Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([CH2:7][O:8][CH3:9])[CH:6]=1.C([Mg]Cl)(C)C.[F:15][C:16]1([F:23])[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1.[Cl-].[NH4+]>C1COCC1>[F:15][C:16]1([F:23])[CH2:21][CH2:20][C:19]([C:2]2[CH:3]=[N:4][N:5]([CH2:7][O:8][CH3:9])[CH:6]=2)([OH:22])[CH2:18][CH2:17]1
Reactant: O=C1CCC(F)(F)CC1
Reactant: COCn1cc(I)cn1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCn1cc(C2(O)CCC(F)(F)CC2)cn1
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
To a solution of 4-iodo-1-(methoxymethyl)-1H-pyrazole (Organic Letters, 2007, 9, 4947-4950; 1.40 g, 5.88 mmol) in THF (15 mL), isopropyl magnesium chloride (2.0 M solution in THF; 3.8 mL, 7.64 mmol) was added with cooling on ice. The reaction solution was stirred for 30 minutes with cooling on ice. Then, 4,4-difluorocyclohexanone (2.30 g, 17.6 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour. To the reaction solution, an aqueous ammonium chloride solution (50 mL) was added, followed by extraction with ethyl acetate (50 mL). The thus obtained organic layer was dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography (hexane/ethyl acetate=7:3) to yield the title compound (0.95 g, 66%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([C:7]([C:9]2[O:10][C:11]3[C:18]([CH2:19][CH2:20][CH3:21])=[CH:17][C:16]([Cl:22])=[C:15]([OH:23])[C:12]=3[C:13]=2[CH3:14])=O)=[CH:5][CH:4]=1.NN.[OH-].[K+]>C(O)CO.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:9]2[O:10][C:11]3[C:18]([CH2:19][CH2:20][CH3:21])=[CH:17][C:16]([Cl:22])=[C:15]([OH:23])[C:12]=3[C:13]=2[CH3:14])=[CH:24][CH:25]=1
Reactant: CCCc1cc(Cl)c(O)c2c(C)c(C(=O)c3ccc(OC)cc3)oc12
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: CCCc1cc(Cl)c(O)c2c(C)c(Cc3ccc(OC)cc3)oc12
Yield: 54.5 %

Procedure:
A solution of 2-(p-methoxybenzoyl)-3-methyl-4-hydroxy-5-chloro-7-propylbenzofuran (90 mg; 0.25 mmole), hydrazine (80 μl) and potassium hydroxide (98 mg) in ethylene glycol (2 mL) was heated at 145° C. for a period of 5 hours. The reaction mixture was cooled, poured in water, and extracted with ether. The organic phase was washed with 20% citric acid, with brine, dried (Na2SO4), and concentrated in vacuo. The residue was chromatographed on silica gel using 20% ethylacetate in hexane as eluent to yield 47 mg (50%) of 2-(p-methoxybenzyl) 3-methyl-4hydroxy-5-chloro-7-propylbenzofuran.
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[CH:8]=[C:9]([N:15]2[C:24]3[C:19](=[CH:20][C:21]([F:26])=[C:22](Cl)[N:23]=3)[C:18](=[O:27])[C:17]([C:28]([OH:30])=[O:29])=[CH:16]2)[C:10]([F:14])=[CH:11][C:12]=1[F:13].Cl.Cl.[NH2:33][C@H:34]1[CH2:38][CH2:37][NH:36][CH2:35]1.[CH2:39]([N:41]([CH2:44][CH3:45])[CH2:42][CH3:43])[CH3:40]>C(O)C>[CH:34]([O:27][CH:18]([CH3:17])[CH3:19])([CH3:38])[CH3:35].[CH2:39]([N:41]([CH2:44][CH3:45])[CH2:42][CH3:43])[CH3:40].[NH2:6][C:7]1[CH:8]=[C:9]([N:15]2[C:24]3[C:19](=[CH:20][C:21]([F:26])=[C:22]([N:36]4[CH2:37][CH2:38][C@H:34]([NH2:33])[CH2:35]4)[N:23]=3)[C:18](=[O:27])[C:17]([C:28]([OH:30])=[O:29])=[CH:16]2)[C:10]([F:14])=[CH:11][C:12]=1[F:13]
Reactant: N[C@H]1CCNC1
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(Cl)nc32)c(F)cc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(C)OC(C)C
Product: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC[C@H](N)C4)nc32)c(F)cc1F
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 142 %

Procedure:
To 1,000 mg of N,N-dimethylformamide were added 220 mg of 1-(3-amino-4,6-difluorophenyl)-7-chloro-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid, 210 mg of (3S)-3-aminopyrrolidine dihydrochloride, and 400 mg of triethylamine. The solution was stirred at 90° C. for 1.5 hours. The reaction solution was allowed to cool down, combined with 10 ml of ethanol, heated at reflux for 5 minutes, and allowed to cool down. The precipitate was collected by filtration and washed with ethanol and then with diisopropyl ether to give 220 mg of the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][S:5][C:4](=[S:7])[N:3]1[NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12].[N:18]1([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[O:34][C:33]([CH:35]=O)=[CH:32][CH:31]=3)=[CH:26][CH:25]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C(O)(=O)C.C(O)(=O)C.C(N)CN.S([O-])(O)=O.[Na+]>CO>[N:18]1([C:24]2[CH:25]=[CH:26][C:27]([C:30]3[O:34][C:33](/[CH:35]=[C:6]4\[C:2](=[O:1])[N:3]([NH:8][C:9]5[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=5[C:11]([OH:13])=[O:12])[C:4](=[S:7])[S:5]\4)=[CH:32][CH:31]=3)=[CH:28][CH:29]=2)[CH2:19][CH2:20][O:21][CH2:22][CH2:23]1
Reactant: O=C(O)c1ccccc1NN1C(=O)CSC1=S
Reactant: O=Cc1ccc(-c2ccc(N3CCOCC3)cc2)o1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: NCCN
Solvent: CO
Solvent: CC(=O)O
Product: O=C(O)c1ccccc1NN1C(=O)/C(=C\c2ccc(-c3ccc(N4CCOCC4)cc3)o2)SC1=S
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.8 %

Procedure:
A mixture of 2-(4-oxo-2-thioxo-thiazolidin-3-ylamino)-benzoic acid (0.089 g, 0.33 mmol), 5-(4-morpholin-4-yl-phenyl)-furan-2-carbaldehyde (0.091 g, 0.35 mmol) and ethylenediamine diacetate (0.063 g, 0.035 mmol) in methanol (10 mL) was stirred at room temperature for 18 h. The reaction mixture was poured into stirred 0.6 N aq sodium hydrogensulfite (50 mL). The mixture was vigorously stirred for 30 mm. The solid product was filtered off and washed on funnel successively with 0.6 N aq sodium hydrogensulfite (1 mL), water (2×2 mL), ether (2×1 mL) and hexanes (2 mL). The material was dried in a vacuum oven at 65° C. for 17 h to afford 2-{5-[1-[5-(4-morpholin-4-yl-phenyl)-furan-2-yl]-meth-(E)-ylidene]-4-oxo-2-thioxo-thiazolidin-3-ylamino}-benzoic acid (147 mg, 87%) as a solid. 1H NMR (400 MHz, DMSO-d6): 3.26 (2H, m), 3.76 (2H, m), 6.53 (1H, d, J=8.4 Hz), 6.87 (1H, m), 7.14 (2H, m), 7.17 (1H, d, J=3.6 Hz), 7.31 (1H, m), 7.40 (1H, d, J=4.0 Hz), 7.71 (1H, s), 7.76 (2H, m), 7.91 (1H, m), 10.4 (1H, bs). LC/MS: APCI 506.1, HPLC 92%.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].C(C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C.O=[C:32]1[CH2:37][CH2:36][CH:35]([CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:34][CH2:33]1>C(Cl)Cl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:32]1[CH2:37][CH2:36][CH:35]([CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:34][CH:33]=1)(=[O:5])=[O:4]
Reactant: CCOC(=O)CC1CCC(=O)CC1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Solvent: ClCCl
Product: CCOC(=O)CC1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
Trifluoromethanesulfonic anhydride (11.9 mL, 70.86 mmol) was added portionwise to a solution of 2,6-di-tert-butyl-4-methylpyridine (18.19 g, 88.58 mmol) in DCM (250 mL). A solution of ethyl 2-(4-oxocyclohexyl)acetate (10.88 g, 59.05 mmol, CAS 58012-34-3) in DCM (100 mL) was then added dropwise and the reaction mixture was allowed to stir open to air and at room temperature overnight. The reaction mixture was washed with water, saturated Na2CO3, saturated brine, dried over MgSO4 and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford the title compound (16.05 g, 86%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([CH:14]=1)[O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].C1N2CN3CN(C2)CN1C3.[C:27](=O)(O)[O-:28].[Na+]>FC(F)(F)C(O)=O>[Cl:1][C:2]1[C:3]([CH:27]=[O:28])=[CH:4][C:5]([O:15][CH3:16])=[C:6]([CH:14]=1)[O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)COc1cc(Cl)ccc1OC
Reactant: O=C([O-])O
Agent: C1N2CN3CN1CN(C2)C3
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)COc1cc(Cl)c(C=O)cc1OC
Temperature: 60 °C
Reaction time: 9 h

Procedure:
To a stirred solution of ethyl 2-(5-chloro-2-methoxy-phenoxy)acetate (606 mg) in trifluoroacetic acid (12 ml) was added hexamethylenetetramine (382 mg) at room temperature, and the mixture was stirred for 9 hours at 60° C. After concentration of the reaction mixture under reduced pressure, a saturated aqueous sodium bicarbonate solution was added to the residue, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. After the solvent was removed under reduced pressure, purification of the residue by flash column chromatography on silica gel (eluent: hexane/ethyl acetate=6/1) gave ethyl 2-(5-chloro-4-formyl-2-methoxyphenoxy)acetate (354 mg).
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]2)=[O:11])[CH2:6][CH2:5]1.[CH2:21]([S:24](Cl)(=[O:26])=[O:25])[CH2:22][CH3:23].CCN(CC)CC>C(Cl)Cl>[CH:18]([N:15]1[CH2:14][CH2:13][N:12]([C:10]([C@H:7]2[CH2:8][CH2:9][C@H:4]([NH:3][S:24]([CH2:21][CH2:22][CH3:23])(=[O:26])=[O:25])[CH2:5][CH2:6]2)=[O:11])[CH2:17][CH2:16]1)([CH3:20])[CH3:19]
Reactant: CC(C)N1CCN(C(=O)[C@H]2CC[C@H](N)CC2)CC1
Reactant: CCCS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)N[C@H]1CC[C@H](C(=O)N2CCN(C(C)C)CC2)CC1
Temperature: 40 °C
Reaction time: 16 h

Procedure:
A mixture of 32.6 mg (0.1 mmol) trans-(4-amino-cyclohexyl)-(4-isopropyl-piperazin-1-yl)-methanone, dihydrochloride, 28 mg (0.2 mmol) propane-1-sulfonyl chloride and 101 mg (1 mmol) NEt3 in 2 ml DCM was stirred for 16 h at 40° C. After evaporation methanol and DMF were added and the mixture was subjected to preparative HPLC purification on reversed phase eluting with a gradient of acetonitrile/water (0.1% NEt3). The combined product fractions were evaporated to dryness to yield 13.9 mg (39%) of the title compound. MS (m/e): 360.4 (MH+).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][NH:4]1.[C:8]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:19][CH2:20][NH:21][C:22](=[O:36])[C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][N:32]=[C:31](Cl)[N:30]=4)=[CH:25][CH:24]=3)[CH:17]=2)[NH:12][CH:11]=1)#[N:9]>>[C:8]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:19][CH2:20][NH:21][C:22](=[O:36])[C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][N:32]=[C:31]([N:4]5[CH2:5][CH2:6][CH2:7][CH:3]5[CH2:2][OH:1])[N:30]=4)=[CH:25][CH:24]=3)[CH:17]=2)[NH:12][CH:11]=1)#[N:9]
Reactant: OCC1CCCN1
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Product: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(N5CCCC5CO)n4)cc3)cc12

Procedure:
Using 2-(hydroxymethyl)-pyrrolidine and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates. MS (ion spray) m/z 467 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1.Cl[C:27](Cl)([O:29][C:30](=[O:36])OC(Cl)(Cl)Cl)Cl.[CH3:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1CO.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:30](=[O:36])[O:29][CH2:27][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[CH3:38])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)c([N+](=O)[O-])c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1ccccc1CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OCc4ccccc4C)c([N+](=O)[O-])c3)c2cc1OC
Yield: 90.7 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-nitroaniline (100 mg) was added to toluene (10 ml) and triethylamine (1 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (140 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, (2-methylphenyl)methanol (54 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (130 mg, yield 91%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH2:10][CH3:11].CC1(C)CCCC(C)(C)N1.C([Li])CCCCC.[CH:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CCCCCC.C1COCC1>[F:8][C:7]1[C:2]([F:1])=[C:3]([O:9][CH2:10][CH3:11])[CH:4]=[CH:5][C:6]=1[CH:29]([OH:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=Cc1ccccc1
Reactant: CCOc1cccc(F)c1F
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOc1ccc(C(O)c2ccccc2)c(F)c1F

Procedure:
1.1 kg/h of a 1M solution of 2,3-difluorophenetole containing 10 mol % of 2,2,6,6-tetramethylpiperidine were introduced into a continuous-flow reactor and mixed with 0.4 kg/h of a 2.5M solution of hexyllithium in hexane at −35° C. After the mixture had passed through the reaction zone, 0.28 kg/h of a 4.7M solution of benzaldehyde in THF were mixed in. After the reaction had finished, the product was collected and worked up in the customary manner, giving 2,3-difluoro-4-ethoxy-α-phenylbenzyl alcohol. The conversion based on the starting compound was 97%.
Reaction SMILES: [ClH:1].Cl.[CH3:3][C:4]1[CH:5]=[CH:6][C:7](OS(C2C=CC=CC=2S(N(CC)C2CCN(CC3C=CC=CC=3)C2)(=O)=O)(=O)=O)=[C:8]([CH:18]=1)[O:9][CH2:10][CH2:11][CH2:12][O:13][NH:14][C:15](=[NH:17])[NH2:16].CC1C=C2C(NC(=O)C2=C(OCCCOC2C=CC=CC=2[O:70][S:71]([C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][C:75]=2[S:80]([N:83]([CH2:96][CH3:97])[CH:84]2[CH2:88][CH2:87][N:86]([CH2:89][C:90]3[CH:95]=[CH:94][CH:93]=[CH:92][CH:91]=3)[CH2:85]2)(=[O:82])=[O:81])(=[O:73])=[O:72])C=1)=O.C(C(=CC1C=CC(O)=CC=1)C(O)=O)#N>>[ClH:1].[ClH:1].[CH3:3][C:4]1[CH:5]=[C:6]([O:70][S:71]([C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][C:75]=2[S:80]([N:83]([CH2:96][CH3:97])[CH:84]2[CH2:88][CH2:87][N:86]([CH2:89][C:90]3[CH:95]=[CH:94][CH:93]=[CH:92][CH:91]=3)[CH2:85]2)(=[O:81])=[O:82])(=[O:73])=[O:72])[CH:7]=[C:8]([CH:18]=1)[O:9][CH2:10][CH2:11][CH2:12][O:13][NH:14][C:15]([NH2:17])=[NH:16]
Reactant: CCN(C1CCN(Cc2ccccc2)C1)S(=O)(=O)c1ccccc1S(=O)(=O)Oc1ccccc1OCCCOc1cc(C)cc2c1C(=O)NC2=O
Reactant: CCN(C1CCN(Cc2ccccc2)C1)S(=O)(=O)c1ccccc1S(=O)(=O)Oc1ccc(C)cc1OCCCONC(=N)N
Agent: Cl
Agent: N#CC(=Cc1ccc(O)cc1)C(=O)O
Product: CCN(C1CCN(Cc2ccccc2)C1)S(=O)(=O)c1ccccc1S(=O)(=O)Oc1cc(C)cc(OCCCONC(=N)N)c1
Yield: 83 %

Procedure:
N-{3-[5-Methyl-3-[(2-(N-ethyl-N-(1-benzyl-3-pyrrolidinyl)aminosulfonyl) phenylsulfonyloxy]phenoxy]propoxy}guanidine dihydrochloride: The title compound was prepared in 83% yield from N-{3-[5-methyl-3-[(2-(N-ethyl-N-(1-benzyl-3-pyrrolidinyl)aminosulfonyl)phenylsulfonyloxy]phenoxy]propoxyphthalimide, as prepared in the preceding step, in a manner analogous to step f of Example 1. 1H-NMR (300 MHz, DMSO-d6) δ 11.15 (br s, 2H), 8.18 (d, J=7.8 Hz, 1H), 8.14 (d, J=7.8 Hz, 1H), 8.00 (t, J=7.6 Hz, 1H), 7.88 (t, J=7.7 Hz, 1H), 7.68 (br s, 4H), 7.38 (m, 5H), 6.74 (s, 1H), 6.52 (s, 1H), 6.48 (s, 1H), 4.66 (br s, 1H), 4.04 (m, 1H), 3.97 (t, J=6.3 Hz, 2H), 3.89 (t, J=6.3 Hz, 2H), 3.50 (m, 2H), 2.75-3.20 (m, 5H), 2.21 (s, 3H), 2.13 (m, 2H), 2.01 (pentet, J=6.2 Hz, 2H), 1.10 (t, J=6.9 Hz, 3H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C30H39N5O7S2: 646.2 (M+H). Found: 646.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[H-].[Na+].[O:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH:16]=[C:15]1[S:23](Cl)(=[O:25])=[O:24]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH:7][S:23]([C:15]2[O:14][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH:16]=2)(=[O:24])=[O:25])[CH:8]=1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Cl)cc1NS(=O)(=O)c1cc2ccccc2o1
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 378 %

Procedure:
To a −10° C. cold yellow solution of 5-chloro-2-nitroaniline (8.00 g, 46.36 mmol) in dry DMF (130 ml) was added sodium hydride 60% (9.27 g, 231.79 mmol) under Ar. The resulting red suspension was stirred at −10° C. for 10 minutes. A solution of 1-benzofuran-2-sulfonyl chloride (12.05 g, 55.63 mmol) in dry DMF (50 ml) was added dropwise with a dropping funnel at −10° C. (10 minutes of addition, exothermic reaction, maximum temperature of addition was 0° C., 5 ml of DMF to rinse the funnel). The resulting orange suspension was stirred at −10° C. for 30 minutes (color changed to brown). The reaction mixture was quenched with half saturated NaHCO3 solution (400 ml) and the product was extracted five times with EtOAc (1×650 ml and 4×300 ml). The combined organic layers were dried over Na2SO4, filtered and the filtrate evaporated to dryness. The crude product was combined with the crude product of an analogously performed 8 g scale attempt to give 61.82 g of an orange oil which was purified by MPLC (crude was dissolved in CH2Cl2/MeOH, preabsorption on silica gel, column D, program 3, 5 runs) to afford Intermediate 4 (28.91 g, 88% yield based on combined starting material) as yellow solid.
Reaction SMILES: [Cr](O)(O)(=O)=O.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[N:17]2[NH:18][C:19](=[O:27])[C:20]([CH:22]3[CH2:25][CH:24]([OH:26])[CH2:23]3)=[CH:21][C:16]2=[N:15][N:14]=1.C(O)(C)C.O>CC(C)=O>[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[N:17]2[NH:18][C:19](=[O:27])[C:20]([CH:22]3[CH2:23][C:24](=[O:26])[CH2:25]3)=[CH:21][C:16]2=[N:15][N:14]=1
Reactant: O=c1[nH]n2c(-c3ccccc3F)nnc2cc1C1CC(O)C1
Agent: O=[Cr](=O)(O)O
Solvent: CC(C)O
Solvent: CC(C)=O
Solvent: O
Product: O=C1CC(c2cc3nnc(-c4ccccc4F)n3[nH]c2=O)C1

Procedure:
8N Chromic acid was added to a solution of 3-(2-fluorophenyl)-7-(3-hydroxycyclobutyl)-1,2,4-triazolo[4,3-b]pyridazin-6-one (0.36 g, 1.2 mmol) in acetone (50 ml) dropwise, until excess was present (red colour remained). The reaction was then stirred for 2 hours before isopropanol was added until the blue colour remained and no excess chromic acid was present. Water (50 ml) was added and the aqueous layer extracted with ethyl acetate (4×50 ml), organic layers were combined, washed with brine (50 ml), dried (MgSO4), filtered and concentrated to give the desired product as a white solid. Data for the title compound: 1H NMR (360 MHz, DMSO) δ 3.41 (2H, s), 3.43 (2H, s), 3.73-3.78 (1H, m), 7.42-7.50 (2H, m), 7.64-7.72 (1H, m), 7.83-7.88 (1H, m), 8.38 (1H, s); MS (ES+) m/e 299 [MH]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.[Cl:21][C:22]1[N:27]=[C:26]([C:28]([C:30]2[CH:39]=[C:38]([CH3:40])[C:33]3[NH:34][C:35](=[O:37])[O:36][C:32]=3[CH:31]=2)=[O:29])[CH:25]=[C:24](Cl)[N:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:21][C:22]1[N:23]=[C:24]([N:17]2[CH2:18][CH2:19][CH:14]([N:10]3[CH2:9][CH2:8][C:7]4[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=4[NH:12][C:11]3=[O:13])[CH2:15][CH2:16]2)[CH:25]=[C:26]([C:28]([C:30]2[CH:39]=[C:38]([CH3:40])[C:33]3[NH:34][C:35](=[O:37])[O:36][C:32]=3[CH:31]=2)=[O:29])[N:27]=1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: Cc1cc(C(=O)c2cc(Cl)nc(Cl)n2)cc2oc(=O)[nH]c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5[nH]c(=O)oc5c4)nc(Cl)n3)CC1)C(=O)N2

Procedure:
275 mg (1.00 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 324 mg (1.00 mmol) 6-(2,6-dichloro-pyrimidine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one and 0.348 mL (2.00 mmol) DIPEA in 5.00 mL DMF were stirred overnight at RT. Then the mixture was purified by preparative HPLC-MS. The fractions containing the product were combined and the organic solvent was evaporated down i. vac. The residue was neutralised with 4N aqueous sodium hydroxide solution and the precipitate formed was suction filtered, washed with water and dried.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[C:21](=[O:25])[N:20]([CH2:26][CH3:27])[CH2:19]2.[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1.C(O)(=O)C>C(#N)C>[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH:15][C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[C:21](=[O:25])[N:20]([CH2:26][CH3:27])[CH2:19]3)=[CH:31][CH:30]=1
Reactant: CCN1Cc2cc(N)ccc2C1=O
Reactant: O=Cc1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CCN1Cc2cc(NCc3ccc(Cl)cc3)ccc2C1=O
Reaction time: 8 h
Yield: 16.1 %

Procedure:
Sodium triacetoxyborohydride (1.28 g, 6.10 mmol) was added to a stirred solution of 5-amino-2-ethyl-2,3-dihydro-isoindol-1-one (540 mg, 3.05 mmol), 4-chlorobenzaldehyde (854 mg, 6.10 mmol) and acetic acid (183 μl, 3.05 mmol) in anhydrous acetonitrile (12 ml) at room temperature. The reaction was stirred overnight and quenched with the addition of water. The organic phase was separated, washed with brine, then dried (MgSO4) and evaporated in vacuo. The resulting residue was purified by flash column chromatography (0 to 20% ethyl acetate in dichloromethane) to yield the title compound as a light brown solid (148 mg, 16%). HPLC retention time 4.23 min. Mass spectrum (ES+) m/z 301 (M+H).
Reaction SMILES: [NH2:1][C:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13](=[O:37])[C@@H:14]([CH2:23][CH2:24][CH2:25][NH:26][C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[NH:15]C(OCC(C)C)=O)=[CH:7][CH:6]=1)=[O:3].[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>>[NH2:1][C:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13](=[O:37])[C@@H:14]([CH2:23][CH2:24][CH2:25][NH:26][C:27]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:28])[NH2:15])=[CH:7][CH:6]=1)=[O:3].[F:38][C:39]([F:44])([F:43])[C:40]([O-:42])=[O:41]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)COC(=O)N[C@H](CCCNC(=O)OCc1ccccc1)C(=O)NCc1ccc(CC(N)=O)cc1
Product: NC(=O)Cc1ccc(CNC(=O)[C@H](N)CCCNC(=O)OCc2ccccc2)cc1
Product: O=C([O-])C(F)(F)F

Procedure:
Prepared analogously to Example if) from (R)-N-[[4-(aminocarbonylmethyl)phenyl]methyl]-N2 -[(2,2-dimethylethoxy)carbonyl]-N5 -(phenylmethoxycarbonyl)-ornithinamide and trifluoroacetic acid in a quantitative yield. Colourless, amorphous substance which was used in the following step without purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[CH:9][C:10](=[O:13])[NH:11][CH:12]=1.[CH3:14][C:15](C)([O-])C.[K+].BrCC>CN(C=O)C>[CH2:14]([N:11]1[CH:12]=[C:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)[CH:8]=[CH:9][C:10]1=[O:13])[CH3:15]
Reactant: CC(C)(C)[O-]
Reactant: O=c1ccc(-c2cnccn2)c[nH]1
Agent: [K+]
Solvent: CCBr
Solvent: CN(C)C=O
Product: CCn1cc(-c2cnccn2)ccc1=O
Reaction time: 0.75 h

Procedure:
A suspension of 5-(2-pyrazinyl)-2(1H)-pyridone (6.5 g) and 6.6 g of potassium t-butoxide in 250 ml of dry DMF is stirred with warming until all the solid is dissolved. The stirred solution is cooled in an ice bath and 4.6 ml of bromoethane are added when the temperature reaches 5° C. The ice bath is removed and stirring is continued for 45 minutes at which time 0.5 ml of additional bromoethane is added. Stirring is continued over the weekend. 10 g of sodium bisulfate in distilled H2O are added to the reaction mixture which is filtered. The filtrate is evaporated and the residue taken up in boiling isopropanol. The isopropanol solution is treating with decolorizing charcoal and filtered while hot. The filtrate is evaporated in vacuum to remove residual DMF, resulting in the formulation of a solid. The solid is recrystallized from acetonitrile with hot filtration. The starting material crystallizes out. The acetonitrile mother liquid is evaporated and the residue chromatographed on 100 g of silica gel. The column is eluted with ethyl acetate, toluene and finally with methanol in ethyl acetate. The early fractions are discarded and the latter fractions are combined and recrystallized from hot toluene/decane and air dried, resulting in the desired 1-ethyl-5-(2-pyrazinyl)-2-pyridone, M.P. 119.5°-120.7° C.