Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:30])[C:6]([CH2:12][N:13]1[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]1=[O:23])=[N:7]2.CC(C)=O.Cl.N([O-])=O.[Na+].[I-:40].[K+]>>[Cl:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:5]1[C:6]([CH2:12][N:13]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]2=[O:23])=[N:7][C:8]2[C:3]([N:4]=1)=[C:2]([I:40])[CH:11]=[CH:10][CH:9]=2
Reactant: [I-]
Reactant: Nc1cccc2nc(CN3C(=O)c4ccccc4C3=O)c(-c3ccccc3Cl)nc12
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1c2ccccc2C(=O)N1Cc1nc2cccc(I)c2nc1-c1ccccc1Cl
Temperature: 0 °C

Procedure:
2-((5-amino-3-(2-chlorophenyl)quinoxalin-2-yl)methyl)isoindoline-1,3-dione (Prepared in Example 97, 0.8364 g, 2.016 mmol) was dissolved in acetone (28.80 mL, 2.016 mmol) and cooled to 0° C. While being stirred, the solution was treated first with 2 M hydrochloric acid (5.645 mL, 11.29 mmol) and then dropwise with 1 M aq. sodium nitrite (6.049 mL, 6.049 mmol) while maintaining the temperature of the mixture at 0° C. After the additions were complete, the mixture was stirred for 15 min and then treated with 5 M aq. potassium iodide (4.839 mL, 24.19 mmol) maintaining the temperature below 5° C. The mixture was then allowed to warm to 15° C. over 3 h. The acetone was removed under reduced pressure, and the residue was partitioned between water (100 mL) and ethyl acetate (100 mL). The organic solution was washed with 10% aqueous sodium bisulfite (100 mL×3) and saturated aqueous sodium bicarbonate (100 mL×1), brine (100 mL×1), dried over MgSO4, filtered, and concentrated under reduced pressure to give a red solid. The red solid was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 25 min and then 50% isocratic of EtOAc in hexane for 25 min as eluent to give 2-((3-(2-chlorophenyl)-5-iodoquinoxalin-2-yl)methyl)-isoindoline-1,3-dione as a solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.48 (1 H, dd, J=7.4, 1.2 Hz), 7.97 (1 H, dd, J=8.2, 1.2 Hz), 7.83-7.91 (4 H, m), 7.51-7.75 (5 H, m), 4.96 (2 H, d, J=21.9 Hz); LC-MS (ESI) m/z 526.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH2:10][OH:11].CCN(C(C)C)C(C)C.Cl[C:22](OCC)=[O:23]>C1COCC1>[O:23]=[C:22]1[NH:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[CH2:10][O:11]1
Reactant: CCOC(=O)Cl
Reactant: N#Cc1ccc(N)c(CO)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc2c(c1)COC(=O)N2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
20 mmol of 4-Amino-3-hydroxymethyl-benzonitrile were dissolved in THF. 1.2 eq. of DIPEA were added and the reaction cooled to 0° C. 3.5 eq of ethyl chloroformate were added dropwise and the reaction warmed to rt and stirred for another 15 min. The crude material was extracted form etyhlacetate and sat. NaHCO3. After separation, and drying of the organic layer the solvent was evaporated and the crude taken up in toluene. 2.5 ml of DBU were added and the reaction mixture refluxed for 4 h. The organic layer was extracted with water and the organic layer separated and reduced resulting in a yellow oil. Crude material was not further characterized.
Reaction SMILES: [CH2:1]([C:3]1[C:12]([CH:13]=[O:14])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:15][CH3:16])[CH:9]=2)[N:4]=1)[CH3:2].[BH4-].[Na+]>C1COCC1>[CH2:1]([C:3]1[C:12]([CH2:13][OH:14])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:15][CH3:16])[CH:9]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccc(OC)cc2cc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1nc2ccc(OC)cc2cc1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To a solution of 2-ethyl-6-methoxyquinoline-3-carbaldehyde SMA 44004 (256 mg, 1.19 mmol) in THF (12 mL) in a 25 mL round-bottomed flask equipped with a magnetic stirrer was added NaBH4 (48 mg, 1.25 mmol) and the mixture was stirred for 2 h at RT, then quenched by careful addition of 2 N aqueous HCl (2.6 mL). After stirring for 30 min at RT, the mixture was basified with 2 N aqueous NaOH (2.6 mL) and THF was removed at 40° C. under vacuum. The residue was diluted with CH2Cl2 (50 mL) and the organic phase was isolated, washed with brine (10 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent cyclohexane:EtOAc=100:0 to 50:50) gave (2-ethyl-6-methoxyquinolin-3-yl)-methanol SMA 44008 as a white solid (173 mg, 67% yield).
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C@@H:6]([OH:13])[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:21][C:22]1[N:26]([CH2:27][C:28]([N:30]2[CH2:35][CH2:34][CH:33]([C:36]3[S:37][CH:38]=[C:39]([C:41](Cl)=[O:42])[N:40]=3)[CH2:32][CH2:31]2)=[O:29])[N:25]=[C:24]([C:44]([F:47])([F:46])[F:45])[CH:23]=1>ClCCl>[CH3:1][N:2]([C@H:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C@@H:6]([OH:13])[CH2:5][CH2:4]1)[C:41]([C:39]1[N:40]=[C:36]([CH:33]2[CH2:34][CH2:35][N:30]([C:28](=[O:29])[CH2:27][N:26]3[C:22]([CH3:21])=[CH:23][C:24]([C:44]([F:45])([F:47])[F:46])=[N:25]3)[CH2:31][CH2:32]2)[S:37][CH:38]=1)=[O:42]
Reactant: CN[C@@H]1CC[C@H](O)c2ccccc21
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)Cl)cs2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)N(C)[C@@H]3CC[C@H](O)c4ccccc43)cs2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (1S,4R)-1,2,3,4-tetrahydro-4-(methylamino)-1-naphthalenol and its enantiomer (283 mg, 1.6 mmol) (i.e. the product of Example 26, Step A) and triethylamine (0.5 mL, 3.6 mmol) in 5 mL of dichloromethane was gradually added 2-[1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-4-thiazolecarbonyl chloride (605 mg, 1.44 mmol) (i.e. the product of Example 19, Step D) at 0° C. The reaction mixture was stirred at room temperature for 1 h, diluted with dichloromethane, and washed with water, 1 N aqueous hydrochloric acid, water, saturated solution of sodium bicarbonate and brine. The filtered reaction mixture was dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by medium-pressure liquid chromatography on silica gel using 0-20% of acetone in ethyl acetate as eluant to give 700 mg of the title compounds, compounds of the present invention as an off-white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:14][CH3:15])[C:5](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:6]([OH:8])=[O:7].S(=O)(=O)(O)O.[CH3:21]O>>[Cl:1][C:2]1[CH:3]=[C:4]([O:14][CH3:15])[C:5](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:6]([O:8][CH3:21])=[O:7]
Reactant: CO
Reactant: COc1cc(Cl)c([N+](=O)[O-])cc1C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc([N+](=O)[O-])c(Cl)cc1OC
Temperature: 0 °C

Procedure:
To a solution of 3.1 g of 4-chloro-5-nitro-o-anisic acid in methanol (100 ml) was added a catalytic amount of sulfuric acid and the resulting mixture was heated under reflux for 3 hours. Then the reaction mixture was poured into ice/water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, 3.3 g of methyl 4-chloro-5-nitro-o-anisate was obtained as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:34])=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:13][C@@H:12]([F:14])[CH2:11][N:10]1[C:15](=[O:30])[CH2:16][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([OH:26])[CH:24]=2)[C:19]([C:27]([NH2:29])=[O:28])=[CH:18]1)=[O:8].C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:42][C:43]1[NH:47][N:46]=[N:45][N:44]=1.Cl>CS(C)=O.O>[Cl:1][C:2]1[C:3]([F:34])=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:13][C@@H:12]([F:14])[CH2:11][N:10]1[C:15](=[O:30])[CH2:16][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH2:42][C:43]3[NH:47][N:46]=[N:45][N:44]=3)[CH:24]=2)[C:19]([C:27]([NH2:29])=[O:28])=[CH:18]1)=[O:8]
Reactant: NC(=O)c1cn(CC(=O)N2C[C@H](F)C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2cc(O)ccc12
Reactant: ClCc1nnn[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1cn(CC(=O)N2C[C@H](F)C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2cc(OCc3nnn[nH]3)ccc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 1-{2-[(2S,4R)-2-(3-chloro-2-fluoro-benzylcarbamoyl)-4-fluoro-pyrrolidin-1-yl]-2-oxo-ethyl}-6-hydroxy-1H-indole-3-carboxylic acid amide Example 578 (148 mg, 0.283 mmol) in DMSO (3 mL) was treated with Cs2CO3 (0.28 g, 0.85 mmol). The mixture was stirred at RT for 5 min, followed by addition of 5-(chloromethyl)-1H-tetrazole (35 mg, 0.098 mmol) and stirring at RT for 36 h. The reaction mixture was neutralised by addition of 1N HCl. Water was then added to the mixture to form a precipitate. The solid material was filtered off, washed with water, and dried in vacuo to afford the title compound as a solid. MS (LC/MS): 573 [M+H]+; tR (HPLC conditions k): 2.92 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[CH2:9][OH:10].[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([O:22][CH3:23])=[C:16]([S:18](Cl)(=[O:20])=[O:19])[CH:17]=1>N1C=CC=CC=1>[Br:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:9][OH:10])=[C:2]([NH:1][S:18]([C:16]2[CH:17]=[C:12]([Cl:11])[CH:13]=[CH:14][C:15]=2[O:22][CH3:23])(=[O:19])=[O:20])[CH:7]=1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Reactant: Nc1cc(Br)ccc1CO
Solvent: c1ccncc1
Product: COc1ccc(Cl)cc1S(=O)(=O)Nc1cc(Br)ccc1CO
Temperature: 0 °C
Reaction time: 72 h
Yield: 81.5 %

Procedure:
A solution of (2-amino-4-bromo-phenyl)-methanol (1.53 g, 7.57 mmol) in pyridine (15 mL) was treated with 5-chloro-2-methoxybenzenesulfonyl chloride (1.85 g, 7.57 mmol) at room temperature and stirred for 72 h, then poured upon ice-cold 2 M aq. hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated to produce a gummy residue, from which the product was precipitated by addition of toluene. The precipitate was collected by filtration and dried to afford N-(5-bromo-2-hydroxymethyl-phenyl)-5-chloro-2-methoxy-benzenesulfonamide (2.51 g, 82%). Off-white solid, MS (ISP)=404.2 (M−H)−.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]([C:15]([O:17]C)=[O:16])=[N:8]1.[OH-].[Li+]>CO.C1COCC1.O.O>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]([C:15]([OH:17])=[O:16])=[N:8]1
Reactant: COC(=O)c1cc([N+](=O)[O-])n(C2CCCCO2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1cc([N+](=O)[O-])n(C2CCCCO2)n1
Reaction time: 16 h
Yield: 177.7 %

Procedure:
Methyl 1-(tetrahydro-2H-pyran-2-yl)-5-nitro-1H-pyrazole-3-carboxylate (500 mg, 0.70 mmol) was dissolved in a mixture of MeOH/THF/H2O (1:2:1, 20 mL). Lithium hydroxide (56.3 mg, 2.35 mmol) was added and the reaction mixture was stirred for 16 hrs. The reaction mixture was diluted with water and washed with DCM. The aqueous phase was evaporated which gave 1-(tetrahydro-2H-pyran-2-yl)-5-nitro-1H-pyrazole-3-carboxylic acid (300 mg, 64%) as a white solid which was used without further purification in the next step.
Reaction SMILES: [F:1][C:2]1([F:14])[O:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[O:4][C:3]1([F:13])[F:12].[B:15]1(B2OC(C)(C)C(C)(C)O2)[O:19]C(C)(C)C(C)(C)[O:16]1.O1CCOCC1.I(O)(=O)(=O)=O>O.CO>[F:13][C:3]1([F:12])[O:4][C:5]2[CH:11]=[CH:10][C:9]([B:15]([OH:19])[OH:16])=[CH:8][C:6]=2[O:7][C:2]1([F:1])[F:14]
Reactant: FC1(F)Oc2ccccc2OC1(F)F
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: [O-][I+3]([O-])([O-])O
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: OB(O)c1ccc2c(c1)OC(F)(F)C(F)(F)O2
Temperature: 100 °C
Reaction time: 2 h
Yield: 78.6 %

Procedure:
2,2,3,3-Tetrafluoro-1,4-benzodioxane (484 mg), bis(pinacolato)diboron (295 mg), [Ir(COD)(OMe)]2 (15.4 mg) and 4,4′di-tert-butyl-2,2′-dipyridyl (12.5 mg) were mixed. 1,4-Dioxane (0.5 mL) was added in a nitrogen atmosphere and stirred at 100° C. for two hours. MeOH (0.5 mL) was added to the reaction solution, and metaperiodic acid (1.06 g) was added in four portions under ice-cooling. Water was added to the reaction solution, followed by extraction with ethyl acetate and concentration. The resulting mixture was purified by silica gel column chromatography to give 2,2,3,3-tetrafluoro-2,3-dihydro-benzo[1,4]dioxin-6-yl-boronic acid (230 mg, 39%).
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:13]([O:15][CH3:16])=[O:14])=[N:6][NH:7][C:8]=1[C:9]([O:11][CH3:12])=[O:10])([O-:3])=[O:2].[CH2:17]([O:20][CH2:21][CH2:22]O)[CH2:18][CH3:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[N+:1]([C:4]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[N:7][N:6]([CH2:22][CH2:21][O:20][CH2:17][CH2:18][CH3:19])[C:5]=1[C:13]([O:15][CH3:16])=[O:14])([O-:3])=[O:2]
Reactant: CCCOCCO
Reactant: COC(=O)c1n[nH]c(C(=O)OC)c1[N+](=O)[O-]
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCOCCn1nc(C(=O)OC)c([N+](=O)[O-])c1C(=O)OC
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Dimethyl 4-nitro-1H-pyrazole-3,5-dicarboxylate (WO00/24745, page 48, preparation 2) (15 g, 60 mmol), 2-propoxyethanol (8.2 mL, 70 mmol) and triphenylphosphine (18.9 g, 70 mmol) were dissolved in tetrahydrofuran (105 mL) and the solution cooled to 0° C. The solution was treated with diisopropyl azodicarboxylate (14.2 mL, 70 mmol) and the reaction mixture stirred at 0° C. for 3 hours before being allowed to warm to room temperature. The reaction mixture was concentrated in vacuo and the residue purified by column chromatography on silica gel eluting with ethyl acetate:pentane 15:85 and then again eluting with dichloromethane to yield the title product. 1H NMR (CD3OD, 400 MHz) δ: 0.82 (t, 3H), 1.47 (q, 2H), 3.34 (t, 2H), 3.78 (t, 2H), 3.91 (s, 6H), 4.76 (t, 2H). MS APCI+ m/z 316 [MH]+
Reaction SMILES: F[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[CH3:19])=O.O.[NH2:21][NH2:22]>CN(C1C=CN=CC=1)C>[Cl:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:2]=1[NH:22][N:21]=[C:9]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[CH3:19]
Reactant: NN
Reactant: COc1ccc(C(=O)c2cccc(Cl)c2F)c(C)c1
Agent: CN(C)c1ccncc1
Solvent: O
Product: COc1ccc(-c2n[nH]c3c(Cl)cccc23)c(C)c1
Yield: 49.7 %

Procedure:
Prepared according to Method D Step A from [2-fluoro-3-chlorophenyl](4-methoxy-2-methylphenyl)methanone (1.26 g, 4.52 mmol), hydrazine hydrate (1.61 mL, 51.7 mmol) and DMAP (0.632 g, 5.17 mmol) to give the product (0.613 g) as a yellow solid.
Reaction SMILES: [CH2:1]1[O:10][C:9]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[O:2]1.[C:11](Cl)(Cl)=[O:12]>C1(C)C=CC=CC=1>[CH2:1]1[O:10][C:9]2[CH:8]=[CH:7][C:5]([N:6]=[C:11]=[O:12])=[CH:4][C:3]=2[O:2]1
Reactant: O=C(Cl)Cl
Reactant: Nc1ccc2c(c1)OCO2
Solvent: Cc1ccccc1
Product: O=C=Nc1ccc2c(c1)OCO2

Procedure:
A mixture of 3,4-methylenedioxyaniline (275 mg; 2.0 mmol) in toluene (15 ml) and phosgene (4.75 ml; 20% in toluene; 9 mmol) was refluxed for 6 h. The solvent was removed under reduced pressure to give crude 3,4-methylenedioxyphenylisocyanate. The crude product was added to 3-[4-(2-chlorophenyl) -1-piperazinyl]propanol (510 mg; 2.0 mmol) in toluene (30 ml) was refluxed for 16 h. The reaction mixture was then concentrated and submitted to flash chromatography on silica gel 60 eluting with toluene graduated to toluene/ethyl acetate (1:3). The product was taken up in ethanol which was treated with hydrogen chloride in ether. Recrystallization from methanol/ether afforded 550 mg of the title compound. M.p. 211°-213° C. MS (70 eV): m/z 37%, M+), 254 (28), 209 (100), 163 (75), 138 (32), 70 (42).
Reaction SMILES: [N+:1]([C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[OH:13])([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:21][CH2:22][O:23][CH3:24]>CC(C)=O>[CH3:24][O:23][CH2:22][CH2:21][O:13][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(O)c1[N+](=O)[O-]
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCCOc1cccc([N+](=O)[O-])c1[N+](=O)[O-]

Procedure:
1.50 g (8.15 mmol) 2,3-Dinitro-phenol were dissolved in 75 mL acetone. Subsequently 1.69 g (12.22 mol) K2CO3, 135.3 mg KI (0.81 mmol) and 0.93 mL (9.77 mmol) 1-bromo-2-methoxy-ethane were added. The reaction mixture was refluxed for 8 h. After that time further 1.69 g (12.22 mol) K2CO3, 400 mg KI and 0.93 mL (9.77 mmol) 1-bromo-2-methoxy-ethane were added. The resulting mixture was refluxed for 16 h and then concentrated under reduced pressure. The residue was dissolved in warm ethyl acetate and purified by flash-chromatography on silica gel using an ethyl acetate/heptane-mixture as eluent to afford 1-(2-Methoxy-ethoxy)-2,3-dinitro-benzene as an orange crystalline material. Yield: 1.35 g MS (ES+): m/e=243.
Reaction SMILES: C([O:8][C:9]1[C:10]([Cl:24])=[CH:11][C:12]([Cl:23])=[C:13]2[C:18]=1[N:17]=[C:16]([CH2:19][N:20]([CH3:22])[CH3:21])[CH:15]=[N:14]2)C1C=CC=CC=1>Cl>[ClH:23].[Cl:24][C:10]1[CH:11]=[C:12]([Cl:23])[C:13]2[N:14]=[CH:15][C:16]([CH2:19][N:20]([CH3:21])[CH3:22])=[N:17][C:18]=2[C:9]=1[OH:8]
Reactant: CN(C)Cc1cnc2c(Cl)cc(Cl)c(OCc3ccccc3)c2n1
Agent: Cl
Product: CN(C)Cc1cnc2c(Cl)cc(Cl)c(O)c2n1
Yield: 166.7 %

Procedure:
A solution of (8-benzyloxy-5,7-dichloro-quinoxalin-2-ylmethyl)dimethylamine (38 mg, 0.105 mmol) in conc HCl (2 mL) was stirred at room temperature for 16 h. The orange solution was concentrated to dryness and the remaining residue was washed with diethyl ether (2 ml×3) to give the desired product as a light yellow solid (27 mg, 83%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:22][S:23]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1.[NH4+:34].[OH-]>>[NH2:34][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:22][S:23]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CN(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Reactant: [NH4+]
Agent: [OH-]
Product: CN(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(N)n2)s1
Temperature: 140 °C
Yield: 31 %

Procedure:
N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(dimethylamino)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide (0.1 g, 0.2 mmol) was taken up in 2 mL 30% NH4OH (aq) and heated to 140° C. for 20 min in a microwave reactor. The solvent was removed under reduced pressure and the residue taken up in EtOAc and washed with 2 mL of 0.1 N HCl (aq). The organic layer was dried over Na2SO4 and evaporated onto silica gel. Purification by flash chromatography (0 to 40% EtOAC/DCM) afforded the title compound (30 mg, 0.061 mmol, 31% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.98 (s, 1H), 7.59-7.70 (m, 2H), 7.26-7.35 (m, 1H), 7.15-7.25 (m, 4H), 7.09 (d, J=7.5 Hz, 1H), 6.48 (s, 2H), 5.68 (d, J=5.3 Hz, 1H), 3.03 (s, 6H)). MS (ESI): 489 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C1(S(O[CH2:22][CH2:23][Cl:24])(=O)=O)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)CC(=O)C>[Cl:24][CH2:23][CH2:22][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: O=S(=O)(OCCCl)c1ccccc1
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: COC(=O)c1ccc(OCCCl)cc1

Procedure:
A mixture of methyl 4-hydroxybenzoate (15.2 g, 0.1 M), 2-(benzenesulphonyloxy)ethyl chloride (28.65 g, 0.12 M) and potassium carbonate (19.15 g, 0.1 M) in 4-methylpentan-2-one (170 ml) was stirred at reflux for 24 hours. After cooling, distilled water (170 ml) was added and the organic phase separated off. Evaporation to dryness gave a yellow solid which was crystallised from ethanol to give the title compound, yield (13.3 g), m.p. 56°-58°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]P(OCC)(OCC)=O)=[CH:6][CH:5]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:30][C:31]1([CH3:49])[C:40]2[C:35](=[CH:36][C:37]([CH:41]([CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH:42]=O)=[CH:38][CH:39]=2)[O:34][CH2:33][CH2:32]1>C1COCC1>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:5]=[CH:6][C:7]([CH:10]=[CH:42][CH:41]([C:37]2[CH:36]=[C:35]3[C:40]([C:31]([CH3:49])([CH3:30])[CH2:32][CH2:33][O:34]3)=[CH:39][CH:38]=2)[CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[CH:8][CH:9]=1
Reactant: CCCCCC(C=O)c1ccc2c(c1)OCCC2(C)C
Reactant: CCOP(=O)(Cc1ccc(C(=O)OC)cc1)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCC(C=Cc1ccc(C(=O)OC)cc1)c1ccc2c(c1)OCCC2(C)C
Temperature: -20 °C
Reaction time: 6 h
Yield: 42.4 %

Procedure:
A solution of 4-(diethoxyphosphorylmethyl)-benzoic acid methyl ester (0.25 g, 0.87 mmole) in 5 mL of THF at −20° C., was treated with 0.88 mL of 1M lithium bis(trimethylsilyl)amide solution in hexanes. The mixture was stirred at −20° C. for 20 minutes before a solution of 2-(4,4-dimethyl-chroman-7-yl)-heptanal (0.16 g, 0.58 mmole) in 5 mL of THF was added. The reaction mixture was stirred at −20° C. for 30 minutes, at room temperature for 6 hours, quenched by the addition of 10 mL of saturated aqueous ammonium chloride solution and extracted with three 10 mL portions of ethyl acetate. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo, to give a yellow oil. The product was purified by flash chromatography (SiO2, 10% ethyl acetate in hexanes) to yield 0.1 g of 4-[3-(4,4-dimethyl-chroman-7-yl)-oct-1-enyl]-benzoic acid methyl ester as a colorless oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:11][C:12]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[O:13])=[C:8](I)[CH:9]=1)(=[O:3])[CH3:2].[C:27](=O)([O-:29])[O-:28].[K+].[K+].[OH-].[Na+]>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.[Cu](I)I>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:11][C:12]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[O:13])=[C:8]([CH:9]=1)[C:27]([OH:29])=[O:28])(=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1ccc(NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c(I)c1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: CC#N
Product: CC(=O)c1ccc(NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c(C(=O)O)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 37.6 %

Procedure:
To a stirring solution of 5-acetyl-2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-1-iodobenzene (4.5 g, 9.53 mmol) in acetonitrile (150 mL) was added potassium carbonate (6.6 g, 47.7 mmol), followed by tetrakis(triphenylphosphine)palladium(0) (0.55 g, 0.48 mmol), and copper iodide (91 mg, 0.48 mmol). The mixture was placed under an atmosphere of carbon monoxide and heated to 80° C. After 3 h, 1 N aqueous sodium hydroxide (50 mL) was added to the hot reaction solution. The solution was stirred for 10 min and concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The aqueous phase was filtered, acidified to pH 3 with citric acid, and extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give 1.4 g (38%) of a white solid.