Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:12]([CH:13]=O)=[CH:11][CH:10]=[C:9]([Si:15]([CH3:18])([CH3:17])[CH3:16])[C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5].Cl.[NH2:20]O.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[Cl:1][C:2]1[C:12]([C:13]#[N:20])=[CH:11][CH:10]=[C:9]([Si:15]([CH3:18])([CH3:17])[CH3:16])[C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5]
Reactant: NO
Reactant: CCNC(=O)c1c([Si](C)(C)C)ccc(C=O)c1Cl
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCNC(=O)c1c([Si](C)(C)C)ccc(C#N)c1Cl
Temperature: 100 °C

Procedure:
A solution of the compound of Example 223 (0.28 g, 1.0 mmol) and hydroxylamine hydrochloride (0.12 g, 1.7 mmol) in pyridine (10 mL) was stirred at RT for 2 h. Acetic anhydride (0.75 mL, 8.0 mmol) was added and the solution was heated at 100° C. for 1.5 h. The mixture was concentrated, water added and the mixture extracted with ether. The organic layers were washed with 0.5 N HCl, sat NaHCO3, brine, dried (MgSO4) and concentrated to afford the title compound. The crude product was purified by recrystallization from ethyl acetate/hexanes to afford 0.21 g of white needles (74%). m.p. 111-112° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@:6]1([C:14](=[O:15])[NH:13][C:12](=[O:16])[N:11]1[CH3:17])[CH2:5]2.[Cl:18]N1C(=O)CCC1=O>CC(O)=O>[NH2:1][C:2]1[C:3]([Cl:18])=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@:6]1([C:14](=[O:15])[NH:13][C:12](=[O:16])[N:11]1[CH3:17])[CH2:5]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: CN1C(=O)NC(=O)[C@]12Cc1ccc(N)cc1C2
Solvent: CC(=O)O
Product: CN1C(=O)NC(=O)[C@]12Cc1ccc(N)c(Cl)c1C2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
(R)-5′-Amino-3-methyl-spiro[imidazolidine-4,2′-indane]-2,5-dione (265 mg, 1.15 mmol, described in Intermediate 8) was dissolved in AcOH (7 mL) and N-chlorosuccinimide (145 mg, 1.09 mmol) was added in one portion. The mixture was stirred at ambient temperature for 5 h, then the solvent was removed in vacuo. The residue was partitioned between saturated aqueous NaHCO3 (20 mL) and CH2Cl2 (70 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:EtOAc—100:0 to 0:100, to give (R)-5′-amino-4′-chloro-3-methyl-spiro[imidazolidine-4,2′-indane]-2,5-dione, which eluted first, and the title compound, which eluted second. MS: m/z=266 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:20]4=[CH:21][C:22]5[O:26][CH2:25][O:24][C:23]=5[CH:27]=[C:19]4[O:18][CH2:17]3)[C:9]2=[O:28])[S:5][CH:6]=1.[CH3:29][N:30](C)C=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:28]=[C:9]1[C:10]2([C:20]3=[CH:21][C:22]4[O:26][CH2:25][O:24][C:23]=4[CH:27]=[C:19]3[O:18][CH2:17]2)[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]1[CH2:7][C:4]1[S:5][CH:6]=[C:2]([C:29]#[N:30])[CH:3]=1
Reactant: O=C1N(Cc2cc(Br)cs2)c2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1csc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)c1
Reaction time: 0.12 h
Yield: 62 %

Procedure:
To a suspended mixture of 1′-[(4-bromo-2-thienyl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.456 g, 1.0 mmol) and zinc cyanide (0.117 g, 1.0 mmol) in anhydrous N,N-dimethylformamide (5 mL) was added tetrakis(triphenylphosphine)palladium (0.04 g, 0.03 mmol). The reaction mixture was put into a microwave reactor set at 100 W at 133° C. for 7 min. The solid was filtered and washed with ethyl acetate (40 mL). The filtrate was concentrated in vacuo to dryness. The residue was purified by column chromatography with ethyl acetate in hexanes (10% to 30% gradient) to give 5-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]thiophene-3-carbonitrile (0.25 g, 62%) as a colorless solid: mp 207-209° C. (dichloromethane/hexane); 1H NMR (300 MHz, DMSO-d6) δ8.48 (d, J=1.3 Hz, 1H), 7.63 (d, J=1.3 Hz, 1H), 7.33 (dd, J=7.8, 1.1 Hz, 1H), 7.23-7.19 (m, 2H), 7.06 (d, J=7.4, 0.8 Hz, 1H), 6.71 (s, 1H), 6.15 (s, 1H), 5.93 (d, J=1.5 Hz, 2H), 5.14 (d, J=4.6 Hz, 2H), 4.81 (d, J=9.4 Hz, 1H), 4.69 (d, J=9.4 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ176.5, 155.4, 148.3, 141.7, 141.5, 141.3, 137.8, 131.5, 128.8, 127.9, 123.7, 123.3, 119.4, 115.1, 109.3, 108.7, 102.8, 101.4, 93.3, 79.7, 57.3, 37.9; MS (ES+) m/z 403.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=O.S(Cl)([Cl:15])=O>>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([Cl:15])=[O:12]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1ccc(Cl)cc1Br
Product: O=C(Cl)Cc1ccc(Cl)cc1Br
Yield: 88.2 %

Procedure:
28.3g (0.113 mol) of 2-bromo-p-chlorophenylacetic acid was mixed with 26.9g (0.226 mol) of thionylchloride and the mixture was refluxed for 2.5 hours. After the excess thionylchloride had been distilled off, the reaction mixture was distilled under reduced pressure to give 26.7g of 2-bromo-p-chlorophenylacetyl chloride as yellow-orange oil. (b.p. 148° - 152°C/15 mmHg)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][NH2:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH2:12]([N:20]=[C:21]=[S:22])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C=O.ClCCl>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][NH:11][C:21]([NH:20][CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[S:22])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: NCc1ccc2[nH]ccc2c1
Reactant: S=C=NCCc1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: S=C(NCCc1ccccc1)NCc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
(1H-indol-5-yl)methylamine (8.5 mg) prepared in Step 1 was dissolved in dimethylformamide (100 μl) and the solution was diluted with dichloromethane (1 ml). To the diluted solution was added phenethylisothiocyanate (40 μl) and the mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure and the obtained residue was chromatographed on a silica gel column eluting with ethyl acetate/hexane (2/3) to yield 1-(1H-indol-5-ylmethyl)-3-phenethylthiourea (15 mg, 83%).
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][NH:11][C:12](SC)=[C:13]([C:16]#[N:17])[C:14]#[N:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O.[NH2:21][NH2:22]>CO>[NH2:15][C:14]1[NH:22][N:21]=[C:12]([NH:11][CH2:10][CH2:9][NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[C:13]=1[C:16]#[N:17]
Reactant: NN
Reactant: CSC(NCCNC(=O)OC(C)(C)C)=C(C#N)C#N
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NCCNc1n[nH]c(N)c1C#N

Procedure:
A mixture of 80.81 g (286.4 mol) of 3-[2-(Boc-amino)-ethylamino]-2-cyano-3-methylmercapto-acrylonitrile, 14.9 ml (300.7 mmol) of hydrazine hydrate and 500 ml of methanol is heated under reflux for 4 hours and then concentrated by evaporation in vacuo at about 50° C., yielding 5-amino-3-[2-(Boc-amino)-ethylamino]-4-cyano-pyrazole; TLC-Rf=0.27 (methylene chloride/methanol [9:1]).
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]2)[O:3][CH2:2]1.Br[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=1.[Mg]>C1COCC1>[F:19][C:16]1[CH:17]=[C:18]([C:7]2([OH:10])[CH2:6][CH2:5][C:4]3([O:3][CH2:2][CH2:1][O:11]3)[CH2:9][CH2:8]2)[CH:13]=[CH:14][C:15]=1[F:20]
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Fc1ccc(Br)cc1F
Agent: [Mg]
Solvent: C1CCOC1
Product: OC1(c2ccc(F)c(F)c2)CCC2(CC1)OCCO2
Yield: 38 %

Procedure:
A solution of 1,4-cyclohexanedione monoethylene ketal (15.6 g, 100 mmole) in dry THF (250 ml) was reacted with a solution of the Grignard reagent prepared from 1-bromo-3,4-difluorobenzene (19 g, 100 mmole) and magnesium (2.4 g, 100 mmole) in dry THF at -60° C. as described in example 3 to give the product (38%, mp: 118-120° C.). Calc'd for C14H16F2O3 : C, 62.22%; H,5.97%. Found: C, 61.97%; H, 6.35%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][OH:17])[CH2:11][CH2:10]2)[CH:3]=1.N1C=CN=C1.[C:23]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])([CH3:25])[CH3:24].O>CN(C)C=O>[Si:27]([O:17][CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][N:9]([C:4]2[CH:3]=[C:2]([Cl:1])[N:7]=[C:6]([CH3:8])[N:5]=2)[CH2:10][CH2:11]1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1nc(Cl)cc(N2CCN(CCO)CC2)n1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(Cl)cc(N2CCN(CCO[Si](C)(C)C(C)(C)C)CC2)n1
Reaction time: 2 h
Yield: 98.3 %

Procedure:
To a solution of 2-(4-(6-chloro-2-methylpyrimidin-4-yl)piperazin-1-yl)ethanol obtained in Step A (1.00 g) and imidazole (0.636 g) in N,N-dimethylformamide (13 mL) was added tert-butyl(chloro)dimethylsilane (0.793 g) at room temperature, and the mixture was stirred for 2 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (1.42 g).
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1.[I-].C[N+]1C=CN([C:15](=[O:24])[N:16]([CH3:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)C=1.C(N(CC)CC)C>C(#N)C>[CH3:7][C:5]1[O:4][N:3]=[C:2]([O:1][C:15](=[O:24])[N:16]([CH3:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=1
Reactant: Cc1cc(O)no1
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(OC(=O)N(C)c2ccccc2)no1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.2 %

Procedure:
A mixture of 3-hydroxy-5-methylisoxazole (0.30 g, 3.00 mmol)), 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (1.03 g, 3.00 mmol) and triethylamine (0.42 ml, 3.00 mmol) in acetonitrile (15 ml) was stirred at room temperature for 18 hours. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (25:75)) yielding the title compound (0.67 g, 96% yield) as a colourless oil.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].C([Si](C)(C)[O:26][C@H:27]1[CH2:31][CH2:30][N:29](/[CH:32]=[CH:33]/[NH:34][C:35](=[NH:38])[CH:36]=[CH2:37])[CH2:28]1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10]([NH:38][C:35]3[CH:36]=[CH:37][C:32]([N:29]4[CH2:30][CH2:31][C@H:27]([OH:26])[CH2:28]4)=[CH:33][N:34]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: C=CC(=N)N/C=C/N1CC[C@H](O[Si](C)(C)C(C)(C)C)C1
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CC[C@H](O)C4)cn3)nc2n1C1CCCC1
Yield: 64.3 %

Procedure:
Following Buchwald Method B, 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (101 mg, 0.35 mmol) and N-{(E)-2-[(S)-3-(tert-butyl-dimethyl-silanyloxy)-pyrrolidin-1-yl]-vinyl}-acrylamidine (153 mg, 0.52 mmol), followed by deprotection with TBAF to give 7-cyclopentyl-2-[5-((S)-3-hydroxy-pyrrolidin-1-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (98 mg, 65%). MS (ESI) m/z 436.3 (M+H)+
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[CH:6][N:5]=2.[CH2:11]([O:15][C:16](=[O:19])[CH2:17]Cl)[CH2:12][CH2:13][CH3:14].C(OCC)(=O)C>C(=O)([O-])[O-].[K+].[K+]>[CH2:11]([O:15][C:16]([CH2:17][S:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[CH:6][N:5]=2)=[O:19])[CH2:12][CH2:13][CH3:14]
Reactant: CCCCOC(=O)CCl
Reactant: Sc1nc2cccnc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCCCOC(=O)CSc1nc2cccnc2s1
Temperature: 25 °C
Yield: 99 %

Procedure:
Twenty-four (24) g of 2-mercaptothiazolo[5,4-b]pyridine was dissolved in 300 ml of N,Ndimethylformamide, and 43.3 g of potassium carbonate and 23.65 g of chloroacetic acid n-butyl ester were added to the solution, followed by one-hour stirring at room temperature. Seven hundred (700) ml of ethyl acetate was added to the solution, which was then washed with water three times, dehydrated over magnesium sulfate, dried and distilled to remove the solvent to obtain the title compound (39.9 g, 99%).
Reaction SMILES: [C:1]([Cl:4])(=[O:3])[CH3:2].Cl.[NH2:6][CH2:7][C:8]([CH3:14])([CH3:13])[CH2:9][C:10](O)=[O:11]>C(O)C>[ClH:4].[CH2:1]([O:3][C:10](=[O:11])[CH2:9][C:8]([CH3:14])([CH3:13])[CH2:7][NH2:6])[CH3:2]
Reactant: CC(C)(CN)CC(=O)O
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CC(C)(C)CN
Temperature: 85 °C
Reaction time: 0.08 h
Yield: 94 %

Procedure:
Acetyl chloride (31 ml) was added dropwise over a time period of 5 minutes to ethanol (180 ml) while stirring and cooling in ice water bath. After additional 5 minutes, the obtained solution was added to a solution of 4-amino-3,3-dimethyl-butyric acid hydrochloride (30.07 grams, 180 mmol) in ethanol (20 ml). The mixture was refluxed at 85° C. for 16 hours, and the solvent was removed under reduced pressure to give to 4-amino-3,3-dimethyl-butyric acid ethyl ester hydrochloride (33.11 grams, 94% yield) as oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:25]#[N:26])[N:8]=[C:9]2[NH:12][C@H:13]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]2)=[CH:4][CH:3]=1.[NH2:27][NH2:28].O>CO>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:25]([NH:27][NH2:28])=[NH:26])[N:8]=[C:9]2[NH:12][C@H:13]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:14]2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(C#N)cc3ccc(Cl)cc23)C1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(C(=N)NN)cc3ccc(Cl)cc23)C1

Procedure:
To a mixture of (S)-tert-butyl 3-((7-chloro-3-cyanoisoquinolin-1-yl)amino)pyrrolidine-1-carboxylate (660 mg, 1.77 mmol) in MeOH (5 mL) was added NH2NH2—H2O (5 mL) and the resulting mixture was heated to reflux for 2 hours. The solvent was subsequently removed to give the title compound as a yellow solid, which was used without further purification (710 mg). ESI-MS m/z [M+H]+ 405.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH:25]2OCCCO2)=[CH:18][CH:17]=1.[O:31]1[CH2:35][C:34](=[O:36])[NH:33][C:32]1=[O:37].N1CCCCC1>C(O)(=O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][CH2:24][CH:25]=[C:35]2[O:31][C:32](=[O:37])[NH:33][C:34]2=[O:36])=[CH:20][CH:21]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCCC2OCCCO2)cc1
Reactant: O=C1COC(=O)N1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCCC=C2OC(=O)NC2=O)cc1
Yield: 25.9 %

Procedure:
A mixture of 2-[3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propyl]-1,3-dioxane (2.0 g), 2,4-oxazolidinedione (0.99 g), piperidine (0.21 g) and acetic acid (50 ml) was heated for 24 hours under reflux. The reaction mixture was concentrated under reduced pressure, to which was added ethyl acetate. The ethyl acetate layer was washed with an aqueous solution of sodium hydrogencarbonate, 2N HCl and water, successively, which was then dried (MgSO4), followed by concentration. The concentrate was purified by means of a silica gel column chromatography. From the fractions eluted with chloroform--ethyl acetate (5:1), 5-[4-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]butylidene]-2,4-oxazolidinedione (0.55 g, 26%) was obtained. Recrystallization from ethyl ether - methanol gave colorless needles, m.p.152°-153° C.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH3:12][N+:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[S:15][C:14]=1SC.C([NH:26][NH2:27])=O>O>[CH3:12][N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[S:15][C:14]1=[N:26][NH2:27]
Reactant: CSc1sc2ccccc2[n+]1C
Reactant: NNC=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: O
Product: Cn1c(=NN)sc2ccccc21

Procedure:
Into a flask equipped with a reflux condenser and magnetic stirrer is charged 50 ml water. Then 28.1 g (0.076 moles) 3-methyl-2-methylthiobenzothiazolium p-toluene sulfonate is dissolved with slight heating. A solution of 9.1 g (0.15 moles) formylhydrazine in 25 ml of water then is added and the mixture is heated at reflux for 15 minutes. The cooled suspension is made acidic until a clear solution results, then made basic. The product precipitates and is filtered, giving 9.1 g (66%), m.p. 134° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[CH3:14])([CH3:4])([CH3:3])[CH3:2].[C:22]([O:26][C:27]([N:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=[C:30]1[CH2:38]Cl)=[O:28])([CH3:25])([CH3:24])[CH3:23].CCN(C(C)C)C(C)C>CC#N>[C:22]([O:26][C:27]([N:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=[C:30]1[CH2:38][N:12]([CH2:11][CH2:10][CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:21])[CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[CH3:14])=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)n1c(CCl)nc2ccccc21
Reactant: CC(NCCCCNC(=O)OC(C)(C)C)c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(c1ccccn1)N(CCCCNC(=O)OC(C)(C)C)Cc1nc2ccccc2n1C(=O)OC(C)(C)C

Procedure:
Using General Procedure A, [4-(1-pyridin-2-ylethylamino)-butyl]-carbamic acid tert-butyl ester, N-(t-butoxycarbonyl)-2-chloromethylbenzimidazole, and KI in anhydrous CH3CN were reacted with DIPEA to obtain 2-{[(4-tert-butoxycarbonylaminobutyl)-(1-pyridin-2-ylethyl)-amino]-methyl}benzimidazole-1-carboxylic acid tert-butyl ester. Conversion to the HBr salt gave COMPOUND 219 as a white solid. 1H NMR (D2O) δ 1.55 (br, 4H), 1.63 (d, 3H, 6.9 Hz), 2.62 (m, 1H), 2.80 (m, 1H), 2.88 (br, 2H), 4.43 (d, 2H, J=2.4 Hz), 4.58 (m, 1H), 7.60 (m, 2H), 7.78 (m, 2H), 7.97 (t, 1H, J=6.6 Hz), 8.12 (d, 1H, J=8.1 Hz), 8.56 (t, 1H, J=8.0 Hz), 8.77 (d, 1H, J=5.7 Hz). 13C NMR (D2O) δ 13.17, 24.44, 24.97, 39.57, 47.46, 52.31, 59.31, 114.26 (2C), 126.57, 126.74, 126.92 (2C), 130.92 (2C), 141.83, 148.12, 152.04, 156.52. ES-MS m/z 324 (M+H). Anal. Calcd. for C19H25N5.3.1HBr.1.8H2O.0.2C4H10O: C, 38.26; H, 5.47; N, 11.27; Br, 39.85. Found: C, 38.22; H, 5.13; N, 11.16; Br, 40.00.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH:14]=2)O1.C([O-])([O-])=O.[K+].[K+].Br[C:30]1[CH:35]=[C:34]([N+:36]([O-:38])=[O:37])[CH:33]=[CH:32][C:31]=1[O:39][CH3:40].O>CN(C=O)C>[CH3:40][O:39][C:31]1[CH:32]=[CH:33][C:34]([N+:36]([O-:38])=[O:37])=[CH:35][C:30]=1[C:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:13][CH:14]=1
Reactant: COc1ccc([N+](=O)[O-])cc1Br
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc([N+](=O)[O-])cc1C1=CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Yield: 45.2 %

Procedure:
To a 250-mL RB-flask containing tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate (3.09 g, 10.0 mmol), K2CO3 (4.14 g, 30.0 mmol) and PdCl2dppf (419 mg) was added a solution of 2-bromo-4-nitroanisole (2.30 g, 10 mmol) in DMF (10.0 mL) at room temperature under argon. The mixture was heated to 80° C. under argon overnight. After cooled to room temperature, water (500 mL) was added to the mixture. The aqueous layer was extracted with EtOAc (2×200 mL) and the combined organic extracts were dried over K2CO3, filtered and concentrated in vacuo. The crude material was purified on flash chromatography (20% EtOAc/hexane) to give tert-butyl 4-(2-methoxy-5-nitrophenyl)-3,6-dihydro-1(2H)-pyridinecarboxylate (1.51 g, 46%): ESMS m/e: 334.9 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].I[C:16]1[C:20]([CH3:21])=[CH:19][NH:18][N:17]=1>>[CH3:8][C:7]1[O:6][N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[C:1]#[C:2][C:16]1[C:20]([CH3:21])=[CH:19][NH:18][N:17]=1
Reactant: C#Cc1c(-c2ccccc2)noc1C
Reactant: Cc1c[nH]nc1I
Product: Cc1c[nH]nc1C#Cc1c(-c2ccccc2)noc1C
Yield: 53 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (73 mg, 0.40 mmol) was converted [using 3-iodo-4-methyl-1H-pyrazole (prepared according to Liebigs Ann. Chem. 595, 200, 1955) instead of 2-chloro-4-iodopyridine] to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 56 mg, 53%) which was obtained as a light brown solid. MS: m/e=264.2 [M+H]+.
Reaction SMILES: Cl.[I:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH:13]3[CH2:15][CH:10]2[CH2:11][NH:12]3)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:23](OC(=O)C)(=[O:25])[CH3:24]>ClCCl>[C:23]([N:12]1[CH2:11][CH:10]2[CH2:15][CH:13]1[CH2:14][N:9]2[C:6]1[CH:5]=[CH:4][C:3]([I:2])=[CH:8][CH:7]=1)(=[O:25])[CH3:24]
Reactant: Ic1ccc(N2CC3CC2CN3)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CC2CC1CN2c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
5-(4-Iodophenyl)-2,5-diazabicyclo[2.2.1]heptane hydrochloride (269 mg, 0.80 mmol) was suspended in dichloromethane (0.3 ml), and triethylamine (0.2 ml) and acetic anhydride (0.09 ml, 0.96 mmol) were added. After stirring at room temperature for 1 hr, dichloromethane was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 2-acetyl-5-(4-iodophenyl)-2,5-diazabicyclo[2.2.1]heptane (255 mg, yield 93%).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([CH2:10]O)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.O=S(Cl)[Cl:16].O>C1COCC1.[Cl-].[Cl-].[Zn+2]>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH2:10][Cl:16])[C:3]=1[O:12][CH3:13]
Reactant: O=S(Cl)Cl
Reactant: COc1cc(Br)c(OC)c(CO)c1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(Br)c(OC)c(CCl)c1
Reaction time: 1 h
Yield: 69 %

Procedure:
To a solution of 52 (7.5 g, 30 mmol) and ZnCl2 (1 g) in THF (100 ml) was added SOCl2 (5.31 g, 45 mmol) dropwise. After 1 hr at rt, the reaction was poured into water and extracted with ether. The ether was dried, concentrated and the product was purified by column chromatography on silica gel (10% EtOAc/hex) to give 53 as an oil (5.5 g, 75%): 1H NMR(DMSO-d6) δ 7.21 (d, 1 H, J=3.0 Hz), 7.08 (d, 1 H, J=3.0 Hz), 4.73 (s, 2 H), 3.78 (s, 3 H), 3.75 (s, 3 H)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]2[C:3]=1[C:4](=O)[C:5](=O)[NH:6]2.[NH2:14][N:15]1[C:19]([NH2:20])=[N:18][N:17]=[C:16]1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1>C(O)C(F)(F)F.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]2[C:3]=1[C:4]1[C:5]([NH:6]2)=[N:20][C:19]2=[N:18][N:17]=[C:16]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[N:15]2[N:14]=1
Reactant: Nc1nnc(Cc2ccc(O)cc2)n1N
Reactant: O=C1Nc2c(Cl)ccc(Cl)c2C1=O
Solvent: OCC(F)(F)F
Solvent: O
Product: Oc1ccc(Cc2nnc3nc4[nH]c5c(Cl)ccc(Cl)c5c4nn23)cc1
Temperature: 125 °C
Reaction time: 16 h

Procedure:
In a pressure tube, 0.60 mmol of 4,7-dichloro-1H-indole-2,3-dione (130 mg) and 0.65 mmol of 4-(4,5-diamino-4H-[1,2,4]triazol-3-ylmethyl)-phenol (133.5 mg) in a mixture of trifluoroethanol (8 mL) and water (4 mL) was stirred at 125° C. overnight (16 hr). The mixture was cooled to room temperature, allowed to crystallize for 2 hours. The precipitated product was collected by filtration, washed with MeOH+water 1:1, then with chilled MeOH. Dried on high vacuum.