Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:28])[C:7]=1[NH:8][C:9]1[N:13]([CH3:14])[C:12]2[C:15]3[CH2:16][C:17]([CH3:27])([CH3:26])[O:18][C:19]=3[C:20]([C:22]([O:24]C)=O)=[CH:21][C:11]=2[N:10]=1.[F:29][C:30]([F:39])([F:38])[C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1.C[Al](C)C>C1(C)C=CC=CC=1>[Cl:28][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[NH:8][C:9]1[N:13]([CH3:14])[C:12]2[C:15]3[CH2:16][C:17]([CH3:27])([CH3:26])[O:18][C:19]=3[C:20]([C:22]([NH:35][C:34]3[CH:36]=[CH:37][C:31]([C:30]([F:29])([F:38])[F:39])=[CH:32][CH:33]=3)=[O:24])=[CH:21][C:11]=2[N:10]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1cc2nc(Nc3c(Cl)cncc3Cl)n(C)c2c2c1OC(C)(C)C2
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cn1c(Nc2c(Cl)cncc2Cl)nc2cc(C(=O)Nc3ccc(C(F)(F)F)cc3)c3c(c21)CC(C)(C)O3
Yield: 57.5 %

Procedure:
The title compound was prepared following the procedure described for Example-143 by using methyl 2-((3,5-dichloropyridin-4-yl)amino)-1,7,7-trimethyl-7,8-dihydro-1H-benzofuro[4,5-d]imidazole-5-carboxylate (Intermediate-60, 0.100 g, 0.237 mmol), 4-(trifluoromethyl) aniline (0.057 g, 0.356 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL), dry toluene (5.0 mL) to afford 0.075 g of the desired product. 1HNMR (DMSO-d6): δ 1.61 (s, 6H), 3.49 (s, 2H), 3.60 (s, 3H), 7.25 (s, 1H), 7.71 (d, J=8.1 Hz, 2H), 7.91 (t, J=8.1 Hz, 2H), 8.47 (s, 2H), 9.94 (s, 1H), 10.91 (s, 1H); MS [M+]+: 550.29.
Reaction SMILES: O[CH2:2][N:3]1[CH2:6][C:5]([CH3:8])([CH3:7])[C:4]1=[O:9].S(Cl)(Cl)=O.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[NH:21][C:22]3[C:27]([CH:28]=2)=[CH:26][C:25]([C:29]#[N:30])=[CH:24][CH:23]=3)[CH:15]=1.[H-].[Na+].[Cl-]>CN(C=O)C.ClCCl>[CH3:7][C:5]1([CH3:8])[CH2:6][N:3]([CH2:2][N:21]2[C:22]3[C:27](=[CH:26][C:25]([C:29]#[N:30])=[CH:24][CH:23]=3)[CH:28]=[C:20]2[C:16]2[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=2)[C:4]1=[O:9]
Reactant: N#Cc1ccc2[nH]c(-c3cccnc3)cc2c1
Reactant: CC1(C)CN(CO)C1=O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC1(C)CN(Cn2c(-c3cccnc3)cc3cc(C#N)ccc32)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A flask is charged with 1-hydroxymethyl-3,3-dimethyl-azetidin-2-one (0.179 g, 1.317 mmol) and dichloromethane (5 mL), and thionyl chloride (0.63 g, 5.27 mmol) is added. The mixture is stirred at room temperature overnight and concentrated in vacuo to yield an oil, which is redissolved in DMF (0.8 mL). 2-Pyridin-3-yl-1H-indole-5-carbonitrile (Example 8, 0.213 g, 0.922 mmol) is dissolved in DMF (5 mL), cooled to 0° C., and NaH (0.053 g, 1.317 mmol) is added portionwise. After 30 min, the chloride solution is added. After 1 h, NaH (0.027 g, 0.67 mmol) is added and the mixture is stirred overnight. The mixture is quenched with a few drops of water and diluted with methanol and DMSO. The mixture is purified on Xbridge C18 eluting with a 9:1 to 1:9 water-acetonitrile gradient to give 1-(3,3-dimethyl-2-oxo-azetidin-1-ylmethyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile. 1H NMR (400 MHz, CDCl3) δ ppm 1.18 (s, 6H), 2.82 (s, 2H), 5.47 (s, 2H), 6.71 (s, 1H), 7.47-7.51 (m, 1H), 7.56 (dd, J=8.6, 1.5 Hz, 1H), 7.73 (d, J=8.6 Hz, 1H), 7.80-7.83 (m, 1H), 8.01 (d, J=1.5 Hz, 1H), 8.75-8.76 (m, 2H). HRMS (ESI) m/z 331.1558 [(M+H)+ Calcd for C20H19N4O: 331.1559].
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]([NH:36][CH:37]([C:39](=O)[CH3:40])[CH3:38])=[O:35])[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].P(Cl)(Cl)(Cl)=O>>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[O:35][C:39]([CH3:40])=[C:37]([CH3:38])[N:36]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(C(=O)NC(C)C(C)=O)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCCc1nc2c(C)cc(-c3nc(C)c(C)o3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 170 from tert.butyl 4'-[[2-n-propyl-4-methyl-6-[N-(1-acetyl-ethyl)-aminocarbonyl]-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and phosphorus-oxychloride.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:32]=[CH:31][C:30](Br)=[C:29]4[C:25]=3[C:26](=[O:35])[N:27]([CH3:34])[CH2:28]4)[C:20]([C:36]([F:39])([F:38])[F:37])=[CH:19][N:18]=2)=[CH:12][CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[C:40]([O:44][C:45]([N:47]1[CH2:52][CH:51]=[C:50](B2OC(C)(C)C(C)(C)O2)[CH2:49][CH2:48]1)=[O:46])([CH3:43])([CH3:42])[CH3:41].C(=O)([O-])[O-].[K+].[K+].ClCCl>[Cl-].[Na+].O.O.C(OCC)(=O)C.O1CCOCC1>[CH2:6]([O:5][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:32]=[CH:31][C:30]([C:50]4[CH2:51][CH2:52][N:47]([C:45]([O:44][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:46])[CH2:48][CH:49]=4)=[C:29]4[C:25]=3[C:26](=[O:35])[N:27]([CH3:34])[CH2:28]4)[C:20]([C:36]([F:38])([F:37])[F:39])=[CH:19][N:18]=2)=[CH:12][CH:11]=1)([O:3][CH2:1][CH3:2])=[O:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)c4c3C(=O)N(C)C4)n2)cc1)OCC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(C4=CCN(C(=O)OC(C)(C)C)CC4)c4c3C(=O)N(C)C4)n2)cc1)OCC
Temperature: 100 °C

Procedure:
Diethyl[4-({4-[(7-bromo-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzyl]phosphonate (200.0 mg, 0.3183 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (Tetrahedron Letters, 2000, 44, pp 3705-3708, 147.6 mg, 0.4774 mmol), potassium carbonate (132.0 mg, 0.9548 mmol) [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (26.0 mg, 0.03183 mmol), 1,4-dioxane (1.0 mL) and water (0.25 mL) were mixed and heated in microwave at 100° C. for 30 minutes. The crude mixture was worked up with ethyl acetate, water and brine. Column chromatography was used to purify the title compound (0-3% methanol in methylene chloride). MS (ES+): m/z 731.33 (100) [MH+]; HPLC: tR=1.53 min (UPLC, Analytical).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=4)=[CH:13][CH:14]=3)[CH2:9]2)[N:5]=[C:4]([NH2:25])[N:3]=1.[CH3:26][N:27]1[CH2:33][CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH3:26][N:27]1[CH2:33][CH2:32][CH2:31][N:30]([C:2]2[CH:7]=[C:6]([N:8]3[CH:17]([CH3:18])[CH2:16][C:15]4[C:10](=[CH:11][C:12]([C:19]5[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=5)=[CH:13][CH:14]=4)[CH2:9]3)[N:5]=[C:4]([NH2:25])[N:3]=2)[CH2:29][CH2:28]1
Reactant: CC1Cc2ccc(-c3cnn(C)c3)cc2CN1c1cc(Cl)nc(N)n1
Reactant: CN1CCCNCC1
Product: CC1Cc2ccc(-c3cnn(C)c3)cc2CN1c1cc(N2CCCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 118 starting from 4-chloro-6-[3-methyl-7-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl]pyrimidin-2-amine and 1-methyl-1,4-diazepane (Aldrich, Cat. No. 186090). LCMS (M+H)+: m/z=433.3.
Reaction SMILES: Br[CH2:2][C:3]([CH2:9]Br)=[C:4]([CH2:7]Br)[CH2:5]Br.[CH3:11][C:12]1[CH:13]=[CH:14][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:16][CH:17]=1.[H-].[Na+]>CN(C)C=O>[C:12]1([CH3:11])[CH:13]=[CH:14][C:15]([S:18]([N:21]2[CH2:7][C:4]3[CH2:5][N:21]([S:18]([C:15]4[CH:16]=[CH:17][C:12]([CH3:11])=[CH:13][CH:14]=4)(=[O:19])=[O:20])[CH2:9][C:3]=3[CH2:2]2)(=[O:20])=[O:19])=[CH:16][CH:17]=1
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Reactant: BrCC(CBr)=C(CBr)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2CC3=C(C2)CN(S(=O)(=O)c2ccc(C)cc2)C3)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 54.1 %

Procedure:
30 g of tetrakis (bromomethyl)ethylene and 30 g of p-toluene sulfonamide were dissolved in 400 ml of dimethylformamide. 150 g of potassium carbonate anhydride (or 50% sodium hydride 17 g) was added and then stirred at room temperature for 24 hours. Thereafter, this reaction mixture was distilled under vacuum to remove solvents. By adding 30 ml of water and 100 ml of ethylacetate, 17 g of the title compound was obtained as pale yellow powder (yield 50%).
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][O:4][C:3]=1[CH3:9].[H-].[Na+].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C>[CH2:12]([O:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][O:4][C:3]=1[CH3:9])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: Cc1occc(=O)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1occc(=O)c1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
3-Hydroxy-2-methyl-4-pyrone (25 g, 0.198 mol) was dissolved in 70 ml of DMF. To the solution was added 8.7 g (0.218 mol) of sodium hydride (60% in mineral oil). The mixture was stirred under ice cooling for 30 min. Benzyl bromide (37.3 g, 0.218 mol) was added dropwise to the reaction solution under ice cooling, and a reaction was allowed to proceed at room temperature overnight. The reaction solution was poured into ice water, followed by extraction with ethyl acetate. The organic layer was washed with water, and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The reddish brown oil thus obtained (64 g) was applied to column chromatography on silica gel (Wako Gel C-200, n-hexane-ethyl acetate) to give 41.6 g (yield 97%) of 3-benzyloxy-2-methyl-4-pyrone.
Reaction SMILES: O/N=[C:3](/[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=1)\[CH2:4][O:5][C:6]1[CH:19]=[CH:18][C:9]([CH2:10][CH:11]2[S:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])=[CH:8][CH:7]=1.[OH-:28].[Na+].CO.C(Cl)Cl>C1COCC1.Cl>[CH3:27][O:26][C:22]1[CH:21]=[C:20]([C:3](=[O:28])[CH2:4][O:5][C:6]2[CH:19]=[CH:18][C:9]([CH2:10][CH:11]3[S:15][C:14](=[O:16])[NH:13][C:12]3=[O:17])=[CH:8][CH:7]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: COc1cccc(/C(COc2ccc(CC3SC(=O)NC3=O)cc2)=N/O)c1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: COc1cccc(C(=O)COc2ccc(CC3SC(=O)NC3=O)cc2)c1

Procedure:
A stirring solution of 5-(4-{[(2Z)-2-(hydroxyimino)-2-(3-methoxyphenyl)ethyl]oxy}benzyl)-1,3-thiazolidine-2,4-dione (0.76 g, 2.0 mmol; Supplier=Kalexsyn; Lot=1003-TTP-124) in THF (5 ml) and 6M HCl (5 ml) was heated to reflux. Little reaction after 4 hours at reflux. Left to reflux overnight. Reaction is complete. 2N NaOH was added until the reaction mixture was ca. pH 8-9. The reaction mixture was extracted with EtOAc (2×25 ml). The combined extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo to give a light yellow oily solid. This material was treated with 5% MeOH/DCM (10 ml) and the resulting white solids were collected by suction filtration and dried to afford 495 mg of final product. 1H-NMR (DMSO-d6): δ 12.03(s, 1H), 7.62(d, J=7.7 Hz, 1H), 7.49((m, 2H), 7.27(dd, J=8.2, 2.6 Hz, 1H), 7.15(d, J=8.7 Hz, 2H), 6.91(d, J=8.5 Hz, 2H), 5.55(s, 2H), 4.88(dd, J=9.1, 4.3 Hz, 1H), 3.83(s, 3H), 3.31(m, 1H), 3.31(m, 1H), 3.05(dd, J=14.1, 9.3 Hz, 1H). HPLC: 3.782 min., 93 area % @ 210 nm; 3.785 min. 100 area % @ 254 nm. MS (ESI−) for C19H17NO5S m/z 370.1 (M−H)−.
Reaction SMILES: Br[CH:2]([CH3:10])[C:3]([C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)=O.C(=O)([O-])O.[Na+].[Si:16]([O:23][CH2:24][C:25]1[CH:26]=[C:27]([C:31]2[CH:32]=[CH:33][C:34]([NH2:37])=[N:35][CH:36]=2)[CH:28]=[CH:29][CH:30]=1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>C(O)C>[Si:16]([O:23][CH2:24][C:25]1[CH:26]=[C:27]([C:31]2[CH:32]=[CH:33][C:34]3[N:35]([C:2]([CH3:10])=[C:3]([C:5]4[S:6][CH:7]=[CH:8][CH:9]=4)[N:37]=3)[CH:36]=2)[CH:28]=[CH:29][CH:30]=1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(-c2ccc(N)nc2)c1
Reactant: CC(Br)C(=O)c1cccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1c(-c2cccs2)nc2ccc(-c3cccc(CO[Si](C)(C)C(C)(C)C)c3)cn12
Temperature: 100 °C
Yield: 67.2 %

Procedure:
In a glass tube, 280 mg of 5-[3-(tert-butyldimethylsilanyloxymethyl)phenyl]pyridin-2-ylamine, 390 mg of 2-bromo-1-thiophen-2-ylpropan-1-one and 190 mg of sodium hydrogencarbonate are dissolved in 5 ml of ethanol. The tube is closed and heated at 100° C. for 20 h. After cooling, the mixture is concentrated under reduced pressure. The residue is purified by silica gel chromatography, elution being carried out with a heptane/ethyl acetate mixture. 260 mg of compound are obtained.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH3:29])[CH2:22][C:23](OCC)=[O:24])=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>O1CCCC1.O>[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([N:28]([CH3:29])[C:30](=[O:31])[O:32][C:33]([CH3:34])([CH3:36])[CH3:35])[CH2:22][CH2:23][OH:24])=[CH:17][CH:16]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)CC(c1ccc(OCc2ccccc2)cc1)N(C)C(=O)OC(C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)OC(C)(C)C)C(CCO)c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
Tetrahydrofuran (100 ml) was added to lithium aluminum hydride (1.02 g, 27 mmol) under an atmosphere of nitrogen, and a solution of ethyl 3-(4-benzyloxyphenyl)-3-[N-(t-butoxycarbonyl)-N-methylamino]propionate (5.56 g, 13 mmol) obtained from Example 115a in tetrahydrofuran was slowly added thereto at −78° C. After stirring the resulting mixture for 30 minutes, the temperature was gradually raised to 0° C. and then the mixture was stirred for 30 minutes. To the reaction mixture was added sequentially water (1 ml), 15% aqueous sodium hydroxide solution (1 ml) and water (3 ml) and the resulting mixture was stirred at room temperature for 30 minutes. To the mixture was added anhydrous magnesium sulfate and the resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column to afford the desired compound (4.78 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[CH2:12]([C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)[CH3:13].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1>CN(C=O)C.CCOC(C)=O>[CH2:12]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:9](=[O:11])[CH2:8][C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)=[CH:16][CH:15]=1)[CH3:13]
Reactant: CCc1ccc(N)cc1
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CCc1ccc(NC(=O)Cc2ccc(O)cc2)cc1

Procedure:
4-Hydroxyphenyl acetic acid (1.55 g, 10.2 mmol), 4-ethyl-phenylamine (1.28 ml, 10.3 mmol), TBTU (4.82 g, 15 mmol), and NMM (8.79 ml, 80 mmol) are stirred in DMF (30 ml) at rt for 5 h. The reaction mixture is taken up in AcOEt (0.2 L), washed with H2O (40 ml, 2×) and brine (40 ml, 2×), dried (Na2SO4), concentrated under reduced pressure, and flash chromatographed (silica gel, 3.5×25 cm, AcOEt/hexane=1:2→2:3) giving the title compound of Stage 16.1 as a colorless solid (1.68 g, 6.59 mmol; 66%) M+H=256.1; 1H-NMR (400 MHz, DMSO-d6): 10.0/9.24 (s/s, 1H, NH/OH), 7.46 (d, 8.5 Hz, 2H, phenyl), 7.09 (d, 8.5 Hz, 4H, phenyl), 6.66 (d, 8.5 Hz, 2H, phenyl), 3.47 (s, 2H, aryl-CH2), 2.53 (qu, 7.5 Hz, 2H, CH2), 1.13 (t, 7.5 Hz, 3H, CH3); R. (AcOEt/hexane=1:1): 0.66; m.p. =146-148° C.
Reaction SMILES: N1N2C=CC=NC2=C(C(O)=O)C=1.NC1C=C(Cl)C=CC=1O.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([O:29]C(C2C=NN3C=CC=NC=23)=O)=[C:25]([NH:41][C:42]([C:44]2[CH:45]=[N:46][N:47]3[CH:52]=[CH:51][CH:50]=[N:49][C:48]=23)=[O:43])[CH:24]=1>S(Cl)(Cl)=O>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([NH:41][C:42]([C:44]2[CH:45]=[N:46][N:47]3[CH:52]=[CH:51][CH:50]=[N:49][C:48]=23)=[O:43])[CH:24]=1
Reactant: O=C(Nc1cc(Cl)ccc1OC(=O)c1cnn2cccnc12)c1cnn2cccnc12
Agent: Nc1cc(Cl)ccc1O
Agent: O=C(O)c1cnn2cccnc12
Solvent: O=S(Cl)Cl
Product: O=C(Nc1cc(Cl)ccc1O)c1cnn2cccnc12
Temperature: 85 °C
Yield: 67 %

Procedure:
Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.5 g, 3.06 mmol) was suspended in thionyl chloride (25 mL) and the resulting mixture was heated at 85° C. for 1.5 hours. The volatiles were then evaporated under high vacuum and the residue was suspended in pyridine (25 mL). 2-Amino-4-chlorophenol (0.46 g, 3.2 mmol) was added and the resulting mixture was heated at reflux overnight. The volatiles were then evaporated under high vacuum, water and dichloromethane were added to the residue and the mixture was evaporated under reduced pressure. The solid residue was washed with a mixture of dichloromethane and methanol (96/4) to give 0.588 g (67% yield) of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (5-chloro-2-hydroxy-phenyl)-amide in mixture with pyrazolo[1,5-a]pyrimidine-3-carboxylic acid 4-chloro-2-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)-amino]-phenyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][CH:3]=1.[Cl-].[O:18]([C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=1)[CH:28]=[N+:29]([CH3:31])[CH3:30])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O(C1C=C(C=CC=1)C=O)C1C=CC=CC=1.CNC>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10]3[C:15]([C:16]=2[CH:28]([N:29]([CH3:31])[CH3:30])[C:27]2[CH:32]=[CH:33][CH:34]=[C:25]([O:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:26]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2cc3ccccc3[nH]2)cc1
Reactant: C[N+](C)=Cc1cccc(Oc2ccccc2)c1
Agent: CNC
Agent: O=Cc1cccc(Oc2ccccc2)c1
Agent: [Cl-]
Product: CN(C)C(c1cccc(Oc2ccccc2)c1)c1c(-c2ccc(F)cc2)[nH]c2ccccc12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-(4-fluoro-phenyl)-1H-indole and (3-phenoxy-benzylidene)-dimethylammonium chloride, which had been prepared in accordance with example 44 from 3-phenoxy-benzaldehyde and dimethylamine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22]([O:24][C:25](=[O:30])[CH2:26][CH2:27][CH2:28]Br)[CH3:23]>CC(=O)CC>[CH2:22]([O:24][C:25](=[O:30])[CH2:26][CH2:27][CH2:28][O:15][C:12]1[CH:11]=[CH:10][C:9]([CH:8]=[CH:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:14][CH:13]=1)[CH3:23]
Reactant: CCOC(=O)CCCBr
Reactant: Oc1ccc(C=Cc2ccncc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)CCCOc1ccc(C=Cc2ccncc2)cc1

Procedure:
One heats a mixture of 30 g (0.15 mol) 4-[2-(4-pyridinyl)-ethenyl]-phenol, 21 g potassium carbonate, 750 ml butanone and 33 ml (0.23 mol) 4-bromobutyric acid ethyl ester to reflux for 24 h, filters, evaporates the filtrate, mixes with water, extracts with dichloromethane, dries the extract, evaporates the triturates the residue with ether. There remain 42.3 g of title compound (89% of theory) of the m.p. 83°-85° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]3=[N:16][C:17]([CH3:20])=[C:18](I)[N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CC1(C)C(C)(C)OB([C:29]2[CH:30]=[N:31][C:32]([NH2:35])=[N:33][CH:34]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O.O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]3=[N:16][C:17]([CH3:20])=[C:18]([C:29]4[CH:30]=[N:31][C:32]([NH2:35])=[N:33][CH:34]=4)[N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2nn3c(I)c(C)nc3s2)cc1OC
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2nn3c(-c4cnc(N)nc4)c(C)nc3s2)cc1OC
Yield: 31.9 %

Procedure:
A mixture of 2-(3,4-dimethoxy-phenyl)-5-iodo-6-methyl-imidazo[2,1-b][1,3,4]thiadiazole (0.041 g, 0.102 mmol, 1 eq), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (0.056 g, 0.255 mmol, 2.5 eq), Pd(Ph3P)2Cl2 (0.007 g, 0.0102 mmol, 0.1 eq) and potassium carbonate (0.07 g, 0.51 mmol, 5 eq) in water (0.3 mL) and dioxane (2.2 mL) was subjected to MW irradiation (120° C., 35 min, 200 W). The solvents were evaporated, and the residue obtained was purified by silica gel chromatography (0-3% MeOH in DCM) and preparative HPLC (RP-C18, ACN/water) to give the desired product (0.012 g). HPLC-MS: (5-100% B in 8 min, 0.8 mL/min, 50° C.): tR=4.08 min, [M+H]+ m/z 369.1
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[C:11]2([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:31]=1[O:38][CH3:39])[N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[CH2:20][CH2:19]1.[N:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][C:48]=2[S:50](Cl)(=[O:52])=[O:51])[CH:43]=[CH:42][CH:41]=1.O>CN(C)C=O>[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([S:50]([C:48]1[CH:47]=[CH:46][CH:45]=[C:44]3[C:49]=1[N:40]=[CH:41][CH:42]=[CH:43]3)(=[O:51])=[O:52])[C:12](=[O:17])[C:11]2([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:31]=1[O:38][CH3:39])[N:18]1[CH2:19][CH2:20][N:21]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[CH2:22][CH2:23]1
Reactant: COc1ccc(C2(N3CCN(c4ccncc4)CC3)C(=O)Nc3ccc(Cl)cc32)c(OC)c1
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C2(N3CCN(c4ccncc4)CC3)C(=O)N(S(=O)(=O)c3cccc4cccnc34)c3ccc(Cl)cc32)c(OC)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 39.5 %

Procedure:
Potassium tert-butoxide (26.6 mg, 0.24 mmol) was added to a solution of 5-chloro-3-(2,4-dimethoxyphenyl)-3-(4-pyridin-4-ylpiperazin-1-yl)-1,3-dihydroindol-2-one (0.10 g, 0.22 mmol) in dimethylformamide (4 mL) at 0° C., and the mixture was stirred at 0° C. for 1 hour. Then 8-quinolinesulfonyl chloride (53.9 mg, 0.24 mmol) was added to the reaction solution while cooling in ice, and the mixture was stirred at room temperature for 12 hours. Water was cautiously added to the mixture, which was extracted twice with ethyl acetate. The combined organic phase was washed with water and saturated brine, dried over sodium sulfate and concentrated under reduced pressure. Chromatographic purification of the residue on silica gel (mobile phase gradient 0-7% methanol in dichloromethane) afforded 57.0 mg of the title compound.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[C:8]1([CH:14]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][N:24]3[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[NH:26][C:25]3=[O:33])[CH2:17][CH2:16]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CC1C=CC=CC=1>O>[C:5]([N:26]1[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[N:24]([CH2:23][CH2:22][CH2:21][N:18]2[CH2:19][CH2:20][N:15]([CH:14]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:16][CH2:17]2)[C:25]1=[O:33])(=[O:7])[CH3:6]
Reactant: O=c1[nH]c2ccccc2n1CCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)n1c(=O)n(CCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)c2ccccc21

Procedure:
A mixture of 1.55 parts of acetic acid anhydride, 3 parts of 1-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one and 22.5 parts of methylbenzene is stirred and refluxed overnight. Water is added to the reaction mixture and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 1-acetyl-3-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 124.4° C.