Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:11][CH3:12])=[CH:5][C:6]=1[C:7]([O:9]C)=O.ClC(Cl)(O[C:17](=[O:23])OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][NH2:41])=[CH:35][CH:34]=1>C(Cl)Cl>[CH2:11]([C:4]1[S:3][C:2]2[NH:1][C:17](=[O:23])[N:41]([CH2:40][CH2:39][C:36]3[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=3)[C:7](=[O:9])[C:6]=2[CH:5]=1)[CH3:12]
Reactant: NCCc1ccc(F)cc1
Reactant: CCc1cc(C(=O)OC)c(N)s1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1cc2c(=O)n(CCc3ccc(F)cc3)c(=O)[nH]c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution (20 mL) of methyl 2-amino-5-ethylthiophene-3-carboxylate (0.5 g) in methylene chloride were added triphosgene (0.35 g) and triethylamine (0.6 mL), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added 2-(4-fluorophenyl)ethanamine (1.06 mL), and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol (20 mL), sodium methoxide (0.73 g) was added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was neutralized with hydrochloric acid (10% methanol solution), insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (859 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([S:19]([CH3:22])(=[O:21])=[O:20])=[N:15][CH:16]=2)[NH:11][C:10]1=[O:23].[H-].[Na+].Br[CH:27]1[CH2:32][CH2:31][CH2:30][CH:29]=[CH:28]1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([S:19]([CH3:22])(=[O:21])=[O:20])=[N:15][CH:16]=2)[N:11]([CH:32]2[CH2:31][CH2:30][CH2:29][CH:28]=[CH:27]2)[C:10]1=[O:23]
Reactant: CS(=O)(=O)c1ncc2c(n1)NC(=O)N(c1c(Cl)cccc1Cl)C2
Reactant: BrC1C=CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ncc2c(n1)N(C1C=CCCC1)C(=O)N(c1c(Cl)cccc1Cl)C2
Yield: 28.6 %

Procedure:
A solution, cooled in ice, of 200 mg (0.54 mmol) of 3-(2,6-dichlorophenyl)-7-methanesulfonyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one in 12 ml of dimethylformamide was treated with 22 mg (0.54 mmol) of sodium hydride (60% w/w). After 30 minutes the mixture was treated with 0.07 ml (0.6 mmol) of 3-bromocyclohexene and then heated at reflux for 4 hours. The mixture was evaporated and 30 ml of dichloromethane and 30 ml of water were added to the residue. The phases were separated and the organic phase was washed with 30 ml of water, dried over magnesium sulfate, filtered and evaporated to give 70 mg (29%) 3-(2,6-dichlorophenyl)-1-[2-cyclohexen-1(RS)-yl]-7-methanesulfonyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one as a brown oil. [Mass spectrum (ESI) MH+ =453].
Reaction SMILES: [NH2:1][C@@H:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[OH-].[Na+].Cl[C:15]([O:17][CH3:18])=[O:16]>O1CCOCC1.CCOC(C)=O>[CH3:18][O:17][C:15]([NH:1][C@@H:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4])=[O:16]
Reactant: COC(=O)Cl
Reactant: N[C@H](C(=O)O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)N[C@H](C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.5 %

Procedure:
To a solution of (S)-2-amino-2-phenylacetic acid (0.5 g, 3.31 mmol) in dioxane at 0° C. was added NaOH (5.46 g, 10.92 mmol) followed by dropwise addition of methyl chloroformate (0.51 mL, 6.62 mmol) and the solution was warmed to room temperature with stirring over 1 h. Diluted with EtOAc, washed with 1 N HCl, brine, dried (Na2SO4), filtered and removed solvent in vacuo to give the title compound (0.35 g, 1.673 mmol, 51%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C@H:10]2[C@H:15]([N:16]([CH3:33])[C:17](=[O:32])[C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=3)[CH2:14][CH2:13][N:12]([C:34]([CH:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)=[O:35])[CH2:11]2)[CH:6]=[CH:7][C:8]=1[Cl:9].C(N(CC)CC)C.[C:49](Cl)(=[O:51])[CH3:50].[OH-].[Na+]>C(#N)C.O>[C:49]([N:39]1[CH2:40][CH2:41][CH:36]([C:34]([N:12]2[CH2:13][CH2:14][C@@H:15]([N:16]([CH3:33])[C:17](=[O:32])[C:18]3[CH:23]=[C:22]([C:24]([F:25])([F:27])[F:26])[CH:21]=[C:20]([C:28]([F:29])([F:31])[F:30])[CH:19]=3)[C@H:10]([C:5]3[CH:6]=[CH:7][C:8]([Cl:9])=[C:3]([Cl:2])[CH:4]=3)[CH2:11]2)=[O:35])[CH2:37][CH2:38]1)(=[O:51])[CH3:50]
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1CCN(C(=O)C2CCNCC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: CC(=O)N1CCC(C(=O)N2CC[C@@H](N(C)C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](c3ccc(Cl)c(Cl)c3)C2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 71 %

Procedure:
To a solution of N-[(3R,4R)-3-(3,4-dichlorophenyl)-1-(piperidin-4-ylcarbonyl)piperidin-4-yl]-N-methyl-3,5-bis(trifluoromethyl)benzamide monohydrochloride (0.35 g) obtained in Example 89 and triethylamine (0.24 mL) in acetonitrile (10 mL) was added acetyl chloride (0.080 mL) at 0° C., and the mixture was stirred at room temperature for 14 hr. The reaction mixture was poured into water, the mixture was made basic with 2N aqueous sodium hydroxide solution, and the resultant product was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH Chromatorex) (solvent gradient; 75→100% ethyl acetate/hexane) to give the title compound (0.25 g, 71%) as a white crystal powder.
Reaction SMILES: F[C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6](=[O:20])[C:7]([C:17]([OH:19])=[O:18])=[CH:8][N:9]2[C@@H:13]2[CH2:15][C@@H:14]2[F:16])=[C:4]([OH:21])[CH:3]=1.C(OC([NH:29][C:30]1([C@@H:33]2[CH2:37][CH2:36][NH:35][CH2:34]2)[CH2:32][CH2:31]1)=O)(C)(C)C.CN1CCCCC1>CS(C)=O>[NH2:29][C:30]1([C@@H:33]2[CH2:37][CH2:36][N:35]([C:2]3[C:11]([CH3:12])=[C:10]4[C:5]([C:6](=[O:20])[C:7]([C:17]([OH:19])=[O:18])=[CH:8][N:9]4[C@@H:13]4[CH2:15][C@@H:14]4[F:16])=[C:4]([OH:21])[CH:3]=3)[CH2:34]2)[CH2:32][CH2:31]1
Reactant: Cc1c(F)cc(O)c2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Reactant: CC(C)(C)OC(=O)NC1([C@@H]2CCNC2)CC1
Solvent: CN1CCCCC1
Solvent: CS(C)=O
Product: Cc1c(N2CC[C@@H](C3(N)CC3)C2)cc(O)c2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Temperature: 80 °C
Reaction time: 66 h

Procedure:
A mixture of 7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-5-hydroxy-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (205 mg, 0.694 mmol), 3-(R)-[1-(tert-butoxycarbonylamino)cyclopropyl]pyrrolidine (314 mg, 1.388 mmol), N-methyl piperidine (0.243 ml, 1.388 mmol), and dimethyl sulfoxide (1.5 ml) was stirred for 66 hours while heating in an oil bath at 80° C. under a nitrogen-replaced atmosphere. After evaporating the solvent, the residue was partitioned in chloroform (50 ml) and 10% aqueous citric acid solution (30 ml), and after separating the organic layer, the aqueous layer was further subject to extraction into chloroform (30 ml). The combined organic layer was then dried over anhydrous sodium sulfate, and after removing the drying agent by filtration, the solvent was evaporated under a reduced pressure to thereby obtain a crude 7-{3-(R)-[1-(tert-butoxycarbonylamino)cyclopropyl]pyrrolidin-1-yl}-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-5-hydroxy-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:6]([CH2:7][C@@:8]2([CH3:29])[N:12]3[C:13]([C:16](O)=[O:17])=[CH:14][N:15]=[C:11]3[N:10]([C:19]3[CH:24]=[C:23]([Cl:25])[C:22](F)=[C:21]([Cl:27])[CH:20]=3)[C:9]2=[O:28])=[CH:5][CH:4]=1)#[N:2].[NH2:32][C@@H:33]([CH3:46])[C:34]([NH:36][C:37]1([C:40]2[N:45]=[CH:44][CH:43]=[CH:42][N:41]=2)[CH2:39][CH2:38]1)=[O:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1.CN(C=O)C>[N:41]1[CH:42]=[CH:43][CH:44]=[N:45][C:40]=1[C:37]1([NH:36][C:34]([C@@H:33]([NH:32][C:16]([C:13]2[N:12]3[C@@:8]([CH2:7][C:6]4[CH:30]=[CH:31][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)([CH3:29])[C:9](=[O:28])[N:10]([C:19]4[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:27])[CH:20]=4)[C:11]3=[N:15][CH:14]=2)=[O:17])[CH3:46])=[O:35])[CH2:38][CH2:39]1
Reactant: C[C@H](N)C(=O)NC1(c2ncccn2)CC1
Reactant: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)c(F)c(Cl)c2)c2ncc(C(=O)O)n21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)c1cnc2n1[C@](C)(Cc1ccc(C#N)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)C(=O)NC1(c2ncccn2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 70.6 %

Procedure:
To a solution of (R)-5-(4-Cyano-benzyl)-7-(3,5-dichloro-4-fluoro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylic acid (85 mg, 0.19 mmol) and (S)-2-Amino-N-(1-pyrimidin-2-yl-cyclopropyl)-propionamide (49 mg, 0.18 mmol) in THF (1.0 mL) and DMF (0.7 mL), was added HATU (80 mg, 0.21 mmol) followed by DIPEA (0.15 mL, 0.88 mmol). The reaction was stirred at room temperature for 20 h. The THF was removed under a stream of N2 and the reaction mixture was purified by reverse phase HPLC. The purified material was then passed through a basic amino group functionalized solid phase extraction cartridge to give 80 mg of the title compound as a solid, m/z 647.34 [M+1]+.
Reaction SMILES: [CH3:1][SiH:2]([N:4](Cl)[C:5]([CH3:8])([CH3:7])[CH3:6])[CH3:3].[Li].[CH2:11]([C:14]1[CH-:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH3:13]>C1COCC1>[CH2:11]([C:14]1[CH:15]([Si:2]([NH:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:3])[CH3:1])[C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH3:13]
Reactant: CCCc1cc2ccccc2[cH-]1
Reactant: C[SiH](C)N(Cl)C(C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: CCCC1=Cc2ccccc2C1[Si](C)(C)NC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.2 %

Procedure:
Dimethylsilyl(t-butylamino)chloride (3.03 g, 0.018 moles) was stirred in THF (100 mL) as lithium-2-propylindenide (3.00 g, 0.018 moles) in THF (20 mL) was added dropwise. This mixture was allowed to stir for 16 hours at room temperature. After the reaction period the volatiles were removed and the residue extracted and filtered using hexane. Removal of the hexane resulted in the isolation of the desired product as a yellow oil (4.67 g, 89.0 percent). This compound was used without further purification or analysis.
Reaction SMILES: [C:1]([NH:8][S:9]([CH:12]1[CH2:14][CH2:13]1)(=[O:11])=[O:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Li]CCCC.Br[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[OH2:28]>C1COCC1.CCOC(C)=O>[C:1]([NH:8][S:9]([C:12]1([O:28][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:14][CH2:13]1)(=[O:10])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: BrCc1ccccc1
Reactant: O
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)C1CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NS(=O)(=O)C1(OCc2ccccc2)CC1
Temperature: -80 °C
Reaction time: 0.17 h
Yield: 30 %

Procedure:
To a stirred solution of compound 77 (500 mg, 2.26 mmol) in anhydrous THF (5 mL) at −80° C. was added nBuLi (2.26 mL, 5.65 mmol) dropwise. The mixture was stirred at −80° C. for 10 min and bromomethylbenzene (271 μL, 3.39 mmol) was added dropwise at −80° C. The mixture was then allowed to warm up to −30° C. Water was then slowly added followed by EtOAc. Organics were dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by chromatography on silica gel (EtOAc/DCM) to yield compound 78 as a white powder in 30% yield.
Reaction SMILES: Cl.[NH2:2]O.C(=O)([O-])[O-].[Na+].[Na+].C[O:11][C:12](=O)[C:13](=[CH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:42])[C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([Cl:41])[CH:35]=3)=[CH:28][N:27]=2)=[CH:21][CH:20]=1)[C:14]([O:16]C)=[O:15].CO>O.C1COCC1>[Cl:41][C:36]1[CH:35]=[C:34]([CH:39]=[CH:38][C:37]=1[Cl:40])[C:33]([NH:32][C:29]1[CH:28]=[N:27][C:26]([O:25][C:22]2[CH:21]=[CH:20][C:19]([CH:18]=[C:13]3[C:14](=[O:15])[O:16][NH:2][C:12]3=[O:11])=[CH:24][CH:23]=2)=[CH:31][CH:30]=1)=[O:42]
Reactant: NO
Reactant: COC(=O)C(=Cc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cn2)cc1)C(=O)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C1NOC(=O)C1=Cc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cn2)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of hydroxylamine hydrochloride (500 mg, 1.0 mmol) in water (0.2 mL) were added sodium carbonate (1.05 g, 9.91 mmol) and a solution of 2-{4-[5-(3,4-dichlorobenzoylamino)pyridin-2-yloxy]benzylidene}malonic acid dimethyl ester (500 mg, 1.0 mmol) in THF (5 mL). To the resulting solution was subsequently added methanol (5 mL) and stirred for 8 hours at 60° C. The reaction solution was concentrated under reduced pressure. Water was added to the residue, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (dichloromethane:methanol=30:1). To the resulting white precipitate was added ethyl acetate, filtered, and the filtrate was washed with diethyl ether, to thereby yield 105 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([O:10][CH3:11])[C:3]=1[C:12](=[O:14])[CH3:13].Br[CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C([O-])(O)=O.[Na+]>C(N(CC)CC)C>[C:18]([CH2:17][CH2:16][NH:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([O:10][CH3:11])[C:3]=1[C:12](=[O:14])[CH3:13])([O:20][CH2:21][CH3:22])=[O:19]
Reactant: COc1ccc(OC)c(C(C)=O)c1N
Reactant: CCOC(=O)CCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNc1c(OC)ccc(OC)c1C(C)=O
Temperature: 10 °C
Reaction time: 2 h

Procedure:
Triethylamine (19.4 g, 192 mM) was added to a mixture of 2'-amino-3',6'-dimethoxyacetophenone (2.5 g, 128 mM) and ethyl 3-bromopropionate (139 g, 770 mM) in a 250 mL flask. The pale solid complex so formed was stirred at 135° for 2 hours with a large and heavy stirring bar. During this time the complex became a homogeneous brown oil. This oil was cooled to 10° C. and 200 mL of 2% NaHCO3 was added to the reaction mixture. The solution was then extracted with CHCl3 (3×100 mL) and the organic layer washed with H2O (100 mL) and then dried over MgSO4. After filtration, the CHCl3 and most of the bromopropionate were removed under reduced pressure. The oily residue was put on a 10×60 cm, SilicAR CC-7 column (500 g) and eluted with 5-20% ethyl acetate/hexane, collecting 1 L fractions. Evaporation of fractions 5 and 6 gave purified 2'-(N-2-carbethoxyethylamino)-3',6'-dimethoxyacetophenone (9.97 g, 26%); IR (neat) μ: 3.3 (CH), 5.78 (CO2Et), 5.8 (COCH3), 6.25 (Ar).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][CH2:7][CH2:8][CH2:9][N:4]2[C:3]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])=[N:2]1.[Cl:18][C:19]1[CH:20]=[C:21]([Mg]Br)[CH:22]=[CH:23][CH:24]=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([Mg]Br)=[CH:30][CH:29]=1>>[Cl:18][C:19]1[CH:20]=[C:21]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:3]2[N:4]3[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]3[CH2:1][N:2]=2)[OH:11])[CH:22]=[CH:23][CH:24]=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:3]2[N:4]3[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]3[CH2:1][N:2]=2)[OH:11])=[CH:30][CH:29]=1
Reactant: Clc1cccc([Mg]Br)c1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: O=C(C1=NCC2CCCCN12)c1ccccc1
Product: OC(C1=NCC2CCCCN12)(c1ccccc1)c1ccc(Cl)cc1
Product: OC(C1=NCC2CCCCN12)(c1ccccc1)c1cccc(Cl)c1

Procedure:
In an analogous manner, reaction of the ketone of Example 2 with m-chlorophenylmagnesium bromide and p-chlorophenylmagnesium bromide gives respectively α-(m-chlorophenyl)-α-phenyl-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyridine-3-methanol and α-(p-chlorophenyl)-α-phenyl-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyridine 3-methanol. Similarly, reaction of the ketone of Example 2 with p-methoxyphenylmagnesium bromide and o-methylphenylmagnesium bromide gives respectively α-(p-methoxyphenyl)-α-phenyl-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyridine-3-methanol and α-(o-methylphenyl)-α-phenyl-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyridine-3-methanol.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH:20]([O:40][CH2:41][N:42]1[CH:47]=[CH:46][C:45]([NH2:48])=[N:44][C:43]1=[O:49])[CH2:21][O:22][C:23](=[O:39])[C@H:24]([CH:36]([CH3:38])[CH3:37])[NH:25]C(OCC1C=CC=CC=1)=O)=[O:17])[CH:13]([CH3:15])[CH3:14])=O)C1C=CC=CC=1.C1CC=CCC=1>[Pd].C(O)(=O)C>[NH2:25][C@H:24]([C:23]([O:22][CH2:21][CH:20]([O:40][CH2:41][N:42]1[CH:47]=[CH:46][C:45]([NH2:48])=[N:44][C:43]1=[O:49])[CH2:19][O:18][C:16](=[O:17])[C@H:12]([CH:13]([CH3:15])[CH3:14])[NH2:11])=[O:39])[CH:36]([CH3:38])[CH3:37]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)OCn1ccc(N)nc1=O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: C1=CCC=CC1
Product: CC(C)[C@H](N)C(=O)OCC(COC(=O)[C@@H](N)C(C)C)OCn1ccc(N)nc1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a cool mixture of 3.44 g of 2-((4-amino-1,2-dihydro-2-oxo-1-pyrimidinyl)methoxy)-1,3-propanediyl bis(N-((benzyloxy)carbonyl)-L-valinate) and 7 g of 10% palladium catalyst in acetic acid was slowly added 8.65 mL of 1,4-cyclohexadiene. The mixture was allowed to stir at room temperature for 18 h. The reaction mixture was filtered through a pad of Celite. The filtrate was then concentrated and dried in the lyophilizer for 48 h. The resulting beige foam was scraped off affording 2.38 g (68% as the acetic acid salt) of the title compound. The elemental analysis (showing 2 M of acetic acid and 1 M of water) UV, 1H, 13C-NMR spectra were consistent with the title structure.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([NH2:17])[N:14]([C@H:18]([CH3:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[C:13]=3[CH:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:32](OC(=O)C)(=[O:34])[CH3:33]>ClCCl>[C:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([NH:17][C:32](=[O:34])[CH3:33])[N:14]([C@H:18]([CH3:23])[C:19]([CH3:20])([CH3:22])[CH3:21])[C:13]=3[CH:24]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@@H](n1c(N)nc2ccc(C#Cc3ccccc3)cc21)C(C)(C)C
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1nc2ccc(C#Cc3ccccc3)cc2n1[C@H](C)C(C)(C)C
Reaction time: 18 h

Procedure:
Add 6-phenylethynyl-1-(1-(R)-methyl-2,2-dimethylpropyl)-1H-benzimidazol-2-ylamine (5.81 g, 0.018 mol), triethylamine (12 mL), dichloromethane (100 mL), N,N-dimethylaminopyridine (0.11 g, 0.9 mmol), and acetic anhydride (7.5 mL) and stir for about 18 hours. Evaporate and redissolve in ethyl acetate and wash with water, 1N HCl (3×), saturated sodium bicarbonate, and saturated sodium chloride. Add 2M ammonia in methanol to organic layer and stir 10 minutes and evaporate. Redissolve in dichloromethane and wash with saturated sodium bicarbonate, saturated sodium chloride, dry magnesium sulfate, and concentrate to give the desired compound as an orange foam (6.92 g, quant).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])[CH:5]=[C:6]([OH:8])[CH:7]=1.C(P(CCCC)CCCC)CCC.[CH2:34](O)[CH2:35][CH2:36][OH:37].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.CCCCCC>[CH3:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:18])([F:19])[F:20])[CH:5]=[C:6]([CH:7]=1)[O:8][CH2:34][CH2:35][CH2:36][OH:37]
Reactant: Cc1cc(O)cc(OCc2ccccc2C(F)(F)F)c1
Reactant: OCCCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(OCCCO)cc(OCc2ccccc2C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.1 %

Procedure:
To a solution of 5-methyl-3-(2-trifluoromethylbenzyloxy)phenol (1.41 g, 5.0 mmol), as prepared in the preceding step, tri-n-butylphosphine (1.62 g, 8.0 mmol) and 1,3-propanediol (1.90 g, 25 rnmol) in anhydrous tetrahydrofuran (50 mL) was added 1,1'-(azodicarbonyl) dipiperidine (2.01 g, 8.0 mmol). The mixture was stirred at ambient temperature overnight. Hexane (100 mL) was added to the mixture and the precipitates were removed by filtration. The filtrate was evaporated in vacuo, and the residue was purified by flash column chromatography (2:1 hexane/ethyl acetate) to give the title compound as a colorless oil (1.50 g, 84%). 1H-NMR (300 MHz, CDCl3) δ 7.74 (d, J=7.8 Hz, 1 H), 7.69 (d, J=7.8 Hz, 1 H), 7.56 (t, J=7.6 Hz, 1 H), 7.41 (t, J=7.7 Hz, 1 H), 6.41 (s, 1 H), 6.37 (s, 2 H), 5.23 (s, 2 H), 4.08 (t, J=6.0 Hz, 2 H), 3.85 (t, J=6.0 Hz, 2 H), 2.29 (s, 3 H), 2.02 (t, J =6.0 Hz, 2 H), 1.76 (s, 1 H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:13]=[CH:12][C:11]2[N:10]([CH2:14][C:15]([NH:17][CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:16])[CH2:9][C@@H:8]3[CH2:25][O:26][CH2:27][CH2:28][N:7]3[C:6]=2[N:5]=1.CI.[CH3:31]COC(C)=O>CN(C=O)C>[Cl:3][C:4]1[N:13]=[CH:12][C:11]2[N:10]([CH2:14][C:15]([N:17]([CH3:31])[CH2:18][CH:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)=[O:16])[CH2:9][C@@H:8]3[CH2:25][O:26][CH2:27][CH2:28][N:7]3[C:6]=2[N:5]=1
Reactant: O=C(CN1C[C@@H]2COCCN2c2nc(Cl)ncc21)NCC1CCOCC1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN(CC1CCOCC1)C(=O)CN1C[C@@H]2COCCN2c2nc(Cl)ncc21
Yield: 70.4 %

Procedure:
Sodium hydride (60% in oil) (12.57 mg, 0.314 mmol) was added to a suspension of (R)-2-(2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide (PREPARATION x26, 100 mg, 0.262 mmol) in DMF (1 mL) at 0° C. The resultant mixture was stirred at room temperature for 30 minutes. Methyl iodide (0.021 mL, 0.340 mmol) was added to the reaction mixture at room temperature, and the resultant mixture was stirred at room temperature for 15 minutes. After addition of EtOAc, the resultant mixture was washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was washed with EtOAc to afford the title compound as a white solid (73 mg, 70.4%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.04-1.38 (m, 2H), 1.48 (d, J=11.12 Hz, 2H), 1.75-1.99 (m, 1H), 2.80-3.01 (m, 4H), 3.09-3.31 (m, 7H), 3.40-3.64 (m, 2H), 3.79-4.06 (m, 5H), 4.17-4.27 (m, 1H), 4.34-4.44 (m, 1H), 7.12-7.29 (m, 1H); ESI-MS m/z [M+H]+ calc'd for C18H26ClN5O3, 396.18. found 396.3.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:7]=2[CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:5]([C:20](Cl)=[O:21])[CH2:4][C:3]1=[O:23].[NH3:24]>CO>[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:7]=2[CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:5]([C:20](=[O:21])[NH2:24])[CH2:4][C:3]1=[O:23]
Reactant: CN1C(=O)CN(C(=O)Cl)C(c2ccccc2)c2cc(Cl)ccc21
Reactant: N
Solvent: CO
Product: CN1C(=O)CN(C(N)=O)C(c2ccccc2)c2cc(Cl)ccc21
Yield: 72 %

Procedure:
A suspension of 1.7 g. (4.87 mmoles) of 1-methyl-4-chlorocarbonyl-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-2-one in 3.5 ml. of concentrated ammonia and 7 ml. of methanol is stirred at room temperature overnight. The mixture is diluted with 30 ml. of water, the separated crude product is filtered off, and recrystallized from ethanol without drying. 1.16 g. (72%) of 1-methyl-4-carbamoyl-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-2-one are obtained; m.p.: 212°-215° C.