Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][C:43]=1F)[C:5]1[C:10]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]4[N:25]([CH:26]5[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)[C:24]5[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:23]=5[N:22]=4)[CH:17]=3)[N:12]=2)=[CH:9][C:8]([O:39][CH3:40])=[CH:7][CH:6]=1.C[O:46][C:47]([C:49]1C=CC2N(C3CCCCC3)C(C3C=C4C(=CC=3)N=C(C3C=C(OC)C=CC=3Br)C=C4)=NC=2C=1)=O.C(OC1C=CC(B(O)O)=CC=1)C>>[CH:26]1([N:25]2[C:24]3[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:23]=3[N:22]=[C:21]2[C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([C:10]2[C:5]([C:4]4[CH:41]=[CH:42][C:43]([O:46][CH2:47][CH3:49])=[CH:2][CH:3]=4)=[CH:6][CH:7]=[C:8]([O:39][CH3:40])[CH:9]=2)[CH:20]=[CH:19]3)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: COc1ccc(-c2ccc(F)c(Cl)c2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Reactant: COC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(OC)ccc4Br)ccc3c1)n2C1CCCCC1
Agent: CCOc1ccc(B(O)O)cc1
Product: CCOc1ccc(-c2ccc(OC)cc2-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)cc1
Yield: 16 %

Procedure:
Following the full procedure and workup for Compound 366, Compound 365b (100 mg, 0.175 mmol) was reacted with 4-ethoxyphenylboronic acid (44 mg, 0.2625 mmol) to produce the title compound (17 mg, 16% yield).
Reaction SMILES: OO.C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:4].[CH3:16][N:17]([CH3:35])[CH2:18][CH2:19][NH:20][C:21]1[N:22]=[N+:23]([O-:34])[C:24]2[CH:30]=[C:29]3[O:31][CH2:32][O:33][C:28]3=[CH:27][C:25]=2[N:26]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.N>[O-:34][N+:23]1[C:24]2[CH:30]=[C:29]3[O:31][CH2:32][O:33][C:28]3=[CH:27][C:25]=2[N+:26]([O-:4])=[C:21]([NH:20][CH2:19][CH2:18][N:17]([CH3:35])[CH3:16])[N:22]=1
Reactant: CN(C)CCNc1nc2cc3c(cc2[n+]([O-])n1)OCO3
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: N
Agent: OO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)CCNc1n[n+]([O-])c2cc3c(cc2[n+]1[O-])OCO3
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 12.7 %

Procedure:
H2O2 (70%, 0.67 mL, ca. 13.5 mmol) was added dropwise to a stirred solution of TFAA (1.9 mL, 13.5 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 223 (374 mg, 1.4 mmol) and TFA (0.52 mL, 6.7 mmol) in DCM (15 mL) at 0° C. The solution was stirred at 20° C. for 8 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCl3 (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-20%) of MeOH/DCM, to give 1,4-dioxide 224 (52 mg, 13%) as a red solid: mp (MeOH/EtOAc) 175-179° C.; 1H NMR δ 7.60 (s, 1H, H-9), 7.59 (s, 1H, H-5), 7.35 (br s, 1H, NH), 6.21 (s, 2H, H-7), 3.61 (br t, J=6.0 Hz, 2H, CH2N), 2.62 (br t, J=6.0 Hz, 2H, CH2N), 2.31 [s, 6H, N(CH3)2]; 13C NMR δ 155.9, 149.7, 148.9, 137.8, 126.7, 103.5, 97.9, 94.1, 57.4, 45.1 (2), 38.8. Anal. calcd for C12H15N5O4.½CH3OH: C, 48.5; H, 5.5; N, 22.6. Found: C, 48.7; H, 5.3; N, 22.6%.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]([C:7]([O:9][CH3:10])=[O:8])[CH2:4][CH:3]([C:11]([O:13][CH3:14])=[O:12])[CH2:2]1.C([O-])([O-])=O.[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(#N)C>[CH2:21]([N:1]1[CH2:2][CH:3]([C:11]([O:13][CH3:14])=[O:12])[CH2:4][CH:5]([C:7]([O:9][CH3:10])=[O:8])[CH2:6]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)C1CNCC(C(=O)OC)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C1CC(C(=O)OC)CN(Cc2ccccc2)C1
Temperature: 23 °C
Reaction time: 4 h

Procedure:
To dimethyl piperidine-3,5-dicarboxylate (7.5 g, 37.3 mmol) in acetonitrile (100 mL) was added K2CO3 (20.6 g, 149.1) and benzylbromide (4.43 mL, 37.3 mmol). The reaction mixture was stirred at 23° C. for 4 hours. The K2CO3 was removed by filtration and the solvent evaporated in vacuo. A solution of NaHCO3 (1M, 150 mL) was added and the organic material extracted with ethyl acetate (3×50 mL), then dried (MgSO4) and concentrated in vacuo. The crude material was purified on a Silica gel column (Biotage flash chromatography system), eluting with a gradient of ethyl acetate/hexane (10:90) to (35:65) to afford the title compound as the cis diastereomer 1.6 g which eluted after the corresponding trans diastereomer. (based on the NMR reported in Synthetic Communications 1997, 27 (1), 69-71.). 1H NMR (400 MHz, CDCl3) δ ppm 7.26-7.36 (5 H, m), 3.68 (6 H, s), 3.59 (2 H, s), 3.15 (2 H, m), 2.66 (2 H, t, J=12.0 Hz), 2.36 (1 H, d, J=13.1 Hz), 2.05 (2 H, t, J=11.4 Hz), 1.56 (1 H, q, J=12.9 Hz). LCMS (+ESI, M+H+) m/z: 292.
Reaction SMILES: B([C:4]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:5]=1[O:6][C@@H:7]([CH3:11])[C:8]([OH:10])=[O:9])(O)O.Br[C:18]1[CH:19]=[C:20]([C:24]#[N:25])[CH:21]=[CH:22][CH:23]=1>C1COCC1>[Cl:16][C:14]1[CH:13]=[CH:12][C:5]([O:6][C@@H:7]([CH3:11])[C:8]([OH:10])=[O:9])=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[CH:19]=2)[CH:15]=1
Reactant: C[C@H](Oc1ccc(Cl)cc1B(O)O)C(=O)O
Reactant: N#Cc1cccc(Br)c1
Solvent: C1CCOC1
Product: C[C@H](Oc1ccc(Cl)cc1-c1cccc(C#N)c1)C(=O)O

Procedure:
The title compound was prepared by the method of example 144 step (i) using the product from example 151 step (iv), 3-bromobenzenenitrile and THF as solvent.
Reaction SMILES: Br.Br.[OH:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.Cl[CH2:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:17][C:18]3[CH:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:19]=3)[CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: COc1cc(CCl)nc(-c2ccccc2)n1
Reactant: Oc1ccc(N2CCNCC2)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(CN2CCN(c3ccc(O)cc3)CC2)nc(-c2ccccc2)n1
Temperature: 80 °C
Reaction time: 0.42 h
Yield: 58.1 %

Procedure:
A mixture of 4.94 g (14.5 mmol) of 1-(4-hydroxyphenyl)piperazine dihydrobromide, 3.29 g (14 mmol) of 4-chloromethyl-6-methoxy-2-phenylpyrimidine and 2.00 g (14.5 mmol) of powdered potassium carbonate in 50 ml of absolute N,N-dimethylformamide (DMF) was warmed to 80° C., and 322 mg of powdered K2CO3 were added with stirring under a nitrogen atmosphere in each case after 10 minutes, after a further 25 minutes, and after a further 60 minutes (total addition of 966 mg (7 mmol) of K2CO3). The mixture was stirred for a further 2.5 hours at 80° C., the DMF was substantially removed by distillation in an oil-pump vacuum in a rotary evaporator, the crystalline residue was mixed with 40 ml of water and 50 ml of CH2Cl2, the pH of the mixture was adjusted to 5-6 using 2N HCl, the phases were separated, and the aqueous phase was extracted three times with CH2Cl2. The combined CH2Cl2 extracts were dried, filtered and evaporated in vacuo. The residue (4.25 g) was chromatographed on a silica gel S/CH2Cl2 column (diameter 2.0 cm, height 23 cm) by elution with CH2Cl2 and CH2Cl2 /C2H5OH mixtures, with increasing C2H5OH content (to a maximum of 4% by volume of C2H5OH). The fractions which were unary according to TLC were combined and crystallized from CH3OH. In this fashion 3.06 g (=58% yield) of 4-(4-hydroxyphenyl)-1-(6-methoxy-2-phenylpyrimidin-4-yl-methyl)piperazine were obtained; melting point 166°-67° C., analysis: C22H24N4O2 (MW 376.46) calc. C 70.19, H 6.43, N 14.88; found C 69.9, H 6.4, N 14.5%.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.C(O)(=O)C.[NH2:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[N:22]1[CH:26]=[CH:25][CH:24]=[CH:23]1>C(O)C>[CH3:21][O:20][C:18]1[CH:19]=[C:14]2[C:15](=[CH:16][CH:17]=1)[N:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:5]1([CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)[NH:13]2
Reactant: COc1ccc(-n2cccc2)c(N)c1
Reactant: CN1CCC(=O)CC1
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc2c(c1)NC1(CCN(C)CC1)c1cccn1-2

Procedure:
3.48 g (0.03 mole) of 1-methyl-4-piperidone and 3 ml. of glacial acetic acid are added to a solution of 5.65 g (0.03 mole) of 1-(2-amino-4-methoxy-phenyl) pyrrole in 100 ml. of absolute ethanol. The solution is refluxed for 15 hours and concentrated, and the residue is dissolved in water. The solution is filtered and basified. A solid precipitates and is filtered, dried and recrystallized from ethanol to give 4,5-dihydro-7-methoxy-1'-methylspiro[pyrrolo(1,2-a)quinoxaline-4,4'-piperidine], m.p. 124°-125° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[Cl:26][C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30]>>[Cl:26][C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29]([N:20]1[CH2:21][CH2:22][CH:17]([N:15]2[C:14](=[O:23])[C:13]([CH3:25])([CH3:24])[C:12]([C:6]3[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=3)=[N:16]2)[CH2:18][CH2:19]1)=[O:30]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4ccccc4Cl)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 2-chlorobenzoyl chloride as starting compounds. The crude product is purified by crystallization from EA and diethyl ether to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:36][CH:37]([F:39])[F:38])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][CH2:26]N[C@@H](C3C=CC=CC=3)C)[N:9]=2)[CH:7]=1.Cl.[NH2:41][CH2:42][C:43]([O:45][CH3:46])=[O:44].CCN(C(C)C)C(C)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:36][CH:37]([F:39])[F:38])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][CH2:26][NH:41][CH2:42][C:43]([O:45][CH3:46])=[O:44])[N:9]=2)[CH:7]=1
Reactant: C[C@@H](NCCn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1)c1ccccc1
Reactant: COC(=O)CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CNCCn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1

Procedure:
Using synthetic method analoguous to that of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[[(1R)-1-phenylethyl]amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide, the title compound was prepared from methyl 2-aminoacetate hydrochloride and DIEA. LCMS (Method 28) [M+H]+=520.1, RT=0.85 min. 1H NMR (300 MHz, DMSO-d6) δ: (ppm) 9.73 (s, 1H), 9.33 (dd, 1H, J=1.8, 6.9 Hz), 8.69-8.67 (m, 2H), 8.36 (s, 1H), 7.65-7.61 (m, 2H), 7.44 (d, 1H, J=9.3 Hz), 7.28 (dd, 1H, J=4.2, 7.2 Hz), 7.00 (t, 1H, J=73.5 Hz), 4.22 (t, 2H, J=6.0 Hz), 3.62 (s, 3H), 3.37 (s, 2H), 2.98 (t, 2H, J=6.0 Hz), 2.27 (br, 1H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH2:4][CH2:5][N:6]=1.C(N(CC)CC)C.Cl.[CH3:15][N:16]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](Cl)=[O:24])[CH3:17]>ClCCl>[CH3:15][N:16]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([N:6]1[CH2:5][CH2:4][N:3]=[C:2]1[CH3:1])=[O:24])[CH3:17]
Reactant: CC1=NCCN1
Reactant: CN(C)CCCCCC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1=NCCN1C(=O)CCCCCN(C)C
Temperature: 25 °C
Yield: 66.3 %

Procedure:
Dichloromethane (400 mL), 2-methyl-2-imidazoline (56.38 g, 0.637 mol), and triethylamine (283.51 g, 2.802 mol) are placed in a 2000 mL three-necked round bottomed flask equipped with a reflux condenser, internal thermometer, mechanical stirrer, addition funnel, and argon inlet. The solution is brought to reflux and 15 min later a solution of 6-(N,N-Dimethylamino)hexanoyl chloride-hydrochloride (150 g, 0.700 mol), prepared as described in example II, dissolved in dichloromethane (300 mL) is added dropwise over 45 min. The mixture is refluxed for an additional 2 h before being cooled to room temperature. The salts are filtered and washed with methylene chloride. The combined flitrates are washed with 5% NaHCO3 solution (3×300 mL) and water (300 mL), After drying over MgSO4 and filtration, the organic layer is concentrated first by rotary evaporation at 50° C. and then by Kugelrohr distillation at 60°-70° C. (0.2 mm Hg) to give 95.20 g (66%) of an oil which solidifies on standing.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH:11]([OH:12])[CH:10]([O:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([OH:20])[CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:21])[CH:8]=2)[O:3]1.[CH:23](O)=[O:24]>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:22])[CH:11]([OH:12])[CH:10]([O:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([OH:20])[CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:21][CH:23]=[O:24])[CH:8]=2)[O:3]1
Reactant: CC1(C)Oc2ccc(N)cc2C(Oc2ccnc(O)c2)C1O
Reactant: O=CO
Solvent: c1ccncc1
Product: CC1(C)Oc2ccc(NC=O)cc2C(Oc2ccnc(O)c2)C1O

Procedure:
A solution of 1 g of 2,2-dimethyl-4-(2-hydroxy-4-pyridyloxy)-6-amino-3-chromanol in 15 ml of HCOOH and 1 ml of pyridine is boiled for 19 hours and evaporated. After customary working up, 2,2-dimethyl-4 - (2-hydroxy-4-pyridyloxy)-6-formamido-3-chromanol is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]=[O:9].[CH3:10][Mg]Br.[Cl-].[NH4+]>O1CCCC1>[CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]([OH:9])[CH3:10]
Reactant: C[Mg]Br
Reactant: Cc1cnccc1C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cnccc1C(C)O
Temperature: 25 °C

Procedure:
3-Methylpyridine-4-carbaldehyde (310.6 mg, 1.00 mmol) in tetrahydrofuran (6 mL) was mixed with methylmagnesium bromide (0.98 M in tetrahydrofuran, 4.74 mL, 4.65 mmol) under −78° C., and the mixture was warmed slowly to room temperature for 16 hours with stirring. After completion of the reaction, the reaction solution was mixed with saturated aqueous ammonium chloride and extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting crude reaction product containing the desired product was used for the next step (310.6 mg).
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[CH:10]=[CH:11][C:12]([C:21](=[N:23][OH:24])[CH3:22])=[N:13][C:14]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:25]I>C1COCC1>[CH3:25][O:24][N:23]=[C:21]([C:12]1[CH:11]=[CH:10][C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[C:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:13]=1)[CH3:22]
Reactant: CI
Reactant: CC(=NO)c1ccc(-c2ccccc2)c(-c2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CON=C(C)c1ccc(-c2ccccc2)c(-c2ccccc2)n1
Reaction time: 1 h

Procedure:
General Procedure Q. To a suspension of NaH (20 mg, 0.80 mmol) in THF (2 ml) at 0° C. was added a solution of 1-(5,6-diphenyl-pyridin-2-yl)-ethanone oxime (Compound 80, 46 mg, 0.16 mmol) in THF (1 ml). After the mixture was stirred at the same temperature for 1 hour, MeI (140 mg, 0.99 mmol) was added and the solution was stirred overnight at room temperature. The reaction was quenched with water, and the products were extracted with ethyl acetate. The combined organic layers were washed with brine and dried over Na2SO4. The filtered solvent was concentrated in vacuo, and the residue was purified by silica gel chromatography (10% ethyl acetate in hexane) to give title compound as an oil.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Br[C:26]1[C:27]([F:37])=[CH:28][C:29]([F:36])=[C:30]([S:32]([NH2:35])(=[O:34])=[O:33])[CH:31]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:26]3[C:27]([F:37])=[CH:28][C:29]([F:36])=[C:30]([S:32]([NH2:35])(=[O:33])=[O:34])[CH:31]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: NS(=O)(=O)c1cc(Br)c(F)cc1F
Product: NS(=O)(=O)c1cc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c(F)cc1F

Procedure:
The title compound was prepared from 7-Difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (340 mg, 1.0 mmol) and commercially available 5-bromo-2,4-difluorobenzenesulfonamide [CAS 287172-65-0] (247 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (310 mg, 58%). MS (ISP) 529.2 [(M+H)+]; mp 256-258° C.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[F:16][C:17]([CH3:21])([CH3:20])[CH2:18]O.N1C(C)=CC=CC=1C>ClCCl>[F:16][C:17]([CH3:21])([CH3:20])[CH2:18][O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:9])=[O:8]
Reactant: CC(C)(F)CO
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(F)COS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
Add trifluoromethanesulphonic anhydride (4.3 mL, 26.0 mmol) to a solution of 2-fluoro-2-methylpropan-1-ol (2.0 g, 21.7 mmol) and 2,6-lutidine (3.0 mL, 26.0 mmol) in dichloromethane (25 mL) at −78° C. Warm slowly to room temperature and stir at room temperature for 1 hour. Add water to quench the reaction, separate the organic layer and extract the aqueous layer with dichloromethane. Combine the organic layers, dry (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with dichloromethane), to give the desired compound as an oil (3.4 g, 70% yield).
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:34]C(OC(C)(C)C)=O)=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH:31]3[CH2:33][CH2:32]3)[C:14]=2[N:15]2[CH2:21][C:20]([F:23])([F:22])[CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[F:42][C:43]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:44]=1B(O)O>>[NH2:34][C:4]1[S:3][C:2]([C:44]2[CH:45]=[C:46]([F:49])[CH:47]=[CH:48][C:43]=2[F:42])=[N:6][C:5]=1[C:7]([NH:9][C:10]1[CH:11]=[N:12][N:13]([CH:31]2[CH2:32][CH2:33]2)[C:14]=1[N:15]1[CH2:21][C:20]([F:23])([F:22])[CH2:19][NH:18][CH2:17][CH2:16]1)=[O:8]
Reactant: CC(C)(C)OC(=O)Nc1sc(Br)nc1C(=O)Nc1cnn(C2CC2)c1N1CCN(C(=O)OC(C)(C)C)CC(F)(F)C1
Reactant: OB(O)c1cc(F)ccc1F
Product: Nc1sc(-c2cc(F)ccc2F)nc1C(=O)Nc1cnn(C2CC2)c1N1CCNCC(F)(F)C1
Yield: 42 %

Procedure:
Following the procedure for Example 105, tert-butyl 4-(4-(2-bromo-5-(tert-butoxycarbonylamino)thiazole-4-carboxamido)-1-cyclopropyl-1H-pyrazol-5-yl)-6,6-difluoro-1,4-diazepane-1-carboxylate and 2,5-difluoro-phenylboronic acid was reacted to give 143 as a beige foam (60 mg, 42% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.92 (s, 1H), 7.92-7.84 (m, 2H), 7.17-7.08 (m, 1H), 7.07-6.99 (m, 1H), 6.15 (s, 2H), 3.68 (t, J=13.2 Hz, 2H), 3.52-3.32 (m, 5H), 3.11 (t, J=5.4 Hz, 2H), 1.95 (s, 1H), 1.26-1.20 (m, 2H), 1.08-1.00 (m, 2H). LCMS (ES+) m/z 496 (M+1).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].C(N(CC)CC)C.Cl[CH2:18][CH2:19][S:20]([F:23])(=[O:22])=[O:21]>C1C=CC=CC=1>[F:23][S:20]([CH2:19][CH2:18][N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:22])=[O:21]
Reactant: O=S(=O)(F)CCCl
Reactant: CCNc1ccccc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCN(CCS(=O)(=O)F)c1ccccc1

Procedure:
N-Ethylaniline (48.4 g 0.4 m), triethylamine (40.4 g 0.4 m) and benzene (100 ml) are stirred together at room temperature and 2-chloroethanesulfonyl fluoride (58.6 g, 0.4 m) is added dropwise. The reaction mixture is heated at reflux for 1.5 hr. after the addition is completed. The reaction mixture is cooled and filtered to remove any insoluble salts, and the benzene is removed by distillation. The crude product is drowned into hexane (150 ml) and purified by filtration and washing with hexane. The product melts at 48°-50° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[N:16]([CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([Cl:27])[CH:21]=3)[N:19]=2)([OH:14])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:33].CO>C(Cl)Cl>[ClH:27].[ClH:33].[Cl:27][C:22]1[CH:21]=[C:20]([C:18]2[N:19]=[C:15]([C:11]3([OH:14])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[N:16]([CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[CH:17]=2)[CH:25]=[CH:24][C:23]=1[F:26]
Reactant: CN(C)CCn1cc(-c2ccc(F)c(Cl)c2)nc1C1(O)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CN(C)CCn1cc(-c2ccc(F)c(Cl)c2)nc1C1(O)CCNCC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Dissolve 4-[4-(3-chloro-4-fluoro-phenyl)-1-(2-dimethylamino-ethyl)-1H-imidazol-2-yl]-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (1.00 equiv; 1.68 mmol; 785.00 mg) in 5 mL DCM and slowly add hydrogen chloride (24.00 mmol; 6.00 mL of 4M in dioxane) at RT. After 5 min, the solution becomes cloudy then an oily white solid comes out of solution. Add 2 mL methanol to get the solid back in solution. At 30 min, HPLC shows 25% starting material. Add 1 mL additional HCl solution. After total of 2 h stirring at RT, concentrate under vacuum. Re-dissolve in DCM and evaporate under vacuum to a white solid; Dry the white solid in a vacuum oven at 45° C. to 900 mg of the title compound. ES(MS): (m/z)=367.0 (M+H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1.[CH:14]1([Mg]Br)[CH2:16][CH2:15]1.C1(C(C2C=CC(Cl)=CC=2)(O)C)CC1>O1CCCC1>[CH:14]1([C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:12])[F:13])=[CH:8][CH:7]=2)([OH:11])[CH3:10])[CH2:16][CH2:15]1
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Reactant: Br[Mg]C1CC1
Agent: CC(O)(c1ccc(Cl)cc1)C1CC1
Solvent: C1CCOC1
Product: CC(O)(c1ccc(C(F)(F)F)cc1)C1CC1

Procedure:
The title compound was prepared starting from 1.50 g (7.97 mmol) of 4′-(trifluoromethyl)acetophenone and 31.9 ml (15.95 mmol) of a 0.5N solution of cyclopropylmagnesium bromide in tetrahydrofuran in analogy to the synthesis of the compound from Example 138A. 1.27 g (69% of theory) of the title compound were obtained.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[C:9]([NH:12][C:13]1[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][C:14]=1[CH2:15]Br)(=[O:11])[CH3:10]>C(Cl)(Cl)(Cl)Cl>[C:9]([NH:12][C:13]1[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][C:14]=1[CH2:15][N:2]([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)[CH3:1])(=[O:11])[CH3:10]
Reactant: CC(=O)Nc1ccc(C(C)(C)C)cc1CBr
Reactant: CNC1CCCCC1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)Nc1ccc(C(C)(C)C)cc1CN(C)C1CCCCC1

Procedure:
24 gm of N-methyl-cyclohexylamine were added to 23 gm of 2-acetylamino-5-tert.butyl-benzylbromide in 1.6 liters of carbon tetrachloride, and the mixture was refluxed for 1 hour. After cooling, the precipitated N-methyl-cyclohexylamine hydrobromide was filtered off, the filtrate was evaporated, and the crude product was purified chromatographically on silicagel with ethyl acetate. The corresponding fractions were combined and evaporated, and the 2-acetylamino-5-tert.butyl-N-cyclohexyl-N-methyl-benzylamine thus obtained was recrystallized from petroleum ether, whereupon it had a melting point of 111°-112.5°C.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH:16]([OH:19])[CH2:17][OH:18])=[O:13].C1(C)C=CC=CC=1.C(C(C)=[O:30])C>C(O)(C)C>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH:16]([OH:19])[CH2:17][OH:18])=[O:13].[C:12]([OH:14])(=[O:13])[C:11]1[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:30]
Reactant: CCC(C)=O
Agent: CCCCCCCCCCCC(=O)OCC(O)CO
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: O=C(O)c1ccccc1O
Yield: 10 %

Procedure:
A fluid solution of 20.0% Lauricidin, 10.0% salicylic acid, and 10.0% DOSS surfactant in isopropanol was prepared by stirring the mixture until the Lauricidin was dissolved. 20% of the fluid solution was combined with 80% of the hardcoat mixture described in Examples 1-11 (i.e., 100 parts of 3M 906 Hardcoat with 12 parts toluene and 12 parts methyl ethyl ketone). The combined solution was coated and cured as described in Examples 1-11. The resulting multi-layer film was clear and transparent. The resulting multi-layer film was then tested for microbial load reduction, as described above in Examples 1-11, and gave 100% microbial load reduction for gram positive pathogens and 99.4% microbial load reduction for gram negative pathogens.