Reactant: CN(C(=O)Oc1ccc(N)cn1)c1ccccc1
Solvent: ClCCl
Product: CN(C(=O)Oc1ccc(NC(=O)CC(C)(C)CC(=O)O)cn1)c1ccccc1

Procedure:
A solution of methyl-phenyl-carbamic acid 5-amino-pyridin-2-yl ester (243 mg, 1.00 mmol) and 3,3-dimethylglutaric anhydride (142 mg, 1.00 mmol) in dichloromethane (10 mL) was stirred at room temperature for 48 hours. Evaporation of the solvent yielded the title compound as a thick oil.
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][C:8]=1[CH3:16].Cl.[NH:19]1[CH2:24][CH2:23][CH:22]([C:25]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)=[O:26])[CH2:21][CH2:20]1>>[O:17]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([N:19]2[CH2:24][CH2:23][CH:22]([C:25](=[O:26])[C:27]3[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=3)[CH2:21][CH2:20]2)=[O:13])=[CH:9][C:8]=1[CH3:16]
Reactant: Cc1cc(C(=O)O)ccc1N1CCCS1(=O)=O
Reactant: Cc1ccc(C(=O)C2CCNCC2)cc1
Agent: Cl
Product: Cc1ccc(C(=O)C2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)c(C)c3)CC2)cc1
Yield: 10.8 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-3-methylbenzoic acid (268 mg) described in Preparation Example and (piperidin-4-yl)(p-tolyl)methanone hydrochloride (252 mg) and by the reaction and treatment in the same manner as in Example 86, the title compound (50 mg) was obtained.
Reaction SMILES: CN1CCN([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:20]=[C:19]([C:21]4[C:22]([C:26]5[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=5)=[N:23][NH:24][CH:25]=4)[CH:18]=[CH:17][N:16]=3)=[CH:10][CH:9]=2)CC1.ClC1C=CC(C2C(C3C=CN=C(NC4C=CC=C([O:58][CH2:59][CH:60]5[CH2:65][CH2:64][N:63]([CH3:66])[CH2:62][CH2:61]5)C=4)N=3)=CNN=2)=CC=1>>[CH3:66][N:63]1[CH2:64][CH2:65][CH:60]([CH2:59][O:58][C:13]2[CH:12]=[C:11]([NH:14][C:15]3[N:20]=[C:19]([C:21]4[C:22]([C:26]5[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=5)=[N:23][NH:24][CH:25]=4)[CH:18]=[CH:17][N:16]=3)[CH:10]=[CH:9][CH:8]=2)[CH2:61][CH2:62]1
Reactant: Cc1ccc(-c2n[nH]cc2-c2ccnc(Nc3ccc(N4CCN(C)CC4)cc3)n2)cc1
Reactant: CN1CCC(COc2cccc(Nc3nccc(-c4c[nH]nc4-c4ccc(Cl)cc4)n3)c2)CC1
Product: Cc1ccc(-c2n[nH]cc2-c2ccnc(Nc3cccc(OCC4CCN(C)CC4)c3)n2)cc1

Procedure:
The title compound is prepared as described in Example 1 using ethyl-4-methylbenzoate (see Example 25) and [3-(1-methyl-piperidin-4-ylmethoxy)-phenyl]-carbamic acid tert-butyl ester (see Example 27).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[N:26]1[C:35]2[C:30](=[C:31]([NH:36]N)[CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1>>[N:26]1[C:35]2[C:30](=[C:31]([N:36]3[C:5]([C:7]4[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]5[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=5)[N:8]=4)=[CH:4][CH:3]=[N:2]3)[CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Reactant: NNc1cccc2ncccc12
Product: O=c1ccn(-c2cccc(OC(F)(F)F)c2)nc1-c1ccnn1-c1cccc2ncccc12

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and quinolin-5-yl-hydrazine according to the method described for example 91. MS: M=450.1 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17](Br)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22]B(O)O.[F-].[K+].O1CCCC1>O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH3:22])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CB(O)O
Reactant: Cc1cc(Br)cnc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Yield: 78.2 %

Procedure:
To a mixture of 4-(5-bromo-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (25 g), methylboronic acid (8.4 g), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloride dichloromethane complex (1:1, 2.9 g) and potassium fluoride (16 g) was added tetrahydrofuran (140 mL), and the mixture was stirred with heating under reflux for 8 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3,5-dimethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (16 g). The obtained 4-(3,5-dimethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (16 g) was dissolved in chloroform (100 mL), 4N hydrogen chloride/ethyl acetate (50 mL) was added, and the mixture was stirred at room temperature overnight. To the reaction mixture was added ethyl acetate (200 mL), and the precipitate was collected by filtration to give the title compound (10 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[CH:5]2.[CH2:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[CH2:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][N:16]1[C:12]([C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([OH:1])[CH:3]=2)[CH:8]=1)=[O:14]
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Reactant: c1ccc2c(c1)CCNC2
Product: O=C(c1ccc2cc(O)ccc2c1)N1CCc2ccccc2C1

Procedure:
The title compound was synthesised from 6-hydroxy-2-naphtoic acid (commercially available) and 1,2,3,4-tetrahydroisochinoline (commercially available) according to the procedure described for Example A. MS (m/e): 302.1 (MH−, 100%)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13].[H-].[Na+].I[CH3:27]>CN(C=O)C.CCOCC>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[N:11]([S:12]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)(=[O:14])=[O:13])[CH3:27]
Reactant: COC(=O)c1cccc(C)c1NS(=O)(=O)c1ccc(OC)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(C)c1N(C)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
To a solution of 1.0 g (2.985 mmol) of the product of Example 3 in 10 mL of DMF was added 0.149 g (3.731 mmol) of 60% sodium hydride. The resulting mixture was stirred for 30 minutes at room temperature and then 0.28 mL (4.478 mmol) of iodomethane was added. The reaction was then stirred for 18 h, and next diluted with ether. The organics were washed with water, dried over MgSO4, filtered and concentrated in vacuo to provide a white solid. The solid was washed with ether/hexanes (1:1) to give 0.788 g (76%) of the desired product as a white solid. Electrospray Mass Spec: 350.1 (M+H).