Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([O:11][CH3:12])[C:3]=1[N:13]1[C:21]2[CH:20]=[CH:19][NH:18][C:17](=[O:22])[C:16]=2[C:15]([C:23]2[CH:24]=[C:25]([C:28]([NH2:30])=[O:29])[S:26][CH:27]=2)=[CH:14]1.[Cl-].[Ca+2].[Cl-].C(O)C>O>[NH2:8][C:6]1[CH:5]=[C:4]([O:11][CH3:12])[C:3]([N:13]2[C:21]3[CH:20]=[CH:19][NH:18][C:17](=[O:22])[C:16]=3[C:15]([C:23]3[CH:24]=[C:25]([C:28]([NH2:30])=[O:29])[S:26][CH:27]=3)=[CH:14]2)=[C:2]([F:1])[CH:7]=1
Reactant: COc1cc([N+](=O)[O-])cc(F)c1-n1cc(-c2csc(C(N)=O)c2)c2c(=O)[nH]ccc21
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: COc1cc(N)cc(F)c1-n1cc(-c2csc(C(N)=O)c2)c2c(=O)[nH]ccc21
Temperature: 100 °C
Reaction time: 2 h
Yield: 71.7 %

Procedure:
To a solution of 4-(1-(2-fluoro-6-methoxy-4-nitrophenyl)-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-3-yl)thiophene-2-carboxamide (45.0 mg) and calcium chloride (11.7 mg) in a mixed solvent of ethanol (5 ml) and water (1 ml) was added reduced iron (29.3 mg), and the mixture was stirred at 100° C. for 2 hr. The insoluble substance was removed by the filtration, and washed with water and ethyl acetate. The filtrate was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (30.0 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.C(N(CC)CC)C.[NH2:17][C:18]([CH3:22])([CH3:21])[CH2:19][OH:20]>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:17][C:18]([CH3:22])([CH3:21])[CH2:19][OH:20])[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: CC(C)(N)CO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(CO)Nc1cc(Cl)nc(Cl)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2,4,6-trichloropyrimidine (20.0 g, 109 mmol) in acetonitrile (500 mL) was added triethylamine (11.03 g, 109 mmol) at 0° C. After 5 min at room temperature, 2-amino-2-methylpropan-1-ol (9.72 g, 109 mmol) was added portionwise. The reaction mixture was stirred for another 1 h at room temperature, filtered and concentrated. Purification via silica gel column (ethyl acetate/petroleum ether=1/10 to 1/1) afforded the title product.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:10][N:11](C)[CH2:12]CO.C([Sn](=O)CCCC)CCC>>[CH3:1][N:2]([CH2:3][C:4]([O:6][CH2:7][CH2:8][N:11]([CH3:12])[CH3:10])=[O:5])[CH3:9]
Reactant: CN(C)CCO
Reactant: CCOC(=O)CN(C)C
Agent: CCCC[Sn](=O)CCCC
Product: CN(C)CCOC(=O)CN(C)C
Temperature: 130 °C

Procedure:
A mixture of 65.5 g (0.5 mol) of ethyl N,N-dimethylglycinate, 44.6 g (0.5 mol) of N,N-dimethylethanolamine and 0.82 g of dibutyltin oxide was heated at about 130° C. The ethanol by-product was collected in a Dean-Stark trap. When the rate of ethanol evolution and amount of ethanol collected showed that the reaction was essentially complete, the reaction was heated at about 180° C. until ethanol evolution ceased. The liquid product was purified by distillation at reduced pressure to provide 2-(N,N-dimethylamino)ethyl N,N-dimethylaminoacetate.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:19][C:20]1[C:21]([CH3:26])=[CH:22][CH:23]=[CH:24][CH:25]=1>O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccccc1N
Reactant: CCCC(=O)c1cnc2c(OC)cccc2c1Cl
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(OC)cccc2c1Nc1ccccc1C
Reaction time: 1 h

Procedure:
A mixture of 3-butyryl-4-chloro-8-methoxyquinoline (6.0 g, 0.023 mol) and o-toluidine (6.0 ml, 0.056 mol) in 1,4-dioxan (100 ml) was heated under reflux with stirring for 1 hour. The mixture was evaporated and chromatographed (silica gel, 2% methanol in dichloromethane) to give 3-butyryl-4-(2-methylphenylamino)-8-methoxyquinoline as an oil which was isolated as the hydrochloride salt (2.12 g, 25.1%), m.p. 215°-217° by crystallisation from ethyl acetate and then recrystallisation from acetone.
Reaction SMILES: O[C:2]1([CH3:11])[CH:6]([CH2:7][C:8]#[CH:9])[C:5](=[O:10])[CH:4]=[CH:3]1.[OH-:12].[Na+].[Na+].[Cl-]>O>[CH2:7]([C:6]1[C:5](=[O:10])[CH2:4][CH:3]([OH:12])[C:2]=1[CH3:11])[C:8]#[CH:9]
Reactant: C#CCC1C(=O)C=CC1(C)O
Reactant: [OH-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: C#CCC1=C(C)C(O)CC1=O
Reaction time: 4 h

Procedure:
Into a reaction vessel, a solution of 4-hydroxy-4-methyl-5-propargyl-2-cyclopentenone (3 g) and MgCl2.6H2O (4.0 g) in water (120 ml) was charged, and the temperature was elevated up to 100° C. The contents were adjusted to pH 6.8 with 0.1 N NaOH solution, and stirring was continued at 100° C. for 4 hours, during which the pH was maintained at 6.8 to 7.0. After cooling, NaCl (40 g) was added to the reaction mixture and extracted with ether (120 ml) 4 times. The extracts were combined together, dried over anhydrous magnesium sulfate and concentrated at 40° C. under reduced pressure to give an oily substance (2.5 g). The oily substance was chromatographed with silica gel (30 g), followed by development with a solvent mixture of ethyl acetate and hexane (1:2 by volume) to give 2-propargyl-3-methyl-4-hydroxy-2-cyclopentenone (2.3 g). Yield, 77%. N.M.R. (CDCl3, internal standard TMS, δ ppm, 90 MHz): 4.60 (broad d, 1H, 4-H); 3.95 (broad s, 1H, 4-OH); 3.04 (d, 2H, --CH2 --C≡H); 2.65 (d of d, 1H, 5-H); 2.38 (d of d, 1H, 5 -H); 2.20 (s, 3H, 3-CH3); 1.98 (s, 1H, C≡CH).
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[C:6]([CH3:9])[N:5]=[CH:4][N:3]=1.[Br-].[F:11][C:12]([F:23])([F:22])[C:13]1[CH:18]=[CH:17][C:16]([C:19]#[C:20][Zn+])=[CH:15][CH:14]=1.O1CCCC1>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.CN(C)C=O>[Cl:1][C:2]1[C:7]([C:20]#[C:19][C:16]2[CH:17]=[CH:18][C:13]([C:12]([F:11])([F:22])[F:23])=[CH:14][CH:15]=2)=[C:6]([CH3:9])[N:5]=[CH:4][N:3]=1
Reactant: Cc1ncnc(Cl)c1I
Reactant: FC(F)(F)c1ccc(C#C[Zn+])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1ncnc(Cl)c1C#Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
4-Chloro-5-iodo-6-methylpyrimidine and [4-(trifluoromethyl)phenyl]ethynylzinc bromide were reacted in a solvent mixture of tetrahydrofuran and N,N-dimethylformamide (1:1) in the presence of tetrakis(triphenylphosphine)palladium while stirring under room temperature to heating to obtain a target substance. The target substance was subjected to e.g., proton nuclear magnetic resonance spectrometry (1H-NMR) and mass spectrometry (MS) and confirmed as the titled compound. Furthermore, MS measurement result is shown.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][CH:13]([CH3:15])[CH3:14])(=[O:11])=[O:10].N1C=CC=CC=1.[F:22][C:23]([F:35])([F:34])[O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>C(Cl)(Cl)Cl>[CH3:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([S:9]([NH:12][CH:13]([CH3:15])[CH3:14])(=[O:11])=[O:10])[C:2]=1[NH:1][C:29](=[O:30])[C:28]1[CH:32]=[CH:33][C:25]([O:24][C:23]([F:22])([F:34])[F:35])=[CH:26][CH:27]=1
Reactant: Cc1cccc(S(=O)(=O)NC(C)C)c1N
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Cc1cccc(S(=O)(=O)NC(C)C)c1NC(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.2 %

Procedure:
To 0.30 g (1.4 mmol) of the material from Step B in 5 mL of chloroform was added 0.28 ml (3.5 mmol) of pyridine and 0.27 mL (1.7 mmol) of 4-(trifluoromethoxy)benzoyl chloride. The reaction mixture was stirred overnight at room temperature and then heated at reflux for 5 hours. After cooling to room temperature the reaction mixture was washed with 1N HCl, dried (sodium sulfate) and filtered. The volatiles were removed with a rotary evaporator. The residue was purified by MPLC (5-25% ethyl acetate in hexanes as eluant) to afford 0.10 g of the title compound, a compound of the invention, as a white solid melting at 104-107° C.
Reaction SMILES: [H][H].[OH:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.C(=O)C1C=CC=CC=1>CO>[OH:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: [H][H]
Solvent: CO
Solvent: O=Cc1ccccc1
Product: OCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A 1.0 g quantity of the catalyst (CuO/ZnO/Aluminium oxide) in 50 ml methanol was placed in a 300 ml capacity Parr reactor. The contents were treated with hydrogen at 170° C., under pressure of 400-500 psig for 2-3 hrs. Cooled to room temperature, depressurized, followed by the addition of 10.0 g of 4-hydroxybenzaldehyde, in 50 ml of methanol. Hydrogenation was carried out at 170° C., under a pressure of 400-500 psig, for 2-3 hrs. The conversion of benzaldehyde was 100% providing 100% selectivity of 4-hydroxybenzyl alcohol, the desired alcohol product.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[I-].[Na+].O>CN(C)C=O>[CH2:18]([NH:25][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=c1ccc2cc(OCCCCCl)ccc2[nH]1
Reactant: NCc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1ccc2cc(OCCCCNCc3ccccc3)ccc2[nH]1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A suspension of 30 g of 6-(4-chlorobutoxy)-carbostyril, 103 ml of benzylamine and 33 g of sodium iodide in 300 ml of dimethylformamide was stirred at 80° C. for 8 hours. The reaction mixture was allowed to cool and then poured into water. The resulting precipitate was collected by filtration. The precipitate was washed with water and diethyl ether in this order to obtain 29.1 g of 6-(4-benzylaminobutoxy)carbostyril.
Reaction SMILES: [CH3:1][C:2]([C:22]([O:24][CH3:25])=[O:23])([CH3:21])[NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)=[O:5].[H-].[Na+].[CH3:28]N(C)C=O.IC>O>[CH3:28][N:3]([C:4]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1)=[O:5])[C:2]([CH3:1])([C:22]([O:24][CH3:25])=[O:23])[CH3:21]
Reactant: CN(C)C=O
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COC(=O)C(C)(C)N(C)C(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
As shown in Reaction Scheme 11, a mixture of methyl 2-methyl-N-[(4′-nitrobiphenyl-4-yl)carbonyl]alaninate (1.32 g, 3.9 mmol), sodium hydride (117 mg, 4.6 mmol), and N,N-dimethylformamide (15 mL) was stirred for 2 h at rt. Iodomethane (0.48 mL, 7.7 mmol) was added, and the reaction mixture was stirred overnight at rt. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (2×10 mL). The combined extracts were evaporated to dryness, and crude product was purified by flash chromatography (Biotage®, 4:1 hexanes/EtOAc) to yield methyl N,2-dimethyl-N-[(4′-nitrobiphenyl-4-yl)carbonyl]alaninate as an off-white solid (1.29 g, 94%). 1H NMR (400 MHz, DMSO-d6) δ 1.47 (s, 6H), 2.93 (s, 3H), 3.58 (s, 3H), 7.52 (d, 2H), 7.84 (d, 2H), 7.98 (d, 2H), 8.30 (d, 2H); LC-MS m/z 356.9 (MH+), retention time 2.98 minutes.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][NH:6][CH2:7][CH2:8][CH:9]=[C:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2].Br[CH2:25][CH3:26].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]([CH2:7][CH2:8][CH:9]=[C:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:25][CH3:26])[CH3:2]
Reactant: CCBr
Reactant: CCOC(=O)CNCCC=C(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CCOC(=O)CN(CC)CCC=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 66.4 %

Procedure:
A mixture of 0.158 g (0.5 mmol) of N-[(4,4-diphenyl)but-3-enyl]glycine ethyl ester (Compound A26), 0.234 g (2.1 mmol) bromoethane, 0.281 g (2 mmol) potassium carbonate and 0.068 g (0.4 mmol) potassium iodide was stirred under argon for 20 hours at room temperature. The reaction mixture was filtered, the solvent evaporated, and the residue chromatographed on a silica gel column with 20% ethyl acetate in hexanes to yield 0.112 g (66%) N-[(4,4-diphenyl)but-3-enyl]-N-ethylglycine ethyl ester (Compound A16) as an oil. NMR spectra showed: 1H NMR (CDCl3, 300 MHz) 7.60–7.00 (m, 10 H), 6.09 (t, 1 H), 4.13 (q. 2 H), 3.27 (s, 2 H), 2.72 (t, 2 H), 2.61 (q, 2 H), 2.28 (dt, 2 H), 1.23 (t, 3 H), 1.01 (t, 3 H); 13C NMR (CDCl3, 75 MHz) 171.77, 142.96, 142.86, 140.33, 130.09, 128.49, 128.35, 127.48, 127.27, 127.19, 60.58, 54.90, 53.98, 48.20, 28.19, 14.57, 12.70.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.Cl[C:12](=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH:6][C:12](=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:4]([F:10])[CH:3]=1
Reactant: Nc1c(F)cc(Br)cc1F
Reactant: CCOC(=O)CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CC(=O)Nc1c(F)cc(Br)cc1F
Reaction time: 1 h
Yield: 64.7 %

Procedure:
To a solution of 4-bromo-2,6-difluoroaniline (10 g, 48 mmol) in DCM (15 mL) was added ethyl 3-chloro-3-oxopropanoate (6.8 mL, 53 mmol) and DIEA (9.2 mL, 53 mmol) and the reaction mixture stirred for 1 h. The reaction mixture was partitioned between H2O and DCM and the layers separated. The DCM portion was washed with satd. NH4Cl and H2O then dried (Na2SO4) and filtered. The filtrate was concentrated under reduced pressure to give Compound 90a (10 g, 65% yield). LCMS=1.60 min using analytical method (Q), 321.9 (M+H). 1H NMR (500 MHz, CDCl3) δ 8.89 (br. s., 1H), 7.20-7.15 (m, 2H), 4.29 (q, J=7.2 Hz, 2H), 3.54 (s, 2H), 1.36-1.31 (m, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[OH:11])([O-:3])=[O:2].Br[CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[O:11][CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])([O-:3])=[O:2]
Reactant: CCOC(=O)C(C)Br
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)Oc1cc(F)ccc1[N+](=O)[O-]

Procedure:
To a solution of 2-nitro-5-fluorophenol (1.0 g, 1 eq, 6.36 mmol) and ethyl 2-bromopropionate (0.91 ml, 1.1 eq, 6.99 mmol) in dry acetone (32 ml) was added anhydrous potassium carbonate (2.63 g, 3 eq, 19.08 mmol) and the reaction mixture was refluxed for 16 h. The reaction mixture was filtered through celite and then condensed on rotavapour. The residue was diluted with ethyl acetate and washed with water and brine to yield ethyl 2-(2-nitro-5-fluorophenoxy)propanoate as crude compound (1.6 g, yield 98%), which was used in step (ii).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[CH:17]([C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23])([CH3:19])[CH3:18]>C(O)C>[CH:17]([C:20]1[CH:21]=[C:22]([NH:23][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:15]#[N:16])[CH:24]=[CH:25][CH:26]=1)([CH3:19])[CH3:18]
Reactant: CC(C)c1cccc(N)c1
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Cl
Solvent: CCO
Product: CC(C)c1cccc(Nc2c(C#N)cnc3ccc([N+](=O)[O-])cc23)c1
Reaction time: 4 h
Yield: 74 %

Procedure:
A mixture of 5.00 g (21.5 mmol) 4-chloro-6-nitro-3-quinolinecarbonitrile, 200 ml ethanol, and 3.48 g (25.8 mmol) 3-isopropylaniline was heated to reflux under N2. At 4 hours, removed heat and made basic with saturated sodium bicarbonate. Stripped solvents and azeotroped with ethanol. Slurried residue with hexane and collected solids. Dissolved in ethyl acetate, stirred with Darco, filtered through celite, stripped solvent and dried in vacuo, giving 5.289 g of yellow solid: mass spectrum (electrospray m/e): M+H=333.1.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:15][CH2:16][C@@H:17]2[CH2:22][CH2:21][NH:20][CH2:19][C@H:18]2[OH:23])=[O:14])[CH:3]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[S:31][C:32]([CH:35]=O)=[CH:33][N:34]=1>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:15][CH2:16][C@@H:17]2[CH2:22][CH2:21][N:20]([CH2:35][C:32]3[S:31][C:30]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=4)=[N:34][CH:33]=3)[CH2:19][C@H:18]2[OH:23])=[O:14])[CH:3]=1
Reactant: O=Cc1cnc(-c2ccccn2)s1
Reactant: CCOc1nc(C(=O)NC[C@@H]2CCNC[C@H]2O)cc(N)c1C#N
Product: CCOc1nc(C(=O)NC[C@@H]2CCN(Cc3cnc(-c4ccccn4)s3)C[C@H]2O)cc(N)c1C#N

Procedure:
According to the same procedure described in Example 101, starting with the compound prepared in Example 268 and the compound prepared in Example 139, the title compound having the following physical data was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]([Cl:8])=[N:6][CH:7]=1.[CH:17](OCC)(OCC)[O:18][CH2:19][CH3:20].C1(C)C(C)=CC=CC=1>C(OC(=O)C)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:9](/[C:10](=[CH:17]/[O:18][CH2:19][CH3:20])/[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:16])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)c1cc(Br)cnc1Cl
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1C
Product: CCO/C=C(\C(=O)OCC)C(=O)c1cc(Br)cnc1Cl
Temperature: 130 °C
Yield: 93.1 %

Procedure:
Ethyl 3-(5-bromo-2-chloropyridin-3-yl)-3-oxopropanoate (Intermediate 12, 1.0 g, 3.26 mmol) was suspended in acetic anhydride (0.83 g, 8.16 mM) and 1,1′,1″-[methanetriyltris(oxy)]triethane (0.725 g, 4.90 mmol) was added. The reaction mixture was heated to 130° C. for 3 h then cooled to room temperature and concentrated under reduced pressure. The residue so obtained was co-distilled with xylene (2-3 times) to obtain ethyl (2Z)-2-[(5-bromo-2-chloropyridin-3-yl)carbonyl]-3-ethoxyprop-2-enoate (1.1 g) which was taken without further purification to the next step.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]1[CH:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:12]1[CH2:11][CH2:10]2)(=O)=O.[CH3:25][N:26](C=O)C>[C-]#N.[C-]#N.[Zn+2].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:25]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]1[CH:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:12]1[CH2:11][CH2:10]2)#[N:26]
Reactant: CN(C)C=O
Reactant: CCOC(=O)C1C2CCc3cc(OS(=O)(=O)C(F)(F)F)ccc3C21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CCOC(=O)C1C2CCc3cc(C#N)ccc3C21
Temperature: 100 °C
Reaction time: 14 h
Yield: 90 %

Procedure:
Ethyl 5-{[(trifluoromethyl)sulfonyl]oxy}-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalene-1-carboxylate (0.2 g, 0.5 mmol) was mixed with Zn(CN)2 (0.82 mmol) and Pd(Ph3P)4 (56 mg, 10 mol %) in DMF (4 ml), bubbled with argon for 5 min and heated at stirring in a closed vial for 14 h at 100° C. Reaction was monitored by GC. The reaction mixture was concentrated by rotary evaporation, mixed with saturated NH4Cl and extracted into ethylacetate (3×15 ml). Organic extract was washed with water and brine, dried under Na2SO4. Concentration gave 0.12 g of product as an oil (yield 90%).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([O:16][C:17]([N:19]1[CH2:23][CH:22]([CH3:24])[C:21]([CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])([C:25]([OH:27])=[O:26])[CH2:20]1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:32]([O:31][C:29](=[O:30])[CH2:28][C:21]1([C:25]([O:27][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:26])[CH:22]([CH3:24])[CH2:23][N:19]([C:17]([O:16][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:18])[CH2:20]1)([CH3:34])([CH3:33])[CH3:35]
Reactant: CC1CN(C(=O)OCc2ccccc2)CC1(CC(=O)OC(C)(C)C)C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1CN(C(=O)OCc2ccccc2)CC1(CC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 5 °C
Yield: 98.2 %

Procedure:
Benzyl bromide (4.48 ml, 37.7 mmol) was added to a mixture of (3RS,4SR)-1-[(benzyloxy)carbonyl]-3-[2-(tert-butoxy)-2-oxoethyl]-4-methylpyrrolidine-3-carboxylic acid obtained in Reference Example 1b (14.5 g, 38.5 mmol), potassium carbonate (10.6 g, 77 mmol) and N,N-dimethylformamide (50 ml) with stirring under ice-cooling (internal temperature: 3 to 7° C.), and the mixture was stirred for one hour, returned to mom temperature and stirred overnight. Water was added to the reaction liquid, which was extracted with ethyl acetate three times. The organic layers were combined, sequentially washed with a saturated aqueous ammonium chloride solution (five times), water (twice) and brine, and then dried over sodium sulfate, filtered and concentrated to give the title compound (17.67 g, yield: 98.2%).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[C:16]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[Cl:29])[CH:17]=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[N-:30]=[N+:31]=[N-:32].[Na+]>CS(C)=O.C(OCC)C>[N:30]([CH2:12][CH:13]1[CH2:22][CH2:21][C:20]2[C:15](=[C:16]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[CH:17]=[CH:18][CH:19]=2)[O:14]1)=[N+:31]=[N-:32]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCc3cccc(-c4ccccc4Cl)c3O2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: [N-]=[N+]=NCC1CCc2cccc(-c3ccccc3Cl)c2O1
Temperature: 70 °C
Yield: 82 %

Procedure:
A solution of [8-(2-chlorophenyl)-3,4-dihydro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate, prepared in Example 1, step 7 (0.25 g, 0.58 mmol) and sodium azide (0.15 g, 2.3 mmol) in anhydrous dimethyl sulfoxide (9.5 mL) was heated to 70° C. under nitrogen for 16 hours. The cooled reaction mixture was then diluted with diethyl ether (50 mL), washed with water (5×25 mL) and saturated brine (25 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford 0.14 g (82%) of 2-azidomethyl-8-(2-chloro-phenyl)-chroman as a colorless oil that was used without further purification.