Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:17]2[CH:26]=[CH:25][C:24]3[C:23]([CH3:28])([CH3:27])[CH2:22][CH2:21][C:20]([CH3:30])([CH3:29])[C:19]=3[CH:18]=2)O1>>[CH3:27][C:23]1([CH3:28])[CH2:22][CH2:21][C:20]([CH3:30])([CH3:29])[C:19]2[CH:18]=[C:17]([C:2]3[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=3)[CH:26]=[CH:25][C:24]1=2
Reactant: Nc1cccc(Br)n1
Reactant: CC1(C)CCC(C)(C)c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Product: CC1(C)CCC(C)(C)c2cc(-c3cccc(N)n3)ccc21

Procedure:
The preparation is carried out as already described starting from 2.30 g (13.0 mmol) of 6-bromopyridin-2-ylamine and 5.22 g (13.7 mmol) of 4,4,5,5-tetramethyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3,2-dioxaborolane.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][CH2:15][CH:16]=[C:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][CH2:20][C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]2=3)[CH2:7]1)=[O:5])C.[OH-].[Na+].[Cl:34]CCl.Cl>C(O)C>[ClH:34].[CH:28]1[C:19]2[CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:17](=[CH:16][CH2:15][O:14][CH2:13][CH2:12][N:8]3[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]3)[C:18]=2[CH:31]=[CH:30][CH:29]=1
Reactant: ClCCl
Reactant: CCOC(=O)[C@@H]1CCCN(CCOCC=C2c3ccccc3CCc3ccccc32)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)[C@@H]1CCCN(CCOCC=C2c3ccccc3CCc3ccccc32)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The above ester (1.7 g, 4.1 mmol) was dissolved in ethanol (15 ml) and a 4 N sodium hydroxide solution (3.5 ml) was added. The mixture was stirred vigorously at room temperature for 5 h. Dichloromethane (300 ml) was added followed by a 4 N hydrochloric acid solution until pH 1. The mixture was stirred vigorously for a few minutes and the phases were separated. The organic phase was dried over sodium sulphate and the solvent was evaporated in vacuo. The residue was re-evaporated twice with acetone, once with ethyl acetate and once with diethyl ether to give 1.7 g of the title compound as a solid which was recrystallized from acetone.
Reaction SMILES: CN(C=O)C.[N+:6]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[CH:12]2)([O-:8])=[O:7].C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O.C(OCC)(=O)C>[CH2:24]([N:14]1[C:15]2[C:11](=[CH:10][C:9]([N+:6]([O-:8])=[O:7])=[CH:17][CH:16]=2)[CH:12]=[N:13]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc2c(cnn2Cc2ccccc2)c1
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 40.8 %

Procedure:
A 12 L 3-necked round-bottomed flask was charged with DMF (2 L), 5-nitroindazole (200 g, 1.22 mol.) and potassium carbonate (186 g, 1.35 mol). Benzyl bromide (230 g, 1.35 mol) was then added to the stirred suspension at a rate as to maintain the temperature below 40° C. Once the addition was complete the mixture was heated to 75° C. for a further 8 hours, the reaction being monitored by TLC (SiO2, 1:1 ethyl acetate:hexanes). The reaction was then cooled to room temperature, water (2 L) added and the resulting slurry stirred at room temperature for 0.5 h. The resulting yellow solids were filtered off and dried at 45° C. and 5 mm Hg vacuum for 48 h. This afforded 424 g of a 1.25:1 mixture of 1- and 2-benzyl-5-nitroindazoles as determined by HPLC analysis (Rt 1-benzyl=14.9 min, Rt 2-benzyl=14.1 min). This material was then split into four approximately 100 g batches and each batch dissolved in acetone (470 mL). Water (156 mL) was then added slowly as a steady stream. After stirring for an additional 1 hour at room temperature the resulting solids were filtered off and vacuum dried. This process afforded a combined total of 126 g (41%) of 1-benzyl-5-nitroindazole, which was 92.1% pure by HPLC analysis, the major contaminant being the 2-benzyl derivative.
Reaction SMILES: [CH2:1]([N:8]1[CH:14]2[CH2:15][CH2:16][CH:9]1[CH:10]1[NH:17][CH:13]2[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18]I>CN(C=O)C>[CH2:1]([N:8]1[CH:9]2[CH2:16][CH2:15][CH:14]1[CH:13]1[N:17]([CH3:18])[CH:10]2[CH2:11][CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2C3CCC2C2CCC3N2)cc1
Reactant: CI
Solvent: CN(C)C=O
Product: CN1C2CCC1C1CCC2N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a cold (0° C.) solution of 9-benzyl-9,10-diazatricyclo[4.2.1.12,5]decane (J. Med. Chem. 2000, 43, 2115-2123) and TEA in an DMF (1-2 ml) was added MeI. The mixture was allowed to warm to rt and stirred for 2-3 h. The rxn mixture was evaporated to dryness and partitioned between ether and satd. NaHCO3 and ether layer separated, washed with brine and dried (Na2SO4). Evaporation of ether afforded 9-benzyl-10-methyl-9,10-diazatricyclo[4.2.1.12,5]decane as a light-brown oil. A stirred suspension of 9-benzyl-10-methyl-9,10-diazatricyclo[4.2.1.12,5]decane in EtOH containing conc. HCl (0.5 ml) and 10% Pd—C was hydrogenated under balloon pressure of hydrogen overnight. The suspension was filtered and filtrate was added dry toluene (10-15 ml) and evaporated to dryness to afford the 9-methyl-9,10-diazatricyclo[4.2.1.12,5]decane and isolated as bis-HCl salt.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:14]=[CH:15][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[N:17][CH:18]=3)[N:11]=[C:10]([C:23]([F:26])([F:25])[F:24])[C:9]=2[Cl:27])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:33]1[N:34]=[CH:35][S:36][CH:37]=1)CCC.[Cl-].[Li+]>O1CCOCC1.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>[Cl:27][C:9]1[C:10]([C:23]([F:26])([F:25])[F:24])=[N:11][N:12]([C:13]2[CH:14]=[CH:15][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[N:17][CH:18]=2)[C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([C:33]2[N:34]=[CH:35][S:36][CH:37]=2)=[CH:3][CH:4]=1
Reactant: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(Cl)c2-c2ccc(Br)cc2)cn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(Cl)c2-c2ccc(-c3cscn3)cc2)cn1
Yield: 84.2 %

Procedure:
A mixture of 5-[5-(4-bromophenyl)-4-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide (236 mg, 0.489 mmol), 4-(tributylstannyl)-1,3-thiazole (238 mg, 0.636 mmol), lithium chloride (27 mg, 0.636 mmol) and tetrakis(triphenylphosphine)palladium (57 mg, 0.0489 mmol) in 1,4-dioxane (10 ml) was refluxed for 5 hr under nitrogen atmosphere. After evaporation, the residue obtained was chromatographed on a column of silica gel (50 g) eluting with ethyl acetate/hexane (3:4) to afford 200 mg (84%) of the title compound as a pale brown gum.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8](I)[C:7]4[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O>>[OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[O:22][CH3:21])[C:7]4[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1
Reactant: O=C1NC(=O)c2c1c(I)cc1[nH]c3ccc(O)cc3c21
Reactant: COc1ccccc1B(O)O
Product: COc1ccccc1-c1cc2[nH]c3ccc(O)cc3c2c2c1C(=O)NC2=O
Yield: 75 %

Procedure:
The reaction of 9-hydroxy-4-iodopyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione, prepared as in example 7, with 2-methoxybenzeneboronic acid according to the procedure described in example 8 gave 9-hydroxy-4-(2-methoxyphenyl)pyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (20) (I, Ar=2-methoxyphenyl) in a 75% yield, mp 216° C. 1H NMR δ [(CD3)2SO] 11.70 (s, 1H), 10.90 (s, 1H), 9.23 (s, 1H), 8.31 (d, J=2.4 Hz, 1H), 7.50 (s, 1H), 7.43 (d. J=8.0 Hz, 1H), 7.43–7.38 (m, 1H), 7.31 (dd, J=8.0, 2.4 Hz, 1H), 7.11–7.01 (m, 3H), 3.68 (s, 3H). Found: C, 69.21; H, 3.80; N, 7.58. C21H14N2O4,1/4H2O requires C, 69.51; H, 4.03; N, 7.72.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][CH2:10][CH2:11][O:12][CH3:13])[N:3]=1.[Cl:14][C:15]1[CH:16]=[C:17](B(O)O)[C:18]([F:21])=[N:19][CH:20]=1.C([O-])(=O)C.[K+]>O1CCOCC1.Cl[Pd]Cl>[Cl:14][C:15]1[CH:16]=[C:17]([C:2]2[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][CH2:10][CH2:11][O:12][CH3:13])[N:3]=2)[C:18]([F:21])=[N:19][CH:20]=1
Reactant: OB(O)c1cc(Cl)cnc1F
Reactant: COCCNc1nc(C)nc(Cl)n1
Agent: Cl[Pd]Cl
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COCCNc1nc(C)nc(-c2cc(Cl)cnc2F)n1
Temperature: 100 °C
Reaction time: 6 h
Yield: 29.5 %

Procedure:
A mixture of 4-chloro-N-(2-methoxyethyl)-6-methyl-1,3,5-triazin-2-amine (300 mg, 1.480 mmol), 5-chloro-2-fluoropyridin-3-ylboronic acid (320 mg, 1.825 mmol), potassium acetate (298 mg, 3.04 mmol), and Am-phos PdCl2 (47 mg, 0.066 mmol) in dioxane (10 mL) was heated at 100° C. under nitrogen. After 6 h, the mixture was cooled to rt and partitioned between water (10 mL) and EtOAc (20 mL). The organic layer was dried over Na2SO4 and concentrated. The oil was purified on silica using EtOAc in hexane (10-80%) to give the product as a yellow solid (130 mg). LCMS (ES, pos.): calcd for C12H13ClFN5O: 297.1. found: 298.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.55 (ddd, J=16.24, 7.92, 2.64 Hz, 1H); 8.27 (br s., 1H); 5.91 (br. s., 1H); 3.72 (quin, J=5.62 Hz, 2H); 3.59 (t, J=5.09 Hz, 2H); 3.40 (2s, 3H); 2.51 (2s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.O[CH2:10][C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][C@@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: Oc1ccc(Br)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc(Br)cc1
Yield: 98.2 %

Procedure:
To a solution of 4-bromophenol (1.73 g) and tert-butyl (2S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (4.0 g) in tetrahydrofuran (50 ml),triphenylphosphine (3.1 g) and a solution of diisopropyl azodicarboxylate (2.4 g) in tetrahydrofuran (10 ml) were added, and the mixture was heated to reflux for 2 hours. After cooling, the reaction solution was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain the title compound (3.5 g).
Reaction SMILES: [CH2:1]([O:4][CH2:5][C@H:6]([CH2:22][CH:23]=[CH2:24])[CH2:7][C@H:8]1[CH2:12][O:11][C:10]([CH3:14])([CH3:13])[N:9]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])C=C>C(Cl)Cl.Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1>[CH3:14][C:10]1([CH3:13])[N:9]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[C@@H:8]([CH2:7][C@H:6]2[CH2:22][CH:23]=[CH:24][CH2:1][O:4][CH2:5]2)[CH2:12][O:11]1
Reactant: C=CCOC[C@H](CC=C)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@@H](C[C@H]2CC=CCOC2)COC1(C)C
Yield: 87.8 %

Procedure:
To a solution of (S)-tert-butyl 4-((R)-2-(allyloxymethyl)pent-4-enyl)-2,2-dimethyloxazolidine-3-carboxylate (700 mg, 2.06 mmol, 1 eq) in anhydrous CH2Cl2 was added Grubbs catalyst 2nd generation ((1,3-Bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(phenylmethylene)(tricyclohexylphosphine)ruthenium) (173 mg, 0.21 mol, 0.1 eq). The resulting mixture was stirred and heated to reflux for 4 h. The solvent was removed under reduced pressure to afford the crude product. It was purified by column chromatography on silica gel (PE:EA=100:1) to give (S)-tert-butyl 2,2-dimethyl-4-(((R,Z)-2,3,4,7-tetrahydrooxepin-3-yl)methyl)oxazolidine-3-carboxylate (563 mg, 88%).
Reaction SMILES: O[C:2]1[CH:10]=C(O)C=C[C:3]=1C(N)=O.[OH:12][C:13]1[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16].C(Br)C=C>>[OH:12][C:13]1[CH:22]=[C:21]([O:23][CH2:10][CH:2]=[CH2:3])[CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1ccc(O)cc1O
Reactant: NC(=O)c1ccc(O)cc1O
Solvent: C=CCBr
Product: C=CCOc1ccc(C(=O)OC)c(O)c1

Procedure:
Scheme B shows methods for the preparation of the 2,4-dihydroxybenzamide starting materials. Methyl 2,4-dihydroxybenzoate (X) is reacted with allyl bromide to give methyl 2-hydroxy-4-allyloxybenzoate (XI) which is heated to produce methyl 2,4-dihydroxy-3-(2-propenyl) benzoate (XII). Reaction of XII with an appropriate amine in the presence of ammonium chloride gives the 2,4-dihydroxy-3-(2-propenyl)benzamide (XIII) which can be hydrogenated to the 3-propyl compound (XIV). Alternatively XII may be reacted with methylene iodide and triisobutylaluminum to give methyl 3-(cyclopropylmethyl)-2,4-dihydroxybenzoate (XV) which is then reacted with an appropriate amine in the presence cf ammonium chloride to give the 2-(cyclopropylmethyl)-2,4-dihydroxybenzamide (XVI).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:20]=[N:19][CH:18]=[C:17](Cl)[N:16]=1.C([O-])([O-])=O.[K+].[K+].CCOCC>C(#N)C>[Cl:14][C:15]1[N:16]=[C:17]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)[CH:18]=[N:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1cncc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2cncc(Cl)n2)CC1
Temperature: 65 °C
Reaction time: 15 h
Yield: 89.9 %

Procedure:
A mixture of tert-butyl 1-piperazinecarboxylate (5.07 g, 27.2 mmol), 2,6-dichloropyrazine (3.38 g, 22.7 mmol), and K2CO3 (4.09 g, 30.0 mmol) in acetonitrile (20 mL) was stirred at 65° C. for 12.5 h and for a further 15 h at room temperature. Ether was added and the suspension was filtered. Concentration in vacuo furnished the crude product as an oil that crystallized upon standing. Purification by chromatography on silica gel using ethyl acetate/n-hexane (6:4) as eluent gave 6.1 g (90%) of the title compound as a solid. HRMS m/z calcd for C13H19ClN4O2 (M)+ 298.1197, found 298.1211. Anal. (C13H19ClN4O2) C, H, N.
Reaction SMILES: [NH2-].[Na+].[Na].N.[OH:5][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1.[CH3:17]I>C(OCC)C>[CH3:17][N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([CH2:7][CH2:6][OH:5])=[CH:9]1
Reactant: OCCc1c[nH]c2ccccc12
Reactant: CI
Agent: N
Agent: [NH2-]
Agent: [Na+]
Solvent: CCOCC
Product: Cn1cc(CCO)c2ccccc21
Reaction time: 0.25 h

Procedure:
To a solution of sodium amide from 0.63 g sodium in 50 ml liquid ammonia is added in dropwise fashion a solution of 3.22 g of 3-(2-hydroxyethyl)indole in 10 ml diethyl ether. After stirring 10 minutes a solution of 1.37 ml methyl iodide in 1.5 ml diethyl ether is added in one portion. The mixture is stirred for 15 minutes and then the ammonia is allowed to evaporate. The residue is mixed with 100 ml water and is extracted into 200 ml diethyl ether. The organic phase is separated and is dried over magnesium sulfate. Filtration and evaporation affords 3.64 g of 1-methyl-3-(2-hydroxyethyl)indole, an oil.
Reaction SMILES: [NH2:1][C:2](=[O:37])[C:3]([NH:6][C:7](=[O:36])[CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]2[CH:23]=[C:22]([C@H:24]3[C@H:29]([OH:30])[C@@H:28]([OH:31])[C@H:27]([OH:32])[C@@H:26]([S:33][CH3:34])[O:25]3)[CH:21]=[CH:20][C:19]=2[CH3:35])=[CH:13][CH:12]=1)([CH3:5])[CH3:4].Cl.N[C:40](C)(C)[C:41]([N:43]1[CH2:48]CN(C)[CH2:45][CH2:44]1)=O>>[CH3:4][C:3]([NH:6][C:7](=[O:36])[CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][C:18]2[CH:23]=[C:22]([C@H:24]3[C@H:29]([OH:30])[C@@H:28]([OH:31])[C@H:27]([OH:32])[C@@H:26]([S:33][CH3:34])[O:25]3)[CH:21]=[CH:20][C:19]=2[CH3:35])=[CH:15][CH:16]=1)([CH3:5])[C:2]([N:1]1[CH2:45][CH2:44][N:43]([CH3:48])[CH2:41][CH2:40]1)=[O:37]
Reactant: CN1CCN(C(=O)C(C)(C)N)CC1
Reactant: CS[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(CCCC(=O)NC(C)(C)C(N)=O)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Agent: Cl
Product: CS[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(CCCC(=O)NC(C)(C)C(=O)N4CCN(C)CC4)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
The same procedure was employed as for amide 11, using 2-amino-2-methyl-1-(4-methylpiperazin-1-yl)propan-1-one hydrochloride, to provide the product 12 as the bisformate salt. 1H NMR (400 MHz, MeOH-d4) δ ppm 8.40 (s, 2 H), 7.11-7.21 (m, 3 H), 7.02-7.11 (m, 4 H), 4.39 (d, J=9.6 Hz, 1 H), 4.13 (d, J=9.1 Hz, 1 H), 3.96 (s, 2 H), 3.74 (br. s., 4 H), 3.34-3.52 (m, 3 H), 2.67 (t, J=4.6 Hz, 4 H), 2.60 (t, J=7.6 Hz, 2 H), 2.47 (s, 3 H), 2.19 (t, J=7.6 Hz, 2 H), 2.21 (s, 3 H), 2.14 (s, 3 H), 1.88 (quin, J=7.5 Hz, 2 H), 1.44 (s, 6 H). MS (ES+) [M+H]+=614.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([NH:9][N:10]=[CH:11][C:12]([C:19]([F:22])([F:21])[F:20])(O)[CH:13]([C:15](O)=[O:16])[CH3:14])=[C:4]([F:23])[CH:3]=1>C(O)(=O)C.N1C=CC=CC=1>[F:23][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([OH:8])=[CH:6][C:5]=1[N:9]1[C:15](=[O:16])[C:13]([CH3:14])=[C:12]([C:19]([F:22])([F:21])[F:20])[CH:11]=[N:10]1
Reactant: CC(C(=O)O)C(O)(C=NNc1cc(O)c(Cl)cc1F)C(F)(F)F
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: Cc1c(C(F)(F)F)cnn(-c2cc(O)c(Cl)cc2F)c1=O
Temperature: 120 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
3-Carboxy-2-trifluoromethyl-2-hydroxy-1-butanal-1-(4-chloro-2-fluoro-5-hydroxyphenylhydrazone) (0.315 g) was dissolved in the mixture of acetic acid (1.0 ml) and pyridine (1.0 ml) under a nitrogen atmosphere, and stirred at 120° C. for 8 hours. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure, and the residue was diluted with diethyl ether (100 ml). Then, the diluted solution was washed with 3N hydrochloric acid (each 20 ml) twice, and saturated sodium bicarbonate (30 ml) once, dried over magnesium sulfate, filtrated and concentrated under reduced pressure. The residue was subjected to column chromatography. Thus, 2-(2-fluoro-4-chloro-5-hydroxyphenyl)-4-methyl-5-trifluoromethylpyridazin-3-on (0.227 g) was obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]=[C:4]([C:11]([OH:13])=[O:12])[CH:3]=1.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>>[N:14]1([C:2]2[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]=[C:4]([C:11]([OH:13])=[O:12])[CH:3]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C1CCNC1
Reactant: O=C(O)c1cc(Cl)cc(C(=O)O)n1
Product: O=C(O)c1cc(N2CCCC2)cc(C(=O)O)n1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
4-chloropyridine-2,6-dicarboxylic acid (0.238 mol, 48.0 g) is slowly added under stirring to a solution of pyrrolidine (0.952 mol, 67.8 g) at room temperature. Take care to avoid a too-fast addition leading to local temperature increase. Observe precipitation of a solid. The reaction mixture is heated at 120° C. for 2 hr. By gradually heating, the reaction mixture becomes solid. After cooling at 60° C., H20 (80 ml) is added and the mixture is stirred for 30 min until the solid is completely dissolved. The solution is then acidified with HCl (2M) until pH=1. The formed precipitate is filtered, washed twice H2O and dried overnight at 70° C. (93%).
Reaction SMILES: N[CH:2]1[C:22](=[O:23])[N:4]2[C:5]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=3)=[O:10])=[CH:6][CH2:7][S:8][C@H:3]12.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=[O:27].Cl>C(N(CC)CC)C>[O:27]=[C:2]1[C:22](=[O:23])[N:4]2[C:5]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=3)=[O:10])=[CH:6][CH2:7][S:8][C@H:3]12
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)C1=CCS[C@@H]2C(=O)C(=O)N12

Procedure:
4-Nitrobenzyl 7-amino-3-cephem-4-carboxylate, trifluoromethanesulfonic anhydride, triethylamine and hydrochloric acid were reacted in the same manners as those of Examples 1-4 to give 4-nitrobenzyl 7-oxo-3-cephem-4-carboxylate. Mp. 141°-142° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([C:20]([O:22]C)=[O:21])=[CH:10][C:11]([CH:18]=[CH2:19])=[C:12]3[C:17]=2[N:16]=[CH:15][CH:14]=[CH:13]3)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].O.Cl>CO>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([C:20]([OH:22])=[O:21])=[CH:10][C:11]([CH:18]=[CH2:19])=[C:12]3[C:17]=2[N:16]=[CH:15][CH:14]=[CH:13]3)[CH:5]=[CH:6][CH:7]=1
Reactant: C=Cc1cc(C(=O)OC)c(-c2cccc(F)c2)c2ncccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=Cc1cc(C(=O)O)c(-c2cccc(F)c2)c2ncccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 8-(3-fluorophenyl)-5-vinylquinoline-7-carboxylate (0.069 g, 0.22 mmol) and 1.0 M sodium hydroxide in water (2 mL, 2 mmol) in methanol (2 mL) was stirred at room temperature overnight. After acidified with 1 N HCl, the mixture was extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate and concentrated to dryness. The crude acid was used directly in the next step (66 mg, 100%). LCMS calculated for C18H13FNO2 (M+H)+: m/z=294.1; Found: 294.0.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:20]2([OH:26])[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]2)[CH:17]=[CH:18][CH:19]=1>>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([N:22]1[CH2:23][CH2:24][CH2:25][C:20]([OH:26])([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH3:12])[CH:15]=2)[CH2:21]1)=[O:5]
Reactant: COc1cccc(C2(O)CCCNC2)c1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Product: COc1cccc(C2(O)CCCN(C(=O)c3ccc(Cl)cc3Cl)C2)c1

Procedure:
The compound of Example 24 was prepared according to the general preparation protocol A from 2,4-dichlorobenzoyl chloride and 3-(3-methoxy-phenyl)-piperidine-3-ol.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].C(=O)([O-])O.[Cs+].[C:15]([O:23][CH2:24][CH2:25]Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN1C(=O)CCC1>[C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O:6][CH2:25][CH2:24][O:23][C:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:22])=[O:5]
Reactant: O=C(OCCCl)c1ccccc1
Reactant: COC(=O)/C=C/C(=O)O
Agent: O=C([O-])O
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COC(=O)/C=C/C(=O)OCCOC(=O)c1ccccc1
Yield: 24 %

Procedure:
Following general procedure A, methyl hydrogen fumarate (0.42 g, 3.3 mmol) in NMP (6 mL) was reacted with CsHCO3 (0.69 g, 3.6 mmol) and chloroethyl benzoate (0.55 g, 3.0 mmol) to afford 0.2 g (24% yield) of the title compound (43) after purification by silica gel flash column chromatography (Biotage) using a mixture of ethyl acetate (EtOAc) and hexanes (1:8) as eluent. 1H NMR (CDCl3, 400 MHz): δ 8.08-8.02 (m, 2H), 7.63-7.56 (m, 1H), 7.49-7.42 (m, 2H), 7.21 (q, J=5.2 Hz, 1H), 6.92 (d, J=16.0 Hz, 1H), 6.85 (d, J=16.0 Hz, 1H), 3.81 (s, 3H), 1.69 (d, J=5.2 Hz, 3H). MS (ESI): m/z 278.99 (M+H)+.