Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[CH:11]=[C:4]2[N:3]=1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:5]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[CH:11]=[C:4]2[N:3]=1
Reactant: C1COCCN1
Reactant: Clc1cc(Cl)n2nc(-c3ccccn3)cc2n1
Solvent: O
Solvent: C1COCCO1
Product: Clc1cc(N2CCOCC2)n2nc(-c3ccccn3)cc2n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 75 %

Procedure:
There was suspended, in 1,4-dioxane (5 mL), 5,7-dichloro-2-pyridin-2-yl-pyrazolo[1,5-a]pyrimidine (348 mg. 1.31 mM), then morpholine (230 μL, 2.64 mM) was added to the suspension and the mixture was stirred at room temperature for 20 minutes. The solvent was distilled off from the reaction mixture, the residue obtained was diluted with water and then extracted with ethyl acetate. The extracts thus obtained were combined, dried over anhydrous sodium sulfate, the solvent was distilled off and the resulting solid was washed with diethyl ether to thus give the title compound (312 mg, yield: 75%). 1H-NMR (300 MHz, CDCl3): δ 3.84-3.87 (m, 4H), 3.99-4.02 (m, 4H), 6.12 (s, 1H), 7.16 (s, 1H), 7.30 (ddd, 1H, J=1.2, 5.0, 7.7 Hz), 7.78 (dt, 1H, J=1.8, 7.7 Hz), 8.11 (d, 1H, J=7.7 Hz), 8.70 (m, 1H); MS (ESI) m/z 316 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[C:16](=[O:18])[CH3:17])[C:12]1[N:8]([CH:9]=[C:10]([C:19]3[N:23]([CH:24]([CH3:26])[CH3:25])[N:22]=[C:21]([CH3:27])[N:20]=3)[N:11]=1)[CH2:7][CH2:6][O:5]2.[BH4-].[Na+].O>CO>[CH3:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[CH:16]([OH:18])[CH3:17])[C:12]1[N:8]([CH:9]=[C:10]([C:19]3[N:23]([CH:24]([CH3:26])[CH3:25])[N:22]=[C:21]([CH3:27])[N:20]=3)[N:11]=1)[CH2:7][CH2:6][O:5]2
Reactant: CC(=O)c1cc2c(cc1C)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1nc(-c2cn3c(n2)-c2cc(C(C)O)c(C)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
To a solution of 1-{12-methyl-4-[3-methyl-1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaen-13-yl}ethan-1-one (2.20 g) in MeOH (50.0 mL) was added NaBH4 (920 mg, 24.2 mmol). The mixture was stirred at room temperature for 2 hrs. Water was added to quench the reaction. The mixture was extracted with ethyl acetate (5×50 mL). The combined organic layers were washed with brine and dried over MgSO4. Removal of the solvent gave the crude product, which was purified by reverse phase Combi-flash eluting with a 25-30% gradient of CH3CN in 0.3% NH4HCO3 to afford the racemic product (800 mg, 58% yield for three steps). 1H NMR (500 MHz, DMSO-d6) δ 8.50 (s, 1H), 7.85 (s, 1H), 6.81 (s, 1H), 5.74 (m, 1H), 5.07 (s, 1H), 4.87 (s, 1H), 4.48-4.44 (m, 4H), 2.28 (s, 3H), 2.25 (s, 3H), 1.46 (s, 6H), 1.33 (s, 3H). LCMS m/z [M+H]+ 368.2
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2OC)(O)[CH:11]([CH3:13])[CH3:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Br.C(O)(=O)C.[OH2:28]>>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[O:28][C:11]2([CH3:13])[CH3:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: COc1ccccc1C(O)(c1ccc(C(C)C)cc1)C(C)C
Reactant: O
Agent: Br
Solvent: CC(=O)O
Product: CC(C)c1ccc(C2c3ccccc3OC2(C)C)cc1
Yield: 89 %

Procedure:
A mixture of 1-(4-isopropylphenyl)-1-(2-methoxyphenyl)-2-methylpropan-1-ol obtained in Reference Example 82 (3.4 g, 11.4 mmol), 48% hydrobromic acid (50 mL) and acetic acid (10 mL) was heated under reflux under argon atmosphere for 16 hours. After cooling, water was added to the reaction solution, which was extracted with ethyl acetate, and the combined organic layer was washed with water, dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to obtain 2.71 g (yield 89%) of the title compound. Oily matter.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([F:20])[CH:14]=2)[CH:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=3)[N:5]=[C:4]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([F:20])[CH:14]=3)[CH:3]=2)=[CH:24][CH:23]=1
Reactant: Oc1ccc2nc(-c3ccc(O)c(F)c3)cc(Br)c2c1
Reactant: OB(O)c1ccc(Cl)cc1
Product: Oc1ccc2nc(-c3ccc(O)c(F)c3)cc(-c3ccc(Cl)cc3)c2c1
Yield: 87 %

Procedure:
This compound was prepared from 6b using 4-chlorophenylboronic acid according to method P. Orange powder; Yield: 87%; mp 140–147° C.; 1H-NMR (400 MHz, DMSO-d6) δ 7.03 (d, J=2.7 Hz, 1H), 7.06 (t, J=8.8 Hz, 1H), 7.32 (dd, J=9.1, 2.7 Hz, 1H), 7.63 (d, J=8.8 Hz, 2H), 7.67 (d, J=8.7 Hz, 2H), 7.87 (s, 1H), 7.93–7.98 (m, 2H), 8.07 (dd, J=13.0, 2.1 Hz, 1H), 9.94 (s, 1H), 10.20 (s, 1H); MS (ESI) m/z 364/366 ([M−H]−), 366/368 ([M+H]+); Anal. Calcd for C21H13ClFNO2: C: 68.95, H: 3.58, N: 3.83. Found: C: 68.23, H: 3.54, N: 3.78.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:9])=[N:7][CH:8]=1.[CH3:10][S-:11].[Na+]>C(O)C>[Cl:9][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][S:11][CH3:10])=[CH:8][N:7]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: C[S-]
Agent: [Na+]
Solvent: CCO
Product: CSCc1ccc(Cl)nc1
Yield: 93.7 %

Procedure:
A solution of 5-chloromethyl-2-chloropyridine (8.1 g, 50 mmol) in ethanol (50 mL) was added to a suspension of sodium thiomethoxide solid (4.2 g, 60 mmol) in 100 mL ethanol under stirring. An exothermic reaction was observed during the addition and the mixture was then stirred at room temperature overnight. The solvent ethanol was removed under reduced pressure and the residue was re-dissolved in ether-EtOAc solvent and mixed with brine. The two phases were separated and the organic layer was dried over anhydrous Na2SO4, filtered, concentrated and purified by eluting through a silica gel plug with 40% EtOAc in hexane to give 8.14 g of 2-chloro-5-[(methylthio)methyl]pyridine (A) as a colorless oil in 94% yield. The product was analytically pure and directly used for the next step reaction. 1H NMR (300 MHz, CDCl3) δ 8.28 (dd, 1H), 7.65 (dd, 1H), 7.30 (d, 1H), 3.63 (s, 2H), 2.00 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:8]Cl)[CH:7]=1.[C-:10]#[N:11].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][C:10]#[N:11])[CH:5]=[N:4][CH:3]=1
Reactant: ClCc1cncc(Br)c1
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.1 %

Procedure:
3-Bromo-5-chloromethyl-pyridine (0.45 g; 2.2 mmol) was dissolved in DMF (10 mL). Potassium cyanide (0.21 g, 3.27 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The organic phases were washed with water, brine and dried over Na2SO3 filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 7% EtOAc in Hexanes to provide 2-(5-bromopyridin-3-yl)acetonitrile (200 mg, 46.5%). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.68 (d, 1H, J=2 Hz), 8.51 (d, 1H, J=2 Hz), 7.88 (t, 1H, J=2 Hz), 3.77 (s, 2H).
Reaction SMILES: C1COCC1.[O:6]([C:13]1[CH:14]=[C:15]([N:19]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30](Br)[CH:29]=2)[CH2:20][CH:21]([OH:26])[C:22]([F:25])([F:24])[F:23])[CH:16]=[CH:17][CH:18]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:35]([Mg]Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[NH4+].[Cl-]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:6]([C:13]1[CH:14]=[C:15]([N:19]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:29]=2)[CH2:20][CH:21]([OH:26])[C:22]([F:25])([F:24])[F:23])[CH:16]=[CH:17][CH:18]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Br[Mg]Cc1ccccc1
Reactant: OC(CN(Cc1cccc(Br)c1)c1cccc(Oc2ccccc2)c1)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(CN(Cc1cccc(Cc2ccccc2)c1)c1cccc(Oc2ccccc2)c1)C(F)(F)F
Yield: 62 %

Procedure:
To a THF (4 mL) solution of 3-[(3-phenoxyphenyl)[[3-bromophenyl]methyl]amino]-1,1,1-trifluoro-2-propanol (0.60 g, 1.3 mmol) from EX-595B was added benzyl-magnesium bromide in THF (2.0 mL, 2.0 M, 4.0 mmol) and Pd(PPh3)4. The resulting yellow solution was refluxed under N2 for 18 h. The cooled solution was poured into saturated aq. NH4Cl, extracted with ethyl acetate, dried (MgSO4) and evaporated to an oil. Purification by flash chromatography on silica gel eluting with 15% ethyl acetate in hexane gave an oil which was dissolved in ETOH, stripped and dried in vacuo to give 0.39 g (62%) of the desired 3-[(3-phenoxyphenyl)[[3-(phenylmethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a colorless oil. Anal. calcd. for C29H26NO2F3.0.4 EtOH: C, 72.17; H, 5.77; N, 2.82. Found: C, 72.17; H, 5.42; N, 2.83. HRMS calcd. 478.1994 ([M+H]+, found: 478.1984. 1H NMR (C6D6) δ 1.58 (d, 1H), 3.22 (dd, 1H), 3.46 (dd, 1H), 3.69 (s, 2H), 3.73 (m, 1H), 4.18 (s, 2H), 6.34 (dd, 1H), 6.47 (dd, 1H), 6.53 (t, 1H), 6.8-7.1 (m 15H).
Reaction SMILES: B.[CH3:2][O:3][CH2:4][CH2:5][CH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=O.CO.Cl>C1COCC1>[CH3:2][O:3][CH2:4][CH2:5][CH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH2:7]1
Reactant: COCCC1C(=O)Nc2ccccc21
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: COCCC1CNc2ccccc21
Temperature: 0 °C

Procedure:
Under a nitrogen atmosphere 12.6 mL (12.6 mmol) of a 1M borane in THF solution was added dropwise to 1.2 g (6.3 mmol) 3-(2-methoxy-ethyl)-1,3-dihydro-indol-2-one in 50 mL THF. The reaction mixture was refluxed for 3 h, cooled to 0° C. and combined with 10 mL methanol and then with 15 mL semi-concentrated hydrochloric acid solution. The reaction mixture was refluxed for 3 h with stirring, cooled and washed twice with ethyl acetate. The aqueous phase was made alkaline with an aqueous 4M sodium hydroxide solution and extracted three times with ethyl acetate. The organic phases were combined, dried on sodium sulphate and evaporated down.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[OH:11]>CO.[Pt]=O>[F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[OH:11]
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=[Pt]
Solvent: CO
Product: Nc1ccc(O)c(F)c1
Temperature: 25 °C
Yield: 101.1 %

Procedure:
A mixture of platinum oxide (0.010 g) and 2-fluoro-4-nitrophenol (Aldrich, 1.24 g, 7.78 mmol, 1.0 eq) in MeOH (100 ml) were stirred under a H2 atmosphere at 50 psi at room temperature. The reaction mixture was filtered through celite and the filtrate concentrated in vacuo to afford the title compound (1.00 g, 100%), as a solid which was used without further purification. 1H NMR (DMSO-d6) δ 8.57 (s, 1H), 6.46-6.47 (m, 1H), 6.33-6.46 (m, 1H), 6.19-6.21 (m, 1H), 4.79 (s, 2H); MS(ESI+) m/z 128 (M+H)+.
Reaction SMILES: [NH2:1][OH:2].[Br:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[C:6]([F:12])[CH:5]=1>O.C(O)C>[Br:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[N:1][OH:2])=[C:6]([F:12])[CH:5]=1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: NO
Solvent: CCO
Solvent: O
Product: ON=Cc1ccc(Br)cc1F
Reaction time: 66 h

Procedure:
A solution of hydroxylamine in water (50%, 5 ml) was added to a solution of 4-bromo-2-fluorobenzaldehyde (1.0 g) in ethanol (5 ml) and the mixture was stirred at room temp. for 66 h. The ethanol was removed under vacuum and the aqueous residue as extracted with ethyl acetate (×2). The organic extracts were washed with water and brine, dried (MgSO4) and concentrated under vacuum. The residue was purified on a Varian Bond-Elut SPE cartridge (silica, 20 g) eluting with cyclohexane:ethyl acetate (100:0 to 50:50) to give the title compound as a white solid (0.94 g).
Reaction SMILES: C(O[CH2:5][CH2:6][N+:7]([O-:9])=[O:8])(=O)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:21]=[CH:20][N:19]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[C:18]=2[C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)=[CH:13][CH:12]=1>C(O)C>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:21]=[CH:20][N:19]([CH:22]3[CH2:23][CH2:24][N:25]([CH2:5][CH2:6][N+:7]([O-:9])=[O:8])[CH2:26][CH2:27]3)[C:18]=2[C:28]2[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=2)=[CH:13][CH:12]=1
Reactant: CC(=O)OCC[N+](=O)[O-]
Reactant: Fc1ccc(-c2ccn(C3CCNCC3)c2-c2ccncc2)cc1
Solvent: CCO
Product: O=[N+]([O-])CCN1CCC(n2ccc(-c3ccc(F)cc3)c2-c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.3 %

Procedure:
186 mg (1.40 mmol) of 2-nitroethyl acetate were added to a solution of 300 mg (0.93 mmol) of 3-(4-fluorophenyl)-1-(piperidin-4-yl)-2-(pyridin-4-yl)-1H-pyrrole (prepared as described in Example 13 above) in 6 ml of ethanol. The resulting mixture was stirred at room temperature for 30 minutes, after which the solvent was distilled off under reduced pressure. A saturated aqueous solution of sodium hydrogencarbonate was added to the residue and then this was extracted with ethyl acetate. The organic extract was washed with water, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure. The residual solid was washed with diethylether to give 280 mg (yield 76%) of the title compound as a white powder.
Reaction SMILES: [C:1]([C:3]1[CH:25]=[CH:24][C:6]([CH2:7][NH:8][C:9](=[O:23])[CH:10]([O:20][CH2:21][CH3:22])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([OH:19])[CH:12]=2)=[CH:5][CH:4]=1)#[N:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]>CN(C=O)C.CCOC(C)=O>[CH2:37]([O:36][C:34](=[O:35])[CH2:33][O:19][C:13]1[CH:12]=[C:11]([CH:10]([C:9](=[O:23])[NH:8][CH2:7][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:25][CH:24]=2)[O:20][CH2:21][CH3:22])[CH:16]=[CH:15][C:14]=1[O:17][CH3:18])[CH3:38]
Reactant: CCOC(=O)CBr
Reactant: CCOC(C(=O)NCc1ccc(C#N)cc1)c1ccc(OC)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1cc(C(OCC)C(=O)NCc2ccc(C#N)cc2)ccc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.8 %

Procedure:
To a stirred solution of (RS)-N-(4-cyano-benzyl)-2-ethoxy-2-(3-hydroxy-4-methoxy-phenyl)-acetamide (0.158 g) at rt in DMF (1.5 ml) were added K2CO3 (0.067 g) and ethyl bromoacetate (0.081 g). The reaction mixture was then stirred at rt under an argon atmosphere for 24 h. The mixture was diluted with EtOAc (10 ml), washed with water (10 ml+10 ml) and brine (10 ml), dried (MgSO4), filtered and concentrated (rotavapor). The product was purified by chromatography (Silicagel (20 g) using a gradient profile: cyclohexane to cyclohexane/EtOAc 45:55) to give (RS)-{5-[(4-cyano-benzylcarbamoyl)-ethoxy-methyl]-2-methoxy-phenoxy}-acetic acid ethyl ester (0.160 g) as a colorless gum.
Reaction SMILES: [CH2:1]1[CH:7](O)[NH:6][P:4]([N:9]([CH2:13][CH2:14][Cl:15])[CH2:10][CH2:11][Cl:12])(=[O:5])[O:3][CH2:2]1.[SH:16][CH2:17][CH2:18][S:19]([OH:22])(=[O:21])=[O:20]>O>[Cl:12][CH2:11][CH2:10][N:9]([CH2:13][CH2:14][Cl:15])[P:4]1(=[O:5])[NH:6][CH:7]([S:16][CH2:17][CH2:18][S:19]([OH:22])(=[O:21])=[O:20])[CH2:1][CH2:2][O:3]1
Reactant: O=S(=O)(O)CCS
Reactant: O=P1(N(CCCl)CCCl)NC(O)CCO1
Solvent: O
Product: O=P1(N(CCCl)CCCl)NC(SCCS(=O)(=O)O)CCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
0.8 g (3.0 mmol) of 4-hydroxycyclophosphamide in 3 ml of water were mixed with 420 mg (3.0 mmol) of 2-mercaptoethanesulphonic acid, with ice water cooling. After 1 hour, the mixture was concentrated under high vacuum and was crystallised.
Reaction SMILES: [H-].[Na+].[CH2:3]([P:14]([O:20][CH:21]([CH3:23])[CH3:22])(=[O:19])[O:15][CH:16]([CH3:18])[CH3:17])[P:4]([O:10][CH:11]([CH3:13])[CH3:12])(=[O:9])[O:5][CH:6]([CH3:8])[CH3:7].C([O:26][C:27](=[O:30])[CH2:28]Br)C.O>C1(C)C=CC=CC=1>[CH:16]([O:15][P:14]([O:20][CH:21]([CH3:23])[CH3:22])([CH:3]([P:4]([O:10][CH:11]([CH3:12])[CH3:13])([O:5][CH:6]([CH3:8])[CH3:7])=[O:9])[CH2:28][C:27]([OH:30])=[O:26])=[O:19])([CH3:18])[CH3:17]
Reactant: CC(C)OP(=O)(CP(=O)(OC(C)C)OC(C)C)OC(C)C
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)OP(=O)(OC(C)C)C(CC(=O)O)P(=O)(OC(C)C)OC(C)C
Reaction time: 0.25 h
Yield: 13.7 %

Procedure:
Sodium hydride (700 mg, 0.29 mmol) was added in small portions under a stream of dry nitrogen to a vigorously stirred solution of tetraisopropyl methane-1,1-bisphosphonate (1) (5.0 gm, 14.5 mmol) in dry toluene (25 ml). After the effervescence had stopped, stirring was continued for 15 minutes. Ethylbromoacetate (3.2 gm, 19.2 mmol) was then added dropwise over a period (2 min) whereupon the flask became warm and a white precipitate began to form. Stirring was continued for a further 2 hours at room temperature. Water (20 ml) was added then carefully and the mixture vigorously stirred. The toluene layer was separated and extracted with water (20 ml). The aqueous extracts were combined, washed with ether (50 ml), acidified to pH 1 and re-extracted with dichloromethane (2×25 ml). The dichloromethane extracts were combined, dried (MgSO4), filtered and solvent evaporated under reduced pressure to leave the acid (3) as a pale yellow liquid (800 mg). The toluene layer was also dried (MgSO4), filtered, and solvent evaporated to leave an oil which was found to be the ethyl ester (2) and unreacted starting material. This oil was dissolved in a methanol:water mixture (20 ml, 3:1) containing lithium hydroxide (1 g, 24 mmol) and the solution stirred at room temperature for 16 h. The methanol was removed by evaporation and water (20 ml) was then added. This aqueous solution was washed with ether (2×20 ml), acidified to pH 1 with dilute HCl and then extracted with dichloromethane (2×25 ml). The dichloromethane extracts were combined, dried (MgSO4), filtered and volatile components removed under reduced pressure to leave the acid (3) (2.77 g) as a pale yellow liquid. The combined product (3) (3.57 g, 61%) was sufficiently pure to be used in subsequent reactions without further purification.
Reaction SMILES: S([O:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])(C(F)(F)F)(=O)=O.[F:16][C@@:17]1([CH2:30]O)[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1.C(N(CC)CC)C>C(Cl)Cl>[F:16][C@@:17]1([CH2:30][O:8][S:9]([C:12]([F:13])([F:14])[F:15])(=[O:10])=[O:11])[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC[C@@](F)(CO)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@](F)(COS(=O)(=O)C(F)(F)F)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 106.5 %

Procedure:
Triflic anhydride (24.06 ml, 142 mmol) was added to a solution of 1,1-dimethylethyl (3S)-3-fluoro-3-(hydroxymethyl)-1-piperidinecarboxylate (30.2 g, 129 mmol) and triethylamine (23.46 ml, 168 mmol) in DCM (100 ml) at −10° C. over 20 min. The mixture was stirred for 2 h, allowing to warm to 0° C., then washed with water and brine, dried and evaporated to give 1,1-dimethylethyl (3S)-3-fluoro-3-({[(trifluoromethyl)sulfonyl]oxy}methyl)-1-piperidinecarboxylate as a dark brown oil (50.2 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:15])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:23][CH2:24][CH3:25].Cl>C(#N)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:15])[CH2:14][CH2:13][N:12]([CH2:23][CH2:24][CH3:25])[CH2:11][CH2:10]1
Reactant: OC1(c2cccc(Cl)c2Cl)CCNCC1
Reactant: CCCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCN1CCC(O)(c2cccc(Cl)c2Cl)CC1

Procedure:
Preparation according to Example 2: 4-(2,3-dichlorophenyl)piperidin-4-ol (0.43 g, 1.75 mmol), acetonitrile (20 ml), potassium carbonate (0.59 g, 4.3 mmol), iodopropane (0.15 ml, 1.9 mmol). Yield: 0.29 g, 57%. The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 181-183° C. MS m/z (relative intensity, 70 eV) 289 (M+, 2), 287 (M+, 4), 260 (64), 258 (bp) 240 (33).
Reaction SMILES: [C:1](Cl)(=[O:5])[O:2][CH2:3][CH3:4].Cl.[NH2:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1>N1C=CC=CC=1>[CH2:3]([O:2][C:1]([NH:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1)=[O:5])[CH3:4]
Reactant: CCOC(=O)Cl
Reactant: Cn1ccnc1N
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1nccn1C
Temperature: 100 °C

Procedure:
Ethyl chlorocarbonate (0.6 g) was added to a solution of 2-amino-1-methylimidazole hydrochloride (0.3 g) in pyridine (5 ml), and the mixture was stirred under heating at 100° C. for 2 hours. The solvent was evaporated under reduced pressure, the residue was dissolved in water, and sodium carbonate was added until the solution became alkaline. The solvent was evaporated under reduced pressure, and then the residue was purified by column chromatography on silica gel (eluent: chloroform) to give 2-ethoxycarbonylamino-1-methylimidazole. This compound was dissolved in dichloromethane, and 4N hydrochloric acid-ethyl acetate (2 ml) was added to form its hydrochloric acid salt. The resulting crude crystals were washed with ether to give 2-ethoxycarbonylamino-1-methylimidazole hydrochloride (0.29 g, Yield: 56%) as colorless prisms.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>O1CCCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccc(Cl)nc1
Reactant: Cc1ccc(N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)Cc2ccc(Cl)nc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 500 mL round-bottom flask were combined 2-(6-chloropyridin-3-yl)acetic acid (10.3 g, 60.0 mmol; Oakwood), p-toluidine (6.43 g, 60.0 mmol; Aldrich) and N,N-diisopropylethylamine (34.3 mL, 198 mmol; Aldrich) in tetrahydrofuran (220 mL). The mixture was stirred at room temperature for 1 hour, and then O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU; 25.1 g, 66.0 mmol; Aldrich) was added. After 16 hours, the reaction was concentrated, the residue dissolved in ethyl acetate (500 mL) and washed with water (50 mL). The organic phase was concentrated and purified by flash chromatography (silica gel, hexanes/ethyl acetate, 2:1) to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 2.28 (s, 3H), 3.71 (s, 2H), 7.11 (d, J=8 Hz, 2H), 7.37-7.46 (m, 3H), 7.81 (dd, J=8, 3 Hz, 1H), 8.33 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 261 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([Cl:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[Cl:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([Cl:28])[C:21]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.CCN(C(C)C)C(C)C>C(O)C>[Cl:14][C:11]([F:13])([F:12])[C:8]1[N:6]2[N:7]=[C:2]([N:25]3[CH2:26][CH2:27][N:22]([C:21]4[C:20]([Cl:28])=[CH:19][N:18]=[CH:17][C:16]=4[Cl:15])[CH2:23][CH2:24]3)[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1
Reactant: FC(F)(Cl)c1nnc2ccc(Cl)nn12
Reactant: Clc1cncc(Cl)c1N1CCNCC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(Cl)c1nnc2ccc(N3CCN(c4c(Cl)cncc4Cl)CC3)nn12
Temperature: 70 °C
Yield: 29.3 %

Procedure:
A solution of 6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-b]pyridazine (obtained as described in Examples 335-338, preparation of starting materials) (53 mg, 0.22 mmol) in ethanol (1 mL) was added to 1-(3,5-dichloropyridin-4-yl)piperazine (77 mg, 0.33 mmol). The reaction mixture was treated with DIPEA (43 mg, 0.33 mmol) and the mixture was heated at 70° C. for 4 hours. The reaction mixture was evaporated to leave an involatile residue that was purified by preparative reverse phase chromatography to give 3-[chloro(difluoro)methyl]-6-[4-(3,5-dichloropyridin-4-yl)piperazin-1-yl][1,2,4]triazolo[4,3-b]pyridazine (28 mg, 29%).