Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[N:9]([CH2:12][C@H:13]([O:56][Si](CC)(CC)CC)[CH2:14][N+:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([C:23]2[N:24]=[CH:25][N:26]3[CH:30]=[C:29]([C:31]4[C@H:32]([CH3:55])[C@@H:33]5[C@@H:50]([C@H:51]([OH:53])[CH3:52])[C:49](=[O:54])[N:34]5[C:35]=4[C:36]([O:38]CC4C=CC([N+]([O-])=O)=CC=4)=[O:37])[S:28][C:27]=23)=[O:22])[CH:16]=1)=[N+]=[N-].O.Cl.C(=O)([O-])O.[Na+]>C1COCC1>[NH2:9][CH2:12][C@@H:13]([OH:56])[CH2:14][N+:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([C:23]2[N:24]=[CH:25][N:26]3[CH:30]=[C:29]([C:31]4[C@H:32]([CH3:55])[C@@H:33]5[C@@H:50]([C@H:51]([OH:53])[CH3:52])[C:49](=[O:54])[N:34]5[C:35]=4[C:36]([O-:38])=[O:37])[S:28][C:27]=23)=[O:22])[CH:16]=1
Reactant: CC[Si](CC)(CC)O[C@@H](CN=[N+]=[N-])C[n+]1cccc(C(=O)c2ncn3cc(C4=C(C(=O)OCc5ccc([N+](=O)[O-])cc5)N5C(=O)[C@H]([C@@H](C)O)[C@H]5[C@H]4C)sc23)c1
Agent: Cl
Agent: O=C([O-])O
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3cn4cnc(C(=O)c5ccc[n+](C[C@H](O)CN)c5)c4s3)[C@H](C)[C@H]12
Reaction time: 24 h

Procedure:
The crude product (398 mg) of 4-nitrobenzyl (1S,5R,6S)-2-[7-[1-((2R)-3-azido-2-triethylsilyloxypropyl)pyridinium-3-yl]carbonylimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate trifluoromethanesulfonate was dissolved in 12 ml of THF and 12 ml of water to prepare a solution. The solution was adjusted to pH 2.2 by the addition of 1 N hydrochloric acid and was stirred for 24 hr. The solution was adjusted to pH 5 by the addition of a 5% aqueous sodium hydrogencarbonate solution, and a reaction was then carried out in the same manner as in step b) of Example 4. Thus, 56 mg of the title compound was prepared.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[CH:10]=[N:9]2)[CH:5]=[CH:4][C:3]=1[C:16]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)([CH3:19])[C:17]#[N:18]>[Zn].C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[CH2:10][NH:9]2)[CH:5]=[CH:4][C:3]=1[C:16]([C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1)([CH3:19])[C:17]#[N:18]
Reactant: CC(C#N)(c1ccc(F)cc1)c1ccc(-n2ncc(=O)[nH]c2=O)cc1Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: CC(C#N)(c1ccc(F)cc1)c1ccc(N2NCC(=O)NC2=O)cc1Cl
Reaction time: 3 h
Yield: 53.6 %

Procedure:
To a stirred and refluxed mixture of 1.5 parts of 2-chloro-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)-α-(4-fluorophenyl)-α-methylbenzeneacetonitrile and 75 parts of acetic acid were added portionwise 3 parts of zinc during a period of 30 minutes. Upon complete addition, stirring was continued for 3 hours at reflux. The reaction mixture was filtered while hot and the filtrate was concentrated in vacuo to 10 parts of its volume. Water was added to the concentrate. The precipitated product was filtered off and purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated in vacuo. The residue was crystallized from acetonitrile. The product was filtered off, washed with 2,2'-oxybispropane and dried, yielding 0.8 parts (53.6%) of 2-chloro-α-(4-fluorophenyl)-α-methyl-4-(3,4,5,6-tetrahydro-3,5-dioxo-1,2,4-triazin-2(1H)-yl)benzeneacetonitrile; mp. 122.5° C. (compound 2).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.O.[NH2:15][NH2:16]>C(O)C>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][C:10](=[N:15][NH2:16])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1
Reactant: O=C1CCN(c2ccncc2)CC1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NN=C1CCN(c2ccncc2)CC1

Procedure:
A solution of 1-(4-pyridyl)-4-piperidone (3.52 g) and hydrazine hydrate (1.25 q) in ethanol (50 ml) was stirred at room temperature for 15 hours. The reaction mixture was concentrated and the residue obtained was crystallized from ether to obtain [1-(4-pyridyl)-4-piperidinylidene]hydrazine (3.51 g) as colorless crystals.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[N:16][C:15]([C:18]([OH:20])=O)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1.C1C=CC2N(O)N=[N:33]C=2C=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+].C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[F:1][C:2]([F:25])([F:26])[C:3]1[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=1[O:5][CH:6]1[CH2:7][CH2:8][N:9]([C:12]2[N:17]=[N:16][C:15]([C:18]([NH2:33])=[O:20])=[CH:14][CH:13]=2)[CH2:10][CH2:11]1
Reactant: O=C(O)c1ccc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)nn1
Reactant: On1nnc2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)nn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 6-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}pyridazine-3-carboxylic acid (250 mg, 0.7 mmol), HOBt (92 mg, 0.7 mmol), HATU (518 mg, 1.4 mmol) and ammonium chloride (74 mg, 1.4 mmol) in DMF (5 mL) was added N,N-diisopropylethylamine (592 μL, 3.4 mmol) at room temperature. The mixture was stirred at room temperature overnight, diluted with water and extracted with EtOAc. The organic extract was washed twice with 1N NaOH, brine, dried (Na2SO4) and concentrated. CombiFlash chromatography (10 g, 80-100% EtOAc in hexanes, 20 mL/min, 18 mL/fraction) gave the title compound as a white powder. 1H NMR (400 MHz, acetone-d6): δ 1.93-1.99 (m, 2H), 2.14-2.20 (m, 2H), 3.93-4.09 (m, 4H), 5.05 (s, 1H), 6.72 (s, 1H), 7.13 (t, 1H), 7.38 (m, 2H), 7.62-7.68 (m, 2H), 7.84 (s, 1H), 7.94 (d, 1H). MS (+ESI) m/z 367 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]2[CH3:14])[N:5]=[C:4]([NH:15][CH:16]2[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17]2)[C:3]=1[CH2:27][CH2:28]O.CS(Cl)(=O)=O.C1CCN2C(=NCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C.[Cl-].[Na+].O>[Cl:1][C:2]1[C:3]2[CH2:27][CH2:28][N:15]([CH:16]3[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:21])[CH2:17]3)[C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]2[CH3:14])[N:7]=1
Reactant: C[C@H]1COCCN1c1nc(Cl)c(CCO)c(NC2CN(C(=O)OC(C)(C)C)C2)n1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@H]1COCCN1c1nc(Cl)c2c(n1)N(C1CN(C(=O)OC(C)(C)C)C1)CC2
Temperature: 15 °C
Reaction time: 2 h
Yield: 83.4 %

Procedure:
A solution of tert-butyl 3-({6-chloro-5-(2-hydroxyethyl)-2-[(3S)-3-methylmorpholin-4-yl]pyrimidin-4-yl}amino)azetidine-1-carboxylate (0.1 g, 0.234 mmol) in DCM (4 mL) was treated with TEA (0.08 mL, 0.57 mmol) and methanesulfonyl chloride (0.026 mL, 0.34 mmol) at 0° C., followed by addition of a catalytic amount of DMAP. The reaction mixture was stirred for 2 h, letting the ice bath slowly warm to about 15° C. The reaction mixture was partitioned between DCM (2×10 mL) and water (10 mL). The organic layer was dried over MgSO4 and reduced to a minimum volume. The residue was taken up in DMF (5 mL), and DBU (0.13 mL, 0.85 mmol) was added. The resulting mixture was crimp sealed and heated at 75° C. for 4 h. The crude mixture was poured into a brine solution (50 mL) and the resulting white solids were collected by filtration and rinsed with water. The solids were dried in a vacuum oven at 50° C. overnight to provide (80 mg, 83%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 4.74-4.65 (m, 1 H), 4.49-4.41 (m, 1 H), 4.18-3.98 (m, 5 H), 3.84 (dd, J=11.3, 3.4 Hz, 1 H), 3.71 (t, J=8.7 Hz, 2 H), 3.66-3.61 (m, 1 H), 3.51 (dd, J=11.4, 3.1 Hz, 1 H), 3.36 (dt, J=11.8, 3.0 Hz, 1 H), 3.05 (dt, J=12.9, 3.7 Hz, 1 H), 2.85 (t, J=8.3 Hz, 2 H), 1.38 (s, 9 H), 1.13 (d, J=6.7 Hz, 3 H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][CH2:12][C:13]2=[O:18].[BH4-].[Na+].O>O1CCCC1.CO>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][CH2:12][CH:13]2[OH:18]
Reactant: Cc1cccc(C)c1-c1cccc2c1CCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cccc(C)c1-c1cccc2c1CCC2O
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.3 %

Procedure:
4-(2,6-Dimethylphenyl)indan-1-one (2.00 g, 8.47 mmol) was dissolved in a mixture of tetrahydrofuran (20 mL) and methanol (10 mL), sodium borohydride (449 mg, 11.9 mmol) was added, and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5%-60% ethyl acetate/hexane) to give the title compound (1.54 g, yield 76%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=[N:13]O)[CH3:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([NH2:13])[CH3:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C(C)=NO)cc1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(C(C)N)cc1OC
Yield: 213.1 %

Procedure:
3′,4′-Dimethoxyacetophenone oxime (1 gram, 5.1 mmol) was dissolved in 10 milliliters of glacial acetic acid, the solution was flushed with N2 and the palladium on carbon (0.2 grams, 5%) was added. The mixture was treated with 60 psi of H2 in a Parr Type Shaker for 24 hours. The catalyst was filtered off and the filtrate was concentrated to afford a yellow oil which was taken up in water, basified to pH 12 with a saturated solution of sodium carbonate and extracted with methylene chloride. The combined extracts were dried over magnesium sulfate and concentrated to afford 1.97 grams (82%) of product as a yellow oil: 1H NMR (CDCl3) δ7.02-6.75 (m, 3H), 4.08 (q, J1=6.6 Hz, J2=13.1 Hz, 1 H), 3.89 (s, 3H), 3.87 (s, 3H), 1.37 (d , J=6.6 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.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>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:3]=[C:4]([CH3:9])[C:5]([NH2:6])=[CH:7][CH:8]=2)=[CH:13][CH:12]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Cc1cc(Br)ccc1N
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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1cc(-c2ccc(Cl)cc2)ccc1N
Temperature: 80 °C
Yield: 70.8 %

Procedure:
To a stirred, degassed solution of 4-bromo-2-methylaniline (20 g, 0.107 mol) in toluene (1200 ml) and ethanol (400 ml), under an atmosphere of nitrogen, is added 4-chlorophenylboronic acid (20.32 g, 0.13 mol) and the reaction mixture is stirred and heated to 80° C. Tetrakis(triphenylphosphine)palladium(0) (2.48 g, 0.002 mol) is added to the reaction mixture, and to this is added 2M aqueous potassium carbonate solution (160 ml). The reaction mixture is heated at reflux for 4 hours, then cooled to room temperature. The reaction mixture was filtered through diatomaceous earth, and the filtrate was evaporated under reduced pressure. The residue is partitioned between ethyl acetate and water. The aqueous phase is extracted with ethyl acetate (3×500 ml) and the organic extracts are combined and concentrated under reduced pressure to give 4′-chloro-3-methylbiphen-4-ylamine (16.5 g).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]4[NH2:27])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[CH:30]([C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][C:34]=1[N:40]1[C:44](=[O:45])[CH2:43][S:42]/[C:41]/1=[N:46]\[C:47](=O)[O:48]C1C=CC([N+]([O-])=O)=CC=1)([CH3:32])[CH3:31].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH:30]([C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][C:34]=1[N:40]1[C:44](=[O:45])[CH2:43][S:42]/[C:41]/1=[N:46]\[C:47]([NH:27][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26][CH:21]1[C:18]1[CH:19]=[CH:20][C:15]([C:12]2[N:13]=[CH:14][N:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:28])[F:29])=[CH:9][CH:8]=3)[N:11]=2)=[CH:16][CH:17]=1)=[O:48])([CH3:32])[CH3:31]
Reactant: NC1CCCCC1c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: Cc1ccc(C(C)C)c(N2C(=O)CS/C2=N\C(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cc1ccc(C(C)C)c(N2C(=O)CS/C2=N\C(=O)NC2CCCCC2c2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)c1
Temperature: 25 °C
Reaction time: 25 h
Yield: 5.9 %

Procedure:
To 2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)cyclohexanamine (CB56) (0.200 g, 0.497 mmol) and (Z)-4-nitrophenyl (3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)carbamate (CA50) (0.205 g, 0.497 mmol) were dissolved in acetonitrile (10 mL) in a vial. Cesium carbonate (0.162 g, 0.497 mmol) was added, and the reaction was stirred at room temperature for 25 hours. The solution was adsorbed onto silica. Purification by reverse-phase flash column chromatography using 0-100% acetonitrile/water as eluent afforded the title compound as a red oil (0.020 g, 6%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH2:11][CH2:12][C:13](=[O:16])[NH:14][N:15]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[OH:8].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH2:11][CH2:12][C:13](=[O:16])[NH:14][N:15]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[O:8][S:23]([C:20]1[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=1)(=[O:25])=[O:24]
Reactant: O=C1CCC(c2cc(Cl)c(O)c(Cl)c2)=NN1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)Oc2c(Cl)cc(C3=NNC(=O)CC3)cc2Cl)cc1

Procedure:
A mixture of 10 g. of 6-(3,5-dichloro-4-hydroxyphenyl)-4,5-dihydro-3(2H)pyridazinone, 7.6 g. of p-toluenesulfonic chloride, 4 g. of triethylamine and 50 ml. of dimethylformamide was stirred at 50° C. for 8 hours. Then, the reaction mixture was treated in the same manner as in Example 11 and recrystallized from dioxane-petroleum ether to give 3.8 g. of the desired product as prisms of m.p. 208° - 209° C.
Reaction SMILES: C(N(CC)CC)C.Cl.[S:9]1[CH:13]=[CH:12][N:11]=[C:10]1[C:14]1[NH:18][N:17]=[C:16]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[N:15]=1.[CH3:25][C:26]1[N:48]=[C:29]2[N:30]=[C:31]([C:40]3[CH:47]=[CH:46][C:43]([CH:44]=O)=[CH:42][CH:41]=3)[C:32]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:33][N:28]2[N:27]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO.CN(C=O)C.C(O)(=O)C>[CH3:25][C:26]1[N:48]=[C:29]2[N:30]=[C:31]([C:40]3[CH:41]=[CH:42][C:43]([CH2:44][N:22]4[CH2:23][CH2:24][CH:19]([C:16]5[N:15]=[C:14]([C:10]6[S:9][CH:13]=[CH:12][N:11]=6)[NH:18][N:17]=5)[CH2:20][CH2:21]4)=[CH:46][CH:47]=3)[C:32]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[CH:33][N:28]2[N:27]=1
Reactant: c1csc(-c2nc(C3CCNCC3)n[nH]2)n1
Reactant: Cc1nc2nc(-c3ccc(C=O)cc3)c(-c3ccccc3)cn2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1nc2nc(-c3ccc(CN4CCC(c5n[nH]c(-c6nccs6)n5)CC4)cc3)c(-c3ccccc3)cn2n1
Temperature: 25 °C

Procedure:
0.25 ml triethylamine is added to a solution of 225 mg 4-(5-thiazol-2-yl-1H-[1,2,4]triazol-3-yl)-piperidine hydrochloride in 7.6 ml methanol. To this solution a solution of 250 mg 4-(2-methyl-6-phenyl[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)benzaldehyde (prepared as described under example 37) in 7.6 ml DMF is added, followed by 0.11 ml glacial acetic acid and 337 mg NaBH(OAc)3. The resulting mixture is stirred at room temperature. Six additional portions of 2 equivalents NaBH(OAc)3 are added over 3 days. The solvent is removed by evaporation and the residue is purified by chromatography on silica gel (dichloromethane/[dichloromethane+7M NH3 in methanol]) to yield the desired compound.
Reaction SMILES: [C:1]([C:5]1[CH:40]=[CH:39][C:8]([C:9]([N:11]2[C@@H:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@@H:14]([C:22]3[CH:27]=[N:26][CH:25]=[CH:24][N:23]=3)[CH2:13][C@@:12]2([CH2:35][CH:36]([CH3:38])[CH3:37])[C:28]([O:30]C(C)(C)C)=[O:29])=[O:10])=[CH:7][C:6]=1[O:41][CH3:42])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>>[C:1]([C:5]1[CH:40]=[CH:39][C:8]([C:9]([N:11]2[C@@H:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C@@H:14]([C:22]3[CH:27]=[N:26][CH:25]=[CH:24][N:23]=3)[CH2:13][C@@:12]2([CH2:35][CH:36]([CH3:37])[CH3:38])[C:28]([OH:30])=[O:29])=[O:10])=[CH:7][C:6]=1[O:41][CH3:42])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1cc(C(=O)N2[C@@H](c3ccccc3)[C@@H](c3cnccn3)C[C@@]2(CC(C)C)C(=O)OC(C)(C)C)ccc1C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)N2[C@@H](c3ccccc3)[C@@H](c3cnccn3)C[C@@]2(CC(C)C)C(=O)O)ccc1C(C)(C)C

Procedure:
The tert-butyl ester from stage A was deprotected with TFA in a similar manner to that described in Example 1, to afford the title compound as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.[N:11]([C:14]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:15]=1[CH:16]=[C:17]([CH3:24])[N:18]=[CH:19]2)=[C:12]=[O:13].N(C1C=CC=C2C=1C=CN=C2)=C=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:12]([NH:11][C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[CH:16]=[C:17]([CH3:24])[N:18]=[CH:19]3)=[O:13])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@H](N)c1ccc(Br)cc1
Reactant: Cc1cc2c(N=C=O)cccc2cn1
Agent: O=C=Nc1cccc2cnccc12
Product: Cc1cc2c(NC(=O)N[C@@H](C)c3ccc(Br)cc3)cccc2cn1

Procedure:
The title compound was prepared using the procedure described in Example 61B using (1S)-1-(4-bromophenyl)ethanamine and the product from Example 154A instead of 4-cyanobenzyl alcohol and the product from Example 61A.
Reaction SMILES: [CH3:1][C:2]([CH2:8][CH3:9])([CH2:6][CH3:7])[C:3](=[O:5])[CH3:4].[Br:10]Br.[Cl-].[Al+3].[Cl-].[Cl-]>C(OCC)C>[Br:10][CH2:4][C:3](=[O:5])[C:2]([CH3:1])([CH2:8][CH3:9])[CH2:6][CH3:7]
Reactant: CCC(C)(CC)C(C)=O
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: CCC(C)(CC)C(=O)CBr
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 9.0 g of 3-methyl-3-ethyl-2-pentanone in 100 ml diethyl ether cooled to about 0°-5° C. with an ice bath was added 3.6 ml bromine. The reaction mixture was allowed to warm to room temperature and a catalytic amount of aluminum chloride was added. The mixture was stirred for 30 minutes and washed with water and a saturated sodium bicarbonate solution. The organic phase was separated, dried over anhydrous sodium sulfate and evaporated under vacuum to provide an oil. The oil was distilled under vacuum to provide 6.3 g of product. bp=100°-114° C. at 16 mm.
Reaction SMILES: [N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)[N:9]=[C:8]2[CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH2:4][CH2:3][CH2:2]1.Cl[C:29]1[C:34]2[O:35][CH2:36][CH2:37][NH:38][C:33]=2[N:32]=[CH:31][N:30]=1>>[N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=3)[N:9]=[C:8]2[CH:22]2[CH2:23][CH2:24][N:25]([C:29]3[C:34]4[O:35][CH2:36][CH2:37][NH:38][C:33]=4[N:32]=[CH:31][N:30]=3)[CH2:26][CH2:27]2)[CH2:2][CH2:3][CH2:4]1
Reactant: FC(F)(F)c1cc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)ccn1
Reactant: Clc1ncnc2c1OCCN2
Product: FC(F)(F)c1cc(-c2cn(CCN3CCC3)c(C3CCN(c4ncnc5c4OCCN5)CC3)n2)ccn1

Procedure:
The title compound was prepared according to the procedure described for the preparation of A1 by using 4-(1-(2-(azetidin-1-yl)ethyl)-2-(piperidin-4-yl)-1H-imidazol-4-yl)-2-(trifluoromethyl)pyridine coupled with 4-chloro-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine; LC-MS (M+H=515, obsd.=515);
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].C([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][N:31]([CH3:39])[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])(C)(C)C>C1COCC1>[CH3:39][N:31]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[O:30][CH2:29][CH2:28][O:27][CH2:26][CH2:25][OH:24]
Reactant: CN(OCCOCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CN(OCCOCCO)C(=O)OC(C)(C)C

Procedure:
TBAF (6.78 mL, 6.78 mmol) was added to O-{2-[2-(tert-Butyl-diphenyl-silanyloxy)-ethoxy]-ethyl}-N-methyl-N-BOC-hydroxylamine (d) (3 g, 6.33 mmol) dissolved in dry THF (15 mL). The reaction was stirred over night. The THF was evaporated off and the residue was dissolved in DCM and washed with NH4Cl (saturated) (40 mL), water and brine. The organic phase was dried (MgSO4) and evaporated off. The residue was purified using flash chromatography on a Companion Combiflash 40 g column (Gradient MeOH 0-5% over 20 minutes in DCM. Structure confirmed by NMR.
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].CCCCCC.BrC1[CH:33]=[C:32](C)[C:16]([O:17][C:18]2[C:23]([CH3:24])=[C:22]([O:25][CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[CH:21]=[C:20]([CH3:31])[N:19]=2)=[C:15]([CH3:35])[CH:14]=1.C(I)C>C1COCC1>[CH2:4]([C:3]1[CH:2]=[C:32]([CH3:33])[C:16]([O:17][C:18]2[C:23]([CH3:24])=[C:22]([O:25][CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[CH:21]=[C:20]([CH3:31])[N:19]=2)=[C:15]([CH3:35])[CH:14]=1)[CH3:5]
Reactant: CCC(CC)Oc1cc(C)nc(Oc2c(C)cc(Br)cc2C)c1C
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: CCI
Solvent: C1CCOC1
Product: CCc1cc(C)c(Oc2nc(C)cc(OC(CC)CC)c2C)c(C)c1
Reaction time: 0.08 h

Procedure:
To a solution of 2.5 N n-BuLi in hexane (0.47 ml, 1.18 mmol) in 5 ml of dry THF was added a solution of 2-(4-bromo-2,6-dimethyl-phenoxy)-4-(1-ethyl-propoxy)-3,6-dimethyl-pyridine (465 mg, 1.18 mmol) in 5 ml of dry THF at −78° C. After stirring at that temperature for 5 min, an excess of ethyl iodide (0.4 ml) was added and the resulting mixture was stirred at −78° C. for 30 min, then at 0° C. for 15 min. The mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was dried and concentrated to give a light brown oil. The oil was purified through silica gel column chromatography using chloroform as eluent to give 260 mg of the title compound as white solid. 1H NMR (CDCl3) δ 6.90 (s, 2H), 6.38 (s, 1H), 4.20 (m, 1H), 2.61 (q, 2H), 2.24 (s, 3H), 2.21 (s, 3H), 2.10 (s, 6H), 1.70 (m, 4H), 1.30 (t, 3H), 0.98 (t, 6H) ppm.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:12]3[N:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[N:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[F:21][C:22]1[CH:23]=[CH:24][C:25](B2OC(C)(C)C(C)(C)O2)=[C:26]([CH:29]=1)[C:27]#[N:28]>>[F:21][C:22]1[CH:23]=[CH:24][C:25]([C:2]2[CH:7]=[C:6]([C:8]3[N:12]4[N:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[N:16][C:11]4=[N:10][CH:9]=3)[CH:5]=[CH:4][N:3]=2)=[C:26]([CH:29]=1)[C:27]#[N:28]
Reactant: FC(F)(F)c1cnn2c(-c3ccnc(Cl)c3)cnc2n1
Reactant: CC1(C)OB(c2ccc(F)cc2C#N)OC1(C)C
Product: N#Cc1cc(F)ccc1-c1cc(-c2cnc3nc(C(F)(F)F)cnn23)ccn1
Yield: 24 %

Procedure:
7-(2-Chloropyridin-4-yl)-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine was reacted with 5-fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzonitrile by a similar procedure to that described in Example 1, step g, to give the title compound in 24% yield: 1H NMR (400 MHz, CD Cl3) δ 7.48 (1H, ddd, J 2.7, 7.8, 8.6), 7.57 (1H, dd, J 2.7, 8.2), 8.01 (1H, dd, J 5.3, 8.8), 8.08 (1H, dd, J 1.8, 5.3), 8.63 (1H, dd, J 1.0, 1.8), 8.82 (1H, s), 8.92 (1H, s), 8.95 (1H, dd, J 1.0, 5.3).