Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH2:10][CH2:11][O:12][CH2:13][C:14](O)=[O:15])[CH:8]=[CH:9][C:2]1=2.B.[Na].C(OCC)(=O)C.Cl>O1CCCC1.O>[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][OH:15])[CH:8]=[CH:9][C:2]1=2
Reactant: O=C(O)COCCc1ccc2sccc2c1
Agent: B
Agent: Cl
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: OCCOCCc1ccc2sccc2c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 92.1 %

Procedure:
In 27 mL of tetrahydrofuran is dissolved 2.70 g of 2-(2-benzo[b]thiophen-5-ylethoxy)-acetic acid. At an ice-cooled temperature, 0.65 g of sodium boron hydride is added to the solution, and stirred at the same temperature as above for 10 minutes. Then, at an ice-cooled temperature, 3.24 g of boron trifluoride diethyl ether complex is added to the reaction mixture over a period of 20 minutes, and the resulting mixture is stirred at the same temperature as above for 30 minutes and then at ambient temperature for 2 hours. The reaction mixture is introduced into a mixture of ethyl acetate and water, pH is adjusted to 1.0 with 2 mol/L hydrochloric acid, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is purified by column chromatography (eluent: n-hexane:ethyl acetate=3:1 to 2:1) to obtain 2.34 g of 2-(2-benzo[b]thiophen-5-ylethoxy)-1-ethanol as an oily product.
Reaction SMILES: [CH3:1][N:2]([CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])[C:3]1[CH:8]=[N:7][CH:6]=[C:5]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[N:4]=1.C(OC(C)C)(C)C>FC(F)(F)C(O)=O>[CH3:1][N:2]([CH2:20][C:21]([OH:23])=[O:22])[C:3]1[CH:8]=[N:7][CH:6]=[C:5]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[N:4]=1
Reactant: CN(CC(=O)OC(C)(C)C)c1cncc(-c2nc(=O)c3ccccc3s2)n1
Solvent: CC(C)OC(C)C
Solvent: O=C(O)C(F)(F)F
Product: CN(CC(=O)O)c1cncc(-c2nc(=O)c3ccccc3s2)n1
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
tert-Butyl {methyl[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyrazinyl]amino}acetate (0.20 g, 0.52 mmol) was dissolved in trifluoroacetic acid (5 ml), and the mixture was stirred for 0.5 hr. Diisopropyl ether was added thereto. The obtained precipitates were recrystallized from ethanol to give the titled compound (0.15 g, 87%) as pale yellow crystals
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)=[C:6]([Cl:16])[CH:5]=[CH:4][N:3]=1.[CH3:17][N:18](C=O)C>O.[C-]#N.[Zn+2].[C-]#N.[Zn].C([O-])(=O)C.[Zn+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Cl:16][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:17]#[N:18])[C:7]=1[CH2:8][O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1
Reactant: CN(C)C=O
Reactant: Clc1ccnc(Cl)c1COC1CCCCO1
Agent: [Fe+2]
Agent: CC(=O)[O-]
Agent: [C-]#N
Solvent: O
Product: N#Cc1nccc(Cl)c1COC1CCCCO1
Temperature: 95 °C

Procedure:
2,4-Dichloro-3-(tetrahydro-pyran-2-yloxymethyl)-pyridine (455 mg. 1.74 mmol) was dissolved in a mixture of DMF (3 mL) and water (30 μL). The following reagents were added subsequently: zinc cyanide (112 mg. 0.95 mmol), zinc dust (9.1 mg. 139 μmol), zinc acetate (25.5 mg. 139 μmol). 1,1′-bis(diphenylphosphino)ferrocene (58 mg. 104 μmol) and tris(dibenzylideneacetone)palladium (0). The reaction mixture was degassed two times and afterwards heated at 95° C. for 4 h. The solvents were removed in vacuo and the residue was pardoned between water (20 mL) and EtOAc (20 mL) and extracted with EtOAc (3×20 ml). The combined organic layers were washed with brine and dried over Na2SO4 filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with hexane/EtOAc 10:1→5:1) to give the title compound. MS (m/z): 253.0 [M+H+].
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]#[C:22][C:23]4[CH:33]=[CH:32][C:26]([C:27]([O:29]CC)=[O:28])=[CH:25][CH:24]=4)[CH:19]=3)[O:14][C:13]([CH3:35])([CH3:34])[CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[OH-].[Na+].Cl>C1COCC1.CCO>[CH3:4][C:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]#[C:22][C:23]4[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:32][CH:33]=4)[CH:19]=3)[O:14][C:13]([CH3:35])([CH3:34])[CH:12]=2)=[CH:9][CH:10]=1)([CH3:1])[CH3:3]
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C(C)(C)C)cc2)=CC(C)(C)O3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)C=C(c2ccc(C(C)(C)C)cc2)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc2O1
Temperature: 35 °C
Reaction time: 8 h
Yield: 73.9 %

Procedure:
To a solution of ethyl 4-[[4-(4-(1,1-dimethylethyl)phenyl)-2,2-dimethyl(2H)-chromen-6-yl]-ethynyl]-benzoate (Compound 269, 72.0 mg, 0.155 mmol) in 3.0 mL THF and 3.0 mL EtOH was added NaOH (120.0 mg, 3.0 mmol, 3.0 mL of a 1M aqueous solution). The resulting solution was heated to 35° C., cooled to room temperature and stirred overnight. The reaction mixture was acidified with 10% aqueous HCl and extracted with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NaCl, and dried (Na2SO4) before the solvent was removed under reduced pressure. The residual solid was recrystallized from CH3CN to give 50.0 mg (74%) the title compound as a colorless solid. 1H NMR (300 MHz, d6 -acetone) δ: 8.00 (2H, d, J=8.3 Hz), 7.57 (2H, d, J=8.3 hz), 7.51 (2H, d, J=8.3 Hz), 7.41 (1H, dd, J=2.0, 8.3 Hz), 7.31 (2H, d, J=8.3 Hz), 7.19 (1H, d, J=2.0 Hz), 6.91 (1H, d, J=8.3 Hz), 5.78 (1H, s), 1.49 (6H, s), 1.35 (9H, s).
Reaction SMILES: ClP([N:5]=[C:6]=[O:7])(Cl)=O.[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1/[C:13](=[N:31]/[O:32][CH3:33])/[C:14]([NH:16][C@@H:17]1[C:29](=[O:30])[N:19]2[C:20]([C:26]([OH:28])=[O:27])=[C:21]([CH2:24][OH:25])[CH2:22][S:23][C@H:18]12)=[O:15].C([O-])(=O)C.[Na+]>C1COCC1.O>[CH3:33][O:32]/[N:31]=[C:13](\[C:14]([NH:16][C@@H:17]1[C:29](=[O:30])[N:19]2[C:20]([C:26]([OH:28])=[O:27])=[C:21]([CH2:24][O:25][C:6]([NH2:5])=[O:7])[CH2:22][S:23][C@H:18]12)=[O:15])/[C:9]1[O:8][CH:12]=[CH:11][CH:10]=1
Reactant: O=C=NP(=O)(Cl)Cl
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12)c1ccco1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1ccco1
Reaction time: 0.25 h

Procedure:
Dichlorophosphinyl isocyanate (1.46 ml,) was added to a solution of (6R,7R)-7-[Z-2-(fur-2-yl)-2-methoxyiminoacetamido]-3-hydroxymethylceph-3-em-4-carboxylic acid (3.81 g) in THF (50 ml) at 22°, the temperature rising to 31°. The reaction mixture was stirred for 15 minutes and then added to a solution of sodium acetate (5.72 g) in water (50 ml). More sodium acetate (1.64 g) was added over 10 minutes to give a stable pH of 4.6. This solution was stirred at 30° for 1 hour and then heated at 45° for 3.5 hours when TLC (as Example 3) showed the reaction to be complete. The solution, pH 4.6, was clarified by filtration, adjusted to pH 7.0 with aqueous NaHCO3 solution and washed twice with ethyl acetate. The aqueous phase was stirred and acidified to pH 1.9 with dilute hydrochloric acid to precipitate the title compound (2.80 g, 66.0%); purity by HPLC 95.8% and by TLC 96%.
Reaction SMILES: IC.[H-].[Na+].[Cl:5][C:6]1[CH:7]=[C:8]2[N:26]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:25]([O:35][C@H:36]3[C@H:40]4[O:41][CH2:42][C@@H:43]([OH:44])[C@H:39]4[O:38][CH2:37]3)=[N:24][C:9]2=[N:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=1.[CH3:45]COC(C)=O.CCCCCC>CN(C=O)C.CCOC(C)=O>[CH3:45][O:44][C@@H:43]1[CH2:42][O:41][C@@H:40]2[C@H:36]([O:35][C:25]3[N:26]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:8]4[C:9]([N:24]=3)=[N:10][C:11]([C:12]3[CH:17]=[CH:16][C:15]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)=[CH:14][CH:13]=3)=[C:6]([Cl:5])[CH:7]=4)[CH2:37][O:38][C@H:39]12
Reactant: CCOC(C)=O
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CI
Product: CO[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Iodomethane (40 μl, 0.640 mmol) and sodium hydride (7.7 mg, 0.193 mmol) were added to a stirred solution of (3R,3aR,6R,6aR)-6-[6-chloro-5-(4-phenylphenyl)-1-(2-trimethylsilylethoxymethyl)imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol (35.6 mg, 0.061 mmol) in DMF (0.2 ml). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was then partitioned between EtOAc (40 ml), water (10 ml), and 2 N HCl (10 ml). The organic layer was washed with water (2×20 ml) and brine (1×10 ml), dried over MgSO4, filtered, and evaporated under reduced pressure to give a pale amber residue. The residue was dissolved in EtOAc and loaded onto a 500 micron 20 cm×20 cm silica gel plate, which was developed using 70% EtOAc/hexane. The silica containing the product bands was collected and eluted with EtOAc (80 ml). The solvent was evaporated under reduced pressure to give the desired product as a colorless residue. LC-MS: calculated for C31H36ClN3O5Si 593.21 observed m/e: 594.24 (M+H)+ (Rt 1.40/2 min)
Reaction SMILES: O[C:2](C)(C#C)[CH2:3][C:4]1[CH:5]=[C:6]([CH:10]2[N:14]([CH3:15])[C:13](=[O:16])[CH2:12][CH2:11]2)[CH:7]=[N:8][CH:9]=1.[H-].[Na+].C1(C)C=CC=CC=1.CC(C)=O>C1(C)C=CC=CC=1>[C:3]([C:4]1[CH:5]=[C:6]([CH:10]2[N:14]([CH3:15])[C:13](=[O:16])[CH2:12][CH2:11]2)[CH:7]=[N:8][CH:9]=1)#[CH:2]
Reactant: C#CC(C)(O)Cc1cncc(C2CCC(=O)N2C)c1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: C#Cc1cncc(C2CCC(=O)N2C)c1
Temperature: 25 °C
Yield: 81.1 %

Procedure:
5-(2-Hydroxy-2-methyl-3-butynyl)-3-(1-methyl-5-pyrrolidin-2-onyl)pyridine (200 mg, 0.77 mmol) was dissolved in toluene (20 mL) and catalytic sodium hydride (5 mg) was added. The solution was heated until several milliliters of toluene-acetone mixture were removed by distillation. The mixture was cooled to 25° C. and water (10 mL) and ethyl acetate (20 mL) were added. The organic phase was separated and the aqueous layer extracted with ethyl acetate (2×20 mL) and the combined organic extracts were washed with brine (10 mL), dried (MgSO4) and concentrated in vacuo. The crude product was purified by silica gel column chromatography with ethyl acetate as eluant to afford 5-ethynyl-3-(1-methyl-5-pyrrolidin-2-onyl)pyridine as a solid (125 mg, 81%). M.p. 83°-84° C.; 1H NMR (CDCl3, 300 MHz): δ 8.69 (d, J=2 Hz, 1H), 8.46 (d, J=2 Hz, 1H), 7.62 (t, J=2 Hz, 1H), 4.57 (dd, J=7, 6 Hz, 1H), 3.28 (s, 1H), 2.70 (s, 3H), 2.45-2.65 (m, 3H), 1.88 (m, 1H).
Reaction SMILES: [NH:1]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C@@H:2]([C:13]([NH:15][C@H:16]([C:27]([O:29][CH3:30])=[O:28])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=1)=[O:14])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][CH:5]=1>C(O)(=O)C.[Pd]>[NH:1]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C@@H:2]([C:13]([NH:15][C@H:16]([C:27]([O:29][CH3:30])=[O:28])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1)=[O:14])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1
Reactant: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)[C@@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)[C@@H](Cc1ccc(N)cc1)NC(=O)OC(C)(C)C

Procedure:
1.6 g (3.00 mmol) Boc-D-Phe(4-NO2)-Phe(4-NO2)—OMe (4a) was dissolved in 150 ml of 90% acetic acid. Then, 160 mg Pd—C was added, purged 3× and hydrogenated overnight at RT. After filtration of the suspension, the solvent was removed in vacuo. The residue was taken up in sat. NaHCO3 soln./EtOAc and the organic phase was washed 3× with sat. NaHCO3 soln. and 2× with sat. NaCl soln. The organic phase was dried with MgSO4, followed by filtration and removal of the solvent in vacuo.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[C:3]=1[N+:11]([O-])=O.O.O.[C:16](O)(=[O:20])[C:17](O)=[O:18]>C(O)C.Cl>[OH:18][C:17]1[C:16]([OH:20])=[N:1][C:2]2[CH:10]=[CH:9][C:5]3[S:6][CH:7]=[CH:8][C:4]=3[C:3]=2[N:11]=1
Reactant: O=C(O)C(=O)O
Reactant: Nc1ccc2sccc2c1[N+](=O)[O-]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Oc1nc2ccc3sccc3c2nc1O
Yield: 38.8 %

Procedure:
A solution of 5-amino-4-nitrobenzo[b]thiophene (0.50 g, 2.6 mmol) in 50 ml of 96% ethanol was hydrogenated at room temperature and atm. pressure in the presence of 5% palladium-on-carbon until the theoretical amount of hydrogen was absorbed. The catalyst was filtered off, and the filtrate was acidified with 1N hydrochloric acid and evaporated to dryness. The residue was refluxed with oxalic acid dihydrate (0.40 g, 3.1 mmol) in 25 ml of 4M hydrochloric acid for 2 h. The mixture was cooled, and the precipitated solid was isolated by filtration, washed with water, ethanol and ether, and dried. The crude product was dissolved in a minimum amount of 2N sodium hydroxide, treated with decolourising charcoal, and filtered. The filtrate was acidified with 4M hydrochloric acid and the resulting precipitate was collected by filtration, washed with water, ethanol and ether to give 0.22 g (39%) of the thienoquinoxaline; m.p. 186.6° C.; IR (KBr): 1680 cm-1 ; H-NMR (DMSO-d6 ): 7.13 (d,J=9 Hz, 1H, ArH), 7.62 (D,J=9 Hz, 1H, ArH), 7.72 (d,J=5 Hz, 1H, ArH), 7.95 (d,J=5 Hz, 1H, ArH); MS m/z: 218 (M+, 100%).
Reaction SMILES: [CH:1](=[O:10])[C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=1.C([O:14][C:15](=[O:17])[CH3:16])(=O)C>C(Cl)(Cl)(Cl)Cl>[C:5]([O:6][CH:5]([O:14][C:15](=[O:17])[CH3:16])[C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([CH:1]([O:17][C:15](=[O:14])[CH3:16])[O:10][C:1](=[O:10])[CH3:2])[CH:3]=1)(=[O:6])[CH3:4]
Reactant: CC(=O)OC(C)=O
Reactant: O=Cc1cccc(C=O)c1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)OC(OC(C)=O)c1cccc(C(OC(C)=O)OC(C)=O)c1
Temperature: 30 °C

Procedure:
Isophtalaldehyde (10.0 g, 0.075 mol) and acetic acid anhydride (16.7 g, 0.164 mol) were mixed under N2 -atmosphere in carbontetrachloride (25 ml). Nafion NR 50 was added and the reaction mixture stirred at 30° C. for several days. During this period additional amounts of catalyst (100 mg) and solvent (5 ml) were added. The catalyst was filtered off and also the reaction mixture was filtered, washing with ether. The crude solid was recrystallized from cyclohexane (540 ml), giving white crystals, m.p. 110-130° C. The yield was 10.3 g, 41% of the theoretical. 1H- and 13C NMR (CDCl3), d (ppm) rel. to TMS: 7.72 (s, 1H, CH(OAc)2), 7.70-7.42 (m, 1+2+1H, Ar-H) and 2.13 (s, 6H, CH3); 168.591 (C=O), 135.908, 128.885, 128.047 and 124.879 (Ar), 89.072 (CH(OAc)2) and 20.717 (CH3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[O:5][CH2:6][CH2:7]Cl.[C:13]([O-:18])(=[O:17])[C:14]([CH3:16])=[CH2:15].[K+].[I-].[K+].C1(C=CC(O)=CC=1)O>CN(C)C=O>[C:13]([O:18][CH2:7][CH2:6][O:5][C:4]1[CH:9]=[CH:10][CH:11]=[CH:12][C:3]=1[O:2][CH3:1])(=[O:17])[C:14]([CH3:16])=[CH2:15]
Reactant: COc1ccccc1OCCCl
Reactant: C=C(C)C(=O)[O-]
Agent: Oc1ccc(O)cc1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)C(=O)OCCOc1ccccc1OC
Temperature: 100 °C
Yield: 78.1 %

Procedure:
Then 25.1 g of 2-(o-methoxyphenoxy) ethyl chloride, 33.40 g of potassium methacrylate, 11.17 g of potassium iodide, 50 ml of N,N-dimethylformamide, and a small amount of hydroquinone were placed in a 200 ml-flask equipped with a stirring device and a cooling pipe. The mixture was heated at 100° C. and stirred. The reacted mixture was refined by column chromatography using silica gel, and 24.8 g of 2-(o-methoxyphenoxy)ethyl methacrylate was produced.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][C:12]([C:15]#[N:16])([CH3:14])[CH3:13])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C)C=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:40]=[CH:41][C:42]=1[F:43])[O:26][C:27]1[N:32]=[C:31]2[S:33][C:34]([NH:36][C:37](=[O:39])[CH3:38])=[N:35][C:30]2=[CH:29][CH:28]=1.O>C(Cl)(=O)C(Cl)=O.CN(C)C(=O)C>[C:37]([NH:36][C:34]1[S:33][C:31]2[C:30]([N:35]=1)=[CH:29][CH:28]=[C:27]([O:26][C:25]1[CH:40]=[CH:41][C:42]([F:43])=[C:23]([NH:22][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][CH:9]=[C:10]([O:11][C:12]([C:15]#[N:16])([CH3:14])[CH3:13])[C:2]=3[Cl:1])[CH:24]=1)[N:32]=2)(=[O:39])[CH3:38]
Reactant: CC(C)(C#N)Oc1cccc(C(=O)O)c1Cl
Reactant: CC(=O)Nc1nc2ccc(Oc3ccc(F)c(N)c3)nc2s1
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1nc2ccc(Oc3ccc(F)c(NC(=O)c4cccc(OC(C)(C)C#N)c4Cl)c3)nc2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.5 %

Procedure:
To a solution of 2-chloro-3-(1-cyano-1-methylethoxy)benzoic acid (0.12 g, 0.5 mmol) in oxalyl chloride (0.5 mL) was added N,N-dimethylformamide (40 μL), and the mixture was stirred at room temperature for 30 min, and concentrated to dryness under reduced pressure. This was dissolved in a mixture of N,N-dimethylacetamide (1 mL) and tetrahydrofuran (1 mL), and a solution was added dropwise to a solution of N-[5-(3-amino-4-fluorophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]acetamide (0.11 g, 0.33 mmol) produced in Example C64(ii) in N,N-dimethylacetamide (1 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 3 hr, and poured into water (100 mL), and the mixture was extracted with ethyl acetate (100 mL×2). The ethyl acetate layers were combined, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→100/0), and recrystallized from methanol to give the title compound (24 mg, 14%) as colorless crystals.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][C:8]([NH:10][C@H:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[CH2:12][SH:13])=[O:9])[C:3]([OH:5])=[O:4].[CH3:21][As:22]([CH3:24])Cl.N1C=CC=CC=1>COCCOC>[CH3:21][As:22]([CH3:24])[S:13][CH2:12][C@@H:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[NH:10][C:8](=[O:9])[CH2:7][CH2:6][C@@H:2]([C:3]([OH:5])=[O:4])[NH2:1]
Reactant: C[As](C)Cl
Reactant: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Solvent: COCCOC
Solvent: c1ccncc1
Product: C[As](C)SC[C@H](NC(=O)CC[C@H](N)C(=O)O)C(=O)NCC(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a 500 mL flask, 7 g of glutathione was used as received from the Aldrich Chemical Co., purity 98% and dissolved in 250 mL of 1,2-dimethoxyethane. To this solution was added 3.3 g of dimethylchloroarsine. This was followed by the addition of 3.5 g of pyridine (redistilled after drying over NaOH pellets). The solution was refluxed for one hour after which time it was stirred at room temperature for three hours.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)=[CH:3][CH:2]=1.[CH3:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]2[C:33]([CH2:34][NH2:35])=[CH:32][CH:31]=[C:30]([C:36]([F:39])([F:38])[F:37])[N:29]=2)[CH2:24][CH2:23]1.C(N(CC)CC)C>CS(C)=O.O>[CH3:21][CH:22]1[CH2:23][CH2:24][N:25]([C:28]2[C:33]([CH2:34][NH:35][C:12]([NH:11][C:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=[CH:2][CH:3]=3)=[O:20])=[CH:32][CH:31]=[C:30]([C:36]([F:39])([F:37])[F:38])[N:29]=2)[CH2:26][CH2:27]1
Reactant: O=C(Nc1ccnc2ccccc12)Oc1ccccc1
Reactant: CC1CCN(c2nc(C(F)(F)F)ccc2CN)CC1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC1CCN(c2nc(C(F)(F)F)ccc2CNC(=O)Nc2ccnc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Phenyl quinolin-4-ylcarbamate (crude 139 mg, 0.53 mmol) and (2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methanamine (144 mg, 0.53 mmol) were dissolved in dimethyl sulfoxide. Then triethylamine (0.15 mL, 1.06 mmol) was added to it. The mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure.
Reaction SMILES: C[O:2][C:3]([C:5]1([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH:9]([Si](C)(C)C)[CH2:8][CH2:7][O:6]1)=[O:4].CC(C)([O-])C.[K+].Cl>CS(C)=O>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:5]2([C:3]([OH:4])=[O:2])[CH2:9][CH2:8][CH2:7][O:6]2)=[CH:15][CH:16]=1
Reactant: COC(=O)C1(c2ccc(F)cc2)OCCC1[Si](C)(C)C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(O)C1(c2ccc(F)cc2)CCCO1
Temperature: 60 °C
Yield: 123.1 %

Procedure:
To a solution of methyl-2-(4-fluorophenyl)-3-trimethylsilyl-2-tetrahydrofuroate (16 mg, 0.0541 mmol) in DMSO (0.5 ml) was added potassium t-butoxide (30 mg, 0.270 mmol). The resulting mixture was heated at 60° C. overnight. TLC showed reaction was complete. The reaction mixture was poured into HCl (1N) and extracted with ethyl acetate. The combined organic layer was dried over MgSO4 and concentrated. The residue was purified by preparative TLC eluting with methylene chloride/methanol/acetic acid=95:5:0.5 to give 2-(4-fluorophenyl)-2-tetrahydrofuroic acid (14 mg).
Reaction SMILES: CS(O[CH:6]([C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)[CH2:7][N:8]1[C:16]2[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[C:10]2[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]1=2)(=O)=O.[N-:29]=[N+:30]=[N-:31].[Na+]>CN(C=O)C.O>[N:29]([CH:6]([C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)[CH2:7][N:8]1[C:16]2[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[C:10]2[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]1=2)=[N+:30]=[N-:31]
Reactant: Cc1ccc2c(c1)c1c(n2CC(OS(C)(=O)=O)c2ccncc2)CCN(C)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CC(N=[N+]=[N-])c2ccncc2)CCN(C)C1
Temperature: 100 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
To a solution of 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-(pyridin-4-yl)ethyl methanesulfonate (900 mg, 2.18 mmol) in DMF (10 mL) was added sodium azide (212.5 mg, 3.2 mmol) and the reaction mixture was stirred at 100° C. for 1 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 5-(2-azido-2-(pyridin-4-yl)ethyl)-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (650 mg). The resulting racemate was purified and resolved by chiral preparative HPLC. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.8 (d, 2H), 8.0 (d, 2H), 7.31 (d, 1H), 7.3 (s, 1H), 7.04 (d, 1H), 5.45 (m, 1H), 4.7 (d, 1H), 4.59 (t, 1H), 4.4 (m, 2H), 3.9 (d, 1H), 3.6 (m, 1H), 3.4 (m, 1H), 3.2 (m, 1H), 3.1 (s, 3H), 2.4 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH:17]=[CH:16][C:15]4[N:18]=[C:19]([C:21]5[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=5)[S:20][C:14]=4[C:13]3=[O:28])=[CH:8][C:7]=2[O:29][CH3:30])[CH2:2]1.C(N(CC)CC)C.[C:38](Cl)(=[O:40])[CH3:39].Cl>C(Cl)Cl>[C:38]([N:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH:17]=[CH:16][C:15]4[N:18]=[C:19]([C:21]5[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=5)[S:20][C:14]=4[C:13]3=[O:28])=[CH:8][C:7]=2[O:29][CH3:30])[CH2:2]1)(=[O:40])[CH3:39]
Reactant: COc1cc(-n2ccc3nc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OC1CNC1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(-n2ccc3nc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OC1CN(C(C)=O)C1
Temperature: 0 °C

Procedure:
Dissolve 5-[4-(azetidin-3-yloxy)-3-methoxy-phenyl]-2-(4-chloro-phenyl)-5H-thiazolo[5,4-c]pyridin-4-one (75 mg, 0.171 mmol) and triethylamine (52.5 μL, 0.376 mmol) in dry CH2Cl2 (700 μL). Chill to 0° C. and add acetylchloride (13.4 μL, 0.188 mmol). Allow to warm to room temperature overnight. Add 1 N HCl solution and extract with CH2Cl2 (3×5 mL). Combine the organic portions and wash with water (2×5 mL). Dry the organic layer with Na2SO4, filter, and concentrate in vacuo. Purify the resulting residue on HPLC with 5 μm 30×75 mm XBridge C18 column; eluent: 34% water (with 10 mM NH4HCO3 added to pH=10/acetonitrile (isocratic) to give 39 mg, (48%). ES/MS m/z (35Cl) 481.8 [M+1]+.