Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[OH:7][C:8]1[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:9]=1[CH:10]=[O:11].Cl[CH2:18][C:19]1[CH2:20][CH2:21][N:22]([CH3:31])[CH2:23][C:24]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C.CCOC(C)=O>[OH:7][C:8]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:18][C:19]2[CH2:20][CH2:21][N:22]([CH3:31])[CH2:23][C:24]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:9]=1[CH:10]=[O:11]
Reactant: O=Cc1c(O)cccc1O
Reactant: CN1CCC(CCl)=C(c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1CCC(COc2cccc(O)c2C=O)=C(c2ccccc2)C1
Temperature: 50 °C
Yield: 26.6 %

Procedure:
To a suspension of K2CO3 (350 mg, 2.56 mmol) and 2,6-dihydroxybenzaldehyde (180 mg, 1.28 mmol) in DMF (3 ml) was added a solution of 4-(chloromethyl)-1-methyl-5-phenyl-1,2,3,6-tetrahydropyridine (140 mg, 0.64 mmol) in DMF (4 mL), the mixture was heated at 50° C. for 3 h, cooled to room temperature, and was diluted with EtOAc, organic layer was separated and aqueous layer was extracted with EtOAc. EtOAc layers were combined, washed with Sat. NaHCO3, brine, dried over Na2SO4, and was concentrated to give crude oil, which was purified by column (Hexane/EtOAc=1:1 followed by DCM/MeOH=90:10) to give 2-hydroxy-6-((1-methyl-5-phenyl-1,2,3,6-tetrahydropyridin-4-yl)methoxy)benzaldehyde (55 mg). 1H NMR (400 MHz, CDCl3) δ (ppm) 11.92 (s, 1H), 10.35 (s, 1H), 7.34 (m, 5H), 7.19 (dd, J=8.4, 8.0 Hz, 1H), 6.46 (d, J=8.4 Hz, 1H), 6.16 (d, J=8.0 Hz, 1H), 4.45 (s, 2H), 3.20 (s, 2H), 2.68 (t, J=5.6 Hz, 2H), 2.47 (m, 2H), 2.42 (s, 3H); MS (ESI) m/z 324.3 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([CH3:13])[C:7](=[O:14])[C:6]=2[CH:5]=[CH:4][C:3]=1[F:15].C([O-])=O.[NH4+]>[Pd].CO>[F:15][C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:14])[N:8]([CH3:13])[CH2:9][CH2:10][O:11][C:12]=2[CH:2]=1
Reactant: CN1CCOc2c(ccc(F)c2Cl)C1=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CN1CCOc2cc(F)ccc2C1=O

Procedure:
A mixture of 9-chloro-8-fluoro-4-methyl-3,4-dihydro-1,4-benzoxazepin-5(2H)-one (1 equivalent), 10% palladium on charcoal (0.1 equivalents) and ammonium formate (10 equivalents) in methanol was heated at reflux for 2 hours. The mixture was allowed to cool, filtered through Celite® and the filtrate concentrated in vacuo. The residue was partitioned between ethyl acetate and water, the organic phase washed with brine, dried (MgSO4), concentrated in vacuo and chromatographed on alumina, eluting with ethyl acetate, to give the desired compound as a colourless solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH3:11]>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>[C:2]1([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=2[CH3:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(Br)cccc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: Cc1c(-c2ccccc2)cccc1[N+](=O)[O-]
Yield: 120.2 %

Procedure:
A 100 mL round bottomed flask under argon was charged with 480 mg of tetrakis(triphenylphosphine)palladium(0), and 3 g of 2-bromo-6-nitrotoluene dissolved in 50 mL of degassed, toluene. To this was added under argon 9 mL of a 2M degassed Na2CO3 aqueous solution, and then 1.7 g of phenylboronic acid dissolved in 20 mL of ethanol was added. The mixture was refluxed for 6 h with stirring. Residual boronic acid was removed by treatment with 30% H2O2 for 1 hour. The mixture was extracted with methylene chloride, washed with saturated brine, the combined organic extracts were dried over anhydrous magnesium sulfate, filtered and the solvent removed. The residue was chromatographed over silica gel using methylene chloride as the eluent to give 1.78 g (60% yield) of brownish crystals.
Reaction SMILES: [C:1]1([S:7]([CH2:10][S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:21][CH2:22][CH2:23]Br.[OH-].[Na+].[Cl-].[NH4+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[C:1]1([S:7]([C:10]2([S:11]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)(=[O:13])=[O:12])[CH2:23][CH2:22][CH2:21]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: BrCCCBr
Reactant: O=S(=O)(CS(=O)(=O)c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Cl-]
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)C1(S(=O)(=O)c2ccccc2)CCC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of bis(phenylsulfonyl)methane (30 g, 100 mmol), tetra-n-butylammonium bromide (3 g, 9.3 mmol), 1,3-dibromopropane (30 ml), dichloromethane (600 ml) and 50% aqueous sodium hydroxide (150 ml) was stirred at room temperature for 3 days. The mixture was poured onto saturated aqueous ammonium chloride solution and extracted into dichloromethane. The combined organic extracts were dried (Na2SO4) and concentrated. The residue was crystallised from i-hexane:diethyl ether to give the title product as a white solid. Yield−24 g (71%).
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[NH:4][CH2:3][CH2:2]2.Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=1.O1CCOCC1>O>[N+:17]([C:16]1[CH:15]=[CH:14][C:13]([CH:2]2[CH2:3][NH:4][CH:5]3[CH2:8][CH2:9][N:1]2[CH2:7][CH2:6]3)=[N:12][CH:11]=1)([O-:19])=[O:18]
Reactant: C1CN2CCC(CC2)N1
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(C2CNC3CCN2CC3)nc1

Procedure:
1,4-diazabicyclo[3.2.2]nonane (6.3 g, 50 mmol) was added to a mixture of 2-chloro-nitropyridine (11.9, 75 mmol), and dioxane (250 ml) at 0° C. The reaction mixture was allowed to reach room temperature. Water (100 ml) was added. The mixture was extracted with dichloromethane (3×50 ml). Chromatography on silica gel with dichloromethane and 10% methanol as solvent gave the title compound as an oil. Yield 8.1 g (65%). Mp. 143-146° C.
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[C:9]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:8][CH:7]=[CH:6][C:5]=1[F:16].[OH-].[Na+]>>[F:16][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([C:10]2[N:11]=[CH:12][CH:13]=[CH:14][N:15]=2)[C:4]=1[C:3]([OH:17])=[O:2]
Reactant: COC(=O)c1c(F)cccc1-c1ncccn1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1c(F)cccc1-c1ncccn1
Temperature: 72 °C
Reaction time: 9 h
Yield: 87.7 %

Procedure:
To a solution of 2-fluoro-6-pyrimidin-2-yl-benzoic acid methyl ester (1.36 g, 5.85 mmol) in 2-methyl-THF (20 mL) was added sodium hydroxide (2 M in water, 9.3 mL, 18.6 mmol). The mixture was heated to 72° C. and stirred for 9 h. The layers were separated and the aqueous layer acified to pH 2 by dropwise addition of 50% HCl(aq) (3.1 mL). The resulting solids were stirred for 1 h, filtered, washed with water, MTBE, and heptanes, and then dried to provide the desired product as a white solid (1.12 g, 88% yield). 1H NMR (400 MHz, CD3OD): 8.83 (d, J=4.9 Hz, 2H), 8.03 (dd, J=7.9, 0.8 Hz, 1H), 7.59 (td, J=8.1, 5.6 Hz, 1H), 7.40 (t, J=4.9 Hz, 1H), 7.34 (ddd, J=9.4, 8.4, 1.0 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:3]=1[O:4]C1C=CN=C2C=C(C3SC=CN=3)SC=12.Cl[C:27]1[CH:32]=[CH:31][N:30]=[C:29]2[CH:33]=[C:34]([C:36]3[N:37]([CH3:45])[C:38]([C:41]([O:43][CH3:44])=[O:42])=[CH:39][N:40]=3)[S:35][C:28]=12>>[F:1][C:2]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:3]=1[O:4][C:27]1[CH:32]=[CH:31][N:30]=[C:29]2[CH:33]=[C:34]([C:36]3[N:37]([CH3:45])[C:38]([C:41]([O:43][CH3:44])=[O:42])=[CH:39][N:40]=3)[S:35][C:28]=12
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4nccs4)sc23)c(F)c1
Reactant: COC(=O)c1cnc(-c2cc3nccc(Cl)c3s2)n1C
Product: COC(=O)c1cnc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)n1C

Procedure:
Following the procedure described above for the synthesis of compound 11 (example 12, step 3, scheme 2) but substituting compound 10 for compound 119, title compound 120 was obtained as a yellow solid (254 mg, 31% yield). MS (m/z) 429.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.[CH:27](=O)[CH:28]([CH3:30])[CH3:29]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:20][CH2:21][N:22]([CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:23][CH2:24]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:25][CH:26]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCNCC2)cc1
Reactant: CC(C)C=O
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCN(CC(C)C)CC2)cc1

Procedure:
Using the general procedure described in Example 3, N1-(4-methoxybenzoyl)-N2-(piperidin-4-ylcarbonyl)-1,2-benzenediamine (0.070 mmol) was reacted with isobutyraldehyde to provide 32 mg of the title product as the free base. Treatment with hydrochloric acid and concentration in vacuo yielded the salt of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](/[C:7](/[CH3:14])=[CH:8]\[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:3][CH:2]=1>[Pd].CCO>[N:1]1[CH:6]=[CH:5][C:4]([CH:7]([CH3:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:3][CH:2]=1
Reactant: CCOC(=O)/C=C(/C)c1ccncc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC(C)c1ccncc1
Yield: 70.7 %

Procedure:
Palladium on carbon (70 mg, 10 wt. %) was added to a solution of (Z)-ethyl 3-(pyridin-4-yl)but-2-enoate (0.70 g, 3.66 mmol) in EtOH (10 ml) and hydrogenated under balloon pressure for 18 h. The reaction mixture was filtered through a pad of celite and washed with EtOH. The filtrate was concentrated under reduced pressure to afford 0.50 g (71.4%) of ethyl 3-(pyridin-4-yl)butanoate as light brown color liquid.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[N:8]=1)=O.[NH:26]([C:28]1[CH:33]=[CH:32][N:31]=[C:30]([Cl:34])[CH:29]=1)[NH2:27]>>[Cl:34][C:30]1[CH:29]=[C:28]([N:26]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:27]2)[CH:33]=[CH:32][N:31]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)ccc1=O
Reactant: NNc1ccnc(Cl)c1
Product: O=c1ccn(-c2ccc(OC(F)(F)F)cc2)nc1-c1ccnn1-c1ccnc(Cl)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-8) and 4-hydrazino-2-chloropyridine according to the method described for example 43. MS: M=434.0 (M+H)+
Reaction SMILES: [Mg].II.Br[CH2:5][C@@H:6]([CH3:9])[CH2:7][CH3:8].[C:10]1([Si:16](Cl)([Cl:18])[Cl:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O1CCCC1.CCCCCC>[CH3:9][C@@H:6]([CH2:7][CH3:8])[CH2:5][Si:16]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([Cl:18])[Cl:17]
Reactant: Cl[Si](Cl)(Cl)c1ccccc1
Reactant: CC[C@H](C)CBr
Agent: II
Agent: [Mg]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC[C@H](C)C[Si](Cl)(Cl)c1ccccc1

Procedure:
Anhydrous tetrahydrofuran (125 mL) was put into a reactor with magnesium (5.7 g, 0.24 mol) and molecular sieves 4A which had been dehydrated and deaerated, followed by charging of argon gas. A small amount of iodine was slowly added to the mixture. (S)-(+)-1-bromo-2-methylbutane (30 g, 0.20 mol) was added dropwise to the slowly stirred mixture so that the reaction mixture was gradually refluxed. After the reaction was complete, the obtained Grignard reagent was transferred to a dropping funnel. The Grignard reagent was added dropwise to a solution being stirred containing phenyltrichlorosilane (50 g, 0.24 mol) in anhydrous tetrahydrofuran (50 mL) in another reactor which had been dehydrated and deaerated, followed by charging of argon gas, at 40° C.-50° C. The reaction mixture was then stirred overnight at room temperature. Hexane (500 mL) was added to the reaction mixture, and the resulting mixture was filtered under pressure, followed by fractional distillation of the filtrate to provide the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:19][C:9]2=[N:10][CH:11]=[C:12]([O:14][CH2:15][CH2:16][CH2:17]Cl)[CH:13]=[C:8]2[CH:7]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH2:1]([O:3][C:4]([C:6]1[NH:19][C:9]2=[N:10][CH:11]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH:13]=[C:8]2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(OCCCCl)cnc2[nH]1
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CCOC(=O)c1cc2cc(OCCCN3CCCCC3)cnc2[nH]1
Temperature: 25 °C
Yield: 68 %

Procedure:
The suspension consistent of 0.20 g (0.71 mmol) 5-(3-chloro-propoxy)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester, 0.12 g (0.85 mmol) potassium carbonate, 0.12 g (0.71 mmol) potassium iodide and 84 ml (72 μg, 0.85 mmol) piperidine was heated under reflux for 17 hours. After cooling down to room temperature the reaction mixture was poured on water and was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was flash-chromatographed on silica gel with dichloromethane:methanol:ammonia (9:1:0.1 v/v) as eluant to give 0.16 g (68%) of the desired compound as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.Cl.[NH2:19][O:20][CH2:21][CH2:22][NH2:23].N1C=CC=CC=1>C(O)C>[ClH:1].[NH2:23][CH2:22][CH2:21][O:20][N:19]=[C:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15]
Reactant: NCCON
Reactant: COCCCCC(=O)c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: COCCCCC(=NOCCN)c1ccc(Cl)c(Cl)c1

Procedure:
A mixture of 14 mmol (3.65 g) of 3', 4'-dichloro-5-methoxyvalerophenone, 14 mmol (2.1 g) of 2-aminooxyethylamine dihydrochloride, 7 ml of pyridine and 14 ml of absolute ethanol was refluxed for 2 hours. The reaction mixture was then further processes as described in Example 4. After crystallization from a mixture of ether and petroleum ether (boiling point 40°-60° C) the above entitled compound was obtained with a melting point of 93°-94° C.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[CH:10]=[C:9]([S:11]([CH:14]=[CH2:15])(=[O:13])=[O:12])[CH:8]=[CH:7][C:6]=1[NH:16][C:17](=[O:25])[C@:18]([OH:24])([CH3:23])[C:19]([F:22])([F:21])[F:20]>CO.C1COCC1>[Cl:4][C:5]1[CH:10]=[C:9]([S:11]([CH2:14][CH2:15][N:2]([CH3:3])[CH3:1])(=[O:13])=[O:12])[CH:8]=[CH:7][C:6]=1[NH:16][C:17](=[O:25])[C@:18]([OH:24])([CH3:23])[C:19]([F:22])([F:21])[F:20]
Reactant: C=CS(=O)(=O)c1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1
Reactant: CNC
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)CCS(=O)(=O)c1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
A 2M solution of dimethylamine (0.06 ml) in anhydrous methanol was added to a deoxygenated solution of (R)-N-[2-chloro-4-(ethenylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 283) (0.044 g) in anhydrous THF (1 ml). The mixture was allowed to stir at ambient temperature under argon for 2 hours then volatile material was removed by evaporation to give the title compound (in 89% yield) as a solid. NMR: 1.69 (s, 3H), 2.65 (s, 6H), 2.55 (t, 2H), 3.55 (t, 2H), 7.9 (d, 1H), 8.08 (s, 1H), 8.34 (d, 1H); MS (ESP−): 403.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C:12]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)([CH2:14][CH2:15]OS(C)(=O)=O)[O:11][CH2:10][C:9]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]1([C:36]2([C:42]([N:44]3[CH2:48][CH2:47][CH2:46][CH2:45]3)=[O:43])[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C.C(Cl)Cl.CCOCC.O>[OH2:11].[ClH:27].[CH2:1]([N:8]1[CH2:13][C:12]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)([CH2:14][CH2:15][N:39]2[CH2:40][CH2:41][C:36]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)([C:42]([N:44]3[CH2:48][CH2:47][CH2:46][CH2:45]3)=[O:43])[CH2:37][CH2:38]2)[O:11][CH2:10][C:9]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N1CCCC1)C1(c2ccccc2)CCNCC1
Reactant: CS(=O)(=O)OCCC1(c2ccc(Cl)c(Cl)c2)CN(Cc2ccccc2)C(=O)CO1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: O=C1COC(CCN2CCC(C(=O)N3CCCC3)(c3ccccc3)CC2)(c2ccc(Cl)c(Cl)c2)CN1Cc1ccccc1
Temperature: 80 °C
Yield: 58.2 %

Procedure:
A mixture of 0.98 g of the compound obtained in step B of EXAMPLE 14, 0.645 g of 4-phenyl-4-(pyrrolidin-1-ylcarbonyl)piperidine and 0.69 g of K2CO3 in 3 ml of DMF is heated at 80° C. for 2 hours. After cooling to RT, the reaction mixture is poured into water and extracted with an AcOEt/ether mixture, the organic phase is washed with water and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H using a DCM/MeOH mixture (100/2; v/v) as the eluent. The product obtained is dissolved in the minimum amount of DCM and acidified to pH 1 by the addition of a saturated solution of gaseous HCl in ether and the precipitate formed is wrung to give 0.42 g of the expected product. M.p.=155-178° C.
Reaction SMILES: [Cl:1][C:2]1[C:7](F)=[C:6]([C:9]2[C:10]([NH:16][CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[N:11][C:12]([NH2:15])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.C([O-])(O)=O.[Na+]>O1CCOCC1>[Cl:1][C:2]1[C:7]2[N:16]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:10]3[N:11]=[C:12]([NH2:15])[N:13]=[CH:14][C:9]=3[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ncc(-c2ccnc(Cl)c2F)c(NC2CCCC2)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])O
Agent: [Li+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: Nc1ncc2c3ccnc(Cl)c3n(C3CCCC3)c2n1
Temperature: 85 °C
Yield: 55.1 %

Procedure:
Compound 193 (3.10 g, 10.1 mmol) was combined with 30 mL of anhydrous 1,4-dioxane. To this was added LiHMDS 1M in THF (30.2 mL, 30.2 mmol) and the solution was heated to 85° C. for 5 hours. The solution was cooled to room temperature and then diluted with ice/sat. NaHCO3. The product was extracted with 15% 2-propanol/DCM and the organics were dried over MgSO4 before being concentrated under vacuum. The residue obtained was purified on CombiFlash column (dry loaded), eluting with a gradient of 2% methanol/DCM to 6% methanol/DCM. Trituration with acetone and ethyl acetate left a light brown solid. Repurification of the supernatants provided additional material. The solids were combined to give compound 194 (1.60 g, 55.2%) as a light brown solid. 1H NMR (500 MHz, DMSO-d6) δ 9.11 (1 H, s), 8.14 (1 H, d, J=4.9 Hz), 7.98 (1 H, d, J=4.9 Hz), 7.07 (2 H, br. s.), 5.90 (1 H, quin, J=8.7 Hz), 2.44-2.49 (2 H, m), 2.04-2.13 (2 H, m), 1.95-2.03 (2 H, m), 1.63-1.73 (2 H, m) ppm; LCMS-ESI (POS), M/Z, M+1: Found 288.1.
Reaction SMILES: [Br:1][C:2]1[C:3]([S:11][C:12]2[NH:13][C:14]3[C:19]([N:20]=2)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]=3)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.Br[CH2:23][CH2:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=1>>[F:32][C:31]([F:33])([F:34])[C:29]1[CH:30]=[C:25]([CH2:24][CH2:23][N:13]2[C:12]([S:11][C:3]3[C:2]([Br:1])=[CH:10][C:6]4[O:7][CH2:8][O:9][C:5]=4[CH:4]=3)=[N:20][C:19]3[C:14]2=[N:15][CH:16]=[N:17][C:18]=3[NH2:21])[CH:26]=[C:27]([C:35]([F:36])([F:37])[F:38])[CH:28]=1
Reactant: Nc1ncnc2[nH]c(Sc3cc4c(cc3Br)OCO4)nc12
Reactant: FC(F)(F)c1cc(CCBr)cc(C(F)(F)F)c1
Product: Nc1ncnc2c1nc(Sc1cc3c(cc1Br)OCO3)n2CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared from 8-(6-bromo-benzo[1,3]dioxol-5-ylsulfanyl)-9H-purin-6-ylamine and 1-(2-bromo-ethyl)-3,5-bis-trifluoromethyl-benzene by a procedure similar to examples 1 and 2. The compound was purified by preparative HPLC. 1H NMR (DMSO-d6) δ 8.13 (s, 1H), 7.79 (s, 1H), 7.66 (s, 2H), 7.23 (s, 1H), 7.01 (s, 1H), 6.09 (s, 2H), 4.59 (t, J=7.4 Hz, 2H), 3.35 (t, J=7.4 Hz, 2H); LC-MS [M+H]+ 607.0
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([N:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)[CH:19]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:43][C:44]1[C:45](F)=[CH:46][C:47]([F:70])=[C:48]([S:50]([N:53]([CH2:59][C:60]2[CH:65]=[CH:64][C:63]([O:66][CH3:67])=[CH:62][C:61]=2[O:68][CH3:69])[C:54]2[S:55][CH:56]=[N:57][N:58]=2)(=[O:52])=[O:51])[CH:49]=1>CS(C)=O>[Cl:43][C:44]1[CH:49]=[C:48]([S:50]([N:53]([CH2:59][C:60]2[CH:65]=[CH:64][C:63]([O:66][CH3:67])=[CH:62][C:61]=2[O:68][CH3:69])[C:54]2[S:55][CH:56]=[N:57][N:58]=2)(=[O:51])=[O:52])[C:47]([F:70])=[CH:46][C:45]=1[O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:16])([F:17])[F:15])=[CH:12][CH:13]=2)=[CH:4][C:3]=1[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([N:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)[CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(-c3cc(-c4ccc(C(F)(F)F)cc4)ccc3O)ccn2)CC1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(-c4ccc(C(F)(F)F)cc4)cc3-c3ccnc(N4CCN(C(=O)OC(C)(C)C)CC4)c3)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.3 %

Procedure:
tert-Butyl 4-(4-(4-hydroxy-4′-(trifluoromethyl)biphenyl-3-yl)pyridin-2-yl)piperazine-1-carboxylate (Preparation 114, 200 mg, 0.400 mmol) was dissolved in dimethyl sulfoxide (3 mL) and potassium carbonate (110 mg, 0.800 mmol) was added followed by 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide (Preparation 16, 185 mg, 0.400 mmol). The reaction was stirred at room temperature for 18 hours and then partitioned between ethyl acetate (10 mL) and water (5 mL). The organic layer was separated and washed with brine (5 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified on silica gel by Biotage™ (7% to 60% ethyl acetate in heptane over 20 CV) to give the title product (340 mg, 90%) as a yellow foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[Cl:23][C:24]1[C:25]([O:33][CH3:34])=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1>C1(C)C=CC=CC=1>[Cl:23][C:24]1[C:25]([O:33][CH3:34])=[C:26]([NH:30][C:31]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:21][CH:20]=2)=[O:32])[CH:27]=[CH:28][CH:29]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: COc1c(Cl)cccc1N=C=O
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4cccc(Cl)c4OC)cc3)c2cc1OC
Yield: 80 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (58 mg) was dissolved in toluene (5 ml) with heat, 3-chloro-2-methoxyphenyl isocyanate (0.1 ml) was added, and the admixture was refluxed with heat for 22 minutes. The resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 75 mg of the title compound (yield: 80%).