Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8](=[O:10])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>>[CH3:13][N:14]([CH3:16])[CH:15]=[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8](=[O:10])[CH3:9]
Reactant: CC(=O)Cc1ccccc1
Reactant: COC(OC)N(C)C
Product: CC(=O)C(=CN(C)C)c1ccccc1

Procedure:
A mixture of phenylacetone (13.4 grams) and dimethylformamide dimethylacetal (13.0 grams) was heated at 90°-95° C. on a steam bath for about 21/2 hours. A crude oil was produced which was then chromatographed on 600 ml of silica gel using ethyl acetate as an eluent. The final product, whose structure was confirmed by NMR, was a yellow oil which crystallized upon standing, yield 15.5 grams.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH:21]=[C:20]([C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:23])[CH:19]=[N:18]2)=[CH:13][CH:12]=1.[Br:30]Br>C(O)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>[Br:30][C:12]1[CH:13]=[C:14]([N:17]2[CH:21]=[C:20]([C:22]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)=[O:23])[CH:19]=[N:18]2)[CH:15]=[CH:16][C:11]=1[O:10][CH2:9][CH2:8][CH2:7][N:3]1[CH2:4][CH2:5][CH2:6][C@H:2]1[CH3:1]
Reactant: C[C@@H]1CCCN1CCCOc1ccc(-n2cc(C(=O)N3CCOCC3)cn2)cc1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Product: C[C@@H]1CCCN1CCCOc1ccc(-n2cc(C(=O)N3CCOCC3)cn2)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.3 %

Procedure:
To a solution of 4-{[1-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-1H-pyrazol-4-yl]carbonyl}morpholine obtained in Example 6 (0.500 g) in acetic acid (8.0 ml), bromine (0.200 g) was added dropwise and stirred overnight at room temperature. The reaction mixture was diluted with saturated aqueous sodium thiosulfate and concentrated under reduced pressure. The resulting residue was diluted with saturated aqueous sodium bicarbonate and extracted with chloroform. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by NH-type silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=1:1) to give the titled compound (0.175 g) as a colorless solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:19]=[CH:18][C:11]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=1.[CH2:20]([NH:22][CH2:23][CH3:24])[CH3:21]>CO>[CH2:20]([N:22]([CH2:23][CH3:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:19]=[CH:18][C:11]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=1)[CH3:21]
Reactant: COC(=O)CCc1ccc(CCCCCCBr)cc1
Reactant: CCNCC
Solvent: CO
Product: CCN(CC)CCCCCCc1ccc(CCC(=O)OC)cc1
Yield: 84.4 %

Procedure:
To 10 ml of methanol was added 2.1 g of methyl p-(6-bromohexyl)dihydrocinnamate and 4.67 g of diethylamine, and the mixture was refluxed for 5 hours. The solvent was evaporated off under a reduced pressure, 50 ml of ethyl acetate was added to the residue, and the mixture was washed twice with 20 ml of water, dried over magnesium sulfate and evaporated under a reduced pressure, to obtain 1.73 g of methyl p-(6-diethylaminohexyl)dihydrocinnamate as a colorless oil. To 1.5 g of this oil was added 4.7 ml of 1N sodium hydroxide aqueous solution, the mixture was stirred with heating at 85° C. for 3 hours, and water was evaporated off under a reduced pressure to obtain a residue, which was then dried in the presence of phosphorus pentaoxide under a reduced pressure to obtain 1.5 g of sodium p-(6-diethylaminohexyl)dihydrocinnamate. To 20 ml of dimethylformamide were added 1.4 g of the above salt and 0.86 g of diethylaminoethylchloride, and the reaction mixture was stirred for 4 hours at 60° C. After adding 50 ml of a saturated sodium chloride aqueous solution, the reaction mixture was extracted three times with 20 ml of ethyl acetate, and the extract was washed three times with water, dried over magnesium sulfate and evaporated under a reduced pressure to obtain 1.43 g of 2-diethylaminoethyl p-(6-diethylaminohexyl)dihydrocinnamate as a residue. Next, 1 g of this compound and 6 ml of ethyl iodide were added to 7 ml of ethanol, and the mixture was refluxed for 8 hours and allowed to stand in a freezer. The resulting crystal was recovered by filtration, washed twice with 10 ml of ethanol, and dried in the presence of phosphorus pentaoxide under a reduced pressure to obtain 0.8 g of the title compound as a colorless crystal.
Reaction SMILES: S(OS([O-])=O)([O-])=O.[Na+].[Na+].[Cl:10][C:11]1[S:12][C:13]([CH:16]=O)=[CH:14][CH:15]=1.[NH2:18][C:19]1[CH:20]=[C:21]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:22]=[CH:23][C:24]=1[NH2:25].O>CN1CCCC1=O>[Cl:10][C:11]1[S:12][C:13]([C:16]2[NH:25][C:24]3[CH:23]=[CH:22][C:21]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:20][C:19]=3[N:18]=2)=[CH:14][CH:15]=1
Reactant: O=Cc1ccc(Cl)s1
Reactant: CCOC(=O)Cc1ccc(N)c(N)c1
Agent: O=S([O-])OS(=O)[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)Cc1ccc2[nH]c(-c3ccc(Cl)s3)nc2c1
Temperature: 110 °C
Reaction time: 18 h

Procedure:
3.1 3.89 g (20.5 mmol) of sodium disulfite are added to a solution of 3.00 g (20.5 mmol) of 2-chlorothiophene-5-carbaldehyde and 3.98 g (20.5 mmol) of ethyl 3,4-diaminophenylacetate in 30 ml of 1-methyl-pyrrolidone, and the mixture is stirred at 110° C. for 18 hours. Water is added to the reaction mixture, which is extracted with dichloromethane. The organic phase is dried using sodium sulfate and evaporated, giving ethyl [2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]acetate as a brown oil (ESI 321), which is employed without further purification for the next reaction.
Reaction SMILES: [CH3:1][C:2]1[CH2:6][CH2:5][C:4](=[O:7])[CH:3]=1.[CH2:8](Cl)[CH:9]=[C:10]([CH3:12])[CH3:11].C1(C)C=CC=CC=1.[OH-].[Na+]>C(O)(=O)C.O>[CH3:1][C:2]1[CH2:6][CH2:5][C:4](=[O:7])[C:3]=1[CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11]
Reactant: CC(C)=CCCl
Reactant: CC1=CC(=O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC(C)=CCC1=C(C)CCC1=O
Temperature: 100 °C
Reaction time: 4 h
Yield: 49.9 %

Procedure:
A mixture of 3-methyl-2-cyclopentenone 24.5 g (0.25 mole) and prenyl chloride 54 g (0.51 mole) was fed into a reaction flask containing 30 ml of toluene, sodium hydroxide 21.3 g, water 21.3 g and Aliquat 3361 g maintaining 100° C. The reaction mass was aged for 4 hours, cooled to 25° C. and neutralized with acetic acid. The organic layer was removed and distilled to give 20.5 g of 3-methyl-2-(3-methyl-2-butenyl)-2-cyclopenten-1-one. The 3-methyl-2-(3-methyl-2-butenyl)-2-cyclopenten-1-one had a Bp of 115° C. at 5 mmHg.
Reaction SMILES: Br[C:2]1[C:3]([CH3:30])=[CH:4][C:5]([N:8]2[C:12]([O:13][CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])=[C:11]([C:22]3[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=3)[CH:10]=[N:9]2)=[N:6][CH:7]=1.CN([CH:34]=[O:35])C.[CH3:36][OH:37].C(N(CC)CC)C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[C:26]([C:25]1[CH:28]=[CH:29][C:22]([C:11]2[CH:10]=[N:9][N:8]([C:5]3[CH:4]=[C:3]([CH3:30])[C:2]([C:36]([O:35][CH3:34])=[O:37])=[CH:7][N:6]=3)[C:12]=2[O:13][CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])=[CH:23][CH:24]=1)#[N:27]
Reactant: CN(C)C=O
Reactant: CO
Reactant: Cc1cc(-n2ncc(-c3ccc(C#N)cc3)c2OCOCC[Si](C)(C)C)ncc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc(-n2ncc(-c3ccc(C#N)cc3)c2OCOCC[Si](C)(C)C)cc1C
Temperature: 120 °C
Reaction time: 8 h

Procedure:
Combined 4-(1-(5-bromo-4-methylpyridin-2-yl)-5-((2-(trimethylsilyl)ethoxy)methoxy)-1H-pyrazol-4-yl)benzonitrile (10.0 g, 20.66 mmol), DMF (60 mL) and MeOH (60 mL) then added triethylamine (6.26 g, 61.98 mmol) and Pd(dppf)Cl2 (756.2 mg, 1.033 mmol). The mixture was stirred at 120° C. under 1 MPa of CO overnight. Then the reaction mixture was evaporated in vacuum to give a residue which was combined with water, filtered, and the aqueous was extracted with EtOAc (100 mL×2). The combined EtOAc layers were washed with brine and dried (Na2SO4), and concentrated to give the title compound (8.67 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:18])[CH:10]=[CH:11]C2C=CC=CC=2)=[CH:4][CH:3]=1.[Cl-:19].[Cl-].[Cl-].[Al+3]>>[ClH:19].[F:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[NH:8][C:9](=[O:18])[CH:10]=[CH:11]2
Reactant: [Cl-]
Reactant: O=C(C=Cc1ccccc1)Nc1ccc(F)cc1
Agent: [Al+3]
Product: Cl
Product: O=c1ccc2cc(F)ccc2[nH]1
Temperature: 100 °C
Yield: 113.8 %
Yield: 5 %

Procedure:
An intimate mixture of N-(4-fluorophenyl)cinnamamide (10 g, 42 mmol) and aluminum trichloride (16.4 g, 123 mmol, 3 eq) was heated rapidly to melting and then heated at 100° C. for 3 h. After cooling to room temperature, ice-water was added and the resultant precipitate was washed with water (300 ml) and then with 5% aqueous hydrochloric acid (3×100 ml) to afford 6-fluoro-1,2-dihydroquinolin-2-one as a brown solid (7.8 g, 88%) which was used without further purification; (ES, m/z): [M+H]+ 164; 1H NMR (300 MHz, DMSO): δ 11.82 (broad s, 1H), 7.86 (d, J=9.4 Hz, 1H), 7.61 (d, J=8.7 Hz, 1H), 7.29-7.40 (m, 2H), 6.54 (d, J=9.4 Hz, 1H).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][NH2:40])=[CH:33][C:32]=2[CH3:41])=[C:28]([CH:42]([CH3:44])[CH3:43])[NH:27][N:26]=1)(=O)C.[NH2:45][C:46]([CH3:50])([CH3:49])[CH2:47][OH:48].NCCN1CC[O:57][CH2:56]C1>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][NH:40][C:56]([NH:45][C:46]([CH3:50])([CH3:49])[CH2:47][OH:48])=[O:57])=[CH:33][C:32]=3[CH3:41])=[C:28]([CH:42]([CH3:43])[CH3:44])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCN)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(C)(N)CO
Reactant: NCCN1CCOCC1
Product: Cc1cc(OCCNC(=O)NC(C)(C)CO)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C

Procedure:
The title compound was prepared in a similar manner to that described in Example 19 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-aminoethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and 2-amino-2-methyl-1-propanol instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-aminopropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole and 4-(2-aminoethyl)morpholine, respectively.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:18][CH2:17][C:12]3([O:16][CH2:15][CH2:14][O:13]3)[CH2:11][CH:10]=2)O1.[O:20]1[CH2:25][CH:24]=[C:23](OS(C(F)(F)F)(=O)=O)[CH2:22][CH2:21]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1(P([Pd-4](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)C=CC=CC=1>[O:20]1[CH2:21][CH:22]=[C:23]([C:9]2[CH2:18][CH2:17][C:12]3([O:13][CH2:14][CH2:15][O:16]3)[CH2:11][CH:10]=2)[CH2:24][CH2:25]1
Reactant: CC1(C)OB(C2=CCC3(CC2)OCCO3)OC1(C)C
Reactant: O=S(=O)(OC1=CCOCC1)C(F)(F)F
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C1=C(C2=CCC3(CC2)OCCO3)CCOC1
Temperature: 100 °C

Procedure:
8-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,4-dioxa-spiro[4.5]dec-7-ene (prepared as described in PCT Int. Appl. WO2006064189, 1.57 g, 5.90 mmol), commercially available 3,6-dihydro-2H-pyran-4-yltrifluoromethanesulfonate (5.23 mmol), and tetrakis (triphenylphosphino)palladium(0) (302 mg, 0.262 mmol) were dissolved in 1,4-dioxane (20 mL), treated with 2M aqueous Na2CO3 (14 mL, 28 mmol), bubbled with argon for a few minutes, and heated to 100° C. under reflux condenser for 24 h. After cooling to ambient temperature, the reaction was diluted with water (30 mL), extracted thrice with dichloromethane, aqueous layer acidified to ca. pH 7, extracted twice more with dichloromethane, and the combined organic layers washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give an orange oil. This was purified by flash chromatography (silica gel, EtOAc) to give the title compound as a colorless crystalline solid.
Reaction SMILES: OC1C(=O)N=C(CC2(N3C4=NC=CC=C4C=C3)CCCC2)N2CCN(C)C(=O)C=12.C([O:37][C:38]1[C:43](=[O:44])[N:42]=[C:41]([CH2:45][C:46]2([N:51]3[C:55]4=[N:56][CH:57]=[CH:58][CH:59]=[C:54]4[CH:53]=[CH:52]3)[CH2:50][CH2:49][CH2:48][CH2:47]2)[N:40]2[CH2:60][CH2:61][N:62]([CH:65]3[CH2:68][CH2:67][CH2:66]3)[C:63](=[O:64])[C:39]=12)C1C=CC=CC=1>>[CH:65]1([N:62]2[CH2:61][CH2:60][N:40]3[C:41]([CH2:45][C:46]4([N:51]5[C:55]6=[N:56][CH:57]=[CH:58][CH:59]=[C:54]6[CH:53]=[CH:52]5)[CH2:47][CH2:48][CH2:49][CH2:50]4)=[N:42][C:43](=[O:44])[C:38]([OH:37])=[C:39]3[C:63]2=[O:64])[CH2:68][CH2:67][CH2:66]1
Reactant: O=C1c2c(OCc3ccccc3)c(=O)nc(CC3(n4ccc5cccnc54)CCCC3)n2CCN1C1CCC1
Agent: CN1CCn2c(CC3(n4ccc5cccnc54)CCCC3)nc(=O)c(O)c2C1=O
Product: O=C1c2c(O)c(=O)nc(CC3(n4ccc5cccnc54)CCCC3)n2CCN1C1CCC1

Procedure:
2-Cyclobutyl-9-hydroxy-6-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (428) was prepared following the same method as described for 9-hydroxy-2-methyl-6-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (408) from 9-benzyloxy-2-cyclobutyl-6-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (427) (55 mg, 0.10 mmol) and was obtained as an off-white solid (37 mg, 81%).
Reaction SMILES: [CH:1]1([S:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[Li][CH2:16]CCC.CI>C1COCC1>[CH3:16][C:1]1([S:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)C1CC1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: CC(C)(C)OC(=O)NS(=O)(=O)C1(C)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of tert-butyl cyclopropylsulfonylcarbamate (4.3 g, 20 mmol) was dissolved in dry THF (100 ml) and cooled to −78° C. To this solution was added n-BuLi (17.6 ml, 44 mmol, 2.5 M in hexane) slowly. The reaction mixture was allowed to warm to room temperature over a period of 1.5 h. This mixture was then cooled to −78° C., and a solution of n-BuLi (20 mmol, 8 ml, 2.5M in hexane) was added, stirred for 1 h and a neat solution of methyl iodide (5.68 g, 40 mmol) was added. The reaction mixture was allowed to warm to room temperature for overnight, quenched with aqueous saturated NH4Cl (100 ml) at room temperature. It was extracted with EtOAc (100 ml). The combined organic layer was washed with brine dried on Na2SO4, filtered and evaporated under reduced pressure to give a yellow oil which was crystallized from hexane to afford the product as a slightly yellow solid. (3.1 g, 81%). 1H NMR (400 MHz, DMSO-d6): δ ppm 10.97 (s, 1H), 1.44 (s, 12H), 1.35-1.33 (m, 2H), 0.93-0.91 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10](=[O:14])[N:11]([CH3:13])[N:12]=1.OO.C(=O)([O-])[O-].[K+].[K+].[Cl:24]CCl>C(O)(=O)C>[Cl:24][C:3]1[C:2]([CH3:1])=[C:7]([C:8]2[O:9][C:10](=[O:14])[N:11]([CH3:13])[N:12]=2)[CH:6]=[CH:5][N:4]=1
Reactant: ClCCl
Reactant: Cc1c[n+]([O-])ccc1-c1nn(C)c(=O)o1
Agent: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CC(=O)O
Product: Cc1c(-c2nn(C)c(=O)o2)ccnc1Cl
Temperature: 80 °C
Yield: 88 %

Procedure:
Step-3: 3-Methyl-4-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyridine-1-oxide: To a stirred solution of step-2 intermediate (1.0 g, 5.23 mmol) in acetic acid (30 mL) was added hydrogen peroxide (0.321 mL, 10.46 mmol) drop-wise at RT and the reaction was heated to 80° C. and maintained for 12 h. The resulting mixture was cooled to RT and basified with solid potassium carbonate. The resulting slurry was diluted with dichloromethane (50 mL) and filtered. The filtrate was concentrated under vacuum to afford 800 mg (88%) of title compound as white solid. 1HNMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H), 8.19 (d, J=5.0 Hz, 1H), 7.67 (d, J=5.0 Hz, 1H), 3.43 (s, 3H), 2.45 (s, 3H).
Reaction SMILES: FC(F)(F)[C:3](O)=[O:4].[C:8]1([C:14]2[NH:18][C:17](=[O:19])[C:16]3([CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH2:25][C@H:26]1[C:39](=[O:40])[N:38]([CH2:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH2:37][C:29]2[C:30]3[CH:31]=[N:32][NH:33][C:34]=3[CH:35]=[CH:36][C:28]=2[CH2:27]1>>[CH3:43][C:42]([CH3:45])([CH3:44])[CH2:41][N:38]1[CH2:37][C:29]2[C:30]3[CH:31]=[N:32][NH:33][C:34]=3[CH:35]=[CH:36][C:28]=2[CH2:27][C@@H:26]([NH:25][C:3]([N:22]2[CH2:23][CH2:24][C:16]3([N:15]=[C:14]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[NH:18][C:17]3=[O:19])[CH2:20][CH2:21]2)=[O:4])[C:39]1=[O:40]
Reactant: CC(C)(C)CN1Cc2c(ccc3[nH]ncc23)C[C@@H](N)C1=O
Reactant: O=C(O)C(F)(F)F
Reactant: O=C1NC(c2ccccc2)=NC12CCNCC2
Product: CC(C)(C)CN1Cc2c(ccc3[nH]ncc23)C[C@@H](NC(=O)N2CCC3(CC2)N=C(c2ccccc2)NC3=O)C1=O
Yield: 25 %

Procedure:
2-Phenyl-1,3,8-triaza-spiro[4.5]dec-1-en-4-one trifluoroacetate (55 mg, 0.16 mmol) and (R)-7-amino-9-neopentyl-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one (40 mg, 0.14 mmol) were reacted in a manner analogous to the preparation of 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [8-oxo-9-(2-piperidin-1-yl-ethyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-amide. C18 preparatory HPLC afforded the title compound as white solid in 25% yield. High resolution MS m/e (M+H)+=542.2888.
Reaction SMILES: COC(=O)CC1CCN(C(OC(C)(C)C)=O)CC1.C(C1C=NC=CC=1[CH2:27][C:28]([CH3:33])([CH3:32])[C:29]([NH2:31])=[O:30])=O.[OH:34][CH:35]([C:54]1[C:55](NC(=O)C(C)(C)C)=[N:56][CH:57]=[CH:58][CH:59]=1)[CH:36]([CH:41]1[CH2:46][CH2:45][N:44]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:43][CH2:42]1)[C:37]([O:39][CH3:40])=[O:38]>>[OH:34][CH:35]([C:54]1[CH:55]=[N:56][CH:57]=[CH:58][C:59]=1[NH:31][C:29](=[O:30])[C:28]([CH3:33])([CH3:32])[CH3:27])[CH:36]([CH:41]1[CH2:42][CH2:43][N:44]([C:47]([O:49][C:50]([CH3:51])([CH3:53])[CH3:52])=[O:48])[CH2:45][CH2:46]1)[C:37]([O:39][CH3:40])=[O:38]
Reactant: COC(=O)C(C1CCN(C(=O)OC(C)(C)C)CC1)C(O)c1cccnc1NC(=O)C(C)(C)C
Reactant: CC(C)(Cc1ccncc1C=O)C(N)=O
Agent: COC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1
Product: COC(=O)C(C1CCN(C(=O)OC(C)(C)C)CC1)C(O)c1cnccc1NC(=O)C(C)(C)C
Yield: 54 %

Procedure:
tert-butyl 4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate (1.33 g, 5.2 mmol) and N-(3-formyl-4-pyridinyl-2,2-dimethylpropanamide (1.0 g, 4.7 mmol) were reacted in a manner analogous to the preparation of tert-butyl 4-(1-hydroxy-3-methoxy-3-oxo-1-(2-pivalamidopyridin-3-yl)propan-2-yl)piperidine-1-carboxylate. Title compound was obtained as white foam in 54% yield. (M+H)+=464.2.
Reaction SMILES: [NH2-:1].[Na+].N.[C:4]1([CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H][H]>O.C1(C)C(C)=CC=CC=1>[C:4]1([CH2:10][CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.[C:4]1([CH2:10][CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][N:16]=[C:17]([C:15]3[CH:14]=[C:13]([CH2:12][CH2:11][CH2:10][C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=4)[CH:18]=[CH:17][N:1]=3)[CH:18]=2)[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: [NH2-]
Reactant: [H][H]
Agent: N
Agent: [Na+]
Agent: c1ccc(CCCc2ccncc2)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: c1ccc(CCCc2ccnc(-c3cc(CCCc4ccccc4)ccn3)c2)cc1

Procedure:
In a one-liter, three-neck flask was made 0.22 mole (5.0 g sodium) of sodamide in the usual way. The ammonia was replaced with 348 cc of xylene. The mixture was brought to reflux at 138° and 299.5 g (1.52 moles) of 4-(3-phenylpropyl)pyridine was added through a dropping funnel. Hydrogen evolution began immediately. Heating was continued for five hours at 138°-153° C. until hydrogen production slowed appreciably. The reaction mixture was cooled to around 100° C. and hydrolyzed with 100 cc of water. The oil layer was separated at room temperature and distilled through a Vigreaux column to give 182.5 g (0.93 moles) of unreacted 4-(3-phenylpropyl)pyridine and 62.9 g (0.16 mole) of 4,4'-di-(3-phenylpropyl)-2,2'-bipyridyl. The yield of 2,2'-bipyridyl product, based on 4-(3-phenylpropyl)pyridine consumed, was 54.0%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:16][CH:15]3[S:17](=[O:19])(=[O:18])[CH:12]([CH2:13][CH2:14]3)[CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:20][Mg]Br.C1(C)C=CC=CC=1.C1COCC1>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:11][CH:12]3[S:17](=[O:19])(=[O:18])[CH:15]([CH2:14][CH2:13]3)[CH2:16]2)([OH:9])[CH3:20])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Br)cc1)C1CC2CCC(C1)S2(=O)=O
Reactant: C[Mg]Br
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(O)(c1ccc(Br)cc1)C1CC2CCC(C1)S2(=O)=O
Reaction time: 0.5 h

Procedure:
To a solution of (4-bromo-phenyl)-(8,8-dioxo-8-thia-bicyclo[3.2.1]oct-3-yl)-methanone (885 mg, 2.58 mmol) in THF (7 ml) at −10° C. to −8° C. was added methylmagnesium bromide 1.4M in toluene/THF 3/1 (3.68 ml, 5.16 mmol). The reaction mixture was stirred for 30 min. The solution was cooled with an ice bath and quenched with a solution of aqueous saturated NH4Cl and water 1/1 (7.5 ml), diluted and extracted with ethyl acetate. The organic phases were combined, washed with brine, dried using Na2SO4, filtered and concentrated in vacuo. The crude product (940 mg, 2.54 mmol, 97%) was used in the next step without further purification.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:13]2[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[C@@H:19]1[CH2:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=2)[CH2:20]1>CS(C)=O>[CH3:36][O:35][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[O:33][CH3:34])[CH2:26][CH2:25][N:21]1[CH2:22][CH2:23][CH2:24][C@H:20]1[CH2:19][N:8]1[C:7]2[CH:6]=[CH:5][CH:4]=[CH:3][C:13]=2[CH2:12][O:11][C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]1=2
Reactant: COc1ccc(CCN2CCC[C@@H](Cl)C2)cc1OC
Reactant: c1ccc2c(c1)COc1ccccc1N2
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(CCN2CCC[C@H]2CN2c3ccccc3COc3ccccc32)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.3 %

Procedure:
Sixty-percent sodium hydride (0.34 g, 8.6 mmols) was washed with petroleum ether, and then suspended in 30 ml of dimethyl sulfoxide. To the suspension were added 1.38 g (7.0 mmols) of 5,11-dihydrodibenzo[b,e][1,4]oxazepine. The mixture was stirred in a nitrogen atmosphere at room temperature for 30 minutes. To this reaction solution was added dropwise a solution of 1.8 g (6.3 mmols) of (R)-(-)-3-chloro-1-(3,4-dimethoxyphenethyl)piperidine [[α]D25 =-20.3° (c=0.9, ethanol)] in 5 ml of dimethyl sulfoxide, and the mixed solution was stirred at room temperature for 12 hours and at 40° C. for 4 hours. The reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with water and with a saturated aqueous solution of sodium chloride in this order, and dried. Subsequently, the solvent was distilled off under reduced pressure. The resulting residue was subjected to column chromatography, and eluted with a mixed solvent of ethyl acetate and hexane at a ratio of 1:5. This mixed solvent was distilled off under reduced pressure. Further, the thus-obtained residue was subjected to column chromatography, and extracted with a mixed solvent of chloroform and methanol at a ratio of 200:1. This mixed solvent was then distilled off under reduced pressure to give 0.85 g of (S)-(-)-5,11-dihydro-5-[1-(3,4-dimethoxyphenethyl)-2-pyrrolidinyl-methyl]dibenzo[b,e][1,4]oxazepine as a pale yellow oil in a yield of 30%.