Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C@@H:7]([C:9]([OH:11])=[O:10])[NH2:8])=[CH:2]1.C(=O)([O-])[O-].[Na+].[Na+].C([N:23]1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33])(OCC)=O.Cl>O.O1CCOCC1>[C:27]1(=[O:28])[N:23]([NH:8][C@H:7]([C:9]([OH:11])=[O:10])[CH2:6][C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[C:24](=[O:33])[C:25]2=[CH:32][CH:31]=[CH:30][CH:29]=[C:26]12
Reactant: N[C@@H](Cc1ccsc1)C(=O)O
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)[C@H](Cc1ccsc1)NN1C(=O)c2ccccc2C1=O
Temperature: 0 °C

Procedure:
3-(3-Thienyl)-L-alanine (2.45 g., 14.3 mmol.) was suspended in water/p-dioxane (22 ml/11 ml.) at room temperature under argon. Sodium carbonate (1.52 g.) was added and the mixture was stirred until homogeneous. N-Carbethoxyphthalimide (3.14 g.) was added, and the resulting mixture was stirred for 3.0 hours and then cooled to 0° C. The pH was adjusted to 1.5 with 6 N hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 10% potassium bisulfate and brine, dried (sodium sulfate), filtered, and concentrated. The crude product was flash chromatographed (Merck silica gel) eluting with 1:1 ethyl acetate/hexane/1% acetic acid. The fractions containing clean desired product were combined, concentrated, azeotroped with ethyl acetate, and washed with water to remove the acetic acid. The organic layer was dried (sodium sulfate), filtered, and concentrated to give 3.22 g. of title compound as a white crystalline product; m.p. 166°-168° C.; [α]D =-146.8° (c=0.46, methylene chloride). TLC (1% acetic acid in 1:1 ethyl acetate/hexane) Rf =0.31.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24]Br)[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2].C(OCC)(=O)C.[CH3:33][CH:34]([CH2:38][CH3:39])[C:35]([OH:37])=[O:36]>CC(C)=O.[OH-].[Na+].O>[CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24][O:37][C:35](=[O:36])[CH:34]([CH3:33])[CH2:38][CH3:39])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2]
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CBr
Reactant: CCC(C)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCC(C)C(=O)OCC(=O)O[C@H]1[C@@H](CC)C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21C

Procedure:
In 30 ml of acetone is dissolved 0.4 ml of 2-methylbutyric acid, and 2.0 ml of 2N-NaOH and 3 ml of water is added, followed by addition of 0.88 g of 16β-ethyl-17β-bromoacetoxy-4-estren-3-one. The mixture is refluxed for 6 hours and allowed to stand at room temperature (15°-25° C.) for 2 days, followed by addition of 150 ml of ethyl acetate. The organic layer is separated, washed with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure and the residue is subjected to column chromatography. Following passage of 100 ml of diisopropyl ether-n-hexane (2:8), elution is carried out with 400 ml of a 1:1 mixture of the same solvents. The eluate is evaporated under reduced pressure to remove the solvent, giving 0.8 g of the above-identified compound as a light-yellow viscous oil.
Reaction SMILES: CO[CH:3]([O:13]C)[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][C:5]=1[F:12].[Cl:15][C:16]1[C:21]([Cl:22])=[CH:20][C:19]([NH2:23])=[C:18]([NH2:24])[CH:17]=1.C1(=O)C=CC(=O)C=C1>CO>[Cl:15][C:16]1[C:21]([Cl:22])=[CH:20][C:19]2[N:23]=[C:8]([C:7]3[CH:10]=[CH:11][C:4]([CH:3]=[O:13])=[C:5]([F:12])[CH:6]=3)[NH:24][C:18]=2[CH:17]=1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: COC(OC)c1ccc(C=O)cc1F
Agent: O=C1C=CC(=O)C=C1
Solvent: CO
Product: O=Cc1ccc(-c2nc3cc(Cl)c(Cl)cc3[nH]2)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.7 %

Procedure:
A mixture of 4-dimethoxymethyl-3-fluorobenzaldehyde (321 mg, 1.62 mmol), 4,5-dichloro-1,2-phenylenediamine (283 mg, 1.60 mg) and 1,4-benzoquinone (173 mg, 1.60 mmol) in methanol (10 mL) was heated to reflux for 2 h. The solvent was removed under reduced pressure. To the residue were added tetrahydrofuran (15 mL) and hydrochloric acid (1 mol/L; 1.6 mL), and the mixture was stirred at room temperature for 16 h. Water was added and the precipitated products were collected by filtration, followed by trituration with ether to afford 5,6-dichloro-2-(3-fluoro-4-formylphenyl)benzimidazole (132 mg, 26%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[N:9][CH:8]=[CH:7][CH:6]=2.[C:23](OC)(OC)(OC)[CH2:24][CH2:25][CH2:26][CH3:27].C1(C)C=CC=CC=1>C1(C)C(C)=CC=CC=1>[CH2:24]([C:23]1[N:12]([CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])[C:11]2[C:10]3[N:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CC(C)(C)OC(=O)NCCNc1c(N)cnc2cccnc12
Reactant: CCCCC(OC)(OC)OC
Solvent: Cc1ccccc1
Solvent: Cc1ccccc1C
Product: CCCCc1nc2cnc3cccnc3c2n1CCNC(=O)OC(C)(C)C
Yield: 47.4 %

Procedure:
1,1-Dimethylethyl N-{2-[(3-amino[1,5]naphthyridin-4-yl)amino]ethyl}carbamate 0.6 g, 2 mmol), trimethyl orthovalerate (0.35 g, 2.1 mmol), and toluene (25 mL) were combined and heated at reflux for 2 hours. Additional trimethyl orthovalerate (1 eq.) was added and the reaction mixture was heated at reflux overnight. Xylene was added and the toluene was distilled off. The reaction was heated at reflux for an additional 8 hours. The bulk of the xylene was distilled off leaving a volume of about 5 mL. The reaction mixture was allowed to cool. The resulting precipitate was isolated by filtration, washed with heptane and dried to provide 0.35 g of 1,1-dimethylethyl N-[2-(2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]carbamate as an ivory powder, m.p. 198-199° C. Analysis: Calculated for C20H27N5O2: %C, 65.01; %H, 7.36; %N, 18.95. Found: %C, 64.75; %N, 7.57; %N, 19.09.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[Si]([O:20][CH:21]1[CH2:26][O:25][C:24]2([CH2:31][CH2:30][CH:29]([N:32]3[C:37](=[O:38])[C:36]([CH2:39][C:40]4[CH:45]=[CH:44][C:43]([C:46]5[C:47]([C:52]#[N:53])=[CH:48][CH:49]=[CH:50][CH:51]=5)=[CH:42][CH:41]=4)=[C:35]([CH2:54][CH2:55][CH3:56])[N:34]4[N:57]=[CH:58][N:59]=[C:33]34)[CH2:28][CH2:27]2)[O:23][CH2:22]1)(C(C)(C)C)(C)C>O.C(OCC)(=O)C>[OH:20][CH:21]1[CH2:26][O:25][C:24]2([CH2:27][CH2:28][CH:29]([N:32]3[C:37](=[O:38])[C:36]([CH2:39][C:40]4[CH:41]=[CH:42][C:43]([C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=5[C:52]5[NH:3][C:4](=[O:7])[O:5][N:53]=5)=[CH:44][CH:45]=4)=[C:35]([CH2:54][CH2:55][CH3:56])[N:34]4[N:57]=[CH:58][N:59]=[C:33]34)[CH2:30][CH2:31]2)[O:23][CH2:22]1
Reactant: [NH3+]O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OCC(O[Si](C)(C)C(C)(C)C)CO3)c2ncnn12
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC3(CC2)OCC(O)CO3)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 51.1 %

Procedure:
A mixture of hydroxylammonium chloride (1.4 g), sodium hydrogen carbonate (2.3 g) and dimethyl sulfoxide (3 mL) was stirred at 40° C. for 30 min, 4′-{[4-(3-{[tert-butyl(dimethyl)silyl]oxy}-1,5-dioxaspiro[5.5]undec-9-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.91 g) was added, and the mixture was stirred at 90° C. for 15 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (5 mL). N,N′-Carbonyldiimidazole (0.27 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.24 mL) were added, and the mixture was stirred at room temperature for 1.5 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was acidified with 1 M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). Tetrabutylammonium fluoride (3.4 mL, 1.0 M tetrahydrofuran solution) was added and the mixture was stirred at 70° C. for 3.5 hr. The reaction mixture was added to 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.426 g, 51%).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[CH2:10][CH2:9][CH:8]=[CH:7]1.N1C=CC=CC=1.CS([Cl:21])(=O)=O>CN(C)C=O>[Cl:21][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[CH2:10][CH2:9][CH:8]=[CH:7]1
Reactant: CS(=O)(=O)Cl
Reactant: OCCCCC1C=CCC1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: ClCCCCC1C=CCC1

Procedure:
3-(4-Hydroxybut-1-yl)cyclopentene {2-cyclopentene-1-butanol} (51 g, 0.37 moles) is diluted in dimethylformamide (100 ml) and added to pyridine (38 g, 0.40 moles). The solution is stirred and methanesulfonyl chloride (46 g, 0.40 moles) is added dropwise over 10 minutes. The reaction is partitioned between hexane (500 ml) and the organic phase separated. The aqueous layer is extracted with hexane (2×500 ml) and the organic extracts combined. The solvent volume is reduced under vacuum and the residue dried over anhydrous magnesium sulfate. The solid is filtered off and the remaining solvent removed leaving a clear yellow oil. The crude product is fractionally distilled under reduced pressure leaving a clear, colorless oil (43 g, 0.27 moles), BP 40°0/0.2 mm.
Reaction SMILES: [Br:1][C:2]1[N:18]=[C:5]2[N:6]=[C:7]([Cl:17])[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:9](Br)[N:4]2[N:3]=1.CO.C1COCC1>C(O)(=O)C>[Br:1][C:2]1[N:18]=[C:5]2[N:6]=[C:7]([Cl:17])[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][N:4]2[N:3]=1
Reactant: Clc1nc2nc(Br)nn2c(Br)c1-c1ccccc1
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Clc1nc2nc(Br)nn2cc1-c1ccccc1
Temperature: 45 °C

Procedure:
A mixture of 29.4 g 2,7-dibromo-5-chloro-6-phenyl[1,2,4]triazolo[1,5-a]pyrimidine, 125 mL methanol, 500 mL THF, 12.9 mL glacial acetic acid and 14.7 g of Zn/Cu pair were stirred at 45° C. After 3 and 5 hours additional portions of 7.3 g Zn/Cu pair were added. The mixture was filtered through celite and the filtrate was diluted with water and ethyl acetate. The phases were separated and the water layer was extracted with ethyl acetate. The combined organic layers were washed with saturated Na2CO3 solution, dried over Na2SO4 and the solvent was evaporated. The solid residue was stirred in a mixture of 2-propanol/ethanol (3:1) for 2 h. The crude product was filtered and dried and was used without further purification.
Reaction SMILES: C[S:2]([C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]([F:23])([F:22])[F:21])[CH:18]=3)[N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH:12]=2)[C:8]([C:34]#[N:35])=[CH:7][N:6]=1)(=O)=O.[C:36]1(S)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.CCN(C(C)C)C(C)C.O[Li].O>C1COCC1.O>[C:36]1([S:2][C:5]2[N:10]=[C:9]([C:11]3[C:19]4[C:14](=[N:15][CH:16]=[C:17]([C:20]([F:23])([F:22])[F:21])[CH:18]=4)[NH:13][CH:12]=3)[C:8]([C:34]#[N:35])=[CH:7][N:6]=2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: Sc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(S(C)(=O)=O)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Agent: [Li]O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cnc(Sc2ccccc2)nc1-c1c[nH]c2ncc(C(F)(F)F)cc12
Reaction time: 1.5 h
Yield: 47 %

Procedure:
2-(methylsulfonyl)-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile (75 mg, 0.15 mmol) was heated with benzenethiol (31 uL, 0.30 mmol, 2.0 Eq.) and DIPEA (78 uL, 0.45 mmol, 3.0 Eq.) in THF (2 mL) under microwave conditions at 100° C. for 10 minutes. A solution of LiOH.H2O (32 mg, 0.75 mmol, 5.0 Eq.) in water (1 mL) was added to the mixture and the reaction left to stir for 90 minutes. The reaction was partitioned between EtOAc and water and the aqueous phase extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The resultant solid was purified by column chromatography (ISCO Companion™, 12 g column, 0-30% EtOAc/Petroleum Ether) and lyophilized to give the title compound as a pale yellow solid (28 mg, 47% over 2 steps).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11]([N+:15]([O-])=O)=[C:12]([CH3:14])[N:13]=2)=[CH:5][CH:4]=1.[H][H].[CH3:20][C:21](O)=[O:22]>C(OC(=O)C)(=O)C.[Pt]>[C:21]([NH:15][C:11]1[NH:10][C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:13][C:12]=1[CH3:14])(=[O:22])[CH3:20]
Reactant: COc1ccc(-c2nc(C)c([N+](=O)[O-])[nH]2)cc1
Reactant: [H][H]
Reactant: CC(=O)O
Agent: [Pt]
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(-c2nc(C)c(NC(C)=O)[nH]2)cc1
Yield: 84 %

Procedure:
A solution of 41 (3.5 g, 0.015 mole) dissolved in glacial HOAc (35 ml)-acetic anhydride (105 ml) was hydrogenated at 50 psi over 5% platinum on charcoal catalyst (0.75 g) until uptake of hydrogen was complete. Catalyst was filtered off and the filtrate was evaporated to dryness under reduced pressure. The residue was dissolved in H2O (50 ml) and heated on a steam bath for 1 hour. The cooled solution was washed with ether (4×10 ml) and then evaporated to dryness in vacuo. Recrystallization of the residue from CHCl3 gave 3.07 g (84%) of 42 in two crops; m.p. 202°-204° C.
Reaction SMILES: [CH:1]1([CH2:7][C:8]([NH:10][C@@H:11]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:12]([N:14]2[C@H:29]([C:30]([OH:32])=O)[CH2:28][C@@:16]3([O:20][C:19](=[O:21])[N:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:17]3)[CH2:15]2)=[O:13])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:37][C@@H:38]([CH2:47][CH2:48][CH3:49])[CH:39]([OH:46])[C:40]([NH:42][CH:43]1[CH2:45][CH2:44]1)=[O:41]>>[CH:1]1([CH2:7][C:8]([NH:10][C@@H:11]([C:33]([CH3:35])([CH3:36])[CH3:34])[C:12]([N:14]2[C@H:29]([C:30]([NH:37][C@@H:38]([CH2:47][CH2:48][CH3:49])[CH:39]([OH:46])[C:40]([NH:42][CH:43]3[CH2:44][CH2:45]3)=[O:41])=[O:32])[CH2:28][C@@:16]3([O:20][C:19](=[O:21])[N:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:17]3)[CH2:15]2)=[O:13])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCC[C@H](N)C(O)C(=O)NC1CC1
Reactant: CC(C)(C)[C@H](NC(=O)CC1CCCCC1)C(=O)N1C[C@]2(C[C@H]1C(=O)O)CN(c1ccccc1)C(=O)O2
Product: CCC[C@H](NC(=O)[C@@H]1C[C@]2(CN(c3ccccc3)C(=O)O2)CN1C(=O)[C@@H](NC(=O)CC1CCCCC1)C(C)(C)C)C(O)C(=O)NC1CC1
Yield: 30.6 %

Procedure:
Following the same procedure as Example 1 step 9 using (5R,8S)-7-((S)-2-(2-cyclohexylacetamido)-3,3-dimethylbutanoyl)-2-oxo-3-phenyl-1-oxa-3,7-diazaspiro[4.4]nonane-8-carboxylic acid (49 mg, 98 μmol) and (3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide (31 mg, 137 μmol, 1.4 eq.) gave 20 mg (30 μmol) of (5R,8S)-7-((S)-2-(2-cyclohexylacetamido)-3,3-dimethylbutanoyl)-N-((3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-yl)-2-oxo-3-phenyl-1-oxa-3,7-diazaspiro[4.4]nonane-8-carboxamide (G2). LC MS+/−: 668.56/666.64 at 3.24 min (10-90%, 3-5 min, Formic Acid).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.[Br:13][CH2:14][CH2:15]Br>>[Br:13][CH2:14][CH2:15][NH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: BrCCBr
Reactant: COC(=O)Cc1cccc(N)c1
Product: COC(=O)Cc1cccc(NCCBr)c1

Procedure:
Methyl (3-aminophenyl)acetate (1 g) and 1,2-dibromoethane (5 ml) were heated at 100° C. for 5 hours. After cooling, the resultant was purified by column chromatography (ethyl acetate: isohexane 7:3) to give the titled compound as an oil. Yield: 280 mg (17%).
Reaction SMILES: [CH2:1]([N:8]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C@H:9]1[CH2:14][CH2:13][C@@H:12]([N:15]([CH:17]([CH3:19])[CH3:18])[CH3:16])C[C@H]1CC#N)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:30]([Li])([CH3:32])[CH3:31].CCCCC.[CH2:39]1[CH2:43][O:42][CH2:41][CH2:40]1>>[CH2:1]([N:8]([CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C@H:9]1[CH2:14][CH2:13][C@@H:12]([N:15]([CH:17]([CH3:19])[CH3:18])[CH3:16])[CH2:43][C@H:39]1[CH2:40][C:41](=[O:42])[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)N(C)[C@@H]1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)[C@H](CC#N)C1
Reactant: C1CCOC1
Reactant: [Li]C(C)C
Solvent: CCCCC
Product: CC(C)C(=O)C[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N(Cc1ccccc1)Cc1ccccc1
Temperature: -7 °C
Reaction time: 2.5 h

Procedure:
Examples 11p and 11q, Step 7: To a solution of 2-((1S,2S,5R)-2-(dibenzylamino)-5-(isopropyl(methyl)amino)cyclohexyl)acetonitrile (0.996 g, 2.56 mmoles) in 10 ml of anhydrous THF at −78° C. was added 0.7M-isopropyl lithium in pentane (5.5 ml, 3.84 mmoles) dropwise, and the mixture was stirred for 2.5 hours while the temperature was raised to −7° C. gradually. The reaction was quenched with saturated NH4Cl and then the solution was made basic with saturated NaHCO3. It was extracted with EtOAc (2×), and the combined extracts were washed with brine, dried over Na2SO4, and evaporated to give an oily residue. It was purified by flash chromatography (silica gel, 0.5:4.5:95 cNH4OH-MeOH—CH2Cl2) to give 0.73 g of 1-((1S,2S,5R)-2-(dibenzylamino)-5-(isopropyl(methyl)amino)cyclohexyl)-3-methylbutan-2-one.
Reaction SMILES: C(N[CH:5]([CH3:7])[CH3:6])(C)C.Br[C:9]1[C:14]([Br:15])=[CH:13][CH:12]=[C:11]([O:16][CH3:17])[N:10]=1.[CH2:18]1COC[CH2:19]1>[Cu](I)I>[Br:15][C:14]1[C:9]([C:18]#[C:19][CH:5]([CH3:6])[CH3:7])=[N:10][C:11]([O:16][CH3:17])=[CH:12][CH:13]=1
Reactant: COc1ccc(Br)c(Br)n1
Reactant: C1CCOC1
Reactant: CC(C)NC(C)C
Agent: I[Cu]I
Product: COc1ccc(Br)c(C#CC(C)C)n1
Temperature: 70 °C
Reaction time: 21 h

Procedure:
In a nitrogen atmosphere, tetrakis-triphenylphosphine palladium (5.15 g), copper iodide (5.95 g), diisopropylamine (15 mL) and 3-methyl-2-butyne (38.1 g) were added to the compound of Example 260 (131 g) in THF (150 mL). The mixture was placed in a sealed vessel and stirred at 70° C. for 21 hours. The resulting salt was removed by filtration and the filtrate was mixed with silica gel for condensation. The silica gel was directly eluted (ether:petroleumether=5:95) and the collected eluate was distilled (93° C., 0.1 mmHg) to afford the title compound as a pale yellow oil (121 g).
Reaction SMILES: [C:1]12([CH2:11][C:12](Cl)=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Cl.[NH2:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[CH:19]=[CH:20][NH:21]2>>[NH:21]1[C:22]2[C:18](=[C:17]([NH:16][C:12](=[O:13])[CH2:11][C:1]34[CH2:10][CH:5]5[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]5)[CH2:2]3)[CH2:8]4)[CH:25]=[CH:24][CH:23]=2)[CH:19]=[CH:20]1
Reactant: Nc1cccc2[nH]ccc12
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Agent: Cl
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nc1cccc2[nH]ccc12
Yield: 63.4 %

Procedure:
Prepared according to the method of Example 1b) from 1-adamantaneacetyl chloride (0.074 g) and 4-aminoindole hydrochloride (0.059 g) to give the title compound as a white solid (0.068 g).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=O.C([N:15](CC)CC)C.[ClH:20].[CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[CH2:31][CH2:32][NH2:33]>C1COCC1>[ClH:1].[ClH:20].[F:12][C:9]1[CH:10]=[CH:11][C:6]([CH:4]([CH2:3][CH2:2][NH:33][CH2:32][CH2:31][C:22]2[CH:23]=[CH:24][C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:21]=2)[NH2:15])=[CH:7][CH:8]=1
Reactant: O=C(CCCl)c1ccc(F)cc1
Reactant: CCN(CC)CC
Reactant: NCCc1ccc2ccccc2c1
Agent: Cl
Solvent: C1CCOC1
Product: NC(CCNCCc1ccc2ccccc2c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-chloro-4'-fluoropropiophenone (9.3 g, 0.05 mole) in 100 ml THF was treated with triethylamine (5.6 g, 0.055 mole) and stirred at room temperature for one hour. The mixture was treated with 2-naphthaleneethylamine hydrochloride (10.4 g, 0.05 mole) and refluxed for six hours. The reaction mixture was cooled to room temperature, and the resulting crystals were collected by filtration, washed with THF, ether, and water; and dried to give the title compound as a homogeneous product by tlc (chloroform-methanol, 9:1) (96%, 17.2 g); mp 208°-210° C.; IR(nujol): C=O @ 1675 cm-1 ; NMR(DMSO-d6, TMS): δ 3.20(t,2H, CH2 --CO), 3.37(m,4H,Ar--CH2 --CH2), 3.60(t,2H,N--CH2) [7.3-7.6(m,5H), 7.7-7.8(m,2H), 8.10(m,2H) aromatic]; Anal. Found: C,70.37; H,5.92; N,3.81. Mass spectrum m/e 321,184.
Reaction SMILES: [F:1][CH2:2][CH:3]([O:6][CH2:7][C:8]1[CH:13]=[C:12]([C:14]([O:16]CC)=[CH2:15])[N:11]=[C:10]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]3)=[C:22]([O:32][CH3:33])[CH:21]=2)[N:9]=1)[CH2:4][F:5].O.Cl>O1CCOCC1>[F:5][CH2:4][CH:3]([O:6][CH2:7][C:8]1[N:9]=[C:10]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]3)=[C:22]([O:32][CH3:33])[CH:21]=2)[N:11]=[C:12]([C:14](=[O:16])[CH3:15])[CH:13]=1)[CH2:2][F:1]
Reactant: C=C(OCC)c1cc(COC(CF)CF)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(Nc2nc(COC(CF)CF)cc(C(C)=O)n2)ccc1-n1cnc(C)c1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 78.8 %

Procedure:
To a solution of 4-((1,3-difluoropropan-2-yloxy)methyl)-6-(1-ethoxyvinyl)-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)pyrimidin-2-amine (47 mg, 0.10 mmol) in dioxane (7.5 mL) was added water (0.5 mL) and HCl (conc., 0.025 mL, 0.31 mmol). The mixture was stirred at 50° C. for 20 minutes. The solvents were evaporated. Sodium bicarbonate solution (50% saturated) was added and the mixture was extracted with DCM. The organic phase was separated on phase separator and evaporated to give the title compound (34 mg, 77%).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1.[Cl:20][C:21]1[NH:26][C:25](=[O:27])[NH:24][C:23](=[O:28])[CH:22]=1>>[Cl:20][C:21]1[N:26]([CH2:3][C:4]2[N:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]3=[N:6][C:5]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:25](=[O:27])[NH:24][C:23](=[O:28])[CH:22]=1
Reactant: ClCc1c(-c2ccc(Cl)cc2)nc2ccccn12
Reactant: O=c1cc(Cl)[nH]c(=O)[nH]1
Agent: Cl
Product: O=c1cc(Cl)n(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)c(=O)[nH]1

Procedure:
The title compound was prepared according to Method B and the experimentals described for compound 92 from 3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochloride and 6-chloropyrimidine-2,4(1H,3H)-dione. M/e+ 387 for C18H13Cl2N4O2 (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 9.35 (bs, 1H), 8.44 (d, J=6.23 Hz, 1H), 7.66 (d, J=9.1 Hz, 1H), 7.55 (d, J=8.4 Hz, 2H), 7.45 (d, J=8.4 Hz, 2H), 7.29 (m, 2H), 6.90 (t, J=6.9 Hz, 1H), 5.74 (d, J=8.0 Hz, 2H) ppm.
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([C:19]([O:21]C)=[O:20])=[CH:12][C:13]([N:16]([CH3:18])[CH3:17])=[CH:14][CH:15]=2)=[CH:6][CH:5]=1>C1COCC1.CO.Cl>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:11]([C:19]([OH:21])=[O:20])=[CH:12][C:13]([N:16]([CH3:17])[CH3:18])=[CH:14][CH:15]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1cc(N(C)C)ccc1-c1ccc(Br)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)c1ccc(-c2ccc(Br)cc2)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.6 %

Procedure:
2M Lithium hydroxide (8.5 mL, 17.0 mmol) was added to a solution of methyl 4′-bromo-4-(dimethylamino)biphenyl-2-carboxylate (1.9 g, 5.69 mmol) in THF (20 mL) and methanol (20 mL) and stirred at r.t. for 18 hrs. The reaction was then diluted with 1M HCl and extracted with EtOAc. The organic layer was washed with water then brine, dried over MgSO4, filtered and then evaporated to give 4′-bromo-4-(dimethylamino)biphenyl-2-carboxylic acid (1.34 g, 4.19 mmol, 74% yield) as a white solid. LCMS: rt=1.54 min. [M+H]+=319 and 321; Phenomenex-Luna C-18 (5μ) (3.0×50 mm); Solvent. A=10% acetonitrile—90% water—0.1% TFA, Solvent B=90% acetonitrile—10% water—0.1% TFA; gradient 0% to 100% solvent B over 2 min. and then hold for 1 min.; 4 mL/min; inj. vol.=5 uL; wavelength=220.