Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[C:12]([O:16][C:17]([NH:19][C@H:20]([C:22](O)=[O:23])[CH3:21])=[O:18])([CH3:15])([CH3:14])[CH3:13].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.CN1CCOCC1>ClCCl>[C:12]([O:16][C:17]([NH:19][C@H:20]([C:22]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2)=[O:23])[CH3:21])=[O:18])([CH3:14])([CH3:15])[CH3:13]
Reactant: Nc1ccc2c(c1)CC(=O)N2
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc2c(c1)CC(=O)N2
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a suspension of 5-amino-2-oxindole (800 mg, 5.4 mM) and N-tert-butoxycarbonylalanine (1020 mg, 5.4 mM) in dichloromethane (50 ml) were added benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (2800 mg, 5.6 mM) and N-methylmorpholine (1.2 ml, 11 mM). The mixture was stirred for 15 h at room temperature. Then the solvent was evaporated under vacuum, the residue suspended in water and extracted 3 times with ethyl acetate. The collected extracts were evaporated and then purified by flash chromatography on silica gel using as eluant cyclohexane/ethylacetate 1:9. Thus pure 5-(N-tert-butoxycarbonylalanylamino)-2-oxindole was obtained (600 mg). A solution of the above compound (250 mg, 0.97 mM) in trifluoroacetic acid (15 ml) was maintained for 1 h at room temperature. Then the solution was concentrated under vacuum and ether added to precipitate 5-(alanylamino)-2-oxindole.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=2)[NH2:9])=[CH:2]1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:28])[CH2:22][O:23][CH2:24][C:25](O)=[O:26])=[C:16]([C:29]([O:31]C)=[O:30])[CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:28])[CH2:22][O:23][CH2:24][C:25]([NH:9][C:8]2[CH:10]=[CH:11][CH:12]=[C:6]([C:3]3[CH:4]=[CH:5][O:1][CH:2]=3)[CH:7]=2)=[O:26])=[C:16]([CH:15]=1)[C:29]([OH:31])=[O:30]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Reactant: Nc1cccc(-c2ccoc2)c1
Product: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1cccc(-c2ccoc2)c1

Procedure:
Using the same method as in Example 1-(ii), 3-(furan-3-yl)aniline was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 5-chloro-2-([(2-([3-(furan-3-yl)phenyl]amino)-2-oxoethoxy)acetyl]amino)benzoic acid.methyl ester (yield: 89%).
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li]CCCC.[CH3:13][C:14]1[S:23][C:22]2[C:21]3[C:24]([CH3:27])=[N:25][O:26][C:20]=3[C@H:19]([CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[NH:18][C:17](=[O:36])[C:16]=2[C:15]=1[CH3:37].IC>C1COCC1>[CH3:13][C:14]1[S:23][C:22]2[C:21]3[C:24]([CH3:27])=[N:25][O:26][C:20]=3[C@H:19]([C@@H:28]([CH3:1])[C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])[NH:18][C:17](=[O:36])[C:16]=2[C:15]=1[CH3:37]
Reactant: Cc1noc2c1-c1sc(C)c(C)c1C(=O)N[C@H]2CC(=O)OC(C)(C)C
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: Cc1noc2c1-c1sc(C)c(C)c1C(=O)N[C@H]2[C@@H](C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 16.6 %

Procedure:
To a round bottomed flask was added THF (50 mL) and diisopropylamine (1.29 mL, 9.10 mmol) before the solution was cooled to 0° C. To this solution was added n-BuLi (3.62 mL, 8.69 mmol) and the reaction was stirred at 0° C. for 10 min before cooling to −78° C. and addition of tert-butyl 2-((6S)-2,3,9-trimethyl-4-oxo-5,6-dihydro-4H-isoxazolo[4,5-e]thieno[3,2-c]azepin-6-yl)acetate (1.5 g, 4.14 mmol), a form of intermediate 17, prepared according to Example 14. The solution was stirred at −78° C. for 1 h before addition of iodomethane (0.285 mL, 4.55 mmol) and warming to room temperature overnight. The reaction was quenched with saturated aqueous NH4Cl solution and then diluted with water and brine. The aqueous layer was extracted with EtOAc and the combined organic layer was dried over Na2SO4, filtered, and concentrated. The crude residue was purified via Biotage (MTBE/hexanes) to afford the titled product (0.259 g, 0.688 mmol).
Reaction SMILES: C(OC([N:8]1[C:12]2=[C:13](Cl)[N:14]=[CH:15][C:16]([C:17](=[O:23])[NH:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[C:11]2[C:10]([CH3:25])=[CH:9]1)=O)(C)(C)C.[F:26][C:27]1[CH:28]=[C:29]([CH:31]=[C:32]([F:34])[CH:33]=1)[NH2:30]>C(OCC)C>[C:19]([NH:18][C:17]([C:16]1[C:11]2[C:10]([CH3:25])=[CH:9][NH:8][C:12]=2[C:13]([NH:30][C:29]2[CH:28]=[C:27]([F:26])[CH:33]=[C:32]([F:34])[CH:31]=2)=[N:14][CH:15]=1)=[O:23])([CH3:20])([CH3:21])[CH3:22]
Reactant: Nc1cc(F)cc(F)c1
Reactant: Cc1cn(C(=O)OC(C)(C)C)c2c(Cl)ncc(C(=O)NC(C)(C)C)c12
Solvent: CCOCC
Product: Cc1c[nH]c2c(Nc3cc(F)cc(F)c3)ncc(C(=O)NC(C)(C)C)c12

Procedure:
Prepared in a similar manner to Example 4(d) from 4-tert-butylcarbamoyl-7-chloro-3-methyl-pyrrolo[2,3-c]pyridine-1-carboxylic acid ter-butyl ester (68 mg) and using 3,5-difluoroaniline (38 ul) instead of 3-bromoaniline. Isolated by MDAP rather than trituration with diethyl ether to give the title compound (28 mg).
Reaction SMILES: C[N:2]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][C:10]=2[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][O:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:14][CH:13]=2)[CH:5]=[CH:4][CH:3]1[C:28](O)=[O:29].Cl.[CH2:32]([NH2:34])[CH3:33]>>[CH2:32]([NH:34][C:28]([C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][O:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:14][CH:13]=3)[CH:9]=[N:8][CH:7]=2)[N:2]=1)=[O:29])[CH3:33]
Reactant: CN1c2c(cncc2-c2ccc(OCCOC3CCOCC3)cc2)C=CC1C(=O)O
Reactant: CCN
Agent: Cl
Product: CCNC(=O)c1ccc2cncc(-c3ccc(OCCOC4CCOCC4)cc3)c2n1
Yield: 31.2 %

Procedure:
Using N-methyl-8-{4-[2-(tetrahydro-2H-pyran-4-yloxy)ethoxy]phenyl}-1,6-naphthyridine-2-carboxylic acid (300 mg, 0.76 mmol) produced in the synthetic process in Example 9 (9a) and ethylamine hydrochloride (616 mg, 7.61 mmol), the desired title compound (100 mg, yield 31%) was obtained by the same method as in Example 10.
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]1=2.Br[CH2:12][CH2:13][C:14](OCC)=[O:15].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].C(OC(C)C)(C)C>CC(C)=O>[S:1]1[CH:5]=[C:4]([O:6][CH2:12][CH2:13][CH2:14][OH:15])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]1=2
Reactant: O=C1CSc2ccccc21
Reactant: CCOC(=O)CCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CC(C)OC(C)C
Product: OCCCOc1csc2ccccc12
Yield: 1.3 %

Procedure:
A mixture of benzo[b]thiophen-3-one (30 g), ethyl 3-bromopropionate (73 g), potassium carbonate (55 g), potassium iodide (1.3 g) and acetone (600 ml) was refluxed for 18 h. Filtration and removal of solvent in vacuo a red oil which was dissolved in ether (200 ml) and dried over magnesium sulfate. The ether solution was added dropwise to a suspension of lithium aluminium hydride (5 g) in ether (100ml) followed by reflux for 1 h. Usual work-up gave a viscous oil which was applied to a silica gel column (eluent: isopropyl ether) giving 3-(benzo[b]thiophen-3-yloxy)-1-propanol (0.54 g) as an oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7](=[O:15])[C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[CH:4]=[C:3]1[C:16]([OH:18])=[O:17].[OH-].[Na+].[BH4-].[Na+].C(O)(=O)C>C(O)C>[CH3:1][N:2]1[CH:6]=[C:5]([CH:7]([OH:15])[C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[CH:4]=[C:3]1[C:16]([OH:18])=[O:17]
Reactant: Cn1cc(C(=O)c2cccc(Cl)c2)cc1C(=O)O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: Cn1cc(C(O)c2cccc(Cl)c2)cc1C(=O)O
Reaction time: 24 h

Procedure:
5 g 1-methyl-4-(3-chloro-benzoyl)pyrrole-2-carboxylic acid (obtained in Example 2) are dissolved in 40 ml aqueous ethanol (96%). 4 ml aqueous sodium hydroxide (d=1.33) and 0.7 g sodium borohydride are added thereto. After 24 hours at room temperature, the solution is made acidic by addition of acetic acid. 3 g of hydroxylated acid precipitate out; m.p.=180° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([C@H:12]1[CH2:16][N:15]([C:17](=S)[CH2:18][C:19](=O)[CH3:20])[C@H:14]([C:23]([O:25][CH3:26])=[O:24])[CH2:13]1)(=[O:11])=[O:10].S(O)(O)(=O)=O.[CH2:32]([NH:40][NH2:41])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH3:26][O:25][C:23]([C@@H:14]1[CH2:13][C@@H:12]([S:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[Cl:1])(=[O:11])=[O:10])[CH2:16][N:15]1[C:17]1[N:40]([CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:41]=[C:19]([CH3:20])[CH:18]=1)=[O:24]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2Cl)CN1C(=S)CC(C)=O
Reactant: NNCCc1ccccc1
Agent: O=S(=O)(O)O
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2Cl)CN1c1cc(C)nn1CCc1ccccc1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-methyl 4-(2-chloro-4-fluorophenylsulfonyl)-1-(3-oxobutanethioyl)pyrrolidine-2-carboxylate (example 464 a) was reacted with 2-phenethyl-hydrazine sulfate (CAS Reg. No. 56-51-4) to give the title compound as yellow oil. MS (ESI): m/z=506.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:13][CH:14]=O)[CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18](=[O:26])[C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1.CC(O)=O.[BH3-]C#N.[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]([CH2:13][CH2:14][NH:25][C:22]1[CH:21]=[CH:20][C:19]([C:18]([O:17][CH3:16])=[O:26])=[CH:24][CH:23]=1)[CH3:12])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CN(CC=O)C(=O)OCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(NCCN(C)C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 334.5 %

Procedure:
A stirred solution of N-benzyloxycarbonyl-N-methylaminoacetaldehyde (1.77 g, 1.1 mmol) in toluene (3 mL) was added methyl-4-aminobenzoate (1.29 g, 8.5 mmol), and the mixture was stirred for 1 hr at room temp. The reaction mixture was evaporated under a reduced pressure and the residue was dissolved into MeCN (15 mL). To the solution was added AcOH (2.44 mL, 43 mmol) and NaBH3CN (2.67 g, 43 mmol), and the resulting mixture was stirred for 15 hr at room temp. The reaction was quenched by the addition of sat. NaHCO3. The mixture was extracted with EtOAc, washed with brine, dried over MgSO4, and evaporated. The residue was chromatographed on silica-gel with n-hexane: EtOAc (7:3, v/v) as eluent to give 1.26 g (43%) methyl 4-[2-(N-benzyloxy carbonyl-N-methylamino)ethylamino]benzoate as a colorless oil. 1H-NMR (CDCl3, 400 MHz) δ2.96 (s, 3H), 3.32 (br m, 2H), 3.50-3.60 (m, 2H), 3.82 (s, 3H), 5.15 (each d, 2H, J=14.6 Hz), 6.35 and 6.58 (m, total 2H), 7.36 (s, 5H), 7.76 and 7.84 (m, total 2H); MS (FAB) m/z 342 (M++1).
Reaction SMILES: [CH2:1]([C:11]1[CH:21]=[CH:20][C:14]([C:15]([N:17]([OH:19])C)=[O:16])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].ON1C2C=CC=C[C:26]=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.Cl.O(N)C.C(N(CC)CC)C>C(Cl)Cl>[CH:1](/[C:11]1[CH:21]=[CH:20][C:14]([C:15]([NH:17][O:19][CH3:26])=[O:16])=[CH:13][CH:12]=1)=[CH:2]/[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: On1nnc2ccccc21
Reactant: CCCCCCCCCCc1ccc(C(=O)N(C)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CON
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCC/C=C\c1ccc(C(=O)NOC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a solution of the benzoic acid prepared in Example 1 Part C (2.0 g, 7.68 mM) in dry CH2Cl2 (20 ml) was added 1-hydroxybenzotriazole (1.25 g, 9.22 mM, 1.2 eq.) and N,N'-dicyclohexylcarbodiimide (1.90 g, 9.22 mM, 1.2 eq.) and the mixture stirred for 1 hour at room temperature. Methoxylamine hydrochloride (1.28 g, 15.36 mM. 2 eq.) and triethylamine (2.14 ml, 15.36 mM, 2 eq.) were added, the mixture stirred for 3 hours at room temperature, then filtered, evaporated, taken up in ethyl acetate and filtered again. The organic phase was washed successively with 5% KHSO4, saturated NaHCO3 and brine, then dried over anhydrous Na2SO4 and evaporated to an oil. The crude oil was flash chromatographed on LPS-1 silica gel eluting with (7:3) hexane-ethyl acetate. Product containing fractions were evaporated to give 2.023 g (91%) of the desired title product, 1.664 g of cis isomer, 359 mg of trans isomer as a low melting white solid with consistent NMR (CDCl3, 60 MHz) spectral data. TLC (1:1) EtOAc-Hex, Rf =0.39 UV and PMA.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Br[C:9]1[N:14]=[C:13]([CH2:15][OH:16])[CH:12]=[CH:11][CH:10]=1>C(#N)C>[N:5]1[CH:6]=[CH:7][C:2]([NH:1][C:9]2[N:14]=[C:13]([CH2:15][OH:16])[CH:12]=[CH:11][CH:10]=2)=[CH:3][CH:4]=1
Reactant: OCc1cccc(Br)n1
Reactant: Nc1ccncc1
Solvent: CC#N
Product: OCc1cccc(Nc2ccncc2)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
1.35 g (14.3 mmol) of 4-aminopyridine and 1.34 g (7.1 mmol) of (6-bromopyridin-2-yl)methanol are stirred at 150° C. for 4 h. After cooling to RT, 50 ml of acetonitrile are added to the reaction mixture, and the mixture is stirred for 20 min. The precipitate formed is filtered off with suction at 0° C. and washed with 10 ml of acetonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH:21]([N:24]1[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]1)([CH3:23])[CH3:22]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:30][CH:27]2[CH2:28][CH2:29][N:24]([CH:21]([CH3:23])[CH3:22])[CH2:25][CH2:26]2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: CC(C)N1CCC(N)CC1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: CC(C)N1CCC(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)CC1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and 1-isopropylpiperidin-4-amine (21.5 mg, 0.12 mmol). The title compound was obtained as a solid (10.7 mg, 23% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.98 (2H, m), 8.63 (1H, d), 8.50 (1H, s), 3.56 (1H, m), 2.77 (2H, m), 2.67 (1H, m), 2.13 (2H, m), 1.76 (2H, m), 1.43 (2H, m), 0.95 (6H, d). MS m/z: 475.15, 477.13 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11](=[O:12])[C:5]=2[CH:4]=[N:3]1.[H-].[Na+].[CH3:15][O:16][C:17](=O)[O:18]C>>[CH3:1][N:2]1[C:6]2[CH2:7][CH2:8][CH2:9][CH:10]([C:17]([O:16][CH3:15])=[O:18])[C:11](=[O:12])[C:5]=2[CH:4]=[N:3]1
Reactant: Cn1ncc2c1CCCCC2=O
Reactant: COC(=O)OC
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C1CCCc2c(cnn2C)C1=O

Procedure:
A solution of 1-methyl-5,6,7,8-tetrahydro-1H-cycloheptapyrazol-4-one (0.75 g, 4.6 mmol) in dimethylcarbonate (3 mL) is treated with 60% dispersion of sodium hydride in oil (0.4 g, 10 mmol) as described in Example 1A to yield the title compound: MS (DCI/NH3) m/z 223 (M+H)+.
Reaction SMILES: Cl[S:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[CH3:12][CH:13]([NH2:17])[CH2:14][CH2:15][CH3:16]>C(OCC)C>[CH3:12][CH:13]([N:17]1[C:5](=[O:6])[C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=2[S:2]1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCC(C)N
Reactant: O=C(Cl)c1ccccc1SCl
Solvent: CCOCC
Product: CCCC(C)n1sc2ccccc2c1=O
Reaction time: 16 h

Procedure:
2-Chlorosulphenylbenzoyl chloride (6 parts, 0.029M) dissolved in diethylether (30 ml) was added dropwise at 0 to 3° C. to a stirred solution of 1-methylbutylamine (7.36 parts, 0.84M ex Aldrich) in diethylether (30 ml). The reactants were stirred for 16 hours whilst allowing the temperature to rise to about 20° C. The ether solution was then screened, washed with water and dried over magnesium sulphate. After evaporation of the ether, the product was obtained as a pale yellow gum (5.5 parts, 86% theory) which gradually solidified on standing. This was recrystallised from hexane. mp=52-54° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[C:10]2[NH:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])=[CH:5][C:4]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[H][H]>CO.[Ni]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]2[NH:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])=[CH:5][C:4]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: [H][H]
Reactant: COc1ccc(C=C2NC(=O)NC2=O)cc1OCc1ccccc1
Agent: [Ni]
Solvent: CO
Product: COc1ccc(CC2NC(=O)NC2=O)cc1OCc1ccccc1
Yield: 47 %

Procedure:
A solution of 16.20 g (0.05 mole) of the benzylidene hydantoin from Example 4 in 100 mL of methanol and 25.0 g (0,055 mole) of 20% tetramethylammonium hydroxide-in-methanol is reduced with hydrogen and Raney nickel catalyst. After the theoretical uptake of hydrogen the mixture is filtered and acetic acid (ca 5 mL) and then water is added until just turbid. The first crop of solid is filtered. This is starting material. An additional 2 L of water is added to precipitate the product as crop 2; wt 7.60 g (47% yield). Recrystallization from methanol gives pure product; mp 155°-157° C.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:21]1([C:27](Cl)=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:21]1([C:27]([N:20]=[C:16]([N:7]2[CH2:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8]2)[O:17][CH2:18][CH3:19])=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Reactant: O=C(Cl)C1CCCCC1
Product: CCOC(=NC(=O)C1CCCCC1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and cyclohexanecarboxylic acid chloride, there is obtained ethyl N-cyclohexylcarbonyl-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a resin, mass spectrum m/e: M+ 376 (13), 347 (16), 293 (100), 194 (60);
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1.N1C=CC=CC=1>ClCCl>[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH:21][S:2]([C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[NH:10][C:9](=[O:14])[CH2:8]3)(=[O:4])=[O:3])=[CH:18][CH:17]=1
Reactant: NCc1ccc(F)cc1
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C1Cc2cc(S(=O)(=O)NCc3ccc(F)cc3)ccc2N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
A suspension of 5-chlorosulfonyl-2-oxindole (5.0 g), 4-fluorobenzylamine (3.0 mL) and pyridine (3.5 mL) in dichloromethane (30 mL) was stirred at room temperature for 4 hours. The precipitate was filtered, washed with dichloromethane and dried to give 5.8 g (84%) of 2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid 4-fluoro-benzylamide.
Reaction SMILES: [C:1]([CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16]([OH:18])=[O:17])=[O:13])=[CH:8][C:7]=1[N+:23]([O-:25])=[O:24])([OH:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C)C=O.C(OCC)(=O)C>[N+:23]([C:7]1[CH:8]=[C:9]([C:12]([C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16]([O:18][CH2:12][C:9]2[CH:10]=[CH:11][CH:6]=[CH:7][CH:8]=2)=[O:17])=[O:13])[CH:10]=[CH:11][C:6]=1[NH:5][CH2:4][C:1](=[O:3])[O:2][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([O-:25])=[O:24]
Reactant: O=C(O)CNc1ccc(C(=O)c2ccccc2C(=O)O)cc1[N+](=O)[O-]
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(CNc1ccc(C(=O)c2ccccc2C(=O)OCc2ccccc2)cc1[N+](=O)[O-])OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 165.6 %

Procedure:
To a solution of 2-({4-[(carboxymethyl)amino]-3-nitrophenyl}carbonyl)benzoic acid (0.26 g, 0.76 mmol) in N,N-dimethyl formamide (5.0 mL), potassium carbonate (0.52 g, 3.80 mmol) was added, followed by the addition of benzyl bromide (0.22 mL, 1.82 mmol). The reaction mixture was stirred for 15 hours at room temperature. It was poured into ice water and diluted with ethyl acetate (50 mL). The organic layer was separated and it was washed with water, 2M aqueous hydrochloric acid and brine. It was dried over anhydrous sodium sulfate. Evaporating the solvent, followed by purification of the crude product by silica gel flash chromatography (hexane:ethyl acetate 4:1 to 3:2 eluent) resulted in phenylmethyl 2-{[3-nitro-4-({2-oxo-2-[(phenylmethyl)oxy]ethyl}amino)phenyl]carbonyl}benzoate (0.33 g, 82% yield) as an amorphous residue. MS (EI) for C30H24N2O7: 524 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:13])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[N+:14]([C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1)([O-:16])=[O:15]>N1C=CC=CC=1.O>[N+:14]([C:17]1[CH:18]=[CH:19][C:20]([C:21]([NH:13][C:5]2[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:22])=[CH:24][CH:25]=1)([O-:16])=[O:15]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: c1ccncc1
Product: COc1cc(NC(=O)c2ccc([N+](=O)[O-])cc2)cc(OC)c1OC

Procedure:
To a stirred solution of 3,4,5-trimethoxybenzenamine (16d, 5g, 27.2 mmol) in pyridine as solvent and base to this 4-nitrobenzoyl chloride (17, 5.5g, 29.9 mmol) is added slowly and reflux for 3h, after completion of the reaction, reaction mixture is poured in water, filter and washed with dil HCl and dried to afford compound 4-nitro-N-(3,4,5-trimethoxyphenyl)benzamide (18d). To a stirred solution of amide (18d, 6g, 18.0 mmol) taken in toluene lawessons reagent (5.1g, 12.6 mmol) is added and refluxed at 110° C. for 6h. after completion of the reaction toluene is evaporated under vacuum and water is added and extracted into chloroform and finally purified by column chromatography to afford pure compound 4-nitro-N-(3,4,5-trimethoxyphenyl) benzothioamide (19d). Treating the thioamide product (19d, 4g, 11.4 mmol) with potassium ferricyanide (4 eq) in aqueous sodium hydroxide (8 eq) solution at 90° C. for 2h cyclization takes place to obtain the 5,6,7-trimethoxy-2-(4-nitrophenyl) benzo[d]thiazole (20d) solid is precipitated from the reaction mixture filtered and washed with water and dried to afforded product 20d. Reduction of the nitro compound (20d, 1 g, 2.8 mmol) is proceeded with SnCl2.2H2O in ethanol and reflux at 80° C. for 2h, after completion of reaction ethanol is evaporated under vacuum and to this saturated sodium bicarbonate solution is added to quench the excess stannous chloride and filtered in celite bed and purified in silica column (60-120) to afforded pure compound (21d). The compound 4-(5,6,7-trimethoxybenzo[d]thiazol-2-yl)benzenamine (21d, 250 mg, 0.79 mmol) on reaction with 3,5-dimethoxybenzaldehyde (22d, 131 mg, 0.79 mmol) in ethanol using catalytic amount of acetic acid and refluxed for 2h after completion reaction mixture is cooled to 0° C. solid is precipitated from the reaction mixture it is filtered and washed with ethanol to gave the enamine product, and immediately proceeded for the next reaction with using (p-tolylsulfonyl) methyl isocyanide (tosmic) (1.5 eq), and potassium carbonate (2 eq) as base, in 10 mL of methanol and 5 mL of DME was heated under reflux for 12 h after completion of reaction as monitored by TLC. It was cooled to room temperature (27° C.); the solution was concentrated in vacuo and partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc and Hexane to gave compound 7d as a brown solid (62%).