Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(O)[CH2:4][CH2:3]1.[OH-].[Na+]>C(O)=O.CS(C)=O.O>[CH3:1][N:2]1[CH2:3][CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:6][CH2:7]1
Reactant: CN1CCC(O)(c2ccccc2Cc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=CO
Solvent: CS(C)=O
Product: CN1CC=C(c2ccccc2Cc2ccccc2)CC1
Reaction time: 16 h

Procedure:
A solution of 8.0 g of 1-methyl-4-(α-phenyl-2-tolyl)-4-piperidinol, Example 1, in 100 ml of 97% formic acid is refluxed with stirring for 16 hours. The solution is poured into 300 ml of water, made strongly basic with a 50% sodium hydroxide solution and the basic mixture extracted thrice with 100 ml of portions of chloroform. The combined chloroform extracts are dried and the chloroform removed leaving an oil. The oil is dissolved in 20 ml of dimethylsulfoxide. The solution is diluted with 250 ml of water leaving a cream colored solid which is recrystallized from dimethylsulfoxide to give colorless crystals, mp 55°-57.5° C. of 1-methyl-4-(α-phenyl-2-tolyl)-1,2,3,6-tetrahydropyridine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:15]([C:17]1([OH:25])[CH:22]2[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]2)[CH2:18]1)#[CH:16].C(N(CC)CC)C>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[OH:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:16]#[C:15][C:17]3([OH:25])[CH:22]4[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]4)[CH2:18]3)=[CH:3][CH:4]=2)=[CH:9][CH:10]=1
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Reactant: C#CC1(O)CN2CCC1CC2
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Oc1ccc(-c2ccc(C#CC3(O)CN4CCC3CC4)cc2)cc1
Temperature: 70 °C
Reaction time: 4 h
Yield: 23 %

Procedure:
A mixture of 4-bromo-4'-hydroxybiphenyl (747 mg), 3-ethynyl-3-hydroxyquinuclidine (453 mg), bis(triphenylphosphine)-palladium (II) chloride (105 mg), copper (I) iodide (55 mg) and dry triethylamine (5.0 ml) in dry dimethylformamide (10 ml) was stirred at 70° C. under an atmosphere of argon for 4 hours. The reaction mixture was cooled and the dimethylformamide and triethylamine were removed by evaporation. The residue was purified by flash column chromatography on alumina (ICN--Alumina N32-63) using a gradient of 10% methanol in ethyl acetate to 20% methanol in ethyl acetate as eluent to give 3-[(4'-hydroxybiphenyl-4-yl)ethynyl]quinuclidin-3-ol (220 mg) as a solid, m.p. 230°-233° C.; microanalysis, found C, 76.7; H, 6.6, N, 4.4%; C21H21NO2.0.5H2O requires C, 76.8; H, 6.7; N, 4.26%; NMR (DMSO-d6): 1.2-1.42(1H, m), 1.5-1.72(1H, m), 1.8-2.0(3H, m), 2.65-2.8(4H, t), 2.8-3.2(2H, d of d), 5.6-5.7(1H, br), 6.8-6.9(2H, d) and 7.48-7.63(6H, m); m/z 320 (M+H).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[NH2:21][C:22]1[CH:23]=[C:24]([CH:30]=[CH:31][C:32]=1[F:33])[C:25]([O:27][CH2:28][CH3:29])=[O:26]>>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:20]=[CH:19][C:16]([CH2:17][NH:21][C:22]3[CH:23]=[C:24]([CH:30]=[CH:31][C:32]=3[F:33])[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)c1ccc(F)c(N)c1
Reactant: CCCCc1ccc(C=Cc2ccc(C=O)cc2)cc1
Product: CCCCc1ccc(C#Cc2ccc(CNc3cc(C(=O)OCC)ccc3F)cc2)cc1

Procedure:
The titled compound was prepared following the procedure A using 4-[(4-butylphenyl)ethenyl]benzaldehyde and ethyl 3-amino-4-fluorobenzoate as a pale yellow oil (61%). 1H NMR (CDCl3, 300 MHz) δ 7.49 (d, J=8.3 Hz, 2H), 7.42 (d, J=7.9 Hz, 2H), 7.35 (m, 4H), 7.14 (d, J=7.9 Hz, 2H), 7.00 (dd, J=11.0, 8.7 Hz, 1H), 4.41 (brs, 2H), 4.30 (q, J=7.2 Hz, 2H), 2.60 (t, J=7.7 Hz, 2H), 1.69-1.53 (m, 4H), 1.34 (t, J=7.2 Hz, 3H), 0.91 (t, J=7.4 Hz, 3H). HPLC, Rt: 5.87 min (Purity: 94.3%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@:6]1([NH:11][C:12]([C@@H:14]2[CH2:18][C@@H:17]([OH:19])[CH2:16][N:15]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:13])[CH2:8][C@H:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2].C(N(C(C)C)CC)(C)C.[N+:36]([C:39]1[CH:47]=[CH:46][C:42]([C:43](Cl)=[O:44])=[CH:41][CH:40]=1)([O-:38])=[O:37]>CN(C)C1C=CN=CC=1.CCOC(C)=O>[CH2:1]([O:3][C:4]([C@@:6]1([NH:11][C:12]([C@@H:14]2[CH2:18][C@@H:17]([O:19][C:43](=[O:44])[C:42]3[CH:41]=[CH:40][C:39]([N+:36]([O-:38])=[O:37])=[CH:47][CH:46]=3)[CH2:16][N:15]2[C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])=[O:13])[CH2:8][C@H:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C)C(=O)OCC
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)CN1C(=O)OC(C)(C)C)C(=O)OCC
Temperature: 5 °C
Reaction time: 2.5 h

Procedure:
To a stirring slurry of (2S,4R)-tert-butyl 2-((1R,2S)-1-(ethoxycarbonyl)-2-vinylcyclopropylcarbamoyl)-4-hydroxypyrrolidine-1-carboxylate (1.69 kg), 4-dimethylaminopyridine (28.0 g), diisopropylethylamine (946 g) and EtOAc (4.82 kg), at 10° C., was added p-nitrobenzoyl chloride (1.06 kg) as a solution in EtOAc (3.48 kg). After 2.5 h at 10° C., the reaction was cooled to 5° C. and quench by the addition of water (1.85 kg). The resulting layers were separated and the organic layer was washed with a 1.0 N aqueous solution of HCl (3.75 kg), 10% aqueous solution of KHCO3 (2×2.8 kg), water (3.1 kg), and a 10% aqueous solution of NaCl (3.1 kg). The organic layer was washed again with a 1.0 N aqueous solution of HCl (1.88 kg), 10% aqueous solution of KHCO3 (4.2 kg), H2O (1.5 kg), and a 10% aqueous solution of NaCl (2×755 g). The organic layer was concentrated under reduced pressure, diluted with EtOAc (5.6 kg), and then concentrated again. The resulting oil was diluted with EtOAc (10.0 kg), filtered, and then concentrated. EtOAc (10.0 kg) was added and then the resulting solution was concentrated to a mass of 7.9 kg. The assay yield was determined on the product-containing solution to be 98%.
Reaction SMILES: [S:1]1[CH2:6][CH:5]=[C:4]([C:7]2[NH:24][C:10]3[N:11]=[CH:12][N:13]=[C:14]([C:15]4[C:16]([CH3:23])=[C:17]([NH2:22])[CH:18]=[C:19]([F:21])[CH:20]=4)[C:9]=3[CH:8]=2)[CH2:3][CH2:2]1.CN(C)[C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1.[C:37](C1C=CC=CC=1C(Cl)=O)([CH3:40])([CH3:39])[CH3:38]>>[C:37]([C:27]1[CH:35]=[CH:34][C:30]([C:31]([NH:22][C:17]2[CH:18]=[C:19]([F:21])[CH:20]=[C:15]([C:14]3[C:9]4[CH:8]=[C:7]([C:4]5[CH2:5][CH2:6][S:1][CH2:2][CH:3]=5)[NH:24][C:10]=4[N:11]=[CH:12][N:13]=3)[C:16]=2[CH3:23])=[O:32])=[CH:29][CH:28]=1)([CH3:40])([CH3:39])[CH3:38]
Reactant: Cc1c(N)cc(F)cc1-c1ncnc2[nH]c(C3=CCSCC3)cc12
Reactant: CN(C)c1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)c1ccccc1C(=O)Cl
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cc(F)cc1-c1ncnc2[nH]c(C3=CCSCC3)cc12

Procedure:
Example 24 was prepared analogue to Example 15 by replacing Intermediate 6 with Intermediate 16 and 4-dimethyaminobenzoyl chloride with tert-butylbenzoyl chloride.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:21][CH2:22][CH3:23])=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]([O:18]CC)=[O:17])=[CH:5]2.O.[OH-].[Li+].C(O)C>C1COCC1.O>[Cl:1][C:2]1[C:3]([O:21][CH2:22][CH3:23])=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]([F:15])([F:13])[F:14])[C:6]([C:16]([OH:18])=[O:17])=[CH:5]2
Reactant: CCOC(=O)C1=Cc2c(ccc(Cl)c2OCC)OC1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CCOc1c(Cl)ccc2c1C=C(C(=O)O)C(C(F)(F)F)O2
Temperature: 80 °C
Yield: 40 %

Procedure:
To the solution of ethyl 6-chloro-5-ethoxy-2-(trifluoromethyl)-2H-chromene-3-carboxylate (300mg, 0.93 mmol) in 3 mL of THF was added a solution of lithium hydroxide hydrate (156 mg, 3.7 mmol) in 4 mL of water, followed by addition of 3 mL of ethanol. The resulting solution was heated to 80° C. for four hrs. After removing the solvent, the residue was acidified at 0° C. with ice-cold dilute hydrochloric acid. The product was extracted with EtOAc. After removing the solvents, the residue was purified on reverse phase HPLC. The product was obtained as white solid (120 mg). LC-MS (ES+) 323.2(M+1, 100). 1H NMR (CDCl3/400 MHz) 8.11(s, 1H), 7.32(d, J=8.8 Hz, 1H), 6.73(d, J=8.4 Hz, 1H), 5.65(q, J=6.8 Hz, 1H), 4.12(m, 2H), 1.44(t, J=7.2 Hz, 3H). 19F NMR(CDCl3/400 MHz) −78.81(d, J=6.8 Hz). 13C NMR(CDCl3/400 MHz) 169.5, 153.5, 152.8, 134.9, 134.3, 123.4(q, J=285.8 Hz), 121.3, 115.8, 115.5, 112.8, 71.6, 70.2(q, J=33.4 Hz), 15.5. HRMS (EI+) m/z calc. For (C13H10ClF3O4) 322.0220 (M+), found:322.0223.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)=[CH:3][CH:2]=1.[C:16]1([C:22]2[N:23]=[C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[S:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:16]1([C:22]2[N:23]=[C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:8]([NH:7][C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)=[O:15])[CH2:29][CH2:28]3)[S:25][CH:26]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(Nc1ccncc1)OCC(Cl)(Cl)Cl
Reactant: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(Nc1ccncc1)N1CCN(c2nc(-c3ccccc3)cs2)CC1
Yield: 19.3 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl pyridin-4-ylcarbamate (360 mg, 1.33 mmol), 1-(4-phenyl-1,3-thiazol-2-yl)piperazine (360 mg, 1.47 mmol) and diisopropylethylamine (0.256 ml, 1.47 mmol) in dimethyl sulfoxide (4.4 ml) was stirred at 70° C. for 8 hours. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from a mixed solvent of hexane and ethyl acetate to give 93.7 mg (19.2%) of the desired product as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][CH2:37][CH3:38])[N:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][CH2:37][CH3:38])[N:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: CCCOc1cccc(Br)n1
Product: CCCOc1cccc(Nc2c(C)noc2-c2ccc(-c3ccc(C4(C(=O)OCC)CC4)cc3)cc2)n1

Procedure:
Prepared according to the procedure described in Example 290, Step 1, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-6-propoxy-pyridine.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([F:10])[C:8]=1[CH3:9])#[CH:2].Br[C:12]1[C:13]([CH:19]=[O:20])=[CH:14][C:15]([Cl:18])=[N:16][CH:17]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1.C(OCC)(=O)C.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>[Cl:18][C:15]1[CH:14]=[C:13]([C:12]([C:2]#[C:1][C:3]2[CH:4]=[N:5][CH:6]=[C:7]([F:10])[C:8]=2[CH3:9])=[CH:17][N:16]=1)[CH:19]=[O:20]
Reactant: O=Cc1cc(Cl)ncc1Br
Reactant: C#Cc1cncc(F)c1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(F)cncc1C#Cc1cnc(Cl)cc1C=O
Temperature: 60 °C
Yield: 77.7 %

Procedure:
A mixture of 3-ethynyl-5-fluoro-4-methyl-pyridine (240 mg, 1.78 mmol), 5-bromo-2-chloro-pyridine-4-carbaldehyde (392 mg, 1.78 mmol), N,N-diisopropylethylamine (0.62 mL, 3.55 mmol), dichlorobis(triphenylphosphine)palladium(II) (64 mg, 0.089 mmol), and cuprous iodide (17 mg, 0.089 mmol) in dioxane (5 mL) was heated at 60° C. for 1 hour. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (50 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo to provide a residue that was purified by flash chromatography (12 g, Silica, 0-70% ethyl acetate in heptane). Desired fractions were combined and evaporated in vacuo to afford the title compound as a pale yellow solid (380 mg, 78%), which was used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:6][C:5]=1[O:16][CH:17]([CH3:19])[CH3:18])([O-:3])=[O:2].[I:20][CH2:21][CH2:22][OH:23].C(OCC)C>C(#N)C>[I-:20].[OH:23][CH2:22][CH2:21][N+:13]1[CH:12]=[CH:11][C:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([O:16][CH:17]([CH3:19])[CH3:18])[CH:6]=2)=[CH:15][CH:14]=1
Reactant: CC(C)Oc1cc(-c2ccncc2)ccc1[N+](=O)[O-]
Reactant: OCCI
Solvent: CC#N
Solvent: CCOCC
Product: CC(C)Oc1cc(-c2cc[n+](CCO)cc2)ccc1[N+](=O)[O-]
Product: [I-]
Temperature: 85 °C
Reaction time: 15 h

Procedure:
A mixture of 100 mg of 4-[4-nitro-3-(propan-2-yloxy)phenyl]pyridine (see method 1) and 0.075 ml of 2-iodoethanol in 1.7 ml of acetonitrile is heated at 85° C. (bath) for 1 h. 75 μl of 2-iodoethanol are then added and the heating is continued for 15 h at 91° C. The mixture is then concentrated under vacuum, so as to obtain a solid which is taken up with 10 ml of ethyl ether. The resulting heterogeneous mixture is filtered and the solid is rinsed with ethyl ether and dried under reduced pressure, so as to obtain 147 mg of 1-(2-hydroxyethyl)-4-[4-nitro-3-(propan-2-yloxy)phenyl]pyridinium iodide in the form of a solid. 44 g of sodium borohydride are added, at a temperature of about 0° C. (ice/water bath) to a solution of 0.142 g of 1-(2-hydroxyethyl)-4-[4-nitro-3-(propan-2-yloxy)phenyl]pyridinium iodide in 2.6 ml of methanol. After 30 minutes, a few drops of water are added and the mixture is left to return to ambient temperature. The mixture is concentrated to dryness under reduced pressure and then diluted with 150 ml of ethyl acetate. The organic phase is washed successively with 120 ml of a saturated sodium hydrogen carbonate solution and then 70 ml of a saturated sodium chloride solution. The organic phase is dried over anhydrous magnesium sulfate, filtered and then concentrated to dryness under reduced pressure, so as to obtain 90 mg of 2-{4-[4-nitro-3-(propan-2-yloxy)phenyl]-3,6-dihydropyridin-1(2H)-yl}ethanol.
Reaction SMILES: [CH2:1]([O:17][CH2:18][C:19](=[CH2:31])[CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][S:27]([CH3:30])(=[O:29])=[O:28])[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][CH3:16].[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH3:30][S:27]([O-:29])(=[O:28])=[O:26].[CH2:1]([O:17][CH2:18][C:19](=[CH2:31])[CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][N+:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=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][CH3:16]
Reactant: C=C(COCCCCCCCCCCCCCCCC)COCCCCOS(C)(=O)=O
Reactant: c1ccncc1
Product: C=C(COCCCCCCCCCCCCCCCC)COCCCC[n+]1ccccc1
Product: CS(=O)(=O)[O-]

Procedure:
1-Hexadecyloxy-3-[4-(methanesulfonyloxy)butoxy]-2-methylenepropane (from Preparation 7) (1.6 g) was heated with dry pyridine (50 ml) at 50° C. for 28 hours. Excess pyridine was removed in vacuo. The product was recrystallized from chloroform/acetone.
Reaction SMILES: [CH:1]1([CH:4]([O:6][C:7]([N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][C:11]([OH:13])=O)=[O:8])[CH3:5])[CH2:3][CH2:2]1.C([N:22](CC)CC)C.ClC(OCC)=O.Cl.[CH3:34][CH:35]1[CH:40]=[C:39]([C:41]([O:43][CH2:44][C:45]([Cl:48])([Cl:47])[Cl:46])=[O:42])[N:38]2[C:49](=[O:52])[CH:50](N)[C@H:37]2[S:36]1>CN(C)CC1C=CC=CC=1.ClCCl>[CH3:34][C:35]1([NH2:22])[CH:40]=[C:39]([C:41]([O:43][CH2:44][C:45]([Cl:48])([Cl:47])[Cl:46])=[O:42])[N:38]2[C:49](=[O:52])[CH:50]([C:11](=[O:13])[CH2:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]([O:6][CH:4]([CH:1]3[CH2:2][CH2:3]3)[CH3:5])=[O:8])[C@H:37]2[S:36]1
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(N)[C@H]2S1
Reactant: CCN(CC)CC
Reactant: CC(OC(=O)N(CC(=O)O)c1ccccc1)C1CC1
Agent: CCOC(=O)Cl
Agent: CN(C)Cc1ccccc1
Agent: Cl
Solvent: ClCCl
Product: CC(OC(=O)N(CC(=O)C1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=CC(C)(N)S[C@H]12)c1ccccc1)C1CC1
Reaction time: 1 h
Yield: 88.2 %

Procedure:
A solution of N-(1-cyclopropylethoxycarbonyl)-phenylglycine (1.63 g), triethylamine (0.60 g) and dimethylbenzylamine (2 drops) in dried dichloromethane (10 ml) was dropwise added at -10° C. to a solution of ethyl chloroformate (0.67 g) in dried dichloromethane (15 ml), and the mixture was stirred for 1 hour. The mixture was cooled at -10° to 15° C. and to the mixture was dropwise added over 10 minutes a solution of 2,2,2-trichloroethyl 2-methyl-7-amino-3-cephem-4-carboxylate hydrochloride (2.2 g) and triethylamine (0.55 g) in dried dichloromethane (20 ml), after which the mixture was stirred for 2.5 hours at the same temperature. After the reaction, the reaction mixture was in turn washed with water, 2% hydrochloric acid, a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution and then dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was pulverized by adding isopropyl ether, after which the powder was collected by filtration and dried to give 2,2,2-trichloroethyl 2-methyl-7-[N-(1-cyclopropylethoxy)carbonylphenylglycyl]-amino-3-cephem-4-carboxylate (3.0 g), mp 165° to 167.5° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8]C(=O)C)=[CH:4][CH:3]=1.CC1C=C(N2CCNCC2)C=CC=1.C(=O)([O-])[O-].[K+].[K+].[Cl:31]C(Cl)Cl>O>[ClH:1].[ClH:31].[N:7]1[CH:2]=[CH:3][CH:4]=[C:5]([NH2:8])[N:6]=1
Reactant: CC(=O)Nc1ccc(Cl)nn1
Reactant: ClC(Cl)Cl
Agent: Cc1cccc(N2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cl
Product: Nc1cccnn1

Procedure:
A mixture of 3.5 parts of N-(6-chloro-3-pyridazinyl)acetamide, 3.6 parts of 1-(3-methylphenyl)piperazine and 2.8 parts of potassium carbonate was stirred for 7 hours 1n an oil bath at 160° C. After cooling, trichloromethane and water were added. The layers were separated. The organic layer was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent. The second fraction was collected and the eluent was evaporated. The residue was converted into the hydrochloride salt in 2-propanol and 2-propanone. The salt was filtered off and dried, yielding 0.5 parts (6.6%) of 6-4-(3-methylphenyl)-1-piperazinyl]-3-pyridazinamine dihydrochloride; mp. 178.5° C. (compound 220).
Reaction SMILES: [F:1][C:2]([Si](C)(C)C)([F:4])[F:3].[F:9][CH:10]([F:34])[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]2[CH:19]=[C:20]([C:25]3[CH:26]=[N:27][N:28]([CH2:30][C:31](=[O:33])[CH3:32])[CH:29]=3)[CH:21]=[C:22]([CH3:24])[CH:23]=2)[N:12]=1.[F-].[Cs+].Cl>C1COCC1.CS(C)=O.O>[F:34][CH:10]([F:9])[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]2[CH:19]=[C:20]([C:25]3[CH:26]=[N:27][N:28]([CH2:30][C:31]([CH3:32])([OH:33])[C:2]([F:4])([F:3])[F:1])[CH:29]=3)[CH:21]=[C:22]([CH3:24])[CH:23]=2)[N:12]=1
Reactant: CC(=O)Cn1cc(-c2cc(C)cc(Nc3nccc(C(F)F)n3)c2)cn1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: Cl
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Cc1cc(Nc2nccc(C(F)F)n2)cc(-c2cnn(CC(C)(O)C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(Trifluoromethyl)trimethylsilane (0.103 ml, 0.70 mmol) was added to a 20° C. solution of 1-(4-(3-((4-(difluoromethyl)pyrimidin-2-yl)amino)-5-methylphenyl)-1H-pyrazol-1-yl)propan-2-one (100 mg, 0.28 mmol) and cesium fluoride (4.3 mg, 0.028 mmol) in THF (1 mL). The reaction was allowed to stir for 60 minutes at room temperature and additional cesium fluoride (4.25 mg, 0.03 mmol) and (trifluoromethyl)trimethylsilane (0.103 ml, 0.70 mmol) were then added. The reaction was stirred for 18 hours and filtered through a plug of glass wool. The filtrate was treated with hydrochloric acid (6N, 1 mL, 6 mmol) and stirred for 30 minutes. The reaction was concentrated under reduced pressure to afford the crude product residue. The crude product residue was dissolved in DMSO/water and purified by mass triggered reverse phase HPLC (ACN/water+0.1% TFA) to afford racemic 3-(4-(3-((4-(difluoromethyl)pyrimidin-2-yl)amino)-5-methylphenyl)-1H-pyrazol-1-yl)-1,1,1-trifluoro-2-methylpropan-2-ol. MS ESI calcd. for C19H19F5N5O [M+H]+ 428. found 428. The racemic mixture was purified by chiral SFC (Chiralpak, IA, 21×250 (mm), 70 mL/min, 25% Methanol/CO2) to afford (S or R)-3-(4-(3-((4-(difluoromethyl)pyrimidin-2-yl)amino)-5-methylphenyl)-1H-pyrazol-1-yl)-1,1,1-trifluoro-2-methylpropan-2-ol
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[CH:12]1[C:21]2[C:20](=[O:22])[CH2:19][CH2:18][CH2:17][C:16]=2[N:15]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[C:14](=[O:33])[NH:13]1)[C:7]#[N:8].[CH3:34][S:35](Cl)(=[O:37])=[O:36].O>O1CCCC1>[Cl:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[CH:12]1[C:21]2[C:20](=[O:22])[CH2:19][CH2:18][CH2:17][C:16]=2[N:15]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:31])([F:32])[F:30])[CH:24]=2)[C:14](=[O:33])[N:13]1[S:35]([CH3:34])(=[O:37])=[O:36])[C:7]#[N:8]
Reactant: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CCC3)c(Cl)c1
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Sodium hydride (60% in mineral oil, 14 mg, 0.36 mmol) is added to a solution of 3-chloro-4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4,5,6,7,8-octahydroquinazolin-4-yl)-benzonitrile (example 56, 60 mg, 0.13 mmol) in tetrahydrofuran (3 mL), and the mixture is stirred at room temperature for 20 min. Methanesulfonyl chloride (21 μL, 0.27 mmol) is added, and the mixture is stirred at room temperature over night. Water is added, and the mixture is extracted with dichloromethane. The phases are separated, and the organic phase is concentrated under reduced pressure. The residue is purified by preparative HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 40 mg; ESI mass spectrum [M+H]+=524; Retention time HPLC: 0.70 min (X012_S01).
Reaction SMILES: [C:1]([C:3]1[C:7]([C:8]#[CH:9])=[CH:6][N:5]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][C:11]=2[Cl:21])[N:4]=1)#[N:2].[Br:22]N1C(=O)CCC1=O.CCOCC.O>CC(C)=O.[N+]([O-])([O-])=O.[Ag+]>[Br:22][C:9]#[C:8][C:7]1[C:3]([C:1]#[N:2])=[N:4][N:5]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([C:17]([F:20])([F:18])[F:19])=[CH:12][C:11]=2[Cl:21])[CH:6]=1
Reactant: C#Cc1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C#N
Reactant: O=C1CCC(=O)N1Br
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CC(C)=O
Solvent: O
Solvent: CCOCC
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C#CBr
Reaction time: 1 h

Procedure:
To a stirred solution of 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-ethynylpyrazole (100 mg, the compound of Example C5) in acetone (5 ml) was added N-bromosuccinimide (54.9 mg) and silver nitrate (5 mg). Stirring was continued at room temperature for 60 minutes. The reaction mixture was then poured into ether (10 ml) and water (10 ml). The organic layer was separated, dried (MgSO4) and evaporated. The residue was purified by column chromatography on silica gel eluted with dichloromethane: hexane (2: 1) to provide the title compound as a white solid m.p. 166-8° C.