Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]([CH3:19])([CH3:18])[C:5]([NH:7][CH2:8][CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O)=[N+]=[N-].[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[CH2:11]([O:10][CH2:9][CH2:8][NH:7][CH2:5][C:4]([NH2:1])([CH3:18])[CH3:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(N=[N+]=[N-])C(=O)NCCOCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(N)CNCCOCc1ccccc1
Temperature: 0 °C

Procedure:
A solution of 2-azido-N-(2-Benzyloxyethyl)-2-methylpropionamide (70 g) in THF (750 ml) was added to a suspension of LiAlH4 (20 g) in THF (500 ml) at 0° C. during 1 h. After reflux for 4 h, the mixture was cooled to 0° C., water (20 ml) and aqueous NaOH (20 ml) were added, the inorganic salts were filtered off and the solvents were dried. Evaporation of the solvents in vacuo gave 8a as an oil: 53 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH2:19][CH2:18][C:17](=[O:20])[C:8]4[CH:9]=[C:10]([O:15][CH3:16])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH:27]=O.[OH-].[Na+]>C(O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:19]=[C:18]([CH2:27][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=4)[C:17](=[O:20])[C:8]4[CH:9]=[C:10]([O:15][CH3:16])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: COc1cc2c3c(c1)c1cc(Br)ccc1n3CCC2=O
Reactant: O=Cc1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc2c(=O)c(Cc3ccccn3)cn3c4ccc(Br)cc4c(c1)c23
Temperature: 25 °C
Reaction time: 12 h
Yield: 63 %

Procedure:
10-bromo-5,6-dihydro-2-methoxy-4H-pyrido[3,2,1-jk]carbazole-4-one (0.7 g) obtained in Example 1, step 3 was suspended in ethanol (30 ml), and pyridine-2-aldehyde (0.7 g) and sodium hydroxide (0.3 g) dissolved in water (5 ml) were added at room temperature. The mixture was stirred at room temperature for 12 hours, and approximately half of the solvent was evaporated under reduced pressure. The precipitated crystals were recovered by filtration, and washed with water, ethanol and ether in succession to obtain the title compound (0.56 g, 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][CH:16]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(COC)OC.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:28]2[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=2)=[CH:17][CH:16]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CCl)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: [I-]
Solvent: COCCOC
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(Cc2ccc(F)cc2)cc1
Yield: 32.7 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-4-(4-fluorobenzyl)benzamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(chloromethyl)benzamide (0.060 g; 0.173 mmol), 4-fluorophenylboronic acid (0.026 g; 0.181 mmol), tetrakis(triphenylphosphine)palladium(0) (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.345 mmol), sodium iodide (0.052 g; 0.345 mmol), in dimethoxyethane (3 mL) and water (1 mL), heated in a sealed tube at 130° C. for 18 hours. Flash chromatography on silica gel (eluent 1 to 10% ethyl acetate in dichloromethane) furnished 0.023 g (33%) of the title compound as a white solid.
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[C:11](Cl)(=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)(=O)C1C(=CC=CC=1)O>C(OCC)C>[C:12]1([C:11]2[O:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:9])[N:10]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NC(=O)c1ccccc1O
Agent: O=C(O)c1ccccc1O
Solvent: CCOCC
Product: O=c1nc(-c2ccccc2)oc2ccccc12
Reaction time: 0.5 h

Procedure:
6.85 g (50 mmol) of salicylic acid amide are added, dropwise, to 11.5 ml of benzoyl chloride and the mixture is heated to 170° C. The mixture is then stirred for 30 minutes at this temperature. During this time, the salicylic acid dissolves to produce, on cooling, a honey-like mass which is then stirred with diethyl ether to yield a white solid which is filtered off, washed with diethyl ether and dried. There are obtained 8.78g of 2-phenyl-4H-1,3-benzoxazin-4-one as a white powder melting at 104-105° C. and having the following elemental analysis:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][C:11]([F:14])([F:13])[F:12])[CH:3]=1.S(N)(=O)(=O)[OH:16].O.O.P([O-])(O)(O)=O.[Na+].Cl([O-])=O.[Na+].C([O-])([O-])=O.[Na+].[Na+].Cl>O1CCOCC1.O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]([OH:16])=[O:7])=[C:4]([O:10][C:11]([F:12])([F:13])[F:14])[CH:3]=1
Reactant: O=Cc1ccc(Br)cc1OC(F)(F)F
Reactant: NS(=O)(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=P([O-])(O)O
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccc(Br)cc1OC(F)(F)F
Temperature: 4 °C
Reaction time: 0.25 h
Yield: 81 %

Procedure:
A solution of 4-bromo-2-trifluoromethoxy-benzaldehyde (550 mg, 2.04 mmol) in 1,4-dioxane (27 mL) and H2O (9 mL) was cooled at 4° C. To the solution were added amidosulfuric acid (296 mg, 3.05 mmol) and sodium dihydrogen phosphate dihydrate (1.4 g, 8.98 mmol). The mixture was stirred at 4° C. for 15 min. To the reaction mixture was added a solution of sodium chlorite (238 mg, 2.63 mmol) in H2O (1.5 mL) and stirred at 4° C. for 15 min. To the reaction mixture was added Na2CO3 (304 mg, 2.41 mmol) and stirred at 4° C. for 15 min. The mixture was acidified with conc-HCl (pH=1), and the aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography (silica gel, 1% MeOH in CHCl3) to give 4-bromo-2-trifluoromethoxy-benzoic acid (471 mg, 81%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]3[CH:19]=[C:18](I)[N:17]=[CH:16]3)[N:9]=2)=[CH:4][CH:3]=1.[C:21]([NH:25][S:26]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)(=[O:28])=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([NH:25][S:26]([C:29]1[CH:34]=[CH:33][C:32]([C:18]2[N:17]=[CH:16][N:15]([C:10]3[N:11]=[C:12]([CH3:14])[CH:13]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]=3)[CH:19]=2)=[CH:31][CH:30]=1)(=[O:28])=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc(-n2cnc(I)c2)n1
Product: Cc1cc(-c2ccc(Cl)cc2)nc(-n2cnc(-c3ccc(S(=O)(=O)NC(C)(C)C)cc3)c2)n1

Procedure:
N-tert-Butyl-4-{1-[6-(4-chloro-phenyl)-4-methyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide was prepared from 4-(4-chloro-phenyl)-2-(4-iodo-imidazol-1-yl)-6-methyl-pyrimidine (example E.69) (0.40 g, 1.0 mmol) and commercially available 4-(tert.-butylsulfamoyl)-phenylboronic acid (0.39 g, 1.5 mmol) according to the general procedure VI. Obtained as a light brown solid (0.64 g) which was subsequently deprotected.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:12]([CH2:15][CH3:16])=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:17][NH:18][CH3:19]>CN(C)C=O>[CH3:17][N:18]([CH3:19])[C:2]1[C:3]2[N:4]([C:12]([CH2:15][CH3:16])=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: CNC
Reactant: CCc1nnc2c(Cl)nc3ccccc3n12
Solvent: CN(C)C=O
Product: CCc1nnc2c(N(C)C)nc3ccccc3n12
Reaction time: 0.33 h
Yield: 42 %

Procedure:
4-Chloro-1-ethyl-[1,2,4]triazolo-[4,3-a]quinoxaline (1.2 g., 0.005 mole), the product of Example 4, and 676 mg. (0.015 mole) of anhydrous dimethylamine in N,N-dimethylformamide (50 ml.) were stirred at 0° C. for 30 minutes and at room temperature for 2 hours. The reaction mixture was poured over ice and stirred for 20 minutes. The precipitate which formed was separated by filtration, washed with water and air dried. Recrystallization from chloroform and then from chloroform/cyclohexane afforded 510 mg. (42% yield) of 4-dimethylamino-1-ethyl-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. 155°-158° C. Mass spectrum: m/e, 241 (P).
Reaction SMILES: [CH2:1]([N:5]1[C:10]([OH:11])=[CH:9][C:8]([CH3:12])=[C:7]([C:13]#[N:14])[C:6]1=[O:15])[CH2:2][CH2:3][CH3:4].CC1C=CC=CC=1N(C)N=[O:21]>>[CH2:1]([N:5]1[C:6](=[O:15])[C:7]([C:13]#[N:14])=[C:8]([CH3:12])[C:9](=[O:21])[C:10]1=[O:11])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccccc1N(C)N=O
Reactant: CCCCn1c(O)cc(C)c(C#N)c1=O
Product: CCCCN1C(=O)C(=O)C(C)=C(C#N)C1=O

Procedure:
Prepared using the method of Example 2, with 1.03 g of 1-butyl-3-cyano-6-hydroxy-4-methylpyrid-2-one and 0.76 g of dimethyl-nitrosoaniline. Recrystallised from petrol/ethyl acetate, yield 0.54 g, m.p. 134°-135° C. This is the compound of formula (5).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](/[CH:8]=[N:9]/[OH:10])[CH:5]=[CH:4][CH:3]=1.[Cl:11]N1C(=O)CCC1=O>CN(C=O)C.C(OCC)(=O)C>[OH:10][N:9]=[C:8]([Cl:11])[C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cccc(/C=N/O)n1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cccc(C(Cl)=NO)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
To a mixture of commercially available (E)-6-methylpicolinaldehyde oxime (2 g, 14.69 mmol) in DMF (25 mL) was added 1-chloropyrrolidine-2,5-dione (2.158 g, 16.16 mmol). The reaction mixture was stirred overnight at room temperature. LCMS shows reaction was complete. The reaction mixture was diluted with ethyl acetate and washed with saturated NaCl (×3). The organic layer was dried with MgSO4, filtered, and concentrated to yield 2.5 g of N-hydroxy-6-methylpicolinimidoyl chloride. MS (m+1)=171. HPLC Peak RT=0.79 minutes (Analytical Method B).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[CH:5][C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[N:3]1.[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[C:17]([CH3:23])[CH:16]=1.O.CC1C=CC(S(O)(=O)=O)=CC=1>CC#N>[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[C:5]2[C:6](=[NH:7])[N:2]([CH3:1])[N:3]=[C:4]2[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[C:17]([CH3:23])[CH:16]=1
Reactant: Cn1nc(-c2ccccn2)cc1N
Reactant: Cc1cc(Br)ccc1C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: O
Product: Cc1cc(Br)ccc1C=C1C(=N)N(C)N=C1c1ccccn1
Temperature: 45 °C
Yield: 64.1 %

Procedure:
A suspension of 1-methyl-3-(pyridin-2-yl)-1H-pyrazol-5-amine (4.50 g, 25.8 mmol, Example #2 step B), 4-bromo-2-methylbenzaldehyde (5.14 g, 25.8 mmol, Astatech) and 4-methylbenzenesulfonic acid hydrate (0.491 g, 2.58 mmol) in MeCN (36 ml) was warmed up to about 45° C. for about 15 min to give a solution then the reaction was allowed to cool to rt. The precipitate was filtered and washed with MeCN to give 4-(4-bromo-2-methylbenzylidene)-1-methyl-3-(pyridin-2-yl)-1H-pyrazol-5(4H)-imine (5.88 g, 16.55 mmol, 64%) as a beige solid: LC-MS (Table 1, Method g) Rt=2.55 min, m/z 355/357 (M+H)+; 1H-NMR (DMSO-d6, Bruker 400 MHz) δ 9.07 (s, 1H), 8.60-8.57 (m, 1H), 8.02-7.95 (m, 2H), 7.91-7.86 (m, 1H), 7.61-7.50 (m, 2H), 7.40-7.31 (m, 1H), 7.19 (s, 1H), 3.96 (s, 3H), 2.62 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[C:30](Cl)(=[O:34])[CH:31]([CH3:33])[CH3:32]>ClCCl>[C:30]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1)(=[O:34])[CH:31]([CH3:33])[CH3:32]
Reactant: CC(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccc(N)c2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)C(=O)Nc1cccc(C2=CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.6 %

Procedure:
Into a solution of 4.00 g (16.0 mmol) of tert-butyl 4-(3-aminophenyl)-3,6-dihydro-1(2H)-pyridinecarboxylate and 5.60 mL (32.0 mmol) of diisopropylethylamine in 100 mL dichloromethane was slowly added 1.90 mL (19.0 mmol) of isobutyryl chloride. The reaction mixture was stirred at room temperature for 2 hours, washed with water, dried (MgSO4), and concentrated in vacuo. The residue was purified by column chromatography (silica, 50:46:3:1, hexanes:dichloromethane:methanol:isopropyl amine) to afford 2.90 g (52.0% yield) of the desired product: 1H NMR (400 MHz, CDCl3) δ 7.69 (s, 1 H), 7.34 (d, 1 H, J=7.8 Hz), 7.27 (t, 1H, J=7.8 Hz), 7.11 (d, 1H, J=7.8 Hz), 6.04 (s, 1H), 4.05 (s, 2H), 3.62 (apparent t, 2 H, J=4.9 Hz), 2.51 (m, 3H), 1.49 (s, 9H), 1.25 (d, 6H, J=7.4 Hz); ESMS m/e: 345.5 (M+H)+. Anal. Calc. for C20H28N2O3+0.175 CHCl3: C, 66.33; H, 7.77; N, 7.67. Found: C, 66.20; H, 7.41; N, 7.88
Reaction SMILES: C(S([C:10]1[N:15]2[N:16]=[CH:17][C:18]([CH:19]=[C:20]3[NH:24][C:23](=[O:25])[NH:22][C:21]3=[O:26])=[C:14]2[N:13]=[C:12]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)[CH:11]=1)=O)C1C=CC=CC=1.[NH2:35][CH2:36][CH2:37][OH:38].O>CN1C(=O)CCC1>[Cl:34][C:30]1[CH:29]=[C:28]([NH:27][C:12]2[CH:11]=[C:10]([NH:35][CH2:36][CH2:37][OH:38])[N:15]3[N:16]=[CH:17][C:18]([CH:19]=[C:20]4[NH:24][C:23](=[O:25])[NH:22][C:21]4=[O:26])=[C:14]3[N:13]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: NCCO
Reactant: O=C1NC(=O)C(=Cc2cnn3c(S(=O)Cc4ccccc4)cc(Nc4cccc(Cl)c4)nc23)N1
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C1NC(=O)C(=Cc2cnn3c(NCCO)cc(Nc4cccc(Cl)c4)nc23)N1
Temperature: 120 °C

Procedure:
To 5-((7-(benzylsulfinyl)-5-(3-chlorophenylamino) pyrazolo[1,5-a]pyrimidin-3-yl) methylene) imidazolidine-2,4-dione (15 mg, 0.0304 mmol) in NMP was added 2-aminoethanol (14.6 μL, 0.242 mmol). The mixture was heated in the microwave at 120° C. for 20 minutes. Water was added to the reaction mixture and the precipitate was collected by filtration. The precipitate was washed with methanol to yield 5-((5-(3-chlorophenylamino)-7-(2-hydroxyethylamino) pyrazolo[1,5-a]pyrimidin-3-yl)methylene) imidazolidine-2,4-dione LCMS (M+1=414). Similar products (shown below) were also obtained as precipitates by addition of water while other reactions were purified by prep HPLC to yield corresponding products.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:12]=[CH:11][C:9](O)=[C:6]([O:7][CH3:8])[CH:5]=1)=[O:3].C1C=CC(N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].[CH3:40][O:41][C:42]1[C:47](B(O)O)=[CH:46][CH:45]=[CH:44][N:43]=1>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.CN1CCCC1=O.O1CCCC1>[CH3:8][O:7][C:6]1[CH:5]=[C:4]([C:2](=[O:3])[CH3:1])[CH:12]=[CH:11][C:9]=1[C:47]1[C:42]([O:41][CH3:40])=[N:43][CH:44]=[CH:45][CH:46]=1
Reactant: COc1ncccc1B(O)O
Reactant: COc1cc(C(C)=O)ccc1O
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: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: COc1cc(C(C)=O)ccc1-c1cccnc1OC
Temperature: 120 °C

Procedure:
A mixture of acetovanillone (0.332 g, 2.0 mmol), N-phenyl-bis(trifluoromethane-sulfonimide) (710 mg, 2.0 mmol), potassium carbonate (830 mg, 6.0 mmol) and tetrahydrofuran (3.0 ml) was heated to 120° C. for 6 min in a microwave oven. 2-Methoxypyridine-3-boronic acid (611 mg, 4 mmol), tetrakis(triphenylphosphine)palladium (0) (115 mg, 100 μmol), N-methylpyrrolidinone (1 ml) were then added and the mixture heated in the microwave at 120° C. for 10 min. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic phase was separated and washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate and the solvent evaporated to give 1-[3-methoxy-4-(2-methoxy-pyridin-3yl)-phenyl]-ethanone in quantitative yield. Reductive amination with ammonium acetate (20 equivalents) in methanol (50 ml) containing sodium cyanoborohydride (1 equivalent) followed by aqueous work-up with saturated aqueous sodium bicarbonate and extraction into ethyl actetate gave, after solvent was evaporated 1-[3-methoxy-4-(2-methoxy-pyridin-3yl)-phenyl]-ethylamine. To 1-[3-methoxy-4-(2-methoxy-pyridin-3yl)-phenyl]-ethylamine was added 2-trifluoromethoxy-benzenesulfonyl chloride (1 equivalent) in dichloromethane, diisopropylethylamine (4 equivalents) and the mixture overnight. The racemic product was isolated by normal phase HPLC on silica gel eluting with heptane/ethyl acetate and the solvent evaporated to give a clear oily solid (72 mg). 1H NMR (400 MHz, CDCl3): δ 8.15 (d, 1H), 7.9 (d, 1H), 7.5 (m, 1H), 7.4 (m, 1H), 7.3-7.2 (m, 2H), 7.05 (d, 1H), 6.9 (m, 1H), 6.75-6.65 (m, 2H), 5.0 (d, 1H), 4.55 (m, 1H), 3.91 (s, 3H), 3.67 (s, 3H), 1.51 (d, 3H) ppm; MS (ESI) m/z: 483.3 [M+1]+. The racemate was resolved by chiral HPLC (CHIRALPAK-AS, eluting with 9:1 isohexane/ethanol) to give the title compound (11 mg) and its enantiomer (11) mg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19](F)[CH:18]=3)=[C:11]3[N:12]=[N:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.O.[C:30](=O)(O)[O-:31].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([O:31][CH3:30])[CH:18]=3)=[C:11]3[N:12]=[N:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2nn3ccnnc3c2-c2ccnc(F)c2)cc1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(-c2c(-c3ccc(F)cc3)nn3ccnnc23)ccn1

Procedure:
To a suspension of 7-(4-fluorophenyl)-8-(2-fluoropyridin-4-yl)pyrazolo[5,1-c][1,2,4]triazine (350 mg) in methanol (2 ml) was added conc. sulfuric acid (0.32 ml) dropwise. The mixture was refluxed for 1 hour, cooled and poured into cold water. The aqueous solution was neutralized with an aqueous saturated sodium bicarbonate solution and the separated oil was extracted with dichloromethane. The extract was washed with brine, dried and concentrated in vacuo. The residue was purified by column chromatography on silica gel and the obtained oil was crystallized from methanol to give 7-(4-fluorophenyl)-8-(2-methoxypyridin-4-yl)pyrazolo[5,1-c][1,2,4]triazine (220 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([CH3:14])[C:9](=[O:10])[CH2:8][C:7](=[O:11])[C:6]([CH3:13])([CH3:12])[O:5]1.C(Cl)(Cl)Cl.C1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Cl:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[CH:50]=[CH:49][C:48]([CH2:51][CH3:52])=[C:47]([Pb+3])[CH:46]=2)=[CH:41][CH:40]=1>ClCCl.Cl>[Cl:38][C:39]1[CH:40]=[CH:41][C:42]([C:45]2[CH:50]=[CH:49][C:48]([CH2:51][CH3:52])=[C:47]([CH:8]3[C:7](=[O:11])[C:6]([CH3:13])([CH3:12])[O:5][C:4]([CH2:3][O:2][CH3:1])([CH3:14])[C:9]3=[O:10])[CH:46]=2)=[CH:43][CH:44]=1
Reactant: COCC1(C)OC(C)(C)C(=O)CC1=O
Reactant: CCc1ccc(-c2ccc(Cl)cc2)cc1[Pb+3]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1C1C(=O)C(C)(C)OC(C)(COC)C1=O
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 23.9 %

Procedure:
To a mixture of 2-methoxymethyl-2,6,6-trimethylpyran-3,5-dione (0.141 g, 0.705 mmol) and N,N-dimethylaminopyridine (0.43 g, 3.52 mmol) in a mixed solvent system of anhydrous chloroform (7.5 ml) and anhydrous toluene (1.75 ml), is added 4′-chloro-4-ethylbiphenyl-3-yllead triacetate (0.465 g, 0.775 mmol) in one portion and the mixture heated at 80° C. for 2 hours. The mixture is allowed to cool to room temperature, diluted with dichloromethane and dilute aqueous hydrochloric acid, and stirred for 5 minutes then filtered through diatomaceous earth to remove inorganic residues (additional washing with solvents). The organic fractions are combined, dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated in vacuo. The residue is purified by column chromatography on silica gel (hexane/ethyl acetate 4:1 ratio). Fractions containing the desired product are combined and evaporated in vacuo. Trituration with hexanes affords 4-(4′-chloro-4-ethylbiphenyl-3-yl)-2-methoxymethyl-2,6,6-trimethylpyran-3,5-dione (0.070 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([I:21])=[CH:15][C:14]=3F)=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:27][OH:28].[Cl-].[NH4+]>CN(C=O)C>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([I:21])=[CH:15][C:14]=3[O:28][CH3:27])=[O:9])=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(I)cc2c1O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1cc(I)cc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc12
Temperature: 135 °C
Yield: 56 %

Procedure:
N-(4-Chlorobenzyl)-8-fluoro-4-hydroxy-6-iodo-3-quinolinecarboxamide (2.95 g) from Example No. 5 and sodium hydride (60% dispersion, 520 mg) is suspended in DMF (60 mL) and to the mixture is added methanol (288 μL). After being heated for 1 h at 135° C., additional sodium hydride (200 mg) is added, and the mixture is heated for an additional 1 h. The reaction mixture is allowed to cool to rt and then is poured into saturated aqueous ammonium chloride (200 mL). The resulting precipitate is filtered and washed with water (20 mL), tert-butyl methyl ether (20 mL), and heptane (20 mL). The crude product is purified by column chromatography (heptane/2-propanol, 9/1; 4/1) to afford 1.68 g (56%) of the title compound as a white solid. Recrystallization (acetic acid, water) affords a hydrate (1H2O).
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])([O-])=[O:7].[K+].[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:23]=[C:22]([CH3:24])[N:21]=[C:20]([CH3:25])[CH:19]=1.[OH-].[NH4+]>>[F:11][C:12]1[CH:17]=[CH:16][C:15]([N+:6]([O-:9])=[O:7])=[CH:14][C:13]=1[C:18]1[CH:19]=[C:20]([CH3:25])[N:21]=[C:22]([CH3:24])[CH:23]=1
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1cc(-c2ccccc2F)cc(C)n1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [NH4+]
Product: Cc1cc(-c2cc([N+](=O)[O-])ccc2F)cc(C)n1
Reaction time: 0.17 h
Yield: 82.5 %

Procedure:
To 55 ml of concentrated sulphuric acid cooled in a salt-ice bath to about -10° to -15° C. was added 10.1 g of potassium nitrate over a 5 minute period. The mixture was allowed to stir for 10 minutes and then to it was added dropwise over a 30 minute period 18.5 g of 4-(2-fluorophenyl)-2,6-dimethylpyridine whereupon a gummy solid separated and a viscous slurry was obtained, the reaction temperature rising to about 0° C. In order to facilitate stirring, another 50 ml portion of concentrated sulphuric acid was added dropwise over a 15 minute period and the resulting mixture was stirred in the salt-ice bath and then stirred for a period of about 5 hours while allowing the temperature of the reaction mixture to rise to room temperature. The reaction mixture was poured onto a large excess of ice and the mixture was neutralized by adding aqueous ammonium hydroxide solution. The resulting light yellow fluffy precipitate was collected, washed with water and air dried. The solid was then dissolved in 300 ml of chloroform, the solution treated with decolorizing charcoal and filtered. The filtrate was concentrated on a rotary evaporator and the residue was slurred with 200 ml of 1:1 ether-n-hexane, the mixture filtered and the collected solid dried at 70°-75° C. to yield 18.67 g (84%) of 4-(2-fluoro-5-nitrophenyl)-2,6-dimethylpyridine, m.p. 169°-171° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:12][CH:13]([CH2:21][CH3:22])[C:14]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15]>>[CH2:17]([O:16][C:14](=[O:15])[CH:13]([NH:12][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[CH2:21][CH3:22])[CH:18]([CH3:19])[CH3:20]
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: CCC(N)C(=O)OCC(C)C
Product: CCC(NC(=O)Cc1ccc(Br)cc1)C(=O)OCC(C)C

Procedure:
Following General Procedure I' above and using 4-bromophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.