Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:14][C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[CH:6]([CH2:15][CH3:16])[N:5]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26]C)=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:4]=2[CH:3]=1.[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:15]([CH:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[C:13]2[S:14][C:2]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:3][C:4]=2[N:5]1[S:17]([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH3:16]
Reactant: CCC1c2ccccc2-c2sc(Br)cc2N1S(=O)(=O)c1ccc(OC)cc1
Reactant: OB(O)c1ccccc1
Product: CCC1c2ccccc2-c2sc(-c3ccccc3)cc2N1S(=O)(=O)c1ccc(O)cc1
Yield: 38.6 %

Procedure:
Starting from 2-bromo-5-ethyl-4-[(4-methoxyphenyl)sulfonyl]-4,5-dihydrothieno[3,2-c]isoquinoline (1.02 g, 2.2 mmol) and substituting phenylboronic acid (0.35 g, 2.9 mmol) in place of 3-thiopheneboronic acid in Step 1, the title compound (0.38 g, 50%, m.p. ° C.) was synthesized in essentially the same manner as described in Example 8, Steps 1-2, for 4-[(5-ethyl-2-thien-3-ylthieno[3,2-c]isoquinolin-4(H)-yl)sulfonyl]phenol.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:13]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][C:37]=1B(O)O>>[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][C:37]=1[C:14]1[CH:15]=[C:10]([CH:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4]([OH:34])=[O:3])[CH:11]=[C:12]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=2)[CH:13]=1
Reactant: CCOC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: OB(O)c1cc(Cl)ccc1Cl
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cc(Cl)ccc2Cl)c1

Procedure:
The title compound was prepared from a Suzuki coupling of 4-Methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (intermediate Example 1g) with 2,5-dichloro-phenylboronic acid under the conditions described in Example 1; 1H NMR (400 MHz, MeOD) δ ppm 0.97-1.08 (m, 6H), 1.59 (dd, J=13.33, 6.72 Hz, 1H), 1.78 (dt, J=13.76, 6.94 Hz, 1H), 2.04 (dd, J=13.45, 7.34 Hz, 1H), 3.85 (t, J=7.70 Hz, 1H), 7.39-7.87 (m, 10H); Calcd for C25H21Cl2F302 (M+Na) 503.09, Found 503.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([Br:9])[CH:6]=[CH:5][CH:4]=1.[CH2:10]([N:17]=[C:18]=[O:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[Br:9][C:7]1[N:8]=[C:3]([N:2]([CH3:1])[C:18]([NH:17][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:19])[CH:4]=[CH:5][CH:6]=1
Reactant: CCCCCCCN=C=O
Reactant: CNc1cccc(Br)n1
Product: CCCCCCCNC(=O)N(C)c1cccc(Br)n1
Temperature: 100 °C
Yield: 71 %

Procedure:
2 g of 6-methylamino-2-brompyridine (prepared according to the procedure of Example 11, step a) are mixed with 3.0 mL of heptyl isocyanate. The mixture is heated for 12 hours at 100° C. The residue is chromatographed on silica gel (9/1 heptane/ethyl acetate). 2.45 g of 1-(6-bromopyrid-2-yl)-1-methyl-3-heptylurea are obtained. Yield=71%.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][N:4]=1)[NH2:2].[F:13][C:14]([F:29])([F:28])[C:15](=O)[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[Cl:26])=O.S(=O)(=O)(O)O>C(O)C(F)(F)F>[Cl:26][C:20]1[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:19]=1[C:17]1[N:1]([C:3]2[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:10])=[O:11])=[CH:5][N:4]=2)[N:2]=[C:15]([C:14]([F:29])([F:13])[F:28])[CH:16]=1
Reactant: CS(=O)(=O)c1ccc(NN)nc1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(Cl)cc1Cl
Agent: O=S(=O)(O)O
Solvent: OCC(F)(F)F
Product: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(Cl)cc2Cl)nc1
Temperature: 25 °C
Yield: 8.3 %

Procedure:
To a mixture of the 2-hydrazino-5-(methylsulfonyl)pyridine (106 mg, 4.05 mmol) and 4,4,4-trifluoro-1-(2,4-dichlorophenyl)-1,3-butanedione (105 mg, 3.68 mmol) in dry trifluoroethanol (6 ml) was added a catalytic amount of concentrated sulfuric acid (about 0.25 ml) and the mixture was refluxed overnight. The reaction mixture was cooled to room temperature, concentrated, and diluted with water (25 ml) and neutralized with saturated NaHCO3 to pH about 7 and then extracted with EtOAc (50ml×3). The organic layer was washed with brine (100 ml), dried (MgSO4) and concentrated to give the crude solid. The solid was purified by flash chromatography eluting with ethyl acetate/hexane (1/4) to give the desired product as a white solid (134 mg, 83% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([OH:14])=O)[CH2:11][CH2:10][CH2:9]2)=[C:4]([O:15][CH3:16])[CH:3]=1.[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][NH2:33])=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][CH2:32][NH:33][C:12]([C:8]2([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=3[O:15][CH3:16])[CH2:9][CH2:10][CH2:11]2)=[O:14])=[CH:29][CH:30]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: NCCc1ccc(OCc2ccccc2)cc1
Reactant: COc1cc(Cl)ccc1C1(C(=O)O)CCC1
Product: COc1cc(Cl)ccc1C1(C(=O)NCCc2ccc(OCc3ccccc3)cc2)CCC1

Procedure:
N-{2-[4-(Benzyloxy)phenyl]ethyl}-1-(4-chloro-2-methoxyphenyl)cyclobutanecarboxamide was prepared analogously to example 65 from 1-(4-chloro-2-methoxyphenyl)cyclobutanecarboxylic acid (3.45 g, 14.3 mmol) and 2-[4-(benzyloxy)phenyl]ethanamine (4.2 g, 15.92 mmol). Yield: 4.7 g (10.45 mmol, 66%).
Reaction SMILES: [Br:1]Br.[CH2:3]([S:19]([NH:22][C:23]1[CH:24]=[C:25]([C:29](=[O:31])[CH3:30])[CH:26]=[CH:27][CH:28]=1)(=[O:21])=[O:20])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(Cl)Cl>C(O)(=O)C>[CH2:3]([S:19]([NH:22][C:23]1[CH:24]=[C:25]([C:29](=[O:31])[CH2:30][Br:1])[CH:26]=[CH:27][CH:28]=1)(=[O:20])=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: BrBr
Reactant: CCCCCCCCCCCCCCCCS(=O)(=O)Nc1cccc(C(C)=O)c1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCS(=O)(=O)Nc1cccc(C(=O)CBr)c1

Procedure:
Bromine, 4.72 g (1.52 ml) was added to 25 g (0.059 M) of the product of Step A in 75 ml of glacial acetic acid at 70° C. Decolorization of bromine was instant. The reaction was followed by thin layer chromatography (CH2Cl2, silica gel) until the starting material was practically absent. The solid precipitated on cooling was collected by filtration, recrystallized from hexane to give 23.5 g of product (about 80% based on m-aminoacetophenone): mp 92°-5° C. Mass spectrum showed some dibrominated material.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][O:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[C:23](O)=[O:24].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C.Cl.[CH3:58][O:59][C:60]([C:62]1([NH2:67])[CH2:66][CH2:65][CH2:64][CH2:63]1)=[O:61]>CN(C=O)C>[CH3:58][O:59][C:60]([C:62]1([NH:67][C:23]([C:14]2[CH:15]=[CH:16][C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:13]=2[O:12][CH2:11][CH:2]2[O:1][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[O:4][CH2:3]2)=[O:24])[CH2:66][CH2:65][CH2:64][CH2:63]1)=[O:61]
Reactant: COC(=O)C1(N)CCCC1
Reactant: O=C(O)c1ccc2ccccc2c1OCC1COc2ccccc2O1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C1(NC(=O)c2ccc3ccccc3c2OCC2COc3ccccc3O2)CCCC1
Reaction time: 0.5 h
Yield: 89 %

Procedure:
To a solution of 84 mg 1-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-naphthalene-2-carboxylic acid in 1 ml abs. DMF under inert atmosphere 42 mg 1-hydroxybenzo-triazole and 60 mg 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 0.65 μl of N,N-diisopropylethylamine were added at 0° C. After 30 minutes at 0° C. 42 mg of 1-amino-cyclopentanecarboxylic acid methyl ester hydrochloride, followed by 0.65 μl of N,N-diisopropylethylamine were added. After 48 h at room temperature the reaction mixture was concentrated, the residue was taken up in ethyl acetate and washed with 2 M HCl, aqueous sodium carbonate solution (10%) and brine. The organic layer was dried over magnesium sulphate, and concentrated to yield 96 mg of 1-{[1-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-naphthalene-2-carbonyl]-amino}-cyclopentanecarboxylic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1([Cl:22])[CH2:4][CH:3]1[CH2:5][O:6][C:7]1[CH:15]=[C:14]2[C:10]([C:11]([C:17](=[N:19][OH:20])[CH3:18])=[N:12][N:13]2[CH3:16])=[CH:9][C:8]=1[F:21].[H-].[Na+].[CH3:25][O:26][C:27](=[O:40])[C:28]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38]Br)=[CH:29][O:30][CH3:31].C(O)(=O)C>CN(C)C=O>[CH3:25][O:26][C:27](=[O:40])[C:28]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38][O:20][N:19]=[C:17]([C:11]1[C:10]2[C:14](=[CH:15][C:7]([O:6][CH2:5][CH:3]3[CH2:4][C:2]3([Cl:1])[Cl:22])=[C:8]([F:21])[CH:9]=2)[N:13]([CH3:16])[N:12]=1)[CH3:18])=[CH:29][O:30][CH3:31]
Reactant: CC(=NO)c1nn(C)c2cc(OCC3CC3(Cl)Cl)c(F)cc12
Reactant: COC=C(C(=O)OC)c1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COC=C(C(=O)OC)c1ccccc1CON=C(C)c1nn(C)c2cc(OCC3CC3(Cl)Cl)c(F)cc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 0.9 g of 1-[6-(2,2-dichlorocyclopropylmethoxy)-5-fluoro-1-methyl-1H-indazol-3-yl]-ethanone oxime in 10 ml of N,N-dimethylformamide is added dropwise to a suspension of 0.2 g of sodium hydride in 15 ml of N,N-dimethylformamide and the reaction mixture is stirred at room temperature for 15 minutes. Then 1.04 g of 2-(α-bromo-o-tolyl)-3-methoxyacrylic acid methyl ester in 10 ml of N,N-dimethylformamide are added dropwise and the reaction mixture is stirred at room temperature for a further 3 hours. The mixture is then acidified with acetic acid and concentrated by evaporation in vacuo at approx. 50° C. The residue is dissolved in ethyl acetate and the solution is washed twice with water and once with saturated sodium chloride solution, dried with sodium sulfate and concentrated by evaporation in vacuo. Purification by flash chromatography (silica gel, ethyl acetate/hexane 1:1) yields the title compound having a melting point of 138-140° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][N:9]2[CH:13]=[CH:12][CH:11]=[CH:10]2)[C:5]([F:14])=[CH:4][N:3]=1.[NH2:15][C:16]1[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1>>[F:14][C:5]1[C:6]([NH:8][N:9]2[CH:13]=[CH:12][CH:11]=[CH:10]2)=[N:7][C:2]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)=[N:3][CH:4]=1
Reactant: Fc1cnc(Cl)nc1Nn1cccc1
Reactant: Nc1cccc(O)c1
Product: Oc1cccc(Nc2ncc(F)c(Nn3cccc3)n2)c1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N-(1H-pyrrol-1-yl)-4-pyrimidineamine was reacted with 3-aminophenol to produce 5-fluoro-N2-(3-hydroxyphenyl)-N4-(1H-pyrrol-1-yl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 10.68 (s, 1H), 9.04 (s, 1H), 9.00 (s, 1H), 8.08 (d, 1H, J=4.11 Hz), 7.01 (d, 1H, J=8.2 Hz), 6.84-6.75 (m, 4H), 6.22 (dd, 1H, J=1.2 and 8.2 Hz), 6.08 (t, 2H, J=2.3 Hz). LCMS: ret. time: 16.24 min.; purity: 94%; MS (m/e): 286 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5](Cl)=[O:6].[NH2:12][N:13]1[CH2:19][CH:18]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17]2[CH:27]=[C:28]([O:33][CH3:34])[C:29]([O:31][CH3:32])=[CH:30][C:16]=2[CH2:15][CH2:14]1.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([NH:12][N:13]1[CH2:19][CH:18]([O:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:17]2[CH:27]=[C:28]([O:33][CH3:34])[C:29]([O:31][CH3:32])=[CH:30][C:16]=2[CH2:15][CH2:14]1)=[O:6]
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Reactant: COc1cc2c(cc1OC)C(Oc1ccccc1)CN(N)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc2c(cc1OC)C(Oc1ccccc1)CN(NC(=O)c1cc(Cl)cc(Cl)c1)CC2
Reaction time: 1 h
Yield: 61.4 %

Procedure:
3,5-Dichlorobenzoyl chloride (1.7 g) was added to a solution of 3-amino-7,8-dimethoxy-1-phenoxy-2,3,4,5-tetrahydro-3-benzazepine (2.1 g) in 100 ml dichloromethane containing sodium bicarbonate (3 g). After one hour, the mixture was filtered and concentrated. The solid residue was eluted through silica with 10% ethyl acetate in dichloromethane to yield 2.4 g of light tan solid, mp 182°-184°. This solid was recrystallized from acetonitrile to yield 2 g of white crystals, mp 184°-185°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[C:10]1(=O)[O:15][C:13](=[O:14])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.C(N(CC)CC)C>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:5]2[C:13](=[O:14])[C:12]3=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]3[C:10]2=[O:15])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Cc1ccc(N)cc1F
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1ccc(N2C(=O)c3ccccc3C2=O)cc1F
Yield: 73.3 %

Procedure:
A mixture of 3-fluoro-4-methylaniline (12.5 g), phthalic anhydride (17.8 g), triethylamine (27.9 ml) and chloroform (100 ml) was heated under reflux for 6 days and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed successively with 2 N HCl and a saturated aqueous sodium chloride solution; the organic layer was then dried with anhydrous sodium sulfate and concentrated under reduced pressure. Subsequently, chloroform was added to the resulting residue and the insoluble matter was filtered off whereas the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, chloroform methanol=98:2) to give 18.7 g of the titled compound (yield, 73%).
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:24](=[O:25])[N:5]2[C:6]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)=[O:12])=[C:7]([OH:10])[CH2:8][S:9][C@H:4]12.C(N(CC)CC)C.NC(N)=O.[S:37]1[CH:41]=[CH:40][CH:39]=[C:38]1[CH2:42][C:43](Cl)=[O:44]>CC(C)=O>[S:37]1[CH:41]=[CH:40][CH:39]=[C:38]1[CH2:42][C:43]([NH:2][CH:3]1[C:24](=[O:25])[N:5]2[C:6]([C:11]([O:13][CH2:14][C:15]3[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=3)=[O:12])=[C:7]([OH:10])[CH2:8][S:9][C@H:4]12)=[O:44]
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Reactant: O=C(Cl)Cc1cccs1
Agent: Cl
Agent: NC(N)=O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Temperature: 25 °C

Procedure:
To a solution of 1.55 g. of p-nitrobenzyl 7-amino-3-hydroxy-3-cephem-4-carboxylate hydrochloride in 30 ml. of acetone containing 364 mg. (0.5 ml., 3.6 mmole) of triethylamine was added 962 mg. of urea. With stirring at room temperature, a solution of 730 mg. (4.4 mmole) of 2-thiophene acetyl chloride in 20 ml. of acetone was added dropwise to the mixture. After 2.5 hours the reaction mixture was filtered and evaporated. The residue was dissolved in ethyl acetate and the solution was washed successively with water, a 5% solution of sodium bicarbonate, 5% hydrochloric acid, and a saturated solution of sodium chloride. The washed solution was dried and then was concentrated by evaporation in vacuo to yield 1.2 g. of the reaction product as a crystalline residue. The product was recrystallized from ethyl acetate to yield pure p-nitrobenzyl 7-[2-(2-thienyl)acetamido]-3-hydroxy-3- cephem-4-carboxylate having the following spectral properties.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[CH:11]1[CH:16]=[CH:15][C:14]([CH2:17][O:18][C:19]([NH:21][C@H:22]([C:27](OC2C=CC([N+]([O-])=O)=CC=2)=[O:28])[CH2:23][C:24]([NH2:26])=[O:25])=[O:20])=[CH:13][CH:12]=1.O>CN(C)C=O>[NH:21]([C:19]([O:18][CH2:17][C:14]1[CH:15]=[CH:16][CH:11]=[CH:12][CH:13]=1)=[O:20])[C@H:22]([C:27]([NH:1][C@H:2]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:28])[CH2:23][C:24](=[O:25])[NH2:26]
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)[C@@H](N)CC(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1
Reaction time: 19 h

Procedure:
16.7 g of H-Leu-OMe and 46.0 g of Z-Asn-ONP are dissolved in 100 ml of freshly distilled dimethylformamide. The solution is allowed to stand for 19 hours at 25°C. Thereafter 1.2 liters of water are added and the crystalline precipitate is filtered off. The dipeptide derivative is dried at 40°C in vacuo and is then twice recrystallised from methanol-water. Melting point 180°-181°C; [α]20D = + 9° (c = 2.05 in chloroform).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:13][C:14]([O:16]CC2C=CC=CC=2)=O)[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[CH2:7][CH2:6]1)=[O:4].[CH3:24][O:25][C:26]1[CH:34]=[CH:33][C:29](C(O)=O)=[CH:28][C:27]=1[O:35][CH2:36][CH2:37][C:38]1[CH:39]=[C:40]([CH3:44])[CH:41]=[CH:42][CH:43]=1>>[CH3:1][O:2][C:3]([C:5]1([NH:13][C:14](=[O:16])[C:29]2[CH:33]=[CH:34][C:26]([O:25][CH3:24])=[C:27]([O:35][CH2:36][CH2:37][C:38]3[CH:39]=[C:40]([CH3:44])[CH:41]=[CH:42][CH:43]=3)[CH:28]=2)[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(NC(=O)OCc2ccccc2)CCCC(=O)CC1
Reactant: COc1ccc(C(=O)O)cc1OCCc1cccc(C)c1
Product: COC(=O)C1(NC(=O)c2ccc(OC)c(OCCc3cccc(C)c3)c2)CCCC(=O)CC1

Procedure:
1-Benzyloxycarbonylamino-4-oxo-cycloheptanecarboxylic acid methyl ester was hydrogenated in analogy to step 3 of example 51 and transformed into the title compound by reaction with 4-methoxy-3-(2-m-tolyl-ethoxy)-benzoic acid in analogy to step 3 of example 1.
Reaction SMILES: [NH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]3[C:11](=[O:14])[C:12](=[O:13])[N:4]([C:5]=23)[CH2:3][C:2]1=[O:15].C1COCC1.[C:21]1([Mg]Br)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Cl-].[NH4+]>C(OCC)C>[OH:14][C:11]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:6]2[C:5]3[N:4]([CH2:3][C:2](=[O:15])[NH:1][C:10]=3[CH:9]=[CH:8][CH:7]=2)[C:12]1=[O:13]
Reactant: O=C1CN2C(=O)C(=O)c3cccc(c32)N1
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C1CN2C(=O)C(O)(c3ccccc3)c3cccc(c32)N1
Reaction time: 8 h

Procedure:
A suspension was prepared from 4.3 g. of 1H-pyrrolo[1,2,3-de]quinoxalin-2,5,6(3H)-trione in 200 ml. of THF. 16 ml. of a 2.83 M phenylmagnesium bromide solution in diethyl ether (phenyl Grignard reagent) were added thereto while maintaining the temperature in the range 10°-15° C. The resulting reaction mixture was stirred overnight after which time, 200 ml. of a saturated aqueous amonium chloride solution were added. An additional 1500 ml. of diethylether were added and the ethereal layer decanted from the solids. The ethereal layer was dried and the ether removed therefrom in vacuo. The resulting residue, comprising 6-hydroxy-6-phenyl-1H-pyrrolo[1,2,3-de]quinoxalin-2,5(3H,6H)-dione melted at 259°-62° C. with decomposition after recrystallization from methanol; yielded = 2.4 g.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C[O-].[Na+].Br[CH2:14][C:15]([OH:17])=[O:16].Cl>CO.C(OCC)(=O)C>[C:15]([CH2:14][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1)([OH:17])=[O:16]
Reactant: O=C(O)CBr
Reactant: c1ccc2[nH]ncc2c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)Cn1ncc2ccccc21
Temperature: 0 °C
Yield: 32.7 %

Procedure:
To a solution of indazole (1.0 g, 8.3 mM) in methanol (10 μl) are added 28% solution of sodium methoxide in methanol (3.53 ml, 18.26 mmole) and bromoacetic acid (1.41 g, 9.96 mmole), and the mixture is heated to reflux for 2 hr. After addition of the same amount of sodium methoxide and bromoacetic acid, the mixture is heated to reflux for another 1 hr. This procedures of addition are repeated two more times and the mixture is cooled to 0° C. After addition of ethyl acetate, the mixture is adjusted to pH 5 with 1N HCl. The organic layer is taken and the aqueous layer extracted with ethyl acetate. Each organic solution is washed with a brine, dried over anhydrous magnesium sulfate and concentrated. The residue, when purified with column chromatography (SiO2, ethyl acetate→ethyl acetate/acetic acid/water, (40:1:1)→(30:1:1)→(8:1:1)), gives 1-carboxymethylindazole (487 mg, yield 33%).
Reaction SMILES: [C:1]([C:3]1([OH:13])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1)#[N:2].Cl.[CH2:15]([OH:17])[CH3:16]>>[CH2:15]([O:17][C:1]([C:3]1([OH:13])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1)=[NH:2])[CH3:16]
Reactant: N#CC1(O)CCCc2ccccc21
Reactant: CCO
Agent: Cl
Product: CCOC(=N)C1(O)CCCc2ccccc21

Procedure:
The cyanohydrin of Example 4 (6.0 g, 34.7 mmol) was dissolved in 60 ml ethanol and perfused with hydrogen chloride for 30 minutes. After a 16 hour reaction period at 0° C. the mixture was evaporated in vacuo to a solid which was triturated with ether. The residue was taken up in 200 ml chloroform and washed with 2×50 ml saturated sodium bicarbonate, 1×50 ml brine, dried over sodium sulfate, filtered, and concentrated to a solid; 5.3 g (71%), mp 84°-86° C.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:10]([CH3:12])[CH3:11])[C:7](O)=[O:8])=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[NH:48][C:47]([C@@H:49]3[CH2:53][C:52]([F:55])([F:54])[CH2:51][NH:50]3)=[N:46][CH:45]=2)=[CH:40][CH:39]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[NH:48][C:47]([C@@H:49]3[CH2:53][C:52]([F:54])([F:55])[CH2:51][N:50]3[C:7](=[O:8])[C@@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[CH:10]([CH3:12])[CH3:11])=[N:46][CH:45]=2)=[CH:40][CH:39]=1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: FC1(F)CN[C@H](c2ncc(-c3ccc(Br)cc3)[nH]2)C1
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: COC(=O)N[C@H](C(=O)N1CC(F)(F)C[C@H]1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 20 ml, pear-shaped flask, (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (416 mg, 2.38 mmol) and HATU (695 mg, 1.83 mmol) were combined with DMF (10 ml) to give a colorless solution. (S)-5-(4-bromophenyl)-2-(4,4-difluoropyrrolidin-2-yl)-1H-imidazole (600 mg, 1.83 mmol) in 2 ml of DMF was added and followed by drop wise addition of DIPEA (1.18 g, 1.6 ml, 9.14 mmol). It was stirred at room temperature for 1 hr then poured into ice/water. It was extracted with EtOAc (2×30 ml), washed with brine and water. The organic layer was dried over MgSO4, concentrated and purified on a silica gel column (CH2Cl2, 1%, 2%, 5% MeOH/CH2Cl2) to afford methyl (S)-1-((S)-2-(5-(4-bromophenyl)-1H-imidazol-2-yl)-4,4-difluoropyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl-carbamate as an orange foaming solid. (650 mg, 73%): ESI-LRMS m/e calcd for C20H25BrF2N4O3 [M+] 485. found 486 [M+H+].
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[N:14][CH:13]=3)[CH2:9][C:8](=[O:18])[NH:7][C:6]=2[CH:19]=1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1B(O)O>>[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[N:14][CH:13]=3)[CH2:9][C:8](=[O:18])[NH:7][C:6]=2[CH:19]=1
Reactant: O=C1CC(c2ccnnc2)=Nc2ccc(Br)cc2N1
Reactant: OB(O)c1cccs1
Product: O=C1CC(c2ccnnc2)=Nc2ccc(-c3cccs3)cc2N1

Procedure:
The title compound was prepared from 8-bromo-4-(pyridazin-4-yl)-1H-benzo[b][1,4]diazepin-2(3H)-one (Example 1; 1 mmol) and commercial available thiophene-2-boronic acid (CAS-No: 6165-68-0)) (1.5 mmol) according to the general procedure G. Obtained as a yellow solid (51%), MS (EI) 321 [(M+1)+].