Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:13]([Cl:14])=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[C:6]([OH:15])[CH:5]=1.Cl[CH2:17][C:18]1[N:19]=[C:20]([CH3:23])[S:21][CH:22]=1.O>CN(C)C=O>[NH2:3][C:4]1[C:13]([Cl:14])=[CH:12][C:7]([C:8]([OH:10])=[O:9])=[C:6]([O:15][CH2:17][C:18]2[N:19]=[C:20]([CH3:23])[S:21][CH:22]=2)[CH:5]=1
Reactant: COC(=O)c1cc(Cl)c(N)cc1O
Reactant: Cc1nc(CCl)cs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(COc2cc(N)c(Cl)cc2C(=O)O)cs1
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
A suspension of 60% sodium hydride/oil dispersion (0.5 g, 12.5 mmoles) in anhydrous dimethylformamide (20 ml) under nitrogen was treated with methyl 4-amino-5-chloro-2-hydroxybenzoate (2.02 g, 10 mmoles), stirred for 30 minutes, then treated with 4-chloromethyl-2-methylthiazole (1.85 g, 12.5 mmoles). The mixture was heated to 95°±5° C. for 1.5 hours, then cooled and added to water (150 ml). The aqueous mixture was extracted with ether (2×100 ml), and the combined ethereal solution was dried (MgSO4), concentrated in vacuo, and taken up in 95% ethanol (20 ml). Water (10 ml) and 50% sodium hydroxide (10 ml) were added, and the mixture was refluxed for one hour, cooled in on ice, and concentrated in vacuo to remove most of the ethanol. Water was added to a total volume of 100 ml, and the aqueous solution was extracted with ether (2×50 ml), cooled in an ice bath, and adjusted to pH 4 with concentrated hydrochloric acid (16 ml). A resultant precipitate was filtered, washed with water, air dried, and recrystallized from 95% ethanol to yield 1.96 g (64%) of tan crystals, mp 188°-189° C.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.P(=O)(O)(O)O.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:28][CH2:29][C:30]([NH2:32])=[O:31])[CH:25]=[CH:26][CH:27]=1.[CH:33](=O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>O.C(O)(=O)C>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]2[CH:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[NH:32][C:30](=[O:31])[CH2:29][CH2:28][C:24]=2[CH:23]=1
Reactant: O=Cc1ccccc1
Reactant: COc1cccc(CCC(N)=O)c1
Agent: O=P(O)(O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2c(c1)CCC(=O)NC2c1ccccc1
Temperature: 170 °C
Yield: 11 %

Procedure:
To a mixture of 73 g. of phosphorus pentoxide and 43.5 ml. of 85% phosphoric acid, rendered homogeneous by heating at 170° C., is added at room temperature a solution of 9.0 g. (0.05 moles) of 3-(3-methoxyphenyl)-propionamide and 5.9 g. (0.055 moles) of benzaldehyde in 104 ml. of glacial acetic acid. Stirring under an atmosphere of nitrogen is maintained for 3 days and then the reaction mixture is poured into 1 liter water; a precipitate appears, which is filtered off, washed neutral with water and dried. After separation by chromatography and recrystallization from ethanol, 1.5 g. (11% of theory) of pure 7-methoxy-1-phenyl-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one is obtained. M.P. 185-186° C.
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.CC1C=CC(S(O[CH2:22][C@@H:23]([CH2:34][O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C@H:24]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH3:25])(=O)=O)=CC=1>CN(C=O)C>[CH2:36]([O:35][CH2:34][C@@H:23]([CH2:22][N:5]1[CH:6]=[N:7][C:8]2[C:4]1=[N:3][CH:2]=[N:1][C:9]=2[NH2:10])[C@H:24]([O:26][Si:27]([C:30]([CH3:31])([CH3:33])[CH3:32])([CH3:28])[CH3:29])[CH3:25])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](COCc2ccccc2)[C@@H](C)O[Si](C)(C)C(C)(C)C)cc1
Reactant: Nc1ncnc2nc[nH]c12
Solvent: CN(C)C=O
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](COCc1ccccc1)Cn1cnc2c(N)ncnc21
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 36.7 %

Procedure:
To a suspension of adenine (1.22 g, 9.1 mmol) in 25 ml of anhydrous DMF was added 2.96 g of Ce2CO3 (hydrate) and the mixture was stirred at 100° C. for 15 min. A solution of 9 (2.9 g, ˜7.4 mmol) in 20 ml of DMF was added in one portion. The reaction was stirred at 100° C. for 4 hrs until no starting material was found by HPLC, then cooled and filtered to remove unreacted adenine and cesium salts. The filtrate was concentrated, re-dissolved in ethyl acetate, washed with water, saturated NaCl and dried under Na2SO4. The crude product obtained after solvent evaporation was chromatographed on silica eluting with a gradient of acetone (20-35%) in ethyl acetate. Concentration of the pure product fractions and drying in vacuo afforded 1.2 g (37%) of 10 as a pale yellow viscous syrup. 1H NMR (CDCl3): δ 8.32 (s, 1H), 7.70 (s, 1H), 7.24 (m, 5H), 5.64 (s, 2H), 4.38 (m, 1H), 4.34 (d, 8.1 Hz, 2H), 4.16 (m, 1H), 4.02 (m, 1H), 3.32 (m, 2H), 2.23 (m, 1H), 1.14 (d, J=6.3 Hz, 3H), 0.85 (s, 9H), 0.015 (s, 3H), 0.00 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:32])[C:5]([CH3:31])=[C:6]([CH2:12][C:13]2[C:14]([O:27]C(=O)C)=[C:15]([CH:24]=[CH:25][CH:26]=2)[C:16]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:4](=[O:32])[C:5]([CH3:31])=[C:6]([CH2:12][C:13]2[C:14]([OH:27])=[C:15]([CH:24]=[CH:25][CH:26]=2)[C:16]([N:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)=[O:17])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)N3CCCCC3)c2OC(C)=O)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)N3CCCCC3)c2O)=C(C)C1=O
Yield: 37.7 %

Procedure:
N-[3-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]piperidine (0.050 g, 0.113 mmol) was dissolved in methanol (3 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=9:1) to obtain the titled compound (0.017 g, 0.0426 mmol, 38%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:30][CH3:31])=[C:8]([S:10]([C:13]2[CH:18]=[C:17]([N+:19]([O-])=O)[C:16]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:15]([Br:29])[CH:14]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4].[CH3:32]COC(C)=O>CCO.CC(O)=O.[Fe]>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:30][CH3:31])=[C:8]([S:10]([C:13]2[CH:14]=[C:15]([Br:29])[C:16]3[N:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:32]=[N:19][C:17]=3[CH:18]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(S(=O)(=O)c2cc(Br)c(Nc3ccccc3)c([N+](=O)[O-])c2)c(SC)s1
Reactant: CCOC(C)=O
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)c1cc(S(=O)(=O)c2cc(Br)c3c(c2)ncn3-c2ccccc2)c(SC)s1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Iron powder (110 mg, 2 mmol) was added to a solution of 4-(3-bromo-5-nitro-4-phenylamino-benzenesulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester (Example 318: step d) in EtOH (4 mL) and 50% aqueous AcOH (1 mL). The reaction was stirred for 30 min at 60° C. during which a new lower spot became evident by TLC analysis. EtOAc (10 mL) was added and the mixture was filtered through a 0.22 μm polypropylene syringe filter. Additional EtOAc (30 mL) was added and the solution was extracted with aq NaHCO3 (3×10 mL) and brine (20 mL). The solution was dried and concentrated in vacuo. One-half of the residue (26 mg) was suspended in formic acid (3 mL) and was heated at 95° C. for 4 h. The formic acid was removed in vacuo and the residue was purified by chromatography to yield the product (23 mg). 1H-NMR (CDCl3): δ 8.56 (d, 1H, J=1.6 Hz), 8.13 (s, 1H), 8.07 (d, 1H, J=1.6 Hz), 8.04 (s, 1H), 7.55 (m, 3H, 7.41 (m, 2H), 3.87 (s, 3H), 2.61 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[C:8]([CH:10]([OH:12])[CH3:11])[C:7]([O:13][CH2:14][C:15]23[CH2:24][CH:19]4[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]4)[CH2:16]2)[CH2:22]3)=[CH:6][C:5]=1[F:25].N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])(=O)=O>ClCCl>[C:15]12([CH2:14][O:13][C:7]3[C:8]([CH:10]([O:12][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[CH3:11])=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:26])=[C:5]([F:25])[CH:6]=3)[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH2:16]1)[CH2:22]2
Reactant: COC(=O)c1cc(C(C)O)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COC(=O)c1cc(C(C)O[Si](C)(C)C(C)(C)C)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl-4-(adamantan-1-ylmethoxy)-2-fluoro-5-(1-hydroxyethyl)benzoate (0.26 g, 0.72 mmol) and 2,6-lutidine (0.17 mL, 1.44 mmol) in anhydrous dichloromethane (5 mL) was added tert-butyldimethylsilyl trifluoromethanesulfonate (0.285 g, 1.08 mmol) at 0° C. The reaction mixture was allowed to warm to ambient temperature and stirred for 1 hour. After dilution with dichloromethane (100 mL), the organic phase was washed with 1 N hydrochloric acid (2×5 mL), brine (10 mL), and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate in vacuo afforded methyl 4-(adamantan-1-ylmethoxy)-5-(1-((tert-butyldimethylsilyl)- oxy)ethyl)-2-fluorobenzoate as a yellowish oil (0.35 g, quant.), which was used without further purification.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH2:7]([O:14][C:15]([NH:17][C@@:18]1([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:23][C:22](=O)[C@@H:21]2[C@H:19]1[C@H:20]2[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.C(OCC)(=O)C>[CH2:7]([O:14][C:15]([NH:17][C@@:18]1([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:23][C:22](=[CH2:1])[C@@H:21]2[C@H:19]1[C@H:20]2[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)[C@H]1[C@@H]2C(=O)C[C@@](NC(=O)OCc3ccccc3)(C(=O)OCC)[C@@H]21
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=C1C[C@@](NC(=O)OCc2ccccc2)(C(=O)OCC)[C@H]2[C@@H]1[C@@H]2C(=O)OCC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under a nitrogen atmosphere, combine methyl-triphenylphosphonium bromide (67.4 g, 184.9 mmol) and tetrahydrofuran (300 mL) with agitation. Add a solution of potassium tert-butoxide (1M) in tetrahydrofuran, 184.9 mL, 184.9 mmol) to the reaction mixture over 15 minutes and stir the resulting slurry at ambient temperature for 3 hours. Dissolve diethyl (1S,2S,5R,6R)-2-benzyloxycarbonylamino-4-oxo-bicyclo[3.1.0]hexane-2,6-dicarboxylate (12.3 kg, 31.6 mol) in tetrahydrofuran (120 mL) and add to the reaction mixture over 1 hour, maintaining the reaction temperature below 30° C. Stir the resulting slurry overnight at ambient temperature, then dilute with ethyl acetate (600 mL) and quench with water (300 mL). After stirring the biphasic mixture for 30 minutes, separate the layers and wash the organics with water (300 mL) followed by 0.25M HCl (300 mL). Dry the organics over Na2SO4, filter, and concentrate in vacuo (45° C.) to afford the crude product as a dark oil (111.0 g). Purify the material by silica gel plug chromatography (1 Kg Kieselgel-60, 4 L 15% EtOAc in heptanes, then 10 L 30% EtOAc in heptanes) to afford the title compound as a clear oil (37.3 g, 87.9% potency, 54.9%). MS (m/z): 388 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH2:7].C([Mg]Cl)(C)C.[CH3:13][C@@:14]1([C:26](OC)=[O:27])[CH2:18][CH2:17][CH2:16][N:15]1C(OC(C)(C)C)=O>C1COCC1>[CH3:13][C@@:14]1([C:26]([NH:7][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)=[O:27])[CH2:18][CH2:17][CH2:16][NH:15]1
Reactant: Nc1cnccn1
Reactant: COC(=O)[C@]1(C)CCCN1C(=O)OC(C)(C)C
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: C[C@@]1(C(=O)Nc2cnccn2)CCCN1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of pyrazin-2-amine (1.56 g, 16.44 mmol) in THF (30 ml) was added isopropyl magnesium chloride (7.8 ml, 15.62 mmol) (2.0 M THF solution) dropwise at 0° C. under nitrogen. The resulting suspension was stirred at RT for 30 min. A solution of (S)-1-tert-butyl 2-methyl 2-methylpyrrolidine-1,2-dicarboxylate (1.0 g, 4.11 mmol) solid was added to the reaction mixture. The reaction mixture was stirred at RT for 6 h, quenched with MeOH, and concentrated. The residue was dissolved in EtOAc (120 ml) and washed with 1N HCl to remove the excess pyrazin-2-amine, water, and brine, dried over Na2SO4. The crude product was dissolved in methanol and 4N HCl in dioxane (4 mL) was added. The reaction mixture was stirred at room temperature overnight and the crude product was used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH:16]1([N:19]2[CH:24]=[C:23]([CH:25]=[CH2:26])[CH:22]=[CH:21][C:20]2=[O:27])[CH2:18][CH2:17]1.[OH-].[K+]>CN1C(=O)CCC1>[CH:16]1([N:19]2[CH:24]=[C:23]([CH2:25][CH2:26][N:6]3[C:7]4[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=4[C:4]4[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]3=4)[CH:22]=[CH:21][C:20]2=[O:27])[CH2:18][CH2:17]1
Reactant: C=Cc1ccc(=O)n(C2CC2)c1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(=O)n(C3CC3)c2)CCN(C)C1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole, 1-cyclopropyl-5-vinylpyridin-2(1H)-one and KOH (5-7 equiv) in NMP, at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:23][C:8]2[C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([NH:16][CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)[C:14]=3[S:15][C:7]=2[C:6]=1[O:24][CH2:25][C:26]([O:28]CC)=[O:27])=[O:4].[Li+].[OH-]>C1COCC1.O>[C:26]([CH2:25][O:24][C:6]1[C:7]2[S:15][C:14]3[C:13]([NH:16][CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)=[CH:12][CH:11]=[CH:10][C:9]=3[C:8]=2[S:23][C:5]=1[C:3]([OH:4])=[O:2])([OH:28])=[O:27]
Reactant: CCOC(=O)COc1c(C(=O)OC)sc2c1sc1c(NC3CCCCC3)cccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)COc1c(C(=O)O)sc2c1sc1c(NC3CCCCC3)cccc12
Temperature: 25 °C

Procedure:
Step C Hydrolysis: To a solution of 7-Cyclohexylamino-1-ethoxycarbonylmethoxy-3,8-dithia-cyclopenta[a]indene-2-carboxylic acid methyl ester (30 mg, 0.07 mmol) in THF/H2O (1.5 mL/0.5 mL) was added 2.0M LiOH (0.15 mL, 0.35 mmol). The reaction was allowed to stir at ambient temperature over a 16-hour period, after which it was judged complete by LCMS. The THF was removed in vacuo and the resultant aqueous solution was acidified to pH ˜1-2 using 10% HCl to precipitate the desired compound which was filtered, rinsed with water, and oven-dried (55° C.). No purification was necessary. (Yield=20 mg, 71%)
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:27][S:26][C@@H:9]2[C@H:10]([NH:13][C:14](/[C:16](/[C:20]3[N:24]=[C:23]([NH2:25])[S:22][CH:21]=3)=[N:17]\[O:18][CH3:19])=[O:15])[C:11](=[O:12])[N:8]2[C:7]=1[C:28]([OH:30])=[O:29])=O.[Na].[CH3:32][C:33]([C:36]1[CH:41]=[CH:40][C:39]([C:42]2[S:46][N:45]=[N:44][C:43]=2[SH:47])=[CH:38][CH:37]=1)([CH3:35])[CH3:34].[K]>O>[NH2:25][C:23]1[S:22][CH:21]=[C:20](/[C:16](=[N:17]/[O:18][CH3:19])/[C:14]([NH:13][CH:10]2[C:11](=[O:12])[N:8]3[CH:9]2[S:26][CH2:27][C:6]([CH2:5][S:47][C:43]2[N:44]=[N:45][S:46][C:42]=2[C:39]2[CH:40]=[CH:41][C:36]([C:33]([CH3:35])([CH3:34])[CH3:32])=[CH:37][CH:38]=2)=[C:7]3[C:28]([OH:30])=[O:29])=[O:15])[N:24]=1
Reactant: CC(C)(C)c1ccc(-c2snnc2S)cc1
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1csc(N)n1
Agent: [K]
Agent: [Na]
Solvent: O
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnsc3-c3ccc(C(C)(C)C)cc3)CSC12)c1csc(N)n1
Temperature: 70 °C
Yield: 12.1 %

Procedure:
A mixture of 0.5 g of Cefotaxime, sodium salt, 0.4 g of 5-[4-(1,1-dimethylethyl)phenyl]-1,2,3-thiadiazole-4-thiol, potassium salt and 16 ml of water was heated at 70° C. for 5.5 hours with pH adjustment to 6.8-7.2, then cooled and filtered. The filtrate was adjusted to pH 5 and extracted with 30 ml of ethyl acetate. The aqueous remainder was filtered through diatomaceous earth and adjusted to pH 2.5 with 2N hydrochloric acid. The resulting solid was collected, washed with water and dried, giving 86 mg of the desired product as a light orange solid [α]D26 =-10°+2 (0.885 DMSO): IR(KBr) 1770 cm-1 (β-lactam --C=O).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([CH2:23][N:24]([CH2:26][C:27]([OH:29])=O)[CH3:25])[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[CH3:31][NH2:32]>>[CH:12]1([CH2:11][CH2:10][CH2:9][C@@H:8]([C:18]2[O:22][N:21]=[C:20]([CH2:23][N:24]([CH3:25])[CH2:26][C:27]([NH:32][CH3:31])=[O:29])[N:19]=2)[CH2:7][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: CN
Reactant: CN(CC(=O)O)Cc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Product: CNC(=O)CN(C)Cc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1

Procedure:
Method as for preparation 56 using [({5-[(1R)-1-(2-tert-butoxy-2-oxoethyl)-4-cyclohexylbutyl]-1,2,4-oxadiazol-3-yl}methyl)(methyl)amino]acetic acid (preparation 133) (618 mg, 1.46 mmol) and methylamine (2M in THF) (1.4 ml, 2.80 mmol) as starting materials.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][C:3]=1[C:4](=[N:6][OH:7])Cl.[CH2:13]([O:15][C:16](=[O:20])[C:17]#[C:18][CH3:19])[CH3:14].CCN(CC)CC>CCOCC>[CH2:13]([O:15][C:16]([C:17]1[C:4]([C:3]2[CH:8]=[C:9]([I:12])[CH:10]=[CH:11][C:2]=2[F:1])=[N:6][O:7][C:18]=1[CH3:19])=[O:20])[CH3:14]
Reactant: ON=C(Cl)c1cc(I)ccc1F
Reactant: CC#CC(=O)OCC
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)c1c(-c2cc(I)ccc2F)noc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.4 %

Procedure:
To a solution of 2-fluoro-5-iodobenzoyl chloride oxime (2.24 g, 7.48 mmol) and ethyl-2-butynoate (1.74 ml, 14.96 mmol, 2 eq.) in Et2O (28 ml) under N2 stirring at 0-5° C., was added dropwise a solution of Et3N (1.35 ml, 9.72 mmol, 1.3 eq) in Et2O (3.6 ml) over 1 h. Reaction was allowed to warm to room temperature and stirred overnight. It was then partitioned between Et2O and H2O, washed with brine, dried (MgSO4), filtered, and concentrated. The crude residue was chromatographed on silica gel using (1-10%) ethyl acetate in hexanes to give the title compound (2.06 g, 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]4[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=4)[N:13]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:34][C@H:35]1[CH2:39][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C@H:37]([C:47]([O:49][CH3:50])=[O:48])[CH2:36]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:21])([F:23])[F:22])[N:15]=[C:14]([NH:24][C:25]4[CH:26]=[CH:27][C:28]([C:29]([NH:34][C@@H:35]5[CH2:39][N:38]([C:40]([O:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[O:41])[C@@H:37]([C:47]([O:49][CH3:50])=[O:48])[CH2:36]5)=[O:30])=[CH:32][CH:33]=4)[N:13]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H]1C[C@@H](N)CN1C(=O)OC(C)(C)C
Reactant: O=C(O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H]1C[C@H](NC(=O)c2ccc(Nc3nc(NC4(c5ccc(Cl)cc5)CC4)nc(OCC(F)(F)F)n3)cc2)CN1C(=O)OC(C)(C)C
Yield: 84.9 %

Procedure:
4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (400 mg, 0.834 mmol), (2S,4R)-1-tert-butyl 2-methyl 4-aminopyrrolidine-1,2-dicarboxylate (224 mg, 0.917 mmol), PyBOP (651 mg, 1.250 mmol), and Hunig's Base (0.728 mL, 4.17 mmol) were stirred in DCM (Volume: 10 mL) for 3 days. The solvent was removed and the crude material was purified by silica gel chromatography using 60% EtOAc/hexanes to give (2R,4S)-1-tert-butyl 2-methyl 4-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)pyrrolidine-1,2-dicarboxylate (500 mg). 1H NMR (400 MHz, MeOD) δ ppm 1.33-1.41 (m, 4H), 1.43 (s, 9H), 2.25-2.48 (m, 2H), 3.39-3.47 (m, 1H), 3.78 (s, 3H), 3.81-3.90 (m, 1H), 4.46 (td, J=7.7, 4.8 Hz, 1H), 4.64 (qd, J=5.8, 5.6 Hz, 1H), 4.85-4.93 (m, 2H), 7.20-7.32 (m, 4H), 7.58-7.71 (m, 3H), 7.76-7.92 (m, 1H); LC-MS (Condition A), MS m/z (M++H) 706.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)Br.CCN(CC)CC.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>O1CCCC1>[CH3:1][O:2][C:3](=[O:12])[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[N:29]1[CH2:30][CH2:31][N:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=2)[CH2:27][CH2:28]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: COC(=O)C(Br)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)C(c1ccccc1)N1CCN(c2ccccn2)CC1
Temperature: 25 °C

Procedure:
To a solution of racemic α-bromophenylacetic acid methyl ester, 5.0 g (22.0 mmol) in 200 mL of tetrahydrofuran was added 3.4 mL (22.0 mmol) of Et3N and 10 mL (66.0 mmol) of 1-(2-pyridyl)-piperazine. The reaction mixture was refluxed for five hours, cooled to rt. and concentrated to dryness. The residue was partitioned between 20% isopropanol/chloroform and water. The mixture was washed with saturated NaHCO3, washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by column chromatography using MeOH/chloroform as eluant and concentrated to dryness to give a quantitative yield of the desired mixture of isomers as a yellow oil. MS (ion spray) 312.2 (M+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20]1)[N:13]=2)[CH:5]=O.C(O)(=O)C.[N+:32]([CH3:35])([O-:34])=[O:33].C([O-])(=O)C.[NH4+]>O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:35][N+:32]([O-:34])=[O:33])[CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:20][CH2:21]1)[N:13]=2
Reactant: O=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])C=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzaldehyde (1.42 g, 3.79 mmol) was added acetic acid (12.6 mL), nitromethane (1.44 mL, 26.5 mmol), and ammonium acetate (0.731 g, 9.48 mmol) before it was stirred at 100° C. for 4 h. The reaction mixture was cooled to ambient temperature. The product crashed out with water, and was filtered, washed with water, and dried in a vacuum oven to give 2-(2-fluoro-4-(2-nitrovinyl)phenyl)-5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine. MS (ESI) m/z: Calculated: 417.1; Observed: 418.4 (M++H).
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10](Cl)[C:5]2=[N:4][CH:3]=1.[CH:12]([NH2:15])([CH3:14])[CH3:13]>>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10]([NH:15][CH:12]([CH3:14])[CH3:13])[C:5]2=[N:4][CH:3]=1
Reactant: CC(C)N
Reactant: Clc1nccn2c(Br)cnc12
Product: CC(C)Nc1nccn2c(Br)cnc12

Procedure:
(3-Bromo-imidazo[1,2-a]pyrazin-8-yl)-isopropyl-amine was prepared by a process analogous to that described in Example 2 starting from 3-bromo-8-chloro-imidazo[1,2-a]pyrazine and isopropylamine.