Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.C(=O)([O-])[O-].[Na+].[Na+].[C:21]1([CH3:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>O1CCOCC1.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>[C:12]1([N:6]2[C:5]3[CH:4]=[CH:3][C:2]([C:2]4[CH:3]=[CH:4][C:5]5[NH:6][C:26]6[C:21]([C:27]=5[CH:14]=4)=[CH:22][CH:23]=[CH:24][CH:25]=6)=[CH:14][C:13]=3[C:12]3[C:7]2=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Cc1ccccc1
Reactant: Brc1ccc2[nH]c3ccccc3c2c1
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: C1COCCO1
Solvent: O
Product: c1ccc(-n2c3ccccc3c3cc(-c4ccc5[nH]c6ccccc6c5c4)ccc32)cc1

Procedure:
24.10 g (97.92 mmol) of 3-bromo-9H-carbazole 22, 30.93 g (107.71 mmol) of compound 25 and 11.56 g of sodium carbonate are suspended in 2500 ml of dioxane, 2500 ml of toluene and 1000 ml of water. 5.79 g (5.01 mmol) of Pd(PPh3)4 are added to this suspension. The reaction mixture is heated under reflux for 5 h. After cooling, the precipitated solid is filtered off with suction, washed with water and ethanol and dried. The residue is extracted with hot toluene and recrystallised from toluene. The yield is 22.0 g (55%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH2:20])[N:13]=2)=[CH:5][CH:4]=1.[CH2:21]=O>C(O)(=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:13]3[CH2:21][NH:20][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[C:12]3=[CH:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: C=O
Reactant: COc1ccc(-c2nc(-c3ccccc3N)c[nH]2)cc1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ncc3n2CNc2ccccc2-3)cc1
Reaction time: 0.03 h

Procedure:
2-(4-Methoxyphenyl)-4-(2-aminophenyl)imidazole (5 g) is dissolved in acetic acid (20 ml) and formaldehyde (37% in water, 1.53 ml) is added. The reaction is stirred for 2 min., diluted with ethyl acetate (100 ml), and extracted with 5%HCl (250 mnl). The aqueous layer is basified with K2CO3, then extracted with ethyl acetate. The organic layer is evaporated under reduced pressure and the residue is recrystallized from dichloromethane to afford 3-(4-methoxyphenyl)-5,6-dihydroimidazo[1,5-c]quinazoline (3 g) as a light brown solid. m.p. 190-191° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][NH:18][CH2:19][C:20]3[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH:34]([S:42](Cl)(=[O:44])=[O:43])=[CH:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.N1CCOCC1.C(O)C(N)(CO)CO>C(Cl)Cl>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][N:18]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=3)[S:42](/[CH:34]=[CH:35]/[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)(=[O:44])=[O:43])=[CH:32][CH:33]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=S(=O)(Cl)C=Cc1ccccc1
Reactant: CCCCc1ccc(C#Cc2ccc(CNCc3ccc(OCC(=O)OC)cc3)cc2)cc1
Agent: NC(CO)(CO)CO
Solvent: C1COCCN1
Solvent: ClCCl
Product: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(OCC(=O)OC)cc3)S(=O)(=O)/C=C/c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.5 %

Procedure:
A solution of methyl {4-[({4-[(4-butylphenyl)ethynyl]benzyl}amino)methyl]phenoxy}-acetate (42 mg, 0.10 mmol) and β-styrene sulfonyl chloride (Aldrich, 23 mg, 0.11 mmol) in DCM (2 mL) was stirred at rt overnight in presence of a morpholine resin (1.5 eq., Novabiochem HL, 3.8 mmol/g) (1.5 eq). Trisamine resin (1 eq, Novabiochem, 3.5 mmol/g) was then added and the mixture stirred at rt for an additional 2 hrs. The reaction mixture was then filtrated and the solvent was removed under reduced pressure to give 55 mg (95%) of the title compound. HPLC, Rt: 5.8 min (purity: 83%). M+(ESI): 608.2.
Reaction SMILES: [CH2:1]([O:17][CH2:18][C@@H:19]1[CH2:23][O:22][C@@H:21]([CH2:24][O:25][C:26]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[O:27])[CH2:20]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(Cl)(=O)C.[Br:40][CH2:41][C:42](Cl)=[O:43]>>[Br:40][CH2:41][C:42]([N:28]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)[C:26]([O:25][CH2:24][C@H:21]1[CH2:20][C@H:19]([CH2:18][O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:23][O:22]1)=[O:27])=[O:43]
Reactant: CCCCCCCCCCCCCCCCOC[C@@H]1CO[C@@H](COC(=O)NCc2ccccn2)C1
Reactant: O=C(Cl)CBr
Solvent: CC(=O)Cl
Product: CCCCCCCCCCCCCCCCOC[C@@H]1CO[C@@H](COC(=O)N(Cc2ccccn2)C(=O)CBr)C1

Procedure:
Following the procedure described in example 24, and using instead of the compound prepared in example 23, the compound prepared in example 9, and instead of acetyl chloride, bromoacetyl chloride, the title compound of this example was obtained as a white solid (57% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[CH:6]2.[OH-].[K+].Cl.Cl[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1>C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[C:6]2[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: COc1cc2cc(O)nc(C)c2cc1OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc2c(C)nc(O)c(Cc3ccc4ccccc4n3)c2cc1OC
Temperature: 115 °C
Reaction time: 0.42 h

Procedure:
To a solution of 6,7-dimethoxy-1-methylisoquinolin-3-ol CCH 18060 (147 mg, 0.67 mmol) in toluene (3 mL) in a 10 mL microwave vial equipped with a magnetic stirrer was added a 2 N aq. KOH solution (0.70 mL, 1.40 mmol) at RT followed by 2-(chloromethyl)quinoline hydrochloride (158 mg, 0.74 mmol) and the mixture was stirred at 115° C. for 25 min under microwave irradiation. Another portion of a 2 N aq. KOH solution (0.30 mL, 0.60 mmol) was then added at RT followed by 2-(chloromethyl)quinoline hydrochloride (70 mg, 0.33 mmol) and the mixture was stirred at 115° C. for 10 min under microwave irradiation. After cooling to RT, the mixture was diluted with H2O (5 mL) and neutralised with a 10% aqueous citric acid solution before extraction with CH2Cl2 (50 mL). The organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 100:7) gave 49 mg of 6,7-dimethoxy-1-methyl-4-(quinolin-2-ylmethyl)isoquinolin-3-ol as a yellow solid. The free base (45 mg) was dissolved in MeOH (10 mL) in a 25 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.09 M HCl solution in MeOH (5.5 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 6,7-dimethoxy-1-methyl-4-(quinolin-2-ylmethyl)isoquinolin-3-ol hydrochloride 23 as a yellow solid (54 mg, 19% yield).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([O:36][CH3:37])=[C:18]([S:20]([O:23][C:24]2[CH:25]=[C:26]([CH:32]=[C:33]([CH3:35])[CH:34]=2)[O:27][CH2:28][CH2:29][CH2:30][OH:31])(=[O:22])=[O:21])[CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:58]1[C:62](=[O:63])[C:61]2=[CH:64][CH:65]=[CH:66][CH:67]=[C:60]2[C:59]1=[O:68]>O1CCCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([O:36][CH3:37])=[C:18]([S:20]([O:23][C:24]2[CH:25]=[C:26]([CH:32]=[C:33]([CH3:35])[CH:34]=2)[O:27][CH2:28][CH2:29][CH2:30][O:31][N:58]2[C:59](=[O:68])[C:60]3=[CH:67][CH:66]=[CH:65][CH:64]=[C:61]3[C:62]2=[O:63])(=[O:21])=[O:22])[CH:19]=1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Oc1cc(C)cc(OCCCO)c1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1S(=O)(=O)Oc1cc(C)cc(OCCCON2C(=O)c3ccccc3C2=O)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99 %

Procedure:
Diethyl azodicarboxylate (0.16 mL, 0.95 mmol) was added dropwise over 6 min to 3-[3-(5-chloro-2-methoxyphenylsulfonyloxy)-5-methylphenoxy]propanol (0.31 g, 0.79 mmol, prepared in the preceding step), triphenylphosphine (0.25 g, 0.93 mmol) and N-hydroxyphthalimide (0.13 g, 0.80 mmol) in anhydrous tetrahydrofuran (7.9 mL) at 0° C. under a nitrogen atmosphere. The solution was stirred 0° C. for an adddional 15 min then at ambient temperature overnight. The reaction mixture was concentrated, and the crude product was purified by flash column chromatography (1% acetone in dichloromethane) to give the title compound (0.417 g, 99%) as a colorless foam. 1H-NMR (300 MHz, CDCl3) δ7.88-7.75 (m, 5H), 7.56 (dd, 1H, J=8.9, 2.7 Hz), 7.05 (d, 1H, J=8.9 Hz), 6.64 (br s, 1H), 6.57 (br s, 1H), 6.43 (t, 1H, J=2 Hz), 4.37 (t, 2H, J=6.1 Hz), 4.12 (t, 2H, J=6.2 Hz), 4.03 (s, 3H), 2.28 (s, 3H), 2.19 (pentet, 2H, J=6.1 Hz). Mass spectrum (MALDI-TOF, gentisic acid matrix) calcd. for C25H22ClNO8S: 554.1 (M+Na). Found: 553.7.
Reaction SMILES: C([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]1[C:23]2[C:22](Cl)=[N:21][CH:20]=[N:19][C:18]=2[CH:17]=[CH:16]1)(=O)C1C=CC=CC=1.[Cl:25][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][C:32]=1[O:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=1)[NH2:29].CN1CCCC1=O.C(=O)([O-])O.[Na+]>O>[Cl:25][C:26]1[CH:27]=[C:28]([NH:29][C:22]2[C:23]3[N:15]([CH2:14][CH2:13][O:12][CH2:11][CH2:10][OH:9])[CH:16]=[CH:17][C:18]=3[N:19]=[CH:20][N:21]=2)[CH:30]=[CH:31][C:32]=1[O:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=1
Reactant: Nc1ccc(Oc2cccc(Cl)c2)c(Cl)c1
Reactant: O=C(OCCOCCn1ccc2ncnc(Cl)c21)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: OCCOCCn1ccc2ncnc(Nc3ccc(Oc4cccc(Cl)c4)c(Cl)c3)c21
Temperature: 120 °C
Reaction time: 2 h
Yield: 67.9 %

Procedure:
A mixture of 2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl benzoate (346 mg), 3-chloro-4-(3-chlorophenoxy)aniline (280 mg) and 1-methyl-2-pyrrolidone (3 mL) was stirred at 120° C. for 2 hrs. Water and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent, ethyl acetate:hexane=30:70→100:0). The object fraction was concentrated under reduced pressure. To a solution of the residue (431 mg) in methanol (10 mL) was added 1N aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at room temperature for 4 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was crystallized from ethyl acetate-diethyl ether to give the title compound (312 mg) as a white powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=O)[CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[CH2:23][C:24]([O:26]CC)=O)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:37][NH2:38]>CCO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[CH2:23][C:24](=[O:26])[NH:38][N:37]=3)=[CH:17][CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(=O)CC(C(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1)c1ccccn1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C3=NNC(=O)CC3c3ccccn3)cc2)CC1
Yield: 54.8 %

Procedure:
A solution of the product from step 3 (4.0 g, 8.3 mmol) and hydrazine hydrate (0.83 g, 16 mmol) in 30 mL of EtOH was stirred at 90° C. overnight. The yellow suspension was reduced to ˜15 mL of EtOH. The solid was collected and washed with cold EtOH to give the product (2.05 g, 55%): Mp 213-214° C.; MS m/z 395 (M-tBu+H).
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:13][C:12]([CH3:15])([OH:14])[C:11]([CH2:16][CH:17]=[CH2:18])=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[CH3:28][O:29][CH2:30]Cl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)(Cl)Cl>[Si:1]([O:8][CH:9]1[CH2:13][C:12]([CH3:15])([O:14][CH2:28][O:29][CH3:30])[C:11]([CH2:16][CH:17]=[CH2:18])=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: COCCl
Reactant: C=CCC1=CC(O[Si](C)(C)C(C)(C)C)CC1(C)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCC1=CC(O[Si](C)(C)C(C)(C)C)CC1(C)OCOC
Yield: 82 %

Procedure:
To a solution mixture of 4.7 g of (1RS,4RS)-3-allyl-4-methyl-4-hydroxy-2-cyclopenten-1-yl (t-butyldimethylsilyl) ether, 6.8 g of N,N-diisopropylethylamine and 50 ml of chloroform was added 2.66 ml of chloromethyl methyl ether under ice-cooling and the resulting mixture was allowed to react at room temperature for 8 hours. Then the reaction liquid was poured into ice-cooled 5% aqueous solution of citric acid and extracted two times with diethyl ether. The combined ether layer was washed successively with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography to obtain 4.5 g of (1RS,4RS)-3-allyl-4-methyl-4-methoxymethoxy-2-cyclopenten-1-yl (t-butyldimethylsilyl) ether. Yield 82%
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][NH:3][C:2]1=[O:7].[H-].[Na+].Br[CH2:11][C:12]([O:14][CH3:15])=[O:13]>CN(C=O)C>[CH3:15][O:14][C:12](=[O:13])[CH2:11][N:3]1[CH2:4][CH2:5][CH2:6][O:1][C:2]1=[O:7]
Reactant: COC(=O)CBr
Reactant: O=C1NCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CN1CCCOC1=O
Reaction time: 8 h
Yield: 19.6 %

Procedure:
A solution of 0.20 g (2.0 mmol) of 1,3-oxazinan-2-one from step A in 2 mL of anhydrous DMF was added to a 10 mL round bottom flask containing 0.13 g (3.2 mmol) of a 60% sodium hydride suspension in mineral oil under an atmosphere of nitrogen. After stirring for 10 min 0.37 g (2.4 mmol) of methyl brornoacetate was added in one portion and the reaction mixture was allowed to stir overnight. The reaction mixture was then quenched with 5 mL of a saturated aqueous ammonium chloride solution and then diluted with 20 mL of water. The resulting suspension was extracted with ethyl acetate (3×10 mL) and the combined organics were washed with water (2×3 mL), brine (1×3 mL) and dried over magnesium sulfate. The mixture was filtered, evaporated and purified by silica gel chromatography eluting with a 5% methanol in ethyl acetate mixture to afford the title compound as a clear oil (0.068 g, 20%). 1HNMR (500 MHz, CDCl3) δ: 4.28 (t, J=5.4 Hz, 2H), 4.03 (s, 2H), 3.70 (s, 3H), 3.36 (t, J=6.2 Hz, 2H), 2.08-2.04 (m, 2H). LC-MS: m/z (ES) 174 (MH)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:6](=[O:12])[CH:7]=[C:8]([CH3:11])[NH:9][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][OH:22]>CN(C=O)C>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([O:12][CH2:20][CH2:21][OH:22])=[CH:7][C:8]([CH3:11])=[N:9][CH:10]=1
Reactant: COCOc1c[nH]c(C)cc1=O
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCOc1cnc(C)cc1OCCO
Temperature: 90 °C
Reaction time: 8 h
Yield: 55.8 %

Procedure:
To a solution of 5-(methoxymethoxy)-2-methylpyridin-4(1H)-on (1.28 g, 7.56 mmol) in N,N′-dimethylformamide (19 mL), potassium carbonate (2.10 g, 15.1 mmol) and 2-bromoethanol (804 μL, 11.3 mmol) were added sequentially, and the mixture was stirred at 90° C. overnight. After the reaction has terminated, the reaction solution was concentrated in vacuo. The obtained residue was dissolved in chloroform/methanol, the solids were filtered, and the filtrate was concentrated in vacuo. The obtained residue was purified by column chromatography (hexane/acetone) and 2-(5-(methoxymethoxy)-2-methylpyridin-4-yloxy)ethanol (900 mg, yield 56%) was obtained as an orange oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10](=[O:20])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19].[CH3:21][NH2:22].O>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:9][C:10](=[O:20])[CH2:11][CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[N:22]1[CH3:21]
Reactant: CN
Reactant: Cc1ccccc1C=CC(=O)C=Cc1ccccc1C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1C1CC(=O)CC(c2ccccc2C)N1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 52 %

Procedure:
1,5-Bis(2-methylphenyl)-1, 4-pentadien-3-one (20ac, 0.50 g, 1.9 mmol) was dissolved in dimethyl formamide (10 ml). Methylamine (51, 1.0 ml, 11.6 mmol, 40% in water) was added and the mixture stirred for 24 hr at room temperature. The mixture was poured into water (50 ml) and stirred for 2 hr at room temperature. The resulting mixture was extracted into ethyl acetate, washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to afford a solid. The crude solid was chromatographed on silica gel with ethyl acetate/hexane to afford a solid that was recrystallized from ethanol to give 0.29 g (52%) of a white solid: mp 155-157° C.; 1H NMR δ 1.82, (s, 3H), 2.40, (s, 6H), 2.44 (d, 2H, J=11.9 Hz), 2.77 (t, 2H, J=13.3 Hz), 3.74 (d, 2H, J=11.9 Hz), 7.16 (m, 6H), 7.67, (d, 2H, J=7.0 Hz); 13C NMR: δ 19.5, 39.9, 49.3, 65.8, 126.7, 126.9, 130.6, 134.8, 140.9, 207.2; Exact mass calcd for C20H23NO: 293.1779, observed (M+H) 294.1856.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1O[C:9]1([C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)[C:10](=O)[CH3:11].O.[NH2:21][NH2:22]>C(O)C>[CH3:11][C:10]1[NH:22][N:21]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[C:9]=1[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1
Reactant: NN
Reactant: CC(=O)C1(c2ccncc2)OC1c1ccccc1C
Solvent: O
Solvent: CCO
Product: Cc1ccccc1-c1n[nH]c(C)c1-c1ccncc1

Procedure:
A solution of 4-(2-methylphenyl)-3-(4-pyridyl)-3,4-epoxy-2-butanone (step 2) (0.11 g, 0.434 mmol) and hydrazine hydrate (0.043 g, 0.868 mmol) in ethyl alcohol (50 ml) was heated at reflux for 20 hours. The solvent was removed and the resulting residue was purified by chromatography to give 4-[5-methyl-3-(2-methylphenyl)-1H-pyrazol-4-yl]pyridine: Anal. Calc'd for C16H15N3 (249.32): C, 77.08; H, 6.06; N, 16.85. Found: C, 76.66; H, 5.91; N, 16.84.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.O=C1CC(=O)N(C2C=CC(C(OCC)=O)=CC=2)C2C=CC3C(C=2N1)=CC=CC=3.[Cl:53][C:54]1[CH:64]=[CH:63][CH:62]=[CH:61][C:55]=1[CH:56]=[CH:57][C:58](Cl)=[O:59].O=C1CC(=O)N(C2C=CC(C(O)=O)=CC=2)C2C=CC3C(C=2N1)=CC=CC=3>>[Cl:53][C:54]1[CH:64]=[CH:63][CH:62]=[CH:61][C:55]=1[CH:56]=[CH:57][C:58]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1)=[O:59]
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: O=C(Cl)C=Cc1ccccc1Cl
Agent: CCOC(=O)c1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: O=C1CC(=O)N(c2ccc(C(=O)O)cc2)c2ccc3ccccc3c2N1
Product: O=C(C=Cc1ccccc1Cl)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 50 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione obtained in Example 1, (3) (40 mg, 0.126 mmol), and 2-chlorocinnamic acid chloride (0.151 mmol), the title compound (30 mg, yield 50%) was obtained as white crystals in the same manner as that of Example 1, (4).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH2:12](Br)/[CH:13]=[C:14](/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])\[CH3:15].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH2:12]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)/[CH:13]=[C:14](/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])\[CH3:15]
Reactant: CC(C)=CCC/C(C)=C/CBr
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OC/C=C(\C)CCC=C(C)C)cc1
Yield: 90.1 %

Procedure:
To a solution of methyl 4-hydroxybenzoate (7.61 g) in acetone (80 ml) were added geranyl bromide (10.9 g) and potassium carbonate (13.8 g). The mixture was refluxed with heating for 6 hours. The reaction solution, after water (150 ml) were added thereto, was extracted with chloroform. The extract was dried over sodium sulfite anhydride and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=9:1), thereby yielding 13.00 g (90%) of methyl 4-geranyloxybenzoate.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]2[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([CH3:19])[N:11]=[C:10](S(C)(=O)=O)[N:9]=2)[CH:4]=[N:3]1.[NH2:24][C@@H:25]1[CH2:30][CH2:29][CH2:28][CH2:27][C@@H:26]1[NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35].CCN(CC)CC>CC(N(C)C)=O>[C:34]([O:33][C:32]([NH:31][C@H:26]1[CH2:27][CH2:28][CH2:29][CH2:30][C@H:25]1[NH:24][C:10]1[N:9]=[C:8]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[C:6]=2[CH3:7])[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([CH3:19])[N:11]=1)=[O:38])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: CCOC(=O)c1c(C)nc(S(C)(=O)=O)nc1-c1cnn(C)c1C
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(C)nc(N[C@@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)nc1-c1cnn(C)c1C

Procedure:
A solution of ethyl 4-(1,5-dimethyl-1H-pyrazol-4-yl)-6-methyl-2-(methylsulfonyl)pyrimidine-5-carboxylate (0.07 g, 0.207 mmol), tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (0.089 g, 0.414 mmol) and Et3N (0.115 mL, 0.827 mmol) in DMA (3 mL) was heated in a sealed tube at 90° C. for 8 h. The reaction mixture was poured slowly onto ice to yield a pale yellow precipitate, which was isolated by vacuum filtration, washed with water, and dried under vacuum to give the title compound. [M+H] calc'd for C24H36N6O4, 473. found, 473.
Reaction SMILES: [N:1]1([C:7]2[N:11]3[CH:12]=[C:13]([O:16][C@@H:17]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[C@@H:20]([NH2:27])[CH2:19][CH2:18]4)[CH:14]=[CH:15][C:10]3=[N:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClC(Cl)(Cl)C[O:31][C:32](=O)[NH:33][C:34]1[N:35]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)[N:36]=[C:37]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:38]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:39]([C:37]1[CH:38]=[C:34]([NH:33][C:32]([NH:27][C@@H:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@@H:17]([O:16][C:13]3[CH:14]=[CH:15][C:10]4[N:11]([C:7]([N:1]5[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]5)=[N:8][N:9]=4)[CH:12]=3)[CH2:18][CH2:19]2)=[O:31])[N:35]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)[N:36]=1)([CH3:42])([CH3:40])[CH3:41]
Reactant: N[C@H]1CC[C@H](Oc2ccc3nnc(N4CCCCC4)n3c2)c2ccccc21
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)cc1
Yield: 20 %

Procedure:
A mixture of Intermediate 55a (120 mg, 0.33 mmol), (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 147 mg, 0.36 mmol), DIPEA (86.0 μL, 110.50 mmol) and 1,4-dioxane (2.5 mL) were heated to 60° C. for 18 h. After cooling the solvent was evaporated in vacuo. The residue was purified by FCC, using 0-10% MeOH in DCM, to give a pale yellow foam. This was lyophilised to provide the title compound as an off-white solid (28 mg, 20%). LCMS (Method 5) Rt 4.76 min, m/z 619 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.26 (9H, s), 1.61 (2H, m), 1.72 (5H, m), 2.02-2.17 (3H, m), 2.35 (3H, s), 3.13 (4H, m), 4.90 (1H, m), 5.58 (1H, m), 6.31 (1H, s), 6.99 (1H, d, J 7.8), 7.19 (1H, dd, J 9.7, 2.2), 7.26-7.43 (8H, m), 7.58-7.64 (2H, m), 7.98 (1H, s).