Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]CC=C)[C:3](=[O:5])[CH3:4].C[N+]1([O-])CC[O:21]CC1.[C:25]([OH:29])(C)([CH3:27])[CH3:26].S(S([O-])=O)([O-])=O.[Na+].[Na+]>O.CC(C)=O.[Os].ClCCl>[OH:21][CH2:26][CH:25]([OH:29])[CH2:27][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][N:2]([CH3:1])[C:3](=[O:5])[CH3:4]
Reactant: C=CCCCCCCCCCN(C)C(C)=O
Reactant: CC(C)(C)O
Reactant: C[N+]1([O-])CCOCC1
Agent: [Os]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)N(C)CCCCCCCCCC(O)CO
Reaction time: 0.5 h
Yield: 70 %

Procedure:
A solution of 1-(N-methylacetamido)-10-undecene (2.0 g, 8.9 mmol), N-methylmorpholine-N-oxide (4 mL of a 60% aqueous solution in water, 18 mmol) and potassium osmate dihydrate (10 mg) in acetone (50 mL), water (30 mL), and t-butanol (10 mL) was stirred at ambient temperature for 17 hours. Sodium dithionite (200 mg) was added to reduce the osmium catalyst. After 30 minutes, the mixture was added to dichloromethane (50 mL) and the layers separated. The aqueous layer was extracted with dichloromethane (3×50 mL). The combined organic layers were washed with saturated aqueous salt solution (50 mL) and dried over sodium sulfate, the solvent being subsequently evaporated under vacuum to a thick residue. The residue was purified by chromatography using silica and a dichloromethane/15% methanol eluant, resulting in 1.61 g of 1,2-dihydroxy-11-(N-methylacetamido)undecane (70% yield). This resulting diol (1.61 g, 6.2 mmol) was stirred in a 30% solution of hydrogen bromide in acetic acid (3.7 mL) for 1 hour. The solution was added to a mixture of sodium bicarbonate (7 g) in water (50 mL) and dichloromethane (25 mL). After bubbling ceased, the layers were separated and an aqueous layer extracted with dichloromethane (2×70 mL). The combined organic layers were washed with water (30 mL) and saturated aqueous salt solution (30 mL), then dried over sodium sulfate. The solvent was removed under vacuum to obtain 2.16 g of 1-(N-methylacetamido)-10-acetoxy-11-bromoundecane as a colorless oil (96% yield). Sodium methoxide (351 mg, 6.5 mmol) was added to a solution of bromoacetate (2.16 g, 5.9 mmol) in methanol (15 mL). After 1 hour of stirring, the mixture was added to water (25 mL) and extracted with dichloromethane (3×25 mL). The combined organic layers were washed with saturated aqueous salt solution (25 mL) and dried over sodium sulfate. The solvent was evaporated under vacuum and the residue purified with chromatography using silica and an ethyl acetate eluant, yielding 831 mg of 1,2-oxido-11-(N-methylacetamido)undecane (58% yield).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:18]=1[CH:19]=O.C(OC(=O)C)(=O)C>CCOCC>[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:18]=1[CH:19]=[CH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: COc1cc2ccnc(C)c2cc1OC
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Product: COc1cc2ccnc(C=Cc3c(Cl)cccc3Cl)c2cc1OC
Reaction time: 3 h
Yield: 78.8 %

Procedure:
A mixture of 20.4 g (0.1 mole) of 1-methyl-6,7-dimethoxyisoquinoline, 18.9 g (0.108 mole) of 2,6-dichlorobenzaldehyde and 15 ml of acetic anhydride is stirred in an oil bath of 150°-160° C. for 3 hours. The termination of the reaction is controlled by thin layer chromatography. The reaction mixture is cooled to a temperature between 5° C. and 10° C. under stirring, 30 ml of ether are added to it, the separated crystals are filtered and washed twice with cold ether. The thus-obtained raw product is recrystallized from a mixture of 600 ml of acetone and 130 ml of water, The clarified solution is stirred at a temperature between 0° C. and 5° C. for 2 hours, the separated substance is filtered, washed with 25 ml of a 6:1.3 mixture of 0° C. acetone and water and dried. Thus 28.4 g (79%) of 1-(2,6-dichlorostyryl)-6,7-dimethoxyisoquinoline are obtained.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[N:14](C(OC(C)(C)C)=O)[C:13]1=[O:26].CN(C)CCN(C)C.C([Li])CCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:50])(=O)=O)=CC=1>O1CCCC1>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1([F:50])[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:26]
Reactant: CC(C)(C)OC(=O)N1C(=O)CCC(N2C(=O)c3ccccc3C2=O)C1=O
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1CCC(F)(N2C(=O)c3ccccc3C2=O)C(=O)N1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1,3-dioxo-2-(1-tert.-butoxycarbonyl-2,6-dioxopiperidin-3-yl)isoindoline (1.0 g, 2.8 mmol) and tetramethylethylene diamine (0.5 g, 4.3 mmol) in tetrahydrofuran (10 mL) is added n-butyl lithium (1.2 mL, 3.0 mmol, 2.5 M) at -78° C. After 30 minutes, N-fluorobenzenesulfonimide (0-8 g, 3.2 mmol) is added to the mixture. The mixture is allowed to reach room temperature and the solvent then removed in vacuo. The residue is stirred with ethyl acetate (10 mL) and IN hydrochloric acid (10 mL) for one hour. The organic layer is separated and the solvent removed in vacuo to yield 1,3-dioxo-2-(2,6-dioxo-3-fluoropiperidin-3-yl)isoindoline which can be further purified through column chromatography.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[S:10][CH:9]=[C:8]([C:11]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=3[CH3:23])[C:17]([OH:19])=O)=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:24]([N:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][C:34]=2[C:40]([F:43])([F:42])[F:41])[CH2:28][CH2:27]1)[CH3:25]>>[NH2:1][C:2]1[C:3]2[S:10][CH:9]=[C:8]([C:11]([NH:13][C:14]3[CH:15]=[C:16]([C:17](=[O:19])[NH:39][C:36]4[CH:37]=[CH:38][C:33]([CH2:32][N:29]5[CH2:28][CH2:27][N:26]([CH2:24][CH3:25])[CH2:31][CH2:30]5)=[C:34]([C:40]([F:43])([F:42])[F:41])[CH:35]=4)[CH:20]=[CH:21][C:22]=3[CH3:23])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cc1ccc(C(=O)O)cc1NC(=O)c1csc2c(N)ncnc12
Reactant: CCN1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Product: CCN1CCN(Cc2ccc(NC(=O)c3ccc(C)c(NC(=O)c4csc5c(N)ncnc45)c3)cc2C(F)(F)F)CC1

Procedure:
The procedure of Step 5 of Example 1 was repeated except for using 3-(4-aminothieno[3,2-d]pyrimidine-7-carboxamido)-4-methylbenzoic acid obtained in Step 4 of Example 8 and 4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzenamine to obtain the title compound (see Table 1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])OC(=O)[CH:3]=1.Cl[C:11]1[C:12]([O:14][C:15](=[O:17])[CH:16]=1)=[O:13]>>[CH3:8][C:6]1[CH:7]=[C:2]([CH3:3])[CH:1]=[C:11]2[C:12]([O:14][C:15](=[O:17])[C:16]=12)=[O:13]
Reactant: O=C1C=C(Cl)C(=O)O1
Reactant: Cc1cc(C)oc(=O)c1
Product: Cc1cc(C)c2c(c1)C(=O)OC2=O
Temperature: 160 °C
Yield: 63.8 %

Procedure:
4,6-dimethyl-2-pyrone (1.0 g, 8.1 mmol) and 2-chloromaleic anhydride (1.5 g, 11 mmol) were stirred with heating at 160° C. for 3 hrs, and the precipitated crystals were purified by silica gel chromatography (chloroform) to give 0.91 g of the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[CH:7]1([NH2:10])[CH2:9][CH2:8]1>CO>[CH2:2]([NH:10][CH:7]1[CH2:9][CH2:8]1)[CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: NC1CC1
Reactant: C=CCCCBr
Solvent: CO
Product: C=CCCCNC1CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 60.3 %

Procedure:
Using an addition funnel, a solution of 5-bromopentene (15.75 g, 106 mmol) in 50 mL of methanol was added over the course of 5 min to a solution of cyclopropylamine (20.6 g, 361 mmol) in 200 mL of methanol. This solution was allowed to stir at rt for 72 h at which time is was refluxed for 1 h. The methanol and excess cyclopropylamine were removed by distillation. The residue, hydrobromide salt of the product, was partitioned between ether and 4 N NaOH. The aqueous phase was washed with ether (2×). The combined ether extracts were dried (MgSO4), filtered, and concentrated to give 8 g (60%) of N-(pent-4-enyl)cyclopropanamine as a yellow oil: 1H NMR (500 MHz, CDCl3) δ 0.31-0.36 (m, 2H) 0.40-0.46 (m, 2H) 1.53-1.63 (m, 2H) 1.87 (brs, 1H) 2.05-2.10 (m, 2H) 2.10-2.14 (m, 1H) 2.69 (t, J=7.32 Hz, 2H) 4.91-5.07 (m, 2H) 5.72-5.88 (m, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[C:14]1[N:15]([CH3:19])[N:16]=[CH:17][CH:18]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>>[CH3:20][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:30]([NH:29][C:26]2[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)=[O:31])=[CH:9][C:8]=1[C:14]1[N:15]([CH3:19])[N:16]=[CH:17][CH:18]=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: CN(C)CCCOc1ccc(N)cc1-c1ccnn1C
Product: COc1ccc(NC(=O)Nc2ccc(OCCCN(C)C)c(-c3ccnn3C)c2)cc1
Reaction time: 2 h
Yield: 89.6 %

Procedure:
To a solution of 4-(3-dimethylamino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (38.3 mg, 0.140 mmol) in CH3Cl2 (2 mL) was added 4-methoxyphenyl isocyanate (0.21 μL, 0.162 mmol) and stirred for two hours. The resulting material was purified by solid phase extraction (SCX, 1 gram cartridge), eluting with methanol (30 mL) followed by 2M NH3 in methanol (30 mL). The NH3 containing fractions were dried in vacuo to afford Compound 131 as a colorless solid (53.1 mg, 90%). LCMS m/z (%)=424 (MH+) (100), 1H NMR (400 MHz, DMSO-d6) δ: 8.49 (bs, 1H), 8.43 (bs, 1H), 7.44 (d, J=1.86 Hz, 1H), 7.42 (dd, J=8.92, 2.73 Hz, 1H), 7.36 (d, J=2.71 Hz, 1H), 7.33 (d, J=9.09 Hz, 2H), 7.07 (d, J=8.96 Hz, 1H), 6.85 (d, J=9.09 Hz, 2H), 6.23 (d, J=1.82 Hz, 1H), 3.96 (t, J=6.35 Hz, 2H), 3.71 (s, 3H), 3.65 (s, 3H), 2.18 (t, J=7.05 Hz, 2H), 2.07 (s, 6H), 1.77-1.69 (m, 2H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:14]([OH:16])=O)=[CH:8][CH:7]=1)[CH2:2][CH:3]=[CH2:4].[CH3:25]N(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH3:50][O:51][C:52](=[O:59])[C@H:53]([CH2:55][CH:56]([CH3:58])[CH3:57])[NH2:54].CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH3:50][O:51][C:52](=[O:59])[C@@H:53]([NH:54][C:14](=[O:16])[C@@H:13]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:12][C:9]1[CH:8]=[CH:7][C:6]([O:5][CH2:1][CH2:2][CH:3]=[CH2:4])=[CH:11][CH:10]=1)[CH2:55][CH:56]([CH2:58][CH3:25])[CH3:57]
Reactant: C=CCCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C=CCCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(C)CC)C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Carboxylic acid 19 (2.60 g, 7.75 mmol), HATU (3.24 g, 8.53 mmol) and leucine methyl ester hydrochloride (2.82 g, 15.5 mmol) were dissolved in DMF (40 mL). DIPEA was added (5.40 mL, 31.0 mmol) and the reaction mixture was stirred at rt for 18 h. before being partitioned between EtOAc and 1M hydrochloric acid. The organic phase was washed sequentially with 1M hydrochloric acid and brine before being dried (MgSO4), filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica using a gradient of EtOAc and (50/70) petroleum ether to yield a white solid, 2.30 g, 64%. Rf=0.34 (1/2 EtOAc/(50/70) petroleum ether).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(OC(=O)C(F)(F)F)=O.[F:36][C:37]([F:52])([F:51])[C:38]([F:50])([F:49])[C:39]([F:48])([F:47])[C:40]([F:46])([F:45])[S:41]([OH:44])(=[O:43])=[O:42].[C:53]([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)([CH3:56])([CH3:55])[CH3:54]>>[F:52][C:37]([F:36])([F:51])[C:38]([F:49])([F:50])[C:39]([F:47])([F:48])[C:40]([F:45])([F:46])[S:41]([O-:44])(=[O:43])=[O:42].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S+:11]([C:60]2[CH:61]=[CH:62][C:57]([C:53]([CH3:56])([CH3:55])[CH3:54])=[CH:58][CH:59]=2)[C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CC(C)(C)c1ccc(S(=O)c2ccc(C(C)(C)C)cc2)cc1
Reactant: CC(C)(C)c1ccccc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(C)(C)c1ccc([S+](c2ccc(C(C)(C)C)cc2)c2ccc(C(C)(C)C)cc2)cc1
Product: O=S(=O)([O-])C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 4 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
48.18 g (0.15 mol) of bis-(4-t-butylphenyl) sulfoxide (prepared from diphenyl sulfide and t-butyl bromide via FeCl3 catalyzed alkylation and subsequent oxidation with 2-chlorobenzoic acid) was dissolved in 400 ml of 4-t-butylbenzene in a 1-liter three-neck round-bottom flask equipped with a stirrer, a thermometer, a dropping funnel, a condenser and a nitrogen inlet. The mixture was cooled to 4° C. with vigorous stirring. A solution of 63.0 g (0.30 mol) of trifluoroacetic anhydride and 45.0 g (0.15 mol) of nonafluorobutane sulfonic acid was added dropwise thereto, while the temperature was maintained under ice cooling. After completion of the addition, the mixture was stirred for 1 hour. The temperature was returned to room temperature, followed by stirring for additional 15 hours. After standing overnight, two separate phases were formed. The upper phase was removed and discarded. The oily bottom phase of approximately 150 ml volume was diluted with 800 ml of diethyl ether, and washed twice with water and a sodium bicarbonate solution. The organic phase was dried over MgSO4. After removal of the solvent, a semicrystalline solid was obtained. The semicrystalline solid was recrystallized from diethyl ether. Thus, 66.1 g (60.2%) of white crystals of tris-(4-t-butylphenyl) sulfonium nonafluorobutane sulfonate (m.p. 198-200° C.) was obtained.
Reaction SMILES: S(Cl)(Cl)=O.C(O[CH:8]([O:13][CH2:14][CH3:15])[CH2:9][C:10]([OH:12])=O)C.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([NH2:27])[CH:21]=[CH:22][C:23]=1[N+:24]([O-:26])=[O:25].N1C=CC=CC=1.Cl>ClCCl>[CH2:14]([O:13]/[CH:8]=[CH:9]/[C:10]([NH:27][C:20]1[CH:21]=[CH:22][C:23]([N+:24]([O-:26])=[O:25])=[C:18]([O:17][CH3:16])[CH:19]=1)=[O:12])[CH3:15]
Reactant: CCOC(CC(=O)O)OCC
Reactant: COc1cc(N)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCO/C=C/C(=O)Nc1ccc([N+](=O)[O-])c(OC)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 109.7 %

Procedure:
Thionyl chloride (1 mL) was added to 3,3-diethoxy-propionic acid (Eur. J. Org. Chem. 2001, 2041) (0.20 g, 1.10 mmol) and the resulting mixture was heated at 80° C. for 1 hour. The reaction mixture was then evaporated under reduced pressure and the residue was dissolved in dichloromethane (2 mL). The resulting solution was added to a mixture of 3-methoxy-4-nitro-phenylamine (0.13 g, 0.77 mmol) and pyridine (0.12 g, 1.54 mmol) in dichloromethane (5 mL) at 0° C. The reaction mixture was stirred at room temperature overnight and then the pH was then neutralized by addition of an aqueous solution of hydrochloric acid (6 M). The resulting mixture was extracted twice with ethyl acetate and the combined organic extracts were washed with water, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give 225 mg of (E)-3-ethoxy-N-(3-methoxy-4-nitro-phenyl)-acrylamide as an orange solid.
Reaction SMILES: [CH3:1][CH:2]([CH2:18][S:19][CH3:20])[C:3]([NH:5][C:6]1[S:10][C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:8][C:7]=1[CH3:17])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>O1CCOCC1>[CH3:1][CH:2]([CH2:18][S:19][CH3:20])[C:3]([NH:5][C:6]1[S:10][C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:8][C:7]=1[CH3:17])=[S:30]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CSCC(C)C(=O)Nc1sc(-c2cccnc2)nc1C
Solvent: C1COCCO1
Product: CSCC(C)C(=S)Nc1sc(-c2cccnc2)nc1C
Temperature: 130 °C

Procedure:
To a microwave reaction vessel was added 2-methyl-N-(4-methyl-2-pyridin-3-yl-thiazol-5-yl)-3-methylsulfanyl-propionamide (0.10 g, 0.32 mmol) in dioxane and Lawesson's reagent (0.19 g, 0.48 mmol). The vessel was capped and heated in a Biotage Initiator microwave reactor for 1 min at 130° C., with external IR-sensor temperature monitoring from the side. The reaction was concentrated to dryness and the crude material was purified by silica gel chromatography (0 to 100% ethyl acetate/hexanes) to give the desired product as a yellow semi solid (0.019 g, 18%): 1H NMR (300 MHz, CDCl3) δ 9.9 (m, 1H), 9.2 (d, 1H), 8.65 (d, 1H), 8.4 (m, 1H), 7.4 (m, 1H), 3.15 (m, 1H), 2.9 (m, 2H), 2.5 (s, 3H), 2.2 (s, 3H), 1.5 (d, 3H); ESIMS m/z 324.12 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([N+:16]([O-])=O)[CH:12]=3)[NH:7][C:6]=2[CH2:5][CH2:4]1.[H][H]>[Ni].C(O)C>[CH3:1][N:2]([CH3:19])[CH:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([NH2:16])[CH:12]=3)[NH:7][C:6]=2[CH2:5][CH2:4]1
Reactant: [H][H]
Reactant: CN(C)C1CCc2[nH]c3ccc([N+](=O)[O-])cc3c2C1
Agent: [Ni]
Solvent: CCO
Product: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1

Procedure:
3-(Dimethylamino)-6-amino-1,2,3,4-tetrahydrocarbazole is prepared by dissolving 0.1 mole of 3-(dimethylamino)-6-nitro-1,2,3,4-tetrahydrocarbazole (Example 10) in 400 ml. absolute ethyl alcohol and hydrogenating over Raney nickel at about 350 psig and at room temperature until the required amount of hydrogen has reacted. The resulting 3-(dimethylamino)-6-amino-1,2,3,4-tetrahydrocarbazole can be isolated and purified using conventional procedures.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[N:3]=1.[CH3:22][NH:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:11]1([CH3:14])[CH:12]=[CH:13][C:8]([C:5]2[N:6]=[CH:7][C:2]([N:23]([CH2:24][CH2:25][CH2:26][CH2:27][OH:28])[CH3:22])=[N:3][C:4]=2[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:9][CH:10]=1
Reactant: Cc1ccc(-c2ncc(Cl)nc2-c2ccc(C)cc2)cc1
Reactant: CNCCCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ncc(N(C)CCCCO)nc2-c2ccc(C)cc2)cc1
Temperature: 100 °C
Reaction time: 26 h
Yield: 75 %

Procedure:
To a solution of 3.00 g of 2-chloro-5,6-di-p-tolylpyrazine and 1.57 g of 4-(methylamino)-1-butanol in 15 ml of N,N-dimethylformamide, 2.26 g of potassium carbonate was added. After heating with stirring at 100° C. for 26 hours, the reaction solution was extracted with diethyl ether after adding ice water. The extract was washed in turn with water and saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and the resulting crystal was washed with diisopropyl ether to obtain 2.76 g of the desired compound as a colorless crystal having a melting point of 94 to 96° C.
Reaction SMILES: CCN(CC)CC.N1C=CC=CC=1.[CH2:14]([O:16][C:17]([C:19]1[NH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][C:24]([C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][N:29]=1)=[CH:23][CH:22]=2)=[O:18])[CH3:15].[CH:38]([O:41][C:42]1[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=1)([CH3:40])[CH3:39]>CC([O-])=O.CC([O-])=O.[Cu+2].C(Cl)Cl>[CH2:14]([O:16][C:17]([C:19]1[N:20]([C:45]2[CH:46]=[CH:47][C:42]([O:41][CH:38]([CH3:40])[CH3:39])=[CH:43][CH:44]=2)[C:21]2[C:26]([CH:27]=1)=[CH:25][C:24]([C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:30][N:29]=1)=[CH:23][CH:22]=2)=[O:18])[CH3:15]
Reactant: CCOC(=O)c1cc2cc(-c3ccc(C(F)(F)F)cn3)ccc2[nH]1
Reactant: CC(C)Oc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2cc(-c3ccc(C(F)(F)F)cn3)ccc2n1-c1ccc(OC(C)C)cc1
Reaction time: 30 h

Procedure:
Anhydrous CH2Cl2 (10 mL), followed by Et3N (92 μL, 0.66 mmol), pyridine (54 μL, 0.66 mmol) and 3 Å molecular sieves (1 g) were added to a mixture of 5-(5-(trifluoromethyl)pyrid-2-yl)indole-2-carboxylic acid ethyl ester (110 mg, 1.33 mmol; see step (b)), Cu(OAc)2 (120 mg, 0.66 mmol), and 4-isopropoxyphenylboronic acid (119 mg, 0.66 mmol). The mixture was stirred vigorously at ambient temperature for 18 h after which additional Cu(OAc)2 (59.9 mg, 0.33 mmol), 4-isopropoxyphenylboronic acid (59.4 mg, 0.33 mmol), Et3N (46.4 μL, 0.33 mmol) and pyridine (27 μL, 0.33 mmol) were added. After a further 30 h of stirring, the mixture was filtered through Celite®. The filter cake was washed with EtOAc and the solvents concentrated and purified by chromatography to give the sub-title compound.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:28]=[CH:27][C:15]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([CH3:26])([CH3:25])[C:22]([NH2:24])=O)=[CH:14][CH:13]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.N1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>ClCCl>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([CH3:25])([CH3:26])[C:22]#[N:24])=[CH:27][CH:28]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(C)(CCCCOc1ccc(OCCCCCn2ccnc2)cc1)C(N)=O
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C#N)CCCCOc1ccc(OCCCCCn2ccnc2)cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
To a solution of 0.97 g 6-[p-[5-(1-imidazolyl)pentyloxy]phenoxy]-2,2-dimethylhexanamide in 50 ml dichloromethane was added 0.94 ml pyridine, the solution was cooled down to -20° C., 1.57 g phosphorus pentachloride was added, and the resulting mixture was stirred to allow the temperature to rise to 15° C. over a period of about one hour. Chloroform (30 ml) and ice water (30 ml) were admixed in that order, and the organic layer was collected and washed with 5% aqueous solution of sodium bicarbonate until the pH of aqueous layer rose to 7.5 to 8.0 and then with saturated sodium chloride solution. After dehydration, the solvent was distilled off, and the residue was purified by silica gel column chromatography, affording 0.82 g of 6-[p-[5-(1-imidazolyl) pentyloxy]phenoxy]-2,2-dimethylhexane-nitrile.
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][C:21]3[CH:24]=[CH:25][S:26][C:20]=3[CH:19]=2)=[CH:8]1)(C)(C)C.Cl.[Cl:28][CH2:29][CH2:30][N:31]1[CH2:36][CH:35]([CH3:37])[O:34][CH:33]([CH3:38])[CH2:32]1>>[ClH:28].[CH3:38][CH:33]1[O:34][CH:35]([CH3:37])[CH2:36][N:31]([CH2:30][CH2:29][O:17][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][C:21]4[CH:24]=[CH:25][S:26][C:20]=4[CH:19]=2)=[CH:8][C:7]3=[N:6][OH:5])[CH2:32]1
Reactant: CC1CN(CCCl)CC(C)O1
Reactant: CC(C)(C)ON=c1cc(-c2cc3sccc3cn2)oc2ccc(O)cc12
Agent: Cl
Product: CC1CN(CCOc2ccc3oc(-c4cc5sccc5cn4)cc(=NO)c3c2)CC(C)O1

Procedure:
6-[2-(2,6-Dimethyl-morpholin-4-yl)-ethoxy]-2-thieno[3,2-c]pyridin-6-yl-chromen-4-one oxime, hydrochloride was prepared in 48% overall yield using the method described in example 127, starting from 6-Hydroxy-2-thieno[3,2-c]pyridin-6-yl-chromen-4-one O-tert-butyl-oxime (example 127B) and 4-(2-Chloro-ethyl)-2,6-dimethyl-morpholine hydrochloride (JACS 1949, 500-505; US2006/14948).