Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.O[C:8]([CH:11]1[C:14]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:13]2[CH2:12]1)([CH3:10])[CH3:9].P(Cl)(Cl)(Cl)=O.Cl>CCOCC>[C:8](=[C:11]1[C:14]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:13]2[CH2:12]1)([CH3:10])[CH3:9]
Reactant: CC(C)(O)C1Cc2ccccc21
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(C)=C1Cc2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.8 %

Procedure:
Into 30 ml of dried pyridine, was dissolved 1.78 g of 1-(1-hydroxy-1-methylethyl)benzocyclobutene. To the solution, was added dropwise 3.37 g of phosphorus oxychloride over a period of 5 minutes at room temperature. The mixture was stirred for 24 hours at room temperature, then poured into 3% aqueous cold hydrochloric acid solution and admixed with ether. After the ether layer was separated, the aqueous layer was extracted twice with ether. The ether layers were combined, washed with saturated aqueous sodium hydrogencarbonate solution, then with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain as the residue 1.5 g of a mixture of the intended product and 1-isopropenylbenzocyclobutene. This mixture was used without further purification as the starting material in the next step of preparation.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.BrN1C(=O)CCC1=O.O.[NH2:21]/[C:22](/[C:27]#[N:28])=[C:23](\[NH2:26])/[C:24]#[N:25]>CS(C)=O.CC(O)=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[C:7](=[O:11])[C:6]3[C:5]([C:4]=2[CH:3]=1)=[N:21][C:22]([C:27]#[N:28])=[C:23]([C:24]#[N:25])[N:26]=3
Reactant: N#C/C(N)=C(/N)C#N
Reactant: O=C1CCc2cc(Cl)ccc21
Agent: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1nc2c(nc1C#N)-c1cc(Cl)ccc1C2=O
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A mixture of 5-chloro-1-indanone (1.05 g, 6.28 mmol) and N-bromosuccinimide (2.23 g, 12.56 mmol) in DMSO (25 ml) was stirred overnight at 40° C. and 5 h at 80° C. under vacuum. Water (125 ml) was added and the mixture was extracted with CH2Cl2 (25 ml). The aqueous phase was saturated with brine and solid NaCl and extracted with CH2Cl2 (4×80 ml). The collected organic phases were dried over Na2SO4 and the solvent evaporated. The crude was dissolved in EtOH (63 ml), diaminomaleonitrile (678 mg, 6.28 mmol) and a catalytic amount of AcOH were added and the mixture stirred at 80° C. for 45 min. The precipitate was collected by filtration and washed with EtOH (464 mg). The filtered solution was evaporated and the crude purified by flash.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([N+:14]([O-:16])=[O:15])=[CH:7][C:3]=1[C:4]([NH2:6])=O.P(Cl)(Cl)(Cl)=O>>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([N+:14]([O-:16])=[O:15])=[CH:7][C:3]=1[C:4]#[N:6]
Reactant: NC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1Cl
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1Cl

Procedure:
A mixture of 31.8 gm. (0.129 mole) of 2-chloro-3,5-dinitrobenzamide and 50 ml. of phosphorous oxychloride is heated under reflux for one hour. The excess phosphorous oxychloride is removed by distillation under reduced pressure. To the residue is cautiously added ice water. The light yellow-green solid is removed by filtration and washed with water. There is obtained 28.0 g. (95%) of material melting at 139-41°.
Reaction SMILES: Cl.Cl[C:3]([C:5]1[CH:6]=[CH:7][N:8]2[C:12]=1[CH2:11][S:10][CH:9]2[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:4].[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=2)[NH2:29])[CH:20]=1.C(N(CC)CC)C.C>O1CCOCC1.C(#N)C>[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:27]=[C:28]([NH:29][C:3]([C:5]3[CH:6]=[CH:7][N:8]4[C:12]=3[CH2:11][S:10][CH:9]4[C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)=[O:4])[CH:30]=[CH:31][CH:32]=2)[CH:20]=1
Reactant: O=C(Cl)c1ccn2c1CSC2c1cccnc1
Reactant: Nc1cccc(Oc2cccnc2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(Nc1cccc(Oc2cccnc2)c1)c1ccn2c1CSC2c1cccnc1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 41.2 %

Procedure:
7-Chloroformyl-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole hydrochloride (6 g) is added, at a temperature between 65° and 72° C., to a solution of 3-(3-pyridyloxy)aniline (3.9 g) and triethylamine (4.05 g) in dioxane (150 cc) which is heated to a temperature in the vicinity of 65° C., in the course of 5 minutes. The suspension obtained is heated, with stirring, at a temperature in the vicinity of 100° C. for 6 hours and 30 minutes and then stirred at a temperature in the vicinity of 20° C. for 16 hours. The solvent is evaporated off under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 60° C. The residue is dissolved in methylene chloride (300 cc). The solution obtained is washed twice with distilled water (300 cc in total), twice with an aqueous 1N sodium hydroxide solution (300 cc in total) and twice with distilled water (300 cc in total) and then dried over anhydrous magnesium sulphate, treated with decolourizing charcoal (0.5 g), filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 60° C. A crude product (8.2 g) is thereby obtained, which is dissolved in boiling acetonitrile (50 cc). Decolourizing charcoal (0.5 g) is added to the solution obtained and the suspension is filtered in the heated state. The filtrate is cooled at a temperature in the vicinity of 20 ° C. for 2 hours. The crystals formed are separated by filtration, washed 3 times with acetonitrile (30 cc in total) and 3 times with diethyl ether (90 cc in total) and then dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 20° C. in the presence of potassium hydroxide pellets. N-[3-(3-pyridyloxy)phenyl]-3-(3-pyridyl)-1H, 3H-pyrrolo[1,2-c]thiazole-7-carboxamide (3.4 g) in the form of cream-coloured crystals, m.p. 154° C., is thereby obtained.
Reaction SMILES: I[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[O:4][C:3]=1[CH2:13][CH2:14][CH3:15].[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:16]1([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:12])[O:4][C:3]=2[CH2:13][CH2:14][CH3:15])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OB(O)c1ccccc1
Reactant: CCCc1oc(=O)c2ccccc2c1I
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: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1oc(=O)c2ccccc2c1-c1ccccc1
Yield: 16.3 %

Procedure:
4-Iodo-3-propyl-1H-isochromen-1-one (intermediate C20.2, 0.80 g, 2.55 mmol), phenylboronic acid (0.39 g, 3.18 mmol), Pd(PPh3)4 (0.15 g, 0.127 mmol) and Cs2CO3 (1.16 g, 3.57 mmol) were reacted in DMF (10 ml) at 80° C. for 3 hrs. The reaction was the partitioned between AcOEt and 1 M HClaqueous, washed with 1 M HClaqueous brine, dried over Na2SO4 and concentrated under reduced pressure. The resulting crude was purified on a silica 500 Biotage cartridge eluting with a gradient of Hexane and AcOEt to give the title compound (0.11 g, 15.9%) as a yellowish oil.
Reaction SMILES: C[C:2]([C:4]1[S:5][C:6]([CH2:9][CH:10]([N:12]=[N+:13]=[N-:14])[CH3:11])=[CH:7][CH:8]=1)=[O:3].BrBr.[OH-:17].[Na+]>>[N:12]([CH:10]([CH3:11])[CH2:9][C:6]1[S:5][C:4]([C:2]([OH:3])=[O:17])=[CH:8][CH:7]=1)=[N+:13]=[N-:14]
Reactant: CC(=O)c1ccc(CC(C)N=[N+]=[N-])s1
Reactant: [OH-]
Agent: BrBr
Agent: [Na+]
Product: CC(Cc1ccc(C(=O)O)s1)N=[N+]=[N-]

Procedure:
For the preparation of the amine starting material of Example 10f, α-methyl-2-thiophenethanol, acetyl chloride and aluminum chloride were reacted in methylene chloride to give (RS)-2-(5-acetyl-2-thienyl)-1-methylethyl acetate. The resulting acetate was saponified with sodium hydroxide in methanol to give 5-[(RS)-2-hydroxypropyl]-2-thienyl methyl ketone which was subsequently reacted with p-toluenesulfonyl chloride to give (RS)-2-(5-acetyl-2-thienyl)-1-methylethyl-p-toluenesulfonate, m.p. 101°-103°. With sodium azide in dimethylsulfoxide there was obtained therefrom 5-[(RS)-2-azidopropyl]-2-thienyl methyl ketone which was oxidized with bromine in sodium hydroxide solution to give 5-[(RS)-2-azidopropyl]-2-thiophenecarboxylic acid. With thionyl chloride, there was obtained therefrom the corresponding acid chloride and from this there was prepared with ammonia 5-[(RS)-2-azidopropyl]-2-thiophenecarboxamide, m.p. 79°-80° C., from diethyl ether. Treatment with triphenylphosphine and hydrolysis gave 5-[(RS)-2-aminopropyl]-2-thiophenecarboxamide, m.p. 91°-92° from acetonitrile.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C@:4]12[O:29][C@:7]3([C@@H:15]4[C@@H:11]([N:12]([C:17]5[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:28])([F:27])[F:26])[CH:18]=5)[C:13](=[O:16])[C@H:14]14)[O:10][CH2:9][CH2:8]3)[C:6](=[O:30])[CH2:5]2>C1COCC1.CO>[OH:30][C@@H:6]1[CH2:5][C@@:4]2([CH3:3])[O:29][C@@:7]31[C@@H:15]1[C@@H:11]([N:12]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:26])([F:27])[F:28])[CH:18]=4)[C:13](=[O:16])[C@H:14]21)[O:10][CH2:9][CH2:8]3
Reactant: C[C@@]12CC(=O)[C@]3(CCO[C@H]4[C@@H]3[C@@H]1C(=O)N4c1ccc(C#N)c(C(F)(F)F)c1)O2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@]12C[C@@H](O)[C@]3(CCO[C@H]4[C@@H]3[C@@H]1C(=O)N4c1ccc(C#N)c(C(F)(F)F)c1)O2
Reaction time: 0.25 h
Yield: 99.5 %

Procedure:
Sodium borohydride (0.56 g, 14.7 mmol) was added in portions to a solution of Example 5 (2.9 g, 7.39 mmol) in THF (10 mL) and MeOH (10 mL) at 0° C. The reaction mixture was stirred for 15 min and quenched with drop-wise addition of aqueous saturated ammonium chloride (20 mL). The organic solvents were removed in vacuo and the residue was extracted with EtOAc. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude material was purified by silica gel chromatography using an 80 g ISCO column eluting with 0-100% EtOAc in CH2Cl2 at 70 mL/min. Concentration of appropriate fractions provided 2.9 g (99%) of Example 6 as a white solid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[S:9][C:8]([CH3:14])([CH3:13])[CH2:7][C:6]2=[O:15].B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[S:9][C:8]([CH3:13])([CH3:14])[CH2:7][C:6]2=[O:15]
Reactant: COc1ccc2c(c1)C(=O)CC(C)(C)S2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC1(C)CC(=O)c2cc(O)ccc2S1
Temperature: -23 °C
Reaction time: 5 h
Yield: 40 %

Procedure:
To a solution of 6-methoxy-2,2dimethylthiochroman-4-one (6.0 g, 27 mmol) in 50 mL CH2Cl2 cooled to −23° C. was added BBr3 (20.0 g, 80.0 mmol; 80.0 mL of a 1M solution in CH2Cl2) over a 20 minute period. After stirring for 5 hours at −23° C. the solution was cooled to −78° C. and quenched by the slow addition of 50 mL of H2O. Upon warming to room temperature, the aqueous layer was extracted with CH2Cl2 and the combined organic layers were washed with saturated aqueous NaHCO3, H2O, and saturated aqueous NaCl before being dried over MgSO4. Removal of the solvents under reduced pressure gave a green-brown solid which upon recrystalization (diethyl ether (Et2O)/hexanes) afforded 2.25 g (40%) of 6-hydroxy-2,2-dimethylthiochroman-4-one as a light brown solid. 1H NMR (300 MHz, CDCl3) δ:7.63 (1H, d, J=2.8 Hz), 7.15 (1H, d, J=8.5 Hz), 7.01 (1H, dd, J=2.8, 8.5 Hz), 2.87 (2H, s), 1.46 (6H, s).
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[N:13]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=2[Cl:25])[N:12]=[CH:11][C:10]=1[N+:26]([O-:28])=[O:27].C(Br)(Br)[Br:30]>>[Cl:25][C:15]1[CH:16]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:19]([Cl:20])[C:14]=1[N:13]1[C:9]([Br:30])=[C:10]([N+:26]([O-:28])=[O:27])[CH:11]=[N:12]1
Reactant: Nc1c([N+](=O)[O-])cnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: BrC(Br)Br
Agent: CC(C)(C)ON=O
Product: O=[N+]([O-])c1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1Br
Yield: 89 %

Procedure:
18 ml (0.16 mole) of t-butyl nitrite are added dropwise to 17.1 g (0.05 mole) of 5-amino-4-nitro-1-(2,6-dichloro-4-trifluoromethyl-phenyl)-pyrazole (compare DE-OS (German Published Specification) No. 3,402,308), supra, in 75 ml of bromoform in the course of 15 minutes, with stirring, whereupon the temperature of the reaction mixture rises to 50° C. When the addition has ended, the mixture is stirred at the reflux temperature for a further hour and concentrated in vacuo. 18.0 g (89% of theory) of 1-(2,6-dichloro-4-trifluoromethyl-phenyl)-4-nitro-5-bromo-pyrazole of melting point 96° C. are obtained.
Reaction SMILES: [OH-:1].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[OH:18])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CC(C)=O>[CH2:3]([O:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[O:18][C:4]([CH3:9])([CH3:5])[C:3]([OH:10])=[O:1])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Oc1ccc(Cl)cc1OCc1ccccc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(Oc1ccc(Cl)cc1OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Powdered sodium hydroxide (0.253 g) was added to a stirred mixture of the product from step (i) (1.5 g) and 1,1,1-trichloro-2-methylpropanol (3.0 g) in acetone (40 ml) at 0° C. After stirring at RT for 1 h the mixture was cooled to 0° C. and a further portion of sodium hydroxide (0.253 g) added. After repeating for a third time, the mixture was stirred at RT overnight, then quenched with 2M hydrochloric acid and extracted with ethylacetate. The organics were dried, evaporated under reduced pressure and the residue purified by chromatography on silica eluting with diethylether:isohexane (1:1). Yield 1.4 g
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.[CH2:27]([O:34][C:35]1[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:20][CH2:21][N:22]([CH2:39][C:38]4[CH:41]=[CH:42][C:35]([O:34][CH2:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)=[CH:36][CH:37]=4)[CH2:23][CH2:24]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:25][CH:26]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCNCC2)cc1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCN(Cc3ccc(OCc4ccccc4)cc3)CC2)cc1

Procedure:
Using the general procedure described in Example 3, N1-(4-methoxybenzoyl)-N2-(piperidin-4-ylcarbonyl)-1,2-benzenediamine (0.070 mmol) was reacted with 4-benzyloxybenzaldehyde to provide 40 mg of the title product as the free base. Treatment with hydrochloric acid and concentration in vacuo yielded the salt of the title compound.
Reaction SMILES: [CH:1]([OH:3])=[O:2].C(N(CC)CC)C.Cl[CH2:12][C:13]([O:15][C:16]([CH3:28])([CH2:18][CH2:19][C:20]([O:23][C:24](=[O:27])[CH2:25]Cl)([CH3:22])[CH3:21])[CH3:17])=[O:14].[C:29]([O:32]CC)(=[O:31])C>>[CH:1]([O:3][CH2:12][C:13]([O:15][C:16]([CH3:28])([CH2:18][CH2:19][C:20]([O:23][C:24](=[O:27])[CH2:25][O:32][CH:29]=[O:31])([CH3:22])[CH3:21])[CH3:17])=[O:14])=[O:2]
Reactant: CC(C)(CCC(C)(C)OC(=O)CCl)OC(=O)CCl
Reactant: CCOC(C)=O
Reactant: O=CO
Solvent: CCN(CC)CC
Product: CC(C)(CCC(C)(C)OC(=O)COC=O)OC(=O)COC=O
Reaction time: 0.5 h

Procedure:
Formic acid (67) (0.921 g, 20 mmol) and triethylamine (2.226 g, 22 mmol) were combined and stirred for 30 minutes. Compound (61) (0.299 g, 1 mmol) was then added and stirred for three days. The solution was dissolved in 10 mL of ethyl acetate and the precipitate was filtered and washed with 10 mL diethylether. The combined filtrate was then washed with brine and dried with sodium sulfate. The solvent was evaporated to get dark brown viscous oil. 1H NMR (400 MHz, CDCl3): δ 1.44 (s, 12H), 1.80 (s, 4H), 4.57 (s, 4H), 8.11 (s, 2H).
Reaction SMILES: [F:1]/[CH:2]=[C:3](\[CH2:13]O)/[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C.CS(Cl)(=O)=O.[Br-:27].[Li+]>CC(C)=O>[Br:27][CH2:13]/[C:3](=[CH:2]\[F:1])/[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)NC/C(=C/F)CO
Reactant: [Br-]
Agent: CS(=O)(=O)Cl
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NC/C(=C/F)CBr
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
To a stirring solution of (Z)-tert-butyl 3-fluoro-2-(hydroxymethyl)-allylcarbamate (0.50 g, 2.44 mmol) in acetone (15 mL) at 0° C. under N2 was added sequentially triethylamine (0.51 mL, 3.65 mmol) and methanesulfonyl chloride (0.23 mL, 2.92 mmol). The resulting mixture was stirred at this temperature for 30 min. The reaction mixture was filtered to remove the precipitated salts and the filter cake was washed with further acetone (10 mL). The filtrate was charged with lithium bromide (1.06 g, 12.18 mmol) and the resulting suspension was stirred at room temperature for 1 h. The reaction mixture was partitioned between water (25 mL) and ethyl acetate (25 mL) and the aqueous layer was extracted with further ethyl acetate (25 mL). The combined organics were washed with brine (25 mL), dried over Na2SO4 and concentrated in vacuo to give (Z)-tert-butyl 2-(bromomethyl)-3-fluoroallylcarbamate as a pale yellow oil (0.63 g, 96%). 1H-NMR (300 MHz; CDCl3) δ ppm: 1.47 (9H, s), 3.80 (2H, br s), 4.09 (2H, d, J 2.6 Hz), 4.75 (1H, br s), 6.65 (1H, d, J 81.9 Hz).
Reaction SMILES: [CH:1](=[O:5])[CH:2]([CH3:4])[CH3:3].[NH:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([N:22]3[CH2:30][C:29]4[CH:28]=[CH:27][N:26]=[CH:25][C:24]=4[CH2:23]3)=[O:21])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1.N1CC=C(C2C=CC(NC(N3CC4C(=CC=CC=4)C3)=O)=CC=2)C[CH2:32]1>>[O:5]1[CH2:32][CH2:3][CH:2]([CH2:4][N:6]2[CH2:11][CH2:10][CH:9]([O:12][C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([N:22]4[CH2:30][C:29]5[CH:28]=[CH:27][N:26]=[CH:25][C:24]=5[CH2:23]4)=[O:21])=[CH:15][CH:14]=3)[CH2:8][CH2:7]2)[CH2:1]1
Reactant: O=C(Nc1ccc(OC2CCNCC2)cc1)N1Cc2ccncc2C1
Reactant: O=C(Nc1ccc(C2=CCNCC2)cc1)N1Cc2ccccc2C1
Reactant: CC(C)C=O
Product: O=C(Nc1ccc(OC2CCN(CC3CCOC3)CC2)cc1)N1Cc2ccncc2C1

Procedure:
The title compound was prepared as described in Example 429, substituting tetrahydrofuran-3-carbaldehyde for isobutyraldehyde and N-(4-(piperidin-4-yloxy)phenyl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxamide for N-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)isoindoline-2-carboxamide. 1H NMR (400 MHz, Pyridine-d5. Temp=90° C.) δ ppm 8.53-8.58 (m, 1H) 8.08 (s, 1H) 7.70-7.77 (m, 2H) 7.10 (d, J=5.19 Hz, 1H) 7.01 (d, J=8.85 Hz, 2H) 4.84 (d, J=7.63 Hz, 4H) 4.19-4.27 (m, 1H) 3.75-3.90 (m, 2H) 3.67-3.72 (m, 1H) 3.56 (dd, J=8.55, 5.80 Hz, 1H) 2.65-2.82 (m, 2H) 2.31-2.45 (m, 1H) 2.15-2.31 (m, 4H) 1.71-2.00 (m, 5H) 1.48-1.59 (m, 1H); MS (APCI(+)) m/e 423 (M+H)+.
Reaction SMILES: [NH2:1]/[C:2](/OCC)=[CH:3]\[C:4](=O)[C:5]([F:8])([F:7])[F:6].[NH2:13][NH2:14]>CCO>[F:6][C:5]([F:8])([F:7])[C:4]1[NH:14][N:13]=[C:2]([NH2:1])[CH:3]=1
Reactant: CCO/C(N)=C/C(=O)C(F)(F)F
Reactant: NN
Solvent: CCO
Product: Nc1cc(C(F)(F)F)[nH]n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of (E)-4-amino-4-ethoxy-1,1,1-trifluorobut-3-en-2-one (5.00 g, 27 mmol) and hydrazine (1.05 g) in anhydrous EtOH (20 mL) was stirred at 80° C. in a sealed vial overnight. The reaction was quenched with water (50 mL), and extracted with EtOAc (100 ml, then 2×50 mL). The EtOAc layers were combined and sequentially washed with water (25 mL), brine (25 mL), dried over Na2SO4 and evaporated to give a light brown oily residue. The crude product was purified by silica chromatography (30-100% EtOAc in hexanes gradient) to give 5-(trifluoromethyl)-1H-pyrazol-3-amine as an off white solid; ESMS m/z 152.0 (MAI).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([OH:21])=[CH:5][C:6]([OH:20])=[C:7]2[C:12](=[O:13])[CH:11]=[C:10]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[O:9][C:8]=12.[CH2:22]=O.[NH:24]([CH2:28][CH2:29][OH:30])[CH2:25][CH2:26][OH:27]>CO>[OH:27][CH2:26][CH2:25][N:24]([CH2:22][C:5]1[C:6]([OH:20])=[C:7]2[C:8](=[C:3]([O:2][CH3:1])[C:4]=1[OH:21])[O:9][C:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:11][C:12]2=[O:13])[CH2:28][CH2:29][OH:30]
Reactant: C=O
Reactant: OCCNCCO
Reactant: COc1c(O)cc(O)c2c(=O)cc(-c3ccccc3)oc12
Solvent: CO
Product: COc1c(O)c(CN(CCO)CCO)c(O)c2c(=O)cc(-c3ccccc3)oc12
Temperature: 55 °C
Reaction time: 4 h

Procedure:
The mixture of Wogonin (28.4 g), methanol (350 ml), 37% formaldehyde solution (8.04 ml), diethanolamine (10.5 g) was stirred under for 4 hours at 55° C., then precipitates were removed by filtration and washed several times with methanol, after drying under reduced pressure at 65° C. to get the product as yellow solid 39.3 g of purity 99.2%. MS: (API-ES) m/z 402.4[M+H]+, 424.4[M+Na]+; 1H NMR (DMSO-d6, 400 MHz): δ 8.05˜8.06 (m, 2H, Ar-2′,6′-H), 7.60˜7.61 (m, 3H, Ar-3′,4′,5′-H), 6.90 (s, 1H, 3-H), 3.94 (s, 2H, CH2), 3.83 (s, 3H, 8-OCH3), 3.63 (m, 4H, O—CH2), 2.55 (m, 4H, N—CH2).
Reaction SMILES: [C:1]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:6]=[CH:5][C:4]([CH:7]2[CH:26]=[C:25]3[C:10](=[C:11](Br)[C:12]4[CH:13]=[C:14]5[C:22]([C:23]([CH3:28])([CH3:27])[C:24]=43)=[C:21]3[C:16]([CH:17]=[CH:18][CH:19]=[CH:20]3)=[N:15]5)[CH:9]=[CH:8]2)=[CH:3][CH:2]=1.[C:36]1([C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)[CH:41]=[CH:40][C:39]([N:42]([C:58]2[CH:63]=[CH:62][C:61]([C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)=[CH:60][CH:59]=2)[C:43]2[CH:48]=[CH:47][C:46](B3OC(C)(C)C(C)(C)O3)=[CH:45][CH:44]=2)=[CH:38][CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>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.C1(C)C=CC=CC=1.C(O)C>[C:1]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:6]=[CH:5][C:4]([CH:7]2[CH:26]=[C:25]3[C:10](=[C:11]([C:46]4[CH:45]=[CH:44][C:43]([N:42]([C:58]5[CH:59]=[CH:60][C:61]([C:64]6[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=6)=[CH:62][CH:63]=5)[C:39]5[CH:40]=[CH:41][C:36]([C:70]6[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=6)=[CH:37][CH:38]=5)=[CH:48][CH:47]=4)[C:12]4[CH:13]=[C:14]5[C:22]([C:23]([CH3:28])([CH3:27])[C:24]=43)=[C:21]3[C:16]([CH:17]=[CH:18][CH:19]=[CH:20]3)=[N:15]5)[CH:9]=[CH:8]2)=[CH:3][CH:2]=1
Reactant: CC1(C)C2=C(C=C3N=c4ccccc4=C31)C(Br)=C1C=CC(c3ccc(-c4ccccc4)cc3)C=C12
Reactant: CC1(C)OB(c2ccc(N(c3ccc(-c4ccccc4)cc3)c3ccc(-c4ccccc4)cc3)cc2)OC1(C)C
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: CC1(C)C2=C(C=C3N=c4ccccc4=C31)C(c1ccc(N(c3ccc(-c4ccccc4)cc3)c3ccc(-c4ccccc4)cc3)cc1)=C1C=CC(c3ccc(-c4ccccc4)cc3)C=C12
Temperature: 73 °C
Reaction time: 10 h
Yield: 63.8 %

Procedure:
10-(biphenyl-4-yl)-7-bromo-12,12-dimethyl-10,12-dihydroindeno[2,1-b]carbazole synthesized in Example 6 (13.0 g), bis(biphenyl-4-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]amine (15.9 g) a toluene/ethanol (4/1, v/v) mixed solvent (250 ml), and a 2M potassium carbonate aqueous solution (51 ml) were added to a nitrogen-substituted reaction vessel and aerated with nitrogen gas for 30 min under ultrasonic irradiation. The mixture was heated after adding tetrakis(triphenylphosphine)palladium (2.1 g), and stirred at 73° C. for 10 hours. After the mixture was cooled to a room temperature, a precipitated crude product was collected by filtration. 1,2-Dichlorobenzene (1.7 L) was added to the crude product, and the crude product was dissolved while being heated, and after removing insoluble matter by filtration, a filtrate was cooled to a room temperature. A precipitated solid was collected by filtration and purified by recrystallization using 1,2-dichlorobenzene (1.7 L) to obtain a white powder of 10-(biphenyl-4-yl)-7-[4-bis(biphenyl-4-yl)amino-phenyl]-12,12-dimethyl-10,12-dihydroindeno[2,1-b]carbazole (13.4 g; yield 63.8%).