Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+:1].[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:16]C1COCCO1)([C:13]([OH:15])=[O:14])[C:10]([O-:12])=[O:11]>CO.CO.O>[Li+:1].[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:16])([C:10]([OH:12])=[O:11])[C:13]([O-:15])=[O:14]
Reactant: O=C([O-])C(Cc1ccccn1)(OC1COCCO1)C(=O)O
Agent: [Li+]
Solvent: CO
Solvent: O
Product: O=C([O-])C(O)(Cc1ccccn1)C(=O)O

Procedure:
A solution of 0.69 g of said compound in 12 ml of MeOH is hydrolysed at r.t. with 9.3 ml of the LiOH in MeOH-H2O solution, to give 0.4 g of 3-(pyrid-2-yl)-2-hydroxy-2-carboxypropanoic acid lithium salt, m.p. >300° C., I.R (nujol) 3400, 1640 cm-1HNMR (D2O) δ (TMS): 3.4 S, 7.2-7.35 m, 7.65-7.8 m, 6.3-8.4 m.
Reaction SMILES: [C:1](=[O:4])([O-])[O-:2].[K+].[K+].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[O:16][CH2:15][C:14](=O)[NH:13][C:12]=2[CH:18]=1.[CH3:19][S:20]([C:23]1[CH:28]=[CH:27]C(F)=[CH:25][CH:24]=1)(=[O:22])=[O:21]>CN1C(=O)CCC1.O>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([O:16][CH2:15][C:1]([OH:2])=[O:4])=[C:12]([NH:13][C:14]2[CH:27]=[CH:28][C:23]([S:20]([CH3:19])(=[O:22])=[O:21])=[CH:24][CH:25]=2)[CH:18]=1
Reactant: CS(=O)(=O)c1ccc(F)cc1
Reactant: O=C([O-])[O-]
Reactant: O=C1COc2ccc(Cl)cc2N1
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CS(=O)(=O)c1ccc(Nc2cc(Cl)ccc2OCC(=O)O)cc1
Temperature: 120 °C

Procedure:
Potassium carbonate (0.265 g) was added to a solution of the product from step (ii) (0.44 g) and 4-fluorophenyl methyl sulfone (0.331 g) in NMP (20 ml) and the mixture heated at 120° C. for 16 h. The reaction was diluted with water and extracted with ethylacetate, the organics were dried and evaporated under reduced pressure. The residue was purified by reverse phase HPLC, yield 0.096 g.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:18]=[C:17]3[CH:19]=[CH:20][N:21]([CH3:22])[C:16]3=[CH:15][C:14]=2[N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH3:12])[N:5]=[C:4](SC)[N:3]=1.O[O:32][S:33]([O-:35])=O.[K+].[C:37](#N)C>O.CCOC(C)=O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:18]=[C:17]3[CH:19]=[CH:20][N:21]([CH3:22])[C:16]3=[CH:15][C:14]=2[N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH3:12])[N:5]=[C:4]([S:33]([CH3:37])(=[O:35])=[O:32])[N:3]=1
Reactant: CSc1nc(N)c(C#N)c(N[C@@H](C)c2nc3ccn(C)c3cc2N2CCOCC2)n1
Reactant: O=S([O-])OO
Reactant: CC#N
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@H](Nc1nc(S(C)(=O)=O)nc(N)c1C#N)c1nc2ccn(C)c2cc1N1CCOCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(S)-4-Amino-6-((1-(1-methyl-6-morpholino-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)-2-(methylthio)pyrimidine-5-carbonitrile (287 mg, 0.676 mmol) in acetonitrile (3 mL) and H2O (3 mL) was cooled to 0° C. Oxone® (1.04 g, 1.690 mmol) was added to give a yellow solution. The reaction mixture was stirred at 0° C. for 30 minutes, warmed to room temperature, and stirred for an additional 3 hours. The reaction mixture was subsequently diluted with EtOAc and washed with H2O (3×5 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give the title compound, which was used without further purification.
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.[N+:19]([C:22]1[CH:32]=[CH:31][C:25]([CH2:26][O:27][C:28](Cl)=[O:29])=[CH:24][CH:23]=1)([O-:21])=[O:20].C(N(CC)CC)C>CO.[Pd].C(Cl)Cl>[OH:18][CH:16]1[CH2:17][N:14]([C:28]([O:27][CH2:26][C:25]2[CH:31]=[CH:32][C:22]([N+:19]([O-:21])=[O:20])=[CH:23][CH:24]=2)=[O:29])[CH2:15]1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CC(O)C1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 37.1 %

Procedure:
A solution of 1-benzhydryl-3-hydroxyazetidine (9.00 g, 37.6 mmol) in methanol (270 ml) was subjected to catalytic hydrogenation in the presence of 10% palladium on charcoal (9.00 g) in a water bath (50° C.) for 5.5 hours. After checking the completion of the reaction, the reaction mixture was filtered in order to remove the catalyst and the filtrate concentrated under reduced pressure. The residue was partitioned between ethyl acetate and distilled water. The organic layer was concentrated under reduced pressure and dried in vacuo to give a crude product. To a solution of the crude product in a mixture of methylene chloride (82 ml) and methanol (55 ml) were added chloroformic acid p-nitrobenzyl ester (8.90 g, 41.3 mmol) and triethylamine (5.79 ml, 41.3 mmol) in an ice bath. The mixture was stirred at room temperature for 1.5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The obtained organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (1:1)→ethyl acetate as the eluant to afford 3-hydroxy-1-(p-nitrobenzyloxycarbonyl)azetidine (3.52 g, yield 37%) as pale yellow crystals.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:31]=[CH:30][C:8]2[N:9]([C:12]3[CH:13]=[C:14]([NH:26][C:27](=[O:29])[CH3:28])[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=4[F:25])[CH:17]=3)[CH:10]=[N:11][C:7]=2[CH:6]=1)=O.[NH2:32][C:33]([NH2:35])=[S:34]>C(O)C>[NH2:35][C:33]1[S:34][C:3]([C:5]2[CH:31]=[CH:30][C:8]3[N:9]([C:12]4[CH:13]=[C:14]([NH:26][C:27](=[O:29])[CH3:28])[CH:15]=[C:16]([C:18]5[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=5[F:25])[CH:17]=4)[CH:10]=[N:11][C:7]=3[CH:6]=2)=[CH:2][N:32]=1
Reactant: CC(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(C(=O)CBr)ccc32)c1
Reactant: NC(N)=S
Solvent: CCO
Product: CC(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cnc(N)s4)ccc32)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 14.7 %

Procedure:
To a solution of N-(5-(5-(2-bromoacetyl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamide (100 mg, 0.20 mmol) in ethanol was added thiourea (20 mg, 0.30 mmol, 1.5 eq). The mixture was stirred at 60° C. for 3 h. The mixture was quenched and extracted as in Example 1(d). The solvent was distilled off to give the crude residue which was purified by preparative HPLC to give the product in 14.7% yield (14 mg). 1H NMR (300 MHz, CD3OD): δ 8.73 (s, 1H), 8.11 (s, 1H), 8.01 (s, 1H), 7.73-7.69 (m, 2H), 7.62-7.50 (m, 2H), 7.45 (d, 1H), 7.10-6.99 (m, 3H), 2.10 (s, 3H); LC-MS (ESI): Calculated mass: 461.4; Observed mass: 462.1 [M+H]+ (rt: 0.80 min).
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:2]([C:7]([NH:9][C:10]2[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=2)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.CCCCCC.S(Cl)([Cl:33])=O>>[C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:2]([C:7]([NH:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([Cl:33])=[O:15])=[CH:12][CH:11]=2)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccc(NC(=O)c2ccccc2-c2ccccc2)cc1
Reactant: O=S(Cl)Cl
Solvent: CCCCCC
Product: O=C(Cl)c1ccc(NC(=O)c2ccccc2-c2ccccc2)cc1

Procedure:
A mixture of 1.39 g of 4-[([1,1'-biphenyl]-2-carbonyl)amino]benzoic acid in 2.0 ml of thionyl chloride is heated on a steam bath for 1 hour. Cold hexane is added and the crystalline solid collected and dried to give 1.34 g of the desired product, m.p. 118°-120° C.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([C:16]([NH2:18])=O)=[C:5]2[C@@H:4]2[CH2:19][CH2:20][N:3]12.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCOCC1.N1C=CC=CC=1>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([C:16]#[N:18])=[C:5]2[C@@H:4]2[CH2:19][CH2:20][N:3]12
Reactant: NC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1ccccc1-2
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: N#Cc1ncn2c1[C@@H]1CCN1C(=O)c1ccccc1-2
Temperature: 0 °C
Reaction time: 2 h
Yield: 82.5 %

Procedure:
A suspension of 78 g (0.78 g mol) of (S)-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxamide in a mixture of 380 ml of dioxan and 68 ml of pyridine was treated dropwise at 0° with 59 ml (0.424 mol) of trifluoroacetic anhydride. The suspension was stirred at 50° for 2 hrs., cooled and poured on to 2 l of ice-water. After vigorous stirring the suspension was suction filtered. There were obtained 60 g (82%) of (S)-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carbonitrile; m.p. 232-234°.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)/[C:4](=[N:11]/O)/[CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([NH2:11])[CH2:3][CH2:2]1
Reactant: O/N=C1\CCOc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NC1CCOc2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.9 %

Procedure:
To a solution of (4E)-2,3-dihydro-4H-chromen-4-one oxime (3.20 g) in tetrahydrofuran (50 ml) under N2 atmosphere was added lithium aluminum hydride (1M THF, 50 ml). The reaction mixture stirred at ambient temperature for 16 h and was quenched with 10 ml of water, 10 ml of 2 N NaOH and 20 ml of water. The reaction mixture was filtered through celite, acidified with 1 N HCl (50 ml), washed with ethyl ether (2×50 ml), basified with 2 N NaOH, extracted methylene chloride (3×100 ml), dried MgSO4, filtered and concentrated. MPLC was run on a biotage 40S column with 2–4% methanol/methylene chloride with 0.5% ammonium hydroxide to provide the title compound as an oil (728 mg, 25%): 1H NMR (300 MHz, CDCl3) δ) 7.34, 7.17, 6.92, 6.85, 4.31–4.24, 4.09, 2.18, 1.91–1.86; HRMS (FAB) calcd for C9H11NO+H 150.0919, found 150.0910.
Reaction SMILES: [C:1]([Cl:4])([Cl:3])=[O:2].[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(Cl)Cl>[Cl-:3].[Cl:4][C:1]([N+:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: c1ccncc1
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)[n+]1ccccc1
Product: [Cl-]
Yield: 95.3 %

Procedure:
280 g (2.83 mols) of phosgene and 224 g (2.83 mols) of pyridine are metered synchronously into 1,600 g of methylene chloride at -10° C. in the course of 180 minutes. A fine-crystalline, pale yellow suspension results. After filtration with suction, with exclusion of moisture, 480 g (=95.5% of theory) of N-chlorocarbonyl-pyridinium chloride of decomposition point 60° C. are obtained.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[S:15][CH:16]=[CH:17][C:18]=1[NH:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]2[NH:26][CH:27]=[CH:28][C:21]=12)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:38](Cl)(=[O:40])[CH3:39]>O1CCCC1>[C:38]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][CH2:10][NH:11][C:12]([C:14]1[S:15][CH:16]=[CH:17][C:18]=1[NH:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]2[NH:26][CH:27]=[CH:28][C:21]=12)=[O:13])(=[O:40])[CH3:39]
Reactant: CC(=O)Cl
Reactant: O=C(NCCNCc1ccccc1)c1sccc1Nc1ccnc2[nH]ccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)N(CCNC(=O)c1sccc1Nc1ccnc2[nH]ccc12)Cc1ccccc1
Yield: 24 %

Procedure:
A solution of 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid (2-benzylamino-ethyl)-amide (95 mg, 0.24 mmol), diisopropylethylamine (84 uL, 0.49 mmol) and acetyl chloride (25 uL, 0.37 mmol) in tetrahydrofuran (2.0 mL) was stirred at room temperature for 18 h. The solution was concentrated in vacuo then purified by ISCO Companion (silica, 10% methanol, methylene chloride, 1% ammonium hydroxide) to afford 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid [2-(acetyl-benzyl-amino)-ethyl]-amide (25 mg, 24%). LCMS (ESI) 434 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.56 (1H, br. s.) 10.16-10.43 (1H, m) 8.15 (0H, t, J=5.00 Hz) 8.02 (1H, t, J=2.71 Hz) 7.72-7.86 (1H, m) 7.44-7.54 (1H, m) 7.13-7.39 (6H, m) 6.83 (1H, dd, J=12.23, 5.49 Hz) 6.36-6.50 (1H, m) 4.49-4.61 (2H, m) 3.34-3.50 (4H, m) 1.91-2.19 (3H, m)
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]([CH2:13]CO)[CH2:10][CH2:11]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:18])=O.[CH:20]([Cl:23])(Cl)Cl>>[ClH:18].[C:1]1([CH2:7][CH2:8][N:9]([CH2:13][CH2:20][Cl:23])[CH2:10][CH2:11][Cl:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClC(Cl)Cl
Reactant: OCCN(CCO)CCc1ccccc1
Reactant: O=S(Cl)Cl
Product: Cl
Product: ClCCN(CCCl)CCc1ccccc1

Procedure:
To a solution of 20.0 g (95 mmoles) of N-(2-phenylethyldiethanolamine in 40 mL of chloroform was added, over a period of 1 hour, 20 mL of thionyl chloride in 20 mL of chloroform. The mixture was heated under reflux for 2 hours and concentrated to give N-(2-phenylethyl)-N,N-bis(2-chloroethyl)amine hydrochloride as an oil. NMR (CDCl3) δ7.2-7.4 (m, 5H); 4.1 (t, 4H); 3.6 (t, 4H); 3.5 (m, 2H) and 3.2 (m, 2H).
Reaction SMILES: S(C)C.[CH3:4][Li].[C:6]([NH:25][C@@H:26]([CH2:29][CH3:30])[CH:27]=[O:28])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH4+].[Cl-]>CCOCC>[C:6]([NH:25][C@@H:26]([CH2:29][CH3:30])[C@H:27]([OH:28])[CH3:4])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: [Li]C
Reactant: CC[C@@H](C=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CSC
Product: CC[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@@H](C)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of CuBr.SMe2 (3 g, 14.6 mmol) in anhydrous ether (100 ml) under an argon atmosphere at −78° C., was added methyl lithium (1.6M in ether, 16.5 ml, 4.0 eq, 26.5 mmol) dropwise and the solution allowed to warm to room temperature over 1 h. The mixture was recooled to −78° C., and a solution of (S)-2-(trityl-amino)-butyraldehyde (2.2 g, 6.62 mmol) in ether (25 ml) was added dropwise with stiffing. The reaction mixture was stirred at this temperature for 2 h then allowed to warm to room temperature over 1 h. A saturated aqueous solution of NH4Cl (50 ml) was added and the two layers separated. The organic phase was washed with brine (50 ml), dried (MgSO4) and evaporated in vacuo. The residue was purified by flash silica gel column chromatography, eluted with hexane:ethyl acetate (80:20) to afford (2R,3S)-3-(trityl-amino)-pentan-2-ol as a light yellow oil; Yield: 1.5 g (66%). (75% de 2R, 3S: 25% de 2S, 3S). 1H-NMR (d6-DMSO, 250 MHz): δ 0.0.47+0.55 (2×t, J=7.50+7.26 Hz —NHCH(CH2CH3)CH(CH3)OH), 0.99-1.12 (m, 5 H, —NHCH(CH2CH3)CH(CH3)OH), 2.01 (1 H, m, —NHCH(CH2CH3)CH(CH3)OH), 3.22-3.43 (m, 1H, —NHCH(CH2CH3) CH(CH3)OH), 4.41 [1 H, d, J=3.3, NHCH(CH2CH3)CH(CH3)OH], 7.14-7.56 (15 H, m, ArH). δC (250 MHz, CDCl3) 146.88 (C), 128.97 (6×CH), 127.83 (6×CH), 126.43 (3×CH), 71.03 (C), 68.13 (CH), 58.77 (CH), 23.09 (CH2), 17.88 (CH3), 10.47 (CH3)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH3:28])=[C:7]([N:9]([CH2:14][C:15]([N:17]([N:19]2[CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20]2)[CH3:18])=[O:16])[CH2:10][C:11]([OH:13])=[O:12])[CH:8]=1)#[N:2].CCN=C=NCCCN(C)C.[C:40](O)([CH3:43])([CH3:42])[CH3:41]>CN(C)C1C=CN=CC=1.ClCCl.C(OCC)(=O)C.CCCCCC>[C:40]([O:12][C:11](=[O:13])[CH2:10][N:9]([C:7]1[CH:8]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=1[CH3:28])[CH2:14][C:15]([N:17]([N:19]1[CH2:20][C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:27]1)[CH3:18])=[O:16])([CH3:43])([CH3:42])[CH3:41]
Reactant: CC(C)(C)O
Reactant: Cc1ccc(C#N)cc1N(CC(=O)O)CC(=O)N(C)N1Cc2ccccc2C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccc(C#N)cc1N(CC(=O)OC(C)(C)C)CC(=O)N(C)N1Cc2ccccc2C1
Reaction time: 8 h
Yield: 74.5 %

Procedure:
The compound (2.06 g, 5.44 mmol) of Example 1, step A, 4-dimethylaminopyridine (1.40 g, 11.5 mmol) and WSC (1.46 g, 7.62 mmol) were dissolved in dichloromethane (22 ml), tert-butanol (1.0 ml, 10 mmol) was added at room temperature, and the mixture was stirred at the same temperature overnight. The reaction mixture was diluted with an ethyl acetate-hexane=1:1 mixed solvent, and the organic layer was washed with 10% aqueous citric acid solution, water, diluted aqueous sodium hydroxide solution and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography (ethyl acetate-hexane) to give the title compound (1.76 g, yield 74%) as a colorless solid.
Reaction SMILES: [C:1]([C:3]1[C:4]([O:30][CH:31]([CH3:33])[CH3:32])=[CH:5][C:6]([NH:9][C:10]([N:12]2[C:21]3[C:16](=[CH:17][C:18]([CH2:27][NH:28][CH3:29])=[C:19]([CH:22]([O:25][CH3:26])[O:23][CH3:24])[N:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])=[N:7][CH:8]=1)#[N:2].CCN(CC)CC.[CH3:41][N:42]([CH3:47])[CH2:43][C:44](Cl)=[O:45]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:1]([C:3]1[C:4]([O:30][CH:31]([CH3:33])[CH3:32])=[CH:5][C:6]([NH:9][C:10]([N:12]2[C:21]3[C:16](=[CH:17][C:18]([CH2:27][N:28]([CH3:29])[C:44](=[O:45])[CH2:43][N:42]([CH3:47])[CH3:41])=[C:19]([CH:22]([O:25][CH3:26])[O:23][CH3:24])[N:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])=[N:7][CH:8]=1)#[N:2]
Reactant: CN(C)CC(=O)Cl
Reactant: CNCc1cc2c(nc1C(OC)OC)N(C(=O)Nc1cc(OC(C)C)c(C#N)cn1)CCC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(OC)c1nc2c(cc1CN(C)C(=O)CN(C)C)CCCN2C(=O)Nc1cc(OC(C)C)c(C#N)cn1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
To a solution of N-(5-cyano-4-isopropoxypyridin-2-yl)-7-(dimethoxymethyl)-6-((methylamino)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 191, 212 mg, 0.466 mmol) in DCM (4 ml) at 0° C. was added NEt3 (0.103 ml, 0.746 mmol) and 2-(dimethylamino)acetyl chloride (91 mg, 0.49 mmol) and the reaction mixture was stirred for 75 min. Additional NEt3 (0.103 ml, 0.746 mmol) was added and the reaction was continued to stir at 0° C. for 30 min. The reaction mixture was allowed to warm to room temperature and a total of NEt3 (0.206 ml, 1.486 mmol) and 2-(dimethylamino)acetyl chloride (273 mg, 1.469 mmol) and DCM (2 ml) were added stepwise during the next 22 h. The reaction mixture was diluted with saturated aqueous NaHCO3 and DCM. Phases were separated and the water phase was extracted with DCM (2×), organic phases were combined and dried using Na2SO4, filtered and concentrated. The crude product was purified using silica gel column chromatography eluting with a gradient of MeOH (3-10%) in DCM. Fractions containing the product were combined and evaporated to yield the title compound as a brown solid. (UPLC-MS 3) tR 0.90 min, ESI-MS 540.3 [M+H]+. 1H NMR (600 MHz, CDCl3) (indicates an overlapping mixture of rotamers of the title compound in an approximate mixture of 0.6:0.4) δ 13.92 (s, 0.6H), 13.83 (s, 0.4H), 8.31-8.26 (m, 1H), 7.90-7.85 (m, 1H), 7.38 (s, 0.6H), 7.23 (s, 0.4H), 5.38 (s, 0.6H), 5.33 (s, 0.4H), 4.83-4.72 (m, 3H), 4.02-3.93 (m, 2H), 3.44 (s, 2.4H), 3.42 (s, 3.6H), 3.18 (s, 1.2H), 3.08 (s, 0.8H), 2.92 (s, 1.8H), 2.87 (s, 1.2H), 2.79-2.72 (m, 2H), 2.34 (s, 3.6H), 2.26 (s, 2.4H), 1.98-1.88 (m, 2H), 1.41-1.34 (m, 6H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[NH:10]([CH2:14]CO)[CH2:11][CH2:12][OH:13].C=[O:18]>O1CCOCC1>[CH:8]1[CH:7]=[N:6][CH:5]=[C:4]([C:1]([CH2:2][CH2:14][NH:10][CH2:11][CH:12]([OH:18])[OH:13])=[O:3])[CH:9]=1
Reactant: C=O
Reactant: CC(=O)c1cccnc1
Reactant: OCCNCCO
Solvent: C1COCCO1
Product: O=C(CCNCC(O)O)c1cccnc1

Procedure:
3-acetylpyridine (126 mg), diethanol amine (114 mg), and paraformaldehyde (36 mg) were reacted in dioxane (0.2 ml) at 150° C. for 2 hours.
Reaction SMILES: [CH2:1]([C:3]1C=C[C:6]([CH2:7][S:8][C:9]2[CH:10]=[C:11]([O:19][CH2:20][O:21][CH3:22])[C:12](=[O:18])[N:13]([CH2:15][O:16][CH3:17])[CH:14]=2)=[CH:5][CH:4]=1)C.ClCC1C=CC=C[N:28]=1>>[CH3:22][O:21][CH2:20][O:19][C:11]1[C:12](=[O:18])[N:13]([CH2:15][O:16][CH3:17])[CH:14]=[C:9]([S:8][CH2:7][C:6]2[CH:5]=[CH:4][CH:3]=[CH:1][N:28]=2)[CH:10]=1
Reactant: CCc1ccc(CSc2cc(OCOC)c(=O)n(COC)c2)cc1
Reactant: ClCc1ccccn1
Product: COCOc1cc(SCc2ccccn2)cn(COC)c1=O

Procedure:
Prepared as described for 5-[(4-ethylbenzyl)sulfanyl]-3-(methoxymethoxy)-1-(methoxymethyl)pyridin-2(1H)-one (Intermediate 17) but using 2-chloromethylpyridine instead of 1-(chloromethyl)-4-ethylbenzene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([OH:14])=O)[C:6](=[O:15])[CH2:5]2.[C:16]([C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>C(Cl)Cl.CN(C=O)C>[C:16]([C:20]1[CH:21]=[CH:22][C:23]([NH:24][C:12](=[O:14])[CH2:11][N:7]2[C:8]3[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)[CH2:5][C:6]2=[O:15])=[CH:25][CH:26]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: O=C(O)CN1C(=O)Cc2cc(Cl)ccc21
Reactant: CC(C)(C)c1ccc(N)cc1
Agent: *CC(*)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)c1ccc(NC(=O)CN2C(=O)Cc3cc(Cl)ccc32)cc1
Reaction time: 40 h

Procedure:
In a 1 ml polypropylene vial, 300 μl of a 0.15 M stock solution of (5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetic acid 59 in a 1/1 CH2Cl2/DMF mixture were added onto N-dicyclohexyl-N-methyl polystyrene (from Novabiochem, loading: 1.9 mmol/g, 35 mg) and N,N-diisopropyl-methyl-polystyrene (from Argonaut, loading: 3.49 mmol/g, 25.4 mg) followed by 4tertbutyl-aniline (0.044 mmol, 6.6 mg). The reaction mixture was stirred 40 h under vortex and quenched with DMF (400 μl). The suspension was allowed to sediment and the liquid was concentrated under vacuo to afford N-(4-tert-butyl-phenyl)-2-(5-chloro-2-oxo-2,3-dihydro-indol-1-yl)-acetamide 85 (10 mg).
Reaction SMILES: [CH2:1]1[S:6][C:4](=[O:5])[NH:3][C@@H:2]1[C:7]([OH:9])=[O:8].P(OC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1O)(OP(OP(O)(O)=O)(O)=O)(=O)[OH:11]>>[C:4]([S:6][CH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[NH2:3])([OH:11])=[O:5]
Reactant: O=C1N[C@H](C(=O)O)CS1
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Product: N[C@@H](CSC(=O)O)C(=O)O

Procedure:
L-2-oxothiazolidine-4-carboxylate is subjected to the action of 5-oxo-L-prolinase in the presence of adenosine triphosphate to produce S-carboxyl cysteine. S-carboxyl cysteine is then decarboxylated to produce cysteine. Cysteine is then metabolized to provide glutathione. See, U.S. Pat. Nos.: 4,335,210; 4,434,158; 4,438,124; 4,665,082; and 4,647,571, the disclosures of which are incorporated herein by reference.
Reaction SMILES: [NH2:1][C:2]1[C:7]([SH:8])=[N:6][C:5]([Cl:9])=[C:4]([Cl:10])[N:3]=1.[C:11](OC(=O)C)(=O)[CH3:12]>C1(C)C(C)=CC=CC=1>[Cl:10][C:4]1[N:3]=[C:2]2[N:1]=[C:11]([CH3:12])[S:8][C:7]2=[N:6][C:5]=1[Cl:9]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc(Cl)c(Cl)nc1S
Solvent: Cc1ccccc1C
Product: Cc1nc2nc(Cl)c(Cl)nc2s1
Temperature: 110 °C
Reaction time: 15 h
Yield: 64 %

Procedure:
A mixture of 9.8 g. (0.05 mol.) of 2-amino-5,6-dichloro-3-mercaptopyrazine and 5.1 g. (0.05 mol.) of acetic anhydride in 100 ml. of xylene was heated at 110° C. for 1 hour. The reaction mixture was cooled, another 5.1 g. of acetic anhydride was added and heating at 110° C. was continued for 15 hours. The reaction mixture was concentrated under reduced pressure to give a dark oil, which solidified under isopropanol-hexane while cooling in ice. The dark solid was purified by sublimation to give 7 g. (64% yield) of white solid, m.p. 58°-60° C.