Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH:16][CH2:17][C:18]([OH:25])([CH2:23][OH:24])[C:19]([F:22])([F:21])[F:20])=[O:15].[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>ClCCl.N1C=CC=CC=1>[CH3:36][C:26]1[CH:31]=[CH:30][C:29]([S:32]([O:24][CH2:23][C:18]([CH2:17][NH:16][C:14]([C:3]2[CH:4]=[N:5][N:6]([C:7]3[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=3)[C:2]=2[NH2:1])=[O:15])([OH:25])[C:19]([F:22])([F:21])[F:20])(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1c(C(=O)NCC(O)(CO)C(F)(F)F)cnn1-c1ccc(F)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC(O)(CNC(=O)c2cnn(-c3ccc(F)cc3)c2N)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 97.9 %

Procedure:
To a stirred solution of 5-amino-1-(4-fluorophenyl)-N-[3,3,3-trifluoro-2-hydroxy-2-(hydroxymethyl)propyl]-1H-pyrazole-4-carboxamide (2.47 g, 6.82 mmol) in anhydrous dichloromethane (20 ml) and anhydrous pyridine (20 ml) cooled in an ice bath under a nitrogen atmosphere was added p-toluenesulphonyl chloride (1.7 g, 8.9 mmol). The mixture was stirred for 6 hours at ice bath temperature before being allowed to warm to room temperature and stirred overnight. The solution was evaporated under vacuum and the residue was partitioned between ethyl acetate (100 ml) and water (30 ml). The separated organic phase was washed with 2M hydrochloric acid (2×30 ml), water (30 ml), saturated sodium hydrogen carbonate (30 ml), water (30 ml) and saturated brine (50 ml) before being dried over sodium sulphate and evaporated under reduced pressure to give a foam (3.45 g). This foam was purified on a Flashmaster column of Silica (100 g) using a 0-100% ethyl acetate in cyclohexane gradient over 1 hour. This afforded the title compound (2.8 g, 79%) as a foam.
Reaction SMILES: [N-:1]=[C:2]=[O:3].[C:4]1([O:10][C:11](=[O:14])[CH2:12][NH2:13])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.N1C=CC=CC=1.Cl.NO.C(OC)(OC)OC>C1COCC1.CO>[O:10]([C:11]([CH2:12][NH:13][C:2](=[O:3])[NH2:1])=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NCC(=O)Oc1ccccc1
Reactant: [N-]=C=O
Agent: Cl
Agent: NO
Solvent: COC(OC)OC
Solvent: c1ccncc1
Solvent: CO
Product: NC(=O)NCC(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 0.1 mol of 4-(allylamino)benzaldehyde ethylene glycol acetal in 100 mL of anhydrous THF is added dropwise over 10 minutes to a solution of 0.1 mol of the glycine phenyl ester isocyanate and 0.35 mol pyridine in 100 mL THF at room temperature under N2. The reaction mixture is stirred at room temperature for 2 hours. After 2 hours the solvent is removed by rotary evaporator. A solution of 0.1 mmol hydroxylamine hydrochloride and 0.1 mol trimethyl orthoformate in CH3OH is added, and the reaction mixture is heated to reflux under N2 for 1 hour. The reaction mixture is reduced to about 1/4 volume by rotary evaporator, and water is added. The product, N-allyl-N-4-(hydroxyiminomethyl)phenyl]-N'-phenoxycarbonylmethylurea, is isolated by filtration and dried in vacuo.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][C:7]([N+:12]([O-])=O)=[CH:8][CH:9]=2)[CH2:4][NH:3]1>CO.[Pd]>[CH3:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][C:7]([NH2:12])=[CH:8][CH:9]=2)[CH2:4][NH:3]1
Reactant: CC1Cc2ccc([N+](=O)[O-])cc2CN1
Agent: [Pd]
Solvent: CO
Product: CC1Cc2ccc(N)cc2CN1

Procedure:
3-Methyl-7-nitro-1,2,3,4-tetrahydroisoquinoline (3.0 g, 13.1 mmol) was dissolved in MeOH (100 ml) and hydrogenated at 50 psi in the presence of a catalytic quantity of 10% Pd-C. After 1 h the mixture was filtered through glass and evaporated to an oil which was used immediately in the next reaction.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:23][CH:22]=2)=[N:5][N:6]2[C:11]([CH2:12][N:13](C)[C:14](=O)C(F)(F)F)=[CH:10][CH:9]=[N:8][C:7]=12)#[N:2].[BH4-].[Na+]>CCO>[CH3:14][NH:13][CH2:12][CH:11]1[N:6]2[N:5]=[C:4]([C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:23][CH:22]=3)[C:3]([C:1]#[N:2])=[C:7]2[NH:8][CH2:9][CH2:10]1
Reactant: CN(Cc1ccnc2c(C#N)c(-c3ccc(Oc4ccccc4)cc3)nn12)C(=O)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CNCC1CCNc2c(C#N)c(-c3ccc(Oc4ccccc4)cc3)nn21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.5 %

Procedure:
To a solution of N-((3-cyano-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidin-7-yl)methyl)-2,2,2-trifluoro-N-methylacetamide (40 mg, 0.089 mmol) in 15 mL of EtOH was added NaBH4 (50 mg). After stirring at rt for 30 mins, the mixture was concentrated. The residue was partitioned between 20 mL of water and 20 mL of EA. The EA layer was concentrated and purified by Pre-TLC (DCM/MeOH=5/1) to give a white solid (20 mg, 63%). MS (ESI) m/e [M+1]+ 359.9.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11](O)=O)=[CH:5][CH:4]=1)#[N:2].[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:21](=[O:31])[C:22]1[CH:27]=[CH:26][C:25]([NH:28][CH3:29])=[C:24]([NH2:30])[CH:23]=1>ClCCl.CO>[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:21]([C:22]1[CH:27]=[CH:26][C:25]2[N:28]([CH3:29])[C:11]([CH2:10][NH:9][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)=[N:30][C:24]=2[CH:23]=1)=[O:31]
Reactant: N#Cc1ccc(NCC(=O)O)cc1
Reactant: CCOC(=O)CN(C(=O)c1ccc(NC)c(N)c1)c1ccccn1
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2C)c1ccccn1
Yield: 24 %

Procedure:
Prepared analogously to Example 25c from N-(4-cyanophenyl)-glycine and 3-amino-4-methylamino-benzoic acid-N-(2-pyridyl)-N-ethoxycarbonylmethyl-amide. Yield: 24% of theory, Rf value: 0.56 (silica gel; dichloromethane/methanol=4:1)
Reaction SMILES: [N:1]1[C:6]2[CH:7]=[CH:8][NH:9][C:5]=2[C:4]([NH:10][C:11]2[CH:12]=[C:13]([CH:19]=[CH:20][CH:21]=2)[C:14]([O:16]CC)=[O:15])=[N:3][CH:2]=1.[OH-].[Na+].Cl>CO>[N:1]1[C:6]2[CH:7]=[CH:8][NH:9][C:5]=2[C:4]([NH:10][C:11]2[CH:12]=[C:13]([CH:19]=[CH:20][CH:21]=2)[C:14]([OH:16])=[O:15])=[N:3][CH:2]=1
Reactant: CCOC(=O)c1cccc(Nc2ncnc3cc[nH]c23)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cccc(Nc2ncnc3cc[nH]c23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.7 %

Procedure:
A mixture of ethyl 3-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)benzoate (3.34 g), 1N aqueous sodium hydroxide solution (25 mL) and methanol (50 mL) was stirred overnight at room temperature. To the reaction mixture was added 1N hydrochloric acid (25 mL), and methanol was evaporated under reduced pressure. The precipitated crystals were collected by filtration and washed with water to give the title compound (3.09 g) as a pale-brown powder.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[CH:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[N+:27]([C:30]1[CH:58]=[CH:57][C:33]([CH2:34][O:35][C:36]([NH:38][CH2:39][CH:40]([SH:56])[CH2:41][NH:42][C:43]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][C:50]([N+:53]([O-:55])=[O:54])=[CH:49][CH:48]=2)=[O:44])=[O:37])=[CH:32][CH:31]=1)([O-:29])=[O:28]>>[CH3:10][C@@H:9]1[C@H:5]2[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:25](=[O:26])[N:6]2[C:7]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[O:13])=[C:8]1[S:56][CH:40]([CH2:39][NH:38][C:36]([O:35][CH2:34][C:33]1[CH:57]=[CH:58][C:30]([N+:27]([O-:29])=[O:28])=[CH:31][CH:32]=1)=[O:37])[CH2:41][NH:42][C:43]([O:45][CH2:46][C:47]1[CH:48]=[CH:49][C:50]([N+:53]([O-:55])=[O:54])=[CH:51][CH:52]=1)=[O:44]
Reactant: O=C(NCC(S)CNC(=O)OCc1ccc([N+](=O)[O-])cc1)OCc1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC(CNC(=O)OCc3ccc([N+](=O)[O-])cc3)CNC(=O)OCc3ccc([N+](=O)[O-])cc3)[C@H](C)[C@@H]12
Yield: 76.2 %

Procedure:
1.0 g of p-nitrobenzyl (1R,5R,6S)-6-[1(R)-hydroxyethyl]-1-methyl-2-oxocarbapenam-3-carboxylate and 2.0 g of 1,3-bis(p-nitrobenzyloxycarbonylamino)-2-mercaptopropane were reacted in the same manner as described in Example 1 to give 1.7 g of p-nitrobenzyl (1R,5R,6S)-1-methyl-2-[1,3-bis-(p-nitrobenzyloxycarbonylamino)propan-2-ylthio]-6-[1(R)-hydroxyethyl]carbapen-2-em-3-carboxylate.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].[F:14][C:15]1[C:20]([F:21])=[C:19](F)[N:18]=[CH:17][N:16]=1.O>O1CCCC1>[O:7]([C:19]1[C:20]([F:21])=[C:15]([F:14])[N:16]=[CH:17][N:18]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: Fc1ncnc(F)c1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Fc1ncnc(Oc2ccccc2)c1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.1 %

Procedure:
A solution of 42.4 g (0.45 mol) of phenol and 50.4 g (0.45 mol) of potassium tert-butoxide in 400 ml of tetrahydrofuran is added dropwise at 0° C. to a solution of 80 g (0.6 mol) of 4,5,6-trifluoropyrimidine in 1 of tetrahydrofuran. When the addition was complete, the reaction mixture was stirred for 30 minutes at 0° C. and then poured into water and extracted using ethyl acetate. The organic phase is dried over sodium sulphate and concentrated in vacuo, and the residue is stirred with low-boiling petroleum ether. 63.8 g (68.1% of theory) of 4-phenoxy-5,6-difluoropyrimidine of melting point 65-66° C. are obtained.
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][Br:8].[P:9](Cl)([Cl:12])([Cl:11])=[O:10]>C(Cl)Cl>[Br:2][CH2:3][CH2:4][N:5]([CH2:6][CH2:7][Br:8])[P:9]([Cl:12])([Cl:11])=[O:10]
Reactant: O=P(Cl)(Cl)Cl
Reactant: BrCCNCCBr
Agent: Br
Solvent: ClCCl
Product: O=P(Cl)(Cl)N(CCBr)CCBr
Reaction time: 8 h
Yield: 34.7 %

Procedure:
TEA (7.12 g, 70 mmol) was added dropwise to a stirred solution of bis(2-bromoethyl)amine hydrobromide (10.00 g, 32 mmol) and phosphorus oxychloride (4.91 g, 32 mmol) in CH2Cl2 (50 ml) at 0° C. under N2. The mixture was allowed to stir overnight and then poured over ice. The layers were separated, and the aqueous layer was extracted with CH2Cl2 (3×50 ml). The organic layers were combined and dried (MgSO4). The filtrate was concentrated under reduced pressure and the residue purified by chromatography (1:4 EtOAc: hexanes) to give 29 as an oil (3.86 g, 35%); 1H NMR (CDCl3) 3.70 (t, 4H, 6.73 Hz), 3.55 (t, 4H, 6.75 Hz)ppm.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][NH2:7])=[O:5].[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1>[C:12]1([S:18]([NH:7][NH:6][C:4](=[O:5])[C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=2[Br:1])(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NNC(=O)c1ccccc1Br
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=C(NNS(=O)(=O)c1ccccc1)c1ccccc1Br
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-bromobenzoic acid hydrazide (132 g) in pyridine (1.2 L) cooled to about 10 C. with an ice bath, was added benzensulfonyl chloride (78.3 ml). After complete addition, the reaction was stirred at ambient temperature for four hours, and then poured into ice-hydrochloric acid to precipitate a yellow solid, 135 g. The material was recrystallized from isopropanol to yield 125 g of 2-bromobenzoic acid 2-phenylsulfonylhydrazide, m.p.=154°-156° C.
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([C:10]2[S:11][CH:12]=[C:13]([CH2:15][N:16]3[C:20](=[O:21])[CH2:19][CH2:18][C:17]3=[O:22])[N:14]=2)[CH2:7]1)(=O)=O.[C:23]([O-:26])(=[S:25])[CH3:24].[K+]>CN(C)C=O>[C:23]([S:25][CH:6]1[CH2:7][N:8]([C:10]2[S:11][CH:12]=[C:13]([CH2:15][N:16]3[C:17](=[O:22])[CH2:18][CH2:19][C:20]3=[O:21])[N:14]=2)[CH2:9]1)(=[O:26])[CH3:24]
Reactant: CC([O-])=S
Reactant: CS(=O)(=O)OC1CN(c2nc(CN3C(=O)CCC3=O)cs2)C1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(CN3C(=O)CCC3=O)cs2)C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 49.1 %

Procedure:
To a solution of 3-methanesulfonyloxy-1-(4-succinimidomethyl-1,3-thiazol-2-yl)azetidine (515 mg, 1.49 mmol) (obtained as described in Reference Example 69(3)) in dimethylformamide (15 ml) was added potassium thioacetate (1.02 g, 8.95 mmol) at room temperature, and then stirred in an oil bath (90° C.) for 8 hours. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate as the eluant to afford 3-acetylthio-1-(4-succinimidomethyl-1,3-thiazol-2-yl)azetidine (238 mg, yield 49%) as a pale brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14]([OH:16])=O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:41][C@@H:42]([CH2:47][OH:48])[CH2:43][CH:44]([CH3:46])[CH3:45]>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:10]([NH:12][C@H:13]([C:14]([NH:41][C@@H:42]([CH2:47][OH:48])[CH2:43][CH:44]([CH3:46])[CH3:45])=[O:16])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=1)[C:30]([OH:32])=[O:31])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Reactant: CC(C)C[C@@H](N)CO
Product: CC(C)C[C@H](CO)NC(=O)[C@H](Cc1ccc(OCC(=O)O)c(C(=O)O)c1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid and D-leucinol (37 uL) according to Method A to give the title compound (51 mg). 1H-NMR (400 MHz, CD3OD) d 7.79 (s, 1H), 7.44 (d, J=8.1 Hz, 1H), 7.29-7.18 (m, 5H), 7.04 (d, J=8.5 Hz, 1H), 4.80 (s, 2H), 4.55 (t, J=7.0 Hz, 1H), 4.25 (dd, J=4.8 Hz, J=9.5 Hz, 1H), 3.86 (m, 1H), 2.75 (dd, J=9.5 Hz, J=13.5 Hz, 1H), 1.35 (s, 9H), 0.82 (m, 6H); IR (KBr) 3312, 2958, 1639 cm−1; HRMS m/z 629.2926 (calc. of monoisotopic mass for C32H43N3O10 gives 629.2948).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11]([CH2:19][O:20][CH2:21][C:22]3([C:35]4[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=4)[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)[CH:10]=2)=[CH:5][CH:4]=1)#[N:2].FC(F)(F)C(O)=O.C(Cl)Cl>>[F:41][C:38]1[CH:37]=[CH:36][C:35]([C:22]2([CH2:21][O:20][CH2:19][C:11]3[CH:10]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)[CH:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:12]=3)[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]2)=[CH:40][CH:39]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(-c3ccc(C#N)cc3)cc(C(F)(F)F)c2)(c2ccc(F)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(-c2cc(COCC3(c4ccc(F)cc4)CCNCC3)cc(C(F)(F)F)c2)cc1

Procedure:
tert-Butyl 4-(((4′-cyano-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (47.0 mg, 0.09 mmol) was treated with a trifluoroacetic acid/methylene chloride mixture (1:1, 2 mL) for 1 h. The solvent was removed in vacuo and the resulting crude mixture passed through a strong cation exchange column. After washing the column with several volumes of methanol, the product was eluted by washing the column with 2 M ammonia in methanol. The solvents were removed in vacuo to afford 37.0 mg (92%). 1H-NMR (CDCl3, 500 MHz) δ 7.75 (s, 1H), 7.73 (s, 1H), 7.66 (s, 1H), 7.58 (s, 1H), 7.57 (s, 1H), 7.41 (s, 1H), 7.40 s, 1H), 7.30-7.33 (m, 2H), 6.96-7.00 (m, 2H), 4.46 (s, 2H), 3.44 (s, 2H), 2.87-2.91 (m, 2H), 2.70-2.75 (m, 2H), 2.11-2.14 (m, 2H), 1.87-1.90 (m, 2H). Mass spec.: 469.33 (MH)+.
Reaction SMILES: [C:1]([C:4]1[C:21]([OH:22])=[C:20]([CH2:23][CH:24]=[CH2:25])[C:7]2[O:8][CH2:9][C:10]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:11]=3[C:12](=[O:13])[C:6]=2[CH:5]=1)(=[O:3])[CH3:2].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C(O)C>[C:1]([C:4]1[C:21]2[O:22][CH:24]([CH3:25])[CH2:23][C:20]=2[C:7]2[O:8][CH2:9][C:10]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:11]=3[C:12](=[O:13])[C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: C=CCc1c(O)c(C(C)=O)cc2c1OCc1cc(OC)ccc1C2=O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCO
Product: COc1ccc2c(c1)COc1c(cc(C(C)=O)c3c1CC(C)O3)C2=O
Yield: 23 %

Procedure:
3.9 g (11 mmol) 2-acetyl-4-allyl-6,11-dihydro-3-hydroxy-8-methoxy-dibenz[b,e]oxepin-11-one is added at 100° C. to a mixture of 9.2 g phosphorus pentoxide and 6 ml ethanol, heated for 30 minutes to 140° C., poured onto ice and filtered. After chromatography on silica gel (eluting agent:ethyl acetate:isohexane 1:1) 0.9 g of the title compound (23% of theory) of melting point 159°-160° C. (from ether) is isolated.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[N+:12]([C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1)([O-:14])=[O:13]>C(O)C>[N+:12]([C:15]1[CH:22]=[CH:21][C:18](/[CH:19]=[N:1]/[C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)=[CH:17][CH:16]=1)([O-:14])=[O:13]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)c1ccc(N)cc1
Solvent: CCO
Product: COC(=O)c1ccc(/N=C/c2ccc([N+](=O)[O-])cc2)cc1
Reaction time: 8 h
Yield: 103.1 %

Procedure:
A mixture of methyl 4-aminobenzoate (1.51 g, 10 mmol) and 4-nitrobenzaldehyde (1.51 g, 10 mmol) in ethanol (30 mL) was stirred overnight to give the yellow slurry. The precipitated off-white solid was collected and dried in vacuo to give (E)-methyl 4-(4-nitrobenzylideneamino)benzoate (2.93 g, 95% yield).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]([CH:17]([CH3:21])[C:18]([OH:20])=O)[C:9]1[CH:16]=[CH:15][C:12]([O:13][CH3:14])=[CH:11][CH:10]=1)=[O:7].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:26][CH:25]=1>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]([CH:17]([CH3:21])[C:18]([N:30]([CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:27]1[CH:26]=[CH:25][C:24]([O:23][CH3:22])=[CH:29][CH:28]=1)=[O:20])[C:9]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[CH:15][CH:16]=1)=[O:7]
Reactant: COc1ccc(N(C(=O)c2ccco2)C(C)C(=O)O)cc1
Reactant: COC(=O)CCCNc1ccc(OC)cc1
Product: COC(=O)CCCN(C(=O)C(C)N(C(=O)c1ccco1)c1ccc(OC)cc1)c1ccc(OC)cc1

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(2-furoyl)-2-(p-anisidino)propionic acid and methyl 4-(p-anisidino)butyrate and suitable processing produces methyl N-[N-(2-furoyl)-2-(p-anisidino)propionyl]-4-(p-anisidino)butyrate (oil), saponification of which and processing of the reaction product yields N-[N-(2-furoyl)-2-(p-anisidino)propionyl]-4-(p-anisidino)butyric acid (M.P. 204° to 206°).
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:9][Si:10]([CH3:17])([CH3:16])[C:11]#[C:12][CH2:13][CH2:14][CH3:15].[Cl-].[Li+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(OCC)(=O)C.O.C(Cl)Cl>[CH2:13]([C:12]1[C:2]2[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:4][C:11]=1[Si:10]([CH3:17])([CH3:16])[CH3:9])[CH2:14][CH3:15]
Reactant: Nc1ccccc1I
Reactant: CCCC#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCc1c([Si](C)(C)C)[nH]c2ccccc12
Temperature: 108.5 °C
Reaction time: 7 h
Yield: 47.9 %

Procedure:
2-Iodoaniline (4.65 g, 21.2 mmol), trimethyl(pent-1-ynyl)silane (3.27 g, 23.3 mmol), lithium chloride (0.96 g, 22.6 mmol) and sodium carbonate (6.75 g, 63.7 mmol) were combined in dimethylformamide (absolute, 64 ml) in an argon atmosphere. The catalyst ([Pd(dppf)Cl2×CH2Cl2], 1.78 g, 2.2 mmol) was then added. The solution was stirred at 105-112° C. (oil bath temperature) for 7 h. The black reaction mixture was cooled to room temperature and water (200 ml) and ethyl acetate (200 ml) were added in succession. After stirring for one hour, the mixture was filtered over Celite. The phases were separated. The organic phase was washed with 10 per cent strength citric acid solution (100 ml) and with saturated sodium chloride solution (100 ml). The organic phase was dried with sodium sulfate. After filtration, the volatile constituents were removed completely in vacuo. The residue (7.03 g of brown oil) was separated by chromatography [silica gel 60 (150 g); cyclohexane/trichloromethane 10:1 (550 ml); cyclohexane/trichloromethane 5:1 (1,650 ml)]. 2.35 g (50%) of 3-propyl-2-trimethylsilanyl-1H-indole were isolated as a brown oil (contaminated).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)=[O:10].CCN(C(C)C)C(C)C>C1COCC1>[N:1]1([CH2:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)=[O:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Reactant: C1COCCN1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CN1CCOCC1)c1ccc([N+](=O)[O-])cc1
Reaction time: 3 h

Procedure:
Morpholine Compound 50b (1.41 mL, 16.2 mmol) was added dropwise to a solution of 2-bromo-1-(4-nitro-phenyl)-ethanone Compound 50a (4.15 g, 16.2 mmol) in THF (50 mL) and DIPEA (3.1 mL, 17.8 mmol). The reaction was stirred for 3 hours and then extracted from 0.5 M NaH2PO4 with EtOAc. The combined extracts were dried over MgSO4, filtered and evaporated down. The residue was recrystallized from EtOAc and hexanes to give 2-morpholin-4-yl-1-(4-nitro-phenyl)-ethanone Compound 50c (2.55 g) as a yellow solid. MS 251 (MH+).
Reaction SMILES: [OH:1][C:2]1([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH3:22][Si:23]([CH3:30])([CH3:29])[CH2:24][CH2:25][O:26][CH2:27]Cl.[NH4+].[Cl-]>ClCCl>[CH3:22][Si:23]([CH3:30])([CH3:29])[CH2:24][CH2:25][O:26][CH2:27][O:1][C:2]1([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: OC1(c2nccs2)CCCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[Si](C)(C)CCOCOC1(c2nccs2)CCCCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 79.7 %

Procedure:
To a solution of the alcohol 2-[(1-Hydroxy)cyclohexyl]thiazole from Step 1 (5.8 g, 32 mmol) and Hunig's base (14 mL, 67 mmol) in dichloromethane (100 mL) at 0° C. was added 2-(trimethylsilyl)ethoxymethyl chloride (6.5 mL, 36.7 mmol). The resulting solution was stirred at 0° C. for 15 min, was heated at reflux temperature for 15 h and then cooled to room temperature. Sat. aq. NH4Cl was added and the resulting mixture was extracted with dichloromethane (3×). The combined organics were washed with water, brine, dried (MgSO4) and concentrated. Flash chromatography of the residue (silica gel; hexane/ethyl acetate 7:3) provided 2-{1-[(2-Trimethylsilylethoxy)methoxy]cyclohexyl}thiazole (8 g).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[CH2:14][N:13]([CH:15]([C:23]([O:25]CC3C=CC=CC=3)=[O:24])[C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)[C:12]2=[O:33])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)Cl.[Cl-].[Al+3].[Cl-].[Cl-].C1(OC)C=CC=CC=1>C(OCC)(=O)C>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[CH2:14][N:13]([CH:15]([C:23]([OH:25])=[O:24])[C:16]3[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=3)[C:12]2=[O:33])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)NC1CN(C(C(=O)OCc2ccccc2)c2ccc(O)cc2)C1=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: COc1ccccc1
Product: O=C(Cc1ccccc1)NC1CN(C(C(=O)O)c2ccc(O)cc2)C1=O
Reaction time: 8 h
Yield: 75.3 %

Procedure:
A mixture of 3-phenylacetamido-1-(α-carbobenzoxy-p-hydroxybenzyl) azetidin-2-one (15 mg), methylene chloride (0.5 ml), aluminum chloride (12 mg) and anisole (0.2 ml) is kept at -20° C. for 8 hours. The reaction mixture is diluted with ethyl acetate, washed with dilute hydrochloric acid and water, dried, and concentrated in vacuo. Crystallizing the residue from a mixture of ethyl acetate and ether gives 3-phenylacetamido-1-(α-carboxy-p-hydroxybenzyl)azetidin-2-one (9 mg) melting at 134°-141° C. Yield: 75%.