Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:6][C:5]2[C:7]([CH3:15])=[C:8]([CH3:14])[C:9]([CH3:13])=[C:10]([CH:11]=O)[C:4]=2[O:3]1.O.[OH-].[Na+].[CH3:20][C:21]([CH3:23])=[O:22]>>[CH3:1][C:2]1([CH3:16])[CH2:6][C:5]2[C:7]([CH3:15])=[C:8]([CH3:14])[C:9]([CH3:13])=[C:10]([CH:11]=[CH:20][C:21](=[O:22])[CH3:23])[C:4]=2[O:3]1
Reactant: Cc1c(C)c(C=O)c2c(c1C)CC(C)(C)O2
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)C=Cc1c(C)c(C)c(C)c2c1OC(C)(C)C2

Procedure:
To a solution of 19.5 g of the 2,3-dihydro-2,2,4,5,6-pentamethylbenzofuran-7-carboxaldehyde in 65 ml of acetone was added 32 ml of water and 36 g of 1% aqueous solution of sodium hydroxide. After refluxing for 20 hours, the reaction mixture was quenched with 2N hydrochloric acid and the aqueous layer was extracted three times with 50 ml of diethyl ether. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to afford a crude product. Final purification was carried by recrystallization to afford 17.6 g of 4-(2,3-dihydro-2,2,4,5,6-pentamethylbenzofuran-7-yl)-3-buten-2-one as a yellow plate crystal.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([OH:10])[N:7]([CH3:11])[N:6]=1)=[O:4].[CH3:12][C:13]1[O:17][N:16]=[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[C:14]=1[CH2:24]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([O:10][CH2:24][C:14]2[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:16][O:17][C:13]=2[CH3:12])[N:7]([CH3:11])[N:6]=1)=[O:4]
Reactant: Cc1onc(-c2ccccn2)c1CO
Reactant: COC(=O)c1cc(O)n(C)n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(OCc2c(-c3ccccn3)noc2C)n(C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.9 %

Procedure:
To a stirred solution of 5-hydroxy-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester (400 mg, 2.6 mmol) and (5-methyl-3-pyridin-2-yl-isoxazol-4-yl)-methanol (500 mg, 2.6 mmol) in THF (10 mL) at 5° C. under argon was added triphenylphosphine (862 mg, 3.3 mmol), then diethyl azodicarboxylate (573 mg, 3.3 mmol) was added dropwise. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was then evaporated. Purification by chromatography (silica, dichloromethane:methanol=9:1) then purification using a 5×50 cm Chiralpak AD column at room temperature using an isopropanol:heptane (2:8) mobile phase with UV detection at 220 nM afforded the title compound (400 mg, 48%) as a white solid. MS: m/e=328.3 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([NH:12][C:13](=[O:15])[CH3:14])[CH:9]=[N:10][CH:11]=1)=[CH2:5])C.Cl.C([O-])(O)=O.[Na+]>CC(C)=O>[C:4]([C:6]1[CH:7]=[C:8]([NH:12][C:13](=[O:15])[CH3:14])[CH:9]=[N:10][CH:11]=1)(=[O:3])[CH3:5]
Reactant: C=C(OCC)c1cncc(NC(C)=O)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(=O)Nc1cncc(C(C)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.1 %

Procedure:
To a solution of N-[5-(1-ethoxyvinyl)pyridin-3-yl]acetamide (2.4 mmol) in acetone (9 mL) was added 1N HCl (1 mL). The reaction mixture was allowed to stir at rt overnight and then basified with sat NaHCO3 and extracted with EtOAc. The organic solutions were combined, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography to give N-(5-acetylpyridin-3-yl)acetamide (0.180 g, 42%) as a white solid. LCMS: (FA) ES+ 179.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8](=[O:31])[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]3[CH:30]=[CH:29][CH:28]=[N:27]3)=[CH:22][CH:21]=1)=[C:10]([CH2:17][CH3:18])[NH:11]2.Cl[C:34](OC(=O)C)([F:36])[F:35]>>[CH3:1][O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([O:31][CH:34]([F:36])[F:35])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]3[CH:30]=[CH:29][CH:28]=[N:27]3)=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2
Reactant: CCc1[nH]c2c(Cl)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(-n2cccn2)cc1
Reactant: CC(=O)OC(F)(F)Cl
Product: CCc1nc2c(Cl)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(-n2cccn2)cc1

Procedure:
The title compound was prepared by the method of Preparation 1d using [8-chloro-2-ethyl-4-oxo-3-(4-pyrazol-1-ylbenzyl)-1,4-dihydroquinolin-5-yloxy]acetic acid methyl ester and acetic acid chlorodifluoromethyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:20]2[CH2:22][O:21]2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([NH2:35])([CH3:34])[CH3:33])=[CH:27][CH:26]=1>C(O)CCC>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:20]([OH:21])[CH2:22][NH:35][C:32]([CH3:34])([CH3:33])[CH2:31][C:28]2[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CC(C)(C)N)cc1
Reactant: O=c1ccc2c(C3CO3)ccc(OCc3ccccc3)c2[nH]1
Solvent: CCCCO
Product: COc1ccc(CC(C)(C)NCC(O)c2ccc(OCc3ccccc3)c3[nH]c(=O)ccc23)cc1

Procedure:
587 mg (2 mmol) 8-benzyloxy-5-oxiranyl-1H-quinolin-2-one and 358 mg (2 mmol) 2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamine are stirred in 5 mL n-butanol for 6 hours at 140° C. Then the solvent is distilled off and the residue is purified by chromatography (reverse phase; water/acetonitrile gradient).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]2[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11](S(C)(=O)=O)[N:10]=2)[CH2:4][C:3]1([CH3:22])[CH3:21].[F:23][C:24]([F:37])([CH3:36])[CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][NH2:35])=[CH:29][CH:28]=1.CCN(C(C)C)C(C)C>C1COCC1>[F:23][C:24]([F:37])([CH3:36])[CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][NH:35][C:11]2[N:10]=[C:9]([NH:8][C@@H:5]3[CH2:6][CH2:7][C@H:2]([OH:1])[C:3]([CH3:22])([CH3:21])[CH2:4]3)[C:14]([C:15]#[N:16])=[CH:13][N:12]=2)=[CH:29][CH:28]=1
Reactant: CC(F)(F)COc1ccc(CCN)cc1
Reactant: CC1(C)C[C@H](Nc2nc(S(C)(=O)=O)ncc2C#N)CC[C@@H]1O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(F)(F)COc1ccc(CCNc2ncc(C#N)c(N[C@@H]3CC[C@H](O)C(C)(C)C3)n2)cc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 30 %

Procedure:
A mixture of 4-(((1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl)amino)-2-(methylsulfonyl)pyrimidine-5-carbonitrile (90 mg, 0.28 mmol), 2-(4-(2,2-difluoropropoxyl)phenyl)ethanamine (70 mg crude) and DIEA (85 mg, 0.66 mmol) in THF (2 mL) was stirred at 100° C. in a microwave reactor for 1.5 h. After cooling to room temperature, the reaction mixture was concentrated and the residue was purified by standard methods to give the title product (38.6 mg, 0.084 mmol, 28% yield). 1H NMR (400 MHz, CD3OD) δ (ppm) 8.15-7.97 (m, 1H), 7.15 (d, J=8.4 Hz, 2H), 6.87 (d, J=8.4 Hz, 2H), 4.39-4.22 (m, 1H), 4.12 (t, J=11.6 Hz, 2H), 3.66-3.49 (m, 2H), 3.41-3.35 (m, 1H), 2.88-2.77 (t, J=7.2 Hz, 2H), 1.96-1.82 (m, 1H), 1.80-1.42 (m, 8H), 1.03-0.95 (m, 6H). MS (ESI) m/z 460.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:26])=[C:4]([CH2:8][N:9]2[C:14]3[N:15]=[C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[S:17][C:13]=3[C:12](=[O:24])[NH:11][C:10]2=[S:25])[CH:5]=[CH:6][CH:7]=1.[CH3:27]I>O1CCCC1>[Cl:1][C:2]1[C:3]([CH3:26])=[C:4]([CH2:8][N:9]2[C:14]3[N:15]=[C:16]([N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)[S:17][C:13]=3[C:12](=[O:24])[N:11]=[C:10]2[S:25][CH3:27])[CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: Cc1c(Cl)cccc1Cn1c(=S)[nH]c(=O)c2sc(N3CCOCC3)nc21
Solvent: C1CCOC1
Product: CSc1nc(=O)c2sc(N3CCOCC3)nc2n1Cc1cccc(Cl)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a vial containing 4-[(3-chloro-2-methylphenyl)methyl]-2-(4-morpholinyl)-5-thioxo-5,6-dihydro[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one (25 mg, 0.061 mmol) in Tetrahydrofuran (THF) (607 μl) was added methyl iodide (4.20 μl, 0.067 mmol). The mixture was stirred at room temperature overnight then concentrated. The residue was purified by reversed-phase HPLC to provide 4-[(3-chloro-2-methylphenyl)methyl]-5-(methylthio)-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one. (6 mg, 23%); LC/MS: MS (ES+) m/e 423 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.44 (s, 3H), 2.47 (s, 3H), 3.52 (m, 4H), 3.63-3.73 (m, 4H), 5.50 (s, 2H), 6.61 (d, J=7.6 Hz, 1H), 7.16 (m, 1H), 7.38 (d, J=7.8 Hz, 1H).
Reaction SMILES: [ClH:1].Cl.[CH2:3]([N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:16][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[ClH:16].[ClH:1].[CH2:3]([N:10]1[CH2:15][CH2:14][N:13]([CH2:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])[CH2:12][CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=C(CCl)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(CN1CCN(Cc2ccccc2)CC1)c1ccccc1
Yield: 67 %

Procedure:
A mixture of N-benzyl-piperazine dihydrochloride (20 mmol, prepared by using the general preparation 3, yield 70%), 2-chloro-1-phenylethanone (24 mmol), K2CO3 (70 mmol) and KI(2 mmol) in 100 ml of acetone was treated according to the general preparation 2 to give N1-benzyl-N4-phenacyl piperazine dihydrochloride (67%).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([N:5]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16]C)[CH2:6]1)=[O:4].B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:19][C:2]([F:1])([F:18])[C:3]([N:5]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])[CH2:6]1)=[O:4]
Reactant: COc1ccccc1C1CCN(C(=O)C(F)(F)F)C1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(N1CCC(c2ccccc2O)C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To the title compound of Example 43 Step A (1.2 g, 4.4 mmol) in CH2Cl2 (15 mL) at 0° C. was added BBr3 (1 M in CH2Cl2, 9.8 mL, 9.8 mmol). After warming to rt and allowing to stir for 18 h, sat'd NaHCO3 (aq.) was added slowly. The reaction was then extracted with CH2Cl2. The combined organic layers were dried and used in the next step without further purification. MS (ESI): mass calcd. for C12H12F3NO2, 259.2; m/z found, 260.1 [M+H]+. 1H NMR (CDCl3): 7.22-7.11 (m, 2H), 6.97-6.88 (m, 1H), 6.87-6.77 (m, 1H), 4.26-4.14 (m, 1H), 4.04-3.94 (m, 0.5H), 3.93-3.84 (m, 0.5H), 3.82-3.71 (m, 1H), 3.70-3.53 (m, 2H), 2.44-2.26 (m, 1.5H), 2.25-2.13 (m, 0.5H).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[CH:16]([OH:31])[C:17]([C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)([OH:24])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[CH:16]([O:31][S:33]([CH3:32])(=[O:35])=[O:34])[C:17]([C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)([OH:24])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCCC(O)(c1cccnc1)C(O)c1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCC(O)(c1cccnc1)C(OS(C)(=O)=O)c1ccc(Cl)cc1Cl
Yield: 50.6 %

Procedure:
23.6 ml (177 mmol) of triethylamine were added dropwise to a mixture of 8.5 g (23 mmol) of 1-(2,4-dichlorophenyl)-2-(pyrid-3-yl)-octane-1,2-diol, 2.5 ml (32 mmol) of methanesulfonyl chloride and 100 ml of methylene chloride at about 20° C. Thereafter, the mixture was washed with 30 ml of saturated sodium bicarbonate solution and 30 ml of water and was worked up in a conventional manner to obtain the product. The crude product was purified by chromatography. Yield: 50.6%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:25]([OH:27])=O)[CH2:10][CH2:11][CH2:12][CH:13]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[NH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:29]([O:36][C:37](=[O:43])[C@@H:38]1[CH2:42][CH2:41][CH2:40][NH:39]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH2:29]([O:36][C:37](=[O:43])[C@@H:38]1[CH2:42][CH2:41][CH2:40][N:39]1[C:25](=[O:27])[C@H:9]([CH2:10][CH2:11][CH2:12][CH:13]([C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])[NH2:14])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCC(N)C(=O)OCc1ccccc1)C(=O)O
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CCCC(N)C(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 8 h

Procedure:
All the obtained oily t-butyloxycarbonyl-ε-carbobenzoxy-L-lysine and L-proline benzylester hydrochloride (4.3 g, 17.8 m mole) were dissolved in methylene dichloride and WSC (3.3 ml, 17.8 m mole) was added thereto while cooling to -15° C. The mixture was stirred overnight and the methylene dichloride was distilled off under reduced pressure. The residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with 1N hydrochloric acid, 5% sodium bicarbonate and water in order, and dried with anhydrous sodium sulfate. The ethyl acetate was distilled off under reduced pressure to obtain an oily t-butyloxycarbonyl-ε-carbobenzoxy-L-lysyl-L-proline benzylester.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:49][C:50]([F:66])([F:65])[O:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[C:58]1[CH:63]=[CH:62][CH:61]=[C:60]([NH2:64])[CH:59]=1>CN(C=O)C>[F:49][C:50]([F:65])([F:66])[O:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[C:58]1[CH:63]=[CH:62][CH:61]=[C:60]([NH:64][C:22]([C:17]2[C:18](=[O:21])[O:19][C:20]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[OH:10])=[O:24])[CH:59]=1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: Nc1cccc(-c2ccccc2OC(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2ccccc2OC(F)(F)F)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Yield: 65.3 %

Procedure:
DIEA (0.011 mL, 0.065 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.012 g, 0.059 mmol) and HATU (0.025 g, 0.065 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 2′-trifluoromethoxy-biphenyl-3-ylamine (0.015 g, 0.059 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.017 g of product in 63% yield: LCMS (ESI) m/z 442 (MH+).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[C:4]([C:14]2[CH:15]=[C:16](B3OC(C)(C)C(C)(C)O3)[CH:17]=[CH:18][CH:19]=2)=[CH:3][CH:2]=1.[Br:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32](Br)[CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.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>[Br:29][C:30]1[CH:31]=[C:32]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:4]3[C:5]4[S:6][C:7]5[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=5[C:9]=4[CH:1]=[CH:2][CH:3]=3)[CH:15]=2)[CH:33]=[CH:34][CH:35]=1
Reactant: CC1(C)OB(c2cccc(-c3cccc4c3sc3ccccc34)c2)OC1(C)C
Reactant: Brc1cccc(Br)c1
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: O
Solvent: Cc1ccccc1
Product: Brc1cccc(-c2cccc(-c3cccc4c3sc3ccccc34)c2)c1
Yield: 79.3 %

Procedure:
2-(3-(dibenzo[b,d]thiophen-4-yl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (8.80 g, 22.78 mmol) and 1,3-dibromobenzene (21.49 g, 91 mmol) were dissolved in toluene (300 mL), and potassium carbonate (9.44 g, 68.3 mmol) in 50 mL of water and the Pd(PPh3)4 catalyst (0.263 g, 0.228 mmol) were then added. The reaction mixture was degassed and refluxed under N2 overnight. The organic layer was then separated, evaporated and subjected to column chromatography on silica gel, eluted with hexane/DCM 9:1 v/v mixture, providing 4-(3′-bromo-[1,1′-biphenyl]-3-yl)dibenzo[b,d]thiophene (7.5 g, 18.06 mmol, 79% yield) as white solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([O:10][C:11]3[N:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13]([OH:15])=O)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([OH:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=1>>[S:1]1[C:5]2[CH:6]=[C:7]([O:10][C:11]3[N:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([OH:31])([CH3:29])[CH3:30])=[CH:24][CH:23]=3)=[O:15])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1cccnc1Oc1ccc2ncsc2c1
Reactant: CC(C)(O)c1ccc(CN)cc1
Product: CC(C)(O)c1ccc(CNC(=O)c2cccnc2Oc2ccc3ncsc3c2)cc1

Procedure:
Prepared from 2-(Benzothiazol-6-yloxy)-nicotinic acid and 2-(4-aminomethyl-phenyl)-propan-2-ol. mp195-7° C.
Reaction SMILES: [CH2:1]([N:5]([CH2:26][CH2:27][CH2:28][CH3:29])[C:6]1[CH:18]=[C:17]2[C:9]([C:10]3[CH:11]=[CH:12][C:13]([C:19]4[S:23][C:22]([CH:24]=O)=[CH:21][CH:20]=4)=[CH:14][C:15]=3[CH2:16]2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:30]([CH2:32][C:33]([OH:35])=[O:34])#[N:31].N1CCCCC1>C(#N)C>[C:30]([C:32](=[CH:24][C:22]1[S:23][C:19]([C:13]2[CH:12]=[CH:11][C:10]3[C:9]4[C:17](=[CH:18][C:6]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:26][CH2:27][CH2:28][CH3:29])=[CH:7][CH:8]=4)[CH2:16][C:15]=3[CH:14]=2)=[CH:20][CH:21]=1)[C:33]([OH:35])=[O:34])#[N:31]
Reactant: N#CCC(=O)O
Reactant: CCCCN(CCCC)c1ccc2c(c1)Cc1cc(-c3ccc(C=O)s3)ccc1-2
Solvent: C1CCNCC1
Solvent: CC#N
Product: CCCCN(CCCC)c1ccc2c(c1)Cc1cc(-c3ccc(C=C(C#N)C(=O)O)s3)ccc1-2
Temperature: 90 °C

Procedure:
Under N2 atmosphere, 0.18 parts of 5-(7-dibutylamino-9H-fluoren-2-yl)-thiophene-2-carbaldehyde (12a), 0.05 parts of cyanoacetic acid, and 0.017 parts of piperidine were added into acetonitrile, followed by stirring and mixing. Then, the reaction mixture was heated to 90° C. and reacted for 6 hours. After the reaction mixture was cooled to room temperature, the reaction mixture was filtrated to obtain a solid. Then, the solid was washed with water, ether, and acetonitrile sequentially to obtain a dark red solid. Finally, this crude was purified with column chromatography method by using dichloromethane/methanol co-solvent as an eluent, to obtain a compound (13a) of the present example. This compound was in a form of a dark red solid, and the yield of this compound was 73%.
Reaction SMILES: [CH2:1]([P:4]([CH3:9])(=[O:8])[O:5][CH2:6][CH3:7])[CH:2]=[CH2:3].C(=O)(O)[O-].[Na+].[Br:15][C:16](Br)=[N:17][OH:18]>C(OCC)(=O)C.O>[Br:15][C:16]1[CH2:3][CH:2]([CH2:1][P:4]([CH3:9])(=[O:8])[O:5][CH2:6][CH3:7])[O:18][N:17]=1
Reactant: C=CCP(C)(=O)OCC
Reactant: ON=C(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOP(C)(=O)CC1CC(Br)=NO1

Procedure:
20 g (0.135 mol) of ethyl allyl(P-methyl)phosphinate are dissolved in 570 ml of ethyl acetate, 49.7 g (0.6 mol) of sodium bicarbonate in 115 ml of water are added and, while stirring vigorously, a solution of 40.6 g (0.2 mol) of dibromoformaldoxime in 115 ml of ethyl acetate is slowly added dropwise. The product is isolated in the form of an oil, 15 g from the ethyl acetate phase, and a further 19 g from the aqueous phase by extraction with dichloromethane at pH 2.
Reaction SMILES: Cl.FC(F)(F)CC[N:6]1[CH2:15][CH2:14][C:13]2[C:12]([NH:16][C:17]3[CH:26]=[CH:25][C:20]4[O:21][CH2:22][CH2:23][O:24][C:19]=4[CH:18]=3)=[N:11][CH:10]=[N:9][C:8]=2[CH2:7]1.[C:29]1([CH3:38])[CH:34]=[CH:33][CH:32]=[C:31](B(O)O)[CH:30]=1.C(N(CC)CC)C>C1COCC1.CC([O-])=O.CC([O-])=O.[Cu+2]>[O:21]1[CH2:22][CH2:23][O:24][C:19]2[CH:18]=[C:17]([NH:16][C:12]3[C:13]4[CH2:14][CH2:15][N:6]([C:31]5[CH:30]=[C:29]([CH3:38])[CH:34]=[CH:33][CH:32]=5)[CH2:7][C:8]=4[N:9]=[CH:10][N:11]=3)[CH:26]=[CH:25][C:20]1=2
Reactant: Cc1cccc(B(O)O)c1
Reactant: FC(F)(F)CCN1CCc2c(ncnc2Nc2ccc3c(c2)OCCO3)C1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cccc(N2CCc3c(ncnc3Nc3ccc4c(c3)OCCO4)C2)c1
Reaction time: 6 h
Yield: 9.6 %

Procedure:
5,6,7,8-Tetrahydro-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyrido[3,4-d]pyrimidin-4-amine from Example 7 (110 mg, 0.39 mmol) was dissolved in anhydrous THF (2 mL). To the mixture was added m-tolylboronic acid (105 mg, 0.78 mmol), Cu(OAc)2 (141 mg, 0.78 mmol) and triethylamine (0.68 g, 0.095 mL) and 390 mg of crushed, activated 4A moleculer seives. The mixture was agitated for 6 h and the solvent was removed under vacuum. The residue was purified using a gradient of ethyl acetate:hexane (0-100%) to give the desired compound as reddish powder (14 mg, 9.6%).
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:20][C:21](=O)[CH3:22]>CN(C)C=O>[CH3:1][N:2]([CH3:10])[C:3]1[CH:8]=[CH:7][C:6]2[C:21]([CH3:22])=[CH:20][O:9][C:5]=2[CH:4]=1
Reactant: CC(=O)CCl
Reactant: CN(C)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1coc2cc(N(C)C)ccc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 20.1 %

Procedure:
140 g of 3-dimethylaminophenol are dissolved in 700 ml of dimethylformamide. 152 g of potassium carbonate and 28 g of potassium iodide are added. 101.8 g of chloroacetone are then added dropwise in the course of one hour; afterwards the mixture is stirred at room temperature for 20 hours. The reaction solution is filtered and the dimethylformamide and unconverted chloroacetone are distilled off (30° C., 1 mm Hg). Water is added to the residue, and the mixture is basified with concentrated sodium hydroxide solution and filtered. The crude product is taken up in 1 litre of ethanol, 115 ml of concentrate hydrochloric acid are added, and the mixture is heated to 80° C. 40 hours later the mixture is cooled down, treated with active carbon and filtered. The alcohol is removed, water is added to the residue, and the mixture is basified with concentrated sodium hydroxide solution. The crude product is filtered off and recrystallized from a mixture of hexane and diethyl ether (10:1) to give 36 g of 6-dimethylamino-3-methylbenzofurane.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].C([BH3-])#N.[Na+].C(OC)(OC)OC.[Si:19]([O:26][CH2:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[CH:34]=[C:33]([CH2:38][CH2:39][CH:40]=O)[CH:32]=[CH:31]2)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>CO>[Si:19]([O:26][CH2:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[CH:34]=[C:33]([CH2:38][CH2:39][CH2:40][N:4]([CH2:5][CH2:6][CH3:7])[CH2:1][CH2:2][CH3:3])[CH:32]=[CH:31]2)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CCCNCCC
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc2cc(CCC=O)ccc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CO
Product: CCCN(CCC)CCCc1ccc2cc(CO[Si](C)(C)C(C)(C)C)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.6 %

Procedure:
Dipropylamine (363 mg) was dissolved in anhydrous methanol (20 ml) and then added with sodium cyanoborohydride (281 mg), trimethyl orthoformate (0.490 ml), and the compound (981 mg) obtained in Example 121-7, followed by stirring overnight at room temperature under a nitrogen atmosphere. After completion of the reaction, the solvent was distilled off. Then, the residue was dissolved in chloroform and added with a saturated aqueous sodium bicarbonate solution, followed by stirring. The solution was extracted with chloroform and the extract was then washed with a saturated aqueous sodium bicarbonate solution and saturated saline solution. After that, the organic layer was dried with anhydrous sodium sulfate. Subsequently, the solvent was distilled off and the residue was then purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (1.28 g) as a brown liquid.