Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][S:7]([O-:10])(=O)=[O:8])[CH2:2]1.[Na+].C1(C)C=CC=CC=1.S(Cl)([Cl:21])=O>CN(C)C=O>[O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][S:7]([Cl:21])(=[O:10])=[O:8])[CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)([O-])CC1CCOC1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)CC1CCOC1

Procedure:
Sodium tetrahydrofuran-3-ylmethanesulfonate (1.0 g) [see Preparation 10] was dissolved in dimethylformamide (0.05m)) and thionyl chloride (5.3 ml) was added. The reaction mixture was heated under reflux for 5 hours, cooled and toluene (10 ml) added. The solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate and water, the organic layer was separated, washed with brine, dried over magnesium sulphate and the solvent removed under reduced pressure to afford tetrahydrofuran-3-ylmethanesulfonyl chloride (0.22 g) as a yellow oil. 1H-NMR (CDCl3) δ: 3.95 (1H, m), 3.90-3.60 (2H, m), 3.45 (1H, m), 3.00 (2H, m), 2.30 (1H, m), 2.10 (1H, m), 1.80 (1H, m).
Reaction SMILES: [CH3:1][C:2]1[CH2:6][CH2:5][CH:4]([C:7]([CH3:9])=[CH2:8])[C:3]=1[CH2:10]Cl.[CH:12](=[O:16])[CH:13]([CH3:15])[CH3:14].[OH-].[Na+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH2:6][CH2:5][CH:4]([C:7]([CH3:9])=[CH2:8])[C:3]=1[CH2:10][C:13]([CH3:15])([CH3:14])[CH:12]=[O:16]
Reactant: CC(C)C=O
Reactant: C=C(C)C1CCC(C)=C1CCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=C(C)C1CCC(C)=C1CC(C)(C)C=O
Yield: 76 %

Procedure:
A mixture of 857 g (5 moles) of 1-methyl-2-chloromethyl-3-isopropenylcyclopentene and 360 g (5 moles) of isobutyraldehyde was added in the course of 5 hours, whilst stirring, to a mixture of 480 g of 50% strength sodium hydroxide solution, 24 g of tetrabutylammonium iodide and 500 ml of toluene, at 80° C. The organic phase was then separated off and washed repeatedly with 200 ml portions of water, the toluene was stripped off and the residue was distilled in a rotary evaporator; boiling point 75°-77° C/0.3 mm Hg; nD25 : 1.4788; the structure was confirmed by the nuclear resonance spectrum; yield: 76%.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[O:15][C:14]([CH2:18][OH:19])([CH:16]=[CH2:17])[CH:13]([O:20]CC2C=CC=CC=2)[CH2:12]1.C(O)=O>CO.[Pd]>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[O:15][C:14]([CH2:16][CH3:17])([CH2:18][OH:19])[CH:13]([OH:20])[CH2:12]1
Reactant: C=CC1(CO)OC(n2cnc3c(N)ncnc32)CC1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Product: CCC1(CO)OC(n2cnc3c(N)ncnc32)CC1O
Yield: 63 %

Procedure:
[5-(6-Amino-purin-9-yl)-3-benzyloxy-2-vinyl-tetrahydro-furan-2-yl]-methanol was added to a flask. A 3.4% solution of HCOOH in methanol and Pd/C were added. The reaction was allowed to stir, was filtered and the solvent evaporated to provide the titled compound in 63% yield.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]([CH:14]([CH3:16])[CH3:15])[C:11]([OH:13])=[O:12].S([O-])(=O)(=O)C.[C:22]([CH:24](O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:26]=1)#[N:23].C(OCC)(=O)C.CCCCCC>C1COCC1.CN(C=O)C.C1COCC1.CCOCC>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]([CH:14]([CH3:16])[CH3:15])[C:11]([O:13][CH:24]([C:22]#[N:23])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:26]=1)=[O:12]
Reactant: CC(C)C(C(=O)O)c1cc2ccccc2s1
Reactant: N#CC(O)c1cccc(Oc2ccccc2)c1
Agent: CS(=O)(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)C(C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1)c1cc2ccccc2s1
Reaction time: 0.17 h

Procedure:
A mixture of 2-(2-benzothienyl)-3-methylbutanoic acid (0.5 g, 21.4 mmol) and KHCO3 (21.4 mmol) in 10 ml THF/DMF (1:1) is stirred for 10 minutes. Then the mesylate of α-cyano-3-phenoxybenzyl alcohol (0.65 g, 21.4 mmol) in 3 ml THF is added followed by stirring overnight. The mixture is diluted with 100 ml ether, washed with water and saturated NaCl, dried and solvent stripped to yield crude product. The product is isolated using thin layer chromatography developing with 15% ethyl acetate/hexane to give α-cyano-3-phenoxybenzyl 2-(2-benzothienyl)-3-methyl-butanoate, viscous liquid.
Reaction SMILES: [C:1]1([CH3:23])[CH:6]=[CH:5][C:4]([C:7]([C:9]2[N:13]3[CH2:14][CH2:15][CH:16]([C:17]([O:19]C(C)C)=[O:18])[C:12]3=[CH:11][CH:10]=2)=[O:8])=[CH:3][CH:2]=1.CO.[OH-].[Na+]>O>[C:1]1([CH3:23])[CH:2]=[CH:3][C:4]([C:7]([C:9]2[N:13]3[CH2:14][CH2:15][CH:16]([C:17]([OH:19])=[O:18])[C:12]3=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:6]=1
Reactant: Cc1ccc(C(=O)c2ccc3n2CCC3C(=O)OC(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(C(=O)c2ccc3n2CCC3C(=O)O)cc1

Procedure:
A solution of 250 mg. of isopropyl 5-p-toluoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate in 8 ml. of methanol is treated under an atmosphere of nitrogen, with a solution of 200 mg. of sodium hydroxide in 1 ml. of water, maintaining the reaction mixture at room temperature for 1.5 hours. The methanol is then removed under reduced pressure and the basic solution which remains is diluted with 5 ml. of water and extracted with ether to remove any unsaponifiable product. The aqueous solution is acidified with 10% hydrochloric acid and extracted three times with ethyl acetate. The combined extracts are dried and evaporated to dryness under reduced pressure, and the residue crystallized from ethyl acetate-hexane, to give 5-p-toluoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid, identical to the product obtained in Example 9.
Reaction SMILES: [CH:1]12[O:9][CH:5]([CH2:6][NH:7][CH2:8]1)[CH2:4][N:3]([CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1)[CH2:2]2.Br[CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:28]([O:27][C:26](=[O:32])[NH:25][CH2:24][CH2:23][N:7]1[CH2:8][CH:1]2[O:9][CH:5]([CH2:4][N:3]([CH2:10][CH2:11][CH2:12][O:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[CH2:2]2)[CH2:6]1)([CH3:31])([CH3:30])[CH3:29]
Reactant: N#Cc1ccc(OCCCN2CC3CNCC(C2)O3)cc1
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCN1CC2CN(CCCOc3ccc(C#N)cc3)CC(C1)O2
Temperature: 60 °C
Reaction time: 8 h
Yield: 46.2 %

Procedure:
4-[3-(9-Oxa-3,7-diazabicyclo[3.3.1]non-3-yl)propoxy]benzonitrile (6.5 g, 0.0226 mol; see WO 01/28992) and tert-butyl 2-bromoethylcarbamate (6 g, 0.0271 mol; see WO 01/28992) were dissolved in 80 mL of dry acetonitrile. Anhydrous potassium carbonate (4.68 g, 0.034 mol) was added and the mixture was stirred at 60° C. overnight. A further portion of tert-butyl 2-bromoethylcarbamate (2.53 g, 0.0113 mol) was added and the reaction heated at 65° C. overnight. The reaction mixture was then filtered and the filtrate concentrated under reduced pressure. The product was purified by column chromatography using methanol-chloroform as eluent to give the sub-title compound (4.5 g) as a yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14](Br)=[CH:15][CH:16]=2)[CH2:11][C@H:10]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:22])=[O:21])[C:9]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][N:31](C=O)C>CO.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C-]#N.[C-]#N.[Zn+2]>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:30]#[N:31])=[CH:15][CH:16]=2)[CH2:11][C@H:10]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:22])=[O:21])[C:9]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1[C@@H](NS(=O)(=O)c2ccccc2)Cc2cc(Br)ccc2N1Cc1ccccc1
Reactant: CN(C)C=O
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CO
Solvent: O
Product: N#Cc1ccc2c(c1)C[C@H](NS(=O)(=O)c1ccccc1)C(=O)N2Cc1ccccc1
Temperature: 25 °C

Procedure:
A mixture of Example 8 (9 mg, 0.018 mmol), tetrakis(triphenylphosphine)-palladium (22 mg, 0.019 mmol), and Zn(CN)2 (15 mg, 0.128 mmol) in DMF (1 mL) stirring under argon was heated to 120° for 1 h. After cooling to RT, the heterogeneous was diluted with a 80% MeOH in H2O solution and filtered. The filtrate was directly injected to reverse phase preparative HPLC, which provided the title compound (7 mg). HPLC/MS retention time=3.3 min (Phenomenex Luna 5 micron C18 4.6 mm×50 mm column eluted with a 0% to 100% B solvent gradient over 4 min; solvent A=90% H2O, 10% MeOH, 10 mM NH4OAc and solvent B=10% H2O, 90% MeOH, 10 mM NH4OAc; flow rate=4.0 mL/min; UV detection at 220 nm); m/z=418 [M+H]+, 416 [M−H]−.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]([OH:10])[CH3:9])[CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](=[O:10])[CH3:9])[CH:3]=1
Reactant: CC(O)c1cc(Br)ccn1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(=O)c1cc(Br)ccn1

Procedure:
To a stirring solution of 1-(4-bromopyridin-2-yl)ethanol (2.93 g, 14.5 mmol) in DCM (50 mL) was added Dess-Martin periodinane (12.93 g, 30.5 mmol) portion-wise over several minutes. The reaction was then quenched with saturated 1:1 Na2S2O3/NaHCO3 solution (200 mL) and stirred until gas evolution ceased. The aqueous layer was extracted with DCM, dried over MgSO4, and purified by column chromatography (gradient 0 to 10% EtOAc in hexanes) to give the product. 1H NMR (400 MHz, CDCl3) δ 8.50 (d, J=5.2 Hz, 1H), 8.20 (d, J=1.9 Hz, 1H), 7.64 (dd, J=5.2, 1.9 Hz, 1H), 2.71 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][OH:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:27]=[C:26]2[C:21]([C:22](O)=[C:23]([C:29]3[CH:34]=[C:33]([CH3:35])[CH:32]=[C:31]([CH3:36])[CH:30]=3)[C:24](=[O:28])[NH:25]2)=[CH:20][C:19]=1[N+:38]([O-:40])=[O:39].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:22]1[C:21]2[C:26](=[CH:27][C:18]([Cl:17])=[C:19]([N+:38]([O-:40])=[O:39])[CH:20]=2)[NH:25][C:24](=[O:28])[C:23]=1[C:29]1[CH:30]=[C:31]([CH3:36])[CH:32]=[C:33]([CH3:35])[CH:34]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C)cc(-c2c(O)c3cc([N+](=O)[O-])c(Cl)cc3[nH]c2=O)c1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc([N+](=O)[O-])c(Cl)cc3[nH]c2=O)c1
Temperature: 25 °C
Reaction time: 64 h
Yield: 74.5 %

Procedure:
To a solution of 2-(2-hydroxyethyl)-piperidine-1-carboxylic acid tert-butyl ester (0.864 g in 38 mL dry tetrahydrofuran) was added 1.56 g of 7-chloro-3-(3,5-dimethylphenyl)-4-hydroxy-6-nitro- 1H-quinolin-2-one followed by 1.19 g of triphenylphosphine and the mixture stirred at room temperature. To this was added 0.72 mL of diethyl azodicarboxylate (DEAD) and stirring was continued for 64 hours. At this time the solvents were removed in vacuo and the residue purified by flash chromatography on silica gel (hexane:ethyl acetate, 6:4) to give the title compound (1.56 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:6][C@H:5]([CH2:7][N:8]2[C:12]([CH3:13])=[C:11](I)[CH:10]=[N:9]2)[CH2:4][O:3]1.C1COCC1.C([Mg]Cl)(C)C.CO[B:28]1[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]1.[NH4+].[Cl-]>>[CH3:1][C:2]1([CH3:15])[O:6][C@H:5]([CH2:7][N:8]2[C:12]([CH3:13])=[C:11]([B:28]3[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]3)[CH:10]=[N:9]2)[CH2:4][O:3]1
Reactant: COB1OC(C)(C)C(C)(C)O1
Reactant: Cc1c(I)cnn1C[C@@H]1COC(C)(C)O1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1c(B2OC(C)(C)C(C)(C)O2)cnn1C[C@@H]1COC(C)(C)O1
Reaction time: 1 h

Procedure:
To a solution of 1-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-4-iodo-5-methyl-1H-pyrazole (67.0 mg, 0.208 mmol) in THF (2 mL, 20 mmol) at rt was added 1.3 M of isopropylmagnesium chloride in THF (0.64 mL, 0.83 mmol), and the mixture was stirred for 1 h. The reaction was quenched with 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.1704 mL, 1.040 mmol), and allowed to stir at rt for 1 h. Sat. NH4Cl was added, and the organic solvent was removed in vacuo. The material was extracted with DCM and water. The organic layer was concentrated in vacuo to afford the title compound as a clear oil. MS (ES+): m/z=322.21/323.20/324.22 (50/100/50) [MH+]. HPLC: tR=1.49 min (polar—3 min, UPLC-ACQUITY).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10](=[O:17])[NH:9][C:8]2[CH:18]=[CH:19][CH:20]=[N:21][C:7]1=2)=[O:5].C(N(CC)CC)C>O1CCOCC1>[C:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10](=[O:17])[NH:9][C:8]2[CH:18]=[CH:19][CH:20]=[N:21][C:7]1=2)(=[O:5])[CH:3]=[CH2:2]
Reactant: O=C1Nc2cccnc2N(C(=O)CCCl)c2ccccc21
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: C=CC(=O)N1c2ccccc2C(=O)Nc2cccnc21

Procedure:
A solution of 11-(3-chloropropionyl)-5,11-dihydro-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one in dioxane was refluxed for one hour in the presence of an excess of triethylamine to obtain a good yield of 11-(acryloyl)-5,11-dihydro-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one which after crystallization from acetonitrile melted at 235° C. with decomposition.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([NH:10][C:11](=[O:18])OCC(Cl)(Cl)Cl)=[CH:8][N:7]=[CH:6][N:5]=1)[CH3:2].[C:19]1([C:25]2[N:26]=[C:27]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[S:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[CH2:1]([O:3][C:4]1[C:9]([NH:10][C:11]([N:33]2[CH2:34][CH2:35][N:30]([C:27]3[S:28][CH:29]=[C:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:26]=3)[CH2:31][CH2:32]2)=[O:18])=[CH:8][N:7]=[CH:6][N:5]=1)[CH3:2]
Reactant: CCOc1ncncc1NC(=O)OCC(Cl)(Cl)Cl
Reactant: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOc1ncncc1NC(=O)N1CCN(c2nc(-c3ccccc3)cs2)CC1
Yield: 43.1 %

Procedure:
A solution of 2,2,2-trichloroethyl (4-ethoxypyrimidin-5-yl)carbamate (315 mg, 1.00 mmol), 1-(4-phenyl-1,3-thiazol-2-yl)piperazine (245 mg, 1.00 mmol), diisopropylethylamine (0.174 ml, 1.00 mmol) and dimethylsulfoxide (5 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of ethyl acetate and hexane to obtain the desired product (177 mg, 43.2%) as a solid.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH2:10](Br)[CH2:11][CH2:12][CH3:13]>C1COCC1>[CH2:10]([CH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)[CH2:11][CH2:12][CH3:13]
Reactant: C1=Cc2ccccc2C1
Reactant: CCCCBr
Solvent: C1CCOC1
Product: CCCCC1C=Cc2ccccc21
Reaction time: 0.67 h

Procedure:
N-BuLi (173 mmol) was added to indene (173 mmol) in THF (70 mL) at ambient temperature using an oil bath as a heat sink. The reaction was stirred for 40 minutes, then added to n-butyl bromide (223 mmol) in THF (70 mL) at 0° C. The reaction was stirred overnight at ambient temperature, followed by standard aqueous workup. Evaporation of solvent followed by distillation under reduced pressure gave pure n-butylindene. n-BuLi (13.5 mmol) was added to n-butylindene (13.5 mmol) in THF (50 mL) and stirred for 1 hour. The solution was then added to ((tBu)3PN)TiCl3 (which was prepared by the reaction of TiCl4 with (tBu)3PN-TMS) slurried in toluene at −78° C. After stirring overnight at ambient temperature and the solvent was removed under vacuum. The residue was extracted into toluene, filtered and the filtrate concentrated. Addition of heptane precipitated the product that was isolated by filtration.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16](Cl)[N:15]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[NH2:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16]([C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([NH2:21])[CH:27]=3)[N:15]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: Nc1cccc(B(O)O)c1
Reactant: COc1cc(Nc2cncc(Cl)n2)cc(OC)c1OC
Product: COc1cc(Nc2cncc(-c3cccc(N)c3)n2)cc(OC)c1OC
Yield: 38.6 %

Procedure:
Using Method C with 1.0 g (3.4 mmol) 2a and 635 mg (4.1 mmol) 3-aminophenyl boronic acid, 463 mg pure title compound were obtained. The filtrate was submitted to purification by preparative HPLC (eluent:AcOEt) and another fraction of 412 mg was obtained. A total of 875 mg CJS 364 (72.9%) were obtained. Reaction time: 28 hours. 1H-NMR (DMSO), δ (ppm), J (Hz): 3.64 (s, 3H, CH3O(4′)), 3.81 (s, 6H, CH3O(3′+5′)), 5.19 (s, 2H, NH2), 6.66 (d, 1H, Harom 4′, J=7.70), 7.13 (t, 1H, Harom 5′, J=7.77), 7.22 (d, 1H, Harom 6′), 7.26 (s, 2H, Harom(2+6)), 7.29 (s, 1H, Harom 2′), 8.11 (s, 1H, HP5), 8.33 (s, 1H, HP3), 9.51 (s, 1H, NHamine);
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[O:13][C:12](=[O:14])[NH:11][CH:10]2[CH2:15]O)=[CH:5][CH:4]=1.ClC(F)C(N(CC)CC)(F)[F:20]>C(Cl)Cl.C(OCC)(=O)C>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[O:13][C:12](=[O:14])[NH:11][CH:10]2[CH2:15][F:20])=[CH:5][CH:4]=1
Reactant: CCN(CC)C(F)(F)C(F)Cl
Reactant: CSc1ccc(C2OC(=O)NC2CO)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CSc1ccc(C2OC(=O)NC2CF)cc1
Yield: 62 %

Procedure:
To a solution of 250 mg (1.0 mmole) of 5-(4-methylthiophenyl)-4-hydroxymethyl-oxazolidin-2-one in 30 ml of methylene chloride was added 0.21 ml (1.3 moles) of N-(2-chloro-1,1,2-trifluoroethyl)-diethylamine. The reaction mixture was heated in a teflon bomb at 110° C for 1.5 hours. The reaction mixture was cooled and diluted with ethyl acetate. The organic layer was washed twice with water, dried and concentrated. Chromatography on silica gel afforded 150 mg (0.62 mmole), 62% of 5-(4-methylthiophenyl)-4-fluoromethyl-oxazolidin-2-one.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([N:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]1.[Cl:25][C:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[C:28]([F:41])[C:27]=1[OH:42].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:1].[ClH:25].[Cl:25][C:26]1[CH:31]=[C:30]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([N:22]([CH3:23])[CH3:24])[CH2:18][CH2:17]2)[CH:29]=[C:28]([F:41])[C:27]=1[OH:42]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](N(C)C)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)nc2c1N[C@H]1CC[C@H](N(C)C)CC1

Procedure:
Following general procedure II, 1-{6-chloro-4-[trans-4-(dimethylamino)cyclohexyl amino)-1,5-naphthyridin-3-yl)ethanone (45 mg, 0.12 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (47 mg, 0.17 mmol) followed by formation of the dihydrochloride salt to afford the desired product (6.9 mg, 11%) as an off-white solid: 1H NMR (500 MHz, CD3OD) δ 9.17 (s, 1H), 8.47 (d, J=9.0 Hz, 1H), 8.34 (d, J=9.0 Hz, 1H), 8.00 (s, 1H), 7.91 (dd, J=11.4, 2.2 Hz, 1H), 5.69-5.59 (m, 1H), 3.52-3.45 (m, 1H), 2.92 (s, 6H), 2.76 (s, 3H), 2.63-2.56 (m, 2H), 2.33-2.26 (m, 2H), 1.89-1.71 (m, 4H). ESI MS m/z 457 [M+H]+; HPLC>99% (AUC), tR=9.32 min.
Reaction SMILES: CC(C[AlH]CC(C)C)C.CON(C)[C:13]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][C:19]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[N:18]2)=[O:14].C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1COCC1>[C:25]1([C:19]2[CH:20]=[N:21][C:22]3[C:17]([N:18]=2)=[CH:16][C:15]([CH:13]=[O:14])=[CH:24][CH:23]=3)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CON(C)C(=O)c1ccc2ncc(-c3ccccc3)nc2c1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=Cc1ccc2ncc(-c3ccccc3)nc2c1
Reaction time: 2.5 h

Procedure:
DIBAL (1.0 M in THF, 2.0 mL, 2.0 mmol was added to a THF (5 mL) solution of N-methoxy-N-methyl-3-phenylquinoxaline-6-carboxamide (198 mg, 0.67 mmol) under N2 over 10 min at −78° C. The reaction was stirred for 2.5 h at the temperature, then satd solution of potassium sodium tartrate (Rochelle salt), was added. The cooling bath was removed immediately after the addition. The reaction was stirred for 30 min turning into a clear orange solution. The crude mixture was extracted with DCM (3×), washed (satd Rochelle salt, brine), dried, concentrated and purified by flash chromatography (SiO2, 0-1.5 % MeOH in DCM) to afford the title compound as a white solid; 1H NMR (400 MHz, CDCl3) δ 10.27 (s, 1H), 9.43 (s, 1H), 8.63 (s, 1H), 8.26-8.20 (m, 4H), 7.65-7.52 (m, 3H). MS (ES+): m/z 235.1 (100) [MH+]; HPLC: tR=3.38 min (OpenLynx, polar—5 min).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][O:6][CH:7]2[C:12]1[NH:13][CH2:14][CH2:15][N:16]=1.C([Sn]([CH2:30][OH:31])(CCCC)CCCC)CCC>>[NH:13]1[CH2:14][CH2:15][N:16]=[C:12]1[CH:7]1[C:8]2[C:3](=[C:2]([CH2:30][OH:31])[CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:5][O:6]1
Reactant: Brc1cccc2c1CCOC2C1=NCCN1
Reactant: CCCC[Sn](CO)(CCCC)CCCC
Product: OCc1cccc2c1CCOC2C1=NCCN1

Procedure:
The title compound was prepared from 2-(5-bromoisochroman-1-yl)-4,5-dihydro-1H-imidazole (50 mg) and (tributylstannyl)methanol (86 mg) by using tetrakis(triphenyl-phosphine)palladium (10.28 mg) as catalyst, and the procedure of synthesis method C and separation methods F and G. (Yield 6.2 mg).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:15][C:16]([C:22]1[O:26][C:25]([C:27]2[C:32]([NH2:33])=[CH:31][C:30]([C:34]([F:37])([F:36])[F:35])=[C:29]([O:38][CH3:39])[N:28]=2)=[N:24][N:23]=1)([CH3:21])[C:17]([F:20])([F:19])[F:18])C1C=CC=CC=1.C([O-])=O.[NH4+]>CCO.[OH-].[OH-].[Pd+2]>[NH2:33][C:32]1[C:27]([C:25]2[O:26][C:22]([C:16]([OH:15])([CH3:21])[C:17]([F:20])([F:19])[F:18])=[N:23][N:24]=2)=[N:28][C:29]([O:38][CH3:39])=[C:30]([C:34]([F:35])([F:37])[F:36])[CH:31]=1
Reactant: COc1nc(-c2nnc(C(C)(OCc3ccccc3)C(F)(F)F)o2)c(N)cc1C(F)(F)F
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: COc1nc(-c2nnc(C(C)(O)C(F)(F)F)o2)c(N)cc1C(F)(F)F

Procedure:
To a stirring solution of 2-(5-(2-(benzyloxy)-1,1,1-trifluoropropan-2-yl)-1,3,4-oxadiazol-2-yl)-6-methoxy-5-(trifluoromethyl)pyridin-3-amine trifluoroacetate (Step 3) (450 mg, 0.973 mmol) in EtOH (25 ml) was added palladium hydroxide on carbon (45.1 mg, 0.321 mmol) followed by ammonium formate (614 mg, 9.73 mmol). The mixture was heated at reflux for 1 h and then filtered through Celite® washing through with EtOH followed by water. The ethanol was removed in vacuo and the resultant aqueous phase was extracted with EtOAc. The combined organic extracts were washed with water, brine, dried (MgSO4) and concentrated in vacuo to afford the title product; 1H NMR (400 MHz, DMSO-d6) δ 7.85 (1H, s), 7.74 (1H, s), 6.74 (2H, s), 3.94 (3H, s), 1.86 (3H, s). LC-MS Rt=1.17 min [M+H]+ 373.1 Method: 2minLC_v003.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[C:17]1([OH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1[O:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Oc1ccccc1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: Nc1nc(Oc2ccccc2)c(Br)c(-c2ccco2)n1

Procedure:
From 5-bromo-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine, phenol and DBU in dioxane. EI-MS m/e (%): 333 (M{81Br}+, 64), 331 (M{79Br}+, 68), 252 ([M—Br]+, 100), 159 (98).