Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([N:28]([CH3:30])[CH3:29])=[CH:24][CH:23]=2)[C:13]2[CH:18]=[CH:17][C:16]([N:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=[CH:3][C:2]1=[O:31].Cl.[NH2:34][OH:35]>C(O)C>[N:34]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=[C:12]([C:13]2[CH:14]=[CH:15][C:16]([N:19]([CH3:20])[CH3:21])=[CH:17][CH:18]=2)[C:22]2[CH:27]=[CH:26][C:25]([N:28]([CH3:29])[CH3:30])=[CH:24][CH:23]=2)=[CH:3][C:2]=1[OH:31])=[O:35]
Reactant: CN(C)c1ccc(C(=CC2=CC(=O)C(=O)c3ccccc32)c2ccc(N(C)C)cc2)cc1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: CN(C)c1ccc(C(=Cc2cc(O)c(N=O)c3ccccc23)c2ccc(N(C)C)cc2)cc1
Reaction time: 5 h
Yield: 47.4 %

Procedure:
2-(1,2-naphthoquinon-4-yl)-1,1-bis(p-dimethylaminophenyl)ethylene (1.63 g; 0.004 mol) was dissolved in absolute ethanol (100 ml) by warming. To the solution, at room temperature, was added hydroxylamine hydrochloride (3.7 g;0.053 mol) and the resulting solution was stirred for 5 hours. The mixture was then evaporated to dryness treated with water and extracted with CH2Cl2. The organic extract was dried, evaporated to dryness and then chromatographed over silica (eluent:diethyl ether) to afford 2-(1-nitroso-2-hydroxynaphthalen-4-yl)-1,1-bis(p-dimethylamin ophenyl)ethylene (0.83 g;49%) as a dark brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:62][CH2:63][C:64]1[CH:65]=[CH:66][C:67]2[C:71]([CH2:74][CH3:75])([CH2:72][CH3:73])[O:70][B:69]([OH:76])[C:68]=2[CH:77]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:26])([F:25])[F:27])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:62][CH2:63][C:64]4[CH:65]=[CH:66][C:67]5[C:71]([CH2:72][CH3:73])([CH2:74][CH3:75])[O:70][B:69]([OH:76])[C:68]=5[CH:77]=4)=[O:20])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCC1(CC)OB(O)c2cc(CN)ccc21
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC1(CC)OB(O)c2cc(CNC(=O)c3ccc(C4=NOC(c5cc(Cl)cc(Cl)c5)(C(F)(F)F)C4)cc3C)ccc21
Reaction time: 0.17 h
Yield: 79.4 %

Procedure:
A solution of 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid (100 mg, 0.24 mmol) and DIPEA (151 mg, 1.17 mmol) in DMF (5.0 mL) was stirred at rt for 5 min and then HATU (180 mg, 0.47 mmol) was added. The mixture was stirred for 10 min prior to the addition of 6-(aminomethyl)-3,3-diethylbenzo[c][1,2]oxaborol-1(3H)-ol hydrochloride (63 mg, 0.25 mmol). And the resulting mixture was stirred at rt overnight. It was then concentrated under vacuum, and the residue was partitioned between 1N HCl and ethyl acetate. The organic layer separated was concentrated under vacuum, and the residue was purified by column chromatography and prep-HPLC to provide the final title compound (118 mg, yield 79%). 1H NMR (400 MHz, DMSO-d6): δ 9.00 (s, 1H), 8.88 (t, 1H), 7.80 (t, 1H), 7.60 (m, 5H), 7.42 (d, 1H), 7.40 (d, 1H), 7.24 (d, 1H), 4.47 (d, 2H), 4.36 (d, 2H), 4.27 (d, 2H), 2.35 (s, 3H), 1.78 (m, 4H), 0.52 (t, 6H) ppm; HPLC purity: 92.43% at 220 nm and 93.69% at 254 nm; MS: m/z=620; 661 [M+CH3CN].
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[Cl:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[F:28])[NH2:24]>>[Cl:20][C:21]1[CH:22]=[C:23]([NH:24][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:18]#[N:19])[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1OCC
Product: CCOc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1OCC

Procedure:
In the manner of Example 105 reaction of 4-chloro-6,7-diethoxy-3-quinolinecarbonitrile with 3-chloro-4-fluoroaniline gave the title compound as an off-white solid, mp 194-198° C.
Reaction SMILES: [Li][CH2:2]CCC.Br[C:7]1[CH:15]=[C:14]([Br:16])[CH:13]=[C:12]([F:17])[C:8]=1[C:9]([OH:11])=[O:10].C=O>CCOC(C)=O>[Br:16][C:14]1[CH:13]=[C:12]([F:17])[C:8]2[C:9](=[O:10])[O:11][CH2:2][C:7]=2[CH:15]=1
Reactant: [Li]CCCC
Reactant: O=C(O)c1c(F)cc(Br)cc1Br
Agent: C=O
Solvent: CCOC(C)=O
Product: O=C1OCc2cc(Br)cc(F)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of n-BuLi (36.7 mL, 91.6 mmol) was added dropwise to a solution of 2,4-dibromo-6-fluorobenzoic acid (13.0 g, 43.6 mmol, in 200 mL of THF) at −70° C. The resulting solution was stirred for 15 minutes before CH2O gas (generated by heating 5.1 g of Para formaldehyde to 200° C.) was bubbled into the mixture at −70° C. The suspension was stirred for 1 hour then warmed to room temperature and stirred for another 2 hours. HCl gas was bubbled into the suspension for 15 minutes to give a clear solution. The mixture was diluted with 1 L of EtOAc and washed subsequently with water, saturated Na2CO3 and brine, then dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography (PE:EtOAc=5:1) to give 5-bromo-7-fluoro-2-benzofuran-1(3H)-one as white solid.
Reaction SMILES: CS[S:3][CH3:4].C(P(CCCC)CCCC)CCC.[C:18]([O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH2:31][CH2:32][N:33]2[CH:37]=[CH:36][N:35]=[C:34]2[CH2:38]O)=[CH:25][CH:24]=1)([CH3:21])([CH3:20])[CH3:19]>N1C=CC=CC=1.C(OCC)(=O)C>[C:18]([O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH2:31][CH2:32][N:33]2[CH:37]=[CH:36][N:35]=[C:34]2[CH2:38][S:3][CH3:4])=[CH:25][CH:24]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CSSC
Reactant: CC(C)(C)Oc1ccc(CCCCn2ccnc2CO)cc1
Agent: CCCCP(CCCC)CCCC
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CSCc1nccn1CCCCc1ccc(OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Dimethyl disulfide (8.94 ml) and tributylphosphine (24.7 ml) were added to a solution of [1-[4-(4-tert-butoxyphenyl)butyl]-1H-imidazol-2-yl]methanol (10.0 g) in pyridine (13.4 ml) at room temperature, and the mixture was stirred at room temperature for 17 hr. The reaction mixture was diluted with ethyl acetate, successively washed with 1N aqueous sodium hydroxide solution (3 times) and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give crude 1-[4-(4-tert-butoxyphenyl)butyl]-2-[(methylthio)methyl]-1H-imidazole. 4N Hydrochloric acid (33 ml) was added to the product, and the mixture was stirred at 50° C. for 2 hr. After cooling, the reaction mixture was combined with water and ethyl acetate and separated. The water layer was adjusted to pH 6 by adding 30% aqueous sodium hydroxide solution to salt out and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was washed with diisopropyl ether to give the titled compound (7.31 g) as a colorless crystal powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:11]=[C:12]([C:17]2([C:32]([F:35])([F:34])[F:33])[O:21][N:20]=[C:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[C:24]([CH3:31])[CH:23]=3)[CH2:18]2)[CH:13]=[C:14]([Cl:16])[CH:15]=1>N1C=CC=CC=1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([C:19]3[CH2:18][C:17]([C:12]4[CH:13]=[C:14]([Cl:16])[CH:15]=[C:10]([Cl:9])[CH:11]=4)([C:32]([F:35])([F:34])[F:33])[O:21][N:20]=3)=[CH:23][C:24]=2[CH3:31])=[N:3][CH:4]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Cl
Reactant: Nc1ccc(Cl)cn1
Solvent: c1ccncc1
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Nc1ccc(Cl)cn1
Yield: 74.3 %

Procedure:
In a solution of 0.59 g of 2-amino-5-chloropyridine in 10 mL of pyridine, 2.0 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methylbenzoyl-chloride synthesized in Step 4 of Synthetic Example 1 was added at room temperature with stirring, and stirred at the same temperature for 15 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in 50 mL of ethyl acetate, then washed with 3N hydrochloric acid (50 mL×1), and then the organic phase was dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with neutral alumina column chromatography that was eluated with chloroform to obtain 1.80 g of the aimed product as white crystal.
Reaction SMILES: [C:1]([O:9]C(=O)C1C=CC=CC=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C2C(=CC(O)=CC=2)C=CN=1>N1C=CC=CC=1>[C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OC(=O)c1ccccc1)c1ccccc1
Agent: Nc1nccc2cc(O)ccc12
Solvent: c1ccncc1
Product: O=C(O)c1ccccc1
Temperature: 125 °C
Yield: 108.2 %

Procedure:
Benzoic anhydride (10.27 g) was added to a solution of 1-aminoisoquinolin-6-ol (3.312 g) in pyridine (53 ml) at ambient temperature. The mixture was heated at 125° C. for 1 h, the pyridine was removed under reduced pressure and excess pyridine was removed by azeotroping with toluene (X2). Water was added and the mixture extracted with dichloromethane (X3), dried (sodium sulphate) and concentrated in vacuo to give a solid precipitate. Recrystallisation with dichloromethane-diethyl ether gave benzoic acid 1-benzylaminoisoqinolin-6-yl ester (6 g), EIMS: m/z=369.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])[N:8]([CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[C:7]2=[O:23].[CH3:24][C@@H:25]1[C:29]2[NH:30][C:31](B3OC(C)(C)C(C)(C)O3)=[CH:32][C:28]=2[C:27](=[O:42])[NH:26]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].O>[C:13]([NH:12][C:9]1[N:8]([CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:7](=[O:23])[C:6]2[C:11](=[C:2]([C:31]3[NH:30][C:29]4[C@@H:25]([CH3:24])[NH:26][C:27](=[O:42])[C:28]=4[CH:32]=3)[CH:3]=[CH:4][CH:5]=2)[N:10]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: C[C@H]1NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)[nH]c21
Reactant: CC(C)(C)Nc1nc2c(Br)cccc2c(=O)n1C1CCOCC1
Agent: Cl[Pd+]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: NCCc1[c-]cccc1
Solvent: O
Solvent: C1COCCO1
Product: C[C@H]1NC(=O)c2cc(-c3cccc4c(=O)n(C5CCOCC5)c(NC(C)(C)C)nc34)[nH]c21
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 12.5 %

Procedure:
A mixture of 8-bromo-2-(tert-butylamino)-3-(tetrahydro-2H-pyran-4-yl)quinazolin-4(3H)-one (515d, 70 mg, 0.184 mmol), (R)-6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (705, 93 mg, 0.276 mmol), X-Phos precatalyst II (7.24 mg, 9.20 μmol), and potassium phosphate (117 mg, 0.552 mmol) in 1,4-dioxane (1.5 mL)/water (0.4 mL) was sparged with nitrogen for 3 min at RT; the reaction mixture was stirred at 40° C. for 1.5 h. The reaction mixture was diluted with EtOAc (100 mL), added to a separatory funnel, and washed with saturated aqueous NaHCO3 (3×75 mL); the organic layer was separated, dried over Na2SO4, and concentrated. The crude product was loaded onto the column and was purified via automated flash chromatography (silica gel) with 0-6% 2 M ammonia in MeOH/DCM to give (R)-2-(tert-butylamino)-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)quinazolin-4(3H)-one (515, 10 mg, 0.023 mmol, 12% yield) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.52 (d, J=6.65 Hz, 3H) 1.65 (s, 9H) 1.85 (d, J=11.15 Hz, 2H) 2.33-2.48 (m, 2H) 3.61 (t, J=11.54 Hz, 2H) 4.17 (dd, J=11.74, 4.50 Hz, 2H) 4.65 (q, J=6.72 Hz, 1H) 4.88 (s, 1H) 5.59-5.68 (m, 1H) 5.70 (s, 1H) 6.82 (d, J=1.17 Hz, 1H) 7.21 (t, J=7.73 Hz, 1H) 8.00 (dd, J=7.73, 1.47 Hz, 1H) 8.04 (dd, J=7.83, 1.37 Hz, 1H) 12.27 (br. s., 1H). MS (ESI, pos. ion) m/z: 436.1 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH:16]1([C:19]2[CH:24]=[CH:23][C:22]([CH:25]=[CH2:26])=[CH:21][N:20]=2)[CH2:18][CH2:17]1.[OH-].[K+]>CN1C(=O)CCC1>[CH:16]1([C:19]2[N:20]=[CH:21][C:22]([CH2:25][CH2:26][CH:3]3[C:4]4[C:12]5[CH:11]=[C:10]([CH3:13])[CH:9]=[CH:8][C:7]=5[NH:6][C:5]=4[CH2:14][CH2:15][N:2]3[CH3:1])=[CH:23][CH:24]=2)[CH2:18][CH2:17]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=Cc1ccc(C2CC2)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2[nH]c3c(c2c1)C(CCc1ccc(C2CC2)nc1)N(C)CC3

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole, 2-cyclopropyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:5][C:6](=[O:35])[CH:7]([CH2:13][C:14]1[CH:15]=[N:16][C:17]([N:20]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[N:18][CH:19]=1)[C:8]([O:10]CC)=[O:9])[CH3:4].CCOC(C)=O>CCO.CCO.C(Cl)Cl>[CH2:3]([O:5][C:6](=[O:35])[CH:7]([CH2:13][C:14]1[CH:15]=[N:16][C:17]([N:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])=[N:18][CH:19]=1)[C:8]([OH:10])=[O:9])[CH3:4]
Reactant: CCOC(=O)C(Cc1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cc1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.2 %

Procedure:
A solution of KOH (106 mg, 1.88 mmol) in EtOH (2 mL) was added to a solution of 2-(2-[N,N-bis(tert-butoxycarbonyl)amino]-pyrimidin-5-ylmethyl)-malonic acid diethyl ester (0.80 g, 1.71 mmol) in EtOH/methylene chloride (2:1, 12 mL) at 0° C. The mixture was stirred for 16 h at room temperature and EtOAc was added. The mixture was washed with 0.5 M HCl and brine, dried and concentrated under reduced pressure to give 2-(2-[N,N-bis(tert-butoxycarbonyl)amino]-pyrimidin-5-ylmethyl)-malonic acid monoethyl ester (0.67 g, 89%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][CH:17]([NH:20]C(OCC4C=CC=CC=4)=O)[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[N:2]1.[H][H]>CO.C1COCC1.[C].[Pd]>[N:1]1([CH2:6][CH2:7][C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH2:15][CH2:16][CH:17]([NH2:20])[CH2:18][CH2:19]3)=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: O=C(NC1CCN(c2ccc(CCn3ccnn3)cc2)CC1)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: NC1CCN(c2ccc(CCn3ccnn3)cc2)CC1

Procedure:
The N-(4-(2-(1,2,3-triazol-1-yl)-ethyl)-phenyl)-4-benzyloxycarbonylaminopiperidine (1.3 g, 50 mmol) obtained in Example 7 (6) was dissolved in methanol (13 ml) and THF (13 ml), and 10% palladium-carbon (hereinafter referred to as Pd—C) (130 mg) was added, followed by stirring at room temperature in an atmosphere of hydrogen gas for 24 hours. After the insoluble material was filtered with Celite, the solvent was evaporated from the filtrate under reduced pressure, thereby obtaining N-(4-(2-(1,2,3-triazol-1-yl)-ethyl)-phenyl)-4-aminopiperidine (870 mg, 99%) as a white solid.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:14][CH2:15]Cl)(=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10].[CH2:17]([N:19]([CH2:37][P:38]([OH:50])([CH2:40][CH2:41][CH2:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:39])[C:20]([N:22]1[CH2:36][CH2:35][CH2:34][C@H:23]1[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])=[O:21])[CH3:18]>CN(C)C=O.C(OCC)(=O)C>[CH2:17]([N:19]([CH2:37][P:38]([O:50][CH2:15][O:14][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])([CH2:40][CH2:41][CH2:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:39])[C:20]([N:22]1[CH2:36][CH2:35][CH2:34][C@H:23]1[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])=[O:21])[CH3:18]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: CCN(CP(=O)(O)CCCCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN(CP(=O)(CCCCc1ccccc1)OCOC(=O)C(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
An equimolar mixture of triethylamine and chloromethyl pivalate are added to a solution of 1-[[ethyl[[hydroxy(4-phenylbutyl)phosphinyl]methyl]amino]carbonyl]-L-proline, phenylmethyl ester in dimethylformamide under argon. The mixture is stirred for several hours at room temperature, diluted with ethyl acetate, washed with water, brine, dried (MgSO4), and evaporated. The crude product is chromatographed to give 1-[[ethyl[[[(2,2-dimethyl-1-oxopropoxy) methoxy](4-phenylbutyl)phosphinyl]methyl]amino]carbonyl]-L-proline, phenylmethyl ester.
Reaction SMILES: C(O[CH:5]([C:28]1[CH:36]=[C:31]2[CH2:32][O:33][CH2:34][CH2:35][N:30]2[N:29]=1)[C:6]1(Br)[C:12](=[O:13])[N:11]2[C@@H:7]1[S:8][CH:9]=[C:10]2[C:14]([O:16]CC1C=CC([N+]([O-])=O)=CC=1)=[O:15])(=O)C.P([O-])([O-])([O-])=O>C1COCC1.[Pd]>[N:29]1[N:30]2[C:31]([CH2:32][O:33][CH2:34][CH2:35]2)=[CH:36][C:28]=1/[CH:5]=[C:6]1\[C@@H:7]2[N:11]([C:12]\1=[O:13])[C:10]([C:14]([OH:16])=[O:15])=[CH:9][S:8]2
Reactant: CC(=O)OC(c1cc2n(n1)CCOC2)C1(Br)C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CS[C@@H]21
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Product: O=C(O)C1=CS[C@@H]2/C(=C\c3cc4n(n3)CCOC4)C(=O)N12
Reaction time: 3 h

Procedure:
To a solution of 4-nitrobenzyl (5R)-6-[(acetyloxy)(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.35 g, 0.6 mmol) in THF (20 ml), under nitrogen, was added 20 ml of a phosphate buffer solution (0.5M, pH 6.5), and 120 mg of 10% Pd/C. The mixture was hydrogenated at 40–50 psi for 3 hr, and then filtered through Celite. The filter pad was washed with THF, and the filtrate was extracted with ethyl acetate. The organic extract was dried over anhydrous magnesium sulfate and evaporated. The residue was washed with ether to give; 0.09 g of a yellow solid; HRMS: calcd for C13H11N3O4S, 305.0470; found (ESI+), 306.05434; 1H NMR (DMSO-d6) δ 4.07–4.09 (t, 2H), 4.13–4.17 (t, 2H), 4.82 (s, 2H), 6.36 (s, 1H), 6.55 (s, 1H), 7.17 (s, 1H), 7.55 (s, 1H), 12.80 (bs, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:19]([F:28])=[CH:18][CH:17]=1)[C:10]([CH3:30])([CH3:29])[CH2:9]2)=[O:5])C.O.[OH-].[Li+].O.Cl>O1CCCC1>[F:28][C:19]1[CH:18]=[CH:17][C:16]([CH:11]2[C:10]([CH3:29])([CH3:30])[CH2:9][C:8]3[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=3)[NH:12]2)=[CH:21][C:20]=1[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(F)c(N3CCOCC3)c1)N2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccc(F)c(N2CCOCC2)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 57.8 %

Procedure:
A mixture of 2-(4-fluoro-5-morpholin-4-yl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.11 g, 0.27 mmol), lithium hydroxide hydrate (0.11 g, 2.7 mmol), water (2 mL) in tetrahydrofuran (10 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-(4-fluoro-3-morpholin-4-yl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (60 mg, 57%) as a white solid: LC/MS m/e calcd for C22H25FN2O3 (M+H)+: 385.5, observed: 385.3.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=2[Cl:21])=[O:12])[N:7]([C:22]2[CH:31]=[C:30]3[C:25]([CH2:26][C@@H:27]([C:39](=[O:41])[NH2:40])[N:28](C(OC(C)(C)C)=O)[CH2:29]3)=[CH:24][CH:23]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]>Cl.O1CCOCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=2[Cl:21])=[O:12])[N:7]([C:22]2[CH:31]=[C:30]3[C:25]([CH2:26][C@@H:27]([C:39](=[O:41])[NH2:40])[NH:28][CH2:29]3)=[CH:24][CH:23]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(-n3nc(C(C)(C)C)cc3NC(=O)Nc3cccc(Cl)c3Cl)ccc2C[C@H]1C(N)=O
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(Cl)c2Cl)n(-c2ccc3c(c2)CN[C@H](C(N)=O)C3)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
A solution of (3S)-2-t-butyl 3-methyl 7-(3-t-butyl-5-(3-(2,3-dichlorophenyl)ureido)-1H-pyrazol-1-yl)-3,4-dihydroiso-quinoline-2,3 (1H)-dicarboxylate (from Example 177, 0.100 g, 0.163 mmol) in 7N NH3/MeOH (3 mL) was stirred at RT overnight. The solvent was removed under reduced pressureand the residue was dissolved in CH2Cl2 (2 mL). Boc anhydride (0.036 g, 0.163 mmol) was added and the solution was stirred at room temperature for 30 min. The solvent was evaporated and the residue was purified by column chromatography to yield (3S)-t-butyl 7-(3-t-butyl-5-(3-(2,3-dichlorophenyl)ureido)-1 H-pyrazol-1-yl)-3-carbamoyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (85 mg, 87% yield) as a white solid. 1H-NMR (400 MHz, acetone-d6): δ 8.66 (brs, 1H), 8.27 (dd, J=8.4, and 2.0 Hz, 1H), 8.21 (brs, 1H), 7.42-7.37 (m, 2H), 7.35-7.29 (m, 2H), 7.24 (dd, J=8.0, and 1.6 Hz, 1H), 6.88 (brs, 1H), 6.49 (s, 1H), 6.33 (brs, 1H), 4.97-4.45 (m, 3H), 3.36-3.09 (m, 2H), 1.47-1.45 (m, 9H), 1.32 (s, 9H); MS (ESI) m/z: 601.2 (M+H+). (3S)-t-butyl 7-(3-t-butyl-5-(3-(2,3-dichlorophenyl)ureido)-1H-pyrazol-1-yl)-3-carbamoyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.085 g, 0.14 mmol) was dissolved in 4N HCl in dioxane (5 mL) and the solution was stirred at RT for 30 min. The solvent was removed under reduced pressureand the residue was dissolved in H2O/MeCN (1:1) and lyophilized to yield 1-(3-t-butyl-1-((3S)-3-carbamoyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1 H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea (65 mg, 85% yield) as a white solid. 1H-NMR (CD3OD) shows rotameric mixture. MS (ESI) m/z: 501.2 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.[NH:12]1[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13]1>CN(C=O)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([N:12]1[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13]1)=[O:11]
Reactant: O[C@H]1CCNC1
Reactant: O=C(O)Cc1ccccc1O
Solvent: CN(C)C=O
Product: O=C(Cc1ccccc1O)N1CC[C@H](O)C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 46.3 %

Procedure:
A mixture of (2-hydroxyphenyl)acetic acid (304 mg, 2.0 mmol) and N,N′-carbonyldiimidazole (405 mg, 2.5 mmol) in DMF (5 nL) was stirred at room temperature for 45 min. A solution of (3S)-pyrrolidin-3-ol (435 mg, 5.0 mmol) in DMF (1.5 mL) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and H2O. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography (0-3% methanol in dichloromethane) to give the subtitled compound (205 mg).