Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.Cl.[F:26][C:27]1([F:31])[CH2:30][NH:29][CH2:28]1.CCN(C(C)C)C(C)C>C(#N)C>[F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([N:29]4[CH2:30][C:27]([F:31])([F:26])[CH2:28]4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1
Reactant: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: FC1(F)CNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(N3CC(F)(F)C3)ccc12
Temperature: 25 °C
Yield: 58.6 %

Procedure:
In a microwave vial 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide (100 mg, 0.27 mmol), 3,3-difluoro-azetidine hydrochloride (347.07 mg, 2.68 mmol) and DIPEA (519.43 mg, 4.02 mmol) in ACN (1.5 mL) was heated at 120° C. for 2 hours under microwave irradiation. After cooling to room temperature, the mixture was concentrated and purified through reverse phase HPLC to provide the desired product (68 mg, 59%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.88 (1H), 6.69 (1H), 4.54 (4H), 3.24 (t, J=6.24 Hz, 2H), 2.04 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 3H), 1.27-1.30 (m, 2H). m/z: 430 [M+H]
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]([CH:15]1[CH:19]([O:20][Si](C(C)(C)C)(C)C)[CH2:18][N:17]([C:28](=[O:36])[C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[CH2:16]1)[C:11](=[O:14])[CH2:12][Cl:13])(C)(C)C>Cl.O1CCOCC1>[NH2:7][CH2:8][CH2:9][N:10]([CH:15]1[CH:19]([OH:20])[CH2:18][N:17]([C:28](=[O:36])[C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)[CH2:16]1)[C:11](=[O:14])[CH2:12][Cl:13]
Reactant: CC(C)(C)OC(=O)NCCN(C(=O)CCl)C1CN(C(=O)c2ccc(Cl)cc2)CC1O[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: NCCN(C(=O)CCl)C1CN(C(=O)c2ccc(Cl)cc2)CC1O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
{2-[[4-(tert-Butyl-dimethyl-silanyloxy)-1-(4-chloro-benzoyl)-pyrrolidin-3-yl]-(2-chloro-acetyl)-amino]-ethyl}-carbamic acid tert-butyl ester (260 mg, 0.45 mmol) was dissolved in 1 mL of 4M HCl in dioxane solution. The mixture was stirred at RT for 1.5 h. After concentrating, a white solid was formed (200 mg). The LC-Mass showed two products as showed above. MS: (ESI), M/Z, 360 (M+1). Retention time: 1,31 min (FA-polar). MS: (ESI), M/Z, 474 (M+1). Retention time: 2.20 min (FA-polar).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)[CH3:2].[CH2:13]([O:15][P:16]([CH2:21][PH:22]([O:24][CH2:25][CH3:26])=[O:23])(=[O:20])[O:17][CH2:18][CH3:19])[CH3:14]>C(#N)C.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.CN1CCOCC1>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([P:22]([CH2:21][P:16]([O:15][CH2:13][CH3:14])([O:17][CH2:18][CH3:19])=[O:20])([O:24][CH2:25][CH3:26])=[O:23])=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(Br)cc1
Reactant: CCO[PH](=O)CP(=O)(OCC)OCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CN1CCOCC1
Product: CCOC(=O)c1ccc(P(=O)(CP(=O)(OCC)OCC)OCC)cc1
Temperature: 25 °C
Reaction time: 0.12 h
Yield: 58.6 %

Procedure:
A sealed pressure flask, flushed with N2, containing a mixture of 4-bromo-benzoic acid ethyl ester (3a) (5 g, 0.0218 mol), ethoxyphosphinoylmethyl-phosphonic acid diethyl ester (3b), (5.86 g, 0.024 mol), NMM (2.88 mL, 0.0262 mmol) and Pd(PPh3)4 (2.017 g, 0.00175 mol) in acetonitrile (20 mL) was stirred at ambient temperature for 5-10 min, then heated at 90° C. for 18 hours. The reaction mixture was filtered through celite, and the celite was washed with EtOAc (3×30 mL) until the filtrate showed little or no evidence of product by HPLC. The combined organics were dried over Na2SO4 and concentrated on rotary evaporator. The desired product (ix) was purified by silica gel flash chromatography to give a pale yellow oil (5.01 g). 1H NMR (300 MHz, CDCl3) δ (ppm)): 0.96 (t, J=7.07 Hz, 3H), 1.13 (m, 9H), 2.41 (t, J=18.2 Hz, 2H), 3.84 (m, 6H), 4.17 (q, J=7.11 Hz, 2H), 7.71 (m, 2H), 7.92 (m, 2H)., 31P NMR (121 MHz, CDCl3) δ32.8 and 19.7.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([Cl:8])[CH:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].[CH2:22](N(CC)CC)C>C(O)C>[CH3:22][C:6]1[N:5]=[C:4]([Cl:8])[CH:3]=[C:2]([N:19]2[CH2:20][CH2:21][N:16]([C:14]([O:13][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:15])[CH2:17][CH2:18]2)[N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1cc(Cl)ncn1
Reactant: CCN(CC)CC
Solvent: CCO
Product: Cc1nc(Cl)cc(N2CCN(C(=O)OC(C)(C)C)CC2)n1

Procedure:
Dichloropyrimidine (24.79 g) and 1-(tert-butoxycarbonyl)piperazine (27.41 g) were stirred in ethanol (500 ml) and triethylamine (41 ml) overnight. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The organic phase was dried (Na2SO2), and evaporated to give 2-methyl-4-chloro-6-[1-(tert-butoxycarbonyl]piperazin-4-yl)pyrimidine as a solid (41.5 g); NMR (CDCl3): 6.35 (s, 1H), 3.65 (m, 4H), 3.5 (m, 4H), 2.5 (s, 3H), 1.45 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][C@H:11]([CH2:13][NH:14][C:15](=[O:17])[CH3:16])[O:10][C:9]2=[O:18])=[CH:4][C:3]=1[F:19].[N:20]([O-])=O.[Na+].Cl[Sn]Cl>CO.O.Cl>[F:19][C:3]1[CH:4]=[C:5]([N:8]2[CH2:12][C@H:11]([CH2:13][NH:14][C:15](=[O:17])[CH3:16])[O:10][C:9]2=[O:18])[CH:6]=[CH:7][C:2]=1[NH:1][NH2:20]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N)c(F)c2)C(=O)O1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(=O)NC[C@H]1CN(c2ccc(NN)c(F)c2)C(=O)O1
Temperature: 25 °C
Yield: 70 %

Procedure:
3 g (11.22 mmol) of (S)—N-((3-(4-amino-3-fluorophenyl)-2-oxooxazolidin-5-yl) methyl)acetamide (7) was dissolved in a blend of 6 mL methanol, 12 mL water and 3 mL concentrated hydrochloric acid. The resultant mixture was stirred for 10 minutes in an ice-salt bath to maintain the internal temperature below −5° C. Then, a NaNO2 solution prepared in advance was slowly dropped into the mixture. After completion of the addition, the mixture was stirred in the ice-salt bath for another 30 minutes to prepare a reaction solution of diazonium salt. Meanwhile, 6.08 g of SnCl2 was dissolved in a concentrated hydrochloric acid under vigorous stirring in an ice-salt bath. The reaction solution of diazonium salt prepared above was slowly dropped into the SnCl2 solution in hydrochloric acid, and then the mixture was warmed naturally to room temperature and stirred for another 2 hours. After completion of the reaction, the reactant was buffered to a pH between 7 and 8 with 1 ON NaOH solution. After the solvent was evaporated in a rotary evaporator, the resultant material was repeatedly grinded with methanol. After the solvent methanol was rotary evaporated, the residue was recrystallized with ethanol and then filtered to afford a light yellow crystalline solid weighed 2.2 g, with a yield of 70%. The product was kept under low temperature and in a dry place.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]2[O:9][CH2:10][O:11][C:5]=2[CH:4]=1.[CH3:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[CH:16]=1)=O>O1CCCC1.BrBr>[Br:21][C:17]1[CH:16]=[C:15]([C:13]([C:3]2[CH:8]=[CH:7][C:6]3[O:9][CH2:10][O:11][C:5]=3[CH:4]=2)=[CH2:12])[CH:20]=[CH:19][CH:18]=1
Reactant: Brc1ccc2c(c1)OCO2
Reactant: CC(=O)c1cccc(Br)c1
Agent: BrBr
Agent: [Mg]
Solvent: C1CCOC1
Product: C=C(c1cccc(Br)c1)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of magnesium turnings (440 mg, 0.01 mol, 1.2 eq) in dry tetrahydrofuran (5 mL), was added 4-bromo-1,2(methylendioxy)benzene (3.1 g, 0.01 mol, 1.1 eq) in dry tetrahydrofuran (10 mL) and bromine (0.5 mL). The resulting solution was refluxed for 2 hours. Then the mixture was cooled at room temperature and a solution of 3-bromoacetophenone (3.0 g, 0.01 mol, 1 eq) in dry tetrahydrofuran (10 mL) was added dropwise and refluxed. After 3 hours the reaction mixture was examined by LC-MS which showed complete conversion to the desired product. The mixture was quenched with 1 M HCl solution (20 mL). The aqueous phase was extracted with ethyl acetate. (3×20 mL), dried (sodium sulfate) and the solvent removed in vacuo. The crude was dissolved in toluene (30 mL) and a catalytic amount of p-toluenesulfonic acid was added. The mixture was heated to reflux for 3 h (using a Dean-Stark water trap). The solvent was removed and the residue was purified by column chromatography (cyclohexane) to afford the title compound as a colorless oil (3.7 g, 80%);
Reaction SMILES: [OH-].[K+].Cl.[OH:4][C:5]1[C:6]([CH2:11][OH:12])=[N:7][CH:8]=[CH:9][CH:10]=1.[CH:13]1([CH2:16]Br)[CH2:15][CH2:14]1.Cl>O.CS(C)=O>[CH:13]1([CH2:16][O:4][C:5]2[C:6]([CH2:11][OH:12])=[N:7][CH:8]=[CH:9][CH:10]=2)[CH2:15][CH2:14]1
Reactant: OCc1ncccc1O
Reactant: BrCC1CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: OCc1ncccc1OCC1CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 43.2 %

Procedure:
Potassium hydroxide (5.2 g, 0.093 mol) was ground to a powder under nitrogen, added to DMSO (30 ml) and stirred for 20 min under nitrogen at room temperature. The mixture was cooled to 0° C. and 3-hydroxy-2-hydroxymethyl pyridine hydrochloride (5.0 g, 0.031 mol) was added. The slurry was stirred at 0° C. for 1 h before the addition of cyclopropylmethyl bromide (3.01 ml, 4.2 g, 0.031 mol). The mixture was allowed to warm to room temperature and stirred under nitrogen overnight. Water (100 ml) was added, and the resultant solution was acidified to pH 1 with hydrochloric acid (5 N). The solution was washed with dichloromethane (3×100 ml), basified to pH 14 with sodium hydroxide solution (4 N), and washed again with dichloromethane (3×100 ml). The organic layers from the second extraction were combined, washed with water (1×100 ml) and saturated sodium chloride solution (1×100 ml), dried over magnesium sulfate and concentrated in vacuo to give 3-cyclopropylmethyloxy-2-hydroxymethyl pyridine as a dark brown solid (2.40 g). 1H NMR (250 MHz, CDCl3) δ 0.35 (2H, m), 0.65 (2H, m), 1.26 (1H, m), 3.85 (2H, d, J=6.8 Hz), 4.33 (1H, br s), 4.77 (2H, s), 7.13 (2H, m), 8.13 (2H, m); MS (ES+) m/e 180 [MH]+.
Reaction SMILES: [CH3:1][C:2]([CH2:4][CH2:5][CH2:6][C:7](=[O:9])[CH3:8])=[CH2:3].[CH3:10][C:11]([CH3:15])=[CH:12][CH:13]=O>[O-2].[Zn+2]>[CH3:3][C:2](=[CH:4][CH:5]=[CH:6][C:7](=[O:9])[CH2:8][CH2:13][CH2:12][C:11]([CH3:15])=[CH2:10])[CH3:1]
Reactant: C=C(C)CCCC(C)=O
Reactant: CC(C)=CC=O
Agent: [O-2]
Agent: [Zn+2]
Product: C=C(C)CCCC(=O)C=CC=C(C)C
Yield: 91 %

Procedure:
120 Parts of 2-methyl-1-hepten-6-one, 40 parts of 3,3-dimethyl-acrolein and 10 parts of zinc oxide are heated for 5 hours at 180° C and a pressure of 60 atmospheres. 63.5 Parts of 2,10-dimethyl-2,4,10-undecatrien-6-one having a boiling point of 120° to 123° C at 0.1 mm is obtained analogously to Example 9. The yield is 91% of theory (based on 3,3-dimethyl-acrolein) at a conversion of 78% of theory.
Reaction SMILES: C([Li])CCC.[C:6](=[N:19][C:20]1[CH:25]=[C:24](Br)[CH:23]=[CH:22][C:21]=1[F:27])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:28][S:29]C.[Cl-].[NH4+]>O1CCCC1.O>[C:6](=[N:19][C:20]1[CH:25]=[C:24]([S:29][CH3:28])[CH:23]=[CH:22][C:21]=1[F:27])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CSC
Reactant: Fc1ccc(Br)cc1N=C(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CSc1ccc(F)c(N=C(c2ccccc2)c2ccccc2)c1
Reaction time: 0.25 h

Procedure:
2.2 mL n-butyl lithium (2.66 M hexane solution) was added dropwise to a solution of 1.85 g benzhydrylidene-(5-bromo-2-fluorophenyl)-amine (compound in Production Example 336) in 10 mL tetrahydrofuran at −70° C., then the mixture was stirred for 15 minutes, a solution of 0.53 mL methyl sulfide in 5 mL tetrahydrofuran was added dropwise thereto, and the mixture was stirred at 0° C. for 2 hours. An aqueous saturated ammonium chloride solution was added thereto, and the reaction mixture was diluted with water, extracted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed, and the resulting crude product was purified by silica gel column chromatography (ethyl acetate/hexane) to give 1.24 g of the title compound (colorless oil).
Reaction SMILES: [C:1]1([CH:7]2[CH2:9][CH:8]2[C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13]([NH:20][C:21]([C:23]1[S:27][C:26]([NH2:28])=[N:25][C:24]=1[CH3:29])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([NH:20][C:21]([C:23]1[S:27][C:26]([NH:28][C:10]([CH:8]2[CH2:9][CH:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:11])=[N:25][C:24]=1[CH3:29])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Reactant: O=C(Cl)C1CC1c1ccccc1
Product: Cc1nc(NC(=O)C2CC2c2ccccc2)sc1C(=O)NCc1ccccc1
Yield: 73 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 2-phenylcyclopropanecarbonyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 73% yield; 1H NMR (DMSO-d6, 300 MHz) δ 7.38-7.03 (m, 10H), 5.87 (s, br, 1H), 4.56-4.50 (m, 2H), 2.70-2.63 (m, 1H), 2.41 (s, 3H), 1.81-1.73 (m, 2H), 1.52-1.23 (m, 1H); MS (ES+) m/z 391.8 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[C:3]=1[CH2:25][C:26]([O:28][CH3:29])=[O:27].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:40]1[CH2:44]OC[CH2:41]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[C:3]=1[CH:25]([CH2:41][CH2:40][CH3:44])[C:26]([O:28][CH3:29])=[O:27]
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1cccc(C(F)(F)F)c1)CCCC3
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCCI
Product: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1cccc(C(F)(F)F)c1)CCCC3
Yield: 81.4 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(3-trifluoromethylphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.260 g; 0.62 mmol), LHMDS 1N in THF (0.7 mL; 0.7 mmol), 1-iodopropane (0.127 mL; 1.3 mmol) in DMF (2.5 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-30%) in heptane furnished 0.233 g (83%) of the title compound as a yellow oil.
Reaction SMILES: Cl.[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[N:8][O:9][C:5]=2[CH:4]=1.[C:18]([O-:21])([O-:20])=O.[K+].[K+].Cl[CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:30]=[C:31]([C:35](=[O:37])[CH3:36])[CH:32]=[CH:33][CH:34]=1>C(#N)C>[C:5]([OH:28])(=[O:9])/[CH:6]=[CH:16]/[C:18]([OH:21])=[O:20].[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:11][CH2:12][N:13]([CH2:25][CH2:26][CH2:27][O:28][C:29]4[CH:30]=[C:31]([C:35](=[O:37])[CH3:36])[CH:32]=[CH:33][CH:34]=4)[CH2:14][CH2:15]3)=[N:8][O:9][C:5]=2[CH:4]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CC(=O)c1cccc(OCCCCl)c1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CC#N
Product: CC(=O)c1cccc(OCCCN2CCC(c3noc4cc(F)ccc34)CC2)c1
Product: O=C(O)/C=C/C(=O)O
Yield: 48.2 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (4.53 g, 20.5 mmol), K2CO3 (4.5 g), 1-[3-(3-chloropropoxy)phenyl]ethanone (6.4 g, 29 mmol) in acetonitrile (60 ml) was heated at reflux for 5 hours. At the end of the reaction, the solvent was removed and the residue was extracted into dichloromethane (300 ml). The inorganic insolubles were filtered off. The dichloromethane solution was concentrated to a small volume (10 ml) and purified on a flash chromatographic column (SiO2, 75 g, eluted with dichloromethane, 900 ml; and 2% methanol in dichloromethane, 800 ml). The fractions containing the pure product were combined and concentrated to an oil (2.87 g, 35%). The oil was dissolved into ethanol and treated with a solution of lumaric acid (841 mg). Recrystallization (twice) from ethanol afforded 2.53 g of 1-[3-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]ethanone fumarate as white crystals, m.p.=172-174C.
Reaction SMILES: N12CCCN=C1CCCCC2.[CH3:12][C:13]1[N:18]2[N:19]=[C:20]([CH2:22][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:21]=[C:17]2[C:16]([CH3:42])=[N:15][CH:14]=1.[Cl-].[CH3:44][N:45]1[C:49]([CH:50]=O)=[N:48][C:47]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[N:46]1>O1CCCC1.C(Cl)Cl>[CH3:12][C:13]1[N:18]2[N:19]=[C:20]([CH2:22][CH2:50][C:49]3[N:45]([CH3:44])[N:46]=[C:47]([C:52]4[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=4)[N:48]=3)[N:21]=[C:17]2[C:16]([CH3:42])=[N:15][CH:14]=1
Reactant: Cc1ncc(C)n2nc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc12
Reactant: Cn1nc(-c2ccccc2)nc1C=O
Agent: [Cl-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ncc(C)n2nc(CCc3nc(-c4ccccc4)nn3C)nc12

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (0.16 mL, 1.07 mmol) was added to a stirred suspension of (5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-ylmethyl)-triphenyl-phosphonium; chloride (0.490 g, 1.07 mmol) and 2-Methyl-5-phenyl-2H-1,2,4-triazole-3-carbaldehyde (0.200 g, 1.07 mmol) in Tetrahydrofuran (6.9 mL) in dry THF (8 mL) and the mixture was stirred at room temperature under an atmosphere of Argon overnight. DCM (50 ml) was added and the organic phase was extracted with water (2×50 ml), dried (MgSO4) and the solvent was evaporated off.
Reaction SMILES: C([O:8][CH2:9][C@@H:10]1[N:15]2[C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=[C:18]([NH2:26])[C:17]=3[N:27]=[C:14]2[CH2:13][O:12][CH2:11]1)C1C=CC=CC=1.CO.C(Cl)(=O)C>[Pd].C(Cl)(Cl)Cl>[NH2:26][C:18]1[C:17]2[N:27]=[C:14]3[CH2:13][O:12][CH2:11][C@H:10]([CH2:9][OH:8])[N:15]3[C:16]=2[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1
Reactant: Nc1nc2ccccc2c2c1nc1n2[C@@H](COCc2ccccc2)COC1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)Cl
Solvent: ClC(Cl)Cl
Product: Nc1nc2ccccc2c2c1nc1n2[C@@H](CO)COC1
Reaction time: 96 h
Yield: 49.3 %

Procedure:
(11S)-11-[(benzyloxy)methyl]-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine (4.5 g, 12 mmol) was added to a mixture of methanol (177 mL) and acetyl chloride (1.3 mL, 19 mmol) in a pressure bottle. Palladium on carbon (10%, 900 mg) was then added and the reaction mixture was shaken under H2 at 48 PSI (3.3×105 Pa). After 4 days, the reaction mixture was filtered through a pad of CELITE filter agent. The pad was rinsed with methanol and the combined filtrates were treated with 2 mL of 50% aqueous NaOH solution and the mixture was concentrated under reduced pressure to afford an oily solid. Chromatography (SiO2, 0-30% CMA/CHCl3) afforded an oil that was concentrated with acetonitrile to give 1.6 g of [(11S)-6-amino-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-11-yl]methanol as a tan solid.
Reaction SMILES: [O:1]([CH2:13][C@H:14]1[O:18][N:17]=[C:16]([C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][N:20]=2)[CH2:15]1)[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].[F:26][C:27]1[CH:28]=[C:29]([N:42]2[CH2:46][C@H:45]([CH2:47][N:48]3[CH:52]=[CH:51][N:50]=[N:49]3)[O:44][C:43]2=[O:53])[CH:30]=[CH:31][C:32]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O.C1(P([Pd-4](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)C=CC=CC=1>[O:1]([CH2:13][C@H:14]1[O:18][N:17]=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:32]3[CH:31]=[CH:30][C:29]([N:42]4[CH2:46][C@H:45]([CH2:47][N:48]5[CH:52]=[CH:51][N:50]=[N:49]5)[O:44][C:43]4=[O:53])=[CH:28][C:27]=3[F:26])=[CH:21][N:20]=2)[CH2:15]1)[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: OC[C@H]1O[C@@H](OC[C@@H]2CC(c3ccc(Br)cn3)=NO2)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: CC1(C)OB(c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)OC1(C)C
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NO[C@H](CO[C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)C3)nc2)c(F)c1
Temperature: 70 °C
Yield: 38.4 %

Procedure:
[(5S)-3-(5-Bromopyridin-2-yl)-4,5-dihydroisoxazol-5-yl]methyl β-D-glucopyranoside (Intermediate 20, 0.150 g, 0.36 mmol), (5R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Intermediate 7, 0.153 g, 0.39 mmol), sodium carbonate (0.152 g, 1.43 mmol), and tetrakis(triphenylphosphino)palladium(0) (0.041 g, 0.036 mmol) were mixed in DMF/water (10:1, 5 mL) under nitrogen and heated at 70° C. bath temperature for 4 hours. The solvent was evaporated under reduced pressure. Chromatography on silica gel with dichloromethane/methanol 5:1 followed by crystallization from ethanol gave the product as colourless solid (83 mg). MS (ESP): 601.06 (MH+) for C27H29FN6O9
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH2:23][OH:24])[O:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.C(OCC)(=O)C>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH2:23][OH:24])[O:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCO[C@](CO)(c2ccc(Cl)c(Cl)c2)CC1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: OC[C@@]1(c2ccc(Cl)c(Cl)c2)CCNCCO1
Reaction time: 8 h
Yield: 157 %

Procedure:
To a solution of tert-butyl (7S)-7-(3,4-dichlorophenyl)-7-(hydroxymethyl)-1,4-oxazepane-4-carboxylate (206.2 mg) in ethanol (2 mL) was added 4 N hydrogen chloride/ethyl acetate solution (2 ml), and the mixture was stirred overnight. The solvent was evaporated under reduced pressure, and the obtained crystals were recrystallized from ethanol and ethyl acetate to give the title compound (134.5 mg).
Reaction SMILES: C1(O)C=CC=CC=1.[OH:8][C@@H:9]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=1)[CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].C([O-])([O-])=O.[K+].[K+].CC1C=CC(S(O[CH2:44][CH:45]2[CH2:50][CH2:49][N:48]([C:51](=[O:53])[CH3:52])[CH2:47][CH2:46]2)(=O)=O)=CC=1>CN(C=O)C.CCOC(C)=O>[C:51]([N:48]1[CH2:49][CH2:50][CH:45]([CH2:44][O:26][C:22]2[CH:21]=[C:20]([C@H:9]([OH:8])[CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:25]=[CH:24][CH:23]=2)[CH2:46][CH2:47]1)(=[O:53])[CH3:52]
Reactant: CC(=O)N1CCC(COS(=O)(=O)c2ccc(C)cc2)CC1
Reactant: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Oc1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)N1CCC(COc2cccc([C@H](O)CCNC(=O)OC(C)(C)C)c2)CC1
Temperature: 90 °C

Procedure:
Phenol (7, Intermediate I) (0.850 g, 3.20 mmol) and K2CO3 (1.32 g, 9.60 mmol) were added to a solution of (1-acetylpiperidin-4-yl)methyl 4-methylbenzenesulfonate (1.0 g, 3.20 mmol) in DMF (10 mL). The reaction mixture was heated at 90° C. overnight. The reaction mixture was diluted with EtOAc and washed with water and brine. Organic layer was dried over anhydrous Na2SO4) and concentrated under reduced pressure to give after purification by column chromatography to give (R)-tert-butyl (3-(3-((1-acetylpiperidin-4-yl)methoxy)phenyl)-3-hydroxypropyl)carbamate as a colorless semi solid. Yield (600 mg, 46%); 1H NMR (400 MHz, DMSO-d6); δ 7.18 (d, J=4.0 Hz, 1H), 6.93 (s, 1H), 6.86 (d, J=7.6 Hz, 1H), 6.76 (d, J=6.0 Hz, 1H), 5.17 (d, J=4.4 Hz, 1H), 4.50 (d, J=4.8 Hz, 1H), 4.39 (d, J=11.6 Hz, 1H), 3.81 (d, J=6.4 Hz, 2H), 3.06-2.94 (m, 4H), 1.99 (s, 3H), 1.78 (t, J=14 Hz, 2H), 1.65 (t, J=7.2, 2H), 1.36 (s, 9H), 1.23 (s, 3H), 1.55-0.88 (m, 1H); MS: m/z 407.05 [M+H]+.