Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.S(Cl)([Cl:9])=O.[Cl:11][C:12]1[CH:19]=[C:18]([O:20][CH:21]([CH3:23])[CH3:22])[CH:17]=[CH:16][C:13]=1[CH2:14]O.O>ClCCl>[Cl:11][C:12]1[CH:19]=[C:18]([O:20][CH:21]([CH3:23])[CH3:22])[CH:17]=[CH:16][C:13]=1[CH2:14][Cl:9]
Reactant: CC(C)Oc1ccc(CO)c(Cl)c1
Reactant: O=S(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)Oc1ccc(CCl)c(Cl)c1
Reaction time: 1 h
Yield: 106483.8 %

Procedure:
Pyridine (0.5 ml) and thionyl chloride (0.18 mg) were successively added to a solution of 2-chloro-4-isopropoxybenzylalcohol (401 mg) in dichloromethane (2 ml) under ice-cooling, and the mixture was stirred for 1 hr. Water was added to the reaction mixture and the resulting product was extracted three times with hexane. The organic layers were combined, washed successively with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the objective compound (353 mg) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[C:9][Si](C)(C)C)=[CH:4][N:3]=1.FC(F)(F)S(O[C:20]1[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][CH:25]=1)(=O)=O>CN(C=O)C.Cl[Cu].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[C:9][C:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH:21]=2)=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: Cc1ncc(C#C[Si](C)(C)C)cn1
Agent: Cl[Cu]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: Cc1ncc(C#CC2=CCN(C(=O)OC(C)(C)C)CC2)cn1
Temperature: 80 °C
Reaction time: 8 h
Yield: 44.8 %

Procedure:
To a solution of CuCl (1 mg, 0.01 mmol) and PdCl2(PPh3)2 (0.003 g, 0.004 mmol) in DMF (2 mL) were added 2-methyl-5-[(trimethylsilyl)ethynyl]pyrimidine (0.088 g, 0.462 mmol) and tert-butyl 4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydropyridine-1(2H)-carboxylate (Example 2e) (0.183 g, 0.555 mmol) at room temperature. The reaction mixture was stirred for 8 h at 80° C. After cooling, the mixture was quenched with 1N HCl and extracted with ether (3×). The combined organic layers were washed with saturated aqueous NaHCO3 solution, brine and dried. Filtration and evaporation afforded a brown oil, which was purified on HPLC to give the subtitle compound (0.062 g, 45%).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N-:22]=[N+:23]=[N-:24].[Na+]>>[N:22]([C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Agent: [Na+]
Product: COc1ccc(N(C)c2nc(N=[N+]=[N-])nc3ccccc23)cc1

Procedure:
The title compound was prepared from (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (150 mg, 0.5 mmol), sodium azide (97.5 mg, 1.5 mmol) in 5 mL of solvent (THF:MeOH:water=0.3:1:1) by a procedure similar to that of example 120 (4%). 1H NMR (CDCl3): 8.45 (d, J=8.4 Hz, 1H), 7.78-7.72 (m, 1H), 7.27-7.22 (m, 2H), 7.19-7.14 (m, 2H), 6.95 (d, J=8.7 Hz, 2H), 3.86 (s, 3H), 3.69 (s, 3H).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([CH2:20][OH:21])[O:17][N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=C[N:24]([C:27](N2C=NC=C2)=[O:28])C=1.[OH-].[NH4+]>C1COCC1>[CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([CH2:20][O:21][C:27](=[O:28])[NH2:24])[O:17][N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: OCc1cc(-c2ccc(NCc3ccccc3)cc2)no1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)OCc1cc(-c2ccc(NCc3ccccc3)cc2)no1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[3-(4-benzylamino-phenyl)-isoxazol-5-yl]-methanol (178 mg, 0.63 mmol) was dissolved in THF (20 ml, 0.03 M), to which was added CDI (154 mg, 0.95 mmol). After the mixture was stirred at room temperature for about 1 hour, 1 ml of ammonium hydroxide was added and the resulting mixture was stirred for another 3 hours. The completion of the reaction was confirmed by liquid chromatography, and the THF was distilled under reduced pressure to obtain a pale yellow solid compound. The solid compound was extracted three times with water and ethyl acetate, the organic solvent layer was dried under reduced pressure, and then a crude compound was purified by column chromatography on silica gel using ethyl acetate/hexane (1:3) to obtain carbamic acid 3-(4-benzylamino-phenyl)-isoxazol-5-ylmethyl ester as a white solid.
Reaction SMILES: [ClH:1].C(OC([N:12]([CH2:20][CH:21]1[C:30]2[C:25](=[CH:26][C:27]([OH:32])=[C:28]([OH:31])[CH:29]=2)[CH2:24][CH2:23][NH:22]1)[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=O)C1C=CC=CC=1.Cl>C(O)(=O)C>[ClH:1].[F:19][C:16]1[CH:15]=[CH:14][C:13]([NH:12][CH2:20][CH:21]2[C:30]3[C:25](=[CH:26][C:27]([OH:32])=[C:28]([OH:31])[CH:29]=3)[CH2:24][CH2:23][NH:22]2)=[CH:18][CH:17]=1
Reactant: O=C(OCc1ccccc1)N(CC1NCCc2cc(O)c(O)cc21)c1ccc(F)cc1
Agent: Cl
Solvent: CC(=O)O
Product: Oc1cc2c(cc1O)C(CNc1ccc(F)cc1)NCC2
Yield: 95.2 %

Procedure:
A mixture of 1-(N-benzyloxycarbonyl-p-fluoroanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (4.6 g), conc. hydrochloric acid (46 ml) and acetic acid (46 ml) was refluxed for 2 hours. The reaction mixture was concentrated to dryness and the residue was dissolved in water and washed with a mixture of ether and ethyl acetate (1:1). The aqueous layer was treated with activated charcoal and concentrated to dryness to give 1-(p-fluoroanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (3.1 g). The product (2.5 g) was converted into its d-camphor-10-sulfonate in a conventional manner and the crystals obtained were recrystallized from water to give the d-camphor-10-sulfonate of the above-mentioned product, mp 213° to 215° C.
Reaction SMILES: [CH3:1][C@H:2]([C@@H:18]([CH3:25])[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])[C:3](N1[C@H](CC2C=CC=CC=2)COC1=O)=[O:4].[H-].[Al+3].[Li+].[H-].[H-].[H-].CO>C1COCC1>[CH3:1][C@H:2]([C@@H:18]([CH3:25])[CH2:19][CH2:20][CH:21]=[C:22]([CH3:23])[CH3:24])[CH2:3][OH:4]
Reactant: CC(C)=CCC[C@H](C)[C@@H](C)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)=CCC[C@H](C)[C@@H](C)CO
Temperature: 25 °C
Reaction time: 6 h
Yield: 58.7 %

Procedure:
A solution of 6.8 g (20 mmol) of 3(2(R),3(S),7-trimethyl-6-octenoyl)-4(R)-phenylmethyl-2-oxazolidinone in 30 mL of THF was added dropwise to a suspension of 1.634 g (43 mmol) of lithium aluminum hydride in 40 mL of THF at 0° C. The reaction mixture was then stirred 6 h at ambient temperature The reaction mixture was then recooled in ice bath and 5 mL of methanol was added dropwise very cautiously. After the effervescence subsided, the reaction mixture was concentrated to about 30% of the original volume The reaction mixture was then stirred with saturated solution of potassium sodium tartrate and extracted with ethyl acetate. The combined ethyl acetate extracts were dried over anhydrous magnesium sulfate. Solvent removal afforded a crude oil, which was purified on silica gel using 10% ethyl acetate in hexane as solvent to give 2.0 g (62%) of the desired alcohol as a colorless oil.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[NH2:11])=O.[NH3:12]>>[NH2:11][C@@H:6]1[CH2:7][CH2:8][CH2:9][CH2:10][C@@H:5]1[C:3]([NH2:12])=[O:2]
Reactant: COC(=O)[C@H]1CCCC[C@H]1N
Reactant: N
Product: NC(=O)[C@H]1CCCC[C@H]1N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of (1S,2R)-2-aminocyclohexanecarboxylic acid methyl ester (16.2 mmol) and aqueous ammonia (28%, 50 mL) was stirred at room temperature for 24 h. The reaction mixture was concentrated to dryness in vacuo. The residue was suspended in toluene (200 mL) and reconcentrated to afford (1S,2R)-2-aminocyclohexanecarboxylic acid amide as a white solid. The crude product was used in the next step without purification or characterization.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:13])=[CH:4][C:5]2[S:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.[CH2:14]([C@H:16]1[O:18][CH2:17]1)[Cl:15]>CCO.O>[Cl:15][CH2:14][CH:16]([OH:18])[CH2:17][NH:1][C:2]1[C:3]([F:13])=[CH:4][C:5]2[S:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1
Reactant: ClC[C@@H]1CO1
Reactant: Nc1cc2c(cc1F)SCC(=O)N2
Solvent: CCO
Solvent: O
Product: O=C1CSc2cc(F)c(NCC(O)CCl)cc2N1
Yield: 57.1 %

Procedure:
A solution of 6-amino-7-fluoro-4H-benzo[1,4]thiazin-3-one (1 g, 5 mmol, Bioscience, Biotechnology, and Biochemistry 1994, 58, 788) and (S)-epichlorohydrin (0.467 g, 5 mmol) in EtOH/H2O (9:1, 20 mL) was heated at 80° C. for 3 d. The volatiles were removed under reduced pressure and the residue was crystallized from MeOH to give a brown solid (0.83 g, 57%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[C:24]([Cl:26])[CH:25]=1)[CH2:5][C:6]1[C:7]([NH:15]C(=O)OC(C)(C)C)=[N:8][N:9]([CH2:12][CH2:13][OH:14])[C:10]=1[CH3:11].Cl>O1CCOCC1>[NH2:15][C:7]1[C:6]([CH2:5][C:4]2[CH:3]=[C:2]([Cl:1])[CH:25]=[C:24]([Cl:26])[CH:23]=2)=[C:10]([CH3:11])[N:9]([CH2:12][CH2:13][OH:14])[N:8]=1
Reactant: Cc1c(Cc2cc(Cl)cc(Cl)c2)c(NC(=O)OC(C)(C)C)nn1CCO
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(Cc2cc(Cl)cc(Cl)c2)c(N)nn1CCO
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of the protected amine of Example 86 (50 mg, 0.13 mmol) in 1,4-dioxan was treated with 4M hydrogen chloride in 1,4-dioxan (320 μL, 1.25 mmol) and stirred at room temperature for 2 days. The solution was concentrated under reduced pressure. The residue was diluted with water (15 ml) and extracted with ethyl acetate (3×10 ml). The combined organic phases were dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure to afford the title compound as a white solid and as the hydrochloride salt (19.5 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([N:14]1[N:18]=[C:17]2[CH:19]=[CH:20][C:21]([CH3:24])=[C:22]([CH3:23])[C:16]2=[N:15]1)[CH2:11][C:12]#[CH:13]>>[F:9][CH2:8][C:4]1[N:3]=[C:2]([C:13]#[C:12][CH2:11][CH2:10][N:14]2[N:18]=[C:17]3[CH:19]=[CH:20][C:21]([CH3:24])=[C:22]([CH3:23])[C:16]3=[N:15]2)[CH:7]=[CH:6][CH:5]=1
Reactant: C#CCCn1nc2ccc(C)c(C)c2n1
Reactant: FCc1cccc(Br)n1
Product: Cc1ccc2nn(CCC#Cc3cccc(CF)n3)nc2c1C
Yield: 39.5 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)-pyridine (79 mg, 0.41 mmol) and 2-but-3-ynyl-4,5-dimethyl-2H-benzo[d][1,2,3]triazole (75 mg, 0.38 mmol, 177(B)). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/MeOH 98:2) to yield 46 mg (0.15 mmol, 40%) of 2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-4,5-dimethyl-2H-benzo[d][1,2,3]triazole as an orange oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([NH:15][C:16]([NH:18]C(=O)C3C=CC=CC=3)=[S:17])=[CH:14][C:9]=2[N:8]=[C:7]1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH3:36])=[CH:30][CH:29]=1)[CH3:2].[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:37]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([NH:15][C:16]([NH2:18])=[S:17])=[CH:14][C:9]=2[N:8]=[C:7]1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH3:36])=[CH:30][CH:29]=1)[CH3:38]
Reactant: CCOc1ccc(Cc2nc3cc(NC(=S)NC(=O)c4ccccc4)ccc3n2CCN(CC)CC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOc1ccc(Cc2nc3cc(NC(N)=S)ccc3n2CCN(CC)CC)cc1
Temperature: 25 °C

Procedure:
N-(1-(2-(diethylamino)ethyl)-2-(4-ethoxybenzyl)-1H-benzo[d]-imidazol-5-ylcarbamothioyl)benzamide 20 (272 mg, 0.513 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL) in a small, argon purged flask fitted with an condenser and magnetic stirbar. 2M NaOH (0.513 mL, 1.026 mmol) added and the solution was heated to reflux for 6 hours and cooled to room temperature overnight. The solution was concentrated and the residue was partitioned between H2O and ethyl acetate, transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with ethyl acetate and the combined organic layers were washed with brine (twice), dried over magnesium sulphate, filtered and concentrated to afford an off white solid which was slurried in hot ethyl acetate to yield white solid 21 [1-(2-Diethylamino-ethyl)-2-(4-ethoxy-benzyl)-1H-benzoimidazol-5-yl]-thiourea. Yield: 110 mg (50.3%). 1H NMR (DMSO) δ: 0.80 (t, 6H, J=7.1), 1.29 (t, 3H, J=7.0), 2.41 (q, 4H, J=7.0), 2.45-2.50 (m, 2H), 3.96 (q, 2H, J=6.9), 4.12 (t, 2H, J=6.7), 4.24 (s, 2H), 6.86 (d, 2H, J=8.6), 7.09 (dd, 1H, J=8.4, 1.5), 7.16 (d, 2H, J=8.7), 7.24 (br, 1-2H), 7.40 (d, 1H, J=8.5), 7.51 (s, 1H), 9.56 (s, 1H). MS (ESI): 426 (MH+, 100%)
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:58][CH:59]([CH3:61])[CH3:60])[C:7]([F:57])=[C:8]([CH:10]([NH:44][C:45]2[CH:50]=[CH:49][C:48]([C:51]3[N:55]=[C:54]([CH3:56])[O:53][N:52]=3)=[CH:47][CH:46]=2)[C:11]2[N:12]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22](=[O:24])[CH3:23])[N:15]=2)[CH:9]=1)[CH3:2].[BH4-].[Na+]>CO>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:58][CH:59]([CH3:60])[CH3:61])[C:7]([F:57])=[C:8]([CH:10]([NH:44][C:45]2[CH:46]=[CH:47][C:48]([C:51]3[N:55]=[C:54]([CH3:56])[O:53][N:52]=3)=[CH:49][CH:50]=2)[C:11]2[N:12]([C:25]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH:22]([OH:24])[CH3:23])[N:15]=2)[CH:9]=1)[CH3:2]
Reactant: CCOc1cc(OC(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nc(-c3ccccc3C(C)=O)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOc1cc(OC(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nc(-c3ccccc3C(C)O)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Yield: 73.7 %

Procedure:
A solution of Intermediate 111.1 (40 mg, 0.05 mmol) and NaBH4 (5 mg) in 1 mL MeOH was stirred for 0.5 h at rt. The reaction mixture was partitioned between EtOAc and H2O, the organic layer was collected, dried (Na2SO4), filtered and concentrated to afford 30 mg of Intermediate 111.2. LCMS (2 min gradient) RT=1.49 min, 814.4 (M+H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[C:8]([CH2:16]O)=[N:9][C:10]([S:14][CH3:15])=[N:11][C:12]=1[CH3:13].CCN(CC)CC>C(Cl)Cl>[Cl:6][C:7]1[C:12]([CH3:13])=[N:11][C:10]([S:14][CH3:15])=[N:9][C:8]=1[CH2:16][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CSc1nc(C)c(Cl)c(CO)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSc1nc(C)c(Cl)c(CS(C)(=O)=O)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
MsCl (248 mg, 2.169 mmol) was added to a stirred, cooled 0° C. mixture of the title compound from Step D (370 mg, 1.808 mmol) in CH2Cl2 (10 mL), followed by addition of Et3N (274 mg, 2.71 mmol). The mixture was stirred at 0° C. for 30 min. TLC showed no starting material left. The mixture was quenched with water (5 mL) and the mixture was washed with more water (10 mL). The organic fraction were washed with brine (saturated, 10 mL), dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel Biotage 40S, eluting with EtOAc/hexane (2/8) to give the title compound as a colorless solid. 1H NMR (CDCl3, 500 MHz) δ 5.40 (s, 2H), 3.20 (s, 3H), 2.61 (s, 3H), 2.59 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:35]2[C:36]([C:41]#[N:42])=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:34])[N:11]([C@H:21]2[CH2:26][CH2:25][C@H:24]([O:27][CH:28]([CH3:33])[CH:29]([OH:32])[CH2:30][F:31])[CH2:23][CH2:22]2)[C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17].[CH3:43]C(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([C:35]2[C:36]([C:41]#[N:42])=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:34])[N:11]([C@H:21]2[CH2:22][CH2:23][C@H:24]([O:27][CH:28]([C:29]3([CH2:30][F:31])[CH2:43][O:32]3)[CH3:33])[CH2:25][CH2:26]2)[C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OC(C)C(O)CF)CC2)c2ncnn12
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OC(C)C3(CF)CO3)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 3′-fluoro-4′-({4-[trans-4-(3-fluoro-2-hydroxy-1-methylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.15 g), Dess-Martin periodinane (0.22 g) and acetonitrile (2 mL) was stirred at room temperature for 12 hr. Saturated aqueous sodium hydrogen carbonate solution and aqueous sodium thiosulfate solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the residue was added to a mixture of trimethylsulfoxonium iodide (0.057 g), sodium hydride (0.010 g) and dimethyl sulfoxide (4 mL) stirred at room temperature for 1 hr in advance, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.079 g, 52%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1.Cl[C:26]1[CH:27]=[CH:28][C:29]2[N:30]([C:32]([C:35]([F:38])([F:37])[F:36])=[N:33][N:34]=2)[N:31]=1>>[F:24][C:21]1[CH:20]=[CH:19][C:18]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:9][CH2:10][CH2:11][N:12]2[CH2:13][CH2:14][N:15]([C:26]3[CH:27]=[CH:28][C:29]4[N:30]([C:32]([C:35]([F:36])([F:38])[F:37])=[N:33][N:34]=4)[N:31]=3)[CH2:16][CH2:17]2)=[CH:23][CH:22]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: Fc1ccc(C(CCCN2CCNCC2)c2ccc(F)cc2)cc1
Product: Fc1ccc(C(CCCN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c2ccc(F)cc2)cc1

Procedure:
A mixture of 1-[4,4-bis(4-fluorophenyl)butyl]piperazine and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 3. The crude product was purified by hplc using a Waters XTerra C18 column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[4,4-bis(4-fluorophenyl)butyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH:13]3[CH2:18][CH2:17][N:16](CC#N)[CH2:15][CH2:14]3)=[N:10][C:9]=2[CH2:22][O:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[CH:4][CH:3]=1.NN.[ClH:31].O>C(O)C>[ClH:31].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[CH2:22][O:23][CH2:24][C:25]([F:26])([F:27])[F:28])=[CH:4][CH:3]=1
Reactant: N#CCN1CCC(c2nc(COCC(F)(F)F)c(-c3ccc(F)cc3)o2)CC1
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: Fc1ccc(-c2oc(C3CCNCC3)nc2COCC(F)(F)F)cc1
Temperature: 75 °C
Reaction time: 3.5 h
Yield: 90.1 %

Procedure:
A 5-l round bottom flask containing {4-[5-(4-fluorophenyl)-4-(2,2,2-trifluoro-ethoxymethyl)-oxazol-2-yl]-piperidin-1-yl} acetonitrile (313 g, 0.788 mole), 35% aqueous hydrazine (156 mL, 1.58 mole), 36% aqueous hydrochloric acid (130 mL, 1.58 mole), water (1 l) and ethanol (2 l) is warmed to 75° C. and stirred for 3.5 hours. The reaction mixture is cooled to room temperature, the solvent volume is reduced to 1.5 l by distillation and 3 N aqueous hydrochloric acid (1.5 l) is added. The aqueous solution is washed with dichloromethane (2×3 l). The combined organic extracts are dried over sodium sulfate (1 Kg), filtered and concentrated to effect crystallization (1.5 l). To complete the crystallization, methyl t-butylether (4 l) is added and the resulting slurry is cooled to 0° C. The solids are collected by filtration, washed with methyl t-butylether (750 mL) and dried to constant weight to give {4-[5-(4-fluorophenyl)-4-(2,2,2-trifluoro-ethoxymethyl)-oxazol-2-yl]-piperidine hydrochloride (280 g, 0.710 mole). 1H NMR (400 MHz, d6 DMSO) d 1.96 (m, 2H), 2.20 (m, 2H), 3.02 (q, 2H), 3.30 (m, 3H), 4.18 (q, 2H), 4.66 (s, 2H), 7.37 (t, 2H), 7.68 (q, 2H), 9.0 (bs, 1H), 9.20 (bs, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=[N:3]1.Cl[C:17]1[CH:18]=[C:19]([C:32]2[N:37]=[C:36]([CH3:38])[N:35]=[C:34]([N:39]([CH2:49][C:50]3[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=3)[CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)[N:33]=2)[C:20]([NH:23][C:24]2[CH:25]=[N:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)=[N:21][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.O1CCOCC1>[CH3:48][O:47][C:44]1[CH:43]=[CH:42][C:41]([CH2:40][N:39]([CH2:49][C:50]2[CH:51]=[CH:52][C:53]([O:56][CH3:57])=[CH:54][CH:55]=2)[C:34]2[N:33]=[C:32]([C:19]3[C:20]([NH:23][C:24]4[CH:25]=[N:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=4)=[N:21][CH:22]=[C:17]([C:5]4[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=4)[CH:18]=3)[N:37]=[C:36]([CH3:38])[N:35]=2)=[CH:46][CH:45]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3Nc3ccc(OC)nc3)n2)cc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(-c4cnn(C)c4)cnc3Nc3ccc(OC)nc3)n2)cc1
Temperature: 140 °C
Yield: 133.7 %

Procedure:
A mixture of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (41.5 mg, 0.199 mmol) (Aldrich), 4-(5-chloro-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (97 mg, 0.166 mmol), Pd2dba3 (6.08 mg, 6.64 μmol) (Strem Chemicals), and 2-(dicyclohexylphosphino)-2′,4′,6′,-tri-i-propyl-1,1′-biphenyl (6.33 mg, 0.013 mmol) (Strem Chemicals) was purged with argon, treated with dioxane (2 mL) and 1 M aqueous sodium carbonate (0.415 mL, 0.415 mmol), and heated in a microwave at 140° C. for 30 min. The reaction mixture was treated with 1 N NaOH and extracted with EtOAc (30 mL), washed with brine and dried over MgSO4, filtered and concentrated to give N,N-bis(4-methoxybenzyl)-4-(2-(6-methoxypyridin-3-ylamino)-5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (140 mg, 0.222 mmol) which was used in the next step without further purification. m/z (ESI, +ve ion) 630.0 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 11.60 (1H, s); 8.83 (1H, d, J=2.5 Hz); 8.41 (1H, d, J=2.5 Hz); 8.27 (1H, d, J=2.7 Hz); 7.89 (1H, dd, J=8.8, 2.7 Hz); 7.68 (1H, s); 7.52 (1H, s); 7.21 (4H, dd, J=13.5, 8.6 Hz); 6.86 (4H, dd, J=13.1, 8.6 Hz); 6.71 (1H, d, J=9.0 Hz); 4.88 (2H, s); 4.82 (2H, s); 3.93 (3H, s); 3.93 (3H, s); 3.81 (3H, s); 3.78 (3H, s); 2.59 (3H, s).