Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COCCN(S(F)(F)[F:11])CCOC.ClC1C=CC(C(C(OCC)=O)(C2[CH:29]=[CH:28][C:26]([Cl:27])=[CH:25]C=2)O)=CC=1.[Cl:35][C:36]1[CH:41]=CC(C(C(OCC)=O)(C2C=CC(Cl)=CC=2)O)=CC=1.[C@@:56]12([OH:65])[N:63]([CH3:64])[C@@H:60]([CH2:61][CH2:62]1)[CH2:59][CH:58]=[CH:57]2.O.[C:67]([O-:70])(O)=[O:68].[Na+]>ClCCl>[C@@:56]12([OH:65])[N:63]([CH3:64])[C@@H:60]([CH2:61][CH2:62]1)[CH2:59][CH:58]=[CH:57]2.[F:11][C:59]([C:58]1[CH:57]=[CH:29][CH:28]=[C:26]([Cl:27])[CH:25]=1)([C:60]1[CH:61]=[CH:62][CH:56]=[C:36]([Cl:35])[CH:41]=1)[C:67]([O-:70])=[O:68]
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CCOC(=O)C(O)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: O=C([O-])O
Agent: CN1[C@@H]2CC=C[C@@]1(O)CC2
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C([O-])C(F)(c1cccc(Cl)c1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1.48 g (0.0067 mol) of bis-(2-methoxyethyl)aminosulfur trifluoride is used in 10 mL of dichloromethane and within 20 minutes at 15° C.-20° C., a solution of 2.09 g of 5g in 65 mL of dichloromethane is added dropwise. The mixture is stirred for 20 hours at ambient temperature, cooled to 0° C., and carefully combined with 80 mL of water with thorough stirring. The mixture is then carefully adjusted to pH 8 with aqueous NaHCO3 solution, the organic phase is separated off, the aqueous phase is again extracted with dichloromethane, the combined organic phases are washed with water, dried over MgSO4, and evaporated to dryness. The hydrochloride is precipitated and recrystallized from acetonitrile/diethylether. Yield: 1.20 g of white crystals (53% of theory); melting point: 136° C.-137° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.Cl[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[OH:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: OCCCCCCCCCl
Reactant: N#CCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCc1ccc(OCCCCCCCCO)cc1
Temperature: 80 °C
Reaction time: 48 h
Yield: 62.5 %

Procedure:
20.0 g (150 mmol) of (4-hydroxyphenyl)acetonitrile and 29.5 g (179 mmol) of 8-chlorooctan-1-ol are dissolved in 400 mL of N,N-dimethylformamide. 41.5 g (300 mmol) of potassium carbonate and 5.0 g (30 mmol) of potassium iodide are added and the suspension is heated to 80° C. After 48 h, the excess of potassium carbonate is filtered off and the resulting filtrate is poured to icy water. The aqueous layer is extracted twice with ethyl acetate. Combined organic layers are washed with brine and evaporated to dryness. The crude is purified twice on column chromatography (SiO2, Heptane/ethyl acetate: 7/3) and dried overnight at 40° C. 24.5 g of {4-[(8-hydroxyoctyl)oxy]phenyl}acetonitrile are obtained as a yellow solid (62% yield). This material proves chromatographically homogenous and displays spectral characteristics consistent with its assigned structure.
Reaction SMILES: C(O[C@@H:5]1[C@H:27](O)[C:26]([CH3:30])([CH3:29])[C@H:25]2[C@@:7]3([O:21][C:11]4[C:12]5[CH2:13][NH:14][C:15](=[O:20])[C:16]=5[CH:17]=[C:18]([OH:19])[C:10]=4[CH2:9][C@:8]3([CH3:32])[C@@H:22]([CH3:31])[CH2:23][CH2:24]2)[CH2:6]1)(=O)C.N1C=CC=CC=1.Cl.[NH2:40][OH:41].O>C(O)C>[OH:19][C:18]1[C:10]2[CH2:9][C@:8]3([CH3:32])[C@@H:22]([CH3:31])[CH2:23][CH2:24][C@H:25]4[C:26]([CH3:29])([CH3:30])[C:27](=[N:40][OH:41])[CH2:5][CH2:6][C@@:7]34[O:21][C:11]=2[C:12]2[CH2:13][NH:14][C:15](=[O:20])[C:16]=2[CH:17]=1
Reactant: CC(=O)O[C@H]1C[C@@]23Oc4c(c(O)cc5c4CNC5=O)C[C@]2(C)[C@@H](C)CC[C@H]3C(C)(C)[C@H]1O
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Solvent: O
Product: C[C@H]1CC[C@H]2C(C)(C)C(=NO)CC[C@]23Oc2c(c(O)cc4c2CNC4=O)C[C@]13C
Temperature: 80 °C
Reaction time: 3 h
Yield: 83.6 %

Procedure:
To a solution of Compound (12) (Step-2 of Example 55) (30 mg, 0.078 mmol) in 3.0 ml of ethanol were added 0.3 ml (3.70 mmol) of pyridine and 9 mg (0.13 mmol) of hydroxylamine hydrochloride, and the mixture stirred for 3 hours at 80° C. After addition of water, the reaction mixture was extracted with ethyl acetate. The extract was washed sequentially with 1N HCl, water, an aqueous saturated sodium hydrogen carbonate solution and water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The crystalline residue was recrystallized from diethyl ether-pentane to give 26 mg (83%) of Compound (51a).
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH3:11])[N:9]=[C:8]([CH3:12])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:13][CH:14]1[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15]1>C(Cl)Cl.C(N(CC)CC)C>[CH2:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:22][CH:14]1[NH:13][C:2]1[C:3]2[N:10]([CH3:11])[N:9]=[C:8]([CH3:12])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: NC1Cc2ccccc2C1
Reactant: Cc1nn(C)c2c(Cl)ncnc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nn(C)c2c(NC3Cc4ccccc4C3)ncnc12
Yield: 62 %

Procedure:
7-chloro-1,3-dimethyl-1H-pyrazolo[4,3-d]pyrimidine (28 mg, 0.15 mmol) (see J. Med. Chem.,31, 454 (1988)), 2-aminoindan (66 mg, 0.50 mmol), and triethylamine (30 μl, 0.2 μmol) in dry methylene chloride (1 ml) were heated to reflux for 2 hours. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel chromatography (hexane:ethyl acetate=1:4) to obtain the title compound (26 mg, 0.093 mmol) having the following physical properties:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:10]([CH3:11])=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][C:4]=1[CH3:12].C(=O)([O-])[O-].[K+].[K+].[C:19](Cl)(=[O:21])[CH3:20]>C(OCC)(=O)C.O>[OH:8][CH2:7][C:6]1[CH:9]=[C:10]([CH3:11])[C:3]([CH2:2][NH:1][C:19](=[O:21])[CH3:20])=[C:4]([CH3:12])[CH:5]=1
Reactant: CC(=O)Cl
Reactant: Cc1cc(CO)cc(C)c1CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)NCc1c(C)cc(CO)cc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-aminomethyl-3,5-dimethylbenzyl alcohol (2.3 g) in ethyl acetate (70 ml) was added a solution of potassium carbonate (2.0 g) in water (35 ml). To this solution was added acetyl chloride (0.95 ml) under ice-cooling. This mixture was stirred at room temperature for 1 hr. The reaction mixture was extracted with ethyl acetate, washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was recrystallized from methanol-ethyl acetate to give the title compound (2.0 g) as white crystals, m.p.=193.5-194.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:14])([CH3:13])[C:9]([O:11]C)=[O:10])[CH:5]=[CH:6][CH:7]=1.[Li+].[OH-]>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:14])([CH3:13])[C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)(C)c1cccc(Br)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C(=O)O)c1cccc(Br)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a Solution of ester from step 1 in THF-MeOH (4:1, 0.5M) was added LiOH (3 eq, 2M) and the mixture was stirred at 50° C. for 1 h. The organic solvent evaporated, aqueous was acidified with HCl 1N and the acid extracted with EtOAc (3×). The organic was washed with brine, dried and solvent evaporated to afford the acid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:7]=1[N+:8]([O-:22])=[C:9]1[C:14](=[N+:15]2[O-:20])[C:13]([OH:21])=[CH:12][CH:11]=[CH:10]1.[CH2:23]([NH:25][CH2:26][CH3:27])[CH3:24].CS(C)=O>C(Cl)(Cl)Cl>[CH2:23]([N:25]([CH2:26][CH3:27])[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:7]=1[N+:8]([O-:22])=[C:9]1[C:14](=[N+:15]2[O-:20])[C:13]([OH:21])=[CH:12][CH:11]=[CH:10]1)[CH3:24]
Reactant: [O-][n+]1c2cccc(OCCCCl)c2[n+]([O-])c2cccc(O)c21
Reactant: CCNCC
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Product: CCN(CC)CCCOc1cccc2c1[n+]([O-])c1cccc(O)c1[n+]2[O-]
Temperature: 25 °C
Reaction time: 22 h

Procedure:
5.0 grams of 6-(3-chloropropoxy)-1-phenazinol 5,10-dioxide and 25ml of diethylamine were placed in a flask. To this was added 50ml of dimethylsulfoxide. The reaction mixture was stirred at room temperature for 22 hours. The reaction mixture was then diluted with 400ml CHCl3 and washed first with very dilute acetic acid and then with water until the water washes were neutral. The CHCl3 layer was extracted with 10 percent aqueous HCl. The combined HCl extracts were neutralized with sodium carbonate and extracted with ethyl acetate. The combined ethyl acetate extracts were washed with water, dried over sodium sulfate and concentrated in vacuo. The residue was slurried with ether/pentane (1:1) and filtered to yield red crystals of 6-(3-diethylaminopropoxy)-1-phenazinol 5,10-dioxide, m.p. 78°-80° (dec.).
Reaction SMILES: C(C1CC1)=C.S(NN)(C1C=CC(C)=CC=1)(=O)=O.[C:18]([C:20]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:22][CH:21]1[CH:23]=[CH2:24])#[N:19]>COCCOCCOC>[C:18]([C:20]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:22][CH:21]1[CH2:23][CH3:24])#[N:19]
Reactant: C=CC1CC1(C#N)c1ccccc1
Agent: C=CC1CC1
Agent: Cc1ccc(S(=O)(=O)NN)cc1
Solvent: COCCOCCOC
Product: CCC1CC1(C#N)c1ccccc1
Reaction time: 1 h
Yield: 51 %

Procedure:
1-Cyano-1-phenyl-2-ethylcyclopropane was prepared by carrying out a reduction on the corresponding 2-vinylcyclopropane derivative, prepared in accordance with the procedure of Example I, employing tosyl hydrazine. The 1-cyano-1-phenyl-2-vinylcyclopropane (10.14 g) was combined with 22.32 g tosyl hydrazine in 70 cc diglyme and the mixture refluxed with stirring for 1 hour. The reaction mixture was extracted with petroleum ether and, upon distillation, 5.23 g 1-cyano-1-phenyl-2-ethylcyclopropane was obtained. Reduction of the vinyl group was confirmed by the nuclear magnetic resonance spectrum in that there was no absorption at δ5.3. Absence of vinyl absorption was also confirmed by infrared analysis.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:5]2[C:10]([CH3:11])=[N:9][N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:15][CH:14]=3)[C:6]=2[N:7]=1.[NH2:31][CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.CC(O)C.CN1C(=O)CCC1>CCOC(C)=O>[CH3:11][C:10]1[C:5]2[C:4]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:3][C:2]([NH:31][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[N:7][C:6]=2[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)[N:9]=1
Reactant: CCOC(=O)c1cc(Cl)nc2c1c(C)nn2Cc1ccc(Oc2ccccc2)cc1
Reactant: NCCN1CCOCC1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1cc(NCCN2CCOCC2)nc2c1c(C)nn2Cc1ccc(Oc2ccccc2)cc1
Temperature: 150 °C
Yield: 26.8 %

Procedure:
(see, e.g., WO2013039988A1). A pressure vessel was charged with 50 (121 mg, 0.29 mmol), 4-(2-aminoethyl)morpholine (1.0 mL, 7.6 mmol) and iPrOH (3 mL) and NMP (1 mL). The vessel was sealed and the reaction mixture was heated at 150° C. overnight. The reaction mixture was diluted with EtOAc (20 mL) and washed with H2O (10 mL×3) to remove NMP. Combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. Crude was subjected to flash column chromatography on silica gel to provide the title compound (40 mg, 26%) as a yellow oil. 1H NMR (500 MHz, CDCl3) δ 7.29 (q, J=7.1, 6.6 Hz, 4H), 7.07 (t, J=7.1 Hz, 1H), 6.96 (d, J=8.6 Hz, 2H), 6.91 (d, J=8.3 Hz, 2H), 6.78 (s, 1H), 5.46 (s, 2H), 4.43 (q, J=7.1 Hz, 2H), 3.76-3.70 (m, 4H), 3.55 (q, J=5.0 Hz, 2H), 2.63 (t, J=5.7 Hz, 2H), 2.58 (s, 3H), 2.49 (s, 4H), 1.42 (t, J=7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 166.00, 157.47, 157.15, 156.51, 152.39, 141.23, 134.44, 132.67, 129.66, 129.31, 123.18, 118.83, 118.77, 107.03, 103.90, 66.92, 61.62, 57.03, 53.40, 49.37, 37.75, 16.16, 14.26.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3([C:18]([OH:20])=O)[CH2:17][CH2:16]3)=[CH:11][C:10]=2[F:21])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:22](Cl)(=[O:26])[C:23](Cl)=O.[C:28]([CH2:31][NH:32][CH2:33][CH:34]([OH:41])[CH2:35][N:36](C)[C:37](=O)C)(=[O:30])[CH3:29].C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[C:28]([CH2:31][NH:32][CH2:33][CH:34]([O:41][C:22](=[O:26])[CH3:23])[CH2:35][NH:36][CH2:37][C:18]([C:15]1([C:12]2[CH:13]=[CH:14][C:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)=[C:10]([F:21])[CH:11]=2)[CH2:17][CH2:16]1)=[O:20])(=[O:30])[CH3:29]
Reactant: CC(=O)CNCC(O)CN(C)C(C)=O
Reactant: O=C(O)C1(c2ccc(-c3ccc(Cl)c(Cl)c3)c(F)c2)CC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)CNCC(CNCC(=O)C1(c2ccc(-c3ccc(Cl)c(Cl)c3)c(F)c2)CC1)OC(C)=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 20.6 %

Procedure:
To a suspension of 1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropane carboxylic acid (1630 mg, 5.012 mmol) in DCM (55 mL) containing a few drops of DMF, under nitrogen atmosphere, at 0° C., oxalyl dichloride (0.849 mL, 10.02 mmol) was added dropwise, and the reaction was stirred at room temperature for 20 minutes. Solvent was evaporated, and the residue taken up with toluene and dried under vacuum, obtaining crude acyl chloride. Acyl chloride was dissolved in DCM (10 mL) and added dropwise, at 0° C., under nitrogen atmosphere, to a solution of N-[3-(acetylmethylamino)-2-hydroxypropyl]-N-methylacetamide (I5) (676 mg, 3.342 mmol) and triethylamine (2.8 mL, 20.08 mmol) in DCM (50 mL). The reaction was stirred at r.t. overnight and then heated at 40° C. for 2 hours. The reaction mixture was diluted with DCM and washed with H2O (2×) and a saturated solution of NaHCO3 (2×). The organic layer was dried with Na2SO4, filtered and concentrated to dryness. The crude thus obtained was purified by silica gel flash chromatography (DCM:methanol 99:1 v/v) affording acetic acid 1-[(acetylmethylamino)methyl]-2-{[1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarbonyl]methylamino}ethyl ester (350 mg, 21% yield) as pale yellow foam.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:14]([CH:16]=[CH2:17])=O.[NH2:18][C:19]1[CH:23]=[C:22]([CH3:24])[O:21][N:20]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C1COCC1.C1CCN2C(=NCCC2)CC1>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:16][CH2:17][NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[O:21][N:20]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: C=CC=O
Reactant: Cc1cc(N)no1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cc(NCCCN2CCC(Cc3ccccc3)CC2)no1
Reaction time: 0.17 h
Yield: 36.7 %

Procedure:
To a solution of 4-benzylpiperidine (3.51 g, 20.0 mmol) and DBU (0.030 ml, 0.20 mmol) in THF (40 ml) was dropwise added a solution of acrolein (90%, 1.485 ml, 20.0 mmol) in THF (10 ml) at −20° C. with stirring over a period of 10 minutes. The mixture was stirred for 1 hour while the temperature of the mixture is elevated from −20° C. to −10° C. To the mixture were added 3-amino-5-methyl isoxazole (1.96 g, 20.0 mmol) and sodium triacetoxyborohydride (8.48 g, 40.0 mmol), successively, at −10° C. The mixture was stirred for 15 hours while the temperature of the mixture is elevated to −10° C. To the mixture was added aqueous solution of 1N-sodium hydroxide (120 ml) under ice cooling, and the mixture was stirred for 30 minutes and extracted with diethyl ether (60 ml×3). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The concentrate was subjected to column chromatography (silica gel 100 g, ethyl acetate/methanol=1/0 to 75/25), and the desired fraction was concentrated under reduced pressure to give the titled compound (2.30 g, 7.34 mmol) as white crystals. Yield 37%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[O:17][CH2:16][CH2:15][CH:14]2[C:19]([OH:21])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][N:23]([CH3:41])[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][NH:31][C:32]2[CH:37]=[CH:36][C:35]([CH:38]([CH3:40])[CH3:39])=[CH:34][CH:33]=2)=[CH:26][CH:25]=1>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[O:17][CH2:16][CH2:15][CH:14]2[C:19]([N:31]([CH2:30][C:27]1[CH:26]=[CH:25][C:24]([N:23]([CH3:41])[CH3:22])=[CH:29][CH:28]=1)[C:32]1[CH:33]=[CH:34][C:35]([CH:38]([CH3:40])[CH3:39])=[CH:36][CH:37]=1)=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1ccc(NCc2ccc(N(C)C)cc2)cc1
Reactant: O=C(O)C1CCOc2c(OCc3ccccc3)cccc21
Product: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCOc3c(OCc4ccccc4)cccc32)cc1
Yield: 98.5 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 8-benzyloxychroman-4-carboxylic acid (0.54 g) and [(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.51 g) as starting materials, 8-benzyloxy-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)chroman-4-carboxamide (1 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]2=[N:6][N:7]=C(C)C(=O)[N:4]2[N:3]=1.[CH2:14]([NH:16][CH2:17][CH:18]([OH:20])[CH3:19])[CH3:15]>C1(C)C=CC=CC=1>[ClH:1].[ClH:1].[CH2:14]([N:16]([CH2:17][CH:18]([OH:20])[CH3:19])[C:2]1[N:3]=[N:4][C:5]([NH:6][NH2:7])=[CH:12][CH:13]=1)[CH3:15]
Reactant: Cc1nnc2ccc(Cl)nn2c1=O
Reactant: CCNCC(C)O
Solvent: Cc1ccccc1
Product: CCN(CC(C)O)c1ccc(NN)nn1
Product: Cl
Temperature: 60 °C
Reaction time: 3 h
Yield: 288.2 %

Procedure:
A solution comprising 480 mg 7-chloro-3-methyl-4-oxo-4H-pyridazino[6,1-c][1,2,4]triazine and 510 mg ethyl-(2-hydroxypropyl)amine in 10 ml toluene is heated to reflux for two hours, toluene is removed by evaporation, the remaining part if taken up with acetone, filtered, and the filtrate concentrated to a small volume. After cooling, 400 mg 7-[ethyl-(2-hydroxypropyl)amino]-3-methyl-4-oxo-4H-pyridazino[6,1-c][1, 2,4]triazine are collected under a vacuum, which melts at 140°-145° C. 1.3 grams 7-[ethyl-(2-hydroxypropyl)amino]-3-methyl-4-oxo-4H-pyridazino[6,1-c][1,2,4]triazine and 1 gram 2,4-dinitrophenylhydrazine are heated, while stirring, to 60° C. for three hours in 60 ml of 15% hydrochloric acid. These are cooled to 0° C. overnight, collected under a vacuum and washed with cold water. The mother liquors, after filtering, are evaporated to a dry condition, the residue being taken up twice with n.butylic alcohol and each time re-evaporated. A solid product is obtained which is triturated with 10 ml n.butylic alcohol, cooled, and collected under vacuum to yield 1 g of 3-[ethyl-(2-hydroxypropyl)amino]-6-hydrazinopyridazine dihydrochloride melting (with decomposition) at 212° C.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].C([O-])([O-])=O.[K+].[K+].F[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24]>CN(C=O)C.CCOC(C)=O>[CH3:22][C:19]1[CH:20]=[CH:21][C:16]([O:2][C:1]2[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=2)=[C:17]([N+:23]([O-:25])=[O:24])[CH:18]=1
Reactant: Oc1ccc(O)cc1
Reactant: Cc1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(Oc2ccc(O)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of hydroquinone (3.2 g, 29.0 mmol) and K2CO3 (8.0 g, 54.0 mmol) in 40 mL of DMF was heated at 100° C. with 1-fluoro-4-methyl-2-nitrobenzene (3.0 g, 19.3 mmol) with stirring for 24 hours. Cooled to room temperature and diluted with EtOAc. Washed with water and dried the organic layer over MgSO4. Filtered and concentrated under vacuum giving the title compound, which was purified by silica gel column chromatography eluting with 5% EtOAc/hexane giving an orange oil (1.89 g, 40%).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:13]([O:15][CH3:16])=[O:14])[CH2:11][OH:12])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[ClH:27].[H][H]>[Pd]>[NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:13]([O:15][CH3:16])=[O:14])[CH2:11][OH:12])=[O:8])[CH2:3][CH:4]([CH3:5])[CH3:6].[ClH:27]
Reactant: COC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Product: COC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(C)C

Procedure:
4.20 Grams of Z-Leu-Ser-OCH3 was suspended in a mixture of 40 ml of methan-1 with 11.46 ml of 1N-hydrochloric acid, then a small amount of palladium black was added to the suspension, stirred for 18 hours under the condition of introducing hydrogen gas. After completion of the reaction the catalyst was removed by suction filtration, the filtrate was subjected to distillation under a reduced pressure, further to the residue obtained was added water and distillation under a reduced pressure were repeated 3 times. The residue thus obtained was dried under a reduced pressure in a desiccator containing phosphorus pentoxide as the desiccant to obtain the desired product.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7](Br)[C:8]#[CH:9].[NH2:11][C:12]1[C:17]2=[C:18]([C:22]([C:24]3[CH:25]=[C:26]([NH:30][C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:35]=4[Cl:41])=[O:32])[CH:27]=[CH:28][CH:29]=3)=[O:23])[CH:19]=[C:20](Br)[N:16]2[N:15]=[CH:14][N:13]=1>[Cu]I.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>[NH2:11][C:12]1[C:17]2=[C:18]([C:22]([C:24]3[CH:25]=[C:26]([NH:30][C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:35]=4[Cl:41])=[O:32])[CH:27]=[CH:28][CH:29]=3)=[O:23])[CH:19]=[C:20]([C:7]#[C:8][CH2:9][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[N:16]2[N:15]=[CH:14][N:13]=1
Reactant: C#CCBr
Reactant: Nc1ncnn2c(Br)cc(C(=O)c3cccc(NC(=O)Nc4ccc(Cl)cc4Cl)c3)c12
Reactant: C1CCNCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: Nc1ncnn2c(C#CCN3CCCCC3)cc(C(=O)c3cccc(NC(=O)Nc4ccc(Cl)cc4Cl)c3)c12
Temperature: 80 °C
Yield: 62 %

Procedure:
A solution of piperidine (2 mL) and propargyl bromide (80 wt % in toluene, 0.02 mL, 0.19 mmol) was purged with argon for 10 minutes. The solution was treated with 95G (20 mg, 0.04 mmol), CuI (1 mg, 0.008 mmol) and PdCl2(PPh3)2 (3 mg, 0.004 mmol). The reaction mixture was heated to 80° C. for one hour and then concentrated. The residue was purified by flash chromatography (SiO2, 0% to 10% MeOH/CH2Cl2) to afford the desired compound (13 mg, 62%). HPLC tR=3.17 min (Chromolith SpeedROD 4.6×50 mm, 10-90% aqueous methanol containing 0.1% TFA, 4 min gradient, monitored at 254 nm). [M+H+]=562.27.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]1[CH:18]=[C:17]2[C:13]([CH2:14][O:15][C:16]2=[O:19])=[C:12](/[N:20]=[CH:21]/[C:22]2[N:23]([CH3:27])[CH:24]=[CH:25][N:26]=2)[CH:11]=1.[O-:28][CH2:29][CH3:30].[Na+].C(O)C>C(OCC)(=O)CC>[F:9][C:10]1[CH:18]=[C:17]([C:16]([O:15][CH2:14][CH3:13])=[O:19])[C:30]2[C:29](=[O:28])[CH:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:21]([C:22]3[N:23]([CH3:27])[CH:24]=[CH:25][N:26]=3)[NH:20][C:12]=2[CH:11]=1
Reactant: O=Cc1ccccc1
Reactant: Cn1ccnc1/C=N/c1cc(F)cc2c1COC2=O
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(=O)CC
Product: CCOC(=O)c1cc(F)cc2c1C(=O)C(c1ccccc1)C(c1nccn1C)N2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
A mixture of benzaldehyde (212 mg, 2 mmol) and (E)-6-fluoro-4-((1-methyl-1H-imidazol-2-yl)methyleneamino)isobenzofuran-1(3H)-one (518 mg, 2 mmol) in ethyl propionate (10 mL) was cooled to 0° C. Then a solution of sodium ethoxide in ethanol (sodium (184 mg, 8 mmol) in ethanol (5 mL)) was added dropwise. After the addition, the mixture was stirred at room temperature for 0.5 hr. The mixture was quenched with water (20 mL) and solvent was removed in vacuum. The residue was dissolved in water and extracted with ethyl acetate three times. The combined organic layers were washed by water and brine, and then evaporated to dryness, the crude product was purified by chromatography to obtain a yellow solid. The solid was dried in vacuum at 50° C. to give the title compound (250 mg, yield 32%). LC-MS (ESI) m/z: 394 (M+W.