Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
6 g of Boc-Phe-PAM resin (substitution 0.36 mmol/g) was suspended and shaken in TFA/CH2Cl2 (1:1 by volume. 3×50 mL) 10 min. each time at room temperature to remove the Boc-group. The product was isolated by filtration and washed (3×50 mL each) with CH2Cl2 8% DIEA in CH2Cl2 and CH2Cl2 to give the free base of Phe-PAM-resin. This was subjected to sequential solid phase synthesis using the Fmoc-protocol. All couplings were performed using the DCC/HOBt procedure. At step 7 the Fmoc-amino acid, DCC, and HOBt were added with the corresponding reaction times as follows: Fmoc-Asp(OtBu)-OH (2.46 g, 6 mmol), DCC (1.24 g, 6 mmol) and HOBt (1.2 g, 9 mmol) were dissolved in 50 m5 of 1:1 by volume DMF/CH2Cl2, and allowed to couple for 60 min at room temperature. Fmoc-Met-OH (2.2 g, 6 mmol), DCC (1.24 g, 6 mmol) and HOBt (1.2 g, 9 mmol) were dissolved in 50 mL of 1:1 by volume DMF/CH2Cl2, and allowed to couple for 60 min at room temperature. Fmoc-Trp-OH (2.6 g, 6 mmol). DCC (1.24 g, 6 mmol) and HOBt (1.2 g, 9 mmol) were dissolved in 50 mL of 1:1 by volume DMF/CH2Cl2, and allowed to couple for 60 min at room temperature. Fmoc-Gly-OH (1.8 g, 6 mmol), DCC (1.24 g, 6 mmol) and HOBt (1.2 g, 9 mmol) were dissolved in 50 mL of 1:1 by volume DMF/CH2Cl2, and allowed to couple for 60 min. Fmoc-Met-OH (2.2 g, 6 mmol). DCC (1.24 g, 6 mmol) and HOBt (1.2 g, 9 mmol) were dissolved an 50 mL of 1:1 by volume DMF/CH2Cl2, and allowed to couple for 60 min at room temperature. At this point the peptide-resin was dried under high vacuum to provide 7.98 g of Fmoc-Met-Gly-Trp-Met-Asp(OtBu)-Phe-PAM resin.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=2)=[O:11])=[O:9])=[CH:4][CH:3]=1.[Cu](C#N)[C:20]#[N:21].[CH3:24][N:25](C=O)C>>[C:20]([C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:24]#[N:25])=[CH:14][CH:13]=2)=[O:11])=[O:9])=[CH:4][CH:3]=1)#[N:21]
Reactant: N#C[Cu]C#N
Reactant: CN(C)C=O
Reactant: O=C(C(=O)c1ccc(Br)cc1)c1ccc(Br)cc1
Product: N#Cc1ccc(C(=O)C(=O)c2ccc(C#N)cc2)cc1
Yield: 48 %

Procedure:
Here we have discovered that the compound can be easily synthesized from commercially available 4,4′-dibromobenzil. The reaction between 4,4′-dibromobenzil and copper cyanide in DMF at 165° C. yielded 4,4′-dicyanobenzil (JYC-I-097-A) as a yellow solid (1.36 g, 48%) after column chromatography. The scheme of the reaction is shown in FIG. 12.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)=O.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([I:19])=[CH:15][N:14]=1>C(#N)C>[OH:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:12]=[C:13]3[CH:18]=[CH:17][C:16]([I:19])=[CH:15][N:14]3[CH:2]=2)=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(O)cc1
Reactant: Nc1ccc(I)cn1
Solvent: CC#N
Product: Oc1ccc(-c2cn3cc(I)ccc3n2)cc1
Temperature: 110 °C
Yield: 78 %

Procedure:
441 mg (corresponding to 2.0 mmol) of 2-bromo-4′-hydroxyacetophenone and 449 mg (corresponding to 2.0 mmol) of 2-amino-5-iodopyridine were dissolved in 15 mL of acetonitrile. The resulting solution was refluxed in an oil bath at 110° C. for 5 hours. After the completion of the reaction, the reaction solution was cooled down to room temperature, and precipitates were filtered and recovered. The precipitates were washed with acetonitrile and dried under reduced pressure. The resulting crude crystals were suspended in a mixed solution of 10 mL of water and 10 mL of methanol. Then, about 10 mL of a saturated sodium hydrogencarbonate solution was added thereto, and the mixture was sonicated for 5 minutes using an ultrasonic washing machine. Precipitates were filtered and recovered from the resulting mixture, sufficiently washed with water, and dried under reduced pressure, to obtain 526 mg (corresponding to 1.56 mmol) of 2-(4′-hydroxyphenyl)-6-iodoimidazo[1,2-a]pyridine (FIG. 2-1, Step 2).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]1[C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([CH2:27][CH:28]=O)[N:22]=[CH:21]2.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO.CC(O)=O>[O:33]1[CH2:34][CH2:35][N:30]([CH2:28][CH2:27][N:23]2[C:24]3[C:20](=[CH:19][C:18]([N:3]4[CH:4]=[CH:5][C:6]([C:8]5[CH:9]=[CH:10][C:11]([C:14]([F:15])([F:17])[F:16])=[CH:12][CH:13]=5)=[CH:7][C:2]4=[O:1])=[CH:26][CH:25]=3)[CH:21]=[N:22]2)[CH2:31][CH2:32]1
Reactant: O=CCn1ncc2cc(-n3ccc(-c4ccc(C(F)(F)F)cc4)cc3=O)ccc21
Reactant: C1COCCN1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: O=c1cc(-c2ccc(C(F)(F)F)cc2)ccn1-c1ccc2c(cnn2CCN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 33.5 %

Procedure:
To a solution of 2-(5-(2-oxo-4-(4-(trifluoromethyl)phenyl)pyridin-1(2H)-yl)-1H-indazol-1-yl)acetaldehyde (84 mg, 0.21 mmol) in CH2Cl2 (4.0 mL), MeOH (1.0 mL) and AcOH (0.50 mL) was added morpholine (0.06 mL, 0.7 mmol) and picoline-borane complex (25 mg, 0.23 mmol). After stirring at ambient temperature under nitrogen atmosphere for 1.5 h, the solution was treated with 1 N HCl (10.0 mL) and stirred vigorously for 30 minutes. The mixture was made basic with saturated aqueous NaHCO3 (25 mL) and extracted with CH2Cl2 (3×25 mL). The organics were dried over Na2SO4, filtered and concentrated to dryness. Purification by flash chromatography (silica gel, CH2Cl2/MeOH, 97:3) gave the title compound (33 mg, 33%) as an off-white solid: 1H NMR (500 MHz, CDCl3) δ 8.14 (d, J=0.7 Hz, 1H), 7.95 (d, J=8.1 Hz, 2H), 7.85-7.77 (m, 5H), 7.48 (dd, J=8.9, 1.9 Hz, 1H), 6.95 (d, J=1.8 Hz, 1H), 6.85 (dd, J=7.1, 2.0 Hz, 1H), 4.63 (t, J=6.5 Hz, 2H), 3.64-3.62 (m, 4H), 2.91 (t, J=6.5 Hz, 2H), 2.54-2.52 (m, 4H); ESI MS m/z 469 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:6]3[C:11]([C:12]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1.C([Li])CCC.[I:33]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1.CO.C(OCC)(=O)C>[I:33][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:6]3[C:11]([C:12]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1
Reactant: II
Reactant: Brc1ccc2c(-c3ccccc3)c3ccccc3c(-c3ccccc3)c2c1
Agent: O=S([O-])([O-])=S
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: Ic1ccc2c(-c3ccccc3)c3ccccc3c(-c3ccccc3)c2c1
Temperature: -78 °C
Reaction time: 12 h
Yield: 90.4 %

Procedure:
Into a 500 mL three neck flask was put 10 g (24 mmol) of 2-bromo-9,10-diphenylanthracene, and the atmosphere in the flask was substituted with nitrogen. Then, 150 mL of tetrahydrofuran was added thereto and dissolved well. This solution was stirred at −78° C. Then, 19 mL of n-butyllithium solution (1.6 mmol/L) was dropped into this solution using a syringe, stirred at −78° C. for one hour, and reacted to precipitate a white solid substance. After the reaction, a solution in which 12 g (49 mmol) of iodine was dissolved into 80 mL of tetrahydrofuran was dropped into the reaction mixture using a funnel for dropping. After the dropping, this mixture was stirred at −78° C. for one hour and then at room temperature for 12 hours. After the reaction, a sodium thiosulfate solution was added to the reaction solution, followed by stirring at room temperature for one hour. Ethyl acetate was added to this mixture, followed by extraction. An organic layer was separated from an aqueous layer and washed with an aqueous solution of sodium thiosulfate and then a saturated saline solution in this order. An organic layer was separated from an aqueous layer and dried with magnesium sulfate. This mixture was suction filtered so that the magnesium sulfate was removed. The obtained filtrate was concentrated to give a solid substance. Methanol was added to this solid substance, followed by washing with ultrasonic wave irradiation, whereby a solid substance was precipitated. This solid substance was collected by suction filtration to give 9.9 g of a light yellow powdered solid substance in 90% yield.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.[C:28](O[BH-](OC(=O)C)OC(=O)C)(=[O:30])[CH3:29].[Na+].C(O)C=O.C(O)(=O)C.C(=O)(O)[O-].[Na+]>CN1CCCC1=O.C(Cl)Cl>[OH:30][CH2:28][CH2:29][N:25]1[CH2:24][CH2:23][N:22]([C:19]2[CH:18]=[CH:17][C:16]([NH:15]/[CH:14]=[C:5]3\[C:6](=[O:13])[NH:7][C:8](=[O:12])[C:9]4[C:4]\3=[CH:3][C:2]([I:1])=[CH:11][CH:10]=4)=[CH:21][CH:20]=2)[CH2:27][CH2:26]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=C1NC(=O)c2ccc(I)cc2/C1=C/Nc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])O
Agent: O=CCO
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: O=C1NC(=O)c2ccc(I)cc2/C1=C/Nc1ccc(N2CCN(CCO)CC2)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 83 %

Procedure:
(4Z)-6-Iodo-4-{[(4-piperazin-1-ylphenyl)amino]methylene}isoquinoline-1,3(2H,4H)-dione (47.4 mg, 0.1 mmol) is dissolved in N-methylpyrrolidinone (1 mL) and methylene chloride (0.3 mL), followed by addition of sodium triacetoxyborohydride (244 mg, 1.15 mmol), glycoaldehyde (155 mg, 2.58 mmol) and acetic acid (0.15 mL, 2.6 mmol). After stirring at room temperature for 40 min, methylene chloride and saturated sodium bicarbonate solution were added. The organic layer is separated and dried to give 43 mg (83%) of the title compound as a yellow solid. MS (ESI) m/z 519.2 (M+H)+1.
Reaction SMILES: [CH:1]1([CH2:4][S:5][C:6]2[N:10]=[CH:9][NH:8][N:7]=2)[CH2:3][CH2:2]1.[CH2:11]([N:13]([CH2:17][CH3:18])[C:14](Cl)=[O:15])[CH3:12].O>N1C=CC=CC=1>[CH2:11]([N:13]([CH2:17][CH3:18])[C:14]([N:8]1[CH:9]=[N:10][C:6]([S:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[N:7]1)=[O:15])[CH3:12]
Reactant: c1nc(SCC2CC2)n[nH]1
Reactant: CCN(CC)C(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCN(CC)C(=O)n1cnc(SCC2CC2)n1
Reaction time: 10 h
Yield: 83.5 %

Procedure:
To a solution of 3-cyclopropylmethylthio-1,2,4-triazole (3.8 g) in pyridine (30 ml), diethylcarbamoyl chloride (3.4 g) was added, and the resultant mixture was allowed to stand at room temperature for 10 hours. Water (250 ml) was added to the reaction mixture, which was then extracted with chloroform (150 ml) two times. The chloroform extract was washed with 1N hydrochloric acid (150 ml) two times and water (200 ml) one time, dried over magnesium sulfate, and concentrated under reduced pressure to give 5.2 g of 1-diethylcarbamoyl-3-cyclopropylmethylthio-1,2,4-triazole (Compound No. 1). Yield, 84%. M.P. 51°-52° C.
Reaction SMILES: [S:1]1[C:10]2[CH2:9][C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[NH:6][CH2:5][C:4]=2[CH:3]=[CH:2]1.[CH3:15][C:16]1[CH:33]=[CH:32][CH:31]=[CH:30][C:17]=1[C:18]([NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)=[O:19].C(N(CC)CC)C>C(Cl)Cl>[S:1]1[C:10]2[CH2:9][C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[N:6]([C:25]([C:24]3[CH:23]=[CH:22][C:21]([NH:20][C:18](=[O:19])[C:17]4[CH:30]=[CH:31][CH:32]=[CH:33][C:16]=4[CH3:15])=[CH:29][CH:28]=3)=[O:26])[CH2:5][C:4]=2[CH:3]=[CH:2]1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: c1ccc2c(c1)Cc1sccc1CN2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3ccsc3Cc3ccccc32)cc1
Yield: 62.3 %

Procedure:
A mixture of 400 mg of 4,10-dihydro-5H-thieno[3,2-c][1]benzazepine and 700 mg of 4-[(2-methylbenzoyl)amino]benzoyl chloride is stirred in 30 ml of methylene chloride in the presence of 3 ml of triethylamine for 8 hours. The volatiles are removed in vacuo to give a residue which is partitioned between chloroform and water. The organic layer is dried (Na2 SO4) and the filtrate evaporated in vacuo to give a residue which is purified by column chromatography on silica gel by elution with 30% ethyl acetate-hexane to give 543 mg of the desired product. M+1=439.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([C:19]2([CH3:22])[CH2:21][O:20]2)=[O:18])=[CH:12][C:11]=1[CH3:23]>>[F:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:18])[C:19]([OH:20])([CH3:21])[CH2:22][O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:12][C:11]=1[CH3:23]
Reactant: Oc1ccc(F)cc1
Reactant: Cc1cc(NC(=O)C2(C)CO2)ccc1F
Product: Cc1cc(NC(=O)C(C)(O)COc2ccc(F)cc2)ccc1F

Procedure:
N-(4-Fluoro-3-methylphenyl)-3-(4-fluorophenoxy)-2-hydroxy-2-methylpropionamide was prepared as described in Example 1c starting from 4-fluorophenol and 2-methyloxirane-2-carboxylic acid (4-fluoro-3-methylphenyl)amide. The crude product was purified by flash chromatography (dichloromethane-1.4% methanol).
Reaction SMILES: Cl[C:2]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:5]([C:6]([O:8][CH2:9][CH2:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:7])=[CH:4][C:3]=1[N+:22]([O-:24])=[O:23].[S:25]([O-:28])([O-:27])=[O:26].[Na+:29].[Na+].O.C(O)(C)C>C(#N)C>[CH:11]1([CH2:10][CH2:9][O:8][C:6]([C:5]2[CH:17]=[C:18]([N+:19]([O-:21])=[O:20])[C:2]([S:25]([O-:28])(=[O:27])=[O:26])=[C:3]([N+:22]([O-:24])=[O:23])[CH:4]=2)=[O:7])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[Na+:29]
Reactant: O=S([O-])[O-]
Reactant: O=C(OCCC1CCCCC1)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Solvent: CC#N
Product: O=C(OCCC1CCCCC1)c1cc([N+](=O)[O-])c(S(=O)(=O)[O-])c([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 90.7 %

Procedure:
50 parts of 2-cyclohexylethyl 4-chloro-3,5-dinitrobenzoate was dissolved in 157 parts of acetonitrile. To the solution was added dropwise the solution of 35.4 parts of sodium sulfite and 72 parts of water at room temperature. To the mixed solution 1965 parts of acetonitrile little by little, and then was added 500 parts of water to obtain uniform solution. The solution was heated to 80° C. and maintained the temperature with stirring for 3 hours. After checking the disapearance of 2-cyclohexylethyl 4-chloro-3,5-dinitrobenzoate by HPLC, the resulting solution was concentrated 80° C. under reduced pressure. To the concentrate was added 80 parts of methanol, and stirred for 30 minutes. The crystals precipitated were filtrated and washed with 40 parts of methanol, and the filtrate was concentrated at 80° C. to obtain yellow crystals. Further, to the crystals was added 400 ml of isopropanol and the mixture was subjected to azeotropic dehydration. The crystals were filtrated and washed with 200 ml of isopropanol, and dried to obtain 42.2 parts of sodium 4-(2-cyclohexylethoxycarbonyl)-2,6-dinitrobenzenesulfonate (Yield:90.7%, Yield:70%).
Reaction SMILES: C(OC1C=CC=CC=1N1CCCN(C[CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:31]=[C:30]3[C:25]([CH:26]=[CH:27][C:28](=[O:32])[NH:29]3)=[CH:24][CH:23]=2)CC1)C.[Br:33]CCCBr.C([O-])([O-])=O.[K+].[K+]>CCO.O>[Br:33][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:31]=[C:30]2[C:25]([CH:26]=[CH:27][C:28](=[O:32])[NH:29]2)=[CH:24][CH:23]=1
Reactant: CCOc1ccccc1N1CCCN(CCCCOc2ccc3ccc(=O)[nH]c3c2)CC1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=c1ccc2ccc(OCCCBr)cc2[nH]1
Yield: 54.6 %

Procedure:
A mixture of intermediate 14 (193 mg, 1.2 mmol), 1,3-dibromopropane (0.37 mL, 3.6 mmol) and anhydrous K2CO3 (166 mg, 1.2 mmol) was dissolved in EtOH and the solution was heated to reflux overnight. The solution was diluted with water and extracted with EtOAc. The combined organic layers were washed with saturated aq NaHCO3, brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel column (elution with PE/EtOAc=2:1) to give 7-(3-bromopropoxy)quinolin-2(1H)-one (intermediate 32) (185 mg, 55%) as a white solid.
Reaction SMILES: C(OC([N:8]1[C:13](=[O:14])[CH:12]2[CH:10]([CH:11]2[C:15]([O-:17])=[O:16])[CH:9]1[C:18]([O-:20])=[O:19])=O)(C)(C)C.Cl.[NH2:22][CH2:23][C:24]([O:26]CC)=[O:25].CCN(CC)CC>C1COCC1.[C-]#N.[K+]>[C:15]([CH:11]1[CH:12]([C:13]([NH:8][CH2:9][C:18]([OH:20])=[O:19])=[O:14])[CH:10]1[CH:23]([C:24]([OH:26])=[O:25])[NH2:22])([OH:17])=[O:16]
Reactant: CC(C)(C)OC(=O)N1C(=O)C2C(C(=O)[O-])C2C1C(=O)[O-]
Reactant: CCOC(=O)CN
Agent: Cl
Agent: [C-]#N
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NC(C(=O)O)C1C(C(=O)O)C1C(=O)NCC(=O)O
Reaction time: 8 h
Yield: 164.2 %

Procedure:
To a solution of ethyl (1SR, 2SR, 5RS, 6RS) 3-tert -butoxycarbonyl-4-oxo-3-azabicyclo[3.1.0]hexane-2,6-dicarboxylate (190 mg, 0.55 mmol) in dry THF (3.5 mL) under argon was added ethyl glycinate hydrochloride (466 mg, 3.34 mmol), potassium cyanide (1.7 mg, 0.02 mmol) and Et3N (0.44 mL, 3.34 mmol). After stirring overnight in an ultrasonic bath, the solvent was removed under reduced pressure. The residue was directly purified by flash chromatography (hexane/ethyl acetate 1/1) to give 235 mg of the desired compound (95% yield).
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[OH:26][CH2:27][CH:28]([NH:31][S:32]([C:35]1[S:39][C:38]([NH2:40])=[N:37][C:36]=1[CH3:41])(=[O:34])=[O:33])[CH2:29][OH:30]>>[OH:26][CH2:27][CH:28]([NH:31][S:32]([C:35]1[S:39][C:38]([NH:40][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=4)=[N:6][C:7]=23)=[O:14])=[N:37][C:36]=1[CH3:41])(=[O:34])=[O:33])[CH2:29][OH:30]
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Cc1nc(N)sc1S(=O)(=O)NC(CO)CO
Product: Cc1nc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)sc1S(=O)(=O)NC(CO)CO

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 2-amino-4-methyl-thiazole-5-sulfonic acid (2-hydroxy-1-hydroxymethyl-ethyl)-amide (example B.16) according to general procedure II. Light yellow solid. MS (ISP) 604.8 [(M−H)−]; mp 217° C.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C.[CH3:40][O:41][C:42](=[O:52])[CH:43]([NH2:51])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[I:50]>C1COCC1>[CH3:40][O:41][C:42](=[O:52])[CH:43]([NH:51][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[I:1])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[I:50]
Reactant: COC(=O)C(N)c1ccccc1I
Reactant: O=C(O)c1ccccc1I
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)C(NC(=O)c1ccccc1I)c1ccccc1I
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-iodobenzoic acid (6.4 g, 25.8 mmol) in THF (90 mL) is added HOBt (3.5 g, 25.8 mmol). After the mixture is stirred at RT for 10 min, EDCl (4.93 g, 25.8 mmol) is added followed by triethylamine (4.9 mL, 34.4 mmol). The mixture is stirred at RT for 40 min then amino-(2-iodophenyl)-acetic acid methyl ester (5.0 g, 17.2 mmol) is added and stirring is continued for 18 h. The solvent is removed under reduced pressure and water is added to the residue. The mixture is extracted with EtOAc and the organic phase is washed with brine and dried over magnesium sulfate. The solvent is removed under reduced pressure and the residue purified by flash chromatography using a gradient of 0-60% EtOAc/hexane as eluent to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17]3[CH:16]=[CH:15][C:14]4[CH2:18][CH2:19][CH2:20][CH2:21][C:13]=4[C:12]=3[NH:11][C:10](=[O:22])[C:9]2=[O:23])[CH:5]=[CH:6][CH:7]=1.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[O:22]=[C:10]1[NH:11][C:12]2[C:13]3[CH2:21][CH2:20][CH2:19][CH2:18][C:14]=3[CH:15]=[CH:16][C:17]=2[N:8]([C:4]2[CH:3]=[C:2]([NH:1][S:30]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:32])=[O:31])[CH:7]=[CH:6][CH:5]=2)[C:9]1=[O:23]
Reactant: Nc1cccc(-n2c(=O)c(=O)[nH]c3c4c(ccc32)CCCC4)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: O=c1[nH]c2c3c(ccc2n(-c2cccc(NS(=O)(=O)c4ccccc4)c2)c1=O)CCCC3
Yield: 54 %

Procedure:
4-(3-Aminophenyl)-1,4,7,8,9,10-hexahydrobenzo[f]quinoxaline-2,3-dione (50 mg, 0.145 mmol) and benzenesulfonyl chloride (38 mg, 0.218 mmol) were used in a process similar to Example 9 to give the titled compound (a white crystal, 35 mg, yield 54%).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].C(N(CC)CC)C.[Cl:12][C:13]1[N:18]=[C:17]([N:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20]2)[C:16]([CH3:29])=[C:15]([CH3:30])[N:14]=1>CN(C)C=O.ClCCl>[ClH:12].[CH3:29][C:16]1[C:17]([N:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20]2)=[N:18][C:13]([NH:4][CH2:1][CH2:2][CH3:3])=[N:14][C:15]=1[CH3:30]
Reactant: CCCN
Reactant: Cc1nc(Cl)nc(N2CCc3ccccc3C2)c1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCNc1nc(C)c(C)c(N2CCc3ccccc3C2)n1
Product: Cl
Temperature: 130 °C
Reaction time: 5 h

Procedure:
Propylamine(0.44 g, 5.4 mmol) and triethylamine(0.38 ml, 2.7 mmol) were added to a mixture solution of 2-chloro-5,6-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(0.5 g, 1.8 mmol) in dimethylformamide(10 ml). The reaction mixture was stirred for 5 hours at 130° C., cooled to a room temperature, diluted with dichloromethane, and then washed with aqueous sodium hydroxide and water. The separated organic layer was dried over anhydrous magnesium sulfate, concentrated under a reduced pressure, and then purified by column chromatography to give free base form of the titled compound. Ethyl ether saturated with hydrochloric acid was added to a mixture solution of the free base form of the titled compound in ethyl ether. The resulting solid was filtered and dried to obtain 490 mg of the titled compound.
Reaction SMILES: I[CH:2]1[CH:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH2:7][C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[NH:4][C:3]1=[O:21].[N-:22]=[N+:23]=[N-:24].[Na+]>CN(C)C=O.C(OCC)(=O)C>[N:22]([CH:2]1[CH:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH2:7][C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[NH:4][C:3]1=[O:21])=[N+:23]=[N-:24]
Reactant: COc1ccc(C2Cc3ccccc3NC(=O)C2I)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(C2Cc3ccccc3NC(=O)C2N=[N+]=[N-])cc1
Temperature: 60 °C
Yield: 69.9 %

Procedure:
A solution of 2,3,4,5-tetrahydro-3-iodo-4-(4-methoxyphenyl)-1H-1-benzazepin-2-one (270 mg, 0.687 mmol) in 2mL of dimethylformamide was treated with sodium azide (65 mg, 1.0 mmol, 1.5eq) and the mixture was heated at 60° C. in an oil bath for 14 hours. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried (MgSO4) and filtered. Removal of the solvent under vacuum followed by column chromatography on silica gel (eluant 2:1; hexane/ethyl acetate) gave 148 mg (70%) of the product as a single isomer. 1H NMR (400 MHz, CDCl3): 295 (dd; 7,14 Hz; 1H), 3.15 (dd; 13, 14 Hz; 1H), 3.75 (m, 1H), 3.80 (s, 3H), 4.11 (d, 7Hz, 1H), 6.89 (d, 8Hz, 2H), 7.04 (d, 8Hz, 1 H), 7.20-7.30 (m, 5H), 7.88 (br s, 1H). FAB-MS: calculated for C17H16N4O2 308; found 309 (40%).