Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]4([O:22][CH3:23])[CH2:21][NH:20][CH2:19]4)[N:14]3[CH3:17])=[C:10]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:9]=2)[C:6]2[CH:30]=[CH:31][CH:32]=[CH:33][C:5]=2[N:4]=1)[CH3:2].[CH3:34][C:35]1([CH3:38])[CH2:37][O:36]1>CC#N>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]4([O:22][CH3:23])[CH2:21][N:20]([CH2:34][C:35]([CH3:38])([OH:36])[CH3:37])[CH2:19]4)[N:14]3[CH3:17])=[C:10]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:9]=2)[C:6]2[CH:30]=[CH:31][CH:32]=[CH:33][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CNC3)n(C)c2n1
Reactant: CC1(C)CO1
Solvent: CC#N
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CN(CC(C)(C)O)C3)n(C)c2n1
Temperature: 80 °C
Reaction time: 20 h
Yield: 27.1 %

Procedure:
To a solution of 2-(2-ethylbenzoimidazol-1-yl)-8-(3-methoxyazetidin-3-yl)-9-methyl-6-morpholin-4-yl-9H-purine (100 mg, 0.22 mmol) in MeCN (2 mL) was added 2,2-dimethyloxirane (198 μL, 2.23 mmol) and the resulting mixture stirred at 80° C. for 3 h before the addition of further 2,2-dimethyloxirane (1.0 mL, 11.15 mmol). The reaction mixture was stirred at 80° C. for a further 20 h then concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-20%) then triturated with Et2O and the resulting solid dried in vacuo affording 833 (31 mg, 27%). LCMS (method I): RT 2.59 min, [M+H]+ 521.3. 1H NMR (DMSO, 400 MHz): δ 8.04-8.04 (1 H, m), 7.66-7.62 (1 H, m), 7.25-7.24 (2 H, m), 4.29 (4 H, brd s), 4.07 (1 H, s), 3.99 (2 H, d, J=8.32 Hz), 3.80 (4 H, t, J=4.57 Hz), 3.70 (3 H, s), 3.52 (2 H, d, J=8.34 Hz), 3.34-3.19 (2 H, m), 3.02 (3 H, s), 2.43 (2 H, s), 1.34 (3 H, t, J=7.43 Hz), 1.05 (6 H, s)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:29])[CH2:15][CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:23]1([CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15][C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[O:29])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)CC(c2ccccc2)c2ccccc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC(c1ccccc1)c1ccccc1)N1CCNCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.8 %

Procedure:
To a solution of 4-(3,3-diphenyl-propionyl)-piperazine-1-carboxylic acid tert-butyl ester (2.15 g, 5.45 mmol) in dry CH2Cl2 (60 ml) was added TFA (20 ml) and resulting mixture stirred at room temperature for 3 hrs. Solvent and excess TFA was then evaporated and the residue was dissolved in CH2Cl2 (150 ml) and washed with sat. NaHCO3 (2×) and dried over MgSO4. Evaporation of solvent gave 1.65 g of pure product.
Reaction SMILES: [CH3:1]/[C:2](/[CH2:8][CH2:9][CH:10]=[CH2:11])=[CH:3]/[C:4]([O:6]C)=[O:5].[Li+].[OH-]>C1COCC1.O>[CH3:1]/[C:2](/[CH2:8][CH2:9][CH:10]=[CH2:11])=[CH:3]/[C:4]([OH:6])=[O:5]
Reactant: C=CCC/C(C)=C\C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C=CCC/C(C)=C\C(=O)O
Reaction time: 96 h
Yield: 56.4 %

Procedure:
A solution of the title compound from Example 20 (6.8 g, 32.5 mmol) in THF (150 mL) was treated with 1 N LiOH (100 mL) and water (125 mL) and stirred vigorously for 4 days. The mixture was diluted with water and washed twice with ether. The aqueous phase was taken to pH 1.5 by addition of 2N HCl and extracted three times with ether. The organic extracts were dried and the solvents evaporated to give the title compound (2.57 g, 56%) as a pale yellow oil.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[C:7]2[NH:12][CH2:13][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17].CC1(C)C(C)(C)OB([C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[CH:33]=[C:32]([NH:37][C:38]([C:40]2[S:41][CH:42]=[CH:43][CH:44]=2)=[O:39])[CH:31]=[CH:30]3)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(Cl)Cl.O>[CH3:17][N:16]([CH3:18])[CH2:15][CH2:14][CH2:13][NH:12][C:7]1[C:8]2[C:3](=[C:2]([C:27]3[CH:28]=[C:29]4[C:34](=[CH:35][CH:36]=3)[CH:33]=[C:32]([NH:37][C:38]([C:40]3[S:41][CH:42]=[CH:43][CH:44]=3)=[O:39])[CH:31]=[CH:30]4)[CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][N:6]=1
Reactant: CC1(C)OB(c2ccc3cc(NC(=O)c4cccs4)ccc3c2)OC1(C)C
Reactant: CN(C)CCCNc1nccc2c(Br)cccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CN(C)CCCNc1nccc2c(-c3ccc4cc(NC(=O)c5cccs5)ccc4c3)cccc12
Reaction time: 0.17 h
Yield: 15 %

Procedure:
To a microwave vial containing 5-bromo-N-(3(dimethylamino)propyl) isoquinolin-1-amine (Step 4, 0.055 g, 0.2 mmol) in 1,4-Dioxane (2 mL), was added N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)thiophene-2-carboxamide (0.076 g, 0.2 mmol), Fibrecat catalyst (0.005 g, 5% by wt.), along with 2 M Potassium Carbonate (0.5 mL, 1 mmol). The mixture was placed into CEM Microwave for 10 minutes at 80° C., while supplying 60 Watts of energy via power-max. Then mixture was diluted with DCM and H2O, and extracted with DCM (3×10 mL). Then dried organics (over sodium sulfate) was filtered, and concentrated in-vacuo. The crude was purified on reverse-phase HPLC. This gave a light yellow amorphous solid after drying, which was titled product (0.026 g, 0.03 mmol). MS (ESI pos. ion) m/z: 481 (M+H). Calc'd Exact Mass for C29H28N4OS: 480
Reaction SMILES: N1C2C(=CC=CC=2)C=CC=1.[NH2:11][C:12]1[C:25]2[C:24](=[O:26])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:27])[C:16]=2[CH:15]=[CH:14][CH:13]=1.[N+]([C:31]1[C:44]2[C:43](=[O:45])[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:36](=[O:46])[C:35]=2[CH:34]=[CH:33][CH:32]=1)([O-])=O>C(O)C>[CH:20]1[CH:19]=[C:18]2[C:17]([C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([NH:11][C:34]4[C:35]5[C:36]([C:37]6[C:42]([C:43](=[O:45])[C:44]=5[CH:31]=[CH:32][CH:33]=4)=[CH:41][CH:40]=[CH:39][CH:38]=6)=[O:46])[C:25]=3[C:24](=[O:26])[C:23]2=[CH:22][CH:21]=1)=[O:27]
Reactant: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Reactant: Nc1cccc2c1C(=O)c1ccccc1C2=O
Solvent: CCO
Solvent: c1ccc2ncccc2c1
Product: O=C1c2ccccc2C(=O)c2c(Nc3cccc4c3C(=O)c3ccccc3C4=O)cccc21
Temperature: 120 °C
Reaction time: 5 h

Procedure:
250 ml of quinoline, 100 g of 1-aminoanthraquinone and 25 g of CaO are warmed to 200° to 210° C. in a 1 l sulphonation beaker with an anchor stirrer and shortpath distillation bridge. 120 g of 1-nitroanthraquinone are added in portions in the course of 2 hours, and the mixture is then stirred for another 5 hours at 200° to 210° C. The mixture is allowed to cool to 120° C., and is diluted slowly and under reflux with 500 ml of ethanol. The mixture is then filtered off under suction, and the residue is washed with ethanol and dried. The dry caked filter residue is heated under reflux in 1 l of water with 100 g of ammonium chloride, and is acidified slowly through the reflux condenser with concentrated hydrochloric acid. After filtering off the mixture under suction, washing the residue until the runnings are neutral, and drying, 190.4 g of 80.4% strength 1,1'-dianthraquinonylamine are obtained.
Reaction SMILES: FC(F)(F)C(O)=O.ClCCl.O1CCCCC1[N:17]1[C:25]2[C:20](=[CH:21][C:22]([NH:26][C:27]3[CH:39]=[CH:38][C:30]([C:31]([O:33]C(C)(C)C)=[O:32])=[CH:29][CH:28]=3)=[CH:23][CH:24]=2)[CH:19]=[N:18]1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[NH:17]1[C:25]2[C:20](=[CH:21][C:22]([NH:26][C:27]3[CH:39]=[CH:38][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=3)=[CH:23][CH:24]=2)[CH:19]=[N:18]1
Reactant: CC(C)(C)OC(=O)c1ccc(Nc2ccc3c(cnn3C3CCCCO3)c2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(Nc2ccc3[nH]ncc3c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.9 %

Procedure:
Trifluoroacetic acid (5 ml) was added to a dichloromethane solution (5 ml) of tert-butyl 4-{1-(2-tetrahydropyranyl)-1H-indazol-5-ylamino}benzoate (205 mg, 0.521 mmol), and the resulting mixture was stirred at room temperature for 3 hours. The mixture was added dropwise to saturated aqueous sodium hydrogencarbonate solution/ethyl acetate and then extracted with ethyl acetate. The extract solution was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and then distilled under reduced pressure to remove the solvent, whereby a crude product was obtained. The crude product was washed by the addition of chloroform containing a small amount of methanol, and then was collected by filtration to obtain 4-(1H-indazole-5-ylamino)benzoic acid (46 mg, 35%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[NH:11][CH2:10][CH2:9][CH2:8][N:7]([CH2:12][C:13]3[C:18]([F:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=3[Cl:21])[C:6]=2[N:22]=1.[O:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][NH:31][C:32]([C:34]2[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=2)=[O:33])[CH2:25][CH2:24]1>>[Cl:21][C:14]1[C:15]([F:20])=[CH:16][CH:17]=[C:18]([F:19])[C:13]=1[CH2:12][N:7]1[CH2:8][CH2:9][CH2:10][NH:11][C:5]2[N:4]=[CH:3][C:2]([C:38]3[CH:39]=[C:34]([CH:35]=[CH:36][CH:37]=3)[C:32]([NH:31][CH2:30][CH2:29][N:26]3[CH2:25][CH2:24][O:23][CH2:28][CH2:27]3)=[O:33])=[N:22][C:6]1=2
Reactant: O=C(NCCN1CCOCC1)c1cccc(B(O)O)c1
Reactant: Fc1ccc(F)c(CN2CCCNc3ncc(Br)nc32)c1Cl
Product: O=C(NCCN1CCOCC1)c1cccc(-c2cnc3c(n2)N(Cc2c(F)ccc(F)c2Cl)CCCN3)c1

Procedure:
The entitled compound can be prepared from 2-Bromo-9-(2-chloro-3,6-difluorobenzyl)-6,7,8,9-tetrahydro-5H-pyrazino[2,3-b][1,4]diazepine and 3-(2-morpholinoethylcarbamoyl)phenyl boronic acid as described in example 1 or 30.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:10]=[CH:9][N:8]2[C:11]([Sn](CCCC)(CCCC)CCCC)=[CH:12][N:13]=[C:7]2[N:6]=1)([F:4])[CH3:3].Br[C:28]1[C:29]([F:41])=[C:30]([C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)[C:31]([F:34])=[CH:32][CH:33]=1>>[F:4][C:2]([C:5]1[CH:10]=[CH:9][N:8]2[C:11]([C:32]3[CH:33]=[CH:28][C:29]([F:41])=[C:30]([C:35]4[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=4)[C:31]=3[F:34])=[CH:12][N:13]=[C:7]2[N:6]=1)([F:1])[CH3:3]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(C)(F)F)ccn12
Reactant: Fc1ccc(Br)c(F)c1-c1cccnc1
Product: CC(F)(F)c1ccn2c(-c3ccc(F)c(-c4cccnc4)c3F)cnc2n1

Procedure:
7-(1,1-Difluoroethyl)-3-tributylstannylimidazo[1,2-α]pyrimidine was reacted with 3-(3-bromo-2,6-difluorophenyl)pyridine following the procedure described in Example 32 to give 7-(1,1-difluoroethyl)-3-[2,4-difluoro-3-(pyridin-3-yl)phenyl]imidazo[1,2-α]pyrimidine as a white solid: δH (360 MHz, CDCl3) 2.16 (1H, t, J 19), 7.22-7.78 (1H, m), 7.31 (1H, d, J 7), 7.59 (1H, ddd, J 8, 3 and 1), 7.52-7.59 (1H, m), 7.85 (1H, dd, J 8 and 1), 8.03 (1H, s), 8.39 (1H, dd, J 7 and 3), 8.69 (1H, d, J 5 and 3), 8.78 (1H, s); m/z (ES+) 373 (M++H).
Reaction SMILES: Cl.[N:2]1([CH2:7][CH2:8][N:9]2[CH:13]=[C:12]([CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]2[CH:20]2[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]2)[CH2:6][CH2:5][CH2:4][CH2:3]1>C(O)(C)C>[N:2]1([CH2:7][CH2:8][N:9]2[CH:13]=[C:12]([CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]2[CH:20]2[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C3CCOCC3)cn2CCN2CCCC2)CC1
Agent: Cl
Solvent: CC(C)O
Product: c1c(C2CCOCC2)nc(C2CCNCC2)n1CCN1CCCC1
Temperature: 50 °C
Reaction time: 6 h
Yield: 89.7 %

Procedure:
Add 5 M hydrogen chloride in isopropyl alcohol (112.7 mL, 5.0 eq) to a solution of tert-butyl 4-(1-(2-(pyrrolidin-1-yl)ethyl)-4-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl)piperidine-1-carboxylate (132.0 g, 274.61 mmol) in isopropyl alcohol (549 mL). Stir the reaction mixture at 50° C. for six hours. Concentrate in vacuo. Dilute with water (1 L) and adjust the pH to 12 with 2 M aqueous sodium hydroxide. Extract with ethyl acetate and dichloromethane. Dry the organics over anhydrous magnesium sulfate and concentrate in vacuo to give 4-(1-(2-pyrrolidin-1-yl-ethyl)-4-(tetrahydro-pyran-4-yl)-1H-imidazol-2-yl)-piperidine (81.9 g, 90%). MS (ES) m/z=333 [M]+.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5]([CH2:19][CH3:20])=[C:6]([CH2:10]P(=O)(OCC)OCC)[CH:7]=[CH:8][CH:9]=1.O=[C:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1.O>O1CCCC1>[Br:3][C:4]1[C:5]([CH2:19][CH3:20])=[C:6]([CH:10]=[C:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)[CH:7]=[CH:8][CH:9]=1
Reactant: CCOP(=O)(Cc1cccc(Br)c1CC)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1c(Br)cccc1C=C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
To a suspension of NaH (0.155 g, 3.88 mmol) in Tetrahydrofuran (THF) (30 mL) was added diethyl [(3-bromo-2-ethylphenyl)methyl]phosphonate (D135) (1 g, 2.98 mmol) at 0° C. The reaction solution was warmed to room temperature and stirred for 1 hour. The reaction solution was cooled to 0° C. again and 1,1-dimethylethyl 4-oxo-1-piperidinecarboxylate (0.713 g, 3.58 mmol) was added. The reaction solution was warmed to room temperature and stirred overnight. Water was added and extracted with ethyl acetate, the organic phases were dried over sodium sulphate, concentrated and purified by ISCO column chromatography to afford 1,1-dimethylethyl 4-[(3-bromo-2-ethylphenyl)methylidene]-1-piperidinecarboxylate (D136) (0.73 g). MS (ES): C19H26BrNO2 requires 379.1. found 324.1 (M+H+-56).
Reaction SMILES: [Na].[CH:2]1([C:5]2[O:9][N:8]=[C:7]([C:10]3[N:11]=[CH:12][N:13]4[C:22]5[C:17](=[C:18](Cl)[CH:19]=[CH:20][CH:21]=5)[C:16](=[O:24])[N:15]([CH3:25])[C:14]=34)[N:6]=2)[CH2:4][CH2:3]1.[CH2:26]([OH:28])[CH3:27]>>[CH:2]1([C:5]2[O:9][N:8]=[C:7]([C:10]3[N:11]=[CH:12][N:13]4[C:22]5[C:17](=[C:18]([O:28][CH2:26][CH3:27])[CH:19]=[CH:20][CH:21]=5)[C:16](=[O:24])[N:15]([CH3:25])[C:14]=34)[N:6]=2)[CH2:4][CH2:3]1
Reactant: CCO
Reactant: Cn1c(=O)c2c(Cl)cccc2n2cnc(-c3noc(C4CC4)n3)c12
Agent: [Na]
Product: CCOc1cccc2c1c(=O)n(C)c1c(-c3noc(C4CC4)n3)ncn21

Procedure:
30 mg of sodium was dissolved in 10 ml of dry ethanol. Then 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4,5-dihydro-4-methyl-5-oxo-6-chloro-imidazo(1,5-a)quinazoline (0.2 g, 0.5 mmol) was added and the resulting mixture was refluxed for 7 hours. The reaction mixture was evaporated. Glacial acetic acid and water was added to the residue whereupon the title compound was isolated by filtration. M.p. 195°-205° C.
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:32])=[C:6]([NH:10][C:11]([C:13]2[C:14]([Cl:31])=[CH:15][C:16]3[O:20][CH:19]([CH2:21][CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:18][C:17]=3[CH:30]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[C:33](OCC)(=O)[C:34]([O:36][CH2:37][CH3:38])=[O:35]>>[Cl:31][C:14]1[C:13]([C:11]([NH:10][C:6]2[C:5]3[O:32][C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:2][C:1](=[O:3])[C:4]=3[CH:9]=[CH:8][CH:7]=2)=[O:12])=[CH:30][C:17]2[CH2:18][CH:19]([CH2:21][CH2:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:20][C:16]=2[CH:15]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1cccc(NC(=O)c2cc3c(cc2Cl)OC(CCCc2ccccc2)C3)c1O
Product: CCOC(=O)c1cc(=O)c2cccc(NC(=O)c3cc4c(cc3Cl)OC(CCCc3ccccc3)C4)c2o1
Yield: 75 %

Procedure:
Following the process described in example 1 (point A), starting from N-(3-acetyl-2-hydroxyphenyl)-6-chloro-2-(3-phenylpropyl)-2,3-dihydrobenzofuran-5-carboxamide and diethyl oxalate, the title compound was prepared, which was purified by chromatography through a silica gel column, eluting with petroleum ether:chloroform, 4:6 (75% yield).
Reaction SMILES: [N:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:52]1[N:57]=[C:56]([S:58][CH2:59][C:60]2[CH:65]=[CH:64][CH:63]=[C:62]([F:66])[C:61]=2[F:67])[N:55]=[C:54]([O:68][CH2:69][CH2:70][OH:71])[CH:53]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:67][C:61]1[C:62]([F:66])=[CH:63][CH:64]=[CH:65][C:60]=1[CH2:59][S:58][C:56]1[N:57]=[C:52]([NH:10][S:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)(=[O:9])=[O:8])[CH:53]=[C:54]([O:68][CH2:69][CH2:70][OH:71])[N:55]=1
Reactant: OCCOc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Reactant: NS(=O)(=O)N1CCOCC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=S(=O)(Nc1cc(OCCO)nc(SCc2cccc(F)c2F)n1)N1CCOCC1
Temperature: 100 °C

Procedure:
A mixture of morpholine-4-sulfonamide (prepared according to patent WO 2004/011443, 0.399 g), tris(dibenzylideneacetone)dipalladium (0) (50 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (50 mg), cesium carbonate (0.585 g) and 2-({6-chloro-2-[(2,3-difluorobenzyl)thio]pyrimidin-4-yl}oxy)ethanol (the product from example 112 step i), 0.400 g) in dioxane (20 ml) was heated at reflux in a microwave at 100° C., 300 W, open vessel with cooling for 30 mins. The reaction mixture was then reduced in vacuo and the residue separated between DCM (150 ml) and H2O (100 ml). The organics were separated and the aqueous layer was re-extracted with DCM (2×150 ml). Organics were combined, dried (MgSO4) and reduced in vacuo and the resulting residue purified by prep HPLC to give the title compound as a white solid. Yield: 0.15 g
Reaction SMILES: [OH:1][CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1.[S:21]1[CH2:25][C:24](=[O:26])[NH:23][C:22]1=[O:27].N1CCCCC1>CCO>[OH:1][CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[C:25]2[S:21][C:22](=[O:27])[NH:23][C:24]2=[O:26])=[CH:7][CH:6]=1
Reactant: COc1cccc(C(O)COc2ccc(C=O)cc2)c1
Reactant: O=C1CSC(=O)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1cccc(C(O)COc2ccc(C=C3SC(=O)NC3=O)cc2)c1
Yield: 57.5 %

Procedure:
To a stirring solution of 4-[2-hydroxy-2-(3-methoxyphenyl)ethoxy]benzaldehyde (1.76 g, 6.46 mmol) in absolute EtOH (50 ml) was added 2,4-thiazolidinedione (0.83 g, 7.11 mmol) and piperidine (0.70 mL, 7.11 mmol), and the resulting solution was heated to reflux. The reaction was refluxed overnight and then evaporated in vacuo. The residue was dissolved in EtOAc and this solution was washed with water (pH adjusted to ca. 5-6 with HOAc), brine, dried (Na2SO4), filtered and adsorbed onto silica gel. After chromatography with 20-30% EtOAc/DCM, the fractions containing compound were combined and evaporated in vacuo to give 1.38 g (58%) of the title compound as a yellow solid. MS (ESI−) for C19H17NO5S m/z 370.1 (M−H)−.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[C:12]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:17]=3[N:18]=2)[C:11]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:10][C:9]=1[C:31]1[O:32][C:33]2[CH:39]=[CH:38][C:37]([C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:36][C:34]=2[N:35]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Br:44]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:44][CH2:23][C:19]1[C:17]2[N:18]=[C:14]([C:12]3[CH:13]=[C:8]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:9]([C:31]4[O:32][C:33]5[CH:39]=[CH:38][C:37]([C:40]([CH3:41])([CH3:43])[CH3:42])=[CH:36][C:34]=5[N:35]=4)=[CH:10][C:11]=3[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[O:15][C:16]=2[CH:22]=[CH:21][CH:20]=1
Reactant: CCCCCCOc1cc(-c2nc3c(C)cccc3o2)c(OCCCCCC)cc1-c1nc2cc(C(C)(C)C)ccc2o1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCCOc1cc(-c2nc3c(CBr)cccc3o2)c(OCCCCCC)cc1-c1nc2cc(C(C)(C)C)ccc2o1
Temperature: 0 °C

Procedure:
A mixture of 2-(2,5-bis(hexyloxy)-4-(4-methylbenzo[d]oxazol-2-yl)phenyl)-5-(tert-butyl)benzo[d]oxazol (3.7 g, 6.35 mmol), N-bromosuccinimide (NBS) (1.13 g, 6.35 mmol), and AIBN (0.1 g, 0.6 mmol) in CCl4 (40 mL) was heated to reflux for 15 h under dry argon atmosphere. The reaction mixture was cooled to 0° C. and the precipitate was removed by filtration while maintaining the temperature at 0° C. After the solvent was evaporated, 4-(bromomethyl)-2-(4-(5-(tert-butyl)benzo[d]oxazol-2-yl)-2,5-bis(hexyloxy)phenyl)benzo[d]oxazole was obtained as an oil, which was used for next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:33]=[C:32]([NH:34][C:35](=[O:48])[CH2:36][C:37]([NH:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[O:46][CH3:47])=[O:38])[CH:31]=[CH:30][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]=[CH:16][N:17]([CH2:19][CH2:20][N:21](C)[C:22](=O)OC(C)(C)C)[CH:18]=3)[S:13][C:6]=12.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:33]=[C:32]([NH:34][C:35](=[O:48])[CH2:36][C:37]([NH:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[O:46][CH3:47])=[O:38])[CH:31]=[CH:30][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]=[CH:16][N:17]([CH2:19][CH2:20][NH:21][CH3:22])[CH:18]=3)[S:13][C:6]=12
Reactant: COc1ccccc1NC(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(-c4cn(CCN(C)C(=O)OC(C)(C)C)cn4)sc23)c(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CNCCn1cnc(-c2cc3nccc(Oc4ccc(NC(=O)CC(=O)Nc5ccccc5OC)cc4F)c3s2)c1
Temperature: 25 °C
Yield: 177.8 %

Procedure:
To a solution of 101 (31 mg, 0.046 mmol) in toluene (1 ml) was added TFA (excess) and the reaction mixture was stirred at RT for an hour. The solvents were removed and the title compound 96 (47 mg, 100% yield) was obtained after trituration of the resultant solid. MS (m/z): 575.1 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[CH:17][C:18]3[CH:19]=[C:20]4[C:25](=[CH:26][CH:27]=3)[NH:24][C:23](=[O:28])[CH2:22][CH2:21]4)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>O1CCOCC1.[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]3[CH:19]=[C:20]4[C:25](=[CH:26][CH:27]=3)[NH:24][C:23](=[O:28])[CH2:22][CH2:21]4)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(N2CCN(CCC=Cc3ccc4c(c3)CCC(=O)N4)CC2)cc1
Agent: [Pd]
Solvent: C1COCCO1
Product: Cc1ccc(N2CCN(CCCCc3ccc4c(c3)CCC(=O)N4)CC2)cc1

Procedure:
1.0 Gram of 6-{4-[4-(4-Methylphenyl)-1-piperazinyl]-1-butenyl}-3,4-dihydrocarbostyril and 0.2 g of palladium black were suspended in 100 ml of dioxane and the mixture was catalytically hydrogenated under an ordinary pressure at an ordinary temperature. The catalyst was removed by filtration and the filtrate was dried under a reduced pressure. The residue was recrsytallized from isopropanol-diisopropyl ether to obtain 6-{4-[4-(4-methylphenyl)piperazinyl]-butyl}-3,4-dihydrocarbostyril in colorless prism-like crystals. Yield: 0.7 g. Melting piont: 160°-161° C.
Reaction SMILES: [CH2:1]([C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[N:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:24][Si:25]([CH3:62])([CH2:41][CH2:42][C:43]([F:61])([F:60])[C:44]([F:59])([F:58])[C:45]([F:57])([F:56])[C:46]([F:55])([F:54])[C:47]([F:53])([F:52])[C:48]([F:51])([F:50])[F:49])[CH2:26][CH2:27][CH2:28][CH2:29]OS(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:29][CH2:28][CH2:27][CH2:26][Si:25]([CH3:62])([CH3:24])[CH2:41][CH2:42][C:43]([F:61])([F:60])[C:44]([F:58])([F:59])[C:45]([F:56])([F:57])[C:46]([F:54])([F:55])[C:47]([F:52])([F:53])[C:48]([F:49])([F:50])[F:51])=[CH:21][CH:22]=2)=[N:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: Cc1ccc(S(=O)(=O)OCCCC[Si](C)(C)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc1
Reactant: CCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCc1cnc(-c2ccc(OCCCC[Si](C)(C)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)nc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A suspension of 4-(5-decyl-pyrimidin-2-yl)-phenol (3.744 g, 13.00 mmol), toluene-4-sulfonic acid 4-[dimethyl-(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluoro-octyl)-silanyl]-butyl ester (7.58 g, 13.00 mmol) and cesium carbonate (4.69 g, 14.4 mmol) in DMF (35 ml) was stirred at room temperature for 24 h. The reaction mixture was washed with water and the organic layer extracted into ethyl acetate/hexane (3×20 ml, 1:1). The combine extracts were washed with brine, dried (MgSO4) and the solvent removed in vacuo. The residues were purified by column chromatography [silica gel, hexane/ethyl acetate (9:1)] to yield a colorless solid, which was recrystallized from acetonitrile.