Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([NH:10][CH2:11][C:12]#[CH:13])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].Br[CH:17]([OH:19])[CH3:18]>CC#N>[C:4]1([CH2:3][C@H:2]([N:10]([CH2:11][C:12]#[CH:13])[CH2:18][CH2:17][OH:19])[CH3:1])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C#CCNC(C)Cc1ccccc1
Reactant: CC(O)Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: C#CCN(CCO)[C@H](C)Cc1ccccc1
Temperature: 25 °C

Procedure:
A mixture of desmethyldeprenyl (Sigma, 150 mg, 0.72 mmol) and NaOH (60 mg, 1.5 mmol), in MeCN (5 ml) was stirred at room temperature for 30 min. To the stirred mixture 1-bromo ethanol (1.0 mmol) was added and the reaction mixture was refluxed for overnight. The reaction mixture was allowed to cool to room temperature and solvent was evaporated under reduced pressure. The residue was partitioned between CH2Cl2 (20 ml) and water (10 ml). The organic phase was separated and washed with saturated NaHCO3 (10 ml) and brine (10 ml). The organic layer was dried over MgSO4 and filtered. The solvent was removed under reduced pressure to obtain the crude product as a light yellow liquid. The crude product was purified by silica-gel column chromatography (hexane/ether 8:2).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N:11]2[C:15]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=4[S:22](=[O:25])(=[O:24])[CH2:23][C:14]=3[C:13]([C:26]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[O:27])=[N:12]2)[CH:6]=1)[NH2:4].[C:34](O)(=O)[CH2:35][CH3:36]>CCOC(C)=O>[CH2:35]([C:36]1[O:1][N:2]=[C:3]([C:5]2[CH:6]=[C:7]([N:11]3[C:15]4[C:16]5[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=5[S:22](=[O:24])(=[O:25])[CH2:23][C:14]=4[C:13]([C:26]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[O:27])=[N:12]3)[CH:8]=[CH:9][CH:10]=2)[N:4]=1)[CH3:34]
Reactant: CCC(=O)O
Reactant: NC(=NO)c1cccc(-n2nc(C(=O)N3CCOCC3)c3c2-c2ccccc2S(=O)(=O)C3)c1
Solvent: CCOC(C)=O
Product: CCc1nc(-c2cccc(-n3nc(C(=O)N4CCOCC4)c4c3-c3ccccc3S(=O)(=O)C4)c2)no1
Temperature: 80 °C

Procedure:
To a solution of N′-hydroxy-3-[3-(morpholin-4-ylcarbonyl)-5,5-dioxidothiochromeno[4,3-c]pyrazol-1(4H)-yl]benzenecarboximidamide (150 mg, 0.32 mmol) in dry EtOAc is added propionic acid (13 μl, 0.32 mmol) under nitrogen followed by TEA (0.13 mL, 0.963 mmol) and propane phosphonic acid cyclic anhydride (0.51 mL, 0.80 mmol) at 0° C. under nitrogen. The reaction mixture is heated to 80° C. for 12 h under nitrogen and concentrated under vacuum. Solid residue is purified by silica gel column chromatography (1.2% MeOH in DCM) to afford the title compound as an off white solid. 1H NMR (DMSO-d6, 400 MHz): δ 8.24-8.22 (d, J=7.4 Hz, 1H), 8.05-8.02 (m, 2H), 7.81-7.77 (m, 2H), 7.64 (m, 1H), 7.57 (m, 1H), 6.93-6.91 (d, J=7.9 Hz, 1H), 4.91 (s, 2H), 3.92-3.90 (m, 2H), 3.67 (m, 4H), 3.61-3.60 (m, 2H), 3.02-3.0 (m, 2H), 1.33-1.29 (t, J=7.6 Hz, 3H). MS (ESI+): 506.0. HPLC (max plot) 97.13%; Rt 4.34 min.
Reaction SMILES: Cl.[NH:2]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[O:4][C:3]1=[O:17].[Cl:18][C:19]1[C:24]2[NH:25][C:26]([CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[N:27][C:23]=2[CH:22]=[C:21]([O:34][C:35]2[CH:40]=[C:39](Cl)[N:38]=[CH:37][N:36]=2)[CH:20]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:18][C:19]1[C:24]2[NH:25][C:26]([CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[N:27][C:23]=2[CH:22]=[C:21]([O:34][C:35]2[N:36]=[CH:37][N:38]=[C:39]([N:14]3[CH2:13][CH2:12][C:5]4([O:4][C:3](=[O:17])[NH:2][C:7]5[N:8]=[CH:9][CH:10]=[CH:11][C:6]4=5)[CH2:16][CH2:15]3)[CH:40]=2)[CH:20]=1
Reactant: Clc1cc(Oc2cc(Cl)c3[nH]c(C4CCOCC4)nc3c2)ncn1
Reactant: O=C1Nc2ncccc2C2(CCNCC2)O1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1Nc2ncccc2C2(CCN(c3cc(Oc4cc(Cl)c5[nH]c(C6CCOCC6)nc5c4)ncn3)CC2)O1

Procedure:
49 mg (0.19 mmol) spiro[piperidin-4,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-one hydrochloride, 70 mg (0.19 mmol) 7-chloro-5-(6-chloropyrimidin-4-yloxy)-2-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazole and 70 μL (0.40 mmol) DIPEA in 2.0 mL DMF were stirred for 3 h at RT and for 3 h at 40° C. The reaction mixture was purified by chromatography. The fractions containing product were combined and evaporated down i.vac.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=1)([O-])=O.[C:14](OCC)(=[O:16])[CH3:15]>[C].[Pd].CO>[N:6]1[C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=[C:4]([NH:1][C:14](=[O:16])[CH3:15])[CH:5]=1
Reactant: CCOC(C)=O
Reactant: O=[N+]([O-])c1cnc2c(c1)CCCC2
Agent: [Pd]
Solvent: CO
Product: CC(=O)Nc1cnc2c(c1)CCCC2
Reaction time: 16 h

Procedure:
10% Palladium-carbon (200 mg) was added to a methanol solution (68 ml) of 3-nitro-5,6,7,8-tetrahydroquinoline (2.41 g], 13.5 mmol) obtained in 2), which was stirred under hydrogen atmosphere for 16 hours. After a catalyst was filtered off, the solvent was distilled out under reduced pressure. The resulting residue was dissolved in pyridine (35 ml). Anhydrous ethyl acetate (1.91 ml, 20.3 mmol) was added to the solution, which was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled out under reduced pressure. Diisopropyl ether-n-hexane (1:8) was added to the resulting residue, to give the titled compound (2.48 g) as a colorless powder.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[Br-].[Mg+2].[Br-].[Br:16][Mg:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.[Br:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[C:32](=[O:36])[N:31]([CH2:37][C:38]1[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[CH:40][CH:39]=1)[C:30]([CH:48]=[O:49])=[C:29]2[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.C(=O)([O-])O.[Na+]>CCCCCC.C1COCC1.O>[Br:16][Mg:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.[Br:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[C:32](=[O:36])[N:31]([CH2:37][C:38]1[CH:39]=[CH:40][C:41]([S:44]([CH3:47])(=[O:45])=[O:46])=[CH:42][CH:43]=1)[C:30]([CH:48]([OH:49])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[C:29]2[C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1
Reactant: CS(=O)(=O)c1ccc(Cn2c(C=O)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Reactant: Cc1ccccn1
Agent: Br[Mg]Cc1ccccn1
Agent: O=C([O-])O
Agent: [Br-]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(Cn2c(C(O)Cc3ccccn3)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Temperature: -20 °C
Reaction time: 0.17 h

Procedure:
Under a nitrogen stream, a solution (1.61M, 15.8 ml) of n-butyllithium in hexane was added to THF (15 ml) at −50° C. or below, and a solution (2.5 ml) of 2-methylpyridine (2.5 g) in THF was added dropwise at −50° C. or below. The reaction mixture was allowed to warm to −20° C. and stirred for 10 min. and then cooled to −50° C. and magnesium bromide (2.5 g) was added. The reaction mixture was allowed to warm to room temperature, stirred for 30 min. and bromo(pyridin-2-ylmethyl)magnesium was prepared. The obtained suspension (4 ml) of bromo(pyridin-2-ylmethyl)magnesium was added to a solution of 6-bromo-2-(4-methanesulfonylbenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carbaldehyde (500 mg) in THF (5 ml), and the mixture was stirred at room temperature for 10 min. To the reaction mixture were added water and saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (400 mg).
Reaction SMILES: [CH3:1][C:2]12[CH2:29][CH:5]([C:6]3([CH3:28])[C:10]1([CH3:11])[C:9]1[CH:12]=[C:13]([C:16]([C:18]4[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=4)=[O:17])[CH:14]=[CH:15][C:8]=1[O:7]3)[CH2:4][CH2:3]2.[OH-].[Na+]>CO>[CH3:1][C:2]12[CH2:29][CH:5]([C:6]3([CH3:28])[C:10]1([CH3:11])[C:9]1[CH:12]=[C:13]([C:16]([C:18]4[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:26][CH:27]=4)=[O:17])[CH:14]=[CH:15][C:8]=1[O:7]3)[CH2:4][CH2:3]2
Reactant: COC(=O)c1ccc(C(=O)c2ccc3c(c2)C2(C)C4(C)CCC(C4)C2(C)O3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC12CCC(C1)C1(C)Oc3ccc(C(=O)c4ccc(C(=O)O)cc4)cc3C21C

Procedure:
2.52 g (6.44 mmol) of the ester obtained in Example 8, in solution in 30 ml of methanol, were treated with 2.5 g of sodium hydroxide and heated at reflux for 3 hours. After the same treatment as in Example 7, followed by recrystallization from hexane, 2.35 g (97%) of the expected coompound, melting at 262°-264° C., are isolated.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.[Cl:20]N1C(=O)CCC1=O>ClCCl>[Cl:20][C:12]1[C:11]2[C:16](=[CH:17][C:8]([C:6]3[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[CH3:19])=[CH:9][CH:10]=2)[CH:15]=[N:14][C:13]=1[NH2:18]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1ccc(F)cc1-c1ccc2cc(N)ncc2c1
Solvent: ClCCl
Product: Cc1ccc(F)cc1-c1ccc2c(Cl)c(N)ncc2c1
Yield: 85.4 %

Procedure:
A solution of 7-(5-fluoro-2-methylphenyl)isoquinolin-3-amine (60.8 mg, 241 μmol) in dichloromethane (2.0 mL) was treated with N-chlorosuccinimide (35.2 mg, 264 μmol) at ambient temperature. After 24 h the mixture was absorbed directly onto silica gel in vacuo and purified by flash chromatography (silica, ISCO, 0-6% methanol in dichloromethane) to yield the title compound as a pale orange solid (59.0 mg, 85%). 1H NMR (400 MHz, CDCl3) δ 8.80 (s, 1H), 7.98 (d, J=8.7 Hz, 1H), 7.73 (s, 1H), 7.62 (d, J=8.7 Hz, 1H), 7.30-7.20 (m, 2H), 7.00 (t, J=8.3 Hz, 2H), 4.95 (s, 2H), 2.25 (s, 3H). 1H NMR (400 MHz, DMSO) δ 8.90 (s, 1H), 7.93 (s, 1H), 7.84 (d, J=8.8 Hz, 1H), 7.70 (d, J=8.8 Hz, 1H), 7.40-7.34 (m, 1H), 7.18-7.12 (m, 2H), 6.40 (s, 2H), 2.24 (s, 3H). LCMS (Method E): RT=5.508 min, M+H+=287.0 & 289.0.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]([NH:13][C:14]2[C:15](Br)=[N:16][C:17]([CH3:21])=[CH:18][C:19]=2Br)=[O:12])[CH2:6][CH2:5]1.[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>>[OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]([NH:13][C:14]2[C:15]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[N:16][C:17]([CH3:21])=[CH:18][C:19]=2[N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:12])[CH2:6][CH2:5]1
Reactant: C1CCNC1
Reactant: Cc1cc(Br)c(NC(=O)CN2CCN(CCO)CC2)c(Br)n1
Product: Cc1cc(N2CCCC2)c(NC(=O)CN2CCN(CCO)CC2)c(N2CCCC2)n1

Procedure:
2-[4-(2-Hydroxyethyl)piperazin-1-yl]-N-[2,4-dibromo-6-methyl-3-pyridyl]acetamide (1.00 g, 2.29 mmol) was dissolved in pyrrolidine (10 mL), and the solution was subjected to reflux for 4 days. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to separation through silica gel column chromatography (developer: hexane:acetone=2:1), to thereby yield a crude product of 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(pyrrolidin-1-yl)-6-methyl-3-pyridyl]acetamide (1.22 g) as a brown foamed substance. The crude product was dissolved in pyridine (20 mL), and acetic anhydride (10 mL) was added thereto under cooling with ice, followed by stirring for 14 hours at room temperature. The reaction mixture was concentrated under reduced pressure. Toluene (70 mL) was added to the residue and then evaporated three times, followed by purification through silica gel column chromatography (developer: chloroform:methanol=20:1→chloroform:ammonia-saturated methanol=50:1→chloroform:ammonia-saturated methanol=20:1), to thereby yield a brown oil (1.05 g). The oil was dissolved in ammonia-saturated methanol (30 mL), and the solution was stirred for 14 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (developer: chloroform:ammonia-saturated methanol=100:1→chloroform:ammonia-saturated methanol=20:1), to thereby yield 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(pyrrolidin-1-yl)-6-methyl-3-pyridyl]acetamide (911 mg, yield 95%) as a pale brown foamed susbtance.
Reaction SMILES: [CH3:1][S-:2].[Na+].Cl[C:5]1[C:6]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:7]=2[S:8][C:9]=1[C:10]([NH2:12])=[O:11]>CN(C=O)C.C(OCC)(=O)C>[CH3:18][O:17][C:15]1[CH:14]=[CH:13][C:7]2[S:8][C:9]([C:10]([NH2:12])=[O:11])=[C:5]([S:2][CH3:1])[C:6]=2[CH:16]=1
Reactant: C[S-]
Reactant: COc1ccc2sc(C(N)=O)c(Cl)c2c1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2sc(C(N)=O)c(SC)c2c1
Reaction time: 1 h
Yield: 72 %

Procedure:
Sodium thiomethoxide (93 mg, 1.32 mmol) is added to a suspension of 3-chloro-5-methoxybenzo[b]thiophene-2-carboxamide (250 mg, 1.03 mmol) in 2 mL of DMF. After 1 hour, an additional amount of sodium thiomethoxide (13 mg) is added. The reaction mixture is diluted with ethyl acetate and washed with 1N NaOH, 1N HCl, water, and brine. The organic layer is dried over MgSO4. Filtration followed by concentration in vacuo and recrystallization from ethyl acetate:hexane gives 5-methoxy-3-(methylthio)benzo[b]thiophene-2-carboxamide in 72% yield; mp=171°-173° C.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][C:3]=1[NH2:4].[N:13]([O-])=O.[Na+]>C(O)(=O)C.O>[CH3:9][C:7]1[CH:8]=[C:2]2[C:3](=[CH:5][C:6]=1[N+:10]([O-:12])=[O:11])[NH:4][N:13]=[CH:1]2
Reactant: Cc1cc(C)c([N+](=O)[O-])cc1N
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc2cn[nH]c2cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 3 h
Yield: 58.1 %

Procedure:
2,4-Dimethyl-5-nitroaniline (1.662 g, 10.00 mmol) was dissolved in glacial acetic acid (100 ml) and the mixture was cooled to 0° C. A solution of sodium nitrite (1 eq, 690 mg) in water (2 ml) was added while maintaining a temperature below 25° C. Stirring was continued for three hours and the mixture was filtered. The filtrate was allowed to stand for three days at room temperature, then was concentrate under reduced pressure. The residue was diluted with water and the resulting mixture was stirred vigorously. The solid product was collected by filtration, washed thoroughly with cold water, and dried. The product was purified by flash chromatography (99:1 dichloromethane/methanol) to give 1.030 g (58.1%) of 5-methyl-6-nitro-1H-indazole as a solid.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([N:10]2[C:22](=[O:23])[C:14]3=[CH:15][N:16]4[C:21]([CH2:20][CH2:19][CH2:18][CH2:17]4)=[C:13]3[CH:12]=[N:11]2)[N:5]=[CH:4][CH:3]=1.[CH3:24][N:25]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[C:27]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([N:47]3[CH2:52][CH2:51][N:50]([CH:53]4[CH2:56][O:55][CH2:54]4)[CH2:49][C@@H:48]3[CH3:57])=[CH:43][N:42]=2)[C:26]1=[O:58].C([O-])(=O)C.[Na+].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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].O.C(#N)C>[CH3:24][N:25]1[C:26](=[O:58])[C:27]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([N:47]3[CH2:52][CH2:51][N:50]([CH:53]4[CH2:54][O:55][CH2:56]4)[CH2:49][C@@H:48]3[CH3:57])=[CH:43][N:42]=2)=[CH:28][C:29]([C:2]2[C:7]([CH:8]=[O:9])=[C:6]([N:10]3[C:22](=[O:23])[C:14]4=[CH:15][N:16]5[C:21]([CH2:20][CH2:19][CH2:18][CH2:17]5)=[C:13]4[CH:12]=[N:11]3)[N:5]=[CH:4][CH:3]=2)=[CH:30]1
Reactant: O=Cc1c(Cl)ccnc1-n1ncc2c3n(cc2c1=O)CCCC3
Reactant: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(B3OC(C)(C)C(C)(C)O3)cn(C)c2=O)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(-n4ncc5c6n(cc5c4=O)CCCC6)c3C=O)cn(C)c2=O)nc1
Temperature: 100 °C
Yield: 44.5 %

Procedure:
A 100-mL round-bottomed flask equipped with a reflux condenser was charged with 4-chloro-2-(4-oxo-7,8,9,10-tetrahydropyridazino[4,5-a]indolizin-3(4H)-yl)nicotinaldehyde 192c (196 mg, 0.60 mmol), (S)-1-methyl-3-(5-(2-methyl-4-(oxetan-3-yl)-piperazin-1-yl)pyridin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 191j (290 mg, 0.60 mmol), sodium acetate (100 mg, 1.2 mmol), K3PO4 (320 mg, 1.2 mmol), PdCl2(dppf) (50 mg, 0.060 mmol), acetonitrile (25 mL), and water (1 mL). After bubbling nitrogen through the mixture for 30 minutes, it was heated at 100° C. for 3 hours under N2 protection. The reaction mixture was cooled to room temperature and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 20:1 methylene chloride/methanol to afford 192d 173 mg, 44%) as a brown solid. MS-ESI: [M+H]+ 648.4.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[CH2:13]([C:20]1[CH:38]=[CH:37][C:23]([C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([NH:35][NH2:36])=[O:34])=[CH:29][CH:28]=2)=[O:25])=[CH:22][CH:21]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>C(O)(=O)C>[CH2:13]([C:20]1[CH:38]=[CH:37][C:23]([C:24]([NH:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]([NH:35][N:36]=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=4)[NH:7][C:6]3=[O:11])=[O:34])=[CH:31][CH:32]=2)=[O:25])=[CH:22][CH:21]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: CCCCCCCc1ccc(C(=O)Nc2ccc(C(=O)NN)cc2)cc1
Solvent: CC(=O)O
Product: CCCCCCCc1ccc(C(=O)Nc2ccc(C(=O)NN=C3C(=O)Nc4ccc(I)cc43)cc2)cc1
Temperature: 100 °C
Yield: 91 %

Procedure:
Into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 4-heptyl-N-[4-(hydrazinocarbonyl)phenyl]-benzamide. After stirring at 100° C. the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 111 mg of the title compound (91%) as a yellow powder in 93.1% purity by HPLC (Rt: 6.3, gradient of 8 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH:6]([CH:8]=[O:9])[CH2:5][CH2:4][O:3]1.[BH4-].[Na+]>C(O)C>[CH3:1][C:2]1([CH3:10])[CH2:7][CH:6]([CH2:8][OH:9])[CH2:5][CH2:4][O:3]1
Reactant: CC1(C)CC(C=O)CCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC1(C)CC(CO)CCO1
Temperature: 25 °C
Yield: 100.2 %

Procedure:
A solution of 2,2-dimethyltetrahydro-2H-pyran-4-carbaldehyde (2.5 g) in ethanol (30 mL) was cooled (ice bath) and sodium borohydride (665 mg) was added with stirring. The ice bath was removed and the mixture was allowed to warm to room temperature. After 2 h the reaction was heated to 50° C. for 1 h, then allowed to cool to room temperature. The solvent was evaporated and the residue was treated with brine, acidified and extracted into DCM (×3). The combined organics were dried through a hydrophobic frit and evaporated to give a clear oil (2.54 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:23][OH:24])[CH2:9][CH2:10][CH:11]=[CH:12][C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])=[CH:4][CH:3]=1.[H-].[Na+]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:23][O:24][CH:11]([CH2:12][C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C(C=CCCC(CO)c1ccc(Br)cc1)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(CC1CCC(c2ccc(Br)cc2)CO1)OCc1ccccc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of benzyl 6-(4-bromophenyl)-7-hydroxyhept-2-enoate (516 mg, 1.326 mmol) in dioxane (20 ml) at room temperature was added 60% NaH (106 mg, 2.65 mmol) and the mixture was stirred at 60° C. for 3 hr. Small amount of title compound was formed with the major SM. So the reaction was added more NaH and heated at 60° C. overnight. The reaction was quenched by sat. aq. NH4Cl and was extracted with EtOAc. The combined organic layer was washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (5 to 100% Acetone/Heptane) to give the title compound 380 mg (yield 74%). MS (ESI) m/z 391.2 (M+2). Retention time 1.62 min (condition A).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:39])=[C:16]([N:19]3[CH2:26][CH:25]4[CH:21]([C:22]([CH2:27][N:28]5C(=O)C6C(=CC=CC=6)C5=O)=[N:23][O:24]4)[CH2:20]3)[N:17]=2)[C:12](=[O:40])[C:11]([C:41]([OH:43])=[O:42])=[CH:10]1.O.NN>C(O)C>[NH2:28][CH2:27][C:22]1[CH:21]2[CH2:20][N:19]([C:16]3[N:17]=[C:18]4[C:13]([C:12](=[O:40])[C:11]([C:41]([OH:43])=[O:42])=[CH:10][N:9]4[C:3]4[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=4[F:1])=[CH:14][C:15]=3[F:39])[CH2:26][CH:25]2[O:24][N:23]=1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2nc(N3CC4ON=C(CN5C(=O)c6ccccc6C5=O)C4C3)c(F)cc2c1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: NCC1=NOC2CN(c3nc4c(cc3F)c(=O)c(C(=O)O)cn4-c3ccc(F)cc3F)CC12

Procedure:
Phthalimide 108 (241 mg; 0.409 mmol) and hydrazine hydrate (0.03 mL) in ethanol (5 mL) were heated at reflux temperature under a nitrogen atmosphere for 23 hours. After cooling, the thick reaction mixture suspension was filtered. The solid was washed with methylene chloride, water and dried to yield amine 200 as an off-white solid.
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:20]=[CH:19][C:8]2[N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14](Br)[CH:13]=3)[CH:10]=[N:11][C:7]=2[CH:6]=1.C([Sn](CCCC)(CCCC)[C:26]1[S:27][CH:28]=[CH:29][CH:30]=1)CCC>CN(C=O)C.O>[CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:20]=[CH:19][C:8]2[N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:26]4[S:27][CH:28]=[CH:29][CH:30]=4)[CH:13]=3)[CH:10]=[N:11][C:7]=2[CH:6]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: CON=Cc1ccc2c(c1)ncn2-c1cccc(Br)c1
Solvent: CN(C)C=O
Solvent: O
Product: CON=Cc1ccc2c(c1)ncn2-c1cccc(-c2cccs2)c1
Temperature: 80 °C

Procedure:
A mixture of 29a from Example 8 (0.7 g, 2.1 mmol), 2-(tributylstannyl)thiophene (1.59 g, 4.3 mmol) and tris(triphenylphosphine)palladium dichloride (50 mg) in DMF (5 ml) is heated to 80° C. over night. The cooled reaction mixture is diluted with 4 volumes of water and extracted with ethyl acetate. The combined organic extracts are dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by column-chromatography on silica gel using a mixture of ethyl acetate and petroleum ether (1:1) as the eluent. Yield: 0.56 g (80%). Mp 184-185° C.
Reaction SMILES: C([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([O:30][CH3:31])=[C:14]([O:19][CH:20]3[CH2:29][CH2:28][C:23]4([O:27][CH2:26][CH2:25][O:24]4)[CH2:22][CH2:21]3)[CH:15]=2)[N:10]=[CH:9]1)C1C=CC=CC=1.[H][H]>C(O)(=O)C.[Pd]>[O:24]1[C:23]2([CH2:28][CH2:29][CH:20]([O:19][C:14]3[CH:15]=[C:16]4[C:11](=[CH:12][C:13]=3[O:30][CH3:31])[N:10]=[CH:9][NH:8][C:17]4=[O:18])[CH2:21][CH2:22]2)[O:27][CH2:26][CH2:25]1
Reactant: [H][H]
Reactant: COc1cc2ncn(Cc3ccccc3)c(=O)c2cc1OC1CCC2(CC1)OCCO2
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1cc2nc[nH]c(=O)c2cc1OC1CCC2(CC1)OCCO2

Procedure:
27.20 g of 3-benzyl-6-(1,4-dioxa-spiro[4.5]dec-8-yloxy)-7-methoxy-3H-quinazolin-4-one are dissolved in 270 ml glacial acetic acid, combined with 2.70 g palladium on activated charcoal (10%) and hydrogenated at 60° C. until the uptake of hydrogen has ended. Then the glacial acetic acid is distilled off using the rotary evaporator and evaporated off with toluene. The flask residue is mixed with water and made alkaline with saturated sodium hydrogen carbonate solution. The precipitate formed is suction filtered and dried.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:16](=[S:18])[NH2:17])=[CH:4][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=1.C(=O)(O)[O-].[Na+].[F:24][C:25]([F:31])([F:30])[C:26]([CH2:28]Br)=[O:27]>O1CCCC1>[Br:1][C:2]1[C:3]([C:16]2[S:18][CH2:28][C:26]([OH:27])([C:25]([F:31])([F:30])[F:24])[N:17]=2)=[CH:4][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(C(N)=S)c(Br)cn1
Reactant: O=C(CBr)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cc(C2=NC(O)(C(F)(F)F)CS2)c(Br)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.1 %

Procedure:
To a 2 L round bottom flask was charged tert-butyl 5-bromo-4-carbamothioylpyridin-2-ylcarbamate (Intermediate 85, 50 g, 151 mmol) in tetrahydrofuran (800 mL), then solid sodium bicarbonate (25.4 g, 302 mmol) was added followed by 1,1,1-trifluoro-3-bromoacetone (31 mL, 290 mmol). The resulting mixture (yellow suspension) was allowed to stir at room temperature overnight. The white suspension was filtered and the solid was washed with water (2.2˜2.5 L). The white solid was dried under vacuum to give 56.8g of white powder (85%)