Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1.[CH2:13](Br)[CH:14]=[CH2:15].[N+](C1C=CC=CC=1)([O-])=[O:18]>>[CH2:13]([N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2](=[O:18])[CH:3]=[C:4]1[CH3:12])[CH:14]=[CH2:15]
Reactant: Cc1cc(N)c2ccccc2n1
Reactant: C=CCBr
Reactant: O=[N+]([O-])c1ccccc1
Product: C=CCn1c(C)cc(=O)c2ccccc21
Reaction time: 3.5 h

Procedure:
The starting material was prepared as follows. A solution of 4-amino-2-methylquinoline (5.0 g.) and allyl bromide (3.32 ml.) in nitrobenzene (13.7 ml.) was stirred at 100° for 1 hour. The reaction mixture was cooled to below 5° and the resulting precipitate filtered off, washed with ether and dried. A suspension of this material in N aqueous NaOH (75 ml.) was stirred at 100° for 3.5 hours. The cooled mixture was extracted with EtOAc (2×75 ml.) and the combined extracts washed, dried and evaporated to give 1-allyl-2-methyl-4-quinolone. Reaction of this compound with toluene-p-sulphonyl chloride gave 1-allyl-4-chloro-2-methylquinolinium toluene-p-sulphonate.
Reaction SMILES: C([Li])(CC)C.[CH:6]([C:9]1[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=1[C:11]([N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[O:12])([CH3:8])[CH3:7].[S:22](=[O:24])=[O:23].[NH3:25]>CCOCC.O1CCCC1>[NH2:25][S:22]([C:18]1[CH:19]=[CH:20][CH:21]=[C:9]([CH:6]([CH3:8])[CH3:7])[C:10]=1[C:11]([N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[O:12])(=[O:24])=[O:23]
Reactant: CCN(CC)C(=O)c1ccccc1C(C)C
Reactant: O=S=O
Reactant: N
Agent: [Li]C(C)CC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1c(C(C)C)cccc1S(N)(=O)=O
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a solution of N,N,N',N'-tetramethylethylenediamide (25.5 g) in anhydrous ether (600 mL) was added s-butyllithium (1.3M, 170 mL) and the mixture was cooled to -70° C. under nitrogen. A solution of 2-isopropyl-N,N-diethylbenzamide (44 g) in anhydrous ether (300 mL) was added dropwise over 20 minutes. The temperature was maintained at or below -60° C. during the addition. After the addition the mixture was stirred at -70° C. for 30 minutes, allowed to warm to -50° C. during 30 minutes, held at -50° C. for 10 minutes, then cooled back to -70° C. By cannulation tube a solution of sulfur dioxide (50 g) in anhydrous ether (50 mL) precooled to -60° C. was added under positive nitrogen pressure over a 10-minute period. The temperature of the reaction mixture during the addition was maintained below -50° C. A white powdery precipitate of aryllithium sulphinate separated out almost immediately. The temperature was allowed to rise to room temperature during one hour. Sulfuryl chloride (54 g) was added dropwise with continued stirring during 15 minutes. After further stirring for 30 minutes at 0°-5° C. a white precipitate was filtered off and washed with anhydrous ether (2 L). Removal of the solvent under vacuum gave a faint yellow oil, which was dissolved in tetrahydrofuran (150 mL). The solution was cooled to 0° C. and concentrated aqueous ammonia (28%, 60 mL) was added in portions over 15 minutes. The temperature was kept at 10° C. or below throughout the addition. After stirring for 15 minutes at ambient temperature the tetrahydrofuran and excess ammonia were removed and the residue was acidified with hydrochloric acid (2N) to pH 1. The resulting white solid was collected, washed with water (200 mL) and hexane (200 mL) and dried affording 2-aminosulfonyl-6-isopropyl-N,N-diethylbenzamide (54 g, 90 % yield).
Reaction SMILES: Cl[C:2]1[C:7]([I:8])=[C:6]([O:9][CH3:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.Cl.[NH2:14][C@@H:15]1[CH2:19][C@H:18]([CH2:20][OH:21])[C@@H:17]([OH:22])[C@H:16]1[OH:23].C(N(CC)CC)C>CCO>[OH:21][CH2:20][C@H:18]1[CH2:19][C@@H:15]([NH:14][C:2]2[C:7]([I:8])=[C:6]([O:9][CH3:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=2)[C@H:16]([OH:23])[C@@H:17]1[OH:22]
Reactant: COc1nc(SC)nc(Cl)c1I
Reactant: N[C@@H]1C[C@H](CO)[C@@H](O)[C@H]1O
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1nc(SC)nc(N[C@@H]2C[C@H](CO)[C@@H](O)[C@H]2O)c1I
Temperature: 130 °C

Procedure:
Compound 3 (5.00 g, 15.7 mmol) and (1R,2S,3R,5R)-3-amino-5-(hydroxymethyl)cyclopentane-1,2-diol hydrochloride (Compound 4) (5.80 g, 31.6 mmol) were dissolved in EtOH (50 mL). Triethylamine (6.60 mL, 47.4 mmol) was added, the reaction was sealed, and heated to 130° C. for 18 h. The reaction mixture was cooled to room temperature and concentrated. The residue was purified via column chromatography on silica gel (EtOAc/hexanes) to give the title compound as a colorless oil. LCMS 1.23 min, 428 (M+H).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:6]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:5]=1.[Li].C(Cl)Cl>C1COCC1>[CH2:27]([O:26][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]=1[O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:3][OH:2])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COC(=O)c1cc(OCc2ccccc2)c(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: [Li]
Solvent: C1CCOC1
Solvent: ClCCl
Product: OCc1cc(OCc2ccccc2)c(OCc2ccccc2)c(OCc2ccccc2)c1

Procedure:
A solution of 20.0 g (0.044 mol) of 3,4,5-trisbenzyloxybenzoic acid methyl ester in 100 ml of THF is added dropwise with vigorous stirring, over a period of 60 minutes at room temperature, to a suspension of 4.00 g (0.11 mol) of lithium alanate in 100 ml of THF, in the course of which the temperature rises to 65° C. (reflux). After a further 2 hours at reflux, excess lithium alanate is cautiously hydrolysed, and the product is isolated in customary manner by extraction with methylene chloride. Amorphous powder, yield 12.0 g (64% of theory).
Reaction SMILES: [C@H:1]12[CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Cl[C:16]1[N:17]=[N:18][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:20][CH:21]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:22]1([C:19]2[N:18]=[N:17][C:16]([N:5]3[CH2:6][CH:1]4[CH2:7][C@H:4]3[CH2:3][N:2]4[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[CH:21][CH:20]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Clc1ccc(-c2ccccc2)nn1
Reactant: CC(C)(C)OC(=O)N1CC2C[C@H]1CN2
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@@H]2CC1CN2c1ccc(-c2ccccc2)nn1

Procedure:
1.0 g (5.0 mmol) of 1,1-dimethylethyl (1S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate, 1.14 g (6.0 mmol) of 3-chloro-6-phenylpyridazine and 0.84 ml (6.0 mmol) of triethylamine in 45 ml of toluene are introduced into a 100 ml three-necked round-bottomed flask and the mixture is refluxed for 72 h.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([Cl:11])[C:3]=1[S:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1.O.O.[Sn](Cl)Cl.[OH-].[Na+]>CCOC(C)=O>[Cl:11][C:4]1[CH:5]=[C:6]([NH2:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[S:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(Sc2ccc3ccccc3c2)c(Cl)c1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1cc(Cl)c(Sc2ccc3ccccc3c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 84 %

Procedure:
To a 0.1M solution 2-(2,6-Dichloro-4-nitro-phenylsulfanyl)-napthalene (89) (774 mg, 2.2 mmol), in EtOAc was added tin(II)chloride dihydrate, obtained from Aldrich, (2.49 g, 11.05 mmol). The resulting mixture was refluxed for 2 hour. The crude reaction mixture was cooled to ambient temperature and excess 2M aqueous NaOH was added and allowed to stir for 15 minutes. Solid tin salts precipitated from the solution, were filtered off through a pad of celite and washed with EtOAc (200 mL). The organic layer was washed twice with brine (200 mL), dried over Na2SO4, and concentrated under vacuum to yield 592 mg (84%) of (90) which was used without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[C:15]1([C:21]2[N:22]=[C:23]([SH:32])[NH:24][C:25]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[H-].[Na+]>CN(C)C=O>[C:15]1([C:21]2[N:22]=[C:23]([S:32][C:2]3[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=3[N+:12]([O-:14])=[O:13])[NH:24][C:25]=2[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Sc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Sc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Yield: 85.5 %

Procedure:
Under stirring and a layer of argon, a solution of 7.45 g of 4-chloro-3-nitrotrifluoromethylbenzene in 40 ml of dimethylformamide is added dropwise to a solution of 7.94 g of 4,5-diphenyl-2-mercaptoimidazole and 0.45 g of sodium hydride (80% strength in white oil) in 150 ml of dimethylformamide. The mixture is agitated for 20 minutes, concentrated under vacuum, and the residue distributed between water and ethyl acetate. The organic solution is dried over sodium sulfate and concentrated to dryness under vacuum. The residue is crystallized from ether, thus obtaining 11.87 g of 4,5-diphenyl-2-(2-nitro-4-trifluoromethylphenylthio)imidazole, mp 234°-236°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-])=O.[CH:12]([Mg]Br)=[CH2:13].[NH4+].[Cl-]>C1COCC1.COCCOC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]2[C:3]=1[NH:9][CH:13]=[CH:12]2
Reactant: C=C[Mg]Br
Reactant: O=[N+]([O-])c1cc(F)ccc1Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: COCCOC
Solvent: C1CCOC1
Product: Fc1ccc(Br)c2[nH]ccc12
Temperature: -78 °C
Reaction time: 4 h
Yield: 57 %

Procedure:
A solution of 1-bromo-4-fluoro-2-nitrobenzene (3.6 g, 16.4 mmol) in THF (100 mL) was added to a solution of 1 M vinylmagnesium bromide in THF (100 mL, 100 mmol) and DME (100 mL) at −78° C. (bath temp). The reaction was stirred at −78° C. for 4 h, and saturated aqueous NH4Cl was added. The layers were separated, and the organic layer was evaporated. The crude product was purified flash chromatography, giving 2 g (57%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[N+:9]([O-])=O.[H][H].[CH3:14]O>[Ni]>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:14]=[N:9][C:3]=12
Reactant: Cc1ccnc(N)c1[N+](=O)[O-]
Reactant: CO
Reactant: [H][H]
Agent: [Ni]
Product: Cc1ccnc2[nH]cnc12
Temperature: 125 °C
Reaction time: 1.75 h
Yield: 70 %

Procedure:
Raney Nickel (2.5 g) is added to a mixture of commercially available 4-methyl-3-nitro-pyridin-2-ylamine x175 (7.0 g, 45.7 mmol) in methanol (300 ml), and the obtained reaction mixture is hydrogenated in the Parr apparatus at the hydrogen pressure 3 atm until the total conversion of compound x175 is attained for approximately 1.5-2 h. The catalyst is separated by filtration, the filtrate is washed with methanol, and the alcohol solution is evaporated to dryness. CH(OMe)3 (100 ml) and PTSA (0.5 g) are added to the residue, and an air reflux condenser is mounted. The apparatus is argon-blown, and the obtained reaction mixture is heated to 125° C. under vigorous stirring for 10 h. The formed solution is evaporated, and the residue is dissolved in 5% HCl (100 ml). The solution is refluxed for 1 h and evaporated to one-third volume. The solution is neutralized to pH 7 and extracted with 10% tert-butanol in chloroform (4×100 ml). The organic layer is dried over anhydrous Na2SO4, and the solvent is evaporated. The residue is purified by chromatography on silicagel (chloroform/methanol) to afford 7-methyl-3H-imidazo[4,5-b]pyridine x176.
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([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.[Br:21][C:22]1[N:26]=[C:25]([Br:27])[NH:24][N:23]=1.C(N(CC)CC)C.O>CN(C=O)C>[Br:21][C:22]1[N:26]=[C:25]([Br:27])[N:24]([C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:23]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Brc1n[nH]c(Br)n1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Brc1nc(Br)n(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 16 h
Yield: 98.8 %

Procedure:
Trityl chloride (6.8 g, 24 mmol) was added to a solution of 3,5-dibromo-1H-1,2,4-triazole (5 g, 22 mmol) and triethylamine (3.4 mL, 24.2 mmol) in DMF (100 mL) and stirred 16 h. The mixture was poured into rapidly stirred water (300 mL). The white precipitate was collected, washed with hexanes and dried on high vacuum to yield 10.2 g of Intermediate 359.1 as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.09-7.17 (m, 6H) 7.28-7.35 (m, 9H).
Reaction SMILES: [CH:1]1([CH:5]([OH:15])[C:6]2[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=2)[CH2:4][CH2:3][CH2:2]1.Cl.[NH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH:1]1([CH:5]([OH:15])[C:6]2[CH:7]=[CH:8][C:9]([C:10]([NH:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:12])=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(O)c1ccc(C(O)C2CCC2)cc1
Reactant: CCOC(=O)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CCNC(=O)c1ccc(C(O)C2CCC2)cc1
Reaction time: 1.5 h
Yield: 104.3 %

Procedure:
N,N-dimethylformamide (9.00 mL) was added to a vial containing 4-(cyclobutyl(hydroxy)methyl)benzoic acid (370 mg, 1.79 mmol), ethyl 3-aminopropanoate hydrochloride (551 mg, 3.59 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′ tetramethyluronium hexafluorophosphate (1.36 g, 3.59 mmol). Diisopropylethylamine (1.56 mL, 8.97 mmol) was then added. The reaction was stirred for 1.5 h, and was then concentrated. Purification by column chromatography (0-50% ethyl acetate in heptane) afforded ethyl 3-(4-(cyclobutyl(hydroxy)methyl)benzamido)propanoate (570 mg, 100% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J=8.2 Hz, 2H), 7.38 (d, J=8.2 Hz, 2H), 4.63 (d, J=7.8 Hz, 1H), 4.17 (q, J=7.2 Hz, 2H), 3.72 (q, J=6.0 Hz, 2H), 2.64 (t, J=5.9 Hz, 2H), 2.61-2.54 (m, 1H), 2.08-1.95 (m, 2H), 1.88-1.75 (m, 4H), 1.27 (t, J=7.1 Hz, 3H). MS (M+1): 306.3.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[F:11].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(N1CCOCC1)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:8])=[CH:4][C:3]=1[F:11]
Reactant: O=C(O)c1ccc(Br)c(F)c1
Reactant: C1COCCN1
Agent: CCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(c1ccc(Br)c(F)c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.5 %

Procedure:
A 500 mL flask was charged with 4-bromo-3-fluorobenzoic acid (5.00 g, 22.83 mmol), 100 mL DMF, morpholine (2.4 ml, 27.5 mmol), and 4-Ethylmorpholine (8.6 ml, 67.9 mmol). HOBt (4.32 g, 32.0 mmol) was added followed by EDC (5.25 g, 27.4 mmol) and the reaction allowed to stir at room temperature for 18 hours. The reaction was concentrated and the resulting orange syrup taken up in 100 mL EtOAc and 100 mL water. The organic layer was washed with 100 mL 2N HCl, 100 mL saturated sodium bicarbonate, and 100 mL saturated sodium chloride. The organic was then dried with MgSO4, filtered, and concentrated to give 6.476 g (98%) of a viscous yellow oil. This material was used without further purification.
Reaction SMILES: [C-:1]#[N:2].[Na+].[N:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[O:11])[CH:5]=1.[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O.C(Cl)Cl.C(OCC)(=O)C>[C:1]([CH:10]([O:11][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:6]1[CH:5]=[N:4][CH:9]=[CH:8][CH:7]=1)#[N:2]
Reactant: O=Cc1cccnc1
Reactant: [C-]#N
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N#CC(OC(=O)c1ccccc1)c1cccnc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 88 %

Procedure:
To a solution of sodium cyanide (1.96 g, 40 mmol) and benzyltridimethylammonium chloride (0.3 g, 1.3 mmol) in 7.5 mL of water was slowly added a solution of 3-pyridinecarboxaldehyde (0.88 mL, 9.3 mmol) in 15 mL of methylene chloride at 0° C. The resulting reaction solution was stirred at 0° C. for 15 min, and then benzoyl chloride (1.16 mL, 10 mmol) was additionally added thereto. After addition was complete, the reaction solution was elevated to room temperature and further stirred for 3 hours. After the reaction was complete, the reaction materials was diluted with 50 mL of ethyl acetate and 50 mL of water to dissolve salts, followed by separation of layers. The obtained organic layer was successively washed twice with 50 mL of a brine solution. The organic layer was dried over magnesium sulfate, filtered, concentrated under reduced pressure and purified by silica gel column chromatography, to give 1.95 g (yield: 95%) of benzoic acid cyano-pyridin-3-yl-methyl ester of the following formula.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([N:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[CH:2].C(O)(=O)C1C=CC=CC=1.[CH2:28]([O:30][C:31](=[O:39])[C:32]1[CH:37]=[CH:36][C:35](I)=[CH:34][CH:33]=1)[CH3:29]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:13]([N:12]([CH2:16][CH2:17][CH3:18])[C:9]1([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[C:2][C:35]3[CH:36]=[CH:37][C:32]([C:31]([O:30][CH2:28][CH3:29])=[O:39])=[CH:33][CH:34]=3)=[CH:4][CH:5]=2)[CH2:10][CH2:11]1)[CH2:14][CH3:15]
Reactant: C#Cc1ccc(C2(N(CCC)CCC)CC2)cc1
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C(O)c1ccccc1
Solvent: CCN(CC)CC
Product: CCCN(CCC)C1(c2ccc(C#Cc3ccc(C(=O)OCC)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using General Procedure F; [1-(4-ethynylphenyl)-cyclopropyl]-dipropylamine (Intermediate 123, 34.0 mg, 0.16 mmol) and ethyl-4-iodo benzoate (Reagent A, 59.0 mg, 0.21 mmol) in triethyl amine (6 mL) was treated with copper(I)iodide (13.0 mg, 0.07 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (49 mg, 0.07 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-4% EtOAc-hexanes) afforded the title compound as a yellow oil.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16][CH2:17][C:18]([C:20]2[CH:21]=[CH:22][C:23]3[C:32]4[CH:31]=[C:30]5[CH2:33][CH2:34][CH:35](Br)[C:36](=[O:37])[C:29]5=[CH:28][C:27]=4[O:26][CH2:25][C:24]=3[CH:39]=2)=[O:19])=[O:15])[CH2:3]1.[C:40]([O:44][C:45]([N:47]1[CH2:51][C@@H:50]([CH2:52][O:53][CH3:54])[CH2:49][C@H:48]1[C:55]([OH:57])=[O:56])=[O:46])([CH3:43])([CH3:42])[CH3:41].C([O-])([O-])=O.[Cs+].[Cs+]>C(Cl)Cl>[CH3:1][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16][CH2:17][C:18]([C:20]2[CH:21]=[CH:22][C:23]3[C:32]4[CH:31]=[C:30]5[CH2:33][CH2:34][CH:35]([O:57][C:55]([C@@H:48]6[CH2:49][C@H:50]([CH2:52][O:53][CH3:54])[CH2:51][N:47]6[C:45]([O:44][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:46])=[O:56])[C:36](=[O:37])[C:29]5=[CH:28][C:27]=4[O:26][CH2:25][C:24]=3[CH:39]=2)=[O:19])=[O:15])[CH2:3]1
Reactant: COC[C@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: C[C@H]1C[C@@H](C(=O)OCC(=O)c2ccc3c(c2)COc2cc4c(cc2-3)CCC(Br)C4=O)N(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Product: COC[C@H]1C[C@@H](C(=O)OC2CCc3cc4c(cc3C2=O)OCc2cc(C(=O)COC(=O)[C@@H]3C[C@H](C)CN3C(=O)OC(C)(C)C)ccc2-4)N(C(=O)OC(C)(C)C)C1
Temperature: 50 °C
Yield: 71 %

Procedure:
(2S,4S)-2-(2-(9-bromo-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)-2-oxoethyl) 1-tert-butyl 4-methylpyrrolidine-1,2-dicarboxylate (709 mg, 1.18 mmol) was treated with a solution of (2S,4S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidine-2-carboxylic acid (614 mg, 2.36 mmol) in Me-THF (12 mL) and Cs2CO3 (384 mg, 1.18 mmol). The stirred reaction mixture was heated to 50° C. for 16 h, then cooled to RT and diluted with CH2Cl2 and extracted 3×. The organic phase was washed with brine, then dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (40% to 100% EtOAc/hexanes) to afford (2S,4S)-2-(2-(9-((2S,4S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidine-2-carbonyloxy)-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)-2-oxoethyl) 1-tert-butyl 4-methylpyrrolidine-1,2-dicarboxylate (651 mg, 71%).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:10]([CH3:12])=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:13]([NH:16][NH2:17])(=[O:15])[CH3:14]>C(O)C>[CH3:1][O:2][N:3]=[C:4]([C:10](=[N:17][NH:16][C:13](=[O:15])[CH3:14])[CH3:12])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CC(=O)NN
Reactant: CCOC(=O)C(=NOC)C(C)=O
Solvent: CCO
Product: CCOC(=O)C(=NOC)C(C)=NNC(C)=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of ethyl 2-methoxyiminoacetoacetate (a mixture of syn and anti isomer) (226.6 g.) and acetohydrazide (78.5 g.) in ethanol (500 ml.) was stirred for 1.5 hours at ambient temperature. Precipitates were collected by filtration, washed with ethanol and ether and dried to give ethyl 2-methoxyimino-3-acetylhydrazonobutyrate (a mixture of syn and anti isomers) (155.7 g.), mp 190° to 191.5° C.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:4](=[O:22])[C:3]=1[C:23](=O)[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N+:31]([O-:33])=[O:32].O.[NH2:36][NH2:37].C(=O)([O-])O.[Na+]>CN(C=O)C>[N+:31]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH2:24][C:23]1[C:3]2[C:4](=[O:22])[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:21])[F:20])[CH:13]=3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:37][N:36]=1)([O-:33])=[O:32]
Reactant: NN
Reactant: O=C(Cc1ccccc1[N+](=O)[O-])c1c(O)c2cccnc2n(-c2cccc(C(F)(F)F)c2)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2c(Cc3ccccc3[N+](=O)[O-])n[nH]c2c2cccnc2n1-c1cccc(C(F)(F)F)c1
Temperature: 115 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-hydroxy-3-(2-nitrophenylacetyl)-1-(3-trifluoromethylphenyl)-1,8-naphthyridin-2(1H)-one (619 mg, 1.3 mmol) produced in Synthesis Example 37 in DMF (6 mL) was added hydrazine monohydrate (purity of 80%, 233 μL), and the mixture was stirred at 110 to 120° C. for 2 hours. To the reaction solution was added a sodium hydrogencarbonate aqueous solution. The resulting precipitate was separated by filtration, washed with water, and dried to give 3-(2-nitrobenzyl)-5-(3-trifluoromethylphenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one as a form of crystal (565 mg, yield 92%).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.[CH2:16]([C:18]1[C:19]([NH:25][CH:26]([CH2:29][CH3:30])[CH2:27][NH2:28])=[N:20][CH:21]=[N:22][C:23]=1[CH3:24])[CH3:17].C(N(C(C)C)CC)(C)C>C(Cl)Cl.CN(C=O)C>[CH2:16]([C:18]1[C:19]([NH:25][CH:26]([CH2:29][CH3:30])[CH2:27][NH:28][C:5](=[O:6])/[CH:4]=[CH:3]/[C:2]([F:9])([F:8])[F:1])=[N:20][CH:21]=[N:22][C:23]=1[CH3:24])[CH3:17]
Reactant: CCc1c(C)ncnc1NC(CC)CN
Reactant: O=C(O)/C=C/C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1c(C)ncnc1NC(CC)CNC(=O)/C=C/C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(E)-4,4,4-Trifluorobut-2-enoic acid (15 mg, 0.11 mmol) was dissolved in DCM (1 ml containing one drop of dimethyl formamide), oxalyl chloride was added (9.5 μl, 0.11 mmol) and the solution was stirred at room temperature for 15 minutes. This solution was added to a solution of N2-(5-Ethyl-6-methyl-pyrimidin-4-yl)butane-1,2-diamine (24.5 mg, 0.1 mmol) and diisopropylethylamine (44 μl, 0.25 mmol) dissolved in DMF (1 ml) and the resulting mixture was stirred at room temperature overnight. The volatiles were removed under reduced pressure and the residue was purified by preparative HPLC (gradient of water containing 0.1% NH3 and acetonitrile) to yield 12.7 mg (0.038 mmol, 38%).