Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:25]([O-])=O)=[C:9]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[CH:10]=1)[CH3:3].O.NN>C(O)C.[Ni]>[NH2:25][C:8]1[CH:7]=[CH:6][C:5]([O:4][CH:2]([CH3:1])[CH3:3])=[CH:10][C:9]=1[NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:14][CH2:13]1
Reactant: CC(C)Oc1ccc([N+](=O)[O-])c(NC2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)Oc1ccc(N)c(NC2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 45 °C
Yield: 99.6 %

Procedure:
A partial solution of 1,1-dimethylethyl 4-({5-[(1-methylethyl)oxy]-2-nitrophenyl}amino)-1-piperidinecarboxylate (D47, 514 mg, 1.35 mmol) in ethanol (20 ml) was treated with Raney Nickel followed by dropwise addition of a solution of hydrazine hydrate (0675 ml, 13.5 mmol) in ethanol. The mixture was heated at 45° C. for 2 hrs, then the Raney Nickel was filtered off washing with ethanol and the filtrate concentrated under vacuum to afford the title compound as a violet coloured oil (470 mg, 99%).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[NH2:8].Cl[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]=1.[H-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[NH:8][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:11]=1
Reactant: Cn1ncc(Br)c1N
Reactant: Clc1cccc(-c2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ncc(Br)c1Nc1cccc(-c2ccccc2)n1
Temperature: 100 °C

Procedure:
4-Bromo-2-methyl-2H-pyrazol-3-ylamine (0.2 g, 1.14 mmol) and 2-chloro-6-phenyl-pyridine (0.32 g, 1.7 mmol) were dissolved in DMF (5 mL) then sodium hydride (60% dispersion in oil, 0.09 g, 2.3 mmol) was added. The reaction was heated to 100° C. for 30 minutes then cooled and submitted to standard aqueous workup. The residue was purified on silica gel (0-40% EtOAc in hexanes) to provide the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])=[CH:13][N:12]=2)[CH:7]=1)=[O:5])C.Cl>[OH-].[K+].C1COCC1>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[O:10][N:9]=2)=[N:12][CH:13]=1
Reactant: CCOC(=O)c1cc(-c2ccc(OCc3ccccc3Cl)cn2)no1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cc(-c2ccc(OCc3ccccc3Cl)cn2)no1
Temperature: 55 °C
Reaction time: 8 h
Yield: 100.8 %

Procedure:
Crude 3-[5-(2-Chloro-benzyloxy)-pyridin-2-yl]-isoxazole-5-carboxylic acid ethyl ester (which may be prepared as described in Preparation of Intermediate 9; 236 mg, 0.66 mmol assumed) was taken up in a mixture of 2 M KOH (12 mL) and THF (3 mL). The mixture was heated at 55° C. for 4 h and then stirred at room temperature overnight. The mixture was cooled to 0° C. and 4 M aqueous HCl (3 mL) was added. The mixture was extracted with EtOAc and the organic layer was dried (Na2SO4), filtered, and evaporated to give 3-[5-(2-chloro-benzyloxy)-pyridin-2-yl]-isoxazole-5-carboxylic acid (220 mg, 100%) as an off-white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11]O)=[O:10])=[CH:4][C:3]=1[C:13]([F:16])([F:15])[F:14].C(N(CC)CC)C.N[C:25]1[CH:41]=[CH:40][C:28]([O:29][C:30]2[CH:35]=[CH:34][N:33]=[C:32]([C:36]([NH:38][CH3:39])=[O:37])[CH:31]=2)=[CH:27][CH:26]=1>CN(C)C=O>[CH3:39][NH:38][C:36]([C:32]1[CH:31]=[C:30]([O:29][C:28]2[CH:27]=[CH:26][C:25]([NH:11][C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:13]([F:16])([F:15])[F:14])[CH:4]=3)=[O:10])=[CH:41][CH:40]=2)[CH:35]=[CH:34][N:33]=1)=[O:37]
Reactant: O=C(NO)Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CNC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)ccn1
Temperature: 125 °C

Procedure:
1-(4-chloro-3-(trifluoromethyl)phenyl)-3-hydroxyurea (5 g, 0.0196 mol) was suspended in N,N-dimethyl formamide (15 ml) with triethyl amine (8.2 ml, 0.0589 mol) and 4-(4-aminophenoxy)-N-methylpicolinamide (4.7 g, 0.0196 mol). The reaction mass was then heated to 125° C. for 4 days. The reaction mass was concentrated under reduced pressure and the obtained residue was quenched with water (50 ml) at room temperature. The aqueous layer was extracted repeatedly with ethyl acetate and the combined ethyl acetate layer was back washed with water. Degassing of the ethyl acetate gave semisolid which upon agitation in acetonitrile (50 ml) at ambient temperature for 2-3 hours gave desired product. The product was filtered and vacuum dried to obtain 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)-N-methylpicolinamide (sorafenib base) (2.5 g).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[NH:9]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CN(C)C=O.C(O)(=O)C>[Br:1][C:2]1[S:6][C:5]([CH2:7][N:9]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: C1CCCNCC1
Reactant: O=Cc1ccc(Br)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Brc1ccc(CN2CCCCCC2)s1
Temperature: 0 °C
Reaction time: 3 h
Yield: 72.9 %

Procedure:
5-Bromo-2-thiophenecarbaldehyde (191 mg, 1 mmol) was diluted in a mixture of dichloromethane (6 mL) and N,N-dimethylformamide (2 mL), and cooled to 0° C. Hexahydro-1H-azepine (0.17 mL, 1.5 mmol, 1.5 eq) was added, followed by sodium triacetoxyborohydride (1.04 g, 4.9 mmol, 4.9 eq) and glacial acetic acid (2 drops). The mixture was stirred at 23° C. for 3 h. The reaction mixture was carefully quenched with saturated aqueous sodium bicarbonate. The reaction mixture was extracted with ethyl acetate, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by isco combiflash, 40 g column, using a 0-70% ethyl acetate in hexanes gradient. The product fractions were concentrated to give the title compound as clear colorless oil (200 mg, 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11](=[O:15])[N:12]([CH3:14])[CH3:13])[CH:8]=[C:7]([Cl:16])[C:3]=1[C:4](O)=[O:5].O=S(Cl)[Cl:19]>>[Cl:1][C:2]1[CH:10]=[C:9]([C:11](=[O:15])[N:12]([CH3:14])[CH3:13])[CH:8]=[C:7]([Cl:16])[C:3]=1[C:4]([Cl:19])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: CN(C)C(=O)c1cc(Cl)c(C(=O)O)c(Cl)c1
Product: CN(C)C(=O)c1cc(Cl)c(C(=O)Cl)c(Cl)c1
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of 2,6-dichloro-4-(dimethylcarbamoyl)benzoic acid (65 mg, 0.21 mmol) in SOCl2 (3 mL) was heated to reflux for overnight and then cooled to room temperature. The mixture was concentrated under reduced pressure to give crude 2,6-dichloro-4-(dimethylcarbamoyl)benzoyl chloride (70 mg, yield: 100%), which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.[C:23]([C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24].C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.C(O)C>[C:23]([C:27]1[CH:28]=[CH:29][C:30]([CH2:31][N:10]2[C:11]3[C@@:12]4([CH3:22])[C:19]([CH3:21])([CH3:20])[C@H:15]([CH2:14][CH2:13]4)[C:16]=3[C:17](=[O:18])[N:9]2[C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[CH:33][CH:34]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Reactant: CC(C)(C)c1ccc(CBr)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(C)(C)c1ccc(Cn2c3c(c(=O)n2-c2ccc(F)cc2F)[C@H]2CC[C@]3(C)C2(C)C)cc1
Temperature: 80 °C
Yield: 68.4 %

Procedure:
A mixture of (4S,7R)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 14; 150 mg, 0.49 mmol), tetrabutylammonium iodide (181 mg, 0.49 mmol) and 4-tert-butylbenzyl bromide (360 μL, 1.96 mmol) in dimethylformamide (3 mL) was heated at 80° C. for 4 days. The solvent was evaporated, dichloromethane (50 mL) was added and the solution was washed with water (2×20 mL), saturated aqueous sodium thiosulfate (20 mL), and brine (20 mL). The solution was dried (magnesium sulfate), filtered, evaporated, and purified by column chromatography, eluting with 60-70% ethyl acetate/petroleum ether, and dried under high vacuum overnight to give a pale yellow foam. This was dissolved in ethanol and treated with charcoal. The mixture was filtered through Celite, and the filtrate was evaporated and dried under high vacuum to give (4S,7R)-1-(4-tert-butyl-benzyl)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (151 mg, 68%). APCI(+)-MS (M+H) 451.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8](OC)=[O:9])=[C:6]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:5]([C:19](OC)=[O:20])=[C:4]([CH3:23])[N:3]=1.O>C1(C)C=CC=CC=1.O1CCCC1>[OH:9][CH2:8][C:7]1[C:2]([CH3:1])=[N:3][C:4]([CH3:23])=[C:5]([CH2:19][OH:20])[C:6]=1[C:12]1[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=1
Reactant: COC(=O)c1c(C)nc(C)c(C(=O)OC)c1-c1ccc(F)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(C)c(CO)c(-c2ccc(F)cc2)c1CO
Temperature: 25 °C
Reaction time: 6 h

Procedure:
25 ml (87.5 mmol) of a 3.5 molar solution of sodium bis-(2-methoxyethoxy)-dihydroaluminate in toluene are added under nitrogen to a solution of 7.9 g (25 mmol) of the compound from Example 19 in 100 ml of dry tetrahydrofuran at 0° C. The mixture is stirred at room temperature for 6 h, cooled again to 0° C. and 200 ml of water are slowly added dropwise. The mixture is extracted three times using 150 ml of ethyl acetate each time, the combined organic phases are washed once with saturated sodium chloride solution, dried over magnesium sulphate and concentrated in vacuo. The residue is stirred with ether, filtered off with suction and dried in a desiccator.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:25][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCc1ccccc1
Reactant: BrCCCCCCOCCCc1ccccn1
Product: c1ccc(CNCCCCCCOCCCc2ccccn2)cc1

Procedure:
2-[3-[(6-Bromohexyl)oxy]propyl]pyridine (17.0 g) was added to benzylamine (50 ml) at 140° under nitrogen. After 1 h at 140° the reaction mixture was cooled and partitioned between 2N sodium hydroxide (250 ml) and ether (250 ml). The organic layer was washed with water and brine, dried and concentrated to a yellow oil. The excess benzylamine was removed by distillation to give the title compound as a yellow oil (18.5 g), t.l.c. (System A 80:20:2) Rf 0.42.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH3:14])[CH3:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:15]([C:17]1[N:21]([CH3:22])[C:20](B(O)O)=[CH:19][CH:18]=1)#[N:16].[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:15]([C:17]1[N:21]([CH3:22])[C:20]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH3:14])[CH3:13])(=[O:10])=[O:9])=[CH:4][CH:3]=2)=[CH:19][CH:18]=1)#[N:16]
Reactant: Cn1c(C#N)ccc1B(O)O
Reactant: CC(C)NS(=O)(=O)c1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)NS(=O)(=O)c1ccc(-c2ccc(C#N)n2C)cc1
Reaction time: 16 h
Yield: 12.4 %

Procedure:
According to general procedure B, 4-bromo-N-isopropylbenzenesulfonamide (111 mg, 0.40 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (72 mg, 0.48 mmol), potassium fluoride (76 mg, 1.3 mmol), and tris(dibenzylideneacetone)dipalladium(0) (10 mg, 0.01 mmol) were placed in an oven dried flask under nitrogen and dry THF (1.0 mL) was added. Tri-t-butylphosphine (60 μL, 0.02 mmol, 10 wt % in hexane) was added and the reaction was stirred for 16 hours. 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-isopropylbenzenesulfonamide (15 mg, 12%) was provided after purification. MS (ESI) m/z 303. HPLC purity 100.0% at 210-370 nm, 10.1 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: C([NH:3][C:4]1[S:5][C:6]([Cl:35])=[C:7]([C:9](=[N:25][O:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl.C(=O)(O)[O-].[Na+]>CO>[NH2:3][C:4]1[S:5][C:6]([Cl:35])=[C:7]([C:9](=[N:25][O:26][CH2:27][C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1nc(NC=O)sc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1nc(N)sc1Cl
Yield: 90.3 %

Procedure:
To a solution of 7-[2-(2-formamido-5-chlorothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer) (2.1 g) in methanol (50 ml) was added conc. hydrochloric acid (1.35 ml) at 32° to 35° C. The mixture was stirred for an hour at the same temperature. The resultant solution was adjusted to pH 5.0 with a saturated aqueous solution of sodium bicarbonate. After removing the solvent, the residual insoluble precipitates were collected by filtration. The precipitates were washed with water and dried over phosphorus pentoxide to give 7-[2-(2-amino-5-chlorothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer) (1.8 g), mp 180° to 185° C. (dec.).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[S:12]([N:15]1[CH2:20][CH2:19][S:18][CH2:17][CH2:16]1)(=[O:14])=[O:13].[H-].[Na+].[OH2:23]>>[Cl:11][C:4]1[C:3]([S:12]([N:15]2[CH2:20][CH2:19][S:18][CH2:17][CH2:16]2)(=[O:14])=[O:13])=[C:2]([OH:23])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)N2CCSCC2)c1Cl
Agent: [H-]
Agent: [Na+]
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)N2CCSCC2)c1O
Yield: 33.5 %

Procedure:
Following the general hydrolysis procedure outlined in example 15, 2,6-dichloro-3-nitro-1-(4-thiomorpholinylsufonyl)benzene (1.04 g, 2.91 mmol), 60% NaH (349 mg, 8.73 mmol) and water (63 μL, 3.50 mmol) were reacted to form the desired product (330 mg, 33%). EI-MS (m/z) 336.89, 338.93 (M−).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[CH:11]=[CH:12][C:13]2[O:17][C:16]([C:18]3[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=3[C:20]([O:22][CH3:23])=[O:21])=[N:15][C:14]=2[CH:28]=1>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:1][CH2:9][C:10]1[CH:11]=[CH:12][C:13]2[O:17][C:16]([C:18]3[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=3[C:20]([O:22][CH3:23])=[O:21])=[N:15][C:14]=2[CH:28]=1
Reactant: COC(=O)c1ccccc1-c1nc2cc(C)ccc2o1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccccc1-c1nc2cc(CBr)ccc2o1
Temperature: 25 °C
Yield: 50.7 %

Procedure:
N-Bromosuccinimide (2.35 g) and azo(bisisobutyronitrile) (60 mg) were added to a solution of compound C (3.2 g) in carbon tetrachloride (60 ml). The mixture was heated under reflux for 4 hours and then cooled to ambient temperature. Insoluble material was removed by filtration and the filtrate was concentrated. The residue was recrystallised from hexane to give methyl 2-(5-bromomethyl-benzoxazol-2-yl)benzoate (D) (2.1 g), m.p. 92°-95° C; NMR: 3.9(s, 3H), 4.65(s, 2H), 7.45(dd, 1H), 7.55(dd, 1H), 7.6-7.7(m, 2H), 7.8-7.85(m, 2H), 8.0-8.1(m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[C:14]([CH3:22])[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:23]#[N:24])[CH:5]=[CH:6][CH:7]=1.CN(C1C=CC=CN=1)C.[C:34](OC(=O)C)(=[O:36])[CH3:35]>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([N:8]([C:9]2[C:18]3[C:13](=[C:14]([CH3:22])[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:23]#[N:24])[C:34](=[O:36])[CH3:35])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc([N+](=O)[O-])cc2c(Nc3cccc(Br)c3)c(C#N)cnc12
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: CC(=O)N(c1cccc(Br)c1)c1c(C#N)cnc2c(C)cc([N+](=O)[O-])cc12

Procedure:
A stirred mixture of 4-[(3-bromophenyl)amino]-8-methyl-6-nitro-3-quinolinecarbonitrile (15.3 g, 40 mmol), 0.37 g (3 mmol) of dimethylaminopyridine, 40 ml of acetic anhydride, and 80 ml of pyridine was refluxed for 3 h and concentrated at 50° C. under vacuum. The residue was stirred with methylene chloride and 0.1 N HCl. After filtration through Celite, the organic layer was washed with water, dried and concentrated. The residue was subjected to chromatography on silica gel with 1% acetic acid in methylene chloride to give 11.2 g of an amber glass, NMR (CDCl3) δ 2.29 (N-acetyl group).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[CH2:11][C:10]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([Cl:26])[CH:24]=3)[NH:19][C:18]=2[CH3:27])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:35][C:36]([O:38]C(C)(C)C)=[O:37]>CN(C=O)C.CCOC(C)=O>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[CH2:11][C:10]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([Cl:26])[CH:24]=3)[N:19]([CH2:35][C:36]([OH:38])=[O:37])[C:18]=2[CH3:27])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1[nH]c2ccc(Cl)cc2c1C1=NN(Cc2ccccc2)C(=O)C(C)(C)C1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(C2=NN(Cc3ccccc3)C(=O)C(C)(C)C2)c2cc(Cl)ccc2n1CC(=O)O
Temperature: 80 °C

Procedure:
The product of step b) (˜0.3 mmol) was dissolved in 5 mL DMF and treated with K2CO3 (1 mmol, 138 mg) and t-butyl bromoacetate (1 mmol, 195 mg). After heating to 80° C. for ½ h, the reaction was cooled, diluted with EtOAc and washed 5× water. The reaction was concentrated, dissolved in EtOH (5 mL) and treated with 1.4 mL of 1M NaOH. After heating to 80° C. for ½ h, the reaction was acidified with 3 M HCl and extracted into DCM (3×).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([C:13]([O:15]C)=O)[CH2:11][C@H:10]([NH:17][C:18]2[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][C:19]=2[C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=2)=[O:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:41][NH2:42]>CO>[C:1]([O:5][C:6]([N:8]1[C@H:12]([C:13](=[O:15])[NH:42][CH3:41])[CH2:11][C@H:10]([NH:17][C:18]2[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][C:19]=2[C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=2)=[O:21])[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: COC(=O)[C@@H]1C[C@H](Nc2ccc([N+](=O)[O-])cc2C(=O)NCc2ccc(OC)c(OC)c2)CN1C(=O)OC(C)(C)C
Reactant: CN
Solvent: CO
Product: CNC(=O)[C@@H]1C[C@H](Nc2ccc([N+](=O)[O-])cc2C(=O)NCc2ccc(OC)c(OC)c2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 2-[(3S,5S)-1-(tert-butoxycarbonyl)-5-(methoxycarbonyl)pyrrolidin-3-ylamino]-N-(3,4-dimethoxylbenzyl)-5-nitrobenzamide (143 mg) and 30% methanol solution of methylamine (4 mL) was stirred for one day at ambient temperature. After evaporation of the solvent, the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine and dried over magnesium sulfate. The residue was subjected to a silica gel column chromatography eluting with ethyl acetate to give 2-[(3S,5S)-1-(tert-butoxycarbonyl)-5-(methylcarbamoyl)pyrrolidin-3-ylamino]-N-(3,4-dimethoxylbenzyl)-5-nitrobenzamide (149 mg).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=1.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>CN(C)C=O>[CH3:9][O:8][C:7]1[C:2]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[N:3][CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[CH:6]=1
Reactant: COc1cc([N+](=O)[O-])cnc1Cl
Reactant: C1CCNC1
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])cnc1N1CCCC1
Yield: 97.7 %

Procedure:
A solution of 3 g (15.91 mmol) of 2-chloro-3-methoxy-5-nitropyridine and 2 ml (23.86 mmol) of pyrrolidine in 30 ml of dimethylformamide is heated at 100° C. for 4 hours. The reaction mixture is subsequently concentrated under reduced pressure and then taken up in 100 ml of water and extracted three times with 100 ml of ethyl acetate. The organic phases are combined, then washed twice with 50 ml of water then once with 50 ml of a saturated sodium chloride solution, dried over sodium sulfate and then concentrated under reduced pressure. 3.47 g of the expected compound are thus isolated in the form of an orangey powder.
Reaction SMILES: OO.[Br:3][C:4]1[CH:5]=[C:6]([O:14][CH3:15])[C:7]([O:12][CH3:13])=[C:8]([CH:11]=1)C=O.[O-:16]S([O-])=O.[Na+].[Na+]>S(=O)(=O)(O)O.C(O)=O.O>[CH3:13][O:12][C:7]1[C:6]([O:14][CH3:15])=[CH:5][C:4]([Br:3])=[CH:11][C:8]=1[OH:16]
Reactant: COc1cc(Br)cc(C=O)c1OC
Reactant: O=S([O-])[O-]
Agent: O=S(=O)(O)O
Agent: OO
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: COc1cc(Br)cc(O)c1OC
Temperature: 25 °C
Yield: 50 %

Procedure:
A freshly prepared mixture of 30% H2O2 (3.9 g), formic acid (11 mL), and concentrated sulfuric acid (3 drops) was maintained for 1 hour at room temperature. The mixture was then cooled to 5° C. and treated with a solution of 5-bromo-2,3-dimethoxybenzaldehyde (4.15 g) in formic acid (25 mL). The mixture was maintained for 4 hours at 5° C. then placed in the 4° C. freezer overnight. Reaction mixture was then treated with a solution of Na2SO3 (3.4 g) in water (100 mL), stirred, and extracted with ethyl acetate (3×50 mL). The combined extracts were washed with 50 mL water followed by 50 mL brine and then organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was dissolved in diethyl ether (20 mL) and after addition of 25% aqueous KOH (220 mL) was vigorously stirred under nitrogen. The organic layer was separated, the aqueous phase acidified to a pH of 3 with 2 N HCl and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum to yield an oily residue which was purified by chromatography on silica in 3:1 hexane/ethyl acetate to provide 2,3-dimethoxy-5-bromophenol in 50% yield. 1H NMR (400 MHz) (CDCl3) δ 3.87 (s, 3H), 3.89 (s, 3H), 5.84 (s, 1H), 6.64 (d, J=4.0 Hz, 1H), 6.80 (d, J=4.0 Hz, 1H).
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]1[CH:12]([CH2:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=3)[NH:13][CH2:14][CH2:15][C:6]2=1.Cl.[CH:28]1(C2C=C3C(NC=C3CCN)=CC=2)[CH2:33][CH2:32]C[CH2:30][CH2:29]1>Cl>[ClH:1].[CH:2]1([C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7]2[CH:12]([CH2:16][C:17]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[CH:20]=[CH:19][CH:18]=4)[NH:13][CH2:14][CH2:15][C:6]3=2)[CH2:32][CH2:33][CH2:28][CH2:29][CH2:30]1
Reactant: NCCc1c[nH]c2ccc(C3CCCCC3)cc12
Reactant: Cc1ccc2[nH]c3c(c2c1)CCNC3Cc1cccc2ccccc12
Agent: Cl
Product: c1ccc2c(CC3NCCc4c3[nH]c3ccc(C5CCCCC5)cc43)cccc2c1
Temperature: 25 °C
Yield: 34.9 %

Procedure:
A suspension of azalactone (prepared as described in Example 5) (1.09 g, 4.59 mmol) and 5-cyclohexyltryptamine hydrochloride (1.28 g, 4.59 mmol) in 1N HCl (70 mL) was heated to reflux for 14 hours under nitrogen atmosphere. The reaction mixture was cooled to ambient temperature and the crude product isolated by filtration. The solid was recrystallized from ethanol (2X) to afford 690 mg of desired product as a pale solid hydrochloride salt.