Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[C:6]([O:10][CH2:11][CH2:12]Cl)=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[F:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:24][CH2:25][CH2:26][NH2:27].O>CS(C)=O>[O:1]1[C:5]2[C:6]([O:10][CH2:11][CH2:12][NH:27][CH2:26][CH2:25][CH2:24][C:18]3[C:17]4[C:21](=[CH:22][CH:23]=[C:15]([F:14])[CH:16]=4)[NH:20][CH:19]=3)=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: ClCCOc1cccc2c1OCC2
Reactant: NCCCc1c[nH]c2ccc(F)cc12
Solvent: CS(C)=O
Solvent: O
Product: Fc1ccc2[nH]cc(CCCNCCOc3cccc4c3OCC4)c2c1
Temperature: 90 °C
Reaction time: 12 h
Yield: 77.2 %

Procedure:
A solution of 2-(2,3-dihydrobenzofuran-7-yloxy)ethylchloride (0.38 g, 1.9 mmol), 3-(5-fluoro-1H-indol-3-yl)propylamine (0.93 g, 4.8 mmol), triethylamnine (0.48 g, 4.8 mmol) in anhydrous DMSO (20 ml) was allowed to stir at 90° C. for 12 hours. The mixture was poured into water (100 ml) and extracted with methylene chloride (3×100 ml). The organic layer was washed with water (3×150 ml), dried over anhydrous sodium sulfate, filtered and the solvent was removed under vacuum. Chromatography (10% methanol-methylene chloride plus ammonium hydroxide) afforded 0.52 g (77%) of product as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:18]([C:19]2[S:23][C:22]([C:24]3[N:25]([CH3:29])[N:26]=[CH:27][N:28]=3)=[N:21][CH:20]=2)=[C:5]2[N:6]=[C:7]([CH3:17])[CH:8]=[C:9]([CH:10]([CH2:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13])[N:4]2[N:3]=1.[Br:30]N1C(=O)CCC1=O>C(#N)C>[Br:30][C:20]1[N:21]=[C:22]([C:24]2[N:25]([CH3:29])[N:26]=[CH:27][N:28]=2)[S:23][C:19]=1[C:18]1[C:2]([CH3:1])=[N:3][N:4]2[C:9]([CH:10]([CH2:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13])=[CH:8][C:7]([CH3:17])=[N:6][C:5]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCC(CCC)c1cc(C)nc2c(-c3cnc(-c4ncnn4C)s3)c(C)nn12
Solvent: CC#N
Product: CCCC(CCC)c1cc(C)nc2c(-c3sc(-c4ncnn4C)nc3Br)c(C)nn12
Temperature: 22 °C
Reaction time: 10 h
Yield: 76.9 %

Procedure:
To a solution of 2,5-dimethyl-3-[2-(2-methyl-2H-[1,2,4]triazol-3-yl)-thiazol-5-yl]-7-(1-propyl-butyl)-pyrazolo[1,5-a]pyrimidine (6 g, 14.65 mmol) in acetonitrile (60 mL) add N-bromosuccinimide (2.74 g, 15.4 mmol) in one portion and stir at 22° C. for 10 h. Evaporate the solvent and dissolve the residue in a mixture of water (50 mL) and methyl-t-butyl ether (100 mL). Separate the organic layer and extract the aqueous layer with additional methyl-t-butyl ether (2×50 mL). Combine the organic portions and evaporate the solvent. Purify the resulting material by filtration through a silica gel pad, eluting with hexanes/ethyl acetate (3/1). Combine the product containing fractions and evaporate the solvent. Add heptanes (25 mL) and triturate the solid. Filter the solid and dry under vacuum to afford the title compound (5.5 g, 77%). ES/MS m/z (79Br/81Br) 488/490 (M+1)+.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:21](=O)[CH3:22])=[C:6]([CH3:20])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[C:12]([Cl:19])[CH:11]=2)[C:8]=1[CH3:9])(=O)[CH3:2].[NH2:24][NH2:25]>>[Cl:19][C:12]1[CH:11]=[C:10]([N:7]2[C:8]([CH3:9])=[C:4]3[C:5]([C:21]([CH3:22])=[N:24][N:25]=[C:1]3[CH3:2])=[C:6]2[CH3:20])[CH:15]=[CH:14][C:13]=1[O:16][CH2:17][CH3:18]
Reactant: CCOc1ccc(-n2c(C)c(C(C)=O)c(C(C)=O)c2C)cc1Cl
Reactant: NN
Product: CCOc1ccc(-n2c(C)c3c(C)nnc(C)c3c2C)cc1Cl

Procedure:
Utilizing the general procedure outlined in Example 48, 1-[4-acetyl-1-(3-chloro-4-ethoxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone and hydrazine reacted to give 6-(3-Chloro-4-ethoxy-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine as yellow solid: 1H NMR (CD3OD, 500 MHz) δ 7.47 (s, 1H), 7.32 (d, 1H), 7.25 (d, 1H), 4.27 (q, 2H), 2.79 (s, 6H), 2.48 (s, 6H), 1.53 (t, 3H); MS (ESI) 330 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[Cl:11][C:12]1[N:17]=[C:16](Cl)[CH:15]=[C:14]([Cl:19])[N:13]=1.C([O-])(=O)C.[Na+]>O.C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:16]2[CH:15]=[C:14]([Cl:19])[N:13]=[C:12]([Cl:11])[N:17]=2)[NH2:10])=[CH:5][CH:4]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: COc1ccc(NN)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(N(N)c2cc(Cl)nc(Cl)n2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of p-methoxyphenylhydrazine (59 g.), 2,4,6-trichloropyrimidine (78.5 g.), and a solution of anhydrous sodium acetate (63 g.) in a mixture of water (260 ml.) and ethanol (1200 ml.) was shaken at room temperature for 2 hours. The crystalline precipitate which had formed was collected by filtration, washed with ethanol (50 ml.) and recrystallised from a mixture of chloroform (200 ml.) and ethanol (800 ml.) to give N-(p-methoxyphenyl)-N-(2,6-dichloropyrimidin-4-yl)hydrazine as a pale yellow solid, m.p. 156°-158° C. From the crystallisation mother liquors there was obtained, after chromatography on silica gel (300 g.) using a mixture containing equal parts by volume of ether and petroleum ether (b.p. 40° C.), N-(p-methoxyphenyl)-N-(4,6-dichloropyrimidin-2-ylhydrazine as a pale yellow solid, m.p. 113°-115° C.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:9][C:10]1([CH3:22])[O:21][CH:18]([CH:19]=[CH2:20])[CH:12]([CH:13]([OH:17])[CH2:14][C:15]#[N:16])[O:11]1.N1C=CN=C1.C(Cl)Cl>C(OCC)C>[CH3:9][C:10]1([CH3:22])[O:21][CH:18]([CH:19]=[CH2:20])[CH:12]([CH:13]([O:17][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:14][C:15]#[N:16])[O:11]1
Reactant: C=CC1OC(C)(C)OC1C(O)CC#N
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CCOCC
Product: C=CC1OC(C)(C)OC1C(CC#N)O[Si](C)(C)C(C)(C)C
Reaction time: 16 h
Yield: 78.9 %

Procedure:
Two grams of tert-butyldimethylsilyl chloride were gradually added at 0° C. to a solution comprising 2.11 g of 4,5-(dimethylmethylenedioxy)-3-hydroxy-6-heptenenitrile, 2.0 g of imidazole and 50 ml of methylene chloride. After stirring was conducted at room temperature for 16 hours, the reaction mixture was diluted with 300 ml of diethyl ether, and washed with 1N hydrochloric acid, a saturated sodium hydrogen carbonate aqueous solution and a sodium chloride aqueous solution in sequence. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to afford 2.63 g of 4,5-(dimethylmethylenedioxy)-3-(tert-butyldimethylsilyloxy)6-heptenenitrile having the following properties (yield 79%).
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][C:5]1[CH:14]=[C:13]([CH:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)(=[O:23])=[O:22])[CH2:17][CH2:16]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:30])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+]>C1COCC1.O>[F:30][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([CH2:4][C:3]([OH:31])=[O:2])[CH:14]=[C:13]2[CH:15]1[CH2:16][CH2:17][N:18]([S:21]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)(=[O:22])=[O:23])[CH2:19][CH2:20]1
Reactant: COC(=O)Cc1cc(C2CCN(S(=O)(=O)c3cccnc3)CC2)c2cc(F)ccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cc1cc(C2CCN(S(=O)(=O)c3cccnc3)CC2)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.7 %

Procedure:
To a stirred solution of {6-fluoro-4-[1-(pyridine-3-sulfonyl)-piperidin-4-yl]-naphthalen-2-yl}-acetic acid methyl ester (85 mg, 0.19 mmol) in THF (6 mL) was added a solution of lithium hydroxide monohydrate (40 mg, 0.95 mmol) in water (1.5 mL) and the reaction mixture was stirred for 24 hours at room temperature. The reaction mixture was concentrated under reduced pressure and washed with diethyl ether (3×5 mL). The washings were discarded. Water (5 mL) was added to the residue, and the mixture acidified (pH ˜2-3) with an aqueous solution of hydrochloric acid (2 N) and extracted with ethyl acetate (3×5 mL). The combined organic extracts were dried over Na2SO4 and evaporated under reduced pressure to give {6-fluoro-4-[1-(pyridine-3-sulfonyl)-piperidin-4-yl]-naphthalen-2-yl}-acetic acid (60 mg, 73%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.38 (br s, 1H), 8.87-9.04 (m, 1H), 8.21 (d, J=7.1 Hz, 1H), 7.77-7.99 (m, 2H), 7.68 (br. s., 2H), 7.35 (br. s., 2H), 3.91 (d, J=11.6 Hz, 2H), 3.71 (s, 2H), 1.96 (d, J=12.1 Hz, 3H), 1.78 (d, J=11.6 Hz, 3H); MS cald. for C22H22FN2O4S [(M+H)+]: 429, obsd. 429.2.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[O:7]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH:25]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[NH:27][CH2:26]4)[CH2:19][CH2:18]3)[C:11]=2[O:10][CH2:9][CH2:8]1.[C:34](O)(=O)C(O)=O.C(O)(=O)C(O)=O.O1C2C=CC=C(N3CCN(CCC4C5C(=CC=CC=5)NC4)CC3)C=2OCC1.[H-].[Na+].IC.C(OCC)(=O)C>O1CCCC1>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[O:7]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH:25]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]([CH3:34])[CH2:26]4)[CH2:19][CH2:18]3)[C:11]=2[O:10][CH2:9][CH2:8]1
Reactant: c1ccc2c(c1)NCC2CCN1CCN(c2cccc3c2OCCO3)CC1
Agent: O=C(O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CI
Product: CN1CC(CCN2CCN(c3cccc4c3OCCO4)CC2)c2ccccc21
Reaction time: 1 h

Procedure:
A solution of 4a (1.5 g) in dry tetrahydrofuran (50 mL) was added dropwise to a suspension of sodium hydride (60% in mineral oil, 0.21 g) in tetrahydrofuran (25 mL) at room temperature. After stirring for 30 min a solution of iodomethane (0.75 g) in dry tetrahydrofuran (25 mL) was added dropwise. Stirring for 1 hour followed by standard work-up with ethyl acetate gave an oil which was purified by flash chromatography (eluent: heptane/ethyl acetate/triethylamine 15:3:2). The resulting oil was converted to the title oxalate salt (0.3 g) from acetone by addition of oxalic acid. Mp 155-65° C. 1H NMR (DMSO-d6) 1.75-1.85 (m, 1H); 2.05-2.15 (m, 1H); 2.70 (s, 3H); 2.90-3.25 (m, 12H); 3.40 (t, 1H); 4.15-4.30 (m, 4H); 6.45-6.55 (m, 3H); 6.65 (t, 1H); 6.75 (t, 1H); 7.05 (t, 1H); 7.10 (d, 1H). MS m/z (%): 380 (MH+, 4%), 178 (4%), 132 (53%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>CC(C)=O>[C:21]([O:20][C:18](=[O:19])[CH2:17][O:9][C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[Br:1])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1ccc(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccc(OCC(=O)OC(C)(C)C)c(Br)c1
Reaction time: 0.17 h
Yield: 99.6 %

Procedure:
A solution of 2-bromo-4-methylphenol (Alfa; 3.00 g; 16.0 mmol) in acetone (30 mL) was treated with potassium carbonate (2.44 g; 17.6 mmol), stirred for 10 minutes then treated with tert-butyl bromoacetate (2.37 mL; 16.0 mmol). The reaction mixture was stirred at 65° C. for 18 hours, then the mixture was filtered, the solid was washed with acetone and the filtrate was concentrated to dryness under vacuum to give the title compound as a pale yellow liquid (4.8 g, 99%).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.Cl.[CH3:18][O:19][C:20](=[O:30])[C@H:21]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH2:22]>>[CH3:18][O:19][C:20](=[O:30])[C@@H:21]([NH:22][C:12](=[O:14])[C:11]1[CH:10]=[CH:9][C:8]([N:5]2[CH2:4][CH2:3][C:2](=[O:1])[CH2:7][CH2:6]2)=[CH:16][CH:15]=1)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C1CCN(c2ccc(C(=O)O)cc2)CC1
Agent: Cl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccc(N2CCC(=O)CC2)cc1

Procedure:
The title compound was prepared from 4-(4-oxo-piperidin-1-yl)-benzoic acid (which was obtained in Example 151) and L-phenylalanine methyl ester hydrochloride according to the procedure of Example 154 as a pale yellowish solid; 1H NMR (300 MHz, DMSO-d6) δ 2.41 (t, J=6.0 Hz, 4 H), 3.05–3.20 (m, 2 H), 3.71 (t, J=6.0 Hz, 4 H), 4.55–4.65(m, 1 H); 6.97 (d, J=8.9 Hz, 2 H), 7.10–7.45 (m, 5 H), 7.73(d, J=8.9 Hz, 2 H), 8.52 (d, J=7.8 Hz, 1 H); MS (ES) m/z: 381.3 (MH+); HRMS Calcd. for C22H25N2O4(MH+): 381.1809. Found: 380.1807.
Reaction SMILES: O[CH2:2][C:3]1[O:7][C:6]([CH:8]=[O:9])=[CH:5][CH:4]=1.[CH3:10][O:11][C:12](=[O:29])[C:13]1[C:14](=[C:19]([NH:23]CCCCC)[CH:20]=[CH:21][CH:22]=1)[C:15]([O:17][CH3:18])=[O:16]>>[CH3:10][O:11][C:12](=[O:29])[C:13]1[C:14](=[C:19]([NH:23][CH2:2][C:3]2[O:7][C:6]([CH2:8][OH:9])=[CH:5][CH:4]=2)[CH:20]=[CH:21][CH:22]=1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: O=Cc1ccc(CO)o1
Reactant: CCCCCNc1cccc(C(=O)OC)c1C(=O)OC
Product: COC(=O)c1cccc(NCc2ccc(CO)o2)c1C(=O)OC
Yield: 76 %

Procedure:
5-Hydroxymethyl-furan-2-carbaldehyde (0.95 ml, 7.5 mmol) was treated in the same manner as described above for the synthesis of 3-pentylamino-phthalic acid dimethyl ester. The residue (oil) was purified by chromatography (SiO2, 40/60 ethyl acetate/hexanes) to give 0.97 g (76%) of yellow oil: 1H NMR (CDCl3) δ 7.35–7.27 (m, 1H), 7.05 (bs, 1H), 6.87–6.83 (m, 2H), 6.21 (d, J=3.1 Hz, 1H), 6.17 (d, J=3.2 Hz, 1H), 4.57 (s, 2H), 4.38 (bs, 2H) 3.86 (s, 3H), 3.83 (s, 3H), 1.98 (bs, 1H).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[CH:14][C:13]([OH:23])=[CH:12][CH:11]=1.S(=O)(=O)(O)O>C(O)(=O)C.ClCCl>[Cl:9][C:10]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[CH:14][C:13]([OH:23])=[C:12]([I:1])[CH:11]=1
Reactant: Oc1ccc(Cl)c(-c2cccc(F)c2)c1
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CC(=O)O
Product: Oc1cc(-c2cccc(F)c2)c(Cl)cc1I
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 47.7 %

Procedure:
N-Iodosuccinimide (261 mg, 1.16 mmol) was added to a mixture of 6-chloro-3′-fluorobiphenyl-3-ol (Preparation 100, 270 mg, 1.21 mmol) and concentrated sulphuric acid (24 μL, 0.43 mmol) in acetic acid (3 mL) and dichloromethane (3 mL). The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with dichloromethane (10 mL) and washed with sodium metabisulfite (0.5M, 10 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography eluting with heptane:dichloromethane (70:30) to give the title compound (193 mg, 46%) as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[N+:6]([CH2:7][C:8]2[CH:9]=[N:10][C:11]([CH3:15])=[N:12][C:13]=2[NH2:14])=[CH:5][S:4][C:3]=1[CH2:16][CH2:17][OH:18].[P:19]([O-])([O-:22])([O-:21])=[O:20].[OH:24][P:25]([O:28][P:29]([OH:32])([OH:31])=[O:30])(=[O:27])[OH:26].CC1N=C(N)C(CO)=CN=1.CC1N=CSC=1CCOP(O)(O)=O>>[O-:26][P:25]([O:28][P:29]([O-:32])([O-:31])=[O:30])(=[O:24])[O-:27].[CH3:1][C:2]1[N+:6]([CH2:7][C:8]2[C:13]([NH2:14])=[N:12][C:11]([CH3:15])=[N:10][CH:9]=2)=[CH:5][S:4][C:3]=1[CH2:16][CH2:17][O:18][P:19]([OH:22])([OH:21])=[O:20]
Reactant: O=P([O-])([O-])[O-]
Reactant: Cc1ncc(C[n+]2csc(CCO)c2C)c(N)n1
Reactant: O=P(O)(O)OP(=O)(O)O
Agent: Cc1ncc(CO)c(N)n1
Agent: Cc1ncsc1CCOP(=O)(O)O
Product: Cc1ncc(C[n+]2csc(CCOP(=O)(O)O)c2C)c(N)n1
Product: O=P([O-])([O-])OP(=O)([O-])[O-]

Procedure:
As noted above, in bacteria and fungi, phosphomethylpyrimidine kinase; (EC 2.7.4.7) catalyzes the reaction of ATP+4-amino-2-methyl-5-phosphomethylpyrimidine to produce ADP+4-amino-2-methyl-5-diphosphomethylpyrimidine; thiamine-phosphate diphosphorylase; (EC 2.5.1.3) catalyzes the reaction of 2-methyl-4-amino-5-hydroxymethylpyrimidine diphosphate+4-methyl-5-(2-phosphono-oxyethyl)thiazole to produce diphosphate+thiamine monophosphate; (EC 3.1.3.-) catalyzes the reaction of thiamine monophosphate to produce thiamine. The present inventor has first recognized the importance of this distinction in providing a target for inhibition of pathogenic microorganisms.
Reaction SMILES: [Li]CCCC.[CH3:6][O:7][C:8](=[O:16])[CH2:9][C@H:10]([CH3:15])[CH2:11][C:12]([OH:14])=[O:13].Cl[C:18]([O:20][CH3:21])=[O:19].Cl>C1COCC1>[CH3:6][O:7][C:8](=[O:16])[CH:9]([C:18]([O:20][CH3:21])=[O:19])[C@H:10]([CH3:15])[CH2:11][C:12]([OH:14])=[O:13]
Reactant: COC(=O)Cl
Reactant: COC(=O)C[C@H](C)CC(=O)O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)C(C(=O)OC)[C@H](C)CC(=O)O
Temperature: -78 °C
Yield: 99.7 %

Procedure:
To a 250 mL round-bottomed flask equipped with a stirbar and purged with nitrogen, was added 30 mL anhydrous THF followed by DIPA (2.21 g, 3.5 eq, 21.85 mmol). The mixture was cooled to −78° C. with stirring, n-BuLi (2.5 M, 3.3 eq, Aldrich) was then added dropwise, and the reaction was stirred for 10 min. To the flask was slowly added (R)-5-methoxy-3-methyl-5-oxopentanoic acid (1 g, 6.25 mmol, in 10.0 mL THF, Sumitomo) over about 2 min. After 30 min stirring at −78° C., a solution of methyl chloroformate (2.1 eq, 13.13 mmol) in THF (10 mL) was slowly added to the mixture. After the addition was complete, the reaction mixture was allowed warm to room temperature overnight. The reaction mixture was adjusted to about pH 5 to 6 (using pH paper), with cooling to maintain about ambient temperature using 2N aq. HCl. The reaction mixture was concentrated under reduced pressure, diluted with 75 mL EtOAc and 25 mL aq. 1N HCl. The layers were separated and the aqueous phase was extracted (2×15 mL EtOAc). The combined organics were washed with saturated aqueous NaCl (1×15 mL), dried over MgSO4, and concentrated under reduced pressure to give the product (1.36 g), which was used in the subsequent step without purification.
Reaction SMILES: C(O[CH:5]1[CH2:12][CH2:11][O:10][C:8](=[O:9])[CH2:7][CH2:6]1)(=O)C.[NH3:13]>>[OH:10][CH2:11][CH2:12][CH:5]1[NH:13][C:8](=[O:9])[CH2:7][CH2:6]1
Reactant: N
Reactant: CC(=O)OC1CCOC(=O)CC1
Product: O=C1CCC(CCO)N1

Procedure:
22.4 g of 4-acetoxycaprolactone were stirred for 1 hour at 330° C. in an autoclave together with 100 g of 25% strength aqueous ammonia. After cooling and depressurizing the autoclave, the reaction product was concentrated on a rotary evaporator (40° C./30 mbar) and purified by short path distillation. In this case, 10.1 g of 5-hydroxyethylpyrrolidone were obtained (61%, based on the 4-acetoxycaprolactone employed) and identified by NMR spectroscopy.
Reaction SMILES: [C@H:1]12[CH2:7][C@H]([CH:5]=[CH:6]1)C(=O)[NH:2]2.S(Cl)([Cl:11])=O.[C:13]([O:16][CH:17](C)C)(=[O:15])[CH3:14]>CO>[ClH:11].[NH2:2][C@H:1]1[CH2:7][C@@H:14]([C:13]([O:16][CH3:17])=[O:15])[CH:5]=[CH:6]1
Reactant: O=C1N[C@@H]2C=C[C@H]1C2
Reactant: O=S(Cl)Cl
Reactant: CC(=O)OC(C)C
Solvent: CO
Product: COC(=O)[C@H]1C=C[C@@H](N)C1
Product: Cl
Temperature: 8 °C
Reaction time: 2 h

Procedure:
A solution of (1S,4R)-2-azabicyclo[2.2.1]hept-5-en-3-one (725 g, 6.64 mol) in MeOH (2.2 L) was stirred in an ice bath to 0° C. Thionyl chloride (290 mL, 3.99 mol) was added dropwise over a 2.25 h period while keeping the temperature below 13° C. The reaction was stirred for 2 h at 8° C. Isopropyl acetate (16.3 L) was added and the slurry stirred for 1 h. The solid was filtered with a Buchner funnel, washed with isopropylacetate (˜1 L) and the solid was allowed to air-dry overnight to afford an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ=8.44 (br. s., 3H), 5.99-6.16 (m, 1H), 5.90 (dt, J=2.4, 5.3 Hz, 1H), 4.17 (br. s., 1H), 3.56-3.79 (m, 4H), 2.56 (m, 1H), 1.84-2.04 (m, 1H).
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[N+:8]([C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1)([O-:10])=[O:9].Cl>N1C=CC=CC=1>[N+:8]([C:11]1[CH:17]=[CH:16][C:14]([NH:15][C:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5])=[CH:13][CH:12]=1)([O-:10])=[O:9]
Reactant: CCCCC(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCC(=O)Nc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Valeryl chloride (12.06 g., 0.10 mole) is added dropwise to a cooled stirred solution of 4-nitroaniline (13.81 g., 0.10 mole) in pyridine (100 ml.). The resulting mixture is stirred at ambient temperature for one hour then heated (80°-100° C.) for twenty-four hours. The cooled solution is poured into cold 1 N hydrochloric acid (500ml.) with stirring. The precipitated solid is collected, washed with water and dried, 21.4 g., m.p. 107°-116° C. Recrystallization from butyl chloride provides material of m.p. 115°-118° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:13]([NH:15][OH:16])=[NH:14])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.C(N(C(C)C)[CH:20]([CH3:22])[CH3:21])C.[C:26](Cl)(=[O:29])[CH2:27][CH3:28].Cl>C1COCC1.C(O)C>[CH2:20]([C:22]1[O:16][N:15]=[C:13]([C:4]2[S:3][C:2]([NH:1][C:26](=[O:29])[CH2:27][CH3:28])=[N:6][C:5]=2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:14]=1)[CH3:21]
Reactant: N=C(NO)c1sc(N)nc1-c1ccccc1
Reactant: CCC(=O)Cl
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: CCC(=O)Nc1nc(-c2ccccc2)c(-c2noc(CC)n2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
2-Amino-N-hydroxy-4-phenyl-thiazole-5-carboxamidine (1.5 g, 6.4 mmol) was dissolved in dry THF (50 mL). Ethyl-diisopropyl-amine (2.5 mL) and propionylchloride (2.8 mL, 5 eq) was added. The reaction mixture was stirred overnight at room temperature. pH was adjusted to pH ˜2 by addition of HCl in ethanol. The reaction mixture was stirred overnight at room temperature. The solvent was evaporated to yield a yellow oil. The crude product was purified by flash column chromatography, eluted with 30% ethyl acetate in hexanes to give the product as a white solid. Yield: 49%.
Reaction SMILES: [OH:1]O.[CH3:3][C:4]1[N:5]=[C:6]([NH:17][C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)[S:7][C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15][CH3:16])=[CH:11][CH:10]=1.[OH-].[Na+]>C(O)(=O)C.O>[CH3:16][S:15]([C:12]1[CH:13]=[CH:14][C:9]([C:8]2[S:7][C:6]([NH:17][C:18]3[CH:23]=[N:22][CH:21]=[CH:20][N:19]=3)=[N:5][C:4]=2[CH3:3])=[CH:10][CH:11]=1)=[O:1]
Reactant: OO
Reactant: CSc1ccc(-c2sc(Nc3cnccn3)nc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1nc(Nc2cnccn2)sc1-c1ccc(S(C)=O)cc1
Yield: 32.4 %

Procedure:
Hydrogen peroxide solution (27% in water) (35 ml, 0.28 mmol) is added to a stirred suspension of [4-methyl-5-(4-methylsulfanyl-phenyl)-thiazol-2-yl]-pyrazin-2-yl-amine (27c) (0.090 g, 0.28 mmol) in acetic acid (5 ml). After 30 minutes the reaction is diluted with water and brought to pH 10 by addition of aqueous sodium hydroxide. The product is extracted with ethyl acetate (3×50 ml), the combined organic extracts are washed with brine (50 ml), dried (MgSO4) and the solvent removed to give the title compound as an orange solid (0.03 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]([NH2:25])=[N:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=1[F:24])=O)[CH3:2].O>N1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:5]1[NH:25][C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=2[F:24])=[N:7][N:6]=1)=[O:26])[CH3:2]
Reactant: CCOC(=O)C(N)=NNC(=O)c1ccncc1Nc1ccc(I)cc1F
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)c1nnc(-c2ccncc2Nc2ccc(I)cc2F)[nH]1

Procedure:
Amino-{[3-(2-fluoro-4-iodo-phenylamino)-pyridine-4-carbonyl]-hydrazono}-acetic acid ethyl ester (1.6 g, 3.4 mmo) in pyridine (10 mL) was stirred at 140° C. for 3 hrs. Cooled, poured into water, Extracted with EtOAc, Combined the organic layer, and washed with Brine, dried over MgSO4, filtered, removed off solvent, got crude product, which was subjected to silica gel column (Hex:EtOAc=1:1). Collected final product 1.02 g. [5.23 min, 454 (M+1)]