Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=O.[N+]([O-])(O)=O.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=1[NH:28][C:29]([NH2:31])=[NH:30]>>[N+:25]([C:22]1[CH:23]=[CH:24][C:19]([CH3:18])=[C:20]([NH:28][C:29]2[N:31]=[C:5]([C:7]3[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=3)[CH:4]=[CH:3][N:30]=2)[CH:21]=1)([O-:27])=[O:26]
Reactant: Cc1ccc([N+](=O)[O-])cc1NC(=N)N
Reactant: CN(C)C=CC(=O)c1cccnc1
Solvent: O=[N+]([O-])O
Product: Cc1ccc([N+](=O)[O-])cc1Nc1nccc(-c2cccnc2)n1

Procedure:
The invention provides a process for preparation of imatinib base and pharmaceutically acceptable acid addition salts thereof, comprising (a) reacting 2-methyl-5-nitroaniline with cyanamide in the presence of hydrochloric acid to obtain 1-(2-methyl-5-nitrophenyl)guanidine hydrochloride; (b) converting 1-(2-methyl-5-nitrophenyl)guanidine hydrochloride to 1-(2-methyl-5-nitrophenyl)guanidine nitrate; (c) condensing 3-acetylpyridine with N,N-dimethylformamide dimethyl acetal to obtain 3-(dimethylamino)-1-(3-pyridinyl)-prop-2-en-1-one; (d) reacting 3-(dimethylamino)-1-(3-pyridinyl)-prop-2-en-1-one with 1-(2-methyl-5-nitrophenyl)guanidine nitrate to obtain N-(5-nitro-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine; (e) reducing N-(5-nitro-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine using hydrazine in the presence of Raney nickel to obtain N-(5-amino-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidine-amine; (f) condensing N-(5-amino-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidine-amine with 4-chloromethylbenzoyl chloride in the presence of an inorganic base to obtain 4-chloromethyl-N-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)benzamide; (g) condensing 4-chloromethyl-N-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)benzamide with an excess of N-methylpiperazine to obtain imatinib base; adding water or a mixture of water and an organic solvent; and isolating said imatinib base; and (h) optionally, converting imatinib base to a pharmaceutically acceptable acid addition salt of imatinib base.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH:29]=[CH:30][CH:31]=2)[CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:13]([NH:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:35])[CH3:36])[CH:27]=4)[CH2:22][CH2:21]3)=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12]2)=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCCC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(Cl)cc4)CCCC3)CC2)c1

Procedure:
Example 31 was prepared from 1-(4-chloro phenyl)cyclopentanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.45–7.42 (m, 1H), 7.33–7.24 (m, 7H), 6.94 (d, 1H, J=7.1 Hz), 6.58–6.52 (m, 1H), 3.26 (q, 2H, J=6.1 Hz), 2.90 (d, 2H, J=10.8 Hz), 2.56–2.40 (m, 4H), 2.29 (t, 2H, J=6.3 Hz), 2.03–1.87 (m, 6H), 1.83–1.76 (m, 4H), 1.60 (dd, 4H, J=6.8, 4.6 Hz), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 510.4 (M+H)+.
Reaction SMILES: B(Br)(Br)Br.[S:5]1[CH:9]=[CH:8][N:7]=[C:6]1[NH:10][C:11]([C:13]1[C:21]2[C:16](=[CH:17][C:18]([O:22]C)=[CH:19][CH:20]=2)[N:15]([CH:24]([CH3:26])[CH3:25])[CH:14]=1)=[O:12].[OH-].[NH4+]>C(Cl)Cl>[S:5]1[CH:9]=[CH:8][N:7]=[C:6]1[NH:10][C:11]([C:13]1[C:21]2[C:16](=[CH:17][C:18]([OH:22])=[CH:19][CH:20]=2)[N:15]([CH:24]([CH3:26])[CH3:25])[CH:14]=1)=[O:12]
Reactant: COc1ccc2c(C(=O)Nc3nccs3)cn(C(C)C)c2c1
Agent: BrB(Br)Br
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)n1cc(C(=O)Nc2nccs2)c2ccc(O)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.2 %

Procedure:
A 1.0M solution of boron tribromide in methylene chloride (2.70 mL, 2.70 mmol) at 25° C. was treated with a solution of 1-isopropyl-6-methoxy-1H-indole-3-carboxylic acid thiazol-2-ylamide (85 mg, 0.27 mmol) in methylene chloride (2.7 mL). The reaction was stirred at 25° C. for 1 h. At this time, the reaction was cooled to 0° C. and then was treated with a 20% aqueous ammonium hydroxide solution (3 mL). The reaction mixture was stirred at 0° C. for 15 min. At this time, the resulting precipitate was collected by filtration to afford (6-hydroxy-1-isopropyl-1H-indole-3-carboxylic acid thiazol-2-ylamide (31.9 mg, 39%) as a yellow solid: mp 239-241° C.; EI-HRMS m/e calcd for C15H15N3O2S (M) 315.1041, found 315.1039.
Reaction SMILES: [ClH:1].O[C:3]1([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1>[Pt]=O.C(O)C>[ClH:1].[CH:3]1([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1
Reactant: OC1(c2ccncc2)CCc2ccccc21
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Product: c1ccc2c(c1)CCC2C1CCNCC1

Procedure:
Ethanol (20 ml), concentrated hydrochloric acid (0.5 ml) and platinum oxide (50 mg) were added to 1-hydroxy-1-pyridin-4-yl-indane (540 mg, 2.6 mmol), and catalytic reduction was carried out at ordinary temperature under ordinary pressure to obtain 420 mg (2.1 mmol, 62% in yield) of the title compound as crystals.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([F:7])=[C:4]([F:6])[F:5].[CH:10]([Cl:13])([Cl:12])[Cl:11]>>[C:10]([C:4]([CH:3]([C:2]([F:9])([F:8])[F:1])[F:7])([F:6])[F:5])([Cl:13])([Cl:12])[Cl:11]
Reactant: FC(F)=C(F)C(F)(F)F
Reactant: ClC(Cl)Cl
Product: FC(C(F)(F)F)C(F)(F)C(Cl)(Cl)Cl
Temperature: 290 °C

Procedure:
A 0.5 inch (12.7 mm) by 40 inch (101.6 cm) plug flow reactor that is packed with Helipack Monel support is heated to 290° C. A 50/50 (molar %) mixture of hexafluoropropene and chloroform is fed into the reactor at about 1.5 g/min. The reactor pressure is maintained at 100 psig. The effluent from the reactor is fed into a distillation column and the unreacted reagents removed by distillation and recycled. The product CCl3CF2CHFCF3 is used in the next reaction.
Reaction SMILES: [S:1]([OH:11])(=[O:10])([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)=[O:2].[OH-].[Na+:13].[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1.Cl>O>[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH:9][C:6]2[CH:5]=[CH:4][C:3]([S:1]([O-:11])(=[O:10])=[O:2])=[CH:8][CH:7]=2)=[CH:17][CH:16]=1.[Na+:13]
Reactant: Fc1ccc(CCl)cc1
Reactant: Nc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=S(=O)([O-])c1ccc(NCc2ccc(F)cc2)cc1

Procedure:
To 17.3 g (0.1 mole) of sulfanilic acid, 100 ml of 5N sodium hydroxide solution and 100 ml of water was added 14.4 g (0.1 mole) of 4-fluorobenzyl chloride which was then mixed and heated to about 45°-55° C. in a 500-ml Erlenmeyer flask for 48 hours. After heating, the reaction mixture was poured over approximately 1 liter of cold water and acidified with concentrated hydrochloric acid. The resulting slurry was slowly filtered through a fine sintered glass funnel and a top clear yellow solution which did not pass through the filter was decanted away and discarded. The remaining off-white solid was mixed with 100 ml of ethanol and aqueous NaOH solution was added slowly until solution was achieved. The solution was then carbon treated, filtered and concentrated under reduced pressure to obtain 9.0 g of the crude product. Recrystallization from 80 ml of glacial acetic acid, followed by vacuum oven drying gave 2.4 g of the purified product, sodium 4-(((4-fluorophenyl)methyl)amino)benzenesulfonate, as white crystals which decomposed at 275° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]=[C:10]=[S:11].[CH2:12]([NH2:14])[CH3:13]>>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10]([NH:14][CH2:12][CH3:13])=[S:11]
Reactant: CCN
Reactant: Cc1cccc(C)c1N=C=S
Product: CCNC(=S)Nc1c(C)cccc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,6-Dimethylphenyl isothiocyanate (16.3 g; 0.1 mol) was added dropwise to 110 mL of 70% aqueous ethylamine solution. The mixture was stirred for 1 hour at ambient temperature. Excess ethylamine was evaporated under a stream of nitrogen. The mixture was diluted with water (100 mL). The solid was collected by filtration and washed with water and dried to give 20.0 g of N-(2,6-dimethylphenyl)-N′-ethylthiourea.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([Cl:10])[CH:3]=1.[O:11]1[C:15]2[CH:16]=[CH:17][C:18](B(O)O)=[CH:19][C:14]=2[CH2:13][CH2:12]1>>[Cl:10][C:4]1[CH:3]=[C:2]([C:18]2[CH:17]=[CH:16][C:15]3[O:11][CH2:12][CH2:13][C:14]=3[CH:19]=2)[CH:8]=[C:7]([F:9])[C:5]=1[NH2:6]
Reactant: Nc1c(F)cc(Br)cc1Cl
Reactant: OB(O)c1ccc2c(c1)CCO2
Product: Nc1c(F)cc(-c2ccc3c(c2)CCO3)cc1Cl
Yield: 36.6 %

Procedure:
The title compound (86 mg) was prepared from 4-bromo-2-chloro-6-fluoroaniline (200 mg, 0.89 mmol) and 2,3-dihydrobenzofuran-5-ylboronic acid (189 mg, 1.16 mmol) as a pale-yellow solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.46 (s, 1H), 7.33-7.25 (m, 3H), 6.75 (d, J 8.3, 1H), 5.36 (s, 2H), 4.52 (t, J 8.7, 2H), 3.18 (t, J 8.6, 2H).
Reaction SMILES: [C:1](=[S:4])([S-:3])[NH2:2].[NH4+].Br[CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]>C(O)C>[NH2:2][C:1]([S:3][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[S:4]
Reactant: NC(=S)[S-]
Reactant: CCOC(=O)CCCBr
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)CCCSC(N)=S
Temperature: 25 °C
Reaction time: 48 h
Yield: 101 %

Procedure:
A mixture of 10 g of ammonium dithiocarbamate (i.e. 34 g of a 30% aqueous solution) and 17.7 g of ethyl 4-bromobutyrate in 70 ml of ethanol is stirred for 2 days at room temperature. The reaction medium is extracted with methylene chloride and the organic phase is dried and then concentrated to give 19 g of ethyl 4-(aminothiocarbonylmercapto)butyrate in the form of a semicrystalline yellow oil.
Reaction SMILES: C(O[C:4]([C:6]1[C:11]([NH:12][C:13](=[O:24])[CH2:14][C:15]2[C:20]([F:21])=[CH:19][C:18]([F:22])=[CH:17][C:16]=2[F:23])=[C:10](CC)[CH:9]=[CH:8][N:7]=1)=[O:5])C.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[F:21][C:20]1[CH:19]=[C:18]([F:22])[CH:17]=[C:16]([F:23])[C:15]=1[CH:14]1[C:4](=[O:5])[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][N:7]=2)[NH:12][C:13]1=[O:24]
Reactant: CCOC(=O)c1nccc(CC)c1NC(=O)Cc1c(F)cc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1Nc2cccnc2C(=O)C1c1c(F)cc(F)cc1F
Reaction time: 18 h

Procedure:
The product from Step 2 (0.80 g) and potassium carbonate (0.40 g) were stirred in dry DMF (10 ml) at 100° C. for 6 hours. The reaction mixture was cooled, stood for 18 hours and the DMF was evaporated to give a solid. This was diluted with water (1 ml), acidified to neutrality and the water was evaporated to give a solid, which was then extracted with methanol. The methanol was evaporated to give 3-(2,4,6-trifluorophenyl)-1H-[1,5]naphthyridine-2,4-dione as a peach coloured solid (0.15 g), which was used without further purification.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][OH:16])[N:10]=[CH:9]2)C=CC=CC=1.Br[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:32]>C(Cl)Cl>[NH:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O:16][CH2:30][C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:32])[N:10]=[CH:9]1
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: O=C(CBr)c1ccccc1
Solvent: ClCCl
Product: O=C(COCCCc1c[nH]cn1)c1ccccc1

Procedure:
5 mmol of 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanol and 5 mmol of 2-bromo-1-phenylethanone are stirred for 72 hours in methylene chloride. The solvent is evaporated off under reduced pressure and the residue is refluxed for 1 hour in 30 ml of 2N HCl and 30 ml of acetone. The solvent is evaporated off under reduced pressure and triphenylmethanol is extracted using diethyl ether. The aqueous phase is alkalized with ammonia, and the crude product is extracted with diethyl ether, purified by rotatory chromatography and crystallized as hydrogen maleate from diethyl ether and ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][CH2:10][C:9]=2[CH2:16][OH:17])=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl.CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:13][C:12]([CH3:14])([CH3:15])[CH2:11][CH2:10][C:9]=2[CH:16]=[O:17])=[CH:6][CH:7]=1
Reactant: CC1(C)CCC(CO)=C(c2ccc(Cl)cc2)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOCC
Product: CC1(C)CCC(C=O)=C(c2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of EXAMPLE 30D (1.25 g) in dichloromethane (20 ml) was slowly added Dess-Martin Periodinane (2.78 g). The reaction mixture was stirred at room temperature for 3 hours and diluted with ether. The resulting mixture was washed with aqueous NaOH and water. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography, eluting with 0-100% dichloromethane in hexane to provide the title compound.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH:7]1([C:10]([C@H:12]2[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[N:13]2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=O)[CH2:9][CH2:8]1>CCOCC.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:7]1([C:10]([C@H:12]2[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[N:13]2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH2:1])[CH2:9][CH2:8]1
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)N1[C@@H](C(=O)C2CC2)COC1(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOCC
Product: C=C(C1CC1)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 40 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
To a suspension of potassium tert-butoxide (9.29 g, 82.80 mmol) in ether (250 mL) at room temperature was added methyltriphenylphosphonium bromide (29.6 g, 82.80 mmol). The mixture turned bright yellow and was heated to 40° C. for 1 hour. The mixture was cooled to room temperature and a solution of (R)-tert-butyl 4-(cyclopropanecarbonyl)-2,2-dimethyloxazolidine-3-carboxylate (Intermediate 231, 11.15 g, 41.40 mmol) in ether (30 mL) was added and the reaction mixture was stirred for 2 hours. The reaction was quenched with water (10 mL) and the layers were separated. The aqueous was extracted once with ether. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%-15% ethyl acetate/hexanes) afforded the title compound as a colorless oil (9.84 g, 89%).
Reaction SMILES: C(O)(=O)C.[NH2:5][C@@H:6]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C@H:7]1[C:13]([O:15][CH3:16])=[O:14].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.C(N(CC)CC)C>O1CCCC1>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:5][C@@H:6]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C@H:7]2[C:13]([O:15][CH3:16])=[O:14])(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)[C@@H]1CCCCC[C@H]1N
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1CCCCC[C@H]1NS(=O)(=O)c1ccc(Cl)cc1
Yield: 25.9 %

Procedure:
A solution of trans-methyl 2-aminocycloheptanecarboxylate acetate (652 mg, 2.82 mmol), 4-chlorobenzene sulfonyl chloride (893 mg, 4.23 mmol), and triethylamine (1.18 mL, 8.46 mmol) was stirred in 20 mL tetrahydrofuran for 2 h. The reaction was partitioned between 100 mL diethyl ether and 100 mL brine. The organic layer was dried over sodium sulfate, concentrated, and purified by flash chromatography on 40 g silica gel with 15 to 40% ethyl acetate in hexane to yield trans-methyl 2-(4-chlorophenylsulfonamido)cycloheptanecarboxylate (253 mg, 26%). 1H NMR (400 MHz, CDCl3) δ ppm 7.77-7.79 (1H, m), 7.74-7.76 (1H, m), 7.44-7.47 (1H, m), 7.42-7.44 (1H, m), 5.21 (1H, d, J=8.56 Hz), 3.68 (1H, qd, J=8.48, 3.78 Hz), 3.43 (3H, s), 2.44 (1H, td, J=8.56, 3.27 Hz), 1.75-1.82 (1H, m), 1.56-1.73 (4H, m), 1.34-1.54 (5H, m). LC/MS R.T.=2.89 min; [M−H]+=344.04; [M+Na]+=368.16; [M−H]−=344.04.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1.[CH3:26][S:27]([C:30]1[N:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=1)(=[O:29])=[O:28].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([NH:36][C:33]3[CH:34]=[N:35][C:30]([S:27]([CH3:26])(=[O:29])=[O:28])=[CH:31][CH:32]=3)[N:3]=2)[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CS(=O)(=O)c1ccc(N)cn1
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(S(C)(=O)=O)nc3)nc12
Temperature: 150 °C
Yield: 53.3 %

Procedure:
A mixture of 2-bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (150 mg, 351 μmol), 6-(methylsulfonyl)pyridin-3-amine (90.7 mg, 526 μmol), xantphos (60.9 mg, 105 μmol), Pd2(dba)3 (32.1 mg, 35.1 μmol) and cesium carbonate (229 mg, 702 μmol) in dioxane (2.4 mL) was heated in a microwave at 150° C. for 20 min. The mixture was cooled then filtered through a pad of celite. The filtrate was concentrated in vacuo then purified by chromatography (silica, 20-95% ethyl acetate in hexanes) to give N-tert-butyl-2-(6-(methylsulfonyl)pyridin-3-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (97 mg, 187 μmol, 53%) as a yellow solid. (EI/CI) m/z: 458.3 [M+H].
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl.C(#N)C>[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C)c(B(O)O)c1
Reactant: O=C(Nc1cc2ccc(Br)cc2cn1)C1CC1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: Cc1ccc(C)c(-c2ccc3cc(NC(=O)C4CC4)ncc3c2)c1
Temperature: 120 °C
Yield: 79 %

Procedure:
A mixture of N-(7-bromoisoquinolin-3-yl)cyclopropanecarboxamide (49.0 mg, 168 mmol), 2,5-dimethylphenylboronic acid (52.0 mg, 347 woe, bis(di-tert-butyl(4-dimethylaminophenyl)-phosphine)dichloropalladium(II) (7.2 mg, 10 μmol) and aqueous sodium carbonate (1.0 M, 0.5 mL) and acetonitrile (1.5 mL) was heated under microwave irradiation (Biotage, 200 watts) at 120° C. for 10 minutes. The cooled reaction mixture was partitioned between ethyl acetate (20 mL) and water (20 mL), and the separated aqueous phase extracted with ethyl acetate (20 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a clear oil. The crude residue was purified by reverse phase HPLC (gradient of acetonitrile in water with 0.1% formic acid) to yield the title compound as a white amorphous solid (42.3 mg, 79%). 1H NMR (400 MHz, DMSO) δ 10.88 (s, 1H), 9.16 (s, 1H), 8.48 (s, 1H), 7.98 (s, 1H), 7.89 (d, J=8.6 Hz, 1H), 7.68 (dd, J=8.5, 1.7 Hz, 1H), 7.22 (d, J=8.2 Hz, 1H), 7.15-7.11 (m, 2H), 2.33 (s, 3H), 2.23 (s, 3H), 2.12-2.03 (m, 1H), 0.91-0.78 (m, 4H). LCMS (Method E): RT=5.442 min, M+H+=317.1.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6](OCC)=[O:7])=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1.OC1C=CC(C(O)=O)=CC=1C1C=CC(OC)=CC=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>C1COCC1>[OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1ccc(O)c(-c2ccc(OC)cc2)c1
Agent: COc1ccc(-c2cc(C(=O)O)ccc2O)cc1
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(CO)ccc2O)cc1

Procedure:
A solution of Ethyl 4-hydroxy-3-(4-methoxyphenyl)benzoate and 4-hydroxy-3-(4-methoxyphenyl)benzoic acid (5.3 g, 19.47 mmol) in anhydrous THF (100 mL) was cooled to 0° C. and treated with LiAlH4 (2.95 g, 77.8 mmol); the mixture was then heated at 65 C for one hour then cooled and aqueous NaOH (5%, 19.4 mL) was added drop wise. The resulting precipitate was filtered off and the filtrate concentrated under reduced pressure to afford 5.54 g of crude product.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=1)#[N:2].[N:25]([Sn](C)(C)C)=[N+:26]=[N-:27]>C1(C)C=CC=CC=1>[NH:25]1[C:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:9]2[C:10]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[N:2][N:27]=[N:26]1
Reactant: N#Cc1ccccc1-c1ccccc1C(=O)OCc1ccccc1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)c1ccccc1-c1ccccc1-c1nnn[nH]1
Yield: 85.6 %

Procedure:
To a solution of benzyl 2′-cyano-2-bipheylcarboxylate (560 mg) in toluene (10 ml), azidotrimethyltin (810 mg) was added. The mixture was refluxed for 12 hours. The reaction mixture was concentrated. 5% aqueous solution of potassium fluoride (4 ml) was added to the residue. The solution was filtered. The filtrate was diluted with ethyl acetate, and the solution was washed with a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=2:1→chloroform:methanol=10:1) to give the title compound (545 mg) having the following physical data.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH3:31])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl>CO>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH3:31])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CCOCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Product: CCOCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 1.6 h
Yield: 42.1 %

Procedure:
A mixture of 7-[2-(2-formamidothiazol-4-yl)-2-(2-ethoxyethoxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 2.2 g.), conc hydrochloric acid (2 ml.) and methanol (30 ml.) was stirred at room temperature for 1.6 hours. After concentrating the resultant solution in vacuo, water was added to the residue, adjusted to pH 6.5 with sodium bicarbonate and washed with ethyl acetate. The aqueous solution was treated with activated charcoal and adjusted to pH 3.0 with conc. hydrochloric acid. The precipitates were collected by filtration, washed with water and dried over anhydrous pentoxide under reduced pressure to give 7-[2-(2-aminothiazol-4-yl)-2-(2-ethoxyethoxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 0.87 g.).