Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:13][C:12]([C:18]3[CH:23]=[C:22]([Br:24])[C:21]([F:25])=[C:20]([Br:26])[CH:19]=3)([C:14]([F:17])([F:16])[F:15])[O:11][N:10]=2)=[CH:5][C:4]=1[Cl:27].C(N(CC)CC)C.[C:35](Cl)(=[O:39])[CH2:36][CH2:37][CH3:38]>ClCCl.C(Cl)(Cl)Cl>[C:35]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:13][C:12]([C:18]3[CH:23]=[C:22]([Br:24])[C:21]([F:25])=[C:20]([Br:26])[CH:19]=3)([C:14]([F:17])([F:16])[F:15])[O:11][N:10]=2)=[CH:5][C:4]=1[Cl:27])(=[O:39])[CH2:36][CH2:37][CH3:38]
Reactant: NCc1ccc(C2=NOC(c3cc(Br)c(F)c(Br)c3)(C(F)(F)F)C2)cc1Cl
Reactant: CCCC(=O)Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCC(=O)NCc1ccc(C2=NOC(c3cc(Br)c(F)c(Br)c3)(C(F)(F)F)C2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(4-aminomethyl-3-chlorophenyl)-5-(3,5-dibromo-4-fluorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole (70.0 mg) and triethylamine (15.0 mg) in dichloromethane (2 mL) was added butyryl chloride (15.4 mg) at 5° C. The reaction mixture was then stirred at room temperature for 1 hour. The resulting mixture was diluted with chloroform (2 mL) and washed with saturated aqueous sodium hydrogencarbonate solution (3 mL) and brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide a residue. The residue was purified by liquid chromatography (medium pressure collection apparatus: Purif-α2 manufactured by Moritex Corporation) eluted with ethyl acetate-hexane (1:10) to afford the title compound as a colorless resin (42.0 mg).
Reaction SMILES: [CH2:1]([P:3](Cl)([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[Cl:22])[CH:8]=[CH:7][C:6]=1[N+:23]([O-:25])=[O:24])=[O:4])[CH3:2].[OH:27][N:28]=[C:29]([CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([P:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[Cl:22])[CH:8]=[CH:7][C:6]=1[N+:23]([O-:25])=[O:24])([O:27][N:28]=[C:29]([CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:4])[CH3:2]
Reactant: CCP(=O)(Cl)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: CCOC(=O)C(C)=NO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)=NOP(=O)(CC)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinic acid (500 mg, 1.22 mmol) and thionyl chloride (4 ml) is heated under reflux for about 1.5 hours. The reaction mixture is then concentrated to dryness to give P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinic chloride. To a solution of the phosphinic chloride and methylene chloride (10 ml) is added slowly a solution of ethyl 2-hydroxyiminopropionate (320 mg, 2 eq.) and methylene chloride (5 ml) containing triethylamine (0.2 ml, 1.2 eq.). The resulting mixture is stirred at RT for 2 hours. The reaction is then worked up in methylene chloride, washed, dried and evaporated to dryness to give an oily product. The oily product is purified by preparative thin layer chromatography (prep. TLC) in silica gel (50% ethyl acetate/hexane) to yield ethyl 2-[P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinyloxyimino]propionate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[CH2:7][C:8]1[CH:23]=[CH:22][C:11]([O:12][C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)=[C:10]([C:24]#[N:25])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][NH2:36])=[CH:30][CH:29]=1.C(NC(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][NH:36][C:17]([C:16]2[CH:15]=[CH:14][C:13]([O:12][C:11]3[CH:22]=[CH:23][C:8]([CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:26])=[CH:9][C:10]=3[C:24]#[N:25])=[CH:21][CH:20]=2)=[O:18])=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(C(=O)O)cc2)c(C#N)c1
Reactant: NCCc1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(C#N)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.7 %

Procedure:
To 4-(4-(2-tert-butoxy-2-oxoethyl)-2-cyanophenoxy)benzoic acid (0.34 g, 0.962 mmol), 2-(4-chlorophenyl)ethanamine (0.165 g, 1.06 mmol) in DMF (5 ml) was added diisopropylamine (0.200 ml, 1.15 mmol) and HBTU (0.149 g, 1.15 mmol). The reaction was stirred at ambient temperature for 90 minutes. The reaction was diluted with water and the product extracted into ethyl acetate. The combined organic layers were dried (MgSO4), filtered and concentrated to give tert-butyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-cyanophenyl)acetate (0.40 g, 85%) as a white solid after column chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([CH2:15][NH:16]C(=O)OC(C)(C)C)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].Cl>O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=[C:11]([C:24]([F:26])([F:27])[F:25])[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(F)(F)F)nc1-c1ccc(F)c(Cl)c1
Agent: Cl
Solvent: C1COCCO1
Product: NCc1ccc(C(F)(F)F)nc1-c1ccc(F)c(Cl)c1
Reaction time: 12 h
Yield: 186.1 %

Procedure:
To a stirred solution of tert-butyl (2-(3-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyridin-3-yl)methylcarbamate (5.27 g, 13.04 mmol) in 1,4-dioxane (5 mL) was added with 1,4-dioxane.HCl (10 mL) under cooling and the reaction mixture was allowed to stir for 12 h. The reaction mixture was concentrated under reduced pressure and was co-distilled with methanol thrice and the solid obtained was filtered through sintered funnel and was washed with 10% ethyl acetate in n-hexane to afford pure (2-(3-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyridin-3-yl)methanamine hydrochloride (4.14 g, 93%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[ClH:14]>C(O)(C)C.[Pd]>[ClH:14].[C:8]1([CH:6]2[NH:7][C:2]([NH2:1])=[N:3][CH2:4][CH2:5]2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Nc1nccc(-c2ccccc2)n1
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Product: NC1=NCCC(c2ccccc2)N1
Reaction time: 3 h
Yield: 55 %

Procedure:
To a solution of 5 g (29.2 mmoles) of 2-amino-4-phenylpyrimidine in 30 ml of a 6N solution of hydrochloric acid in isopropanol was added 0.1 g of palladium on carbon catalyst (10% wt/wt). The suspension was hydrogenated under 40 psi pressure at room temperature during 3 h. The catalyst was removed by filtration and the solvent evaporated under reduced pressure. Diethyl ether was added and the resulting solution was refiltered and the solvent removed by evaporation under reduced pressure to give 4.0 g (55%) of compound as a crude oil which was used as such.
Reaction SMILES: C(=O)(O)[O-].[Na+].[I-].[K+].[F:8][C:9]1[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:10]=1[O:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.Cl[CH2:27][CH2:28][CH2:29][C:30]1[C:34]2[CH:35]=[CH:36][C:37]([F:39])=[CH:38][C:33]=2[O:32][N:31]=1>CN(C)C=O.O>[F:39][C:37]1[CH:36]=[CH:35][C:34]2[C:30]([CH2:29][CH2:28][CH2:27][N:15]3[CH2:16][CH2:17][CH:12]([O:11][C:10]4[C:18]([F:25])=[C:19]([F:24])[C:20]([F:23])=[C:21]([F:22])[C:9]=4[F:8])[CH2:13][CH2:14]3)=[N:31][O:32][C:33]=2[CH:38]=1
Reactant: Fc1c(F)c(F)c(OC2CCNCC2)c(F)c1F
Reactant: Fc1ccc2c(CCCCl)noc2c1
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc2c(CCCN3CCC(Oc4c(F)c(F)c(F)c(F)c4F)CC3)noc2c1
Temperature: 68 °C
Reaction time: 5.5 h
Yield: 38.3 %

Procedure:
A mixture of 10 g of sodium bicarbonate, and 0.10 g of potassium iodide, 4.13 g of 4-(2,3,4,5,6-pentafluorophenoxy)piperidine and 75 ml of dimethylformamide was treated with a solution of 3.41 g of 3-(3-chloropropyl)-6-fluoro-1,2-benzisoxazole in 25 ml dimethylformamide and stirred at 68° C. for 5.5 hours. The mixture was then cooled, poured into water, and then extracted with ethyl acetate. The organic layer was washed with water followed by a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtering, evaporation of the volatiles afforded a residue which was purified by means of high pressure liquid chromatography (silica gel; elution with ethyl acetate) to yield 2.63 g of 1-[-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-4-(2,3,4,5,6-pentafluorophenoxy)piperidine as an oil. The oil was dissolved in diethyl ether and the solution acidified to pH 1 with etheral hydrogen chloride to precipitate the corresponding hydrochloride salt. Recrystallization from isopropanol afforded 1.80 g (15.4%) of 1-[ -(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-4-(2,3,4,5,6-pentafluorophenoxy)piperidine hydrochloride, m.p. 187°-189° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:17][C:18]2[N:28]=[C:27]3[C:21]([N:22]([CH3:35])[C:23](=[O:34])[CH2:24][CH2:25][N:26]3[CH:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:20][N:19]=2)=[CH:4][C:5]([F:16])=[C:6]([CH:15]=1)[C:7]([NH:9][C@@H:10]1[CH2:14][CH2:13][NH:12][CH2:11]1)=[O:8].[C:36](O)(=O)C.C([O-])(=O)C.[Na+].C([BH3-])#N.[Na+]>C=O>[Cl:1][C:2]1[C:3]([NH:17][C:18]2[N:28]=[C:27]3[C:21]([N:22]([CH3:35])[C:23](=[O:34])[CH2:24][CH2:25][N:26]3[CH:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:20][N:19]=2)=[CH:4][C:5]([F:16])=[C:6]([CH:15]=1)[C:7]([NH:9][C@@H:10]1[CH2:14][CH2:13][N:12]([CH3:36])[CH2:11]1)=[O:8]
Reactant: CN1C(=O)CCN(C2CCCC2)c2nc(Nc3cc(F)c(C(=O)N[C@@H]4CCNC4)cc3Cl)ncc21
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Product: CN1CC[C@@H](NC(=O)c2cc(Cl)c(Nc3ncc4c(n3)N(C3CCCC3)CCC(=O)N4C)cc2F)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.4 %

Procedure:
5-chloro-4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-10-yl)amino]-2-fluoro-N-[(3R)-pyrrolidin-3-yl]benzamide (Example 321; 95 mg, 0.19 mmol) was dissolved in 37% aqueous formaldehyde solution (1.1 mL) and acetic acid (120 μl, 1.89 mmol). Sodium acetate (156 mg, 1.89 mmol) was added and the mixture cooled in an ice/water bath. Sodium cyanoborohydride (12 mg, 0.19 mmol) was added and the mixture allowed to warm to room temperature. After stirring for 1 hour, the mixture was absorbed on to an SCX column, and subsequently washed with methanol and eluted with ammonia in methanol. The product containing fractions were concentrated and purified by column chromatography (2% 7N ammonia in methanol/DCM) to yield the title compound as a white foam (69 mg, 70%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH:8]([C:12](=[O:23])[NH:13][C:14]1[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[O:16][N:15]=1)[CH2:9][CH2:10]C)([CH3:4])([CH3:3])[CH3:2].NC1C=CON=1>>[C:1]([O:5][C:6](=[O:24])[NH:7][CH:8]([C:12](=[O:23])[NH:13][C:14]1[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[O:16][N:15]=1)[CH2:9][CH3:10])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCCC(NC(=O)OC(C)(C)C)C(=O)Nc1cc(C(C)(C)C)on1
Agent: Nc1ccon1
Product: CCC(NC(=O)OC(C)(C)C)C(=O)Nc1cc(C(C)(C)C)on1

Procedure:
Prepared by the analogous method for the preparation of [1-(5-tert-butyl-isoxazol-3-ylcarbamoyl)butyl]-carbamic acid tert-butyl ester, starting with an appropriate amino-isoxazole (1 a-b) together with an appropriate N-t-BOC-amino acid methyl or ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[CH:8]=2)[C:3]=1[C:18]([OH:20])=O.Cl.C(N=C=NCCCN(C)C)C.[F:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[CH:36][CH:35]=1>ClCCl>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:15])([F:16])[F:17])[CH:8]=2)[C:3]=1[C:18]([N:43]1[CH2:42][CH2:41][N:40]([C:37]2[CH:36]=[CH:35][C:34]([F:33])=[CH:39][CH:38]=2)[CH2:45][CH2:44]1)=[O:20]
Reactant: Nc1onc(-c2cccc(OC(F)(F)F)c2)c1C(=O)O
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Nc1onc(-c2cccc(OC(F)(F)F)c2)c1C(=O)N1CCN(c2ccc(F)cc2)CC1
Yield: 73.4 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-amino-3-(3-(trifluoromethoxy)phenyl)isoxazol-4-carboxylic acid (530 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(4-fluorophenyl)piperazine (332 mg, 1.84 mmol), a white solid required compound (609 mg, 1.35 mmol, 73%) was obtained.
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])[OH:2].[NH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][N:8]=1.[N+:17]([O-])([O-:19])=[O:18].[K+]>O>[NH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([N+:17]([O-:19])=[O:18])=[CH:9][N:8]=1.[OH:4][S:1]([OH:5])(=[O:3])=[O:2]
Reactant: Nc1nccc2ccccc12
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: Nc1ncc([N+](=O)[O-])c2ccccc12
Temperature: 0 °C
Yield: 62 %

Procedure:
Cool sulfuric acid (900 mL) to 5° C. using an ice/acetone bath, then add 1-aminoisoquinoline (208.8 g, 1448 mmol) over 45 min keeping the internal temperature of the mixture <20° C. Cool the dark mixture to 0° C. under nitrogen with mechanical stirring then treat with KNO3 (149.4 g, 1477 mmol) in portions over 45 min keeping the reaction mixture's temperature <10° C. Stir the mixture for 2 hours while warming to 15° C. Pour the mixture into water/ice (3 kg) then dilute with additional water (6 L). Stir the slurry for 45 min then filter. Wash the cake with water (6×1.5 L). Partially dry the golden material by air overnight then place in a vacuum oven (50-55° C., ca. 10 torr, nitrogen bleed, 24 h) to afford 1-amino-4-nitroisoquinoline H2SO4 (256.8 g, 62% yield). (ES+): m/z 190 (M++H).
Reaction SMILES: [C:1]([C:9]1[CH:15]=[C:14]([C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([OH:13])=[CH:11][C:10]=1[OH:24])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:27](Cl)[CH:28]=[CH2:29]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:29]([C:11]1[C:12]([OH:13])=[C:14]([C:16](=[O:23])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:15]=[C:9]([C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:10]=1[OH:24])[CH:28]=[CH2:27]
Reactant: C=CCCl
Reactant: O=C(c1ccccc1)c1cc(C(=O)c2ccccc2)c(O)cc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Product: C=CCc1c(O)c(C(=O)c2ccccc2)cc(C(=O)c2ccccc2)c1O
Yield: 67 %

Procedure:
A round bottomed flask equipped with a reflux condenser and magnetic stirrer was charged with 6.36 g (20 mmol) of 4,6-dibenzoylresorcinol, as prepared in Example 1, and 22 ml of 1.0N aqueous NaOH. 63 mg of tetrabutylammonium bromide and 10.0 ml of allyl chloride were added to produce a reaction mixture. The reaction mixture was stirred vigorously and heated at reflux for about 5 hours. Excess allyl chloride was distilled and recovered and 1 ml of 5% aqueous HCl was added to neutralize any excess base. The resulting solid was filtered and recrystallized from an ethanol/chloroform mixture to yield 4.8 g (67%) of 2-allyl-4,6-dibenzoylresorcinol.
Reaction SMILES: C([NH:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=1)[C:10]([OH:12])=O)(OC(C)(C)C)=O.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[C:54]([OH:60])([C:56]([F:59])([F:58])[F:57])=[O:55]>CN(C=O)C.C(Cl)Cl.CCN(CC)CC>[F:57][C:56]([F:59])([F:58])[C:54]([OH:60])=[O:55].[NH2:8][CH:9]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]#[N:21])=[CH:18][CH:19]=1)[C:10]([N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:12]
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(C#N)cc1)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(CC(N)C(=O)N2CCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4.06 g of 2-[N-(Boc)amino]-3-(4-cyanophenyl)propionic acid are mixed with 1.15 ml of pyrrolidine and 7.5 g of BOP in 20 ml of DMF; the mixture is left stirring for 2 hours at RT while maintaining at pH 7 by addition of Et3N. After evaporating to dryness, the residue is chromatographed on silica, eluting with a chloroform/methanol mixture (9/0.5; v/v). After evaporating off the solvents, the solid obtained is treated with 20 ml of TFA in 20 ml of DCM for 30 minutes at RT. The solvents are evaporated off and the residue is taken up in ether and then dried in order to obtain 3.95 g of the expected product.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SC)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[NH:34]1[CH2:39][CH2:38][CH2:37][C@@H:36]([C:40]([OH:42])=[O:41])[CH2:35]1>>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:29])([F:31])[F:30])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:34]4[CH2:39][CH2:38][CH2:37][C@@H:36]([C:40]([OH:42])=[O:41])[CH2:35]4)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: O=C(O)[C@@H]1CCCNC1
Product: O=C1N=C(N2CCC[C@@H](C(=O)O)C2)SC1=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1

Procedure:
1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidine-3-(R)-carboxylic acid was prepared from 5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and piperidine-3-(R)-carboxylic acid following General Procedure C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].[F:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16]>N1C=CC=CC=1>[F:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([NH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11])=[O:16]
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Reactant: O=C(Cl)c1ccccc1F
Solvent: c1ccncc1
Product: O=C(Nc1c(O)cccc1[N+](=O)[O-])c1ccccc1F
Yield: 85.1 %

Procedure:
1.57 g (10 mmol) of 2-amino-3-nitrophenol was dissolved in 20 ml of pyridine and 3.36 g (21 mmol) of 2-fluorobenzoyl chloride was added thereto under stirring. After heating under reflux for 4 hours, the mixture was concentrated. Then dilute hydrochloric acid and ethyl acetate were added thereto. The organic layer was separated and washed with water. After concentrating, 20 ml of tetrahydrofuran and 20 ml of 1N sodium hydroxide were added and the mixture was heated under reflux for 4 hours. After cooling, it was neutralized with hydrochloric acid and concentrated. After adding ethyl acetate and water, the organic layer was separated, washed with water and dried over magnesium sulfate. After concentrating, the residue was purified by silica gel column chromatography. Thus 2.35 g of 2-fluoro-N-(2-hydroxy-6-nitrophenyl)benzamide was obtained. 553 mg (2 mmol) of this powder was dissolved in 20 ml of dimethylformamide and 332 mg (2.4 mmol) of potassium carbonate and 20 mg of a copper powder were added thereto. After heating under reflux for 3 hours and concentrating, ethyl acetate and dilute hydrochloric acid were added to the residue. The formed insoluble matters were filtered off and the organic layer was separated, washed with water, dried over magnesium sulfate and concentrated. Then the residue was purified by silica gel column chromatography. Thus 400 mg of the title compound was obtained.
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: O=C(Cl)c1ccccc1
Reactant: Cc1ccc2c(c1)ncn2-c1ccc2[nH]ccc2c1
Agent: CC[Mg]Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCOCC
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]1([CH2:7][C:8]([NH:10][CH:11]2[C:45](=[O:46])[N:13]3[C:14]([C:29]([O:31][CH:32]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[O:30])=[C:15]([CH2:19][S:20][C:21]4[N:22]=[N:23][N:24]([CH2:26][C:27]#[CH:28])[N:25]=4)[CH2:16][S:17](=O)[C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)C=O.P(Cl)(Cl)Cl>O>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:45](=[O:46])[N:13]3[C:14]([C:29]([O:31][CH:32]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[O:30])=[C:15]([CH2:19][S:20][C:21]4[N:22]=[N:23][N:24]([CH2:26][C:27]#[CH:28])[N:25]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#CCn1nnc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)Cc4ccccc4)[C@H]3S(=O)C2)n1
Solvent: CN(C)C=O
Solvent: O
Solvent: ClP(Cl)Cl
Product: C#CCn1nnc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)Cc4ccccc4)[C@H]3SC2)n1
Temperature: -30 °C
Reaction time: 0.83 h
Yield: 91.8 %

Procedure:
A mixture of benzhydryl 7-(2-phenylacetamido)-3-[2-(2-propynyl)-2H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylate-1-oxide (16.0 g) and dry N,N-dimethylformamide (160 ml) was cooled to -30° C. and thereto was added phosphorus trichloride (6.7 g). The resulting solution was stirred for 50 minutes at -30° C. The reaction mixture was allowed to warm to ambient temperature, added to water (200 ml) and then extracted with ethyl acetate (×3). The extracts were combined, washed successively with a saturated aqueous solution of sodium bicarbonate (×3) and water (×3), dried over magnesium sulfate, treated with activated charcoal and then evaporated. The residue was pulverized in a mixture of isopropyl ether and n-hexane, collected by filtration, washed with n-hexane and then dried to give benzhydryl 7-(2-phenylacetamido)-3-[2-(2-propynyl)-2H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylate (14.33 g).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:14][S:15]([CH2:18][CH2:19]COS(C)(=O)=O)(=[O:17])=[O:16]>>[CH3:14][S:15]([CH2:18][CH2:19][CH2:6][N:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)CCCOS(C)(=O)=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CS(=O)(=O)CCCN1CCNCC1

Procedure:
The title compound was prepared from 1-tert-butyloxycarbonyl-piperazine and methanesulfonic acid 3-methanesulfonyl-propyl ester (prepared according to Baerlocher, F. J. et al. Aust. J. Chem. 1999, 52, 167-172) in an analogous manner as described in example 21.