Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S=C1[N:6]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18](=[O:20])[CH3:19])=[C:13]([O:21][CH3:22])[CH:12]=2)=[O:8])[CH2:5][CH2:4]S1.[CH2:23](N)[CH2:24][CH2:25][CH2:26][CH2:27]CC.C(N(CC)CC)C>ClCCl>[C:18]([O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][O:9][C:7](=[O:8])[NH:6][CH2:5][CH2:4][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:12][C:13]=1[O:21][CH3:22])(=[O:20])[CH3:19]
Reactant: COc1cc(COC(=O)N2CCSC2=S)ccc1OC(C)=O
Reactant: CCCCCCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCNC(=O)OCc1ccc(OC(C)=O)c(OC)c1

Procedure:
A yellow solution of VII (87 mg, 0.255 mmol), n-heptylamine (31 mg, 1.05×0.255 mmol) and triethylamine (26 mg, 36 μL, 0.255 mmol) in 3 mL of dichloromethane was stirred at room temperature overnight. The reaction was worked up as described for 7. The product was purified by preparative thick layer chromatography using dichloromethane/diisopropyl ether, 9:1, v/v, as the developing solvent. The result was 58 mg (67%) of 6 as a clear oil: Rf=0.53 (dichloromethane/acetone, 97:3, v/v); 1HNMR (CDCl3) δ 6.98 (d, 3J=8.0 Hz, 1H), 6.94 (s, 1H), 6.91 (d, 3J=8.0 Hz, 1H), 4.98 (s, 2H), 4.73 (bs 1H, NH), 3.81 (s, 3H), 3.18-3.14 (m, 2H), 2.29 (s, 3H), 1.50-1.43 (m, 2H), 1.31-1.19 (m, 8H) and 0.85 (t, 3J=7.0 Hz, 3H). Exact mass (FAB+) calculated for C18H27NO5 [M+] 337.1889. found 337.1895.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=2[OH:17])[C:12]#[N:13])[C:4]1=[O:18].[Cl:19][C:20]1[CH:21]=[CH:22][C:23]2[CH:27]=[C:26]([S:28](Cl)(=[O:30])=[O:29])[S:25][C:24]=2[CH:32]=1>>[C:12]([C:11]1[CH:14]=[CH:15][C:16]([OH:17])=[C:9]([CH:10]=1)[CH2:8][N:5]1[CH2:6][CH2:7][C@H:3]([NH:2][S:28]([C:26]2[S:25][C:24]3[CH:32]=[C:20]([Cl:19])[CH:21]=[CH:22][C:23]=3[CH:27]=2)(=[O:30])=[O:29])[C:4]1=[O:18])#[N:13]
Reactant: O=S(=O)(Cl)c1cc2ccc(Cl)cc2s1
Reactant: N#Cc1ccc(O)c(CN2CCC(N)C2=O)c1
Agent: Cl
Product: N#Cc1ccc(O)c(CN2CC[C@H](NS(=O)(=O)c3cc4ccc(Cl)cc4s3)C2=O)c1

Procedure:
The title compound is prepared from 3-[(3-amino-2-oxo-pyrrolidin-1-yl)-methyl]-4-hydroxy-benzonitrile hydrochloride as described in EXAMPLE 17, Part G substituting 6-chlorobenzo[b]thiophene-2-sulfonyl chloride in place of 4,6-dichlorobenzo[b]thiophene-2-sulfonyl chloride. The crude product is triturated with Et2O to give the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([CH:11]=[N:12][NH:13][C:14]([NH2:16])=[S:15])[CH:9]=2)[NH:4][N:3]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>>[C:17]([NH:16][C:14](=[N:13]/[N:12]=[CH:11]/[C:8]1[CH:9]=[C:10]2[C:2]([CH3:1])=[N:3][NH:4][C:5]2=[N:6][CH:7]=1)[SH:15])(=[O:19])[CH3:18]
Reactant: Cc1n[nH]c2ncc(C=NNC(N)=S)cc12
Reactant: CC(=O)OC(C)=O
Product: CC(=O)NC(S)=N/N=C/c1cnc2[nH]nc(C)c2c1
Temperature: 80 °C

Procedure:
The staring material 1-((3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methylene)thiosemicarbazide (500 mg, 2.0 mmol) and acetic anhydride (20 ml) was mixed and heated to 80° C. for 1 hour. The reaction mixture was then cooled down to room temperature. The yellow solid was precipitated out and was filtered off. The yellow solid was washed with ether (50 ml). The product was obtained in quantitative yield and used for the next step without further purification.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:8]=[C:7]([OH:9])[C:6]([CH:10]([CH3:12])[CH3:11])=[CH:5][C:4]=1[C:13]([N:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)[CH:21]=2)[CH2:16]1)=[O:14].[CH3:31][N:32]([CH3:36])[C:33](Cl)=[O:34]>N1C=CC=CC=1>[CH3:31][N:32]([CH3:36])[C:33]([O:2][C:3]1[C:4]([C:13]([N:15]2[CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)[CH:21]=3)[CH2:16]2)=[O:14])=[CH:5][C:6]([CH:10]([CH3:11])[CH3:12])=[C:7]([O:9][C:13](=[O:14])[N:15]([CH3:23])[CH3:16])[CH:8]=1)=[O:34]
Reactant: CC(C)c1cc(C(=O)N2Cc3ccc(N4CCN(C)CC4)cc3C2)c(O)cc1O
Reactant: CN(C)C(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)c1cc(C(=O)N2Cc3ccc(N4CCN(C)CC4)cc3C2)c(OC(=O)N(C)C)cc1OC(=O)N(C)C
Temperature: 140 °C

Procedure:
A mixture of (2,4-dihydroxy-5-isopropyl-phenyl)-[5-(4-methyl-piperazin-1-yl)-1,3-dihydro-isoindol-2-yl]-methanone hydrochloride salt (100 mg) and dimethylcarbamyl chloride (420 μl; 20 equivalents) in pyridine (1 ml) was heated at 140° C. for 20 minutes in a CEM discover microwave synthesiser then evaporated and re-evaporated with toluene (×3). The crude material was purified by preparative LC/MS and 55 mg of the title compound were isolated as a brown solid (formate salt). 1H NMR (400 MHz, DMSO-d6): 8.15 (1H, s), 7.42 (1H, d), 7.25-7.10 (1H, m), 7.05-6.85 (3H, m), 4.70 (2H, d), 4.54 (2H, d), 3.20-3.10 (4H, m), 3.09 (3H, s), 3.08-3.00 (1H, m), 2.95 (3H, s), 2.88 (3H, s), 2.79 (3H, s) 2.65-2.47 (4H, m), 2.35 (3H, d), 1.20 (6H, d). MS: [M+H]+ 538.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:11][CH3:12])[C:4]1[O:8][C:7]([CH2:9][OH:10])=[CH:6][CH:5]=1.[OH-].[Na+].[CH2:15]([CH:17]1[O:19][CH2:18]1)Cl>C(C(C)=O)C>[CH3:1][O:2][CH:3]([O:11][CH3:12])[C:4]1[O:8][C:7]([CH2:9][O:10][CH2:15][CH:17]2[O:19][CH2:18]2)=[CH:6][CH:5]=1
Reactant: COC(OC)c1ccc(CO)o1
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CCC(C)=O
Product: COC(OC)c1ccc(COCC2CO2)o1
Reaction time: 0.5 h

Procedure:
5-Glycidoxymethyl furfuraldehyde dimethyl acetal was prepared by adding a total of 6.0 g (0.035 mole) of 5-hydroxymethyl furfuraldehyde dimethyl acetal (HMFA) to 1.54 g sodium hydroxide (0.038 mole) in a 100 ml round bottom flask equipped with magnetic stir bar, reflux condenser, and nitrogen inlet. After stirring for 30 min., 3.89 g (0.042 mole) of epichlorohydrin in 50 ml. of methyl ethyl ketone was added quickly, and the reaction mixture was allowed to reflux overnight under an inert (nitrogen) atmosphere. The mixture was then cooled, filtered, and the solvent removed under vacuum. The resulting oil was mixed with 250 ml of toluene and the toluene was distilled off at atmospheric pressure to remove any residual epichlorohydrin. The sample was freed of toluene by subjecting it to high vacuum overnight.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[NH2:10].CC1C=CC=CC=1.[Cl:18][CH2:19][C:20](Cl)=[O:21]>O>[Cl:18][CH2:19][C:20]([NH:10][C:4]1[CH:5]=[C:6]([CH3:9])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])=[O:21]
Reactant: O=C(Cl)CCl
Reactant: COc1ccc(C)cc1N
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C)cc1NC(=O)CCl
Reaction time: 1.5 h
Yield: 66 %

Procedure:
To a stirred solution of 49.2 parts of 2-methoxy-5-methylbenzenamine and 270 parts of methylbenzene were added dropwise 22.5 parts of 2-chloroacetyl chloride while cooling (ice-bath) at 10°-20° C. Upon completion, stirring was continued for 1.50 hours at room temperature. 200 Parts of water were added. The organic phase was separated, washed with water, dried, filtered and evaporated. The oily residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 28.2 parts (66%) of 2-chloro-N-(2-methoxy-5-methylphenyl)acetamide; mp. 83.9° C. (intermediate 66).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C@@H:14]([O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1)[CH2:15][C:16]([O:18]CC)=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[OH-].[Na+]>O>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C@@H:14]([O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1)[CH2:15][C:16]([OH:18])=[O:17])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C[C@@H](CCNC(=O)OCc1ccccc1)OC1CCCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C[C@@H](CCNC(=O)OCc1ccccc1)OC1CCCCO1
Reaction time: 2 h
Yield: 81.9 %

Procedure:
Into a 500-ml four-necked flask were poured 61.8 g (0.163 mole) of ethyl (3R)-5-benzyloxycarbonylamino-3-(2-tetrahydropyranyloxy)pentanoate (2-b) obtained by the above process A and 124 ml of methanol. Then, the contents of the flask were cooled with ice. Furthermore, 72 ml of a 10 wt% aqueous sodium hydroxide solution were added to the contents, and the contents were allowed to completely hydrolyze for 2 hours at the same temperature. Into the solution was added 90 ml of water, and the aqueous mixture was extracted with two 75 ml portions of butyl acetate. 125 ml of toluene and 100 ml of a 5 wt % aqueous hydrochloric acid solution were added to the aqueous layer to thereby adjust the pH to 4.5. The toluene layer was washed with a saturated sodium chloride solution and then dried with magnesium sulfate. After removing the solvent by distillation, 46.9 g (82% yield) of the intended oily product was obtained.
Reaction SMILES: O.Br[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][C:4]=1[F:12].C(=O)([O-])[O-].[Na+].[Na+].[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[F:12][C:4]1[CH:5]=[C:6]([CH2:9][C:10]#[N:11])[CH:7]=[CH:8][C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: N#CCc1ccc(Br)c(F)c1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: N#CCc1ccc(-c2ccccc2)c(F)c1

Procedure:
A biphasic mixture of water (3 mL) and toluene (10 mL) containing (4-bromo-3-fluoro-phenyl)-acetonitrile (457 mg, 2.14 mmol), sodium carbonate (1.00 g, 9.45 mmol), phenyl boronic acid (781 mg, 6.41 mmol) was sparged with nitrogen for 10 min, tetrakis(triphenylphosphine)palladium (250 mg) was added and the mixture heated to reflux for 48 hrs. After cooling, the solution was diluted with EtOAc, washed with water, the organic phase dried (MgSO4), filtered and evaporated to dryness. The residue was purified by column chromatography (0 to 10% EtOAc in hexanes) to afford (2-fluoro-biphenyl-4-yl)-acetonitrile as a colorless solid. 1H NMR (500 MHz, CDCl3) δ 7.54 (2H, m), 7.46 (3H, m), 7.40 (1H, m), 7.17 (2H, m), 3.79 (3H, s).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[CH2:10][CH2:11][S:12][CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[C:27](O)=[C:26]([Cl:29])[C:25]([Cl:30])=[C:24]([Cl:31])[C:23]=1[Cl:32].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[Cl:21][C:22]1[C:27]([O:19][C:18](=[O:20])[CH2:17][NH:16][C:14](=[O:15])[C@H:9]([CH2:10][CH2:11][S:12][CH3:13])[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[C:26]([Cl:29])[C:25]([Cl:30])=[C:24]([Cl:31])[C:23]=1[Cl:32]
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Reactant: Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Temperature: 0 °C

Procedure:
1.9 g. (6.2 mmole) of tert.-butyloxycarbonyl-L-methionyl-glycine [M.A. Ondetti, I. Phuscec, E.F. Sabo, J.T. Sheehan, N-Williams; J. Am. Chem. Soc. 92, 195 (1970)] and 1.92 g. (7.2 mmole) of pentachlorophenol are dissolved in 31 ml. of dimethyl formamide. The solution is cooled to 0° C., the solution of 1.41 g. (6.85 mmole) of dicyclohexyl carbodiimide in 6.2 ml. of dimethyl formamide is added dropwise under stirring and the mixture is stirred for a further hour at the same temperature. The mixture is allowed to stand over night; on the following day the precipitated dicyclohexyl urea is filtered off and the filtrate is evaporated to dryness under reduced pressure. The evaporation residue is triturated with ether, the product filtered, washed with a minor amount of ether and recrystallized from a 15-fold amount of ether. 2.19 g. of tert.-butyloxycarbonyl-L-methionyl-glycine pentachlorophenyl ester (63.6% of the theoretical yield) are obtained; m.p. 169°-171° C.; Rf (in the 8:2 mixture of chloroform and ethanol) = 0.8.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[C:6]([CH:9]=1)[C:7]#[N:8].Cl.[F:12][C@H:13]1[CH2:17][CH2:16][NH:15][CH2:14]1.CCN(C(C)C)C(C)C>CC#N>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:15]2[CH2:16][CH2:17][C@H:13]([F:12])[CH2:14]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(Br)cnc1Cl
Reactant: F[C@H]1CCNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: N#Cc1cc(Br)cnc1N1CC[C@H](F)C1

Procedure:
5-Bromo-2-chloro-nicotinonitrile (6) (5.0 g, 23.0 mmol) was dissolved in MeCN (100 mL). (S)-3-Fluoropyrrolidine hydrochloride (5.7 g, 53.0 mmol) and DIPEA (12.0 mL, 68.9 mmol) were added and the mixture was stirred at reflux for 1 hour. The solvent was evaporated in vacuo and the residue partitioned between EtOAc (100 mL) and H2O (50 mL). The layers were separated and the organic phase washed with saturated brine solution (50 mL), then dried (MgSO4), filtered and the solvent evaporated in vacuo. The title compound was obtained as an off-white solid (6.2 g, 100%); LCMS, Rt=2.91 min (MeOH-FA method), m/z 270, 272 (MH+).
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[CH:5]=[C:6]([CH3:11])[CH:7]=[CH:8][C:9]=1[Cl:10].Cl[C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:16]([N+:22]([O-:24])=[O:23])=[CH:15][C:14]=1[C:25]([F:28])([F:27])[F:26].Cl>CN(C)C=O.O>[Cl:10][C:9]1[CH:8]=[CH:7][C:6]([CH3:11])=[CH:5][C:4]=1[NH:3][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:16]([N+:22]([O-:24])=[O:23])=[CH:15][C:14]=1[C:25]([F:26])([F:28])[F:27]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(C(F)(F)F)c1
Reactant: Cc1ccc(Cl)c(N)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(Cl)c(Nc2c([N+](=O)[O-])cc([N+](=O)[O-])cc2C(F)(F)F)c1
Reaction time: 0.08 h

Procedure:
Powdered potassium hydroxide (2.0 g.) was added in portions over 5 minutes to a stirred solution of 3-amino-4-chlorotoluene (2.8 g.) in dimethylformamide (15 ml.) at the ambient temperature and stirring was continued for a further 5 minutes. A solution of 2-chloro-3,5-dinitro-benzotrifluoride (5.4 g.) in dimethylformamide (15 ml.) was then added over 5 minutes, and following the addition, the mixture was stirred for 30 minutes. After acidification with concentrated hydrochloric acid the mixture was poured into water (15 ml.). The precipitated solid was separated from the supernatant liquid by decantation and recrystallised from methylated spirit to yield 2(2-chloro-5-methylanilino)-3,5-dinitrobenzotrifluoride, with a melting point of 127° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:15][CH:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])[CH2:13]2)=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Na+].Cl>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:15][CH:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])[CH2:13]2)=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Cl)cnc1N1CC(Nc2ccc(F)cc2F)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cc(Cl)cnc1N1CC(Nc2ccc(F)cc2F)C1
Temperature: 60 °C
Reaction time: 12 h
Yield: 99.1 %

Procedure:
To a solution of methyl 5-chloro-2-(3-((2,4-difluorophenyl)amino)azetidin-1-yl)nicotinate (D85) (37 mg, 0.104 mmol) in a mixture 3:1 1,4-dioxane/water (4 ml), 1M NaOH (0.157 ml) was added and the resulting mixture was stirred 12 h at 60° C. After cooling the reaction mixture was acidified to pH 1 by addition of 1M HCl. The resulting precipitate was collected by filtration and afforded the title compound (D118) (35 mg).
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3Cl)[C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:19][N:20]([CH3:24])[CH2:21][CH2:22][NH2:23]>O>[CH3:19][N:20]([CH3:24])[CH2:21][CH2:22][NH:23][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[NH:23][CH2:22][CH2:21][N:20]([CH3:24])[CH3:19])[C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2cccc(Cl)c2C(=O)c2c(Cl)cccc21
Reactant: CN(C)CCN
Solvent: O
Product: CN(C)CCNc1cccc2c1C(=O)c1c(NCCN(C)C)cccc1C2=O
Temperature: 25 °C

Procedure:
A mixture of 1,8-dichloroanthraquinone (5.5 g, 20 mmol) and N,N-dimethylethylenediamine (40 mL) was refluxed for 18 h. The mixture was cooled to room temperature and diluted with water to precipitate the title compound which was recrystallised from methanol to afford Compound 6 (4.5 g). The structure of Compound 6 is given below:
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[C:10]([C:11]2[S:12][C:13]([NH:16][C:17](=[O:30])[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH2:27][CH2:28]Cl)[CH:20]=3)=[N:14][N:15]=2)=[N:9][O:8][N:7]=1)=O.[NH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.CCO>O>[N:33]1([CH2:28][CH2:27][CH2:26][O:25][C:21]2[CH:20]=[C:19]([CH2:18][C:17]([NH:16][C:13]3[S:12][C:11]([C:10]4[C:6]([NH2:5])=[N:7][O:8][N:9]=4)=[N:15][N:14]=3)=[O:30])[CH:24]=[CH:23][CH:22]=2)[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1
Reactant: C1CNCCN1
Reactant: O=C(Cc1cccc(OCCCCl)c1)Nc1nnc(-c2nonc2NC(=O)C(F)(F)F)s1
Solvent: O
Solvent: CCO
Product: Nc1nonc1-c1nnc(NC(=O)Cc2cccc(OCCCN3CCNCC3)c2)s1

Procedure:
N-Trifluoroacetyl-4-(5-(3-(3-chloro-propoxy)-phenylacetyl)amino-[1,3,4]thiadiazol-2-yl)-furazan-3-ylamine (0.05 g, 0.1 mmol), piperazine (0.035 g, 0.4 mmol) and EtOH (0.3 mL) were heated by microwave irradiation at 120° C. for 2×10 minutes. The reaction was diluted with water and purified by preparative HPLC. Yield: 0.03 g (33%). 1H-NMR (MeOD) δ 7.25 (t, 1H), 6.90–6.95 (m, 2H), 6.85 (d, 1H), 4.12 (t, 2H), 3.82 (s, 2H), 3.3.10–3.15 (m, 6H), 3.00 (t, 3H), 2.10–2.15 (m, 3H). LCMS 445.2 (M+1), HPLC Method B Rt 1.6 minutes.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:11]=[CH:12][N:13]=2)[CH:10]=1)[NH2:4].[Cl:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=O)=[CH:17][N:16]=1.N>>[Cl:14][C:15]1[N:16]=[CH:17][C:18]([C:19]2[O:1][N:2]=[C:3]([C:5]3[CH:6]=[CH:7][C:8]4[N:9]([CH:11]=[CH:12][N:13]=4)[CH:10]=3)[N:4]=2)=[CH:22][CH:23]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: NC(=NO)c1ccc2nccn2c1
Agent: N
Product: Clc1ccc(-c2nc(-c3ccc4nccn4c3)no2)cn1

Procedure:
The title compound was prepared according to Method D using N′-hydroxyimidazo[1,2-a]pyridine-6-carboximidamide (Bionet) and 6-chloronicotinoyl chloride (Aldrich). 1H NMR (300 MHz, DMSO-d6) δ 7.70 (d, J=1.2 Hz, 1 H), 7.74-7.84 (m, 2 H), 7.87 (d, J=8.3 Hz, 1 H), 8.20 (s, 1 H), 8.59 (dd, J=8.5, 2.6 Hz, 1 H), 9.20 (dd, J=2.4, 0.8 Hz, 1 H), 9.47 (t, J=1.4 Hz, 1 H) ppm; MS (DCI/NH3) m/z 298 (M+H)+, 300 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.Cl.Cl[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.CN1CCOCC1>CN1CCCC1=O>[N:17]1[CH:18]=[CH:19][C:14]([N:1]2[CH2:2][CH2:3][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10][CH2:11]2)=[CH:15][CH:16]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: Clc1ccncc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN1CCCC1=O
Product: CCOC(=O)C1CCN(c2ccncc2)CC1

Procedure:
Ethyl isonipecotate (6.0 g, 38.66 mmol), 4-chloropyridine hydrochloride (5.9 g, 38.66 mmol) and N-methylmorpholine (9.3 mL, 85.0 mmol) were dissolved in N-methylpyrrolidinone (50 mL) and the resulting solution heated at 100° for 48 h. The solution was concentrated in vacuo and the residue dissolved in ethyl acetate (200 mL), washed with water and brine (2×100 mL), then dried (Na2SO4) and evaporated. The resulting residue was purified by flash chromatography (5%MeOH/CH2Cl2) to afford 21-1 as a crystalline solid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.F[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21].C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>CN(C=O)C>[F:1][C:2]([F:11])([F:12])[O:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:8][CH:9]=1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1Oc1ccc(OC(F)(F)F)cc1

Procedure:
4-(trifluoromethoxy)phenol (1.36 ml, 10.6 mmol), 2-fluoro-1-nitrobenzene (0.74 ml, 7 mmol), potassium carbonate (1.46 g, 10.5 mmol) were mixed together in DMF (4 ml) and heated at reflux for 5 h. Allowed to cool, and evaporated in-vacuo. Residue partitioned between diethyl ether and sodium hydroxide (1 M). Organic layers combined and dried over anhydrous magnesium sulphate and evaporated in-vacuo, to afford a yellow oil, 2.34 g, >100%. Rf: 0.72 (DCM), 1HNMR (CDCl3, 270 MHz) δ 7.03 (3H, m, Ar HD, Ar HF), 7.20 (2H, dd, J=0.9, 10.1 Hz, Ar HE), 7.23 (1H, m, Ar HB), 7.53 (1H, m, Ar HC), 7.97 (1H, dd, J=1.5, 8.2 Hz, Ar HA).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:34]=[CH:33][C:6]([CH2:7][NH:8][CH2:9][C:10]([C:13]2[CH:17]=[C:16]([NH:18][C:19](=[O:32])[C:20]([CH3:31])([S:22]([CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)(=[O:24])=[O:23])[CH3:21])[O:15][N:14]=2)([CH3:12])[CH3:11])=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:41](Cl)(=[O:43])[CH3:42]>C1COCC1>[C:41]([N:8]([CH2:7][C:6]1[CH:33]=[CH:34][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH2:9][C:10]([C:13]1[CH:17]=[C:16]([NH:18][C:19](=[O:32])[C:20]([CH3:21])([S:22]([CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)(=[O:24])=[O:23])[CH3:31])[O:15][N:14]=1)([CH3:12])[CH3:11])(=[O:43])[CH3:42]
Reactant: CC(=O)Cl
Reactant: COc1ccc(CNCC(C)(C)c2cc(NC(=O)C(C)(C)S(=O)(=O)C3CCOCC3)on2)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1ccc(CN(CC(C)(C)c2cc(NC(=O)C(C)(C)S(=O)(=O)C3CCOCC3)on2)C(C)=O)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 75 %

Procedure:
To a solution of N-{3-[2-(4-methoxy-benzylamino)-1,1-dimethyl-ethyl]-isoxazol-5-yl}-2-methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionamide (143 mg, 0.29 mmol) in THF (1.5 mL) are added pyridine (0.035 mL, 0.44 mmol) and acetyl chloride (0.031 mL, 0.44 mmol). The reaction mixture is stirred at room temperature for 3.5 h. After this time, more pyridine (0.018 mL, 0.22 mmol) and acetyl chloride (0.016 mL, 0.22 mmol) are added to the reaction mixture and the stirring is continued for 1 h. After this time, the reaction mixture is quenched with saturated aqueous NaHCO3 solution and extracted with ethyl acetate twice. The organic extracts are combined and washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using methanol/DCM provides the title compound. Yield: 75%; LC-MS retention time: 1.62 mins. ESI+ion mode. Zorbax SB-C18 column (3.5 μm, 4.6×30 mm). Gradient: 5% B to 80% B (0 min to 1.7 mins), 80% B to 95% B (1.7 mins to 2 mins), 95% B to 95% B (2 mins to 2.1 mins). Flow rate: 2.5 mL/min. A=(Water+0.1% Formic Acid), B=(Acetonitrile+0.1% Formic Acid). Diode Array Detector; m/z 536 [M+H].
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:18][CH:19]1[CH2:21][CH2:20]1.Cl>CC#N.CCOC(C)=O>[CH:19]1([CH2:18][O:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:21][CH2:20]1
Reactant: BrCC1CC1
Reactant: O=[N+]([O-])c1ccccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=[N+]([O-])c1ccccc1OCC1CC1
Temperature: 85 °C
Yield: 97 %

Procedure:
A mixture of 2-nitrophenol (1 g, 7.19 mmol), K2CO3 (1.192 g, 8.63 mmol), and (bromomethyl)cyclopropane (0.837 ml, 8.63 mmol) in CH3CN (40 ml) was heated to 85° C. overnight. The mixture was portioned between EtOAc and HCl 1N. The organic phase was dried over Na2SO4 and the solvent was removed. 1-(cyclopropylmethoxy)-2-nitrobenzene was obtained as a crude (1.352 g, 7.00 mmol, 97% yield) and used in the next step without further purification.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[S:12](Cl)(=[O:15])(=[O:14])[NH2:13].ClS(N=C=O)(=O)=O>O>[NH2:13][S:12]([O:11][C:7]1[CH:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:10]=[CH:9][CH:8]=1)(=[O:15])=[O:14]
Reactant: CC(=O)Nc1cccc(O)c1
Reactant: NS(=O)(=O)Cl
Agent: O=C=NS(=O)(=O)Cl
Solvent: O
Product: CC(=O)Nc1cccc(OS(N)(=O)=O)c1

Procedure:
By the same method described for Example 62, the title compound was prepared from m-acetamidophenol (12.10 g, 0.08 m), reacting with the sulfamoyl chloride generated from water and chlorosulfonyl isocyanate. The crude product contained desired product and starting material. The product was isolated by chromatography on 100 g silica gel, eluted first with 7:3 methylene chloride/acetonitrile and then increasing the proportion of acetonitrile in the eluting solvent. The main fraction was evaporated and triturated with isopropyl alcohol/isopropyl ether to give 4 g of white solid, recrystallized from acetonitrile/isopropyl ether, and dried in vacuum at 60° C. overnight to give 3.73 g of solid, mp 148°-149° C.