Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CNCCN(C)C.[Li].[CH2:9]([Li])[CH2:10][CH2:11]C.[CH:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cu](C#N)C#N.C(Br)C=C>O1CCCC1>[CH2:11]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH:14]=[O:21])[CH:10]=[CH2:9]
Reactant: [Li]CCCC
Reactant: O=Cc1ccccc1
Agent: N#C[Cu]C#N
Agent: CNCCN(C)C
Agent: [Li]
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCc1ccccc1C=O
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 55.6 %

Procedure:
To a stirred solution of 20.2 g (198.0mmol) of lithium trimethylethylenediamine in 500 ml of dry tetrahydrofuran (THF) under nitrogen at -30° C. was added 79 ml (198.0 mmol) of 2.5M butyllithium (nBuLi) in hexanes dropwise over 15 minutes. The solution became pale yellow and was stirred at -30° C. for 30 minutes. To this solution was added 20.0 g (188.5 mmol) of benzaldehyde dropwise over 30 minutes. The solution became cloudy as the complex was formed and was stirred 1 hour. To this slurry was added 113 ml (283 mmol) of 2.5M nBuLi hexanes dropwise over 1 hour. This slurry was stirred for 24 hours and gradually cleared. The solution was then transferred via cannula into a slurry of 50.6 g (565 mmol) of copper cyanide in 500 ml of dry tetrahydrofuran under nitrogen at -78° C. The mixture was allowed to warm to -30° C. and stirred for 30 minutes. To this slurry was added 49 ml (565 mmol) of allyl bromide. The mixture instantly darkened upon addition. The reaction was quenched after 30 minutes with 3% aqueous ammonium hydroxide and saturated ammonium chloride. This biphasic solution was stirred overnight to ensure complete copper removal. The aqueous layer was extracted repetitively with ether to remove all product. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The yellow oil was purified by distillation at 62° C. at 0.03 torr affording 15.32 g (56%) of o-allylbenzaldehyde. 1H NMR: ε3.82 (d; 2H, J=6.17 Hz, CH2CH=CH2), 4.99 (d; 1H, J=17.1 Hz, one of CH=CH2), 5.09 (d; 1H, J=10.2 Hz, one of CH=CH2), 6.04 (m, 1H CH=CH2), 7.3 (d; 1H, J=7.8 Hz, aryl H), 7.40 (dd; 1H, J=7.6 Hz, aryl H), 7.54 (dd; 1H, J=7.4 Hz, 7.8 Hz, aryl H), 7.86 (d; 1H, J=7.6 Hz, aryl H), 10.26 (s; 1H aldehyde H).
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)[CH3:3].[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[CH:35]=[CH:34][S:33][CH:32]=4)[CH2:28][CH2:27][C:26]([C:36](O)=[O:37])=[CH:25][C:24]=3[CH:39]=2)=[CH:16][CH:15]=1)[CH2:7][CH2:8][CH3:9].S(Cl)(Cl)=O>O1CCCC1>[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[CH:35]=[CH:34][S:33][CH:32]=4)[CH2:28][CH2:27][C:26]([C:36]([NH:29][C:23]4[CH:24]=[CH:39][C:20]([CH2:4][N:2]([CH3:1])[CH:3]5[CH2:12][CH2:11][O:10][CH2:6][CH2:7]5)=[CH:21][CH:22]=4)=[O:37])=[CH:25][C:24]=3[CH:39]=2)=[CH:18][CH:19]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2ccsc2)cc1
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3Cc2ccsc2)cc1
Reaction time: 1 h

Procedure:
One droplet of DMF was added to a solution of 7-(4-butoxyethoxyphenyl)-1-(3-thienylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (250 mg) in tetrahydrofuran (10 ml). Then, thionyl chloride (187 mg) was added at 0° C., the temperature was returned to room temperature, and the mixture was stirred under nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were evaporated under reduced pressure, the resulting residue was suspended in tetrahydrofuran (25 ml), and the suspension was added to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (131 mg) and triethylamine (638 mg) in tetrahydrofuran (10 ml) at 0° C. The suspension was stirred under nitrogen atmosphere at room temperature overnight, to the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, the resulting residue was separated and purified with silica gel column chromatography (methanol:ethyl acetate=1:8), which was recrystallized from hexane-ethyl acetate to give 7-(4-butoxyethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1-(3-thienylmethyl)-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 58) (233 mg) as yellow crystals.
Reaction SMILES: [CH:1]1([CH:7]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([N:31]([CH3:39])[CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])=[O:30])=[CH:25][CH:24]=2)[C:8]2[S:16][C:15]3[C:10](=[N:11][CH:12]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:14]=3)[C:9]=2[CH3:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]([N:31]([CH3:39])[CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:30])=[CH:27][CH:28]=2)[C:8]2[S:16][C:15]3[C:10](=[N:11][CH:12]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:14]=3)[C:9]=2[CH3:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2sc3cc(C(F)(F)F)cnc3c2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCCC2)sc2cc(C(F)(F)F)cnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
To a mixture of ethyl 3-[{[4-({cyclohexyl[3-methyl-6-(trifluoromethyl)thieno[3,2-b]pyridin-2-yl]methyl}amino)phenyl]carbonyl}(methyl)amino]propanoate (310 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (2.00 mL), and the mixture was stirred at room temperature for 1 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), 1N hydrochloric acid (2.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (284 mg, 96%) as a white solid.
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[C:5]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[O:6][CH:7]=1.[BH3-]C#N.[Na+]>CN(P(N(C)C)(N(C)C)=O)C.[I-].C[P+](OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>[CH3:2][C:3]1[N:4]=[C:5]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[O:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CCC[C@@H]1c1nc(CO)co1
Agent: C[P+](Oc1ccccc1)(Oc1ccccc1)Oc1ccccc1
Agent: [BH3-]C#N
Agent: [I-]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cc1coc([C@H]2CCCN2C(=O)OCc2ccccc2)n1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 17.3 %

Procedure:
To a solution of (R)-benzyl 2-(4-(hydroxymethyl)oxazol-2-yl)pyrrolidine-1-carboxylate (1.1 g, 3.64 mmoles) in HMPA (18 mL), was added methyltriphenoxyphosphonium iodide (3.29 g, 7.28 mmoles) and stirred for 30 min. Then NaCNBH3 was added and the reaction was heated at 50° C. for 3 h and poured into 100 mL of ice-cold water and extracted with ether (2×100 mL). The organic layer was dried on Na2SO4, concentrated, and chromatographed on silica gel (50% ethyl acetate/50% hexanes) to yield 180 mg of (R)-benzyl 2-(4-methyloxazol-2-yl)pyrrolidine-1-carboxylate.
Reaction SMILES: [OH:1][CH:2]1[C:8]([CH3:10])([CH3:9])[CH2:7][C:6](=[O:11])[C:5]([CH3:12])=[CH:4][CH:3]1[O:13][C:14](=[O:24])[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1.[CH2:25](O)[CH3:26]>>[CH2:25]([O:11][C:6]12[O:1][CH:2]([C:8]([CH3:9])([CH3:10])[CH2:7]1)[CH:3]([O:13][C:14](=[O:24])[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)[CH:4]=[C:5]2[CH3:12])[CH3:26]
Reactant: CCO
Reactant: CC1=CC(OC(=O)c2ccc([N+](=O)[O-])cc2)C(O)C(C)(C)CC1=O
Product: CCOC12CC(C)(C)C(O1)C(OC(=O)c1ccc([N+](=O)[O-])cc1)C=C2C
Yield: 64 %

Procedure:
5-Hydroxy-4-(4-nitrobenzoyloxy)-2,6,6-trimethyl-2-cyclohepten-1-one (1.00 g, 3.0 mM) obtained in Example 44 was treated with ethanol (20 ml) according to the procedures described in Example 99 and crystallized from a mixed solution of ethyl acetate and hexane to obtain 0.7 g (64%) of 1-ethoxy-4-(4-nitrobenzoyloxy)-2,6,6-trimethyl-8-oxabicyclo[3.2.1]oct-2-ene (AU246) as light yellow flakes. Melting point: 144° to 146° C.
Reaction SMILES: C1CCC([N:7]=[C:8]=[N:9]C2CCCCC2)CC1.ON1C(=O)CCC1=O.[C:24]([NH:32][C@H:33]([C:38]([OH:40])=O)[CH2:34][CH:35]([CH3:37])[CH3:36])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.N#CN.[Na]>C(#N)C.C1COCC1.O>[C:24]([NH:32][C@H:33]([C:38]([NH:9][C:8]#[N:7])=[O:40])[CH2:34][CH:35]([CH3:37])[CH3:36])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC(C)C[C@H](NC(=O)c1ccccc1)C(=O)O
Agent: N#CN
Agent: O=C1CCC(=O)N1O
Agent: [Na]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: O
Product: CC(C)C[C@H](NC(=O)c1ccccc1)C(=O)NC#N
Reaction time: 2 h
Yield: 42.9 %

Procedure:
DCC (2.41 g, 0.0117 mol) and N-hydroxysuccinimide (1.35 g, 0.0117 mol) were added to a solution of N-benzoyl-L-leucine (2.75 g, 0.0117 mol) in 100 ml of acetonitrile at ice bath temperature. The reaction was allowed to proceed at this temperature for 2 hours. The reaction mixture was filtered to remove the bulk of the DCU and the filtrate was evaporated in vacuo to dryness. The resulting semi-solid residue was redissolved in THF and the mixture filtered to remove any residual DCU. The filtrate was evaporated in vacuo to give crude N-benzoyl-L-leucine N-hydroxysuccinimide ester as a foamy residue IR (neat, cm-1) 3340 (NH), 3060 (C6H5), 1820, 1790, 1740 and 1650 (C=O); NMR (Silanor C, δ from TMS) 7.3-7.9 (m, C6H5), 5.1-5.3 (m, --NH--CH--C=O), 2.8 (s, cycl. --CH2 --CH2 --), 1.6-2.2 (m, CH--CH2 --), 0.9-1.1 (d, (CH3)3CH). This was dissolved in 100 ml of THF and added drop-wise to a solution of sodium cyanamide (1.50 g, 0.0234 mol) in 100 ml of distilled water at ice bath temperature. The reaction was allowed to proceed at room temperature for 24 hours. The reaction mixture was then concentrated in vacuo to half its original volume and filtered. The filtrate (pH 9) was extracted with ethyl acetate (2×50 ml). The aqueous layer was separated, acidified to pH 1.5 with 10% HCl, and extracted with methylene chloride (3×50 ml). The methylene chloride extract was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated in vacuo to give 2.80 g (92.4% yield) of crude product as a tacky white solid. This was triturated with diethyl ether and collected to give 1.30 g (42.9% yield of white powdery 11, mp 136°-137° C. [α]D23 +0.7° (c 1.0, CH3OH); TLC: Rf =0.93 in EtOAc/petroleum ether/THF/CH2Cl2 /AcOH (50:50:10:50:4) and 0.24 in EtOAc/petroleum ether/AcOH (50:100:1), detected by UV quenching and orange color with ferricyanide spray reagent; IR (Nujol, cm-1) 3300, 3100 (NH), 2230 (C≡N), 1750 and 1630 (C=O); NMR (Silanor-DMSO, δ from TMS) 7.4-8.0 (d, C6H5 --), 4.2-4.6 (m, --NH--CH--C=O), 1.4-1.9 (m, CH--CH2 --), 0.8-1.1 (d, (CH3)2CH--). Anal. Calcd for C14H 17 N3O2 : C, 64.85; H, 6.61; N, 16.20. Found C, 64.62; H, 6.73; N, 15.93.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][N:6]1[CH2:20][CH2:19][C:18]2[C:9](=[N:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]=2[CH3:21])[CH2:8][CH2:7]1)C.[ClH:23]>>[ClH:23].[ClH:23].[CH3:21][C:17]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=[C:9]2[CH2:8][CH2:7][N:6]([CH2:5][C:4]([OH:22])=[O:3])[CH2:20][CH2:19][C:18]=12
Reactant: CCOC(=O)CN1CCc2nc3ccccc3c(C)c2CC1
Agent: Cl
Product: Cc1c2c(nc3ccccc13)CCN(CC(=O)O)CC2
Yield: 72 %

Procedure:
2-[1,2,4,5-Tetrahydro-11-methyl-3H-azepino[4,5-b]quinoline-3-yl]acetic acid dihydrochloride was prepared by hydrolysis of 2-[1,2,4,5-tetrahydro-11-methyl-3H-azepino[4,5-b]quinoline-3-yl]acetic acid ethyl ester in 2 N hydrochloric acid at the boiling point.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:18][CH:17]=2)[C:7]=1[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:5])[CH3:2].[F:32][C:33]([F:45])([F:44])[O:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:37]3[CH:38]=[CH:39][CH:40]=[C:35]([O:34][C:33]([F:32])([F:44])[F:45])[CH:36]=3)[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:24])[CH3:25])=[CH:18][CH:17]=2)[C:7]=1[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(OC(C)C)cc1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3cccc(OC(F)(F)F)c3)ccc2n1-c1ccc(OC(C)C)cc1

Procedure:
The sub-title compound was prepared in accordance with step (a) Example 24 from 1-(4-isopropoxyphenyl)-2-ethoxycarbonylmethyl-5-hydroxyindole-3-carboxylic acid ethyl ester (212 mg, 0.50 mmol, see (b) Example 12) and 3-trifluoromethoxyphenylboronic acid. Yield 142 mg (48%).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH3:4].[CH2:5]([Al](CC(C)C)CC(C)C)[CH:6](C)C.[Al].C=C>[Cl-].[Cl-].C1(C(=[Zr+2](C2C=CC=C2)C2C3CC4C(=CC=CC=4)C=3C=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO.CCCCCC>[CH2:1]=[CH:2][CH3:3].[CH2:1]=[CH:2][CH2:3][CH3:4].[CH2:5]=[CH2:6]
Reactant: CC(C)C[Al](CC(C)C)CC(C)C
Agent: C1=CC([Zr+2](=C(c2ccccc2)c2ccccc2)c2cccc3c2Cc2ccccc2-3)C=C1
Agent: C=C
Agent: C=CCC
Solvent: CO
Solvent: CCCCCC
Product: C=CC
Temperature: 35 °C
Reaction time: 0.08 h

Procedure:
500 ml of dry hexane, 240 g of 1-butene, and 1.0 mmol of triisobutylaluminum were introduced at normal temperature into a polymerization apparatus (polymerization vessel) having a volume of 2000 ml thoroughly purged with nitrogen. Then, the temperature inside the polymerization vessel was raised to 35° C., and the polymerization vessel was pressurized with propylene to 0.6 MPa, and subsequently pressurized with supplied ethylene to 0.62 MPa. Thereafter, a toluene solution in which 0.005 mmol of diphenylmethylene(cyclopentadienyl)fluorenylzirconium dichloride and 1.5 mmol, relative to aluminum, of methylaluminoxane (manufactured by Tosoh Finechem Corp.) were contacted with each other was added to the polymerization vessel, and polymerization was conducted for 5 minutes while maintaining the internal temperature at 35° C. and the polymerization vessel pressure at 0.62 MPa by supplying ethylene. 20 ml of methanol was added to terminate the polymerization. After depressurizing, a polymer was precipitated out from the polymerization solution in 2 L of methanol, and was dried under vacuum at 130° C. for 12 hours.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]1[NH:10][C:9](=[O:11])[CH2:8][CH2:7][O:6][CH2:5]1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C>[CH2:12]([N:10]1[C:9](=[O:11])[CH2:8][CH2:7][O:6][CH2:5][CH:4]1[CH3:3])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC1COCCC(=O)N1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1COCCC(=O)N1Cc1ccccc1
Temperature: 23 °C
Reaction time: 0.33 h

Procedure:
Sodium hydride (95%, 553 mg, 21.9 mmol, 1.15 equiv) was added to a solution of 3-methyl-1,4-oxazepan-5-one (4-2, 2.46 g, 19.0 mmol, 1 equiv) in DMF (40 mL) at 0° C. and the resulting mixture was stirred for 20 min. Benzyl bromide (2.49 mL, 20.9 mmol, 1.10 equiv) was added and the mixture was warmed to 23° C. and stirred for 20 h. The reaction mixture was partitioned between brine (100 mL) and ethyl acetate (2×100 mL), and the combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (20% EtOAc in hexanes initially, grading to 100% EtOAc) to give 4-benzyl-3-methyl-1,4-oxazepan-5-one (4-3) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.36-7.25 (m, 5H), 5.05 (d, 1H,J=14.6 Hz), 4.17 (d, 1H,J=14.6 Hz), 4.00 (ddd, 1H,J=12.5, 6.1, 3.3 Hz), 3.80 (dd, 1H,J=12.8, 4.0 Hz), 3.56 (dd, 1H,J=12.5 Hz), 3.42 (d, 1H,J=12.8 Hz), 3.31 (m, 1H), 3.02 (ddd, 1H,J=15.0, 11.9, 3.4 Hz), 2.75 (ddd, 1H,J=16.2, 4.9, 1.2 Hz), 1.31 (d, 3H,J=7.3 Hz). LRMS m/z (M+H) 220.3 found, 220.1 required.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[N:10]=[C:9]([CH:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:14][N:13]([C:27]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:28])[CH2:12]2)[O:8][N:7]=1.[ClH:35]>O>[Cl:35][C:6]1[N:10]=[C:9]([CH:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:14][N:13]([C:27]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:28])[CH2:12]2)[O:8][N:7]=1
Reactant: Cl
Reactant: Nc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)n1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(Cl)no2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 2.59 g (37.6 mmol) of sodium nitrite in 10 ml of water was added dropwise at 0° C. to a solution of 8.00 g (18.8 mmol) of the amine from Example 22A in 200 ml of concentrated hydrogen chloride solution. After the addition had ended, the mixture was stirred at 0° C. for 1 h and then at RT for 2 h. The reaction mixture was diluted with 1 N aqueous hydrogen chloride solution and extracted with dichloromethane. The organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by means of preparative HPLC. Yield: 5.83 g (70% of theory)
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Br:7][C:8]1[CH:16]=[C:12]([C:13]([OH:15])=[O:14])[C:11]([OH:17])=[CH:10][CH:9]=1.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21](F)[N:20]=1.Cl>CS(C)=O.O>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([O:17][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([F:18])[N:20]=2)=[C:12]([CH:16]=1)[C:13]([OH:15])=[O:14]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: Fc1cccc(F)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1cc(Br)ccc1Oc1cccc(F)n1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
A mixture of cesium carbonate (3.20 mL, 40.0 mmol), 5-bromosalicylic acid (4.34 g, 20.00 mmol) and 2,6-difluoropyridine (5.52 g, 48.0 mmol) in 8 mL of DMSO was stirred at 110° C. for 3 h. After cooling to rt, the reaction mixture was dissolved in water and the pH was adjusted to ˜3 with 1 N HCl. The reaction mixture was extracted with EtOAC (3×25 mL), washed with brine and evaporated to dryness to give crude 5-bromo-2-(6-fluoropyridin-2-yloxy)benzoic acid which was used directly in the next step.
Reaction SMILES: [CH:1]1([CH2:7]C2CCCCN2CC(C2C=CC=C(Br)C=2)C)[CH2:6][CH2:5]C[CH2:3][CH2:2]1.C([Li])CCC.C([O:31][CH2:32][CH3:33])C>>[CH3:7][C:1]1[CH:6]=[CH:5][C:33]([CH:32]=[O:31])=[CH:3][CH:2]=1
Reactant: CC(CN1CCCCC1CC1CCCCC1)c1cccc(Br)c1
Reactant: CCOCC
Agent: [Li]CCCC
Product: Cc1ccc(C=O)cc1

Procedure:
Following a procedure similar to that described in Example 3, 18.9 g. (0.05 mole) of 2-cyclohexylmethyl-1-[2-(3-bromophenyl)propyl]piperidine was reacted with 0.1 mole of n-butyl lithium in diethyl ether and the resulting lithio derivative reacted directly with 12.3 g. (0.103 mole) of 4-methylbenzaldehyde to give 16.9 g. of 2-cyclohexylmethyl-1-{2-[3-(α-hydroxy-4-methylbenzyl)phenyl]propyl}piperidine as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:5]([C:6](O)=[O:7])[C:4]=1[C:12](O)=[O:13].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1.CCOCC>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:5]([CH2:6][OH:7])[C:4]=1[CH2:12][OH:13]
Reactant: COc1cccc(C(=O)O)c1C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cccc(CO)c1CO
Yield: 71.3 %

Procedure:
A solution of 3-methoxyphthalic acid (19.6 g, 0.1 mol) in 100 ml of tetrahydrofuran was added to 10 g (0.263 mol) of lithium aluminum hydride in 500 ml of anhydrous ether at a rate sufficient to maintain a constant reflux. The mixture was refluxed for 2 hours after the addition was completed. It was cooled and decomposed by the addition of 10 ml of water, 20 ml of 10% sodium hydroxide and 40 ml of water. The resulting solid was separated by filtration and washed with tetrahydrofuran. The combined filtrates were concentrated to give 12 g of 3-methoxy-o-xylene-α,α'-diol; m.p. 95°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:29]=[CH:28][C:12]([CH2:13][N:14]2[C:18]([C:19](OCC)=[O:20])=[CH:17][N:16]=[C:15]2[S:24][CH2:25][CH2:26][CH3:27])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:29]=[CH:28][C:12]([CH2:13][N:14]2[C:18]([CH2:19][OH:20])=[CH:17][N:16]=[C:15]2[S:24][CH2:25][CH2:26][CH3:27])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCSc1ncc(C(=O)OCC)n1Cc1ccc(OCc2ccccc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCSc1ncc(CO)n1Cc1ccc(OCc2ccccc2)cc1
Reaction time: 1 h
Yield: 84.2 %

Procedure:
A solution of 2.05 g of 1-(4-benzyloxybenzyl)-2-propylthio-5-carboethoxyimidazole in 10 mL of tetrahydrofuran was added dropwise to 10 mL of 1M lithium aluminum hydride in THF at 0° such that the reaction temperature remained below 5°. The resulting solution then was stirred at 0° for 1 hour. At this point, the reaction mixture was quenched by sequential dropwise addition of 0.40 mL of water, 0.40 mL of 15% aqueous sodium hydride, and 1.20 mL of water. The resulting suspension was filtered employing diethyl ether, and the filtrate was concentrated to furnish 1.55 g of 1-(4-benzyloxybenzyl)-2-propylthio-5-hydroxymethylimidazole; NMR (200 MHz, CDCl3): δ7.41-7.29 (m, 5H); 7.03-6.86 (m, 5H); 5.22 (s, 2H); 5.01 (s, 2H); 4.45 (s, 2H); 3.01 (t, 2H); 2.32 (bs, 1h); 1.66 (sext., 2H); 0.97 (t, 3H).
Reaction SMILES: C(OC1C(F)=CC(Br)=C2C=1C([CH2:21][C:22]([OH:24])=[O:23])=CN2C)C1C=CC=CC=1.[Br:25][C:26]1[CH:27]=[C:28]2[O:41][CH2:40][CH2:39][O:38][C:29]2=[C:30]2[C:34]=1[N:33]([CH2:35][CH2:36][CH3:37])[CH:32]=[CH:31]2>>[Br:25][C:26]1[CH:27]=[C:28]2[O:41][CH2:40][CH2:39][O:38][C:29]2=[C:30]2[C:34]=1[N:33]([CH2:35][CH2:36][CH3:37])[CH:32]=[C:31]2[CH2:21][C:22]([OH:24])=[O:23]
Reactant: Cn1cc(CC(=O)O)c2c(OCc3ccccc3)c(F)cc(Br)c21
Reactant: CCCn1ccc2c3c(cc(Br)c21)OCCO3
Product: CCCn1cc(CC(=O)O)c2c3c(cc(Br)c21)OCCO3
Yield: 74 %

Procedure:
Following the procedure (step 3, scheme 333) used to prepare compound 33-4, compound 40-3 gave compound 40-4 in 74% yield as a yellow solid. LCMS: calc 353.0 found 353.9 [MH]+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([OH:19])[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[NH2:20][C@@H:21]([C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH:32][C:33]([CH3:36])([CH3:35])[CH3:34])(=[O:31])=[O:30])=[CH:25][CH:24]=1)[CH3:22].CCN(C(C)C)C(C)C.O.C(#N)C>CN1C(=O)CCC1>[C:33]([NH:32][S:29]([C:26]1[CH:25]=[CH:24][C:23]([C@H:21]([NH:20][C:2]2[N:3]=[C:4]([OH:19])[C:5]3[N:11]=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)[CH:9]=[CH:8][C:6]=3[N:7]=2)[CH3:22])=[CH:28][CH:27]=1)(=[O:31])=[O:30])([CH3:36])([CH3:34])[CH3:35]
Reactant: Oc1nc(Cl)nc2ccc(-c3ccc(F)cc3)nc12
Reactant: C[C@@H](N)c1ccc(S(=O)(=O)NC(C)(C)C)cc1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Nc1nc(O)c2nc(-c3ccc(F)cc3)ccc2n1)c1ccc(S(=O)(=O)NC(C)(C)C)cc1
Temperature: 120 °C
Yield: 162.3 %

Procedure:
A mixture of 2-chloro-6-(4-fluorophenyl)pyrido[3,2-d]pyrimidin-4-ol (377 mg), (R)-4-(1-aminoethyl)-N-tert-butylbenzenesulfonamide (456 mg) and DIEA (243 ml) in NMP (4 ml) was heated at 120° C. overnight. The reaction mixture was then added to H2O/ACN (9:1) with vigorous stirring and extracted with EtOAc. The organic layer was dried and concentrated to give 1.1 g crude (R)—N-tert-butyl-4-(1-(6-(4 fluorophenyl)-4-hydroxypyrido[3,2-d]pyrimidin-2-ylamino)ethyl)benzenesulfonamide as golden brown oil, which was used in the next step without purification.