Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=O)[C:11]3[CH:15]=[CH:16][S:17][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:12]1[C:11]2[CH:15]=[CH:16][S:17][C:10]=2[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c(-c2ccc(Br)cc2)cc2sccc12
Product: Clc1nc(-c2ccc(Br)cc2)cc2sccc12
Temperature: 100 °C

Procedure:
6-(4-Bromophenyl)-5H-thieno[3,2-c]pyridin-4-one (4.87 g) was added to phosphorus oxychloride (30 ml), and the resulting mixture was heated at 100° C. for 3 hr. The reaction solution was evaporated, and to the resulting residue were added ethyl acetate and water. The organic layer was washed with water, an aqueous solution of saturated sodium bicarbonate and brine, and dried over magnesium sulfate. The solvent was evaporated, to give 4-chloro-6-(4-bromophenyl)thieno[3,2-c]pyridine.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:3]=1.[CH2:19]([O:21][C:22]([CH3:31])([CH3:30])[C:23]([C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)=[O:24])[CH3:20]>>[CH2:19]([O:21][C:22]([CH3:30])([CH3:31])[C:23]([C:25]1[S:26][C:27]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]3[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]3)[N:3]=2)=[CH:28][CH:29]=1)=[O:24])[CH3:20]
Reactant: CCOC(C)(C)C(=O)c1cccs1
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Product: CCOC(C)(C)C(=O)c1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)s1

Procedure:
The title compound was prepared analogous to Method C, starting from (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine and 2-ethoxy-2-methyl-1-thiophen-2-yl-propan-1-one.
Reaction SMILES: C(O)C.[OH-].[K+].C([O:8][C:9](=[O:32])[CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][C:22]=1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:19][C:18]([CH3:30])([CH3:29])[C:17]2=[O:31])C>O>[CH2:23]([C:22]1[CH:21]=[C:20]2[C:16]([C:17](=[O:31])[C:18]([CH3:30])([CH3:29])[CH2:19]2)=[CH:15][C:14]=1[O:13][CH2:12][CH2:11][CH2:10][C:9]([OH:32])=[O:8])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCc1cc2c(cc1OCCCC(=O)OCC)C(=O)C(C)(C)C2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCc1cc2c(cc1OCCCC(=O)O)C(=O)C(C)(C)C2
Yield: 87.8 %

Procedure:
A mixture of 60 ml of ethanol, 0.4 g (7.2 mmol) of potassium hydroxide, 1.8 g (4.8 mmol) of ethyl4-(6-hexyl-2,2-dimethyl-3-oxoindan-5-yloxy)butyrate and 20 ml of water is heated for 2 hours at the reflux point of the solvents. The solvents are evaporated off and the residue is placed in water and extracted with ether. The aqueous phase is acidified and then extracted with ether. Concentration of the solvents gives 1.46 g of product, which is purified by flash chromatography (95/5 dichloromethane/methanol): 1.18 g; m.p.: 82° C.; 71%.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:16][C:17]([C:19]2([C:22]3[CH:30]=[CH:29][C:25]4[O:26][CH2:27][O:28][C:24]=4[CH:23]=3)[CH2:21][CH2:20]2)=[O:18])[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8]2.C(N(CC)CC)C.[C:38](Cl)(=[O:40])[CH3:39]>CN(C=O)C>[C:38]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:16][C:17]([C:19]2([C:22]3[CH:30]=[CH:29][C:25]4[O:26][CH2:27][O:28][C:24]=4[CH:23]=3)[CH2:20][CH2:21]2)=[O:18])[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8]2)(=[O:40])[CH3:39]
Reactant: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)cc(CN)c2[nH]1
Reactant: CC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)NCc1cc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc2cc(C(C)(C)C)[nH]c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N-(7-(Aminomethyl)-2-tert-butyl-1H-indol-5-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (20 mg, 0.049 mmol) was dissolved in DMF (0.5 mL) containing triethylamine (20.6 μL, 0.147 mmol) and a magnetic stir bar. Acetyl chloride (4.2 μL, 0.054 mmol) was then added to the reaction mixture. The reaction mixture was allowed to stir for 16 h at room temperature. The crude product was purified by preparative HPLC using a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield N-(7-(acetamidomethyl)-2-tert-butyl-1H-indol-5-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 447.2. found 448.3 (M+1)+. Retention time of 1.76 minutes.
Reaction SMILES: [C:1]([C:3]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22])([CH2:10][CH2:11][C:12]([O:14]C)=O)[CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7])#[N:2].[H-].[Na+].CO>C1(C)C=CC=CC=1>[C:1]([C:3]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[CH2:4][CH:5]([C:6]([O:8][CH3:9])=[O:7])[C:12](=[O:14])[CH2:11][CH2:10]1)#[N:2]
Reactant: COC(=O)CCC(C#N)(CCC(=O)OC)c1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)C1CC(C#N)(c2ccccc2F)CCC1=O
Yield: 92.8 %

Procedure:
Dimethyl 4-cyano-4-(2-fluorophenyl)heptanedioate (D18, 35.86 g, 0.12 mol) was stirred under Ar in toluene (500 ml) as sodium hydride (80% in mineral oil, 3.5 g, 0.12 mol) was added. Methanol (10 ml) was added dropwise, and the mixture was then stirred at reflux for 16 h, partitioned between ethyl acetate and dilute HCl, and separated. The organic portion was washed with brine, dried (Na2SO4) and evaporated to an oil. This was dissolved in dichloromethane (500 ml), filtered, and evaporated to give the title compound (30.66 g, 95%) as a cream solid.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12].[NH:13]1[CH:17]=[C:16]([CH:18]=[O:19])[N:15]=[CH:14]1.Cl>O1CCCC1>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH2:5][CH2:4][CH2:3][CH:18]([C:16]1[N:15]=[CH:14][NH:13][CH:17]=1)[OH:19]
Reactant: Clc1ccccc1CCCBr
Reactant: O=Cc1c[nH]cn1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: OC(CCCc1ccccc1Cl)c1c[nH]cn1
Temperature: 25 °C

Procedure:
3.3 g of magnesium turnings are covered with 40 ml of dry tetrahydrofuran. To the mixture is added 32.0 g of 1-(3-bromopropyl)-2-chlorobenzene (prepared according to Baddar, F. G. et al., J. Chem. Soc., 1959, 1027) in 100 ml of dry tetrahydrofuran at such a rate that a smooth reaction is maintained. When the magnesium turnings have reacted the solution is cooled to room temperature. 4.3 g of imidazole-4-carbaldehyde in 40 ml of dry tetrahydrofuran is then added dropwise to the Grignard reagent and the reaction mixture is refluxed for one hour. The cooled reaction mixture is poured into a cold dilute hydrochloric acid solution. Tetrahydrofuran is distilled off under reduced pressure and the residue is cooled. The resulting precipitate is filtered and washed with water. The crude product is recrystallized from ethanol. The yield is 8.0 g. Melting point of the hydrochloride salt is 152-154° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[B:16]1[O:20][C:19]([CH3:22])([CH3:21])[C:18]([CH3:24])([CH3:23])[O:17]1)([O-])=O>C(OCC)(=O)C.[C].[Pd]>[N:10]1([C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[C:5]([B:16]3[O:20][C:19]([CH3:22])([CH3:21])[C:18]([CH3:24])([CH3:23])[O:17]3)[CH:6]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: CC1(C)OB(c2cc(N3CCCCC3)ccc2[N+](=O)[O-])OC1(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1(C)OB(c2cc(N3CCCCC3)ccc2N)OC1(C)C
Temperature: 5 °C
Reaction time: 1 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 1-(4-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (600.0 mg, 1.81 mmol, 1.00 equiv) in ethyl acetate (30.0 mL), then Palladium carbon (10%) (150 mg) was added next. The gas of H2 was introduced in. The resulting solution was stirred for 1 h at 0=5° C. The Pd/C was filtered out and the filtrate was collected and concentrated under vacuum. This resulted in 545.8 mg (99%) of 4-(piperidin-1-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenamine as a green to yellow solid. The target product was unstable, it was used to the next reaction step rapidly
Reaction SMILES: Cl.[Cl:2][C:3]1[N:7]([CH3:8])[C:6]([CH2:9]Cl)=[N:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][C:18]1[N:23]=[C:22]([SH:24])[N:21]=[C:20]([OH:25])[CH:19]=1>CC(C)=O>[Cl:2][C:3]1[N:7]([CH3:8])[C:6]([CH2:9][S:24][C:22]2[N:21]=[C:20]([OH:25])[CH:19]=[C:18]([CH3:17])[N:23]=2)=[N:5][CH:4]=1
Reactant: Cn1c(Cl)cnc1CCl
Reactant: Cc1cc(O)nc(S)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(O)nc(SCc2ncc(Cl)n2C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
5-chloro-2-(chloromethyl)-1-methyl-1H-imidazole hydrochloride (1.0 g, 5.0 mmol), potassium carbonate (1.65 g, 12 mmol), and 6-methyl-2-sulfanylpyrimidin-4-ol (560 mg, 4.0 mmol) were mixed in acetone (20 mL). The mixture was stirred at room temperature overnight. Acetone was then removed under reduced pressure. The crude solid was purified by column chromatography to provide the title compound as a white solid (850 mg, 79% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.20 (s, 3H), 3.60 (s, 3H), 4.51 (s, 2H), 6.04 (br, 1H), 6.93 (s, 1H); M+ 271.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:29](O)=[O:30])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([N:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1)[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][C:38]=1[N:39]1[CH2:44][C@H:43]([C:45]([F:48])([F:47])[F:46])[CH2:42][C@H:41]([NH:49][C:50](=[O:56])[O:51][C:52]([CH3:55])([CH3:54])[CH3:53])[CH2:40]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:52]([O:51][C:50]([NH:49][C@H:41]1[CH2:42][C@@H:43]([C:45]([F:48])([F:47])[F:46])[CH2:44][N:39]([C:38]2[CH:37]=[CH:36][N:35]=[CH:34][C:33]=2[NH:32][C:29]([C:13]2[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:21][C:20]3[C:15](=[CH:16][C:17]([N:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)=[CH:18][CH:19]=3)[N:14]=2)=[O:30])[CH2:40]1)=[O:56])([CH3:55])([CH3:53])[CH3:54]
Reactant: CN1CCN(c2ccc3cc(NC(=O)OCc4ccccc4)c(C(=O)O)nc3c2)CC1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](C(F)(F)F)CN(c2ccncc2N)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc3cc(NC(=O)OCc4ccccc4)c(C(=O)Nc4cnccc4N4C[C@@H](NC(=O)OC(C)(C)C)C[C@@H](C(F)(F)F)C4)nc3c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 3-{[(benzyloxy)carbonyl]amino}-7-(4-methylpiperazin-1-yl)quinoline-2-carboxylic acid (0.014 g, 0.034 mmol), tert-butyl [(3S,5R)-1-(3-aminopyridin-4-yl)-5-(trifluoromethyl)piperidin-3-yl]carbamate (0.015 g, 0.041 mmol) and HATU (0.033 g, 0.086 mmol) in DMF (0.14 mL), DIPEA (0.018 mL, 0.10 mmol) was added. The mixture was stirred at room temperature for 2 h, then quenched with 5 mL of EtOAc and 3 mL of 1 M NaOH. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at a flow rate of 30 mL/min.) to afford the sub-title compound. LCMS calc. for C39H46F3N8O5 [M+H]+: m/z=763.4. found: 763.5.
Reaction SMILES: C(OC([N:8]([C:36]1[N:37]=[C:38]2[CH:44]=[CH:43][N:42]([S:45]([C:48]3[CH:54]=[CH:53][C:51]([CH3:52])=[CH:50][CH:49]=3)(=[O:47])=[O:46])[C:39]2=[N:40][CH:41]=1)[CH2:9][C:10]([CH:12]1[CH:17]([CH3:18])[CH2:16][CH2:15][N:14]([C:19]([O:21][CH2:22][CH:23]2[C:35]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:29]3[C:24]2=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:20])[CH2:13]1)=[O:11])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:18][CH:17]1[CH2:16][CH2:15][N:14]([C:19]([O:21][CH2:22][CH:23]2[C:35]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:29]3[C:24]2=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:20])[CH2:13][CH:12]1[C:10](=[O:11])[CH2:9][NH:8][C:36]1[N:37]=[C:38]2[CH:44]=[CH:43][N:42]([S:45]([C:48]3[CH:49]=[CH:50][C:51]([CH3:52])=[CH:53][CH:54]=3)(=[O:47])=[O:46])[C:39]2=[N:40][CH:41]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(N(CC(=O)C4CN(C(=O)OCC5c6ccccc6-c6ccccc65)CCC4C)C(=O)OC(C)(C)C)cnc32)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(NCC(=O)C4CN(C(=O)OCC5c6ccccc6-c6ccccc65)CCC4C)cnc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (9H-fluoren-9-yl)methyl 3-(2-(tert-butoxycarbonyl(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)amino)acetyl)-4-methylpiperidine-1-carboxylate (0.627 g, 0.836 mmol, prepared using W from Preparation #20, LL, Z from Example #8, Step A) in DCM (10 mL) was added TFA (1.50 mL, 19.5 mmol) and the resulting mixture was stirred at ambient temperature under nitrogen for about 1 h. The solution was concentrated and the residue was partitioned between saturated aqueous NaHCO3 (25 mL) and EtOAc (25 mL). The organic phase was washed with brine (20 mL), dried over anhydrous MgSO4, filtered, and concentrated to yield crude (9H-fluoren-9-yl)methyl 4-methyl-3-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)acetyl)-piperidine-1-carboxylate as an amorphous brown solid. The crude material was added to 1,4-dioxane (5 mL), Lawesson's reagent (0.203 g, 0.502 mmol) was added, and the resulting suspension was heated at about 80° C. for about 20 min. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography eluting with a gradient of 0 to 1.5% MeOH/DCM to give (9H-fluoren-9-yl)methyl 4-methyl-3-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidine-1-carboxylate as an off-white solid (0.21 g, 40%): LC/MS (Table 2, Method a) Rt=2.68 min; MS m/z: 632 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:22])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[N:31]=[C:32]=[O:33]>CC(N(C)C)=O.CS(C)=O>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:22][C:32]([NH:31][C:25]2[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:24]=2[F:23])=[O:33])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: Cn1ncc(Br)c1-c1cc(N)ccc1OCCN1CCCC1
Solvent: CC(=O)N(C)C
Solvent: CS(C)=O
Product: Cn1ncc(Br)c1-c1cc(NC(=O)Nc2ccc(F)cc2F)ccc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
To a solution of 3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (0.96 g, 2.47 mmol) in 10 mL of DMA was added 2,4-difluoro phenyl isocyanate (0.42 g, 2.71 mmol), and the mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with DMSO and was purified by RP-HPLC. The fractions containing the product were pooled and evaporated to a small volume. The aqueous solution was neutralized with 1N NaOH to a pH of 9.0 and the product was extracted with ethyl acetate (2×, 50 mL). The organic layer was dried with sodium sulfate, filtered and evaporated to dryness to produce 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3-(2,4-difluoro-phenyl)-urea as a colorless solid in 59% yield. LCMS m/z (%)=520 (M+H79Br, 100), 522 (M+H81Br, 98). 1H NMR (400 MHz. DMSO-d6) δ: 9.03 (bs, 1H), 8.49 (bs, 1H), 8.01-8.1 (m, 1H), 7.61 (s, 1H), 7.51 (dd, J=8.96 and 2.73 Hz, 1H), 7.35 (d, J=2.72 Hz, 1H), 7.27-7.33 (m, 1H), 7.15 (d, J=9.04 Hz, 1H), 7.04-7.09 (m, 1H), 4.01-4.11 (m, 2H), 3.67 (s, 3H), 2.51-2.73 (m, 2H), 2.34-2.38 (bs, 4H), 1.59-1.63 (bs, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.Br[CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.C(Cl)(Cl)Cl>[O:13]([CH2:12][CH2:11][NH:9][C:4]1[C:3](=[CH:8][CH:7]=[CH:6][CH:5]=1)[O:2][CH3:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccccc1N
Reactant: BrCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: COc1ccccc1NCCOc1ccccc1
Yield: 52.6 %

Procedure:
A suspension of 6.2 g (50 mmol) o-anisidine M10, 12.1 g (60 mmol) β-bromophenetole M20 and 8.3 g (60 mmol) K2CO3 in 25 ml acetonitrile was heated at reflux for 18 hours. The mixture was cooled, diluted with 100 ml CHCl3 and washed with 100 ml water and 100 ml saturated NaCl. The organic layer was dried over Na2SO4. The solvent was evaporated to give 14.5 g crude oil. This oil was purified by a plug packed with 60 g silica gel 100 with cyclohexane as eluant, wherein 6.4 g pure product were obtained (yield: 51%).
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:9]([OH:11])=[O:10].[CH3:16]N(C)C=O>CO>[CH3:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:9]([O:11][CH3:16])=[O:10]
Reactant: CN(C)C=O
Reactant: Cc1ccc(C(=O)O)cc1C
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)c1ccc(C)c(C)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Thionyl chloride (80 ml; 2 equiv.) was added at room temperature to a solution of 3,4-dimethylbenzoic acid (35 g; 1 equiv.) and dimethylformamide (1 ml) in 227 ml of methanol. The resulting reaction mixture was stirred for 12 h at room temperature and then concentrated under reduced pressure. The resulting residue was taken up in dichloromethane and washed with 5% sodium carbonate solution. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The methyl 3,4-dimethylbenzoate so obtained (38.2 g) was used in the next stage without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[C:8]([O:21][CH3:22])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH:23](N)=O>>[CH3:22][O:21][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][C:9]=1[O:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[N:1]=[CH:23][NH:6][C:4]2=[O:5]
Reactant: COc1cc(C(N)=O)c(N)cc1OCCOc1ccncc1
Reactant: NC=O
Product: COc1cc2c(=O)[nH]cnc2cc1OCCOc1ccncc1
Temperature: 50 °C
Yield: 49 %

Procedure:
5-Methoxy-2-nitro-4-(2-(4-pyridyloxy)ethoxy)benzamide (2.15 g, 6.4 mmol) and 10% palladium-on-charcoal catalyst (100 mg) were suspended in methanol (400 ml) and placed under hydrogen at atmospheric pressure. The reaction mixture was heated at 40° C. for 1 hour, cooled to ambient temperature, filtered through diatomaceous earth and the solvent was removed by evaporation. The precipitate was slurried with ether and collected by filtration to give 2-amino-5-methoxy-4-(2-(4-pyridyloxy)ethoxy)benzamide as a cream solid (1.95 g, 99%). 2-Amino-5-methoxy-4-(2-(4-pyridyloxy)ethoxy)benzamide (1.95 g, 6.4 mmol) and formamide (10 ml) were heated at 190-200° C. for 1 hour. The reaction mixture was allowed to cool to 50° C. as the product precipitated out. Water (50 ml) was added and the solid was collected by filtration, washed with more water and ether and dried under vacuum to give 6-methoxy-7-(2-(4-pyridyloxy)ethoxy)-3,4-dihydroquinazolin-4-one (0.99 g, 49%) as a cream solid. The 6-methoxy-7-(2-(4-pyridyioxy)ethoxy)-3,4-dihydroquinazolin-4-one (312 mg, 1 mmol) was heated at reflux in thionyl chloride (10 ml) and DMF (5 drops) for 1 hour, then evaporated to dryness and partitioned between a saturated solution of sodium hydrogen carbonate and methylene chloride. The methylene chloride phase was dried by filtration through a phase separator paper and the solvent was removed by evaporation to give crude 4-chloro-6-methoxy-7-(2-(4-pyridyloxy)ethoxy)quinazoline which was used without further purification.
Reaction SMILES: Cl.[CH3:2][S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C@@H:12]2[CH2:16][NH:15][C@H:14]([C:17]3[NH:18][C:19]([C:22]4[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:32])[O:30][CH3:31])=[CH:24][CH:23]=4)=[CH:20][N:21]=3)[CH2:13]2)[CH2:8][CH2:7]1)(=[O:5])=[O:4].[CH3:33][C:34]([O:37][C:38]([NH:40][C@H:41]([C@H:43]1[CH2:48][CH2:47][C@H:46]([C:49](O)=[O:50])[CH2:45][CH2:44]1)[CH3:42])=[O:39])([CH3:36])[CH3:35]>>[CH3:31][O:30][C:29]([NH:28][C:25]1[CH:24]=[CH:23][C:22]([C:19]2[NH:18][C:17]([C@@H:14]3[CH2:13][C@H:12]([CH:9]4[CH2:8][CH2:7][N:6]([S:3]([CH3:2])(=[O:4])=[O:5])[CH2:11][CH2:10]4)[CH2:16][N:15]3[C:49]([C@H:46]3[CH2:45][CH2:44][C@H:43]([C@@H:41]([NH:40][C:38](=[O:39])[O:37][C:34]([CH3:36])([CH3:35])[CH3:33])[CH3:42])[CH2:48][CH2:47]3)=[O:50])=[N:21][CH:20]=2)=[CH:27][CH:26]=1)=[O:32]
Reactant: C[C@H](NC(=O)OC(C)(C)C)[C@H]1CC[C@H](C(=O)O)CC1
Reactant: COC(=O)Nc1ccc(-c2cnc([C@@H]3C[C@H](C4CCN(S(C)(=O)=O)CC4)CN3)[nH]2)cc1
Agent: Cl
Product: COC(=O)Nc1ccc(-c2cnc([C@@H]3C[C@H](C4CCN(S(C)(=O)=O)CC4)CN3C(=O)[C@H]3CC[C@H]([C@H](C)NC(=O)OC(C)(C)C)CC3)[nH]2)cc1

Procedure:
Following the procedure described in Example 8, the compound prepared in Example 66 was treated with trans-4-[(1S)-1-({[(2-methyl-2-propanyl)oxy]carbonyl}amino)ethyl]cyclohexanecarboxylic acid to give the title compound as a light brown solid.
Reaction SMILES: [C:1]([OH:12])(=O)[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[NH2:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][NH:25][S:26]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]2[C:44]3[C:39](=[C:40]([Cl:46])[CH:41]=[C:42]([Cl:45])[CH:43]=3)[CH2:38][N:37]([CH3:47])[CH2:36]2)[CH:30]=1)(=[O:28])=[O:27]>>[Cl:45][C:42]1[CH:43]=[C:44]2[C:39](=[C:40]([Cl:46])[CH:41]=1)[CH2:38][N:37]([CH3:47])[CH2:36][CH:35]2[C:31]1[CH:30]=[C:29]([S:26]([NH:25][CH2:24][CH2:23][O:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][NH:13][C:6](=[O:8])[C:5]2[CH:4]=[CH:3][C:2]([C:1]([NH:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][NH:25][S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]4[C:44]5[C:39](=[C:40]([Cl:46])[CH:41]=[C:42]([Cl:45])[CH:43]=5)[CH2:38][N:37]([CH3:47])[CH2:36]4)[CH:30]=3)(=[O:28])=[O:27])=[O:12])=[CH:10][CH:9]=2)(=[O:28])=[O:27])[CH:34]=[CH:33][CH:32]=1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCN)c2)C1
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCNC(=O)c3ccc(C(=O)NCCOCCOCCOCCNS(=O)(=O)c4cccc(C5CN(C)Cc6c(Cl)cc(Cl)cc65)c4)cc3)c2)C1
Yield: 58.7 %

Procedure:
Compound 216 was prepared following the procedure outlined in Example 215 using terephthalic acid (10.7 mg, 0.0646 mmol) and N-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)-3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide (Compound 28, 100 mg, 0.129 mmol). Purification by preparative HPLC gave the title compound (46.3 mg) as a TFA salt. 1H-NMR (400 MHz, CD3OD): δ 7.87 (m, 6H), 7.73 (s, 2H), 7.59 (t, 2H), 7.52-7.49 (m, 4H) m, 6.80 (s, 2H), 4.77-4.69 (m, 4H), 4.49 (d, 2H), 3.587 (qs, 2H), 3.67-3.54 (m, 27H), 3.45 (t, 5H), 3.40 (t, 5H), 3.13 (s, 7H), 2.99 (t, 4H). MS (m/z): 1224.34 [M+H]+.
Reaction SMILES: [CH2:1]([N:5]1[C:13](=[O:14])[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6]1)[CH2:2][C:3]#[CH:4].Br[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][F:23])[N:17]=1>>[F:23][CH2:22][C:18]1[N:17]=[C:16]([C:4]#[C:3][CH2:2][CH2:1][N:5]2[C:13](=[O:14])[N:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]3=[N:6]2)[CH:21]=[CH:20][CH:19]=1
Reactant: FCc1cccc(Br)n1
Reactant: C#CCCn1nc2ccccn2c1=O
Product: O=c1n(CCC#Cc2cccc(CF)n2)nc2ccccn12
Yield: 18.1 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-(but-3-ynyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (70 mg, 0.37 mmol, Example 39(A)) and 2-bromo-6-(fluoromethyl)pyridine (78 mg, 0.41 mmol, Example 190(E)). The crude residue was purified by flash chromatography (DCM/MeOH 98:2) to yield 20 mg (67 μmol, 18%) of 2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one as an orange solid (M.P.=106-107° C.).