Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[C:17]2[C:16]3[CH:15]=[C:14]([CH:18]=[CH2:19])[CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:20])[C:8]=2[N:7]=[CH:6]1)[CH:2]([CH3:4])[CH3:3].C12BC(CCC1)CCC2.[OH:30]O.[OH-].[Na+]>O.O1CCCC1>[NH2:20][C:9]1[C:8]2[N:7]=[CH:6][N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:17]=2[C:16]2[CH:15]=[C:14]([CH2:18][CH2:19][OH:30])[CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: OO
Reactant: C=Cc1ccc2nc(N)c3ncn(CC(C)C)c3c2c1
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Cn1cnc2c(N)nc3ccc(CCO)cc3c21
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A 500 mL round bottom flask was charged with 1-isobutyl-8-vinyl-1H-imidazo[4,5-c]quinolin-4-amine (850 mg, 3.2 mmol) and 200 mL of tetrahydrofuran. The flask was purged with nitrogen. A solution of 9-borabicyclo[3.3.1]nonane (0.5M in tetrahydrofuran, 8.5 mL, 4.25 mmol) was added in one portion and the reaction was stirred overnight. Additional 9-borabicyclo[3.3.1]nonane (0.5M in tetrahydrofuran, 12.5 mL, 6.25 mmol) was added and the mixture was stirred for approximately 24 hours. The reaction was cooled to 0° C. with an ice/water bath and 30% H2O2 (2 mL) was added dropwise. After 5 minutes, 10% NaOH (5 mL) was added dropwise. The reaction was stirred for 30 minutes, diluted with water (100 mL) and then extracted with chloroform (3×100 mL). The combined organic fractions were concentrated under reduced pressure and purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with a gradient of 0-30% CMA in chloroform) followed by recrystallization from acetonitrile to provide 580 mg of 2-(4-amino-1-isobutyl-1H-imidazo[4,5-c]quinolin-8-yl)ethanol as an off-white solid, mp 214-216° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]2[C:11]=1[NH:10][CH:9]=[C:8]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:7]2=[O:20].[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl.ClCCl>[F:21][C:5]1[CH:4]=[CH:3][C:2]([C:23]2[O:22][CH:26]=[CH:25][CH:24]=2)=[C:11]2[C:6]=1[C:7](=[O:20])[C:8]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=[CH:9][NH:10]2
Reactant: COc1ccc(-c2c[nH]c3c(Br)ccc(F)c3c2=O)cc1
Reactant: OB(O)c1ccco1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: COc1ccc(-c2c[nH]c3c(-c4ccco4)ccc(F)c3c2=O)cc1
Temperature: 180 °C
Yield: 70 %

Procedure:
8-bromo-5-fluoro-3-(4-methoxyphenyl)-1H-quinolin-4-one (150 mg, 0.43 mmol), 2-furan boronic acid (145 mg, 1.3 mmol), 1,1′-bis(diphenylphosphino)ferrocene dichloro palladium (II)-dichloromethane complex (PdCl2(DPPF)) (35 mg, 0.04 mmol) and a 2N sodium carbonate aqueous solution (1 ml) were added to 1,2-dimethoxyethane (3 ml), and the mixture was heated at 180° C. for 10 minutes (microwave reactor). After the reaction mixture was cooled to room temperature, dichloromethane was added, and then filtration with Celite was carried out. The filtrate was extracted with dichloromethane and washed with water. The organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was then purified by silica gel column chromatography (dichloromethane). The purified product was concentrated under reduced pressure, and the residue was recrystallized from n-hexane-ethyl acetate to thereby obtain 100 mg of powdery slightly orange 5-fluoro-8-furan-2-yl-3-(4-methoxyphenyl)-1H-quinolin-4-one (yield: 70%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[NH:22]1[C:26]2([CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)[CH2:25][CH2:24][CH2:23]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[C:35]([O:34][C:32]([N:29]1[CH2:28][CH2:27][C:26]2([N:22]([C:12]([C:10]3[CH:9]=[CH:8][C:7]([N:15]4[CH2:18][C:17]([F:20])([F:19])[CH2:16]4)=[C:6]([O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[N:11]=3)=[O:14])[CH2:23][CH2:24][CH2:25]2)[CH2:31][CH2:30]1)=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCN2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC2(CCCN2C(=O)c2ccc(N3CC(F)(F)C3)c(OCC3CC3)n2)CC1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with tert-butyl 1,8-diazaspiro[4.5]decane-8-carboxylate hydrochloride (851325-42-3) in the presence of TBTU and DIEA to obtain the title compound as yellow oil; MS (EI): m/e=507.6 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[N:33]([C:36]1[CH:41]=[CH:40][C:39]([C:42](=[O:44])[CH3:43])=[CH:38][CH:37]=1)=[C:34]=[O:35]>ClCCl>[C:42]([C:39]1[CH:40]=[CH:41][C:36]([NH:33][C:34]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:35])=[CH:37][CH:38]=1)(=[O:44])[CH3:43]
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Reactant: CC(=O)c1ccc(N=C=O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1ccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.9 %

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (80 mg, 0.21 mmol) (from Example 25a supra) in dichloromethane (2 mL) was added triethylamine (53.8 mg, 0.525 mmol) (Aldrich), followed by the addition of 1-(4-isocyanato-phenyl)-ethanone (41.2 mg, 0.25 mmol) (Aldrich). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layer was washed with water, brine, dried over MgSO4 and concentrated. The residue was purified by chromatography to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid (4-acetyl-phenyl)-amide as a white solid (Yield 45 mg, 39%).
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH2:6]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=2)[CH:15]=[C:14]1[CH:24]([CH3:26])[CH3:25])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CN([CH:30]=[O:31])C>CCOC(C)=O>[CH2:6]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=2)[C:15]([CH:30]=[O:31])=[C:14]1[CH:24]([CH3:26])[CH3:25])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COc1ccc2cc(C(C)C)n(Cc3ccccc3)c2c1
Reactant: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(C=O)c(C(C)C)n(Cc3ccccc3)c2c1
Reaction time: 0.5 h

Procedure:
POCl3 (0.48 ml, 5.23 mmol) was added dropwise to anhydrous DMF (2 ml) at 0° C. under argon. After stirred for 30 min, this solution was added dropwise to a solution of 1-benzyl-2-isopropyl-6-methoxy-1H-indole (Compound 4, 583 mg, 2.09 mmol) in anhydrous DMF (8 ml) at 0° C. under argon. The reaction was stirred for 1 h at 0° C. and 30 min at room temperature, diluted with EtOAc, washed with aqueous NaHCO3, brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→30% EtOAc-hexanes) to yield the title compound as a light yellow syrup.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:20][OH:21])[CH:5]=[C:6]([F:19])[C:7]=1[O:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1.Cl[C:23]1[CH:24]=[C:25]2[N:32]([CH3:33])[C:31]([CH3:35])([CH3:34])[CH2:30][N:26]2[C:27](=[O:29])[N:28]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:19])[C:7]=1[O:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:14]=1)[CH2:20][O:21][C:23]1[CH:24]=[C:25]2[N:32]([CH3:33])[C:31]([CH3:35])([CH3:34])[CH2:30][N:26]2[C:27](=[O:29])[N:28]=1
Reactant: OCc1cc(F)c(Oc2cncc(C(F)(F)F)c2)c(F)c1
Reactant: CN1c2cc(Cl)nc(=O)n2CC1(C)C
Product: CN1c2cc(OCc3cc(F)c(Oc4cncc(C(F)(F)F)c4)c(F)c3)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3,5-difluoro-4-((5-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol and 7-chlo-ro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[NH2:12][CH2:13][CH2:14][OH:15]>CS(C)=O>[NH2:1][C:2]1[N:3]=[C:4]([NH:12][CH2:13][CH2:14][OH:15])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: NCCO
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Solvent: CS(C)=O
Product: Nc1nc(NCCO)ccc1[N+](=O)[O-]

Procedure:
2-[(6-Amino-5-nitropyridin-2-yl)amino]ethanol (Example 48A) is prepared in analogy to Example 36A from 2-amino-6-chloro-3-nitropyridine (400 mg, 2.3 mmol) and 2-aminoethanol (282 mg, 4.6 mmol) in DMSO (110° C., 4 h). Removal of the solvent results in a crude product which is precipitated from dichloromethane. The product is filtered off with suction and dried. 283 mg (62% of theory) of the product are obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([N:15]2[CH2:19][CH2:18][CH2:17][CH:16]2[CH3:20])[N:3]=1.[Br:21][C:22]1[CH:23]=[C:24]([CH3:35])[C:25]([N:28]2[CH2:33][CH2:32][NH:31][C@H:30]([CH3:34])[CH2:29]2)=[N:26][CH:27]=1.C([O-])(O)=O.[Na+]>CCO>[Br:21][C:22]1[CH:23]=[C:24]([CH3:35])[C:25]([N:28]2[CH2:33][CH2:32][N:31]([C:2]3[CH:7]=[C:6]([C:8]4[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=4)[N:5]=[C:4]([N:15]4[CH2:19][CH2:18][CH2:17][CH:16]4[CH3:20])[N:3]=3)[C@H:30]([CH3:34])[CH2:29]2)=[N:26][CH:27]=1
Reactant: CC1CCCN1c1nc(Cl)cc(-c2ccc(F)cc2)n1
Reactant: Cc1cc(Br)cnc1N1CCN[C@H](C)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(Br)cnc1N1CCN(c2cc(-c3ccc(F)cc3)nc(N3CCCC3C)n2)[C@H](C)C1

Procedure:
Heat a mixture of 4-chloro-6-(4-fluoro-phenyl)-2-(2-methyl-pyrrolidin-1-yl)-pyrimidine (1.30 g, 4.44 mmol), 1-(5-bromo-3-methyl-pyridin-2-yl)-3-(R)-methyl-piperazine (1.2 g, 4.44 mmol), and NaHCO3 (0.71 g, 8.46 mmol) in EtOH at 50° C. for 20 h. Concentrate under reduced pressure and partition between EtOAc and brine. Dry the organic layer (Na2SO4) and concentrate under reduced pressure. Purify the residue by flash column chromatography eluting with EtOAc-hexanes (1:4) to afford the title compound as a white solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]([F:19])([F:18])[C:9]1[C:14]([C:15]([OH:17])=O)=[CH:13][N:12]=[CH:11][CH:10]=1.CN(C)C=O.Br.[CH2:26]([N:33]1[C:37](=[NH:38])[S:36][CH:35]=[N:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl>[CH2:26]([N:33]1[C:37](=[N:38][C:15]([C:14]2[CH:13]=[N:12][CH:11]=[CH:10][C:9]=2[C:8]([F:7])([F:19])[F:18])=[O:17])[S:36][CH:35]=[N:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(O)c1cnccc1C(F)(F)F
Reactant: N=c1scnn1Cc1ccccc1
Agent: Br
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(N=c1scnn1Cc1ccccc1)c1cnccc1C(F)(F)F
Temperature: 20 °C
Reaction time: 1 h
Yield: 15.7 %

Procedure:
Oxalyl chloride (0.6 ml) was added to a suspension of 4-trifluoromethylnicotinic acid (1 g) and a catalytic amount of N,N-dimethylformamide in dichloromethane, and stirred at 20° C. for 1 hour. 4-Benzyl-5-imino-1,3,4-thiadiazoline hydrobromide (1.44 g) was added under ice cooling, and was stirred at 20° C. for 1 hour. The mixture was then washed (water), dried (magnesium sulfate), evaporated and the residue recrystallized (ethanol) to give 4-benzyl-5-(4-trifluoromethyl-3-pyridylcarbonyl)imino-1,3,4-thiadiazoline (0.3 g, Compound E-39).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][N:9]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([CH2:23][C:24]([O:26]C)=[O:25])[C:18](=[O:28])[CH2:17]3)[S:10]([CH3:13])(=[O:12])=[O:11])[CH2:3][CH2:2]1.[ClH:29]>O1CCOCC1>[ClH:29].[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][N:9]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([CH2:23][C:24]([OH:26])=[O:25])[C:18](=[O:28])[CH2:17]3)[S:10]([CH3:13])(=[O:12])=[O:11])[CH2:3][CH2:2]1
Reactant: COC(=O)CN1C(=O)Cc2cc(N(CCN3CCOCC3)S(C)(=O)=O)ccc21
Agent: Cl
Solvent: C1COCCO1
Product: CS(=O)(=O)N(CCN1CCOCC1)c1ccc2c(c1)CC(=O)N2CC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of methyl 2-(5-(N-(2-morpholinoethyl)methylsulfonamido)-2-oxoindolin-1-yl)acetate (0.100 g, 0.243 mmol) in dioxane (5 ml), aqueous 37% HCl (5 ml) was added, and the mixture was stirred at room temperature overnight. The volatiles were removed under vacuum and crude 2-(5-(N-(2-morpholinoethyl)-methylsulfonamido)-2-oxoindolin-1-yl)acetic acid hydrochloride (0.105 g, 0.242 mmol, 100% yield, MS/ESI+ 398.0 [MH]+) was used as such in the next step.
Reaction SMILES: N[C:2]1[C:10]([I:11])=[C:9]([CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C1C=CN=CC=1.[FH:19].N([O-])=O.[Na+]>>[F:19][C:2]1[C:10]([I:11])=[C:9]([CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: F
Reactant: Cc1ccc(C(=O)O)c(N)c1I
Agent: O=N[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)O)c(F)c1I
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89 %

Procedure:
2-Amino-3-iodo-4-methylbenzoic acid (3.9 g, 14 mmol) was added slowly at 0° C. to HF-pyridine (30 mL). The mixture was stirred for 15 min and then sodium nitrite (1.5 g, 21 mmol) was added slowly at 0° C. The resulting mixture was stirred at 0° C. for 15 min and warmed up to RT for 15 min, then heated at 90° C. for 1.5 h. The mixture was cooled to 50° C., ice-water (100 mL) was added and the mixture was extracted with EtOAc (3×80 mL). The combined organic extracts were washed with brine (100 mL) and dried over sodium sulfate. The solvent was removed in vacuo to give the title compound (3.5 g, 89%). MS (M+H)+ 281.
Reaction SMILES: Br[CH:2]=[CH:3]Br.[Li]CCCC.[CH3:10][O:11][C@H:12]1[CH2:17][CH2:16][C@H:15]2[C@H:18]3[C@H:28]([CH2:29][CH2:30][C@:13]12[CH3:14])[C@:26]1([CH3:27])[C@@H:21]([CH2:22][C:23](=[O:31])[CH2:24][CH2:25]1)[CH2:20][CH2:19]3>C1COCC1.C(Cl)Cl>[C:2]([C@@:23]1([OH:31])[CH2:24][CH2:25][C@@:26]2([CH3:27])[C@H:21]([CH2:20][CH2:19][C@@H:18]3[C@@H:28]2[CH2:29][CH2:30][C@@:13]2([CH3:14])[C@H:15]3[CH2:16][CH2:17][C@@H:12]2[O:11][CH3:10])[CH2:22]1)#[CH:3]
Reactant: CO[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: BrC=CBr
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: C#C[C@@]1(O)CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](OC)CC[C@@H]32)C1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 78.3 %

Procedure:
A solution of 1,2-dibromoethylene (1.6 mL, 3.7 g, 19.71 mmol) in dry THF (10 mL) was treated with n-BuLi (16.4 mL, 2.4M in THF, 39.4 mmol) at −75° C. After stirring the mixture at −78° C. for 0.25 hr, a solution of 17β-methoxy-5β-androstan-3-one (2 g, 6.57 mmol) in THF (20 mL) was added and the mixture was stirred at −78° C. for 15 min. The cooling bath was then removed and the mixture was quenched with NH4Cl solution (3 mL). The solvents were removed and the residue was extracted with EtOAc. The organic layer was washed with water, and brine. After drying over anhyd. MgSO4 the solution was filtered and evaporated to yield the crude product. This crude product was then dissolved in a small amount of CH2Cl2 and poured on a column of silica gel. Elution with toluene:acetone mixture (95:5) gave 3β-ethynyl-3α-hydroxy-17β-methoxy-5β-androstane (1.70 g) as a colorless solid; mp 62-65° C.; TLC Rf (toluene:acetone 95:5)=0.23.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH:15]=[CH2:16])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17]C(CCCC)C(N[C@@H](CC=C)C(O)=O)=O>>[C:1]([O:5][C:6]([N:8]([CH3:17])[C@@H:9]([CH2:13][CH2:14][CH:15]=[CH2:16])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC[C@H](NC(=O)C(C)CCCC)C(=O)O
Reactant: C=CCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: C=CCC[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Yield: 98 %

Procedure:
Step K (1): Same procedure as Step D (3). (S)-2-(tert-Butoxycarbonyl-amino)hex-5-enoic acid (was used in place of (2S)-2-(2-methylhexanamido)pent-4-enoic acid. The procedure provided 2.06 g (98% yield) of (S)-2-(tert-butoxycarbonyl(methyl)amino)hex-5-enoic acid. LRMS (M−H)−=242.1; 1H NMR (500 MHz, CDCl3) δ ppm 1.45 (d, J=15.26 Hz, 9H) 1.86 (s, 1H) 1.99-2.19 (m, 3H) 2.82 (d, J=18.01 Hz, 3H) 4.36-4.72 (m, 1H) 4.96-5.12 (m, 2H) 5.71-5.87 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][C:13](=[O:15])[CH2:12][C:11](=[O:16])[CH2:10]1.[C:17]([O-])(=[O:19])[CH3:18].[Na+].C(C1C(=O)CC(C2C=CC(F)=CC=2)CC1=O)(=O)C>>[C:17]([CH:12]1[C:11](=[O:16])[CH2:10][CH:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:14][C:13]1=[O:15])(=[O:19])[CH3:18]
Reactant: COc1ccccc1C1CC(=O)CC(=O)C1
Reactant: CC(=O)[O-]
Agent: CC(=O)C1C(=O)CC(c2ccc(F)cc2)CC1=O
Agent: [Na+]
Product: COc1ccccc1C1CC(=O)C(C(C)=O)C(=O)C1

Procedure:
The title compound was prepared from 5-(2-methoxy-phenyl)-cyclohexane-1,3-dione (1.0 g, 4.58 mmol), example 1/a, and sodium acetate (376 mg, 4.58 mmol), following the procedure describing the synthesis of 2-acetyl-5-(4-fluoro-phenyl)-cyclohexane-1,3-dione (example 3/a stage 1).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[N:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:17]([OH:25])(=[O:24])[C:18]([CH2:20][C:21](O)=[O:22])=[CH2:19]>>[F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[N:13]=[CH:12][C:11]([N:14]3[C:21](=[O:22])[CH2:20][CH:18]([C:17]([OH:25])=[O:24])[CH2:19]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: Nc1ccc(OCc2ccc(F)cc2)nc1
Product: O=C(O)C1CC(=O)N(c2ccc(OCc3ccc(F)cc3)nc2)C1
Yield: 47 %

Procedure:
In an analogous manner to that described in Example 36 c), the reaction of 6-(4-fluoro-benzyloxy)-pyridin-3-ylamine with itaconic acid yields the crude (RS)-1-[6-(4-fluoro-benzyloxy)-pyridin-3-yl]-5-oxo-pyrrolidine-3-carboxylic acid as a green solid (yield 47% of theory).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8]2[N:9]=[C:10]([NH2:14])[N:11]=[C:12]([Cl:13])[C:7]=2[CH:6]=[CH:5]1.[CH3:15][NH:16][CH2:17][CH2:18][N:19]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[NH2:14][C:10]1[N:11]=[C:12]([Cl:13])[C:7]2[CH:6]=[CH:5][N:4]([CH2:3][CH2:2][N:16]([CH3:15])[CH2:17][CH2:18][N:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[F:28])[CH3:20])[C:8]=2[N:9]=1
Reactant: Nc1nc(Cl)c2ccn(CCBr)c2n1
Reactant: CNCCN(C)c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN(CCN(C)c1ccc(F)cc1F)CCn1ccc2c(Cl)nc(N)nc21
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a solution of the title A compound, 7-(2-bromoethyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-amine (206.4 mg, 0.75 mmol) and N-(2,4-difluorophenyl)-N,N′-dimethylethylene-1,2-diamine (150 mg, 0.75 mmol) in 5.0 mL of anhydrous acetone is added potassium carbonate (311 mg, 2.25 mmol) at RT under positive N2 pressure. The mixture is stirred at 50° C. for 24 h. The solvent is removed in vacuo after the reaction mixture is cooled down to RT. The residue is absorbed directly onto silica gel and chromatographed to yield N1-(2-(2-amino-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl)-N2-(2,4-difluorophenyl)-N1,N2-dimethylethane-1,2-diamine as a brown gummy solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[C:6](=[O:17])[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([O:15][CH3:16])[CH:9]=2.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:29](I)[CH3:30].CCOCC>O1CCCC1>[CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[C:6](=[O:17])[N:7]([CH2:29][CH3:30])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([O:15][CH3:16])[CH:9]=2
Reactant: CCI
Reactant: COC(=O)Cc1cc2ccc(OC)cc2[nH]c1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCn1c(=O)c(CC(=O)OC)cc2ccc(OC)cc21
Yield: 79.9 %

Procedure:
A slurry of (7-methoxy-2-oxo-1,2-dihydro-quinolin-3-yl)-acetic acid methyl ester (5.0 g, 20 mmol) in tetrahydrofuran (40 mL) was treated with potassium bis(trimethylsilyl)amide (0.5 M in toluene, 41 mL, 21 mmol) at 25° C. and the mixture heated to reflux. After 1 h at reflux, ethyl iodide (16 mL, 200 mmol) was added. After an additional 3 h at reflux, the cooled mixture was quenched with 0.1N aqueous HCl (50 mL) and concentrated in vacuo. Water (200 mL) was added and the aqueous phase extracted with chloroform (3×200 mL). The extracts were dried (K2CO3) and concentrated in vacuo to give the crude product (5.3 g). Flash chromatography (225 g silica; 2:1, then 1:1 hexane-ether, then 100% ether) gave the title compound (4.4 g, 79% yield) as a white solid.
Reaction SMILES: OP([O-])(O)=O.[K+].[OH-].[Na+].S([O-])([O-])(=O)=O.C([N+:18]([CH2:27][CH2:28]CC)([CH2:23][CH2:24]CC)[CH2:19][CH2:20][CH2:21][CH3:22])CCC.C([N+:35](CCCC)(CCCC)CCCC)CCC.[CH3:48][CH2:49][CH2:50]CCC>>[CH3:28][CH2:27][N:18]([C:19]1[CH:20]=[CH:21][C:22]([NH2:35])=[C:49]([CH3:50])[CH:48]=1)[CH2:23][CH3:24]
Reactant: CCCCCC
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=P([O-])(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Product: CCN(CC)c1ccc(N)c(C)c1
Temperature: 25 °C
Reaction time: 336 h

Procedure:
In a 500-mL Parr® hydrogenation vessel, Compound CD-1 (8.74 g, 38 mmol) was dissolved in hexane (20 mL) and aqueous pH 7.4 buffer (20 mL; Fisher Scientific: SB110-1; potassium phosphate monobasic-sodium hydroxide buffer, 0.05 M). RhCl3.xH20 (1.0 g, 3.8 mmol; Alfa Aesar) and tetrabutylammonium sulfate solution (4.4 mL, 50 wt % in H2O; 4.4 g, 3.8 mmol) were added sequentially. The biphasic mixture was shaken under hydrogen atmosphere (53 psi) for 14 days at rt. The reaction mixture was filtered through a Celite® pad. The aq. layer was separated and extracted with EtOAc (3×15 mL). The combined organic layers was washed with brine (˜25 mL), dried over anhydrous MgSO4, filtered, and concentrated by rotary evaporation under reduced pressure. The crude product was purified by flash silica gel chromatography (Isco Combiflash Rf®; 80 g RediSep silica gel cartridge, 0-100% EtOAc/hexanes over 20 column volumes @ 80 mL/min). Eluent from column volumes 1-6, containing unreacted Compound CD-1, were discarded, while column volumes 7-20 were combined and concentrated to give desired product, Compound CD-2, as an off-white solid (6.67 g, 74% yield).
Reaction SMILES: C(=O)(O)[O-].[Na+].Br[CH:7]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=[CH:8]1.[O:15]=[C:16]1[NH:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[NH:19][CH2:18][CH:17]1[NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>CN(C)C=O>[O:15]=[C:16]1[NH:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[N:19]([CH:7]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=[CH:8]2)[CH2:18][CH:17]1[NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]
Reactant: BrC1C=CCCCCC1
Reactant: CC(C)(C)OC(=O)NC1CNc2ccccc2NC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CN(C2C=CCCCCC2)c2ccccc2NC1=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 44.2 %

Procedure:
Sodium bicarbonate (606 mg) and 3-bromocyclooctene (1.36 g) were added to a solution of 2-oxo-3-tert-butoxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (1 g) in N,N-dimethylformamide (20 ml), the mixture was stirred overnight at 80° C. After the reaction mixture was allowed to cool, ice-water was added thereto, extracted with ethyl acetate, the organic layer was washed with saturated brine. The resultant mixture was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and diisopropyl ether was added to the residue for crystallization, and collected by filtration, to thereby obtain 615 mg of the title compound as the mixture of diastereomer compounds.