Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[C:12]([CH2:17][OH:18])=[N:13][CH:14]=[CH:15][CH:16]=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:26][S:27](Cl)(=[O:29])=[O:28].O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:11]2[C:12]([CH2:17][O:18][S:27]([CH3:26])(=[O:29])=[O:28])=[N:13][CH:14]=[CH:15][CH:16]=2)([CH3:10])[CH3:9])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(c1ccc(Cl)cc1)c1cccnc1CO
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(c1ccc(Cl)cc1)c1cccnc1COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.1 %

Procedure:
To a solution cooled (0° C.) solution of {3-[1-(4-chloro-phenyl)-1-methyl-ethyl]-pyridin-2-yl}-methanol (206 mg, 0.768 mmol) and Et3N (165 μL, 1.15 mmol) in CH2Cl2 (4 mL) was added MsCl (67 μL, 0.845 mmol). The mixture was warmed to ambient temperature and stirred for 1 h. Water (10 mL) was added and the mixture was extracted with CH2Cl2 (3×30 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to afford methanesulfonic acid 3-[1-(4-chloro-phenyl)-1-methyl-ethyl]-pyridin-2-ylmethyl ester (269 mg, 99%) as a yellow solid. 1H NMR (CDCl3) δ 1.70 (s, 6H), 3.01 (s, 3H), 4.78 (s, 2H), 7.05 (d, 2H, J=6.0 Hz), 7.29 (d 2H, J=6.0 Hz), 7.37 (dd, 1H, J=6.0, 3.0 Hz), 7.96 (dd, 1H, J=7.5, 3.0 Hz), 8.59 (dd, 1H, J=6.0, 3.0 Hz).
Reaction SMILES: [CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2([C:15](=[O:16])[NH:14][CH2:13][CH2:12]2)[CH:10]([OH:19])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.FC(F)(F)S(O[C:74]1[CH2:75][O:76][C:77](=[O:80])[C:78]=1[CH3:79])(=O)=O.O>CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2([C:15](=[O:16])[N:14]([C:74]3[CH2:75][O:76][C:77](=[O:80])[C:78]=3[CH3:79])[CH2:13][CH2:12]2)[CH:10]([OH:19])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NCCC12CCN(Cc1ccccc1)CC2O
Reactant: CC1=C(OS(=O)(=O)C(F)(F)F)COC1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: O
Solvent: CCOC(C)=O
Product: CC1=C(N2CCC3(CCN(Cc4ccccc4)CC3O)C2=O)COC1=O
Temperature: 60 °C

Procedure:
To a flask charged with 8-benzyl-6-hydroxy-2,8-diazaspiro[4.5]decan-1-one (520 mg, 2.0 mmol) and a stir bar was added palladium acetate (22 mg, 0.10 mmol), K2CO3 (550 mg, 4.00 mmol), Xantphos (120 mg, 0.20 mmol), 4-methyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (640 mg, 2.6 mmol), and water (110 mg, 6.0 mmol). The mixture was heated to 60° C. for 2 hours. LC showed complete reaction at that point. The reaction was diluted with EtOAc, washed with water, and the phases separated. The crude solution was dried over Na2SO4, filtered and concentrated to an oil. The oil was loaded onto a silica gel column, and purified by MPLC with Hexane and EtOAc. Two spots were separated with the desired molecular weight in a ratio of about 1 to 7. The more polar spot was the major product. LCMS: m/z 357 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:17])[CH2:10][CH2:11][CH:12]([Br:16])[C:13]([OH:15])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(Cl)(Cl)C(=N)O[C:22]([CH3:25])([CH3:24])[CH3:23].CN(C)C(=O)C.CCCCCC>C(Cl)(Cl)Cl.C1CCCCC1.B(F)(F)F.CCOCC>[C:22]([O:14][C:13](=[O:15])[CH:12]([Br:16])[CH2:11][CH2:10][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:17])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Reactant: O=C(CCC(Br)C(=O)O)OCc1ccccc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)C(Br)CCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 79.1 %

Procedure:
To a solution of α-bromoglutaric acid-5-benzylester (See Example 18a(i)(a); 1.2 g, 4.0 mmol) in chloroform (Merck, 5 mL) a solution of tert-butyl 2,2,2-trichloroacetimidate (Fluka, 1.57 mL, 8.52 mmol) in cyclohexane (Merck, 5 mL) was added dropwise over 5 minutes. N,N-Dimethylacetamide (Fluka, 0.88 mL) was added followed by boron trifluoride ethyl etherate (Aldrich, 80 μL) as catalyst. The reaction mixture was stirred for 5 days at room temperature. Hexane was added and the organic phase washed with brine three times, dried over sodium sulphate and evaporated under reduced pressure. The crude product was purified using normal phase chromatography (Silica column (40 g), solvents: A=hexane, B=ethyl acetate, gradient: 10 to 35% B over 15 min, flow rate 40 mL/min, UV detection at 214 and 254 nm) affording 1.13 g (79%) of the pure product. Structure was verified by NMR
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[N:9]=[C:10]([C:11]3[NH:12][CH2:13][CH2:14][N:15]=3)[C:3]=12.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+].[OH-].[Na+]>CS(C)=O>[C:20]([O:19][C:17](=[O:18])[CH2:16][N:8]1[C:4]2=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]2[C:10]([C:11]2[NH:15][CH:14]=[CH:13][N:12]=2)=[N:9]1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)Cn1nc(C2=NCCN2)c2c(N)ncnc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)Cn1nc(-c2ncc[nH]2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.2 %

Procedure:
To a mixture of tert-Butyl 2-(4-amino-3-(4,5-dihydro-1H-imidazol-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acetate (84 g, 0.265 mol) and DMSO (900 mL) in an ice water bath was added Dess-Martin periodinane (169.6 g, 0.4 mol) in portions while keeping the internal temperature below 25° C. The mixture was stirred for 2 h at room temperature and then poured into ice water (2 L) which contained 84 g of Na2S2O3. The mixture was adjusted to pH 12-14 with 3 N NaOH and filtered to give a solid, which was washed with water, re-suspended in ice-water (2 L), filtered, washed with water (500 mL), EtOAc (100 mL×2) and Et2O (100 mL×2), and dried in vacuo to give (2-(4-amino-3-(1H-imidazol-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acetic acid tert-butyl ester (66.2 g, 80% yield). MS (ES) m/z 316.1 (M+H+).
Reaction SMILES: [NH2:1][C:2](N)=[S:3].[NH2:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[CH:11][N:12]2[CH2:15][O:16][CH2:17][CH2:18][O:19]C(=O)C2C=CC=CC=2)=C(Cl)N=1>C(O)(C)C>[OH:19][CH2:18][CH2:17][O:16][CH2:15][N:12]1[CH:11]=[N:10][C:9]2[C:2](=[S:3])[NH:1][C:6]([NH2:5])=[N:14][C:13]1=2
Reactant: NC(N)=S
Reactant: Nc1nc(Cl)c2ncn(COCCOC(=O)c3ccccc3)c2n1
Solvent: CC(C)O
Product: Nc1nc2c(ncn2COCCO)c(=S)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.5 %

Procedure:
Thiourea (0.28 g) was added to a refluxing solution of 2-amino-6-chloro-9-(2-benzoyloxyethoxymethyl)purine (1.27 g) in isopropanol (40 ml). The reaction mixture was heated at reflux for 11/2 hours and then chilled. 9-(2-benzoyloxyethoxymethyl)-thioguanine (0.58 g, m.p. 199°-202° C.) was removed by filtration. This was added to 40 ml of aqueous ammonia (about 7 N) and the mixture heated on a steam bath for 10 minutes and then stirred overnight at room temperature. The water and ammonia were removed in vacuo and the residue triturated with acetone and then with ether to remove benzamide. The remaining solid was recrystallized twice from water to give yellow flakes of 9-(2-hydroxyethoxymethyl)thioguanine (0.26 g, m.p. 251°-254° C.).
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]([CH:35]=[CH:36][CH:37]=1)[CH2:12][N:13]1[C:17]([CH3:19])([CH3:18])[C:16](=[O:20])[N:15]([C:21]2[CH:22]=[N:23][N:24]([CH2:26][C:27]3[C:28]([CH3:33])=[N:29][O:30][C:31]=3[CH3:32])[CH:25]=2)[C:14]1=[O:34])(C(C)(C)C)(C)C.Cl>CO>[CH3:33][C:28]1[C:27]([CH2:26][N:24]2[CH:25]=[C:21]([N:15]3[C:16](=[O:20])[C:17]([CH3:19])([CH3:18])[N:13]([CH2:12][C:11]4[CH:35]=[CH:36][CH:37]=[C:9]([OH:8])[CH:10]=4)[C:14]3=[O:34])[CH:22]=[N:23]2)=[C:31]([CH3:32])[O:30][N:29]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)N(Cc3cccc(O[Si](C)(C)C(C)(C)C)c3)C(C)(C)C2=O)cn1
Agent: Cl
Solvent: CO
Product: Cc1noc(C)c1Cn1cc(N2C(=O)N(Cc3cccc(O)c3)C(C)(C)C2=O)cn1
Temperature: 50 °C
Reaction time: 16 h
Yield: 96.1 %

Procedure:
1-(3-(tert-butyldimethylsilyloxy)benzyl)-3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-5,5-dimethylimidazolidine-2,4-dione (Example 12-1a) (2.00 g, 3.82 mmol) was dissolved in methanol (200 mL) and treated with HCl (2.0 M solution in diethyl ether, 10 equivalents). The solution was stirred for 16 hours at 50° C. then allowed to cool down to room temperature and the solvent was removed under reduced pressure. The residue was dissolved in ethanol and recrystallized at 4° C. to give 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1-(3-hydroxybenzyl)-5,5-dimethylimidazolidine-2,4-dione (1.50 g, 3.67 mmol, 96%) as a white solid. 1H NMR (DMSO-d6, 400 MHz): 1.31 (s, 6H), 2.16 (s, 3H), 2.42 (s, 3H), 4.47 (s, 2H), 5.20 (s, 2H), 6.65 (ddd, J=0.8, 2.4, 8 Hz, 1H), 6.79 (m, 2H), 7.11 (t, J=8 Hz, 1H), 7.83 (d, J=0.8 Hz, 1H), 8.21 (d, J=0.8 Hz, 1H), 9.36 (s, H). MS 410 (MH+). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.05 μM
Reaction SMILES: CO[C:3](=[O:18])[C:4]([CH3:17])([CH3:16])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.[C:19](#[N:21])[CH3:20].[H-].[Na+]>C1(C)C=CC=CC=1.Cl>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][O:6][CH2:5][C:4]([CH3:16])([CH3:17])[C:3](=[O:18])[CH2:20][C:19]#[N:21])=[CH:13][CH:12]=1
Reactant: CC#N
Reactant: COC(=O)C(C)(C)COCc1ccc(OC)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc(COCC(C)(C)C(=O)CC#N)cc1
Temperature: 25 °C
Yield: 104.2 %

Procedure:
A solution of 3.66 g (14.5 mmol) of 2,2-dimethyl-3-(4-methoxybenzyl-oxy)-propionic acid methyl ester and 1.07 mL (20.5 mmol) of acetonitrile in anhydrous toluene (10 mL) is added dropwise to a refluxing suspension of 0.83 g (20.5 mmol) of sodium hydride (60% dispersion in mineral oil) in toluene (20 mL). After the addition is complete, the mixture is stirred at reflux for 3 h, then allowed to cool to room temperature. The reaction mixture is then diluted with 1M aqueous HCl solution to neutral pH, and extracted with ethyl acetate (3×40 mL). The combined organic extracts are washed with water and brine, then dried over Na2SO4 and filtered. The filtrate is concentrated under reduced pressure to afford 3.95 g of 5-(4-methoxy-benzyloxy)-4,4-dimethyl-3-oxo-pentanenitrile, which is used in the next step without further purification. Yield: assumed quantitative, no spectroscopic analysis performed.
Reaction SMILES: [H-].[Na+].[C:3]([NH:13][C@H:14]([C:17]([OH:19])=[O:18])[CH2:15][OH:16])([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[C:20]1([C:26]2[O:27][CH:28]=[C:29]([CH2:31][CH2:32][O:33][C:34]3[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=3)[CH2:37]Br)[N:30]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>CO.CN(C=O)C.C1COCC1>[C:20]1([C:26]2[O:27][CH:28]=[C:29]([CH2:31][CH2:32][O:33][C:34]3[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=3)[CH2:37][O:16][CH2:15][C@@H:14]([C:17]([OH:19])=[O:18])[NH:13][C:3]([O:5][CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[O:4])[N:30]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(N[C@@H](CO)C(=O)O)OCc1ccccc1
Reactant: BrCc1cccc(OCCc2coc(-c3ccccc3)n2)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(N[C@@H](COCc1cccc(OCCc2coc(-c3ccccc3)n2)c1)C(=O)O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
0.448 g of 60% NaH/oil (0.27 g, 11.1 mM of NaH) was added to 40 mL of dry THF and cooled to 0° C. 1.21 g (5.08 mM of CBZ-serine was added dropwise as a dry DMF solution (10 mL) over 5 minutes. The resulting mixture was stirred at 0° C. for 1 hr. 2.00 g (5.58 mmoles) of 3-[2-(2-phenyl-4-oxazolyl)ethoxy]benzyl bromide, prepared as described in Example 22, Part B, was also added dropwise as a dry DMF solution (10 mL) over 5 minutes. The final mixture was stirred for 5 h at 0° C. and was then allowed to warm to ambient over 12 h. The reaction was quenched with 20 mL of methanol and one equivalent of HCl. After concentrating to a small volume under reduced pressure, the mixture was diluted with 200 mL EtOAc, washed with 200 mL water (2×) and 200 mL brine. The organic phase was dried over MgSO4, filtered and concentrated to a yellow, opaque oil. The product was purified using silica column chromatography, (25:5:1 CHCl3:MeOH:NH4OH>>>3:4 MeOH:EtOAc), and recrystallized from Et2O. to provide 714 mg 49.6%) of product as a white, waxy solid.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([C@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.[Br:16][C:17]1[C:22]2[NH:23][CH2:24][CH2:25][O:26][C:21]=2[CH:20]=[C:19]([O:27][CH3:28])[CH:18]=1>>[Br:16][C:17]1[C:22]2[N:23]([C:2]3[C:3](=[O:15])[N:4]([C@H:9]([CH:12]4[CH2:14][CH2:13]4)[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=3)[CH2:24][CH2:25][O:26][C:21]=2[CH:20]=[C:19]([O:27][CH3:28])[CH:18]=1
Reactant: COc1cc(Br)c2c(c1)OCCN2
Reactant: CC[C@@H](C1CC1)n1cc(Cl)nc(Cl)c1=O
Product: CC[C@@H](C1CC1)n1cc(Cl)nc(N2CCOc3cc(OC)cc(Br)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 556 using 3,5-dichloro-1-[(1S)-1-cyclopropylpropyl]-2(1H)-pyrazinone and 5-bromo-7-methoxy-3,4-dihydro-2H-1,4-benzoxazine as the starting materials to give an oil. 1H NMR (300 MHz, CDCl3): δ 7.03 (s, 1H), 6.73 (d, J=2.9 Hz, 1H), 6.45 (d, J=2.9 Hz, 1H), 4.44–3.89 (m, 5H), 3.75 (s, 3H), 1.96–1.70 (m, 2H), 1.12–1.00 (m, 1H), 0.92 (t, J=7.3 Hz, 3H), 0.92 (t, J=7.3 Hz, 3H), 0.84–0.72 (m, 1H), 0.56–0.44 (m, 2H), 0.35–0.25 (m, 1H); HRMS (ESI) m/z 454.0518 [(M+H)+, calcd for C19H22N3O3BrCl 454.0533].
Reaction SMILES: [ClH:1].[C:2]1([CH2:8][CH2:9][C:10]#[N:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][OH:13]>CCOCC>[ClH:1].[CH3:12][O:13][C:10](=[NH:11])[CH2:9][CH2:8][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCCc1ccccc1
Reactant: CO
Agent: Cl
Solvent: CCOCC
Product: COC(=N)CCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Hydrogen chloride is bubbled into a cold (0° C.) solution of 3-phenypropionitrile (5.43 g, 41.4 mmol) in methanol (2.5 mL, 62.1 mmol) for 5 min, and the mixture stirred at rt for 3 h. The solid that formed is suspended in Et2O and filtered to give 7.8 g of the product 242. 1H NMR (CDCl3) δ 12.65 (s, 1H), 11.65 (s, 1H), 7.40-7.15 (m, 5H), 4.24 (s, 3H), 3.08 (s, 4H)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:3]=1[CH3:19].[N:20]1([C:26]2[CH:31]=[C:30]3[NH:32][CH2:33][C:34]4([CH2:39][CH2:38][S:37](=[O:41])(=[O:40])[CH2:36][CH2:35]4)[C:29]3=[CH:28][CH:27]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.CC(C)([O-])C.[Na+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+]>[F:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([N:32]3[C:30]4[C:29](=[CH:28][CH:27]=[C:26]([N:20]5[CH2:25][CH2:24][O:23][CH2:22][CH2:21]5)[CH:31]=4)[C:34]4([CH2:39][CH2:38][S:37](=[O:40])(=[O:41])[CH2:36][CH2:35]4)[CH2:33]3)=[C:3]([CH3:19])[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:5]2)=[CH:10][CH:9]=1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Cl
Reactant: O=S1(=O)CCC2(CC1)CNc1cc(N3CCOCC3)ccc12
Agent: Cl[Pd+]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC2(CCS(=O)(=O)CC2)c2ccc(N3CCOCC3)cc21

Procedure:
Prepared according to procedure Y using 4-chloro-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (29.6 mg, 0.109 mmol), 6-morpholin-4-yl-1,2,2′,3′,5′,6′-hexahydrospiro[indole-3,4′-thiopyran]1′,1′-dioxide (35 mg, 0.109 mmol), sodium tert-butoxide (20.9 mg, 0.217 mmol) and XPhos precatalyst (8.02 mg, 10.86 μmol). Purification by reverse phase HPLC gave 1-(7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)-6-(4-morpholinyl)-1,2,2′,3′,5′,6′-hexahydrospiro[indole-3,4′-thiopyran]1′,1′-dioxide. 1H NMR (400 MHz, chloroform-d) δ ppm 8.74 (1H, dt, J=4.9, 1.4 Hz), 7.82-7.96 (3H, m), 7.75 (1H, dd, J=9.2, 6.1 Hz), 7.39-7.44 (1H, m), 7.24-7.29 (1H, m), 7.19 (1H, d, J=8.2 Hz), 6.35 (1H, dd, J=8.2, 2.2 Hz), 5.61 (1H, d, J=2.2 Hz), 3.94-3.99 (1H, m), 3.87-3.92 (1H, m), 3.68-3.78 (4H, m), 3.07-3.26 (4H, m), 2.91-3.03 (4H, m), 2.61-2.76 (2H, m), 2.29-2.49 (5H, m). Mass Spectrum (ESI) m/e=559.0 (M+1)
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:13]([O:17][C:18](ON=C(C1C=CC=CC=1)C#N)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C>CO.Cl.[Pd].ClCCl>[C:13]([O:17][C:18](=[O:19])[NH:5][CH2:4][C:3]1[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:2]=1[F:1])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1F
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCc1ccc(N)cc1F
Reaction time: 16 h

Procedure:
A solution of 2-fluoro-4-nitrobenzonitrile (0.541 g, 2.43 mmol) in methanol (20 mL) and hydrochloric acid (3 mL, 6 N) was hydrogenated (55 psi) over 10% palladium on carbon (164 mg) overnight. The reaction mixture was filtered and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (5 mL) and treated with 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (0.517 mg, 2.10 mmol) and triethylamine (0.6 mL, 4.3 mmol). After 16 h at rt, the reaction mixture was diluted with dichloromethane and washed with sodium bicarbonate solution and brine, dried (MgSO4), and concentrated under reduced pressure. The residue was purified by silica gel chromatography (gradient from 0 to 50% ethyl acetate in hexanes) to give 1-63A-(0.287 g, 60%) as a colorless oil which solidified on standing.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:17]I.O>CN(C=O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH3:17])[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][N:14]=2)=[CH:6][CH:7]=1
Reactant: Ic1ccc(Nc2ncccn2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1ccc(I)cc1)c1ncccn1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
Under an argon atmosphere, a solution of N-(4-iodophenyl)pyrimidin-2-amine (1.47 g) in anhydrous DMF (10 ml) was added dropwise to a suspension of sodium hydride (218 mg) in anhydrous DMF (8 ml), and the resulting mixture was stirred at room temperature for 75 minutes. Methyl iodide (0.37 ml) was added dropwise to the reaction solution and the resulting mixture was stirred at room temperature for another 1 hour. Water was added thereto and the resulting mixture was extracted with ethyl acetate. Organic layer was washed twice with water and once with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was recrystallized from hexane to obtain N-(4-iodophenyl)-N-methylpyrimidin-2-amine (1.38 g). NMR (H1, CDCl3): δ 3.49 (3H, s), 6.58 (1H, t, J=4.6 Hz), 7.07-7.09 (2H, m), 7.67-7.69 (2H, m), 8.32 (2H, d, J=4.6 Hz)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:4]=1[C:5]([O:7]C)=[O:6].CC(C)([O-])C.[K+].CCCCCC.C(OCC)(=O)C.Cl>CS(C)=O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:4]=1[C:5]([OH:7])=[O:6]
Reactant: CCCCCCCCCCCCCCCc1cccc(OC)c1C(=O)OC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCCCCC
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCc1cccc(OC)c1C(=O)O
Temperature: 70 °C
Yield: 8.7 %

Procedure:
To a stirred solution of Methyl 2-methoxy-6-pentadecylbenzoate (10 g, 240 mmol) in dimethyl sulfoxide (40 mL) was added potassium tert-butoxide (10 g, 890 mmol) in portions. The solution was heated to 70° C. on a water bath for 2 h, and the progress of the reaction was monitored by TLC using a hexane-ethyl acetate (8:2) solvent system. The reaction mass was cooled to 10° C., poured into ice water, and then acidified with 5% dilute hydrochloric acid. The precipitated solid was filtered and washed thoroughly with distilled water, and the crude mass was recrystallized in hexane (50 mL) to yield an off-white solid of 2-Methoxy-6-pentadecylbenzoic Acid (7.6 g, 80%).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([O:7][CH2:8][CH2:9][OH:10])=[C:5]([CH3:13])[CH:4]=1)#[CH:2].Br[C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][N:16]=1.C(NC(C)C)(C)C>C1COCC1.[Cu]I>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([C:2]#[C:1][C:3]2[CH:12]=[CH:11][C:6]([O:7][CH2:8][CH2:9][OH:10])=[C:5]([CH3:13])[CH:4]=2)=[N:16][CH:17]=1
Reactant: C#Cc1ccc(OCCO)c(C)c1
Reactant: Brc1ccc(Br)nc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cc1cc(C#Cc2ccc(Br)cn2)ccc1OCCO
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.26 g (1.36 mmol) of CuI was added to a degassed solution of 11.98 g (68.00 mmol) of 2-(4-ethynyl-2-methylphenoxy)ethanol, 16.11 g (68.00 mmol) of 2,5-dibromopyridine, 0.96 g (1.36 mmol) of bis(triphenylphosphane)palladium (II) chloride, and 19.22 mL (136.00 mmol) of diisopropylamine in 500 mL of THF and the mixture was stirred for 4 hours at RT. The reaction mixture was evaporated down in vacuo and the residue taken up in 800 mL of EtOAc. The organic phase was with water and saturated aqueous NaCl solution washed, dried over sodium sulfate, and evaporated down in vacuo. The crude product was purified by column chromatography (silica gel, gradient DCM/EtOAc 90:10→80:20). Yield: 13.20 g (58% of theoretical); C16H14BrNO2 (M=332.192); calc.: molpeak (M+H)+: 332/334 (Br); found: molpeak (M+H)+: 332/334 (Br); Rf value: 0.39 (silica gel, cyc/EtOAc 1:1).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:4][C:3]1=2.[O:16]1[CH2:20][CH2:19][CH:18]([CH:21]=O)[CH2:17]1.N1CCCC1.C(OCC)(=O)C.CCCCCC>CO>[O:1]=[C:2]1[C:11](=[CH:21][CH:18]2[CH2:19][CH2:20][O:16][CH2:17]2)[CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:4][C:3]1=2
Reactant: O=CC1CCOC1
Reactant: COC(=O)c1ccc2c(c1)CCCC2=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCNC1
Product: COC(=O)c1ccc2c(c1)CCC(=CC1CCOC1)C2=O
Temperature: 45 °C
Reaction time: 4 h
Yield: 58.2 %

Procedure:
To a solution of methyl 5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate (240 mg, 1.2 mmol) in methanol (3 mL) was added (±)-tetrahydrofuran-3-carboxaldehyde (240 mg, 2.4 mmol) and pyrrolidine (0.20 mL, 2.4 mmol). The solution was stirred for twenty hours at ambient temperature and for four hours at 45° C. The reaction was concentrated in vacuo. Chromatography (on silica, ethyl acetate/hexane) provided (±)-methyl 5-oxo-6-((tetrahydrofuran-3-yl)methylene)-5,6,7,8-tetrahydronaphthalene-2-carboxylate as an orange oil (200 mg, 58% yield). LC/MS on 4.6×50 mm C-18 column, tR=2.52 minutes (10 to 90% acetonitrile/water over 4 minutes at 4 mL/minute with detection 254 nm, at 50° C.); ES-MS m/z 287 (M+H).