Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][C:8]1[CH:13]=[C:12]([NH:14][C:15]([CH3:17])=[O:16])[CH:11]=[CH:10][C:9]=1Br.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:7][C:8]1[CH:13]=[C:12]([NH:14][C:15]([CH3:17])=[O:16])[CH:11]=[CH:10][C:9]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(=O)Nc1ccc(Br)c(C)c1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(=O)Nc1ccc(-c2ccccc2)c(C)c1

Procedure:
225 g of sodium carbonate and 0.15 g of PdCl2(PPh3)2 in 450 ml of methanol are heated to reflux temperature. A solution of 342 g of 4-bromo-3-methylacetanilide and 270 g of the ethylene glycol ester of phenylboronic acid in 225 ml of methanol, which has been heated to 50° C., is added dropwise over a period of 60 minutes. During the addition, methanol is distilled off in such an amount that the internal temperature can be kept at at least 85° C. After addition is complete, a further 0.1 g of the Pd catalyst is added and the reaction mixture is refluxed for another 6 hours. After this time, the monitoring of the reaction by HPLC indicates a conversion of 99.9%. The remaining methanol is distilled off as completely as possible (620 ml), with the reaction mixture having to remain stirrable. 1250 ml of chlorobenzene are subsequently added. Hydrolysis is carried out by addition of 85 ml of water. At 70-80° C., the phases are separated and the aqueous phase is discarded. The organic phase is washed once with 50 ml of water and is subsequently filtered through a 0.5 cm thick layer of aluminum oxide. The chlorobenzene is distilled off at 300-500 mbar. The residue of crude 2-methyl-4-acetaminobiphenyl which remains is used further without further purification. The yield is quantitative.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:13])=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[C:5]([Cl:8])=[CH:6][CH:7]=1.N(C([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=O)=[N+]=[N-].C[N:26](C)[CH:27]=[O:28]>>[NH2:12][S:9]([C:4]1[C:3]([OH:13])=[C:2]([NH:1][C:27]([NH:26][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[O:28])[CH:7]=[CH:6][C:5]=1[Cl:8])(=[O:11])=[O:10]
Reactant: [N-]=[N+]=NC(=O)c1ccccn1
Reactant: CN(C)C=O
Reactant: Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Product: NS(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2ccccn2)c1O
Reaction time: 20 h
Yield: 62 %

Procedure:
Under Argon, a solution of 3-amino-6-chloro-2-hydroxybenzenesulfonamide (300 mg, 1.35 mmol) and 2-(azidocarbonyl)-pyridine (400 mg, 2.70 mmol) in 5 mL of N,N-dimethyl-formamide was heated to 80° C. for 2 hours. The mixture was kept at room temperature for another 20 hours. Purification upon Gilson HPLC, eluting with acetonitrile/water (10/90, v/v to 90/10, v/v, over 10 min), gave the desired product (287 mg, 62%). LC-MS (m/z) 343.0 (M+).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[CH2:10]([O:17][C:18](=[O:23])[CH2:19][C:20](O)=[O:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(Cl)CCl>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[CH3:1][S:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:20](=[O:21])[CH2:19][C:18]([O:17][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:23])=[CH:5][CH:4]=1
Reactant: O=C(O)CC(=O)OCc1ccccc1
Reactant: CSc1ccc(N)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CSc1ccc(NC(=O)CC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 45.9 %

Procedure:
4-(methylthio)aniline (500 mg, 3.59 mmol), 3-(benzyloxy)-3-oxopropanoic acid (1046 mg, 5.39 mmol), DMAP (527 mg, 4.31 mmol), and EDC (1377 mg, 7.18 mmol) were dissolved in DMF (7 ml). The reaction was stirred at RT for 4 hours. The reaction mixture was diluted with water, and the precipitate was washed with water, dissolved in EtOAc and extracted with HCl 1N, Na2CO3 sat. sol. and brine. The organic phase was dried over Na2SO4 and concentrated under vacuum to give benzyl 3-(4-(methylthio)phenylamino)-3-oxopropanoate (520 mg, 45.9% yield).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[SH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1>C1COCC1>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](=[O:7])[S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: Sc1ccccn1
Reactant: O=C(Cl)c1ccc(I)cc1
Solvent: C1CCOC1
Product: O=C(Sc1ccccn1)c1ccc(I)cc1

Procedure:
Following the general procedure described above, reaction of 4-iodobenzoyl chloride (8.01 g, 30.0 mmol) with 2-mercaptopyridine (3.33 g, 30.0 mmol) in THF (60 mL) for 30 min at room temperature afforded pale yellow solid after precipitation (9.61 g, 94%): mp 127° C.; 1H NMR δ 7.30-7.38 (m, 1H), 7.70-7.76 (m, 3H), 7.77-7.83 (m, 1H), 7.84-7.89 (m, 2H), 8.64-8.71 (m, 1H); Anal. Calcd for C12H8INOS: C, 42.25; H, 2.36; N, 4.11. Found: C, 42.27; H, 2.38; N, 4.05.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH3:10])[C:3]=1[C:11]([F:14])([F:13])[F:12].[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[CH:16]=[CH2:17].C(N(CC)CC)C>CC([O-])=O.CC([O-])=O.[Pd+2].CN(C)C=O>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2](/[CH:17]=[CH:16]/[C:15]([O:19][CH2:20][CH3:21])=[O:18])=[C:3]([C:11]([F:14])([F:13])[F:12])[C:4]=1[CH3:10]
Reactant: C=CC(=O)OCC
Reactant: COc1ccc(Br)c(C(F)(F)F)c1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1ccc(OC)c(C)c1C(F)(F)F
Temperature: 110 °C
Reaction time: 8 h

Procedure:
Into a 10-mL sealed tube (1 atm) purged and maintained with an inert atmosphere of nitrogen, was placed 1-bromo-4-methoxy-3-methyl-2-(trifluoromethyl)benzene (300 mg, 1.12 mmol, 1.00 equiv), ethyl prop-2-enoate (560 mg, 5.59 mmol, 5.02 equiv), P(Tol)3 (61 mg, 0.20 mmol, 0.18 equiv), Pd(OAc)2 (30 mg, 0.13 mmol, 0.12 equiv), triethylamine (566 mg, 5.59 mmol, 5.02 equiv), N,N-dimethylformamide (2.0 mL). The resulting solution was stirred overnight at 110° C. in an oil bath. The reaction progress was monitored by GCMS. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3×15 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2×20 mL of H2O. The mixture was dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:6). This resulted in 0.16 g (50%) of ethyl (2E)-3-[4-methoxy-3-methyl-2-(trifluoromethyl)phenyl]prop-2-enoate as a yellow solid.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][NH2:41])=[CH:33][C:32]=2[CH3:42])=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=O)C.[OH:46][CH2:47][CH2:48][N:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1.NCCN1CC[O:61][CH2:60]C1>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][NH:41][C:60]([N:52]4[CH2:53][CH2:54][N:49]([CH2:48][CH2:47][OH:46])[CH2:50][CH2:51]4)=[O:61])=[CH:33][C:32]=3[CH3:42])=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: NCCN1CCOCC1
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCN)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: OCCN1CCNCC1
Product: Cc1cc(OCCCNC(=O)N2CCN(CCO)CC2)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C

Procedure:
The title compound was prepared in a similar manner to that described in Example 19 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-aminopropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and 1-(2-hydroxyethyl)piperazine instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-aminopropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole and 4-(2-aminoethyl)morpholine, respectively.
Reaction SMILES: [CH:1]1([CH:7]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:28])=[CH:23][CH:22]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCCCCC.C(O)C.C(O)C.[OH-].[Na+]>O1CCCC1>[CH:1]1([CH:7]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[CH:25][CH:26]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(OC)cc3c2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCCCCC
Product: COc1ccc2oc(C(Nc3ccc(C(=O)N(C)CCC(=O)O)cc3)C3CCCCC3)c(C)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl 3-{[(4-{[cyclohexyl(5-methoxy-3-methyl-1-benzofuran-2-yl)methyl]amino}phenyl)carbonyl](methyl)amino}propanoate (795 mg) synthesized above was fractionated by high performance liquid chromatography (column: CHIRALPAK AD (50 mm ID×500 mL, manufactured by Daicel Chemical Industries, Ltd., mobile phase: hexane/ethanol (400/600), flow rate: 60 mL/min, column temperature: 30° C.). The fraction containing an optically active form having a shorter retention time under the above-mentioned high performance liquid chromatography conditions was concentrated to give an amorphous form (413 mg, 99.9% ee). To a mixture of the obtained amorphous form, ethanol (5 mL) and tetrahydrofuran (5 mL) was added 1N aqueous sodium hydroxide solution (2.00 mL), and the mixture was stirred at room temperature for 2 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (2.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (355 mg, 47%, 99.9% ee) as a white solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH2:9].C(O[C:13]([CH2:15][O:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH:22]2[S:26][C:25](=[O:27])[NH:24][C:23]2=[O:28])=[CH:19][CH:18]=1)=O)C.Cl.C(=O)([O-])O.[Na+]>O1CCCC1.O.O1CCOCC1>[CH3:1][N:2]1[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:9]=[C:13]1[CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][CH:22]2[S:26][C:25](=[O:27])[NH:24][C:23]2=[O:28])=[CH:29][CH:30]=1
Reactant: CCOC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CNc1ccccc1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccccc21
Yield: 43.2 %

Procedure:
A mixture of 1.0 g of N-methyl-1,2-phenylenediamine, 3.8 g of 5-[4-(ethoxycarbonylmethoxy)benzyl]thiazolidine-2,4-dione [prepared as described in step (d) above], 20 ml of concentrated aqueous hydrochloric acid, 10 ml of 1,4-dioxane and 10 ml of water was heated under reflux for 5 hours. At the end of this time, the insoluble materials which had precipitated from the reaction mixture were collected by filtration and the precipitate thus obtained was dissolved in tetrahydrofuran. Water was then added to the solution. The resulting aqueous mixture was neutralized by adding sodium hydrogencarbonate and then extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel using ethyl acetate and then ethanol as the eluent. The product was then recrystallized twice from a mixture of tetrahydrofuran and ethyl acetate, to give 1.3 g of the title compound, melting at 230-231° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:21][C@H:22]([CH3:25])[CH2:23][OH:24])[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][N:36]([C:39](=[O:41])[CH3:40])[CH2:35][CH2:34]2)=[CH:29][CH:28]=1.C[Si](Cl)(C)C>C(O)CCC>[OH:24][CH2:23][C@H:22]([NH:21][C:4]1[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=[C:2]([NH:26][C:27]2[CH:28]=[CH:29][C:30]([N:33]3[CH2:34][CH2:35][N:36]([C:39](=[O:41])[CH3:40])[CH2:37][CH2:38]3)=[CH:31][CH:32]=2)[N:3]=1)[CH3:25]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(N[C@H](C)CO)nc(Cl)nc32)cc1
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CC(=O)N1CCN(c2ccc(Nc3nc(N[C@H](C)CO)c4ccn(S(=O)(=O)c5ccc(C)cc5)c4n3)cc2)CC1
Temperature: 116 °C
Reaction time: 48 h
Yield: 8.4 %

Procedure:
A mixture of (R)-2-(2-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)propan-1-ol (200 mg, 0.525 mmol), 1-(4-(4-aminophenyl)piperazin-1-yl)ethanone (140 mg, 0.639 mmol) and trimethylsilyl chloride (0.130 mL, 1.03 mmol) in nBuOH (4 mL) was stirred at 116° C. for 48 h. It was concentrated in vacuo. The residue was purified by HPLC to give (R)-1-(4-(4-(4-(1-hydroxypropan-2-ylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone (25 mg).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=2)[C:8]2[NH:13][N:12]=[C:11](I)[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4].[Cl:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]#[CH:33].C(N(CC)CC)C>CN(C)C=O.ClCCl.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH2:1]([C:5]1[N:6]=[C:7]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=2)[C:8]2[NH:13][N:12]=[C:11]([C:33]#[C:32][CH2:31][CH2:30][CH2:29][CH2:28][Cl:27])[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(NCc2ccc(OC)c(OC)c2)c2[nH]nc(I)c2n1
Reactant: C#CCCCCCl
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCc1nc(NCc2ccc(OC)c(OC)c2)c2[nH]nc(C#CCCCCCl)c2n1
Reaction time: 0.08 h
Yield: 75.4 %

Procedure:
A nitrogen degassed stirred mixture of 5-butyl-N-(3,4-dimethoxybenzyl)-3-iodo-1H-pyrazolo[4,3-d]pyrimidin-7-amine (4.58 g, 9.7 mmol), copper(I) iodide (278 mg, 1.46 mmol) and bis(triphenylphosphine)palladium(II)dichloride (515 mg, 0.734 mmol) in anhydrous N,N-dimethylformamide (105 mL) was warmed to 60° C. under a nitrogen atmosphere before addition of a solution of 6-chloro-1-hexyne (1.712 g, 14.69 mmol) and triethylamine (2.047 mL, 14.69 mmol) in anhydrous nitrogen degassed N,N-dimethylformamide (15 mL), dropwise over 5 minutes. The reaction was stirred at 60° C. for 6 hours. The cooled reaction mixture was evaporated in-vacuo and the resultant oil partitioned between 1:1 water/brine and ethyl acetate. The organic layer was separated, passed through a hydrophobic frit and evaporated in-vacuo to yield an orange oil. The oil was dissolved in the minimum volume of dichloromethane, loaded onto a 330 g silica pre-conditioned cartridge and purified by chromatography using cyclohexane over 1 column volume followed by 0-100% ethyl acetate in cyclohexane gradient over 14 column volumes followed by ethyl acetate over 2 column volumes. Appropriate fractions were combined and evaporated in-vacuo to yield the title compound as a yellow foam (3.334 g)
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([NH:7][CH2:8][C:9]2[C:14]([C:15]([N:17]([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])=[O:16])=[C:13](F)[N:12]=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.CC[N:33]([CH:37]([CH3:39])C)[CH:34]([CH3:36])C.[NH2:40][CH2:41][C:42]1C=CC=CN=1>CC(O)(C)C>[C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([NH:7][CH2:8][C:9]2[C:14]([C:15]([N:17]([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])=[O:16])=[C:13]([NH:40][CH2:41][C:42]3[CH:36]=[CH:34][N:33]=[CH:37][CH:39]=3)[N:12]=[CH:11][CH:10]=2)=[CH:3][CH:2]=1
Reactant: NCc1ccccn1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)N(C(=O)c1c(CNc2ccc(-c3ccccc3)cc2)ccnc1F)C(C)C
Solvent: CC(C)(C)O
Product: CC(C)N(C(=O)c1c(CNc2ccc(-c3ccccc3)cc2)ccnc1NCc1ccncc1)C(C)C
Temperature: 200 °C
Reaction time: 0.08 h

Procedure:
To a microwave tube was added 4-(biphenyl-4-ylaminomethyl)-2-fluoro-N,N-diisopropyl-nicotinamide (240 mg, 0.59 mmol, Step B), t-BuOH (3 mL), DIEA (1 mL, and aminomethyl pyridine (0.2 mL). The contents of the microwave tube were stirred for 5 min and subjected to microwave heating at 200° C. for 1 h. The volatiles were removed under reduced pressure, and the residue was purified by flash column chromatography (15% MeOH in EtOAc). MS (ES+): 494.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[CH:6]=[CH:5][C:4]=1[NH:15][CH:16]=O.[CH:18]1([CH2:21][O:22][C:23]2[C:28]3[N:29]=C(S(C)(=O)=O)[N:31]=[CH:32][C:27]=3[CH:26]=[CH:25][N:24]=2)[CH2:20][CH2:19]1>>[CH:18]1([CH2:21][O:22][C:23]2[C:28]3[N:29]=[C:16]([NH:15][C:4]4[CH:5]=[CH:6][C:7]([C:9]5[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=5)=[CH:8][C:3]=4[O:2][CH3:1])[N:31]=[CH:32][C:27]=3[CH:26]=[CH:25][N:24]=2)[CH2:19][CH2:20]1
Reactant: CS(=O)(=O)c1ncc2ccnc(OCC3CC3)c2n1
Reactant: COc1cc(-c2cnn(C)c2)ccc1NC=O
Product: COc1cc(-c2cnn(C)c2)ccc1Nc1ncc2ccnc(OCC3CC3)c2n1
Yield: 52 %

Procedure:
The title compound was prepared according to Example 40 using N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)formamide (Preparation 56) and 8-(cyclopropylmethoxy)-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine (Preparation 69). The residue was purified by silica gel column chromatography eluting with 0 to 75% EtOAc in cyclohexane to give the title compound (27 mg, 52%).
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:7]=1)=[O:4].[F:19][C:20]([F:34])([F:33])[C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:24]Br.C(N(C(C)C)CC)(C)C.N>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)(Cl)Cl.O1CCOCC1>[F:19][C:20]([F:33])([F:34])[C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:28]=1)[CH2:24][N:15]1[CH2:16][CH2:17][CH:12]([C:8]2[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH:2]([CH3:18])[CH3:1])[CH:11]=[CH:10][CH:9]=2)[CH2:13][CH2:14]1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N
Agent: [I-]
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)c1
Yield: 25.8 %

Procedure:
A mixture of 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide (28.3 mg, 0.100 mmol), 3,5-bis(trifluoromethyl)benzyl bromide (38.4 mg, 0.125 mmol), diisopropylethylamine (0.50 mL), catalytic amount of tetrabutylammonium iodide and dioxane (2.0 mL). Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (12.2 mg, 25.8% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 7.83 (s, 2H), 7.77 (s, 1H), 7.53 (s, 1H), 7.30-7.21 (m, 2H), 7.16 (s, 1H), 6.98 (apparent d, 1H, J=7.6 Hz), 3.62 (s, 2H), 2.94 (d, 2H, J=9.4 Hz), 2.51 (apparent sept, partially hidden, 2H, J=6.6 Hz), 2.14 (m, 2H), 1.82 (m, 4H), 1.25 (d, 6H, J=6.6 Hz); ESMS m/e: 473.2 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)=[CH:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH2:34]([N:36]1[CH2:41][CH2:40][CH:39]([NH2:42])[CH2:38][CH2:37]1)[CH3:35]>CN(C=O)C>[CH2:34]([N:36]1[CH2:41][CH2:40][CH:39]([NH:42][CH2:2]/[C:3](/[CH2:15][O:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)=[CH:4]/[C:5]2[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=2)[CH2:38][CH2:37]1)[CH3:35]
Reactant: COC(=O)c1ccc(C=C(CBr)COc2cccc3ccccc23)cc1
Reactant: CCN1CCC(N)CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN1CCC(NC/C(=C/c2ccc(C(=O)OC)cc2)COc2cccc3ccccc23)CC1
Yield: 46 %

Procedure:
Methyl 4-[2-bromomethyl-3-(naphthalen-1-yloxy)-propenyl]-benzoate (412 mg, 1 mmol) was dissolved in N,N′-dimethylformamide (2.5 ml) in a 100 ml flask at 0° C., and to the resulting solution, triethylamine (0.17 ml, 1.2 mmol, 1.2 eq.) and 1-ethylpiperidin-4-ylamine (128 ml, 1.0 mmol, 1.0 eq.) were added while stirring. The resulting mixture was heated from 0° C. to room temperature, and then reacted for 4 hours. After the completion of reaction, the mixture was concentrated under reduced pressure, and the residue thus obtained was extracted with ethyl ester. The organic layer was separated, washed with an aqueous saturated sodium bicarbonate solution and brine in order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography to obtain 211 mg of the title compound as pale yellow oil (yield 46%).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([CH:13]3[CH2:18][CH2:17][N:16]([O:19][CH3:20])[CH2:15][CH2:14]3)[CH:10]=[CH:9][C:8]=2[NH:21][C:22]([C:24]2[N:25](COCC[Si](C)(C)C)[CH:26]=[C:27]([C:29]#[N:30])[N:28]=2)=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40]>C(Cl)Cl.CCO>[F:42][C:41]([F:44])([F:43])[C:39]([OH:45])=[O:40].[C:1]1([C:7]2[CH:12]=[C:11]([CH:13]3[CH2:18][CH2:17][N:16]([O:19][CH3:20])[CH2:15][CH2:14]3)[CH:10]=[CH:9][C:8]=2[NH:21][C:22]([C:24]2[NH:28][C:27]([C:29]#[N:30])=[CH:26][N:25]=2)=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CON1CCC(c2ccc(NC(=O)c3nc(C#N)cn3COCC[Si](C)(C)C)c(C3=CCCCC3)c2)CC1
Solvent: ClCCl
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CON1CCC(c2ccc(NC(=O)c3ncc(C#N)[nH]3)c(C3=CCCCC3)c2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 58 %

Procedure:
To a solution of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(1-methoxy-piperidin-4-yl)-phenyl]-amide (as prepared in previous step, 31 mg, 0.020 mmol) in DCM (0.5 mL) and EtOH (11 μL) was added TFA (0.1 mL). The resulting solution was stirred at RT for 6 h. The reaction mixture was concentrated in vacuo and the resulting residue was dried for 1 h, suspended in ether (10 mL) and sonicated for 5 min. The solid formed was collected by suction filtration to obtain the title compound (17.3 mg, 58%). 1H-NMR (DMSO; 400 MHz): δ 9.70 (s, 1H), 8.30 (s, 1H), 7.83 (d, 1H, J=8.4 Hz), 7.14 (d, 1H, J=8.4 Hz), 7.05 (s, 1H), 5.71 (br s, 1H), 3.30-3.55 (m, 5H), 2.41-2.62 (m, 2H), 2.12-2.19 (m, 4H), 1.60-1.85 (m, 8H). Mass spectrum (ESI, m/z): Calcd. for C23H27N5O2, 406.2 (M+H). found 406.1.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:17][CH2:16][C:10]2[N:11]=[N:12][C:13](Cl)=[CH:14][C:9]=2[CH2:8]1)=[O:6])[CH:2]=[CH2:3].C(O)(=O)/C=C\C(O)=O.ClC1[N:32]=[N:31]C2CCNCC=2C=1.C(OC(Cl)=O)C=C>>[CH2:1]([O:4][C:5]([N:7]1[CH2:17][CH2:16][C:10]2[N:11]=[N:12][C:13]([NH:31][NH2:32])=[CH:14][C:9]=2[CH2:8]1)=[O:6])[CH:2]=[CH2:3]
Reactant: Clc1cc2c(nn1)CCNC2
Reactant: C=CCOC(=O)N1CCc2nnc(Cl)cc2C1
Agent: C=CCOC(=O)Cl
Agent: O=C(O)/C=C\C(=O)O
Product: C=CCOC(=O)N1CCc2nnc(NN)cc2C1

Procedure:
The 3-chloro-5,6,7,8-tetrahydro-6-pyrido [4,3-c]pyridazinecarboxylic acid allyl ester, required as starting material, may be obtained in a manner analogous to that described in Example 8 (g), from 3-chloro-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine maleate and chloroformic acid allyl ester. The oily crude product is used for the next reaction without purification.