Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[CH:5]=1)([O-:3])=[O:2].[CH3:20][O:21][C:22](=[O:29])[C@H:23]([CH2:25][CH2:26][S:27][CH3:28])[NH2:24].Cl.C(N=C=NCCCN(C)C)C.ON1C(=O)C2C=CC=CC=2N=N1>>[CH3:20][O:21][C:22](=[O:29])[C@H:23]([CH2:25][CH2:26][S:27][CH3:28])[NH:24][C:8](=[O:10])[C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19]
Reactant: Cc1ccccc1-c1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: COC(=O)[C@@H](N)CCSC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=c1c2ccccc2nnn1O
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc([N+](=O)[O-])cc1-c1ccccc1C
Yield: 98 %

Procedure:
4-Nitro-2-(2-methylphenyl)benzoic acid (2.31 g, 9 mmol), prepared as in Example 178B, was coupled with L-methionine methyl ester (1.0 eq) in the presence of ethyl dimethylaminopropyl carbodiimide hydrochloride (EDCI, 1.0 eq) and 3-hydroxy-1,2,3-benzotriazin-4(3H)-one (HOBT, 1.0 eq) to give [4-nitro-2-(2-methylphenyl)benzoyl]methionine methyl ester as a pale yellow oil (3.54 g, 98% yield); 1H NMR showed diastereomers due to restricted carbon-carbon bond rotation; 1H NMR (CDCl3) δ 8.26-8.30 (d, J=8.5 Hz, 1H), 8.10 (s, 1H), 8.03-8.09 (m, 1H), 7.27-7.42 (m, 3.5H), 7.18 (d, J=7.4 Hz, 0.5H), 6.03 (br, 1H, amide), 4.59-4.67 (m, 1H), 3.67 (s, 3H), 2.23 (s, 1.5H, PhCH3), 2.06 (s, 1.5H, PhCH3), 1.98-2.03 (m, 5H), 1.81-1.93 (m, 1H), 1.59-1.69 (m, 1H).
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N:17]3[CH:21]=[CH:20][N:19]=[CH:18]3)[CH:15]=2)[C:10]([CH3:22])=[CH:9][C:8]1=[O:23].FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[N:17]1([C:14]2[CH:15]=[C:16]3[C:11]([C:10]([CH3:22])=[CH:9][C:8](=[O:23])[N:7]3[CH2:6][CH:2]=[O:1])=[CH:12][CH:13]=2)[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: Cc1cc(=O)n(CC2OCCO2)c2cc(-n3ccnc3)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(=O)n(CC=O)c2cc(-n3ccnc3)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 70 mg of 1-(1,3-dioxolan-2-ylmethyl)-7-(1H-imidazol-1-yl)-4-methylquinolin-2(1H)-one, 2 mL of 80% aqueous trifluoroacetic acid solution, was added, and stirred at room temperature for 1 hour, thereafter allowed to stand at room temperature for 14 hours. Ethyl acetate was added, neutralized with aqueous saturated sodium hydrogen carbonate solution, ethyl acetate was added, the organic layer was separated, and the aqueous layer was extracted 3 times with ethyl acetate. The organic layer and extracts were combined, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give (7-(1H-imidazol-1-yl)-4-methyl-2-oxo-1,2-dihydroquinolin-1-yl)acetaldehyde as a white solid.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[C:11]([CH2:13][S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[N:10]=[C:9]([C:23]3[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].Cl[C:36]([O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:37]>O1CCOCC1>[N:1]1([C:7]2[CH:12]=[C:11]([CH2:13][S:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)(=[O:15])=[O:16])[N:10]=[C:9]([C:23]3[CH:24]=[CH:25][C:26]([NH:29][C:36](=[O:37])[O:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[CH:27][CH:28]=3)[N:8]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccc(-c2nc(CS(=O)(=O)c3ccccc3)cc(N3CCOCC3)n2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(Nc1ccc(-c2nc(CS(=O)(=O)c3ccccc3)cc(N3CCOCC3)n2)cc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
(4-{4-Morpholin-4-yl-6-[(phenylsulfonyl)methyl]pyrimidin-2-yl}phenyl)amine (1 g, 2.44 mmol) was dissolved in dioxane (10 mL). Sodium bicarbonate (307 mg, 3.65 mmol) was added, followed by phenyl chloroformate (0.307 mL, 2.44 mmol) and the reaction stirred at room temperature for 2 hours. The solvent was removed in vacuo, and the resultant oil partitioned between 10 mL DCM and 10 mL water. The organic phase was dried over magnesium sulphate, filtered and concentrated in vacuo. The cream solid obtained was chromatographed on silica, eluting with 0-50% ethyl acetate in DCM, to give the desired material as a white solid (790 mg).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[C:12]([OH:14])=O.CCN(C(C)C)C(C)C.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][N:34]([C:12]([C:3]2[S:4][C:5]3[N:6]=[CH:7][NH:8][C:9](=[O:11])[C:10]=3[C:2]=2[CH3:1])=[O:14])[CH2:33][CH2:32]1
Reactant: Cc1c(C(=O)O)sc2nc[nH]c(=O)c12
Reactant: Fc1ccccc1N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)N2CCN(c3ccccc3F)CC2)sc2nc[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
To a solution of 5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid, (2 g, 9.5 mmol) in DMF (20 mL) was added DIEA (5 mL, 28.5 mmol), 1-(2-fluorophenyl)piperazine (1.7 g, 9.5 mmol), and HATU (4.7 g, 12.3 mmol). The reaction mixture was stirred at RT overnight. The reaction mixture was diluted with EtOAc (60 mL) and the organic layer was washed successively with sat. NaHCO3 aq. (50 mL) and brine (50 mL). The organic layer was separated, dried over Na2SO4, and concentrated to give crude product as a gummy solid. Purification by flash column chromatography using EtOAc as the eluant afforded the 3.0 g of pure 6-(4-(2-fluorophenyl)piperazine-1-carbonyl)-5-methylthieno[2,3-d]pyrimidin-4(3H)-one, (yield: 86%).
Reaction SMILES: C([NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[NH:29][C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:22][CH2:23][CH:24]4[CH2:28][CH2:27][CH2:26][O:25]4)[C:16]=3[C:15]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:10][CH:9]=1)(=[O:7])=[O:6])C=C.C[N+]1([O-])CC[O:40]CC1.[CH3:44][C:45]([CH3:47])=[O:46]>O.C(O)(C)(C)C.O=[Os](=O)(=O)=O>[OH:46][CH:45]([CH2:47][OH:40])[CH2:44][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[NH:29][C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:22][CH2:23][CH:24]4[CH2:28][CH2:27][CH2:26][O:25]4)[C:16]=3[C:15]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:10][CH:9]=1)(=[O:7])=[O:6]
Reactant: C[N+]1([O-])CCOCC1
Reactant: CC(C)=O
Reactant: C=CCNS(=O)(=O)c1ccc(-c2[nH]c3ncnc(NCC4CCCO4)c3c2-c2ccccc2)cc1
Agent: O=[Os](=O)(=O)=O
Solvent: CC(C)(C)O
Solvent: O
Product: O=S(=O)(NCC(O)CO)c1ccc(-c2[nH]c3ncnc(NCC4CCCO4)c3c2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 26 h

Procedure:
A solution of 26 mg (0.1 mmol) of N-allyl-4-{5-phenyl-4-[(tetrahydro-furan-2-ylmethyl)-amino]-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-benzenesulfonamide (Example 12) in 2.8 ml acetone and 1 ml water was treated with 62 μl (0.005 mmol) of a 2.5 wt. % solution of OsO4 in tert-butanol and 19 mg (0.2 mmol) of 4-methylmorpholine-N-oxide. The yellow solution was stirred at room temperature for 26 h, then was quenched with water (10 ml) and extracted with dichloromethane (3×). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was purified by chromatography on silica gel (CH2Cl2:MeOH, 22:3) to give the title compound. 1H-NMR (DMSO-d6) δ 1.29-1.40 (m, 1 H), 1.53-1.84 (m, 3 H), 2.40-2.49 (m, 1 H), 2.53-2.63 (m, 1 H), 2.82-2.90 (m, 1 H), 3.21-3.59 (m, 6 H), 3.69-3.77 (m, 1 H), 4.51 (t, J=5.6 Hz, 1 H), 4.75 (d, J=5.1 Hz, 1 H), 4.97-5.03 (m, 1 H), 7.37-7.42 (m, 3 H), 7.44-7.53 (m, 5 H), 7.65 (d, J=8.5 Hz, 2 H), 8.21 (s, 1 H), 12.34 (br s, 1 H). Mass Spectrum (ESI) m/e=524.0 (M+1).
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:34]=[CH:33][C:23]([O:24][C:25]2[CH:26]=[CH:27][C:28]([Br:32])=[C:29]([OH:31])[CH:30]=2)=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:35]([O:39]CC)(=[O:38])[CH2:36]O>>[CH2:1]([N:8]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:24][C:25]2[CH:26]=[CH:27][C:28]([Br:32])=[C:29]([CH:30]=2)[O:31][CH2:36][C:35]([OH:39])=[O:38])=[CH:33][CH:34]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CO
Reactant: Cc1c(N(Cc2ccccc2)Cc2ccc(Oc3ccc(Br)c(O)c3)cc2)cccc1[N+](=O)[O-]
Product: Cc1c(N(Cc2ccccc2)Cc2ccc(Oc3ccc(Br)c(OCC(=O)O)c3)cc2)cccc1[N+](=O)[O-]

Procedure:
The product from Example 63F and ethyl glycolate were processed as described in Example 62A to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:22][OH:23])=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[N:7]([S:12]([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.C(N(C(C)C)C(C)C)C.CS(C)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]2[N:7]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:6]=[CH:5][C:4]=2[C:3]=1[CH:22]=[O:23]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(CO)c(Cl)cc(C)c32)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(C=O)c(Cl)cc(C)c32)cc1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To a solution of (5-chloro-7-methyl-1-tosyl-1H-indol-4-yl)methanol (3.3 g, 9.5 mmol) and N-ethyl-diisopropylamine (8.3 mL, 47.3 mmol) in CH2Cl2 (20 mL)/DMSO (1 mL) was added SO3.Py (4.5 g, 28.4 mmol) at 0° C. The mixture was stirred at 0° C. for 2.5 h, and then stirred at room temperature for 15 h. The reaction was quenched by MeOH. The mixture was stirred for 1 h. The mixture was partially concentrated. The mixture was diluted with H2O, and then the resulted solid was collected by filtration. The resulting residue was triturated with MeOH to give the title compound. 1H NMR (400 MHz, ACETONITRILE-d3) δ 10.56 (s, 1H), 8.00 (d, J=3.80 Hz, 1H), 7.62 (d, J=3.80 Hz, 1H), 7.60 (d, J=8.60 Hz, 2H), 7.35 (d, J=8.60 Hz, 2H), 7.22 (s, 1H), 2.60 (s, 3H), 2.37 (s, 3H).
Reaction SMILES: O=[C:2]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:5]=1.[CH:21]([O-:23])=O.[NH4+:24]>O>[CH:21]([NH:24][CH:2]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:5]=1)=[O:23]
Reactant: O=C[O-]
Reactant: [NH4+]
Reactant: COC(=O)Cc1ccc(CC(=O)c2cccnc2)cc1
Solvent: O
Product: COC(=O)Cc1ccc(CC(NC=O)c2cccnc2)cc1
Yield: 2.6 %

Procedure:
To 13 g of methyl 4-[2-oxo-2-(3-pyridyl)ethyl]phenylacetate was added 8.0 g of ammonium formate, and reacted at 150° C. for four hours. After cooling, water was added, followed by extraction with chloroform. The chloroform phase obtained was washed in saturated aqueous sodium chloride solution and dried over magnesium sulfate, followed by distillation of the solvent, to produce 0.38 g of methyl 4-[2-formamido-2-(3-pyridyl)ethyl]phenylacetate.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9](Cl)=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=2)=[O:5])[CH2:3][CH2:2]1.[C:16]([NH:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>>[CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9]([N:27]3[CH2:26][CH2:25][CH:24]([NH:23][C:16](=[O:17])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH2:29][CH2:28]3)=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=C(c1ccc(Cl)c([N+](=O)[O-])c1)C1CC1
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(C(=O)C3CC3)cc2[N+](=O)[O-])CC1
Yield: 95 %

Procedure:
Method 1 was followed using 4-chloro-3-nitrophenyl cyclopropyl ketone (1.0 eq), 4-(N-Boc-amino)piperidine (1.2 eq), and TEA (1.5 eq) at 55° C. for 48 hours yielding tert-butyl 1-(4-(cyclopropanecarbonyl)-2-nitrophenyl)piperidin-4-ylcarbamate (95%). LCMS (m/z): 390.1 (MH+); LC Rt=3.25 min.
Reaction SMILES: Br[C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][CH:9]=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.[Si:18]([O:25][CH2:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[C:31]([CH2:33][O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH:32]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].CCOC(C)=O>C1COCC1.O.Cl[Pd]Cl>[Si:18]([O:25][CH2:26][C:27]1[CH:28]=[C:29]([C:9]2[CH:10]=[CH:11][C:12]3[C:17]4=[C:16]5[C:5](=[CH:4][CH:3]=[CH:2][C:15]5=[CH:14][CH:13]=3)[CH:6]=[CH:7][C:8]=24)[CH:30]=[C:31]([CH2:33][O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH:32]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: Brc1ccc2ccc3cccc4ccc1c2c34
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(CO[Si](C)(C)C(C)(C)C)cc(B(O)O)c1
Agent: Cl[Pd]Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1cc(CO[Si](C)(C)C(C)(C)C)cc(-c2ccc3ccc4cccc5ccc2c3c45)c1
Reaction time: 48 h

Procedure:
Following the scheme shown in FIG. 5, PdCl2 (dppf) (0.122 g, 5 mol %) was added to 1-bromopyrene (0.686 g, 2.44 mmol) in a darkroom, and then dissolved with THF/H2O (12 ml). 3,5-bis-tert-butyldimethylsilyloxymethyl phenylboronic acid (1.0 g, 2.19 mmol) dissolved in THF/H2O (24 ml) was added, 2N NaOHaq (3.66 ml, 3 eq) was injected, the reaction was initiated in a 65° C. oil bath with light shielding, and the mixture was agitated for 2 days. Strong fluorescence was confirmed with the naked eye in TLC (Hex:EtOAc=5:1). After the reaction was confirmed, this was extracted with ethyl acetate, and the organic layer was washed with saturated saline and dried by addition of anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the target product as a mixture (1.28 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](Cl)[C:5]([N+:9]([O-])=O)=[CH:4][N:3]=1.[CH3:12][O:13][CH2:14][CH2:15][NH2:16].C(N(CC)CC)C.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>CN1C(=O)CCC1>[CH3:12][O:13][CH2:14][CH2:15][NH:16][C:6]1[CH:7]=[C:2]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:3]=[CH:4][C:5]=1[NH2:9]
Reactant: COCCN
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1cnc(Cl)cc1Cl
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: COCCNc1cc(N2CCOCC2)ncc1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,4-Dichloro-5-nitro-pyridine (500 mg; 2.46 mmol), 2-methoxyethylamine (225 n1; 2.46 mmol) and triethylamine (400 μl; 2.82 mmol) are suspended in 2.5 ml NMP and stirred for 1 h at 25° C. To this suspension morpholine (500 μl; 5.71 mmol) is added and the resulting mixture is stirred for 16 h at 50° C. The crude intermediate is purified using reversed phase chromatography (prep. HPLC1). This intermediate is dissolved in 30 ml THF and palladium on carbon is added. The reaction mixture is stirred for 3 h at 25° C. and 4 bar hydrogen pressure. The solid material is filtered off and the solvent is evaporated.
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[CH:18]1([C:24]2[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.[B][B][B][B][B][B][B][B][B][B]>CO>[CH:18]1([C:24]2[CH:25]=[CH:26][C:27]([NH:28][CH:2]3[C:10]4[C:5](=[CH:6][C:7]([C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])=[CH:8][CH:9]=4)[CH2:4][CH2:3]3)=[CH:29][CH:30]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: CCCCOC(=O)c1ccc2c(c1)CCC2=O
Reactant: Nc1ccc(C2CCCCC2)cc1
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CO
Product: CCCCOC(=O)c1ccc2c(c1)CCC2Nc1ccc(C2CCCCC2)cc1
Reaction time: 60 h

Procedure:
A mixture of butyl 1-oxoindane-5-carboxylate (2.00 g, 8.60 mmol), 4-cyclohexylaniline (2.28 g, 13.00 mmol), decaborane (0.32 g, 2.60 mmol) in dry MeOH (30 mL) was stirred under nitrogen for 60 h. Yellow precipitates were collected by filtration and washed with MeOH (3×5 mL) to give butyl 1-[(4-cyclohexylphenyl)amino]indane-5-carboxylate as a white solid. HPLC/MS: m/z=392.6 (M+1), Rt=4.97 min. 1H NMR (CDCl3): δ 8.00 (1H, s), 7.97 (1H, d, J=8.0 Hz), 7.48 (1H, d, J=8.0 Hz), 7.14 (2H, d, J=8.0 Hz), 6.74 (2H, d, J=8.0 Hz), 5.07 (1H, t, J=7.0 Hz), 4.39 (2H, t, J=6.5 Hz), 3.92 (1H, br s), 3.12-3.07 (1H, m), 3.00-2.94 (1H, m), 2.72-2.66 (1H, m), 2.52-2.47 (1H, m), 2.02-1.80 (8H, m), 1.60-1.31 (7H, m), 1.08 (3H, t, J=7.5 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([N:15]3[CH2:21][CH:20]4[N:22]([CH3:23])[CH:17]([CH2:18][CH2:19]4)[CH2:16]3)=[O:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:24]([O:27][C:28](=[O:30])[CH3:29])(=[O:26])[CH3:25].[OH-:31].[Na+]>ClCCl>[C:28]([OH:27])(=[O:30])/[CH:29]=[CH:11]/[C:13]([OH:14])=[O:31].[CH3:23][N:22]1[CH:20]2[CH2:19][CH2:18][CH:17]1[CH2:16][N:15]([C:13]([C:11]1[O:12][C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:24](=[O:26])[CH3:25])=[CH:3][CH:4]=3)=[CH:9][CH:10]=1)=[O:14])[CH2:21]2
Reactant: CC(=O)OC(C)=O
Reactant: CN1C2CCC1CN(C(=O)c1ccc(-c3ccc(N)cc3)o1)C2
Reactant: [OH-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)Nc1ccc(-c2ccc(C(=O)N3CC4CCC(C3)N4C)o2)cc1
Product: O=C(O)/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of [5-(4-amino-phenyl)-furan-2-yl]-(8-methyl-3,8-diaza-bicyclo[3.2.1]oct-3-yl)-methanone (0.40, 1.28 mmol), acetic acid anhydride (197 mg, 1.93 mmol) and dichloromethane (5 ml) was stirred at room temperature for 5 hours. Aqueous sodium hydroxide (5 ml, 1M) was added and the mixture was extracted twice with dichloromethane (2×10 ml). Chromatography on silica gel with dichloromethane, 10% methanol and 1% aqueous ammonia as solvent gave the title compound. The corresponding salt was obtained by addition of a diethyl ether and methanol mixture (9:1) saturated with fumaric acid. Mp. 257-259° C. Yield 515 mg (86%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([OH:16])=[C:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=1.Br[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:29]([O:28][C:26](=[O:27])[CH2:25][O:16][C:7]1[C:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:5][C:4]([C:3]([O:2][CH3:1])=[O:23])=[CH:9][C:8]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)c1cc(-c2ccccc2)c(O)c(-c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(-c2ccccc2)c(OCC(=O)OC(C)(C)C)c(-c2ccccc2)c1
Temperature: 70 °C
Yield: 96.2 %

Procedure:
To the phenol from Step 2 (3.50 g, 11.5 mmol) in acetonitrile (40 mL) was added tert-butyl bromoacetate (3.39 mL, 23 mmol) and K2CO3 (1.93 g, 12.65 mmol). The mixture was heated for 2 h at 70° C. then cooled to room temperature and concentrated. The residue was partitioned between ethyl acetate/H2O. The organic phase was dried (MgSO4) and concentrated to give crude product. The compound was purified by passing it through a short filter column (SiO2) using hexane as the elutant. Concentration afforded 4.63 g (96%) of product as a clear oil. 1H NMR (DMSO-d6) δ 7.86 (s, 2H), 7.60–7.40 (m, 10H), 3.85 (2s, 5H), 1.19 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][C@H:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][C@@H:14]1[F:26])=[CH:9][C:8]([Br:27])=[C:7]([F:28])[CH:6]=2.CO.C(Cl)Cl.[CH2:34](C(CC)(CC)C([O-])([O-])[O-])[CH3:35]>>[Br:27][C:8]1[C:7]([F:28])=[CH:6][C:5]2[N:4]=[CH:3][C:2]3[N:1]=[C:34]([CH3:35])[N:12]([C@H:13]4[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20])[CH2:15][C@@H:14]4[F:26])[C:11]=3[C:10]=2[CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2c(N)cnc3cc(F)c(Br)cc23)[C@@H](F)C1
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Solvent: CO
Solvent: ClCCl
Product: Cc1nc2cnc3cc(F)c(Br)cc3c2n1[C@H]1CCN(C(=O)OC(C)(C)C)C[C@@H]1F

Procedure:
(3S,4S)-tert-butyl 4-((3-amino-6-bromo-7-fluoroquinolin-4-yl)amino)-3-fluoropiperidine-1-carboxylate (27 g, 0.059 mol) was heated in triethylorthoacetate (150 mL) under N2 atmosphere for 5 h at 120° C. The reaction was monitored by TLC (5% MeOH/DCM). The volatiles were concentrated under vacuum, the obtained crude product was purified by column chromatography on silica gel (0-3% MeOH/DCM) to afford (3S,4S)-tert-butyl 4-(8-bromo-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidine-1-carboxylate (15 g, yield from two steps). 1HNMR (CDCl3, 400 MHz): δ 9.28-9.23 (d, 1H), 8.43-8.34 (dd, 1H), 8.01-7.99 (d, 1H), 5.60-5.35 (m, 1H), 5.25-4.85 (m, 1H), 4.75-4.35 (m, 2H), 3.15-2.95 (m, 2H), 2.79 (s, 3H), 2.40-2.05 (m, 2H), 1.57 (s, 9H); LCMS: 100%, m/z=480.8 (M+); HPLC: 97.31%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]=[C:5]2O.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[N:8]=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=1
Reactant: Oc1cc(-c2ccccc2)nc2ccc(F)cc12
Reactant: O=P(Cl)(Cl)Cl
Product: Fc1ccc2nc(-c3ccccc3)cc(Cl)c2c1

Procedure:
A mixture of 30.4 g (0.127 mol) of 6-fluoro-2-phenyl-4-quinolinol, and 65 ml of phosphorus oxychloride was stirred and heated under reflux for 2 hr. This mixture was concentrated in vacuo, diluted with methylene chloride, and poured onto ice. The aqueous phase was neutralized with 3N sodium hydroxide. The organic phase was separated, and the aqueous phase extracted with methylene chloride. The organic phases were combined, washed with water and with brine, dried over sodium sulfate, and concentrated in vacuo to leave 34.8 g of residue. This was dissolved in methylene chloride, and the solution filtered through a plug of alumina. Concentration of the filtrate left 23.7 g of 4-chloro-6-fluoro-2-phenylquinoline, mp 96°-99°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[CH:6]([Cl:17])[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)C=[CH:9][CH:8]=1.COC1C=C(C=CC=1)C(O)C1C2C(=CC=CC=2)[N:30]=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[CH:6]([Cl:17])[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:30]=[CH:9][CH:8]=1
Reactant: COc1cccc(C(Cl)c2cccc3ccccc23)c1
Reactant: COc1cccc(C(O)c2ccnc3ccccc23)c1
Product: COc1cccc(C(Cl)c2ccnc3ccccc23)c1

Procedure:
The compound 27 was prepared by following the synthesis procedure as described for compound 2, but substituting compound 1 for compound 26.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)/[C:5](=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])/[O:4][C:3]1=[O:23].C(N(CC)CC)C.CC(C)(O)C#N>C(#N)C>[CH3:1][C:2]1([CH3:24])[C:11]2[N:10]=[CH:9][CH:8]=[N:7][C:6]=2[C:5](=[O:4])[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:20])([F:21])[F:22])[C:3]1=[O:23]
Reactant: CC1(C)C(=O)O/C(=C\c2ccccc2C(F)(F)F)c2nccnc21
Agent: CC(C)(O)C#N
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC1(C)C(=O)C(c2ccccc2C(F)(F)F)C(=O)c2nccnc21
Reaction time: 16 h
Yield: 111.8 %

Procedure:
To a stirred solution of 8,8-dimethyl-5-[1-(2-trifluoromethyl-phenyl)-meth-(Z)-ylidene]-5,8-dihydro-pyrano[3,4-b]pyrazin-7-one (0.170 g) in acetonitrile (1.7 ml) at ambient temperature was added triethylamine (0.154 g) and 4□ molecular sieves. After 10 min acetone cyanohydrin (0.013 g) was added and the reaction mixture stirred for 16 hours. The reaction mixture was concentrated and the residue purified by chromatography on silica gel (eluent 5-95% ethyl acetate in isohexane) to give the crude 8,8-dimethyl-6-(2-trifluoromethyl-phenyl)-8H-quinoxaline-5,7-dione (compound E1 of Table E) (0.190 g) which was carried over to the next step.