Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[CH2:15][CH2:14][CH2:13][C:12]3=[O:16])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Li+].CC([N-]C(C)C)C.Br[CH2:26][C:27]1[C:32]([Cl:33])=[CH:31][C:30]([O:34][CH3:35])=[CH:29][C:28]=1[Cl:36]>O1CCCC1>[Cl:33][C:32]1[CH:31]=[C:30]([O:34][CH3:35])[CH:29]=[C:28]([Cl:36])[C:27]=1[CH2:26][CH:13]1[CH2:14][CH2:15][N:11]([CH:8]2[CH2:7][CH2:6][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:10][CH2:9]2)[C:12]1=[O:16]
Reactant: COc1cc(Cl)c(CBr)c(Cl)c1
Reactant: O=C1CCCN1C1CCC2(CC1)OCCO2
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(Cl)c(CC2CCN(C3CCC4(CC3)OCCO4)C2=O)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Cool a solution of 1-(1,4-Dioxa-spiro[4.5]dec-8-yl)-pyrrolidin-2-one (5 g, 22.2 mmol) in tetrahydrofuran (100 mL) to −78° C. under nitrogen purge. Add LDA (2.0 M, 15 mL, 30 mmol) at a rate such that the internal reaction temperature did not reach above −67° C. Stir 30 min at −78° C., add a solution of 2-bromomethyl-1,3-dichloro-5-methoxy-benzene, 6.6 g, 24.4 mmol) in tetrahydrofuran (20 mL) over a 1-2 minute period, remove the cold bath and allow reaction to warm over 3 hr. Quench the reaction with saturated aqueous ammonium chloride (100 mL), extract with ethyl acetate (3×100 mL), combine the extracts and dry over anhydrous sodium sulfate. Purify on silica column eluting with 8:2 hexanes:ethyl acetate to 1:1 hexanes:ethyl acetate to afford the product as a ivory solid, 6.5 g, 71%. 1H NMR (CDCl3) δ 6.86 (s, 2H), 4.06-4.12 (m, 1H), 3.94 (s, 4H), 3.77 (s, 3H), 3.32-3.41 (m, 2H), 3.15-3.21 (m, 1H), 2.83-2.97 (m, 2H), 1.68-2.04 (m, 8H). LCMS (m+1) 414.
Reaction SMILES: Cl[N:2]1C(=O)CCC1=O.CN1CC[O:15][B:14]([C:18]2[CH:19]=[C:20]([S:24]([O-:26])=[O:25])[CH:21]=[N:22][CH:23]=2)[O:13]CC1.[Li+].[OH-].[NH4+]>C(Cl)Cl>[S:24]([C:20]1[CH:21]=[N:22][CH:23]=[C:18]([B:14]([OH:15])[OH:13])[CH:19]=1)(=[O:26])(=[O:25])[NH2:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CN1CCOB(c2cncc(S(=O)[O-])c2)OCC1
Agent: [Li+]
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: NS(=O)(=O)c1cncc(B(O)O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.4 %

Procedure:
Step 3) N-Chlorosuccinimide (0.937 g, 7.01 mmol) was added to a suspension of the above prepared lithium 5-(6-methyl-[1,3,6,2]dioxazaborocan-2-yl)-pyridine-3-sulfinate (2 g, 7.24 mmol) in CH2Cl2 (14 mL) and the mixture was stirred for 2 h at rt. A solution of 25% ammonium hydroxide (1.00 mL, 13.4 mmol) was added and the mixture was stirred again for 2 h at rt, then completely evaporated to give the title compound as an off-white solid (1.28 g, 88%) (according to Bioorg. Med. Chem. 2005, 13, 2305-2312). MS (ISP) 201.4 [(M−H)−].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][CH:5]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)[CH2:6][N+:7]([O-:9])=[O:8].[C:18]([O:22][CH3:23])(=[O:21])[CH:19]=[CH2:20].Cl>C(O)(C)(C)C.C(OCC)C>[CH3:1][O:2][C:3](=[O:17])[CH2:4][CH:5]([C:10]1[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=1)[CH:6]([N+:7]([O-:9])=[O:8])[CH2:20][CH2:19][C:18]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)CC(C[N+](=O)[O-])c1ccc(C)cc1
Reactant: C=CC(=O)OC
Agent: Cl
Solvent: CC(C)(C)O
Solvent: CCOCC
Product: COC(=O)CCC(C(CC(=O)OC)c1ccc(C)cc1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 94 h

Procedure:
A solution of 356 g of 4-nitro-3-(4-methylphenyl)-butanoic acid methyl ester, 138 g of methyl acrylate and 25 ml of Triton B in 500 ml of t-butanol is allowed to stir at room temperature for 94 hours. Excess aqueous hydrochloric acid (1 N) is added and the solution is diluted with diethyl ether. The organic layer is separated, dried over anhydrous magnesium sulfate and evaporated to give 4-nitro-3-(4-methylphenyl)heptanedioic acid dimethyl ester.
Reaction SMILES: [CH3:1][CH:2]1[CH:6]([CH3:7])[O:5][C:4]2([CH2:12][C:11]([CH3:17])([C:13]([F:16])([F:15])[F:14])[C:10](/[CH:19]=[CH:20]/[Sn](CCCC)(CCCC)CCCC)([OH:18])[C:9]([CH3:34])=[CH:8]2)[O:3]1.[CH:35]1(/[C:38](/I)=[CH:39]/[C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:37][CH2:36]1.[F-].[K+]>CC#N.CC#N.Cl[Pd]Cl.O1CCCC1>[CH:35]1(/[C:38](/[CH:20]=[CH:19]/[C:10]2([OH:18])[C:11]([CH3:17])([C:13]([F:16])([F:14])[F:15])[CH2:12][C:4]3([O:5][CH:6]([CH3:7])[CH:2]([CH3:1])[O:3]3)[CH:8]=[C:9]2[CH3:34])=[CH:39]/[C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:37][CH2:36]1
Reactant: CCCC[Sn](/C=C/C1(O)C(C)=CC2(CC1(C)C(F)(F)F)OC(C)C(C)O2)(CCCC)CCCC
Reactant: CCOC(=O)/C=C(\I)C1CC1
Agent: Cl[Pd]Cl
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C=C\C1(O)C(C)=CC2(CC1(C)C(F)(F)F)OC(C)C(C)O2)C1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 36 %

Procedure:
Under argon, 2,3,7,9-tetramethyl-8-[(E)-2-(tributylstannyl)vinyl]-9-(trifluoromethyl)-1,4-dioxaspiro[4.5]dec-6-en-8-ol (150 mg, 0.25 mmol) and ethyl (2Z)-3-cyclopropyl-3-iodoacrylate (67 mg, 0.25 mmol) in a round-bottom flask that had been dried by heating were dissolved in abs. tetrahydrofuran (4 ml), dichlorobis(acetonitrile)palladium(II) (3 mg, 0.01 mmol) was added and the mixture was stirred at room temperature for 3 h. After the addition of potassium fluoride solution, the reaction mixture was stirred further at room temperature overnight. The aqueous phase was then repeatedly extracted thoroughly with diethyl ether, and the combined organic phases were then dried over magnesium sulfate, filtered and concentrated under reduced pressure. By final column chromatography purification of the resulting crude product (ethyl acetate/heptane gradient), ethyl (2Z,4E)-3-cyclopropyl-5-[8-hydroxy-2,3,7,9-tetramethyl-9-(trifluoromethyl)-1,4-dioxaspiro[4.5]dec-6-en-8-yl]penta-2,4-dienoate (40 mg, 36% of theory) was obtained in the form of a colorless oil. 1H-NMR (400 MHz, CDCl3 δ, ppm) 7.80/7.78 (d, 1H), 6.40/6.38 (d, 1H), 5.62/5.60 (s, 1H), 5.52/5.44 (s, 1H), 4.28/3.63 (m, 2H), 4.18 (q, 2H), 2.52/2.41 (d, 1H), 2.03/1.94 (d, 1H), 2.00 (br. s, 1H, OH), 1.72/1.69 (s, 3H), 1.62/1.55 (m, 1H), 1.40-1.34 (m, 3H), 1.29-1.17 (m, 6H), 0.92 (t, 3H), 0.83 (m, 2H), 0.58 (m, 2H).
Reaction SMILES: [C:1]([C:4]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][C:7]([O:8][CH2:9][C:10]2([NH:13][C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:12][CH2:11]2)=[C:6]([O:29][CH3:30])[CH:5]=1)(=[O:3])[CH3:2].CO[CH:33](OC)[N:34]([CH3:36])[CH3:35]>CN(C=O)C.O>[CH3:33][N:34]([CH3:36])[CH:35]=[CH:2][C:1]([C:4]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][C:7]([O:8][CH2:9][C:10]2([NH:13][C:14]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:15])[CH2:12][CH2:11]2)=[C:6]([O:29][CH3:30])[CH:5]=1)=[O:3]
Reactant: COc1cc(C(C)=O)c([N+](=O)[O-])cc1OCC1(NC(=O)OCc2ccccc2)CC1
Reactant: COC(OC)N(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)C=CN(C)C)c([N+](=O)[O-])cc1OCC1(NC(=O)OCc2ccccc2)CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
A mixture of the compound of Example 2 (1.7 g, 4.1 mmol) and N,N-dimethylformamide dimethylacetal (0.9 g, 8.2 mmol) in DMF (6 mL) was stirred at 100° C. for 2 h. After cooling at room temperature, the reaction mixture was diluted with water (30 mL) and extracted with AcOEt (3×50 mL). The combined organic phases were washed with brine (2×50 mL), dried and evaporated to give 1-[(4-(3-dimethylaminopropenoyl)-2-methoxy-5-nitrophenoxy)methyl]-N-benzyloxycarbonyl-1-aminocyclopropane (1.9 g, yield: 95%) as a yellow solid.
Reaction SMILES: Br[C:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:4]([CH2:15][CH3:16])[C:3]=1[C:17](=[O:20])[CH2:18][CH3:19].C(O)C.[NH2:24][S:25]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)(=[O:27])=[O:26].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[N:4]([CH2:15][CH3:16])[C:3]([C:17](=[O:20])[CH2:18][CH3:19])=[C:2]([C:31]3[CH:32]=[CH:33][C:28]([S:25]([NH2:24])(=[O:27])=[O:26])=[CH:29][CH:30]=3)[C:6]=2[CH3:7])=[CH:9][CH:10]=1
Reactant: CCC(=O)c1c(Br)c(C)c(-c2ccc(Cl)cc2)n1CC
Reactant: NS(=O)(=O)c1ccc(B(O)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: Cc1ccccc1
Solvent: CCO
Product: CCC(=O)c1c(-c2ccc(S(N)(=O)=O)cc2)c(C)c(-c2ccc(Cl)cc2)n1CC
Temperature: 25 °C
Yield: 32.9 %

Procedure:
To the solution of 1-(3-bromo-5-(4-chlorophenyl)-1-ethyl-4-methyl-1H-pyrrol-2-yl)propan-1-one (compound 51c, 0.5 g, 1.41 mmol) in a mixture of toluene: ethanol (3:12 ml) was added 4-aminosulfonylbenzene boronic acid (0.34 g, 1.69 mmol) and potassium carbonate (0.48 g, 3.52 mmol) at a temperature of about 25° C. in a sealed tube and a nitrogen gas was bubbled through the reaction mixture for 15 minutes. To the reaction mixture was then added tetrakis(triphenylphosphine)palladium(0) (0.16 g, 0.14 mmol) under nitrogen atmosphere and the reaction mixture was heated at about 90° C. to 95° C. for 18 hr under stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25° C. and filtered through celite. The celite cake was washed with 10% methanol in dichloromethane (2×20 ml). The combined filtrate was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography over silicagel (100-200 mesh) using 30-35% ethyl acetate in hexanes as an eluent to obtain the title compound (0.2 g, 32.9%).
Reaction SMILES: [CH3:1][CH:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].CS(O[CH2:20][CH2:21][CH2:22][C:23]#[CH:24])(=O)=O>O1CCCC1>[CH3:1][C:2]([CH2:24][CH2:23][CH2:22][C:21]#[CH:20])([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: C#CCCCOS(C)(=O)=O
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCCCC(C)(C(=O)OCC)C(=O)OCC

Procedure:
A solution of diethyl methylmalonate (Aldrich Chemical Company, 35.6 ml) in dry tetrahydrofuran (200 ml) was added, dropwise, to a stirred suspension of sodium hydride (60% dispersion in mineral oil, 9.1 g) in tetrahydrofuran (50 ml) under nitrogen. After the addition was complete, the mixture was heated to gentle reflux for 1 hour and then allowed to cool before a solution of pent-4-ynyl methanesulphonate (35.2 g) in tetrahydrofuran (50 ml) was added. The resulting mixture was heated to gentle reflux for a further 2 hours. The bulk of the solvent was then removed in vacuo and the residue was partitioned between diethyl ether and water. The organic phase was separated and washed with water and brine before drying over anhydrous magnesium sulphate and evaporation under reduced pressure. Distillation gave diethyl 2-methyl-2-(pent-4-ynyl)malonate (45.8 g) as a colourless oil (b.p. 92°-97°, 0.5 mm Hg).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:8]([OH:10])=O.O.ON1C2C=CC=CC=2N=N1.[C:26](=[N:29]O)([NH2:28])[CH3:27]>>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:8]2[O:10][N:29]=[C:26]([CH3:27])[N:28]=2)[CH:11]=[CH:12][C:13]=1[CH3:14]
Reactant: CC(N)=NO
Reactant: COCOc1cc(C(=O)O)ccc1C
Agent: On1nnc2ccccc21
Solvent: O
Product: COCOc1cc(-c2nc(C)no2)ccc1C
Temperature: 140 °C
Reaction time: 2 h

Procedure:
A mixture of 3-methoxymethoxy-4-methyl-benzoic acid (1.96 g, 10 mmol), 1-(3-dimethyl-aminopropyl-3-ethylcarbodiimide (1.92 g, 10 mmol, Aldrich), and 1-hydroxybenzotriazole hydrate (1.5 g, 10 mmol, Aldrich) was stirred at room temperature for 30 minutes. Acetamide oxime (0.74 g, 10 mmol) (GFS Chemicals) was added and the mixture heated at 140° C. with magnetic stirring for 2 hours. After cooling, the mixture was partitioned between ethyl acetate (2×100 mL) and saturated aqueous sodium bicarbonate solution (100 mL). Ethyl acetate solutions were combined and concentrated to give crude 5-(3-methoxymethoxy-4-methyl-phenyl)-3-methyl-[1,2,4]oxadiazole. (Yield 1.23 g, 52.5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:23])=[C:5]([C:14]([O:21][CH3:22])=[C:15]([O:19][CH3:20])[C:16]=1[O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:36](O)=[O:37]>>[CH3:1][O:2][C:3]1[C:4]([CH3:23])=[C:5]([C:14]([O:21][CH3:22])=[C:15]([O:19][CH3:20])[C:16]=1[O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([CH:8]=1)[CH:36]=[O:37]
Reactant: COc1c(C)c(Cc2ccc(O)cc2)c(OC)c(OC)c1OC
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Product: COc1c(C)c(Cc2ccc(O)c(C=O)c2)c(OC)c(OC)c1OC
Temperature: 80 °C
Yield: 78 %

Procedure:
4-(3,4,5,6-Tetramethoxy-2-methylbenzyl)phenol (14.5 g, 45.60 mmol) and hexamethylenetetramine (8.30 g, 59.29 mmol) were dissolved in trifluoroacetic acid (100 ml) and the solution was stirred under heating at 80° C. for 4 hours. After the completion of reaction, the solvent was removed by distillation and to the obtained residue, water (100 ml) was added. The resulting solution was stirred for 30 minutes and extracted with methylene chloride. The extract was washed with water and then dried, the solvent was removed by distillation and the obtained residue was purified by silica gel column chromatography (hexand:ethyl acetate=4:1) to obtain the titled compound (12.20 g, 35.26 mmol, 78%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][C:12]([N+:21]([O-])=[O:22])([CH3:20])[CH2:13][CH2:14][CH:15]1[O:19][CH2:18][CH2:17][O:16]1.C(O)(=O)C>C(O)C.[Zn]>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[N+:21]([C:12]([CH3:20])([CH3:11])[CH2:13][CH2:14][CH:15]1[O:16][CH2:17][CH2:18][O:19]1)[O-:22]
Reactant: O=Cc1ccc(F)cc1F
Reactant: CC(C)(CCC1OCCO1)[N+](=O)[O-]
Agent: [Zn]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(CCC1OCCO1)[N+]([O-])=Cc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 10 h
Yield: 68.7 %

Procedure:
A suspension of 2,4-difluorobenzaldehyde (290.6 mg, 2.04 mmol), 2-(3-methyl-3-nitrobutyl)-1,3-dioxolane (776.8 mg, 4.11 mmol) and zinc (402.7 mg, 6.16 mmol) in ethanol (5 ml) was cooled to 0° C. in ice-water bath. Acetic acid (0.69 ml, 12.0 mmol) was added dropwise to the mixture. The mixture was gradually warmed to room temperature and stirred for 10 hours and let stand overnight. The mixture was filtered through Celite® bed and the filtrate was concentrated and purified by silica gel chromatography (hexane/ethyl acetate=4/1-1/1) to give the title compound (419.4 mg; 69%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]2[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)=[O:13])[CH:5]=[CH:4][N:3]=1.[CH3:29][N:30]([CH2:32][CH2:33][NH2:34])[CH3:31]>N1C=CC=CC=1>[CH3:29][N:30]([CH3:31])[CH2:32][CH2:33][NH:34][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]2[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[CH:16]=2)=[O:13])[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)c1ccccc1NCc1ccnc(Br)c1
Reactant: CN(C)CCN
Solvent: c1ccncc1
Product: CN(C)CCNc1cc(CNc2ccccc2C(=O)Nc2cccc(C(F)(F)F)c2)ccn1
Temperature: 200 °C

Procedure:
90 mg (0.2 mmol) of 2-[(2-bromo-pyridin-4-ylmethyl)-amino]-N-(3-trifluoromethyl-phenyl)-benzamide is dissolved in 3 ml of pyridine and mixed with 1 ml of N,N-dimethyl-aminoethylamine and heated in a pressure vessel for 5 hours to a bath temperature of 200° C. After cooling, it is concentrated by evaporation, and 90 mg of 2-{[2-(2-dimethylamino-ethylamino)-pyridin-4-ylmethyl]-amino}-N-(3-trifluoromethyl-phenyl)-benzamide is obtained.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][N:4]=1)#[CH:2].[N:13]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1)=[N+:14]=[N-:15]>O1CCOCC1.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH3:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[NH:5][N:4]=[C:3]2[C:1]1[N:15]=[N:14][N:13]([C:16]2[CH:17]=[CH:18][C:19]([CH:20]=[O:21])=[CH:22][CH:23]=2)[CH:2]=1
Reactant: [N-]=[N+]=Nc1ccc(C=O)cc1
Reactant: C#Cc1n[nH]c2ccc(C)cc12
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc2[nH]nc(-c3cn(-c4ccc(C=O)cc4)nn3)c2c1
Temperature: 90 °C
Reaction time: 3.5 h
Yield: 99.9 %

Procedure:
3-Ethynyl-5-methyl-1H-indazole (1.0 g; 6.4 mmol; 1.0 eq.) and 4-azidobenzaldehyde (prepared as described in Chem. Med. Chem. (2009), 4(7), 1182-1188; 1.30 g; 7.04 mmol; 1.1 eq.) were dissolved in 1,4-dioxane (15 mL). D-(−)-isoascorbic acid sodium salt (127 mg; 0.64 mmol; 0.10 eq.) followed by a solution of copper sulfate pentahydrate (32 mg; 0.13 mmol; 0.02 eq.) in water (1.5 mL) were added and the reaction mixture was stirred at 90° C. for 3.5 hours. To complete the reaction more D-(−)-isoascorbic acid sodium salt (127 mg; 0.64 mmol; 0.10 eq.) and copper sulfate pentahydrate (32 mg; 0.13 mmol; 0.02 eq.) were added again and the reaction mixture was heated at 10° C. for 8 h. 1,4-dioxane was removed under reduced pressure an the residue was sonicated in a mixture of EtOAc and water (1:1). The resulting solid was filtered and dried to afford the title compound as a beige solid (1.94 g, 100%). 1H NMR (300 MHz, DMSO-d6) δ: 13.29 (brs, 1H), 10.11 (s, 1H), 9.46 (s, 1H), 8.34 (d, J=8.6 Hz, 2H), 8.18 (d, J=8.6 Hz, 2H), 8.14 (m, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.28 (dd, J=8.4 Hz, 1.4 Hz, 1H), 2.49 (s, 3H).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]#[CH:11])=[CH:6][CH:5]=1)[CH2:2][CH3:3].[C:12]([O:16][C:17]([O:19][C:20]1[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(C1C=CC(Br)=CC=1)CC.C[Si](C#C)(C)C.Cl>O>[C:12]([O:16][C:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([C:11]#[C:10][C:7]2[CH:6]=[CH:5][C:4]([CH2:1][CH2:2][CH3:3])=[CH:9][CH:8]=2)=[CH:22][CH:21]=1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)Oc1ccc(Br)cc1
Reactant: C#Cc1ccc(CCC)cc1
Agent: C#C[Si](C)(C)C
Agent: CCCc1ccc(Br)cc1
Agent: Cl
Solvent: O
Product: CCCc1ccc(C#Cc2ccc(OC(=O)OC(C)(C)C)cc2)cc1

Procedure:
The reaction was carried out in the same manner as in the step (i), except for using 4-n-propylphenylacetylene synthesized in the step (ii) and 1-(tert-butoxycarbonyloxy)-4-bromobenzene synthesized in the Example 4 instead of 1-n-propyl-4-bromobenzene and trimethylsilylacetylene, respectively. After completion of the reaction, the reaction solution was poured into an iced water, and the resultant solution was acidified by adding hydrochloric acid. After the resultant solid was collected by filtration, the collected solid was washed with water, dried, and recrystallized successively from hexane and ethanol to provide 4.1 g (12.1 mmol) of 1-[4-(tert-butoxycarbonyloxy)phenyl]-2-(4-n-propylphenyl)acetylene.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:28][C:29]1[CH:38]=[C:37]2[C:32]([CH:33]=[CH:34][CH:35]=[N:36]2)=[CH:31][CH:30]=1>CN(C=O)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])[N:5]=[CH:4][N:3]=[C:2]2[O:28][C:29]1[CH:38]=[C:37]2[C:32]([CH:33]=[CH:34][CH:35]=[N:36]2)=[CH:31][CH:30]=1
Reactant: Oc1ccc2cccnc2c1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4cccnc4c3)ncnc2cc1OCCCS(C)(=O)=O
Temperature: 90 °C
Yield: 81.4 %

Procedure:
4-Chloro-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline (0.15 g, 0.45 mmol), (prepared as described for the starting material in Example 50), potassium carbonate (94 mg, 0.68 mmol) and 7-hydroxyquinoline (79 mg, 0.54 mmol) were suspended in anhydrous DMF (1.5 ml) and heated to 90° C. overnight. The compound was precipitated upon addition of water. The precipitate was collected by filtration, washed with water and dried under vacuum over phosphorus pentoxide to give 6-methoxy-7-(3-methylsulphonylpropoxy)4-(quinolin-7-yloxy)quinazoline (161 mg, 81%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([O:24][C:25]([N:27]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([CH2:37][CH2:38][OH:39])[N:35]=2)[CH2:30][CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].[CH2:40]([O:42][C:43](=[O:59])[CH2:44][CH:45]([N:49]1[C:57]2[C:52](=[CH:53][C:54](O)=[CH:55][CH:56]=2)[CH:51]=[CH:50]1)[CH2:46][CH2:47][CH3:48])[CH3:41].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:20]([O:24][C:25]([N:27]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([CH2:37][CH2:38][O:39][C:54]3[CH:53]=[C:52]4[C:57](=[CH:56][CH:55]=3)[N:49]([CH:45]([CH2:44][C:43]([O:42][CH2:40][CH3:41])=[O:59])[CH2:46][CH2:47][CH3:48])[CH:50]=[CH:51]4)[N:35]=2)[CH2:30][CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: CCCC(CC(=O)OCC)n1ccc2cc(O)ccc21
Reactant: CC(C)(C)OC(=O)N1CCCc2ccc(CCO)nc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCC(CC(=O)OCC)n1ccc2cc(OCCc3ccc4c(n3)N(C(=O)OC(C)(C)C)CCC4)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 13 %

Procedure:
Triphenylphosphine (0.20 g, 0.77 mmol) was added to a solution of 7-(2-hydroxy-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester (0.16 g, 0.58 mmol) and 3-(5-hydroxy-indol-1-yl)-hexanoic acid ethyl ester (0.10 g, 0.38 mmol) in THF (4 mL) at 0° C. Diisopropylazodicarboxylate (0.15 g, 0.77 mmol) was added dropwise and the reaction was stirred at room temperature overnight. The solution was then concentrated. The residue was purified by flash chromatography on silica gel (30% ethyl acetate in hexane) to give the title compound (13% yield). 1H NMR (CDCl3) δ 7.30 (m, 2H), 7.09 (m, 2H), 6.96 (d, 1H, J=7.6 Hz), 6.86 (m, 1H), 6.41 (d, 1H, J=3.2 Hz), 4.78 (m, 1H), 4.39 (t, 2H, J=6.9 Hz), 3.98 (q, 2H, J=7.1 Hz), 3.75 (m, 2H), 3.21 (t, 2H, J=6.9 Hz), 2.86 (m, 2H), 2.77 (m, 2H), 1.85 (m, 4H), 1.50 (s, 9H), 1.20 (m, 2H), 1.06 (t, 3H, J=7.1 Hz), 0.85 (t, 3H, J=7.4 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:17]=[C:16]2[C:12]([N:13]=[C:14]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:22][CH2:21]3)[N:15]2[CH3:18])=[C:11]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[N:10]=1.[F:36][C:37]([F:42])([F:41])[C:38](O)=O>>[CH3:18][N:15]1[C:14]([CH2:19][N:20]2[CH2:21][CH2:22][CH:23]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:24][CH2:25]2)=[N:13][C:12]2[C:16]1=[N:17][C:9]([N:8]1[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=[C:38]1[C:37]([F:42])([F:41])[F:36])=[N:10][C:11]=2[N:30]1[CH2:31][CH2:32][O:33][CH2:34][CH2:35]1
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Nc3ccccc3N)nc21
Reactant: O=C(O)C(F)(F)F
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-n3c(C(F)(F)F)nc4ccccc43)nc21

Procedure:
Following the procedures for 157, 2-(1-((2-(2-aminophenylamino)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol and trifluoroacetic acid were reacted to give 186. LCMS m/z: 559.3 (MH+)
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[N:22][C:23]#[N:24])OC2C=CC=CC=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH2:27][CH:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH3:29].C(N(CC)CC)C>C(#N)C>[C:23]([NH:22][C:14]([NH:13][C:5]1[CH:4]=[C:3]([C:2]([F:1])([F:26])[F:25])[CH:8]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:6]=1)=[N:27][CH:28]([CH3:29])[C:30]([CH3:33])([CH3:32])[CH3:31])#[N:24]
Reactant: N#CN=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Oc1ccccc1
Reactant: CC(N)C(C)(C)C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(N=C(NC#N)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(C)(C)C
Yield: 46 %

Procedure:
A solution of N-[3,5-bis(trifluoromethyl)phenyl]-N'-cyano-O-phenylisourea (0.8 mmol, 300 mg), 2-amino-3,3-dimethylbutane (0.88 mmol, 0.09 g) and triethylamine (0.88 mmol, 0.123 ml) in acetonitrile (2 ml) was stirred for 8 h at 75° C. After concentration the residue was purified by column chromatography (heptane:ethyl acetate 2:1) to give the title compound (140 mg, 46%) as white crystals. Mp 165.5-166.5° C.; EI SP/MS: 380 (M+); 1H-NMR (CDCl3): δ 0.92 (s, 9H),1.13 (d, 3H), 3.8 (m, 1H), 4.8 (br d, 1H), 7.74 (br s, 3H), 8.5 ppm (br, 1H); MA calc for C16H18F6N4 : C, 50.53%; H, 4.77%; N, 14.73%. Found: C, 50.48%; H, 4.74%; N, 14.45%.