Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)(=[O:14])=[O:13].CI.[C:26]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]([CH3:26])[S:12]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)(=[O:14])=[O:13]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)Cc1ccccc1NS(=O)(=O)c1ccc(Cl)c(Cl)c1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)Cc1ccccc1N(C)S(=O)(=O)c1ccc(Cl)c(Cl)c1
Reaction time: 8 h

Procedure:
2-(2-(3,4-Dichlorophenylsulfonamido)phenyl)acetic acid methyl ester (14.3 g, 38.21 mmol) and methyl iodide (8.2 ml, 132.25 mmol) were dissolved in acetone (300 ml); K2CO3 (7.3 g, 52.90 mmol) was added thereto, and stirring was carried out overnight at 40° C. in a closed flask. The suspension was cooled and then filtered, concentrated, filtered over silica gel (eluant DCM) and concentrated.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:16][CH3:17])=[N:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1.C([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)(OC(C)(C)C)=O>>[CH:11]1([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[CH:10]=3)[C:6]([CH2:16][CH3:17])=[N:7]2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CCc1nn(C2CCCC2)c2cc(Br)ccc12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CCc1nn(C2CCCC2)c2cc(N3CCNCC3)ccc12

Procedure:
Prepared by the method outlined for Example 1 using 6-bromo-1-cyclopentyl-3-ethyl-1H-indazole (CAS [199172-02-6]) as the aryl halide and N BOC-piperazine as the amine component. Oil and gum (88% for two steps). LC/MS 4.56 min, [M+1]+ 299.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[O:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: C1=COCCC1
Reactant: O=Cc1cccc(O)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1cccc(OC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-hydroxy-benzaldehyde (6.51 g, 53.3 mmol) and 3,4-dihydro-2H-pyran (7.3 mL, 80.0 mmol) in 150 mL methylene chloride was added pyridinium p-toluenesulfonate (1.34 g, 5.33 mmol). The reaction mixture was stirred at room temperature overnight. The layers were separated and the organic layer was washed with saturated aqueous sodium bicarbonate. The organic layer was dried (magnesium sulfate), filtered, and concentrated. Medium pressure silica gel chromatography of the residue (5% ethyl acetate/hexanes to 10% ethyl acetate/hexanes) aforded 10.34 g (94%) of the title compound of Step A.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:11]=[C:12]([S:16](Cl)(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1>O1CCCC1.O>[NH2:1][C:2]1[C:7]([NH:8][S:16]([C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([Cl:9])[CH:11]=2)(=[O:18])=[O:17])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: Nc1cccnc1N
Solvent: O
Solvent: C1CCOC1
Product: Nc1ncccc1NS(=O)(=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.2 %

Procedure:
1.97 g (18 mmol) of 2,3-diaminopyridine was dissolved in a mixed solution of tetrahydrofuran and water, and a tetrahydrofuran solution containing 1.90 g (9.0 mmol) of 3-chlorobenzenesulfonyl chloride was added thereto. After stirring at room temperature overnight, the mixture was concentrated, and water and dichloromethane were added to the residue. The organic layer was separated, and the wall of the reactor was rubbed. The resulting crystals were collected by filtration, to give 1.41 g of N-(2-amino-3-pyridiny)-3-chlorobenzenesulfonamide. 530 mg (1.87 mmol) of the crystals was dissolved in methanol and 367 mg (1.87 mmol) of an aqueous 40% chloroacetoaldehyde solution was added thereto. After heating under reflux for 4 hours, the mixture was concentrated to dryness. A small amount of methanol was added to the residue and the crystals were collected by filtration, to give 373 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.CC1C=CC(S(O)(=O)=O)=CC=1.O.[O:23]1[CH:28]=[CH:27][CH2:26][CH2:25][CH2:24]1>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH:24]1[CH2:25][CH2:26][CH2:27][CH2:28][O:23]1
Reactant: Brc1cccc2[nH]ncc12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: Brc1cccc2c1cnn2C1CCCCO1
Yield: 80.1 %

Procedure:
A mixture of 4-bromo-1H-indazole (0.5 g, 2.53 mmol), p-TsOH.H2O (50 mg, 0.25 mmol), and 3,4-dihydro-2H-pyran (0.64 g, 7.61 mmol) in THF (20 mL) was degassed then heated to reflux overnight. After the solvent was removed, the residue was partitioned between DCM (300 mL) and water (50 mL). The organic layer was separated, dried (MgSO4), filtered and concentrated. The crude residue was purified by SiO2 chromatography eluting with a DCM/MeOH gradient (0.5 to 1% MeOH) to afford 570 mg (81%) of 4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (196) as yellow solid: MS (ESI) m/z=282.2 [M+1]+.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8]2[O:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([O:17]C)[C:10]=3[CH:9]=2)=[CH:5][CH:4]=1)[CH3:2].B(Br)(Br)Br>>[CH2:1]([C:3]1[S:7][C:6]([C:8]2[O:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([OH:17])[C:10]=3[CH:9]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(-c2cc3c(OC)cccc3o2)s1
Agent: BrB(Br)Br
Product: CCc1ccc(-c2cc3c(O)cccc3o2)s1
Yield: 81.8 %

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 5 using 2-(5-ethylthiophen-2-yl)-4-methoxybenzo(b)furan (1.00 g) and boron tribromide (1.0 ml), the title compound (774 mg) was obtained as colorless crystals, melting point 87–90° C.
Reaction SMILES: [CH2:1]([Li])CCC.[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[CH:15]=[CH:14][S:13][C:12]=2[CH:16]=1>C1COCC1.C([O-])(O)=O.[Na+]>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[CH:15]=[C:14]([CH3:1])[S:13][C:12]=2[CH:16]=1
Reactant: [Li]CCCC
Reactant: COc1ccc2ccsc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2cc(C)sc2c1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
A 2.5 M solution of n-butyllithium in hexanes (20 ml, 50 mmole) was added under argon to a solution of 6-methoxybenzo[b]thiophene 1a (3.68 g, 22.4 mmole) in THF (150 ml) at −75°. After stirring at −75° for a further 30 minutes, the cooling bath was exchanged and the reaction warmed to −10° C. prior to addition of CH3l (4.2 ml, 9.58 g, 67 mmole). The resultant mixture was stirred at 0° C. for an additional 30 minutes, then allowed to gradually warm to room temperature before diluting with saturated NaHCO3 (150 ml). The layers were separated and the aqueous phase was extracted with EtOAc (2×100 ml). The combined organic extracts were dried over Na2SO4 and concentrated, in vacuo, to give 4.2 g of an amber oil which was purified by silica gel chromatography. Elution with hexane: Et2O (98:2) and evaporation of the appropriate fractions gave 3.63 g (91%) of a colourless oil. 1H NMR (DMSO-d6) δ7.57 (1H, d, J=8.7 Hz), 7.43 (1H, d, J=2.4 Hz), 6.99 (1H, s), 6.92 (1H, dd, J=2.4, 8.7 Hz), 3.78 (3H, s), 2.50 (3H, s). Anal. Calcd. for C10H10OS: C, 67.38; H, 5.66; S, 17.99. Found: C, 67.42; H, 5.74; S, 17.87.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:17])[N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[C:18](O)(=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N=C=NC(C)C)(C)C>C(Cl)Cl.N1C=CC=CC=1>[C:19]1([C:18]2[O:1][N:2]=[C:3]([N:4]3[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[CH2:8][CH2:9]3)[N:17]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=N)NO)CC1
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCN(c2noc(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.9 %

Procedure:
To a solution of tert-butyl 4-[(hydroxyamino)(imino)methyl]piperazine-1-carboxylate (7 g, 28.6 mmol) in anhydrous DCM (150 mL) was added benzoic acid (3.49 g, 28.6 mmol) followed by diisopropyl carbodiimide (DIC, 3.6 g, 28.6 mmol). The reaction mixture was stirred at RT for 8 hours and filtered. The filtrate was evaporated and the residue obtained was refluxed in pyridine (100 mL) for 3 hours. The solvent was removed under vacuum and the residue was dissolved in DCM. The organic layer was washed with a 10% aqueous solution of sodium bicarbonate, water and brine. The organic layer was dried and the solvent was evaporated. The residue was purified by chromatography using petrol ether/EtOAc (9/1) as eluent to afford 5 g (53%) of the title compound as a solid. TLC—Pet ether/EtOAc (9/1): Rf=0.7). HPLC purity: 96%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[O:9][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]
Reactant: Oc1cc(I)ccc1Cl
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1cc(I)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-chloro-5-iodophenol (509 mg, 2.00 mmol) in dimethylformamide were added potassium carbonate (415 mg, 3.00 mmol) and t-butyl bromoacetate (0.440 ml, 3.00 mmol) and the mixture was stirred for 1 hour at room temperature. Thereto was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with 10% aqueous citric acid solution, water, an aqueous saturated sodium hydrogencarbonate solution and an aqueous saturated sodium chloride solution in the order, and dried over magnesium sulfate. The solvent was removed and purified with silica gel chromatography (hexane:ethyl acetate, 20:1) to give t-butyl (2-chloro-5-iodophenoxy)acetate (851 mg, quantitatively) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:20]([C:22]3[O:23][C:24]4[C:29]([C:30](=[O:39])[C:31]=3[C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:21])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18]C)[CH:12]=3)[C:3]=12>ClCCl.B(Br)(Br)Br>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:20]([C:22]3[O:23][C:24]4[C:29]([C:30](=[O:39])[C:31]=3[C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:21])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([OH:18])[CH:12]=3)[C:3]=12
Reactant: COc1cc(-c2nn(C(C)c3oc4ccccc4c(=O)c3-c3cccc(F)c3)c3ncnc(N)c23)ccc1Cl
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(c1oc2ccccc2c(=O)c1-c1cccc(F)c1)n1nc(-c2ccc(Cl)c(O)c2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 46.8 %

Procedure:
To a solution of Example 95 (0.055 g, 0.1012 mmoles) in dichloromethane (4 ml), BBr3 (1M in dichloromethane, 0.5 ml) was added at 0° C. and the reaction mixture was warmed to RT and then stirred for 12 h. The reaction mixture was quenched with 1.5N HCl solution and extracted with dichloromethane. The organic layer was dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as pale green solid (0.025 g, 86% yield). MP: 134-136° C. 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 10.50(s,1H),8.18(s,1H), 8.05(d, J=8.0Hz, 1H), 7.87(t, J=7.0Hz,1H), 7.64(d, J=8.4Hz, 1H), 7.54(t, J=7.6Hz, 1H), 7.50(d, J=8.0Hz, 2H), 7.29(br s,1H), 7.21(d, J=1.6Hz, 1H), 7.07-6.93(m, 4H), 6.07(q, J=6.9 Hz, 1H),1.90(d, J=7.0Hz, 3H). Mass: 527.76(M+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][C:14]2[CH:15]=[C:16]([Cl:20])[CH:17]=[N:18][CH:19]=2)=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][C:23]=1[S:31](Cl)(=[O:33])=[O:32]>>[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][C:23]=1[S:31]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][C:14]2[CH:15]=[C:16]([Cl:20])[CH:17]=[N:18][CH:19]=2)=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:33])=[O:32]
Reactant: CCOC(=O)c1cc(N)ccc1Oc1cncc(Cl)c1
Reactant: Cc1ccc([N+](=O)[O-])cc1S(=O)(=O)Cl
Product: CCOC(=O)c1cc(NS(=O)(=O)c2cc([N+](=O)[O-])ccc2C)ccc1Oc1cncc(Cl)c1
Yield: 89 %

Procedure:
The title compound was prepared using the procedure described in Example 3, beginning with 0.1 g of the aniline of Example 1 and 2-methyl-5-nitrobenzenesulfonyl chloride and adding poly(4-vinylpyridine) (250 mg, 60 mesh) to the reaction mixture. After workup, 0.15 g (89%) of the title sulfonamide was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.Cl.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[CH2:31][CH:30]([C:32](Cl)=[O:33])[O:29][N:28]=2)[CH:22]=1>C(Cl)Cl>[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[CH2:31][CH:30]([C:32]([NH:1][C:2]3[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=3)=[O:33])[O:29][N:28]=2)[CH:22]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=C(Cl)C1CC(c2cccnc2)=NO1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(O)c1ccc(NC(=O)C2CC(c3cccnc3)=NO2)cc1
Reaction time: 8 h
Yield: 36.9 %

Procedure:
A solution of 4-aminobenzoic acid (0.020 mol) and N-ethyl-N-(1-methylethyl)-2-propanamine, (0.020 mol) in CH2Cl2 (100 ml) was cooled to 0° C. (±)-4,5-dihydro-3-(3-pyridinyl)-5-isoxazolecarbonyl chloride monohydrochloride (0.020 mol) was added. The resulting brown suspension was stirred overnight. The precipitate was filtered off, washed with CH2Cl2, then dried. The filtrate was evaporated under reduced pressure. The residue was purified by short column chromatography over silica gel (eluent: CH2Cl2/CH3OH 95/5). The pure fractions were collected and the solvent was evaporated under reduced pressure. The residue was stirred in methanol, filtered off, then dried, yielding 2.3 g of (±)-4-[[[4,5-dihydro-3-(3-pyridinyl)-5-isoxazolyl]-carbonyl]amino]benzoic acid (interm. 19).
Reaction SMILES: C(OC([N:6]1[CH:10]=[C:9]([C:11]2[CH:34]=[CH:33][C:14]3[N:15]([C:18]4[CH:19]=[C:20]([NH:24][C:25]([NH:27][CH2:28][C:29]([F:32])([F:31])[F:30])=[O:26])[CH:21]=[CH:22][CH:23]=4)[CH:16]=[N:17][C:13]=3[CH:12]=2)[CH:8]=[N:7]1)C)C.[ClH:35].O>O1CCCC1>[NH:6]1[CH:10]=[C:9]([C:11]2[CH:34]=[CH:33][C:14]3[N:15]([C:18]4[CH:19]=[C:20]([NH:24][C:25]([NH:27][CH2:28][C:29]([F:32])([F:31])[F:30])=[O:26])[CH:21]=[CH:22][CH:23]=4)[CH:16]=[N:17][C:13]=3[CH:12]=2)[CH:8]=[N:7]1.[ClH:35]
Reactant: CCOC(C)n1cc(-c2ccc3c(c2)ncn3-c2cccc(NC(=O)NCC(F)(F)F)c2)cn1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCC(F)(F)F)Nc1cccc(-n2cnc3cc(-c4cn[nH]c4)ccc32)c1
Temperature: 25 °C

Procedure:
The mixture of N-(3-{5-[1-(1-ethoxyethyl)-1H-pyrazol-4-yl]-1H-benzimidazol-1-yl}phenyl)-N′-(2,2,2-trifluoroethyl)urea (190 mg, 0.40 mmol) and 1.0 M hydrogen chloride in water (3 mL, 3 mmol) in tetrahydrofuran (5 mL) was stirred at r.t. 2 hours. The reaction mixture was concentrated under reduced pressure to dryness to afford the desired compound as HCl salt which was directly used in next step reaction without further purification. LCMS (M+H)+: m/z=401.2.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:16][CH3:17])[C:4]1[C:13]([CH:14]=O)=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1.[CH3:18][NH:19][CH3:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][CH:3]([O:16][CH3:17])[C:4]1[C:13]([CH2:14][N:19]([CH3:20])[CH3:18])=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1
Reactant: COC(OC)c1nc2c(cc1C=O)CCCN2
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(OC)c1nc2c(cc1CN(C)C)CCCN2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridine-3-carbaldehyde (intermediate 41, 300 mg, 1.15 mmol) and dimethylamine (7.9 M in water, 1.45 ml, 11.5 mmol) in DCM (7 ml) was added sodium triacetoxyborohydride (486 mg, 2.29 mmol). The reaction mixture was stirred at room temperature overnight. Then, dimethylamine (7.9 M in water, 1.45 ml, 11.5 mmol) was added followed by sodium triacetoxyborohydride (486 mg, 2.29 mmol) and the reaction mixture was stirred room temperature for 8 h, then dimethylamine (7.9 M in water, 1.45 ml, 11.5 mmol) was added followed by sodium triacetoxyborohydride (486 mg, 2.293 mmol) and the reaction mixture was stirred room temperature overnight. The reaction mixture was poured into sat. aq. NaHCO3 and extracted with DCM (3×). The organic phase was then dried over Na2SO4, filtered and evaporated. The crude material was purified by normal phase chromatography (24 g silica gel cartridge, DCM/(DCM/(7 M NH3 in MeOH) 9/1) 100:0 to 0:100) to give the title compound as a yellow solid. (UPLC-MS 3) tR 0.37 min; ESI-MS 266.2 [M+H]+.
Reaction SMILES: C1(C)C(S([N:10]2[CH:14]=[CH:13][CH:12]=[C:11]2[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([CH2:22][NH:23]C(=O)C(F)(F)F)=[CH:18][CH:17]=2)(=O)=O)=CC=CC=1.[OH-].[K+]>CCO>[NH2:23][CH2:22][C:19]1[CH:18]=[CH:17][C:16]([C:15]([C:11]2[NH:10][CH:14]=[CH:13][CH:12]=2)=[O:30])=[CH:21][CH:20]=1
Reactant: Cc1ccccc1S(=O)(=O)n1cccc1C(=O)c1ccc(CNC(=O)C(F)(F)F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: NCc1ccc(C(=O)c2ccc[nH]2)cc1
Temperature: 25 °C
Yield: 86.5 %

Procedure:
To a stirred EtOH (10 mL) solution containing N-toluenesulfonyl-2-(4-(trifluoroacetylaminomethyl)benzoyl)pyrrole (1.00 g, 2.20 mmol), was added 40% KOH solution (2 mL) and the mixture was heated at reflux until TLC analysis showed complete consumption of the starting material. The reaction mixture was then cooled to room temperature worked up as in Example 7. The crude product was suspended in H2O, filtered and dried to afford the purified product 2-(4-aminomethylbenzoyl)pyrrole (381 mg, 86%). 1H NMR (500 MHz, CD3OD, 25° C.) δ2.43 (s, 3H), 4.53 (s, 2H), 6.42 (m, 1H), 6.77 (m, 1H), 7.41 (d, 2H), 7.72 (d, 2H), 7.85 (m, 1H), 7.95 (d, 2H), 8.39 (t, 1H); 13C NMR (100 MHz, CD3OD, 25° C.) δ44.6, 109.7, 119.4, 125.6, 126.5, 128.4, 130.4, 136.8, 146.1, 184.6; HRMS (EI): m/z 200.0940 (100) {M}+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=O)C)[CH:5]=[CH:6][C:7]=1[CH3:8].[Cl:13]C1[N:19]=[C:18]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:17]=[CH:16][N:15]=1.Cl>CN(C=O)C>[ClH:13].[CH3:8][C:7]1[C:2]([NH2:1])=[CH:3][C:4]([NH:9][C:10]2[N:19]=[C:18]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)[CH:17]=[CH:16][N:15]=2)=[CH:5][CH:6]=1
Reactant: CC(=O)Nc1ccc(C)c(N)c1
Reactant: Clc1nccc(-c2cccnc2)n1
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1ccc(Nc2nccc(-c3cccnc3)n2)cc1N
Temperature: 100 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
To a solution of N-(3-amino-4-methylphenyl)acetamide (5 g, 25 mmol, commercially available) in DMF (5 mL) was added 2-chloro-4-(pyridin-3-yl)-pyrimidine (4 g, 35 mmol, commercially available) and KI (0.5 g, 3 mmol). After stirring at 100° C. overnight, the reaction mixture was cooled to 10° C., quenched with H2O, (100 mL), extracted with CH2Cl2 (2×100 mL) and the combined organic layers were dried (Na2SO4) and concentrated. The residue was dissolved in conc. HCl (10 mL), stirred at 80° C. for 2 h, and then concentrated to yield 6-methyl-N′-(4-(pyridin-3-yl)pyrimidin-2-yl)benzene-1,3-diamine hydrochloride (4.5 g, 65% yield) as the HCl salt. 1H NMR (300 MHz, CDCl3): δ 7.93-7.96 (m, 2H), 7.50-7.47 (m, 1H), 7.47-7.41 (m, 5H), 7.25-7.27 (m, 2H), 2.21 (s, 3H); MS (ESI) m/e: 277 (M+H+).
Reaction SMILES: [H-].[Na+].[C:3]([N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8][CH:7]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21])(=[O:5])[CH3:4].Cl[CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>CN(C=O)C>[C:3]([N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8][CH:7]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])(=[O:5])[CH3:4]
Reactant: CCOC(=O)CCCCl
Reactant: CC(=O)N1c2ccccc2SC1c1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccccc1C1Sc2ccccc2N1C(C)=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To the suspension of 1.59 g of sodium hydride in 30 ml of anhydrous DMF, the solution of 8.13 g of 3-acetyl-2-(2-hydroxyphenyl)benzothiazoline in 30 ml of anhydrous DMF is added dropwise under nitrogen atmosphere at room temperature. After the addition, the reaction mixture is stirred for 20 minutes at room temperature. To the reaction mixture, the solution of 4.95 g of ethyl 4-chlorobutyrate in 15 ml of anhydrous DMF is added and stirred for 5 hours at 70° C. After cooling to room temperature the reaction mixture is poured into ice-water and extracted with ethyl acetate.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[S:6][C@@H:5]2[C@H:7]([NH:10][C:11]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:12])[C:8](=[O:9])[N:4]2[C@H:3]1[C:20]([O-:22])=[O:21].[K+].C(=O)(O)[O-].[Na+]>O1CCOCC1>[CH3:1][C:2]1([CH3:23])[S:6][C@@H:5]2[C@H:7]([NH:10][C:11]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:12])[C:8](=[O:9])[N:4]2[C@H:3]1[C:20]([OH:22])=[O:21]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)[O-]
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)O

Procedure:
Reaction of potassium benzylpenicillin with α-chlorodiethylcarbonate in an aqueous solution of 70% dioxane in the presence of sodium bicarbonate. The 1-ethoxycarbonyloxyethyl ester of benzylpenicillin which is obtained is subjected to the reaction of removing the phenylacetic chain, via the iminochloride-iminoether, in order to obtain the 1-ethoxycarbonyloxyethyl ester of the 6-aminopenicillanic acid, which is isolated as the hydrochloride.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[C@@H:12]1[CH2:16][O:15][CH2:14][C@@H:13]1[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21].O.NN>C(O)C>[NH2:3][C@@H:12]1[CH2:16][O:15][CH2:14][C@@H:13]1[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23]
Reactant: CC(C)(C)OC(=O)N[C@H]1COC[C@H]1N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1COC[C@H]1N
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Tert-butyl ((3R,4S)-4-(1,3-dioxoisoindolin-2-yl)tetrahydrofuran-3-yl)carbamate (13.08 g, 39.4 mmol) was dissolved into ethanol (98 mL, 0.4 M)). Hydrazine monohydrate (1.97 g, 39.4 mmol) was added, and the reaction was stirred 30 minutes at 50° C. and then 2 hours at 75° C. The reaction was then cooled to room temperature and the white solid was removed by filtration. The filtrate was concentrated down and dried, then treated with ethanol (about 15 mL). Additional white solid was removed by filtration, then filtrate was concentrated down and dried to yield tert-butyl ((3R,4S)-4-aminotetrahydrofuran-3-yl)carbamate as a thick, clear oil (8.724 g at 90% purity; 99%).