Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(O)C=CC=CC=1.[OH:8][C@@H:9]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=1)[CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].C([O-])([O-])=O.[K+].[K+].CC1C=CC(S(O[CH2:44][CH:45]2[CH2:50][CH2:49][N:48]([C:51](=[O:53])[CH3:52])[CH2:47][CH2:46]2)(=O)=O)=CC=1>CN(C=O)C.CCOC(C)=O>[C:51]([N:48]1[CH2:49][CH2:50][CH:45]([CH2:44][O:26][C:22]2[CH:21]=[C:20]([C@H:9]([OH:8])[CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:25]=[CH:24][CH:23]=2)[CH2:46][CH2:47]1)(=[O:53])[CH3:52]
Reactant: CC(=O)N1CCC(COS(=O)(=O)c2ccc(C)cc2)CC1
Reactant: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Oc1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)N1CCC(COc2cccc([C@H](O)CCNC(=O)OC(C)(C)C)c2)CC1
Temperature: 90 °C

Procedure:
Phenol (7, Intermediate I) (0.850 g, 3.20 mmol) and K2CO3 (1.32 g, 9.60 mmol) were added to a solution of (1-acetylpiperidin-4-yl)methyl 4-methylbenzenesulfonate (1.0 g, 3.20 mmol) in DMF (10 mL). The reaction mixture was heated at 90° C. overnight. The reaction mixture was diluted with EtOAc and washed with water and brine. Organic layer was dried over anhydrous Na2SO4) and concentrated under reduced pressure to give after purification by column chromatography to give (R)-tert-butyl (3-(3-((1-acetylpiperidin-4-yl)methoxy)phenyl)-3-hydroxypropyl)carbamate as a colorless semi solid. Yield (600 mg, 46%); 1H NMR (400 MHz, DMSO-d6); δ 7.18 (d, J=4.0 Hz, 1H), 6.93 (s, 1H), 6.86 (d, J=7.6 Hz, 1H), 6.76 (d, J=6.0 Hz, 1H), 5.17 (d, J=4.4 Hz, 1H), 4.50 (d, J=4.8 Hz, 1H), 4.39 (d, J=11.6 Hz, 1H), 3.81 (d, J=6.4 Hz, 2H), 3.06-2.94 (m, 4H), 1.99 (s, 3H), 1.78 (t, J=14 Hz, 2H), 1.65 (t, J=7.2, 2H), 1.36 (s, 9H), 1.23 (s, 3H), 1.55-0.88 (m, 1H); MS: m/z 407.05 [M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=O)[C:7]2=[O:16])=[CH:2]1.[F:17][C:18]([F:27])([F:26])[C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22]>>[S:1]1[CH:5]=[CH:4][C:3]([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[N:22][C:21]3[CH:23]=[CH:24][CH:25]=[C:19]([C:18]([F:17])([F:26])[F:27])[CH:20]=3)[C:7]2=[O:16])=[CH:2]1
Reactant: O=C1C(=O)N(c2ccsc2)c2ccccc21
Reactant: Nc1cccc(C(F)(F)F)c1
Product: O=C1C(=Nc2cccc(C(F)(F)F)c2)c2ccccc2N1c1ccsc1
Temperature: 140 °C
Yield: 18.2 %

Procedure:
A mixture of 1-(3-thienyl)-2H-indole-2,3-dione (25 mg, 0.11 mmol) (prepared as described below) and 3-trifluoromethylaniline (14 uL, 0.11 mmol) was heated neat at 140° C. for 2 h. The crude material was purified by preparative TLC using a mixture of 3:7 ethyl acetate and hexane as the eluent, giving the desired product as a yellow solid (7.3 mg, 0.02 mmol, 22%). 1H NMR (400 MHz) δ 7.62-7.19 (m, 9H), 6.94 (d, J=8.0, 1H), 6.76 (t, J=7.6, 1H); ESI-MS m/z found 373 (MH+).
Reaction SMILES: [N+:1]([C:4]1[S:5][CH:6]=[CH:7][C:8]=1[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])([O-])=O>O1CCOCC1.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Fe+2]>[NH2:1][C:4]1[S:5][CH:6]=[CH:7][C:8]=1[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)Cc1ccsc1[N+](=O)[O-]
Agent: [Fe+2]
Agent: O=S(=O)([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)Cc1ccsc1N
Yield: 90 %

Procedure:
Ethyl 2-nitrothiophene-3-acetate (4 g, 18.6 mmol) was dissolved in aqueous dioxan (40 ml, 4:1 dioxan/water) and treated with reduced iron powder (3.5 g, 62.7 mmol) and iron sulfate heptahydrate (400 mg, 1.44 mmol). The reaction mixture was heated at reflux for 2 hours then filtered through celite filter-aid and washed through with diethyl ether. The organic phase was washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. The organic phase was dried over magnesium sulfate and evaporated to a red/black liquid and then chromatographed on silica gel using hexane/ethyl acetate (3:1) as eluent to give 3.1 g of ethyl 2-aminothiophene-3-acetate. MS(ES): m/e 186 [M+H].
Reaction SMILES: [Co:1].[N+:2]([O-:5])([OH:4])=[O:3].[N+:6]([O-:9])([O-:8])=[O:7].[Co+2].[N+]([O-])([O-])=[O:12]>>[N+:2]([O-:5])([O-:4])=[O:3].[Co+2:1].[N+:6]([O-:9])([O-:8])=[O:7].[Co:1]=[O:12]
Reactant: [Co]
Reactant: O=[N+]([O-])O
Agent: [Co+2]
Agent: O=[N+]([O-])[O-]
Product: O=[Co]
Temperature: 500 °C

Procedure:
A concentrated cobalt nitrate solution is prepared by reacting 255 parts of electrolytic grade cobalt with 2,060 parts of 40 percent nitric acid. About 5 percent of the concentrated cobalt nitrate solution is reserved for later use in this example as described below. The remainder of the solution is reduced in volume by evaporation and transferred to an aluminum pan. The highly concentrated cobalt nitrate solution is heated in a furnace at 500° C. for 4 hours to form a first porous mass of cobalt oxide. The decomposition of the nitrate begins in solution and no crystals of cobalt nitrate are observed to form. This porous mass is cooled to ambient temperature and saturated with the portion of cobalt nitrate solution previously reserved. Then, the saturated mass is heated in the furnace at 500° C. for 4 hours to produce a second porous mass of cobalt oxide, consisting essentially of Co3O4 and containing 48.9 percent trivalent cobalt, Co+3. This second porous mass of cobalt oxide is cooled to ambient temperature, ground, and screened to provide a particulate cobalt oxide catalyst having a specific surface area of 0.2 m2 /g and a bulk density of 1.7 g./ml. The catalyst is in the form of irregular particles of length and mean diameter about equal and in the range 1.4 to 4.0 mm., said particles having a mean crushing strength of 4,200 grams per particle.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:17]=2)[CH:12]=[C:13]([OH:15])[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[C:33]([F:35])[CH:34]=1>>[CH3:1][O:2][C:3](=[O:27])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([C:23]([F:26])([F:24])[F:25])[CH:17]=2)[CH:12]=[C:13]([O:15][C:31]2[CH:30]=[C:29]([F:28])[CH:34]=[C:33]([F:35])[CH:32]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)C(CC(C)C)c1cc(O)cc(-c2ccc(Cl)c(C(F)(F)F)c2)c1
Reactant: OB(O)c1cc(F)cc(F)c1
Product: COC(=O)C(CC(C)C)c1cc(Oc2cc(F)cc(F)c2)cc(-c2ccc(Cl)c(C(F)(F)F)c2)c1
Yield: 49 %

Procedure:
The title compound was prepared in 49% yield from 2-(5-hydroxy-4′-chloro-3′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid methyl ester (prepared in Example A) and 3,5-difluorophenylboronic acid under the conditions described in Example 15, step (g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]([N:8]([N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[CH2:9][CH2:10][C:11]([O:13]C)=O)=[O:7])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.CN(C=O)C>[O:7]=[C:6]1[CH:5]([C:4]([O:3][CH2:1][CH3:2])=[O:21])[C:11](=[O:13])[CH2:10][CH2:9][N:8]1[N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CCOC(=O)CC(=O)N(CCC(=O)OC)N1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)C1C(=O)CCN(N2CCCCC2)C1=O
Temperature: 77 °C

Procedure:
To a solution of methyl N-(3-ethoxy-3-oxopropanoyl)-N-(1-piperidinyl)-β-alaninate (43 g, 143 mmol) in a mixture of THF (2.26 L) and DMF (1.00 L) was added Cs2CO3 (140 g, 430 mmol). The resulting mixture was heated at reflux (77° C.) for 48 h. The cooled reaction was filtered, and the filtrate was evaporated. The filtrate residue and filtered solid were combined and purified by flash chromatography using 7:3 CH2Cl2/MeOH as eluant, to give 11.36 g of partially pure title material. LC-MS m/z 269.19 (MH+), retention time 2.20 min (method 2).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3]I.C(=O)([O-])[O-].[K+].[K+].[CH2:13]1[C:16]2([CH2:20][C:19]([C:21]3[CH:26]=[N:25][C:24]4[NH:27][N:28]=[CH:29][C:23]=4[C:22]=3[NH:30][CH:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[N:18][O:17]2)[CH2:15][CH2:14]1>CN(C)C=O.O>[CH2:15]1[C:16]2([CH2:20][C:19]([C:21]3[CH:26]=[N:25][C:24]4[N:27]([CH2:3][C:2]([F:6])([F:5])[F:1])[N:28]=[CH:29][C:23]=4[C:22]=3[NH:30][CH:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)=[N:18][O:17]2)[CH2:13][CH2:14]1
Reactant: FC(F)(F)CI
Reactant: c1nc2[nH]ncc2c(NC2CCOCC2)c1C1=NOC2(CCC2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)Cn1ncc2c(NC3CCOCC3)c(C3=NOC4(CCC4)C3)cnc21
Temperature: 80 °C

Procedure:
1,1,1-Trifluoro-2-iodoethane (0.07 gm, 0.33 mmol) and potassium carbonate (0.125 gm, 0.9 mmol) were added to the solution of 5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (0.1 gm, 0.3 mmol) (example 29) in dimethylformamide and the reaction mixture was heated at 80° C. for about 3 hours. It was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[S:8][C:9]([CH2:11][O:12][C:13]3[C:14]([F:23])=[C:15]([C:19]([F:22])=[CH:20][CH:21]=3)[C:16]([NH2:18])=[O:17])=[N:10][C:5]2=[CH:4][CH:3]=1.[CH3:24][N:25]1[CH:29]=[CH:28][N:27]=[C:26]1[Sn](CCCC)(CCCC)CCCC.O>CN(C=O)C.[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>[F:23][C:14]1[C:13]([O:12][CH2:11][C:9]2[S:8][C:6]3[C:5]([N:10]=2)=[CH:4][CH:3]=[C:2]([C:26]2[N:25]([CH3:24])[CH:29]=[CH:28][N:27]=2)[N:7]=3)=[CH:21][CH:20]=[C:19]([F:22])[C:15]=1[C:16]([NH2:18])=[O:17]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccn1C
Reactant: NC(=O)c1c(F)ccc(OCc2nc3ccc(Br)nc3s2)c1F
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ccnc1-c1ccc2nc(COc3ccc(F)c(C(N)=O)c3F)sc2n1
Temperature: 120 °C

Procedure:
To a solution of 3-(5-bromo-thiazolo[5,4-b]pyridin-2-ylmethoxy)-2,6-difluoro-benzamide (0.10 g, 0.24 mmol) in 5 ml of anhydrous DMF was added 1-methyl-2-tributylstannanyl-1H-imidazole (0.120 g, 0.32 mmol) and degassed the reaction mixture for the 10 minutes. Tetrakis(triphenylphosphine) palladium (0) (0.004 g, 0.0037 mmol) was then added and the reaction mixture was heated at 120° C. for 12 h under the nitrogen atmosphere. The reaction mixture was then cooled to room temperature, added water (25 mL) and extracted the compound with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The compound was purified by column chromatography on silica (230-400 M) using ethyl acetate/hexane (40:60) as the eluent to provide the title compound as brick red solid (0.020 g, 20%). 1H NMR (DMSO-d6, 400 MHz): δ 3.14 (s, 3H), 5.67 (s, 2H), 7.07 (m, 1H), 7.28-7.37 (m, 2H), 7.87 (m, 2H), 8.28 (s, 1H), 8.53 (s, 1H) and 8.75 (br s, 1H). MS ES+ (402.22), HPLC (method I) Rt=12.05 min.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]([CH2:20][C:21]([N:23]2[CH2:28][CH2:27][S:26][CH2:25][CH2:24]2)=[O:22])[C:3]1=[O:29].[CH3:30][C:31]1[CH:32]=[C:33]([N:37]=[C:38]=[O:39])[CH:34]=[CH:35][CH:36]=1>C(Cl)Cl>[F:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:7]1[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]([CH2:20][C:21]([N:23]2[CH2:24][CH2:25][S:26][CH2:27][CH2:28]2)=[O:22])[C:3](=[O:29])[CH:2]([NH:1][C:38]([NH:37][C:33]2[CH:34]=[CH:35][CH:36]=[C:31]([CH3:30])[CH:32]=2)=[O:39])[N:8]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: NC1N=C(c2ccccc2F)c2ccccc2N(CC(=O)N2CCSCC2)C1=O
Solvent: ClCCl
Product: Cc1cccc(NC(=O)NC2N=C(c3ccccc3F)c3ccccc3N(CC(=O)N3CCSCC3)C2=O)c1
Reaction time: 8 h
Yield: 68.7 %

Procedure:
To a solution of (3RS)-3-amino-2,3-dihydro-5-(2-fluorophenyl)-1-(thiomorpholin-4-yl)carbonylmethyl-1H-1,4-benzodiazepin-2-one (0.11 g) in dry methylene chloride (10 ml) was added dropwise a solution of 3-methylphenyl isocyanate (0.043 g) in dry methylene chloride (5 ml) at ambient temperature. After completion of addition, the mixture was stirred at the same condition overnight. The reaction mixture was concentrated in vacuo to afford a crude product. The product was purified by column chromatography on silica gel with an eluent of a mixture of chloroform and methanol (100:1) to afford N-[(3RS)-2,3-dihydro-5-(2-fluorophenyl)-2-oxo-1-(thiomorpholin-4-yl) carbonylmethyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl)urea as a colorless crystalline solid (0.10 g).
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[O:9][C:8]([CH3:11])([CH3:10])[O:7][C@@H:6]([CH2:12][C:13]([OH:15])=[O:14])[CH2:5]1)#[N:2].N.O.[H][H]>CO>[NH2:2][CH2:1][CH2:3][C@H:4]1[O:9][C:8]([CH3:11])([CH3:10])[O:7][C@@H:6]([CH2:12][C:13]([OH:15])=[O:14])[CH2:5]1
Reactant: [H][H]
Reactant: CC1(C)O[C@H](CC#N)C[C@H](CC(=O)O)O1
Agent: N
Solvent: CO
Solvent: O
Product: CC1(C)O[C@H](CCN)C[C@H](CC(=O)O)O1
Temperature: 45 °C
Yield: 52.8 %

Procedure:
A solution of 1.04 g (4.88 mmol) of (±)-cis-6-(cyanomethyl)-2,2-dimethyl-1,3-dioxane-4-acetic acid in 100 mL of methanol saturated with anhydrous ammonia is added to a Parr shaker bottle containing 0.53 g of water wet Raney nickel #30. The solution is heated at 45° C. and 50 psig hydrogen pressure for 17 hours. The suspension is cooled and filtered to remove the Raney nickel through filter aid and the precipitate washed with methanol. The filtrate is concentrated at reduced pressure. The residue is dissolved in methanol saturated with anhydrous ammonia treated with decolorizing charcoal, filtered through filter aid and evaporated to give 0.56 g of (±)-cis-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetic acid, mp 165° with decomposition at 169° C. Fourier Transform Infrared (FTIR) (KBr): 1201.1, 1399.2, 1561.2, 2924.4, 3569.9 cm-1.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C[O:12][C:13]([C:15]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([Br:24])[CH:22]=2)[N:17]([S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])[C:16]=1[CH2:34][N:35]([CH2:46][C:47]#[N:48])S(C1C=CC(C)=CC=1)(=O)=O)=O>C1COCC1>[C:28]1([S:25]([N:17]2[C:16]3[CH:34]=[N:35][C:46]([C:47]#[N:48])=[C:13]([OH:12])[C:15]=3[C:23]3[CH:22]=[C:21]([Br:24])[CH:20]=[N:19][C:18]2=3)(=[O:27])=[O:26])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COC(=O)c1c(CN(CC#N)S(=O)(=O)c2ccc(C)cc2)n(S(=O)(=O)c2ccccc2)c2ncc(Br)cc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ncc2c(c1O)c1cc(Br)cnc1n2S(=O)(=O)c1ccccc1
Temperature: -10 °C
Yield: 59.7 %

Procedure:
Lithium bis(trimethylsilyl)amide (2.34 mL of a 1N solution in THF, 2.34 mmol) was added dropwise to a cooled (−78° C.) suspension of 1-benzenesulfonyl-5-bromo-2-{[cyanomethyl-(toluene-4-sulfonyl)amino]methyl}-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid methyl ester (0.48 g, 0.78 mmol) in dry THF (12 mL). The reaction mixture was allowed to slowly warm to −10° C. and then quenched with saturated aqueous ammonium chloride solution (8 mL). The reaction mixture was diluted with water and washed with DCM (2×10 mL). The combined organic phase was dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant residue was purified by flash chromatography (silica, 5 g cartridge, Si-SPE, 10-100% THF in DCM) to afford the title compound as a brown solid (0.20 g, 60%). LCMS (Method B): RT=3.83 min, M+H+=429/431.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][N:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C(CC)CNC1N=CC=CC=1C(OCC)=[O:27])C>>[CH2:1]([N:8]1[C:9]2[CH:10]=[CH:11][N:12]=[CH:13][C:14]=2[C:15](=[O:16])[O:17][C:18]1=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cccnc1NCC(CC)CC
Reactant: COC(=O)c1cnccc1NCc1ccccc1
Product: O=c1oc(=O)n(Cc2ccccc2)c2ccncc12

Procedure:
The title compound is prepared according to the procedure of Example 3B substituting the product of Example 180A for the product of Example 3A.
Reaction SMILES: [C:1]([C:6]1([CH3:16])[CH2:10][CH:9]([CH3:11])[C:8](=[O:12])[C:7]1(C#N)[OH:13])([O:3][CH2:4][CH3:5])=[O:2].C([O-])(=O)C.[Na+].C(=O)([O-])O.[Na+]>O>[C:1]([C:6]1([CH3:16])[CH2:10][C:9]([CH3:11])=[C:8]([OH:12])[C:7]1=[O:13])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)C1(C)CC(C)C(=O)C1(O)C#N
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C1(C)CC(C)=C(O)C1=O
Yield: 716.4 %

Procedure:
66.3 g (0.03 mol) of the foregoing 3-carboethoxy-2-cyano-2-hydroxy-3,5-dimethylcyclopentanone and 30.2 g (0.4 mol) of anhydrous sodium acetate are treated with 350 ml of water. The mixture is refluxed for 6 hours. For the working-up, the mixture is adjusted to pH 7 with saturated sodium hydrogen carbonate solution and then extracted four times with methylene chloride. The organic phases are dried over sodium sulphate, concentrated and dried in a high vacuum for 1 hour. (The product can, however, also be directly crystallised from the reaction mixture). There are obtained 42.6 g (73%) of crystalline 2-carboethoxy-2,4-dimethylcyclopent-4-en-5-olone of melting point 92°-93° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:15]=3)[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.C(N(C(C)C)CC)(C)C.[C:39](Cl)(=[O:41])[CH3:40].Cl>O1CCCC1>[CH2:16]([N:14]1[CH:15]=[C:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][N:3]=[C:2]3[NH:1][C:39](=[O:41])[CH3:40])[N:12]=[N:13]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)n1nc(N)c2cc(-c3cn(Cc4ccccc4)nn3)ccc21
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)Nc1n[nH]c2ccc(-c3cn(Cc4ccccc4)nn3)cc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of Example 64A (20 mg, 0.051 mmol) and diisopropylethylamine (0.063 mL, 0.35 mmol) in tetrahydrofuran (1.5 mL) was added acetyl chloride (0.013 mL, 0.17 mmol) and the reaction mixture was stirred at ambient temperature for about 1.5 hours. Hydrochloric acid (4 N in dioxane, 1.5 mL) was added and the mixture stirred at ambient temperature for about 16 hours. The solvent was removed under reduced pressure and the crude material was purified by reverse-phase HPLC using acetonitrile/water (0.05 M ammonium acetate) gradient elution method to afford the title compound as the acetate salt. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.35 (s, 1H), 8.57 (s, 1H), 8.22 (s, 1H), 7.81 (d, J=8.7 Hz, 1H), 7.48 (d, J=8.7 Hz, 1H), 7.33-7.42 (m, 5H), 5.64 (s, 2H), 2.13 (s, 3H). MS (ESI−) m/z 331 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([NH:13][C:14]2[CH:15]=[C:16]([N:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]3)[CH:17]=[CH:18][C:19]=2[C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH3:12])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[ClH:39]>ClCCl.CO.C(OCC)C>[ClH:39].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([NH:13][C:14]2[CH:15]=[C:16]([N:26]3[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]3)[CH:17]=[CH:18][C:19]=2[C:20](=[O:25])[C:21]([F:22])([F:24])[F:23])[CH3:12])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1cc(OC)cc(C(C)Nc2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc2C(=O)C(F)(F)F)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: COc1cc(OC)cc(C(C)Nc2cc(N3CCNCC3)ccc2C(=O)C(F)(F)F)c1
Reaction time: 3 h
Yield: 97 %

Procedure:
To a solution of t-butyl 4-(3-(1-(3,5-dimethoxyphenyl)ethylamino)-4-(2,2,2-trifluoroacetyl)phenyl)piperazine-1-carboxylate (231 mg, 0.43 mmol) in dichloromethane (2.0 mL) and methanol (0.5 mL) was added a saturated solution of HCl in diethyl ether (20 mL). The reaction mixture was stirred for 3 hours. The solvent was removed by rotary evaporation to afford the title compound (198 mg, 97% yield). 1H NMR (400 MHz, CD3OD): δ 7.62 (m, 1H), 6.52 (s, 2H), 6.36 (m, 2H), 5.49 (s, 1H), 4.66 (m, 1H), 3.57 (m, 2H), 3.50 (m, 2H), 3.21 (m, 4H), 1.58 (d, 3H); MS (ESI) m/z: Calculated for C22H27F3N3O3: 438.2; Observed: 439.5 (M++1) [corresponding to the free base].
Reaction SMILES: C([O:3][C:4](=[O:23])[C@@H:5]([O:20][CH2:21][CH3:22])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([C:17]([OH:19])=O)([CH3:16])[CH3:15])=[CH:9][CH:8]=1)C.[CH2:24]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][CH2:34][NH2:35])[CH3:25].C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH2:21]([O:20][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][C:14]([C:17](=[O:19])[NH:35][CH2:34][CH2:33][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[O:26][CH2:24][CH3:25])([CH3:15])[CH3:16])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:23])[CH3:22]
Reactant: CCOC(=O)[C@H](Cc1ccc(OC(C)(C)C(=O)O)cc1)OCC
Reactant: CCOc1ccccc1CCN
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CCOc1ccccc1CCNC(=O)C(C)(C)Oc1ccc(C[C@H](OCC)C(=O)O)cc1

Procedure:
The title compound was prepared from (2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-ethoxy-propionic acid ethyl ester (EXAMPLE 49, step 2) and 2-(2-ethoxy-phenyl)-ethylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C25H33NO6 [M+H]+: 444.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH2:19][CH:20]2[O:22][CH2:21]2)[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:23]([NH2:27])([CH3:26])([CH3:25])[CH3:24]>>[C:1]([C:5]1[CH:9]=[C:8]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH2:19][CH:20]([OH:22])[CH2:21][NH:27][C:23]([CH3:26])([CH3:25])[CH3:24])[O:7][N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)N
Reactant: CC(C)(C)c1cc(C=Cc2ccccc2OCC2CO2)on1
Product: CC(C)(C)NCC(O)COc1ccccc1C=Cc1cc(C(C)(C)C)no1

Procedure:
7 g (0.023 mole) of 3-tert.-butyl-5-[2-(2,3-epoxypropoxy)-styryl]-isoxazole and 3.4 g (0.047 mole) of tert.-butylamine are reacted by the method described in Example 4. 6.8 g (72% of theory) of colorless crystals are obtained. Melting point 207°-208° C.
Reaction SMILES: F[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.IC1C2C(=CC([C:42]([F:45])([F:44])[F:43])=CC=2)N(S(C2C=CC=CC=2)(=O)=O)C=1>>[C:14]1([S:11]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([C:42]([F:45])([F:44])[F:43])[CH:10]=3)[C:6]([C:20]3[CH:21]=[N:22][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:24]=3)=[CH:7]2)(=[O:12])=[O:13])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)n1cc(-c2cn(S(=O)(=O)c3ccccc3)c3cc(F)ccc23)cn1
Reactant: O=S(=O)(c1ccccc1)n1cc(I)c2ccc(C(F)(F)F)cc21
Product: CC(C)(C)OC(=O)n1cc(-c2cn(S(=O)(=O)c3ccccc3)c3cc(C(F)(F)F)ccc23)cn1

Procedure:
Following the general method as outlined in Intermediate 4, starting from 3-iodo-1-(phenylsulfonyl)-6-(trifluoromethyl)-1H-indole (Intermediate 40; 300 mg; 0.66 mmol) 0.40 g (94%) of the title compound was obtained as a black oil, which was used directly without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[N:12]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:11]([CH2:27][CH3:28])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]=2[CH:3]=1.C1CCCCC=1.B(Br)(Br)Br>ClCCl>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[N:12]([S:16]([C:19]3[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=3)(=[O:18])=[O:17])[CH:11]([CH2:27][CH3:28])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]=2[CH:3]=1
Reactant: CCC1c2ccccc2-c2cc(Br)ccc2N1S(=O)(=O)c1ccc(OC)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: C1=CCCCC1
Product: CCC1c2ccccc2-c2cc(Br)ccc2N1S(=O)(=O)c1ccc(O)cc1
Temperature: 25 °C
Yield: 89.8 %

Procedure:
A stirred and cooled solution of 2-bromo-6-ethyl-5-[(4-methoxyphenyl)sulfonyl]-5,6-dihydrophenanthridine (1.13 g, 2.46 mmol) and cyclohexene (2.5 mL, 24.6 mmol) in dichloromethane (5 mL) was treated drop-wise under nitrogen at −30° C. with boron tribromide (2.5 mL, 24.6 mmol). After the addition was completed, the reaction mixture was allowed to warm to room temperature and stirred for four hours. The reaction was cooled to −30° C. and quenched with methanol (1 mL). The solvent was removed in vacuo to yield the title compound as a gray powder (0.982 g, 2.21 mmol, 90%), which was confirmed by LCMS (ES−, FA, CV=20 or 5).