Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)Cl.[OH:4][C:5](CBr)=[C:6]([N:14]1[C:17](=[O:18])[CH:16]([NH:19][C:20](=[O:29])[CH2:21][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:15]1[S:30][CH:31]=O)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]>C(O)(=O)C>[O:22]([CH2:21][C:20]([NH:19][CH:16]1[C:17](=[O:18])[N:14]2[C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[C:5]([OH:4])[CH2:31][S:30][C@H:15]12)=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)C(=C(O)CBr)N1C(=O)C(NC(=O)COc2ccccc2)C1SC=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)C1=C(O)CS[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To 0.391 g. (1.mmol.) of mercuric acetate in a mixture of 15 ml. of methylene chloride and 15 ml. of acetic acid was added, as a neat solid, 0.435 g. (1 mmol.) of t-butyl 3-hydroxy-4-bromo-2-(2-formylthio-4-oxo-3-phenoxyacetamido-1-azetidinyl)-2-butenoate. The resulting mixture was stirred for five minutes at room temperature after which time the solution became cloudy. Hydrogen sulfide was bubbled into the mixture, and the mixture was filtered through a filter aide an charcoal. The filtrate was evaporated to a residue to obtain t-butyl 7-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylate.
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]2[CH2:12][C@H:11]([CH3:13])[O:10][C@H:9]([CH3:14])[CH2:8]2)=[N:4][C:3]=1[C:15]#[N:16].[CH3:17][C:18]1[CH:23]=[C:22](B(O)O)[CH:21]=[C:20]([CH3:27])[N:19]=1.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:14][C@H:9]1[O:10][C@@H:11]([CH3:13])[CH2:12][N:7]([C:5]2[S:6][C:2]([C:22]3[CH:21]=[C:20]([CH3:27])[N:19]=[C:18]([CH3:17])[CH:23]=3)=[C:3]([C:15]#[N:16])[N:4]=2)[CH2:8]1
Reactant: Cc1cc(B(O)O)cc(C)n1
Reactant: C[C@@H]1CN(c2nc(C#N)c(Br)s2)C[C@H](C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(-c2sc(N3C[C@@H](C)O[C@@H](C)C3)nc2C#N)cc(C)n1
Temperature: 130 °C
Yield: 85 %

Procedure:
A mixture of Intermediate 3 (20 g, 66.18 mmol), 2,6-dimethylpyridine-4-boronic acid, pinacol ester ([325142-95-8], 20 g, 85.79 mmol), tetrakis(triphenylphosphine)palladium (4.59 g, 3.97 mmol), 1,4-dioxane (120 mL), sodium carbonate (21.04 g, 198.55 mmol) in ethanol/water 1/1 (120 mL) was stirred and heated under nitrogen atmosphere at 130° C. for 6 h. The solvent was evaporated. The residue was taken up in DCM and washed twice with water. The organic layer was separated, dried with MgSO4 and evaporated. The residue was purified by column chromatography on silica gel (eluent gradient from 100% DCM to 98/2 DCM/MeOH). The desired fractions were collected and evaporated. The resulting residue was recrystallized from DIPE/CH3CN, yielding 18.5 g (85%) of Intermediate 4, after drying overnight under vacuum at 50° C.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[CH:14]=[C:13]([C:15]([OH:17])=O)[CH:12]=[N:11]2)[CH:6]=[CH:7][CH:8]=1.[NH2:20][C:21]1[C:22](=[O:32])[N:23]([CH2:29][CH2:30][CH3:31])[C:24](=O)[NH:25][C:26]=1[NH2:27].C(N(CC)CC)C.S(Cl)(Cl)=[O:41]>C(#N)C>[NH2:27][C:26]1[NH:25][CH2:24][N:23]([CH2:29][C:30](=[O:41])[CH3:31])[C:22](=[O:32])[C:21]=1[NH:20][C:15]([C:13]1[CH:12]=[N:11][N:10]([CH2:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:19])[F:18])[CH:4]=2)[CH:14]=1)=[O:17]
Reactant: O=C(O)c1cnn(Cc2cccc(C(F)(F)F)c2)c1
Reactant: CCCn1c(=O)[nH]c(N)c(N)c1=O
Reactant: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)CN1CNC(N)=C(NC(=O)c2cnn(Cc3cccc(C(F)(F)F)c3)c2)C1=O
Reaction time: 16 h

Procedure:
A solution of 1-{[3-(trifluoromethyl)phenyl]methyl}pyrazole-4-carboxylic acid (1 g, 3.7 mmol) in thionyl chloride (1 ml) was heated at 70° C. for 4 hours. Excess thionyl chloride was distilled off, and the residue treated with methylene chloride/hexanes. The solvent was removed under reduced pressure, and the residue dissolved in acetonitrile. This solution was added to a suspension of 5,6-diamino-3-propyl-1,3-dihydropyrimidine-2,4-dione (2.3 g, 126 mmol) and triethylamine (1 ml) in acetonitrile (20 ml) at 0° C., and stirred for 16 hours. The reaction mixture was quenched with water (5 ml), acidified with hydrochloric acid, stirred for 30 minutes, and the precipitate filtered off. The product was washed with ether, to provide N-(6-amino-2,4-dioxo-3-propyl(1,3-dihydropyrimidin-5-yl))(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazol-4-yl)carboxamide, a compound of formula (13).
Reaction SMILES: [Mg].II.Br[CH2:5][CH2:6][CH:7]=[CH2:8].[Cl:9][C:10]1[CH:29]=[CH:28][C:13]([CH2:14][C:15]2([NH:25][CH:26]=[O:27])[CH2:18][CH:17]([C:19](N(OC)C)=[O:20])[CH2:16]2)=[CH:12][CH:11]=1>C1COCC1>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:14][C:15]2([NH:25][CH:26]=[O:27])[CH2:16][CH:17]([C:19](=[O:20])[CH2:8][CH2:7][CH:6]=[CH2:5])[CH2:18]2)=[CH:28][CH:29]=1
Reactant: C=CCCBr
Reactant: CON(C)C(=O)C1CC(Cc2ccc(Cl)cc2)(NC=O)C1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CCCC(=O)C1CC(Cc2ccc(Cl)cc2)(NC=O)C1
Temperature: 0 °C
Reaction time: 0.2 h
Yield: 97.5 %

Procedure:
Magnesium powder (0.548 g, 22.6 mmol) was placed into a round-bottomed flask with a small piece of iodine. Dry THF was added to cover the magnesium and the solution was heated to a gentle reflux until the color had dissipated (approximately 30 minutes). While refluxing, a second solution of 4-bromo-1-buten (2.3 mL, 22.6 mmol) in dry THF (5 mL) was added. After 12 min, the mixture was cooled 0° C. and added to a solution of 3-(4-chlorobenzyl)-3-formamido-N-methoxy-N-methylcyclobutanecarboxamide (0.5 g, 1.61 mmol) in dry THF (30 mL). After 2 h, the reaction was allowed to warm to room temperature and stir overnight. The reaction was quenched with saturated aqueous NH4Cl and extracted with diethyl ether (×2). The combined organic layers were washed successively with 1M HCl, water and saturated aqueous sodium chloride, dried over MgSO4, filtered and concentrated to give the crude product (0.48 g) that was used to the next step without further purification. ESI MS found for C17H20ClNO2 m/z [306.3 (M+1), 328.3 (M+Na+), 304.5 (M−1)].
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[S:9][C:10]([Br:13])=[CH:11][CH:12]=1)(=[O:7])=[O:6].CCN(C(C)C)C(C)C.[C:23](Cl)(=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25].O>C(Cl)Cl>[Br:13][C:10]1[S:9][C:8]([S:5]([NH:4][CH2:3][CH2:2][NH:1][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])(=[O:6])=[O:7])=[CH:12][CH:11]=1
Reactant: NCCNS(=O)(=O)c1ccc(Br)s1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCCNS(=O)(=O)c1ccc(Br)s1
Temperature: 0 °C
Yield: 94.8 %

Procedure:
A mixture of N-(2-aminoethyl)-5-bromothiophene-2-sulfonamide (2.5 g, 8.77 mmol, 1.0 eq) and DIPEA (3.4 g, 26.3 mmol, 3.0 eq) in CH2Cl2 (100 mL) was stirred at 0° C., pivaloyl chloride (2.1 g, 17.5 mmol, 2 equiv.) was added drop-wise. Then, the mixture was stirred at 0° C. for 0.5 h. Water was added and the reaction was extracted with EA (3×80 ml). The combined organic layers were dried (Na2SO4), filtered, evaporated and purified by silica gel chromatography (PE/EA=10:1 as eluant) to afford N-(2-(5-bromothiophene-2-sulfonamido)ethyl)pivalamide (3.07 g, 95.0%). LC-MS (m/z)=368.9 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]C)=[O:17])=[CH:4][CH:3]=1.C(COC)OC.Br[CH2:27][CH2:28][CH2:29][CH3:30]>C(O)C.[OH-].[K+]>[CH2:27]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:6][CH:7]=1)[CH2:28][CH2:29][CH3:30]
Reactant: CCCCBr
Reactant: COC(=O)CCCCCCCCc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: COCCOC
Solvent: CCO
Product: CCCCOc1ccc(CCCCCCCCC(=O)O)cc1
Reaction time: 24 h
Yield: 43.5 %

Procedure:
A mixture of 7 gms 9(4-hydroxyphenyl)nonanoic acid, methyl ester, 1.45 gms KOH, 100 ml dry dimethoxyethane, and 3.6 gms 1-bromobutane was refluxed with stirring for 24 hrs. The reaction was cooled, filtered through diatomaceous earth, and the solvent was removed in vacuo. The residue was dissolved in CHCl3, washed twice with 5% Na2CO3, twice with water and once with NaCl solution, and dried over MgSO4. The drying agent was filtered off and the solvent removed in vacuo to give an oil. This oil was stirred overnight at room temperature in a mixture of 70 ml ethanol and 30 ml 10% KOH solution. The solvent was then evaporated in vacuo, the residue dissolved in hot water, cooled, acidified, and the precipitated solid filtered off. The solid was boiled with hexane, filtered, and the solid boiled with cyclohexane and filtered. The insoluble material was again dissolved in water, the aqueous phase acidified with HCl, and the resulting solid was boiled with hexane and filtered. All hexane and cyclohexane solutions were combined and evaporated in vacuo to give 3.5 gms of solid m.p. 45°-8°, which was used directly in the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:8]([C:9]([OH:11])=[O:10])[C:7]([OH:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:14](OC(=O)C)(=[O:16])[CH3:15].S(=O)(=O)(O)O>>[C:14]([O:13][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])(=[O:16])[CH3:15]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1O
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: CC(=O)Oc1ccc([N+](=O)[O-])cc1C(=O)O
Temperature: 55 °C
Reaction time: 1 h

Procedure:
A mixture of 5-nitrosalicyclic acid (5 g), acetic anhydride (13 ml) and sulfuric acid (0.3 ml) was heated at 55° C. for 10 minutes. After the solution was removed from the hot water bath and stirred at room temperature for 1 hour it was poured into water (200 ml). The mixture was stirred for 10 minutes and filtered. The solid was stirred with water (100 ml), filtered by suction and air dried to give the title compound, m.p. ca, 165°-168° C.
Reaction SMILES: [CH2:1]([CH:3]([CH2:9][CH3:10])[CH2:4][CH2:5][C:6]([OH:8])=O)[CH3:2].[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl>CN(C=O)C.C(OCC)(=O)C.O>[CH2:9]([CH:3]([CH2:1][CH3:2])[CH2:4][CH2:5][C:6]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:8])[CH3:10]
Reactant: C1CCNCC1
Reactant: CCC(CC)CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCC(CC)CCC(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Ethylhexanoic acid (47.0 g) was dissolved in DMF (190 mL). To the solution were added piperidine (34.0 mL), HOBt.H2O (52.7 g) and WSC.HCl (66.1 g). The mixture was stirred at RT overnight. To the reaction mixture were added ethyl acetate (300 mL) and 1 N hydrochloric acid (100 mL) at ice temperature. The aqueous layer was removed and the organic layer was washed with saturated aqueous sodium bicarbonate (150 mL×2) and brine (100 mL×2), then dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated in vacuo to give the title compound (59.8 g) as a crude product.
Reaction SMILES: C[C@]1(NC2C=NC(C(F)(F)F)=CN=2)CCC[C@@H]1NC(C1C(N2N=CC=N2)=CC=CN=1)=O.[CH3:32][C@:33]1([NH:39][C:40]2[CH:45]=[N:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][N:41]=2)[CH2:37][CH2:36][CH2:35][C@@H:34]1[NH2:38].[F:50][C:51]1[CH:52]=[CH:53][C:54]([N:60]2[N:64]=[CH:63][CH:62]=[N:61]2)=[C:55]([CH:59]=1)[C:56](O)=[O:57]>>[F:50][C:51]1[CH:52]=[CH:53][C:54]([N:60]2[N:64]=[CH:63][CH:62]=[N:61]2)=[C:55]([CH:59]=1)[C:56]([NH:38][C@H:34]1[CH2:35][CH2:36][CH2:37][C@:33]1([CH3:32])[NH:39][C:40]1[CH:45]=[N:44][C:43]([C:46]([F:49])([F:47])[F:48])=[CH:42][N:41]=1)=[O:57]
Reactant: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1N
Reactant: O=C(O)c1cc(F)ccc1-n1nccn1
Agent: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1NC(=O)c1ncccc1-n1nccn1
Product: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1NC(=O)c1cc(F)ccc1-n1nccn1

Procedure:
Prepared according to the procedure for N-[(1S,2S)-2-methyl-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxamide (Example 77) from (1S,2S)-1-methyl-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine (Intermediate 25; 80 mg, 0.31 mmol) and 5-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 8; 76 mg, 0.37 mmol) except this was purified by column chromatography (0 to 50% ethyl acetate/petrol) followed by a trituration in pentane/diethyl ether to afford the title compound.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[CH:14]=[CH:13][C:12](O)=[CH:11][CH:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:17][CH2:18][CH2:19][CH2:20][Cl:21].CN(C)C=[O:25]>>[Cl:21][CH2:20][CH2:19][CH2:18][CH2:17][O:25][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: ClCCCCBr
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: ClCCCCOc1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
To a suspension of sodium hydride (60%, 4.7 g, 117 mmol) in dimethylformamide (400 mL) was added 4-phenylphenol (10 g, 60 mmol) portionwise. The mixture was stirred at room temperature for 2 hours, then 1-bromo-4-chlorobutane (13 mL, 117 mmol) was added, and the mixture allowed to stir at room temperature overnight. The reaction was quenched with methanol (30 mL) and filtered through Celite®. The filtrate was taken up in ether (500 mL), washed thrice with water (250 mL) and dried over sodium sulfate. The solution was concentrated to give 12.2 g (78%) of 4-chlorobutoxy-phenylbenzene as an amber oil. 1H NMR (CDCl3): δ7.61-6.88(m.9H), 4.01(t,2H), 3.62(t.2H), 2.01(m,1H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1C(OC)=O.[CH3:13][Mg]Br.CC[O:18][CH2:19][CH3:20]>>[NH2:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:19]([OH:18])([CH3:20])[CH3:13]
Reactant: COC(=O)c1ccc(Cl)cc1N
Reactant: C[Mg]Br
Reactant: CCOCC
Product: CC(C)(O)c1ccc(Cl)cc1N

Procedure:
This compound was prepared using General Method 1 (EXAMPLE 1) from methyl 2-amino-4-chlorobenzoate (2.8 g) and methyl magnesium bromide (3 M in diethyl ether, 20 mL) in 75 mL ether to afford 2-(2-amino-4-chlorophenyl)propan-2-ol.
Reaction SMILES: C([N:8]([CH2:19][CH:20]([OH:40])[CH2:21][O:22][C:23]1[CH:32]=[C:31]2[C:26]([C:27](=[O:39])[CH:28]=[C:29]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[O:30]2)=[CH:25][CH:24]=1)[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=1)C1C=CC=CC=1.C1CCCCC=1.C(O)(=O)C>O.[Pd]>[CH2:12]([CH2:11][CH2:10][CH2:9][NH:8][CH2:19][CH:20]([OH:40])[CH2:21][O:22][C:23]1[CH:32]=[C:31]2[C:26]([C:27](=[O:39])[CH:28]=[C:29]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[O:30]2)=[CH:25][CH:24]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=1
Reactant: O=c1cc(-c2ccccc2)oc2cc(OCC(O)CN(CCCCc3cccnc3)Cc3ccccc3)ccc12
Agent: [Pd]
Solvent: O
Solvent: CC(=O)O
Solvent: C1=CCCCC1
Product: O=c1cc(-c2ccccc2)oc2cc(OCC(O)CNCCCCc3cccnc3)ccc12
Yield: 54 %

Procedure:
A suspension of 7-[3-[N-benzyl,N-(3-nicotinylpropyl)amino]-2-hydroxypropoxy]flavone (4.50 g, 8.64 mmol), Example 17b, palladium black (0.1 g), cyclohexene (30 ml), and acetic acid (30 ml) was refluxed for 6 hours. The solvent was evaporated to give a residue which was dissolved in water and washed with chloroform (twice) to remove impurities. The aqueous solution was basified with 2.5N NaOH and then extracted with methylene chloride several times. The extracts were washed with water, dried (MgSO4), and evaporated to afford a yellow solid of 2.9 g. Recrystallization from isopropyl alcohol gave light yellow crystals (2.0 g; 54% yield), mp 116°-119° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[C:13](=[C:15]2\[C:16](=[C:22]([CH3:24])[CH3:23])[C:17](O[C:20]\2=[O:21])=[O:18])/[CH3:14])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[CH3:12][O:11][C:7]1[CH:6]=[C:5](/[C:13](=[C:15]2\[C:16](=[C:22]([CH3:23])[CH3:24])[C:17]([N:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]\2=[O:21])=[O:18])/[CH3:14])[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: Nc1ccccc1
Reactant: COc1cc(/C(C)=C2/C(=O)OC(=O)C2=C(C)C)cc(OC)c1OC
Solvent: Cc1ccccc1
Product: COc1cc(/C(C)=C2/C(=O)N(c3ccccc3)C(=O)C2=C(C)C)cc(OC)c1OC
Reaction time: 2 h

Procedure:
(E)-α-(3,4,5-trimethoxyphenyl) ethylideneisopropylidene succinic anhydride (4 parts), prepared as in Example 3, in toluene (40 parts by volume), and aniline (1 part) were heated (12 hours) at 70°. Petrol was added and the liberated succinamic acid separated. The dry acid (1.8 parts) was dissolved in acetyl chloride (40 parts by volume) boiled for 2 hours and the solvent removed. Crystallization of the product from a toluene/petrol mixture gave (E)-α-(3,4,5-trimethoxyphenyl) ethylideneisopropylidene-N-phenylsuccinimide as pale yellow needles, melting point 169.5°. The compound shows similar photochromic properties to the corresponding (E)-anhydride.
Reaction SMILES: C([NH:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7](=[O:18])[CH2:6]1)C=C.CN1C(=O)CC(=O)N(C)C1=O>C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7](=[O:18])[CH2:6]1
Reactant: C=CCNC1CCN(Cc2ccccc2)C(=O)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN1C(=O)CC(=O)N(C)C1=O
Solvent: ClCCl
Product: NC1CCN(Cc2ccccc2)C(=O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.3 %

Procedure:
A mixture of racemic 4-allylamino-1-benzyl-piperidin-2-one (430 mg, 1.76 mmol), 1,3-dimethyl barbituric acid (824 mg 5.28 mmol) and Pd(PPh3)4 (204 mg, 0.18 mmol) in DCM (20 mL) was stirred at ambient temperature for 2 hours then concentrated under vacuum. The resulting residue was purified by Isolute® SCX-2 column (gradient: DCM to 5 to 60% 2M NH3 in methanol solution in DCM) to afford 260 mg (72%) of racemic 4-amino-1-benzyl-piperidin-2-one. LCMS (Method H, ESI): RT=0.35 min, m+H=204.9; 1H NMR (400 MHz, CDCl3) δ: 7.29 (m, 5H), 4.60 (m, 2H), 3.34-3.13 (m, 3H), 2.74 (ddd, 1H), 2.37-2.23 (m, 1H), 2.01 (m, 3H), 1.64 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:22][Si:23]([CH3:30])([CH3:29])[CH2:24][CH2:25][O:26][CH2:27]Cl>CN(C)C=O.O1CCCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)/[C:7](=[O:11])[N:8]2[CH2:27][O:26][CH2:25][CH2:24][Si:23]([CH3:30])([CH3:29])[CH3:22])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=C1Nc2cc(Cl)ccc2/C1=C/c1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCN1C(=O)/C(=C\c2cccc(Cl)c2)c2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
To a solution of E/Z-6-chloro-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one prepared in example 1a (2.3 g, 7.9 mmol) in N,N-dimethyl-formamide (20 mL) at 0° C. was added NaH (60% in mineral oil) (0.32 g, 7.9 mmol) (Aldrich), followed by the dropwise addition of 2-(trimethylsilyl)ethoxymethyl chloride (1.32 g, 7.9 mmol) in tetrahydrofuran (20 mL). The reaction mixture was stirred at 0° C. for 0.5 h, then poured into ice-water. The crude was extracted with ethyl acetate twice. The combined organic layer was dried over Na2SO4. The solvent was removed and the residue was purified by chromatography (EtOAc:hexanes=1:5) to give E/Z-6-chloro-3-(3-chloro-benzylidene)-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-dihydro-indole-2-one as yellow oil (Yield 3.0 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][CH:37]=1)[C:5]([C:7]1[CH:34]=[CH:33][C:10]2[N:11]([CH2:15][CH2:16][O:17][C:18]3[CH:32]=[CH:31][C:21]([O:22][C:23]([CH3:30])([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:20][CH:19]=3)[C:12](=[O:14])[S:13][C:9]=2[CH:8]=1)=O.Cl.[CH3:39][O:40][NH2:41].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:5](=[N:41][O:40][CH3:39])[C:7]2[CH:34]=[CH:33][C:10]3[N:11]([CH2:15][CH2:16][O:17][C:18]4[CH:19]=[CH:20][C:21]([O:22][C:23]([CH3:29])([CH3:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:31][CH:32]=4)[C:12](=[O:14])[S:13][C:9]=3[CH:8]=2)[CH:35]=[CH:36][CH:37]=1
Reactant: CON
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCn2c(=O)sc3cc(C(=O)c4cccc(Cl)c4)ccc32)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCn2c(=O)sc3cc(C(=NOC)c4cccc(Cl)c4)ccc32)cc1
Temperature: 0 °C

Procedure:
A solution of the compound obtained in Step A (1.00 g) and O-methylhydroxylamine hydrochloride (309 mg) in 15 ml of pyridine is heated at reflux for 3 hours. The reaction mixture is hydrolysed using 100 ml of ice-cold water and acidified using 6N HCl. The precipitate obtained is filtered off, washed with water and then recrystallised from petroleum ether by cooling in a freezer to yield the title compound in the form of a white powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[C:11]2[C:10]([S:12]([O-:15])(=[O:14])=[O:13])=[CH:9][CH:8]=[C:7]3[CH2:16][CH2:17][NH+:5]([C:6]=23)[CH:4]=[C:3]1/[CH:18]=[CH:19]/[CH:20]=[CH:21]/N(C1C=CC=CC=1)C(=O)C.[C:33]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]1([CH3:58])[C:50]2[C:49]([S:51]([O-:54])(=[O:53])=[O:52])=[CH:48][CH:47]=[C:46]3[CH2:55][CH2:56][NH+:44]([C:45]=23)[CH:43]=[C:42]1[CH3:57])([OH:35])=[O:34].N1C=CC=CC=1>C(OC(=O)C)(=O)C>[C:33]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]1([CH3:58])[C:50]2[C:45]3=[C:46]([CH2:55][CH2:56][NH+:44]3[CH:43]=[C:42]1/[CH:57]=[CH:21]/[CH:20]=[CH:19]/[CH:18]=[C:3]1\[C:2]([CH3:1])([CH3:32])[C:11]3[C:10]([S:12]([O-:15])(=[O:13])=[O:14])=[CH:9][CH:8]=[C:7]4[C:6]=3[N:5]\1[CH2:4][CH2:17][CH2:16]4)[CH:47]=[CH:48][C:49]=2[S:51]([OH:54])(=[O:53])=[O:52])([OH:35])=[O:34]
Reactant: CC(=O)N(/C=C/C=C/C1=C[NH+]2CCc3ccc(S(=O)(=O)[O-])c(c32)C1(C)C)c1ccccc1
Reactant: CC1=C[NH+]2CCc3ccc(S(=O)(=O)[O-])c(c32)C1(C)CCCCCC(=O)O
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC1(CCCCCC(=O)O)C(/C=C/C=C/C=C2/N3CCCc4ccc(S(=O)(=O)[O-])c(c43)C2(C)C)=C[NH+]2CCc3ccc(S(=O)(=O)O)c1c32
Temperature: 110 °C

Procedure:
To a stirring mixture of 6,6-dimethyl-5-((1E,3E)-4-(N-phenylacetamido)buta-1,3-dienyl)-1,2,3,6-tetrahydropyrrolo[3,2,1-ij]quinolinium-7-sulfonate and 6-(5-carboxypentyl)-5,6-dimethyl-1,2,3,6-tetrahydropyrrolo[3,2,1-ij]quinolinium-7-sulfonate in 5 mL acetic anhydride was added 5 mL pyridine. The reaction was heated to 110° C. for 2 hours. After cooling to room temperature the product was precipitated with ethyl acetate, washed with Et2O, and isolated by vacuum filtration. The final product was purified by reverse-phase HPLC yielding a blue solid. MS m/z calculated for C36H43N2O8S2 (M+H): 695.25. Found 695.3 (M+H, ESI+).
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][C:18](=[O:29])[C:19]2([S:26][CH2:27][CH3:28])[S:23][CH2:24][CH3:25])[C@H:15]2[C@@:6]1([F:32])[C@:7]1([CH3:31])[C:12]([CH2:13][CH2:14]2)=[CH:11][C:10](=[O:30])[CH:9]=[CH:8]1)(=O)C.[OH-].[Na+].O>CO.O1CCCC1>[CH2:27]([S:26][C:19]1([S:23][CH2:24][CH3:25])[C:18](=[O:29])[CH2:17][C@H:16]2[C@H:15]3[C@:6]([F:32])([C@@H:5]([OH:4])[CH2:22][C@:20]12[CH3:21])[C@:7]1([CH3:31])[C:12](=[CH:11][C:10](=[O:30])[CH:9]=[CH:8]1)[CH2:13][CH2:14]3)[CH3:28]
Reactant: CCSC1(SCC)C(=O)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](OC(C)=O)C[C@@]21C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCSC1(SCC)C(=O)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C

Procedure:
11β-(Acetyloxy)-17,17-bis(ethylthio)-9-fluoroandrosta-1,4-diene-3,16-dione was dissolved in a mixture of methanol (3.0 ml) and tetrahydrofuran (3.0 ml) and was exposed to 3 M sodium hydroxide (0.3 ml) for 1.0 hour under an atmosphere of nitrogen. The mixture was then added to water and was extracted with chloroform. The chloroform solution was washed with water, dried (MgSO4) and was evaporated to afford the title compound as a solid (80 mg). One crystallization of this form ethyl acetate-hexane followed by drying gave the analytical specimen of the title compound (58 mg), melting point 268°-270° C. (dec., discoloration starts from ca. 200° C.).