Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:43]1[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=1)[CH2:10][N:11]([CH2:19][C@@H:20]1[CH2:29][CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:30]3[CH:31]=[CH:32][C:33]4[C:38](=[O:39])[O:37][C:36](C)(C)[O:35][C:34]=4[CH:42]=3)[CH:26]=2)[O:21]1)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO>[C:14]([O:13][C:12]([N:11]([CH2:19][C@@H:20]1[CH2:29][CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:30]3[CH:31]=[CH:32][C:33]([C:38]([O:37][CH3:36])=[O:39])=[C:34]([OH:35])[CH:42]=3)[CH:26]=2)[O:21]1)[CH2:10][C@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[C:43]1[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=1)=[O:18])([CH3:15])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N(C[C@@H]1CCc2cc(-c3ccc4c(c3)OC(C)(C)OC4=O)ccc2O1)C[C@H](O[Si](C)(C)C(C)(C)C)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1ccc(-c2ccc3c(c2)CC[C@@H](CN(C[C@H](O[Si](C)(C)C(C)(C)C)c2cccnc2)C(=O)OC(C)(C)C)O3)cc1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 94 %

Procedure:
To a solution of the compound of Example 179 in methanol (10 mL) was added potassium carbonate (0.12 g) at room temperature. The reaction mixture was allowed to stir at room temperature for 18 hours and then concentrated under reduced pressure. The resulting residue was washed with distilled water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford the desired product as pale yellow oil (0.68 g, 94%). LC-MS: 649.8 (MH+), retention time: 3.80 min.
Reaction SMILES: CS([C:5]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[S:7][N:6]=1)(=O)=O.[CH2:17]([OH:21])[C:18]#[C:19][CH3:20].[H-].[Na+].[Cl-].[Na+]>CN(C)C=O>[F:16][C:12]1[CH:11]=[C:10]([C:8]2[S:7][N:6]=[C:5]([O:21][CH2:17][C:18]#[C:19][CH3:20])[N:9]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: CC#CCO
Reactant: CS(=O)(=O)c1nsc(-c2cccc(F)c2)n1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC#CCOc1nsc(-c2cccc(F)c2)n1
Reaction time: 0.17 h
Yield: 85.9 %

Procedure:
In 3 ml of N,N-dimethylformamide, 350 mg of 3-methylsulfonyl-5-(3-fluorophenyl)-1,2,4-thiadiazole and 105 mg of 2-butyne-1-ol were dissolved, to the resulting solution was added 65 mg of sodium hydride (60% oily) with ice-cooling, and the mixture was stirred for 10 minutes, and further stirred at room temperature for 4 hours. Then, the reaction mixture was poured into an aqueous saturated sodium chloride solution, and the mixture was extracted with t-butyl methyl ether. The residue obtained by concentration of the organic layer was subjected to silica gel column chromatography to obtain 289 mg of 5-(3-fluorophenyl)-3-(2-butynyloxy)-1,2,4-thiadiazole (the compound (6) of the present invention).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([C:26]2[O:27][C:28]([CH3:31])=[CH:29][N:30]=2)[CH:13]=[C:14]([O:17]COCC[Si](C)(C)C)[C:15]=1[Br:16])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C1COCC1.O>[CH2:2]([O:9][C:10]1[C:15]([Br:16])=[C:14]([OH:17])[CH:13]=[C:12]([C:26]2[O:27][C:28]([CH3:31])=[CH:29][N:30]=2)[CH:11]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cc1cnc(-c2cc(OCOCC[Si](C)(C)C)c(Br)c(OCc3ccccc3)c2)o1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1cnc(-c2cc(O)c(Br)c(OCc3ccccc3)c2)o1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Concentrated hydrochloric acid (3 mL) was added to a solution of 2-(3-(benzyloxy)-4-bromo-5-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-5-methyloxazole (0.60 g, 1.22 mmol) in THF (8 mL) and stirred at room temperature for three hours. The solution was diluted with water and extracted with 1:1 ethyl acetate/diethyl ether (4×). The extracts were washed with saturated sodium bicarbonate, brine, dried over magnesium sulfate and concentrated to a solid. The solid was triturated with heptane (2×) and dried under vacuum to provide 3-(benzyloxy)-2-bromo-5-(5-methyloxazol-2-yl)phenol as an off white solid (412 mg). MS (M+1)=360.2. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.52 (d, J=7.07 Hz, 2H), 7.36-7.43 (m, 2H), 7.28-7.35 (m, 2H), 7.23 (d, J=1.52 Hz, 1H), 6.86 (d, J=1.52 Hz, 1H), 5.24 (s, 2H), 4.21 (q, J=6.74 Hz, 2H), 2.41 (d, J=1.01 Hz, 3H), 1.50 (t, J=6.82 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Mg]Br.O>C1COCC1>[Cl:1][C:2]1[C:11]([CH:12]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[O:17][CH3:16])[OH:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1
Reactant: COc1ccccc1[Mg]Br
Reactant: COc1ccc2nc(Cl)c(C=O)cc2c1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2nc(Cl)c(C(O)c3ccccc3OC)cc2c1
Temperature: -78 °C

Procedure:
2-Chloro-6-methoxyquinoline-3-carbaldehyde (2.66 g, 12 mmol) was dissolved in THF (40 mL) under nitrogen and cooled to −78° C. At this temperature, a solution of 2-methoxyphenyl magnesium bromide (1M, 12.1 mL, 13.32 mmol) in THF was added by drops. Then the mixture was heated slowly to room temperature. The batch was mixed with water and extracted several times with ethyl acetate. The combined organic phases were washed with water until neutral, dried (sodium sulfate) and concentrated. Yield: 3.9 g (11.8 mmol, 99%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH3:10].[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>CCCCCC.[Ti](Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)=[CH2:10]
Reactant: CC(=O)c1ccc(F)cc1F
Reactant: C1CCNC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCCCCC
Product: C=C(c1ccc(F)cc1F)N1CCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 36.6 %

Procedure:
To a solution of 1-(2,4-difluorophenyl)ethanone (10.0 g, 64.0 mmol) and pyrrolidine (32.1 mL, 384 mmol) in hexane (150 mL) was added titanium tetrachloride (3.86 mL, 35.2 mmol) dropwise at 0° C. over 15 minutes. The reaction mixture was stirred at room temperature for 24 hours and filtered. The filtrate was evaporated in vacuo to give pale yellow oil, which was distilled under reduced pressure (0.3 mmHg, 90-120° C.) to give the title compound as a pale yellow oil (4.90 g, 36%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[N:26][N:27]([CH3:34])[C:28]2=[O:33]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:21][O:20][C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[C:5]2[C:4]=1[C:8]([CH3:18])([CH3:19])[CH2:9][C:10]([OH:17])([C:13]([F:14])([F:15])[F:16])[CH:11]2[NH:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[N:26][N:27]([CH3:34])[C:28]2=[O:33]
Reactant: COc1c(C)cccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Reactant: Cn1ncc2c(N)cccc2c1=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1c(C)ccc2c1C(C)(C)CC(O)(C(F)(F)F)C2Nc1cccc2c(=O)n(C)ncc12
Yield: 4.3 %

Procedure:
Analogously to Example 10, the corresponding imine is produced starting from 600 mg of 4-(3-methyl-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 316 mg of 5-amino-2-methylphthalazin-1-one. As in Example 3, 460 mg of the imine is reacted by reaction with 5.2 ml of titanium tetrachloride (1 M in dichloromethane) in 23 ml of dichloromethane, and 36 mg of the title compound is obtained.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([O:15][CH3:16])=[CH:7][C:6]=1[CH:17]=[CH2:18].[OH2:19]>COCCOC.[Ti](Cl)(Cl)(Cl)Cl>[CH3:3][O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([O:15][CH3:16])=[CH:7][C:6]=1[CH2:17][CH2:18][OH:19]
Reactant: O
Reactant: C=Cc1cc(OC)c2ccccc2c1OC
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc(CCO)c(OC)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.61 g of titanium tetrachloride were added to a mixture of 0.65 g of sodium borohydride and 20 ml of dry ethylene glycol dimethyl ether, and the resulting mixture was stirred at room temperature for 1 hour. A solution of 1.83 g of 1,4-dimethoxy-2-vinylnaphthalene [prepared as described in step (b) above] in 40 ml of dry ethylene glycol dimethyl ether was then added dropwise to the resulting mixture, and the mixture was stirred for 21 hours. At the end of this time, the reaction mixture was poured into water, after which it was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 1:2 by volume mixture of hexane and ethyl acetate as the eluent, to give 0.40 g of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([C:6]1([CH:12]=[CH2:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].C12CCCC(CCC1)B12[H]B2(C3CCCC2CCC3)[H]1.[OH:34]O.[OH-].[Na+]>C1COCC1.O>[CH2:1]([C:6]1([CH2:12][CH2:13][OH:34])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: C=CC1(CCCCC)CCCCC1
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCC1(CCO)CCCCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 71 %

Procedure:
A solution of 2-5 (90 mg, 0.50 mmol) in THF (3.4 mL) was added to a solution of 9-BBN dimer (206 mg, 0.84 mmol) in THF (3 mL). The reaction was placed in a 60° C. oil bath and after 2.5 h, a solution of H2O2 (35%, 1.4 mL)/NaOH (0.5 M, 1.4 mL)/H2O (0.35 mL) was added. The reaction was heated to reflux for 1 h and then allowed to cool to room temperature. H2O (20 mL) was added and the mixture was extracted with ethyl acetate (3×25 mL). The combined ethyl acetate solution was washed with brine and then was dried (Na2SO4), filtered and evaporated. The residue was purified by flash chromatography using a Combiflash system by Teledyne Isco (4 g silica gel, 0→30% ethyl acetate/hexanes) which gave the title compound (70 mg, 71%).
Reaction SMILES: C1(C[NH:8][C:9]2[C:14]3[CH2:15][O:16][CH2:17][C:18]4[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[C:19]=4[C:13]=3[CH:12]=[CH:11][C:10]=2[O:30][CH3:31])C=CC=CC=1>[Pd].C(OCC)(=O)C>[CH3:31][O:30][C:10]1[CH:11]=[CH:12][C:13]2[C:19]3[C:20]([O:28][CH3:29])=[C:21]([O:26][CH3:27])[C:22]([O:24][CH3:25])=[CH:23][C:18]=3[CH2:17][O:16][CH2:15][C:14]=2[C:9]=1[NH2:8]
Reactant: COc1ccc2c(c1NCc1ccccc1)COCc1cc(OC)c(OC)c(OC)c1-2
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1N)COCc1cc(OC)c(OC)c(OC)c1-2
Yield: 24.1 %

Procedure:
The N-phenylmethyl-3,9,10,11-tetramethoxy-5,7-dihydrodibenzo[c,e]oxepin-4-amine (45.3 mg) and palladium on charcoal (10% w/w; 2.3 mg) in ethyl acetate (3 mL) in a steel autoclave was stirred under hydrogen (2 bar) for 2.5 hours. The mixture was then passed through a plug of alumina and concentrated in vacuo to afford a green oil. Column chromatography, eluting with chloroform-methanol 49:1), afforded the title compound as a pale orange gum (8.6 mg, 24%); High Resolution Mass Spectrometry Found: M+Na+ 354.1319 (C18H21NO5Na requires 354.1317); νmax/cm−1 (thin film) 3364, 2946, 2850, 1599, 1572; NMR Spectrum δH (400 MHz, CDCl3) 3.65 (3H, s, OCH3), 3.88-3.90 (1H, m, 5-H or 7-H), 3.91 (3H, s, OCH3), 3.92 (3H, s, OCH3), 3.95 (3H, s, OCH3), 3.95-3.98 (1H, m, 5-H or 7-H), 4.37 (1H, d, J 11.5 Hz, 5-H or 7-H), 4.70 (1H, d, J 11.5 Hz, 5-H or 7-H), 6.74 (1H, s, 8-H), 6.88 (1H, d, J 8.3 Hz, 2-H or 1-H), 6.94 (1H; d, J 8.3 Hz, 1-H or 2-H); NMR Spectrum δC (100 MHz, CDCl3) 56.04, 56.31, 56.74, 56.85, 62.53, 71.48, 107.05, 114.42, 114.68, 118.32, 128.60, 129.76, 130.46, 131.96, 132.58, 146.78, 147.42, 147.53; m/z (ES) 331 (M, 100%); Rf (chloroform-methanol 49:1) 0.18.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:15]4[N:16]([CH:21]([CH3:23])[CH3:22])[N:17]=[C:18]([CH3:20])[N:19]=4)=[CH:10]3)[C:6]=2[CH:24]=1.[CH3:25][N:26]1[CH2:31][CH2:30][CH:29]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][NH:33]2)[CH2:28][CH2:27]1.CC(C)([O-])C.[Na+]>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:21]([N:16]1[C:15]([C:9]2[N:8]=[C:7]3[C:6]4[CH:24]=[CH:2][C:3]([N:33]5[CH2:34][CH2:35][CH2:36][CH2:37][CH:32]5[CH:29]5[CH2:28][CH2:27][N:26]([CH3:25])[CH2:31][CH2:30]5)=[CH:4][C:5]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:19][C:18]([CH3:20])=[N:17]1)([CH3:23])[CH3:22]
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(Br)ccc2OCC3)n(C(C)C)n1
Reactant: CN1CCC(C2CCCCN2)CC1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1nc(-c2cn3c(n2)-c2ccc(N4CCCCC4C4CCN(C)CC4)cc2OCC3)n(C(C)C)n1
Temperature: 100 °C
Yield: 12 %

Procedure:
A mixture of 9-bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene from Example 6 (200 mg, 0.51 mmol), l′-methyl-[2,4]bipiperidinyl (234 mg, 1.28 mmol), sodium tertbutoxide (148 mg, 1.5 mmol) and Pd(P(tBu)3)2 (13 mg, 0.026 mmol) in dioxane was degassed with a stream of argon and then heated at 100° C. for 1 h in a sealed tube. After cooling to RT, the mixture was diluted with water and extracted with EtOAc (×3). The combined organic phases were concentrated in vacuo and then purified by column chromatography (Si-PCC, gradient 0-10% MeOH in EtOAc, and then with 20% 2M NH3/MeOH in DCM) followed by HPLC purification (Phenomenex Gemini 5 μm C18 on a 25 min gradient 50-95% 0.1% NH4OH in acetonitrile/water) affording 215 (30 mg, 12%). LCMS: RT 2.98 min [M+H]+ 490.2. 1H NMR (CDCl3, 400 MHz): δ 8.27 (1H, d, J=8.98 Hz), 7.51 (1H, s), 6.63 (1H, dd, J=9.25, 2.95 Hz), 6.38 (1H, d J=2.95 Hz), 6.00-5.88 (1H, m), 4.46-4.39 (2H, m), 4.38-4.30 (2H, m), 3.68-3.59 (2H, m), 3.11-3.02 (1H, m), 2.95-2.88 (1H, m), 2.85-2.78 (1H, m), 2.4 (3H, s), 2.25 (3H, s), 1.98-1.60 (11H, m), 1.56 (6H, d, J=7.15 Hz), 1.40-1.19 (2H, m)
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][N:3]=1.[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[CH2:19][OH:20]>>[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[CH2:19][O:20][C:2]1[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: OCC1CCCCO1
Product: O=C(O)c1ccc(OCC2CCCCO2)nc1
Reaction time: 1.5 h
Yield: 34 %

Procedure:
The title compound was synthesized as described for Intermediate example I-92 in 34% yield starting from ethyl 6-chloronicotinate and tetrahydro-2H-pyran-2-ylmethanol, the final reaction mixture was stirred for 1.5 h; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.69 (d, 1 H), 8.13 (dd, 1 H), 6.91 (d, 1 H), 4.26 (d, 2 H), 3.87 (d, 1 H), 3.58-3.68 (m, 1 H), 3.37-3.44 (m, 1 H, obscured by H2O), 1.72-1.86 (m, 1 H), 1.62 (d, 1 H), 1.39-1.55 (m, 3 H), 1.23-1.36 (m, 1 H); MS (ESI) m/z 238[M+H+].
Reaction SMILES: [ClH:1].[OH:2][NH:3][C:4]([C:6]1([S:15]([C:18]2[CH:23]=[CH:22][C:21]([S:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:11][CH2:10][N:9]([CH2:12][C:13]#[CH:14])[CH2:8][CH2:7]1)=[O:5].C([O-])([O-])=O.[K+].[K+].C(Br)C=C>CN(C=O)C>[ClH:1].[OH:2][NH:3][C:4]([C:6]1([S:15]([C:18]2[CH:19]=[CH:20][C:21]([S:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH2:11][CH2:10][N:9]([CH2:12][CH:13]=[CH2:14])[CH2:8][CH2:7]1)=[O:5]
Reactant: C#CCN1CCC(C(=O)NO)(S(=O)(=O)c2ccc(Sc3ccccc3)cc2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C=CCBr
Product: C=CCN1CCC(C(=O)NO)(S(=O)(=O)c2ccc(Sc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Part A: To a solution of the amine hydrochloride salt of Example 9, part E (4.78 g, 10.8 mmol) in DMF (25 mL) were added K2CO3 (2.98 g, 21.6 mmol) and allyl bromide (0.935 mL, 10.8 mmol), and the solution was stirred for 5 hours at ambient temperature. The solution was partitioned between ethyl acetate and H2O, and the organic layer was washed with H2O and saturated NaCl, and dried over magnesium sulfate. Filtration through a pad of silica (hexane/ethyl acetate) provided the allyl amine as an oil (4.80 g, quantitative yield).
Reaction SMILES: [CH3:1][CH:2]([CH2:17]S(C1C=CC=CC=1)(=O)=O)[CH2:3][CH:4]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=O.CC(C)([O-])C.[K+]>>[CH3:17][CH:2]1[CH2:3][C:4]2[C:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=2)=[CH:1]1
Reactant: CC(CC1CCCCCCCCCCC1=O)CS(=O)(=O)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CC1C=C2CCCCCCCCCC=C2C1

Procedure:
0.756 g (2 mmole) of 2-(2-methyl-3-phenylsulfonyl-prop-1-yl)-cyclododecanone and 0.672 g (6 mmole) of potassium tert-butoxide were progressively heated to 160° under 0.02 Torr and the formed title compound directly distilled from the reaction mixture. There were thus isolated 0.216 g (50% yield) of the desired compound.
Reaction SMILES: [C:1]([CH2:9][CH2:10][C:11]([OH:13])=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:15][NH2:16]>C(O)C>[C:2]1([C:1]2[CH2:9][CH2:10][C:11](=[O:13])[NH:15][N:16]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(O)CCC(=O)c1ccccc1
Solvent: CCO
Solvent: O
Product: O=C1CCC(c2ccccc2)=NN1

Procedure:
A mixture of 3-benzoylpropionic acid (89 g), 80% hydrazine hydrate (25.5 ml) in ethanol (1000 ml) is refluxed for 6 hrs, cooled and filtered to give 75.6 g of 6-phenyl-4,5-dihydro-3(2H)-pyridazinone. Bromine (70 g) is added dropwise to a solution of the above pyridazinone in acetic acid (200 ml) at 80° C. After the addition is over, the mixture is heated to 100° C. for 15 minutes, cooled, filtered and washed with isopropyl ether. The solid is slurried in water, adjusted to pH 10 and filtered to give 60 g of the product 6-phenyl-3(2H)-pyridazinone.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28]([CH3:33])=[CH:27]2.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[N:5]=[CH:4][N:3]=[C:2]2[O:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28]([CH3:33])=[CH:27]2
Reactant: Cc1cc2cc(O)ccc2[nH]1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCCCN1CCCC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 46.2 %

Procedure:
A suspension of 4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (0.13 g, 0.4 mmol), 5-hydroxy-2-methylindole (74 mg, 0.5 mmol) and potassium carbonate (83 mg, 0.6 mmol) in DMF (1.5 ml) was stirred at 100° C. for 2 hours. After cooling to ambient temperature, water (20 ml) was added. The precipitate was collected by filtration, washed with water and dried under vacuum at 60° C. to give 6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (80 mg, 46%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[C:11]([CH3:13])[C:8]([CH:9]=O)=[C:7]([CH3:14])[C:6]=1[CH3:15])[CH:2]=[CH2:3]>CC(C)=O>[CH2:1]([O:4][C:5]1[CH:12]=[C:11]([CH3:13])[C:8]([CH:9]=[CH:3][CH2:2][CH:1]=[O:4])=[C:7]([CH3:14])[C:6]=1[CH3:15])[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(C)c(C=O)c(C)c1C
Solvent: CC(C)=O
Product: C=CCOc1cc(C)c(C=CCC=O)c(C)c1C

Procedure:
The 5-(4-allyloxy-2,3,6-trimethyl-phenyl)-3-methyl-penta-2,4-diene-1-triphenylphosphonium bromide employed as the starting material can be prepared by the procedure of Example 3. This procedure is carried out by alkylation of 1,3,5-trimethylphenol with allyl bromide to give 1,3,5-trimethyl-phenyl allyl ether (boiling point 76°-80° C./0.05 mmHg), by formylation of the ether obtained to give 4-allyloxy-2,3,6-trimethyl-benzaldehyde (boiling point 90°-102° C./0.15 mmHg), by condensation of the aldehyde obtained with acetone to give 4-(4-allyloxy-2,3,6-trimethyl-phenyl)-but-3-en-1-al (boiling point 135°-138° C./0.05 mmHg), by reaction of the ketone obtained with acetylene to give 5-(4-allyloxy-2,3,6-trimethyl-phenyl)-3-methyl-3-hydroxy-penta-4-en-1-yne, by partial hydrogenation of the tertiary acetylene carbinol obtained to give 5-(4-allyloxy-2,3,6-trimethyl-phenyl)-3-methyl-3-hydroxy-penta-1,4-diene and by reaction of the tertiary ethylene carbinol obtained with triphenylphosphine hydrobromide. There is obtained 5-(4-allyloxy-2,3,6-trimethyl-phenyl)-3-methyl-penta-2,4-diene-triphenylphosphonium bromide which melts at 114°-116° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:26]Br>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:26][C:25]2[CH:28]=[CH:29][C:30]([F:31])=[C:23]([F:22])[CH:24]=2)=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(O)cc1
Reactant: Fc1ccc(CBr)cc1F
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(OCc2ccc(F)c(F)c2)cc1
Yield: 57.2 %

Procedure:
Followed the same procedure as that of step 2 in Example 91 with the use of (R)-2-(4-hydroxy-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (150 mg, 0.5 mmol) and 3,4-difluoro-benzyl bromide (145 mg, 0.6 mmol) to afford the title product, (120 mg, 55% yield); LCMS; 100% APCI+, Calcd: 419.5; Found m/z: 421.4 (M+2); 1H NMR (400 MHz, CDCl3); δ 1.47 (s, 9H), 1.80-2.09 (m, 4H), 3.28-3.46 (m, 2H), 3.69-3.91 (m, 1H), 4.02-4.18 (m 2H), 4.95 (s, 2H), 6.84-6.88 (m, 4H), 7.55-7.28 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[F:32][C:33]([F:47])([F:46])[C:34]1[CH:35]=[C:36]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[CH2:37][NH2:38]>>[F:32][C:33]([F:46])([F:47])[C:34]1[CH:35]=[C:36]([CH:39]=[C:40]([C:42]([F:45])([F:43])[F:44])[CH:41]=1)[CH2:37][NH:38][C:21](=[O:22])[C:20]1[CH:24]=[CH:25][CH:26]=[C:18]([C:16]2[CH:15]=[N:14][C:10]3[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]4[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[C:28]([F:31])([F:30])[F:29])[C:9]=3[CH:17]=2)[CH:19]=1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: O=C(NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 3,5-bis(trifluoromethyl)benzylamine as in General Procedure 10 to give the title compound. LCMS: m/z=672.88 (M+H+); retention time=1.11 minutes.