Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[N:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]2=[N:10][CH:11]=[C:12]([OH:14])[CH:13]=[C:8]2[CH:7]=1)=[O:5].[CH:23]([N:26]1[CH2:31][CH2:30][CH:29](O)[CH2:28][CH2:27]1)([CH3:25])[CH3:24].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH3:1][CH2:2][O:3][C:4]([C:6]1[N:15]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[C:9]2=[N:10][CH:11]=[C:12]([O:14][CH:29]3[CH2:30][CH2:31][N:26]([CH:23]([CH3:25])[CH3:24])[CH2:27][CH2:28]3)[CH:13]=[C:8]2[CH:7]=1)=[O:5]
Reactant: CC(C)N1CCC(O)CC1
Reactant: CCOC(=O)c1cc2cc(O)cnc2n1C(=O)OC(C)(C)C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(OC3CCN(C(C)C)CC3)cnc2n1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 21 %

Procedure:
To the turbid solution of 0.2 g (0.65 mmol) 5-hydroxy-pyrrolo[2,3-b]pyridine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (as prepared in WO 05/000849) and 1-isopropyl-piperidin-4-ol (commercially available) in 6 ml tetrahydrofuran, 0.26 g (1.3 mmol) tributylphosphine were added and the mixture was cooled to 0° C. Within 60 min. 32.9 mg (1.3 mmol) 1,1′-(azodicarbonyl)dipiperidine were added under stirring and the reaction was allowed to reach room temperature. After 19 hours the brown suspension was filtered and evaporated. The residue was stirred in tert butyl methyl ether, filtered and the clear filtrate was evaporated and flash-chromatographed on silica gel with dichloromethane:methanol:ammonia (9:1:0.1 v/v) to give 60 mg (21%) of the product as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[NH2:12][C:13]([CH3:17])([CH3:16])[CH2:14][OH:15]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13]([CH3:17])([CH3:16])[CH2:14][OH:15])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: CC(C)(N)CO
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Solvent: C1CCOC1
Product: CC(C)(CO)Nc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 88.7 %

Procedure:
As shown in Scheme ??, mix 5-bromo-2-fluoronitrobenzene (11.2 g, 50.5 mmol) and 2-amino-2-methyl-1-propanol (10.5 mL, 110 mmol) in THF (120 mL). Heat at reflux for 48 h and then cool to room temperature. Remove most of the THF under reduced pressure and then partition the residue between water and EtOAc. Wash the organic layer a second time with water and the dry (MgSO4) and concentrate to give an orange solid. Triturate the solid with hexane (200 mL) and dry to yield 12.95 g (89%) title compound. MS (es) 288 (M−1). HPLC (ISO80-10M) t=2.67 (100%).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([S:12][CH3:13])[C:5]2[N:6]([C:8](I)=[CH:9][N:10]=2)[CH:7]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH:22]1([NH:25][C:26]([C:28]2[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=2)=[O:27])[CH2:24][CH2:23]1.C(OCC)(=O)C>C1COCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Br:1][C:2]1[N:3]=[C:4]([S:12][CH3:13])[C:5]2[N:6]([C:8]([C:31]3[CH:32]=[CH:33][C:28]([C:26]([NH:25][CH:22]4[CH2:23][CH2:24]4)=[O:27])=[CH:29][CH:30]=3)=[CH:9][N:10]=2)[CH:7]=1
Reactant: CSc1nc(Br)cn2c(I)cnc12
Reactant: O=C(NC1CC1)c1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CSc1nc(Br)cn2c(-c3ccc(C(=O)NC4CC4)cc3)cnc12
Temperature: 45 °C
Reaction time: 8 h
Yield: 56.2 %

Procedure:
To a stirred solution of intermediate example 3-1 6-bromo-3-iodo-8-methylsulfanyl-imidazo[1,2-a]pyrazine (25.00 g, 67.6 mmol) in THF (214 mL) and water (100 mL) was subsequently added 43 g tripotassium phosphate (203 mmol, 3 eq), 18.01 g [4-[(cyclopropylamino)carbonyl]phenyl]-boronic acid (87.8 mmol, 1.3 eq) and 5.52 g Pd(dppf)Cl2 (6.8 mmol, 0.1 eq) in one portion at rt under argon atmosphere. After stirring overnight at 45° C., ethyl acetate was added and the organic phase was washed with sat. sodium chloride solution, dried over sodium sulphate and filtered. After removal of the solvent, purification by flash chromatography (n-hexane/ethyl acetate 85:15) yielded 15.33 g (56.26%) 4-(6-bromo-8-methylsulfanyl-imidazo[1,2-a]pyrazin-3-yl)-N-cyclopropyl-benzamide: 1H-NMR (300 MHz, CDCl3): δ=8.07 (1H, s), 7.92 (2H, d), 7.77 (1H, s), 7.60 (2H, d), 6.32 (1H, bs), 2.95 (1H, m), 2.70 (3H, s), 0.92 (2H, m), 0.67 (2H, m) ppm. UPLC-MS: RT=1.12 min; m/z 404.3 [MH+]; required MW=403.3.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](C=O)[CH:2]=1.[CH2:9]([NH2:11])[CH3:10]>C(Cl)(Cl)Cl>[N:1]1[CH2:2][C:3](=[N:11][CH2:9][CH3:10])[CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1cccnc1
Reactant: CCN
Solvent: ClC(Cl)Cl
Product: CCN=C1C=CC=NC1
Yield: 101.2 %

Procedure:
A solution of 3-pyridinecarboxaldehyde (1 g, 9.3 mmol) and ethylamine (661 mg, 10.2 mmol, 70% wt in water) was stirred at room temperature for 18 h. The reaction mixture was diluted with chloroform (20 mL) and dried over anhydrous K2CO3. The solution was filtered and the solvent was evaporated to afford N-(3-pyridylidene)-ethylamine (XVII) 1.15 g (92%), which was used immediately without further purification.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9]C)[C:4]=1[S:11][CH3:12].B(Br)(Br)Br.O>C(Cl)Cl>[CH3:12][S:11][C:4]1[C:5]([OH:9])=[CH:6][CH:7]=[CH:8][C:3]=1[OH:2]
Reactant: COc1cccc(OC)c1SC
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CSc1c(O)cccc1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1,3-dimethoxy-2-methylsulfanylbenzene (2.8 g, 15 mmol) in methylene chloride (40 mL) is added BBr3 (30 mL, 30 mmol, 1M in methylene chloride) and the mixture is stirred at RT for 18 h. Water is added and the organic phase is washed with water and brine then is dried over sodium sulfate. The solvent is removed under reduced pressure to give the title compound as a pink solid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@@H:9]([O:13][C:14]1[NH:15][C:16]([NH2:25])=[C:17]2[C:21]([N:22]=1)=[N:20][C:19]([O:23][CH3:24])=[N:18]2)[CH2:10][CH2:11][CH3:12].Br[CH2:27][CH2:28][C@H:29]1[CH2:33][CH2:32][O:31][CH2:30]1>>[CH3:8][C@@H:9]([O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]2[CH2:27][CH2:28][C@H:29]2[CH2:33][CH2:32][O:31][CH2:30]2)=[C:16]([NH2:25])[N:15]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCC[C@@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Reactant: BrCC[C@H]1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@@H](C)Oc1nc(N)c2nc(OC)n(CC[C@H]3CCOC3)c2n1

Procedure:
Prepared similarly to Intermediate 216 from 2-{[(1R)-1-methylbutyl]oxy}-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and (3R)-3-(2-bromoethyl)tetrahydrofuran.
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:30])[CH:25]=[CH:26][CH2:27][CH2:28][CH3:29])[CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.[CH2:31]([CH2:33][NH2:34])[OH:32]>>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:30])[CH2:25][CH:26]([NH:34][CH2:33][CH2:31][OH:32])[CH2:27][CH2:28][CH3:29])[CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=2)(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: NCCO
Reactant: CCCC=CC(=O)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Product: CCCC(CC(=O)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1)NCCO

Procedure:
N-Cyclopropyl-N-{1-[3-(2-hydroxyethylamino)hexanoyl]piperidin-4-yl}-3-trifluoromethylbenzenesulfonamide (40) was prepared by reacting N-cyclopropyl-N-(1-hex-2-enoyl-piperidin-4-yl)-3-trifluoromethyl-benzenesulfonamide (250 mg, 0.56 mmol) and ethanolamine (2 mL) as described in Example 26 above. The reaction mixture was cooled and partitioned between ether (100 mL) and 1M sodium hydroxide solution (100 mL). The organic phase was separated, dried (MgSO4) and the solvent evaporated to dryness in vacuo to leave a colourless gum. The residue was chromatographed over flash silica eluting with ethyl acetate:methanol:ammonia (100:10:1) to give the free base 40 (100 mg). This was converted to the fumarate salt (95 mg, 27%) which was a white solid. LC: 100%. MS: m/z=506.2, 507.3, 508.2 (M+H). 1H NMR (400 MHz, DMSO-d6): (1:1 mixture of rotamers) δ 8.22 (1H, d, J=7.5 Hz), 8.13 (2H, m), 7.92 (1H, t, J=7.5 Hz), 6.47 (1H, s), 4.43 (1H, d, J=13.3 Hz), 4.10 (1H, t, J=13.3 Hz), 3.88 (1H, d, J=13.3 Hz), 3.55 (2H, m), 3.25 (1H, m), 3.05 (1H, t, J=13.3 Hz), 2.85 (2H, m), 2.70-2.50 (3H, m), 1.96 (1H, m), 1.80-1.20 (8H, m), 0.88-0.65 (7H, m).
Reaction SMILES: [H-].[Na+].[C:3]12([C:13]3[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:14]=3[OH:20])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.[CH3:21]I.O>C1COCC1>[C:3]12([C:13]3[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:14]=3[O:20][CH3:21])[CH2:4][CH:5]3[CH2:11][CH:9]([CH2:8][CH:7]([CH2:6]3)[CH2:12]1)[CH2:10]2
Reactant: Oc1ccc(Br)cc1C12CC3CC(CC(C3)C1)C2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Br)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To a suspension of sodium hydride (80% in oil, 4.32 g, 144 mmol) in 50 ml of THF, there are slowly added, while maintaining the temperature at 20° C., 36.8 g (120 mmol) of 2-(1-adamantyl)-4-bromophenol. The mixture is stirred for 1 hour at ambient temperature at which point 9 ml (144 mmol) of methyl iodide are added. The mixture is then stirred for 2 hours at 20° C., poured into water, extracted with ether, dried and evaporated. The product is purified by passage through a silica column (10×30 cm), eluting with a mixture of hexane (90%) and dichloromethane (10%). On evaporation, 26.2 g of a white solid are obtained. Yield--68%. Melting point: 138°-139° C.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[C:8]([CH3:20])=[C:9]2[C:13](=[CH:14][CH:15]=1)/[C:12](=[CH:16]/[C:17]([OH:19])=[O:18])/[CH2:11][CH2:10]2.Cl[CH2:22]Cl>>[OH:6][C:7]1[C:8]([CH3:20])=[C:9]2[C:13](=[CH:14][CH:15]=1)[C@@H:12]([CH2:16][C:17]([O:19][CH3:22])=[O:18])[CH2:11][CH2:10]2
Reactant: ClCCl
Reactant: COc1ccc2c(c1C)CC/C2=C\C(=O)O
Agent: BrB(Br)Br
Product: COC(=O)C[C@H]1CCc2c1ccc(O)c2C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 1.0 M solution of boron tribromide in dichloromethane (16.2 mL, 16.2 mmol) was added to an ice-cold solution methyl (R)-(5-methoxy-4-methyl-indan-1-yl)acetate (1.52 g, 6.49 mmol, from Step F) in dichloromethane (5 mL). The cooling bath was removed and the reaction mixture stirred at ambient temperature. After 1 hr, the reaction mixture was slowly transferred to an ice-old solution of methanol (50 mL). Methanol was removed in vacuo, and the residue was partitioned between EtOAc and sat. NaH2PO4. The organic layer was washed with H2O, brine, and dried over MgSO4. The mixture was filtered, concentrated in vacuo and purified by flash chromatography (5, 10% EtOAc/hexanes) on SiO2 to afford 1.22 g of the title compound as a white solid: 1H NMR (500 MHz, CDCl3) δ 1.71-1.78 (m, 1H), 2.16 (s, 3H), 2.35-2.44 (m, 2H), 2.71-2.79 (m, 2H), 2.86-2.90 (m, 1H), 3.54 (p, 1H, J=7.3 Hz), 3.72 (s, 3H), 4.83 (s, 1H), 6.61 (d, 1H, J=8.0 Hz), 6.85 (d, 1H, J=8.0 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH:10]2[C:15](=[O:16])[CH2:14][C:13]([CH3:18])([CH3:17])[CH2:12][C:11]2=O)[CH:5]=[CH:6][CH:7]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:30]2)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[S:30][C:11]3[CH2:12][C:13]([CH3:18])([CH3:17])[CH2:14][C:15](=[O:16])[C:10]=3[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1(C)CC(=O)C(CC(=O)c2cccc(Br)c2)C(=O)C1
Solvent: Cc1ccccc1
Product: CC1(C)CC(=O)c2cc(-c3cccc(Br)c3)sc2C1
Yield: 33.1 %

Procedure:
2-(2-(3-Bromophenyl)-2-oxoethyl)-5,5-dimethylcyclohexane-1,3-dione (2.77 g, 8.2 mmol) and 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide (Lawesson's reagent) (2.29 g, 5.4 mmol) were refluxed in toluene (100 mL) for 6 hr. The reaction mixture was concentrated in vacuo and purified on silica gel using a gradient elution of 0-10% ethyl acetate in 40-60 petroleum ether to afford the title compound (0.6 g, 22%).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:14][OH:15])[CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])(C)(C)C.[ClH:17]>O1CCOCC1>[ClH:17].[NH2:7][C@@H:8]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:14][OH:15]
Reactant: CC(C)(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)C[C@H](N)CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ((S)-1-hydroxymethyl-3,3-dimethyl-butyl)-carbamic acid tert-butyl ester (200 mg, 0.605 mmol) in dioxane (4 mL) was added HCl (4N in dioxane, 6.05 mL, 24.21 mmol). The reaction mixture was stirred at RT overnight and concentrated to give the desired material as a white powder which was used without further purification in the next. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.79 (bs, 3H), 5.37 (m, 1H), 3.60 (m, 1H), 3.40 (overlap with water, m, 1H), 3.09 (m, 1H), 1.47 (dd, 1H), 1.33 (dd, 1H), 0.92 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]([C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=1[CH3:22])[C:15]([O:17][CH3:18])=[O:16])[C:5]2=[O:23].[C:24]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])(=[O:27])[CH:25]=[CH2:26].C(N(CC)CC)C>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].CC(P(C(C)(C)C)C1[CH-]C=CC=1)(C)C.C1C=CC([C-]2C(C3C=CC=CC=3)=C(C3C=CC=CC=3)C(C3C=CC=CC=3)=C2C2C=CC=CC=2)=CC=1.[Fe+2]>[C:29]([O:28][C:24](=[O:27])/[CH:25]=[CH:26]/[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]([C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=1[CH3:22])[C:15]([O:17][CH3:18])=[O:16])[C:5]2=[O:23])([CH3:32])([CH3:31])[CH3:30]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(C)c(-n2cnc3ccc(Br)cc3c2=O)c1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)P(c1ccc[cH-]1)C(C)(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C)c(-n2cnc3ccc(/C=C/C(=O)OC(C)(C)C)cc3c2=O)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of methyl 3-(6-bromo-4-oxoquinazolin-3(4H)-yl)-4-methylbenzoate (5.00 g), bis(dibenzylideneacetone)palladium (0.19 g) and 1,2,3,4,5-pentaphenyl-1-(di-tert-butylphosphino)ferrocene (0.47 g) in anhydrous DMF (30 ml) under an argon atmosphere was added tert-butyl acrylate (4.3 ml) followed by triethylamine (4.5 ml). The reaction mixture was stirred at room temperature for 72 hours, then heated at 100° C. for 5 hours and poured onto brine. The resulting mixture was extracted with ethyl acetate and the combined organic layers were washed with water, dried (magnesium sulphate) and concentrated to give methyl 3-[6-[(1E)-3-tert-butoxy-3-oxoprop-1-en-1-yl]-4-oxoquinazolin-3(4H)-yl]-4-methylbenzoate as a solid (5.83 g). NMR Spectrum: (DMSOd6) 1.51 (s, 9H), 2.20 (s, 3H), 3.88 (s, 3H), 6.67 (d, 1H), 7.63 (d, 1H), 7.75 (d, 1H), 7.77 (d, 1H), 8.04 (m, 2H), 8.28 (m, 1H), 8.34 (s, 1H), 8.40 (d, 1H); Mass Spectrum: M+H+ 421.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:13][CH2:14][CH3:15])[NH:6]2.[F:16][C:17]([F:36])([F:35])[C:18]1[CH:19]=[C:20]([C:28]2[O:32][N:31]=[C:30]([CH2:33]Cl)[N:29]=2)[CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1>>[F:36][C:17]([F:16])([F:35])[C:18]1[CH:19]=[C:20]([C:28]2[O:32][N:31]=[C:30]([CH2:33][N:6]3[C:7]4[C:3](=[C:2]([Cl:1])[C:10]([C:11]#[N:12])=[CH:9][CH:8]=4)[CH:4]=[C:5]3[CH2:13][CH2:14][CH3:15])[N:29]=2)[CH:21]=[C:22]([C:24]([F:26])([F:25])[F:27])[CH:23]=1
Reactant: FC(F)(F)c1cc(-c2nc(CCl)no2)cc(C(F)(F)F)c1
Reactant: CCCc1cc2c(Cl)c(C#N)ccc2[nH]1
Product: CCCc1cc2c(Cl)c(C#N)ccc2n1Cc1noc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1

Procedure:
Synthesized as described in Example 4 from 4-chloro-2-propyl-1H-indole-5-carbonitrile and 5-[3,5-bis(trifluoromethyl)phenyl]-3-(chloromethyl)-1,2,4-oxadiazole: 1H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 2H), 8.50 (s, 1H), 7.96 (s, 1H), 7.77 (d, J=8.7 Hz, 1H), 7.59 (d, J=8.7 Hz, 1H), 5.87 (s, 2H), 2.97-2.82 (m, 2H), 1.70-1.56 (m, 2H), 0.97-0.89 (m, 3H); MS (ES) m/z 513 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[Cl:25][C:26]1[N:31]=[C:30]([NH:32][CH:33]([CH2:41][CH3:42])[C:34]2[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=2)[CH:29]=[C:28]([CH2:43][CH3:44])[N:27]=1.[F:45][C:46]1[C:51]([F:52])=[C:50](F)[C:49]([F:54])=[C:48]([F:55])[C:47]=1[C:56]([F:59])([F:58])[F:57].[OH-].[K+].CN1CCN(C)C1=O>C(OCC)(=O)C.C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[Cl:25][C:26]1[N:31]=[C:30]([NH:32][CH:33]([CH2:41][CH3:42])[C:34]2[CH:39]=[CH:38][C:37]([O:40][C:50]3[C:49]([F:54])=[C:48]([F:55])[C:47]([C:56]([F:57])([F:59])[F:58])=[C:46]([F:45])[C:51]=3[F:52])=[CH:36][CH:35]=2)[CH:29]=[C:28]([CH2:43][CH3:44])[N:27]=1
Reactant: CCc1cc(NC(CC)c2ccc(O)cc2)nc(Cl)n1
Reactant: Fc1c(F)c(F)c(C(F)(F)F)c(F)c1F
Agent: COc1cc(CNCCCNCCCCNCCCN)ccc1O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCN(C)C1=O
Solvent: CCOC(C)=O
Product: CCc1cc(NC(CC)c2ccc(Oc3c(F)c(F)c(C(F)(F)F)c(F)c3F)cc2)nc(Cl)n1
Temperature: 70 °C
Reaction time: 8 h
Yield: 111.7 %

Procedure:
A mixture of 1 g of dl-5-chloro-6-ethyl-4-(α-ethyl-4-hydroxybenzylamino)pyrimidine, 1 g of perfluorotoluene, 0.24 g of powdery potassium hydroxide and 20 ml of 1,3-dimethyl-2-imidazolidinone (DMI) was heated under stirring at 70° C. for 8 hours. After completion of the reaction, the reaction mixture was poured into water, and extracted with toluene. The extract was washed with water, dried over anhydrous sodium sulfate and then toluene was evaporated under reduced pressure. The oily product obtained was isolated by column chromatography (Wako gel C-200, eluted with toluene:ethyl acetate=30:1) to give 1.5 g of the desired product as colorless crystals.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][C:24]=2[CH3:25])[C:21]([NH2:26])=[N:20][CH:19]=[CH:18]3)[CH2:10][CH2:9]1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[CH3:25][C:24]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][N:20]=[C:21]2[NH2:26])=[CH:16][C:15]=1[O:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: Cc1cc2c(N)nccc2cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(N)nccc2cc1OC1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 1-amino-7-methylisoquinolin4-ol (430 mg, 2.4 mmol), 4-methanesulfonyloxypiperidine-1-carboxylic acid tert-butyl ester (1.0 g) and K2CO3 (510 mg, 3.7 mmol) in anhydrous N, N-dimethylformamide (8 ml) were microwaved at 100° C. for 10 minutes. A further equivalent of 4-methanesulfonyloxypiperidine-1-carboxylic acid tert-butyl ester in N, N-dimethylformamide (4 ml) was added and the mixture microwaved at 100° C. for a further 10 minutes. The mixture was diluted with water, acidified with acetic acid and further diluted with methanol. The mixture was loaded onto a pre-acidified SCX column, washed with methanol and then eluted with 2M ammonia in methanol. The crude product was isolated and further purified using flash chromatography on silica (eluent: 9:1:0.1 dichloromethane : methanol :ammonium hydroxide) to afford 4-(1-amino-7-methylisoquinolin-6-yloxy)piperidine-1-carboxylic acid tert-butyl ester (327 mg). A mixture of the 4-(1-amino-7-methylisoquinolin-6-yloxy)-piperidine-1-carboxylic acid tert-butyl ester in dichloromethane (5 ml) and trifluoroacetic acid (2 ml) was stirred at ambient temperature overnight. The mixture was concentrated in vacuo to give a residue. The residue was loaded onto a pre-acidified SCX column, washed with methanol and then eluted with 2M ammonia in methanol to give 7-methyl-6-(piperidin-4-yloxy)isoquinolin-1-ylamine (270 mg), El-MS: m/z=258.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6](B(O)O)[CH:7]=1.Cl[C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]#[N:20])[CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([C:19]#[N:20])[CH:14]=2)[CH:7]=1
Reactant: OB(O)c1cc(Cl)ccc1O
Reactant: N#Cc1cc(Cl)ccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1cc(-c2cc(Cl)ccc2O)ccn1
Temperature: 100 °C
Yield: 8.6 %

Procedure:
(5-Chloro-2-hydroxyphenyl)boronic acid (2.0 g, 0.012 mol), 4-chloropyridine-2-carbonitrile (1.61 g, 0.012 mol), (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (0.424 g, 0.00058 mol) and sodium carbonate (3.7 g, 0.035 mol) in 1,4-dioxane (20.0 mL) and deionised water (1.0 mL) were degassed with nitrogen (×3) before heating at 100° C. for 18 hours under nitrogen. The reaction was cooled and hydrochloric acid (2.0 M aqueous solution, 30.0 mL) added. Reaction was filtered, washing with ethyl acetate (50.0 mL). The organic layer was concentrated in vacuo and purified by flash column chromatography on the ISCO™ (40 g SiO2) eluting with ethyl acetate:heptane (gradient 0:1 to 7:3, by volume) to afford the title compound as a yellow solid, 0.23 g, 8.6% yield.
Reaction SMILES: [C:1]([O:14]C)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH3:12].O.[OH-].[K+].II>CCOC(C)=O.C(O)(C)C>[C:1]([OH:14])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH3:12]
Reactant: CCC=CCCCCCCCC(=O)OC
Agent: II
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)O
Product: CCC=CCCCCCCCC(=O)O
Yield: 88.3 %

Procedure:
Methyl 9-dodecenoate (1273 g, 6.00 mol), water (540 mL), and isopropanol (300 mL) were added to a 5 L, 4-neck round-bottom flask at room-temperature. The flask was fitted with an over-head stirrer, condenser, a thermocouple, and an addition flask. Nitrogen was passed through the headspace for thirty-minutes while stirring. Potassium hydroxide (10 M, 660 mL, 6.60 mol) was added drop-wise over thirty-minutes. After stirring for about 45 minutes, an exotherm was observed and the mixture became homogenous. Within the next hour, stirring became impeded by formation of a gel. To re-enable stirring, an additional 300 mL of isopropanol was kneaded into the mixture with a metal spatula. The reaction was monitored by thin layer chromatography (10% EtOAc in hexanes eluent, iodine stain); reaction aliquots were quenched with aqueous hydrochloric acid, washed with water, then taken up in iPrOH. When all starting material had been consumed, the reaction was placed in an ice bath and acidified with 37% aqueous HCl (600 mL) while maintaining a temperature below 40° C. The reaction mixture was transferred into a large separatory funnel and washed with brine (3×250 mL), dried with magnesium sulfate, filtered, and dried in vacuo. The reaction was purified by vacuum distillation to give 9-dodecenoic acid (1054 g, 5.3 mol, 89% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:15]=[CH:16][C:17]3[O:26][CH2:25][CH2:24]C4N(N=C(C5N(CC(F)(F)F)N=CN=5)C=4)[C:18]=3[CH:37]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].BrC1C=CC2OCC[C:48]3[C:44](=[N:45][N:46]([C:52]4[N:53]([C:57]5[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=5[Cl:63])[N:54]=[CH:55][N:56]=4)[CH:47]=3)C=2C=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:15]=[CH:16][C:17]3[O:26][CH2:25][CH2:24][C:48]4[C:44](=[N:45][N:46]([C:52]5[N:53]([C:57]6[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=6[Cl:63])[N:54]=[CH:55][N:56]=5)[CH:47]=4)[C:18]=3[CH:37]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc3c(c2)-n2nc(-c4ncnn4CC(F)(F)F)cc2CCO3)CC1
Reactant: Clc1ccccc1-n1ncnc1-n1cc2c(n1)-c1cc(Br)ccc1OCC2
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc3c(c2)-c2nn(-c4ncnn4-c4ccccc4Cl)cc2CCO3)CC1
Yield: 80 %

Procedure:
4-{2-[2-(2-Chloro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen-9-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester was prepared similarly to 4-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulen-9-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester from 9-bromo-2-[2-(2-chloro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene (500 mg, 1.13 mmol) to give 4-{2-[2-(2-Chloro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen-9-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as a colourless gum (490 mg, 80%). LCMS RT=5.14 min, M+Na+=567