Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:24]=[O:25])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=3[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]21.[CH2:26]([Mg]Br)[CH2:27][CH:28]=[CH2:29]>O1CCCC1.[Cl-].[NH4+]>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:20]([CH3:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([OH:25])[CH2:29][CH2:28][CH:27]=[CH2:26])=[CH:4][CH:3]=1
Reactant: C=CCC[Mg]Br
Reactant: Cc1cc(Cl)cc(Cl)c1N1CCCn2c1nc1c(Cl)ccc(C=O)c12
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(C)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 9-chloro-1-(2,4-dichloro-6-methylphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (150 mg, 0.380 mmol) in tetrahydrofuran (3.8 mL) was added dropwise 3-butenylmagnesium bromide (ca. 0.8 M solution in diethyl ether, 0.900 mL) at 0° C., and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with aqueous saturated ammonium chloride, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture to give the two title compounds as colorless solids.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:31])[CH:13]2[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[F:39])=[O:11])=[N:7][CH:8]=1)#[N:2].[OH:40]O.[OH-].[Na+]>CS(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:31])[CH:13]2[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[F:39])=[O:11])=[N:7][CH:8]=1)(=[O:40])[NH2:2]
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccc(C#N)cn2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C(N)=O)cn2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 42.8 %

Procedure:
To the solution of rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (5-cyano-pyridin-2-yl)-amide (12 mg, 0.02 mmol) prepared in Example 199 in DMSO (0.2 mL) at 0° C. was added an aqueous solution (30% Aldrich) of H2O2 (0.04 g, 0.3 mmol), then aqueous solution (1N) of NaOH (0.1 mL, 0.1 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 1 h. The mixture was partitioned between ethyl acetate and saturated aqueous Na2SO3 solution. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (50-100% EtOAc in dichloromethane) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (5-carbamoyl-pyridin-2-yl)-amide as a light yellow solid (Yield 5 mg, 40%)
Reaction SMILES: C([S:4][CH2:5][CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[C:18](=[O:33])[NH:19][C:20](=[O:32])[C:21]=2[C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]([CH3:31])[CH:23]=2)=[CH:9]1)(=O)C.N>CO.CN(C=O)C.[Cl-].[Na+]>[SH:4][CH2:5][CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[C:18](=[O:33])[NH:19][C:20](=[O:32])[C:21]=2[C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]([CH3:31])[CH:23]=2)=[CH:9]1
Reactant: CC(=O)SCCCn1cc(C2=C(c3cn(C)c4ccccc34)C(=O)NC2=O)c2ccccc21
Agent: N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cn1cc(C2=C(c3cn(CCCS)c4ccccc34)C(=O)NC2=O)c2ccccc21
Reaction time: 17 h
Yield: 83.7 %

Procedure:
350 mg of the product of Example 99 in 20 ml of 50% methanol/DMF were treated with 0.5 ml of 33% aqueous ammonia. The mixture was stirred for 17 hours, then diluted with 20 ml of sodium chloride solution and extracted with ethyl acetate. The ethyl acetate extracts were dried and evaporated. Chromatography of the residue on silica gel with ethyl acetate/hexane (3:1) gave 266 mg of 3-[-1-(3-mercaptopropyl)-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione, m.p. 155°-157° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:5]=1[CH2:6][N:7]([CH2:15][CH2:16][OH:17])[C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[Cl:23][C:24]1[CH:25]=[C:26]([N+:31]([O-:33])=[O:32])[CH:27]=[CH:28][C:29]=1F.O>CN(C)C=O>[Cl:23][C:24]1[CH:25]=[C:26]([N+:31]([O-:33])=[O:32])[CH:27]=[CH:28][C:29]=1[O:17][CH2:16][CH2:15][N:7]([CH2:6][C:5]1[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:4]=1[F:3])[C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N(CCO)Cc1ccc(F)cc1F
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N(CCOc1ccc([N+](=O)[O-])cc1Cl)Cc1ccc(F)cc1F
Temperature: -2.5 °C
Reaction time: 0.17 h
Yield: 106.1 %

Procedure:
Sodium hydride (0.101 g, 3.83 mmol, 95% in oil) was added to N,N-dimethyl formamide (20 mL) at −5 to 0° C. under nitrogen. The suspension was stirred for 10 minutes and to the resulting cooled mixture was added a solution of tert-butyl 2,4-difluorobenzyl(2-hydroxyethyl)carbamate (1.1 g, 4.21 mmol) in N,N-dimethylformamide (10 mL), maintaining the temperature at −5 to 0° C. during addition. The reaction mixture was stirred further for 20 minutes and then a solution of 3-chloro-4-fluoro-nitrobenzene (0.67 g, 3.83 mmol) in N,N-dimethyl formamide (10 mL), was added dropwise, maintaining the temperature in the range −5 to 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 30 minutes. Water (300 mL) was then added to the reaction mixture and the resulting mixture was extracted with EtOAc (3×50 mL). The combined organic extracts were washed with brine (2×30 mL), dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by column chromatography on neutral silica gel using 5-20% EtOAc in hexane to give the title compound (1.8 g, 60%).
Reaction SMILES: [Cl-].[NH4+].[F:3][CH:4]([F:23])[C@H:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[C:15]([F:22])[CH:14]=2)=[CH:9][CH:8]=1)[OH:6]>C(O)C.O.[Fe]>[NH2:19][C:17]1[CH:18]=[C:13]([C:10]2[CH:9]=[CH:8][C:7]([C@H:5]([OH:6])[CH:4]([F:23])[F:3])=[CH:12][CH:11]=2)[CH:14]=[C:15]([F:22])[CH:16]=1
Reactant: O=[N+]([O-])c1cc(F)cc(-c2ccc([C@H](O)C(F)F)cc2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cc(F)cc(-c2ccc([C@H](O)C(F)F)cc2)c1
Temperature: 25 °C

Procedure:
Ammonium chloride (24.2 mg, 0.453 mmol) was added to a mixture of (1S)-2,2-difluoro-1-(3′-fluoro-5′-nitrobiphenyl-4-yl)ethanol (269 mg, 0.905 mmol) and iron (253 mg, 4.53 mmol) in ethanol (6 mL) and water (3 mL). The mixture was heated to reflux for 1.5 hours. Upon cooling to room temperature, the reaction mixture was filtered through CELITE and washed with ethyl acetate. The filtrate was washed with saturated aqueous NaHCO3 and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate/hexanes) to yield (1S)-1-(3′-amino-5′-fluorobiphenyl-4-yl)-2,2-difluoroethanol. MS ESI calc'd. for C14H13F3NO [M+H]+ 268, found 268.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][CH:2]=1.[C:9]1(=[O:16])[O:15][C:13](=[O:14])[CH:12]=[C:10]1[CH3:11]>O1CCCC1>[NH2:7][C:4]1[CH:5]=[CH:6][C:1]([NH:8][C:13](=[O:14])/[CH:12]=[C:10](/[CH3:11])\[C:9]([OH:16])=[O:15])=[CH:2][CH:3]=1
Reactant: CC1=CC(=O)OC1=O
Reactant: Nc1ccc(N)cc1
Solvent: C1CCOC1
Product: C/C(=C/C(=O)Nc1ccc(N)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.6 %

Procedure:
Under a nitrogen atmosphere, into a reaction vessel were charged 10.0 g (92.5 mmol) of 1,4-phenylenediamine and 250 ml of tetrahydrofuran. A solution prepared by dissolving 10.4 g (92.5 mmol) of citraconic anhydride in 20 ml of tetrahydrofuran was dropped into this under cooling with ice over a period of 20 minutes, then, the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the deposited crystal was isolated by filtration, and dried to obtain 15 g of coarse (2Z)-4-[(4-aminophenyl)amino]-2-methyl4-oxo-2-butenoic acid. Five grams (5 g) of coarse (2Z)-4-[(4-aminophenyl)amino]-2-methyl4-oxo-2-butenoic acid was repulped with 2-propanol and methanol each at 50° C. for 3 hours, then, repulped with chloroform, to obtain 13.1 g of (2Z)-4-[(4-aminophenyl)amino]-2-methyl-4-oxo-2-butenoic acid as a yellow solid. Yield: 64.3%.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][N:5]([CH3:22])[C:6]([CH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:9]1)=[O:7].[CH3:23]I.O>C1COCC1>[CH3:3][O:4][N:5]([CH3:22])[C:6]([CH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]([CH3:23])[C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])[CH2:9]1)=[O:7]
Reactant: CI
Reactant: CON(C)C(=O)C1CCCC(NC(=O)OC(C)(C)C)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CON(C)C(=O)C1CCCC(N(C)C(=O)OC(C)(C)C)C1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 92.5 %

Procedure:
To a suspension of NaH (60%, 340 mg, 8.38 mmol) in THF (10 mL) was added dropwise a solution of tert-butyl 3-{[methoxy(methyl)amino]carbonyl}cyclohexylcarbamate (2.00 g, 6.98 mmol) in THF (10 mL)followed by methyl iodide (1.09 g, 7.68 mmol). The mixture was stirred at 60° C. for 0.5 hr. After cooled to room temperature, the mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=1/1) to give tert-butyl N-[3-(N-methoxy-N-methylcarbamoyl)cyclohexyl]-N-methylcarbamate as a colorless oil (1.94 g, yield; 93%).
Reaction SMILES: [O:1]=[C:2]1[CH:11]2[CH2:12][CH2:13]O[C:10]2=[C:9]2[C:4]([C:5]([CH3:15])=[CH:6][CH:7]=[CH:8]2)=[N:3]1.[CH3:16][O:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20]>C(O)COCCO.O>[CH3:16][O:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[N:20]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([CH3:15])[C:4]=3[NH:3][C:2](=[O:1])[C:11]=2[CH2:12][CH2:13]1
Reactant: Cc1cccc2c1=NC(=O)C1CCOC=21
Reactant: COc1ccccc1N
Solvent: O
Solvent: OCCOCCO
Product: COc1ccccc1N1CCc2c1c1cccc(C)c1[nH]c2=O
Temperature: 250 °C
Yield: 79 %

Procedure:
4-Oxo-6-methyl-2,3-dihydrofuro[3,2-c]quinoline (201 mg, 1.0 mmol) was dissolved in 10 ml of diethylene glycol and 2-methoxyaniline (282 μl, 2.5 mmol) was added under nitrogen. The reaction mixture was heated at 250° C. for 15 hours. The reaction mixture was diluted with 20 ml of salt water and the aqueous layer was extracted with methylene chloride (15 ml×3). After washing with water (15 ml×3), the organic layer was dried by anhydrous magnesium sulfate and filtered, and concentrated under reduced pressure. The residue was purified with ethyl acetate as eluent by silica gel chromatography to obtain 242 mg of desired compound as solid in 79% of yield.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13](=O)[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([O:21][CH3:22])=[CH:16][CH:15]=3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O=P(Cl)(Cl)[Cl:26]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([Cl:26])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([O:21][CH3:22])=[CH:16][CH:15]=3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc2c(=O)[nH]c(-c3ccc(C(C)(C)C)cc3)cc2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(Cl)nc(-c3ccc(C(C)(C)C)cc3)cc2c1
Yield: 28 %

Procedure:
A solution of 3-(4-(tert-butyl)phenyl)-6-methoxyisoquinolin-1(2H)-one (0.7 g, 2.277 mmol) in POCl3 (7 ml) was refluxed for overnight. The solvent was evaporated under reduced pressure and the residue was diluted with cold water. The aqueous solution was basified by solid sodium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography (10% ethyl acetate in pet ether) to get desired compound (0.21 g, 28.0%) as solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.34(s, 1H), 8.18-8.16 (d, J=8 Hz, 1H), 8.08-8.06 (d, J=8 Hz, 2H), 7.57-7.55 (d, J=8 Hz, 2H), 7.41 (s, 1H), 7.40-7.38 (d, J=8 Hz, 1H), 3.97 (s, 3H), 1.34 (s, 9H); MS: MS m/z 362.2 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][C:12]([N+:15]([O-])=[O:16])([CH3:14])[CH3:13].C(O)(=O)C>C(O)C.[Zn]>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[N+:15]([C:12]([CH3:14])([CH3:13])[CH3:11])[O-:16]
Reactant: CC(C)(C)[N+](=O)[O-]
Reactant: O=Cc1ccc(F)cc1F
Agent: [Zn]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)[N+]([O-])=Cc1ccc(F)cc1F
Temperature: 5 °C

Procedure:
To a suspension of 2,4-difluorobenzaldehyde (608.9 mg, 4.28 mmol), 1,1-dimethylnitroethane (881.9 mg, 8.55 mmol) and zinc (840.0 mg, 12.8 mmol) in ethanol (15 ml) was added acetic acid (1.54 g, 25.6 mmol) dropwise at 5° C. while stirring. The mixture was stirred at room temperature for one day. After the mixture was cooled to 5° C., zinc acetate was filtered off and the filtrate was concentrated and purified by silica gel chromatography (hexane/ethyl acetate=4/1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([CH2:12][O:13][C:14]2[N:19]=[N:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=2)=[CH:10][O:9][N:8]=1.[CH:23]1([NH2:26])[CH2:25][CH2:24]1>>[CH:23]1([NH:26][C:20]([C:17]2[N:18]=[N:19][C:14]([O:13][CH2:12][C:11]3[C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[N:8][O:9][CH:10]=3)=[CH:15][CH:16]=2)=[O:22])[CH2:25][CH2:24]1
Reactant: NC1CC1
Reactant: O=C(O)c1ccc(OCc2conc2-c2ccccn2)nn1
Product: O=C(NC1CC1)c1ccc(OCc2conc2-c2ccccn2)nn1
Yield: 66 %

Procedure:
As described for example 123 g, 6-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid (70 mg, 0.24 mmol) was converted, using cyclopropylamine instead of isopropylamine, to the title compound (52 mg, 66%) which was obtained as a white solid. MS: m/e=338.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([F:30])[C:3]=1[O:4][C:5]1[CH:21]=[CH:20][C:8]2[N:9]([CH3:19])[C:10](=[O:18])[C:11]([CH3:17])([C:13](=[N:15][OH:16])[CH3:14])[O:12][C:7]=2[CH:6]=1.[H-].[Na+].Br[CH2:34][CH3:35].Cl>CN(C=O)C>[Cl:1][C:2]1[CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[C:22]([F:30])[C:3]=1[O:4][C:5]1[CH:21]=[CH:20][C:8]2[N:9]([CH3:19])[C:10](=[O:18])[C:11]([CH3:17])([C:13](=[N:15][O:16][CH2:34][CH3:35])[CH3:14])[O:12][C:7]=2[CH:6]=1
Reactant: CC(=NO)C1(C)Oc2cc(Oc3c(F)cc(C(F)(F)F)cc3Cl)ccc2N(C)C1=O
Reactant: CCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCON=C(C)C1(C)Oc2cc(Oc3c(F)cc(C(F)(F)F)cc3Cl)ccc2N(C)C1=O
Reaction time: 2 h
Yield: 94.1 %

Procedure:
To a DMF (10 ml) solution of 7-(2-chloro-6-fluoro-4-trifluoromethylphenoxy)-2,4-dimethyl-2-[1(hydroxyimino)ethyl]-3,4-dihydro-3-oxo-2H-1,4-benzoxazine (Compound 101) (0.3 g) obtained in Example 16 was added, under ice-cooling, 60% sodium hydride (0.03 g), and after stirring for 20 minutes, bromoethane (0.1 g) was dropwise added thereto. After stirring for 2 hours, 1N hydrochloric acid was added and the mixture extracted twice with ethyl acetate (20 ml). The extract was then washed with water and with saturated aqueous sodium chloride, and dried over magnesium sulfate. The solvent was evaporated under a reduced pressure, and the residue purified by silica gel chromatography (eluant: n-hexane/ethyl acetate=4/1) to give 0.3 g of the title compound (colorless oil).
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1.[CH:19](=O)[CH2:20][CH2:21][CH3:22].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[CH2:19]([NH:8][C:7]1[C:2]([CH3:1])=[C:3]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:11][CH:10]=2)[CH:4]=[CH:5][CH:6]=1)[CH2:20][CH2:21][CH3:22]
Reactant: Cc1c(N)cccc1-c1ccc(C(F)(F)F)cc1
Reactant: CCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCCNc1cccc(-c2ccc(C(F)(F)F)cc2)c1C
Yield: 57.1 %

Procedure:
To a solution of 2-methyl-4′-(trifluoromethyl)-1,1′-biphenyl-3-ylamine (0.32 g, 1.26 mmol) in anhydrous CH2Cl2 (10 mL) under nitrogen at room temperature was added butyraldehyde (0.114 mL, 1.26 mmol), followed 10 min later by sodium triacetoxyborohydride (0.374 g, 1.76 mmol) and acetic acid (72 μL, 1.26 mmol). The resultant mixture was stirred for 22 h at room temperature. The reaction mixture was quenched with sat. NaHCO3 aq. (15 mL), then extracted with CH2Cl2 (2×20 mL). The organic solution was passed through a hydrophobic frit and the solvent was removed in vacuo. Purification by SPE (20 g Silica cartridge) eluted with 1:200 EtOAc:cyclohexane afforded the title compound as a colourless oil (221 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:20]=[CH:19][C:18]([O:21]C(=O)C)=[CH:17][C:15]=4[CH:16]=3)=[N:9]2)=[CH:4][CH:3]=1>CO.[OH-].[Na+].CN(C)C=O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:15]=4[CH:16]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(=O)Oc1ccc2oc(-c3ccc4ccc(Cl)cc4n3)cc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: Oc1ccc2oc(-c3ccc4ccc(Cl)cc4n3)cc2c1
Reaction time: 24 h
Yield: 82.8 %

Procedure:
To a suspension of 7-chloro-2-(5-acetoxybenzofuran-2-yl)quinoline (16.7 g) in methanol (400 ml), 1N aqueous sodium hydroxide (50 ml) was added at ambient temperature. The mixture was stirred for 1 day. After the solvent was removed under reduced pressure, the residue was suspended with water, and adjusted to pH 6-7 with diluted aqueous hydrochloric acid. After the resulting suspension was stirred at ambient temperature for 1 hour, the precipitates were collected by filtration, washed with water and dried in vacuo to give crude material (15 g). The crude material was dissolved in N,N-dimethylformamide (200 ml) at 80° C., and the resulting solution was allowed to stand at ambient temperature. The resulting crystals were filtered off and washed with N,N-dimethylformamide. The filtrate was poured into Water (500 ml). The resulting precipitates were collected by filtration, washed with water and dried in vacuo to give 7-chloro-2-(5-hydroxybenzofuran-2-yl)quinoline (12.1 g).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([C@H:12]([CH3:17])[C:13]([O:15][CH3:16])=[O:14])[CH2:7][CH2:6]2.[Al+3].[Cl-].[Cl-].[Cl-].CCS>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([C@H:12]([CH3:17])[C:13]([O:15][CH3:16])=[O:14])[CH2:7][CH2:6]2
Reactant: COC(=O)[C@@H](C)[C@@H]1CCc2cc(OC)ccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCS
Product: COC(=O)[C@@H](C)[C@@H]1CCc2cc(O)ccc21
Temperature: 2.5 °C
Reaction time: 4 h
Yield: 79.4 %

Procedure:
A solution of methyl (2S)-2-[(1S)-5-methoxy-2,3-dihydro-1H-inden-1-yl]propanoate (Example 13) (5.70 g, 0.024 mol) in CH2Cl2 (70 mL), under argon, was cooled to 0-5° C. and AlCl3 (16.22 g, 0.122 mol) was added portion-wise while maintaining the temperature below 10° C. To this mixture was added EtSH (9.0 mL, 0.122 mol) and the resulting mixture was stirred at 0-5° C. for 4 h. The reaction mixture was then slowly poured into vigorously stirred ice-water (200 mL) and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with water, brine, dried (Na2SO4), filtered, and concentrated to dryness under vacuum. The resulting crude product was purified by silica gel flash chromatography (gradient of 10-40% ethyl acetate/hexanes) to give 4.2 g (80%) of the title compound. 1H NMR (400 MHz, CDCl3): δ 6.93 (d, 1H), 6.70 (s, 1H), 6.63 (dd, 1H), 3.72 (s, 3H), 3.50 (q, 1H), 2.83 (m, 3H), 2.19 (m, 1H), 1.90 (m, 1H), 1.08 (d, 3H); GC-MS: RT=8.60 min, (M+H)+ 220.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH2:12][CH2:13][CH3:14])=[C:10]2[C:5]([C:6](=[O:19])[CH:7]=[C:8]([C:15]([O:17][CH3:18])=[O:16])[O:9]2)=[CH:4][CH:3]=1.[CH2:20]([C:23]1[CH:35]=[C:34]([C:36]([O:38][CH3:39])=[O:37])[CH:33]=[CH:32][C:24]=1[O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br)[CH:21]=[CH2:22]>>[C:15]([C:8]1[O:9][C:10]2[C:5]([C:6](=[O:19])[CH:7]=1)=[CH:4][CH:3]=[C:2]([O:1][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][O:25][C:24]1[CH:32]=[CH:33][C:34]([C:36]([O:38][CH3:39])=[O:37])=[CH:35][C:23]=1[CH2:20][CH:21]=[CH2:22])[C:11]=2[CH2:12][CH2:13][CH3:14])([O:17][CH3:18])=[O:16]
Reactant: CCCc1c(O)ccc2c(=O)cc(C(=O)OC)oc12
Reactant: C=CCc1cc(C(=O)OC)ccc1OCCCCCBr
Product: C=CCc1cc(C(=O)OC)ccc1OCCCCCOc1ccc2c(=O)cc(C(=O)OC)oc2c1CCC
Yield: 95.7 %

Procedure:
Using the procedure of Example 2, 4.14 g (15.8 mmole) of methyl 7-hydroxy-8-n-propylchromone-2-carboxylate and 5.63 g (16.5 mmole) of the compound from Example 10 gave 7.9 g (96%) of the title compound, mp 87°-88°. Calc: C, 68.95; H, 6.61; Found; C, 68.49; H, 6.54.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][CH2:6][CH2:7]Br)[CH3:2].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[CH2:21]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=1)[CH3:22]>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:9])[CH2:5][CH2:6][CH2:7][N:23]([CH2:21][CH3:22])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=1)[CH3:2]
Reactant: CCNc1cccc(C)c1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCN(CC)c1cccc(C)c1
Temperature: 95 °C
Reaction time: 17 h

Procedure:
4-Bromobutyric acid ethyl ester (17.1 ml), potassium carbonate (20.5 g), and DMF (80 ml) were added to N-ethyl-m-toluidine (8 g), and the mixture was stirred at 95° C. for 17 hours. The reaction mixture was diluted with ethyl acetate, washed with water, and dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (hexane-ethyl acetate) to give the title compound (14.1 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([N+]([O-])=O)[C:4]=1[C:5]#[N:6].[CH2:18]([OH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[K+]>O1CCOCC1.O>[CH2:18]([O:25][C:7]1[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=[C:3]([O:2][CH3:1])[C:4]=1[C:5]#[N:6])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1cc(C(F)(F)F)cc([N+](=O)[O-])c1C#N
Reactant: OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(C(F)(F)F)cc(OCc2ccccc2)c1C#N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 200 mg (0.813 mmol) 2-methoxy-6-nitro-4-trifluoromethyl-benzonitrile in 2 ml dioxane under argon at 0° C., was added 425.3 ul (4.065 mmol) benzyl alcohol, followed by a dropwise addition of a solution of 82.2 mg (1.260 mmol) potassium hydroxide in 600 ul water. The mixture was stirred at 0° C. for 30 minutes and then at room temperature overnight. The reaction mixture was poured into ice water. The resulting suspension was filtered and dried in vacuo to provide 196 mg (y: 78.5%) of the title compound as a white solid.