Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN(C=O)C.O=S(Cl)Cl.CCN(C(C)C)C(C)C.[Cl:30][C:31]([F:41])([F:40])[O:32][C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1>C1(C)C=CC=CC=1.C1COCC1>[Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:37][C:36]1[CH:38]=[CH:39][C:33]([O:32][C:31]([Cl:30])([F:40])[F:41])=[CH:34][CH:35]=1)=[O:9]
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Reactant: Nc1ccc(OC(F)(F)Cl)cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(Br)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
5-Bromo-6-chloro-nicotinic acid (8 g, 33.8 mmol) was suspended in toluene (70 mL). DMF (0.77 mL, 10.15 mmol) was added followed by slow addition of SOCl2 (7.4 mL, 102 mmol) and the RM was stirred for 1 h at 80° C. After cooling at RT, the toluene was evaporated off under reduce pressure. The residue was dissolved in THF (70 mL) and cooled to −10-15° C. and treated with DIPEA (11.8 mL, 67.7 mmol) followed by the slow addition of a solution of 4-(chloro-difluoro-methoxy)aniline (6.88 g, 35.5 mmol) in THF (70 mL) over 10 min. The RM was allowed to warm at RT and stirred for 1 h, the solvent was evaporated off under reduced pressure. The residue was dissolved in TBME, the solution was washed with 1 M HCl, 10% aq. NaHCO3 and brine, dried over Na2SO4 and concentrated under reduced pressure until crystallisation started. n-Heptane was then added and the product was filtered and dried to afford the title compound as a beige crystalline powder. HPLC (Condition 4) tR=6.46 min, UPLC-MS (Condition 3) tR=1.29 min, m/z=411 [M+H]+.
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5]CC)=[O:4].[CH:9]1([NH2:12])[CH2:11][CH2:10]1.N1C=CC=CC=1.[OH-].[Na+].Cl.[Cl-].[Na+]>ClCCl>[CH:9]1([NH:12][C:2](=[O:8])[C:3]([OH:5])=[O:4])[CH2:11][CH2:10]1
Reactant: CCOC(=O)C(=O)Cl
Reactant: NC1CC1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(O)C(=O)NC1CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Ethyl chloro(oxo)acetate (96 mL, 0.86 mol) was added over 10 minutes to a −20° C. solution of cyclopropylamine (60 mL, 0.86 mol) and pyridine (70 mL, 0.86 mol) in dichloromethane (740 mL), and the reaction mixture was stirred at 0° C. for 1 hour, then at 20° C. for 20 hours. The reaction mixture was washed with aqueous hydrochloric acid (1 M, 3×185 mL), then the organic layer was stirred with aqueous sodium hydroxide solution (1 M, 930 mL, 0.93 mol) for 30 minutes. The resulting aqueous layer was acidified to pH 1 with concentrated hydrochloric acid (78 mL), treated with sodium chloride (100 g), and extracted with dichloromethane (6×500 mL) and ethyl acetate (6×500 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo; the resulting solid was mixed with ethyl acetate (150 mL) and warmed to reflux. After cooling to room temperature over 16 hours with stirring, the solid was collected via filtration and washed with ethyl acetate, affording the product as a sparkling white solid. Yield: 67.8 g, 0.525 mol, 61%. LCMS m/z 130.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 13.73 (br s, 1H), 8.83 (br d, J=4.0 Hz, 1H), 2.68-2.77 (m, 1H), 0.61-0.68 (m, 2H), 0.54-0.61 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]([CH:20]3[CH2:24][CH2:23][N:22]([CH2:25][C:26](=[O:45])[N:27]4[CH2:32][CH2:31][N:30]([C:33]5[CH:38]=[CH:37][C:36]([C:39]6[N:44]=[CH:43][CH:42]=[CH:41][N:40]=6)=[CH:35][CH:34]=5)[CH2:29][CH2:28]4)[CH2:21]3)=[O:19])=[CH:14][CH:15]=2)[C:10]([NH2:46])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:47](Cl)(=[O:49])[CH3:48]>C(Cl)Cl.N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]([CH:20]3[CH2:24][CH2:23][N:22]([CH2:25][C:26](=[O:45])[N:27]4[CH2:28][CH2:29][N:30]([C:33]5[CH:34]=[CH:35][C:36]([C:39]6[N:40]=[CH:41][CH:42]=[CH:43][N:44]=6)=[CH:37][CH:38]=5)[CH2:31][CH2:32]4)[CH2:21]3)=[O:19])=[CH:14][CH:15]=2)[C:10]([NH:46][C:47](=[O:49])[CH3:48])=[N:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)n1nc(N)c2cc(NC(=O)C3CCN(CC(=O)N4CCN(c5ccc(-c6ncccn6)cc5)CC4)C3)ccc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1nn(C(=O)OC(C)(C)C)c2ccc(NC(=O)C3CCN(CC(=O)N4CCN(c5ccc(-c6ncccn6)cc5)CC4)C3)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 36 from Step 1 in CH2Cl2 (0.3 mL) and pyridine (0.3 mL) was added acetyl chloride (50 ul, 0.7 mmol) at rt. The crude was stirred at rt for 30 mins. The crude was quenched with sat. NaHCO3 at rt. The crude was partitioned between EtOAc and H2O. The organic layer was washed with H2O, brine, dried over MgSO4, filtered, and evaporated. The crude was chromatographed to give 20 mg of the product.
Reaction SMILES: [O-:1][C:2]#[N:3].[Na+].FC(F)(F)C(O)=O.[NH2:12][CH2:13][CH2:14][O:15][CH:16]1[C:22]2[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=2[N:20]([C:28](=[O:47])[C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:36](=[O:44])[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[Cl:43])=[CH:31][C:30]=2[O:45][CH3:46])[CH2:19][CH2:18][CH2:17]1.C(=O)([O-])O.[Na+]>CN(C)C=O.CCCCCC>[NH:12]([CH2:13][CH2:14][O:15][CH:16]1[C:22]2[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=2[N:20]([C:28](=[O:47])[C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:36](=[O:44])[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[Cl:43])=[CH:31][C:30]=2[O:45][CH3:46])[CH2:19][CH2:18][CH2:17]1)[C:2]([NH2:3])=[O:1]
Reactant: COc1cc(NC(=O)c2ccccc2Cl)ccc1C(=O)N1CCCC(OCCN)c2cc(Cl)ccc21
Reactant: N#C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCCC
Product: COc1cc(NC(=O)c2ccccc2Cl)ccc1C(=O)N1CCCC(OCCNC(N)=O)c2cc(Cl)ccc21
Temperature: 80 °C
Reaction time: 1 h
Yield: 75.8 %

Procedure:
0.12 g of sodium cyanate and 0.22 ml of trifluoro-acetic acid were added to a solution of 0.5 g of 5-(2-amino-ethoxy)-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine dissolved in 15 ml of dry dimethylformamide. The mixture was stirred at 80° C. for 1 hour. After cooling, the reaction mixture was mixed with slight amounts of a saturated aqueous sodium hydrogen-carbonate solution and hexane, followed by extraction with ethyl acetate. The organic layer was water-washed, then dried over magnesium sulfate and subjected to vacuum distillation to remove the solvent. The resiude was recrystallized from acetone-n-hexane to obtain 0.41 g (76%) of 5-(2-ureidoethoxy)-7-chloro-1-[2-methoxy-4-(2-chloro-benzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:51])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[C@@H:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:18][N:17]([S:37]([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)(=[O:39])=[O:38])[C@@H:16]([CH2:47][C:48]([OH:50])=O)[CH2:15]2)=[CH:10][CH:9]=1.[CH2:52]([NH:54][CH2:55][CH3:56])[CH3:53]>>[CH2:52]([N:54]([CH2:55][CH3:56])[C:48](=[O:50])[CH2:47][C@H:16]1[CH2:15][C@H:14]([C:11]2[CH:12]=[CH:13][C:8]([CH2:7][O:6][CH2:5][C@@H:4]([CH3:51])[CH2:3][O:2][CH3:1])=[CH:9][CH:10]=2)[C@@H:19]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]3[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=3[CH:36]=2)[CH2:18][N:17]1[S:37]([C:40]1[CH:41]=[CH:42][C:43]([CH3:46])=[CH:44][CH:45]=1)(=[O:39])=[O:38])[CH3:53]
Reactant: CCNCC
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CC(=O)O)C[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Product: CCN(CC)C(=O)C[C@H]1C[C@H](c2ccc(COC[C@@H](C)COC)cc2)[C@@H](OCc2ccc3c(c2)N(CCCOC)CCO3)CN1S(=O)(=O)c1ccc(C)cc1

Procedure:
According to general procedure D, 1.0 mmol of [(2R,4R,5R)-4-[4-((S)-3-methoxy-2-methyl-propoxymethyl)-phenyl]-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-acetic acid (example 1g) are reacted with diethylamine to afford the title compound which is identified based on its Rf-value.
Reaction SMILES: [CH:1]1[C:6]([O-:7])=[CH:5][CH:4]=[C:3]([S:8]([O-:11])(=[O:10])=[O:9])[CH:2]=1.[Na+:12].[Na+].[Cl:14][CH:15]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:16](Cl)=[O:17]>>[Cl:14][CH:15]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:16]([O:7][C:6]1[CH:1]=[CH:2][C:3]([S:8]([O-:11])(=[O:9])=[O:10])=[CH:4][CH:5]=1)=[O:17].[Na+:12]
Reactant: O=S(=O)([O-])c1ccc([O-])cc1
Reactant: CCCCCCCC(Cl)C(=O)Cl
Agent: [Na+]
Product: CCCCCCCC(Cl)C(=O)Oc1ccc(S(=O)(=O)[O-])cc1
Reaction time: 0.08 h
Yield: 68 %

Procedure:
Anhydrous disodium p-phenolsulfonate (28.5 g; 0.130 mole) and 30.3 g (0.1436 mole) of 2-chlorononanoyl chloride were combined in a 500 ml round-bottomed flask. The flask was then immersed in an oil bath which had been preheated to 110° C. Within five minutes an exothermic reacting occurred which caused the entire mixture to congeal. After cooling, the mixture was triturated three times with 150-200 ml portions of ether and the product was vacuum dried. Elemental and nmr analyses of the resulting tan powder, 46.2 g, indicated that it was composed of 11.5% NaCl, 17.7% disodium p-phenolsulfonate, and 70.8% of sodium p-(2-chlorononanoyloxy)benzene sulfonate. This represents a 68% yield of the desired product.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>C(Cl)Cl>[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:2](=[O:4])[C:1]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH2:6])=[CH:16][CH:15]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: ClCCl
Product: Nc1ccccc1C(=O)Nc1ccc(Cl)cc1
Temperature: 120 °C

Procedure:
A mixture of 20 g (123 mmol) isatoic anhydride (formed by treating anthranilic acid with phosgene) and 15.64 g (123 mmol) 4-chloroaniline was heated at 120° C. for 2 hours. The reaction was cooled to room temperature, mixed with CH2Cl2 and filtered.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][C:3]=1[O:17][CH3:18].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:27][C:28]1[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[N:32][CH:33]=1>C(#N)C.O>[CH3:18][O:17][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:2]=1[O:1][CH2:27][C:28]1[CH:33]=[N:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)[CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: COc1cc(CNC(=O)OC(C)(C)C)ccc1O
Reactant: COc1ccc(CCl)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1ccc(COc2ccc(CNC(=O)OC(C)(C)C)cc2OC)cn1
Temperature: 25 °C
Reaction time: 23 h
Yield: 96.2 %

Procedure:
To a stirred solution of tert-butyl 4-hydroxy-3-methoxybenzylcarbamate (22.44 g, 88.59 mmol) in acetonitrile (250 mL) was added potassium carbonate (30.61 g, 221.5 mmol) and 5-(chloromethyl)-2-methoxypyridine hydrochloride (18.33 g, 94.46 mmol). The resulting mixture was heated to reflux and stirred. After 23 h, the light green suspension was allowed to cool to room temperature and was diluted with water (600 mL), resulting in the formation of a precipitate. The solids were isolated by filtration and washed with water. The moist solids were dissolved in dichloromethane (300 mL), and a small amount of water separated and was removed. The organic phase was dried over magnesium sulfate, filtered, and concentrated to provide 31.92 g (96%) of tert-butyl 3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzylcarbamate as an off-white solid.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])=[C:13](C(OC)=O)[C:12]2=[O:29])=[CH:2]1.[OH-].[K+]>C(O)C>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[C:12](=[O:29])[CH:13]=[C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[O:15]2)=[CH:2]1
Reactant: COC(=O)C1=C(NCc2ccccc2F)OC(=Cc2c[nH]c3ncccc23)C1=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C=C(NCc2ccccc2F)OC1=Cc1c[nH]c2ncccc12
Temperature: 25 °C
Yield: 14.3 %

Procedure:
To a solution of the compound (0.10 g, 0.25 mmol) of Example 101 in ethanol (4.0 mL), 50% potassium hydroxide solution (2.0 mL, 0.036 mol) was added at ambient temperature. The mixture was refluxed for 2 h. Cooled to ambient temperature, the solvent was removed under reduced pressure. Water was added to this residue, the mixture was washed with ethyl acetate then 1M hydrochloric acid was added to adjust pH to acidic, and then extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrate then purified by chromatography on silica gel(dichloromethane/methanol) to afford the titled compound as solid (0.012 g, y. 14%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Br[C:13]([C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])=[CH2:14].C([O-])([O-])=O.[K+].[K+]>C1COCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]([C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])=[CH2:14])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: C=C(Br)C(F)(F)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)C(F)(F)F
Temperature: 80 °C
Yield: 66.2 %

Procedure:
A mixture of 3,5-dichlorophenylboronic acid (793 mg, 4.15 mmol), 2-bromo-3,3,4,4,4-pentafluorobut-1-ene (1.0 g, 4.57 mmol), K2CO3 (1.14 g, 8.3 mmol) and Pd(PPh3)2Cl2 (58 mg, 0.08 mmol) in THF (4 mL) and H2O (2 mL) was heated at 80° C. in a sealed tube for 4 h. The mixture was cooled to rt and partitioned between EA (50 mL) and H2O (50 mL). The aqueous layer was extracted with EA (50 mL) and the combined organic layers were dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by column chromatography on silica gel to give the crude desired product (800 mg; 66% yield) as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[O:18])[NH:9][CH2:10][C:11]([O:13][C:14](C)(C)[CH3:15])=[O:12])[CH:5]=[CH:4][C:3]=1[NH:19][S:20]([CH:23]1[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][CH2:26][CH2:25][CH2:24]1)(=[O:22])=[O:21].Cl>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[O:18])[NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:4][C:3]=1[NH:19][S:20]([CH:23]1[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][CH2:26][CH2:25][CH2:24]1)(=[O:22])=[O:21]
Reactant: CCOC(=O)C1=CCCCC1S(=O)(=O)Nc1ccc(C(=O)NCC(=O)OC(C)(C)C)cc1Cl
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)CNC(=O)c1ccc(NS(=O)(=O)C2CCCC=C2C(=O)OCC)c(Cl)c1
Temperature: 25 °C
Reaction time: 51 h
Yield: 82.9 %

Procedure:
Ethyl 6-[N-[2-chloro-4-(N-t-butoxycarbonylmethylcarbamoyl)phenyl]sulfamoyl]-1-cyclohexene-1-carboxylate (23 mg) was dissolved in ethyl acetate (0.5 ml) and then admixed with a 4N solution of hydrogen chloride in ethyl acetate (1.8 ml) and the mixture was stirred at room temperature for 51 hours. The reaction mixture was diluted with ethyl acetate and then washed twice with saturated brine. The ethyl acetate layer was dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane=11:14) to yield ethyl 6-[N-[2-chloro-4-(N-ethoxycarbonylmethylcarbamoyl)phenyl]sulfamoyl]-1-cyclohexene-1-carboxylate (Compound 63; 18 mg) as a colorless oil.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17]/[CH:18]=[C:19](\[CH3:32])/[CH2:20][N:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24][CH2:23][C:22]3=[O:31])[CH2:13][CH2:12]2)[CH:8]=[C:7]([C:33]([F:36])([F:35])[F:34])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][CH:19]([CH3:32])[CH2:20][N:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24][CH2:23][C:22]3=[O:31])[CH2:15][CH2:16]2)[CH:8]=[C:7]([C:33]([F:35])([F:36])[F:34])[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C/C(=C\CN1CCN(c2cc(C(F)(F)F)nc(C(C)(C)C)n2)CC1)CN1C(=O)CCc2ccccc21
Agent: [Pd]
Solvent: CO
Product: CC(CCN1CCN(c2cc(C(F)(F)F)nc(C(C)(C)C)n2)CC1)CN1C(=O)CCc2ccccc21
Reaction time: 12 h
Yield: 27.6 %

Procedure:
Pd/C (10%, 10.0 mg) was added to a solution of 1-((2E)-4-{4-[2-tert-butyl-6-(trifluoro-methyl)pyrimidin-4-yl]piperazin-1-yl}-2-methylbut-2-enyl)-3,4-dihydroquinolin-2(1H)-one (0.08 mmol, 49.99 mg) from example 12 in methanol (10 ml), and hydrogenation was then carried out at room temperature for 12 hours. 11.10 mg of the title compound were obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13](=[O:31])[NH:14][C:15]1[CH:16]=[C:17]([C:22]2[CH:27]=[CH:26][C:25]([C:28](O)=[O:29])=[CH:24][CH:23]=2)[C:18]([Cl:21])=[CH:19][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:32][S:33]([N:36]1[CH2:41][CH2:40][N:39]([CH2:42][C:43]2[CH:48]=[CH:47][C:46]([NH2:49])=[CH:45][CH:44]=2)[CH2:38][CH2:37]1)(=[O:35])=[O:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13](=[O:31])[NH:14][C:15]1[CH:16]=[C:17]([C:22]2[CH:23]=[CH:24][C:25]([C:28](=[O:29])[NH:49][C:46]3[CH:47]=[CH:48][C:43]([CH2:42][N:39]4[CH2:38][CH2:37][N:36]([S:33]([CH3:32])(=[O:35])=[O:34])[CH2:41][CH2:40]4)=[CH:44][CH:45]=3)=[CH:26][CH:27]=2)[C:18]([Cl:21])=[CH:19][CH:20]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)N1CCN(Cc2ccc(N)cc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)Nc1ccc(Cl)c(-c2ccc(C(=O)O)cc2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)Nc1ccc(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(S(C)(=O)=O)CC4)cc3)cc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of (R)-2-(4′-Carboxy-6-chloro-biphenyl-3-ylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (100 mg), 4-(4-methanesulfonyl-piperazin-1-ylmethyl)-phenylamine (86 mg) and HBTU (121 mg) in dry DMF (4 ml) containing N-methylmorpholine (69 μl) was stirred at room temp for 18 h.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[N:21]=[C:20]3[NH:22][N:23]=[C:24]([C:25]4[CH:30]=[CH:29][N:28]=[C:27](S(C)=O)[N:26]=4)[C:19]3=[CH:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH2:38][NH2:39]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[N:21]=[C:20]3[NH:22][N:23]=[C:24]([C:25]4[CH:30]=[CH:29][N:28]=[C:27]([NH:39][CH2:38][C:37]5[CH:40]=[CH:41][CH:42]=[C:35]([Cl:34])[CH:36]=5)[N:26]=4)[C:19]3=[CH:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)c1nccc(-c2n[nH]c3nc(NCC4CCN(C(=O)OC(C)(C)C)CC4)ncc23)n1
Reactant: NCc1cccc(Cl)c1
Product: CC(C)(C)OC(=O)N1CCC(CNc2ncc3c(-c4ccnc(NCc5cccc(Cl)c5)n4)n[nH]c3n2)CC1
Temperature: 130 °C
Reaction time: 2 h

Procedure:
The mixture of 4-{[3-(2-methanesulfinyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester (from Example 15 supra) (200 mg, 0.42 mmol) and 3-chlorobenzylamine (238 mg, 1.7 mmol) was heated at 130° C. with stirring for 2 hours. The resulting oil was purified by chromatography (silica gel, 7 g, 200-300 mesh, eluting with dichloromethane:methanol, 50:1 to 30:1) to afford 4-({3-[2-(3-chloro-benzylamino)-pyrimidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester. (Yield 200 mg, 86.2%).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([CH3:30])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:31][NH2:32]>>[CH3:29][O:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:21]1[C:15]2[O:14][CH:13]([CH2:12][NH:32][CH3:31])[CH2:17][C:16]=2[CH:18]=[C:19]([CH3:30])[CH:20]=1
Reactant: COc1ccccc1-c1cc(C)cc2c1OC(COS(=O)(=O)c1ccc(C)cc1)C2
Reactant: CN
Product: CNCC1Cc2cc(C)cc(-c3ccccc3OC)c2O1

Procedure:
The title compound was prepared (0.041 g, 32%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2-methoxyphenyl) 5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.17 g, 0.40 mmol) and methylamine (0.124 g, 4.0 mmol). mp 165-166° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([Cl:21])[CH:15]=3)=[CH:12][C:11]([C:22]([O:24]CC)=[O:23])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[Li+].O.Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([Cl:21])[CH:15]=3)=[CH:12][C:11]([C:22]([OH:24])=[O:23])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.11 g (12.9 mmol) of the compound of Example 21A are provided in 142 ml of tetrahydrofuran and, at room temperature, 3.08 g (129 mmol) of lithium hydroxide and 47 ml of water are added. The mixture is stirred at room temperature overnight and a 1N aqueous hydrogen chloride solution is subsequently added until the pH is acidic, the mixture extracted with ethyl acetate, and the organic phase is washed with water, dried over sodium sulfate, filtered and concentrated. 4.51 g (90% of theory) of the title compound are obtained.
Reaction SMILES: [P:1]([O:9][CH2:10][C@H:11]1[O:15][C@@H:14]([N:16]2[C:25]3[N:24]=[CH:23][N:22]=[C:20]([NH2:21])[C:19]=3[N:18]=[CH:17]2)[C@H:13]([OH:26])[C@@H:12]1[OH:27])([O:4][P:5]([OH:8])([OH:7])=[O:6])(=[O:3])[OH:2].C([O-])(=O)C.[Mg+2:32].C([O-])(=O)C>>[P:1]([O:9][CH2:10][C@H:11]1[O:15][C@@H:14]([N:16]2[C:25]3[N:24]=[CH:23][N:22]=[C:20]([NH2:21])[C:19]=3[N:18]=[CH:17]2)[C@H:13]([OH:26])[C@@H:12]1[OH:27])([O:4][P:5]([OH:7])([OH:8])=[O:6])(=[O:2])[OH:3].[Mg:32]
Reactant: [Mg+2]
Agent: CC(=O)[O-]
Agent: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Product: [Mg]

Procedure:
ADP substrate (>99.999% pure with respect to ATP), magnesium acetate and extractant reagent (0.15% cationic detergent and 0.25% tertiary diamine per final volume) is supplied from source (10) in sufficient quantity to provide 0.1 mM ADP and 10 mM magnesium ions in the reaction vessel, the magnet deenergised and stirrer operated and extraction/ADP conversion allowed to proceed for a set period between of 1 or 5 minutes before the stirrer is stopped, the magnet energised and the liquid removed to the luminometer flow cell (11) using the peristaltic tubing (3) and reversible pumps (4) and (12) while simultaneously mixing it with an effective volume of luciferase/luciferin reagent of depleted adenylate kinase content from source (13). Using an adenylate kinase modified Celsis LDR reagent of otherwise standard amounts of active ingredients this volume is about one half of the volume of the sample. Light emitted in the flow cell is related to the amount of E. coli captured by reference to standard curves obtained by performance of the assay with known numbers of cells.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH:10]([NH2:14])[CH2:9][CH2:8]2)([CH3:4])([CH3:3])[CH3:2].C(N[C@H](C(O)=O)CC(C)C)(=O)C>CO>[C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C@@H:10]([NH2:14])[CH2:9][CH2:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc2c(c1)CCC2N
Agent: CC(=O)N[C@@H](CC(C)C)C(=O)O
Solvent: CO
Product: CC(C)(C)c1ccc2c(c1)CC[C@@H]2N
Temperature: 65 °C

Procedure:
5-tert-Butyl-2,3-dihydro-1H-inden-1-ylamine (25.51 g, 93% potency), N-acetyl-(L)-leucine (23.34 g), and methanol (315 mL) were combined and heated at 65° C. for 1 hour. The solution was allowed to cool to ambient temperature. The solids were filtered and washed with toluene. The solid was then resuspended in methanol (125 mL) and brought to reflux. The solution was allowed to cool to ambient temperature and the solids were filtered. The solid was dried at 40° C. under reduced pressure to provide the title compound (98.7% ee).