Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[CH3:15][C:16]1([CH3:25])[C:20]([CH3:22])([CH3:21])[O:19][B:18]([CH:23]=[CH2:24])[O:17]1.CCN(CC)CC>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.C1(C)C=CC=CC=1>[CH3:21][C:20]1([CH3:22])[C:16]([CH3:25])([CH3:15])[O:17][B:18](/[CH:23]=[CH:24]/[C:2]2[CH:14]=[CH:13][C:5]([CH2:6][N:7]3[CH2:12][CH2:11][O:10][CH2:9][CH2:8]3)=[CH:4][CH:3]=2)[O:19]1
Reactant: Brc1ccc(CN2CCOCC2)cc1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
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
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC1(C)OB(/C=C/c2ccc(CN3CCOCC3)cc2)OC1(C)C
Temperature: 80 °C

Procedure:
To a mixture of 4-(4-bromobenzyl)morpholine (4.18 g, 16.3 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (3 mL, 17.7 mmol, 1.1 eq.) and toluene (30 mL) in a 20 mL microwave vial was added Et3N (4.56 mL, 32.4 mmol, 2 eq.), followed by Pd(PtBu3)2 (83 mg, 0.16 mmol, 1 mol %). The resulting mixture was purged with argon, then capped and heated at 80° C. oil bath for 1 h. After cooling to rt, the reaction was diluted with half saturated NaHCO3 (40 mL) and the product was extracted with EtOAc (2×60 mL). The organic layer was dried (Na2SO4) and the solvent was evaporated in vacuo. Trituration with hexane and sonication provided a solid that was collected by suction filtration (white solid, 2.55 g). After evaporation of the solvent in vacuo, the residue solidified and a second crop of crystals was obtained by suction filtration from a small amount of hexane (pale yellow crystals, 0.22 g). Evaporation of the mother liquor provided a yellow liquid which was purified using Biotage Isolera (20-80% EtOAc in hexane, SNAP-50 g column) to give a third portion of the product (yellow solid, 1.58 g; total yield 4.35 g, 71%). 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J=8.0 Hz, 2H), 7.40 (d, J=18.4 Hz, 1H), 7.31 (d, J=8.0 Hz, 2H), 6.16 (d, J=18.0 Hz, 1H), 3.72 (t, J=4.4 Hz, 4H), 3.50 (s, 2H), 2.47-2.42 (m, 4H), 1.32 (s, 12H); MS ESI 330.1 [M+H]+, calcd for [C19H28BNO3+H]+ 330.2.
Reaction SMILES: [C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][C:4]([C@@:7]2(O)[CH2:11][N:10]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[C@H:9]([C:22]([O:24][CH3:25])=[O:23])[CH2:8]2)=[CH:3][CH:2]=1.[CH2:33]([SH:37])[CH2:34][CH2:35][CH3:36]>C(#N)C.FC(F)(F)S([O-])(=O)=O.[Sc+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][C:4]([C@:7]2([S:37][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:11][N:10]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[C@H:9]([C:22]([O:24][CH3:25])=[O:23])[CH2:8]2)=[CH:3][CH:2]=1
Reactant: COC(=O)[C@@H]1C[C@@](O)(c2ccc(-c3ccccc3)cc2)CN1C(=O)OCc1ccccc1
Reactant: CCCCS
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: CC#N
Product: CCCCS[C@]1(c2ccc(-c3ccccc3)cc2)C[C@@H](C(=O)OC)N(C(=O)OCc2ccccc2)C1
Reaction time: 26 h
Yield: 43.3 %

Procedure:
To a clear solution of (2S,4R)-1-benzyl 2-methyl 4-(biphenyl-4-yl)-4-hydroxypyrrolidine-1,2-dicarboxylate (2.59 g, 6 mmol) and 1-butanethiol (0.773 mL, 7.20 mmol) in acetonitrile (30 mL) was added Scandium(III) trifluoromethanesulfonate (0.295 g, 0.600 mmol) as solid by one portion at room temperature. The formed pink solution was stirred at this temperature for 26 h. TLC analysis showed starting material was completely consumed. Quenched with sat. ammonium chloride, extracted with EtOAc. Washed the organic with brine, dried over MgSO4, filtered, evaporated in vacuo. The residue was purified by BIOTAGE® column, eluted with gradient 5˜40% EtOAc-hexane to afford the mixture of diastereomers 2.54 g (84%). This oily mixture was purified by BIOTAGE® again, eluted with gradient 0˜20% EtOAc-toluene. The first peak collected from the column afforded by-product (2S,4S)-1-benzyl 2-methyl 4-(biphenyl-4-yl)-4-(butylthio)pyrrolidine-1,2-dicarboxylate (1.54 g, 2.60 mmol, 43.3% yield) as a wax. 1H NMR (500 MHz, CHLOROFORM-d) ppm 0.77 (t, J=7.17, 3H), 1.21-1.24 (m, 2H), 1.28-1.34 (m, 2H), 2.20-2.29 (m, 2H), 2.41-2.46 (m, 1H), 2.86 (dd, J=12.82, 7.32 Hz, 1H), 3.53, 3.75 (s, rotomer, 3H), 3.89 (dd, J=17.09, 11.29 Hz, 1H), 4.23-4.36 (m, 1H), 4.69-4.77 (m, 1H) 5.22-5.30 (m, 2H) 7.28-7.44 (m, 10H), 7.53-7.60 (m, 4H). LC-MS (retention time: 3.28 min, method B), MS m/z 504 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=[C:5]2[C:18]([O:20]CC)=O.B(Br)(Br)Br.C(Cl)Cl.[CH3:30][NH2:31].C1COCC1>ClCCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=[C:5]2[C:18]([NH:31][CH3:30])=[O:20]
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)[nH]c2ccc(Br)cc12
Reactant: CN
Agent: BrB(Br)Br
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: ClCCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)[nH]c2ccc(Br)cc12
Temperature: 25 °C
Yield: 70 %

Procedure:
A suspension of ethyl 5-bromo-2-(4-fluorophenyl)-1H-indole-3-carboxylate (90 mg, 0.25 mmol) in 1,2-dichloroethane (3 mL) was cooled in an ice bath under an atmosphere of N2. A solution of boron tribromide in CH2Cl2 (1 M, 0.75 mL, 0.75 mmol) was added the reaction was allowed warm to r.t. under N2 over 4 h. Then the reaction was then quenched by the addition of a solution of methylamine in THF (2 M, 5 mL, 10 mmol). The reaction was partitioned between EtOAc and water, the organic phase was washed with water and brine, dried over Na2SO4, filtered, and concentrated to give a colorless oil. Et2O/hexanes was added and a white precipitate formed. The powder was collected by filtration, washed with Et2O, and air dried to give the title compound (60 mg, 70% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.93 (s, 1H) 7.82 (d, J=1.83 Hz, 1H) 7.71-7.78 (m, 3H) 7.32-7.41 (m, 3H) 7.29 (dd, J=8.55, 1.83 Hz, 1H) 2.75 (d, J=4.58 Hz, 3H). LC/MS was performed on a Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. LC/MS method: solvent A=5% CH3CN/95% H2O/10 mM NH4OAc, solvent B=95% CH3CN/5% H2O/10 mM NH4OAc, start % B=0, final % B=100, gradient time=2 min, stop time=3 min, flow rate=5 ml/min, column: XBridge C18 5 μm 4.6×50 mm; HPLC Rt=1.26, (ES+) m/z (MH+)=347, 349 (1:1 ratio).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[C:20]([CH3:22])[C:19]([CH3:23])=[CH:18][C:17]=1[C:24](=O)[CH3:25].[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][NH2:34].O>C(O)C.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[C:20]([CH3:22])[C:19]([CH3:23])=[CH:18][C:17]=1[C:24](=[N:34][NH:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=1)[CH3:25]
Reactant: NNc1ccccn1
Reactant: COc1cc2nccc(Oc3cc(C)c(C)cc3C(C)=O)c2cc1OC
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: CCO
Product: COc1cc2nccc(Oc3cc(C)c(C)cc3C(C)=NNc3ccccn3)c2cc1OC
Temperature: 60 °C
Reaction time: 8 h
Yield: 34.4 %

Procedure:
1-[2-(6,7-Dimethoxy-quinolin-4-yloxy)-4,5-dimethylphenyl]-1-ethanone (compound 38) (30 mg) was dissolved in ethanol (1 ml) to prepare a solution. (2-Pyridyl)hydrazine (28 mg) was added to the solution, and the mixture was stirred at 60° C. overnight. Ytterbium triflate (1 mg) was added to the reaction solution, and the mixture was stirred at 60° C. for 5 days. The reaction solution was cooled to room temperature, water was then added to the cooled solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin layer chromatography using hexane-acetone to give the title compound (13 mg, yield 39%).
Reaction SMILES: Br[C:2]1[C:3]([CH3:12])=[CH:4][C:5]2[O:9][C:8]([F:10])=[CH:7][C:6]=2[CH:11]=1.[NH2:13][C:14]1[CH:19]=[N:18][C:17](B2OC(C)(C)C(C)(C)O2)=[CH:16][N:15]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(=O)OCC>C(#N)C.O1CCOCC1.O>[F:10][C:8]1[O:9][C:5]2[CH:4]=[C:3]([CH3:12])[C:2]([C:17]3[N:18]=[CH:19][C:14]([NH2:13])=[N:15][CH:16]=3)=[CH:11][C:6]=2[CH:7]=1
Reactant: CC1(C)OB(c2cnc(N)cn2)OC1(C)C
Reactant: Cc1cc2oc(F)cc2cc1Br
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc2oc(F)cc2cc1-c1cnc(N)cn1
Temperature: 85 °C
Yield: 25.4 %

Procedure:
A mixture of 5-bromo-2-fluoro-6-methyl-benzofuran (230) (0.3 mmol), 2-aminopyrazine-5-boronic acid pinacol ester (133 mg, 2 eq), bis(ditertbutyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II) (42 mg, 10% mol) and K3PO4 (127 mg, 0.6 mmol) in 1 ml ACN, 1 ml dioxane, 0.5 ml H2O was bubbled with argon before heated at 85° C. for 2 h. After cooling down to r.t., the reaction mixture was taken up in EA, washed with aq. NaHCO3 and brine. Org. phase was dried over Na2SO4, concentrated and then subjected to silica gel flash column chromatography (0-100% B, A: hexane; B: EA) to give 5-(2-fluoro-6-methylbenzo[b]furan-5-yl)-pyrazine-2-ylamine (234) (18.5 mg, purity>95%, yield: 25.4%) as yellow solid.
Reaction SMILES: FC1C=C(C=CC=1S(C)(=NC#N)=O)CN1C(=[O:15])C2C(=CC=CC=2)C1=O.[C:26]([O:30][C:31](=[O:46])[NH:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([S:40]([CH3:44])=[N:41][C:42]#[N:43])=[CH:36][C:35]=1[F:45])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([O:30][C:31](=[O:46])[NH:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([S:40]([CH3:44])(=[N:41][C:42]#[N:43])=[O:15])=[CH:36][C:35]=1[F:45])([CH3:29])([CH3:27])[CH3:28]
Reactant: CS(=NC#N)c1ccc(CNC(=O)OC(C)(C)C)c(F)c1
Reactant: CS(=O)(=NC#N)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1F
Product: CC(C)(C)OC(=O)NCc1ccc(S(C)(=O)=NC#N)cc1F

Procedure:
The title compound is prepared following the procedure described for preparation 15c, using (2-fluoro-4-(N-cyano-S-methylsulfinimidoyl)-benzyl)-carbamic acid tert-butyl ester (preparation 18c) as starting material. ESI mass spectrum: [M+H]+=312; r.t. HPLC: 0.68 min (5-95AB).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O>[CH2:17]([O:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[OH:1])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N#Cc1ccc(O)c(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCc2ccccc2)c(O)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
1.0 g (7.41 mmol) of 3,4-dihydroxybenzonitrile was dissolved in 10 ml of N,N-dimethylformamide. 1.12 g (8.15 mmol) of potassium carbonate and 0.88 ml (7.41 mmol) of benzyl bromide were added to the obtained solution, and they were stirred at 50° C. for 2 hours. After the treatment with ethyl acetate as the extraction solvent in an ordinary manner, the solvent was evaporated, and the obtained residue was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[CH:6]=1.[I-:14].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CC(C)=O>[I:14][CH2:2][CH2:3][CH2:4][C:5]1[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[CH:6]=1
Reactant: [I-]
Reactant: ClCCCc1cc2ccccc2s1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(C)=O
Product: ICCCc1cc2ccccc2s1
Temperature: 25 °C

Procedure:
A mixture of 2-(3-Chloro-propyl)-benzo[b]thiophene (902 mg, 4.28 mmol) and sodium iodide (1.29 g, 8.6 mmol) was heated to 50° C. in acetone (5 ml) for 72 h, then cooled to room temperature. Aqueous sodium thiosulphate (1 M, 10 ml) was added and the product was extracted with diethyl ether (2×20 ml). The organic layer was dried (K2CO3), filtered and concentrated in vacuo to give a white solid that was filtered through Celite and eluted with heptanes. The filtrate was concentrated in vacuo to give a white solid. Yield 1.038 g (80%). 1H NMR (CDCl3): δ2.24 (tt, 2H), 3.04 (dt, 2H), 3.27 (t, 2H), 7.07 (q, 1H), 7.28 (m, 2H), 7.68 (m, 1H), 7.77 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2)[CH3:2].Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH:35]([CH3:37])[CH3:36])=[CH:30][CH:29]=2)[O:25][C:26]=1[CH3:27].[H-].[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][N:11]2[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH:35]([CH3:37])[CH3:36])=[CH:30][CH:29]=2)[O:25][C:26]=1[CH3:27])[CH3:2]
Reactant: Cc1oc(-c2ccc(OC(C)C)cc2)nc1CCl
Reactant: CCOC(=O)C(Cc1cccc2[nH]ccc12)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1cccc2c1ccn2Cc1nc(-c2ccc(OC(C)C)cc2)oc1C)OCC

Procedure:
In analogy to the procedures described in examples 1 a] and 1 b], rac-2-ethoxy-3-(1H-indol-4-yl)-propionic acid ethyl ester was reacted with 4-chloromethyl-2-(4-isopropoxy-phenyl)-5-methyl-oxazole in N,N-dimethylformamide in the presence of sodium hydride to yield rac-2-ethoxy-3-{1-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethyl]-1H-indol-4-yl}-propionic acid ethyl ester, which was subsequently saponified to yield rac-2-ethoxy-3-{1-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethyl]-1H-indol-4-yl}-propionic acid as light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][NH2:30])[CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+].Cl>C(O)C.O>[ClH:1].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:22][CH2:23][N:24]([CH2:27][CH2:28][CH2:29][NH:30][C:2]2[N:12]=[CH:11][CH:10]=[CH:9][C:3]=2[C:4]([N:6]([CH3:8])[CH3:7])=[O:5])[CH2:25][CH2:26]1
Reactant: COc1ccccc1N1CCN(CCCN)CC1
Reactant: CN(C)C(=O)c1cccnc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1ccccc1N1CCN(CCCNc2ncccc2C(=O)N(C)C)CC1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 66.7 %

Procedure:
A mixture of 2-chloro-N,N-dimethylnicotinamide (174.3 g, 0.94 mmol), prepared as in Example 13, 3-[4-(2-methoxyphenyl)piperazin-1-yl]propylamine (224 g, 0.9 mmol), prepared as in Example 7, and potassium carbonate (250.5 g, 1.81 mmol) in 4 L of xylenes was heated at gentle reflux (133° to 136° C.) for 39 hours. The mixture was allowed to cool to 50° C. and then 1 L of water was added. The organic layer was separated, washed with water (2×500 mL) and concentrated under reduced pressure. The residue was dissolved in 6 L of ethyl acetate and the solution was washed with water (3×1 L) and saturated sodium chloride (2×250 mL), dried (MgSO4) and filtered. The filter was rinsed with 1 L of ethyl acetate and the combined filtrate was concentrated to approximately 4.8 L. A solution of 3.8N hydrochloric acid (175 mL, 0.67 mmol) in ethanol was added and the mixture was aged at room temperature for 90 minutes and then filtered. The filtered residue was washed with ethyl acetate (4×500 mL), dried under reduced pressure at 79° C. for 18 hours to give 2-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propylamino}-N,N-dimethylnicotinamide hydrochloride (259.4 g, 0.6 mmol), m.p. 204°-206° C. Anal.: Calcd. for C22H31N5O2.HCl: C, 60.89; H, 7.43; N, 16.14%; Found: C, 61.14; H, 7.46; N, 15.96%.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]([NH2:14])=[O:13])[CH:4]=[CH:3]1.[CH3:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20]([C:25](=O)[C:26](OC)=[O:27])=[CH:21][NH:22]2)=[CH:18][CH:17]=1.CC(C)([O-])C.[K+].C1COCC1>CN(C=O)C>[CH3:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20]([C:25]3[C:26](=[O:27])[NH:14][C:12](=[O:13])[C:11]=3[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]4[C:10]=3[N:2]([CH3:1])[CH:3]=[CH:4]4)=[CH:21][NH:22]2)=[CH:18][CH:17]=1
Reactant: Cn1ccc2cccc(CC(N)=O)c21
Reactant: COC(=O)C(=O)c1c[nH]c2cc(C)ccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1ccc2c(C3=C(c4cccc5ccn(C)c45)C(=O)NC3=O)c[nH]c2c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 46.3 %

Procedure:
To a solution of 2-(1-methyl-1H-indol-7-yl)acetamide (260 mg, 1.38 mmol) and methyl 2-(6-Methyl-1H-indol-3-yl)oxoacetate (300 mg, 1.38 mmol) in DMF (5.4 mL) was added a 1.0 M solution of potassium tert-butoxide in THF (1.38 mL, 1.38 mmol) at 4° C. under N2. The reaction was stirred for 20 min at this temperature, and additional KOtBu (2.76 mL, 2.76 mmol) was added. The resulting dark red solution was heated to 50° C. and stirred overnight. The mixture was cooled to room temperature and quenched with 1.0 N HCl (9 mL) and poured into EtOAc (300 mL). The organic layer was separated, washed with saturated aqueous NaHCO3 (150 mL), and brine (3×150 mL). The solution was dried (MgSO4), filtered, and concentrated to a red solid. Flash chromatography (SiO2, 30% EtOAc/hexanes) gave the title compound (227 mg, 46%) as a red solid, mp 200–220° C. dec. 1H NMR (DMSO-d6) δ 11.72 (s, 1H), 11.09 (s, 1H), 7.90 (s, 1H), 7.59 (m, 1H), 7.24 (s, 1H), 7.10 (s, 1H), 6.96 (m, 1H), 6.83 (m, 1H), 6.45 (s, 1H), 6.27 (m, 1H), 6.11 (m, 1H), 3.64 (s, 3H), 2.18 (s, 3H). MS (APCI): m/z=356 [C22H17N3O2+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:6]([C:7]([OH:9])=O)=[C:5]([SH:14])[CH:4]=1.[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)#[N:16]>N1C=CC=CC=1>[CH3:13][O:12][C:11]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[S:14][C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[N:16][C:7](=[O:9])[C:6]=2[CH:10]=1
Reactant: COc1cc(S)c(C(=O)O)cc1OC
Reactant: N#Cc1ccccn1
Solvent: c1ccncc1
Product: COc1cc2sc(-c3ccccn3)nc(=O)c2cc1OC
Yield: 55.5 %

Procedure:
A mixture of 4,5-dimethoxy-2-mercaptobenzoic acid (2.20 g, 10.2 mmol), 2-cyanopyridine (1.10 g, 10.2 mmol) and pyridine (15.0 ml) was refluxed for 20 hrs as described in Example 9. After cooling, the precipitated crystals were collected by filtration and recrystallized from hexane-chlorobenzene to give the titled compound (1.70 g, 55%)
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH2:11][CH2:12][CH2:13][CH:14]([O:15]CC3C=CC=CC=3)[C:7]2=[N:6][C:5]=1[CH3:23].[H][H].C(OCC)C>Cl.[Pd].C(N(CC)CC)C.CO.CCCCCC>[Cl:1][CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH2:11][CH2:12][CH2:13][CH:14]([OH:15])[C:7]2=[N:6][C:5]=1[CH3:23]
Reactant: Cc1nc2n(c(=O)c1CCCl)CCCC2OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: CO
Product: Cc1nc2n(c(=O)c1CCCl)CCCC2O
Reaction time: 36 h

Procedure:
At room temperature, 3-(2-chloroethyl)-2-methyl-9-benzyloxy-6,7,8,9-tetrahydro-pyrido[1,2-a]pyrimidin-4-one 4.0 g (0.0122 mole) was charged into a 250 mL three-necked bottle, 80 mL methanol was added, and then concentrated hydrochloric acid (about 25 drops) was added dropwise with stirring to adjust pH to 3.0. After the dissolution was completed, 1.8 g of wet 5% Pd—C (water content: 56%) (W/W: 10/1) was added, argon gas was fed to exchange atmosphere for three times, hydrogen gas was fed to exchange atmosphere for three times, the reaction was conducted at 27° C. for about 36 hours, and TLC (ethyl ether:n-hexane:methanol:triethylamine=2 mL:0.5 mL:6 drops:6 drops) was used to detect the debenzylated product. The reaction was stopped after all starting materials were consumed.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:26][C:27]1[C:36]2[C:31](=[CH:32][C:33]([S:37](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:39])=[O:38])=[CH:34][CH:35]=2)[CH:30]=[C:29]([Cl:52])[N:28]=1>C1COCC1.[Cl-].[NH4+].O>[Br:26][C:27]1[C:36]2[C:31](=[CH:32][C:33]([S:37]([N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:15][CH:14]=3)[C:9]3[S:10][CH:11]=[CH:12][N:13]=3)(=[O:39])=[O:38])=[CH:34][CH:35]=2)[CH:30]=[C:29]([Cl:52])[N:28]=1
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(Br)nc(Cl)cc2c1
Reactant: COc1ccc(CNc2nccs2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Br)nc(Cl)cc3c2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 93.3 %

Procedure:
A round-bottom flask was charged with N-(4-methoxybenzyl)thiazol-2-amine (238 mg, 1.081 mmol) and THF (4912 μl) to give an opaque solution. The flask was cooled in a dry ice-acetone bath for 5 min to give a milky suspension, then lithium bis(trimethylsilyl)amide (1M in THF) (1081 μl, 1.081 mmol) was added. The flask was removed from the bath for 2 min to give a clear solution, then resubmerged. The mixture appeared to remain a solution. After 5 min, a solution of perfluorophenyl 1-bromo-3-chloroisoquinoline-6-sulfonate (480 mg, 0.982 mmol) in THF (3 mL with a 2 mL wash) was added drop wise. After 25 min, the mixture was diluted with saturated aq. ammonium chloride solution and warmed to room temperature. The mixture was diluted with water and extracted with EtOAc. The organic extract was dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (0 to 40% EtOAc/Heptane) to give 1-bromo-3-chloro-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (481 mg, 0.916 mmol, 93% yield) as a white foam: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm=8.32 (d, J=9.0 Hz, 1H), 8.04 (d, J=1.8 Hz, 1H), 7.83 (dd, J=1.9, 9.0 Hz, 1H), 7.67 (s, 1H), 7.44 (d, J=3.6 Hz, 1H), 7.30 (d, J=8.8 Hz, 2H), 7.07 (d, J=3.5 Hz, 1H), 6.75-6.71 (m, 2H), 5.12 (s, 2H), 3.74 (s, 3H). m/z (ESI) 546.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][CH:11]([OH:17])[CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C>CS(C)=O>[C:1]([O:5][C:6]([N:8]([CH2:10][C:11](=[O:17])[CH2:12][CH2:13][CH:14]([CH3:15])[CH3:16])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)CCC(O)CN(C)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)CCC(=O)CN(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
To a solution of 1-(N-t-butoxycarbonyl-N-methylamino)-2-hydroxy-5-methylhexane (2.45 g) and triethylamine (3.03 g) in dimethyl sulfoxide (20 ml) was added sulfur trioxide pyridine complex (4.77 g) under ice-bath cooling. After the mixture was stirred at ambient temperature overnight, the reaction mixture was poured into ice-water (100 ml). The mixture was extracted with diethyl ether (100 ml×2). The extract was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (20% ethyl acetate in n-hexane as eluent) to give 1-(N-t-butoxycarbonyl-N-methylamino)-2-oxo-5-methylhexane (2.15 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:4](=[O:19])[CH:3]=1.[N:20]([O-])=[O:21].[Na+]>O.C(O)(=O)C>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:4](=[O:19])[C:3]=1[N:20]=[O:21]
Reactant: COc1ccc(Cn2c(=O)cc(N)n(C)c2=O)cc1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(Cn2c(=O)c(N=O)c(N)n(C)c2=O)cc1
Temperature: 70 °C
Reaction time: 4 h
Yield: 85.9 %

Procedure:
To a solution of 6-amino-3-(4-methoxybenzyl)-1-methylpyrimidine-2,4(1H,3H)-dione (4.3 g, 16.45 mmol) in water (20 mL) and acetic acid (20 mL) was added sodium nitrite (3.4 g, 49.4 mmol) in small portions at 70° C. After addition, the mixture was stirred at 70° C. for 4 h. The reaction was cooled and concentrated. The solids were collected, washed with water and dried under vacuum to give 6-amino-3-(4-methoxybenzyl)-1-methyl-5-nitrosopyrimidine-2,4(1H,3H)-dione (4.1 g, 85.9% yield) as purple solid. LCMS retention time 0.885 min; LCMS MH+ 291.