Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@@H:1]1([N:10]2[CH2:15][CH2:14][C:13]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:16]#[N:17])[CH2:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(OC(=O)C)(=[O:27])C.[OH-].[Na+]>C(O)=O>[C@@H:1]1([N:10]2[CH2:11][CH2:12][C:13]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:16]([NH2:17])=[O:27])[CH2:14][CH2:15]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)OC(C)=O
Reactant: N#CC1(Nc2ccccc2)CCN([C@H]2CCc3ccccc32)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: NC(=O)C1(Nc2ccccc2)CCN([C@H]2CCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(S)-1-Indan-1-yl-4-phenylamino-piperidine-4-carbonitrile (27 mmol) was added dropwise at room temperature to a mixture of acetic anhydride and formic acid (40 ml each). The mixture was stirred for 16 h at room temperature. Sodium hydroxide solution was added (pH=7) and the mixture extracted with ethyl acetate. Organic phases were pooled, dried with sodium sulfate and concentrated. Chromatography on silica gel (ethyl acetate) yielded the formulated amine which was dissolved in t-butanol (60 ml). Ammonia (28%, 10 ml), water (10 ml) and hydrogen peroxide solution (33% in water, 5 ml) were added. The mixture was stirred for 2.5 h at room temperature (RT, about 22° C.), quenched with cold water (50 ml) and extracted with methylene chloride. Organic phases were pooled, dried with sodium sulfate and concentrated. Chromatography on silica gel (methylene chloride/methanol, 98:2) yielded the desired product as a solid. 1.0 g (11%) of (S)-1-indan-1-yl-4-phenylamino-piperidine-4-carboxylic acid amide, m.p. 194-195° C. and MS: m/e=336.2 (M+H+).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:10]2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:30]1[N:31]=[CH:32][S:33][CH:34]=1)CCC.[F-].[Cs+].O>CN(C=O)C.[Cu]I.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>[O:19]=[C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]([CH2:8][C:5]2[CH:6]=[N:7][C:2]([C:30]3[N:31]=[CH:32][S:33][CH:34]=3)=[CH:3][CH:4]=2)[N:10]=[C:11]1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Reactant: CCOC(=O)c1nn(Cc2ccc(Br)nc2)c2ccccc2c1=O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(Cc2ccc(-c3cscn3)nc2)c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl 1-[(6-bromopyridin-3-yl)methyl]-4-oxo-1,4-dihydrocinnoline-3-carboxylate (897 mg, 2.31 mmol), 4-(tributylstannanyl)-1,3-thiazole (1.04 g, 2.77 mmol, 1.2 equiv), copper(I)iodide (176 mg, 0.924 mmol, 0.4 equiv), cesium fluoride (702 mg, 4.62 mmol, 2 equiv) and tetrakis(triphenylphosphine)palladium(0) (534 mg, 0.462 mmol, 0.2 equiv) were combined in degassed N,N′-dimethylformamide (6 mL) and stirred for 1 hour at ambient temperature. The mixture was poured into water and extracted twice with ethyl acetate. The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in chloroform, treated with potassium fluoride on Celite (8 g, 10 weight equiv) and after stirring vigorously for 24 hours, was filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel gradient chromatography (100:0 to 0:100; hexanes:ethyl acetate; then 100:0 to 95:5; chloroform:methanol), providing the titled compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10]1[C:11](=[O:21])[N:12](CC(O)=O)[C:13]([CH3:16])=[CH:14][N:15]=1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]N>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10]1[C:11](=[O:21])[N:12]([NH:12][C:11](=[O:21])[CH2:10][CH2:26][C:25]2[CH:28]=[CH:29][CH:30]=[C:23]([Cl:22])[CH:24]=2)[C:13]([CH3:16])=[CH:14][N:15]=1
Reactant: Cc1cnc(NCCc2ccccn2)c(=O)n1CC(=O)O
Reactant: NCc1cccc(Cl)c1
Product: Cc1cnc(NCCc2ccccn2)c(=O)n1NC(=O)CCc1cccc(Cl)c1

Procedure:
The title compound was prepared from 3-[2-(2-pyridyl)ethylamino]-6-methyl-1-carboxymethylpyrazinone and 3-chlorobenzylamine using the procedure of EXAMPLE V, Step F, mp 201°-207° C.: MS (FAB) 412 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]([CH2:9][C:10]([O:12]C)=[O:11])=[CH:7][O:8][C:4]=2[CH:3]=1.Cl[CH2:17][C:18]1[CH:19]=[C:20]([C:24]2[C:29]([CH3:30])=[CH:28][C:27]([O:31][CH2:32][CH2:33][CH2:34][S:35]([CH3:38])(=[O:37])=[O:36])=[CH:26][C:25]=2[CH3:39])[CH:21]=[CH:22][CH:23]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>CN(C)C=O.O>[CH3:39][C:25]1[CH:26]=[C:27]([O:31][CH2:32][CH2:33][CH2:34][S:35]([CH3:38])(=[O:36])=[O:37])[CH:28]=[C:29]([CH3:30])[C:24]=1[C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([CH2:17][O:1][C:2]2[CH:15]=[CH:14][C:5]3[C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:7][O:8][C:4]=3[CH:3]=2)[CH:19]=1
Reactant: COC(=O)Cc1coc2cc(O)ccc12
Reactant: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(CCl)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(COc2ccc3c(CC(=O)O)coc3c2)c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
To a solution of methyl (6-hydroxy-1-benzofuran-3-yl)acetate (17.7 g) and 3′-(chloromethyl)-2,6-dimethyl-4-[3-(methylsulfonyl)propoxy]biphenyl (31.5 g) in N,N-dimethylformamide (60 mL) was added tripotassium phosphate (27.4 g), and the mixture was stirred at 70° C. for 3 hr. The mixture was allowed to cool to room temperature, toluene (240 mL) and water (240 mL) were added, and an extraction operation was performed. The aqueous phase was extracted with toluene (240 mL), and the extract was washed with water (240 mL) and saturated brine (240 mL), and concentrated. The obtained solid was dissolved in dimethyl sulfoxide (100 mL), and 2N sodium hydroxide (47.2 mL) was added at room temperature. After stirring at 70° C. for 1 hr and at 25° C. for 20 hr, the aqueous layer was acidified with 6N hydrochloric acid to pH 1-2, water (240 mL) and ethyl acetate (240 mL) were added, and an extraction operation was performed. The aqueous layer was extracted with ethyl acetate (200 mL), and the combined organic layer was washed with water (240 mL) and concentrated. The crude product was recrystallized from acetone (120 mL)-water (240 mL), and the obtained solid was dried at 60° C. under reduced pressure to give the title compound (34.1 g) as white crystals.
Reaction SMILES: [P:1]([Cl:15])(Cl)([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)=[O:2].Cl.[CH2:17]([O:19][C:20](=[O:24])[C@H:21]([CH3:23])[NH2:22])[CH3:18].CCN(CC)CC>C(Cl)Cl>[Cl:15][P:1]([NH:22][C@H:21]([C:20]([O:19][CH2:17][CH3:18])=[O:24])[CH3:23])([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)=[O:2]
Reactant: CCOC(=O)[C@H](C)N
Reactant: O=P(Cl)(Cl)Oc1cccc2ccccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@H](C)NP(=O)(Cl)Oc1cccc2ccccc12

Procedure:
Following the procedure described for Example 1, step 2, treatment of a solution in DCM (0.144 M) of 1-naphthyl dichlorophosphate with L-alanine ethyl ester hydrochloride (1.0 eq.) and Et3N (2.0 eq.) provided the title compound as a colorless oil as a 1:1.1* mixture of diastereoisomers. 31P NMR (300 MHz, CDCl3) δ: 9.47 and 9.14*.
Reaction SMILES: OC1C(=O)NN=C(CCC2C=CC=CC=2)C=1.C([O:24][C:25]1[N:26]=[N:27][C:28]([C:39]#[C:40][C:41]2[C:46]([F:47])=[CH:45][CH:44]=[CH:43][C:42]=2[F:48])=[CH:29][C:30]=1[O:31]CC1C=CC=CC=1)C1C=CC=CC=1>CO>[F:48][C:42]1[CH:43]=[CH:44][CH:45]=[C:46]([F:47])[C:41]=1[CH2:40][CH2:39][C:28]1[CH:29]=[C:30]([OH:31])[C:25](=[O:24])[NH:26][N:27]=1
Reactant: Fc1cccc(F)c1C#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: O=c1[nH]nc(CCc2ccccc2)cc1O
Solvent: CO
Product: O=c1[nH]nc(CCc2c(F)cccc2F)cc1O
Yield: 24.8 %

Procedure:
Prepared by the same method as for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[2-(2,6-difluorophenyl)ethynyl]pyridazine (Intermediate 33) except that the solvent mixture used for the hydrogenation was methanol and the final material was purified by preparative HPLC (0.035 g, 24.8% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[N+:9]([C:12]1[CH:13]=[C:14]([C:18]2[O:22][C:21]([CH:23]=O)=[CH:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)([O-:11])=[O:10]>>[N+:9]([C:12]1[CH:13]=[C:14]([C:18]2[O:22][C:21]([CH:23]=[N:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[OH:8])=[CH:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)([O-:11])=[O:10]
Reactant: Nc1ccccc1O
Reactant: O=Cc1ccc(-c2cccc([N+](=O)[O-])c2)o1
Product: O=[N+]([O-])c1cccc(-c2ccc(C=Nc3ccccc3O)o2)c1

Procedure:
Using 2-aminophenol and 5-(3-nitrophenyl)furan-2-carbaldehyde, 3.51 g of 2-{[5-(3-nitrophenyl)furan-2-yl]methyleneamino}phenol were obtained as a yellow powder (yield 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]([C:18](=[O:20])[CH3:19])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1.CC(C)([O-])C.[K+].C(OCC)C>C(O)(C)(C)C.O>[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][C:10]([CH2:9][CH2:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)([C:18](=[O:20])[CH3:19])[C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])=[CH:24][CH:23]=1
Reactant: CC(=O)C(CCc1ccc(Cl)cc1)C(=O)OC(C)(C)C
Reactant: ClCc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CCOCC
Solvent: O
Product: CC(=O)C(CCc1ccc(Cl)cc1)(Cc1ccc(Cl)cc1)C(=O)OC(C)(C)C
Yield: 321.5 %

Procedure:
1.94 g of tert-butyl 2-{2-(4-chlorophenyl)ethyl}-3-oxobutanoate was dissolved in 10 ml of tert-butanol, and 0.17 g of p-chlorobenzyl chloride and 0.90 g of potassium tert-butoxide were added thereto. The mixture was heated and refluxed for 1 hour. Then, ethyl ether and water were added to the reaction solution for liquid separation. The organic layer was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The drying agent was separated by filtration and then the solvent was distilled off under reduced pressure. The residue was subjected to medium pressure liquid chromatography (hexane/ethyl acetate=9/1) to obtain 1.43 g (yield: 52%) of tert-butyl 2-(4-chlorobenzyl)-2-{2-(4-chlorophenyl)ethyl}-3-oxobutanoate.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([N:9]2[CH2:15][CH:14]([N:16]([CH3:18])[CH3:17])[C:11]3([CH2:13][CH2:12]3)[CH2:10]2)[C:6]([F:19])=[C:5]([NH:20][NH2:21])[N:4]=1)[CH3:2].[CH:22]1([CH2:27][C@H:28]([CH2:32][N:33]([CH:42]=[O:43])[O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:29](O)=[O:30])[CH2:26][CH2:25][CH2:24][CH2:23]1.CN1CCOCC1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CN(C=O)C>[CH:22]1([CH2:27][C@@H:28]([C:29]([NH:21][NH:20][C:5]2[C:6]([F:19])=[C:7]([N:9]3[CH2:15][CH:14]([N:16]([CH3:17])[CH3:18])[C:11]4([CH2:12][CH2:13]4)[CH2:10]3)[N:8]=[C:3]([CH2:1][CH3:2])[N:4]=2)=[O:30])[CH2:32][N:33]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:42]=[O:43])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CCc1nc(NN)c(F)c(N2CC(N(C)C)C3(CC3)C2)n1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OCc1ccccc1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCc1nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)c(F)c(N2CC(N(C)C)C3(CC3)C2)n1
Reaction time: 8 h
Yield: 71.3 %

Procedure:
To a solution of racemic 5-(2-ethyl-5-fluoro-6-hydrazino-4-pyrimidinyl)-N,N-dimethyl-5-azaspiro[2.4]heptan-7-amine (0.0818 g, 0.278 mmol) in DMF (3 mL) was added (2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoic acid (0.0778 g, 0.255 mmol), N-methylmorpholine (0.140 mL, 1.273 mmol), 1-hydroxy-7-azabenzotriazole (42 mg, 0.309 mmol), and EDC (59 mg, 0.308 mmol). The solution was stirred overnight and then purified directly by Gilson RPLC to give [(2R)-2-(cyclopentylmethyl)-3-(2-{6-[7-(dimethylamino)-5-azaspiro[2.4]hept-5-yl]-2-ethyl-5-fluoro-4-pyrimidinyl}hydrazino)-3-oxopropyl][(phenylmethyl)oxy]formamide (0.1058 g, 71% yield, mixture of diastereomers) as a yellow oil. LCMS: (M+H)+: 582.3.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:12][C:13]1[CH:14]=[C:15]([CH2:20][C:21]([OH:23])=O)[CH:16]=[CH:17][C:18]=1[Cl:19])[CH:9]1[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:24]1([NH2:27])[CH2:26][CH2:25]1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:12][C:13]1[CH:14]=[C:15]([CH2:20][C:21](=[O:23])[NH:27][CH:24]2[CH2:26][CH2:25]2)[CH:16]=[CH:17][C:18]=1[Cl:19])[CH:9]1[CH2:10][CH2:11]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NC1CC1
Reactant: CC(C)(C)OC(=O)N(Cc1cc(CC(=O)O)ccc1Cl)C1CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(Cc1cc(CC(=O)NC2CC2)ccc1Cl)C1CC1
Reaction time: 1 h
Yield: 65.8 %

Procedure:
To a sol. of {3-[(tert-butoxycarbonyl-cyclopropyl-amino)-methyl]-4-chloro-phenyl}-acetic acid (4.30 g, 12.6 mmol) in CH2Cl2 (130 mL) was added 1-chloro-N,N-2-trimethylpropenyl amine (1.87 mL, 15.2 mmol), and the mixture was stirred for 60 min. A sol. of cyclopropylamine (3.62 mL, 50.6 mmol) in CH2Cl2 (50 mL) was added, and the mixture was stirred for 60 min. More CH2Cl2 was added, and the mixture was washed with water and brine, was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 7:3) yielded the title compound (3.14 g, 65%). LC-MS: tR=0.97 min; ES+: 323.29.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:17])[N:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[C:5](=[O:8])[NH:6][N:7]=1.[C:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)#[N:19].N1C=CC=CC=1.[N+]1([O-])C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][N:4]2[C:3](=[O:17])[C:2]([Br:1])=[N:7][N:6]([C:24]3[CH:25]=[C:20]([CH:21]=[CH:22][CH:23]=3)[C:18]#[N:19])[C:5]2=[O:8])=[CH:11][CH:12]=1
Reactant: O=c1[nH]nc(Br)c(=O)n1Cc1ccc(Cl)cc1
Reactant: N#Cc1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [O-][n+]1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1cccc(-n2nc(Br)c(=O)n(Cc3ccc(Cl)cc3)c2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.8 %

Procedure:
According to Scheme 2 Step 3: To a solution of 6-bromo-4-(4-chlorobenzyl)-1,2,4-triazine-3,5(2H,4H)-dione (0.600 g, 1.9 mmol) in DCM (8 ml) were added 3-cyanophenylboronic acid (0.42 g, 2.8 mmol), copper(II) acetate (0.069 g, 0.38 mmol), pyridine (0.3 g, 3.8 mmol) and pyridine N-oxide (0.2 g, 2.1 mmol) and the mixture was stirred overnight at room temperature. The reaction mixture was quenched with a saturated sodium bicarbonate solution and extracted with ethyl acetate (×3). The combined organic layers were washed with water then with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography, 30 g prepacked column, cyclohexane/ethyl acetate 85/15 to afford 3-(4-(4-chlorobenzyl)-6-bromo-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)benzonitrile (300 mg, 38%) which was used in the next step without any purification
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[N:8]1[CH2:20][C:19]2[C:10](=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][CH:15]=[CH:14]3)[C:9]1=[O:21].C([O:25][CH2:26][CH3:27])(=O)C>C(O)C.[Pd]>[OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[N:8]1[CH2:20][C:19]2[C:18]3[C:13](=[CH:14][CH2:15][CH2:16][N:17]=3)[C:12]([CH2:11][CH:10]3[CH2:19][CH2:27][C:26](=[O:25])[NH:8][CH2:9]3)=[CH:11][C:10]=2[C:9]1=[O:21]
Reactant: CCOC(C)=O
Reactant: O=C1c2ccc3cccnc3c2CN1[C@H]1CCCC[C@@H]1O
Agent: [Pd]
Solvent: CCO
Product: O=C1CCC(Cc2cc3c(c4c2=CCCN=4)CN([C@H]2CCCC[C@@H]2O)C3=O)CN1
Reaction time: 15 h

Procedure:
To a solution of 5-{[6-benzyloxy)pyridine-3-yl]methyl}-8-[(1S,2S)-2-hydroxycyclohexyl]-8,9-dihydro-7H-pyrrolo[3,4-h]quinolin-7-one (Example 19, 0.070 g, 0.15 mmol) in a mixture of 1 mL of ethyl acetate and 1 mL of ethanol under an atmosphere of nitrogen was added palladium on carbon (1.6 mg, 0.015 mmol). The mixture was placed under an atmosphere of hydrogen (1 atm) for 15 hr, filtered through a pad of Celite and concentrated in vacuo. The residue was purified via preparative reverse phase HPLC to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 394.2134 for [M+H]+ [Calc'd for C23H28N3O3, [M+H]+=394.2134]: 1H NMR (400 MHz, CD3OD) δ 7.54-7.51 (m, 1H), 7.21 (d, J=1.8 Hz, 1H), 6.90 (s, 1H), 6.59 (d, J=9.4 Hz, 1H), 4.33-4.22 (m, 2H), 4.00-3.82 (m, 1H), 3.82 (s, 2H), 3.75-3.69 (m, 1H), 3.37-3.32 (m, 1H), 2.84-2.69 (m, 3H), 2.11-2.09 (m, 1H), 1.97-1.92 (m, 2H), 1.92-1.67 (m, 3H), 1.64-1.57 (m, 1H), 1.44-1.29 (m, 4H) ppm.
Reaction SMILES: Cl.Cl.[CH2:3]([N:10]1[CH2:17][CH:16]2[O:18][CH:12]([CH2:13][NH:14][CH2:15]2)[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].CC1C=C(C)C=C(C)C=1S(O[CH2:34][CH2:35][CH2:36][NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])(=O)=O>C1(C)C=CC=CC=1>[C:41]([O:40][C:38](=[O:39])[NH:37][CH2:36][CH2:35][CH2:34][N:14]1[CH2:15][CH:16]2[O:18][CH:12]([CH2:11][N:10]([CH2:3][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:17]2)[CH2:13]1)([CH3:44])([CH3:43])[CH3:42]
Reactant: Cc1cc(C)c(S(=O)(=O)OCCCNC(=O)OC(C)(C)C)c(C)c1
Reactant: c1ccc(CN2CC3CNCC(C2)O3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCCCN1CC2CN(Cc3ccccc3)CC(C1)O2
Temperature: 65 °C
Reaction time: 0.25 h
Yield: 90.1 %

Procedure:
To 3-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane dihydrochloride (25.08 g, 86.12 mmol; see Preparation O above) was added 2.5 M sodium hydroxide (115 mL). 3-(tert-Butyloxycarbonylamino)propyl 2,4,6-trimethylbenzenesulfonate (32.35 g, 90.50 mmol; see Preparation L above) and toluene (65 mL) were then added and the reaction mixture heated at 65° C. for 12 hours. The phases were separated at 65° C. and the lower (aqueous) layer discarded. The organic phase was re-heated to 65° C. and then extracted with 10% w/w aqueous citric acid (125 mL). The phases were separated and the upper (organic) phase discarded. To the aqueous citric acid phase was added isopropyl acetate (150 mL) and 5 M sodium hydroxide (75 mL). The resulting mixture was stirred at room temperature for 15 minutes. The phases were separated and the lower (aqueous) phase discarded. The resulting organic phase was dried (MgSO4), filtered and the solvent removed in vacuo to give the title compound as a colourless oil (29.13 g, 77.60 mmol, 90%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[CH:21][C:22]4[N:27]5[C:28]([C:31]([O:33]CC)=O)=[N:29][N:30]=[C:26]5[CH2:25][O:24][C:23]=4[N:36]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+:44]>[OH-].[NH4+]>[C:31]([C:28]1[N:27]2[C:22]3[CH:21]=[C:20]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:19]([C:16]4[CH:17]=[CH:18][C:13]([C:9]5([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][CH2:11][CH2:12]5)=[CH:14][CH:15]=4)=[N:36][C:23]=3[O:24][CH2:25][C:26]2=[N:30][N:29]=1)(=[O:33])[NH2:44]
Reactant: [NH4+]
Reactant: CCOC(=O)c1nnc2n1-c1cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc1OC2
Agent: [Cl-]
Agent: [OH-]
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(nnc3C(N)=O)CO4)cc2)CCC1
Temperature: 100 °C
Yield: 57.4 %

Procedure:
A suspension of ethyl 7-(4-(1-((tert-butoxycarbonyl)amino)cyclobutyl)phenyl)-8-phenyl-4H-pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]oxazine-1-carboxylate (70 mg, 0.123 mmol) and ammonium chloride (10 mg, 0.19 mmol) in ammonium hydroxide (1 ml) was heated to 100° C. for 10 minutes under microwave irradiation. The resulting reaction mixture was concentrated to dryness under reduced pressure and purified by Biotage silica gel chromatography (gradient 0% to 10% ethyl acetate in cyclohexane) to give the title compound (38 mg, 13%). LCMS (Method D): RT=1.347 min, M+1=539. 1H-NMR (500 MHz, CD3OD) δ 9.10 (1H, s), 7.47-7.40 (1H, bs), 7.40-7.37 (2H, d), 7.32-7.27 (6H, m), 5.59 (2H, s), 2.59-2.39 (4H, m), 2.14-2.01 (1H, m), 1.88-1.76 (1H, m), 1.44-1.33 (9H, bs).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])CCC.[CH3:11][C:12]1([CH3:32])[CH:29]=[C:28]([CH3:30])[C:27]2[C:14](=[CH:15][CH:16]=[C:17]3[C:26]=2[C:25](=[O:31])[O:24][C:23]2[C:18]3=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:13]1.[NH4+].[Cl-]>O1CCCC1.C(OCC)(=O)C.CCCCCC>[OH:24][C:23]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:17]1[C:26]([C:25]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:31])=[C:27]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([CH3:11])([CH3:32])[CH:29]=[C:28]2[CH3:30]
Reactant: CC1=CC(C)(C)Nc2ccc3c(c21)c(=O)oc1ccccc13
Reactant: C1CCNC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1=CC(C)(C)Nc2ccc(-c3ccccc3O)c(C(=O)N3CCCC3)c21
Reaction time: 0.5 h
Yield: 82 %

Procedure:
Pyrrolidine (135 μL, 1.62 mmol) was dissolved in anhydrous tetrahydrofuran (1 mL), and 1.6 M hexane solution of n-butyl litium was added dropwise thereto at 0° C. After the reaction mixture was stirred at same temperature for 30 minutes, an anhydrous tetrahydrofuran solution (3 mL) of 2,2,4-trimethyl-1,2-dihydro-6-oxa-1-azachrysen-5-one (Reference Compound No. 1-1, 80 mg, 0.27 mmol) was dropped and then the reaction mixture was stirred for 30 minutes more. After the saturated aqueous NH4Cl solution (5 mL) was added to the reaction mixture, the reaction mixture was diluted with ethyl acetate (100 mL). The whole was washed with water (100 mL) and saturated brine (50 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (80.2 mg) as a pale yellow solid. (Yield 82%)
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:8]2[CH:9]=[C:10]([C:13]3[NH:17][C:16]([C:18]#[N:19])=[CH:15][CH:14]=3)[CH:11]=[CH:12][C:7]=2[NH:6][C:5](=[O:20])[CH2:4][O:3]1.I[CH3:23]>>[CH3:1][C:2]1([CH3:21])[C:8]2[CH:9]=[C:10]([C:13]3[N:17]([CH3:23])[C:16]([C:18]#[N:19])=[CH:15][CH:14]=3)[CH:11]=[CH:12][C:7]=2[NH:6][C:5](=[O:20])[CH2:4][O:3]1
Reactant: CC1(C)OCC(=O)Nc2ccc(-c3ccc(C#N)[nH]3)cc21
Reactant: CI
Product: Cn1c(C#N)ccc1-c1ccc2c(c1)C(C)(C)OCC(=O)N2

Procedure:
Prepared from 5-(5,5-dimethyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-7-yl)-1H-pyrrole-2-carbonitrile and iodomethane generally according to the procedure of example 3. 1H-NMR (DMSO-d6) δ 10.06 (s, 1H), 7.40 (d, J=1.87 Hz, 1H), 7.34 (dd, J=1.87, 8.32 Hz, 1H), 7.20 (d, J=8.38 Hz, 1H), 7.03 (d, J=3.99 Hz, 1H), 6.35 (d, J=4.00, 1H), 4.27 (s, 2H), 3.71 (s, 3H), 1.58 (s, 6H); MS (FI) m/z 294 ([M−H]−, 100%)