Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[Br:14][C:15]1[C:16](CC)=[CH:17][CH:18]=[C:19]([CH:21]2[C:25](=[O:26])[CH:24]=[CH:23][CH:22]2[OH:27])[CH:20]=1>CC(C)=O>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:1][CH3:2])=[C:19]([CH:21]2[C:22](=[O:27])[CH:23]=[CH:24][C:25]2=[O:26])[CH:20]=1
Reactant: CCc1ccc(C2C(=O)C=CC2O)cc1Br
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: CCc1ccc(Br)cc1C1C(=O)C=CC1=O
Reaction time: 0.33 h
Yield: 98.5 %

Procedure:
Jones' reagent (75 ml of 1.67 M solution, 125 mmol) is added dropwise over 30 minutes to a cooled (ice-bath) solution of 5-(5-bromo-4-ethylphenyl)-4-hydroxycyclopent-2-enone (33 g, 117 mmol) in acetone (400 ml). The mixture is stirred for 20 minutes, then the cooling bath is removed and the mixture is stirred for 1 hour at room temperature. Isopropanol (150 ml) is added to the yellow slurry and the mixture is stirred at room temperature for 2 hours. The mixture is diluted with ethyl acetate and washed with brine, dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated under reduced pressure to give 2-(5-bromo-2-ethylphenyl)cyclopent-4-ene-1,3-dione (32.17 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:23](OCC)(=[O:30])[CH2:24][C:25](OCC)=[O:26].[OH-].[Na+]>C(O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:25](=[O:26])[CH2:24][C:23](=[O:30])[N:13]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)[C:11]2=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Nc1ccc([N+](=O)[O-])cc1)Nc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C1CC(=O)N(c2ccc([N+](=O)[O-])cc2)C(=O)N1c1ccc([N+](=O)[O-])cc1

Procedure:
1,3-Di-(4-nitrophenyl)urea (1.8 g, 0.006 mole), diethyl malonate (1 ml, 0.006 mole), and sodium hydroxide (0.24 g, 0.006 mole) were refluxed in ethanol (100 ml) for three hours. 1,3-Di-(4-nitrophenyl)-2,4,6-(1H,3H,5H)-pyrimidinetrione precipitated as a yellow powder, m.p. greater than 250° C.
Reaction SMILES: [CH2:1]([C:3]1[S:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21]COC)=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[N:7]=1)[CH3:2].Cl>CO>[CH2:1]([C:3]1[S:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([OH:21])=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[N:7]=1)[CH3:2]
Reactant: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2OCOC)cs1
Agent: Cl
Solvent: CO
Product: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2O)cs1
Temperature: 50 °C
Reaction time: 1 h
Yield: 106.9 %

Procedure:
To a solution of 2-ethyl-4-{(E)-2-[3-(methoxymethoxy)-1-phenyl-1H-pyrazol-4-yl]ethenyl}-1,3-thiazole (4.49 g) in methanol (50 mL) was added concentrated hydrochloric acid (2.17 mL) at room temperature, and the mixture was stirred at 50° C. for 1 hr. The reaction mixture was evaporated under reduced pressure and the residue was washed with ethyl acetate-diethyl ether to give 4-[(E)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-ol (4.18 g, yield 95%) as orange crystals. hydrochloride. melting point: 222-224° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH3:18])[N:10]=[CH:11][C:12]=2[C:13]([O:15]CC)=[O:14])=[C:4]([CH:19]([O:27][CH3:28])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[CH:3]=1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH3:18])[N:10]=[CH:11][C:12]=2[C:13]([OH:15])=[O:14])=[C:4]([CH:19]([O:27][CH3:28])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[CH:3]=1
Reactant: CCOC(=O)c1cnn(C)c1-c1ccc(Cl)cc1C(OC)c1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COC(c1ccccc1Cl)c1cc(Cl)ccc1-c1c(C(=O)O)cnn1C

Procedure:
The starting material is prepared analogously as the 2-fluoro analog of Example 6.77 g of 3-[4-chloro-2-(2-chloro-α-methoxy-benzyl)-phenyl]-ethoxycarbonyl-2-methyl-pyrazole are dissolved in 900 ml of ethanol and 240 ml of N aqueous sodium hydroxide and the solution is refluxed for 2 hours. After cooling the aqueous phase is separated, washed with diethyl ether and acidified with hydrochloric acid. It is extracted with methylene chloride, the extract dried and evaporated. The residue is recrystallized from 200 ml of diethyl ether to yield the 3-[4-chloro-2-(2-chloro-α-methoxy-benzyl)-phenyl]-2-methylpyrazole-4-carboxylic acid melting at 210°-213°.
Reaction SMILES: [Cl-].[CH2:2]([P+](CCCC)(CCCC)CCCC)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(Cl)C1C=CC=CC=1.[CH3:30][SiH:31]([Cl:33])[Cl:32]>>[CH2:2]([CH2:30][SiH:31]([Cl:33])[Cl:32])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C[SiH](Cl)Cl
Reactant: CCCC[P+](CCCC)(CCCC)Cc1ccccc1
Agent: [Cl-]
Solvent: ClCc1ccccc1
Product: Cl[SiH](Cl)CCc1ccccc1
Yield: 240.6 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.26 g (0.79 mmol) of benyltributylphosphonium chloride, 1.00 g (7.90 mmol) of benzyl chloride, and 2.73 g (23.7 mmol) of methyldichlorosilane were reacted at 200° C. for 2 hrs. The resulting mixture was distilled to give 0.39 g of benzylmethyldichlorosilane (yield; 24%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]([CH3:28])[C:18]3[NH:23][C:22](=[O:24])[O:21][C:20]([CH3:26])([CH3:25])[C:19]=3[CH:27]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:29]O>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]([CH3:28])[C:18]3[NH:23][C:22](=[O:24])[O:21][C:20]([CH3:25])([CH3:26])[C:19]=3[CH:27]=2)=[O:29])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OO
Reactant: Cc1cc(OCCCCSc2ccc(Cl)c(Cl)c2)cc2c1NC(=O)OC2(C)C
Product: Cc1cc(OCCCCS(=O)c2ccc(Cl)c(Cl)c2)cc2c1NC(=O)OC2(C)C

Procedure:
Prepared analogously to Example 2 from 6-[4-(3,4-dichloro-phenylmercapto)-butoxy]-4,4,8-trimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][NH:21][O:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[N:8]=[CH:7][C:6](Br)=[CH:5][C:4]=2[N:3]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27](B(O)O)[CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][NH:21][O:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[N:8]=[CH:7][C:6]([C:27]3[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=3)=[CH:5][C:4]=2[N:3]=1
Reactant: OB(O)c1cccnc1
Reactant: CONCc1nc2c(N)nc3cc(Br)cnc3c2n1CC(C)(C)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CONCc1nc2c(N)nc3cc(-c4cccnc4)cnc3c2n1CC(C)(C)O
Temperature: 25 °C
Yield: 28.5 %

Procedure:
A stream of nitrogen was bubbled through a stirring suspension of 1-{4-amino-7-bromo-2-[(methoxyamino)methyl]-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl}-2-methylpropan-2-ol (0.590 g, 1.49 mmol),3-pyridineboronic acid (0.220 g, 1.79 mmol), and potassium carbonate (0.681 g, 4.93 mmol) in ethylene glycol dimethyl ether (10 mL) and water (5 mL) in a pressure vessel for 5 minutes. Dichlorobis(triphenylphosphine)palladium(III) (0.031 g, 0.045 mmol) was added and nitrogen was bubbled through for an additional 5 minutes. The pressure vessel was capped and placed in a 110° C. oil bath for 10 minutes. The resulting solution was cooled to ambient temperature and concentrated. The residue was purified by column chromatography using a HORIZON HPFC system (silica cartridge, eluting with 5-25% 1M ammonia/methanol in dichloromethane). The resulting yellow solid was crystallized from acetonitrile and isolated by filtration to yield 167 mg of 1-{4-amino-2-[(methoxyamino)methyl]-7-(pyridin-3-yl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl}-2-methylpropan-2-ol as a light yellow solid, mp 195-197° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[C:10]([N:17]3[CH:21]=[CH:20][CH:19]=[N:18]3)[CH:9]=2)[CH2:4][CH2:3]1>[Pd].CCO>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([N:17]3[CH:21]=[CH:20][CH:19]=[N:18]3)[CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(-n3cccn3)c2)CC1
Agent: [Pd]
Solvent: CCO
Product: CN1CCN(c2ccc(N)c(-n3cccn3)c2)CC1

Procedure:
1-Methyl-4-(4-nitro-3-pyrazol-1-yl-phenyl)-piperazine was treated under standard hydrogenation conditions (H2, EtOH, 10% Pd/C) to yield desired 4-(4-Methyl-piperazin-1-yl)-2-pyrazol-1-yl-phenylamine as a crude oil, which was used for the subsequent reaction without further purification; LC/MS (m/e) 258.24 (M+H).
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[CH:9]=[C:8]2[C:3]=1[NH:4][C:5](=[O:15])[C:6](=[O:14])[NH:7]2.S(=O)(=O)(O)O.[N+:21]([O-])([O-:23])=[O:22].[K+]>>[N+:21]([C:9]1[C:10]([F:13])=[C:11]([F:12])[C:2]([F:1])=[C:3]2[C:8]=1[NH:7][C:6](=[O:14])[C:5](=[O:15])[NH:4]2)([O-:23])=[O:22]
Reactant: O=c1[nH]c2cc(F)c(F)c(F)c2[nH]c1=O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c2c(F)c(F)c(F)c([N+](=O)[O-])c2[nH]c1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To 5,6,7-trifluoro-1,4-dihydro-2,3-quinoxalinedione (93 mg, 0.43 mmol) is added concentrated sulfuric acid (0.5 mL). While the flask is in an ice bath, KNO3 is slowly added, giving a brown mixture, which is stirred overnight. The reaction mixture, now dark red, is then added to ice water (5 mL), instantly giving an orange precipitate, which is collected by centrifugation. The powder is crystallized from EtOH (5 mL) and dried in vacuo to yield 24 mg (20%) of pale orange microcrystals. 1H NMR (DMSO-d6), 11.9 (br s, 1H), 12.6 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O.C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:52]1[C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[CH2:55][CH2:54][CH2:53]1>CN(C=O)C>[Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([N:52]1[C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[CH2:55][CH2:54][CH2:53]1)=[O:9]
Reactant: c1ccc2c(c1)CCCN2
Reactant: O=C(O)c1ccccc1Oc1cc(Cl)ccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccccc1Oc1cc(Cl)ccc1Cl)N1CCCc2ccccc21
Temperature: 50 °C
Reaction time: 1 h
Yield: 18.3 %

Procedure:
To a solution of 2-(2,5-dichloro-phenoxy)-benzoic acid (50.0 mg, 0.177 mmol, 1.0 equiv) in anhydrous DMF (1 mL) was added N-ethyldiisopropylamine (114.4 mg, 151 μL, 0.89 mmol, 5.0 equiv; [CAS RN 7087-68-5]) and HATU (80.8 mg, 0.21 mmol, 1.2 equiv; [CAS RN 148893-10-1]). After stirring of the reaction mixture at 50° C. for 1 h, 1,2,3,4-tetrahydro-quinoline (28.3 mg, 27 μL, 0.21 mmol, 1.2 equiv; [CAS RN 635-46-1]) was added and stirring at 50° C. continued over night. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 12.9 mg (18%) of the title compound. MS (ISP): 398.2 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[CH3:20][C@H:21]1[CH2:26][CH2:25][CH2:24][C@@H:23]([CH3:27])[NH:22]1.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([N:8]2[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:22]3[C@H:23]([CH3:27])[CH2:24][CH2:25][CH2:26][C@@H:21]3[CH3:20])[CH2:6][CH2:7]2)=[CH:12][C:13]=1[O:18][CH3:19]
Reactant: C[C@@H]1CCC[C@H](C)N1
Reactant: COc1cc(N2CCN(C(=O)CCl)CC2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1cc(N2CCN(C(=O)CN3[C@H](C)CCC[C@@H]3C)CC2)ccc1Cl

Procedure:
In a 4 mL vial was added 2-chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone (1) (200 mg, 0.66 mmol, 1.0 equiv), (2S,6R)-2,6-dimethyl-piperidine (100 μL, 0.72 mmol, 1.10 equiv), K2CO3 (365 mg, 2.64 mmol, 4.0 equiv) and 2.4 mL of NMP. A stir bar was placed in the vial and the vial was then capped. The resultant mixture stirred at 60° C. overnight. The crude product was purified by reversed phase HPLC (acetonitrile —H2O with 0.1% TFA as the eluent) to yield 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-ethanone (23): HPLC retention time=1.31 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 ml/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expected, 379.9, found, 380.0.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([NH:16][C:17]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][C:25]=5[O:27][C@H:28]([CH3:33])[C:29]([O:31]C)=O)[N:20]=[CH:19][N:18]=4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)[N:3]=[CH:2]1.[CH3:34][NH2:35]>>[CH3:34][NH:35][C:29](=[O:31])[C@H:28]([O:27][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:26]=1[C:17]([NH:16][C:12]1[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=1)[N:7]([CH2:6][C:4]1[N:3]=[CH:2][S:1][CH:5]=1)[N:8]=[CH:9]3)=[N:18][CH:19]=[N:20]2)[CH3:33]
Reactant: COC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cscn4)c3)c12
Reactant: CN
Product: CNC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cscn4)c3)c12
Yield: 78 %

Procedure:
Using the same procedure as in Example 5, methyl (2R)-2-[(4-{[1-(1,3-thiazol-4-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (200 mg, 0.43 mmol) was reacted with methylamine to give the title compound as a white solid (156 mg, 78%); NMR Spectrum 1.65 (d, 3H), 2.68 (d, 3H), 5.16 (q, 1H), 5.80 (s, 2H), 7.00 (d, 1H), 7.36 (d, 1H), 7.51 (s, 1H), 7.79-7.71 (m, 3H), 8.12 (s, 1H), 8.39 (m, 1H), 8.52 (m, 2H), 9.05 (s, 1H), 10.68 (br s, 1H); Mass spectrum MH+ 460.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:17][CH:16]=2)=O)=[CH:7][CH:6]=1)=[O:4].Cl.[OH:28][NH2:29]>C(O)C.C(OCC)(=O)C.ClCCCl.[O-2].[Mn+4].[O-2]>[CH2:22]([O:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]2[CH:12]=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=3)[O:28][N:29]=2)=[CH:16][CH:17]=1)[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: NO
Reactant: CCCCCOc1ccc(C(=O)C=Cc2ccc(C(=O)OC)cc2)cc1
Agent: [Mn+4]
Agent: Cl
Agent: [O-2]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CCCCCOc1ccc(-c2cc(-c3ccc(C(=O)OC)cc3)on2)cc1
Yield: 23.6 %

Procedure:
A solution of 1-(4-Methoxycarbonylphenyl)-3-(4-n-pentyloxyphenyl)-1-propen-3-one (4.0 g) and hydroxyamine hydrochloride (3.93 g) in ethanol (40 ml) was refluxed for 4 hours. The mixture was diluted with ethyl acetate, and the organic layer was washed with water (×2), brine and dried over magnesium sulfate. The solvents were removed under reduced pressure to give crude oxime. To a solution of crude oxime in 1,2-dichloroethane (20 ml) was added activated-manganese(IV) oxide (10.0 g). The reaction mixture was refluxed for 2 hours and filtered. The residue was washed with dichloromethane. The solvents were removed under reduced pressure and the residue was triturated with acetonitrile. The solid was collected by filtration and dried to give Methyl 4-[3-(4-n-pentyloxyphenyl)isoxazol-5-yl]benzoate (0.98 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:34]([O:36]C)=[O:35])=[N:11][C:12]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>O.CO>[CH2:1]([O:8][C:9]1[C:10]([C:34]([OH:36])=[O:35])=[N:11][C:12]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1nc(NCCCCCCNC(=O)OC(C)(C)C)c2cccnc2c1OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCCCCNc1nc(C(=O)O)c(OCc2ccccc2)c2ncccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Methyl 8-(benzyloxy)-5-(6-(tert-butoxycarbonylamino)hexylamino)-1,6-naphthyridine-7-carboxylate (Example 1.1; 0.58 g; 1.08 mmol) was dissolved in a mixture of water (2 ml) and methanol (2 ml). NaOH (100 mg; 2.7 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 4 hours. H2O and HCl 2 N were added until pH=4-5 was reached. The mixture was extracted with EtOAc (2×). The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][C:6](=[C:8]([C:11]#[N:12])[C:9]#[N:10])[CH:7]=1.[C:19]1([C:25]2[CH2:29][CH:28]([C:30]3[C:43]4[C:44]5=[C:45]6[C:40](=[CH:41][CH:42]=4)[CH:39]=[CH:38][CH:37]=[C:36]6[CH:35]=[CH:34][C:33]5=[CH:32][CH:31]=3)[N:27]([C:46]3[CH:53]=[CH:52][C:49]([CH:50]=O)=[CH:48][CH:47]=3)[N:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.N1CCCCC1>C(O)C>[C:13]1([C:4]2[O:3][C:2]([CH:1]=[CH:50][C:49]3[CH:48]=[CH:47][C:46]([N:27]4[CH:28]([C:30]5[C:43]6[C:44]7=[C:45]8[C:40](=[CH:41][CH:42]=6)[CH:39]=[CH:38][CH:37]=[C:36]8[CH:35]=[CH:34][C:33]7=[CH:32][CH:31]=5)[CH2:29][C:25]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)=[N:26]4)=[CH:53][CH:52]=3)=[CH:7][C:6](=[C:8]([C:11]#[N:12])[C:9]#[N:10])[CH:5]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC1=CC(=C(C#N)C#N)C=C(c2ccccc2)O1
Reactant: O=Cc1ccc(N2N=C(c3ccccc3)CC2c2ccc3ccc4cccc5ccc2c3c45)cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: N#CC(C#N)=C1C=C(C=Cc2ccc(N3N=C(c4ccccc4)CC3c3ccc4ccc5cccc6ccc3c4c56)cc2)OC(c2ccccc2)=C1
Temperature: 75 °C

Procedure:
As shown in the following reaction 6, 0.5 g (2.13 mmol) of 2-(2-methyl-6-phenyl-pyran-4-ylidene)-malononitrile and 0.961 g (2.13 mmol) of 4-(3-phenyl-5-pyren-1-yl-4,5-dihydro-pyrazol-1-yl)-benzaldehyde were added into 50 ml of ethanol, and 0.27 g (3.2 mmol) of piperidine was added thereto. The reaction solution was heated at 75° C. for 10 hours.
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[CH3:47][C:48]1[CH:56]=[CH:55][C:51]([C:52](Cl)=[O:53])=[CH:50][CH:49]=1.O>N1C=CC=CC=1>[NH:18]1[CH:19]=[N:20][C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:41]=[C:42]([NH:46][C:52]([C:51]3[CH:55]=[CH:56][C:48]([CH3:47])=[CH:49][CH:50]=3)=[O:53])[CH:43]=[CH:44][CH:45]=2)=[N:17]1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)Nc2cccc(-c3n[nH]c4ccc(-c5nc[nH]n5)cc34)c2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 66.1 %

Procedure:
To a solution of 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.140 g, 0.23 mmol) in pyridine (2 mL) was 0.35 added 4-methylbenzoyl chloride (0.053 mL, 0.40 mmol). The reaction was stirred at room temperature for 15 h. Water (10 mL) was added and the solid collected by suction filtration. The solid was dried in a vacuum oven for 3 h. The residue was dissolved in 4 N hydrochloric acid in 1,4-dioxane (10 mL) and the mixture was stirred at room temperature for 2 h. After neutralization with aqueous sodium bicarbonate, the reaction mixture was extracted with ethyl acetate. The combined organic fractions were dried over anhydrous sodium sulfate, filtered and evaporated. Addition of dichloromethane (10 mL) to the residue gave the title compound (0.060 g, 65% yield) which was isolated by filtration: 1H NMR (DMSO-d6) δ 10.41 (s, 1H), 8.74 (s, 1H), 8.46 (s, 1H), 8.33 (s, 1H), 8.10 (d, 1H), 7.94 (d, 3H), 7.72 (m, 2H), 7.54 (t, 1H), 7.36 (d, 2H), 2.40 (s, 3H); ES-MS (m/z) 395 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:11]=[C:12]([CH:15]=[C:16](F)[CH:17]=1)[C:13]#[N:14].C([O-])([O-])=O.[K+].[K+]>CN(C)C(=O)C.CCOC(C)=O.O>[Br:9][C:10]1[CH:11]=[C:12]([CH:15]=[C:16]([O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:17]=1)[C:13]#[N:14]
Reactant: N#Cc1cc(F)cc(Br)c1
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: N#Cc1cc(Br)cc(Oc2ccc(F)cc2)c1
Temperature: 160 °C

Procedure:
A mixture of 4-fluorophenol (0.3 g, 2.7 mmol), 3-bromo-5-fluorobenzonitrile (0.53 g, 2.7 mmol), K2CO3 (1.1 g, 8.0 mmol) in N,N-dimethylacetamide (3 mL) was heated to 160° C. for 3 hr. The reaction mixture was cooled to room temperature and diluted with EtOAc and water. The organic layer was separated, dried (MgSO4), concentrated, and purified by chromatography on silica gel (EtOAc/hexanes) to afford 3-bromo-5-(4-fluorophenoxy)benzonitrile.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([CH2:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=1)[CH2:5][CH2:6][Cl:7]>Cl>[Cl:1][CH2:2][CH2:3][N:4]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:17][CH:18]=1)[CH2:5][CH2:6][Cl:7]
Reactant: COC(=O)c1ccc(CN(CCCl)CCCl)cc1
Agent: Cl
Product: O=C(O)c1ccc(CN(CCCl)CCCl)cc1
Yield: 94.1 %

Procedure:
Concentrated hydrochloric acid (50 ml) was added to 9.5 g (32.7 mmol) of methyl 4-[N,N-bis(2-chloroethyl)aminomethyl]benzoate, followed by stirring under heating and reflux for 2 hours. After the solvent was distilled out under reduced pressure, the residue was washed with acetone, whereby 8.5 g of white powder were obtained.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:6]([CH2:20][CH3:21])=[C:7]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:8]=[C:9]([O:11][CH2:12][CH:13]=[CH2:14])[CH:10]=1)[CH:2]=[CH2:3].[C:22](O)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)([O-])O.[Na+]>FC(F)(F)C(O)=O>[CH2:12]([O:11][C:9]1[C:8]([C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:7]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:6]([CH2:20][CH3:21])=[C:5]([O:4][CH2:1][CH:2]=[CH2:3])[CH:10]=1)[CH:13]=[CH2:14]
Reactant: C=CCOc1cc(CC(=O)OC)c(CC)c(OCC=C)c1
Reactant: O=C(O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: C=CCOc1cc(OCC=C)c(C(=O)c2ccccc2)c(CC(=O)OC)c1CC
Temperature: 4 °C
Reaction time: 18 h
Yield: 56.6 %

Procedure:
Methyl 3,5-diallyloxy-2-ethylphenylacetate (0.31 g, 1.3 mmol) obtained in Example 5, Step 3 was dissolved in trifluoroacetic acid (2.0 mL). After the solution was cooled to 4° C., benzoic acid (0.40 g, 3.3 mmol) and trifluoroacetic anhydride (1.0 mL) were added thereto, followed by stirring for 18 hours, while the temperature of the reaction mixture was raised to room temperature. The reaction mixture was gradually added to a saturated aqueous solution of sodium hydrogencarbonate for neutralization, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/9-1/4) to obtain methyl 3,5-diallyloxy-2-benzoyl-6-ethylphenylacetate (0.29 g, 55%).
Reaction SMILES: [Si:1]([N:8]1[C@H:11]([CH:12]=[C:13](Br)Br)[CH2:10][C:9]1=[O:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[NH4+].[Cl-]>>[Si:1]([N:8]1[C@H:11]([C:12]#[CH:13])[CH2:10][C:9]1=[O:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)C[C@H]1C=C(Br)Br
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Product: C#C[C@@H]1CC(=O)N1[Si](C)(C)C(C)(C)C
Temperature: -75 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
To a solution of (s)-N-tert-butyldimethylsilyl-4 (2,2-dibromoethenyl)-2-azetidinone (0.63 g) was added lithium bis(trimethylsilyl)amide (3.75 ml, 1 mol solution in n-hexane) at −75° C. After stirring at −75° C. for 1 hour, a saturated aqueous NH4Cl solution was added and extracted with ethyl acetate. The extract was washed with water and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by chromatography on silica gel eluting with (diethyl ether:n-hexane=1:5) to give (S)-N-tert-butyldimethylsilyl-4-ethynyl-2-azetidinone (0.20 g) as an colorless oil.