Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:31]=[CH:30][C:29]([C:32](=O)[CH2:33]Br)=[CH:28][C:10]=1[C:11]([NH:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([C:24]([F:27])([F:26])[F:25])[CH:15]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36]([NH2:39])(=[S:38])[CH3:37].C(=O)([O-])O.[Na+].C(O)C>O>[CH2:1]([O:8][C:9]1[CH:31]=[CH:30][C:29]([C:32]2[N:39]=[C:36]([CH3:37])[S:38][CH:33]=2)=[CH:28][C:10]=1[C:11]([NH:13][C:14]1[CH:19]=[C:18]([C:20]([F:22])([F:23])[F:21])[CH:17]=[C:16]([C:24]([F:27])([F:25])[F:26])[CH:15]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(N)=S
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1nc(-c2ccc(OCc3ccccc3)c(C(=O)Nc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2)cs1
Yield: 67.5 %

Procedure:
A mixture of 2-benzyloxy-5-(2-bromoacetyl)-N-[3,5-bis(trifluoromethyl)phenyl]benzamide (280 mg, 0.5 mmol), thioacetamide (41 mg, 0.55 mmol), sodium hydrogen carbonate (50 mg, 0.6 mmol) and ethanol (15 mL) was refluxed for 1 hour. The reaction mixture was poured into water, neutralized by sodium hydrogen carbonate, and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (hexane:ethyl acetate=4:1) to give the title compound (181 mg, 67.5%) as a white solid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11](=S)[S-:12].C([NH+](CC)CC)C.C(N(CC)CC)C.C(Cl)(=O)OCC>C(Cl)(Cl)Cl>[F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[N:10]=[C:11]=[S:12]
Reactant: Fc1ccc(NC(=S)[S-])c(F)c1F
Agent: CCOC(=O)Cl
Agent: CC[NH+](CC)CC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Fc1ccc(N=C=S)c(F)c1F
Reaction time: 1 h
Yield: 78.3 %

Procedure:
Triethylammonium N-(2,3,4-trifluorophenyl)dithiocarbamate (92.0 g) and triethylamine (31.5 g) were added to chloroform (360 ml) and thereto ethyl chlorocarbonate (33.8 g) was added dropwise at 2°-6° C. with stirring over a period of 1 hour. The mixture was stirred for 10 minutes and washed with 3N hydrochloric acid and then with water. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The obtained residue ws purified by silica-gel column chromatography (Silica gel 60, 230-400 mesh, made by Merck Co., 220 g, eluent: hexane) under medium pressure, followed by distillation under reduced pressure to give the title compound (42.0 g) as colorless liquid, b.p.: 96°-97° C./17 mmHg.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:10][C:11]2[C:12]([CH3:18])=[N:13][N:14]([CH3:17])[C:15]=2[CH3:16])[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[OH:19]S(O)(=O)=O.[OH-].[Na+]>O>[Br:1][C:2]1[CH:3]=[C:4]([O:10][C:11]2[C:12]([CH3:18])=[N:13][N:14]([CH3:17])[C:15]=2[CH3:16])[C:5]([C:8]([NH2:9])=[O:19])=[N:6][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1nn(C)c(C)c1Oc1cc(Br)cnc1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nn(C)c(C)c1Oc1cc(Br)cnc1C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A flask was charged with 5-bromo-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)picolinonitrile (7.0 g, 23 mmol) and H2SO4 (56 g, 570 mmol) and the reaction was stirred at ambient temperature overnight. The reaction was cooled in an ice bath and water (100 mL) was carefully added. 40% NaOH solution was slowly added till the pH was about 12. The mixture was extracted with ethyl acetate and dichloromethane, and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to afford 5-bromo-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)picolinamide (7.4 g, 23 mmol, 100% yield) as light yellow solid.
Reaction SMILES: [CH3:1][CH:2]1[C:6](=[O:7])[CH:5](C(OCC)=O)[C:4]2([CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[O:3]1.[OH-].[Na+]>>[CH3:1][CH:2]1[C:6](=[O:7])[CH2:5][C:4]2([CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[O:3]1
Reactant: CCOC(=O)C1C(=O)C(C)OC12CCN(C)CC2
Agent: [Na+]
Agent: [OH-]
Product: CC1OC2(CCN(C)CC2)CC1=O
Temperature: 25 °C
Yield: 81.4 %

Procedure:
Ethyl 2,8-dimethyl-3-oxo-1-oxa-8-azaspiro[4,5]decane-4-carboxylate (3.08 g) was dissolved in 50 ml of 1N--HCL, and the solution was heated under reflux for eight hours. The reaction mixture was allowed to cool to room temperature, then cooled in an ice-water bath, and basified by addition of 20% aqueous solution of caustic soda. This alkaline solution was extracted thrice with about 80 ml of chloroform, and the combined extract was washed with saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. Distilling off the solvent under reduced pressure from the dried solution left 2 g of yellow residue, which was purified by silica gel column chromatography by using, as eluent, a mixed solvent of chloroform/methanol (20:1 by volume), giving 1.8 g of 2,8-dimethyl-1-oxa-8-azaspiro[4,5]decan-3-one as oil. It was dissolved in ether, and ethanolic hydrogen chloride was added thus giving its hydrochloride as crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][N:12]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-])=O)[CH:19]=2)=[C:16]([Cl:27])[N:15]=[C:14]([Cl:28])[C:13]1=[O:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCOC(C)=O.Cl>CCO.[Fe]>[ClH:27].[CH2:1]([O:8][C:9]([CH2:11][N:12]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=2)=[C:16]([Cl:27])[N:15]=[C:14]([Cl:28])[C:13]1=[O:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cn1c(-c2cccc([N+](=O)[O-])c2)c(Cl)nc(Cl)c1=O)OCc1ccccc1
Agent: [Fe]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1cccc(-c2c(Cl)nc(Cl)c(=O)n2CC(=O)OCc2ccccc2)c1
Temperature: 75 °C
Reaction time: 0.67 h
Yield: 80 %

Procedure:
By following the method of Example 1 and substituting 3-nitrobenzaldehyde for benzaldehyde, 1-benzyloxycarbonylmethyl-3,5-dichloro-6-(3-nitrophenyl)pyrazinone (EX-100A) was obtained. The pyrazinone, 1-benzyloxycarbonylmethyl-3,5-dichloro-6-(3-nitrophenyl)pyrazinone (EX-100A), (15.01 g, 34.6 mmol) was taken up in 325 mL of 50% EtOH (w/w) and heated to 75° C. EtOAc was added until the solution was homogeneous (about 80 mL). Iron powder (9.4 g, 168 mmol) was added, followed by 0.57 mL of 12 M HCl (6.8 mmol) in about 0.6 mL of 50% EtOH. The reaction was monitored by TLC (80% EtOAc/hexanes) and was complete within 40 minutes. The reaction mixture was cooled to room temperature, and the iron was removed by filtration through Celite. The yellow solution was diluted with 600 mL of EtOAc and 300 mL of water. Saturated NaCl was added to help separate the layers. The organic phase was washed with saturated NaHCO3 (2×250 mL), saturated NaCl (1×250 mL), dried over MgSO4, filtered, and the solvents were removed under reduced pressure. The residue was taken up in 20-25 mL of 3.4 M HCl in EtOAc. Additional EtOAc (about 25 mL) was added, and the mixture was heated to dissolve all of the compound. The volatile components were removed under reduced pressure. The residue (crusty solid) was taken up in EtOAc and slowly dripped into hexanes. The pale yellow solid that precipitated was filtered and dried under vacuum at room temperature to yield 12.19 g (80% yield) of 1-benzyloxycarbonylmethyl-3,5-dichloro-6-(3-aminophenyl)pyrazinone hydrochloride (EX-100B) as a pale yellow solid: 1H NMR (300 MHz, CD3OD) δ 4.61 (AB q, 2H, J=17 Hz), 5.20 (AB q, 2H, J=12 Hz), 7.31-7.51 (m, 7H), 7.63-7.67 (m, 2H); HPLC purity (retention time): 91% (3.0 min); LRMS m/z 404 (M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.S(Cl)(Cl)=O.[NH2:15][C:16]1[S:17][C:18]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[C:19]([C:21]2[O:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:15][C:16]2[S:17][C:18]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)=[C:19]([C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)=[O:7])[CH:8]=[CH:9][N:10]=1
Reactant: O=C(O)c1ccnc(Cl)c1
Reactant: Nc1nc(-c2ccco2)c(N2CCOCC2)s1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: O=C(Nc1nc(-c2ccco2)c(N2CCOCC2)s1)c1ccnc(Cl)c1
Yield: 66 %

Procedure:
2-Chloroisonicotinic acid (5.00 g, 31.7 mmol) was added to thionyl chloride (40 mL), followed by stirring under heating and reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in dichloromethane (1 mL). The resulting solution was added to a pyridine (16 ml) solution of 2-amino-4-(2-furyl)-5-morpholinothiazole (880 mg, 5.00 mmol) obtained in Step 1 of Example 29, and then N,N-dimethylaminopyridine (48.8 mmol, 0.400 mmol) was added thereto, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=1:3 to ethyl acetate) to afford the entitled Compound 39 (1.05.g, 66%)
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6](Cl)=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][C:9]=2[Cl:22])=[O:4].[CH2:24]([NH:26][CH3:27])[CH3:25]>>[Cl:21][C:11]1[CH:12]=[C:13]2[C:8](=[C:9]([Cl:22])[CH:10]=1)[N:7]=[C:6]([N:26]([CH2:24][CH3:25])[CH3:27])[C:5]([C:3]([OH:2])=[O:4])=[C:14]2[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCNC
Reactant: COC(=O)c1c(Cl)nc2c(Cl)cc(Cl)cc2c1-c1ccccc1
Product: CCN(C)c1nc2c(Cl)cc(Cl)cc2c(-c2ccccc2)c1C(=O)O

Procedure:
The title compound was prepared in analogy to example 21 step D from 2,6,8-trichloro-4-phenyl-quinoline-3-carboxylic acid methyl ester (prepared as described in example 21 step C) and ethyl-methyl-amine. Brown foam. MS (ESI): 375.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[S:8][C:7]2=[N:9][C:10]([C:12]([F:15])([F:14])[F:13])=[CH:11][N:6]2[N:5]=1.[CH2:16]=[O:17].Cl.O>S1(CCCC1)(=O)=O>[CH3:1][O:2][CH2:3][C:4]1[S:8][C:7]2=[N:9][C:10]([C:12]([F:15])([F:13])[F:14])=[C:11]([CH2:16][OH:17])[N:6]2[N:5]=1
Reactant: C=O
Reactant: COCc1nn2cc(C(F)(F)F)nc2s1
Agent: Cl
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: COCc1nn2c(CO)c(C(F)(F)F)nc2s1
Temperature: 110 °C
Yield: 57.7 %

Procedure:
2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazole a2 (10 g, 42.16 mmol, 1 eq), formaldehyde (16 g, 421.6 mmol, 10 eq) and hydrochloric acid (37%, 8.2 ml, 2 eq) are diluted in sulfolane (250 ml). The reaction mixture is heated at 110° C. overnight. Water (500 ml) is added and the mixture is heated at 50° C. for 2 h. The solvent is then removed under reduced pressure. The residue is purified by chromatography over silicagel (gradient; eluent: CH2Cl2/MeOH/NH4OH from 100/0/0 to 99/1/0.1) to afford 6.5 g of [2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methanol a3 as a yellow solid.
Reaction SMILES: Br[C:2]1[C:7]2[N:8]([CH3:23])[C:9]([C@@H:11]([NH:13][C:14]3[N:22]=[CH:21][N:20]=[C:19]4[C:15]=3[N:16]=[CH:17][NH:18]4)[CH3:12])=[N:10][C:6]=2[CH:5]=[CH:4][C:3]=1[F:24].[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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>[F:24][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([C@@H:11]([NH:13][C:14]3[N:22]=[CH:21][N:20]=[C:19]4[C:15]=3[N:16]=[CH:17][NH:18]4)[CH3:12])[N:8]([CH3:23])[C:7]=2[C:2]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)c(Br)c2n1C
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)c(-c3ccccc3)c2n1C
Temperature: 140 °C
Yield: 74.5 %

Procedure:
A mixture of [(S)-1-(7-bromo-6-fluoro-1-methyl-1H-benzoimidazol-2-yl)ethyl]-(9H-purin-6-yl)amine, (0.10 g, 0.26 mmol), phenylboronic acid (0.041 g, 0.33 mmol), tetrakis(triphenylphosphine)palladium(0) (0.015 g, 0.01 mmol) and caesium carbonate (0.17 g, 0.51 mmol) in dioxane (3 mL) and water (1.5 mL) was placed in a sealed tube and degassed with nitrogen for 5 minutes, then heated for 45 minutes at 140° C. by microwave irradiation. The resulting mixture was loaded onto an Isolute® SCX-2 cartridge then washed with MeOH and the product eluted with 2M NH3/MeOH and concentrated in vacuo. The residue was purified by chromatography (SiO2, 0-10% (2M ammonia in methanol) in DCM) then by preparative HPLC (Phenomenex Gemini 5 μm C18 on a 78 min gradient 20-98% 0.1% HCO2H in acetonitrile/water). The relevant fractions were concentrated to approximately ⅓ volume and partitioned between DCM (3×) and saturated aqueous NaHCO3. The combined DCM extracts were dried (Na2SO4) and concentrated in vacuo to give 431 as a white solid (0.075 g, 76%). LCMS (Method K): RT 3.21 min [M+H]+ 388.0. 1H NMR (DMSO-d6, 400 MHz): δ 12.98 (1H, s), 8.26-8.11 (2H, m), 7.93-7.86 (1H, m), 7.64 (1H, dd, J=8.82, 4.74 Hz), 7.54-7.39 (5H, m), 7.15-7.08 (1H, m), 5.82-5.71 (1H, m), 3.21 (3H, s), 1.65 (3H, d, J=6.74 Hz). Signals split due to presence of tautomers
Reaction SMILES: [CH3:1][C@@H:2]1[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][CH:12]=1>>[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][N:4]2[C:3](=[O:8])[C@H:2]([CH3:1])[NH:6][C:5]2=[O:7])=[CH:13][CH:12]=1
Reactant: C[C@@H]1NC(=O)NC1=O
Reactant: COc1ccc(CCl)cc1
Product: COc1ccc(CN2C(=O)N[C@@H](C)C2=O)cc1

Procedure:
Using (S)-5-methylimidazolidine-2,4-dione (2.00 g) and 4-methoxybenzyl chloride (2.85 mL) and by the reaction and treatment in the same manner as in Preparation Example 51, the title compound (3.13 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][N:3]=1.[H-].[Na+].[CH3:12]I>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH3:12])=[CH:4][N:3]=1
Reactant: CI
Reactant: OCc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1ccc(Cl)nc1
Reaction time: 0.17 h
Yield: 80.1 %

Procedure:
To a solution of 2-chloro-5-hydroxymethylpyridine (1 g, 6.97 mmol) in THF (34.8 ml) was added sodium hydride (60% wt) (0.418 g, 10.45 mmol). The reaction was stirred for 10 minutes and treated with methyl iodide (0.653 ml, 10.45 mmol). The reaction was stirred at ambient temperature for 4 hrs. The reaction mixture was quenched with saturated NH4Cl and extracted with EtOAc. The organic portion was concentrated and purified in 10-40% EtOAc/Heptanes to give the title compound (880 mg, 5.58 mmol, 80% yield) as a tan solid. MS m/z=157.9 (M+H).
Reaction SMILES: Cl.[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=1.N>>[ClH:13].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@@H:5]3[NH:12][C:18](=[O:19])[C:17]3[CH:21]=[CH:22][C:14]([Cl:13])=[CH:15][CH:16]=3)[CH2:3]1)[CH2:9]2
Reactant: NC1C2CC3CC1CN(C3)C2
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1ccc(Cl)cc1

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and 4-chlorobenzoic acid (Aldrich) according to methods A and C; yield 49 mg, 0.17 mmol (63%): 1H NMR (300 MHz, methanol-d4) δ 1.96 (d, J=14 Hz, 2H), 2.20 (s, 1H), 2.32 (d, J=14 Hz, 2H), 2.46 (s, 2H), 3.57 (s, 2H), 3.67 (s, 4H), 4.39 (s, 1H), 7.49 (d, J=8 Hz, 2H), 7.83 (d, J=8 Hz, 2H); MS (DCI/NH3) m/z 291 (M+H)+; Anal. C16H19ClN2O.HCl: C, H, N.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][N:4]=[C:5]([NH2:18])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[N:11]=1.[CH3:21][O:22][C:23]1[C:26](=O)[C:25](=[O:28])[C:24]=1[O:29]C>CO>[F:20][C:2]([F:1])([F:19])[CH2:3][N:4]=[C:5]([NH2:18])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:26]2[C:25](=[O:28])[C:24](=[O:29])[C:23]=2[O:22][CH3:21])[N:11]=1
Reactant: NCCCCCc1csc(NC(N)=NCC(F)(F)F)n1
Reactant: COc1c(OC)c(=O)c1=O
Solvent: CO
Product: COc1c(NCCCCCc2csc(NC(N)=NCC(F)(F)F)n2)c(=O)c1=O
Yield: 40.6 %

Procedure:
To 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(5-aminopentyl)thiazole (0.4 g.) in methanol (1.5 ml.) was added 1,2-dimethoxycyclobutene-3,4-dione (0.2 g.). After 2.5 hours at room temperature the mixture was evaporated to dryness, and the residue purified by preparative thin layer chromatography using methanol/chloroform 1:9 v/v as developing solvent. The appropriate band was isolated to give 1-[5-(2-[2-(2,2,2-trifluoroethyl)guanidino]thiazol-4-yl)pentylamino]-2-methoxycyclobutene-3,4-dione (0.22 g.) which was dissolved in propargylamine (1 g.) and the mixture allowed to stand at room temperature overnight. The mixture was then evaporated to dryness, and the residue purified by preparative thin layer chromatography using chloroform/methanol/aqueous ammonia 90:10:1 v/v/v as developing solvent. The product from this purification was treated in methanol/acetone with excess maleic acid and the resulting salt precipitated by the addition of diethyl ether to give 1-[5-(2-[2-(2,2,2-trifluoroethyl)guanidino]-thiazol-4-yl)pentylamino]-2-propargylaminocyclobutene-3,4-dione hydrogen maleate. The n.m.r. spectrum in d6 dimethylsulphoxide using tetramethylsilane as internal standard (δ=0) included the following resonances (δ):-1.5 (multiplet, 6H); 3.3 (singlet, 1H); 3.5 (multiplet, 2H); 4.1 (quartet, 2H); 4.8 (quartet, 2H); 6.6 (singlet, 1H).
Reaction SMILES: [Cl-].[C:2]1([N+:8]2[C:13]([Cl:14])=[C:12]([Cl:15])[C:11]([NH2:16])=[CH:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17]C(N)=O.[OH-].[Na+]>>[Cl-:14].[C:2]1([N+:8]2[C:13]([NH2:17])=[C:12]([Cl:15])[C:11]([NH2:16])=[CH:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(N)=O
Reactant: Nc1cn[n+](-c2ccccc2)c(Cl)c1Cl
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Product: Nc1cn[n+](-c2ccccc2)c(N)c1Cl
Yield: 82.5 %

Procedure:
15 parts of 1-phenyl-4-amino-5,6-dichloropyridazinium chloride is slowly introduced into a melt of 50 parts of urea (temperature about 130°C). After fifteen minutes the melt is cooled and 150 parts of a 10% by weight caustic soda solution is added. A crystalline substance separates out (melting point 180° to 181°C after having been recrystallized from acetonitrile) which is dissolved in 50 parts of concentrated hydrochloric acid. The hydrochloric acid solution is evaporated and the oil which remains is caused to crystallize with a mixture of butyl acetate and alcohol. 11.5 parts (82.5% of theory) of 1-phenyl-4-amino-5-chloro-6-aminopyridazinium chloride is obtained; C10H10N4Cl2. The substance melts at above 300°C. The chlorine number is 27.9% (calculated 27.65%). The perchlorate melts at 160° to 163°C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].C(N(CC)CC)C.Cl[CH2:20][C:21](Cl)=[O:22].[H-].[Na+]>C1COCC1>[N+:8]([C:6]1[CH:5]=[CH:4][C:3]2[O:11][CH2:20][C:21](=[O:22])[NH:1][C:2]=2[CH:7]=1)([O-:10])=[O:9]
Reactant: O=C(Cl)CCl
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1COc2ccc([N+](=O)[O-])cc2N1
Yield: 39.6 %

Procedure:
Using 2-amino-4-nitrophenol (10 g, 65 mmol), triethylamine (11.7 mL, 84 mmol) and chloroacetyl chloride (5.4 mL, 68 mmol) in THF (150 mL) followed by sodium hydride (5.2 g of a 60% suspension in oil, 130 mmol) to yield the title compound as a grey solid (5 g, 33%). δH (DMSO-d6) 4.78 (2H, s), 7.15 (1H, d, J 8.9 Hz), 7.74 (1H, d, J 2.4 Hz), 7.84 (1H, dd, J 8.9, 2.6 Hz), 11.09 (1H, s).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:23][CH2:24][CH3:25])=[C:13]([C:15]2[CH:20]=[C:19]([NH2:21])[N:18]=[C:17]([NH2:22])[CH:16]=2)[CH:14]=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:23][CH2:24][CH3:25])=[C:13]([C:15]2[CH:16]=[C:17]([NH2:22])[N:18]=[C:19]([NH:21][C:30]3[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=3)[CH:20]=2)[CH:14]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCOc1ccc(Cl)cc1-c1cc(N)nc(N)c1
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ccc(Cl)cc1-c1cc(N)nc(Nc2ccc(Cl)cc2)c1
Yield: 30 %

Procedure:
Following the method described in Example 8, 4-(5-chloro-2-ethoxy-phenyl)-pyridine-2,6-diamine trifluoroacetic acid salt and 4-chloro-phenylboronic acid provided the title compound (30% yield). 1H NMR (acetone-d6) δ1.35 (t, 3H, J=7.0 Hz, CH3), 4.08 (q, 2H, J=7.0 Hz, CH2), 5.32 (bs, 2H, NH2), 6.21 (d, 1H, J=1H, J=1.2 Hz, Ar), 6.32 (t, 1H, J=1.1 Hz, Ar), 7.09 (d, 2H, J=8.6 Hz, Ar), 7.23 (d, 2H, J=8.9 Hz, Ar), 7.31-7.78 (m, 2H, Ar), 8.04 (s, 1H, NH).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15]S(C)(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:20][C:21]1[CH:26]=[C:25]([C:27]2[CH2:28][CH2:29][N:30]([S:33]([CH3:36])(=[O:35])=[O:34])[CH2:31][CH:32]=2)[CH:24]=[CH:23][C:22]=1O>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][O:15][C:22]2[CH:23]=[CH:24][C:25]([C:27]3[CH2:32][CH2:31][N:30]([S:33]([CH3:36])(=[O:35])=[O:34])[CH2:29][CH:28]=3)=[CH:26][C:21]=2[F:20])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Reactant: CS(=O)(=O)N1CC=C(c2ccc(O)c(F)c2)CC1
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(C3=CCN(S(C)(=O)=O)CC3)cc2F)CC1

Procedure:
Prepared essentially as Preparation 2 (step 2) using 4-methanesulfonyloxymethyl-piperidine-1-carboxylic acid tert-butyl ester and 2-fluoro-4-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-phenol as starting materials. MS (m/z) 414 (M−55).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH2:5]([SH:11])[C:6]1[O:10][CH:9]=[CH:8][CH:7]=1>>[CH3:2][C:1]([S:11][CH2:5][C:6]1[O:10][CH:9]=[CH:8][CH:7]=1)=[O:3]
Reactant: SCc1ccco1
Reactant: CC(=O)Cl
Product: CC(=O)SCc1ccco1

Procedure:
Furfurylthiol acetate was prepared by reacting acetic chloride or anhydride with furfurylmercaptan according to the method described in Houben-Weyl, 4th ed., vol. 9, 753 (1955). The product has a b.p. of 90°-92°C./12 mm. Hg.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][CH2:13][C:14](=[O:16])[CH3:15])[CH:7]=1)=[O:4].[OH:19][S:20]([Cl:23])(=O)=[O:21]>C(Cl)Cl>[O:16]=[C:14]([CH3:15])[CH2:13][CH2:12][C:8]1[CH:7]=[C:6]([NH:5][C:3](=[O:4])[C:2]([F:17])([F:18])[F:1])[CH:11]=[CH:10][C:9]=1[S:20]([Cl:23])(=[O:21])=[O:19]
Reactant: CC(=O)CCc1cccc(NC(=O)C(F)(F)F)c1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: CC(=O)CCc1cc(NC(=O)C(F)(F)F)ccc1S(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.4 %

Procedure:
To 2,2,2-trifluoro-N-(3-(3-oxobutyl)phenyl)acetamide (2 g, 8 mmol) was added HOSO2Cl (9 g, 77 mmol) dropwise at 0° C. The mixture was stirred at r.t. for 3 hrs. The reaction mixture was diluted with DCM and washed with water, the organics was dried over Na2SO4 and concentrated to give 2-(3-oxobutyl)-4-(2,2,2-trifluoroacetamido)benzene-1-sulfonyl chloride (1.5 g, yield 54%). 1H NMR: (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.76 (d, 1H), 7.70 (t, 1H), 7.63 (d, 1H), 3.31 (t, 2H), 2.82 (t, 2H), 2.14 (s, 3H).