Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2]([CH3:5])C=O.[N-]=[N+]=[N-].[Na+].N([C:13]1[CH:14]=[C:15]([CH:19]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])[CH2:20]C)[CH:16]=[CH:17][CH:18]=1)=[N+]=[N-].C(O)(C)C>O>[CH3:30][O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[O:22][CH:19]([C:15]1[CH:14]=[CH:13][CH:18]=[CH:17][CH:16]=1)[CH2:20][CH2:5][NH2:2]
Reactant: CN(C)C=O
Reactant: CCC(Oc1ccccc1OC)c1cccc(N=[N+]=[N-])c1
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: COc1ccccc1OC(CCN)c1ccccc1
Temperature: 95 °C

Procedure:
A solution of 2.6 g. of sodium azide in 10 ml. of water was placed in a 100 ml. three-neck, round-bottom flask equipped with stirrer, condenser and thermometer. A second solution containing 2.76 g. of 3-chloro-1-(o-methoxyphenoxy)propylbenzene (as provided by the procedure of Example 2) in 30 ml. of dimethylformamide was added to the sodium azide solution, and the resulting mixture heated at 95° C. overnight. The reaction mixture was cooled, diluted with water and extracted three times with ether. The ether extracts were combined, the combined extracts were washed five times with water followed by a saturated aqueous sodium chloride wash, and were then dried. Evaporation of the ether in vacuo yielded a colorless liquid comprising 3-azido-1-(o-methoxyphenoxy)propylbenzene. Forty-one grams of this latter compound were dissolved in 350 ml. of isopropanol. The resulting solution was placed in a 1 l. round-bottom flask equipped with magnetic stirrer condenser and drying tube. Fifteen and two-tenths grams of 96% sodium borohydride in the solid form were added to the azide solution. The resulting mixture was heating to refluxing temperature overnight and then cooled. The alcohol was evaporated therefrom in vacuo. About 1.5 l. of water were added, and the resulting aqueous mixture acidified cautiously with 2N aqueous hydrochloric acid. 3-(o-methoxyphenoxy)-3-phenylpropylamine produced in the above reaction was soluble in the aqueous acidic layer as the hydrochloride salt. The acidic aqueous layer was extracted three times with ether, and the ether extracts saved to recover unreacted starting material. The acidic layer was then made basic with 5N aqueous sodium hydroxide. The primary amine, being insoluble in base, separated and was extracted into ether. The ether layer was separated, and the aqueous alkaline layer extracted twice more with ether. The ether extracts were combined, and the combined layers washed with a saturated aqueous sodium chloride solution. Evaporation of the ether in vacuo yielded about 17 g. of 3-(o-methoxyphenoxy)-3-phenylpropylamine which was converted to the oxalate sale by the procedure of Example 1. 3-(o-methoxyphenoxy)-3-phenylpropylamine oxalate thus prepared melted at 118°-121° C. after recrystallization from an ethyl acetate-cyclohexane solvent mixture. The oxalate salt was converted to the hydrochloride salt by forming the free base in ether solution and then saturating the ether solution with gaseous hydrogen chloride. The hydrochloride salt melted at 77°-8° C. Analysis calc.: C, 65.91; H, 6.86; N, 4.77; Cl, 12.07; Found: C, 65.13; H, 7.12; N, 4.61; Cl, 12.21.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21]1([C:24](=[S:26])[NH2:25])[CH2:23][CH2:22]1.Cl[CH2:28][CH:29]=O>CN(C)C=O.O>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:16])([F:15])[F:17])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21]1([C:24]2[S:26][CH:28]=[CH:29][N:25]=2)[CH2:23][CH2:22]1
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C1(C(N)=S)CC1
Reactant: O=CCCl
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C1(c2nccs2)CC1
Temperature: 25 °C
Yield: 9.4 %

Procedure:
A mixture of Example 119 (100 mg, 0.24 mmol) and chloroacetaldehyde (22 mg, 0.28 mmol) in N,N-dimethylformamide (2 ml) was heated at 90° C. for 2 h. The reaction mixture was cooled to room temperature, diluted with water and extracted with dichloromethane (×3). The combined extracts were dried (MgSO4) and concentrated in vacuo. The residue was dissolved in acetonitrile (2 ml) and purified by automated preparative liquid chromatography (Gilson system, 150 mm×30 mm Phenomenex LUNA C18(2) 10 μm column) using an acetonitrile:water gradient [50:50 to 98:2]. The appropriate fractions were concentrated in vacuo to give the titled compound (10 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=O)[CH2:23][CH2:24][CH3:25])[C:17](OCC)=[O:18])=[C:11]([F:27])[CH:10]=1)#[N:2].[O:28]1[CH2:33][CH2:32][CH2:31][CH:30]([NH:34][C:35]2[NH:39][CH:38]=[N:37][N:36]=2)[CH2:29]1>>[F:27][C:11]1[CH:10]=[C:9]([C:4]2[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:14]=[CH:13][C:12]=1[CH2:15][C:16]1[C:17](=[O:18])[N:34]([CH:30]2[CH2:31][CH2:32][CH2:33][O:28][CH2:29]2)[C:35]2[N:36]([N:37]=[CH:38][N:39]=2)[C:22]=1[CH2:23][CH2:24][CH3:25]
Reactant: c1nnc(NC2CCCOC2)[nH]1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1F)C(=O)OCC
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCCOC2)c2ncnn12
Temperature: 250 °C
Reaction time: 0.33 h
Yield: 60.6 %

Procedure:
A mixture of ethyl 2-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxohexanoate (0.42 g) and N-(tetrahydro-2H-pyran-3-yl)-4H-1,2,4-triazol-3-amine (0.1 g) was stirred at 250° C. for 20 min under microwave irradiation. The obtained reaction mixture was purified by silica gel column chromatography to give the title compound as a colorless solid (0.17 g, 60%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:35]=[CH:34][C:24]2[N:25]([CH3:33])[C:26](=[O:32])[CH2:27][CH2:28][C:29]([CH3:31])([CH3:30])[C:23]=2[CH:22]=1.Cl>O1CCOCC1.COCCO>[Cl:19][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:20][C:21]2[CH:35]=[CH:34][C:24]3[N:25]([CH3:33])[C:26](=[O:32])[CH2:27][CH2:28][C:29]([CH3:31])([CH3:30])[C:23]=3[CH:22]=2)=[N:3][CH:4]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CN1C(=O)CCC(C)(C)c2cc(N)ccc21
Agent: Cl
Solvent: COCCO
Solvent: C1COCCO1
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C(C)(C)CCC(=O)N3C)ncc1Cl
Yield: 36 %

Procedure:
Combined 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (94 mg, 0.316 mmol), 7-Amino-1,5,5-trimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (67 mg, 0.307 mmol), 4 N HCl in dioxane (100 ul) and 2-methoxyethanol (4 mL). Heated reaction to 120° C. for 1.5 hours. Filtered off solid, then purified the solid with normal phase chromatography eluting with 97/3/1 CH2Cl2/MeOH/NH4OH to yield an off-white solid, 2-[5-Chloro-2-(1,5,5-trimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide (53 mg, 35%). LCMS: m/z=479.42 (M+H+), 1H NMR (400 MHz, CDCl3) δ 11.15 (s, 1H), 8.66 (d, 1H, J=8.3 Hz), 8.14 (d, 1H, J=1.3 Hz), 7.72 (dd, 1H, J=8.7, 2.1 Hz), 7.52 (d, 1H, J=7.8 Hz), 7.45 (m, 1H), 7.33 (s, 1H), 7.11 (m, 2H), 6.97 (s, 1H), 6.23 (br s, 1H), 3.31 (s, 3H), 3.06 (d, 3H, J=4.8 Hz), 2.33 (m, 2H), 2.05 (m, 2H), 1.31 (s, 6H).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].[Br-].O>CN(C)C=O>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[S:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Sc1ccccn1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(Sc2ccccn2)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.11 g of 2-mercaptopyridine and 0.48 of 50% sodium hydride were dissolved in 25 ml of dimethyl formamide, and the mixture was stirred at room temperature for 1 hour. A solution of 6.5 g of polyprenyl bromide of general formula (II) in which n is 15 and A2 is Br in 5 ml of N,N-dimethylformamide was added dropwise. After the addition, the mixture was stirred overnight at room temperature. The reaction mixture was poured into about 50 ml of water, and extracted with diethyl ether. Then, the diethyl ether layer was washed with water and dried over anhydrous magnesium sulfate. The ether was distilled off to give a yellow liquid. The liquid was purified by silica gel column chromatography using hexane/ethyl acetate as an eluent to give 3.9 g of a slightly yellow liquid. The NMR analysis of this liquid showed that the signal (doublet, δ=3.91) assigned to --CH2Br of the starting polyprenyl bromide disappeared, and a signal (doublet, δ=3.78) assigned to --CH2S and a signal (multiplet, δ=6.75-8.35) assigned to --S--C5H4N newly appeared. The FD-MASS analysis of this liquid gave m/e=1335.
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][N:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:17]1[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[O:23])[CH2:18]1>>[OH:1][C:2]1([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][N:10]=2)[CH2:7][CH2:6][CH:5]([N:17]2[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=3)=[O:23])[CH2:18]2)[CH2:4][CH2:3]1
Reactant: COc1ccc(C2(O)CCC(=O)CC2)nc1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: COc1ccc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)nc1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 4-hydroxy-4-(5-methoxy-pyridin-2-yl)-cyclohexanone, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: C([CH:3]([C:24]([OH:26])=[O:25])[N:4]([CH2:15][P:16]([S:21][CH2:22][CH3:23])([S:18][CH2:19][CH3:20])=[S:17])[C:5](OCC1C=CC=CC=1)=O)C.Br.[CH3:28]COCC>C(O)(=O)C>[CH2:5]([N:4]([CH2:15][P:16]([S:21][CH2:22][CH3:23])([S:18][CH2:19][CH3:20])=[S:17])[CH2:3][C:24]([OH:26])=[O:25])[CH3:28]
Reactant: CCSP(=S)(CN(C(=O)OCc1ccccc1)C(CC)C(=O)O)SCC
Reactant: CCOCC
Agent: Br
Solvent: CC(=O)O
Product: CCSP(=S)(CN(CC)CC(=O)O)SCC

Procedure:
Ethyl-N-[bis(ethylthio)phosphinothioylmethyl]-N-(benzyloxycarbonyl)glycine (4.0 g.) was dissolved in 10 ml. of 35% hydrobromic acid in acetic acid and stirred for one hour. Ether was then added to precipitate the desired material as the hydrobromide salt. The residue was washed three additional times with ether. The residue was then dissolved in benzene and treated with excess propylene oxide. The propylene oxide-benzene solution was then concentrated in vacuo to yield a yellow oil (1.5 g.) which was chromatographed on fluorosil with diethyl ether as an eluant to yield ethyl-N-[bis(ethylthio)phosphinothioylmethyl]glycine as an oil, ND25 =1.582.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:34]=[CH:33][C:6]([CH2:7][NH:8][CH2:9][C:10]([C:13]2[CH:17]=[C:16]([NH:18][C:19](=[O:32])[C:20]([CH3:31])([S:22]([CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)(=[O:24])=[O:23])[CH3:21])[O:15][N:14]=2)([CH3:12])[CH3:11])=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:41](Cl)(=[O:43])[CH3:42]>C1COCC1>[C:41]([N:8]([CH2:7][C:6]1[CH:33]=[CH:34][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH2:9][C:10]([C:13]1[CH:17]=[C:16]([NH:18][C:19](=[O:32])[C:20]([CH3:21])([S:22]([CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)(=[O:24])=[O:23])[CH3:31])[O:15][N:14]=1)([CH3:12])[CH3:11])(=[O:43])[CH3:42]
Reactant: COc1ccc(CNCC(C)(C)c2cc(NC(=O)C(C)(C)S(=O)(=O)C3CCOCC3)on2)cc1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ccc(CN(CC(C)(C)c2cc(NC(=O)C(C)(C)S(=O)(=O)C3CCOCC3)on2)C(C)=O)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 75 %

Procedure:
To a solution of N-{3-[2-(4-methoxy-benzylamino)-1,1-dimethyl-ethyl]-isoxazol-5-yl}-2-methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionamide (143 mg, 0.29 mmol) in THF (1.5 mL) are added pyridine (0.035 mL, 0.44 mmol) and acetyl chloride (0.031 mL, 0.44 mmol). The reaction mixture is stirred at room temperature for 3.5 h. After this time, more pyridine (0.018 mL, 0.22 mmol) and acetyl chloride (0.016 mL, 0.22 mmol) are added to the reaction mixture and the stirring is continued for 1 h. After this time, the reaction mixture is quenched with saturated aqueous NaHCO3 solution and extracted with ethyl acetate twice. The organic extracts are combined and washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using methanol/DCM provides the title compound. Yield: 75%; LC-MS retention time: 1.62 mins. ESI+ion mode. Zorbax SB-C18 column (3.5 μm, 4.6×30 mm). Gradient: 5% B to 80% B (0 min to 1.7 mins), 80% B to 95% B (1.7 mins to 2 mins), 95% B to 95% B (2 mins to 2.1 mins). Flow rate: 2.5 mL/min. A=(Water+0.1% Formic Acid), B=(Acetonitrile+0.1% Formic Acid). Diode Array Detector; m/z 536 [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([O:17]CC)=[O:16])=[C:10]3[CH2:9][N:8]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:6]=2[CH:26]=1.[OH-].[Na+]>CCO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([OH:17])=[O:16])=[C:10]3[CH2:9][N:8]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:6]=2[CH:26]=1
Reactant: CCOC(=O)c1ncn2c1CN=C(c1ccccc1)c1cc(Br)ccc1-2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ncn2c1CN=C(c1ccccc1)c1cc(Br)ccc1-2
Yield: 96.6 %

Procedure:
The ester 5 (2 g) was dissolved in EtOH (50 mL) and aq sodium hydroxide (10 mL, 2N) was added to the solution. The mixture was heated to reflux for half an hour. After the EtOH was removed under reduced pressure, the solution was allowed to cool. The pH value was adjusted to 4 by adding 10% aq HCl dropwise. The mixture was filtered and the solid was washed with water and ethyl ether. The solid was dried to provide 27 (1.8 g, 96.6%): mp>250° C.; IR (KBr) 3450 (b), 2844, 1707, 1615, 1493, 1166, 700 cm−1; 1H NMR (300 MHz, DMSO-d6) δ 4.14 (d, 1H, J=12.6 Hz), 5.79 (d, 1H, 12.6 Hz), 7.41-7.54 (m, 6H), 7.88 (d, 1H, J=8.7 Hz), 8.03 (dd, 1H, J=8.7 Hz, J=2.1 Hz), 8.47 (s, 1H); MS (EI) m/e (rel intensity) 381 (M+, 20), 383 (19).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[CH:17][S:18][C:11]=12)[NH2:5].C(N(CC)CC)C.Cl[C:27](=[O:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:27](=[O:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[CH:17][S:18][C:11]=12
Reactant: CCOC(=O)C(=O)Cl
Reactant: Nc1ccc(Oc2ccnc3ccsc23)c(F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)Nc1ccc(Oc2ccnc3ccsc23)c(F)c1
Reaction time: 0.25 h
Yield: 60.7 %

Procedure:
To a stirred solution of 3-fluoro-4-(thieno[3,2-b]pyridin-7-yloxy)aniline (prepared in Example 1, Step B; 0.78 g, 3.0 mmol), triethylamine (0.84 mL, 6.0 mmol), and CH2Cl2 (5 mL) was added a solution of ethyl 2-chloro-2-oxoacetate (0.45 g, 3.3 mmol) in CH2Cl2 (1 mL) dropwise at room temperature. Stirring was continued for 15 minutes. The mixture was washed with water (3×5 mL), dried (Na2SO4), filtered, and concentrated. The resulting crude was purified by Biotage Flash 40 silica gel chromatography, eluting with 30% EtOAc/hexanes, then 1:1 EtOAc/hexanes. The product was obtained as a white powder (656 mg, 61%). 1H NMR (400 MHz, CDCl3) δ 9.10 (s, 1H), 8.53 (d, J=6 Hz, 1H), 7.85 (d, J=12 Hz, 1H), 7.76 (d, J=6 Hz, 1H), 7.58 (d, J=6 Hz, 1H), 7.39 (d, J=9 Hz, 1H), 7.30 (d, J=9 Hz, 1H), 6.52 (d, J=6 Hz, 1H), 4.44 (q, J=7 Hz, 2H), 1.44 (t, J=7 Hz, 3H). LRMS (APCI pos) m/e 361 (M+1). HPLC: 99% purity (220 nm).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([CH:15]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=2[CH3:25])[CH3:16])[CH:12]=[CH:11][C:10]=1[N:26]1[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]1)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].O>CCO.[Pd]>[OH:8][C:9]1[CH:14]=[C:13]([CH:15]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=2[CH3:25])[CH3:16])[CH:12]=[CH:11][C:10]=1[N:26]1[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]1
Reactant: Cc1cc(C)c(C(C)c2ccc(N3CC(=O)NS3(=O)=O)c(OCc3ccccc3)c2)c(C)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1cc(C)c(C(C)c2ccc(N3CC(=O)NS3(=O)=O)c(O)c2)c(C)c1

Procedure:
A solution of 5-{2-benzyloxy-4-[1-(2,4,6-trimethylphenyl)-ethyl]-phenyl}-1,1-dioxo-1,2,5-thiadiazolidin-3-one and K2CO3 (60 mg) in EtOH (5 mL)/water (7 mL) is hydrogenated at 1 atm over 10% Pd/C (50 mg) for 10 days. The catalyst is filtered and the solvent evaporated to give the title compound as a pale-yellow solid: (M−1)−=373. HPLC retention time: 1.45 min (Method A).
Reaction SMILES: Br[CH2:2][C:3]1([CH3:29])[CH:7]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:6]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:5]2[S:4]1.[CH:30]([OH:33])([CH3:32])[CH3:31]>O1CCCC1.F[B-](F)(F)F.[Ag+]>[CH3:29][C:3]1([O:33][CH:30]([CH3:32])[CH3:31])[CH:7]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:6]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C@H:5]2[S:4][CH2:2]1
Reactant: CC(C)O
Reactant: CC1(CBr)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Product: CC(C)OC1(C)CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Reaction time: 1 h

Procedure:
2,2,2-Trichloroethyl 2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.55 g) was dissolved in a mixture of tetrahydrofuran (5 ml) and isopropanol (5 ml). To this solution was added silver fluoroborate (0.24 g) under ice-cooling and the mixture was stirred for 1 hour. The reaction mixture was concentrated and the obtained residue was dissolved in chloroform. This solution was washed with a saturated sodium bicarbonate aqueous solution and with water and then dried over magnesium sulfate. The residue obtained by distilling off the solvent was purified by chromatography on silica gel using chloroform as developing solvent to give oily 2,2,2-trichloroethyl 3-methyl-3-isopropoxy-7-(2-phenylacetamido)-cepham-4-carboxylate (0.10 g).
Reaction SMILES: Cl[C:2]([O:4][C:5]([CH3:7])=[CH2:6])=[O:3].[CH:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[C:10]([OH:17])[CH:9]=1.N1C=CC=CC=1>C(Cl)(Cl)Cl>[C:2](=[O:3])([O:17][C:10]1[CH:11]=[CH:12][C:13]([N+:14]([O-:16])=[O:15])=[CH:8][CH:9]=1)[O:4][C:5]([CH3:7])=[CH2:6]
Reactant: C=C(C)OC(=O)Cl
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: C=C(C)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Isopropenyl chloroformate (5.0 g) was added to an ice cold suspension of p-nitrophenol in chloroform (100 mL). To the stirred reaction mixture, pyridine (3.32 g) was added dropwise over 20 minutes. After stirring at ice bath temperature for 15 minutes, the reaction mixture was allowed to warm up and stirred at room temperature overnight. The reaction mixture was washed with water, IN HCl, ice-cold 1% aqueous sodium hydroxide, water and brine. The organic layer was dried over sodium sulfate and evaporated. The solid residue weighed at 8.7 g. It was crystallized from benzene-hexane m.p. 71-72° . 1H NMR (CDCl3) δ 2.05 (3H, s), 4.82 (2H, s), 7.44 (2H, d) and 8.01 (2H, d); 13C NMR (CDCl3) δ19.59, 102.49, 128.25, 128.79, 131.29, 139.8, 153.07 and 163.84; 1R (KBr) 1770, 1521, 1352, 1266, 1207, 859 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:15])=O>C1C=CC=CC=1>[F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(F)c(F)cc1F
Solvent: c1ccccc1
Product: O=C(Cl)c1cc(F)c(F)cc1F

Procedure:
To 20 ml of anhydrous benzene were added 3.4 g of 2,4,5-trifluorobenzoic acid and 10 ml of thionyl chloride, and the mixture was refluxed for 2 hours. After removing the solvent, excess thionyl chloride was removed three times as an azeotropic mixture with benzene to obtain 2,4,5-trifluorobenzoyl chloride.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:5]([C:18]([O:20]CC)=O)=[C:6]([CH3:17])[N:7]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:8]=1.O.[OH-].[Li+]>C(O)C.O>[CH3:17][C:6]1[N:7]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:8]=[C:4]2[CH2:3][CH2:2][NH:1][C:18](=[O:20])[C:5]=12
Reactant: CCOC(=O)c1c(CCN)cn(COCC[Si](C)(C)C)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c2c(cn1COCC[Si](C)(C)C)CCNC2=O
Temperature: 120 °C

Procedure:
A solution of Example 93e (3.36 g, 10.29 mmol) and lithium hydroxide monohydrate (3.17 g, 76 mmol) in ethanol (47.5 mL) and water (2.5 mL) was added to 100 mL microwave reaction vessel with stir bar. The mixture was heated at 120° C. for 30 minutes in a Ethos Microsynth multimode microwave reactor (Milestone Inc.), then cooled to ambient temperature. The reaction mixture was added to 200 mL water and stirred for 15 minutes. The mixture extracted with 3×200 mL 10% methanol/dichloromethane and the combined dichloromethane extracts dried over anhydrous sodium sulfate. Filtration and solvent removal provided a brown oil which was chromatographed on a 40 g silica cartridge eluting with 0-10% methanol/dichloromethane to provide the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=1.[OH:31][C:32]1[C:36]([CH:37]=[O:38])=[CH:35][N:34]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:33]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:37]([C:36]1[C:32]([O:31][CH2:2][C:3]2[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11]([C:15]4[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=4)[O:12][C:13]=3[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=2)=[N:33][N:34]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:35]=1)=[O:38]
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(CCl)cc3OC)c(C)o2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4C=O)cc3OC)c(C)o2)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
A mixture of ethyl (4-{4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate (0.51 g), 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (0.21 g), potassium carbonate (0.15 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 1 hr. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give ethyl (4-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate as colorless crystals (0.55 g, yield 86%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 157-158° C.