Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[CH:6]2.[C:13]1([CH3:22])[CH:18]=[CH:17][C:16]([C:19](Cl)=[O:20])=[CH:15][CH:14]=1.[Cl-].[Cl-].[NH4+]>ClCCl.[Cl-].[Zn+2].[Cl-]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[C:6]2[C:19]([C:16]1[CH:17]=[CH:18][C:13]([CH3:22])=[CH:14][CH:15]=1)=[O:20]
Reactant: COc1ccc2[nH]c(C)cc2c1
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn+2]
Solvent: ClCCl
Product: COc1ccc2[nH]c(C)c(C(=O)c3ccc(C)cc3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.9 %

Procedure:
To a solution of 5-methoxy-2-methylindole (816 mg, 5.06 mmol) in dichloromethane (15 ml) were added zinc chloride (1.52 g, 11.14 mmol) and ethyl magnesium bromide diethy ether (3.0 mol/l, 2.02 ml, 6.07 mmol) and the mixture was stirred for 1 hour at room temperature. Thereto was added p-toluoyl chloride (1.25 g, 8.10 mmol). After stirring for 1 hour, thereto was added alminium chloride (337 mg, 2.53 mmol) and the mixture was stirred at room temperature for 20 hours. To the reaction mixture was added an aqueous saturated ammonium chloride solution and the mixture was extracted with chloroform. The organic layer was washed with a saturated sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography and by recrystallization to give the subject compound (833 mg, 59%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)=[O:3].C(O[CH:19](OCC)[N:20]([CH3:22])[CH3:21])C>>[CH3:19][N:20]([CH3:22])[CH:21]=[CH:1][C:2]([C:4]1[CH:5]=[C:6]([O:14][CH3:15])[C:7]([O:12][CH3:13])=[C:8]([O:10][CH3:11])[CH:9]=1)=[O:3]
Reactant: CCOC(OCC)N(C)C
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Product: COc1cc(C(=O)C=CN(C)C)cc(OC)c1OC

Procedure:
0.5 g (2.38 mmol) of 3,4,5-trimethoxyacetophenone is stirred in 2.7 ml of dimethylformamide diethylacetal for 96 h at 110°. After cooling to 0°, filtering and drying, 3-dimethylamino-1-(3,4,5-trimethoxy-phenyl)-2-propen-1-one is obtained; 1H-NMR (DMSO): 2.9 (3H,s), 3.1 (3H,s), 3.7 (3H,s), 3.85 (6H,s), 5.83 (1H,d), 7.19 (2H,s), 7.7 (1H,d).
Reaction SMILES: [CH2:1]([C:3]1[C:11]([CH2:12][OH:13])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2]>O1CCCC1.O=[Mn]=O>[CH2:1]([C:3]1[C:11]([CH:12]=[O:13])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nn2ccccc2c1CO
Agent: O=[Mn]=O
Solvent: C1CCOC1
Product: CCc1nn2ccccc2c1C=O
Reaction time: 1.5 h
Yield: 98.3 %

Procedure:
To a solution of (2-ethyl-pyrazolo[1,5-a]pyridin-3-yl)-methanol (9.67 g, 54.9 mmol) in tetrahydrofuran (500 mL) was added MnO2 (23.88 g, 274.5 mmol, 85%, dried in oven at 120° C. for 16 h) and stirred at the reflux temperature for 1.5 h. The reaction mixture was filtered through a Celite pad, and concentrated under reduced pressure to give 9.4 g (98%) of product, which was used without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:12]=[C:11]([CH3:13])[C:10]([C:14]([OH:16])=O)=[CH:9][N:8]=1.[CH3:17][O:18][C:19]1[N:24]=[C:23]2[C:25]([CH3:29])=[CH:26][N:27]([NH2:28])[C:22]2=[CH:21][CH:20]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:17][O:18][C:19]1[N:24]=[C:23]2[C:25]([CH3:29])=[CH:26][N:27]([NH:28][C:14]([C:10]3[C:11]([CH3:13])=[N:12][C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[N:8][CH:9]=3)=[O:16])[C:22]2=[CH:21][CH:20]=1
Reactant: Cc1nc(-c2ccccn2)ncc1C(=O)O
Reactant: COc1ccc2c(n1)c(C)cn2N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(n1)c(C)cn2NC(=O)c1cnc(-c2ccccn2)nc1C
Yield: 46.6 %

Procedure:
A solution of 2-pyridin-2-yl-4-methyl-pyrimidine-5-carboxylic acid (1.69 mmol), 5-methoxy-3-methyl-pyrrolo[3,2-b]pyridin-1-ylamine (1.69 mmol), DIPEA (5.01 mmol) and HATU (2.03 mmol) in anhydrous DMF (8 mL) is stirred at 90° C. for 16 h. DMF is evaporated in vacuo. The residue is dissolved in EtOAc (40 mL), and washed with water (3×10 mL) and brine (10 mL). The organic layer is dried (Na2SO4), filtered, and concentrated in vacuo. The residue is purified by silica gel column chromatography eluting with 0-15% MeOH in DCM to afford 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (5-methoxy-3-methyl-pyrrolo[3,2-b]pyridin-1-yl)-amide (295 mg) as a solid. MS: 375 (M+H); 1H NMR (300 MHz, CD3OD): δ 2.40 (s, 3H), 2.84 (s, 3H), 4.02 (s, 3H), 6.70 (d, H), 7.13 (s, H), 7.41 (m, H), 7.50 (d, H), 7.85 (t, H), 8.51 (m, 2H), 8.78 (s, 2H), 10.57 (br, N—H).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2OC)[C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][CH:15]=O)=[CH:10][CH:9]=2)=[N:6][N:7]=1)[CH3:2].[OH-].[Na+].[C:27](OCC)(=[O:29])C.O>O1CCCC1.C1(C)C=CC=CC=1>[CH2:1]([C:3]1[N:4]([C:17]2[CH:18]=[CH:19][C:20]([O:29][CH3:27])=[CH:21][CH:22]=2)[C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][CH3:15])=[CH:10][CH:9]=2)=[N:6][N:7]=1)[CH3:2]
Reactant: CCOC(C)=O
Reactant: CCc1nnc(-c2ccc(NC=O)cc2)n1-c1ccccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1nnc(-c2ccc(NC)cc2)n1-c1ccc(OC)cc1
Temperature: 7 °C
Reaction time: 1 h

Procedure:
At ambient temperature, 30 g of the product of Step A were dissolved in 1,200 ml of tetrahydrofuran and the solution was cooled to 7° C. Then, 120 ml of 25% of diethyldihydroaluminate in toluene in 120 ml of tetrahydrofuran were added with stirring for 1 hour at 5°-7° C. After returning to ambient temperature, the mixture was stirred for 2 hours, then cooled again to 7° C. after which 120 ml of sodium hydroxide were added slowly with stirring. Then, the mixture was poured into a mixture of 3,600 ml of ethyl acetate and 600 ml of water. Aftering stirring, the aqueous phase was decanted, and the organic phase was washed with an aqueous solution of sodium hydroxide and then with sodium chloride. Each washing solution was extracted with ethyl acetate and the combined extracts were dried and concentrated to dryness to obtain 23.5 g of crude product which was purified by dissolving it at reflux in 220 ml of ethanol. By filtering hot, washing with refluxing ethanol, concentrating to 110 ml under ambient pressure, cooling, separating, washing with ethanol and drying at 60° C., 10.2 g of 4-[5-ethyl-4-(4-methoxyphenyl)-4H-1,2,4-triazol-3-yl]-N-methyl-benzenamine melting at 198.5° C. were obtained.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:14])[C:4]1[CH:9]=[CH:8][C:7]([S:10](=[O:13])(=[O:12])[NH2:11])=[CH:6][CH:5]=1.[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([C:28]2[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[N:31]=[C:30]([C:38](O)=O)[N:29]=2)[CH:21]=[CH:22][C:23]=1[C:24]([F:27])([F:26])[F:25])[CH3:16]>>[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([C:28]2[CH:33]=[C:32]([C:34]([F:36])([F:37])[F:35])[N:31]=[C:30]([C:38]3[O:1][N:2]=[C:3]([C:4]4[CH:9]=[CH:8][C:7]([S:10]([NH2:11])(=[O:12])=[O:13])=[CH:6][CH:5]=4)[N:14]=3)[N:29]=2)[CH:21]=[CH:22][C:23]=1[C:24]([F:25])([F:26])[F:27])[CH3:16]
Reactant: N=C(NO)c1ccc(S(N)(=O)=O)cc1
Reactant: CCOc1cc(-c2cc(C(F)(F)F)nc(C(=O)O)n2)ccc1C(F)(F)F
Product: CCOc1cc(-c2cc(C(F)(F)F)nc(-c3nc(-c4ccc(S(N)(=O)=O)cc4)no3)n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from N-hydroxy-4-sulfamoyl-benzamidine [CAS-No. 4476-10-2] (0.16 g, 0.75 mmol) and 4-(3-ethoxy-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine-2-carboxylic acid (example D.4) (0.19 g, 0.5 mmol) according to the general procedure V. Obtained as a light yellow solid (0.114 g, 41%). MS (ISP) 560.2 [(M+H)+]; mp 250.5° C.
Reaction SMILES: [ClH:1].[NH2:2][C:3]([NH2:5])=[NH:4].C[O-].[Na+].[OH:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:18]=[C:19]([N:21]2[CH:25]=[CH:24][CH:23]=[CH:22]2)[CH:20]=1)[C:14](OC)=[O:15].O>CN(C)C=O.CO>[ClH:1].[OH:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:18]=[C:19]([N:21]2[CH:22]=[CH:23][CH:24]=[CH:25]2)[CH:20]=1)[C:14]([N:4]=[C:3]([NH2:5])[NH2:2])=[O:15]
Reactant: COC(=O)c1cc(CO)cc(-n2cccc2)c1
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: NC(N)=NC(=O)c1cc(CO)cc(-n2cccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.1 %

Procedure:
To a solution of guanidine hydrochloride (62.1 g) in N,N-dimethylformamide (150 ml) was added 28% sodium methoxide in methanol (106 ml) under nitrogen. After being stirred for 30 minutes at room temperature, to the reaction mixture was added a solution of methyl 3-hydroxymethyl-5-(pyrrol-1-yl)benzoate (30.0 g) in N,N-dimethylformamide (150 ml). After being stirred for 21 hours at room temperature, the reaction mixture was poured into water (1.5 l) with stirring. The resulting precipitate was collected by filtration, washed with water and purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (10:1). The eluted fractions containing the desired product were collected and evaporated in vacuo. The residue was dissolved in ethanol (70 ml) and crystallized from slight excess 4N-hydrogen chloride-ethyl acetate. The crystalline was recrystallized from an aqueous ethanol to afford 2-[3-hydroxymethyl-5-(pyrrol-1-yl)benzoyl]guanidine hydrochloride (7.3 g).
Reaction SMILES: ClC1C=CC(C2OC3C=CC=CC=3C=2)=CC=1.COC1C=CC(S(Cl)(=O)=O)=CC=1.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[O:37][C:38]3[CH:55]=[CH:54][CH:53]=[CH:52][C:39]=3[C:40]=2[S:41]([C:44]2[CH:49]=[CH:48][C:47]([O:50]C)=[CH:46][CH:45]=2)(=[O:43])=[O:42])=[CH:32][CH:31]=1>>[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]2[O:37][C:38]3[CH:55]=[CH:54][CH:53]=[CH:52][C:39]=3[C:40]=2[S:41]([C:44]2[CH:49]=[CH:48][C:47]([OH:50])=[CH:46][CH:45]=2)(=[O:42])=[O:43])=[CH:34][CH:35]=1
Reactant: COc1ccc(S(=O)(=O)c2c(-c3ccc(Cl)cc3)oc3ccccc23)cc1
Agent: COc1ccc(S(=O)(=O)Cl)cc1
Agent: Clc1ccc(-c2cc3ccccc3o2)cc1
Product: O=S(=O)(c1ccc(O)cc1)c1c(-c2ccc(Cl)cc2)oc2ccccc12

Procedure:
Acylation of 2-(p-chlorophenyl)benzofuran with 4-methoxybenzenesulfonyl chloride as described in Example 1 followed by demethylation of the 2-(4-chlorophenyl)-3-(4-methoxyphenylsulfonyl)benzofuran thus formed also as described therein, gives 2-(4-chlorophenyl)-3-(4-hydroxyphenylsulfonyl)benzofuran.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][N:6]([CH3:8])[CH2:5][CH2:4][N:3]1[C:9]1[C:14]([F:15])=[C:13]([NH:16][NH2:17])[N:12]=[C:11]([CH3:18])[N:10]=1.C(N(C(C)C)CC)(C)C.[CH:28]1([CH2:33][C@H:34]([CH2:38][N:39]([CH:48]=[O:49])[O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:35](O)=[O:36])[CH2:32][CH2:31][CH2:30][CH2:29]1.C(O)(C)C.CN1CCOCC1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CN(C)C=O.CCOCC>[CH:28]1([CH2:33][C@@H:34]([C:35]([NH:17][NH:16][C:13]2[C:14]([F:15])=[C:9]([N:3]3[CH2:4][CH2:5][N:6]([CH3:8])[CH2:7][C@H:2]3[CH3:1])[N:10]=[C:11]([CH3:18])[N:12]=2)=[O:36])[CH2:38][N:39]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:48]=[O:49])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OCc1ccccc1
Reactant: Cc1nc(NN)c(F)c(N2CCN(C)C[C@H]2C)n1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)c(F)c(N2CCN(C)C[C@H]2C)n1
Reaction time: 8 h
Yield: 92 %

Procedure:
To a solution of 4-[(2R)-2,4-dimethyl-1-piperazinyl]-5-fluoro-6-hydrazino-2-methylpyrimidine (8.04 g, assumed 31.4 mmol) in N,N-dimethylformamide (125 mL) was added (2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoic acid diisopropylethylamine salt, isopropanol solvate (15.48 g, 31.3 mmol), N-methylmorpholine (17.21 mL, 156 mmol), 1-hydroxy-7-azabenzotriazole (5.11 g, 37.6 mmol), and EDC (7.20 g, 37.6 mmol). The solution was stirred overnight, and then diluted with Et2O (150 mL) and washed with water (2×100 mL). The combined aqueous phase was extracted with a fresh portion of Et2O (150 mL), and this organic phase was washed with water (75 mL). The total combined aqueous phase was extracted with another fresh portion of Et2O (150 mL), and this organic phase was washed with water (75 mL). The combined organic phase was diluted with DCM (100 mL), and dried over anhydrous Na2SO4. The mixture was filtered and concentrated in vacuo to give crude [(2R)-2-(cyclopentylmethyl)-3-(2-{6-[(2R)-2,4-dimethyl-1-piperazinyl]-5-fluoro-2-methyl-4-pyrimidinyl}hydrazino)-3-oxopropyl][(phenylmethyl)oxy]formamide (15.60 g, 28.8 mmol, 92% yield) as a light brown foam. LCMS: (M+H)+: 541.7.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH:18]([OH:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:22][C:23]([OH:25])=[O:24]>C1COCC1>[CH2:3]([N:10]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]1[O:20][CH2:22][C:23]([OH:25])=[O:24])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C1c2ccccc2C(O)N1Cc1ccccc1
Reactant: O=C(O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)COC1c2ccccc2C(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.2 %

Procedure:
To a suspension of sodium hydride (1.1 g, 38.5 mmol) in THF (30 mL) at room temperature was added a solution of compound 20 (2.0 g, 8.37 mmol) in THF (15 mL) and the resulting reaction mixture was allowed to stir at room temperature for 1 hour. Thereafter a solution of bromo acetic acid (2.68 g, 19.25 mmol) in THF (5 mL) was added dropwise and the resulting reaction mixture was allowed to stir at room temperature for 18 hours. The reaction mixture is poured onto water and extracted with ethyl ether (3×100 mL) and the combined ethyl ether extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. Chromatography (SiO2, 20 to 70% EtOAc-Hexanes eluant) provided 1.0 g of 22 as a clear oil (2.48 g, theoretical, 40% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:15]([N:17]([CH2:21][CH3:22])[CH2:18][CH2:19][NH2:20])[CH3:16]>>[CH2:15]([N:17]([CH2:21][CH3:22])[CH2:18][CH2:19][NH:20][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1)[CH3:16]
Reactant: Clc1ccc(Oc2ccccc2)cn1
Reactant: CCN(CC)CCN
Product: CCN(CC)CCNc1ccc(Oc2ccccc2)cn1

Procedure:
To a solution of 3.9 g 6-chloro-3-phenoxypyridine in 5 ml n-butnaol, is added 22 g β-diethylaminoethylamine and the solution is refluxed for 72 hours. The mixture is concentrated at reduced pressure. The residue is shaken with 500 ml dichloromethane and excess dilute sodium hydroxide. The organic phase is separated, dried and distilled; bp 115°-145° C./0.1 mm. The oil is chromatographed over 150 g basic alumina (Woelm, grade I) in toluene and eluted with 0.4% MeOH in toluene. The fractions containing pure product are combined, concentrated and distilled to give 6-(β-diethylaminoethylamino)-3-phenoxypyridine; bp 143°-145° C./0.1 mm.
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[CH:3]([OH:13])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1>CO.C(OCC)(=O)C.[Pd]>[CH3:14][CH:2]([CH:3]([OH:13])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)[CH3:1]
Reactant: Cc1ccc(/C=C/C(O)C(C)C)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc(CCC(O)C(C)C)cc1
Reaction time: 8 h
Yield: 91.6 %

Procedure:
To a solution of trans-4-methyl-1-p-tolyl-1-penten-3-ol (43.2 g, 0.227 mol) in methanol (35 mL) was added 2 micro-spoon of palladium, 10% on activated carbon and the reaction mixture was hydrogenated overnight at 40 psi. The solution was diluted with ethyl acetate, filtered over celite and evaporated to give 40 g of 2-methyl-5-(p-tolyl)-3-pentanol as a colorless oil and used without further purification in the next step (step g). 1H NMR (300 MHz; CDCl3): 0.90 (d, J=6.9 Hz, 6 H), 1.70 (m, 4 H), 2.31 (s, 3 H), 2.62 (m, 1 H), 2.78 (m, 1 H), 3.39 (m, 1 H), 7.09 (s, 4 H).
Reaction SMILES: ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.[NH2:29][C:30]1[C:35]([OH:36])=[C:34]([F:37])[C:33]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[C:32]([CH3:44])[C:31]=1[C:45]#[N:46].[O:47]1[CH:51]=[CH:50][CH:49]=[C:48]1[CH2:52][C:53](O)=O>C(#N)C>[F:37][C:34]1[C:33]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[C:32]([CH3:44])[C:31]([C:45]#[N:46])=[C:30]2[C:35]=1[O:36][C:53]([CH2:52][C:48]1[O:47][CH:51]=[CH:50][CH:49]=1)=[N:29]2
Reactant: O=C(O)Cc1ccco1
Reactant: Cc1c(C#N)c(N)c(O)c(F)c1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1c(-c2ccccc2)c(F)c2oc(Cc3ccco3)nc2c1C#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.5 %

Procedure:
With cooling with ice, 1-hydroxybenzotriazole (134 mg, 0.991 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (174 mg, 0.908 mmol) and triethylamine (127 μl, 0.980 mmol) were added to an acetonitrile (8 ml) solution of 4-amino-6-fluoro-5-hydroxy-2-methylbiphenyl-3-carbonitrile (I-41) (200 mg, 0.826 mmol) and 2-furylacetic acid (115 mg, 0.908 mmol), followed by stirring at room temperature for 16 hours. The reaction liquid was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, then concentrated under reduced pressure, and the resulting residue was dissolved in xylene (20 ml), then pyridinium p-toluenesulfonate (50 mg) was added, followed by heating under reflux in an oil bath at 160° C. for 1 hour. The reaction liquid was concentrated under reduced pressure, then the residue was dissolved in ethyl acetate, washed with saturated brine. After drying over anhydrous sodium sulfate, the insoluble matter was separated by filtration, and the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=4:1, v/v) to obtain the entitled compound (155 mg, 57%) as a pale yellow solid.
Reaction SMILES: [O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:33])[N:13]2[C:16](=[C:30]([OH:32])[CH3:31])[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34]1([CH3:44])[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1.C(N(CC)CC)C.O>CN(C)C=O>[O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:33])[N:13]2[C:16](=[C:30]([O:32][S:40]([C:37]2[CH:38]=[CH:39][C:34]([CH3:44])=[CH:35][CH:36]=2)(=[O:42])=[O:41])[CH3:31])[C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)=[O:18])[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(OS(=O)(=O)c1ccc(C)cc1)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21
Temperature: -70 °C
Yield: 51.6 %

Procedure:
To a solution of p-nitrobenzyl α-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-hydroxyethylidene)acetate (940 mg) in dimethylformamide containing 10% tetrahydrofuran (5 ml) is added toluene-p-sulfonyl chloride (456 mg). After cooling to -70° C, the solution is mixed with triethylamine (0.3 ml). The reaction mixture is allowed to warm slowly up to room temperature, poured into water, and extracted with ethyl acetate. The extract solution is washed with water, dried, and evaporated. The obtained residue is chromatographed over silica gel containing 10% water using benzene containing 5% ethyl acetate to give p-nitrobenzyl α-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-toluene-p-sulfonyloxyethylidene)acetate (644 mg).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].Br[CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=1[O:20][CH3:21]>O1CCCC1>[N:1]1([CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=2[O:20][CH3:21])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cn2ccnc2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0.39 g (5.8 mmol) of imidazole are dissolved in 50 mL of tetrahydrofuran and, after the addition of 305.6 mg (6.4 mmol) of sodium hydride (50% in oil), stirred for 10 minutes at ambient temperature. Then 1.5 g (5.8 mmol) of methyl 4-(bromomethyl)-3-methoxybenzoate are added and the mixture is stirred for a further 16 hours. The solvent is distilled off, decomposed with water and extracted with ethyl acetate. The combined organic extracts are dried and concentrated by evaporation. Yield: 1.4 g (99%); C13H14N2O3 (246.268); mass spectrum: (M+H)+=247
Reaction SMILES: Br[C:2]1[C:3]([C:21]([O:23][CH3:24])=[O:22])=[C:4]([NH:7][C:8](=[O:20])[CH2:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][CH:14]=[N:15]3)[S:5][CH:6]=1.[C:25]([Cu])#[N:26].CN[C@@H]1CCCC[C@H]1NC>CN(C=O)C>[C:25]([C:2]1[C:3]([C:21]([O:23][CH3:24])=[O:22])=[C:4]([NH:7][C:8](=[O:20])[CH2:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][CH:14]=[N:15]3)[S:5][CH:6]=1)#[N:26]
Reactant: N#C[Cu]
Reactant: COC(=O)c1c(Br)csc1NC(=O)Cc1cccc2ncccc12
Agent: CN[C@@H]1CCCC[C@H]1NC
Solvent: CN(C)C=O
Product: COC(=O)c1c(C#N)csc1NC(=O)Cc1cccc2ncccc12
Temperature: 150 °C

Procedure:
A 20 mL microwave vessel was charged with methyl 4-bromo-2-(2-(quinolin-5-yl)acetamido)thiophene-3-carboxylate (560 mg, 1.38 mmol), CuCN (540 mg, 6 mmol), DMF (8 mL), and (1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (300 uL). The reaction mixture was flushed with nitrogen and sealed under a teflon cap before being heated to 150° C. using microwave radiation for 0.5 h. The reaction mixture was concentrated under reduced pressure to give an oil that was partitioned between an organic layer of 10% iPrOH/chloroform and an aqueous layer saturated with sodium bicarbonate. The heterogeneous organic layer was filtered and concentrated under reduced pressure to give a green oil. The crude product was purified by column chromatography with 60-70% ethyl acetate/hexanes. Yield: 40 mg (8%). Method [1]: rt=1.401 min; MH+ 352.0.
Reaction SMILES: [F:1][CH:2]([F:27])[O:3][C:4]1[CH:26]=[CH:25][C:7]2[NH:8][C:9](C3C([N+]([O-])=O)=CN(C4CCCCO4)N=3)=[N:10][C:6]=2[CH:5]=1.FC(F)OC1C=CC2NC([C:38]3[C:42]([NH2:43])=[CH:41][N:40]([CH:44]4[CH2:49][CH2:48][CH2:47][CH2:46][O:45]4)[N:39]=3)=NC=2C=1>>[F:27][CH:2]([F:1])[O:3][C:4]1[CH:26]=[CH:25][C:7]2[NH:8][C:9]([NH:43][C:42]3[CH:38]=[N:39][N:40]([CH:44]4[CH2:49][CH2:48][CH2:47][CH2:46][O:45]4)[CH:41]=3)=[N:10][C:6]=2[CH:5]=1
Reactant: O=[N+]([O-])c1cn(C2CCCCO2)nc1-c1nc2cc(OC(F)F)ccc2[nH]1
Reactant: Nc1cn(C2CCCCO2)nc1-c1nc2cc(OC(F)F)ccc2[nH]1
Product: FC(F)Oc1ccc2[nH]c(Nc3cnn(C4CCCCO4)c3)nc2c1

Procedure:
By proceeding in a manner similar to Reference Example 49(a) above but using 5-difluoromethoxy-2-[4-nitro-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-3-yl]-1H-benzoimidazole [Reference Example 50(e)], there was prepared 3-(5-difluoromethoxy-1H-benzoimidazol-2-yl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-4-ylamine (730 mg) as a pale brown solid. LC-MS (METHOD N): RT=3.27 minutes, 350.29 (M+H)+.
Reaction SMILES: [CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24]C)=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:2]([CH3:4])[CH3:3].[C:26]([O:30][C:31]([NH:33][C@H:34]([C:45]([OH:47])=O)[CH2:35][S:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[CH3:44][C:41]1[CH:40]=[CH:39][C:38]([CH2:37][S:36][CH2:35][C@H:34]([NH:33][C:31]([O:30][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:32])[C:45]([NH:11][CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]([N:5]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:1][CH:2]([CH3:4])[CH3:3])[C:12]([OH:14])=[O:13])=[O:47])=[CH:43][CH:42]=1
Reactant: Cc1ccc(CSC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: CCc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCN)C(=O)O)cc1
Product: Cc1ccc(CSC[C@H](NC(=O)OC(C)(C)C)C(=O)NCCCC[C@@H](C(=O)O)N(CC(C)C)S(=O)(=O)c2ccc(C)cc2)cc1

Procedure:
The title compound was prepared from Nα-isobutyl-Nα-(4-ethylbenzenesulfonyl)-L-ysine (100 mg, 0.29 mmol, example 1, step E) as described in general procedure Bc using commercially available Nα-tert-butoxycarbonyl-S-(4-methylbenzyl)-L-cysteine (67 mg, 0.3 mmol). The final product was triturated with ether to yield 130 mg (65%) of the desired material.