Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([Br:18])[C:6]([Br:17])=[C:7]3[C:15](=[O:16])[O:14][C:12](=[O:13])[C:8]3=2)[C:3]=1[Br:19].C12C(=O)OC(=[O:31])C1=CC=C1C=2C=CC=C1.BrBr>>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([Br:18])[C:6]([Br:17])=[C:7]([C:15]([OH:14])=[O:16])[C:8]=2[C:12]([OH:31])=[O:13])[C:3]=1[Br:19]
Reactant: O=C1OC(=O)c2c1ccc1ccccc21
Reactant: O=C1OC(=O)c2c1c(Br)c(Br)c1c(Br)c(Br)ccc21
Agent: BrBr
Product: O=C(O)c1c(Br)c(Br)c2c(Br)c(Br)ccc2c1C(=O)O

Procedure:
Tetrabromonaphthalene-1,2-dicarboxylic anhydride: 2.0 g of naphthalene-1,2-dicarboxylic anhydride, 0.05 g of ferrum reductum and 5.2 ml of bromine are heated at 210° C. for 6 hours using a long intensive condenser. Working up analogously to Example 61a) gives 5.0 g of tetrabromonaphthalene-1,2-dicarboxylic acid, which is converted into the anhydride with acetic anhydride. Yield: 4.8 g (94%), bromine content: 62.4% (theoretical 62.7%).
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+].[CH:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([C:24]([CH2:26]Br)=[O:25])[CH:18]=1>CC(C)=O>[Cl:23][C:21]1[CH:20]=[C:19]([C:24](=[O:25])[CH2:26][O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([N:2]([CH3:10])[CH3:1])[CH:4]=2)[CH:18]=[CH:17][CH:22]=1
Reactant: O=C(CBr)c1cccc(Cl)c1
Reactant: CN(C)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN(C)c1cccc(OCC(=O)c2cccc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 47.3 %

Procedure:
A slurry of 3.0 g of 3-dimethylaminophenol, 6.05 g of milled potassium carbonate and 75 ml of acetone was stirred at room temperature under nitrogen for 30 minutes and then a solution of 7.66 g of α-bromo-3-chloroacetophenone in 75 ml of acetone was added dropwise. The slurry was stirred at room temperature for 72 hours. Filtration and evaporation gave a residue which was purified by high performance liquid chromatography (7:1 hexane-ethyl acetate). The resulting solid was recrystallized from ethyl acetate-hexane to give 3.0 g of 1-(3-chlorophenyl)-2-[3-(dimethylamino)phenoxy]ethanone, m.p. 101°-103° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH:8]1([NH:11][C:12]([N:14]2[C:22]3[C:17](=[CH:18][C:19]([O:23][C:24]4[CH:29]=[CH:28][N:27]=[C:26]([N:30](C(OC5C=CC=CC=5)=O)[C:31](=[O:39])OC5C=CC=CC=5)[CH:25]=4)=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)=[O:13])[CH2:10][CH2:9]1.C1(NC(N2C3C(=CC(OC4C=CN=C(NC(N5CCC(N6CCCC6)CC5)=O)C=4)=CC=3)C=C2)=O)CC1>CN(C)C=O>[CH:8]1([NH:11][C:12]([N:14]2[C:22]3[C:17](=[CH:18][C:19]([O:23][C:24]4[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C:31]([N:5]5[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]5)=[O:39])[CH:25]=4)=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)=[O:13])[CH2:10][CH2:9]1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc3c(ccn3C(=O)NC3CC3)c2)ccn1
Reactant: OC1CCNCC1
Agent: O=C(Nc1cc(Oc2ccc3c(ccn3C(=O)NC3CC3)c2)ccn1)N1CCC(N2CCCC2)CC1
Solvent: CN(C)C=O
Product: O=C(Nc1cc(Oc2ccc3c(ccn3C(=O)NC3CC3)c2)ccn1)N1CCC(O)CC1
Reaction time: 8 h
Yield: 59.5 %

Procedure:
N,N-Dimethylformamide (5 ml) and 4-hydroxypiperidine (433 mg, 4.29 mmol) were added to a mixture (470 mg) of phenyl N-(4-(1-cyclopropylaminocarbonyl-1H-5-indolyl)oxy-2-pyridyl)-N-(phenoxycarbonyl)carbamate and phenyl N-(4-(1-cyclopropylaminocarbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamate obtained in Example 68; the reaction mixture was stirred overnight; the reaction mixture was partitioned between ethyl acetate and water; and the organic layer was concentrated to yield the title compound as white crystals (220 mg, 0.51 mmol, 39%).
Reaction SMILES: [F:1][C:2]1[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)=[CH:18][C:17]([CH3:27])=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]([OH:14])[C:8]=1[CH3:15])=O>C1COCC1>[F:1][C:2]1[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)=[CH:18][C:17]([CH3:27])=[CH:16][C:3]=1[CH2:4][NH:6][C:7]1[C:8]([CH3:15])=[C:9]([OH:14])[CH:10]=[CH:11][C:12]=1[CH3:13]
Reactant: Cc1cc(C(=O)Nc2c(C)ccc(O)c2C)c(F)c(-c2cccc(F)c2)c1
Solvent: C1CCOC1
Product: Cc1cc(CNc2c(C)ccc(O)c2C)c(F)c(-c2cccc(F)c2)c1
Temperature: 60 °C
Yield: 38.9 %

Procedure:
To a solution of 2-fluoro-3-(3-fluorophenyl)-N-(3-hydroxy-2,6-dimethyl-phenyl)-5-methyl-benzamide (588 mg, 1.6 mmol, 1.0 eq) in THF (10 mL) at 0° C. under N2 was added a solution of BH3 (1M in THF, 9.6 mL, 9.6 mmol, 6.0 eq) dropwise. The reaction mixture was heated at 60° C. overnight. The reaction was cooled to room temperature, quenched with H2O and extracted with EtOAc. The combined organic layers were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum ether:EtOAc, 50:1 to 20:1) to give the title compound as white solid (220 mg, 39%)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:5]=[CH:4][C:3]=1[CH2:16][OH:17]>[O-2].[O-2].[Mn+4].C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:5]=[CH:4][C:3]=1[CH:16]=[O:17]
Reactant: Cc1cc(OCc2ccccn2)ccc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: Cc1cc(OCc2ccccn2)ccc1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
To 0.72 g of [2-methyl-4-(2-pyridylmethoxy)phenyl]methanol were added 30 mL of CHCl3 and 7.2 g of manganese dioxide, and the mixture was stirred at room temperature for 2 hours. Insoluble matter was filtered off from the reaction mixture, and the mother liquor was concentrated to give 0.70 g of the title compound (99% yield).
Reaction SMILES: [C:1]([C:7]([O:9][CH3:10])=[O:8])#[C:2][C:3]([O:5][CH3:6])=[O:4].[Si]([CH:15]=[N+:16]=[N-:17])(C)(C)C.Cl>C1COCC1>[NH:16]1[CH:15]=[C:2]([C:3]([O:5][CH3:6])=[O:4])[C:1]([C:7]([O:9][CH3:10])=[O:8])=[N:17]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COC(=O)C#CC(=O)OC
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)c1c[nH]nc1C(=O)OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 111.9 %

Procedure:
To a solution of dimethyl acetylenedicarboxylate (1.73 mL, 14.07 mmol) in THF (65 mL) at 0° C. was added dropwise TMS-diazomethane (7.74 mL, 15.48 mmol, 2M/hexanes) and the mixture was allowed to warm to ambient temperature in 2 h. After 18 h, 1M hydrochloric acid (10 mL) was added until bubbling stopped and stirring at ambient temperature continued for 30 min. The mixture was diluted with EtOAc and washed with saturated sodium bicarbonate/water. The organic layer was dried over sodium sulfate and concentrated to provide the title compound as a yellowish solid (2.9 g, 99%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.95 (s, 1H), 8.2 (s, 1H), 3.8 (s, 3H), 3.7 (s, 3H); ES-LCMS: 184.9 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C([O:11][CH:12]=[C:13]([C:19](OCC)=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])C.C1(OC2C=CC=CC=2)C=CC=CC=1>C(O)C>[OH:11][C:12]1[C:3]2[C:2](=[CH:7][CH:6]=[CH:5][C:4]=2[OH:8])[N:1]=[CH:19][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1cccc(O)c1
Solvent: CCO
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2cccc(O)c2c1O
Temperature: 80 °C

Procedure:
A mixture of 3-aminophenol (5.457 g) and diethyl ethoxymethylenemalonate (10.81 g) is heated to 130° C. for 2 h with removal of ethanol by a Dean-Stark trap. The reaction is cooled to 80° C. and 50 ml of diphenyl ether is added. The mixture is heated to 250° C. for 30 min with removal of ethanol by a Dean-Stark trap. The solution is cooled to 80° C. and the resulting solid is collected and washed with hexanes. A portion of this solid is adsorbed onto silica and chromatographed, eluting with 5% MeOH/CH2Cl2. Fractions homogeneous by TLC are combined and concentrated in vacuo to yield ethyl 4,5-dihydroxyquinoline-3-carboxylate as a gold solid. A mixture of this ester (0.125 g) and 4-chlorobenzylamine (0.379 g) are heated to 180° C. for 1 h. The solution is cooled to room temperature. The crude reaction is chromatographed on silica, eluting with 2% MeOH/CH2Cl2. Fractions homogeneous by TLC are combined and concentrated in vacuo. The residue is sonicated with CH2Cl2 /hexanes. The resulting solid is collected and dried to yield 0.050 g of the desired product as a pale-yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>N1C=CC=CC=1>[CH:10]1([CH2:9][O:8][C:7]2[CH:6]=[CH:5][C:4]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:3][C:2]=2[NH:1][S:19]([CH3:18])(=[O:21])=[O:20])[CH2:11][CH2:12]1
Reactant: COC(=O)Cc1ccc(OCC2CC2)c(N)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COC(=O)Cc1ccc(OCC2CC2)c(NS(C)(=O)=O)c1
Yield: 94.3 %

Procedure:
To a solution of crude methyl 2-(3-amino-4-(cyclopropylmethoxy)phenyl)acetate (theoric 4.74 mmol) in pyridine (50 ml), methanesulfonyl chloride (0.406 ml, 5.10 mmol) was added, and the mixture was reacted for 3 hours at RT. The solvent was evaporated to dryness, and the residue was partitioned between EtOAc and HCl 1N; the aqueous phase was extracted with EtOAc (3×), and the combined organic layers were dried over Na2SO4. The solvent was removed under vacuum affording methyl 2-(4-(cyclopropylmethoxy)-3-(methylsulfonamido)phenyl)acetate (1.4 g, 4.47 mmol, 94.3% yield over 3 steps, MS/ESI+ 313.9 [MH]+). This intermediate was used without any additional purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.Br[C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][N:16]([C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][C:31]=1[CH3:32])[C:25]([O:27][CH3:28])=[O:26])[C:15]2=[O:33]>>[CH3:32][C:31]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=1[N:16]1[C:15](=[O:33])[C:14]2[C:19](=[CH:20][CH:21]=[C:12]([N:8]3[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:6][CH2:7]3)[CH:13]=2)[N:18]=[CH:17]1
Reactant: COC(=O)c1ccc(C)c(-n2cnc3ccc(Br)cc3c2=O)c1
Reactant: COCCN1CCNCC1
Product: COCCN1CCN(c2ccc3ncn(-c4cc(C(=O)OC)ccc4C)c(=O)c3c2)CC1

Procedure:
Using an analogous procedure to that described paragraph (B) in the portion of Example 1 which is concerned with the preparation of starting material N-(2-methoxyethyl)piperazine was reacted with methyl 3-(6-bromo-4-oxoquinazolin-3(4H)-yl)-4-methylbenzoate to give methyl 4-methyl-3-[6-(4-(2-methoxyethyl)piperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]benzoate; NMR Spectrum: (DMSOd6) 2.18 (s, 3H), 2.55 (t, 2H), 2.60 (m, 4H), 3.25 (s, 3H), 3.27 (m, 4H), 3.50 (t, 2H), 3.88 (s, 3H), 7.47 (s, 1H), 7.62 (m, 3H), 7.97 (s, 1H), 8.01 (m, 1H), 8.09 (s, 1H); Mass Spectrum: M+H+ 437.
Reaction SMILES: [CH2:1]([N:11]1[C:15](=[O:16])[CH:14]=[CH:13][C:12]1=[O:17])[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.[C:18]([C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1)#[N:19].[NH2:28][C@H:29](C(O)=O)[CH2:30][OH:31]>>[O:7]1[C:8]2[CH:9]=[CH:10][C:2]([CH2:1][N:11]3[C:12](=[O:17])[CH:13]4[CH:29]([CH2:30][OH:31])[NH:28][CH:24]([C:23]5[CH:26]=[CH:27][C:20]([C:18]#[N:19])=[CH:21][CH:22]=5)[CH:14]4[C:15]3=[O:16])=[CH:3][C:4]=2[O:5][CH2:6]1
Reactant: O=C1C=CC(=O)N1Cc1ccc2c(c1)OCO2
Reactant: N[C@@H](CO)C(=O)O
Reactant: N#Cc1ccc(C=O)cc1
Product: N#Cc1ccc(C2NC(CO)C3C(=O)N(Cc4ccc5c(c4)OCO5)C(=O)C23)cc1

Procedure:
7.B)r) (1RS,3SR,3aRS,6aSR)-4-[5-(Benzo[1,3]dioxol-5-ylmethyl)-3-hydroxymethyl-4,6-dioxo-octahydro-pyrrolo[3,4-c]pyrrol-1-yl]-benzonitrile was prepared from N-piperonylmaleimide, 4-cyano-benzaldehyde and L-serine analogously to Example 4.B)g). ISP-MS: 406 ([M+H]+, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:13][CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18].O>N1C=CC=CC=1>[Cl:13][CH2:14][CH2:15][CH2:16][C:17]([NH:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:18]
Reactant: O=C(Cl)CCCCl
Reactant: CCOC(=O)c1ccccc1N
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)c1ccccc1NC(=O)CCCCl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 2-aminobenzoate (5 g) in pyridine (50 mL) was added 4-chlorobutanoyl chloride (3.6 mL) at 0° C., and the mixture was warmed to room temperature and stirred overnight. The reaction mixture was poured into water, and the mixture was partitioned twice with ethyl acetate. The organic layers were combined, and the mixture was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (8.03 g).
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([C:15](=O)C)=[CH:11][CH:10]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:18]([O-])=O.[NH4+:21].[ClH:22]>O>[ClH:22].[CH3:18][NH:21][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:10][CH:11]=1
Reactant: [NH4+]
Reactant: O=C[O-]
Reactant: CC(=O)c1ccc(CCc2ccccc2)cc1
Agent: Cl
Solvent: O
Product: CNCc1ccc(CCc2ccccc2)cc1
Yield: 73 %

Procedure:
A mixture of 87.5 g (0.39 mole) of 4'-phenethylacetophenone, M.P. 67°-70° C., prepared according to R. E. Lutz et al., J. Org. Chem. 12, 617 (1947), and 98.5 g (1.56 mole) of ammonium formate is slowly heated to 150° C. with stirring. After the initial foaming has subsided the temperature of the heating bath is raised to 185°-190° C. for a period of 4 hours. Upon cooling, the mixture is treated with several portions of water. To the residue is added 75 ml of concentrated HCl. The mixture is refluxed for 2 hours and is allowed to cool. The resulting solid is collected, washed with several portions of benzene and is recrystallized from isopropanol containing about 5% of water to yield 74.0 g (73% yield) of the desired product, M.P. 212°-214° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:30])[CH:20]=[C:21]([C:22]4[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[Cl:29][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([Cl:28])[C:22]=1[C:21]1[C:15]2[O:14][CH:13]([CH2:12][N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[CH2:17][C:16]=2[CH:18]=[C:19]([F:30])[CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(F)cc(-c4c(Cl)cccc4Cl)c3O2)cc1
Reactant: C1CCNCC1
Product: Fc1cc2c(c(-c3c(Cl)cccc3Cl)c1)OC(CN1CCCCC1)C2

Procedure:
The title compound was prepared (0.074 g, 69%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-([5-fluoro-7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.12 g, 0.26 mmol) and piperidine (0.22 g, 2.6 mmol). mp 184-186° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH:11]=O)[S:8][C:6]=2[N:7]=1.[CH3:19][N:20]([CH3:29])[C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22]>>[CH3:19][N:20]([CH3:29])[C:21]([N:23]1[CH2:24][CH2:25][N:26]([CH2:11][C:9]2[S:8][C:6]3[N:7]=[C:2]([Cl:1])[N:3]=[C:4]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)[C:5]=3[CH:10]=2)[CH2:27][CH2:28]1)=[O:22]
Reactant: CN(C)C(=O)N1CCNCC1
Reactant: O=Cc1cc2c(N3CCOCC3)nc(Cl)nc2s1
Product: CN(C)C(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1

Procedure:
Reaction between 2-chloro-4-morpholin-4-yl-thieno[2,3-d]pyrimidine-6-carbaldehyde (General Procedure D-2) and piperazine-1-carboxylic acid dimethylamide using General Procedure B-3 yielded 4-(2-chloro-4-morpholin-4-yl-thieno[2,3-d]pyrimidin-6-ylmethyl)-piperazine-1-carboxylic acid dimethylamide.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([NH2:13])=[O:12])=[CH:5][CH:4]=1.[Cl:16][CH2:17][C:18]([CH2:20]Cl)=O.O>C1(C)C=CC=CC=1>[Cl:16][CH2:17][C:18]1[N:13]=[C:11](/[CH:10]=[CH:9]/[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:14])([F:15])[F:1])=[CH:8][CH:7]=2)[O:12][CH:20]=1
Reactant: NC(=O)/C=C/c1ccc(C(F)(F)F)cc1
Reactant: O=C(CCl)CCl
Solvent: O
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccc(/C=C/c2nc(CCl)co2)cc1
Yield: 63.1 %

Procedure:
A solution of (E)-3-(4-trifluoromethylphenyl)-2-propenamide (17.9 g) and 1,3-dichloroacetone (14.8 g) in toluene (83 ml) was refluxed under heating for 9 hours using a Dean-Stark apparatus. After cooling, water was added; the reaction mixture was extracted with ethyl acetate and washed with saturated saline, after which it was dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (eluent: hexane-methyl acetate=6:1→5:1) to yield the titled compound (15.1 g) as a colorless needle crystal.
Reaction SMILES: [C:1](#[N:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:11][C:12]1[NH:16][N:15]=[C:14]([NH2:17])[CH:13]=1.[CH3:18][O:19][CH2:20][CH2:21][NH2:22]>>[CH3:18][O:19][CH2:20][CH2:21][NH:22][C:3]1[CH:2]=[C:1]([NH:17][C:14]2[CH:13]=[C:12]([CH3:11])[NH:16][N:15]=2)[N:10]=[C:1]([CH:2]=[CH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:10]=1
Reactant: COCCN
Reactant: Cc1cc(N)n[nH]1
Reactant: N#CC=Cc1ccccc1
Product: COCCNc1cc(Nc2cc(C)[nH]n2)nc(C=Cc2ccccc2)n1

Procedure:
Example 163 was synthesized via Scheme 6 according to the general scheme provided above with the appropriate starting materials cinnamonitrile, 5-methyl-1H-pyrazole-3-amine, and 2-methoxyethanamine. Structure of the target was confirmed by 1H-NMR. The 1H-NMR is attached.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[O:9][CH:10]([C:13]([F:16])([F:15])[F:14])[CH2:11][OH:12].[CH2:17]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:33]=[N:34][C:35](Cl)=[CH:36][CH:37]=2)=[CH:28][CH:27]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C1(C)C=CC=CC=1>[CH2:17]([C:26]1[CH:27]=[CH:28][C:29]([C:32]2[N:33]=[N:34][C:35]([O:12][CH2:11][CH:10]([O:9][CH:4]3[CH2:5][CH2:6][CH2:7][CH2:8][O:3]3)[C:13]([F:14])([F:15])[F:16])=[CH:36][CH:37]=2)=[CH:30][CH:31]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: OCC(OC1CCCCO1)C(F)(F)F
Reactant: CCCCCCCCCc1ccc(-c2ccc(Cl)nn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCCCCCc1ccc(-c2ccc(OCC(OC3CCCCO3)C(F)(F)F)nn2)cc1

Procedure:
A mixture of sodium hydride (100 mg) with toluene (10 ml) was stirred under ice cooling, followed by gradually dropwise dropping a mixed solution of optically active 2-(2-tetrahydropyranyloxy)-3,3,3-trifluoro-1-propanol obtained in Example 3 (450 mg) with toluene (4 ml), stirring the mixture at room temperature for one hour, pouring a solution of 3-(4-nonylphenyl)-6-chloropyridazine (540 mg) in toluene (10 ml) in the mixture, stirring at 80° C. for 2 hours, extracting the reaction mixture with toluene, washing till the washing liquid became neutral, removing the solvent, purifying according to silica gel chromatography, and drying the residue by a vacuum pump, to obtain 3-(4-nonylphenyl)-6-(2-(2-tetrahydropyranyloxy)-3,3,3-trifluoropropoxy)pyridazine. Yield: 700 mg. m.p. 96.1° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7](=[O:16])[CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([Cl:15])[CH:10]=2)=[CH:4][CH:3]=1.CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>CN(C)C=O>[Cl:1][C:2]1[S:6][C:5]([C:7](=[O:16])[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([Cl:15])[CH:10]=2)=[CH:19][N:20]([CH3:22])[CH3:21])=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccnc(Cl)c1)c1ccc(Cl)s1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)C=C(C(=O)c1ccc(Cl)s1)c1ccnc(Cl)c1
Temperature: 25 °C
Yield: 63.8 %

Procedure:
To a suspension of 1-(5-chloro-2-thienyl)-2-(2-chloropyridin-4-yl)ethanone (15.8 mmol) in 10 mL N,N-dimethylformamide, was added N,N-dimethylformamide dimethyl acetal (53.7 mmol). The mixture was refluxed for 2 h and then allowed to cool to room temperature. The solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic extracts were dried over MgSO4 filtered and concentrated. The residue was purified by chromatography on silica gel (ethyl acetate:heptane 6:4 to 1:0) to afford 3.3 g (60% yield) of 1-(5-chloro-2-thienyl)-3-(dimethylamino)-2-(2-chloropyridin-4-yl)prop-2-en-1-one.
Reaction SMILES: Br[CH:2]([C:4]1[O:5][C:6](=[O:21])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3].[NH:22]1[C:26]2=[N:27][CH:28]=[N:29][C:30]([NH2:31])=[C:25]2[CH:24]=[N:23]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:31][C:30]1[N:29]=[CH:28][N:27]=[C:26]2[N:22]([CH:2]([C:4]3[O:5][C:6](=[O:21])[C:7]4[C:12]([C:13]=3[C:14]3[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=3)=[CH:11][CH:10]=[CH:9][CH:8]=4)[CH3:3])[N:23]=[CH:24][C:25]=12
Reactant: Cc1cc(-c2c(C(C)Br)oc(=O)c3ccccc23)ccn1
Reactant: Nc1ncnc2[nH]ncc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2c(C(C)n3ncc4c(N)ncnc43)oc(=O)c3ccccc23)ccn1
Yield: 3 %

Procedure:
The title compound was made in a similar way as that of the compound of example 15, 3-(1-bromoethyl)-4-(2-methylpyridin-4-yl)-1H-isochromen-1-one (intermediate C14, 98 mg, 0.285 mmol), 1H-pyrazolo[3,4-d]pyrimidin-4-amine (57.7 mg, 0.43 mmol) and K2CO3 (59 mg, 0.42 mmol) in DMF (2 ml) at 50° C. for 6 hrs to give the title compound (3.4 mg, 3%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]=1[C:14]#[N:15].[OH-:16].[Na+]>C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]=1[C:14]([NH2:15])=[O:16]
Reactant: N#Cc1c(N)cccc1-c1ccccc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1c(N)cccc1-c1ccccc1
Yield: 73 %

Procedure:
A solution of 3-aminobiphenyl-2-carbonitrile (4 g, 20 mmol) in ethanol (20 mL) and aqueous NaOH (8 g, 200 mmol) was heated at 100° C. in the microwave reactor for 1 h 30 min. After this time, the ethanol was evaporated under reduced pressure and the resulting residue was extracted with ethyl acetate. The organic extracts were concentrated under reduced pressure to yield a residue. The residue was purified by silica gel chromatography (50% EtOAc in hexane) to give 3-aminobiphenyl-2-carboxamide (3.1 g, 72% yield) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.40-7.30 (m, 5H), 7.15 (br s, 1H), 7.11 (t, 1H, J=8 Hz), 6.72 (dd, 1H, J=0.8, 8 Hz), 6.52 (dd, 1H, J=0.8, 8 Hz), 5.13 (s, 1H). LCMS Method W: retention time 1.28 min; [M+1]=213.0.
Reaction SMILES: CN(C)C=O.[CH2:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]2([CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[O:16]2)[CH2:8][NH:7]1.C(=O)(O)[O-].[Na+].Cl[CH2:30][C:31]#[N:32]>O>[C:31]([CH2:30][N:7]1[CH2:8][C:9]2([CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[O:16]2)[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6]1)#[N:32]
Reactant: c1ccc2c(c1)CC1(CNCc3ccccc31)O2
Reactant: N#CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCN1Cc2ccccc2C2(Cc3ccccc3O2)C1

Procedure:
To dry dimethylformamide is added spiro[benzofuran-2(3H),4'(2'H)-isoquinoline] (11.0 g), sodium bicarbonate (8.4 g) and chloroacetonitrile (6.8 g) and the mixture is heated to 70° for four hours. The dimethylformamide is evaporated to give an oil, which is stirred with water (300 ml) for 15 minutes and then extracted with ether/dichloromethane. The organic extract is washed with water (2X), saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. After filtering, the solvents are evaporated to an oil which solidifies to the product (10.6 g), 83%), as an off-white solid upon trituration with petroleum ether/ether. For analysis, a sample is recrystallized twice from hexane/acetone to yield platelets.