Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:5]([C:7]([O:9]C)=O)[N:6]=1.[NH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24]>>[Cl:1][C:2]1[S:3][C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:5]([C:7]([NH:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:9])[N:6]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: COC(=O)c1nc(Cl)sc1-c1ccccc1
Product: CC(C)(C)OC(=O)NCCNC(=O)c1nc(Cl)sc1-c1ccccc1
Yield: 22.5 %

Procedure:
5.4 g (21.3 mmol) of methyl 2-chloro-5-phenyl-4-thiazolecarboxylate and 3.6 g (22.3 mmol) of t-butyl (2-aminoethyl)carbamate were stirred under reduced pressure for 22 hours at a bath temperature of 110°, whereby the methanol formed was distilled off continuously. The reaction mixture was cooled, dissolved in methylene chloride and chromatographed on 150 g of silica gel with methylene chloride and a 4:1 mixture of methylene chloride and ethyl acetate as the eluting agent. The fractions which were pure according to the thin-layer chromatogram were combined and evaporated. Crystallization of the residue from ethyl acetate/hexane yields 1.83 g (27.5%) of t-butyl [2-(2-chloro-5-phenyl-4-thiazolecarboxamido)ethyl]carbamate as white crystals, melting point 114°-116°.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22](Cl)(=[O:24])=[O:23])([O-:15])=[O:14].N1C=CC=CC=1>C(Cl)Cl>[F:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][S:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N+:13]([O-:15])=[O:14])(=[O:23])=[O:24])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: Nc1ccc(F)c2cccnc12
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)Nc1ccc(F)c2cccnc12
Yield: 67.7 %

Procedure:
In a similar fashion using route 14 general procedure 26, 5-fluoro-quinolin-8-ylamine (Intermediate 50) (350 mg, 2.0 mmol), 2-nitro-benzenesulfonyl chloride (575 mg, 2.59 mmol), pyridine (0.35 ml, 4.3 mmol) and DCM (12 ml) gave the title compound (470 mg, 63%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [OH-:1].[Na+].F[C:4]1[C:5]([N+:13]([O-:15])=[O:14])=[C:6]([O:11][CH3:12])[CH:7]=[C:8]([F:10])[CH:9]=1>CS(C)=O.Cl>[F:10][C:8]1[CH:7]=[C:6]([O:11][CH3:12])[C:5]([N+:13]([O-:15])=[O:14])=[C:4]([OH:1])[CH:9]=1
Reactant: COc1cc(F)cc(F)c1[N+](=O)[O-]
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc(F)cc(O)c1[N+](=O)[O-]
Yield: 50.5 %

Procedure:
In 10N NaOH (13.1 ml, 131 mmol) and DMSO (25 ml), 3,5-difluoro-2-nitroanisole (8.29 g, 43.8 mmol) was stirred at 50° C. for 5 hours. After cooling, the reaction mixture was poured in 1N HCl (200 ml), followed by extraction with ethyl acetate (300 ml). The extract was washed with saturated brine (2×100 ml), dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from hexane-ethyl acetate (4:1) eluate fractions, the title compound (4.14 g, 51%) was obtained as a yellow oil.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=1[OH:11])=[O:3].[CH2:12]([CH:14]1[O:16][CH2:15]1)Br.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[OH:11][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH2:12][CH:14]2[O:16][CH2:15]2)=[CH:9][C:4]=1[C:2]([CH3:1])=[O:3]
Reactant: CC(=O)c1cc(O)ccc1O
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1cc(OCC2CO2)ccc1O

Procedure:
A solution containing 3.00 g (0.020 mole) of 2,5-dihydroxyacetophenone, 3.37 ml (0.040 mole) of epibromhydrine and 5.06 g (0.040 mole) of K2CO3 in 30 ml of acetone are heated for 8 hours under reflux. The solvent is evaporated off, 20 ml of a saturated solution of NaH2PO4 and 120 ml of water are added, and an extraction carried out with ethyl acetate.
Reaction SMILES: [CH2:1]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].[CH3:22][SnH:23]([CH3:25])[CH3:24]>>[C:18]1([CH3:21])[CH:19]=[CH:20][C:15]([S:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][Sn:23]([CH3:25])([CH3:24])[CH3:22])(=[O:14])=[O:13])=[CH:16][CH:17]=1
Reactant: C[SnH](C)C
Reactant: C=CCCCCCCCCCS(=O)(=O)c1ccc(C)cc1
Product: Cc1ccc(S(=O)(=O)CCCCCCCCCCC[Sn](C)(C)C)cc1

Procedure:
The procedure described in Example 1 was employed except that 13.1 g (42.5 mmoles) of 10-undecenyl-p-tolyl sulfone and 14.0 g (85 mmoles) of trimethyltin hydride were the reactants. The reaction mixture was irradiated for 189 hours. The excess trimethyltin hydride was allowed to evaporate from the reaction mixture under a flow of nitrogen. The residual oil weighed 15.5 g. One-half of the crude product was chromatographed on a column containing silica gel using toluene and 2% acetone in toluene as eluents. The product, 11-(p-tolylsulfonyl)-undecyltrimethylstannane, was obtained as an oil. The presence of both the sulfonyl and trimethyltin groups was indicated by the strong infrared absorption bands at 1315 cm-1, 1300 cm-1, 1285 cm-1, 1140 cm-1 (--SO2 ) and 760 cm-1 [(CH3)3Sn--]. NMR showed the following:
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[C@H:18]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:17][CH2:16]3)=[C:6]([O:30][CH3:31])[CH:5]=1)=[S:3].Cl[CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][C:34]1=O>CCO>[CH3:31][O:30][C:6]1[CH:5]=[C:4]([C:2]2[S:3][C:33]3[CH2:38][CH2:37][CH2:36][CH2:35][C:34]=3[N:1]=2)[CH:29]=[CH:28][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[C@H:18]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:17][CH2:16]2
Reactant: O=C1CCCCC1Cl
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(C(N)=S)cc3OC)ccc21
Solvent: CCO
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(-c4nc5c(s4)CCCC5)cc3OC)ccc21
Yield: 59.4 %

Procedure:
A solution of ethyl ((1S)-5-{3-[4-(aminocarbonothioyl)-2-methoxyphenoxy]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (Example 146, 90 mg, 0.2 mmol) and 2-chlorocyclohexanone (215 mg 1.6 mmol) in anhydrous EtOH (8 mL) was stirred at 70° C. for 48 h. The reaction was cooled, and the solvent was removed under reduced pressure. The residue was purified by silica gel flash chromatography (2:1 hexanes/ethyl acetate) to provide the title compound (62 mg, 58%) as clear oil. LC-MS: RT=4.08 min, (M+H)+ 522.5.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15]2=[N:16][C:17]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)[N:19]=[C:14]2[CH:13]=[CH:12]1)[CH3:2].[Br:35]N1C(=O)CCC1=O>C(Cl)Cl>[Br:35][C:13]1[C:14]2[C:15](=[N:16][C:17]([C:27]3[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=3)=[C:18]([C:20]3[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=3)[N:19]=2)[N:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:34])[CH:12]=1
Reactant: CCOC(=O)CCCCCCn1ccc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CCOC(=O)CCCCCCn1cc(Br)c2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
7-(2,3-Di-p-tolyl-pyrrolo[2,3-b]pyrazin-5-yl)-heptanoic acid ethyl ester (Intermediate B) (135 mg, 0.296 mmol) in DCM (5 ml) was treated with N-bromosuccinimide (52.7 mg, 0.296 mmol) and the reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with DCM (50 ml) and washed with water (×2), brine (×1) and the organic solvent was removed under reduced pressure. Purification of the crude product by chromatography on silica using a gradient from 0-10% EtOAc in iso-hexane afforded the titled compound as an orange oil;
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:13][CH2:12]1.C(N(C(C)C)CC)(C)C>COCCO>[CH2:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][CH:11]([CH2:10][NH:9][C:2]2[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:12][CH2:13]1)=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Fc1cccnc1Cl
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCO
Product: O=C(OCc1ccccc1)N1CCC(CNc2ncccc2F)CC1

Procedure:
A solution of 2-chloro-3-fluoropyridine (prepared in a manner similar to that described by W. J. Link, R. F. Borne and F. L. Setliff, J. Heterocyclic Chem. 4, 641–3, 1967) (131 mg 1 mmol), benzyl 4-(aminomethyl)piperidine-1-carboxylate (EXAMPLE 13, STEP 1) (248 mg, 1 mol) and diisopropylethylamine (129 mg, 1 mmol) were heated to reflux in 2-methoxyethanol for 2 days under nitrogen. The reaction mixture was concentrated, partitioned between ethyl acetate and water, the organic layer washed with brine, dried over anhydrous sodium sulfate and solvent evaporated to give the crude product purified by chromatography on silica. M.S. (M+1): 344.3
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.CN1CCCC1=O.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O>[C:19]([NH:9][NH:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NNC(=O)c1ccc(Br)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(NNC(=O)c1ccc(Br)cc1)c1ccccc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
In a 200 mL three-necked flask were placed 15 g (71 mmol) of 4-bromobenzoylhydrazine and 20 mL of N-methyl-2-pyrrolidone (abbreviation: NMP). To this mixture was dripped a solution of 9.4 mL (81 mmol) of benzoyl chloride in 5 mL solution of N-methyl-2-pyrrolidone through a 50 mL dropping funnel. This solution was stirred at 80° C. for 3 hours under a stream of nitrogen. After a predetermined time, this solution was added to about 100 mL of water, and the precipitated solid was collected by suction filtration. The collected solid was washed with methanol, and 19 g of a white powder, which was a target substance, was obtained at a yield of 84%.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]([CH:8]=O)=[CH:6][CH:7]=1.[F:10][C:11]([F:25])([F:24])[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH2:21][C:22]#[N:23])(=[O:20])=[O:19])=[CH:14][CH:13]=1>>[CH3:1][S:2][C:3]1[S:4][C:5](/[CH:8]=[C:21](/[S:18]([C:15]2[CH:14]=[CH:13][C:12]([C:11]([F:25])([F:10])[F:24])=[CH:17][CH:16]=2)(=[O:20])=[O:19])\[C:22]#[N:23])=[CH:6][CH:7]=1
Reactant: CSc1ccc(C=O)s1
Reactant: N#CCS(=O)(=O)c1ccc(C(F)(F)F)cc1
Product: CSc1ccc(/C=C(\C#N)S(=O)(=O)c2ccc(C(F)(F)F)cc2)s1

Procedure:
Reaction of 2-methylmercaptothiophen-5-carboxaldehyde and 4-trifluoromethylphenylsulfonylacetonitrile as in Example 1 gave (E)-3-(2-methylmercaptothien-5-yl)-2-[4-(trifluoromethyl)phenylsulfonyl]acrylonitrile
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH2:20][CH:21]1[CH2:23][O:22]1)[N:15]=[CH:14][CH:13]=[C:12]2[O:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)=[O:33])=[C:27]([F:42])[CH:26]=1)#[N:8]>O1CCCC1>[C:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH2:20][CH:21]([OH:22])[CH2:23][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[N:15]=[CH:14][CH:13]=[C:12]2[O:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)=[O:33])=[C:27]([F:42])[CH:26]=1)#[N:8]
Reactant: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)c(F)c3)ccnc2cc1OCC1CO1
Reactant: C1CCNCC1
Solvent: C1CCOC1
Product: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)c(F)c3)ccnc2cc1OCC(O)CN1CCCCC1
Temperature: 50 °C

Procedure:
After adding tetrahydrofuran (1.5 ml) and piperidine (0.08 ml) to N-[4-(6-cyano-7-oxiranylmethoxyquinolin-4-yloxy)-2-fluorophenyl]-N′-(4-fluorophenyl)urea (78 mg), the mixture was heated at 50° C. for 30 minutes. The reaction solution was purified by NH silica gel column chromatography (ethyl acetate-methanol system) to obtain the title compound (32 mg) as light yellow crystals.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([N+:17]([O-])=O)=[CH:15][CH:14]=[C:13]3[C:9]=2/[C:10](=[CH:21]/[C:22]2[NH:23][CH:24]=[CH:25][C:26]=2[O:27][CH3:28])/[C:11](=[O:20])[NH:12]3)=[CH:4][CH:3]=1.[Cl-].[NH4+]>O.CO.[Zn]>[NH2:17][C:16]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:20])/[C:10]/2=[CH:21]\[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(-c3ccc(O)cc3)c21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(N)c(-c3ccc(O)cc3)c21
Yield: 49.7 %

Procedure:
Using Method L above, (Z)-1,3-dihydro-4-(4-hydroxyphenyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-2H-indol-2-one (84 mg, 0.22 mmol) (from Example 37 supra) was reduced with zinc (130 mg, 2.0 mmol) and ammonium chloride (25.9 mg, 0.48 mmol) in 10% water in methanol (20 mL) at reflux for 18 h to give (Z)-5-amino-1,3-dihydro-4-(4-hydroxyphenyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (yield: 38 mg, 49%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]([CH3:21])([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:22](OC)(OC)(OC)[CH2:23][CH2:24][CH3:25]>C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[CH3:21][C:14]([CH3:20])([CH2:13][N:12]1[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=[C:22]1[CH2:23][CH2:24][CH3:25])[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCCC(OC)(OC)OC
Reactant: CCOC(=O)C(C)(C)CNc1c(N)cnc2ccccc12
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: CCCc1nc2cnc3ccccc3c2n1CC(C)(C)C(=O)OCC
Yield: 21.3 %

Procedure:
Ethyl 3-[(3-aminoquinolin-4-yl)amino]-2,2-dimethylpropanoate (8.2 g, 29 mmol) was treated according to a modification of the method described in Part B of Example 8. Prior to the addition of trimethyl orthobutyrate (5.3 g, 36 mmol) and pyridinium p-toluenesulfonate (0.10 g, 0.40 mmol), the reaction was heated at reflux for ten minutes. During the work-up procedure, the solution was dried over potassium carbonate. The crude product was purified by column chromatography on silica gel (eluting with 93:7 dichloromethane:methanol containing 3 mL concentrated ammonium hydroxide per liter of eluent) to provide 2.1 g of ethyl 2,2-dimethyl-3-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propanoate as an orange oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[CH:14]=[C:15]([NH:19][C:20]3[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=[CH:22][N:21]=3)[CH:16]=[CH:17][CH:18]=1)[CH:7]=[CH:6]2.[Br:29]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl>[Br:29][C:4]1[C:3]([O:2][CH3:1])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8]([C:13]1[CH:14]=[C:15]([NH:19][C:20]3[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=[CH:22][N:21]=3)[CH:16]=[CH:17][CH:18]=1)=[CH:9]2
Reactant: COc1ccc2cc(-c3cccc(Nc4ncccc4[N+](=O)[O-])c3)ccc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1ccc2cc(-c3cccc(Nc4ncccc4[N+](=O)[O-])c3)ccc2c1Br
Yield: 52.3 %

Procedure:
The mixture of 2-[3-(6-methoxy-2-naphthyl)phenylamino]-3-nitropyridine (5.2 g), N-bromosuccinimide (3.24 g) and benzoylperoxide (678 mg) in chloroform (30 ml) was refluxed for 3 hours. The mixture was concentrated in vacuo and was purified by column chromatography (silica gel) to obtain 2-[3-(5-bromo-6-methoxy-2-naphthyl)phenylamino]-3-nitropyridine (3.3 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=O)=[CH:2]1.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[CH:13]=1>ClCCl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[N:18]\[C:14]2[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=2)=[CH:2]1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: Nc1cccnc1
Solvent: ClCCl
Product: C(=N\c1cccnc1)\c1c[nH]c2ccccc12
Temperature: 25 °C

Procedure:
A mixture of indole-3-carbaldehyde (1 g, 6.9 mmol, 1.0 eq.) and pyridin-3-ylamine (843 mg, 9.0 mmol, 1.3 eq.) in anhydrous dichloromethane (15 mL) was heated in a sealed tube at reflux temperature for 36 hours. The reaction was allowed to cool to room temperature and then, the insoluble was filtered, washed with dichloromethane and diethyl ether to afford (Z)-(1H-indol-3-ylmethylene)-pyridin-3-amine as a beige powder (1.5 g, Rdt: 98%).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=2[O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:11](O)=[O:12])[C:5]2[CH:24]=[CH:25][NH:26][C:4]=2[C:3]1=[O:27].C(Cl)(=O)C([Cl:31])=O.CN(C)C=O>ClCCl>[CH3:1][N:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=2[O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:11]([Cl:31])=[O:12])[C:5]2[CH:24]=[CH:25][NH:26][C:4]=2[C:3]1=[O:27]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cn1cc(-c2cc(C(=O)O)ccc2Oc2ccccc2)c2cc[nH]c2c1=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc(C(=O)Cl)ccc2Oc2ccccc2)c2cc[nH]c2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.5 %

Procedure:
A solution of Example 10 (0.24 g, 0.67 mmol) in dichloromethane (10 mL) was treated with oxalyl chloride (0.17 g, 1.33 mmol) and dimethylformamide (5 mg, 10 mol %). The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure to afford the title compound (0.25 g, quantitative).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[N:12]=[C:13]3[C:19]([C:20]([NH:22][C:23]([CH3:27])([CH3:26])[CH2:24][OH:25])=[O:21])=[CH:18][N:17](COCC[Si](C)(C)C)[C:14]3=[N:15][CH:16]=1)[N:6]=[CH:5]2.FC(F)(F)C(O)=O>ClCCl>[OH:25][CH2:24][C:23]([NH:22][C:20]([C:19]1[C:13]2[C:14](=[N:15][CH:16]=[C:11]([N:7]3[C:8]4[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=4)[CH:5]=[N:6]3)[N:12]=2)[NH:17][CH:18]=1)=[O:21])([CH3:27])[CH3:26]
Reactant: CC(C)(CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-n3ncc4cc(F)ccc43)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CO)NC(=O)c1c[nH]c2ncc(-n3ncc4cc(F)ccc43)nc12
Reaction time: 15 h
Yield: 0.1 %

Procedure:
To a stirred solution of 2-(5-fluoro-1H-indazol-1-yl)-N-(1-hydroxy-2-methylpropan-2-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (50 mg, 100 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL). After 15 h, the mixture was concentrated in vacuo and a Jan. 10, 1960 mixture of ammonium hydroxide/methanol/dichloromethane (25 mL) added. After 1 h the mixture was concentrated in vacuo and purified by chromatography (silica, 24 g Analogix column, 0-4% methanol containing 10% ammonium hydroxide in dichloromethane) to give 2-(5-fluoro-indazol-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (25 mg, 68%). MS (M−H)−=367; 1H NMR (DMSO-d6) δ: 9.04 (s, 1H), 8.70 (dd, J=9.3, 4.6 Hz, 1H), 8.52 (d, J=0.8 Hz, 1H), 8.41 (s, 1H), 7.76 (dd, J=8.9, 2.3 Hz, 1H), 7.63 (s, 1H), 7.49 (d, J=2.6 Hz, 1H), 3.57-3.62 (m, 2H), 1.44 (s, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10](OC)[CH:9]=[C:8](Cl)[C:5]=1[CH:6]=O)([O-])=O.C(O)C.Cl.Cl.[NH2:20][C:21](N)=N>C1C=CC=CC=1.[Fe]>[N:1]1[C:4]2[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[N:20][CH:21]=1
Reactant: N=C(N)N
Reactant: COc1cc(Cl)c(C=O)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: c1ccccc1
Product: c1ccc2ncncc2c1

Procedure:
The nitro group of 2-nitro-4-methoxy-6-chlorobenzaldehyde (1 equivalent) is reduced to the amine by refluxing in benzene or ethanol with iron powder (the powder having been pretreated with concentrated hydrochloric acid). This amine is then treated with guanidine hydrochloride as described above (step k) to yield the quinazoline (COMPOUND XXIII) which is purified by column chromatography and/or crystallization. Benzoylation of this product is performed as described above (step d), to yield COMPOUND XXII.
Reaction SMILES: [NH2:1][C:2]1[O:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([NH2:16])[N:12]=3)[CH:7]=[CH:6][C:5]=2[CH:4]([C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([Br:27])[CH:18]=2)[C:3]=1[C:28]#[N:29].[CH2:30]([N:32]=[C:33]=[O:34])[CH3:31]>C(#N)C>[NH2:1][C:2]1[O:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([NH:16][C:33]([NH:32][CH2:30][CH3:31])=[O:34])[N:12]=3)[CH:7]=[CH:6][C:5]=2[CH:4]([C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([Br:27])[CH:18]=2)[C:3]=1[C:28]#[N:29]
Reactant: CCN=C=O
Reactant: COc1cc(C2C(C#N)=C(N)Oc3c2ccc2ccc(N)nc32)cc(Br)c1OC
Solvent: CC#N
Product: CCNC(=O)Nc1ccc2ccc3c(c2n1)OC(N)=C(C#N)C3c1cc(Br)c(OC)c(OC)c1
Temperature: 60 °C
Yield: 72.5 %

Procedure:
3,6-Diamino-1-(3-bromo-4,5-dimethoxy-phenyl)-1H-4-oxa-5-aza-phenanthrene-2-carbonitrile (20) (45 mg, 0.1 mmol) and ethylisocyanate (8.4 mg, 0.12 mmol) were taken in 2 ml dry acetonitril and stirred at 60° C. monitoring the reaction with LC-MS. The solvent was evaporated after the completion of the reaction. The residue was separated on HPLC (high pressure liquid chromatography) (21 mm×250 mm, RP18, 5 mm) with a methanol/water gradient (5% MeOH to MeOH in 25 min, flow 21 ml/min) to get the title compound (38 mg, 73%).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]#[N:13])(=O)OCC)C.[CH3:14][N:15]1[C:19]([NH:20][C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([CH:40]=O)[CH:17]=[N:16]1>O1CCCC1>[CH3:14][N:15]1[C:19]([NH:20][C:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([CH:40]=[CH:11][C:12]#[N:13])[CH:17]=[N:16]1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: Cn1ncc(C=O)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1ncc(C=CC#N)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 60.9 %

Procedure:
To a suspension of sodium hydride (55% dispersion in mineral oil, 26.2 g, 600 mmol) in tetrahydrofuran (1000 ml) was added diethyl(cyanomethyl)phosphonate (106.3 g, 600 mmol) under ice-cooling. The mixture was stirred under ice-cooling for 20 minutes. To the mixture was added 1-methyl-5-triphenylmethylaminopyrazole-4-carbaldehyde (197 g, 530 mmol), and the mixture was stirred for 2 hours. The reaction mixture was poured into ice-cold water. The mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was triturated with diethyl ether to give 3-(1-methyl-5-triphenylmethylaminopyrazol-4-yl)acrylonitrile (E, Z mixture, 126 g) as a solid.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1([CH3:19])[CH:14]=[CH:13][C:12](S(O)(=O)=O)=[CH:11][CH:10]=1>O1CCCC1.CN(C)C=O>[CH2:1]([O:8][CH2:19][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: c1ccc(COCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In a manner similar to that described in Example I, 0.68 ml of benzyl alcohol and 7 mg of p-toluenesulfonic acid are added to a solution of 350 mg of Compound Z-1(DMTD) in a mixture of 7 ml of tetrahydrofuran and 3 ml of dimethylformamide and the mixture stirred at room temperature for 24 hours. At the end the volatiles are removed in vacuo to obtain a residue which is purified on a preparative HPLC column using water/acetonitrile (40/60) as eluant. The appropriate fractions are combined and lyophilized to obtain benzyl ether of Z-1(DMTD).