Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:14][CH2:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][P:26]([O:31][CH2:32][CH3:33])([O:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=2)=[O:17])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[N:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40](O)=[O:41].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[N:6]=[C:2]([NH:1][C:40]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][N:34]=3)=[O:41])[S:3][C:4]=2[CH2:14][CH2:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][P:26]([O:28][CH2:29][CH3:30])([O:31][CH2:32][CH3:33])=[O:27])=[CH:21][CH:20]=2)=[O:17])=[CH:12][CH:11]=1
Reactant: CCOP(=O)(Cc1ccc(NC(=O)CCc2sc(N)nc2-c2ccc(Cl)cc2)cc1)OCC
Reactant: O=C(O)c1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(Cc1ccc(NC(=O)CCc2sc(NC(=O)c3ccccn3)nc2-c2ccc(Cl)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 3-[2-amino-4-(4-chlorophenyl)-5-thiazolyl]-N-[4-(diethylphosphonomethyl)phenyl]propionamide (500 mg), pyridine-2-carboxylic acid (145 mg), 1-hydroxybenzotriazole (180 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (225 mg) and N,N-dimethylformamide (10 ml) was stirred at room temperature for 24 hrs. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated to give 3-{4-(4-chlorophenyl)-2-[(2-pyridinylcarbonyl)amino)-5-thiazolyl}-N-[4-(diethylphosphonomethyl)phenyl]propionamide was obtained as crystals (560 mg). Recrystallization from ethyl acetate gave colorless prism crystals (350 mg, yield: 58%). melting point: 184–185° C.
Reaction SMILES: [O:1]1[CH2:5][C:4](=O)[CH2:3][C:2]1=[O:7].[CH2:8]1[C:12]2([CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[CH2:11][CH2:10][NH:9]1.C(O)(=O)C>CC(O)C>[CH2:8]1[C:12]2([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH2:11][CH2:10][N:9]1[C:4]1[CH2:5][O:1][C:2](=[O:7])[CH:3]=1
Reactant: O=C1COC(=O)C1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNC2)CC1
Solvent: CC(=O)O
Solvent: CC(C)O
Product: O=C1C=C(N2CCC3(CCNCC3)C2)CO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Commercially available furan-2,4(3H,5H)-dione (0.433 g, 4.33 mmol) and tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate (commercially available from multiple vendors, acetic acid salt, 0.65 g, 2.2 mmol) in 20 mL i-PrOH was heated in a sealed tube at 110° C. overnight. The solid was filtered off and the filtrate was concentrated under vacuum. The residue was dissolved in 30 mL DCM and 5 mL TFA and stirred at rt for 1 h. The mixture was concentrated, and the residue was purified by preparative TLC (10% 2N NH3 in methanol-DCM). LCMS: [(M+1)]+=223
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:10])=[O:9])C.[OH-].[Na+].O>C(O)C>[C:11]1([S:8]([NH:7][CH2:6][CH2:5][C:4]([OH:17])=[O:3])(=[O:10])=[O:9])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)CCNS(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCNS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Next, to a solution of 3-benzenesulfonylaminopropionic acid ethyl ester (340 mg, 1.32 mmol) in ethanol (15 mL) is added aqueous 1M NaOH (4 mL, 4.0 mmol) and the mixture is stirred at room temperature for 4 hours. The mixture is poured into water and is extracted with ether. The aqueous phase is acidified with aqueous 1M HCl and the solution is lyophilized to give 3-benzenesulfonylaminopropionic acid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([CH3:11])=[CH:4][C:3]=1[N+:12]([O-])=O.Cl.[OH-].[Na+]>C(O)C>[NH2:12][C:3]1[CH:4]=[C:5]([CH3:11])[CH:6]=[C:7]([NH2:8])[C:2]=1[Cl:1]
Reactant: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(N)c(Cl)c(N)c1
Reaction time: 1 h
Yield: 70 %

Procedure:
4-chloro-3,5-dinitrotoluene (9.0 gm.) is dissolved in 50% ethanol (30 ml.). Electrolytically reduced iron powder (14.2 gm.) is added and the stirred reaction mixture heated to reflux. Concentrated HCl (1 ml.) in 50 % ethanol (5 ml.) is added dropwise and refluxing continued for one hour. The reaction mixture is allowed to cool slightly and made basic (pH 8) with 20% NaOH, then the iron removed by filtration. The filtrate is taken to dryness under reduced pressure and the residue extracted with hot Skellysolve "B" (700 ml.). The product precipitates in long needles that were collected by filtration (4.57 gm., m.p. 114°-115.5°, 70% yield).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[NH3:14].Cl>C1COCC1.O>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:14])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: N
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1ccc(S(N)(=O)=O)cc1
Reaction time: 1 h

Procedure:
Commercially available 4-acetyl-benzenesulfonyl chloride (1.25 g, 5.7 mmol) was dissolved in THF (20 mL) and slowly added to a stirred solution of 25% NH3 in H2O (50 mL). The reaction mixture was stirred at it for 1 h. The reaction mixture was acidified using conc. HCl to pH=2. The white precipitation was collected by filtration, washed with H2O and dried in vacuo affording 975 mg of the title compound as off-white crystals.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH:11]=[CH:12][CH:13]=[C:14]([O:15]CC3C=CC=CC=3)[C:7]2=[N:6][C:5]=1[CH3:23].[H][H]>[Pd].CO>[Cl:1][CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH2:11][CH2:12][CH2:13][CH:14]([OH:15])[C:7]2=[N:6][C:5]=1[CH3:23]
Reactant: Cc1nc2c(OCc3ccccc3)cccn2c(=O)c1CCCl
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1nc2n(c(=O)c1CCCl)CCCC2O
Yield: 99 %

Procedure:
To a stirred mixture of 84 parts of phosphoryl chloride and 540 parts of methylbenzene were added 20 parts of 3-(phenylmethoxy)-2-pyridinamine. The mixture was stirred at 50° C. and 22 parts of 3-acetyl-4,5-dihydro-2(3H)-furanone were added. The reaction mixture was stirred for 5 hours at 90° C. Another portion of 22 parts of 3-acetyl-4,5-dihydro-2(3H)-furanone was added and stirring was continued for 30 minutes at 90° C. The solution was allowed to stand overnight at 90° C. The whole was poured into crushed ice and treated with an ammonium hydroxide solution 25%. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was stirred in 2-propanol. The product was filtered off, washed with a mixture of 2-propanol and 1,1′-oxybisethane and dried at 50° C., yielding 20.5 parts (62.3%) of 3-(2-chloroethyl)-2-methyl-9-(phenylmethoxy)-4H-pyrido[1,2-a]pyrimidin-4-one; mp. 141.1° C. (intermediate 1) b) A mixture of 3.3 parts of 3-(2-chloroethyl)-2-methyl-9-(phenylmethoxy)-4H-pyrido[1,2-a]pyrimidin-4-one and 120 parts of methanol was hydrogenated at normal pressure and at room temperature with 2.0 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated to dry, yielding 2.4 parts (99%) of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one as an oily residue. (intermediate 2)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].[Cl:14][C:15]1[N:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18]>C(OCC)(=O)C>[Cl:14][C:15]1[C:16]([C:17]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:9])([F:10])[F:11])[CH:3]=2)=[O:18])=[CH:20][CH:21]=[CH:22][N:23]=1
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-aminobenzotrifluoride (Ruka, Buchs, Switzerland; 2.5 mL, 2.90 g, 18 mmol) in ethyl acetate (40 mL) is added to a stirred aqueous solution of sodium hydroxide (40 mL of 1 M, at room temperature. This stirred solution is then treated dropwise over 30 minutes with a solution of 2-chloronicotinoyl chloride (Lancaster Synthesis, Lancashire, England; 3.52 g, 20 mmol) in dry ethyl acetate (25 mL). The resulting mixture is then stirred for 2 h at ambient temperature. The mixture is then extracted with ethyl acetate (3×100 mL) and the combined extracts are sequentially washed with water (2×100 mL), hydrochloric acid (2×100 mL of 2M), water (2×100 mL), saturated aqueous sodium hydrogen carbonate solution (2×100 mL) and saturated aqueous sodium chloride (1×100 mL), dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by recrystallisation from ethyl acetate-hexane to give the title compound as a colourless crystalline solid, m.p. 117-118° C.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]([CH3:27])[C:8]([C:10]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[CH:14][N:13]=[C:12](S(C)(=O)=O)[N:11]=1)=[O:9].O1[CH2:42][CH2:41]OCC1>>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]([CH3:27])[C:8]([C:10]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[CH:14][N:13]=[C:12]([N:11]2[CH2:42][CH2:41][N:7]([CH3:6])[CH2:8][CH2:10]2)[N:11]=1)=[O:9]
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1nc(S(C)(=O)=O)ncc1-c1ccccc1Cl
Reactant: C1COCCO1
Product: CN1CCN(c2ncc(-c3ccccc3Cl)c(C(=O)N(C)Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)CC1
Reaction time: 16 h
Yield: 179.7 %

Procedure:
To a solution of 0.40 g (0.72 mmol) 5-(2-chloro-phenyl)-2-methylsulfonyl-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide in 10 ml dioxan 0.20 ml (1.81 mmol) 1-methyl-piperazine was added. The reaction mixture was stirred for 16 hrs. After evaporation of the solvent, the residue was distributed between 50 ml CH2Cl2 and 50 ml H2O. The aqueous layer was extracted with 50 ml CH2Cl2, the combined organic layers dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/MeOH/NH4OH 110:10:1) to give 0.37 g (89%) 5-(2-chloro-phenyl)-2-(4-methyl-piperazin-1-yl)-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide as a white foam, MS (ISP): 572.1 (M+H+).
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:7]2[CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:10][C:6]=2[CH:5]=1)(=O)[CH3:2].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH:25][CH:1]([C:4]2[CH:17]=[CH:16][C:7]3[CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:10][C:6]=3[CH:5]=2)[CH3:2])=[CH:22][CH:21]=1
Reactant: COc1ccc(CN)cc1
Reactant: CCOC(=O)c1cc2ccc(C(C)=O)cc2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2ccc(C(C)NCc3ccc(OC)cc3)cc2s1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
Ethyl 6-acetyl-1-benzothiophene-2-carboxylate (0.3 g, 1.21 mmol) was dissolved in DCE (3.0 mL). 4-methoxybenzyl amine was then added to the reaction followed by acetic acid (0.1 mL, 1.69 mmol) and NaBH(OAc)3 (0.41 g, 1.93 mmol). The reaction was allowed to stir for 5 d at room temperature before it was quenched with saturated sodium bicarbonate solution. The reaction mixture was then extracted with ethyl acetate (3×) and the combined organic layers was dried over Na2SO4. After concentrating in vacuo, the crude reaction mixture was purified by flash column chromatography to provide the amine. 1H (600 MHz, CDCl3) δ 8.03 (s, 1H), 7.84 (s, 1H), 7.82 (s, 1H), 7.41 (d, J=8.9 Hz, 1H), 7.18 (d, J=8.5 Hz, 2H), 6.85 (d, J=8.5 Hz, 2H), 4.40 (q, J=7.1 Hz, 2H), 3.93 (q, J=6.5 Hz, 1H), 3.79 (s, 3H), 3.57 (dd, J=21.0, 12.9 Hz, 2H), 1.42-1.26 (m, 6H). MS: cal'd (MH+) 370, exp (MH+): 370.
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[NH:8][C:7]1=S)[CH2:2][CH2:3][CH2:4][CH3:5].[NH2:17][NH2:18]>O>[CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[NH:8]/[C:7]/1=[N:17]\[NH2:18])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: NN
Reactant: CCCCCn1c(=S)[nH]c(=O)c2[nH]cnc21
Solvent: O
Product: CCCCCn1/c(=N/N)[nH]c(=O)c2[nH]cnc21
Temperature: 100 °C
Yield: 79.4 %

Procedure:
3-Pentyl-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one (6.0 g, 16 mmol) was mixed with hydrazine (10 mL, 300 mmol) and water (10 mL). The mixture was heated at 100° C. for 8 h. The solid formed was filtered and washed with water to give the desired product (3.0 g, 78%). LCMS calculated for C10H17N6O (M+H): 237.1. found: 237.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[CH:18][CH:17]=[CH:16]4)=[O:12])=[CH:9][N:10]=2)[N:7]=1.[F:23][C:24]([Si](C)(C)C)([F:26])[F:25].[F-].[K+].Cl>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[CH:18][CH:17]=[CH:16]4)([OH:12])[C:24]([F:26])([F:25])[F:23])=[CH:9][N:10]=2)[N:7]=1
Reactant: O=C(c1ccc2ncccc2c1)c1cnc2ccc(Cl)nn12
Reactant: C[Si](C)(C)C(F)(F)F
Agent: Cl
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC(c1ccc2ncccc2c1)(c1cnc2ccc(Cl)nn12)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-quinolin-6-yl-methanone (Stage 1.2, 50 mg, 0.162 mmol) was dissolved in DMF (5 mL) and (trifluoromethyl)trimethylsilane (1.294 mL, 8.10 mmol) and KF (4.70 mg, 0.081 mmol) were introduced. After 30 min at rt, 1 N HCl was added to the RM. It was stirred at rt for 20 h. the reaction was not completed. It was then heated at 150° C. under microwave irradiations for 5 min. It was extracted with EtOAc twice. Combined organic layers was washed with brine and dried over Na2SO4. It was filtered and the solvent was removed to afford as brown solid 1-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-2,2,2-trifluoro-1-(quinolin-6-yl)ethanol (tR 0.8 min (conditions 2), MH+=379).
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([N:8]([CH:34]([CH3:36])[CH3:35])[C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[CH:17]2[CH2:26][CH2:25][C:24]3[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=3[CH2:18]2)=O)=[CH:4][CH:3]=1.[N:39]1([C:47](=O)[CH2:48]Cl)[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>>[N:39]1([CH2:47][CH2:48][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][N:8]([CH:34]([CH3:36])[CH3:35])[C:9]3[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=3[CH:17]3[CH2:26][CH2:25][C:24]4[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20][C:19]=4[CH2:18]3)=[CH:37][CH:38]=2)[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: O=C(CCl)N1CCCCCCC1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)cc2)C(C)C)c1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(N(Cc2ccc(OCCN3CCCCCCC3)cc2)C(C)C)c1
Yield: 61.7 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8tetrahydronaphthalen-2-yl ester (30 mg) and 1-azocan-1-yl-2-chloroethanone (22 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (20 mg) was obtained.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](Cl)=[O:13])=[CH:7][CH:6]=1)=[N+:2]=[N-:3].[C:15]([O:18][CH2:19][C:20]1[CH2:27][S:26][CH:25]2[N:22]([C:23](=[O:29])[CH:24]2[NH2:28])[C:21]=1[C:30]([OH:32])=[O:31])(=[O:17])[CH3:16]>C(OCC)(=O)C>[C:15]([O:18][CH2:19][C:20]1[CH2:27][S:26][CH:25]2[N:22]([C:23](=[O:29])[CH:24]2[NH:28][C:12](=[O:13])[CH2:11][C:8]2[CH:9]=[CH:10][C:5]([CH2:4][N:1]=[N+:2]=[N-:3])=[CH:6][CH:7]=2)[C:21]=1[C:30]([OH:32])=[O:31])(=[O:17])[CH3:16]
Reactant: [N-]=[N+]=NCc1ccc(CC(=O)Cl)cc1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Solvent: CCOC(C)=O
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3ccc(CN=[N+]=[N-])cc3)C2SC1

Procedure:
A mixture of p-azidomethylphenylacetyl chloride (1.38 g) and 3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (1.38 g) in 250 ml of ethyl acetate was refluxed for 45 minutes. The solvent was removed under vacuum at 35° C. yielding a solid residue which was purified by chromotography using 200 g of silica gel eluting with benzene-acetone to give 3-[(acetyloxy)methyl]-7-[[2-[4-(azidomethyl)phenyl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid. M.P. 135°-136° C.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([Cl:14])=[CH:9][C:8]=1[N+:15]([O-:17])=O)=[O:5])#[N:2].[OH-].[Na+].Cl>N1C=CC=CC=1.O>[C:1]([C:3]1[C:4](=[O:5])[NH:6][C:7]2[C:8]([N+:15]=1[O-:17])=[CH:9][C:10]([Cl:14])=[C:11]([Cl:13])[CH:12]=2)#[N:2]
Reactant: N#CCC(=O)Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: N#Cc1c(=O)[nH]c2cc(Cl)c(Cl)cc2[n+]1[O-]
Reaction time: 4 h
Yield: 71.3 %

Procedure:
To a stirred solution of 142 (0.552 g, 2 mmol) in pyridine (4 mL), 1N NaOH (4 mL, 4 mmol) was added. The resulting mixture was stirred for 4 h, then diluted with water (50 mL) and acidified with 2N HCl to pH 2. The precipitated crude product was washed with water, dried on a filter and washed with ether (5×5 mL) to give 0.365 g (72%) of the title compound as an orange solid: mp 294°-296° C. (from EtOH); IR (KBr) 3104, 3048, 2231, 1675, 1623, 1453, 1399 and 1176 cm-1 ; 1H NMR (DMSO-d6) δ7.54 (s, 1H), 8.25 (s, 1H), 12.20 (s, 1H, N--H). HPLC: 95%; HRMS Calcd for C9H3N3O2Cl2 : 254.9602. Found: 254.9604.
Reaction SMILES: [Na].[CH3:2][C:3]([C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:6]=1[OH:12])=[O:4].[C:13](OCC)(=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15].Cl>C(O)C>[OH:11][C:9]1[CH:10]=[C:5]2[C:6](=[CH:7][CH:8]=1)[O:12][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:2][C:3]2=[O:4]
Reactant: CC(=O)c1cc(O)ccc1O
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1cc(=O)c2cc(O)ccc2o1
Temperature: 25 °C

Procedure:
1.1 3.8 g of sodium are dissolved in portions in 300 ml of ethanol with stirring. A solution of 5.0 g of 2,5-dihydroxyacetophenone and 17.8 ml of diethyl oxalate in 25 ml of ethanol is subsequently added dropwise. The reaction mixture is then heated at 800 for 3 hours and cooled to room temperature, and 10 ml of 32% HCl are added dropwise. The mixture is heated at 90° for 30 minutes and cooled, and the solvent is removed. Conventional work-up gives 5.6 g of 6-hydroxy-2-ethoxycarbonylchromen-4-one (“AA”).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH3:12][CH2:13][C:14](=O)[CH2:15][CH3:16].N1CCCC1>CO>[CH2:13]([C:14]1([CH2:15][CH3:16])[CH2:9][C:8](=[O:10])[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:7]=2)[O:11]1)[CH3:12]
Reactant: CC(=O)c1cc(F)ccc1O
Reactant: CCC(=O)CC
Solvent: C1CCNC1
Solvent: CO
Product: CCC1(CC)CC(=O)c2cc(F)ccc2O1
Temperature: 60 °C
Yield: 89.3 %

Procedure:
1-(5-Fluoro-2-hydroxyphenyl)ethanone (30.2 g, 196 mmol) and MeOH (300 mL) were stirred at ambient temperature and 3-pentanone (41.6 mL, 392 mmol) and pyrrolidine (17.8 mL, 216 mmol) were added. The mixture was heated to 60° C. for 62 h at which point LCMS analysis showed clean conversion to product. The reaction was cooled, concentrated to a minimal volume of MeOH, and MTBE (300 mL) was added. The organics were washed with 2N HCl (150 mL), brine (60 mL), 2N NaOH (150 mL), and brine (60 mL). The solution was passed through a plug of silica gel (30 g), washing with MTBE (150 mL). The filtrate was concentrated, giving the title compound (38.8 g, 175 mmol, 89%) as a light brown oil. MS (DCI/NH3) m/z 240 (M+NH4)+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:13][C:12]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=3)([C:14]([F:17])([F:16])[F:15])[O:11][N:10]=2)=[CH:5][CH:4]=1.[C:26]1(=[O:36])[NH:30][C:29](=[O:31])[C:28]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]12.[K]>CN(C)C=O.C(OCC)(=O)C>[Cl:25][C:20]1[CH:19]=[C:18]([C:12]2([C:14]([F:17])([F:15])[F:16])[O:11][N:10]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([CH2:2][N:30]4[C:29](=[O:31])[C:28]5=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]5[C:26]4=[O:36])=[CH:8][CH:7]=3)[CH2:13]2)[CH:23]=[C:22]([Cl:24])[CH:21]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CC(c2ccc(CCl)cc2)=NO1
Agent: [K]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.6 %

Procedure:
In a solution of 1.20 g of 3-[4-(chloromethyl)phenyl]-5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole in 20 mL of N,N-dimethylformamide, 0.54 g of potassium phthalimide was added and stirred at room temperature for 20 hours. After the completion of the reaction, the reaction mixture was diluted with 100 mL of ethyl acetate, washed with water (50 mL×3) and then dehydrated with and dried over saturated sodium chloride aqueous solution and anhydrous magnesium sulfate in that order, and the solvent was distilled off under reduced pressure to obtain 1.50 g of the aimed product as white crystal.
Reaction SMILES: [I:1]I.[CH2:3]([S:10]/[C:11](/[Sn](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[CH:12]\[CH:13]=[C:14](\[S:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)/[C:15]#[C:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(Cl)Cl>[CH2:3]([S:10]/[C:11](/[I:1])=[CH:12]\[CH:13]=[C:14](/[S:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)\[C:15]#[C:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C[Si](C)(C)C#C/C(=C\C=C(/SCc1ccccc1)[Sn](c1ccccc1)(c1ccccc1)c1ccccc1)SCc1ccccc1
Reactant: II
Solvent: ClCCl
Product: C[Si](C)(C)C#C/C(=C/C=C(/I)SCc1ccccc1)SCc1ccccc1
Temperature: 25 °C
Yield: 95 %

Procedure:
Iodine (36 mg, 0.14 mmol) in CH2Cl2 (8 mL) was added over a period of 2 h at 0° C. to 7 (85 mg, 0.114 mmol) in CH2Cl2 (12 mL) under argon. Analysis by TLC (1:6CH2Cl2 :hexanes) indicated the disappearance of 7. The solution was warmed to room temperature, washed with NaHSO3 (2×20 mL) and KF (10 mL) solutions, dried (MgSO4), concentrated in vacuo, and the residue purified by flash column chromatography (1:4 CH2Cl2 :hexanes) to give 8 as a yellow solid (56.4 mg, 95% yield): 1H NMR δ 7.52 (d, J=10.5 Hz, 1 H), 7.2-7.4 (m, 10 H), 6.74 (d, J=10.5 Hz, 1 H), 4.11 (s, 2 H), 3.97 (s, 2 H), 0.27 (s, 9 H); 13C NMR δ 143.93, 136.42, 132.89, 129.20, 128.60, 127.62, 127.34, 120.75, 101.91, 95.48, 43.28, 37.36, -0.08; Anal., Calcd for C23H25IS2Si, C, 53.07; H, 4.84. Found C, 53.27; H, 5.00.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:3]=1[NH:4][CH2:5][CH:6]=[O:7].C(=O)([O-])[O-].[Na+].[Na+].C1C=CC=CC=1.[Cl:28][CH2:29][C:30](Cl)=[O:31]>O>[Cl:28][CH2:29][C:30]([N:4]([CH2:5][CH:6]=[O:7])[C:3]1[CH:8]=[C:9]([C:12]([F:13])([F:14])[F:15])[CH:10]=[CH:11][C:2]=1[CH3:1])=[O:31]
Reactant: O=C(Cl)CCl
Reactant: Cc1ccc(C(F)(F)F)cc1NCC=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: Cc1ccc(C(F)(F)F)cc1N(CC=O)C(=O)CCl
Temperature: 25 °C

Procedure:
The dimethyl acetal of 2-(2-methyl-5-trifluoromethylanilino)acetaldehyde (0.1 mole), sodium carbonate (0.06 mole) dissolved in water (50 ml) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and cooling means. The mixture is cooled to a temperature of about 0° C. and α-chloroacetyl chloride (0.11 mole) is incrementally added with stirring. After the addition is completed stirring is continued and the reaction mixture is permitted to warm to room temperature. After this time the mixture is filtered, washed with dilute hydrochloric acid and stripped of solvent to yield the desired product the dimethyl acetal of 2-(N-α-chloroacetyl-2-methyl-5-trifluoromethylanilino)-acetaldehyde.