Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Br[CH2:7][C:8]1[N:12]([CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[N:11]=[C:10]([CH2:23][CH3:24])[C:9]=1[O:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=1.[H-].[Na+]>CN(C)C=O>[Cl:33][C:28]1[CH:27]=[C:26]([CH:31]=[C:30]([Cl:32])[CH:29]=1)[O:25][C:9]1[C:10]([CH2:23][CH3:24])=[N:11][N:12]([CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:8]=1[CH2:7][N:1]1[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CCc1nn(CCNC(=O)OC(C)(C)C)c(CBr)c1Oc1cc(Cl)cc(Cl)c1
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nn(CCNC(=O)OC(C)(C)C)c(Cn2cccn2)c1Oc1cc(Cl)cc(Cl)c1
Reaction time: 5 h
Yield: 86.7 %

Procedure:
Pyrazole (23 mg, 0.330 mmol) was added in one portion to a stirred solution of the bromide of Example 137 (148 mg, 0.300 mmol) and sodium hydride (60% dispersion in oil, 13.2 mg, 0.330 mmol) in N,N-dimethylformamide (2 ml) at room temperature under nitrogen. The reaction was stirred for 5 hours, quenched with water (1.00 ml) and concentrated under reduced pressure. The residue was dissolved in dichloromethane (30 ml) and the resulting solution was washed with 1M aqueous potassium carbonate solution (10 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol (98:2, by volume) to provide the title compound (125 mg) as a colourless oil.
Reaction SMILES: O[CH2:2]/[CH:3]=[C:4](/[CH2:6][CH2:7]/[CH:8]=[C:9](/[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])\[CH3:10])\[CH3:5].P(Br)(Br)[Br:18]>CCOCC>[CH3:5]/[C:4](/[CH2:6][CH2:7]/[CH:8]=[C:9](\[CH3:10])/[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])=[CH:3]\[CH2:2][Br:18]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CO
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CBr
Yield: 215.5 %

Procedure:
A solution of 1.00 g (4.5 mmol) of (E,E)-farnesol (Aldrich, further purified by flash chromatography) in 10 mL of distilled ether at 0° C. under argon in the dark was treated dropwise with a solution of 195 μL (2.05 mmol, 0.45 eq.) of PBr3 in 2 mL of diethyl ether (ether). The resultant mixture was stirred at 0° C. for one hour, then quenched with water and separated. The organic phase was washed with 5 mL of H2O, 5 mL of saturated NaHCO3, and 5 mL of brine, dried over Na2SO4 and evaporated to give 1.26 g (98%) of crude bromide as a clear oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:10])[CH:9]=1)[CH:5]=[O:6].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1O.C([O-])(=O)C.[Pb+4].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.O>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=2)[CH:7]=[C:8]([Br:10])[CH:9]=1
Reactant: Nc1ccccc1O
Reactant: O=Cc1cc(Br)cc(Br)c1
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: CC(=O)O
Solvent: O
Product: Brc1cc(Br)cc(-c2nc3ccccc3o2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
10 g (37.9 mmol) of 3,5-dibromobenzaldehyde and 5 g (45.5 mmol) of 2-aminophenol were dissolved in 200 mL of acetic acid. The solution was agitated at room temperature for 30 minutes. Next, 20.2 g (45.5 mmol) of lead(IV) acetate was added thereto. The resulting product was agitated at 50° C. for 1 hour. Then, water was added to the obtained reactant. The mixture was extracted with ethyl acetate and treated under a reduced pressure to remove the solvent, obtaining 5.7 g (Y=42%) of a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([CH:6]2[CH2:15][CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:7]2)=[CH:4][CH:3]=1.C1(=O)O[CH2:21][CH2:20][O:19]1.[OH-].[Na+]>[I-].C[N+](C)(C)C.O.C(O)C>[OH:19][CH2:20][CH2:21][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]2[CH2:15][CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:7]2)=[CH:16][CH:17]=1
Reactant: Oc1ccc(C2CCc3ccccc3O2)cc1
Reactant: O=C1OCCO1
Agent: C[N+](C)(C)C
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OCCOc1ccc(C2CCc3ccccc3O2)cc1
Yield: 44.4 %

Procedure:
4'-Hydroxyflavan (2.26 g.), ethylene carbonate (8.8 g.) and tetramethylammonium iodide (0.30 g.) were heated together at 140° C. for 4 hrs. Sodium hydroxide (6.5 g) in water (20 ml.) and ethanol (250 ml.) was added, and the solution boiled under reflux for 5 hrs. The solution was filtered, diluted with water, and extracted 3 times with ether. The combined extracts were dried and evaporated, and the residue chromatographed on neutral alumina. The product was eluted with chloroform and after evaporation of the solvent was recrystallised from 60°-80° C. petroleum ether to yield 4'-(2-hydroxyethoxy) flavan (1.2 g.) m.p. 84°-85° C.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH3:32][N:33]([CH3:38])[CH2:34][CH2:35][NH:36][CH3:37].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:32][N:33]([CH3:38])[CH2:34][CH2:35][N:36]([CH2:27][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:9]2[CH2:10][CH2:11][N:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH2:7][CH2:8]2)[CH:26]=[CH:25][CH:24]=1)[CH3:37]
Reactant: CNCCN(C)C
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CN(C)CCN(C)C)c4)cc23)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (45.0 mg, 0.101 mmol) in DCM (2 mL) was added N,N,N′-trimethyl-1,2-ethanediamine (116 ul, 0.90 mmol). The reaction solution was stirred at ambient temperature for 1 hr prior to addition of NaBH(OAc)3 (69 mg, 0.326 mmol). The resulting mixture was stirred overnight at ambient temperature, and additional NaBH(OAc)3 (128 mg, 0.606 mmol) was added. The reaction was stirred for another 2 h, after which time the solvent was removed under reduced pressure. The crude product was purified by reverse phase HPLC (water/CH3CN, 0.1% TFA 10-90%) to give the title compound
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Br.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:26][C:25]3[CH:28]=[CH:29][CH:30]=[C:23]([Cl:22])[CH:24]=3)([C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: COc1cc(OC)cc(C2C(=O)Nc3cc(Cl)ccc32)c1
Reactant: Clc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(OC)cc(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)c1
Temperature: 60 °C

Procedure:
A mixture of rac-6-chloro-3-(3,5-dimethoxy-phenyl)-1,3-dihydro-indol-2-one (0.1 g, 0.33 mmol) (from Example 40b supra), 3-chlorobenzyl bromide (0.080 g, 0.38 mmol) (Aldrich), potassium iodide (0.065 g, 0.38 mmol) and potassium carbonate (0.098 g, 0.71 mmol) in acetone (5 mL) was heated at 60° C. for 2 hours. After cooling, mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried (Na2SO4), filtered and concentrated. Residue was purified by chromatography to give rac-6-chloro-3-(3-chloro-benzyl)-3-(3,5-dimethoxy-phenyl)-1,3-dihydro-indol-2-one as a white solid. (Yield 0.1 g, 71.4%).
Reaction SMILES: [CH2:1]([C:9]1[C:13]([C:14](Cl)=[O:15])=[C:12]([CH3:17])[O:11][N:10]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[NH4+:19]>C(OCC)C>[CH2:1]([C:9]1[C:13]([C:14]([NH2:19])=[O:15])=[C:12]([CH3:17])[O:11][N:10]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cc1onc(CCc2ccccc2)c1C(=O)Cl
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCOCC
Product: Cc1onc(CCc2ccccc2)c1C(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 24.9 g. (0.10 mole) 3-phenethyl-5-methyl-isoxazole-4-carboxylic acid chloride in 100 ml. diethyl ether is added to 7.7 g. (0.2 mole) of concentrated ammonium hydroxide while maintaining the temperature at 0° to 10° C. The mixture is stirred at room temperature overnight and filtered. The resulting solid is washed with water and dried to give 3-phenethyl-5-methyl-isoxazole-4-carboxamide; m.p. 135° to 136° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[S:26][C:25]([C:27]3([OH:32])[CH2:31][CH2:30][NH:29][CH2:28]3)=[N:24][CH:23]=2)=[CH:18][CH:17]=1)=[O:14].[C:33](O)(=O)C.C=O>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:10])([F:11])[F:9])=[CH:4][C:3]=1[NH:12][C:13]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[S:26][C:25]([C:27]3([OH:32])[CH2:31][CH2:30][N:29]([CH3:33])[CH2:28]3)=[N:24][CH:23]=2)=[CH:20][CH:21]=1)=[O:14]
Reactant: CC(=O)O
Reactant: O=C(Nc1ccc(-c2cnc(C3(O)CCNC3)s2)cc1)Nc1cc(C(F)(F)F)ccc1F
Agent: C=O
Solvent: CO
Product: CN1CCC(O)(c2ncc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)cc3)s2)C1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To an ambient solution of Example 14 (0.050 g, 0.107 mmol) in methanol containing 1% v/v acetic acid 1 mL) was added formaldehyde (0.012 mL, 0.161 mmol, 37 wt % in H2O) and MP-CNBH3 (0.054 g, 0.161 mmol, 3.0 mmol/g). The reaction was heated to 50° C. and shaken for 16 h. The reaction was then filtered and concentrated under reduced pressure. The residue was purified by RP-HPLC (preparative reversed-phase high pressure liquid chromatography) using a Zorbax SB-C18 7M 21.2×250 mm column with UV detection analyzed at 220 and 254 nM (preparative method: water with 0.1% trifluoroacetic acid and CH3CN with 0.1% trifluoroacetic acid gradient 5-95% CH3CN over 30 minutes at 15 mL/min). The fractions containing the desired product were diluted with saturated aqueous NaHCO3 and extracted with ethyl acetate. The organic layer was dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound as a white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 2.01-2.13 (m, 1 H), 2.25-2.33 (m, 3 H), 2.35-2.46 (m, 1 H), 2.51-2.58 (m, 1 H), 2.73-2.94 (m, 3 H), 6.22-6.31 (m, 1 H), 7.37-7.44 (m, 1 H), 7.47-7.56 (m, 3 H), 7.56-7.62 (m, 2 H), 7.98 (s, 1 H), 8.62 (m, 1 H), 8.92 (m, 1 H), 9.32 (s, 1 H); MS (ESI) m/z 481 [M+H]+.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11]([CH3:28])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2OS(C(F)(F)F)(=O)=O)[CH:10]([CH3:29])[CH2:9]1)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH:30]([Sn](CCCC)(CCCC)CCCC)=[CH2:31].[Cl-].[Li+].C(C1C=C(O)C(=CC=1)O)(C)(C)C>O1CCCC1.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>[C:1]([N:8]1[CH2:13][CH2:12][C:11]([CH3:28])([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:30]=[CH2:31])[CH:15]=2)[CH:10]([CH3:29])[CH2:9]1)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC(=O)N1CCC(C)(c2ccccc2OS(=O)(=O)C(F)(F)F)C(C)C1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)c1ccc(O)c(O)c1
Agent: [Cl-]
Solvent: C1CCOC1
Product: C=Cc1cccc(C2(C)CCN(C(=O)CCCCC)CC2C)c1
Reaction time: 16 h

Procedure:
To a stirred solution of 1-hexanoyl-3,4-dimethyl-4-(trifluoromethanesulfonyloxyphenyl)piperidine (Preparation 6, 3.0 g, 6.90 mmol) in tetrahydrofuran (30 mL) at room temperature were added sequentially vinyltributyltin (2.12 mL, 7.24 mmol), lithium chloride (585 mg, 13.8 mmol), and tetrakis(triphenylphosphine)palladium(0) (80 mg, 0.69 mmol). The mixture was heated to reflux under a nitrogen atmosphere for 1½ hours at which time a few crystals of 4-tert-butylcatechol were added. Heating at reflux was then continued for a further 16 hours. The mixture was cooled and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a gradient of ethyl acetate:hexane (1:10 to 1:3). The title compound was obtained as a clear oil (2.1 g).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=1.NO.Cl>CO.[Pd]>[F:14][C:11]([F:12])([F:13])[C:5]1[CH:6]=[C:7]([NH2:8])[CH:2]=[N:3][CH:4]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1Cl
Agent: [Pd]
Agent: Cl
Agent: NO
Solvent: CO
Product: Nc1cncc(C(F)(F)F)c1
Reaction time: 16 h
Yield: 8 %

Procedure:
2-Chloro-3-nitro-5-(trifluoromethyl)pyridine (0.850 g, 3.75 mmol) was dissolved in methanol (17 mL) and palladium on carbon (800 mg of 10%, 50% wet, 0.375 mmol) was added. The mixture was hydrogenated at 60 psi and 20° C. for 16 h. LCMS showed no remaining starting material or hydroxylamine (M+H 213/215, 3:1) intermediate, and showed a mixture of partially reduced product (M+H 163; UVmax 214, 258, & 332 nm) and the fully reduced product (M+H 169; no UV). The mixture was filtered; and the filtrate was rinsed thoroughly, and concentrated in vacuo to give 0.74 g, of the product as the HCl salt. The product was purified by prep HPLC/MS using a 30 mm×100 mm C18 column; 20% CH3CN—H2O (0.1% NH4OH), 1 min, to 40% at 6 min; 60 mL/min; detector set at m/z 163; retention time, 4.4 min. Fractions containing the pure product were combined and concentrated to give an oil, 52 mg, 8% yield. 1H NMR (CDCl3) δ 8.26 (s, 1H); 8.24 (d, 1H); 7.15 (t, 1H); 4.00 (s, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.[NH3:21]>[Cu-]=O>[NH:11]1[CH2:12][CH2:13][CH:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:21])[CH:7]=2)[CH2:9][CH2:10]1
Reactant: N
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccnc(Cl)c2)CC1
Agent: O=[Cu-]
Product: Nc1cc(C2CCNCC2)ccn1
Yield: 36 %

Procedure:
To a stirred solution of tert-butyl 4-(2-chloropyridin-4-yl)piperidine-1-carboxylate (24 g, 0.08 mol, 1 equiv) in ammonia (250 mL) was added copper(I) oxide (5 g, 0.03 mols, 0.4 equiv.) and stirred 10 h at 200° C. under 2.2 MPa of ammonia. The reaction was monitored by LC-MS to completion. The mixture was cooled, extracted with dichloromethane (5×250 mL), dried over Na2SO4, then concentrated to obtain compound 4-(piperidin-4-yl)pyridin-2-amine (8.5 g, 36%).
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:13])[CH2:9][C:10]([OH:12])=O)=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[Br:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1[NH:60][CH:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1>CN(C=O)C.O>[C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:2]=[CH:3][C:4]([NH:7][C:8](=[O:13])[CH2:9][C:10]([N:64]2[CH2:63][CH2:62][CH:61]([NH:60][C:55]3[CH:56]=[CH:57][CH:58]=[CH:59][C:54]=3[Br:53])[CH2:66][CH2:65]2)=[O:12])=[CH:5][CH:6]=1
Reactant: Brc1ccccc1NC1CCNCC1
Reactant: O=C(O)CC(=O)Nc1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC(=O)N1CCC(Nc2ccccc2Br)CC1)Nc1ccc(-c2ccccc2)cc1
Reaction time: 8 h
Yield: 18.1 %

Procedure:
To a stirred solution of N-biphenyl-4-yl-malonamic acid (0.071 g, 0.00028 mole) in DMF (2 mL) was added DIPEA (0.089 g, 0.0007 mole), HOBt (0.046 g, 0.00034 mole) and EDCI.HCl (0.065 g, 0.00034 mole). After 2 minutes (2-bromo-phenyl)-piperidin-4-yl-amine dihydrochloride (0.082 g, 0.00028 mole) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The organic layer was washed with aqueous sodium bicarbonate solution, brine and concentrated. The resulting residue was purified by column chromatography using silica gel 60-120 mesh (70% ethyl acetate in hexane) to afford 0.025 g (17%) of N-biphenyl-4-yl-3-[4-(2-bromo-phenylamino)-piperidin-1-yl]-3-oxo-propionamide. LC-MS purity: 492 (M+1)+, 92.2%, 1H NMR (CDCl3): δ 10.0 (s, 1H), 7.66 (d, 2H), 7.58 (m, 4H), 7.44 (t, 3H), 7.34 (t, 1H), 7.18 (t, 1H), 6.68 (d, 1H), 6.6 (t, 1H), 4.45 (d, 1H), 4.0 (d, 1H), 3.65 (bs, 1H), 3.5 (s, 2H), 3.35 (t, 1H), 3.1 (t, 1H), 2.2 (m, 2H), 1.5 (m, 2H).
Reaction SMILES: [CH3:1]C1C=C(O)C=CC=1O.CC1C(C)=C(C=CC=1O)O.[CH3:20][C:21]1[C:22]([OH:30])=[C:23]([CH3:29])[C:24]([CH3:28])=[C:25]([CH:27]=1)[OH:26]>[Zn].CO>[CH3:20][C:21]1[C:22]([OH:30])=[C:23]([CH3:29])[C:24]([CH3:28])=[C:25]([OH:26])[C:27]=1[CH3:1]
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: Cc1cc(O)ccc1O
Agent: Cc1c(O)ccc(O)c1C
Agent: [Zn]
Solvent: CO
Product: Cc1c(C)c(O)c(C)c(C)c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into an autoclave (inner volume: 9 ml, made of SUS 316, equipped with a manometer) were charged 0.092 g of methylhydroquinone, 3.895 g of methanol and 7.2 mg of zinc powders (manufactured by High Purity Chemicals Co.). The reaction was started by elevating the temperature up to 350° C. with sand bath. The pressure during the reaction was 17 MPa. After 2 hours, the autoclave was quickly cooled and the reaction solution was taken out from the autoclave when the temperature was cooled back to the room temperature. The measurement according to the process described above revealed that the conversion of methylhydroquinone was 23% by mole, the selectivity of dimethylhydroquinone was 92% by mole, the selectivity of trimethylhydroquinone was 8% by mole and no tetramethylhydroquinone was produced.
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=[O:5])C.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]=[C:32]=[O:33])[CH:26]=1>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:5])[N:31]([C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([F:24])[CH:26]=3)[C:32]2=[O:33])[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Reactant: O=C=Nc1cccc(F)c1
Product: COc1cccc2c1ncc1c(=O)n(-c3cccc(F)c3)c(=O)n(C3CCCC3)c12
Yield: 56.7 %

Procedure:
1-Cyclopentyl-3-(3-fluoro-phenyl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (23 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.1 mmol) and 1-fluoro-3-isocyanato-benzene (0.5 mmol) following general procedure C. LCMS: m/z 406 [M+1]+. 1H NMR (400 MHz, CDCl3): δ 9.45 (s, 1H), 7.84 (d, 1H), 7.62 (d, 1H), 7.51 (t, 1H), 7.20 (m, 1H), 7.18 (m, 1H), 7.12 (m, 1H), 7.09 (s, 1H), 5.06 (p, 1H), 4.15 (s, 3H), 2.42 (m, 2H), 2.06-2.18 (m, 4H), 1.26 (m, 2H) ppm.
Reaction SMILES: C[O:2][C:3]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]2[C:4]=1[C@@:5]1([CH3:26])[C@H:14]([CH2:15][O:16]2)[C@:13]2([CH3:23])[C@H:8]([C:9]([CH3:25])([CH3:24])[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1.CN1C(=O)CCC1>CCOC(C)=O>[CH3:22][O:21][C:19]1[CH:18]=[C:17]2[C:4]([C@@:5]3([CH3:26])[C@H:14]([CH2:15][O:16]2)[C@:13]2([CH3:23])[C@H:8]([C:9]([CH3:25])([CH3:24])[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]3)=[C:3]([OH:2])[CH:20]=1
Reactant: COc1cc(OC)c2c(c1)OC[C@@H]1[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]21C
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COc1cc(O)c2c(c1)OC[C@@H]1[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]21C
Temperature: 180 °C
Yield: 43 %

Procedure:
In a microwave tube, (1R,10R,11S,16S)-3,5-dimethoxy-1,11,15,15-tetramethyl-8-oxatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene (Compound No. 38) (0.15 g, 0.42 mmol), Na2S (0.20 g, 2.6 mmol) and NMP (3 mL) were placed. The tube was sealed and subjected to microwave heating at 180° C. for 1 h. The reaction was cooled to room temperature, diluted with EtOAc (100 mL) and washed with water (50 mL). The organic layer was separated, dried (Na2SO4) and concentrated. Purification by column chromatography on silica gel (Hexanes/EtOAc, 4:1) gave (1R,10R,11S,16S)-5-methoxy-1,11,15,15-tetramethyl-8-oxatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-trien-3-ol (Compound No. 39) (0.06 g, 43%) as a colourless solid. 1H NMR (CDCl3): δ 6.15 (d, 1H), 6.00 (d, 1H), 4.93 (s, 1H), 4.27 (m, 1H), 3.97 (t, 1H), 3.68 (s, 3H), 3.00 (m, 1H), 1.75-1.40 (m, 8H), 1.37 (s, 3H), 1.20-0.93 (m, 2H), 0.92 (s, 3H), 0.90 (m, 1H) 0.68 (s, 3H), 0.62 (s, 3H). MS m/z 345 (C22H32O3+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]#[C:8][C:9]([CH3:12])([CH3:11])[CH3:10])[S:4][C:3]=1[C:13]([O:15][CH3:16])=[O:14].CO[C:19]([CH3:21])=[CH2:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl.CCOC(C)=O.C(O)(=O)C>[CH3:10][C:9]([CH3:11])([CH3:12])[C:8]#[C:7][C:5]1[S:4][C:3]([C:13]([O:15][CH3:16])=[O:14])=[C:2]([NH:1][CH:19]([CH3:21])[CH3:20])[CH:6]=1
Reactant: C=C(C)OC
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1NC(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
Methyl 3-amino-5-(3,3-dimethylbut-1-ynyl)thiophene-2-carboxylate (see WO 2008058393) (12.0 g, 50.6 mmol) in dichloromethane (150 mL) was placed in a cool water bath (12 deg C.) and treated dropwise with 2-methoxyprop-1-ene (14.6 mL, 152 mmol) over about 6 minutes followed by acetic acid (8.7 mL) over about 5 minutes. Sodium triacetoxyborohydride (16.1 g, 152 mmol) was added portionwise over about 30 minutes. The reaction mixture was allowed to warm to ambient temperature and was stirred for 16 h. The resulting light orange solution was poured into cold sodium bicarbonate (sat aq, 200 mL). The organic layer was separated and the aqueous layer was extracted twice with dichloromethane (150 mL each). The combined organic layers were washed with sodium bicarbonate (sat aq) and brine, dried over sodium sulfate (anhyd), filtered and concentrated to an orange oil. Silica gel chromatography (0-15% EtOAc:Hex) afforded 13.0 g (92% yield) of the desired methyl 5-(3,3-dimethylbut-1-ynyl)-3-(isopropylamino)thiophene-2-carboxylate as a light yellow oil which solidified upon standing to a waxy crystalline solid, and was used in the subsequent step.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[CH:4][C:3]=1/[CH:21]=[CH:22]/[N:23]1[CH:31]=[N:30][C:29]2[C:24]1=[N:25][CH:26]=[N:27][C:28]=2[NH:32][CH3:33]>CO.[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=2)=[CH:4][C:3]=1[CH2:21][CH2:22][N:23]1[CH:31]=[N:30][C:29]2[C:24]1=[N:25][CH:26]=[N:27][C:28]=2[NH:32][CH3:33]
Reactant: CNc1ncnc2c1ncn2/C=C/c1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1C
Agent: [Pd]
Solvent: CO
Product: CNc1ncnc2c1ncn2CCc1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1C
Reaction time: 48 h

Procedure:
To a solution of (E)-N-(4-methyl-3-(2-(6-(methylamino)-9H-purin-9-yl)vinyl)phenyl)-3-(trifluoromethyl)benzamide (0.10 g) in MeOH was added a catalytic amount of 10% palladium on carbon. The resulting mixture was hydrogenated under 50 psi H2 for 48 h at which point HPLC indicated completion. The catalyst was removed by filtration and the filtrate was concentrated on a rotavap and further dried under vacuum yielding the desired product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[N:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3I)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C(OC([N:29]1[CH2:36][C@@H:35]2[C@@H:31]([CH2:32][NH:33][CH2:34]2)[CH2:30]1)=O)(C)(C)C.[ClH:37]>>[ClH:37].[F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[N:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[N:29]2[CH2:36][C@@H:35]3[C@@H:31]([CH2:32][NH:33][CH2:34]3)[CH2:30]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CNC[C@H]2C1
Reactant: O=S(=O)(c1cccc(F)c1)c1cnc2c(I)cccc2c1
Agent: Cl
Product: O=S(=O)(c1cccc(F)c1)c1cnc2c(N3C[C@H]4CNC[C@H]4C3)cccc2c1

Procedure:
0.145 g of 3-(3-Fluoro-benzenesulfonyl)-8-(3aR,6aS)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl-quinoline hydrochloride were prepared by analogy to the methods of Examples 27 and 28 by coupling of 3-(3-fluorophenylsulfonyl)-8-iodoquinoline with commercially available (3aR,6aS)-Hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester and subsequent deprotection of the tert-butyl-oxycarbonyl derivative with HCl in isoproanol.