Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:18]([NH:26][C:27]1[CH:39]=[C:38](Br)[CH:37]=[CH:36][C:28]=1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>[Pd+2].C1(P(C2CCCCC2)C2C=CC=CC=2)CCCCC1.CN(C)C(=O)C>[C:18]([NH:26][C:27]1[CH:39]=[C:38]([C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([CH2:2][OH:1])[CH:8]=2)[CH:37]=[CH:36][C:28]=1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OCc1cccc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1NC(=O)c1ccccc1
Agent: [Pd+2]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)c1ccc(-c2cccc(CO)c2)cc1NC(=O)c1ccccc1
Temperature: 90 °C
Reaction time: 15 h

Procedure:
42 mg of 3-hydroxymethylphenylboronic acid, 49 mg of sodium carbonate and 6 mg of polymer supported di(acetato)dicyclohexylphenylphosphine palladium(II) were added to 2.5 mL of N,N-dimethylacetamide solution containing 70 mg of tert-butyl 2-(benzamido)-4-bromobenzoate, and stirred at 90° C. for 15 hours. After the reaction mixture was cooled do room temperature, 6 mg of polymer supported di(acetato) dicyclohexylphenylphosphine palladium(II) was added and stirred at 110° C. for 9 hours and 30 minutes. After the reaction mixture was cooled to room temperature, insoluble were removed by filtration and ethyl acetate and 10% citric acid aqueous solution were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with 10% citric acid aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate=4:1] to obtain tert-butyl 2-(benzamido)-4-(3-(hydroxymethyl)phenyl)benzoate.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:26][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[O:22][CH2:21][CH2:20][CH2:19]4)(=O)=O)=CC=1.[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[C:37]1[CH2:38][CH2:39][NH:40][CH2:41][CH:42]=1.C(OCC)(=O)C>CS(C)=O>[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[C:37]1[CH2:38][CH2:39][N:40]([CH2:12][CH:13]2[O:26][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[O:22][CH2:21][CH2:20][CH2:19]4)[CH2:41][CH:42]=1
Reactant: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(c3O2)CCCO4)cc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Fc1ccc2[nH]cc(C3=CCN(CC4COc5ccc6c(c5O4)CCCO6)CC3)c2c1
Temperature: 25 °C
Yield: 53.9 %

Procedure:
A solution of 0.55 g (1.5 mmole) of (2R)-2,3,9,10-tetrahydro-8H-[1,4]dioxino[2,3-f]chromen-2-ylmethyl 4-methylbenzenesulfonate and 1.0 g (4.6 mmole) of 5-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole in 10 mL of DMSO was heated under nitrogen at 80° C. for 6 hours. After the reaction had cooled to room temperature, 400 mL of ethyl acetate was added and the solution was washed with 250 mL portions of saturated aqueous sodium bicarbonate, water and saturated brine, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was column chromatographed on silica gel with 0.5% methanol in chloroform to give 0.34 g of the desired product as a pale yellow foam. This was crystallized from ethanol with the addition of 0.10 g of fumaric acid to give 0.24 g of the (S)-enantiomer of the title compound as a pale yellow solid, m.p. 205-206° C.
Reaction SMILES: [F:1][C:2]1[C:3]([O:19][CH3:20])=[C:4]([C:8]2([CH2:11][C:12](=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[F:21][C:22]([Si](C)(C)C)([F:24])[F:23].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[F:1][C:2]1[C:3]([O:19][CH3:20])=[C:4]([C:8]2([CH2:11][C:12]([OH:18])([C:22]([F:24])([F:23])[F:21])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)CC1(c2cccc(F)c2OC)CC1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(O)(CC1(c2cccc(F)c2OC)CC1)C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
9.6 g (34.3 mmol) of ethyl 3-[1-(3-fluoro-2-methoxyphenyl)cyclopropyl]-2-oxopropionate and 34.5 ml (233 mmol) of (trifluoromethyl)trimethylsilane in 343 ml of DMF are admixed with 46.9 g of caesium carbonate at 0° C. The reaction mixture is stirred at 0° C. for 2 h and then poured into water. It is extracted repeatedly with ethyl acetate and the extracts are washed with saturated sodium chloride solution, dried with sodium sulphate and concentrated in vacuo. Purification by chromatography on silica gel (hexane/ethyl acetate 10%-40%) affords 10.4 g of ethyl 3-[1-(3-fluoro-2-methoxyphenyl)-cyclopropyl]-2-hydroxy-2-(trifluoromethyl)propanoate as a yellow oil. This oil, in 297 ml of diethyl ether, is admixed at 0° C. with 2.25 g (59.4 mmol) of lithium aluminum hydride and the mixture is stirred at RT for a further hour. 20 ml of saturated ammonium chloride solution are added cautiously to the batch at 0° C., followed by 15 minutes of vigorous stirring. The mixture is extracted repeatedly with diethyl ether and the extracts are washed with saturated sodium chloride solution, dried with sodium sulphate and concentrated in vacuo. Purification by chromatography on silica gel (hexane/ethyl acetate 10%-50%) affords 5.6 g of 3-[1-(3-fluoro-2-methoxyphenyl)cyclopropyl]-2-(trifluoromethyl)propane-1,2-diol. 5.6 g (18.1 mmol) of diol in 100 ml of dichloromethane and 61 ml of DMSO are admixed with 12.4 ml (89 mmol) of triethylamine and over 10 minutes with 11 g (70 mmol) of pyridine SO3 complex in portions. The mixture is stirred for 3 hours and saturated ammonium chloride solution is added. The mixture is stirred for a further 15 minutes and the phases are separated and subjected to extraction with dichloromethane. The extracts are washed with water and dried over sodium sulphate. The solvent is removed in vacuo, and purification by chromatography on silica gel (hexane/ethyl acetate, 0-50%) affords 5.9 g of product.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([O:11][C:12]([NH:14][C:15]1([C:30]([NH:32][C@H:33]([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=2)[CH2:34][C:35](OC)=[O:36])=[O:31])[CH2:20][CH2:19][N:18]([C:21]2[C:22]3[CH:29]=[CH:28][NH:27][C:23]=3[N:24]=[CH:25][N:26]=2)[CH2:17][CH2:16]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>C1COCC1>[Cl:45][C:42]1[CH:41]=[CH:40][C:39]([C@@H:33]([NH:32][C:30]([C:15]2([NH:14][C:12](=[O:13])[O:11][C:7]([CH3:9])([CH3:8])[CH3:10])[CH2:16][CH2:17][N:18]([C:21]3[C:22]4[CH:29]=[CH:28][NH:27][C:23]=4[N:24]=[CH:25][N:26]=3)[CH2:19][CH2:20]2)=[O:31])[CH2:34][CH2:35][OH:36])=[CH:44][CH:43]=1
Reactant: COC(=O)C[C@H](NC(=O)C1(NC(=O)OC(C)(C)C)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](CCO)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.2 %

Procedure:
LiAlH4 (2.280 mL, 2.28 mmol) was added dropwise to (S)-methyl 3-(4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamido)-3-(4-chlorophenyl)propanoate (Intermediate 21) (1.27 g, 2.28 mmol) in THF (70 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 20° C. for 1 hour. The reaction mixture was quenched with sodium hydroxide (2M) (2 mL) and water (1 mL). The solution was filtered and was diluted with EtOAc (200 mL), and washed sequentially with water (100 mL), water (100 mL), and saturated brine (100 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford (S)-tert-butyl 4-(1-(4-chlorophenyl)-3-hydroxypropylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (1.04 g, 86%) as a white solid. M/z (ESI+) (M+H)+=529; HPLC tR=2.00 min.
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[OH:14][N:15]=[C:16]([C:23]#[N:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>O1CCCC1>[C:9]([C:8]1[CH:12]=[CH:13][C:5]([S:2]([O:14][N:15]=[C:16]([C:23]#[N:24])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:4])=[O:3])=[CH:6][CH:7]=1)([OH:11])=[O:10]
Reactant: N#CC(=NO)c1ccccc1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: C1CCOC1
Product: N#CC(=NOS(=O)(=O)c1ccc(C(=O)O)cc1)c1ccccc1
Reaction time: 2 h

Procedure:
In the temperature range from -10° C. to 0° C. and with stirring, a solution of 7.55 g of p-chlorosulfonylbenzoic acid in 25 g of tetrahydrofuran is slowly added to a solution of 5 g of α-hydroxyiminobenzyl cyanide in 24 g of tetrahydrofuran. The reaction mixture is heated, with stirring, to room temperature. After 2 hours, the reaction mixture is poured into 600 ml of 0.12N hydrochloric acid. The precipitated product is isolated by filtration, washed with water and dried at 40° C. in vacuo. Melting point: 250°-251° C.
Reaction SMILES: [F:1][C:2]([F:14])([O:6][C:7]1[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4].[Br:15]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(OCC)(=O)C>[F:1][C:2]([F:14])([O:6][C:7]1[CH:8]=[C:9]([CH2:13][Br:15])[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:4])[F:5]
Reactant: Cc1cccc(OC(F)(F)C(F)F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Product: FC(F)C(F)(F)Oc1cccc(CBr)c1

Procedure:
To a solution of 3-(1,1,2,2-tetrafluoroethoxy)toluene (27.8 g, 133 mmol) in ethyl acetate (250 ml) were added N-bromosuccinimide (26.1 g, 147 mmol) and 2,2′-azobis(isobutyronitrile) (440 mg, 2.67 mmol), and the mixture was heated under reflux for 5 hrs. After concentration of the reaction solution, crystals were filtered with hexane and the filtrate was concentrated to give 3-(1,1,2,2-tetrafluoroethoxy)-α-bromotoluene. To a solution of ethyl 3-[4-(benzyloxy)phenyl]-3-oxopropanoate (37.8 g, 127 mmol) in 1,2-dimethoxyethane (250 ml) was added sodium hydride (60% in oil, 5.07 g, 127 mmol) under ice-cooling, and the mixture was stirred at room temperature for 30 min. To the reaction solution was dropwise added a solution of 3-(1,1,2,2-tetrafluoroethoxy)-α-bromotoluene prepared earlier in 1,2-dimethoxyethane (50 ml), and the mixture was stirred overnight at room temperature. The reaction solution was poured into water (500 ml), and the mixture was extracted with ethyl acetate (500 ml×2). The extract was washed with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-1:1) and recrystallized from ethyl acetate-hexane to give the objective substance (43.4 g, 68%).
Reaction SMILES: [Br-].[O:2]1[CH2:7][CH2:6][CH2:5][O:4][CH:3]1[CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:29]12([C:39]3[C:40]([O:51][SiH:52]([CH3:54])[CH3:53])=[C:41]([CH:44]=[CH:45][C:46]=3[C:47]([CH3:50])([CH3:49])[CH3:48])[CH:42]=O)[CH2:38][CH:33]3[CH2:34][CH:35]([CH2:37][CH:31]([CH2:32]3)[CH2:30]1)[CH2:36]2.O>C1COCC1>[C:29]12([C:39]3[C:40]([O:51][SiH:52]([CH3:54])[CH3:53])=[C:41]([CH:42]=[CH:9][CH2:8][CH:3]4[O:2][CH2:7][CH2:6][CH2:5][O:4]4)[CH:44]=[CH:45][C:46]=3[C:47]([CH3:50])([CH3:48])[CH3:49])[CH2:30][CH:31]3[CH2:37][CH:35]([CH2:34][CH:33]([CH2:32]3)[CH2:38]1)[CH2:36]2
Reactant: c1ccc([P+](CCC2OCCCO2)(c2ccccc2)c2ccccc2)cc1
Reactant: C[SiH](C)Oc1c(C=O)ccc(C(C)(C)C)c1C12CC3CC(CC(C3)C1)C2
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: C[SiH](C)Oc1c(C=CCC2OCCCO2)ccc(C(C)(C)C)c1C12CC3CC(CC(C3)C1)C2
Temperature: 0 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
33 g (72.1 mmoles) of [2-(1,3-dioxan-2-yl)ethyl] triphenylphosphonium bromide are suspended in 100 ml of THF. The suspension is cooled to 0° C. and 8.5 g (75.6 mmoles) of potassium terbutylate are added in small amounts. The mixture is left to stand until its temperature reaches 20° C. It is then stirred for 1 hour at which point it is cooled to 0° C. There is then slowly added a solution of 3-(1-adamantyl)-4-tert.butyl-dimethylsilyloxybenzaldehyde in 100 ml of TMF. Once the addition has ended, the mixture is left to stand until its temperature reaches ambient temperature at which point it is stirred for 2 hours, then poured into water, and extracted with methylene chloride. The organic phase is decanted, washed with water, dried over MgSO4 and the solvents evaporated. The residue is purified by passage through a silica column (eluant: 50:50 mixture of CH2Cl2 and hexane), yielding 19.4 g (95% yield) of the expected mixture containing more than 90% of isomer Z, and less than 10% of isomer E.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([CH3:30])([CH3:29])[C:25](OC)=[O:26])=[CH:20][CH:19]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]([CH3:30])([CH3:29])[CH2:25][OH:26])=[CH:22][CH:23]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)(C)c1ccc(Cc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Solvent: C1CCOC1
Product: CC(C)(CO)c1ccc(Cc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Temperature: 55 °C
Reaction time: 2 h
Yield: 103.7 %

Procedure:
A 25-mL round bottom flask was charged with methyl 2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)methyl)phenyl)-2-methylpropanoate (0.144 g, 0.31 mmol) and THF (5 mL) at rt. Borane-dimethylsulfide complex (0.090 mL, 0.95 mmol) was added and the resulting solution was stirred at 55° C. for 2 h. LCMS analysis indicated only partial reduction. Borane-dimethylsulfide complex (0.100 mL, 1.05 mmol) was added and the resulting solution was stirred at 55° C. for a further 20 h until the starting material was consumed (monitored by LCMS analysis). The reaction was quenched with methanol then treated with 2N aqueous HCl (0.1 mL) and concentrated under reduced pressure. The residue was diluted with methanol and then concentrated under reduced pressure. The residue absorbed onto silica (2 g) then purified by column chromatography on silica using hexanes/ethyl acetate (10:0 to 0:10) as the eluent to afford 2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)methyl)phenyl)-2-methylpropan-1-ol (0.126 g, 100%) as a colorless oil. MW=391.93. 1H NMR (CDCl3, 500 MHz) δ 7.93-7.91 (m, 1H), 7.79-7.76 (m, 1H), 7.37-7.30 (m, 4H), 7.26 (s, 1H), 7.15 (d, J=8.0 Hz, 2H), 3.95 (s, 2H), 3.60 (d, J=8.0 Hz, 2H), 3.08 (t, J=8.0 Hz, 2H), 2.88 (t, J=7.5 Hz, 2H), 2.14 (quin, J=7.5 Hz, 3H), 1.32 (s, 6H), 1.18 (t, J=8.0 Hz, 1H). MS: ESI+, m/z 392 [M+H]+. Treatment with 1.25M HCl in methanol (0.52 mL, 2.0 eq.) afforded the title compound (0.121 g, 89%) as a white solid. MW=428.39. M.p. 95-97° C. 1H NMR (DMSO-d6, 500 MHz) δ 8.10-8.07 (m, 1H), 7.99-7.94 (m, 1H), 7.86 (br s, 1H), 7.58-7.52 (m, 2H), 7.31-7.27 (m, 2H), 7.23-7.19 (m, 2H), 4.01 (s, 2H), 3.37 (s, 2H), 3.05 (t, J=7.5 Hz, 2H), 2.92 (t, J=7.5 Hz, 2H), 2.11 (quin, J=7.5 Hz, 2H), 1.17 (s, 6H); APCI MS m/z 392 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][C@H:8]([CH3:11])[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.CS(C)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:12])[NH:7][CH:8]([CH3:11])[CH:9]=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H](CO)NC(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 101.3 %

Procedure:
(R)-(2-hydroxy-1-methyl-ethyl)-carbamic acid tert-butyl ester (2.0 g, 11.4 mmol) in 10 mL of CH2Cl2 was added dropwise to a stirred solution of oxalyl chloride (1.1 mL, 12.6 mmol) and DMSO (1.62 mL, 22.8 mmole) in 20 mL of CH2Cl2 at −60° C. The reaction mixture was stirred for 5 minutes before TEA (5.6 ml, 57.1 mmole) was added slowly. The resultant reaction mixture was warmed to room temperature over 1 hour. The organics were washed with water, and the aqueous fractions back extracted with CH2Cl2. The organics were combined and dried over sodium sulfate. The solvent was evaporated under reduced pressure to provide 2.0 g (99%) of (1-methyl-2-oxo-ethyl)-carbamic acid tert-butyl ester (Intermediate VIa) (1H-NMR (CDCl3, ppm) 1.34 d (3H); 1.45 s (9H); 3.10 q (1H); 9.45 (1H)).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[C:11]([CH3:13])[O:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[CH3:23][N:24]([CH3:38])[CH:25]([CH3:37])[CH2:26][O:27][C:28]1[CH:29]=[C:30]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[NH2:31]>>[CH3:23][N:24]([CH3:38])[CH:25]([CH3:37])[CH2:26][O:27][C:28]1[CH:29]=[C:30]([NH:31][C:20]([C:17]2[CH:16]=[CH:15][C:14]([C:3]3[CH:4]=[CH:5][C:6]([C:8]4[N:12]=[C:11]([CH3:13])[O:10][N:9]=4)=[CH:7][C:2]=3[CH3:1])=[CH:19][CH:18]=2)=[O:21])[CH:32]=[CH:33][C:34]=1[O:35][CH3:36]
Reactant: Cc1nc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)no1
Reactant: COc1ccc(N)cc1OCC(C)N(C)C
Product: COc1ccc(NC(=O)c2ccc(-c3ccc(-c4noc(C)n4)cc3C)cc2)cc1OCC(C)N(C)C

Procedure:
The title compound was prepared from 2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-carboxylic acid (EP 0533268 A1) and 3-(2-dimethylaminopropoxy)-4-methoxyaniline (D7) using a similar procedure to Example 1 (34%) mp 105°-110° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C:7]([O:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[CH:18]=O)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:30]=[C:29]2[C:25]([CH2:26][C:27](=[O:31])[NH:28]2)=[CH:24][CH:23]=1.N1CCCC1>CO>[C:1]([O:5][C:6](=[O:20])[C:7]([O:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[CH:18]=[C:26]1[C:25]2[C:29](=[CH:30][C:22]([Cl:21])=[CH:23][CH:24]=2)[NH:28][C:27]1=[O:31])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(Cl)cc1C=O
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: CO
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(Cl)cc1C=C1C(=O)Nc2cc(Cl)ccc21
Yield: 46.1 %

Procedure:
In a manner similar to the method described in Example 227b, 2-(4-chloro-2-formyl-phenoxy)-2-methyl-propionic acid tert-butyl ester (9 g, 30 mmol) was reacted with 6-chlorooxindole (5.1 g, 30 mmol) and pyrrolidine (2.49 g, 35 mmol) in methanol to give E/Z 2-[4-chloro-2-(6-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-phenoxy]-2-methyl-propionic acid tert-butyl ester as a yellow oil (6.2 g).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:24][CH2:25][CH3:26])=[C:8]([N:10]=[C:11]2[N:15]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:14](=[O:23])[CH2:13][S:12]2)[CH:9]=1)(=[O:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:37](Br)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C1COCC1>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:24][CH2:25][CH3:26])=[C:8]([N:10]=[C:11]2[N:15]([CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:14](=[O:23])[CH:13]([CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[S:12]2)[CH:9]=1)(=[O:3])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCNc1ccc(C(C)=O)cc1N=C1SCC(=O)N1Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCNc1ccc(C(C)=O)cc1N=C1SC(Cc2ccccc2)C(=O)N1Cc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 8 %

Procedure:
To a stirred solution of 2-(5-acetyl-2-ethylamino-phenylimino)-3-benzyl-thiazolidin-4-one (0.11 g, 0.30 mmol) in THF (3 mL, anhyd) chilled to 0° C. was added dropwise 1.0 M solution of lithium bis(trimethylsilyl)amide in THF (0.30 mL, 0.30 mmol). After 5 min benzyl bromide (36 μL, 0.30 mmol) was added to the reaction mixture, which was stirred at 0° C. for 2 h and then allowed to warm to ambient temperature. After 1 h the reaction mixture was quenched with satd NH4Cl and extracted with EtOAc. The organic layer was isolated, washed with brine, dried over anhyd Na2SO4, concentrated and chromatographed (silica gel, 0:100 to 20:80 EtOAc-Hex) to yield the title product (11 mg) as a white solid. 1H-NMR (CDCl3): δ 7.66 (1H, dd, J=8.5 Hz, 2.0 Hz), 7.49 (1H, d, J=2.0 Hz), 7.19-7.35 (10H, m), 6.48 (1H, d, J=8.5 Hz), 5.00 (2H, m), 4.48 (1H, dd, J=9.0 Hz, 3.8 Hz), 3.92 (1H, hr t), 3.53 (1H, dd, J=14.1 Hz, 3.8 Hz), 3.17 (1H, dd, J=14.1 Hz, 9.0 Hz), 3.02 (2H, m), 2.47 (3H, s), 1.02 (3H, t); MS (ESI): 458 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8](Br)[CH:7]=[CH:6]2.[H-].[Ca+2].[H-].[C:17]([O:24][CH3:25])(=[O:23])[CH2:18][CH2:19][CH2:20][C:21]#[CH:22]>C(NCC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:22]#[C:21][CH2:20][CH2:19][CH2:18][C:17]([O:24][CH3:25])=[O:23])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc(Br)ccc2c1
Reactant: C#CCCCC(=O)OC
Agent: [Ca+2]
Agent: [H-]
Solvent: CCNCC
Product: COC(=O)CCCC#Cc1ccc2cc(OC)ccc2c1

Procedure:
Into a solution of 2.51 g (9.2 mmol) of 6-methoxy-2-naphthyl bromide in 31 ml of diethylamine distilled with calcium hydride were charged 324 mg (0.46 mmol) of bistriphenylphosphine palladium dichloride and 192 mg of cupric iodide (1.01 mmol), followed by stirring. To the mixture was gradually added 1.06 g (9.4 mmol) of methyl 5-hexynoate, and the mixture was stirred at room temperature overnight (about 15 hours). Diethylamine was evaporated under a reduced pressure, to the residue were added ethyl acetate and water, and the mixture was extracted with ethyl acetate. Anhydrous magnesium sulfate was introduced into the organic layer for drying.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6][C:7]#[C:8][CH2:9][N:10]1[CH:15](/[CH:16]=[CH:17]/[C:18](=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][CH2:13][CH2:12][C:11]1=[O:25]>C(#N)C.P([O-])([O-])([O-])=O>[O:25]=[C:11]1[CH2:12][CH2:13][CH2:14][CH:15](/[CH:16]=[CH:17]/[C:18](=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[N:10]1[CH2:9][C:8]#[C:7][CH2:6][CH2:5][CH2:4][C:3]([OH:26])=[O:2]
Reactant: CCCCCC(=O)/C=C/C1CCCC(=O)N1CC#CCCCC(=O)OC
Agent: O=P([O-])([O-])[O-]
Solvent: CC#N
Product: CCCCCC(=O)/C=C/C1CCCC(=O)N1CC#CCCCC(=O)O
Reaction time: 18.5 h
Yield: 10.9 %

Procedure:
Rabbit liver esterase (134 units/mg, 3 mg) was added to a solution of 7-[2-oxo-6-((E)-3-oxo-oct-1-enyl)-piperidin-1-yl]-hept-5-ynoic acid methyl ester (18 mg, 0.45 mmol) in acetonitrile (0.3 mL) and pH 7.2 phosphate buffer (3.0 mL). After 18.5 h, acetonitrile (10 mL) was added and the reaction mixture was concentrated to dryness in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→3% MeOH/CH2Cl2, gradient) afforded 17 mg (97%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[C@@H:21]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][C:27]4[O:32][CH2:31][CH2:30][N:29]([CH2:33][CH2:34][CH2:35][O:36][CH3:37])[C:28]=4[CH:38]=3)[CH2:20][N:19]([S:39]([C:42]3[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=3)(=[O:41])=[O:40])[C@H:18]([CH2:49][C:50]([CH3:55])([CH3:54])[C:51]([OH:53])=O)[CH2:17]2)=[CH:12][CH:11]=1>>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C@@H:16]2[C@@H:21]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][C:27]4[O:32][CH2:31][CH2:30][N:29]([CH2:33][CH2:34][CH2:35][O:36][CH3:37])[C:28]=4[CH:38]=3)[CH2:20][N:19]([S:39]([C:42]3[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=3)(=[O:40])=[O:41])[C@H:18]([CH2:49][C:50]([CH3:55])([CH3:54])[C:51]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[O:53])[CH2:17]2)=[CH:14][CH:15]=1
Reactant: CN1CCNCC1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](CC(C)(C)C(=O)O)C[C@@H]3c3ccc(OC)cc3)cc21
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](CC(C)(C)C(=O)N4CCN(C)CC4)C[C@@H]3c3ccc(OC)cc3)cc21

Procedure:
Similar to example 102, 1-methylpiperazine is reacted with 3-[(2S,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-2,2-dimethyl-propionic acid (from example 65b) to afford 3-[(2S,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-2,2-dimethyl-1-(4-methyl-piperazin-1-yl)-propan-1-one which is subsequently deprotected according to general procedure A to afford the title compound.