Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2([CH2:16][C:17]#N)[CH2:15][CH:14]=[C:10]3[CH:11]=[CH:12][CH:13]=[C:9]3[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[OH-:21].[Na+].[OH2:23]>>[C:1]1([C:7]2([CH2:16][C:17]([OH:23])=[O:21])[CH2:15][CH:14]=[C:10]3[CH:11]=[CH:12][CH:13]=[C:9]3[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O
Reactant: N#CCC1(c2ccccc2)CC=C2C=CC=C2O1
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CC1(c2ccccc2)CC=C2C=CC=C2O1

Procedure:
A suspension of 24.68 g of the product of Step A, 200 ml of methanol, 100 ml of water and 160 ml of a ION sodium hydroxide solution was refluxed for 16 hours and the methanol was eliminated. The product was taken up in water and washed with methylene chloride. Acidification was carried out with 150 ml of a 12N hydrochloric acid solution. The product was separated out, made into a paste in water and dried to obtain 22 g of the desired product melting at 139.1° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:14][CH3:15])=[C:9]([N+:16]([O-])=O)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:31]([N:38]1[C:42](=[O:43])[C:41](=[C:44]2[N:48]([CH3:49])[C:47]3[CH:50]=[CH:51][CH:52]=[CH:53][C:46]=3[S:45]2)[S:40][CH2+:39]1SC)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[C:1]([O:5][C:6](=[O:19])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:14][CH3:15])=[C:9]([N:16]=[C:39]2[N:38]([CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:42](=[O:43])[C:41](=[C:44]3[N:48]([CH3:49])[C:47]4[CH:50]=[CH:51][CH:52]=[CH:53][C:46]=4[S:45]3)[S:40]2)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCNc1ccc(C(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Reactant: CS[CH2+]1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNc1ccc(C(=O)OC(C)(C)C)cc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1

Procedure:
In a manner similar to Example 30, intermediate 4-ethylamino-3-nitrobenzoic acid tert-butyl ester was hydrogenated and then condensed with 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazolium p-toluenesulfonate to afford the title compound. 1H-NMR (CDCl3): δ 7.69 (1H, dd), 7.61 (1H, d), 7.52 (1H, dd), 7.45–7.49 (2H, m), 7.27–7.37 (4H, m), 7.18 (1H, m), 7.06 (1H, d), 6.51 (1H, d), 5.19 (2H, s), 4.11 (1H, br t), 3.79 (3H, s), 3.04 (2H, m), 1.57 (9H, s), 1.04 (3H, t); MS(ESI): 573 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[C:22]([N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)[N:21]=[C:20]([C:31]([OH:33])=O)[CH:19]=2)[CH2:14][CH2:13]1)=[O:10].Cl.[O:35]([NH2:37])[CH3:36]>>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[N:23]=[C:22]([N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)[N:21]=[C:20]([C:31]([NH:37][O:35][CH3:36])=[O:33])[CH:19]=2)[CH2:16][CH2:17]1)=[O:10]
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(=O)O)nc(N4CCN(C)CC4)n3)CC2)c(Cl)c1Cl
Reactant: CON
Agent: Cl
Product: CONC(=O)c1cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc(N2CCN(C)CC2)n1

Procedure:
The title compound was synthesized by an analogous method to Example 8 starting from 6-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-2-(4-methylpiperazin-1-yl)pyrimidine-4-carboxylic acid (Example 196) and methoxylamine hydrochloride.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([OH:21])=O.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[OH-].[Na+]>CN(C)C=O.O>[C:23]1([NH:22][C:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=2)=[O:21])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(O)c1ccccn1
Reactant: Nc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)c1ccccn1
Reaction time: 0.5 h
Yield: 32.3 %

Procedure:
To a solution of carbonyldiimidazole (8.10 g) in dry dimethylformamide (100 mL) under N2 atmosphere, was added the picolinic acid (15.0 g) portionwise, then stirred for 30 minutes. Aniline (10.93 mL) was added rapidly dropwise, then stirred for 18 hours at room temperature. The reaction mixture was poured into water (400 mL), basified with 2.5N NaOH (25 mL) and stirred for 30 minutes while solid precipitated. The solid was collected by vacuum filtration, washed with water, and dried in vacuo. This tan solid was recrystallized from ether/hexane (1/1) to afford 7.69 g (32.3%) of an off-white solid, m.p. 75°-77° C.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH2:15][CH2:14]1>C(Cl)(Cl)Cl.C(O)(=O)C>[NH3:12].[NH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21]([CH2:20][CH2:19][N:16]2[CH2:15][CH2:14][CH:13]([N:12]3[C:1](=[O:11])[C:2]4[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:4]3=[O:6])[CH2:18][CH2:17]2)=[CH:22]1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NC1CCN(CCc2c[nH]c3ccccc23)CC1
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: N
Product: O=C1c2ccccc2C(=O)N1C1CCN(CCc2c[nH]c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Phthalic anhydride (2.96 g, 0.02 mol, finely ground) and 4-amino-1-[2-(indol-3-yl)ethyl]piperidine (4.86 g, 0.02 mol) were suspended in chloroform (40 cm3) and the suspension stirred at room temperature overnight. The solvent was then evaporated and acetic anhydride (40 cm3) added to the residue. This mixture was heated on a steam bath for 2 hours then the solvent removed in vacuo to give a glassy solid which was dissolved in very dilute aqueous acetic acid. Basification of the solution with 0.880 ammonia gave the title compound as a gum which solidified on trituration with methanol. (4.31 g, 57.8%). A suspension of the base in ethanolic HCl was stirred overnight to give the hydrochloride, mp. 252°-260° after extensive decomposition above 240° C.
Reaction SMILES: C1(C2N=CC=CC=2C(O)=O)C=CC=CC=1.[C:16]1([C:22]2[C:27]([NH2:28])=[CH:26][CH:25]=[CH:24][N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([CH:22]2[CH:27]([NH2:28])[CH2:26][CH2:25][CH2:24][NH:23]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Nc1cccnc1-c1ccccc1
Agent: O=C(O)c1cccnc1-c1ccccc1
Product: NC1CCCNC1c1ccccc1

Procedure:
First, a carboxyl group of a 2-phenylnicotinic acid derivative is amidated and applied to Hofmann's reaction. Then, the resulting 2-phenyl-3-aminopyridine derivative is reduced to produce a 2-phenyl-3-aminopiperidine derivative, and further subjecting the resulting compound to acylation or alkylation, if desired.
Reaction SMILES: C(=S)=S.[CH:4]1([P:10]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[Cl-:23].Cl.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C(O)C>[Cl-:23].[CH:17]1([PH+:10]([CH:4]2[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]2)[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: Cl
Agent: [Cl-]
Solvent: CCO
Solvent: S=C=S
Product: C1CCC([PH+](C2CCCCC2)C2CCCCC2)CC1
Reaction time: 1 h

Procedure:
225 g cyclohexyl chloride and 750 ml diethylether are mixed. 100 ml of this mixture is added to 48.0 g magnesium turnings, and the reaction is started by adding 1 ml 1,2-dibromethane. The remaining cyclohexyl chloride mixture is added to the magnesium turnings within 3.5 hours under cooling at 38-40° C. The suspension is stirred again for one hour, cooled down to room temperature, and the cyclohexyl magnesium chloride solution is decanted from the remaining magnesium turnings. 156.7 g of the Grignard solution obtained in this manner is mixed with 120 ml tetrahydrofuran and slowly added to a mixture of 18.1 g phosphorus trichloride and 60 ml tetrahydrofuran at −20° C., and to an additional 100 ml tetrahydrofuran 20° C. After one hour of stirring at 37° C., the reaction mixture is added to 110 ml of a 15% ammonium chloride solution in water and 70 ml water at 20° C. The lower phase is separated and discarded. To the organic phase is added 10.1 g carbon disulfide. During this process, a reddish-brown precipitate is obtained, which is filtered off after 3 days, and washed three times each with 20 ml petrolether. After drying the solid at 35° C. under vacuum, 25.4 g (54%) of a tricyclohexylphosphine carbon disulfide adduct (CAS-Nr.: 4635-58-9) is obtained as a reddish-brown solid. From a mixture of 17.8 g of the tricyclohexyl phosphine carbon disulfide adduct and 100 ml ethanol, 80 ml of solvent is distilled off at 78-79° C. The oily residue is taken up in 80 ml tert-butylmethylether, and the tricyclohexyl phosphine solution is treated with hydrogen chloride at 20° C. The resulting suspension is diluted with 70 ml tert-butylmethylether. After complete precipitation of the tricyclohexyl phosphine as hydrochloride salt the solvent is evaporated off, and the solid residue is taken up in 100 ml tert-butylmethylether. The solid is filtered off, washed twice with 10 ml tert-butylmethylether each, and dried at 0.02 mbar. 13.1 g of a colorless hygroscopic solid is obtained. It contains 22.5% chloride so that it is assumed that in addition to the hydrochloride an additional equivalent hydrogen chloride is bound in the crystal (calculated for PCy3*2 HCl: 20.1% chloride). If a sample of the solid is left at open atmosphere, it will melt after one hour.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:32])([CH3:31])[CH:11]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:12]([O:14][CH2:15][CH2:16][O:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:13])(=[O:7])=[O:6].[N-:33]=[N+:34]=[N-:35].[Na+]>CS(C)=O>[N:33]([CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:32])([CH3:31])[C@@H:11]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:12]([O:14][CH2:15][CH2:16][O:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:13])(=[O:7])=[O:6])=[N+:34]=[N-:35]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)OCCOC(=O)C(OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCCl
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)OCCOC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCN=[N+]=[N-]

Procedure:
Following the general procedure for the preparation of azides of Description 16, (ethoxycarbonyloxy)ethyl (2R/S)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoate (37a) (4.5 g max.) dissolved in 50 mL of anhydrous dimethyl sulfoxide (DMSO) was reacted with 0.88 g (13.5 mmol) of sodium azide (NaN3). After work-up, the crude title compound (37b) was obtained and used in the next step without further purification. The analytical data was consistent with the data obtained for (ethoxycarbonyloxy)ethyl (2R)-4-[(3-azidopropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoate (32b).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:26])[F:25])=[O:17])[CH2:12][CH2:11]2)=[N:8][CH:9]=1)([O-])=O.[H][H]>C1COCC1.CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:11][CH2:12][N:13]([C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:26])[F:25])=[O:17])[CH2:14][CH2:15]2)=[N:8][CH:9]=1
Reactant: [H][H]
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nc1
Yield: 86.3 %

Procedure:
A mixture of [4-(5-nitropyridin-2-yl)piperazin-1-yl]-(2-trifluoromethylphenyl)-methanone (0.15 g, 0.4 mmol) and Pd—C (76 mg) in THF (5 mL) and MeOH (5 mL) was exposed to a hydrogen atmosphere at 25° C. for 2 h. The reaction mixture was filtered and the solution was concentrated in vacuo to provide the title compound as a dark purple solid (0.121 g, 86% yield). MS (ES+) m/z 351.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6](=[O:12])[NH:7][CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=1[CH:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=1[CH:25]([NH:32][C:9]([CH2:8][NH:7][C:6](=[O:12])[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:14][CH:13]=1)=[O:11])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NC(c1ccccc1)c1cc([N+](=O)[O-])ccc1Cl
Reactant: O=C(O)CNC(=O)c1ccc(F)cc1
Product: O=C(CNC(=O)c1ccc(F)cc1)NC(c1ccccc1)c1cc([N+](=O)[O-])ccc1Cl

Procedure:
Prepared in analogy to example 1.1 from 4-fluoro-hippuric acid (CA [366-79-0]) and rac-C-(2-chloro-5-nitro-phenyl)-C-phenyl-methylamine (example 4.4).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:16]=[CH:17][CH:18]=1)[NH:8][C:9](=[O:15])[CH:10]=[CH:11]OCC)=[O:4]>S(=O)(=O)(O)O>[CH3:1][O:2][C:3]([C:5]1[CH:18]=[CH:17][CH:16]=[C:7]2[C:6]=1[CH:11]=[CH:10][C:9](=[O:15])[NH:8]2)=[O:4]
Reactant: CCOC=CC(=O)Nc1cccc(C(=O)OC)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc2[nH]c(=O)ccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10 Grams of m-methoxycarbonyl-N-(β-ethoxyacryloyl)aniline was added to 100 ml of concentrated sulfuric acid gradually, and this mixture was stirred at a room temperature for 2 hours, then at 45° C. for 4 hours. The reaction mixture was poured in ice-water, and the precipitated crystals were collected by filtration and were washed with water. Thus obtained crude crystals were recrystallized from methanol-chloroform to obtain 6.97 g of 5-methoxycarbonylcarbostyril.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[OH:8][CH:9]([C:16]1[CH:17]=[C:18]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:19]=[N:20][C:21]=1[O:22][CH3:23])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.O>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([O:8][CH:9]([C:16]1[CH:17]=[C:18]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:19]=[N:20][C:21]=1[O:22][CH3:23])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)(=[O:3])[CH3:2]
Reactant: COc1nnc(-c2ccccc2)cc1C(O)c1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1nnc(-c2ccccc2)cc1C(OC(C)=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5.0 ml of acetic acid anhydride was slowly added dropwise into a solution of 1.39 g of 5-(α-hydroxybenzyl)-3-phenyl-6-methoxypyridazine, 174 mg of 4-dimethylaminopyridine and 1.0 ml of triethylamine in 10 ml of dichloromethane under ice-cooling. After stirring at room temperature for one hour, water was added to the reaction solution. After extracting with dichloromethane, the organic phase was washed with brine. After removing the solvent, the residue was subjected to NH-silica gel (Fuji Silicia) and eluted with ethyl acetate, to give 1.58 g of the target compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[CH2:5][CH2:6][C:7]1[NH:8][CH:9]=[C:10]([CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[N:19][CH:20]=2)[C:11](=[O:13])[N:12]=1.[Cu][C:26]#[N:27]>CN1C(=O)CCC1>[F:24][C:23]1[CH:22]=[CH:21][C:4]([CH2:5][CH2:6][C:7]2[NH:8][CH:9]=[C:10]([CH2:14][C:15]3[CH:16]=[N:17][CH:18]=[N:19][CH:20]=3)[C:11](=[O:13])[N:12]=2)=[CH:3][C:2]=1[C:26]#[N:27]
Reactant: O=c1nc(CCc2ccc(F)c(Br)c2)[nH]cc1Cc1cncnc1
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: N#Cc1cc(CCc2nc(=O)c(Cc3cncnc3)c[nH]2)ccc1F
Temperature: 200 °C
Yield: 80.6 %

Procedure:
A mixture of 2-(3-bromo-4-fluorophenethyl)-5-(pyrimidin-5-ylmethyl)pyrimidin-4(1H)-one (1.5 g, 3.7 mmol), copper(I) cyanide (399 mg, 4.4 mmol) in NMP (5 mL) was heated with a microwave reactor at 200° C. for 1.5 h. After cooling to room temperature, the mixture was filtered. The filtrate was partitioned between ethyl acetate (20 mL) and water (30 mL). The organic phase was collected, washed with water (30 mL×2), brine (20 mL), dried over Na2SO4, filtered, and concentrated to give the title compound as a gray solid (1.0 g, 55% yield), which was used without further purification. LCMS: rt=1.31 min, [M+H+]=336
Reaction SMILES: C([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:69]/[O:70]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)/[C:27]([NH:29][CH:30]2[C:67](=[O:68])[N:32]3[C:33]([C:51]([O:53]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:52])=[C:34](/[CH:37]=[CH:38]/[CH2:39][N:40]4[C:44]5[CH:45]=[C:46]([OH:50])[C:47]([OH:49])=[CH:48][C:43]=5[N:42]=[CH:41]4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>FC(F)(F)C(O)=O.C(OC(C)C)(C)C>[NH2:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:69]/[OH:70])/[C:27]([NH:29][CH:30]2[C:67](=[O:68])[N:32]3[C:33]([C:51]([OH:53])=[O:52])=[C:34](/[CH:37]=[CH:38]/[CH2:39][N:40]4[C:44]5[CH:45]=[C:46]([OH:50])[C:47]([OH:49])=[CH:48][C:43]=5[N:42]=[CH:41]4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1
Reactant: O=C(OC(c1ccccc1)c1ccccc1)C1=C(/C=C/Cn2cnc3cc(O)c(O)cc32)CS[C@@H]2C(NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)C(=O)N12
Solvent: CC(C)OC(C)C
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(/C(=N/O)C(=O)NC2C(=O)N3C(C(=O)O)=C(/C=C/Cn4cnc5cc(O)c(O)cc54)CS[C@H]23)cs1
Temperature: 25 °C
Yield: 13 %

Procedure:
Diphenylmethyl 7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-[(E)-(5,6-dihydroxybenzimidazol-1-yl)-1-propen-1-yl]-3-cephem-4-carboxylate (XIb) (125 mg was dissolved in trifluoroacetic acid (TFA, 1.2 ml), stirred at room temperature for an hour and diluted with isopropyl ether to precipitate 63 mg of a crude product. The product was chromatographed on a column of Prep C18 (Waters) with water and 5% acetonitrile in water as eluants. The desired fractions, checked by HPLC*, were combined, concentrated to a small volume and freeze-dried to afford 7 mg (13% yield) of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([Cl:21])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.C(OC(=O)C(C1C=CC(S(C)(=O)=O)=C(Cl)C=1)CC1CCCC1)C.[OH-].[K+]>C(O)C.O>[Cl:21][C:13]1[CH:12]=[C:11]([CH:4]([CH2:5][CH:6]2[CH2:10][CH2:9][CH2:8][CH2:7]2)[C:3]([OH:22])=[O:2])[CH:16]=[CH:15][C:14]=1[S:17]([CH3:20])(=[O:19])=[O:18]
Reactant: COC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: CCOC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
The mixture of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid methyl ester and 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid ethyl ester, from above, (937 mg) was dissolved in ethanol (30 mL) and allowed to dissolve. To this solution was then added a solution of potassium hydroxide (733 mg, 13.1 mmol) in water (7 mL). The yellow solution was then stirred for 3 h at 25° C. It was concentrated in vacuo to remove the ethanol and then IN hydrochloric acid was added until the pH=2. This was then extracted with methylene chloride (3×15 mL). The organic layers were then dried over sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 75/25 hexanes/ethyl acetate plus 1% acetic acid) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (787 mg, 82% over two steps) as a white solid: mp: 123.9-126.2° C.; FAB-HRMS m/e calcd for C15H19O4SCl (M+H)+331.0771, found 331.0776.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1.[NH3:15]>CCO>[NH2:15][CH2:3][CH:2]([OH:1])[CH2:4][N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1
Reactant: c1ccc2c(c1)CCN(CC1CO1)C2
Reactant: N
Solvent: CCO
Product: NCC(O)CN1CCc2ccccc2C1
Temperature: 80 °C
Yield: 96 %

Procedure:
To a solution of 2-(oxiran-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline (17 g, 0.09 mol) in EtOH (300 mL) at −78° C. was slowly bubbled NH3 (g). The reaction mixture was then sealed and heated at 80° C. for 3 h. The reaction mixture was concentrated and the crude product was used in next step without further purification (18 g, Yield 96%). LCMS (m/z): 207.1 (M+1).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[H-].[Na+].Cl[C:10]1[C:19]2[C:14](=[C:15]([C:20]3[N:24]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH:32]([CH3:34])[CH3:33])=[C:27]([Cl:35])[CH:26]=4)[O:22][N:21]=3)[CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][N:11]=1>CS(C)=O>[Cl:35][C:27]1[CH:26]=[C:25]([C:23]2[O:22][N:21]=[C:20]([C:15]3[CH:16]=[CH:17][CH:18]=[C:19]4[C:14]=3[CH:13]=[CH:12][N:11]=[C:10]4[NH:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3])[N:24]=2)[CH:30]=[CH:29][C:28]=1[O:31][CH:32]([CH3:34])[CH3:33]
Reactant: C[C@H](N)C(=O)O
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(Cl)nccc34)no2)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(N[C@@H](C)C(=O)O)nccc34)no2)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.2 %

Procedure:
A mixture of L-alanine (27.8 mg, 0.312 mmol) and sodium hydride (60%; 9.99 mg, 0.250 mmol) in dimethyl sulfoxide (DMSO) (2 ml) were stirred at room temp for 30 mins. 1-Chloro-5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)isoquinoline (D7; 50 mg, 0.125 mmol) was added and the reaction mixture was left to stir at 120° C. under nitrogen for 48 hrs. The reaction mixture was loaded onto a 10 g SCX column and washed with acetonitrile, then eluted with 10% ammonia in acetonitrile. The solvent was evaporated from the appropriate fractions and the residue was dissolved in dichloromethane and washed with water. The organic phase was passed through a hydrophobic frit and the solvent was removed in vacuo to give the title compound as an orange solid (29 mg)
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10]C(=O)[C:8]2=[O:13])[CH3:2].[OH-:14].[Na+].OO.Cl>>[NH2:10][C:11]1[C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=[CH:6][C:7]=1[C:8]([OH:13])=[O:14]
Reactant: [OH-]
Reactant: CCc1cccc2c1NC(=O)C2=O
Agent: Cl
Agent: OO
Agent: [Na+]
Product: CCc1cccc(C(=O)O)c1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1.0 g of crude 7-ethyl-1H-indole-2,3-dione and 3 ml of a 2N aqueous sodium hydroxide solution was added dropwise to 2 g of aqueous hydrogen peroxide (30%) at room temperature, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was adjusted to pH 4 by an addition of 2N hydrochloric acid, and a deposited precipitate was collected by filtration. The resulting filter cake was partitioned between ethyl acetate and a saturated sodium hydrogen carbonate solution. The aqueous layer was adjusted to pH 4 by an addition of 2N hydrochloric acid, and a deposited precipitate was collected by filtration to obtain 0.42 g of 2-amino-3-ethylbenzoic acid of the formula:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][N:4]=1.[N:12](OC(C)(C)C)=[O:13].CC([O-])(C)C.[K+].Cl>C1COCC1.O.CCOC(C)=O>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([C:9](=[O:11])/[CH:10]=[N:12]/[OH:13])=[CH:7][CH:8]=1
Reactant: CC(C)(C)ON=O
Reactant: COc1ccc(C(C)=O)cn1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)/C=N/O)cn1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 37.8 %

Procedure:
2-Methoxy-5-acetylpyridine (12.1 g) and t-butyl nitrite (9.92 g) were dissolved in THF (120 ml). The solution was cooled at 0-5° C. To the solution was added t-BuOK (10.8 g) at 5-25° C. The reaction mixture was stirred at 25° C. for 2 hours. To the mixture was added 1N HCl (105 ml). The solution was portioned to EtOAc and water. The organic layer was separated. The aqueous layer was extracted with EtOAc. The combined organic solution was washed with 10% aq. NaOAc and brine successively, dried over MgSO4. Evaporation of solvent in vacuo gave solid residue. The residue was pulverized with IPE (150 ml). The precipitated crystals were collected by filtration, to give (1E)-(6-methoxy-3-pyridyl)(oxo)acetaldehyde oxime as a solid (5.45 g) (anti, syn mixture (anti:syn=1:1)). Evaporation of solvent in the filtrate gave a residue. The residue was pulverized with IPE. The precipitated crystals were collected by filtration, to give (1E)-(6-methoxy-3-pyridyl)(oxo)acetaldehyde oxime as a solid (2.5 g) (anti, syn mixture (anti:syn=1:1)).