Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[C:5]([N+:10]([O-])=O)[C:4]=1[CH3:13]>C1COCC1.[H][H].[Ni]>[Br:9][C:6]1[CH:7]=[CH:8][C:3]([N:2]([CH3:14])[CH3:1])=[C:4]([CH3:13])[C:5]=1[NH2:10]
Reactant: [H][H]
Reactant: Cc1c(N(C)C)ccc(Br)c1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Product: Cc1c(N(C)C)ccc(Br)c1N
Yield: 90.5 %

Procedure:
15 g of N,N-dimethyl-4-bromo-2-methyl-3-nitroaniline is dissolved in about 200 ml of THF and hydrogenated at 20° C. under 5bars pressure of hydrogen using Raney nickel as catalyst. 12 g of 2-bromo-5-dimethylamino-6-methylaniline is obtained as a brown oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[CH2:21]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31]Cl)=[CH:27][CH:26]=1)[CH2:22][CH3:23].[Cl-].[NH4+]>CS(C)=O>[CH2:21]([O:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][N:1]2[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]2)=[CH:29][CH:30]=1)[CH2:22][CH3:23]
Reactant: CCCOc1ccc(CCl)cc1
Reactant: CCOC(=O)C1CCNCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCOc1ccc(CN2CCC(C(=O)OCC)CC2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
To a stirred solution of 47.5 grams (0.30 mole) of ethyl piperidin-4-ylcarboxylate in 70 mL (0.40 mole) of N, N-diisopropylethylamine was added dropwise a solution of 52.5 grams (0.29 mole) of 4-propoxyphenylmethyl chloride in 50 mL of dimethyl sulfoxide. The reaction caused the reaction mixture temperature to rise to about 35° C. Upon completion of the addition the reaction mixture was stirred for 30 minutes, warmed to 40° C., and then allowed to cool to ambient temperature. After this time the reaction mixture was poured into 500 mL of aqueous 10% ammonium chloride. The mixture was extracted with three 250 mL portions of diethyl ether, and the combined extracts were washed with two 250 mL portions of an aqueous solution saturated with ammonium chloride, one 250 mL portion of water, and one 250 mL portion of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 80.0 grams of ethyl N-(4-propoxyphenylmethyl)piperidin-4-ylcarboxylate. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.O(CC)CC.C([Li])CCC.[CH2:17]([N:21]1[C:25]2[CH:26]=[CH:27][C:28]([CH:30]=[O:31])=[CH:29][C:24]=2[N:23]=[N:22]1)[CH2:18][CH2:19][CH3:20]>CCCCCC>[CH2:17]([N:21]1[C:25]2[CH:26]=[CH:27][C:28]([CH:30]([C:2]3[CH:6]=[CH:5][S:4][CH:3]=3)[OH:31])=[CH:29][C:24]=2[N:23]=[N:22]1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCn1nnc2cc(C=O)ccc21
Reactant: Brc1ccsc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CCCCn1nnc2cc(C(O)c3ccsc3)ccc21
Temperature: 0 °C
Yield: 58.9 %

Procedure:
To a stirred and cooled (-78° C.) solution of 7.2 parts of 3-bromothiophene in 70 parts of 1,1'-oxybisethane were added 30 parts of a 1-butyllithium solution 1.6M in hexane. After stirring for 20 minutes at this low temperature, a solution of 6 parts of butyl-1H-benzotriazole-5-carboxaldehyde was added to the previous mixture. The reaction mixture was stirred for 2 hours at -78~-40° C. The whole was poured into 200 parts of ice water and the product was extracted three times with 56 parts of 1,1'-oxybisethane. The combined extracts were dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (98.2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 5 parts (58.9%) of 1-butyl-α-(3-thienyl)-1H-benzotriazole-5-methanol; mp. 80° C. (int. 58).
Reaction SMILES: C[O:2][C:3]1[C:12]2[S:11][CH2:10][C:9](=O)[CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH3:14][NH:15][CH3:16].[ClH:17]>C1(C)C=CC=CC=1>[ClH:17].[OH:2][C:3]1[C:12]2[S:11][CH2:10][CH:9]([N:15]([CH3:16])[CH3:14])[CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1SCC(=O)C2
Reactant: CNC
Agent: Cl
Solvent: Cc1ccccc1
Product: CN(C)C1CSc2c(O)cccc2C1
Reaction time: 0.5 h

Procedure:
To a solution of 5 g of 8-methoxy-3,4-dihydro-2H-[1]-benzothiopyran-3-one (J. Chem. Soc. 1948, 1610), and 4 g of anhydrous dimethylamine in 50 ml of toluene is stirred with 4 A molecular sieves for 2 hours. The reaction mixture is filtered and the solvent removed in vacuo. This residue is added to a solution of 3.2 g of sodium cyanoborohydride in 10 ml of acetic acid and 50 ml of ethanol. After 30 minutes at room temperature, the reaction mixture is poured onto 3N hydrochloric acid, and washed with ether. After basification of the aqueous layer followed by ether extraction, the organic layer is dried over magnesium sulfate and the solvent removed in vacuo. The residue is added to a solution of lithium diphenylphosphide prepared from 4.9 g diphenylphosphine, 19 ml of 1.3M butyl lithium in hexane and 70 ml of dry tetrahydrofuran, and the mixture is refluxed for 1 hour. The reaction mixture is poured onto 2N hydrochloric acid and washed with ether. After neutralization of the aqueous layer with sodium bicarbonate, the product is extracted with ether and the solvent is removed in vacuo after drying over magnesium sulfate. The residue is dissolved in ethanol; after acidification with 5.4N ethanolic hydrogen chloride and cooling, 8-hydroxy-3,4-dihydro-N,N-dimethyl-2H-[1]-benzothiopyran-3-amine hydrochloride, melting point 172°-173°, is obtained.
Reaction SMILES: [F:1][C:2]([F:20])([C:16]([F:19])([F:18])[F:17])[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9]=2[CH:15]=1)=[O:4].Cl[C:22]1[C:27]([CH3:28])=[CH:26][C:25]([N+:29]([O-])=O)=[CH:24][N:23]=1>>[NH2:29][C:25]1[CH:26]=[C:27]([CH3:28])[C:22]([O:4][CH:3]([C:5]2[CH:6]=[CH:7][C:8]3[O:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9]=3[CH:15]=2)[C:2]([F:1])([F:20])[C:16]([F:18])([F:17])[F:19])=[N:23][CH:24]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Reactant: CC1(C)Cc2cc(C(=O)C(F)(F)C(F)(F)F)ccc2O1
Product: Cc1cc(N)cnc1OC(c1ccc2c(c1)CC(C)(C)O2)C(F)(F)C(F)(F)F

Procedure:
5-Amino-3-methyl-2-[1-(2,3-dihydro-2,2-dimethylbenzofuran-5-yl)-2,2,3,3,3-pentafluoropropoxy]pyridine was prepared from 2,2,3,3,3-pentafluoro-1-(2,3-dihydro-2,2-dimethylbenzofuran-5-yl)propan-1-one, by the method of Example 42. 2-Chloro-3-methyl-5nitropyridine was used in place of 2-chloro-5-nitropyridine.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[CH:7]=[N:8][N:9]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[C:10]=2[CH:11]=[CH:12][CH:13]=1)=[O:4].[OH-].[Na+].Cl>O.CO>[F:20][C:17]1[CH:16]=[CH:15][C:14]([N:9]2[C:10]3[CH:11]=[CH:12][CH:13]=[C:5]([C:3]([OH:4])=[O:2])[C:6]=3[CH:7]=[N:8]2)=[CH:19][CH:18]=1
Reactant: COC(=O)c1cccc2c1cnn2-c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cccc2c1cnn2-c1ccc(F)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of 1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid methyl ester (2.0 g, 7.4 mmol) in water (20 mL) and methanol (20 mL) is added a solution of 2N sodium hydroxide (10 mL). The solution is warmed at reflux for 1 hour. The solution is cooled to room temperature and acidified to pH 3-4 with 1N aqueous HCl. The mixture is filtered, and the resulting solid is washed with MeOH (30 mL) and dried to afford 1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH2:11])[CH:5]=[C:4]([Cl:12])[N:3]=1.C([O-])([O-])=O.[K+].[K+].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>CN(C=O)C.O>[Cl:12][C:4]1[N:3]=[C:2]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH2:11])[CH:5]=1
Reactant: Nc1cc(Cl)nc(Cl)c1[N+](=O)[O-]
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(Cl)nc(N2CCOCC2)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2,6-dichloro-3-nitro-pyridin-4-ylamine (970 mg, 4.66 mmol) in DMF (5 mL), K2CO3 (3.20 g, 23.0 mmol) was added, followed by addition of morpholine (0.410 mL, 4.60 mmol). The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was diluted with water and extracted with EtOAc (3×10 mL). The organic layers were combined, dried (Na2SO4) and concentrated. The resulting residue was purified on silica (0:100-50:50 EtOAc-hexanes) to yield 6-chloro-2-morpholin-4-yl-3-nitro-pyridin-4-ylamine. 1H-NMR (400 MHz, CDCl3) δ: 5.99-6.20 (m, 3H), 3.72-3.82 (m, 4H), 3.40-3.50 (m, 4H).
Reaction SMILES: Br[C:2]1[C:3]([CH2:20][CH2:21][CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[N:5]2[C:10]=1[C:9]([NH2:11])=[N:8][CH:7]=[N:6]2.[Cl:28][C:29]1[CH:30]=[C:31]([CH:44]=[CH:45][CH:46]=1)[O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][C:34]=1[O:42][CH3:43].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:28][C:29]1[CH:30]=[C:31]([CH:44]=[CH:45][CH:46]=1)[O:32][C:33]1[CH:38]=[CH:37][C:36]([C:2]2[C:3]([CH2:20][CH2:21][CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[N:5]3[C:10]=2[C:9]([NH2:11])=[N:8][CH:7]=[N:6]3)=[CH:35][C:34]=1[O:42][CH3:43]
Reactant: COc1cccc(-c2c(CCCN3CCCC3)c(Br)c3c(N)ncnn23)c1
Reactant: COc1cc(B(O)O)ccc1Oc1cccc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(-c2c(CCCN3CCCC3)c(-c3ccc(Oc4cccc(Cl)c4)c(OC)c3)c3c(N)ncnn23)c1
Temperature: 90 °C
Yield: 41.1 %

Procedure:
To a solution of the compound (43 mg, 0.01 mmol) prepared in Example 15, the compound (29.4 mg, 0.15 mmol) prepared in Example 10, potassium phosphate (2N, 0.1 mL, 0.2 mmol), Pd(PPh3)4 (3 mg, 0.003 mmol) in DMF (3 mL) was deoxygenated by nitrogen gas for 5 minutes, and the reactor was sealed, heated at 90° C. for 6 hours. The mixture was concentrated, purified by prep TLC using 5% methanol in DCM (with 3% ammonium hydroxide solution) to give crude product which was further purified by prep HPLC to obtain the title compound (2.4 mg) having the following physical data.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[N:10]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:13][C:12]=2[Cl:22])[N:9]=[C:8]([CH:23]=[N:24][OH:25])[C:7]=1[S:26]([CH3:28])=[O:27].C(N(CC)CC)C>O1CCCC1>[C:1]([O:25][N:24]=[CH:23][C:8]1[C:7]([S:26]([CH3:28])=[O:27])=[C:6]([NH2:5])[N:10]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:13][C:12]=2[Cl:22])[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CS(=O)c1c(C=NO)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)ON=Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(C)=O
Reaction time: 1 h

Procedure:
Acetyl chloride (0.27 ml) was added to a solution of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboxaldehyde oxime (1.0 g) and triethylamine (0.56 ml) in tetrahydrofuran at 0° C. and the mixture stirred for 1 hour. The solvent was evaporated and the residue chromatographed on silica gel eluting with 3:1 dichloromethane/ethyl acetate to give 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboxaldehyde O-(acetyl)oxime (0.83 g)as an orange solid m.p.130-134° C. Compound 10.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[NH:10][CH:11]([CH3:23])[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([OH:22])[CH:20]=2)[CH:15]=[N:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](=O)([O-])[O-].[Cs+].[Cs+].IC.[Cl-].[NH4+]>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:24])[NH:10][CH:11]([CH3:23])[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:25])[CH:20]=2)[CH:15]=[N:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(Cn1ncc2ccc(O)cc21)NC(=O)OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Agent: [NH4+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc2cnn(CC(C)NC(=O)OCc3ccccc3)c2c1
Reaction time: 3 h
Yield: 58.2 %

Procedure:
To a solution of the product from Step A (0.95 g, 3.19 mmol) in DMF (10 mL) was added cesium carbonate (1.26 g, 3.70 mmol) followed by iodomethane (0.23 mL, 3.70 mmol) at room temperature. After stirring for 3 h, saturated aqueous ammonium chloride (30 mL) was added and the mixture extracted with ethyl acetate (3×65 mL). The combined extracts were washed with brine (10 mL), dried (MgSO4) and evaporated to a residue which was purified by chromatography (silica, 20% ethyl acetate in hexane to 30% ethyl acetate in hexane) to give a syrup (0.63 g, 92%): MS (ES) m/z 340(M+).
Reaction SMILES: [Li+].[OH-].[CH3:3][C:4]1[CH:9]=[C:8]([C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:11])[CH:7]=[C:6]([CH3:18])[C:5]=1[C:19]1[CH:27]=[CH:26][C:25]([F:28])=[C:24]2[C:20]=1[CH2:21][CH2:22][C@H:23]2[O:29][C:30]1[CH:43]=[CH:42][C:33]2[C@H:34]([CH2:37][C:38]([O:40]C)=[O:39])[CH2:35][O:36][C:32]=2[CH:31]=1>C(O)C.O>[CH3:3][C:4]1[CH:9]=[C:8]([C:10]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)=[O:11])[CH:7]=[C:6]([CH3:18])[C:5]=1[C:19]1[CH:27]=[CH:26][C:25]([F:28])=[C:24]2[C:20]=1[CH2:21][CH2:22][C@H:23]2[O:29][C:30]1[CH:43]=[CH:42][C:33]2[C@H:34]([CH2:37][C:38]([OH:40])=[O:39])[CH2:35][O:36][C:32]=2[CH:31]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(C(=O)N6CCOCC6)cc5C)ccc(F)c43)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(C(=O)N2CCOCC2)cc(C)c1-c1ccc(F)c2c1CC[C@H]2Oc1ccc2c(c1)OC[C@H]2CC(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
LiOH×H2O (4.1 mg) is added to a solution of methyl 2-((S)-6-((R)-4-(2,6-dimethyl-4-(morpholine-4-carbonyl)phenyl)-7-fluoro-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (55 mg) in ethanol (1.9 mL) and water (0.5 mL) and the mixture is stirred for 24 hours at room temperature. After concentration the mixture is diluted with water, acidified with aqueous citric acid solution and extracted with dichloromethane. The organic phase is dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 50:50) to give the title compound. Yield 10 mg, LC (method 20): tR=5.73 min; Mass spectrum (ESI+): m/z=546 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][CH:5]=O)[CH2:3][CH2:2]1.[C:7]([O:11][CH2:12][CH3:13])(=[O:10])[NH:8][NH2:9]>CCO>[CH2:12]([O:11][C:7]([NH:8][N:9]=[CH:5][CH2:4][CH:1]1[CH2:2][CH2:3]1)=[O:10])[CH3:13]
Reactant: CCOC(=O)NN
Reactant: O=CCC1CC1
Solvent: CCO
Product: CCOC(=O)NN=CCC1CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 85 %

Procedure:
The solution of 2-cyclopropylethanal was diluted with 50 mL EtOH. Ethyl carbazate (5.14 g, 49.3 mmol) was added and the solution stirred at room temperature for 12 h, upon which it was concentrated in vacuo and the crude material was purified by flash column chromatography (0-5% MeOH in CH2Cl2) to give 7.1 g (85%) of the hydrazone (4a) as a colorless crystalline solid. 1H-NMR (400 MHz, CDCl3): 8.21 (br s, 1H); 7.21 (s, 1H); 4.23 (m, 2H); 2.17 (t, 3H, J=5.9 Hz) 1.06 (m, 2H); 0.80 (m, 1H); 0.1 (d, 2H); 0.48 (m, 2H); 0.13 (m, 2H) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:11])[C:9]=1[OH:10])[CH:5]=O.[CH2:12]([NH:19][S:20]([CH2:23][C:24]#[N:25])(=[O:22])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([NH:19][S:20](/[C:23](=[CH:5]/[C:4]1[CH:3]=[C:2]([CH3:1])[C:9]([OH:10])=[C:8]([CH3:11])[CH:7]=1)/[C:24]#[N:25])(=[O:22])=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: N#CCS(=O)(=O)NCc1ccccc1
Reactant: Cc1cc(C=O)cc(C)c1O
Product: Cc1cc(/C=C(\C#N)S(=O)(=O)NCc2ccccc2)cc(C)c1O

Procedure:
The titled compound was prepared with 3,5-dimethyl-4-hydroxybenzaldehyde and N-benzyl cyanomethylsulfonamide under the similar conditions as described for EXAMPLE 12 (part B).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N:12]1[CH:17]=[CH:16][NH:15][C:14](=O)[C:13]1=[O:19].CN(C)C=O.C(Br)(=O)C([Br:28])=O>C(Cl)Cl>[Br:28][C:14]1[C:13](=[O:19])[N:12]([C:3]2[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=2[Cl:1])[C:6]([O:8][CH3:9])=[O:7])[CH:17]=[CH:16][N:15]=1
Reactant: COC(=O)c1ccc(Cl)c(-n2cc[nH]c(=O)c2=O)c1
Reactant: O=C(Br)C(=O)Br
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cl)c(-n2ccnc(Br)c2=O)c1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A suspension of methyl 4-chloro-3-(2,3-dioxo-3,4-dihydropyrazin-1(2H)-yl)benzoate (Example 330d, 8 g) in DCM (80 mL) was treated with N,N-dimethylformamide (0.220 mL) and oxalyl bromide (2.94 mL) dropwise over 5 min at room temperature under nitrogen. The resulting mixture was stirred at 20° C. for 16 h. The reaction mixture turned black and was evaporated to afford crude product. Purification (SiO2 chromatography eluting with 30% diethyl ether in dichloromethane) gave the subtitle compound (6.33 g).
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][CH2:5][C:6]([OH:8])=O.[CH2:9]([C@H:16]1[CH2:20][NH:19][C@H:18]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)=[CH:26][CH:25]=2)=[O:22])[CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([C@H:16]1[CH2:20][N:19]([C:6](=[O:8])[CH2:5][CH2:4][O:3][CH3:2])[C@H:18]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)=[CH:26][CH:25]=2)=[O:22])[CH2:17]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COCCC(=O)O
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Agent: Cl
Product: COCCC(=O)N1C[C@H](Cc2ccccc2)C[C@H]1C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 24.1 %

Procedure:
Proceeding as in Example 1, but substituting 3-methoxypropanoic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 90, (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(3-methoxypropanoyl)pyrrolidine-2-carboxamide (6.9 mg, 24.1%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): 9.90 (s, 1H), 7.54 (m, 2H), 7.30-7.25 (m, 3H), 7.21-7.16 (m, 6H), 6.92 (m, 2H), 4.44 (m, 1H), 3.66 (m, 1H), 3.51 (m, 3H), 3.19 (s, 3H), 2.63 (m, 4H), 2.09 (m, 1H), 1.88 (m, 2H). MS (EI) for C28H29FN2O4. found 477.5 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[Br:12]N1C(=O)CCC1=O>ClCCl>[Br:12][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:3]=1[N:2]([CH3:11])[CH3:1])[C:7]#[N:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: CN(C)c1ccc(C#N)cc1
Solvent: ClCCl
Product: CN(C)c1ccc(C#N)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.9 %

Procedure:
A mixture of 4-dimethylaminobenzonitrile (2.92 g, 20 mmol) and N-bromosuccinimide (3.56 g, 20 mmol) in dichloromethane (50 mL) was stirred at room temperature overnight. The solution was washed with water (20 mL), dried over magnesium sulfate and concentrated to afford 3-bromo-4-dimethylaminobenzonitrile as a white solid (4.27 g).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:7].[CH:14]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](O)=[O:25])=[CH:19][CH:18]=1)([CH3:16])[CH3:15].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[NH:7][C:24](=[O:25])[CH2:23][C:20]1[CH:21]=[CH:22][C:17]([CH:14]([CH3:15])[CH3:16])=[CH:18][CH:19]=1
Reactant: NC(c1ccccc1)c1ncco1
Reactant: CC(C)c1ccc(CC(=O)O)cc1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)c1ccc(CC(=O)NC(c2ccccc2)c2ncco2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.1 %

Procedure:
The crude 1-(1,3-oxazol-2-yl)-1-phenylmethanamine (0.10 g, 0.57 mmol) was mixed with 4-isopropylpheylacetic acid (0.10 g, 0.57 mmol), HOAt (0.086 g, 0.63 mmol) and EDC (0.12 g, 0.63 mmol) in DMF (1.0 mL) and stirred at room temperature for 0.5 h. Purification by reverse-phase HPLC gave the product (0.025 g, 13%). ES-MS [M+1]+: 335.1. 1H NMR (CDCl3, 400 MHz) δ 7.58 (s, 1H), 7.31-7.28 (m, 3H), 7.22-7.20 (m, 6H), 7.07 (s, 1H), 6.73 (d, J=8.0 Hz, 1H), 6.32 (d, J=7.6 Hz, 1H), 3.62 (s, 2H), 2.90 (m, J=6.8 Hz, 1H), 1.24 (d, J=6.8 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[C:4]([Cl:24])[CH:3]=1.C(N(CC)C(C)C)(C)C.[CH3:34][C:35]1[C:40]([C:41](Cl)=[O:42])=[CH:39][CH:38]=[CH:37][N:36]=1>C(Cl)Cl>[CH:21]1[CH:20]=[CH:19][N:11]2[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:8]([C:6]([C:5]3[CH:22]=[CH:23][C:2]([NH:1][C:41]([C:40]4[C:35]([CH3:34])=[N:36][CH:37]=[CH:38][CH:39]=4)=[O:42])=[CH:3][C:4]=3[Cl:24])=[O:7])[CH2:9][C:10]=12
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)c(Cl)c1
Reactant: Cc1ncccc1C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ncccc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1.1 g of 10, 11-dihydro-10-(4-amino-2-chlorobenzoyl)-5H-pyrrolo[2, 1-c][1, 4]benzodiazepine and 3 ml of N,N-diisopropylethylamine in 100 ml of methylene chloride is stirred while a solution of 600 mg of 2-methylpyridine-3-carbonyl chloride in 15 ml of methylene chloride is added slowly. The reaction mixture is stirred at room temperature for 2 hours. The reaction mixture is quenched with water and the organic layer washed with water, dried(MgSO4), filtered and evaporated in vacuo to a residue. The product is purified by column chromatography on silica gel by elution with 1:1 ethyl acetate:hexane to give the desired product as a pale yellow residue. M+ =456.
Reaction SMILES: C1C=CC2N([OH:10])N=NC=2C=1.[CH2:11]1[CH2:16][CH2:15][CH:14]([N:17]=[C:18]=[N:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:13][CH2:12]1>C1COCC1>[CH:20]1([NH:19][C:18](=[O:10])[NH:17][CH:14]2[CH2:13][CH2:12][CH2:11][CH2:16][CH2:15]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 13 (52 mg, 0.058 mmol), HOBT (10 mg, 0.065 mmol) and DCC (16 mg, 0.079 mmol) in THF (2 ml) was stirred for 1 hour at room temperature and filtered to remove resulting dicyclohexyl urea. The filtrate was concentrated and the residue was dissolved in 1 ml of 50% aqueous dioxane. To the mixture was added a solution of D-3,4-dihydroxyphenylalanine (D-DOPA) (24 mg, 0.12 mmol) and triethylamine (20 μl, 0.14 mmol) in 1 ml of 50% aqueous dioxane. The mixture was stirred for 1 day at room temperature and then dioxane was removed under reduced pressure. To the residue was added 50 ml of H2O and the mixture was acidified with 1N HCl to pH 2. The precipitate formed was collected by filtration and chromatographed on a column of C-18 silica gel (Bondpak C18, 20 i.d.×200 mm). The column was eluted with 30-40% acetonitrile-1/1000N HCl and the desired fraction was concentrated and lyophilized to give 4'N-CBZ protected title compound (23 mg, yield 37%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([O:12]C)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:15][NH2:16]>>[NH:15]([C:10](=[O:12])[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[NH2:16]
Reactant: COC(=O)CNC(=O)OC(C)(C)C
Reactant: NN
Solvent: O
Product: CC(C)(C)OC(=O)NCC(=O)NN

Procedure:
To a stirred solution of methyl (tert-butyloxycarbonyl)glycinate (8.54 g, 45.1 mmol) was added hydrazine hydrate (4.4 mL, 90.5 mmol) and the reaction was heated under reflux for 16 hours. The solvent was removed in vacuo and the residue partitioned between dichloromethane (100 mL) and water (100 mL). The phases were separated, the aqueous phase evaporated in vacuo to low volume and extracted with 5% methanol/dichloromethane (2×100 mL) The organic extracts were combined, dried over magnesium sulfate and concentrated in vacuo to give the product as a white crystalline solid, 5.27 g (62%).