Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.[CH2:13]([O:15][C:16](=[O:30])[C:17]([C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:18]OCC)[CH3:14]>C1(C)C=CC=CC=1>[CH2:13]([O:15][C:16](=[O:30])[C:17]([C:22](=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[CH:18][NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][C:4]=1[C:9]([F:10])([F:11])[F:12])[CH3:14]
Reactant: Nc1ccc(F)cc1C(F)(F)F
Reactant: CCOC=C(C(=O)OCC)C(=O)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CNc1ccc(F)cc1C(F)(F)F)C(=O)c1ccccc1
Reaction time: 18 h
Yield: 62.1 %

Procedure:
A mixture of 4-fluoro-2-trifluoromethyl-aniline (5.0 g, 27.89 mmol) and 2-benzoyl-3-ethoxy-acrylic acid ethyl ester (6.9 g, 27.89 mmol) in toluene (125 mL) was heated at reflux. After 18 hr, the reaction was cooled, concentrated and purified by column chromatography (eluent 10% to 40% Et2O/hexanes) to give 2-benzoyl-3-(2-trifluoromethyl-4-fluoro-phenylamino)-acrylic acid ethyl ester (6.6 g, 62%); MS (ESI) m/z 382 (M+H)+; 1H NMR E:Z (mixture 1:1) (CDCl3): δ 0.88 (t, J=5.38 Hz, 3H), 0.95 (t, J=5.38 Hz, 3H), 4.02 (q, J=5.38 Hz, 2H), 4.07 (t, J=5.38 Hz, 2H), 7.29-7.51 (m, 10H), 7.53-7.56 (dt, J=9.67, 1.54 Hz, 2H), 7.66-7.68 (dt, J=8.33, 1.41 Hz, 2H), 8.10-8.13 (d, J=12.68 Hz, 2H), 8.36-8.39 (d, J=12.43 Hz, 2H), 11.17-11.20 (d, J=12.68 Hz, 1H), 12.39-12.42 (d, J=12.43 Hz, 1H).
Reaction SMILES: C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[N:30]1[CH:35]=[C:34]([C:36]([NH:38][C:39]2([C:42]([OH:44])=O)[CH2:41][CH2:40]2)=[O:37])[CH:33]=[N:32][CH:31]=1.[F:45][CH:46]([F:64])[O:47][C:48]1[CH:63]=[CH:62][C:51]([O:52][C:53]2[CH:58]=[CH:57][C:56]([CH:59]([NH2:61])[CH3:60])=[CH:55][CH:54]=2)=[CH:50][CH:49]=1>CN(C=O)C>[F:45][CH:46]([F:64])[O:47][C:48]1[CH:63]=[CH:62][C:51]([O:52][C:53]2[CH:58]=[CH:57][C:56]([CH:59]([NH:61][C:42]([C:39]3([NH:38][C:36]([C:34]4[CH:33]=[N:32][CH:31]=[N:30][CH:35]=4)=[O:37])[CH2:40][CH2:41]3)=[O:44])[CH3:60])=[CH:55][CH:54]=2)=[CH:50][CH:49]=1
Reactant: O=C(NC1(C(=O)O)CC1)c1cncnc1
Reactant: CC(N)c1ccc(Oc2ccc(OC(F)F)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(NC(=O)C1(NC(=O)c2cncnc2)CC1)c1ccc(Oc2ccc(OC(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
376 μL (2.70 mmol) of triethylamine and 0.52 g (1.62 mmol) of TBTU were added to a solution of 0.28 g (1.35 mmol) of 1-[(pyrimidin-5-carbonyl)-amino]-cyclo-propanecarboxylic acid (from 1b) in 5 mL DMF and the mixture was stirred for 5 min at RT. Then 0.42 g (1.50 mmol) of 1-[4-(4-difluoromethoxy-phenoxy)-phenyl]-ethylamine was added and the mixture was stirred for 30 min at ambient temperature. The reaction mixture was purified by chromatography (reversed phase). The acetonitrile was distilled off, the aqueous phase was made basic with ammonia and extracted with dichloromethane. The organic phase was dried and evaporated down.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[CH:15]1([CH2:18][CH2:19][NH:20][C:21]([C:23]2[N:24]=[N:25][C:26]([N:29]3[CH2:35][CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[CH:27][CH:28]=2)=[O:22])[CH2:17][CH2:16]1>>[CH:15]1([CH2:18][CH2:19][NH:20][C:21]([C:23]2[N:24]=[N:25][C:26]([N:29]3[CH2:35][CH2:34][CH2:33][N:32]([C:7](=[O:8])[C:6]4[CH:10]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[C:11]([F:14])([F:13])[F:12])[CH2:31][CH2:30]3)=[CH:27][CH:28]=2)=[O:22])[CH2:16][CH2:17]1
Reactant: O=C(Cl)c1cc(F)ccc1C(F)(F)F
Reactant: O=C(NCCC1CC1)c1ccc(N2CCCNCC2)nn1
Product: O=C(NCCC1CC1)c1ccc(N2CCCN(C(=O)c3cc(F)ccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 3, making variations only as required to use 5-fluoro-2-trifluoromethylbenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-[1,4]diazepan-1-ylpyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white solid (60% yield). 1H NMR (CDCl3, 300 MHz) δ 8.07-7.85, 7.71-7.6, 7.23-7.08, 6.94-6.88, 6.34-6.31, 4.24-4.12, 3.98-3.73, 3.67-3.36, 3.29-3.25, 2.19-1.73, 1.53-1.46, 0.81-0.68, 0.48-0.4, 0.11-0.03. 13C NMR (CDCl3, 75 MHz) δ 167.3, 167.2, 165.7, 163.1, 162.9, 162.3, 158.9, 158.4, 144.8, 144.6, 137.1, 129.7-129.2, 127.4, 127.2, 125.0, 121.4, 116.7, 116.6, 116.4, 116.3, 114.9, 114.8, 114.6, 114.5, 111.5, 111.3, 48.8, 48.6, 47.6, 47.5, 45.8, 45.7, 44.1, 39.6, 34.5, 26.8, 25.4, 8.6, 4.2. MS (ES+) m/z 480.1 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:14][C:15]([Cl:22])([Cl:21])[CH2:16][O:17][C:18](Cl)=[O:19]>CCOCC>[Cl:14][C:15]([Cl:22])([Cl:21])[CH2:16][O:17][C:18]([N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)=[O:19]
Reactant: C1CNCCN1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C(OCC(Cl)(Cl)Cl)N1CCNCC1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of 0.5 mol of piperazine and 0.5 mol of triethylamine in ether is added dropwise 0.25 mol of 2,2,2-trichloroethylchloroformate. The reaction mixture is stirred for 1-6 hours at room temperature (ca. 25° C.) and is then worked up with aqueous weak basic solution to give 1-(2,2,2-trichloroethoxycarbonyl)piperazine. This is reacted with p-nitrobenzenesulfonyl chloride in a non-polar solvent, e.g., tetrahydrofuran, to give 1-(p-nitrobenzenesulfonyl)-4-(2,2,2-trichloroethoxycarbonyl)piperazine.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C@@H:7]([OH:8])[CH:6]=[CH:5][CH2:4]1.ClC1C=CC=C(C(OO)=[O:17])C=1>C(Cl)Cl>[OH:1][CH2:2][C@@H:3]1[CH2:4][C@H:5]2[C@H:6]([O:17]2)[C@@H:7]1[OH:8]
Reactant: OC[C@@H]1CC=C[C@@H]1O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: OC[C@@H]1C[C@@H]2O[C@@H]2[C@@H]1O
Temperature: 0 °C
Reaction time: 4 h
Yield: 75.7 %

Procedure:
(1S,5S)-5-(Hydroxymethyl)cyclopent-2-en-1-ol (3.19 g, 27.9 mmol) was dissolved in DCM (143 mL) and the solution was cooled to 0° C. 3-Chloroperbenzoic acid (7.52 g, 33.5 mmol) was added and the mixture was stirred at 23° C. for 4 h. TLC indicated complete conversion. Silica gel (20 g) was added, the mixture was concentrated to dryness and was purified via silica gel chromatography eluting with a gradient of 0 to 100% EtOAc in DCM to afford the title compound (2.75 g, 76%). 1H NMR (CDCl3, 300 MHz) δ: 4.58 (d, J=8.1 Hz, 1H), 3.69 (s, 1H), 3.68 (s, 1H), 3.60 (s, 1H), 3.52 (s, 1H), 2.47-2.40 (m, 1H), 2.14 (ddd, J=1.5, 10.2, 15.3 Hz, 1H), 2.01 (dd, J=1.5, 15.3 Hz, 1H), 1.62 (bs, 2H) ppm. LC/MS: Rt=0.37 nm, ES+ 131 (AA standard).
Reaction SMILES: [CH2:1]([N:8]([CH2:21][CH2:22][C:23](=[O:26])[CH2:24]Br)[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=[O:29])C.[K+].Cl.C(Cl)Cl>C(O)(=O)C>[CH2:1]([N:8]([CH2:21][CH2:22][C:23](=[O:26])[CH2:24][OH:29])[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)[O-]
Reactant: O=C(CBr)CCN(Cc1ccccc1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(CO)CCN(Cc1ccccc1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 112.5 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
A mixture of N-benzyl-N-(4-bromo-3-oxobutyl)-2-nitrobenzenesulfonamide (16 g, 36.3 mmol) and potassium acetate (8.90 g, 91 mmol) in acetic acid (130 ml) was heated to 110-115° C. (slow reflux visible) and stirred for 1 hour (complete by HPLC). Cooled, acetic acid (80 ml) removed under reduced pressure, the residue distributed between DCM (120 ml) and water (120 ml). The organic phase was washed with water, evaporated to half of the volume, diluted with 2-propanol (65.0 ml), the rest of DCM removed. Water (18.20 ml) was added followed by concentrated hydrochloric acid (2.102 ml, 25.4 mmol), residual DCM was distilled off at atmospheric pressure until head temperature reached 77° C., then stirred under reflux for 3 hours. Diluted with water (65 ml), 2-propanol removed at 60° C./180 mbar, to the biphasic residue EA (80 ml) was added followed by sodium bicarbonate with stirring until evolution of gas stopped. The organic phase was dried (MgSO4), evaporated to dryness to give N-benzyl-N-(4-hydroxy-3-oxobutyl)-2-nitrobenzenesulfonamide (13.2 g, 34.9 mmol, 96% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:41])[C@:4]([C:22]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH2:13][C:14]1[N:18]=[C:17]([CH:19]([OH:21])[CH3:20])[NH:16][CH:15]=1)[N:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[S:42](Cl)([C:45]1[CH:51]=[CH:50][C:48]([CH3:49])=[CH:47][CH:46]=1)(=[O:44])=[O:43]>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:41])[C@:4]([C:22]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([CH2:13][C:14]1[N:18]=[C:17]([CH:19]([O:21][S:42]([C:45]2[CH:51]=[CH:50][C:48]([CH3:49])=[CH:47][CH:46]=2)(=[O:44])=[O:43])[CH3:20])[NH:16][CH:15]=1)[N:5]=[CH:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COC(=O)[C@](Cc1c[nH]c(C(C)O)n1)(N=Cc1ccccc1)C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: COC(=O)[C@](Cc1c[nH]c(C(C)OS(=O)(=O)c2ccc(C)cc2)n1)(N=Cc1ccccc1)C(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
To the solution of compound 2·III from Step C is added 0.5 ml of pyridine and then 190.5 mg (1 mmole) of tosyl chloride. After 30 minutes at 25° C. the solution is washed three times with water, once with brine, and dried with K2CO3 and filtered. The filtrate is used directly in the next step.
Reaction SMILES: [H-].[Na+].F[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[N:13]1[CH:17]=[N:16][C:15]([CH3:18])=[N:14]1.[CH2:19]([OH:22])[CH:20]=[CH2:21]>CN(C=O)C>[CH2:19]([O:22][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[N:13]1[CH:17]=[N:16][C:15]([CH3:18])=[N:14]1)[CH:20]=[CH2:21]
Reactant: C=CCO
Reactant: Cc1ncn(-c2ccc([N+](=O)[O-])cc2F)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1cc([N+](=O)[O-])ccc1-n1cnc(C)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50.2 %

Procedure:
A suspension of NaH (2.295 g 57.4 mmol, 60% dispersion in mineral oil) in DMF (85 mL) was cooled at 0° C. and a solution 1-(2-fluoro-4-nitrophenyl)-3-methyl-1H-1,2,4-triazole (8.50 g 38.3 mmol) was added dropwise. Allyl alcohol (2.67 g, 49.9 mmol) was added via syringe over 10 min. The reaction mixture was allowed to warm to room temperature. After 30 min, TLC showed completion of reaction. The reaction mixture was slowly quenched with water (20 mL), treated with 200 mL of brine and extracted with EtOAc (3×200 mL). The combined organic extracts were washed with water (3×200 mL) and brine solution (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude reaction mixture was purified using silica gel chromatography (20-80% EtOAc/hexane, linear gradient). Pure fractions were concentrated under reduced pressure to afford 1-(2-(allyloxy)-4-nitrophenyl)-3-methyl-1H-1,2,4-triazole (5 g, 19.21 mmol 50% yield) as a yellow colored solid. LC-MS (M+H)+=261.0. 1H NMR (400 MHz, CDCl3) δ ppm 8.906 (s, 1H), 8.09 (d, 1H, J=8.8 Hz), 7.99-7.94 (m, 2H), 6.13-6.03 (m, 1H), 5.50-5.54 (m, 2H), 4.80-4.79 (m, 2H), 2.497 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:17]#[N:18])=[N:4][C:5]([C:9]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH3:16])[CH:10]=2)=[CH:6][N+:7]=1[O-:8].Br.CC(O)=[O:22].[OH-].[Na+]>O>[NH2:1][C:2]1[C:3]([C:17]([NH2:18])=[O:22])=[N:4][C:5]([C:9]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH3:16])[CH:10]=2)=[CH:6][N+:7]=1[O-:8]
Reactant: Cn1cc(-c2c[n+]([O-])c(N)c(C#N)n2)ccc1=O
Reactant: CC(=O)O
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1cc(-c2c[n+]([O-])c(N)c(C(N)=O)n2)ccc1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Amino-6-(1-methyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazinecarbonitrile 4-oxide (97 g) was added to 25% hydrogen bromide solution of AcOH (700 ml) at 25-30° C. The mixture was stirred for 2 hours at ambient temperature. To the mixture was added 12% aq. NaOH (2100 ml) and water (1000 ml). The mixture was stirred overnight at the refrigerator. The resultant precipitated crystals were collected by filtration, and washed with water, and dried in vacuo, to give 3-amino-6-(1-methyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazinecarboxamide 4-oxide as powder (52 g).
Reaction SMILES: O.[OH:2][CH2:3][C:4]1([CH2:17][OH:18])[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2.[CH3:19]I.[H-].[Na+]>C1COCC1>[CH3:19][O:2][CH2:3][C:4]1([CH2:17][OH:18])[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: CI
Reactant: OCC1(CO)c2ccccc2-c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCC1(CO)c2ccccc2-c2ccccc21
Yield: 62.1 %

Procedure:
Under nitrogen atmosphere and water-free conditions, to a reactor were added in succession 80 ml of THF, 22.6 g of 9,9-bis(hydroxymethyl)fluorene and 57 g of methyl iodide. After the reaction mixture was admixed homogeneously by stirring, 4.6 g of 52% NaH in mineral oil was added batch-wise over 2 hours at room temperature. Upon completing the addition, the reaction mixture was stirred for further 2 hours. The unreacted methyl iodide was recovered by distillation. The remainder was diluted with 100 ml of water, and extracted twice using 100 ml of diethyl ether for each time. The combined diethyl ether extract was dried over anhydrous sodium sulfate. After drying, the ether solution was evaporated to dryness to give 22.8 g of crude. The crude was purified through column chromatography to give 14.9 g of 9-methoxymethyl-9-hydroxymethyl-fluorene (yield 62%).
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[N:27]1[C:36]2[C:31](=[CH:32][C:33]([C:37](O)=[O:38])=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:37]([C:33]5[CH:32]=[C:31]6[C:36](=[CH:35][CH:34]=5)[N:27]=[CH:28][CH:29]=[CH:30]6)=[O:38])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: O=C(O)c1ccc2ncccc2c1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1)c1ccc2ncccc2c1

Procedure:
The title compound, white solid (107 mg, 89%), MS (ISP) m/z=484.5 [(M+H)+], mp 238° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and quinoline-6-carboxylic acid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]1([CH3:14])[CH2:12][O:11][NH:10][C:9]1=[O:13].[CH3:15][O:16][C:17](=[O:28])[NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25]Br)=[C:21]([Cl:27])[CH:20]=1>C(#N)C.O1CCOCCOCCOCCOCCOCC1>[Cl:27][C:21]1[CH:20]=[C:19]([NH:18][C:17]([O:16][CH3:15])=[O:28])[CH:24]=[CH:23][C:22]=1[CH2:25][N:10]1[C:9](=[O:13])[C:8]([CH3:14])([CH3:7])[CH2:12][O:11]1
Reactant: COC(=O)Nc1ccc(CBr)c(Cl)c1
Reactant: CC1(C)CONC1=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Nc1ccc(CN2OCC(C)(C)C2=O)c(Cl)c1
Reaction time: 16 h
Yield: 45.1 %

Procedure:
To a stirred suspension of 2.4 grams (0.017 mole) of potassium carbonate and 0.1 gram (0.02 eq.) of 1,4,7,10,13,16-hexaoxacyclooctadecane in 60 ml of acetonitrile, at ambient temperature, was added dropwise a mixture of 2.0 grams (0.017 mole) of 4,4-dimethyl-3-isoxazolidinone and 4.8 grams (0.017 mole) of methyl(4-bromomethyl-3-chlorophenyl)carbamate in 30 ml of acetonitrile. The complete addition required 30 minutes, after which the reaction mixture stirred for 16 hours. The reaction mixture was filtered to collect a solid. The solid was slurried with 300 ml of water and the insoluble material collected by filtration. The filter cake was recrystallized from hexane/ethyl acetate to give 2.4 grams of 2-[2-chloro-4-(methyloxycarbonylamino)phenyl]methyl-4,4-dimethyl-3-isoxazolidinone; m.p. 165°-167° C. (Compound 14)
Reaction SMILES: Cl[CH:2]([CH3:24])[C:3]([N:5]([CH:14]1[CH:21]2[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:23][CH:15]1[CH2:16]3)[CH2:20]2)[NH:6]C(OC(C)(C)C)=O)=[O:4].FC(F)(F)C(O)=O>ClCCl>[CH:21]12[CH2:20][CH:19]3[CH2:18][CH:17]([CH2:16][CH:15]([CH2:23]3)[CH:14]1[N:5]1[C:3](=[O:4])[CH:2]([CH3:24])[NH:6]1)[CH2:22]2
Reactant: CC(Cl)C(=O)N(NC(=O)OC(C)(C)C)C1C2CC3CC(C2)CC1C3
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1NN(C2C3CC4CC(C3)CC2C4)C1=O
Reaction time: 1 h
Yield: 53.7 %

Procedure:
A solution of t-butyl 2-(2-chloropropanoyl)-2-(adamantan-2-yl)hydrazinecarboxylate (200 mg, 0.560 mmol) in dichloromethane (3 mL) was added with trifluoroacetic acid (3 mL) at room temperature, and the resultant was stirred at the same temperature for 1 hour. The reaction solution was concentrated, and the obtained residue was purified using silica gel chromatography (hexane:ethyl acetate=1:1), 2-(adamantan-2-yl)-4-methyl-1,2-diazetidin-3-one (66.3 mg, 53.7%) was obtained as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH2:7][C:8]([OH:10])=O)[O:4][N:3]=1.[NH2:11][CH:12]1[C:26](=[O:27])[N:14]2[C:15]([C:23]([OH:25])=[O:24])=[C:16]([CH2:19][N:20]=[N+:21]=[N-:22])[CH2:17][S:18][C@H:13]12>C(#N)C>[CH3:1][C:2]1[N:6]=[C:5]([CH2:7][C:8]([NH:11][CH:12]2[C:26](=[O:27])[N:14]3[C:15]([C:23]([OH:25])=[O:24])=[C:16]([CH2:19][N:20]=[N+:21]=[N-:22])[CH2:17][S:18][C@H:13]23)=[O:10])[O:4][N:3]=1
Reactant: Cc1noc(CC(=O)O)n1
Reactant: [N-]=[N+]=NCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Solvent: CC#N
Product: Cc1noc(CC(=O)NC2C(=O)N3C(C(=O)O)=C(CN=[N+]=[N-])CS[C@H]23)n1
Yield: 35 %

Procedure:
Using the same procedure, 5.51 mmol of 3-methyl-1,2,4-oxadiazol-5-yl-acetic acid and 5.51 mmol of 7-amino-3-azidomethyl-3-cephem-4-carboxylic acid (90% purity) in 55 ml of dry acetonitrile were reacted for one hour at room temperature and 11/2 hours at 50° C. to obtain a 35% yield of pure 7-[3-methyl-1,2,4-oxadiazol-5-yl-acetamido]-3-azidomethyl-3-cephem-4-carboxylic acid with a recovery of 45% of 7-amino-3-azidomethyl-cephalosporanic acid.
Reaction SMILES: [CH:1]1([C:6](=O)[CH:7]([C:13]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.O.Cl.[NH2:23]O>CCO>[CH:1]1([C:6]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:13]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[O:14][N:23]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NO
Reactant: CCOC(=O)C(C(=O)C1CCCC1)C(=O)C1CCCC1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c(C2CCCC2)noc1C1CCCC1

Procedure:
A solution of ethyl 3-cyclopentyl-2-(cyclopentylcarbonyl)-3-oxopropanoate (2.20 g, 7.84 mmol) in EtOH (6.4 mL) was stirred as water (1.2 mL) followed by hydroxylamine hydrochloride (1.02 g, 14.7 mmol) was added. The solution was then heated to reflux for 3 hours. The solution was concentrated and the residue was partitioned between ether and saturated aqueous NaHCO3 solution. The organic layer was washed with brine, dried with MgSO4, filtered and concentrated to yield ethyl 3,5-dicyclopentyl-4-isoxazolecarboxylate as a yellow oil (1.58 g, crude yield 73%). 1H NMR (400 MHz, DMSO-d6): δ 4.23 (q, J=7 Hz, 2H), 3.78-3.72 (m, 1H), 3.45-3.37 (m, 1H), 2.00-1.92 (m, 4H), 1.83-1.49 (m, 12H), 1.26 (t, J=7 Hz, 3H). ESI-LCMS m/z 278 (M+H)+.
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:39])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]([N:26]2[CH2:30][CH2:29][CH2:28][C@@H:27]2[C:31]([O:33]C(C)(C)C)=[O:32])=[O:25])[C:17]=1[CH3:38])=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[C:31]([C@H:27]1[CH2:28][CH2:29][CH2:30][N:26]1[C:24](=[O:25])[CH2:23][O:22][C:18]1[C:17]([CH3:38])=[C:16]([CH:21]=[CH:20][CH:19]=1)[O:15][CH2:14][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[C:6]([OH:7])=[O:5])=[O:39])([OH:33])=[O:32]
Reactant: Cc1c(OCC(=O)N2CCC[C@@H]2C(=O)OC(C)(C)C)cccc1OCC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(OCC(=O)N2CCC[C@@H]2C(=O)O)cccc1OCC(=O)N1CCC[C@@H]1C(=O)O
Reaction time: 8 h
Yield: 94.6 %

Procedure:
A solution of 300 mg (0.55 mmol) (R)-1-[[3-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-2-methyl-phenoxy]-acetyl]-pyrrolidine-2-carboxylic acid tert-butyl ester in 4 ml trifluoroacetic acid was stirred for 3 h at room temperature. The solvent was removed in vacuo and the residue suspended in 10 ml ether. The resulting suspension was stirred overnight. Filtration and drying gave 226 mg (95%) of the title compound as a white powder. MS m/e (%): 457 (M+Na+, 54), 452 (M+NH4+, 55), 435 (M+H+, 100).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:29][CH3:30])=[C:5]([C:10]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[CH2:24][CH2:25][CH2:26][CH2:27][OH:28])(=[O:16])=[O:15])=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])[CH3:2].[CH3:31][S:32](Cl)(=[O:34])=[O:33].N1C=CC=CC=1>ClCCl>[CH2:1]([C:3]1[C:4]([O:29][CH3:30])=[C:5]([C:10]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[CH2:24][CH2:25][CH2:26][CH2:27][O:28][S:32]([CH3:31])(=[O:34])=[O:33])(=[O:16])=[O:15])=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])[CH3:2]
Reactant: CCc1ccc(NS(=O)(=O)c2ccc(F)cc2CCCCO)c(C(=O)OC)c1OC
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCc1ccc(NS(=O)(=O)c2ccc(F)cc2CCCCOS(C)(=O)=O)c(C(=O)OC)c1OC
Yield: 96.6 %

Procedure:
A solution of Example 615C (288 mg, 0.66 mmol), methanesulfonyl chloride (188 mg, 1.64 mmol) and pyridine (104 mg, 1.32 mmol) in dichloromethane (5 mL) was stirred at ambient temperature overnight. Dichloromethane (20 mL) was added and the solution was washed with 1N HCl (2×10 mL) and brine (2×10 mL). The solution was then dried (MgSO4), filtered, and concentrated to provide the desired product (0.33 g, 97%).
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(Cl)Cl.[C:13](Cl)(=[O:16])[CH2:14][CH3:15]>C(N(CC)CC)C>[C:1]1([CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=1[O:7][C:13](=[O:16])[CH2:14][CH3:15]
Reactant: CCC(=O)Cl
Reactant: Cc1ccccc1O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCC(=O)Oc1ccccc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
At 0° C., to a mixture of o-cresol 10 g and chloroform 100 ml was added propionyl chloride 10 g and triethylamine 28 g. The resulting mixture was raised to room temperature and was stirred for two hours. Then the reaction mixture was extracted with chloroform and the organic layer was washed with water and was dried over anhydrous magnesium sulfate, and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give propionic acid o-tolyl ester 14 g.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrBr>CO>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15](=[O:17])[CH2:16][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1
Agent: BrBr
Solvent: CO
Product: O=C(CCc1ccccc1)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 189.6 %

Procedure:
To a solution of 1-(4-(benzyloxy)phenyl)ethanone (5.0 g, 0.02 mol) in MeOH (120 mL) was added a solution of Br2 (4.22 g, 0.026 mol) in MeOH (13 mL). The reaction mixture was stirred at RT for 3 h and then concentrated in vacuo. The residue was then treated with HCl (1N, 20 mL), quenched with ice, and the resulting solid precipitate was filtered and dried in vacuo to afford 1-(4-(benzyloxy)phenyl)-3-phenylpropan-1-one (6 g, 89%) as a white solid.