Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][S:11](Cl)(=[O:13])=[O:12].[OH:15][CH2:16][CH2:17][NH:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([I:28])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>CCOC(C)=O>[CH3:10][S:11]([O:15][CH2:16][CH2:17][NH:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([I:28])=[CH:24][CH:23]=1)(=[O:21])=[O:20])(=[O:13])=[O:12]
Reactant: O=S(=O)(NCCO)c1ccc(I)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CS(=O)(=O)OCCNS(=O)(=O)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 45.3 %

Procedure:
Diisopropylethylamine (585 μl, 3.36 mmol) followed by methane sulphonyl chloride (260 μl, 3.36 mmol) was added to a stirred solution of N-(2-hydroxyethyl)-4-iodobenzenesulphonamide (Method 45; 1 g, 3.06 mmol) in EtOAc (25 ml) at 5° C., under nitrogen. The reaction was allowed to warm to ambient temperature and stirred for 24 hours. The reaction mixture was washed with 1M hydrochloric acid (3×25 ml), saturated aqueous sodium hydrogen carbonate solution (3×25 ml), brine (2×25 ml), an then dried. The volatiles were removed by evaporation and the residue purified by chromatography on silica, eluting with DCM/MeOH (100:0 increasing in polarity to 99:1) to give the title compound (562 mg, 45%) as a white solid. NMR: 3.08 (m, 2H), 3.12 (s, 3H), 4.08 (t, 2H), 7.55 (d, 2H), 7.98 (d, 2H), 8.03 (t, 1H); m/z 405.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([O:20][CH3:21])=[C:7]([O:18][CH3:19])[CH:8]=2)[N:3]=1.[CH2:22]([O:24][C:25]1[CH:26]=[C:27]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[CH2:28][N:29]1[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]1)[CH3:23]>C(O)CO>[CH3:19][O:18][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[O:20][CH3:21])[N:3]=[C:2]([NH:35][CH:32]1[CH2:33][CH2:34][N:29]([CH2:28][C:27]3[CH:36]=[CH:37][C:38]([O:39][CH3:40])=[C:25]([O:24][CH2:22][CH3:23])[CH:26]=3)[CH2:30][CH2:31]1)[N:11]=[C:10]2[N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1OC
Reactant: COc1cc2nc(Cl)nc(N3CCCCC3)c2cc1OC
Solvent: OCCO
Product: CCOc1cc(CN2CCC(Nc3nc(N4CCCCC4)c4cc(OC)c(OC)cc4n3)CC2)ccc1OC
Yield: 16 %

Procedure:
A solution of 2-chloro-6,7-dimethoxy-4-piperidin-1-yl-quinazoline (30.8 mg, 0.10 mmol 1.0 equiv; commercially available) and 1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (39.7 mg, 0.15 mmol, 1.5 equiv; intermediate A1) in ethylene glycol (2 mL) was heated by microwave irradiation to 220° C. for 20 min. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 8.7 mg (16%) of the title compound. MS (ISP): 391.4 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([N:23]2[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[C:12]([F:21])[CH:11]=1)=[O:8].[NH:29]1[CH:33]=[CH:32][CH:31]=[N:30]1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>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.CCO.O>[F:21][C:12]1[CH:11]=[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:22]=[C:2]([C:31]3[NH:30][N:29]=[CH:33][CH:32]=3)[C:3]([N:23]3[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]3)=[N:4][CH:5]=2)[CH:15]=[CH:14][C:13]=1[O:16][C:17]([F:20])([F:19])[F:18]
Reactant: c1cn[nH]c1
Reactant: O=C(Nc1ccc(OC(F)(F)F)c(F)c1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: O=C(Nc1ccc(OC(F)(F)F)c(F)c1)c1cnc(N2CC[C@@H](O)C2)c(-c2ccn[nH]2)c1

Procedure:
A mixture of (R)-5-bromo-N-(3-fluoro-4-(trifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 13.2, 100 mg, 0.215 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (104 mg, 0.321 mmol), Pd(PPh3)2Cl2 (15.2 mg, 0.022 mmol), Na2CO3 (91 mg, 0.862 mmol), DME (914 μL), water (261 μL) and EtOH (131 μL) in a MW vial was sealed, evacuated/purged 3 times with argon and subjected to MW irradiation at 125° C. for 20 min. The RM was diluted with DME (3 mL), then stirred overnight with Si-Thiol (Silicycle 1.44 mmol/g, 90 mg, 0.129 mmol). The mixture was centrifuged and the supernatant was filtered through a 0.45 μm PTFE filter and the solvent was evaporated off under reduced pressure to give a residue which was purified by preparative SFC (Column DEAP, from 15% to 20% in 6 min) to yield the title compound as a yellow transparent oil. UPLC-MS (Condition 3) tR=1.28 min, m/z=581.2 [M+H]+, m/z=580.4 [M−H]−.
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=[O:6].[F-:13].[K+]>>[F:13][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=[O:6]
Reactant: O=C1OC(=O)c2c(Cl)cccc21
Reactant: [F-]
Agent: [K+]
Product: O=C1OC(=O)c2c(F)cccc21
Temperature: 235 °C
Yield: 69 %

Procedure:
A mixture of 20 parts of 3-chlorophthalic anhydride, and 20 parts of anhydrous potassium fluoride was heated and maintained at about 235° C. for about 9 hours. The reaction mixture was then cooled and the crude product removed by vacuum distillation and recrystallized from chloroform to yield 12.65 parts of purified 3-fluorophthalic anhydride (69% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[CH3:25])=[C:15]([CH2:26]O)[CH:14]=3)[O:10][N:9]=2)[CH:7]=1.[CH2:30]([N:32](C(C)C)[CH:33](C)C)C.CS(Cl)(=O)=O.CNC>C(Cl)Cl.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[CH3:25])=[C:15]([CH2:26][N:32]([CH3:33])[CH3:30])[CH:14]=3)[O:10][N:9]=2)[CH:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1ccc(F)cc1-c1noc(-c2ccc(-c3ccccc3C)c(CO)c2)n1
Agent: CNC
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Product: COc1ccc(F)cc1-c1noc(-c2ccc(-c3ccccc3C)c(CN(C)C)c2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of Example 77 (115 mg; 0.29 mmol; 1 eq.) in DCM (6 mL) is added at 0° C. N-ethyldiisopropylamine (250 μL; 1.47 mmol; 5 eq.) and methanesulfonyl chloride (27 μL; 0.35 mmol; 1.2 eq.). After 15 min, dimethylamine (2M; 440 μL; 0.88 mmol; 3 eq.) was added and the reaction mixture stirred at room temperature for 2 hours. Water (5 mL) was added and the organic layer washed with water. The organic phase was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by mass triggered preparative HPLC (increasing amount of ACN in water) to afford the title compound as a brown oil.
Reaction SMILES: [CH3:1][C:2]12[CH2:13][NH:12][C:10]3[C:11]1=[C:6]([CH:7]=[CH:8][CH:9]=3)[NH:5][C:4](=[O:14])[CH2:3]2.[Br:15]N1C(=O)CCC1=O>C(Cl)Cl>[Br:15][C:7]1[C:6]2[NH:5][C:4](=[O:14])[CH2:3][C:2]3([CH3:1])[CH2:13][NH:12][C:10]([C:11]=23)=[CH:9][CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC12CNc3cccc(c31)NC(=O)C2
Solvent: ClCCl
Product: CC12CNc3ccc(Br)c(c31)NC(=O)C2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (±)-2a-methyl-1,2,2a,5-tetrahydropyrrolo[4,3,2-de]quinolin-4(3H)-one from Step A (525 mg, 2.79 mmol) in CH2Cl2 (15 mL) at 0° C. was added N-bromosuccinimide (496 mg, 2.79 mmol) and the mixture was allowed to warm slowly to ambient temperature. After 5 h, the reaction mixture was quenched with saturated aqueous NaHCO3 (10 mL) and extracted with EtOAc (150 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:CH3CN—100:0 to 75:25, to give the title compound. MS: m/z=267 (M+1).
Reaction SMILES: [CH2:1]([N:3]([C@@H:8]1[CH2:14][CH2:13][CH2:12][C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[C@H:9]1[OH:19])[C:4](=[O:7])[CH2:5]Cl)[CH3:2].[H-].[Na+].O>CN(C)C=O>[CH2:1]([N:3]1[C:4](=[O:7])[CH2:5][O:19][C@@H:9]2[C:10]3[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=3[CH2:12][CH2:13][CH2:14][C@@H:8]12)[CH3:2]
Reactant: CCN(C(=O)CCl)[C@@H]1CCCc2ccccc2[C@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1C(=O)CO[C@@H]2c3ccccc3CCC[C@H]21

Procedure:
The residue from Step A was dissolved in 50 ml of dimethyl formamide and added dropwise to a solution of 0.7 g (0.0146 m) of a 50% oil dispersion of sodium hydride in 50 ml of dimethyl formamide with stirring. After stirring one hour, excess sodium hydride was decomposed by the addition of water. The mixture was extracted twice with ethyl acetate and the extract was back washed with water, dilute, cold hydrochloric acid and saturated aqueous sodium bicarbonate solution. After drying (Na2SO4) the ethyl acetate solution was concentrated to dryness in vacuo to provide crude product.
Reaction SMILES: O1CCCC1.[C:6]([C:8]1([CH2:21][CH2:22][OH:23])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)#[N:7].[CH3:24][S:25](Cl)(=[O:27])=[O:26].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.C(N(CC)CC)C>[C:6]([C:8]1([CH2:21][CH2:22][O:23][S:25]([CH3:24])(=[O:27])=[O:26])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:10][CH2:9]1)#[N:7]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(CCO)CC1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(C#N)(CCOS(C)(=O)=O)CC1
Reaction time: 0.5 h

Procedure:
To 10 mL of a tetrahydrofuran solution containing 1.0 g of tert-butyl 4-cyano-4-(2-hydroxyethyl)piperidine-1-carboxylate, 0.77 mL of triethylamine was added at room temperature, thereto was added 0.37 mL of methane sulfonyl chloride under cooling with ice, and the mixture was stirred at the same temperature for 2 hours and 30 minutes. The reaction mixture was added with an aqueous saturated sodium hydrogen carbonate solution and ethyl acetate. The organic layer was separated, washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 1.3 g of a brown oily substance, tert-butyl 4-cyano-4-(2-((methylsulfonyl)oxy)ethyl)piperidine-1-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH2:13][CH:6]3[CH2:5][C:4]=2[C:3]=1[C:14]([O:16][CH3:17])=[O:15].[Br:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[S:26](Cl)(=[O:28])=[O:27]>N1C=CC=CC=1.C(Cl)Cl.C(OCC)(=O)C>[Br:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[S:26]([NH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH2:13][CH:6]3[CH2:5][C:4]=2[C:3]=1[C:14]([O:16][CH3:17])=[O:15])(=[O:28])=[O:27]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Br
Reactant: COC(=O)c1c(N)ccc2c1CC1CCCN21
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1CC1CCCN21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.2 %

Procedure:
A mixture of methyl 7-amino-2,3,9,9a-tetrahydro-1H-pyrrolo[1,2-a]indole-8-carboxylate (Intermediate 29, 0.400 g) and 2-bromo-4-fluorobenzenesulfonyl chloride (0.565 g) in pyridine (4 mL) and DCM (12 mL) was stirred at room temperature for 30 minutes. The mixture was diluted with ethyl acetate and washed with aqueous potassium carbonate solution (10%) and brine, dried (MgSO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM, with a gradient of 0-2%. The resultant solid was re-purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, containing 1% triethylamine, with a gradient of 0-100% to give a yellow solid which was again purified by chromatography on silica, eluting with a mixture of DCM and cyclohexane (50%), followed by DCM (100%). The resultant solid was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 5-30%, to give methyl 7-(2-bromo-4-fluorobenzenesulfonylamino]-2,3,9,9a-tetrahydro-1H-pyrrolo[1,2-a]indole-8-carboxylate (0.317 g) as a yellow gum.
Reaction SMILES: Cl.N[CH:3]([CH3:21])[CH2:4][CH:5]1[O:10][CH2:9][CH:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)[CH2:7][O:6]1.C([N:24](CC)CC)C.Cl[C:30]([O:32][CH2:33][CH3:34])=[O:31].Cl>ClCCl>[C:11]1([CH:8]2[CH2:9][O:10][CH:5]([CH2:4][CH2:3][CH2:21][NH:24][C:30](=[O:31])[O:32][CH2:33][CH3:34])[O:6][CH2:7]2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: CCN(CC)CC
Reactant: CC(N)CC1OCC(c2cccc3ccccc23)CO1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)NCCCC1OCC(c2cccc3ccccc23)CO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4 g (13 mmol) of 2-aminopropyl-5-(naphthalen-1-yl)-1,3-dioxane hydrochloride are stirred at ambient temperature for 10 min. with 4 ml of triethylamine in 200 ml of dichloromethane, 1.4 g (13 mmol) of ethyl chloroformate in 20 ml of dichloromethane are then added, drop by drop, and the mixture is stirred at ambient temperature for 3 h. Dilute hydrochloric acid is added, and the organic phase is separated, washed with water and with a saturated solution of sodium hydrogen carbonate, dried over magnesium sulphate, filtered and evaporated to dryness. An oil is obtained which crystallises in pentane; the solid is filtered and purified by chromatography on a silica gel column eluted with ethyl acetate. 2.4 g (7 mmol) of product are finally isolated.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:19](=[O:38])[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([CH:35]3[CH2:37][CH2:36]3)[CH:30]=2)[CH:24]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:35]1([C:31]2[CH:30]=[C:29]([C:25]3[CH:24]=[C:23]([C:21]4[CH2:20][C:19](=[O:38])[NH:18][C:9]5[CH:10]=[C:11]([C:14]([F:15])([F:17])[F:16])[CH:12]=[CH:13][C:8]=5[N:7]=4)[CH:28]=[CH:27][CH:26]=3)[CH:34]=[CH:33][N:32]=2)[CH2:36][CH2:37]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccnc(C3CC3)c2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-c3ccnc(C4CC4)c3)c2)=Nc2ccc(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from (2-{3-[3-(2-cyclopropyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M266) (274 mg, 0.51 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (168 mg, 78%).
Reaction SMILES: Br[CH:2]1[C:7]([CH3:9])([CH3:8])[O:6][C:5]2[CH:10]=[CH:11][S:12][C:4]=2[CH:3]1O.[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.CN(C)C=[O:23]>>[OH:23][CH:2]1[C:7]([CH3:9])([CH3:8])[O:6][C:5]2[CH:10]=[CH:11][S:12][C:4]=2[CH:3]1[N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C1CCNCC1
Reactant: CN(C)C=O
Reactant: CC1(C)Oc2ccsc2C(O)C1Br
Product: CC1(C)Oc2ccsc2C(N2CCCCC2)C1O

Procedure:
The title compound was prepared as described in Example 18 starting with 6-bromo-5,6-dihydro-7-hydroxy-5,5-dimethyl-7H-thieno[3,2-b]pyran (1.5 g, 5.7 mmol) and piperidine (1.7 mL, 17.1 mmol) in N,N-dimethylformamide (25 mL) to give an off white solid, 0.977 (64%): mp 68°-70° C.; IR (KBr): 2937, 1549 and 1396 cm-1 ; MS: m/z 162 (MH+); 1H NMR (CDCl3): δ1.20(s, 3H), 1.50(s, 3H), 1.52(m, 2H), 1.61(m, 4H), 2.65(m, 2H), 2.78(m, 2H), 3.20(bs, 1H, exchanges with D2O), 3.55(d, J=9.3 Hz, 1H), 3.68(d, J=9.3 Hz, 1H), 6.58(d, J=5.4 Hz, 1H) and 7.04(d, J=5.4 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:16][C:17](=O)[CH3:18]>CC(C)=O.ClC1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[S:8][CH:16]=[C:17]([CH3:18])[C:4]=2[CH:3]=1
Reactant: CC(=O)CCl
Reactant: Sc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: Clc1ccccc1
Product: Cc1csc2ccc(Br)cc12
Yield: 52 %

Procedure:
A mixture of 4-bromothiophenol (3.9 g, 20 mmol), K2CO3 (5.5 g, 40 mmol) and chloroacetone (6.6 mL, 82 mmol) in acetone (50 mL) was heated at reflux over night. The reaction mixture was filtered and the solvent was evaporated giving 5.0 g crude product. The intermediate thioether was dissolved in chlorobenzene (50 mL) and polyphosphoric acid (PPA, 2.5 g) was added (Plé et al., (1988) J. Heterocyclic Chem. 25, 1271-1272). After reflux for 24 h, the solvent was decanted and the PPA residue was treated with CH2Cl2. The combined organic extracts were washed with water and dried. Evaporation of the solvents afforded the crude product which was purified on silica (heptane as eluent) to give the title compound (2.36 g, 50% over two steps). 1H NMR (400 MHz, CDCl3) δ ppm 2.41 (d, J=1.20 Hz, 3 H) 7.11 (qd, J=1.20, 0.54 Hz, 1 H) 7.44 (ddd, J=8.53, 1.90, 0.54 Hz, 1 H) 7.70 (dd, J=8.53, 0.54 Hz, 1 H) 7.85 (dd, J=1.90, 0.54 Hz, 1 H).
Reaction SMILES: [Na].[Cl:2][C:3]1[C:15]([Cl:16])=[C:14]([O:17][CH2:18][C:19]#[N:20])[CH:13]=[C:12]2[C:4]=1[C:5]1[C:10]([CH2:21][CH2:22][CH3:23])([CH2:11]2)[CH2:9][CH2:8][C:7](=[O:24])[CH:6]=1.Cl.Cl.[CH2:27](N)[CH2:28][NH2:29].Cl>CO>[Cl:2][C:3]1[C:15]([Cl:16])=[C:14]([O:17][CH2:18][C:19]2[NH:29][CH2:28][CH2:27][N:20]=2)[CH:13]=[C:12]2[C:4]=1[C:5]1[C:10]([CH2:21][CH2:22][CH3:23])([CH2:11]2)[CH2:9][CH2:8][C:7](=[O:24])[CH:6]=1
Reactant: CCCC12CCC(=O)C=C1c1c(cc(OCC#N)c(Cl)c1Cl)C2
Reactant: NCCN
Agent: Cl
Agent: [Na]
Solvent: CO
Product: CCCC12CCC(=O)C=C1c1c(cc(OCC3=NCCN3)c(Cl)c1Cl)C2
Reaction time: 4 h

Procedure:
To a solution of sodium metal (20 mg) in methanol (30 ml) was added (+) [(5,6-dichloro-2,3,9,9a-tetrahydro-3-oxo-9a-propy-1H-fluoren-7-yl)oxy]-acetonitrile (1.05 g, 3.0 mMole). The reaction mixture was stirred for 11/4 hours in a nitrogen atmosphere then treated with ethylenediamine dihydrochloride (410 mg, 3.1 mMole) and stirring was continued for 2 hours. Ethanolic hydrogen chloride was added until the reaction mixture was just acidic. After 1/2 hour, the methanol was distilled at reduced pressure, the residue dissolved in water, treated with 10N sodium hydroxide (1 ml), extracted with ether containing 5% tetrahydrofuran, washed with water, brine, dried over potassium carbonate and evaporated to dryness to give the (+)-enantiomer of 2-[(5,6-dichloro-2,3,9,9a-tetrahydro-3-oxo-9a-propyl-1H-fluoren-7-yl)-oxymethl]imidazoline which melts at 152°-154° C.
Reaction SMILES: Cl.[F:2][C:3]([F:27])([F:26])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[N:18]=[CH:19][C:20]([C:23](O)=[O:24])=[N:21][CH:22]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH2:58][CH:59]1[CH2:64][CH2:63][N:62]([C:65]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66])[CH2:61][CH2:60]1>CN(C)C=O>[F:26][C:3]([F:2])([F:27])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[N:18]=[CH:19][C:20]([C:23]([NH:58][CH:59]4[CH2:60][CH2:61][N:62]([C:65]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66])[CH2:63][CH2:64]4)=[O:24])=[N:21][CH:22]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: O=C(O)c1cnc(OC2CCN(c3ccc(C(F)(F)F)cc3)CC2)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cnc(OC3CCN(c4ccc(C(F)(F)F)cc4)CC3)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.7 %

Procedure:
To a stirred mixture of 5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)pyrazine-2-carboxylic acid hydrochloric acid salt (0.10 g, 0.25 mmol) in anhydrous N,N-dimethylformamide (3 mL) was added triethylamine (0.56 g, 0.55 mmol), 1-hydroxybenzotriazole hydrate (0.04 g, 0.3 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.06 g, 0.3 mmol), and tert-butyl 4-aminopiperidine-1-carboxylate (0.06 g, 0.3 mmol). The mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue obtained was purified by flash chromatography (silica gel, ethyl acetate/hexanes=1/1) to afford tert-butyl 4-(5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)pyrazine-2-carboxamido)piperidine-1-carboxylate (compound 19) as a white solid (0.06 g, 44%). 1H-NMR (CDCl3, 300 MHz): δ 8.89 (m, 1H), 8.06 (m, 1H), 7.50 (m, 3H), 6.96 (m, 2H), 5.33 (m, 1H), 4.10 (m, 3H), 3.64 (m, 2H), 3.25 (m, 2H), 2.95 (m, 2H), 2.15 (m, 2H), 1.97 (m, 4H), 1.56 (m, 2H), 1.47 (s, 9H) ppm; MS (ESI): 550.7 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10])#[CH:2].Br[C:12]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:13]=1[CH:14]=[O:15].C(N(CC)CC)C>CN(C)C=O>[CH3:10][O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]#[C:2][C:12]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:13]=1[CH:14]=[O:15]
Reactant: C#Cc1ccccc1OC
Reactant: COc1ccc(Br)c(C=O)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(C#Cc2ccccc2OC)c(C=O)c1
Yield: 67.3 %

Procedure:
The resulting 2-ethynylanisole (0.79 g) and 2-bromo-5-methoxybenzaldehyde (1.14 g) were reacted in dimethylformamide (50 ml) in the presence of dichloro-bis-triphenylphosphine palladium (1.0 g), cuprous iodide (0.5 g) and triethylamine (15 ml), in nitrogen atmosphere at 50° C. for 6 hr. The resulting reaction solution was evaporated, and to the resulting residue were added ethyl acetate and water. The resulting organic layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system), to give 0.95 g of the title compound as a pale yellow oil.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH2:19][C:20]([OH:22])=O)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18].P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:29]N(C=O)C>>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([C:19]2[C:20](=[O:22])[C:8]3[C:1](=[CH:3][C:4]([OH:5])=[CH:6][CH:7]=3)[O:2][CH:29]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: COc1ccc(CC(=O)O)cc1OC
Reactant: CN(C)C=O
Reactant: Oc1cccc(O)c1
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: COc1ccc(-c2coc3cc(O)ccc3c2=O)cc1OC
Yield: 80 %

Procedure:
This compounds was synthesised in the same manner as described above. Resorcinol (0.66 g, 6 mmol), 3,4-dimethoxy-phenylacetic acid (1.18 g, 6 mmol), BF3Et2O (4 ml), PCl5 (1.9 g, 9.1 mmol), DMF (5 ml and 10 ml). The precipitate formed was filtered and re-crystallized from methanol to give 3-(3,4-Dimethoxy-phenyl)-7-hydroxy-chromen-4-one as a pale orange solid (1.43 g, 80%); Rf 0.9 ethyl acetate/hexane (75/25).