Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[C:12](S(C)(=O)=O)=[CH:11][N:10]=1.[CH3:29][O-:30].[Na+].CO>COCCOC>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[C:12]([O:30][CH3:29])=[CH:11][N:10]=1
Reactant: C[O-]
Reactant: CS(=O)(=O)c1cnc(-c2ccc(F)cc2F)nc1-c1cccc(C(F)(F)F)c1
Agent: [Na+]
Solvent: CO
Solvent: COCCOC
Product: COc1cnc(-c2ccc(F)cc2F)nc1-c1cccc(C(F)(F)F)c1
Yield: 83.5 %

Procedure:
2.1 g of 2-(2,4-difluorophenyl)-4-(3-trifluoromethylphenyl)-5-methanesulfonylpyrimidine, 0.3 g of sodium methoxide and 20 ml of methanol were added to 120 ml of ethylene glycol dimethyl ether and the resulting mixture was heated under reflux for 5 hours. The solvent was distilled away under reduced pressure. The residue was washed with water and then dried to obtain 1.55 g of 2-(2,4-difluorophenyl)-4-(3-trifluoromethylphenyl)-5-methoxypyrimidine (Compound 77).
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.I[C:18]1[CH:19]=[C:20]([CH3:25])[CH:21]=[C:22]([CH3:24])[CH:23]=1.C(O)CO>[Cu]I.CCCCCC.C(OCC)(=O)C.CC(O)C>[CH2:9]([NH:16][C:18]1[CH:19]=[C:20]([CH3:25])[CH:21]=[C:22]([CH3:24])[CH:23]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1cc(C)cc(I)c1
Reactant: NCc1ccccc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1cc(C)cc(NCc2ccccc2)c1
Yield: 83.8 %

Procedure:
The general procedure under argon or air was followed using copper(I) iodide (10 mg, 0.05 mmol), K3PO4 (425 mg, 2.00 mmol), benzylamine (131 μL, 1.20 mmol), 5-iodo-m-xylene (144 μl, 1.00 mmol), ethylene glycol (111 μL, 2.00 mmol) and 2-propanol (1.0 mL). Column chromatography using a solvent mixture (hexane/ethyl acetate=20/1, Rf=0.5) afforded 5-(N-benzyl)amino-m-xylene (177 mg, 84% isolated yield) as colorless liquid. The spectral data (1H NMR) matched with the literature references and GC analysis indicated >95% purity. See Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 2000, 65, 1144–1157.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[H-].[Na+].Br[CH2:18][CH2:19][N:20]([CH2:23][CH3:24])[CH2:21][CH3:22].[I-].[K+]>O1CCCC1.C(OCC)(=O)C.O>[CH2:19]([N:20]([CH2:23][CH3:24])[CH2:21][CH2:22][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1)[CH3:18]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CCN(CC)CCBr
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC)CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.9 %

Procedure:
To a solution of 4,4,5,5-tetramethyl-2-(1H-pyrazol-4-yl)-1,3,2-dioxaborolane (250 mg, 1.29 mmol) and sodium hydride (61.8 mg, 2.58 mmol) in tetrahydrofuran at 0° C. was added 2-bromo-N,N-diethylethanamine (558 mg, 2.58 mmol). The reaction was allowed to warm up to room temperature and was monitored by LCMS. After 90 minutes there was still no reaction and potassium iodide (1.71 g, 10.3 mmol) was added and the reaction was heated at 50° C. overnight. The reaction mixture was diluted with a large volume of ethyl acetate and water and partitioned. The organic layer containing the product was washed with brine and concentrated in vacuo to give clear thick oil confirmed by LCMS to be 100% pure N,N-diethyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethanamine (340 mg, yield 90%, M+1 294.2)
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].C(N(CC)C(C)C)(C)C.FC(F)(F)S(O)(=O)=O.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.C([Sn](CCCC)(CCCC)[C:65]1[N:66]2[CH:72]=[N:71][CH:70]=[C:67]2[S:68][CH:69]=1)CCC>C(#N)C.C(OCC)(=O)C.CN1CCCC1=O.O.[Cl-].[Zn+2].[Cl-].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)=[O:13])=[C:8]([C:65]3[N:66]4[CH:72]=[N:71][CH:70]=[C:67]4[S:68][CH:69]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Reactant: CCCC[Sn](CCCC)(CCCC)c1csc2cncn12
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3csc4cncn34)[C@H](C)[C@H]12
Reaction time: 0.5 h
Yield: 35.4 %

Procedure:
To a solution of 491 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate in 12 ml of dry acetonitrile was added dropwise 0.59 ml of N,N-diisopropylethylamine followed by 0.227 ml of anhydrous trifluoromethanesulfonic acid under the atmosphere of argon at −15° C. After the reaction mixture was stirred at the same temperature for 30 minutes, it was diluted with 40 ml of ethyl acetate and washed sequentially with semi-saturated aqueous saline, a mixed solvent of semi-saturated aqueous saline and 1N aqueous hydrochloric acid (pH 1.1), a mixed solvent of semi-saturated aqueous saline and saturated aqueous sodium hydrogen carbonate(pH 8.9), and semi-saturated aqueous saline. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The residue thus obtained was dissolved in 4 ml of dry N-methylpyrrolidinone, mixed with 37 mg of tri-2-furylphosphine, 370 mg of zinc chloride, 37 mg of tris(dibenzylideneacetone)dipalladium (0), and a solution of 765 mg of 3-(tri-n-butylstannyl)imidazo[5,1-b]thiazole in 2 ml of dry N-methylpyrrolidinone, and the mixture was stirred under the atmosphere of argon at 50° C. for 40 minutes. The reaction mixture was diluted with 200 ml of ethyl acetate and 200 ml of water, and the organic layer was separated. The organic layer was diluted with 100 ml semi-saturated aqueous sodium hydrogen carbonate and stirred for 30 minutes to remove insolubles by filtration. The organic layer of the filtrate was separated, washed three times with 200 ml of semi-saturated aqueous saline, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by column chromatography on silica gel (chloroform:methanol=30:1) to give 225 mg of 4-nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-3-yl)-1-methyl-1-carbapen-2-em-3-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][CH:19]3[CH2:21][CH2:20]3)=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[NH2:22][CH2:23][C@@:24]([CH3:29])([CH:26]1[CH2:28][CH2:27]1)[OH:25]>>[CH:26]1([C@:24]([OH:25])([CH3:29])[CH2:23][NH:22][C:13](=[O:15])[C:12]2[CH:16]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:9]([O:17][CH2:18][CH:19]3[CH2:21][CH2:20]3)=[N:10][CH:11]=2)[CH2:28][CH2:27]1
Reactant: C[C@](O)(CN)C1CC1
Reactant: O=C(O)c1cnc(OCC2CC2)c(-c2ccc(F)cc2)c1
Product: C[C@](O)(CNC(=O)c1cnc(OCC2CC2)c(-c2ccc(F)cc2)c1)C1CC1

Procedure:
The title compound was synthesized in analogy to Example 5d, using 5-(4-fluoro-phenyl)-6-cyclopropylmethoxy-nicotinic acid and (R)-α-(aminomethyl)-α-methyl-cyclopropanemethanol as starting materials, MS (ISP) 385.2 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]([C:5]1[O:6][C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:9]=1)[CH2:3]O.COC(OC)(OC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[C:10]1([C:8]2[N:9]=[C:5]([C@@H:2]3[CH2:3][O:1]3)[O:6][C:7]=2[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OC[C@H](O)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: COC(C)(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: c1ccc(-c2nc([C@@H]3CO3)oc2-c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
To a solution of 2-((1S)-1,2-dihydroxyethyl)-4,5-diphenyloxazole (20 g) in CH2Cl2 (400 ml) were added orthoacetic acid trimethyl ester (12.8 ml) and p-toluenesulfonic acid (130 mg) at room temperature under N2, After being stirred for 30 minutes, the solvent was evaporated in vacuo. The residue was diluted with CH2Cl2 (200 ml) and acetyl bromide (7.6 ml) was added to the solution at 0° C. under N2. After being stirred for 2 hours at room temperature, the solvent was evaporated in vacuo, the residue was diluted with methanol (200 ml), and K2CO3 (16 g) was added to the solution at 0° C. The mixture was stirred for 30 minutes at the same temperature and partitioned between ethyl acetate and water. The organic layer was washed with 1N-HCl, water, sat. NaHCO3 and brine. The dried solvent was evaporated in vacuo and the residue was purified by trituration with ether-hexane to give (2S)-2-(4,5-diphenyloxazol-2-yl)oxirane (14.2 g). MS (m/z): 264 (M+ +1) IR (Neat): 1460 cm-1NMR (CDCl3, δ): 3.23 (1H, dd, J=4.0, 5.6 Hz), 3.43 (1H, dd, J=2.6, 5.6 Hz), 4.08 (1H, dd, J=2.6, 4.0 Hz), 7.2-7.6 (10H, m) HPLC; chiralcel OD, 10% isopropanol/hexane, 11.3 ml/min
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:26]1([CH3:35])[C:27]([N:32]=[C:33]=[O:34])=[CH:28][CH:29]=[CH:30][CH:31]=1>ClCCl>[CH3:35][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][C:33](=[O:34])[O:18][C:15]1[CH:16]=[C:17]2[C:12]([CH2:11][CH2:10][CH2:9][N:8]2[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:13][CH:14]=1
Reactant: Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Reactant: Cc1ccccc1N=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1NC(=O)Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Temperature: 35 °C

Procedure:
A mixture of 1-benzyl-1,2,3,4-tetrahydroquinolin-7-ol (550 mg, 2.30 mM) and triethylamine (0.4 mL) in dry dichloromethane (DCM, 10 mL) was stirred for half an hour under nitrogen atmosphere at room temperature (35° C.). To the stirred reaction mixture, o-tolyl isocyanate (428 mg/ml, 3.45 mM) was added at once and then the reaction mixture was further stirred for 72 hours under N2 atmosphere at RT. The reaction mixture was concentrated under vacuum and then was added distilled water (15 mL) followed by the extraction with ether (3×15 mL). The ether layer was dried over sodium sulphate and concentrated under vacuum to afford the crude product, which was finally chromatographed using chloroform-hexane (1:9) to give 8a as colorless oil. Yield: 700 mg, 81.78%.
Reaction SMILES: [Si]([O:8][C:9]1[CH:19]=[CH:18][C:12]2[N:13]([CH3:17])[C:14](=[O:16])[O:15][C:11]=2[CH:10]=1)(C(C)(C)C)(C)C.[Si](OC1C=CC2OC(=O)N(C)C=2C=1)(C(C)(C)C)(C)C>>[OH:8][C:9]1[CH:19]=[CH:18][C:12]2[N:13]([CH3:17])[C:14](=[O:16])[O:15][C:11]=2[CH:10]=1
Reactant: Cn1c(=O)oc2cc(O[Si](C)(C)C(C)(C)C)ccc21
Agent: Cn1c(=O)oc2ccc(O[Si](C)(C)C(C)(C)C)cc21
Product: Cn1c(=O)oc2cc(O)ccc21

Procedure:
Following the procedure as described in PREPARATION 19C, and making non-critical variations using 6-{[tert-butyl(dimethyl)silyl]oxy}-3-methyl-1,3-benzoxazol-2(3H)-one to replace 5-{[tert-butyl(dimethyl)silyl]oxy}-3-methyl-1,3-benzoxazol-2(3H)-one, 6-hydroxy-3-methyl-1,3-benzoxazol-2(3H)-one was obtained (99%) as a tan solid: 1H NMR (300 MHz, DMSO-d6) δ9.50 (br s, 1H), 7.02 (d, J=8.4 Hz, 1H), 6.75 (d, J=2.1 Hz, 1H), 6.62 (dd, J=8.4, 2.1 Hz, 1H), 3.27 (s, 3H); MS (ES−) m/z 164.2 (M−1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([OH:13])[CH:7]=[CH:6]2)#[N:2].[CH2:14]=[O:15].C1N2CN3CN(C2)CN1C3.S(=O)(=O)(O)O>C(Cl)(Cl)Cl.O.C(O)(=O)C>[CH:14]([C:9]1[C:10]2[C:5](=[CH:4][C:3]([C:1]#[N:2])=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:8]=1[OH:13])=[O:15]
Reactant: C=O
Reactant: N#Cc1ccc2cc(O)ccc2c1
Agent: C1N2CN3CN1CN(C2)C3
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1ccc2c(C=O)c(O)ccc2c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 48 %

Procedure:
65 milliliters of acetic acid was added to 20 g of 6-cyano-2-naphthol, 3.6 g of paraformaldehyde and 16.6 g of hexamethylenetetramine, followed by stirring at 80° C. for 4 hours. Furthermore, to the reaction mixture was added a solution comprising 53 ml of acetic acid, 10.5 ml of water and 17.8 g of concentrated sulfuric acid at 60° C., followed by stirring at 80° C. for 4 hours. After cooling, 95 ml of water was added to the resulting solution, followed by stirring, and the precipitate was collected by filtration and washed with 40 ml of warm water. To the collected precipitate was added 350 ml of chloroform, followed by refluxing for 1 hour. Thereafter, the precipitate was filtered and the filtrate was concentrated under reduced pressure to obtain a crude product. This product was subjected to silica gel column chromatography using chloroform as an eluent, and the desired fractions were collected, and the solvent was distilled off under reduced pressure. To the residue was added 100 ml of n-hexane and the mixture was stirred for a while, and the precipitate was collected by filtration to obtain 11.2 g of the desired product.
Reaction SMILES: [Cl-].[NH4+].[CH3:3][N:4]1[C:9](=[O:10])[C:8]2[C:11]([S:25][C:26]3[CH:31]=[CH:30][C:29]([N+:32]([O-])=O)=[CH:28][N:27]=3)=[C:12]([CH2:14][C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=[CH:17][CH:16]=3)[S:13][C:7]=2[N:6]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:5]1=[O:39].[OH-].[Na+].C(OCC)(=O)C>C(O)C.O.[Fe]>[NH2:32][C:29]1[CH:30]=[CH:31][C:26]([S:25][C:11]2[C:8]3[C:9](=[O:10])[N:4]([CH3:3])[C:5](=[O:39])[N:6]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:7]=3[S:13][C:12]=2[CH2:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)=[N:27][CH:28]=1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Sc3ccc([N+](=O)[O-])cn3)c(Cc3cccc4ccccc34)sc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(Sc3ccc(N)cn3)c(Cc3cccc4ccccc34)sc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.1 %

Procedure:
Iron powder (0.85 g) and ammonium chloride (0.81 g) were added to a stirred suspension of 3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-5-[(5-nitropyridin-2-yl)thio]thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione (Example 37, 2.02 g) in ethanol (10 ml) and water (10 ml). The mixture was heated at reflux for 3 hours, then cooled to room temperature. 2M Sodium hydroxide solution (50 ml) was added and the mixture was stirred vigorously for 1 hour, ethyl acetate (100 ml) was added and the two-phase mixture was filtered. The solid and aqueous layer were in turn washed with ethyl acetate (100 ml). 2M Hydrochloric acid (25 ml) was added to the solid and the mixture was stirred for 1 hour, then added to the sodium hydroxide solution and extracted with ethyl acetate (2×100 ml). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was recrystallised from ethyl acetate to give the title compound (1.07 g). The mother liquors were evaporated and purified by column chromatography over silica, eluting with ethyl acetate, and then recrystallised from ethyl acetate to give further title compound (0.665 g).
Reaction SMILES: [C:1]([N:3]=[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)OC)#[N:2].[CH3:13][CH:14]([NH2:23])[CH:15]([OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl.C(N(CC)CC)C>CO>[C:1]([NH:3][C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[N:23][CH:14]([CH3:13])[CH:15]([OH:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)#[N:2]
Reactant: COC(=NC#N)c1ccccn1
Reactant: CC(N)C(O)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(N=C(NC#N)c1ccccn1)C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 53.3 %

Procedure:
Methyl N-cyano-2-pyridinecarboximidate (0.24 g, 1.5 mmol) was dissolved in methanol (5 ml), DL-phenylpropanolamine hydrochloride (0.31 g, 1.7 mmol, supplied by Tokyo Chemical Industry Co. Ltd.) and triethylamine (0.17 g, 1.7 mmol) were added, and the resulting mixture was stirred at room temperature for 5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue thus obtained was extracted with ethyl acetate (30 ml×3). The ethyl acetate layer was washed with water (100 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrated residue thus obtained was crystallized from diethyl ether to give the title compound (0.23 g, 0.8 mmol, yield: 54%) as colorless crystals.
Reaction SMILES: [NH:1]1[C:5]2[C:6]3[C:11]([CH2:12][C:4]=2[CH:3]=[N:2]1)=[CH:10][C:9]([CH:13]=[O:14])=[CH:8][CH:7]=3.[I:15]N1C(=O)CCC1=O>CN(C)C=O>[I:15][C:3]1[C:4]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH:13]=[O:14])[CH:10]=3)[C:5]=2[NH:1][N:2]=1
Reactant: O=Cc1ccc2c(c1)Cc1cn[nH]c1-2
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: O=Cc1ccc2c(c1)Cc1c(I)n[nH]c1-2
Temperature: 25 °C

Procedure:
A solution of Example 316 (2.13 g, 11.6 mmol) and N-iodosuccinimide (3.13 g, 13.9 mmol) in N,N-dimethylformamide (45 mL) was heated to about 80° C. for about 5 hours. The reaction mixture was cooled to room temperature and was concentrated in high vacuum. The residue was partitioned between water and ethyl acetate, the layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried (MgSO4), filtered and concentrated under vacuum. The residue was purified by flash chromatography on silica gel using hexane/ethyl acetate (2:1) as eluent to provide the desired product. MS (ESI): m/z 309 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH3:13].[NH2-].[Na+].C1(C)C=CC=CC=1.[CH2:23]([O:25][C:26](=O)[O:27]CC)[CH3:24]>C(OCC)C>[CH2:23]([O:25][C:26](=[O:27])[CH2:13][C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][CH:7]=1)[CH3:24]
Reactant: COc1ccc2nccc(C)c2c1
Reactant: CCOC(=O)OCC
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCOC(=O)Cc1ccnc2ccc(OC)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 16 %

Procedure:
6-Methoxy-4-methyl-quinoline (0.791 g, 4.572 mmol) was dissolved in anhydrous diethyl ether and cooled to 0° C. under an argon atmosphere. To the stirred mixture was added sodamide as a 50% w/w slurry in toluene (0.36 g, 4.57 mmol). The resulting slurry was allowed to warm to room temperature and was stirred for 1 hour. To this was added diethylcarbonate (0.28 ml, 2.29 mmol). The reaction mixture was then stirred at reflux for 10 hours after which time it was quenched with water (2 ml). The mixture was partitioned between ethyl acetate (2×100 ml) and water (20 ml). The organic phases were combined and dried over magnesium sulfate. The volatiles were removed under reduced pressure and the residue subjected to purification on silica gel using an ethyl acetate-hexane gradient. This provided the desired product as a brown oil (90 mg, 7%).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([OH:11])[C:8]([OH:12])=[CH:7][C:5]=2[N:6]=1.[N+:13]([O-])([OH:15])=[O:14]>C(OCC)(=O)C.ClCCl>[CH3:1][C:2]1[S:3][C:4]2[C:10]([N+:13]([O-:15])=[O:14])=[C:9]([OH:11])[C:8]([OH:12])=[CH:7][C:5]=2[N:6]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1nc2cc(O)c(O)cc2s1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1nc2cc(O)c(O)c([N+](=O)[O-])c2s1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-Methyl-benzothiazole-5,6-diol was dissolved in ethyl acetate and a solution of nitric acid in dichloromethane (2M, 0.38 ml) was gradually added at 20° C. into. The solution was stirred 10 min at room temperature and then it was poured into ice water and extracted into ethyl acetate and evaporated. The product was purified by column chromatography using toluene-ethyl acetate-acetic acid 8:1:1 as the eluent.
Reaction SMILES: Cl[C:2]1[CH:20]=[CH:19][C:5]([CH:6](OC2CNC2)[C:7]2C=CC(Cl)=CC=2)=[CH:4][CH:3]=1.[N-]=C=O.Cl[C:25]1[CH:50]=[C:49]([Cl:51])[CH:48]=[CH:47][C:26]=1[CH:27]([O:35][CH:36]1[CH2:39][N:38]([C:40]([NH:42]C(C)(C)C)=[O:41])[CH2:37]1)[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1>>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([CH:27]([O:35][CH:36]2[CH2:39][N:38]([C:40]([NH:42][CH2:7][CH2:6][C:5]3[CH:19]=[CH:20][CH:2]=[CH:3][CH:4]=3)=[O:41])[CH2:37]2)[C:26]2[CH:25]=[CH:50][C:49]([Cl:51])=[CH:48][CH:47]=2)=[CH:33][CH:32]=1
Reactant: Clc1ccc(C(OC2CNC2)c2ccc(Cl)cc2)cc1
Reactant: CC(C)(C)NC(=O)N1CC(OC(c2ccc(Cl)cc2)c2ccc(Cl)cc2Cl)C1
Agent: [N-]=C=O
Product: O=C(NCCc1ccccc1)N1CC(OC(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1

Procedure:
This material was prepared from 3-(4,4′-dichlorobenzhydryloxy)azetidine (36) and the corresponding commercially available isocyanate, using the procedure described for compound (5).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([S:16][C:17]4[CH:18]=[C:19]5[C:24](=[CH:25][CH:26]=4)[N:23]=[CH:22][C:21]([N:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[CH:20]5)=[N:14][N:15]=3)[CH:12]=2)[CH:4]=[N:3]1.[F:33][C:34]([F:38])([F:37])[CH2:35]I.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([S:16][C:17]4[CH:18]=[C:19]5[C:24](=[CH:25][CH:26]=4)[N:23]=[CH:22][C:21]([N:27]4[CH2:32][CH2:31][N:30]([CH2:35][C:34]([F:38])([F:37])[F:33])[CH2:29][CH2:28]4)=[CH:20]5)=[N:14][N:15]=3)[CH:12]=2)[CH:4]=[N:3]1
Reactant: FC(F)(F)CI
Reactant: Cn1cc(-c2ccc3nnc(Sc4ccc5ncc(N6CCNCC6)cc5c4)n3c2)cn1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(-c2ccc3nnc(Sc4ccc5ncc(N6CCN(CC(F)(F)F)CC6)cc5c4)n3c2)cn1
Temperature: 120 °C
Yield: 21.2 %

Procedure:
A suspension of 6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-3-(piperazin-1-yl)quinoline (Example 27—see in Table below) (12 mg, 0.027 mmol), 1,1,1-trifluoro-2-iodoethane (56.9 mg, 0.271 mmol) and DIPEA (17.5 mg, 0.136 mmol) in DMF (1 mL) was sealed in a microwave vial and heated at 120° C. for 6 hours. The solvent was removed and the residue was purified by prep-HPLC to give the title compound as yellow solid (3 mg, yield 20%). [Method 1C]
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)=[CH:14][C:13]=3[C:24]([F:27])([F:26])[F:25])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.OC1CCNC1.[OH:34][C@H:35]1[CH2:39][NH:38][C@@H:37]([C:40]([OH:42])=[O:41])[CH2:36]1>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:19]=[CH:20][N:21]=[C:22]([N:38]5[CH2:39][CH:35]([OH:34])[CH2:36][CH:37]5[C:40]([OH:42])=[O:41])[CH:23]=4)=[CH:14][C:13]=3[C:24]([F:25])([F:26])[F:27])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=C(O)[C@H]1C[C@@H](O)CN1
Reactant: FC(F)(F)c1cc(-c2ccncc2)ccc1Sc1ccc2c(c1)OCCO2
Agent: OC1CCNC1
Product: O=C(O)C1CC(O)CN1c1cc(-c2ccc(Sc3ccc4c(c3)OCCO4)c(C(F)(F)F)c2)ccn1

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 118 (0.033 g, 0.0779 mmol) and 3-hydroxypyrrolidine with cis-4-hydroxy-D-proline. A yellow solid 130 was obtained (0.038 g, 74%). 1H-NMR (CDCl3, 400 MHz) δ 2.34-2.42 (m, 1H), 2.64-2.68 (m, 2H), 3.73-3.82 (m, 1H), 3.94-4.00 (m, 1H), 4.28-4.34 (m, 4H), 4.68-4.74 (m, 1H), 6.92-7.12 (m, 6H), 7.52 (br, 1H), 7.80 (s, 1H), 8.04 (br, 1H); MS (APCI) m/z 519 (M+H)+.