Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.[C:9](Cl)(=[O:13])[C:10](C)=[CH2:11].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[CH3:8][C:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][C:2]=1[C:9](=[O:13])[CH:10]=[CH2:11]
Reactant: C=C(C)C(=O)Cl
Reactant: Cc1ccc(C)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C=CC(=O)c1cc(C)ccc1C

Procedure:
Paraxylene (0.5 mL), methacryloyl chloride (110 mg), and aluminium chloride (150 mg) were reacted in dichloromethane (1.5 mL) at from 0° C. to room temperature for 4 hours. The resultant was treated in the same manner as described in Example 1 to obtain the title compound (89 mg).
Reaction SMILES: C([CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]2C=CC=C[CH:13]=2)[CH:4]1[OH:18])C.C(N([CH2:24][CH3:25])CC)C.CS(Cl)(=O)=O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:12]([C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH2:11][CH:3]([C:25]1[CH:24]=[CH:5][CH:4]=[CH:3][CH:11]=1)[C:4]2=[O:18])[CH3:13]
Reactant: CCC1Cc2c(-c3ccccc3)cccc2C1O
Reactant: CCN(CC)CC
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CCc1cccc2c1CC(c1ccccc1)C2=O
Temperature: 0 °C
Yield: 134.6 %

Procedure:
To a 1-liter four-necked round flask (equipped with a stirrer, a dropping funnel and a thermometer) were fed 29.3 g (123.9 mmol) of 2-ethyl-1-hydroxy-4-phenylindane, 51.6 g (371.4 mmol) of triethylamine, 0.75 g (6.3 mmol) of 4-dimethylaminopyridine and 294 ml of methylene chloride. Then, a solution obtained by dissolving 19.2 ml (247.5 mmol) of methanesulfonyl chloride in 19.5 ml of methylene chloride was dropwise added slowly to the system while cooling with ice in a nitrogen atmosphere. After the addition was completed, the resulting mixture was reacted for another 3.5 hours at the same temperature. The reaction mixture was poured in 500 ml of ice water, then the organic phase was separated, and the aqueous phase was further extracted twice with 150 ml of methylene chloride. The whole organic phase was successively washed with a saturated NaHCO3 solution and a saturated salt solution, and dried with anhydrous Na2SO4. The solvent was distilled off under reduced pressure, and the residue was separated by silica gel chromatography (developed with hexane), to obtain 19.7 g of the aimed product (mixture of two kinds of isomers) as a light yellow liquid (yield: 73%)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N+:9]([O-])[CH:8]=[CH:7]2.CC(OC(C)=O)=[O:15]>>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:15])[NH:9][CH:8]=[CH:7]2
Reactant: Cc1cccc2cc[n+]([O-])cc12
Reactant: CC(=O)OC(C)=O
Product: Cc1cccc2cc[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 10 h
Yield: 71 %

Procedure:
A solution of 8-methylisoquinoline 2-oxide (1.4 g, 8.8 mmol) in Ac2O (20 mL) was refluxed for 3 hours. The mixture was concentrated under vacuum and the residue was dissolved in MeOH (20 mL). To the reaction mixture was added aq. NaOH (20 mL, 1M). The mixture was refluxed for 1 hour and stirred at room temperature for 10 hours. The mixture was concentrated under vacuum. The residue was diluted with water (20 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (2×10 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether/EtOAc, 3:1) to give 8-methylisoquinolin-1(2H)-one (76a, 1 g, 71%) as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N:7]([C:15]([O:17]CC(Cl)(Cl)Cl)=O)C(OC(Cl)(Cl)Cl)=O)=[CH:5][CH:4]=[N:3]1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[N:31]=[C:32]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[S:33][CH:34]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[N:31]=[C:32]([N:35]2[CH2:36][CH2:37][N:38]([C:15]([NH:7][C:6]3[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=3)=[O:17])[CH2:39][CH2:40]2)[S:33][CH:34]=1
Reactant: Cn1nccc1N(C(=O)OCC(Cl)(Cl)Cl)C(=O)OC(Cl)(Cl)Cl
Reactant: Fc1ccccc1-c1csc(N2CCNCC2)n1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nccc1NC(=O)N1CCN(c2nc(-c3ccccc3F)cs2)CC1
Temperature: 70 °C
Reaction time: 16 h
Yield: 18.8 %

Procedure:
A mixture of trichloromethyl 2,2,2-trichloroethyl (1-methyl-1H-pyrazol-5-yl)imidodicarbonate (255 mg, 0.570 mmol), 4-[4-(2-fluorophenyl)-1,3-thiazol-2-yl]piperazine (300 mg, 1.14 mmol) and diisopropylethylamine (0.198 ml, 1.14 mmol) in dimethyl sulfoxide (3.8 ml) was stirred at 70° C. for 16 hours. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate), and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 41.4 mg (18.8%) of the desired product as a solid.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)[C:3]=1[C:20]#[N:21].[Br:22][CH:23]([CH:26]=O)[CH:24]=O>CCO>[Br:22][C:23]1[CH:24]=[N:1][C:2]2[N:6]([N:5]=[C:4]([C:7]3[CH:8]=[CH:9][C:10]([O:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[CH:11][CH:12]=3)[C:3]=2[C:20]#[N:21])[CH:26]=1
Reactant: O=CC(Br)C=O
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)n[nH]c1N
Solvent: CCO
Product: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2cc(Br)cnc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.1 %

Procedure:
A mixture of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile (28 mg, 0.1 mmol), 2-bromomalonaldehyde (15 mg, 0.1 mmol) in EtOH (5 mL) was stirred at RT for 2 hr. Then, the mixture was filtered to give the crude product (20 mg, 62.9%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.89 (d, J=2.0 Hz, 1H), 8.95 (d, J=2.0 Hz, 1H), 8.08 (d, J=8.4 Hz, 2H), 7.52-7.43 (m, 2H), 7.27-7.19 (m, 3H), 7.15 (d, J=7.6 Hz, 2H). MS (ESI, m/e) [M+1]+ 391.9.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([F:14])[C:11]([CH:15]([O:19][CH2:20][CH3:21])[C:16]([OH:18])=O)=[C:10]([F:22])[CH:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:24][CH2:25][C:26]1[C:33]([F:34])=[CH:32][C:29]([C:30]#[N:31])=[CH:28][C:27]=1[F:35]>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([F:22])[C:11]([CH:15]([O:19][CH2:20][CH3:21])[C:16]([NH:24][CH2:25][C:26]3[C:27]([F:35])=[CH:28][C:29]([C:30]#[N:31])=[CH:32][C:33]=3[F:34])=[O:18])=[C:12]([F:14])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1cc(F)c(CN)c(F)c1
Reactant: CCOC(C(=O)O)c1c(F)cc(-c2ccc(N)nc2)cc1F
Agent: Cl
Product: CCOC(C(=O)NCc1c(F)cc(C#N)cc1F)c1c(F)cc(-c2ccc(N)nc2)cc1F

Procedure:
According to general procedure C, (RS)-[4-(6-amino-pyridin-3-yl)-2,6-difluoro-phenyl]-ethoxy-acetic acid (intermediate from example 334.4, contains 2 equivalent of NaCl) was reacted with 4-aminomethyl-3,5-difluoro-benzonitrile hydrochloride (example 318.1) to give (RS)-2-[4-(6-amino-pyridin-3-yl)-2,6-difluoro-phenyl]-N-(4-cyano-2,6-difluoro-benzyl)-2-ethoxy-acetamide as off-white solid. MS 459.6 ([M+H]+)
Reaction SMILES: [CH2:1]([N:3]([CH2:10][CH2:11][CH3:12])[C:4](=[O:9])[C:5]([O:7]C)=[O:6])[CH3:2].[OH-].[Na+:14]>CO.O>[CH2:1]([N:3]([CH2:10][CH2:11][CH3:12])[C:4](=[O:9])[C:5]([O-:7])=[O:6])[CH3:2].[Na+:14]
Reactant: CCCN(CC)C(=O)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCN(CC)C(=O)C(=O)[O-]
Yield: 98.2 %

Procedure:
475 mg (2.75 mmole) of methyl N-ethyl-N-n-propyloxamate was dissolved in 10 ml of methanol. The resulting mixture was stirred under ice-cooling. 109 mg (2.75 mmole) of sodium hydroxide was dissolved in 5 ml of water, and the resulting solution was added dropwise to said mixture. After completion of the dropwise addition, the reaction mixture was stirred for 3 hours at room temperature. Methanol was distilled off from the reaction solution under reduced pressure and the remaining aqueous layer was washed with 5 ml of methylene chloride. The aqueous layer was then separated and distilled under reduced pressure, to afford 495 mg (2.7 mmole) of sodium N-ethyl-N-n-propyloxamate as white solids.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([NH2:12])[CH2:7][CH2:6][CH2:5]2.[F:13][C:14]([F:25])([F:24])[C:15]([NH:17][C:18]1([C:21](O)=[O:22])[CH2:20][CH2:19]1)=[O:16]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([NH:12][C:21]([C:18]1([NH:17][C:15](=[O:16])[C:14]([F:13])([F:24])[F:25])[CH2:19][CH2:20]1)=[O:22])[CH2:7][CH2:6][CH2:5]2
Reactant: O=C(NC1(C(=O)O)CC1)C(F)(F)F
Reactant: NC1CCCc2cc(Br)ccc21
Product: O=C(NC1(C(=O)NC2CCCc3cc(Br)ccc32)CC1)C(F)(F)F

Procedure:
In analogy to the procedure described for the preparation of intermediate A-1 [B] and A-1 [C], (rac)-6-bromo-1,2,3,4-tetrahydronaphthalen-1-amine has been coupled with 1-(2,2,2-trifluoroacetamido)cyclopropanecarboxylic acid (intermediate A-1 [A]) to give 1-(2,2,2-trifluoro-acetylamino)-cyclopropanecarboxylic acid ((rac)-6-bromo-1,2,3,4-tetrahydro-naphthalen-1-yl)-amide, which was subsequently reacted with 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) to yield the title compound as light brown oil. MS: 453.2 (MH+).
Reaction SMILES: [N:1]([CH:4]([CH2:15][N:16]=[N+]=[N-])[CH2:5][N:6]([CH2:13][CH3:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[N+]=[N-]>CO.[Pt](=O)=O>[CH2:13]([N:6]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH2:5][CH:4]([NH2:1])[CH2:15][NH2:16])[CH3:14]
Reactant: CCN(CC(CN=[N+]=[N-])N=[N+]=[N-])c1ccccc1
Agent: O=[Pt]=O
Solvent: CO
Product: CCN(CC(N)CN)c1ccccc1
Yield: 98.3 %

Procedure:
To a solution of rac-(2,3-diazido-propyl)-ethyl-phenyl-amine (0.245 g, 1 mmol) in methanol (5 ml) was added platinum(IV)-oxide (50 mg) and the mixture was hydrogenated at atmospheric pressure overnight. The catalyst was removed by filtration over celite and the filtrate was evaporated. The residue was purified by chromatography (column: Isolute® Flash-NH2 from Separtis; eluent: ethyl acetate) to yield a light yellow liquid (0.19 g, 98%); MS (ISP): 194.1 ((M+H)+).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[C:9]([C:10]3[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:11]=3[O:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH:22][C:23]4[N:24]=[CH:25][S:26][CH:27]=4)(=[O:21])=[O:20])=[CH:15][C:14]=3[C:28]#[N:29])=[CH:8][CH:7]=[N:6]2)[CH2:2]1.[CH2:35](N(CC)CC)[CH3:36].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)C>CO.ClCCl>[Cl:34][C:32]1[CH:31]=[CH:30][C:11]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([NH:22][C:23]3[N:24]=[CH:25][S:26][CH:27]=3)(=[O:21])=[O:20])=[CH:15][C:14]=2[C:28]#[N:29])=[C:10]([C:9]2[N:5]([CH:3]3[CH2:2][N:1]([CH2:35][CH3:36])[CH2:4]3)[N:6]=[CH:7][CH:8]=2)[CH:33]=1
Reactant: CCN(CC)CC
Reactant: N#Cc1cc(S(=O)(=O)Nc2cscn2)ccc1Oc1ccc(Cl)cc1-c1ccnn1C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCN1CC(n2nccc2-c2cc(Cl)ccc2Oc2ccc(S(=O)(=O)Nc3cscn3)cc2C#N)C1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 4-[2-(1-azetidin-3-yl-1H-pyrazol-5-yl)-4-chlorophenoxy]-3-cyano-N-1,3-thiazol-4-ylbenzenesulfonamide, Example 809 (500 mg, 0.000797 mol) in methanol (4 mL) and dichloromethane (4 mL) was added triethylamine (161 mg, 0.00159 mol) and the reaction cooled to 0° C. in an ice/water bath. To the suspension was added sodium triacetoxyborohydride (422 mg, 0.00199 mol) and the reaction was then stirred at 0° C. for 10 minutes. Acetaldehyde (105 mg, 0.00239 mol) was added dropwise and the reaction stirred at 0° C. for 1.5 hours. The solvent was removed in vacuo to give an orange oil which was partitioned between dichloromethane (25 mL) and water (25 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (2×20 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (20 mL) and filtered through a phase separator. The solvent was removed in vacuo to give a pink solid which was triturated in hot ethyl acetate (10.0 mL), allowed to cool to room temperature and then filtered to give the title compound as a white solid, (431 mg).
Reaction SMILES: COC(Cl)=O.ClC1C=NC(OC2CCCCC2)=C(C=1)C(O)=O.NCC[C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[C:28]([O:35][CH3:36])[CH:27]=1.Cl>O1CCCC1.C(N(CC)CC)C>[CH3:36][O:35][C:28]1[CH:27]=[CH:26][CH:34]=[CH:33][C:29]=1[C:30]([OH:32])=[O:31]
Reactant: COc1cc(CCN)ccc1C(=O)O
Agent: COC(=O)Cl
Agent: Cl
Agent: O=C(O)c1cc(Cl)cnc1OC1CCCCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccccc1C(=O)O
Reaction time: 0.5 h

Procedure:
6 g of triethylamine and 1.9 g of chloroformic acid methyl ester are added, while stirring and cooling with ice, to 5 g of 5-chloro-2-cyclohexyloxy-nicotinic acid in 150 ml of tetrahydrofuran. Stirring is continued for 30 minutes at 0° C. and, while stirring, 4.6 g of 4-(2-aminoethyl)-2-methoxybenzoic acid are added in the form of its hydrochloride. The mixture is further stirred for 4 hours at room temperature, the solvent removed under reduced pressure, the residue reprecipitated from ammonia and recrystallized from ethanol or ethyl acetate. The 4-(2-<5-chloro-2-cyclohexyloxy-nicotinamido>-ethyl)-2-methoxy-benzoic acid obtained melts at 170°-172° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:16]4[C:21]([CH3:22])=[CH:20][C:19]([N+:23]([O-])=O)=[CH:18][N:17]=4)[CH2:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[CH:4][CH:3]=1>[Pd].O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:16]4[N:17]=[CH:18][C:19]([NH2:23])=[CH:20][C:21]=4[CH3:22])[CH2:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[CH:4][CH:3]=1
Reactant: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ncc([N+](=O)[O-])cc1C
Agent: [Pd]
Solvent: C1CCOC1
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ncc(N)cc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
A mixture of 10-chloro-7-(1-ethylpropyl)-1-(3-methyl-5-nitropyridin-2-yl)-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]benzimidazole (43 mg, 0.100 mmol) and 10% palladium on carbon (4.3 mg) in tetrahydrofuran (1.0 mL) was stirred under hydrogen atmosphere at room temperature for 4 hr. Catalyst was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 50-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound (36 mg, 0.090 mmol, 90%) as a pale yellow amorphous.
Reaction SMILES: Cl.[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][NH:11]2)=[O:9])[CH2:6][CH2:5]1)#[N:3].[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=1>>[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][N:11]2[C:30](=[O:31])[C:29]2[CH:33]=[CH:34][C:26]([F:25])=[CH:27][CH:28]=2)=[O:9])[CH2:6][CH2:5]1)#[N:3]
Reactant: O=C(O)c1ccc(F)cc1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Agent: Cl
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2C(=O)c2ccc(F)cc2)CC1

Procedure:
(2S,4R)-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide hydrochloride from experiment K4 was coupled with 4-fluoro benzoic acid in analogy to experiment A1 to give (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-(4-fluoro-benzoyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide as an amorphous white solid. MS: 476.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][P:4]([O-:8])[O:5][CH2:6][CH3:7])[CH3:2].[CH3:9][C:10]1[CH2:15][CH2:14][CH2:13][C:12](=[O:16])[CH:11]=1.Cl>>[CH3:9][C:10]1([P:4]([O:5][CH2:6][CH3:7])(=[O:8])[O:3][CH2:1][CH3:2])[CH2:11][C:12](=[O:16])[CH2:13][CH2:14][CH2:15]1.[CH3:9][C:10]1([P:4]([OH:3])(=[O:5])[OH:8])[CH2:11][C:12](=[O:16])[CH2:13][CH2:14][CH2:15]1
Reactant: CC1=CC(=O)CCC1
Reactant: CCOP([O-])OCC
Agent: Cl
Product: CC1(P(=O)(O)O)CCCC(=O)C1
Product: CCOP(=O)(OCC)C1(C)CCCC(=O)C1

Procedure:
Diethyl 1-methyl-5-oxocyclohexanephosphonate (B.Pt. 130°-2°/0.8 mm) was prepared by the base catalysed addition of diethylphosphite to 3-methyl-2-cyclohexen-1-one. Hydrolysis of this ester with concentrated HCl gave 1-methyl-5-oxocyclohexanephosphonic acid as a viscous oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][C:11](Cl)=[N:12][OH:13])=[N:2]1.C([N:17](CC)CC)C>C(Cl)(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][C:11](=[N:12][OH:13])[NH2:17])=[N:2]1
Reactant: ON=C(Cl)Cc1noc2ccccc12
Reactant: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: NC(Cc1noc2ccccc12)=NO
Reaction time: 4 h
Yield: 27.5 %

Procedure:
To a solution of 1,2-benzisoxazole-3-acetohydroximic chloride (0.4 g) in chloroform (80 ml) was added a solution of triethylamine (3.2 g) in chloroform (40 ml) under ice-cooling and the mixture was stirred for 4 hours under ice-cooling. The mixture was distilled under a reduced pressure to remove the solvent. To the residue was added benzene and the precipitate of triethylamine hydrochloride was filtered off. To the filtrate was passed through ammonia gas under ice-cooling for a period of 1 hour and further at reflux temperature for 3 hours. The mixture was distilled under a reduced pressure to remove the solvent and the residue was subjected to silica gel column chromatography and eluted with 5 % methanol-chloroform. The resulting crystallines were recrystallized from ethanol to give the desired compound (0.1 g). m.p. 160° to 162°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)(O)[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:26]=1>C(O)(=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12]([C:14]3[CH:15]=[C:16]([O:24][CH3:25])[C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=3)=[CH:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:26]=1
Reactant: COc1ccc2c(c1)CCCCC2(O)c1cc(OC)c(OC)c(OC)c1
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CCCC=C2c1cc(OC)c(OC)c(OC)c1
Yield: 90.9 %

Procedure:
A mixture of the 32 (800 mg, 2.23 mmol) in 20 mL of acetic acid and 100 mL of water, taken in a 250 mL round bottom flask were refluxed for 12 h. The reaction mixture was cooled and extracted with dichloromethane (3×25 mL) and the combined organic phases were dried over magnesium sulfate. The solvent evaporated and the crude product was purified by flash column chromatography (10:90 EtOAc:Hexanes), to afford 690 mg (91%) of 2 as white crystals. Rf: 0.43 (30:70, EtOAc:Hexanes).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH:28]2[CH2:30][O:29]2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([N:21]1[CH2:22][CH2:23][N:24]([CH2:27][CH:28]([OH:29])[CH2:30][N:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH2:25][CH2:26]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: CC(C)(C)OC(=O)N1CCN(CC2CO2)CC1
Product: CC(C)(C)OC(=O)N1CCN(CC(O)Cn2c3ccccc3c3ccccc32)CC1
Yield: 82 %

Procedure:
The same method as employed in the preparation of Example 1 but starting from 9H-carbazole and (±)-4-oxiranylmethyl-piperazine-1-carboxylic acid tert-butyl ester (prepared according to the procedure of Toldy, L. et al., WO 97/14685) gives after flash chromatography the title compound as a pale yellow foam in a 82% yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH:7]([N:12]1[C:18](=[O:19])[CH:17]2[CH:13]1[S:14][C:15]([CH3:21])([CH3:20])[NH:16]2)[CH2:8][C:9]([OH:11])=[O:10])(C)(C)C.F[C:24](F)(F)C(O)=O>>[CH3:1][O:5][C:6](=[O:22])[CH:7]([N:12]1[C:18](=[O:19])[CH:17]2[CH:13]1[S:14][C:15]([CH3:21])([CH3:20])[NH:16]2)[CH2:8][C:9]([O:11][CH3:24])=[O:10]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)C(CC(=O)O)N1C(=O)C2NC(C)(C)SC21
Product: COC(=O)CC(C(=O)OC)N1C(=O)C2NC(C)(C)SC21
Reaction time: 18 h

Procedure:
A mixture of 0.025 g of the isomer B of α-(3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo[3,2,0]heptyl)-α-(carboxymethyl)-acetic acid tert.-butyl ester (Example 39) and 1 ml of trifluoroacetic acid is kept for 18 hours at 0°, is then evaporated under reduced pressure, and the residue containing the α-(3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo[3,2,0]heptyl)-α-(carboxymethyl)-acetic acid, is taken up in 1 ml of dioxane and then mixed with an ether solution of diazomethane until saturated. After 3 minutes reaction time, the mixture is evaporated under reduced pressure and the residue is filtered through a silica gel column (diameter: 0.8 cm; hight: 10 cm), a 2:1-mixture of hexane and ethyl acetate being used for elution; the isomer B of α-(3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo[3,2,0]heptyl)-α-(carbomethoxymethyl)-acetic acid methyl ester of the formula ##STR56## which is obtained as a crude product, melts at 136°-137° after recrystallisation from a mixture of ether, methylene chloride and hexane.
Reaction SMILES: [C:1]([N:6]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1)(=[O:5])[CH:2]([CH3:4])[CH3:3].Cl.CO>CO>[CH3:3][CH:2]([CH3:4])[C:1]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5]
Reactant: CC(C)C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CO
Product: CC(C)C(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 132.9 %

Procedure:
To a stirred mixture of tert-butyl 4-isobutyrylpiperazine-1-carboxylate (6.8 g, 26.5 mmol) in methanol (15 mL) was added hydrochloride/methanol (30 mL, 3M)) at 0° C. After the addition, the mixture was allowed to stir at room temperature overnight. The mixture was concentrated to give 2-methyl-1-(piperazin-1-yl)propan-1-one (5.5 g, yield 100%) as an off-white solid. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 0.99-1.00 (d, J=6.4 Hz, 6H), 2.84-2.89 (m, 1H), 3.03-3.07 (d, 4H), 3.68-3.74 (d, 4H), 9.58 (s, 2H); LC-MS (ESI) m/z: 157 (M+1)+.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[NH2:14][C@@H:15]([C:19]([OH:21])=[O:20])[C@H:16]([CH3:18])[OH:17].C([O-])([O-])=O.[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:14][C@H:15]([C@@H:16]([OH:17])[CH3:18])[C:19]([OH:21])=[O:20])=[CH:3][C:4]=1[C:10]([F:13])([F:12])[F:11])#[N:7]
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@H](O)[C@@H](Nc1ccc(C#N)c(C(F)(F)F)c1)C(=O)O
Temperature: 75 °C
Reaction time: 24 h
Yield: 55.6 %

Procedure:
4-fluoro-2-(trifluoromethyl)benzonitrile (194853-86-6) (2.0 g, 10.6 mmol) was mixed together with H-D-Thr-OH (1.51 g, 12.69 mmol) in DMSO (30 mL). K2CO3 (3.06 g, 22.21 mmol) was added to the reaction mixture and stirred at 75° C. for 24 h. The reaction mixture was cooled to room temperature and poured slowly into a 10% citric acid solution and stirred for 10 min at room temperature. The solution was extracted with EtOAc several times to get the crude product. The crude product was chromatographed with a gradient of hexanes/EtOAc and then with EtOAc, 100% to get the pure final product (1.7 g): 1H NMR (500 MHz, CDCl3, δ in ppm) 9.02 (br s, 1H), 7.76 (d, J=9 Hz, 1H), 7.52 (s, 1H), 7.39 (d, J=9 Hz, 1H), 6.41 d, J=9 Hz, 1H), 4.42 (m, 1H), 4.01 (m, 1H), 1.24 (d, J=6 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6](=NO)[NH2:7])=[CH:4][CH:3]=1.[C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)=[CH:16][CH:15]=1)#[N:13]>C(#N)C1C=CC=CC=1>[C:12]([C:14]1[CH:15]=[CH:16][C:17]([C:20]2[O:21][C:22]([C:2]3[CH:11]=[CH:10][C:5]([C:6]#[N:7])=[CH:4][CH:3]=3)=[CH:23][CH:24]=2)=[CH:18][CH:19]=1)#[N:13]
Reactant: N#Cc1ccc(-c2ccco2)cc1
Reactant: NC(=NO)c1ccc(Br)cc1
Solvent: N#Cc1ccccc1
Product: N#Cc1ccc(-c2ccc(-c3ccc(C#N)cc3)o2)cc1

Procedure:
in good yield. In contrast, under N-coupling conditions the benzamidoxime was converted to benzonitrile (Anbazhagan et al., (2002) Tetrahedron Lett. 43: 4221) and attempted Heck coupling of 4-bromobenzamidoxime with 2(4-cyanophenyl)furan yielded 2,5-bis(4-cyanophenyl)furan.