Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2.[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16]Br.C([O-])([O-])=O.[Cs+].[Cs+].[I-].[Cs+]>CN(C=O)C>[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2
Reactant: COC(CBr)OC
Reactant: O=C1NCCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Product: COC(COc1ccc2c(c1)CCNC2=O)OC

Procedure:
6-Hydroxy-1-oxo-1,2,3,4-tetrahydroisoquinoline is treated with bromacetaldehyde dimethyl acetal, in the presence of Cs2CO3 and CsI in DMF to yield 6-(2,2-dimethoxyethoxy)-1-oxo-1,2,3,4-tetrahydroisoquinoline. Treatment with 2-chloromethylpyridine hydrochloride in the presence of sodium hydride in DMF yields 6-(2,2-dimethoxyethoxy)2-(2-pyridylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline. Hydrolysis with 20% aqueous sulfuric acid in THF yields α-[2-(2-pyridylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yloxy]-acetaldehyde which is then converted to 2-(2-pyridylmethyl)-6-[2-(N-hydroxyamino)-ethoxy]-1-oxo-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [N:1]([C@H:4]1[C@H:11]([OH:12])[C@@H:10]([CH2:13][OH:14])[O:9][CH:6]([O:7][CH3:8])[C@@H:5]1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[N+:2]=[N-:3].[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>N1C=CC=CC=1>[N:1]([C@H:4]1[C@H:11]([OH:12])[C@@H:10]([CH2:13][O:14][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:9][CH:6]([O:7][CH3:8])[C@@H:5]1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[N+:2]=[N-:3]
Reactant: COC1O[C@H](CO)[C@@H](O)[C@H](N=[N+]=[N-])[C@H]1OCc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: COC1O[C@H](COC(=O)c2ccccc2)[C@@H](O)[C@H](N=[N+]=[N-])[C@H]1OCc1ccccc1
Yield: 78 %

Procedure:
Methyl 3-azido-2-O-benzyl-3-deoxy-D-glucopyranoside (93 mg) was dissolved in 0.84 mL of pyridine. Benzoyl chloride (45 μL) was added to the solution at −20° C. with stirring, and the mixture was stirred at −20° C. for one hr. Water (14 μL) was added thereto, and the mixture was stirred at −20° C. for 30 min. The contents were concentrated to dryness. Chloroform (10 mL) was added thereto, and the mixture was washed three times with 5 mL of a saturated aqueous sodium bicarbonate solution, three times with 5 mL of a 5% aqueous potassium bisulfate solution and three times with 5 mL of water, was dried over a Glauber's salt and was concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (25 g, hexane:ethyl acetate=3:1) to give the title compound (97 mg, yield 78%).
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[C:12]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17](CO)[CH:16]=4)[CH:11]=[C:10]([C:23]([NH:25][CH2:26][C:27]4[C:28](=[O:35])[NH:29][C:30](C)=[CH:31][C:32]=4[CH3:33])=[O:24])[C:9]=3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:36]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:55]([Br:59])(Br)(Br)Br.O>C(Cl)Cl>[Br:59][CH2:55][C:17]1[CH:16]=[C:15]([C:12]2[CH:11]=[C:10]([C:23]([NH:25][CH2:26][C:27]3[C:28](=[O:35])[N:29]([CH3:36])[CH:30]=[CH:31][C:32]=3[CH3:33])=[O:24])[C:9]3[CH:8]=[N:7][N:6]([CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[C:14]=3[CH:13]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3cccc(CO)c3)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Reactant: BrC(Br)(Br)Br
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: Cc1ccn(C)c(=O)c1CNC(=O)c1cc(-c2cccc(CBr)c2)cc2c1cnn2C1CCCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72.1 %

Procedure:
To a stirred solution of 1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-6-(3-(hydroxymethyl)phenyl)-1H-indazole-4-carboxamide (1.2 g, 2.6 mmol) in DCM (15 mL), triphenyl phosphine (2 g, 7.7 mmol) was added and reaction mixture stirred at room temperature for 10 min. Finally CBr4 (2.53 g, 7.65 mmol) was added portion-wise and resulting solution was stirred at room temperature for 18 h. On completion, water was added to the reaction mixture and aqueous layer extracted with 10% MeOH/DCM. Combined organic layer was dried over sodium sulfate and concentrated to give crude material which was purified by column chromatography over silica gel (60-120 mesh size) to afford 6-(3-(bromomethyl)phenyl)-1-cyclopentyl-N-((dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indazole-4-carboxamide (1.0 g, 74.1%).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:21])[CH:10]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([O:19][CH3:20])[CH:13]=2)[OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:23][CH2:24][CH2:25][Cl:26].C(=O)([O-])[O-].[K+].[K+].C([O-])(=O)C(C1C=CC=CC=1)O>CC(C)=O>[C:1]1([CH2:7][O:8][C:9](=[O:21])[CH:10]([OH:11])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:23][CH2:24][CH2:25][Cl:26])=[C:14]([O:19][CH3:20])[CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cc(C(O)C(=O)OCc2ccccc2)ccc1O
Reactant: ClCCCBr
Agent: O=C([O-])C(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(C(O)C(=O)OCc2ccccc2)ccc1OCCCCl
Yield: 21.8 %

Procedure:
A mixture of 2.92 g (0.008 mole) of 4-hydroxy-3-methoxymandelic acid (phenylmethyl) ester, 2 ml (0.02 mole) of 1-bromo-3-chloropropane, and 2.80 g (0.02 mole) of potassium carbonate in 40 ml of acetone was heated at reflux for 16 hours under nitrogen atmosphere during which time the solution changed from colorless to light-yellow. TLC (silica gel, hexanes/acetone 4:1) showed that the mandelate derivative had reacted, but 30-40% of unknown impurities had formed. The inorganic materials were separated by filtration, washed with acetone, and the filtrate was concentrated in vacuo at 60° C. to give 3.65 g of crude product. The material was purified by column chromatography (diameter 25 mm, using 80 g of silica gel) eluted with cyclohexane/ethyl acetate (6:1). The fractions containing the product were collected and the solid recrystallized from ethyl ether/hexanes to give 0.637 g (22%) of material as a white powder.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[I-].[K+].C(=O)(O)[O-].[K+].[C:14]1([C:20]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([CH2:23][CH2:24]Br)[C:21]#[N:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O>[C:26]1([C:20]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([CH2:23][CH2:24][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:21]#[N:22])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: N#CC(CCBr)(c1ccccc1)c1ccccc1
Reactant: C1CCNCC1
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: O
Product: N#CC(CCN1CCCCC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 66.6 %

Procedure:
1.96 Parts piperidine, 1.91 parts potassium iodide and 25 parts deionized water are combined and gently heated under a nitrogen atmosphere. To this slurry is then added 2.75 parts of potassium bicarbonate, followed by 7.51 parts of 2,2-diphenyl-4-bromobutyronitrile. The mixture is heated to reflux and maintained thereat for 4.5 hours. After cooling to room temperature, the reaction mixture is extracted three times with 14 part portions of ethyl ether. The ether extracts are combined, and extracted six times with 25 parts by volume portions of dilute acetic acid solution. The acid extracts are combined, basified to about pH 10 - 12 with 50% sodium hydroxide solution, and again extracted with ethyl ether. The ether extracts are combined, washed with water and saturated sodium chloride solution, and dried over anhydrous potassium carbonate. Removal of the solvent affords 2,2-diphenyl-4-piperidinobutyronitrile, identical to the product of Example 22, in a 66.6% yield.
Reaction SMILES: [CH:1]1([C:7]2[CH:31]=[CH:30][C:10]([O:11][CH2:12][CH:13]3[O:29][C:16]4=[N:17][C:18](=[O:28])[C:19]([S:21][C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)=[CH:20][N:15]4[CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B1([O-])O[O:33]1.[OH2:36].[OH2:37].O.O.[Na+].[OH-].[Na+]>CC(O)=O>[C:22]1([S:21]([C:19]2[C:18](=[O:28])[N:17]=[C:16]3[O:29][C@H:13]([CH2:12][O:11][C:10]4[CH:30]=[CH:31][C:7]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]5)=[CH:8][CH:9]=4)[CH2:14][N:15]3[CH:20]=2)(=[O:37])=[O:36])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[C:22]1([S:21]([C:19]2[C:18](=[O:28])[N:17]=[C:16]3[O:29][C@H:13]([CH2:12][O:11][C:10]4[CH:30]=[CH:31][C:7]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]5)=[CH:8][CH:9]=4)[CH2:14][N:15]3[CH:20]=2)=[O:33])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: [O-]B1OO1
Reactant: O
Reactant: O=c1nc2n(cc1Sc1ccccc1)CC(COc1ccc(C3CCCCC3)cc1)O2
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=c1nc2n(cc1S(=O)(=O)c1ccccc1)C[C@@H](COc1ccc(C3CCCCC3)cc1)O2
Product: O=c1nc2n(cc1S(=O)c1ccccc1)C[C@@H](COc1ccc(C3CCCCC3)cc1)O2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(4-cyclohexyl-phenoxymethyl)-6-phenylsulfanyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one (0.313 g, 0.675 mmol) (prepared in accordance with the procedures set forth in Example 93), in HOAc (6 mL) was added sodium perborate tetrahydrate (0.277 g, 1.80 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was then neutralized with NaOH (2N) to PH˜9. The mixture was extracted with EtOAc three times. The organic phase was washed with brine and dried (Na2SO4). Silica gel chromatography (0-6% 2-propanol/CH2Cl2) provided 0.026 g of (S)-6-benzenesulfonyl-2-(4-cyclohexyl-phenoxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one, 0.022 g of (S)-6-benzenesulfinyl-2-(4-cyclohexyl-phenoxymethyl)-2,3-dihydro-oxazolo[32-a]pyrimidin-7-one (Diastereomer 1) and 0.086 g of (S)-6-benzenesulfinyl-2-(4-cyclohexyl-phenoxymethyl)-2,3-dihydro-oxazolo[32-a]pyrimidin-7-one (diastereomer 2).
Reaction SMILES: C[O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:11]=2)[N:6]=[CH:5][CH:4]=1.[CH3:17][Mg]Cl.Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].Cl>O1CCCC1.CO>[CH2:24]([O:23][C:21]([N:6]1[C:7]2[C:12](=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[C:3](=[O:2])[CH2:4][CH:5]1[CH3:17])=[O:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COc1ccnc2ccc(C(F)(F)F)cc12
Reactant: C[Mg]Cl
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CC1CC(=O)c2cc(C(F)(F)F)ccc2N1C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
4-Methoxy-6-trifluoromethylquinoline (5.0 g, 22.0 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL). The mixture was cooled to -78 ° C., and methyl magnesium chloride (73 mL of a 3.0M solution in tetrahydrofuran, 220 mmol) was added to the resulting slurry. After addition, benzyl chloroformate (41 mL, 286 mmol) was added to the slurry. After stirring at room temperature overnight, 75 mL of methanol was added followed by 75 mL of a 1N aqueous HCl solution. After hydrolysis of the intermediate enol ether was judged to be complete by thin layer chromatography, the volatiles were removed in vacuo, and the remaining aqueous phase was extracted with ethyl acetate (3×150 mL). The organic phases were combined and washed with a saturated sodium bicarbonate solution (2×75 mL), brine (100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give 47 g of crude product. Purification by silica gel chromatography using 10% ethyl acetate/hexanes as eluent afforded 5.54 g of the title product (69%).1H NMR (CDCl3) δ 1.25 (d, 3H, J=7 Hz), 2.62 (dd, 1H, J=17, 2 Hz), 3.05 (dd, 1H, J=17, 6 Hz), 5.1-5.2 (m, 1H), 5.28 (d, 1H, J=12 Hz), 5.35 (d, 1H, J=12 Hz), 7.3-7.5 (m, 5H), 7.71 (dd, 1H, J=9,2 Hz), 8.05 (d, 1H, J=9 Hz), 8.27 (d, 1H, J=2 Hz).
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2](C(Cl)=O)=[CH:3][CH:4]=[CH:5][CH:6]=1.Cl.Cl.[CH3:18][N:19]([CH3:33])[CH2:20][CH2:21][CH2:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[NH:29][CH2:28][CH2:27][CH2:26]2.C(N(CC)CC)C.[C:41](OCC)(=[O:43])C>CN(C)C=O>[C:10]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:11]=[CH:12][C:13]([C:41]([N:29]2[C:30]3[C:25](=[CH:24][C:23]([CH2:22][CH2:21][CH2:20][N:19]([CH3:18])[CH3:33])=[CH:32][CH:31]=3)[CH2:26][CH2:27][CH2:28]2)=[O:43])=[CH:14][CH:15]=1
Reactant: O=C(Cl)c1ccccc1-c1ccccc1
Reactant: CCOC(C)=O
Reactant: CN(C)CCCc1ccc2c(c1)CCCN2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)CCCc1ccc2c(c1)CCCN2C(=O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Biphenylcarbonyl chloride (327 mg, 1.51 mmol) was added to a solution of N,N-dimethyl-3-(1,2,3,4-tetrahydro-6-quinolinyl)-1-propanamine dihydrochloride (400 mg, 1.37 mmol) obtained in Reference Example 4 and triethylamine (669 ml, 4.81 mmol) in dimethylformamide under cooling with ice-bath, and the mixture was stirred at room temperature for 3 days. Ethyl acetate was added to the reaction solution which was then washed with an aqueous saturated sodium bicarbonate solution and a saturated saline solution and dried over anhydrous sodium sulfate, and the solvent was distilled away under reduced pressure. The resultant residues were purified by alumina column chromatography (developing solvent; hexane:ethyl acetate=3:1) and crystallized from hexane, whereby the title compound (113 mg) was obtained as colorless powder with a mp. of 100 to 101° C.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([C:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[NH:15][CH:14]=3)=[O:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:27][C:28](=[N:30][C:31]([NH:33]C(=O)C(F)(F)F)=[CH2:32])[CH3:29].[CH3:40]N(C=O)C>>[NH2:33][C:31]1[N:30]=[C:28]([CH2:29][N:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22](=[O:23])[C:13]([C:11]([C:9]3[CH:8]=[CH:7][C:6]4[O:1][CH2:2][CH2:3][O:4][C:5]=4[CH:10]=3)=[O:12])=[CH:14]2)[CH:27]=[CH:40][CH:32]=1
Reactant: C=C(N=C(C)CBr)NC(=O)C(F)(F)F
Reactant: O=C(c1ccc2c(c1)OCCO2)c1c[nH]c2ccccc2c1=O
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: Nc1cccc(Cn2cc(C(=O)c3ccc4c(c3)OCCO4)c(=O)c3ccccc32)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The mixture of 3-(2,3-Dihydro-benzo[1,4]dioxine-6-carbonyl)-1H-quinolin-4-one 70 mg (0.228 mmol) in DMF (1 mL) and sodium hydride 11.8 mg (0.296 mmol ) was stirred at room temperature for 60 min, followed by the addition of N-[1-(2-Bromo-1-methyl-ethylideneamino)-vinyl]-2,2,2-trifluoro-acetamide 83.8 mg (0.296 mmol). The mixture was stirred for 60 min, quenched with water, taken up with ethyl acetate, dried over sodium sulfate and purified with flash chromatography. The purified product was treated with Diethylamine in methanol over weekend, filtered to give the desired product 10 mg. LCMS observed for (M+H)+: 414.
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[S:13])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20](=[O:26])[CH:21](Cl)[C:22](=O)[CH3:23])[CH3:18]>C(O)C>[CH2:17]([O:19][C:20]([C:21]1[S:13][C:12]([C:11]2[CH:10]=[CH:9][C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:16][CH:15]=2)=[N:14][C:22]=1[CH3:23])=[O:26])[CH3:18]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: NC(=S)c1ccc(Oc2ccccc2)cc1
Solvent: CCO
Product: CCOC(=O)c1sc(-c2ccc(Oc3ccccc3)cc2)nc1C
Temperature: 25 °C
Yield: 93.8 %

Procedure:
A mixture of 4-phenoxy-thiobenzamide (1.02 g, 4.43 mmole) and 2-chloro-3-oxo-butyric acid ethyl ester (625 μl, 4.52 mmole) in ethanol (15 ml) was refluxed for 18 h before it was cooled to room temperature and concentrated in vacuo. It was partitioned between ethyl acetate and saturated sodium bicarbonate, the organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a yellow solid (1.41 g). MS: (+) m/z 340.07 (M+1).
Reaction SMILES: [CH:1]([O:6]C)([O:4][CH3:5])OC.[CH3:8][OH:9].OS(O)(=O)=O.N1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:8][O:9]/[C:17](/[C:18]1[CH:19]=[CH:18][CH:17]=[CH:16][C:19]=1[CH3:20])=[CH:16]/[C:1]([O:4][CH3:5])=[O:6]
Reactant: COC(OC)OC
Reactant: CO
Reactant: c1ccncc1
Agent: O=S(=O)(O)O
Product: COC(=O)/C=C(/OC)c1ccccc1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 94 %

Procedure:
A mixture of 1280 g (6.7 mol ) of methyl 2-methylbenzoyl acetate, 848 g (8.0 mol) of trimethyl orthoformate, 400 ml of methanol and 10 ml of concentrated H2SO4 is stirred at room temperature for 12 h. The mixture is subsequently neutralized with 20 ml of pyridine and then concentrated, and the residue is fractionally distilled (boiling point 120-123° C./0.6 torr). 1300 g (94%) of methyl (E)-β-methoxy-2-methylcinnamate are obtained as a pale yellow oil.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:17][C:16]3[C:11](=[N:12][CH:13]=[CH:14][C:15]=3[O:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=3[F:28])[CH:10]=2)=[CH:5][CH:4]=1.[CH2:29]([CH2:31][NH2:32])[OH:30]>COCCOC>[F:28][C:20]1[CH:21]=[C:22]([N+:25]([O-:27])=[O:26])[CH:23]=[CH:24][C:19]=1[O:18][C:15]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:10]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([CH2:2][NH:32][CH2:31][CH2:29][OH:30])=[CH:8][CH:7]=3)[S:17][C:16]=12
Reactant: NCCO
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(CCl)cc4)sc23)c(F)c1
Solvent: COCCOC
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(CNCCO)cc4)sc23)c(F)c1
Yield: 41.4 %

Procedure:
To a suspension of the chloride 52 (500 mg, 1.1 mmol) in DME (10 mL) was added ethanolamine (336 mg, 5.5 mmol). The reaction mixture refluxed for 2 hrs, the solvent was removed under reduced pressure; the residue was dissolved in EtOAc and washed with water. The organic phase was collected, dried over sodium sulfate, filtered and evaporated. The remaining solid was triturated with Et2O to afford the title compound 59 as a yellow solid (200 mg, 41% yield). 1H NMR (DMSO) δ (ppm): 8.57 (d, J=5.5 Hz, 1H), 8.47 (dd, J=2.7 and 10.4 Hz, 1H), 8.21 (m, 1H), 8.17 (s, 1H), 7.83 (d, J=8.0 Hz, 1H), 7.71 (t, J=8.6 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H), 6.91 (d, J=5.5 Hz, 1H), 4.48 (t, J=5.5 Hz, 1H), 3.75 (s, 2H), 3.45 (q, J=5.6 Hz, 2H), 3.33 (m, 1H), 3.15 (d, J=5.1 Hz, 2H), 2.56 (t, J=5.7 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:17]([O:18][CH3:19])=[CH:16][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([NH:14][CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]3)=[C:30]([CH3:41])[CH:29]=2)[C:24]([Cl:42])=[CH:23][N:22]=1>>[Cl:42][C:24]1[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]3)=[C:30]([CH3:41])[CH:29]=2)=[N:26][C:21]([NH:1][C:2]2[C:17]([O:18][CH3:19])=[CH:16][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C:12]([NH:14][CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:22][CH:23]=1
Reactant: Cc1cc(Nc2nc(Cl)ncc2Cl)ccc1N1CCN(C)CC1
Reactant: CNC(=O)CN1CCc2cc(N)c(OC)cc2CC1
Product: CNC(=O)CN1CCc2cc(Nc3ncc(Cl)c(Nc4ccc(N5CCN(C)CC5)c(C)c4)n3)c(OC)cc2CC1

Procedure:
The title compound was prepared from 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N-methyl-acetamide and (2,5-Dichloro-pyrimidin-4-yl)-[3-methyl-4-(4-methyl-piperazin-1-yl)-phenyl]-amine in an analogous manner to Example 61e. Product isolated as an off-white solid (0.008 g, 8%). MP: 179-185° C. 1HNMR (400 MHz, CDCl3, δ, ppm): 8.05 (s, 1H), 8.03 (s, 1H), 7.58-7.53 (m, 1H), 7.48 (s, 1H), 7.39-7.31 (m, 1H), 7.21-7.18 (m, 1H), 7.04 (d, 1H, J=8.8 Hz), 6.91 (s, 1H), 6.61 (s, 1H), 3.85 (s, 3H), 3.09 (s, 2H), 2.97-2.92 (m, 4H), 2.90 (d, 3H, J=4.8 Hz), 2.86-2.81 (m, 2H), 2.75-2.53 (m, 9H), 2.38 (s, 3H), 2.30 (s, 3H). MS: 579.29 (MH)+.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([OH:8])[CH:2]=1.CN(C)C=O.[N+:14]([C:17]1[O:21][C:20]([CH:22]=[CH:23][C:24]2[N:33]=[C:32](Cl)[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=2)=[CH:19][CH:18]=1)([O-:16])=[O:15]>O>[N+:14]([C:17]1[O:21][C:20]([CH:22]=[CH:23][C:24]2[N:33]=[C:32]([NH:7][C:6]3[CH:5]=[CH:4][C:3]([OH:8])=[CH:2][CH:1]=3)[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=2)=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: Nc1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(C=Cc2nc(Cl)c3ccccc3n2)o1
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(C=Cc2nc(Nc3ccc(O)cc3)c3ccccc3n2)o1
Reaction time: 72 h
Yield: 64.1 %

Procedure:
A 250 ml Erlenmeyer flask equipped with a magnetic stirrer and oil bath for heating was charged with 8.0 g (0.07 mole) of p-aminophenol and 25 ml of dimethylformamide. After the p-aminophenol was dissolved by stirring, 9.05 g (0.03 mole) of 2-[2-(5-nitro-2-furyl)vinyl]-4-chloroquinazoline (IV) was added. The reaction mixture was then heated at 70°-90°C for 2 hours after which 60 ml of water was added and the solution after cooling was placed in a refrigerator for crystallization. After three days, the brown yellow solid was collected, washed first with water, then methanol and then dried to obtain 7.20 g of product melting at 250°-60°C with decomposition. Recrystallization from a 1:1 dimethylformamidemethanol mixture gave 6.5 g of orange crystals of the purified product which melted at 270°-2°C with decomposition.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([NH2:18])=[O:17])=[CH:13][CH:14]=2)[CH:9]=[N:8]1.[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24](Cl)=[O:25].C([N:29]([CH2:32][CH3:33])CC)C>O1CCCC1>[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24]([NH:29][C:32]1[CH:33]=[C:2]([C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[C:12]([C:16]([NH2:18])=[O:17])[CH:11]=3)[N:7]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[N:8]=2)[CH:3]=[CH:4][CH:5]=1)=[O:25]
Reactant: O=C(Cl)c1ccco1
Reactant: NC(=O)c1ccc2c(cnn2C2CCCCO2)c1
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Product: NC(=O)c1ccc2c(c1)c(-c1cccc(NC(=O)c3ccco3)c1)nn2C1CCCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(3-aminophenyl)-]-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide (0.200 g, 0.59 mmol) in 6 mL of tetrahydrofuran was added 2-furanoic acid chloride (0.064 mL, 0.65 mmol), followed by triethyl amine (0.091 mL, 0.65 mmol). The reaction was stirred at room temperature overnight. The crude mixture was partitioned between water and ethyl acetate. The extracts were concentrated to dryness. The crude was not purified (yield not calculated). ES-MS (m/z) 431 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([SH:13])=[CH:9][C:8]=1[CH2:14][CH2:15][CH3:16])[CH3:2].[CH3:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=1.FC(F)(F)C(OI(C1C=CC=CC=1)OC(=O)C(F)(F)F)=O>FC(F)(F)C(O)C(F)(F)F>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:23]2[CH:22]=[CH:21][C:20]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:36])[F:35])=[CH:29][CH:28]=3)=[C:19]([CH3:18])[CH:24]=2)=[CH:9][C:8]=1[CH2:14][CH2:15][CH3:16])[CH3:2]
Reactant: Cc1ccccc1OCc1ccc(C(F)(F)F)cc1
Reactant: CCCc1cc(S)ccc1OCC(=O)OCC
Agent: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Solvent: OC(C(F)(F)F)C(F)(F)F
Product: CCCc1cc(Sc2ccc(OCc3ccc(C(F)(F)F)cc3)c(C)c2)ccc1OCC(=O)OCC
Reaction time: 0.25 h
Yield: 59.9 %

Procedure:
Compound 4.4 (5.0 g, 19.66 mmol) was dissolved in 1,1,1,3,3,3-hexafluoro-2-propanol (30 mL) under argon atmosphere. To the solution was added compound 4.1 (5.23 g, 19.66 mmol) and [bis(trifluoroacetoxy)iodo]benzene (10.14 g, 23.59 mmol) slowly, while maintaining the reaction temperature between 10° C. and 17° C. After stirring for 15 min, the reaction mixture was concentrated in vacuo to give a residue which was purified using silica gel column chromatography (hexane/EtOAc=20/1) to give 4.5 (6.11 g). 1H NMR (400 MHz) (CDCl3) δ 7.64 (2H, d, J=8.2 Hz); 7.54 (2H, d, J=8.1 Hz); 7.20-7.06 (4H, m); 6.76 (1H, d, J=8.4 Hz); 6.62 (1H, d, J=8.4 Hz); 5.11 (2H, s); 4.60 (2H, s); 4.25 (2H, q, J=7.1 Hz); 2.63-2.56 (2H, m); 2.24 (3H, s); 1.67-1.55 (2H, m); 1.28 (3H, t, J=7.1 Hz); 0.92 (3H, t, J=7.4 Hz).