Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].II.Br[CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1.[CH:13]12[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[C:14]1=[O:23])[CH2:20]2.Cl>C1COCC1>[CH2:6]([C:7]1[CH:8]=[C:9]([C:14]2([OH:23])[CH:15]3[CH2:21][CH:19]4[CH2:18][CH:17]([CH2:22][CH:13]2[CH2:20]4)[CH2:16]3)[CH:10]=[CH:11][CH:12]=1)[CH3:5]
Reactant: O=C1C2CC3CC(C2)CC1C3
Reactant: BrCCc1ccccc1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CCc1cccc(C2(O)C3CC4CC(C3)CC2C4)c1
Temperature: 25 °C
Yield: 91.8 %

Procedure:
A stirring mixture of magnesium turnings (0.89 g, 36.6 mmol) and iodine (catalytic) in dry THF (60 mL) was treated with 3-bromoethylbenzene (5 mL, 36.6 mmol), refluxed for 3 h, cooled to room temperature, treated with a solution of 2-adamantanone (5.0 g, 33.3 mmol) in dry THF (20 mL) and refluxed for 2 h. The mixture was cooled to room temperature, treated with 3-M HCl (20 mL), extracted with EtOAc (2×20 mL), the combined extracts were washed with water (10 mL), dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2; heptane-EtOAc (9:1)] to give the product (7.84 g, 92 %) as a white solid: mp 63-65° C.; IR νmax (Nujol)/cm−1 3442, 3281, 2921, 2855, 1604, 1451, 1101, 1043, 1009, 803 and 708; NMR δH (400 MHz, CDCl3) 1.23 (3H, t, J 7.5 Hz), 1.61-1.70 (9H, m), 1.89 (1H, s), 2.38-2.41 (2H, m), 2.56 (2H, s), 2.65 (2H, q, J 7.5 Hz), 3.46 (1H, s), 7.11 (1H, d, J 7.5 Hz) and 7.24-7.36 (3H, m); Anal. Calcd for C18H24O: C, 84.32; H, 9.43. Found: C, 84.24; H, 9.28.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:10])=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].C([O-])([O-])=O.[Na+].[Na+].Br[CH2:18][C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20]>CN(C=O)C.O>[NH2:1][C:2]1[C:3]([F:10])=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[O:9][CH2:18][C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20]
Reactant: CC(C)OC(=O)CBr
Reactant: Nc1c(F)ccc(O)c1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)OC(=O)COc1ccc(F)c(N)c1F
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 70.6 %

Procedure:
To a stirred solution of 3-amino-2,4-difluoro-phenol (intermediate X(a)) (713 mg, 4.91 mmol, 1.0 eq) in DMF (20 mL) was added Na2CO3 (1.56 g, 14.8 mmol, 3.0 eq). The resulting mixture was stirred at room temperature for 35 min, then isopropyl bromoacetate (1.07 g, 5.90 mmol, 1.2 eq) was added and the reaction stirred at room temperature overnight. The reaction was diluted with water then extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by chromatography (EtOAc:petroleum ether, 0:1 to 1:6) to give the title compound (intermediate IV(b)) as an oil (850 mg, 71%).
Reaction SMILES: [CH2:1]1[O:21][C:4](O)([C:5]2[CH:10]=[CH:9][C:8]([C:11]([N:13]3[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]3)=[O:12])=[CH:7][CH:6]=2)[O:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[OH:41].Cl>CN(C=O)C>[CH2:1]1[O:21][C:4]([NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[OH:41])([C:5]2[CH:6]=[CH:7][C:8]([C:11]([N:13]3[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]3)=[O:12])=[CH:9][CH:10]=2)[O:3][CH2:2]1
Reactant: Nc1ccccc1O
Reactant: O=C1CCN(C(=O)c2ccc(C3(O)OCCO3)cc2)CC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C1CCN(C(=O)c2ccc(C3(Nc4ccccc4O)OCCO3)cc2)CC1
Reaction time: 0.5 h

Procedure:
A solution of 4-(4-oxopiperidinocarbonyl)benzoic acid ethylene ketal (291 mg, 1 mmol) in DMF (3 ml) was treated with 1,1'-carbonyldiimidazole (162 mg, 1 mmol) and stirred for 30 min. 2-Aminophenol (109 mg, 1 mmol) was added and stirring continued for 22 h. The mixture was acidified with dilute HCl, extracted with ethyl acetate, washed with brine, dried over sodium sulphate and concentrated under vacuum. The residue was purified by flash column chromatography on silica, eluting with ethyl acetate, to furnish a clear glass, MS (+CI) 383 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:19])=[CH:4][C:5]([N+:16]([O-:18])=[O:17])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11](Cl)[N:10]=2)[CH:7]=1.[OH-].[NH4+:21].[NH4+]>CC(O)C>[Br:1][C:2]1[C:3]([F:19])=[CH:4][C:5]([N+:16]([O-:18])=[O:17])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH2:21])[N:10]=2)[CH:7]=1
Reactant: O=[N+]([O-])c1cc(F)c(Br)cc1Nc1ccnc(Cl)n1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CC(C)O
Product: Nc1nccc(Nc2cc(Br)c(F)cc2[N+](=O)[O-])n1
Temperature: 90 °C
Reaction time: 15 h
Yield: 72 %

Procedure:
To a solution of N-(5-bromo-4-fluoro-2-nitrophenyl)-2-chloropyrimidin-4-amine (1.05 g, 3.02 mmol) in 2-propanol (12 mL) in a pressure vessel was added ammonium hydroxide (12 mL, 303 mmol) carefully at RT. The reaction vessel was sealed and stirred at 90° C. for 15 hr (4 bar). Extra aqueous ammonium (4 mL, 100 mmol) was added and the reaction heated at 90° C. for 1 hr then cooled to 0° C. The resultant orange precipitate was filtered and dried by suction filtration to afford the title compound as an orange solid (713 mg, 63% yield); 1H NMR (500 MHz, DMSO) delta 9.55 (s, 1H), 8.44 (d, J=6.6 Hz, 1H), 8.17 (d, J=8.6 Hz, 1H), 7.98 (d, J=5.6 Hz, 1H), 6.31 (s, 2H), 6.19 (d, J=5.6 Hz, 1H); LC-MS: m/z+329.80 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[C:6]([CH3:11])=[N:7][NH:8][C:9]=1[CH3:10].Cl[CH2:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][OH:20])=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[C:9]([CH3:10])=[N:8][N:7]([CH2:14][C:15]2[CH:22]=[CH:21][C:18]([CH2:19][OH:20])=[CH:17][CH:16]=2)[C:6]=1[CH3:11]
Reactant: OCc1ccc(CCl)cc1
Reactant: COC(=O)Cc1c(C)n[nH]c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Cc1c(C)nn(Cc2ccc(CO)cc2)c1C

Procedure:
(3,5-dimethyl-1H-pyrazol-4-yl)-acetic acid methyl ester (3 g, 18 mmol), 4-(chloromethyl)benzyl alcohol (3.59 g, 18 mmol) and K2CO3 (5.18 g, 37 mmol) were refluxed in 10 ml acetonitrile for 3 h. After cooling, the mixture was filtered, and the solvent was removed under reduced pressure. The residue was purified by MPLC (silica gel, CH2Cl2/methanol 9:1).
Reaction SMILES: CN(C)C=O.[Br:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]([Br:16])[C:8]=1OS(C(F)(F)F)(=O)=O.[I-:25].[Na+]>O>[Br:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]([Br:16])[C:8]=1[I:25]
Reactant: O=[N+]([O-])c1cc(Br)c(OS(=O)(=O)C(F)(F)F)c(Br)c1
Reactant: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Br)c(I)c(Br)c1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 82.8 %

Procedure:
Dimethylformamide (4 L) and trifluoromethane sulfonic acid 2,6-dibromo-4-nitrophenyl ester (1135 g, 2.65 moles) were charged into a 22 L jacketed vessel equipped with a mechanical stirrer, a condenser, and a nitrogen purge. Sodium iodide (1595 g, 10.64 moles) was added to the reaction mixture in portions while maintaining the reaction temperature below 25° C. The reaction mixture was then heated to 100° C. and monitored for completion by HPLC. Upon completion, the reaction mixture was cooled to 0° C. Water (4 L) was added while maintaining the temperature below 14° C. The reaction mixture was stirred for 30 min, then filtered and washed with water (1.5 L). The resultant solid product was dried overnight by evaporation under air flow at room temperature to yield 1,3-dibromo-2-iodo-5-nitrobenzene (892.7 g, 82.9%). The product may optionally be purified further by recrystallization from ethanol.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:14]([O:16]C)=[O:15])=[N:5][O:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].[OH-].[Na+].C(O)(=O)C>CO>[CH2:1]([C:3]1[C:4]([C:14]([OH:16])=[O:15])=[N:5][O:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2]
Reactant: CCc1c(C(=O)OC)noc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CCc1c(C(=O)O)noc1-c1ccccc1
Reaction time: 0.33 h
Yield: 81.2 %

Procedure:
A solution of methyl 4-ethyl-5-phenylisoxazole-3-carboxylate (194 mg, 0.839 mmol) and 1N aqueous sodium hydroxide (1.26 mL, 1.258 mmol) in methanol (3 mL) was heated to 100° C. for 10 minutes under microwave. The reaction mixture was acidified with acetic acid until the pH was about 4. The mixture was concentrated, and the residue was suspended in water (2 mL) and stirred for 20 minutes. The solid was collected by vacuum filtration and dried to give 4-ethyl-5-phenylisoxazole-3-carboxylic acid (148 mg). The compound had an HPLC ret. time=2.93 min.−Column: YMC S5 COMBISCREEN® 4.6×50 mm; Gradient time: 4 min; Flow rate=4 ml/min; Solvent A=10% MeOH−90% Water−0.2% H3PO; Solvent B=90% MeOH−10% water−0.2% H3PO4; Start % B=0; Final % B=100. LC-MS: M+1=218+.
Reaction SMILES: [CH2:1]([S:4]([C:6]1[N:10]=[CH:9][NH:8][N:7]=1)=[O:5])[CH2:2][CH3:3].[CH2:11]([N:13]([CH2:17][CH3:18])[C:14](Cl)=[O:15])[CH3:12].O1CCCC1>C(N(CC)CC)C>[CH2:11]([N:13]([CH2:17][CH3:18])[C:14]([N:8]1[CH:9]=[N:10][C:6]([S:4]([CH2:1][CH2:2][CH3:3])=[O:5])=[N:7]1)=[O:15])[CH3:12]
Reactant: CCCS(=O)c1nc[nH]n1
Reactant: CCN(CC)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCS(=O)c1ncn(C(=O)N(CC)CC)n1

Procedure:
A mixture of 4.8 g. 3-propylsulphinyl-1,2,4-triazole, 4.48 g. diethylcarbamoyl chloride, 40 ml. dry tetrahydrofuran and 6 ml. dry triethylamine was refluxed under anhydrous conditions for 5 hours. The cooled reaction mixture was filtered to remove triethylamine hydrochloride. The filtrate was diluted with petroleum ether (b.p. 40° - 60° C.), causing the deposition of an oil which gradually solidified. The solid product was collected and recrystallized from a mixture of ether and petroleum ether (b.p. 40° - 60° C.) to give 1-diethylcarbamoyl-3-propylsulphinyl-1,2,4-triazole, m.p. 50.5° - 51.5° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:6]=1[N+:15]([O-])=O.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C1(C)C=CC=CC=1.[Pd]>[CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:6]=1[NH:15][C:19](=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)Cc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: Cc1ccccc1
Product: COC(=O)Cc1ccc(C(F)(F)F)cc1NC(C)=O
Temperature: 25 °C
Yield: 94.9 %

Procedure:
Hydrogenation and acetylation of (2-nitro-4-trifluoromethylphenyl)-acetic acid methyl ester (25 g, 0.095 mol) in the presence of 5% Pd—C (2.5 g, 50% wet) and acetic anhydride (38 g, 0.37 mol) in toluene (200 mL) was carried out under vigorous stirring at room temperature and atmospheric pressure for about 4-5 h (reaction monitored by TLC). The catalyst was removed by filtration and washed with toluene two times. The combined organics were evaporated in vacuo to yield the product (24.8 g, 95%), which was used without further purification in the next step. A small sample was crystallized from hexane to yield the product as a yellow solid, mp 92-94° C. 1H NMR (CDCl3) 8.86 (s, 1H), 8.21 (s, 1H), 7.36 (d, J=8.1 Hz, 1H), 7.31 (d, J=8.1 Hz, 1H), 3.74 (s, 3H), 3.68 (s, 2H), 2.23 (s, 3H).
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.Cl.[OH:14][C:15]1[C:22]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:21][C:18]([CH:19]=O)=[CH:17][C:16]=1[C:27]([CH3:30])([CH3:29])[CH3:28]>C(O)C>[OH:14][C:15]1[C:22]([C:23]([CH3:25])([CH3:24])[CH3:26])=[CH:21][C:18]([CH:19]=[N:1][N:2]2[CH:6]=[CH:5][N:4]=[C:3]2[N:7]2[CH2:8][CH2:9][O:10][CH2:11][CH2:12]2)=[CH:17][C:16]=1[C:27]([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: Nn1ccnc1N1CCOCC1
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1cc(C=Nn2ccnc2N2CCOCC2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.18 g of 1-amino-2-morpholinoimidazole are dissolved in 50 ml of ethanol and treated with 3.5 ml of 2N hydrochloric acid. After the addition of 1.65 g of 4-hydroxy-3,5-di-tert.-butylbenzaldehyde, the reaction mixture is stirred at room temperature overnight. The solvent is subsequently removed by evaporation in a vacuum. The residue is treated with 20 ml of water and saturated sodium carbonate solution is added up to an alkaline reaction. The separated, colorless product is removed by filtration and purified by column chromatography (eluent methylene chloride/methanol 10%). By recrystallization from water/methanol, there is obtained pure 1-(4-hydroxy-3,5-di-tert.-butylbenzylideneamino)-2-morpholinoimidazole of m.p. 185°-187°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:14])[C:10]=1[O:11][CH2:12][CH3:13])[C:5]([OH:7])=O.[NH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([Cl:26])[CH:17]=1>>[Cl:14][C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([Cl:1])[C:10]=1[O:11][CH2:12][CH3:13])[C:5]([NH:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([Cl:26])[CH:17]=1)=[O:7]
Reactant: COC(=O)c1ccc(N)cc1Cl
Reactant: CCOc1c(Cl)cc(C(=O)O)cc1Cl
Product: CCOc1c(Cl)cc(C(=O)Nc2ccc(C(=O)OC)c(Cl)c2)cc1Cl
Yield: 39 %

Procedure:
Methyl 4-(3,5-dichloro-4-ethoxybenzamido)-2-chlorobenzoate (AAA-017) (175 mg, 39%) was prepared in essentially the same manner as in Step (iii) for AAA-001, except that 3,5-dichloro-4-ethoxybenzoic acid was used instead of 3,5-dichloro-4-(cyclopentyloxy)benzoic acid and methyl 4-amino-2-chlorobenzoate was used instead of methyl 4-aminobenzoate: m/z 402 (M−H)− (ES−). 1H NMR (400 MHz, CDCl3) δ: 7.93 (2H, d), 7.85 (1H, s), 7.83 (1H, d), 7.80 (2H, s), 4.18 (2H, q), 3.93 (3H, s), 1.49 (3H, t).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:11][C:12]([OH:14])=O.[Cl-].[Al+3].[Cl-].[Cl-]>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[CH2:9][CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:11][C:12]2=[O:14]
Reactant: COc1ccccc1CC(CC(=O)O)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COc1cccc2c1CC(c1ccccc1)CC2=O
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 36.1 %

Procedure:
4-(2'-Methoxyphenyl)-3-phenylbutyric acid (29.1 g, 108 mmol), from Step 5, was dissolved in 50 mL of thionyl chloride and heated to 60° C. for 10 min. After stirring an additional 30 min at ambient temperature, the solvent was removed in vacuo. The crude product was dissolved in 60 mL of methylene chloride and the resultant solution was added dropwise to 15.8 g (118 mmol) of aluminum chloride in 240 mL of methylene chloride precooled to 0° C. After the addition, the reaction was allowed to proceed at 0° C. for 1 h, and then quenched by the addition of 500 g of ice. The methylene chloride layer was separated and washed with 3×200 mL of water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 9.84 g (36% yield) of 5-methoxy-3-phenyl-1,2,3,4-tetrahydro-1-naphthalenone as a clear yellow oil; 1H NMR (CDCl3 )δ2.48 (dd, 1H), 2.65-2.8 (m, 2H), 3.20 (dd, 1H), 3.7-3.85 (m, 1H), 3.82 (s, 3H), 6.85-6.95 (m, 2H), 7.08 (dd, 1H), 7.2-7.3 (m, 1H), 7.35-7.4 (m, 2H), 7.57 (dt, 1H), 7.73 (d, 1H); DCl MS M/Z: 270 (M+NH4)+, 253 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:15])[C:11](OC)=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH3:16]>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:15])[C:11]([NH2:16])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: COC(=O)C(C)c1ccc([N+](=O)[O-])cc1
Reactant: N
Product: CC(C(N)=O)c1ccc([N+](=O)[O-])cc1

Procedure:
A solution of methyl 2-(4-nitrophenyl)propionate (20.0 g) in aqueous ammonia (d=0.88, 350 ml) was stirred at room temperature for 36 h. The resultant solid was collected and dried in vacuo at 50° to give the title compound (13.4 g). A sample (0.1 g) was crystallised from water to give analytically pure material m.p. 120°-121°.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.ClCl.[CH3:13]O>>[CH3:13][O:9][C:8]([C:5]1[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][N:6]=1)=[O:10]
Reactant: CO
Reactant: Cc1cnc(C(=O)O)cn1
Agent: ClCl
Product: COC(=O)c1cnc(C)cn1
Reaction time: 4 h

Procedure:
Commercially available 5-methylpyrazine 2-carboxylic acid (2.05 g) was dissolved in methanol (0.6 ml) and chlorine gas was blown into the solution for 5 minutes. After four hours, the reaction solution was concentrated and 1 mol/l aqueous solution of sodium hydroxide was added, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The resulting solid was recrystallized from hexane/ethyl acetate. The deposited crystals were collected by filtration and dried under reduced pressure to obtain the title compound (1.44 g) as light brown scale-like crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([CH:10]=O)=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([CH3:24])([CH3:23])[NH2:22])=[CH:15][CH:14]=1>>[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([NH:22][CH2:10][CH:8]([OH:9])[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)([CH3:23])[CH3:24])=[CH:15][CH:14]=1
Reactant: Cc1ccc(CCC(C)(C)N)cc1
Reactant: O=CC(=O)c1cccc(Cl)c1
Product: Cc1ccc(CCC(C)(C)NCC(O)c2cccc(Cl)c2)cc1

Procedure:
The title compound was prepared in the manner described in Example 9 using 3-chlorophenylglyoxal and 3-(4-methylphenyl)-1,1-dimethylpropanamine. The chromatographed material was recrystallized from cyclohexane to give the title compound m.p. 136. τ(CDCL3 +d6DMSO) 8.9 (6H, s), 8.2-8.4 (2H, m), 7.7 (3H, s), 7.0-7.6 (4H, m), 5.35 (1H, dd), 2.9 (4H, s), 2.5-2.7 (5H, m).
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C@@H:3]([NH:5][CH2:6][CH2:7][C@:8]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)([NH2:12])[CH2:9][CH:10]=[CH2:11])[CH3:4].C(N(CC)CC)C.Cl[C:30](Cl)([O:32]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH2:9]([C@:8]1([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:7][CH2:6][N:5]([C@H:3]([C:2]([CH3:20])([CH3:1])[CH3:21])[CH3:4])[C:30](=[O:32])[NH:12]1)[CH:10]=[CH2:11]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C=CC[C@@](N)(CCN[C@@H](C)C(C)(C)C)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)C(C)(C)C)C(=O)N1
Reaction time: 2 h
Yield: 131.6 %

Procedure:
To a solution of (R)—N1—((S)-3,3-dimethylbutan-2-yl)-3-(4-fluorophenyl)hex-5-ene-1,3-diamine (600 mg, 2.05 mmol) and triethylamine (1.04 g, 10.25 mmol) in CH2Cl2 (10 mL) was added triphosgene (203 mg, 0.68 mmol) at 0° C., and the mixture was stirred for 2 h. The reaction was quenched with water, and the mixture was extracted with CH2Cl2. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by preparative TLC to afford (R)-4-allyl-1-((S)-3,3-dimethylbutan-2-yl)-4-(4-fluorophenyl)tetrahydropyrimidin-2(1H)-one (285 mg, 44%). 1H NMR (CDCl3): 0.72 (s, 9H), 1.01 (d, 3H), 1.79 (m, 1H), 2.06 (m, 1H), 2.34 (m, 1H), 2.56 (m, 1H), 2.73 (m, 1H), 3.03 (m, 1H), 4.49 (m, 1H), 4.92 (5, 1H), 5.04-5.13 (m, 2H), 5.26 (m, 1H), 6.95-6.99 (m, 2H), 7.22-7.25 (m, 2H).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([C:21](=O)[NH:22][CH3:23])[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:7])([CH3:4])[CH3:3].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:26].C([O-])(O)=O.[Na+]>C1COCC1>[CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([C:21]([NH:22][CH3:23])=[S:26])[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:7])([CH3:4])[CH3:3]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CNC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CNC(=S)[C@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 125 %

Procedure:
Phenylmethyl N2-{[(1,1-dimethylethyl)oxy]carbonyl}-N1-methyl-L-α-asparaginate (4.20 g, 12.48 mmol) and phosphorus pentasulfide (3.33 g, 7.49 mmol) were dissolved in THF (105 mL) and the reagents were stirred at room temperature for 4 h. Saturated NaHCO3 was added and the reaction was extracted with EtOAc. The organic layer was concentrated and the residue was dissolved in CH2Cl2:Et2O (1:1) and filtered through a well packed silica gel column to give the titled product (3.3 g, 75%) as a white solid. 1H-NMR (CDCl3) δ: 1.461 (9H, s), 2.960 (1H, m), 3.149 (3H, d, J=5.2 Hz), 3.270 (1H, m), 4.820 (1H, s), 5.137 (2H, m), 5.770 (1H, s), 7.374 (5H, m), 8.380 (1H, s). LC-MS (ES) m/e 353.6 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:8][C:9]2([OH:17])[CH2:14][CH2:13][CH2:12][C:11]([CH3:16])([CH3:15])[CH2:10]2)[C:6]=1[CH3:7].[H-].[Na+].I[CH3:21]>CN(C)C=O.CCOCC>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:8][C:9]2([O:17][CH3:21])[CH2:14][CH2:13][CH2:12][C:11]([CH3:15])([CH3:16])[CH2:10]2)[C:6]=1[CH3:7]
Reactant: Cc1c(Br)cnn1CC1(O)CCCC(C)(C)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC1(Cn2ncc(Br)c2C)CCCC(C)(C)C1
Reaction time: 0.17 h

Procedure:
A solution of EXAMPLE 157B (0.62 g) was dissolved in N,N-dimethylformamide (10 mL) and treated with NaH (0.062 g, 60% in mineral oil). After 10 minutes, iodomethane (0.16 mL) was added. After 1 hour, additional sodium hydride (0.5 eq.) and iodomethane (0.5 eq.) were added and stirring was continued at room temperature for 3 hours. The reaction was diluted with ether (75 mL) and washed with water (50 mL) and brine (50 mL), dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with a gradient of 1.5% to 15% ethyl acetate/hexanes provided the title compound.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[Cl:15][C:16]1[CH:17]=[C:18]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([NH:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:31])=[N:28][CH:29]=2)[CH:19]=[C:20]([CH:22]=O)[CH:21]=1.[F:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]2[CH:52]=[CH:51][C:50]([NH2:53])=[CH:49][CH:48]=2)=[CH:43][CH:42]=1.CC(O)=O>ClCCCl>[Cl:15][C:16]1[CH:17]=[C:18]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([NH:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:31])=[N:28][CH:29]=2)[CH:19]=[C:20]([CH2:22][NH:53][C:50]2[CH:49]=[CH:48][C:47]([C:44]3[CH:45]=[CH:46][C:41]([F:40])=[CH:42][CH:43]=3)=[CH:52][CH:51]=2)[CH:21]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(Cl)cc(C=O)c2)cn1
Reactant: Nc1ccc(-c2ccc(F)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(Cl)cc(CNc3ccc(-c4ccc(F)cc4)cc3)c2)cn1
Temperature: 50 °C

Procedure:
Solid NaBH(OAc)3 (106 mg, 0.50 mmol) was added to a DCE solution (10 mL) of ethyl 3-(5-(3-chloro-5-formylphenyl)picolinamido)propanoate (90 mg, 0.25 mmol), 4′-fluoro-[1,1′-biphenyl]-4-amine (47 g, 0.25 mmol), and AcOH (0.06 mL, 1.00 mmol) and the resulting mixture was heated to 50° C. After 16 h the mixture was concentrated and purified via column chromatography to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11](O)=[S:12])=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.[CH3:21][NH:22][O:23][CH3:24].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:24][O:23][N:22]([CH3:21])[C:11]([C:6]1[NH:7][C:8]2[C:4]([C:5]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)=[S:12]
Reactant: OC(=S)c1[nH]c2ccc(Cl)cc2c1-c1ccccc1
Reactant: CNOC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON(C)C(=S)c1[nH]c2ccc(Cl)cc2c1-c1ccccc1

Procedure:
The title compound was prepared from 5-chloro-3-phenylthioindole-2-carboxylic acid (1.0 g, 3.30 mmol)) N,O-dimethylhydroxylamine hydrochloride (0.64 g, 6.6 mmol), triethylamine (1.0 mL, 7 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorphosphate (1.64 g, 3.6 mmol) in dimethylformamide according to the general procedure described in Example 1 for the preparation of N-(3-pyridylmethyl)-5-chloro-3-phenylthio-2-carboxamide.