Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCC1.[Br-].[F:7][C:8]([F:13])([F:12])[C:9]([Zn+])=[CH2:10].[Cl:14][C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][C:16]=1[C:22]([F:25])([F:24])[F:23]>CCCCCC>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:9]([C:8]([F:13])([F:12])[F:7])=[CH2:10])=[CH:17][C:16]=1[C:22]([F:25])([F:24])[F:23]
Reactant: C=C([Zn+])C(F)(F)F
Reactant: FC(F)(F)c1cc(I)ccc1Cl
Agent: [Br-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=C(c1ccc(Cl)c(C(F)(F)F)c1)C(F)(F)F
Temperature: 25 °C

Procedure:
In a nitrogen atmosphere, to 53 mL of a 1M tetrahydrofuran solution of 1-trifluoromethylethenyl zinc bromide prepared according to a method described in the literatures, 7.1 g of 2-chloro-5-iodobenzotrifluoride and 0.65 g of dichlorobis(triphenylphosphine) palladium (II) were added and the resultant mixture was stirred while heating the mixture to reflux for 2.5 hours. After the completion of the reaction, the reaction mixture was left to be cooled down to room temperature and 200 mL of hexane was added to the reaction mixture, followed by filtering off the deposited insoluble substance. The resultant filtrate was washed with water (50 mL×1) and then dehydrated and dried over saturated saline and anhydrous sodium sulfate in this order and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography eluting with hexane to obtain 4.8 g of the objective substance as a colorless oily substance.
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>CN(C=O)C>[CH3:17][N:18]([CH3:20])/[CH:19]=[CH:1]/[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(OC)N(C)C
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1C
Solvent: CN(C)C=O
Product: COC(=O)c1cccc([N+](=O)[O-])c1/C=C/N(C)C
Temperature: 115 °C
Reaction time: 17 h

Procedure:
A mixture of methyl 2-methyl-3-nitrobenzoate (5.0 g, 25.6 mmol) and N,N-dimethylformamide dimethyl acetal (9.18 g, 77 mmol) in DMF (30 mL) was stirred at 115° C. for 17 h. The volatiles were removed under reduced pressure to give (E)-methyl 2-(2-(dimethylamino)-vinyl)-3-nitrobenzoate as brown oil.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH3:19])=[CH:10][C:9]=1[CH2:20][OH:21].[Br:22]C(F)(F)C(F)(F)Br.O>C1COCC1>[CH3:6][O:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH3:19])=[C:10]([Br:22])[C:9]=1[CH2:20][OH:21]
Reactant: COc1cc(CO)c(OC)c2ccccc12
Reactant: FC(F)(Br)C(F)(F)Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1c(Br)c(CO)c(OC)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.2 %

Procedure:
n-Butyllithium (2.9 mL, 7.33 mmol, 2.5 M in hexanes) was added dropwise to a solution of 23a (400 mg, 1.83 mmol) in THF (25 mL) at −78° C. under argon. The reaction mixture was slowly warmed to room temperature and stirred for 1 h. 1,2-dibromotetrafluoroethane (0.26 mL, 2.20 mmol) was added dropwise and the solution was stirred for 1 h. Water (10 mL) was added and the mixture was extracted with EtOAc (3×). The combined organic layers were dried (MgSO4), filtered and evaporated. Column chromatography of the crude product (35:65 EtOAc:hexanes) afforded 23d (273 mg, 50%, 63% based on recovered 23a, 84 mg) as a yellow solid; Rf=0.62 (35:65 EtOAc:hexanes); mp=115-117° C.; 1H NMR (CDCl3): δ 8.11 (m, 2H), 7.57 (m, 2H), 5.03 (s, 2H), 4.02 (s, 3H), 3.99 (s, 3H), 2.36 (bs, 1H).
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH3:17])[N:10]=2)[N:3]=1.P(Cl)(Cl)([Cl:20])=O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[Cl:20][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH3:17])[N:10]=2)[N:3]=1
Reactant: CCCc1cccc(-c2nc(C)cc(O)n2)n1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCc1cccc(-c2nc(C)cc(Cl)n2)n1
Yield: 93.9 %

Procedure:
To solution of 4-hydroxy-6-methyl-2-(6-n-propyl-2-pyridinyl)pyrimidine (2 g) in toluene (20 ml), was added phosphoryl chloride (2 g). The mixture was heated under refluxing for one hour and left to stand to room temperature. Aqueous sodium carbonate solution was added thereto until the reaction solution became about pH 8 to be separated into two layers. Toluene layer was collected and washed with water and dried over anhydrous magnesium sulfate. The toluene layer was concentrated under reduced pressure to obtain 4-chloro-6-methyl-2-(6-n-propyl-2-pyridinyl)pyrimidine (2.03 g).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16](O)=[O:17])=[N:4][NH:3]1.ON1C2C=CC=CC=2N=N1.[CH3:32][NH:33][C:34]([C:36]1[N:37]=[C:38]([C:45]([F:48])([F:47])[F:46])[N:39]2[CH2:44][CH2:43][NH:42][CH2:41][C:40]=12)=[O:35].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C)C=O>[CH3:32][NH:33][C:34]([C:36]1[N:37]=[C:38]([C:45]([F:48])([F:46])[F:47])[N:39]2[CH2:44][CH2:43][N:42]([C:16](=[O:17])[C:15]3[CH:19]=[CH:20][CH:21]=[C:13]([CH2:12][C:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C:2](=[O:1])[NH:3][N:4]=4)[CH:14]=3)[CH2:41][C:40]=12)=[O:35]
Reactant: CNC(=O)c1nc(C(F)(F)F)n2c1CNCC2
Reactant: O=C(O)c1cccc(Cc2n[nH]c(=O)c3ccccc23)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)c1cccc(Cc3n[nH]c(=O)c4ccccc34)c1)CC2
Reaction time: 12 h
Yield: 89.9 %

Procedure:
3-[(4-Oxo-3H-phthalazin-1-yl)methyl]benzoic acid 15a (186 mg, 0.67 mmol) was dissolved in 20 mL of N,N-dimethylformamide, followed by addition of 1-hydroxybenzotriazole (98 mg, 0.73 mmol), crude N-methyl-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide 13a (150 mg, 0.61 mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (173 mg, 0.91 mmol) and triethylamine (253 μL, 1.82 mmol). After stirring for 12 hours, the reaction mixture was was concentrated under reduced pressure, added with 50 mL of H2O and extracted with ethyl acetate (50 mL×3). The organic phase was combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain N-methyl-7-[3-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1-carboxamide 21 (280 mg, yield 90.0%) as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[NH:6][CH2:5][CH:4]([CH2:7][O:8][CH:9]([CH3:11])[CH3:10])[O:3]1.[C:13]1([CH3:25])[CH:18]=[CH:17][C:16]([S:19]([N:22]=[C:23]=[O:24])(=[O:21])=[O:20])=[CH:15][CH:14]=1>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:12])[N:6]([C:23](=[O:24])[NH:22][S:19]([C:16]2[CH:17]=[CH:18][C:13]([CH3:25])=[CH:14][CH:15]=2)(=[O:20])=[O:21])[CH2:5][CH:4]([CH2:7][O:8][CH:9]([CH3:10])[CH3:11])[O:3]1
Reactant: CC(C)OCC1CNC(C)(C)O1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Solvent: c1ccccc1
Product: Cc1ccc(S(=O)(=O)NC(=O)N2CC(COC(C)C)OC2(C)C)cc1

Procedure:
To 20.8 milliliters of 25 percent w/v, 2,2-dimethyl-5-isopropoxymethyl oxazolidine solution in 50 milliliters of benzene was added 5.9 grams of p-toluene sulfonyl isocyanate. Upon completion of the reaction the solvent, benzene, was removed in vacuo. There was obtained 12.8 grams of the title compound, as a glass. Analytical data supports the structure.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)[CH:12]([CH3:14])[NH:13][C:8]=2[CH:7]=[C:6]([NH:22][C:23](=[O:27])[O:24][CH2:25][CH3:26])[N:5]=1.[CH2:28](Cl)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[NH2:3][C:4]1[C:9]2[N:10]=[C:11]([C:15]3[CH:16]=[CH:17][C:18]([O:21][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:19][CH:20]=3)[CH:12]([CH3:14])[NH:13][C:8]=2[CH:7]=[C:6]([NH:22][C:23](=[O:27])[O:24][CH2:25][CH3:26])[N:5]=1
Reactant: ClCc1ccccc1
Reactant: CCOC(=O)Nc1cc2c(c(N)n1)N=C(c1ccc(O)cc1)C(C)N2
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)Nc1cc2c(c(N)n1)N=C(c1ccc(OCc3ccccc3)cc1)C(C)N2
Reaction time: 0.2 h

Procedure:
To a stirred suspension of NaH (13.5 mg of 60% oil-dispersion, washed 1× hexane) in deoxygenated (N2) DMSO was added 14 (101 mg, 0.30 mmol). After stirring 0.2 hour, the nearly-clear amber solution was treated with benzyl chloride (36 mg, 0.29 mmol), stirred 18 hours under N2, and evaporated to dryness. The residue was triturated with de-oxygenated (N2) H2O (10 mL) to give a solid, which was purified by flash chromatography (45 g, CHCl3 --MeOH, 99:1) followed by recrystallization from EtOAc-hexane to afford 17 as a pale yellow solid: yield, 44 mg.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH:5]([O:25][CH2:26][CH3:27])[CH:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][NH:17]C(OC(C)(C)C)=O)=[CH:10][CH:9]=1)O)[CH3:2].C([SiH](CC)CC)C>FC(F)(F)C(O)=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:28])[CH:5]([O:25][CH2:26][CH3:27])[CH2:6][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][NH2:17])=[CH:10][CH:9]=1)[CH3:2]
Reactant: CCOC(=O)C(OCC)C(O)c1ccc(OCCNC(=O)OC(C)(C)C)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cc1ccc(OCCN)cc1)OCC
Temperature: 25 °C
Reaction time: 60 h
Yield: 73.9 %

Procedure:
The compound obtained in Step b (53.7 mg) was dissolved in trifluoroacetic acid (2 ml), added with triethylsilane (0.4 ml, Aldrich) and stirred at room temperature for 2.5 days. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine, dried over magnesium sulfate and concentrated. The resulting residue was applied on a silica gel column and eluted with chloroform/methanol (10:1) to obtain the title compound (28.1 mg).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:30])[N:6]2[C@H:22]1[CH2:27][CH2:26][C@H:25]([O:28][CH3:29])[CH2:24][CH2:23]1.I[CH3:32]>>[Cl:1][C:2]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[N:8]=[C:7]2[C:3]=1[N:4]([CH3:32])[C:5](=[O:30])[N:6]2[C@H:22]1[CH2:23][CH2:24][C@H:25]([O:28][CH3:29])[CH2:26][CH2:27]1
Reactant: CO[C@H]1CC[C@H](n2c(=O)[nH]c3c(Cl)nc(-n4cnc5ccc(C#N)cc54)nc32)CC1
Reactant: CI
Product: CO[C@H]1CC[C@H](n2c(=O)n(C)c3c(Cl)nc(-n4cnc5ccc(C#N)cc54)nc32)CC1

Procedure:
Dark brown solid (76% crude yield). Synthesized using 3-(6-chloro-9-(trans-4-methoxycyclohexyl)-8-oxo-8,9-dihydro-7H-purin-2-yl)-3H-benzo[d]imidazole-5-carbonitrile (0.7 g, 1.65 mmol) and iodomethane (0.61 mL, 10 mmol, 6 equiv.). MS (EI) m/z 438 (MH)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C:14](=[O:15])[CH2:13][C:12]2([C:23]3[C:18](=[CH:19][CH:20]=[C:21]([Cl:24])[CH:22]=3)[NH:17][C:16]2=[O:25])[C:11]1=[O:26])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].O>O1CCCC1>[CH2:32]([O:31][C:29](=[O:30])[CH2:28][N:17]1[C:18]2[C:23](=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:12]2([CH2:13][C:14](=[O:15])[N:10]([CH2:3][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:11]2=[O:26])[C:16]1=[O:25])[CH3:33]
Reactant: CCOC(=O)CBr
Reactant: O=C1CC2(C(=O)Nc3ccc(Cl)cc32)C(=O)N1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CN1C(=O)C2(CC(=O)N(Cc3ccccc3)C2=O)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
A stirred suspension of sodium hydride (60% dispersion in oil [39 mg, 0.969 mmol]) in anhydrous tetrahydrofuran (10 ml) was treated with 1′-benzyl-5-chloro-1H-spiro[indole-3,3′-pyrrolidine]-2,2′,5′-trione, intermediate 14 (300 mg, 0.88 mmol). After stirring at ambient temperature for 30 min, the clear solution was treated with ethyl bromoacetate (0.13 ml, 1.16 mmol). The resultant suspension was stirred for 3 hours and then left to stand overnight. Water (50 ml) was added and the mixture extracted with ethyl acetate (3×50 ml). The combined extracts were washed with brine (50 ml), dried (MgSO4) and the solvent removed in vacuo to give the crude (1′-benzyl-5-chloro-2,2′,5′-trioxo-spiro[indole-3,3′-pyrrolidin]-1-yl)-acetic acid ethyl ester. Purification by flash chromatography (silica) eluting with petroleum ether (40-60) containing an increasing amount (0 to 50%) of ethyl acetate, followed by trituration with di-isopropyl ether gave a white solid (264 mg, 70%), m.pt. 143-144° C.
Reaction SMILES: C([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([Br:21])=[C:16]([CH2:17][CH2:18][CH2:19][NH2:20])[C:11]=2[O:10][CH:9]1[CH2:22][CH3:23])=O)(C)(C)C.Cl.[CH2:25](Cl)Cl>O1CCOCC1>[C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([Br:21])=[C:16]([CH2:17][CH2:18][CH2:19][NH2:20])[C:11]=2[O:10][CH:9]1[CH2:22][CH3:23])(=[O:5])[CH3:25]
Reactant: ClCCl
Reactant: CCC1Oc2c(ccc(Br)c2CCCN)N1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCC1Oc2c(ccc(Br)c2CCCN)N1C(C)=O
Reaction time: 2 h
Yield: 40 %

Procedure:
A solution of N-t-butoxycarbonyl 7-(3-aminopropyl)-6-bromo-2-ethylbenzoxazole (30 mg, 0.078 mmol), in methylene chloride (1 mL) was treated with 4 M HCl in dioxane (1 mL) and stirred for 2 hours. The solvent was evaporated and the residue was taken up in pyridine (2 mL) and treated with acetic anhydride (100 μL). After stirring for 2 hours, the reaction was diluted with EtOAc (5 mL) and washed with saturated aqueous copper (II) sulfate (2×5 mL). The organic layer was dried with magnesium sulfate and evaporated. The product was purified on a silica gel column and eluted with 25% EtOAc/hexanes to give a clear oil (10 mg, 40%).
Reaction SMILES: C([O:4][C:5]1[CH:9]=[C:8]([N:10](C(=O)C)[C:11](=[O:13])[CH3:12])[N:7]([C:17]2[CH:22]=[C:21]([S:23][CH2:24][C:25]([F:28])([F:27])[F:26])[C:20]([CH3:29])=[CH:19][C:18]=2[F:30])[N:6]=1)(=O)C.O.N>C(O)C>[C:11]([NH:10][C:8]1[N:7]([C:17]2[CH:22]=[C:21]([S:23][CH2:24][C:25]([F:26])([F:27])[F:28])[C:20]([CH3:29])=[CH:19][C:18]=2[F:30])[N:6]=[C:5]([OH:4])[CH:9]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)Oc1cc(N(C(C)=O)C(C)=O)n(-c2cc(SCC(F)(F)F)c(C)cc2F)n1
Agent: N
Solvent: O
Solvent: CCO
Product: CC(=O)Nc1cc(O)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.7 %

Procedure:
10.6 g of 5-amino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-hydroxypyrazole was dissolved in 200 mL of toluene, and to this solution, 20.0 g of acetyl chloride was added, followed by reflux with heating for 12 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:4) to obtain 9.4 g of 3-acetoxy-5-(N,N-diacetylamino)-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}pyrazole. Then, 9.4 g of the obtained 3-acetoxy-5-(N,N-diacetylamino)-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}pyrazole was dissolved in 100 mL of ethanol, and 10 mL of a 25 mass % ammonia water was added, followed by stirring at room temperature for 30minutes. Then, the solvent was distilled off under reduced pressure, and the obtained solid was washed with diisopropyl ether to obtain 7.0 g of 5-acetylamino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-hydroxypyrazole in the form of white crystals (melting point: 223-225° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[CH:25]([NH:26][C:27](=O)[O:28]C4C=CC=CC=4)[CH2:24][C:23]([CH3:37])([CH3:36])[O:22][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:4][CH:3]=1.[NH2:38][NH2:39]>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]3[CH:25]([NH:26][C:27]([NH:38][NH2:39])=[O:28])[CH2:24][C:23]([CH3:37])([CH3:36])[O:22][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:6][CH:7]=1
Reactant: NN
Reactant: CC1(C)CC(NC(=O)Oc2ccccc2)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2O1
Solvent: CCO
Product: CC1(C)CC(NC(=O)NN)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2O1

Procedure:
A solution of the product of Step A (77 mg, 0.14 mmol) and hydrazine (8.7 μL, 0.28 mmol) in 5.0 mL of EtOH was refluxed for 3 h. The reaction mixture was then concentrated to give the product, which was used directly in the next step without further purification.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@H:7]([C@@H:9]([CH2:11]O)[OH:10])[OH:8])[OH:6])[OH:4].O.[NH2:14][NH2:15]>CO>[CH:11](=[N:14][NH2:15])[C@@H:9]([C@H:7]([C@H:5]([C@@H:3]([CH2:2][OH:1])[OH:4])[OH:6])[OH:8])[OH:10]
Reactant: NN
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Solvent: CO
Solvent: O
Product: NN=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Reaction time: 8 h

Procedure:
A 2.0 g portion of D-galactose was dissolved in a mixture of 5 ml of methanol and 5 ml of hydrazine hydrate and stirred overnight, then evaporated to dryness in vacuo. About 5 ml of methanol was added, the mixture was stirred for 48 hours and the solid was collected giving 1.9 g of D-galactose hydrazone.
Reaction SMILES: [CH:1]([N:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17](=[O:26])[NH:16][C:15]1=[O:27])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH3:29]>CC#N.C1COCC1>[CH:1]([N:14]1[CH:19]=[C:18]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:17](=[O:26])[N:16]([CH3:29])[C:15]1=[O:27])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=c1[nH]c(=O)n(C(c2ccccc2)c2ccccc2)cc1-c1ccccc1
Reactant: CI
Solvent: CC#N
Solvent: C1CCOC1
Product: Cn1c(=O)c(-c2ccccc2)cn(C(c2ccccc2)c2ccccc2)c1=O
Yield: 43 %

Procedure:
The title compound was obtained according to the procedure described for the synthesis of Example 16 (Step 1) starting from 1-benzhydryl-5-phenyl-pyrimidine-2,4-dione (prepared as in Example 14, Step 2) (0.37 g, 1.01 mmol); a 1:1 mixture of was dry MeCN/THF and iodomethane were used herein. The crude was purified by column chromatography using a Teledyne ISCO apparatus (cyclohexane:EtOAc 80:20) to afford the title compound (0.16 g, 43%) as a light-red solid. 1H NMR (400 MHz, CDCl3): δ 3.46 (s, 3H), 7.19-7.24 (m, 6H), 7.28-7.43 (m, 11H). MS (ESI) m/z: 369 [m-H]+.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:18][C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[CH2:8][CH2:7]1)=[O:5])C.O.[OH-].[Li+]>C1COCC1>[CH2:8]1[C:9]2[NH:10][C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17]=2[CH2:18][CH:6]([C:4]([OH:5])=[O:3])[CH2:7]1
Reactant: CCOC(=O)C1CCc2[nH]c3ccccc3c2C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1CCc2[nH]c3ccccc3c2C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 0.1 %

Procedure:
2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid ethyl ester (34.5 g, 142 mol) was dissolved in 375 mL of THF. Lithium hydroxide hydrate (23.8 g, 566 mmol) was added. The mixture was stirred at room temperature 48 h, at which time TLC showed complete consumption of starting ester. The mixture was acidified with 1 N HCl and was extracted with ethyl acetate. The organic layer was washed with brine, then was dried over sodium sulfate, filtered, and concentrated in vacuo to afford 30.4 g (99%) of the title compound.
Reaction SMILES: [F:1][C:2](F)([CH2:12][CH:13](I)[Si](C)(C)C)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11])=O.[NH3:20]>O1CCCC1>[F:1][C:2]1[CH:12]=[CH:13][NH:20][C:3]=1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11]
Reactant: N
Reactant: Cc1ccccc1C(=O)C(F)(F)CC(I)[Si](C)(C)C
Solvent: C1CCOC1
Product: Cc1ccccc1-c1[nH]ccc1F
Temperature: 25 °C
Reaction time: 14 h
Yield: 78 %

Procedure:
To a solution (20 mL) of 2,2-difluoro-4-iodo-1-(2-methylphenyl)-4-trimethylsilylbutan-1-one (2.5 g) in tetrahydrofuran was added 28% aqueous ammonia solution (6 mL), and the mixture was stirred at room temperature for 14 hr. The reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in acetonitrile (15 mL) and water (8 mL), and potassium fluoride (0.75 g) was added. The reaction mixture was stirred at 60° C. for 3 hr, and concentrated under reduced pressure. The residue was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=20:1) to give the title compound as a pale-yellow oil (yield 0.87 g, 78%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]1([CH:19]2[CH2:23][CH2:22][CH2:21][C:20]2=[O:24])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:25](C#N)(=[O:29])[O:26][CH2:27][CH3:28]>C1COCC1>[O:24]=[C:20]1[CH:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:23][CH2:22][CH:21]1[C:25]([O:26][CH2:27][CH3:28])=[O:29]
Reactant: O=C1CCCC1c1ccccc1
Reactant: CCOC(=O)C#N
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C1CCC(c2ccccc2)C1=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 73.1 %

Procedure:
To a solution of diisopropylamine (6.62 mL, 46.8 mmol) in THF (200 mL) at −78° C. was added a 1.6 M solution of n-butyllithium in hexanes (29.3 mL, 46.8 mmol). The solution was stirred for 30 min at −78° C. and treated with a solution of 2-phenylcyclopentanone (5 g, 31.2 mmol) in 50 mL of dry THF. After stirring for 30 min at −78° C., ethyl carbonocyanidate (3.36 mL, 34.3 mmol) was added to the reaction mixture. The resulting solution was warmed to 25° C. with stirring over 3 h. The reaction mixture was quenched with 10 mL of water, washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuum, and purified by column chromatography on silica gel to afford ethyl 2-oxo-3-phenylcyclopentanecarboxylate (5.3 g, 22.82 mmol, 73% yield) as colorless oil. LC-MS (M+K)+=273.2. 1H NMR (500 MHz, CDCl3) δ ppm 7.32-7.39 (2H, m), 7.25-7.31 (1H, m), 7.19-7.25 (2H, m), 4.18-4.32 (2H, m), 3.29-3.55 (2H, m), 1.87-2.62 (4H, m), 1.28-1.39 (3H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[N:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[N:11]([CH2:19][CH3:20])[C:10](=[O:21])[C:9]=2[CH2:22][CH2:23][CH2:24]OS(C)(=O)=O)[CH:5]=[CH:6][CH:7]=1.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1.[I-].[K+].Cl>O.C1COCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[N:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[N:11]([CH2:19][CH3:20])[C:10](=[O:21])[C:9]=2[CH2:22][CH2:23][CH2:24][N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C1CCNC1
Reactant: CCn1c(=O)c(CCCOS(C)(=O)=O)c(-c2cccc(Cl)c2)c2ccc(C)nc21
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCn1c(=O)c(CCCN2CCCC2)c(-c2cccc(Cl)c2)c2ccc(C)nc21
Temperature: 60 °C

Procedure:
To a 10 ml THF solution containing 700 mg of 4-(3-chlorophenyl)-1-ethyl-3-(3-methanesulfonyloxypropyl)-7-methyl-1,8-naphthyridin-2(1H)-one were added 0.5 ml of pyrrolidine and 300 mg of potassium iodide, followed by stirring under heating at an oil bath temperature of 60° C. for 1.5 hours. After cooling to room temperature, water and 1M hydrochloric acid were added thereto, and the whole was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated and the residue was purified by a silica gel column chromatography (chloroform-methanol-aqueous ammonia). The resulting compound was dissolved in ethyl acetate and a 4M hydrogen chloride-ethyl acetate solution was added thereto. Thereafter, the residue obtained by evaporation of the solvent was recrystallized from ethyl acetate-acetonitrile to obtain 133 mg of 4-(3-chlorophenyl)-1-ethyl-7-methyl-3-[3-(pyrrolidin-1-yl)propyl]-1,8-naphthyridin-2(1H)-one monohydrochloride as colorless crystals.