Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C@@H:8]([CH2:12][C:13]2[CH:18]=[C:17](OC)[C:16]([O:21][CH3:22])=[C:15](OC)[CH:14]=2)[C:9]([OH:11])=[O:10])[CH:2]=1.COC1C=CC(C[C@@H](C(O)=O)N)=CC=1>>[C:1]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C@@H:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:21][CH3:22])=[CH:15][CH:14]=2)[C:9]([OH:11])=[O:10])[CH:2]=1
Reactant: COc1cc(C[C@H](Nc2cccc(-c3ccccc3)c2)C(=O)O)cc(OC)c1OC
Agent: COc1ccc(C[C@H](N)C(=O)O)cc1
Product: COc1ccc(C[C@H](Nc2cccc(-c3ccccc3)c2)C(=O)O)cc1

Procedure:
The title compound is prepared as described for (S)-2-(Biphenyl-3-ylamino)-3-(3,4,5-trimethoxy-phenyl)-propionic acid (example 1) but using O-methyl-L-tyrosine (Bachem). Purification by MPLC (CH3CN/H2O/TFA) afforded the title compound; ES-MS: 348.3 [M+H]+; HPLC: single peak at tR=9.52 min (System 1).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=O)[C:10]([OH:12])=[O:11])[N:8]=1)=[O:2].C(=O)(O)[O-].[Na+].Cl.[CH2:20]([O:23][NH2:24])[CH:21]=[CH2:22].Cl>O.C(OCC)(=O)C>[CH2:20]([O:23][N:24]=[C:9]([C:7]1[N:8]=[C:4]([NH:3][CH:1]=[O:2])[S:5][CH:6]=1)[C:10]([OH:12])=[O:11])[CH:21]=[CH2:22]
Reactant: O=CNc1nc(C(=O)C(=O)O)cs1
Reactant: C=CCON
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCON=C(C(=O)O)c1csc(NC=O)n1
Temperature: 25 °C
Reaction time: 7 h
Yield: 66.1 %

Procedure:
To a solution of 2-(2-formamidothiazol-4-yl)glyoxylic acid (30 g) and sodium bicarbonate (12.6 g) in water (1300 ml) was added allyloxyamine hydrochloride (19.8 g), and the mixture was stirred for 7 hours at ambient temperature at pH 6. To the reaction mixture was added ethyl acetate (500 ml). After the mixture was adjusted to pH 1.9 with 10% hydrochloric acid, the ethyl acetate layer was separated. The ethyl acetate layer was washed with an aqueous solution of sodium chloride, dried over magnesium sulfate and then the solvent was distilled off. The residue was pulverized in diisopropyl ether, collected by filtration and then dried to give 2-allyloxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer)(25.3 g).
Reaction SMILES: Cl[C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4]([NH:24][C@H:25]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:26]([OH:28])=[O:27])[N:3]=1.[CH3:33][N:34]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[N:35]1>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:21][O:20][C:13]1[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:12]=1[CH2:11][N:9]1[CH2:10][C:6]2[C:5]([F:23])=[C:4]([NH:24][C@H:25]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:26]([OH:28])=[O:27])[N:3]=[C:2]([C:37]3[CH:36]=[N:35][N:34]([CH3:33])[CH:38]=3)[C:7]=2[C:8]1=[O:22]
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@H](CC(C)C)C(=O)O)nc(Cl)c3C2=O)c(OC)c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(CN2Cc3c(F)c(N[C@H](CC(C)C)C(=O)O)nc(-c4cnn(C)c4)c3C2=O)c(OC)c1

Procedure:
A solution of (R)-2-(4-chloro-2-(2,4-dimethoxybenzyl)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)-4-methylpentanoic acid (1.1 g, 2.361 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.456 g, 11.81 mmol) and bis(triphenylphosphine)palladium chloride (1.657 g, 2.361 mmol) in dioxane (10 mL) and saturated aq Na2CO3 (10.00 mL) was heated to 120° C. for 30 min. After filtering out the solids, the solvent was removed from the filtrate. The resulting residue was dissolved in MeOH and DCM and was purified via preparative HPLC eluting with water (0.05% TFA) and ACN (40-70% gradient, 0.035% TFA). The collected fractions were combined and the solvent stripped to dryness via rotary evaporation to yield the title compound. [M+H] calc'd for C26H30FN5O5, 512; found, 512.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[C:4]([CH2:17]O)[CH:3]=1.C1C=CC(P([N:33]=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[NH2:33][CH2:17][C:4]1[CH:3]=[C:2]([Cl:1])[CH:16]=[CH:15][C:5]=1[CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CO
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CN
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 4-chloro-2-(hydroxymethyl)benzylcarbamate (10 g, 36.8 mmol) in anhydrous THF (100 ml) was added DPPA (8.3 ml, 38.6 mmol) and DBU (5.79 ml, 38.6 mmol). The mixture was stirred overnight and then was partitioned between ethyl acetate and water. The organic layer was washed with brine, and was concentrated in vacuo to a crude oil (14.6 g). Purification was accomplished by silica gel chromatography, eluting a gradient of ethyl acetate-hexane (10, 15, 20, 25, 50%) to give tert-butyl 2-(aminomethyl)-4-chlorobenzylcarbamate.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[S:13][C:12]([S:14](Cl)(=[O:16])=[O:15])=[CH:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1.[NH2:18][C:19]1[CH:20]=[C:21]([C:25]2[NH:29][N:28]=[N:27][N:26]=2)[CH:22]=[CH:23][CH:24]=1>>[CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[S:13][C:12]([S:14]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[NH:29][N:28]=[N:27][N:26]=4)[CH:20]=3)(=[O:16])=[O:15])=[CH:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Reactant: CSc1nccc(-c2ccc(S(=O)(=O)Cl)s2)n1
Product: CSc1nccc(-c2ccc(S(=O)(=O)Nc3cccc(-c4nnn[nH]4)c3)s2)n1
Yield: 43.1 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, starting from 5-[2-(methylthio)pyrimidin-4-yl]thiophene-2-sulfonyl chloride (17 mg, 0.055 mmol) and 5-(3-aminophenyl)tetrazole (8 mg, 0.05 mmol) giving 9.3 mg (43%) of the title compound. MS (ESI+) calcd for C16H13N7O2S3 431.029285, found 431.029205.
Reaction SMILES: [ClH:1].C[C:3]1C=C2[C:6]([NH:7]C=C2CCN)=[C:5](Br)[CH:4]=1.Cl.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[NH:25]N>>[ClH:1].[CH3:24][C:21]1[CH:22]=[CH:23][C:18]([CH3:17])=[C:19]2[C:20]=1[C:4]([CH2:5][CH2:6][NH2:7])=[CH:3][NH:25]2
Reactant: Cc1cc(Br)c2[nH]cc(CCN)c2c1
Reactant: Cc1ccc(C)c(NN)c1
Agent: Cl
Product: Cc1ccc(C)c2c(CCN)c[nH]c12

Procedure:
4,7-dimethyltryptamine hydrochloride was prepared (0.94 g) as described for 5-methyl-7-bromotryptamine hydrochloride in Example 4, except using 2,5-dimethyl-phenylhydrazine hydrochloride (16.8 g) as starting material. ##STR47##
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[C:12]([C:19]3[C:28]4[C:23](=[CH:24][N:25]=[CH:26][CH:27]=4)[C:22]([NH2:29])=[N:21][CH:20]=3)=[C:11]2[CH3:30])(=O)=O)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.C(O)C(F)(F)F>[CH3:30][C:11]1[NH:10][C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[C:12]=1[C:19]1[C:28]2[C:23](=[CH:24][N:25]=[CH:26][CH:27]=2)[C:22]([NH2:29])=[N:21][CH:20]=1
Reactant: Cc1c(-c2cnc(N)c3cnccc23)c2cccnc2n1S(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: OCC(F)(F)F
Product: Cc1[nH]c2ncccc2c1-c1cnc(N)c2cnccc12
Yield: 80 %

Procedure:
A mixture of 23 g of 4-(1-benzenesulfonyl-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,7-naphthyridin-1-ylamine and 26 g of caesium carbonate in 400 ml of THF/trifluoroethanol (1:1 vol) is heated under reflux for 20 h. The mixture is cooled, the solvent is removed, and the product is purified by means of flash chromatography over 220 g of silica with a methanol gradient in ethyl acetate with 150 ml/min with UV detection at 254 nm, giving 12.2 g of 4-(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,7-naphthyridin-1-ylamine, M˜275.31, M+H found 276.2;
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[CH3:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]2[CH:19]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[S:21][C:11]1=2.O>ClCCCl>[C:5]([C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[N:10]([CH3:9])[C:11]1[S:21][C:20]([C:22]([O:24][CH3:25])=[O:23])=[CH:19][C:12]2=1)(=[O:7])[CH3:6]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1cc2c3ccccc3n(C)c2s1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: O
Product: COC(=O)c1cc2c3cc(C(C)=O)ccc3n(C)c2s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a slurry of 870 mg AlCl3 in 50 ml dry 1,2-dichloroethane was added 465 μl acetyl chloride. The mixture was stirred for 30 min. at room temperature. 800 mg of (6) was added, and stirring continued overnight. Another 870 mg AlCl3 and 465 μl acetyl chloride was added, and stirring continued overnight. Water was added, and the organic phase dried and evaporated to dryness giving a brown powder, which was crystallized from acetic acid and petrol ether giving (64). Yield 210 mg. M. p. 196°-8° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2([C:12]3[N:16]4[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:15]4=[N:14][N:13]=3)[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[CH3:23][S:24](Cl)(=[O:26])=[O:25].N1C=CC=CC=1>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH3:23][S:24]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]2([C:12]3[N:16]4[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:15]4=[N:14][N:13]=3)[CH2:8][CH2:9][CH2:10][CH2:11]2)[CH2:3][CH2:2]1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: C1CCCn2c(nnc2C2(C3CCNCC3)CCCC2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)N1CCC(C2(c3nnc4n3CCCCCC4)CCCC2)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
3-(1-Piperidin-4-ylcyclopentyl)-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocine (302 mg) was dissolved in methylene chloride (5 ml) and then methanesulfonyl chloride (0.09 ml) and pyridine (0.24 ml) were added thereto, followed by stirring at room temperature for 6 hours. Furthermore, methanesulfonyl chloride (0.09 ml) and pyridine (0.57 ml) were added thereto, followed by stirring at room temperature for 16 hours. The reaction solution was diluted with a saturated aqueous sodium bicarbonate solution, followed by extraction with chloroform (10 ml×2). The organic layer was dried over anhydrous sodium sulfate and filtered and then the solvent was removed by evaporation under reduced pressure. The resulting residue was purified by column chromatography (methanol:chloroform=1:9) and then the resulting solid washed with ethyl acetate to obtain 117 mg of 3-{1-[1-(methylsulfonyl)-4-piperidinyl]cyclopentyl}-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocine (white solid).
Reaction SMILES: [NH2:1][CH:2](/[CH:6]=[C:7](\[CH3:13])/[CH2:8][P:9]([OH:12])([OH:11])=[O:10])[C:3]([OH:5])=[O:4].Cl.[CH2:15](O)[CH3:16]>>[CH2:15]([O:4][C:3](=[O:5])[CH:2]([NH2:1])/[CH:6]=[C:7](\[CH3:13])/[CH2:8][P:9]([OH:12])([OH:11])=[O:10])[CH3:16]
Reactant: CCO
Reactant: C/C(=C\C(N)C(=O)O)CP(=O)(O)O
Agent: Cl
Product: CCOC(=O)C(N)/C=C(\C)CP(=O)(O)O

Procedure:
2.0 g of E-2-amino-4-methyl-5-phosphono-3-pentenoic acid are placed in 50 ml of ethanol and the whole is saturated with hydrogen chloride gas for 21/2 hours at 50°. After concentration, the residue is dissolved in 20 ml of ethanol, 20 ml of propylene oxide are added and the precipitate is filtered off. Recrystallisation from water/ethanol (1:3) yields E-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester, m.p. 193°-194°.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[N:8]=1.[Br:14][C:15]1[CH:16]=[CH:17][C:18]([O:23][CH3:24])=[C:19]([CH:22]=1)[CH:20]=[O:21].[Cl-].[NH4+]>C1COCC1>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([O:23][CH3:24])=[C:19]([CH:20]([C:12]2[C:7]([F:6])=[N:8][C:9]([F:13])=[CH:10][CH:11]=2)[OH:21])[CH:22]=1
Reactant: Fc1cccc(F)n1
Reactant: COc1ccc(Br)cc1C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(Br)cc1C(O)c1ccc(F)nc1F

Procedure:
DIPA (8.0 mL, 56.6 mmol) was dissolved in dry THF (40 mL) under nitrogen and cooled in a dry ice bath to −78°. n-Butyllithium solution, 2.5 m in hexanes (23.0 mL, 57.5 mmol) was added and the solution stirred for a few minutes prior to dropwise addition of 2,6-difluoropyridine (5.0 mL, 55.1 mmol) in dry THF (10 mL) via an addition funnel over 10 minutes. The pale yellow solution was stirred for 30 minutes then additional dry THF (70 mL) was added dropwise via an addition funnel. Solid 5-bromo-2-methoxybenzaldehyde (11.85 g, 55.1 mmol) was added in one portion and the reaction stirred for 5 minutes. Additional dry THF (100 mL) was added dropwise to keep the mixture stirring freely. After 15 minutes saturated ammonium chloride (20 mL) was added to quench followed by ethyl acetate (200 mL) and water (200 mL). The phases were mixed and separated and the organic dried with magnesium sulfate before evaporating to dryness under reduced pressure. Purification using silica chromatography (hexane to DCM gradient) gave (5-bromo-2-methoxyphenyl)(2,6-difluoropyridin-3-yl)methanol.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH2:10][C:11]1[N:16]=[C:15]([C:17]2[S:18][C:19]3[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=3[C:21](=[O:23])[N:22]=2)[CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:34][N:35]([CH3:39])[C:36](Cl)=[O:37]>C(#N)C>[CH3:34][N:35]([CH3:39])[C:36]([NH:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([C:17]2[S:18][C:19]3[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=3[C:21](=[O:23])[N:22]=2)[N:16]=1)=[O:37]
Reactant: NCCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Reactant: CN(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CN(C)C(=O)NCCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79.5 %

Procedure:
A mixture of 2-[6-(2-aminoethyl)-2-pyridyl]-4H-1,3-benzothiazine-4-one trifluoroacetic acid salt (0.45 g, 1.1 mmol), potassium carbonate (0.46 g, 3.3 mmol) and acetonitrile (20 ml) was stirred at room temperature for 20 minutes. Successively N,N-dimethylcarbamoyl chloride (0.47 g, 4.3 mmol) was added to the mixture, and the mixture was stirred at room temperature for 3 hrs. The precipitates were filtered, and the filtrate was concentrated. The residue was subjected to a silica gel column chromatography. The fractions eluted with chloroform-ethanol (20:1, v/v) were collected, concentrated and recrystallized from chloroform-hexane to give the titled compound (0.31 g, 77%) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[C:4]([N:8]1[C@H:11]([S:12]SC2SC3C=CC=CC=3N=2)[C@@H:10]([O:23][C:24](=[O:33])[CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:9]1=[O:34])=[C:5]([CH3:7])[CH3:6].[BH4-].[Na+].[C:38](Br)(=[O:40])[CH3:39].C1C=CC=CC=1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:35])[C:4]([N:8]1[C@H:11]([S:12][C:38](=[O:40])[CH3:39])[C@@H:10]([O:23][C:24](=[O:33])[CH2:25][O:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:9]1=[O:34])=[C:5]([CH3:6])[CH3:7]
Reactant: CC(=O)Br
Reactant: COC(=O)C(=C(C)C)N1C(=O)[C@H](OC(=O)COc2ccccc2)[C@H]1SSc1nc2ccccc2s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: COC(=O)C(=C(C)C)N1C(=O)[C@H](OC(=O)COc2ccccc2)[C@H]1SC(C)=O
Reaction time: 0.17 h

Procedure:
A solution of 687 mg (1.29 mmole) of 2-[(3S,4R)-4-(benzthiazol-2-yldithio)-3-phenoxyacetoxy-2-oxoazetidin-1-yl]-3-methylcrotonic acid methyl ester in 14 ml of dimethylformamide is added to a solution, cooled to -20°, of 76 mg (2 mmole) of sodium borohydride in 10 ml of dimethylformamide and the mixture is stirred at the same temperature for 10 minutes. 7 ml of freshly distilled acetyl bromide are added to the reaction mixture, which is further stirred at 0° for 40 minutes. After adding 400 ml of benzene, the reaction mixture is washed in succession with aqueous sodium bicarbonate solution, water and sodium chloride solution, dried over sodium sulphate and concentrated by evaporation in vacuo. After chromatography over silica gel with toluene/ethyl acetate (19:1) the residue yields the title compound in the form of an oil, which is further purified on silica gel plates with toluene/ethyl acetate (4:1). The title compound is obtained in oily form.
Reaction SMILES: [Cl:1][C:2]1[C:8](Cl)=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH:14]1[C:19]([OH:21])=[O:20].C(=O)([O-])[O-].[Na+].[Na+].O>C1(O)CCCCC1>[C:19]([CH:14]1[NH:13][CH2:18][CH2:17][N:16]([C:8]2[C:2]([Cl:1])=[CH:3][C:4]([N+:10]([O-:12])=[O:11])=[C:5]([CH:7]=2)[NH2:6])[CH2:15]1)([OH:21])=[O:20]
Reactant: O=C(O)C1CNCCN1
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: OC1CCCCC1
Product: Nc1cc(N2CCNC(C(=O)O)C2)c(Cl)cc1[N+](=O)[O-]
Temperature: 150 °C
Reaction time: 14 h
Yield: 72.1 %

Procedure:
To a solution of 2.10 g of 4,5-dichloro-2-nitroaniline and 2.20 g of 2-piperazinecarboxylic acid in 20 ml of cyclohexanol, 4.80 g of sodium carbonate was added, followed by 14 hours' stirring at 150° C. After cooling the reaction liquid to room temperature, water was added and the system was washed with chloroform. The aqueous layer was purified with an ion-exchange resin (Diaion HP-20, Mitsubishi Kasei, eluent: methanol). Upon condensing the fraction containing the object product under reduced pressure, 2.20 g of the title compound was obtained.
Reaction SMILES: C([O-])=O.Cl[C:5]1C=CC(C=O)=C[CH:6]=1.[CH2:13]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([NH:24][S:25]([C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]([CH2:38][NH:39][CH:40]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH2:20][CH2:19]1)=[O:17])[CH3:14].C(OC(N1CCC(NS(C2C3C(=CC=CC=3)C(CN)=CC=2)(=O)=O)CC1)=O)C>>[CH2:13]([O:15][C:16]([N:18]1[CH2:19][CH2:20][CH:21]([NH:24][S:25]([C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]([CH2:38][N:39]([CH:40]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)[CH2:5][CH3:6])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH2:22][CH2:23]1)=[O:17])[CH3:14]
Reactant: CCOC(=O)N1CCC(NS(=O)(=O)c2ccc(CNC3CCCCC3)c3ccccc23)CC1
Reactant: O=Cc1ccc(Cl)cc1
Agent: CCOC(=O)N1CCC(NS(=O)(=O)c2ccc(CN)c3ccccc23)CC1
Agent: O=C[O-]
Product: CCOC(=O)N1CCC(NS(=O)(=O)c2ccc(CN(CC)C3CCCCC3)c3ccccc23)CC1

Procedure:
The title compound was prepared as its formate salt following the general procedure in Scheme 13, substituting acetaldehyde for 4-chloro-benzaldehyde, and substituting 4-(4-cyclohexylaminomethyl-naphthalene-1-sulfonylamino)-piperidine-1-carboxylic acid ethyl ester (G-8) for 4-(4-aminomethyl-naphthalene-1-sulfonylamino)-piperidine-1-carboxylic acid ethyl ester. 1H NMR (300 MHz, MeOD) δ 8.79 (m, 1H), 8.36 (m, 2H), 8.27 (dd, 1H), 7.77 (m, 3H), 4.62 (s, 2H), 4.05 (q, 2H), 3.80 (d, 2H), 3.25 (m, 1H), 3.05 (m, 3H), 2.75 (m, 2H), 2.10 (d, 2H), 1.80 (d, 2H), 1.65 (m, 3H), 1.48 (m, 2H), 1.22 (m, 11H); LC/MS m/z 502 (M+H)+
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH:8]([CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH3:9])[CH:5]=[C:4]([OH:15])[CH:3]=1.O[C:17]([C:20]1[CH2:25][CH:24]=[C:23]([O:26][CH3:27])[CH2:22][CH:21]=1)([CH3:19])[CH3:18].B(F)(F)F.CCOCC>C1C=CC=CC=1>[CH3:27][O:26][C:23]12[CH2:22][CH:21]([C:20](=[C:17]([CH3:18])[CH3:19])[CH2:25][CH2:24]1)[C:3]1=[C:4]([OH:15])[CH:5]=[C:6]([CH:8]([CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH3:9])[CH:7]=[C:2]1[O:1]2
Reactant: COCCCC(C)c1cc(O)cc(O)c1
Reactant: COC1=CCC(C(C)(C)O)=CC1
Agent: FB(F)F
Solvent: c1ccccc1
Solvent: CCOCC
Product: COCCCC(C)c1cc(O)c2c(c1)OC1(OC)CCC(=C(C)C)C2C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1.05 g. of 1,3-dihydroxy-5-(5-methoxy-2-pentyl)- benzene and 1.06 g. (6 mmoles) of 1-(2-hydroxy-2-propyl)- 4methoxy-1,4-cyclohexadiene [R.A. Archer et. al. J. Org. Chem., 42, 2277 (1977)]are dissolved in 25 ml. of abs. benzene. 0.5 ml. (3.4 mmoles) of borontrifluoride etherate are added and the mixture is stirred at room temperature for 5 hours. Further 0.40 g. (2.4 mmoles) diene are added and the mixture is stirred overnight. The solution is poured off from the precipitated gum and extracted with 3 ×10 ml. of 1 N sodium hydroxide. The benzene solution is dried, evaporated and the residue is chromatographed on a column with a 8.1 mixture of benzene: ethyl acetate. The product is a colorless resin.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[CH2:20]([C:6]1([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:5]2[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:8][C:7]1=[O:11])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1ccc(C2C(=O)Nc3cc(Cl)ccc32)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(C2(Cc3ccccc3)C(=O)Nc3cc(Cl)ccc32)cc1
Temperature: 60 °C

Procedure:
A mixture of rac-6-chloro-3-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one (0.16 g, 0.6 mmol) (from Example 4b supra), benzyl bromide (0.12 g, 0.7 mmol) (Aldrich), potassium iodide (0.12 g, 0.71 mmol) and potassium carbonate (0.18 g, 1.3 mmol) in acetone (5 mL) was heated at 60° C. for 23 hours in a capped pressure tube. After cooling, mixture was diluted with ethyl acetate (50 mL) and extracted with water (2×50 mL) and brine (50 mL). Aqueous layers were back washed with ethyl acetate (50 mL). Organic layers were combined, dried (MgSO4), filtered and concentrated. Residue was purified by flash chromatography (Biotage 40S, dichloromethane, then 5% ethyl acetate in dichloromethane as solvent) to give product. Attempts to recrystallize the product failed. Sample was concentrated to give rac-3-benzyl-6-chloro-3-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one as a colorless glass. (Yield 0.17 g, 77.9%).
Reaction SMILES: [CH:1](=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:7]=[CH:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2)[CH3:2].[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1(=O)NC(=O)CC1>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:2][CH:1]=[C:3]1[C:4]2[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=2[CH:6]=[CH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=2
Reactant: CC=C1c2ccccc2C=Cc2ccccc21
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCC=C1c2ccccc2C=Cc2ccccc21

Procedure:
To 2.8 g (12.8 mmol) of 5-ethylidene-5H-dibenzo [a,d]cycloheptene dissolved in 150 ml of carbon tetrachloride is added 1 equivalent of dry N-bromosuccinimide and a few milligrams of benzoylperoxide. The mixture is warmed and lightened with a 150 W lamp and after a few minutes the reaction is finished as indicated by succinimide floating at the surface. The mixture is cooled, filtered and evaporated to dryness. NMR indicates an almost quantitative yield. The compound is used as such, without further purification.