Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3](=[O:28])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[CH:5]=2.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[N:55]1[C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[CH:58]=[C:57](B(O)O)[CH:56]=1>>[F:18][C:12]1[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=1[C:10]1[C:9]2[C:4](=[CH:5][C:6]([O:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:7][CH:8]=2)[C:3](=[O:28])[C:2]=1[C:57]1[CH:56]=[N:55][C:64]2[C:59]([CH:58]=1)=[CH:60][CH:61]=[CH:62][CH:63]=2
Reactant: OB(O)c1cnc2ccccc2c1
Reactant: O=C1C(Br)=C(c2ccc(F)cc2F)c2ccc(OCCN3CCOCC3)cc21
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: O=C1C(c2cnc3ccccc3c2)=C(c2ccc(F)cc2F)c2ccc(OCCN3CCOCC3)cc21
Yield: 85 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-3-(2,4-difluorophenyl)-6-{2-(morpholin-4-yl)ethoxy}-1H-inden-1-one obtained in Step 1 of Example 124 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one and 3-quinolinylboronic acid instead of 3-pyridinylboronic acid to obtain the title compound (85%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]=O)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:19]1[C:20](=[O:49])[N:21]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[CH:22]=[C:23]([NH:25][C:26]([C:28]2[CH:29]=[N:30][N:31]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=3)[CH:32]=2)=[O:27])[CH:24]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[F:51][CH:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][N:55]3[CH2:56][CH2:57][CH:52]([F:51])[CH2:53][CH2:54]3)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:19]1[C:20](=[O:49])[N:21]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[CH:22]=[C:23]([NH:25][C:26]([C:28]2[CH:29]=[N:30][N:31]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=3)[CH:32]=2)=[O:27])[CH:24]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(Cn2cc(C(=O)Nc3cc(-c4cc5cc(C=O)ccc5n4C(=O)OC(C)(C)C)c(=O)n(COCC[Si](C)(C)C)c3)cn2)cc1
Reactant: FC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccc(Cn2cc(C(=O)Nc3cc(-c4cc5cc(CN6CCC(F)CC6)ccc5n4C(=O)OC(C)(C)C)c(=O)n(COCC[Si](C)(C)C)c3)cn2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of intermediate (8f), 5-Formyl-2-[5-{[1-(4-methyl-benzyl)-1H-pyrazole-4-carbonyl]-amino}-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1-carboxylic acid tert-butyl ester, (150 mg, 0.22 mmol) in dichloromethane (10 mL) was added 4-fluoropiperidine hydrochloride (61 mg, 0.44 mmol), sodium triacetoxyborohydride (140 mg, 0.66 mmol) and acetic acid (1 drop). The reaction mixture was stirred at ambient temperature for 3 hours and then diluted with ethyl acetate. The mixture was washed with saturated aqueous sodium bicarbonate solution, brine, dried (Na2SO4) and concentrated in vacuo. The resultant crude product was purified by flash chromatography on SiO2 with hexane—ethyl acetate (gradient) and then ion exchange using an SCX-2 column to afford the title compound as a yellow solid, 96 mg, 57%.
Reaction SMILES: Br[C:2]1[CH:22]=[C:21]([CH3:23])[C:5]([O:6][C:7]2[C:12]([CH3:13])=[C:11]([NH:14][CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:10]=[C:9]([CH3:20])[N:8]=2)=[C:4]([CH3:24])[CH:3]=1.C([Li])CCC.C1C[O:33][CH2:32]C1>>[CH2:16]([CH:15]([NH:14][C:11]1[CH:10]=[C:9]([CH3:20])[N:8]=[C:7]([O:6][C:5]2[C:21]([CH3:23])=[CH:22][C:2]([CH:32]=[O:33])=[CH:3][C:4]=2[CH3:24])[C:12]=1[CH3:13])[CH2:18][CH3:19])[CH3:17]
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(Br)cc2C)c1C
Reactant: C1CCOC1
Agent: [Li]CCCC
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C=O)cc2C)c1C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of [2-(4-bromo-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-ethyl-propyl)-amine in dry THF was added n-butyllithium at −78° C. After stirring at −78° C. for 10 min, n,N-dimethylformamide was added and the resulting mixture was stirred at −78° C. for 20 min, the dry-ice bath was removed. After stirring for 5 min, the mixture was quenched with diluted HCl, water and adjusted to pH7.5 and extracted with ethyl acetate. The organic layer was separated, dried, and concentrated to dryness. The residue was purified through silica gel chromatography to give the title compound. 1H NMR(CDCl3) d 9.93(s,1H), 7.60(s,2H), 6.10(s,1H), 3.75(d,1H), 3.35(m1H), 2.17(s,6H), 2.13(s,3H), 2.12(s,3H), 1.4-1.8(m,4H), 0.97(t,6H) ppm.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15]C(=O)C)=[CH:11][C:10]=2[F:19])[CH:3]=1.Cl.C([O-])([O-])=O.[Na+].[Na+]>CO>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[CH:3]=2)=[C:10]([F:19])[CH:11]=1
Reactant: CC(=O)Nc1ccc(Oc2cc(N)ncn2)c(F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: Nc1ccc(Oc2cc(N)ncn2)c(F)c1
Yield: 94.9 %

Procedure:
A mixture of N-(4-(6-aminopyrimidin-4-yloxy)-3-fluorophenyl)acetamide (175 mg, 0.67 mmol), 1 M HCl (6 mL), and MeOH (2 mL) was heated at reflux for 3 h. The reaction mixture was cooled, made basic (pH 8) with aqueous Na2CO3 solution and extracted with EtOAc (2×25 mL). The combined extracts were dried (MgSO4) and concentrated in vacuo to give the title compound (140 mg, 96%) as a brown solid. 1H NMR (DMSO-d6) δ 8.02 (s, 1H), 6.89 (dd, 1H, J=9.0, 9.0 Hz), 6.80 (br s, 2H), 6.43 (dd, 1H, J=12.7, 2.8 Hz), 6.35 (dd, 1H, J=8.8, 2.2 Hz), 5.67 (s, 1H), 5.34 (br s, 2H).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[CH:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=1>CCOCC>[N:9]1[CH:10]=[CH:11][CH:12]=[C:7]([CH:13]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[OH:20])[CH:8]=1
Reactant: O=Cc1cccnc1
Reactant: Brc1cccnc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: OC(c1cccnc1)c1cccnc1
Reaction time: 1 h

Procedure:
n-BuLi (42 mL, 1.6M, 67 mmol) was added to a solution of 3-bromopyridine (5.9 mL, 9.74 g, 62 mmol) in ether (200 mL) at −78 C. The resulting yellow suspension was stirred for 1 h. A solution of nicotinaldehyde (5.3 mL, 6 g, 56 mmol) in ether (25 mL) was then added. After stirring for 0.5 h, the reaction mixture was allowed to warm gradually to 0 C. The reaction mixture was then quenched by addition of half saturated brine (100 mL). The resulting mixture was extracted once with ethyl acetate and once with chloroform. Drying (1:1 Na2SO4/K2CO3) and concentration gave dipyridin-3-ylmethanol as a very viscous orange oil which was used without further purification.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]1[O:10][C@@H:9]1[CH2:11]OS(C1C=C([N+]([O-])=O)C=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[O:7]([CH2:11][C@@H:9]1[CH2:8][O:10]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: c1ccc(OC[C@@H]2CO2)cc1
Temperature: 25 °C
Yield: 99.9 %

Procedure:
A solution of phenol (9.4 g, 100 mmol) and (2S)-(+)glycidyl 3-nitrobenzenesulfonate(25.9 g, 100 mmol) in 500 mL of acetone was treated with 3 equivalents of potassium carbonate (41.5 g, 300 mmol) and stirred at reflux for 1 day. The suspension was cooled to ambient temperature; the solid was filtered; and the filtrate concentrated to dryness. The residue was partitioned between methylene chloride and water and the aqueous layer was extracted with methylene chloride. The organic layers were combined and dried over magnesium sulfate and concentrated to give the title compound (15.0 g, 99%) as an orange oil; 1H NMR (300 MHz, CDCl3) δ2.76 (dd, J=4.9, 2.6 Hz, 1 H), 2.90 (dd, J=4.9, 4.9 Hz, 1 H), 3.30-3.40 (m, 1 H), 3.95 (dd, J=11.0, 5.4 Hz, 1 H), 4.18 (dd, J=11.0, 3.0 Hz, 1 H), 6.85-7.00 (m, 3 H), 7.25-7.35 (m, 2 H); MS (ES) m/z: 151.0 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9](OC)=[O:10])[CH:5]=[N:6][C:7]=1[CH3:8].CC(C[AlH]CC(C)C)C.C(C(C(C([O-])=O)O)O)([O-])=O>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[N:6][C:7]=1[CH3:8]
Reactant: COC(=O)c1cnc(C)c(C)c1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Solvent: ClCCl
Product: Cc1cc(CO)cnc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.8 %

Procedure:
To a solution of methyl 5,6-dimethyl-3-pyridinecarboxylate (276 mg, 1.671 mmol) in DCM (6 ml), DIBAL-H (1.5 M solution in toluene, 3.34 ml, 5.01 mmol) was added dropwise at −78° C. under N2. The reaction mixture was allowed to warm to rt and stirred overnight. To this solution was added saturated, aqueous NaK-tartrate solution followed by DCM. The organic phase was separated, dried and concentrated to afford 175 mg of the crude material. Purification by flash chromatography using Flashmaster II, a 5 g silica gel cartridge, and mixtures of DCM/MeOH as eluent afforded 105 mg of desired compound.
Reaction SMILES: C[Li].C([O:5][CH2:6][CH3:7])C.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21]C(N(OC)C)=O)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.O>O1CCCC1>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:6](=[O:5])[CH3:7])=[CH:17][CH:16]=2)=[CH:13][CH:14]=1
Reactant: CON(C)C(=O)Cc1ccc(-c2ccc(Br)cc2)cc1
Reactant: CCOCC
Agent: [Li]C
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Cc1ccc(-c2ccc(Br)cc2)cc1
Reaction time: 0.5 h
Yield: 70.3 %

Procedure:
A solution of methyllithium in diethyl ether (40 mL, 44 mmol) was diluted with tetrahydrofuran (120 mL), and a solution of 2-(4′-bromobiphenyl-4-yl)-N-methoxy-N-methylacetamide (12 g, 37 mmol) in tetrahydrofuran (50 mL) was added at −78° C., followed by stirring at the same temperature for 30 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate, and subsequently the solvent was distilled off under reduced pressure. The resulting residue was purified by chromatography on a silica gel column (Moritex Corporation, elution solvent: hexane/ethyl acetate), and a fraction corresponding to the Rf value=0.50 (hexane/ethyl acetate=4/1) by thin layer chromatography was concentrated under reduced pressure to afford the title compound (7.6 g, 26 mmol) as a white solid (yield 71%).
Reaction SMILES: [OH:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[CH:16]=3)[O:12][N:11]=2)=[N:8][CH:9]=1)=O.C(Cl)(=O)C(Cl)=O.[Cl-].[NH4+].[N:30]1C=CC=CC=1.N>ClCCl>[NH2:30][C:2]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[CH:16]=3)[O:12][N:11]=2)=[N:8][CH:9]=1)=[O:1]
Reactant: c1ccncc1
Reactant: O=C(O)c1ccc(-c2noc(-c3cccc(Br)c3)n2)nc1
Agent: N
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Solvent: ClCCl
Product: NC(=O)c1ccc(-c2noc(-c3cccc(Br)c3)n2)nc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 3-(5-hydroxycarbonylpyrid-2-yl)-5-(3-bromophenyl)-1,2,4-oxadiazole (269.4 mg, 0.78 mmol) in dichloromethane (15 mL) was treated with 2M oxalyl chloride (0.90 mL, 1.8 mmol, dichloromethane) and a catalytic amount N,N-dimethylformaide. The resulting mixture was stirred at ambient temperature for 1.5 hours and the solvent and excess oxalyl chloride removed, in vacuo. The acid chloride in dichloromethane (5 mL) was then treated with solid ammonium chloride (450 mg, 8.4 mmol) and pyridine (1.5 mL, 18.5 mmol). The mixture was stirred vigorously at ambient temperature for 15 hours, and then treated with 2M ammonia (5 mL, 10 mmol, methanol). The solvent was then removed in vacuo, and the residue treated with water. Collection of the precipitate by filtration afforded crude 3-(5-aminocarbonylpyrid-2-yl)-5-(3-bromophenyl)-1,2,4-oxadiazole.
Reaction SMILES: [Br:1][C:2]1[N:11]=[C:5]2[CH:6]=[C:7]([NH2:10])[CH:8]=[CH:9][N:4]2[N:3]=1.[CH2:12]([O:14][C:15]([C:17]1[CH:18]=[N:19][N:20]([CH3:25])[C:21]=1[C:22](O)=[O:23])=[O:16])[CH3:13].CCCP(=O)=O.C(N(CC)C(C)C)(C)C>O1CCCC1>[CH2:12]([O:14][C:15]([C:17]1[CH:18]=[N:19][N:20]([CH3:25])[C:21]=1[C:22](=[O:23])[NH:10][C:7]1[CH:8]=[CH:9][N:4]2[N:3]=[C:2]([Br:1])[N:11]=[C:5]2[CH:6]=1)=[O:16])[CH3:13]
Reactant: Nc1ccn2nc(Br)nc2c1
Reactant: CCOC(=O)c1cnn(C)c1C(=O)O
Agent: CCCP(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(Br)nc2c1
Yield: 82.7 %

Procedure:
A mixture of 2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-amine (2.39 g, 11.2 mmol), 4-(ethoxycarbonyl)-1-methyl-1H-pyrazole-5-carboxylic acid (2.22 g, 11.2 mmol), propylphosphonic anhydride (50% in ethyl acetate, 16.5 ml, 28.0 mmol) and N,N-diisopropylethylamine (5.72 ml, 33.7 mmol) in tetrahydrofuran (80 ml) was refluxed for 18 hours under argon atmosphere. The solvent was evaporated and the resulting yellowish oil was triturated with sat. sodium hydrogencarbonate solution. The precipitated solid was filtered off, washed with water 4 times and dried in vacuo affording 5-(2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (3.64 g, 82.5%) as a light yellow solid. mp: 177-180° C., MS: m/z=393.0/395.0 (M+H+)
Reaction SMILES: [CH2:1]([Li])CCC.[Si:6]([O:13][C@@H:14]1[CH2:19][CH:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:17][C@@H:16]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[C:15]1=O)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:21]([O:20][CH:18]1[CH2:17][C@@H:16]([O:28][Si:29]([C:32]([CH3:35])([CH3:33])[CH3:34])([CH3:30])[CH3:31])[C:15](=[CH2:1])[C@H:14]([O:13][Si:6]([C:9]([CH3:10])([CH3:11])[CH3:12])([CH3:8])[CH3:7])[CH2:19]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: [Li]CCCC
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC(OCc2ccccc2)C[C@@H](O[Si](C)(C)C(C)(C)C)C1=O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1[C@H](O[Si](C)(C)C(C)(C)C)CC(OCc2ccccc2)C[C@H]1O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 98.3 %

Procedure:
To a suspension of methyltriphenylphosphonium bromide (1.55 g, 4.34 mmol) in dry THF (10 mL) cooled to 0° C. was added n-butyl lithium (n-BuLi, 2.71 mL, 4.34 mmol, 1.6 M solution in hexane), and the mixture was stirred for 10 min, and further stirred for 1 h at room temperature. To the resulting orange mixture was added over ca. 20 min period a solution of Compound 6 (1.0 g, 2.15 mmol) dissolved in dry THF (10 mL). After being stirred for 1 h at 0° C. and for 17 h at room temperature, the reaction mixture was poured into ice water, and extracted with AcOEt. The organic layer was rinsed with saturated brine, and dried over anhydrous MgSO4. The solvent was removed by evaporation. The residue was purified by silica gel column chromatography (5 g; 2% AcOEt/hexane), to yield Compound 7 (978.5 mg, 98%, single compound).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:20][CH2:19][N:18]([S:21]([C:24]2[C:29]([Cl:30])=[CH:28][CH:27]=[C:26]([NH:31][C:32]3[C:35](=[O:36])[C:34](=[O:37])[C:33]=3[NH:38][C@@H:39]([C@H:42]3[CH2:46][CH2:45][C@@H:44]([CH3:47])[O:43]3)[CH2:40][CH3:41])[C:25]=2[OH:48])(=[O:23])=[O:22])[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl.C([O-])(O)=O.[Na+]>[Cl:30][C:29]1[CH:28]=[CH:27][C:26]([NH:31][C:32]2[C:35](=[O:36])[C:34](=[O:37])[C:33]=2[NH:38][C@@H:39]([C@H:42]2[CH2:46][CH2:45][C@@H:44]([CH3:47])[O:43]2)[CH2:40][CH3:41])=[C:25]([OH:48])[C:24]=1[S:21]([N:18]1[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]1)(=[O:22])=[O:23]
Reactant: CC[C@@H](Nc1c(Nc2ccc(Cl)c(S(=O)(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c2O)c(=O)c1=O)[C@H]1CC[C@@H](C)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@@H](Nc1c(Nc2ccc(Cl)c(S(=O)(=O)N3CCNCC3)c2O)c(=O)c1=O)[C@H]1CC[C@@H](C)O1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.4 ml of TFA are added dropwise to an ice-cooled solution of 54 mg of 4-(6-chloro-2-hydroxy-3-{2-[(R)-1-((2R,5R)-5-methyl-tetrahydrofuran-2-yl)-propylamino]-3,4-dioxo-cyclobut-1-enylamino}-benzene sulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (Ex. 17) in 1 ml of dry DCM under an inert atmosphere of nitrogen. After stirring at rt for 4 hours, a reaction mixture obtained is diluted with 25 ml DCM and 25 ml NaHCO3(aq) are added. An organic portion is separated and washed with 3×NaHCO3(aq), dried over MgSO4 and solvent is evaporated. The title compound is obtained. MH+ 513.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH:9][C:10]([NH:12][NH:13][C:14](=O)[CH2:15][C@@H:16]2[CH2:20][CH2:19][N:18]([C:21]([CH:23]3[CH2:25][CH2:24]3)=[O:22])[CH2:17]2)=[O:11])=[C:4]([F:27])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[C:14]([CH2:15][C@@H:16]3[CH2:20][CH2:19][N:18]([C:21]([CH:23]4[CH2:25][CH2:24]4)=[O:22])[CH2:17]3)=[N:13][NH:12][C:10]2=[O:11])=[C:4]([F:27])[CH:3]=1
Reactant: O=C(C[C@@H]1CCN(C(=O)C2CC2)C1)NNC(=O)Nc1cc(F)c(Br)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2cc(F)c(Br)cc2F)C1
Temperature: 115 °C
Yield: 23.2 %

Procedure:
To a round bottom flask were added N-(4-bromo-2,5-difluorophenyl)-2-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]acetyl}hydrazinecarboxamide (1.80 g, 4.04 mmol) and potassium carbonate (1.955 g, 14.15 mmol) and water (200 mL). The resulting suspension was refluxed for 16 h at 115° C. The pH of the solution was lowered to ˜6 with 1N aq HCl and then partitioned with 150 mL of ethyl acetate. The aqueous phase was extracted with ethyl acetate (3×) and the combined organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes, then 0-25% isopropanol/ethyl acetate), and the desired fractions were combined and concentrated in vacuo to afford the title product as an off-white solid (400 mg, 31%). MS(ES)+ m/e 426.9, 428.8 M+H]+.
Reaction SMILES: C(=O)CCCC=O.[C:8]([O-:15])(=[O:14])/[CH:9]=[CH:10]/[C:11]([O-:13])=[O:12].[NH4+:16].[NH4+].[Cl-].[Mg+2].[Cl-]>P([O-])([O-])([O-])=O>[NH2:16][C@H:9]([C:8]([OH:15])=[O:14])[CH2:10][C:11]([OH:13])=[O:12]
Reactant: O=C([O-])/C=C/C(=O)[O-]
Reactant: [NH4+]
Agent: O=CCCCC=O
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Product: N[C@@H](CC(=O)O)C(=O)O

Procedure:
The microbial cells of Escherichia coli TA5004 (10 g) was suspended in 0.05 M phosphate buffer (pH 8.5, 50 ml) and sonicated at 9 Kc for 15 minutes. Then, the suspension was centrifuged and the resulting supernatant (40 ml) was passed through a column packed with Duolite-A7 (a weak basic anion exchange resin manufactured by Diamond Shamrock Chemical Co. in U.S.A.) (60 ml) at room temperature at 30 ml/hr. Then, the column was subjected to cross-linking treatment with a solution containing 0.1 M phosphate buffer (pH 8.5, 300 ml) and 0.4% glutaraldehyde (300 ml) for 30 minutes and excess glutaraldehyde was thoroughly washed out to give an immobilized enzyme. The immobilized enzyme was packed in a column (volume 50 ml) and 1 M ammonium fumarate solution containing 1 mM magnesium chloride (pH 8.5, 500 ml) was passed through the column at the flow rate of 25 ml/hr. The combined effluent was adjusted to pH 2.8 to precipitate crystals. The crystals were filtered off to give L-aspartic acid (55 g).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[N:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)(=[O:3])[CH3:2].C(OCC)(=O)C.CCCCCC>C(O)C.[Pd]>[CH3:2][C:1]([NH:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH2:6]1)=[O:3]
Reactant: CC(=O)Nc1cnc2ccccc2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCO
Product: CC(=O)NC1CNc2ccccc2C1

Procedure:
300 mg of the 3-(acetylamino)quinoline (Rf (D)=0.43) obtained by a single recrystallization from ethyl acetate/hexane are hydrogenated in 10 ml of ethanol in the presence of 60 mg of palladium-on-charcoal (10% of Pd) at 50° C. under normal pressure for 20 h. After the reaction mixture has been filtered over Celite® 545 and the crude product has been purified by chromatography over 25 g of silica gel (mobile phase P), 3(R,S)-methylcarbonylamino-1,2,3,4-tetrahydroquinoline is obtained: Rf (P)=0.49; MS: (M)+ =190.
Reaction SMILES: O[CH2:2][CH2:3][CH:4]1[O:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1.N1C=CN=C1.[Br:22]C(Br)(Br)Br>C(Cl)Cl>[Br:22][CH2:2][CH2:3][CH:4]1[O:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCOC(CCO)C1
Reactant: BrC(Br)(Br)Br
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCOC(CCBr)C1
Reaction time: 8 h
Yield: 95 %

Procedure:
To a 25 mL round-bottomed flask at 0° C. was added tert-butyl 2-(2-hydroxyethyl)morpholine-4-carboxylate (0.176 g, 0.762 mmol), DCM (4 mL), 1H-imidazole (0.104 g, 1.524 mmol), perbromomethane (0.379 g, 1.143 mmol), and triphenylphoshphine (0.190 g, 0.723 mmol). The mixture was stirred overnight slowly reaching room temperature. The yellow solution was further diluted with 50 mL of DCM, washed with water, brine, dried over sodium sulfate, and filtered. The crude product was then pushed through a plug of silica gel and the solvent was removed to give 213 mgs of a light yellow oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.40 (s, 9H), 1.94 (q, J=6.86 Hz, 1H), 2.56-2.66 (m, 1H), 2.76-2.91 (m, 1H), 3.35-3.47 (m, 4H), 3.50-3.61 (m, 1H), 3.68 (br. s., 1H), 3.74-3.86 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]1[N:9](CC2C=CC=CC=2)[CH:10]=[C:11]([O:15]CC2C=CC=CC=2)[C:12](=[O:14])[CH:13]=1.O.[C:31]1([CH3:41])[CH:36]=[CH:35][C:34]([S:37]([OH:40])(=[O:39])=[O:38])=[CH:33][CH:32]=1.[H][H]>CN(C)C=O.[Pd]>[C:31]1([CH3:41])[CH:32]=[CH:33][C:34]([S:37]([OH:40])(=[O:38])=[O:39])=[CH:35][CH:36]=1.[OH:15][C:11]1[C:12](=[O:14])[CH:13]=[C:8]([CH2:7][N:3]2[CH2:4][CH2:5][NH:6][C:2]2=[O:1])[NH:9][CH:10]=1
Reactant: O=C1NCCN1Cc1cc(=O)c(OCc2ccccc2)cn1Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C1NCCN1Cc1cc(=O)c(O)c[nH]1
Yield: 84.4 %

Procedure:
To a solution of 2-[(2-oxo-1-imidazolidinyl)methyl]-5-(phenylmethoxy)-1-(phenylmethyl)-4(1H)pyridinone (4.98 g; 12.8 mmol) in dimethylformamide (90 ml) was added p-toluenesulfonic acid monohydrate (4.86 g; 25.6 mmol) and palladium on charcoal (1.0 g), and hydrogen was bubbled through the mixture for 30 minutes. The catalyst was filtered off by suction and the filtrate evaporated in vacuo. The residue was triturated with dichloromethane and ether, and the product filtered off by suction, yielding 4.12 g of the title compound, melting point 195° C.
Reaction SMILES: [H-].C(O[Al](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].[C:19]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]1[CH:33]([C:34]#[N:35])[CH:32]([OH:36])[CH2:31][C:30]1=[O:37])([O:21][CH3:22])=[O:20].CC(C)=O.S([O-])([O-])(=O)=O.[NH4+].[NH4+]>O1CCCC1>[C:19]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]1[CH:33]([C:34]#[N:35])[CH:32]([OH:36])[CH2:31][CH:30]1[OH:37])([O:21][CH3:22])=[O:20]
Reactant: COC(=O)CCCCCCC1C(=O)CC(O)C1C#N
Agent: CC(C)(C)O[Al](OC(C)(C)C)OC(C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: COC(=O)CCCCCCC1C(O)CC(O)C1C#N
Reaction time: 0.5 h
Yield: 79.4 %

Procedure:
Into a suspension of 8 g of lithium tri-t-butoxyaluminum hydride in 90 ml of absolute tetrahydrofuran was added dropwise 4.0 g of 2-(6'-carbomethoxyhexyl)-3-cyano-4-hydroxy-cyclopentanone under ice-cooling. The obtained mixture remained under ice-cooling for 1.5 hours and then at room temperature for 0.5 hours. After cooling, acetone and an aqueous solution saturated with ammonium sulfate were added to the reaction mixture to decompose the excess lithium tri-t-butoxyaluminum hydride and the complex salt product. The resultant oily layer was extracted with ethyl acetate, and the extract was washed with water, dried and then concentrated to afford 3.2 g of 2-(6'-carbomethoxyhexyl)-3-cyano-cyclopentane-1,4-diol as an oily substance, which was purified using chromatography on silica gel.