Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cu:1].[Ba].[C:3]([O-])(=O)[C:4]([O-:6])=[O:5].[K+].[K+]>[Y]>[C:4]([O-:6])(=[O:5])[CH3:3].[Cu+2:1].[C:4]([O-:6])(=[O:5])[CH3:3]
Reactant: O=C([O-])C(=O)[O-]
Reactant: [Cu]
Agent: [Ba]
Agent: [K+]
Agent: [Y]
Product: CC(=O)[O-]
Product: [Cu+2]

Procedure:
The copper, barium, and yttrium solutions were mixed and the potassium oxalate solution was added all at once with vigorous stirring. The pH of the solution was 11.3. A brown gelatinous precipitate formed, and it was filtered, washed thoroughly with water, dried at 120° C., and crushed to a fine powder. The elemental analysis shown in the table below suggested YBa2Cu3 (OH)3 (Ox)2O3.H2O.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.C([N:11](CC)CC)C.[C:16](Cl)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]>C(Cl)Cl>[C:16]([C:6]1[CH:7]=[CH:2][N:3]=[C:4]([NH2:8])[C:5]=1[NH2:11])(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: Nc1cccc(N)n1
Reactant: CCN(CC)CC
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)C(=O)c1ccnc(N)c1N
Temperature: 25 °C

Procedure:
To a solution of 2,6-diaminopyridine (10 g, 91.743 mmol) and triethylamine (11.14 g, 110.091 mmol, 1.2 equiv.) in DCM (100 mL) at 0° C. is added dropwise a solution of pivaloyl chloride (12.11 g, 100.917 mmol, 1.1 equiv.) in DCM (50 mL) over 2 hours. After completion of the addition the mixture is allowed to warm to room temperature over 30 minutes, at which point LC-MS shows full conversion to the desired material. The mixture is filtered to remove the triethylammonium chloride, and the solvent is removed under vacuum to afford a solid that is not processed further.
Reaction SMILES: [CH:1]([C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[C:8]([CH:13]([CH3:15])[CH3:14])[CH:7]=[C:6]([CH:16]([CH3:18])[CH3:17])[C:5]=1[S:19]([OH:22])(=[O:21])=[O:20])([CH3:3])[CH3:2].C(#N)C.[Ag:26]=O>CC(C)=O>[CH:1]([C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[C:8]([CH:13]([CH3:14])[CH3:15])[CH:7]=[C:6]([CH:16]([CH3:18])[CH3:17])[C:5]=1[S:19]([O-:22])(=[O:21])=[O:20])([CH3:2])[CH3:3].[Ag+:26]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)O)c(C(C)C)c1[N+](=O)[O-]
Reactant: O=[Ag]
Solvent: CC#N
Solvent: CC(C)=O
Product: CC(C)c1cc(C(C)C)c(S(=O)(=O)[O-])c(C(C)C)c1[N+](=O)[O-]
Product: [Ag+]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Into a flask were charged 20 parts of 2,4,6-triisopropyl-3-nitrobenzenesulfonic acid, 80 parts of acetonitrile and 40 parts of acetone, and the mixture was stirred at room temperature for 16 hours. To this was added 7.46 parts of silver oxide, and the mixture was stirred at room temperature for 16 hours, and then filtered and concentrated to obtain 23.68 parts of silver 2,4,6-triisopropyl-3-nitrobenzenesulfonate.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH:12]1([NH:15][C:16](=[O:41])[C:17]2[CH:22]=[C:21]([F:23])[C:20]([CH3:24])=[C:19]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([N:33]4[CH2:38][CH2:37][CH2:36][CH:35]([CH2:39][CH3:40])[CH2:34]4)=[O:32])=[CH:27][N:26]=3)[CH:18]=2)[CH2:14][CH2:13]1>C(Cl)(Cl)Cl.CO>[CH:12]1([NH:15][C:16](=[O:41])[C:17]2[CH:22]=[C:21]([F:23])[C:20]([CH3:24])=[C:19]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([N:33]4[CH2:38][CH2:37][CH2:36][CH:35]([CH2:39][CH3:40])[CH2:34]4)=[O:32])=[CH:27][N+:26]=3[O-:9])[CH:18]=2)[CH2:14][CH2:13]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCC1CCCN(C(=O)c2ccc(-c3cc(C(=O)NC4CC4)cc(F)c3C)nc2)C1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCC1CCCN(C(=O)c2ccc(-c3cc(C(=O)NC4CC4)cc(F)c3C)[n+]([O-])c2)C1
Temperature: 60 °C

Procedure:
mCPBA (57-86%, 10 mg) dissolved in chloroform (0.1 ml) was added to a solution of N-cyclopropyl-3-{5-[(3-ethylpiperidin-1-yl)carbonyl]pyridin-2-yl}-5-fluoro-4-methylbenzamide (Intermediate 33, 10.5 mg) in chloroform (2 ml) at 60° C. and the reaction maintained at 60° C. for 5 hrs. The reaction was allowed to cool, diluted with methanol, and passed through an aminopropyl SPE (1 g). The filtrate was reduced to dryness under vacuum and the residue triturated with ether to give N-cyclopropyl-3-{5-[(3-ethyl-1-piperidinyl)carbonyl]-1-oxido-2-pyridinyl}-5-fluoro-4-methylbenzamide as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[NH:8][CH:9]=[N:10][C:6]=2[C:5]([C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.[N+:14]([O-])([O-:16])=[O:15].[K+]>OS(O)(=O)=O>[CH3:1][C:2]1[C:7]2[NH:8][CH:9]=[N:10][C:6]=2[C:5]([C:11]([OH:13])=[O:12])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1ccc(C(=O)O)c2nc[nH]c12
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1c([N+](=O)[O-])cc(C(=O)O)c2nc[nH]c12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of 7-Methyl-1H-benzimidazole-4-carboxylic Acid (22) (4.944 g, 28.10 mmol) and concentrated H2SO4 (30 mL) is heated to about 60° C. to obtain a solution which is then cooled to about 0° C. To this solution is added KNO3 (3.12 g, 30.9 mmol) portionwise, so as to maintain the internal reaction temperature <10° C. Following complete addition, the cooling source is removed and the reaction mixture is allowed to warm to ambient temperature, whereupon the mixture is stirred for about 1 hour. The reaction mixture is then added to ice water (100 mL) and held at about 0° C. for about 4 hours. The resulting solids are filtered, washed with water, and dried to provide 7-Methyl-6-nitro-1H-benzimidazole-4-carboxylic Acid (23) as an off white solid (6.12 g, 98% yield).
Reaction SMILES: CI.[Br:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[C:6]([CH3:13])[CH:5]=1.[C:14](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:10][CH3:14])=[O:9])=[C:6]([CH3:13])[CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(Br)ccc1C(=O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)c1ccc(Br)cc1C
Reaction time: 18 h
Yield: 79 %

Procedure:
Methyl iodide (10.0 mL, 160 mmol) was added to a mixture of 4-bromo-2-methylbenzoic acid (25.0 g, 116 mmol) and potassium carbonate (20.0 g, 145 mmol) in anhydrous dimethylformamide (75 mL) at room temperature under a nitrogen atmosphere and stirred for 18 h. The mixture was poured into water and extracted with ethyl acetate (3×50 mL). The organic phases were combined, washed with copper sulfate solution (50 mL) and brine (50 mL), dried and evaporated. Purification by column chromatography on silica gel using 9:1 hexane/ethyl acetate as eluant provided 21.0 g (79%) of methyl 4-bromo-2-methylbenzoate as a clear liquid: 1H NMR (CDCl3) δ7.85 (d, 1H), 7.42-7.47 (m, 2H), 3.95 (s, 3H), 2.64 (s, 3H); IR (neat) 1726 cm1 ; Mass spectrum m/z 197, 199 (M+H-OCH3).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH2:7].[H-].[Na+].[CH:11]([C:14]1[S:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[C:15]=1[S:23](Cl)(=[O:25])=[O:24])([CH3:13])[CH3:12]>C1COCC1>[Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH:7][S:23]([C:15]1[C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[S:18][C:14]=1[CH:11]([CH3:13])[CH3:12])(=[O:24])=[O:25]
Reactant: CC(C)c1sc2ccccc2c1S(=O)(=O)Cl
Reactant: Cc1noc(N)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(NS(=O)(=O)c2c(C(C)C)sc3ccccc23)c1Br

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-2-i-propylbenzo[b]thiophene-3-sulfonamide was prepared by the method of Example 41 using 4-bromo-3-methyl-5-aminoisoxazole (0.55 mmoles, 9.7 mg), NaH (1.4 mmoles, 5.5 mg), 2-i-propylbenzo[b]thiophene-3-sulfonyl chloride (0.60 mmoles, 0.17 g) and THF (2 ml). Recrystallization from chloroform and hexanes provided 89 mg (39%) of a tan crystalline solid, m.p. 157.5-159° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:13][CH:12]([OH:14])[CH2:11]2)=[N:8][CH:9]=1)([O-])=O.[C:15]1([C:21]2[O:22][C:23]([C:29]([F:32])([F:31])[F:30])=[C:24]([C:26](O)=[O:27])[N:25]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN(CC)CC.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CCO.C(O)(=O)C.[Pd]>[OH:14][CH:12]1[CH2:13][N:10]([C:7]2[N:8]=[CH:9][C:4]([NH:1][C:26]([C:24]3[N:25]=[C:21]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[O:22][C:23]=3[C:29]([F:31])([F:32])[F:30])=[O:27])=[CH:5][CH:6]=2)[CH2:11]1
Reactant: O=[N+]([O-])c1ccc(N2CC(O)C2)nc1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: [Pd]
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(Nc1ccc(N2CC(O)C2)nc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.1 %

Procedure:
1-(5-Nitro-pyridin-2-yl)-azetidin-3-ol (400 mg, 2 mmol) was hydrogenated at 35 psi for 2¾ hrs with 10% Pd/C (40 mg) in EtOH (30 mL) and acetic acid (2 drops). The mixture was filtered through a celite plug, evaporated and then co-evaporated with toluene. The residue was dissolved in DMF (15 mL). One half of this solution (7.5 mL, ˜1 mmol) was removed. To this was added 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (257 mg, 1 mmol), Et3N (422 uL, 3 mmol) and BOP (464 mg. 1.05 mmol). The reaction was stirred for 1 hr at room temperature. Following work-up as above, the crude material was purified by flash chromatography to yield 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(3-hydroxyazetidin-1-yl)-pyridin-3-yl]-amide as an off-white solid (41 mg). ES-MS calcd for C19H15F3N4O3 (m/e) 404.35, obsd 405.1 (M+H).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([C:10](OCC)=O)[C:5]([O:7]CC)=[O:6].BrC[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[C:19]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:18]=1.O>O1CCCC1>[CH3:3][CH:4]([CH2:10][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[C:19]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:18]=1)[C:5]([OH:7])=[O:6]
Reactant: BrCc1nc(-c2ccccc2)cc2ccccc12
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(Cc1nc(-c2ccccc2)cc2ccccc12)C(=O)O
Reaction time: 1 h
Yield: 72.8 %

Procedure:
Sodium hydride (2.1 g, 60% strength in oil) and anhydrous tetrahydrofuran (50 cc) are placed under nitrogen. A solution of diethyl methylmalonate (9.1 g) in anhydrous tetrahydrofuran (50 cc) is added dropwise. Stirring is continued for 1 hour at room temperature (approximately 20° C.) and a solution of 1-bromomethyl-3-phenylisoquinoline (10.4 g) in anhydrous tetrahydrofuran (100 cc) is added. After 20 hours of contact, water (200 cc) is added and the aqueous phase extracted with ethyl acetate (3×50 cc). After removal of the solvents under reduced pressure, the product (19 g) recovered is brought to boiling for 20 hours in concentrated hydrochloric acid (70 cc) and acetic acid (70 cc). After being cooled, the mixture is poured into water (1000 cc) and alkalinised to pH 10 with sodium hydroxide solution, and the aqueous phase is washed with ethyl acetate (100 cc) acidified with hydrochloric acid and extracted with chloroform (3×200 cc). The organic phase is dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure. α-Methyl-3-phenyl-1-isoquinolinepropanoic acid (7.4 g), m.p. 184° C., is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:37]=1)[N:7]=[C:8]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:9][C:10]([C:12](=[O:28])[N:13]([CH2:17][CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:14][CH2:15][CH3:16])=[CH:11]2.CC1(C)C(C)(C)OB([C:46]2[CH:51]=[CH:50][C:49]([CH2:52][C:53]([O:55][CH2:56][CH2:57][CH3:58])=[O:54])=[CH:48][CH:47]=2)O1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:32]([O:31][C:30]([NH:29][C:8]1[CH2:9][C:10]([C:12](=[O:28])[N:13]([CH2:17][CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:26])([CH3:25])[CH3:27])([CH3:23])[CH3:22])[CH2:14][CH2:15][CH3:16])=[CH:11][C:5]2[CH:4]=[CH:3][C:2]([C:46]3[CH:51]=[CH:50][C:49]([CH2:52][C:53]([O:55][CH2:56][CH2:57][CH3:58])=[O:54])=[CH:48][CH:47]=3)=[CH:37][C:6]=2[N:7]=1)=[O:36])([CH3:34])([CH3:35])[CH3:33]
Reactant: CCCN(CCCO[Si](C)(C)C(C)(C)C)C(=O)C1=Cc2ccc(Br)cc2N=C(NC(=O)OC(C)(C)C)C1
Reactant: CCCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCOC(=O)Cc1ccc(-c2ccc3c(c2)N=C(NC(=O)OC(C)(C)C)CC(C(=O)N(CCC)CCCO[Si](C)(C)C(C)(C)C)=C3)cc1
Temperature: 100 °C

Procedure:
tert-butyl (1E,4E)-8-bromo-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-3H-benzo[b]azepin-2-ylcarbamate, propyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (1.5 equiv), tetrakis(triphenylphosphine)palladium(0), 2M aqueous potassium carbonate (3 equiv) were combined in 2 mls of acetonitrile in a microwave reaction vial. This mixture was heated in a microwave to 100° C. for 30 minutes. The mixture was then diluted with EtOAc, washed twice with brine, dried over sodium sulfate, and concentrated under reduced pressure. Preparative thin layer chromatography (2×0.5 mm plates, 7% MeOH/DCM) afforded propyl 2-(4-((1E,4E)-2-(tert-butoxycarbonylamino)-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)phenyl)acetate.
Reaction SMILES: [NH2:1][C:2](=[O:37])[C@@H:3]([NH:20][C:21]([C:23]1([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:22])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][CH:6]=1.Br[C:39]1[CH:40]=[CH:41][C:42]2[NH:47][C:46](=[O:48])[CH2:45][S:44][C:43]=2[CH:49]=1.[C:50](=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[NH2:1][C:2](=[O:37])[C@@H:3]([NH:20][C:21]([C:23]1([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1)=[O:22])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:39]2[CH:40]=[CH:41][C:42]3[N:47]([CH3:50])[C:46](=[O:48])[CH2:45][S:44][C:43]=3[CH:49]=2)=[CH:9][CH:10]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C(N)=O)CCOCC1
Reactant: O=C1CSc2cc(Br)ccc2N1
Agent: [Na+]
Solvent: CC#N
Product: CN1C(=O)CSc2cc(-c3ccc(C[C@H](NC(=O)C4(NC(=O)OC(C)(C)C)CCOCC4)C(N)=O)cc3)ccc21
Temperature: 85 °C

Procedure:
(S)-tert-Butyl 4-(1-amino-1-oxo-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 16, step (i), 241 mg) in acetonitrile (8 mL) with 7-bromo-4-methyl-2H-benzo[b][1,4]thiazin-3(4H)-one (Example 28, step (i), 120 mg) was treated with aqueous sodium carbonate solution (2M, 0.465 mL) and then nitrogen was bubbled through the mixture. 1,1 bis(Di-tert-butylphosphino)ferrocene palladium dichloride (5 mg) was added and the mixture was heated at 85° C. under nitrogen for 18 h. A further addition of sodium carbonate solution (2M, 0.2 mL) and 1,1 bis(di-tert-butylphosphino)ferrocene palladium dichloride (5 mg) was made and the mixture was heated at 85° C. for a further 18 h. A further addition of (S)-tert-butyl 4-(1-amino-1-oxo-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 16, step (i), 20 mg) was made and the mixture was heated at 85° C. for 18 h. The mixture was purified by chromatography on silica eluting with ethyl acetate/isohexane (50:50 to 100:0) to afford the sub-titled compound (132 mg).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:15]=2)[CH2:9]1)C1C=CC=CC=1.[Cl:25]C(OCCCl)=O>ClCCCl>[ClH:25].[C:19]1([C:16]2[N:15]=[C:14]([CH:10]3[O:11][CH2:12][CH2:13][NH:8][CH2:9]3)[O:18][N:17]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: c1ccc(CN2CCOC(c3nc(-c4ccccc4)no3)C2)cc1
Reactant: O=C(Cl)OCCCl
Solvent: ClCCCl
Product: Cl
Product: c1ccc(-c2noc(C3CNCCO3)n2)cc1
Temperature: 70 °C

Procedure:
To a stirred solution of 4-benzyl-2-(3-phenyl-1,2,4-oxadiazol-5-yl)morpholine (intermediate 21, 2.0 g, 6.22 mmol) in 1,2-dichloroethane (10 ml) was added chloroethyl chloroformate (2.0 ml, 18.7 mmol), and the reaction mixture was stirred for at 70° C. 4 hours. The reaction mixture was concentrated in vacua After removal of the solvent, the residue was dissolved in methanol (10 ml), and the reaction solution was stirred for one hour under reflux. When the reaction was complete (checked by thin layer chromatography), the reaction mixture was concentrated in vacuo. The resulting 2-(3-phenyl-[1,2,4]oxadiazol-5-yl)-morpholine hydrochloride (intermediate 22) was used for next reaction without further purification.
Reaction SMILES: [N+:1]([C:4]1[C:23]([N+:24]([O-])=O)=[C:22]([O:27][CH3:28])[CH:21]=[CH:20][C:5]=1/[CH:6]=[CH:7]\[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=1)([O-])=O.S([O-])([O-])(=O)=S.[Na+].[Na+].O>CC(C)=O.O>[NH2:1][C:4]1[C:23]([NH2:24])=[C:22]([O:27][CH3:28])[CH:21]=[CH:20][C:5]=1/[CH:6]=[CH:7]\[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=1
Reactant: COc1cc(/C=C\c2ccc(OC)c([N+](=O)[O-])c2[N+](=O)[O-])cc(OC)c1OC
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(/C=C\c2cc(OC)c(OC)c(OC)c2)c(N)c1N
Temperature: 50 °C

Procedure:
A well-stirred solution of 2′,3′-Dinitro-3,4,4′,5-tetramethoxy-(Z)-stilbene (0.422 g, 1.08 mmol) in a mixture of acetone-water (2:1) was heated to 50° C. Then sodium thiosulfate (1.88 g, 10.81 mmol, 10.0 equiv) was added and the reaction mixture was heated to reflux for 6 hours. The reaction was cooled to room temperature and water was added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (4×25 mL). The combined organic layer were washed with brine, dried over Na2SO4 and concentrated in vacuo. The mixture was then subjected to preparative TLC to give the 2′,3′-Diamino-3,4,4′,5-tetramethoxy-(Z)-stilbene.
Reaction SMILES: C([O:4][C:5]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])C=C.CN(C)[C:18]1[CH:23]=CC=C[CH:19]=1>>[Cl:15][C:13]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([OH:4])[C:14]=1[CH2:23][CH:18]=[CH2:19]
Reactant: CN(C)c1ccccc1
Reactant: C=CCOc1cc(Cl)ccc1C(=O)OC
Product: C=CCc1c(Cl)ccc(C(=O)OC)c1O
Yield: 71.1 %

Procedure:
A solution of methyl 2-allyloxy-4-chlorobenzoate (3f) (50.6 g, 0.22 mol) in 100 ml of N,N-dimethylaniline was heated under argon in an oil bath at 190°-205° C. for 20 hours. The solvent was removed by distillation and the residue purified by column chromatography (silica gel, CH2Cl2 /hexane) to give 4f (36.0 g, 71.1% yield) as a very light oil. IR (nujol) 1665 (C=0) cm-1. NMR (CDCl3) δ 11.23 (s, 1H, OH), 7.47 (d, 1H, J=9 Hz, aromatic proton meta to Cl), 6.77 (d, 1H, aromatic proton alpha to Cl), 6.17-4.77 (m, 3H, olefinic orotons), 3.87 (s, 3H, CH3) and 3.50 (m, 2H, CH2).
Reaction SMILES: NC(C1C=CC2C(=CC=C(O[C@H]3CC[C@H](C(C)(C)C)CC3)C=2)N=1)(C)CO.C(O)(C(F)(F)F)=O.C([O:36][C:37](=O)[C:38]([NH2:65])([C:40]1[CH:49]=[CH:48][C:47]2[C:42](=[CH:43][CH:44]=[C:45]([O:54][C@H:55]3[CH2:60][CH2:59][C@H:58]([C:61]([CH3:64])([CH3:63])[CH3:62])[CH2:57][CH2:56]3)[C:46]=2[C:50]([F:53])([F:52])[F:51])[N:41]=1)[CH3:39])C>>[NH2:65][C:38]([C:40]1[CH:49]=[CH:48][C:47]2[C:42](=[CH:43][CH:44]=[C:45]([O:54][C@H:55]3[CH2:56][CH2:57][C@H:58]([C:61]([CH3:64])([CH3:63])[CH3:62])[CH2:59][CH2:60]3)[C:46]=2[C:50]([F:51])([F:52])[F:53])[N:41]=1)([CH3:39])[CH2:37][OH:36]
Reactant: CCOC(=O)C(C)(N)c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1
Agent: CC(N)(CO)c1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1
Solvent: O=C(O)C(F)(F)F
Product: CC(N)(CO)c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1

Procedure:
2-Amino-2-[6-(trans-4-tert-butyl-cyclohexyloxy)-5-trifluoromethyl-quinolin-2-yl]-propan-1-ol was synthesized as per 2-amino-2-[6-(trans-4-tert-butyl-cyclohexyloxy)-quinolin-2-yl]-propan-1-ol (Example 18) in 49% yield (TFA salt) using 2-amino-2-[6-(trans-4-tert-butyl-cyclohexyloxy)-5-trifluoromethyl-quinolin-2-yl]-propionic acid ethyl ester as starting material (TFA salt). MS: m/z=425.20 [M+H]+. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm: 8.70 (d, J=8.8 Hz, 1H), 8.15 (d, J=9.5 Hz, 1H), 7.62 (d, J=9.5 Hz, 1H), 7.50 (d, J=9.3 Hz, 1H), 4.33-4.45 (m, 1H), 4.08-4.25 (m, 2H), 2.15-2.27 (m, 2H), 1.85-1.98 (m, 2H), 1.78 (s, 3H), 1.48-1.64 (m, 2H), 1.04-1.24 (m, 3H), 0.90 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][C@@H:19]2[CH3:24])[C:5]2[CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][C:6]=2[N:7]=1.[CH3:25][NH:26][C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=1)=[O:28]>>[CH3:25][NH:26][C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([C:2]2[N:3]=[C:4]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][C@@H:19]3[CH3:24])[C:5]3[CH2:10][NH:9][CH2:8][C:6]=3[N:7]=2)=[CH:32][CH:31]=1)=[O:28]
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1CN(C(=O)OC(C)(C)C)C2
Reactant: CNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CNC3)cc1

Procedure:
Method as described for example 3 using intermediate 1 and 1-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea as starting materials. The boc protected intermediate was purified by prep HPLC (high pH).
Reaction SMILES: C([O-])(=O)C.[K+].Cl[C:7]1[N:12]=[CH:11][N:10]=[C:9]2[NH:13][N:14]=[CH:15][C:8]=12.[F:16][C:17]1[C:22](B(O)O)=[CH:21][CH:20]=[CH:19][N:18]=1.O>CCO>[F:16][C:17]1[C:22]([C:7]2[N:12]=[CH:11][N:10]=[C:9]3[NH:13][N:14]=[CH:15][C:8]=23)=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: Clc1ncnc2[nH]ncc12
Reactant: OB(O)c1cccnc1F
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Fc1ncccc1-c1ncnc2[nH]ncc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of potassium acetate (13 g, 130 mmol), PdCl2(P-t-Bu2Ph)2 (1.1 g, 1.7 mmol), 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (6.70 g, 43 mmol) and 2-fluoropyridin-3-ylboronic acid (7.3 g, 52 mmol) in EtOH (300 ml)-water (100 ml) was sonicated until the solid became a fine powder and degassed under vacuum. The mixture was refluxed under N2 overnight. After cooling to rt solvent was removed in vacuo and to the residues was added water (200 ml) and NaHCO3 (sat. 150 ml). The mixture was stirred for 15 min. The solid was filtered and washed with water. The solid was dissolved in MeOH-DCM and preloaded on silica gel and purified by flash chromatography eluting with MeOH/DCM (1-5%) to give 4-(2-fluoropyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidine. MS Found: (ESI pos. ion) m/z 216 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:8][CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:26][O:27][C:28]1[C:29](=[O:52])[C:30]([CH3:51])=[C:31]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:47][C:48](=[O:50])[CH3:49])=[C:42]([CH:46]=2)[C:43](O)=[O:44])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]>C(Cl)Cl>[CH3:9][O:8][C:3]1[C:2]([NH:1][C:43](=[O:44])[C:42]2[CH:46]=[C:38]([CH2:37][C:31]3[C:32](=[O:36])[C:33]([O:34][CH3:35])=[C:28]([O:27][CH3:26])[C:29](=[O:52])[C:30]=3[CH3:51])[CH:39]=[CH:40][C:41]=2[O:47][C:48](=[O:50])[CH3:49])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Reactant: COc1ncccc1N
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3cccnc3OC)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.8 %

Procedure:
3-Amino-2-methoxypyridine (0.149 g, 1.203 mmol), triethylamine (0.122 g, 1.203 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.203 g, 1.203 mmol) were added to a methylene chloride solution (150 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.300 g, 0.802 mmol) and the resulting solution was stirred at room temperature for 4 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=50:1) to obtain the titled compound (0.250 g, 0.520 mmol, 65%).