Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([CH:34]=CC)=[C:20]([NH:23][C:24]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:25])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[O:37]1CCCC1>O.O=[Os](=O)(=O)=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3[C:19]([CH:34]=[O:37])=[C:20]([NH:23][C:24]([O:26][CH2:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[O:25])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: CC=Cc1c(NC(=O)OCc2ccccc2)ccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc(NC(=O)OCc4ccccc4)c(C=O)c3O2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution {(2R)-7-{[(benzyloxy)carbonyl]amino}-8-[1-propenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl 4-methylbenzenesulfonate (4.5 g, 8.84 mmole) in tetrahydrofuran (225 mL) was added OsO4 (1.65 mL, 0.270 mmole). Then a solution of NaIO4 (9.45 g, 44.2 mmole) in water (100 mL) was added dropwise. The reaction was stirred at room temperature under nitrogen overnight. Water (250 mL) was added to the mixture and it was then extracted with ethyl acetate. The organic phase was then washed with brine, dried over magnesium sulfate, filtered and evaporated to 4.45 g (>95%) of the (R)-enantiomer of the title compound as a yellow solid. 1H (CDCl3) broad singlet 10.8 δ (1 H); singlet 10.1 δ (1 H); doublet 7.9 δ (1 H); doublet 7.8 δ (2 H); multiplet 7.4 δ (7 H); doublet 7.0 δ (1 H); singlet 5.2 δ (2 H); multiplet 4.5 δ (1 H); multiplet 4.2 δ (3 H); multiplet 4.1 δ (1 H); singlet 2.4 δ (3 H).
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(Cl)[Cl:19]>>[ClH:19].[C:6]([O:5][C:3](=[O:4])[CH2:2][NH:17][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: ClCCl
Product: CC(C)(C)OC(=O)CNCc1ccccc1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-Berzylglycine t-butyl ester ##STR118## A solution of t-butyl bromoacetate (1.5 mL, 10.1 mmol) in CH2Cl2 (10 mL) was added dropwise to a stirred solution of benzylamine (10.9 mL, 100 mmol) in CH2Cl2 (40 mL) at 0° C., the mixture was stirred for 1 h and then warmed to room temperature and stirred for an additional 3 d. The mixture was washed with water (3×50 mL), dilute HCl (1 N) and the combined aqueous washings were extracted with Et2O. The organic phase was washed with saturated aqueous NaHCO3, dried (Na2SO4) and evaporated in vacuo. The residue was dissolved in Et2O, treated with a solution of HCl in ether (0.5 M) and the resulting precipitate was collected and dissolved in EtOAc. This solution was filtered through hyflo, and partially evaporated in vacuo to give a thick slurry. The solid was collected by filtration, washed with Et2O and then dried to give N-benzylglycine t-butyl ester hydrochloride (1.03 g, 4.00 mmol) as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH2:12][CH2:11][CH2:10]2.[CH3:16][C:17]1[S:18][C:19]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C@H:28]([OH:36])[CH2:29][N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[CH:22][C:20]=2[N:21]=1.CCN(C(C)C)C(C)C>CCO>[CH2:12]1[C:13]2[C:9](=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:33]3[CH2:34][CH2:35][N:30]([CH2:29][C@@H:28]([OH:36])[CH2:27][O:26][C:23]4[CH:24]=[CH:25][C:19]5[S:18][C:17]([CH3:16])=[N:21][C:20]=5[CH:22]=4)[CH2:31][CH2:32]3)=[CH:15][CH:14]=2)[CH2:10][CH2:11]1
Reactant: Cc1nc2cc(OC[C@H](O)CN3CCNCC3)ccc2s1
Reactant: BrCCCCOc1ccc2c(c1)CCC2
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cc(OC[C@H](O)CN3CCN(CCCCOc4ccc5c(c4)CCC5)CC3)ccc2s1
Temperature: 25 °C

Procedure:
A solution of 4-bromo-1-indan-5-yloxybutane (934 mg, 3.46 mmol, crude) in EtOH (10 mL) was treated with (2R)-1-(2-methylbenzothiazol-5-yloxy)-3-piperazinylpropan-2-ol as prepared in Example 3A (250 mg, 0.81 mmol) and DIEA (0.57 mL, 3.3 mmol) and refluxed for 14 hours. Upon cooling to RT, the solution was then concentrated under reduced pressure and purified via an Isco™ (100% EtOAc 4 min, 10 min gradient to 25% MeOH/EtOAc, hold 6 min.) to afford (2R)-3-[4-(4-indan-5-yloxybutyl)piperazinyl]-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[N:9]2)[CH:5]=[CH:4][C:3]=1[OH:17].O[CH:19]([C:23]1[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:24]=1)[CH2:20][CH2:21][CH3:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC=[N+]=[N-])=O)=NC([O-])=O>O1CCCC1>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[N:9]2)[CH:5]=[CH:4][C:3]=1[O:17][CH:19]([C:23]1[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:24]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCC(O)c1ccc(C(=O)OCC)cc1
Reactant: Cc1cc(-n2cc(C(F)(F)F)cn2)ccc1O
Agent: [N-]=[N+]=CCOC(=O)N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCC(Oc1ccc(-n2cc(C(F)(F)F)cn2)cc1C)c1ccc(C(=O)OCC)cc1
Reaction time: 17 h
Yield: 24.3 %

Procedure:
2-Methyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenol (200 mg, 0.83 mmol) was combined with ethyl 4-(1-hydroxybutyl)benzoate (see Intermediate 5) (19 mg, 0.87 mmol) and dissolved in anhydrous tetrahydrofuran (5 mL). Triphenylphosphine (347 mg, 1.3 mmol) was added at 0° under stirring followed by 0.83 ml of 1.5 M solution of diazoethyl azodicarboxylate (1.24 mmol). The reaction was stirred at room temperature as a yellow solution. At 17 hours, the reaction was concentrated and 10 ml of ethyl acetate and 5 ml of heptanes were added. Solid was filtered off and the mother liquor was loaded on silica gel. Chromatography on a silica gel column (gradient from 5% to 40% of ethyl acetate in heptane) gave the target product as a colorless glass (90 mg, 24%). MS (M+1): 447.2.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:11]([CH3:13])[CH3:12])[CH2:6]2.[CH3:14][C:15]1[CH:16]=[C:17]([Mg]Br)[CH:18]=[C:19]([CH3:21])[CH:20]=1>CCOCC.Cl[Ni](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>[CH3:14][C:15]1[CH:16]=[C:17]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH:4]=[C:5]([CH:11]([CH3:13])[CH3:12])[CH2:6]3)[CH:18]=[C:19]([CH3:21])[CH:20]=1
Reactant: Cc1cc(C)cc([Mg]Br)c1
Reactant: CC(C)C1=Cc2c(Cl)cccc2C1
Agent: Cl[Ni](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOCC
Product: Cc1cc(C)cc(-c2cccc3c2C=C(C(C)C)C3)c1

Procedure:
4-chloro-2-isopropylindene (10 g, 54 mmol) and NiCl2(PPh3)2 (1.8 g, 2.8 mmol) were dissolved in 150 mL of Et2O. 3,5-Dimethylphenylmagnesium bromide (54 mmol) as a Et2O solution was added under vigorous stirring and the reaction was stirred overnight at room temperature. After overnight stirring, the reaction was slowly quenched with H2O to neutralize unreacted Grignard. The solution was subsequently treated with 100 mL of 10% HCl(aq), and neutralized with saturated sodium bicarbonate aqueous solution. The organic layer was dried with magnesium sulfate and the solvent was removed by rotary evaporation. The remaining residue was loaded onto a silica gel column and eluted with hexane. Yield was 5.5 g (39%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH3:11])=[C:6]([NH2:12])[CH:5]=1.[F:14][C:15]([S:18][C:19]1[CH:28]=[CH:27][C:22]2[N:23]=[C:24]([NH2:26])[S:25][C:21]=2[CH:20]=1)([F:17])[F:16].[C:29](N1C=CN=C1)(N1C=CN=C1)=S>C(Cl)CCl>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:10]([CH3:29])[C:11]([NH:26][C:24]3[S:25][C:21]4[CH:20]=[C:19]([S:18][C:15]([F:14])([F:16])[F:17])[CH:28]=[CH:27][C:22]=4[N:23]=3)=[N:12][C:6]=2[CH:5]=1)=[O:13]
Reactant: CNc1ccc(C(=O)OC)cc1N
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1nc2ccc(SC(F)(F)F)cc2s1
Solvent: ClCCCl
Product: COC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(SC(F)(F)F)cc3s1)n2C
Yield: 65.3 %

Procedure:
1-Methyl-2-(6-trifluoromethylsulfanyl-benzothiazol-2-ylamino)-1H-benzo-imidazole-5-carboxylic acid methyl ester (1.43 g) was prepared by following General Procedure D starting from 3-amino-4-methylamino-benzoic acid methyl ester (0.9 g), 6-trifluoromethylsulfanyl-benzothiazol-2-ylamine (1.25 g), 1,1′-thiocarbonyldiimidazole (1.07 g), and EDC (1.15 g). LC/MS: m/z 440. 1H NMR (DMSO-d6, 400 MHz): δ 8.23 (s, 2H), 7.89 (br, 1H), 7.76 (br, 1H), 7.69 (d, 2H), 7.54 (d, 1H), 3.88 (s, 3H), and 3.68 (s, 3H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[Cl:26][C:27]1[CH:28]=[C:29]([S:34](Cl)(=[O:36])=[O:35])[CH:30]=[C:31]([Cl:33])[CH:32]=1>>[Cl:33][C:31]1[CH:30]=[C:29]([S:34]([N:20]2[CH2:21][CH2:22][CH:17]([N:15]3[C:14](=[O:23])[C:13]([CH3:25])([CH3:24])[C:12]([C:6]4[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=4)=[N:16]3)[CH2:18][CH2:19]2)(=[O:35])=[O:36])[CH:28]=[C:27]([Cl:26])[CH:32]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4cc(Cl)cc(Cl)c4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 3,5-dichlorobenzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from EA and diethyl ether to yield the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33](=[O:53])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[CH:44]=[C:43]([CH2:45][O:46][CH:47]3[CH2:52][CH2:51][CH2:50][CH2:49][O:48]3)[O:42][N:41]=2)[CH:35]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[C:11]([C:20]([F:21])([F:22])[F:23])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33](=[O:53])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[CH:44]=[C:43]([CH2:45][O:46][CH:47]3[CH2:52][CH2:51][CH2:50][CH2:49][O:48]3)[O:42][N:41]=2)[CH:35]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C(F)(F)F)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cc(COC3CCCCO3)on2)c1
Product: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2cc(COC3CCCCO3)on2)c1

Procedure:
The title compound was prepared from (2-amino-5-morpholin-4-yl-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J1) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-isoxazol-3-yl]-phenyl}-propionic acid tert.-butyl ester (Example K11) according to the general procedure M. Obtained as a light yellow foam (774 mg).
Reaction SMILES: Br[C:2]1[N:30]=[CH:29][CH:28]=[CH:27][C:3]=1[C:4]([NH:6][C@H:7]([C:9]1[N:10]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:11](=[O:20])[C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])[CH3:8])=[O:5].[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>O1CCOCC1>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[C:11](=[O:20])[N:10]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:9]([C@@H:7]([NH:6][C:4](=[O:5])[C:3]1[CH:27]=[CH:28][CH:29]=[N:30][C:2]=1[N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)[CH3:8])=[CH:18]2
Reactant: C[C@H](NC(=O)c1cccnc1Br)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Reactant: C1COCCN1
Solvent: C1COCCO1
Product: C[C@H](NC(=O)c1cccnc1N1CCOCC1)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Temperature: 140 °C
Reaction time: 6 h

Procedure:
To a mixture of (S)-2-bromo-N-(1-(8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)nicotinamide (52) (150 mg, 0.31 mmol) in anhydrous 1,4-dioxane (3 mL) in a sealed tube, morpholine (1 mL, excess amount) was added and the resulting mixture was stirred at 140° C. for 6 h. The mixture was allowed to cool to RT and then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by ISCO column chromatography (silica gel cartridge, 0-10% MeOH-DCM) followed by prep-TLC plate purification (10% MeOH-DCM) to afford the product (S)—N-(1-(8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)-2-morpholinonicotinamide (compound 53). ESI-MS m/z: 489.0 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][C:16]([OH:18])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:41][N:42]([CH:59]([C:67](=[O:70])[NH:68][CH3:69])[CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[C:43](=[O:58])[CH:44]([NH:56][CH3:57])[CH2:45][C:46]1[CH:55]=[CH:54][C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:47]=1.C(N(C(C)C)CC)(C)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][CH2:15][C:16](=[O:18])[N:56]([CH3:57])[C@@H:44]([C:43](=[O:58])[N:42]([CH3:41])[C@@H:59]([C:67](=[O:70])[NH:68][CH3:69])[CH2:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[CH2:45][C:46]2[CH:55]=[CH:54][C:53]3[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=3)[CH:47]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(OCC(=O)O)CC1
Reactant: CNC(=O)C(Cc1ccccc1)N(C)C(=O)C(Cc1ccc2ccccc2c1)NC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)COC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 68.9 %

Procedure:
A solution of 4-(carboxymethoxy)piperidine-1-carboxylic acid tert-butyl ester (228 mg, 0.88 mmol), 1-hydroxy-7-azabenzotriazole (120 mg, 0.88 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (186 mg, 0.97 mmol) was stirred for 30 min at room temperature. N-Methyl-2-methylamino-N-(1-methylcarbamoyl-2-phenylethyl)-3-(naphthalen-2-yl)propionamide (355 mg, 0.88 mmol) in 5 ml of dichloromethane was added followed by diisopropylethylamine (0.2 ml, 1.14 mmol) and the mixture was stirred for 2 days at room temperature. The mixture was washed with water (5 ml) aqueous sodium bicarbonate (5 ml), water (2×5 ml), brine (5 ml), dried over magnesium sulfate and concentrated in vacuo. The crude product was chromatographed on silica (30 g) with ethyl acetate as eluent to give 391 mg of 4-([N-methyl-N-{(1R)-1-(N-methyl-N-[(1R)-1-(methyl carbamoyl)-2-phenylethyl]carbamoyl)-2-(2-naphthyl)ethyl}carbamoyl]methoxy]piperidin-1-carboxylic acid tert-butylester. The product was taken up in 50% trifluoromethane/dichloromethane and allowed to stand for 10 min. Then saturated sodium bicarbonate was added until pH was about 8 and the organic layer was separated. The aqueous phase was extracted with dichloromethane (2×10 ml) and the combined organic phases were washed with brine (5 ml), dried over magnesium sulfate and concentrated in vacuo. The crude product was chromatographed on silica (15 g) with dichloromethane:methanol (9:1) to give 327 mg of the title compound.
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12]([OH:14])=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.S([O:20][CH3:21])(OC)(=O)=O.[C:22]([O-])([O-])=O.[K+].[K+].O>CC(C)=O>[CH3:22][O:1][C:2]1[C:11]([C:12]([O:20][CH3:21])=[O:14])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: COS(=O)(=O)OC
Reactant: O=C(O)c1cc2ccccc2cc1O
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1cc2ccccc2cc1OC
Reaction time: 2 h

Procedure:
2-Hydroxy-3-naphthoic acid (18.8 g; 100 mmol), dimethyl sulfate (1 eq.) and anhydrous K2CO3 (4.8 eq.) in 500 cm3 of anhydrous acetone are maintained at reflux for 6 h. 25 cm3 of water are added to the cooled mixture, which is stirred at room temperaure for 2 h. After filtration, ether is added and the solution is dried over MgSO4. The solvent is evaporated off to give the compound, which is purified by flash chromatography on silica gel (eluent: ether/petroleum ether). Oil.
Reaction SMILES: [C:1]1(C)[C:2]([S:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.Br[CH2:18][CH2:19][Cl:20].[CH2:21](N(CC)CC)C>C1C=CC=CC=1>[Cl:20][CH2:19][CH2:18][N:13]1[CH2:12][CH2:11][N:10]([S:7]([C:2]2[CH:1]=[CH:6][C:5]([CH3:21])=[CH:4][CH:3]=2)(=[O:8])=[O:9])[CH2:15][CH2:14]1
Reactant: CCN(CC)CC
Reactant: Cc1ccccc1S(=O)(=O)N1CCNCC1
Reactant: ClCCBr
Solvent: c1ccccc1
Product: Cc1ccc(S(=O)(=O)N2CCN(CCCl)CC2)cc1
Yield: 80.6 %

Procedure:
After refluxing for 72 hours a reaction mixture consisting of 60 g (0.25 mol) of p-toluenesulfonylpiperazine (III), 41 ml (0.5 mol) of 1-bromo-2-chloroethane and 35 ml (0.25 mol) of triethylamine in 1 liter of benzene, the solution was filtered and white needle crystal were obtained from the filtrate. N-β-chloroethyl-N'-p-toluenesulfonylpiperazine 61 g (yield: 79%) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([CH2:15][O:14][C:13]4[CH:16]=[C:17]5[C:21](=[CH:22][C:12]3=4)[CH2:20][CH2:19][O:18]5)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.CC1C2C=[C:30]3[C:35]4(C5C(=CC=CC=5)NC4=O)[CH2:34][O:33][C:31]3=[CH:32]C=2ON=1.CC1C=CC(S(OC[C@H]2CCCO2)(=O)=O)=CC=1.BrCC1OC(C(F)(F)F)=CC=1>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([CH2:15][O:14][C:13]4[CH:16]=[C:17]5[C:21](=[CH:22][C:12]3=4)[CH2:20][CH2:19][O:18]5)[C:7](=[O:11])[N:8]2[CH2:32][C@H:31]2[CH2:30][CH2:35][CH2:34][O:33]2)=[CH:4][CH:3]=1
Reactant: O=C1Nc2cc(F)ccc2C12COc1cc3c(cc12)CCO3
Reactant: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Agent: FC(F)(F)c1ccc(CBr)o1
Product: O=C1N(C[C@H]2CCCO2)c2cc(F)ccc2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 6′-fluoro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, 6′-fluoro-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1H)-one was obtained (47%) as a colorless solid: mp 137-139° C. (diethyl ether/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.08-7.03 (m, 1H), 6.88-6.83 (m, 1H), 6.73-6.66 (m, 1H), 6.46 (s, 1H), 6.38 (s, 1H), 4.74 (ABq, 2H), 4.52 (t, J=9.0 Hz, 2H), 4.25-4.20 (m, 1H), 3.96-3.60 (m, 4H), 2.98 (t, J=9.0 Hz, 2H), 2.08-1.86 (m, 3H), 1.73-1.64 (m, 1H); 13C NMR (75 MHz, CDCl3) δ178.0, 161.9, 161.2, 128.1, 124.7, 120.0, 118.8, 109.5, 109.2, 98.8, 98.4, 93.2, 80.6, 72.4, 68.3, 57.3, 44.8, 29.2, 28.9, 25.7; MS (ES+) m/z 382.0 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11](Cl)[N:10]=2)[CH:5]=[CH:4][N:3]=1.[CH:16]([Sn](CCCC)(CCCC)CCCC)=[CH2:17].[C:31]1(C)C=CC=C[CH:32]=1>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:16]([C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([CH:31]=[CH2:32])[N:10]=2)[CH:5]=[CH:4][N:3]=1)=[CH2:17]
Reactant: Clc1nccc(Oc2ccnc(Cl)n2)n1
Reactant: Cc1ccccc1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: C=Cc1nccc(Oc2ccnc(C=C)n2)n1
Temperature: 115 °C
Yield: 61 %

Procedure:
The 2-chloropyrimidinyl ether intermediate (500 mg, 0.896 mmol) (see Example 1), vinyltributyltin (600 mg, 1.89 mmol), BHT (20 mg), and (PPh3)4Pd (50 mg, 0.045 mmol) were suspended in degassed toluene (10 mL) under argon and heated to 115° C. for 3 h. The reaction mixture was cooled, diluted with EtOAc (100 mL), washed with brine (10 mL), and dried over MgSO4. Silica gel chromatography (gradient elution, 0% to 80% EtOAc in hexanes) provided the desired 2-vinylpyrimidinyl ether intermediate (302 mg, 61%) as a pale yellow solid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].N1C=CC=CC=1.[OH:11][CH2:12][C:13]#[C:14][C:15]([C:17]1[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=1)=[O:16].P([O-])([O-])([O-])=O>C(Cl)Cl>[C:1]([O:11][CH2:12][C:13]#[C:14][C:15](=[O:16])[C:17]1[CH:18]=[C:19]([O:27][CH3:28])[C:20]([O:25][CH3:26])=[C:21]([O:23][CH3:24])[CH:22]=1)(=[O:3])[CH3:2]
Reactant: COc1cc(C(=O)C#CCO)cc(OC)c1OC
Reactant: CC(=O)Cl
Agent: O=P([O-])([O-])[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(C(=O)C#CCOC(C)=O)cc(OC)c1OC
Reaction time: 1 h

Procedure:
0.815 g of acetyl chloride and 0.827 g of pyridine were added simultaneously to a solution of 2.0 g (7.99 mmol) of 4-hydroxy-1-(3,4,5-trimethoxyphenyl)-2-butyn-1-one in 20 ml of methylene chloride. The reaction mixture was stirred at 0° for 1 hour, whereupon it was treated with 30 ml of phosphate buffer (pH 6) and the aqueous phase was extracted twice with methylene chloride. The combined organic phases were dried over magnesium sulphate and evaporated. The residue was recrystallized from ethyl acetate/hexane and there was obtained 3-(3,4,5-trimethoxy-benzoyl)-2-propynyl acetate of melting point 104°-105°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])O[C:6](=[O:13])[CH2:5]2.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1>C1(C)C=CC=CC=1.C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:21]([CH2:20][C:19]1[CH:22]=[CH:23][C:16]([O:15][CH3:14])=[CH:17][CH:18]=1)[C:6](=[O:13])[CH2:5]2
Reactant: O=C1Cc2cc(Br)ccc2C(=O)O1
Reactant: COc1ccc(CN)cc1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COc1ccc(CN2C(=O)Cc3cc(Br)ccc3C2=O)cc1
Yield: 82.7 %

Procedure:
A mixture of 6-bromo-isochroman-1,3-dione (0.6 g) (product of step ii)) and 4-methoxybenzylamine (0.313 g) in toluene:acetic acid (4:1, 20 mL) was heated at reflux for 17 hours. The reaction mixture was evaporated and the residue was dissolved in dichloromethane before washing with 2N hydrochloric acid. The organic phase was dried, filtered and evaporated then triturated with diethyl ether to yield the sub-title compound (680 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8][OH:9])=[CH:5][CH:4]=1.[Cl:13][C:14]1[CH:19]=[N:18][CH:17]=[C:16](Cl)[N:15]=1>O1CCOCC1.ClCCl.CCOCC>[Cl:13][C:14]1[CH:19]=[N:18][CH:17]=[C:16]([O:9][CH2:8][CH2:7][C:6]2[CH:10]=[CH:11][C:3]([N:2]([CH3:1])[CH3:12])=[CH:4][CH:5]=2)[N:15]=1
Reactant: CN(C)c1ccc(CCO)cc1
Reactant: Clc1cncc(Cl)n1
Solvent: CCOCC
Solvent: ClCCl
Solvent: C1COCCO1
Product: CN(C)c1ccc(CCOc2cncc(Cl)n2)cc1
Temperature: 0 °C
Reaction time: 0.2 h
Yield: 80 %

Procedure:
K-t-BuO (2.27 g, 20.3 mmol) was added to a stirred solution of 4-(dimethylamino)phenethyl alcohol (3.55 g, 21.5 mmol) in dioxane (35 mL) at 0° C. (ice-bath). After being stirred for 5 min at 0° C. and 12 min at room temperature, the mixture was chilled to 0° C. (ice-bath) and 2,6-dichloropyrazine (2.62 g, 17.6 mmol) was added. The reaction mixture was stirred at 0° C. for 5 min and at room temperature for 20 min and diluted with dichloromethane/ether (1:1). Filtration through a pad of Celite, covered with K2CO3, and concentration in vacuo furnished a yellow oil. This material was purified by chromatography on silica gel (15×5 cm) using n-hexane/ethyl acetate (85:15). A second chromatograhic run on silica gel (14×5 cm) using n-hexane/ethyl acetate (88:12) furnished 3.91 g (80%) of the title compound as a colorless oil. Anal. (C14H16ClN3O) C, H, N.