Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:11]12(O)[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2.S(=O)(=O)(O)O>ClCCl>[OH:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([C:11]23[CH2:20][CH:15]4[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]4)[CH2:12]2)[CH2:18]3)=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1ccc(O)cc1O
Reactant: OC12CC3CC(CC(C3)C1)C2
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: O=Cc1cc(C23CC4CC(CC(C4)C2)C3)c(O)cc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5 g (36.2 mmol) of 2,4-dihydroxybenzaldehyde, 5.8 g (38.1 mmol) of 1-adamantanol of 200 ml of dichloromethane were introduced into a round-bottomed flask. 2 ml of concentrated sulfuric acid were added and the mixture was stirred at room temperature for eight hours. The reaction mixture was evaporated to dryness, the residue was taken up in water, neutralized with sodium bicarbonate and extracted with ethyl ether and the extract was dried over magnesium sulfate and evaporated.
Reaction SMILES: CS(C)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Cl:18][C:19]1[CH:20]=[C:21]([CH:26]([OH:35])[CH:27]([C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[OH:28])[CH:22]=[CH:23][C:24]=1[Cl:25].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl>[Cl:18][C:19]1[CH:20]=[C:21]([C:26](=[O:35])[C:27]([C:29]2[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=2)=[O:28])[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: OC(c1ccncc1)C(O)c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(C(=O)c1ccc(Cl)c(Cl)c1)c1ccncc1
Temperature: 0 °C
Yield: 73.3 %

Procedure:
To a stirring solution of methyl sulfoxide (38.3 g, 35 mL, 490 mmol) in dichloromethane (750 mL) at -78° C. was added trifluoroacetic anhydride (77 g, 52 mL, 368 mmol) dropwise. After ten minutes, 1-(3,4-dichlorophenyl)-2-pyridin-4-yl-ethane-1,2-diol (31.7 g, 112 mmol) in dichloromethane (500 mL) was added dropwise. After another ten minutes, triethylamine (70 g, 96 mL, 690 mmol) was added dropwise and the reaction mixture immediately warmed to 0° C. and poured into saturated aqueous sodium hydrogen carbonate (300 mL). The aqueous layer was extracted with ethyl acetate (3×200 mL) and the organic layers were combined, dried over anhydrous magnesium sulfate, filtered and concentrated at reduced pressure. The resulting solid was triturated with ethyl acetate to give the dione as a yellow solid (23 g). 1H NMR (300 MHz,CDCl3) d 8.90 (dd, J=3.7 and 2.9 Hz, 2H), 8.09 (d, J=1.9 Hz, 1H), 7.85-7.73 (m, 3H), 7.63 (d, J=8.3 Hz, 1H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([C:15]([OH:17])=O)[CH:9]=[CH:8]2)(=[O:3])[CH3:2].S(Cl)([Cl:20])=O>>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([C:15]([Cl:20])=[O:17])[CH:9]=[CH:8]2)(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Oc1ccc2cc(C(=O)O)ccc2c1
Product: CC(=O)Oc1ccc2cc(C(=O)Cl)ccc2c1
Temperature: 79 °C
Yield: 101.8 %

Procedure:
30 Grams (130.3 mmol) of 6-acetoxy-2-naphthoic acid and 155 g (260 mmol) of purified thionyl chloride were placed in a reactor, and the mixture was refluxed under heat (79° C.) for 4 hours. Thionyl chloride was distilled off under atmospheric pressure, 150 ml of toluene was added, and toluene and thionyl chloride were distilled off under reduced pressure, to give 33 g of an end compound (yield 98%).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Br:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([O:16][CH2:17][CH3:18])[CH:10]=1.C([O-])(=O)C.[K+].O>CN(C)C=O.C(OCC)(=O)C>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:11]([O:16][CH2:17][CH3:18])[CH:10]=1
Reactant: CCOc1cc(Br)ccc1O
Reactant: CCOC(=O)CBr
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)COc1ccc(Br)cc1OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl bromoacetate (1.04 mL) was added to a mixture of 4-bromo-2-ethoxyphenol (1.69 g) and potassium acetate (1.62 g) in N,N-dimethylformamide (10 mL), and the mixture was stirred at room temperature overnight. Water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with water and brine, and dried over an hydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: diethyl ether/n-hexane=1/10) to afford ethyl (4-bromo-2-ethoxyphenoxy)acetate (2.26 g).
Reaction SMILES: [CH3:1][Si:2]([CH3:29])([CH3:28])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([C:21]4([CH2:25][C:26]#[N:27])[CH2:24][NH:23][CH2:22]4)[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.[CH2:30]([S:32](Cl)(=[O:34])=[O:33])[CH3:31]>C(OCC)(=O)C>[CH2:30]([S:32]([N:23]1[CH2:22][C:21]([CH2:25][C:26]#[N:27])([N:19]2[CH:20]=[C:16]([C:15]3[C:10]4[CH:9]=[CH:8][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:28])([CH3:1])[CH3:29])[C:11]=4[N:12]=[CH:13][N:14]=3)[CH:17]=[N:18]2)[CH2:24]1)(=[O:34])=[O:33])[CH3:31]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ncnc21
Reactant: CCS(=O)(=O)Cl
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)N1CC(CC#N)(n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.8 %

Procedure:
To a solution of crude 2-(3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (16, 423.7 g, 1.03 mol) in ethyl acetate (EtOAc, 6.5 L) at 0-5° C. was added a solution of ethane sulfonyl chloride (EtSO2Cl, 117 mL, 1.23 mol, 1.2 equiv) in ethyl acetate (110 mL) drop wise. The resulting reaction mixture was allowed to warm gradually to room temperature and stirred at room temperature for overnight. When LCMS analysis showed that no starting material remained and the reaction mixture was transferred to a 22 L separation funnel and washed with water (4 L), brine (2 L) and saturated aqueous sodium bicarbonate solution (NaHCO3, 2 L). The combined aqueous layer was back extracted with ethyl acetate (EtOAc, 2 L). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate (Na2SO4) and concentrated under reduced pressure. The crude material was purified on silica gel eluted with dichlormethane/ethyl acetate (100/0 to 0/100). The fractions containing the pure desired product (12) were combined and concentrated under reduced pressure to a minimum volume before being treated with heptane at room temperature. The solids were collected by filtration and washed with heptane to afford 2-(1-(ethylsulfonyl)-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (12, 397 g, 516.7 g theoretical, 76.8% yield) as white solids, which was found to be identical to the material prepared by method A in every comparable aspect. For 12: 1H NMR (CDCl3, 300 MHz), δ 8.86 (s, 1H), 8.45 (s, 1H), 8.35 (s, 1H), 7.43 (d, 1H), 6.80 (d, 1H), 5.68 (s, 2H), 4.65 (d, 2H), 4.27 (d, 2H), 3.55 (s, 2H), 3.4 (t, 2H), 3.07 (m, 2H), 1.42 (m, 3H), 0.92 (m, 2H), −0.05 (s, 9H) ppm; C22H31N7O3SSi (MW, 501.68), LCMS (EI) m/e 502 (M++H).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][N:5]([CH3:15])[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1>CCO.[Pd]>[CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][N:5]([CH3:15])[C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1
Reactant: CN(C)CCN(C)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CN(C)CCN(C)c1ccc(N)cc1
Reaction time: 4.5 h

Procedure:
A suspension of 5.770 g (25.842 mmol), N,N′-trimethyl-N′-(4-nitro-phenyl)-ethane-1,2-diamine (141a) and 0.60 g Pd/C (10%) in EtOH was hydrogenated for 4.5 h at 50 psi. The catalyst was filtered off and the filtrate evaporated down i. vac. The crude product was further reacted immediately.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10](Cl)=[O:11])[CH2:3][CH2:2]1.[CH3:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25].C(N(CC)CC)C>C(Cl)Cl>[CH3:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:10](=[O:11])[C:9]2[CH:13]=[CH:14][CH:15]=[C:7]([N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[CH:8]=2)=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25]
Reactant: O=C(Cl)c1cccc(N2CCOCC2)c1
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1[N+](=O)[O-]
Reaction time: 18 h
Yield: 19.3 %

Procedure:
3-Morpholinobenzoyl chloride (6.22 g) was added to a solution of 4-methyl-3-nitroaniline (4.20 g) and triethylamine (11.0 ml) in methylene chloride (150 ml) at ambient temperature under argon. The reaction mixture was stirred for 18 hours then diluted to 250 ml with methylene chloride. The mixture was washed with water (3×150 ml) and saturated sodium bicarbonate solution (2×100 ml), dried and evaporated to give a dark brown oil. The oil was triturated with diethyl ether and the solid collected and dried to yield N-(4-methyl-3-nitrophenyl)-3-morpholinobenzamide (1.82g); NMR: (CDCl3) 2.53 (s, 3H), 3.22 (t, 4H), 3.83 (t, 4H), 7.06 (dd, 1H), 7.23 (d, 1H), 7.37 (m, 2H), 7.42 (d, 1H), 7.88 (dd, 1H), 7.97 (s, 1H), 8.21 (d, 1H); m/z 340 (MH+); m.p. 149-150° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]1([CH2:13][C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[OH-].[Na+]>C1COCC1.O.C(OCC)C>[N:7]1([CH2:13][C:14]2[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=2)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1
Reactant: N#Cc1ccc(CN2CCOCC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: NCc1ccc(CN2CCOCC2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
Under a nitrogen atmosphere, add lithium aluminum hydride (1.13 g, 29.7 mmol) to THF (50 mL) at 0° C. followed by a solution of 4-(morpholin-4-ylmethyl)-benzonitrile (2 g, 9.89 mmol) in THF (10 mL). Stir at 0° C. for 1 h and at room temperature overnight. Cool the mixture to 0° C., and carefully add water (1.15 mL). Add diethyl ether (125 mL), 3N aqueous NaOH (1.15 mL), water (3.45 mL), and stir for 1 h at room temperature. Filter the solid residue and concentrate the filtrate in vacuo to obtain the title compound as a colorless oil (1.87 g, 94%). MS (APCI+) m/z: 207 (M+H)+.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[CH2:13]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)=[O:17])[CH3:14].[I:31][C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[C:34](O)=[O:35].O>C(Cl)Cl>[I:31][C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[C:34]([NH:30][C:27]1[CH:26]=[CH:25][C:24]([N:21]2[CH2:22][CH2:23][N:18]([C:16]([O:15][CH2:13][CH3:14])=[O:17])[CH2:19][CH2:20]2)=[CH:29][CH:28]=1)=[O:35]
Reactant: CCOC(=O)N1CCN(c2ccc(N)cc2)CC1
Reactant: O=C(O)c1ccccc1I
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)N1CCN(c2ccc(NC(=O)c3ccccc3I)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.7 %

Procedure:
1-Ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (0.096 mol) was added at room temperature to a mixture of 4-(4-aminophenyl)-1-piperazinecarboxylic acid ethyl ester (0.08 mol), 2-iodo benzoic acid (0.096 mol) and,1-hydroxybenzotriazole (HOBT) (0.096 mol) in DCM (500 ml). The mixture was stirred at room temperature overnight. Water was added. The mixture was extracted with DCM. The organic layer was separated, dried, filtered, and the solvent was evaporated. The residue was taken up in DIPE. The precipitate was filtered off and dried, yielding 39 g of 4-[4-[(2-iodobenzoyl)-amino]phenyl]-1-piperazinecarboxylic acid, ethyl ester (intermediate 27).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=2[F:18])[N:5]=[C:4]([S:19][CH3:20])[N:3]=1.B.Cl.[OH-].[Na+]>>[NH2:9][CH2:8][C:7]1[C:6]([NH:10][C:11]2[C:12]([F:18])=[CH:13][CH:14]=[CH:15][C:16]=2[F:17])=[N:5][C:4]([S:19][CH3:20])=[N:3][C:2]=1[Cl:1]
Reactant: CSc1nc(Cl)c(C#N)c(Nc2c(F)cccc2F)n1
Agent: B
Agent: Cl
Agent: [Na+]
Product: CSc1nc(Cl)c(CN)c(Nc2c(F)cccc2F)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 102.1 %

Procedure:
To the solution of 4-chloro-6-[(2,6-difluorophenyl)amino]-2-(methylthio)-5-pyrimidinecarbonitrile (0.938 g) was added borane.THF complex (1.0 M, 15 mL). The reaction mixture was then heated at reflux for about 4 h until all the starting material disappeared. The solution was cooled to r.t., mixed with HCl solution (6 M, 5 mL), and stirred at room temperature for about 30 minutes. The solution was then mixed with NaOH solution (3 M) to pH 9.0-10.0. The organic phase was separated and the aqueous layer was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (50 mL), collected, dried over Na2SO4 and concentrated to afford the title compound 0.97 g (quantative). LC-MS m/z 317 (M+H)+, 1.5 min (ret. time).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:40]=[CH:39][C:24]([NH:25][C:26]2[C:35]3[C:30](=[CH:31][C:32](O)=[C:33]([O:36][CH3:37])[CH:34]=3)[N:29]=[CH:28][N:27]=2)=[C:23]([F:41])[CH:22]=1.C(O)CC.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[Cl:20][C:21]1[CH:40]=[CH:39][C:24]([NH:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=3)[N:29]=[CH:28][N:27]=2)=[C:23]([F:41])[CH:22]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCO
Solvent: ClCCl
Product: COc1ccc2ncnc(Nc3ccc(Cl)cc3F)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
Triphenylphosphine (2.46 g, 9.3 mmol) was added to a suspension of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (1.0 g, 3.1 mmol), (prepared as described for the starting material in Example 2), in methylene chloride (25 ml) and the suspension stirred at 0° C. for 30 minutes. A solution of 3-N-tert-butoxycarbonylamino)-1-propanol (0.65 g, 3.7 mmol) in methylene chloride (3 ml) was added and then diethyl azodicarboxylate (1.47 ml, 7.6 mmol) was added dropwise. The reaction mixture was allowed to warm to ambient temperature and stirred for 18 hours. The reaction mixture was diluted with methylene chloride and washed with aqueous sodium hydrogen carbonate solution, water and then brine. The resultant solution was dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol/triethylamine (100/0/0 and then 95/4/1) to give 7-(3-N-tert-butoxycarbonylamino)propoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline (620 mg, 42%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:13]2[C:8](=[C:9]([O:16]C)[C:10]([O:14]C)=[CH:11][CH:12]=2)[CH2:7][CH:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:5]=1.B(Cl)(Cl)[Cl:25].CO>ClC(Cl)C>[ClH:25].[NH2:2][CH2:3][C:4]1[C:13]2[C:8](=[C:9]([OH:16])[C:10]([OH:14])=[CH:11][CH:12]=2)[CH2:7][CH:6]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:5]=1
Reactant: COc1ccc2c(c1OC)CC(c1ccccc1)C=C2CN
Reactant: ClB(Cl)Cl
Agent: Cl
Solvent: CC(Cl)Cl
Solvent: CO
Product: NCC1=CC(c2ccccc2)Cc2c1ccc(O)c2O
Temperature: 25 °C
Reaction time: 18 h
Yield: 56 %

Procedure:
A slurry of 10 g (25 mmol) of 1-aminomethyl-3,4-dihydro-5,6-dimethoxy-3-phenyl-naphthalene hydrochloride, from Step 2, in 150 mL of dichloroethane was cooled to 10° C. under a nitrogen atmosphere. Boron trichloride was passed through the reaction mixture until 27 g (230 mmol) had been added. The reaction mixture was allowed to warm to ambient temperature and stirred for 18 h. The reaction mixture was then recooled in ice and 100 mL of methanol was added dropwise. The reaction mixture was again allowed to warm to ambient temperature and concentrated in vacuo. Twice, 500 mL portions of methanol were added to the residue and it was reconcentrated. The resultant foam was dissolved in 40 mL of ethanol, filtered and the solution was treated with 40 mL of methylene chloride and 80 mL of heptane. Off-white crystals of 1-aminomethyl-3,4-dihydro-5,6-dihydroxy-3-phenyl naphthalene hydrochloride (5.1 g, 56% yield) were collected by filtration, m.p. 204°-205° C. The 1H NMR spectrum was identical to the spectrum for the product of Example 2A.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1>C(Cl)Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][O:11]1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: Clc1ncnc2c1ncn2C1CCCCO1
Reaction time: 3 h
Yield: 99.8 %

Procedure:
To a solution of 6-chloropurine (2.70 g, 17.5 mmol) and p-toluenesulfonic acid monohydrate (0.14 g, 0.71 mmol) in methylene chloride (30 mL) was added dihydropyran (2.39 mL, 26.2 mmol). The suspension was stirred for 3 h. The reaction mixture was washed with 2.5% Na2CO3 solution (100 mL×2), and brine (50 mL). The organic layer was dried over sodium sulfate and concentrated. The oil was treated with hexanes (100 mL) and stirred. The hexanes layer was decanted. The oil solidified upon standing to give the desired product (4.17 g, 98%).
Reaction SMILES: [CH:1](=O)[CH2:2][CH3:3].[CH2:5]([NH:9][CH2:10][CH:11]([CH3:13])[CH3:12])[CH:6]([CH3:8])[CH3:7]>>[CH2:5]([N:9]([CH:1]=[CH:2][CH3:3])[CH2:10][CH:11]([CH3:13])[CH3:12])[CH:6]([CH3:8])[CH3:7]
Reactant: CCC=O
Reactant: CC(C)CNCC(C)C
Product: CC=CN(CC(C)C)CC(C)C
Yield: 29 %

Procedure:
Following a procedure similar to that described in Example 64(i), but using propionaldehyde and diisobutylamine as starting materials, the title compound was obtained as a colorless oily substance (yield 29%), boiling at 63-66° C./10 mmHg
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4](I)[CH:3]=1.[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH2:12].C(=O)(O)[O-].[Na+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][C:4]=1/[CH:12]=[CH:11]/[C:10]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: Nc1ccc(Br)cc1I
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cc(Br)ccc1N
Temperature: 70 °C
Yield: 91.4 %

Procedure:
To a solution of 4-bromo-2-iodoaniline (750 g, 2.51 mol, 1.0 equiv) in DMF (5.0 L) was added ethyl acrylate (277 g, 2.76 mol, 1.1 equiv, Avra) and sodium bicarbonate (680 g, 6.29 mol, 2.5 equiv). The reaction mixture was degassed with nitrogen for 20 min followed by the addition of palladium acetate (28.8 g, 128.27 mmol, 0.05 equiv, Hindustan Platinum). The reaction mixture was heated at 70° C. for 3 h. The reaction was filtered through celite and the celite bed was washed with ethyl acetate (2×500 mL). The filtrate was concentrated under reduced pressure to obtain the crude residue which was purified by column chromatography (silica gel; mesh size 60-120, elution 0-20% ethyl acetate in hexanes) to obtain (E)-ethyl 3-(2-amino-5-bromophenyl)acrylate (620 g, 77.0%), as yellow solid. TLC solvent system: 20% ethyl acetate in hexanes. Product's Rf: 0.4. MS (ESI, positive ion) m/z; 270.2 (M+1). 1H NMR (400 MHz, DMSO) δ 7.75 (d, J=16.1 Hz, 1H), 7.57 (d, J=2.0 Hz, 1H), 7.16 (dd, J=9.1, 2.4 Hz, 1H), 6.66 (d, J=8.6 Hz, 1H), 6.43 (d, J=8.6 Hz, 1H), 5.81 (s, 2H), 4.20 (q, J=7.2 Hz, 2H), 1.27 (t, J=7.2 Hz, 3H).
Reaction SMILES: C1[C:9]2[C:4](=CC=CC=2)[CH:3]=[C:2]1[C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.C(/C=C\C(OCC)=[O:24])#N>Cl[Sn](Cl)(Cl)Cl.[Al+3].[Cl-].[Cl-].[Cl-].C([Al](Cl)Cl)C.[Al](Cl)(CC)CC.C(O)(C(F)(F)F)=O.C(Cl)Cl.C1(C)C=CC=CC=1>[O:24]=[C:4]1[CH:3]=[CH:2][C:10]2[C:18]([C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=2)=[CH:9]1
Reactant: CCOC(=O)/C=C\C#N
Reactant: C1=C(c2cc3ccccc3[nH]2)Cc2ccccc21
Agent: CC[Al](Cl)CC
Agent: CC[Al](Cl)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1C=CC2=Nc3ccccc3C2=C1

Procedure:
In Method B (FIG. 2), a 2-(heteroaryl)indole derivative (1-3), or 2-(aryl)indole derivative such as 2-(2-indenyl)indole 4 is reacted with ethyl cis-β-cyanoacrylate in the presence of a catalyst such as SnCl4, AlCl3, EtAlCl2, Et2AlCl or TFA in CH2Cl2, C2H4Cl2 or toluene as solvent to give the 6-oxo carbazole compounds of formula I of the invention.
Reaction SMILES: [CH:1](=[N:8][C:9]([CH3:24])([CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[C:10](OCC)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[CH2:1]([NH:8][C:9]([CH3:24])([CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[CH2:10][OH:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(CCOC1CCCCO1)N=Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(CO)(CCOC1CCCCO1)NCc1ccccc1
Yield: 92.1 %

Procedure:
A solution of ethyl 2-benzylideneamino-2-methyl-4-((tetrahydro-2H-pyran-2-yl)oxy)butyrate (12C, 100.0 g, 0.3 mol) in THF (100 mL) was added slowly to a suspension of lithium aluminum hydride (Alfa, 22.77 g, 0.6 mol) rapidly stirred in dry THF (1 L) at such a rate to maintain a gentle reflux. After addition was complete the mixture was refluxed for 4 h. The reaction mixture was cooled and treated successively with H2O (23 mL), 15N NaOH (23 mL) and H2O (45 mL). The solid was removed by filtration and washed with THF (200 mL). The organic layers were combined and concentrated by rotary evaporation to give 2-benzylamino-2-methyl-4-((tetrahydro-2H-pyran-2-yl)oxy)butanol (81.1 g, 92.0%) as a thick oil which was used without further purification.
Reaction SMILES: CN([CH2:4][C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([OH:15])=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=1)C.[CH2:20]=[CH:21][CH:22]=[CH2:23]>C1(C)C=CC=CC=1>[C:16]([C:7]1[C:8](=[O:15])[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:10][C:5]2([CH2:23][CH2:22][CH:21]=[CH:20][CH2:4]2)[CH:6]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CN(C)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: C=CC=C
Solvent: Cc1ccccc1
Product: CC(C)(C)C1=CC2(C=C(C(C)(C)C)C1=O)CC=CCC2
Temperature: 205 °C
Yield: 93.7 %

Procedure:
A 300 mL Parr autoclave was charged with a solution of 10.52 g (40 mmols) of N,N-dimethyl-4-aminomethyl-2,6-di-t-butylphenol in 90 g of toluene, sealed and evacuated by a water aspirator, and then charged with 4.38 g (80 mmols) of 1,3-butadiene. The reaction mixture was heated to approximately 205° C. for 10 hours. A maximum pressure of 120 psig was obtained. After cooling, the reaction mixture was poured into a 500 mL separatory funnel, washed with approximately 2N HCl (1×50 mLs), water (1×50 mLs), and brine (1×50 mLs), dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford 10.21 g (94% yield) of 2,4-di-t-butylspiro[5.5]undeca-1,4,8-trien-3-one as a brown solid. The brown solid was recrystallized from 80% ethanol to give the product as colorless crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[N:5]=[C:4]([NH:18][C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)[N:3]=1.[NH3:27]>CC(O)C.O1CCOCC1>[NH2:27][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[N:5]=[C:4]([NH:18][C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)[N:3]=1
Reactant: Cc1cc(C)c(Nc2nc(Cl)nc(Nc3ccc(C#N)cc3)n2)c(C)c1
Reactant: N
Solvent: C1COCCO1
Solvent: CC(C)O
Product: Cc1cc(C)c(Nc2nc(N)nc(Nc3ccc(C#N)cc3)n2)c(C)c1
Yield: 66.1 %

Procedure:
As an alternative for the preparation of this compound, a mixture of 4-[[4-chloro-6-[(2,4,6-trimethylphenyl)amino]-1,3,5-triazin-2-yl]amino]benzonitrile (0.0230 mol) in NH3 in 2-propanol (2.0 M; 60 ml) and NH3 in 1,4-dioxane (0.5 M; 20 ml) was heated at 95° C. for 21 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate, washed with 1 N NaOH, water and brine, dried, filtered and the filtrate was evaporated. The residue was recrystallized with acetonitrile, yielding 5.25 g (66.1%) of 4-[[4-amino-6-[(2,4,6-trimethylphenyl)amino]-1,3,5-triazin-2-yl]amino]benzonitrile.