Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[C:3]=1[CH2:4][N:5]1[C:10]2[S:11][C:12]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][O:31][CH3:32])=[O:29])=[CH:23][CH:22]=3)=[C:13]([CH2:14][N:15]([CH2:17][CH2:18][O:19][CH3:20])[CH3:16])[C:9]=2[C:8](=[O:33])[N:7]([CH2:34][CH2:35]O)[C:6]1=[O:37].[NH:43]1[CH:47]=[N:46][N:45]=[N:44]1>>[F:42][C:38]1[CH:39]=[CH:40][CH:41]=[C:2]([F:1])[C:3]=1[CH2:4][N:5]1[C:10]2[S:11][C:12]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][O:31][CH3:32])=[O:29])=[CH:23][CH:22]=3)=[C:13]([CH2:14][N:15]([CH2:17][CH2:18][O:19][CH3:20])[CH3:16])[C:9]=2[C:8](=[O:33])[N:7]([CH2:34][CH2:35][N:43]2[CH:47]=[N:46][N:45]=[N:44]2)[C:6]1=[O:37]
Reactant: c1nnn[nH]1
Reactant: COCCN(C)Cc1c(-c2ccc(NC(=O)NOC)cc2)sc2c1c(=O)n(CCO)c(=O)n2Cc1c(F)cccc1F
Product: COCCN(C)Cc1c(-c2ccc(NC(=O)NOC)cc2)sc2c1c(=O)n(CCn1cnnn1)c(=O)n2Cc1c(F)cccc1F

Procedure:
The similar reaction as described in Example 6 by using the compound obtained in Example 8 (250 mg, 0.414 mmol) and tetrazole (145 mg, 2.07 mmol) gave the title compound 2-yl form (66 mg, 24%) and 1-yl form (27 mg, 10%) as white amorphous compounds.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1>[C:25]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][CH:13]([NH:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:14][CH2:15]2)=[CH:4][CH:3]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(CCN2CCC(NC(=O)c3ccccc3)CC2)cc1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(CCN2CCC(NC(=O)c3ccccc3)CC2)cc1
Reaction time: 24 h

Procedure:
1-[2-(p-Aminophenyl)ethyl]-4-benzamidopiperidine (2.3 g.) was refluxed for 2 hours with acetic anhydride (22 ml.) in anhydrous pyridine (100 ml.). The solution was refrigerated for 24 hours and a crystalline product was filtered off, which after washing with ether yielded the title compound, m.p. 270°-275° C. (dec.). Found: C, 72.6; N, 7.55; N, 11.6. C22H27N3O2 requires C, 72.3; H, 7.45; N, 11.5%).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][C@@H:15]([O:49][C:50](=[O:61])[CH2:51][CH2:52][NH:53]C(OC(C)(C)C)=O)[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:29]([C:30]#[N:31])=[C:28]([S:32][CH2:33][C:34]3[N:35]=[C:36]([C:39]4[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=4)[O:37][CH:38]=3)[N:27]=[C:26]([NH2:46])[C:25]=2[C:47]#[N:48])=[CH:20][CH:19]=1)=[O:12])=O)(C)(C)C.[ClH:62]>ClCCl.C(OCC)C>[ClH:45].[ClH:62].[NH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][C@@H:15]([O:49][C:50](=[O:61])[CH2:51][CH2:52][NH2:53])[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:29]([C:30]#[N:31])=[C:28]([S:32][CH2:33][C:34]3[N:35]=[C:36]([C:39]4[CH:40]=[CH:41][C:42]([Cl:45])=[CH:43][CH:44]=4)[O:37][CH:38]=3)[N:27]=[C:26]([NH2:46])[C:25]=2[C:47]#[N:48])=[CH:20][CH:19]=1)=[O:12]
Reactant: CC(C)(C)OC(=O)NCCC(=O)OC[C@H](COc1ccc(-c2c(C#N)c(N)nc(SCc3coc(-c4ccc(Cl)cc4)n3)c2C#N)cc1)OC(=O)CCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: N#Cc1c(N)nc(SCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OC[C@@H](COC(=O)CCN)OC(=O)CCN)cc1
Reaction time: 1 h

Procedure:
An amount of 123 mg (0.140 mmol) of the compound from example 28A was introduced in 2 ml of dichloromethane and admixed with 1.4 ml (2.807 mmol) of a 2M solution of hydrogen chloride gas in diethyl ether. After 1 hour of stirring, the precipitated solid was isolated by filtration, washed with dichloromethane and diethyl ether and dried under reduced pressure. This gave 79 mg (75% of theory) of the target compound.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:4][NH:3]1.CC(C)([O-])C.[K+].[Br:24][C:25]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][C:26]=1[NH:27][C:28](=[O:31])[CH2:29]Cl>CN(C)C=O>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2](=[O:1])[N:3]([CH2:29][C:28]([NH:27][C:26]2[CH:32]=[C:33]([C:36]([F:37])([F:38])[F:39])[CH:34]=[CH:35][C:25]=2[Br:24])=[O:31])[N:4]=1)[CH3:17]
Reactant: CCOC(=O)Cc1n[nH]c(=O)c2ccccc12
Reactant: O=C(CCl)Nc1cc(C(F)(F)F)ccc1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1nn(CC(=O)Nc2cc(C(F)(F)F)ccc2Br)c(=O)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 4-oxo-3H-phthalazin-1-ylacetate (3.36 g) and potassium t-butoxide (1.62 g) in dimethylformamide (15 ml) was slowly added a solution of 2'-bromo-5'-trifluoromethyl-2-chloroacetanilide (4.55 g) in dimethylformamide (15). After stirring the resulting solution overnight at room temperature, it was poured onto water (50 ml) and the resulting white precipitate was collected and air dried (yield 4.3 g; m.p. 160° C.).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:13](O)=[O:14])[C:8](=[O:20])[C:7]3=[CH:21][NH:22][C:5]([C:6]=23)=[N:4][CH:3]=1.Cl.[NH:24]1[CH2:27][CH:26]([C:28]#[N:29])[CH2:25]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>C1COCC1>[Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([C:16]([CH3:18])([CH3:19])[CH3:17])[C:13]([N:24]3[CH2:27][CH:26]([C:28]#[N:29])[CH2:25]3)=[O:14])[C:8](=[O:20])[C:7]3=[CH:21][NH:22][C:5]([C:6]=23)=[N:4][CH:3]=1
Reactant: N#CC1CNC1
Reactant: CC(C)(C)[C@H](C(=O)O)N1Cc2c(Cl)cnc3[nH]cc(c23)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)[C@H](C(=O)N1CC(C#N)C1)N1Cc2c(Cl)cnc3[nH]cc(c23)C1=O
Yield: 13.6 %

Procedure:
To an 8 mL scintillation vial equipped for stirring was added (R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3,3-dimethylbutanoic acid (25 mg, 0.078 mmol) under nitrogen. THF (0.5 mL), azetidine-3-carbonitrile hydrochloride (18.45 mg, 0.155 mmol), HATU and 4-methylmorpholine (11.79 mg, 0.117 mmol) were added and the solution was stirred at 25° C. for 1 h. The reaction mixture was purified via preparative mass trigger LC-MS (AcCN/H2O, 15-40%). The fractions were collected, concentrated, and dried in vacuo to afford the title compound as a yellow semi-solid (4.1 mg, 13.7%). 1H NMR (400 MHz, CD3OD) δ 1.17 (s, 9 H) 3.50-3.78 (m, 1 H) 4.17 (br. s., 1 H) 4.25-4.37 (m, 1 H) 4.41-4.69 (m, 2 H) 5.17-5.30 (m, 2 H) 5.44 (s, 1 H) 7.87 (br. s., 1 H) 8.25 (s, 1 H). [M+H] calc'd for C19H20ClN5O2, 386; found, 386.4.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[CH:8][NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:10]=[O:11].C(N(CC)CC)C>CC(C)=O>[C:1]([C:5]1[CH:9]=[CH:8][N:7]([CH2:10][OH:11])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc[nH]n1
Reactant: C=O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(C)(C)c1ccn(CO)n1
Temperature: 130 °C
Reaction time: 7 h
Yield: 67.3 %

Procedure:
The mixture of 1.28 g of 3-t-butyl-1H-pyrazole, 0.66 g of paraformaldehyde and 0.3 g of triethylamine was stirred at 130° C. for 7 hours. After the reaction mixture was cooled to room temperature, acetone was added to the reaction mixture. The mixture was filtered. The filterate was concentrated under reduced pressure. Hexane was added to the residue, and then crystalline was formed. The crystalline was collected to obtain 1.07 g of 3-t-butyl-1H-pyrazole-1-ylmethanol.
Reaction SMILES: C([O:5][C:6]([CH2:8][C:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=1[N:15]1[C:20](=[O:21])[CH:19]=[CH:18][C:17]([C:22]2[C:23]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[N:24][N:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=23)=[N:16]1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:6]([CH2:8][C:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=1[N:15]1[C:20](=[O:21])[CH:19]=[CH:18][C:17]([C:22]2[C:23]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[N:24][N:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=23)=[N:16]1)([OH:7])=[O:5]
Reactant: CC(C)(C)OC(=O)CC1=C(n2nc(-c3c(-c4ccccc4)nn4ccccc34)ccc2=O)CCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CC1=C(n2nc(-c3c(-c4ccccc4)nn4ccccc34)ccc2=O)CCCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 69.4 %

Procedure:
To a solution of 3-[2-(2-tert-butoxycarbonylmethyl-1-cyclohexenyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (248 g) in dichloromethane (500 ml) was added dropwise trifluoroacetic acid (396 ml) at 5° C. After addition, a reaction mixture was allowed to warm to ambient temperature, and stirred for 20 hours. Solvent was removed by distillation and toluene azeotrope (500 ml×2). A residue was dissolved in a mixture of 1N-aqueous sodium hydroxide solution (3.5 l) and water (0.5 l), which was washed with ethyl acetate (600 ml). Aqueous layer was added dichloromethane (2 l) and the pH was adjusted to pH 3.5 with 2N-aqueous hydrochloric acid. Organic layer was separated and aqueous layer was reextracted with dichloromethane (1 l). Organic layer was combined, which was washed with water (1 l×2) and dried over magnesium sulfate. Evaporation of the solvent gave a crude solid, which was recrystallized from 85% aqueous ethanol (1.25 l) and collected by filtration to give 3-[2-(2-carboxymethyl-1-cyclohexenyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (152.2 g). Mother liquor was concentrated to give crude solid, which was recrystallized in the similar manner to give the second crystal of the object compound (27.63 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]2=[C:4]([Cl:11])[CH:3]=1.[C:12]1(B(O)O)[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=1>>[Cl:11][C:4]1[CH:3]=[C:2]([C:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=2)[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]=12
Reactant: OB(O)C1=CCCCC1
Reactant: Clc1cc(Cl)c2c(n1)CCC2
Product: Clc1cc(C2=CCCCC2)nc2c1CCC2
Yield: 66.2 %

Procedure:
Following general procedure F, 2,4-dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine (0.157 g, 0.84 mmol) was reacted with cyclohex-1-en-1-ylboronic acid (0.142 g, 1.13 mmol) to afford crude product (0.130 g) as an oil. MW=233.74. 1H NMR (CDCl3, 500 MHz) δ 7.13 (s, 1H), 7.08 (s, 1H), 6.70-6.66 (m, 1H), 3.06 (t, J=7.5 Hz, 2H), 2.96 (t, J=7.5 Hz, 2H), 2.47-2.42 (m, 2H), 2.27-2.22 (m, 2H), 2.17-2.09 (m, 2H), 1.82-1.75 (m, 2H), 1.69-1.63 (m, 2H); APCI MS m/z 234 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[C:4](=O)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[NH2:17][CH2:18][CH2:19][CH2:20][OH:21].O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[C:4](=[N:17][CH2:18][CH2:19][CH2:20][OH:21])[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1
Reactant: NCCCO
Reactant: O=C(Cn1ccnc1)c1ccc(Cl)cc1Cl
Solvent: O
Solvent: Cc1ccccc1
Product: OCCCN=C(Cn1ccnc1)c1ccc(Cl)cc1Cl
Yield: 95.6 %

Procedure:
153.2 g (0.60 mole) of N-(2,4-dichlorophenacyl)-imidazole and 53.0 g (0.705 mole) of 3-amino-1-propanol are suspended or dissolved in 400 ml of toluene, and the mixture is heated under reflux with a water trap until no more water of reaction separates out. The reaction solution is then washed 3 times with water, the organic phase is dried with sodium sulfate and, after the solvent has been evaporated off, 179 g of 1-(2-(2,4-dichlorophenyl)-2-(3-hydroxypropylimino)ethyl)-1H-imidazole are obtained as a highly viscous oil. (Yield: 95.6%). 1-(2-(2,4-Dichlorophenyl)-2-(3-hydroxypropylamino)ethyl)-1H-imidazole
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:21]=[CH:20][C:19]([O:22]CC)=[CH:18][N:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH3:3].[OH-].[Na+].C(O)COCCO.Cl>O>[CH2:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:21]=[CH:20][C:19]([OH:22])=[CH:18][N:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH3:3]
Reactant: CCCOCCCCCc1ccc(-c2ncc(OCC)cn2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: CCCOCCCCCc1ccc(-c2ncc(O)cn2)cc1
Temperature: 180 °C
Yield: 75.8 %

Procedure:
A mixture of 7.5 g of 2-[4-(5-[propyloxy]-1-pentyl)phenyl]-5-(ethoxy)pyrimidine, 10 g of sodium hydroxide and 120 ml of diethylene glycol was heated at 180° C. for 8 hours. The reaction mixture was poured into 100 ml of water, acidified with concentrated hydrochloric acid, then extracted three times with 50 ml of diethyl ether each time. The combined organic phases were washed twice with 100 ml of concentrated sodium chloride solution, dried over magnesium sulfate, filtered and subsequently concentrated. Chromatography of the residue on silica gel with hexane/ethyl acetate (vol. 7:3) and recrystallization from ethyl alcohol gave 5.2 g of 2-[4-(5-[propyloxy]-1-pentyl)phenyl]-5-hydroxypyrimidine.
Reaction SMILES: [Cl:1][CH:2](Cl)[B:3]1[O:7][C:6]([CH3:9])([CH3:8])[C:5]([CH3:11])([CH3:10])[O:4]1.[CH2:13]([Mg]Br)[CH:14]=[CH2:15]>O1CCCC1>[Cl:1][CH:2]([B:3]1[O:7][C:6]([CH3:9])([CH3:8])[C:5]([CH3:11])([CH3:10])[O:4]1)[CH2:15][CH:14]=[CH2:13]
Reactant: CC1(C)OB(C(Cl)Cl)OC1(C)C
Reactant: C=CC[Mg]Br
Solvent: C1CCOC1
Product: C=CCC(Cl)B1OC(C)(C)C(C)(C)O1
Temperature: -78 °C
Reaction time: 18 h
Yield: 70.6 %

Procedure:
2 g (9.48 mmol) of 2-(dichloromethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane were dissolved in 30 ml of tetrahydrofuran and the solution was cooled under a nitrogen atmosphere to -78° C. 9.5 ml (9.5 mmol) of 1M allylmagnesium bromide were added dropwise and the solution was stirred at room temperature for 18 hours. The solution was partitioned between ethyl acetate, saturated sodium chloride solution and 2M hydrochloric acid solution. The aqueous layer was extracted with ethyl acetate and the organic layers were combined and dried over anhydrous sodium sulphate. After filtration and evaporation the oil obtained was distilled to give 1.45 g of 2-(1(RS)-chloro-3-butenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane; b.p. 53° C./0.4 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:30]([O:34][CH2:35][CH2:36]O)[CH2:31][CH2:32][CH3:33].Cl>>[ClH:1].[CH2:16]([O:17][CH2:18][CH2:20][O:24][C:23]([C:18]1([C:20]([O:22][CH2:36][CH2:35][O:34][CH2:30][CH2:31][CH2:32][CH3:33])=[O:21])[O:17][C:16]2[CH:26]=[CH:27][C:13]([CH2:12][CH:11]([NH:10][CH2:9][CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[OH:29])[CH3:28])=[CH:14][C:15]=2[O:19]1)=[O:25])[CH2:15][CH2:14][CH3:13]
Reactant: CCCCOCCO
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Agent: Cl
Product: CCCCOCCOC(=O)C1(C(=O)OCCOCCCC)Oc2ccc(CC(C)NCC(O)c3cccc(Cl)c3)cc2O1

Procedure:
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and 2-butoxyethanol accord-ing to the procedure of Example 1 as a colorless oil; 1H NMR (300 MHz, CDCl3): δ 0.78-0.93 (m, 6H), 1.15-1.78 (m, 12H), 2.70-3.62 (brm, 5H), 3.31-3.47 (m, 4H), 3.57-3.73 (m, 4H), 4.29-4.53 (m, 4H), 5.47-5.57 (brs, 1H), 6.70-6.95 (m, 3H), 7.20-7.49 (m, 4H); MS (ES) m/z (relative intensity): 622 (M+ -HCl, 20), 214 (10), 158 (10).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:11]=[C:10]([C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[CH2:9]2)[N:3]=1.[C:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O)(=[O:29])[CH3:28].C(=O)([O-])[O-].[Na+].[Na+].C(O)C>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.C1(C)C=CC=CC=1>[C:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:11]=[C:10]([C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[CH2:9]2)[N:3]=1)(=[O:29])[CH3:28]
Reactant: FC(F)(F)C(F)(F)C1=NN(c2ccccc2Cl)C(c2cccc(Br)n2)C1
Reactant: CC(=O)c1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(=O)c1ccccc1-c1cccc(C2CC(C(F)(F)C(F)(F)F)=NN2c2ccccc2Cl)n1
Temperature: 80 °C
Reaction time: 1 h
Yield: 40.5 %

Procedure:
5-(2-Bromo-pyridin-6-yl)-1-(2-chloro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (20.0 mg, 0.04 mmol) prepared in Step 4 of Preparation 9, 2-acetylphenylboronic acid (11.0 mg, 0.07 mmol), Pd(PPh3)4 (2.0 mg, cat.) and a 2N sodium carbonate solution (210.0 uL) were added to a mixed solvent of ethanol (210.0 uL) and toluene (310.0 uL). The reaction mixture was stirred at 80° C. for 1 hour and then filtered through celite pad. A saturated solution of ammonium chloride was added to the filtrate, which was then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/6) to give 8.0 mg of the titled compound as a white liquid.
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.Cl[C:22]1[N:23]=[N:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH:38]=[CH:37][CH:36]=[N:35]3)=[CH:30][C:29]=2[O:39][CH3:40])=[CH:26][CH:27]=1>C1COCC1>[CH3:40][O:39][C:29]1[CH:30]=[C:31]([N:34]2[CH:38]=[CH:37][CH:36]=[N:35]2)[CH:32]=[CH:33][C:28]=1[C:25]1[N:24]=[N:23][C:22]([O:7][CH:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]2)=[CH:27][CH:26]=1
Reactant: COc1cc(-n2cccn2)ccc1-c1ccc(Cl)nn1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cc(-n2cccn2)ccc1-c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)nn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 89 %

Procedure:
Potassium tert-butoxide (1.0 M in THF, 0.82 mL, 0.82 mmol) was added to tert-butyl 4-hydroxypiperidine-1-carboxylate (0.17 g, 0.82 mmol) in THF (3 mL) at 0° C. and the mixture was stirred for 10 min at 0° C. 3-Chloro-6-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)pyridazine Intermediate 2-1 (0.13 g, 0.45 mmol) was added to the reaction at 0° C. and the mixture was stirred for 1 h at RT. After evaporation under reduced pressure, the crude material was purified by silica chromatography (70 to 100% EtOAc in heptane) to give tert-butyl 4-((6-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)pyridazin-3-yl)oxy)piperidine-1-carboxylate (0.18 g, 89%) as a colorless solid.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH:3]([CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[O:4][Si:5]([CH2:10][CH3:11])([CH2:8][CH3:9])[CH2:6][CH3:7].C(N(CC)CC)C.[CH:27]1([C:30](Cl)=[O:31])[CH2:29][CH2:28]1.C(=O)(O)[O-].[Na+]>ClCCl>[CH:27]1([C:30]([N:15]2[CH2:16][CH2:17][CH:12]([CH:3]([O:4][Si:5]([CH2:8][CH3:9])([CH2:6][CH3:7])[CH2:10][CH3:11])[C:2]([F:18])([F:1])[F:19])[CH2:13][CH2:14]2)=[O:31])[CH2:29][CH2:28]1
Reactant: CC[Si](CC)(CC)OC(C1CCNCC1)C(F)(F)F
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[Si](CC)(CC)OC(C1CCN(C(=O)C2CC2)CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.3 %

Procedure:
4-[2,2,2-Trifluoro-1-(triethylsiloxy)ethyl]piperidine (250 mg, 0.841 mmol) was dissolved in dichloromethane (5.0 mL). To this, triethylamine (0.176 mL, 1.26 mmol) and cyclopropanecarbonyl chloride (0.114 mL, 1.26 mmol) were added at 0° C. and the mixture was stirred at room temperature for 2 hours. The reaction was stopped by addition of a saturated aqueous sodium bicarbonate solution to the reaction mixture, and extraction with dichloromethane was performed, followed by drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=7/3) to give 1-cyclopropanecarbonyl-4-[2,2,2-trifluoro-1-(triethyl-siloxy)ethyl]piperidine (259 mg, yield: 84%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1OS(C(F)(F)F)(=O)=O)[N:9]=[CH:8][CH:7]=[C:6]2[O:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1.O.[CH3:32][N:33](C)C=O>[C-]#N.[Zn+2].[C-]#N>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[C:32]#[N:33])[N:9]=[CH:8][CH:7]=[C:6]2[O:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1
Reactant: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3)ccnc2cc1OS(=O)(=O)C(F)(F)F
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3)ccnc2cc1C#N
Temperature: 110 °C
Reaction time: 2 h

Procedure:
After dissolving trifluoromethanesulfonic acid 6-methoxy-4-(4-nitrophenoxy)quinolin-7-yl ester (500 mg) in dimethylformamide (5 ml), there were added zinc cyanide (260 mg) and tetrakistriphenylphosphine palladium (0) (130 mg) and the mixture was heated and stirred at 110° C. for 2 hours under a nitrogen stream. Water was added, extraction was performed with ethyl acetate, the organic layer was washed with water and saturated saline in that order and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Ethyl acetate was used for recrystallization to obtain the title compound (300 mg).
Reaction SMILES: [CH:1]([CH:3]=[CH:4][N:5]1[CH2:9][CH2:8][NH:7][C:6]1=[N:10][N+:11]([O-:13])=[O:12])=[O:2].[H-].[Na+].CN(C=O)C.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28]Cl)=[CH:24][N:23]=1>O>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][N:7]2[CH2:8][CH2:9][N:5]([CH:4]=[CH:3][CH:1]=[O:2])[C:6]2=[N:10][N+:11]([O-:13])=[O:12])=[CH:24][N:23]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: O=CC=CN1CCNC1=N[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=CC=CN1CCN(Cc2ccc(Cl)nc2)C1=N[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 45.6 %

Procedure:
A mixture comprising 3.0 g of 1-(formylvinyl)-2-nitroiminoimidazolidine, 0.7 g of sodium hydride and 30 ml of DMF was stirred at 40° C. for 15 minutes. After this was cooled to room temperature, 3.2 g of 2-chloro-5-chloromethylpyridine was added thereto and stirred at 60° C for 2 hours. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried (with anhydrous MgSO4) and concentrated to give an oily residue. This was purified by column chromatography (silica gel, eluent: ethyl acetate) to give 2.3 g of 1-(2-chloropyridin-5-ylmethyl)-2-nitroimino-3-(2-formylvinyl)imidazolidine.
Reaction SMILES: [C:1]([N:9]1[CH2:19][CH2:18][C:12]2[N:13]=[N:14][C:15](Cl)=[CH:16][C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:21][NH2:22]>>[C:1]([N:9]1[CH2:19][CH2:18][C:12]2[N:13]=[N:14][C:15]([NH:21][NH2:22])=[CH:16][C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(c1ccccc1)N1CCc2nnc(Cl)cc2C1
Solvent: O
Product: NNc1cc2c(nn1)CCN(C(=O)c1ccccc1)C2

Procedure:
A suspension of 21.6 g of 6-benzoyl-3-chloro-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine in 80 cc of hydrazine hydrate is boiled at reflux at an oil bath temperature of 110° for 1 hour. After a reaction time of approximately 15 minutes the material dissolves completely. The crude title compound resulting after cooling the mixture, is washed with a small amount of absolute ethanol and dissolved in 60 cc of dimethyl formamide. 60 cc of absolute ethanol are added to the solution, whereupon the title compound crystallizes. M.P. 220°-223° (decomp.).