Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:34])[C@@H:4]([O:6][C:7]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]2[C:8]=1[C:9]([CH3:33])=[C:10]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]3[CH:32]=[CH:31][CH:30]=[N:29]3)=[CH:24][CH:23]=1)[C:11]([CH:18]1[CH2:20][CH2:19]1)=[N:12]2)[CH3:5].[OH-].[Li+].Cl>O1CCCC1.O>[CH:18]1([C:11]2[C:10]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([N:28]4[CH:32]=[CH:31][CH:30]=[N:29]4)=[CH:26][CH:27]=3)=[C:9]([CH3:33])[C:8]3[C:13](=[C:14]([F:17])[CH:15]=[CH:16][C:7]=3[O:6][C@@H:4]([CH3:5])[C:3]([OH:34])=[O:2])[N:12]=2)[CH2:20][CH2:19]1
Reactant: COC(=O)[C@H](C)Oc1ccc(F)c2nc(C3CC3)c(Cc3ccc(-n4cccn4)cc3)c(C)c12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(Cc2ccc(-n3cccn3)cc2)c(C2CC2)nc2c(F)ccc(O[C@@H](C)C(=O)O)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.9 %

Procedure:
A solution of (S)-2-[2-cyclopropyl-8-fluoro-4-methyl-3-(4-pyrazol-1-ylbenzyl)quinolin-5-yloxy]propionic acid methyl ester (0.033 g) in tetrahydrofuran (0.18 mL) and water (0.18 mL) was treated with lithium hydroxide (0.018 g), and the resulting mixture was stirred at room temperature for 4 hours. The mixture was cooled to 0° C., diluted with water (10 mL) and acidified by the addition of 1.0 M aqueous hydrochloric acid. The mixture was extracted with ethyl acetate and the combined extracts were dried over magnesium sulfate and concentrated under reduced pressure to afford title compound as a yellow solid (0.023 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[C:11]#[C:12][Si](C)(C)C)[CH3:2]>CN(C=O)C.[F-].[K+].CCOCC>[CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[C:11]#[CH:12])[CH3:2]
Reactant: CCOC(=O)c1cccnc1C#C[Si](C)(C)C
Agent: [F-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C#Cc1ncccc1C(=O)OCC
Temperature: 25 °C

Procedure:
6.2 g of 2-(2'-trimethylsilylethynyl)-nicotinic acid ethyl ester are dissolved in 50 ml of DMF and 3 g of KF.2H2O are added. After stirring at RT, the reaction mixture is diluted with 300 ml of ether filtered through celite, shaken with 150 ml of water and refiltered. The aqueous phase is extracted four times with 100 ml ether and the combined ether extracts dried over MgSO4, filtered and dried under vacuum. The intermediate can be further purified by chromatography over silica with ethylacetate/hexane.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].COC(N1[C:13](=[O:14])[CH:12]=[CH:11][C:10]1=[O:15])=O.S(=O)(=O)(O)O>C(=O)(O)[O-].[Na+]>[OH:2][CH2:1][CH2:3][N:4]1[C:13](=[O:14])[CH:12]=[CH:11][C:10]1=[O:15]
Reactant: NCCO
Reactant: COC(=O)N1C(=O)C=CC1=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C1C=CC(=O)N1CCO
Temperature: 0 °C
Yield: 96.1 %

Procedure:
As shown in FIG. 1, to a solution of ethanolamine (1.8 g, 29.5 mmol) in saturated sodium bicarbonate solution (100 ml) was added N-methoxycarbonylmaleimide (95 g, 32.3 mmol) in portions with vigorous stirring at 0° C. The mixture was allowed to warm to room temperature and stirred for 1 hour. The pH of the mixture was adjusted to 6-7 by careful addition of concentrated sulfuric acid (5 ml). The resultant solution was freeze dried and the solid residue extracted with ethyl acetate (2×400 ml) by stirring for 30 min. with each extraction. The ethyl acetate extracts were collected by filtration and evaporated in vacuo to afford N-(2-hydroxyethyl)maleimide (formula I) as a white solid (4.0 g, 96% yield); thin layer chromatography (TLC), Rf=0.27, ethyl acetate/petroleum ether 1:1.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:10]1[CH:11]=[N:12][CH:13]=[C:14]([O:16][CH3:17])[CH:15]=1>C(N(CC)CC)C.[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:17][O:16][C:14]1[CH:13]=[N:12][CH:11]=[C:10]([C:8]#[C:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:15]=1
Reactant: COc1cncc(Br)c1
Reactant: C#Cc1ccccc1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COc1cncc(C#Cc2ccccc2)c1
Temperature: 80 °C
Yield: 65.6 %

Procedure:
Add phenylacetylene (0.180 mL, 1.6 mmol), copper (I) iodide (0.029 g, 0.15 mmol) and bis(triphenylphosphine)palladium (II) dichloride (0.053 g, 0.08 mmol) to a solution of 3-bromo-5-methoxypyridine (0.282 g, 1.5 mmol) in degassed triethylamine (8 mL) and heat at 80° C. for 16 h. Cool the reaction mixture to room temperature, filter through diatomaceous earth, wash with ethyl acetate, and concentrate. Purify the residue by silica gel chromatography, eluting with 50:50 to 0:100 hexanes:ethyl acetate to give the title compound (0.206 g, 66%).
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([CH2:28][NH:29][C:30]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=3)=[O:31])[N:27]=2)[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:18][CH:19]1[CH2:20][N:21]([C:23]2[S:24][CH:25]=[C:26]([CH2:28][NH:29][C:30]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=3)=[O:31])[N:27]=2)[CH2:22]1
Reactant: CC(C)(C)[Si](OC1CN(c2nc(CNC(=O)OCc3ccc([N+](=O)[O-])cc3)cs2)C1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(NCc1csc(N2CC(O)C2)n1)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 4.5 h
Yield: 87.1 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-[4-(p-nitrobenzyloxycarbonylaminomethyl)-1,3-thiazol-2-yl]azetidine (867.2 mg, 1.44 mmol) (obtained as described in Reference Example 62(2)) in anhydrous tetrahydrofuran (45 ml) were added acetic acid (0.1 ml, 1.75 mmol) and 1.0 M tetra-n-butylammonium fluoride in tetrahydrofuran (1.72 ml, 1.72 mmol) in an ice bath and the mixture was stirred in an ice bath for 4.5 hours. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate methanol (15:1) as the eluant to afford 3-hydroxy-1-[4-(p-nitrobenzyloxycarbonylaminomethyl)-1,3-thiazol-2-yl]azetidine (457 mg, yield 87%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].[Br:13][C:14]1[C:15](Cl)=[N:16][C:17]([Cl:20])=[N:18][CH:19]=1.C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[Br:13][C:14]1[C:15]([NH:1][C:2]2[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([NH:6][CH3:7])=[O:5])=[N:16][C:17]([Cl:20])=[N:18][CH:19]=1
Reactant: CNC(=O)c1cccc(F)c1N
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Br
Yield: 28.5 %

Procedure:
A solution of 2-amino-3-fluoro-N-methyl-benzamide (625 mg, 3.72 mmol), 5-bromo-2,4-dichloro-pyrimidine (1025 mg, 4.498 mmol), and N,N-diisopropylethylamine (1250 uL, 7.18 mmol) in N-methylpyrrolidinone (10.0 mL) was heated at 100° C. overnight. Solvent was removed by rotary evaporation and the residue was triturated with DCM to afford 2-(5-bromo-2-chloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide as a yellow solid (381 mg, 28%) that had the following properties: 1H-NMR (DMSO-d6, 400 MHz): δ 9.74 (s, 1H), 8.61 (m, 1H), 8.51 (s, 1H), 7.51-7.44 (m, 3H), 2.73 (d, J=4.4, 3H).
Reaction SMILES: [C:1]([O:6][C@@H:7]([C:9]1[NH:14][C:13](=[O:15])[CH:12]=[CH:11][N:10]=1)[CH3:8])(=[O:5])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[C:1]([O:6][C@@H:7]([C:9]1[N:14]=[C:13]([O:15][S:24]([CH3:23])(=[O:26])=[O:25])[CH:12]=[CH:11][N:10]=1)[CH3:8])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)O[C@H](C)c1nccc(=O)[nH]1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)O[C@H](C)c1nccc(OS(C)(=O)=O)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice cold solution of (R)-2-(1-butyryloxy-ethyl)-3H-pyrimidin-4-one (prepared according to the method of Preparation Fourteen, 17.8 g, 97.8 mmol) and triethylamine (9.9 g, 97.8 mmol) in dichloromethane (100 mL) was added methanesulfonyl chloride (11.21 g, 97.8 mmol) dropwise and stirred for 1 h. The mixture was washed successively with saturated aqueous sodium bicarbonate and water, dried over magnesium sulfate and filtered. The filtrate was evaporated to give the title compound as an oil, 24.1 g (94%). 1H NMR (CDCl3, 300 MHz) δ 0.99 (t, 3H), 1.54 (d, 3H), 1.68 (m, 2H), 2.48 (t, 2H), 3.81 (s, 3H), 5.54 (q, 1H), 6.38 (d, 1H), 8.24 (d, 1H); MS (CI) 261 (MH+); [α]D+28.8 (c 1.0, MeOH).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[N:3]=1.[Na].[N:15]12CCN(CC1)C[CH2:16]2.O>CS(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([C:16]#[N:15])[CH:5]=[C:4]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[N:3]=1
Reactant: C1CN2CCN1CC2
Reactant: Nc1nc(Cl)cc(-c2ccco2)n1
Agent: [Na]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1cc(-c2ccco2)nc(N)n1
Temperature: 0 °C
Reaction time: 96 h
Yield: 762.7 %

Procedure:
A solution of 2-amino-4-chloro-6-(2-furyl)pyrimidine (9.78 g, 50.0 mmol) in DMSO (200 mL) was treated with sodium cyamide (14.7 g, 300 mmol) and 1,4-diazabicyclo[2.2.2]octane (DABCO) (0.56 g, 5.0 mmol). The suspension was stirred for 4 days, and more DABCO (5.04 g, 45 mmol) and DMSO (100 mL) were added. The suspension was stirred for a further 2 days, poured onto a mixture of ice (750 g) and water (750 mL), the crude product was filtered off, washed with water and MeCN, and dried in air to give the title compound (7.1 g, 77%) as a brown solid; m.p. 193-194° C.; NMR δH (400 MHz, DMSO) 6.74 (1H, q, J 1.6 Hz), 7.32 (2H, br s), 7.39 (1H, d, J 3.6 Hz), 7.43 (1H, s) and 7.98 (1H, d, J 1.2 Hz); M/Z 187 (M+H)+.
Reaction SMILES: [C:1]([N:5]1[CH:13]=[C:12]2[C:7]([C:8](=[O:26])[NH:9][C:10]3([CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)[CH2:11]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[ClH:27]>C(OCC)(=O)C.O1CCOCC1>[ClH:27].[C:1]([N:5]1[CH:13]=[C:12]2[C:7]([C:8](=[O:26])[NH:9][C:10]3([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH2:11]2)=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)Cc1cn(C(C)(C)C)nc1C(=O)N2
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)n1cc2c(n1)C(=O)NC1(CCNCC1)C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 2′-tert-butyl-7′-oxo-2′,4′,6′,7′-tetrahydrospiro[piperidine-4,5′-pyrazolo[3,4-c]pyridine]-1-carboxylate (70 mg, 0.19 mmol) in ethyl acetate (5 mL) was added 4 M hydrochloric acid in 1,4-dioxane (2 mL) and the mixture was stirred 3 hours at room temperature. The volatiles were removed under reduced pressure and the resultant colorless solid was triturated from heptanes (10 mL) and dried under reduced pressure to yield 2′-tert-butyl-4′,6′-dihydrospiro[piperidine-4,5′-pyrazolo[3,4-c]pyridin]-7′(2′H)-one hydrochloride salt (56 mg) as an off-white solid. +ESI (M+H) 263.1; 1H NMR (500 MHz, DMSO-d6, δ): 8.72 (m, 2H), 7.92 (s, 1H), 7.75 (s, 1H), 3.20 (br. s, 2H), 3.09 (br. s., 2H), 2.78 (s, 2H), 1.79 (m, 4H), 1.48 (s, 9H).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.O[N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[O:25]=[C:16]1[C:17]2[C:18](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](=[O:20])[N:15]1[O:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(ON2C(=O)c3ccccc3C2=O)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 52.5 %

Procedure:
To an ice-cold solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (1.0 g, 5.5 mmol), N-hydroxyphthalimide (0.90 g, 5.5 mmol) and triphenylphosphine (1.4 g, 5.5 mmol) in THF (30 mL) was added a solution of diethyl azodicarboxylate (0.96 mL, 6.1 mmol) in THF (5 mL) dropwise. The stirred reaction mixture was allowed to warm to ambient temperature. After 3 days, most of the THF was removed under reduced pressure. The residue was partitioned between CH2Cl2 (40 mL) and H2O (30 mL). The organic layer was separated and washed with saturated NaCl (20 mL), dried (Na2SO4) and concentrated under reduced pressure. Purification by column chromatography (silica gel, 75:25 hexanes/EtOAc to 50:50 hexanes/EtOAc) gave tert-butyl 3-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]pyrrolidine-1-carboxylate (0.96 g, 52%): 1H NMR (300 MHz, CDCl3) δ1.49 (9H, s), 1.97-2.20 (1H, s), 2.25-2.31 (1H, m), 3.53-3.78 (4H, m), 4.95-5.00 (1H, m), 7.75-7.87 (4H, m).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]3[NH:16][N:17]=[C:18]([O:19][C@@H:20]4[O:46][C@H:45]([CH2:47][O:48][C:49](=[O:54])[C:50]([CH3:53])([CH3:52])[CH3:51])[C@@H:37]([O:38][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])[C@H:29]([O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C@H:21]4[O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:11]=23)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:62](Cl)(=[O:67])[C:63]([CH3:66])([CH3:65])[CH3:64].Cl>ClCCl>[C:23]([O:22][C@@H:21]1[C@@H:29]([O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C@H:37]([O:38][C:39](=[O:44])[C:40]([CH3:41])([CH3:42])[CH3:43])[C@@H:45]([CH2:47][O:48][C:49](=[O:54])[C:50]([CH3:53])([CH3:52])[CH3:51])[O:46][C@H:20]1[O:19][C:18]1[C:11]2[C:12](=[N:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][C:5]2[CH:4]=[CH:3][C:2]([O:1][C:62](=[O:67])[C:63]([CH3:66])([CH3:65])[CH3:64])=[CH:7][CH:6]=2)[NH:16][N:17]=1)(=[O:28])[C:24]([CH3:25])([CH3:26])[CH3:27]
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2n[nH]c3nccc(CCc4ccc(O)cc4)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2n[nH]c3nccc(CCc4ccc(OC(=O)C(C)(C)C)cc4)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-[2-(4-hydroxyphenyl)ethyl]-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazolo[3,4-b]pyridine (1.6 g) in dichloromethane (20 mL) were added triethylamine (0.44 mL) and pivaloyl chloride (0.31 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 0.5 mol/L hydrochloric acid, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=2/1-1/1) to give the title compound (1.76 g).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].C[O-].[Na+:7].CN(C)/[CH:10]=[CH:11]/[C:12](=O)[CH:13]([O:16][CH3:17])[O:14][CH3:15]>CO>[CH3:15][O:14][CH:13]([O:16][CH3:17])[C:12]1[CH:11]=[CH:10][N:4]=[C:2]([S-:3])[N:1]=1.[Na+:7]
Reactant: COC(OC)C(=O)/C=C/N(C)C
Reactant: NC(N)=S
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(OC)c1ccnc([S-])n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of thiourea (64.7 g, 850 mmol, 1.13 equiv.), sodium methanolate (95%, 40.5 g, 751 mmol, 1.0 equiv.) in methanol (500 mL, 1.5 M) was stirred at room temperature for 30 minutes. A solution of (E)-4-(dimethylamino)-1,1-dimethoxybut-3-en-2-one (1) (130 g, 751 mmol) in methanol (200 mL) was added and the reaction stirred at room temperature for 2 h. The crude sodium 4-(dimethoxymethyl)pyrimidine-2-thiolate (2) was used directly in the next step without further purification. LC-MS m/z 209 (M+1). Reference: WO 2006/0097341A1 (incorporated by reference), pg 67.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:19]([NH:21][C@H:22]([C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])[CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])=[O:20])[CH2:3][C:4]1[N:8]=[CH:7][N:6]([S:9]([C:12]2[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=1.S(O)(C1C=CC(C)=CC=1)(=O)=O.O.O>O1CCOCC1>[NH2:1][C@H:2]([C:19]([NH:21][C@H:22]([C:38]([O:40][CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)=[O:39])[CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])=[O:20])[CH2:3][C:4]1[N:8]=[CH:7][N:6]([S:9]([C:12]2[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)n2cnc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCCCNC(=O)OCc3ccccc3)C(=O)OCc3ccccc3)c2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cnc(C[C@H](N)C(=O)N[C@@H](CCCCNC(=O)OCc3ccccc3)C(=O)OCc3ccccc3)c2)cc1
Yield: 86.3 %

Procedure:
5.0 g of Boc-His(Tos)-Lys(Z)-OBzl was added to 9.8 g of TosOH.H2O dissolved in 26 of dioxane, which was then left at room temperature for an hour with occasional shaking. Next, water was added to it and the mixture was extracted with ethyl acetate. The extract was washed with sodium bicarbonate aqueous solution and saturated saline, and dried over sodium sulfate anhydride. Thereafter, the solvent was distilled off to obtain 3.75 g of His(Tos)-Lys(Z)-OBzl as a pale brown oily matter.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:14][CH2:15][C:16](Cl)=[O:17].C([O-])(O)=O.[Na+]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:14][CH2:15][C:16]([O:13][C@@H:8]1[CH2:9][CH2:10][CH2:11][CH2:12][C@H:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:17]
Reactant: O=C(Cl)CCl
Reactant: O[C@@H]1CCCC[C@H]1c1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(CCl)O[C@@H]1CCCC[C@H]1c1ccccc1
Yield: 100.3 %

Procedure:
A mixture of 790 g (4.48 mole) of pure (-)-(1R,2S)-2-phenylcyclohexanol, 1.5 L of methylene chloride, 450 mL (5.625 mole) of chloroacetyl chloride, and 2.2 g (0.96 mole) of 4-dimethylaminopyridine was heated at reflux for 8 hours. On cooling, the reaction mixture was stirred with 2 ×1.5 L=3.0 L of saturated NaHCO3 for 30 minutes. The organic layer was dried (Na2SO4) and evaporated to dryness, finally at 0.5 mm for 4 hours to afford 1.136 kg of the title compound (100%) as an oil.
Reaction SMILES: C([O:3][C:4](=[O:37])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Na+]>C(O)C>[CH:31]1([O:30][C:27]2[CH:26]=[CH:25][C:24]([C:20]3[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]4[CH:11]=[CH:10][C:9]([O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:37])=[O:3])=[CH:14][CH:13]=4)[N:19]=3)=[CH:29][CH:28]=2)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(OC4CCCCC4)cc3)oc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1oc(-c2ccc(OC3CCCCC3)cc2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1
Yield: 95 %

Procedure:
A solution of 2-(4-{2-[2-(4-cyclohexyloxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid ethyl ester (0.339 g, 0.667 mmol) in ethanol (40 mL) was treated with 5 N NaOH (0.8 mL) and the reaction heated to reflux for 1 h. The reaction mixture was cooled and the solvent removed in vacuo. The resultant oil was acidified with 1 N HCl and extracted with EtOAc and water. The organic layer was dried (MgSO4) and the solvent removed in vacuo to afford 0.304 g (95%) of 2-(4-{2-[2-(4-cyclohexyloxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid. 1H NMR (500 MHz, CDCl3) δ 7.94-7.85 (m, 2H), 6.89-6.73 (m, 4H), 6.71 (d, 2H, J=9.28 Hz), 4.30-4.23 (m, 1H), 4.14-4.05 (m, 2H), 2.95-2.85 (m, 2H), 2.29 (s, 3H), 1.98-1.85 (m, 2H), 1.80-1.75 (m, 2H), 1.58-1.40 (m, 8H), 1.38-1.20 (m, 4H); HRMS (ES+) m/z exact mass calcd for C28H34NO6 480.2386, found 480.2381 The following compound was prepared using tetrahydro-2H-pyran-4-ol:
Reaction SMILES: C([O:5][C:6]([CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[N:19]=[C:18]([C:32]#[N:33])[N:17]=2)[CH2:12][CH2:11]1)=[O:7])(C)(C)C.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>ClCCl>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[C:6]([CH2:8][CH2:9][N:10]1[CH2:11][CH2:12][N:13]([C:16]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:29])[F:31])[CH:23]=3)[N:19]=[C:18]([C:32]#[N:33])[N:17]=2)[CH2:14][CH2:15]1)([OH:7])=[O:5]
Reactant: CC(C)(C)OC(=O)CCN1CCN(c2cc(-c3cccc(C(F)(F)F)c3)nc(C#N)n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1nc(-c2cccc(C(F)(F)F)c2)cc(N2CCN(CCC(=O)O)CC2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirring solution of the compound of Example 4 (22 mg) in dichloromethane (2 ml) was added trifluoroacetic acid (1 ml). The resulting solution was stirred at room temperature for 1 hr before concentrating in vacuo. The residue was then purified using preparative HPLC to give 4-[4-(2-carboxy-ethyl)-piperazin-1-yl]-6-(3-trifluoromethyl-phenyl)-pyrimidine-2-carbonitrile trifluoroacetic acid salt as a white solid (8.5 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[NH2:15])[O:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[C:16](OCC)(=O)[CH:17]=[O:18]>C1(C)C=CC=CC=1>[O:18]=[C:17]1[CH:16]=[N:1][C:2]2[C:14](=[CH:13][CH:12]=[C:4]([O:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:3]=2)[NH:15]1
Reactant: CCOC(=O)COc1ccc(N)c(N)c1
Reactant: CCOC(=O)C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)COc1ccc2[nH]c(=O)cnc2c1
Temperature: 90 °C
Yield: 71.7 %

Procedure:
To a solution of ethyl 2-(3,4-diaminophenoxy)acetate (1.3 g, 6.18 mmol) in toluene (10 mL) was added ethyl glyoxalate solution (2.52 mL, 12.37 mmol) and the reaction mixture was heated at 90° C. for 4 h. The reaction was cooled to room temperature. The solid was filtered, washed with diethyl ether (10 mL) and dried to yield ethyl 2-((2-oxo-1,2-dihydroquinoxalin-6-yl)oxy)acetate (1.1 g, 68%). LCMS: RT 1.18 min. LCMS (ES-API), m/z 247(−ve mode).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][C:5]1[N:6]=[CH:7][N:8]2[CH:12]=[C:11]([C:13]3[C@H:14]([CH3:27])[C@@H:15]4[C@@H:22]([C@H:23]([OH:25])[CH3:24])[C:21](=[O:26])[N:16]4[C:17]=3[C:18]([O-:20])=[O:19])[S:10][C:9]=12.[Na+:28].Cl.C(O[CH:33]=[NH:34])C.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH:33]([NH:1][CH2:2][CH2:3][S:4][C:5]1[N:6]=[CH:7][N:8]2[CH:12]=[C:11]([C:13]3[C@H:14]([CH3:27])[C@@H:15]4[C@@H:22]([C@H:23]([OH:25])[CH3:24])[C:21](=[O:26])[N:16]4[C:17]=3[C:18]([O-:20])=[O:19])[S:10][C:9]=12)=[NH:34].[Na+:28]
Reactant: CCOC=N
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3cn4cnc(SCCN)c4s3)[C@H](C)[C@H]12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3cn4cnc(SCCNC=N)c4s3)[C@H](C)[C@H]12
Reaction time: 1 h

Procedure:
Sodium (1S,5R,6S)-2-[7-(2-aminoethyl)thioimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (45.7 mg) was suspended in 3 ml of water under ice cooling. Ethylformimidate hydrochloride (46 mg) was added to the suspension. While adjusting the mixture to pH 8 to 9 by the addition of an aqueous sodium carbonate solution, the mixture was stirred at that temperature for one hr, and then at room temperature for 1.5 hr. The reaction product was then purified by column chromatography on Cosmosil 40C18-PREP (a 20% aqueous methanol solution) to prepare 5.4 mg of the title compound.