Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5](/[CH:7]=[C:8]2\[CH2:9][N:10](C)[CH2:11][CH2:12][CH2:13]\2)[O:4][N:3]=1.[Cl:15]C(OC(Cl)=O)C>C1(C)C=CC=CC=1>[ClH:15].[CH3:1][C:2]1[CH:6]=[C:5](/[CH:7]=[C:8]2\[CH2:9][NH:10][CH2:11][CH2:12][CH2:13]\2)[O:4][N:3]=1
Reactant: Cc1cc(/C=C2/CCCN(C)C2)on1
Reactant: CC(Cl)OC(=O)Cl
Solvent: Cc1ccccc1
Product: Cc1cc(/C=C2/CCCNC2)on1
Product: Cl

Procedure:
To a solution of (Z)-3-(3-methyl-5-isoxazolyl)methylene-1-methylpiperidine (1.3 g, 6.5 mmol) in toluene (50 ml) was added 1-chloroethylchloroformate (1.3 g, 10 mmol). The reaction mixture was heated at reflux for 5 h. The reaction mixture was evaporated and methanol (50 ml) was added. The reaction mixture was heated at reflux for 1 h and evaporated. The crude compound was purified by column chromatography (eluent: methylene chloride/methanol/ammonium hydroxide (25%): 8/2/0.5). The free base was crystallized as the hydrochloride from ethyl acetate giving the title compound in 350 mg yield. M.p. 232-235° C. (Compound 5).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:11][C:10]([C:12]([OH:14])=O)=[CH:9][CH:8]=1.CCN(CC)CC.ClC(OCC(C)C)=O.[N-:30]=[N+:31]=[N-:32].[Na+]>CC(C)=O.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:11][C:10]([C:12]([N:30]=[N+:31]=[N-:32])=[O:14])=[CH:9][CH:8]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)c1ccc(-c2ccccn2)s1
Agent: CC(C)COC(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)=O
Product: [N-]=[N+]=NC(=O)c1ccc(-c2ccccn2)s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
20 g (97.45 mmol) of 5-(2-pyridyl)-thiophene-2-carboxylic acid are dissolved in 200 ml of acetone, and the solution is treated with 15.94 ml (115 mmol) of Et3N and cooled to 0° C. A solution of 14.85 ml (115 mmol) of isobutyl chloroformate in 88 ml of acetone is slowly added dropwise with stirring to the reaction solution thus obtained. After 1 h at 0° C., a solution of 9.5 g (146 mmol) of sodium azide in 44 ml of water is added dropwise, and the mixture is stirred at 0° C. for 1 h and allowed to come to room temperature. The reaction mixture is tipped onto ice water and the precipitate is filtered off with suction and reacted further as it is.
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[C:8]([OH:12])([CH3:11])([CH3:10])[CH3:9].[CH3:13][C:14]1[N:19]=[C:18]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([C:26]3[CH:27]=[C:28]([NH2:32])[CH:29]=[CH:30][CH:31]=3)[N:21]=2)[CH:17]=[C:16]([C:33]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=2)[CH:15]=1.C(N(CC)CC)C>ClCCl>[C:8]([O:12][C:6]([NH:5][S:2]([NH:32][C:28]1[CH:29]=[CH:30][CH:31]=[C:26]([C:22]2[N:21]=[C:20]([C:18]3[CH:17]=[C:16]([C:33]4[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=4)[CH:15]=[C:14]([CH3:13])[N:19]=3)[CH:25]=[CH:24][N:23]=2)[CH:27]=1)(=[O:4])=[O:3])=[O:7])([CH3:11])([CH3:10])[CH3:9]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(N)c3)n2)n1
Reactant: CC(C)(C)O
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(NS(=O)(=O)NC(=O)OC(C)(C)C)c3)n2)n1
Yield: 34.6 %

Procedure:
To a stirred and cooled solution of commercially available chlorosulfonyl isocyanate (0.215 mL, 2.47 mmol) in dichloromethane (5 mL) was added tert-butanol (0.232 mL, 2.47 mmol) and the mixture was stirred at 0° C. for 30 min. Then 3-{4-[6-methyl-4-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-pyrimidin-2-yl}-phenylamine (example 326) (0.200 g, 0.494 mmol) and triethyl amine (0.42 mL, 2.96 mmol) were added and the mixture was stirred at 23° C. for 0.5 h. Diluted with DCM, washed with sat. NaHCO3-sol. and water, dried the organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product which was purified by silica gel column chromatography with heptane/EtOAc/THF, followed by trituration with diethyl ether to give the title compound as an off-white solid (0.100 g, 35%). MS (ISP) 586.2 [(M+H)+].
Reaction SMILES: NC1C=CC(O[CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]C2)=CC=1.[CH2:22]([N:26]1[CH:30]=[C:29]([C:31]2[O:35][C:34]([C:36]([OH:38])=O)=[CH:33][CH:32]=2)[CH:28]=[N:27]1)[CH:23]([CH3:25])[CH3:24].C(OC([N:49]1CC(C(O)=O)C1)=O)C1C=CC=CC=1>>[CH2:22]([N:26]1[CH:30]=[C:29]([C:31]2[O:35][C:34]([C:36]([NH:49][C@H:7]3[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:9]3)=[O:38])=[CH:33][CH:32]=2)[CH:28]=[N:27]1)[CH:23]([CH3:25])[CH3:24]
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)C1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2)CC1
Reactant: CC(C)Cn1cc(-c2ccc(C(=O)O)o2)cn1
Product: CC(C)Cn1cc(-c2ccc(C(=O)N[C@H]3CCN(C(=O)OC(C)(C)C)C3)o2)cn1

Procedure:
The title compound was prepared as described in Example 1A, substituting (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate for tert-butyl 4-(4-aminophenoxy)piperidine-1-carboxylate and 5-(1-isobutyl-1H-pyrazol-4-yl)furan-2-carboxylic acid for 1-(benzyloxycarbonyl)azetidine-3-carboxylic acid.
Reaction SMILES: [CH2:1](O)[CH:2]=[CH2:3].S(=O)(=O)(O)O.[Cl:10][C:11]1[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:12]=1[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([OH:27])=[O:26])=[CH:20][CH:19]=1.O>C1C=CC=CC=1>[Cl:10][C:11]1[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:12]=1[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([O:27][CH2:3][CH:2]=[CH2:1])=[O:26])=[CH:20][CH:19]=1
Reactant: O=C(O)Cc1ccc(-c2ccc(O)cc2Cl)cc1
Reactant: C=CCO
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Solvent: O
Product: C=CCOC(=O)Cc1ccc(-c2ccc(O)cc2Cl)cc1

Procedure:
After allyl alcohol (7.0 ml, 103 mmol) and concentrated sulfuric acid (0.1 ml) were successively added to a solution of (2′-chloro-4′-hydroxy-1,1′-biphenyl-4-yl)acetic acid (1.93 g, 7.35 mmol) obtained in Example (13-1) in benzene (30 ml), the mixture was heated under reflux for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate (twice). The organic layer was successively washed with water (twice) and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=90/10-65/35) to give allyl (2′-chloro-4′-hydroxy-1,1′-biphenyl-4-yl)acetate as a white powder (1.97 g, yield: 899.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH2:6][CH2:7][NH2:8].CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.Cl[C:31]([O:33][CH:34]([Cl:36])[CH3:35])=[O:32]>C(Cl)(Cl)Cl>[Cl:36][CH:34]([O:33][C:31]([NH:8][CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:32])[CH3:35]
Reactant: COc1ccc(CCN)cc1OC
Reactant: CC(Cl)OC(=O)Cl
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: ClC(Cl)Cl
Product: COc1ccc(CCNC(=O)OC(C)Cl)cc1OC
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 1.8 g of 3,4-dimethoxyphenethylamine in 50 ml of chloroform 2.2 g of proton sponge® was added. The reaction mixture was cooled in an ice bath. To the ice-cold solution was added with stirring 1.4 g of 1-chloroethyl chloroformate. The cooling bath was removed and the reaction mixture was kept stirred at room temperature for 72 hours. It was then washed with water, 3N HCl and water. After drying over sodium sulfate, the chloroform solution was evaporated to a thick oil weighing 2.1 g. NMR (CDCl3) δ1.75 (3H, d, J=7 Hz, CH3CH), 2.78 (2H, t, J=6 Hz, ArCH2), 3.4 (2H, broad t, NHCH2), 3.9 (6H, s, OMe), 4.9 (1H, broad NH) and 6.4-6.85 (CHCl and aromatic). IR (film) ν3350, 1722, 1512, 1260, 1240, 1138 cm-1.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][C:12]1[CH:20]=[CH:19][C:18]2[N:14]([C:15]([C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])=[C:16]([CH2:30][C:31]([CH3:38])([CH3:37])[C:32]([O:34]CC)=[O:33])[C:17]=2[C:21]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[O:22])[CH:13]=1.[OH-].[Na+].Cl>C1COCC1.CO>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][C:12]1[CH:20]=[CH:19][C:18]2[N:14]([C:15]([C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])=[C:16]([CH2:30][C:31]([CH3:38])([CH3:37])[C:32]([OH:34])=[O:33])[C:17]=2[C:21]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[O:22])[CH:13]=1
Reactant: CCOC(=O)C(C)(C)Cc1c(C(=O)c2ccc(Cl)cc2)c2ccc(OCc3nc4ccccc4s3)cn2c1C(=O)C(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)c1c(CC(C)(C)C(=O)O)c(C(=O)c2ccc(Cl)cc2)c2ccc(OCc3nc4ccccc4s3)cn12
Temperature: 23 °C
Yield: 81.5 %

Procedure:
A solution of ethyl 3-[6-(1,3-benzothiazol-2-ylmethoxy)-1-[(4-chlorophenyl)carbonyl]-3-(2,2-dimethylpropanoyl)indolizin-2-yl]-2,2-dimethylpropanoate (74 mg, 0.12 mmol) in THF (0.5 mL), MeOH (1.0 mL), and 6M aqueous NaOH (1.0 mL) is heated at 70° C. for 1 h then cooled to 23° C. and acidified to pH=1 with concentrated aqueous HCl. The mixture is partitioned between CH2Cl2 and brine and organics are collected, dried with MgSO4, filtered, and concentrated in vacuo. Purification of the crude by flash chromatography (SiO2, CH2Cl2 to 10% MeOH in CH2Cl2) gives the title compound (59 mg, 83%).
Reaction SMILES: C([O:5][CH2:6][CH:7]([CH2:12][CH3:13])[CH2:8][CH2:9][CH2:10][CH3:11])(=O)C=C.C(=O)([O-])[O-:15].[Cs+].[Cs+]>CCCCCC>[CH3:11][CH2:10][CH2:9][CH2:8][CH:7]([C:6]([OH:5])=[O:15])[CH2:12][CH3:13]
Reactant: C=CC(=O)OCC(CC)CCCC
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCC
Product: CCCCC(CC)C(=O)O
Temperature: 25 °C
Yield: 8029.1 %

Procedure:
A mixture of TMIT (2.37 g, 15 mmol), 2-ethylhexyl acrylate (2.76 g, 15 mmol) and cesium carbonate (0.12 g, 0.38 mmol, 2.5 mole % based on acrylate) was heated in a sand bath at 100–120 ° C. for 2 h, while the progress of the reaction was being followed by IR spectroscopy. The reaction mixture was cooled to room temperature, and to the resulting thick oil was added hexane (40 mL), and the mixture was filtered to remove solid cesium carbonate. Solvent evaporation from the filtrate yielded product as a light-yellow oil (4.4 g, 86%). IR: 3323, 2961, 1733, 1481 cm−1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:22]=[C:21]3[C:16]([CH:17]=[CH:18][CH:19]=[N:20]3)=[C:15](OS(C(F)(F)F)(=O)=O)[N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[NH2:31][CH2:32][C@@H:33]1[C@@H:37]([CH3:38])[NH:36][C:35](=[O:39])[CH2:34]1.C(N(C(C)C)CC)(C)C.FC(F)(F)C(O)=O>CC(N(C)C)=O>[CH3:38][C@H:37]1[NH:36][C:35](=[O:39])[CH2:34][C@@H:33]1[CH2:32][NH:31][C:15]1[N:14]=[C:13]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=2)[CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][CH:19]=[N:20]2
Reactant: COc1cc(-c2cc3ncccc3c(OS(=O)(=O)C(F)(F)F)n2)cc(OC)c1OC
Reactant: C[C@H]1NC(=O)C[C@@H]1CN
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(-c2cc3ncccc3c(NC[C@H]3CC(=O)N[C@@H]3C)n2)cc(OC)c1OC
Temperature: 80 °C

Procedure:
100 mg 6.1 and 33 mg (4R,5R)-4-(aminomethyl)-5-methylpyrrolidine-2-one (2.26) were dissolved in dimethylacetamide. 0.175 mL Diisopropylethylamine was added and the mixture was heated at 80° C. for 85 min. The mixture was acidified with trifluoroacetic acid and purified via chromatography (RP-HPLC) and the corresponding fractions were freeze-dried.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][C:8](=[N:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C.CO.O>C1COCC1>[C:1]([N:5]1[CH2:6][CH2:7][CH:8]([NH:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NN=C1CCN(C(C)(C)C)CC1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NNC1CCN(C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
To a solution of tert-butyl 2-(1-tert-butylpiperidin-4-ylidene)hydrazinecarboxylate (400 mg, 1.49 mmol) in THF (40 mL) was added DIBAl-H (15 mL, 15 mmol) under nitrogen atmosphere. The resulting mixture was stirred at 25° C. overnight. Methanol (5 mL) was added at −78° C. After being stirred at room temperature for 1 h, water (10 mL) was added. The solid was filtered off and washed with EtOAc. The combined filtrate was partitioned and extracted with EtOAc (3×50 mL), dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography eluting with EtOAc/petroleum ether (1:10) to give tert-butyl 2-(1-tert-butylpiperidin-4-yl)hydrazinecarboxylate (350 mg, 87% yield) as colorless oil. LCMS (ESI) m/z: 272.4 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.[C:27]([NH:30][C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=1)(=[O:29])[CH3:28]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:20][CH2:21][N:22]([CH2:35][C:34]4[CH:33]=[CH:32][C:31]([NH:30][C:27](=[O:29])[CH3:28])=[CH:38][CH:37]=4)[CH2:23][CH2:24]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:25][CH:26]=1
Reactant: CC(=O)Nc1ccc(C=O)cc1
Reactant: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCNCC2)cc1
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCN(Cc3ccc(NC(C)=O)cc3)CC2)cc1

Procedure:
Using the general procedure described in Example 3, N1-(4-methoxybenzoyl)-N2-(piperidin-4-ylcarbonyl)-1,2-benzenediamine (0.045 mmol) was reacted with 4-acetamidobenzaldehyde to provide 23 mg of the title product as the free base. Treatment with hydrochloric acid and concentration in vacuo yielded the salt of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH:9]=[CH:10]N(C)C)[C:6]([N+:14]([O-])=O)=[CH:5][N:4]=1)#[N:2].[ClH:17]>[Pd].CO>[ClH:17].[ClH:17].[NH2:2][CH2:1][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][N:4]=1)[NH:14][CH:10]=[CH:9]2
Reactant: CN(C)C=Cc1cc(C#N)ncc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCc1cc2cc[nH]c2cn1

Procedure:
A suspension of 2-cyano-4-(2-dimethylaminoethenyl)-5-nitropyridine (3.8 g) and 10% palladium on carbon (3 g) in 6 M HCl (10 mL) and methanol (50 mL) was shaken on a Parr apparatus under hydrogen (55 psi). After 16 h the mixture was filtered through celite, washing with methanol, and was basified with ammonium hydroxide and evaporated in vacuo. The crude product was purified by flash column chromatography (80:19:1 chloroform/methanol/ammonium hydroxide) to give the title compound as the free base. The free base was dissolved in a minimum volume of methanol and 1 M HCl in ether (2 equivalents) was added and after dilution with ether the solids were collected by filtration to give the title compound as a tan solid:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH3:20])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.BrC[CH2:23][CH2:24][CH2:25][C:26]12[CH2:37][CH2:36][CH2:35][C:33]3[C:34]1=[C:29]([CH:30]=[CH:31][CH:32]=3)[NH:28][C:27]2=[O:38].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(O)C.[C].[Pd].O>[CH3:20][C:11]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][CH2:13][N:8]([CH2:1][CH2:23][CH2:24][CH2:25][C:26]23[CH2:37][CH2:36][CH2:35][C:33]4[C:34]2=[C:29]([CH:30]=[CH:31][CH:32]=4)[NH:28][C:27]3=[O:38])[CH2:9][CH2:10]1
Reactant: CC1(c2ccccc2)CCN(Cc2ccccc2)CC1
Reactant: O=C1Nc2cccc3c2C1(CCCCBr)CCC3
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(c2ccccc2)CCN(CCCCC23CCCc4cccc(c42)NC3=O)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 50 %

Procedure:
1-Benzyl-4-methyl-4-phenylpiperidine (62 mg, 0.24 mmol) was dissolved in ethanol (2 ml). Thereto was added palladium-carbon (10 mg), and the resulting solution was stirred at a room temperature for 17 hours in an atmosphere of argon. The reaction solution was filtered, the solvent was evaporated from the resulting mother liquor under a reduced pressure, and the thus obtained material was dissolved in anhydrous N,N-dimethylformamide (2 ml). The resulting solution was mixed with 2a-(4-bromobutyl)-2a,3,4,5-tetrahydrobenz[cd]indole-2(1H)-one (79 mg, 0.26 mmol) and potassium carbonate (51mg, 0.37mmol) and then the mixture was stirred at 60° C. for 3 hours. The reaction solution was mixed with ethyl acetate and water, and the reaction product was extracted with ethyl acetate, washed with saturated brine and dried with anhydrous sodium sulfate. Then the compound obtained by the evaporation of the solvent under a reduced pressure was separated and purified by a silica gel column chromatography to obtain 50 mg of the title compound (0.12 mmol, 53% in yield).
Reaction SMILES: [NH:1]([C:15](OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@@H:2](C(O)=O)[CH2:3][CH2:4][C:5](=[O:11])[O:6]C(C)(C)C.C(=O)[CH2:33][CH:34]([CH3:36])[CH3:35].[NH:38]([C:50]([O:52]C(C)(C)C)=O)[C@@H:39]([C:47]([OH:49])=O)[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C1C=NC2N(O)N=NC=2C=1.CC(C)N=C=NC(C)C>O>[CH2:40]([C@@H:39]1[C:47](=[O:49])[N:1]([CH2:15][CH2:33][CH:34]([CH3:36])[CH3:35])[C@H:2]([CH2:3][CH2:4][C:5]([OH:6])=[O:11])[C:50](=[O:52])[NH:38]1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)CC[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CC(C)CC=O
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2cccnc21
Solvent: O
Product: CC(C)CCN1C(=O)[C@@H](Cc2ccccc2)NC(=O)[C@H]1CCC(=O)O

Procedure:
Hydroxymethyl PAM resin was coupled with Fmoc-D-Glu(OtBu)-OH (Mukaiyama conditions) and reductively alkylated with isovaleraldehyde. Boc-D-Phe was coupled with HOAt/DIC and after Box-deprotection the DKP formed in 4% TEA/toluene (12h). Yield: 88 mg (37%). 1H-NMR (400 MHz, CD3 OD):δ=0.67-0.70 (m, 1 H), 1.09 (2 d, J=6.5 Hz, 6 H), 1.49-1.73 (m, 3 H), 1.80-1.90 (m, 1 H), 2.01-2.10 (m, 1 H), 2.15-2.32 (m, 1 H), 3.13 (dd, J=4.5, 13.7 Hz, 1 H), 3.19 (ddd, J=5.1, 10.1, 15.1 Hz, 1 H), 3.39 (dd, J=5.2, 13.7 Hz, 1 H), 3.81 (ddd, J=5.5, 9.6, 15.1 Hz, 1 H), 3.92 (dd, J=3.6, 9.6 Hz, 1 H), 4.41 (dd, J=5.2, 5.5 Hz, 1 H), 7.30-7.48 (m, 5 H). 13C-NMR (101 MHz, CD3OD): δ=22.8, 27.4, 29.0, 31.1, 36.8, 40.8, 44.8, 57.9, 59.7, 128.5, 129.7, 131.4, 167.3, 169.1, 177.0. Anal. Calcd. for C16H26N2O4.2 H2O: C, 59.67; H, 7.91; N, 8.09, found: C, 59.09; H, 7.06; N, 7.31.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([NH2:13])[CH:5]=1.N1C=CC=CC=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].O>ClCCl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([NH:13][S:22]([CH3:21])(=[O:24])=[O:23])[CH:5]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1cc(N)cc([N+](=O)[O-])c1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cc(NS(C)(=O)=O)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
3-amino-5-nitro-benzoic acid methyl ester (25 g; 0.13 mol) was dissolved in to dichloromethane (300 ml) and treated at 0° C. with 11 ml of pyridine. Methanesulfonylchloride (11 ml; 0.14 mol) was added and the reaction mixture was stirred overnight at room temperature. Water was added and the precipitate filtered and washed with dichloromethane/diethylether. 32 g (0.11 mmol; 89% yield) of 3-methylsulfonylamino-5-nitro-benzoic acid methyl ester were obtained as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[O-:18][C:19]#[N:20].[Na+].C(O)(=O)C(C1C=CC=CC=1)O.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:19]([NH2:20])=[O:18])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1
Reactant: COC1=Cc2ccccc2Nc2ccccc21
Reactant: N#C[O-]
Agent: O=C(O)C(O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COC1=Cc2ccccc2N(C(N)=O)c2ccccc21
Temperature: 25 °C
Yield: 83.8 %

Procedure:
A suspension of 10 g of 10-methoxyiminostilbene in 200 ml toluene was treated with 20 g of sodium cyanate and 39 g of mandelic acid and was heated to reflux for about 10 hrs. The reaction mixture was cooled to room temperature and charged with sodium hydroxide solution and maintained for 19 hrs. The resulting suspension was filtered, washed with water and dried to give 10 g of 10-methoxy carbamazepine.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[CH2:6][C:7]3([O:21][C:4]=2[CH:3]=1)[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:10][N:9]([C:17](=[S:20])[NH:18][CH3:19])[CH2:8]3.[I:24]C.[CH3:26]COCC>CO.C(O)C>[IH:24].[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[CH2:6][C:7]3([O:21][C:4]=2[CH:3]=1)[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:10][N:9]([C:17](=[SH:20][CH3:26])[NH:18][CH3:19])[CH2:8]3
Reactant: CI
Reactant: CCOCC
Reactant: CNC(=S)N1Cc2ccccc2C2(Cc3ccc(Cl)cc3O2)C1
Solvent: CCO
Solvent: CO
Product: CNC(=[SH]C)N1Cc2ccccc2C2(Cc3ccc(Cl)cc3O2)C1
Product: I
Yield: 99 %

Procedure:
A solution of 6-chloro-2'-(N-methylthiocarbamyl)spiro[benzofuran-2(3H),4'(2'H)-isoquinoline] (12.0 g) and iodomethane (7.4 g) in methanol (150 ml) and ethanol (100 ml) is heated under reflux for four hours. Removal of solvents in vacuo yields a solid which, upon trituration with ether, yields product as a solid (16.4 g, 99%). An analytical sample is recrystallized from ethyl acetate/methanol to yield a white solid, 181°-182° (dec.).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@H:12]([NH:16][C:17](=[O:30])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([C:28]#[N:29])[CH:19]=2)[CH2:13][CH2:14][OH:15])=[CH:7][CH:6]=1)=O.[NH2:31][C:32]1[C:37]([CH3:38])=[CH:36][CH:35]=[CH:34][N:33]=1.C([O-])(O)=O.[Na+]>CC(O)C>[C:28]([C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=1[O:24][CH:25]([CH3:27])[CH3:26])[C:17]([NH:16][C@@H:12]([CH2:11][C:8]1[CH:7]=[CH:6][C:5]([C:3]2[N:31]=[C:32]3[C:37]([CH3:38])=[CH:36][CH:35]=[CH:34][N:33]3[CH:2]=2)=[CH:10][CH:9]=1)[CH2:13][CH2:14][OH:15])=[O:30])#[N:29]
Reactant: CC(C)Oc1ccc(C(=O)N[C@H](CCO)Cc2ccc(C(=O)CBr)cc2)cc1C#N
Reactant: Cc1cccnc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1cccn2cc(-c3ccc(C[C@@H](CCO)NC(=O)c4ccc(OC(C)C)c(C#N)c4)cc3)nc12
Reaction time: 7 h
Yield: 70.3 %

Procedure:
To a solution of N-((1S)-1-{[4-(bromoacetyl)phenyl]methyl}-3-hydroxypropyl)-3-cyano-4-[(1-methylethyl)oxy]benzamide (300 mg, 0.634 mmol) in i-PrOH (6 mL) was added 2-amino-3-picoline (Aldrich, 69 mg, 0.634 mmol) followed by solid NaHCO3 (64 mg, 0.761 mmol). The resultant suspension was heated to 80° C. After 7 h, a majority of the i-PrOH was removed under reduced pressure and the residue was dissolved in 3% MeOH/EtOAc (30 mL) and washed with water (10 mL) and brine (10 mL). The combined aqueous layers were extracted with 3% MeOH/EtOAc (30 mL) and the combined extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (MeCN/H2O with 0.1% TFA) and the clean fractions were adjusted to pH ˜8 with saturated aqueous NaHCO3 and extracted with 3% MeOH/EtOAc (3×30 mL). The extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to give 215 mg (70%) of the title compound as a pale yellow solid. LC/MS (ES) m/e 483.2 (M+H)+.
Reaction SMILES: [CH2:1]([C:8]1[C:13]([C:14](=O)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:12][CH:11]=[CH:10][C:9]=1[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28](=O)[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:23]=1[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:42][NH2:43].Cl.[C:45]([BH3-])#[N:46].[Na+]>CO>[CH2:1]([C:8]1[C:13]([CH:14]([NH:43][CH3:42])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:12][CH:11]=[CH:10][C:9]=1[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([NH:46][CH3:45])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:23]=1[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [BH3-]C#N
Reactant: CN
Reactant: CCCCCC(=O)c1cccc(Oc2cccc(C(=O)CCCCC)c2Cc2ccccc2)c1Cc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCCCC(NC)c1cccc(Oc2cccc(C(CCCCC)NC)c2Cc2ccccc2)c1Cc1ccccc1
Reaction time: 8 h

Procedure:
A solution of benzyl-3-(hexanoyl)phenyl ether (2.8 g.), 40% aqueous methylamine (1.5 ml) and methanol adjusted to pH 6 with 5% aqueous hydrochloric acid is treated with a methanolic solution of sodium cyanoborohydride. The reaction is stirred overnight. The methanol is removed in vacuo and the remaining mixture is extracted with methylene chloride. The organic extract is dried (MgSO4) and concentrated to an oil.