Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[CH:11]=[CH:10][C:9]=2[C:17]([NH2:19])=[O:18])[CH2:3][CH2:2]1.[CH:20](=O)[CH3:21].C([BH3-])#N.[Na+].C(O)(=O)C>CO.O>[CH2:20]([N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[CH:11]=[CH:10][C:9]=2[C:17]([NH2:19])=[O:18])[CH2:3][CH2:2]1)[CH3:21]
Reactant: CC=O
Reactant: NC(=O)c1ccc(C(N)=O)c(NC2CCNCC2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CCN1CCC(Nc2cc(C(N)=O)ccc2C(N)=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.7 %

Procedure:
To a solution of N4-[8-(5-acetylpyridin-2-yl)-8-azabicyclo[3.2.1]oct-3-endo-yl]-2-(piperidin-4-ylamino)benzene-1,4-dicarboxamide (130 mg, 0.28 mmol) in methanol were added acetaldehyde (12 mg, 0.28 mmol), sodium cyanoborohydride (18 mg, 0.28 mmol) and acetic acid (17 mg, 0.28 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h. Then the reaction mixture was poured into water (250 mL), extracted with ethyl acetate (2×50 mL), dried over sodium sulfate, filtered and concentrated to a volume of 10 mL. The precipitate thus formed was collected by filtration to give N4-[8-(5-acetylpyridin-2-yl)-8-azabicyclo[3.2.1]oct-3-endo-yl]-2-[(1-ethylpiperidin-4-yl)amino]benzene-1,4-dicarboxamide (16 mg, 12% yield). 1H NMR (400 MHz, methanol-d4): 8.70 (s, 1H), 8.06 (d, J=9.2 Hz, 1H), 7.69 (d, J=8.2 Hz, 1H), 7.14 (s, 1H), 6.98 (d, J=8.2 Hz, 1H), 6.77 (d, J=9.2 Hz, 1H), 4.70 (br, s, 2H), 4.02 (m, 1H), 3.82-3.45 (m, 2H), 3.20-3.05 (m, 6H), 3.00 (s, 6H), 2.53 (s, 3H), 2.40-2.1 (m, 10H), 2.05 (m, 2H), 1.34 (t, J=7.2 Hz, 3H). MS (EI) for C29H38N6O3: 519 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].[C:24]1(C)C=C[CH:27]=[CH:26][CH:25]=1.ClC(Cl)([O:34][C:35](=O)[O:36]C(Cl)(Cl)Cl)Cl.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)CCC.C(N(CC)CC)C>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:35](=[O:34])[O:36][CH2:27][CH2:26][CH2:25][CH3:24]
Reactant: Cc1ccccc1
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCOC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl
Yield: 66 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-butanol (17 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (50 mg, yield 66%).
Reaction SMILES: N[CH:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH:12]([CH2:17][C:18]([O:20]C)=[O:19])[C:13]([O:15]C)=[O:14])[CH:5]=[N:4][C:3]1=2.C(O)(=[O:24])C.N([O-])=O.[Na+].C(OCC)C>O>[O:24]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH:12]([C:13]([OH:15])=[O:14])[CH2:17][C:18]([OH:20])=[O:19])[CH:5]=[N:4][C:3]1=2
Reactant: COC(=O)CC(Cn1cnc2c1N=CNC2N)C(=O)OC
Reactant: CC(=O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: O=C(O)CC(Cn1cnc2c(=O)[nH]cnc21)C(=O)O
Yield: 31 %

Procedure:
2.00 g (6.82 mmol) of 2-[(1,6-dihydro-6-amino-9H-purin-9-yl)methyl]butanedioic acid, dimethyl ester (AIT-0073) was placed into a 50 ml round bottom flask equipped with a magnetic stirring bar. Then 10 ml glacial acetic acid was added and the solution was stirred until homogeneous. 2.35 g (34.10 mmol) of NaNO2 in 4 ml of H2O was added to the stirring solution dropwise. The stoppered solution was stirred for 24 hours at room temperature. An additional 0.775 g (11.23 mmol) of NaNO2 in 1 ml H2O was added and the solution was stirred for another 24 hours. The acetic acid was removed under reduced pressure on the rotary evaporator. Water was added and was removed in the same manner. This was repeated again until little or no more acetic acid was left. 10 ml of H2O was added to the semi-solid residue to completely dissolve the mixture. This solution was extracted with 30 ml-40 ml of acetonitrile and the aqueous layer was discarded. The organic layer was washed twice with 30 ml of saturated brine. Upon evaporation of the solvent, a light orange oil was obtained. This was treated with 35 ml of ethyl ether and triturated with methanol to yield 615 mg of 3-[(1,6-dihydro-6-oxo-9H-purin-9-yl)methyl]butanedioicacid, methyl diester (AIT-0075) as an off-white solid. Yield: 31% m.p. 130°-135° C.
Reaction SMILES: C[O:2][C:3]([C@@H:5]([NH:10][CH:11]([C:13]([N:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1[C:17]([OH:19])=[O:18])=[O:14])[CH3:12])[CH2:6][CH2:7][S:8][CH3:9])=[O:4].[OH-].[Na+]>O>[C:3]([C@@H:5]([NH:10][C@H:11]([C:13]([N:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1[C:17]([OH:19])=[O:18])=[O:14])[CH3:12])[CH2:6][CH2:7][S:8][CH3:9])([OH:4])=[O:2]
Reactant: COC(=O)[C@H](CCSC)NC(C)C(=O)N1CCC[C@H]1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CSCC[C@H](N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O)C(=O)O
Reaction time: 2 h

Procedure:
A solution of N-(1(S)-methoxycarbonyl-3-methylthiopropyl)-DL-alanyl-L-proline (127.5 mg; 0.384 mM) in 2 ml of water is treated under nitrogen with 7.82 ml 0.100N sodium hydroxide (0.782 mM) and stirred for 21/2 hr. at room temperature. The product is absorbed from the reaction mixture onto 30 ml of Dowex 50 (H+) and eluted with 4% aqueous pyridine to yield 73.5 mg., which is further purified over a LH-20 column to yield 55.7 mg. of product. The nmr spectrum in D2O shows S-CH3 at 2.1; -CH3 at 1.5 and 1.6δ and no methyl ester. The mass spectrogram on silylated material shows the expected molecular ion at 462 m/e.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7](SC)=[CH:8][CH:9]=1)([O-:3])=[O:2].[S:12](=[O:16])(=O)(O)[OH:13].[Mn]([O-])(=O)(=O)=O.[K+].[CH3:23]C(C)=O>>[N+:1]([C:4]1[CH:5]=[N:6][C:7]([S:12]([CH3:23])(=[O:16])=[O:13])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=S(=O)(O)O
Reactant: CC(C)=O
Reactant: CSc1ccc([N+](=O)[O-])cn1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Product: CS(=O)(=O)c1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
3-Nitro-6-(methylthio)pyridine (22.0 g, 129.3 mmol) was dissolved in acetone (140 mL). Sulfuric acid (2N, 230 mL) was then added dropwise to above solution to form a slurry. Potassium permanganate (KMnO4) (26.5 g, 168.1 mmol, dissolved in 500 mL of H2O) was added to the above mixture dropwise. The mixture that resulted was stirred at room temperature overnight. The solid was filtered and stirred with a warm mixture of ethanol/methanol (10/1). The insoluble salt was filtered, the filtrate was concentrated to provide a pale yellow solid. The crude product was recrystallized from ethanol to furnish the title compound (17.8 g, 70%).
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[C:8]12([C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([NH:28][C:29]4[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:30]=4[C:31]([O:33][CH3:34])=[O:32])=[O:27])=[CH:22][CH:21]=3)=O)[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2.C([SiH](CC)CC)C>C(OCC)(=O)C>[C:8]12([CH2:18][C:20]3[CH:21]=[CH:22][C:23]([C:26]([NH:28][C:29]4[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:30]=4[C:31]([O:33][CH3:34])=[O:32])=[O:27])=[CH:24][CH:25]=3)[CH2:9][CH:10]3[CH2:11][CH:12]([CH2:13][CH:14]([CH2:16]3)[CH2:15]1)[CH2:17]2.[C:8]12([CH:18]([O:2][C:1](=[O:7])[C:3]([F:6])([F:5])[F:4])[C:20]3[CH:21]=[CH:22][C:23]([C:26]([NH:28][C:29]4[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:30]=4[C:31]([O:33][CH3:34])=[O:32])=[O:27])=[CH:24][CH:25]=3)[CH2:9][CH:10]3[CH2:11][CH:12]([CH2:13][CH:14]([CH2:16]3)[CH2:15]1)[CH2:17]2
Reactant: O=C(O)C(F)(F)F
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)c1ccc(C(=O)C23CC4CC(CC(C4)C2)C3)cc1
Agent: CC[SiH](CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Cl)ccc1NC(=O)c1ccc(C(OC(=O)C(F)(F)F)C23CC4CC(CC(C4)C2)C3)cc1
Product: COC(=O)c1cc(Cl)ccc1NC(=O)c1ccc(CC23CC4CC(CC(C4)C2)C3)cc1
Reaction time: 17 h
Yield: 62 %
Yield: 21 %

Procedure:
4 mL of TFA was added at room temperature to 350 mg (0.77 mmol) of methyl 2-({[4-(adamantan-1-ylcarbonyl)phenyl]carbonyl}amino)-5-chlorobenzoate obtained in Example 56-(ii). 360 mg (3.1 mmol) of triethyl silane was added thereto, and the mixture was stirred for 17 hours. The reaction mixture was diluted with ethyl acetate, and washed with an aqueous saturated sodium hydrogen carbonate solution and saturated saline. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was separated and purified by silica gel chromatography, thereby giving 70 mg of methyl 2-({[4-(adamantan-1-ylmethyl)phenyl]carbonyl}amino)-5-chlorobenzoate (yield: 21%) and 262 mg of methyl 2-{[(4-{adamantan-1-yl[(trifluoro-acetyl)oxy]methyl]phenyl)carbonyl}amino}-5-chlorobenzoate (yield: 62%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1N=NC(Cl)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.C(C1C=CC([F:62])=CC=1)#C>>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:25]2[CH:30]=[CH:29][C:28]([F:62])=[CH:27][CH:26]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C(#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1)c1ccccc1
Reactant: C#Cc1ccc(F)cc1
Agent: Clc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Product: Fc1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1
Yield: 72 %

Procedure:
Prepared as described for 3,4-bis(benzyloxy)-6-(phenylethynyl)pyridazine (Intermediate 2) from 3,4-bis(benzyloxy)-6-chloropyridazine (Intermediate 1) and 1-ethynyl-4-fluorobenzene in 72% yield.
Reaction SMILES: Cl.Cl.Cl.[CH2:4]1[CH:17]2[N:8]([CH2:9][C:10]3[CH:11]=[C:12]([NH2:18])[CH:13]=[CH:14][C:15]=3[CH2:16]2)[CH2:7][CH2:6][NH:5]1.C[S:20](C)=O.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[CH2:4]1[CH:17]2[N:8]([CH2:9][C:10]3[CH:11]=[C:12]([NH:18][C:24]([C:25]4[S:20][CH:28]=[CH:27][CH:26]=4)=[NH:23])[CH:13]=[CH:14][C:15]=3[CH2:16]2)[CH2:7][CH2:6][NH:5]1
Reactant: Nc1ccc2c(c1)CN1CCNCC1C2
Reactant: c1ccncc1
Reactant: CS(C)=O
Agent: Cl
Solvent: O
Product: N=C(Nc1ccc2c(c1)CN1CCNCC1C2)c1cccs1
Temperature: 50 °C
Reaction time: 7 h

Procedure:
To a stirred mixture of 2,3,4,6,11,11a-hexahydro-1H-pyrazino[1,2-b]isoquinolin-8-amine trihydrochloride (1.8 g, 5.76 mmol) and methyl sulfoxide (20 ml) was added pyridine (0.94 ml) followed by S-methyl-2-thiophenethiocarboximide hydrochloride (2.13 g). The mixture was heated at 50° C., with stirring, for 7 h. The reaction mixture was then poured into water (150 ml) and, after stirring for 1 hour, the mixture was clarified by filtration. The filtrate was basified with 2.5N sodium hydroxide solution but no precipitate formed. An attempt to extract the product into dichloromethane caused the product to crystallize from the mixture. The product was isolated, washed with dichloromethane and dried; yield 1.28 g. This material was purified by chromatography using silica gel and 7% methanol saturated with ammonia in dichloromethane to yield N-(2,3,4,6,11,11a-hexahydro-1H-pyrazino[1,2-b]isoquinolin-8-yl)-2-thiophenecarboximidamide (0.83 g), m.p. 228° C. (dec.), MS 313 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH:13]3[CH2:15][O:14]3)=[CH:7][C:5]=2[N:6]=1.[N:16]1([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>C(O)C>[C:25]([O:24][C:22]([N:16]1[CH2:21][CH2:20][N:19]([CH2:15][CH:13]([OH:14])[CH2:12][O:11][C:8]2[CH:9]=[CH:10][C:4]3[S:3][C:2]([CH3:1])=[N:6][C:5]=3[CH:7]=2)[CH2:18][CH2:17]1)=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: Cc1nc2cc(OCC3CO3)ccc2s1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCO
Product: Cc1nc2cc(OCC(O)CN3CCN(C(=O)OC(C)(C)C)CC3)ccc2s1
Temperature: 85 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To 2-methyl-5-(oxiran-2-ylmethoxy) benzothiazole (2.21 g, 10 mmol), a compound of formula (3), was added tert-butyl 1-piperazinecarboxylate (1.86 g, 10 mmol), a compound of formula (4), and ethanol (30 ml). The resulting solution was heated to 85° C. and stirred for 8 hours. The solvent was evaporated under reduced pressure, and the residue was chromatographed on silica gel, eluting with 5% methanol/methylene chloride, to yield 4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-piperazine-1-carboxylic acid tert-butyl ester as a clear oil (2.9 g, 7.1 mmol).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:36])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([N:17]2[CH2:22][CH2:21][CH:20]([CH2:23][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:25]3[CH2:27][CH2:26]3)[CH2:19][CH2:18]2)=[O:16])=[C:9]([CH3:35])[CH:8]=1.[OH-].[Na+]>C1COCC1.O>[C:31]([O:30][C:28]([N:24]([CH2:23][CH:20]1[CH2:21][CH2:22][N:17]([C:15](=[O:16])[CH2:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([C:6]([OH:36])=[O:5])=[CH:8][C:9]=2[CH3:35])[CH2:18][CH2:19]1)[CH:25]1[CH2:27][CH2:26]1)=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: COC(=O)c1ccc(CCC(=O)N2CCC(CN(C(=O)OC(C)(C)C)C3CC3)CC2)c(C)c1
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(=O)O)ccc1CCC(=O)N1CCC(CN(C(=O)OC(C)(C)C)C2CC2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
Lithium hydroxide monohydrate (142 mg, 3.4 mmol) was added to a solution of 4-(3-{4-[(tert-butoxycarbonyl-cyclopropyl-amino)-methyl]-piperidin-1-yl}-3-oxo-propyl)-3-methyl-benzoic acid methyl ester from Example E86.1 (1.41 g, 3.1 mmol) in THF (20 ml) and water (2 ml). The mixture was stirred for 16 h at room temperature then 1M NaOH solution (5 ml) was added. The mixture was heated at 60° C. for 3 h then concentrated in vacuo. The residue was dissolved in EtOAc, washed with 1M HCl then brine, dried and concentrated in vacuo to yield the title compound (1.25 g, 91%).
Reaction SMILES: ClC1C=CC(S(N(C2C=C(Cl)C=CC=2Cl)[C@H:12]([CH3:26])[CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]2[CH2:21][S:22]([CH3:25])(=[O:24])=[O:23])(=O)=O)=CC=1.Cl[C:36]1[CH:41]=[CH:40][C:39]([S:42]([N:45](C2C=C(Cl)C=CC=2Cl)[C@H](C)CCCBr)(=[O:44])=[O:43])=[CH:38][CH:37]=1.[CH3:60]S(CC1CCCCN1)(=O)=O>C(Cl)Cl>[CH3:25][S:22]([CH2:21][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][N:15]1[C@:14]([C:36]1[CH:37]=[CH:38][C:39]([S:42]([NH2:45])(=[O:43])=[O:44])=[CH:40][CH:41]=1)([CH3:60])[CH2:13][CH2:12][CH3:26])(=[O:23])=[O:24]
Reactant: C[C@H](CCN1CCCCC1CS(C)(=O)=O)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Reactant: C[C@H](CCCBr)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Reactant: CS(=O)(=O)CC1CCCCN1
Solvent: ClCCl
Product: CCC[C@](C)(c1ccc(S(N)(=O)=O)cc1)N1CCCCC1CS(C)(=O)=O
Yield: 28 %

Procedure:
4-chloro-N-(2,5-dichlorophenyl)-N-[4-[[2-(methylsulfonyl)methyl-1-piperidinyl]-1(R)-methylbutyl]benzenesulfonamide was prepared analogous to 4-chloro-N-(2,5-dichlorophenyl)-N-(3-(2-((methylsulfonyl)methyl)-1-piperidinyl)-1(R)-methylpropyl)benzenesulfonamide by reacting 4-chloro-N-[2,5-dichlorophenyl]-N-[(R)-1-methyl-4-bromobutyl]benzenesulfonamide with 2-(methylsulfonylmethyl)piperidine. Yield=28%; yellow foam: IR (neat, CH2Cl2) 1467, 1296, 1166, 1138, 1095, 622, cm−1; MS (ESI+), 581 (M+H)+.
Reaction SMILES: P([O-])(O)(O)=O.[Na+].Cl([O-])=O.[Na+].[OH:11]O.[CH3:13][O:14][C:15]1[C:16]([CH3:44])=[C:17]([C:35]([O:42][CH3:43])=[C:36]([O:40][CH3:41])[C:37]=1[O:38][CH3:39])[CH2:18][C:19]1[C:20]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=[O:23]>O.C(#N)C>[CH3:13][O:14][C:15]1[C:16]([CH3:44])=[C:17]([C:35]([O:42][CH3:43])=[C:36]([O:40][CH3:41])[C:37]=1[O:38][CH3:39])[CH2:18][C:19]1[C:20]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:21]([CH:24]=[CH:25][CH:26]=1)[C:22]([OH:11])=[O:23]
Reactant: COc1c(C)c(Cc2cccc(C=O)c2OCc2ccccc2)c(OC)c(OC)c1OC
Reactant: OO
Agent: O=P([O-])(O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC#N
Solvent: O
Product: COc1c(C)c(Cc2cccc(C(=O)O)c2OCc2ccccc2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 98 %

Procedure:
An aqueous solution (7 ml) of sodium dihydrogenphosphate (4.01 g, 33.42 mmol), an aqueous solution (7 ml) of sodium chlorite (1.74 g, 19.33 mmol) and aqueous hydrogen peroxide (1.89 ml, 30%) were added to an acetonitrile solution (12 ml) of 3-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-benzyloxybenzaldehyde (1.87 g, 4.28 mmol) and the resulting solution was stirred at room temperature for 5 hours. The reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with an aqueous saturated sodium hydrosulfite (Na2S2O4) solution and saturated brine, then dried and concentrated to obtain the titled compound (1.90 g, 4.20 mmol, 98%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH2:16][CH:17]=[C:18](Cl)[CH3:19])([CH2:13][CH2:14][CH3:15])[C:8]2=[O:12])=[CH:4][C:3]=1[CH2:21][CH2:22][C:23]([OH:25])=[O:24].S(=O)(=O)(O)[OH:27].O>C(Cl)Cl>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH2:16][CH2:17][C:18](=[O:27])[CH3:19])([CH2:13][CH2:14][CH3:15])[C:8]2=[O:12])=[CH:4][C:3]=1[CH2:21][CH2:22][C:23]([OH:25])=[O:24]
Reactant: O=S(=O)(O)O
Reactant: CCCC1(CC=C(C)Cl)Cc2cc(CCC(=O)O)c(Cl)c(Cl)c2C1=O
Solvent: ClCCl
Solvent: O
Product: CCCC1(CCC(C)=O)Cc2cc(CCC(=O)O)c(Cl)c(Cl)c2C1=O
Temperature: 5 °C
Reaction time: 1 h

Procedure:
3-[6,7-Dichloro-2-(3-chloro-2-butenyl)-2,3-dihydro-1-oxo-2-propyl-1H-inden-5-yl]propionic acid (6.8 g, 0.0168 mole) dissolved in methylene chloride (65 ml) was added over 15 minutes to a mixture of sulfuric acid (75 ml) and methylene chloride (35 ml) at 5° C., stirred at 5° C. for 1 hour, poured over ice and water, and extracted with methylene chloride. The organic extracts were washed with water, dried over MgSO4 and concentrated under vacuum. The residue was recrystallized from butyl chloride to obtain the product mp 131°-3° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C@@H:5]([C:7]([OH:9])=[O:8])[NH2:6].[ClH:10].[CH3:11]O>O1CCOCC1>[ClH:10].[CH3:11][O:8][C:7](=[O:9])[C@H:5]([CH2:4][CH2:3][O:2][CH3:1])[NH2:6]
Reactant: CO
Reactant: COCC[C@H](N)C(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: COCC[C@H](N)C(=O)OC
Reaction time: 84 h

Procedure:
A solution of 13.3 g of O-methyl homoserine in 370 ml of methanol and 180 ml of a 6 N solution of hydrogen chloride in dioxane is allowed to stand at room temperature for 3 to 4 days. The solvent is removed under reduced pressure and the residue lyophilized to give O-methyl homoserine methyl ester hydrochloride which is represented by the following formula ##STR51## Substitution of an equivalent quantity of O-methyl homoserine methyl ester hydrochloride for the methyl D-methioninate hydrochloride of Example 35 and substantial repetition of the procedures described in Examples 35 through 39 provides methyl DL-2,6-dimethyltyrosyl-DL-O-methylhomoseryl-glycyl-L-phenylalanyl-3-amino-1-adamantanecarboxylate hydrochloride which is represented by the following formula ##STR52##
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[N:7]([CH2:16][C:17]([OH:19])=O)[N:6]=1)=[O:4].C1C=CC2N(O)N=NC=2C=1.[CH2:32]([NH:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:33][CH3:34].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[CH2:36]([N:35]([CH2:32][CH2:33][CH3:34])[C:17](=[O:19])[CH2:16][N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)[C:5]([C:3](=[O:4])[C:2]([CH3:1])([CH3:21])[CH3:20])=[N:6]1)[CH2:37][CH2:38][CH3:39]
Reactant: COc1ccc2c(C(=O)C(C)(C)C)nn(CC(=O)O)c2c1
Reactant: CCCCNCCC
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCCCN(CCC)C(=O)Cn1nc(C(=O)C(C)(C)C)c2ccc(OC)cc21
Temperature: 45 °C
Reaction time: 2 h

Procedure:
Weigh 29.0 mg [3-(2,2-dimethylpropanoyl)-6-methoxy-1H-indazol-1-yl]acetic acid, 23.0 mg HOBt, and 38.3 mg EDC into a 13×100 mm screw cap tube. Add 17.3 mg N-propylbutylamine followed by 1 mL DMF and 45.2 mg DIEA in that order. The mixture was stirred at 45° C. for two hours and purified by RP-HPLC using 65-100% MeCN gradient. The pure product fractions were pooled and lyophilized to give the title compound as white solid. LC-MS: 4.20 min. (m/Z=388.3, 410.3).
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([C:9]([OH:11])=O)[NH:6][N:5]=1)(=[O:3])[CH3:2].CCN(C(C)C)C(C)C.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.[NH2:43][CH2:44][CH2:45][C:46]1[O:50][N:49]=[C:48]([C:51]2[CH:58]=[CH:57][C:54]([C:55]#[N:56])=[C:53]([Cl:59])[C:52]=2[CH3:60])[CH:47]=1>C(Cl)Cl>[C:1]([C:4]1[CH:8]=[C:7]([C:9]([NH:43][CH2:44][CH2:45][C:46]2[O:50][N:49]=[C:48]([C:51]3[CH:58]=[CH:57][C:54]([C:55]#[N:56])=[C:53]([Cl:59])[C:52]=3[CH3:60])[CH:47]=2)=[O:11])[NH:6][N:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Reactant: Cc1c(-c2cc(CCN)on2)ccc(C#N)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1cc(C(=O)NCCc2cc(-c3ccc(C#N)c(Cl)c3C)no2)[nH]n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 39.6 %

Procedure:
3-Acetyl-1H-pyrazole-5-carboxylic acid (31 mg; 0.203 mmol) and DIPEA (0.106 ml) were dissolved in 5 ml of dry DCM. HOBt hydrate (47 mg; 0.304 mmol) and EDCI (58 mg; 0.304 mmol) were added at RT. 4-(5-(2-aminoethyl) isoxazol-3-yl)-2-chloro-3-methylbenzonitrile (53 mg; 0.203 mmol) was added and the reaction was stirred at RT for 4 h. DCM 10 ml of was added and organic layer washed with 1M HCl, saturated NaHCO3 and brine. The organic phase was dried over Na2SO4, filtered and evaporated to dryness. The crude product was triturated with n-heptane to give the title product 32 mg. 1H-NMR (400 MHz; d6-DMSO): δ 2.44 (s, 3H), 2.51 (s, 3H), 3.12 (t, 2H), 3.63 (m, 2H), 6.75 (s, 1H), 7.30 (bs, 1H), 7.62 (d, 1H), 7.94 (d, 1H), 8.73 (bs, 1H), 14.20 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1C2C(=CC=CC=2)C=C1CNC.[CH2:14]1[C:18]2=[C:19]([CH:26]=O)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[N:17]2[CH2:16][CH2:15]1.CN1C2C(=CC=CC=2)C(C)=C1C=O>>[CH3:1][NH:2][CH2:26][C:19]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=2[N:17]2[CH2:16][CH2:15][CH2:14][C:18]=12
Reactant: CNCc1cc2ccccc2n1C
Reactant: O=Cc1c2n(c3ccccc13)CCC2
Agent: Cc1c(C=O)n(C)c2ccccc12
Product: CNCc1c2n(c3ccccc13)CCC2
Yield: 54 %

Procedure:
According to the procedure of Preparation 40 (c), except substituting 2,3-dihydro-1H-3a-azacyclopenta[a]indene-8-carboxaldehyde (0.17 g, 0.92 mmole) for the 1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (0.1 g, 54%) was prepared as a yellow oil: MS (ES) m/e 201 (M+H)+.
Reaction SMILES: [N-:1]([C:4]#[N:5])[C:2]#[N:3].[Na+].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]([CH3:21])[CH2:16][C:17](=[O:20])[NH:18][N:19]=2)=[CH:10][CH:9]=1.C(O)(=O)C.Cl>O>[C:2]([N:1]=[C:4]([NH2:5])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]([CH3:21])[CH2:16][C:17](=[O:20])[NH:18][N:19]=2)=[CH:10][CH:9]=1)#[N:3]
Reactant: N#C[N-]C#N
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC1CC(=O)NN=C1c1ccc(NC(N)=NC#N)cc1
Yield: 24.8 %

Procedure:
A solution of sodium dicyanamide (0.5 g) in water (20 ml) was added to a solution of 6-(4-aminophenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone (1.0 g) in a mixture of aqueous acetic acid (20 ml) and 10M hydrochloric acid (0.5 ml). The resultant solution was stirred at room temperature for 3 days. A precipitate formed which was collected, washed with water and then with ethanol, and dried to give the title compound (0.33 g), thin layer chromatography and nuclear magnetic resonance spectroscopy showed this to be consistent with the product of Example 6, m.p. 257°-260° C. (decomp).