Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[OH:11].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14])[C:5]=1[OH:11]
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: COC(=O)c1cccc(O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCCOc1cccc(C(=O)OC)c1O
Yield: 16 %

Procedure:
A mixture of 1.0 g (5.95 mmol) of 2,3-dihydroxybenzoic acid methyl ester, 1.98 g (5.95 mmol) of 1-bromooctadecane and 0.825 g (5.95 mmol) of potassium carbonate in 20 ml of acetone and 4 ml of DMF was stirred at reflux for 40 hours. The usual workup followed by purification by chromatography on 40 g of silica gel (230-400 mesh) using 50% toluene-hexane gave 0.40 g (16% yield, mp 57°-60°) of 2-hydroxy-3-(octadecyloxy)benzoic acid methyl ester. The structure was established by nmr and mass spectra.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:21][CH2:22][Cl:23].O>CN(C=O)C>[Cl:23][CH2:22][CH2:21][N:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=[CH:9]1
Reactant: c1ccc(-c2nc[nH]c2-c2ccccc2)cc1
Reactant: ClCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: ClCCn1cnc(-c2ccccc2)c1-c1ccccc1
Temperature: 60 °C
Yield: 17.7 %

Procedure:
Step 1): A solution of 4,5-diphenylimidazole (2.5 g, 11.3 mmol) in dry DMF (20 ml) was added to a suspension of NaH (0.33 g, 13.8 mmol) in dry DMF (5 ml) at 50° C. under nitrogen atmosphere. The reaction mixture was heated at 60° C. for 2 hours. After heating, the mixture was added dropwise to a solution of 1-bromo-2-chloroethane (4.9 g, 33.9 mmol) in dry DMF (30 ml) over 1 hour at 50° C. The reaction mixture was heated continuously at 40° C. for 5 hours, then poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried (MgSO4) and concentrated. The precipitates were filtered off. The filtrate was concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate and hexane) to give 1-(2-chloroethyl)-4,5-diphenylimidazole (17.7%).
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([N:10]=[C:11]=[O:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]1([CH:25]([CH3:28])[CH2:26][OH:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:19]1([CH:25]([CH3:28])[CH2:26][O:27][C:11](=[O:12])[NH:10][C:8](=[O:9])[CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(CO)c1ccccc1
Reactant: O=C=NC(=O)C(c1ccccc1)c1ccccc1
Product: CC(COC(=O)NC(=O)C(c1ccccc1)c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 131° C. and MS: m/e=373.5 (M+H+) was prepared in accordance with the general method of example 1 from diphenylacetyl isocyanate and (RS)-2-phenyl-propan-1-ol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([OH:27])[CH:10]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1)[C:11]([O:13]CC)=[O:12].[OH-].[Na+].Cl>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([OH:27])[CH:10]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:19][CH:18]=1)[C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
To a solution of ethyl (2RS,3RS)-3-(2,4-difluorophenyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionate (8.1 g, 20.8 mmol) in methanol (40 ml) was added 2N aqueous sodium hydroxide solution (20.8 ml, 41.6 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was acidified with 1N hydrochloric acid and extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give (2RS,3RS)-3-(2,4-difluorophenyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionic acid (6.0 g, 80%).
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH:24][CH2:25][CH2:26][OH:27])=[CH:18][CH:17]=1)([O-:15])=[O:14]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[N+:13]([C:16]1[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][N:24]2[CH2:25][CH2:26][O:27][C:6]2=[O:7])=[CH:20][CH:21]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1ccc(CCNCCO)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C1OCCN1CCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
CDI (89 mmoles) is added to a solution of the compound obtained in Step A (44.5 mmoles) and DMAP (44.5 mmoles) in DCM (250 ml). After stirring for 4 hours at ambient temperature, the reaction mixture is diluted with 300 ml of DCM and then washed with 2M HCl solution (5×200 ml). The organic phase is dried over magnesium sulphate, filtered and evaporated to dryness to yield the title product in the form of an orange solid, which is used directly in the next Step.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)=[CH:8][C:7]=1[N+:21]([O-])=O.[C:24](O)(=O)[CH3:25]>[Fe]>[O:13]1[C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=[C:12]1[C:9]1[CH:10]=[CH:11][C:6]2[N:5]([CH2:4][CH2:3][S:2][CH3:1])[C:24]([CH3:25])=[N:21][C:7]=2[CH:8]=1
Reactant: CSCCNc1ccc(-c2nc3ccccc3o2)cc1[N+](=O)[O-]
Reactant: CC(=O)O
Agent: [Fe]
Product: CSCCn1c(C)nc2cc(-c3nc4ccccc4o3)ccc21
Yield: 84 %

Procedure:
To N-(2-(methylthio)ethyl)-4-(benzoxazol-2-yl)-2-nitroaniline (370 mg, 1.12 mmol) was added iron powder (188 mg, 3.37 mmol) and acetic acid (5 mL), and this was heated to reflux for 10 hours. After the reaction solution was cooled, it was concentrated. The residue obtained was purified by silica gel column chromatography to yield the title compound (305 mg, 84% yield) as pink crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3(O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:11]=[CH:10][C:9]=2[NH:21][C:22]([C:24]2[NH:25][CH:26]=[C:27]([C:29]#[N:30])[N:28]=2)=[O:23])=[CH:4][CH2:3]1.O=S(Cl)Cl.[CH3:36][O:37][CH2:38][CH2:39][NH2:40]>C(Cl)Cl.CCOC(C)=O>[CH3:31][C:2]1([CH3:1])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3([NH:40][CH2:39][CH2:38][O:37][CH3:36])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]3)[CH:11]=[CH:10][C:9]=2[NH:21][C:22]([C:24]2[NH:25][CH:26]=[C:27]([C:29]#[N:30])[N:28]=2)=[O:23])=[CH:4][CH2:3]1
Reactant: COCCN
Reactant: CC1(C)CC=C(c2cc(C3(O)CCCCC3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COCCNC1(c2ccc(NC(=O)c3nc(C#N)c[nH]3)c(C3=CCC(C)(C)CC3)c2)CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.6 %

Procedure:
To a suspension of 4-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-(1-hydroxy-cyclohexyl)-phenyl]-amide (as prepared in Example 1, 42.0 mg, 0.100 mmol) in 1.5 mL of DCM at −15° C. was added SOCl2 (22.0 μL, 0.300 mmol) under Ar. After stirring at RT for 1 h, the mixture was cooled to −15° C. To the reaction was then added 2-methoxyethylamine (70.0 μL, 0.800 mmol) and the resulting mixture was stirred at RT for 2 h. The mixture was diluted with EtOAc (30 mL) and washed with H2O (2×10 mL) and brine (10 mL). After drying over Na2SO4 and concentrating in vacuo, the residue was purified by silica gel chromatography (1-5% MeOH/DCM) to afford the title compound (21.7 mg, 46%) as a white solid. 1H-NMR (1:1 CDCl3/CD3OD; 400 MHz): δ 8.40 (d, 1H, J=8.6 Hz), 7.79 (s, 1H), 7.44 (m, 1H), 7.32 (br s, 1H), 5.81 (m, 1H), 3.48 (t, 2H, J=5.1 Hz), 3.27 (s, 3H), 2.60 (t, 2H, J=5.1 Hz), 2.35-2.45 (m, 2H), 2.28-2.35 (m, 2H), 2.09-2.15 (m, 2H), 1.87-1.98 (m, 2H), 1.68-1.78 (m, 2H), 1.61 (t, 2H, J=6.3 Hz), 1.34-1.60 (m, 4H), 1.12 (s, 6H). Mass spectrum (APCI-neg, m/z): Calcd. for C28H37N5O2, 474.3 (M−H). found 474.5.
Reaction SMILES: Cl.[F:2][C:3]([F:24])([F:23])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][NH:17][CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[CH:25]1([N:31]=[C:32]=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[F:24][C:3]([F:2])([F:23])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][N:17]([C:32]([NH:31][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:33])[CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1
Reactant: O=C=NC1CCCCC1
Reactant: FC(F)(F)c1ccccc1C(OC1CNC1)c1ccc(Cl)cc1
Agent: Cl
Product: O=C(NC1CCCCC1)N1CC(OC(c2ccc(Cl)cc2)c2ccccc2C(F)(F)F)C1

Procedure:
This material was prepared from 3-[2-(trifluoromethyl)-4′-chlorobenzhydryloxy]azetidine hydrochloride (98) (0.55 mmol) and cyclohexyl isocyanate (0.55 mmol) using the procedure described for compound (10) (146 mg, 59%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11]O)=[CH:5][CH:4]=1)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O>C(Cl)Cl>[Br:32][CH2:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1ccc(CCCO)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCc1ccc(CCCBr)cc1
Reaction time: 1 h
Yield: 83 %

Procedure:
Compound 39-2 (1.97 g) was dissolved in methylene chloride (40 ml), triphenylphosphine (3.50 g) and N-bromosuccinimide (2.35 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and at room temperature for 1 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (2.26 g) as a colorless oil.
Reaction SMILES: C([NH:8][C:9](=[O:29])[C:10]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])=[CH:14][C:13]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:12][CH:11]=1)C1C=CC=CC=1.S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>CS(O)(=O)=O>[N:23]1([C:13]2[CH:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[C:10]([C:9]([NH2:8])=[O:29])=[CH:11][N:12]=2)[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1
Reactant: Cc1ccccc1-c1cc(N2CCOCC2)ncc1C(=O)NCc1ccccc1
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Product: Cc1ccccc1-c1cc(N2CCOCC2)ncc1C(N)=O
Temperature: 25 °C
Reaction time: 22 h
Yield: 39.1 %

Procedure:
0.5 g (1.29 mMol) N-Benzyl-6-morpholin-4-yl-4-o-tolyl-nicotinamide was dissolved in 2.5 ml methanesulfonic acid and 0.25 ml sulfuric acid and heated to 100° C. for 1 hour. A second portion of 0.25 ml sulfuric acid was added and heating was pursued for 22 hours. After cooling to room temperature, the reaction mixture was poured onto 75 ml aqueous saturated sodium carbonate, cooled with ice and extracted with ethyl acetate. The combined organic extracts were washed with aqueous saturated sodium carbonate and brine, dried (Na2SO4) and concentrated. The residue was flash chromatographed (eluent: dichloromethane/methanol 95:5) to yield 0.15 g (39%) 6-morpholin-4-yl-4-o-tolyl-nicotinamide as a yellow resin.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[CH:16]([OH:19])[CH:17]=[CH2:18])=[C:6](F)[CH:5]=1>C1COCC1>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]2[C:10]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[CH:16]([CH:17]=[CH2:18])[O:19][C:6]=2[CH:5]=1
Reactant: C=CC(O)c1cnccc1-c1ccc(Cl)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC1Oc2cc(Cl)ccc2-c2ccncc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of NaH (0.182 g, 7.58 mmol) in THF (30 mL) was added 1-(4-(4-chloro-2-fluorophenyl)pyridin-3-yl)prop-2-en-1-ol (0.5 g, 1.896 mmol) dissolved in THF (5 mL) and the reaction mixture was stirred at room temperature for 2 h. The reaction was quenched by addition of saturated aqueous ammonium chloride solution (5 mL) and extracted with ethyl acetate (3×10 mL). The combined organic extracts were washed with brine (1×10 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude 8-chloro-5-vinyl-5H-chromeno[3,4-c]pyridine was used without purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH:26]=[O:27])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[O-:28][Mn](=O)(=O)=O.[K+].[OH-].[K+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[C:26]([OH:28])=[O:27])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(C=O)c[nH]c34)no2)cc1Cl
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(C(=O)O)c[nH]c34)no2)cc1Cl
Temperature: 55 °C
Reaction time: 8 h

Procedure:
To a solution of 7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indole-3-carbaldehyde (D71) (1.1 g) in THF (20 mL) was added KMnO4 (0.9 g) and aqueous KOH (10 mL). The reaction was stirred at 55° C. overnight. After cooled to room temperature, the mixture was diluted with THF (20 mL) and filtered. The filtrate was concentrated and the aqueous suspension was acidified with aqueous HCl (2 M) to pH 5-6. The resulting solid was collected by filtration, washed with water, dried in vacuo to give the crude compound, which was purified by column chromatography (20% ethyl acetate in hexane) to afford 7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indole-3-carboxylic acid as a white solid (D94) (1.0 g). δH (DMSO-d6, 400 MHz): 1.36 (6H, d), 4.90 (1H, m), 7.38 (1H, t), 7.46 (1H, d), 8.02 (2H, m), 8.22 (1H, dd), 8.30 (1H, dd), 8.41 (1H, d), 11.66 (1H, br s). MS (ES): C20H16ClN3O4 requires 397; found 398.1 (M+H+).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[CH:19]([S:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[F:27]>C(Cl)Cl.CCOCC>[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[CH:19]([S:28]([C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)=[O:9])[C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[F:27]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2ccncc2Cl)c1
Solvent: ClCCl
Solvent: CCOCC
Product: O=S(c1ccc(Cl)cc1)C(c1cc(F)ccc1F)c1ccncc1Cl
Reaction time: 3 h

Procedure:
After 3-chloroperbenzoic acid (33 mg, 0.20 mmol) was added to a solution of the 3-chloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine (75 mg, 0.20 mmol), which had been obtained in Example 341, in methylene chloride (10 ml), the mixture was stirred for 3 hours under ice cooling. The reaction mixture was diluted with ether (80 ml). The solution was washed with water and brine, and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=3:1), whereby the title compound (48 mg, 60%) was obtained as a diastereomeric mixture (1:1).
Reaction SMILES: [BH4-].[Na+].Cl[CH:4]([C:14]1[O:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[CH:18]=1)[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.COCCOCCOC.[OH-].[Na+]>CCCCCC>[N+:11]([C:8]1[CH:7]=[CH:6][C:5]([CH2:4][C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[CH:18]=2)=[CH:10][CH:9]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc(C(Cl)c2cc3ccccc3o2)cc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOCCOC
Solvent: CCCCCC
Product: O=[N+]([O-])c1ccc(Cc2cc3ccccc3o2)cc1

Procedure:
A mixture of 13.6 g. (0.36 mol.) of sodium borohydride and 14.4 g. (0.05 mol.) of 2-(α-chloro-4'-nitrobenzyl)benzofuran in 200 ml. of 80% aqueous diglyme is stirred at 50° for four hours. The reaction mixture is then cooled and hexane followed by 4.0 g. (0.1 mol.) of sodium hydroxide are added. The layers are separated and the organic phase is dried (MgSO4) and concentrated to give 2-(4'-nitrobenzyl)benzofuran.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:30])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](F)(F)F)=[CH:21][CH:20]=3)=[CH:14][C:13]=2[Cl:29])=[O:11])[CH:9]=1)=[N+:2]=[N-:3].NC1C=CC(C)=C(C(C2C=CC(NC3C=CC([Cl:53])=CC=3C)=CC=2Cl)=O)C=1>>[N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:30])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([Cl:53])=[CH:25][C:24]=3[CH3:23])=[CH:14][C:13]=2[Cl:29])=[O:11])[CH:9]=1)=[N+:2]=[N-:3]
Reactant: Cc1ccc(N=[N+]=[N-])cc1C(=O)c1ccc(Nc2ccc(C(F)(F)F)cc2)cc1Cl
Reactant: Cc1cc(Cl)ccc1Nc1ccc(C(=O)c2cc(N)ccc2C)c(Cl)c1
Product: Cc1cc(Cl)ccc1Nc1ccc(C(=O)c2cc(N=[N+]=[N-])ccc2C)c(Cl)c1

Procedure:
The reaction was carried out similarly as described in the preparation of compound 416, using compound 444 (0.09 mmol). The crude product was used without any further purification.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.[CH2:10]([NH2:13])[CH:11]=[CH2:12]>C1COCC1>[CH2:10]([NH:13][C:3](=[O:5])[C:2]([F:1])([F:8])[F:9])[CH:11]=[CH2:12]
Reactant: CCOC(=O)C(F)(F)F
Reactant: C=CCN
Solvent: C1CCOC1
Product: C=CCNC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.92 h

Procedure:
To an ice-cold solution of ethyl trifluoroacetate (15 mL, 142.2 mmol) in THF (40 mL) was added allylamine (12 mL, 57.1 mmol). The reaction was allowed to warm to room temperature then stirred for 55 min. After the mixture was concentrated under reduced pressure, the residue was dried under vacuum to give acetamide 30. Yield (18.79 g, 98%): 1H NMR (400 MHz, CDCl3) δ 6.46 (br s, 1H), 5.79-5.89 (m, 1H), 5.23-5.29 (m, 2H), 3.98 (t, J=5.6 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:8]([CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])[S:9]([C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[O:25][CH:26]=[CH:27][N:28]=4)=[CH:20][C:19]=3[CH2:29]O)=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])=[N:4][O:5][C:6]=1[CH3:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:57]>CN(C=O)C.O>[Br:57][CH2:29][C:19]1[CH:20]=[C:21]([C:24]2[O:25][CH:26]=[CH:27][N:28]=2)[CH:22]=[CH:23][C:18]=1[C:13]1[C:12]([S:9]([N:8]([C:3]2[C:2]([CH3:1])=[C:6]([CH3:7])[O:5][N:4]=2)[CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])(=[O:11])=[O:10])=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrC(Br)(Br)Br
Reactant: COCCOCN(c1noc(C)c1C)S(=O)(=O)c1ccccc1-c1ccc(-c2ncco2)cc1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: COCCOCN(c1noc(C)c1C)S(=O)(=O)c1ccccc1-c1ccc(-c2ncco2)cc1CBr
Reaction time: 5 h
Yield: 68.6 %

Procedure:
To a solution of the title compound of step E (0.37 g, 072 mmol) in 5 mL of DMF at 5° C., triphenylphosphine (0.283 g, 1.08 mmol) and carbon tetrabromide (0.358 g, 1.08 mmol) were added and the mixture stirred for 5 hours. The solution was then diluted with 100 mL of water and the aqueous solution was extracted with 3×100 mL of EtOAc. The combined organic extracts were then washed once with water and dried and evaporated. The residue thus obtained was chromatographed on 20 g of silica gel using 2:1 hexane:EtOAc to afford 0.285 g (69%) of the title compound of this step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]([CH3:20])([CH3:19])[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:21]([O:23][CH3:24])=[O:22])[CH:15]=3)[NH:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(N(CC)C(C)C)(C)C.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>ClCCl>[C:34]([NH:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]([CH3:19])([CH3:20])[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:21]([O:23][CH3:24])=[O:22])[CH:15]=3)[NH:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(N)cc(Cl)c1)N2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(Cl)cc(NC(=O)c3ccccc3)c1)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.9 %

Procedure:
To a solution of methyl 2-(3-amino-5-chlorophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (100 mg, 0.29 mmol) and N,N-diisopropylethylamine (75 mg, 0.58 mmol) in dichloro methane (4 mL) was added benzoyl chloride (49 mg, 0.35 mmol) slowly via syringe under nitrogen. The mixture was stirred at room temperature for 1 h. Solid precipitated and was collected by filtration to afford 65 mg of methyl 2-(3-benzamido-5-chlorophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a white solid. Yield: 50%; MS (ESI+APCI) M+1-water=431.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:5]([N:15]=1)=[N:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][C:9]=2[CH3:10].[H-].[Na+].[Br:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[CH2:29]Br.C(OC(C)C)(C)C>CN(C)C=O>[Br:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[CH2:29][N:15]1[C:5]2=[N:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][C:9]([CH3:10])=[C:4]2[N:3]=[C:2]1[CH3:1]
Reactant: COC(=O)c1cc(C)c2[nH]c(C)nc2n1
Reactant: BrCc1ccc2ccccc2c1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)OC(C)C
Product: COC(=O)c1cc(C)c2nc(C)n(Cc3ccc4ccccc4c3Br)c2n1
Reaction time: 0.5 h
Yield: 104.5 %

Procedure:
To a suspension of methyl 2,7-dimethyl-1H-imidazo[4,5-b]pyridine-5-carboxylate (625 mg) in N,N-dimethylformamide (6 ml) was added sodium hydride (70% in mineral oil, 125 mg) under ice-cooling, and the mixture was stirred for 30 min. 1-Bromonaphthalen-2-ylmethyl bromide (1.05 g) was added to the reaction mixture, and the mixture was stirred under ice-cooling for 3 hr. Diisopropyl ether (12 ml) was added to the reaction mixture and the precipitate was collected by filtration to give the objective compound (1.35 g) as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6](=[O:8])[CH3:7].[CH3:14][Mg]Cl>C1COCC1>[Br:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([CH3:14])([OH:8])[CH3:7]
Reactant: CC(=O)COc1ccc(F)cc1Br
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)(O)COc1ccc(F)cc1Br
Temperature: 0 °C
Yield: 41.6 %

Procedure:
Cool a solution of 1-(2-bromo-4-fluoro-phenoxy)-propan-2-one (520 mg, 2.10 mmol) in THF (4 mL) to 0° C. in an ice bath under nitrogen. Add methylmagnesium chloride (3.0 M in THF, 0.84 mL, 2.53 mmol) dropwise. Stir the mixture at 0° C. for an additional half an hour. Add water and extract with ethyl acetate. Wash the solution with aqueous saturated sodium chloride. Dry over sodium sulfate. Concentrate the solution in vacuo. Purify by column chromatography (hexane to 30% ethyl acetate in hexane) to give the title compound as a yellow oil (230 mg, 42%). MS (ES) m/z 285 [M+Na]+.