Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:9]2[N:13]([CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[C:12](=[O:22])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.C(=O)(O)[O-].[Na+]>Br>[OH:2][C:3]1[CH:4]=[C:5]([CH:9]2[N:13]([CH2:14][CH2:15][N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)[C:12](=[O:22])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C2CCC(=O)N2CCN2CCOCC2)c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C1CCC(c2cccc(O)c2)N1CCN1CCOCC1
Temperature: 100 °C
Yield: 27 %

Procedure:
5-(3-Methoxyphenyl)-1-[2-(4-morpholinyl)ethyl]-2-pyrrolidinone (12.8 g) was dissolved, in 48% hydrobromic acid (100 ml) and warmed at 100° C. for 4.5 hrs. The reaction mixture was cooled to ambient temperature, neutralized with saturated sodium bicarbonate solution, and the mixture was extracted with dichloromethane (6 times). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by flash column chromatography (silica gel, ether). The appropriate fractions were collected and concentrated to give 3.3 g (55%) of 5-(3-hydroxyphenyl)-1-[2-(4-morpholinyl)ethyl]-2-pyrrolidinone.
Reaction SMILES: [N:1]1([NH2:7])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:8][O:9][C:10]([C:12]1[CH:13]=[C:14]([CH3:34])[C:15]2[O:21][C:20]3[C:22]([Cl:30])=[CH:23][C:24]([NH:26][CH2:27][CH2:28]Cl)=[CH:25][C:19]=3[CH2:18][S:17](=[O:32])(=[O:31])[C:16]=2[CH:33]=1)=[O:11].O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[CH3:8][O:9][C:10]([C:12]1[CH:13]=[C:14]([CH3:34])[C:15]2[O:21][C:20]3[C:22]([Cl:30])=[CH:23][C:24]([NH:26][CH2:27][CH2:28][NH:7][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:25][C:19]=3[CH2:18][S:17](=[O:31])(=[O:32])[C:16]=2[CH:33]=1)=[O:11]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCCl)cc(Cl)c1O2
Reactant: NN1CCOCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCNN3CCOCC3)cc(Cl)c1O2
Temperature: 120 °C
Reaction time: 5.5 h

Procedure:
Morpholin-4-ylamine (0.1 mL, 1.16 mmol) and tetrabutylammonium iodide (0.075 g, 0.2 mmol) were sequentially added with stirring to a solution of the carboxylic acid of Example 56k (0.250 g, 0.59 mmol) in dry DMF (4 mL). The reaction mixture was then stirred at 120° C. for 5.5 h in an atmosphere of nitrogen. It was treated with cold water and the solid that precipitated was filtered, washed with water, and dried. The solid was treated with a methanolic HCl solution and refluxed at 70° C. for 3 h. The solution was concentrated and treated with an aqueous sodium bicarbonate solution. The solid that precipitated was filtered, washed with water, dried and purified using flash chromatography (silica gel, 2% methanol/chloroform) to obtain the title compound. Yield: 0.105 g, (36.45%). 1H NMR (DMSO-d6): δ 2.50-2.60 (m, 4H, 2CH2), 2.70 (s, 3H, CH3), 2.80 (t, 2H, CH2), 2.80 (t, 2H, CH2), 3.62-3.70 (m, 4H, 2CH2), 3.90 (s, 3H, OCH3), 5.20 (s, 2H, CH2), 6.20 (t, 1H, NH), 6.85 (s, 2H, 2Ar), 8.15 (s, 1H, Ar), 8.25 (s, 1H, Ar); MS: m/e (CI+) 496 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C:5]2=[O:23].[CH3:24][S:25](Cl)(=[O:27])=[O:26]>N1C=CC=CC=1>[CH3:24][S:25]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14])[C:5]2=[O:23])(=[O:27])=[O:26]
Reactant: Nc1ccc2c(c1)C(=O)N(CC(=O)OCc1ccccc1)C2=O
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc2c(c1)C(=O)N(CC(=O)OCc1ccccc1)C2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.9 %

Procedure:
To a solution of benzyl 2-(5-amino-1,3-dioxoisoindolin-2-yl)acetate (1.0 g, 3.22 mmol) in pyridine (8 ml) cooled to 0° C., methanesulfonyl chloride (0.377 ml, 4.83 mmol) was added drop wise, and the resulting mixture was stirred at room temperature for 3 hours. The solvent was removed under vacuum and the residue was partitioned between 2N HCl and DCM; the aqueous phase was extracted with DCM and the combined organic layers were dried over Na2SO4 and evaporated to dryness. The crude was triturated with Et2O (15 ml) to give benzyl 2-(5-(methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetate (1.1 g, 2.83 mmol, 88% yield, MS/ESI+ 388.8 [MH]+).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:14]([OH:16])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.N[C@@H](C(O)=O)CC1C2C(=CC=CC=2)NC=1.C([S:40][C@H:41]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:42](O)=[O:43])(=O)C1C=CC=CC=1.C(S[C@@H](CC1C=CC=CC=1)C(O)=O)(=O)C1C=CC=CC=1>>[SH:40][CH:41]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:42]([NH:2][C@H:3]([C:14]([OH:16])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:43]
Reactant: O=C(S[C@H](Cc1ccccc1)C(=O)O)c1ccccc1
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: Cl
Agent: N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: O=C(S[C@@H](Cc1ccccc1)C(=O)O)c1ccccc1
Product: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)C(S)Cc1ccccc1

Procedure:
The operation is carried out as in Stage 1 of Example 24 using, instead of the hydrochloride of the methyl ester of L-Tryptophan, the hydrochloride of the methyl ester of D-Tryptophan and, instead of (R)-2-(benzoylthio)-3-phenylpropanoic acid, (S)-2-(benzoylthio)-3-phenylpropanoic acid (prepared according the same reference). After purification by chromatography on silica with a methylene chloride-ethyl acetate: 95-5 mixture as eluant, 564 mg of expected product (SR isomer) (colourless foam) is obtained.
Reaction SMILES: CS(O[CH2:6][CH:7]([N:9]1[C:22]2[CH:21]=[C:20]([C:23]#[N:24])[CH:19]=[CH:18][C:17]=2[S:16][C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH3:8])(=O)=O.[CH3:25][CH:26]1[CH2:30][CH2:29][CH2:28][NH:27]1>C1(C)C=CC=CC=1>[CH3:25][CH:26]1[CH2:30][CH2:29][CH2:28][N:27]1[CH2:6][CH:7]([N:9]1[C:22]2[CH:21]=[C:20]([C:23]#[N:24])[CH:19]=[CH:18][C:17]=2[S:16][C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH3:8]
Reactant: CC(COS(C)(=O)=O)N1c2ccccc2Sc2ccc(C#N)cc21
Reactant: CC1CCCN1
Solvent: Cc1ccccc1
Product: CC1CCCN1CC(C)N1c2ccccc2Sc2ccc(C#N)cc21
Temperature: 100 °C
Reaction time: 48 h

Procedure:
A solution of D series 2-(2-cyano-10-phenothiazinyl)-propyl methanesulphonate (6.8 g) in toluene (80 cc) and (2RS)-2-methylpyrrolidine (3.5 cc) is heated with stirring at 100° C. for 48 hours. After cooling to 25° C., the mixture is transferred into a separating funnel where it is washed with distilled water (2×200 cc) and brine (50 cc). The organic phase is dried over magnesium sulphate and filtered, and the filtrate is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) to give a residue which is purified by chromatography on a column (height: 35 cm; diameter: 3.2 cm) of silica (0.2-0.06 mm), eluting with a mixture of cyclohexane and ethyl acetate 70-30 (by volume) (1 liter), collecting fractions of 60 cc. Fractions 11 to 14 are pooled and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) to give 10-{1-[(2RS)-2-methyl-1-pyrrolidinyl]-2-propyl}-2-phenothiazinecarbonitrile, D series (0.5 g), in the form of a yellow oil.
Reaction SMILES: [C:1]1([CH2:7][O:8][CH:9]([C:27]([F:30])([F:29])[F:28])[CH2:10][CH:11]2[CH2:16][CH2:15][C:14]3[CH:17]=[C:18]([NH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:19]=[CH:20][C:13]=3[O:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:37][O:38][CH2:39][C@H]1COC(=O)O1>CN(C)C=O.O>[C:1]1([CH2:7][O:8][CH:9]([C:27]([F:30])([F:28])[F:29])[CH2:10][CH:11]2[CH2:16][CH2:15][C:14]3[CH:17]=[C:18]([N:21]4[CH2:26][C@H:25]([CH2:37][O:38][CH3:39])[O:24][C:22]4=[O:23])[CH:19]=[CH:20][C:13]=3[O:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)Nc1ccc2c(c1)CCC(CC(OCc1ccccc1)C(F)(F)F)O2
Reactant: COC[C@H]1COC(=O)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC[C@H]1CN(c2ccc3c(c2)CCC(CC(OCc2ccccc2)C(F)(F)F)O3)C(=O)O1

Procedure:
A solution of 4.2 g (9.9 mmol) of 2-(2-phenylmethoxy-3,3,3-trifluoropropyl)-6-ethoxycarbonylamino-3,4-dihydro-2H-1-benzopyran in 40 ml of dimethylformamide is stirred for 24 hours, at 130° C., in the presence of 140 mg (1.0 mmol) of potassium carbonate and of 3.4 g (26 mmol) of 4(S)-methoxymethyl-1,3-dioxolan-2-one added in 3 hours. The mixture is cooled, diluted with water and the product is extracted with diethyl ether. The organic phase is then dried over sodium sulfate, concentrated under reduced pressure and chromatographed on a silica column using a 30/70 mixture of ethyl acetate and cyclohexane. The product obtained is used as such in the following step.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C@@H:28]([NH2:30])[CH3:29])=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C>>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C@@H:28]([NH:30][C:3]2[S:4]/[C:5](=[CH:9]\[C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][CH:14]=[CH:13]4)/[C:6](=[O:8])[N:7]=2)[CH3:29])=[CH:24][CH:23]=1
Reactant: COc1ccc([C@H](C)N)cc1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc([C@H](C)NC2=NC(=O)/C(=C/c3ccc4ncccc4c3)S2)cc1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, 1-(S)-(4-methoxy-phenyl)-ethylamine and DIEA to give 2-[(S)-1-(4-methoxy-phenyl)-ethylamino]-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 390 (MH+).
Reaction SMILES: Cl.[CH:2]([C:5]1[S:9][C:8]([NH:10][S:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[CH2:19][CH:18]([NH2:23])[CH2:17]3)(=[O:13])=[O:12])=[N:7][N:6]=1)([CH3:4])[CH3:3].CN(C)C=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:53]([O:55][C:56]1[CH:64]=[C:63]([C:65]([F:68])([F:67])[F:66])[CH:62]=[CH:61][C:57]=1[C:58](O)=[O:59])[CH3:54]>C(N(CC)CC)C>[CH2:53]([O:55][C:56]1[CH:64]=[C:63]([C:65]([F:66])([F:67])[F:68])[CH:62]=[CH:61][C:57]=1[C:58]([NH:23][CH:18]1[CH2:17][C:16]2[C:20](=[CH:21][CH:22]=[C:14]([S:11](=[O:13])(=[O:12])[NH:10][C:8]3[S:9][C:5]([CH:2]([CH3:4])[CH3:3])=[N:6][N:7]=3)[CH:15]=2)[CH2:19]1)=[O:59])[CH3:54]
Reactant: CC(C)c1nnc(NS(=O)(=O)c2ccc3c(c2)CC(N)C3)s1
Reactant: CCOc1cc(C(F)(F)F)ccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1cc(C(F)(F)F)ccc1C(=O)NC1Cc2ccc(S(=O)(=O)Nc3nnc(C(C)C)s3)cc2C1
Temperature: 25 °C

Procedure:
The mixture of 2-amino-indan-5-sulfonic acid (5-isopropyl-[1,3,4]thiadiazol-2-yl)-amide hydrochloride (40 mg), 1.5 ml of dimethyl formamide, 0.037 ml of triethylamine, 41 mg of HATU and 25 mg of 2-ethoxi-4-trifluoromethyl-benzoic acid was stirred at room temperature over night. The solvents were evaporated in vacuo and the resulting crude material was purified by column chromatography (silica gel, eluent: dichloromethane:methanol=95:5).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[N+:20]([C:23]1[S:27][C:26]([CH:28]=O)=[CH:25][CH:24]=1)([O-:22])=[O:21].OS(O)(=O)=O>CC(O)=O.O>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[C:14](=[CH:28][C:26]2[S:27][C:23]([N+:20]([O-:22])=[O:21])=[CH:24][CH:25]=2)[CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C1C(=Cc2ccc([N+](=O)[O-])s2)CCc2cc(OCCn3ccnc3)ccc21
Yield: 96 %

Procedure:
6-(2-Imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.200 g, 0.78 mmol) was reacted with 5-nitrothiophene-2-carboxaldehyde (0.123 g, 0.78 mmol) in a mixture of HOAc (1 mL) and concentrated H2SO4 (0.100 mL) at room temperature overnight. The reaction was diluted with water, and the resulting precipitate was collected, washed well with water, and dried in vacuo at 60° C. to afford 0.296 g (80%) of the title compound as a brown powder, mp >240° C.: APCI-MS m/e 396.1 M++1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:9]=1[CH:17]1[CH2:22][CH2:21][S:20](=[O:24])(=[O:23])[NH:19][CH2:18]1.[CH2:25](Br)[CH:26]=[CH2:27]>C(#N)C>[F:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:9]=1[CH:17]1[CH2:22][CH2:21][S:20](=[O:24])(=[O:23])[N:19]([CH2:27][CH:26]=[CH2:25])[CH2:18]1
Reactant: C=CCBr
Reactant: O=[N+]([O-])c1ccc(C2CCS(=O)(=O)NC2)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCN1CC(c2ccc([N+](=O)[O-])cc2F)CCS1(=O)=O

Procedure:
Anhydrous potassium carbonate (3.6 g, 26.1 mmol) is added to a solution of of 4-(2-fluoro-4-nitrophenyl)tetrahydro-2H-1,2-thiazine 1,1-dioxide (1.795 g, 6.54 mmol) and allyl bromide (2.0 ml, 23.1 mmol) in dry acetonitrile (25 ml). The mixture is heated to reflux for 5 min then cooled. After filtration and evaporation the residue is chromatographed over silica gel (150 g) eluting with 0-1% methanol-chloroform. The title compound is obtained as flakes (1.70 g, 83%) mp 121°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[CH3:10])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.C(Cl)Cl.[N-:19]=[N+:20]=[N-:21].[Na+].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9]([CH3:10])=[N:21][N:20]=[N:19]2)=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1
Reactant: CC(=O)Nc1ccc(Br)cc1C(F)(F)F
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: Cc1nnnn1-c1ccc(Br)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
A suspension of N-(4-bromo-2-trifluoromethyl-phenyl)-acetamide (2.41 g, 8.54 mmol) in acetonitrile (40 mL) was treated with methylene chloride (5 mL) to obtain a clear solution at 25° C. The resulting solution was treated with sodium azide (1.24 g, 19.1 mmol), and the reaction mixture was then cooled to 0° C. The reaction mixture was then treated with trifluoromethanesulfonic anhydride (3.59 g, 12.7 mmol). The resulting reaction mixture was allowed to warm to 25° C. where it was stirred overnight, at which time, thin layer chromatography analysis of the reaction mixture indicated the absence of starting material. The reaction mixture was then concentrated in vacuo. The resulting residue was diluted with ethyl acetate (50 mL) and water (50 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×30 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 2/1 hexanes/ethyl acetate) afforded 1-(4-bromo-2-trifluoromethyl-phenyl)-5-methyl-1H-tetrazole (1.85 g, 70%) as a white solid: EI-HRMS m/e calcd for C9H6BrF3N4 (M+) 305.9728, found 305.9733.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH3:16])=[CH:8]1.[C:17]([O-])(=[O:19])C.[Na+]>CN(C=O)C>[CH3:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH3:16])=[C:8]1[CH:17]=[O:19]
Reactant: CC(=O)[O-]
Reactant: Cc1cn(C)c2ccccc12
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1c(C=O)n(C)c2ccccc12
Temperature: 99 °C
Yield: 97 %

Procedure:
Phosphorous oxychloride (0.0.93 mL, 9.7 mmol) was added dropwise with stirring to DMF (5 mL) at 10° C. over 20 min. 1,3-dimethyl-1H indole (1.3 g mg, 8.9 mmol) in DMF (5 mL) was added slowly with stirring and the mixture was heated for 3 h at 98-100° C. Excess concentrated aqueous solution of sodium acetate was added. The mixture was stirred for 30 min at 28° C. and extracted with ethyl acetate, dried and evaporated. The crude mixture was chromatographed over silica gel eluting with hexane/ether to afford the title compound (1.5 g, 97%). 1H NMR (400 MHz, DMSO-d6) δ 10.15 (s, 1H), 7.74 (d, J=7.6 Hz, 1H), 7.53 (d, J=7.8 Hz, 1H), 7.42 (t, J=8.0 Hz, 1H), 7.15 (t, J=7.6 Hz, 1H), 3.99 (s, 3H), 2.60 (s, 3H)
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=2)=[N:8][CH2:7]1)=[O:5].C1C2C(CCCC2)CCC1.Cl>[Pd].O>[CH3:2][O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=2)=[N:8][CH:7]=1)=[O:5]
Reactant: COC(=O)C1CN=C(Cc2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc21
Agent: [Pd]
Agent: Cl
Solvent: C1CCC2CCCCC2C1
Solvent: O
Product: COC(=O)c1cnc(Cc2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc12
Yield: 115.3 %

Procedure:
A mixture of 3.9 g of 3,4-dihydro-6,7-dimethoxy-1-[(3,4-dimethoxyphenyl)methyl]-4-isoquinoline carboxylic acid methyl ester, hydrochloride, 100 ml of decalin and 2 g of 10% palladium on carbon was stirred and refluxed for 2 hours. The cooled mixture was diluted with water, acidified with 6N hydrochloric acid, and the catalyst was removed by filtration. The aqueous solution was washed with ether, made basic with excess ammonium hydroxide, and the product was extracted with ethyl acetate, dried, and evaporated to give 4.1 g of crude 6,7-dimethoxy-1-[(3,4-dimethoxyphenyl)methyl]-4-isoquinolinecarboxylic acid methyl ester. Crystallization from ether provided the analytically pure material, mp 127°-128°.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[CH:18][C:19]([CH3:32])=[C:20]([C:22]5[CH:27]=[CH:26][C:25]([S:28](O)(=[O:30])=[O:29])=[CH:24][CH:23]=5)[CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.O=S(Cl)[Cl:35].CN(C=O)C>O=P(Cl)(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[CH:18][C:19]([CH3:32])=[C:20]([C:22]5[CH:27]=[CH:26][C:25]([S:28]([Cl:35])(=[O:30])=[O:29])=[CH:24][CH:23]=5)[CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(S(=O)(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(S(=O)(=O)Cl)cc1
Temperature: 75 °C

Procedure:
5′-[(1-Benzo[1,3]dioxol-5-yl-cyclopropanecarbonyl)-amino]-2′-methylbiphenyl-4-sulfonic acid (1.9 g, 4.3 mmol) was dissolved in POCl3 (30 mL) followed by the addition of SOCl2 (3 mL) and DMF (100 μl). The reaction mixture was heated at 70-80° C. for 15 min. The reagents were evaporated and re-evaporated with chloroform-toluene. The residual brown oil was diluted with chloroform (22 mL) and immediately used for sulfonylation. ESI-MS m/z calc. 469.0, found 470.1 (M+1).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH:30]1[C:39]2[CH:38]=[CH:37][CH:36]=[C:35](B(O)O)[C:34]=2[CH:33]=[CH:32][N:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(#N)C>[CH:30]1[C:39]2[C:34](=[C:35]([C:2]3[N:3]=[C:4]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:5]4[S:10][C:9]([CH2:11][N:12]5[CH2:17][CH2:16][CH:15]([N:18]6[CH2:23][CH2:22][O:21][CH2:20][CH2:19]6)[CH2:14][CH2:13]5)=[CH:8][C:6]=4[N:7]=3)[CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][N:31]=1
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CCC(N4CCOCC4)CC3)cc2n1
Reactant: OB(O)c1cccc2cnccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: c1cc(-c2nc(N3CCOCC3)c3sc(CN4CCC(N5CCOCC5)CC4)cc3n2)c2ccncc2c1
Temperature: 130 °C
Yield: 27.2 %

Procedure:
A sealable tube was charged with 2-chloro-4-morpholin-4-yl-6-(4-morpholin-4-yl-piperidin-1-ylmethyl)-thieno[3,2-d]pyrimidine (0.100 g, 0.229 mmol), isoquinoline-5-boronic acid (0.048 g, 0.275 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.008 g, 0.012 mmol), 1 N aqueous sodium carbonate solution (1 mL) and acetonitrile (3 mL). The vessel was evacuated and back-filled with argon three times then sealed and heated at 130° C. for 90 min. The reaction mixture was cooled, concentrated, redissolved in ethyl acetate and filtered through celite. The filtrates were concentrated then purified by chromatography (silica, 10 to 20% methanol in dichloromethane) to give 101 (0.033 g, 27%) as a yellow solid. MS m/e 531 [M+H]+; 1H NMR (300 MHz, CDCl3) δ ppm 1.54-1.71 (m, 2 H) 1.87 (d, J=11.3 Hz, 2 H) 2.09-2.30 (m, 3 H) 2.52-2.63 (m, 4 H) 3.01-3.11 (m, 2 H) 3.70-3.78 (m, 4 H) 3.85 (s, 2 H) 3.87-3.94 (m, 4 H) 4.03-4.12 (m, 4 H) 7.35 (s, 1 H) 7.67-7.75 (m, 1 H) 8.06 (d, J=8.3 Hz, 1 H) 8.31-8.37 (m, 1 H) 8.52-8.58 (m, 1 H) 8.61-8.67 (m, 1 H) 9.30 (s, 1 H)
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([NH2:18])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH:24]=O>C(O)(C)C.Cl.C(Cl)(Cl)Cl>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([N:18]=[CH:24][C:20]2[O:19][CH:23]=[CH:22][CH:21]=2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2]
Reactant: CCOCc1nc2cnc3ccccc3c2n1N
Reactant: O=Cc1ccco1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: CCOCc1nc2cnc3ccccc3c2n1N=Cc1ccco1
Reaction time: 48 h
Yield: 93.8 %

Procedure:
A solution of 2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-amine (1.50 g, 6.19 mmol) in 20 mL of isopropanol was treated with 2-furaldehyde (1.08 mL, 13.0 mmol) and 2 drops of concentrated HCl and heated to reflux under an atmosphere of nitrogen. After 48 h, the reaction was concentrated under reduced pressure to yield a brown oil. The oil was dissolved in 30 mL of CHCl3 and washed with 5% Na2CO3 solution, water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to yield N-(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)(furan-2-ylmethylene)amine (1.86 g) as a light brown solid.
Reaction SMILES: [OH:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[I:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20](O)=[CH:19][CH:18]=2)=[CH:13][CH:12]=1>>[I:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:1][CH:2]3[CH:7]4[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]4)[CH2:3]3)=[CH:19][CH:18]=2)=[CH:15][CH:16]=1
Reactant: Oc1ccc(-c2ccc(I)cc2)cc1
Reactant: OC1CN2CCC1CC2
Product: Ic1ccc(-c2ccc(OC3CN4CCC3CC4)cc2)cc1

Procedure:
3-Hydroxy quinuclidine (Aldrich, 508 mg, 4 mmol) was coupled with 4′-iodo-1,1′-biphenyl-4-ol (Avacado, 592 mg, 2 mmol) according to the procedure of Example 5A. The title product was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.30) as solid (480 mg, yield, 59%). 1H NMR (MeOH-d4, 300 MHz) δ 1.43-1.57 (m, 1H), 1.62-1.88 (m, 2H), 1.97-2.12 (m, 1H), 2.14-2.21 (m, 1H), 2.72-3.00 (m, 5H), 3.31-3.43 (m, 1H), 4.51-4.60 (m, 1H), 6.98 (d, J=8.8 Hz, 2H), 7.35 (d, J=8.5 Hz, 2H), 7.53 (d, J=8.8 Hz, 2H), 7.74 (d, J=8.5 Hz, 2H) ppm. MS (DCl/NH3) m/z 406 (M+H)+.