Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:17]([F:20])([F:19])[F:18])=[CH:6][C:7]([C:11]#[C:12][Si](C)(C)C)=[C:8]([CH:10]=1)[NH2:9])([O-:3])=[O:2]>CN(C=O)C.[Cu]I>[N+:1]([C:4]1[CH:10]=[C:8]2[C:7]([CH:11]=[CH:12][NH:9]2)=[CH:6][C:5]=1[C:17]([F:20])([F:19])[F:18])([O-:3])=[O:2]
Reactant: C[Si](C)(C)C#Cc1cc(C(F)(F)F)c([N+](=O)[O-])cc1N
Agent: [Cu]I
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc2[nH]ccc2cc1C(F)(F)F
Temperature: 135 °C
Yield: 30.6 %

Procedure:
To a solution of 5-nitro-4-(trifluoromethyl)-2-((trimethylsilyl)ethynyl)aniline (6.0 g, 19.85 mmol) in DMF (30 mL) was added CuI (1.9 g, 9.976 mmol) under an atmosphere of nitrogen. The reaction mixture was heated at 135° C. in a sealed pressure flask overnight. The reaction mixture was then filtered and the filtrate was washed with water, dried over Na2SO4 and concentrated. The crude product was purified by silica gel column chromatography (5 to 20% EtOAc in petroleum as eluant) to obtain 6-nitro-5-(trifluoromethyl)-1H-indole (1.4 g, 31%). 1H NMR (400 MHz, CDCl3): δ 8.83 (br s, 1H), 8.15 (s, 1H), 8.11 (s, 1H), 7.58-7.57 (m, 1H), 6.80-6.79 (m, 1H); 19F NMR (282.4 MHz, CDCl3): δ −57.82; MS (ESI): m/z [M−H]− 229.
Reaction SMILES: [CH3:1]N(C)CCNC.[CH:8]([N:11]([CH:39](C)C)[CH2:12][CH2:13][NH:14][C:15]([N:17]1[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][C:21]([O:29][CH3:30])=[C:22]([O:27][CH3:28])[CH:23]=2)[CH:18]1[C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)=[O:16])(C)C>>[CH3:28][O:27][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[O:29][CH3:30])[CH:18]([C:31]1[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=1)[N:17]([C:15]([N:14]([CH2:13][CH2:12][N:11]([CH3:39])[CH3:8])[CH3:1])=[O:16])[CH2:26][CH2:25]2
Reactant: CNCCN(C)C
Reactant: COc1ccc(C2c3cc(OC)c(OC)cc3CCN2C(=O)NCCN(C(C)C)C(C)C)cc1
Product: COc1ccc(C2c3cc(OC)c(OC)cc3CCN2C(=O)N(C)CCN(C)C)cc1

Procedure:
Substitution of an equivalent quantity of N,N,N'-trimethylethylenediamine for the 2-diisopropylaminoethylamine used above and substantial repetition of the foregoing procedure affords 6,7-dimethoxy-N-(2-dimethylaminoethyl)-1-(4-methoxyphenyl)-N-methyl-3,4-dihydro-2(1H)-isoquinolinecarboxamide.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]1([CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[OH:29])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O[CH2:31][CH2:32][CH:33]1[CH2:37][CH2:36][CH2:35][N:34]1[CH3:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH3:38][N:34]1[CH2:35][CH2:36][CH2:37][CH:33]1[CH2:32][CH2:31][O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[CH2:22][CH2:21][CH2:20][CH2:19][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CN1CCCC1CCO
Reactant: Oc1ccccc1CCCCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CN1CCCC1CCOc1ccccc1CCCCc1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 38.6 %

Procedure:
522 mg of diethyl azodicarboxylate were added, whilst ice-cooling and stirring, to a solution of 226 mg of 2-(4-phenylbutyl)phenol (prepared as described in Preparation 3), 390 mg of 2-(2-hydroxyethyl)-1-methylpyrrolidine and 790 mg of triphenylphosphine in 40 ml of methylene chloride, and the resulting mixture was stirred at room temperature for 14 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the resulting residue was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The resulting yellow oily concentrate was purified by column chromatography through silica gel, using a 10:1 by volume mixture of methylene chloride and methanol as the eluent, to give 130 mg (yield 38%) of the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=3)=[C:12]([F:13])[C:7]=2[N:6]([CH3:21])[C:5]1=[O:22].Br[C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.[Cu]I>[CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=3)[O:20][C:26]3[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=3)=[C:12]([F:13])[C:7]=2[N:6]([CH3:21])[C:5]1=[O:22]
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(-c3cccc(O)c3)c(F)c21
Reactant: N#Cc1ccc(Br)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(-c3cccc(Oc4ccc(C#N)cc4)c3)c(F)c21
Reaction time: 2 h

Procedure:
A solution of 1-(2,2-dimethylpropyl)-4-fluoro-5-(3-hydroxyphenyl)-3-methyl-1,3-dihydro-2H-benzimidazol-2-one (7-15, 55 mg, 0.17 mmol) in NMP (1 ml) was sequentially charged with 4-Bromobenzonitrile (61.0 mg, 0.34 mmol, 2.0 eq), Cesium carbonate (109 mg, 0.34 mmol, 2.0 eq) and Copper(I) iodide (31.9 mg, 0.17 mmol, 1.0 eq). The resulting mixture was irradiated in a microwave at 195 deg C. for 2 h. LC/MS analysis showed only partial conversion, therefore additional amounts of 4-Bromobenzonitrile (61.0 mg, 0.34 mmol, 2.0 eq) and Cu(I)I (31.9 mg, 0.17 mmol, 1.0 eq) were added and the reaction was irradiated again at 195 deg C. for 1 h. The completed reaction was filtered and the filtrate purified via reverse-phase HPLC (Acetonitrile/Water gradient with 0.1% TFA present) to afford the title compound, 4-{3-[1-(2,2-dimethylpropyl)-4-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl]phenoxy}benzonitrile (9-1), as a tan solid-oil. 1H NMR (400 MHz, CDCl3) δ 7.62 (d, 2H, J=8.9 Hz), 7.50-7.46 (m, 1H), 7.39 (m, 1H), 7.25 (s, 1H), 7.09-7.04 (m, 4H), 6.87 (d, 1H, J=8.2 Hz), 3.67 (s, 2H), 3.64 (s, 3H), 1.05 (s, 9H). LRMS m/z: Calc'd for C26H24FN3O2(M+H) 430.2, found 430.5.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][N:6]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[CH2:3][OH:4].[N:23]#[C:24]Br>>[F:22][C:18]1[CH:17]=[C:16]([N:6]([CH2:5][C@H:2]2[CH2:3][O:4][C:24]([NH2:23])=[N:1]2)[CH2:7][C:8]2[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: COc1ccc(CN(C[C@H](N)CO)c2cccc(F)c2)cc1
Reactant: N#CBr
Product: COc1ccc(CN(C[C@H]2COC(N)=N2)c2cccc(F)c2)cc1

Procedure:
In analogy to example 1.d (S)-2-amino-3-[(3-fluoro-phenyl)-(4-methoxy-benzyl)-amino]-propan-1-ol was reacted with cyanogen bromide to give (S)-4-{[(3-fluoro-phenyl)-(4-methoxy-benzyl)-amino]-methyl}-4,5-dihydro-oxazol-2-ylamine. Light yellow gum. MS (ISP): 330.3 ([M+H]+)
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[S:7][CH:8]=[C:9]([P:19]([O:24][CH2:25][CH3:26])([O:21][CH2:22][CH3:23])=[O:20])[C:10]=1[P:11]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])=[O:12])CCC.I[C:36]1[S:37][CH:38]=[CH:39][CH:40]=1.[F-].[K+]>C1COCC1.[Cu]Cl>[CH2:14]([O:13][P:11]([C:10]1[C:9]([P:19]([O:21][CH2:22][CH3:23])([O:24][CH2:25][CH3:26])=[O:20])=[CH:8][S:7][C:6]=1[C:36]1[S:37][CH:38]=[CH:39][CH:40]=1)([O:16][CH2:17][CH3:18])=[O:12])[CH3:15]
Reactant: Ic1cccs1
Reactant: CCCC[Sn](CCCC)(CCCC)c1scc(P(=O)(OCC)OCC)c1P(=O)(OCC)OCC
Agent: Cl[Cu]
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)c1csc(-c2cccs2)c1P(=O)(OCC)OCC
Yield: 88 %

Procedure:
In THF, 0.600 g (0.930 mmols) of 2-tributylstannyl-3,4-bis(diethoxyphosphoryl)thiophene and 0.1013 g (1.023 mmols) of commercially available copper(I) chloride were dissolved, to which 0.2344 g (1.116 mmols) of 2-iodothiophene was added at room temperature. Thereafter, the reaction mixture was heated and stirred under reflux for 4 hours. After the reaction, the reaction mixture was cooled down to room temperature, to which a potassium fluoride aqueous solution was added, followed by stirring for 2 hours. Subsequently, the resulting solid was removed by celite filtration and the filtrate was extracted with ethyl acetate. The organic phase was washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was removed by distilling off under reduced pressure, and the resulting crude product was purified with a silica gel column (ethyl acetate:methanol=15:1) to obtain the specified substance at a yield of 0.3595 g (yield: 88%).
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]([C:8]1[O:9][CH:10]=[CH:11][CH:12]=1)=[O:7])(=[O:3])[CH3:2].[H-].[Na+].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[C:1]([NH:4][CH:5]([C:6]([C:8]1[O:9][CH:10]=[CH:11][CH:12]=1)=[O:7])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:3])[CH3:2]
Reactant: CCOC(=O)CBr
Reactant: CC(=O)NCC(=O)c1ccco1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC(NC(C)=O)C(=O)c1ccco1
Yield: 40.6 %

Procedure:
2.6 g of N-acetyl-(2-furylcarbonyl)methylamine, 0.74 g of 61% sodium hydride and 2.9 g of ethyl bromoacetate are treated in the same manner as described in Preparation 1-(2). 1.6 g of ethyl 3-acetylamino-3-(2-furylcarbonyl)propionate are thereby obtained. Yield: 41%
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][C@@H:11]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C@H:10]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:9]1.[Br:30][C:31]1[N:36]=[C:35]([C:37](O)=[O:38])[CH:34]=[CH:33][C:32]=1[F:40]>>[Br:30][C:31]1[N:36]=[C:35]([C:37]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[N:8]2[CH2:13][CH2:12][C@@H:11]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C@H:10]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:9]2)=[O:38])[CH:34]=[CH:33][C:32]=1[F:40]
Reactant: O=C(O)c1ccc(F)c(Br)n1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(c2ccncc2N)CC[C@H]1O[Si](C)(C)C(C)(C)C
Product: CC(C)(C)OC(=O)N[C@@H]1CN(c2ccncc2NC(=O)c2ccc(F)c(Br)n2)CC[C@H]1O[Si](C)(C)C(C)(C)C

Procedure:
Following Method 11 of Example 305, tert-butyl (3R,4R)-1-(3-aminopyridin-4-yl)-4-(tert-butyldimethylsilyloxy)piperidin-3-ylcarbamate and 6-bromo-5-fluoropicolinic acid were coupled to yield tert-butyl (3R,4R)-1-(3-(6-bromo-5-fluoropicolinamido)pyridin-4-yl)-4-(tert-butyldimethylsilyloxy)piperidin-3-ylcarbamate. LCMS (m/z): 510.0/512.0 (MH+); LC Rt=4.51 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2nc3ccccc3o2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(-c2nc3ccccc3o2)cc1
Temperature: 25 °C

Procedure:
A stirred solution of 20.9 g (0.1 mole) of 2-(4-methylphenyl)benzoxazole, 17.8 g (0.1 mole) of N-bromosuccinimide, and 0.4 g (0.2 mole %) of benzoyl peroxide in carbon tetrachloride is heated at reflux for 20 hours. After cooling to room temperature, the reaction is diluted by the addition of carbon tetrachloride, and the solid byproducts are removed by filtration. The filtrate is concentrated in vacuo, and the product is purified by recrystallization from benzene.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[C:4]([CH:7]=[CH:8][N:9]=1)[CH:5]=[O:6].[BH4-].[Na+]>CO>[NH2:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[C:4]([CH2:5][OH:6])[CH:7]=[CH:8][N:9]=1
Reactant: Nc1nccc(C=O)c1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Nc1nccc(CO)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 69 %

Procedure:
To a suspension of the aldehyde obtained above (850 mg, 5.1 mmol) in MeOH (25 mL) at 0° C. was added sodium tetrahydroborate (190 mg, 5.10 mmol) and the reaction mixture warmed to RT for 2 hr and then quenched by the addition of hydrochloric acid (1 M, 5.0 mL) The mixture was diluted with sat aq. NaHCO3 (40 mL) and was extracted with DCM (80 mL, 6×100 mL). The combined organic extracts were dried and evaporated in vacuo to afford (2-amino-3-nitropyridin-4-yl)methanol as an orange solid (630 mg, 69%); Rt 0.40 min (Method 2); m/z 170 (M+H)+, (ES+).
Reaction SMILES: Br[CH:2]([S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[O:18]=[C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](=[O:28])[N:20]1[CH2:29][C:30](=[S:32])[NH2:31].C(=O)([O-])O.[Na+]>CN(C)C=O>[C:5]1([C:3]2[N:31]=[C:30]([CH2:29][N:20]3[C:19](=[O:18])[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21]3=[O:28])[S:32][C:2]=2[S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: NC(=S)CN1C(=O)c2ccccc2C1=O
Reactant: O=C(c1ccccc1)C(Br)Sc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1nc(-c2ccccc2)c(Sc2ccccc2)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.2 %

Procedure:
To a solution of 2-bromo-1-phenyl-2-(phenylthio)ethanone (3.2 g) in N,N-dimethylformamide (25 mL) was added 2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethanethioamide (2.3 g) and the mixture was stirred at room temperature for 3 hr. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound as white crystals (yield 3.0 g, yield 71%).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:19][CH2:18][CH:17]([N:20]2[C:25]3[N:26]=[C:27]([NH2:31])[N:28]=[C:29]([CH3:30])[C:24]=3[CH:23]=[C:22]([C:32]3[CH:33]=[N:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=3)[C:21]2=[O:40])[CH2:16]1)=O)(C)(C)C>ClCCl>[NH2:31][C:27]1[N:28]=[C:29]([CH3:30])[C:24]2[CH:23]=[C:22]([C:32]3[CH:33]=[N:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=3)[C:21](=[O:40])[N:20]([CH:17]3[CH2:18][CH2:19][NH:15][CH2:16]3)[C:25]=2[N:26]=1
Reactant: COc1ccc(-c2cc3c(C)nc(N)nc3n(C3CCN(C(=O)OC(C)(C)C)C3)c2=O)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2cc3c(C)nc(N)nc3n(C3CCNC3)c2=O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
The TFA (0.56 ml, 10 eq.) was added into the solution of 3-[2-Amino-6-(6-methoxy-pyridin-3-yl)-4-methyl-7-oxo-7H-pyrido[2,3-d]pyrimidin-8-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (328 mg, 0.725 mmol) in 2 ml dichloromethane at room temperature. The reaction mixture was stirred at room temperature overnight. The reaction was complete and the solvent was removed. The residue was partitioned in EA/sat. sodium bicarbonate. The EA layer was dried and concentrated to obtain the title compound as a solid (237 mg, 92.8% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[CH2:15][CH2:14][C@H:13]([NH:16][C:17](=O)OC(C)(C)C)[CH2:12]3)=[N:7][C:6]=12.IC.[H-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[CH2:15][CH2:14][C@H:13]([NH:16][CH3:17])[CH2:12]3)=[N:7][C:6]=12
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccn3ncc(Br)c3n2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN[C@H]1CCN(c2ccn3ncc(Br)c3n2)C1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 97.7 %

Procedure:
(S)-tert-butyl (1-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-3-yl)carbamate (3.6 g, 9.4 mmol) taken up in 15 mL DMF and cooled to 0° C. in an ice bath. Iodomethane (1.026 mL, 16.5 mmol) added and stirred 5 minutes. Then sodium hydride 60% in oil (754 mg, 18.8 mmol) was slowly added. Reaction stirred 5 minutes at 0° C. then removed from ice bath and stirred 30 minutes at room temperature. Reaction was quenched with ice then extracted with ethyl acetate 2×. Ethyl acetate fractions combined dried over magnesium sulfate filtered reduce in vacuo. This was then taken up in 26 mL DCM and 4 mL TFA added. Stirred 1 hour until complete by LC/MS. Reaction washed with 1N NaOH, DCM layer removed dried over magnesium sulfate filtered, reduced in vacuo to get 2.72 g crude product carried on as is to part C. LRMS (ESI) m/z 296/298 [(M+H)]+, calc'd for C11H14BrN5: 296.17.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=1[CH2:18][CH3:19])[CH3:11].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[CH2:10]([C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][C:17]=1[CH2:18][CH3:19])[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8])[CH3:11]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCc1ccccc1CC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCc1ccc(C(=O)c2ccccc2)cc1CC

Procedure:
A mixture of benzoyl chloride (1 eq) and 3,4-diethylbenzene (1.15 eq) was dissolved in 1,2-dichloroethane in a dry flask under argon and cooled in an ice bath with stirring. Aluminum chloride (1.3 eq) was added in portions to the reaction mixture at a rate to maintain the temperature below 10° C. Upon complete addition of the aluminum chloride, the ice bath was removed and the reaction mixture was stirred at room temperature for 18 h, then poured into cold water (100 mL) and extracted into ether (2×100 mL). The combined ether extracts were washed with water (25 mL), sodium bicarbonate solution (2×25 mL), water (25 mL), brine (25 mL), dried (MgSO4) and concentrated to provide the title compound as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]#[N:10])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:11][C:12](O)([CH2:14][CH:15]([OH:17])[CH3:16])[CH3:13]>S(=O)(=O)(O)O>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[O:17][CH:15]([CH3:16])[CH2:14][C:12]([CH3:13])([CH3:11])[N:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CC(O)CC(C)(C)O
Reactant: CCOC(=O)C1(C#N)CC1
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1(C2=NC(C)(C)CC(C)O2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 61730.3 %

Procedure:
To concentrated sulfuric acid (102 mL) was added 1-cyano-cyclopropanecarboxylic acid ethyl ester (60 g, 0.43 mol) dropwise followed by 2-methylpentan-2,4-diol (52 g, 0.44 mmol) dropwise at 0° C. The mixture was stirred for an additional 1 h at 0° C. then poured onto ice-water. The aqueous phase was washed with AcOEt (3×200 mL) and then basified to pH 12 with 10 M NaOH. The resulting mixture was extracted with EtOAc (3×500 mL). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel to give 1-(4,4,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-yl)-cyclopropanecarboxylic acid ethyl ester (65 g, yield: 63.2%). 1H NMR (CDCl3 400 MHz): δ4.21-4.06 (m, 3H), 1.73-1.69 (m, 1H), 1.40-1.10 (m, 17H).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].Br[CH2:10][C:11]#[N:12]>>[C:2]1([CH3:8])[CH:3]=[CH:4][CH:5]=[C:6]([O:7][CH2:10][C:11]#[N:12])[CH:1]=1
Reactant: N#CCBr
Reactant: Cc1cccc(O)c1
Product: Cc1cccc(OCC#N)c1

Procedure:
The title compound was prepared following the same protocol as described in Step 1, Example 36, using the m-cresol instead of the p-cresol and the bromoacetonitrile instead of the methyl bromoacetate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]1[CH2:14][CH2:15][CH2:16][CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][C:19]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](O)=[O:22].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:21](=[O:22])[C:20]2[CH:24]=[CH:25][CH:26]=[C:27]([CH3:28])[C:19]=2[CH3:18])[CH2:10][C@@H:9]1[CH2:14][CH2:15][CH2:16][CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: Cc1cccc(C(=O)O)c1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: CCCC[C@H]1CN(C(=O)c2cccc(C)c2C)CCN1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared according to the procedure described for Example 1, Step A except using 1-tert-butoxycarbonyl-2(S)-n-butylpiperazine (1.26 g, 5.20 mmol), 2,3-dimethylbenzoic acid (0.820 g, 5.46 mmol), HOBT (0.70 g, 5.20 mmol), EDC.HCl (1.09 g, 5.72 mmol) and triethylamine to adjust the pH to 7. The crude product was chromatographed on silica gel with 20% ethyl acetate in hexane. The title compound was obtained as a thick oil (1.76 g). NMR (300 MHz, DMSO-d6) δ 7.15 (2H, m), 6.06 (1H,m), 4.42 (1H,m), 3.6-4.2 (2H, m), 2.7-3.24 (4H, m), 2.24 (3H, s), 2.03-2.20 (3H, 4s), 1.10-1.6 (15H, m), 0.72-1.00 (3H, m).
Reaction SMILES: [CH2:1]([N:8]([CH3:13])[C:9]([NH2:12])=[N:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:21]=[C:22]1[O:26][C:24](=O)[CH2:23]1>C1C=CC=CC=1>[CH2:23]([C:24]1[O:11][N:10]=[C:9]([N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH3:13])[N:12]=1)[C:22]([CH3:21])=[O:26]
Reactant: C=C1CC(=O)O1
Reactant: CN(Cc1ccccc1)C(N)=NO
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(=O)Cc1nc(N(C)Cc2ccccc2)no1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cooled mixture of 2.8 g of 1-benzyl-1-methylhydroxyguanidine and 1.3 g of triethylamine in 30 ml of benzene was added dropwise 1.3 ml of diketene under nitrogen. The reaction mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. After adding 50 ml of toluene to the residue, the resultant solution was heated under reflux for 4 hours with a water separator. The solvent was evaporated in vacuo and the residue was chromatographed on silica gel using chloroform-methanol (70:1) as eluent to give 1.7 g of 5-acetonyl-3-(N-benzyl-N-methylamino)-1,2,4-oxadiazole as a colorless oil, IR νmaxneat cm-1 : 1725, 1590, 1410, 1355, 1155.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][NH:12][C:13]2[N:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8]C.[F:21][C:22]([F:33])([F:32])[O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][N:12]([C:13]2[N:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][N:14]=2)[CH2:28][C:27]2[CH:30]=[CH:31][C:24]([O:23][C:22]([F:21])([F:32])[F:33])=[CH:25][CH:26]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CCc1cnc(NCCc2ccc(OC)c(Cl)c2)nc1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Product: CCc1cnc(N(CCc2ccc(O)c(Cl)c2)Cc2ccc(OC(F)(F)F)cc2)nc1

Procedure:
Similarly prepared from N-[2-(3-chloro-4-methoxyphenyl)ethyl]-5-ethylpyrimidin-2-amine and 4-trifluoromethoxy benzyl bromide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([CH3:12])[C:4]=1[CH3:13].[Li][CH:15](CC)C.CI>O1CCCC1>[CH2:12]([C:5]1[C:4]([CH3:13])=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])[CH3:15]
Reactant: COc1ccc(C(=O)O)c(C)c1C
Reactant: [Li]C(C)CC
Solvent: CI
Solvent: C1CCOC1
Product: CCc1c(C(=O)O)ccc(OC)c1C
Temperature: 78 °C
Reaction time: 0.5 h

Procedure:
2.50 g of 4-methoxy-2,3-dimethylbenzoic acid (G1) are dissolved in 160 ml of tetrahydrofuran under a nitrogen atmosphere and cooled to (−) 78° C. 11.5 ml of sec-BuLi are subsequently added dropwise at such a rate that the temperature of the reaction solution does not exceed (−) 65° C. When the addition is complete, the reddish reaction solution is stirred for a further 30 min with cooling. 3.59 ml of methyl iodide are then slowly added drop-wise. The cooling is subsequently removed, and the mixture is stirred for 1 h. For work-up, 160 ml of water are carefully added. The solution is subsequently extracted twice with 130 ml of ethyl acetate each time. The aqueous phase is cooled in an ice bath with stirring, acidified using 1.0 M HCl and filtered after 30 min. The filter cake is rinsed with cold water and subsequently recrystallised from 2-propanol. The crystals are filtered off with suction and dried for 2 h at 70° C. in vacuo, giving 1.90 g of the title compound as a colourless, crystalline solid having a melting point of 176.7° C.; MS: 194.2 (M+); TLC: Rf=0.29 (diethyl ether/petroleum ether 1:1 parts by volume).