Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:6]([OH:31])([CH2:21][C:22]2[O:23][C:24]([CH3:30])([CH3:29])[O:25][C:26](=[O:28])[CH:27]=2)[C:7]#[C:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3([C:18]#[N:19])[CH2:17][CH2:16]3)=[C:11]([F:20])[CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>CCO.[OH-].[OH-].[Pd+2]>[CH:1]1([C:6]([OH:31])([CH2:21][C:22]2[O:23][C:24]([CH3:29])([CH3:30])[O:25][C:26](=[O:28])[CH:27]=2)[CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3([C:18]#[N:19])[CH2:17][CH2:16]3)=[C:11]([F:20])[CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)OC(=O)C=C(CC(O)(C#Cc2ccc(C3(C#N)CC3)c(F)c2)C2CCCC2)O1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)OC(=O)C=C(CC(O)(CCc2ccc(C3(C#N)CC3)c(F)c2)C2CCCC2)O1
Reaction time: 6 h
Yield: 99 %

Procedure:
To a solution of 1-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-but-1-ynyl]-2-fluoro-phenyl}-cyclopropanecarbonitrile (1.0 g, 2.4 mmol) from Step 5 above dissolved in EtOH (20 mL) was added Pd(OH)2/C (20% wt dry basis, 100 mg) and the reaction was stirred under a hydrogen atmosphere for 6 hours. The palladium catalyst was removed by filtration, and the solvent removed by rotary evaporation. The resulting oil was used without further purification (1.02 g, 99% yield).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]([F:52])([F:51])[C:10]1[CH:11]=[C:12]([CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=1)[CH2:13][N:14]([C:38]1[N:39]=[N:40][N:41]([CH3:43])[N:42]=1)[C@H:15]1[CH2:21][CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[C:17]2[CH:29]=[C:30]([C:34]([F:37])([F:36])[F:35])[C:31]([CH3:33])=[CH:32][C:16]1=2.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:51][C:9]([F:8])([F:52])[C:10]1[CH:11]=[C:12]([CH:44]=[C:45]([C:47]([F:50])([F:48])[F:49])[CH:46]=1)[CH2:13][N:14]([C:38]1[N:39]=[N:40][N:41]([CH3:43])[N:42]=1)[C@H:15]1[CH2:21][CH2:20][CH2:19][NH:18][C:17]2[CH:29]=[C:30]([C:34]([F:35])([F:36])[F:37])[C:31]([CH3:33])=[CH:32][C:16]1=2
Reactant: Cc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(cc1C(F)(F)F)NCCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
Add trifluoroacetic acid (10 mL) to a solution of (S)-tert-butyl 5-[(3,5-bistrifluoromethylbenzyl)-(2-methyl-2H-tetrazol-5-yl)amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (2.04 g, 3.13 mmol) in methylene chloride (50 mL) at 0° C. under nitrogen. Warm the mixture to room temperature, stir for 8 h and pour the mixture into saturated aqueous sodium bicarbonate solution (200 mL). Extract the mixture with methylene chloride (200 mL) and wash the combined organic extracts with brine (50 mL), dry over anhydrous sodium sulfate and filter. Remove the solvent under reduced pressure to provide the title compound as a colorless oil (1.73 g, >99%), which is used in the next step without purification. APCI MS m/z 553 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.Cl.[NH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[C:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:12]=1.[BH3-]C#N.[Na+]>C(O)(=O)C.CO>[C:15]([OH:17])(=[O:16])[CH3:14].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[C:13]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:12]=2)[CH:2]=1
Reactant: O=Cc1cccnc1
Reactant: Nc1ccc(C(=O)O)c(-c2ccccc2)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(O)c1ccc(NCc2cccnc2)cc1-c1ccccc1
Reaction time: 0.17 h
Yield: 186.5 %

Procedure:
3-Pyridinecarboxaldehyde (1.2 mL, 12.8 mmol) and 4-amino-2-phenylbenzoic acid hydrochloride (3.2 g, 12.8 mmol), prepared in Example 190A, were dissolved in 100 mL 1% acetic acid in methanol. After stirring for 10 minutes, NaBH3CN was added, and stirring was continued for 18 hours. The reaction was evaporated to dryness under reduced pressure and partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate. The organic extracts were combined, washed with brine, and dried over Na2SO4 to give 4-(3-Pyridylmethylamino)-2-phenylbenzoic acid acetic acid salt (4.35 g, 90%) of the title compound. MS m/e 305 (M+H)+. 1H NMR (d6-DMSO, 300 MHz) δ 4.41 (s, 2H), 6.45 (d, J=3 Hz, 1H), 6.60 (m, 1H), 7.15-7.90 (m, 10H), 8.48 (m, 1H), 8.60 (m, 1H).
Reaction SMILES: [F:1][C:2]1([F:53])[CH2:5][N:4]([C:6]2[N:11]=[C:10]([CH2:12][N:13]3[C@@H:17]([CH3:18])[C@@H:16]([C:19]4[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([F:29])[CH:20]=4)[O:15][C:14]3=[O:30])[C:9]([C:31]3[CH:32]=[C:33]([C:39]4[CH:51]=[CH:50][C:42]([C:43]([O:45]C(C)(C)C)=[O:44])=[CH:41][C:40]=4[CH3:52])[CH:34]=[N:35][C:36]=3[O:37][CH3:38])=[CH:8][N:7]=2)[CH2:3]1.C(O)(C(F)(F)F)=O>ClCCl>[F:53][C:2]1([F:1])[CH2:5][N:4]([C:6]2[N:11]=[C:10]([CH2:12][N:13]3[C@@H:17]([CH3:18])[C@@H:16]([C:19]4[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([F:29])[CH:20]=4)[O:15][C:14]3=[O:30])[C:9]([C:31]3[CH:32]=[C:33]([C:39]4[CH:51]=[CH:50][C:42]([C:43]([OH:45])=[O:44])=[CH:41][C:40]=4[CH3:52])[CH:34]=[N:35][C:36]=3[O:37][CH3:38])=[CH:8][N:7]=2)[CH2:3]1
Reactant: COc1ncc(-c2ccc(C(=O)OC(C)(C)C)cc2C)cc1-c1cnc(N2CC(F)(F)C2)nc1CN1C(=O)O[C@H](c2cc(F)cc(C(F)(F)F)c2)[C@@H]1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ncc(-c2ccc(C(=O)O)cc2C)cc1-c1cnc(N2CC(F)(F)C2)nc1CN1C(=O)O[C@H](c2cc(F)cc(C(F)(F)F)c2)[C@@H]1C
Reaction time: 1 h
Yield: 47.7 %

Procedure:
To a solution of tert-butyl 4-{5-[2-(3,3-difluoroazetidin-1-yl)-4-({(4S,5R)-5-[3-fluoro-5-(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)pyrimidin-5-yl]-6-methoxypyridin-3-yl}-3-methylbenzoate (Step A, 98 mg, 0.132 mmol) in dichloromethane (0.700 mL), cooled to 0° C. was added TFA (0.700 mL). The ice bath was removed and the reaction mixture was stirred for 1 hour. Upon completion the solvent was removed under reduced pressure and the resultant residue was dissolved in acetonitrile:water (1:1) for direct purification by reverse phase HPLC (C18) followed by lyophilization of appropriate fractions to yield 4-{5-[2-(3,3-difluoroazetidin-1-yl)-4-({(4S,5R)-5-[3-fluoro-5-(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)pyrimidin-5-yl]-6-methoxypyridin-3-yl}-3-methylbenzoic acid (50.4 mg, 0.063 mmol) as a white fluffy solid. LCMS (M+H)+: 688.1. 1H NMR (500 MHz, CD3OD) δ8.27 (s, 1H), 8.23 (s, 1H), 7.97 (s, 1H), 7.91 (d, 1H, J=7.8 Hz), 7.71 (s, 1H), 7.50 (m, 2H), 7.39 (m, 2H), 5.76 (d, 1H, J=8.6 Hz), 4.67 (d, 1H, J=17.0 Hz), 4.53 (m, 4H), 4.38 (m, 1H), 4.16 (d, 1H, J=17.0 Hz), 4.01 (s, 3H), 2.39 (s, 3H), 0.75 (d, 3H, J=6.5 Hz). RTA IC50: 9 nM.
Reaction SMILES: [C:1](=[N:4][O:5][CH2:6][CH2:7][OH:8])([CH3:3])[CH3:2].[Br:9][CH:10]([CH3:14])[C:11](Br)=[O:12]>>[Br:9][CH:10]([CH3:14])[C:11]([O:8][CH2:7][CH2:6][O:5][N:4]=[C:1]([CH3:3])[CH3:2])=[O:12]
Reactant: CC(C)=NOCCO
Reactant: CC(Br)C(=O)Br
Product: CC(C)=NOCCOC(=O)C(C)Br

Procedure:
by using 2-isopropylideneaminooxy-ethanol and 2-bromopropionyl bromide there is obtained 2-isopropylideneaminooxy-ethyl 2-bromopropionate, nD20 1.4710.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=O.C1C=C[C:18]2N(O)N=[N:21][C:19]=2[CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CC(N)C.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([NH:21][CH:19]([CH3:20])[CH3:18])=[O:7]
Reactant: Nc1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: On1nnc2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)N
Solvent: CN(C)C=O
Product: CC(C)NC(=O)c1cc(N)cc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
To a solution of 3-amino-5-(trifluoromethyl)benzoic acid (0.25 g, 1.22 mmol) in DMF (3 mL) is added HOBt (0.494 g, 3.66 mmol) followed by HATU (0.695 g, 1.83 mmol), propan-2-amine (0.311 mL, 3.66 mmol) and DIEA (0.96 mL, 5.48 mmol). After stirring at it overnight the solution is concentrated and the residue is dissolved in EtOAc, washed with sat aq NaHCO3, brine, and dried over Na2SO4. Following concentration the residue is carried on to next step without further purification. MS (ESI) ni/z 247.1 (M+1).
Reaction SMILES: [N+](C1C=CC(C2C=CC(C(NCCCCC3C=NC=CC=3)=O)=CC=2)=CC=1)([O-])=O.S(Cl)([Cl:31])=O.[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]O.[OH-].[Na+]>ClCCl>[Cl:31][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][N:33]=1
Reactant: O=S(Cl)Cl
Reactant: OCCCCCc1ccccn1
Agent: O=C(NCCCCc1cccnc1)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: ClCCCCCc1ccccn1
Temperature: -5 °C
Reaction time: 17 h

Procedure:
A solution of 4 1 mL of thionyl chloride in 30 mL of dichloromethane was added over 10 minutes to a stirred solution of 6.65 g of 2-pyridinepentanol in 60 mL of dichloromethane maintained at -5° C. After the addition was complete. the mixture was stirred at room temperature for 17 hours, then was rechilled to 5° C. as 150 ml of 1N NaOH was added droPwise over 10 minutes. The layers were separated and the aqueous layer was extracted with 75 mL of dichloromethane. The organic layers were washed with brine, then were combined. dried (K2CO3) and evaporated to yield 7.4 g of 2-(5-chloropentyl)pyridine as an oil.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([CH3:15])=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.[NH2:17][NH2:18]>O1CCOCC1>[Br:1][C:2]1[C:3]([NH:17][NH2:18])=[N:4][C:5]([CH3:15])=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1
Reactant: NN
Reactant: Cc1cc(-c2ccc(Cl)cc2)c(Br)c(Cl)n1
Solvent: C1COCCO1
Product: Cc1cc(-c2ccc(Cl)cc2)c(Br)c(NN)n1
Temperature: 65 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a suspension of 3-bromo-2-chloro-4-(4-chlorophenyl)-6-methylpyridine (0.18 g, 0.56 mmol) in dioxane (4 mL) at room temperature was added anhydrous hydrazine (0.4 mL). The resulting mixture was stirred at 65° C. for 1 h. Analysis by HPLC/MS indicated the reaction was not complete. Additional anhydrous hydrazine (0.3 mL) was added, and the reaction mixture was stirred at 65° C. for 4 h more. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. To the residue was added water, and the resulting suspension was sonicated for 5 min. The resulting slurry was filtered, and the collected solid was washed with water (10 mL×2), then dried in a 45° C. vacuum oven for 16 h to afford 160 mg (90%) of the title compound as a white solid. HPLC/MS: retention time=2.53 min, [M+H]+=312.1.
Reaction SMILES: [O:1]([CH2:8][C:9](=[O:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:12]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>ClC(Cl)(Cl)Cl>[Br:12][CH:8]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9](=[O:11])[CH3:10]
Reactant: CC(=O)COc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)C(Br)Oc1ccccc1

Procedure:
Phenoxy-2-propanone (0.10 mol), N-bromosuccinimide (0.10 mol) and a catalytic amount of 2,2'-azobis(2-methylpropionitrile) were stirred together in tetrachloromethane (100 ml) at 80° C. for 61/2 hours. The solvent was distilled off and the residue distilled under vacuum to give (1-bromo-2-oxopropyl) oxybenzene. Yield: 10.4 g (45%), b.p. 66°-68° C./0.01 mm Hg. 1H NMR (CDCl3, δ): 2.50 (s, CH3) 6.40 (s, --CHBr--), 6.9-7.5 (5H, Ph).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(CC)C(C)C)(C)C.[I:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][C:26]=1[CH3:34].C(OCC)C>ClCCl>[I:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:4]3[CH:3]=[CH:2][CH:1]=[C:5]3[CH2:6]2)=[O:30])=[CH:27][C:26]=1[CH3:34]
Reactant: Cc1cc(C(=O)Cl)ccc1I
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1I
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
To a solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (9.38 g, 0.0509 mol) and N,N-diisopropylethylamine (13.31 mL, 0.0764 mol) in dry dichloromethane (250 mL) at 0° C. under nitrogen was added dropwise a solution of 4-iodo-3-methyl-benzoyl chloride (10.71 g, 0.0382 mol) in dry dichloromethane (30 mL) over ca. 10 minutes. The reaction mixture was allowed to warm slowly to room temperature with stirring over 3 hours then quenched by the addition of water (100 mL). The organic phase was separated, washed with 1 M hydrochloric acid (2×200 mL) and 5% wt/v aqueous sodium carbonate solution (200 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford a cream solid. Diethyl ether (150 mL) was added and the resulting suspension stirred vigorously for 3 hours then filtered to afford the title compound (14.73 g, 90%) as a white solid, m.p. 152-153° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:5][NH:4][C:3]1=[O:14].Br[C:16]1[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][N:2]1[CH:6]([C:7]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8])[CH2:5][N:4]([C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[C:3]1=[O:14]
Reactant: Cc1cccnc1Br
Reactant: CN1C(=O)NCC1C(=O)OC(C)(C)C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccnc1N1CC(C(=O)OC(C)(C)C)N(C)C1=O
Temperature: 25 °C
Yield: 80.1 %

Procedure:
A solution of 1,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (600 mg, 3 mmol) (prepared as described in step (iii) of Example 13, starting from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) and 2-bromo-3-methylpyridine (515 mg, 3 mmol) in 1,4-dioxane (20 ml) was treated with cesium carbonate (1464 mg, 4.5 mmol), Xantphos™ (130 mg, 0.225 mmol) and tris(dibenzylideneacetone)dipalladium(0) (68.6 mg, 0.075 mmol) and the mixture was heated under reflux under argon for 18 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with water and brine and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with 0-100% ethyl acetate in isohexane to give 1,1-dimethylethyl 3-methyl-1-(3-methyl-2-pyridinyl)-2-oxo-4-imidazolidinecarboxylate (700 mg, 80%). LC/MS [M+H]+=292. (ii) A solution of 1,1-dimethylethyl 3-methyl-1-(3-methyl-2-pyridinyl)-2-oxo-4-imidazolidinecarboxylate (700 mg, 2.4 mmol) in TFA/DCM (1:2, 12 ml) was stirred at room temperature for 6 hours. The solution was evaporated and the residue was co-evaporated with toluene and dried to give 3-methyl-1-(3-methyl-2-pyridinyl)-2-oxo-4-imidazolidinecarboxylic acid TFA salt (assume ˜2.4 mmol) which was used in the next step. LC/MS [M+H]+=236.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1.C[Mg]Br.CCOCC.[F:16][C:17]1[CH:18]=[C:19]([CH:26]=[CH:27][N:28]=1)[C:20](N(OC)C)=[O:21]>C(Cl)Cl>[F:16][C:17]1[CH:18]=[C:19]([C:20]([C:2]2[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=2)=[O:21])[CH:26]=[CH:27][N:28]=1
Reactant: CON(C)C(=O)c1ccnc(F)c1
Reactant: Cn1cncc1Br
Agent: C[Mg]Br
Solvent: CCOCC
Solvent: ClCCl
Product: Cn1cncc1C(=O)c1ccnc(F)c1
Temperature: 4 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-bromo-1-methyl-1H-imidazole (0.964 g, 5.99 mmol) in CH2Cl2 (6 mL) at room temperature was added 3.0 Methylmagnesium bromide in Et2O (2.0 mL, 6.00 mmol) dropwise. The mixture changed to a white suspension briefly then to clear yellow. After 15 min stirring, the mixture was cooled to 4° C. A solution of 2-fluoro-N-methoxy-N-methylisonicotinamide (1.05 g, 5.70 mmol, Intermediate 13, step a) in CH2Cl2 (6 mL) was introduced via cannula and some hard solid formed. The cooling bath was removed, and the mixture was stirred for 2 days. NH4Cl (aqueous) was added, the organic layer was separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was diluted with small amount of CH2Cl2. The undissolved solid was filtered, washed with Et2O, and dried under vacuum to provide the title compound as a white solid. The filtrate was concentrated and purified by flash column chromatography (40 g silica gel column, 100% EtOAc) to give more title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)=[CH:27][C:4]=1[CH2:5][O:6][CH2:7][C:8]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]1.FC(F)(F)C(O)=O.CN(C)C>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)=[CH:27][C:4]=1[CH2:5][O:6][CH2:7][C:8]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1
Reactant: COc1ccc(-c2ccncc2)cc1COCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: CN(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2ccncc2)cc1COCC1(c2ccccc2)CCNCC1
Reaction time: 1 h

Procedure:
tert-Butyl 4-((2-methoxy-5-(pyridin-4-yl)benzyloxy)methyl)-4-phenylpiperidine-1-carboxylate (26 mg, 0.053 mmol) was dissolved in trifluoroacetic acid (33% in dichloromethane, 4 mL) and stirred for 1 h. The reaction was concentrated and purified by column chromatography (5% methanol/dichloromethane/2% trimethylamine in ethanol→10% methanol/dichloromethane/2% trimethylamine in ethanol) to give 30.7 mg (quant.) as a colorless oil. The product was tainted with trimethylamine 2,2,2-trifluoroacetate. 1H NMR (500 MHz, CDCl3) δ ppm 13.28 (bs, 2H), 9.55 (m, 2H), 8.71 (d, J=5.2 Hz, 2H), 7.79 (d, J=5.2 Hz, 2H), 7.60 (m, 2H), 7.34 (m, 4H), 7.26 (m, 1H), 6.94 (d, J=8.6, 1H), 4.48 (s, 2H), 3.84 (s, 3H), 3.49 (s, 2H), 3.31 (m, 2H); 13C NMR (126 MHz, CDCl3) δ ppm 159.1, 154.0, 144.0, 140.5, 129.2, 128.6, 127.7, 127.4, 127.2, 126.9, 122.5, 110.8, 80.0, 67.5, 55.7, 41.2, 40.6. Mass spec.: 389.33 (MH)+. Accurate mass spec.: m/z 389.2228 [MH]+, Δ=0.3 ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[C:13]3[N:14]=[CH:15][C:16]([CH:18]=C)=[CH:17][C:12]=3[C:11]3=[N:20][CH:21]=[N:22][N:10]3[C:9]2=[O:23])=[CH:5][CH:4]=1.I([O-])(=O)(=O)=[O:27].[Na+]>O1CCCC1.O.[Os](=O)(=O)(=O)=O.C(O)(C)(C)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:13]3[N:14]=[CH:15][C:16]([CH:18]=[O:27])=[CH:17][C:12]=3[C:11]3=[N:20][CH:21]=[N:22][N:10]3[C:9]2=[O:23])=[CH:24][CH:25]=1
Reactant: C=Cc1cnc2c(c1)c1ncnn1c(=O)n2Cc1ccc(OC)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Cn2c(=O)n3ncnc3c3cc(C=O)cnc32)cc1
Reaction time: 4 h
Yield: 103.5 %

Procedure:
6-(4-Methoxybenzyl)-9-vinylpyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one (3.96 g, 11.9 mmol) was suspended in tetrahydrofuran (80 ml) and heated with a heat gun to effect dissolution. Similarly sodium periodate (5.84 g, 27.3 mmol) was heated in water (40 ml) to effect dissolution. The above solutions were combined with vigorous stifling. While the stirred mixture was still at 40° C., osmium(VIII) oxide in tert-butanol (2.90 ml, 2.5%, 0.30 mmol) was added and the mixture was stirred vigorously for 4 hours. It was diluted with water (300 mL) and extracted with ethyl acetate (3×150 mL) and DCM (3×150 mL). The combined extracts were dried (MgSO4) and concentrated to afford 4.13 g (99%) of the title compound as a black solid which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 3.77 (s, 3H), 5.80 (s, 2H), 6.83 (d, J=8.66 Hz, 2H), 7.61 (d, J=8.66 Hz, 2H), 8.41 (s, 1H), 9.10 (d, J=2.13 Hz, 1H), 9.26 (d, J=2.13 Hz, 1H), 10.21 (s, 1H). LCMS (MH+, 336.2).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@H:7]2[O:9][C@@H:8]2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:6]=1.[CH2:16]([O:18][CH2:19][CH2:20][NH2:21])[CH3:17]>>[CH2:16]([O:18][CH2:19][CH2:20][NH:21][CH:7]([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[CH:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[OH:9])[CH3:17]
Reactant: c1ccc([C@H]2O[C@@H]2c2ccccc2)cc1
Reactant: CCOCCN
Product: CCOCCNC(c1ccccc1)C(O)c1ccccc1
Temperature: 140 °C
Reaction time: 10 h
Yield: 79.9 %

Procedure:
A mixture of trans-stilbene oxide (1.96 g, 0.010 mol) and 2-ethoxyethylamine (2.67 g, 0.030 mol) was heated at 140° C. for 6 hours. After standing at ambient temperature for 10 hours, the solidified reaction mixture was triturated with isooctane and filtered to obtain a white solid (2.28 g, 80% yield) that was recrystallized from isooctane; mp 128°-130° C.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[CH3:4][N:5]([CH3:14])[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1>>[CH2:1]([NH:3][CH2:10][C:9]1[CH:12]=[CH:13][C:6]([N:5]([CH3:14])[CH3:4])=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCN
Reactant: CN(C)c1ccc(C=O)cc1
Product: CCNCc1ccc(N(C)C)cc1

Procedure:
prepared by reaction of ethylamine with 4-dimethylamino-benzaldehyde
Reaction SMILES: CCN(C(C)C)C(C)C.[O:10]=[C:11]1[NH:15][C:14]2[CH:16]=[CH:17][C:18]([C:20]3[NH:24][N:23]=[C:22]([C:25]([OH:27])=O)[CH:21]=3)=[CH:19][C:13]=2[O:12]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:50][CH2:51][C:52]([N:54]1[CH2:59][CH2:58][N:57]([C:60](=[O:72])[C:61]2[CH:66]=[C:65]([F:67])[CH:64]=[CH:63][C:62]=2[C:68]([F:71])([F:70])[F:69])[CH2:56][CH2:55]1)=[O:53]>CN(C=O)C.O>[F:67][C:65]1[CH:64]=[CH:63][C:62]([C:68]([F:70])([F:69])[F:71])=[C:61]([CH:66]=1)[C:60]([N:57]1[CH2:58][CH2:59][N:54]([C:52](=[O:53])[CH2:51][NH:50][C:25]([C:22]2[CH:21]=[C:20]([C:18]3[CH:17]=[CH:16][C:14]4[NH:15][C:11](=[O:10])[O:12][C:13]=4[CH:19]=3)[NH:24][N:23]=2)=[O:27])[CH2:55][CH2:56]1)=[O:72]
Reactant: NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1
Reactant: O=C(O)c1cc(-c2ccc3[nH]c(=O)oc3c2)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1)c1cc(-c2ccc3[nH]c(=O)oc3c2)[nH]n1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 21.3 %

Procedure:
DIPEA (120 mg, 0.16 mL, 0.927 mmol) was added to a stirred solution of 5-(2-oxo-2,3-dihydro-benzooxazol-6-yl)-1H-pyrazole-3-carboxylic acid (65 mg, 0.26 mmol) in DMF (2.5 mL). HOBT (37.6 mg, 0.27 mmol) and EDCI (53.4 mg, 0.2783 mmol) were then added at room temperature. After 2 minutes, 2-amino-1-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (98 mg, 0.265 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue recrystallized from EtOAc to afford 31 mg (21% yield) of 5-(2-Oxo-2,3-dihydro-benzooxazol-6-yl)-1H-pyrazole-3-carboxylic acid {2-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide. LCMS Purity: 80.27%. 1H NMR (DMSO-d6): δ 13.7 (s, 1H), 11.8 (s, 1H), 8.0 (m, 1H), 7.9 (m, 1H), 7.7 (m, 1H), 7.5 (m, 3H), 7.06 (m, 2H), 4.1 (m, 2H), 3.4 (m, 6H), 3.1 (m, 2H).