Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[C:15]([Cu])#[N:16].CO.ClCCl>CN(C=O)C>[C:15]([C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6])#[N:16]
Reactant: N#C[Cu]
Reactant: O=C(O)c1cc(Br)cc(C(F)(F)F)c1
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: N#Cc1cc(C(=O)O)cc(C(F)(F)F)c1
Temperature: 150 °C
Reaction time: 15.5 h

Procedure:
In a 3-neck 100 mL round-bottomed flask, 3-bromo-5-(trifluoromethyl)benzoic acid (10.0, 1.0 eq.) was dissolved in DMF (100 mL, 10 Vol). CuCN was added at RT and the reaction was stirred at 150° C. for 15-16 hr. Reaction completion was monitored on TLC using MeOH:dichloromethane (1:9) mobile phase. Reaction mixture was quenched into the ice-water slurry (1000 mL) and filtered over celite. Compound was extracted in the ethyl acetate (250 mL×3). Organic layer was washed with water (150 mL) followed by drying using anhydrous sodium sulphate. Organic layer was concentrated under reduced pressure. Then again the crude was dissolved in ethyl acetate and extracted with (250 mL×3). Combined aqueous layer was again acidified with dil HCl (350 mL) to get pH 3. Then aqueous layer was extracted with ethyl acetate (250 mL×3). This combined organic layer was washed with water (150 mL) followed by drying using anhydrous sodium sulphate. Organic layer was concentrated under reduced pressure to afford 6.0 g of crude compound, Yield (75.4%). This crude material was directly used for next step without purification; Mass: (ES−) 214.14 (M−1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[NH:13][C:14]1[C:22]3[O:21][CH:20]=[CH:19][C:18]=3[C:17](I)=[CH:16][CH:15]=1)=[CH:10][C:9]([O:24][CH3:25])=[C:8]([O:26][CH3:27])[CH:7]=2)#[N:2].CN(C)[CH:30]=[O:31]>>[C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[NH:13][C:14]1[C:22]3[O:21][CH:20]=[CH:19][C:18]=3[C:17]([CH:18]=[CH:19][C:20]([O:31][CH3:30])=[O:21])=[CH:16][CH:15]=1)=[CH:10][C:9]([O:24][CH3:25])=[C:8]([O:26][CH3:27])[CH:7]=2)#[N:2]
Reactant: CN(C)C=O
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(I)c4ccoc34)c2cc1OC
Product: COC(=O)C=Cc1ccc(Nc2c(C#N)cnc3cc(OC)c(OC)cc23)c2occc12
Temperature: 115 °C

Procedure:
The 3-cyano-6,7-dimethoxy-4-(4-iodobenzofuran-7-ylamino)quinoline (0.275 g) was suspended in N,N-dimethylformamide (15 ml) in a nitrogen-flushed vessel, then palladium (II) acetate (16 mg) was added, followed by methyl acrylate (1.1 ml) and triethylamine (0.6 ml). The reaction was heated to 115° C. for 5 hours before filtration and evaporation of solvents under reduced pressure. The residue was purified by column chromatography on silica using increasingly polar mixtures of iso-hexane with ethyl acetate as eluent The resulting product was triturated with diethyl ether and filtered. There was thus obtained the title compound (0.203 g), as a yellow solid; NMR Spectrum: (DMSOd6) 3.77 (s, 3H), 3.94 (s, 3H), 3.99 (s, 3H), 6.73 (d, 1H), 7.31 (d, 1H), 7.40(s, 1H), 7.47 (d, 1H), 7.76 (d, 1H), 7.86 (s, 1H), 7.97 (d, 1H), 8.08 (d, 1H), 8.56 (s, 1H), 10.02 (br s, 1H); Mass Spectrum: M+H+ 430.
Reaction SMILES: Br[C:2]1[C:7]2[N:8]=[C:9]([C@:11]3([CH3:26])[CH2:15][CH2:14][CH2:13][N:12]3[C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cu][C:28]#[N:29].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O.[Cl-].[Na+].O>[C:28]([C:2]1[C:7]2[N:8]=[C:9]([C@:11]3([CH3:26])[CH2:15][CH2:14][CH2:13][N:12]3[C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1)#[N:29]
Reactant: C[C@@]1(c2nc3c(Br)cccc3s2)CCCN1C(=O)OCc1ccccc1
Reactant: N#C[Cu]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@]1(c2nc3c(C#N)cccc3s2)CCCN1C(=O)OCc1ccccc1

Procedure:
A mixture of EXAMPLE 5D (100 mg) and copper(I) cyanide (35.3 mg) in N,N-dimethylformamide (2.5 mL) was heated in a microwave reactor at 205° C. for 30 minutes. This reaction was repeated twice, and after cooling, the combined three reaction mixtures were treated with 5% aqueous citric acid and brine and extracted with ethyl acetate. The aqueous layer was treated with 5% aqueous potassium sodium tartrate and ethyl acetate. The combined organic layers were washed with aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated, and the residue purified by flash chromatography using 98:2 dichloromethane/ethyl acetate to afford the title compound.
Reaction SMILES: C([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:15]=[C:16]([CH:20]3[N:24]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=4[F:32])[N:23]=[C:22]([C:33]([F:39])([F:38])[C:34]([F:37])([F:36])[F:35])[CH2:21]3)[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>ClCCl>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[F:32][C:26]1[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:25]=1[N:24]1[CH:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=3)[CH:15]=2)[CH2:21][C:22]([C:33]([F:38])([F:39])[C:34]([F:36])([F:37])[F:35])=[N:23]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2cccc(C3=CCNCC3)c2)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 108.7 %

Procedure:
5-[3-(1-BOC-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-1-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (800.0 mg, 1.32 mmol) prepared in Example 60 and trifluoroacetic acid (1011.0 uL, 13.21 mmol) were added at 0° C. to dichloromethane (6.6 mL). The reaction mixture was stirred at room temperature for 3 hours and then concentrated under reduced pressure to give 820.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]([O:18][C@@H:19]1[C@@:23]([CH2:43][O:44]S(C2C=CC(C)=CC=2)(=O)=O)([CH2:24][O:25][Si:26]([C:39]([CH3:42])([CH3:41])[CH3:40])([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:22][C@@H:21]([N:55]2[C:72]3[N:71]=[CH:70][N:69]=[C:59]([NH:60][C:61](=O)[C:62]4[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=4)[C:58]=3[N:57]=[CH:56]2)[C@@H:20]1O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:11]([O:18][C@@H:19]1[C@@:23]2([CH2:43][O:44][C@H:20]1[C@H:21]([N:55]1[C:72]3[N:71]=[CH:70][N:69]=[C:59]([NH:60][CH2:61][C:62]4[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=4)[C:58]=3[N:57]=[CH:56]1)[O:22]2)[CH2:24][O:25][Si:26]([C:39]([CH3:42])([CH3:41])[CH3:40])([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@]2(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O[C@@H](n3cnc4c(NC(=O)c5ccccc5)ncnc43)[C@H](O)[C@@H]2OCc2ccccc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OC[C@@]12CO[C@@H]([C@H](n3cnc4c(NCc5ccccc5)ncnc43)O1)[C@@H]2OCc1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
In a stream of nitrogen, sodium bis(trimethylsilyl)amide (1.0 M in THF, 0.58 ml, 0.572 mmol) was added to a tetrahydrofuran solution (8.0 ml) of Compound 41 (210.5 mg, 0.238 mmol) at room temperature, and the mixture was stirred for 3 hours at room temperature. A saturated sodium bicarbonate solution was added to the reaction mixture, and then the system was extracted 3 times with methylene chloride. The organic phase was washed with a saturated sodium chloride solution, and then dried over sodium sulfate. The solvents were distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (CHCl3-MeOH, 30:1) to obtain a white powder, Compound 42 (169.5 mg, 0.238 mmol, quant.).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[I:18]N1C(=O)CCC1=O.O>C(O)(=O)C>[I:18][C:11]1[CH:10]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:16])([F:17])[F:1])[CH:4]=2)[CH:14]=[CH:13][C:12]=1[OH:15]
Reactant: Oc1ccc(-c2cccc(C(F)(F)F)c2)cc1
Reactant: O=C1CCC(=O)N1I
Solvent: O
Solvent: CC(=O)O
Product: Oc1ccc(-c2cccc(C(F)(F)F)c2)cc1I
Temperature: 25 °C
Yield: 39.2 %

Procedure:
To a solution of 3′-(trifluoromethyl)biphenyl-4-ol (Preparation 1, 2.17 g, 9.11 mmol) in acetic acid (20 mL) at 0° C. was added N-iodosuccinimide (2.05 g, 9.11 mmol). The reaction was allowed to warm to room temperature and stirred for 48 hours before the addition of water (20 mL). The reaction mixture was extracted with dichloromethane (2×20 mL) and the combined extracts were washed with saturated aqueous sodium thiosulfate solution, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (2%-20% ethyl acetate in heptane gradient elution) to afford the title compound (1.30 g, 39%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:21])[C:12](=[O:13])[CH:11]=[C:10](/[CH:14]=[CH:15]/[C:16]3[CH:20]=[CH:19][S:18][CH:17]=3)[O:9]2)=[CH:4][CH:3]=1.[CH2:22]([SH:29])[C@@H:23]([OH:28])[C@H:24]([OH:27])[CH2:25][SH:26]>>[OH:27][C@@H:24]([C@H:23]([OH:28])[CH2:22][SH:29])[CH2:25][S:26][CH:15]([C:16]1[CH:20]=[CH:19][S:18][CH:17]=1)[CH2:14][C:10]1[O:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)([CH3:21])[C:12](=[O:13])[CH:11]=1
Reactant: O[C@H](CS)[C@H](O)CS
Reactant: CC1(c2ccc(F)cc2)OC(/C=C/c2ccsc2)=CC1=O
Product: CC1(c2ccc(F)cc2)OC(CC(SC[C@@H](O)[C@H](O)CS)c2ccsc2)=CC1=O

Procedure:
Following the procedure of Method C, Example 1, (E)-2-(4-fluorophenyl)-2-methyl-5-[2-(3-thienyl)ethenyl]-3(2H)-furanone was reacted with 1,4-dithio-DL-threitol to give 5-(2-{[(2S*,3S*)-2,3-dihydroxy-4-mercaptobutyl]thio}-2-thien-3-ylethyl)-2-(4-fluorophenyl)-2methylfuran-3(2H)-one: 1H NMR (DMSO-d6) δ1.53, 1.57 and 1.60 (overlapped singlets, 3H), 4.60 (m, 1H), 5.56 and 5.57 (overlapped singlets, 1H), 7.12-7.60 (m, 7H); MS (LR-ESI) m/z 455 (M+H calcd. for C21H24FO4S3 455).
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[N:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1>O.CO>[N:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:16][CH2:17][N:18]([C:21]3[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=3)[CH2:19][CH2:20]2)=[CH:11][CH:10]=1
Reactant: O=[N+]([O-])c1ccc(N2CCN(c3ccncc3)CC2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Nc1ccc(N2CCN(c3ccncc3)CC2)cc1
Yield: 81.2 %

Procedure:
A solution of sodium dithionite (2.5 g) in water (10 ml) was added to a warmed solution of 1-(4-pyridyl)-4-(4-nitrophenyl)piperazine (0.551 g) in methanol (50 ml) and the mixture was allowed to reflux for 2 hours. The methanol was removed by evaporation and the resulting concentrated solution was basified with solid Na2SO4. The organic material was extracted into ethyl acetate, washed with water, brine, dried (Na2SO4) and evaporated to give 1-(4-pyridyl)-4-(4-aminophenyl)piperazine (0.4 g) as an oil. NMR: (CDCl3) 3.14(t,4H), 3.48(t, 4H), 6.68(m,4H), 6.85(d,2H), 8.31(bd,2H): MS: m z 255 (MH)−.
Reaction SMILES: [C:1]([N:8]1[C@@H:12]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C@H:11]([CH2:20][CH:21]2[S:26](=[O:28])(=[O:27])[CH2:25][CH2:24][CH2:23][S:22]2(=[O:30])=[O:29])[O:10][C:9]1([CH3:32])[CH3:31])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:33]I>C1COCC1.CCCCCC.CCOCC>[C:1]([N:8]1[C@@H:12]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C@H:11]([CH2:20][C:21]2([CH3:33])[S:26](=[O:27])(=[O:28])[CH2:25][CH2:24][CH2:23][S:22]2(=[O:30])=[O:29])[O:10][C:9]1([CH3:32])[CH3:31])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CC2CCCCC2)[C@H](CC2S(=O)(=O)CCCS2(=O)=O)OC1(C)C
Reactant: CI
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H](CC2CCCCC2)[C@H](CC2(C)S(=O)(=O)CCCS2(=O)=O)OC1(C)C
Reaction time: 1 h

Procedure:
A solution of 0.98 g of 2-[(4S,5S)-3-BOC-4-cyclohexylmethyl-2,2-dimethyl-5-oxazolidinyl-methyl]-1,3-dithiane 1,1,3,3-tetroxide in 300 ml of THF is mixed at -30° with 1.3 ml of a 1.6 molar solution of butyl-Li in hexane. The mixture is stirred for 1 h and then 0.56 g of methyl iodide is added and the mixture is stirred for 24 h in a thawing cooled bath, diluted with 50 ml of ether, and worked up as usual to give 2-[(4S,5S)-3-BOC-4-cyclohexylmethyl-2,2-dimethyl-5-oxazolidinyl-methyl]-2-methyl-l,3-dithiane 1,1,3,3-tetroxide, m.p. 176°-177°.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1.[C:11](Cl)(=[O:14])[CH2:12][CH3:13].C1CCCCC1>C1(C)C=CC=CC=1>[C:11]([NH:1][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1)(=[O:14])[CH2:12][CH3:13]
Reactant: CCC(=O)Cl
Reactant: Nc1nc(C(Cl)(Cl)Cl)ns1
Solvent: C1CCCCC1
Solvent: Cc1ccccc1
Product: CCC(=O)Nc1nc(C(Cl)(Cl)Cl)ns1
Temperature: -15 °C
Yield: 91 %

Procedure:
A solution of 21.8 grams (0.1 mole) 5-amino-3-trichloromethyl-1,2,4-thiadiazole and 18.5 grams (0.2 mole) propionyl chloride in 300 milliliters toluene was refluxed at about 110° C. for 14 hours. The product precipitated (18.4 grams, 91% yield) upon cooling to -15° C. and was isolated by filtration. A pure product of m.p. 150.0° C. was obtained by recrystallization from cyclohexane.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH:11]1(NC2CCCCC2)CCCC[CH2:12]1.C([Si](C)(C)C)#C.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C.O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:11]([C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1)#[CH:12]
Reactant: C1CCC(NC2CCCCC2)CC1
Reactant: Brc1cnc2ccccn12
Agent: Cl[Pd]Cl
Agent: C#C[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Solvent: O
Product: C#Cc1cnc2ccccn12
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To 3-bromoimidazo[1,2-a]pyridine (5 g, 0.0254 mol) in acetonitrile (50 mL) in a sealed tube was added bis(triphenylphosphine) palladium(II) dichloride (0.445 g, 0.634 mmol), Cul (0.17 g, 0.89 mmol), dicyclohexylamine (5.6 mL, 0.028 mol) and ethynyltrimethylsilane (7.2 mL, 0.051 mol). The solution was purged with argon for 15 minutes, sealed and heated at 80° C. for 3 h. At this point the HPLC did not show any starting bromide. The solvents were concentrated and to the residue was added water and dichloromethane (25 mL each). The organic layer was separated and the aqueous layer was repeatedly extracted with dichloromethane (3×20 mL). The combined extracts were dried (Na2SO4), and concentrated (Rf, 0.47 in 1/1 hexanes/ethyl acetate). The resulting residue was dissolved in THF (100 mL) and treated with tetrabutyl ammonium fluoride monohydrate (8.3 g, 0.032 mol) in water (5 mL) and the mixture was stirred at rt for 2 h. The solvents were concentrated and the resuting residue was partitioned between water (25 mL) and dichloromethane (150 mL). The aquesous layer was extracted with dichloromethane (2×30 mL). The combined extracts were dried (Na2SO4), and concentrated. The resulting residue was purified by combiflash on silica gel using hexanes/ethyl acetate. The desired product was eluted with 50/50 hexane/ethyl acetate and isolted as an off-white solid: MS (M+H)+ 200.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O(C1C=C(C=CC=1)C(O)=O)C1C=CC=CC=1>>[O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][OH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Agent: O=C(O)c1cccc(Oc2ccccc2)c1
Product: OCc1cccc(Oc2ccccc2)c1

Procedure:
After filtering off the catalyst, the filtrate (reaction mixture), which consists of an organic phase containing the 3-phenoxy-benzaldehyde and an aqueous-alkaline phase containing the 3-phenoxy-benzoic acid is extracted with ether. After drying the combined ether extracts over sodium sulphate and stripping off the ether under nitrogen, 9.4 g of a residue which, according to analysis by gas chromatography, contains 96.9% of 3-phenoxy-benzaldehyde and 1.3% of still unreacted 3-phenoxy-benzyl alcohol remain. This gives a 3-phenoxy-benzyl alcohol conversion of 98.8%, a 3-phenoxy-benzaldehyde yield of 93% of theory and a selectivity for 3-phenoxy-benzaldehyde of 94%.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:28])=[C:5]([C:21]([O:23][CH2:24][CH2:25][CH2:26]Br)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].[ClH:29].[C:30]1([C:36]2([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[ClH:29].[CH3:1][C:2]1[NH:3][C:4]([CH3:28])=[C:5]([C:21]([O:23][CH2:24][CH2:25][CH2:26][N:39]2[CH2:40][CH2:41][C:36]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:37][CH2:38]2)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCBr)C1c1cccc([N+](=O)[O-])c1
Reactant: c1ccc(C2(c3ccccc3)CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCN2CCC(c3ccccc3)(c3ccccc3)CC2)C1c1cccc([N+](=O)[O-])c1
Reaction time: 16 h
Yield: 82.2 %

Procedure:
86.6 g of 3-methyl 5-(3-bromopropyl) (-)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate, 50 g of 4,4-diphenylpiperidine hydrochloride and 69 g of finely milled potassium carbonate are heated together in 300 ml of dimethylformamide for 5 h at 100° C. with vigorous stirring and under a nitrogen atmosphere. After cooling, 500 ml of ethyl acetate and 1 l of water are added in succession and the mixture is stirred thoroughly. After phase separation, the organic phase is washed 4 times with water, dried over sodium sulphate and evaporated in vacuo. The residue is dissolved in 1 l of dioxane and 15.2 ml of concentrated hydrochloric acid solution (12.5 M, d=1.19) are added to the cooled solution; about 200 ml of the solvent mixture are then distilled off in vacuo. On standing at room temperature, the product crystallises spontaneously or after seeding or trituration; it is filtered off under suction after 16 h, washed with dioxane and diisopropyl ether and dried in vacuo at 80°-100° C. For purification, the product is dissolved in dichloromethane. After the addition of 800 ml of dioxane, the dichloromethane is distilled off again. The product which has crystallised out after seeding and standing at room temperature for 16 hours is filtered off under suction, washed with dioxane and diisopropyl ether and dried at 100° C. 97 g of the title compound of m.p. 158°-160° C. and [α]22 436 =-39° (c=1, methanol) or [α]22D =-14.4° (c=1. methanol) are obtained.
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:15])=[O:4].Cl.O1CCOCC1.Cl[C:24]1[CH:29]=[CH:28][N:27]=[C:26]2[CH:30]=[C:31]([C:33]3[N:34]([CH3:38])[CH:35]=[CH:36][N:37]=3)[S:32][C:25]=12.C([O-])(O)=O.[Na+]>CC(O)C.O.CCOC(C)=O>[CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:24]3[CH:29]=[CH:28][N:27]=[C:26]4[CH:30]=[C:31]([C:33]5[N:34]([CH3:38])[CH:35]=[CH:36][N:37]=5)[S:32][C:25]=34)=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:15])=[O:4]
Reactant: CNC(=O)n1c(C)cc2cc(N)ccc21
Reactant: Cn1ccnc1-c1cc2nccc(Cl)c2s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CC(C)O
Product: CNC(=O)n1c(C)cc2cc(Nc3ccnc4cc(-c5nccn5C)sc34)ccc21
Temperature: 25 °C
Yield: 83.2 %

Procedure:
To a stirred slurry of 5-amino-2-methylindole-1-carboxylic acid methylamide (632 mg, 3.1 mmole), prepared in Example 1(a) step (iii), in 2-propanol (35 ml) was added 4.0 M HCl in 1,4-dioxane (0.75 ml, 3 mmole) followed by 7-chloro-2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridine (500 mg, 2 mmole), prepared as described in PCT application WO-99/24440, Example 149. The resultant solution was heated at reflux for 54 hours. After cooling to room temperature, the crude reaction mixture was poured into sat'd NaHCO3 (150 ml), then diluted with water (50 ml). The precipitate that formed was collected by filtration, then washed with water (2×50 ml) and EtOAc (3×30 ml). The solid obtained was suspended in EtOAc (15 ml), filtered and washed with Et2O (3×10 ml) to give 693 mg (83%) of a beige solid. 1H NMR (DMSO-d6): δ 8.76 (1H, s), 8.22 (1H, d, J=5.5 Hz), 8.20 (1H, q, J=5.4 Hz), 7.68 (1H, s), 7.60 (1H, d, J=8.7 Hz), 7.35 (1H, d, J=0.2 Hz), 7.34 (1H, d, J=1.9Hz), 7.08 (1H, dd, J=1.9, 8.7Hz), 6.98 (1H, d, J=0.2 Hz), 6.67 (1H, d, J=5.5Hz), 6.36 (1H, s), 3.94 (3H, s), 2.88 (3H, d, J=5.4 Hz), 2.48 (3H, s). Anal. Calcd. for C22H20N6OS.1.0H2O: C, 60.81; H, 5.10; N, 19.34; S, 7.38. Found: C, 60.53; H, 5.13; N, 19.07; S, 7.50.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)=[N:15][N:16]4[C:21]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27])=[CH:20][CH:19]=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=NN=N1.C(N(C(C)C)[P:45](=[O:62])([O:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)(C)C.CC(CC(O)=O)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[P:45]([O:27][CH2:26][CH2:25][CH2:24][CH2:23][NH:22][C:21]1[N:16]2[N:15]=[C:14]([C:28]3[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=3)[C:13]([C:11]3[CH:10]=[CH:9][N:8]=[C:7]([NH:6][CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[N:12]=3)=[C:17]2[CH:18]=[CH:19][CH:20]=1)([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)([O:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)=[O:62]
Reactant: CC(C)N(C(C)C)P(=O)(OCc1ccccc1)OCc1ccccc1
Reactant: COc1ccc(-c2nn3c(NCCCCO)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Agent: CC(=O)CC(=O)O
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: COc1ccc(-c2nn3c(NCCCCOP(=O)(OCc4ccccc4)OCc4ccccc4)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Reaction time: 0.33 h
Yield: 53 %

Procedure:
To a room temperature solution of 4-{[3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butan-1-ol (22 mg, 0.05 mmol) in dichloromethane (5 mL) was added 1-H-tetrazole (7 mg, 0.1 mmol) and dibenzyl N,N-diisopropylphosphoramidate (0.32 mL of a stock solution prepared from 0.2 mL of dibenzyl N,N-diisopropylphosphoramidate in 3.2 mL of dichloromethane). The resultant solution was stirred at room temperature for 1 hour and then cooled to 0° C. lodobenzene diacetate (16.5 mg, 0.05 mmol) was added and the mixture was stirred for 20 minutes. Saturated aqueous sodium thiosulfate and saturated aqueous sodium bicarbonate were added and the layers separated. The organic layer was washed with brine. The aqueous layer was extracted with dichloromethane and the combined organics were dried over sodium sulfate. Filtration and concentration followed by flash chromatography (1:4 hexanes-ethyl acetate) provided dibenzyl 4-{[3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butyl phosphate (18 mg, 53%). 1H NMR (CDCl3): δ 8.03 (d, 1 H), 7.81 (d, 1 H), 7.61 (d, 2 H), 7.38–7.32 (m, 11 H), 7.01 (d, 2 H), 6.36 (d, 1 H), 6.06 (m, 1 H), 5.98 (d, 1 H), 5.13–5.01 (m, 5 H), 4.40 (m, 1 H), 4.05 (m, 2 H), 3.91 (s, 3 H), 3.37 (m, 2 H), 2.16–1.54 (m, 12 H); MS m/z 733 (M+1).