Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:30]([F:33])([F:32])[F:31])[O:13][N:12]=[C:11]([C:14]3[S:18][C:17]([C:19]([NH:21][CH2:22][C:23]([OH:25])=O)=[O:20])=[C:16]4[CH2:26][CH2:27][CH2:28][CH2:29][C:15]=34)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CN(C(O[N:42]1N=[N:49][C:44]2C=CC=N[C:43]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.Cl.NCC#N>C(Cl)Cl.O>[C:43]([CH2:44][NH:49][C:23](=[O:25])[CH2:22][NH:21][C:19]([C:17]1[S:18][C:14]([C:11]2[CH2:10][C:9]([C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)([C:30]([F:33])([F:32])[F:31])[O:13][N:12]=2)=[C:15]2[CH2:29][CH2:28][CH2:27][CH2:26][C:16]=12)=[O:20])#[N:42]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)CNC(=O)c1sc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2c1CCCC2
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N#CCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: N#CCNC(=O)CNC(=O)c1sc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2c1CCCC2
Yield: 44.7 %

Procedure:
Stir a mixture of 2-(3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamido)acetic acid (230 mg, 0.44 mmol), HATU (251 mg, 0.66 mmol) and NEt3 (133 mg, 1.32 mmol) in DCM (5 mL) at room temperature for 15 min, followed by addition of 2-aminoacetonitrile hydrochloride (61 mg, 0.65 mmol). Stir the reaction mixture at room temperature for additional 1.5 hour. Dilute the reaction mixture with water (20 mL) and extract with DCM (20 mL×3). The combined organic layers are washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum. Purify the residue by preparative HPLC to afford N-(2-(cyanomethylamino)-2-oxoethyl)-3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamide as a white solid (110 mg, 44.7%). MS (m/z): 559.1 (M+1). 1H NMR (DMSO-d6, 400 MHz) δ 8.64 (t, J=5.6 Hz, 1H), 8.22 (t, J=5.6 Hz, 1H), 7.81-7.80 (m 1H), 7.68 (s, 2H), 4.35-4.22 (m, 2H), 4.16-4.15 (m, 2H), 3.88-3.86 (m, 2H), 2.94-2.86 (m, 4H), 1.70-1.69 (m, 4H).
Reaction SMILES: C[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N+]#[C-].C(#N)C.ClCl.[N-]=[N+]=[N-].[Na+].[CH3:20][C:21]([CH3:23])=[O:22]>O>[CH:21]([O:22][CH:6]([CH3:7])[CH3:8])([CH3:23])[CH3:20].[CH3:6][CH2:7][CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CC(C)=O
Reactant: [C-]#[N+]c1ccc(C)cc1C
Agent: ClCl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C)OC(C)C
Product: CCCCCC
Reaction time: 1 h

Procedure:
A solution of 2,4-dimethylphenylisonitrile (Ugi, et al., Angew. Chem. Internat. Ed. (Engl.) 4, 472 (1965)) (14.8 g., 0.11 mole) in 100 ml. of acetonitrile was stirred at ice bath temperature while chlorine gas was bubbled in. When tlc indicated that the isonitrile had been consumed, the solvent was removed in vacuo, leaving 22.7 g. of the oily isocyanodichloride. To a solution of the latter in 130 ml. of acetone was added a solution of 7.3 g. (0.11 mole) of sodium azide in 25 ml. of water. After one hour, the acetone was evaporated in vacuo and the aqueous residue was extracted with ethyl acetate. The extract was washed with water and brine, dried (Na2SO4) and evaporated to provide 24.5 g. of a waxy solid. Trituration with isopropyl ether-hexane gave 18.9 g. of the chlorotetrazole, m.p. 75°-77°.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=2)[NH2:12])[O:3]1.C(N(CC)CC)C.[O:24]1[CH2:29][CH2:28][O:27][CH2:26][CH:25]1[C:30](Cl)=[O:31]>CN(C)C(=O)C.C(OCC)(=O)C>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:16])([CH3:1])[O:3][B:4]([C:9]2[CH:10]=[C:11]([NH:12][C:30]([CH:25]3[CH2:26][O:27][CH2:28][CH2:29][O:24]3)=[O:31])[CH:13]=[CH:14][CH:15]=2)[O:5]1
Reactant: O=C(Cl)C1COCCO1
Reactant: CC1(C)OB(c2cccc(N)c2)OC1(C)C
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CC1(C)OB(c2cccc(NC(=O)C3COCCO3)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
To a solution of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (220 mg) and triethylamine (0.182 mL) in N,N-dimethylacetamide (1.5 mL) chilled to 0° C. was added 1,4-dioxane-2-carbonyl chloride (prepared from 1,4-dioxane-2-carboxylic acid (159 mg) and oxalyl chloride (0.15 mL) in dichloromethane (2.5 mL)) dropwise. After being stirred at room temperature for 1 h, the reaction mixture was diluted with ethyl acetate and washed with 1 M citric acid aqueous solution (3 times) then brine. The organics were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (10-100% ethyl acetate in hexanes) gave the product (270 mg, 81%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C:11](=[O:13])[C:10]2([CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([N:8]1[CH2:12][CH:11]([OH:13])[C:10]2([CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CN(Cc2ccccc2)C(=O)C12CCCC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC1CN(Cc2ccccc2)CC12CCCC2
Temperature: 85 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
To a solution of 2-benzyl-2-azaspiro[4.4]nonane-1,4-dione (10.00 g, 41.10 mmol) in THF (240 mL) was added LiAlH4 (3.12 g, 80.20 mmol) portionwise at 0° C. After addition, the reaction mixture was stirred at 85° C. for 1 hour, then cooled down to 0° C. and quenched carefully with water (3.12 mL) and 15% KOH aqueous solution (3.12 mL) followed by another water (9.36 mL). After that, anhydrous MgSO4 (20 g) was added to the above mixture and stirred at rt for 15 min, then filtered through a pad of Celite. The filtrate was extracted with DCM (100 mL×3) and then the separated organic layer was concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=100/1 to 5/1) to give the title compound as yellow oil (8.89 g, 93.5%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(NC(C)C)(C)C.[CH3:30][O:31][CH2:32]Cl>C(Cl)Cl>[CH3:30][O:31][CH2:32][O:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: COCCl
Reactant: O=[N+]([O-])c1ccc(N2CCN(c3ccc(O)cc3)CC2)cc1
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: COCOc1ccc(N2CCN(c3ccc([N+](=O)[O-])cc3)CC2)cc1
Reaction time: 16 h
Yield: 83 %

Procedure:
To a mixture of 10 (263.4 mg, 0.88 mmol) and diisopropylamine (DIPEA) (170.6 mg, 1.32 mmol) in CH2Cl2 (12 mL) was added slowly chloromethyl methyl ether (77.9 mg, 0.97 mmol) at room temperature. The reaction was stirred for 16 h, and then quenched by the addition of saturated aqueous ammonium chloride (10 mL). The resulting solution was extracted with more CH2O2, dried (Na2SO4), filtered, and concentrated to yield the crude product, which was purified by column chromatography (neat CH2Cl2→100:1 CH2Cl2-Acetone) to afford 11 (250.8 mg, 83%) as a yellow amorphous solid; 1H NMR (400 MHz, CDCl3, δH) 8.20-8.08 (m, 2H), 7.07-6.97 (m, 2H), 6.97-6.82 (m, 4H), 5.13 (s, 2H), 3.62-3.51 (m, 4H), 3.48 (s, 3H), 3.30-3.18 (m, 4H); 13C NMR (100 MHz, CDCl3, δC) 154.99, 151.98, 146.31, 138.84, 126.18, 118.59, 117.58, 113.04, 95.28, 56.13, 50.42, 47.43. MALDI-MS: 344.2 (M+H+), 366.2 (M+Na+).
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.Cl.[NH2:12][C:13]1[CH:14]=[C:15]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH2:16][NH:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([Cl:28])[CH:26]=2)[N:21]=[CH:20][N:19]=1>O>[CH:1]([NH:12][C:13]1[CH:14]=[C:15]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH2:16][NH:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([Cl:28])[CH:26]=2)[N:21]=[CH:20][N:19]=1)=[O:2]
Reactant: COc1ccc(CNc2ncnc3ccc(Cl)cc23)cc1N
Reactant: O=CO
Agent: Cl
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(CNc2ncnc3ccc(Cl)cc23)cc1NC=O
Temperature: 50 °C

Procedure:
1 g of powdered iron was added in portions to a mixture comprising 1 g of 4-(3-nitro-4-methoxybenzyl)amino-6-chloroquinazoline, 4 ml of acetic acid, 4 ml of water and 40 ml of ethanol, while heating the mixture under mild reflux. The obtained mixture was heated under reflux for 2 hours and filtered to remove insolubles. Concentrated hydrochloric acid was added in portions to the brown filtrate obtained above to give a yellow transparent solution. This solution was cooled with ice to precipitate crystals. The crystals were recovered by filtration and dried to give 1.1 g of 4-(3-amino-4-methoxybenzyl)amino-6-chloroquinazoline hydrochloride. This hydrochloride was dissolved in ethanol/water and the obtained solution was made alkaline by adding a 15% aqueous solution of sodium hydroxide in portions. Water was added to the resulting alkaline solution in portions to precipitate crystals. The crystals were recovered by filtration, washed with water and dried to give 770 mg of 4-(3-amino-4-methoxybenzyl)amine-6-chloroquinazoline (an aniline derivative), Separately. 1 ml of formic acid was dropped into 2 ml of acetic anhydride under cooling with ice and the obtained mixture was heated at 50° C. for 15 minutes and immediately cooled with ice, followed by the addition of the above aniline derivative as such (in a crystalline state), The obtained mixture was reacted at that temperature for one hour and at room temperature for one hour, followed by the addition of water. The crystals thus formed were recovered by filtration, washed with water and dried to give 130 mg of the title compound.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:26]2[CH:27]=[N:28][C:29]([S:32][CH3:33])=[CH:30][CH:31]=2)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I([O-])(=O)(=O)=[O:35].[Na+]>CO.O>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:26]2[CH:27]=[N:28][C:29]([S:32]([CH3:33])=[O:35])=[CH:30][CH:31]=2)=[CH:20][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CSc1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cn1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CS(=O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.8 %

Procedure:
A solution of 1-benzenesulfonyl-2-[2-cyclopentyl-1-(6-methylsulfanyl-pyridin-3-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (400 mg, 0.84 mmol) in methanol (12 mL) was added a sodium metaperiodate (540 mg, 2.53 mmol) solution in water (4 mL). The resulting mixture was stirred for 12 h at room temperature, extracted with ethyl acetate (3×20 mL), dried over anhydrous sodium sulfate, concentrated in vacuo to afford 1-benzenesulfonyl-2-[2-cyclopentyl-1-(6-methanesulfinyl-pyridin-3-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (412 mg, 100%) which was used in the next step without purification: LC/MS m/e calcd for C26H25N3O3S2 [M+H]+ 492.64, observed 492.2.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([O:11]C2C=CC(C)=CC=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[OH2:23]>C1(C)C=CC=CC=1>[OH:23][C:4]1[CH:5]=[CH:6][C:1]([CH3:7])=[CH:2][C:3]=1[C:9](=[O:11])[CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(OC(=O)CCc2ccccc2)cc1
Reactant: O
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: Cc1ccc(O)c(C(=O)CCc2ccccc2)c1
Temperature: 178 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
p-Tolyl 3-phenylpropanoate (13.0 g, 54.1 mmol) was added to aluminium chloride (9.38 g, 70.3 mmol) and the mixture was heated under stirring to 178° C. for 2 h. Heating was removed and toluene was added (30 ml). Stirring was continued for 15 min to obtain a brown solution, which was cooled with an ice bath prior to the careful, dropwise addition of water (30 ml). The resulting biphasic mixture was further stirred until it reached room temperature, then diluted with toluene. The organic layer was washed 3 times with water, then twice with 1N aq. NaOH solution (50 ml). The organic layer was then neutralized by washing three times with half saturated aq. NaCl, then dried over MgSO4 and concentrated in a rotary evaporator to obtain 9.44 g (73%) of crude brown oil, which was short-path distilled at 129° C./0.05 mbar to obtain 1-(2-hydroxy-5-methylphenyl)-3-phenylpropan-1-one (4.39 g, 34%). The product was further purified by column flash chromatography on silica to obtain 3.68 g (28%) of product, which was finally recrystallized from hexane to yield 2.93 g (25%) of product as white crystals, melting point 40.3° C.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[NH2:39][C:40]1[CH:49]=[C:48]2[C:43]([CH2:44][CH2:45][CH2:46][N:47]2[CH3:50])=[CH:42][CH:41]=1>C(Cl)Cl>[CH3:50][N:47]1[C:48]2[C:43](=[CH:42][CH:41]=[C:40]([NH:39][C:11](=[O:13])[C:10]3[CH:14]=[CH:15][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:8][CH:9]=3)[CH:49]=2)[CH2:44][CH2:45][CH2:46]1
Reactant: O=C(O)c1ccc(-c2ccccc2)nc1
Reactant: CN1CCCc2ccc(N)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CN1CCCc2ccc(NC(=O)c3ccc(-c4ccccc4)nc3)cc21
Reaction time: 8 h

Procedure:
To a solution of 6-phenylnicotinic acid (D48) (500 mg, 2.51 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (963 mg, 5.03 mmol) and 1-hydroxybenzotriazole hydrate (340 mg, 2.51 mmol) in DCM (20 ml) was added a solution of 7-amino-1-methyl-1,2,3,4-tetrahydroquinoline (D3) (407 mg, 2.51 mmol) in DCM (5 ml). The reaction mixture was stirred overnight then washed with sat. aq. sodium hydrogen carbonate solution (2×20 ml) and brine (20 ml). The organics were dried over MgSO4 and concentrated in vacuo to give the crude product which was purified by flash column chromatography. Elution with 10-20% EtOAc/DCM gave the title compound as a yellow solid. 1H NMR (250 MHz, CDCl3) δ (ppm): 9.14 (d, 1H), 8.25 (dd, 1H), 8.07 (m, 2H), 7.85 (d, 1H), 7.71 (br, 1H), 7.48 (m, 3H), 7.03 (br, 1H), 6.93 (d, 1H), 6.75 (dd, 1H), 3.25 (m, 2H), 2.93 (s, 3H), 2.75 (t, 2H), 1.98 (m, 2H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][SH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[C:14](F)[CH:13]=1)#[N:11].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:10]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[C:14]([S:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:13]=1)#[N:11]
Reactant: SCCc1ccccc1
Reactant: N#Cc1ccc(C=O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(C=O)c(SCCc2ccccc2)c1
Temperature: 75 °C

Procedure:
Phenylethylmercaptan (2.14 ml, 16 mmol) was added to a stirred suspension of 4-cyano-2-fluorobenzaldehyde (2.23 g, 15 mmol) and potassium carbonate (2.21 g, 16 mmol) in dimethylformamide (10 ml) at room temperature under nitrogen atmosphere. The mixture was heated to 75° C. for 1 hour, then cooled and diluted with water (15 ml). A yellow solid precipitated and was filtered, washed with water and then crystallised from cyclohexane (250 ml) to give pale needles of 4-cyano-2-(2-phenylethylthio)benzaldehyde, m.p. 89° C.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:21]([NH2:23])[CH3:22]>CN(C=O)C>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:23][CH2:21][CH3:22])=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: CCN
Agent: Cl
Solvent: CN(C)C=O
Product: CCNC1=C(c2ccccc2)S(=O)(=O)N(C(C)(C)C)C1=O
Temperature: 130 °C
Yield: 55.3 %

Procedure:
2-tert-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.175 g, 0.58 mmol), ethylamine hydrochloride (0.056 g, 0.69 mmol) and TEA (0.23 g, 2.31 mmol) was dissolved in dry DMF (3 ml) and heated in a microwave reactor at 130° C. for 30 mins. The reaction mixture was purified by preparative HPLC to yield the title compound (0.099 g, 55%). 1H NMR (500 MHz, CDCl3): δ 7.51-7.46 (m, 2H), 7.43-7.38 (m, 3H), 5.21-5.12 (m, 1H), 2.89-2.80 (m, 2H), 1.72 (s, 9H), 1.01 (t, 3H); 13C NMR (125 MHz, CDCl3): δ 159.9, 135.2, 131.7, 129.7, 128.7, 125.4, 107.1, 61.7, 39.3, 27.8, 15.0; Mass Spectrum: M−H+ 309.
Reaction SMILES: CN1CCOCC1.CN(C1C=CC=CN=1)C.[C:17]([NH:21][C:22]([C:24]1[C:28]([C:29](O)=[O:30])=[C:27]([CH3:32])[O:26][N:25]=1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>ClCCl>[C:17]([N:21]1[C:29](=[O:30])[C:28]2[C:24](=[N:25][O:26][C:27]=2[CH3:32])[C:22]1=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: Cc1onc(C(=O)NC(C)(C)C)c1C(=O)O
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1onc2c1C(=O)N(C(C)(C)C)C2=O
Yield: 91.5 %

Procedure:
6.3 g )62.2 mmol) of methylmorpholine, 2.4 g (20 mmol) of dimethylaminopyridine and 14.6 g of a 50% strength solution of propanephosphonic anhydride (23 mmol) in dichloromethane were added dropwise in succession to 3.8 g (16.8 mmol) of 3-tert-butylaminocarbonyl-5-methylisoxazole-4-carboxylic acid in 150 ml of dichloromethane at -5° C. and the mixture was then refluxed for 6 hours. Working up was carried out as described above. 3.2 g (91%) of N-tert-butyl-5-methylisoxazole-3,4-dicarboximide were obtained as a solid of melting point 48°-50° C. (Example No. 2.001).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:22]1[N:23]=[C:24]([NH2:27])[S:25][CH:26]=1)[C:5]([NH:7][CH:8]1[C:20](=[O:21])[N:10]2[C:11]([C:17]([O-:19])=[O:18])=[C:12]([C:15]#[CH:16])[CH2:13][S:14][C@H:9]12)=[O:6].[Na+].[C:29]([O:35][CH2:36]I)(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31].O>C(OCC)(=O)C>[CH3:1][O:2][N:3]=[C:4]([C:22]1[N:23]=[C:24]([NH2:27])[S:25][CH:26]=1)[C:5]([NH:7][CH:8]1[C:20](=[O:21])[N:10]2[C:11]([C:17]([O:19][CH2:36][O:35][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])=[O:18])=[C:12]([C:15]#[CH:16])[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: C#CC1=C(C(=O)[O-])N2C(=O)C(NC(=O)C(=NOC)c3csc(N)n3)[C@H]2SC1
Reactant: CC(C)(C)C(=O)OCI
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: C#CC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(NC(=O)C(=NOC)c3csc(N)n3)[C@H]2SC1
Yield: 61.4 %

Procedure:
To a solution of sodium 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-ethynyl-3-cephem-4-carboxylate (syn isomer) (1.1 g) was added iodomethyl pivalate (0.744 g) under ice-cooling and the resultant mixture was stirred at the same temperature for 10 minutes. After the reaction mixture was added to a stirred mixture of water and ethyl acetate, the separated organic solution was washed in turn with water, saturated aqueous sodium bicarbonate and brine, and dried over magnesium sulfate. The solution was evaporated in vacuo to give pivaloyloxymethyl 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)-acetamido]-3-ethynyl-3-cephem-4-carboxylate (syn isomer) (0.82 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[N:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=O)[CH:2]=1.[OH:17][CH2:18][C@H:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>S(Cl)(Cl)=O.N1C=CC=CC=1.C(Cl)Cl>[OH:17][CH2:18][C@H:19]([NH:26][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][CH:15]=[N:16][C:8]=1[O:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N[C@@H](CO)c1ccccc1
Reactant: O=C(O)c1cccnc1Oc1cccnc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: O=C(N[C@@H](CO)c1ccccc1)c1cccnc1Oc1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-(Pyridin-3-yloxy)-nicotinic acid (0.250 grams, 1.2 mmole) in thionyl chloride (10 ml) was heated to reflux. After 1 hour the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was suspended in tetrahydrofuran (10 ml) and added dropwise to a solution of (R)-2-hydroxy-1-phenyl ethylamine (0.160 grams, 1.2 mmole) in pyridine (5 ml) at 0° C. After 30 minutes the mixture was warmed to room temperature, stirred at room temperature for 1 hour and concentrated to remove pyridine. The crude product was purified by chromatography on silica gel eluting with ethyl acetate to give a yellow oil. HRMS 336.1324; α=+63.9° 12.3 mg/ml in methylene chloride. 1H NMR (400 mhz, CDCl3) d 2.76 (bs, 1H), 3.95-4.02 (m, 2H), 5.31-5.36 (m, 1H), 7.16-7.40 (m, 1H), 8.19 (dd, J=2.1 Hz, 4.8 Hz, 1H), 8.48-8.61 (m, 4H).
Reaction SMILES: CC1(C)O[C:6](=[O:8])[CH:5]=[C:4]([CH3:9])[O:3]1.[C:11]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH2:22])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12]>C1(C)C=CC=CC=1.CCOC(C)=O>[C:11]([C:15]1[CH:16]=[CH:17][C:18]([CH2:21][NH:22][C:6](=[O:8])[CH2:5][C:4](=[O:3])[CH3:9])=[CH:19][CH:20]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC1=CC(=O)OC(C)(C)O1
Reactant: CC(C)(C)c1ccc(CN)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)CC(=O)NCc1ccc(C(C)(C)C)cc1
Temperature: 130 °C
Yield: 55.9 %

Procedure:
2,2,6-Trimethyl-4H-1,3-dioxin-4-one (1.6 ml, 12.09 mmol) and (4-tert-butylphenyl)methanamine (2.0 ml, 11.36 mmol) were dissolved in toluene (2 ml) and heated at 130° C. for 28 hours. Reaction was cooled to room temperature and diluted with EtOAc (40 ml). The organic phase was washed with HCl (2*30 ml, 1M) and NaHCO3 (2*30 ml, sat aq), dried over MgSO4 and evaporated. The crude product was purified by precipitation from toluene/pet.ether to give 1.57 g (56%) of N-(4-tert-butylbenzyl)-3-oxobutanamide as a pale powder.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:16]2[CH:15]([C:17]3([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=4)[CH2:20][CH2:19][CH2:18]3)[N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2.C(N(CC)CC)C.[CH2:42]([S:45](Cl)(=[O:47])=[O:46])[CH2:43][CH3:44].Cl>N1C=CC=CC=1.ClCCl>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C:17]2([CH:15]3[C:16]4[N:4]([CH2:3][CH2:2][NH:1][S:45]([CH2:42][CH2:43][CH3:44])(=[O:47])=[O:46])[C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[C:11]=4[CH2:12][CH2:13][NH:14]3)[CH2:20][CH2:19][CH2:18]2)=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CCN)c3ccccc23)C1C1(c2ccc(Cl)cc2)CCC1
Reactant: CCCS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCS(=O)(=O)NCCn1c2c(c3ccccc31)CCNC2C1(c2ccc(Cl)cc2)CCC1

Procedure:
tert-Butyl 9-(2-aminoethyl)-1-[1-(4-chlorophenyl)cyclobutyl]-1,3,4,9-tetrahydro-2H-b-carboline-2-carboxylate (90 mg, 0.187 mmol) was dissolved in pyridine (2 mL). Triethylamine (38 mg, 0.375 mmol) followed by propane-1-sulfonyl chloride (40 mg, 0.280 mmol) were added. The reaction mixture was stirred over night. The solvent was evaporated in vacuo. The residue was treated with dichloromethane (10 mL) and washed successively with saturated ammonium chloride solution (2×10 mL) and water (10 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. The crude intermediate was purified by flash chromatography (silica, dichloromethane, methanol). The obtained compound (58 mg, 0.099 mmol) was dissolved in dichloromethane (2 mL) and excess 5M isopropanolic hydrochloric acid was added. The reaction mixture was stirred over night at room temperature. The solvent was evaporated in vacuo. Yield: 35 mg (0.067 mmol, 68%).
Reaction SMILES: [C:1]1(=[O:16])[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[H][H]>C(O)C.[Pd]>[CH2:8]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1](=[O:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=C1C=CCCCCCCCCCCC=C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C1CCCCCCCCCCCCCC1
Yield: 94 %

Procedure:
A solution of 1.00 g (4.55 mMole) of cyclopentadeca-2,14-dien-1-one in 20 ml of ethanol was hydrogenated in the presence of 50 mg of palladium on charcoal. Hydrogen uptake (230 ml) was complete after 1 h at 20°. The mixture was filtered, evaporated and distilled to give 0.96 g (94%) of EXALTONE® having b.p. 115°/0.1 Torr; m.p. 65°-66°.