Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:7]=[N:8][OH:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:10].OOS([O-])=O.[K+]>CN(C=O)C>[Cl:10][O:9][N:8]=[CH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cl
Reactant: ON=CC1CCCCC1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: ClON=CC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the oxime formed in Example 1 (1 g, 8.25 mmol) in HCl (0.5 M in dioxane; 18.16 ml, 9.08 mmol) and DMF (40 ml) was added oxone (2.79 g, 4.54 mmol) and the resulting mixture was stirred overnight at room temperature. The reaction was partitioned between diethylether and water and the layers were separated. The organic layer was washed with saturated ammonium chloride, dried over sodium sulfate, then concentrates in vacuo using a room temperature water bath. The resulting low boiling liquid was carried on directly to the next step. 1H NMR (CDCl3) δ 1.0-2.2 (m, 10H), 2.35 (m, 1H), 7.8 (bd, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=1[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19].[CH:22]1([CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38]O)[CH:33]=2)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:24][CH2:23]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C1(C)C=CC=CC=1>[CH:22]1([CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][O:16][C:13]3[CH:14]=[CH:15][C:10]([C:3]4[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=4[F:1])=[C:11]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=3)[CH:33]=2)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:24][CH2:23]1
Reactant: COc1ccc(F)c(-c2ccc(O)cc2CC(C)(C)C)c1
Reactant: CCOC(=O)CC(c1cccc(CO)c1)C1CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(c1cccc(COc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 56.9 %

Procedure:
To a solution of 2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-ol (388 mg), ethyl 3-cyclopropyl-3-(3-(hydroxymethyl)phenyl)propanoate (261 mg) and triphenylphosphine (413 mg) in THF (10 mL) was added a 40% solution of diethyl azodicarboxylate in toluene (620 μL) at 0° C., and the mixture was stirred at room temperature for 70 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (310 mg) as a pale-yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([N:13]3[CH2:18][CH2:17][N:16]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH2:15][CH2:14]3)[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.Br[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:36]=1[N:35]=[CH:34][CH:33]=[CH:32]2.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([N:13]3[CH2:14][CH2:15][N:16]([CH:19]4[CH2:24][CH2:23][N:22]([CH2:26][C:27]5[CH:28]=[CH:29][CH:30]=[C:31]6[C:36]=5[N:35]=[CH:34][CH:33]=[CH:32]6)[CH2:21][CH2:20]4)[CH2:17][CH2:18]3)[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2
Reactant: BrCc1cccc2cccnc12
Reactant: COc1cc(N2CCN(C3CCNCC3)CC2)c2ncccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cc(N2CCN(C3CCN(Cc4cccc5cccnc45)CC3)CC2)c2ncccc2c1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
To a mixture of 6-methoxy-8-(4-piperidin-4-ylpiperazin-1-yl)quinoline (Step 2, 0.06 g) and 8-(bromo)methylquinoline (commercially available, 0.055 g) in anhydrous dimethylsulfoxide (5 mL) was added anhydrous K2CO3 (0.051 g). The resulting mixture was stirred at 70° C. for 18 hours. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was washed with water and brine and was then dried over anhydrous Na2SO4, filtered and concentrated on a rotary evaporator to give the desired product, which was converted to its dihydrochloride salt in CH2Cl2 using 1N HCl/Et2O to give 0.31 g of a light yellow solid; MS (ES) m/z (relative intensity); 468 (M+H)+ (100).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]2[C:17]3[C:12](=[CH:13][C:14]([NH2:18])=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.I.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](SC)=[NH:26].ClCCl>C(O)C.C(=O)(O)[O-].[Na+]>[N:1]1([CH2:7][CH2:8][N:9]2[C:17]3[C:12](=[CH:13][C:14]([NH:18][C:25]([C:21]4[S:20][CH:24]=[CH:23][CH:22]=4)=[NH:26])=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CSC(=N)c1cccs1
Reactant: Nc1ccc2c(ccn2CCN2CCCCC2)c1
Agent: I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: N=C(Nc1ccc2c(ccn2CCN2CCCCC2)c1)c1cccs1
Reaction time: 3 h
Yield: 44.9 %

Procedure:
A solution of compound 95 (0.200 mg, 0.822 mmol) in absolute ethanol (3 mL) was treated with methyl thiophene-2-carbimidothioate hydroiodide (0.350 g, 1.23 mmol) at room temperature and the resulting mixture was stirred for 3 hours. The reaction was diluted with saturated aqueous sodium bicarbonate (5 mL) followed by dichloromethane (30 mL) and transferred to a separatory funnel. The aqueous was extracted twice more with dichloromethane (2×30 mL). The combined organics were washed with brine and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2M ammonia in methanol:dichloromethane, 5:95) to obtain compound 96 (130 mg, 45%) as a yellow oil. 1H NMR (CDCl3) δ 7.43 (d, J=2.7 Hz, 1H), 7.41 (s, 1H), 7.34 (d, J=8.7 Hz, 1H), 7.21 (d, J=1.2 Hz, 1H), 7.14 (d, J=3.0 Hz, 1H), 7.08 (t, J=4.2 Hz, 1H), 6.67 (dd, J=1.8, 8.7 Hz, 1H), 6.42 (d, J=3.0 Hz, 1H), 4.24 (t, J=7.5 Hz, 2H), 2.73 (t, J=7.5 Hz, 2H), 2.47 (m, 4H), 1.61 (m, 4H); ESI-MS (m/z, %): 353 (M+1); ESI-HRMS calculated for C20H25N4S (MH+): 353.1794, Observed: 353.1796.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][CH2:7][NH:8][C:9]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])C.C(O)(=O)C.Cl>C(O)C>[O:3]=[CH:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10]
Reactant: CCOC(CCCNC(=O)C1CCCCC1)OCC
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: O=CCCCNC(=O)C1CCCCC1
Reaction time: 16 h

Procedure:
1.09 g (4 mmol) 20A, 5 mL acetic acid, 2.5 mL 1N aqueous hydrochloric acid and 20 mL ethanol are put together and stirred for 16 hours under argon atmosphere. Ethanol is evaporated. Then the resulting residue is dispersed in dichloromethane and extracted with saturated sodium bicarbonate solution. The organic phase is dried with sodium sulfate and the solvent evaporated in vacuum. The crude product is obtained in almost quantitative yield.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].[F:23][C:24]([F:37])([F:36])[O:25][C:26]1[CH:35]=[CH:34][C:29]([C:30](=O)[CH2:31]Br)=[CH:28][CH:27]=1>>[N+:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:6]1[C:5]([C:3]([OH:2])=[O:4])=[CH:10][C:9]([C:11]2[S:13][CH:31]=[C:30]([C:29]3[CH:28]=[CH:27][C:26]([O:25][C:24]([F:23])([F:36])[F:37])=[CH:35][CH:34]=3)[N:12]=2)=[CH:8][CH:7]=1)([O-:22])=[O:21]
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Reactant: O=C(CBr)c1ccc(OC(F)(F)F)cc1
Product: O=C(O)c1cc(-c2nc(-c3ccc(OC(F)(F)F)cc3)cs2)ccc1-c1ccccc1[N+](=O)[O-]
Yield: 62 %

Procedure:
2′-Nitro-4-[4-(4-trifluoromethoxy-phenyl)-thiazol-2-yl]-biphenyl-2-carboxylic acid (190 mg, 62%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 4-(trifluoromethoxy)phenacyl bromide (available from Matrix Scientific) using the procedure described for the preparation of Example 1. 1H NMR (300 MHz, DMSO-d6) δ 13.17 (s, 1H), 8.58 (d, J=2.0 Hz, 1H), 8.13-8.28 (m, 4H), 7.63-7.82 (m, 2H), 7.41-7.51 (m, 4H).
Reaction SMILES: [CH:1]1[C:6]2[C:7]([C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=3)=[N:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].[C:29](=O)(O)[O-].[Na+]>C(O)=O.O>[CH3:29][N:8]1[CH:7]([C:16]2[CH:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=2)[C:6]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[O:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]1=2
Reactant: O=C([O-])O
Reactant: CCOC(=O)c1ccc(C2=Nc3ccccc3Oc3ccccc32)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: CCOC(=O)c1ccc(C2c3ccccc3Oc3ccccc3N2C)cc1
Temperature: 4 °C
Reaction time: 1.5 h
Yield: 77 %

Procedure:
Title compound 4 (0.508 g, 1.48 mmol) was dissolved in formic acid (5.0 mL) and the mixture was cooled at 4° C. Sodium borohydride (0.502 g) was added and the reaction mixture was stirred at room temperature for 90 min. The mixture was diluted in water (50 mL) and solid sodium bicarbonate was added until alkaline (pH=8-9). This mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over sodium sulfate and evaporated. The crude was purified by flash chromatography with 10% ethyl acetate in hexanes to afford title compound 7 (408 mg, 77%) as a colorless oil. LRMS (ESI): (calc) 359.15 (found) 360.3 (MH)+.
Reaction SMILES: CN(C)C1C=CC=CC=1.[C:10]([CH:12]=[C:13]1[C:19]2=[CH:20][S:21][CH:22]=[C:18]2[C:17](=O)[NH:16][C:15]2=[CH:24][S:25][CH:26]=[C:14]12)#[N:11].P(Cl)(Cl)([Cl:29])=O>>[Cl:29][C:17]1[C:18]2[C:19](=[CH:20][S:21][CH:22]=2)[C:13](=[CH:12][C:10]#[N:11])[C:14]2[C:15](=[CH:24][S:25][CH:26]=2)[N:16]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#CC=C1c2cscc2NC(=O)c2cscc21
Solvent: CN(C)c1ccccc1
Product: N#CC=C1c2cscc2N=C(Cl)c2cscc21
Yield: 96 %

Procedure:
140 ml of phosphorus oxychloride and 1.5 ml of N,N-dimethylaniline are added to 14.0 g (54 mmoles) of 9-cyanomethylene-4,5-dihydro-dithieno[3,4-b:4',3'-e]azepin-5-one (cis/trans-isomer mixture) and the mixture is refluxed under nitrogen for 1 hour. After all the excess phosphorus oxychloride and dimethylaniline have been distilled off under reduced pressure from an oil pump, the residue is partitioned between methylene chloride and water, the aqueous phase is extracted twice more with methylene chloride and the combined organic phases are washed thoroughly with dilute HCl and water. Drying and concentrating the organic phase gives 14.4 g (96%) of 5-chloro-9-cyanomethylene-dithieno[3,4-b:4',3'-e]azepine, which is sufficiently pure for the further reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12](O)=[O:13].C([O-])(=O)C.[NH4+:23]>>[Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH2:23])=[O:13]
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1Cl
Reactant: [NH4+]
Agent: CC(=O)[O-]
Product: NC(=O)c1ccncc1Nc1ccc(I)cc1Cl

Procedure:
3-[(2-chloro-4-iodophenyl)amino]isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 6 mmol of 3-[(2-chloro-4-iodophenyl)amino]isonicotinic acid (intermediate 2) and 12 mmol of ammonium acetate. LC/MS [8.29 min; 374 (M+1)]
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.F[C:21]1[C:26]([F:27])=[C:25]([F:28])[CH:24]=[CH:23][C:22]=1[N+:29]([O-:31])=[O:30]>C1COCC1>[F:27][C:26]1[C:25]([F:28])=[CH:24][CH:23]=[C:22]([N+:29]([O-:31])=[O:30])[C:21]=1[NH:4][C:3]1[CH:5]=[CH:6][C:7]([I:9])=[CH:8][C:2]=1[F:1]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Reactant: Nc1ccc(I)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 2-fluoro-4-iodoaniline (11.40 g, 47 mmol) in 100 ml anhydrous THF at 0° C., 47 ml of a 1M solution of LHMDS in THF (47 mmol) was added dropwise. The color of the solution turned dark purple. The solution was transferred via cannula to a dropping funnel, and the solution (containing the amine free base) was added in small portions to a solution of 2,3,4-trifluoronitrobenzene (8.321 g, 47.0 mmol) in anhydrous THF (50 ml) at 0° C. After completion of addition the mixture was stirred under argon at room temperature for 15 hours. The volume of the solvent was reduced, followed by extraction using ethyl acetate and brine. The organic layer was dried over sodium sulfate, the solvent was removed, and the obtained dark oil was purified by flash chromatography (EtOAc/hexane 1:5, Rf=0.58) yielding the crude product, which became a brown solid upon drying in vacuo (yield: 6.23 g, 33.6%); m/z=393 [M−1]−.
Reaction SMILES: Br[CH:2]1[C:10]2[C:5](=[CH:6][C:7]([F:11])=[CH:8][CH:9]=2)[C:4](=[O:12])[CH2:3]1.C(COC)[O:14]C>O.C(=O)([O-])[O-].[Ag+2]>[OH:14][CH:2]1[C:10]2[C:5](=[CH:6][C:7]([F:11])=[CH:8][CH:9]=2)[C:4](=[O:12])[CH2:3]1
Reactant: COCCOC
Reactant: O=C1CC(Br)c2ccc(F)cc21
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: O
Product: O=C1CC(O)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-bromo-6-fluoro-1-indanone (2.50 g, 10.0 mmoles) and silver carbonate (4.19 g, 15.2 mmoles, Aldrich) in dimethoxyethane (85 mL) and water (65 mL) was stirred overnight at ambient temperature. The mixture was filtered through a pad of celite, and the filtrate was diluted with water (500 mL) and extracted with ethyl acetate (4×100 mL). The combined extracts were washed with water (100 mL) and brine (75 mL), dried over sodium sulfate, filtered, and evaporated in vacuo to give 2.80 g (quantitative) of crude 3-hydroxy-6-fluoro-1-indanone which was used without further purification. Chromatography of 0.41 g on silica gel, eluting with hexane: ethyl acetate (3:4) gave 0.050 g of analytically pure 3-hydroxy-6-fluoro-1-indanone as a tan solid, mp 73°-76° C.;
Reaction SMILES: [C:1]([NH:9][C:10]1[C:11]2[N:12]=[CH:13][N:14]([C:24]=2[N:25]=[CH:26][N:27]=1)[C@@H:15]1[O:23][C@H:20]([CH2:21][OH:22])[C@@H:18]([OH:19])[C@H:16]1[OH:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28](Cl)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(Cl)(Cl)Cl>N1C=CC=CC=1>[C:1]([NH:9][C:10]1[C:11]2[N:12]=[CH:13][N:14]([C:24]=2[N:25]=[CH:26][N:27]=1)[C@@H:15]1[O:23][C@H:20]([CH:21]([C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[OH:22])[C@@H:18]([OH:19])[C@H:16]1[OH:17])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O)c1ccccc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=C(Nc1ncnc2c1ncn2[C@@H]1O[C@H](C(O)C(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H](O)[C@H]1O)c1ccccc1

Procedure:
Compounds 6 and 7 are prepared by treating N6 -benzoyl adenosine with tritylchloride in pyridine and refluxing for 2 hours. N6 -benzoyl-5'-trityladenosine is isolated by extraction with chloroform. The water from the chloroform phase is removed by drying with sodium sulfate N6 -benzoyl-2',5'-di-O-trityladenosine and N6 -benzoyl-3',5'-di-O-trityladenosine are isolated by preparative silica gel thin layer chromatography in chloroform/ethanol. Compounds 6 and 7 are prepared by treating the isolated compounds with n-pentylchloride and n-heptylchloride, respectively, under reflux in a suspension of sodium hydroxide in benzene. The solution is neutralized by refluxing in acetic acid followed by the addition of diethyl ether and water. The reaction products are extracted with chloroform followed by thin layer chromatography with chloroform:methanol (4:1) on silica gel plates. The trityl and benzoyl groups are removed by refluxing in acetic acid for one hour, cooling, extraction with diethyl ether, followed by concentration and cooling to yield crystalline compounds 6 and 7. This method of preparation is carried out according to Blank, H. U., Franne, D., Myles, A. and Pfleiderer, W., Justus Liebigs Ann. Chem. 742, 34 (1970), which is incorporated herein by reference.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].CC1(C)C(C)(C)OB([C:29]2[CH:37]=[C:36]3[C:32]([CH2:33][NH:34][C:35]3=[O:38])=[CH:31][CH:30]=2)O1>>[O:38]=[C:35]1[C:36]2[C:32](=[CH:31][CH:30]=[C:29]([C:2]3[CH:3]=[CH:4][N:5]4[C:10]([C:11]=3[CH3:12])=[C:9]([CH:13]3[CH2:15][CH2:14]3)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]4=[O:20])[CH:37]=2)[CH2:33][NH:34]1
Reactant: CC1(C)OB(c2ccc3c(c2)C(=O)NC3)OC1(C)C
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc4c(c3)C(=O)NC4)ccn2c1=O
Yield: 87.8 %

Procedure:
Methyl 8-(3-oxoisoindolin-5-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (106.5 mg, 0.41 mmol). The precipitate was rinsed with DCM and dried in a vacuum stove to afford the title compound as a yellow solid (116 mg, 87%).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[S:10][C:11]([CH3:17])=[C:12]([CH3:16])[C:13]=1[C:14]#[N:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]([N:26]=[C:27]=[S:28])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:1]([N:8]([C:9]1[S:10][C:11]([CH3:17])=[C:12]([CH3:16])[C:13]=1[C:14]#[N:15])[C:27]([NH:26][C:18](=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[S:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Cc1sc(NCc2ccccc2)c(C#N)c1C
Product: Cc1sc(N(Cc2ccccc2)C(=S)NC(=O)c2ccccc2)c(C#N)c1C

Procedure:
Prepared as in Example 1a from 2-(benzylamino)-4,5-dimethylthiophene-3-carbonitrile (Example 20b) and benzoyl isothiocyanate. MS 406 (MH+).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([OH:15])=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[N:10][CH:9]=[CH:8]2)=O.[NH3:16]>>[OH:15][C:6]1[C:5]([C:3]([NH2:16])=[O:2])=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][N:10]=[CH:11]2
Reactant: N
Reactant: COC(=O)c1ccc2cnccc2c1O
Product: NC(=O)c1ccc2cnccc2c1O

Procedure:
5-Hydroxy-6-isoquinolinecarboxylic acid methyl ester as reported by Dyke, S. F. et al., in Tetrahedron 1973, 29(6), 857-62, is reacted with excess ammonia in a steel bomb for 12-18 hr. The excess ammonia is allowed to evaporate and the residue is crystallized from a suitable solvent mix such as ethyl acetate-toluene to give the title compound.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[CH:31]=[N:30][CH:29]=[CH:28][N:27]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[CH:31]=[N:30][CH:29]=[CH:28][N:27]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Reactant: Clc1cnccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4cnccn4)cc3CC[C@@H]12
Yield: 48.8 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloropyrazine (53 mg, 0.46 mmol) and 1 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (80%ethyl acetate/hexanes eluent) to give 63 mg (49%) of the title compound as an off white solid. mp 94°-95°. FDMS: m/e=339. α[D]589 =+88.14 (c=0.92, chloroform).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].[CH3:13][C:14]1[C:15](B(O)O)=[CH:16][S:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[C:15]1[C:14]([CH3:13])=[CH:18][S:17][CH:16]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(Br)c(C)c1
Reactant: Cc1cscc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2cscc2C)c(C)c1
Yield: 91.7 %

Procedure:
A suspension of methyl 4-bromo-3-methylbenzoate (ABCR AV19078; 3 g; 13.10 mmol; 1 eq.), 4-methyl-3-thiopheneboronic acid (Aldrich 542393; 2.05 g; 14.41 mmol; 1.10 eq.), potassium carbonate (9.05 g; 65.48 mmol; 5 eq.) and tetrakis(triphenylphosphine)palladium(0) (1.51 g; 1.31 mmol; 0.10 eq.) in toluene (15 mL) and water (15 mL) was refluxed for 3 hours. The resulting mixture was filtered through a short pad of Celite, which was further washed with toluene. After evaporation of the solvent, the residue taken up in ethyl acetate and washed successively with sat. aq. NaHCO3, water and brine, dried over magnesium sulfate and concentrated in vacuo to afford the title compound (2.96 g, 92%) as a brown oil.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[NH:18][C:17]2[C:16](=[O:19])[N:14]([CH3:15])[C:13](=[O:20])[N:12]([CH3:21])[C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([CH:24]([C:28](Cl)=[O:29])[C:25](Cl)=[O:26])C>O1CCOCC1.C(#N)C>[CH2:1]([N:8]1[C:9]2=[N:10][C:11]3[N:12]([CH3:21])[C:13](=[O:20])[N:14]([CH3:15])[C:16](=[O:19])[C:17]=3[N:18]2[C:28]([OH:29])=[CH:24][C:25]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(=O)c2[nH]c(NCc3ccccc3)nc2n(C)c1=O
Reactant: CCC(C(=O)Cl)C(=O)Cl
Solvent: C1COCCO1
Solvent: CC#N
Product: Cn1c(=O)c2c(nc3n(Cc4ccccc4)c(=O)cc(O)n23)n(C)c1=O
Temperature: 25 °C

Procedure:
Add 8-benzylaminotheophylline (30 g) and ethyl malonyl chloride (35.1 gm) to 600 ml of 1:1 dioxan/acetonitrile. Heat the reaction mixture to reflux under a nitrogen atmosphere until the 8-benzylaminotheophylline is consumed (ca. 3.5 hrs.). Cool the reaction mixture to room temperature and pour the solution into 800 ml of ether. Filter off the precipitate. Wash the precipitate with ether and dry the product to obtain the title compound, mp 205.5°-209° C.
Reaction SMILES: [C:1]([O:9]/[C:10](/[C:32]([O:34][CH3:35])=[O:33])=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[C:14]([CH3:26])[C:13]=1[CH2:27][O:28][C:29](=[O:31])[CH3:30])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>ClCCl>[C:1]([O:9][C@H:10]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20])=[C:14]([CH3:26])[C:13]=1[CH2:27][O:28][C:29](=[O:31])[CH3:30])[C:32]([O:34][CH3:35])=[O:33])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: COC(=O)/C(=C/c1ccc(NC(=O)OC(C)(C)C)c(C)c1COC(C)=O)OC(=O)c1ccccc1
Solvent: ClCCl
Product: COC(=O)[C@@H](Cc1ccc(NC(=O)OC(C)(C)C)c(C)c1COC(C)=O)OC(=O)c1ccccc1

Procedure:
(Z)-1-(2-(acetoxymethyl)-4-(tert-butoxycarbonylamino)-3-methylphenyl)-3-methoxy-3-oxoprop-1-en-2-yl benzoate (20.00 g, 41.4 mmol) in dichloromethane (120.00 ml) was added (−)-1,2-bis((2R,5R)-2,5-diethylphospholano)benzene(cyclooctadiene)rhodium (I) tetrafluoroborate (280.00 mg, 0.424 mmol) under nitrogen atmosphere. The reaction mixture was hydrogenated at 60 psi pressure of hydrogen for 12 h. The solvent was removed and crude product was carried to the next step as such. MS (ESI) 508 (M+H); Rf=2.53.