Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=3)[CH:5]=[CH:4][C:3]1=2.O[Li].O>C1COCC1.O>[CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:30][CH:31]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C)cc2)=CCC3(C)C)cc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C2=CCC(C)(C)c3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)cc1

Procedure:
A solution of 142.6 mg (0.339 mmol) of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)-2-naphthalenyl)ethynyl]benzoate (Compound 1) and 35.6 mg (0.848 mmol) of LiOH—H2O in 12 ml of THF/water (4:1, v/v), was stirred overnight at room temperature. The reaction mixture was extracted with hexanes, and the hexane fraction extracted with 5% aqueous NaOH. The aqueous layers were combined and acidified with 1M HCl, and then extracted with EtOAc and Et2O. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give the title compound as a colorless solid. 1H NMR (d6-DMSO): δ 7.91 (2H, d, J=8.4 Hz), 7.60 (2H, d, J=8.4 Hz), 7.47 (2H, s), 7.23 (4H, q, J=8.1 Hz), 7.01 (1H, s), 6.01 (1H, t, J=4.6 Hz), 2.35 (3H, s), 2.33 (2H, d, J=4.8 Hz), 1.30 (6H, s).
Reaction SMILES: [C:1]([O:7][CH2:8][C@@H:9]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:10]1[C:11]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[C:12]2[C:17](=[CH:18][C:19]=1Cl)[N:16]=[C:15](C)[CH:14]=[CH:13]2)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:34](OC[C@H](C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1C)N=CC=C2)O)(=O)C(C)(C)C>>[C:1]([O:7][CH2:8][C@@H:9]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:10]1[C:11]([C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:34])[N:16]=[CH:15][CH:14]=[CH:13]2)(=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5]
Reactant: Cc1ccc2c(-c3ccc(Cl)cc3)c([C@@H](COC(=O)C(C)(C)C)OC(C)(C)C)c(Cl)cc2n1
Reactant: Cc1cc2ncccc2c(-c2ccc(Cl)cc2)c1[C@H](O)COC(=O)C(C)(C)C
Product: Cc1cc2ncccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C

Procedure:
Compound 3J was prepared following the procedure used to prepare compound 1J of Example 1, except that (S)-2-(5-(4-chlorophenyl)-7-methylquinolin-6-yl)-2-hydroxyethyl pivalate (3I) was used instead of compound 1I. LCMS-ESI+ (m/z): 454.3, 456.3 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:10]([CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]3)=[O:11])[CH:5]=[C:6]([Br:9])[C:7]=1[NH2:8].[OH:28]O>>[Br:1][C:2]1[CH:3]=[C:4]([S:10]([CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]3)(=[O:28])=[O:11])[CH:5]=[C:6]([Br:9])[C:7]=1[NH2:8]
Reactant: OO
Reactant: Nc1c(Br)cc(S(=O)CCCCOc2ccc3c(c2)CCC(=O)N3)cc1Br
Product: Nc1c(Br)cc(S(=O)(=O)CCCCOc2ccc3c(c2)CCC(=O)N3)cc1Br

Procedure:
Prepared analogous to Example 124 from 6-[4-(3,5-dibromo-4-amino-phenylsulfinyl)-butoxy]-3,4-dihydro-carbostyril and hydrogen peroxide.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]([CH:10]([CH3:12])[CH3:11])[CH:8]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[N:7]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[N:6]=1)=[O:4].C1COCC1>C1COCC1.O>[CH3:1][O:2][C:3]([C:5]1[C:9]([CH:10]([CH3:12])[CH3:11])=[C:8]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[N:7]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)C1=NN(c2ccc(F)cc2)C(C(=O)OCc2ccccc2)C1C(C)C
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1nn(-c2ccc(F)cc2)c(C(=O)OCc2ccccc2)c1C(C)C
Yield: 65 %

Procedure:
To a solution of 1-(4-fluoro-phenyl)-4-isopropyl-4,5-dihydro-1H-pyrazole-3,5-dicarboxylic acid 5-benzyl ester 3-methyl ester (29.3, 73.5 mmol) in THF:Water (1:1, 500 mL) at 0° C. was slowly added ceric ammonium nitrate (80.5 g, 147 mmol; commercially available from Sigma Aldrich). The reaction was stirred at 0° C. for 1 hr after which time the THF was removed under reduced pressure and DCM (500 mL) was added. The organic layer was separated and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated, and the product was purified by silica gel chromatography (5-15% EtOAc/Hex) to provide 1-(4-fluoro-phenyl)-4-isopropyl-1H-pyrazole-3,5-dicarboxylic acid 5-benzyl ester 3-methyl ester (18.95 g, 65%):: H-NMR (CDCl3) δ 7.29-7.21 (m, 5 H), 7.07 (d, 2 H), 6.94 (t, 2 H), 5.12 (s, 2 H), 3.89 (s, 3 H), 3.88-3.80 (m, 1 H), 1.31 (d, 6 H).
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[CH:4][C:5]([CH3:12])=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:7]=1.BrC1C=C([F:23])C(C)=C(N)C=1>>[Br:1][C:2]1[CH:3]=[C:4]([F:23])[C:5]([CH3:12])=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:7]=1
Reactant: Cc1c(N)cc(Br)cc1F
Reactant: Cc1cc(F)c(Br)cc1CC(=O)O
Product: Cc1c(F)cc(Br)cc1CC(=O)O

Procedure:
(5-Bromo-3-fluoro-2-methyl-phenyl)-acetic acid was prepared analogously to the synthesis of (5-bromo-4-fluoro-2-methyl-phenyl)-acetic acid (preparation example P5, step P5.3) starting from 5-bromo-3-fluoro-2-methyl-phenylamine (preparation example P7, step P7.1) by making use of the procedures described under step P5.1, step P5.2 and step P5.3. The title acid was obtained as a solid, mp: 147° C.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C@@H:12]([CH3:22])[O:11][C@H:10]1[N:23]1[CH:38]=[C:37](I)[C:27]([NH:28][C:29]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:30])=[N:26][C:24]1=[O:25])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:40][Si:41]([C:44]#[CH:45])([CH3:43])[CH3:42]>C(Cl)Cl.CCN(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Si:1]([O:8][C@@H:9]1[C@H:13]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C@@H:12]([CH3:22])[O:11][C@H:10]1[N:23]1[CH:38]=[C:37]([C:45]#[C:44][Si:41]([CH3:43])([CH3:42])[CH3:40])[C:27]([NH:28][C:29]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:30])=[N:26][C:24]1=[O:25])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCCCCOC(=O)Nc1nc(=O)n([C@@H]2O[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]2O[Si](C)(C)C(C)(C)C)cc1I
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCOC(=O)Nc1nc(=O)n([C@@H]2O[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]2O[Si](C)(C)C(C)(C)C)cc1C#C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 26 %

Procedure:
To a solution of 2',3'-bis-O-(tert-butyldimethylsilyl)-5'-deoxy-5-iodo-N4 -(n-pentyloxycarbonyl)cytidine (130 mg, 0.18 mmol) in CH2Cl2 (2 ml) and Et3N(2 ml) Cul (10.7 mg, 0.1056 mmol), Pd(PPh3)2Cl2 (2.6 mg, 0.0036 mmol), and trimethylsilyl-acetylene (58.6 μl, 0.40 mmol) were added and stirred for 2 hours at room temperature under Ar in the dark. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in EtOAc(25 ml×3), washed with 2% aq. EDTA.2Na(10 ml×2), water and brine, dried over Na2SO4 and filtered. The filtrate was evaporated under reduced pressure. The crude product was purified by flash chromatography on SiO2 (eluent: 10% EtOAc/n-hexane) to give 2',3'-bis-O-(tert-butyidimethylsilyl)-5'-deoxy-5-[(trimethylsilyl)ethynyl]-N4 -(n-pentyloxycarbonyl)-cytidine as a colorless amorphous solid. (30.2 mg, 26% yield)
Reaction SMILES: [NH2:1][C@H:2]1[CH2:21][N:6]2[C:7]3[C:12]([C:13]([CH2:14][C:15]([O:17][CH2:18][CH2:19][CH3:20])=[O:16])=[C:5]2[CH2:4][CH2:3]1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[F:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH:1][C@H:2]2[CH2:21][N:6]3[C:7]4[C:12]([C:13]([CH2:14][C:15]([O:17][CH2:18][CH2:19][CH3:20])=[O:16])=[C:5]3[CH2:4][CH2:3]2)=[CH:11][CH:10]=[CH:9][CH:8]=4)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](N)CC2
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NS(=O)(=O)c1ccc(F)cc1)CC2
Temperature: 25 °C
Reaction time: 12 h
Yield: 97 %

Procedure:
To a CH2Cl2 solution (0.2 M) of propyl ([7R]-7-amino-6,7,8,9-tetrahydro-pyrido[1,2-α]indo1-10-yl)acetate from Step 6 was added 4-fluorobenzenesulfonyl chloride (1.1 equiv.) followed by triethylamine (3 equiv.) and DMAP (1 equiv.). The reaction mixture was stirred for 12 h at rt. The mixture was concentrated under reduced pressure, diluted with EtOAc, and washed with aqueous NaHCO3, water and finally with brine. The organic layer was dried with Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel using a CombiFlashRF (Teledyne ISCO) eluting with EtOAc/Hex (10:90 to 50:50) to give the title compound (97%) as a colorless foam.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N:7]([C@H:10]1[C@@H:13]([CH2:14][O:15][CH2:16][C:17]([O:19]C)=[O:18])[NH:12][C:11]1=[O:21])=[N+:8]=[N-:9].Cl>O.O1CCCC1>[N:7]([C@H:10]1[C@@H:13]([CH2:14][O:15][CH2:16][C:17]([OH:19])=[O:18])[NH:12][C:11]1=[O:21])=[N+:8]=[N-:9]
Reactant: COC(=O)COC[C@H]1NC(=O)[C@H]1N=[N+]=[N-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: [N-]=[N+]=N[C@@H]1C(=O)N[C@@H]1COCC(=O)O
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of potassium carbonate (7.335 g, 53.08 mmole) in water (80 ml) was cooled to 0° C. and deoxygenated with argon. A solution of (±)-(cis)-[(3-azido-2-oxo-4-azetidinyl)methoxy]acetic acid, methyl ester (2.261 g, 10.62 mmole) in tetrahydrofuran (60 ml) was added and the mixture stirred at 0° C. for five minutes and then at room temperature for 5.5 hours. The reaction was cooled and acidified with 6N hydrochloric acid to pH 7. The tetrahydrofuran was mostly removed in vacuo, and the aqueous residue (pH ca. 8) was extracted with ethyl acetate. The aqueous layer was cooled to 0° C., acidified with 6N hydrochloric acid to pH 2, saturated with sodium chloride, and extracted with ethyl acetate (fifteen 80 ml portions). The organic extracts were dried (sodium sulfate), filtered, and concentrated in vacuo. The yield of crude acid was 1.503 g.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:17])(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21]>O1CCCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:21][C:20]1[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=1[CH3:18])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:17])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(C)cccc2c1Cl
Reactant: Cc1ccccc1N
Solvent: C1CCOC1
Product: CCCC(=O)c1cnc2c(C)cccc2c1Nc1ccccc1C
Yield: 20.4 %

Procedure:
3-Butyryl-4-chloro-8-methylquinoline (4.95 g, 20 mmol), 2-methylaniline (4.27 ml, 40 mmol) and tetrahydrofuran (20 ml) were heated at reflux for 30 minutes, the solvent evaporated and the residue triturated with ethyl acetate/ethanol. The hydrochloride salt was filtered off, converted to free base and recrystallised from ethyl acetate/petroleum ether then from aqueous methanol, to give 3-butyryl-4-(2-methylphenylamino)-8-methylquinoline (1.3 g), m.p. 110°-112°.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:19])[C:8](=[O:18])[N:9]2[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1.[N+:20]([O-])([OH:22])=[O:21]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:19])[C:8](=[O:18])[N:9]2[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)Cn1c(=O)c(=O)[nH]c2ccc(F)cc21
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc21
Temperature: 0 °C
Yield: 96 %

Procedure:
In 15 ml of concentrated sulfuric acid, under below 0° C., 1.20 g of ethyl 2-(7-fluoro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl)acetate were added to dissolve the latter in the former. While stirring, 0.21 ml of fuming nitric acid (d=1.52) was added dropwise to the resulting solution and they were stirred at the same temperature for 30 minutes. The reaction mixture was poured into ice water. The crystals so precipitated were collected by filtration, washed with water and then, dried under reduced pressure to give 1.35 g (96%) of ethyl 2-(7-fluoro-6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl)acetate.
Reaction SMILES: [CH3:1][S:2]([C:5]1[S:9][C:8]([N:10]=[C:11]=[O:12])=[N:7][N:6]=1)(=[O:4])=[O:3].[CH2:13]([NH:16][CH:17]([CH2:20][O:21][CH3:22])[CH:18]=[O:19])[CH2:14][CH3:15]>C1C=CC=CC=1>[CH2:13]([N:16]([CH:17]([CH2:20][O:21][CH3:22])[CH:18]=[O:19])[C:11]([NH:10][C:8]1[S:9][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[N:6][N:7]=1)=[O:12])[CH2:14][CH3:15]
Reactant: CCCNC(C=O)COC
Reactant: CS(=O)(=O)c1nnc(N=C=O)s1
Solvent: c1ccccc1
Product: CCCN(C(=O)Nc1nnc(S(C)(=O)=O)s1)C(C=O)COC

Procedure:
5-Methylsulfonyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 2-propylamino-3-methoxypropionaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 30 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. This residue is then recrystallized to yield the desired product the dimethyl acetal of 2-[1-propyl-3-(5-methylsulfonyl-1,3,4-thiadiazol-2-yl)ureido]-3-methoxypropionaldehyde.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:21][CH2:22][F:23]>C(#N)C>[F:23][CH2:22][CH2:21][NH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:11])([F:12])[F:13])[CH:3]=1
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: N#Cc1ccc(NCCF)cc1C(F)(F)F
Temperature: 120 °C
Yield: 79.8 %

Procedure:
To a solution of 4-amino-2-(trifluoromethyl)benzonitrile (0.100 g, 0.54 mmol) in acetonitrile (3 mL) was added cesium carbonate (0.438 g, 1.34 mmol) and 1-bromo-2-fluoroethane (0.340 g, 2.68 mmol). The mixture was heated in a microwave at 120° C. for 15 min. Upon cooling, additional 1-bromo-2-fluoroethane (0.340 g, 2.68 mmol) was added and the reaction was heated in the microwave at 140° C. for 20 min. Upon cooling, the solids were filtered off and washed with ethyl acetate. The filtrate was concentrated in vacuo and the residue was purified by radial chromatography (10-40% ethyl acetate-hexane gradient) to give 0.100 g of a mixture (6:1) of the title compound and 4-[bis(2-fluoroethyl)amino]-2-(trifluoromethyl)benzonitrile as a white solid, which was used as such in the next reaction.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=2[N+:24]([O-])=O)[C:9](OC)=[O:10])=[CH:4][CH:3]=1.[H][H]>[Pd].CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:9](=[O:10])[NH:24][C:15]3[C:14](=[CH:23][CH:22]=[C:17]([C:18]([O:20][CH3:21])=[O:19])[CH:16]=3)[NH:13]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(NC(C(=O)OC)c2ccc(F)cc2)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc2c(c1)NC(=O)C(c1ccc(F)cc1)N2
Temperature: 30 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask, was placed methyl 4-(1-(4-fluorophenyl)-2-methoxy-2-oxoethylamino)-3-nitrobenzoate (3.5 g, 9.67 mmol, 1.00 equiv), methanol (50 mL), and palladium on carbon (10%) (500 mg). Hydrogen gas was introduced to the reaction, and it was stirred overnight at 30° C. in an oil bath. Then the solids were filtered off and the filtrate was concentrated in vacuo. This resulted in 2.6 g (90%) of methyl 2-(4-fluorophenyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate as a light yellow solid.
Reaction SMILES: [C:1]([N:9]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[C:19]1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(=O)C.[Na+]>CO>[C:1]([N:9]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:10]1[C:11]([O:13][CH3:19])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)c1ccccc1
Temperature: 25 °C

Procedure:
A 5-liter flask was installed in an oil bath on a magnetic stirrer, provided with a reflux condenser and charged with 3.0 liters of methanol and 750 g (3.2 moles) of (trans)-1-benzoyl-4-hydroxy-L-proline. 19 grams of p-toluenesulfonic acid monohydrate (0.1 moles) were added. The mixture was heated to reflux and the esterification followed by TLC. Refluxing was continued until starting material was no longer detectable. 8 grams (0.1 moles) of sodium acetate was added to neutralize the catalyst acid. The condenser was set for distillation and the mixture concentrated at atmospheric pressure until the pot temperature reached 80° C. The distillate was then discarded. The clear residue was rapidly diluted with 2 liters of warm water. The flask was swirled for quick mixing and to permit the ester to crystallize. The slurry was cooled to room temperature with occasional swirling and maintained at room temperature for at least another hour. The crystals were collected on a filter and the filtrate recycled to aid in the transfer. The cake was pressed down and washed with one liter of cold water. The cake was sucked dry as possible and the product dried via a laboratory fluid bed dryer to constant weight. The combined filtrate was vacuum concentrated from the first crop to a small volume and the resulting slurry cooled to room temperature. A second crop of crystals was collected on a filter and washed with a minimum of cold water. The cake was pressed down and suction applied until no more liquid emerged. The second crop was dried to constant weight.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].Cl[C:26]1[N:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[C:19]2[N:20]=[CH:21][CH:22]=[CH:23][N:24]=2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:26]1[N:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1
Reactant: Cc1ccc(-c2ncccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-c2ncccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(C(F)(F)F)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A45 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(pyrimidin-2-yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. MS (ESI) 471 (M+H). 1H NMR (500 MHz, CD3OD) δ 8.90-6.60 (m, 8H), 5.15-3.00 (m, 5H), 2.45-0.65 (m, 11H).
Reaction SMILES: [C:1]([N:8]([CH3:28])[CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:30]1[CH:35]=[CH:34][C:33]([N:36]([CH3:39])[CH:37]=[O:38])=[CH:32][CH:31]=1>>[CH:37]([N:36]([CH3:39])[C:33]1[CH:34]=[CH:35][C:30]([C:19]2[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:17]([CH2:16][NH:15][CH:12]3[CH2:13][CH2:14][CH:9]([N:8]([CH3:28])[C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH2:10][CH2:11]3)[CH:18]=2)=[CH:31][CH:32]=1)=[O:38]
Reactant: CN(C=O)c1ccc(Br)cc1
Reactant: COc1ccc(B(O)O)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2ccc(N(C)C=O)cc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 4 (260 mg, 0.66 mmol) is coupled to aryl bromide 51 (170 mg, 0.79 mmol) using Method B to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH:13]2[CH2:15][CH2:14]2)[C@H:11]([C:16]([O:18]C)=[O:17])[O:10][C:9]1([CH3:21])[CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>CO.O>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH:13]2[CH2:14][CH2:15]2)[C@H:11]([C:16]([OH:18])=[O:17])[O:10][C:9]1([CH3:21])[CH3:20])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1C1CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@@H](C2CC2)[C@H](C(=O)O)OC1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.5 %

Procedure:
To a solution of 2.66 g of methyl (4S,5R)--3-tert-butoxycarbonyl-2,2-dimethyl-4-cyclopropyl-5-oxazolidinecarboxylate in 60 ml of methanol is added dropwise a solution of 255 mg of lithium hydroxide in 30 ml of water under ice-cooling. The reaction mixture is warmed to room temperature, stirred for one hour and evaporated under reduced pressure to remove methanol. Chloroform is added to the residue. The pH of the mixture is adjusted to about pH 2 with 10% hydrochloric acid under ice--cooling thereto. The chloroform layer is washed with brine, dried, and evaporated under reduced pressure to remove the solvent to give 2.65 g of (4S,5R)-3-tert-butoxycarbonyl-2,2-dimethyl-4-cyclopropyl-5-oxazolidinecarboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][S:18]([CH2:21][CH2:22][CH2:23]Cl)(=[O:20])=[O:19])=[CH:13][CH:12]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH3:1][C:2]1[C:3]2[N:4]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][S:18]([CH2:21][CH2:22][CH2:23][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)(=[O:20])=[O:19])=[CH:13][CH:12]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C1CCNCC1
Reactant: Cc1cccn2cc(-c3ccc(NS(=O)(=O)CCCCl)cc3)nc12
Product: Cc1cccn2cc(-c3ccc(NS(=O)(=O)CCCN4CCCCC4)cc3)nc12
Temperature: 25 °C

Procedure:
The product of Step A (65 mg) and piperidine (1.0 mL) were heated at 100° C. for 1.5 hours. The reaction was cooled to ambient temperature and partitioned between ethyl acetate (15 mL) and saturated sodium bicarbonate solution (15 mL). The aqueous portion was extracted with a fresh portion of ethyl acetate (15 mL) (2×) and the organic portions combined and washed with brine (15 mL). The organic portions were dried over magnesium sulfate, filtered and evaporated. The residue was purified via silica gel chromatography (dichloromethane/methanol) to give the title compound (26 mg). ). 1H-NMR (CD3OD) δ 1H-NMR (CD3OD) δ8.14 (d, J=7.0 Hz, 1H), 8.00 (s, 1H), 7.81 (m, 2H), 7.23 (m, 2H), 6.98 (m, 1H), 6.70 (t, J=7.0 Hz, 1H), 3.07 (m, 2H), 2.49 (s, 3H), 2.31 (m, 6H), 1.87 (m, 2H), 1.44 (m, 4H), 1.33 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:13][CH3:14])=[CH:7][NH:8][C:9]2=O)=[CH:4][C:3]=1[O:15][CH3:16].O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:15][CH3:16])=[C:2]([F:1])[CH:11]=2)[C:6]([O:13][CH3:14])=[CH:7][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2c(OC)c[nH]c(=O)c2cc1F
Product: COc1cc2c(OC)cnc(Cl)c2cc1F
Yield: 24.3 %

Procedure:
A solution of 7-fluoro-4,6-dimethoxyisoquinolin-1(2H)-one (7.6 g, 34.1 mmol) in POCl3 (50 ml) was refluxed for 18 h. The solvent was evaporated under reduced pressure and the residue was diluted with cold water. The aqueous solution was basified by solid sodium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography (20% ethyl acetate in pet ether) to get desired compound (2 g, 24.3%) as pale yellow solid. 1H NMR (400 MHz, CDCl3): δ ppm 7.88-7.85 (d, J=12 Hz, 1H), 7.75 (s, 1H), 7.54-7.52 (d, J=8 Hz, 1H), 4.05 (s, 3H); MS: MS m/z 242.0 (M++1).