Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[C@H:11]([CH2:12][CH3:13])[CH2:10][C@H:9]([NH:14][C:15]2[N:20]=[CH:19][C:18]([Br:21])=[CH:17][N:16]=2)[C@@H:8]1[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:6])([CH3:3])[CH3:2].[H-].[Na+].[Cl:31][C:32]1[CH:33]=[C:34]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[CH2:35]Br>CN(C=O)C>[CH:1]([O:4][C:5]([N:7]1[C@H:11]([CH2:12][CH3:13])[CH2:10][C@H:9]([N:14]([C:15]2[N:20]=[CH:19][C:18]([Br:21])=[CH:17][N:16]=2)[CH2:35][C:34]2[CH:37]=[C:38]([C:40]([F:41])([F:42])[F:43])[CH:39]=[C:32]([Cl:31])[CH:33]=2)[C@@H:8]1[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:6])([CH3:2])[CH3:3]
Reactant: FC(F)(F)c1cc(Cl)cc(CBr)c1
Reactant: CC[C@@H]1C[C@H](Nc2ncc(Br)cn2)[C@H](Cc2ccccc2)N1C(=O)OC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@@H]1C[C@H](N(Cc2cc(Cl)cc(C(F)(F)F)c2)c2ncc(Br)cn2)[C@H](Cc2ccccc2)N1C(=O)OC(C)C
Reaction time: 3.5 h
Yield: 73.2 %

Procedure:
To a suspension of (2S,3S,5R)-2-benzyl-3-(5-bromo-pyrimidin-2-ylamino)-5-ethyl-pyrrolidine-1-carboxylic acid isopropyl ester (0.064 mmol; 28.6 mg) and sodium hydride (60% dispersion in mineral oil, 0.19 mmol; 7.6 mg) in DMF (0.6 mL) is added 3-chloro-5-trifluoromethylbenzyl bromide (0.13 mmol; 35.6 mg) at room temperature under N2. After 3.5 hours, additional sodium hydride (60% dispersion in mineral oil, 0.19 mmol; 7.6 mg) is added to the suspension. The reaction mixture is stirred for 20 minutes, and quenched with water and saturated aqueous ammonium chloride solution. The product is extracted three times with EtOAc. The combined organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent: n-hexane/EtOAc) to give (2S,3S,5R)-2-Benzyl-3-[(5-bromo-pyrimidin-2-yl)-(3-chloro-5-trifluoromethyl-benzyl)-amino]-5-ethyl-pyrrolidine-1-carboxylic acid isopropyl ester (30.0 mg, 73%); ESI-MS m/z: 639 [M+1]+, Retention time 2.68 min (condition A).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:12]1[CH:17]=[CH:18][C:19]1[N:20]([CH3:24])[CH:21]=[CH:22][N:23]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27].O>C(OCC)(=O)C.CN(C)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:13][C@H:12]1[CH:17]=[CH:18][C:19]1[N:20]([CH3:24])[CH:21]=[CH:22][N:23]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cn1ccnc1C=C[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Agent: CN(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1ccnc1C=C[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccccc1

Procedure:
To a solution of (2S,4R)-1-benzyloxycarbonyl-4-hydroxy-2-[2-(1-methylimidazol-2-yl)vinyl]pyrrolidine (5.45 g) in a mixture of ethyl acetate (60 ml) and trimethylamine (3.01 ml) was added dropwise methanesulfonyl chloride (1.42 ml) under ice-cooling with stirring and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture were added ethyl acetate (100 ml) and water (50 ml). The organic layer was washed successively with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (150 g) eluting with a mixture of dichloromethane and methanol (19:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4R)-1-benzyloxycarbonyl-4-methanesulfonyloxy-2-[2-(1-methylimidazol-2-yl)vinyl]pyrrolidine (5.70 g).
Reaction SMILES: Br[C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][C:9]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.[C:25]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26].P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C)C=O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[C:25]([C:29]1[CH:34]=[CH:33][C:32]([C:2]2[C:15]3[C:16]4=[C:17]5[C:12](=[CH:13][CH:14]=3)[CH:11]=[CH:10][C:9]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)=[C:8]5[CH:7]=[CH:6][C:5]4=[CH:4][CH:3]=2)=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: Clc1ccc(-c2ccc3ccc4c(Br)ccc5ccc2c3c54)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(-c2ccc3ccc4c(-c5ccc(Cl)cc5)ccc5ccc2c3c54)cc1
Temperature: 130 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
A mixed solution of 4.0 g of 1-bromo-6-(4-chlorophenyl)pyrene, 2.0 g of 4-t-butylphenylboronic acid, 4.8 g of tripotassium phosphate, 0.72 g of tetrabutylammonium bromide, 52 mg of palladium acetate and 100 ml of dimethylformamide was heated and stirred under a nitrogen gas stream at 130° C. for 3 hours. The solution was cooled to room temperature and 100 ml of water was poured into the solution, followed by filtration. The resulting solid was dissolved at 140° C. by adding 100 ml of xylene. The solution was cooled to 100° C. and then filtered through Celite. The filtrate was evaporated, and then the resulting solid was washed with 50 ml of methanol and vacuum-dried to obtain 3.0 g of 1-(4-t-butylphenyl)-6-(4-chlorophenyl)pyrene.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].[C:11]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])[CH3:12].[Cl:19][C:20]1[N:25]=[C:24]([NH:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[C:23]([CH:33]=[O:34])=[CH:22][CH:21]=1.O>C1COCC1.C(OCC)(=O)C.[Cl-].[Na+].O>[C:15]([O:14][C:11](=[O:13])[CH2:12][CH:33]([C:23]1[C:24]([NH:26][C:27](=[O:32])[C:28]([CH3:30])([CH3:29])[CH3:31])=[N:25][C:20]([Cl:19])=[CH:21][CH:22]=1)[OH:34])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)C(=O)Nc1nc(Cl)ccc1C=O
Reactant: CC(=O)OC(C)(C)C
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Cl-]
Agent: [Li]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(O)c1ccc(Cl)nc1NC(=O)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
A first intermediate compound, 7-Chloro-1H-[1,8]naphthyridin-2-one, was produced as follows: To a stirred solution of lithium hexamethyldisilazane (26.3 mmol, 1.0 M in THF) in THF (10 mL) at −78° C. is added t-butyl acetate (3.53 mL, 26.3 mmol) dropwise. The mixture is stirred at −78° C. for 30 min and N-(6-chloro-3-formyl-pyridin-2-yl)-2,2-dimethyl-propionamide (3.00 g, 12.5 mmol) in THF (20 mL) is added dropwise. A yellow precipitate forms and the mixture is stirred at −78° C. for 30 minutes and warmed to room temperature over 3 hours. H2O (10 mL) is added, the mixture stirred for 5 minutes and then diluted with ethyl acetate (20 mL) and brine (10 mL). The organic layer is separated, washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under vacuum. The compound is recrystallized from ethyl acetate and hexanes to yield 3-[6-chloro-2-(2,2-dimethyl-propionylamino)-pyridin-3-yl]-3-hydroxy-propionic acid tert-butyl ester (3.52 g, 79%); mp 130–132° C., 1H NMR (400 MHz, CDCl3) δ 8.25 (br s, 1H), 7.76 (d, 1H), 7.16 (d, 1H), 5.05–4.98 (m, 1H), 4.08 (d, 1H), 2.80 (dd, 1H), 2.70 (dd, 1H), 1.41 (s, 9H), 1.36 (s, 9H); MS ES+ 357.03 (M+H)+.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]([C:21]#[CH:22])([O:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[N+:18]([O-])=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].CO.[ClH:25].C(=O)([O-])[O-].[Na+].[Na+]>O.[Fe]>[ClH:25].[C:1]([N:4]1[CH2:9][CH2:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[NH2:18])([C:21]#[CH:22])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: C#CC1(Oc2ccc(F)cc2[N+](=O)[O-])CCN(C(C)=O)CC1
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: O
Product: C#CC1(Oc2ccc(F)cc2N)CCN(C(C)=O)CC1
Reaction time: 1 h
Yield: 17.7 %

Procedure:
To a stirred solution of 3.14 g of 1-acetyl-4-ethynyl-4-(4-fluoro-2-nitrophenoxy)piperidine and 42 ml of methanol was added a solution of 3 ml of concentrated hydrochloric acid in 12 ml water. To the stirred mixture in a water bath was added 6.1 g of iron (powdered electrolytic) The mixture was stirred for 1 hr, poured into ice, made basic by the addition of sodium carbonate solution, extracted twice with methylene chloride and washed with saturated sodium chloride solution. The mixture was dried over anhydrous potassium carbonate, filtered and the solvent evaporated to provide an oil. The oil was purified on a Waters Prep 500 High Pressure Liquid Chromatograph instrument, using a silica gel column and eluting with 2% methanol/dichloromethane. The appropriate fractions were evaporated and the residue was treated with ethereal hydrogen chloride to provide 0.57 g (17.7%) of product, mp 206°-208°, after recrystallization from ethanol/methanol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:6][CH:7]=1.CS[C:16]1[C:20]2[S:21][CH:22]=[CH:23][C:19]=2[S:18](=[O:25])(=[O:24])[N:17]=1>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:16]2[C:20]3[S:21][CH:22]=[CH:23][C:19]=3[S:18](=[O:25])(=[O:24])[N:17]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(Br)cnc1CCCCN
Reactant: CSC1=NS(=O)(=O)c2ccsc21
Solvent: CCO
Product: Cc1cc(Br)cnc1CCCCNC1=NS(=O)(=O)c2ccsc21
Reaction time: 4 h

Procedure:
A mixture of 0.514 g (0.0021 mole) of 4-(5-bromo-3-methyl-2-pyridinyl)butylamine and 0.463 g (0.0021 mole) of 3-(methylthio)thieno[2,3-d]isothiazole 1,1-dioxide in 35 ml of ethanol was heated under reflux with stirring for 4 hours. The reaction solution was cooled in ice giving a crystalline product which amounted to 0.71 g, m.p. 191°-193° C.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C@H:6]([CH2:11][OH:12])[CH2:7][CH:8]([CH3:10])[CH3:9])=[O:4].[H-].[Na+].O>O1CCCC1>[CH3:9][CH:8]([CH3:10])[CH2:7][C@@H:6]1[NH:5][C:3](=[O:4])[CH2:2][O:12][CH2:11]1
Reactant: CC(C)C[C@@H](CO)NC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C[C@H]1COCC(=O)N1
Reaction time: 14 h

Procedure:
(S)-2-Chloro-N-[1-(hydroxymethyl)-3-methylbutyl]acetamide, 26.34 g (0.136 mol), is dissolved in 450 ml of tetrahydrofuran, the solution is cooled to 0°-5° C. and 7.8 g (0.195 mol) of 60% sodium hydride in mineral oil dispersion is slowly added. The mixture is allowed to reach room temperature and is stirred for 14 hours. Water, 10 ml, is added, the solvents evaporated in vacuo and the residue suspended in 250 ml of chloroform and washed with 100 ml of water and then a saturated aqueous solution of sodium chloride, 2×200 ml. The chloroform layer is separated, dried over sodium sulfate, and evaporated in vacuo. The residue is purified by chromatography using silica gel and eluting with dichloromethane methanol (95:5) to give (S)-5-(2-methylpropyl)-3-morpholinone, 5.1 g, mp 69°-70°; [α]D25 -13.7° (c 1.11, methanol).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:15]=[CH:14][C:6](/[CH:7]=[CH:8]/[C:9](OCC)=[O:10])=[CH:5][CH:4]=1.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:15]=[CH:14][C:6](/[CH:7]=[CH:8]/[CH2:9][OH:10])=[CH:5][CH:4]=1
Reactant: CCOC(=O)/C=C/c1ccc(C(F)(F)F)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: OC/C=C/c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 94.9 %

Procedure:
In 15 ml of toluene were dissolved 3.00 g (12.3 mmol) of ethyl trans-4-(trifluoromethyl)cinnamate, and 16.4 ml (24.6 mmol) of a 1.5M diisobutyl aluminum hydride-toluene solution were added to the solution with stirring at 0° C. After 20 minutes, ice-water was added to the reaction mixture and the mixture was stirred for 10 minutes, followed by removal of the insolubles by filtration using Celite. The filtrate was extracted with ethyl acetate and, after drying, the solvent was distilled off to obtain a crystalline residue. The residue was recrystallized from a mixed solvent of benzene-hexane to obtain 2.36 g (yield: 96%) of the title compound having a melting point of 53 to 55° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[C:12]([CH3:18])=[N:13][N:14]([CH3:17])[C:15]=1[CH3:16])([O-])=O>C(OCC)(=O)C.[Pd]>[CH3:17][N:14]1[C:15]([CH3:16])=[C:11]([NH:10][C:5]2[C:4]([NH2:1])=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:12]([CH3:18])=[N:13]1
Reactant: Cc1nn(C)c(C)c1Nc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1nn(C)c(C)c1Nc1ccccc1N
Reaction time: 15 h
Yield: 99.9 %

Procedure:
To a solution of (2-Nitro-phenyl)-(1,3,5-trimethyl-1H-pyrazol-4-yl)-amine (8.6 g, 35 mmol) in ethyl acetate (175 mL) was added 10% palladium on carbon (1 g). The solution was stirred under a hydrogen atmosphere (50 psi) for 15 h and subsequently filtered through a bed of celite, washed with ethyl acetate, and concentrated in vacuo to yield the title compound (7.56 g): 1HNMR (CDCl3, 300 MHz) δ 6.74 (m, 3H), 6.32 (d, 1H, J=1.9, 7.2), 4.6 (s, 1H), 3.75 (s, 3H), 3.1 (s, 2H), 2.05 (m, 6H); low resolution MS(FAB) m/z 217 (MH+).
Reaction SMILES: C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36](=[O:50])[CH:37]([NH:43][C:44](=O)[C:45]([F:48])([F:47])[F:46])[C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:32][CH:31]=1>C(Cl)Cl>[F:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]2[O:50][C:44]([C:45]([F:46])([F:47])[F:48])=[N:43][C:37]=2[C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:34][CH:35]=1
Reactant: CCOC(=O)C(NC(=O)C(F)(F)F)C(=O)c1ccc(F)cc1
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc(C(F)(F)F)oc1-c1ccc(F)cc1
Reaction time: 0.08 h
Yield: 0.9 %

Procedure:
Triethylamine (64 mL, 0.46 mmol)) was added to a solution of triphenylphosphine (60 mg, 0.23 mmol) and iodine (58 mg, 0.23 mmol) in dry DCM (0.5 mL) and stirred for 5 min. Then a solution of ethyl 3-(4-fluorophenyl)-3-oxo-2-(2,2,2-trifluoroacetamido)propanoate (37 mg, 12 mmol) in dry DCM (0.7 mL) was added and the reaction mixture was stirred for 1 hr. The solvent was removed under reduced pressure, and the residue was purified by SiO2 chromatography on silica gel (isocratic DCM) to yield a white solid (31 mg, 88% yield). 1HNMR (400 MHz, CDCl3): d 8.12 (m, 2H), 7.18 (t, 2H, J=8.8 Hz), 4.43 (q, 2H, J=7.2 Hz), 1.39 (t, 3H, J=7.2 Hz). 19FNMR (400 MHz, CDCl3): d −66.10, −107.21. MS (ESI): m/z MS (ESI): m/z 303.9 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1.[CH3:12][O:13][P:14]([CH2:18][C:19](O)=[O:20])([O:16][CH3:17])=[O:15].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH3:12][O:13][P:14]([CH2:18][C:19]([NH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1)=[O:20])([O:16][CH3:17])=[O:15]
Reactant: COP(=O)(CC(=O)O)OC
Reactant: COC(=O)c1cc(N)ccn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COC(=O)c1cc(NC(=O)CP(=O)(OC)OC)ccn1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 1.0 g of methyl 4-aminopicolinate, 1.0 g of α-(dimethylphosphono)-acetic acid and 1.0 g of dicyclohexylcarbodiimide in 10 ml of methylene chloride is stirred at room temperature for 6 hours. After filtration and removal of solvent the residue is chromatographed on silica gel with 5% methanol/methylene chloride as the eluent to afford methyl 4-(α-dimethylphosphonoacetamido)-picolinate as a viscous oil.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[N:14]=[C:13](/[CH:15]=[C:16]3/[C:17](=[O:22])[NH:18][C:19](=[O:21])[NH:20]/3)[CH:12]=[CH:11][N:10]=2)[CH2:5][CH2:4]1.[N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[CH:33]=O.C(N(C(C)C)CC)(C)C.[Na]>C(Cl)Cl.CS(C)=O>[N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[CH2:33][NH:1][CH2:2][CH:3]1[CH2:4][CH2:5][N:6]([C:9]2[N:14]=[C:13](/[CH:15]=[C:16]3/[C:17](=[O:22])[NH:18][C:19](=[O:21])[NH:20]/3)[CH:12]=[CH:11][N:10]=2)[CH2:7][CH2:8]1
Reactant: O=Cc1ccc2ccccc2n1
Reactant: NCC1CCN(c2nccc(/C=C3\NC(=O)NC3=O)n2)CC1
Agent: [Na]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1NC(=O)/C(=C/c2ccnc(N3CCC(CNCc4ccc5ccccc5n4)CC3)n2)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.9 %

Procedure:
A 2 dram round bottomed vial was charged with (Z)-5-((2-(4-(aminomethyl)piperidin-1-yl)pyrimidin-4-yl)methylene)imidazolidine-2,4-dione (17 mg, 0.056 mmol), quinoline-2-carbaldehyde (8.84 mg, 0.056 mmol, 1 equiv.), diisopropylethylamine (0.1 mL, 0.573 mmol, 10 equiv.), and DMSO (1 mL). The reaction mixture was shaken for 1 h at room temperature then treated with sodium triacetoxyhydroborate (23.83 mg, 0.112 mmol, 2 equiv.) and DCM (0.5 mL). The reaction mixture was shaken overnight. The sample was then filtered through a 0.45 micron syringe filter. The DMSO solution was purified using reverse phase HPLC (MS-triggered fraction collection) with an acetonitrile/water gradient and trifluoroacetic acid as the modifier. The pure fractions were then concentrated under reduced pressure (Genevac HT-4) to provide the desired product (3.2 mg, 24.9 mg theoretical, 12.8%). LC-MS m/z 444 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH:12]([CH3:14])[CH3:13])=[C:3]1[C:15]([NH:17][C@H:18]([C:22]([NH:24][CH:25]([C:34](=[O:44])[CH2:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[F:43])[CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])=[O:23])[CH:19]([CH3:21])[CH3:20])=[O:16].C(O)(C(F)(F)F)=O>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH:12]([CH3:14])[CH3:13])=[C:3]1[C:15]([NH:17][C@H:18]([C:22]([NH:24][CH:25]([C:34](=[O:44])[CH2:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[F:43])[CH2:26][C:27]([OH:29])=[O:28])=[O:23])[CH:19]([CH3:20])[CH3:21])=[O:16]
Reactant: CC(C)Cc1c(C(=O)N[C@H](C(=O)NC(CC(=O)OC(C)(C)C)C(=O)COc2ccccc2F)C(C)C)n(C)c2ccccc12
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Cc1c(C(=O)N[C@H](C(=O)NC(CC(=O)O)C(=O)COc2ccccc2F)C(C)C)n(C)c2ccccc12
Yield: 36.4 %

Procedure:
Treatment of N-[(1-methyl-3-isobutyl-indole-2-carbonyl)valinyl]-3-amino-4-oxo-5-(2-fluorophenyloxy)-pentanoic acid, tert-butyl ester (76 mg, 0.124 mmol) with TFA as described in Example 80 gave the titled product (25.0 mg, 36%) as a white powder. MS C30H36FN3O6, [M+Na]+ =554, [M−H]− =552. TLC (hexane/EtOAc, 50/50): Rf=0.21.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:15][CH3:16])=[CH:4][C:5]2[CH:9](O)[CH:8]([CH2:11][CH3:12])[S:7][C:6]=2[C:13]=1[Cl:14].B(F)(F)F.CCOCC.[OH-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[C:3]([O:15][CH3:16])=[CH:4][C:5]2[CH:9]=[C:8]([CH2:11][CH3:12])[S:7][C:6]=2[C:13]=1[Cl:14]
Reactant: CCC1Sc2c(cc(OC)c(Cl)c2Cl)C1O
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCc1cc2cc(OC)c(Cl)c(Cl)c2s1
Reaction time: 1 h
Yield: 95 %

Procedure:
A mixture of 2.7 g of 6,7-dichloro-2-ethyl-2,3-dihydro-3-hydroxy-5-methoxy-benzo[b]thiophene in 10 ml of glacial acetic acid containing 3 ml of boron trifluoride etherate is warmed on a steam bath until a clear solution is formed. The mixture is allowed to stand at room temperature for 1 hour and poured into a chilled solution of dilute sodium hydroxide. Extraction with ether, followed by drying over anhydrous magnesium hydroxide and concentrating in vacuo, gives 2.4 g 6,7-dichloro-2-ethyl-5-methoxybenzo[b]thiophene as yellow needles, mp 73°-74.5°.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][S:11][C:5]=2[N:4]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:3]1=[O:16].[N+:17]([C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1)([O-:19])=[O:18]>>[OH:25][CH:24]([C:23]1[CH:22]=[CH:21][C:20]([N+:17]([O-:19])=[O:18])=[CH:27][CH:26]=1)[C:10]1[S:11][C:5]2[N:4]([CH2:12][CH:13]([CH3:14])[CH3:15])[C:3](=[O:16])[N:2]([CH3:1])[C:7](=[O:8])[C:6]=2[CH:9]=1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2ccsc21
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Product: CC(C)Cn1c(=O)n(C)c(=O)c2cc(C(O)c3ccc([N+](=O)[O-])cc3)sc21

Procedure:
Prepared from 3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidin-2,4(1H,3H)-dione (Example 51, step c) and 4-nitrobenzaldehyde following the method of Example 51, step d.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:11][CH2:12][C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=2[F:20])[C:5]([N+:8]([O-])=O)=[N:6][CH:7]=1.Cl.C([O-])(=O)C.[Na+]>C(O)C.[Fe]>[Cl:1][C:2]1[CH:3]=[C:4]([O:11][CH2:12][C:13]2[C:14]([F:20])=[CH:15][CH:16]=[CH:17][C:18]=2[F:19])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1ncc(Cl)cc1OCc1c(F)cccc1F
Agent: [Fe]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCO
Product: Nc1ncc(Cl)cc1OCc1c(F)cccc1F
Temperature: 0 °C

Procedure:
59.7 g of 5-chloro-3-[(2,6-difluorobenzyl)oxy]-2-nitropyridine (Example 16A; 199 mmol, 1 equivalent) were initially charged in 600 ml of ethanol, 34.4 g of iron powder (616 mmol, 3.1 equivalents) were added and the mixture was heated to reflux. 152 ml of concentrated hydrochloric acid were slowly added dropwise and the mixture was boiled at reflux for a further 30 min. The reaction mixture was cooled and stirred into an ice/water mixture. The resulting mixture was adjusted to pH 5 using sodium acetate, and the solid was filtered off, washed with water, air-dried and then dried under reduced pressure at 50° C. This gave 52.7 g (98% of theory) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH2:16][O:17][C:18](=[O:26])[NH:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)([CH3:4])([CH3:3])[CH3:2].[CH3:28][C:29]1[O:33][C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[N:31][C:30]=1[CH2:40][CH2:41]OS(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:27])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:41][CH2:40][C:30]2[N:31]=[C:32]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[O:33][C:29]=2[CH3:28])=[CH:11][C:10]=1[CH2:16][O:17][C:18](=[O:26])[NH:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CCc1ccc(O)cc1COC(=O)NC1CCCCC1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(COC(=O)NC2CCCCC2)c1
Temperature: 55 °C
Yield: 58.1 %

Procedure:
A 40 mL Carousel tube was charged with 3-(2-cyclohexylcarbamoyloxymethyl-4-hydroxyphenyl)propionic acid tert-butyl ester (0.10 g, 0.26 mmol) in anhydrous DMF (1.0 mL). Toluene-4-sulfonic acid 2-(5-methyl-2-phenyloxazol-4-yl)ethyl ester (0.104 g, 0.292 mmol) and cesium carbonate (0.13 g, 0.40 mmol) were added. The mixture was stirred and heated at 55° C. under a nitrogen atmosphere for 30 h and was concentrated. The residue was diluted with EtOAc (50 mL) and washed twice with brine (2×), dried (Na2SO4), and concentrated. The crude residue was purified using radial chromatography (EtOAc: CH2Cl2 2:98 to 5:95) to give a white solid (0.085 g, 57%). 1H NMR (400 MHz, CDCl3) 1.07-1.19 (m, 3H), 1.24-1.38 (m, 2H), 1.42 (s, 9H), 1.56-1.60 (m, 1H), 1.67-1.70 (m, 2H), 1.91-1.93 (m, 2H), 2.37 (s, 3H), 2.46 (t, J=7.8 Hz, 2H), 2.88 (t, J=7.8 Hz, 2H), 2.96 (t, J=7.8 Hz, 2H), 3.48-3.50 (m, 1H), 4.22 (t, J=6.8 Hz, 2H), 4.69-4.71 (m, 1H), 5.07 (s, 2H), 6.80 (dd, J=8.3, 2.4 Hz, 1H), 6.90 (d, J=2.4 Hz, 1H), 7.10 (d, J=8.3 Hz, 1H), 7.39-7.45 (m, 3H), 7.98 (dd, J=4.2, 2.2 Hz, 2H). MS (ES) m/e 563 (M+1).