Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:15]([O:17][CH3:18])=[O:16])[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[C:45](C1NC=CN=1)(=[O:49])[CH:46]([CH3:48])[CH3:47].[Cl-].[NH4+]>O1CCCC1.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:15]([O:17][CH3:18])=[O:16])[CH:10]([C:45](=[O:49])[CH:46]([CH3:48])[CH3:47])[C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)C[C@@H](NC(=O)OC(C)(C)C)C(=O)OC
Reactant: CC(C)C(=O)c1ncc[nH]1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(C(=O)C(C)C)[C@@H](NC(=O)OC(C)(C)C)C(=O)OC
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 62.5 %

Procedure:
A solution of 2.61 g (10 m mol) of dimethyl (R)-N-tert-butoxycarbonylaspartate in 10 ml of tetrahydrofuran was added dropwise to a lithium diisopropylamide solution [prepared from 4.62 ml (33 m mol) of diisopropylamine and 21 ml (33 m mol) of butyllithium-hexane solution, in 30 ml of tetrahydrofuran]at -78° C. in a stream of nitrogen, and the mixture was stirred for 10 minutes at -78° C. Then, a solution of 2.76 g (20 m mol) of isobutyrylimidazole in 15 ml of tetrahydrofuran was added dropwise to the reaction mixture, and the mixture was stirred for 10 minutes at -78° C. and further in a dry ice-acetone bath of -40° C. The mixture was further stirred until the temperature reached -20° C., to which a saturated ammonium chloride solution was added and stirred at room temperature. The reaction mixture was diluted with water and and extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over sodium sulfate and distilled. The residue was subjected to a silica gel column (2.5×40 cm) chromatography (ethyl acetate:hexane=1:3→1:2) to obtain 2.07 g (62%) of dimethyl (R)-N-tert-butoxycarbonyl-3-isobutyrylaspartate as colorless oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:11][CH2:10][C:9]2([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[C:4]([CH3:21])([CH2:5][CH2:6][CH:7]([NH2:20])[CH2:8]2)[CH2:3]1.[C:22]1(=O)[O:27][C:25](=[O:26])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12>C1(C)C=CC=CC=1>[C:22]1(=[O:27])[NH:2][C:25](=[O:26])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12.[CH3:1][N:2]1[CH2:11][CH2:10][C:9]2([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[C:4]([CH3:21])([CH2:5][CH2:6][CH:7]([NH2:20])[CH2:8]2)[CH2:3]1
Reactant: O=C1OC(=O)c2ccccc21
Agent: COc1cccc(C23CCN(C)CC2(C)CCC(N)C3)c1
Solvent: Cc1ccccc1
Product: O=C1NC(=O)c2ccccc21

Procedure:
Amine 20 (1.70 g, 0.0058 mol) was dissolved in anhydrous toluene (100 mL) followed by the addition of phthalic anhydride (2.61 g, 0.018 mol), and the mixture was refluxed with Dean-Stark trap overnight. The solution was then cooled, washed with 1 N NaOH (3×50 mL) and water. The organic layer was collected, dried (Na2SO4) and the solvent removed under reduced pressure yielding crude product. The crude product was purified by flash chromatography (30% EtOAc/hexanes on neutral Al2O3 Brockman activity II-III) to afford 2.22 g (90%) of 21 as a white solid: LCMS (ESI): m/z 419.9 (M+H)+; 1H NMR (CDCl3, 300 MHz) δ 7.80-7.83 [m, 2H], 7.68-7.71 [m, 2H], 7.23-7.27 [m, 3H], 6.77-6.79 [m, 1H], 4.81 [m, 1H], 3.85 [s, 3H], 3.28 [t, J=12 Hz, 1H], 3.01 [d, J=12 Hz, 1H], 2.83-2.85 [m, 1H], 2.65-2.81 [m, 1H], 2.40-2.47 [m, 2H], 2.37 [s, 3H], 2.16-2.20 [m, 1H], 1.89 [ddd, J1=J2=15 Hz, J3=6 Hz, 1H], 1.48-1.58 [m, 3H], 1.33-1.39 [m, 1H], 1.26 [s, 3H]; 13CNMR (CDCl3, 300 MHz) δ 168.8, 159.2, 148.4, 134.1, 132.4, 128.7, 123.3, 121.8, 116.0, 111.0, 64.8, 55.5, 52.9, 47.8, 47.2, 43.8, 36.7, 35.6, 34.1, 26.7, 24.3.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][C:5]1[S:9][C:8]([NH2:10])=[N:7][CH:6]=1.[C:12]1([C:18](Cl)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:11])[CH2:4][C:5]1[S:9][C:8]([NH:10][C:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[N:7][CH:6]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)Cc1cnc(N)s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)Cc1cnc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)s1
Yield: 91.9 %

Procedure:
Methyl-(2-amino-1,3-thiazole-5-yl)acetate (1 g, 5.8 mmol) in CH2Cl2 (15 ml) was reacted with triphenylmethyl chloride (1.73 g, 6.2 mmol) and triethylamine (0.89 ml, 6.4 mmol) at 0° C. for 1.5 hour. Water was added to the mixture which was extracted with ethyl acetate, dried, purified by silica gel chromatography to give title compound (2.21 g, 91%).
Reaction SMILES: CC(C)([O-])C.[K+].COP([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])(OC)=O.[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([O:30][CH:31]([F:33])[F:32])=[C:26]([CH:29]=1)[CH:27]=O.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([O:30][CH:31]([F:32])[F:33])=[C:26](/[CH:27]=[CH:13]/[C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH:29]=1
Reactant: COP(=O)(CC(=O)OC(C)(C)C)OC
Reactant: O=Cc1cc(Cl)ccc1OC(F)F
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)/C=C/c1cc(Cl)ccc1OC(F)F
Reaction time: 4 h

Procedure:
To a solution of potassium tert-butoxide (0.407 g, 3.63 mmol) in THF (10 mL) were added tert-butyl 2-(dimethoxyphosphoryl)acetate (0.528 mL, 2.66 mmol) and 5-chloro-2-(difluoromethoxy)benzaldehyde (0.50 g, 2.420 mmol) at 0° C. After 4 hrs, NH4Cl solution was added and the reaction mixture was diluted with EtOAc, washed with sat'd NH4Cl solution, sat'd NaHCO3, and brine. The organic phase was dried over Na2SO4, filtered and concentrated. The crude product was purified by normal phase chromatography. Intermediate 15A was obtained as a white solid 550 mg (74%). MS (ESI) m/z: 327.0 (M+Na)+. 19F NMR (376 MHz, CDCl3) δ: −81.11 (1F, s) ppm.
Reaction SMILES: [CH3:1][C:2]1[N:9]2[C:5]([S:6][CH:7]=[CH:8]2)=[CH:4][N:3]=1.[CH2:10]([O:13][C:14]([N:16]1[C@H:20]([CH:21]=[O:22])[CH2:19][C@@H:18]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:17]1)=[O:15])[CH:11]=[CH2:12]>>[CH2:10]([O:13][C:14]([N:16]1[C@H:20]([CH:21]([OH:22])[C:7]2[S:6][C:5]3=[CH:4][N:3]=[C:2]([CH3:1])[N:9]3[CH:8]=2)[CH2:19][C@@H:18]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:25])[CH3:26])[CH2:17]1)=[O:15])[CH:11]=[CH2:12]
Reactant: Cc1ncc2sccn12
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O
Product: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(O)c1cn2c(C)ncc2s1
Yield: 18.5 %

Procedure:
The procedure of Synthesis Example 10-a) is repeated, except that 1.53 g of 5-methylimidazo[5,1-b]thiazole and 3.46 g of (3R,5S)-1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5-formylpyrrolidine is used and the purification is successively performed by column chromatography on silica gel (ethyl acetate:methanol=9:1) and on Sephadex LH-20 (dichloromethane:methanol=1:1) to give 0.92 g of (3R,5S)-1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5-[1-hydroxy-1-(5-methylimidazo[5,1-b]thiazol-2-yl)methyl]pyrrolidine (a diastereomer mixture) as a slightly yellow amorphous material.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:4][CH2:3]1.[CH:28]1[C:33]([C@H:34]([OH:37])[CH2:35][NH2:36])=[CH:32][C:31]([OH:38])=[C:30]([OH:39])[CH:29]=1>>[OH:38][C:31]1[CH:32]=[C:33]([C@@H:34]([OH:37])[CH2:35][NH:36][CH:2]2[CH2:3][CH2:4][N:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:16])=[O:17])[CH2:6][CH2:7]2)[CH:28]=[CH:29][C:30]=1[OH:39]
Reactant: NC[C@@H](O)c1ccc(O)c(O)c1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccccc2N2CCC(=O)CC2)cc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccccc2N2CCC(NC[C@H](O)c3ccc(O)c(O)c3)CC2)cc1

Procedure:
The title compound was prepared from N-{(4-[2-(4-oxo-piperidin-1-yl)-phenylsulfamoyl]-phenyl}-acetamide (which was obtained in Example 222) and L-norepinephrine according to the procedure of Example 255 as a grey solid; 1H NMR (300 MHz, DMSO-d6) δ 1.30–1.52 (m, 2 H), 1.70–1.90 (m, 2 H), 1.89 (s, 3 H), 2.50–3.50 (m, 7 H), 4.40–4.55 (m, 1 H), 6.00 (brs, 1 H) 6.50–6.80 (m, 3 H), 6.95–7.15 (m, 2 H), 7.25–7.40 (m, 2 H), 7.60–7.75 (m, 4 H), 10.30 (s, 1 H); MS (ES) m/z: 541.4 (MH+); HRMS Calcd. for C27H33N4O6S (MH+): 541.2121. Found: 541.2110.
Reaction SMILES: Cl.[C:2]1([C:8]#[C:9][C:10]2[S:14][C:13]([C:15]3[N:16]=[C:17]4[CH:22]=[N:21][CH:20]=[CH:19][N:18]4C=3N)=[CH:12][CH:11]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CI.CC(=O)OCC.[CH3:35][N:36]([CH:38]=O)[CH3:37]>>[CH3:35][N:36]([CH3:37])[C:38]1[N:18]2[CH:19]=[CH:20][N:21]=[CH:22][C:17]2=[N:16][C:15]=1[C:13]1[S:14][C:10]([C:9]#[C:8][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:11][CH:12]=1
Reactant: Nc1c(-c2ccc(C#Cc3ccccc3)s2)nc2cnccn12
Reactant: CN(C)C=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CI
Product: CN(C)c1c(-c2ccc(C#Cc3ccccc3)s2)nc2cnccn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
790 mg (2.5 mmol) of 2-(5-phenylethynyl-thiophen-2-yl)-imidazo[1,2-a]pyrazin-3-ylamine hydrochloride (Example 83) were dissolved in DMF (8 ml). After addition of 300 mg (7.5 mmol) of sodium hydride (60% dispersion in mineral oil) in portions, the mixture was stirred at RT for 30 min. 0.3 ml (5.0 mmol) of methyl iodide dissolved in DMF (2 ml) was then added dropwise. The reaction solution was stirred at RT for a further 4 h and then quenched with water (20 ml) and extracted with EA (2×50 ml). The combined organic phases were dried over MgSO4, filtered and evaporated under a vacuum. 351 mg (1.0 mmol, 40% of theoretical) of dimethyl-[2-(5-phenylethynyl-thiophen-2-yl)-imidazo[1,2-a]pyrazin-3-yl]-amine were obtained from the group by crystallisation (EA).
Reaction SMILES: [C:1]([OH:11])(=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:25]([NH2:27])[CH3:26])[CH:16]=[C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:18]=1.CCN=C=NCCCN(C)C.Cl.CCN(CC)CC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:12][C:13]1[CH:14]=[C:15]([CH:25]([NH:27][C:1](=[O:11])[CH:2]=[CH:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:26])[CH:16]=[C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:18]=1
Reactant: CC(N)c1cc(F)cc(N2CCOCC2)c1
Reactant: O=C(O)C=Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(NC(=O)C=Cc1ccccc1)c1cc(F)cc(N2CCOCC2)c1
Reaction time: 16 h

Procedure:
A mixture of cinnamic acid (44 mg), 1-(3-fluoro-5-morpholin-4-yl-phenyl)ethylamine, Preparation 24 (66 mg), DMAP (36 mg), EDC.HCl (120 mg), and Et3N (120 mg) in CH2Cl2 (4 mL) was stirred for 16 hours. Purification of the crude product by flash chromatography over silica gel (elution with 50% ethyl acetate in hexane) gave 78 mg of the title compound as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:6]2.[S:24](Cl)([Cl:26])=[O:25]>CCCCCCC>[Cl:26][S:24]([C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:25]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)c1cc2cc(OC)ccc2n1Cc1ccccc1
Solvent: CCCCCCC
Product: CCOC(=O)c1c(S(=O)Cl)c2cc(OC)ccc2n1Cc1ccccc1
Reaction time: 0.5 h
Yield: 81 %

Procedure:
A suspension of 7.0 g (0.023 mole) of 5-methoxy-1-phenylmethyl-1H-indole-2-carboxylic acid, ethyl ester (Y. Murakami, et al, Synthesis, 738 (1984)) in 75 ml of n-heptane under an argon atmosphere was cooled in ice and treated with 15.0 ml (24.5 g; 0.21 mole) of thionyl chloride. The mixture was stirred for 30 minutes, and the precipitated sulfinyl chloride intermediate was filtered and washed several times with hexane to yield 7.3 g (76% yield) of 3-(chlorosulfinyl)-5-methoxy-1-phenylmethyl-1H-indole-2-carboxylic acid, ethyl ester.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:19]=[CH:18][C:17]3[CH2:16][N:15]([C:20]4[CH:21]=[CH:22][C:23]([C:26](O)=[O:27])=[N:24][CH:25]=4)[CH2:14][CH2:13][C:12]=3[N:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:30][NH2:31]>>[CH3:30][NH:31][C:26]([C:23]1[CH:22]=[CH:21][C:20]([N:15]2[CH2:14][CH2:13][C:12]3[N:11]=[C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[CH:19]=[CH:18][C:17]=3[CH2:16]2)=[CH:25][N:24]=1)=[O:27]
Reactant: O=C(O)c1ccc(N2CCc3nc(OCCCN4CCCC4)ccc3C2)cn1
Reactant: CN
Agent: Cl
Product: CNC(=O)c1ccc(N2CCc3nc(OCCCN4CCCC4)ccc3C2)cn1
Yield: 35 %

Procedure:
The title compound was prepared from the product of example 62 and methylamine hydrochloride, using a similar method to that of example 64, as a yellow gum in 35% yield.
Reaction SMILES: [CH:1]1([CH:7]=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:9]=[O:10]>[OH-].[Na+]>[OH:8][CH2:7][C:1]1([CH:9]=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=O
Reactant: O=CC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Product: O=CC1(CO)CCCCC1
Temperature: 25 °C
Yield: 59.2 %

Procedure:
To a cold (0° C. mixture of 100 g (0.891 mole) of cyclohexanecarboxaldehyde, 76.5 g of 37% of formaldehyde in 225 ml of mnethanol was added dropwise 90 ml of 1 N Sodium hydroxide in 1 h. The reaction mixture was stirred at room temperature over 48 then was evaporated to remove methanol. The reaction mixture was diluted with water and extracted with methylene chloride. The organic layer was washed with water, brine, and dried over sodium sulfate and concentrated under vacuum to give 75 g (59.7%) of thick oil. Proton NMR and mass spectra were consistent with the product.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:15][C:14]=2[N+:24]([O-])=O)[CH:3]=1.CO.[H][H]>[Pt].C(OCC)(=O)C>[NH2:24][C:14]1[CH:15]=[C:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH:17]=[CH:18][C:13]=1[NH:12][C:4]1[CH:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: [H][H]
Reactant: COC(=O)Cc1ccc(Nc2cc(Cl)ccc2C(=O)OC)c([N+](=O)[O-])c1
Agent: [Pt]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc(Nc2cc(Cl)ccc2C(=O)OC)c(N)c1
Temperature: 25 °C
Yield: 95.1 %

Procedure:
A mixture of Example 6B (0.73 g, 1.93 mmol), 5% Pt/C, methanol (15 mL) and ethyl acetate (15 mL) was equipped with a balloon of hydrogen gas and stirred at room temperature. After uptake of the hydrogen was complete, the solution was filtered through diatomaceous earth (Celite®). The filtrate was concentrated under vacuum and the residue was purified by flash column chromatography on silica gel with 7:3 hexanes/ethyl acetate to provide 0.64 g (95%) of the desired product. MS (DCI) m/e 349 (M+H)+, 366 (M+NH4)+; 1H NMR (500 MHz, DMSO-d6) δ 8.81 (s, 1H), 7.85 (d, J=8.5 Hz, 1H), 6.96 (d, J=8.1 Hz, 1H), 6.69-6.72 (m, 2H), 6.50 (dd, J=7.8, 1.8 Hz, 1H), 6.40 (d, J=2.1 Hz, 1H), 5.00 (s, 2H), 3.86 (s, 3H), 3.63 (s, 3H), 3.55 (s, 2H).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])[C:10]([OH:20])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:22][C:23]1[CH:42]=[CH:41][C:26]([O:27][CH2:28][C:29]2[N:30]=[C:31]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[O:32][C:33]=2[CH3:34])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[C:10]([O:20][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([O:27][CH2:28][C:29]3[N:30]=[C:31]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[O:32][C:33]=3[CH3:34])=[CH:41][CH:42]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Reactant: CCOC(=O)CCc1cn(Cc2ccccc2)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2nn(Cc3ccccc3)cc2CCC(=O)O)cc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 89.1 %

Procedure:
A mixture of ethyl 3-(1-benzyl-3-hydroxy-1H-pyrazol-4-yl)propionate (900 mg), 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (1.06 g), potassium carbonate (690 mg) and N,N-dimethylformamide (10 ml) was stirred at 60° C. for 5 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and a colorless oil was obtained from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). A mixture of the obtained colorless oil, 1N aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hrs. 1N Hydrochloric acid (5 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to give 3-[1-benzyl-3-[-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1H-pyrazol-4-yl]propionic acid (1.53 g, yield 89%). The crystals were recrystallized from acetone-hexane. melting point: 125–126° C.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Si:27]([O:34][C@H:35]1[CH2:39][N:38]([C:40]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][C:47]([N+:50]([O-:52])=[O:51])=[CH:46][CH:45]=2)=[O:41])[C@H:37]([C:53]([C:55]2[N:56]=[CH:57][N:58]3[CH:62]=[C:61]([Sn](CCCC)(CCCC)CCCC)[S:60][C:59]=23)=[O:54])[CH2:36]1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>>[Si:27]([O:34][C@H:35]1[CH2:39][N:38]([C:40]([O:42][CH2:43][C:44]2[CH:45]=[CH:46][C:47]([N+:50]([O-:52])=[O:51])=[CH:48][CH:49]=2)=[O:41])[C@H:37]([C:53]([C:55]2[N:56]=[CH:57][N:58]3[CH:62]=[C:61]([C:8]4[C@H:9]([CH3:10])[C@@H:5]5[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:25](=[O:26])[N:6]5[C:7]=4[C:12]([O:14][CH2:15][C:16]4[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=4)=[O:13])[S:60][C:59]=23)=[O:54])[CH2:36]1)([C:30]([CH3:31])([CH3:32])[CH3:33])([CH3:29])[CH3:28]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CN3C(=O)OCc3ccc([N+](=O)[O-])cc3)c2s1
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)[C@@H]5C[C@@H](O[Si](C)(C)C(C)(C)C)CN5C(=O)OCc5ccc([N+](=O)[O-])cc5)c4s3)[C@H](C)[C@H]12
Yield: 49 %

Procedure:
4-Nitrobenzyl (1S,5R,6S)-2-[7-[(2S,4R)-4-t-butyldimethylsilyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-2-yl]carbonylimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (369 mg) was prepared in the same manner as in step a) of Example 1, except that 312 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 707 mg of 7-[(2S,4R)-4-t-butyldimethylsilyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-2-yl]carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:28][C:13]3=[N:14][CH:15]=[C:16]([C:18]4[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=4)[C:21]([O:23]C)=[O:22])[CH:17]=[C:12]3[C:11]=2[C:29](=[O:32])[NH:30][CH3:31])=[CH:6][CH:5]=1>CO.CCOC(C)=O>[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:28][C:13]3=[N:14][CH:15]=[C:16]([C:18]4[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=4)[C:21]([OH:23])=[O:22])[CH:17]=[C:12]3[C:11]=2[C:29](=[O:32])[NH:30][CH3:31])=[CH:6][CH:5]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ncc(-c3cccc(C(=O)OC)c3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ncc(-c3cccc(C(=O)O)c3)cc12
Reaction time: 8 h
Yield: 94.9 %

Procedure:
NaOH (0.297 mL, 0.297 mmol, 1M aq.) was added to a stirring solution of methyl 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3-b]pyridin-5-yl)benzoate (24 mg, 0.059 mmol) in MeOH (2 mL) at room temperature. It was allowed to stir overnight. The mixture was diluted with EtOAc and washed with 1M HCl, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to give the expected product 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3-b]pyridin-5-yl)benzoic acid (22 mg, 0.056 mmol, 95% yield) consistent by LCMS. LC-MS retention time: 0.90 min; m/z (MH+): 391. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [CH3:1][OH:2].Cl[CH2:4][N:5]([CH3:10])[S:6]([Cl:9])(=[O:8])=[O:7].C1CCCCC1>C(N(CC)CC)C>[CH3:1][O:2][CH2:4][N:5]([CH3:10])[S:6]([Cl:9])(=[O:8])=[O:7]
Reactant: CO
Reactant: CN(CCl)S(=O)(=O)Cl
Solvent: C1CCCCC1
Solvent: CCN(CC)CC
Product: COCN(C)S(=O)(=O)Cl
Temperature: 40 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
500 parts of methanol are added in the course of 2 minutes at 25° C. to a mixture of 400 parts of N-chloromethyl-N-methylsulfamic acid chloride and 1,000 parts of cyclohexane. 227 parts of triethylamine are then added in the course of 30 minutes at from 0 to 7° C. The reaction mixture is then stirred for one hour at 40° C., after which it is concentrated under reduced pressure. The hydrochloride which has precipitated is filtered off and the filtrate is distilled, giving 282 parts (72% of theory) of N-methoxymethyl-N-methylsulfamic acid chloride of boiling point 84°-87° C./12 mbar and nD25 = 1.4536.
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:7]=1[CH2:8][NH2:9].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.O(C(C)(C)C)[Na]>C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[Cl:14][C:11]1[CH:12]=[CH:13][C:6]2[O:5][CH2:4][C:3]3[CH:15]=[CH:16][CH:17]=[CH:18][C:2]=3[NH:9][CH2:8][C:7]=2[CH:10]=1
Reactant: NCc1cc(Cl)ccc1OCc1ccccc1Br
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Clc1ccc2c(c1)CNc1ccccc1CO2
Temperature: 120 °C
Yield: 51 %

Procedure:
To a stirred mixture of 2-(2-Bromo-benzyloxy)-5-chloro-benzylamine Example 348B (112 mg, 0.34 mmol), BINAP (43.1 mg, 69.3 mmol), and NaO-t-Bu (100 mg, 34.7 mmol) in anhydrous toluene (3.0 mL) under argon was added Pd(dba)2 (20.0 mg, 1.04 mmol). This mixture was heated at 120° C. in a sealed tube for 1 hour and then cooled to room temperature. The mixture was diluted with saturated NaHCO3 solution (40 mL), further saturated with solid NaHCO3, and then extracted with EtOAc (2×60 mL). The combined EtOAc extracts were dried (MgSO4), filtered and concentrated in vacuo. The crude was purified by a ISCO auto CombiFlash with a RediSep 10 g column, eluted with CH2Cl2-EtOAc, detected at 220 nM to give 44 mg of desired 2-Chloro-11,12-dihydro-6H-5-oxa-11-aza-dibenzo[a,e]cyclooctene Example 348C in 51% yield. HPLC Rt=2.05 min (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm) LC/MS: M+H=246