Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1([C:13]2[C:21]3[C:16](=[C:17]([N+:22]([O-:24])=[O:23])[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].[CH3:25][O-].[Na+].IC>CN(C)C=O.CCOCC>[CH2:1]([C:3]1([C:13]2[C:21]3[C:16](=[C:17]([N+:22]([O-:24])=[O:23])[CH:18]=[CH:19][CH:20]=3)[N:15]([CH3:25])[CH:14]=2)[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: C[O-]
Reactant: CCC1(c2c[nH]c3c([N+](=O)[O-])cccc23)CCc2cc(F)ccc21
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CI
Product: CCC1(c2cn(C)c3c([N+](=O)[O-])cccc23)CCc2cc(F)ccc21
Yield: 95.6 %

Procedure:
Combine 3-(1-ethyl-5-fluoro-indan-1-yl)-7-nitro-1H-indole (0.33 g, 1.02 mmol), sodium methoxide (110 mg, 2.04 mmol), and iodomethane (0.10 ml, 1.53 mmol) in dimethylformamide (5 ml) and stir at room temperature under nitrogen overnight. Dilute with ether, wash with water (2×), dry over sodium sulfate, filter, and concentrate to obtain the title compound as a yellow amorphous solid (0.33 g, 94%). LC-MS m/z 339.1 (M++1).
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1O)([O-:19])=[O:18]>N1C=CC=CC=1.CCOC(C)=O.C(O)(C)C>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([O:10][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N+:17]([O-:19])=[O:18])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Reactant: O=[N+]([O-])c1ccccc1O
Solvent: CCOC(C)=O
Solvent: CC(C)O
Solvent: c1ccncc1
Product: O=C(Oc1ccccc1[N+](=O)[O-])C(c1ccccc1)c1ccccc1
Temperature: 0 °C

Procedure:
A solution of diphenylacetic acid (30.0 g; 141 mmol) and o-nitrophenol (39.3 g; 282 mmol) in pyridine (250 mL) was cooled to 0° C. N,N1 -dicyclohexylcarbodiimide (27.6 g; 134 mmol) was added at 0° C. The solution was stirred at 0° C. for several hours, warmed to room temperature and stirred overnight. The resulting heterogeneous solution was diluted with EtOAc and filtered. The filtrate was concentrated to afford a thick oil which was dissolved in a minimal amount of warm isopropanol. Upon cooling the sub-title compound began to crystallize from solution. The crystals were collected and dried under vacuum to afford the sub-title compound (37.3 g; 82%) as an off-white powder.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH:12]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13]1)=[N:10][OH:11].[OH-].[K+].O.[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31]>C(O)C>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31].[F:8][C:6]1[CH:5]=[CH:4][C:3]2[C:9]([CH:12]3[CH2:16][CH2:15][N:14]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:13]3)=[N:10][O:11][C:2]=2[CH:7]=1
Reactant: ON=C(c1ccc(F)cc1F)C1CCN(Cc2ccccc2)C1
Agent: O=C(O)/C=C/C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Fc1ccc2c(C3CCN(Cc4ccccc4)C3)noc2c1
Yield: 74.8 %

Procedure:
A mixture of (2,4-difluorophenyl)[1-(phenylmethyl)-3-pyrrolidinyl]methanone oxime (10.8 g, 34.2 mmol), potassium hydroxide (10 g), water (100 ml), and ethanol (100 ml) was heated at reflux for 2 hours. At the end of the reaction, the solution was cooled and ethanol was removed on a rotary evaporator. The aqueous mixture was diluted with water (100 ml) then extracted with dichloromethane (500 ml). The organic solution was washed with brine and dried over anhydrous MgSO4. The solution was concentrated to an oil (9.8 g). The crude product was purified by flash chromatography over a silica gel column. The product thus obtained weighed 4.46 g (44%) as a light yellow oil. The oily product was dissolved in ethanol, and then treated with a solution of fumaric acid (1.73 g, 1.0 eq) in ethanol. Crystallization took place slowly with the addition of isopropyl ether. Recrystallization from ethanol (15 ml) gave 4.6 g of 6-fluoro-3-[1-(phenylmethyl)-3-pyrrolidinyl]-1,2-benzisoxazole fumarate as white crystals, m.p.=142-144° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:21][C:22]1[C:26](B2OC(C)(C)C(C)(C)O2)=[C:25]([C:36]2([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH2:38][CH2:37]2)[O:24][N:23]=1>CO.O1CCOCC1.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>[C:42]([O:41][C:40]([NH:39][C:36]1([C:25]2[O:24][N:23]=[C:22]([CH3:21])[C:26]=2[C:2]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH2:38][CH2:37]1)=[O:46])([CH3:45])([CH3:44])[CH3:43]
Reactant: Cc1noc(C2(NC(=O)OC(C)(C)C)CC2)c1B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1cc(Cl)ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)c1cc(Cl)ccc1-c1c(C)noc1C1(NC(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 85.6 %

Procedure:
A re-sealable vial containing methyl 2-bromo-5-chlorobenzoate (0.205 g, 0.822 mmol), Pd(Ph3P)4 (0.042 g, 0.036 mmol), and anhydrous potassium phosphate, tribasic (0.275 g, 1.296 mmol) was evacuated and purged with N2 (g) (3×). To the solids was added a solution of tert-butyl 1-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazol-5-yl)cyclopropyl-carbamate (0.236 g, 0.648 mmol) in MeOH (2×1 mL, 2 mL total) and 1,4-Dioxane (2×1 mL, 2 mL total). The suspension was evacuated and purged with N2 (g) (3×), the vial was sealed, and the contents heated to 80° C. LC-MS analysis indicated complete conversion to desired product with in 4 h. After 4 h, the reaction mixture was cooled to room temperature and filtered over Celite. The filter cake was washed with MeOH (3×) and the filtrate was concentrated to give a brown oil. The oil was purified on Biotage system (5% EtOAc:95% Hexanes to 30% EtOAc:70% Hexanes, then isocratic 30% EtOAc:70% Hexanes). The product methyl 2-(5-(1-(tert-butoxycarbonylamino)cyclopropyl)-3-methylisoxazol-4-yl)-5-chlorobenzoate (0.226 g, 0.555 mmol, 86% yield) was isolated as a clear oil. LC/MS m/z 407 [M+H]+.
Reaction SMILES: [H-].[Na+].CS(C)=O.[Br:7][C:8]1[C:17]([OH:18])=[CH:16][C:15]2[C:14]([CH3:20])([CH3:19])[CH2:13][CH2:12][C:11]([CH3:22])([CH3:21])[C:10]=2[CH:9]=1.[CH2:23](Br)[CH2:24][CH3:25]>CN(C)C=O>[Br:7][C:8]1[C:17]([O:18][CH2:23][CH2:24][CH3:25])=[CH:16][C:15]2[C:14]([CH3:20])([CH3:19])[CH2:13][CH2:12][C:11]([CH3:22])([CH3:21])[C:10]=2[CH:9]=1
Reactant: CC1(C)CCC(C)(C)c2cc(Br)c(O)cc21
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: CCCOc1cc2c(cc1Br)C(C)(C)CCC2(C)C
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
1.4 g of sodium hydride, 50% in mineral oil, were suspended in 50 ml of abs. dimethyl sulphoxide and treated dropwise while cooling with ice with 8.5 g of 2-bromo-3-hydroxy-5,5,8,8-tetra-methyl-5,6,7,8-tetrahydro-naphthalene dissolved in 60 ml of abs. dimethylformamide. The reaction mixture was stirred at 40° C. for 1/2 hour and subsequently a solution of 4.4 g of propyl bromide in 20 ml of dimethylformamide was added while cooling with ice. After stirring at room temperature for 20 hours the mixture was poured into ice-water, extracted with ethyl acetate and the crude product obtained after drying and evaporation of the solvent was filtered over a silica gel column (eluent hexane/ethyl acetate=9:1). 9.5 g of 2-bromo-3-propoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene were obtained as a brownish oil. This oil was dissolved in 100 ml of abs. tetrahydrofuran and treated dropwise at -78° C. with 40 ml of tert.butyllithium, 1.4 molar in pentane. After stirring at -78° C. for 1/2 hour 75 ml of abs. dimethylformamide were added dropwise and the mixture was stirred at room temperature for 1 hour. The pale beige suspension was poured into ice-water and extracted with ethyl acetate. After drying and evaporation of the organic phase the crude product was filtered over a silica gel column (eluent hexane/5% ether). There were obtained 6.6 g of 2-formyl-3-propoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene as a pale yellow oil which solidified upon cooling, melting point 51°-52° C.
Reaction SMILES: Cl.Cl.N[C:4]1[C:5]([NH2:18])=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[CH:7]=[CH:8][C:9]=1[CH3:10].[CH3:19][C:20]([CH:22]=[CH2:23])=O>C(O)C.[Cl-].[Zn+2].[Cl-]>[CH3:19][C:20]1[C:4]2[C:5](=[C:6]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]4[C:12]=3[N:18]=[CH:5][CH:4]=[C:9]4[CH3:8])[CH:7]=[CH:8][C:9]=2[CH3:10])[N:18]=[CH:23][CH:22]=1
Reactant: C=CC(C)=O
Reactant: Cc1ccc(-c2ccc(C)c(N)c2N)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCO
Product: Cc1ccnc2c(-c3ccc(C)c4c(C)ccnc34)ccc(C)c12
Yield: 48.1 %

Procedure:
To a solution of 110 g (0.386 mol) of diaminodimethylbiphenyl dihydrochloride, 418 g (1.55 mol) of ferric chloride hexahydrate, and 10.2 g (0.075 mol) zinc chloride in 500 ml of 95% ethanol heated to 50° C. was added 55.6 g (0.78 mol) of methylvinyl ketone over a 90 minute period. The solution was refluxed for 2 hours then allowed to stand over night. Most of the ethanol was removed at reduced pressure and the residue made basic with 25% sodium hydroxide. The basic solution was evaporated to dryness and the dark residue was extracted four times with 400 ml portions of benzene. The extracts were evaporated to dryness to give a dark brown residue. Extraction of the residue with 150 ml of ethanol resulted in a light brown solid which was sublimed (250° C, 0.1 torr) to give 29 g (24%) of 4,4',5,5'-tetramethyl-8,8'-biquinoline, mp 290°-295° C. Crystallization from benzene/hexane afforded an analytical sample, mp 292°-295° C.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][N:9]2[C:30](=[O:31])[N:12]3[CH:13]=[CH:14][C:15]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)=[C:16]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)[C:11]3=[N:10]2)=[CH:6][CH:5]=[C:4]([C:32]([F:35])([F:34])[F:33])[N:3]=1.[CH3:36][NH2:37]>CS(C)=O.O>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:15]2[CH:14]=[CH:13][N:12]3[C:30](=[O:31])[N:9]([CH2:8][C:7]4[C:2]([NH:37][CH3:36])=[N:3][C:4]([C:32]([F:33])([F:35])[F:34])=[CH:5][CH:6]=4)[N:10]=[C:11]3[C:16]=2[C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:24][CH:25]=1
Reactant: CN
Reactant: O=c1n(Cc2ccc(C(F)(F)F)nc2Cl)nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn12
Solvent: CS(C)=O
Solvent: O
Product: CNc1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn2c1=O
Temperature: 25 °C
Yield: 63 %

Procedure:
A solution of 2-((2-chloro-6-(trifluoromethyl)pyridin-3-yl)methyl)-7-(4-chlorophenyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (26 mg, 0.05 mmol) in DMSO (0.5 mL) and 40 wt. % methylamine in water (0.5 mL) was heated in a microwave oven at 200° C. for 30 min. After cooling to room temperature, the reaction mixture was diluted with water and extracted with EtOAc (10 mL×2). The combined EtOAc extracts were concentrated under reduced pressure. The crude product was purified using preparative reverse phase HPLC (Phenomenex Luna 5 μm C-18 21.2×100 mm column eluted with a linear gradient of 50% to 90% B over 8 min (A=0.1% trifluoroacetic acid, 90% water, 10% methanol and B=0.1% trifluoroacetic acid, 90% methanol, 10% water) with flow rate at 20 mL/min and UV detection at 220 nm). The desired fractions were concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with saturated aqueous Na2CO3 once, water twice, then saturated aqueous NaCl, dried over Na2SO4 and evaporated. The residue was dissolved in acetonitrile, frozen and lyophilized to afford 16 mg (63%) of the title compound as a yellow powder. HPLC/MS: retention time=3.28 min, [M+H]+=511.2.
Reaction SMILES: [Br:1][C:2]([F:13])([F:12])[C:3]([F:11])([F:10])[CH2:4][CH2:5][CH2:6][C:7](Cl)=[O:8].[BH4-].[Na+].S(=O)(=O)(O)O>COCCOC>[Br:1][C:2]([F:12])([F:13])[C:3]([F:10])([F:11])[CH2:4][CH2:5][CH2:6][CH2:7][OH:8]
Reactant: O=C(Cl)CCCC(F)(F)C(F)(F)Br
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOC
Product: OCCCCC(F)(F)C(F)(F)Br
Temperature: 50 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
In nitrogen atmosphere, 500 g (1.75 mol) of 6-bromo-5,5,6,6-tetrafluorohexanoyl chloride was dissolved in 1500 mL of ethylene glycol dimethyl ether, followed by the addition of 53 g (1.40 mol) of sodium borohydride. Upon stirring it at 50° C. for 2 hours, a reaction solution was added to a diluted sulfuric acid aqueous solution, followed by extraction with diisopropyl ether. (At this time, the reaction solution was analyzed by gas chromatography, thereby confirming that the production ratio of the objective product 6-bromo-5,5,6,6-tetrafluorohexan-1-ol to the by-product 5,5,6,6-tetrafluorohexan-1-ol was 100%:0%. See Table 1.) After distilling a solvent off, distillation under reduced pressure (113° C./3.8 kPa) was conducted, thereby obtaining 332 g of the objective 6-bromo-5,5,6,6-tetrafluorohexan-1-ol in the form of a colorless transparent liquid (94% yield, 99.3% GC purity).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:16][CH3:17])=[CH:5][C:6]=1[C:7](=[O:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14].N1C=CC=CC=1.[CH3:24][CH2:25][O:26]CC.C(Cl)(=O)C>O>[C:25]([NH:1][C:2]1[S:3][C:4]([CH2:16][CH3:17])=[CH:5][C:6]=1[C:7](=[O:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14])(=[O:26])[CH3:24]
Reactant: CCOCC
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(N)s1
Solvent: O
Solvent: c1ccncc1
Solvent: CC(=O)Cl
Product: CCc1cc(C(=O)c2ccccc2Cl)c(NC(C)=O)s1

Procedure:
To a mixture of 46.4 g of 2-amino-3-(o-chlorobenzoyl)-5-ethylthiophene, 46.4 g of pyridine and 1160 ml of anhydrous ether is added dropwise 46.4 g of acetyl chloride. Then the reaction mixture is stirred under reflux for 2 hours. After cooling, the reaction mixture is poured into water. The ether layer is separated and washed with water, and dried over sodium sulfate. The solvent is removed under reduced pressure to give crystals of 2-acetylamino-3-(o-chlorobenzoyl)-5-ethylthiophene, which are recrystallized from ethanol-ether to give crystals having a melting point of 132° - 134°C; yield 42.44 g (79%).
Reaction SMILES: C([N:8]1[CH2:14][C:13]2[CH:15]=[CH:16][C:17]([F:24])=[C:18]([C:19]3[CH:23]=[CH:22][O:21][CH:20]=3)[C:12]=2[O:11][CH2:10][CH2:9]1)C1C=CC=CC=1.[Cl:25]C(OC(Cl)C)=O>C1(C)C=CC=CC=1>[ClH:25].[F:24][C:17]1[CH:16]=[CH:15][C:13]2[CH2:14][NH:8][CH2:9][CH2:10][O:11][C:12]=2[C:18]=1[C:19]1[CH:23]=[CH:22][O:21][CH:20]=1
Reactant: CC(Cl)OC(=O)Cl
Reactant: Fc1ccc2c(c1-c1ccoc1)OCCN(Cc1ccccc1)C2
Solvent: Cc1ccccc1
Product: Cl
Product: Fc1ccc2c(c1-c1ccoc1)OCCNC2
Yield: 32.1 %

Procedure:
A solution of 4-benzyl-8-fluoro-9-furan-3-yl-2,3,4,5-tetrahydro-1,4-benzoxazepine (104 mg, 0.323 mmol), 1-chloroethyl chloroformate (0.0418 ml, 0.387 mmol) in toluene (2 ml) was stirred at 90° C. for 2 hr, and the solvent was evaporated under reduced pressure. Water and 1N sodium hydroxide were added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=4:1). To ethyl acetate solution of the residue was added 4N hydrogen chloride-ethyl acetate. The precipitate was collected by filtration and was recrystallized from a mixed solvent of ethanol and diisopropyl ether to give the desired product (28 mg, 32.3%) as a solid.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-])=O)[CH:20]=4)[CH2:15][CH2:14]3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1>CO.[Pd]>[O:4]1[C:5]2([CH2:6][CH2:7][CH:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][N:16]([C:19]4[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=4)[NH2:25])[CH2:17][CH2:18]3)[CH2:9][CH2:10]2)[O:1][CH2:2][CH2:3]1
Reactant: O=[N+]([O-])c1cccc(N2CCN(CCC3CCC4(CC3)OCCO4)CC2)c1
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(N2CCN(CCC3CCC4(CC3)OCCO4)CC2)c1
Reaction time: 17 h
Yield: 93.8 %

Procedure:
To a cooled solution of 2.6 g (7.1 mmol) of 1-[2-(1,4-dioxaspiro[4.5]dec-8-yl)ethyl]-4-(3-nitrophenyl)piperazine in 50 mL of methanol are added under inert atmosphere, 0.5 g of 10% palladium on activated carbon. The mixture is hydrogenated at 40° C. under 4 bar for 17 hours. The suspension is filtered over celite and the filtrate is concentrated under reduced pressure to give 2.3 g (97%) of 3-{4-[2-(1,4-dioxaspiro[4.5]dec-8-yl)ethyl]piperazin-1-yl}aniline.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][CH2:30][C@@H:3]12.Cl.[CH3:32][NH2:33].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:32][NH:33][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH2:12][C:9]3[CH:10]=[N:11][C:5]4[N:4]5[CH2:28][CH2:29][CH2:30][C@H:3]5[C:2](=[O:1])[NH:7][C:6]=4[CH:8]=3)[CH2:18][CH2:17]2)=[CH:20][CH:21]=1
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)cc1
Reactant: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)cc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 47.2 %

Procedure:
(S)-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoic acid (87 mg, 0.214 mmol) and methanamine hydrochloride (21.62 mg, 0.320 mmol) were suspended in DMF (1 ml) and treated with DIPEA (0.186 ml, 1.068 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (162 mg, 0.427 mmol). The reaction mixture was stirred at room temperature for 23 h and purified using HPLC (25-95% acetonitrile in water, NH4HCO3 buffered) to afford (S)—N-methyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide (42.4 mg, 0.101 mmol, 47.2% yield) as a light yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 1.83-2.01 (m, 3 H) 2.11-2.25 (m, 1 H) 2.39-2.48 (m, 4 H) 2.73 (d, J=4.55 Hz, 3 H) 3.13-3.27 (m, 4 H) 3.34-3.44 (m, 3 H) 3.52-3.64 (m, 1 H) 3.96-4.02 (m, 1 H) 6.92 (d, J=9.09 Hz, 2 H) 6.98 (d, J=2.02 Hz, 1H) 7.62 (d, J=1.77 Hz, 1 H) 7.69 (d, J=9.09 Hz, 2 H) 8.13 (q, J=4.29 Hz, 1 H) 10.44 (s, 1 H); [M+H] calc'd for C23H28N6O2, 421; found, 421.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].[OH:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18](=O)[CH2:19][C:20]#[N:21])=[CH:12][C:11]=1[O:23][CH3:24]>C(O)(=O)C>[NH2:21][C:20]1[N:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)[N:2]=[C:18](/[CH:17]=[CH:16]/[C:13]2[CH:14]=[CH:15][C:10]([OH:9])=[C:11]([O:23][CH3:24])[CH:12]=2)[CH:19]=1
Reactant: COc1cc(/C=C/C(=O)CC#N)ccc1O
Reactant: NNc1ccccn1
Solvent: CC(=O)O
Product: COc1cc(/C=C/c2cc(N)n(-c3ccccn3)n2)ccc1O
Temperature: 120 °C
Yield: 20 %

Procedure:
2-hydrazinopyridine (62 mg, 0.57 mmol) was added to a solution of Compound 10 (113 mg, 0.520 mmol) synthesized in Step 1 of Example D in acetic acid (3 mL), followed by stirring under reflux at 120° C. for 30 minutes. The reaction solution was concentrated by distillation under reduced pressure, and ethyl acetate (5 mL) and water (5 mL) were added thereto, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then separated by column chromatography (n-Hex/EtOAc=3/1 (v/v)) to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:10])[NH:4][C:5](=[O:9])[NH:6][C:7]=1[CH3:8].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([N:6]1[C:7]([CH3:8])=[C:2]([CH3:1])[C:3](=[O:10])[NH:4][C:5]1=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: Cc1[nH]c(=O)[nH]c(=O)c1C
Product: Cc1c(C)n(Cc2ccccc2)c(=O)[nH]c1=O

Procedure:
substituting 5,6-dimethyl-2,4(1H,3H)-pyrimidinedione and benzyl bromide gave 1-benzyl-5,6-dimethyl-2,4(1H,3H)-pyrimidinedione, m.p. 187°-189° C.;
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19](O)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([C:24]1[CH:29]=[CH:28][C:27]([NH:30][CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)=[CH:26][CH:25]=1)[CH3:23]>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:30]([C:27]1[CH:26]=[CH:25][C:24]([CH2:22][CH3:23])=[CH:29][CH:28]=1)[CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1ccc(NCCN2CCCCC2)cc1
Reactant: O=C(O)C1CCCc2c(OCc3ccccc3)cccc21
Product: CCc1ccc(N(CCN2CCCCC2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Yield: 111.3 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.72 g) and (4-ethylphenyl) (2-piperidinoethyl)amine (0.50 g) as starting materials, 5-benzyloxy-N-(4-ethylphenyl)-N-(2-piperidinoethyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.19 g) was obtained. By the reaction and treatment in the same manner as in Example 105 using this compound, N-(4-ethylphenyl)-5-hydroxy-N-(2-piperidinoethyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.77 g) was obtained.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[C:6](=[O:18])[NH:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)=[N:9][N:10]=1)[CH2:3][CH3:4].[CH:19]1([C:24](Cl)=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20]1>>[Br:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[NH:7][C:6](=[O:18])[C:5]([CH:2]([NH:1][C:24]([CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:25])[CH2:3][CH3:4])=[N:10][N:9]=2)=[CH:12][CH:13]=1
Reactant: CCC(N)c1nnc(-c2ccc(Br)cc2)[nH]c1=O
Reactant: O=C(Cl)C1CCCC1
Product: CCC(NC(=O)C1CCCC1)c1nnc(-c2ccc(Br)cc2)[nH]c1=O

Procedure:
In analogy to the procedure for Example 36A, 3.35 g (10.8 mmol) 6-(1-aminopropyl)-3-(4-bromophenyl)-1,2,4-triazin-5(4H)-one, 2.16 g (16.3 mmol) cyclopentanecarbonyl chloride and proportionate amounts of the other reagents are used.