Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1.C(N(CC)CC)C.[C:14](Cl)(=[O:17])[CH2:15][CH3:16]>ClCCl>[O:4]1[CH2:5][CH2:6][CH:2]([NH:1][C:14](=[O:17])[CH2:15][CH3:16])[CH2:3]1
Reactant: NC1CCOC1
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)NC1CCOC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 50 g of 3-aminotetrahydrofuran in 200 ml of dichloromethane was mixed with 63.8 g (0.63 mol) of triethylamine. 58.4 g (0.63 mol) of propionyl chloride were added dropwise with ice-cooling. The mixture was stirred at room temperature for 2 days, resulting in a white precipitate. The solution was filtered and the filtrate was distilled. B.p. 145° C. (12 mm), yield 81 g. 1H NMR (270 MHz, in CDCl3): δ=1.14 (t, 3 H), 1.83 (m, 1H), 2.22 (q, 2H), 2.31 (m, 1H), 3.64 (dd, 1H), 3.72-3.98 (m, 3H), 4.50 (m, 1H), 6.57 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([O:10][CH3:11])=[O:9])[CH2:3]1.[CH2:12](O)[CH2:13][OH:14].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C1(C)C=CC=CC=1.O>[CH2:12]1[CH2:13][O:14][C:2]2([CH2:7][CH2:6][CH2:5][CH:4]([C:8]([O:10][CH3:11])=[O:9])[CH2:3]2)[O:1]1
Reactant: COC(=O)C1CCCC(=O)C1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C1CCCC2(C1)OCCO2
Temperature: 95 °C

Procedure:
A solution composed of 30 g (192 mmol) of crude methyl 3-oxocyclohexanecarboxylate and 430 cm3 of toluene is introduced into a one-liter three-necked flask equipped with a Dean and Stark apparatus, and 14.3 g (230 mmol) of ethylene glycol are then added with 814 mg (4.3 mmol) of para-toluenesulfonic acid monohydrate. The mixture is heated to reflux, the toluene-water azeotrope forms instantaneously and, after 40 min, no further refluxing of azeotrope (95° C.) takes place. The mixture is maintained for 6 h under reflux of the toluene (110° C.). After cooling, sodium hydrogen carbonate solution is added and the solution is then washed with saturated sodium chloride solution and dried over sodium sulfate. After concentration, 39 g of a yellow oil are obtained, which product is either distilled or chromatographed on a column of 215 g of silica (eluant: cyclo-hexane/ether, 98:2).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1>O1CCCC1>[CH3:1][N:2]([CH2:3][CH2:4][OH:5])[S:13]([C:10]1[CH:11]=[CH:12][C:7]([Cl:6])=[CH:8][CH:9]=1)(=[O:15])=[O:14]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CNCCO
Solvent: C1CCOC1
Product: CN(CCO)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 50 °C

Procedure:
To 20 parts of tetrahydrofuran is added 3.9 parts of N-methyl-ethanolamine. To this solution, 10 parts of tetrahydrofuran containing 5 parts of p-chlorobenzenesulfonyl chloride is added with stirring. After completion of the addition, the resultant mixture is stirred as it is for a while, and then heated for about 1 hour on a water bath at 50° C. to terminate the reaction. Then, the salt is removed by filtration, and the filtrate is freed from the solvent, whereby an oily substance is obtained. This oily substance is subjected to distillation under reduced pressure to obtain 4.2 parts of a distillate, b.p. 180° C./0.5 mmHg.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][N:10]=[CH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(O)(=O)[CH2:15][C:16]([OH:18])=[O:17]>C(O)(=O)C.C(O)C>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][NH:10][CH:11]2[CH2:15][C:16]([OH:18])=[O:17])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(c1)C=NCC2
Reactant: O=C(O)CC(=O)O
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(O)CC1NCCc2ccc([N+](=O)[O-])cc21
Temperature: 120 °C

Procedure:
A suspension of 7-nitro-3,4-dihydroisoquinoline (10.0 g, 56.1 mmol) and malonic acid (11.7 g, 112 mmol) in acetic acid (55 ml) was heated at 120° C. for 0.5 h. Upon cooling, the solvent was concentrated to give a red oil which was taken up in aqueous ethanol (50 ml of 75%). After crystallization had occurred, the solvent was cooled to 0° C. and the product collected. The title compound was isolated as a tan solid (10.9 g, 81%), m.p. 264-5° C. (dec.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[C:4]([F:19])[CH:3]=1.C([Li])CCC.[B:25](OC)([O:28]C)[O:26]C.FC1C(F)=CC=CC=1B(O)O>C1COCC1>[F:19][C:4]1[CH:3]=[C:2]([B:25]([OH:28])[OH:26])[CH:7]=[CH:6][C:5]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCOc1ccc(Br)cc1F
Reactant: COB(OC)OC
Agent: OB(O)c1cccc(F)c1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCOc1ccc(B(O)O)cc1F

Procedure:
Quantities: compound 12 (9.84 g, 0.03 mol) in anhydrous THF (120 ml), n-butyllithium (12.5 ml, 2.5M in hexane, 0.031 mol), trimethyl borate (6.24 g, 0.06 mol) in anhydrous THF (50 ml). The experimental procedure was as described for the preparation of compound 2.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[N+:12]([O-])([O-:14])=[O:13].[K+]>S(=O)(=O)(O)O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:12]([O-:14])=[O:13])[C:7](=[O:11])[CH2:6][CH2:5]2
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1ccc2c(c1)CCC2=O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1cc2c(cc1[N+](=O)[O-])C(=O)CC2
Temperature: 0 °C
Yield: 55.3 %

Procedure:
This step was performed according to the method described in Journal of Medicinal Chemistry, 2006, 49, 7502-7512. 5-Methylindan-1-one (3.27 g, 22.4 mmol) was dissolved in concentrated sulfuric acid (27 ml), a solution of potassium nitrate (2.28 g, 22.6 mmol) in concentrated sulfuric acid (5 ml) was added dropwise over 10 min under ice-cooling with stirring, and the mixture was stirred at the same temperature for 2 hr. The reaction mixture was added to ice water, and extracted with an ethyl acetate-hexane=1:1 mixed solvent. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography (ethyl acetate-hexane) to give the title compound (2.37 g, yield 55%) as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH3:23])[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[O:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=2)[CH2:31][CH2:30]1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>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>[CH:24]1([N:22]([CH3:23])[C:4]2[C:5]([CH3:21])=[C:6]([C:7]([NH:9][CH2:10][C:11]3[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=3[CH3:17])=[O:8])[CH:20]=[C:2]([C:39]3[CH:38]=[CH:37][C:36]([CH2:35][N:32]4[CH2:33][CH2:34][O:29][CH2:30][CH2:31]4)=[CH:41][CH:40]=3)[CH:3]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)C3CCCC3)c2C)c(=O)[nH]1
Reactant: OB(O)c1ccc(CN2CCOCC2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN4CCOCC4)cc3)cc(N(C)C3CCCC3)c2C)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 2 h
Yield: 16 %

Procedure:
A solution of 5-bromo-3-(cyclopentyl(methyl)amino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide (1 equiv.), (4-(morpholinomethyl)phenyl)boronic acid (1.2 equiv.) and Pd(PPh3)4 (0.1 equiv.) in 1,4-dioxane (4 mL) was purged with argon for 10 min. Then, a 2 M Na2CO3 solution (3.6 equiv.) was added to it and argon was purged again for 10 min. The reaction mixture was stirred at 100° C. for 2 h. After completion of the reaction, water was added to it and extraction was carried out using DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography over silica gel (60-120 mesh size) to afford the desired compound (0.02 g, 16%). LCMS: 543.22 (M+1)+; HPLC: 99.53% (@254 nm) (Rt; 4.181; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.46 (s, 1H), 8.17 (t, 1H, J=4.4 Hz), 7.98 (s, 1H), 7.73 (d, 1H, J=7.6 Hz), 7.57 (d, 2H, J=7.6 Hz), 7.37 (s, 2H), 7.17 (s, 1H), 5.85 (s, 1H), 4.27 (d, 2H, J=4.8 Hz), 3.44-3.57 (m, 7H), 2.54 (s, 3H), 2.32-2.36 (m, 4H), 2.23 (s, 3H), 2.19 (s, 3H), 2.09 (s, 3H), 1.69-1.72 (m, 2H), 1.61 (m, 2H), 1.43-1.50 (m, 4H).
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:13]([CH3:14])=[CH:12][N:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)[CH:10]=2)[OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O[C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32]C)=[O:31])=[CH:28][CH:27]=1.C(P(CCCC)CCCC)CCC.N(C([O-])=O)=NC([O-])=O>O1CCCC1>[CH:1]1([CH:7]([C:9]2[C:13]([CH3:14])=[CH:12][N:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:22])[F:23])[CH:16]=3)[CH:10]=2)[O:8][C:26]2[CH:35]=[CH:34][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cn(-c2cccc(C(F)(F)F)c2)cc1C(O)C1CCCCC1
Reactant: COC(=O)c1ccc(O)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C([O-])N=NC(=O)[O-]
Solvent: C1CCOC1
Product: Cc1cn(-c2cccc(C(F)(F)F)c2)cc1C(Oc1ccc(C(=O)O)cc1)C1CCCCC1
Yield: 87.4 %

Procedure:
To a solution (15 mL) of cyclohexyl{4-methyl-1-[3-(trifluoromethyl)phenyl]-1H-pyrrol-3-yl}methanol (0.81 g) synthesized in Example 298 (6) in tetrahydrofuran were added methyl 4-hydroxybenzoate (0.4 g), tributylphosphine (1.2 mL) and dipiperidide azodicarboxylate (1.2 g) with stirring under ice-cooling. The ice bath was removed, and the reaction mixture was stirred at room temperature overnight. Hexane was added to the reaction mixture, and the precipitate was filtered through celite. Water was added to the filtrate and the mixture was extracted with ethyl acetate. The extract was purified by silica gel chromatography (ethyl acetate:hexane=1:1, volume ratio) to give a methyl ester form of the title compound (0.96 g). This was dissolved in ethanol (5 mL), 1N sodium hydroxide (4 mL) was added at 60° C. and the mixture was stirred for 1 hr. Ethanol was evaporated under reduced pressure, and 1N hydrochloric acid (4 mL) was added to the residue to give the title compound (0.88 g, 80%) as an amorphous form.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:8]([C:10]1[CH:30]=[CH:29][C:13]2[N:14]([CH3:28])[C:15]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[NH:27])[NH2:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9].O.C(=O)([O-])[O-].[K+].[K+].N1([C:50]([O:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])=[O:51])C=CN=C1>C(#N)C>[CH3:58][CH2:57][CH2:56][CH2:55][CH2:54][CH2:53][O:52][C:50](/[N:27]=[C:25](\[NH2:26])/[C:22]1[CH:21]=[CH:20][C:19]([NH:18][CH2:17][C:15]2[N:14]([CH3:28])[C:13]3[CH:29]=[CH:30][C:10]([C:8]([N:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:9])=[CH:11][C:12]=3[N:16]=2)=[CH:24][CH:23]=1)=[O:51]
Reactant: CCCCCCOC(=O)n1ccnc1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCCCCCOC(=O)/N=C(\N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccn4)ccc3n2C)cc1
Temperature: 15 °C
Reaction time: 0.25 h

Procedure:
1-methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide compound of formula-5 (100 g) was added to acetonitrile (1200 ml) and water (800 ml) at 25-35° C. and then cooled to 12-18° C. Potassium carbonate (138 g) was added to the reaction mixture and stirred for 15 minutes at 12-18° C. A solution of hexyl 1H-imidazole-1-carboxylate compound of formula-4 (66 g) in acetonitrile (150 ml) was slowly added to the reaction mixture over a period of 25 minutes at 12-18° C. and stirred for 14 hours at 15-20° C. After completion of the reaction, water was added to the reaction mixture and stirred for 30 minutes. Filtered the solid, washed with acetonitrile followed by aqueous acetonitrile and then dried to get title compound. Dichloromethane was added to the obtained compound and stirred for 15 minutes. Water was added to the reaction mixture and stirred for 20 minutes at 25-35° C. Both the organic and aqueous layers were separated, and the dichloromethane layer was washed with water followed by sodium chloride and then distilled off completely under reduced pressure. Acetone (600 ml) was added to the obtained residue and stirred for 45 minutes at 25-35° C. to obtain a clear solution. Water (500 ml) was added to the obtained solution and stirred for 45 minutes at 25-35° C. to get the solid. Filtered the solid, washed with water and finally with methyl tertiary butyl ether and then dried to get the pure title compound. Further the obtained solid recrystallized from ethylacetate and ethanol.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1I)[C:15]#[N:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:21]([NH:24][C:25](=[CH2:30])[C:26]([O:28][CH3:29])=[O:27])(=[O:23])[CH3:22].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:21]([NH:24][C:25](=[CH:30][C:19]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=1[O:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:26]([O:28][CH3:29])=[O:27])(=[O:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)NCCOc1cc(C#N)ccc1I
Reactant: C=C(NC(C)=O)C(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C(=Cc1ccc(C#N)cc1OCCNC(=O)OC(C)(C)C)NC(C)=O
Temperature: 115 °C
Reaction time: 4 h

Procedure:
18.0 g (46.4 mmol) of 3-[2-(t-butoxycarbonylamino)ethoxy]-4-iodobenzonitrile was dissolved in 200 ml of dimethylformamide (DMF). 13.3 g (92.8 mmol) of methyl 2-acetamidoacrylate, 2.82 g (9.28 mmol) of tris(2-methylphenyl)phosphine, 1.04 g (4.64 mmol) of palladium (II) acetate and 12.9 ml (92.8 mmol) of triethylamine were added to the obtained solution, and they were stirred at 115° C. for 4 hours. The solvent was evaporated to obtain the crude product, which was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@@H:4](OS(C)(=O)=O)[CH2:5][CH2:6][O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].[I-:21].[Na+]>CC(=O)CC>[CH3:1][O:2][C:3](=[O:20])[CH:4]([I:21])[CH2:5][CH2:6][O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: [I-]
Reactant: COC(=O)[C@H](CCO[Si](C)(C)C(C)(C)C)OS(C)(=O)=O
Agent: [Na+]
Solvent: CCC(C)=O
Product: COC(=O)C(I)CCO[Si](C)(C)C(C)(C)C
Temperature: 90 °C

Procedure:
A solution of 2.89 g (8.85 mmol) of (S)-4-(tert-butyl-dimethyl-silanyloxy)-2-methanesulfonyloxy-butyric acid methyl ester in 90 ml of 2-butanone was treated with 2.65 g (17.70 mmol) of sodium iodide and stirred at 90° C. for 1¼ h. The reaction was cooled, filtered and evaporated. The residue was suspended in dichloromethane treated with Na2SO4 and filtered to give after evaporation 2.94 g (93%) of the title compound as dark brown oil. MS: 343.0 (M-CH3)+.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C@@H:51]([CH:56]([CH3:58])[CH3:57])[C:52]([O:54][CH3:55])=[O:53])[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1.[Cl:59][C:60]1[C:61]([F:69])=[C:62]([CH:66]=[CH:67][CH:68]=1)[C:63](Cl)=[O:64]>>[Cl:59][C:60]1[C:61]([F:69])=[C:62]([CH:66]=[CH:67][CH:68]=1)[C:63]([NH:34][C:35]1[CH:36]=[CH:37][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C@@H:51]([CH:56]([CH3:58])[CH3:57])[C:52]([O:54][CH3:55])=[O:53])[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:39][CH:40]=1)=[O:64]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: O=C(Cl)c1cccc(Cl)c1F
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4cccc(Cl)c4F)cc3)cc2C1=O
Yield: 77 %

Procedure:
The compound of example 204 was prepared analogous to compound of example 97 by reaction of compound of example 6 with 3-chloro-2-fluoro benzoyl chloride.
Reaction SMILES: C(O[CH:5]([C:24]1(Br)[C:30](=[O:31])[N:29]2[C@@H:25]1[S:26][CH:27]=[C:28]2[C:32]([O:34]CC1C=CC([N+]([O-])=O)=CC=1)=[O:33])[C:6]1[N:23]=[C:9]2[N:10]=[CH:11][C:12]3[CH2:17][N:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:15][CH2:14][C:13]=3[N:8]2[N:7]=1)(=O)C.C(#N)C>C1COCC1.[Pd]>[CH2:21]([O:20][C:18]([N:16]1[CH2:15][CH2:14][C:13]2[N:8]3[N:7]=[C:6](/[CH:5]=[C:24]4\[C@@H:25]5[N:29]([C:30]\4=[O:31])[C:28]([C:32]([OH:34])=[O:33])=[CH:27][S:26]5)[N:23]=[C:9]3[N:10]=[CH:11][C:12]=2[CH2:17]1)=[O:19])[CH3:22]
Reactant: CCOC(=O)N1CCc2c(cnc3nc(C(OC(C)=O)C4(Br)C(=O)N5C(C(=O)OCc6ccc([N+](=O)[O-])cc6)=CS[C@@H]54)nn23)C1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CC#N
Product: CCOC(=O)N1CCc2c(cnc3nc(/C=C4/C(=O)N5C(C(=O)O)=CS[C@H]45)nn23)C1
Temperature: 3 °C

Procedure:
ethyl 2-[(acetyloxy)((5R)-6-bromo-2-{[(4-nitrobenzyl)oxy]carbonyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-en-6-yl)methyl]-8,9-dihydropyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidine-7(6H)-carboxylate (220 mg, 0.28 mmol) was dissolved in THF (20 mL) and acetonitrile (20 mL) and phophate buffer (6.5 pH) (20 ml) and hydrogenated over Pd/C (10%) (200 mg) under 40 psi pressure. At the end, reaction mixture was filtered, cooled to 3° C., and 0.1 N NaOH was added to adjust the pH to 8.5. The filtrate was washed with ethyl acetate and the aqueous layer was separated. The aqueous layer was concentrated under high vacuum at 35° C. to give a yellow precipitate. The product was purified by HP21 resin reverse phase column chromatography. Initially the column was eluted with deionized water (2 L) and latter with 10% acetonitrile:water. The fractions containing the product were collected and concentrated under reduced pressure at room temperature. The yellow solid was washed with acetone, filtered and dried. Yield: 15 mg, 2%; Yellow crystals; mp>250° C. (Dec); (M+H+Na) 449. 1H NMR (DMSO-d6) δ 8.61 (s, 1H), 7.01 (s, 1H), 6.90(s, 1H), 6.44(s, 1H), 4.74(m, 2H, CH2), 4.13 (q, 2H, J=5.4 Hz), 3.84(s, m, 2H, CH2), 1.22(t, 3H, CH3, J=5.7 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:7][CH:8]=1.C1(=O)O[C:16](=[O:17])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12>C([O-])(=O)C.[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[CH:9]=[C:10]1[C:19]2[C:15](=[CH:14][CH:22]=[CH:21][CH:20]=2)[C:16](=[O:17])[O:12]1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: COc1cccc(CC(=O)O)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Product: COc1cccc(C=C2OC(=O)c3ccccc32)c1
Temperature: 240 °C
Yield: 69.7 %

Procedure:
A mixture of 15 g (89 mmol) of m-methoxyphenyl acetic acid, 13.2 g (89 mmol) of phthalic anhydride and 246 mg (2.9 mmol) of sodium acetate was heated to 240° C. for 6 hours and water was continuously removed from the reaction. The solid formed in the reaction flask on cooling. This was recrystallized from absolute ethanol to obtain 15.6 g (62 mmol, 69%) of 1 as yellow powder.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:7][CH2:8][CH2:9][CH2:10]Br.C(=O)([O-])[O-].[Na+].[Na+]>O>[Br:7][CH2:8][CH2:9][CH2:10][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrCCCBr
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: BrCCCN1CCCCC1

Procedure:
Combine piperidine (5.0 g, 58.7 mmol), fused sodium acetate (4.82 g, 58.7 mmol) and 1,3-dibromopropane (11.85 g, 58.7 mmol) and reflux for several hours. Pour the mixture into water and add sodium carbonate to create a basic pH. Remove the unreacted 1,3-dibromopropane by distillation. Extract the left-over residue with ether and evaporate to obtain the final, desired compound.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[CH:14]([NH:17][NH:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:16])[CH3:15].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>CN(C=O)C>[Br:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([N:17]([CH:14]([CH3:16])[CH3:15])[NH:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:8]
Reactant: CC(C)NNC(=O)c1ccccc1
Reactant: O=C(O)COc1ccc(F)cc1Br
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1ccc(F)cc1Br
Yield: 69.7 %

Procedure:
A solution of (2-bromo-4-fluoro-phenoxy)-acetic acid (2.00 g, 8.03 mmol) and benzoic acid N′-isopropyl-hydrazide (1.72 g, 9.63 mmol) in DMF (20 mL) was treated with diisopropylethyl amine (3.5 mL, 20.07 mmol) and bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP, 5.62 g, 12.04 mmol) at room temperature overnight. The reaction mixture was partitioned between 1N HCl and ethyl acetate. The organic layer was successively washed with saturated sodium bicarbonate and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-30% ethyl acetate/hexanes gradient to afford the product as a white crystalline solid (2.29 g, 70%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[OH-].[Na+].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].ClCCl>O>[OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:6][CH2:5]1
Reactant: OCCN1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: O=C(OCc1ccccc1)N1CCN(CCO)CC1

Procedure:
A mechanically-stirred solution of 1-(2-hydroxyethyl)piperazine (10.0 g, 9.4 mL, 0.07 mol) in 30 mL of deionized water is cooled to 0 C. Then portions of 4N sodium hydroxide (total 28 mL) and portions of benzyl chloroformate (18.8 g, 15.7 mL, 0.11 mol) are added over 15 minute periods, keeping the temperature at 0 C. to 5 C. At the end of the additions, 4N sodium hydroxide solution is added to bring the pH of the reaction mixture to 10. After 1 hour dichloromethane (200 mL) is added and the layers are separated. The organic solution is dried over anhydrous sodium sulfate and evaporated under reduced pressure to give 1-(2-hydroxyethyl)-4-carbobenzyloxypiperazine.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:10]1[CH:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5]=1[O:4][CH3:3]
Reactant: BrBr
Reactant: CCOC(=O)c1ccc(-c2ccc(OC)cc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(-c2ccc(OC)c(Br)c2)cc1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
A solution of bromine (14.6 g, 91.3 mmol) in carbon tetrachloride (100 mL) is added to a stirred mixture of 4'-Methoxy-[1,1'-biphenyl]-4-carboxylic acid, ethyl ester (23.4 g, 91.3 mmol) and silica gal (100 g of particle size 0.040-0.063 mm; Merck 1.09385) in carbon tetrachloride (350 mL). The mixture is stirred at 20° C. for 4 h after which the silica gel is removed by filtration. The filtrate is washed with aqueous sodium hydrogen carbonate (200 mL of 1 M) followed by aqueous sodium thiosulphate (50 mL of 2 M), dried (Na2SO4), filtered and evaporated to dryness under reduced pressure to give the crude product which is recrystallised from ether-cyclohexane to give 3'-bromo-4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid, ethyl ester as a colourless crystalline solid, m.p. 114-115° C.