Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][CH2:11][CH2:12][SH:13])[CH:6]=[CH:7][C:8]=1[Cl:9].[OH-].[K+].Br[CH2:17][C:18]([OH:20])=O.C(OC(=O)C)(=O)C>>[Cl:2][C:3]1[CH:4]=[C:5]([N:10]2[CH2:11][CH2:12][S:13][CH2:17][C:18]2=[O:20])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: O=C(O)CBr
Reactant: SCCNc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Product: O=C1CSCCN1c1ccc(Cl)c(Cl)c1
Temperature: 35 °C
Reaction time: 0.29 h
Yield: 56.7 %

Procedure:
A 3-necked 3 L round bottomed flask equipped with overhead stirrer, temperature probe, and nitrogen inlet was charged with 100 grams (0.387 mol) of 2-(3,4-dichloro-phenylamino)-ethanethiol hydrochloride and 1 L of 2B-ethanol. To the resulting suspension was charged 76 grams (1.35 mol, 3.5 equivalents) of potassium hydroxide. The addition resulted in a temperature increase to approximately 35° C. This suspension was stirred at room temperature for 15-20 minutes, then cooled to 5-10° C. and treated with a solution of 59.1 grams (0.425 mol, 1.1 equivalents) of bromoacetic acid in 152 mL of 2B-ethanol. After stirring at room temperature for approximately 3 hours, the reaction mixture was concentrated under vacuum to a volume of approximately 225 mL. To this suspension was added 864 mL (9.15 mol, 23.6 equivalents) of acetic anhydride with no external cooling which resulted in a temperature increase to approximately 100° C. The flask was fitted with a condenser and receiving flask, and heated to 105-110° C. at which point distillate began to be collected. With continued heating, the internal temperature rose to 115° C., the reaction flask was refitted with a reflux condenser and the reaction mixture held at reflux for 1 hour. After allowing to cool to room temperature, the reaction mixture was poured into a 3-necked 5 L round bottomed flask containing 1700 mL of water and 864 mL of methylene chloride and stirred for 10-20 minutes at 20-25° C. The layers were separated and the organic layer was washed with 1 L of water then treated with 2 L of 10% aqueous sodium hydroxide which brought the pH to 9-10. The layers were separated, the organic layer was dried over magnesium sulfate, and concentrated atmospherically to a volume of approximately 200 mL. Displacement of the methylene chloride by isopropyl ether was accomplished by continuing to charge isopropyl ether and concentrating until an internal temperature of 68° C. was attained. The solution was then cooled to room temperature. Solids began to precipitate at 45° C. The resulting slurry was stirred at room temperature for two hours. The solids were collected by filtration, washed with isopropyl ether and vacuum dried at 45-50° C. to yield 57.5 grams (56.7% yield) of the title compound as a white solid, mp 81-83° C. 1H NMR (CDCl3) δ7.44 (d, J=8.7 Hz, 1H), 7.38 (d, J=2.5 Hz, 1H), 7.13 (d, J=2.5 Hz, 1H), 3.93 (t, J=11.5 Hz, 2H), 3.43 (s, 2H), 3.01 (t, J=11.5 Hz, 2H). 13C NMR (CDCl3) δ168.10, 143.04, 134.201, 132.25, 132.09, 129.42, 126.83, 53.32, 31.81, 27.86. HRMS (FAB) calcd for C10H9Cl2NOS: 261.9860; found: 261.9839.
Reaction SMILES: CN(C)C=[N:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[CH:21]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)[CH:19]=[C:18]([CH3:32])[N:17]=3)[CH:11]=2)[N:9]=1.Cl.[OH-].[Na+]>C1COCC1>[CH3:32][C:18]1[N:17]=[C:16]([C:12]2[CH:11]=[C:10]([C:8]3[N:9]=[C:5]([NH2:4])[S:6][CH:7]=3)[CH:15]=[CH:14][CH:13]=2)[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][CH:23]=2)[CH:19]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3csc(N=CN(C)C)n3)c2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3csc(N)n3)c2)n1
Yield: 96.7 %

Procedure:
The above described N,N-dimethyl-N′-(4-{3-[6-methyl-4-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-phenyl}-thiazol-2-yl)-formamidine (880 mg, 1.886 mmol) was treated with 3 M HCl (20 mL) in THF (20 mL) at 50° C. for 16 h. Added 2 N NaOH until pH 10 was reached, extracted twice with EtOAc, dried combined organic layer over Na2SO4, filtered off and evaporated totally to give a crude product, which was triturated with ether to give the title compound (750 mg, 53%) as a white solid. MS (ISP) 412.2 [(M+H)+]; mp>250° C.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][O:8][CH2:9][CH2:10][O:11][CH3:12])[C:5]2[CH:13]=[C:14]([Cl:20])[C:15]([N+:17]([O-:19])=[O:18])=[CH:16][C:4]=2[N:3]=1.[CH2:21]([O:23][C:24]([C:26]1[CH:27]=[N:28][NH:29][CH:30]=1)=[O:25])[CH3:22].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:21]([O:23][C:24]([C:26]1[CH:27]=[N:28][N:29]([C:2]2[N:6]([CH2:7][O:8][CH2:9][CH2:10][O:11][CH3:12])[C:5]3[CH:13]=[C:14]([Cl:20])[C:15]([N+:17]([O-:19])=[O:18])=[CH:16][C:4]=3[N:3]=2)[CH:30]=1)=[O:25])[CH3:22]
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: COCCOCn1c(Cl)nc2cc([N+](=O)[O-])c(Cl)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(-c2nc3cc([N+](=O)[O-])c(Cl)cc3n2COCCOC)c1
Temperature: 60 °C
Yield: 99.4 %

Procedure:
To a solution of 2,6-dichloro-1-(2-methoxy-ethoxymethyl)-5-nitro-1H-benzoimidazole (6.15 g, 19.2 mmol), 1H-pyrazole-4-carboxylic acid ethyl ester (2.96 g, 21.1 mmol) and DMF (40 mL) was added cesium carbonate (12.5 g, 38.4 mmol) in a sealable pressure vessel. The vessel was purged with nitrogen, sealed, and heated at 60° C. for 2 h. The reaction mixture was poured into a 1:1 mixture of brine/water (80 mL), and was extracted with EtOAc (3×125 mL). The combined organic layers were washed with brine (3×125 mL), dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) (5-45% EtOAc/hexanes) to yield the titled compound (8.09 g, 98%) as a mixture of regioisomers. MS (ESI/CI): mass calcd. for C17H18ClN5O6, 423.1; m/z found, 424.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.93 (d, J=0.6 Hz, 1H), 8.28 (s, 1H), 8.22 (d, J=0.6 Hz, 1H), 7.83 (s, 1H), 6.26 (s, 2H), 4.37 (q, J=7.1 Hz, 2H), 3.73-3.67 (m, 2H), 3.49-3.44 (m, 2H), 3.29 (s, 3H), 1.39 (t, J=7.1 Hz, 3H).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][C:27]=1B(O)O>>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([O:32][C:33]([F:34])([F:35])[F:36])=[CH:30][C:31]=1[C:5]1[C:4]([C:3]([OH:2])=[O:24])=[CH:9][C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Reactant: OB(O)c1cc(OC(F)(F)F)ccc1Cl
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1cc(OC(F)(F)F)ccc1Cl
Yield: 1 %

Procedure:
Using the conditions of General Procedure A for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 111 mg, 0.25 mmol) was reacted 2-chloro-5-(trifluoromethoxy)phenylboronic acid (available from Frontier Scientific, Inc.; 120 mg, 0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2′-chloro-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-5′-trifluoromethoxy-biphenyl-2-carboxylic acid (1.3 mg, 1%). LCMS analysis indicated that the material was ˜100% pure, as measured by UV at 214 nm.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([NH2:17])=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]=1[CH3:11])=[O:5])[CH3:2].[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([NH:17][C:18](=[O:20])[CH3:19])=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(N)c(C(=O)OCC)c1C
Reactant: CC(=O)OC(C)=O
Product: CCOC(=O)c1sc(NC(C)=O)c(C(=O)OCC)c1C

Procedure:
A solution of 23.0 g. (0.09 mol) of 2,4-diethoxycarbonyl-3-methyl-5-aminothiophene in 250 ml. of acetic anhydride was heated to 100° C. for 1.5 hrs. The resulting mixture was cooled in an ice bath and the precipitated crystals were filtered to yield 2,4-diethoxycarbonyl-3-methyl-5-acetylamino-thiophene, m.p. 130°-131° C.
Reaction SMILES: CN(C=O)C.[Cl:6][C:7]1[CH:12]=[C:11]([OH:13])[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:8]=1[C:17]1[C:18](=[O:28])[N:19]([CH3:27])[C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:36]([CH3:42])[C:37]([O:39][CH2:40][CH3:41])=[O:38]>O>[Cl:6][C:7]1[CH:12]=[C:11]([O:13][CH:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH3:42])[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:8]=1[C:17]1[C:18](=[O:28])[N:19]([CH3:27])[C:20]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:22]=1
Reactant: Cn1c(C(F)(F)F)ccc(-c2cc([N+](=O)[O-])c(O)cc2Cl)c1=O
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)Oc1cc(Cl)c(-c2ccc(C(F)(F)F)n(C)c2=O)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 2 h
Yield: 60771136 %

Procedure:
To 10 ml of DMF, 0.8 g (2.2 mmol) of 3-(2-chloro-4-hydroxy-5-nitrophenyl)-1-methyl-6-trifluoromethyl-2(1H)-pyridone, 0.42 g (3.0 mmol) of potassium carbonate and 0.56 g (3.3 nmol) of ethyl 2-bromopropionate were added, followed by heating and stirring at 60° C. for 2 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The organic layer was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 0.90 g (yield: 94%) of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][NH:23][CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.[C:25]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:28])[CH:26]=[CH2:27].C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:24]=[N:23][N:22]([CH2:27][CH2:26][C:25]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:21]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:13])=[CH:4][CH:3]=1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cn[nH]c2)c2ccc(F)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)CCn1cc(-c2cn(S(=O)(=O)c3ccccc3)c3cc(F)ccc23)cn1
Temperature: 80 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
A mixture of 6-fluoro-1-(phenylsulfonyl)-3-(1H-pyrazol-4-yl)-1H-indole (Intermediate 5; 100 mg; 0.29 mmol), tert-butyl acrylate (77 mg; 0.60 mmol) and Cs2CO3 (293 mg; 0.90 mmol) in MeCN (10 mL) was stirring at 80° C. overnight under nitrogen. The reaction mixture was filtered to remove solid and concentrated to afford 112 mg (82%) of the title compound as a yellow solid, which was used directly without further purification.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([C:9]([F:12])([F:11])[F:10])[C:5]([F:13])=[C:4]([F:14])[C:3]=1[N:15]1[C:19]([NH:20][C:21]([CH2:23][OH:24])=[O:22])=[C:18]([N+:25]([O-:27])=[O:26])[CH:17]=[N:16]1.C(N(CC)CC)C.[CH3:35][NH:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[F:1][C:2]1[C:7]([F:8])=[C:6]([C:9]([F:12])([F:11])[F:10])[C:5]([F:13])=[C:4]([F:14])[C:3]=1[N:15]1[C:19]([NH:20][C:21]([CH2:23][O:24][S:37]([NH:36][CH3:35])(=[O:39])=[O:38])=[O:22])=[C:18]([N+:25]([O-:27])=[O:26])[CH:17]=[N:16]1
Reactant: CNS(=O)(=O)Cl
Reactant: O=C(CO)Nc1c([N+](=O)[O-])cnn1-c1c(F)c(F)c(C(F)(F)F)c(F)c1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNS(=O)(=O)OCC(=O)Nc1c([N+](=O)[O-])cnn1-c1c(F)c(F)c(C(F)(F)F)c(F)c1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 11.8 %

Procedure:
A stirred solution of 0.48 gram (0.0012 mole) of 1-(2,3,5,6-tetrafluoro-4-trifluoromethylphenyl)-5-hydroxymethylcarbonylamino-4-nitropyrazole and 0.27 gram (0.0027 mole) of triethylamine in 28.5 mL of methylene chloride was cooled in an ice-water bath. Methylaminosulfonyl chloride (0.55 gram, 0.0043 mole) was added dropwise, and the mixture was allowed to warm to room temperature and stir for four hours. The reaction mixture was filtered to remove a salt that had formed. The filtrate was extracted in succession with water, dilute hydrochloric acid, a saturated, aqueous sodium bicarbonate solution, and water. The organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure, leaving a brown oil. This oil was purified by column chromatography on silica gel, which was eluted with ethyl acetate: n-heptane (1:1) to yield an oil. This oil crystallized in methylene chloride and n-heptane to yield 0.07 gram of 1-(2,3,5,6-tetrafluoro-4-trifluoromethylphenyl)-5-methylaminosulfonyloxymethylcarbonylamino -4-nitropyrazole as an ivory-colored solid (Compound 21 of Table 1). The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.[CH3:8][Si:9]([CH3:16])([CH3:15])[CH2:10][CH2:11][O:12][CH2:13]Cl.O>C1COCC1>[NH:3]1[CH:7]=[CH:6][N:5]=[C:4]1[CH2:13][O:12][CH2:11][CH2:10][Si:9]([CH3:16])([CH3:15])[CH3:8]
Reactant: c1c[nH]cn1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCc1ncc[nH]1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 63.9 %

Procedure:
A stirred suspension of 1.2 grams of 60% sodium hydride (0.03 mole-in mineral oil) in 25 mL of THF was cooled to 0° C. to 5° C., and a solution of 2.0 grams (0.03 mole) of imidazole in 30 mL of THF was added dropwise. Upon completion of addition, the reaction mixture was stirred at 0° C. for an additional 15 minutes, then a solution of 4.7 grams (0.03 mole) of 2-(trimethylsilyl)ethoxymethyl chloride in 10 mL of THF was added dropwise. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature as it stirred during an 18 hour period. After this time, the reaction mixture was stirred with 50 mL of water, and the mixture was extracted with ethyl acetate. The extract was washed with an aqueous solution saturated with sodium chloride and was then dried with magnesium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure to a residual oil. The residue was distilled under reduced pressure, yielding 3.8 grams of the subject compound; bp 71° C./0.1 torr. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=2)[CH2:3]1.N1C=CC=CC=1.[C:30]1([S:36](Cl)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:13])[F:14])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:17]=[C:18]([NH:22][S:36]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)(=[O:38])=[O:37])[CH:19]=[CH:20][CH:21]=2)[CH2:3]1
Reactant: CC1(C)CC(c2cccc(N)c2)Nc2ccc(C(F)(F)F)cc21
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)CC(c2cccc(NS(=O)(=O)c3ccccc3)c2)Nc2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.2 %

Procedure:
To a stirred solution of 3-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (100 mg, 0.31 mmol) in pyridine (49 mg, 0.62 mmol) and dichloromethane (1.5 mL) at 0° C. was added dropwise a solution of benzenesulfonyl chloride (66 mg, 0.37 mmol) in dichloromethane (0.5 mL). The mixture was stirred at room temperature overnight. The mixture was quenched with water (5 mL) and extracted with dichloromethane (5 mL×2). The combined organic layers were dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography on silica gel to afford N-[3-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-benzenesulfonamide (113 mg, 79.3%) as a white solid. MS (ESI+APCI) M+1=461.1.
Reaction SMILES: C(=O)([O-])O.[Na+].CS(C)=O.Cl.[NH2:11][OH:12].[CH2:13]([C:17]1[N:18]=[C:19]([CH3:45])[N:20]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=2[C:32]#[N:33])=[N:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]>O>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:45])[N:20]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=2[C:32](=[N:11][OH:12])[NH2:33])=[N:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1nc(C)n(-c2ccccn2)c(=O)c1Cc1ccc(-c2ccccc2C#N)nc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCc1nc(C)n(-c2ccccn2)c(=O)c1Cc1ccc(-c2ccccc2C(N)=NO)nc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
Process 2: Sodium hydrogen carbonate (2.02 mg, 24.0 mmol) was added to dimethyl sulfoxide solution (20 mL) of hydroxylamine hydrochloride (1.42 g, 20.4 mmol) and stirred for 1 hour at 40° C. Dimethyl sulfoxide solution (3 mL) of 2-{5-{[4-butyl-2-methyl-6-oxo-1-(pyridin-2-yl)-1,6-dihydropyrimidin-5-yl]methyl}pyridin-2-yl}benzonitrile (430 mg, 0.987 mmol) was added to the reaction mixture and stirred for 19 hours at 90° C. The reaction mixture was added water and extracted with ethyl acetate. The organic layer was combined, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residues were subjected to silica gel column chromatography (ethyl acetate) to give 2-{5-{[4-butyl-2-methyl-6-oxo-1-(pyridin-2-yl)-1,6-dihydropyrimidin-5-yl]methyl}pyridin-2-yl}-N′-hydroxybenzimidamide (430 mg, 93%) as a white solid.
Reaction SMILES: C(O)(C(F)(F)F)=O.C([O:12][C:13]([C:15]([C:40]([O:42]C(C)(C)C)=[O:41])([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH:38]=[CH2:39])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:14])(C)(C)C>C(Cl)Cl>[CH2:25]([C:26]([OH:28])=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][C:15]([C:40]([OH:42])=[O:41])([C:13]([OH:14])=[O:12])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH:38]=[CH2:39]
Reactant: C=CCCCCCCCCCC(CCCCCCCCCCC(=O)O)(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCCCCCCCCCC(CCCCCCCCCCC(=O)O)(C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
TFA (2 mL) is added to a compound from step 4 (0.022 mmol) and the reaction is stirred at r.t. for 1 hour. The mixture is diluted with DCM (10 mL) and concentrated. The material is taken up in EtOAc (10 mL) and washed with H2O (20 mL). The organic layer is dried over Na2SO4, filtered and concentrated. The crude material is dissolved in 1 mL MeOH and purified via MS-triggered HPLC (Sunfire 30×50 mm 5 um column ACN/H2O w/0.1% TFA 75 ml/min, 1.5 ml injection, 45-70% ACN over 3.5 min).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11]C2CCCCO2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:18][N:19]1[CH2:23][CH2:22][CH2:21][CH:20]1[CH2:24][CH2:25][OH:26].CC(C)([O-])C.[K+].C(O)(C)(C)C>C1(C)C=CC=CC=1>[CH3:18][N:19]1[CH2:23][CH2:22][CH2:21][CH:20]1[CH2:24][CH2:25][O:26][C:2]1[C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CN1CCCC1CCO
Reactant: Clc1ncccc1OCCOC1CCCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: CN1CCCC1CCOc1ncccc1OCCO
Temperature: 50 °C
Reaction time: 48 h
Yield: 53.8 %

Procedure:
A solution of 2-chloro-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]pyridine (from Example 4; 100 mg, 0.39 mmol), 1-methyl-2-pyrrolidineethanol (79 μl, 0.58 mmol) and 1.0 M potassium tert-butoxide in tert-butanol (0.8 mL, 0.80 mmol) in 4 mL of toluene was heated at 100° C. for 1 day. The organic phase was washed with 3×2 mL of water and 2 mL of brine. The organic phase was shaken at 50° C. with 4 mL of 2.0 M acetic acid for 2 days. The aqueous phase was washed with 3×3 mL of ethyl acetate, made basic by addition of potassium hydroxide, saturated with sodium chloride and extracted with 3×2 mL of ethyl acetate. The organic phase was dried (MgSO4) and concentrated under reduced pressure to give 55 mg (0.21 mmol, 53%) of the title compound as a colorless oil. LC-UV purity 95%. MS m/z 267 (M+1)+, calc. 267 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][N+:7]=1[O-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[NH3:26]>C(Cl)(Cl)Cl.O1CCOCC1>[NH2:26][C:6]1[N:7]=[C:2]([CH3:1])[N:3]=[N:4][C:5]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1nnc(-c2ccccc2)c[n+]1[O-]
Reactant: N
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: Cc1nnc(-c2ccccc2)c(N)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-methyl-6-phenyl-[1,2,4]triazine-4-oxide (3 g, 16 mmol) in chloroform (80 ml) was added p-toluenesulfonyl chloride (3.05 g, 16 mmol) and the mixture stirred under nitrogen at room temperature for 30 min. To this mixture was added aqueous ammonia (48 ml of 12%) and ammonia in dioxane (160 ml of a 0.5 M solution) and stirred at room temperature for 72 h. The organic layer was separated from the aqueous which was extracted with dichloromethane (2×20 ml), the combined organic layers dried over MgSO4 and evaporated in vacuo. The residue was purified by flash chromatography (SiO2; 20% EtOAc in hexanes) to afford the title compound (1.7 g). δH (400 MHz; d6-DMSO) 2.42 (3H, s), 6.50-7.40 (2H, vbs), 7.49-7.63 (5H, m). m/z (ES+) 187 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH:7]2[S:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])=[CH:4][CH:3]=1.F[C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1.C([O-])([O-])=O.[Cs+].[Cs+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.C(OCC)(=O)C>[O:12]=[C:10]1[NH:9][C:8](=[O:13])[CH:7]([CH2:6][C:5]2[CH:14]=[CH:15][C:2]([O:1][C:17]3[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=3)=[CH:3][CH:4]=2)[S:11]1
Reactant: O=Cc1ccc(F)cc1
Reactant: O=C1NC(=O)C(Cc2ccc(O)cc2)S1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(Oc2ccc(CC3SC(=O)NC3=O)cc2)cc1
Temperature: 100 °C
Yield: 65.6 %

Procedure:
To a solution of 52 (5.35 g, 24 mmol) in DMF (150 mL) was added 4-fluorobenzaldehyde (3.00 g, 24 mmol) and Cs2CO3 (20 g, 62 mmol) and the mixture was heated to 100° C. for 2 h. The mixture was poured over vigorously stirring 10% citric acid (200 mL) and ethyl acetate (200 mL). The organic layer was washed with water (300 mL), brine (300 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude product was triturated in hexanes-ethyl acetate (2:1) to yield a white solid (5.15 g, 65%). 1H NMR: (400 MHz, DMSO-d6): δ 12.07 (bs, 1H), 9.92 (s, 1H), 7.92 (d, J=8.8 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H), 7.12 (d, J=8.4 Hz, 2H), 7.09 (d, J=8.4 Hz, 2H) 4.94 (dd, J=8.4 and 4.4 Hz, 1H), 3.41 (dd, J=14.4 and 4.4 Hz, 1H), 3.17 (dd, J=14.4 and 9.2 Hz, 1H).
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]2[C:15]([CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=1.[CH3:24][O:25][C:26]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:27]=1[NH2:28].C(=O)([O-])O.[Na+]>CN1CCCC1=O>[CH3:24][O:25][C:26]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:27]=1[NH:28][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]2[C:15]([CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=1
Reactant: CCOC(=O)CCCn1c(Cl)nc2cccc(C(CC)CC)c21
Reactant: COc1ccc(N)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)CCCn1c(Nc2ccc(OC)cc2OC)nc2cccc(C(CC)CC)c21
Temperature: 110 °C
Reaction time: 14 h
Yield: 89.4 %

Procedure:
A mixture of ethyl 4-[2-chloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butanoate (475.2 mg, 1.41 mmol), 2,4-dimethoxyaniline (0.60 mL, 4.23 mmol) and 1-methyl-2-pyrrolidone (0.5 mL) was stirred at 110° C. for 14 hr. After cooling, the reaction mixture was neutralized with aqueous saturated sodium hydrogen carbonate and extracted with ethyl acetate (×3). The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-30% ethyl acetate/n-hexane gradient mixture to give the title compound as a brown solid (570.0 mg, 1.26 mmol, 89%).