Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([O:12]CC)=[O:11])[N:5]=[C:4]1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH3:2].[OH-].[K+].Cl>CO>[CH2:1]([N:3]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([OH:12])=[O:11])[N:5]=[C:4]1[C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)[CH3:2]
Reactant: CCOC(=O)Cn1nc(-c2ccc(OC)cc2)n(CC)c1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCn1c(-c2ccc(OC)cc2)nn(CC(=O)O)c1=O
Reaction time: 8 h
Yield: 111.4 %

Procedure:
205 mg (0.67 mmol) of ethyl 4-ethyl-[3-(4-methoxyphenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-acetate from Example 109A are dissolved in 0.46 ml of methanol, treated with 0.18 ml 20% aqueous potassium hydroxide and stirred overnight. Next it is brought to a pH of 1 with 1 N hydrochloric acid, evaporated and the residue dried in vacuo. 207 mg of the target compound is thus obtained as crude product, which is further reacted as such.
Reaction SMILES: C(=O)(O)[O-:2].[Na+].Cl.NO.[F:9][C:10]([F:23])([F:22])[CH:11]([CH3:21])[O:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]#[N:20])[CH:14]=1>C(O)C>[F:23][C:10]([F:9])([F:22])[CH:11]([CH3:21])[O:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]([NH2:20])=[O:2])[CH:14]=1
Reactant: O=C([O-])O
Reactant: CC(Oc1ccnc(C#N)c1)C(F)(F)F
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: CCO
Product: CC(Oc1ccnc(C(N)=O)c1)C(F)(F)F
Reaction time: 8 h
Yield: 94.2 %

Procedure:
To 4 ml of ethanol were added 0.38 g of sodium bicarbonate and 0.32 g of hydroxylamine hydrochloride, and the mixture was heated to reflux for 1 hour. After allowing to cool, 0.49 g of 4-(2,2,2-trifluoro-1-methylethoxy)pyridine-2-carbonitrile was added at room temperature, and the mixture was stirred for 8 hours, and concentrated. To the residue was added water, the resultant solution was extracted with ethyl acetate three times, and the organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was washed with hexane three times to obtain 0.5 g of 4-(2,2,2-trifluoro-1-methylethoxy)pyridine-2-carboxamide=oxime.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[N:5]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH:6]=[CH:7][N:8]=1.[H-].[Na+].Cl[CH2:23][C:24]1[N:25]=[C:26](/[CH:29]=[CH:30]/[C:31]2[CH:36]=[CH:35][C:34]([CH2:37][CH3:38])=[CH:33][CH:32]=2)[O:27][CH:28]=1.O>CN(C=O)C>[CH2:37]([C:34]1[CH:35]=[CH:36][C:31](/[CH:30]=[CH:29]/[C:26]2[O:27][CH:28]=[C:24]([CH2:23][O:19][C:16]3[CH:15]=[CH:14][C:13]([CH2:12][CH2:11][CH2:10][CH2:9][N:5]4[CH:6]=[CH:7][N:8]=[C:4]4[CH2:3][CH2:2][OH:1])=[CH:18][CH:17]=3)[N:25]=2)=[CH:32][CH:33]=1)[CH3:38]
Reactant: OCCc1nccn1CCCCc1ccc(O)cc1
Reactant: CCc1ccc(/C=C/c2nc(CCl)co2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1ccc(/C=C/c2nc(COc3ccc(CCCCn4ccnc4CCO)cc3)co2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.1 %

Procedure:
To a solution of 4-[4-[2-(2-hydroxyethyl)-1H-imidazol-1-yl ]butyl]phenol (260 mg) in DMF (4 ml), 60% oily sodium hydride (44 mg) was added under ice cooling. After stirring at room temperature for 30 minutes, (E)-4-chloromethyl-2-[2-(4-ethylphenyl)ethenyl]oxazole (272 mg) was added under ice cooling. After stirring overnight at room temperature, water was added under ice cooling. The precipitate was collected by filtration and washed with water. The precipitate was dissolved in ethyl acetate and dried (magnesium sulfate), after which it was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to yield the titled compound (297 mg) as colorless crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([NH2:14])[CH2:12][NH2:13]>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:13][CH2:12][CH2:11][NH2:14])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: NCCN
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Product: NCCNc1ccc([N+](=O)[O-])cc1

Procedure:
From 1-chloro-4-nitrobenzene by heating in neat ethylene diamine to give N*1*-(4-nitro-phenyl)-ethane-1,2-diamine, followed by treatment with trifluoro-methanesulfonic acid 4,6-dimethyl-pyridin-2-yl ester (itself prepared according to J. Org. Chem., 63, 10048-51 (1998) using pyridine as base) in diglyme at reflux to afford N-(4,6-dimethyl-pyridin-2-yl)-N′-(4-nitro-phenyl)-ethane-1,2-diamine. Dimethylation with methyl iodide in THF in the presence of sodium hydride followed by catalytic hydrogenation over Raney nickel in methanol gives the required aniline.
Reaction SMILES: [Mg].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12]Br)=[CH:6][CH:5]=1.BrCCCl.[CH:18]1[N:19]=[CH:20][N:21]2[CH2:26][CH2:25][CH2:24][C:23](=[O:27])[C:22]=12>C1COCC1>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][C:23]2([OH:27])[CH2:24][CH2:25][CH2:26][N:21]3[CH:20]=[N:19][CH:18]=[C:22]23)=[CH:6][CH:5]=1
Reactant: COc1ccc(CCCBr)cc1
Reactant: O=C1CCCn2cncc21
Agent: [Mg]
Solvent: ClCCBr
Solvent: C1CCOC1
Product: COc1ccc(CCCC2(O)CCCn3cncc32)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A three-necked flask with dropping funnel and reflux condenser is charged with 285.000 mmol of magnesium turnings in 50 ml of THF. With stirring at an oil bath temperature of 70° C. a solution of 37.100 mmol of 3-(4-methoxyphenyl)bromopropane [57293-19-3] and 28.500 mmol 1-bromo-2-chloroethane in 40 ml of THF is added dropwise over 45 minutes. The mixture is subsequently stirred at 70° C. for 2 hours and then cooled to room temperature and the supernatant solution is transferred using a transfer cannula into a second three-necked flask, fitted with dropping funnel. The Grignard solution thus obtained is admixed dropwise, with ice-bath cooling, with 28.500 mmol of 6,7-dihydro-5H-imidazo[1,5-a]pyridin-8-one [426219-51-4] in solution in 50 ml of THF over 10 minutes. When addition is complete the reaction mixture is stirred at room temperature for 1 hour. It is quenched with 150 ml of 0.5M aqueous HCl and extracted with dichloromethane (3×). The combined organic phases are dried over sodium sulphate and evaporated. From the residue the title compound is obtained by means of flash chromatography (SiO2 60F) as an amber oil. Rf=0.08 (dichloromethane-ethanol=98:2); Rt=5.50.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccc([N+](=O)[O-])c2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2cccc(N)c2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 71.3 %

Procedure:
To a solution of 1,2,3,6-tetrahydro-4-(3-nitrophenyl)pyridine-1-carboxylic acid tert-butyl ester (1.7 g), which is prepared according to the method disclosed in Synthesis, 993 (1991), in ethanol (100 ml) is added 10% palladium on carbon (wet, 1.7 g), and the mixture is stirred at 25° C. under hydrogen atmosphere for 5 hours. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: gradient, 0% to 100% ethyl acetate/hexane) to give the title compound (1.1 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:10][C:11](=O)[C:12](F)(F)F)=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.C(OC([NH:24][C@H:25]1[CH2:30][CH2:29][C@H](COS(C(F)(F)F)(=O)=O)[CH2:27][CH2:26]1)=O)(C)(C)C>>[NH2:24][CH:25]1[CH2:30][CH2:29][CH:12]([CH2:11][NH:10][C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[C:5]([O:8][CH3:9])[N:4]=2)[CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](COS(=O)(=O)C(F)(F)F)CC1
Reactant: COc1ccc(Cl)c(NC(=O)C(F)(F)F)n1
Product: COc1ccc(Cl)c(NCC2CCC(N)CC2)n1

Procedure:
This compound is prepared from N-(3-chloro-6-methoxypyridin-2-yl)-2,2,2-trifluoroacetamide (Int. BB step 1) and trans-trifluoro-methanesulfonic acid 4-tert-butoxycarbonylamino-cyclohexylmethyl ester (Int. B step 1) analogously to Intermediate B step 2 and 3; 1H NMR (d6-DMSO, 400 MHz) δ 7.86 (3H, br), 7.42 (1H, d), 6.48 (1H, t), 5.91 (1H, d), 3.77 (3H, s), 3.21 (2H, t), 2.92 (1H, m), 1.94 (2H, m), 1.78 (2H, m), 1.59 (1H, m), 1.28 (2H, m), 1.01 (2H, m).
Reaction SMILES: [CH:1](=[C:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[CH:13][CH:14]=2)[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.[C].[Pd]>[CH2:1]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[CH:13][CH:14]=2)[C:9]1=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1)C(=O)C(=Cc1ccccc1)C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1ccc2c(c1)C(=O)C(Cc1ccccc1)C2
Yield: 91.3 %

Procedure:
To a solution of 2-benzylidene-6-methoxy-1-indanone (12.25 g, 48.9 mmol) in ethanol (500 ml) was added 10% hydrous palladium-carbon (1.5 g) and catalytic reduction was carried out in a hydrogen stream at atmospheric temperature and pressure. The palladium-carbon was then filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane=2:8) to provide the title compound (yield 11.26 g, 92%; oil).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7](=O)[CH2:8][CH2:9][O:10]2)=[CH:5][CH:4]=1)=[CH2:2].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>C1(C)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[CH:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:8][CH2:9][O:10]2)=[CH:5][CH:4]=1)=[CH2:2]
Reactant: C1COCCN1
Reactant: C=Cc1ccc2c(c1)OCCC2=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: C=Cc1ccc2c(c1)OCC=C2N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
To a mixture of 7-vinylchroman-4-one (Preparation 2D, 0.370 g, 2.12 mmol) and morpholine (0.925 mL, 10.6 mmol) in toluene (8 mL) at 0° C. was added titanium(IV) chloride (1.0 M in toluene) (1.17 mL, 1.17 mmol) dropwise. The ice-bath was removed, and the orange, heterogeneous reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered under reduced pressure through a pad of CELITE®, which was rinsed with toluene (3×10 mL). The pale yellow filtrate was concentrated under reduced pressure to give 4-(7-vinyl-2H-chromen-4-yl)morpholine (0.448 g, 1.84 mmol, 87% yield) as a yellow oil. 1H NMR (500 MHz, CDCl3) δ ppm 2.85-2.90 (m, 4), 3.84-3.89 (m, 4), 4.71 (d, J=4.16 Hz, 2), 5.10 (t, J=4.16 Hz, 1), 5.27 (d, J=11.37 Hz, 1), 5.76 (d, J=17.48 Hz, 1), 6.67 (dd, J=17.62, 10.96 Hz, 1), 6.98-7.03 (m, 2H), and 7.29 (s, 1H).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)[CH3:6])C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[NH2:13][C:10]1[CH:9]=[CH:8][C:7]([CH:5]([CH3:6])[CH2:4][OH:3])=[CH:12][CH:11]=1
Reactant: CCOC(=O)C(C)c1ccc(N)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(CO)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 99.1 %

Procedure:
To a stirred solution of 2-(4-amino-phenyl)-propionic acid ethyl ester (5.0 g, 25.9 mmol, Takahashi, I. et al., Heterocycles 1996, 43, 2343-2346.) in tetrahydrofurane (200 ml) was slowly added lithiumaluminium hydride (1.96 g, 51.8 mmol), and the mixture was stirred at room temperature for 14 h. The reaction mixture was quenched with 25% ammonia solution (50 ml) under ice-bath cooling. The resulting precipitate was filtered off, and the filtrate concentrated under reduced pressure to afford 3.88 g (99%) of the title compound as slight brown syrup.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:8]2[CH:9]=[C:10]3[C:15](=[O:16])[O:14][C:12](=O)[C:11]3=[CH:17][CH:18]=2)=[O:7])=[CH:4][CH:3]=1.C(O)(=O)C.[NH2:25][CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:9]=[C:10]3[C:11](=[CH:17][CH:18]=2)[C:12](=[O:14])[N:25]([CH2:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[C:15]3=[O:16])=[O:7])=[CH:19][CH:20]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc2c(c1)C(=O)OC2=O
Reactant: NCc1cccnc1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: O=C(c1ccc(Cl)cc1)c1ccc2c(c1)C(=O)N(Cc1cccnc1)C2=O
Yield: 97.1 %

Procedure:
To a mixture of 870 mg of 4-(4-chlorobenzoyl) phthalic acid anhydride, 10 ml of acetic acid and 10 ml of toluene was added 394 mg of 3-aminomethylpyridine, and the resultant mixture was refluxed under heating for 2 hours. The reaction mixture was concentrated in vacuo, and the resultant residue was chromatographed on a column of silica gel, eluting with ethyl acetate to give 1.11 g of the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:21](N1C=CN=C1)([N:23]1C=CN=C1)=O.CN>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:23][CH3:21])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)Cn1c(-c2ccc(F)cc2)nc2cccnc21
Agent: CN
Solvent: C1CCOC1
Product: CNC(=O)Cn1c(-c2ccc(F)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.9 %

Procedure:
A mixture of 2-(4-fluorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.01845 mole) and 1,1'-carbonyldiimidazole (2.99 g, 0.01845 mole) was stirred at room temperature in dry tetrahydrofuran (100 ml) for three hours with a stream of nitrogen bubbling through it. A solution of methylamine in tetrahydrofuran (37 ml of a 3.03M solution, 0.111 mole) was added and the reaction mixture was stirred at room temperature under nitrogen overnight. The solvents were removed under reduced pressure and the residue was triturated in water (100 ml). The solid was collected by filtration, rinsed twice with water, twice with a 5% potassium hydroxide solution and twice again with water. The solid was dissolved in hot isopropyl alcohol, filtered hot, cooled to room temperature and isopropyl ether was added to the cloud point. The resulting solid was collected by filtration, rinsed with isopropyl ether, and dried under high vacuum at 42° C. overnight to give 2.30 g (44%) of title compound, mp. 215°- 217° C.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH3:5].[OH:6][C@@H:7]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[S:22][C:21]3[C:16](=[N:17][CH:18]=[CH:19][C:20]=3[Cl:23])[CH:15]=2)=[O:13])[CH2:8]1>>[Cl:23][C:20]1[CH:19]=[CH:18][N:17]=[C:16]2[CH:15]=[C:14]([C:12]([N:9]3[CH2:10][CH2:11][C@H:7]([O:6][CH2:2][CH2:3][O:4][CH3:5])[CH2:8]3)=[O:13])[S:22][C:21]=12
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CC[C@@H](O)C1
Reactant: COCCBr
Product: COCCO[C@H]1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1

Procedure:
The title compound was prepared from 1-bromo-2-methoxy-ethane and (3R)-(3-hydroxy-pyrrolidin-1-yl)-[7-chloro-thieno[3,2-b]pyridin-2-yl]-methanone by a procedure analogous to Example 67B. MS: 341.2/343.2 (MH+); HPLC Rf: 4.236 min.; HPLC purity: 77%.
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.Br[CH2:11][C:12](=O)[CH2:13][CH2:14][C:15]#[C:16][Si:17]([CH3:20])([CH3:19])[CH3:18]>>[F:8][C:6]1[CH:7]=[C:2]([F:1])[C:3]2[N:4]([CH:11]=[C:12]([CH2:13][CH2:14][C:15]#[C:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:9]=2)[CH:5]=1
Reactant: Nc1ncc(F)cc1F
Reactant: C[Si](C)(C)C#CCCC(=O)CBr
Product: C[Si](C)(C)C#CCCc1cn2cc(F)cc(F)c2n1
Yield: 49.1 %

Procedure:
The title compound was prepared in accordance with the general method of Example 223(D), from 3,5-difluoropyridin-2-amine (492 mg, 3.78 mmol) and 1-bromo-6-(trimethylsilyl)hex-5-yn-2-one (compound 223(C), 1.87 mg, 7.56 mmol). The crude residue was purified over silicagel chromatography (prepacked 25 g silicagel column, from DCM/Cyclohexane: 70/30 to DCM/MeOH: 95/5 as eluent) to afford 517 mg of 6,8-difluoro-2-(4-(trimethylsilyl)but-3-ynyl)-imidazo[1,2-a]pyridine (Yield: 49%) as a brown oil.
Reaction SMILES: [C:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:6]=[CH:5][C:4]=1[C:15]([O:17]CC)=[O:16])#[N:2].[OH-].[K+].C([OH:24])C>O>[C:15]([C:4]1[CH:5]=[N:6][N:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[C:3]=1[C:1]([NH2:2])=[O:24])([OH:17])=[O:16]
Reactant: CCO
Reactant: CCOC(=O)c1cnn(-c2ccc(F)cc2)c1C#N
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: NC(=O)c1c(C(=O)O)cnn1-c1ccc(F)cc1

Procedure:
A 2.5 g. portion of ethyl 5-cyano-1-(4-fluorophenyl)-4-pyrazolecarboxylate was combined with 2.6 g. of potassium hydroxide and stirred under reflux in 100 ml. of denatured ethanol for 4 hours. It was then cooled, made acid, diluted with water, and concentrated under vacuum to obtain 2.8 g. of the desired compound, m.p. 232° dec. after recrystallization from acetone. It was identified by elemental analysis.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][CH:3]=1.[Li]CCCC.CN([CH:26]=[O:27])C>C1COCC1>[F:10][C:9]([F:12])([F:11])[C:8]([C:6]1[N:7]=[C:2]([CH:26]=[O:27])[CH:3]=[CH:4][CH:5]=1)([OH:17])[C:13]([F:16])([F:15])[F:14]
Reactant: CN(C)C=O
Reactant: OC(c1cccc(Br)n1)(C(F)(F)F)C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cccc(C(O)(C(F)(F)F)C(F)(F)F)n1
Reaction time: 0.17 h

Procedure:
To a stirred solution of 261 (0.5 g, 1.54 mmol) in dry THF, cooled to 0° C., n-BuLi (0.118 g, 1.85 mmol) was added drop wise and continued stirring for 10 min. Then DMF (0.224 g, 3.08 mmol) was added to the reaction mixture while stirring for another 2 h. After completion of the reaction, it was quenched with saturated ammonium chloride solution. The organic layer was separated and aqueous phase was extracted again with diethyl ether, the combined organic layer was dried over sodium sulphate and concentrated to get the crude compound 6-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)picolinaldehyde 262.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14]C(C)C)=O)(C)(C)C.[CH3:21][Si](C=[N+]=[N-])(C)C>C(O)C.CCOCC>[NH2:8][C@H:9]([C:18]([O:20][CH3:21])=[O:19])[CH2:10][CH2:11][CH2:12][CH2:13][NH2:14]
Reactant: CC(C)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCO
Solvent: CCOCC
Product: COC(=O)[C@@H](N)CCCCN

Procedure:
Nα-tert-Butyloxycarbonyl-Nε-isopropyl lysine (SennChem) was reacted with trimethylsilyldiazomethan in ethanol. The resulting methyl ester amine was reacted with 2-(pinacolborono)benzyl bromide in ether and TEA to give Nα-tert-butyloxycarbonyl, Nε-isopropyl, Nε-(2-pinacolboronobenzyl) methyl lysinate:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[CH3:15])[N:5]=[C:4]([CH3:16])[N:3]=1.[NH2:17][C:18]1[CH:26]=[C:25]2[C:21]([CH:22]=[N:23][NH:24]2)=[CH:20][CH:19]=1>>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([CH3:15])=[C:8]([C:6]2[N:5]=[C:4]([CH3:16])[N:3]=[C:2]([NH:17][C:18]3[CH:26]=[C:25]4[C:21]([CH:22]=[N:23][NH:24]4)=[CH:20][CH:19]=3)[CH:7]=2)[CH:13]=1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: Cc1nc(Cl)cc(-c2cc(Cl)ccc2C)n1
Product: Cc1nc(Nc2ccc3cn[nH]c3c2)cc(-c2cc(Cl)ccc2C)n1
Yield: 64 %

Procedure:
Following the method described in Example 38 (alternate method), 4-chloro-6-(5-chloro-2-methyl-phenyl)-2-methyl-pyrimidine and 6-aminoindazol provided the title compound (64% yield). 1H NMR (DMSO-d6) δ 2.32 (s, 3H, CH3), 2.57 (s, 3H, CH3), 6.78 (s, 1H, Ar), 7.18 (dd, 1H, J=8.7 Hz, J=1.6 Hz, Ar), 7.36 (d, 1H, J=8.2 Hz, Ar), 7.43 (dd, 1H, J=8.2 Hz, J=2.3 Hz, Ar), 7.49 (d, 1H, J=2.2 Hz, Ar), 7.69 (d, 1H, J=8.6 Hz, Ar), 7.97 (s, 1H, Ar), 8.33 (s, 1H, Ar), 9.75 (s, 1H, NH), 12.89 (s, 1H, NH).
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:8][C:9]=1[CH3:10])=[N+]=[N-]>C(O)C.[Pd]>[CH3:10][C:9]1[NH:8][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:6][C:5]=1[CH2:4][NH2:1]
Reactant: Cc1[nH]c(-c2ccccc2)nc1CN=[N+]=[N-]
Agent: [Pd]
Solvent: CCO
Product: Cc1[nH]c(-c2ccccc2)nc1CN
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
To solution of 4-azidomethyl-5-methyl-2-phenyl-1H-imidazole (1.22 g) in ethanol (50 ml) was added 10% Pd/C (0.10 g). The reaction mixture was hydrogenated at room temperature and 1.1 bar for 30 minutes, the catalyst was filtered off over a pad of celite. The filtrate was evaporated to dryness under high vacuum to obtain C-(5-methyl-2-phenyl-1H-imidazol-4-yl)-methylamine (1.06 g) as a light yellow foam which was sufficiently pure to be used directly in the next step.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:10]=[C:11]([CH:15]([OH:18])[CH:16]=[CH2:17])[CH:12]=[CH:13][CH:14]=1.Br[C:20]1[CH:30]=[CH:29][CH:28]=[CH:27][C:21]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].[Li+].[Cl-].[Li]OC(C)=O.O.O>CN(C=O)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:10]=[C:11]([C:15](=[O:18])[CH2:16][CH2:17][C:27]2[CH:28]=[CH:29][CH:30]=[CH:20][C:21]=2[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1ccccc1Br
Reactant: C=CC(O)c1cccc(COC2CCCCO2)c1
Agent: [Cl-]
Agent: [Li+]
Agent: [Li]OC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccccc1CCC(=O)c1cccc(COC2CCCCO2)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
The allylic alcohol of Step 10 (24.8 g, 100 mmol) and ethyl 2-bromobenzoate (25.2 g, 110 mmol) were dissolved in DMF (200 mL). LiCl (4.2 g, 100 mmol), LiOAc.2H2O (25.5 g, 250 mmol) and n-Bu4N+Cl- (55 g, 200 mmol) were added and the resulting mixture was degassed three times. Pd(OAc)2 (1 g) was then added and the mixture was degassed three more times before heating it at 100° C. with stirring for 1 hour. After cooling to r.t., the reaction mixture was poured onto H2O (600 mL), 10% aq. NaHCO3 (200 mL) and Et2O. The crude product was extracted with Et2O (2×), washed with H2O and brine, and dried over Na2SO4 before concentrating in vacuo. Purification on a short silica gel column (20% EtOAc in hexanes) gave 34 g (86%) of the title compound. 1H NMR (CD3COCD3): δ8.02 (1H, br s), 7.92 (1H, d), 7.88 (1H, d), 7.65 (1H, d), 7.50 (3H, m), 7.32 (1H, br t), 4.8 (1H, d), 4.70 (1H, br s), 4.54 (1H, d), 4.3 (2H, q), 3.82 (1H, m), 3.50 (1H, m), 3.35 (2H, m), 1.9-1.45 (8H, m), 1.32 (3H, t).
Reaction SMILES: [C:1]1([CH:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:8]([O:10][CH:11]2[CH2:16][NH:15][C:14](=[N:17][N+:18]([O-:20])=[O:19])[NH:13][CH2:12]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:27]I.[H-].[Na+]>CN(C=O)C>[C:21]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]([O:10][CH:11]2[CH2:16][N:15]([CH3:27])[C:14](=[N:17][N+:18]([O-:20])=[O:19])[NH:13][CH2:12]2)=[O:9])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(OC1CNC(=N[N+](=O)[O-])NC1)C(c1ccccc1)c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CC(OC(=O)C(c2ccccc2)c2ccccc2)CNC1=N[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-nitroiminohexahydropyrimidin-5-yl diphenylacetate (0.4 g) and methyl iodide (0.16 g) in DMF (4 ml), 80% sodium hydride (0.06 g) was added. The mixture was then stirred at room temperature overnight. The solvent was removed and the residue taken up with methylene chloride/water. The organic layer was evaporated and the residue was purified by column chromatography (eluent methylene chloride/methanol 98:2) to afford 1-methyl-2-nitroiminohexahydropyrimidin-5-yl diphenylacetate. M.p. 187° C.