Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3]C1.[C:6]12([OH:17])[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][C:8]([OH:16])([CH2:9]3)[CH2:7]1)[CH2:13]2.[H-].[Na+].[CH2:20]([CH:22]1[O:24][CH2:23]1)Cl>C(Cl)(Cl)Cl>[CH2:20]([O:17][C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][C:8]([O:16][CH2:3][CH:4]4[O:1][CH2:5]4)([CH2:9]3)[CH2:7]1)[CH2:13]2)[CH:22]1[O:24][CH2:23]1
Reactant: ClCC1CO1
Reactant: C1CCOC1
Reactant: OC12CC3CC(C1)CC(O)(C3)C2
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: C1C2CC3(OCC4CO4)CC1CC(OCC1CO1)(C2)C3
Reaction time: 12 h
Yield: 6.4 %

Procedure:
300 ml of dehydrated tetrahydrofuran containing 16.8 g (0.1 mol) of 1,3-adamantanediol and 5.3 g (0.22 mol) of sodium hydride was stirred in a nitrogen atmosphere at the reflux temperature for 2 hours. Thereto was dropwise added 20.4 g (0.22 mol) of epichlorohydrin, followed by stirring at the reflux temperature for 12 hours. To the reaction mixture was added 200 ml of chloroform. The chloroform layer was washed with water and dried with magnesium sulfate. The dried chloroform layer was subjected to distillation under reduced pressure for solvent removal, to obtain oily matter. It was purified by silica gel column chromatography to obtain 1.79 g (yield: 6.4%) of oily matter.
Reaction SMILES: N[C@H](C(O)=O)CO.[OH:8][CH2:9][CH:10]([C:19]([OH:21])=O)[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[CH2:22]([O:29][NH2:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN=C=NCCCN(C)C.Cl>>[OH:8][CH2:9][CH:10]([C:19]([NH:30][O:29][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21])[NH:11][C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13]
Reactant: NOCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC(CO)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N[C@@H](CO)C(=O)O
Product: CC(C)(C)OC(=O)NC(CO)C(=O)NOCc1ccccc1

Procedure:
The 2,3-diaminopropionic acid esters, NH2—CH—[CH(R3)—NH2]—C(O)ester, are prepared as follows. t-Boc protected serine, HOCH2CH(NH-t-Boc)COOH, is coupled with O-benzylhydroxylamine at pH 4-5 with EDC HCl to provide the hydroxamate, HOCH2CH(NH-t-Boc)CONHOBn. The latter is cyclized in acetonitrile with triphenylphosphene-carbon tetrachloride in the presence of triethylamine to form the β-lactam, 1-benzyloxy-3-t-Boc-aminoazetidin-2-one. The β-lactam is then saponified with lithium hydroxide to provide, in 100% yield, the 2,3-diaminopropionic acid derivative, BnONHCH2CH(NH-t-Boc)COOH. In the above Bn is benzyl. The carboxylic acid group of the derivative obtained is esterified for use in the coupling reaction of Reaction scheme 3. The OBn protecting group is left intact during the coupling reaction while the t-Boc protecting group is removed to provide the free amino group involved in the coupling. Following amide formation the OBn group is removed via hydrogenation to provide the free amino amide ester for cyclization to the imidazoline. The above sequence of reactions is illustrated below.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:28])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[C:22](I)[CH:21]=3)=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[O:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B(O)O)[CH3:30].C(OC(C1CCN(C2C=CC(C(=O)NC3C=CC(C4C=CC=CC=4)=C(C)C=3)=CN=2)CC1)=O)C>>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:28])[NH:19][C:20]3[CH:21]=[C:22]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[O:29][CH3:30])[C:23]([CH3:26])=[CH:24][CH:25]=3)=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc(C)c(I)c3)cn2)CC1
Reactant: COc1ccccc1B(O)O
Agent: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc(-c4ccccc4)c(C)c3)cn2)CC1
Product: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc(C)c(-c4ccccc4OC)c3)cn2)CC1

Procedure:
5′-(2′-Methoxy-6-methyl-biphenyl-3-ylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid ethyl ester was prepared from 5′-(3-iodo-4-methyl-phenylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4 carboxylic acid ethyl ester and 2-methoxylphenyl boronic acid following a method similar to the one described in the synthesis of 5′-(2-methyl-biphenyl-4-ylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid ethyl ester above. The product was isolated after silica gel column purification with 20-40% EtOAc in hexanes gradient. HRMS m/z calcd for C28H31N3O4 [M+H]+: 474.2388. Found: 474.2387.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)(=O)=O.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][CH2:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(O)cc1Cl
Reactant: CS(=O)(=O)OCC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(OCC2CCCC2)cc1Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 92.6 %

Procedure:
To a solution of 3-chloro-4-methylphenol (1.00 g) in N,N-dimethylformamide (8 ml) was added potassium carbonate powder (1.44 g) and the mixture was heated to 80° C. Thereto was added cyclopentylmethyl methanesulfonate (1.57 g) and the mixture was stirred at 120° C. for 3 hr. The reaction mixture was cooled to room temperature. Water was added and the mixture was extracted 3 times with hexane. The organic layers were combined and washed successively with 1N aqueous sodium hydroxide solution, water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by column chromatography (silica gel, hexane) to give 2-chloro-4-((cyclopentyl)methyloxy)toluene (1.46 g) as a colorless oil.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([CH2:8][C:9]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[Cl:24])([OH:16])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1)(=[O:7])[NH2:6].N1C=CC=CC=1>C(#N)C>[OH2:3].[C:1]([NH:6][C:5]([CH2:8][C:9]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[Cl:24])([OH:16])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1)=[O:7])(=[O:3])[CH3:2].[C:1]([NH:6][C:5]([CH2:8][C:9]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[Cl:24])([OH:16])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1)=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: NC(=O)CC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: CC(=O)NC(=O)CC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Product: O
Temperature: 25 °C
Reaction time: 18 h
Yield: 18.3 %

Procedure:
A solution of acetyl chloride (0.12 g, 1.5 mmole) in dry acetonitrile (2 ml) was added dropwise to a stirred solution of 3-carbamoyl-2-(2,4-dichlorophenyl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol (0.314 g., 1 mmole) and pyridine (0.12 g., 1.5 mmole) in dry acetonitrile (2 ml) at -20° C. The solution was allowed to warm to room temperature and was stirred at room temperature for a further 18 hours. The solvent was then removed under reduced pressure and the residue was partitioned between water (10 ml) and chloroform (40 ml). The organic phase was separated, dried over MgSO4 and evaporated. The residue was chromatographed on silica eluting with 10:1 (v:v) chloroform/methanol and the fractions containing the product were combined, evaporated, and recrystallized from diisopropyl ether to furnish the title compound, (67 mg., 19%), m.p. 148°-150° C.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.CCOCC.C(=O)([O-])[O-].[Na+].[Na+].[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(OCC)(=O)C.O>[C:23]([N:1]1[CH2:2][CH2:3][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10][CH2:11]1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C1CCN(C(=O)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a ice cold, stirred mixture of 55 g of ethyl isonipecotate, 200 mL of ether, 200 mL of saturated sodium carbonate and 200 mL of water was added dropwise 40 mL of benzoyl chloride. The resulting mixture was allowed to warm and stir overnight, diluted with 200 mL of ethyl acetate and separated. The organic layer was washed with 200 mL of 1N hydrochloric acid, dried over MgSO4, and concentrated. Drying the residue under vacuum gave 83.3 g (92%) of ethyl 1-benzoyl-4-piperidinecarboxylate as a white solid.
Reaction SMILES: [CH3:1][CH:2]1[O:23][C:22]2[C:5](=[CH:6][C:7]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9][C:8]=3[CH:21]=2)[NH:4][CH2:3]1.CI.[C:26](=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:1][CH:2]1[O:23][C:22]2[C:5](=[CH:6][C:7]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:10][CH2:9][C:8]=3[CH:21]=2)[N:4]([CH3:26])[CH2:3]1
Reactant: O=C([O-])[O-]
Reactant: CC1CNc2cc3c(cc2O1)CCN(C(=O)OC(C)(C)C)CC3
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CC1CN(C)c2cc3c(cc2O1)CCN(C(=O)OC(C)(C)C)CC3
Reaction time: 13 h
Yield: 43.9 %

Procedure:
To a solution of 120 mg of t-butyl 2-methyl-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylate in 4 ml of DMF were added 0.026 ml of methyl iodide and 104 mg of potassium carbonate at room temperature, followed by stirring for 13 hours. To the reaction mixture were added 0.012 ml of methyl iodide and 26 mg of potassium carbonate, followed by further stirring for 3 hours. To the reaction mixture was added water, followed by extraction with EtOAc twice. The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: HEX-EtOAc) to obtain 55 mg of t-butyl 2,4-dimethyl-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylate as a brown solid.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C[Al](C)C.C([O:11][C:12]([C:14]1[N:19]2[N:20]=[C:21]([NH:23][C:24]([NH:26][CH2:27][CH3:28])=[O:25])[N:22]=[C:18]2[CH:17]=[C:16]([Br:29])[CH:15]=1)=O)C>O1CCCC1.CCCCCCC.ClCCl>[CH:1]1([NH:4][C:12]([C:14]2[N:19]3[N:20]=[C:21]([NH:23][C:24]([NH:26][CH2:27][CH3:28])=[O:25])[N:22]=[C:18]3[CH:17]=[C:16]([Br:29])[CH:15]=2)=[O:11])[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: CCNC(=O)Nc1nc2cc(Br)cc(C(=O)OCC)n2n1
Agent: C[Al](C)C
Solvent: CCCCCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCNC(=O)Nc1nc2cc(Br)cc(C(=O)NC3CC3)n2n1

Procedure:
Cyclopropylamine (0.136 g, 2.38 mmol) was suspended in tetrahydrofuran (2.00 mL) and cooled in an ice bath. This solution was charged with 2 molar trimethylaluminum in heptane (0.300 mL). After 20 minutes the solution was charged with 7-bromo-2-(3-ethyl-ureido)-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid ethyl ester produced as in Example 6, (0.248 g, 0.696 mmol) and shaken. After 24 hours the reaction was dissolved in dichloromethane and washed with saturated aqueous ammonium chloride. The organic layers were dried over magnesium sulfate and concentrated to afford 7-bromo-2-(3-ethyl-ureido)-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid cyclopropylamide MS (ACPI+): m/z 368.2 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[N:4][CH:3]=1.[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH2:19][OH:20]>>[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH2:19][O:20][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[N:7]=1
Reactant: OCc1ccco1
Reactant: Clc1cncc(N2CCNCC2)n1
Product: c1coc(COc2cncc(N3CCNCC3)n2)c1
Temperature: 110 °C
Reaction time: 7.5 h
Yield: 74 %

Procedure:
K-t-BuO (1.55 g, 13.8 mmol) was added to a mixture of the product from step 2 above (1.40 g, 7.05 mmol) and 2-furanmethanol (5.3 g, 54 mmol). After being stirred for 7.5 h at 110° C., the mixture was applied onto a bed of silica (16×6 cm). Elution with CHCl3/MeOH (95:5 followed by 90:10) furnished 1.35 g (74%) of the title compound as an oil. HRMS m/z calcd for C13H16N4O2(M)+ 260.1273, found 260.1276. Anal. (C13H16N4O2) C, H, N.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[CH:20](O)=[O:21]>O1CCCC1>[CH:13]([C:12]1[CH:11]=[CH:10][C:9]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][CH:20]=[O:21])=[C:3]([N+:17]([O-:19])=[O:18])[CH:4]=2)=[CH:16][CH:15]=1)=[O:14]
Reactant: Nc1ccc(Oc2ccc(C=O)cc2)cc1[N+](=O)[O-]
Reactant: O=CO
Solvent: C1CCOC1
Product: O=CNc1ccc(Oc2ccc(C=O)cc2)cc1[N+](=O)[O-]

Procedure:
4-[(4-amino-3-nitrophenyl)oxy]benzaldehyde (1.4 g, 5.4 mmol), 10 mL of 96% formic acid and 25 mL of tetrahydrofuran were heated at reflux for approximately 18 hours. The reaction was concentrated and the residue was heated to reflux in 96% formic acid for six hours. The reaction mixture was concentrated to give {4-[(4-formylphenyl)oxy]-2-nitrophenyl}formamide. (M-1) 285.1, 2.22 min (LC/MS method A)
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][N:7]=[C:8]([C:16]1[CH:21]=[CH:20][C:19]([O:22][S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24])=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)=[O:5])[CH3:2].[H-].[Na+].[H][H].[Cl:34][C:35]([Cl:39])([Cl:38])[S:36]Cl>O1CCCC1>[CH2:1]([O:3][C:4]([N:6]([S:36][C:35]([Cl:39])([Cl:38])[Cl:34])[N:7]=[C:8]([C:16]1[CH:21]=[CH:20][C:19]([O:22][S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24])=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)=[O:5])[CH3:2]
Reactant: ClSC(Cl)(Cl)Cl
Reactant: CCOC(=O)NN=C(c1ccc(Cl)cc1)c1ccc(OS(=O)(=O)C(F)(F)F)cc1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)N(N=C(c1ccc(Cl)cc1)c1ccc(OS(=O)(=O)C(F)(F)F)cc1)SC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 30 %

Procedure:
A solution of 4-chloro-4'-trifluoromethylsulfonyloxybenzophenone-N-ethoxYcarbonylhydrazone (0.5 g) in tetrahydrofuran (6 ml) was stirred at room temperature under a nitrogen atmosphere, during which an oily mixture (50 mg) of sodium hydride containing 60% (w/w) sodium hydride was added to the solution at a time. After stirring at room temperature for 15 minutes and finding no evolution of hydrogen gas, the mixture was cooled to -78° C., and trichloromethanesulfenyl chloride (0.3 g) was added dropwise over 3 minutes. The reaction mixture was warmed to room temperature over 4 hours, and then poured into ice-water. Further, a saturated saline solution was added thereto. The aqueous layer was extracted with ethyl acetate, and the extract was combined with the organic layer. The combined organic layer was dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel chromatography, which afforded 0.2 g of 4-chloro-4'-trifluoromethylsulfonyloxybenzophenone-N-ethoxycarbonyl-N-trichloromethanesulfenylhydrazone (compound 31 ).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:14][C:15]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:16]=1[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[O:18]>>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH:14][C:15]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:16]=2[C:17]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)=[O:18])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(NC(=O)c2cc(C)ccc2N)cc1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Product: COc1ccc(NC(=O)c2cc(C)ccc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Yield: 46 %

Procedure:
Using the procedure described in Example 93, Part A, 4-tert-butylbenzoyl chloride (1.3 mmol) and 2-amino-N-(4-methoxyphenyl)-5-methylbenzamide (1.2 mmol) yielded 0.23 g (47%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1.[Br:15]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11]([CH2:14][Br:15])=[CH:12][CH:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccccc2F)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccccc1-c1ccc(CBr)cc1

Procedure:
A mixture of 2-fluoro-4′-methylbiphenyl (8.70 g), N-bromosuccinimide (8.32 g), 2,2′-azobisisobutyronitrile (0.10 g) and carbon tetrachloride (150 ml) is refluxed by heating for five hours. The reaction solution is washed with water. The residue, which is obtained by concentrating the organic layer, is purified using silica gel column chromatography (eluate: hexane/ethyl acetate=9/1) and thus, preliminarily purified 2-fluoro-4′-bromomethylbiphenyl is obtained. Furthermore, crystallization using hexane produced 2-fluoro-4′-bromomethylbiphenyl (4.93 g). 1H-NMR (CDCl3, δ): 4.55 (2H, s), 7.13-7.23 (2H, m), 7.33 (1H, m), 7.43 (1H, m), 7.47 (2H, d, J=8.1 Hz), 7.54 (2H, d, J=8.1 Hz).
Reaction SMILES: [CH3:1][CH:2]([C@@H:15]1[C@:32]2([CH3:33])[C@H:18]([C:19]3[C@H:29]([CH2:30][CH2:31]2)[C@:27]2([CH3:28])[C:22]([CH2:23][C@@H:24]([O:39][C:40]([O:42][CH3:43])=[O:41])[CH2:25][C@@H:26]2[O:34][C:35]([O:37][CH3:38])=[O:36])=[CH:21][CH:20]=3)[CH2:17][CH2:16]1)[CH2:3]OS(C1C=CC(C)=CC=1)(=O)=O.[I-:44].[Na+]>CC(C)=O>[I:44][CH2:3][CH:2]([CH3:1])[C@@H:15]1[C@:32]2([CH3:33])[C@H:18]([C:19]3[C@H:29]([CH2:30][CH2:31]2)[C@:27]2([CH3:28])[C:22]([CH2:23][C@@H:24]([O:39][C:40]([O:42][CH3:43])=[O:41])[CH2:25][C@@H:26]2[O:34][C:35]([O:37][CH3:38])=[O:36])=[CH:21][CH:20]=3)[CH2:17][CH2:16]1
Reactant: [I-]
Reactant: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)COS(=O)(=O)c5ccc(C)cc5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)CI)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Yield: 77.2 %

Procedure:
To a solution of 53 mg of 20-methyl-1α,3β-bis-(methoxycarbonyloxy)-21-p-toluenesulfonyloxypregna-5,7 -diene in 5 ml of acetone was added 120 mg of sodium iodide and the mixture was heated under reflux for 4 hours. The reaction mixture was cooled, then the acetone was distilled off under reduced pressure, water was added to the residue, and the resulting mixture was extracted with diethyl ether. The extract was washed with water, an aqueous solution of sodium thiosulfate, water, an aqueous solution of sodium hydrogen carbonate and an aqueous solution of sodium chloride, then dried over sodium sulfate and concentrated. Purification of the residue by silica gel column chromatography gave 38 mg of 21-iodo-20-methyl-1α,3β-bis(methoxycarbonyloxy)-pregna-5,7-diene.
Reaction SMILES: [NH:1]([C:66]([O:68][CH2:69][C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1)=[O:67])[C@@H:2]([C:15]([NH:17][C@H:18]([C:26]([NH:28][C@H:29]([C:39]([NH:41][C@H:42]([C:46]([NH:48][C@H:49]([C:62]([O:64][CH3:65])=[O:63])[CH2:50][C:51]1[CH:56]=[CH:55][C:54]([O:57]C(C)(C)C)=[CH:53][CH:52]=1)=[O:47])[CH:43]([CH3:45])[CH3:44])=[O:40])[CH2:30][CH2:31][C:32](=[O:38])[O:33]C(C)(C)C)=[O:27])[CH2:19][CH2:20][CH2:21][NH:22][C:23](=[NH:25])[NH2:24])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7]C(OC(C)(C)C)=O.Cl.O>FC(F)(F)C(O)=O>[NH:1]([C:66]([O:68][CH2:69][C:70]1[CH:71]=[CH:72][CH:73]=[CH:74][CH:75]=1)=[O:67])[C@@H:2]([C:15]([NH:17][C@H:18]([C:26]([NH:28][C@H:29]([C:39]([NH:41][C@H:42]([C:46]([NH:48][C@H:49]([C:62]([O:64][CH3:65])=[O:63])[CH2:50][C:51]1[CH:56]=[CH:55][C:54]([OH:57])=[CH:53][CH:52]=1)=[O:47])[CH:43]([CH3:45])[CH3:44])=[O:40])[CH2:30][CH2:31][C:32](=[O:33])[OH:38])=[O:27])[CH2:19][CH2:20][CH2:21][NH:22][C:23](=[NH:24])[NH2:25])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].[CH3:31][C:32]([OH:38])=[O:33]
Reactant: COC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)[C@@H](NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1)C(C)C
Agent: Cl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)O
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](CCCCN)NC(=O)OCc1ccccc1)C(C)C

Procedure:
3.6 g (3.3 mmoles) of Z-D-Lys(Boc)-Arg-Glu(OBut)-Val-Tyr(But)-OMe.HCl are dissolved in 30 ml of 90 percent strength trifluoroacetic acid and the product is worked up analogously to Example 27 D. Yield 2.81 g (94%), [α]D23 =-32.4° (c=1, water).
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH:12]([CH3:14])[CH3:13])[C:9]2[CH:15]=[C:16]([Br:21])[C:17]([O:19][CH3:20])=[CH:18][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>[Cl-].[Na+].O>[Br:21][C:16]1[C:17]([O:19][CH3:20])=[CH:18][C:8]2[CH2:7][CH2:6][NH:5][CH2:11][CH:10]([CH:12]([CH3:14])[CH3:13])[C:9]=2[CH:15]=1
Reactant: COc1cc2c(cc1Br)C(C(C)C)CN(C(=O)C(F)(F)F)CC2
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc2c(cc1Br)C(C(C)C)CNCC2
Reaction time: 8 h
Yield: 1117.7 %

Procedure:
A solution of N-trifluoroacetyl-8-bromo-1-isopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (0.013 g, 0.03 mmol) methanol (0.5 mL) was treated with 15% aqueous NaOH (0.5 mL), and stirred overnight at 20 C. The product mixture was diluted with brine (5 mL), extracted twice with EtOAc (5 mL), dried with MgSO4, and concentrated to give 0.10 g of a clear oil. 1H NMR (400 MHz, CD3OD) d 7.08 (s, 1H), 6.64 (s, 1H), 3.72 (s, 3H), 3.2-3.10 (m, 3H), 2.7-2.5 (m, 3H), 2.3-2.1 (m, 2H), 0.96 (d, 3H), 0.63 (d, 3H). MS calculated for C14H20BrNO+H: 298, observed: 298.
Reaction SMILES: [N:1](=[C:3]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16]CC)=[O:15])=[CH:12][CH:11]=1)[OH:2].[OH-].[K+].C(O)C>O>[N:1](=[C:3]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[CH:19][CH:20]=1)[OH:2]
Reactant: CCCCCCCCCCC(CCCCCNc1ccc(C(=O)OCC)cc1)=NO
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCC(CCCCCNc1ccc(C(=O)O)cc1)=NO

Procedure:
A solution of the ethyl 4-(6-oximinohexadecylamino)benzoate, 1.0 g. of potassium hydroxide and 15 ml. of ethanol in 15 ml. of water is stirred under reflux for 2 hours, evaporated, and then treated with 15 ml. of water and 2.3 ml. of concentrated hydrochloric acid. The mixture is extracted with methylene chloride and the dried extract is evaporated. Crystallization from ethanol-water affords the product as a white solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([CH3:23])=[C:6]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([C:21]#[N:22])[CH:16]=2)[C:7]([O:13][CH3:14])=[C:8]([CH:10](Cl)[CH3:11])[CH:9]=1.[NH2:24][C:25]1[N:30]=[CH:29][N:28]=[C:27]2[NH:31][N:32]=[CH:33][C:26]=12.O>CN(C)C=O>[NH2:24][C:25]1[N:30]=[CH:29][N:28]=[C:27]2[N:31]([CH:10]([C:8]3[C:7]([O:13][CH3:14])=[C:6]([C:15]4[CH:20]=[CH:19][N:18]=[C:17]([C:21]#[N:22])[CH:16]=4)[C:5]([CH3:23])=[C:4]([Cl:3])[CH:9]=3)[CH3:11])[N:32]=[CH:33][C:26]=12
Reactant: Nc1ncnc2[nH]ncc12
Reactant: COc1c(C(C)Cl)cc(Cl)c(C)c1-c1ccnc(C#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(C(C)n2ncc3c(N)ncnc32)cc(Cl)c(C)c1-c1ccnc(C#N)c1
Temperature: 30 °C
Reaction time: 8 h

Procedure:
Sodium hydride (20.0 mg, 0.50 mmol) was added to a mixture of 4-[3-chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]pyridine-2-carbonitrile (from Example 16, Step 3) (90 mg, 0.28 mmol), 4-aminopyrazolo[3,4-d]pyrimidine (from Acros Organics) (57 mg, 0.42 mmol) in N,N-dimethylformamide (4 mL) and the reaction was stirred at 30° C. overnight. The mixture was treated with water and then filtered to provide the desired product. LCMS calculated for C21H19ClN7O (M+H)+: m/z=420.1; Found: 420.1
Reaction SMILES: [CH:1]([NH:4][S:5]([C:8]1[CH:19]=[C:12]2[C:13]([O:15]C(=O)[NH:17][C:11]2=[CH:10][CH:9]=1)=O)(=[O:7])=[O:6])([CH3:3])[CH3:2].[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C(Cl)Cl.C(OCC)C>[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:13](=[O:15])[C:12]2[C:11](=[CH:10][CH:9]=[C:8]([S:5](=[O:6])(=[O:7])[NH:4][CH:1]([CH3:2])[CH3:3])[CH:19]=2)[NH2:17])[CH2:23][CH2:22]1
Reactant: CN1CCNCC1
Reactant: CC(C)NS(=O)(=O)c1ccc2[nH]c(=O)oc(=O)c2c1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)NS(=O)(=O)c1ccc(N)c(C(=O)N2CCN(C)CC2)c1

Procedure:
In a manner analogous to that described in Example 1, the reaction of 5-(N-isopropylsulfamoyl)-isatoic anhydride with 1-methylpiperazine yields 5-(N-isopropylsulfamoyl)-anthranilic acid (4-methyl)-piperazide with a melting point of 118°-122° (from methylene chloride/diethyl ether; melting point of the methanesulfonate: 232°-234°).