Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.[C:14]1([C:20]2[O:24][N:23]=[CH:22][C:21]=2[CH2:25][CH2:26][C:27](O)=[O:28])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O.C(N(CC)CC)C>[NH:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([CH2:4][CH2:3][NH:2][C:27](=[O:28])[CH2:26][CH2:25][C:21]2[CH:22]=[N:23][O:24][C:20]=2[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:6]1
Reactant: O=C(O)CCc1cnoc1-c1ccccc1
Reactant: NCCc1c[nH]c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(CCc1cnoc1-c1ccccc1)NCCc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
A mixture of 3-(2-aminoethyl)indole hydrochloride (0.46 g), triethylamine (0.6 ml) and N,N-dimethylformamide (20 ml) was stirred at room temperature for 1 hr. To the obtained mixture was added 3-(5-phenyl-4-isoxazolyl)propionic acid (0.42 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.37 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.45 g), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-[2-(3-indolyl)ethyl]-3-(5-phenyl-4-isoxazolyl)propionamide (0.63 g, yield 91%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). NMR (CDCl3) δ: 2.32–2.44 (2H, m), 2.88–3.04 (4H, m), 3.54–3.66 (2H, m), 5.45 (1H, br s), 6.93 (1H, d, J=2.2 Hz), 7.04–7.28 (2H, m), 7.32–7.62 (5H, m), 7.64–7.74 (2H, m), 8.05 (1H, br s), 8.17 (1H, s).
Reaction SMILES: S(Cl)(Cl)=O.FC(F)(F)C(O)=O.[CH3:12][O:13][C:14]1[C:15]([O:26][CH2:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[CH:16][C:17]([N+:23]([O-:25])=[O:24])=[C:18]([CH:22]=1)[C:19](O)=[O:20].C[N:37](C=O)C>>[CH3:12][O:13][C:14]1[C:15]([O:26][CH2:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[CH:16][C:17]([N+:23]([O-:25])=[O:24])=[C:18]([CH:22]=1)[C:19]([NH2:37])=[O:20]
Reactant: COc1cc(C(=O)O)c([N+](=O)[O-])cc1OCCCN1CCOCC1
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(N)=O)c([N+](=O)[O-])cc1OCCCN1CCOCC1
Temperature: 50 °C

Procedure:
Thionyl chloride (15 ml) and DMF (0.05 ml) were added to 5-methoxy-4-(3-morpholinopropoxy)-2-nitrobenzoic acid trifluoroacetate (7.54 g, 16.6 mmol). The mixture was heated at 50° C. for 1 hour, the excess thionyl chloride was removed by evaporation and by azeotroping with toluene (x2). The resulting solid was suspended in THF (200 ml) and ammonia was bubbled through the mixture for 30 minutes. The precipitate was removed by filtration, washed with THF and discarded. After concentration of the filtrate by evaporation, the product crystallised and was collected by filtration to give 5-methoxy-4-(3-morpholinopropoxy)-2-nitrobenzamide (5.25 g, 93%yield) as light yellow crystals which were used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH3:35])[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[CH:16][C:15]([C:18]3[CH:19]=[C:20]([CH:33]=[CH2:34])[C:21]4[S:25][C:24]([NH:26][C:27]([NH:29][CH2:30][CH3:31])=[O:28])=[N:23][C:22]=4[CH:32]=3)=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C1COCC1.C(O)(=O)C.C([O-])=O.[NH4+]>CCO.[Pd]>[CH2:1]([O:3][C:4]([C:6]1([CH3:35])[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[CH:16][C:15]([C:18]3[CH:19]=[C:20]([CH2:33][CH3:34])[C:21]4[S:25][C:24]([NH:26][C:27]([NH:29][CH2:30][CH3:31])=[O:28])=[N:23][C:22]=4[CH:32]=3)=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: C=Cc1cc(-c2cnc(N3CCC(C)(C(=O)OCC)CC3)nc2)cc2nc(NC(=O)NCC)sc12
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: C1CCOC1
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(CC)c2s1
Temperature: 60 °C
Reaction time: 96 h
Yield: 70.1 %

Procedure:
1-{5-[2-(3-Ethyl-ureido)-7-vinyl-benzothiazol-5-yl]-pyrimidin-2-yl}-4-methyl-piperidine-4-carboxylic acid ethyl ester (27 mg) was dissolved in EtOH (5 mL), THF (0.5 mL) and acetic acid (0.5 mL) and 10% palladium on carbon (6 mg) and ammonium formate (168 mg) added. The flask was evacuated and purged with N2 (×2) and stirred at 60° C. for four days. The mixture was cooled to rt and filtered through a PTFE filter. The filter was rinsed with EtOH/DCM and the filtrate concentrated under reduced pressure. The residue was then taken up in EtOAc and washed with Na2CO3 (sat, aq). The aqueous layer was washed with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography, Biotage, 12 g Grace cartridge, DCM to 4% MeOH in DCM and the relevant fractions combined and concentrated under reduced pressure to give the desired product as a white solid (19 mg, 70%). m/z: 497 [M+H]+.
Reaction SMILES: [C:1]([NH:4][C@H:5]([CH2:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[C:6](O)=[S:7])(=[O:3])[CH3:2].[N+]([O-])(O)=O.[N+:20]([O:23][CH2:24][CH2:25][NH2:26])([O-:22])=[O:21]>>[N+:20]([O:23][CH2:24][CH2:25][NH:26][C:6](=[S:7])[C@H:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])([O-:22])=[O:21]
Reactant: CC(=O)N[C@H](CC(=O)C(C)(C)C)C(O)=S
Reactant: NCCO[N+](=O)[O-]
Solvent: O=[N+]([O-])O
Product: CC(=O)N[C@H](CC(=O)C(C)(C)C)C(=S)NCCO[N+](=O)[O-]
Yield: 74.5 %

Procedure:
The procedures of Example 1 were analogously repeated using 0.70 g of (2R)-2-acetylamino-3-pivaloylthiopropionic acid and 574 mg of 2-nitrooxyethylamine nitrate to give 0.72 g of the title compound as colorless crystals.
Reaction SMILES: [C:1]([NH:4][NH2:5])(=[O:3])[CH3:2].[N:6]([CH3:9])=[C:7]=[S:8]>CO>[C:1]([NH:4][NH:5][C:7](=[S:8])[NH:6][CH3:9])(=[O:3])[CH3:2]
Reactant: CC(=O)NN
Reactant: CN=C=S
Solvent: CO
Product: CNC(=S)NNC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
To a stirred solution of acetohydrazide (3.7 g, 50 mmol) in methanol (30 mL) was added a solution of compound isothiocyanatomethane (3.65 g, 50 mmol) in methanol (50 mL) at 0° C. After the addition, the mixture was stirred at room temperature overnight. The mixture was concentrated to give crude product (7 g) as a white solid which was used in the next step without further purification. LC-MS (ESI) m/z: 148 (M+1)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[N:24]=[CH:23][CH:22]=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:44]=[C:35]5[CH2:36][N:37]([CH2:40][CH:41]([F:43])[F:42])[CH2:38][CH2:39][N:34]5[N:33]=4)[C:28](=[O:45])[N:27]([CH3:46])[CH:26]=3)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO.ClCCl>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:19][OH:20])=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:44]=[C:35]5[CH2:36][N:37]([CH2:40][CH:41]([F:43])[F:42])[CH2:38][CH2:39][N:34]5[N:33]=4)[C:28](=[O:45])[N:27]([CH3:46])[CH:26]=3)[CH:22]=[CH:23][N:24]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1cc(-c2ccnc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2C=O)cc(Nc2cc3n(n2)CCN(CC(F)F)C3)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cn1cc(-c2ccnc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2cc3n(n2)CCN(CC(F)F)C3)c1=O
Reaction time: 1 h
Yield: 59.8 %

Procedure:
To a solution of 135e (100 mg, 0.158 mmol) in methanol/dichloromethane(4/4 mL) was added NaBH4 (18 mg, 0.475 mmol) at room temperature. After the reaction was stirred for 1 h, LCMS indicated the reaction was complete. The reaction mixture was quenched with water (20 mL) and extracted with dichloromethane (3×20 mL). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford 135 (60 mg, 60%) as a white solid. MS-ESI: [M+H]+ 635.3. 1H NMR (500 MHz, CDCl3) δ 8.66 (d, J=5.0 Hz, 1H), 8.35 (d, J=2.5 Hz, 1H), 8.00 (d, J=2.5 Hz, 1H), 7.59-7.58 (m, 1H), 7.56-7.55 (m, 1H), 7.53-7.52 (m, 2H), 7.45 (s, 1H), 6.07-5.83 (m, 1H), 5.72 (s, 1H), 4.51-4.49 (m, 2H), 4.11-4.08 (m, 2H), 4.05-4.03 (m, 1H), 3.94 (s, 2H), 3.73 (s, 3H), 3.13-3.10 (m, 2H), 3.00-2.94 (m, 2H), 1.45 (s, 9H).
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:9]=2)[N:4]=[C:3]1[C:16]([O:18][CH2:19][CH3:20])=[O:17].[N+:21]([O-:24])([O-])=[O:22].[K+].[C:26]1(C)C=CC=C[CH:27]=1.ICC>S(=O)(=O)(O)O.[Ag]=O.CCCCCC.C(OCC)(=O)C>[CH2:26]([O:1][C:2]1[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([F:13])([F:15])[F:14])=[C:7]([N+:21]([O-:24])=[O:22])[CH:6]=2)[CH3:27]
Reactant: Cc1ccccc1
Reactant: CCOC(=O)c1nc2ccc(C(F)(F)F)cc2[nH]c1=O
Reactant: O=[N+]([O-])[O-]
Agent: O=[Ag]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCI
Product: CCOC(=O)c1nc2cc([N+](=O)[O-])c(C(F)(F)F)cc2nc1OCC
Temperature: 0 °C
Reaction time: 3 h
Yield: 41 %

Procedure:
To a solution of ethyl 3,4-dihydro-3-oxo-6-trifluoromethylquinoxaline-2-carboxylate (500 mg, 1.75 mmol) in concentrated sulfuric acid (5 ml) was added potassium nitrate (354 mg, 3.50 mmol) at 40° C., and the mixture was stirred for 3 hours at the same temperature. The reaction mixture was poured into ice water (100 ml), which was extracted with ethyl acetate. After dried over anhydrous sodium sulfate, solvent was distilled off. Silver oxide (I)(811 mg, 3.50 mmol) was added to the residue obtained which was suspended into toluene (10 ml). Then, iodoethane (280 μl, 3.50 mmol) was added dropwise at 100° C. and the mixture was refluxed for 2 hours. After cooling, the insolubles were filtered off using celite and the solvent was distilled off. The residue obtained was submitted to silica gel column chromatography [hexane-ethyl acetate=8:1] to obtain 255 mg of the title compound as yellowish brown oily product. Yield 41%.
Reaction SMILES: [NH2:1][C@@H:2]1[C:13](=[O:14])[N:4]2[C:5]([C:10]([OH:12])=[O:11])=[C:6]([CH3:9])[CH2:7][S:8][C@H:3]12.C(N(CC)CC)C.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH2:27][C:28](Cl)=[O:29]>C(Cl)Cl>[CH3:9][C:6]1[CH2:7][S:8][C@@H:3]2[C@H:2]([NH:1][C:28](=[O:29])[CH2:27][C:23]3[S:22][CH:26]=[CH:25][CH:24]=3)[C:13](=[O:14])[N:4]2[C:5]=1[C:10]([OH:12])=[O:11]
Reactant: O=C(Cl)Cc1cccs1
Reactant: CC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.5 %

Procedure:
A suspension of the polymer ester of (6R,7R)-7-amino-3-methylceph-3-em-4-carboxylic acid (5.00g, 5.0 m.mole, from example 18) in methylene chloride (100 ml) was stirred at room temperature (18°-21° ) under nitrogen for 30 minutes. After cooling to 0°, triethylamine (3.03g. 0.03 mole) was added, and stirring continued for 30 minutes. Thienylacetyl chloride (3.0 ml, 3.89g, 0.024 mole) was then added dropwise over a period of 10 minutes maintaining the temperature at 0°-5°. When addition was completed stirring was continued for 15 minutes at 0°-5° and for a further 5 hours at room temperature (18°-21° ). The reaction mixture was filtered and pulled as dry as possible. The product was washed with methylene chloride (3 × 100 ml) acetone (2 × 100 ml), water (4 × 100 ml), acetone (2 × 100 ml), and methylene chloride 3 × 100 ml): and dried to constant weight in vacuo at 40° to give a light brown coloured polymer ester of (6R,7R)-3-methyl-7-(2-thienyl) acetamidoceph-3-em-4-carboxylic acid (5.41g). The composition was confirmed by microanalytical data. ν max (Nujol) 3320w (NH), 1780s (β-lactam CO), 1722s (ester CO) abnd 1688s (amide CO) cm-1, τ [CDCl3 and CF3COOH (2:1)] 2.66 (triplet, J = 3.3 Hz: 2-thienyl proton), 2.97 (doublet, J = 3.3 Hz: 3-thienyl protons): 4.27 (double doublet, J 4.5, 9.0 Hz; 7-H), 4.88 (doublet J 4.5 Hz: 6-H), 5.99 (singlet: --CH2CO--), 6.41 and 6.77 (2 doublets, J 18 - 19 Hz: s-CH2), and 7.70 (singlet, --CH3).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[CH:24]=[C:23]([Cl:25])[S:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[N:15]=1>>[N:19]1[CH:18]=[CH:17][C:16]([C:14]2[N:15]=[C:10]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:11]3[CH:24]=[C:23]([Cl:25])[S:22][C:12]=3[N:13]=2)=[CH:21][CH:20]=1
Reactant: NCc1ccccc1
Reactant: Clc1cc2c(Cl)nc(-c3ccncc3)nc2s1
Product: Clc1cc2c(NCc3ccccc3)nc(-c3ccncc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(pyridin-4-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-benzylamino-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[NH:10][C:11](=O)[C:12]1[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][C:13]=1[O:20][CH2:21][CH3:22].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C1(C)C(C)=CC=CC=1>[ClH:8].[Cl:9][C:5]1[C:6]([Cl:8])=[CH:7][C:2]2[N:1]=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][C:13]=3[O:20][CH2:21][CH3:22])[NH:10][C:3]=2[CH:4]=1
Reactant: CCOc1cc(C#N)ccc1C(=O)Nc1cc(Cl)c(Cl)cc1N
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Cc1ccccc1C
Product: CCOc1cc(C#N)ccc1-c1nc2cc(Cl)c(Cl)cc2[nH]1
Product: Cl
Yield: 165.2 %

Procedure:
A suspension of N-(2-amino-4,5-dichlorophenyl)-2-ethoxy-4-cyanobenzamide (19 g, 54.2 mmol) and P2O5 (19 g, 134 mmol) in xylene (380 ml) was refluxed for 24 h. Additional P2O5 (9.5 g, 67 mmol) was added and the mixture was refluxed for 48 h. Solvent was removed under reduced pressure. The residue was treated with 30% NaOH (80 ml) and water (100 ml) and then acidified with 37% HCl. The solid was filtered, washed with water and dried under vacuum at 50° C. to give 16.5 g of the title compound as a light brown powder (yield 82.6%), mp>250° C.
Reaction SMILES: [CH3:1][C:2]([S@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[Br:8][C:9]1[C:10]([CH3:18])=[C:11]([C:15](=O)[CH3:16])[CH:12]=[CH:13][CH:14]=1>C1COCC1.C(O[Ti](OCC)(OCC)OCC)C>[Br:8][C:9]1[C:10]([CH3:18])=[C:11](/[C:15](=[N:7]/[S@@:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])/[CH3:16])[CH:12]=[CH:13][CH:14]=1
Reactant: CC(=O)c1cccc(Br)c1C
Reactant: CC(C)(C)[S@](N)=O
Agent: CCO[Ti](OCC)(OCC)OCC
Solvent: C1CCOC1
Product: C/C(=N\[S@](=O)C(C)(C)C)c1cccc(Br)c1C
Temperature: 75 °C

Procedure:
To a stirring solution of (R)-2-methylpropane-2-sulfinamide (326 mg, 2.69 mmol) and Intermediate 12A (600 mg, 2.82 mmol) in THF (2 mL) at rt was added tetraethoxytitanium (1.06 mL, 5.12 mmol). The reaction mixture was heated at 75° C. for 16 h. The reaction mixture was cooled and used directly in the next step. LCMS=2.12 min [M+1]=318.0 (Method B).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].FC(F)CN>ClCCCl.C(Cl)Cl.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>[C:1]([N:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: NCC(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCCCC1
Reaction time: 18 h
Yield: 129.1 %

Procedure:
To a stirred solution of 1-Boc-4-piperidone (0.300 g, 1 eq) and 2,2-difluoroethylamine (0.244 g, 2 eq) in 1,2-dichloroethane (6 mL) is added NaBH(OAc)3 (0.640 mg, 2 eq). After 18 h, the solution is diluted with CH2Cl2, washed with NaHCO3 (sat.), brine, dried over Na2SO4 and concentrated. The resulting residue is purified by flash chromatography Hex/EtOAc (1:1) to give the corresponding N-Boc piperidine (0.360 g, 90%). The obtained N-Boc piperidine (29 mg, 1.5 eq) is dissolved in a solution HCl in dioxane (4 M, 0.5 mL) and stirred during 30 min at RT. The solution is concentrated, the resulting residue is dissolved in DMSO (0.5 mL), Et3N (40 μL, 4 eq) is added followed by 50d (35 mg, 1 eq). The solution is heated at 50° C. for 1 h and ammonium acetate (500 mg) is added and the heating is pursued at 140° C. during 4 h. The solution is diluted with H2O/AcOH and purified by prep HPLC to give 5004 (10 mg, 24%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7](=[O:14])[C:6]2=[CH:15]O.C(O)(=O)C.[CH2:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)=[O:27])[CH:22]([CH3:24])[CH3:23]>C1C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7](=[O:14])[C:6]2=[CH:15][N:31]1[CH2:30][CH2:29][N:28]([C:26]([O:25][CH2:21][CH:22]([CH3:24])[CH3:23])=[O:27])[CH2:33][CH2:32]1
Reactant: CC(C)COC(=O)N1CCNCC1
Reactant: COc1cc2c(cc1OC)C(=CO)C(=O)N2
Solvent: O
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: COc1cc2c(cc1OC)C(=CN1CCN(C(=O)OCC(C)C)CC1)C(=O)N2
Reaction time: 0.33 h

Procedure:
5.00 g. of 5,6-Dimethoxy-3-hydroxymethylene oxindole, 2.5 g. acetic acid and 6.5 g. piperazine-N-carboxylic acid isobutyl ester (U.S. Pat. No. 3,635,979) in 40 ml. benzene was refluxed using a water separator to remove the water as it formed. After 20 minutes, 200 ml. benzene was added and the solution extracted with potassium carbonate and water. The benzene sollution was treated with magnesium sulfate and charcoal, filtered, concentrated and the residue crystallized from isopropyl alcohol and ether to give 5.50 g. product, m.p. 195°-197° C.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[CH3:23][C@H:24]1[C@@:29]23[C:35]([O:36][C@H:27]([CH2:28]2)[CH2:26][C@@H:25]1[C:39]1[CH:40]=[CH:41][C:42]2[O:47][CH2:46][O:45][C:43]=2[CH:44]=1)=[CH:34][C:32](=O)[C:31]([O:37][CH3:38])=[CH:30]3>C1(C)C=CC=CC=1>[O:47]1[C:42]2[CH:41]=[CH:40][C:39]([CH:25]3[CH:24]([CH3:23])[C:29]45[CH2:28][CH:27]([O:36][C:35]4=[CH:34][C:32](=[S:10])[C:31]([O:37][CH3:38])=[CH:30]5)[CH2:26]3)=[CH:44][C:43]=2[O:45][CH2:46]1
Reactant: COC1=C[C@]23C[C@H](C[C@H](c4ccc5c(c4)OCO5)[C@H]2C)OC3=CC1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: COC1=CC23CC(CC(c4ccc5c(c4)OCO5)C2C)OC3=CC1=S
Temperature: 60 °C

Procedure:
Lawesson's reagent (119.3 mg, 0.3 mmoles) is added to a stirred solution of futoenone (200 mg, 0.59 mmoles) in toluene (4 ml). The reaction is heated to 60° C. in an oil bath for 2-3 h. TLC of the reaction mixture shows almost complete conversion of starting material. The reaction turns from a green to violet upon heating. The reaction is concentrated in vacuo and purified by MPLC on silica gel using ethyl acetate. A purple foam (154.2 mg, 73.5%) forms upon drying in vacuo. M+(CI)=357. 1H NMR ppm: 0.59 (3H, d), 1.72 (1H, t), 2.07 (1H, m), 2.21 (1H, d), 2.30 (1H, m), 2.43 (1H, m), 2.58 (1H, m), 3.71 (3H, s), 5.08 (1H, t), 5.46 (1H, s), 5.92 (2H, s), 6.65 (4H, m).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH:6]([C:16](=O)[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[C:7](=O)[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[CH3:2].[C:26]1([NH:32][NH2:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(O)(=O)C>C1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[N:33][N:32]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[CH3:2]
Reactant: CCOC(=O)CC(C(=O)c1ccc(Cl)cc1)C(=O)c1ccc(Cl)cc1
Reactant: NNc1ccccc1
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)Cc1c(-c2ccc(Cl)cc2)nn(-c2ccccc2)c1-c1ccc(Cl)cc1
Yield: 91 %

Procedure:
12.0 grams 3,3-bis-(p-chlorobenzoyl)-propionic acid ethyl ester, 3.9 grams phenylhydrazine and 2.7 grams glacial acetic acid were mixed and the mixture was heated in a nitrogen atmosphere to the boiling temperature under reflux for 6 hours. To the reaction mixture were than added benzene, and the pH was adjusted to 2-3, followed by extraction with water. The benzene was evaporated from the benzene phase and the dry, crystalline residue was recrystallized from a mixture of cyclohexane and petroleum ether boiling in a range from 50°-70° C. 13.0 grams 1-phenyl-3,5-bis-(p-chlorophenyl)-pyrazol-4-acetic acid ethyl ester, melting at 120°-122° C., were obtained, representing a yield of 91%.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[S:27]([C:30]1[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[C:32]([OH:39])[CH:31]=1)(=[O:29])=[O:28]>>[CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][S:27]([C:30]2[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[C:32]([OH:39])[CH:31]=2)(=[O:29])=[O:28])=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Reactant: Oc1ccc(CCc2c(Cc3ccccc3)sc3ccccc23)cc1
Product: O=C(O)c1ccc(S(=O)(=O)Oc2ccc(CCc3c(Cc4ccccc4)sc4ccccc34)cc2)cc1O

Procedure:
The title compound was prepared according to the procedure in Example 4 using 4-[2-(2-benzyl-benzo[b]thiophen-3-yl)-ethyl]-phenol (0.400 g, 1.16 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.550 g, 2.32 mmol). Purification on 2% H3PO4 /MeOH treated silica gel, eluting with 20% EtOAc/hexane gave the title compound as an off white solid, mp 57-59° C. 1H NMR (DMSO-d6) δ 2.74 (t, 2 H), 3.09 (t, 2 H), 4.00 (s, 2 H), 6.97 (d, 2 H), 7.19-7.23 (m, 5 H), 7.27-7.38 (m, 6 H), 7.76 (d, 1 H), 7.83 (dd, 1 H), 7.98 (d, 1 H). IR (KBr) 3400, 2950, 1675, 1390 and 1190 cm-1. mass spectrum (-ESI) m/z 543 (M-H).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][C:11]([C:13]1[CH:18]=[N:17][C:16]([C:19]#[N:20])=[CH:15][N:14]=1)=[O:12])[CH3:9].Cl.[NH2:22][OH:23]>CCO>[NH2:20][C:19](=[N:22][OH:23])[C:16]1[N:17]=[CH:18][C:13]([C:11]([O:10][CH2:8][CH3:9])=[O:12])=[N:14][CH:15]=1
Reactant: NO
Reactant: CCOC(=O)c1cnc(C#N)cn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1cnc(C(N)=NO)cn1
Temperature: 80 °C
Reaction time: 12 h
Yield: 62.1 %

Procedure:
Triethylamine (7.08 mL, 51.9 mmol) was added to a solution of 5-cyano-pyrazine-2-carboxylic acid ethyl ester (4.0 g, 22.6 mmol), hydroxylamine hydrochloride (3.45 g, 49.7 mmol) and EtOH (32 mL) and stirred at 80° C. for 12 hours. The reaction mixture was cooled to room temperature, concentrated in vacuo and dissolved in H2O (30 mL). The aqueous solution was extracted with CHCl3 (3×30 mL) and the combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to yield the title compound (2.95 g, 62%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1([Cl:10])[C:4]([CH3:6])([CH3:5])[CH:3]1[C:7](Cl)=[O:8].[C:11]([CH:13]([OH:27])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)#[CH:12].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1([Cl:10])[C:4]([CH3:6])([CH3:5])[CH:3]1[C:7]([O:27][CH:13]([C:11]#[CH:12])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:8]
Reactant: CC1(C)C(C(=O)Cl)C1(Cl)Cl
Reactant: C#CC(O)c1cccc(Oc2ccccc2)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C#CC(OC(=O)C1C(C)(C)C1(Cl)Cl)c1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2,2-dichloro-3,3-dimethylcyclopropanoyl chloride (2.7g), alpha-ethynyl-3-phenoxybenzyl alcohol (3.0g) and triethylamine (3.0g) were dissolved in toluene (65 ml) at 10° C and the solution was stirred at room temperature for 16 hours. The mixture was filtered and the solvent was removed from the filtrate under reduced pressure. The residue was purified by chromatography on silica gel using toluene as eluant to give the desired product as an oil nD20 1.5660.