Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]([C@@H:5]1[C@:22]2([CH3:23])[C@H:8]([C@H:9]3[C@H:19]([CH2:20][CH2:21]2)[C@:17]2([CH3:18])[C:12](=[C:13]([N+:25]([O-])=O)[C:14](=[O:24])[CH2:15][CH2:16]2)[CH2:11][CH2:10]3)[CH2:7][CH2:6]1)[CH3:4].N1C2C(=CC=CC=2)C=CC=1>C(O)C.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[NH2:25][C:13]1[C:14](=[O:24])[CH2:15][CH2:16][C@@:17]2([CH3:18])[C:12]=1[CH2:11][CH2:10][C@@H:9]1[C@@H:19]2[CH2:20][CH2:21][C@@:22]2([CH3:23])[C@H:8]1[CH2:7][CH2:6][C@@H:5]2[CH:3]([CH2:2][OH:1])[CH3:4]
Reactant: CC(CO)[C@H]1CC[C@H]2[C@@H]3CCC4=C([N+](=O)[O-])C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCO
Solvent: c1ccc2ncccc2c1
Product: CC(CO)[C@H]1CC[C@H]2[C@@H]3CCC4=C(N)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 24 h

Procedure:
A solution of 20-hydroxymethyl-4-nitropregn-4-en-3-one (2.01 g, 5.35 mM) in absolute ethanol (28 mL) is treated sequentially with Lindlar's catalyst (5% Pd on CaCO3 with 5.2% Pb, 0.81 g) and with quinoline (37 μl) and kept under hydrogen at between 40-55 p.s.i. for 24 hours. The mixture is then filtered through celite, and the filtrate is concentrated to a yellow solid which is purified by short path chromatography to give 4-amino-20-hydroxymethylpregn-4-en-3-one, m.p. 180°-185° C. (aqueous isopropanol).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([C:13]2[N:14]=[CH:15][N:16]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:17]=2)([OH:12])[CH:9]([CH3:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=1)CCC.O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:10][CH:9]([CH3:11])[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=2)[CH:3]=1)([C:13]1[N:14]=[CH:15][N:16]([C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=1)[OH:12]
Reactant: CC(C)C(O)(c1cccc(Br)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)C(O)(c1cccc(-c2ccccn2)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 80 °C
Reaction time: 5 h
Yield: 50.3 %

Procedure:
1-(3-Bromophenyl)-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol (1.15 g) and a solution of tri-n-butyl(2-pyridyl)tin (1.01 g) in DMF (10 ml) was deaerated and tetrakis(triphenylphosphine)palladium(0) (73.1 mg) was added. The mixture was stirred under an argon atmosphere at 80° C. for 5 h and copper(I) iodide (20.1 mg) and tetrakis(triphenylphosphine)palladium(0) (48.7 mg) were added. The mixture was stirred at 100° C. for 18 h. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate, washed with 5% aqueous ethylenediamine solution, water (twice) and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chomatography (eluent; hexane:ethyl acetate=3:1→2:1). Recrystallization from ethyl acetate-hexane gave the title compound (577 mg, 51%) as colorless powder crystals.
Reaction SMILES: [NH:1]([C:3]1[S:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)[NH2:2].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:22]2[C@H:31]3[C@H:26]([CH2:27][CH2:28][CH2:29][CH2:30]3)[C:25](=[O:32])N(CCO)N=2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]>>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:22]2[C@H:31]3[C@H:26]([CH2:27][CH:28]=[CH:29][CH2:30]3)[C:25](=[O:32])[N:1]([C:3]3[S:4][C:5]4[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=4[N:7]=3)[N:2]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: COc1ccc(C2=NN(CCO)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Reactant: NNc1nc2ccccc2s1
Product: COc1ccc(C2=NN(c3nc4ccccc4s3)C(=O)[C@H]3CC=CC[C@@H]23)cc1OC

Procedure:
Prepared from compound C and 2-hydrazinobenzothiazole as described for compound 35. Crystallized from ethyl acetate/petroleum ether (60°-80° C). M.p. 176°-177° C.
Reaction SMILES: I[CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[CH:26]([NH:27][C:28](=[O:58])/[C:29](=[N:55]\[O:56][CH3:57])/[C:30]3[N:31]=[C:32]([NH:35]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[S:33][CH:34]=3)[C:25](=[O:59])[N:7]2[C:8]=1[C:9]([O:11]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:10].[S:60]1[C:68]2[CH:67]=[CH:66][N:65]=[CH:64][C:63]=2[N:62]=[CH:61]1>CS(C)=O.C(OCC)(=O)C>[NH2:35][C:32]1[S:33][CH:34]=[C:30](/[C:29](=[N:55]/[O:56][CH3:57])/[C:28]([NH:27][CH:26]2[C:25](=[O:59])[N:7]3[C:8]([C:9]([O-:11])=[O:10])=[C:3]([CH2:2][N+:65]4[CH:66]=[CH:67][C:68]5[S:60][CH:61]=[N:62][C:63]=5[CH:64]=4)[CH2:4][S:5][C@H:6]23)=[O:58])[N:31]=1
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: c1cc2scnc2cn1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccc4scnc4c3)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21 %

Procedure:
A mixture of benzhydryl 3-iodomethyl-7-[(Z)-2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-cephem-4-carboxylate [VIIa] (1.50 g, 1.61 mmoles) and thiazolo[4,5-c]-pyridine (300 mg, 2.20 mmoles) in dry dimethylsulfoxide (DMSO) (7.5 mL) was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (20 mL), washed with water (5 mL), dried and evaporated to dryness. To a solution of the residue in CHCl3 (5 mL) was added ether (50 mL) to give the quaternized blocked cephalosporin [XIIIa] (1.7 g), which was collected by filtration and treated with 90% trifluoroacetic acid [TFA] (17 mL) at room temperature for 1 hour. After evaporation of the solvent, the residue was triturated with ether, filtered and dissolved in CH3OH (2 mL). The solution was treated with 1M sodium 2-ethylhexanoate [SEH] in ethyl acetate (3.2 mL) at room temperature for 30 minutes to afford 774 mg of the crude title compound (Ia), which was purified by HPLC (Column, Lichrosorb RP-18, 8×300 mm; eluted with 0.01M ammonium phosphate buffer, pH 7.2--15% CH3OH) and HP-20 column chromatography (3×30 cm, washed with 1 L of water and eluted with 700 mL of 30% CH3OH). The fractions containing the desired product were collected, concentrated and lyophilized to afford 180 mg (22%) of the title compound (Ia) as a colorless powder, mp 165° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:11]=[C:10]([NH:12][C:13]([N:15]3[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]3)=[O:14])[S:9][C:5]=2[N:6]=[CH:7][N:8]=1.[Cl:22][C:23]1[CH:24]=[C:25]([Mg]Br)[CH:26]=[CH:27][CH:28]=1>O1CCCC1>[CH3:1][O:2][C:3]1[C:4]2[N:11]=[C:10]([NH:12][C:13]([N:15]3[CH2:20][CH2:19][C:18]([C:27]4[CH:26]=[CH:25][CH:24]=[C:23]([Cl:22])[CH:28]=4)([OH:21])[CH2:17][CH2:16]3)=[O:14])[S:9][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: Clc1cccc([Mg]Br)c1
Reactant: COc1ncnc2sc(NC(=O)N3CCC(=O)CC3)nc12
Solvent: C1CCOC1
Product: COc1ncnc2sc(NC(=O)N3CCC(O)(c4cccc(Cl)c4)CC3)nc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 44 %

Procedure:
A solution of 4-oxo-piperidine-1-carboxylic acid (7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-amide (as prepared in Example 59, 100 mg, 0.33 mmol) in tetrahydrofuran (35 mL) cooled to 0° C. was treated with 3-chlorophenyl magnesium bromide (0.5 M in tetrahydrofuran, 1.6 mL, 0.8 mmol). The resulting mixture was stirred at 25° C. for 3 h. At this time, the reaction mixture was cooled to 0° C. and was treated with an additional amount of 3-chlorophenyl magnesium bromide (0.5 M in tetrahydrofuran, 6 mL, 3.0 mmol). The mixture was then allowed to warm to 25° C. and to stir at 25° C. overnight. At this time, the reaction was quenched with methanol and absorbed onto silica gel (6 g). ISCO chromatography (120 g, Silica, gradient elution 7/93 methanol/methylene chloride) afforded 4-(3-chloro-phenyl)-4-hydroxy-piperidine-1-carboxylic acid (7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-amide (61 mg, 44%) as a light brown solid; LRMS for C18H18ClN5O3S (M+H)+ at m/z=420. The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[CH2:23]([S:30]([CH2:33][CH2:34][CH2:35][CH2:36]Cl)(=[O:32])=[O:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[ClH:20].[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:36][CH2:35][CH2:34][CH2:33][S:30]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:31])=[O:32])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: O=S(=O)(CCCCCl)Cc1ccccc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCS(=O)(=O)Cc2ccccc2)CC1
Yield: 65.4 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (2 g) and 4-(benzylsulfonyl)butyl chloride (1.46 g) were reacted and treated in the same manner as in Example 199 to give 0.96 g of 4-amino-N-((1-(4-(benzylsulfonyl)butyl)piperidin-4-yl)-methyl)-5-chloro-2-methoxybenzamide hydrochloride.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[CH3:5][C:6]1[NH:10][N:9]=[C:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])[N:7]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:5][C:6]1[NH:10][N:9]=[C:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:18]=[C:1]=[S:2])[N:7]=1
Reactant: S=C(Cl)Cl
Reactant: Cc1nc(Cc2ccccc2N)n[nH]1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(Cc2ccccc2N=C=S)n[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5.41 g of thiophosgene in 30 ml of methylene chloride is added dropwise at 0° a solution of 7.5 g of 5-methyl-3-(o-aminobenzyl)-1,2,4-triazole and 8.07 g of triethylamine in 285 ml of methylene chloride over a period of 45 minutes. The mixture is stirred at room temperature overnight, washed first with 10% aqueous potassium bicarbonate, then with water, dried over magnesium sulfate, decolorized with charcoal and evaporated to dryness to give 5-methyl-3-(o-isothiocyanatobenzyl)-1,2,4-triazole; IR 2080 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][NH:5][C:6](=[O:10])[CH2:7][C:8]#[N:9].[CH3:15][C:16](=O)[CH2:17][C:18](=O)[CH3:19].N1CCCCC1>C(O)C>[Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][N:5]1[C:16]([CH3:15])=[CH:17][C:18]([CH3:19])=[C:7]([C:8]#[N:9])[C:6]1=[O:10]
Reactant: CC(=O)CC(C)=O
Reactant: N#CCC(=O)NCc1ccccc1Cl
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C)n(Cc2ccccc2Cl)c(=O)c1C#N
Yield: 87 %

Procedure:
A solution of N-(2'-chlorobenzyl)-2-cyanoacetamide 179 g. (0.86 mole) and 2,4-pentanedione 86 g. (0.86 mole) in 500 ml. of 95% ethanol containing 10 ml. of piperidine is refluxed for 24 hours, after cooling the white crystalline product is isolated by vacuum filtration washed with ether and dried in vacuo to give 237.3 g. (87% yield) mp>250° C.;ν2210 (CN) and 1650 cm.-1 (C=O).
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH:28]=[CH:29][CH:30]=1)[CH2:10][N:11]1[C:16](=[O:17])[CH:15]=[CH:14][C:13]([C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=2)=[N:12]1)=[O:5])[CH3:2].[OH-].[Li+]>O1CCCC1.O>[CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH:28]=[CH:29][CH:30]=1)[CH2:10][N:11]1[C:16](=[O:17])[CH:15]=[CH:14][C:13]([C:18]2[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:26][CH:27]=2)=[N:12]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)Nc1cccc(Cn2nc(-c3ccc(C(=O)OC)cc3)ccc2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)Nc1cccc(Cn2nc(-c3ccc(C(=O)O)cc3)ccc2=O)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
42 g (22 mmol) of methyl 4-[1-(3-ethoxycarbonylaminobenzyl)-6-oxo-1,6-dihydropyridazin-3-yl]benzoate (contaminated with triphenylphosphine oxide) are dissolved in 300 ml of tetrahydrofuran and 30 ml of water, 1.6 g (66 mmol) of lithium hydroxide are added, and the mixture is stirred at room temperature for 15 h. The reaction mixture is evaporated. The residue is dissolved in 400 ml of water and 200 ml of ethyl acetate, the organic phase is separated off, and the aqueous phase is extracted with 2×200 ml of ethyl acetate. The organic phase is discarded, conc. HCl is added to the aqueous phase to pH 4-5. During this operation, a precipitate deposits, which is filtered off with suction, washed with water and dried.
Reaction SMILES: [OH:1][S:2]([C:5]([F:8])([F:7])[F:6])(=[O:4])=[O:3].[NH2:9][C:10]1[C:18]2[C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[S:15][C:14]=2[CH:13]=[CH:12][CH:11]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>N1C=CC=CC=1.O>[OH:4][S:2]([C:5]([F:8])([F:7])[F:6])(=[O:3])=[O:1].[C:23]([NH:9][C:10]1[C:18]2[C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[S:15][C:14]=2[CH:13]=[CH:12][CH:11]=1)(=[O:25])[CH3:24]
Reactant: Nc1cccc2sc3ccccc3c12
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1cccc2sc3ccccc3c12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of the aminodibenzothiophene triflate (200 mg, 0.58 mmol) in pyridine (4.0 ml), was added acetic anhydride (0.29 ml, 2.88 mmol) dropwise. The reaction mixture was stirred at room temperature for 12 hours, diluted with water (20 ml), and extracted with ethyl acetate (3×10 ml). The combined organic layers were washed successively with water (2×20 ml), saturated aqueous sodium bicarbonate solution (1×20 ml) and brine (1×20 ml), dried (Na2SO4) and evaporated in vacuo. The residual solid was triturated with petrol to give the title compound (xii).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:12]([O:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH2:11][C:3]1[CH:4]=[CH:8][CH:9]=[CH:10][CH:2]=1)=[O:6])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1c(O)cccc1C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(OCc2ccccc2)cccc1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 174.7 %

Procedure:
To a solution of 3-hydroxy-2-methylbenzoic acid (1.52 g) in DMF (25 mL) were added benzyl bromide (3.40 g) and potassium carbonate (4.14 g), and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the precipitated crystals were collected by filtration, and dried to give the title compound (2.90 g) as a white solid. This compound was used for the next step without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[C:14]4[CH:15]=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=4[N:12]=[CH:11]3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C([Mg]Br)C.CCOCC.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])O.[Na+]>C1C=CC=CC=1>[C:29]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([N:10]3[C:14]4[CH:15]=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=4[N:12]=[CH:11]3)[CH:5]=2)[NH:1][CH:2]=1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Cc1ccc2c(c1)ncn2-c1ccc2[nH]ccc2c1
Reactant: O=C(Cl)c1ccccc1
Agent: CC[Mg]Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: c1ccccc1
Product: Cc1ccc2c(c1)ncn2-c1ccc2[nH]cc(C(=O)c3ccccc3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 6.6 %

Procedure:
To a stirred solution of 1-(indol-5-yl)-5-methylbenzimidazole (1.00 g, 4.04 mmol, 2.0 equivalents) in anhydrous benzene (10 mL) at 0° C. under nitrogen was added a solution of ethyl magnesium bromide in ether (3.0M, 1.33 mL, 4.00 mmol, 2.0 equivalents) dropwise, and the resulting reaction solution was stirred at 0° C. under nitrogen for 30 minutes. Then, benzoyl chloride (0.23 mL, 1.98 mmol) was added dropwise rapidly to the reaction solution, and the resulting mixture was stirred at room temperature under nitrogen for 30 min. A saturated solution of sodium hydrogen carbonate (25 mL) was then added to the reaction mixture, and the resulting aqueous mixture was extracted with ethyl acetate (2×25 mL). The extracts were combined, dried (MgSO4), and evaporated under reduced pressure. The residue (2.1 g) was column chromatographed using silica gel (approximately 100 g) and eluted with ethyl acetate/hexanes (1:1) to afford the title compound (0.045 g, 0.13 mmol, 6%) as a white foam. Rf =0.65 in ethyl acetate/hexanes (1:1); 1H NMR (CD3OD) d 8.05-7.95 (m, 3H), 7.81 (d, J=6.8 Hz, 1H), 7.71 (d, J=8.5 Hz, 1H), 7.61-7.39 (m, 7H), 7.18 (d, J=8.4 Hz, 1H), 2.48 (s, 3H); FAB LRMS (m/z, relative intensity) 352 ([MH]+, 78%), 248 ([MH]+ --Ph(CO), 100).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[CH2:14][C:15]([O:17]C)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[OH-].[Na+]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([CH2:14][C:15]([OH:17])=[O:16])[CH2:19][C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CN(Cc1ccc(Cl)cc1)C1CCN(C(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(N(CC(=O)O)Cc2ccc(Cl)cc2)C1
Temperature: 80 °C

Procedure:
A solution of 3-[(4-chloro-benzyl)-methoxycarbonylmethyl-amino]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.5 g, 1.31 mmol) in methanol (4.00 mL) and 1.0 N NaOH (aqueous) (4.00 mL) was heated to reflux at 80° C. for 2.5 h. The reaction mixture was concentrated, acidified to pH 5.0 using 1.0 N HCl and extracted with dichloromethane (3×). The product was used for the next step without further purification. ESI-MS m/z: 369(M+1), UV retention time: 1.85 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([OH:22])[C:3]=1[O:23][CH3:24].[CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][C:26]=1[C:35](Cl)=[O:36].C(N(CC)CC)C>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:17])[F:18])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([O:22][C:35]([C:26]2[CH:27]=[CH:28][C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:25]=2)=[O:36])[C:3]=1[O:23][CH3:24]
Reactant: COc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1O
Reactant: O=C(Cl)c1ccc2ccccc2c1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1OC(=O)c1ccc2ccccc2c1
Reaction time: 2 h

Procedure:
3-(4-chloro-6-fluoro-2-hydroxy-3-methoxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione (0.10 g, 0.27 mmol) was dissolved in dioxane (10 ml) and the solution added with 2-naphthoyl chloride (0.062 g, 0.33 mmol), triethylamine (0.033 g, 0.33 mmol). After stirred for 2 hr, solvent was evaporated and the residue purified by column chromatography (silica gel, hexane/ether=4/1). Yield: 0.12 g, 0.23 mmol.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:19][CH:20]=[CH2:21])[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1([CH2:19][CH2:20][CH3:21])[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: C=CCC1(C(=O)OCC)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CCO
Product: CCCC1(C(=O)OCC)CCN(C(=O)OC(C)(C)C)CC1

Procedure:
5% Pd/C (0.6 g, 50% wet) is added to a stirred solution of 4-allylpiperidine-1,4-dicarboxylicacid-1-tert-butylester-4-ethyl ester (2.1 g, 0.007 mol) in ethanol (20 mL). Hydrogen gas is bubbled through the reaction mixture at room temperature for 20 minutes. Reaction mixture is filtered through celite bed and washed with methanol (3×5 mL). Combined filtrate is concentrated under reduced pressure to give 4-propylpiperidine-1,4-dicarboxylic acid-1-tert-butyl ester-4-ethyl ester.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1)#[N:2].[N-:13]=[N+:14]=[N-:15].[Na+].[Cl-].[Li+].O>COCCO>[CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[C:1]1[NH:15][N:14]=[N:13][N:2]=1
Reactant: N#Cc1ccc2ccccc2c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: COCCO
Solvent: O
Product: c1ccc2cc(-c3nnn[nH]3)ccc2c1
Temperature: 25 °C
Reaction time: 80 h

Procedure:
A mixture of 10 g of 2-cyanonaphthalene, 10.61 g of sodium azide, and 7.67 g of lithium chloride was placed in a reaction vessel, and 240 ml of 2-methoxyethanol serving as solvent was added thereto. The above mixture was refluxed with stirring for 80 hours. The mixture was cooled to room temperature, and 500 ml of water was added to the mixture.
Reaction SMILES: [CH3:1][N:2]([CH2:11]/[CH:12]=[CH:13]/[C:14]1[CH:19]=[C:18]([CH3:20])[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:16][CH:15]=1)[S:3]([CH2:6][C:7](OC)=[O:8])(=[O:5])=[O:4].[NH2:27][OH:28]>>[OH:28][NH:27][C:7](=[O:8])[CH2:6][S:3]([N:2]([CH3:1])[CH2:11]/[CH:12]=[CH:13]/[C:14]1[CH:19]=[C:18]([CH3:20])[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:16][CH:15]=1)(=[O:5])=[O:4]
Reactant: COC(=O)CS(=O)(=O)N(C)C/C=C/c1ccc(-c2ccccc2)c(C)c1
Reactant: NO
Product: Cc1cc(/C=C/CN(C)S(=O)(=O)CC(=O)NO)ccc1-c1ccccc1

Procedure:
In a manner similar to Example 1 (b), methyl 2-({methyl-[3-(2-methylbiphen-4-yl)-trans-prop-2-enyl]amino}sulfonyl)acetate was reacted with hydroxylamine to give the titled compound as a colourless solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22]I)=[CH:14][CH:13]=3)[CH:10]([CH2:24][CH2:25][CH:26]([OH:34])[C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[C:9]2=[O:35])=[CH:4][CH:3]=1.[CH3:36][NH:37][CH2:38][CH2:39][S:40]([OH:43])(=[O:42])=[O:41].C(=O)([O-])[O-].[K+].[K+]>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9](=[O:35])[CH:10]([CH2:24][CH2:25][CH:26]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[OH:34])[CH:11]2[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][N:37]([CH3:36])[CH2:38][CH2:39][S:40]([OH:43])(=[O:42])=[O:41])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CNCCS(=O)(=O)O
Reactant: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(OCCCCI)cc2)N1c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CN(CCCCOc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)CCS(=O)(=O)O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
64.5 mg of 1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-hydroxypropyl]-4-[4-(4-iodobutoxy)phenyl]azetidin-2-one are dissolved in 3 ml of methanol. 60.7 mg of 2-methylaminoethanesulfonic acid are then dissolved in 1 ml of water, and 30.4 mg of potassium carbonate are added. The reaction is stirred at 50° C. for 8 h. After concentration using a rotary evaporator at 40° C., the residue is passed over a reverse-phase cartridge (methanol). The resulting crude product is dissolved in hot methanol. The precipitate formed on cooling is filtered off, and the mother liquor is concentrated using a rotary evaporator. The product is obtained as an oil. C31H36F2N2O6S (602) MS (ESI): M+-18