Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([O:14][CH2:15][C:16]2[C:24]3[O:23][CH:22]=[CH:21][C:20]=3[CH:19]=[C:18](Br)[CH:17]=2)[C@@H:9]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:32][N:33]1[C:37]([Sn](CCCC)(CCCC)CCCC)=[CH:36][N:35]=[N:34]1>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([O:14][CH2:15][C:16]2[C:24]3[O:23][CH:22]=[CH:21][C:20]=3[CH:19]=[C:18]([C:37]3[N:33]([CH3:32])[N:34]=[N:35][CH:36]=3)[CH:17]=2)[C@@H:9]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](OCc2cc(Br)cc3ccoc23)[C@@H]1c1ccccc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnnn1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: Cn1nncc1-c1cc(CO[C@H]2CCCN(C(=O)OC(C)(C)C)[C@H]2c2ccccc2)c2occc2c1
Temperature: 25 °C
Yield: 45.7 %

Procedure:
Bis(triphenylphosphine)palladium dichloride (5.0 mg) was added to a degassed solution of [2S,3S]-1-tert-butoxycarbonyl-2-phenyl-3-[(5-bromobenzofuran-7-yl)methyloxy]piperidine (111 mg), and 1-methyl-5-tributylstannanyl-1H-[1,2,3]triazole (165 mg) in dry toluene (5.0 ml) under a dry nitrogen atmosphere. The resulting solution was warmed to reflux for 18 hours. After this time the reaction was cooled to room temperature and the solvent removed under reduced pressure. The residue was partitioned between aqueous NaHCO3 solution (10 ml, sat) and ethyl acetate. The organic layer was washed with brine (10 ml), dried over MgSO4, filtered and the solvent removed under pressure. Purification by MPLC (1:1 ethyl acetate/n-hexane) afforded [2S,3S]-1-tert-butoxycarbonyl-2-phenyl-3-{[5-(1-methyl-1H-[1,2,3]triazol-5-yl)benzofuran-7-yl]methyloxy}piperidine as a yellow foam (51 mg). 1H NMR (360 MHz,CDCl3)δ1.45 (9H, s), 1.51-1.83 (5H, m), 2.73 (1H, t d, J=7.0, 3.0 Hz), 3.94 (1H, m), 3.96 (3H, s), 5.02 (2H, d, J=1.0 Hz), 5.76 (1H, br s), 6.84 (1H, d, J=1.0 Hz), 7.26 (4H, m), 7.55 (3H, m), 7.70 (2H, br s); MS m/z CI+ 489 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:31])=[C:12]([C:26](OCC)=[O:27])[C:13](=[O:25])[N:14]3[CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[N:9][CH:8]=2)=[CH:4][CH:3]=1.[NH2:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][OH:40]>CCO>[F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:31])=[C:12]([C:26]([NH:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][OH:40])=[O:27])[C:13](=[O:25])[N:14]3[CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[N:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: NCCOCCO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCC2=O)c1=O
Solvent: CCO
Product: O=C(NCCOCCO)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCC2=O)c1=O

Procedure:
A mixture of ethyl 7-(4-fluorobenzyl)-4-hydroxy-2-oxo-1-[2-(2-oxopyrrolidin-1-yl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate (30 mg, 0.066 mmol) and 2-[(2-aminoethyl)oxy]ethanol (100 μL) was heated in EtOH (3 mL) at 175° C. for 45 min. in a microwave. The reaction mixture was evaporated in vacuo and partitioned between 1N NaHSO4 and CH2Cl2. The aqueous phase was back-extracted with CH2Cl2 and the combined organic layers were dried over MgSO4, filtered, evaporated in vacuo and triturated with Et2O to provide the product as a white solid: 1H NMR (d6-DMSO) δ 10.35 (1H, t, J=5 Hz), 8.54 (1H, s), 8.09 (1H, s), 7.39 (2H, dd, J=5, 9 Hz), 7.11 (2H, t, J=9 Hz), 4.59 (1H, t, J=5 Hz), 4.36 (2H, t, J=6 Hz), 4.14 (2H, s), 3.33-3.56 (12H, m), 1.93 (2H, t, J=8 Hz), 1.74 (2H, t, J=7 Hz); ES+ MS: 513 (M+H+).
Reaction SMILES: C([Mg]Cl)(C)C.[CH:6]([S:9]([N:12]1[C:16]2[CH:17]=[C:18](I)[CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[NH2:22])(=[O:11])=[O:10])([CH3:8])[CH3:7].CN(OC)[C:25](=[O:41])[CH:26]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[Cl-].[NH4+]>O1CCCC1>[CH:6]([S:9]([N:12]1[C:16]2[CH:17]=[C:18]([C:25](=[O:41])[CH:26]([O:33][Si:34]([C:37]([CH3:39])([CH3:38])[CH3:40])([CH3:36])[CH3:35])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[NH2:22])(=[O:11])=[O:10])([CH3:8])[CH3:7]
Reactant: CC(C)S(=O)(=O)n1c(N)nc2ccc(I)cc21
Reactant: CON(C)C(=O)C(O[Si](C)(C)C(C)(C)C)c1ccccc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)n1c(N)nc2ccc(C(=O)C(O[Si](C)(C)C(C)(C)C)c3ccccc3)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
Add isopropylmagnesium chloride (2.0 M in THF, 235 mL, 470 mmol) over 15 minutes to a solution of 1-isopropylsulfonyl-2-amino-6-iodobenzimidazole (42.9 g, 118 mmol) in tetrahydrofuran (850 mL) at −70° C. under a nitrogen atmosphere. Stir for 1 hour at 0° C. and then add a solution of N-[methyl] N-[methoxy] 2-(tert-butyldimethylsilyl)oxy-2-(phenyl)acetamide (90.0 g, 294 mmol) (Tius, et al., Tetrahedron, 56, 3339-3351-(2000)) in tetrahydrofuran (150 mL) via cannula. Stir the resulting slurry at 0-5° C. for 1 hour and then at room temperature for 1.5 hours. Cool the mixture to 10° C. and then add saturated aqueous ammonium chloride. Stir the mixture 15 minutes and separate the layers. Extract the aqueous layer with ethyl acetate (400 mL), dry the combined organic layers over sodium sulfate, and concentrate under reduced pressure. Purify the residue by silica gel chromatography, eluting with 1-10% acetonitrile in dichloromethane containing 0.5% triethylamine to provide a 50% yield of the title compound as a white solid. MS(ES+): m/z=488.1 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]2[C:18]3[O:17][CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)=[C:5]([CH3:7])[N:6]=1.C(OCC)(=O)C.[ClH:32]>C(OCC)(=O)C>[ClH:32].[CH3:1][C:2]1[S:3][C:4]([C:8]2[C:18]3[O:17][CH2:16][CH2:15][NH:14][CH2:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1nc(C)c(-c2cccc3c2OCCN(C(=O)OC(C)(C)C)C3)s1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1nc(C)c(-c2cccc3c2OCCNC3)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
A mixture of tert-butyl 9-(2,4-dimethyl-1,3-thiazol-5-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (240 mg, 0.666 mmol), ethyl acetate (2 ml) and 4N hydrogen chloride-ethyl acetate solution (4 ml) was stirred at room temperature for 1 hr, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of methanol and ether to give the desired product (180 mg, 90.9%) as a solid.
Reaction SMILES: [F:1][C:2]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].[CH2:18]([Mg]Cl)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>C1COCC1>[F:1][C:2]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][C:3]=1[C:4](=[O:5])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cl[Mg]CCc1ccccc1
Reactant: CON(C)C(=O)c1cccc(C(F)(F)F)c1F
Agent: Cl
Solvent: C1CCOC1
Product: O=C(CCc1ccccc1)c1cccc(C(F)(F)F)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cooled (0° C.) solution of 2-fluoro-N-methoxy-N-methyl-3-trifluoromethyl-benzamide (5.0 g, 20 mmol) in THF (50 ml) was added phenethyl magnesium chloride (50 ml of 1.0M in THF) and the reaction was warmed to r.t. After 2 hr, the reaction was poured into 2N HCl and extracted with ether. The organic layer was dried (MgSO4), and concentrated and the product was purified by column chromatography (eluent 5% EtOAc/Hexane) to give 1-(2-fluoro-3-trifluoromethyl-phenyl)-3-phenyl-propan-1-one as a clear oil (4.8 g). MS (ES) m/z 297.0.
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=3)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH3:23]>CC(O)C>[F:20][C:19]([F:22])([F:21])[O:18][C:14]1[CH:13]=[C:12]([C:10]2[CH:9]=[CH:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH2:23])[C:3]=3[N:11]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: N
Reactant: FC(F)(F)Oc1cccc(-c2ccc3ncnc(Cl)c3n2)c1
Solvent: CC(C)O
Product: Nc1ncnc2ccc(-c3cccc(OC(F)(F)F)c3)nc12
Temperature: 35 °C
Reaction time: 8 h
Yield: 17 %

Procedure:
The brown solid 4-chloro-6-(3-(trifluoromethoxy)phenyl)pyrido[3,2-d]pyrimidine obtained from step 2 was added to a solution of NH3 in propan-2-ol (50 mL, 12%), and stirred at 35° C. overnight. The reaction was concentrated under reduce pressure and the residue was purified by silica gel column chromatography (66% Ethyl acetate in Pentane) to afford 6-(3-(trifluoromethoxy)phenyl)pyrido[3,2-d]pyrimidin-4-amine (0.2 g, 17% yield) as a brown solid.
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1[N:22]2[C:23](=[O:33])[C@@H:24]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@H:21]2[S:20][CH2:19][C:18]=1[CH:34]=[CH:35]OS(C(F)(F)F)(=O)=O)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:44][C:45]1[S:46][C:47]2[CH:55]=[CH:54][CH:53]=[CH:52][C:48]=2[C:49](=[O:51])[CH:50]=1.C(N(C(C)C)C(C)C)C.C(OCC)(=O)C>CN(C=O)C>[CH:1]([O:14][C:15]([C:17]1[N:22]2[C:23](=[O:33])[C@@H:24]([NH:25][C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[C@H:21]2[S:20][CH2:19][C:18]=1[CH:34]=[CH:35][S:44][C:45]1[S:46][C:47]2[CH:55]=[CH:54][CH:53]=[CH:52][C:48]=2[C:49](=[O:51])[CH:50]=1)=[O:16])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=COS(=O)(=O)C(F)(F)F)CS[C@H]12
Reactant: O=c1cc(S)sc2ccccc12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CSc3cc(=O)c4ccccc4s3)CS[C@H]12
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.2 %

Procedure:
7β-Tert-butoxycarbonylamino-3-(2-trifluoromethanesulfonyloxyvinyl)-3-cephem-4-carboxylic acid benzhydryl ester (trans isomer) (3.9 g, 6.1 mmol) was dissolved in anhydrous DMF (80 ml), added with 2-mercapto-4-oxo-4H-1-benzothiopyran (3.5 g, 18.3 mmol) and N-ethyldiisopropylamine (0.63 g, 4.87 mmol), successively, and stirred at room temperature under argon gas atmosphere for 24 hours. The reaction product was added with ethyl acetate (350 ml), washed with an aqueous solution of saturated sodium hydrogencarbonate (150 ml×2 times) and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography (Wago Gel™ C-200, methylene chloride-ethyl acetate (8:1)) to obtain 3.56 g (yield: 85.4%) of 7β-tert-butoxycarbonylamino-3-[2-(4-oxo-4H-1-benzothiopyran-2-yl)thiovinyl]-3-cephem-4-carboxylic acid benzhydryl ester as yellow-red froth.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]([CH2:15][CH2:16][C:17](=[N:25][S@:26]([C:28]([CH3:31])([CH3:30])[CH3:29])=[O:27])[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:11](=[O:14])[O:12][CH3:13])[CH3:9])=[CH:4][CH:3]=1.[CH2:32]([Mg]Br)[CH:33]=[CH2:34]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]([CH2:15][CH2:16][C@:17]([NH:25][S@:26]([C:28]([CH3:30])([CH3:29])[CH3:31])=[O:27])([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[CH2:34][CH:33]=[CH2:32])[C:11](=[O:14])[O:12][CH3:13])[CH3:9])=[CH:6][CH:7]=1
Reactant: C=CC[Mg]Br
Reactant: COC(=O)N(CCC(=N[S@@](=O)C(C)(C)C)c1ccc(F)cc1)[C@@H](C)c1ccc(Br)cc1
Solvent: C1CCOC1
Product: C=CC[C@@](CCN(C(=O)OC)[C@@H](C)c1ccc(Br)cc1)(N[S@@](=O)C(C)(C)C)c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 4 h
Yield: 43.4 %

Procedure:
To a solution of methyl (1S)-1-(4-bromophenyl)ethyl(3-((S)-tert-butylsulfinylimino)-3-(4-fluorophenyl)propyl)carbamate (200 mg, 0.4 mmol) in anhydrous THF (5 mL) was added 1M allylmagnesium bromide (1.2 mL, 1.2 mmol) at −78° C. The reaction mixture was stirred at −78° C. for 4 h and allowed to warm to rt. After stirring for 2 h at rt, the reaction mixture was quenched with satd aq NH4Cl and extracted with EtOAc (2×). The combined organic phases were dried, filtered and concentrated to give a residue, which was purified by TLC to provide methyl (S)-1-(4-bromophenyl)ethyl((S)-3-((S)-1,1-dimethylethylsulfinamido)-3-(4-fluorophenyl)hex-5-enyl)carbamate (96 mg, 45%). 1H NMR (CD3OD): 1.28 (m, 9H), 1.48 (m, 3H), 2.10 (m, 1H), 2.30 (m, 1H), 2.72 (m, 4H), 3.66 (m, 3H), 5.08 (m, 2H), 5.40 (m, 2H), 7.10 (m, 4H), 7.32 (m, 2H), 7.50 (m, 2H).
Reaction SMILES: [CH3:1][CH:2]([CH2:7][CH:8]([CH3:10])[CH3:9])[CH2:3][C:4](=O)[CH3:5].[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:12].C([O-])(=O)C.[NH4+].CC1CCCCC1>O.C(O)(=O)C>[C:14]([C:13](=[C:4]([CH3:5])[CH2:3][CH:2]([CH3:1])[CH2:7][CH:8]([CH3:10])[CH3:9])[C:11]#[N:12])([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)CC#N
Reactant: CC(=O)CC(C)CC(C)C
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC1CCCCC1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(C#N)=C(C)CC(C)CC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
A 250 ml round-bottom flask equipped with a Dean-Stark apparatus is charged in succession with 25.6 g of 4,6-dimethylheptanone (0.18 mol), 14.34 g of ethyl cyanoacetate (0.127 mol), 1.95 g of ammonium acetate, 6 g of acetic acid, and 100 ml of methylcyclohexane. The mixture is heated to reflux, the water formed being separated off as it is formed. After one hour, the mixture is cooled to ambient temperature and then washed to neutrality with saturated sodium bicarbonate solution. The residue is distilled under vacuum (6 torr) for recovery of the excess ketone (6.5 g) and then under a high vacuum for isolation of the cyano ester VI. 25.8 g of a colorless liquid are collected (b.p.=100-104° C./2.10−1 torr), corresponding to a yield of 85%.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[F:28])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:29][NH2:30]>>[CH3:29][NH:30][CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[C:15]=2[O:14]1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4ccccc4F)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2cccc(-c3ccccc3F)c2O1

Procedure:
The title compound was prepared (0.147 g, 66%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.300 g, 0.753 mmol) and methylamine (0.92 g, 29.5 mmol). mp 148-150° C.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1[C:15]([O:16][CH3:17])=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[O:18][CH3:19].[CH3:20]O>>[CH3:6][C:7]1[C:8]([O:18][CH3:19])=[CH:9][C:10]([C:11]([O:13][CH3:20])=[O:12])=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: CO
Reactant: COc1cc(C(=O)O)cc(OC)c1C
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(OC)c(C)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
Concentrated sulphuric acid (1 mL), was added dropwise to a solution of 4-methyl-3,5-dimethoxybenzoic acid (186) (5.01 g, 25.56 mmol) in refluxing methanol (20 mL). The reaction mixture was heated at reflux for a further 5 hours and then cooled to room temperature and concentrated to a third of its original volume. The concentrate was poured onto crushed ice (c. 150 mL) and allowed to stand for 30 minutes. The aqueous mixture was extracted with ethyl acetate (3×100 mL) and the combined organic phase washed with distilled water (3×100 mL), brine (2×100 mL) and dried over anhydrous MgSO4. Removal of excess solvent under reduced pressure afforded the product as a beige solid (187) (4.865 g, 23.17 mmol, 91%); 1H NMR (270 MHz, CDCl3) δ 7.21 (s, 2H), 3.91 (s, 3H), 3.86 (s, 6H), 2.13 (s, 3H); 13C NMR (67.8 MHz, CDCl3) δ 171.57, 167.28, 158.16, 158.10, 128.23, 120.39, 105.20, 104.70, 55.85, 52.13, 8.77, 8.66.
Reaction SMILES: [C:1]([C:5]1[CH:18]=[CH:17][C:16]2[C:7](=[C:8]3[C:13](=[C:14](Cl)[N:15]=2)[CH:12]=[CH:11][C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:9]3)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CO[CH:26](OC)[CH2:27][NH2:28]>COCCOCCOC>[C:1]([C:5]1[CH:18]=[CH:17][C:16]2[N:15]3[CH:26]=[CH:27][N:28]=[C:14]3[C:13]3[CH:12]=[CH:11][C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:9][C:8]=3[C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(CN)OC
Reactant: CC(C)(C)c1ccc2nc(Cl)c3ccc(C(C)(C)C)cc3c2c1
Solvent: COCCOCCOC
Product: CC(C)(C)c1ccc2c(c1)c1cc(C(C)(C)C)ccc1n1ccnc21
Temperature: 25 °C
Reaction time: 96 h
Yield: 55 %

Procedure:
2,9-Di-t-butyl-6-chlorophenanthridine (3.7 grams, 11.0 mmole) was added to a reaction flask containing aminoacetaldehyde dimethylacetal (2.4 grams, 23 mmole) dissolved into 200 mL of diglyme, heated to reflux and stirred under a nitrogen atmosphere. After 96 hours the reaction was complete as determined by TLC. The reaction mixture was cooled to room temperature and the excess solvent removed by distillation. The residue was taken up into methylene chloride. The solvent was dried over magnesium sulfate filtered and concentrated. The crude product was purified by silica gel chromatography using 10% ethyl acetate and 90% methylene chloride as the eluents. The purified product was collected, washed with hexanes, and dried to give 7,10-di-tert-butyl-imidazo[1,2-f]phenanthridine (2.0 grams, 56% yield) as a white solid.
Reaction SMILES: [N:1]1([C:5]2[C:6]3[CH2:28][CH2:27][CH:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:7]=3[N:8]=[C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH:22]=[C:21]([Cl:23])[N:20]=[CH:19]4)=[C:14]([O:24][CH3:25])[CH:13]=3)[N:10]=2)[CH2:4][CH2:3][CH2:2]1.CO.CO.C(Cl)(Cl)Cl>C(=O)=O>[N:1]1([C:5]2[C:6]3[CH2:28][CH2:27][C@H:26]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:7]=3[N:8]=[C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH:22]=[C:21]([Cl:23])[N:20]=[CH:19]4)=[C:14]([O:24][CH3:25])[CH:13]=3)[N:10]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(Nc2nc3c(c(N4CCC4)n2)CCC3c2ccccc2)ccc1-n1cnc(Cl)c1
Agent: O=C=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc(Nc2nc3c(c(N4CCC4)n2)CC[C@@H]3c2ccccc2)ccc1-n1cnc(Cl)c1

Procedure:
A racemic mixture of 4-(azetidin-1-yl)-N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine (Example 6) was purified using chiral SFC to afford peak A (Example 6A) and peak B (Example 6B). SFC Method: Chiralpak OJ-H (4.6×250 mm, 5 μM), 35% methanol (0.1% diethylamine) in CO2, 35° C., flow rate 2.0 mL/min for 30 min, absorbance 268 nm, injection 5 μL of 2 mg/mL solution in 50:50 methanol/chloroform (multiple stacked injections), tR (peak A)=5.9 min, tR (peak B) 24.6 min. The absolute stereochemistry of individual enantiomers (Examples 6A and 6B) was not determined LC-MS and 1H NMR analytical data for the separated enantiomers was identical to the racemate (Example 6).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:32]=[CH:31][C:7]([C:8]([C:10]2[N:14]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]3[CH:20]=[CH:21][C:22]([C:24]([N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[O:25])=[CH:23][C:12]=3[N:11]=2)=[O:9])=[CH:6][CH:5]=1)[CH3:2].[BH4-].[Na+]>CCO>[CH2:1]([O:3][C:4]1[CH:32]=[CH:31][C:7]([CH:8]([OH:9])[C:10]2[N:14]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]3[CH:20]=[CH:21][C:22]([C:24]([N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[O:25])=[CH:23][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(C(=O)c2nc3cc(C(=O)N(CC)CC)ccc3n2CCC(C)C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1ccc(C(O)c2nc3cc(C(=O)N(CC)CC)ccc3n2CCC(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(4-ethoxybenzoyl)-N,N-diethyl-1-(3-methylbutyl)-1H-benzimidazole-5-carboxamide (110 mg, 0.252 mmol) was dissolved in 3 mL of EtOH. NaBH4 (12 mg, 1.2 eq) was added and the solution stirred at rt for 1 h. The solvent was concentrated and the residue dissolved in EtOAc. The organic phase was washed with saturated NaHCO3 solution, brine and dried over anhydrous MgSO4. The crude product was directly purified by reversed-phase chromatography (C-18 column) using a gradient of 10–65% CH3CN/H2O and then lyophilized affording the title compound. The product was isolated as the corresponding TFA salt. Yield: 102 mg (73%); 1H NMR (400 MHz, CD3OD) δ 7.85 (br s, 2H), 7.62 (br s, 1H), 7.40 (br s, 2H), 7.01 (br s, 2H), 6.33 (br s, 1H), 4.29 (br s, 2H), 4.06 (br s, 2H), 3.62 (br s, 2H), 3.32 (br s, 2H), 1.55 (br, 2H), 1.38 (br s, 3H), 1.30 (br s, 3H), 1.17 (br s, 2H), 0.90 (s, 3H), 0.83 (s, 3H); MS (ESI) (M+H)+=438.30; Anal. Calcd for C26H35N3O3+1.2 TFA: C, 59.38; H, 6.35; N, 7.32. Found: C, 59.36; H, 5.97; N, 7.37.
Reaction SMILES: [CH2:1]([SiH:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[Cl:6])[CH:2]([CH3:4])[CH3:3].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:15][C:16](=[C:18]([CH3:20])[CH3:19])[CH3:17].C1(OC)C=CC=CC=1>>[C:16]([Si:5]([CH2:7][CH:8]([CH3:10])[CH3:9])([CH2:1][CH:2]([CH3:4])[CH3:3])[Cl:6])([CH:18]([CH3:20])[CH3:19])([CH3:17])[CH3:15]
Reactant: CC(C)=C(C)C
Reactant: CC(C)C[SiH](Cl)CC(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1
Product: CC(C)C[Si](Cl)(CC(C)C)C(C)(C)C(C)C
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A flask equipped with a stirrer, reflux condenser, dropping funnel and thermometer was charged with 35.8 g (0.2 mol) of diisobutylchlorosilane and 2.7 g (0.02 mol) of aluminum chloride and heated at 50° C. Once the internal temperature became constant, 16.8 g (0.2 mol) of 2,3-dimethyl-2-butene was added dropwise over one hour. After the completion of dropwise addition, the reaction solution was stirred for one hour at 50° C. The aluminum chloride was deactivated by adding 4.3 g (0.04 mol) of anisole. The reaction solution was distilled, collecting 32.5 g of a boiling point 83° C./133 Pa fraction.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:20])[C:7]([C:15]([O:17]CC)=[O:16])=[C:8]3[S:14][CH2:13][CH2:12][N:9]32)=[CH:4][C:3]=1[F:21].[OH-].[Na+].O.C(O)C>C(O)(=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:20])[C:7]([C:15]([OH:17])=[O:16])=[C:8]3[S:14][CH2:13][CH2:12][N:9]32)=[CH:4][C:3]=1[F:21]
Reactant: CCOC(=O)c1c2n(c3cc(Br)c(F)cc3c1=O)CCS2
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: O=C(O)c1c2n(c3cc(Br)c(F)cc3c1=O)CCS2
Yield: 93 %

Procedure:
Then 1.0 gram of the fractioned ethyl 8-bromo-7-fluoro-5-oxo-1,2-dihydro-5H-thiazolo(3,2-a)-quinoline-4-carboxylate was suspended in a solution of 2.0 grams of sodium hydroxide (0.05 mmol), 50 ml of water and 20 ml of ethanol, the mixture was heated to reflux for four hours, the transparent solution was acidified with acetic acid after being cooled, crystals separated out were collected by filtration, washed with water, and dried. Thus, 860 mg (93.5 percent) of the title compound was obtained. Colorless powdery crystals were then recrystallized from dimethyl formamide. Melting point was 228° to 290° C. (decomposition).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:15]1=[O:30].[C:31](=O)([O-])[O-].[K+].[K+].IC.O>CN(C=O)C>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:12][CH2:13][C:14]1([CH3:31])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[C:15]1=[O:30]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1C(=O)C(CCN2C(=O)c3ccccc3C2=O)c2ccccc21
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C(=O)C(C)(CCN2C(=O)c3ccccc3C2=O)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.5 %

Procedure:
To a mixture of tert-butyl 3-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-2-oxoindoline-1-carboxylate (1.00 g, 2.46 mmol) and potassium carbonate (679 mg, 4.92 mmol) in DMF (5 mL) was added iodomethane (524 mg, 3.69 mmol) at ˜0° C. to 5° C. The resulting reaction mixture was stirred at room temperature for 16 h. The resulting mixture was treated with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to give a crude product, which was purified by silica gel column chromatography (10-25% ethyl acetate in petroleum ether to afford the title compound (700 mg, 1.66 mmol, 67% yield) as a brown solid. MS (ESI) m/z 421.1 [M+H]+.