Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].[C:12]1([Mg]Br)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(OCC)C>C1COCC1>[OH:5][C:4]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[NH:1][C:2]1=[O:3]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: Br[Mg]c1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2C1(O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79 %

Procedure:
Dissolve isatin (1.47 g, 10 mmol) in anhydrous THF (40 mL) in an oven-dried flask under nitrogen. Cool in an ice bath and add slowly a 3M solution of phenylmagnesium bromide in diethyl ether (7.4 mL, 22 mmol). After 5 min remove the ice bath and stir at room temperature for 18 h. Pour the reaction over saturated NH4Cl solution and extract with ethyl acetate (200 mL, 2×100 mL). Wash combined organic portions with brine and dry (Na2SO4), filter, and concentrate in vacuo to give a yellow solid. Triturate in diethyl ether, filter and dry under house vacuum to give 1.77 g (79%) of the title compound as a yellow solid. MS (ES): m/z=208 (M+1−H2O), 224 (M−1); 1H NMR(DMSO-d6): δ10.39 (s, 1H), 7.32-7.23 (m, 6H), 7.09 (d, J=7.3 Hz, 1H), 6.96 (dt, J=0.9 Hz, J=7.5 Hz, 1H), 6.90 (d, J=7.7 Hz, 1H), 6.61 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.[OH-].[K+].Cl[C:13]1[C:18]([C:19]#[N:20])=[CH:17][N:16]=[C:15]2[C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[S:23][C:14]=12>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:13]2[C:18]([C:19]#[N:20])=[CH:17][N:16]=[C:15]3[C:21]4[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=4[S:23][C:14]=23)=[C:4]([F:9])[CH:3]=1
Reactant: Oc1ccc(Cl)cc1F
Reactant: N#Cc1cnc2c(sc3ccccc32)c1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: N#Cc1cnc2c(sc3ccccc32)c1Oc1ccc(Cl)cc1F
Yield: 55 %

Procedure:
A mixture of 0.59 mL (5.5 mmol) of 4-chloro-2-fluorophenol and 100 mg (1.78 mmol) of potassium hydroxide is heated until a homogeneous solution is formed. To this is added 245 mg (1.00 mmol) of 4-chlorobenzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile and the mixture is heated for 2 hours. Ethyl acetate is added and the solution is washed with 1N NaOH. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo. The solid is collected and recrystallized from ethyl acetate to give 195 mg (55%) of a light beige solid, mp 174-175° C.
Reaction SMILES: C([C:3](CC)([P:18]([OH:21])([OH:20])=[O:19])[O:4][C@H:5]([CH3:17])[CH2:6][N:7]1[CH:15]=[N:14][C:13]2[C:8]1=[N:9][CH:10]=[N:11][C:12]=2[NH2:16])C.Br>C(O)(=O)C.Cl.CC(O)C>[P:18]([CH2:3][O:4][C@H:5]([CH3:17])[CH2:6][N:7]1[CH:15]=[N:14][C:13]2[C:8]1=[N:9][CH:10]=[N:11][C:12]=2[NH2:16])([OH:20])([OH:21])=[O:19]
Reactant: CCC(CC)(O[C@H](C)Cn1cnc2c(N)ncnc21)P(=O)(O)O
Agent: Br
Agent: Cl
Solvent: CC(C)O
Solvent: CC(=O)O
Product: C[C@H](Cn1cnc2c(N)ncnc21)OCP(=O)(O)O
Temperature: 92.5 °C

Procedure:
Dealkylation of (R)-9-[2-(Diethyl phosphonomethoxy)propyl]adenine is carried out in presence of a suitable dealkylating reagents selected from mineral acids like aq. HBr, aq. HCl, HBr in acetic acid or HCl gas in IPA with mole ratio ranging from 3 to 15 preferably 7.5 moles and typically at a temperature of about 25 to 110° C., usually at 90 to 95° C. (R)-9-[2-(Diethyl phosphonomethoxy)propyl]adenine and one of the acid described above are maintained at 90 to 95° C. for about 3 to 15 hrs, after completion of reaction, the reaction mass is washed with Methylenedichloride and pH is adjusted to about 1.5 to 3.5 preferably at 2.5 to 3.0 with caustic lye solution. Reaction mass is cooled to about 25 to 35° C. and finally to about 0 to 5° C. over 4 to 10 hrs. The precipitated product is filtered and the wet material is recrystallized in water to get pure (R)-9-[2-(phosphonomethoxy)propyl]adenine with improved yield.
Reaction SMILES: [CH3:1][S:2](F)(=[O:4])=[O:3].[NH:6]([CH2:9][CH3:10])[CH2:7][CH3:8]>>[CH3:1][S:2]([N:6]([CH2:9][CH3:10])[CH2:7][CH3:8])(=[O:4])=[O:3]
Reactant: CCNCC
Reactant: CS(=O)(=O)F
Product: CCN(CC)S(C)(=O)=O
Yield: 96.5 %

Procedure:
Chem. Abstracts 56:7116f, abstracting Sokolsku et al., Izvest. Akad Nauk S.S.S.R., Otdel Khem Nauk 1606 (1968), describes the reaction of CH3SO2F with (C2H5)2NH after one day to give 96.5% CH3SO2N(C2H5)2.
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1.CCCCCC>[C:9]([O:8][C:6]([NH:5][C@H:4]([CH:3]=[O:2])[C@H:13]([CH2:15][CH3:16])[CH3:14])=[O:7])([CH3:10])([CH3:12])[CH3:11]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC[C@H](C)[C@@H](C=O)NC(=O)OC(C)(C)C
Temperature: -78 °C
Yield: 98 %

Procedure:
A mixture of L-isoleucine methyl ester (24.3 g., 0.134 mmoles) and triethylamine (13.5 g., 0.134 mmoles) in methylene chloride (210 ml.) was prepared and a solution of ditertbutyldicarbonate (Aldrich, 29.1 g., 0.134 mmoles) in methylene chloride (25 ml.) was added dropwise to this mixture at 0° C. After completion of this addition, the mixture was allowed to warm to room temperature overnight and was then filtered. The filtrate was washed successively with water (1×100 ml.) and a saturated sodium bicarbonate solution (1×75 ml.), dried over magnesium sulfate and evaporated to yield N-(t-butoxycarbonyl)-L-isoleucine methyl ester as an oil [30.7 g.; 93% yield; 1H-NMR (CDCl3): delta 0.92 (d, J=7,6H), 1.43 (s, 9H), 3.70 (s, 3H), 4.17 (dd, J=5, 9, 1H), 5.03 (d, J=9, 1H)]. A solution of the N-(t-butoxycarbonyl)-L-isoleucine methyl ester oil (15.0 g., 61.1 mmoles) in dry toluene (260 ml.) was cooled to -78° C., and a 1M solution of diisobutyl aluminum hydride in hexane (153 ml.) was added dropwise thereto at such a rate that the temperature of the exothermic reaction did not exceed -65° C. Following 15 minutes of addition stirring at -78° C. after completion of this addition, the mixture was carefully quenched with 15 ml. of methanol (the mixture temperature was not allowed to exceed -65° C.) followed by 200 ml. of Rochelle salt solution. After warming to room temperature, the organic layer was separated and extracted with ether (3×200 ml.); additional Rochelle salt solution was added when necessary to dissolve the aluminum salts. The combined organic extract was dried over sodium sulfate and evaporated to afford a crude product as an oil. The oil was stored at -78° C. to avoid possible racemization and was used without purification in the next step [132 g., 98% yield, Rf=0.32 in 35% ether in hexane; 1H-NMR (CDCl3): delta 1.00 (d, J=7,6H), 1.46 (s, 9H), 9.65 (s, 1H)].
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:18][C:19](=[O:25])[C:20]([O:22]CC)=[O:21])[CH:7]=[C:8]([NH:10][C:11](=[O:17])[C:12]([O:14]CC)=[O:13])[CH:9]=1)([OH:3])=[O:2].Cl>[OH-].[Na+].O>[C:1]([C:4]1[CH:9]=[C:8]([NH:10][C:11](=[O:17])[C:12]([OH:14])=[O:13])[CH:7]=[C:6]([NH:18][C:19](=[O:25])[C:20]([OH:22])=[O:21])[CH:5]=1)([OH:3])=[O:2]
Reactant: CCOC(=O)C(=O)Nc1cc(NC(=O)C(=O)OCC)cc(C(=O)O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C(=O)Nc1cc(NC(=O)C(=O)O)cc(C(=O)O)c1

Procedure:
Diethyl N,N'-(5-carboxy-m-phenylene)dioxamate (1.0 gram) is stirred in 1.0 N aqueous sodium hyroxide (50 ml.) for 0.5 hour. The reaction mixture is diluted with water (100 ml.) and the pH adjusted to 3 with concentrated hydrochloric acid. The resulting precipitate is collected by filtration (0.80 gram, M.P. >320°).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9]C(=O)[C:7]2=[O:12].[OH-:13].[Na+].OO.Cl>O>[NH2:9][C:10]1[C:2]([I:1])=[CH:3][CH:4]=[CH:5][C:6]=1[C:7]([OH:12])=[O:13]
Reactant: [OH-]
Reactant: O=C1Nc2c(I)cccc2C1=O
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: O
Product: Nc1c(I)cccc1C(=O)O
Temperature: 25 °C

Procedure:
To a ice cold solution of 7-iodoindoline-2,3-dione (2.9 g, 0.0106 mol) in an aq. solution of 2 N NaOH (15 mL) was added drop wise an aq. solution of 35% H2O2 (3 mL) and then allowed to stir at room temperature over night. After the reaction is completed, the reaction mixture was diluted with water (50 mL), adjusted the pH to 2 with conc. HCl.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:18]([CH3:23])([CH3:22])[C:19](=[O:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C[Si](C)(C)[C:32]([F:35])([F:34])[F:33].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[F:33][C:32]([F:35])([F:34])[C:19]([CH3:20])([OH:21])[C:18]([CH3:22])([CH3:23])[CH:17]([C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[N:9]=[CH:10]2)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(=O)C(C)(C)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1)C(C)(O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 71 %

Procedure:
To a solution of the compound of Example 120, 4-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3,3-dimethyl-4-phenylbutan-2-one (12 mg, 0.031 mmol) in THF (1 ml) at 0° C. was added trimethyl(trifluoromethyl)silane (22 mg, 0.155 mmol) and tetrabutylammonium fluoride in THF (0.031 ml, 0.031 mmol, 1M THF solution). The reaction mixture was stirred at 0° C. for 10 minutes, and then at room temperature for 45 minutes. Additional trimethyl(trifluoromethyl)silane (22 mg, 0.155 mmol) was added to the reaction mixture, after which stirring was continued for 2 hours. The reaction was quenched with saturated NH4Cl and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and concentrated to give the crude product. The crude material was purified via chromatography on silica gel eluting with 10% ethyl acetate in hexane to afford the compound of Example 135 as a white solid (10 mg, 71% yield). It is a mixture of diastereomers in 1:1 ratio. 1H NMR (400 MHz, MeOD) δ ppm 8.17 (1 H, s) 7.98 (1 H, d, J=16.79 Hz) 7.68 (3 H, dd, J=8.90, 4.83 Hz) 7.58 (2 H, d, J=8.14 Hz) 7.54 (1 H, d, J=7.63 Hz) 7.20-7.33 (4 H, m) 7.12 (1 H, t, J=7.12 Hz) 4.55 (1 H, d, J=5.09 Hz) 1.31 (3 H, 2 singlets) 1.22 (3 H, 2 singlets) 1.13 (3 H, 2 singlets). LC/MS (m/z) 387.20 [(M+H)+]; HPLC Rt: 3.758 min.
Reaction SMILES: [C:1]([C:3]1([CH3:14])[CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1)#[N:2].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18]>ClCCl>[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[CH3:14][C:3]1([C:1]#[N:2])[CH2:6][NH:5][CH2:4]1
Reactant: CC1(C#N)CN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C#N)CNC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 3-cyano-3-methylazetidine-1-carboxylate (30.0 mg, 0.15 mmol) in dichloromethane (5 ml) was added trifluoroacetic acid (2 ml) and the solution stirred at room temperature for 1 hr. The reaction was concentrated and dried under vacuum to give a viscous oil which was used crude in subsequent chemistry.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[O:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.O=[C:17]1[CH2:22][CH2:21][CH:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH:17]2[CH2:22][CH2:21][CH:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]2)[CH2:8][CH2:7]1
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: Clc1ccc(OC2CCNCC2)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)C1CCC(N2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)CC1
Reaction time: 8 h
Yield: 67.9 %

Procedure:
4-(3,4-Dichlorophenoxy)piperidine (Method B, 1.44 g), ethyl 4-oxocyclohexanecarboxylate (1.0 g) and acetic acid (0.34 ml) were combined in THF 10 ml and the solution was cooled in ice. Sodium triacetoxy borohydride (1.45 g) was added and the mixture was stirred overnight and allowed to come to ambient temperature. The reaction mixture was poured onto a stirred saturated aq solution of sodium bicarbonate. The mixture was extracted with ethyl acetate thrice, the organic phases were washed with brine, dried, filtered and evaporated. The residue was purified on an SCX cartridge (International Sorbent Technology Isolute® Flash SCX-2), washed with methanol and then product eluted with 0.7M ammonia in methanol. Further purification by chromatography (silica, 90:9:1 DCM:methanol:triethylamine) gave the subtitle compound (1.59 g; MS [M+H]+ (APCI+) 400/402) as a mixture of cis/trans isomers.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:26]([O-:28])=[O:27])=[C:6]([CH:25]=1)[C:7]([NH:9][C:10]1[S:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)=[CH:13][N:14]=1)=[O:8].[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>CN(C)C=O.C(OCC)(=O)C>[N+:26]([C:5]1[CH:4]=[CH:3][C:2]([N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:25][C:6]=1[C:7]([NH:9][C:10]1[S:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)=[CH:13][N:14]=1)=[O:8])([O-:28])=[O:27]
Reactant: O=C(Nc1ncc(-c2cccc(C(F)(F)F)c2)s1)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: C1CCNCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Nc1ncc(-c2cccc(C(F)(F)F)c2)s1)c1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Yield: 76 %

Procedure:
To a solution of 5-chloro-2-nitro-N-(5-(3-(trifluoromethyl)phenyl)thiazol-2-yl)benzamide (2.6 g, 6.08 mmol, 1.00 equiv) in N,N-dimethylformamide (20 mL) was added and piperidine (20 mL) and the resulting solution was stirred for 3 h at 100° C. in an oil bath. The mixture was diluted with 200 mL of ethyl acetate, washed with 2×50 mL of brine, dried over anhydrous sodium sulfate and then concentrated under vacuum to give 2.2 g (76%) of product as a yellow solid.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][C@H:12]([NH:14][CH2:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10][N:9]1[C:26](=[O:35])[C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[C:29]([Cl:34])[CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36]1([N:42]=[C:43]=[O:44])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[CH:18][CH:17]=2)[C:43](=[O:44])[NH:42][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:11][CH2:10][N:9]1[C:26](=[O:35])[C:27]1[CH:28]=[C:29]([Cl:34])[CH:30]=[C:31]([Cl:33])[CH:32]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccccc1
Reactant: O=C(c1cc(Cl)cc(Cl)c1)N1CC[C@@H](NCc2ccnc3ccccc23)C[C@@H]1Cc1ccccc1
Product: O=C(Nc1ccccc1)N(Cc1ccnc2ccccc12)[C@H]1CCN(C(=O)c2cc(Cl)cc(Cl)c2)[C@H](Cc2ccccc2)C1

Procedure:
200 mg (0.396 mmol) of (2S*,4R*)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(4-quinolylmethyl)-4-piperidinamine are reacted with 45 mg (0.377 mmol) of phenyl isocyanate in analogy to Example 16a. The title compound ##STR80## is obtained as solid residue (129 mg, 52%). TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.42, FD-MS: M+ 622, 624.
Reaction SMILES: Cl[C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Cl:13][C:14]1[N:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].CS(C)=O>CC(O)=O>[Cl:13][C:14]1[N:19]=[CH:18][C:17]([S:20]([NH:23][C:2]2[C:11]([Cl:12])=[N:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)(=[O:21])=[O:22])=[CH:16][CH:15]=1
Reactant: NS(=O)(=O)c1ccc(Cl)nc1
Reactant: Clc1nc2ccccc2nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: O=S(=O)(Nc1nc2ccccc2nc1Cl)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 96.6 %

Procedure:
2,3-dichloroquinoxaline (1.09 g, 5.48 mmol), 6-chloropyridine-3-sulfonamide (1.05 g, 5.45 mmol), K2CO3 (753 mg, 5.45 mmol) and dry DMSO (30 mL) were combined and heated to 150 C with vigorous stirring for 3-4 hr. The reaction mixture was allowed to cool to room temperature, then poured into 1% AcOH in ice water (300 mL) with vigorous stirring. The resulting solids were filtered, washed with H2O and dried under high vacuum to give 6-chloro-N-(3-chloroquinoxalin-2-yl)pyridine-3-sulfonamide (1.87 g, 96%). MS (EI) for C13H8Cl2N4O2S: 354.99 (MH+).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7]([N:14]1[C:18](=[O:19])[C:17](=[C:20]2[N:24]([CH3:25])[C:23]3[CH:26]=[C:27]([OH:30])[CH:28]=[CH:29][C:22]=3[S:21]2)[S:16][C:15]1=[N:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[NH:40][CH2:41][CH3:42])[C:35]#[N:36])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Br[CH2:44][C:45]([O:47][CH3:48])=[O:46]>CC(=O)CC>[CH3:48][O:47][C:45](=[O:46])[CH2:44][O:30][C:27]1[CH:28]=[CH:29][C:22]2[S:21][C:20](=[C:17]3[S:16][C:15](=[N:31][C:32]4[CH:33]=[C:34]([C:35]#[N:36])[CH:37]=[CH:38][C:39]=4[NH:40][CH2:41][CH3:42])[N:14]([CH2:7][C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:18]3=[O:19])[N:24]([CH3:25])[C:23]=2[CH:26]=1
Reactant: COC(=O)CBr
Reactant: CCNc1ccc(C#N)cc1N=C1SC(=C2Sc3ccc(O)cc3N2C)C(=O)N1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCNc1ccc(C#N)cc1N=C1SC(=C2Sc3ccc(OCC(=O)OC)cc3N2C)C(=O)N1Cc1ccccc1
Temperature: 75 °C

Procedure:
To a suspension of K2CO3 (41 mg, 5 equiv) in 2-butanone (2 mL) were added the product of Example 57 (31 mg, 0.06 mmol) and methyl 2-bromoacetate (7 μL, 1.2 equiv). The resulting suspension was heated at 75° C. overnight. After cooling, the reaction mixture was filtered, and the filtrate was evaporated to give a crude material, which was purified by chromatography on silica gel, eluting with MeOH-DCM (0:100 to 3:97) to give the title compound (5 mg). 1H-NMR (CDCl3): δ 7.63 (1H, d), 7.28-7.39 (6H, m), 7.13 (1H, d), 7.08 (1H, d), 6.84 (1H, dd), 6.62 (1H, d), 5.13 (2H, s), 4.98 (1H, t), 4.88 (2H, s), 3.79 (3H, s), 3.68 (3H, s), 3.05 (2H, m), 0.99 (3H, t); MS(ESI): 586 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH2:15][O:16][CH3:17])([CH2:12][O:13][CH3:14])[CH:9]3[O:18][CH:8]3[C:7]=2[CH:19]=1)#[N:2].[C:20]([C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)#[N:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH2:15][O:16][CH3:17])([CH2:12][O:13][CH3:14])[C@@H:9]([OH:18])[C@H:8]([N:24]3[C:25]4[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:22]([C:20]#[N:21])=[CH:23]3)[C:7]=2[CH:19]=1)#[N:2]
Reactant: N#Cc1c[nH]c2ccccc12
Reactant: COCC1(COC)Oc2ccc(C#N)cc2C2OC21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCC1(COC)Oc2ccc(C#N)cc2[C@@H](n2cc(C#N)c3ccccc32)[C@@H]1O
Yield: 64.3 %

Procedure:
A reaction mixture containing 6-cyano-3,4-epoxy-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran (300 mg), 3-cyanoindole (210 mg) and potassium carbonate (480 mg), in dimethylformamide (3 ml), was stirred at 80° C. for 2.5 hours. The reaction mixture was diluted with ethyl acetate, washed with water, 1N-hydrochloric acid, an aqueous solution of sodium hydrogencarbonate and brine, dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2) to give 298 mg of the title compound.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)C>[CH:1](=[N:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=Cc1ccccc1
Solvent: CCO
Product: C(=Nc1ccccc1)c1ccccc1
Reaction time: 0.25 h

Procedure:
Benzaldehyde (0.20 mole) was treated with aniline (0.20 mole) with vigorous stirring in a 1 liter Erlenmeyer Flask. After 15 mins., 33 cc of 95% ethanol was added and the reaction mixture was stirred vigorously for an additional 5 minutes. The reaction mixture was left standing at room temperature for 10 min.; then it was placed in an ice-bath for 0.5 hours. The crystals which formed were collected, washed with 95% ethanol, and air-dried. Recrystallization from 85% ethanol gave N-benzylideneaniline. m.p. 50°-51.5° C.
Reaction SMILES: [CH2:1]1[C:3]([NH2:7])([C:4]([OH:6])=[O:5])[CH2:2]1.[CH3:8][C:9]1[CH:30]=[CH:29][CH:28]=[CH:27][C:10]=1[C:11]([O:13][CH2:14][CH2:15][O:16][C:17](ON1C(=O)CCC1=O)=[O:18])=[O:12]>>[CH3:8][C:9]1[CH:30]=[CH:29][CH:28]=[CH:27][C:10]=1[C:11]([O:13][CH2:14][CH2:15][O:16][C:17]([NH:7][C:3]1([C:4]([OH:6])=[O:5])[CH2:2][CH2:1]1)=[O:18])=[O:12]
Reactant: Cc1ccccc1C(=O)OCCOC(=O)ON1C(=O)CCC1=O
Reactant: NC1(C(=O)O)CC1
Product: Cc1ccccc1C(=O)OCCOC(=O)NC1(C(=O)O)CC1
Yield: 43.3 %

Procedure:
Following the general procedure for the synthesis of acyloxyalkyl carbamates, ACPC (121 mg, 1.2 mmol) and (2,5-dioxoazolidinyloxycarbonyloxy)ethyl 2-methylbenzoate (321 mg, 1.0 mmol) were reacted to provide 133 mg (43% yield) of the title compound (3) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (CDCl3, 400 MHz): δ=7.85 (d, 1H), 7.40 (t, 1H), 7.21 (t, 2H), 7.01 (q, 1H), 5.79 (br s, 0.3H), 5.41 (s, 0.7H), 2.58 (s, 3H), 1.60 (m, 5H), 1.30 (m, 2H). MS (ESI) m/z 325.17 (M+NH4)+; 330.12 (M+Na)+; 306.15 (M−H)−.
Reaction SMILES: C(=O)(O)[O-].[Na+].O.[OH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[N:14]#[C:15]Br>C(Cl)Cl>[C:15]([N:11]1[CH2:12][CH2:13][CH:8]([OH:7])[CH2:9][CH2:10]1)#[N:14]
Reactant: N#CBr
Reactant: OC1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: N#CN1CCC(O)CC1
Reaction time: 0.5 h
Yield: 91 %

Procedure:
A 5-liter, 3-neck flask was equipped with mechanical stirring, a reflux condenser, and a powder addition funnel. Sodium bicarbonate (840 g, 10 mmol) was added via the powder funnel while stirring, then water (ca. 300-400 mL) was gradually added while vigorously stirring to form a thick, uniform slurry. The flask was then placed in an ice bath, and a solution of 4-hydroxypiperidine (506 g, 5.00 mol) in CH2Cl2 (1.0 L) was added, and the contents were vigorously mixed while cooling. A solution of cyanogen bromide (640 g, 6.0 mol) in CH2Cl2 (600 mL) was added in a dropwise fashion over 2 h, and stirring was continued for an additional 30 min. The ice bath was removed, and the mechanical stirrer was replaced by a magnetic stirrer, and the reaction mixture was stirred for 16 h. The flask was once again placed under mechanical stirring, and sodium carbonate (100 g) was added in order to ensure complete neutralization. MgSO4 (500 g) was added, and vigorous stirring was continued for 15 min. The resulting suspension was filtered, rinsing with CH2Cl2 (2.0 L). A light amber, viscous oil was obtained upon solvent removal to give 1-cyano-4-hydroxypiperidine (574 g, 91% yield. 1H NMR (CDCl3) δ 3.80 (m, 1H), 3.39 (m, 2H), 3.05 (m, 2H), 1.87 (m, 2H), 1.70 (br s, 1H), 1.62 (m, 2H); MS m/z 212.1 (M+).