Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([C:25]2([OH:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15](CC3C=CC=CC=3)[CH2:14][CH2:13]2)[CH:6]=[CH:7][CH:8]=1.C([O-])=O.[Na+].C(O)=O>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([C:25]2([OH:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]2)[CH2:10][CH2:11][N:12]2[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C(=CCN2CCN(Cc3ccccc3)CC2)C2(O)CCCCC2)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: CCO
Product: COc1cccc(C(CCN2CCNCC2)C2(O)CCCCC2)c1

Procedure:
A solution of 1-[1-(3-methoxyphenyl)-3-[4-(phenylmethyl)-1-piperazinyl]-1-propenyl]cyclohexanol (3.09 g, 7.1 mmole) in ethanol (50 mL) containing sodium formate (0.5 g, 7.1 mmole) and formic acid (1.5 g, 30 mmole) was added to a suspension of 10% Pd/C (3.0 g) in ethanol (50 mL) and the mixturre refluxed for 2 hours under nitrogen. The catalyst was filtered and the filtrate evaporated. The residue was partitioned between 4N sodium hydroxide (200 mL) and ethyl acetate (200 mL). The layers were separated. The aqueous phase was extracted with ethyl acetate. The combined organic solution was washed with brine, dried over magnesium sulfate and evaporated to obtain the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10](Cl)[C:9]2[C:4](=[C:5]([Br:13])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:14]1([OH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[K+]>C(Cl)Cl>[CH3:1][C:2]1[CH:11]=[C:10]([O:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]2[C:4](=[C:5]([Br:13])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Oc1ccccc1
Reactant: Cc1cc(Cl)c2cccc(Br)c2n1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1cc(Oc2ccccc2)c2cccc(Br)c2n1
Temperature: 120 °C
Yield: 84.9 %

Procedure:
Part B: A mixture of 5.0 g (19.5 mmol) of 2-methyl-4-chloro-8-bromo-quinoline, 18.3 g (195 mmol) of phenol and 2.5 g (87%, 39 mmol) of KOH was heated at 120° C. under nitrogen for 30 min. After cooling 500 ml of CH2Cl2 was added and the mixture was extracted with 250 ml of 1N NaOH. After concentration of the organic layer in vacuo the residue was dissolved in ether and again extracted with 50 ml of 1N NaOH and 50 ml of brine. The organic layer was dried over magnesium sulphate and concentrated in vacuo. A total of 5.2 g of 2-methyl-4-phenoxy-8-bromo-quinoline was obtained as a white solid (85% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH:8]([CH2:14]/[CH:15]=[CH:16]/[CH:17]=O)[CH2:7][CH2:6]2.[F:19][C:20]([F:35])([F:34])[C:21]1[CH:22]=[C:23]([CH2:27][NH:28][CH:29]=[CH:30][C:31](=[O:33])[CH3:32])[CH:24]=[CH:25][CH:26]=1>>[C:31]([C:30]1[CH:15]([CH2:14][CH:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]2=[O:13])[CH:16]=[CH:17][N:28]([CH2:27][C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([C:20]([F:34])([F:35])[F:19])[CH:22]=2)[CH:29]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)C=CNCc1cccc(C(F)(F)F)c1
Reactant: COc1ccc2c(c1)CCC(C/C=C/C=O)C2=O
Product: COc1ccc2c(c1)CCC(CC1C=CN(Cc3cccc(C(F)(F)F)c3)C=C1C(C)=O)C2=O

Procedure:
The title compound 65 is prepared according to the procedure reported in step D of Example 8 with aldehyde 54 (100 mg, 0.41 mmol) and enamine 66 (100 mg, 0.41 mmol) as reactants. Purification by column chromatography on SiO2 (Petroleum Ether/EtOAc=2:1) afford the title compound 65 as a pale yellow solid. (Yield 65 mg, 39%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][N:12]=1)[CH3:2].N1C=CC=CC=1.[Cl:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][C:42]=1[Cl:43])[C:37](Cl)=[O:38].Cl>C(O)C.[C].[Pd]>[Cl:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][C:42]=1[Cl:43])[C:37]([NH:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][C:9]2[CH:8]=[CH:7][C:6]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:5][C:4]=2[O:3][CH2:1][CH3:2])=[N:12][CH:13]=1)=[O:38]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)CCc1ccc(Oc2ccc([N+](=O)[O-])cn2)c(OCC)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)CCc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cn2)c(OCC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 3-[3-ethoxy-4-(5-nitropyridin-2-yloxy)phenyl]propionate (0.82 g, 2.3 mmol) in ethanol (40 mL) was added 10% palladium-carbon (0.15 g) under a nitrogen atmosphere, and the resulting solution was stirred under a hydrogen atmosphere at atmospheric pressure for 1 hour at room temperature. The palladium-carbon was removed by filtration, and the filtrate was concentrated. The obtained filtrate (0.58 g) was dissolved in dichloromethane (30 mL), and to the resulting solution were added pyridine (0.17 mL, 2.1 mmol) and 3,4-dichlorobenzoyl chloride (0.39 g, 1.84 mmol) under ice cooling. The resulting solution was stirred under ice cooling for 1 hour, and then stirred for 12 hours at room temperature. The reaction solution was made acidic by adding 10% hydrochloric acid, and extracted with dichloromethane. The dichloromethane layer was washed with a saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and evaporated, to thereby yield 0.94 g of the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.Br[CH2:15][C:16]#[CH:17]>>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:17][C:16]#[CH:15])=[CH:9][CH:8]=1
Reactant: C#CCBr
Reactant: Oc1ccc(Cc2ncc[nH]2)cc1
Product: C#CCOc1ccc(Cc2ncc[nH]2)cc1

Procedure:
The above compound is prepared in analogy to Example 1 from 4-(1-imidazolylmethyl)-phenol and 1-bromo-2-propyne.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[C:21]([Cl:22])=[C:20]([Cl:23])[C:10]2[S:11][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:13][C:9]=2[CH:8]=1)C.[OH-].[Na+]>C(O)C>[Cl:22][C:21]1[C:7]([O:6][CH2:5][C:4]([OH:24])=[O:3])=[CH:8][C:9]2[CH:13]=[C:12]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[S:11][C:10]=2[C:20]=1[Cl:23]
Reactant: CCOC(=O)COc1cc2cc(-c3ccccc3)sc2c(Cl)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)COc1cc2cc(-c3ccccc3)sc2c(Cl)c1Cl
Yield: 94.2 %

Procedure:
A mixture of 4.47 g of ethyl[ (6,7-dichloro-2-phenylbenzo[b]thien-5-yl)oxy]acetate and 150 ml of 95% ethanol was treated with 150 ml of 20% sodium hydroxide solution. The mixture is refluxed for 3 hours and concentrated in vacuo to remove ethanol. Acidification at 0°-10°, followed by ether extraction, yields 3.9 g of [(6,7-dichloro-2-phenylbenzo[b]thien-5-yl)oxy]acetic acid as white needles, mp 209°-211°.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: BrCCCCCBr
Reactant: Oc1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: BrCCCCCOc1cccc2[nH]ccc12
Temperature: 90 °C
Reaction time: 4 h
Yield: 66 %

Procedure:
To a stirred suspension of 4-hydroxyindole (10.0 g, 75.2 mmol) and 1,5-dibromo-pentane (26.0 g, 112.8 mmol) in N-methylpyrrolidinone (100 mL) was added potassium carbonate (16.0 g, 112.8 mmol). The resulting mixture was stirred at 90° C. for 4 hours and then quenched with water (30 mL) followed by extraction with ethyl acetate (30 mL×3). The organic layers were combined, washed with brine, and then concentrated under vacuum. The resulting residue was purified by silica gel chromotography to give 4-(5-bromo-pentyloxy)-1H-indole (14.0 g, 49.6 mmol, 66%) as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:27])[C@@H:4]([N:9]1[CH2:13][C:12]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:22]([OH:25])([CH3:24])[CH3:23])[CH:16]=2)=[CH:11][C:10]1=[O:26])[CH2:5][CH:6]([CH3:8])[CH3:7].O.[OH-].[Li+]>O1CCCC1.O>[OH:25][C:22]([CH3:24])([CH3:23])[CH2:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[O:14][C:12]1[CH2:13][N:9]([C@@H:4]([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]([OH:27])=[O:2])[C:10](=[O:26])[CH:11]=1
Reactant: COC(=O)[C@H](CC(C)C)N1CC(Oc2cccc(CC(C)(C)O)c2)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C[C@@H](C(=O)O)N1CC(Oc2cccc(CC(C)(C)O)c2)=CC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
To a solution of (S)-2-{4-[3-(2-hydroxy-2-methyl-propyl)-phenoxy]-2-oxo-2,5-dihydro-pyrrol-1-yl}-4-methyl-pentanoic acid methyl ester (0.480 g, 1.28 mmol) in tetrahydrofuran (10 mL) and water (2 mL) was added lithium hydroxide monohydrate (0.058 g 1.35 mmol). The mixture was stirred at room temperature for 2 h. The reaction mixture was poured into water and washed with diethyl ether. The aqueous phase was acidified with 1N aqueous hydrochloric acid solution (pH<2), and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was precipitated from dichloromethane with an excess of hexanes to afford (S)-2-{4-[3-(2-hydroxy-2-methyl-propyl)-phenoxy]-2-oxo-2,5-dihydro-pyrrol-1-yl}-4-methyl-pentanoic acid (0.410 g, 89%), as an off-white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23]([NH2:25])=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23](=[S:35])[NH2:25])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCc1ccc(C2CC(C(N)=O)CN(C(=O)N3CCOCC3)C2)cc1
Product: CCc1ccc(C2CC(C(N)=S)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
910 mg (2.63 mmol) of 5-(4-ethylphenyl)-1-(morpholin-4-ylcarbonyl)piperidine-3-carboxamide (Example 139A) and 586 mg (1.45 mmol) of Lawesson reagent were reacted according to the General Method 10A. Yield: 849 mg (89% of theory).
Reaction SMILES: [C:1]12([C:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:14][C:15]1[CH:16]=[C:17]([O:23][CH3:24])[C:18]([O:21][CH3:22])=[CH:19][CH:20]=1>C(N(CC)CC)C>[CH3:24][O:23][C:17]1[CH:16]=[C:15]([NH:14][C:11]([C:1]23[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]4)[CH2:2]2)[CH2:8]3)=[O:12])[CH:20]=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: COc1ccc(N)cc1OC
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)C23CC4CC(CC(C4)C2)C3)cc1OC

Procedure:
Subject 1.35 g. (6.8 mmoles) of adamantane carboxylic acid chloride, 1.0 g. (6.5 mmoles) of 4-amino veratrole and 4.0 ml. of triethylamine to the process of Example 11 and obtain thereby the title product, m.p. 224°-226°C.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[CH2:8][CH2:9][CH2:10][C:11]1[N:15]([C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:14]=[N:13][N:12]=1.[Cl:35][C:36]1[CH:37]=[C:38]([OH:57])[CH:39]=[CH:40][C:41]=1[CH:42]([CH3:56])[C:43]([C:49]1[CH:54]=[CH:53][N:52]=[C:51]([Cl:55])[CH:50]=1)([OH:48])[C:44]([F:47])([F:46])[F:45].O>CN1CCCC1=O>[Cl:55][C:51]1[CH:50]=[C:49]([C:43]([OH:48])([CH:42]([C:41]2[CH:40]=[CH:39][C:38]([O:57][CH2:8][CH2:9][CH2:10][C:11]3[N:15]([C:16]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:14]=[N:13][N:12]=3)=[CH:37][C:36]=2[Cl:35])[CH3:56])[C:44]([F:47])([F:46])[F:45])[CH:54]=[CH:53][N:52]=1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Reactant: ClCCCc1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(c1ccc(OCCCc2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Temperature: 60 °C
Yield: 51.5 %

Procedure:
To a suspension of K2CO3 (93 mg), KI (90 mg) in N-methyl-2-pyrrolidone (0.5 mL) were added 5-(3-chloropropyl)-1-(triphenylmethyl)-1H-tetrazole (137 mg, CAS 823797-34-8, preparation see Bosmans et al., WO2005003124 A1, page 23) and 3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenol (99 mg, Example 133). The mixture was heated to 60° C. for 20 hours and TLC confirmed almost complete conversion. The mixture was allowed to cool and poured into water. The aqueous layer was extracted with ethyl acetate and the organic extracts were washed with brine, dried and evaporated. The residue was purified by flash chromatography (silica gel, gradient of ethyl acetate in heptane) to give the title compound as a colorless solid (100 mg). MS (neg. ion, m/e)=716.2 ((M−H)−).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:6]=[CH:7][CH:8]=1.C1CCN2C(=NCCC2)CC1>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)C=C1CCCCC1c1cccc(OC)c1
Solvent: c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)CC1=C(c2cccc(OC)c2)CCCC1
Reaction time: 72 h
Yield: 93.3 %

Procedure:
To a solution of ethyl [2-(3-methoxyphenyl)-cyclohexylidene]acetate (1.5 g) in benzene (20 ml) was added 1,8-diazabicyclo[5.4.0]-7-undecene (1 ml) and the mixture was stirred for 3 days under reflux. And then the mixture was washed with water, 1N-hydrochloric acid, saturated sodium bicarbonate aqueous solution, and brine. The dried solvent was evaporated to give 1-(3-methoxyphenyl)-2-(ethoxycarbonylmethyl)cyclohexene (1.4 g).
Reaction SMILES: [CH3:1][C:2]([CH3:53])([CH3:52])[CH2:3][NH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]4[N:26]=[CH:25][N:24](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:23]=4)[CH:20]=3)[N:15](C3CCCCO3)[N:14]=2)[CH:8]=1)=[O:6].Cl.C(=O)(O)[O-].[Na+]>O1CCOCC1>[NH:23]1[C:22]([C:19]2[CH:20]=[C:21]3[C:16](=[CH:17][CH:18]=2)[NH:15][N:14]=[C:13]3[C:9]2[CH:8]=[C:7]([C:5]([NH:4][CH2:3][C:2]([CH3:53])([CH3:52])[CH3:1])=[O:6])[CH:12]=[CH:11][CH:10]=2)=[N:26][CH:25]=[N:24]1
Reactant: CC(C)(C)CNC(=O)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)CNC(=O)c1cccc(-c2n[nH]c3ccc(-c4ncn[nH]4)cc23)c1
Temperature: 60 °C
Yield: 21.2 %

Procedure:
To a stirred solution of N-(2,2-dimethylpropyl)(3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenyl methyl)(1,2,4-triazol-3-yl)](1H-indazol-3-yl)}phenyl)carboxamide (0.337 g, 0.481 mmol) was added dioxane (4.0 mL) and aqueous 6 N hydrochloric acid (4.0 mL) and the mixture heated at 60° C. for 4 h. The mixture was cooled and poured into aqueous saturated sodium bicarbonate (50 mL). The aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and evaporated. Addition of ethyl acetate (5 mL) initiated crystal growth and the ethyl acetate layer was pipetted off. Filtration of the crystals and washing with hexanes gave the title compound (0.0381 g, 21% yield). 1H NMR (CD3OD) δ 8.80 (s, 1H), 8.60 (br t, 1H), 8.45 (t, 1H), 8.20 (dt, 1H), 8.12 (br d, 1H), 7.89 (dt, 1H), 7.70 (d, 1H), 7.67 (t, 1H), 3.27 (s, 2H), 1.01 (s, 9H). ES-MS (m/z) 375 [M+1]+
Reaction SMILES: [Mg].II.Cl[CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH3:10].[CH:11]1([CH2:14][O:15][C:16]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:17]=2[C:18]([C@@H:20]2[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]2)=[O:19])[CH2:13][CH2:12]1>C1COCC1>[CH:11]1([CH2:14][O:15][C:16]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:17]=2[C@:18]([C@@H:20]2[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:27])[CH2:21]2)([OH:19])[CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH3:10])[CH2:12][CH2:13]1
Reactant: COCCCCCl
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2cccc(F)c2OCC2CC2)C1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: COCCCC[C@@](O)(c1cccc(F)c1OCC1CC1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 91.1 %

Procedure:
A flame dried 50 mL three-necked flask was charged with magnesium turnings (380 mg, 15.8 mmol) and a small crystal of iodine in THF (5 mL). The flask was evacuated and refilled with N2. Then a solution of 1-chloro-4-methoxybutane (1.6 g, 13.2 mmol) in THF (10 mL) was added dropwise slowly to the mixture. The reaction mixture was stirred under reflux for 2.5 h and most of the magnesium was consumed. The resulting Grignard reagent was used as follows. To another 100 mL three-necked flask was added (R)-tert-butyl 3-(2-(cyclopropylmethoxy)-3-fluorobenzoyl)piperidine-1-carboxylate (0.5 g, 1.32 mmol) and THF (10 mL). The flask was evacuated and refilled with N2. The mixture was cooled with a dry ice-acetone bath and the Grignard reagent (250 mL) was added. The reaction mixture was allowed to warm slowly to rt while stirring overnight. The mixture was quenched with sat'd aq NH4Cl (10 mL), extracted with EtOAc (3×), and the combined organic layers were dried over Na2SO4 Evaporation of the solvent and purification by flash column chromatography, eluting with 10% EtOAc/PE afforded (R)-tert-butyl 3-((S)-1-(2-(cyclopropylmethoxy)-3-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate (560 mg, 91%). 1H NMR (400 MHz, CDCl3): 0.35 (m, 2H), 0.63 (m, 2H), 1.05 (m, 1H), 1.43 (s, 9H), 1.55-1.20 (m, 9H), 1.85 (m, 1H), 2.55 (m, 1H), 2.67 (m, 1H), 3.27 (s, 3H), 3.33 (m, 2H), 3.85 (m, 1H), 4.05 (m, 2H), 4.25 (m, 1H), 6.97 (m, 3H). MS (E/Z): 466 (M+H+).
Reaction SMILES: [CH2:1]([N:8]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@H:9]1[CH2:13][CH2:12][CH2:11][C:10]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][Mg]Br.O>C(OCC)C.Cl>[CH2:15]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@H:9]1[CH2:13][CH2:12][CH2:11][C@@:10]1([CH3:22])[OH:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C[Mg]Br
Reactant: O=C1CCC[C@@H]1N(Cc1ccccc1)Cc1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: C[C@@]1(O)CCC[C@@H]1N(Cc1ccccc1)Cc1ccccc1
Temperature: -78 °C
Reaction time: 4 h
Yield: 39.8 %

Procedure:
To a solution of (2S)-2-(dibenzylamino)cyclopentanone (8.31 g, 29.7 mmol) in diethyl ether (149 mL) at −78° C. is added methyl magnesium bromide (29.7 mL, 89.1 mmol, 3 M in diethyl ether) slowly. The mixture is stirred at −78° C. for 4 h and then the reaction is allowed to warm to room temperature. Water is added to the reaction, resulting in an emulsion. Aqueous 1 M hydrochloric acid is added to break up the emulsion while keeping the aqueous phase basic. The aqueous phase is extracted twice with EtOAc. The combined organic portions are dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue is purified by silica gel chromatography (10% EtOAc/hexanes) to obtain the product. The material is dissolved in 1 M hydrochloric acid and extracted four times with EtOAc. The combined organic layers are dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound as an orange solid (3.49 g, 40%). ES/MS m/z 296 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([C:17]([F:20])([F:19])[F:18])=[N:8][C:9]([C:13]([Cl:16])([F:15])[F:14])=[CH:10][C:11]=1[OH:12])=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:27](I)[CH3:28]>CC(C)=O>[Cl:16][C:13]([F:14])([F:15])[C:9]1[N:8]=[C:7]([C:17]([F:20])([F:18])[F:19])[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:11]([O:12][CH2:27][CH3:28])[CH:10]=1
Reactant: CCOC(=O)c1c(O)cc(C(F)(F)Cl)nc1C(F)(F)F
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1c(OCC)cc(C(F)(F)Cl)nc1C(F)(F)F
Yield: 82.2 %

Procedure:
This product was prepared as described in Example 4, 25.5 g (0.080 mol) of product of Example 3, 14.3 g (0.103 mol) of K2CO3, 37.5 ml (0.470 mol) of ethyl iodide in 100 ml of acetone were reacted affording 22.86 g of oil which was purified by HPLC using 3% ethyl acetate/cyclohexane as eluting solvent to give 14.73 g of solid. Crystallization in hot hexane gave 11.11 g (41.6%) of solid. A portion (0.98 g) of this solid was kugelrohr distilled at 29 Pa, pot temperature 70° C., to give 0.81 g of product as a white solid; mp 54.5°-56.5° C.
Reaction SMILES: [CH2:1]([Li])CCC.CC1(C)CCCC(C)(C)N1.[Cl:16][C:17]1[CH:22]=[N:21][CH:20]=[C:19]([Cl:23])[N:18]=1.IC>O1CCCC1>[Cl:16][C:17]1[C:22]([CH3:1])=[N:21][CH:20]=[C:19]([Cl:23])[N:18]=1
Reactant: Clc1cncc(Cl)n1
Reactant: [Li]CCCC
Agent: CC1(C)CCCC(C)(C)N1
Solvent: CI
Solvent: C1CCOC1
Product: Cc1ncc(Cl)nc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of n-butyl lithium (1.6M in hexanes; 29 mL, 47 mmol) in tetrahydrofuran (200 mL) at −30° C. was added 2,2,6,6-tetramethylpiperidine (8.6 mL, 50 mmol). This solution was allowed to warm to 0° C. over 20 minutes then cooled to −78° C. To this solution was added a solution of 2,6-dichloropyrazine (5 g, 34 mmol) in tetrahydrofuran (200 mL) dropwise via cannula. After 30 minutes, iodomethane (21 mL, 340 mmol.) was added. After 1 h, the reaction mixture was quenched with a mixture of EtOH (25 mL), THF (25 mL) and 1N aqueous HCl (5 mL). The reaction mixture was allowed to warm to room temperature then concentrated to a crude oil. The crude oil was partitioned between water (500 mL) and CH2Cl2 (500 mL). The organic layer was washed with brine (250 mL). The first aqueous layer was back-extracted with CH2Cl2 (500 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography (EtOAc/Hexanes gradient) to afford 3,5-dichloro-2-methylpyrazine as a yellow oil. LRMS (ESI) calculated for C5H4Cl2N2 [M+H]+, 163.0; found 163.1.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[C:5]([F:16])=[C:4]([F:17])[CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[F:17][C:4]1[CH:3]=[C:2]([C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[C:5]=1[F:16]
Reactant: O=C1NCCn2c1cc1c(F)c(F)cc(Br)c12
Reactant: OB(O)c1ccc(F)cc1
Product: O=C1NCCn2c1cc1c(F)c(F)cc(-c3ccc(F)cc3)c12

Procedure:
The title compound, grey solid (70 mg, 89%), MS (ISP) m/z=317.1 [(M+H)+], mp 283.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-8,9-difluoro-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 4) (75.3 mg, 0.25 mmol) and commercially available 4-fluoro-phenylboronic acid (45.5 mg, 0.325 mmol).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]2([CH2:23][OH:24])[CH2:21][O:20][C:19]([CH3:22])=[N:18]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[OH:24][CH2:23][C:17]1([CH2:16][CH2:15][C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)[CH2:21][O:20][C:19]([CH3:22])=[N:18]1
Reactant: CC1=NC(CO)(CCc2ccc(OCc3ccccc3)cc2)CO1
Agent: [Pd]
Solvent: CO
Product: CC1=NC(CO)(CCc2ccc(O)cc2)CO1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of {4-[2-(4-benzyloxy-phenyl)-ethyl]-2-methyl-4,5-dihydro-oxazol-4-yl}-methanol (26.1 g, 0.08 mol) in methanol (800 ml) is added palladium on charcoal (2.6 g, 10% wt), and the reaction mixture is stirred under hydrogen atmosphere at RT for 5 hours. The reaction mixture is then filtered through celite and concentrated under vacuum. (R/S)-4-[2-(4-Hydroxymethyl-2-methyl-4,5-dihydro-oxazol-4-yl)-ethyl]-phenol is isolated in quantitative yield after crystallization with ethyl acetate and hexanes.