Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1CCC[C@@H]1C[N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][O:10][C:9]2[CH:18]=[CH:19][CH:20]=[CH:21][C:8]1=2.C(OC(NC1C=CC(CCCl)=CC=1)=O)(C)(C)C.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(#N)C>[CH:17]1[C:12]2[C:13](=[N:7][C:8]3[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=3[O:10][CH:11]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: c1ccc2c(c1)COc1ccccc1N2C[C@H]1CCCN1
Agent: CC(C)(C)OC(=O)Nc1ccc(CCCl)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: C1=c2ccccc2=Nc2ccccc2O1
Temperature: 90 °C

Procedure:
(R)-5,11-dihydro-5-(2-pyrrolidinylmethyl)dibenzo[b,e][1,4]oxazepine (Preparation Example 1) (220 mg, 0.78 mmol), 2-[4-(N-t-butoxycarbonylamino)phenyl]ethyl chloride (400 mg, 1.02 mmol), sodium carbonate (110 mg, 1.02 mmol) and sodium iodide (20 mg, 0.13 mmol) were added to acetonitrile (15 ml), and the mixture was heated under reflux at 90° C. for 15 hours. The solvent was evaporated under reduced pressure, and the residue was partitioned in ethyl acetate and water. The organic layer was washed with water and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was treated by the column chromatography and then eluted with dichloromethane as the eluent. A suitable fraction was collected, and the solvent was evaporated under reduced pressure to obtain (R)-5,11-dihydro-5-[1-[2-(4-N-t-butoxycarbonylamino)phenyl)ethyl]-2-pyrrolidinylmethyl]dibenzo[b,e][1,4]oxazepine in the form of a light yellow oil (380 mg, 97%).
Reaction SMILES: C[O:2][C:3](=[O:49])[CH2:4][CH2:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]C)=[O:19])=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:39]=[CH:38][C:32]2[C:33](=[O:37])[CH2:34][CH2:35][O:36][C:31]=2[C:30]=1[CH2:40][CH2:41][CH2:42]C1C=CC=CC=1.[OH-].[Li+]>O1CCCC1>[C:18]([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]2[CH:39]=[CH:38][C:32]3[C:33](=[O:37])[CH2:34][CH2:35][O:36][C:31]=3[C:30]=2[CH2:40][CH2:41][CH3:42])[C:6]=1[CH2:5][CH2:4][C:3]([OH:49])=[O:2])([OH:20])=[O:19]
Reactant: COC(=O)CCCCCOc1cccc(CCCCCCOc2ccc3c(c2CCCc2ccccc2)OCCC3=O)c1CCC(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCc1c(OCCCCCCc2cccc(OCCCCCC(=O)O)c2CCC(=O)O)ccc2c1OCCC2=O
Yield: 98 %

Procedure:
The 2-[6-[[3,4-dihydro-4-oxo-8-(3-phenylpropyl)-2H-1-benzopyran-7-yl)oxy]hexyl]-6-[(6-methoxy-6-oxohexyl)oxy]benzenepropanoic acid methyl ester from the preceding example (0.38 g; 0.565 mmol) was saponified by stirring with 2 mL of 3N aqueous lithium hydroxide, in 15 mL of tetrahydrofuran for 24 hr, at room temperature. Work-up as in example 4 followed by flash-chromatography on silica gel (eluting with 96:3:1 chloroform-methanol-acetic acid) and recrystallization from hexane-ethyl acetate gave 0.36 g (98%) of the title compound as a colorless solid, mp 97°-98° C.
Reaction SMILES: [CH2:1]([C@@:4]1([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:33][CH3:34])[CH2:25][NH:26][S:27]([CH:30]2[CH2:32][CH2:31]2)(=[O:29])=[O:28])[C:5]1=[O:35])[CH:2]=[CH2:3].[H-].[Na+].I[CH3:47]>C1COCC1>[CH2:1]([C@@:4]1([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH2:33][CH3:34])[CH2:25][N:26]([CH3:47])[S:27]([CH:30]2[CH2:31][CH2:32]2)(=[O:28])=[O:29])[C:5]1=[O:35])[CH:2]=[CH2:3]
Reactant: CI
Reactant: C=CC[C@@]1(COCC[Si](C)(C)C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CNS(=O)(=O)C2CC2)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC[C@@]1(COCC[Si](C)(C)C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN(C)S(=O)(=O)C2CC2)C1=O

Procedure:
A solution of N-((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)piperidin-1-yl)butyl)cyclopropanesulfonamide (Example 414, Step C, 1.5 g, 2.253 mmol) in THF was treated with sodium hydride (60% dispersion in mineral oil, 6.76 mmol) and iodomethane (0.280 ml, 4.51 mmol) at room temperature for 3 hours. The reaction mixture was quenched with HCl (1N) and diluted with DCM. The organic extract was washed with satd NaCl and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as an oil. The product was purified by chromatography through a RediSep® pre-packed silica gel column (Teledyne Isco, Lincoln, Nebr.) (4 g), eluting with a gradient of 0% to 80% EtOAc in hexane, to provide the title compound as an oil.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[S:8][C:9]([NH:11][C:12](=[O:23])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=3)=[N:10][C:5]2=[CH:4][CH:3]=1.[CH3:24][C:25]1[C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][NH:27][N:26]=1>>[OH:22][C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]([NH:11][C:9]2[S:8][C:6]3[C:5]([N:10]=2)=[CH:4][CH:3]=[C:2]([C:29]2[C:25]([CH3:24])=[N:26][NH:27][CH:28]=2)[N:7]=3)=[O:23])=[CH:14][CH:15]=1)([CH3:21])[CH3:20]
Reactant: Cc1n[nH]cc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(O)c1ccc(C(=O)Nc2nc3ccc(Br)nc3s2)cc1
Product: Cc1n[nH]cc1-c1ccc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)sc2n1
Yield: 11 %

Procedure:
The titled compound (yield=11%, white solid) was prepared using a procedure analogous to that described in connection with 9 (Example 9) except 1D (Example 1) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole were used as starting materials. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (s, 6H) 2.58 (s, 3H) 7.66 (d, J=8.59 Hz, 2H) 7.74 (d, J=8.59 Hz, 1H) 8.09 (d, J=8.59 Hz, 4H) 12.86 (s, 1H); ESI-MS: m/z 394.0 (M+H)+.
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:25])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]2[NH:21][CH2:22][CH2:23][N:24]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].NC1C=CC(C=O)=C(C2NCCN=2)C=1.ClC1C=CC(C(=O)CC2C=CC=CC=2)=C(C2NCCN=2)C=1.N1CCN=C1C1C=CC=CC=1C1C=CSC=1C(C1SC=CC=1C1C=CC=CC=1C1NCCN=1)=O>>[CH2:1]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2([OH:25])[C:14]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:20]3=[N:21][CH2:22][CH2:23][N:24]23)=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1ccc(C(=O)c2ccccc2C2=NCCN2)cc1
Agent: Nc1ccc(C=O)c(C2=NCCN2)c1
Agent: O=C(Cc1ccccc1)c1ccc(Cl)cc1C1=NCCN1
Agent: O=C(c1sccc1-c1ccccc1C1=NCCN1)c1sccc1-c1ccccc1C1=NCCN1
Product: CCCCCCc1ccc(C2(O)c3ccccc3C3=NCCN32)cc1

Procedure:
In a similar manner, the following sulfates are synthesized: 4'-hexyl-2-(2-imidazolin-2-yl)benzophenone; 4-amino-2-(2-imidazolin-2-yl)benzaldehyde; 4'-chloro-2'-(2-imidazolin-2-yl)-2-phenylacetophenone; and 2-(2-imidazolin-2-yl)phenyl-2-thienyl ketone which are then contacted with a base to respectively afford the following: 5-(4-hexylphenyl)2,3-dihydro-5H-imidazo[2,1-a]isoindol-5-ol; 8-amino-2,3-dihydro-5H-imidazo[2,1-a]isoindol-5-ol; 8-chloro-5-(4-ethylphenyl)-2,3-dihydro-5H-imidazo[2,1-a]isoindol-5-ol; and 2,3-dihydro-5-(2-thienyl)-5H-imidazo[2,1-a]isoindol-5-ol.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:9]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:11]3[C:16](=O)O[C:13](=[O:14])[C:12]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:36][C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][C:45]=1[NH2:46])[C:40]([OH:42])=[O:41]>C(O)(=O)C>[C:1]1([C:7]2[C:8]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:9]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:10]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[C:11]3[C:12]=2[C:13](=[O:14])[N:46]2[C:45]4[CH:44]=[CH:43][C:39]([C:40]([OH:42])=[O:41])=[CH:38][C:37]=4[N:36]=[C:16]23)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccc(C(=O)O)cc1N
Reactant: O=C1OC(=O)c2c1c(-c1ccccc1)c(-c1ccccc1)c(-c1ccccc1)c2-c1ccccc1
Solvent: CC(=O)O
Product: O=C(O)c1ccc2c(c1)nc1n2C(=O)c2c(-c3ccccc3)c(-c3ccccc3)c(-c3ccccc3)c(-c3ccccc3)c2-1
Temperature: 105 °C
Reaction time: 72 h

Procedure:
Into a reaction vessel equipped with a condenser, light nitrogen purge and magnetic stirrer, 10 g (0.022 mol) of tetraphenylphthalic anhydride and 3.35 g (0.022 mol) of 3,4 diaminobenzoic acid are added, along with 100 ml of acetic acid. The gray colored reaction mixture is heated to reflux temperature. After several hours the reaction begins to take-on a dark yellow color. The reaction mixture is then left for a further 72 hours at slightly below reflux temperature (105° C.).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8](Br)=[C:7]([O:14][CH3:15])[CH:6]=1)[CH3:2].C([Li])CCC.[B:21](OC)([O:24]C)[O:22]C.S(=O)(=O)(O)O>O1CCCC1>[CH2:1]([O:3][CH2:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([B:21]([OH:24])[OH:22])=[C:7]([O:14][CH3:15])[CH:6]=1)[CH3:2]
Reactant: COB(OC)OC
Reactant: CCOCc1cc(OC)c(Br)c(OC)c1
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOCc1cc(OC)c(B(O)O)c(OC)c1
Reaction time: 1 h
Yield: 81.5 %

Procedure:
Under nitrogen atmosphere, to a solution of 4-bromo-3,5-dimethoxybenzyl ethyl ether (440.0 g) in tetrahydrofuran (4.0 L) was added dropwise n-butyl lithium (1.6 M n-hexane solution, 1.1 L) at −60° C. After stirring for 15 minutes at the same temperature, trimethyl borate (249.3 g) was added. The temperature of the mixture was gradually elevated, followed by stirring for 1 hour under ice-cooling. To the mixture was added dropwise 10% aqueous sulfuric acid solution (835 g). The mixture was extracted with ethyl acetate and the organic layer was washed with water and saturated aqueous NaCl solution. After drying over magnesium sulfate, the solvent was removed in vacuo. The residue was dissolved in isopropyl ether with heating and cooled. The crystalline precipitates were collected by filtration and dried to yield 4-ethyoxymethyl-2,6-dimetoxyphenylboronic acid (312.9 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6](=[O:7])[N:5]([CH:8]([CH3:12])[C:9]([OH:11])=O)[C:4](=[O:13])[NH:3]1.C(Cl)Cl.CCN(CC)CC.[Br:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1>CN(C=O)C.CCOC(C)=O>[Br:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:9](=[O:11])[CH:8]([N:5]2[C:6](=[O:7])[C:2]([CH3:1])([CH3:14])[NH:3][C:4]2=[O:13])[CH3:12])=[CH:28][CH:27]=1
Reactant: CC(C(=O)O)N1C(=O)NC(C)(C)C1=O
Reactant: Nc1ccc(Br)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C(=O)Nc1ccc(Br)cc1)N1C(=O)NC(C)(C)C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 2-(4,4-dimethyl-2,5-dioxoimidazolodin-1-yl)propanoic acid CAS#876709-28-3 (130 mg, 0.65 mmol), CH2Cl2 (3 mL), Et3N (645 mg, 6.5 mmol), 4-Bromoaniline (60 mg, 0.65 mmol) was added PPAA (50% solution in DMF, 0.6 mL, 1.09 mmol). The mixture was stirred for 18 h at RT. The reaction was diluted with EtOAc washed with aq. NaHCO3 (1N solution), dried with MgSO4 and solvent removed. The crude mixture was purified by silicagel chromatography. The title compound was isolated as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([O:9]CC)=O)[N:5]=[C:4]2[C:12]([CH3:30])([CH3:29])[N:13]([C:15]([NH:17][C@@H:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:19][N:20]([CH3:22])[CH3:21])=[O:16])[CH2:14][C:3]=12.CCN(C(C)C)C(C)C.[Cl:40][C:41]1[C:46](C(Cl)=O)=[C:45]([F:50])[C:44]([CH3:51])=[CH:43][CH:42]=1.[OH-].[Na+]>>[Cl:40][C:41]1[C:46]([C:7]([NH:6][C:2]2[C:3]3[CH2:14][N:13]([C:15]([NH:17][C@@H:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:19][N:20]([CH3:21])[CH3:22])=[O:16])[C:12]([CH3:30])([CH3:29])[C:4]=3[NH:5][N:1]=2)=[O:9])=[C:45]([F:50])[C:44]([CH3:51])=[CH:43][CH:42]=1
Reactant: Cc1ccc(Cl)c(C(=O)Cl)c1F
Reactant: CCOC(=O)n1nc2c(c1N)CN(C(=O)N[C@H](CN(C)C)c1ccccc1)C2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(Cl)c(C(=O)Nc2n[nH]c3c2CN(C(=O)N[C@H](CN(C)C)c2ccccc2)C3(C)C)c1F

Procedure:
To a 13×100 mm test tube were added one 3×6 mm stir bar, compound 71b, (0.1 M in CH2Cl2, 80 μmol, 1.0 eq), DIPEA solution (2 M in CH2Cl2, 160 μmol, 2.0 equiv), and 6-chloro-2-fluoro-3-methylbenzoyl chloride (0.1 M in CH2Cl2, 160 μmol, 2.0 eq.). The reaction was covered and stirred at RT for 12 h. NaOH (1M, 1000 μmol, 12.5 equiv) was added, and the reaction mixture was agitated for 15 minutes. After centrifugation, the top layer was removed. The organic layer was evaporated. MeOH (500 μL) and TEA (500 μL) were added, and the reaction mixture was allowed to stir at RT overnight. The solvents were evaporated, and the residue was reconstituted in DMSO. 1H NMR (500 MHz, D2O) d ppm 1.52 (s, 3H) 1.59 (s, 3H) 2.13 (s, 6H) 2.21 (s, 3H) 2.34 (dd, J=12.22, 5.63 Hz, 1H) 2.59 (dd, J=12.91, 10.16 Hz, 1H) 4.48 (d, J=11.81 Hz, 1H) 4.52 (d, J=12.09 Hz, 1H) 4.81 (q, J=5.77 Hz, 1H) 6.18 (br. s., 1H) 7.14 (t, J=7.55 Hz, 1H) 7.21-7.27 (m, 3H) 7.28-7.38 (m, 3H). LCMS: M+H+: 513.2
Reaction SMILES: [NH3:1].Cl[C:3]1[C:4]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH:10]=[CH:9][C:5]=2[N:6]=[CH:7][N:8]=1>CO>[NH2:1][C:3]1[C:4]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH:10]=[CH:9][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: N
Reactant: Fc1ccc(-c2ccc3ncnc(Cl)c3n2)cc1
Solvent: CO
Product: Nc1ncnc2ccc(-c3ccc(F)cc3)nc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 83 %

Procedure:
To an ammonia solution in methanol (5 ml of a 6 M solution) was added 4-chloro-6-(4-fluorophenyl)-pyrido[3,2-d]pyrimidine (26 mg, 0.1 mmol). The mixture was stirred at room temperature for 12 hours. After concentration under reduced pressure, the residue was purified by silica gel flash chromatography, the mobile phase being a mixture of methanol and dichloromethane, in a volume ratio of 1:30, yielding the title compound (20 mg, yield 83%) as a white solid which was characterised by its mass spectrum as follows: MS (m/z): 241 ([M+H]+, 100).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH:10]([CH2:15][OH:16])[CH2:9]1)C1C=CC=CC=1.[ClH:17].O1CCOCC1>CO.[OH-].[OH-].[Pd+2]>[ClH:17].[OH:16][CH2:15][CH:10]1[CH:11]([OH:14])[CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: OCC1CN(Cc2ccccc2)CCC1O
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: OCC1CNCCC1O
Reaction time: 16 h
Yield: 86 %

Procedure:
A solution of 1 g (4.52 mmol) (rac)-1-benzyl-3-hydroxymethyl-piperidin-4-ol (ca 1:1 diast mixture, Synthesis (1999), 11, 1937-1943) in 25 ml of MeOH was treated with a solution of HCl in dioxane (1.24 ml, 4 M in dioxane, 4.97 mmol) and 95 mg of Pd(OH)2/C (20%) and was stirred over H2-atmosphere for 16 h. After filtration, new catalyst was added (95 mg of Pd(OH)2/C (20%)) and stirred over H2-atmosphere for 2 days. After filtration, the solution was evaporated under reduced pressure to yield 0.66 g (86%) of the title compound as a ca 1:1 cis/trans mixture, MS: 132.3 (MH+).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[C:14]([F:17])([F:16])[F:15])[C:8]([OH:10])=O)(=[O:3])[CH3:2].C(Cl)(=O)C(Cl)=O.CN(C=O)C.Cl.[CH3:30][O:31][C:32]([C:34]1([NH2:43])[CH2:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35]1)=[O:33]>C(Cl)Cl.C(=O)([O-])O.[Na+]>[CH3:30][O:31][C:32]([C:34]1([NH:43][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][C:13]([C:14]([F:17])([F:16])[F:15])=[C:5]([O:4][C:1](=[O:3])[CH3:2])[CH:6]=2)[CH2:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35]1)=[O:33]
Reactant: COC(=O)C1(N)Cc2ccccc2C1
Reactant: CC(=O)Oc1cc(C(=O)O)ccc1C(F)(F)F
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)C1(NC(=O)c2ccc(C(F)(F)F)c(OC(C)=O)c2)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24 %

Procedure:
To a solution of 2.7 g (10.9 mmol) of the compound of step 1 in 16.3 ml of a 2 M solution of oxalyl chloride in DCM (32.6 mmol), 80 mg of DMF were added and the mixture was stirred for 30 min at room temperature. The solvent was evaporated, 20 ml of DCM were added and the mixture was evaporated again. The residue was dissolved in 20 ml of DCM and the solution added within 5 min at 0° C. to a solution of 2.48 g (10.9 mmol) of 2-amino-indane-2-carboxylic acid methyl ester hydrochloride in 50 ml of DCM and 30 ml of a saturated sodium hydrogencarbonate solution. After stirring overnight, the phases were separated, the organic phase was dried over sodium sulfate, evaporated, and the residue was purified by silica gel chromatography (HEP/EA gradient). 1.1 g of the title compound were obtained.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CCN(CC)CC.Cl.[CH3:22][O:23][NH2:24].O>C1COCC1>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:24][O:23][CH3:22])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CON
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CONS(=O)(=O)c1ccc(C(C)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.4 %

Procedure:
Ex-30A: To a solution of 4-acetylbenzenesulfonyl chloride (2.18 g, 10.0 mmol) in 100 ml of THF at 0° C., Et3N (2.5 g, 25 mmol) was added followed by O-methyl hydroxyamine hydrochloride (0.84 g, 10 mmol). The mixture was stirred for 1 hr at room temperature and then poured into water, and the precipitate was filtered and dried. Recrystallization from THF/hexanes gave 1.5 g (65.8%) of 4-acetyl-N-methoxybenzenesulfonamide as a white solid. 1H-NMR (300 MHz, CDCl3) δ 8.10 (d, J=8 Hz, 2H), 8.03 (d, J=8 Hz, 2H), 7.23 (brs, 1H), 3.82 (s, 3H), 2.66 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:32])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([C:30]#[N:31])([CH3:29])[CH3:28])[CH:22]=2)=[CH:15][C:14]=1[OH:33])#[N:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:30]([C:27]([C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[C:20]([NH:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]#[N:12])=[C:14]([O:33][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH:15]=1)=[O:32])([CH3:29])[CH3:28])#[N:31]
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(C#N)c(O)c2)c1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(C#N)c(Oc3ccc([N+](=O)[O-])cn3)c2)c1
Temperature: 80 °C
Reaction time: 20 h
Yield: 24.3 %

Procedure:
To a solution of 2-chloro-5-nitropyridine (1.06 g, 6.68 mmol) and N-(4-cyano-3-hydroxyphenyl)-3-(1-cyano-1-methylethyl)benzamide (2.0 g, 6.55 mmol) in N,N-dimethylformamide (15 mL) was added potassium carbonate (1.35 g, 9.82 mmol), and the mixture was stirred at 80° C. for 20 hr. The reaction mixture was cooled to room temperature, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (300 mL), washed with water (150 mL) and saturated brine (150 mL×2), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20→40/60), and further purified by basic silica gel column chromatography (hexane/ethyl acetate=70/30→0/100). The obtained solution was concentrated under reduced pressure to give the title compound (0.68 g, 24%) as a pale-yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:12])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[S:5][C:6]=1[CH3:7].[CH3:13][N:14]([CH3:18])[C:15](Cl)=[S:16].N12CCN(CC1)CC2>CN(C=O)C>[Br:1][C:2]1[C:3]([O:12][C:15]([N:14]([CH3:18])[CH3:13])=[S:16])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[S:5][C:6]=1[CH3:7]
Reactant: CN(C)C(=S)Cl
Reactant: COC(=O)c1sc(C)c(Br)c1O
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Product: COC(=O)c1sc(C)c(Br)c1OC(=S)N(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.8 %

Procedure:
Methyl 4-bromo-3-hydroxy-5-methyl-2-thiophenecarboxylate (2.5 g, 10 mmoles) is stirred under argon in DMF (20 mL). Dimethylthiocarbamyl chloride (2.65 g, 21 mmoles) and 1,4-diazabicyclo[2.2.2]octane (2.4 g, 21 mmoles) are added. The mixture is stirred at room temperature for 2 hours, then at 50° C. for 20 hours, then poured into ice water (200 mL) and extracted twice with toluene. The combined extracts are washed successively with 2N HCl, water, 0.5 M NaHCO3, and water, then dried over MgSO4. Removal of the solvent under reduced pressure, followed by recrystallization from ethyl acetate affords the product (2.7 g); mp 152°-154° C.
Reaction SMILES: F[C:2]1[C:7]([CH:8]2[CH2:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.O>[O:11]1[CH2:12][CH2:13][CH2:14][CH:8]([C:7]2[C:2]([O:28][C:25]3[CH:24]=[CH:23][C:22]([NH:21][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=4)=[CH:27][CH:26]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)[CH2:9][CH2:10]1
Reactant: Fc1ncccc1C1CCCOCC1
Reactant: Oc1ccc(Nc2ccccn2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: c1ccc(Nc2ccc(Oc3ncccc3C3CCCOCC3)cc2)nc1
Temperature: 120 °C
Reaction time: 17 h

Procedure:
2-Fluoro-3-(oxepan-4-yl)pyridine (0.061 g, 0.31 mmol), 4-(pyridin-2-ylamino)phenol (0.18 g, 0.94 mmol), and cesium carbonate (0.31 g, 0.94 mmol) were mixed in NMP (0.75 mL). The reaction mixture was placed under a nitrogen atmosphere and stirred at 120° C. for 17 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (2×). The combined organic layers were washed with 1 M aqueous sodium hydroxide, washed with sat. sodium chloride, dried over magnesium sulfate, and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography to give N-(4-(3-(oxepan-4-yl)pyridin-2-yloxy)phenyl)pyridin-2-amine MS (ESI, pos. ion) m/z: 362.2 (M+1). IC50 (uM) 0.026.
Reaction SMILES: Br[CH2:2][C:3]([C:28]([F:31])([F:30])[F:29])([OH:27])[CH:4]([NH:15][C:16]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:17]=1[CH:18]=[CH:19][C:20]([CH3:26])=[N:21]2)[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:6]=1[O:13][CH3:14].[CH2:32]([SH:34])[CH3:33].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:12][C:7]1[C:6]([O:13][CH3:14])=[C:5]([CH:4]([NH:15][C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[CH:18]=[CH:19][C:20]([CH3:26])=[N:21]3)[C:3]([CH2:2][S:34][CH2:32][CH3:33])([C:28]([F:31])([F:30])[F:29])[OH:27])[CH:10]=[C:9]([F:11])[CH:8]=1
Reactant: CCS
Reactant: COc1c(F)cc(F)cc1C(Nc1cccc2nc(C)ccc12)C(O)(CBr)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCSCC(O)(C(Nc1cccc2nc(C)ccc12)c1cc(F)cc(F)c1OC)C(F)(F)F

Procedure:
Analogously to example 45 100 mg (0.24 mmol) {[3,5-difluoro-2-methoxyphenyl][2-(trifluoromethyl)oxiranyl]methyl}-2-methylquinolin-5-amine (example 14) are reacted with 0.25 ml of the 1 M ethanthiol solution under the presence of 148 mg Caesium carbonate in DMF. The typical work up after 2 hours yields 49 mg of the title compound after preparative thin layer chromatography on silica gel (acetone in hexane 50%).