Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([CH:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[Br-].[CH3:22][C:23]1[CH:24]=[CH:25][C:26]([Zn+])=[N:27][CH:28]=1>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:22][C:23]1[CH:24]=[CH:25][C:26]([C:2]2[CH:3]=[C:4]([CH:12]=[C:13]([CH:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[CH:14]=2)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])=[N:27][CH:28]=1
Reactant: Cc1ccc([Zn+])nc1
Reactant: CC(C)(C)OC(=O)c1cc(Br)cc(C(O)C(F)(F)F)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Br-]
Solvent: C1COCCO1
Product: Cc1ccc(-c2cc(C(=O)OC(C)(C)C)cc(C(O)C(F)(F)F)c2)nc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 3-bromo-5-(2,2,2-trifluoro-1-hydroxyethyl)benzoate (5.0 g, 14.1 mmol) and bis(tri-tert-butylphosphine)palladium(0) (0.22 g, 0.42 mmol) in dioxane (70 mL) was added 5-methyl-2-pyridylzinc bromide (0.5 M in THF; 56.3 mL, 28.2 mmol). The reaction mixture was heated to 70° C. After 1 h, additional 5-methyl-2-pyridylzinc bromide (0.5 M in THF; 10 mL, 5.0 mmol) and bis(tri-tert-butylphosphine)palladium(0) (40 mg, 0.078 mmol) were added. After 30 min, the reaction was concentrated. Saturated aqueous sodium potassium tartrate tetrahydrate and saturated aqueous sodium bicarbonate were added. The mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→70% hexanes/ethyl acetate) gave the title compound. MS 368.2 (M+1).
Reaction SMILES: [O:1]=[C:2]1[C:15]2N([C:7](=[O:22])[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)CCN1.C(N(CC)CC)C.CS(C)=[O:32]>>[O:32]=[C:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=2[C:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:15]([CH:2]=[O:1])[O:22]1
Reactant: O=C1NCCn2c1c(-c1ccccc1)c1ccccc1c2=O
Reactant: CS(C)=O
Solvent: CCN(CC)CC
Product: O=Cc1oc(=O)c2ccccc2c1-c1ccccc1

Procedure:
The compound obtained in Process 1 (2.5 g) was oxidized with SO3 -pyridine complex in DMSO in the presence of triethylarnine to yield 1-oxo-4-phenyl-1H-2-benzopyran-3-carboxaldehyde as colorless crystals (2.38 g).
Reaction SMILES: Cl[C:2]1[C:30]([F:31])=[CH:29][CH:28]=[C:27]([F:32])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:15]3[CH:16]=[N:17][C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:19][CH:20]=3)=[CH:14][C:6]1=2.[C:33]([Cu])#[N:34]>CN(C=O)C>[F:32][C:27]1[C:3]([CH2:4][N:5]2[CH2:10][CH2:9][NH:8][C:7]3[N:11]=[CH:12][C:13]([C:15]4[CH:16]=[N:17][C:18]([N:21]5[CH2:22][CH2:23][O:24][CH2:25][CH2:26]5)=[CH:19][CH:20]=4)=[CH:14][C:6]2=3)=[C:2]([C:30]([F:31])=[CH:29][CH:28]=1)[C:33]#[N:34]
Reactant: N#C[Cu]
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(-c4ccc(N5CCOCC5)nc4)cc32)c1Cl
Solvent: CN(C)C=O
Product: N#Cc1c(F)ccc(F)c1CN1CCNc2ncc(-c3ccc(N4CCOCC4)nc3)cc21
Temperature: 150 °C
Yield: 37 %

Procedure:
1-(2-Chloro-3,6-difluorobenzyl)-7-(6-morpholin-4-yl-pyridin-3-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (300 mg) was dissolved in anhydrous DMF. CuCN (5.0 eq) was added and the resulting mixture was heated to 150° C. in a microwave for 30 minutes. The reaction mixture was concentrated, taken up in CH2Cl2, washed three (3) times with an aqueous solution of NH4OH (10%), and the organic phase was dried, filtered, and concentrated. The residue was purified via silica gel chromatography (0-100% ethyl acetate in hexanes followed by 5% methanol in ethyl acetate) to give the title compound (37% yield). M.p 188-190° C., LCMS: m/z=449.05 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.24-3.31 (m, 2H), 3.48-3.56 (m, 6H), 3.80-3.88 (m, 4H), 4.51 (s, 2H), 4.86 (bs, 1H), 6.65-6.73 (m, 1H), 6.98-7.06 (m, 2H), 7.09-7.19 (m, 2H), 7.59-7.64 (m, 2H), 8.36 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[CH:13]=[C:12]([CH3:14])[N:11]([S:15]([CH3:18])(=[O:17])=[O:16])[N:10]=2)=[C:4]([F:19])[CH:3]=1.S(Cl)([Cl:23])(=O)=O>C(Cl)(Cl)(Cl)Cl>[Cl:23][C:13]1[C:9]([C:5]2[CH:6]=[C:7]([CH3:8])[C:2]([Cl:1])=[CH:3][C:4]=2[F:19])=[N:10][N:11]([S:15]([CH3:18])(=[O:17])=[O:16])[C:12]=1[CH3:14]
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1cc(-c2cc(C)n(S(C)(=O)=O)n2)c(F)cc1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(-c2nn(S(C)(=O)=O)c(C)c2Cl)c(F)cc1Cl

Procedure:
0.8 g (2.7 mmol) of 3-(4-chloro-2-fluoro-5-methylphenyl)-5-methyl-1-methylsulfonyl-1H-pyrazole and 0.4 g (3.0 mmol) of sulfuryl chloride were reacted in 50 ml of carbon tetrachloride by the method of Example 2. Yield: 0.1 g.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:25])[N:9]=[C:10]([C:11]3[C:12]([O:23][CH3:24])=[CH:13][C:14]([O:21][CH3:22])=[C:15]([S:17](O)(=[O:19])=[O:18])[CH:16]=3)[C:5]2=[CH:4][N:3]=1.S(Cl)([Cl:28])=O>>[NH2:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:25])[N:9]=[C:10]([C:11]3[C:12]([O:23][CH3:24])=[CH:13][C:14]([O:21][CH3:22])=[C:15]([S:17]([Cl:28])(=[O:19])=[O:18])[CH:16]=3)[C:5]2=[CH:4][N:3]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc(OC)c(S(=O)(=O)O)cc1-c1nn(C)c2nc(N)ncc12
Product: COc1cc(OC)c(S(=O)(=O)Cl)cc1-c1nn(C)c2nc(N)ncc12
Temperature: 120 °C
Reaction time: 8 h

Procedure:
5-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2,4-dimethoxy-benzenesulfonic acid (Example 113) (629 mg, 1.72 mmol) is suspended in thionyl chloride (25 ml), the reaction mixture is heated to 120° C. for 5 hours then stood overnight at room temperature. The resulting precipitate is removed by filtration, the filtrate is concentrated in vacuo and the resulting residue is azeotroped with toluene to afford the title compound as a solid.
Reaction SMILES: O[N:2]=[C:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[CH2:9][C:10]#[N:11].C1(S(Cl)(=O)=[O:19])C=CC=CC=1.[OH-].[Na+]>CC(C)=O.O>[O:19]=[C:3]1[NH:2][CH:4]([CH2:9][C:10]#[N:11])[CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: N#CCC1CCCCC1=NO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: N#CCC1CCCCC(=O)N1

Procedure:
The product of Example 150 is reacted with benzenesulfonyl chloride and sodium hydroxide in acetone/water by the method of Example 67 to generate the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH:14]2[CH2:19][CH2:18][NH:17][CH:16]([CH3:20])[CH2:15]2)[CH:8]=1)=[O:5].C=O.[C:28](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C@H:14]2[CH2:19][CH2:18][N:17]([CH3:28])[C@@H:16]([CH3:20])[CH2:15]2)[CH:8]=1)=[O:5]
Reactant: CC(=O)O
Reactant: CC1CC(Oc2cccc(NC(=O)c3ccc(F)cc3Cl)c2)CCN1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H]1C[C@@H](Oc2cccc(NC(=O)c3ccc(F)cc3Cl)c2)CCN1C
Reaction time: 0.17 h
Yield: 85 %

Procedure:
Combine 2-chloro-4-fluoro-N-[3-(2-methyl-piperidin-4-yloxy)-phenyl]-benzamide cis isomer 1 (example 57, 0.26 g, 0.72 mmol), dichloromethane (20 mL), and 37% aqueous formaldehyde (0.58 mL, 7.2 mmol) with stirring. After 10 min., add glacial acetic acid (0.08 mL, 1.44 mmol) followed by sodium triacetoxyborohydride (0.23 g, 1.08 mmol). After 3 hr., partition between 1M aqueous sodium hydroxide solution (50 mL) and dichloromethane (50 mL). Separate the organic layer, wash with aqueous NaCl solution, dry over sodium sulfate, filter and concentrate. Purify residue by silica gel flash chromatography eluting with 10% (2M ammonia/methanol) in dichloromethane to obtain of the title compound (0.46 g, 85%). Mass spectrum: Obs. m/z 377.1443; Calc. m/z 377.1432; mp: 152° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N:8]=[N+:9]=[N-:10])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][CH2:15][CH2:16][CH2:17][N:18]([CH3:23])[CH2:19][CH2:20][CH2:21][NH2:22]>CCOCC>[NH2:14][CH2:15][CH2:16][CH2:17][N:18]([CH3:23])[CH2:19][CH2:20][CH2:21][NH:22][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[N+:9]=[N-:10])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: [N-]=[N+]=Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: CN(CCCN)CCCN
Solvent: CCOCC
Product: CN(CCCN)CCCNc1ccc(N=[N+]=[N-])cc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
The reaction was carried out in the dark. A solution of 4-fluoro-3-nitrophenyl azide (0.91 g, 5.0 mmol, Sigma) in 10 ml dry ether was added dropwise with stirring to a solution of 3.2 ml of N-(3-aminopropyl)-N-methyl-1,3-propanediamine (10 mmol, Aldrich) in 20 ml dry ether and the mixture was stirred for 30 min. The reaction was monitored using TLC (alumina, elution with methanol). The solvent was removed and the red oil was dissolved in 25 ml water, 25 ml 1.0M NaOH and then extracted into ethyl acetate (2×50 ml). The organic phase was dried over MgSO4 and the solvent then removed in vacuum. TLC: (I) alumina, eluted with methanol, Rf=0.43 (II) silica gel, elution with 1:9 AcOH/H2O, Rf between Rf=0.23 and Rf=0.55. 1H NMR (CDCl3 /TMS) δ: 1.45 (2H, broad s, NH), 1.64 (2H, m, CH2), 1.87 (2H, p, J=6.52 Hz, CH2), 2.25 (3H, s, CH3), 2.43 (2H, t, CH2), 2.47 (2H, t, J=6.46 Hz, CH2), 2.73 (2H, t, J=6.89 Hz, CH2), 3.37 (2H, m, J=6.61 Hz, CH2), 6.89 (1H, d, J=9.23 Hz, ArH), 7.10 (1H, dd, J=2.73, 9.20 Hz, ArH), 7.79 (1H, d, J=2.74 Hz, ArH), 8.47 (1H, m, NH). 13C NMR (CDCl3 /TMS) δ: 143.23 (Q), 131.24 (Q), 127.91 (CH), 127.16 (Q), 115.73 (CH), 115.44 (CH), 55.70 (CH2), 55.40 (CH2), 42.03 (CH2), 41.90 (CH3), 40.50 (CH2), 30.94 (CH2), 26.20 (CH2).
Reaction SMILES: [CH3:1][C:2]([NH:4][C:5]1[CH:10]=[CH:9][C:8](Cl)=[CH:7][CH:6]=1)=[O:3].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1.CCCCCC>C(OCC)(=O)C>[C:16]1([CH3:19])[CH:17]=[CH:18][C:13]([NH:12][C:8]2[CH:9]=[CH:10][C:5]([NH:4][C:2](=[O:3])[CH3:1])=[CH:6][CH:7]=2)=[CH:14][CH:15]=1
Reactant: Cc1ccc(N)cc1
Reactant: CC(=O)Nc1ccc(Cl)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=O)Nc1ccc(Nc2ccc(C)cc2)cc1
Yield: 98.2 %

Procedure:
Following the general procedure, 4-chloroacetanilide (85 mg, 0.5 mmol) was coupled with p-toluidine (80 mg, 0.75 mmol) with the reaction temperature of 90° C. and the reaction time of 14 h. Chromatography on silica gel column with 2:1 hexane:ethyl acetate gave 118 mg (98%) of the title compound as a pink solid.
Reaction SMILES: C1(C)C=CC=CC=1.[CH2:8]([O:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20]([O:26][C:27]3[CH:32]=[CH:31][C:30]([NH2:33])=[C:29]([F:34])[CH:28]=3)=[CH:21][CH:22]=[N:23]2)=[CH:18][C:17]=1[C:35]#[N:36])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[F:37][C:38]1[CH:43]=[CH:42][C:41]([N:44]=[C:45]=[O:46])=[CH:40][CH:39]=1>C(#N)C>[CH2:8]([O:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20]([O:26][C:27]3[CH:32]=[CH:31][C:30]([NH:33][C:45]([NH:44][C:41]4[CH:42]=[CH:43][C:38]([F:37])=[CH:39][CH:40]=4)=[O:46])=[C:29]([F:34])[CH:28]=3)=[CH:21][CH:22]=[N:23]2)=[CH:18][C:17]=1[C:35]#[N:36])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: N#Cc1cc2c(Oc3ccc(N)c(F)c3)ccnc2cc1OCc1ccccc1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: CC#N
Solvent: Cc1ccccc1
Product: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)c(F)c3)ccnc2cc1OCc1ccccc1

Procedure:
After adding 210 mg of toluene and 20 ml of acetonitrile to 6.95 g of the 7-benzyloxy-6-cyano-4-(3-fluoro-4-aminophenoxy)quinoline obtained in Production Example 8, the mixture was heated to reflux. Next, 2.67 ml of 4-fluorophenyl isocyanate was added and the mixture was further heated to reflux for 1 hour. After cooling, the precipitated solid was filtered out and dried under reduced pressure to obtain 7.45 g of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[O:11][N:10]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=1.[Br:17]N1C(=O)CCC1=O>FC(F)(F)C(O)=O.C(OCC)(=O)C>[Br:17][C:8]1[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:10][O:11][C:7]=1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cc(-c2ccccn2)on1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCOC(=O)c1noc(-c2ccccn2)c1Br
Yield: 69.1 %

Procedure:
A solution of ethyl 5-(pyridin-2-yl)isoxazole-3-carboxylate (212 mg, 0.972 mmol) and N-bromosuccinimide (432 mg, 2.43 mmol) in trifluoroacetic acid (6 mL) was heated to 150° C. for 30 minutes via microwave. Concentration under reduced pressure afforded a yellow oil which was diluted with ethyl acetate (80 mL), washed with a saturated aqueous solution of sodium bicarbonate (20 mL), washed with brine (20 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure followed by purification by flash silica gel chromatography using a 1:3 mixture ethyl acetate and hexane afforded ethyl 4-bromo-5-(pyridin-2-yl)isoxazole-3-carboxylate (0.217 g, 0.672 mmol, 69% yield). The product had an HPLC retention. time=2.65 min.—Column: YMC S5 COMBISCREEN® 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=299.02. 1H NMR (400 MHz, CDCl3) δ ppm 1.48 (t, J=7.15 Hz, 3H), 4.52 (q, J=7.28 Hz, 2H), 7.43-7.48 (m, 1H), 7.90 (td, J=7.78, 1.76 Hz, 1H), 8.11 (d, J=8.03 Hz, 1H), and 8.84 (d, 1H).
Reaction SMILES: C(N(C(C)C)C(C)C)C.[N:10]1([C:16]2[CH:25]=[C:24]3[C:19]([C:20](=O)[NH:21][CH:22]=[N:23]3)=[CH:18][CH:17]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.P(Cl)(Cl)([Cl:29])=O>>[Cl:29][C:20]1[C:19]2[C:24](=[CH:25][C:16]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)=[CH:17][CH:18]=2)[N:23]=[CH:22][N:21]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2cc(N3CCOCC3)ccc12
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ncnc2cc(N3CCOCC3)ccc12
Temperature: 115 °C
Reaction time: 2 h

Procedure:
1.3 ml (7.57 mmol) of N-ethyldiisopropylamine were slowly added dropwise to a suspension of 3.5 g (15.11 mmol) of 7-morpholin-4-yl-3H-quinazolin-4-one in 20 ml of phosphoryl chloride. The reaction mixture was subsequently stirred at 115° C. for 2 h. Conventional work-up gave 3.75 g of 4-chloro-7-morpholin-4-ylquinazoline; HPLC/MS (M+H)+=250 as solid.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1>>[F:18][C:19]1[CH:24]=[C:23]([N:1]2[CH:5]=[C:4]([C:6]3[C:7]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[N:8][O:9][C:10]=3[CH3:11])[N:3]=[CH:2]2)[CH:22]=[CH:21][CH:20]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]cn1
Reactant: OB(O)c1cccc(F)c1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2cccc(F)c2)cn1
Yield: 25 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (112.6 mg, 0.5 mmol) was converted, using 3-fluorophenylboronic acid instead of 4-fluorophenylboronic acid, to the title compound (40 mg, 25%) which was obtained as a white solid. MS (ESI): m/e=320.0 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]3[CH2:16][C:15]([CH3:18])([CH3:17])[S:14][C:9]=3[C:10]([CH3:13])([CH3:12])[O:11][C:6]=2[CH:5]=[C:4]([CH:19]([CH:21]([CH3:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH3:20])[CH:3]=1.[BrH:28].[N:29]1([CH2:34][CH2:35][CH2:36][C:37](O)=[O:38])[CH2:33][CH2:32][CH2:31][CH2:30]1.C1(N=C=NC2CCCCC2)CCCCC1>>[BrH:28].[CH3:27][CH:21]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:19]([C:4]1[CH:3]=[C:2]([O:1][C:37](=[O:38])[CH2:36][CH2:35][CH2:34][N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[C:7]2[C:8]3[CH2:16][C:15]([CH3:17])([CH3:18])[S:14][C:9]=3[C:10]([CH3:12])([CH3:13])[O:11][C:6]=2[CH:5]=1)[CH3:20]
Reactant: O=C(O)CCCN1CCCC1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CC(C)(C)S1
Agent: Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CCCCCC(C)C(C)c1cc(OC(=O)CCCN2CCCC2)c2c(c1)OC(C)(C)C1=C2CC(C)(C)S1

Procedure:
By reacting 1,2-dihydro-9-hydroxy-7-(3-methyl-2-octyl)-2,2,4,4-tetramethyl-4H-thieno-[2,3-c][1]benzopyran with γ-pyrrolidinobutyric acid hydrobromide salt and dicyclohexylcarbodiimide according to the method of Example 10 there is obtained 1,2-dihydro-7-(3-methyl-2-octyl)-9-[4-(pyrrolidino)butyryloxy]-2,2,4,4-tetramethyl-4H-thieno-[2,3-c][1]benzopyran hydrobromide.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@@H:9]2[CH2:11][N:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.[N:15]1[NH:16][C:17](=[O:21])[CH:18]=[CH:19][CH:20]=1>>[CH3:13][N:12]([CH2:11][C@H:9]1[CH2:10][C@@H:8]1[C:5]1[CH:6]=[CH:7][C:2]([N:16]2[C:17](=[O:21])[CH:18]=[CH:19][CH:20]=[N:15]2)=[CH:3][CH:4]=1)[CH3:14]
Reactant: CN(C)C[C@H]1C[C@@H]1c1ccc(Br)cc1
Reactant: O=c1cccn[nH]1
Product: CN(C)C[C@H]1C[C@@H]1c1ccc(-n2ncccc2=O)cc1

Procedure:
Following the general procedure, reaction of 7d (2.13 g assayed, 8.37 mmol) with 3(2H)-pyridazinone (1.05 g, 10.5 mmol) afforded a solution of the free base of 8d in an assayed yield of 1.57 g (5.8 mmol, 70% assay yield, 93% peak area).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[N:6]2[CH3:11].[NH3:18]>>[CH3:11][N:6]1[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:4][C:3]2[C:7]1=[N:8][CH:9]=[N:10][C:2]=2[NH2:18]
Reactant: N
Reactant: Cn1c(-c2ccccc2)nc2c(Cl)ncnc21
Product: Cn1c(-c2ccccc2)nc2c(N)ncnc21
Temperature: -196 °C

Procedure:
6-chloro-9-methyl-8-phenylpurine was added in a steel vial to ammonia cooled to −196° C. using liquid nitrogen. The reaction mixture was allowed to warm to 16° C. for 70 hours; after that, the ammonia was allowed to evaporate at room temperature and the residue was chromatographed and/or crystallized to give 9-methyl-8-phenylpurine-6-ylamine, a compound of Formula (I).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([CH:12]([C:18](=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:10][CH3:11]>>[CH2:8]([C:12](=[C:18]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:10][CH3:11]
Reactant: CCCCC(C(=O)OCC)C(=O)C(=O)OCC
Reactant: Nc1ccccc1
Product: CCCCC(C(=O)OCC)=C(Nc1ccccc1)C(=O)OCC
Temperature: 75 °C
Reaction time: 72 h
Yield: 45.2 %

Procedure:
A mixture of 1 g of aniline with 2.65 g of the product of Step A and 150 mg of SiliporiteRNK10 was stirred for 3 days at 75° C. and then the reaction mixture was cooled down and chromatographed on silica (eluant: hexane-ethyl acetate (9-1) to obtain 1.55 g of the expected product.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[O:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]1.[CH3:23][Si:24](Cl)([CH3:26])[CH3:25]>O1CCCC1>[CH3:22][O:21][C:19](=[C:16]1[CH2:17][CH2:18][O:13][CH2:14][CH2:15]1)[O:20][Si:24]([CH3:26])([CH3:25])[CH3:23]
Reactant: COC(=O)C1CCOCC1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(O[Si](C)(C)C)=C1CCOCC1
Reaction time: 0.33 h

Procedure:
To a stirred solution of diisopropylamine (5.2 mL, 37 mmol) in tetrahydrofuran (15 mL) was added dropwise n-butyllithium (1.6 M in hexane, 21 mL, 34 mmol) at 0° C. and stirred for 20 min. A mixture of methyl tetrahydro-2H-pyran-4-carboxylate (4.5 g, 31 mmol) and trimethylsilyl chloride (4.3 mL, 34 mmol) was added to the mixture at −40° C., then trimethylsilyl chloride (0.4 mL, 0.3 mmol) was added to the mixture. The mixture was stirred at room temperature for 2 h. The volatile components were removed by evaporation and the residual mixture was filtered through a pad of celite washing with hexane. The filtrate was evaporated to give 6.9 g (quant.) of the title compound as a clear yellow oil.
Reaction SMILES: [C:1]([O:9]CC)(=O)[CH2:2][C:3](OCC)=O.[H-].[Na+].BrC1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=1[N+:22]([O-])=O.C(OCC)(=O)C>CS(C)=O>[CH2:2]1[C:1](=[O:9])[NH:22][C:16]2[CH:17]=[C:18]([Br:21])[CH:19]=[CH:20][C:3]1=2
Reactant: O=[N+]([O-])c1cc(Br)ccc1Br
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C1Cc2ccc(Br)cc2N1
Temperature: 0 °C
Yield: 85 %

Procedure:
Under ice cooling, diethyl malonate (500 g) was added dropwise into a suspension of sodium hydride (125 g) in dimethyl sulfoxide (800 ml). After the solution became homogeneous, the resultant mixture was heated to 100° C. and a solution of 2,5-dibromonitrobenzene (500 g) in dimethyl sulfoxide (400 ml) was added dropwise thereinto followed by stirring the resultant mixture at 100° C. for 5 hr. Then the reaction solution was diluted with ice water (2 l), mixed with ethyl acetate (8 l), and the layers were separated. The organic layer was washed successively with water (2 l) four times and brine and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was diluted with ethanol (2.5 l) followed by the addition of tin (380 g). Under ice cooling, conc. hydrochloric acid (1.5 l) was added dropwise into the reaction mixture. After the completion of the addition, the resultant mixture was heated under reflux for 3 hr and diluted with ice water (8 l). The resulting crystalline precipitates were collected by filtration, washed with water and hexane, and air dried at 50° C. for 24 hr to give the title compound (321 g) (yield: 84%).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)=[O:11]>>[Cl:18][C:14]1[CH:13]=[C:12]([C:10](=[O:11])[CH:9]=[CH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)c1cccc(Cl)c1
Reactant: O=Cc1ccccc1
Product: O=C(C=Cc1ccccc1)c1cccc(Cl)c1

Procedure:
By a procedure similar to that of example 1.59.1, starting from benzaldehyde and 3-chloroacetophenone, 1-(3-chlorophenyl)-3-phenylprop-2-en-1-one was obtained as yellowish solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[F:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[C:22]([F:24])[CH:23]=1.N1C=CC=CC=1>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])=[CH:7][N:8]2[C:20]2[CH:19]=[C:18]([F:17])[CH:23]=[C:22]([F:24])[CH:21]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)C(F)(F)F
Reactant: OB(O)c1cc(F)cc(F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1cn(-c2cc(F)cc(F)c2)c2cc(Cl)ccc12)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 71 %

Procedure:
To a solution of 1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone (described in US 2004067939) in CH2Cl2 (in the presence of 0.4 nM molecular sieve) were added anhydrous Cu(OAc)2 (2 eq.), 3,5-difluorophenylboronic acid (3 eq.) and pyridine (4 eq.). The reaction mixture was stirred at RT for 16 h under an air atmosphere, filtered over decalite, washed with CH2Cl2 and concentrated in vacuo. Chromatography (hexane/EtOAc: 9:1) gave the title compound in 71% yield.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[CH:7][C:6]([OH:9])=[C:5]([SH:10])[CH:4]=1.Br[CH2:12]Br>CN(C=O)C.C(=O)([O-])[O-].[K+].[K+]>[S:10]1[C:5]2[CH:4]=[C:3]([CH2:2][OH:1])[N:8]=[CH:7][C:6]=2[O:9][CH2:12]1
Reactant: OCc1cc(S)c(O)cn1
Reactant: BrCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCc1cc2c(cn1)OCS2
Reaction time: 0.17 h
Yield: 70.4 %

Procedure:
To a solution of 6-(hydroxymethyl)-4-mercapto-3-pyridinol (500 mg, 3.2 mmol) in anhydrous DMF, potassium carbonate was added. The reaction mixture was stirred for 10 minutes and dibromomethane (0.44 mL, 6.4 mmol) was added. The reaction mixture was stirred at 70° C. for 18 hours under an argon atmosphere. DMF was removed in vacuo and the residue was partitioned between 5% MeOH in dichloromethane and water. The aqueous layer was extracted several times with 5% methanol in dichloromethane. The combined organic extracts were dried over magnesium sulfate and evaporated under vacuum. The residue was chromatographed on silica gel eluting with 3-5% methanol in dichloromethane to afford the product as a solid (381 mg, 70%); MS (+ve ion electrospray) m/z 170 (MH+).