Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH:6]1[C:14]2[C:9](=[C:10]([F:16])[C:11]([F:15])=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)C.[Li+].[BH4-]>CCOC(C)=O.C1COCC1.CO.[Pd]>[F:16][C:10]1[C:11]([F:15])=[CH:12][CH:13]=[C:14]2[C:9]=1[CH2:8][CH2:7][CH:6]2[CH2:5][CH2:4][OH:3]
Reactant: CCOC(=O)CC1CCc2c1ccc(F)c2F
Agent: [Pd]
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: OCCC1CCc2c1ccc(F)c2F

Procedure:
A mixture of E- and Z-(4,5-difluoro-indan-1-ylidene)-acetic acid ethyl ester (Intermediate TWENTY-3) (1.1 g) in EtOAc (25 mL) was hydrogenated with 10% Pd/C (0.16 g) under H2 (balloon) at rt for 16 h. The mixture was filtered through a bed of Celite® and the filtrate was evaporated under vacuum. The ester, (4,5-difluoro-indan-1-yl)-acetic acid ethyl ester (1.1 g, 4.58 mmol) in THF (60 mL) and MeOH (1 mL) was treated with LiBH4 (0.21 g, 8.5 mmol) at 65° C. for 5 h. The mixture was cooled and THF was removed under vacuum. The solution was diluted with EtOAc and sat. NH4Cl. The layers were separated and the organic layer was dried over MgSO4 and filtered. After evaporation, the alcohol, 2-(4,5-difluoro-indan-1-yl)-ethanol (Intermediate TWENTY-4) was isolated as a clear, colorless oil, 1.7 g, (88%). Use, 2-(4,5-difluoro-indan-1-yl)-ethanol (Intermediate TWENTY-4) in Method SEVENTEEN produced 4-(4,5-difluoro-indan-1-ylmethyl)-1,3-dihydro-imidazole-2-thione (Compound 156).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](I)[C:6]([F:10])=[CH:5][C:4]=1[CH3:11].[Li]CCCC.[B:17](OC)([O:20]C)[O:18]C>C1COCC1>[CH3:1][O:2][C:3]1[C:4]([CH3:11])=[CH:5][C:6]([F:10])=[C:7]([B:17]([OH:20])[OH:18])[CH:8]=1
Reactant: COB(OC)OC
Reactant: COc1cc(I)c(F)cc1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(B(O)O)c(F)cc1C
Reaction time: 0.17 h
Yield: 69 %

Procedure:
To 122D (750 mg, 2.8 mmol) in THF (10 mL) was added n-BuLi (1.6M in hexane, 2.3 mL) at −78° C. After stirring for 10 min, trimethyl borate (0.63 mL) was introduced. The mixture was stirred from −78° C. to rt for 3 h before it was quenched by 1N HCl and extracted with ethyl acetate. The organic extracts were washed with saturated Na2S2O3, brine and dried over MgSO4. Evaporation of the solvent gave product 122E (356 mg, 69% yield) as a solid. 1H NMR (400 MHz, CDCl3) δ ppm 2.18 (s, 3H) 3.80 (s, 3H) 6.80-6.86 (m, 2H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.N1C2C=CC=C[C:9]=2N=N1.[C:15]1([C:21]#[C:22][C:23]2[S:24][C:25]([CH:28]=O)=[CH:26][N:27]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1COCC1>C(O)C>[C:15]1([C:21]#[C:22][C:23]2[S:24][C:25]([CH:28]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH3:9])=[CH:26][N:27]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C1CCNC1
Reactant: O=Cc1cnc(C#Cc2ccccc2)s1
Reactant: c1ccc2[nH]nnc2c1
Solvent: C1CCOC1
Solvent: CCO
Product: CC(c1cnc(C#Cc2ccccc2)s1)N1CCCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 36.8 %

Procedure:
In a culture tube was added pyrrolidine (17.8 mg, 0.250 mmol) and benzotriazole (29.8 mg, 0.250 mmol) in ethanol (1.0 mL). After stirring at room temperature for 10 minutes, the solution was treated with 2-phenylethynyl-thiazole-5-carbaldehyde (Example 205, 53.3 mg, 0.250 mmol) and THF (0.5 to 1.0 mL) and stirred at room temperature for 1 hour. The volatiles were then removed under reduced pressure, the residue dissolved in ethanol (1.0 mL) and THF (1.0 mL) and the volatiles removed again under reduced pressure. The residue was dissolved once more in THF (1.0 mL), concentrated under reduced pressure and kept under high vacuum for about 1 hour. The residue was then dissolved in THF (1.0 mL) and treated with methyl magnesium bromide (170 μL of a 3.0 M solution in diethyl ether, 0.50 mmol) and the reaction was stirred at room temperature. The reaction was quenched by adding saturated aqueous sodium bicarbonate (4 mL) and diluted with EtOAc (4 mL). After stirring vigorously for a few minutes, the layers were separated and the aqueous layer was stirred again with EtOAc (4 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified on a reversed phase liquid chromatography/mass spectrometry (RP-HPLC/MS) purification system. Gradient: acetonitrile in water, 28-95% in 3.6 minutes with a cycle time of 5 min. A shallow gradient between 38-68% of acetonitrile was used between 0.75-3.3 min to separate close-eluting impurities. Flow rate: 100 mL/min. Mobile phase additive: 96 mM of ammonium formate. Column: Inertsil® C18, 30×50 mm, 5 μm particle size (GL Sciences, Tokyo, Japan)). Fractions were concentrated under reduced pressure and the solid obtained was partitioned between EtOAc (5 mL) and saturated aqueous sodium bicarbonate (5 mL). After stirring vigorously for a few seconds, the layers were separated and the aqueous layer was stirred again with EtOAc (5 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the titled compound, 2-phenylethynyl-5-(1-pyrrolidin-1-yl-ethyl)-thiazole, (26 mg, 37%) as an amber oil.
Reaction SMILES: [Li+].[CH3:2][Si]([N-][Si](C)(C)C)(C)C.[CH3:11][O:12][C:13](=[O:32])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])=[CH:17][CH:16]=1.Br[C:34]1[C:35](C)=[C:36]2[C:41](=[O:42])[NH:40][C:38](=[O:39])[C:37]2=[CH:43][CH:44]=1>C1COCC1>[O:42]=[C:41]1[C:36]2[C:37](=[CH:43][CH:44]=[CH:34][CH:35]=2)[C:38](=[O:39])[N:40]1[CH2:2][CH:14]([C:15]1[CH:20]=[CH:19][C:18]([O:21][Si:22]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:29]([CH3:31])[CH3:30])=[CH:17][CH:16]=1)[C:13]([O:12][CH3:11])=[O:32]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COC(=O)Cc1ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc1
Reactant: Cc1c(Br)ccc2c1C(=O)NC2=O
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(CN1C(=O)c2ccccc2C1=O)c1ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of LiHMDS in THF cooled to −78° C. was added a cooled solution (approx −78° C.) of methyl-2-(4-(triisopropylsilyloxy)phenyl)acetate (E2) in THF via syringe. The solution was stirred at −78° C. for 30 min. Bromo-methyl phthalimide was added directly to the anion, and the solution was immediately removed from the −78° C. bath and placed in an ice bath and stirred for 2 h. The reaction was then poured into NH4Cl(sat) and extracted with EtOAc. The organics were dried (Na2SO4), filtered, and evaporated. Column chromatography 0-20% EtOAc/Hexanes gave pure methyl 3-(1,3-dioxoisoindolin-2-yl)-2-(4-(triisopropylsilyloxy)phenyl)propanoate (E3).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.[CH2:12]([Br:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(OCC)(=O)C>[Br-:19].[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N+:7]=1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: c1ccc(C2OCCO2)nc1
Solvent: CCOC(C)=O
Product: [Br-]
Product: c1ccc(C[n+]2ccccc2C2OCCO2)cc1
Temperature: 80 °C
Yield: 100 %

Procedure:
A mixture of 716 g (4.74 mol) of 2-(1,3-dioxolan-2-yl)pyridine and 859 g (5 mol) of benzyl bromide in a 5 L flask was heated on a steam-bath to 80° C. where an exothermic reaction caused the reaction temperature to reach 146° C. The reaction mixture was allowed to cool to 90° C. and the mixture was heated on a steam-bath for 2 h. The reaction mixture was cooled to room temperature, the resulting solid product was heated on a steam-bath with ethyl acetate, and ethyl acetate was decanted. The treatment with ethyl acetate was repeated three times to afford 1526.8 g of 2-(1,3-dioxolan-2-yl)-1-benzylpyridinium bromide (Formula VI: R1 =R2 =R7 =H; Z- --=Br-).
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH2:10][CH2:9]2.O>CS(C)=O>[CH2:11]1[C:12]2[C:8](=[CH:7][C:6]([CH2:5][C:1]#[N:2])=[CH:14][CH:13]=2)[CH2:9][CH2:10]1
Reactant: [C-]#N
Reactant: ClCc1ccc2c(c1)CCC2
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCc1ccc2c(c1)CCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred, partial solution of NaCN (11.4 g, 0.232 mol) in DMSO 75 mL) was added 5-chloromethylindan (35.2 g, 0.211 mol) dropwise over 45 minutes. (The internal temperature was maintained below 65° C.). The resulting mixture was stirred at room temperature overnight. H2O (250 mL) was added and the mixture was extracted with ether. The organic phase was washed with H2O (200 mL), 6N HCl (100 mL), H2O (200 mL), saturated aqueous NaHCO3 (100 mL), and saturated aqueous NaCl, dried (MgSO4), and concentrated. The crude product was distilled under reduced pressure (0.6 mm) to give 28.1 g (85%) as a colorless oil, b.p. 131°) C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH:11]=2)=[C:7]([NH2:9])[CH:8]=1.C(N(CC)C(C)C)(C)C.Cl.[N:32]1([CH2:38][CH2:39][O:40][C:41]2[CH:49]=[CH:48][C:44]([C:45](Cl)=[O:46])=[CH:43][CH:42]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.[Cl-].[NH4+]>O1CCCC1.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH:11]=2)=[C:7]([NH:9][C:45](=[O:46])[C:44]2[CH:43]=[CH:42][C:41]([O:40][CH2:39][CH2:38][N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:49][CH:48]=2)[CH:8]=1
Reactant: O=C(Cl)c1ccc(OCCN2CCCCC2)cc1
Reactant: COc1ccc(-c2ccc3cc(OC)ccc3c2)c(N)c1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc3cc(OC)ccc3c2)c(NC(=O)c2ccc(OCCN3CCCCC3)cc2)c1
Temperature: 60 °C
Reaction time: 48 h
Yield: 46.5 %

Procedure:
To a solution of 5-methoxy-2-(6-methoxynaphthalen-2-yl)phenylamine (275 mg) in tetrahydrofuran (8 ml) were sequentially added triethylamine (1.3 ml), N,N-diisopropylethylamine (1 ml) and 4-(2-piperidine-1-ylethoxy)benzoyl chloride hydrochloride (1.1 g), and the solution was stirred for 2 days at 60° C. A saturated aqueous solution of ammonium chloride was added thereto, the solution was extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to provide N-[5-methoxy-2-(6-methoxynaphthalen-2-yl)phenyl]-4-(2-piperidin-1-ylethoxy)benz amide (234 mg). To a suspension of lithium aluminum hydride (50 mg) in tetrahydrofuran (4 ml) was added aluminum chloride (176 mg) on an ice bath under a nitrogen atmosphere, the solution was stirred for 20 minutes at room temperature, N-[5-methoxy-2-(6-methoxynaphthalen-2-yl)phenyl]-4-(2-piperidin-1-ylethoxy)benzamide (226 mg) was added thereto followed by stirring overnight at room temperature. Obtained by sequentially adding tetrahydrofuran and aqueous ammonia, the suspension was filtered through celite pad, and the filtrate was concentrated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (213 mg).
Reaction SMILES: C1(C(=[N:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][C:30]=3[F:31])[N:27]([CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)[N:26]=[CH:25]4)=[C:17]([F:38])[CH:16]=2)C2C=CC=CC=2)C=CC=CC=1.Cl.CCOC(C)=O>C1COCC1.O>[F:38][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][C:30]=1[F:31])[N:27]([CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][O:33]1)[N:26]=[CH:25]2)[NH2:14]
Reactant: Fc1cc(N=C(c2ccccc2)c2ccccc2)ccc1Oc1cc2cnn(C3CCCCO3)c2cc1F
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1ccc(Oc2cc3cnn(C4CCCCO4)c3cc2F)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.8 %

Procedure:
To a solution of N-(diphenylmethylene-3-fluoro-4-(6fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yloxy)aniline (1.45 g, 2.85 mmol) in THF (30 mL) and water (5 mL) is added 1N aqueous HCl (5.69 mL, 5.69 mmol). The reaction is stirred at RT for 2 hours. EtOAc is added and the mixture is washed with saturated aqueous NaHCO3 solution, saturated aqueous sodium chloride, dried over Na2SO4, filtered and evaporated. The residue is purified by chromatography eluting with DCM then EtOAc:hexane (1:1) to offer the desired product as a pale gel (0.53 g, 54% yield). MS (m/z): 346 (M+H).
Reaction SMILES: [CH2:1]([C:8]1[CH:20]=[CH:19][C:11]([O:12][CH2:13][C@H:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32]>CN(C=O)C>[CH3:34][O:33][C:31](=[O:32])[CH2:30][CH2:29][N:15]1[CH2:16][CH2:17][CH2:18][C@@H:14]1[CH2:13][O:12][C:11]1[CH:19]=[CH:20][C:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1
Reactant: c1ccc(Cc2ccc(OC[C@H]3CCCN3)cc2)cc1
Reactant: COC(=O)CCBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CCN1CCC[C@@H]1COc1ccc(Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.3 %

Procedure:
To a solution of Example 1 (0.2 g, 0.66 mmol) in DMF (5 mL) was added triethylamine (0.16 mL, 1.14 mmol) and methyl 3-bromopropionate (0.07 mL, 0.64 mmol). The resulting slurry was stirred at ambient temperature overnight. The solvent was removed under reduced pressure and the crude residue was extracted into ethyl acetate. The organic portion was washed with water, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel flash chromatography using hexane/EtOAc (gradient system) to give the title compound (0.03 g, 13%); 1H NMR (400 MHz, CDCl3); δ 1.68-1.80 (m, 3H), 1.93-2.04 (m, 1H), 2.29 (q, J=8.4 Hz, 1H), 2.53 (t, J=7.2 Hz, 2H), 2.70 (m, 1H), 2.87 (m, 1H), 3.13 (m, 1H), 3.24 (m, 1H), 3.66 (s, 3H), 3.75 (m, 1H), 3.92 (s, 2H), 3.93 (m, 1H), 6.82 (d, J=8.8 Hz, 2H), 7.08 (d, J=8.4 Hz, 2H), 7.16-7.20 (m, 3H), 7.27 (m, 2H); MS (m/z) 354.2 (M+1); LC (100.0%).
Reaction SMILES: C12(COC3C(C4CC4)=CC(C(O)=O)=C(F)C=3)CC3CC(CC(C3)C1)C2.[C:26]12([CH2:36][O:37][C:38]3[C:46]([Cl:47])=[CH:45][C:41]([C:42](O)=[O:43])=[C:40]([F:48])[CH:39]=3)[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[CH2:27]1)[CH2:33]2.CS(N)(=O)=O.[CH3:54][O:55][C:56]1[CH:72]=[CH:71][C:59]([CH2:60][O:61][C@H:62]2[CH2:66][CH2:65][N:64]([S:67]([NH2:70])(=[O:69])=[O:68])[CH2:63]2)=[CH:58][CH:57]=1>>[C:26]12([CH2:36][O:37][C:38]3[C:46]([Cl:47])=[CH:45][C:41]([C:42]([NH:70][S:67]([N:64]4[CH2:65][CH2:66][C@H:62]([O:61][CH2:60][C:59]5[CH:71]=[CH:72][C:56]([O:55][CH3:54])=[CH:57][CH:58]=5)[CH2:63]4)(=[O:69])=[O:68])=[O:43])=[C:40]([F:48])[CH:39]=3)[CH2:27][CH:28]3[CH2:34][CH:32]([CH2:31][CH:30]([CH2:29]3)[CH2:35]1)[CH2:33]2
Reactant: COc1ccc(CO[C@H]2CCN(S(N)(=O)=O)C2)cc1
Reactant: O=C(O)c1cc(Cl)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Agent: CS(N)(=O)=O
Agent: O=C(O)c1cc(C2CC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Product: COc1ccc(CO[C@H]2CCN(S(=O)(=O)NC(=O)c3cc(Cl)c(OCC45CC6CC(CC(C6)C4)C5)cc3F)C2)cc1

Procedure:
Following the procedure as described in Example 50 step 5 and making variations as required to replace 4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with 4-(adamantan-1-ylmethoxy)-5-chloro-2-fluorobenzoic acid and methanesulfonamide with (S)-3-((4-methoxybenzyl)oxy)pyrrolidine-1-sulfonamide, the title compound was obtained as colorless solid (0.17 g, 47%): MS (ES+) m/z 607.1, 609.1 (M+1); MS (ES−) m/z 605.3, 607.3 (M−1).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([CH:19]=[N:20][OH:21])[C:3]=1[S:22]([CH3:24])=[O:23].[CH3:25][N:26]=[C:27]=[O:28]>C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC.ClCCl>[CH3:25][NH:26][C:27]([O:21][N:20]=[CH:19][C:4]1[C:3]([S:22]([CH3:24])=[O:23])=[C:2]([NH2:1])[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=1)=[O:28]
Reactant: CS(=O)c1c(C=NO)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Reactant: CN=C=O
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: ClCCl
Product: CNC(=O)ON=Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(C)=O
Yield: 71.2 %

Procedure:
A mixture of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboxaldehyde oxime (1.5 g), methyl isocyanate (0.705 g), and dibutyltin diacetate (2 drops) was stirred in dichloromethane at 20° C. in a sealed bottle for 2 days. The mixture was partitioned between water and dichloromethane, the organic layer dried (Na2SO4) and evaporated and the residue crystallized from ethyl acetate/hexane to give 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboxaldehyde O-(N-methylcarbamoyl)oxime (1.22 g) m.p.146-147° C. Compound 18.
Reaction SMILES: [CH:1]1([N:4]([CH3:28])[CH:5]2[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[C:11]3[CH:10]=[C:9]([NH:17][C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=4)=[O:19])[CH:8]=[CH:7][C:6]2=3)[CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C)[CH:60]=[O:61].[CH3:63][OH:64]>CCCCCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.C(N(CC)CC)C>[CH3:63][O:64][C:60](=[O:61])[C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:18]([NH:17][C:9]2[CH:8]=[CH:7][C:6]3[CH:5]([N:4]([CH:1]4[CH2:3][CH2:2]4)[CH3:28])[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[C:11]=3[CH:10]=2)=[O:19])=[CH:22][CH:23]=1
Reactant: CN(C)C=O
Reactant: CN(C1CC1)C1CCC(C)(C)c2cc(NC(=O)Nc3ccc(I)cc3)ccc21
Reactant: CO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(NC(=O)Nc2ccc3c(c2)C(C)(C)CCC3N(C)C2CC2)cc1

Procedure:
Following General Procedure E and using 1-[5-(cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yl]-3-(4-iodo-phenyl)-urea (Intermediate 58, 0.13 g, 0.267 mmol), palladium acetate (0.02 g, 0.09 mmol), 1,3-bis(diphenylphosphino)propane (0.042 g, 0.101 mmol), N,N-dimethylformamide (3 mL), methanol (3 mL) and triethyl amine (1 mL) followed by flash column chromatography over silica gel (230–400 mesh) using 30–40% ethyl acetate in hexane as the eluent the title compound was obtained (0.045 g, 40%).
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH3:16])[C:10](=[O:15])[CH2:11][C:12](=O)[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1)#[N:18].[F:27][C:28]([F:40])([F:39])[C:29]1[CH:30]=[C:31]([NH:35][C:36]([NH2:38])=[O:37])[CH:32]=[CH:33][CH:34]=1>O1CCCC1>[CH2:1]([O:8][CH:9]([CH3:16])[C:10]([C:11]1[CH:23]([C:22]2[CH:25]=[CH:26][C:19]([C:17]#[N:18])=[CH:20][CH:21]=2)[NH:38][C:36](=[O:37])[N:35]([C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([C:28]([F:39])([F:40])[F:27])[CH:30]=2)[C:12]=1[CH3:13])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)CC(=O)C(C)OCc1ccccc1
Reactant: NC(=O)Nc1cccc(C(F)(F)F)c1
Reactant: N#Cc1ccc(C=O)cc1
Solvent: C1CCOC1
Product: CC1=C(C(=O)C(C)OCc2ccccc2)C(c2ccc(C#N)cc2)NC(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 16 h

Procedure:
To a stirred solution of 5-(benzyloxy)hexane-2,4-dione (250 mg, 1.13 mmol; Example 8A), 4-cyanobenzaldehyde (149 mg, 1.13 mmol) and N-[3-(trifluoromethyl)phenyl]urea (232 mg, 1.13 mmol) in tetrahydrofuran (5 ml) is added polyphosphoric acid ethyl ester (700 mg). After 16 hours, the reaction solution is purified directly by preparative HPLC (RP18 column; eluent: acetonitrile/0.1% aq. formic acid 10:90→90:10). The fractions containing product are concentrated and again purified by preparative HPLC (RP18 column; eluent: acetonitrile/0.1% aq. formic acid 10:90→90:10).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15]O)[N:10]=1)(=[O:8])[CH3:7].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][Cl:3])[N:10]=1)(=[O:8])[CH3:7]
Reactant: CC(=O)c1cccc(CO)n1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)c1cccc(CCl)n1

Procedure:
Phosphorus oxychloride (7.8 ml) was dropwise added to a mixture of 2-acetyl-6-hydroxymethylpyridine (10.0 g) and N,N-dimethylformamide (15.4 ml) in ethyl acetate (100 ml) under ice-cooling with stirring and the mixture was stirred at the same temperature for 3 hours. The reaction mixture was added to water and adjusted to pH 7.5 with potassium carbonate. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated to give 2-acetyl-6-chloromethylpyridine (10.85 g) as an oil.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[Cl:13][C:14]1[CH:19]=[C:18]([NH:20][NH2:21])[N:17]=[C:16]([CH3:22])[N:15]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:30][C:31]1[CH:32]=[CH:33][C:34]([C:37]([F:40])([F:39])[F:38])=[N:35][CH:36]=1>C1COCC1.O>[Cl:13][C:14]1[N:15]=[C:16]([CH3:22])[N:17]2[C:5](=[O:11])[N:21]([CH2:30][C:31]3[CH:36]=[N:35][C:34]([C:37]([F:40])([F:38])[F:39])=[CH:33][CH:32]=3)[N:20]=[C:18]2[CH:19]=1
Reactant: FC(F)(F)c1ccc(CCl)cn1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1nc(Cl)cc(NN)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(Cl)cc2nn(Cc3ccc(C(F)(F)F)nc3)c(=O)n12
Temperature: 60 °C
Reaction time: 8 h
Yield: 63.3 %

Procedure:
To a stirred solution of triphosgene (2.86 g, 9.66 mmol) in THF (10 mL) at room temperature under argon was added a suspension of 4-chloro-6-hydrazinyl-2-methylpyrimidine (10.0 mmol) in THF (15 mL). The reaction mixture was stirred overnight. Analysis by HPLC/MS indicated that no starting material remained. Solvent was removed under reduced pressure. DMF (5 mL) was added to the residue, followed by K2CO3 (2.76 g, 20.0 mmol) and 5-(chloromethyl)-2-(trifluoromethyl)pyridine (2.34 g, 12.0 mmol). The resulting mixture was heated at 60° C. for 2 h, after which time analysis by HPLC/MS indicated that the reaction was complete. After cooling the reaction mixture to room temperature, water (20 mL) was added. The resulting mixture was extracted with EtOAc (2×20 mL). The combined organic layers were washed with saturated aqueous NaCl (20 mL), then dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography eluted with ethyl acetate-dichloromethane to obtain 2.1 g of the title compound a solid. HPLC/MS: retention time=2.82 min, [M+H]30 =344.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][N:11]2C(OC(C)(C)C)=O)=[CH:4][CH:3]=1.[C:21](O)([C:23](F)(F)F)=O>C(Cl)Cl>[ClH:1].[ClH:1].[N:7]1[CH:2]=[CH:3][C:4]([CH:21]=[CH:23][C:3]2[CH:4]=[C:5]([O:8][CH2:9][C@@H:10]3[CH2:13][CH2:12][NH:11]3)[CH:6]=[N:7][C:2]=2[Cl:1])=[CH:5][CH:6]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1ccc(Cl)nc1
Solvent: ClCCl
Product: Cl
Product: Clc1ncc(OC[C@@H]2CCN2)cc1C=Cc1ccncc1
Yield: 79 %

Procedure:
To a solution of 5-2-(4-Pyridinyl)vinyl)-6-chloro-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine from step 89a (176 mg) in methylene chloride (3 mL) and TFA (1.5 mL) was stirred at room temperature for 3 hours. The solvent was removed, and the residue was chromatographed on a silica gel column, eluting with chloroform:methanol:NH4OH 10:1:0.1 to afford the free base of the title compound (102 mg, 79% yield). MS (DCI/NH3) m/z 302 (M+H)+. 1 H NMR (CDCl3, 300 MHz) δ: 2.24-2.48 (m, 2H), 3.42-2.54 (m, 1H), 3.76 (q, J=7.5 Hz, 1H), 4.02-4.17 (m, 2H), 4.26-4.39 (m, 1H), 7.0 (d, J=11.0 Hz, 1H), 7.36-7.44 (m, 2H), 7.52-7.62 (m, 2H), 8.05 (d, J=3.0 Hz, 1H), 8.58-8.73 (m, 2H). The base was treated with HCl in ethanol to afford the hydrochloride salt. mp 195°-197° C. MS (CI/NH3) m/z 302 (M+H)+. 1H NMR (D2O, 300 MHz) δ1.17 (d, J=6, 1H), 2.52-2.66 (m, 2H), 2.68-2.89 (m, 4H), 4.96-5.25 (m, 5H), 6.97-7.12 (m, 1H), 7.33 (d, J=3, 1H), 7.48-7.54 (m, 1H), 7.86-7.95 (m, 1H), 8.04-8.22 (m, 2H), 8.44-8.53 (m, 1H), 8.63-8.71 (m, 1H). Anal. Calcd for C16H16N3OCl·1.5 C6H8O7 ·0.5 H2O: C, 50.13; H, 4.88; N, 7.01. Found: C, 49.95; H, 4.80; N, 7.31. [α]25D =-1.14° (c 0.18, MeOH).