Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([CH:37]=O)=[N:29]1>CO.N1CCCCC1>[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30](/[CH:37]=[C:8]2\[O:9][C:5]3[C:4]([CH2:13][CH2:14][CH:15]4[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:29]1
Reactant: O=Cc1n[nH]c2ccccc12
Reactant: COc1ccc2c(c1CCC1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Solvent: CO
Solvent: C1CCNCC1
Product: COc1ccc2c(c1CCC1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 72.3 %

Procedure:
A solution of tert-butyl 4-[2-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)ethyl]piperidine-1-carboxylate (0.0542 g, 0.144 mmol) in methanol (3 mL) was added with 1H-indazole-3-carboxaldehyde (0.0211 g, 0.144 mmol) and piperidine (5 drops), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl (Z)-4-(2-{2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}ethyl)piperidine-1-carboxylate (0.0524 g, 72%).
Reaction SMILES: N[C:2]1[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[CH:10][CH:9]=2)=[C:5](N)[NH:4][N:3]=1.P(=O)(O)(O)O.N([O-])=O.[Na+].[OH-].[Na+]>O>[CH2:14]([C:11]1[CH:12]=[CH:13][C:8]([CH2:7][C:6]2[CH:2]=[N:3][NH:4][CH:5]=2)=[CH:9][CH:10]=1)[CH3:15]
Reactant: CCc1ccc(Cc2c(N)n[nH]c2N)cc1
Agent: O=N[O-]
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: O
Product: CCc1ccc(Cc2cn[nH]c2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 37 %

Procedure:
The above 3,5-diamino-4-(4-ethylphenylmethyl)pyrazole (1.30 g) was added to 50% aqueous phosphoric acid solution (19 ml), and further added thereto was water (10 ml). The mixture was cooled to 0° C., and thereto was added dropwise an aqueous solution (4 ml) of sodium nitrite (912 mg). The mixture was stirred at the same temperature for 30 minutes, and further stirred at room temperature for 4 hours. The reaction mixture was cooled again to 0° C., 10% aqueous sodium hydroxide solution was added thereto to adjust pH of the reaction mixture to 7. The mixture was extracted with ethyl acetate, washed successively with water and brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol=100:0-90:10) to give the desired 4-(4-ethylphenylmethyl)pyrazole (414 mg) as a pale brown semisolid. APCI-Mass m/Z 187 (M+H).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[C:6]([C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](O)=[O:11])=O.O.[NH2:23][NH2:24]>C(O)C>[F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C:6]2[C:8]3[N:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10](=[O:11])[NH:24][N:23]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)c1cccnc1C(=O)c1cccc(C(F)(F)F)c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: O=c1[nH]nc(-c2cccc(C(F)(F)F)c2)c2ncccc12

Procedure:
A mixture of 2-(3-trifluoromethylbenzoyl)nicotinic acid (1.5 g) and hydrazine hydrate (0.4 g) in ethanol was heated at the reflux temperature for 5 hours. On cooling and reduction of the volume of solvent by evaporation, a precipitate formed which was collected by filtration, to give the title compound as a white solid, 1.08 g, m.p. 210°-215° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:5]=2[CH:6]=O)[CH2:3][CH2:2]1.[C:13](Br)(Br)([Br:15])[Br:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH:1]1([C:4]2[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:5]=2[CH:6]=[C:13]([Br:15])[Br:14])[CH2:3][CH2:2]1
Reactant: Cc1cccc(C2CC2)c1C=O
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1cccc(C2CC2)c1C=C(Br)Br

Procedure:
1-Cyclopropyl-2-(2,2-dibromo-vinyl)-3-methyl-benzene was prepared from 2-cyclopropyl-6-methyl-benzaldehyde, carbon tetrabromide and triphenylphosphine in analogy to Example 1d): colourless oil; 1H-NMR (CDCl3): 0.69 (2H, m, CH2), 0.94 (2H, m, CH2), 1.87 (1H, m, CH), 2.26 (3H, s, CH3), 6.77 (1H, d, ArH), 7.03 (1H, d, ArH), 7.17 (1H, t, ArH), 7.52 (1H, s, CH═CBr2).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:19])=[CH:5][C:6]=1[CH:7]1[CH2:16][C:15]2[N:14]=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=[O:18])[CH2:8]1.ClC1C=CC=C(C(OO)=[O:28])C=1.C(=O)([O-])O.[Na+].N([O-])=O.[Na+]>C1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[S:3][C:4]([Cl:19])=[CH:5][C:6]=1[CH:7]1[CH2:16][C:15]2[N+:14]([O-:28])=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=[O:18])[CH2:8]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccnc2c1C(=O)CC(c1cc(Cl)sc1Cl)C2
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: Cc1cc[n+]([O-])c2c1C(=O)CC(c1cc(Cl)sc1Cl)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
In benzene (15 ml) was dissolved 7-(2,5-dichlorothiophen-3-yl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (1.09 g), and to the solution was added m-chloroperbenzoic acid (0.963 g). The mixture was stirred at room temperature for 1 hour, and to the mixture were added ethyl acetate (150 ml), saturated sodium hydrogen carbonate solution (200 ml) and sodium nitrite(200 mg). The mixture was shaken, and the separated upper layer was washed with water and concentrated under reduced pressure. The residue was washed with a mixture of isopropylether and ethyl acetate (2:1) to give 7-(2,5-dichlorothiophen-3-yl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one-1-oxide (1.04 g) as yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1F)[N:8]([CH2:14][CH2:15][F:16])[CH:7]=[C:6]([C:17]([OH:19])=[O:18])[C:5]2=[O:20].[C:21]([O:25][C:26]([NH:28][C@H:29]1[C@@H:33]([CH3:34])[CH2:32][NH:31][CH2:30]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C1CCN2C(=NCCC2)CC1>C(#N)C>[C:21]([O:25][C:26]([NH:28][C@H:29]1[C@@H:33]([CH3:34])[CH2:32][N:31]([C:11]2[C:10]([F:13])=[C:9]3[C:4]([C:5](=[O:20])[C:6]([C:17]([OH:19])=[O:18])=[CH:7][N:8]3[CH2:14][CH2:15][F:16])=[CH:3][C:2]=2[F:1])[CH2:30]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: C[C@H]1CNC[C@H]1NC(=O)OC(C)(C)C
Reactant: O=C(O)c1cn(CCF)c2c(F)c(F)c(F)cc2c1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C[C@H]1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(CCF)c3c2F)C[C@H]1NC(=O)OC(C)(C)C
Yield: 62.8 %

Procedure:
A mixture of 6,7,8-trifluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.5 g), anhydrous acetonitrile (5 ml), cis-3-t-butoxycarbonylamino-4-methylpyrrolidine (0.5 g) and DBU (0.27 g) was refluxed for an hour and then concentrated. The resulting residue was dissolved in chloroform and the solution was washed with 10% aqueous citric acid solution. After concentration of the chloroform layer, the resulting precipitate was triturated in water, and collected by filtration and washed with water, methanol and ether successively to give the title compound (0.51 g) as white powder, mp 217°-219° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[N:7][CH:6]=[C:5]2[OH:12].Br[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O>[CH2:14]([O:12][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([I:1])[CH:3]=2)[N:8]=[N:7][CH:6]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cnnc2ccc(I)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Ic1ccc2nncc(OCc3ccccc3)c2c1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
Into a 250 mL round-bottom flask, was placed a solution of 6-iodocinnolin-4-ol (as prepared in the previous step, 6.5 g, 23.90 mmol, 1.00 equiv) in N,N-dimethylformamide (120 mL), 1-(bromomethyl)benzene (4.4 g, 25.88 mmol, 1.10 equiv) and Cs2CO3 (5.47 g, 16.78 mmol, 0.70 equiv). The reaction mixture was stirred for 3 h at 60° C. in an oil bath. The reaction was then quenched by the addition of 50 mL of water. The resulting solution was extracted with 3×100 ml, of ethyl acetate, and the combined organic layers washed with 2×100 mL of sodium chloride, dried (Na2SO4), and concentrated under vacuum. The title compound was obtained as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:5]2[NH:10][C:9](=[O:11])[CH2:8][O:7][C:6]=2[N:12]=1.[F:19][CH2:20][CH2:21]I.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:5]2[N:10]([CH2:21][CH2:20][F:19])[C:9](=[O:11])[CH2:8][O:7][C:6]=2[N:12]=1
Reactant: FCCI
Reactant: O=C1COc2nc(Br)c(-c3ccccc3)cc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1COc2nc(Br)c(-c3ccccc3)cc2N1CCF
Reaction time: 3 h
Yield: 45.6 %

Procedure:
A mixture of 6-bromo-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (400 mg, 1.311 mmol), 1-fluoro-2-iodoethane (684 mg, 3.93 mmol) and potassium carbonate (544 mg, 3.93 mmol) in DMF (4 ml) was heated under stirring for 3 h. The reaction mixture was cooled down and diluted with water (20 ml), the resulted mixture was extracted with DCM (3×20 ml). The combined organic phase was washed with water, brine, dried over sodium sulfate, concentrated to give the crude material which was purified by column chromatography eluted with ethyl acetate/cyclohexane 0-40% to give product 0.21 g. 1H NMR (500 MHz, CDCl3): 7.39-7.48 (m, 5H), 4.89 (s, 2H), 4.77 (t, 1H), 4.67 (t, 1H), 4.21 (t, 1H), 4.16 (t, 1H), LCMS (Method D): RT=1.24 min, M+H+=353.0.
Reaction SMILES: N1C=C[CH:4]=[CH:3][C:2]=1[CH:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)[CH3:8].[N:22]1C=CC(C(O)C)=[CH:24][CH:23]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.C(N1CCNCC1)(OC(C)(C)C)=O>CCOC(C)=O.CO.CS(C)=O.C(Cl)Cl>[N:22]1[CH:4]=[CH:3][C:2]([CH:7]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:13][CH2:14]2)[CH3:8])=[CH:24][CH:23]=1
Reactant: CC(c1ccccn1)N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(O)c1ccncc1
Agent: CC(C)(C)OC(=O)N1CCNCC1
Agent: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(c1ccncc1)N1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
This was prepared using the same procedure as for tert-butyl 4-(1-(pyridin-2-yl)ethyl)piperazine-1-carboxylate, but here using 1-(pyridin-4-yl)ethanol (J. Chem. Soc., Perkin Trans. 1, 2000, 4439-4444) (100 mg, 0.81 mmol), triethylamine (5.0 eq, 4.05 mmol, 0.56 mL), MsCl (2.0 eq, 1.62 mmol, 0.13 mL), CH2Cl2 (4 mL) at 0° C. for 30 minutes, then N—BOC piperazine (4.0 eq, 3.24 mmol, 605 mg), DMSO (3 mL) at 60° C. for 18 h. Work up as described for tert-butyl 4-(1-(pyridin-2-yl)ethyl)piperazine-1-carboxylate, followed by column chromatography (EtOAc-MeOH, 95:5) gave the product (163 mg, 69% for two steps) as a colourless oil; 1H-NMR (500 MHz, CDCl3) 1.50 (s, 9H, C(CH3)3), 1.72 (s, br, 3H, CH3), 2.42-2.60 (m, 4H, piperazine N(CH2)2), 3.49 (s, br, 5H, CH & piperazine N(CH2)2), 7.32 (d, J=5.7 Hz, 2H, pyridine H-3 & H-5), 8.59 (d, J=5.7 Hz, 2H, pyridine H-2 & H-6);
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9](Br)[C:5]2[O:6][CH2:7][CH2:8][C:4]=2[CH:3]=1.C([Li])CCC.[Cl-].[NH4+]>C(OCC)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][CH2:8][C:4]=2[CH:3]=1
Reactant: Brc1cc(Br)c2c(c1)CCO2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: Brc1ccc2c(c1)CCO2
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
5,7-Dibromo-2,3-dihydrobenzo[b]furan (see WO 02/070020) (3.0 g) in diethyl ether was cooled to −78° C. under argon atmosphere, and thereto was added dropwise n-butyl lithium (2.44 M hexane solution, 5.09 ml). The mixture was stirred at the same temperature for 30 minutes, and poured into a saturated aqueous ammonium chloride solution. The mixture was extracted with diethyl ether, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 5-bromo-2,3-dihydrobenzo[b]furan (2.0 g) as pale yellow crystals, which was used in the subsequent step without further purification.
Reaction SMILES: [C:1]1([N:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]#[C:25][C:26]([O:28]CC)=O.[Cl-].[Al+3].[Cl-].[Cl-].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[CH3:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:9]([CH3:10])[C:26](=[O:28])[CH:25]=1
Reactant: CCC(=Nc1ccccc1)c1ccccc1
Reactant: CCOC(=O)C#Cc1ccccc1C
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: Cc1ccccc1-c1cc(=O)c(C)c(-c2ccccc2)n1-c1ccccc1
Temperature: 60 °C
Yield: 3.7 %

Procedure:
To 300 ml of toluene were added 7.5 g (0.036 mole) of N-phenyl-1-phenylpropaneimine, 5.8 g (0.031 mole) of ethyl 2-methylphenylpropiolate and 6.0 g (0.045 mole) of aluminum chloride. The reaction mixture was stirred with heating at 60° C. for 3 days in a nitrogen atmosphere. After cooling, the reaction mixture was poured into 500 ml of 2N sulfuric acid, followed by extraction with chloroform. After washing the organic layer with water, it was dried over anhydrous sodium sulfate. Subsequent to removal of the sodium sulfate, the solvent was distilled off and the residue was purified by chromatography on a silica gel column (eluent: ethyl acetate). The resultant crystals were washed with a 2:1 mixed solvent of acetone and hexane to obtain 0.4 g of 6-(2-methyl-phenyl)-3-methyl-1,2-diphenyl-4(1H)-pyridinone having a melting point of 188°-191° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[CH2:19]([NH2:22])[CH2:20][NH2:21].C(Cl)Cl>CN1CCCC1=O.CO>[NH2:21][CH2:20][CH2:19][NH:22][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)ccc2c1=O
Reactant: NCCN
Solvent: ClCCl
Solvent: CO
Solvent: CN1CCCC1=O
Product: NCCNc1ccc2c(=O)c(C(=O)O)cn(C3CC3)c2c1
Temperature: 130 °C
Yield: 41.8 %

Procedure:
To a solution of 7-chloro-1-cyclopropyl-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (2.0 g) in 1-methyl-2-pyrrolidinone (20 mL) was added ethylenediamine (2.3 g). The mixture was heated at 130° C. for 10 h. The reaction mixture was cooled and poured into DCM (20 mL). The precipitate obtained was dispersed in MeOH, filtered to give the title compound (910 mg).
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([C:8]1[C:9]([C:32]2[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=2[Cl:39])=[N:10][O:11][C:12]=1[C:13]1[CH:14]=[N:15][N:16]([C:22]2[CH:23]=[C:24]([NH:28][C:29](=[O:31])[CH3:30])[CH:25]=[CH:26][CH:27]=2)[C:17]=1[C:18]([F:21])([F:20])[F:19])=[O:7])(=O)[CH3:2].C(OC(=O)C)(=O)C>C(O)(=O)C.O>[Cl:39][C:33]1[CH:34]=[CH:35][CH:36]=[C:37]([F:38])[C:32]=1[C:9]1[C:8]([C:6]2[O:7][C:1]([CH3:2])=[N:4][N:5]=2)=[C:12]([C:13]2[CH:14]=[N:15][N:16]([C:22]3[CH:23]=[C:24]([NH:28][C:29](=[O:31])[CH3:30])[CH:25]=[CH:26][CH:27]=3)[C:17]=2[C:18]([F:20])([F:19])[F:21])[O:11][N:10]=1
Reactant: CC(=O)NNC(=O)c1c(-c2c(F)cccc2Cl)noc1-c1cnn(-c2cccc(NC(C)=O)c2)c1C(F)(F)F
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1cccc(-n2ncc(-c3onc(-c4c(F)cccc4Cl)c3-c3nnc(C)o3)c2C(F)(F)F)c1
Temperature: 140 °C

Procedure:
The intermediate N-(3-(4-(4-(2-acetylhydrazinecarbonyl)-3-(2-chloro-6-fluorophenyl) isoxazol-5-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)acetamide (25.0 mg, 0.044 mmol) was dissolved in acetic acid (1.50 mL). Acetic anhydride (104 μL, 1.1 mmol) was added and the reaction mixture was heated in the microwave to 140° C. for 8 h. The reaction mixture was diluted with water (40 mL) and extracted with CH2Cl2 (3×20 mL). The combined organic layers were washed with water (10 mL), dried over Na2SO4 and concentrated in vacuo.
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.[CH:10]1([O:16][C:17]2[N:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[Na+].[Na+].CCOC(C)=O>COCCOC.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>[CH:10]1([O:16][C:17]2[N:22]=[CH:21][C:20]([C:2]3[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=3)=[CH:19][CH:18]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: OB(O)c1ccc(OC2CCCCC2)nc1
Reactant: Nc1ncc(F)cc1Br
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: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: Nc1ncc(F)cc1-c1ccc(OC2CCCCC2)nc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 93.1 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (36.3 mg) was added to a suspension of 3-bromo-5-fluoropyridin-2-amine (200 mg), 6-(cyclohexyloxy)pyridin-3-ylboronic acid (255 mg) and sodium carbonate (222 mg) in DME (5 mL) and water (1 mL) and the mixture was stirred at 90° C. under nitrogen for 3 hr. Water and EtOAc were added and the organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) and washed with IPE to give the title compound (280 mg) as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@H:16]([O:17][S:18]([C:21]2[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C@@H:15]([CH2:28][O:29]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[O:14][C@H:11]([O:12][CH3:13])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:8][C@@H:9]1[C@H:16]([O:17][S:18]([C:21]2[CH:22]=[CH:23][C:24]([CH3:25])=[CH:26][CH:27]=2)(=[O:20])=[O:19])[C@@H:15]([CH2:28][OH:29])[O:14][C@H:11]([O:12][CH3:13])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[C@@H]1C[C@H](OCc2ccccc2)[C@H](OS(=O)(=O)c2ccc(C)cc2)[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)O1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CO[C@@H]1C[C@H](OCc2ccccc2)[C@H](OS(=O)(=O)c2ccc(C)cc2)[C@@H](CO)O1
Reaction time: 0.08 h
Yield: 83.3 %

Procedure:
Methyl 3-O-benzyl-4-O-tosyl-6-O-trityl-2-deoxy-α-D-ribo-hexopyranoside (15.3 g; 23.01 mmoles) was dissolved in methylene chloride (200 ml). Aqueous trifluoroacetic acid (70% TFA in water, 9.6 ml) was added with vigorous stirring. The vigorous stirring was continued for five minutes (bright yellow color appears), then the reaction was quenched by the addition of saturated aqueous sodium carbonate solution (40 ml) with vigorous stirring (note: the reaction becomes colorless). The methylene chloride layer was separated and the aqueous layer extracted with methylene chloride. The combined methylene chloride extracts were dried (MgSO4), filtered and the solvent was evaporated in vacuo to give crude product. This product was chromatographed on 650 g of silica gel eluting with 3 L of methylene chloride to remove triphenyl carbinol from the column followed by elution with 10% (by volume) acetone in methylene chloride. When a faintly visible opaque band of product neared the bottom of the column the fractions containing the product were collected and the solvent was evaporated in vacuo to leave 8.1 g of methyl 3-O-benzyl-4-O-tosyl-2-deoxy-α-D-ribo-hexopyranoside, m.p. 100°-101° C., [α]D25 =115.07 (c, 0.48, CHCl3)
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]2[CH2:6][CH2:5][C:4]1=2.C=O.[C:18]1(C)C=CC(S(O)(=O)=O)=CC=1>C(OC(=O)C)(=O)C.C(O)(=O)C>[C:7]123[CH2:4][CH2:5][C:6]1=[C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:3][CH2:2][O:1][CH2:18]3
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: OCC1CCCCCCCCC2=C1CC2
Agent: C=O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: C1CCCCOCC23CCC2=C3CCCC1

Procedure:
A mixture of the alcohol obtained as indicated above (1 g), 0.2 g of paraformaldehyde, 0.1 g of p-toluenesulphonic acid and 10 ml of acetic acid in the presence of a few drops of acetic anhydride was heated for 41/2 hour at 95° while stirring. The usual treatments of extraction, separation, drying, and evaporation gave 0.7 g of a product which was distilled on a bulb apparatus. The purity of the thus obtained compound was of about 95 % as shown by gas chromatographic analysis. This compound was in all respects identical to that prepared in Example 1.
Reaction SMILES: [CH:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.C([BH3-])#N.[Na+].FC(F)(F)C(OC(=O)C(F)(F)F)=O.[OH-].[K+]>CO.O>[CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH2:2]1
Reactant: c1cc2c3c(c1)ccn3CCC2
Agent: [BH3-]C#N
Agent: [K+]
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CO
Solvent: O
Product: c1cc2c3c(c1)CCN3CCC2
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.5 %

Procedure:
A solution of 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline (4.0 g, 25.5 mmol) in methanol (100 ml) was treated with sodium cyanoborohydride (1.5 g, 23.9 mmol) then cooled to 0° C. Trifluoroacetic anhydride (15 ml) was added dropwise over 15 minutes, then the reaction was allowed to warm to room temperature and stirred for a further 2 hours. The reaction was basified with 5M aqueous potassium hydroxide then diluted with water (500 ml). The mixture was extracted with dichloromethane (3×100 ml) and the combined organic extracts were dried with anhydrous sodium sulfate and evaporated to dryness to obtain 1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline as a colorless oil (4.0 g) which was used without further purification. LCMS: 160 [M+H].
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[F:17][C:18]([F:52])([F:51])[C:19]1[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)[N:22]=[C:21]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([C:41]3[CH:42]=[C:43]([S:47](Cl)(=[O:49])=[O:48])[CH:44]=[CH:45][CH:46]=3)[CH:36]=2)[N:20]=1>C1COCC1>[CH2:1]([NH:8][S:47]([C:43]1[CH:44]=[CH:45][CH:46]=[C:41]([C:37]2[CH:36]=[C:35]([C:21]3[N:20]=[C:19]([C:18]([F:17])([F:51])[F:52])[CH:24]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:27][CH:26]=4)[N:22]=3)[CH:40]=[CH:39][N:38]=2)[CH:42]=1)(=[O:48])=[O:49])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Reactant: NCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S(=O)(NCc1ccccc1)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Temperature: 0 °C
Yield: 79.7 %

Procedure:
To a cooled (ice-water bath) and stirred mixture of benzylamine (0.32 g, 3.0 mmol), triethylamine (0.29 ml, 2.1 mmol) and THF (4 ml) was added drop wise a solution of 3-{4-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonyl chloride hydrochloride (example I.1) (0.58 g, 1.0 mmol) in THF (6 ml). The mixture was allowed to stir at room temperature for 16 h. Purification of the reaction mixture by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (dichloromethane/MeOH/hexane) yielded the title compound as a white solid (0.49 g, 85%). MS (ISP) 614.8 [(M+H)+]; mp 202.5° C.