Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[O:16]=[C:17]1[C:26]2[C:21](=[CH:22][C:23](B(O)O)=[CH:24][CH:25]=2)[CH2:20][CH2:19][NH:18]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].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].O>[CH2:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([C:23]3[CH:22]=[C:21]4[C:26](=[CH:25][CH:24]=3)[C:17](=[O:16])[NH:18][CH2:19][CH2:20]4)=[CH:3][N:4]=2)[N:7]=1)[CH2:13][CH2:14][CH3:15]
Reactant: O=C1NCCc2cc(B(O)O)ccc21
Reactant: CCCCNc1ccc2ncc(Br)n2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: CCCCNc1ccc2ncc(-c3ccc4c(c3)CCNC4=O)n2n1
Temperature: 160 °C
Yield: 44 %

Procedure:
A mixture of 3-bromo-N-butylimidazo[1,2-b]pyridazin-6-amine (160 mg, 0.61 mmol), (1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)boronic acid (200 mg, 0.73 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (50 mg, 0.06 mmol), potassium phosphate (250 mg, 1.2 mmol), DME (1.5 mL) and H2O (0.5 mL) was heated in a sealed conical vessel at 160° C. for 360 s by microwave irradiation. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 mL). The combined organic layers were concentrated under reduced pressure to afford an oil that was purified by reverse phase HPLC to afford 6-(6-butylamino-imidazo[1,2-b]pyridazin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one (90 mg, 44%) as a white solid: 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.11-8.20 (m, 2H), 7.94 (d, J=8.2 Hz, 1H), 7.84 (s, 1H), 7.57 (d, J=9.7 Hz, 1H), 6.67 (d, J=9.7 Hz, 1H), 3.50 (t, J=6.7 Hz, 2H), 3.34 (t, J=7.2 Hz, 2H), 3.00 (t, J=6.6 Hz, 2H), 1.60-1.75 (m, 2H), 1.36-1.50 (m, 2H), 0.95 (t, J=7.4 Hz, 3H); LCMS (ESI) m/e 336.2 [(M+H)+, calcd for C19H22N6O 336.2].
Reaction SMILES: [OH:1][CH:2]1[C:9](=[CH2:10])[CH2:8][C@H:7]2[C@@H:3]1[CH2:4][C@@H:5]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[C@H:6]2/[CH:11]=[CH:12]/[C@@H:13]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(N(CC)CC)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>C(Cl)Cl>[CH3:42][S:43]([O:1][CH:2]1[C:9](=[CH2:10])[CH2:8][C@H:7]2[C@@H:3]1[CH2:4][C@@H:5]([O:27][Si:28]([C:31]([CH3:33])([CH3:32])[CH3:34])([CH3:29])[CH3:30])[C@H:6]2/[CH:11]=[CH:12]/[C@@H:13]([O:19][Si:20]([C:23]([CH3:24])([CH3:25])[CH3:26])([CH3:21])[CH3:22])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:45])=[O:44]
Reactant: C=C1C[C@@H]2[C@H](/C=C/[C@H](CCCCC)O[Si](C)(C)C(C)(C)C)[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]2C1O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C1C[C@@H]2[C@H](/C=C/[C@H](CCCCC)O[Si](C)(C)C(C)(C)C)[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]2C1OS(C)(=O)=O
Temperature: -25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
The (1S,2RS,5S,6S,7R)-2-hydroxy-3-methylene-6-[(E,3S)-3-t-butyldimethylsilyloxy-l-octenyl]-7-t-butyldimethylsilyloxybicyclo[3.3.0]octane (127 mg, 0.25 mmole) obtained in Example 3 was dissolved in 1 ml of methylene chloride. The solution was cooled to -25° C., and triethylamine (38 mg, 0.375 mmole) and then a solution of methanesulfonyl chloride (43 mg, 0.375 mmole) in 1 ml of methylene chloride were added. The mixture was stirred for 2 hours. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The separated organic layer was washed with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated. The crude product was subjected to column chromatography (silica gel 15 g; hexane/ethyl acetate=30/1) to give (1S,2RS,5S,6S,7R)-2-methanesulfonyloxy-3-methylene-6-[(E,3S)-3-t-butyldimethylsilyloxy-1-octenyl]-7-t-butyldimethylsilyloxybicyclo[3.3.0]octane (123 mg, 0.21 mmole, 84%).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:16](=[O:17])[NH:15][C:7]2[N:8]=[C:9]([S:13][CH3:14])[N:10]=[C:11]([CH3:12])[C:6]=2[CH:5]=1.[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1>CN(C=O)C>[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][N:15]2[C:7]3[N:8]=[C:9]([S:13][CH3:14])[N:10]=[C:11]([CH3:12])[C:6]=3[CH:5]=[C:4]([Br:3])[C:16]2=[O:17])=[CH:22][CH:21]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CSc1nc(C)c2cc(Br)c(=O)[nH]c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)c(Br)cc3c(C)nc(SC)nc32)cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a mixture of sodium hydride (60% dispersion in mineral oil) (90 mg, 1.5 equiv.) and anhydrous DMF (5 mL) was added 6-bromo-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (429 mg, 1.5 mmol) and the mixture stirred for 30 minutes at 50° C. Solution was then cooled a little and p-methoxybenzylchloride (281 mg, 1.2 equiv) in 1 mL DMF was then added dropwise. Heated to 50° C. for 3 hours and then stirred at rt overnight. Cooled to rt, partitioned between water and AcOEt, water further washed with AcOEt, pooled organic extracts washed with saturated sodium bicarbonate, brine and dried over MgSO4. Filtration and solvent removal afforded crude material which was used without further purification. Yield 675 mg.
Reaction SMILES: [OH-].[K+].[C:3]([C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]([O:27]CC)=[O:26])=[CH:20][C:19]=3[CH3:30])=[CH:14][CH:13]=2)[C:9]([CH3:31])=[N:8][C:7]=1[CH3:32])(=[O:5])[NH2:4].C(O)(=O)C>C(O)(C)(C)C.C(O)C>[C:3]([C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]([OH:27])=[O:26])=[CH:20][C:19]=3[CH3:30])=[CH:14][CH:13]=2)[C:9]([CH3:31])=[N:8][C:7]=1[CH3:32])(=[O:5])[NH2:4]
Reactant: CCOC(=O)Cc1ccc(-c2ccc(-c3nc(C(N)=O)c(C)nc3C)cc2)c(C)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Product: Cc1cc(CC(=O)O)ccc1-c1ccc(-c2nc(C(N)=O)c(C)nc2C)cc1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
Powdered potassium hydroxide (65.9 mg, 1.17 mmol) was added in one portion to ethyl 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-methylbiphenyl-4-yl)acetate (Intermediate 12-1; 79 mg, 0.20 mmol) in tert-butanol (2 mL) at 45° C. under nitrogen. The resulting solution was stirred at 45° C. for 1 hour. The mixture was treated with acetic acid (0.090 mL, 1.57 mmol) in ethanol (1 mL) and stirred at room temperature for 10 minutes. The mixture was then evaporated under vacuum to give an off white solid. This was triturated with water (10 mL), filtered off and washed with water (10 mL), before drying under vacuum to give desired product.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[Br:10][C:11]1[C:12]([F:20])=[C:13]([CH2:18]O)[C:14]([Cl:17])=[CH:15][CH:16]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([CH2:18][F:7])[C:12]=1[F:20]
Reactant: OCc1c(Cl)ccc(Br)c1F
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: FCc1c(Cl)ccc(Br)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.8 %

Procedure:
A solution of diethylamino sulfur trifluoride (7.6 g, 0.047 mol) in methylene chloride (25 mL) was slowly added to (3-bromo-6-chloro-2-fluorophenyl) methanol (10.3 g, 0.043 mol) in methylene chloride (150 mL) at 0° C. The solution was stirred at ambient temperature for 1 hour. A saturated solution of sodium bicarbonate (100 mL) was cautiously added and the mixture extracted with methylene chloride (2×100 mL). The combined organic phases were dried (sodium sulfate) and concentrated. The dark residual oil was purified by chromatography (5% ethyl acetate in hexanes) to give 1-bromo-4-chloro-3-fluoromethyl-2-fluorobenzene (6.20 g, 0.024 mol): 1H NMR (CDCl3): δ 7.55(m, 1H) 7.18 (dd, 1H) 5.6 (d, 2H).
Reaction SMILES: [C-:1]#[N:2].[K+].[CH2:4]([CH:6]([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:7]Br)[CH3:5]>CN(C=O)C>[CH2:4]([CH:6]([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:7][C:1]#[N:2])[CH3:5]
Reactant: CCCCC(CC)CBr
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCC(CC)CC#N
Reaction time: 2 h

Procedure:
A solution of KCN (3.8 g, 58 mmol) was stirred in DMF (150 mL) at room temperature. After the mixture was stirred for 2 h, a solution of 2-ethylhexylbromide (10 g, 52 mmol) in DMF (250 mL) was added dropwise at the same temperature. After stirring for 12 h at room temperature, the reaction mixture was concentrated by evaporation in vacuo. The crude product was diluted with water (100 mL) and diethyl ether (100 mL). The organic layer was separated and the aqueous layer was extracted with diethyl ether. The combined organic layers were subsequently washed with NaOH-solution (2.5 M), saturated bicarbonate solution and brine, dried over MgSO4 and concentrated by evaporation in vacuo. The resulting brown oil was purified by vacuum distillation (45° C., 10−2 mbar) to afford a clearly yellow oil (VI). (3.2 g, 44%). 1H-NMR (CDCl3): δ=2.82-2.69 (m, 2H), 2.22-2.15 (m, 1H), 1.55-1.00 (m, 11H), 0.83-0.68 (m, 3H)
Reaction SMILES: C[Si](N[Si](C)(C)C)(C)C.C(O)(=O)C.[C:14]1(=O)[CH2:18][CH2:17][CH2:16]C1.[C:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])#[N:21]>O>[C:20]([C:22](=[C:16]1[CH2:17][CH2:18][CH2:14]1)[C:23]([O:25][CH2:26][CH3:27])=[O:24])#[N:21]
Reactant: O=C1CCCC1
Reactant: CCOC(=O)CC#N
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(C#N)=C1CCC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 75.9 %

Procedure:
HMDS (69.6 g, 0.43 mol) was added dropwise to 350 mL of acetic acid at ambient temp over 5 minutes. Cyclopentanone (20.3 g, 0.29 mol) and ethyl cyanoacetate (65.0 g, 0.57 mol) were added in single portions to the resulting solution. The mixture was stirred at 70° C. overnight after which it was cooled to ambient temperature and the reacting mixture was poured into 600 mL of water, and extracted with ethyl acetate (500 mL×3). The combined organic layers were dried over Na2SO4, filtered, and concentrated to afford the crude product, which was purified by flash chromatography (petroleum ether: ethyl acetate=10:1) to give the title compound as a yellow solid (37.0 g, 0.22 mol, 77.2%). LC-MS: m/e=166.2 (M+H+).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:22])[CH2:7][NH:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=3)[NH:11][N:10]=2)[CH2:2]1.[O:23]1[C:27]2[CH:28]=[CH:29][C:30]([CH:32]3[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]3)=[CH:31][C:26]=2[O:25][CH2:24]1>>[O:23]1[C:27]2[CH:28]=[CH:29][C:30]([CH:32]3[CH2:37][CH2:36][CH:35]([N:1]4[CH2:2][CH:3]([NH:5][C:6](=[O:22])[CH2:7][NH:8][C:9]5[C:17]6[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:20])([F:19])[F:21])[CH:16]=6)[NH:11][N:10]=5)[CH2:4]4)[CH2:34][CH2:33]3)=[CH:31][C:26]=2[O:25][CH2:24]1
Reactant: O=C(CNc1n[nH]c2ccc(C(F)(F)F)cc12)NC1CNC1
Reactant: O=C1CCC(c2ccc3c(c2)OCO3)CC1
Product: O=C(CNc1n[nH]c2ccc(C(F)(F)F)cc12)NC1CN(C2CCC(c3ccc4c(c3)OCO4)CC2)C1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide (as prepared in Example 41, Step A) and 4-benzo[1,3]dioxol-5-yl-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].Cl[C:26]1[N:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1>>[Cl:32][C:29]1[CH:28]=[N:27][C:26]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[C:19]2[N:20]=[CH:21][CH:22]=[CH:23][N:24]=2)=[O:11])=[N:31][CH:30]=1
Reactant: C[C@@H]1CCCN(C(=O)c2cc(F)ccc2-c2ncccn2)[C@@H]1CN
Reactant: Clc1cnc(Cl)nc1
Product: C[C@@H]1CCCN(C(=O)c2cc(F)ccc2-c2ncccn2)[C@@H]1CNc1ncc(Cl)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-fluoro-2-(pyrimidin-2-yl)phenyl)methanone and 2,5-dichloropyrimidine. ESI-MS (m/z): 441 [M+1]+.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.Cl[CH:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([NH:28][C:29](=[O:31])[CH3:30])([CH3:27])[CH3:26])=[CH:21][CH:20]=1)[CH3:18]>>[F:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([NH:28][C:29](=[O:31])[CH3:30])([CH3:27])[CH3:26])=[CH:21][CH:20]=3)[CH3:18])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: CC(=O)NC(C)(C)c1ccc(C(C)Cl)cc1
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: Cl
Product: CC(=O)NC(C)(C)c1ccc(C(C)N2CCN(c3ccc(F)cc3)CC2)cc1

Procedure:
By similar reaction and treatment to that in Example 1(5) using 1-(4-fluorophenyl)piperazine dihydrochloride instead of phenylpiperazine and N-(1-(4-(1-chloroethyl)phenyl)-1-methylethyl)acetamide instead of N-(4-chloromethylphenylmethyl)acetamide, the title compound was obtained as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17](O)=[O:18])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH2:17][OH:18])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc2c(ccn2-c2ccc(F)cc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc2c(ccn2-c2ccc(F)cc2)c1
Temperature: 0 °C

Procedure:
A solution of the crude 1-(4-fluorophenyl)-1H-indole-5-carboxylic acid in tetrahydro-furan (700 mL) was added cautiously to a mixture of lithium aluminum hydride (9.8 g) in tetrahydrofuran (400 mL) at 0° C. The resulting mixture was boiled under reflux for 2 h. After cooling to 0° C., water (10 mL), 14% aqueous sodium hydroxide (10 mL) and water (10 mL) was added. Filtration using celite and evaporation of the solvents afforded crystalline title compound 10a (27 g): Mp 69-70° C.; 1H NMR (CDCl3) δ 1.85-1.95 (broad s, 1H), 4.75 (s, 2H), 6.65 (d, 1H), 7.15-7.25 (m, 3H), 7.25 (d, 1H), 7.35-7.45 (m, 3H), 7.65 (broad s, 1H).
Reaction SMILES: [BrH:1].C(O)(=O)C.[C:6]([C:8]1[CH:9]=[C:10]([C:14](=O)[CH2:15][S:16][C:17]#[N:18])[CH:11]=[CH:12][CH:13]=1)#[N:7].O>C(O)(=O)C>[Br:1][C:17]1[S:16][CH:15]=[C:14]([C:10]2[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=2)[C:6]#[N:7])[N:18]=1
Reactant: Br
Reactant: N#CSCC(=O)c1cccc(C#N)c1
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1cccc(-c2csc(Br)n2)c1
Temperature: 130 °C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
A 25% hydrogen bromide/acetic acid (10 ml) solution was added to a solution of 2-(3-cyanophenyl)-2-oxoethyl thiocyanate (1.0 g, 4.94 mmol) in acetic acid (10 ml), and the mixture was stirred at 130° C. for 2 hours and at room temperature for 1 hour. Water was poured to the reaction mixture, and crystals were collected by filtration and washed with water to give 990 mg (75.6%) of the desired product as a solid.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH2:15][N:14]([CH:16]([C:33]([CH3:35])=[CH2:34])[C:17]([O:19][CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[C:13]1=[O:36])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl.C(N(CC)CC)C>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH2:15][N:14]([C:16](=[C:33]([CH3:34])[CH3:35])[C:17]([O:19][CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[C:13]1=[O:36])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(C)C(C(=O)OC(c1ccccc1)c1ccccc1)N1CC(NC(=O)COc2ccccc2)C1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)=C(C(=O)OC(c1ccccc1)c1ccccc1)N1CC(NC(=O)COc2ccccc2)C1=O
Yield: 100 %

Procedure:
To a solution of 50 mg of benzhydryl 2-(3-phenoxyacetamido-2-oxoazetidin-1-yl)-3-methyl-3-butenoate in 10 ml of methylene chloride was added 3 drops of triethylamine. After 2 hours at room temperature the reaction mixture was washed thoroughly with brine and dilute acid. After drying, the solution was evaporated in vacuo to dryness to provide 50 mg of the title product: nmr (CDCl3) δ 2.05 (s, 3, CH3), 2.25 (s, 3, CH3), 3.60 (2, m, azetidinone C4 --H), 5.02 (m, 1, C3 --H), 4.55 (s, 2, --OCH2CO--), and 7.2 (b, 15, ArH).
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C.[C:29]([C:32]1[CH:33]=[C:34]([NH:38][CH:39]([C:43]2[CH:48]=[CH:47][C:46]([CH2:49][CH2:50][OH:51])=[C:45]([CH2:52][CH3:53])[CH:44]=2)[C:40](O)=[O:41])[CH:35]=[CH:36][CH:37]=1)(=[O:31])[NH2:30].[CH:54]([S:57][C:58]1[CH:64]=[CH:63][C:61]([NH2:62])=[CH:60][C:59]=1[CH2:65][NH:66][CH3:67])([CH3:56])[CH3:55]>CCOC(C)=O>[NH2:62][C:61]1[CH:63]=[CH:64][C:58]([S:57][CH:54]([CH3:56])[CH3:55])=[C:59]([CH:60]=1)[CH2:65][N:66]([CH3:67])[C:40](=[O:41])[CH:39]([NH:38][C:34]1[CH:33]=[C:32]([CH:37]=[CH:36][CH:35]=1)[C:29]([NH2:30])=[O:31])[C:43]1[CH:48]=[CH:47][C:46]([CH2:49][CH2:50][OH:51])=[C:45]([CH2:52][CH3:53])[CH:44]=1
Reactant: CCc1cc(C(Nc2cccc(C(N)=O)c2)C(=O)O)ccc1CCO
Reactant: CNCc1cc(N)ccc1SC(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCc1cc(C(Nc2cccc(C(N)=O)c2)C(=O)N(C)Cc2cc(N)ccc2SC(C)C)ccc1CCO
Temperature: 50 °C
Reaction time: 4 h

Procedure:
EDCI (67 mg, 0.35 mmol), HOAt (80 mg, 0.58 mmol) and triethylamine (0.79 mL, 0.58 mmol) were added to a solution of 46C (100 mg, 0.3 mmol) and 16D (67 mg, 0.3 mmol) and stirred at 50° C. for 4 h. The reaction mixture was diluted with EtOAc, washed with water, brine, dried over Na2SO4 and concentrated in vacuo. The crude oil was purified by flash chromatography (0% to 20% MeOH in CH2Cl2) to yield 46D as a yellow solid. MS (ESI) m/z 535.4 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([CH:16](C(OC)=O)[C:17]([O:19]C)=[O:18])=[C:12]([N+:25]([O-:27])=[O:26])[CH:11]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2]>Cl>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=[O:18])=[C:12]([N+:25]([O-:27])=[O:26])[CH:11]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1cccc(-c2ccc(C(C(=O)OC)C(=O)OC)c([N+](=O)[O-])c2)c1
Agent: Cl
Product: CCOc1cccc(-c2ccc(CC(=O)O)c([N+](=O)[O-])c2)c1

Procedure:
Crude dimethyl 3′-ethoxy-3-nitrobiphenyl-4-malonate was heated at 100° C. in 60 mL of 6N hydrochloric acid for 4 days and then cooled. The precipitate was collected by filtration, washed with water and hexane, and dried to give 4.7 g of crude 3′-ethoxy-3-nitrobiphenyl-4-acetic acid as a light tan solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:12])=[O:5])[CH3:2].CCN(C(C)C)C(C)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=1[OH:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCCCC1=O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1=C(O)CCCC1
Yield: 145.3 %

Procedure:
Combine 2-oxo-cyclohexanecarboxylic acid ethyl ester (10.0 g, 55.0 mmol), Hunig's base (23.0 mL, 132.0 mmol), dichloromethane (100.0 mL), and trifluoromethane sulphonic anhydride (11.1 mL, 66.0 mmol) at −78° C. and then stir at room temperarture for 18 hours under a nitrogen atmosphere. Add water, then wash with sat sodium bicarbonate solution, citric acid, then brine, and dry over sodium sulfate. Concentrate under vacuum and flash chromatograph using 10% to 40% DCM/hexanes eluent to yield the titled compound (13.6 g, 82%). TLC Rf=0.25 in 40% DCM/hexanes. 1H NMR (CDCl3): 4.26 (q, 2H, J=7.0 Hz), 2.5 (m, 2H), 2.4 (m, 2H), 1.8 (m, 2H), 1.7 (m, 2H), 1.3 (t, 3H, J=7 Hz).
Reaction SMILES: [ClH:1].CCOCC.[C:7]([O:11][C:12](=[O:39])[C@@H:13]([N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[CH2:29][NH:30]C(OC(C)(C)C)=O)[C:20]1=[O:38])[CH2:14][CH2:15][C:16](=[O:18])[NH2:17])([CH3:10])([CH3:9])[CH3:8]>C(Cl)Cl>[ClH:1].[C:7]([O:11][C:12](=[O:39])[C@@H:13]([N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[CH2:29][NH2:30])[C:20]1=[O:38])[CH2:14][CH2:15][C:16](=[O:18])[NH2:17])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)NCc1cccc2c1C(=O)N([C@@H](CCC(N)=O)C(=O)OC(C)(C)C)C2=O
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)[C@H](CCC(N)=O)N1C(=O)c2cccc(CN)c2C1=O
Reaction time: 5 h
Yield: 97 %

Procedure:
2N HCl/ether (14 mL) was added to a stirred solution of (2S)-2-[4-(t-butoxycarbonylamino-methyl)-1,3-dioxo-1,3-dihydro-isoindol-2-yl]-4-carbamoyl-butyric acid t-butyl ester (2.5 g, 5.4 mmol) in CH2Cl2 (25 mL). The mixture was stirred for 5 hours. Solid was collected by filtration to give (2S)-2-(4-aminomethyl-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-4-carbamoyl butyric acid t-butyl ester hydrochloride (2.1 g, 97%): 1H NMR (DMSO-d6) δ 1.37 (s, 9H), 2.08-2.37 (m, 4H), 4.47-4.51 (m, 2H), 4.73-4.79 (dd, J=4.6 and 10.0 Hz, 1H), 6.73 (s, 1H), 7.25 (s, 1H), 7.92-8.03 (m, 3H), 8.68 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6](Cl)=[CH:7][CH:8]=2)[N:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.[OH-].[K+]>>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6]([O:20][C:17]3[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=3)=[CH:7][CH:8]=2)[N:3]=1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: Oc1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Product: Nc1ccc2ccc(Oc3ccc(Cl)cc3)nc2n1
Temperature: 140 °C
Yield: 73.4 %

Procedure:
A mixture consisting of 2-amino-7-chloro-1,8-naphthyridine (1.8 g), 4-chlorophenol (12.85 g) and 85% strength potassium hydroxide pellets (1.1 g) is heated for 8 hours at 140° C. The reaction mixture is poured into distilled water (200 cc) and made alkaline to a pH of 10 with 4N sodium hydroxide. The suspension obtained is filtered and washed with distilled water to a pH of approximately 7. The solid obtained is air-dried to give 2-amino-7-(4-chlorophenoxy)-1,8-naphthyridine (2 g), m.p. 177° C.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6](OCC)=[O:7])=[CH:4][C:3]=1[O:13][C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[F:1][C:2]1[CH:12]=[CH:11][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[O:13][C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1
Reactant: CCOC(=O)c1ccc(F)c(Oc2cnccn2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCc1ccc(F)c(Oc2cnccn2)c1

Procedure:
The product of Example 128B and LiAlH4 were processed according to the method of Example 124B to provide the product. MS (ESI+) m/z 221(M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][Si:10]([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([Cl:27])[CH:3]=1.[CH2:28](I)[CH:29]([CH3:31])[CH3:30]>>[Si:10]([O:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:3][C:4]=1[Cl:27])([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)[Si](OCc1ccc(Br)cc1Cl)(c1ccccc1)c1ccccc1
Reactant: CC(C)CI
Product: CC(C)Cc1ccc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(Cl)c1

Procedure:
In the same manner as in Preparation Example 70-2, the objective compound (1.644 g, 76%) was obtained as a colorless oil from 4-bromo-1-((tert-butyldiphenylsilyloxy)methyl)-2-chlorobenzene and isobutyl iodide.
Reaction SMILES: [CH:1]1([O:6][C:7]2[N:8]=[C:9]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26]CC)=O)=[CH:19][CH:18]=3)[C:10]3[CH2:15][CH2:14][CH2:13][C:11]=3[N:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH3:29]>CO>[CH:1]1([O:6][C:7]2[N:8]=[C:9]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][C:24]([NH2:29])=[O:26])=[CH:19][CH:18]=3)[C:10]3[CH2:15][CH2:14][CH2:13][C:11]=3[N:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N
Reactant: CCOC(=O)Cc1ccc(Nc2nc(OC3CCCC3)nc3c2CCC3)cc1
Solvent: CO
Product: NC(=O)Cc1ccc(Nc2nc(OC3CCCC3)nc3c2CCC3)cc1
Yield: 30 %

Procedure:
Following General Procedure C, ethyl 2-(4-((2-(cyclopentyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)phenyl)acetate (0.100 g, 0.26 mmol) was reacted with ammonia in methanol (7.0 M, 4 mL) to afford the title compound (0.030 g, 30%) as a brown solid. MW=352.43. 1H NMR (DMSO-d6, 300 MHz) δ 9.28 (s, 1H), 7.66 (d, J=8.6 Hz, 2H), 7.37 (s, 1H), 7.13 (d, J=8.6 Hz, 2H), 6.83 (s, 1H), 5.56-540 (m, 1H), 3.28 (s, 2H), 2.74 (t, J=7.6 Hz, 2H), 2.64 (t, J=7.6 Hz, 2H), 2.07-1.91 (m, 4H), 1.82-1.69 (m, 4H), 1.69-1.56 (m, 2H); APCI MS m/z 353 [M+H]+.