Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[CH3:9][N:10]1[C:18]2[CH2:17][CH2:16][CH2:15][C:14](=[O:19])[C:13]=2[CH:12]=[CH:11]1.CC(C)([O-])C.[K+].Cl>CC(O)(C)C>[CH3:9][N:10]1[C:18]2[CH:17]=[CH:16][C:15]([CH2:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[C:14]([OH:19])[C:13]=2[CH:12]=[CH:11]1
Reactant: Cn1ccc2c1CCCC2=O
Reactant: O=Cc1cccnc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Product: Cn1ccc2c(O)c(Cc3cccnc3)ccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 74 %

Procedure:
500 cm3 of 2-methyl-2-propanol, 75 g of pyridine-3-carboxaldehyde and 100 g of 1-methyl-1,5,6,7-tetrahydroindol-4-one were introduced into a 1-liter reactor equipped with a mechanical stirrer and surmounted by a condenser and a thermometer. After 10 minutes of stirring, 157 g of potassium tert-butoxide were added in small portions over 15 minutes. Following addition, the temperature was held at 75° C. for 1 hour. The reaction mixture was allowed to return to room temperature and then was neutralized (pH=6) with 20% hydrochloric acid. It was poured into 2 kg of ice-water. The precipitate obtained was filtered off with suction and washed with diisopropyl ether and with petroleum ether. It was dried over potash under vacuum at 30° C. This gave 120 g of 1-methyl-5-pyridin-3-ylmethyl-1H-indol-4-ol with a yield of 74%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:10][C:11]([CH3:13])=O>C(O)C>[CH3:13][C:11]1[CH:10]=[CH:8][C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[N:1]=1
Reactant: CC(C)=O
Reactant: Nc1ncccc1C=O
Solvent: CCO
Product: Cc1ccc2cccnc2n1
Temperature: 25 °C
Yield: 70.2 %

Procedure:
The compound was prepared according to the procedure as described by E. M. Hawes and D. G. Wibberley, J. Chem. Soc. (C), 1966, 315. To a solution of 2-amino-3-pyridinecarboxaldehyde (2 g, 16 mmol) in ethanol 3 ml) was added acetone (1.9 g, 32 mmol) and peperidine (0,34 g, 4 mmol) and the reaction mixture was refluxed 24 hours. Reaction mixture was cooled to room temperature then concentrated in vacuum. Ether was added to concentrated residue. Solid was filtered and dried to give 1.62 g (69%) yellow solid. NMR (CD3OD) δ 2.76 (s, 3H), 7.52-7.58 (m, 2H), 8.30 (d, 2H, J=8.33 Hz), 8.36-8.39 (m, 1H), 8.39-8.99 (m, 1H).
Reaction SMILES: Cl.[CH2:2]1[C:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[S:10][C:6]=2[CH2:5][CH2:4][NH:3]1.Cl[CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24].C([O-])([O-])=O.[Na+].[Na+]>CC(C)CC(=O)C>[CH2:2]1[C:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[S:10][C:6]=2[CH2:5][CH2:4][N:3]1[CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: c1ccc2c3c(sc2c1)CCNC3
Reactant: CC(C)(C)OC(=O)NCCCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: CC(C)(C)OC(=O)NCCCCN1CCc2sc3ccccc3c2C1
Temperature: 25 °C

Procedure:
A mixture of 1,2,3,4-tetrahydro[1]benzothieno[3,2-c]pyridine HCl (1:1) (0.02 mol), 1,1-dimethylethyl (4chlorobutyl)carbamate (0.044 mol), Na2CO3 (0.05 mol) and KI (catalytic quantity) in 4-methyl-2-pentanone (200 ml) was stirred and refluxed overnight, then cooled to room temperature and the solvent was evaporated. The residue was washed with water and extracted with CH2Cl2. The separated organic layer was dried, filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 90/10). The desired fractions were collected and the solvent was evaporated, yielding 1,1-dimethylethyl [4-(3,4-dihydro[1]benzothieno[3,2-c]pyridine-2(1H)-yl)butyl]carbamate (interim.1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15].[C:31]1([CH:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[C:27]([O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][N:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:40]1[CH2:41][CH2:42][CH:37]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:38][CH2:39]1)[CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)NCCN(CCCCCCBr)Cc1ccccc1OC(C)(C)C
Reactant: c1ccc(C2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCN(CCCCCCN1CCC(c2ccccc2)CC1)Cc1ccccc1OC(C)(C)C
Temperature: 25 °C
Yield: 73 %

Procedure:
The compound 15 (1.9 g, 4.46 mmol), 4-phenylpiperidine (1.128 g, 6.99 mmol) and K2CO3 (0.64 g, 4.66 mmol) were added to 50 mL CH3CN, and the solution was refluxed under argon atmosphere for 16 h. After cooling to room temperature, the solvent was evaporated to dryness. Purification was carried out on a silica gel TLC plate that was developed in 3% methanolic NH3 (7 M NH3 in methanol)/97% CH2Cl2. The product was obtained as pale yellow oil (73%). 1H NMR (CDCl3) δ 7.382 (d, 1H, Ar), 7.289 (m, 2H, Ar), 7.229 (m, 2H, Ar), 7.186 (m, 1H, Ar), 7.136 (m, 1H, Ar), 7.013 (m, 2H, Ar), 3.587 (s, 2H, —CH2—), 3.160 (m, 2H, —CH2—), 3.071 (d, 2H, —CH2—), 2.519 (overlapping m, 2H, —CH2—), 2.496 (overlapping m, 1H, —CH—), 2.419 (t, 2H, —CH2—), 2.355 (m, 2H, —CH2—), 2.045 (m, 2H, —CH2—), 1.837 (m, 4H, —CH2—CH2—), 1.525 (m, 2H, —CH2—), 1.472 (m, 2H, —CH2—), 1.437 (s, 9H, —C(CH3)3), 1.426 (s, 9H, —C(CH3)3), 1.280 (m, 4H, —CH2—CH2—). Mass Spec=566.43 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH:19]=O)[CH:13]=1)[CH:8]1[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH:22]1([NH2:25])[CH2:24][CH2:23]1.[BH4-].[Na+]>CO>[C:1]([O:5][C:6](=[O:21])[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH2:19][NH:25][CH:22]2[CH2:24][CH2:23]2)[CH:13]=1)[CH:8]1[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(Cl)c(C=O)c1)C1CC1
Reactant: NC1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N(Cc1ccc(Cl)c(CNC2CC2)c1)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.7 %

Procedure:
A mixture of (4-chloro-3-formyl-benzyl)-cyclopropyl-carbamic acid tert-butyl ester (563 mg, 1.82 mmol) and cyclopropylamine (0.195 mL, 2.73 mmol) in MeOH (18 mL) was heated to reflux for 4 h. The mixture was allowed to cool to rt, and NaBH4 (103 mg, 2.73 mmol) was added in portions. The mixture was stirred for 1 h, and the solvents were removed under reduced pressure. The resulting oil was diluted with EtOAc (100 mL), and the resulting mixture was washed with aq. sat. NaHCO3 and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (CH2Cl2/MeOH 95:5) yielded the title compound (343 mg, 54%). LC-MS: tR=0.78 min; ES+: 351.39.
Reaction SMILES: [ClH:1].C([O:9][C:10]1[CH:33]=[CH:32][C:13]([O:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][C:20]([OH:31])([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)[CH2:19][CH2:18]2)=[CH:12][CH:11]=1)C1C=CC=CC=1.[H][H].CCOCC>CO.[OH-].[OH-].[Pd+2]>[ClH:1].[OH:9][C:10]1[CH:11]=[CH:12][C:13]([O:14][CH2:15][CH2:16][N:17]2[CH2:18][CH2:19][C:20]([OH:31])([CH2:23][C:24]3[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=3)[CH2:21][CH2:22]2)=[CH:32][CH:33]=1
Reactant: [H][H]
Reactant: Cc1ccc(CC2(O)CCN(CCOc3ccc(OCc4ccccc4)cc3)CC2)cc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Product: Cc1ccc(CC2(O)CCN(CCOc3ccc(O)cc3)CC2)cc1
Reaction time: 8 h
Yield: 99.9 %

Procedure:
1-[2-(4-Hydroxyphenoxy)ethyl]-1-hydroxy-4-(4-methylbenzyl)piperidine hydrochloride. To a solution of 1-[2-(4-benzyloxyphenoxy)ethyl]-4-hydroxy-4-(4-methylbenzyl)piperidine hydrochloride (0.25 g, 0.53 mmol) in 30 mL of methanol was added 62.5 mg of 20% Pd(OH)2. The resulting mixture was hydrogenated at 20 psi of hydrogen for 3 h. The catalyst was removed through a short column of celite (5 g) and washed with methanol (3×15 mL). Methanol was evaporated in vacuo to give a residue, to which 50 mL of ether was added. The resulting mixture was stirred overnight. A white solid was collected by filtration and dried in vacuo, giving 200 mg (100%) of the title product: mp 133-135° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([NH2:11])=[S:10])=[N:6][CH:7]=1.[Br:12][CH2:13][C:14]([CH2:16]Br)=O.O>CN(C=O)C>[Br:12][CH2:13][C:14]1[N:11]=[C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)[S:10][CH:16]=1
Reactant: O=C(CBr)CBr
Reactant: NC(=S)Nc1ccc(Br)cn1
Solvent: CN(C)C=O
Solvent: O
Product: BrCc1csc(Nc2ccc(Br)cn2)n1
Temperature: 70 °C
Reaction time: 2 h
Yield: 16 %

Procedure:
(5-Bromo-pyridine-2-yl)-thiourea (2.5 mmol) is dissolved in DMF (5 ml) and 1,3-dibromacetone (1 eq.) is added and stirred 2 h at 70° C. After cooling to RT, the reaction solution is poured into water and the resulting precipitate is filtered, washed with water and dried 16 h in vacuo at 40° C. After column chromatography (ethyl acetate/methanol) (4-bromomethyl-thiazole-2-yl)-(5-bromo-pyridine-2-yl)-amine is obtained as a colourless powder with a yield of 16%. HPLC (method C): 1.92 min; LC-MS (method A): 1.977 min, 347.95 (M+H+); 1H-NMR (DMSO-d6, 300 MHz): δ [ppm] 11.583 (s, 1H), 8.391 (d, 1H, J=2.4 Hz), 7.902 (dd, 1H, J=2.4 Hz, J=8.9 Hz), 7.119 (s, 1H), 7.023 (d, 1H, J=8.9 Hz), 4.622 (s, 2H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]([O:17][C@@H:18]([C:23]([O:36][CH3:37])([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19]([O:21]C)=[O:20])[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>CO.O>[CH2:1]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]([O:17][C@@H:18]([C:23]([O:36][CH3:37])([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:19]([OH:21])=[O:20])[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H](Oc1nc(C)cc(COCc2ccccc2)n1)C(OC)(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(c1ccccc1)(c1ccccc1)[C@H](Oc1nc(C)cc(COCc2ccccc2)n1)C(=O)O
Temperature: 25 °C
Yield: 87.9 %

Procedure:
To a solution of the compound of Example 13 (1.17 g, 2.34 mmol) in methanol (20 mL) is added a solution of potassium hydroxide (0.987 g, 23.4 mmol) in water (10 mL) and the reaction stirred at reflux for 5 hr. The reaction is cooled to room temperature and the methanol removed under reduced pressure on a rotary evaporator. The aqueous residue is washed with ethyl acetate (2×25 mL) and then the pH is adjusted to 2-3 with 2N HCl. The aqueous phase is extracted with ether (2×50 mL) to yield the title compound (0.997 g, 88%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH:13]1[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(N(CC)C(C)C)(C)C>CS(C)=O>[F:9][C:8]([F:11])([F:10])[C:4]1[N:3]=[C:2]([N:15]2[CH2:16][CH2:17][NH:12][CH:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14]2)[CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)C1CNCCN1
Reactant: FC(F)(F)c1cccc(Br)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCOC(=O)C1CN(c2cccc(C(F)(F)F)n2)CCN1
Temperature: 80 °C
Reaction time: 96 h

Procedure:
2-Bromo-6-(trifluoromethyl)pyridine (13.56 g, 60 mmol) and ethyl piperazine-2-carboxylate (U.S. Patent App. Publ. US2004/0147559, 9.49 g, 60.0 mmol) were mixed in dry dimethyl sulfoxide (40 mL) and then treated with N,N-diisopropylethylamine (31.1 mL, 180 mmol). The mixture was heated to 80° C. and stirred for 4 days. The solution was concentrated, and the residue was purified on a silica gel column (hexane:ethyl acetate=1:3) to give the title compound. 1H NMR (300 MHz, methanol-d4) δ ppm 1.27 (t, 3H, J=7 Hz), 2.83 (ddd, 1H, J=12, 9, 3 Hz), 3.11 (ddd, 1H, J=12, 5, 3 Hz), 3.33-3.38 (m, 1 H), 3.41-3.50 (m, 1 H), 3.56-3.62 (m, 1 H), 3.81 (ddd, 1H, J=13, 4, 3 Hz), 4.15-4.25 (m, 3 H), 7.00 (t, 2H, J=8 Hz), 7.65-7.75 (m, 1 H); MS (DCI) m/z 304 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=1[CH2:17][C:18]([CH3:22])([CH3:21])[C:19]#[N:20].[CH:23]1([CH:26]([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([CH2:39]O)[CH:34]=2)[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:25][CH2:24]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[C:19]([C:18]([CH3:22])([CH3:21])[CH2:17][C:11]1[CH:12]=[C:13]([O:16][CH2:39][C:35]2[CH:34]=[C:33]([CH:26]([CH:23]3[CH2:24][CH2:25]3)[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:38]=[CH:37][N:36]=2)[CH:14]=[CH:15][C:10]=1[C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[F:1])#[N:20]
Reactant: CCOC(=O)CC(c1ccnc(CO)c1)C1CC1
Reactant: COc1ccc(F)c(-c2ccc(O)cc2CC(C)(C)C#N)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCOC(=O)CC(c1ccnc(COc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C#N)c2)c1)C1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.4 %

Procedure:
To a solution of 3-(2′-fluoro-4-hydroxy-5′-methoxybiphenyl-2-yl)-2,2-dimethylpropanenitrile (151 mg), ethyl 3-cyclopropyl-3-(2-(hydroxymethyl)pyridin-4-yl)propanoate (168 mg) and tributylphosphine (0.25 mL) in toluene (5.0 mL) was added 1,1′-(azodicarbonyl)dipiperidine (256 mg), and the mixture was stirred at room temperature for 3 hr. Hexane was added to the reaction mixture, and the mixture was filtered through celite. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (234 mg) as a colorless oil.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:8]([CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:9])=[CH:19][CH:18]=1
Reactant: Fc1ccccc1
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(Cc1ccccc1)c1ccc(F)cc1
Temperature: 0 °C

Procedure:
28.4 g of phenylacetyl chloride was dissolved in 130 ml of fluorobenzene and cooled in ice. This solution was added to 27.0 g of freshly powdered aluminum chloride with continued cooling and stirring. After the vigorous reaction subsided, the mixture was stirred at room temperature overnight and then poured onto 150 g of ice containing 50 ml of concentrated hydrochloric acid. Extraction gave a pale brown solid. Recrystallization from petroleum ether gave 4-fluorodeoxybenzoin, 2A, as a white solid, mp: 80°-81° C.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([C:11](=[O:14])[C:12]=1I)=[CH:9][C:8]([F:15])=[CH:7][CH:6]=2)[CH3:2].[F:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[C:21]([F:23])[CH:22]=1.C([O-])([O-])=O.[Na+].[Na+]>C(#N)C.O.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>[F:16][C:17]1[CH:18]=[C:19]([C:12]2[C:11](=[O:14])[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([F:15])[CH:9]=3)[NH:4][C:3]=2[CH2:1][CH3:2])[CH:20]=[C:21]([F:23])[CH:22]=1
Reactant: CCc1[nH]c2ccc(F)cc2c(=O)c1I
Reactant: OB(O)c1cc(F)cc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCc1[nH]c2ccc(F)cc2c(=O)c1-c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred mixture of 2-ethyl-6-fluoroquinolin-4(1H)-one (4.00 g, 21 mmol), I2 (10.62 g, 2.0 eq) and Na2CO3 (3.33 g, 1.5 eq) in THF (100 mL) was stirred at rt overnight. To the reaction mixture was added Na2S2O3 solution, after 2 min the resulted mixture was filtered, washed with water and dried in the air to give a white solid as 2-ethyl-6-fluoro-3-iodoquinolin-4(1H)-one. Mass Spectrum (ESI) m/e=318 (M+1). A mixture of 2-ethyl-6-fluoro-3-iodoquinolin-4(1H)-one (400 mg, 1.3 mmol), 3,5-difluorophenylboronic acid (398 mg, 2.0 eq), Na2CO3 (401 mg, 3.0 eq) and tetrakis(triphenylphosphine)palladium(0) (73 mg, 0.05 eq) in acetonitrile/water (15 mL/5 mL) was purged with N2 and heated to reflux. After overnight, the reaction mixture was cooled at rt, partitioned between water and EtOAc. The layers were separated and the aq layer was extracted with EtOAc (10 mL×2). The combined organic layers were washed with water (10 mL×2), brine (10 mL), dried over Na2SO4, filtered, and concd under reduced pressure. The residue was purified by combiflash on silica gel (EtOAc/DCM, 1:2) to give 3-(3,5-difluorophenyl)-2-ethyl-6-fluoroquinolin-4(1H)-one as a white solid. Mass Spectrum (ESI) m/e=304 (M+1).
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[CH3:7][C:8]1([CH3:49])[N:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][S:22]([CH2:24][CH2:25][CH2:26][C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])=[O:23])[C:11](=[O:34])[N:10]([C:35]2[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[C:37]([C:44]([F:47])([F:46])[F:45])[CH:36]=2)[C:9]1=[O:48].O>C1COCC1>[CH3:7][C:8]1([CH3:49])[N:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][S:22]([CH2:24][CH2:25][CH2:26][C:27]([F:32])([F:33])[C:28]([F:31])([F:30])[F:29])(=[O:1])=[O:23])[C:11](=[O:34])[N:10]([C:35]2[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[C:37]([C:44]([F:46])([F:47])[F:45])[CH:36]=2)[C:9]1=[O:48]
Reactant: O=S([O-])OO
Reactant: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCCCCCCS(=O)(=O)CCCC(F)(F)C(F)(F)F
Temperature: 23 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
Oxone® (566 mg, 0.93 mmole) is added to a solution of the compound of Example 2 (200 mg, 0.31 mmole) in THF (6 ml). The reaction mixture is completed with water (3 ml) and stirred at 23° C. for 3 h 30, the time necessary for the total conversion of the starting product. The mixture is then poured into water (25 ml) and extracted with AcOEt (2×25 ml). After decantation, the organic phases are combined and washed with salt water (20 ml), dried over Na2SO4, filtered and concentrated to dryness under vacuum. The evaporation residue is purified on a silica column (eluent: Heptane/AcOEt: 1/1 to 3/7). The expected compound is obtained in the form of a colourless oil with a yield of 89% (185 mg).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:24])[C@H:4]([CH3:23])[N:5](C(OC(C)(C)C)=O)[C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][NH:2][C:3](=[O:24])[C@H:4]([CH3:23])[NH:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1
Reactant: CNC(=O)[C@H](C)N(C(=O)OC(C)(C)C)c1ccc2ccccc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)[C@H](C)Nc1ccc2ccccc2c1
Reaction time: 48 h

Procedure:
A solution of Intermediate 5 (12.46 g) in dichloromethane (124 ml) at 0° C. was treated dropwise with neat trifluoroacetic acid (120 ml). The resulting pale yellow solution was allowed to reach room temperature over 48 h. The solvent was subsequently removed and the crude product dissolved in the minimum volume of 1N hydrochloric acid at 0° C. The aqueous phase was extracted with dichloromethane to remove any impurities. The aqueous phase was then taken to pH 8.5, initially using solid sodium bicarbonate and then a few drops of 3N sodium hydroxide. A white precipitate formed which was filtered, and the residue washed with water and dried in vacuo (7.2 g 83%). TLC Rf 0.10 (EtOAc).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[C:11]([NH2:16])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[NH2:8].[CH3:17][N:18]([CH3:36])[C:19]1[CH:35]=[CH:34][C:22]([C:23]([NH:25][C:26]2[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=2)=[O:24])=[CH:21][CH:20]=1>>[NH:8]1[C:7]2[CH:6]=[CH:5][C:4]([C:9]3[CH:15]=[CH:14][C:12]4[N:13]=[C:30]([C:29]5[CH:32]=[CH:33][C:26]([NH:25][C:23](=[O:24])[C:22]6[CH:34]=[CH:35][C:19]([N:18]([CH3:36])[CH3:17])=[CH:20][CH:21]=6)=[CH:27][CH:28]=5)[NH:16][C:11]=4[CH:10]=3)=[CH:3][C:2]=2[N:1]=[C:30]1[C:29]1[CH:28]=[CH:27][C:26]([NH:25][C:23](=[O:24])[C:22]2[CH:34]=[CH:35][C:19]([N:18]([CH3:36])[CH3:17])=[CH:20][CH:21]=2)=[CH:33][CH:32]=1
Reactant: Nc1ccc(-c2ccc(N)c(N)c2)cc1N
Reactant: CN(C)c1ccc(C(=O)Nc2ccc(C=O)cc2)cc1
Product: CN(C)c1ccc(C(=O)Nc2ccc(-c3nc4cc(-c5ccc6nc(-c7ccc(NC(=O)c8ccc(N(C)C)cc8)cc7)[nH]c6c5)ccc4[nH]3)cc2)cc1

Procedure:
Compound 265 was prepared according to the procedure similar to that described in Scheme III from 3,3′-diaminobenzidine and 4-(4-dimethylaminobenzamido)benzaldehyde. [M+H]+ calcd for C44H38N8O2: 711.31; found: 711.38.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@H:4]1[CH2:8][C@@H:7]([OH:9])[CH2:6][N:5]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].[CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:1][O:2][C:3](=[O:20])[C@H:4]1[CH2:8][C@H:7]([O:9][C:23]2[CH:22]=[CH:21][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)[CH2:6][N:5]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: COC(=O)[C@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Reactant: Oc1ccc2ccccc2c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H]1C[C@H](Oc2ccc3ccccc3c2)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 212.2 %

Procedure:
A solution of 15.0 g (53.7 mmol) of N-Cbz-cis-4-hydroxy-D-proline methyl ester, 11.3 g (78.4 mmol) of β-naphthol, and 20.5 g (78.2 mmol) of triphenylphosphine in 300 mL of THF was treated with 12.3 mL (78.1 mmol) of diethyl azidodicarboxylate over 0.5 hour. The reaction was stirred at room temperature for 18 hours and was quenched by the addition of 100 mL sat'd aq NaCl. The two layers were separated and the organic solution dried (Na2SO4). Evaporation of the solvent gave 46.2 g of an oil which was purified by flash chromatography (SiO2 ; gradient of 25 percent to 50 percent EtOAc in hexanes) to afford 15.2 g (37.5 mmol; 70 percent) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([N:17]2[CH2:22][CH2:21][C@:20]([CH2:30][CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[O:19][C:18]2=[O:40])[CH3:16])=[CH:11][CH:10]=1.[H-].[Na+].I[CH3:44]>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([N:17]2[CH2:22][CH2:21][C@:20]([CH2:30][CH2:31][N:32]([CH3:44])[C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:38])[CH3:37])([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[O:19][C:18]2=[O:40])[CH3:16])=[CH:11][CH:10]=1
Reactant: CI
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCNC(=O)OC(C)(C)C)(c2ccc(F)cc2)OC1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCN(C)C(=O)OC(C)(C)C)(c2ccc(F)cc2)OC1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.3 %

Procedure:
To a solution of tert-butyl 2-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethylcarbamate (53 mg, 0.1 mmol) in tetrahydrofuran was added NaH (300 mg, 12.5 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h. Then iodomethane (1.3 g, 9.15 mmol) was added to the above mixture and the mixture was stirred for 2 h. The reaction was quenched with H2O and extracted with EtOAc to give the organic layer which was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated to give tert-butyl 2-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl(methyl)carbamate (36 mg, 66%).