Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18].[N:19]1([C:25]2[CH:30]=[C:29]([C:31](O)=[O:32])[CH:28]=[CH:27][N:26]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:31](=[O:32])[C:29]3[CH:28]=[CH:27][N:26]=[C:25]([N:19]4[CH2:20][CH2:21][O:22][CH2:23][CH2:24]4)[CH:30]=3)[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18]
Reactant: O=C(O)c1ccnc(N2CCOCC2)c1
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1Cl
Product: CCOc1cc(CN2CCC(NC(=O)c3ccnc(N4CCOCC4)c3)CC2)ccc1Cl
Yield: 34 %

Procedure:
The title compound (16 mg, 34%) was prepared analogously to example 1 by coupling of 1-(4-chloro-3-ethoxy-benzyl)piperidin-4-ylamine with 2-(4-morpholinyl)-4-pyridinecarboxylic acid. MS: 459.4 (MH+)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH2:13][CH2:12][CH:11]([N:14]3[CH2:19][CH2:18][C:17]([C:27]#[N:28])([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:37]>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)[CH2:9][CH2:10][CH:11]([N:14]3[CH2:19][CH2:18][C:17]([C:27](=[O:37])[NH2:28])([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:16][CH2:15]3)[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: N#CC1(Nc2ccccc2)CCN(C2CCC(c3ccc(F)cc3)(c3ccc(F)cc3)CC2)CC1
Solvent: O
Product: NC(=O)C1(Nc2ccccc2)CCN(C2CCC(c3ccc(F)cc3)(c3ccc(F)cc3)CC2)CC1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To 16.5 g of 1-[4,4-bis(p-fluorophenyl)cyclohexyl]-4-cyano-4-anilinopiperidine is added gradually a solution of 180 g of concentrated sulfuric acid and 20 ml of water under cooling. After the addition is complete, the resulting mixture is stirred at 70° C for 1 hour and then cooled. The reaction mixture is poured into water, and the precipitated powder is collected by filtration. Then water is added to the powder, the aqueous mixture is made alkaline with potassium carbonate, and the alkaline solution is extracted with chloroform. The extract is washed with water and dried over sodium sulfate, and the solvent is removed. The precipitated crystals are collected by filration and recrystallized from a mixture of chloroform and acetone to give 1-[4,4-bis(p-fluorophenyl)cyclohexyl]-4-carbamoyl-4-anilinopiperidine as white crystals, melting at 224°-227° C.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[F:9][C:10]1[CH:11]=[C:12]([CH:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]=2)[C:21]#[N:22])[CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1.[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1.C(Cl)Cl>[F:9][C:10]1[CH:11]=[C:12]([C:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]=2)([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:21]#[N:22])[CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1
Reactant: BrCc1ccccc1
Reactant: N#CC(c1cc(F)cc(C(F)(F)F)c1)c1ccc(F)cn1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: N#CC(Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(F)cn1
Temperature: -78 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
To a solution of LDA (2.0 M in THF, 3.7 mL) in THF (20 mL) at −78° C. under argon was added dropwise a solution of 2-(3-fluoro-5-(trifluoromethyl)phenyl)-2-(5-fluoropyridin-2-yl)acetonitrile (1.7 g, 5.7 mmol), prepared as described in Procedure 3, in THF (4 mL). The resulting solution was stirred at −78° C. for 1 h. Benzylbromide (0.88 mL, 7.4 mmol) was added to the reaction mixture and allowed to warm to room temperature. The reaction mixture was stirred at rt for 1 h, concentrated under reduced pressure and diluted with EtOAc (approx 100 mL). The resulting solution was washed with water (30 mL) and sat. NaCl (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to yield a yellow oil. The yellow oil was dissolved in CH2Cl2 and loaded directly onto a silica gel ISCO cartridge (40 g) with elution at 35 mL/min gradient 0 to 30% EtOAc in hexane over 35 min (RT=27-32 min). 2-(3-Fluoro-5-(trifluoromethyl)phenyl)-2-(5-fluoropyridin-2-yl)-3-phenylpropanenitrile (1.6 g, 72% yield) was isolated as a pale yellow oil. LCMS: RT=2.17 min [M+H] 389.0 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); HPLC: RT=4.24 min (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.2% PPA; 4 mL/min, monitoring at 220 nm); NMR: 400 MHz 1H (CDCl3) ppm 3.59 (d, J=13.18 Hz, 1 H), 3.90 (d, J=13.62 Hz, 1 H), 6.89 (d, J=6.59 Hz, 2 H), 7.09-7.15 (m, 3 H), 7.20 (d, J=7.91 Hz, 1 H), 7.32 (td, J=8.35, 3.08 Hz, 1H), 7.37 (d, J=9.23 Hz, 1 H), 7.45-7.48 (m, 1 H), 7.49 (s, 1 H), 8.50 (d, J=2.64 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[N+:24]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pt]>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:17])([F:19])[F:18])[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pt]
Product: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N

Procedure:
The title compound was prepared from [2-nitro-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert.-butyl ester (Example B7) by hydrogenation with 5% Pt/C according to the general procedure J (method a). Obtained as a yellow solid (17.374 g).
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[Cl:24])[N:16]=[C:15](C(OC)=O)[CH:14]=3)=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH3:29][Mg]Br.CC[O:34][CH2:35][CH3:36]>C1COCC1>[N:1]1([C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[Cl:24])[N:16]=[C:15]([C:35]([OH:34])([CH3:36])[CH3:29])[CH:14]=3)=[CH:11][CH:12]=2)=[O:6])[CH2:2][CH2:3][CH2:4]1
Reactant: CCOCC
Reactant: C[Mg]Br
Reactant: COC(=O)c1cc(-c2ccc(C(=O)N3CCC3)cc2)n(-c2ccccc2Cl)n1
Solvent: C1CCOC1
Product: CC(C)(O)c1cc(-c2ccc(C(=O)N3CCC3)cc2)n(-c2ccccc2Cl)n1
Temperature: 25 °C
Yield: 31 %

Procedure:
To a cooled (−78° C.) solution of methyl 5-(4-(azetidine-1-carbonyl)phenyl)-1-(2-chlorophenyl)-1H-pyrazole-3-carboxylate (138 mg, 0.35 mmol) in THF (5 mL) was added methylmagnesium bromide (0.3 mL of a 3.0M solution in ether, 0.9 mmol). The resulting brown solution was allowed to slowly warm to ambient temperature overnight. The reaction was then quenched by the addition of saturated aqueous ammonium chloride solution and EtOAc. The aqueous was extracted with EtOAc (3×) and the combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to afford a yellow film. This crude product was purified by flash column chromatography eluting with a gradient of 0% to 10% MeOH in CH2Cl2. The main peak was collected and was ˜85% pure by HPLC. This material was further purified by reverse phase preparative HPLC eluting with MeCN/H2O with 0.1% TFA. The product fractions from the HPLC were made basic by the careful addition of solid Na2CO3. The resulting mixture was concentrated to remove most of the MeCN. The resulting aqueous suspension was extracted with CH2Cl2 (3×), and the combined extracts were dried over Na2SO4 overnight, filtered and concentrated under reduced pressure to afford azetidin-1-yl(4-(1-(2-chlorophenyl)-3-(2-hydroxypropan-2-yl)-1H-pyrazol-5-yl)phenyl)methanone (43 mg, 31% yield) as a pale brown powder. 1H NMR (400 MHz CDCl3): δ 7.54-7.48 (2H, m), 7.46-7.40 (2H, m), 7.39-731 (2H, m), 7.24-7.19 (2H, m), 6.54 (1H, s), 4.32-4.16 (4H, m), 2.63 (1H, s), 2.38-2.28 (2H, m), 1.68 (6H, s). MS(ES): 396 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[Cl:9].F[C:11](F)(F)[S:12](O)(=[O:14])=[O:13]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:12]([CH3:11])(=[O:14])=[O:13])=[C:4]([Cl:8])[C:3]=1[Cl:9]
Reactant: Clc1cccc(Cl)c1Cl
Reactant: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(Cl)c(Cl)c1Cl

Procedure:
A mixture of 133 g (1.38 mol) of methanesulfonic acid and 67 g (0.56 mol) of thionyl chloride was heated to reflux with stirring for one hour. The temperature increased from 50° C. to 160° C. as the reaction to form methanesulfonic acid anhydride progressed. The resulting mixture was cooled to below 50° C. and then 50.0 g (0.28 mol) of 1,2,3-trichlorobenzene and 4.2 g (0.028 mol) of trifluoromethanesulfonic acid were added. This mixture was heated with stirring and allowed to react at 140° C. for 18 hours and at 160° C. for 2 hours. The resulting mixture solidified on cooling. It was taken up in 600 mL of dichloromethane and the resulting solution was washed with 2×100 mL of water, 100 mL of 1 M aqueous sodium bicarbonate solution, and 100 mL of water, dried over sodium sulfate, and concentrated by evaporation under reduced pressure to obtain 58.5 g of a 9:1 mixture of the title compound and its isomer. This was recrystallized from ethanol to obtain 46 g (63 percent of theory) of the title compound as a white solid melting at 159-160° C. The structure was confirmed by its 1H NMR spectrum (CDCl3): 8.02(d, 1H, J=8.6 Hz), 7.60(d, 1H, 8.7 Hz), 3.28 (s, 3H) and its 13C NMR spectrum (CDCl3): 140.1, 138.5, 134.6, 132.8, 126.7, 42.6.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH3:18][C:19]1[C:23]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[O:25])=[C:22]([CH3:33])[NH:21][C:20]=1[CH:34]=O>C(O)C.N1CCCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10](=[CH:34][C:20]2[NH:21][C:22]([CH3:33])=[C:23]([C:24]([N:26]4[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]4)=[O:25])[C:19]=2[CH3:18])[C:11](=[O:17])[NH:12]3)=[CH:6][CH:7]=1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Reactant: O=C1Cc2c(cccc2-c2ccc(Br)cc2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(Br)cc4)c32)c(C)c1C(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 29.3 %

Procedure:
To a solution of 4-(4-bromo-phenyl)-1,3-dihydro-indol-2-one (72 mg, 0.25 mmol) and 3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide 4-[4-bromo-phenyl)-3-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (38 mg, 29%)
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]2[N:11]=[CH:10][C:9]([C:12]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[O:13])=[C:8]([OH:23])[C:6]=2[N:7]=1.C(N(CC)CC)C.[CH2:31]([OH:34])[C:32]#[CH:33].[NH4+].[Cl-]>CN(C=O)C.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>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][NH:14][C:12]([C:9]2[CH:10]=[N:11][C:5]3[CH:4]=[N:3][C:2]([C:33]#[C:32][CH2:31][OH:34])=[N:7][C:6]=3[C:8]=2[OH:23])=[O:13])=[CH:17][CH:18]=1
Reactant: C#CCO
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2cnc(Br)nc2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2cnc(C#CCO)nc2c1O
Temperature: 90 °C

Procedure:
A mixture of 2-bromo-N-(4-chlorobenzyl)-8-hydroxypyrido[3,2-d]pyrimidine-7-carboxamide (Preparation 6, 1.97 g), (Ph3P)2PdCl2 (175 mg), and triethylamine (5.0 mL) in DMF (50 mL) is heated to 90° C. Propargyl alcohol (2.5 mL) is slowly added to the mixture over 20 h. The reaction mixture is allowed to cool to room temperature, poured into saturated aqueous NH4Cl solution (200 mL), and extracted with ethyl acetate (3×100 mL). The combined organic layers are dried (MgSO4) and concentrated. The crude product is purified by column chromatography.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[CH:11]=[C:12]4[C:16](=[CH:17][CH:18]=3)[NH:15][N:14]=[C:13]4[I:19])[CH:7]=[N:6][CH:5]=2)[CH2:3][CH2:2]1.[O:20]1[CH:25]=[CH:24][CH2:23][CH2:22][CH2:21]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[CH:11]=[C:12]4[C:16](=[CH:17][CH:18]=3)[N:15]([CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25][O:20]3)[N:14]=[C:13]4[I:19])[CH:7]=[N:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: Ic1n[nH]c2ccc(-c3cncc(C4CC4)n3)cc12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: Ic1nn(C2CCCCO2)c2ccc(-c3cncc(C4CC4)n3)cc12
Temperature: 25 °C
Yield: 58.5 %

Procedure:
A mixture of 5-(6-cyclopropylpyrazin-2-yl)-3-iodo-1H-indazole (192 mg, 0.53 mmol), 3,4-dihydro-2 h-pyran (96 μL, 1.06 mmol) and p-toluenesulfonic acid monohydrate (20 mg, 0.106 mmol) in THF (3 mL) was heated at reflux overnight (9 h). After cooling to RT, the mixture was concentrated to about 1 mL. The mixture was diluted with EtOAc and saturated NaHCO3 (aq.) and the layers were separated. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude was purified by silica gel chromatography, eluting with a gradient of 0-30% EtOAc in hexanes, to provide 5-(6-cyclopropylpyrazin-2-yl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (140 mg, 0.31 mmol, 59% yield) as a pale yellow foam. MS (ESI, pos. ion) m/z: 447.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)=[C:12]([NH2:17])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:26][CH3:27])=[C:5]([CH3:28])[O:4][N:3]=1.[O:29]1[CH2:34][CH2:33][CH:32]([C:35](Cl)=O)[CH2:31][CH2:30]1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:1][C:2]1[C:6]([C:7]2[C:8]([O:26][CH3:27])=[CH:9][C:10]3[C:11]4[N:18]([CH2:19][C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=5)[C:35]([CH:32]5[CH2:33][CH2:34][O:29][CH2:30][CH2:31]5)=[N:17][C:12]=4[CH:13]=[N:14][C:15]=3[CH:16]=2)=[C:5]([CH3:28])[O:4][N:3]=1
Reactant: COc1cc2c(NCc3ccccn3)c(N)cnc2cc1-c1c(C)noc1C
Reactant: O=C(Cl)C1CCOCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc2c(cc1-c1c(C)noc1C)ncc1nc(C3CCOCC3)n(Cc3ccccn3)c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 21 %

Procedure:
To a solution of 7-(3,5-dimethyl-4-isoxazolyl)-6-(methoxy)-N4-(2-pyridinylmethyl)-3,4-quinolinediamine (for a preparation see Intermediate 38, 0.5 g, 1.33 mmol) in DCM (20 ml) was added tetrahydro-2H-pyran-4-carbonyl chloride (1.1 eq., 1.46 mmol, 0.15 g, Apollo Scientific) at 0° C., the mixture was stirred at 0° C. for 30 minutes. The reaction mixture was hydrolysed with saturated aqueous Sodium hydrogen carbonate and extracted with DCM. The organic phase was dried over Na2SO4 and concentrated to give the crude product which was used in the next step without purification. AcOH (5 ml) was added to the crude product and the mixture was stirred at 100° C. overnight. The reaction mixture was concentrated under reduce pressure, hydrolised with sodium hydroxide 1N and extracted with DCM. The organic phase was dried over over Na2SO4, evaporated under reduce pressure. The residue was purified by flash chromatography on silica gel (DCM/MeOH, 95:5) and the compound was re-crystallised from acetonitrile to give the title compound as an off-white powder (0.13 g, 21%)
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]=1.[CH:12]1([CH2:15][CH2:16][NH:17][C:18]([C:20]2[N:21]=[N:22][C:23]([N:26]3[CH2:31][CH2:30]N[CH2:28][CH2:27]3)=[CH:24][CH:25]=2)=[O:19])[CH2:14][CH2:13]1>C(O)C>[CH:12]1([CH2:15][CH2:16][NH:17][C:18]([C:20]2[N:21]=[N:22][C:23]([N:26]3[CH2:27][CH2:28][N:1]([C:2]4[C:10]5[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=5)[C:4](=[O:11])[N:3]=4)[CH2:30][CH2:31]3)=[CH:24][CH:25]=2)=[O:19])[CH2:14][CH2:13]1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Reactant: NC1=NC(=O)c2ccccc21
Solvent: CCO
Product: O=C(NCCC1CC1)c1ccc(N2CCN(C3=NC(=O)c4ccccc43)CC2)nn1
Yield: 40 %

Procedure:
3-Aminoisoindol-1-one (0.292 g, 2.00 mmol) and 6-piperazin-1-ylpyridazine-3-carboxylic acid (2-cyclopropylethyl)amide (0.825 g, 3.00 mmol) were boiled together in ethanol (20 mL) for 48 hours. The solution was concentrated in vacuo. This residue was purified by column chromatography. The title compound was obtained as a white solid in 40% yield (0.328 g). 1H NMR (300 MHz, CDCl3) δ 8.07 (d, J=9.5 Hz, 1H), 7.97 (t, J=5.8 Hz, 1H), 7.76 (d, J=7.0 Hz, 1H), 7.64 (d, J=7.3 Hz, 1H), 7.52 (m, 1H), 7.01 (d, J=9.5 Hz, 1H), 4.42-4.35 (m, 4H), 4.23-4.20 (m, 2H), 3.93-3.89 (m, 2H), 3.54 (dd, J=6.7 and 13.2 Hz, 1H), 1.49 (m, 1H), 0.79-0.66 (m, 1H), 0.47-0.41 (m, 2H), 0.10-0.05 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 181.5, 174.6, 162.9, 159.6, 145.6, 138.1, 134.9, 132.5, 131.7, 127.3, 124.0 123.3, 112.2, 47.2, 46.4 44.5, 43.2, 39.7, 34.5, 8.7, 4.2. MS (ES+) m/z 405.1 (M+1).
Reaction SMILES: [CH:1]1([CH2:7][N:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18].[P:22]([O:27]C)([O:25][CH3:26])[O:23][CH3:24].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[CH:10]1([CH2:9][N:8]([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[P:22]([O:25][CH3:26])([O:23][CH3:24])=[O:27])[C:17](=[O:18])[O:19][CH2:20][CH3:21])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: C(=NCC1CCCCC1)c1ccccc1
Reactant: CCOC(=O)Cl
Reactant: COP(OC)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N(CC1CCCCC1)C(c1ccccc1)P(=O)(OC)OC
Temperature: -5 °C

Procedure:
The solution of N-(cyclohexylmethyl)phenylmethanimine in chloroform was diluted to 100 mL with fresh chloroform. This solution was stirred and cooled to -5° C. Ethyl chloroformate (11.0 mL, 0.12 mole) was added, and the mixture was stirred for ten minutes. Trimethyl phosphite (13.0 mL, 0.11 mole) was added, and the cold mixture was stirred for an additional ten minutes. The mixture was allowed to warm to room temperature and stir for 30 minutes. This mixture was poured slowly into an aqueous solution of potassium carbonate. The resultant mixture was extracted with chloroform. The extract was washed with an aqueous solution saturated with sodium chloride and then was dried over anhydrous magnesium sulfate. The dried solution was filtered, and the filtrate was evaporated under reduced pressure, leaving an oil. This oil was purified by column chromatography on silica gel to yield ethyl N-cyclohexylmethyl-N-[phenyl(dimethoxyphosphinyl)methyl]carbamate as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][C@H:5]([CH2:7][OH:8])[CH2:4][O:3]1.N1C=CC=CC=1.Cl[C:17]([O:19][CH2:20][Cl:21])=[O:18]>CCOCC>[C:17](=[O:18])([O:8][CH2:7][C@@H:5]1[CH2:4][O:3][C:2]([CH3:9])([CH3:1])[O:6]1)[O:19][CH2:20][Cl:21]
Reactant: O=C(Cl)OCCl
Reactant: CC1(C)OC[C@@H](CO)O1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC1(C)OC[C@@H](COC(=O)OCCl)O1
Temperature: 25 °C
Reaction time: 20 h
Yield: 100 %

Procedure:
(R)-Glycerol acetonide (10 g) was dissolved in anhydrous ether (200 ml) and, after adding pyridine (6.6 g) at −10° C., a solution of chloromethyl chloroformate (10.7 g) in anhydrous ether (20 ml) was added dropwise over the period of 10 minutes. After the reaction mixture was stirred at room temperature for 20 hours, the deposited pyridine hydrochloride was removed by filtration. The filtrate was washed with a saturated sodium chloride aqueous solution (200 ml×2), and then dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by subjecting to silica gel chromatography (eluent: hexane→ethyl acetate/hexane=1/5→ethyl acetate/hexane=3/5) to obtain chloromethyl [(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl carbonate (17 g) as a colorless oily product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:12](=[O:31])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][C:16](/[CH:26]=[CH:27]/[C:28]([OH:30])=O)=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C([N:39]=C=NCCCN(C)C)C.[NH4+].ON1C2C=CC=CC=2N=N1.O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:12](=[O:31])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][C:16](/[CH:26]=[CH:27]/[C:28]([NH2:39])=[O:30])=[CH:15][CH:14]=2)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(/C=C/C(=O)O)ccc2c1=O
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(/C=C/C(N)=O)ccc2c1=O
Yield: 93.1 %

Procedure:
A solution of (E)-3-[3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-2-propenic acid (0.33 g, 0.7 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.27 g, 1.4 mmol) and 1-hydroxybenzotriazole ammonium salt (0.21 g, 1.4 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-diisopropyl ether to give (E)-3-[3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-2-propenamide (0.31 g, 93.9%) as crystals.
Reaction SMILES: O.C(=O)([O-])[O-].[K+].[K+].[NH2:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[C:29](=[O:30])[C:28]([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)=[CH:27][N:26]([CH2:38][C:39]([F:42])([F:41])[F:40])[CH:25]=3)=[O:23])=[CH:17][CH:16]=2)=[CH:13][C:12](Br)=[CH:11][N:10]=1.[CH3:44][O:45][C:46]1[CH:47]=[C:48](B(O)O)[CH:49]=[CH:50][CH:51]=1>O1CCOCC1.C(OCC)(=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>[NH2:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[C:29](=[O:30])[C:28]([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)=[CH:27][N:26]([CH2:38][C:39]([F:42])([F:41])[F:40])[CH:25]=3)=[O:23])=[CH:17][CH:16]=2)=[CH:13][C:12]([C:50]2[CH:49]=[CH:48][CH:47]=[C:46]([O:45][CH3:44])[CH:51]=2)=[CH:11][N:10]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: Nc1ncc(Br)cc1-c1ccc(NC(=O)c2cn(CC(F)(F)F)cc(-c3ccc(F)cc3)c2=O)cc1
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: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc(-c2cnc(N)c(-c3ccc(NC(=O)c4cn(CC(F)(F)F)cc(-c5ccc(F)cc5)c4=O)cc3)c2)c1
Temperature: 90 °C
Reaction time: 17 h
Yield: 10 %

Procedure:
Water (0.1 ml), potassium carbonate (70 mg) and tetrakis(triphenylphosphine)palladium (19 mg) were added to a solution of the compound obtained in Step 1 of Example 31 (95 mg) and 3-methoxyphenylboronic acid (31 mg) in 1,4-dioxane (1.5 ml), and the mixture was stirred at 90° C. for 17 hours. After leaving to cool, the reaction solution was diluted with ethyl acetate. The organic layer was washed with water and brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate:methanol=300:1->100:1 (v/v)] to give 10 mg of the title compound as a solid.