Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][CH2:2][C:3]([OH:5])=[O:4].[OH-].[K+].Cl[C:9]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:12]=[C:11]([CH3:20])[C:10]=1[CH:21]=O>C(O)C>[CH3:20][C:11]1[C:10]2[CH:21]=[C:2]([C:3]([OH:5])=[O:4])[S:1][C:9]=2[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:12]=1
Reactant: Cc1nn(-c2ccccn2)c(Cl)c1C=O
Reactant: O=C(O)CS
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nn(-c2ccccn2)c2sc(C(=O)O)cc12
Reaction time: 2 h

Procedure:
In a 1.0-liter egg plant-type flask, mercaptoacetic acid (10.3 g, 0.15 mol) and potassium hydroxide (35.6 g, 0.54 mol) were added to an ethanol (600 mL) solution of 5-chloro-3-methyl-1-pyridin-2-yl-1H-pyrazole-4-carbaldehyde (30.0 g, 0.14 mol), and stirred for 2 hours with heating under reflux. Ethanol was removed from the reaction solution under reduced pressure, then the residue was diluted with water and made acidic with aqueous 5 N hydrochloric acid solution added thereto, and the formed precipitate was taken out through filtration, washed with methanol and ethyl acetate in that order, and dried under reduced pressure to obtain the title compound as a pale brown solid.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH2:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]2[CH:17]=[C:18]([C:20]([O-])=[O:21])[S:19][C:12]=12.[Li+]>>[N:1]1([CH2:7][CH2:8][NH:9][C:20]([C:18]2[S:19][C:12]3[C:13](=[N:14][CH:15]=[CH:16][C:11]=3[Cl:10])[CH:17]=2)=[O:21])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Reactant: NCCN1CCOCC1
Agent: [Li+]
Product: O=C(NCCN1CCOCC1)c1cc2nccc(Cl)c2s1

Procedure:
The title compound was prepared from 2-morpholine-4-yl-ethylamine and lithium 7-chloro-thieno[3,2-b]pyridine-2-carboxylate by a procedure analogous to Example 1B. MS: 326/328 (MH+); HPLC Rf: 3.45 min.; HPLC purity 94%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)=[CH:6][CH:5]=1.[C:19]([N:26]1[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>>[C:22]([O:21][C:19]([N:26]1[CH2:31][CH2:30][CH:29]([NH:17][C:14]2[CH:15]=[CH:16][C:11]([CH2:10][C:7]3[CH:6]=[CH:5][C:4]([C:3]([O:2][CH3:1])=[O:18])=[CH:9][CH:8]=3)=[CH:12][CH:13]=2)[CH2:28][CH2:27]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COC(=O)c1ccc(Cc2ccc(N)cc2)cc1
Product: COC(=O)c1ccc(Cc2ccc(NC3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc1
Yield: 37.9 %

Procedure:
Using general procedure A, 4-(4-amino-benzyl)-benzoic acid methyl ester (0.66 g, 2.7 mmol) and 1-Boc-4-piperidone (545 mg, 2.74 mmol) gave 4-[4-(4-methoxycarbonyl-benzyl)-phenylamino]-piperidine-1-carboxylic acid tert-butyl ester as a yellow foam (434 mg, 36%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:29])[CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH2:27])[CH:22]=3)=[CH:16][C:15]=2[F:28])=[O:12])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:37](Cl)(=[O:40])[CH2:38][CH3:39].[OH-].[Na+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:29])[CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:27][C:37](=[O:40])[CH2:38][CH3:39])[CH:22]=3)=[CH:16][C:15]=2[F:28])=[O:12])=[CH:6][CH:7]=1
Reactant: CCC(=O)Cl
Reactant: Nc1cc(Oc2ccc(NC(=O)CC(=O)Nc3ccc(F)cc3)c(F)c2)ccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(=O)Nc1cc(Oc2ccc(NC(=O)CC(=O)Nc3ccc(F)cc3)c(F)c2)ccn1
Reaction time: 8 h
Yield: 39 %

Procedure:
N-(4-Fluorophenyl)-N′-[4-(2-aminopyridin-4-yloxy)-2-fluorophenyl]malonamide (20.2 mg) was dissolved in N,N-dimethylformamide (0.5 ml), and then triethylamine (0.042 ml) and propionyl chloride (0.013 ml) were added dropwise thereto under a nitrogen atmosphere at room temperature, followed by stirring overnight. To the reaction mixture was added a 1 N aqueous solution of sodium hydroxide (1.5 ml), followed by stirring and extracting with ethyl acetate. The organic layer was concentrated under a reduced pressure to give a residue, which was purified by silica gel column chromatography (FUJI Silysia NH, eluent; ethyl acetate). Fractions containing the target compound were concentrated to give a residue, which was then dried in vacuum to provide the titled compound (9.0 mg, 39%) as pale yellow powder.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[NH:10][CH:11]=[CH:12][C:5]=12.[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>C1COCC1>[Br:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[N:10]([S:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)(=[O:21])=[O:20])[CH:11]=[CH:12][C:5]=12
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Brc1ccnc2[nH]ccc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1ccc2c(Br)ccnc21
Reaction time: 0.17 h

Procedure:
To a stirred suspension of sodium hydride (1.12 g; 60% dispersion in mineral oil) in THF (3 ml) kept below 15° C., a suspension of 4-bromo-1H-pyrrolo[2,3-b]pyridine (5 g) (prepared for example, according to the method described in Organic Letters, 2003, 5, 5023) in THF (27 ml) was added over 20 minutes. The reaction was left to stir for 10 minutes. Then a solution of benzenesulfonyl chloride (3.6 ml) in THF (6 ml) was added over 5 minutes. The reaction was left to stir at RT for 1 hour, then 0.5M hydrochloric acid solution (10 ml) was added. The layers were separated and the organic layer washed with brine, dried over magnesium sulphate and the solvent removed in vacuo and left on the vacuum line for 3 days. The solid was triturated using methanol (30 ml) then dried in the oven for 5 hours to give the title compound as a pale pink solid (7.42 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3C(OCC3C=CC=CC=3)=O)=[N:9][C:10]=2Br)[CH:5]=[CH:6][N:7]=1.[F:27][C:28]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[CH:39][C:29]=1[C:30]([NH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1)=[O:31]>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:12]3[CH2:16][CH2:15][CH2:14][NH:13]3)=[N:9][C:10]=2[C:41]2[CH:40]=[CH:39][C:29]([C:30]([NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)=[O:31])=[C:28]([F:27])[CH:42]=2)[CH:5]=[CH:6][N:7]=1
Reactant: CC1(C)OB(c2ccc(C(=O)Nc3ccccn3)c(F)c2)OC1(C)C
Reactant: Nc1nccn2c([C@@H]3CCCN3C(=O)OCc3ccccc3)nc(Br)c12
Product: Nc1nccn2c([C@@H]3CCCN3)nc(-c3ccc(C(=O)Nc4ccccn4)c(F)c3)c12
Yield: 76 %

Procedure:
This intermediate was prepared, in an analogous manner as described for intermediate 2, from (S)-benzyl 2-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (Intermediate 1e) and 2-Fluoro-N-(pyridin-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (intermediate 16) to afford the title compound (160 mg, 76%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@:19]([CH2:28][C:29]([OH:32])([CH3:31])[CH3:30])([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:18][C:17]3=[O:33])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[N+:34]([O-])=O>[Pd].CO.O1CCCC1.[H][H]>[NH2:34][C:3]1[CH:4]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@:19]([CH2:28][C:29]([OH:32])([CH3:30])[CH3:31])([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[O:18][C:17]3=[O:33])[CH3:15])=[CH:12][CH:13]=2)[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: [H][H]
Reactant: C[C@@H](c1ccc(-c2ccc(N)c([N+](=O)[O-])c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H](c1ccc(-c2ccc(N)c(N)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
A mixture of 3-[(S)-1-(4′-amino-3′-nitro-biphenyl-4-yl)-ethyl]-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one (0.50 g) and 10% palladium on carbon (0.10 g) in a mixture of methanol (10 mL) and tetrahydrofuran (10 mL) was shaken in hydrogen atmosphere (3 bar) at room temperature for 3.5 h. Then, the catalyst was separated by filtration and the filtrate was concentrated under reduced pressure to afford the title compound as an oil.
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[C:10]([S:13][CH3:14])[CH:11]=[CH:12][C:7]=2[O:6][C:5]2[CH:15]=[CH:16][C:17]([CH3:19])=[CH:18][C:4]=2[CH2:3]1.[N:20]1([CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][C:29]2=[O:34])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>C(Cl)(Cl)Cl>[CH3:19][C:17]1[CH:16]=[CH:15][C:5]2[O:6][C:7]3[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][C:8]=3[CH:2]([N:23]3[CH2:24][CH2:25][N:20]([CH2:26][CH2:27][N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][C:29]4=[O:34])[CH2:21][CH2:22]3)[CH2:3][C:4]=2[CH:18]=1
Reactant: CSc1ccc2c(c1)C(Cl)Cc1cc(C)ccc1O2
Reactant: O=C1CCCCN1CCN1CCNCC1
Solvent: ClC(Cl)Cl
Product: CSc1ccc2c(c1)C(N1CCN(CCN3CCCCC3=O)CC1)Cc1cc(C)ccc1O2

Procedure:
A solution of 3 g. of 10-chloro-10,11-dihydro-2-methyl-8-methylthio-dibenz[b,f]oxepin and 5.73 g. of 1-[2-(1-piperazinyl)-ethyl]-2-piperidone in 18 ml. of chloroform is heated at reflux for 20 hours. The solvent is removed in vacuo. The residue is partitioned between benzene and 10% aqueous sodium carbonate solution. The benzene solution is extracted with dilute hydrochloric acid. The acid-aqueous solution is made alkaline with sodium bicarbonate and extracted with benzene. The benzene extract is washed several times with water, dried, evaporated in vacuo, and there is obtained 1-[2-{4-[10,11-dihydro-2-methyl-8-methylthio-dibenz[b,f]-oxepin-10-yl]-1-piperazinyl}-ethyl]-2-piperidone. The dihydrochloride is prepared in ethanol by the addition of an excess of alcoholic hydrogen chloride. By the addition of ether, there are obtained crystals having a melting point of 183°-185° C. (with decomposition). By re-dissolving the dihydrochloride in water, there is obtained the monohydrochloride having a melting point of 117°-120° C.
Reaction SMILES: [CH3:1][C:2]([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=O.[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl>[N:14]1([CH:2]([CH3:1])[CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][CH:6]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C1CCNCC1
Reactant: CC(=O)Cc1c[nH]c2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(Cc1c[nH]c2ccccc12)N1CCCCC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 42.7 %

Procedure:
To a solution of indole-3-acetone (5.0 g, 29 mmol) in anhydrous 1,2-dichloroethane (100 ml) under an atmosphere of nitrogen was added piperidine (2.9 ml, 29 mmol), and glacial acetic acid (1.66 ml, 29 mmol) followed by sodium triacetoxyborohydride (6.8 g, 32 mmol). On complete addition the reaction mixture was stirred at room temperature for 17 hours. The mixture was basified by the addition of a saturated solution of sodium hydrogen carbonate, the layers were separated and the organic layer dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue was purified by column chromatography on silica elution with 5% CH3OH in CH2Cl2+0.5% 0.88 ammonia to give the title product (3 g, 43%); δH (360 MHz; CDCl3) 0.99 (3H, d, J 6.5 Hz, —CH3), 1.43-1.51 (2H, m, aliphatics), 1.60-1.69 (4H, m, aliphatics), 2.56-2.70 (5H, m, aliphatics+indole CHACHB), 2.87-2.99 (1H, m, indole CHAHBCH (piperidine)), 3.12 (1H, dd, J 13.9 and 3.6 Hz, indole CHACHB), 7.02 (1H, d, J 1.9 Hz, indole H2), 7.09 (1H, m, indole H6), 7.17 (1H, m, indole H5), 7.34 (1H, d, J 8.0 Hz, indole H7), 7.61 (1H, d, J 7.6 Hz, indole H4), 8.01 (1H, bs, indole NH); m/z (ES+) 243 (M++H, 100%).
Reaction SMILES: [Na].[CH2:2]([OH:4])[CH3:3].[NH2:5][C:6]1[N:14]=[C:13]2[C:9]([NH:10][CH:11]=[N:12]2)=[C:8](Cl)[N:7]=1>C(O)(=O)C>[CH3:3][CH2:2][O:4][C:8]1[C:9]2[NH:10][CH:11]=[N:12][C:13]=2[N:14]=[C:6]([NH2:5])[N:7]=1
Reactant: CCO
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Agent: [Na]
Solvent: CC(=O)O
Product: CCOc1nc(N)nc2nc[nH]c12
Yield: 69 %

Procedure:
Sodium (0.5 g, 22 mmol) was added to anhydrous ethanol (50 ml) under nitrogen. When all of the sodium had reacted, 2-amino-6-chloropurine (750 mg, 4.42 mmol) was added. The reaction was refluxed for 3 h. After cooling, the reaction mixture was neutralised with glacial acetic acid and the solvent was removed. Recrystallisation from water gave the product as a white solid (548 mg, 69%), m.p.>230° C.; (Found: C, 46.76; H, 4.97; N, 39.09. Calc. for C7H9N5O: C, 46.92; H, 5.06; N, 39.09%); νmax (cm−1) 3505, 3484, 3432, 3324, 3191, 3110, 2984, 2901, 2705, 2544 (NH, C—H, NH2); δH (200 MHz, d6-DMSO) 7.808 (1H, s, C(8)H), 6.224 (2H, s, NH2), 4.437 (2H, q, J=7.1 Hz, OCH2), 1.353 (3H, t, J=7.1 Hz. CH2CH3); m/z 179 (M+, 100%), 169 (19), 164 (35), 151 ([MH—Et]+, 36%), 135 ([MH—OEt]+, 43%), 131 (38), 119 (34), 109 (54), 81 (41), 69 (39), 60 (21), 55 (31), 41 (48),
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11](N1C2C(=CC=CC=2)CCC1)=[O:12].[Cl:28][C:29]1[CH:30]=[C:31]([N:37]([CH:39]2[CH2:41][CH2:40]2)[CH3:38])[C:32]([NH2:36])=[CH:33][C:34]=1[F:35]>CCCCCCC.C(OCC)(=O)C>[Cl:28][C:29]1[C:34]([F:35])=[CH:33][C:32]([NH:36][C:11](=[O:12])[C:6]2[C:5]([O:4][C:3]3[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:2]=3[Cl:1])=[CH:10][CH:9]=[N:8][CH:7]=2)=[C:31]([N:37]([CH:39]2[CH2:40][CH2:41]2)[CH3:38])[CH:30]=1
Reactant: CN(c1cc(Cl)c(F)cc1N)C1CC1
Reactant: O=C(c1cnccc1Oc1cc(Cl)ccc1Cl)N1CCCc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CN(c1cc(Cl)c(F)cc1NC(=O)c1cnccc1Oc1cc(Cl)ccc1Cl)C1CC1

Procedure:
The title compound was prepared in analogy to Example 1, from 4-(2,5-dichloro-phenoxy)-nicotinic acid (Example 1, intermediate) and 4-chloro-N2-cyclopropyl-5-fluoro-N2-methyl-benzene-1,2-diamine and using a gradient of n-heptane:ethyl acetate (100:0 to 30:70) for the chromatographic purification. Colorless solid (70%). MS (ESI): m/z=446.083 [M+H]+.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[Cl:5][C:6]1[S:10][C:9]([C:11](Cl)=[O:12])=[CH:8][CH:7]=1>N1C=CC=CC=1>[CH2:1]([NH:4][C:11]([C:9]1[S:10][C:6]([Cl:5])=[CH:7][CH:8]=1)=[O:12])[CH:2]=[CH2:3]
Reactant: O=C(Cl)c1ccc(Cl)s1
Reactant: C=CCN
Solvent: c1ccncc1
Product: C=CCNC(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
An ice-cooled solution of 2.63 ml (35 mmol) of allylamine in 14.2 ml of absolute pyridine and 14.2 ml of absolute TUE is admixed dropwise with 5-chloro-thiophene-2-carbonyl chloride (7.61 g, 42 mmol). Ice-cooling is removed and the mixture is stirred at room temperature for 3 h and then concentrated under reduced pressure. The residue is admixed with water and the solid is filtered off. The crude product is purified by flash chromatography over silica gel (dichloromethane).
Reaction SMILES: [C:1]([C:3]1[C:8](=O)[NH:7][C:6]([C:10]2[CH:21]=[CH:20][C:13]([C:14]([O:16]C(C)C)=[O:15])=[CH:12][CH:11]=2)=[CH:5][C:4]=1[S:22][CH3:23])#[N:2].P(Cl)(Cl)([Cl:26])=O.CN(C=O)C.Cl>O>[Cl:26][C:8]1[N:7]=[C:6]([C:10]2[CH:21]=[CH:20][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=2)[CH:5]=[C:4]([S:22][CH3:23])[C:3]=1[C:1]#[N:2]
Reactant: CSc1cc(-c2ccc(C(=O)OC(C)C)cc2)[nH]c(=O)c1C#N
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CSc1cc(-c2ccc(C(=O)O)cc2)nc(Cl)c1C#N
Temperature: 110 °C
Yield: 97.7 %

Procedure:
A suspension of isopropyl 4-(5-cyano-4-(methylthio)-6-oxo-1,6-dihydropyridin-2-yl)benzoate (1.6 g, 4.87 mmol) in phosphoryl trichloride (14.94 g, 97 mmol) was heated to 110° C. for 60 h, cooled to room temperature and carefully added to cold water (50 mL). The resultant mixture was carefully quenched with saturated. NaHCO3(200 mL), and extracted with ethyl acetate (3×200 mL). The combined organic extracts were washed with brine (100 mL), dried (MgSO4) and concentrated to give a mixture of acid and ester. The material was treated with DMF (10 ml) and 6 N HCl (10 ml), heated to 100° C. for 1 h, cooled to room temperature and diluted with water (50 ml) and filtered. The solid was washed with water (10 ml), dried under vacuum to give 4-(6-chloro-5-cyano-4-(methylthio)pyridin-2-yl)benzoic acid (1.45 g. 70% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.31 (2H, d, J=8.53 Hz), 8.10 (2H, d, J=8.53 Hz), 7.95 (1H, s), 2.87 (3H, s); MS (ES+) m/z: 305 (M+H); LC retention time: 3.45 min (analytical HPLC Method A).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:38]/[O:39][C:40]([CH3:49])([CH3:48])[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])/[C:15]([NH:17][C@@H:18]2[C:21](=[O:22])[NH:20][C@@H:19]2[CH2:23][NH:24][CH2:25][CH2:26][NH:27][CH2:28][CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:16])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN([C:55](N2C=NC=C2)=[O:56])C=1>C(Cl)(Cl)Cl>[C:33]([O:32][C:31]([NH:30][CH2:29][CH2:28][N:27]1[CH2:26][CH2:25][N:24]([CH2:23][C@@H:19]2[C@H:18]([NH:17][C:15](=[O:16])/[C:14](=[N:38]\[O:39][C:40]([CH3:49])([CH3:48])[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])/[C:12]3[N:13]=[C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[S:10][CH:11]=3)[C:21](=[O:22])[NH:20]2)[C:55]1=[O:56])=[O:37])([CH3:35])([CH3:36])[CH3:34]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)NCCNCCNC[C@H]1NC(=O)[C@H]1NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c1csc(NC(=O)OC(C)(C)C)n1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NCCN1CCN(C[C@H]2NC(=O)[C@H]2NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c2csc(NC(=O)OC(C)(C)C)n2)C1=O

Procedure:
Prepared in analogous manner to example 3 step 3, using tert-butyl 2-(((Z)-(1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-(((2R,3S)-2-(11,11-dimethyl-9-oxo-10-oxa-2,5,8-triazadodecyl)-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoate (135 mg, 0.189 mmol), CDI (46.1 mg, 0.284 mmol), TEA (132 μl, 0.947 mmol) and chloroform (1.9 mL). The crude residue was used as such in the following step. LC/MS: R=1.02 min, m/z=739.4 (M+1) Method 2m_acidic.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH:7]1[O:11][CH2:10][CH2:9][O:8]1.[Br:12]N1C(=O)CCC1=O>C(#N)C>[Br:12][C:4]1[S:3][C:2]([CH3:1])=[C:6]([CH:7]2[O:11][CH2:10][CH2:9][O:8]2)[CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1sccc1C1OCCO1
Solvent: CC#N
Product: Cc1sc(Br)cc1C1OCCO1
Temperature: 25 °C
Reaction time: 7 h
Yield: 63.9 %

Procedure:
To a solution of 2-(2-methylthiophen-3-yl)-1,3-dioxolane (2.30 g) synthesized above in acetonitrile (25 mL) was added N-bromosuccinimide (2.65 g), and the mixture was stirred at room temperature for 7 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (5% ethyl acetate/hexane) to give the title compound (2.15 g, 64%) as a pale-yellow oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].[NH:15]1[CH:19]=[CH:18][N:17]=[CH:16]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N:15]1([CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:6])[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: c1c[nH]cn1
Reactant: O=C(CCCBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(CCCn1ccnc1)OCc1ccccc1
Temperature: 25 °C
Yield: 32.4 %

Procedure:
A mixture of benzyl 4-bromobutyrate (23.7 g), imidazole (8.1 g), potassium carbonate (14.0 g) and acetone (400 ml) was stirred under reflux for 6 hours. After cooling the mixture to room temperature, the insoluble material was filtered off, and the filtrate was concentrated. The residual oil was subjected to column chromatography on silica gel. The fractions eluted with ethyl acetate/methanol (20/1, v/v) gave benzyl 4-(1-imidazolyl)butyrate (7.3 g, 33%) as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:13])([CH3:12])[C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[CH:14](NC(C)C)(C)[CH3:15].C(I)C.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:14]([O:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:13])([CH3:12])[C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1)[CH3:15]
Reactant: CC(=O)C(C)(C)c1cccc(O)c1
Reactant: CC(C)NC(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCI
Solvent: CCO
Product: CCOc1cccc(C(C)(C)C(C)=O)c1

Procedure:
The mixture of 3-(3-hydroxy-phenyl)-3-methyl-butan-2-one (3.4 g, 19.08 mmol), diisopropylamine (16.7 mL, 95.4 mmoL) and ethyl iodide (6.2 mL, 76.32 mmol) in 60 mL of ethanol was heated at refluxed overnight. Thin layer chromatography still showed starting material. Potassium carbonate (9 g) was added, and the mixture was heated at reflux for 12 h. It was concentrated in vacuo, and the residue was taken in ethyl acetate. After being washed with water and brine, the organic layer was dried over anhydrous sodium sulfate. The solids were filtered off, and the filtrate was concentrated to give 3.727 g of 3-(3-ethoxy-phenyl)-3-methyl-butan-2-one as light brown oil. It was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[C:11](Cl)(=[O:16])[CH2:12][CH:13]([CH3:15])[CH3:14].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[Cl:8][C:7]1[C:2]([Cl:1])=[C:3]([O:9][CH3:10])[CH:4]=[CH:5][C:6]=1[C:11](=[O:16])[CH2:12][CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)CC(=O)Cl
Reactant: COc1cccc(Cl)c1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)CC(C)C)c(Cl)c1Cl
Temperature: 5 °C

Procedure:
A stirred mixture of 2,3-dichloroanisole (265 g., 1.50 mole) and isovaleryl chloride (200 g., 1.64 mole) in methylene chloride (1.2 l.) is cooled to 5° C. and treated with aluminum chloride (220 g., 1.64 mole) during a two-hour period. The reaction is allowed to warm to 25° C. and after 24 hours is poured into ice water (3 l.) and hydrochloric acid (600 ml.). The organic phase is washed with 10% sodium hydroxide and water and dried over magnesium sulfate. After evaporation of the solvent, the product is crystallized from hexane affording 295 g. of 2',3'-dichloro-4'-methoxyisovalerophenone which melts at 49°-54° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=2)[N:3]=1.[NH2:17][CH2:18][CH2:19][OH:20]>O1CCOCC1>[CH3:16][O:15][C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[CH:11][C:2]([NH:17][CH2:18][CH2:19][OH:20])=[N:3]2)=[CH:8][C:7]=1[N+:12]([O-:14])=[O:13]
Reactant: COc1cc2nc(Cl)ccc2cc1[N+](=O)[O-]
Reactant: NCCO
Solvent: C1COCCO1
Product: COc1cc2nc(NCCO)ccc2cc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 63.3 %

Procedure:
A mixture of 2-chloro-7-methoxy-6-nitro-quinoline (0.1 g, 0.42 mmol) and 2-aminoethanol (38 μL, 0.63 mmol) in anhydrous 1,4-dioxane (5 mL) was heated at 90° C. overnight. A second aliquot of 2-aminoethanol (38 μL, 0.63 mmol) was added and the resulting mixture was heated at 90° C. overnight. The reaction mixture was then concentrated under reduced pressure, the residue was washed with water, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give 70 mg of 2-(7-methoxy-6-nitro-quinolin-2-ylamino)-ethanol as a solid without further purifications. MS=264 [M+H]+.
Reaction SMILES: C[O:2][C:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]C)=[O:17])=[O:4].[OH-].[Na+]>C(O)C>[CH2:20]([CH:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:3]([OH:4])=[O:2])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCCCCCC(CCCCCC(=O)OC)CCCCCC(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCCCC(CCCCCC(=O)O)CCCCCC(=O)O

Procedure:
A solution of the diester (0.2 g; from example 75) in ethanol (5 ml) was treated with 10% aqueous NaOH (2.5 ml) exactly as in example 5 to provide a crystalline solid, m.p. 48°-50° C.