Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH:10]([NH2:11])[CH:9]2[N:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:6]1[CH2:7][CH2:8]2)=[O:4].Cl.[CH3:21][C:22]1[CH:31]=[C:30]([CH2:32][O:33][C:34]2[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:1][O:2][C:3]([CH:5]1[CH:10]([NH:11][S:40]([C:37]2[CH:38]=[CH:39][C:34]([O:33][CH2:32][C:30]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=[C:22]([CH3:21])[CH:31]=3)=[CH:35][CH:36]=2)(=[O:41])=[O:42])[CH:9]2[N:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:6]1[CH2:7][CH2:8]2)=[O:4]
Reactant: COC(=O)C1C(N)C2CCC1N2C(=O)OC(C)(C)C
Reactant: Cc1cc(COc2ccc(S(=O)(=O)Cl)cc2)c2ccccc2n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1C(NS(=O)(=O)c2ccc(OCc3cc(C)nc4ccccc34)cc2)C2CCC1N2C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 23.5 %

Procedure:
To a mixture of 3-amino-7-aza-bicyclo[2.2.1]heptane-2,7-dicarboxylic acid 7-tert-butyl ester 2-methyl ester (0.2 g, 0.87 mmol] and 4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonyl chloride hydrochloride (0.4 g, 1.0 mmol) in N,N-dimethylformamide (DMF, 10 mL) at 0° C. was added N,N-diisopropylethylamine (0.4 mL, 2.23 mmol). The solution was allowed to warm up to 25° C. over 19 h. The DMF was removed in vacuo and the solid was partitioned between ethyl acetate (100 mL) and water (30 mL). The aqueous layer was washed with ethyl acetate (2×50 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified on a Biotage Flash 40S chromatography, eluting with 1:4 ethyl acetate-hexanes, to afford 3-[4-(2-methyl-quinolin-4-ylmethoxy)-benzene sulfonylamino]-7-aza-bicyclo [2.2.1]heptane-2,7-dicarboxylic acid 7-tert-butyl ester-2-methyl ester as a white solid (0.150 g, 23.5%). MS: 582 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:9][C:8]([NH2:10])=[CH:7][CH:6]=1)=[O:4].[OH:11][C:12](=[C:17]1C(=O)OC(C)(C)[O:19][C:18]1=O)[CH2:13][C:14](=O)[CH3:15].CS(O)(=O)=O>O1CCOCC1.C1(C)C=CC=CC=1>[OH:11][C:12]1[CH:13]=[C:14]([CH3:15])[N:10]([C:8]2[O:9][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)[C:18](=[O:19])[CH:17]=1
Reactant: CC(=O)CC(O)=C1C(=O)OC(C)(C)OC1=O
Reactant: COC(=O)c1ccc(N)o1
Agent: CS(=O)(=O)O
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-n2c(C)cc(O)cc2=O)o1
Temperature: 98 °C
Reaction time: 12 h
Yield: 44.1 %

Procedure:
To a room temperature solution of methyl-2-amino-5-furoate (4.85 g, 34.4 mmol) in 1,4 dioxane (28.0 mL) was added 5-(1-hydroxy-3-oxobutylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (8.16 g, 44.3 mmol). The reaction was stirred vigorously and heated quickly (within 8 minutes) to an internal temperature of 98° C. Upon reaching temperature, the reaction was maintained for 1.0 hour. At this time, the reaction was cooled to room temperature rapidly using an ice-bath and methane sulfonic acid (3.30 g, 34.4 mmol) was added. The reaction mixture was once again brought to an internal temperature of approximately 100° C. After 1.0 hour the reaction was diluted with 10 mL of toluene and allowed to cool to room temperature on its own accord. A solid formed after 3.0 hours that was collected and subsequently recrystallized from methanol/ethyl acetate (1:1). The developing crystals were allowed to form and stand for 12.0 hours prior to collection to furnish the desired product as a solid (3.78 g, 44%). 1H NMR (400 MHz, d7-DMF) δ 11.34 (s, 1H), 7.43 (app d, J=3.6 Hz, 1H), 6.79 (app d, J=3.6 Hz, 1H), 6.01 (s, 1H), 5.63 (d, J=2.0 Hz, 1H), 3.87 (s, 3H), 2.02 (s, 3H); LC/MS C-18 column, tr=1.47 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 250 (M+H). ES-HRMS m/z 250.0696 (M+H calcd for C12H12NO5 requires 250.0710). Step 2: Preparation of methyl 5-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-2-furoate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([Cl:11])[CH:5]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14])=[C:6]([Cl:11])[CH:5]=1
Reactant: CCCCCCCCCCCCCCBr
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)OC)cc1Cl
Yield: 96 %

Procedure:
A mixture of 100.0 g of 3-chloro-4-(hydroxy)benzoic acid methyl ester, 148.6 g of 1-bromotetradecane, 170.4 g of potassium carbonate and 1 L of acetone is heated at reflux temperature for 40.5 hours. The cooled reaction is filtered, concentrated in vacuo and purified by column chromatography (silica gel:0-2% ethyl acetate/hexane) to give 197.1 g of the desired product as colorless crystals.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([O:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=1)[C:11]([OH:13])=O)[CH2:5][CH3:6].[NH2:25][C:26]1[CH:30]=[CH:29][N:28]([CH3:31])[N:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][CH2:3][C@@H:4]([O:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=1)[C:11]([NH:25][C:26]1[CH:30]=[CH:29][N:28]([CH3:31])[N:27]=1)=[O:13])[CH2:5][CH3:6]
Reactant: CC[C@@H](COC)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Reactant: Cn1ccc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@H](COC)Oc1cc(OCc2ccccc2)cc(C(=O)Nc2ccn(C)n2)c1
Yield: 77.5 %

Procedure:
To a solution of 3-({(1S)-1-[(methyloxy)methyl]propyl}oxy)-5-[(phenylmethyl)oxy]benzoic acid (4.75 g, 14.4 mmol) and 3-amino-1-methyl-1H-pyrazole (2.04 g, 21 mmol) in DMF (25 mL) was added HATU (8.53 g, 22.4 mmol) then DIPEA (7.0 mL, 40 mmol) and the resulting mixture was stirred for 16 hours. The mixture was partitioned between ethyl acetate (100 mL) and water (30 mL). The organic layer was separated, washed with 1N citric acid (30 mL), water (30 mL), saturated sodium bicarbonate (30 mL), water (30 mL) and brine (30 mL) then dried (MgSO4) and evaporated. The residue was purified by column chromatography, eluting with 50% ethyl acetate in isohexane, to give the title compound as a colourless oil (4.57 g).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].O1CCCC1.[Cl:16][C:17]1[CH:25]=[C:24]([C:26]#[C:27][CH2:28][O:29][CH3:30])[C:20]2[O:21][CH2:22][O:23][C:19]=2[C:18]=1[NH2:31].Cl[C:33]1[C:42]2[C:37](=[CH:38][C:39]([O:50][CH2:51][CH2:52][CH2:53][N:54]3[CH2:59][CH2:58][O:57][CH2:56][CH2:55]3)=[CH:40][C:41]=2[O:43][CH:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)[N:36]=[CH:35][N:34]=1>CN(C=O)C>[Cl:16][C:17]1[CH:25]=[C:24]([C:26]#[C:27][CH2:28][O:29][CH3:30])[C:20]2[O:21][CH2:22][O:23][C:19]=2[C:18]=1[NH:31][C:33]1[C:42]2[C:37](=[CH:38][C:39]([O:50][CH2:51][CH2:52][CH2:53][N:54]3[CH2:55][CH2:56][O:57][CH2:58][CH2:59]3)=[CH:40][C:41]=2[O:43][CH:44]2[CH2:45][CH2:46][O:47][CH2:48][CH2:49]2)[N:36]=[CH:35][N:34]=1
Reactant: Clc1ncnc2cc(OCCCN3CCOCC3)cc(OC3CCOCC3)c12
Reactant: COCC#Cc1cc(Cl)c(N)c2c1OCO2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCN4CCOCC4)cc(OC4CCOCC4)c23)c2c1OCO2
Temperature: -10 °C
Reaction time: 1.5 h
Yield: 36.2 %

Procedure:
A solution of sodium bis(trimethylsilyl)amide (1.28 ml) in tetrahydrofuran (1.0M, 1.28 mmol) was added to a suspension of 5-chloro-7-(3-methoxyprop-1-yn-1-yl)-1,3-benzodioxol-4-amine (0.153 g) and 4-chloro-7-(3-morpholin-4-ylpropoxy)-5-(tetrahydro-2H-pyran-4-yloxy)quinazoline (0.260 g) in DMF (4 ml) that had been cooled to −10° C. and the mixture was stirred for 90 minutes. A further portion of sodium bis(trimethylsilyl)amide (0.64 ml) in tetrahydrofuran (1.0M, 0.64 mmol) was added and the reaction was allowed to warm to room temperature and then stirred for a further 2 hours. The reaction mixture was quenched into water and saturated ammonium chloride solution was added. This was then extracted into dichloromethane and the organic portion was then washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of dichloromethane and methanol as eluent. The product material gathered after chromatography as a foam was triturated with diethyl ether giving an off-white solid. This was then re-dissolved into dichloromethane and then evaporated under reduced pressure. The resulting solid was triturated with diethyl ether and air-dried. There was thus obtained the title compound (0.141 g) as a white solid; NMR Spectrum: (CDCl3) 2.00 (m, 4H), 2.23 (m, 2H), 2.48 (m, 4H), 2.54 (t, 2H), 3.46 (s, 3H), 3.63 (dq, 2H), 3.73 (t, 4H), 4.02 (dt, 2H), 4.16 (t, 2H), 4.35 (s, 2H), 4.76 (tt, 1H), 6.11 (s, 2H), 6.51 (d, 1H), 6.85 (d, 1H), 7.06 (s, 1H), 8.52 (s, 1H), 9.26 (s, 1H); Mass Spectrum: M+H+ 611/613.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][C:19]([Br:25])=[CH:18][C:8]=3[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:10][CH2:11][C:5]2=[N:4][N:3]=1.[CH2:26]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[CH3:27]>>[Br:25][C:19]1[CH:20]=[C:21]([N+:22]([O-:24])=[O:23])[C:7]2[N:6]3[C:2]([N:31]4[CH2:32][CH2:33][N:28]([CH2:26][CH3:27])[CH2:29][CH2:30]4)=[N:3][N:4]=[C:5]3[CH2:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:8]=2[CH:18]=1
Reactant: O=[N+]([O-])c1cc(Br)cc2c1-n1c(Br)nnc1CN=C2c1ccccn1
Reactant: CCN1CCNCC1
Product: CCN1CCN(c2nnc3n2-c2c(cc(Br)cc2[N+](=O)[O-])C(c2ccccn2)=NC3)CC1

Procedure:
In the manner given in Example 1, 1,8-dibromo-10-nitro-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine is heated with 1-ethylpiperazine to give 8-bromo-10-nitro-1-(4-ethylpiperazino)-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([N:12]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:13][C@H:14]([OH:23])[CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][OH:11])=[CH:4][CH:3]=1.[CH2:31]([N:33]=[C:34]=[O:35])[CH3:32]>ClCCl>[CH2:24]([N:12]([C@H:9]([CH2:10][OH:11])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:34]([NH:33][CH2:31][CH3:32])=[O:35])=[CH:3][CH:4]=1)[CH2:13][C@H:14]([OH:23])[CH2:15][O:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCN=C=O
Reactant: Nc1ccc(C[C@@H](CO)N(Cc2ccccc2)C[C@H](O)COc2ccccc2)cc1
Solvent: ClCCl
Product: CCNC(=O)Nc1ccc(C[C@@H](CO)N(Cc2ccccc2)C[C@H](O)COc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To an ice-cooled solution of (2S)-3-(4-aminophenyl)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-1-propanol (83 mg) in dichloromethane (0.8 ml) was added dropwise ethyl isocyanate (0.016 ml). The mixture was stirred at the same temperature for 1.5 hours and partitioned between chloroform and saturated sodium bicarbonate solution. The organic layer was separated, washed with brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated and the residue was purified by column chromatography (silica gel, chloroform/methanol) to give N-[4-[(2S)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-3-hydroxypropyl]phenyl]-N′-ethylurea (84 mg) as a white amorphous powder.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:5]([OH:17])=[CH:4][CH:3]=1.C1C(=O)N([Cl:25])C(=O)C1>CC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[NH:9][C:10]3[C:15]([C:16]=2[Cl:25])=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:5]([OH:17])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)nc1-c1cc2ccccc2[nH]1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(C)=O
Product: Oc1ccc(Cl)nc1-c1[nH]c2ccccc2c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.5 %

Procedure:
A mixture of 6-chloro-2-(1H-indol-2-yl)pyridin-3-ol (244 mg, 1 mmol, described in Example 1) and NCS (160 mg, 1.2 mmol) in Acetone (2 mL) was stirred at room temperature for 1 hour. The mixture was then concentrated and purified using prep-TLC (petroleum ether:EtOAc=2:1) to provide 6-chloro-2-(3-chloro-1H-indol-2-yl)pyridin-3-ol (180 mg, yield: 64.7%). 1H-NMR (CDCl3, 400 MHz) δ 9.03 (s, 1H), 7.61 (d, J=7.6 Hz, 1H), 7.15˜7.36 (m, 5H), 6.20˜6.40 (br s, 1H). MS (M+H)+: 279/281.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:36])[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH:23][C:24]2[S:25][C:26]3[CH:32]=[C:31]([N+:33]([O-])=O)[CH:30]=[CH:29][C:27]=3[N:28]=2)=[CH:18][CH:17]=1)([CH3:4])([CH3:3])[CH3:2].O.O.[Sn](Cl)Cl.C([O-])(=O)C.[NH4+]>C1COCC1.CO.O>[C:1]([O:5][C:6](=[O:37])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:36])[C:16]1[CH:17]=[CH:18][C:19]([CH2:22][NH:23][C:24]2[S:25][C:26]3[CH:32]=[C:31]([NH2:33])[CH:30]=[CH:29][C:27]=3[N:28]=2)=[CH:20][CH:21]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(CNc2nc3ccc([N+](=O)[O-])cc3s2)cc1
Agent: CC(=O)[O-]
Agent: Cl[Sn]Cl
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(CNc2nc3ccc(N)cc3s2)cc1
Yield: 76.9 %

Procedure:
To a suspension of compound 141 (200 mg, 0.385 mmol) in a mixture of THF/MeOH/H2O (10 mL/10 mL/10 mL) were successively added tin(II) chloride dihydrate (1.35 g, 8.46 mmol) and ammonium acetate (1.09 g, 14.12 mmol). The mixture was refluxed for 2 days, the tin salts were filtered off and the filtrate was concentrated in vacuo. The residue was partitioned between EtOAc and H2O (brine was added to break the emulsion). Organic phase was successively washed with saturated aqueous NaHCO3 and brine, dried over MgSO4, and concentrated in vacuo to afford the title compound 143 (145 mg, 77% yield). 1H NMR: (DMSO-d6) δ (ppm): 12.89 (bs, 1H), 10.79 (s, 1H), 8.12 (d, J=2.0 Hz, 1H), 8.05 (d, J=8.8 Hz, 2H), 7.90-7.68 (m, 3H), 7.62 (d, J=8.4 Hz, 2H), 7.48 (bs, 1H), 7.21 (dd, J=4.9, 3.7 Hz, 1H), 4.65 (s, 2H). m/z: 490.5 (MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([NH2:21])[S:19][CH:20]=2)[CH2:9][CH2:8]1.[OH2:22]>>[OH2:22].[CH3:20][C:16]1[N:17]=[C:18]([NH2:21])[S:19][C:15]=1[CH2:14][CH2:13][N:10]1[CH2:11][CH2:12][N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:8][CH2:9]1.[CH3:20][C:16]1[N:17]=[C:18]([NH2:21])[S:19][C:15]=1[CH2:14][CH2:13][N:10]1[CH2:11][CH2:12][N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:8][CH2:9]1
Reactant: Nc1nc(CCCN2CCN(c3ccccn3)CC2)cs1
Solvent: O
Product: Cc1nc(N)sc1CCN1CCN(c2ccccn2)CC1

Procedure:
mp 135°-150° C. and EXAMPLE 1i 4-[3-[4-(2-Pyridinyl)-1-piperazinyl]-propyl]-2-thiazolamine, containing 1/4 of a mole of water; mp 132°-137° C.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[S:7][C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=1.[OH-].[Na+].S(=O)(O)[O-].[Na+].[BrH:22]>[Cu]>[Br:22][C:6]1[S:7][C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=1
Reactant: Br
Reactant: Nc1nnc(C(F)(F)F)s1
Agent: [Cu]
Agent: O=N[O-]
Agent: O=S([O-])O
Product: FC(F)(F)c1nnc(Br)s1

Procedure:
To a rapidly stirred suspension of copper bronze (6.1 g.) in 48% HBr (975 ml.) was added over a 1 hour period and cooling to -15° a mixture of NaNO2 (195 g., 2.83 mol.) and 2-amino-5-trifluoromethyl-1,3,4-thiadiazole (103 g., 0.61 mol.) [I. Lalezari and N. Sharghi, J. Hetero. Chem. 3:336 (1966)]. The resultant mixture was stirred for 0.75 hour with ice bath cooling and for 1.5 hour without cooling. The mixture was adjusted to pH 8 using 50% NaOH and maintaining the temperature below 20°. Saturated sodium bisulfite was added until a negative starch-iodide test was obtained. The mixture was made strongly acidic with HCL and extracted with petroleum ether. The extracts were washed with water, dried (MgSO4) and evaporated to the product. Distillation gave 2-bromo-5-trifluoromethyl-1,3,4-thiadiazole; b.p 56°-57°/11 mm.
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1.Cl.[NH:19]1[CH2:24][CH2:23][CH:22]([C:25]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)=[O:26])[CH2:21][CH2:20]1>>[O:17]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([N:19]2[CH2:24][CH2:23][CH:22]([C:25](=[O:26])[C:27]3[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=3)[CH2:21][CH2:20]2)=[O:14])=[CH:15][CH:16]=1
Reactant: O=C(O)c1ccc(CN2CCCS2(=O)=O)cc1
Reactant: Cc1ccc(C(=O)C2CCNCC2)cc1
Agent: Cl
Product: Cc1ccc(C(=O)C2CCN(C(=O)c3ccc(CN4CCCS4(=O)=O)cc3)CC2)cc1
Yield: 50.8 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-ylmethyl)benzoic acid (268 mg) described in Preparation Example 18 and (piperidin-4-yl)(p-tolyl)methanone hydrochloride (252 mg) and by the reaction and treatment in the same manner as in Example 86, the title compound (235 mg) was obtained.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][OH:5].N1C=CN=C1.[C:11]([Si:15](Cl)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:14])([CH3:13])[CH3:12]>ClCCl>[C:11]([Si:15]([O:5][CH2:4][C@@H:2]1[CH2:3][O:1]1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: OC[C@@H]1CO1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](OC[C@@H]1CO1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99.6 %

Procedure:
To an ice-chilled mixture of (2R)-oxiran-2-ylmethanol (2.00 g, 27.0 mmol) and imidazole (3.68 g, 54.0 mmol) in anhydrous dichloromethane (60 mL) was added tert-butyl(chloro)diphenylsilane (8.40 mL, 32.4 mmol) dropwise, causing the formation of a white precipitate. The mixture was stirred at 0° C. for 15 minutes, then the cooling bath removed and stirring continued at room temperature for one hour. Aqueous ammonium chloride solution (2M, 100 mL) was added and the layers separated. The aqueous layer was extracted with dichloromethane (100 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (eluting with a gradient of 0-30% ethyl acetate in heptane), affording tert-butyl[(2S)-oxiran-2-ylmethoxy]diphenylsilane (296h, 8.40 g, 99% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.65-7.76 (m, 4H), 7.36-7.49 (m, 6H), 3.88 (dd, J=11.86, 3.30 Hz, 1H), 3.74 (dd, J=11.80, 4.71 Hz, 1H), 3.10-3.20 (m, 1H), 2.76 (dd, J=5.14, 4.16 Hz, 1H), 2.63 (dd, J=5.14, 2.69 Hz, 1H), 1.09 (s, 9H). MS: 330 [M+1].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:19][OH:20])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=1.Cl[C:22]1[CH:23]=[C:24]2[N:31](C(OC(C)(C)C)=O)[C:30]([CH3:40])([CH3:39])[CH2:29][N:25]2[C:26](=[O:28])[N:27]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:13][CH:14]=1)[CH2:19][O:20][C:22]1[CH:23]=[C:24]2[NH:31][C:30]([CH3:40])([CH3:39])[CH2:29][N:25]2[C:26](=[O:28])[N:27]=1
Reactant: CC(C)(C)OC(=O)N1c2cc(Cl)nc(=O)n2CC1(C)C
Reactant: OCc1ccc(Oc2ccc(C(F)(F)F)nc2)c(F)c1
Product: CC1(C)Cn2c(cc(OCc3ccc(Oc4ccc(C(F)(F)F)nc4)c(F)c3)nc2=O)N1

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3-fluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol and tert-butyl 7-chloro-2,2-dimethyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: [N:1]([C@H:4]([CH2:28][O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C@H:5]1[O:11][CH:8]([O:9]C)[C@H:7]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:6]1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[N+:2]=[N-:3].FC(F)(F)C(O)=O.O>O1CCCC1>[N:1]([C@H:4]([CH2:28][O:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C@H:5]1[O:11][CH:8]([OH:9])[C@H:7]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C@H:6]1[O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[N+:2]=[N-:3]
Reactant: COC1O[C@H]([C@@H](COCc2ccccc2)N=[N+]=[N-])[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: O
Product: [N-]=[N+]=N[C@H](COCc1ccccc1)[C@H]1OC(O)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: -10 °C
Reaction time: 24 h
Yield: 91.2 %

Procedure:
Methyl 5-azido-2,3,6-tri-O-benzyl-5-deoxy-D-glucofuranoside (10.8 g, 22.2 mmol) was dissolved at room temperature in tetrahydrofuran (20 mL). The solution was cooled at -10° C. and trifluoroacetic acid (120 mL) was added dropwise followed by addition of water (20 mL). The mixture was stirred at 0° C. during 24 h. The mixture was evaporated under reduced pressure without heating. The residue was taken with ether and washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. Flash chromatography on silica gel and elution with a 20:80 mixture of ethyl acetate and hexane afforded 5-azido-2,3,6-tri-O-benzyl-5-deoxy-D-glucofuranose as a colorless oil (9.63 g, 90%).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])=[CH2:2].C(C1C=C(O)C=CC=1)=C.C(C1C=CC(O)=CC=1)=C>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])[CH3:2]
Reactant: C=Cc1ccccc1O
Agent: C=Cc1ccc(O)cc1
Agent: C=Cc1cccc(O)c1
Solvent: Cc1ccccc1
Product: CCc1ccccc1O

Procedure:
As a result, 3.5 liters of a toluene solution containing 1.5 mols of a vinylphenol mixture of 37.0 mol% o-vinylphenol, 24.7 mol% m-vinylphenol, 36.9 mol% p-vinylphenol and 1.4 mol% ethylphenol was obtained as the extract. As the raffinate, 10.4 liters of a toluene solution containing 2.6 mols of an ethylphenol mixture of 9.9 mol% o-ethylphenol, 4.0 mol% m-ethylphenol, 85.1 mol% p-ethylphenol and 1.0 mol% vinylphenol was obtained.
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].[N+:27]([C:30]1[CH:68]=[CH:67][C:33]([CH2:34][O:35][C:36]([N:38]2[CH2:43][CH2:42][CH:41]([C:44]([C:46]3[N:47]=[CH:48][N:49]4[CH:53]=[C:52]([Sn](CCCC)(CCCC)CCCC)[S:51][C:50]=34)=[O:45])[CH2:40][CH2:39]2)=[O:37])=[CH:32][CH:31]=1)([O-:29])=[O:28]>>[OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)=[O:13])=[C:8]([C:52]3[S:51][C:50]4=[C:46]([C:44]([CH:41]5[CH2:40][CH2:39][N:38]([C:36]([O:35][CH2:34][C:33]6[CH:67]=[CH:68][C:30]([N+:27]([O-:29])=[O:28])=[CH:31][CH:32]=6)=[O:37])[CH2:43][CH2:42]5)=[O:45])[N:47]=[CH:48][N:49]4[CH:53]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
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
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)C3CCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)CC3)c2s1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)C5CCN(C(=O)OCc6ccc([N+](=O)[O-])cc6)CC5)c4s3)[C@H](C)[C@H]12
Yield: 59.1 %

Procedure:
4-Nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-[1-(4-nitrobenzyloxycarbonyl)piperidin-4-yl]carbonylimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate (1.16 g) was prepared in the same manner as in step a) of Example 1, except that 938 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 1.91 g of 7-[1-(4-nitrobenzyloxycarbonyl)piperidin-4-yl]carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds.