Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([NH2:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+]>CC#N>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][NH:12][CH:10]1[CH2:11][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]1)[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CNC1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 13 h
Yield: 80.8 %

Procedure:
A mixture of tert-butyl3-aminoazetidine-1-carboxylate (10.0 g, 58 mmol), ethyl 2-bromoacetate (10.7 g, 64 mmol) and potassium carbonate (24.0 g, 174 mmol) in MeCN (200 mL) was stirred at rt for 13 hrs. The reaction mixture was filtered and concentrated. The crude material was purified by silica gel column chromatography (gradient elution 0˜66% EtOAc/petroleum ether) to afford tert-butyl 3-(2-ethoxy-2-oxoethylamino)azetidine-1-carboxylate (12.1 g, 81%) as a white solid. ESI-MS (EI+, m/z): 259.0 [M+H]+.
Reaction SMILES: [S:1]1[C:5]([CH:6]=[O:7])=[CH:4][C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.OS([O-])=O.[Na+].[C-:17]#[N:18].[K+]>C1COCC1.O.[Cl-].[Na+].O>[S:1]1[C:5]([CH:6]([OH:7])[C:17]#[N:18])=[CH:4][C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2
Reactant: O=Cc1cc2ccccc2s1
Reactant: [C-]#N
Agent: O=S([O-])O
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: N#CC(O)c1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 22 h
Yield: 42.7 %

Procedure:
To a solution of benzo[b]thiophene-2-carbaldehyde (2.19 g, 13.5 mmol) in anhydrous THF (200 mL) was added a solution of NaHSO3 (6.18 g, 59.4 mmol) in water (50 mL). KCN (3.248 g, 49.9 mmol) was added and the mixture was stirred at room temperature for 22 hours. The reaction mixture was then heated at 45° C. for 1 hour. After cooling to room temperature, the mixture was diluted with water and brine and extracted with EtOAc three times. The combined organics were washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification by chromatography (0-25% EtOAc-hexanes) gave 2-(benzo[b]thiophen-2-yl)-2-hydroxyacetonitrile as an off-white solid (1.09 g, 46% yield).
Reaction SMILES: C[O:2][C:3]1[N:4]=[N:5][C:6]([S:9]([C:12]2[O:13][C:14]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:15]=3[C:16]=2[CH3:17])(=[O:11])=[O:10])=[CH:7][CH:8]=1.Cl>O1CCOCC1>[F:22][C:19]1[CH:20]=[CH:21][C:14]2[O:13][C:12]([S:9]([C:6]3[CH:7]=[CH:8][C:3](=[O:2])[NH:4][N:5]=3)(=[O:11])=[O:10])=[C:16]([CH3:17])[C:15]=2[CH:18]=1
Reactant: COc1ccc(S(=O)(=O)c2oc3ccc(F)cc3c2C)nn1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(S(=O)(=O)c2ccc(=O)[nH]n2)oc2ccc(F)cc12
Temperature: 100 °C
Yield: 83.8 %

Procedure:
A mixture of 3-methoxy-6-(5-fluoro-3-methyl-benzofuran-2-sulfonyl)-pyridazine (2.4 mmol, 775 mg), conc. HCl (1.5 mL), and dioxane (3 mL) was heated at 100° C. for 2 hours. The reaction mixture was cooled and evaporated to dryness. The dried residue was triturated with water (10 mL), and filtered to obtain the desired product, 6-(5-fluoro-3-methyl-benzofuran-2-sulfonyl)-2H-pyridazin-3-one (84%, 620 mg); mp 232° C.-233° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:13][CH:14]([NH2:16])[CH3:15]>>[CH:14]([NH:16][C:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][CH2:2][CH2:3]2)=[O:12])([CH3:15])[CH3:13]
Reactant: CC(C)N
Reactant: O=C(O)c1ccc2c(c1)CCN2
Product: CC(C)NC(=O)c1ccc2c(c1)CCN2

Procedure:
The title compound was prepared by following the similar procedure as described in Intermediate-10 using indoline-5-carboxylic acid and propan-2-amine (0.315 g, 31%); MS: 205 (M+1).
Reaction SMILES: C1(C=CC(O)=CC=1)O.OO.[CH2:11]1[C:16]2[NH:17][C:18]3[C:23]([C:24](=[O:25])[C:15]=2[CH2:14][C:13]2[NH:26][C:27]4[C:32]([C:33](=[O:34])[C:12]1=2)=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:22][CH:21]=[CH:20][CH:19]=3>>[CH:30]1[CH:31]=[C:32]2[C:33]([C:12]3[C:13]([NH:26][C:27]2=[CH:28][CH:29]=1)=[CH:14][C:15]1[C:24]([C:23]2[C:18]([NH:17][C:16]=1[CH:11]=3)=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:25])=[O:34]
Reactant: O=c1c2c([nH]c3ccccc13)Cc1c([nH]c3ccccc3c1=O)C2
Agent: OO
Agent: Oc1ccc(O)cc1
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12

Procedure:
While the hydroquinone assisted hydrogen peroxide oxidation of 6,13-dihydroquinacridone produces a gamma-I quinacridone, surprisingly a combination of hydroquinone and pyrazolylmethyl quinacridone generates a gamma-II quinacridone. It is further surprising that the oxidation of 6,13-dihydroquinacridone in the presence of 2-naphthol creates a gamma-III quinacridone.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.Cl[C:31](=[O:38])[C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:31]([C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33])=[O:38])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)OC(=O)C(=O)Cl
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)C(=O)OC(C)C)c1

Procedure:
Prepared as described in Example 1 using (1R,2S)-1-[1-(4-fluorophenyl)-indazol-5-yl]oxy-1-(3-methoxyphenyl)-propan-2-amine (53 mg, 0.14 mmol) and isopropyl 2-chloro-2-oxoacetate (0.035 mL, 0.27 mmol) [prepared according to G. Bucher at al, Eur J Org Chem, 545-552 (2001); b.p. 54-55° C., 30 mmHg]. Yield 54 mg (79%).
Reaction SMILES: [C:1]([C:3]1[CH:9]([C:10]#[N:11])[NH:8][C:7]([OH:18])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[C:5]([CH3:19])[N:4]=1)#[N:2].[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.N1CCCCC1>>[C:1]([C:3]1[N:4]=[C:5]([CH3:19])[C:6](=[CH:26][C:25]2[CH:28]=[CH:29][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)[C:7]([OH:18])([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:8][C:9]=1[C:10]#[N:11])#[N:2]
Reactant: COc1ccc(C=O)cc1
Reactant: CC1=CC(O)(c2ccccc2)NC(C#N)C(C#N)=N1
Solvent: C1CCNCC1
Product: COc1ccc(C=C2C(C)=NC(C#N)=C(C#N)NC2(O)c2ccccc2)cc1

Procedure:
In the presence of a catalytic amount of HCl (4N=4 mol/l), 1 mol of diaminomaleonitrile was reacted with 1 mol of benzoylacetone in a solvent (benzene) at 45° C. for 6 hours to give 2,3-dicyano-5-hydroxy-5-phenyl-7-methyl-4H-1,4-diazepine (compound 1a). The diazepine compound (1a) thus obtained was reacted with 4-methoxybenzaldehyde in the presence of piperidine to give the object compound 2,3-dicyano-5-hydroxy-5-phenyl-6-(4-methoxyphenylmethylidene)-7-methyl-4H-1,4-diazepine (compound 1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([OH:13])[C:6]([OH:14])=[N:5]2.Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17].Cl>[OH-].[Na+]>[Cl:12][C:11]1[CH:10]=[C:9]2[C:4](=[CH:3][C:2]=1[NH:1][C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:5]=[C:6]([OH:14])[C:7]([OH:13])=[N:8]2
Reactant: CCOC(=O)Cl
Reactant: Nc1cc2nc(O)c(O)nc2cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)Nc1cc2nc(O)c(O)nc2cc1Cl
Reaction time: 1 h
Yield: 9792.4 %

Procedure:
A solution of 10 g (47,3 mmol) 6-amino-7-chloro-2,3-dihydroxyquinoxaline in 200 ml 0,5N sodium hydroxide was ice-cooled, and then 30 ml (0,36 mmol) ethyl chloroformate was added. Stirring was continued at 0° C. for 1 h and at 25° C. for 1 h. To the reaction mixture was added 1N hydrochloric acid to pH 2-3, and the precipitated product was filtered off and washed with water to give 12 g of a crude product. Recrystallization (dimethylsulfoxide-0,5N hydrochloric acid) gave 10 g (75%) 6-chloro-7-ethoxycarbonylamino-2,3-dihydroxyquinoxaline, m.p.>300° C. NMR (DMSO-d6): 11.9 (2H, broad s), B.9 (1H, broad s), 7.37 (1H,s), 7.17 (1H,s), 4.1 (2H,q), 1.28 (3H,t).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CC(C)=O.[C:17](=[O:19])=O.[Cl:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]([C:31](=[O:40])[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=1[Cl:39])[CH2:26][CH2:25][C:24]2=O.CI.Cl>O1CCCC1.C(OCC)(=O)C.O.CCCCCC>[Cl:20][C:21]1[CH:30]=[C:29]2[C:28](=[CH:23][CH:22]=1)[N:27]([C:31](=[O:40])[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=1[Cl:39])[CH2:26][CH:25]([CH3:24])[C:17]2=[O:19]
Reactant: O=C=O
Reactant: O=C1CCN(C(=O)c2ccc(Cl)cc2Cl)c2ccc(Cl)cc21
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: CC(C)=O
Product: CC1CN(C(=O)c2ccc(Cl)cc2Cl)c2ccc(Cl)cc2C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a cooled (-20° C. to -15° C.) solution of diisopropylamine (4.7 g) in anhydrous tetrahydrofuran (100 ml) was added dropwise n-hexane solution (29 ml) of 1.6 N butyl lithium over a 30-minute period in a nitrogen atmosphere, and stirring was continued for 30 minutes after the mixed solution was returned to 0° C. Then the solution was cooled to -75° C. with acetone-dry ice and 15 g of 6-chloro-1-(2,4dichloro-benzoyl)-2,3-dihydro-4(1H)-quinolinone dissolved in 150 ml of anhydrous tetrahydrofuran was added dropwise over a 1-hour period. The reaction mixture was stirred for another 1 hour at -75° C., and methyl iodide (18 g) was added dropwise with stirring over a 30-minute period. The reaction mixture was then slowly warmed to 0° C. over two hour, and acidified under cooling with 2 N hydrochloric acid to be weakly acidic. The reaction mixture was poured into 300 ml of water, then shaken with ethyl acetate (500 ml). The organic layer was washed once with saturated aqueous NaCl solution (200 ml) and dried over anhydrous sodium aulfate. Ethyl acetate was removed in vacuo and the residue was subjected to silica gel column chromatography using a hexane-ethyl acetate mixture (4: 1) to obtain 6-chloro-1-(2,4-dichlorobenzoyl)-2,3-dihydro-3-methyl-4(1H) -quinolinone (yield 7.8 g) as white crystal.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][S:10][C@H:9]1[C:13]([O:15][C@H:16]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH:34]([F:36])[F:35])=[C:29]([O:37][CH2:38][CH:39]2[CH2:41][CH2:40]2)[CH:28]=1)[CH2:17][C:18]1[C:23]([Cl:24])=[CH:22][N+:21]([O-:25])=[CH:20][C:19]=1[Cl:26])=[O:14])=O)(C)(C)C.Cl.C(OCC)(=O)C>C(OCC)(=O)C>[ClH:24].[Cl:26][C:19]1[CH:20]=[N+:21]([O-:25])[CH:22]=[C:23]([Cl:24])[C:18]=1[CH2:17][C@@H:16]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH:34]([F:36])[F:35])=[C:29]([O:37][CH2:38][CH:39]2[CH2:41][CH2:40]2)[CH:28]=1)[O:15][C:13]([C@H:9]1[NH:8][CH2:12][CH2:11][S:10]1)=[O:14]
Reactant: CC(C)(C)OC(=O)N1CCS[C@H]1C(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1)[C@H]1NCCS1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 168.7 %

Procedure:
4-((S)-2-((S)-3-(tert-butoxycarbonyl)thiazolidine-2-carbonyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (4.22 g, 6.64 mmol) was dissolved in ethyl acetate (10 ml). HCl/ethyl acetate 4.2 M (50 ml) was added, and the reaction was stirred at RT for 5 minutes. A white precipitate formed, and it was filtered, washed with ethyl acetate (2×) and hexane and dried in the vacuum oven to yield 3,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((S)-thiazolidine-2-carbonyloxy)ethyl)pyridine 1-oxide hydrochloride (3.19 g, 5.6 mmol, 84% Yield)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18]C)=[C:14]([CH3:20])[CH:13]=2)[C:6]=1[CH2:7][C:8]([OH:10])=[O:9].O>Br.C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH3:20])[CH:13]=2)[C:6]=1[CH2:7][C:8]([OH:10])=[O:9]
Reactant: COc1ccc(Cn2c(-c3ccccc3)nc(Cl)c2CC(=O)O)cc1C
Agent: Br
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(Cn2c(-c3ccccc3)nc(Cl)c2CC(=O)O)ccc1O
Yield: 14.2 %

Procedure:
4-Chloro-1-(4-methoxy-3-methylbenzyl)-2-phenylimidazole-5-acetic acid (2.2 g) was stirred in 20 ml of 57% hydrobromic acid at 100°-110° C. for 2 hours. To the reaction mixture was then added 80 ml of water and the mixture was allowed to stand. The resulting syrupy precipitate was dissolved in 50 ml of ethyl acetate and washed with water. The ethyl acetate layer was evaporated to dryness and the residue was purified by column chromatography using 50 g of silica gel. The desired fractions were combined and crystallized from acetone-diethyl ether to give 0.3 g of 4-chloro-1-(4-hydroxy-3-methylbenzyl)-2-phenylimidazole-5-acetic acid as colorless needles, m.p. 190°-193° C. (decompn.).
Reaction SMILES: C([O:8][CH2:9][CH:10]1[O:24][C:14]2=[C:15]3[C:20](=[CH:21][CH:22]=[C:13]2[O:12][CH2:11]1)[N:19]=[C:18]([CH3:23])[CH:17]=[CH:16]3)C1C=CC=CC=1>C(Cl)Cl>[CH3:23][C:18]1[CH:17]=[CH:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]3[O:12][CH2:11][CH:10]([CH2:9][OH:8])[O:24][C:14]3=2)[N:19]=1
Reactant: Cc1ccc2c3c(ccc2n1)OCC(COCc1ccccc1)O3
Solvent: ClCCl
Product: Cc1ccc2c3c(ccc2n1)OCC(CO)O3
Reaction time: 1 h
Yield: 69 %

Procedure:
To a solution of 2[(benzyloxy)methyl-8-methyl-2,3-dihydro[1,4]dioxino [2,3-f]quinoline (0.30 g, 0.94 mmol) in CH2Cl2 (8 mL) being cooled in an ice-bath, FeCl3 (0.77 g, 4.7 mmol) was added. After 1 h, the ice-bath was removed and the reaction mixture was stirred for another 4 h. CH2Cl2 (30 mL) and 1N NaOH (25 mL) were added to result in a suspension which was then filtered. The filtered solid was washed with CH3OH (50 mL). The combined organic layers were concentrated in vacuo. Purification on SiO2, eluted with (10:1) CHCl3:/PrOH gave 0.15 g (68%) of the title compound as an off-white solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[S:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([S:22]([CH3:25])(=[O:24])=[O:23])[CH:17]=3)=[CH:14][CH:15]=2)[N:8]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:32])[N:7]=1)=O)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:42])=CC=1.C1(C)C=CC=CC=1.C1C=CC=CC=1>CCOCC>[CH2:1]([NH:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[S:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([S:22]([CH3:25])(=[O:24])=[O:23])[CH:17]=3)=[CH:14][CH:15]=2)[N:8]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:32])[N:7]=1)=[S:42])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCNC(=O)c1cc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n(-c2ccccc2Cl)n1
Solvent: c1ccccc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCNC(=S)c1cc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n(-c2ccccc2Cl)n1
Temperature: 25 °C
Yield: 37.7 %

Procedure:
To a dry, N2 purged 50 mL round bottom flask attached with condenser was added 1-(2-Chloro-phenyl)-5-[5-(3-methanesulfonyl-phenyl)-thiophen-2-yl]-1H-pyrazole-3-carboxylic acid ethylamide (100 mg, 206 μmol), Lawesson's reagent (200 mg, 494 μmol), and anhydrous toluene (8 mL). The reaction solution was allowed to stir at reflux for 14 hrs. The reaction solution was allowed to cool to room temperature prior to addition of a 1:1 mixture of benzene and Et2O. The resulting precipitate was removed by vacuum filtration through a Buchner funnel. The filtrate was concentrated on the Rotavapor and the crude residue was chromatographed through a 12 g SiO2 column using a mobile phase gradient of 100% Hx to 50% EtOAc to afford 39 mg (38% yield) of the title compound. 1H NMR (400 MHz, CDCl3) δ 8.68 (br s, 1H), 8.02 (s, 1H), 7.83 (d, 1H), 7.72 (d, 1H), 7.48-7.70 (m, 5H), 7.42 (s, 1H), 7.22 (d, 1H), 6.83 (d, 1H), 3.87 (m, 2H), 3.07 (s, 3H), 1.36 (t, 3H). MS (ES) 502.3, 504.3 [M+H]+.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[N:12]=[N:11][C:10]([NH:13][C:14](=[O:22])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)#[N:2].N[NH:24][C:25]([NH2:27])=[S:26].FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>O>[NH2:27][C:25]1[S:26][C:1]([CH2:3][CH2:4][CH2:5][CH2:6][C:7]2[N:12]=[N:11][C:10]([NH:13][C:14](=[O:22])[CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:9][CH:8]=2)=[N:2][N:24]=1
Reactant: NNC(N)=S
Reactant: N#CCCCCc1ccc(NC(=O)Cc2ccccc2)nn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Nc1nnc(CCCCc2ccc(NC(=O)Cc3ccccc3)nn2)s1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
N-(6-(4-cyanobutyl)pyridazin-3-yl)-2-phenylacetamide (14.7 g, 50.2 mmol) was charged into a 250 mL round bottom flask fitted with an open top reflux condenser. To the flask was added thiosemicarbazide (5.03 g, 55.2 mmol) and trifluoroacetic acid (88 mL). The reaction slurry was heated in a 65° C. bath for 2 h. After cooling to RT, H2O (150 mL) was added and stirred for 30 minutes. The mixture was then slowly transferred to a stirred 7.5% sodium bicarbonate solution (1400 mL) cooled in a 0° C. bath. The precipitate was collected by suction filtration, rinsed with water (2×200 mL), diethyl ether (2×200 mL) and dried under high vacuum overnight. The off-white solid was slurried in DMSO (200 mL) and heated in an 80° C. bath until the internal temperature reached 65° C. DMSO (105 mL) was used to rinse sides of flask. H2O (120 mL) was slowly added until the solution became slightly cloudy and then the mixture was removed from heat bath and allowed to cool to ambient temperature while stirring. The pale green precipitate was collected by suction filtration, rinsed with water (200 mL) and diethyl ether (2×200 mL). The solid was dried overnight under high vacuum to provide N-(6-(4-(5-amino-1,3,4-thiadiazol-2-yl)butyl)pyridazin-3-yl)-2-phenylacetamide (1024, 15.01 g). 1H NMR (300 MHz, DMSO-d6) δ 11.28 (s, 1H), 8.23 (d, J=8.916 Hz, 1H), 7.59 (d, J=8.826 Hz, 1H), 7.36 (m, 5H), 7.07 (s, 2H), 3.78 (s, 2H), 2.87 (t, J=6.799 Hz, 4H), 1.69 (bm, 4H)
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][C@H:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([C:22]2[N:23]([CH3:31])[C:24]3[C:29]([CH:30]=2)=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[CH2:11]1)=[O:7])(C)(C)C.[NH2:32][C:33]1[C:41]([Cl:42])=[CH:40][C:36](C(O)=O)=[C:35]([O:43][CH3:44])[CH:34]=1>>[NH2:32][C:33]1[C:41]([Cl:42])=[CH:40][C:36]([C:6]([NH:8][CH2:9][C@H:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([C:22]3[N:23]([CH3:31])[C:24]4[C:29]([CH:30]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:21])[CH2:11]2)=[O:7])=[C:35]([O:43][CH3:44])[CH:34]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: Cn1c(C(=O)NCCCCN2CC[C@H](CNC(=O)OC(C)(C)C)C2)cc2ccccc21
Product: COc1cc(N)c(Cl)cc1C(=O)NC[C@H]1CCN(CCCCNC(=O)c2cc3ccccc3n2C)C1

Procedure:
N-(4-((3R)-3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)-butyl)-1-methyl-1 H-indole-2-carboxamide (0.95 g) as starting compound was reacted and treated in the same manner as in Example 67 using 4-amino-5-chloro-2-methoxybenzoic acid (0.45 g) to give N-(4-((3R)-3-(4-amino-5-chloro-2-methoxybenzoylaminomethyl)pyrrolidin-1-yl)butyl)-1-methyl-1 H-indole-2-carboxamide.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:14][C:15]1[CH:16]=[C:17]([CH:30]=[CH:31][CH:32]=1)[C:18]([NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)=[O:19])(=[O:13])=[O:12].[CH:33]1C2C(=CC=CC=2)C=C[C:34]=1S(Cl)(=O)=O>>[CH2:33]([O:26][C:25](=[O:27])[C:24]1[CH:28]=[CH:29][C:21]([NH:20][C:18](=[O:19])[C:17]2[CH:30]=[CH:31][CH:32]=[C:15]([NH:14][S:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)(=[O:12])=[O:13])[CH:16]=2)=[CH:22][CH:23]=1)[CH3:34]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: O=C(O)c1ccc(NC(=O)c2cccc(NS(=O)(=O)c3ccc4ccccc4c3)c2)cc1
Product: CCOC(=O)c1ccc(NC(=O)c2cccc(NS(=O)(=O)c3ccc4ccccc4c3)c2)cc1

Procedure:
4-[3-(Naphthalene-2-sulfonylamino)-benzoylamino]-benzoic acid, MS (ISP): m/e=445.1 (M−H), was prepared in analogy to example 1, steps A to D. Step C was performed using naphthalene-2-sulfonyl chloride and yielded 4-[3-(naphthalene-2-sulfonylamino)-benzoylamino]-benzoic acid ethyl ester, which was hydrolyzed in step D.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[H-].[Na+].F[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[N+:19]([O-:21])=[O:20]>CN(C)C=O>[F:18][C:14]1[C:13]([N+:19]([O-:21])=[O:20])=[C:12]([NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[F:1])[CH:17]=[CH:16][CH:15]=1
Reactant: O=[N+]([O-])c1c(F)cccc1F
Reactant: Nc1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1c(F)cccc1Nc1ccccc1F
Reaction time: 0.17 h

Procedure:
To 2-fluoroaniline (1.55 g, 13.9 mmol) in anhydrous dimethylformamide (10 mL) was added sodium hydride (0.56 g, 13.9 mmol) and the reaction stirred for 10 minutes prior to the addition of 2,6-difluoronitrobenzene (2 g, 15.5 mmol) dissolved in anhydrous dimethylformamide (2 mL). Upon disappearance of 2-fluoroaniline the reaction was partitioned between saturated ammonium chloride (50 mL) and ethyl acetate (50 mL) and the organics were dried over sodium sulfate. The product was purified on silica gel using the ISCO (0-70% ethyl acetate/hexane) to give (3-Fluoro-2-nitro-phenyl)-(2-fluoro-phenyl)-amine as a slightly impure off-white solid (1.5 g, 43%). (3-Fluoro-2-nitro-phenyl)-(2-fluoro-phenyl)-amine (1.5 g, 6 mmol) and a spatula tip of 5% Pd/C in methanol (100 mL) were reduced in the parr shaker. Upon complete reduction, the reaction was filtered through a pad of celite and concentrated onto silica gel. The product was purified on silica gel using the ISCO (0-70% ethyl acetate/hexane) to give 3-fluoro-N1-(2-fluorophenyl)benzene-1,2-diamine as a brown oil (0.5 g, 38%). MS (ES) m/z 221.1
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7]CN2CC(C)NS2(=O)=O)[CH2:3][CH2:2]1.N1CCC([CH2:23][CH2:24][N:25]2[CH:29](C)[CH2:28][NH:27][S:26]2(=[O:32])=[O:31])CC1.Cl>>[NH:1]1[CH2:2][CH2:3][CH:4]([CH2:7][N:27]2[CH2:28][CH2:29][CH:24]([CH3:23])[NH:25][S:26]2(=[O:31])=[O:32])[CH2:5][CH2:6]1
Reactant: CC1CNS(=O)(=O)N1CCC1CCNCC1
Reactant: CC1CN(CCC2CCNCC2)S(=O)(=O)N1
Agent: Cl
Product: CC1CCN(CC2CCNCC2)S(=O)(=O)N1

Procedure:
2-[2-(4-piperidyl)ethyl]-4-methyl-1,2,5-thiadiazolidine-1,1-dioxide and 2-[2-(4-piperidyl)ethyl]-3-methyl-1,2,5-thiadiazolidine-1,1-dioxide as a 3:1 mixture (crude hydrochloride, oil).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Cl:20])[CH:19]=1.Cl[C:22](OC)=[O:23].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Cl:20])[C:19]=1[CH2:22][OH:23]
Reactant: COC(=O)Cl
Reactant: Clc1cncc(Br)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: OCc1c(Cl)cncc1Br
Temperature: -30 °C
Reaction time: 0.33 h

Procedure:
To a solution of diisopropylamine (0.963 ml, 6.76 mmol) in THF (45 ml) at −78° C. was added n-butyllithium (2.5M in hexanes, 2.5 mL, 6.24 mmol). The reaction mixture was stirred for 15 minutes, at which time 3-bromo-5-chloropyridine (CAS#73583-39-8, 1.0 g, 5.20 mmol) in THF (10.0 mL) was added followed by a 1.5 mL THF wash. After 10 minutes methyl chloroformate (0.443 ml, 5.72 mmol) was added. The reaction was stirred for 20 minutes and then quenched at −78° C. with 5% AcOH in MeOH. The reaction was then diluted with saturated aqueous ammonium chloride and placed at room temperature. The reaction was then diluted with DCM and saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting ester was used without further purification. To a solution of lithium aluminum hydride (109 mg, 2.87 mmol) in THF (30 ml) at −78° C. was added a solution of the ester prepared above (450 mg, 1.797 mmol) in THF (7.0 mL). The reaction was permitted to warm to −30° C. and stirred for 45 minutes. The reaction was then quenched with 0.9 mL of a 9:1 THF/H2O solution followed by 2 N NaOH (0.3 mL). The reaction was placed at rt and water (1.0 mL) was added followed by THF (9 mL). The reaction was stirred for 5 minutes and then charged with magnesium sulfate (ca. 1.0 g). The resulting mixture was filtered through a pad of Celite® and the filtrate was concentrated. The resulting residue was purified by silica gel flash chromatography (ethanol-dichloromethane, 0 to 7%) to afford (3-bromo-5-chloro-pyridin-4-yl)-methanol; 1H NMR (400 MHz, CDCl3) δ ppm 4.94 (s, 2H), 8.52 (s, 1H), 8.62 (s, 1H).