Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([C:19]([NH:21][CH:22]([C:30]([OH:32])=[O:31])[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:20])=[CH:16][CH:17]=2)[C:12]([NH:33][C:34]([NH2:36])=[NH:35])=[N:11][CH:10]=1.Cl.NC(N)=N.[C:42](OC(=O)C(CC1C=CC=CC=1)NC(C1C=C2C(C(Cl)=CN=C2Cl)=CC=1)=O)([CH3:45])([CH3:44])[CH3:43].O>CS(C)=O>[C:42]([O:31][C:30](=[O:32])[CH:22]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH:21][C:19]([C:15]1[CH:14]=[C:13]2[C:18]([C:9]([Cl:8])=[CH:10][N:11]=[C:12]2[NH:33][C:34]([NH2:36])=[NH:35])=[CH:17][CH:16]=1)=[O:20])([CH3:45])([CH3:44])[CH3:43]
Reactant: N=C(N)Nc1ncc(Cl)c2ccc(C(=O)NC(Cc3ccccc3)C(=O)O)cc12
Reactant: CC(C)(C)OC(=O)C(Cc1ccccc1)NC(=O)c1ccc2c(Cl)cnc(Cl)c2c1
Agent: Cl
Agent: N=C(N)N
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)C(Cc1ccccc1)NC(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 46.8 %

Procedure:
N-[(4-Chloro-1-guanidino-7-isoquinolinyl)carbonyl]-DL-phenylalanine trifluoroacetate ##STR68## NaH (78 mg, 60% dispersion in mineral oil, 1.95 mmol) was added to a solution of guanidine hydrochloride (188 mg, 1.97 mmol) in DMSO (6 mL) at 50° C. and the solution was stirred for 15 min. N-[(1,4-Dichloro-7-isoquinolinyl)carbonyl]-DL-phenylalanine t-butyl ester (350 mg, 0.79 mmol) was added and the mixture heated at 80° C. overnight. The cooled mixture was poured into water (50 mL) and extracted with EtOAc (2×25 mL). The combined organics were washed with brine, dried (Na2SO4) and evaporated in vacuo. The residue was crystallised with CH2Cl2 -i-Pr2O to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)carbonyl]-DL-phenylalanine t-butyl ester (172 mg, 0.37 mmol) as a cream coloured solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][CH2:20][N:21]3[S:24]([C:27]3[CH:32]=[C:31]([Cl:33])[CH:30]=[C:29]([Cl:34])[CH:28]=3)(=[O:26])=[O:25])=[CH:16][CH:15]=2)=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:36]1C=C(S(Cl)(=O)=O)C=C(Cl)C=1>>[CH3:36][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([NH:11][C:12]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][CH2:20][N:21]3[S:24]([C:27]3[CH:32]=[C:31]([Cl:33])[CH:30]=[C:29]([Cl:34])[CH:28]=3)(=[O:26])=[O:25])=[CH:16][CH:15]=2)=[O:13])=[CH:10][C:2]=1[Cl:1]
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Reactant: O=C(Nc1ccc(C(=O)O)c(Cl)c1)c1ccc2c(c1)N(S(=O)(=O)c1cc(Cl)cc(Cl)c1)CCC2
Product: COC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(Cl)cc(Cl)c2)CCC3)cc1Cl

Procedure:
2-Chloro-4-{[1-(3,5-dichloro-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-benzoic acid, m/z (ES+): 539.17 (M+H+.), was prepared in analogy to example 40, steps 1 to 5. Step 4 was performed using 3,5-dichloro-benzenesulfonyl chloride, yielding 2-chloro-4-{[1-(3,5-dichloro-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-benzoic acid methyl ester, which was hydrolyzed in step 5.
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH:23]2[CH2:25][CH2:24]2)[C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)#[N:2].[OH:26][NH:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)=N>>[CH:23]1([N:9]([CH:6]2[CH2:5][CH2:4][N:3]([C:1]3[O:26][N:27]=[C:28]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)[N:2]=3)[CH2:8][CH2:7]2)[C:10](=[O:22])[C:11]2[CH:12]=[CH:13][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:15][CH:16]=2)[CH2:25][CH2:24]1
Reactant: N=C(NO)c1ccccn1
Reactant: N#CN1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2nc(-c3ccccn3)no2)CC1

Procedure:
The title compound is prepared from N-(1-cyano-piperidin-4-yl)-N-cyclopropyl-4-oxazol-5-yl-benzamide and N-hydroxy-pyridine-2-carboxamidine following a procedure analogous to that described in Example 1. LC (method 6): tR=1.60 min; Mass spectrum (ESI+): m/z=457 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:49]=[CH:48][C:11]([CH2:12][C:13]3[N:14]([C:26]4[CH:27]=[C:28]([N:32]5[S:36](=[O:38])(=[O:37])[N:35]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:34](=[O:47])[CH2:33]5)[CH:29]=[CH:30][CH:31]=4)[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=4[Cl:25])[N:17]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.NC(N)=[S:52]>C(O)C.O.CCOC(C)=O>[Cl:25][C:19]1[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=1[C:16]1[N:17]=[C:13]([CH2:12][C:11]2[CH:48]=[CH:49][C:8]([C:5]3[N:6]=[N:7][C:2]([SH:52])=[CH:3][CH:4]=3)=[CH:9][CH:10]=2)[N:14]([C:26]2[CH:27]=[C:28]([N:32]3[S:36](=[O:38])(=[O:37])[N:35]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:34](=[O:47])[CH2:33]3)[CH:29]=[CH:30][CH:31]=2)[CH:15]=1
Reactant: NC(N)=S
Reactant: C[Si](C)(C)CCOCN1C(=O)CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(Cl)nn4)cc3)c2)S1(=O)=O
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: C[Si](C)(C)CCOCN1C(=O)CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(S)nn4)cc3)c2)S1(=O)=O

Procedure:
5-{3-[2-[4-(6-Chloro-pyridazin-3-yl)-benzyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one (76 mg, 0.1 mmol) was dissolved in 1 mL dry ethanol. Thiourea (76 mg, 1 mmol) was added and the mixture was refluxed under nitrogen over night. At completion, the reaction mixture was then diluted with water/EtOAc. The combined organic layer washed with water, and brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give 5-(3-{4-(2,4-dichloro-phenyl)-2-[4-(6-mercapto-pyridazin-3-yl)-benzyl]-imidazol-1-yl}-phenyl)-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one, which was then treated as described in general procedure K using 1-bromo-2-cyclohexylethane (79 μL, 0.5 mmol) to give 5-{3-[2-{4-[6-(2-cyclohexyl-ethylsulfanyl)-pyridazin-3-yl]-benzyl}-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]([C:14]2[N:18]=[CH:17][NH:16][N:15]=2)=[CH:10][NH:11][CH:12]=O)[CH:6]=[CH:7][CH:8]=1>CO>[F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[C:14]3[N:15]([N:16]=[CH:17][N:18]=3)[CH:12]=[N:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=CNC=C(c1cccc(C(F)(F)F)c1)c1nc[nH]n1
Solvent: CO
Product: FC(F)(F)c1cccc(-c2cncn3ncnc23)c1

Procedure:
The amide from the preceeding example, N-[2-(3-trifluoromethyl-phenyl)-2-(1,2,4-triazol-3-yl)ethenyl]formamide, is dissolved in methanol and the mixture is heated to the reflux temperature for about 60 hours. The solvent is evaporated and the residue is crystallized with the aid of petroleum ether and collected; the product is thereby obtained and is identical with that obtained in Example 16.
Reaction SMILES: I.CS[C:4]1[NH:8][C@@H:7]2[CH2:9][CH2:10][CH2:11][CH2:12][C@H:6]2[N:5]=1.C1(C(C2C=CC=CC=2)CN)C=CC=CC=1.[ClH:28].CC(=O)CC>CO>[ClH:28].[NH:8]1[C@@H:7]2[CH2:9][CH2:10][CH2:11][CH2:12][C@H:6]2[N:5]=[CH:4]1
Reactant: CSC1=N[C@@H]2CCCC[C@H]2N1
Agent: Cl
Agent: I
Agent: NCC(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: CCC(C)=O
Product: C1=N[C@@H]2CCCC[C@H]2N1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
A flask containing 2-methylthio-trans-3a,4,5,6,7,7a-hexahydro-1H-benzimidazole hydroiodide (4.39 g, 1.47×10-2 mole) and 2,2-diphenylethylamine (2.90 g, 1.47×10-2 mole) was immersed in an oil bath which had been preheated to ca. 155° C. The reaction was stirred at between 155°-165° C. for 40 minutes. The resulting yellow glass was dissolved in methanol. The methanol was evaporated at reduced pressure and isopropanol was added periodically during the course of the evaporation. When the solution had been concentrated to ca. 20 ml, it was set aside to cool. After 4 days the solution had deposited a solid which was collected by filtration. This guanidine hydroiodide was dissolved in a two phase mixture of 5 molar aqueous NaOH (100 ml) and CH2Cl2 (100 ml). After stirring overnight the CH2Cl2 layer was separated. The aqueous alkaline layer was extracted with CH2Cl2 (2×). The CH2Cl2 layers were combined, washed with H2O (2×), washed with saturated aqueous NaCl, and dried over anhydrous Na2SO4. The drying agent was removed by filtration and the filtrate was evaporated at reduced pressure leaving a colorless foam which was dissolved in methanol (50 ml). The solution was cooled to 0° C. before being treated with a methanolic solution of HCl. The methanol was evaporated at reduced pressure leaving a foam. The foam was dissolved in methanol (10-15 ml) and 2-butanone was added. The solution was then concentrated on the steam bath. When the temperature of the solution reached ca. 75° C. a solid began to precipitate and the evaporation was stopped. After standing 2 hours the precipitate was collected by filtration affording a solid. This material was recrystallized from methanol/2-butanone affording 2-2,2-diphenylethylamino)-trans-3a,4,5,6,7,7a-hexahydro-1H-benzimidazole hydrochloride as a colorless solid: 3.86 g (74%), m.p. 216°-218° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[N:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])SC)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl.[CH3:37][O:38][NH2:39]>C(#N)C.[N+]([O-])([O-])=O.[Ag+]>[C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH:39][O:38][CH3:37])=[N:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CSC(=NC(=O)OC(C)(C)C)Nc1ccc(CCNC(=O)OC(C)(C)C)cc1
Reactant: CON
Agent: [Ag+]
Agent: Cl
Agent: O=[N+]([O-])[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CONC(=NC(=O)OC(C)(C)C)Nc1ccc(CCNC(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 39.6 %

Procedure:
To a mixture of the compound (190 mg) obtained in Example 289, triethylamine (0.14 ml), O-methylhydroxylamine hydrochloride (84 mg) and acetonitrile (5 ml), a solution of silver nitrate (90 mg) in acetonitrile (2 ml) was added and stirred at 0° C. for 15 min. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, chloroform:ethyl acetate=3:1) to give the 75 mg of titled compound (yield, 38%).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.C[O:14][C:15](=[O:36])[C@H:16]([CH2:25][CH2:26][CH2:27][N:28]=CC1C=CC=CC=1)[N:17]=CC1C=CC=CC=1.Cl[CH:38]([F:40])[F:39].Cl>CCCCCC.O1CCCC1>[F:39][CH:38]([F:40])[C:16]([NH2:17])([CH2:25][CH2:26][CH2:27][NH2:28])[C:15]([OH:14])=[O:36]
Reactant: COC(=O)[C@H](CCCN=Cc1ccccc1)N=Cc1ccccc1
Reactant: FC(F)Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: NCCCC(N)(C(=O)O)C(F)F
Temperature: 40 °C

Procedure:
Under nitrogen, a solution (500 ml) of 2 M butyllithium in hexane is added to a stirred solution of diisopropylamine (143.1 ml) in tetrahydrofuran (1.5 l) at -78° C. after which dibenzylidene ornithine methyl ester (261 g, 0.81 mole) in tetrahydrofuran (1.5 l) is added. Upon completion of the addition, the reaction temperature is raised to 40° C. and maintained between 40° and 50° C. for 3 hours during which time chlorodifluoromethane gas is bubbled through the mixture with stirring. The reaction mixture is then treated with a saturated solution of sodium chloride. The organic material is extracted with ether, and the ether extract washed several times with sodium chloride solution, dried over magnesium sulfate and evaporated to give a viscous oil. The oil is stirred with 1 N HCl (1.5 l) for 3 hours, the mixture extracted several times with chloroform and the aqueous solution evaporated to dryness. The oily residue is refluxed with 12 N hydrochloric acid (1.5 l) for 16 hours, the cooled solution clarified by chloroform extraction before concentration, decolorization (charcoal), and further concentration to about 750 ml. The pH of the solution is adjusted to 3.5 by the addition of triethylamine, the solution treated again with charcoal before concentration to about 500 ml and dilution with acetone (7-8 l). The precipitated product is filtered off and washed with ethanol. The crude product is recrystallized by dissolving in hot water (about 150 ml) and treatment of the solution with hot ethanol (450 ml). On cooling crystals of 2-difluoromethyl-2,5-diaminopentanoic acid as the hydrochloride monohydrate separate (71 g): m.p. 183° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:23])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[O:19][CH:20]=[CH:21][CH:22]=3)[S:17][C:10]=12.[C:24]1([CH2:30][C:31]([N:33]=[C:34]=[S:35])=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[F:1][C:2]1[CH:3]=[C:4]([NH:23][C:34]([NH:33][C:31](=[O:32])[CH2:30][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[S:35])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[O:19][CH:20]=[CH:21][CH:22]=3)[S:17][C:10]=12
Reactant: Nc1ccc(Oc2ccnc3cc(-c4ccco4)sc23)c(F)c1
Reactant: O=C(Cc1ccccc1)N=C=S
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3cc(-c4ccco4)sc23)c(F)c1

Procedure:
Prepared from 3-fluoro-4-(2-(furan-2-yl)thieno[3,2-b]pyridin-7-yloxy)benzenamine (100 mg, 0.306 mmol) obtained in Step A and 2-phenylethanoyl isothiocyanate (109 mg, 0.613 mmol; prepared according to the procedure described by J. Org. Chem. 1964, 29, 1115-1119) using the procedure described for Example 96, Step D. Collected the product (6 mg, 4%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 12.6 (s, 1H), 8.53 (s, 1H), 8.39 (d, J=6.6 Hz, 1H), 8.07 (d, J=13.2 Hz, 1H), 7.90 (s, 1H), 7.61 (d, J=6.2 Hz, 1H), 7.44 (m, 7H), 7.04 (s, 1H), 6.73 (d, J=6.2 Hz, 1H), 6.62 (s, 1H), 3.78 (s, 2H). LRMS (APCI+) m/e 504 (M+1) detected.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:12]=[C:13]2[O:19][C:18]([N:20]3[CH:26]4[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]4)[CH2:22][CH2:21]3)=[N:17][C:14]2=[N:15][CH:16]=1>>[C:1]1([C:11]2[CH:12]=[C:13]3[O:19][C:18]([N:20]4[CH:26]5[CH2:25][CH2:24][N:23]([CH2:28][CH2:27]5)[CH2:22][CH2:21]4)=[N:17][C:14]3=[N:15][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1cnc2nc(N3CCN4CCC3CC4)oc2c1
Product: c1ccc(-c2cnc3nc(N4CCN5CCC4CC5)oc3c2)cc1
Yield: 27 %

Procedure:
The title compound was prepared according to the procedure detailed in Example 44 using phenyl boronic acid and 4-(6-bromo-oxazolo[4,5-b]pyridin-2-yl)-1,4-diaza-bicyclo[3.2.2]nonane (prepared in Example 47) in 27% yield: 1H NMR (CDCl3, 400 MHz) δ 8.48 (d, 1H, J=2.1 Hz), 7.62 (d, 1H, J=2.1 Hz), 7.57-7.55 (m, 2H), 7.47-7.43 (m, 2H), 7.40-7.34 (m, 1H), 4.62 (br s, 1H), 4.00 (t, 2H, J=5.8 Hz), 3.20-3.15 (m, 4H), 3.08-3.01 (m, 2H), 2.19-2.08 (m, 2H), 1.90-1.81 (m, 2H); MS (Cl) m/z 321.2 (M+1).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:28])[CH2:6][C:7]1[N:8]=[C:9]([C:13]2[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:16]([OH:23])=[C:15]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:14]=2)[O:10][C:11]=1[CH3:12].CO.Cl>O.C1COCC1>[C:19]([C:17]1[CH:18]=[C:13]([C:9]2[O:10][C:11]([CH3:12])=[C:7]([CH2:6][C:5]([OH:28])=[O:4])[N:8]=2)[CH:14]=[C:15]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:16]=1[OH:23])([CH3:20])([CH3:21])[CH3:22]
Reactant: COC(=O)Cc1nc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)oc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1oc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)nc1CC(=O)O
Reaction time: 1 h
Yield: 86.6 %

Procedure:
Sodium hydroxide (2N, 5.0 mL, 10.0 mmol) was added to a solution of [2-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyloxazol-4-yl]-acetic acid methyl ester (1.5 g, 4.18 mmol), MeOH (15 mL), and THF (15 mL). After stirring for 1 hour, the mixture was poured into water, acidified with HCl(2N) and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and crystallization from acetone/ethyl ether/hexane gave a white solid (1.25 g, 87% yield), m.p. 205°-206° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[C@@H:4]1[CH2:8][C@H:7]([OH:9])[CH2:6][NH:5]1.C(N(CC)CC)C.[C:18]([C:20]1[CH:21]=[C:22]([S:26](Cl)(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1)#[N:19]>C(Cl)Cl>[C:18]([C:20]1[CH:21]=[C:22]([S:26]([N:5]2[CH2:6][C@@H:7]([OH:9])[CH2:8][C@H:4]2[C:3]([O:2][CH3:1])=[O:10])(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1)#[N:19]
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](O)CN1S(=O)(=O)c1cccc(C#N)c1
Reaction time: 1 h

Procedure:
To a solution of cis-4-hydroxy-L-proline methyl ester (10.0 g, 68.8 mmol), triethylamine (13.9 g, 138 mmol), and CH2Cl2 (200 mL) was added 3-cyanobenzene-1-sulfonyl chloride (13.9 g, 68.8 mmol). After 1 h, the reaction was partitioned between saturated aqueous NaHCO3 (75 mL) and CH2Cl2 (100 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (3×75 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated. The residue was purified on silica gel (1:99→30:70 ethyl acetate-hexanes) to afford the title compound as a colorless crystalline solid: 1H NMR (500 MHz, CDCl3) δ 8.19-8.18 (m, 1H), 8.13-8.11 (m, 1H), 7.89-7.85 (m, 1H), 7.69-7.65 (t, 1H), 4.52-4.50 (m, 1H), 4.44-4.43 (m, 1H), 3.67 (s, 3H), 3.52 (dd, 1H), 3.47-3.41 (m, 1H), 3.1 (d, 1H), 2.33-2.27 (m, 1H), 2.20-2.17 (m, 1H); LRMS (ESI) m/z 311 (311 calcd for C13H14N2O5S, M+H).
Reaction SMILES: FC(F)(F)C(O)=O.C[N:9]([CH:11]=[C:12]([N:18]1[CH:22]=[C:21]([C:23]#[N:24])[N:20]=[CH:19]1)[C:13]([O:15]CC)=O)C.[NH:25]([C:27]1[N:32]=[CH:31][N:30]=[C:29]([N:33]2[CH2:36][CH:35]([OH:37])[CH2:34]2)[CH:28]=1)N>C(OCC)(=O)C>[OH:37][CH:35]1[CH2:36][N:33]([C:29]2[N:30]=[CH:31][N:32]=[C:27]([N:25]3[C:13](=[O:15])[C:12]([N:18]4[CH:22]=[C:21]([C:23]#[N:24])[N:20]=[CH:19]4)=[CH:11][NH:9]3)[CH:28]=2)[CH2:34]1
Reactant: CCOC(=O)C(=CN(C)C)n1cnc(C#N)c1
Reactant: NNc1cc(N2CC(O)C2)ncn1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cn(-c2c[nH]n(-c3cc(N4CC(O)C4)ncn3)c2=O)cn1
Temperature: 100 °C
Reaction time: 10 h

Procedure:
46 μl (68 mg, 0.6 mmol) of trifluoroacetic acid are added to a mixture of 700 mg (3.0 mmol) of the compound from Example 6A and 541 mg (3.0 mmol) of the compound from Example 10A in 10 ml of ethyl acetate, and the mixture is stirred at 100° C. for 10 h. The reaction mixture is concentrated under reduced pressure and taken up in 5 ml of ethanol, and the precipitate is filtered off. The solid is suspended in 10 ml of water, and 1 N aqueous sodium hydroxide solution (pH=9) is added until the solid is dissolved. The pH is then adjusted to 7 using 1 N hydrochloric acid, the mixture is concentrated to a volume of about 5 ml and the precipitate formed is filtered off. The residue is washed with water and diisopropyl ether and chromatographed by preparative HPLC (Method 8). The solid is then suspended in 10 ml of water, and 1 N aqueous sodium hydroxide solution (pH=9) is added until the solid is dissolved. The pH is then adjusted to 7 using 1 N hydrochloric acid, the mixture is concentrated to a volume of about 2.5 ml and the precipitate formed is filtered off. The filtrate is concentrated to about 2 ml and filtered again. Both residues are combined, washed with water and ethyl acetate and dried under reduced pressure. Yield: 78 mg (8% of theory)
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[OH2:13].CN([CH:17]=[O:18])C>>[O:18]1[C:17]2[CH:4]=[CH:3][CH:7]=[CH:8][C:9]=2[O:13][CH2:1][C@@H:2]1[CH2:10][N:5]1[C:1](=[O:11])[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]1=[O:6]
Reactant: O
Reactant: CN(C)C=O
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Product: O=C1c2ccccc2C(=O)N1C[C@H]1COc2ccccc2O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The white solid was combined with potassium phthalimide (14.4 g, 78 mmol) in DMF (250 mL) and heated to reflux for 1 h, cooled to room temperature and poured into vigorously stirring water (1.5 L) and stirred 30 min. White solid was filtered and the solid was washed several times with water, 2% NaOH, and water again and let air dry to yield a (2S)-2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethyl)-isoindole-1,3-dione as white powdery solid.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[C:4](F)[CH:3]=1.C(N(C(C)C)CC)(C)C.[NH2:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1>CN(C)C=O>[F:8][C:7]1[C:2]([Br:1])=[CH:3][C:4]([NH:22][CH:23]2[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH2:28]2)=[C:5]([N+:9]([O-:11])=[O:10])[CH:6]=1
Reactant: O=[N+]([O-])c1cc(F)c(Br)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(Br)c(F)cc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Bromo-2,5-difluoronitrobenzene (0.60 g, 2.5 mmole) was dissolved in dry dimethylformamide (10 ml) and diisopropylethylamine (0.39 g, 3.0 mmole), and 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate (0.53 g, 2.6 mmole) were added at room temperature and subsequently stirred for 1 hour. The mixture was then stirred at 80° C. for 2.5 h, then cooled to room temperature. The mixture was concentrated to dryness under vacuum and the residue partitioned between ethyl acetate and dilute aqueous potassium carbonate solution. The organic layer was dried over MgSO4, filtered and evaporated, and the residue was purified by silica gel chromatography eluting with 10 to 50% diethyl ether in 40-60 pet ether to afford the title compound as an orange/red solid, 0.91 g, 87%. LC/MS—97% m/e-416/418 (M−H).
Reaction SMILES: C(OC(=O)[NH:6][C:7]1([C:10]2[CH:15]=[N:14][CH:13]=[CH:12][N:11]=2)[CH2:9][CH2:8]1)C=C.N1CCOCC1>C1COCC1.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>[N:11]1[CH:12]=[CH:13][N:14]=[CH:15][C:10]=1[C:7]1([NH2:6])[CH2:9][CH2:8]1
Reactant: C=CCOC(=O)NC1(c2cnccn2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: NC1(c2cnccn2)CC1
Temperature: 50 °C
Reaction time: 3 h
Yield: 14.3 %

Procedure:
To a solution of (1-Pyrazin-2-yl-cyclopropyl)-carbamic acid allyl ester (67 mg, 0.31 mmol) and morpholine (0.31 mL, 3.1 mmol) in THF (3 mL) was added Pd(PPh3)4 (27 mg, 0.02 mmol) and the yellow mixture was stirred at 50° C. for 3 h. The solvent was removed under a stream of N2 and the residue was purified by flash chromatography (silica, 4→7% MeOH/CH2Cl2) to give 6 mg of the title compound as an orange oil, m/z 136.04 [M+1]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6](Cl)(=[O:8])=[O:7].[NH2:10][C:11]1[CH:12]=[C:13]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15]>N1C=CC=CC=1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:10][C:11]1[CH:12]=[C:13]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15])(=[O:8])=[O:7]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NS(=O)(=O)c1cccs1
Yield: 89 %

Procedure:
Prepared according to the procedure described for Example 121 using 2-thiophenesulfonyl chloride (1.82 g, 10 mmol), 3-amino-4-methoxy-N-phenyl-benzamide (2.43 g, 10 mmol), and pyridine (25 mL) to afford the product (3.457 g); m.p. 180-183° C. after trituration in hexanes/ethyl acetate (1:1).