Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[Si:20]([CH3:23])([CH3:22])[CH3:21]>C(OCC)C>[CH3:21][Si:20]([CH3:23])([CH3:22])[N:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1
Reactant: CCOC(=O)C1CCNCC1
Reactant: C[Si](C)(C)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN([Si](C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.3 %

Procedure:
Under a nitrogen atmosphere, a stirred solution of 100.0 grams (0.64 mole) of ethyl piperidin-4-ylcarboxylate and 94 mL (0.67 mole) of triethylamine in 1400 mL of diethyl ether was cooled to 15° C., and a solution of 86 mL (0.68 mole) of chlorotrimethylsilane in 100 mL of diethyl ether was added dropwise during a 30 minute period. Upon completion of the addition, the thick reaction mixture was stirred vigorously for one hour while warming to ambient temperature. The reaction mixture was then filtered, and the collected solid was washed with diethyl ether. The combined wash and filtrate were concentrated under reduced pressure to a residual oil. The oil was distilled under reduced pressure, yielding 115.0 grams (79% yield) of ethyl N-(trimethylsilyl)piperidin-4-ylcarboxylate, bp 75° C./0.1 mm Hg. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5]O.P(Br)(Br)[Br:12].O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5][Br:12]
Reactant: OCc1ccc(F)c(Br)c1
Reactant: BrP(Br)Br
Solvent: Cc1ccccc1
Solvent: O
Product: Fc1ccc(CBr)cc1Br
Yield: 242.5 %

Procedure:
20.5 g (0.1 mol) of 3-bromo-4-fluoro-benzyl alcohol were dissolved in 100 ml of anhydrous toluene, and 10 g of phosphorus tribromide were added dropwise at 0° to 10° C., while stirring. The mixture was then stirred at room temperature for 2 hours. The reaction batch was subsequently poured into 500 ml of water, the organic phase was separated off and dried over magnesium sulphate and the solvent was distilled off under a waterpump vacuum. The residue was distilled in vacuo. 24 g (89.6% of theory) of 3-bromo-4-fluoro-benzyl bromide with a boiling point of 99°-100° C./3 mbars were obtained.
Reaction SMILES: [CH3:1][C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Se](=O)=[O:14]>O1CCOCC1.O>[C:4]([C:3]1[C:2]([CH:1]=[O:14])=[N:12][CH:11]=[CH:10][CH:9]=1)([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1cccnc1C
Reactant: O=[Se]=O
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cccnc1C=O
Temperature: 25 °C
Yield: 50.2 %

Procedure:
To a stirred solution of ethyl 2-methylnicotinate (1.657 g, 10.0 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was added selenium dioxide (1.568 g, 14.1 mmol) and the resultant mixture was heated to reflux overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (3:1 hexanes/ethyl acetate) and provided the title compound (0.90 g, 50%) as a yellow oil. 1H NMR (CDCl3) δ 1.41 (t, 3H, J=7.5 Hz), 4.45 (q, 2 H; J=7.5 Hz), 7.56 (dd, 1H, J=6.0, 6.0 Hz), 8.11 (dd, 1H, J=6.0, 1.0 Hz), 8.87 (dd, 1H, J=6.0, 1.0 Hz), 10.34 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].[C:20]1([C:26](Cl)([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)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:20]1([C:26]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)CCCCCCCCCCCCCCCO
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)CCCCCCCCCCCCCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 15.9 %

Procedure:
A solution of 16-hydroxyhexadecanoic acid (1.36 g, 5.00 mmol), triphenylmethyl chloride (1.53 g, 5.50 mmol), triethylamine (1.25 ml) and 4-dimethylaminopyridine (10.03 g, 0.25 mmol) is stirred overnight in dry dimethylformamide at ambient temperature under nitrogen. After 16 hours stirring, the brown cloudy solution is poured into ice-water and extracted with dichloromethane (5×50 ml). The organic phases are washed with saturated ammonium chloride solution (2×100 ml), water (2×100 ml) and dried over MgSO4. The solvent is removed under reduced pressure and the product purified by flash chromatography on a silica column with dichloromethane/methanol (20:1) as eluant to yield the title compound as a yellow oil (0.41 g). 13C NMR (75 MHz, CDCl3): δ 24.9, 25.7, 26.3, 29.2, 29.5, 29.6, 29.7, 30.0, 32.8, 34.1, 62.9, 63.7, 86.2, 144.5, 177.2. MS (CI): 515 (M+H)
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[OH:26][C:27]([CH3:33])([CH3:32])[CH2:28][C:29](O)=[O:30]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:29](=[O:30])[CH2:28][C:27]([OH:26])([CH3:33])[CH3:32])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: CC(C)(O)CC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: CC(C)(O)CC(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (18.7 mg, 62%), MS (ISP) m/z=431.4 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (25.7 mg, 0.070 mmol) and 3-hydroxy-3-methylbutanoic acid
Reaction SMILES: S(Cl)(Cl)=O.[N:5]1([CH:10](O)[CH:11]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[C:12]([CH3:15])([CH3:14])[CH3:13])[CH:9]=[N:8]N=C1.[N:27]1C=CC=C[CH:28]=1>ClCCl>[N:5]1([CH:10]=[C:11]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[C:12]([CH3:13])([CH3:14])[CH3:15])[CH:9]=[N:8][CH:28]=[N:27]1
Reactant: c1ccncc1
Reactant: CC(C)(C)C(COc1ccc(Cl)cc1Cl)C(O)n1cnnc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(C)(C)C(=Cn1cncn1)COc1ccc(Cl)cc1Cl
Yield: 75 %

Procedure:
With stirring, 100 ml of dichloromethane and 10 ml of thionyl chloride are cooled to -30° C. and then 17.5 g (0.05 mole) of 1-(1H-1,3,4-triazolyl)-2-(2,4-dichlorophenoxymethyl)-3,3-dimethylbutanol are added in portions. The reaction mixture is stirred for 2 hours and then a solution of 15 ml of pyridine in 30 ml of dichloromethane is added dropwise and the mixture is stirred for about 12 hours at room temperature. The clear solution is concentrated in vacuo and, after addition of ice, the residue is made alkaline with sodium carbonate and extracted with diethyl ether. The combined extracts are dried over sodium sulfate, filtered and concentrated. The yellowish oily residue is purified by column chromatography over silica gel with ethyl acetate as eluant. Yield: 75% of theory.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[F:27][CH2:28][CH2:29][CH2:30][OH:31]>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)=[C:2]([O:31][CH2:30][CH2:29][CH2:28][F:27])[CH:7]=1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Reactant: OCCCF
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3OCCCF)n2)c1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (75 mg; 0.197 mmol), intermediate 42.1, and 3-fluoropropan-1-ol (59 mg; 0.736 mmol), example 54 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: CCCCCCCCBr
Reactant: O=Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(Br)cc1C=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 5-bromosalicylaldehyde (5.00 g) and potassium carbonate (10.3 g) in N,N-dimethylformamide (50 ml) was added octyl bromide (4.52 ml), and the mixture was stirred at room temperature for 1.5 hr, and further at 50° C. for 3.5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine 3 times, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the object product (7.72 g) as a white solid.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:24]S(OC)(=O)=O.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:24][N:17]([CH2:16][CH:13]1[CH2:14][CH2:15][N:10]([C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:9])[CH2:11][CH2:12]1)[C:18](=[O:23])[C:19]([F:20])([F:21])[F:22]
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)C(F)(F)F)CC1
Reactant: COS(C)(=O)=O
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CC1CCN(C(=O)OC(C)(C)C)CC1)C(=O)C(F)(F)F
Reaction time: 0.67 h

Procedure:
Under nitrogen, 0.21 g (5.25 mM) of 60% sodium hydride-liquid paraffin was added to a solution of 1.51 g (4.87 mM) of N-(1-tert-butoxycarbonylpiperidin-4-ylmethyl)trifluoroacetamide in N,N-dimethylformamide (10 ml) at 0° C. and the mixture was stirred at the prevailing temperature for 40 minutes. To this reaction mixture was added 0.5 ml (5.90 mM) of methyl methanesulfonate and the mixture was stirred at room temperature for 112 hours. The mixture was further stirred at 100° C. for 2.5 hours, at the end of which time the reaction was stopped by adding saturated aqueous solution of sodium hydrogen carbonate. The reaction mixture was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride and dried over MgSO4. The crude product thus obtained was purified by column chromatography (ethyl acetate-hexane 40%) to provide the title compound.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[O:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([N:8]1[C:9]([O:10][C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]1=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cc1cc(C)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: BrCc1ccccc1
Product: Cc1cc(C)cc(Oc2c(C(C)C)c(=O)[nH]c(=O)n2Cc2ccccc2)c1
Yield: 72.5 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and benzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (264 mg, yield: 72.5%).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[CH2:4][CH:5]=[CH2:6].Br[CH2:9][C:10]([OH:12])=[O:11]>C1COCC1>[CH2:3]([O:7][CH2:9][C:10]([OH:12])=[O:11])[CH2:4][CH:5]=[CH2:6]
Reactant: C=CCCO
Reactant: O=C(O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCCOCC(=O)O
Reaction time: 2 h
Yield: 126.8 %

Procedure:
To 480 mg of NaH (50% in mineral oil, ˜20 mmol) in 10 ml of abs. THF was added at 0° 721 mg of 3-buten-1-ol (10 mmol) and the mixture stirred for 5 Min. (H2-evolution). 1.39 g of bromo-acetic acid (10 mmol), dissolved in 10 ml of THF, was then added and the mixture kept for additional 5 Min. at 0° and for 2 h at ambient temperature. Pouring onto crashed ice/HCl dil., twofold extraction with AcOEt, washing with brine, drying over sodium sulfate and evaporation of the solvents afforded 1.65 g of the title compound, contaminated with mineral oil, but sufficiently pure for the next step.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[CH2:9]([NH:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:11][CH3:12].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1(C)C=CC=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]>[CH2:9]([N:13]([CH2:14][CH2:15][CH2:16][CH3:17])[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1)[CH2:10][CH2:11][CH3:12]
Reactant: Cc1ccc(Cl)cc1
Reactant: CCCCNCCCC
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CCCCN(CCCC)c1ccc(C)cc1
Reaction time: 4 h
Yield: 89.3 %

Procedure:
The above general procedure was followed using 4-chlorotoluene (126 mg, 1.00 mmol) and dibutylamine (129 mg, 1.00 mmol) with 1 mol % Pd(dba)2 and 0.8 mol % tri-t-butylphosphine in 1.0 mL of toluene. After 4 hours at 70° C., the reaction mixture was adsorbed onto silica gel and chromatographed with 2% ethyl acetate/hexanes to give 196 mg (90%) of N,N-dibutyl-p-toluidine.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[F:6][C:7]([F:15])([F:14])[CH:8]([OH:13])[C:9]([F:12])([F:11])[F:10].C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.OS(O)(=O)=O.O=S(=O)=O>>[C:1]([O:13][CH:8]([C:9]([F:12])([F:11])[F:10])[C:7]([F:15])([F:14])[F:6])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)Cl
Reactant: OC(C(F)(F)F)C(F)(F)F
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: C=CC(=O)OC(C(F)(F)F)C(F)(F)F
Yield: 95.7 %

Procedure:
With reference to scheme (13) above, a 1000 mL three-neck flask can be equipped with a thermometer, agitator, and dropping funnel with a dip tube. Into the flask can be added about 130.6 grams of acryloyl chloride, 168.8 grams 1,1,1,3,3,3-hexafluoropropan-2-ol, and 1 grain of 2,6-di-tert-butyl-4-methylphenol to form a mixture. About 30% (wt/wt) oleum can then be added to the mixture through the dip tube while maintaining the mixture at 60° C.-75° C. After addition, the mixture can be maintained at 60° C.-70° C. for about 4 hours. Single stage vacuum distillation of the mixture can yield about 183 grains of crude product 1,1,1,3,3,3-hexafluoropropan-2-yl acrylate being about 95.7% (area percent by as chromatography). The crude 1,1,1,3,3,3-hexafluoropropan-2-yl can be distilled further to increase purity to 99.7% (area percent by gas chromatography).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:21][CH3:22])[CH2:4][N:5]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([O:15][CH3:16])[C:8](=[O:17])[C:7]([C:18]([OH:20])=O)=[CH:6]1.C(N(CC)C(C)C)(C)C.Cl.[F:33][C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=1[C@H:41]([NH2:43])[CH3:42].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[F:33][C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=1[C@H:41]([NH:43][C:18]([C:7]1[C:8](=[O:17])[C:9]([O:15][CH3:16])=[C:10]([C:11]([O:13][CH3:14])=[O:12])[N:5]([CH2:4][CH:3]([O:2][CH3:1])[O:21][CH3:22])[CH:6]=1)=[O:20])[CH3:42]
Reactant: C[C@@H](N)c1ccc(F)cc1F
Reactant: COC(=O)c1c(OC)c(=O)c(C(=O)O)cn1CC(OC)OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1c(OC)c(=O)c(C(=O)N[C@H](C)c2ccc(F)cc2F)cn1CC(OC)OC
Reaction time: 1 h

Procedure:
1-(2,2-dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (1-A, 0.315 g, 1.00 mmol), was suspended in acetonitrile (4 ml) and treated with N,N-diisopropylethylamine (DIPEA) (0.348 mL, 2.00 mmol), (R)-1-(2,4-difluorophenyl)ethanamine HCl salt (0.213 mg, 1.10 mmol) and HATU (0.418 g, 1.10 mmol). The reaction mixture was stirred for 1 hour and partitioned between dichloromethane and HCl (10% aq). The organic layer was separated and washed sodium bicarbonate (1M aq), dried over sodium sulfate, filtered and concentrated to afford crude (R)-methyl 5-(1-(2,4-difluorophenyl)ethylcarbamoyl)-1-(2,2-dimethoxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylate which was used without purification in the next step. LCMS-ESI+ (m/z): [M+H]+ calculated for C21H25F2N2O7: 455.16; found: 455.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[NH:15][N:16]=[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]3[N:15]([S:34]([CH3:33])(=[O:36])=[O:35])[N:16]=[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:24]2[CH:25]=[CH:26][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:28][CH:29]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)c1ccc(-c2nc3c(-c4ccccc4)n[nH]c3c(=O)n2-c2ccc(Cl)cc2)cc1
Solvent: ClCCl
Product: CC(C)c1ccc(-c2nc3c(-c4ccccc4)nn(S(C)(=O)=O)c3c(=O)n2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-(4-chloro-phenyl)-5-(4-isopropyl-phenyl)-3-phenyl-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one (20.0 mg, 0.045 mmol) in DCM (0.5 mL) are added MsCl (7.05 μL, 0.091 mmol) and TEA (12.64 μL, 0.091 mmol). The reaction mixture is stirred at room temperature for overnight before removal of the solvent, The residue is purified by preparative LC/MS to provide the title compound; 1H NMR (CDCl3, 400 MHz) δ 8.47 (dd, 2H), 7.48 (m, 3H), 7.34 (d, 2H), 7.28 (d, 2H), 7.14 (m, 4H), 3.77 (s, 3H), 2.87 (m, 1H), 1.22 (s, 3H), 1.21 (s, 3H); HPLC-MS calculated for C27H23ClN4O3S (M+H+) 519.1. Found: 519.1.
Reaction SMILES: Cl.[CH3:2][O:3][N:4]([CH3:20])[C:5]([C@@:7]1([NH2:19])[C@@H:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@H:8]1[CH2:16][O:17][CH3:18])=[O:6].[F:21][C:22]([F:38])([F:37])[C:23]1[O:27][N:26]=[C:25]([C:28]2[S:32][C:31]([S:33](Cl)(=[O:35])=[O:34])=[CH:30][CH:29]=2)[CH:24]=1>N1C=CC=CC=1>[CH3:2][O:3][N:4]([CH3:20])[C:5]([C@@:7]1([NH:19][S:33]([C:31]2[S:32][C:28]([C:25]3[CH:24]=[C:23]([C:22]([F:21])([F:37])[F:38])[O:27][N:26]=3)=[CH:29][CH:30]=2)(=[O:34])=[O:35])[C@@H:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@H:8]1[CH2:16][O:17][CH3:18])=[O:6]
Reactant: COC[C@@H]1[C@H](c2ccccc2)[C@]1(N)C(=O)N(C)OC
Reactant: O=S(=O)(Cl)c1ccc(-c2cc(C(F)(F)F)on2)s1
Agent: Cl
Solvent: c1ccncc1
Product: COC[C@@H]1[C@H](c2ccccc2)[C@]1(NS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)on2)s1)C(=O)N(C)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.2 %

Procedure:
The (1R*,2R*,3R*)-1-amino-2-methoxymethyl-3-phenyl-cyclopropanecarboxylic acid methoxy-methyl-amide hydrochloride (22 mg, 0.082 mmol) was dissolved in 1 mL of pyridine. To this solution was added 5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonyl chloride (25 mg, 0.079 mmol) and the mixture was stirred at room temperature overnight. After concentration, the reaction mixture was diluted with EtOAc and washed with sat. NaHCO3 (2×) and brine. After drying over MgSO4, the solution was concentrated and purified using prep-TLC (1:1 hexanes/EtOAc) to afford 13 mg of the desired product (32%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[O:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CO.Cl[CH2:19][N:20]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][C:26]([O:35][CH3:36])=[CH:27][C:28]=2[CH:32]([CH3:34])[CH3:33])[S:21]1(=[O:23])=[O:22]>O>[CH3:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH2:19][N:20]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][C:26]([O:35][CH3:36])=[CH:27][C:28]=3[CH:32]([CH3:34])[CH3:33])[S:21]2(=[O:22])=[O:23])=[O:8])[O:4][N:3]=1
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CCl)C2=O
Reactant: Cc1cc(C(=O)O)on1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CO
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COC(=O)c1cc(C)no1)C2=O
Reaction time: 0.5 h
Yield: 84.5 %

Procedure:
A mixture of 3-methylisoxazole-5-carboxylic acid (0.63 g, 5.0 mmol), cesium carbonate (0.8 g, 2.45 mmol) and methanol was stirred for 30 minutes. The solvent was removed in vacuo and the residue was dried in high vacuum for 1 hour. The residue was suspended in DMF (30 ml) and 2-chloromethyl-4-isopropyl-6-methoxysaccharin (1.0 g, 3.3 mmol) was added. The mixture was stirred at room temperature for 19 hours and was poured into water. The mixture was extracted with ethyl acetate/ether (4/1, 300 ml) and the organic layer was separated and wash with water, then brine. The solvent was removed in vacuo and the residue was purified by flash chromatography (30% ethyl acetate/hexanes) to afford 1.1 g (85%) of 4-isopropyl-6-methoxy-2-saccharinylmethyl 3-methylisoxazole-5-carboxylate as a white powder, m.p. 157°-158° C.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[CH2:7]([O:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14](Cl)=[N:13][CH:12]=1)[CH3:8].[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1.O.O.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>[CH2:7]([O:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:13][CH:12]=1)[CH3:8]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1ccc(-c2ccccc2)nc1
Yield: 57 %

Procedure:
Na2CO3 (228 mg, 2.16 mmol) was added to a stirred solution of 6-chloro nicotinic acid ethyl ester (200 mg, 1.08 mmol) in toluene:H2O (5:1, 6 mL). Pd (PPh3)4 (250 mg, 0.216 mmol) and phenylboronic acid (168 mg, 1.29 mmol) were then added and the reaction mixture was heated to reflux for 3 hrs. The reaction mixture was then diluted with water and the product was extracted with ethyl acetate. The organic layer was washed with saturated brine solution, dried over sodium sulphate and concentrated to afford 140 mg (64.4% yield) of 6-phenyl-nicotinic acid ethyl ester. LCMS Purity %: 98.2
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N:20]1[CH:25]=[CH:24][C:23]([CH:26]=O)=[CH:22][CH:21]=1>>[N:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:22][CH:21]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=Cc1ccncc1
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4ccncc4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with pyridine-4-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(pyridin-4-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.