Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([O:8][CH2:9][C:10]1[CH2:11][S:12][C@@H:13]2[C@H:20]([NH:21][C:22](=[O:32])[C:23](=[N:30][OH:31])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:19](=[O:33])[N:14]2[C:15]=1[C:16]([OH:18])=[O:17])(=[O:7])[CH3:6].C(OCC)(=O)C>C(Cl)Cl>[C:1]([O:31][N:30]=[C:23]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:22]([NH:21][C@@H:20]1[C:19](=[O:33])[N:14]2[C:15]([C:16]([OH:18])=[O:17])=[C:10]([CH2:9][O:8][C:5](=[O:7])[CH3:6])[CH2:11][S:12][C@H:13]12)=[O:32])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)C(=NO)c3ccccc3)[C@H]2SC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)C(=NOC(C)=O)c3ccccc3)[C@H]2SC1
Temperature: 25 °C
Yield: 62 %

Procedure:
To a solution of acetyl chloride (8 ml.) in methylene chloride (8 ml.) was added 3-acetoxymethyl-7β-(2-hydroxyimino-2-phenylacetamido)-ceph-3-em-4-carboxylic acid (syn-isomer) (500 mg.) in portions over ten minutes with vigorous stirring at room temperature. A gem formed, and ethyl acetate (8 ml.) was added to achieve solution. After stirring for two hours at room temperature, the mixture was added slowly to petroleum spirit (300 ml.) with vigorous stirring. The precipitate was filtered off, washed thoroughly with petroleum spirit, dissolved in chloroform (10 ml.) stirred with activated charcoal and filtered. The filtrate was added dropwise to petroleum spirit (250 ml.) with stirring. The precipitate was filtered off and dried giving the title acid, (350 mg; 62%), τ (DMSO-d6) values include -0.11 (doublet, J 8 Hz; NH), 2.2-2.6 (multiplet; aromatic protons), 7.76 (singlet; CH3. CO2N=), 7.94 (singlet; Ch3C0). Signals at τ 0.05 (doublet, J 9 Hz; NH) and 7.78 (singlet; CH3CO2 =) indicated the presence of about 30% of the anti-isomer.
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[N:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15][CH:16]=O)[CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3]1.[CH2:18]1[C:26]2[C:21](=[C:22]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[CH:23]=[CH:24][CH:25]=2)[CH2:20][O:19]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.CCOC(C)=O>[CH2:18]1[C:26]2[C:21](=[C:22]([N:27]3[CH2:32][CH2:31][N:30]([CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:8]4[N:9]=[C:10]5[C:5]([CH:4]=[CH:3][C:2](=[O:1])[NH:11]5)=[CH:6][CH:7]=4)[CH2:29][CH2:28]3)[CH:23]=[CH:24][CH:25]=2)[CH2:20][O:19]1
Reactant: O=CCCCOc1ccc2ccc(=O)[nH]c2n1
Reactant: c1cc2c(c(N3CCNCC3)c1)COC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: O=c1ccc2ccc(OCCCCN3CCN(c4cccc5c4COC5)CC3)nc2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 15.3 %

Procedure:
To a suspension of 4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde (0.257 g, 1.107 mmol, 1.1 eq) and 1-(1,3-dihydro-isobenzofuran-4-yl)-piperazine (0.204 g, 0.998 mmol, 1 eq) in dichloroethane (5 mL) was added NaBH(OAc)3 (0.433 g, 2.043 mmol, 1.84 eq). The slurry was allowed to stir overnight at room temperature (18 h). The mixture was diluted with EtOAc and quenched with saturated NaHCO3. The organic phase was then washed with brine, dried over Na2SO4, filtered and evaporated in vacuo. Purification by silica gel chromatography (2% MeOH/CH2Cl2) followed by formation of the HCl salt using 1N HCl in ether provided the title compound (0.064 g, 12%). CHN Found: C, 64.37; H, 6.54; N, 12.13. This calculates out for C24H28N4O3×0.74HCl.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]2[C:22]([NH:23][C:24]([CH:26]3[CH2:28][CH2:27]3)=O)=[C:21]([CH3:29])[C:20]([Br:30])=[CH:19][N:18]=2)=[CH:11][CH:10]=1)#[N:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH:26]1([C:24]2[N:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[C:1]#[N:2])=[CH:10][CH:11]=3)[C:17]3=[N:18][CH:19]=[C:20]([Br:30])[C:21]([CH3:29])=[C:22]3[N:23]=2)[CH2:28][CH2:27]1
Reactant: Cc1c(Br)cnc(NCc2ccc(-c3ccccc3C#N)cc2)c1NC(=O)C1CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c(Br)cnc2c1nc(C1CC1)n2Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 3 h
Yield: 89.2 %

Procedure:
Toluene (20 ml) was added to 2.0 g (4.3 mmol) of 2-(2'-cyanobiphenyl-4-yl)methylamino-3-cyclopropanecarboxamido-5-bromo-4-methylpyridine, p-toluenesulfonic acid monohydrate (200 mg) and Molecular Sieves 4A (500 mg), followed by heating under reflux with stirring for 3 hours. The reaction solution was brought to room temperature and filtered through Celite to remove insolubles. Chloroform (100 ml) and an aqueous solution (100 ml) of sodium hydrogencarbonate were added to the filtrate and the obtained mixture was caused liquid-liquid separation. The aqueous phase was further extracted with chloroform (50 ml) twice. The organic phases were combined, dried over anhydrous magnesium sulfate and subjected to vacuum concentration. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to give 1.7 g of 2-cyclopropyl-3-(2'-cyanobiphenyl-4-yl)methyl-6-bromo-7-methyl-3H-imidazo-[4,5-b]pyridine (yield 88%).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C:24]([C:29]([O:31]C)=[O:30])=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:19][CH:18]=2)[C:7]2[C:12]([C:13](=[O:15])[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>C(O)C>[CH2:1]([C:5]1[N:6]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[C:24]([C:29]([OH:31])=[O:30])=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:21][CH:22]=2)[C:7]2[C:12]([C:13](=[O:15])[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc(=O)c2ccccc2n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1cc(=O)c2ccccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Using the procedure of Example 2, the product of Example 19 and 3 ml of N sodium hydroxide and 2 ml of ethanol were reacted to obtain after crystallization from dimethylformamide, 155 mg of the desired product melting at >260° C.
Reaction SMILES: [O:1]=[C:2]([N:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)[CH2:3][C:4]1[NH:8][C:7]2[CH:9]=[C:10]([NH:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:29])([F:28])[F:27])=[O:19])[CH:11]=[C:12]([C:13]([O:15]C)=[O:14])[C:6]=2[N:5]=1.O.[OH-].[Li+]>CO.O>[O:1]=[C:2]([N:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)[CH2:3][C:4]1[NH:8][C:7]2[CH:9]=[C:10]([NH:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:28])([F:29])[F:27])=[O:19])[CH:11]=[C:12]([C:13]([OH:15])=[O:14])[C:6]=2[N:5]=1
Reactant: COC(=O)c1cc(NC(=O)c2ccccc2C(F)(F)F)cc2[nH]c(CC(=O)N3CCCC3)nc12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(Nc1cc(C(=O)O)c2nc(CC(=O)N3CCCC3)[nH]c2c1)c1ccccc1C(F)(F)F
Yield: 83.6 %

Procedure:
A solution of methyl 2-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxylate (74 mg) and lithium hydroxide hydrate (66 mg) in MeOH-water (1:1, 2 mL) was stirred at 50° C. for 30 minutes. The solvent was removed under reduced pressure, water was added, and the residue was neutralized by 1N hydrochloric acid under ice-cooling. The precipitate was collected by filtration, washed with diethyl ether, and dried under reduced pressure to obtain the titled compound (60 mg) as pale yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.C(O)C.Br[C:15]1[CH:16]=[N:17][C:18]([N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([C:30]([O:32][CH3:33])=[O:31])[CH:28]=3)[C:23]([S:34][CH3:35])=[CH:22]2)=[N:19][CH:20]=1>COCCOC.C(=O)([O-])[O-].[Na+].[Na+].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>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:15]1[CH:20]=[N:19][C:18]([N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([C:30]([O:32][CH3:33])=[O:31])[CH:28]=3)[C:23]([S:34][CH3:35])=[CH:22]2)=[N:17][CH:16]=1
Reactant: COC(=O)c1ccc2c(SC)cn(-c3ncc(Br)cn3)c2c1
Reactant: OB(O)c1ccccc1F
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: CCO
Solvent: COCCOC
Product: COC(=O)c1ccc2c(SC)cn(-c3ncc(-c4ccccc4F)cn3)c2c1
Temperature: 90 °C

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.15 g, 0.13 mmol), 2-fluorophenylboronic acid (0.93 g, 6.64 mmol) and ethanol (40 mL) were added under an argon atmosphere to a mixture of 51b) (2.0 g, 5.3 mmol) in DME (40 mL) and 2M sodium carbonate solution (5.3 mL). The resulting mixture was heated at 90° C. for 3 h and then filtered through a pad of celite that was subsequently rinsed with dichloromethane (2×50 mL). The filtrate was concentrated and the remnant purified by column chromatography [100-200 mesh silica; dichloromethane/hexane=1:1]. White solid. Yield: 2.0 g (96% of theory). HPLC-MS (method 5): Rt=4.41 min; m/z [M+H]+=394
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(OC([NH:31][CH2:32][CH2:33][C:34](O)=[O:35])=O)(C)(C)C>>[NH2:31][CH2:32][CH2:33][C:34]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH2:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=3)[N:9]=2)[CH:3]=1)=[O:35]
Reactant: Nc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Product: NCCC(=O)Nc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 24 was coupled to 3-tert-butoxycarbonylamino-propionic acid by procedure K. The resulting product was deprotected by procedure G. LC-MS showed the product had the expected M+H+ of 377. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.6 (d, 1H) 8.4 (d, 1H) 8.1 (s, 1H) 7.8 (d, 1H) 7.5 (t 3H), 7.2 (d, 1H), 7.1 (d, 2H), 6.7 (d 2H), 3.6 (d, 2H), 3.1 (d, 2H), 2.8 (d, 2H), 2.5 (d, 2H).
Reaction SMILES: N1C=CC=CC=1C1C=CC=CN=1.[BH4-].[Na+].[N:15]([CH:18]1[CH:24]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)[O:23][CH2:22][CH2:21][N:20]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:19]1)=[N+]=[N-].C(O)(=O)C>C(O)C.[Co](Br)Br>[NH2:15][CH:18]1[CH:24]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)[O:23][CH2:22][CH2:21][N:20]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(N=[N+]=[N-])C1
Agent: Br[Co]Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(N)C1
Temperature: 2.5 °C
Reaction time: 0.08 h
Yield: 75.8 %

Procedure:
To a solution of cobalt bromide (15 mg) in ethanol (5 mL) was added 2,2′-bipyridyl (33 mg), sodium tetrahydroborate (53 mg) was added, and the mixture was stirred at 0-5° C. for 5 min. To the reaction mixture was added a solution of tert-butyl (6SR,7SR)-6-azido-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (270 mg) in ethanol (5 mL), and the mixture was stirred at 0-5° C. for 30 min. Acetic acid was added to the reaction mixture, and the mixture was stirred at room temperature for 5 min. The solvent was evaporated under reduced pressure. The residue was neutralized with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (191 mg).
Reaction SMILES: BrC1N=C(C(=O)NC)C(NC2C(C(F)(F)F)=CN=C(NC3C=CC(CCP(=O)OCCCN4C=C(B5OC(C)(C)C(C)(C)O5)C=N4)=CC=3OC)N=2)=CC=1.[Br:54][C:55]1[N:60]=[C:59]([C:61](=[O:64])[NH:62][CH3:63])[C:58]([NH:65][C:66]2[C:71]([C:72]([F:75])([F:74])[F:73])=[CH:70][N:69]=[C:68]([NH:76][C:77]3[CH:89]=[CH:88][C:80]([CH2:81][P:82](=[O:87])([OH:86])[O:83][CH2:84][CH3:85])=[CH:79][C:78]=3[O:90][CH3:91])[N:67]=2)=[CH:57][CH:56]=1.[CH3:92][C:93]1([CH3:111])[C:97]([CH3:99])([CH3:98])[O:96][B:95]([C:100]2[CH:101]=[N:102][N:103]([CH2:105][C:106]3([CH2:109]O)[CH2:108][CH2:107]3)[CH:104]=2)[O:94]1>>[Br:54][C:55]1[N:60]=[C:59]([C:61](=[O:64])[NH:62][CH3:63])[C:58]([NH:65][C:66]2[C:71]([C:72]([F:75])([F:73])[F:74])=[CH:70][N:69]=[C:68]([NH:76][C:77]3[CH:89]=[CH:88][C:80]([CH2:81][P:82](=[O:86])([O:87][CH2:109][C:106]4([CH2:105][N:103]5[CH:104]=[C:100]([B:95]6[O:94][C:93]([CH3:111])([CH3:92])[C:97]([CH3:99])([CH3:98])[O:96]6)[CH:101]=[N:102]5)[CH2:108][CH2:107]4)[O:83][CH2:84][CH3:85])=[CH:79][C:78]=3[O:90][CH3:91])[N:67]=2)=[CH:57][CH:56]=1
Reactant: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)c(OC)c1
Reactant: CC1(C)OB(c2cnn(CC3(CO)CC3)c2)OC1(C)C
Agent: CNC(=O)c1nc(Br)ccc1Nc1nc(Nc2ccc(CC[PH](=O)OCCCn3cc(B4OC(C)(C)C(C)(C)O4)cn3)cc2OC)ncc1C(F)(F)F
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)c(OC)c1)OCC1(Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Yield: 61.5 %

Procedure:
Prepared analogously to Compound 61A using ethyl hydrogen (4-{[4-{[6-bromo-2-(methylcarbamoyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 38C, 670 mg, 1.1 mmol) and (1-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]methyl}cyclopropyl)methanol (Compound 63B, 300 mg, 1.08 mmol) to afford 584 mg of the title compound as a racemic mixture (62%). MS (ESI): m/z=879.92/881.81 [M+H]+. UPLC: tR=1.61 min (UPLC-TOF: polar—2 min).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.Br[CH2:13][CH2:14][C:15]([OH:17])=[O:16].Cl>O.[OH-].[Na+]>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][CH2:13][CH2:14][C:15]([OH:17])=[O:16]
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: O=C(O)CCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCOc1cccc(C(F)(F)F)c1
Reaction time: 0.75 h
Yield: 33.4 %

Procedure:
Sodium hydroxide (4.24 g, 106 mmol) was dissolved in water (50 ml). 3-Trifluoromethyl-phenol (5.19 g, 32 mmol) was dissolved in 25 ml of the sodium hydroxide solution and heated to reflux. 3-Bromopropionic acid (9.79g, 64 mmol) in the other 25 ml of sodium hydroxide solution was added dropwise over 15 minutes. The reflux was continued for 45 minutes more, with portions of 10M sodium hydroxide solution added to maintain the pH of the solution at appoximately pH 10. The reaction mixture was then cooled, acidified with hydrochloric acid, and extracted with ethyl acetate. The combined organic layers were extracted with saturated aqueous sodium bicarbonate, and the aqueous layers acidified with hydrochloric acid. The acidified aqueous layers were extracted with diethyl ether. The ether layers were dried with magnesium sulfate, and the solvent removed under vacuum to give 2.5 g of the crude product which was used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[CH2:11]Br.[C-:14]#[N:15].[Na+]>CO>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[CH2:11][C:14]#[N:15]
Reactant: [C-]#N
Reactant: COC(=O)c1cccc(F)c1CBr
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cccc(F)c1CC#N
Temperature: 50 °C
Reaction time: 2 h

Procedure:
2-Bromomethyl-3-fluoro-benzoic acid methyl ester (5.1 g, 21 mmol) was dissolved in methanol (50 ml), and sodium cyanide aqueous solution (4.2 ml, 5 ml, 21 mmol) was added dropwise thereto. After completion of the dropwise addition, the mixture was stirred at 50° C. for 2 hours. The residue obtained by evaporating the solvent from the reaction solution under a reduced pressure was mixed with ethyl acetate, washed with water and saturated brine and then dried with anhydrous it magnesium sulfate. The solvent was removed by evaporation from the organic layer under a reduced pressure, and the thus obtained material was separated and purified by a silica gel column chromatography to obtain 3.3 g (17 mmol, 82% in yield) of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:15][C:16]2[S:20][N:19]=[C:18]([Cl:21])[C:17]=2[S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])=[C:6]1[CH3:31].[OH-].[Li+]>O1CCCC1>[C:25]1([S:22]([C:17]2[C:18]([Cl:21])=[N:19][S:20][C:16]=2[CH2:15][C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=3)[N:5]([CH2:4][C:3]([OH:32])=[O:2])[C:6]=2[CH3:31])(=[O:23])=[O:24])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COC(=O)Cn1c(C)c(Cc2snc(Cl)c2S(=O)(=O)c2ccccc2)c2cc(F)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(Cc2snc(Cl)c2S(=O)(=O)c2ccccc2)c2cc(F)ccc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 79.2 %

Procedure:
A mixture of [3-(4-benzenesulfonyl-3-chloroisothiazol-5-ylmethyl)-5-fluoro-2-methylindol-1-yl]acetic acid methyl ester (0.065 g), tetrahydrofuran (20 mL) and 1.0 M aqueous lithium hydroxide solution (4.0 mL) was stirred at room temperature for 5 minutes. The mixture was concentrated under reduced pressure, acidified by the addition of 1.0 M aqueous hydrochloric acid solution and extracted with ethyl acetate. The combined organic extract was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by preparative reverse-phase HPLC, eluting with a mixture of acetonitrile and water (1:19 to 19:1 by volume) to afford the title compound as a white solid (0.050 g).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[Cl-].[CH3:12][O:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[CH:16]=[N+:17]([CH3:19])[CH3:18]>>[CH3:12][O:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[CH:16]([N:17]([CH3:18])[CH3:19])[C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]=1[CH3:1]
Reactant: COc1ccccc1C=[N+](C)C
Reactant: Cc1cc2ccccc2[nH]1
Agent: [Cl-]
Product: COc1ccccc1C(c1c(C)[nH]c2ccccc12)N(C)C

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-methyl-1H-indole and (2-methoxy-benzylidene)-dimethyl-ammonium chloride.
Reaction SMILES: [Br:1]C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1CC.[CH2:23]([C:25]1[C:26]([NH:33][CH:34]2[C:43]3[C:38](=[C:39]([O:44][CH3:45])[CH:40]=[CH:41][CH:42]=3)[CH2:37][CH2:36][CH2:35]2)=[N:27][C:28]([CH2:31][CH3:32])=[CH:29][N:30]=1)[CH3:24]>>[Br:1][C:29]1[N:30]=[C:25]([CH2:23][CH3:24])[C:26]([NH:33][CH:34]2[C:43]3[C:38](=[C:39]([O:44][CH3:45])[CH:40]=[CH:41][CH:42]=3)[CH2:37][CH2:36][CH2:35]2)=[N:27][C:28]=1[CH2:31][CH3:32]
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Reactant: CCc1cnc(CC)c(NC2CCCc3c(OC)cccc32)n1
Product: CCc1nc(NC2CCCc3c(OC)cccc32)c(CC)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 3,6-diethyl-N-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ) 7.18, 6.97, 6.79, 5.37, 4.53, 2.87–2.76, 2.70–2.64, 2.54, 2.01–1.86, 1.35–1.24; HRMS (FAB) calcd for C19H24BrN3O+H 390.1181, found 390.1186.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([O:6][C:7]2[CH:15]=[C:14]3[C:10]([CH:11]=[CH:12][NH:13]3)=[CH:9][CH:8]=2)[CH2:2]1.[CH3:16][C:17]1[C:22](/[CH:23]=[CH:24]/[N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=[CH:19][C:18]=1[NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1>[CH3:16][C:17]1[C:22]([CH:23]([C:11]2[C:10]3[C:14](=[CH:15][C:7]([O:6][CH:3]4[CH2:4][CH2:5][O:1][CH2:2]4)=[CH:8][CH:9]=3)[NH:13][CH:12]=2)[CH2:24][N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=[CH:19][C:18]=1[NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: Cc1c(/C=C/[N+](=O)[O-])cccc1NC(=O)OCc1ccccc1
Reactant: c1cc2ccc(OC3CCOC3)cc2[nH]1
Solvent: C1CCOC1
Product: Cc1c(NC(=O)OCc2ccccc2)cccc1C(C[N+](=O)[O-])c1c[nH]c2cc(OC3CCOC3)ccc12
Yield: 46.4 %

Procedure:
6-(Tetrahydrofuran-3-yloxy)-1H-indole (0.632 g, 3.11 mmol) and (E)-benzyl 2-methyl-3-(2-nitrovinyl)phenylcarbamate (0.800 g, 2.56 mmol) were dissolved in THF (50 mL). The solution was then concentrated under vacuum to dryness. The solid mixture was melted at 130° C. and heated at this temperature for 6 hr. The mixture was subjected to ISCO (120 g silica gel, solid loading, 25-65% ethyl acetate/hexane) to afford the desired product (0.612 g, 1.187 mmol, 46.3% yield) as a beige solid.
Reaction SMILES: C[O:2][C:3](=[O:33])[C@@H:4]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[C:20]=1[O:31][CH3:32])(=[O:18])=[O:17])[CH2:5][NH:6][C:7]([C:9]1[S:10][C:11]([Cl:14])=[CH:12][CH:13]=1)=[O:8].[OH-].[Na+].Cl>C1COCC1>[Cl:14][C:11]1[S:10][C:9]([C:7]([NH:6][CH2:5][C@H:4]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]3[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=3)[C:20]=2[O:31][CH3:32])(=[O:18])=[O:17])[C:3]([OH:33])=[O:2])=[O:8])=[CH:13][CH:12]=1
Reactant: COC(=O)[C@H](CNC(=O)c1ccc(Cl)s1)NS(=O)(=O)c1cccc(-c2ccncc2)c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1c(-c2ccncc2)cccc1S(=O)(=O)N[C@@H](CNC(=O)c1ccc(Cl)s1)C(=O)O
Yield: 99.9 %

Procedure:
Intermediate 81 (1.08 g, 2.12 mmol) was dissolved in 20 ml of THF and sodium hydroxide (1 N water solution) (4.24 ml, 4.24 mmol) was added. After 16 h stirring at RT 1 N HCl (9 ml) was added, solvents were evaporated and n-butanol was added. The organic layer was dried with Na2SO4, filtered and evaporated to dryness. 1.05 g (yield: 99%) of crude product. The intermediate was directly used in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:26])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[C:10]([O:12]CC)=[O:11])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:26])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:25])[F:23])[CH:17]=2)[C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Cc1cccc(C(F)(F)F)c1)C(O)c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(Cc1cccc(C(F)(F)F)c1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
To a solution of ethyl (2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-(3-trifluoromethylbenzyl)propionate (7.9 g, 21.3 mmol) in methanol (50 ml) was added 1N aqueous sodium hydroxide solution (42.7 ml, 42.7 mmol) and the mixture was stirred at room temperature for 3 hrs. The reaction solution was acidified with 1N hydrochloric acid (100 ml) and extracted with ethyl acetate (200 ml×2). The extract was washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was crystallized from a mixture of hexane and diethyl ether to give (2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-(3-trifluoromethylbenzyl)propionic acid (6.20 g, 85%).
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4](=[O:12])[CH:3]=1.C(N(CC)CC)C.[Cl:20][C:21]1[CH:22]=[C:23]([N:28]=[C:29]=[O:30])[CH:24]=[CH:25][C:26]=1[Cl:27].[N-]=C=O>CC(C)=O>[Cl:20][C:21]1[CH:22]=[C:23]([CH:24]=[CH:25][C:26]=1[Cl:27])[NH:28][C:29]([C:3]1[C:4](=[O:12])[O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:2]=1[OH:1])=[O:30]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: O=c1cc(O)c2ccccc2o1
Agent: [N-]=C=O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: O=C(Nc1ccc(Cl)c(Cl)c1)c1c(O)c2ccccc2oc1=O

Procedure:
To 8.1 g (0.05 mole) of 4-hydroxy-2-oxo-2H-1-benzopyran dissolved in 200 ml acetone is added 5.6 g (0.05 mole) of triethylamine, followed by the addition of 3,4-dichlorophenyl isocyanate. The mixture is heated to reflux, and in 1/2 hour none of the isocyanate is left as determined by infra-red. The acetone solution is concentrated and the yellow viscous liquid is taken up in chloroform and washed with dilute hydrochloric acid. A white solid precipitates from the chloroform-acid mixture and is collected by filtration. The insoluble white solid is slurried in boiling acetone to yield 11.0 g of pure white powder, the product, m.p. 227°C to 228°C.