Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[C:15]([F:24])[CH:14]=1)#[CH:12].N>>[F:24][C:15]1[CH:14]=[C:13]([C:11]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[CH:12]=2)[CH:18]=[CH:17][C:16]=1[O:19][C:20]([F:21])([F:22])[F:23]
Reactant: C#Cc1ccc(OC(F)(F)F)c(F)c1
Reactant: ON=C(Cl)c1cccnc1
Agent: N
Product: Fc1cc(-c2cc(-c3cccnc3)no2)ccc1OC(F)(F)F

Procedure:
The titled compound was prepared as the hydrochloride salt according to Method CB using the product of Example 1A (78 mg, 0.5 mmol) and 4-ethynyl-2-fluoro-1-(trifluoromethoxy)benzene (Apollo, 102 mg, 0.5 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.69 (dd, J=8.0, 4.9 Hz, 1H), 7.78-7.96 (m, 3H), 8.11 (dd, J=11.0, 1.9 Hz, 1H), 8.38 (dt, J=8.1, 1.9 Hz, 1H), 8.79 (dd, J=4.9, 1.2 Hz, 1H), 9.15 (d, J=1.0 Hz, 1H) ppm; MS (DCI/NH3) m/z 325 (M+H)+.
Reaction SMILES: C([NH:4][C:5]1[CH:18]=[CH:17][N:8]([C@@H:9]2[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([OH:12])[CH2:10]2)[C:7](=[O:19])[N:6]=1)(=O)C.N>>[C@@H:9]1([N:8]2[CH:17]=[CH:18][C:5]([NH2:4])=[N:6][C:7]2=[O:19])[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([OH:12])[CH2:10]1
Reactant: CC(=O)Nc1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)n1
Agent: N
Product: Nc1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)n1
Yield: 84.6 %

Procedure:
2′-deoxy-4-N-acetylcytidine is treated with methanolic ammonia overnight. The solution is concentrated in vacuo, and the residue is dissolved in water (100 mL) and is washed with dichloromethane (2×50 mL). The aqueous phase is evaporated in vacuo and the residue is purified on a column of Dowex 1-X2 (OH−)resin. The product is eluted with water, and the fractions are collected, evaporated and the residue is crystallized in methanol to give 2′-deoxycytidine (0.902 g, 84.6%). Melting point 208-210° C. 1H NMR (DMSO) d 1.94(dt, J=13.2, 6.1 Hz, 1, H2′), 2.12 (ddd, J=13.2, 6.0, 3.3 Hz, 1, H2″),3.07 (m, 2, H5′,5″), 3.77 (dd, J=6.9, 3.8 Hz, 1, H3′), 4.21 (dd, J=5.9, 3.2 Hz, 1, H4′), 5.02 (t, J=5.0 Hz, 1, OH5′), 5.23 (d, J=4.1 Hz, 1, OH3′), 5.75 (d, J=7.4 Hz, 1, H5), 6.17 (t, J=6.7 Hz, 1, H1′), 7.21 (br s, 2, NH2), 7.81 (d, J=7.4 Hz, 1, H6) ppm. MS (FAB) m/z 228.0990 (MH+[C9H14N3O4]=228.0984).
Reaction SMILES: [SH:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:12]([C:14]1[N:19]=[C:18]([CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:17]=[CH:16][CH:15]=1)#[N:13]>N1C=CC=CC=1>[CH3:11][C:9]1[CH:8]=[CH:7][C:3]2[C:4](=[O:6])[N:13]=[C:12]([C:14]3[N:19]=[C:18]([CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:17]=[CH:16][CH:15]=3)[S:1][C:2]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)CCc1cccc(C#N)n1
Reactant: Cc1ccc(C(=O)O)c(S)c1
Solvent: c1ccncc1
Product: Cc1ccc2c(=O)nc(-c3cccc(CCC(=O)OC(C)(C)C)n3)sc2c1
Yield: 53.5 %

Procedure:
2-Mercapto-4-methylbenzoic acid (1.56 g, 9.3 mmol) and tert-butyl 3-(6-cyano-2-pyridyl)propanoate (1.46 g, 6.3 mmol) were dissolved in pyridine (15 ml), and the mixture was refluxed for 6 hrs. The reaction mixture was concentrated under reduced pressure, subjected to silica gel column chromatography, eluted with hexane-ethyl acetate (3:2, v/v) and recrystallized from ethyl acetate-hexane to give the titled compound (1.29 g, 53%).
Reaction SMILES: [Br:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N1C=CC=CC=1.B(O)O>C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:15]1[CH:16]=[CH:17][C:18]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[C:13]([F:12])[CH:14]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1
Reactant: Fc1ccc2[nH]ncc2c1Br
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: OBO
Solvent: c1ccncc1
Product: Fc1cc(-n2ncc3c(Br)c(F)ccc32)ccc1OCc1ccccc1
Reaction time: 24 h
Yield: 49.7 %

Procedure:
A mixture of 4-bromo-5-fluoro-1H-indazole (D15) (1.008 g, 4.69 mmol), {3-fluoro-4-[(phenylmethyl)oxy]phenyl}boronic acid 1.730 g, 7.03 mmol), copper(II) acetate (1.277 g, 7.03 mmol) and pyridine (0.758 mL, 0.742 g, 9.38 mmol) were stirred together vigorously under an air atmosphere with powdered 4A molecular sieves (5 g) at room temperature. After 6 days another 580 mg of boronic acid were added and stirring continued for a further 24 hrs. The mixture was filtered through celite, the celite was washed with dichloromethane and the combined filtrate was washed with water, dried over Na2SO4 and evaporated. Chromatography (silica gel, 0-100% dichloromethane in isohexane), followed by trituration of the product with diethyl ether gave the title compound (D16) (0.968 g) as a white solid.
Reaction SMILES: [Br:1][CH:2]([CH2:17][CH2:18]Br)[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)=[O:4].[H-].[Na+]>O1CCCC1.O>[Br:1][CH:2]1[CH2:17][CH2:18][N:5]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[C:3]1=[O:4]
Reactant: O=C(NCc1ccc(C(F)(F)F)cc1)C(Br)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1C(Br)CCN1Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.4 %

Procedure:
To a suspension of 2,4-dibromo-N-(4-(trifluoromethyl)benzyl)butanamide (6.8 g, 16.9 mmol) in tetrahydrofuran (200 mL) was added NaH (1.35 g, 34 mmol) and the reaction was stirred at rt for 4 h. The reaction mixture was then diluted with water and twice extracted with 30 mL of ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified by silica gel chromatography eluting with 0-40% ethyl acetate/hexanes to afford 2.8 g of 3-bromo-1-(4-(trifluoromethyl)benzyl)pyrrolidin-2-one (48%). LCMS (method Q) RT 0.90 min, m/z 322.1 (M+H+; 1H NMR (400 MHz, chloroform-d) δ 12.39 (d, J=8.0 Hz, 2H), 12.16 (d, J=8.0 Hz, 2H), 9.46-9.38 (m, 1H), 9.25 (d, J=1.8 Hz, 2H), 8.27-8.17 (m, 1H), 7.99 (s, 1H), 7.43-7.31 (m, 1H), 7.14-7.05 (m, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([O:15]CC)=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[C:22]([O:39][CH3:40])[CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[C:22]([O:39][CH3:40])[CH:21]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: COc1cc(COc2nn(Cc3ccccc3)cc2C(=O)O)ccc1OCc1nc(-c2ccco2)oc1C
Yield: 84.4 %

Procedure:
To a mixture of ethyl 1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1H-pyrazole-4-carboxylate (0.70 g), tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (5 mL) and the mixture was heated under reflux for 2 hrs. 1N Hydrochloric acid (5 mL) and water were added to the reaction mixture and the precipitated crystals were collected by filtration to give 1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1H-pyrazole-4-carboxylic acid as crystals (0.56 g, yield 84%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 167-168° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[OH:9].CN(C)C=O.Cl[C:16]([F:21])([F:20])C([O-])=O.[Na+].C(=O)([O-])[O-].[Cs+].[Cs+].O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[O:9][CH:16]([F:21])[F:20]
Reactant: Oc1cc(Cl)ccc1Br
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)Oc1cc(Cl)ccc1Br
Temperature: 100 °C
Reaction time: 16 h
Yield: 80.8 %

Procedure:
The title compound was prepared according to the procedure disclosed in Published PCT Patent Application No. WO2011/003065 A2. To a solution of 2-bromo-5-chlorophenol (4.34 g, 20.92 mmol) (the oil from above) in N,N-dimethylformamide (21.8 mL, 20.9 mmol) was added sodium chlorodifluoroacetate (7.34 g, 48.1 mmol), cesium carbonate (9.54 g, 29.3 mmol), and water (2.18 mL, 20.9 mmol). The reaction was stirred at 100° C. for 16 h. The reaction was cooled to room temperature and partitioned between EtOAc (100 mL) and water (50 mL). The aqueous layer was extracted with EtOAc (2×70 mL). The organic layers were combined and washed with water (2×50 mL), 10% aq. citric acid (1×30 mL), brine, dried over MgSO4, filtered, and concentrated to afford 1-bromo-4-chloro-2-(difluoromethoxy)benzene (4.35 g, 16.9 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.30 (dd, J=2.3, 8.6 Hz, 1H), 7.37 (t, J=73 Hz, 1H), 7.49 (dt, J=2.40, 0.81 Hz, 1H), 7.79 (d, J=8.6 Hz, 1H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.C1C=C(O)C([S:20]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])=CC=1.[OH-].[Na+]>O.ClC1C=CC=CC=1Cl>[CH:6]1[C:1]([OH:7])=[CH:2][CH:3]=[C:4]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH:5]=1
Reactant: Oc1ccccc1
Reactant: O=S(=O)(c1ccc(O)cc1)c1ccccc1O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Clc1ccccc1Cl
Solvent: O
Product: O=S(=O)(c1ccc(O)cc1)c1ccc(O)cc1
Yield: 91.2 %

Procedure:
A mixture of 290 g (3.09 moles) of phenol, 146 g of 98% sulfuric acid and 150 g of o-dichlorobenzene is heated with stirring. When the temperature of the reaction system reaches about 150° C., the mixture begins to boil, giving off an azeotropic mixture of water and o-dichlorobenzene, which is condensed and separated into two phases, i.e., water and o-dichlorobenzene. The o-dichlorobenzene is continuously returned to the reaction mixture. With continuous heating, when the amount of the aqueous phase reaches 52 ml, the temperature of reaction mixture is about 180° C. Subsequently o-dichlorobenzene containing small amounts of water and phenol is completely distilled off over a period of 3 hours by reducing a pressure of the reaction system to produce the dried reaction mixture in a solid state, while adjusting the temperature to 175° to 185° C. When analyzed by gas chromatography, the dried reaction mixture is found to contain 0.9% by weight of 2,4'-dihydroxydiphenylsulfone based on 4,4'-dihydroxydiphenylsulfone present therein (hereinafter referred to as isomer content). A solution of 62 g of sodium hydroxide in 3.5 l of water is added to the residue, 5 g of active carbon is added to the solution, the mixture is filtered and the filtrate is neutralized with sulfuric acid. The resulting crystals are filtered off, then washed with water and dried, giving 332 g of 4,4'-dihydroxydiphenylsulfone, melting at 248° C., in a yield of 91.2% based on the sulfuric acid starting material. When analyzed by gas chromatography, the product is found to contain 0.8% of isomer content.
Reaction SMILES: O=[C:2]1[CH2:10][C@@H:9]2[C@@H:4]([CH2:5][CH:6]=[CH:7][CH2:8]2)[CH2:3]1.C(O)C.Cl.[OH:15][NH2:16].[OH-].[Na+]>O>[OH:15][N:16]=[C:2]1[CH2:10][C@@H:9]2[C@@H:4]([CH2:5][CH:6]=[CH:7][CH2:8]2)[CH2:3]1
Reactant: O=C1C[C@H]2CC=CC[C@H]2C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: ON=C1C[C@H]2CC=CC[C@H]2C1
Reaction time: 1 h

Procedure:
To a mixed solution of 8-oxo-cis-bicyclo[4,3,0]nona-3-ene (10 g), ethyl alcohol (100 ml), water (20 ml) and hydroxyamine hydrochloride (20 g), was added sodium hydroxide (37 g) at room temperature. After being stirred for one hour, the reaction mixture was poured into water. The crystals were gathered by filtration and washed with water. After drying, there was obtained 8-hydroxyimino-cis-bicyclo[4,3,0]nona-3-ene.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[CH3:20][NH:21][CH2:22][C:23]([NH2:25])=[O:24]>>[C:23]([CH2:22][N:21]([CH3:20])[C:17]([C:15]1[CH:16]=[C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])[CH:12]=[N:13][CH:14]=1)=[O:19])(=[O:24])[NH2:25]
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Reactant: CNCC(N)=O
Product: CCc1cc(-c2cncc(C(=O)N(C)CC(N)=O)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and 2-methylamino-acetamide to afford the title compound. MS: m/e=329 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[C:13]([CH2:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:16][CH3:17])[N:5]=[C:4]([CH3:18])[C:3]=1[CH2:19][N:20]1[CH2:25][CH2:24][O:23][C:22]([CH3:27])([CH3:26])[CH2:21]1.[OH:28][C:29]1[CH:37]=[C:36]([OH:38])[CH:35]=[CH:34][C:30]=1[C:31]([NH2:33])=[O:32].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN1CCCC1=O.[Cu].O>[CH2:16]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([CH2:14][CH3:15])[C:8]=1[C:6]1[N:5]=[C:4]([CH3:18])[C:3]([CH2:19][N:20]2[CH2:25][CH2:24][O:23][C:22]([CH3:27])([CH3:26])[CH2:21]2)=[C:2]([O:38][C:36]2[CH:35]=[CH:34][C:30]([C:31]([NH2:33])=[O:32])=[C:29]([OH:28])[CH:37]=2)[CH:7]=1)[CH3:17]
Reactant: CCc1cccc(CC)c1-c1cc(Cl)c(CN2CCOC(C)(C)C2)c(C)n1
Reactant: NC(=O)c1ccc(O)cc1O
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: CCc1cccc(CC)c1-c1cc(Oc2ccc(C(N)=O)c(O)c2)c(CN2CCOC(C)(C)C2)c(C)n1
Temperature: 150 °C

Procedure:
A mixture of 4-[4-chloro-6-(2,6-diethyl-phenyl)-2-methyl-pyridin-3-ylmethyl]-2,2-dimethyl-morpholine (30 mg, 0.08 mmol), 2,4-dihydroxy-benzamide (24 mg, 0.16 mmol), copper powder (10 mg) and K2CO3 (22 mg, 0.16 mmol) in 1-methyl-2-pyrrolidinone (1 mL) is heated at 150° C. overnight. After cooling, EtOAc (10 mL) and water (10 mL) are added to the mixture. The organic layer is separated, washed with brine (3×), dried (Na2SO4) and concentrated. The crude is purified by PTLC (1:1 Hexane/EtOAc) to give to give the title compound. 1H NMR (CDCl3) 12.41 (s, 1H), 7.35 (d, 2H), 7.23 (m, 1H), 7.10 (m, 2H), 6.63 (s, 1H), 6.51 (m, 2H), 5.85 (br, 2H), 3.72 (m, 2H), 3.56 (s, 2H), 2.74 (s, 3H), 2.41-2.30 (m, 6H), 1.20 (s, 6H), 1.76 (m, 2H), 1.01 (t, 6H).
Reaction SMILES: [F:1][C:2]1[C:7]([N:8]2[C:12](OS(C(F)(F)F)(=O)=O)=[CH:11][C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:26][C:27]1[CH:28]=[C:29]([SH:33])[CH:30]=[CH:31][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>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].C(OCC)(=O)C>[Br:26][C:27]1[CH:28]=[C:29]([S:33][C:12]2[N:8]([C:7]3[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=3)[N:9]=[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:11]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: CCOC(=O)c1cc(OS(=O)(=O)C(F)(F)F)n(-c2cccnc2F)n1
Reactant: Sc1cccc(Br)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(Sc2cccc(Br)c2)n(-c2cccnc2F)n1
Temperature: 110 °C
Reaction time: 16 h

Procedure:
A solution of ethyl 1-(2-fluoropyridin-3-yl)-5-{[(trifluoromethyl)sulfonyl]oxy}-1H-pyrazole-3-carboxylate (767 mg), 3-bromobenzenethiol (567 mg) and sodium carbonate (424 mg) in toluene (10 mL) was sufficiently deaerated, tris(dibenzylideneacetone)dipalladium(0) (92 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (116 mg) were added, and the mixture was further deaerated. Under an argon atmosphere at 110° C., the reaction mixture was stirred for 16 hr, and allowed to cool to room temperature. Ethyl acetate was added and the mixture was filtered through a basic silica gel pad. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=9:1→2:1) to give the title compound as a crude yellow oil (yield 869 mg).
Reaction SMILES: C([O:4][C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[CH:8]=[CH:9][C:10]([O:19][CH3:20])=[CH:11][C:12]=1[C:13]2=[O:18])(C)C.B(Cl)(Cl)Cl>C(Cl)Cl>[OH:4][C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[CH:8]=[CH:9][C:10]([O:19][CH3:20])=[CH:11][C:12]=1[C:13]2=[O:18]
Reactant: COc1ccc2c(c1)C(=O)c1cccc(OC(C)C)c1-2
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: COc1ccc2c(c1)C(=O)c1cccc(O)c1-2
Yield: 45.1 %

Procedure:
Combine 5-isopropoxy-2-methoxy-fluoren-9-one (0.78 g, 2.9 mmole) with boron trichloride (6.50 mL of 1.0 M in methylene chloride) in 20 mL methylene chloride at a temperature between 0° and -50° C. Stir the reaction for 1 hour at 5° C., then quench with 20 mL of water, ensuring the temperature is kept below 20° C. The solution changes from a dark brown solution to red as a flocculent solid precipitates. m.p 245°-248° C. Filter the precipitate to obtain 0.296 g of a red solid. m.p 245°-248° C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][N:9]=1>[Pd]>[CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[N:9]=[CH:10][C:11]([NH2:14])=[CH:12][CH:13]=1
Reactant: C[C@H]1COCCN1c1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Product: C[C@H]1COCCN1c1ccc(N)cn1
Yield: 100.9 %

Procedure:
1.35 g (6 mmol) of the product obtained in step 29.1 are hydrogenated in the presence of 10% Pd/C at atmospheric pressure at 50° C. The solution obtained is evaporated under reduced pressure to give 1.17 g of 6-((S)-3-Methylmorpholin-4-yl)pyridin-3-ylamine.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:23][CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:26]I.O>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:23][CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH3:26])[C:13]=2[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: O=C(OCc1ccccc1)N1CCc2c([nH]c3ccccc23)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c2c(c3ccccc31)CCN(C(=O)OCc1ccccc1)C2
Temperature: 25 °C
Reaction time: 12 h
Yield: 99 %

Procedure:
To a stirred solution of 2-benzyloxycarbonyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole (5.0 g. 16.3 mmole) in dry DMF (75 mL) at 5° C. was added 60% NaH (0.7 g, 17.5 mmole). After 10 min. methyliodide (11.57 g. 81.5 mmole) was added and the reaction was allowed to warm to RT and stir for 12 hr. The reaction contents were poured into H2O (100 mL) and extracted with EtOAc (2×100 mL). The combined organic phases were washed sequentially with H2O and brine, then were dried over Na2SO4. Concentration under reduced pressure and purification on silica (hexanes/EtOAc, 1:1) afforded the title compound (5.17 g, 99%) as a white solid: MS (ES) m/e 321 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH3:13])[C:4]1[CH:5]=[C:6]([OH:12])[C:7](=[CH:10][CH:11]=1)[CH:8]=O)[CH3:2].[NH2:14][CH2:15][C:16]([NH2:19])([CH3:18])[CH3:17]>>[CH2:1]([N:3]([C:4]1[CH:5]=[C:6]([OH:12])[C:7](=[CH:10][CH:11]=1)[CH:8]=[N:14][CH2:15][C:16]([CH3:18])([N:19]=[CH:8][C:7]1[C:6](=[CH:5][C:4]([N:3]([CH3:13])[CH2:1][CH3:2])=[CH:11][CH:10]=1)[OH:12])[CH3:17])[CH3:13])[CH3:2]
Reactant: CC(C)(N)CN
Reactant: CCN(C)c1ccc(C=O)c(O)c1
Product: CCN(C)c1ccc(C=NCC(C)(C)N=Cc2ccc(N(C)CC)cc2O)c(O)c1

Procedure:
Synthesis and working up are carried out as in Example 9, starting from 500 mg (2.79 mmol) of 4-(ethylmethylamino)salicylaldehyde and 117 mg (1.33 mmol) of 1,2-diamino-2-methylpropane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([C:21]([OH:23])=O)[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[NH2:25][CH:26]([CH2:29][CH3:30])[CH2:27][OH:28]>>[OH:28][CH2:27][CH:26]([NH:25][C:21]([C:17]1[N:18]([CH3:20])[N:19]=[C:15]([O:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][O:10][C:11]=2[CH3:24])[CH:16]=1)=[O:23])[CH2:29][CH3:30]
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)O)n(C)n1
Reactant: CCC(N)CO
Product: CCC(CO)NC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2C)nn1C
Yield: 63 %

Procedure:
As described for example 55, 5-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid (200 mg, 0.6 mmol) was converted, using rac-2-amino-1-butanol instead of 2-amino-2-methyl-1-propanol, to the title compound (155 mg, 63%) which was obtained as a colorless gum. MS: m/e=403.2 [M+H]+.
Reaction SMILES: N([O-])=O.[Na+].[CH3:5][O:6][C:7]([C:9]1[C:10]([CH3:20])=[C:11]([CH:15]=[CH:16][C:17]=1[S:18][CH3:19])[C:12](N)=[O:13])=[O:8].S(=O)(=O)(O)[OH:22]>O.C(O)(=O)C>[CH3:5][O:6][C:7]([C:9]1[C:10]([CH3:20])=[C:11]([CH:15]=[CH:16][C:17]=1[S:18][CH3:19])[C:12]([OH:22])=[O:13])=[O:8]
Reactant: COC(=O)c1c(SC)ccc(C(N)=O)c1C
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1c(SC)ccc(C(=O)O)c1C

Procedure:
Sodium nitrite (2.4 g) was added dropwise to a stirred solution of 3-methoxycarbonyl-2-methyl-4-methylsulphenylbenzamide (4.2 g) in a mixture of concentrated sulphuric acid (50 ml), water (40 ml) and glacial acetic acid (70 ml) whilst maintaining the temperature below 5° C. The mixture was stirred without cooling for 0.5 hours. The brown solution was recooled to 0° C. and water (200 ml) was added. The mixture was extracted with ether (3×150 ml). The combined organic extracts were washed with water (2×150 ml), dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness to give 3-methoxycarbonyl-2-methyl-4-methylsulphenylbenzoic acid (4.6 g) as a sticky orange solid NMR (CDCl3) 2.1(s,3H), 2.5(s,3H), 3.9(s,3H), 7.0(d,1H), 7.85(d,1H), 9.0(bs, 1H).
Reaction SMILES: O(C1C=CC(C(O)=O)=CC=1)C1C=CC=CC=1.C(#N)CC#N.[C:22]([C:24]([C:40]#[N:41])=[C:25](O)[C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:28][CH:27]=1)#[N:23].C[Si](C=[N+:47]=[N-:48])(C)C.O.NN>>[NH2:23][C:22]1[C:24]([C:40]#[N:41])=[C:25]([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:28][CH:27]=2)[NH:48][N:47]=1
Reactant: N#CC(C#N)=C(O)c1ccc(Oc2ccccc2)cc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: NN
Agent: O=C(O)c1ccc(Oc2ccccc2)cc1
Solvent: O
Solvent: N#CCC#N
Product: N#Cc1c(N)n[nH]c1-c1ccc(Oc2ccccc2)cc1

Procedure:
First, 4-amino-3-(4-phenoxyphenyl)-1H-pyrazole[3,4-d]pyrimidine may be prepared in accordance with procedures described in WO 2008/039218, for instance by converting 4-phenoxybenzoic acid to the corresponding acyl chloride (by using thionyl chloride), which latter product may be reacted with malononitrile to prepare 1,1-dicyano-2-hydroxy-2-(4-phenoxyphenyl)ethene. The methoxy moiety is then methylated using trimethylsilyldiazomethane, and that methylated product is the treated with hydrazine hydrate to provide 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole, which is reacted with formamide to provide 4-amino-3-(4-phenoxyphenyl)-1H-pyrazole[3,4-d]pyrimidine, as illustrated in the following scheme:
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.[Br:49]C1C=C(C=CC=1)N>C(O)(=O)C>[Br:49][C:3]1[CH:2]=[C:1]([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=1
Reactant: Nc1cccc(Br)c1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Agent: COC(=O)c1scc(-c2ccccc2)c1N
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: O=c1c2scc(-c3ccccc3)c2ncn1-c1cccc(Br)c1
Yield: 12 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (200 mg, 0.86 mmol), triethyl orthoformate (2 ml), 3-bromoaniline (280 mg, 1.63 mmol), and acetic acid (0.2 ml) were used to give 40 mg (0.10 mmol, 12% yield) of the title compound.