Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)[O:3]1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=1[N:28]=[C:29]=[O:30]>O1CCCC1>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=1[NH:28][C:29]([NH:13][C:12]1[CH:14]=[CH:15][C:9]([B:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:10][CH:11]=1)=[O:30]
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)OC1(C)C
Reaction time: 1 h

Procedure:
To an ambient solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.0 g, 9.13 mmol) in tetrahydrofuran (30 mL) was added 2-fluoro-5-trifluoromethylphenyl isocyanate (1.32 mL, 9.13 mmol). After 1 h, the mixture was concentrated under reduced pressure to afford the title compound as a white solid. MS (ESI) m/z 425 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[C:8]([Cl:32])=[C:9]([C:28]([Cl:31])=[CH:29][CH:30]=1)[CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([CH3:22])[CH:18]=[C:17]2[N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)[CH3:6])=[O:4].[CH3:33][N:34]([CH3:48])[C:35]([C:37]1[CH:47]=[CH:46][C:40]([CH:41]=[CH:42][C:43](O)=[O:44])=[CH:39][CH:38]=1)=[O:36].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:32][C:8]1[C:7]([N:5]([C:3](=[O:4])[CH2:2][NH:1][C:43](=[O:44])[CH:42]=[CH:41][C:40]2[CH:46]=[CH:47][C:37]([C:35](=[O:36])[N:34]([CH3:48])[CH3:33])=[CH:38][CH:39]=2)[CH3:6])=[CH:30][CH:29]=[C:28]([Cl:31])[C:9]=1[CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([CH3:22])[CH:18]=[C:17]2[N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1
Reactant: Cc1cc(-n2ccnc2)c2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)c2n1
Reactant: CN(C)C(=O)c1ccc(C=CC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: Cc1cc(-n2ccnc2)c2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(C(=O)N(C)C)cc4)c3Cl)c2n1
Reaction time: 3 h
Yield: 91 %

Procedure:
To a solution of 8-[3-(N-glycyl-N-methylamino)-2,6-dichlorobenzyloxy]-4-(imidazol-1-yl)-2-methylquinoline (80 mg), 4-(dimethylcarbamoyl)cinnamic acid (41 mg) and 1-hydroxybenzotriazole (29.9 mg) in dichloromethane (0.8 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (39.1 mg) at ambient temperature, and the mixture was stirred for 3 hours at the same temperature. To the mixture was added saturated sodium bicarbonate solution, and the separated organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (chloroform:methanol, 10:1, v/v) to give 8-[2,6-dichloro-3-[N-[4-(dimethylcarbamoyl)cinnamoylglycyl]-N-methylamino]benzyloxy]-4-(imidazol-1-yl)-2-methylquinoline (104 mg) as colorless amorphous.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[CH:22][N:21]=3)[CH2:16][CH2:15]2)[N:3]=1.[NH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:37][C:34]1[CH:35]=[CH:36][C:31]([NH:30][C:2]2[CH:7]=[C:6]([N:8]3[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]3)[N:5]=[C:4]([N:14]3[CH2:19][CH2:18][N:17]([C:20]4[C:25]([C:26]([F:27])([F:28])[F:29])=[CH:24][CH:23]=[CH:22][N:21]=4)[CH2:16][CH2:15]3)[N:3]=2)=[CH:32][CH:33]=1
Reactant: FC(F)(F)c1cccnc1N1CCN(c2nc(Cl)cc(N3CCCCC3)n2)CC1
Reactant: Cc1ccc(N)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1ccc(Nc2cc(N3CCCCC3)nc(N3CCN(c4ncccc4C(F)(F)F)CC3)n2)cc1
Temperature: 90 °C

Procedure:
A mixture of 4-chloro-6-(1-piperidinyl)-2-{4-[3-(trifluoromethyl)-2-pyridinyl]-1-piperazinyl}pyrimidine (75.0 mg, 0.176 mmol), p-toluidine (23.1 mg, 0.216 mmol), 1,1′-(bisdiphenylphosphino)-1,1′-binaphthol (8.4 mg), tris(dibenzylidene acetone)dipalladium(0) (8.2 mg), and sodium tert-butoxide (86.4 mg) in dry toluene (1 mL) was heated at 90° C. in a sealed tube for 90 minutes. The solvent was removed and the crude material was purified by preparative TLC, eluting with hexane/ethyl acetate (4:1). N-(4-Methylphenyl)-6-(1-piperidinyl)-2-{4-[3-(trifluoromethyl)-2-pyridinyl]-1-piperazinyl}-4-pyrimidinamine was obtained, from the band at Rf=0.4, as a solid (59.5 mg, 0.119 mmol, 68%).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]([CH3:12])=[CH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:13]1[C:15]2([CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH2:14]1>C(O)C>[CH2:1]([N:8]([CH2:14][C:15]1([OH:13])[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]1)[CH2:9][C:10]([CH3:12])=[CH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C)CNCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Solvent: CCO
Product: C=C(C)CN(Cc1ccccc1)CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Yield: 100.1 %

Procedure:
A mixture of N-benzyl-2-methyl-prop-2-en-1-amine (0.57 g, 3.52 mmol) and tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (0.75 g, 3.52 mmol) in ethanol (4 mL) was heated at 80° C. in a sealed vial for 16 hours. The reaction mixture was cooled and concentrated in vacuo to give tert-butyl 4-[[benzyl(2-methylallyl)amino]methyl]-4-hydroxy-piperidine-1-carboxylate (1.32 g, 100%) as a colorless oil. ESI-MS m/z calc. 374.5. Found 375.7 (M+1)+; Retention time: 1.24 minutes (3 min run).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[N:3]=1.[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C)C=O>[N:25]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[N:3]=1)=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)c1ccc(-c2ccc(Cl)nc2-c2ccc(F)cc2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-c2ccc(N=[N+]=[N-])nc2-c2ccc(F)cc2)cc1
Yield: 37 %

Procedure:
A solution of 1.00 g (2.76 mMol) of 2-chloro-6-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]pyridine (Example 1) and 539 mg (8.29 mMol) of sodium azide in 15 ml of dimethylformamide was stirred in an oil bath at 100° C. for two days. After cooling, the mixture was partitioned between dichloromethane and water. The aqueous layer was further extracted with dichloromethane, the combined organic extracts were dried over sodium sulfate, filtered, and evaporated. Chromatography of the residue over silica gel using ethyl acetate as eluent gave the title compound (376 mg) as a pale yellow crystalline solid: m.p. 229° C. (DSC). Anal. Calc'd for C18H13N4O2S·1/4 H2O (MW 372.89): C, 57.98; H, 3.51; N, 15.03. Found: C, 58.35; H, 3.82; N, 14.70.
Reaction SMILES: [CH2:1]([NH:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[O:15]C)[CH2:6]1)[CH2:2][CH3:3].[S:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=[C:18]1[CH2:26][C:27](O)=O.B(Br)(Br)Br>C1(C)C(C)=CC=CC=1>[CH2:1]([N:4]([CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[OH:15])[CH2:6]1)[CH2:27][CH2:26][C:18]1[S:17][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=1)[CH2:2][CH3:3]
Reactant: O=C(O)Cc1cc2ccccc2s1
Reactant: CCCNC1CCc2c(cccc2OC)C1
Agent: BrB(Br)Br
Solvent: Cc1ccccc1C
Product: CCCN(CCc1cc2ccccc2s1)C1CCc2c(O)cccc2C1

Procedure:
A mixture of 2-(N-n-propylamino)-5-methoxytetralin, 2-benzothienyl acetic acid and trimethylaminoborohydride in dry xylene is refluxed under an atmosphere of nitrogen as described by Horn et al, Pharm. Weekbld. Sci. Ed. 7 208-211, 1985. The resulting methoxy intermediate is demethylated using boron tribromide as described in the above article to yield the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH2:14]([N:16]([CH2:28][CH3:29])[C:17]1[CH:26]=[C:25]2[C:20]([CH2:21][CH2:22][NH:23][CH:24]2[CH3:27])=[CH:19][CH:18]=1)[CH3:15]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:23]3[CH2:22][CH2:21][C:20]4[C:25](=[CH:26][C:17]([N:16]([CH2:28][CH3:29])[CH2:14][CH3:15])=[CH:18][CH:19]=4)[CH:24]3[CH3:27])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CCN(CC)c1ccc2c(c1)C(C)NCC2
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CCN(CC)c1ccc2c(c1)C(C)N(C(=O)c1cc3ncc(Br)cn3n1)CC2

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with Diethyl-(1-methyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-amine to provide the title compound in moderate yield.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]2C(=O)C3=CC=CC=C3C2=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>C(O)C>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][NH2:17])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCN1CCN(Cc2ccccc2)CC1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCN1CCN(Cc2ccccc2)CC1
Reaction time: 2.5 h
Yield: 86.2 %

Procedure:
To a solution of N-[3-(4-benzyl-1-piperazinyl)propyl]phthalimide (22.4 g) in ethanol (250 m) was added 100% hydrazine hydrate (8.02 g). The resulting mixture was refluxed with stirring for 2.5 hours. The reaction mixture was cooled and then filtered. The filter cake was washed with ethanol. The filtrate and washing were combined and evaporated under reduced pressure. To the residue was added 5% aqueous solution of potassium hydroxide and the mixture was extracted with chloroform. The extract was washed with water, dried over magnesium sulfate and then evaporated under reduced pressure to give an oil of 3-(4-benzyl-1-piperazinyl)propylamine (12.4 g).
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@:15]3([CH2:25][C:26]4[CH:27]=[N:28][C:29]([Cl:32])=[CH:30][CH:31]=4)[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[OH-].[Na+].Cl.CC#N.O>O1CCCC1>[Cl:32][C:29]1[N:28]=[CH:27][C:26]([CH2:25][C@@:15]2([O:14][C:12]3[CH:11]=[CH:10][C:9]4[C@H:5]([CH2:4][C:3]([OH:33])=[O:2])[CH2:6][O:7][C:8]=4[CH:13]=3)[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[F:24])[CH2:17][CH2:16]2)=[CH:31][CH:30]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@]3(Cc4ccc(Cl)nc4)CCc4cccc(F)c43)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Solvent: C1CCOC1
Product: O=C(O)C[C@@H]1COc2cc(O[C@@]3(Cc4ccc(Cl)nc4)CCc4cccc(F)c43)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
{(S)-6-[(R)-(6-Chloro-pyridin-3-ylmethyl)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzo-furan-3-yl}-acetic acid methyl ester (18.6 mg) is dissolved in tetrahydrofuran (4 mL) and 1N aqueous sodium hydroxide solution (0.4 mL) is added. The mixture is stirred at room temperature overnight and then acidified with 1N aqueous hydrochloric acid (0.4 mL). The solution is submitted to HPLC on reversed phase (MeCN/water) to give the title compound. LC (method 6): tR=0.66 min; Mass spectrum (ESI−): m/z=452/454 (Cl) [M−H]−.
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[H][H].[OH-].[Na+]>[C].[Pd].O>[NH2:1][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
A 1-liter electromagnetically stirred glass reactor was charged with 2.53 g (0.01 mole) of 1-nitroanthraquinone (roughly purified product with no impurity detected by thin-layer chromatography), 52 g of water and 0.051 g of 5% palladium-carbon. The inside of the reactor was purged with nitrogen, and with stirring at room temperature, the 1-nitroanthraquinone was hydrogenated. In 4.5 hours when 0.03 mole of hydrogen was absorbed, the hydrogen inside the reactor was replaced by nitrogen, and 2.1 g (0.052 mole) of sodium hydroxide was added. The inside of the reactor was purged with hydrogen, and the hydrogenation was continued at room temperature. In 1 hour, the absorption of hydrogen was stopped. The amount of hydrogen absorbed until then was 0.01 mole. The reaction mixture completely dissolved. The inside of the reactor was purged with nitrogen, and the reaction mixture was filtered in an atmosphere of nitrogen to separate the catalyst. The filtrate was oxidized with air at 20° to 30° C. for 2 hours with stirring to afford 2.08 g of 1-aminoanthraquinone having a purity of 98% by weight in a yield of 93% of theory. By a thin-layer chromatographic analysis, no impurity was detected.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]#[N:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:13](OCC)(OCC)[O:14][CH2:15][CH3:16].C(OC(=O)C)(=O)C.C(OCC)(=O)C>CO>[CH2:15]([O:14][CH:13]=[C:10]([S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:8])=[O:9])[C:11]#[N:12])[CH3:16]
Reactant: CCOC(OCC)OCC
Reactant: N#CCS(=O)(=O)c1ccccc1
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C#N)S(=O)(=O)c1ccccc1
Yield: 56.7 %

Procedure:
A solution of (phenylsulfonyl)acetonitrile (10.5 g, 0.089 mol) in triethyl orthoformate (21 mL, 0.14 mol) and acetic anhydride (21 mL, 0.2 mol) was heated at 160° C. with removal of ethyl acetate (35 mL). The dark oily residue was dissolved in methanol (60 mL) and the solution was concentrated and recrystallized from hexanes/ethyl acetate to yield (11.98 g, 78%) of the desired product.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:11]([F:15])([F:14])[CH2:12][CH3:13])[N:10]=[C:6]2[N:5]=[C:4]([CH3:16])[CH:3]=1.[F:17][C:18]([F:27])([F:26])[C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>C(O)C>[F:14][C:11]([C:9]1[N:10]=[C:6]2[N:5]=[C:4]([CH3:16])[CH:3]=[C:2]([NH:23][C:22]3[CH:24]=[CH:25][C:19]([C:18]([F:17])([F:26])[F:27])=[CH:20][CH:21]=3)[N:7]2[N:8]=1)([F:15])[CH2:12][CH3:13]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CCC(F)(F)c1nc2nc(C)cc(Cl)n2n1
Solvent: CCO
Product: CCC(F)(F)c1nc2nc(C)cc(Nc3ccc(C(F)(F)F)cc3)n2n1
Temperature: 50 °C

Procedure:
A suspension of Intermediate 7 (0.1 g, 0.405 mmol) and 4-(trifluoromethyl)aniline (ALDRICH, 0.051 mL, 0.405 mmol) in ethanol (5 mL) was heated at 50° C. for 1 h. The reaction mixture was concentrated under vacuum, redissolved in DCM (20 mL) and washed with aq. Na2CO3 (2×15 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum to afford a white solid.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[N:10]=[C:9]([C:12](=[O:20])[NH:13][O:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19])[CH:8]=[C:7]([C:21]([O:23]C)=[O:22])[C:6]=2[C:5]2[NH:25][C:26]([C:28]([O:30]C)=[O:29])=[CH:27][C:4]=2[C:3]21OCC[O:32]2.Cl.C(Cl)Cl.CO.[Li+].[OH-]>C1COCC1>[O:32]=[C:3]1[C:2](=[O:1])[C:11]2[N:10]=[C:9]([C:12](=[O:20])[NH:13][O:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19])[CH:8]=[C:7]([C:21]([OH:23])=[O:22])[C:6]=2[C:5]2[NH:25][C:26]([C:28]([OH:30])=[O:29])=[CH:27][C:4]1=2
Reactant: C=CCCCONC(=O)c1cc(C(=O)OC)c2c(n1)C(=O)C1(OCCO1)c1cc(C(=O)OC)[nH]c1-2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: C=CCCCONC(=O)c1cc(C(=O)O)c2c(n1)C(=O)C(=O)c1cc(C(=O)O)[nH]c1-2
Temperature: 25 °C
Reaction time: 24 h
Yield: 51 %

Procedure:
A solution of the product from EXAMPLE 3 (4, 32 mg, 64 μMol) in THF (6 mL) was treated with 1N HCl (0.6 mL) was kept at 45-47° C. for 24 hours. The reaction mixture was cooled to room temperature. TLC (DCM-MeOH 95:5) shows no 4 (Rf=0.75) and one major product (Rf=0.4). The solution was concentrated on a rotary evaporator to remove THF. The resulting mixture was partitioned between EtOAc (25 mL) and saturated aqueous NaCl (25 mL). The organic layer was separated and allowed to stand for 15 minutes. The organic solution was decanted from some aqueous droplets. It was then evaporated at reduced pressure to give an orange solid. The solid was dissolved in 0.25 M LiOH (1 mL, 0.25 mMol). The resulting black solution was stirred at room temperature for 24 hours. The reaction mixture was then acidified by dropwise addition of concentrated HCl (3 drops from a Pasteur pipet) to give a slurry of an orange solid. The slurry was cooled on an ice bath for 10 minutes then the solid was collected by filtration, rinsing with ice-cold water (2×2 mL) and Et2O (2×2 mL). The solid was then dried under vacuum for 6 hours to afford 5 (13.5 mg, 51%). MS (AP− taken from a MeOH solution) 444 (M+MeOH−1), 412 (m−1). NMR (DMSO-d6, δ), 13.55 (br, 1H, CO2H), 12.65 (br, 1H, CO2H), 12.02 (br, 1H, CONH), 11.83 (br, 1H, NH), 8.24 (s, 1H, H-8), 7.20 (s, 1H, H-3), 5.87 (m, 1H, vinyl-H), 5.05 (dd, 1H, vinyl-H), 4.99 (dd, 1H, vinyl-H), 4.03 (t, 2H, OCH2), 2.18 (q, 2H, allyl-CH2), 1.75 (m, 2H, CH2).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C=Cc1ccc(OC)nc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(OC)nc1
Yield: 100.2 %

Procedure:
Ethyl 3-(6-methoxy-3-pyridyl)acrylate (32.33 g), in ethanol (160 ml) was hydrogenated at 344 kPa at 40° using palladium-on-charcoal catalyst (5%, 0.2 g). The mixture was filtered and the filtrate was evaporated to give ethyl 3-(6-methoxy-3-pyridyl)propionate (32.7 g), as an oil.
Reaction SMILES: C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C.[Br:23][C:24]1[CH:29]=[CH:28][C:27]([C@:30]23[C@H:37]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH2:36][C:35](=[O:44])[C@@:34]2([OH:45])[C:33]2[C:46]([O:53][CH2:54][CH3:55])=[CH:47][C:48]([O:50][CH2:51][CH3:52])=[CH:49][C:32]=2[O:31]3)=[CH:26][CH:25]=1.C(=O)(O)[O-].[Na+]>C(#N)C>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([C@:30]23[C@H:37]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH2:36][C@@H:35]([OH:44])[C@@:34]2([OH:45])[C:33]2[C:46]([O:53][CH2:54][CH3:55])=[CH:47][C:48]([O:50][CH2:51][CH3:52])=[CH:49][C:32]=2[O:31]3)=[CH:26][CH:25]=1
Reactant: CCOc1cc(OCC)c2c(c1)O[C@@]1(c3ccc(Br)cc3)[C@H](c3ccccc3)CC(=O)[C@@]21O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[N+](C)(C)C
Agent: O=C([O-])O
Solvent: CC#N
Solvent: CC(=O)O
Product: CCOc1cc(OCC)c2c(c1)O[C@@]1(c3ccc(Br)cc3)[C@H](c3ccccc3)C[C@@H](O)[C@@]21O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.2 ml of glacial acetic acid are added to 814 mg (3.09 mmol) of tetramethylammonium triacetoxyborohydride in 1.2 ml of acetonitrile under argon, and the mixture is stirred at RT for 0.5 h. Then 105 mg (0.21 mmol) of (3S*,3aR*,8bR*)-3a-(4-bromophenyl)-6,8-diethoxy-8b-hydroxy-3-phenyl-2,3,3a,8b-tetrahydrocyclopenta[b]benzofuran-1-one are added dropwise as solution in 12 ml of acetonitrile. The mixture is stirred at RT overnight. At 0° C., saturated sodium bicarbonate solution is added to the reaction mixture, the aqueous phase is extracted twice with dichloromethane, and the combined organic phases are dried over sodium sulfate, filtered and concentrated. Gradient chromatography on silica gel 60 (mobile phase: toluene/ethyl acetate) results in 77 mg (71% of theory) of the product as racemic mixture.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:9][S:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[CH3:18][N:19]([CH3:23])[C:20](Cl)=[O:21]>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([CH2:9][S:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:20](=[O:21])[N:19]([CH3:23])[CH3:18])=[CH:13][CH:12]=2)=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1
Reactant: Nc1ccc(SCc2nc(Cl)ccc2Cl)cc1
Reactant: CN(C)C(=O)Cl
Solvent: c1ccncc1
Product: CN(C)C(=O)Nc1ccc(SCc2nc(Cl)ccc2Cl)cc1
Reaction time: 15 h

Procedure:
A solution of 4-(((3,6-dichloro-2-pyridinyl)methyl)thio)benzenamine (10 grams; 0.035 mole) in 25 ml. of dry pyridine was prepared and dimethyl carbamoyl chloride (3.77 grams; 0.035 mole) added thereto while maintaining the temperature of the reaction mixture at 24°-45° C. The resulting reaction mixture was stirred at ambient temperatures for a period of about 15 hours and then mixed with ice and allowed to stand for a period of about 2 hours. The aqueous layer was decanted and the residue washed with water and recrystallized twice from ether. As a result of the above operations, the desired N'-(4-(((3,6-dichloro-2-pyridinyl)methyl)thio)phenyl)-N,N-dimethyl urea compound was recovered as a crystalline solid having a melting point of 112°-113.5° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[C:13]4[S:18][CH:17]=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C([BH3-])#N.[Na+].[C:29](O)(=[O:31])[CH3:30]>>[O:22]1[CH2:21][CH2:20][N:19]([C:12]2[C:13]3[S:18][CH:17]=[CH:16][C:14]=3[N:15]=[C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[CH2:3][CH2:2][N:1]4[C:29](=[O:31])[CH3:30])[N:11]=2)[CH2:24][CH2:23]1
Reactant: c1cc(-c2nc(N3CCOCC3)c3sccc3n2)c2cc[nH]c2c1
Reactant: CC(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC(=O)N1CCc2c(-c3nc(N4CCOCC4)c4sccc4n3)cccc21
Temperature: 60 °C

Procedure:
To a solution of 2-(1H-Indol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine 199 (100 mg) in acetic acid (2 ml) was added sodium cyanoborohydride (76 mg) and the reaction mixture was heated at 60° C. overnight. The mixture was then basified and extracted into dichloromethane, organic layer was dried (Mg2SO4), filtered and volatiles removed in vacuo. Flash chromatography and recrystallization from hot dichloromethane/hexane gave 228 (11 mg). NMR: (DMSO-d6): 2.21 (3H, s), 3.70 (2H, t, J=8.6), 3.80-3.86 (4H, m), 3.98-4.04 (4H, m), 4.17 (2H, t, J=8.5), 7.30 (1H, t, J=7.9), 7.55 (1H, d, J=5.6), 8.00 (1H, d, J=8.4), 8.25 (1H, d, J=7.8), 8.30 (1H, d, J=5.6) MS: (ESI+): 381
Reaction SMILES: [C:1]([C:4]1[C:8]([CH3:9])=[CH:7][NH:6][C:5]=1[CH3:10])(=[O:3])[CH3:2].[H-].[Na+].I[CH3:14]>CN(C=O)C>[CH3:14][N:6]1[CH:7]=[C:8]([CH3:9])[C:4]([C:1](=[O:3])[CH3:2])=[C:5]1[CH3:10]
Reactant: CI
Reactant: CC(=O)c1c(C)c[nH]c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1c(C)cn(C)c1C
Reaction time: 1 h

Procedure:
A solution of 3-acetyl-2,4-dimethylpyrrole (2.0 g) in dry DMF (30 ml) was added dropwise, with stirring, to a suspension of sodium hydride (78% dispersion in oil; 565 mg) in dry DMF (15 ml) at 0° under nitrogen and stirring was continued at room temperature for 1 h. Iodomethane (1.14 ml) was added dropwise at 0° and stirring was continued for 1.5 h. The suspension was evaporated, treated with 8% aqueous sodium bicarbonate (80 ml) and extracted with ethyl acetate (2×80 ml). The combined, dried organic extracts were evaporated to give a solid (2.1 g) which was dissolved in dichloromethane (20 ml) and adsorbed onto silica gel (Merck 7734, 6 g). This was applied to an FCC column and elution with System B (1:3) afforded the title compound (1.89 g) as crystals, m.p. 68°-70°.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH:9]3[O:13][CH:10]32)=[CH:6][CH:5]=1)([O-:3])=[O:2].O.[Cl-].[Na+].[OH-].[NH4+:18]>>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][C@@H:9]([OH:13])[C@@H:10]2[NH2:18])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(c1)C1OC1C2
Reactant: [NH4+]
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N[C@@H]1c2cc([N+](=O)[O-])ccc2C[C@H]1O
Temperature: 45 °C

Procedure:
A suspension of 6-nitro-1,2-epoxyindane in concentrated ammonium hydroxide (250 mL) was heated overnight in an oil bath at 45° C. The next day water was added and the basic aqueous layer was saturated with sodium chloride. The cloudy reaction mixture was extracted with tetrahydrofuran until no more product could be seen in the aqueous layer by TLC. The organic layers were combined, dried over magnesium sulfate, filtered, concentrated, and recrystallized from ethyl acetate to give 11.54 g of the title compound. (91% over two steps).