Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].CN(C=O)C.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:30])=[C:13]([C@H:15]([OH:29])[C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]2)[CH:14]=1.Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>C1COCC1>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:30])=[C:13]([C@H:15]([O:29][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:17]2)[CH:14]=1
Reactant: CCOC(=O)CBr
Reactant: Cc1ccc(Cl)cc1[C@H](O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)CO[C@@H](c1cc(Cl)ccc1C)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
To a suspension of NaH (5.64 g, 0.141 mol) in the mixed solvent of DMF (70 mL) and THF (70 mL) at −25° C. was added dropwise a solution of (R)-tert-butyl 3-((R)-(5-chloro-2-methylphenyl)(hydroxy)methyl)piperidine-1-carboxylate (16 g, 47 mmol) in anhydrous THF (100 mL), the reaction mixture was stirred for 1 hr at rt. A solution of ethyl bromoacetate (15.6 g, 94 mmol) in anhydrous THF (70 mL) was added dropwise to the above mixture at −10-−5° C. After addition, the reaction mixture was stirred for 2-3 hr at rt. The reaction was quenched with saturated NH4Cl solution (100 mL) and EtOAc (500 mL) was added. The organic layer was washed with water (5×50 mL) and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography to afford (R)-tert-butyl 3-((R)-(5-chloro-2-methylphenyl)(2-ethoxy-2-oxoethoxy)methyl)piperidine-1-carboxylate (8 g, 18.8 mmol).
Reaction SMILES: [Cl:1][C:2]1[C:4]([Cl:6])([Cl:5])[C:3]=1[Cl:7].[O:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:9]2[O:8][CH:12]([C:4]([Cl:6])([Cl:5])[C:3]=1[Cl:7])[CH:11]=[CH:10]2
Reactant: ClC1=C(Cl)C1(Cl)Cl
Reactant: c1ccoc1
Solvent: Cc1ccccc1
Product: ClC1=C(Cl)C(Cl)(Cl)C2C=CC1O2

Procedure:
A stirred mixture of 1,2,3,3-tetrachlorocyclopropene (60 g) and furan (22.97 g) in dry toluene (600 ml) was heated to reflux for 30 hours. The solvent was evaporated under reduced pressure to afford the required product, 75.4 g. 1H NMR (CDCl3) δ: 6.90 (1H, dd), 6.45 (1H, dd), 5.41 (1H, d), 4.93 (1H, d).
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.C(O)(=O)C.S(=O)(=O)(O)O.O[CH2:22][NH:23][C:24](=[O:27])[CH2:25][Cl:26]>O>[CH3:1][CH:2]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[C:8]([CH2:22][NH:23][C:24](=[O:27])[CH2:25][Cl:26])[CH:9]=2)[CH2:4][CH2:3]1
Reactant: CC1CCc2cc(O)ccc21
Reactant: O=C(CCl)NCO
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CC1CCc2cc(O)c(CNC(=O)CCl)cc21
Reaction time: 2 h

Procedure:
A solution of 850 mg of 1 methyl-5-indanol in 5 ml of a mixed solution of acetic acid and sulfuric acid (10:1 by volume) solution was mixed with 850 mg of N-hydroxymethyl chloroacetamide at room temperature under stirring for 2 hours. After reaction the reaction mixture was poured into 20 ml of water, extracted with ethyl acetate. The extract was washed with water, dried with anhydrous magnesium sulfate and concentrated under vacuum. The crude product thus obtained was purified by column chromatography on 100 g of Kiesel gel using an eluting agent comprising a mixture (20:1 by volume) of methylene chloride and ethyl acetate to provide 590 mg of the titled compound.
Reaction SMILES: [NH:1]([C:7]([O:9][CH2:10][CH:11]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[CH2:2][CH2:3][C:4]([OH:6])=[O:5].[NH2:24][CH:25]([CH2:28][OH:29])[CH2:26][OH:27].[C:30](Cl)([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)([C:39]1[CH:46]=[CH:45][C:42]([O:43][CH3:44])=[CH:41][CH:40]=1)[C:31]1[CH:38]=[CH:37][C:34]([O:35][CH3:36])=[CH:33][CH:32]=1.CO>N1C=CC=CC=1>[NH:1]([C:7]([O:9][CH2:10][CH:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]2[C:23]1=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:8])[CH2:2][CH2:3][C:4]([O:6][C:30]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)([C:39]1[CH:46]=[CH:45][C:42]([O:43][CH3:44])=[CH:41][CH:40]=1)[C:31]1[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[CH:37][CH:38]=1)=[O:5].[NH2:24][CH:25]([CH2:28][OH:29])[CH2:26][OH:27]
Reactant: O=C(O)CCNC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: NC(CO)CO
Solvent: CO
Solvent: c1ccncc1
Product: COc1ccc(C(OC(=O)CCNC(=O)OCC2c3ccccc3-c3ccccc32)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 0.25 h

Procedure:
N-Fmoc-β-Ala-Serinol (1, 93 g, 242 mmol) is co-evaporated 2×400 mL anh. pyridine, and then dissolved in 300 mL of the same solvent with magnetic stirring. The mixture is cooled in a ice bath, and DMT-Cl (86.1 g, 254 mmol) in 465 mL pyridine is added dropwise over a period of 1.5 hours. The ice bath is removed and the mixture is allowed to react for another hour at room temperature. Methanol (100 mL) is added and stirred for 15 min. to quench the remaining DMT-Cl. After evaporation in vacuo, the residue co-evaporated 3×400 mL with toluene. Silica gel column purification using ethyl acetate/methanol/triethylamine (95:5:0.25) as mobile phase yielded 90.6 g (55%) grams of isolated product 2.
Reaction SMILES: N#N.[CH3:3][C:4]1([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[O:14][CH:15]=[C:16]([C:18](Cl)=[O:19])[N:17]=2)[O:8][CH2:7][CH2:6][O:5]1.[N-:21]=[N+:22]=[N-:23].[Na+]>CC(C)=O.O>[CH3:3][C:4]1([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[O:14][CH:15]=[C:16]([C:18]([N:21]=[N+:22]=[N-:23])=[O:19])[N:17]=2)[O:8][CH2:7][CH2:6][O:5]1
Reactant: CC1(CCCCc2nc(C(=O)Cl)co2)OCCO1
Reactant: [N-]=[N+]=[N-]
Agent: N#N
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC1(CCCCc2nc(C(=O)N=[N+]=[N-])co2)OCCO1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), this crude 2-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-oxazole-4-carbonyl chloride was dissolved in acetone (18.0 mL). The solution was cooled to 0° C. and a solution of sodium azide (314 mg, 4.79 mmol) in H2O (2.0 mL) was added over 1 h. The reaction mixture was stirred at 0° C. for 1.5 h then at rt for 45 min. The mixture was concentrated under reduced pressure (coevaporation with toluene) then dissolved in CH2Cl2 and filtered. The filtrate was concentrated under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions 02: tR=0.89 min [M+H]+=281.38.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[OH:9][CH:10]1[CH2:15][CH2:14][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]1>CN(C=O)C.C(=O)(O)[O-].[Na+].C(OCC)(=O)C.C(OCC)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14][CH2:15]2)=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)cn1
Reactant: CCOC(=O)C1CCC(O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCOC(=O)C1CCC(Oc2ncc(Br)cn2)CC1
Reaction time: 16 h

Procedure:
To a solution of 5-bromo-2-chloro pyrimidine (1.00 g, 5.17 mmol) and ethyl 4-hydroxycyclohexanoate (0.834 mL, 5.17 mmol) in DMF (20 mL) was added sodium hydride NaH (60% weight in mineral oil, 0.227 g, 5.69 mmol). The reaction mixture was stirred for 16 hours before being diluted with saturated aqueous sodium bicarbonate (50 mL), ethyl acetate (50 mL), and diethyl ether (50 mL). The layers were separated and the organic layer was washed with water (3×50 mL) and then brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (ethyl acetate/hexanes) to yield ethyl 4-[(5-bromopyrimidin-2-yl)oxy]cyclohexanecarboxylate as a mixture of cis and trans isomers. MS ESI calc'd. for C13H18BrN2O3 [M+H]+ 329 and 331. found 329 and 331.
Reaction SMILES: [NH:1]([CH2:6][C:7]([OH:9])=[O:8])[CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].[OH:12][CH:13]([C:15](=[CH2:19])[C:16]([O-:18])=[O:17])[CH3:14]>O>[C:16]([CH:15]([CH:13]([OH:12])[CH3:14])[CH2:19][N:1]([CH2:6][C:7]([OH:9])=[O:8])[CH2:2][C:3]([OH:5])=[O:4])([OH:18])=[O:17]
Reactant: O=C(O)CNCC(=O)O
Reactant: C=C(C(=O)[O-])C(C)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(O)C(CN(CC(=O)O)CC(=O)O)C(=O)O
Temperature: 80 °C
Reaction time: 20 h
Yield: 49 %

Procedure:
(0.1 mole) of iminodiacetic acid were suspended in 100 ml. of water and neutralized with sodium hydroxide to pH=10-12. 14.4 g (0.1 mole) ethyl----2--(1--hydroxyethyl)propenoate was added and the pH was maintained at 10-12 by further addition of sodium hydroxide. The reaction mixture was stirred at 80°C for 20 hours and then cooled at room temperature and acidified to pH=2. The solvent was distilled under reduced pressure to one-third of the weight of the solution and sodium chloride was filtered off. The filtrate was poured in 400 ml. of methanol/acetone (50/50) and the precipitate was washed with acetone and dried in vacuum to 12.3 g of a white powder. The yield was 49% of theoretical.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH2:15][CH2:16][NH:17][CH2:18][CH:19]=3)=[CH:10][C:9]=2[F:20])=[N:6][CH:7]=1.C(N(CC)CC)C.[Cl:28][CH2:29][C:30](Cl)=[O:31]>ClCCl.CN(C)C=O>[Cl:28][CH2:29][C:30]([N:17]1[CH2:16][CH:15]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:5]3[N:6]=[CH:7][C:2]([F:1])=[CH:3][N:4]=3)=[C:9]([F:20])[CH:10]=2)[CH2:19][CH2:18]1)=[O:31]
Reactant: O=C(Cl)CCl
Reactant: Fc1cnc(-c2ccc(C3=CCNCC3)cc2F)nc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)N1CC=C(c2ccc(-c3ncc(F)cn3)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
5-Fluoro-2-[2-fluoro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-pyrimidine (22AB) (1.94 g, 7.1 mmol, 1 equiv) was dissolved in a (3v:1v) mixture of dichloromethane (30 mL) and N,N-dimethyl formamide (10 mL) and triethylamine (862 mg, 1.19 mL, 8.52 mmol, 1.2 equiv) was added, followed by slow addition of chloroacetyl chloride (962 mg, 678 uL, 8.52 mmol, 1.2 equiv) at room temperature. The mixture was then stirred for about 4 hours at room temperature.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[C:15](OC)=[O:16].[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[CH2:15][OH:16]
Reactant: COC(=O)c1cc(OC)c2ccccc2c1OC
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1cc(CO)c(OC)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
A solution of 5.32 g of methyl 1,4-dimethoxy-2-naphthoate [prepared as described in step (a) above] in 15 ml of tetrahydrofuran was added dropwise to a suspension of 0.98 g of lithium aluminum hydride in 15 ml of tetrahydrofuran, whilst ice-cooling. The resulting mixture was then stirred at room temperature for 1 hour, after which 20 ml of a saturated aqueous solution of ammonium chloride was added. The precipitate which formed was filtered off, and then the product was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and then concentrated by evaporation under reduced pressure, to give 3.97 g of the title compound as a pale yellow solid, melting at 63°-66° C.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[O:21][C:8]2=[C:9]3[C:14](=[C:15]([CH3:17])[CH:16]=[C:7]2[CH2:6]1)[NH:13][C:12](=[O:18])[CH2:11][C:10]3([CH3:20])[CH3:19])=[N+]=[N-].[H][H]>CN(C)C=O.[Pd]>[NH2:1][CH2:4][CH:5]1[O:21][C:8]2=[C:9]3[C:14](=[C:15]([CH3:17])[CH:16]=[C:7]2[CH2:6]1)[NH:13][C:12](=[O:18])[CH2:11][C:10]3([CH3:19])[CH3:20]
Reactant: Cc1cc2c(c3c1NC(=O)CC3(C)C)OC(CN=[N+]=[N-])C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Product: Cc1cc2c(c3c1NC(=O)CC3(C)C)OC(CN)C2

Procedure:
The compound obtained in Example 265 (2.69 g, 9.41 mmol) was dissolved in N,N-dimethylformamide (40 ml). To the resultant solution, 10% palladium-on-carbon (1.2 g) was added, followed by stirring at room temperature for 3 hours in the atmosphere of hydrogen.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[O:7]1[CH2:12][CH2:11][CH:10]([CH2:13][C:14](O)=[O:15])[CH2:9][CH2:8]1>C1COCC1>[O:7]1[CH2:12][CH2:11][CH:10]([CH2:13][CH2:14][OH:15])[CH2:9][CH2:8]1
Reactant: O=C(O)CC1CCOCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCC1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.1 %

Procedure:
To a suspension of 0.55 g of LiAlH4 (13.9 mmol) in THF (10 mL) is added dropwise a solution of 2 g (13.9 mmol) of (tetrahydro-pyran-4-yl)-acetic acid in THF (10 mL) under nitrogen atmosphere (CAUTION: highly exothermic reaction!). Upon complete addition, the reaction is stirred at room temperature for 18 h. The reaction is cooled in an ice-bath and quenched with addition of 1M aqueous NH4Cl solution (2 mL). The resulting precipitate is removed by filtration through Celite® and is rinsed with ethyl acetate (3×100 mL). The filtrate is dried over Na2SO4, filtered and concentrated under reduced pressure to afford 1.63 g of 2-(tetrahydro-pyran-4-yl)-ethanol as a colorless oil. Yield: 90%; ES-MS m/z 131 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11](=[O:14])[O:12][CH:13]=2)=[CH:5][CH:4]=1.[C:15]([O:19][CH3:20])(=[O:18])[CH:16]=[CH2:17].B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[NH:10][C:11](=[O:14])[O:12][C:13]=2[CH:16]([CH3:17])[C:15]([O:19][CH3:20])=[O:18])=[CH:7][CH:8]=1
Reactant: C=CC(=O)OC
Reactant: COc1ccc(-c2coc(=O)[nH]2)cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COC(=O)C(C)c1oc(=O)[nH]c1-c1ccc(OC)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 20.7 %

Procedure:
4-(4-Methoxyphenyl)-2-oxo-4-oxazoline (1.00 g), methyl acrylate (0.94 mL) was dissolved in toluene (20 mL) and boron trifluoride etherate (1.31 mL) was added. The obtained mixture was heated to 90° C., and after stirring for 2 h, the solvent was concentrated under reduced pressure to give an oily substance. The obtained oily substance was subjected to silica gel column chromatography and eluted with n-hexane-ethyl acetate (1:1). The solvent was evaporated and the obtained oil was crystallized from ethanol. Isopropyl ether (10 mL) was added and the mixture was stirred at not higher than 5° C. for 1 h. The crystals were collected by filtration and washed with isopropyl ether to give the title compound (0.30 g; yield 20.7%) as gray-white crystals.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].[CH3:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([CH3:26])[CH:25]=1)[C:20]([OH:22])=O>CCCCCCC.CCOC(C)=O>[CH3:26][C:24]1[CH:23]=[C:19]([CH:18]=[C:17]([CH3:16])[CH:25]=1)[C:20]([N:2]([CH3:1])[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])=[O:22]
Reactant: Cc1cc(C)cc(C(=O)O)c1
Reactant: CNc1cnccc1-c1ccccc1C
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Cc1cc(C)cc(C(=O)N(C)c2cnccc2-c2ccccc2C)c1

Procedure:
The title compound was prepared in analogy to example 90, from N-methyl-4-o-tolylpyridin-3-amine (example 1, intermediate a) and 3,5-dimethylbenzoic acid (CAS RN 499-06-9) and using a gradient of n-heptane:EtOAc (100:0 to 0:100) for the chromatographic purification. Brown oil (3%). MS (ESI): m/z=331.18 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([O:28][CH3:29])[C:23]([O:25]CC)=[O:24])=[CH:17][CH:16]=1)[CH3:11].[OH-].[Na+]>O.CC(C)=O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([O:28][CH3:29])[C:23]([OH:25])=[O:24])=[CH:17][CH:16]=1)[CH3:11]
Reactant: CCOC(=O)C(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: COC(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)C(=O)O
Temperature: 25 °C
Yield: 76.4 %

Procedure:
Lipase from Rhizopus delemar (300 mg, ex Biocatalysts Ltd.) was stirred in deionised water (125 ml) and the pH of the mixture adjusted to 7.0. To this mixture, at ambient temperature (23° C.), was added a solution of methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-methoxypropanoate (690 mg) (enantiomer ratio 8:92 as prepared in example 1) in acetone (5 ml). The resulting reaction mixture was stirred at ambient temperature and pH 7.0 was maintained by autotitration with 0.1M sodium hydroxide solution until hydrolysis was complete. 0.1M Sodium hydroxide solution was added to bring the reaction mixture to pH 9.5 after which it was washed with dichloromethane. The aqueous phase was acidified with hydrochloric acid to pH1 and the acid extracted into dichloromethane, washed, dried (magnesium sulphate), and evaporated. The resulting solid was triturated with hexane to yield 490 mg of (+)3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-methoxypropanoic acid as a white solid; m.p. 121°-123° C.; enantiomer ratio 92:8 (by HPLC assay); [α]D25 +13°, MeOH, c 0.5. Enantiomer ratios of 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-methoxypropanoic acid were determined by HPLC on a chiral AGP column eluting with 4.8% acetonitrile in 0.01M sodium dihydrogen phosphate solution at pH 7.0 and detecting products by UV monitoring at 245 nm. Enantiomer ratios are quoted in the order of elution.
Reaction SMILES: C(OC([N:8]([C:16]1[C:21]([C:22]#[CH:23])=[N:20][C:19]([C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH:33]([CH3:35])[CH3:34])(=[O:32])=[O:31])=[CH:26][CH:25]=2)=[CH:18][N:17]=1)C(=O)OC(C)(C)C)=O)(C)(C)C.[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)(C(F)(F)F)=O>C1COCC1.C(Cl)Cl.Cl[Pd]Cl.[Cu]I>[NH2:8][C:16]1[C:21]([C:22]#[C:23][C:36]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:43])=[N:20][C:19]([C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH:33]([CH3:34])[CH3:35])(=[O:32])=[O:31])=[CH:26][CH:25]=2)=[CH:18][N:17]=1
Reactant: C#Cc1nc(-c2ccc(S(=O)(=O)C(C)C)cc2)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: O=C(Cl)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(C#CC(=O)c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-butyl N-tert-butoxycarbonyl-N-[3-ethynyl-5-(4-isopropylsulfonylphenyl)pyrazin-2-yl]carbamate (200 mg, 0.3987 mmol), benzoyl chloride (56.04 mg, 46.28 μL, 0.3987 mmol), TEA (44.38 mg, 61.13 μL, 0.4386 mmol) was added to a solution of dichloropalladium; triphenylphosphane (27.98 mg, 0.03987 mmol) and CuI (15.19 mg, 0.07974 mmol) in degassed THF (4 mL). The reaction mixture was stirred overnight at ambient temperature. The reaction mixture was concentrated in vacuo. The residue was partitioned between DCM and NaHCO3 aq sat. The combined organic extract was dried (MgSO4) and concentrated in vacuo yielding an oil that was dissolved in DCM (10 mL). TFA (1 mL) was added and the mixture was stirred at ambient temperature for 30 min. The mixture was concentrated in vacuo to provide the sub-titled product which was used in the next reaction without further purification. LC/MS m/z 406.1 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:10][CH2:11][CH2:12][OH:13])[CH:3]=[CH:2]1.O1CCOCC1.[H-].[Na+].Cl[C:23]1[C:28]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[N:27][CH:26]=[CH:25][N:24]=1>O>[N:29]1([C:28]2[C:23]([O:13][CH2:12][CH2:11][O:10][C:8]3[CH:7]=[CH:6][CH:5]=[C:4]4[C:9]=3[NH:1][CH:2]=[CH:3]4)=[N:24][CH:25]=[CH:26][N:27]=2)[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1
Reactant: OCCOc1cccc2cc[nH]c12
Reactant: Clc1nccnc1N1CCNCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: c1cc(OCCOc2nccnc2N2CCNCC2)c2[nH]ccc2c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
The product obtained in Step 1 above (0.200 g, 1 .13 mmol) and dioxane (4 mL) was placed in a reaction tube and NaH (60% in oil; 0.060 g, 1.50 mmol) was added. When the gas evolution had ceased, 2-chloro-3-(1-piperazinyl)pyrazine (0.228 g, 1.15 mmol. from Example 90, Step 1) was added and the tube sealed. The mixture was stirred at 100° C. for 3 h. After cooling, the reaction mixture was poured into water and extracted with EtOAc. The organic layer was extracted with 0.5 M aqueous HCl. The pH of the aqueous phase was adjusted to pH 11 with NaOH and extracted with EtOAc. The organic layer was dried (MgSO4) and concentrated to give 0.31 g (81%) of the title product. Pos-EI-MS shows M+ and 9 ions supporting the stated structure HRMS m/z calcd for C18H21N5O2 (M)+ 339.1695, found 339 1696.
Reaction SMILES: Br[CH2:2][C:3]([F:15])=[CH:4][C:5]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)([CH3:7])[CH3:6].C(=O)([O-])[O-].[K+].[K+].[F:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][C:24]=1[O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1(C)C=CC=CC=1.C(O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]([CH3:7])([CH3:6])[CH:4]=[C:3]([F:15])[CH2:2][C:26]2[CH:27]=[CH:28][C:23]([F:22])=[C:24]([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:25]=2)=[CH:9][CH:10]=1
Reactant: CC(C)(C=C(F)CBr)c1ccc(Cl)cc1
Reactant: OB(O)c1ccc(F)c(Oc2ccccc2)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C=C(F)Cc1ccc(F)c(Oc2ccccc2)c1)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 91 %

Procedure:
Under a nitrogen atmosphere, a mixture of 1-bromo-4-(p-chlorophenyl)-2-fluoro-4-methyl-2-pentene, (Z)- (320.8 mg, 1.1 mmol), bis(dibenzylideneacetone)palladium(0) (Pd(dba)2, 31.6 mg, 0.055 mmol) in toluene (8 mL) is treated with potassium carbonate (608 mg, 4.4 mmol), degassed, treated with a solution of 4-fluoro-3-phenoxybenzeneboronic acid (331.8 mg, 1.43 mmol) in ethanol (2 mL), refluxed for 45 minutes, cooled to room temperature, and filtered through diatomaceous earth. The filtrate is diluted with ethyl acetate, and the resultant solution is washed sequentially with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a residue. Flash column chromatography of the residue using silica gel and a 1:9 ethyl acetate/hexanes solution gives the title product as a colorless liquid (401 mg, 91% yield) which is identified by NMR spectral analyses.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[O:21][CH:20]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:19][CH2:18]2)([O-])=O.C1(C2CCC3C(=CC=C(OC4C=CC=CC=4N)C=3)O2)C=CC=CC=1>C(O)(=O)C.[Zn]>[F:13][C:10]([F:11])([F:12])[C:8]1[CH:7]=[CH:6][C:5]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[O:21][CH:20]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:19][CH2:18]3)=[C:4]([CH:9]=1)[NH2:1]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Oc1ccc2c(c1)CCC(c1ccccc1)O2
Agent: Nc1ccccc1Oc1ccc2c(c1)CCC(c1ccccc1)O2
Agent: [Zn]
Solvent: CC(=O)O
Product: Nc1cc(C(F)(F)F)ccc1Oc1ccc2c(c1)CCC(c1ccccc1)O2

Procedure:
2-Nitro-1-(2-phenylchroman-6-yloxy)-4-trifluoromethylbenzene (0.311 g) was reduced in 25 ml of glacial acetic acid with zinc (1.48 g) as described for 2-(2-phenylchroman-6-yloxy)-aniline in Example 29. Product was purified by column chromatography (CH2Cl2:n-heptane/70:30 as the eluant). 1H-NMR (300 MHz; d6-DMSO): δ 7.48-7.28 (m, 5H), 7.06 (d, 1H, J=2.2 Hz), 6.86 (dd, 1H, J=7.8 Hz, J=1.5 Hz), 6.85-6.56 (m, 3H), 6.72 (d, 1H, J=8.4 Hz), 5.40 (s, 2H), 5.10 (dd, 1H, J=10.0 Hz; J=2.3 Hz), 3.04-2.87 (m, 1H), 2.78-2.65 (m, 1H), 2.24-2.10 (m, 1H), 2.08-1.89 (m, 1H).