Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]([OH:13])=O)=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:14][O:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[C:18]=1[NH2:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:14][O:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[NH:8][N:9]=2)=[O:13])[C:18]=1[NH2:24]
Reactant: O=C(O)c1n[nH]c2ncc(Br)cc12
Reactant: COC(=O)c1cccc(N)c1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc(NC(=O)c2n[nH]c3ncc(Br)cc23)c1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid Compound 1c (0.3 g, 1.17 mmol), 2,3-diamino-benzoic acid methyl ester Compound 8a (3.43 g, 20.64 mmol), HATU (7.85 g, 20.66 mmol), DIPEA (8.64 mL, 62 mmol) in DMF (250 mL) was stirred at room temperature overnight. The solvent was removed and the residue was purified by silica gel chromatography (10% to 90% of ethyl acetate in hexanes) to yield 2-amino-3-[(5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-amino]-benzoic acid methyl ester Compound 8b (5.1 g, 63% yield) as a colorless gel. 1H NMR (300 MHz, CD3OD) δ 9.03 (d, 1H, J=2.1 Hz), 8.78 (d, 1H, J=2.1 Hz), 7.58 (d, 1H, J=7.8 Hz), 7.26 (d, 1H, J=7.8 Hz), 7.15 (t, 1H, J=7.8 Hz), 3.49 (s, 3H); MS (ESI) m/z: 391 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9](Br)=[CH:8]2)=[O:4].[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.Cl>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].CCOC(C)=O.O>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:26]([F:37])([F:36])[F:25])=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ncc2c(cc(Br)c(=O)n2Cc2ccccc2)c1O
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ncc2c(cc(-c3ccccc3C(F)(F)F)c(=O)n2Cc2ccccc2)c1O
Temperature: 100 °C
Yield: 30.5 %

Procedure:
A mixture of 1-benzyl-3-bromo-5-hydroxy-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (100 mg, 0.26 mmol), 2-(trifluoromethyl)phenylboronic acid (73 mg, 0.39 mmol), K3PO4 (109 mg, 0.51 mmol), H2O (9.3 mg, 0.51 mmol), SPhos (5.3 mg, 0.013 mmol) and Pd(OAc)2 (5.2 mg, 0.0077 mmol) in toluene (5 mL) was heated at 100° C. under nitrogen atmosphere for 20 h. After the mixture was cooled to r.t., water and EtOAc were added. 1 M HCl was added until pH was about 2, and the aqueous layer was extracted with additional EtOAc. The organic layers were combined, dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (5-50% EtOAc/hexanes+1% AcOH) to give 36 mg of the title compound. MS: (+) m/z 455.28 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[H-].[Na+].[CH3:14][Si:15]([CH3:22])([CH3:21])[CH2:16][CH2:17][O:18][CH2:19]Cl.O>CN(C=O)C>[Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([CH2:19][O:18][CH2:17][CH2:16][Si:15]([CH3:22])([CH3:21])[CH3:14])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2[nH]cc(I)c12
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)ncnc21
Reaction time: 2 h

Procedure:
A solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (20.0 g) in DMF (50 ml) was slowly added to a solution of sodium hydride (3.4 g) in DMF (190 ml) under ice cooling. Thereafter, 2-(trimethylsilyl)ethoxymethyl chloride (13.3 ml) was added thereto, and stirred at the same temperature for 2 hours. 2-(Trimethylsilyl)ethoxymethyl chloride (1.3 ml) was additionally added to the reaction mixture, and stirred at room temperature for 1 hour. The reaction mixture was poured into water (600 ml), and stirred at room temperature for 15 minutes. The resulting precipitate was collected by filtration and washed with water and diisopropyl ether, followed by dissolution with ethyl acetate again. Insoluble matter was then filtered off by filtration. The solvent of the filtrate was distilled off under reduced pressure. Heptane was added to the resulting residue to collect the precipitate by filtration. The precipitate was washed with heptane, and dried under reduced pressure to obtain the title compound (21.2 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C@:11]([OH:17])([CH3:16])[C:12]([F:15])([F:14])[F:13].[SH:19][CH2:20][CH2:21][OH:22].C[O-].[Na+]>N1C=CC=CC=1.N1C2C(=CC=CC=2)C=CC=1.C(OCC)(=O)C.[Cu]Cl>[Cl:1][C:2]1[CH:7]=[C:6]([S:19][CH2:20][CH2:21][OH:22])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C@:11]([OH:17])([CH3:16])[C:12]([F:15])([F:14])[F:13]
Reactant: C[C@@](O)(C(=O)Nc1ccc(I)cc1Cl)C(F)(F)F
Reactant: OCCS
Agent: Cl[Cu]
Agent: C[O-]
Agent: [Na+]
Solvent: c1ccc2ncccc2c1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C[C@@](O)(C(=O)Nc1ccc(SCCO)cc1Cl)C(F)(F)F
Temperature: 190 °C

Procedure:
A solution of (R)-N-[2-chloro-4-iodophenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 197) (0.8 g) in pyridine (1 ml) was added to a deoxygenated solution of 2-mercaptoethanol (0.18 ml), sodium methoxide (0.14 g) and copper (I) chloride (0.2 g) in quinoline (2 ml) and pyridine (2 ml). The mixture was heated to 190° C. under argon for 18 hours. The mixture was allowed to cool to room temperature then dissolved in ethyl acetate (100 ml), washed with dilute aqueous hydrochloric acid (2×50 ml) and brine (2×50 ml) then dried. Volatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 10-60% ethyl acetate/iso-hexane to give the title compound as a gum. NMR (CDCl3): 1.76 (s, 3H), 3.10 (t, 2H), 3.75-80 (m, 2H), 7.31-7.34 (m, 1H), 7.47 (s, 1H), 8.31 (d, 1H), 8.86 (s, 1H); MS (ESP−): 342.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:15][C:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[CH:17]=2)[C:9](=[O:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[F:24][C:25]([F:37])([F:36])[O:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe].O>[CH3:23][C:18]1[CH:17]=[C:16]([CH:21]=[C:20]([CH3:22])[CH:19]=1)[CH2:15][N:8]([C:5]1[CH:6]=[CH:7][C:2]([C:30]2[CH:29]=[CH:28][C:27]([O:26][C:25]([F:24])([F:36])[F:37])=[CH:32][CH:31]=2)=[CH:3][CH:4]=1)[C:9](=[O:14])[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)C(=O)N(Cc1cc(C)cc(C)c1)c1ccc(Br)cc1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)C(=O)N(Cc1cc(C)cc(C)c1)c1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.3 %

Procedure:
A mixture of methyl N-(4-bromophenyl)-N-(3,5-dimethylbenzyl)oxamate (707 mg, 1.88 mmol), 4-(trifluoromethoxy)phenylboronic acid (500 mg, 2.44 mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (300 mg, 0.357 mmol), potassium carbonate (389 mg, 2.82 mmol), dioxane (10 ml) and water (1 ml) was stirred at 80° for 4 hours. The reaction mixture was cooled to room temperature, and filtered through celite. The residue obtained by concentration of the filtrate under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=10:1) to give the title compound (630 mg, 73%) as a light brown oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][C:9]([C:11]1[C:12]2[CH:21]=[C:20]([C:22](OC)([O:24]C)[CH3:23])[O:19][C:13]=2[C:14]([O:17][CH3:18])=[N:15][CH:16]=1)=[O:10].FC(F)(F)C(O)=O.O>C(Cl)(Cl)Cl.ClCCl>[CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][C:9]([C:11]1[C:12]2[CH:21]=[C:20]([C:22](=[O:24])[CH3:23])[O:19][C:13]=2[C:14]([O:17][CH3:18])=[N:15][CH:16]=1)=[O:10]
Reactant: COc1ncc(C(=O)Nc2ccncc2C)c2cc(C(C)(OC)OC)oc12
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: COc1ncc(C(=O)Nc2ccncc2C)c2cc(C(C)=O)oc12
Yield: 83.7 %

Procedure:
2-(1,1-Dimethoxyethyl)-7-methoxyfuro[2,3-c]pyridine-4-carboxylic acid (3-methylpyridin-4-yl)amide (0.15 g), trifluoroacetic acid (0.23 ml) and water (0.50 ml) were stirred at 50° C. in chloroform (20 ml) for 4 h. The mixture was cooled and diluted with dichloromethane (30 ml), washed with saturated sodium bicarbonate solution (30 ml) then water (30 ml), dried over magnesium sulfate, filtered and the solvent removed in vacuo to give the title compound (0.11 g) as a cream solid.
Reaction SMILES: C(O/[C:4](=[C:6]1/C(=O)O[C:9](=[O:17])[C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]/1=2)/[CH3:5])C.[C:19]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])(=[O:22])[NH:20][NH2:21].C(O)C>>[C:24]([O:23][C:19](=[O:22])[NH:20][N:21]1[C:4]([CH3:5])=[CH:6][C:11]2[C:10](=[C:15]([F:16])[CH:14]=[CH:13][CH:12]=2)[C:9]1=[O:17])([CH3:27])([CH3:26])[CH3:25]
Reactant: CCO/C(C)=C1/C(=O)OC(=O)c2c(F)cccc21
Reactant: CC(C)(C)OC(=O)NN
Solvent: CCO
Product: Cc1cc2cccc(F)c2c(=O)n1NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 56 %

Procedure:
A suspension of 4-[1-Ethoxy-eth-(E)-ylidene]-8-fluoro-2-benzopyran-1,3-dione (5.25 g, 21.0 mmol), tert-butyl carbazate (3.43 g, 26.0 mmol) in ethanol (25.0 mL, 428 mmol) was heated under reflux for 30 min with intensive gas formation. The obtained clear purple solution was allowed to cool to r.t. with formation of white precipitate, cooled on dry ice—ethanol bath, filtered, washed with cold ethanol (3×10 ml) to give 3.436 g of the pure title product. Supernatant was quenched with water (200 ml), sat. aq. NaHCO3 (50 ml) and diisopropyl ether (ca 20 ml), shaked, then quenched with heptane (100 ml) and sonicated. White precipitated was separated from this bilayer system by filtration to give 470 mg more of the title product; total yield 63.7%. LC-MS (m/z) 293.0 (traces, MH+), fragments: 237.3, 193.2 (major, M-Boc), 176.3. 1H NMR (500 MHz, DMSO-d6), 88:12 mixture of rotamers A and B: 1.29 (s, 1.1H, tBu of B), 1.47 (s, 7.9H, tBu of A), 2.21 (s, 2.6H, Me of A), 2.21 (s, 0.4H, Me of B), 6.52 (s, 1H, C4-H), 7.17 (dd, J=8.3 Hz, J (H—F)=11.6 Hz, 1H, C7-H), 7.36 (d, J=7.9 Hz, 1H, C5-H), 7.68 (dt, J=7.8 Hz, J (H—F)=4.9 Hz, 1H, C6-H), 9.33 (s, 0.12H, NH of B), 9.8 (s, 0.88H, NH of A). 13C APT NMR (125.76 MHz, dmso-d6=39.89 ppm): 18.96 (Me), 27.99 (tBu of B), 28.31 (tBu of A), 80.98 (C of tBu), 103.59 (C4-H), 112.81 (d, J=20.9 Hz, C7-H), 113.25 (d, J=5 Hz, C9), 122.03 (d, J=3.5 Hz, C5-H), 134.62 (d, J=9.9 Hz, C6-H), 139.64 (C10), 143.96 (C3), 155.39 (NHCO2), 157.88 (d, J=4.5 Hz, C1=O), 161.77 (d, J=262 Hz, C8-F). 19F NMR (470.59 MHz): −111.47 (unres. dd, J=11 Hz, J<4 Hz, rotamer A), −111.35 (unres. dd, J=10.5 Hz, rotamer B). VT 1H NMR (T=353 K, 250 MHz): all doubled signals corresponding to rotamers A and B have coalesced.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[C:12](OC2C=CC(NC)=C(N)C=2)[CH:11]=[CH:10][N:9]=1)=[O:7])(C)(C)C.NC(N)=S.IC.C(OC(C1C=C([O:43][C:44]2[CH:65]=[CH:64][C:47]3[N:48]([CH3:63])[C:49]([NH:51][C:52]4[CH:57]=[CH:56][C:55]([Cl:58])=[C:54]([C:59]([F:62])([F:61])[F:60])[CH:53]=4)=[N:50][C:46]=3[CH:45]=2)C=CN=1)=O)(C)(C)C.FC(F)(F)C(O)=O>CO.C(Cl)Cl>[Cl:58][C:55]1[CH:56]=[CH:57][C:52]([NH:51][C:49]2[N:48]([CH3:63])[C:47]3[CH:64]=[CH:65][C:44]([O:43][C:8]4([C:6]([OH:7])=[O:5])[CH:13]=[CH:12][CH:11]=[CH:10][NH:9]4)=[CH:45][C:46]=3[N:50]=2)=[CH:53][C:54]=1[C:59]([F:62])([F:61])[F:60]
Reactant: CNc1ccc(Oc2ccnc(C(=O)OC(C)(C)C)c2)cc1N
Reactant: Cn1c(Nc2ccc(Cl)c(C(F)(F)F)c2)nc2cc(Oc3ccnc(C(=O)OC(C)(C)C)c3)ccc21
Agent: NC(N)=S
Solvent: O=C(O)C(F)(F)F
Solvent: CI
Solvent: CO
Product: Cn1c(Nc2ccc(Cl)c(C(F)(F)F)c2)nc2cc(OC3(C(=O)O)C=CC=CN3)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To tert-butyl4-[3-amino-4-(methylamino)phenoxy]pyridine-2-carboxylate (1 eq) in methanol was added 4-chloro-3-(trifluoromethyl)benzeneisothiocyanate (1 eq) and stir at ambient temperature for 16 h. Formation of the corresponding thiourea was followed by LC/MS. To it was then added iodomethane (1 eq) and heated to 60° C. for 2 h. Formation of tert-butyl4-(2-{[4-chloro-3-(trifluoromethyl)phenyl]amino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylate was followed by LC/MS. To it in methylene chloride was added trifluoroacetic acid and stirred at ambient temperature overnight. Resulting 4-(2-{[4-chloro-3-(trifluoromethyl)phenylamino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylic acid was purified by preparative chromatography. MS: MH+=462.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH3:12][C:13]([OH:37])([CH3:36])[CH2:14][N:15]1[C:27]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]=[CH:19][C:18]=2[N:17]=[C:16]1[CH2:28][CH2:29][C:30]1([CH3:35])[O:34][CH2:33][CH2:32][O:31]1>C(Cl)(Cl)Cl>[CH3:36][C:13]([OH:37])([CH3:12])[CH2:14][N:15]1[C:27]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N+:20]([O-:9])=[CH:19][C:18]=2[N:17]=[C:16]1[CH2:28][CH2:29][C:30]1([CH3:35])[O:34][CH2:33][CH2:32][O:31]1
Reactant: CC(C)(O)Cn1c(CCC2(C)OCCO2)nc2cnc3ccccc3c21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(C)(O)Cn1c(CCC2(C)OCCO2)nc2c[n+]([O-])c3ccccc3c21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
mCPBA (2.2 g of 60% pure material, 7.7 mmol) was added in portions over a period of five minutes to a stirred solution of 2-methyl-1-{2-[2-(2-methyl-1,3-dioxolan-2-yl)ethyl]-1H-imidazo[4,5-c]quinolin-1-yl}propan-2-ol (2.5 g, 7.0 mmol) in chloroform (47 mL), and the reaction was stirred at room temperature for 20 minutes. The reaction mixture was partitioned between dichloromethane (200 mL) and saturated aqueous sodium carbonate (100 mL). The organic layer was separated and washed with saturated aqueous sodium carbonate (100 mL). The combined aqueous fractions were extracted with dichloromethane (50 mL). The combined organic fractions were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 2-methyl-1-{2-[2-(2-methyl-1,3-dioxolan-2-yl)ethyl]-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl}propan-2-ol as a tan solid.
Reaction SMILES: [CH3:1][C:2]([C:22]([O:24][CH3:25])=[O:23])([CH3:21])[NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)=[O:5].[H-].[Na+].[CH3:28]N(C)C=O.IC>O>[CH3:28][N:3]([C:4]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1)=[O:5])[C:2]([CH3:1])([C:22]([O:24][CH3:25])=[O:23])[CH3:21]
Reactant: CN(C)C=O
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COC(=O)C(C)(C)N(C)C(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
As shown in Reaction Scheme 11, a mixture of methyl 2-methyl-N-[(4′-nitrobiphenyl-4-yl)carbonyl]alaninate (1.32 g, 3.9 mmol), sodium hydride (117 mg, 4.6 mmol), and N,N-dimethylformamide (15 mL) was stirred for 2 h at rt. Iodomethane (0.48 mL, 7.7 mmol) was added, and the reaction mixture was stirred overnight at rt. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (2×10 mL). The combined extracts were evaporated to dryness, and crude product was purified by flash chromatography (Biotage®, 4:1 hexanes/EtOAc) to yield methyl N,2-dimethyl-N-[(4′-nitrobiphenyl-4-yl)carbonyl]alaninate as an off-white solid (1.29 g, 94%). 1H NMR (400 MHz, DMSO-d6) δ 1.47 (s, 6H), 2.93 (s, 3H), 3.58 (s, 3H), 7.52 (d, 2H), 7.84 (d, 2H), 7.98 (d, 2H), 8.30 (d, 2H); LC-MS m/z 356.9 (MH+), retention time 2.98 minutes.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[S:25][CH:24]=[C:23]([CH3:26])[N:19]3[C:20](=[O:22])[CH:21]=2)[CH2:3][CH2:2]1.[I:27]N1C(=O)CCC1=O.C1(COC2C(OC)=CC=CC=2/C=C/C2N=C3SC=CN3C(=O)C=2I)CC1>C(#N)C>[CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[S:25][CH:24]=[C:23]([CH3:26])[N:19]3[C:20](=[O:22])[C:21]=2[I:27])[CH2:3][CH2:2]1
Reactant: COc1cccc(/C=C/c2cc(=O)n3c(C)csc3n2)c1OCC1CC1
Reactant: O=C1CCC(=O)N1I
Agent: COc1cccc(/C=C/c2nc3sccn3c(=O)c2I)c1OCC1CC1
Solvent: CC#N
Product: COc1cccc(/C=C/c2nc3scc(C)n3c(=O)c2I)c1OCC1CC1

Procedure:
To a solution of Step 3 intermediate (700 mg, 1.810 mmol) in acetonitrile (10 ml) was added N-iodosuccinimide (641 mg, 2.841 mmol) and reacted according to the procedure described in Step 4, Intermediate 2 to afford 600 mg of the desired compound; 1H NMR (300 MHz, CDCl3) δ 0.32-0.35 (m, 2H), 0.52-0.58 (m, 2H), 1.18-1.22 (m, 1H), 2.64 (s, 3H), 3.76-3.78 (m, 2H), 7.01-7.14 (m, 3H), 7.25-7.28 (m, 1H), 7.49 (d, J=15.6 Hz, 1H), 8.10-8.16 (d, J=15.9 Hz, 1H); ESI-MS (m/z) 494.99 (M+H)+.
Reaction SMILES: [CH3:1][Li].[C:3]([B:7](OC(C)C)[O:8][CH:9]([CH3:11])[CH3:10])([CH3:6])([CH3:5])[CH3:4].[B]>>[C:3]([B:7]([CH3:1])[O:8][CH:9]([CH3:11])[CH3:10])([CH3:6])([CH3:5])[CH3:4]
Reactant: [Li]C
Reactant: CC(C)OB(OC(C)C)C(C)(C)C
Agent: [B]
Product: CB(OC(C)C)C(C)(C)C

Procedure:
The reaction was run following the procedure described in Example 1 using methyllithum (38.4 mmol, 24.6 mL) and tert-butyldiisopropoxyborane (7.15 g, 38.3 mmol). Volatiles were removed at atmospheric pressure and the product distilled to yield 3.9 g (27.5 mmol, 73%), bp 90°-92° C. (741 mm Hg); proton NMR (CDCl3) δ4.30 (septet, J=18 Hz, 1H), 1.15 (d, J=18 Hz, 6H), 0.83 (s, 9H), 0.30 (brs, 3H); boron NMR (neat) δ+52.9 ppm (s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8][CH2:9][C:10]2[CH:11]=[C:12]([C:21](=[O:27])[C:22]([O:24]CC)=[O:23])[N:13]([CH3:20])[C:14]=2[C:15]([O:17]CC)=[O:16])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([S:8][CH2:9][C:10]2[CH:11]=[C:12]([C:21](=[O:27])[C:22]([OH:24])=[O:23])[N:13]([CH3:20])[C:14]=2[C:15]([OH:17])=[O:16])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)c1cc(CSc2cccc(Cl)c2)c(C(=O)OCC)n1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1c(C(=O)C(=O)O)cc(CSc2cccc(Cl)c2)c1C(=O)O
Yield: 91.2 %

Procedure:
Ethyl 4(m-chlorophenylthio)methyl-5-ethoxycarbonyl-1-methyl-α-oxopyrrole-2-acetate (1.28 g, 3.1 mmol) is dissolved in refluxing ethanol (10 ml) and 2.5 N aqueous sodium hydroxide (9 ml, 22.5 mmol) is added. The mixture is heated at reflux for 1.5 hours after the solution becomes homogeneous, then it is cooled in ice and acidified to pH 2.0 with 6 N aqueous HCl. The resulting solid is collected, filtered and dried to give 1.00 g of 4-(m-chlorophenylthio)methyl-5-hydroxycarbonyl-1-methyl-α-oxopyrrole-2-acetic acid.
Reaction SMILES: [Cl:1]C1CCN(C)C1.[CH2:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CCOCC>[CH2:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[ClH:1]
Reactant: CN1CCC(Cl)C1
Solvent: CCOCC
Solvent: NCc1ccccc1
Product: Cl

Procedure:
Compound 3-chloro-1-methyl pyrrolidine, 1.33 g (0.0111 mol), and 6.9 ml (6.3 g, 0.063 mol) benzylamine were combined and gently refluxed at 150° for 8 hr. Et2O was added to the cooled reaction and the white solid that formed (benzylamine.HCl) was filtered. The filtrate was distilled at atmospheric pressure to remove Et2O, then at water aspirator vacuum to remove benzylamine (bp 78°-85°) and then at 0.1 mm Hg to yield 1.24 g (52%) colorless liquid, bp 85°-88°. This was dissolved in 150 ml Et2O, treated with 2.3 ml 6N ethanolic HCl, stirred in ice for 1 hr, and filtered. Trituration in hot abs. EtOH followed by filtration yielded 0.55 g white solid, mp 105°-110°. An additional 0.1 g crystallized from the mother liquor, mp 113°-118°. A white solid weighting 0.5 g, mp 90°- 98°, was precipitated from the mother liquor with Et2O. The HCl.salt, mp 113°-118°, analyzed as an hydrate. Analysis calculated for C12H18N2.2HCl.H2O (percent): C, 51.25; H, 7.89; N, 9.96. Found (percent): C, 51.04; H, 7.61; N, 9.78.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:10][CH2:9][O:8][C:6]1=[O:7])(=[O:3])[CH3:2].[CH3:11][SH:12]>>[C:1]([NH:4][C@H:5]([C:6]([OH:8])=[O:7])[CH2:10][CH2:9][S:12][CH3:11])(=[O:3])[CH3:2]
Reactant: CS
Reactant: CC(=O)NC1CCOC1=O
Product: CSCC[C@H](NC(C)=O)C(=O)O

Procedure:
Subsequently the N-acetyl-2-aminobutyrolactone (1 eq) was reacted with various bases in MeSH to give N-acetylmethionine. A mixture of N-acetylaminolactone, base and MeSH (14 eq) was heated in a sealed autoclave. After cooling, expansion and removal of MeSH, the remaining oil was analysed by HPLC. Further details and the yield of N-acetyl-L-methionine achieved are listed in the table below:
Reaction SMILES: C([N:3](CC)CC)C.ClC(OCC)=O.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH2:22][CH:21]([C:26]([OH:28])=O)[CH2:20][CH2:19]2.[NH4+].[OH-]>CC(C)=O>[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH2:22][CH:21]([C:26]([NH2:3])=[O:28])[CH2:20][CH2:19]2
Reactant: COc1ccc2c(c1)CCC(C(=O)O)C2
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(C)=O
Product: COc1ccc2c(c1)CCC(C(N)=O)C2
Temperature: -10 °C
Reaction time: 8 h
Yield: 59.2 %

Procedure:
A solution of triethylamine (2.7 ml, 0.019 mol) and ethyl chloroformate (2 ml, 0.021 mol) in acetone (40 ml) is added to a solution of the acid obtained in step (i) (3 g, 0.014 mol) in acetone (50 ml) cooled to -10° C. After 1,5 hours at -10° C., concentrated NH4OH (4.5 ml, 0.036 mol) is added dropwise and the reaction mixture is allowed to stand at -10° C. for 1 hour and at room temperature overnight. The solution is concentrated under vacuum, ethyl acetate (150 ml) is added to the obtained residue and the solution is washed sequentially with water, a saturated sodium bicarbonate solution, 6N hydrochloric acid, and water, then it is dried and concentrated to dryness. The residue is triturated with isopropyl ether and filtered thus affording 1.7 g of the above indicated amide; m.p. 136°-138° C.; [α]=+40.2° (c= 1.4%, CHCl3).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][C:7]1[S:11][C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[N:9][C:8]=1[CH3:22])C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH3:22][C:8]1[N:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[S:11][C:7]=1[CH2:6][CH2:5][CH2:4][OH:3]
Reactant: CCOC(=O)CCc1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCCO
Temperature: 0 °C
Reaction time: 5 h
Yield: 67.9 %

Procedure:
A solution of 3-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propionic acid ethyl ester (470 mg, 1.4 mmol) in tetrahydrofuran (5 ml) was added to a suspension of lithium aluminum hydride (53 mg, 1.4 mmol) in tetrahydrofuran (5 ml) under an argon atmosphere at ambient temperature within 5 min. The mixture was stirred for 5 h, cooled to 0° C. and treated cautiously with water (5 ml) and 10% aqueous NaOH (1 ml). The reaction mixture was filtered over celite, ice water/ethyl acetate 1/1 was added and the layers were separated. The aqueous layer was extracted one more time with ethyl acetate, the combined organic layers were washed with ice water/brine 1/1 and dried over sodium sulfate. Removal of the solvent under reduced pressure gave a yellow oil which was purified by column chromatography (silica gel, heptane/AcOEt) to yield 285 mg (950 μmol, 69%) of the title compound as colorless oil.