Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH2:19][O:20][CH3:21])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:22]([C:29]2[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][CH:30]=2)=[CH:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)(=O)=O)C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH:24]1([CH:23]=[C:22]([C:11]2[NH:10][C:14]3=[N:15][CH:16]=[C:17]([CH2:19][O:20][CH3:21])[CH:18]=[C:13]3[CH:12]=2)[C:29]2[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][CH:30]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: COCc1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCc1cnc2[nH]c(C(=CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Yield: 91.8 %

Procedure:
A solution of 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-methoxymethyl-1H-pyrrolo[2,3-b]pyridine (600 mg, 1.09 mmol) in tetrahydrofuran (0.5 mL) and a tetrabutylammonium fluoride solution in tetrahydrofuran (1 M, 5 mL, 5 mmol) was stirred at room temperature for 12 h. The mixture was diluted with ethyl acetate (150 mL), washed with a saturated aqueous ammonium chloride solution and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-methoxymethyl-1H-pyrrolo[2,3-b]pyridine (411 mg, quant.) as a white solid: LC/MS m/e calcd for C23H26N2O3S [M+H]+ 411.54, observed 411.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[CH:20][C:21](O)=[O:22])=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([CH:19]=[CH:20][C:21]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:22])=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: C1COCCN1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(C=CC(=O)O)cc2)=C(C)C1=O
Product: COC1=C(OC)C(=O)C(Cc2ccc(C=CC(=O)N3CCOCC3)cc2)=C(C)C1=O
Yield: 43.1 %

Procedure:
3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]acrylic acid (200 mg, 0.58 mmol) obtained in Example 2 and morpholine (65 mg, 0.75 mmol) were used, and a method similar to that described in Example 3 was employed to obtain the title compound (102 mg, 0.25 mmol, yield 43%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:13][C@@H:12]3[C@H:8]2[CH2:9][N:10](C(OCC2C=CC=CC=2)=O)[CH2:11]3)[CH:2]=1>CO.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:13][C@@H:12]3[C@H:8]2[CH2:9][NH:10][CH2:11]3)[CH:2]=1
Reactant: O=C(OCc1ccccc1)N1C[C@@H]2CN(c3cccnc3)[C@@H]2C1
Agent: [Pd]
Solvent: CO
Product: c1cncc(N2C[C@H]3CNC[C@H]32)c1

Procedure:
The product of Example 52E (190 mg, 0.61 mmol) in methanol (10 mL) was treated with 10% palladium on carbon (100 mg) under H2 according to the procedure described in Example 40C. The title compound was obtained as a yellow oil (100 mg, yield, 94%). 1H NMR (MeOH-d4, 300 MHz) δ2.53(dd, J=12.5, 3.4 Hz, 1H), 2.72 (dd, J=12.5, 6.4 Hz, 1H), 3.20 (m, 2H), 3.63 (dd, J=7.8, 3.4 Hz, 1H), 3.90 (t, J=7.8 Hz, 1H), 4.65 (dd, J=6.1, 3.4 Hz, 1H), 6.88 (ddd, J=8.4, 3.0, 1.3 Hz, 1H), 7.18 (dd, J=8.5, 4.8 Hz, 1H), 7.73 (d, 3.1 Hz, 1H), 7.83 (dd, 4.7, 1.4 Hz, 1H) m/z 176 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=O)=[C:4]([F:14])[CH:3]=1.C([Mg]Br)C.[CH2:19]([O:21]CC)[CH3:20]>C1COCC1>[Br:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][C:19](=[O:21])[CH3:20])=[C:4]([F:14])[CH:3]=1
Reactant: CON(C)C(=O)c1ccc(Br)cc1F
Reactant: CCOCC
Agent: CC[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)Cc1ccc(Br)cc1F
Reaction time: 6 h
Yield: 74 %

Procedure:
A solution of 4-bromo-2-fluoro-N-methoxy-N-methyl-benzamide (CAS [801303-33-3]) (24.9 g, 95.0 mmol) in THF (100 mL) at −78° C. was treated with a 3 N solution of ethyl magnesium bromide in diethyl ether (33.25 mL, 115 mmol) and allowed to warm to 0 C and stir for a 6 h period, after which time the reaction mixture was quenched with a half saturated aqueous solution of NH4Cl (200 mL) and EtOAc (100 mL). The mixture was separated and the organic component, washed with brine (2×50 mL), dried over MgSO4, filtered, and evaporated to an oil which was purified by silica gel flash chromatography with 20% EtOAc/hexanes as eluant to afford 1-(4-bromo-2-fluorophenyl)-propanone as a pale yellow solid (16.25 g, 74%). The propanone (21.15 g, 91.6 mmol) was then dissolved in ethanol (100 mL), treated with hydrazine hydrate (4.9 mL, 100.7 mmol), and heated at reflux for 4 h. The reaction mixture was then evaporated and dissolved in ethylene glycol (100 mL) and heated at 160-165° C. for 8 h after which time the cooled reaction mixture was poured onto water (500 mL) with stirring. The aqueous mixture was neutralized, with rapid stirring, using a small amount of an aqueous saturated solution of NaHCO3 to afford a pale yellow precipitate. The solids were filtered, washed with water, and air dried to afford cyclized indazole product (16.1 g, 78%).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].Cl[CH2:12][CH2:13][C:14]([CH3:17])([OH:16])[CH3:15]>CN1CCCC1=O>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH2:12][CH2:13][C:14]([CH3:17])([OH:16])[CH3:15])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: CC(C)(O)CCCl
Solvent: CN1CCCC1=O
Product: Cc1cc(OCCC(C)(C)O)cc(C)c1Br
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
10.0 g (49.7 mmol) 4-bromo-3,5-dimethylphenol and 10.3 g (74.6 mmol) K2OC3 are mixed with 20.0 mL N-methylpyrrolidone and heated to 100° C. 37.0 g (64.7 mmol) 4-chloro-2-methylbutan-2-ol (toluene solution from step 1) is added and the funnel is rinsed with 10.0 ml N-methylpyrrolidone. The reaction mixture is heated to 115° C. for approx. 3 h before 30.0 ml of the solvent is distilled off in vacuum. After full conversion the mixture is cooled to 20° C., 60.0 ml water is added and stirring is continued for 5 min. 90.0 ml n-heptane is added and the aqueous phase is separated. The organic phase is washed twice with 30.0 ml water. 20.0 ml solvent is distilled off and the mixture is cooled to 15° C. Seeds are added and stirring is continued for 1 h at 15° C. The suspension is cooled to −15° C. and stirred for 1 h. The product is filtered off, washed twice with cooled n-heptane and dried. Yield: 11.7 g; TLC: Rf=0.40 (silicagel, EtOAc:PE 2:8).
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[C:7]([C:12]#[N:13])[CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=[CH:3]1.P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:2]1[C:11]2[C:6](=[C:7]([C:12]#[N:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cccc2c(=O)cc[nH]c12
Reactant: O=P(Cl)(Cl)Cl
Product: N#Cc1cccc2c(Cl)ccnc12

Procedure:
4-Oxo-1,4-dihydroquinoline-8-carbonitrile (0.40 g, 0.24 mmol, WO2004/113303) and phosphorous oxychloride (10 mL) were heated to 100° C. for 1.5 h. Solvent removed in vacuo. EtOAc (50 mL) was added and organic phase washed with sat. aqueous Na2CO3 solution, brine (20 mL) and dried (MgSO4). Solvent removed in vacuo to give the title compound: RT=3.09 min; m/z (ES+)=189.0 [M+H]+.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([C:11]([OH:13])=[O:12])[NH:2]1.[OH-].[Na+].[C:16]([S:24][CH2:25][CH:26]([CH3:30])[C:27](Cl)=[O:28])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N1CCNCC1>O.C(Cl)Cl>[C:16]([S:24][CH2:25][CH:26]([CH3:30])[C:27]([N:2]1[CH:3]([C:11]([OH:13])=[O:12])[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1)=[O:28])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)C1Cc2ccccc2CN1
Reactant: CC(CSC(=O)c1ccccc1)C(=O)Cl
Agent: C1CNCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(CSC(=O)c1ccccc1)C(=O)N1Cc2ccccc2CC1C(=O)O
Temperature: 5 °C
Reaction time: 8 h

Procedure:
To a solution of (-)1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (5.0 g., 0.028 M) and sodium hydroxide (1.12 g., 0.028 M) in water (100 ml.) at 10° C. was slowly added (-)3-benzoylthio-2-methylpropionyl chloride (6.82 g., 0.028 M). At the same time, from a separate dropping funnel, was added a solution of sodium hydroxide (1.12 g., 0.028 M) in water (20 ml.), at such a rate that the solution was maintained at a pH between 9.5 and 7.5 pH units (final pH 7.5). After stirring overnight at 5° C., the reaction mixture was filtered and the clear filtrate acidified with dilute hydrochloric acid. The product was extracted into methylene dichloride, washed and dried over sodium sulfate. After filtration the solvent was removed by evaporation at reduced pressure, leaving a residue (8 g.). To a solution containing 0.5 g of this material in methylene dichloride was added piperazine (0.058 g., 0.67 mM). The solvent was removed and the product recrystallized from acetonitrile, giving a white solid, the title compound, as a hemipiperazine salt, m.p. 154°-155° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:41]=[CH:42][CH:43]=4)[O:24][CH2:25][C:26]([NH:28][C@@H:29]4[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30]4)=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:41]=[CH:42][CH:43]=4)[O:24][CH2:25][C:26]([NH:28][C@@H:29]4[CH2:33][CH2:32][NH:31][CH2:30]4)=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)COc2cccc(-c3nc(Nc4ccc5[nH]ncc5c4)c4ccccc4n3)c2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1)N[C@@H]1CCNC1

Procedure:
To (3R)-tert-butyl 3-(2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetamido)pyrrolidine-1-carboxylate was added a solution of 1:1 TFA:CH2Cl2 (3 mL) and stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and the crude product was purified by prep HPLC (method 10-35—90 mins) to afford 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N—((R)-pyrrolidin-3-yl)acetamide. (45 mg, 0.094 mmol)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[O:11][C:10](=[O:21])[NH:9]2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:48]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)#[CH:49]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:20][O:19][C:15]1[CH:14]=[C:13]([C@H:12]2[O:11][C:10](=[O:21])[NH:9][C@@H:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:49]#[C:48][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[CH:3]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: C#Cc1ccccc1
Reactant: COc1cccc([C@H]2OC(=O)N[C@@H]2c2cccc(Br)c2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COc1cccc([C@H]2OC(=O)N[C@@H]2c2cccc(C#Cc3ccccc3)c2)c1
Temperature: 25 °C

Procedure:
A suspension of (+)-(4R,5R)-4-(3-bromophenyl)-5-(3-methoxyphenyl)oxazolidin-2-one (2.4 g, 6.89 mmol) in triethylamine (24 mL, 172 mmol) was purged with nitrogen for 1 h (volume dropped by ca. 5 mL). The reaction was treated with triphenylphosphine (0.152 g, 0.579 mmol) and ethynylbenzene (0.776 mL, 7.07 mmol), and purged 10 minutes longer. To this was added PdCl2(PPh3)2 (0.034 g, 0.048 mmol) and copper(I) iodide (7.88 mg, 0.041 mmol). After purging 10 min longer, the reaction was warmed to a vigorous reflux. The reaction was heated at reflux overnight. In the morning, the reaction was cooled to room temperature, diluted with diethyl ether, washed with water (3×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (25%-->40% EtOAc/Hex) gave 2.2 g (80%) as a colorless foam solid. 1H-NMR (CDCl3, 500 MHz) δ 7.56 (m, 4H), 7.36-7.45 (m, 4H), 7.34 (m, 1H), 7.30 (m, 1H), 6.92-6.98 (m, 1H), 6.85-6.90 (m, 2H), 5.93 (bs, 1H), 5.31 (d, J=7.3, 1H), 4.78 (d, J=7.3, 1H), 3.84 (s, 3H). 13C-NMR (CDCl3, 126 MHz) δ 160.2, 158.6, 138.92, 138.85, 132.3, 131.8, 130.2, 129.6, 129.4, 128.7, 128.5, 126.4, 124.6, 122.9, 118.1, 115.0, 111.2, 90.6, 88.6, 85.9, 64.6, 55.5. Mass spec.: 370.18 (MH)+.
Reaction SMILES: Cl.Cl[C:3]([C:5]1[CH:6]=[CH:7][N:8]2[C:12]=1[CH2:11][S:10][CH:9]2[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:4].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[N:21]=1.C(N(CC)CC)C.C>O1CCOCC1.C(Cl)Cl.C(O)CCC>[F:26][C:22]1[N:21]=[C:20]([NH:19][C:3]([C:5]2[CH:6]=[CH:7][N:8]3[C:12]=2[CH2:11][S:10][CH:9]3[C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:4])[CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccn2c1CSC2c1cccnc1
Reactant: Nc1cccc(F)n1
Agent: Cl
Solvent: ClCCl
Solvent: CCCCO
Solvent: C1COCCO1
Product: O=C(Nc1cccc(F)n1)c1ccn2c1CSC2c1cccnc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 39.1 %

Procedure:
7-Chloroformyl-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole hydrochloride (12 g) is added, at a temperature between 60° and 70° C., to a solution of 2-amino-6-fluoropyridine (4.5 g) and triethylamine (8.1 g) in dioxane (250 cc) which is heated to a temperature in the vicinity of 60° C., in the course of 5 minutes. The suspension obtained is heated at a temperature in the vicinity of 100° C. for 6 hours and 45 minutes and then stirred at a temperature in the vicinity of 20° C. for 16 hours. The solvent is evaporated off under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 60° C. The residue obtained is dissolved in methylene chloride (500 cc) and the solution obtained is washed twice with distilled water (300 cc in total), twice with an aqueous 2N sodium hydroxide solution (300 cc in total) and twice with distilled water (300 cc in total) and then dried over anhydrous magnesium sulphate, treated with decolorizing charcoal (0.5 g), filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 50 ° C. A crude product (11.4 g) is thereby obtained, which is dissolved in boiling butan-1-ol (70 cc). Decolorizing charcoal (0.5 g) is added to the solution obtained and the suspension is filtered in the heated state. The filtrate is cooled at a temperature in the vicinity of 4° C. for 2 hours. The crystals formed are separated by filtration, washed 3 times with butan-1-ol (45 cc in total), twice with ethanol (50 cc in total) and 3 times with diethyl ether (90 cc in total) and then dried under the reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 20° C. in the presence of potassium hydroxide pellets. N-(6-fluoro-2-pyridyl)-3-(3-pyridyl)-1H, 3H-pyrrolo[1,2- c]thiazole-7-carboxamide (5.3 g) in the form of beige-coloured crystals, m.p. 198° C., is thereby obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([O:12][C@H:13]([CH3:38])[CH2:14][N:15]1[C:19]([CH3:20])=[C:18]([C:21]([O:23]CC2C=CC=CC=2)=[O:22])[C:17](=[O:31])[N:16]1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([O:12][C@H:13]([CH3:38])[CH2:14][N:15]1[C:19]([CH3:20])=[C:18]([C:21]([OH:23])=[O:22])[C:17](=[O:31])[N:16]1[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1c(C(=O)OCc2ccccc2)c(=O)n(-c2ccccc2)n1C[C@@H](C)OC(=O)CNC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C[C@@H](C)OC(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.9 %

Procedure:
A mixture of (R)-benzyl 1-(2-(2-(tert-butoxycarbonylamino)acetoxy)propyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylate (485 mg, 0.926 mmol) and 10% Pd/C (60 mg) in methanol (8 mL) was stirred for 3 h at rt. TLC analysis showed that the starting material was consumed completely. The catalyst was removed by filtration and the reaction mixture was concentrated in vacuo. The residue was purified by a silica gel column chromatography (100% EtOAc) to afford the title compound as a yellow solid (172 mg, 43% yield).
Reaction SMILES: C[O:2][C:3](=[O:26])[CH:4]([N:12]([C:16](=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[Cl:24])[CH2:13][C:14]#[CH:15])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[Li+]>C1COCC1.CO.O>[Cl:24][C:18]1[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=1[C:16]([N:12]([CH2:13][C:14]#[CH:15])[CH:4]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:26])=[O:2])=[O:25]
Reactant: C#CCN(C(=O)c1ccc(Cl)cc1Cl)C(Cc1ccccc1)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C#CCN(C(=O)c1ccc(Cl)cc1Cl)C(Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a THF:MeOH:H2O (3:2:1) (3 mL) solution of 2-[(2,4-Dichloro-benzoyl)-prop-2-ynyl-amino]-3-phenyl-propionic acid methyl ester (30 mg, 0.076 mmol), 1N aqueous solution of lithium hydroxide (0.46 mL, 0.46 mmol) was added and the reaction mixture was stirred at room temperature for 6 h. Solvents were removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The water layer was acidified using 10% KHSO4 solution and then the organic layer was separated, dried (Na2SO4), concentrated. The residue was purified by column chromatography (ethyl acetate:hexane 1:1 to ethyl acetate) to obtain 2-[(2,4-dichloro-benzoyl)-prop-2-ynyl-amino]-3-phenyl-propionic acid, 23 mg (81%) as a white solid. The compound contains two other minor rotamers. 1H NMR (CDCl3, 400 MHz): δ7.45-7.05 (m, 8H), 6.77 (dd, minor rotamer), 5.70 (d, minor rotamer), 4.99 (bs, minor rotamer), 4.64-4.59 (m, minor rotamer), 4.28 (d, minor rotamer), 4.29-4.18 (m, minor rotamer), 3.79-3.09 (m, 5H), 2.37 (t, minor rotamer), 2.31 (t, minor rotamer), 2.17 (t, 1H). ESI− (M−H): 375.
Reaction SMILES: C(O[C:4](=[O:20])[C:5](=[N:9][NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[C:12]=1[O:18][CH3:19])[C:6](=O)[CH3:7])C.Cl.[CH3:22][C:23]1[CH:24]=[C:25]([NH:30][NH2:31])[CH:26]=[CH:27][C:28]=1[CH3:29].C([O-])(=O)C.[Na+]>C(O)(=O)C.O>[CH3:22][C:23]1[CH:24]=[C:25]([N:30]2[C:4](=[O:20])[C:5](=[N:9][NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[C:12]=3[O:18][CH3:19])[C:6]([CH3:7])=[N:31]2)[CH:26]=[CH:27][C:28]=1[CH3:29]
Reactant: Cc1ccc(NN)cc1C
Reactant: CCOC(=O)C(=NNc1cccc(Br)c1OC)C(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1c(Br)cccc1NN=C1C(=O)N(c2ccc(C)c(C)c2)N=C1C

Procedure:
A solution of ethyl-2-[(3-bromo-2-methoxyphenyl)hydrazono]-3-oxobutanoate (10 g) prepared as in Example 15, and 3,4-dimethylphenylhydrazine hydrochloride (6.05 g) and sodium acetate (2.63 g) in acetic acid (150 mL) was stirred and heated to about 80° C. to about 90° C. for about 3 hours. The reaction mixture was cooled to about room temperature and stirred for about 1 hour. The reaction mixture was filtered to give a solid, which was washed with acetic acid. The solid obtained was stirred in water for about 30 minutes at about room temperature, which was then filtered, washed with water and dried at about 55° C. to about 60° C. Yield: 11 g
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.O[CH:10]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:23]=[C:24]([NH:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH:25]=[CH:26][CH:27]=2)[CH2:18][CH2:17]1.Cl>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:10]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[CH:23]=[C:24]([NH:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH:25]=[CH:26][CH:27]=3)[CH2:18][CH2:17]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccccc3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(Oc3ccc(F)cc3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 4-fluorophenol and N-{3-[1-(6-hydroxy-6-phenylhexyl)-4-piperidinyl]phenyl}-2-methylpropanamide: 1H NMR (400 MHz, CDCl3), HCl salt δ 8.05 (s, br, 1H), 7.72–6.70 (m, 13H), 5.06–4.96 (m, 1H), 3.66–3.51 (m, 2H), 3.01–2.82 (m, br, 2H), 2.82–2.57 (m, br, 4H), 2.57–2.34 (m, br, 2H), 2.05–1.78 (m, br; 6H), 1.64–1.52 (m, br, 1H), 1.52–1.16 (m, br, 3H), 1.25 (d, 6H, J=7.2 Hz); ESMS m/e: 517.0 (M+H)+.
Reaction SMILES: [C:1]1([C@H:7]([O:9][C:10](=[O:26])[NH:11][C:12]2[C:13]([CH2:24][CH3:25])=[N:14][O:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)=[O:31])[CH3:28]>>[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38]([C:20]3[CH:21]=[CH:22][C:17]([C:16]4[O:15][N:14]=[C:13]([CH2:24][CH3:25])[C:12]=4[NH:11][C:10]([O:9][C@@H:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH3:8])=[O:26])=[CH:18][CH:19]=3)=[CH:37][CH:36]=2)[CH2:33][CH2:34]1)=[O:31])[CH3:28]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: CCc1noc(-c2ccc(Br)cc2)c1NC(=O)O[C@H](C)c1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(CC)c4NC(=O)O[C@H](C)c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 6 using [5-(4-bromo-phenyl)-3-ethyl-isoxazol-4-yl]-carbamic acid (R)-1-phenyl-ethyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[O:13][C:8]2([CH2:12][CH2:11][CH2:10][CH2:9]2)[O:7][C@@H:6]([CH2:14][C:15]([OH:17])=[O:16])[CH2:5]1)#[N:2].N.O.[H][H]>CO>[NH2:2][CH2:1][CH2:3][C@H:4]1[O:13][C:8]2([CH2:12][CH2:11][CH2:10][CH2:9]2)[O:7][C@@H:6]([CH2:14][C:15]([OH:17])=[O:16])[CH2:5]1
Reactant: N#CC[C@@H]1C[C@H](CC(=O)O)OC2(CCCC2)O1
Reactant: [H][H]
Agent: N
Solvent: O
Solvent: CO
Product: NCC[C@@H]1C[C@H](CC(=O)O)OC2(CCCC2)O1
Temperature: 45 °C
Yield: 47.2 %

Procedure:
A solution of 1.17 g (4.88 mmol) of (±)-cis-9-(cyanomethyl)-6,10-dioxaspiro[4.5]decane-7-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 pounds per square inch gage (psig) hydrogen pressure for 17 hours. The suspension is cooled and filtered to remove the Raney nickel through filter aid and the precipitate is 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-9-(2-aminoethyl)-6,10-dioxaspiro[4.5]decane-7-acetic acid.