Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1.[Cu](C#N)C#N.[C:19]([O:24][CH3:25])(=[O:23])[C@H:20]1[O:22][CH2:21]1.[Cl-].[NH4+]>CCCCC>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:21][C@H:20]([OH:22])[C:19]([O:24][CH3:25])=[O:23])=[CH:8][CH:9]=1
Reactant: COC(=O)[C@@H]1CO1
Reactant: Brc1ccc(Br)cc1
Agent: N#C[Cu]C#N
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Product: COC(=O)[C@@H](O)Cc1ccc(Br)cc1
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 133.4 %

Procedure:
100 ml (170 mmol) of a 1.7 M solution of tert-butyllithium in pentane are added dropwise to a solution of 48 g (204 mmol) of 1,4-dibromobenzene in 160 ml of tert-butyl dimethyl ether, cooled to −30° C., followed by addition of 7.3 g (82 mmol) of copper cyanide. The reaction medium is stirred for 15 minutes and a solution of 6 ml (68 mmol) of (S)-methyl glycidate in 10 ml of tert-butyl dimethyl ether is then added. After stirring for 20 minutes at −30° C., the reaction medium is hydrolysed with 150 ml of saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase is washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with heptane, and the polarity is then increased up to a 6/4 heptane/ethyl acetate mixture. 23.5 g (44%) of methyl 3-(4-bromophenyl)-2(S)-hydroxypropanoate are obtained.
Reaction SMILES: C[O-].[Na+].C([O:12][CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]([CH3:25])[CH:23]=O)=[O:15])(=O)C1C=CC=CC=1.O>ClCCl>[OH:12][C:13]1[C:14](=[O:15])[C:16]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:22]([CH3:23])[CH:25]=1
Reactant: CN(C=O)c1ccccc1C(=O)COC(=O)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cn1cc(O)c(=O)c2ccccc21

Procedure:
Sodium methoxide (17.75 g) was added to a stirred solution of 2-[2-(N-methylformamido) phenyl]-2-oxoethyl benzoate, obtained as described in Example 2a-d, (186 g) in dichloromethane (1300 ml) at 0° under nitrogen resulting in an exotherm to 25 to 30°. The mixture was recooled at 0° and a second portion of sodium methoxide (17.75 g) added resulting in a further exotherm and the resultant mixture stirred for 1 hour. Sodium methoxide (35.5 g) was then again added in two equal portions and the resultant mixture stirred at 0 to 10° for 1 hour. Water (1860 ml) was added over 70 minutes maintaining the temperature below 6°. The phases were separated and the dichloromethane phase was extracted with aqueous sodium hydroxide (0.5M, 930 ml). The combined aqueous phase and extract were washed with dichloromethane (930 ml) and then cooled to 0°. Hydrochloric acid ( 5M, 300 ml) was added dropwise to pH 3 to 4 followed by aqueous sodium hydroxide (5M, 38 ml) and then aqueous sodium bicarbonate (1M, 250 ml) to pH 8. The resultant solid was collected by filtration and washed with water (3×200 ml) to give 3-hydroxy-1-methyl-4-quinolone, m.p. 239°-241°.
Reaction SMILES: [C:1]([CH:3]1[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:6][CH:5]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:4]1)#[N:2].[CH3:21][C:22]1[CH:23]=[C:24]([NH:28][C:29](=[O:35])[NH:30][CH2:31][C:32](O)=[O:33])[CH:25]=[CH:26][CH:27]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(#N)C>[C:1]([CH:3]1[CH:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:6]([C:32](=[O:33])[CH2:31][NH:30][C:29]([NH:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([CH3:21])[CH:23]=2)=[O:35])[CH:5]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:4]1)#[N:2]
Reactant: CC(C)(C)OC(=O)C1CC(C#N)C(c2ccccc2)N1
Reactant: Cc1cccc(NC(=O)NCC(=O)O)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Product: Cc1cccc(NC(=O)NCC(=O)N2C(C(=O)OC(C)(C)C)CC(C#N)C2c2ccccc2)c1
Yield: 71.1 %

Procedure:
The reaction is carried out in a way analogous to that described in Example 2B, but from 1 g of tert-butyl (2RS,4RS,5SR)-4-cyano-5-phenylpyrrolidine-2-carboxylate, 0.76 g of 2-[3-(3-methylphenyl)ureido]acetic acid and 0.76 g of N,N'-dicyclohexylcarbodiimide in 50 cm3 of acetonitrile. After treatment, there are obtained 1.2 g of tert-butyl (2RS,4RS,5SR)-4-cyano-1-{2-[3-(3-methylphenyl)ureido]acetyl}-5-phenylpyrrolidine-2-carboxylate, melting at 150° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8]([C:12](OC)=[O:13])=[CH:7][C:6]=2[CH:16]=1.CC(C[AlH]CC(C)C)C>C(OCC)C.C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8]([CH2:12][OH:13])=[CH:7][C:6]=2[CH:16]=1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2CCC1
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCC1=Cc2cc(Br)ccc2CCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
To a solution of methyl 2-bromo-6,7-dihydro-5H-benzo[7]annulene-8-carboxylate from step A4 (170 mg, 0.605 mmol) in diethyl ether (2 mL) and THF (1 mL) was added 1.0 M DIBAL-H/hexanes (0.726 mL, 0.726 mmol) at −78° C. The mixture was stirred at rt for 16 h. Another 0.726 mL portion of DIBAL-H was added at 0° C., and the mixture was stirred at rt for an additional 2 h. The reaction mixture was diluted with 50 mL of diethyl ether, quenched with water, and extracted with EtOAc (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to give (2-bromo-6,7-dihydro-5H-benzo[7]annulen-8-yl)methanol (150 mg, 0.593 mmol, 98% yield). 1H NMR (500 MHz, chloroform-d) δ 7.30 (s, 1H), 7.22 (dd, J=7.9, 1.8 Hz, 1H), 6.98 (d, J=7.9 Hz, 1H), 6.45 (s, 1H), 4.21 (br. s., 2H), 2.81-2.71 (m, 2H), 2.34 (t, J=6.4 Hz, 2H), 2.08-1.98 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([CH3:14])[C@H:10]([C:15]([OH:17])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[C@H]1C[CH2:23][NH:22][CH2:21][C@H]1C(O)=O.C(N(CC)CC)C.Cl.CNC.C(N1C=CN=C1)(N1C=CN=C1)=O>O1CCCC1>[CH3:21][N:22]([CH3:23])[C:15]([C@H:10]1[C@@H:11]([CH3:14])[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1)=[O:17]
Reactant: C[C@H]1CCNC[C@H]1C(=O)O
Reactant: C[C@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1C(=O)O
Agent: CNC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1C(=O)N(C)C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a solution of cis-1-(tert-butoxycarbonyl)-4-methylpiperidine-3-carboxylic acid (prepared by N-Boc protection of cis-4-methylpiperidine-3-carboxylic acid, synthesized by the method described in Bulletin de la Societe Chimique de France 1986, 4, 663-8.) (0.4 g, 1.64 mmol) in tetrahydrofuran were added triethylamine (0.2 mL, 1.64 mmol), dimethylamine hydrochloride (132 mg, 1.64 mmol), and 1,1′-carbonyldiimidazole (CDI, 265 mg, 1.64 mmol). After 2 h, the mixture was quenched with water and the aqueous layer was extracted with ethyl acetate (2×10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford cis-tert-butyl 3-(dimethylcarbamoyl)-4-methylpiperidine-1-carboxylate (0.3 g, 68%) as a yellow solid. The material was used without further purification.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]#[N:16])[CH:13]=2)[NH:8][CH:7]=1.C(C1C=C2C(=CC=1)NC=C2)#N.ClCCCC(Cl)=[O:33]>>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]#[N:16])[CH:13]=2)[NH:8][CH:7]=1)=[O:33]
Reactant: O=C(Cl)CCCCl
Reactant: N#Cc1ccc2[nH]cc(CCCCCl)c2c1
Agent: N#Cc1ccc2[nH]ccc2c1
Product: N#Cc1ccc2[nH]cc(C(=O)CCCCl)c2c1

Procedure:
As per the process described in the JMC Article, 3-(4-chlorobutyl)-1H-indole-5-carbonitrile is prepared by reacting 5-cyanoindole with 4-chlorobutyryl chloride in the presence of isobutyl-AlCl2 to produce 3-(4-chlorobutyryl)-1H-indole-5-carbonitrile, which is then subjected to selective desoxygenation of the keto function with sodium bis(2-methoxyethoxy)aluminum hydride (Vitride/Red-Al) to produce the 3-(4-chlorobutyl)-1H-indole-5-carbonitrile.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH2:14]Cl)=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[CH2:23]([O:25][C:26](=[O:29])[CH2:27][NH2:28])[CH3:24]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH2:14][NH:28][CH2:27][C:26]([O:25][CH2:23][CH3:24])=[O:29])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)CCl)CC1
Reactant: CCOC(=O)CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CNCC(=O)N1CCN(C(=O)OCC)CC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 78.1 %

Procedure:
To a solution of 1-ethoxycarbonyl-4-chloromethylcarbonylpiperazine (520 mg, 2.21 mmol) in DMF (40 mL) was added cesium carbonate (2.0 g, 6.20 mmol) and glycine ethyl ester hydrochloride (310 mg, 2.21 mmol). The resulting reaction mixture was stirred at 50° C. After 1 hour, the reaction mixture was diluted with ethyl acetate (200 mL), washed with water (3×150 mL) and brine, and concentrated in vacuo to afford 1-ethoxycarbonyl-4-(ethoxycarbonylmethyl)aminomethylcarbonylpiperazine as an oil (520 mg), which was used without purification.
Reaction SMILES: [C:1]1([C:13]2[C:14](=[O:28])[NH:15][C:16](=[O:27])[C:17]=2[C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.[H][H]>[Pd].CO>[C:1]1([C@H:13]2[C@@H:17]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[C:16](=[O:27])[NH:15][C:14]2=[O:28])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1
Reactant: O=C1NC(=O)C(c2cn3c4c(cccc24)CCC3)=C1c1c[nH]c2ccccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C1NC(=O)[C@@H](c2cn3c4c(cccc24)CCC3)[C@H]1c1c[nH]c2ccccc12
Yield: 57.1 %

Procedure:
A suspension of 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4(1H-indol-3-yl)pyrrole-2,5-dione (16 g, 43.6 mmol) and 10% palladium on carbon (Pd/C, wet catalyst) (8 g) were stirred under 1 atmosphere of hydrogen in methanol (600 ml) at room temperature for 48 hours. The catalyst was then filtered through a bed of Celite and the filtrate evaporated to dryness. The residue was re-dissolved in methanol and the product precipitated by the addition of cold water. The precipitate was filtered, washed with water and dried under vacuum to yield (±)-cis-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4(1H-indol-3-yl)pyrrolidine-2,5-dione (9.2 g). 1H NMR (DMSO-d6) 400 MHz δ: 11.56(s, 1H), 10.66(s, 1H), 7.43(d, 1H, J=7.6 Hz), 7.14(d, 2H, J=8 Hz), 6.86-6.97(m, 4H), 6.78(t, 1H, J=7.2 Hz), 6.69(d, 1H, J=6.8 Hz), 4.88(dd, 2H, J=9.2 and 45.6 Hz), 3.88(m, 2H), 2.76(t, 2H, J=5.6 Hz), 1.94(t, 2H, J=6 Hz).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8](Br)=[CH:7][N:6]=1)(=[O:3])[CH3:2].C(N(CCCC)CCCC)CCC.[C:26]([OH:30])(=[O:29])[CH:27]=[CH2:28].C(=O)(O)[O-].[Na+]>C1(C)C(C)=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>[C:1]([NH:4][C:5]1[N:6]=[CH:7][C:8](/[CH:28]=[CH:27]/[C:26]([OH:30])=[O:29])=[CH:9][C:10]=1[CH3:11])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ncc(Br)cc1C
Reactant: C=CC(=O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Solvent: CCCCN(CCCC)CCCC
Product: CC(=O)Nc1ncc(/C=C/C(=O)O)cc1C
Temperature: 150 °C
Reaction time: 7 h
Yield: 84.2 %

Procedure:
To a solution of 2-acetamido-5-bromo-3-methylpyridine (110 mg) and tri-n-butylamine (196 mg) in xylene were added palladium(II) acetate (1 mg) and triphenylphosphine (1 mg) under nitrogen atmosphere, and the mixture was heated at 150° C. Acrylic acid (41.5 mg) was added thereto, and the mixture was stirred for 7 hours at the same temperature. After cooling to ambient temperature, ethyl acetate and saturated sodium bicarbonate solution were added to the reaction mixture, and separated aqueous layer was adjusted to pH 4 with 4N hydrochloric acid. The mixture was extracted with chloroform. The extract was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was collected by filtration and washed with diisopropyl ether to give (E)-3-(6-acetamido-5-methylpyridin-3-yl)acrylic acid (89 mg).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]3[CH:20]=2)=[CH:8][CH:7]=1>C(O)C.CO.[Pt](=O)=O>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH2:19][CH2:18][CH2:17][CH2:16][N:15]3[CH:20]=2)=[CH:8][CH:7]=1
Reactant: ClCCCOc1ccc(-c2cn3ccccc3n2)cc1
Agent: O=[Pt]=O
Solvent: CO
Solvent: CCO
Product: ClCCCOc1ccc(-c2cn3c(n2)CCCC3)cc1
Reaction time: 4 h
Yield: 96.4 %

Procedure:
To a Parr bottle charged with a mixture of platinum (IV) oxide (30 mg) in ethanol (3 mL) was added a solution of the product of Step A (90 mg) in methanol (6 ml). The mixture was hydrogenated at 40 psi for 4 hours and filtered through a Celite pad which was rinsed with several additional milliliters of methanol and ethanol. The filtrate was collected and evaporated in vacuo to yield the title compound (88 mg) which was used without further purification.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([NH2:10])=[CH:8][CH:9]=1.C(N(CC)CC)C.Br[C:19]1[C:20]2[N:21]([C:26]([F:29])=[CH:27][N:28]=2)[N:22]=[C:23]([Cl:25])[CH:24]=1>CCO>[Cl:25][C:23]1[CH:24]=[C:19]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([O:3][CH2:2][CH3:1])=[CH:5][CH:6]=2)[C:20]2[N:21]([C:26]([F:29])=[CH:27][N:28]=2)[N:22]=1
Reactant: CCOc1ccc(N)cc1
Reactant: Fc1cnc2c(Br)cc(Cl)nn12
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOc1ccc(Nc2cc(Cl)nn3c(F)cnc23)cc1
Temperature: 80 °C

Procedure:
p-Phenetidine (0.044 ml, 0.34 mmol) and triethylamine (0.1 ml, 0.75 mmol) were added to a mixture of 8-bromo-6-chloro-3-fluoroimidazo[1,2-b]pyridazine (0.085 g, 0.34 mmol) from 1a in EtOH (1.7 mL). The mixture was heated to 80° C. and stirred for 16 hors. The solution was then concentrated in vacuo to give crude 6-chloro-N-(4-ethoxyphenyl)-3-fluoroimidazo[1,2-b]pyridazin-8-amine.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[C:9]([O:13][C:14](=[O:17])[CH2:15]Br)([CH3:12])([CH3:11])[CH3:10].[CH3:18][O:19][C:20](=[O:29])[C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([CH3:28])[CH:22]=1>CC(C)=O>[CH3:18][O:19][C:20](=[O:29])[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:15][C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:17])=[C:23]([CH3:28])[CH:22]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)c1ccc(O)c(C)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCC(=O)OC(C)(C)C)c(C)c1
Yield: 90 %

Procedure:
Potassium carbonate (4.6 g, 33 mmol), potassium iodide (0.25 g, 1.5 mmol) and tert-butylbromoacetate (2.5 ml, 16.5 mmol) were added to a solution of 4-hydroxy-3-methyl-benzoic acid methyl ester from Example E29 (2.5 g, 15 mmol) in acetone (150 ml) and the mixture was heated at reflux for 20 h. The solid was filtered off and the filtrate concentrated in vacuo. The residue was dissolved in EtOAc, washed with 1N KHSO4, water then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 15% EtOAc:85% hexane) to yield the title compound (3.8 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:10]=[C:11]([CH3:25])[C:12]3[CH:16]([CH2:17][C:18]([O:20]CC)=[O:19])[O:15][B:14]([OH:23])[C:13]=3[CH:24]=2)[CH:3]=1.[OH-].[Na+]>CO.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:10]=[C:11]([CH3:25])[C:12]3[CH:16]([CH2:17][C:18]([OH:20])=[O:19])[O:15][B:14]([OH:23])[C:13]=3[CH:24]=2)[CH:3]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cc(Cl)ccn3)cc(C)c21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(Oc2cc(Cl)ccn2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 2-(6-(4-chloropyridin-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate in MeOH/THF (8 mL, 1:1) was added aqueous NaOH (200 mg in 2 mL of water). After stirring at room temperature for two hours, the reaction mixture was evaporated and acidified to PH 5 using 1 M HCl and then concentrated. HPLC purification gave desired product as a white powder. 1H NMR (400 MHz, DMSO-d6) δ 9.20 (b, 1H), 8.11 (d, J=5.2 Hz, 1H), 7.24 (dd, J=5.6, 2 Hz, 1H), 7.21 (d, m, 2H), 7.05 (d, J=1.6 Hz, 1H), 5.50 (dd, J=9.6, 2.4 Hz, 1H), 3.07 (dd, J=15.6, 2.8 Hz, 1H), 2.28 (s, 3H), 2.12 (dd, J=15.6, 9.6 Hz, 1H). 1 protons assumed to be exchanged with solvents. MS (ESI) m/z=334 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10])(=[O:5])=[O:4].S(=O)(=O)(O)O.[CH3:20]O>>[CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([O:11][CH3:20])=[O:10])(=[O:4])=[O:5]
Reactant: CO
Reactant: CNS(=O)(=O)c1cccc(C(=O)O)c1
Agent: O=S(=O)(O)O
Product: CNS(=O)(=O)c1cccc(C(=O)OC)c1
Yield: 53.5 %

Procedure:
3-(N-methylsulfamoyl)benzoic acid (200 mg, 0.929 mmol) was refluxed in the presence of concentrated sulfuric acid (6.01 mg, 0.046 mmol) in methanol at 70° C. for overnight. Reaction was monitored by TLC. After completion of the reaction, the solvent was removed by vacuum and then compound was purified by flash chromatography afforded the methyl 3-(N-methylsulfamoyl)benzoate (120 mg, 0.497 mmol, 53.5% yield). 1H NMR (CDCl3, 400 MHz): δ 8.51 (m, 1H), 8.25 (m, 1H), 8.06 (dt, 1H, J=1.2 & 8.0 Hz), 7.63 (t, 1H, J=7.6 Hz), 3.96 (s, 3H), 2.69 (s, 3H). Mass [M+H]+:230.1
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:35])[C@H:13]([CH3:34])[NH:14][CH:15]([C:29]([O:31]CC)=[O:30])[CH2:16][CH2:17][CH2:18][C:19]1([O:28][CH2:27][CH2:26][O:25]1)[C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)C>[C:1]([O:5][C:6](=[O:36])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:35])[C@H:13]([CH3:34])[NH:14][CH:15]([C:29]([OH:31])=[O:30])[CH2:16][CH2:17][CH2:18][C:19]1([O:25][CH2:26][CH2:27][O:28]1)[C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(=O)C(CCCC1(c2cccs2)OCCO1)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Solvent: CCO
Product: C[C@H](NC(CCCC1(c2cccs2)OCCO1)C(=O)O)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Reaction time: 24 h

Procedure:
Aqueous N-sodium hydroxide solution (2.5 ml.) was added to a solution of N-[1-ethoxycarbonyl-5,5-ethylenedioxy-5-(2-thienyl)pentyl]-L-alanyl-L-proline t-butyl ester (Example 17; 1.2 g.) in ethanol (7.5 ml.) and the mixture was stirred at laboratory temperature for 24 hours and the ethanol was then removed by evaporation under reduced pressure. Water (10 ml.) was added, the solution was washed with dichloromethane and then acidified to pH 5 with aqueous 2N hydrochloric acid, and the mixture was filtered. There was thus obtained as solid residue Isomer A of N-[1-carboxy-5,5-ethylenedioxy-5-(2-thienyl)pentyl]-L-alanyl-L-proline t-butyl ester.
Reaction SMILES: [CH2:1]([NH:13][C:14]([C:16]1[CH:44]=[CH:43][C:19]([CH2:20][N:21]([CH2:29][CH:30]2[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]2)[C:22](=[O:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=1)=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[ClH:45]>C(Cl)Cl.O1CCOCC1>[ClH:45].[CH2:26]([O:25][C:23](=[O:24])[C:22]([N:21]([CH2:20][C:19]1[CH:18]=[CH:17][C:16]([C:14]([NH:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:15])=[CH:44][CH:43]=1)[CH2:29][CH:30]1[CH2:31][CH2:32][NH:33][CH2:34][CH2:35]1)=[O:28])[CH3:27]
Reactant: CCCCCCCCCCCCNC(=O)c1ccc(CN(CC2CCN(C(=O)OC(C)(C)C)CC2)C(=O)C(=O)OCC)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCCCCCCCCCCCNC(=O)c1ccc(CN(CC2CCNCC2)C(=O)C(=O)OCC)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 73 %

Procedure:
To a cold (0° C.) solution of tert-butyl 4-({{4-[(dodecylamino)carbonyl]benzyl}[ethoxy(oxo)acetyl]amino}methyl)piperidine-1-carboxylate (3.84 g, 6.24 mmol) in DCM (25 mL) was added a 4 N solution of HCl in dioxane (31.1 mL) and the resulting reaction mixture was stirred 4 h at 0° C. Evaporation of the solvents gave a white amorphous solid (73%). 1H NMR (DMDO-d6, 300 MHz) δ 9.03 (m, 0.5H), 8.70 (m, 0.5H), 8.50 (m, 1H), 7.85 (m, 2H), 7.33 (m, 2H), 4.56 (d, 2H, J=8.9 Hz), 4.40-4.20 (m, 2H), 3.35-3.10 (m, 7H), 2.80 (m, 2H), 1.70 (m, 2H), 1.52 (m, 2H), 1.43-1.15 (m, 21H), 0.86 (m, 3H). M−(LC/MS(ESI)): 514.4; M+(LC/MS(ESI)): 516.4. HPLC (Condition A), Rt: 4.68 min (HPLC purity: 99.4%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@H:7]([C@@H:8]([CH2:42][CH3:43])[C@@H:9]([O:32][C:33](=[O:41])[C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([I:40])[CH:35]=3)[C@@H:10]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH2:6]1)(=[O:3])[CH3:2].CC(O)(C)C.[Cl:49]C1C(Cl)=C(I)C=CC=1>C(Cl)Cl>[C:1]([O:4][C@@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@H:7]([C@@H:8]([CH2:42][CH3:43])[C@@H:9]([O:32][C:33](=[O:41])[C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([I:40])[CH:35]=3)[C@@H:10]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@:14]2([Cl:49])[C@H:15]([CH3:22])[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: Clc1cccc(I)c1Cl
Reactant: CC[C@H]1[C@@H](OC(=O)c2cccc(I)c2)[C@@H]2[C@H](CC[C@]3(C)[C@@H]([C@H](C)CCC(=O)OC)CC[C@@H]23)[C@@]2(C)CC[C@@H](OC(C)=O)C[C@@H]12
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: CC[C@H]1[C@@H](OC(=O)c2cccc(I)c2)[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC[C@]3(Cl)[C@H](C)CCC(=O)OC)[C@@]2(C)CC[C@@H](OC(C)=O)C[C@@H]12
Yield: 91.3 %

Procedure:
To a solution of 4 (3.5 g, 4.95 mmol) in CH2Cl2 (280 ml) containing 0.3 M tBuOH (8.2 ml), dichloroiodobenzene (3.38 g, 12.4 mmol) was added. The mixture was deoxygenated for 3 min by bubbling dry N2. Then the mixture was photolyzed at 0° C. using a tungsten lamps (200 W) for 1 h. The solvent was then evaporated under reduced pressure and the residue was quickly purified by flash chromatography eluting with petroleum ether/EtOAc (8:2, v/v) to yield 3.35 g (4.52 mmol, 92%) of the 17-chloro derivative 5 as white solid.
Reaction SMILES: [CH2:1]([N:8]1[C:14](=[O:15])[CH2:13][C:12](=S)[NH:11][C:10]2[CH:17]=[CH:18][CH:19]=[CH:20][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([NH:24][NH2:25])(=O)[CH3:22]>C(O)CCC>[CH2:1]([N:8]1[C:14](=[O:15])[CH2:13][C:12]2=[N:25][N:24]=[C:21]([CH3:22])[N:11]2[C:10]2[CH:17]=[CH:18][CH:19]=[CH:20][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC(=S)Nc2ccccc2N1Cc1ccccc1
Reactant: CC(=O)NN
Solvent: CCCCO
Product: Cc1nnc2n1-c1ccccc1N(Cc1ccccc1)C(=O)C2
Reaction time: 24 h
Yield: 36.5 %

Procedure:
A solution of 1-benzyl-4-thioxo-4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one (50 mg, 0.18 mmol) and acetohydrazide (40 mg, 0.53 mmol) in 20 mL of n-butanol was heated to reflux, and stirred for 24 h under N2 atmosphere. The solvent was evaporated in vacuo and the residue was purified by prep-TLC (DCM:MeOH=25:1) to give 6-benzyl-1-methyl-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-5(6H)-one (20 mg, 38%). 1H NMR (300 MHz, CD3OD): δ 2.36 (s, 3H), 3.77 (d, J=14.1 Hz, 1H), 3.98 (d, J=14.1 Hz, 1H), 4.69 (d, J=15 Hz, 1H), 5.64 (d, J=15 Hz, 1H), 6.77-6.80 (m, 2H), 7.13-7.16 (m, 3H), 7.49-7.62 (m, 3H), 7.82-7.85 (m, 1H). LRMS (M+H)+: 304 m/z.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][C:25]=1[N+:26]([O-])=O)[O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Ca+2].[Cl-].C(O)C>[Fe].O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][N:14]=2)[CH:23]=[CH:24][C:25]=1[NH2:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(Oc2ccc([N+](=O)[O-])c(OCc3ccccc3)c2)nc1
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)c1ccc(Oc2ccc(N)c(OCc3ccccc3)c2)nc1
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 109.9 %

Procedure:
A mixture of 2-[3-(benzyloxy)-4-nitrophenoxy]-5-(methylsulfonyl)pyridine (45.56 g), iron powder (31.7 g), calcium chloride (1.26 g), ethanol (400 mL) and water (100 mL) was stirred at 80° C. for 3.5 h. The mixture was filtered through celite and the filtrate was concentrated. The residual solid was washed successively with water, ethanol, and diethyl ether to give the title compound (46.31 g, 100%) as a brownish-yellow solid. MS 371 (MH+).