Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[O:5][C:6]1[C:17]2[C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:14](=[O:27])[C:13]=2[C:12]([OH:28])=[C:11]2[C:7]=1[N:8]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:9]=[N:10]2)[CH3:2].[C:37]1([C:43]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[N+]=[N-])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>ClCCCl>[CH2:1]([O:3][C:4](=[O:36])[O:5][C:6]1[C:17]2[C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[C:14](=[O:27])[C:13]=2[C:12]([O:28][CH:43]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[C:11]2[C:7]=1[N:8]([CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH:9]=[N:10]2)[CH3:2]
Reactant: CCOC(=O)Oc1c2c(c(O)c3ncn(Cc4ccccc4)c13)C(=O)N(Cc1ccc(F)cc1)C2=O
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: ClCCCl
Product: CCOC(=O)Oc1c2c(c(OC(c3ccccc3)c3ccccc3)c3ncn(Cc4ccccc4)c13)C(=O)N(Cc1ccc(F)cc1)C2=O
Temperature: 70 °C
Yield: 78.6 %

Procedure:
Carbonic acid 3-benzyl-6-(4-fluoro-benzyl)-8-hydroxy-5,7-dioxo-3,5,6,7-tetrahydro-1,3,6-triaza-s-indacen-4-yl ester ethyl ester 256 (140 mg, 0.28 mmol, 1 equiv.) was dissolved in 1,2 dichloroethane (20 mL) and to this was added diphenyldiazomethane (72 mg, 0.37 mmol, 1.3 equiv.) and heated at 70° C. under a nitrogen atmosphere for 24 hours. The reaction was then concentrated in vacuo and purified by silica gel chromatography using 7/3 Hexanes/Ethyl acetate to obtain carbonic acid 8-benzhydryloxy-3-benzyl-6-(4-fluoro-benzyl)-5,7-dioxo-3,5,6,7-tetrahydro-1,3,6-triaza-s-indacen-4-yl ester ethyl ester 257 (78%, 135 mg, 0.22 mmol). 1H NMR (300 MHz) CDCl3 δ 8.17 (s, 1 H), 7.91 (s, 1 H), 7.68 (d, J=7.2 Hz, 4 H), 7.21-7.42 (m, 12 H), 6.95-7.06 (s, 4 H), 5.49 (s, 2 H), 4.76 (s, 2 H), 4.11 (q, J=6.9 Hz, 2 H), 1.17 (t, J=6.9 Hz, 3 H). MS: 678.1 (M+23). TLC Rf: 0.3 Hexanes/Ethyl acetate (7/3)
Reaction SMILES: N=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]2)[NH:5][C:4](=[O:13])[N:3]1[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:15]=1.C[OH:27].[OH-].[NH4+].[Cl-].[Na+]>C(OCC)(=O)C>[O:13]=[C:4]1[N:3]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:15]=2)[C:2](=[O:27])[C:6]2([CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]2)[NH:5]1
Reactant: CN1CCC2(CC1)NC(=O)N(c1ccc(C#N)c(C(F)(F)F)c1)C2=N
Reactant: CO
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CN1CCC2(CC1)NC(=O)N(c1ccc(C#N)c(C(F)(F)F)c1)C2=O

Procedure:
Using the procedure of Example 2, 3 g of the product of Example 22, 70 ml of methanol and 17 ml of 2N hydrochloric were reacted and the solution was refluxed for 90 minutes. It was poured into 200 ml of ammonium hydroxide +100 g of ice saturated with sodium chloride and extraction was carried out 4 times with ethyl acetate. The extracts were washed with salt water, dried and purified on silica with methylene chloride-methanol: 9-1 as eluant. After crystallization from methylene chloride-isopropyl ether, 2.12 g of the expected product (white crystals) melting at 188°-189° C were obtained.
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH:6]2[CH2:11][CH2:10][CH:9]([C:12]([O:14]CC)=[O:13])[CH2:8][CH2:7]2)[CH2:3][CH2:2]1.CO.[OH-].[Na+].C1(CO[C@H]2CC[C@H](C(O)=O)CC2)CC1>C1COCC1>[CH:1]1([CH2:4][O:5][CH:6]2[CH2:11][CH2:10][CH:9]([C:12]([OH:14])=[O:13])[CH2:8][CH2:7]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)C1CCC(OCC2CC2)CC1
Agent: O=C(O)[C@H]1CC[C@H](OCC2CC2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1CCC(OCC2CC2)CC1

Procedure:
Ethyl 4-[(cyclopropylmethyl)oxy]cyclohexanecarboxylate (D42, 20.8 g, 45.8 mmol) was taken up in THF (50 mL)/methanol (50 mL). Sodium hydroxide (20 mL, 250 mmol, concentrated) was added to the solution which was left to stir o/n. The THF/methanol was evaporated and the crude residue washed with Et2O. The aqueous layer was acidified with 5 M HCl and extracted with EtOAc (2×). The EtOAc organics were combined, dried (Na2SO4) and the solvent evaporated to give a mixture of cis and trans 4-[(cyclopropylmethyl)oxy]cyclohexanecarboxylic acid (D43, 9.47 g, 94%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])[CH:3]=1.C(=O)=O.Cl.[CH3:30][NH:31][O:32][CH3:33].O>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:31]([O:32][CH3:33])[CH3:30])=[O:7])=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:24])([F:25])[F:23])[CH:16]=2)(=[O:14])=[O:13])[CH:3]=1
Reactant: CNOC
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Agent: O=C=O
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CON(C)C(=O)c1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.3 %

Procedure:
To a solution of 4-chloro-2-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-benzoic acid (5.0 g, 12.1 mmol) in THF (20 mL) was added N,N′-carbonyldiimidazole (CDI, 2.45 g, 15.13 mmol) in portions (Caution!: CO2↑). The resulting reaction mixture was then heated at reflux. After 4 hours, reaction mixture was cooled to room temperature and charged with N,O-dimethylhydroxylamine hydrochloride (1.3 g, 13.31 mmol) and heated at reflux for 1 hour. Water (100 mL) was added followed by EtOAc (100 mL) with stirring. EtOAc layer was separated and aqueous layer was further extracted with EtOAc (2×50 mL). Combined EtOAc layers were washed with aq. 2N HCl (50 mL), saturated NaHCO3 solution (50 mL), brine (50 mL), dried (Na2SO4) and evaporated. Obtained crude product was purified by automated normal-phase chromatography (50% EtOAc in hexanes) to afford title compound (4.0 g) in 73% yield. MS (ES) M+H expected 457.0. found 456.9.
Reaction SMILES: C([N:8]1[CH:13]2[CH:14]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:15][C:9]1([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH:10]([O:25][CH2:26][C:27]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:28]=1)[CH2:11][CH2:12]2)C1C=CC=CC=1>[Pd].C(O)C>[F:36][C:33]([F:34])([F:35])[C:31]1[CH:32]=[C:27]([CH2:26][O:25][C@@H:10]2[CH2:11][CH2:12][C@@H:13]3[NH:8][C@@:9]2([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:15][C@H:14]3[S:16]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:28]=[C:29]([C:37]([F:40])([F:38])[F:39])[CH:30]=1
Reactant: O=S(=O)(c1ccccc1)C1CC2(c3ccccc3)C(OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CCC1N2Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=S(=O)(c1ccccc1)[C@@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@H]2OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
A mixture of (1R*,2R*,5S*,6R*)-8S*)-8-benzyl-2-[3,5-bis(trifluoromethyl)-phenylmethoxy]-1-phenyl-6-phenylsulphonyl-8-azabicyclo[3.2.1]octane (Example 1; 450 mg, 0.68 mmol), 5% palladium on charcoal (1 g, 0.47 mmol) and ethanol (20 ml) was stirred under hydrogen atmosphere (1 atm) at +65° C. for 8 hours. The reaction mixture was cooled to room temperature, flushed with nitrogen gas and filtered through a pad of Celite™. The filtrate was concentrated and purified by flash chromatography to give the title compound (233 mg, 60%). The hydrochloride salt of the title compound was prepared by treatment with ethereal HCl.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:17]2[C:16]3[C:11]4=[C:12]([O:18][CH2:19][CH:20]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[N:10]4[C:9]=2[CH:8]=[CH:7][CH:6]=1)[CH:13]=[CH:14][CH:15]=3.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].[NH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>CN(C=O)C>[N:35]1([CH2:2][CH2:3][O:4][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:17]=2[C:16]2[C:11]4=[C:12]([O:18][CH2:19][CH:20]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[N:10]34)[CH:13]=[CH:14][CH:15]=2)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: ClCCOc1cccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(C2COc3cccc4c5c(OCCN6CCCCC6)cccc5n2c34)cc1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
To a mixture of 7-(2-chloroethoxy)-1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazole (0.28 g, 0.769 mmol) in dry DMF (6 mL) is added sodium iodide (0.09 g, 0.6 mmol), potassium carbonate (0.207 g, 1.5 mmol), and piperidine (0.13 g, 1.5 mmol). The mixture is heated at 70° C. for 6 h and then at room temperature for 18 h. The mixture is then partitioned between water and ether. The ether layer is washed three times with water (80 mL). The organic layer is dried over sodium sulfate and concentrated. Column chromatography (50 mL) silica gel using 1% methanol in CH2C2 as eluent gave 1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl 2-(1-piperidinyl)ethyl ether (TLC: acetone/hexane, 20/80, Rf=0.42) which is converted to the methanesulfonate salt to give 0.134 g (34%) of 1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl 2-(1-piperidinyl)ethyl ether.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:10]2[N:11]=[C:12]([CH2:15][O:16][C:17]3[CH:28]=[CH:27][C:20]([O:21][CH2:22][C:23]([O:25]C)=[O:24])=[C:19]([CH3:29])[CH:18]=3)[S:13][CH:14]=2)[CH2:3][CH2:2]1.[Li+].[OH-].Cl.CCOC(C)=O>C1COCC1.O>[CH:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:10]2[N:11]=[C:12]([CH2:15][O:16][C:17]3[CH:28]=[CH:27][C:20]([O:21][CH2:22][C:23]([OH:25])=[O:24])=[C:19]([CH3:29])[CH:18]=3)[S:13][CH:14]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)COc1ccc(OCc2nc(-c3ccccc3C3CC3)cs2)cc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(OCc2nc(-c3ccccc3C3CC3)cs2)ccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The solution of methyl 2-(4-((4-(2-cyclopropylphenyl)thiazol-2-yl)methoxy)-2-methylphenoxy)acetate from Step A is diluted with THF (1 mL), then a solution of 1 M LiOH in H2O (0.2 mL) is added and the mixture is stirred for 3 h at rt. The mixture is acidified with 1 M HCl (0.25 mL), EtOAc (10 mL) is added and the organic layer washed with brine (5 mL). The organic layer is dried (MgSO4), filtered, concentrated and purified on reverse phase HPLC (H2O/MeCN gradient) to afford the title compound B1 as a white solid: 1H-NMR (400 MHz, CDCl3) δ=7.57 (dd, J=1.6, 7.6 Hz, 1H), 7.48 (s, 1H), 7.30 (dt, J=1.6, 7.6 Hz, 1H), 7.24 (dt, J=1.2, 7.2 Hz, 1H), 7.03 (d, J=7.6 Hz, 1H), 6.90 (d, J=2.8 Hz, 1H), 6.78 (dd, J=2.8, 8.8 Hz, 1H), 6.69 (d, J=8.8 Hz, 1H), 5.41 (s, 2H), 4.62 (s, 2H), 2.28 (s, 3H), 2.10 (m, 1H), 0.89 (m, 2H), 0.72 (m, 2H). MS calcd. for C22H22NO4S (M+H+) 396.1. found 396.1.
Reaction SMILES: ClC1C=CC([N:8]2[CH:16](S)[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9]2=[O:18])=C(F)C=1.C1(N2C(=[O:31])C3=CC=CC=C3C2=S)C=CC=CC=1>C1(C)C=CC=CC=1>[C:9]1(=[O:18])[NH:8][C:16](=[O:31])[C:15]2=[CH:14][CH:13]=[CH:12][CH:11]=[C:10]12
Reactant: O=C1C2=C(CCCC2)C(S)N1c1ccc(Cl)cc1F
Reactant: O=C1c2ccccc2C(=S)N1c1ccccc1
Solvent: Cc1ccccc1
Product: O=C1NC(=O)c2ccccc21

Procedure:
In 30 ml of toluene were dissolved 3.0 g of 2-(4-chloro-2-fluorophenyl)-2,3,4,5,6,7-hexahydro-3-mercapto-1H-isoindol 1-one and 2.8 g of N-phenylthio-phthalimide, and the solution was heated under reflux for 3 hours. Upon cooling, there resulted crystals (phthalimide), which were filtered out, and the filtrate was concentrated under reduced pressure. A small amount of toluene was added and, upon standing overnight, there resulted crystals, which were collected by filtration and dried, thereby producing 2.7 g (yield of 67%) of the subject compound. Recrystallization from toluene yielded white crystals m.p. 127°-129° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH:3]1[C:8]([O:10][CH2:11][CH3:12])=[O:9].CCN(CC)CC.[O:20](C(OC(C)(C)C)=O)[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=O.CCCCCC>C(Cl)Cl>[O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:20])[CH2:4][CH:3]1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1CNCCC1=O
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
To a solution of ethyl 4-oxopiperidine-3-carboxylate (180.0 g, 0.87 mol, 1.0 eq.) in DCM (2.7 L) was added Et3N (352.14 g, 3.48 mol, 4.0 eq.) dropwise at 15° C. and stirred for 30 min followed by addition of (BOC)2O (210.0 g, 0.96 mol, 1.10 eq.) maintaining the temperature below 10° C. The resulted mixture was stirred at rt overnight, and concentrated to give a crude product that was stirred with hexane (3.5 L) for 1 h and filtered. The filtered cake was washed with hexanes. The combined organic phase was concentrated to furnish the title compound (226.0 g, 0.83 mol, 95.4%).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[N+:9]([C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1)([O-:11])=[O:10].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.ClCCl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:8][C:7]1[C:2]([C:16]2[CH:17]=[C:12]([N+:9]([O-:11])=[O:10])[CH:13]=[CH:14][CH:15]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cccnc1Br
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: Cc1cccnc1-c1cccc([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 84.5 %

Procedure:
To a suspension of 2-bromo-3-methylpyridine (1.72 g), 3-nitrophenylboronic acid (2.17 g) and tetrakis(triphenylphosphine)-palladium (577 mg) in 1,2-dimethoxyethane (20 ml) was added 2M aqueous solution of sodium carbonate (13 ml). The mixture was stirred at 80° C. for 5 hours under a nitrogen atmosphere, then cooled to room temperature and diluted with dichloromethane. The organic layer was separated, washed with water and brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 75g, dichloromethane:n-hexane=67:33 to 100:0) to give 3-(3-methylpyridin-2-yl)-nitrobenzene (1.81 g).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:6][CH2:7][CH2:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1)(=[O:4])=[O:3]
Reactant: O=Cc1ccc(OCCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCOc1ccc(C=O)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Methanesulfonylchloride (3.3 mL) was added dropwise over 5 min to a solution of 4-(2-hydroxyethoxy)benzaldehyde (example 108, step a) (6.4 g) and triethylamine (6.4 mL) in DCM (30 mL) at 0° C. under argon. The resulting mixture was stirred at 0° C. for 10 min and then at RT for 1 h. The reaction mixture was washed with brine (2×30 mL), dried over sodium sulphate, filtered and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with 40-50% EtOAc in petroleum ether (40-60° C.) to give the subtitled compound as a viscous yellow oil. Yield 8.87 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](OC)(OC)[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1>C(O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: COC(=O)C(Cc1ccc(Cl)cc1)(OC)OC
Solvent: O=CO
Product: COC(=O)CCc1ccc(Cl)cc1
Temperature: 67.5 °C

Procedure:
A mixture of methyl 3-(4-chlorophenyl)-2,2dimethoxypropionate (6.09 g) and formic acid (27 ml) was heated at 65 to 70° C. for 4 hours with stirring. The reaction mixture was cooled and extracted with methylene chloride. The extract was washed with water, dried over magnesium sulfate and evaporated in vacuo to give methyl 3-(4-chlorophenyl)propionate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[Cl:12][C:13]1[C:14](F)=[CH:15][C:16]2[O:21][CH:20]([C:22]([F:25])([F:24])[F:23])[C:19]([C:26]([O:28]CC)=[O:27])=[CH:18][C:17]=2[CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:5]([C:4]1[CH:8]=[CH:9][C:10]([O:11][C:14]2[C:13]([Cl:12])=[CH:31][C:17]3[CH:18]=[C:19]([C:26]([OH:28])=[O:27])[CH:20]([C:22]([F:24])([F:25])[F:23])[O:21][C:16]=3[CH:15]=2)=[C:2]([Cl:1])[CH:3]=1)([OH:7])=[O:6]
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Reactant: O=C(O)c1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(O)C1=Cc2cc(Cl)c(Oc3ccc(C(=O)O)cc3Cl)cc2OC1C(F)(F)F

Procedure:
The title compound was prepared from 3-chloro-4-hydroxybenzoic acid and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4. (Note: In the step similar to Example 183, Step 3, an additional equivalent of potassium carbonate was added.) mp >300° C. 1H NMR (acetone-d6 /300 MHz) 8.18 (d, 1H, J=2.0 Hz), 8.03 (dd, 1H, J=8.5 Hz 2.0 Hz), 7.93 (s, 1H), 7.78 (s, 1H), 7.23 (d, 1H, J=8.7 Hz), 6.77 (s, 1H), 5.87 (q, 1H, J=7.0 Hz). 19F NMR (acetone-d6 /282 MHz) -79.4 (d, J=6.5 Hz). ESHRMS m/z 446.9625 (M-H, Calc'd 446.9650). Anal. Calc'd for C18H9Cl2F3O6 : C, 48.13; H, 2.02; Cl, 15.79. Found: C, 47.96; H, 1.90; Cl, 15.65.
Reaction SMILES: [NH2:1][C@@H:2]([C@H:8]([OH:13])[C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]([O:5]CC)=[O:4]>Cl>[NH2:1][C@@H:2]([C@H:8]([OH:13])[C:9]([CH3:11])([CH3:10])[CH3:12])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)[C@@H](N)[C@H](O)C(C)(C)C
Agent: Cl
Product: CC(C)(C)[C@@H](O)[C@H](N)C(=O)O
Temperature: 130 °C
Reaction time: 1 h

Procedure:
In a round-bottomed flask, ethyl (2S*,3R*)-2-amino-3-hydroxy-4,4-dimethyl-pentanoate (0.596 g, 3.7 mmol) was dissolved in a 6.0 M HCl solution (70 mL). The resulting solution was divided into two equal aliquots and stirred at 130° C. for 1 h. All portions were joined and the reaction mixture extracted with Et2O (3×50 ml). The aqueous phase was concentrated under reduced pressure and the resulting yellowish solid crude product (0.675 g, 93%) was used without further purification in the following reaction. MS (ESI) m/z: 162 [M−H]+; (ESI) m/z: 160 [M−H]−. 1H NMR (DMSO-d6) δ 0.91 (s, 9H), 3.66 (d, J=3.24 Hz, 1H), 3.89 (s, 1H), 5.95 (d, J=6.39 Hz, 1H), 7.92 (s, 3H), 13.88 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:14](=[O:16])[CH3:15])[CH:5]=[C:6]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:7]=1[O:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[CH3:25][CH2:26][O:27][CH2:28][CH3:29]>CN(C)C=O.BrOBr>[C:10]([C:6]1[CH:5]=[C:4]([C:14](=[O:16])[CH3:15])[CH:3]=[C:2]([N:1]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:7]=1[O:8][CH3:9])([CH3:11])([CH3:12])[CH3:13]
Reactant: COc1c(N)cc(C(C)=O)cc1C(C)(C)C
Reactant: CCOCC
Agent: BrOBr
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: COc1c(N2CCOCC2)cc(C(C)=O)cc1C(C)(C)C
Temperature: 80 °C
Reaction time: 48 h

Procedure:
After dissolving 1-[3-amino-5-(tert-butyl)-4-methoxyphenyl]-1-ethanone (180 g) in dimethylformamide (800 ml), dibromoether (125 ml), potassium carbonate (225 g) and sodium iodide (12.2 g) were added and the mixture was stirred at 80° C. for 48 hours. The reaction mixture was cooled to room temperature, 3 l of ether was added and the mixture was washed 3 times with water. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (76 g) as yellow crystals.
Reaction SMILES: Br[C:2]1[C:21]([F:22])=[CH:20][C:5]2[O:6][CH2:7][CH:8]([OH:19])[C:9]3[S:13][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:11][C:10]=3[C:4]=2[CH:3]=1.[C:23]([C@:25]1([OH:32])[CH2:29][CH2:28][N:27]([CH3:30])[C:26]1=[O:31])#[CH:24]>>[F:22][C:21]1[C:2]([C:24]#[C:23][C@:25]2([OH:32])[CH2:29][CH2:28][N:27]([CH3:30])[C:26]2=[O:31])=[CH:3][C:4]2[C:10]3[N:11]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[S:13][C:9]=3[CH:8]([OH:19])[CH2:7][O:6][C:5]=2[CH:20]=1
Reactant: C#C[C@]1(O)CCN(C)C1=O
Reactant: CCOC(=O)c1nc2c(s1)C(O)COc1cc(F)c(Br)cc1-2
Product: CCOC(=O)c1nc2c(s1)C(O)COc1cc(F)c(C#C[C@]3(O)CCN(C)C3=O)cc1-2

Procedure:
Ethyl 9-bromo-8-fluoro-4-hydroxy-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxylate was reacted with (3R)-3-ethynyl-3-hydroxy-1-methyl-pyrrolidin-2-one similarly to as described in General Procedure F to afford ethyl 8-fluoro-4-hydroxy-9-(((R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxylate which was directed subjected to General Procedure M to afford 12.9 mg and 17.1 mg (22% overall yield) after reverse phase purification then chiral separation. The absolute stereochemistry at the 4-hydroxyl substitution position for each isomer was not determined.
Reaction SMILES: [CH:1]1([C:6]2[C:7]([OH:17])=[CH:8][C:9]([N+:14]([O-])=O)=[C:10]([CH:13]=2)[C:11]#[N:12])[CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)C.[Pd]>[NH2:14][C:9]1[CH:8]=[C:7]([OH:17])[C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[CH:13][C:10]=1[C:11]#[N:12]
Reactant: N#Cc1cc(C2CCCC2)c(O)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: N#Cc1cc(C2CCCC2)c(O)cc1N
Reaction time: 2 h
Yield: 98.9 %

Procedure:
A flask containing 10% Pd/C (4 mg) was evacuated and placed under a N2 atmosphere and suspended in ethanol (2 mL). To this was added 5-cyclopentyl-4-hydroxy-2-nitrobenzonitrile (42 mg, 0.18 mmol) as a solution in ethanol (1.5 mL). The reaction was stirred under H2 atmosphere for 2 h, then filtered and concentrated in vacuo to provide 2-amino-5-cyclopentyl-4-hydroxybenzonitrile as a yellow oil (36 mg, quantitative yield). LC/MS m/z 203.1 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])/[C:7](=[CH:10]/[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][CH:12]=2)/[S:6][C:5]1=[O:20].[C:21]([C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1)#[N:22].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(OC1C=CC(/C=C2/C(=O)N(CCNC)C(=O)S/2)=CC=1)C>>[CH2:18]([O:17][C:14]1[CH:15]=[CH:16][C:11](/[CH:10]=[C:7]2/[C:8](=[O:9])[N:4]([CH2:3][CH2:2][NH:1][CH2:27][C:26]3[CH:29]=[CH:30][C:23]([C:21]#[N:22])=[CH:24][CH:25]=3)[C:5](=[O:20])[S:6]/2)=[CH:12][CH:13]=1)[CH3:19]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CCOc1ccc(/C=C2\SC(=O)N(CCN)C2=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CCOc1ccc(/C=C2\SC(=O)N(CCNC)C2=O)cc1
Agent: [Na+]
Product: CCOc1ccc(/C=C2\SC(=O)N(CCNCc3ccc(C#N)cc3)C2=O)cc1

Procedure:
The title compound 23e was prepared from compound 76 (146 mg, 0.50 mmol), 4-cyanobenzaldehyde (37 μL, 0.50 mmol) and sodium triacetoxyborohydride (318 mg, 1.50 mmol) in a manner similar to that described for 23a in 69.0% (140 mg) yield as a light-yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].C(=O)([O-])[O-].[Na+].[Na+].[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>O>[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[CH3:11])(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cc([N+](=O)[O-])ccc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2ccc([N+](=O)[O-])cc2C)cc1
Reaction time: 3 h

Procedure:
152g (1 mole) of 4-amino-3-methyl-nitrobenzene, 80g of sodium carbonate and 500g of water are mixed, 230g (1.2 moles) of p-toluenesulfonyl chloride were added thereto while stirring, and the reaction was carried out for 3 hours at 70° C to obtain 290g of 4-(N-p-toluenesulfonyl)amino-3-methylnitrobenzene.