Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=[O:8])[CH2:2]2.[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH-].[Na+]>C(O)C>[C:10]1([CH:9]=[C:2]2[C:3](=[O:8])[CH:4]3[CH2:7][N:1]2[CH2:6][CH2:5]3)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1CN2CCC1C2
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C(=Cc2ccccc2)N2CCC1C2

Procedure:
A mixture of 1-azabicyclo [2.2.1] heptan-3-one (2.65 g), benzaldehyde (3.64 ml) and sodium hydroxide (1.15 g) in ethanol (25 ml) was heated at reflux for 40 min. After cooling the solvent was removed in vacuo and the residue partitioned between dichloromethane (300 ml) and water (300 ml). The aqueous layer was further extracted with dichloromethane (2×300 ml). The organic extracts were combined, backwashed with brine (100 ml), dried and concentrated in vacuo to give an orange oil (5.84 g). The oil was purified by FCC, using gradient elution with petrol/ethyl acetate 6:1 to 3:1 to give the title compound as a yellow solid (3.80 g). m.p. 61–63°.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([Cl:10])[N:5]=[CH:4][N:3]=1.[NH:11]1[CH2:14][CH2:13][CH2:12]1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[N:11]1([C:2]2[C:7]([CH:8]=[O:9])=[C:6]([Cl:10])[N:5]=[CH:4][N:3]=2)[CH2:14][CH2:13][CH2:12]1
Reactant: C1CNC1
Reactant: O=Cc1c(Cl)ncnc1Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=Cc1c(Cl)ncnc1N1CCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4,6-dichloropyrimidine-5-carbaldehyde (1.00 g, 5.65 mmol) in chloroform at 0° C. were added azetidine (99%, 0.392 mL, 5.71 mmol) and triethylamine (5 drops). The reaction mixture was allowed to warm to room temperature and then stirred for 18 hours. The reaction mixture was filtered, and the filtrate was purified by silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) to provide the product. Yield: 880 mg, 4.45 mmol, 79%. LCMS m/z 198.1, 200.1 (M+1). 1H NMR (400 MHz, CD3OD) δ 2.34-2.43 (m, 2H), 4.12-4.33 (br m, 4H), 8.30 (s, 1H), 10.28 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1C=O.S(Cl)([Cl:14])(=O)=O>ClC1C=CC=CC=1Cl>[Cl:14][C:3]1[C:4]([CH3:8])=[N:5][N:6]([CH3:7])[C:2]=1[Cl:1]
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1nn(C)c(Cl)c1C=O
Solvent: Clc1ccccc1Cl
Product: Cc1nn(C)c(Cl)c1Cl
Temperature: 20 °C
Reaction time: 3 h

Procedure:
To 300 g of a 22.7% solution of 5-chloro-1,3-dimethyl-1H-pyrazole-4-carbaldehyde in 1,2-dichlorobenzene are added dropwise at 80° C. 58 g of sulphuryl chloride within 120 minutes. After the metered addition has ended, the reaction solution is stirred for a further 3 hours. The reaction solution is cooled to 20° C. and the solution is analyzed by GC. 4,5-Dichloro-1,3-dimethyl-1H-pyrazole has formed quantitatively.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:14]=[N:15][CH:16]=[C:11]2[C:10]([CH2:25][OH:26])=[C:9]1[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.[C:43](O)(=[O:45])[CH3:44].C(=O)([O-])O.[Na+]>O1CCCC1.O>[C:43]([O:26][CH2:25][C:10]1[C:11]2[C:12](=[C:13]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:14]=[N:15][CH:16]=2)[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]=1[CH3:27])(=[O:45])[CH3:44]
Reactant: CC(=O)O
Reactant: Cc1c(CO)c2cnnc(OCc3ccccc3)c2n1Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)OCc1c(C)n(Cc2ccccc2)c2c(OCc3ccccc3)nncc12

Procedure:
A solution of 1.65 g (4.59 mmol) of 1-benzyl-7-benzyloxy-3-hydroxymethyl-2-methylpyrrolo [2,3-d]pyridazine, 3.8 g (18.6 mmol) of dicyclohexylcarbodiimide and 1.6 ml (27.4 mmol) of glacial acetic acid in 50 ml of anhydrous tetrahydrofuran is stirred at room temperature for 18 h. The solution is then treated with 50 ml of water, rendered neutral with saturated sodiumhydrogen carbonate solution and extracted with 3×50 ml of dichloromethane. The organic extracts are washed with 50 ml of water, dried over magnesium sulfate and concentrated. The residue which remains is chromatographed on silica gel (eluent: ethyl acetate). After crystallization from diisopropyl ether, 1.3 g (71%) of the title compound are isolated. M.p.: 121°-122° C.
Reaction SMILES: CC1N=C(N2C(=O)N(CC3C=CC(C(F)(F)F)=CC=3)N=C2)SC=1C(O)=O.[F:27][C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[C:37](=[O:38])[N:36]([C:39]3[S:40][C:41]([C:45](O)=[O:46])=[C:42]([CH3:44])[N:43]=3)[CH:35]=[N:34]2)=[CH:30][CH:29]=1.Cl.[O:51]1[CH:55]=[CH:54][N:53]=[C:52]1[CH2:56][NH2:57]>>[F:27][C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[C:37](=[O:38])[N:36]([C:39]3[S:40][C:41]([C:45]([NH:57][CH2:56][C:52]4[O:51][CH:55]=[CH:54][N:53]=4)=[O:46])=[C:42]([CH3:44])[N:43]=3)[CH:35]=[N:34]2)=[CH:30][CH:29]=1
Reactant: NCc1ncco1
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Agent: Cc1nc(-n2cnn(Cc3ccc(C(F)(F)F)cc3)c2=O)sc1C(=O)O
Agent: Cl
Product: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)NCc1ncco1
Yield: 57 %

Procedure:
Following the procedure as described in Example 21, making variations as required to replace 4-methyl-2-(5-oxo-1-(4-(trifluoromethyl)benzyl)-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylic acid with 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylic acid to react with oxazol-2-ylmethanamine hydrochloride, the title compound was obtained as a white solid in 57% yield: mp 152-153° C. (ethyl acetate/hexane); 1H NMR (300 MHz, CDCl3) δ 8.26 (s, 1H), 7.65 (s, 1H 7.41-7.32 (m, 2H), 7.09 (s, 1H), 7.07-6.98 (m, 2H), 6.54 (t, J=5.2 Hz, 1 H), 4.98 (s, 2H), 4.73 (d, J=5.2 Hz, 2H), 2.67 (s, 3H); MS (ES+) m/z 415.1 (M+1).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[CH3:2].C[Si](C)(C)CCOCN1C=CN=C1C=O.[CH3:31][Si:32]([CH3:45])([CH3:44])[CH2:33][CH2:34][O:35][CH2:36][N:37]1[CH:41]=[CH:40][N:39]=[C:38]1[CH2:42][NH2:43]>>[CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:43][CH2:42][C:38]2[N:37]([CH2:36][O:35][CH2:34][CH2:33][Si:32]([CH3:45])([CH3:44])[CH3:31])[CH:41]=[CH:40][N:39]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(OCC)c1ccc(C=O)cc1
Reactant: C[Si](C)(C)CCOCn1ccnc1CN
Agent: C[Si](C)(C)CCOCn1ccnc1C=O
Product: CCOC(OCC)c1ccc(CNCc2nccn2COCC[Si](C)(C)C)cc1

Procedure:
The same procedure as a series of reactions of Example 1, except that 4-(diethoxymethyl)benzaldehyde was used in place of 1-({[2-(trimethylsilyl)ethyloxy]methyl}-1H-imidazole-2-carboaldehyde and 1-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)methaneamine was used in place of {[4-(methyloxy)phenyl]methyl}amine, to obtain the title compound having the following physical properties.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:15][Si](C=[N+]=[N-])(C)C>C(OCC)C.CO>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([C:11]([F:14])([F:12])[F:13])=[CH:7][C:3]=1[C:4]([O:6][CH3:15])=[O:5]
Reactant: O=C(O)c1cc(C(F)(F)F)cnc1Cl
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)c1cc(C(F)(F)F)cnc1Cl
Temperature: -20 °C
Reaction time: 1 h
Yield: 56.7 %

Procedure:
A solution of 2-chloro-5-(trifluoromethyl)nicotinic acid (500 mg, 2.21 mmole, available from Apollo #PC9219) in a mixture diethyl ether/methanol (5 ml)/(15 ml) was cooled to −20° C. then trimethylsilyldiazomethane (2M solution in diethyl ether) (2.15 ml, 4.43 mmol) was added dropwise. The reaction mixture was stirred at −20° C. for 1 h then allowed to warm to room temperature. After solvent evaporation, the obtained residue was loaded on SPE-Si cartridge (10 g) eluting with a mixture cyclohexane/dichloromethane from 80/20 to 60/40. Collected fractions, after solvent evaporation, afforded the title compound (D66) (300 mg)
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=O)[CH2:2]1.[NH2:9][CH:10]=[C:11]([CH3:14])[CH:12]=O.C(N(CC)CC)C.C([O-])(=O)C.[NH4+]>CCOCC>[CH3:14][C:11]1[CH:10]=[N:9][C:3]2[CH2:4][CH2:5][CH2:6][C:1](=[O:8])[C:2]=2[CH:12]=1
Reactant: O=C1CCCC(=O)C1
Reactant: CC(C=O)=CN
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Cc1cnc2c(c1)C(=O)CCC2
Reaction time: 12 h

Procedure:
A mixture of cyclohexane-1,3-dione (11.2 g. 0.1 m), 3-amino-2-methylacrolein (8.5 g. 0.1m) triethylamine (5 ml.) and ammonium acetate (100 mg) were heated with stirring at 120° in an oil bath for 12 hours. The cooled reaction mixture was diluted with ether (50 ml.) and the solution washed with 2N HCl (3 × 15 ml.) The combined washings were adjusted to pH 9.0 with sodium carbonate and extracted with ether (3 × 50 ml.) The combined extracts were dried, evaporated in vacuo and the residual oil distilled at 0.2 mm Hg to give the 3-methyl-7,8-dihydro-5(6H)-quinolone as a colorless crystalline solid b.p. 80° (7.5 g. 48%). A mixture of 3-methyl-7,8-dihydro-5(6H)-quinolone (20 g.), hydrazine hydrate (14 ml), diethylene glycol (150 ml.) and sodium hydroxide (14 g) was heated at reflux with stirring for 1 hour. The condenser was replaced by a Dean and Stark Water Separator and the heating continued for a further 3 hours. The cooled reaction mixture was diluted with water (200 ml.) and extracted with ether (3 × 150 ml.). The combined extracts were dried (MgSO4) and the solvent removed in vacuo and the residual oil distilled at 15 mm Hg to give the title compound as a colourless oil b.p.116° (17 g, 93%) G.L.C. (3% SE30, T=150°) RF =3.5 min.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[C:18]([OH:25])[CH:19]=[CH:20][CH:21]=4)[N:16]=3)=[CH:13][N:14]=[C:8]2[CH:7]=1.O[CH:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.CCOC(C)=O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[C:18]([O:25][CH:27]5[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]5)[CH:19]=[CH:20][CH:21]=4)[N:16]=3)=[CH:13][N:14]=[C:8]2[CH:7]=1
Reactant: COCCOc1ccn2c(-c3ccc4cccc(O)c4n3)cnc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCCOc1ccn2c(-c3ccc4cccc(OC5CCN(C(=O)OC(C)(C)C)CC5)c4n3)cnc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.5 %

Procedure:
2-(7-(2-Methoxyethoxy)imidazo[1,2-a]pyridin-3-yl)quinolin-8-ol (0.030 g, 0.0895 mmol), tert-butyl 4-hydroxypiperidine-1-carboxylate (0.0198 g, 0.0984 mmol), triphenylphosphine (0.0352 g, 0.134 mmol) and diethyl azodicarboxylate (0.0211 ml, 0.134 mmol) were combined in anhydrous THF (1 mL). The reaction mixture was stirred overnight at ambient temperature, then diluted with EtOAc and washed with saturated NaHCO3 and brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified via flash column chromatography (dichloromethane followed by 40:1 dichloromethane/MeOH) which provided 29.0 mg of the desired product as a brown residue.
Reaction SMILES: Br[C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][C:9]([C:18]2[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[CH:21]=[CH:20][CH:19]=2)=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.[CH3:28][C:29]1([CH3:63])[C:53]2[C:33]([CH:34]=[C:35]3[CH:52]=[C:51]4[C:38]([C:39]5[C:44]([C:45]6[C:50]4=[CH:49][CH:48]=[CH:47][CH:46]=6)=[CH:43][CH:42]=[CH:41][CH:40]=5)=[CH:37][C:36]3=2)=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30]1.C([O-])([O-])=O.[Na+].[Na+].CCO>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>[CH3:63][C:29]1([CH3:28])[C:53]2[C:33]([CH:34]=[C:35]3[CH:52]=[C:51]4[C:38]([C:39]5[C:44]([C:45]6[C:50]4=[CH:49][CH:48]=[CH:47][CH:46]=6)=[CH:43][CH:42]=[CH:41][CH:40]=5)=[CH:37][C:36]3=2)=[CH:32][C:31]([C:2]2[C:15]3[C:16]4=[C:17]5[C:12](=[CH:13][CH:14]=3)[CH:11]=[CH:10][C:9]([C:18]3[C:27]6[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=6)[CH:21]=[CH:20][CH:19]=3)=[C:8]5[CH:7]=[CH:6][C:5]4=[CH:4][CH:3]=2)=[CH:30]1
Reactant: Brc1ccc2ccc3c(-c4cccc5ccccc45)ccc4ccc1c2c43
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)C=C2C=c3cc4c5ccccc5c5ccccc5c4cc3=C21
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC1(C)C=C(c2ccc3ccc4c(-c5cccc6ccccc56)ccc5ccc2c3c54)C=C2C=c3cc4c5ccccc5c5ccccc5c4cc3=C21
Temperature: 90 °C
Yield: 46.8 %

Procedure:
A mixture of 7 g (17.2 mmol) of 1-bromo-6-(naphthalen-1-yl)pyrene, 8.1 g (17.2 mmol) of 2-(10,10-dimethyl-10H-indeno[1,2-b]triphenylen-12-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 0.2 g (0.172 mmol) of Tetrakis(triphenylphosphine)Palladium, 13 ml of 2M Na2CO3, 30 ml of EtOH and 100 ml toluene was degassed and placed under nitrogen, and then heated at 90° C. for 24 h. After the reaction finish, the mixture was allowed to cool to room temperature. Than 500 ml MeOH was added, while stirring and the precipitated product was filtered off with suction. To give 5.4 g (yield 47%) of yellow product which was recrystallized from toluene. MS(m/z,FAB+): 670.1; 1H NMR (CDCl3, 400 MHz): chemical shift(ppm) 9.11 (s, 1H), 8.89 (d, J=8.00 Hz, 1H), 8.82 (d, J=8.00 Hz, 1H), 8.78 (s, 1H), 8.72 (d, J=8.00 Hz, 2H), 8.38 (d, J=9.20 Hz, 1H), 8.30˜8.26 (m, 3H), 8.19˜8.05 (m, 7H), 8.02˜7.98 (m, 2H), 7.83˜7.82 (m, 2H), 7.78˜7.68 (m, 5H), 7.61˜7.59 (m, 2H), 1.79 (s, 6H).
Reaction SMILES: [C-:1]#[N:2].[K+].[C:4]([C:8]1[C:13]([OH:14])=[C:12]([CH3:15])[C:11]([CH2:16]Cl)=[C:10]([CH3:18])[CH:9]=1)([CH3:7])([CH3:6])[CH3:5].O>CN(C)C=O>[C:4]([C:8]1[CH:9]=[C:10]([CH3:18])[C:11]([CH2:16][C:1]#[N:2])=[C:12]([CH3:15])[C:13]=1[OH:14])([CH3:7])([CH3:6])[CH3:5]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C)c1CCl
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C(C)(C)C)c(O)c(C)c1CC#N
Temperature: 0 °C
Reaction time: 7 h

Procedure:
To 41 grams of potassium cyanide dispersed in 300 ml of N,N-dimethylformamide, was slowly added a solution of 97.2 grams of the compound of Example 1, the reaction temperature rising from 25° to 35° C. The reaction mixture was then heated at 70° to 75° for 71/2 hours. Since a sample analyzed after 7 hours reaction time indicated that some unreacted starting 6-tert.-butyl-3-chloromethyl-2,4-dimethylphenol remained unreacted, an additional 13.7 grams of potassium cyanide was added and the reaction mixture heated for an additional 2 hours at 60° to 65° C. The reaction mixture was poured on crushed ice, and water added to make the total volume 1.8 liters. The mixture was stirred until the ice melted, the aqueous solid dispersion was filtered by suction, and the filtercake washed well with water. The filtercake was taken up in a toluene-benzene mixture, the resulting solution being successively washed with water, 6N aqueous hydrochloric acid and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration and treating the clear filtrate with activated charcoal, the solvent was evaporated at reduced pressures. The resulting residue was allowed to crystallize from toluene yielding white crystals melting at 134° to 139°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([CH2:17]O)[CH:14]=[CH:13][C:12]=1[C:19]#[N:20])([CH3:4])([CH3:3])[CH3:2].[Cl:22][C:23]1[CH:24]=[CH:25][C:26](=[O:60])[N:27]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][C:36]3[N:37]=[CH:38][N:39](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:40]=3)=[CH:31][N:30]=2)[CH:28]=1.CCN(C(C)C)C(C)C.O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([CH2:17][N:37]2[C:36]([CH2:35][C:32]3[CH:33]=[CH:34][C:29]([N:27]4[CH:28]=[C:23]([Cl:22])[CH:24]=[CH:25][C:26]4=[O:60])=[N:30][CH:31]=3)=[CH:40][N:39]=[CH:38]2)[CH:14]=[CH:13][C:12]=1[C:19]#[N:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=c1ccc(Cl)cn1-c1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cn1
Reactant: CC(C)(C)OC(=O)NCCOc1cc(CO)ccc1C#N
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCOc1cc(Cn2cncc2Cc2ccc(-n3cc(Cl)ccc3=O)nc2)ccc1C#N
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cooled solution (-78° C.) of [2-(2-cyano-5-hydroxymethylphenoxy)-ethyl]-carbamic acid tert-butyl ester from step 3 (248 mg, 0.85 mmol) and 5-chloro-5'-(1-trityl-1H-imidazol-4-ylmethyl)-[1,2']bipyridinyl-2-one from Example 23, Step 5 (450 mg, 0.85 mmol) in CH2Cl2 (4.5 ml) was added DIEA (325 μl, 1.87 mmol) followed immediately by the addition of Tf2O (215 μl, 1.27 mmol). The reaction mixture stirred at -78° C. for 1 hour and was then transferred to an ice bath and stirred at 0° C. for another hour. The solvent was removed in vacuo. The residue was then dissolved in MeOH (4.5 ml) and heated to 60° C. for 4 hours. The MeOH was then removed in vacuo and the residue treated with saturated NaHCO3 and extracted with CH2Cl2. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography with 0 to 4% MeOH(NH4OH 5%) in CH2Cl2 to yield the desired product.
Reaction SMILES: [CH:1]12[O:7][CH:6]1[CH2:5][CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:2]2.[N-:18]=[N+:19]=[N-:20].[Na+].[Cl-].[NH4+]>CO.O>[N:18]([C@H:1]1[C@H:6]([OH:7])[CH2:5][CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:2]1)=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(OCc1ccccc1)N1CCC2OC2C1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: [N-]=[N+]=N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1O
Temperature: 65 °C
Yield: 100.4 %

Procedure:
Benzyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (6.78 g, 29.1 mmol), sodium azide (3.78 g, 2 equiv), and ammonium chloride (1.56 g, 1 equiv) were dissolved in methanol (100 mL) and water (20 mL). The mixture was heated at 65° C. for 18 h. The mixture was cooled to rt and methanol was removed under vacuum. The aqueous residue was extracted with ether (3×120 mL). The combined ether layers were washed with brine (30 mL) and dried over Na2SO4. Concentration afforded (3R,4R)-benzyl 3-azido-4-hydroxypiperidine-1-carboxylate (8.07 g, quant.) which was used for without further purification. LC-MS (3 min) tR=1.45 min., m/z 277 (M+1).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([CH3:28])=[CH:10][N:11]([C:16]3[CH:17]=[C:18]([CH:24]=[CH:25][C:26]=3[CH3:27])[C:19]([NH:21][CH2:22][CH3:23])=[O:20])[C:12]2=[O:15])=[CH:7][CH:6]=1.[I-].[K+].[CH3:31][NH:32][CH:33]([CH3:35])[CH3:34]>CC(N(C)C)=O.C(OCC)(=O)C>[CH2:22]([NH:21][C:19](=[O:20])[C:18]1[CH:24]=[CH:25][C:26]([CH3:27])=[C:16]([N:11]2[CH:10]=[C:9]([CH3:28])[C:8]3[C:13](=[CH:14][C:5]([O:4][CH2:3][CH2:2][N:32]([CH:33]([CH3:35])[CH3:34])[CH3:31])=[CH:6][CH:7]=3)[C:12]2=[O:15])[CH:17]=1)[CH3:23]
Reactant: CNC(C)C
Reactant: CCNC(=O)c1ccc(C)c(-n2cc(C)c3ccc(OCCCl)cc3c2=O)c1
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCNC(=O)c1ccc(C)c(-n2cc(C)c3ccc(OCCN(C)C(C)C)cc3c2=O)c1
Temperature: 150 °C

Procedure:
A mixture of 3-[7-(2-chloroethoxy)-4-methyl-1-oxoisoquinolin-2(1H)-yl]-N-ethyl-4-methylbenzamide (90 mg), potassium iodide (75 mg), and N-methylisopropylamine (0.14 ml) were stirred in DMA (2 ml) and heated under microwave irradiation conditions (Personal Chemistry Emrys Optimizer with 300 W magnetron) at 150° C. for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with water (×5), brine (×2), dried (magnesium sulfate) and concentrated. Purification by column chromatography on a silica column eluting using initially 10% methanol/ethyl acetate and then a 99:1 mixture of 110% methanol/ethyl acetate and aqueous ammonia solution gave N-ethyl-3-[7-{2-[isopropyl(methyl)amino]ethoxy}-4-methyl-1-oxoisoquinolin-2(1H)-yl]-4-methylbenzamide (68 mg) as a cream solid; NMR Spectrum: (DMSOd6) 0.98 (d, 6H), 1.12 (t, 3H), 2.11 (s, 3H), 2.25 (s, 3H), 2.27 (s, 3H), 2.78 (t, 2H), 2.85 (m, 1H), 3.29 (m, 2H), 4.15 (m, 2H), 7.10 (s, 1H), 7.45-7.51 (m, 2H), 7.70-7.77 (m, 3H), 7.88 (d, 1H), 8.47 (t, 1H); Mass Spectrum: M+H+ 436.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][C:18]1=[O:23]>CN(C)C=O.C(Cl)(Cl)Cl>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:20]2[CH2:21][CH2:22][NH:17][C:18](=[O:23])[CH2:19]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: O=C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C1CN(c2ccc([N+](=O)[O-])cc2)CCN1
Temperature: 140 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
To a solution of 1.275 g (9.04 mmol) of 4-fluoronitrobenzene in 30 mL of N,N-dimethylformamide were added 1.87 g (13.56 mmol) of potassium carbonate and 905 mg (9.04 mmol) of piperazine-2-one, and the mixture was stirred for 1 hour at 130° C. and for 1 hour at 140° C. The reaction mixture was cooled to room temperature and diluted with chloroform, then, insoluble substances were removed off by filtration. The filtrate was condensed under reduced pressure and the resulting solid was washed with ethanol to give 859 mg (43%) of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:9][N:8]=2)[CH:2]=1.[H-].[Na+].Br[CH2:20][C:21]([C:23]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:24]=1[O:31][CH3:32])=[O:22]>>[CH3:32][O:31][C:24]1[CH:25]=[CH:26][C:27]([O:29][CH3:30])=[CH:28][C:23]=1[C:21](=[O:22])[CH2:20][N:9]1[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:11][C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[N:8]1
Reactant: COc1ccc(OC)c(C(=O)CBr)c1
Reactant: CCOC(=O)c1cc(-c2cccnc2)n[nH]1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1cc(-c2cccnc2)nn1CC(=O)c1cc(OC)ccc1OC
Reaction time: 8 h

Procedure:
To a flame dried flask equipped with a stirbar cooled under argon was added ethyl 3-(pyridin-3-yl)-1H-pyrazole-5-carboxylate (0.02 grams, 0.092 mmol, 0.1 M in THF). While stirring at room temperature NaH (0.0055 grams, 1.8 mmol, 60% in mineral oil, purchase from Aldrich) was added. After fifteen minutes 2-bromo-1-(2,5-dimethoxyphenyl)ethanone (0.047 grams, 0.14 mmol, purchased from Aldrich) was added as a solid. The reaction was stirred overnight. The next day, the reaction was quenched with 0.1M HCl and the organic material extracted using ethyl acetate. The aqueous layer was salted out using sodium chloride and washed twice with ethyl acetate. The combined organic material was then dried with sodium sulfate, filtered, and concentrated. Purification was done on preparative thin layer chromatography using hexanes/ethyl acetate (1:2) to afford the desired compound. Yield, 10%. 1H-NMR δ9.07 (bs, 1H), 8.58 (bs, 1H), 8.13 (d, 1H), 7.47 (d, 1H), 7.31 (bs, 1H), 7.29 (s, 1H), 7.14 (dd, 1H), 7.00 (d, 1H), 6.03 (s, 2H), 4.32 (q, 2H), 3.99 (s, 3H), 3.79 (s, 3H), 1.35 (t, 3H). Calculated mass for C21H21N3O5, 395.15, observed, 396.3 (M+1).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1.Cl.[Cl:18][C:19]1[CH:25]=[C:24]([F:26])[C:22]([NH2:23])=[C:21]([F:27])[CH:20]=1.CCCCCC>C(O)(C)C>[ClH:2].[Cl:18][C:19]1[CH:25]=[C:24]([F:26])[C:22]([NH:23][C:3]2[C:12]3[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)[N:6]=[CH:5][N:4]=2)=[C:21]([F:27])[CH:20]=1
Reactant: Nc1c(F)cc(Cl)cc1F
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: Cl
Solvent: CCCCCC
Solvent: CC(C)O
Product: COc1cc2ncnc(Nc3c(F)cc(Cl)cc3F)c2cc1OC
Yield: 14.5 %

Procedure:
4-Chloro-6,7-dimethoxyquinazoline hydrochloride (210 mg, 0.8 mmol), (prepared as described for the starting material in Example 1 but without the aqueous work up), and 4-chloro-2,6-difluoroaniline hydrochloride (177 mg, 0.89 mmol) in isopropanol (8 ml) were heated at reflux for 2 hours. The reaction mixture was then allowed to cool, hexane added and the precipitated product collected by filtration, washed with isopropanol and dried to give 4-(4-chloro-2,6-difluoroanilino)-6,7-dimethoxyquinazoline hydrochloride (45 mg, 16%).