Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C@@H:5]2[O:7][C@H:8]([CH:10]=[O:11])[CH2:9][C@@H:4]2[O:3]1.[CH3:13][Mg]Br>C1COCC1>[CH3:1][C:2]1([CH3:12])[O:6][C@@H:5]2[O:7][C@H:8]([CH:10]([OH:11])[CH3:13])[CH2:9][C@@H:4]2[O:3]1
Reactant: C[Mg]Br
Reactant: CC1(C)O[C@@H]2O[C@H](C=O)C[C@@H]2O1
Solvent: C1CCOC1
Product: CC(O)[C@@H]1C[C@@H]2OC(C)(C)O[C@@H]2O1
Temperature: -20 °C
Reaction time: 20 h
Yield: 212.5 %

Procedure:
To a solution of (3aS,5S,6aS)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxole-5-carbaldehyde (compound 25f, 800 mg, 1 mmol) in THF (20 mL) was added methyl magnesium bromide (2M in THF, 0.7 mL, 1.4 mmol) at −20° C. under argon. After being stirred at −20° C. for 20 hours, the reaction was quenched by saturated NH4Cl solution, extracted with EtOAc (30 mL) three times. The organic layers were combined and concentrated in vacuo to afford 400 mg crude product of 1-[(3aS,5S,6aS)-2,2-dimethyl-3a,5,6,6a-tetrahydro furo[2,3-d][1,3]dioxol-5-yl]ethanol (compound 25g), which was used in next step without further purification. MS obsd. (ESI+) [(M+NH4)+]: 206.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[C:5]([Cl:18])=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:21]=[C:22]([CH2:26][CH2:27][OH:28])[CH:23]=[CH:24][CH:25]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>O1CCOCC1>[Cl:18][C:5]1[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[N:7][C:2]([NH:19][C:20]2[CH:21]=[C:22]([CH2:26][CH2:27][OH:28])[CH:23]=[CH:24][CH:25]=2)=[N:3][CH:4]=1
Reactant: Nc1cccc(CCO)c1
Reactant: COc1cccc(CNc2nc(Cl)ncc2Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(CNc2nc(Nc3cccc(CCO)c3)ncc2Cl)c1
Temperature: 105 °C
Yield: 71.5 %

Procedure:
Into a reaction flask were added 2,5-dichloro-N-(3-methoxybenzyl)pyrimidin-4-amine (0.33 g, 1.2 mmol) (prepared according to Example 1, step A), 1,4-dioxane (20 mL), 2-(3-aminophenyl)ethanol (0.22 g, 1.6 mmol), and p-toluenesulfonic acid monohydrate (0.080 g, 0.42 mmol). The mixture was heated at 105° C. for 3 hours and then an aqueous solution of NaHCO3 (saturated) was added. The organic solvent was removed under vacuum followed by the addition of water and EtOAc. The aqueous layer was extracted with EtOAc twice. The organic layers were combined, dried over Na2SO4, and concentrated under vacuum. The crude was purified by silica gel column chromatography to provide the desired product as a white solid (0.33 g, 74% yield). LCMS for C20H22ClN4O2 (M+H)+: m/z=385.1.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=[O:2].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S([CH2:28][N+:29]#[C-:30])(=O)=O)=CC=1>CO>[O:2]1[C:1]([C:3]2[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=2)=[CH:30][N:29]=[CH:28]1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1ccc(-c2cnco2)cc1
Yield: 79.9 %

Procedure:
Methyl 4-formylbenzoate (Aldrich Chemical Co., St. Louis, Mo.) (5.0 g, 30.5 mmol), anhydrous potassium carbonate (4.55 g, 33 mmol) and p-toluenesulfonylmethyl isocyanide (TOSMIC, Aldrich Chemical Co.) (6.83 g, 30.5 mmol) were refluxed in methanol (100 ml) for 3.5 hours. The mixture was then concentrated to dryness in vacuo. The residue was dissolved in ethyl acetate, washed twice with water, dried and concentrated in vacuo to give methyl 4-(1,3-oxazol-5-yl)benzoate as a beige solid (4.95 g).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5](Cl)([CH3:7])=[O:6].[O:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1>C(Cl)Cl>[O:9]1[C:18]2[C:13](=[CH:14][C:15]([C:5](=[O:6])[CH3:7])=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1
Reactant: CC(=O)Cl
Reactant: c1ccc2c(c1)CCCO2
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)CCCO2
Reaction time: 0.25 h
Yield: 80.1 %

Procedure:
AlCl3 (11.8 g, 88.2 mmol) was added in small portions to a stirred solution of AcCl (11.9 mL, 167.5 mmol) in dry DCM (250 mL) at −10° C. and the mixture stirred until homogeneous (15 min). The solution was added, via a cannula, to a stirred solution of chroman (229) (11.8 g, 88.2 mmol) in dry DCM (200 mL) at −10° C. and the solution stirred for 30 min at −10° C. and then poured into ice/cHCl (5:1 v/v, 1.5 L). The mixture was stirred for 2 h, extracted with DCM (3×100 mL), the combined organic fraction dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (10-20%) of EtOAc/pet. ether, to give 1-(3,4-dihydro-2H-chromen-6-yl)ethanone (230) (12.45 g, 80%) as a white solid: 1H NMR δ 7.68-7.22 (m, 2H, H-5, H-7), 6.82 (d, J=9.2 Hz, 1H, H-8), 4.24 (br dd, J=5.3, 5.2 Hz, 2H, H 2), 2.83 (br t, J=6.5 Hz, 2H, H-4), 2.53 (s, 3H, CH3), 2.00-2.06 (m, 2H, H-3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11]O)[CH:10]=1)[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[N:6]=[CH:5]2.[CH3:17][O:18][C:19]([C:21]1[CH:29]=[CH:28][C:24]2[NH:25][CH:26]=[N:27][C:23]=2[CH:22]=1)=[O:20]>>[CH3:17][O:18][C:19]([C:21]1[CH:29]=[CH:28][C:24]2[N:25]([CH2:11][C:9]3[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]4[C:8]=3[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[N:6]=[CH:5]4)[CH:26]=[N:27][C:23]=2[CH:22]=1)=[O:20]
Reactant: COC(=O)c1ccc2[nH]cnc2c1
Reactant: CC(C)Cn1ncc2cc(Cl)cc(CO)c21
Product: COC(=O)c1ccc2c(c1)ncn2Cc1cc(Cl)cc2cnn(CC(C)C)c12
Yield: 40 %

Procedure:
Compound 34 was prepared following general method 3A, using compound 17 as a starting material and 1H-benzoimidazole-5-carboxylic acid methyl ester as the heterocycle. Yield: 40%.
Reaction SMILES: C[O:2][C:3](=[O:18])[C@H:4]([CH2:14][CH2:15][CH2:16][CH3:17])[NH:5][C:6]([O:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13])=[O:7].[OH-].[Na+].CCOC(C)=O.Cl>C1COCC1>[CH2:9]([O:8][C:6]([NH:5][C@H:4]([C:3]([OH:18])=[O:2])[CH2:14][CH2:15][CH2:16][CH3:17])=[O:7])[CH2:10][CH2:11][CH:12]=[CH2:13]
Reactant: C=CCCCOC(=O)N[C@@H](CCCC)C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCCCOC(=O)N[C@@H](CCCC)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.2 %

Procedure:
To a solution of [(4-pentenyloxy)carbonyl]-L-norleucine methyl ester (1.8 g, 7.0 mmol) in THF (5 mL) at RT was added 1M sodium hydroxide solution (5 mL). The reaction mixture was stirred at RT for 3 h. The reaction mixture was then worked up with EtOAc and 1M HCl. The organic layer was separated and washed with H2O, brine, dried over Na2SO4, filtered and concentrated to give [(4-pentenyloxy)carbonyl]-L-norleucine (1.4 g, 82% yield). 1H NMR (500 MHz, CD3OD) ppm: δ 5.82 (m, 1H), 5.05 (d, 1H), 4.98 (d, 1H), 4.86 (brs, 2H), 4.10 (m, 1H), 4.08 (t, 2H), 2.16 (q, 2H), 1.82 (m, 1H), 1.72 (m, 3H), 1.38 (m, 4H), 0.93 (t, 3H).
Reaction SMILES: [C:1]([C:11]1[S:27][C:14]2[C:15]3[S:23][C:22]4[C:21]5[S:24][CH:25]=[CH:26][C:20]=5[S:19][C:18]=4[C:16]=3[S:17][C:13]=2[C:12]=1[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>[Pt].C(OCC)(=O)C>[CH2:1]([C:11]1[S:27][C:14]2[C:15]3[S:23][C:22]4[C:21]5[S:24][CH:25]=[CH:26][C:20]=5[S:19][C:18]=4[C:16]=3[S:17][C:13]=2[C:12]=1[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCC#Cc1sc2c(sc3c2sc2c4sccc4sc23)c1CCCCCCCCCC
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CCCCCCCCCCc1sc2c(sc3c2sc2c4sccc4sc23)c1CCCCCCCCCC
Reaction time: 24 h

Procedure:
2-dec-1-ynyl-3-decanyldithieno[2,3-d:2′,3′-d′]thieno[3,2-b:4,5-b′]dithiophene (107) (2.2 g, 4.15 mmol) was dissolved into ethyl acetate (30 mL). To this solution, 5% Pt/C (0.5 g) was added. The mixture was stirred under a H2 atmosphere (90 psi) for 24 hours. The solution was then filtered. After removal of the ethyl acetate, the residue was purified by chromatography on silica gel eluted with hexane to produce the target compound (2.00, 90.5%). Mp. 50.9-52.5° C. 1H NMR: solvent, CD2Cl2 δ 7.41 (d, 1H), 7.33 (d, 1H), 2.83 (t, 2H), 2.50 (t, 2H), 1.73-1.26 (m, 32H), 0.87 (m, 6H). 13C NMR: 140.85, 140.40, 139.93, 133.38, 133.14, 132.22, 129.69, 121.17, 120.09, 98.92, 32.29, 32.25, 29.99, 29.94, 29.72, 29.63, 29.52, 29.33, 29.18, 29.06, 28.94, 23.05, 14.23.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1.[Br:12][C:13]1[CH:14]=[C:15]([C:20]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:29]=2[C:35]#[N:36])=[N:21]S(C(C)(C)C)=O)[CH:16]=[CH:17][C:18]=1[F:19]>>[Br:12][C:13]1[CH:14]=[C:15]([C:20]2([C:2]3[CH:7]=[CH:6][N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=3)[C:28]3[C:29](=[C:30]([F:34])[CH:31]=[CH:32][CH:33]=3)[C:35]([NH2:36])=[N:21]2)[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: FC(F)(F)c1cc(Br)ccn1
Reactant: CC(C)(C)S(=O)N=C(c1ccc(F)c(Br)c1)c1cccc(F)c1C#N
Product: NC1=NC(c2ccnc(C(F)(F)F)c2)(c2ccc(F)c(Br)c2)c2cccc(F)c21
Yield: 35 %

Procedure:
The title compound was synthesized as described for Example 11i in 35% yield, starting from of 4-bromo-2-(trifluoromethyl)pyridine (0.159 g, 0.71 mmol) and N-((3-bromo-4-fluorophenyl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (0.300 g, 0.71 mmol);
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][C:7]2=[O:12].[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[O:12]=[C:7]1[C:8]2[C:3](=[C:2]([NH:1][C:13](=[O:15])[CH3:14])[CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:5][NH:6]1
Reactant: Nc1cccc2c1CCNC2=O
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1cccc2c1CCNC2=O
Temperature: 0 °C
Yield: 56 %

Procedure:
To 1.0 g (6.17 mmol) of 5-amino-3,4-dihydro-1(2H)-isoquinolinone was added 3 ml of acetic anhydride and the solution was warmed on a steam bath for one hour. It was poured into ice water and heated on a steam bath until all material dissolved. The solution was allowed to cool, the solid was collected, washed with water, and dried to give 0.7 g (56%) of product; mp 244°-246°.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@H:11]1[CH2:14][C@H:13]([NH2:15])[CH2:12]1.[Cl:16][C:17]1[C:22](Cl)=[N:21][CH:20]=[CH:19][N:18]=1>C(O)(C)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@H:11]1[CH2:12][C@H:13]([NH:15][C:22]2[C:17]([Cl:16])=[N:18][CH:19]=[CH:20][N:21]=2)[CH2:14]1
Reactant: Clc1nccnc1Cl
Reactant: N[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Solvent: CC(C)O
Product: Clc1nccnc1N[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Temperature: 150 °C

Procedure:
Trans-N1-(benzo[d]thiazol-2-yl)cyclobutane-1,3-diamine (intermediate 11, 0.058 g, 0.264 mmol) and 2,3-dichloropyrazine (0.035 ml, 0.336 mmol) were suspended in isopropanol (1 mL) in a microwave vial. The mixture was heated at 150° C. for 90 minutes. The mixture was evaporated to dryness under reduced pressure and purified using silica chromatography (hexane to ethyl acetate gradient) to give trans-N1-(benzo[d]thiazol-2-yl)-N3-(3-chloropyrazin-2-yl)cyclobutane-1,3-diamine (0.0594 g, 0.179 mmol, 67.7% yield) as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([N:12]([CH3:14])[CH3:13])=[CH:8][C:9]=2[CH3:11])[S:4][C:3]=1[C:15]([NH2:17])=[O:16].[NH:18]1C=CN=[CH:19]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.CCOC(C)=O>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([N:12]3[CH:13]=[CH:19][N:18]=[CH:14]3)=[CH:8][C:9]=2[CH3:11])[S:4][C:3]=1[C:15]([NH2:17])=[O:16]
Reactant: Cc1cc(N(C)C)nc2sc(C(N)=O)c(N)c12
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(-n2ccnc2)nc2sc(C(N)=O)c(N)c12
Temperature: 80 °C
Reaction time: 2 h
Yield: 20.2 %

Procedure:
To a solution of 20 mg (0.067 mmol) of starting 4-methylpyridine triflate intermediate (see Example 2) in 1.2 mL of 1,4-dioxane was added 9.2 mg of imidazole. The resulting mixture was stirred for 2 h at 80° C. After that time 0.5 mL of 2M solution of sodium carbonate was added. The stirring was continued overnight at 100° C. The reaction mixture was then cooled to room temperature, diluted with EtOAc, dried with sodium sulfate and concentrated. The crude product was chromatographed (preparative TLC on silica gel eluting with 10% MeOH/methylene chloride, Rf=0.56) to afford 3.7 mg of product, which was further purified by HPLC (reverse phase—solvent system: isocratic 60% water/acetonitrile providing 2.7 mg (14.7%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:18])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]2=[CH:15][CH:16]=[CH:17][N:13]2[N:12]=[CH:11][N:10]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:29][C:30](=[NH:33])SC)=[O:28])=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([NH:18][C:30]([NH:29][C:27](=[O:28])[CH2:26][C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)=[NH:33])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]2=[CH:15][CH:16]=[CH:17][N:13]2[N:12]=[CH:11][N:10]=1
Reactant: CSC(=N)NC(=O)Cc1ccc(F)cc1
Reactant: Nc1ccc(Oc2ncnn3cccc23)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: N=C(NC(=O)Cc1ccc(F)cc1)Nc1ccc(Oc2ncnn3cccc23)c(F)c1
Temperature: 110 °C
Reaction time: 6 h

Procedure:
To a test tube containing 3-fluoro-4-(pyrrolo[2,1-f][1,2,4]triazin-4-yloxy)benzenamine (20 mg, 0.082 mmol) and 1-(2-(4-fluorophenyl)acetyl)-2-methylisothiourea (20 mg, 0.086 mmol) was added 0.3 mL of toluene followed by diisopropylethylamine (15 μL, 0.086 mmol). The reaction was stirred at 110° C. for 6 h. Additional portions of 1-(2-(4-fluorophenyl)-acetyl)-2-methylisothiourea (20 mg, 0.086 mmol) and diisopropylethylamine (15 μL, 0.086 mmol) were added. After stirring at 110° C. overnight, the reaction was cooled to room temperature and purified directly by flash chromatography on silica gel (SiO2, EtOAc/Hexane 1:1) to give the title compound as a white solid. The solid was treated with 4 N HCl in dioxane at 0° C. for 30 min. The solution was concentrated in vacuo to give the HCl salt of the title compound (15 mg, 40%) as a white powder. 1H NMR (CDCl3) δ 13.8 (br s, 1H), 11.5 (br s, 1H), 9.48 (br s, 1H), 7.85 (s, 1H), 7.78 (dd, 1H, J=2.5, 1.4 Hz), 7.30 (m, 5H), 7.01 (m, 3H), 6.85 (m, 1H); MS(ESI+) m/z 423.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=1[CH3:17].C(O[C:21](=[NH:23])[CH3:22])C.[C:24]([OH:27])(=[O:26])[CH3:25]>C(#N)C>[C:24]([OH:27])(=[O:26])[CH3:25].[NH:23]=[CH:21][CH2:22][NH:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=1[CH3:17]
Reactant: COc1cc(C)c(-c2c(C)n[nH]c2N)c(C)c1
Reactant: CCOC(C)=N
Solvent: CC(=O)O
Solvent: CC#N
Product: COc1cc(C)c(-c2c(C)n[nH]c2NCC=N)c(C)c1
Reaction time: 8 h

Procedure:
To a solution of 5-amino-4-(4-methoxy-2,6-dimethylphenyl)-3-methylpyrazole (1.89 g) (prepared from 4-methoxy-2,6-dimethyl benzaldehyde according to Example 1 C-F) in acetonitrile (30 mL) add ethylacetimidate (free base, 1.8 mL) followed by acetic acid (0.47 mL). Collect the precipitate that formed upon stirring overnight by filtration. Wash the solid with dry ether and dry to afford 2.61 g of (iminoethyl)[4-(4-methoxy-2,6-dimethylphenyl)-3-methylpyrazol−5-yl]amine acetate salt as a white powder.
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5].Br[C:13]1([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15]C1>FC(F)(F)S([O-])(=O)=O.[Ag+]>[CH3:19][C:13]1([O:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: CCOC(=O)/C(=N\O)C(C)=O
Reactant: CC1(Br)CCCCC1
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Product: CCOC(=O)/C(=N\OC1(C)CCCC1)C(C)=O
Yield: 50.1 %

Procedure:
Ethyl (Z)-2-(hydroxyimino)-3-oxobutyrate (5.86 g, 36.8 mmol), 1-bromo-1-methylcyclohexane (6.01 g 36.8 mmol), and silver trifluoromethanesulphonate (9.45 g, 36.8 mmol) were reacted together by a similar method to that described in Example 9a to give the title compound (4.45 g, 50%); νmax (film) 2970, 1745, 1690, 1590, 1370, 1320, 1230, 1070, and 990 cm-1 ; δH (60 MHz, CDCl3), 1.31 (3H, t, J 7 Hz), 1.48 (3H, s), 1.1-2.2 (8H, m), 2.35 (3H, s), and 4.30 (2H, q, J 7 Hz).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][C:8]#[C:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])=[CH:12][CH:11]=1)[C:3]([O:5][CH3:6])=[O:4]>[O-]S(C(F)(F)F)(=O)=O.[Ag+]>[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][NH:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]2[CH2:8][CH2:7][C@@H:2]([C:3]([O:5][CH3:6])=[O:4])[N:1]=2)=[CH:11][CH:12]=1
Reactant: COC(=O)[C@@H](N)CC#Cc1ccc(NCc2ccccc2F)cc1
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Product: COC(=O)[C@@H]1CCC(c2ccc(NCc3ccccc3F)cc2)=N1
Yield: 29.5 %

Procedure:
A solution of methyl (2S)-2-amino-5-(4-{[(2-fluorophenyl)methyl]amino}phenyl)-4-pentynoate (D66, 132 mg) and silver triflate (11 mg, 0.045 mmol) was stirred at room temperature 6.5 h. Then silica gel was added and the solvent evaporated. The residue was purified using flash chromatography eluting with a cyclohexanes:ethyl acetate gradient (12%-100%) to afford the title compound (39 mg, 26%). MS: (ES/+) m/z: 327 [MH]+, C19H19FN2O2 requires 326.
Reaction SMILES: [OH-:1].[K+].C(P(C(C)(C)C)C1C=CC=CC=1[C:14]1[C:19](C(C)C)=[CH:18][C:17](C(C)C)=[CH:16][C:15]=1[CH:26](C)C)(C)(C)C>C1(C)C=CC=CC=1.CCOC(C)=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]>[CH2:26]([O:1][CH2:26][C:15]1[CH:14]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:14]=1
Reactant: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Reactant: [OH-]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: c1ccc(COCc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 1.25 h

Procedure:
Method C) Compound 10 was dissolved in toluene (8 mml/mmol) and to the solution was added potassium hydroxide (2 eq, 11.7N) and the solution was degassed. To the solution was added properly substituted benzyl bromide (1.1 eq), 2-di-t-butylphosphino-2′,4′,6′-triisopropylbiphenyl (0.06 eq) and tris-(dibenzylideneaceton)-dipalladium(0) (0.03 eq). The mixture was stirred at 60° C. for 1.25 hrs. The mixture was cooled to room temperature, diluted with EtOAc and washed with 5% NaHCO3 solution (10 ml/mmol). The organic layers were dried on MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to give compound 12 in yields varying from 30-80%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]#[N:10])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.[CH:17]([OH:20])([CH3:19])[CH3:18].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([O:20][CH:17]([CH3:19])[CH3:18])[C:5]([C:9]#[N:10])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1
Reactant: N#Cc1c(Cl)nc(N)nc1-c1ccccc1
Reactant: CC(C)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: CC(C)Oc1nc(N)nc(-c2ccccc2)c1C#N

Procedure:
From 2-amino-4-chloro-6-phenyl-pyrimidine-5-carbonitrile, isopropanol and DBU in DME. EI-MS m/e (%): 254 (M+, 41), 212 ([M—C3H6]+, 55), 184 (35), 170 (100).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:15][N:16]1[C:24]2[C:19](=[CH:20][C:21]([C:25]([OH:34])([C:30]([F:33])([F:32])[F:31])[C:26]([F:29])([F:28])[F:27])=[CH:22][CH:23]=2)[CH:18]=[C:17]1[CH3:35].[CH3:36][Mg]Br>C1COCC1.C(OCC)C>[F:29][C:26]([F:27])([F:28])[C:25]([C:21]1[CH:20]=[C:19]2[C:24](=[CH:23][CH:22]=1)[N:16]([CH2:15][C:3]1[N:4]=[C:5]([C:7]3[CH:8]=[CH:9][C:10]([CH:11]([OH:12])[CH3:36])=[CH:13][CH:14]=3)[O:6][C:2]=1[CH3:1])[C:17]([CH3:35])=[CH:18]2)([OH:34])[C:30]([F:33])([F:32])[F:31]
Reactant: Cc1oc(-c2ccc(C=O)cc2)nc1Cn1c(C)cc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc21
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1oc(-c2ccc(C(C)O)cc2)nc1Cn1c(C)cc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc21
Reaction time: 1 h
Yield: 85 %

Procedure:
A solution of 50 mg (0.1 mmol) of 4-{5-methyl-4-[2-methyl-5-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-indol-1-ylmethyl]-oxazol-2-yl}-benzaldehyde in 1 ml of THF was cooled to 0° C. and treated with 0.13 ml (0.4 mmol) of a 3M methylmagnesium bromide solution in diethylether. The mixture was stirred and allowed to reach RT within 1 hr. Distribution of the crude between a saturated aqueous solution of NH4Cl and EtOAc, drying of the combined organic phases over Na2SO4, evaporation of the solvent, and chromatography on silica gel with heptane/EtOAc 4:1 gave 44 mg (85%) of 1,1,1,3,3,3-hexafluoro-2-(1-{2-[4-(1-hydroxy-ethyl)-phenyl]-5-methyl-oxazol-4-ylmethyl}-2-methyl-1H-indol-5-yl)-propan-2-ol, off-white solid, MS: 513 (MH+).
Reaction SMILES: [C:1]([C:3]([CH3:14])([CH3:13])[N:4]1[CH2:9][CH2:8][N:7]([C:10]([OH:12])=[O:11])[CH2:6][CH2:5]1)#[N:2].C([O-])([O-])=O.[K+].[K+].OO.[OH2:23]>CS(C)=O>[C:3]([O:11][C:10]([N:7]1[CH2:8][CH2:9][N:4]([C:3]([C:1](=[O:23])[NH2:2])([CH3:14])[CH3:13])[CH2:5][CH2:6]1)=[O:12])([CH3:14])([CH3:13])[CH3:1]
Reactant: O
Reactant: CC(C)(C#N)N1CCN(C(=O)O)CC1
Agent: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(C(C)(C)C(N)=O)CC1
Temperature: 40 °C

Procedure:
To a cooled (ice/water bath) solution of 4-(cyano-dimethyl-methyl)-piperazine-1-carboxylic acid tent-butyl ester (102.9 mg) in dry DMSO was added K2CO3 (9.8 mg) followed by 28% hydrogen peroxide solution (200 μL) dropwise. The resultant was heated at 40° C. overnight. Water was added and the white solid collected, washed with water and air dried to give 4-(1-carbamoyl-1-methyl-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (59.6 mg). (See Tetrahedron 2002, 58, 3217). Treatment of this compound with HCl in DCM/MeOH yielded the desired amine, which was isolated as the hydrochloride salt.
Reaction SMILES: F[B-](F)(F)F.C[N+](C)=C(N(C)C)ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[C:30]([C:32]1[CH:37]=[CH:36][C:35]([CH:38]2[C:47]3[C:46](=[O:48])[CH2:45][CH2:44][CH2:43][C:42]=3[N:41]([C:49]3[CH:54]=[CH:53][CH:52]=[C:51]([C:55]([F:58])([F:57])[F:56])[CH:50]=3)[C:40](=[O:59])[N:39]2[CH2:60][C:61]([OH:63])=O)=[CH:34][CH:33]=1)#[N:31].[CH3:64][N:65]1[C:69]2[CH2:70][NH:71][CH2:72][C:68]=2[CH:67]=[N:66]1>CN(C)C=O>[CH3:64][N:65]1[C:69]2[CH2:70][N:71]([C:61](=[O:63])[CH2:60][N:39]3[CH:38]([C:35]4[CH:34]=[CH:33][C:32]([C:30]#[N:31])=[CH:37][CH:36]=4)[C:47]4[C:46](=[O:48])[CH2:45][CH2:44][CH2:43][C:42]=4[N:41]([C:49]4[CH:54]=[CH:53][CH:52]=[C:51]([C:55]([F:57])([F:56])[F:58])[CH:50]=4)[C:40]3=[O:59])[CH2:72][C:68]=2[CH:67]=[N:66]1
Reactant: N#Cc1ccc(C2C3=C(CCCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2CC(=O)O)cc1
Reactant: Cn1ncc2c1CNC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1ncc2c1CN(C(=O)CN1C(=O)N(c3cccc(C(F)(F)F)c3)C3=C(C(=O)CCC3)C1c1ccc(C#N)cc1)C2

Procedure:
N,N,N′,N′-Tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate (161 mg, 0.50 mmol) and triethylamine (210 μL, 1.51 mmol) are added to a mixture of 2-(4-(4-cyanophenyl)-2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,5,6,7,8-hexahydroquinazolin-3(4H)-yl)acetic acid (example 32, 235 mg, 0.50 mmol) in N,N-dimethylform-amide (2 mL). After 5 min a solution of 1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole (123 mg, 1.00 mmol) in N,N-dimethylformamide (3 mL) is added, and the mixture is stirred over night and purified by preparative HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% NH3). Yield: 86 mg; ESI mass spectrum [M+H]+=575; Retention time HPLC: 0.86 min (Z011_S03).