Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]=[C:8]1[N:12]([CH3:13])[C@H:11]([CH:14]=O)[CH2:10][CH2:9]1)=[O:6])[CH:2]=[CH2:3].C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[C:23]([CH3:27])[C:24](=[O:26])[CH3:25])C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:4][C:5]([N:7]=[C:8]1[N:12]([CH3:13])[C@H:11]([CH:14]=[C:23]([CH3:27])[C:24](=[O:26])[CH3:25])[CH2:10][CH2:9]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N=C1CC[C@@H](C=O)N1C
Reactant: CC(=O)C(C)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: C=CCOC(=O)N=C1CC[C@@H](C=C(C)C(C)=O)N1C
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of (2S)-5-allyloxycarbonylimino-2-formyl-1-methylpyrrolidine (0.46 g) in toluene (20 ml) was added 3-triphenylphosphoranylidenebutan-2-one and the mixture was stirred at 80° C. for 2 hours. The solvent was evaporated and the residue was chromatographed on silica gel eluting with a mixture of n-hexane and ethyl acetate (1:2 V/V) to give (2S)-5-allyloxycarbonylimino-1-methyl-2-(2-methyl-3-oxo-1-butenyl)pyrrolidine (0.54 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2([CH3:24])[C:19](=[O:20])[C:18]3[C:13](=[C:14]([Br:22])[CH:15]=[C:16]([Br:21])[CH:17]=3)[NH:12][C:11]2=[O:23])[CH:5]=[CH:6][C:7]=1[O:8]C.B(Br)(Br)Br.CCCCCC>CCOC(C)=O>[NH2:1][C:2]1[CH:3]=[C:4]([C:10]2([CH3:24])[C:19](=[O:20])[C:18]3[C:13](=[C:14]([Br:22])[CH:15]=[C:16]([Br:21])[CH:17]=3)[NH:12][C:11]2=[O:23])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COc1ccc(C2(C)C(=O)Nc3c(Br)cc(Br)cc3C2=O)cc1N
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC1(c2ccc(O)c(N)c2)C(=O)Nc2c(Br)cc(Br)cc2C1=O
Yield: 51.8 %

Procedure:
The objective compound was prepared by the same procedure for the example 13, using a 3-(3-amino-4-methoxy-phenyl)-6,8-dibromo-3-methyl-1H-quinoline-2,4-dione (36 mg, 0.079 mmol) and BBr3(0.4 mL, 1.0 M solution in dichloromethane). After normal workup, the pure objective compound (18 mg, 52%) was obtained as pale yellow solid by a flash column chromatography (n-hexane:EtOAc=3:1): 1H NMR (200 MHz, CDCl3) δ 1.64 (s, 3H, CH3), 4.85 (br s, 3H, NH2 & OH), 6.41 (d, J=2.4 Hz, 1H, ArH), 6.37 (dd, J=8.6, 2.4 Hz, 1H, ArH), 6.55-6.61 (m, 2H, ArH), 7.86 (d, J=2.0 Hz, 1H, ArH); HRMS m/e cacld. for C16H12N2O3Br2 437.9215, found 437.9211.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:18][O:19][C:20](=[O:32])[CH:21]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22][SH:23].C(OCC)(=O)C>CN(C=O)C.CCCCCCC>[CH3:18][O:19][C:20](=[O:32])[C@@H:21]([NH:24][C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:22][S:23][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: COC(=O)C(CS)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COC(=O)[C@H](CSCc1ccc(N)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
A mixture of 1-bromomethyl-4-nitro-benzene (2.15 g, 9.95 mmol), cesium carbonate (6.49 g, 19.9 mmol) and 2-tert-butoxycarbonylamino-3-mercapto-propionic acid methyl ester (2.46 g, 10.5 mmol) in DMF (25 mL) was stirred at room temperature. Upon completion of the reaction (TLC control: 30% ethyl acetate in heptane), the reaction mixture was quenched with water (50 mL) and extracted with diethyl ether (3×50 mL). The combined extract was washed sequentially with water and brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification by flash chromatography (SiO2; 30% ethyl acetate in heptane as eluent) yielded the thioether as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([F:23])[C:3]=1[C:4]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].Cl.[Cl:25][CH2:26][CH2:27][NH2:28]>C(N(CC)CC)C>[CH3:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([F:23])[C:3]=1[C:4]([C:6](=[CH:12][NH:28][CH2:27][CH2:26][Cl:25])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1c(C)c(F)c(F)c(F)c1F
Reactant: NCCCl
Agent: Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=CNCCCl)C(=O)c1c(C)c(F)c(F)c(F)c1F
Yield: 100.4 %

Procedure:
Employing ethyl 2-(2-methyl-3,4,5,6-tetrafluorobenzoyl)-3-ethoxyacrylate (5.0 g), 2-chloroethylamine hydrochloride (1.74 g) and triethylamine (1.97 g), the procedure of Reference Example 21 is repeated to give ethyl 2-(2-methyl-3,4,5,6-tetrafluorobenzoyl)-3-(2-chloroethyl)aminoacrylate (5.52 g), which is then treated with 60% sodium hydride (0.72 g) as in Reference Example 22 to give ethyl 1-(2-chloroethyl)-5-methyl-6,7,8-trifluoro-l,4-dihydro-4-oxoquinoline-3-carboxylate (3.90 g), as colorless needles (recrystallized from ethyl acetate--n-hexane), m.p. 161.5°-163.5° C. (dec.)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH:8]([OH:13])[CH2:9][CH:10]([CH3:12])[CH3:11])[CH:5]=[C:4]([CH3:14])[C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[CH3:56][O:57][C:58](=[O:71])[CH2:59][CH2:60][NH:61][C:62](=[O:70])[C:63]1[CH:68]=[CH:67][C:66](O)=[CH:65][CH:64]=1>C1(C)C=CC=CC=1>[CH3:56][O:57][C:58](=[O:71])[CH2:59][CH2:60][NH:61][C:62](=[O:70])[C:63]1[CH:68]=[CH:67][C:66]([O:13][CH:8]([C:6]2[CH:5]=[C:4]([CH3:14])[C:3]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=3)=[C:2]([CH3:1])[CH:7]=2)[CH2:9][CH:10]([CH3:12])[CH3:11])=[CH:65][CH:64]=1
Reactant: Cc1cc(C(O)CC(C)C)cc(C)c1-c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)CCNC(=O)c1ccc(O)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)CCNC(=O)c1ccc(OC(CC(C)C)c2cc(C)c(-c3ccc(C(F)(F)F)cc3)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-yl)-3-methyl-butan-1-ol (270 mg, 0.8 mmol) in toluene (8 mL) is added 1,1′-(azodicarbonyl) dipiperidine (ADDP, 304 mg, 1.21 mmol) at 0° C., followed by the addition of tributylphosphine (0.3 mL, 12.1 mmol) and 3-(4-hydroxy-benzoylamino)-propionic acid methyl ester (215 mg, 0.96 mmol). The reaction mixture is warmed up to room temperature and stirred overnight. The mixture is loaded on silica gel, eluted with hexanes with a gradient from 0% of ethyl acetate to 100% of ethyl acetate giving 3-{4-[1-(2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-yl)-3-methyl-butoxy]-benzoylamino}-propionic acid methyl ester. The ester product is taken into methanol (2 mL), treated with sodium hydroxide (5N aqueous, 1 mL) for 5 h at room temperature. The mixture is concentrated, diluted with ethyl acetate, acidified with 5 N HCl (1.1 mL), extracted with ethyl acetate. The organic layers are dried and concentrated to afford 51 mg of the titled compound. MS (ES): 528.3 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:12]3[CH:13]=[C:14]([F:18])[C:15]([F:17])=[CH:16][C:11]=3[N:10]=[C:9]2[C:19]2[C:20]([OH:25])=[N:21][CH:22]=[CH:23][CH:24]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:32][O:33][C:34](=[O:45])[CH2:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43]Br)=[CH:39][CH:38]=1>CC(C)=O>[CH3:32][O:33][C:34](=[O:45])[CH2:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43][O:25][C:20]2[C:19]([C:9]3[N:8]([CH2:7][CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[C:12]4[CH:13]=[C:14]([F:18])[C:15]([F:17])=[CH:16][C:11]=4[N:10]=3)=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:39][CH:38]=1
Reactant: COC(=O)COc1ccc(CBr)cc1
Reactant: Oc1ncccc1-c1nc2cc(F)c(F)cc2n1CC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(COc2ncccc2-c2nc3cc(F)c(F)cc3n2CC2CCCCC2)cc1
Yield: 50 %

Procedure:
To a stirred solution of 3-(1-cyclohexylmethyl-5,6-difluoro-1H-benzoimidazol-2-yl)-pyridin-2-ol (58 mg, 0.17 mmol) in acetone (10 ml) was added cesium carbonate (0.085 g, 0.26 mmol) followed by (4-bromomethyl-phenoxy)-acetic acid methyl ester (49 mg, 0.19 mmol; CAS Reg. No. 104508-23-8) and the reaction mixture was refluxed for 2 h. The reaction mixture was filtered, and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography using silica gel (50-60% ethyl acetate/n-hexane) to yield the desired compound as a brown solid (50%). MS (Turbo Spray): m/z=522.5 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:16][CH2:17][C:18]([O-:20])=[O:19])=[CH:4][C:5]2[CH:9]=[C:8]([C:10]([OH:13])([CH3:12])[CH3:11])[S:7][C:6]=2[C:14]=1[Cl:15].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[C:3]([O:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:4][C:5]2[CH:9]=[C:8]([C:10]([OH:13])([CH3:12])[CH3:11])[S:7][C:6]=2[C:14]=1[Cl:15]
Reactant: CC(C)(O)c1cc2cc(OCC(=O)[O-])c(Cl)c(Cl)c2s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(O)c1cc2cc(OCC(=O)O)c(Cl)c(Cl)c2s1

Procedure:
To 8.5 g of t-butyl[[(6,7-dichloro-2-(1-hydroxy-1-methylethyl)benzo[b]thien-5-yl]oxy]acetate in 200 ml of ethanol is added 150 ml of a 6N sodium hydroxide solution and the mixture is refluxed at 100° for 30 mins. The cooled mixture is concentrated in vacuo to a white slurry which is diluted with 200 ml of ice water and 200 ml of ethyl ether. With stirring and efficient cooling, the mixture is acidified with 6N hydrochloric acid. The acidic mixture is extracted with ethyl ether and the ether extracts are washed, dried over anhydrous magnesium sulfate, filtered and the solvent is removed. Recrystallization of the residue from acetone and pentane gives 6.8 g of [[(6,7-dichloro-2-(1-hydroxy-1-methylethyl)benzo[b]thien-5-yl]oxy]acetic acid, mp 194°-196°.
Reaction SMILES: [C:1]([C:9]1[N:13]2[CH2:14][CH2:15][CH:16]([C:17]([OH:19])=[O:18])[C:12]2=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH2:22])=[N-]>ClCCl>[C:1]([C:9]1[N:13]2[CH2:14][CH2:15][CH:16]([C:17]([O:19][CH3:22])=[O:18])[C:12]2=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1ccc2n1CCC2C(=O)O
Reactant: C=[N+]=[N-]
Solvent: ClCCl
Product: COC(=O)C1CCn2c(C(=O)c3ccccc3)ccc21
Temperature: 25 °C

Procedure:
A solution of 200 mg. of 5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid in 5 ml. of dichloromethane is treated with an excess of ethereal diazomethane, and the reaction mixture is maintained at room temperature for 30 minutes. The solvents and excess reagent are eliminated under reduced pressure and the residue crystallized from ethyl acetate-methanol, to yield methyl 5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[O:12][CH:13]=[C:14]([C:16]3[N:17]=[N:18][NH:19][N:20]=3)[N:15]=2)[CH2:7][CH2:6]1.Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[Br:1][C:2]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[O:12][CH:13]=[C:14]([C:16]3[N:17]=[N:18][N:19]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:20]=3)[N:15]=2)[CH2:7][CH2:6]1
Reactant: Fc1ccc(Br)c(OC2CCN(c3nc(-c4nn[nH]n4)co3)CC2)c1
Reactant: CCOC(=O)CBr
Product: CCOC(=O)Cn1nnc(-c2coc(N3CCC(Oc4cc(F)ccc4Br)CC3)n2)n1

Procedure:
The title compound was prepared in a similar manner as described for Example 6, step 7, from 4-(2-bromo-5-fluorophenoxy)-1-[4-(2H-tetrazol-5-yl)-1,3-oxazol-2-yl]piperidine and ethy bromoacetate. The mixture of regioisomers was purified by Combiflash chromatography (SiO2-12 g, gradient elution of 15-50% EtOAc/hexanes over 25 min) to afford the title product as the more polar isomer.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:14])=[CH:4][C:5]2[CH:9]=[C:8]([CH2:10][CH3:11])[S:7][C:6]=2[C:12]=1[Cl:13].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[C:3]([O:14][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:4][C:5]2[CH:9]=[C:8]([CH2:10][CH3:11])[S:7][C:6]=2[C:12]=1[Cl:13]
Reactant: CCOC(=O)CBr
Reactant: CCc1cc2cc(O)c(Cl)c(Cl)c2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc2cc(CC)sc2c(Cl)c1Cl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 83.8 %

Procedure:
A mixture of 1.15 g of 6,7-dichloro-2-ethyl-5-hydroxybenzo[b]thiophene, 0.87 g of ethyl bromoacetate, 0.4 g of potassium carbonate and 12 ml of dimethylformamide is stirred at 90° for 20 min. The cooled mixture is diluted with 100 g of ice water and the solid collected by filtration. Recrystallization of the crude product from pentane gives 1.3 g of ethyl [(6,7-dichloro-2-ethylbenzo[b]thien-5-yl)oxy]acetate as colorless prisms, mp 67°-68°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([CH2:12][C:13]1[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[N:15]=[CH:16][N:17]=1)[CH2:6][CH2:5]2.C(N(CC)CC)C.[F:34][C:35]([F:52])([F:51])[C:36]1[CH:41]=[CH:40][C:39]([C:42]2[C:43]([C:48](Cl)=[O:49])=[CH:44][CH:45]=[CH:46][CH:47]=2)=[CH:38][CH:37]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][N:14]2[C:13]([CH2:12][N:7]3[CH2:6][CH2:5][C:4]4[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:48]([C:43]5[C:42]([C:39]6[CH:40]=[CH:41][C:36]([C:35]([F:34])([F:51])[F:52])=[CH:37][CH:38]=6)=[CH:47][CH:46]=[CH:45][CH:44]=5)=[O:49])[CH:3]=4)[CH2:8]3)=[N:17][CH:16]=[N:15]2)=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: COc1ccc(Cn2ncnc2CN2CCc3cc(N)ccc3C2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Cn2ncnc2CN2CCc3cc(NC(=O)c4ccccc4-c4ccc(C(F)(F)F)cc4)ccc3C2)cc1
Reaction time: 4 h
Yield: 97 %

Procedure:
The title product of Example 3 (0.38 g, 1.1 mmol) and triethylamine (0.17 mL, 1.2 mmol) were dissolved in methylene chloride (14 mL) and stirred at room temperature while a solution of 4'-trifluoromethylbiphenyl-2-carbonyl chloride (0.31 g, 1.1 mmol) in methylene chloride (40 mL) was added dropwise. After four hours, 10% aq sodium carbonate solution was added and the mixture was stirred for thirty minutes. The methylene chloride layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo to afford the title product as a hard foam, 0.63 g, 97% yield. 1H NMR (CDCl3) δ 7.79 (s, 1), 7.72 (d, 1), 7.64 (d, 2), 7.58-7.34 (m, 6), 7.12 (d, 2), 7.01 (s, 1), 6.90-6.72 (m, 4), 5.38 (s, 2), 3.73 (s, 3), 3.69 (s, 2), 3.50 (s, 2), 2.79 (t, 2), 2.68 (t, 2). IR (KBr) 1668, 1615, 1599, 1567, 1536, 1514 cm-1. Mass spectrum: m/z: 598 (M+ -1).
Reaction SMILES: C(OC([NH:8][C@H:9]([C@@H:31]([OH:42])[CH2:32][C@H:33]([C:35](=[O:41])[NH:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH3:34])[CH2:10][C@@H:11]([CH:28]([CH3:30])[CH3:29])[CH2:12][NH:13][C:14](=[O:27])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH2:22][CH2:23][CH2:24][O:25][CH3:26])=O)(C)(C)C.[ClH:43]>O1CCOCC1>[ClH:43].[NH2:8][C@H:9]([C@@H:31]([OH:42])[CH2:32][C@H:33]([C:35](=[O:41])[NH:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH3:34])[CH2:10][C@@H:11]([CH:28]([CH3:30])[CH3:29])[CH2:12][NH:13][C:14](=[O:27])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH2:22][CH2:23][CH2:24][O:25][CH3:26]
Reactant: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](C[C@H](CNC(=O)c1ccccc1OCCCOC)C(C)C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCCCNC(=O)[C@H](C)C[C@H](O)[C@@H](N)C[C@H](CNC(=O)c1ccccc1OCCCOC)C(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(2S,4S,5S,7R)-N-[4-(tert-Butoxycarbonyl)amino-7-butylcarbamoyl-5-hydroxy-2-isopropyl-octyl]-2-(3-methoxypropoxy)-benzamide (82 mg) is dissolved at 0° C. in 3 ml of a 4N hydrochloric acid solution in dioxane, and the solution is stirred at 0° C. for 2 hours. The reaction mixture is lyophilised and (2S,4S,5S,7R)-N-(4-amino-7-butylcarbamoyl-5-hydroxy-2-isopropyl-octyl)-2-(3-methoxypropoxy)-benzamide hydrochloride is obtained in the form of a white foam: Rf (L)=0.12. HPLC Rt =11.6 min. MS(FAB) m/e 494 (M+ +1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:33]([O:35][C:36](=[O:46])[C:37]1[CH:42]=[CH:41][C:40]([N:43]=[C:44]=[O:45])=[CH:39][CH:38]=1)[CH3:34]>ClCCl>[CH2:33]([O:35][C:36](=[O:46])[C:37]1[CH:42]=[CH:41][C:40]([NH:43][C:44]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:45])=[CH:39][CH:38]=1)[CH3:34]
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Reactant: CCOC(=O)c1ccc(N=C=O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (0.15 g, 0.40 mmol) (from Example 25a supra) in dichloromethane (3 mL) was added triethylamine (0.139 ul, 1.0 mmol) (Aldrich), followed by the addition of 4-isocyanato-benzoic acid ethyl ester (92.0 mg, 0.48 mmol) (Aldrich). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography to give rac-4-({3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1Hindol-3-yl]-piperidine-1-carbonyl}-amino)-benzoic acid ethyl ester as a white solid. (Yield 0.14 g, 60.8%).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:15][CH2:16][CH3:17])([CH2:12][CH2:13][CH3:14])[C:4](=[O:18])[C:3]=1[C:19]1[NH:24][C:23]2[CH:25]=[CH:26][C:27]([OH:29])=[CH:28][C:22]=2[S:21](=[O:31])(=[O:30])[N:20]=1.Br[CH2:33][C:34]([NH2:36])=[O:35].C(=O)([O-])[O-].[Cs+].[Cs+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][CH2:13][CH3:14])([CH2:15][CH2:16][CH3:17])[C:4](=[O:18])[C:3]=1[C:19]1[NH:24][C:23]2[CH:25]=[CH:26][C:27]([O:29][CH2:33][C:34]([NH2:36])=[O:35])=[CH:28][C:22]=2[S:21](=[O:30])(=[O:31])[N:20]=1
Reactant: CCCC1(CCC)C(=O)C(C2=NS(=O)(=O)c3cc(O)ccc3N2)=C(O)c2ccccc21
Reactant: NC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCCC1(CCC)C(=O)C(C2=NS(=O)(=O)c3cc(OCC(N)=O)ccc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.4 %

Procedure:
A solution of the product of Example 2G (14 mg, 0.032 mmol), 2-bromoacetamide (9 mg, 0.064 mmol), cesium carbonate (22 mg, 0.067 mmol) and tetrabutylammonium iodide (3 mg) in N,N-dimethylformamide (0.5 mL) was stirred at 25° C. for 18 hours. The solution was acidified with 1M citric acid solution (1 mL) and extracted with ethyl acetate. The organic layer was washed with water (3×) and saturated sodium chloride solution, dried (Na2SO4), filtered and concentrated in vacuo. A suspension of the residue in acetonitrile (2 mL) was treated with 1N sodium hydroxide solution (26 μL) and stirred at 25° C. for 2 hours. The solution was lyophilized to afford the title compound (12 mg, 52%). 1H NMR (300 MHz, DMSO-d6): δ 8.12 (d, J=8.09 Hz, 1 H), 7.61 (m, 4 H), 7.31 (m, 2 H), 4.55 (s, 2 H), 2.15 (m, 2H), 1.87 (m, 2 H), 1.29 (m, 2 H), 0.87 (m, 2 H), 0.60 (m, 7 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7](Br)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.I[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>ClCCl.[Cu]>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)=[O:14]
Reactant: COC(=O)c1ccc(Br)c([N+](=O)[O-])c1
Reactant: Ic1ccccc1
Agent: [Cu]
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccccc2)c([N+](=O)[O-])c1
Temperature: 218 °C

Procedure:
The product from Example 212a (0.100 g, 0.384 mmol) was combined with iodobenzene (0.375 mL, 3.35 mmol) and copper powder (0.188 g, 2.96 mmol) and the mixture heated in a sealed tube to 218° C. for 90 minutes. The reaction mixture was subsequently diluted with dichloromethane and filtered through celite. The crude product, obtained by concentration under vacuum, was purified by flash chromatography on silica gel (ethyl acetate-hexanes) to give the title compound (0.0847 g, 86
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([I:9])[CH:8]=1)[NH2:5].O.[N:11]([O-])=O.[Na+].O.O.Cl[Sn]Cl>Cl>[I:1][C:2]1[CH:3]=[C:4]([NH:5][NH2:11])[CH:6]=[C:7]([I:9])[CH:8]=1
Reactant: O=N[O-]
Reactant: Nc1cc(I)cc(I)c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1cc(I)cc(I)c1
Temperature: -10 °C
Reaction time: 0.67 h

Procedure:
3,5-Diiodoaniline was obtained by the procedure of M. Bérubé (M. Bérubé, et al. Synthesis of Simplified Hybrid Inhibitors of Type 1 17β-Hydroxysteroid Dehydrogenase via the Cross-Metathesis and the Sonogashira Coupling Reactions, Organic Lett. 6 (2004) 3127-3130). 5 g (14.5 mmol) of 3,5-diiodoaniline were stirred with the solution of 5 mL of concentrated hydrochloric acid and 5 mL of water. The mixture was cooled to about −10° C. and 5.5 mL of 20% aqueous solution of NaNO2 was added dropwise with continuous stirring. The suspension was allowed to stir for another 40 minutes. Next, the cooled solution of 10.8 g (47.9 mmol) of SnCl2.2H2O in 11 mL of concentrated HCl was added dropwise at −10° C. to the suspension of diazocompound. The reaction mixture was kept −10° C. for one hour and at 5° C. overnight. The obtained precipitate of a double salt with tin chloride was filtered off and washed with water. The residue was resuspended in water and added concentrated aqueous solution of NaOH to alkaline medium. The 3,5-diiodophenylhydrazine was extracted with ether, the organic layer was washed in turn with aqueous NaOH, Na2S2O3 and water, and dried with CaCl2. Ether was evaporated to give 4.2 g of 3,5-diiodophenylhydrazine. 1H-NMR (200 MHz, DMSO-d6), δ, ppm: 7.10 (2H, d, 1.2 Hz, arom.), 6.92 (1H, d, 1.2 Hz, arom.), 5.51 (1H, s, NH), 4.12 (2H, broad s, NH2).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][C:9]([C:15]#[N:16])=[C:8]2O)(=[O:3])[CH3:2].O=P(Cl)(Cl)[Cl:20]>>[C:1]([NH:4][C:5]1[N:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][C:9]([C:15]#[N:16])=[C:8]2[Cl:20])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc2ncc(C#N)c(O)c2n1
Reactant: O=P(Cl)(Cl)Cl
Product: CC(=O)Nc1ccc2ncc(C#N)c(Cl)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19 %

Procedure:
A solution of 6-acetamido-4-hydroxyl-[1.5]naphthyridine-3-carbonitrile (1.0 g, 4.386 mmol) was heated at reflux in POCl3 (20 ml) under nitrogen for 5 hrs. After cooling, the solvent was removed by rotary evaporation. Ice water was added to the black residue, which was cooled (ice bath) and stirred for 1 hr. The mixture was warmed to room temperature and stirred at room temperature for 1 hr. The mixture was cooled with ice bath, and made basic with NH4OH. The aqueous layer was extracted with CH2Cl2. The combined extracts were washed with water, dried (Na2SO4) and concentrated to give the title compound as a dark blue solid (200 mg, 19%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH:11]=O.[C:13]1([NH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:19].S(=O)(O)[O-].[Na+]>C1COCC1.Cl.C(OCC)(=O)C>[NH:19]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:20]=[C:11]1[C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=2)[NH:7][N:6]=1
Reactant: Nc1ccccc1N
Reactant: O=Cc1n[nH]c2ccc(Br)cc12
Agent: Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Brc1ccc2[nH]nc(-c3nc4ccccc4[nH]3)c2c1
Temperature: 25 °C
Yield: 50 %

Procedure:
5-Bromo-1H-indazole-3-carbaldehyde (50 mg, 0.222 mmol) and o-phenylene diamine (24 mg, 0.222 mmol) were dissolved in dry THF (10 mL). One drop of 2N HCl was added. The solution was heated at a gentle reflux for 30 min and then 1N sodium bisulfite (1 mL) was added. After overnight at reflux, the solution was cooled to room temperature, and then diluted with ethyl acetate (30 mL). The mixture was washed with water and brine, dried over Na2SO4, and concentrated. Purification by flash chromatography (20% ethyl acetate/hexane) afforded the title compound as a pale yellow solid in a 50% yield. 1H NMR (400 MHz, CDCl3): δ 8.73 (d, 1H, J=1.2 Hz), 7.80 (m, 1H), 7.48-7.45 (m, 2H), 7.37 (d, 1H, J=8.8 Hz), 7.23 (m, 2H); ESI-MS [M+H]+: 313.0.