Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[CH3:11][C:12]1[CH:21]=[C:20]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH2:33][CH:34]([NH:42][OH:43])[CH:35]=[C:36]3[CH2:41][CH2:40][S:39][CH2:38][CH2:37]3)(=[O:32])=[O:31])=[CH:26][CH:25]=2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1>O1CCCC1>[OH:43][N:42]([CH:34]([CH:35]=[C:36]1[CH2:37][CH2:38][S:39][CH2:40][CH2:41]1)[CH2:33][S:30]([C:27]1[CH:26]=[CH:25][C:24]([O:23][CH2:22][C:20]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]([CH3:11])[CH:21]=2)=[CH:29][CH:28]=1)(=[O:31])=[O:32])[CH:1]=[O:2]
Reactant: O=CO
Reactant: Cc1cc(COc2ccc(S(=O)(=O)CC(C=C3CCSCC3)NO)cc2)c2ccccc2n1
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: Cc1cc(COc2ccc(S(=O)(=O)CC(C=C3CCSCC3)N(O)C=O)cc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
A mixture of formic acid (3.0 mL) and acetic anhydride (0.4 mL) premixed for 30 minutes at 0° C. was added to a solution of 0.28 g (0.58 mmol) of N-{2-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonyl]-1-(tetrahydrothiopyran-4-ylidenemethyl)ethyl}hydroxylamine (III-17) in tetrahydrofuran (4 mL) at 0° C., and stirred for another 2 hours at room temperature. After the reaction was completed, the solvent was removed under a reduced pressure, and then subjected to azeotropic distillation with toluene. The resulting residue was dissolved in a mixed solution of methanol (1 mL) and chloroform (3 mL) and stirred for 1 hour at room temperature. Then, the solvent was removed under a reduced pressure, and the obtained residue was subjected to medium pressure column chromatography on silica gel (developing solvent; chloroform:methanol=30: 1) to obtain 0.1 g (yield 34%) of the title compound as a white crystal. Its physical properties are shown below.
Reaction SMILES: CO[CH:3](OC)[CH2:4][C:5]([CH3:11])=[C:6]([C:9]#[N:10])[C:7]#[N:8].C(C(C#N)=C(C)C=C[O:20]C)#N>O>[C:7]([C:6]1[C:9](=[O:20])[NH:10][CH:3]=[CH:4][C:5]=1[CH3:11])#[N:8]
Reactant: COC(CC(C)=C(C#N)C#N)OC
Reactant: COC=CC(C)=C(C#N)C#N
Solvent: O
Product: Cc1cc[nH]c(=O)c1C#N

Procedure:
treating the mixture of 4,4-dicyano-3-methyl-3-butenal dimethyl acetal and 1,1-dicyano-4-methoxy-2-methyl-1,3-butadiene so produced with a strong acid and water, to yield 3-cyano-4-methyl-2-pyridone
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11](=O)[NH:12]C(C)(C)C)=[C:5]2[CH2:18][C:19]([O:21][CH3:22])=[O:20].O=P(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]#[N:12])=[C:5]2[CH2:18][C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)Cc1c(C(=O)NC(C)(C)C)[nH]c2ccc(Br)cc12
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)Cc1c(C#N)[nH]c2ccc(Br)cc12
Temperature: 80 °C
Reaction time: 6 h
Yield: 50.2 %

Procedure:
Step J (1): To a solution of methyl 2-(5-bromo-2-(tert-butylcarbamoyl)-1H-indol-3-yl)acetate (124 mg, 0.34 mmol) in toluene was added POCl3 (182 mg, 1.19 mmol). The mixture was stirred at 80° C. for 6 h. The solvent was removed. The product was isolated by flash chromatography to give 50 mg of methyl 2-(5-bromo-2-cyano-1H-indol-3-yl)acetate (yield 50.2%). MS (ESI) (M+H)+=295.03. 1H NMR (500 MHz, CDCl3) δ ppm 3.77 (s, 3 H) 3.89 (s, 2 H) 7.11 (d, J=8.85 Hz, 1 H) 7.36 (dd, J=8.85, 1.83 Hz, 1 H) 7.72 (d, J=1.83 Hz, 1 H) 9.00 (s, 1 H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[S:7][CH:8]=[CH:9][C:10]=1[C:11]([NH2:13])=[O:12]>N1C=CC=CC=1>[C:1]([NH:5][C:6]1[S:7][CH:8]=[CH:9][C:10]=1[C:11]([NH2:13])=[O:12])(=[O:3])[CH3:2]
Reactant: NC(=O)c1ccsc1N
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1sccc1C(N)=O
Temperature: 25 °C
Yield: 97.2 %

Procedure:
Acetyl chloride (4.2 mL, 59 mmol) was added dropwise to a solution of 2-amino-thiophene-3-carboxylic acid amide (7.7 g, 54.2 mmol) in pyridine (100 mL) at 0° C. The temperature of the reaction mixture was raised to room temperature over a 3 h period until no remaining starting material was present based on LC-MS. The solvent was then removed under vacuum to give the above titled compound as brown solid (9.7 g, 52.7 mmol, 97.2% yield). LCMS [M+H]]+ m/z 185.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8]OS(C1C=CC(C)=CC=1)(=O)=O)[CH:2]=[CH2:3].[OH:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=1.[OH-].[K+]>C(O)C>[CH2:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=1)[CH:2]=[CH2:3]
Reactant: O=Cc1ccc(O)cc1
Reactant: C=CCOCCCCOS(=O)(=O)c1ccc(C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C=CCOCCCCOc1ccc(C=O)cc1

Procedure:
4-allyloxybutyl-p-toluene sulfonate is reacted with p-hydroxybenzaldehyde in the presence of KOH and C2H5OH to form 4-(4-allyloxybutoxy)benzaldehyde which is reacted with malonic acid in the presence of pyridine to form p-(4-allyloxybutoxy)cinnamic acid. The acid is esterified with CH3OH and sulfuric acid to yield the methylester, namely methyl p-(4-allyloxybutoxy)cinnamic carboxylate. This methyl ester is then reacted with TosMIC in Et2O/DMSO in the presence of sodium hydride or other strong base to form the substituted pyrrole, represented as follows: ##STR7##
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1.[CH3:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:31]2[CH2:32][CH2:33][N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([CH3:21])[CH:23]=3)[CH2:29][CH2:30]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1
Reactant: CCOC(=O)Nc1nc2cc(OC)ccc2nc1OC
Reactant: Cc1cccc(N2CCNCC2)c1
Product: COc1ccc2nc(OC)c(NC(=O)N3CCN(c4cccc(C)c4)CC3)nc2c1
Yield: 95 %

Procedure:
Ethyl N-(2,6-dimethoxyquinoxalin-3-yl)carbamate and 1-(3-methylphenyl)piperazine were reacted by the same way with the example 64 to obtain the titled compound (yield, 95%). 1H NMR (300 MHz, CDCl3): δ 2.33 (s, 3H), 3.26 (s, 4H), 3.72-3.89 (m, 6H), 4.09-4.18 (m, 4H), 6.72-6.78 (m, 4H), 7.03-7.37 (m, 3H), 7.57-7.65 (m, 1H).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:14][C:13]([C@H:31]3[CH2:36][CH2:35][CH2:34][CH2:33][N:32]3[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])([O:15]C(=O)[C@](OC)(C3C=CC=CC=3)C(F)(F)F)[CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[OH:15][C:13]1([C@H:31]2[CH2:36][CH2:35][CH2:34][CH2:33][N:32]2[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:12][N:11]([C:9]([O:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:10])[CH2:14]1
Reactant: CO[C@@](C(=O)OC1([C@H]2CCCCN2C(=O)OC(C)(C)C)CN(C(=O)OCc2ccccc2)C1)(c1ccccc1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCC[C@@H]1C1(O)CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.1 %

Procedure:
1,1-Dimethylethyl (2R)-2-(1-{[(phenylmethyl)oxy]carbonyl}-3-{[(2R)-3,3,3-trifluoro-2-(methyloxy)-2-phenylpropanoyl]oxy}azetidin-3-yl)piperidine-1-carboxylate (122.8 mg, 0.21 mmol) was taken into methanol (4 mL) followed by addition of 1M aqueous sodium hydroxide (1 mL) and the resulting solution was stirred for one hour at room temperature. The solution was then partitioned with ethyl acetate and 1N aqueous hydrochloric acid. The organic layer was washed with brine, dried over anhydrous magnesium sulfate then filtered and concentrated. The residue was purified by silica gel flash chromatography using hexanes:ethyl acetate 2:1 to give 1,1-dimethylethyl (2R)-2-(3-hydroxy-1-{[(phenylmethyl)oxy]carbonyl}azetidin-3-yl)piperidine-1-carboxylate (60.8 mg, 81% yield) a colorless amorphous solid. 1,1-dimethylethyl (2S)-2-(3-hydroxy-1-{[(phenylmethyl)oxy]carbonyl}azetidin-3-yl)piperidine-1-carboxylate (87.4 mg, 75% yield) was prepared analogously.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2.[C:13](OC(=O)C)(=[O:15])C.C(O)=O>>[CH:13]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2)=[O:15]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc2ccc(O)cc12
Solvent: O=CO
Product: O=CNc1cccc2ccc(O)cc12
Temperature: 50 °C

Procedure:
Ten grams of 8-amino-2-naphthol were added to a mixture of acetic anhydride/formic acid (40 mL:20 mL). The mixture was warmed at 50° C. for one hour and then quenched on ice. After stirring for some time, the product solidified and was filtered off. Recrystallization from ethanol gave 6 g of 8-formamido-2-naphthol melting at 203°-205° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][CH2:9][CH3:10])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].[CH3:12][C:13]([CH3:17])=[CH:14][CH:15]=O>C1(C)C=CC=CC=1.[Cl-].[NH4+].[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[CH2:9]([O:8][C:7]1[C:2]([CH3:1])=[C:3]2[C:4]([CH:15]=[CH:14][C:13]([CH3:17])([CH3:12])[O:11]2)=[CH:5][CH:6]=1)[CH3:10]
Reactant: CCOc1cccc(O)c1C
Reactant: CC(C)=CC=O
Agent: [Ti+4]
Agent: CC[O-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CCOc1ccc2c(c1C)OC(C)(C)C=C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.7 %

Procedure:
To a solution of 5.7 g (25 millimoles) of titanium tetraethoxide in 50 ml of toluene a solution of 13.8 g (100 millimoles) of 2-methyl-3-ethoxy-phenol and 50 ml of toluene is added at 20° C. under nitrogen. The orangered solution is heated to boiling for an hour, and subjected to slow distillation until the ethanol is removed. The mixture is cooled to room temperature and a mixture of 10.6 g (150 millimoles) of dimethyl acroleine and 200 ml of toluene is added dropwise. The reaction mixture is heated to boiling for 8 hours, diluted with a saturated ammonium chloride solution and extracted with ether. The solvent is removed and the residue purified as described in Example 3. This 10.2 g of the desired compound are obtained in the form of a colorless oil, yield 50%.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][CH:7]([CH3:10])[CH2:8][O:9][C:4]=2[C:3]=1[F:13].C(O[CH:17]=[C:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])C>>[F:1][C:2]1[CH:12]=[CH:11][C:5]2[N:6]([CH:17]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:7]([CH3:10])[CH2:8][O:9][C:4]=2[C:3]=1[F:13]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CC1COc2c(ccc(F)c2F)N1
Product: CCOC(=O)C(=CN1c2ccc(F)c(F)c2OCC1C)C(=O)OCC
Reaction time: 1.17 h
Yield: 113.9 %

Procedure:
To 1.13 g of (-)-7,8-difluoro-2,3-dihydro-3-methyl-4H-[1,4]benzoxazine was added 1.58 g of diethyl ethoxymethylenemalonate, and the mixture was stirred at 130° to 140° C. for 70 minutes. The reaction mixture was subjected as such to column chromatography using 50 g of silica gel and eluted with chloroform to obtain 2.47 g of diethyl [(-)-7,8-difluoro-3-methyl-2,3-dihydro-4H-[1,4]benzoxazin-4-yl]methylenemalonate. This product was dissolved in 5 ml of acetic anhydride, and 10 ml of a mixture of acetic anhydride and concentrated sulfuric acid (2/1 by volume) with stirring under ice-cooling, followed by stirring at 50° to 60° C. for 40 minutes. To the reaction mixture were added ice and an aqueous solution of sodium bicarbonate, and the reaction product was extracted three times with 150 ml portions of chloroform. The combined extract was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. When a solid began to precipitate, a small amount of diethyl ether was added thereto, and the precipitate was collected by filtration. The precipitate was washed with a small amount of diethyl ether to yield 1.32 g of (-)-ethyl 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7]2.[N-:16]=[N+]=[N-].[Na+]>ClCCl.CS(O)(=O)=O>[F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:16][CH2:8][CH2:7]2
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1CCc2cc(OC(F)(F)F)ccc21
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1NCCc2cc(OC(F)(F)F)ccc21
Temperature: 20 °C
Reaction time: 16 h
Yield: 49 %

Procedure:
To a solution of 158f (650 mg, 3 mmol) in dichloromethane (6 mL) and methanesulfonic acid (3 mL) was added sodium azide (0.293 mg, 4.5 mmol). See FIG. 4. The reaction mixture was stirred at 20° C. for 16 h. The reaction mixture was partitioned between DCM (50 mL) and aqueous sodium hydroxide solution (50 mL, 1.0 M). The aqueous layer was extracted with DCM (20 mL×3). The combined organic layers were washed sequentially with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:petroleum ether=1:2) to give 6-(trifluoromethoxy)-3,4-dihydroisoquinolin-1(2H)-one 158g (340 mg, 49%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.21 (br s, 1H), 7.20 (s, 1H), 7.13 (d, J=8.8 Hz, 1H), 6.89 (d, J=8.8 Hz, 1H), 2.89 (t, J=7.6 Hz, 2H), 2.48-2.31 (m, 2H)
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]2[N:12]([C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[C:11](=[O:19])[CH2:10][CH2:9]2)=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[O:36]1CN1>C1COCC1>[C:1]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@H:8]2[N:12]([C:13](=[O:18])[C:14]([CH3:16])([CH3:17])[CH3:15])[C:11](=[O:19])[C@H:10]([OH:36])[CH2:9]2)=[CH:5][CH:6]=1
Reactant: CC(C)(C)C(=O)N1C(=O)CC[C@H]1Cc1ccc(-c2ccccc2)cc1
Reactant: C1NO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)N1C(=O)[C@H](O)C[C@H]1Cc1ccc(-c2ccccc2)cc1
Temperature: -78 °C
Yield: 49.8 %

Procedure:
(S)-5-Biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)pyrrolidin-2-one (40 g, 120 mmol) was dissolved in anhydrous THF (400 mL) and stirred at −78° C. under nitrogen To this was added 1.5 eq of a 2.0M THF solution of sodium bis(trimethylsilyl)amide dropwise over 5 minutes. The light yellow mixture was stirred for 20 minutes under nitrogen at −78° C., followed by the slow dropwise addition of oxaziridine (53 g, 180 mmol) as a 200 mL solution in THF. The mixture was stirred for 0.5 hour. The reaction was quenched with saturated aqueous NH4Cl, and the mixture was extracted with EtOAc (1 L). The extract was washed with 1N HCl (1 L), dried over MgSO4, and concentrated to a 500 mL volume. The precipitated white solid was filtered, the filtrate was concentrated to remove solvent after the addition of silica gel (200 g). The residue was put on a column (8×80 cm) of silica gel (900 g), which was previously packed in hexanes. Elution was carried out initially with DCM:hexanes (1:1). Once the oxaziridine and imine were completely collected, the column was eluted with DCM to obtain (3R,5R)-5-Biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-hydroxypyrrolidin-2-one (21 g, 98% purity) as yellow oil.
Reaction SMILES: C(OC([NH:8][C:9]([NH:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]1[NH:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([CH3:36])[CH:34]=2)[N:29]=[C:28]([C:37]([NH:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)=[O:38])[N:27]=1)=[N:10]C(OC(C)(C)C)=O)=O)(C)(C)C.C(OCC)(=O)C.[ClH:54]>CO.C(Cl)(Cl)Cl>[ClH:54].[ClH:54].[NH2:10][C:9]([NH:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]1[NH:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([CH3:36])[CH:34]=2)[N:29]=[C:28]([C:37]([NH:39][C:40]2[CH:41]=[CH:42][C:43]([O:46][CH3:47])=[CH:44][CH:45]=2)=[O:38])[N:27]=1)=[NH:8]
Reactant: COc1ccc(NC(=O)c2nc(N[C@H]3CCCC[C@H]3NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c3cc(C)ccc3n2)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(NC(=O)c2nc(N[C@H]3CCCC[C@H]3NC(=N)N)c3cc(C)ccc3n2)cc1

Procedure:
To a solution of 2.07 g of 4-{[(1S,2R)-2-({(tert-butoxycarbonyl)amino[(tert-butoxycarbonyl)imino]methyl}amino)cyclohexyl]amino}-N-(4-methoxyphenyl)-6-methylquinazoline-2-carboxamide in 10 ml of methanol and 10 ml of chloroform, 40 ml of a 4N-hydrogen chloride-ethyl acetate solution was added, and then the mixture was reacted at 50° C. for 15 hours. The reaction solution was concentrated and recrystallized from methanol-diisopropyl ether to obtain 952 mg of the desirable compound as a yellow powder.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH2:15]([Mg]Br)[CH3:16].[Cl-].[NH4+]>O1CCCC1>[CH2:15]([C:2]1([OH:1])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)[CH3:16]
Reactant: CC[Mg]Br
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.1 %

Procedure:
1,1-Dimethylethyl 4-oxo-1-piperidinecarboxylate (10.1 g, 50.7 mmol) in tetrahydrofuran (40 mL) was added dropwise over 30 minutes to a stirred, cooled (0° C.) solution of ethyl magnesium bromide (1.0M in tetrahydrofuran, 50.7 mL, 50.7 mmol) in tetrahydrofuran (30 mL). The mixture was allowed to warm to room temperature and stirred for 4 hours. The mixture was poured into saturated aqueous ammonium chloride (150 mL) and extracted with ethyl acetate (2×150 mL). The combined organic fractions were washed with brine, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with 3:1 isohexane:ethyl acetate, to give the title compound (8.5 g, 73%). m/z (ES+) 230 (M+1).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[S:11]1[C:15]([C:16](Cl)=[O:17])=[CH:14][C:13]2[CH:19]=[CH:20][CH:21]=[CH:22][C:12]1=2>N1C=CC=CC=1>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:1][C:16]([C:15]1[S:11][C:12]2[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=2[CH:14]=1)=[O:17]
Reactant: O=C(Cl)c1cc2ccccc2s1
Reactant: Nc1nc2ccccc2s1
Solvent: c1ccncc1
Product: O=C(Nc1nc2ccccc2s1)c1cc2ccccc2s1

Procedure:
Using 2-amino-benzothiazole and benzo[b]thiophene-2-carboxylic acid chloride in pyridine the title compound was obtained as a light yellow solid (86% yield), MS: m/e=311.1 (M+H+).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:20]([O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=O)[CH2:21][CH2:22][CH3:23]>>[CH2:20]([O:24][C:25]1[CH:26]=[C:27]([CH2:28][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)[CH:30]=[CH:31][CH:32]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCOc1cccc(C=O)c1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: CCCCOc1cccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 3-butoxybenzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(3-butoxyphenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([NH:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:4][N:3]=1.Cl.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH:18]1[C:23](O)=[O:24].CCN(C(C)C)C(C)C>CS(C)=O.O.CCOCC.CCO>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:9]([CH:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[C:23](=[O:24])[CH:18]3[CH2:19][O:20][CH2:21][CH2:22][N:17]3[C:6]=2[N:7]=1
Reactant: Clc1ncc(NC2CCOCC2)c(Cl)n1
Reactant: O=C(O)C1COCCN1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: O=C1C2COCCN2c2nc(Cl)ncc2N1C1CCOCC1
Temperature: 100 °C
Reaction time: 16 h
Yield: 20.4 %

Procedure:
In a 100 mL round bottomed flask containing 2,4-dichloro-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-5-amine (0.336 g, 1.354 mmol) in 2.0 mL of DMSO was added morpholine-3-carboxylic acid hydrochloride (0.295 g, 1.761 mmol) and DIPEA (1.183 ml, 6.77 mmol). The reaction mixture was stirred at 100° C. for 16 h. The reaction was cooled to room temperature, diluted with 30 mL of water, transferred to an appropriate separatory funnel and extracted with EtOAc (3×25 mL). The organic layers were combined, washed with sat. NaCl, dried over Na2SO4, filtered and concentrated in vacuo affording an oil. The oil was suspended in 10 mL of Et2O, added 2 drops of EtOH and sonicated until a yellow precipitate appeared. Let mixture sit at room temperature for 1 h, collected solids by vacuum filtration, washed with additional Et2O, hexanes and dried under high vacuum affording 2-chloro-5-(tetrahydro-2H-pyran-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one. (90 mg, 20.4% yield) as a light yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.54-1.65 (m, 1H) 1.70 (dd, J=12.88, 2.02 Hz, 1H) 2.51-2.70 (m, 2H) 3.03 (ddd, J=13.58, 12.32, 3.92 Hz, 1H) 3.41-3.66 (m, 4H) 4.03 (dd, J=11.87, 3.79 Hz, 4H) 4.32-4.47 (m, 2H) 4.59 (tt, J=12.47, 4.07 Hz, 1H) 8.05 (s, 1H). MS [M+H] found 325.2.
Reaction SMILES: O.O.[Sn](Cl)Cl.[N+:6]([C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][O:13][C:14]2=[O:19])([O-])=O.C(=O)(O)[O-].[Na+].O>C1COCC1.CCOC(C)=O>[NH2:6][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][O:13][C:14]2=[O:19]
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cccc2c(=O)occc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 97 %

Procedure:
Tin(II) chloride dihydrate (41.9 g, 185.7 mmol) was added to a stirred solution of 5-nitro-1H-isochromen-1-one (7.1 g, 37.1 mmol) in anhydrous THF (120 mL). The reaction mixture was stirred at room temperature for 18 h. The resulting mixture was diluted with EtOAc (400 mL) and treated with saturated aqueous sodium bicarbonate to pH=10. Water (100 mL) was added and the layers were separated. The aqueous phase was extracted with ethyl acetate (2×150 mL) and the combined organic fractions were dried over Na2SO4, filtered and evaporated to yield 5-amino-1H-isochromen-1-one (5.8 g, 36.0 mmol, 97%) as a yellow solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[NH2:17][C:18]1[N:19]=[CH:20][C:21]2[C:27](=[O:28])[N:26]([C:29]3[CH:34]=[C:33]([N+:35]([O-:37])=[O:36])[CH:32]=[CH:31][C:30]=3[CH3:38])[CH2:25][CH2:24][C:22]=2[N:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[CH3:38][C:30]1[CH:31]=[CH:32][C:33]([N+:35]([O-:37])=[O:36])=[CH:34][C:29]=1[N:26]1[CH2:25][CH2:24][C:22]2[N:23]=[C:18]([NH:17][C:2]3[CH:7]=[CH:6][C:5]([C:8]([N:10]4[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]4)=[O:9])=[CH:4][CH:3]=3)[N:19]=[CH:20][C:21]=2[C:27]1=[O:28]
Reactant: CN1CCN(C(=O)c2ccc(I)cc2)CC1
Reactant: Cc1ccc([N+](=O)[O-])cc1N1CCc2nc(N)ncc2C1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1ccc([N+](=O)[O-])cc1N1CCc2nc(Nc3ccc(C(=O)N4CCN(C)CC4)cc3)ncc2C1=O

Procedure:
A mixture of 4,5-Bis(diphenylphos-phino)-9,9-dimethylxanthene(xanthopos)(8.6 mg, 0.0148 mmol) and Tris(dibenzylideneacetone)dipalladium(0)[Pd2(dba)3] (6.81 mg, 0.0074 mmol) in dry 1,4-dioxane (5 ml) was stirred vigorously and nitrogen was bubbled through the suspension for 30 minutes. (4-Iodo-phenyl)-(4-methyl-piperazin-1-yl)-methanone (41.1 mg, 0.1247 mmol), 2-Amino-6-(2-methyl-5-nitro-phenyl)-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one (37.3 mg, 0.1247 mmol) and dry cesium carbonate (100 mg, 0.31 mmol) was added. Nitrogen was bubbled through for another 30 minutes; the mixture was allowed to reflux overnight. The mixture was cooled, diluted with ethylacetate, water was added and the layers were separated. The aqueous layer was extracted with ethyl acetate and the two organic extracts were combined. The organics were washed with brine, then dried (sodium sulfate), filtered and concentrated. Silica gel chromatography using 5-10% ethyl acetate/hexane as eluent provided 6-(2-Methyl-5-nitro-phenyl)-2-[4-(4-methyl-piperazine-1-carbonyl)phenylamino]-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one [22] as a yellow solid [Yield: 12.3 mg, 19.7%]