Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]([Cl:28])([Cl:27])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15]C(C)(C)C)=O)[N:8]1C(OC(C)(C)C)=O)=[O:6].FC(F)(F)C(O)=O.[NH:36]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[C@H:37](C(N[C@H](C(O)=O)C)=O)[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(N(CC)C(C)C)(C)C.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F>ClCCl.C(#N)C.C(OCC)(=O)C>[Cl:28][C:2]([Cl:1])([Cl:27])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:15])[C@@H:37]([NH:36][C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[NH:8]1)=[O:6]
Reactant: C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.3 %

Procedure:
To a solution of (S)-tetrahydro-pyridazine-1,2,3-tricarboxylic acid 1,2-di-tert-butyl ester 3-(2,2,2-trichloro-ethyl)ester (1.0 g, 2.2 mmol) in anhydrous dichloromethane (7 mL) at room temperature and under an atmosphere of nitrogen was added trifluoroacetic acid (6.7 mL, 86.6 mmol). The solution was warmed to room temperature and stirred for 16 h. The reaction was concentrated in vacuo and the residue co-evaporated from toluene (3×). The resulting brown viscous oil was dissolved in anhydrous acetonitrile (2 mL) and added to a solution of Boc-Phe-Ala-OH (574 mg, 2.2 mmol), N,N-diisopropylethylamine (1.5 mL, 8.7 mmol) and 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (821 mg, 2.5 mmol) in anhydrous acetonitrile (10 mL) that had been previously stirred at 0° C. for 20 minutes. The reaction was warmed to room temperature and stirred for 16 h. The reaction was cooled to 0° C. diluted with ethyl acetate and quenched with hydrochloric acid (1 M). The organic layer was separated and washed with a saturated aqueous solution of sodium bicarbonate and brine. The organic layer was then dried through a hydrophobic frit and concentrated in vacuo. The residue was purified by silica gel chromatography using iso-hexanes/ethyl acetate 1:1 to give the title compound (1.0 g, 91%) as a white foam. 1H NMR (300 MHz, CDCl3) δ 1.43 (s, 9H), 1.45-1.51 (m, 1H), 1.72-1.95 (m, 2H), 2.14-2.33 (m, 1H), 2.61-2.76 (m, 1H), 2.84-3.10 (m, 3.58 (d, J=11.6 Hz, 1H), 4.34-4.48 (m, 1H), 4.76, 4.76 (ABq, J=12.4 Hz, 2H), 5.18-5.31 (m, 1H), 5.46-5.61 (m, 2H), 7.17-7.36 (m, 5H). LCMS (m/z) 508.0 [M+H], Tr=3.18 min.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15](=[O:18])[NH:16][CH3:17])[CH2:11][CH2:10]2)[CH:5]=[CH:4][N:3]=1.[NH2:19][C:20]1[N:21]=[CH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CCOC(C)=O>[CH3:17][NH:16][C:15]([N:12]1[CH2:13][CH2:14][N:9]([CH2:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:19][C:20]3[N:21]=[CH:22][C:23]4[C:28]([CH:29]=3)=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:7]=2)[CH2:10][CH2:11]1)=[O:18]
Reactant: Nc1cc2ccccc2cn1
Reactant: CNC(=O)N1CCN(Cc2ccnc(Cl)c2)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CNC(=O)N1CCN(Cc2ccnc(Nc3cc4ccccc4cn3)c2)CC1

Procedure:
1-(2-Chloro-pyridin-4-ylmethyl)-4-(N-methylcarbamoyl)piperazine (1.0 equiv) (Preparation B-12) was mixed with 3-aminoisoquinoline (1.0 equiv), Pd2(dba)3 (0.1 equiv), xantphos (0.15 equiv), and Cs2CO3 (1.4 equiv) in toluene. The mixture was refluxed overnight, and EtOAc was added in to dilute the mixture. After filtration, the filtrate was concentrated and applied onto a silica gel column. The title compound was obtained as a yellow solid (63 mg, 28% yield): 1H NMR (CDCl3, 300 MHz) δ: 2.49 (t, J=4.4 Hz, 4H, PyridylCH2NCH2CH2), 2.83 (s, 6H, N(CH3)2), 3.29 (t, J=4.8 Hz, 4H, NCH2CO), 3.52 (s, 2H, pyridylCH2), 6.88-8.98 (m, 9H, isoquinolyl+pyridyl).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:10](=[O:11])[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6]1)=[O:4].CCN(C(C)C)C(C)C.[CH3:28][O:29][CH2:30]Cl>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH2:6][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:9][C:10]=1[O:11][CH2:28][O:29][CH3:30])=[O:4]
Reactant: COCCl
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOC1=C(C(=O)OC)CN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred mixture of 4-oxo-piperidine-1,3-dicarboxylic acid 1-tert-butylester 3-methyl ester (10 mmol, 2.71 g) and DIEA (1 mL) in DCM was added methoxymethyl chloride (1.3 mL) drop-wise and continued stirring for 16 h at room temperature. Volatiles were removed under reduced pressure, the resultant residue was taken up in ethyl acetate (50 mL), washed with water (25 mL), dried the organic layer, filtered and concentrated under reduced pressure. The resultant residue was purified by flash column chromatography using mixture of hexanes and ethyl acetate to provide 4-methoxymethoxy-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:24][C:25]([C:27]2[O:31][N:30]=[C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:28]=2)=O)=[N:6][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:22])[F:21])=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])([O-])=O>CC(O)=O.[Fe]>[C:32]([C:29]1[CH:28]=[C:27]([C:25]2[NH:1][C:4]3[C:5]([N:24]=2)=[N:6][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:21])([F:23])[F:22])=[CH:8][C:9]=3[C:10]([F:13])([F:12])[F:11])[O:31][N:30]=1)([CH3:33])([CH3:35])[CH3:34]
Reactant: CC(C)(C)c1cc(C(=O)Nc2nc(-c3ccccc3C(F)(F)F)cc(C(F)(F)F)c2[N+](=O)[O-])on1
Agent: [Fe]
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(-c2nc3nc(-c4ccccc4C(F)(F)F)cc(C(F)(F)F)c3[nH]2)on1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A solution of 3-tert-butyl-isoxazole-5-carboxylic acid [3-nitro-4-trifluoromethyl-6-(2-trifluoromethyl-phenyl)-pyridin-2-yl]-amide (14.6 mg, 0.029 mmol, prepared as described in STEP E above) in AcOH (3 mL) was treated with iron powder (8.12 mg, 0.145 mmol), and the resulting mixture was stirred at 100° C. for 2 h and concentrated in vacuo. The residue was taken up in saturated aqueous NaHCO3 (30 mL) and extracted twice with EtOAc (25 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 4-g SEPRA Si 50 SPE column (Flow rate=10 mL/min; Eluent=EtOAc-hexanes, 1:99 for 10 min, then 1:99 to 1:4 over 40 min) to yield 2-(3-tert-butyl-isoxazol-5-yl)-7-trifluoromethyl-5-(2-trifluoromethyl-phenyl)-1H-imidazo[4,5-b]pyridine as a white solid. 1H-NMR (400 MHz, CD3OD) δ: 7.77 (d, J=7.6 Hz, 1H), 7.63-7.69 (m, 1H), 7.58-7.62 (m, 2H), 7.52-7.58 (m, 1H), 7.26 (s, 1H), 1.33 (s, 9H). Mass Spectrum (LCMS, APCI pos.): Calculated for C21H16N4OF6: 455.1 (M+H). Measured: 455.1.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[N:11]=[C:10]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[NH:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=[C:30]1[CH2:38][CH2:39][OH:40]>>[OH:40][CH2:39][CH2:38][C:30]1[N:29]([C:2]2[N:3]=[C:4]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[C:5]3[N:11]=[C:10]([CH2:12][N:13]4[CH2:14][CH2:15][CH:16]([C:19]([OH:22])([CH3:20])[CH3:21])[CH2:17][CH2:18]4)[CH:9]=[CH:8][C:6]=3[N:7]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=1
Reactant: CC(C)(O)C1CCN(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Reactant: OCCc1nc2ccccc2[nH]1
Product: CC(C)(O)C1CCN(Cc2ccc3nc(-n4c(CCO)nc5ccccc54)nc(N4CCOCC4)c3n2)CC1

Procedure:
2-(1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol from Example 8 (0.15 g) was reacted with 2-(1H-benzo[d]imidazol-2-yl)ethanol via General Procedure D to produce 19 mg of 168 following reverse phase HPLC purification. MS (Q1) 532.3 (M)+
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:26])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[N:14][O:15][C:16]=2[CH2:17][OH:18])[CH:9]=1)=[O:4].COC(C1N(C)N=C(OCC2C(C3C=CC(F)=CC=3)=NOC=2CO)C=1)=O>>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:13]2[C:12]([CH2:11][O:10][C:8]3[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[N:6]([CH3:26])[N:7]=3)=[C:16]([CH2:17][OH:18])[O:15][N:14]=2)=[CH:20][CH:21]=1
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(Cl)cc3)noc2CO)nn1C
Agent: COC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2CO)nn1C
Product: Cn1nc(OCc2c(-c3ccc(Cl)cc3)noc2CO)cc1C(=O)O
Yield: 91.6 %

Procedure:
As described for example 93a, 5-[3-(4-chloro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (500 mg, 1.32 mmol), instead of 5-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester, was converted to the title compound (440 mg, 91%) which was obtained as a white solid. MS: m/e=361.9 [M−H]−.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([Cl:11])=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([O:22][CH3:23])[CH:16]=1.C(N(CC)CC)C>CN(C=O)C.O>[Cl:11][C:10]1[C:3]2[C:2]([NH:12][CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([O:22][CH3:23])[CH:16]=3)=[N:7][CH:6]=[N:5][C:4]=2[S:8][CH:9]=1
Reactant: Clc1csc2ncnc(Cl)c12
Reactant: COc1cc(CCN)ccc1O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(CCNc2ncnc3scc(Cl)c23)ccc1O
Yield: 76 %

Procedure:
A solution of 4,5-dichlorothieno[2,3-d]pyrimidine (2.0 g, 9.8 mmol), 4-(2-aminoethyl)-2-methoxyphenol (1.8 g, 10.7 mmol) and triethylamine (1.2 g, 11.8 mmol) in DMF (15 mL) was stirred overnight. The solution was diluted with H2O and the product collected by filtration yielding an off white powder, 2.5 g, 7.4 mmol, 76 percent yield.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[C:4]([F:14])[C:3]=1[F:15].[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>CN(C)C(=O)C>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[C:4]([F:14])[C:3]=2[F:15])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)S(=O)(=O)c1ccc(F)c(F)c1F
Solvent: CC(=O)N(C)C
Product: CC(C)S(=O)(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(F)c1F
Temperature: 90 °C

Procedure:
To 7.6 mmol 1,2,3-trifluoro-4-(propane-2-sulfonyl)-benzene in 20 ml N,N-dimethylacetamide was added 15.9 mmol tert-butyl-1-piperazine carboxylate, and the mixture was heated at 90° C. for 1 h. The mixture was then cooled to room temperature and concentrated in vacuo. The residue was chromatographed on silica gel (eluant: ethyl acetate/heptane 1:2) to afford the title compound.
Reaction SMILES: [CH:1]([C@:4]1([C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]([F:25])([F:24])[F:23])=[CH:17][CH:18]=3)[CH2:13]2)=[O:11])[CH2:8][CH2:7][C@@H:6]([NH2:9])[CH2:5]1)([CH3:3])[CH3:2].[OH:26][C:27]1([C:34]2[O:35][CH:36]=[CH:37][N:38]=2)[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[CH:1]([C@:4]1([C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]([F:25])([F:23])[F:24])=[CH:17][CH:18]=3)[CH2:13]2)=[O:11])[CH2:8][CH2:7][C@@H:6]([NH:9][CH:30]2[CH2:31][CH2:32][C:27]([C:34]3[O:35][CH:36]=[CH:37][N:38]=3)([OH:26])[CH2:28][CH2:29]2)[CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)[C@]1(C(=O)N2CCc3ccc(C(F)(F)F)cc3C2)CC[C@@H](N)C1
Reactant: O=C1CCC(O)(c2ncco2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)[C@]1(C(=O)N2CCc3ccc(C(F)(F)F)cc3C2)CC[C@@H](NC2CCC(O)(c3ncco3)CC2)C1
Reaction time: 8 h

Procedure:
To a solution of (1R,3S)-3-isopropyl-3-{[7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}cyclopentanamine (113.0 mg, 0.3188 mmol) of Step C-2 of Example 1 in THF (1 mL) was added 4-hydroxy-4-(1,3-oxazol-2-yl)cyclohexanone (80.3 mg, 0.443 mmol) followed by triethylamine (0.5 mL, 3.6 mmol) and finally sodium triacetoxyborohydride (135 mg, 0.638 mmol). After being stirred overnight, the reaction was quenched by addition of NaOH solution. The resulting solution was extracted with methylene chloride. The extract was dried over MgSO4 and evaporated in vacuo. The residue was purified by flash chromatography eluting with EtOAc/1% NH4OH to give two isomers. Isomer 1: 73 mg. MS calculated for C28H36F3N3O3: (M+H)+520; found 520.1. Isomer 2: 56 mg. MS found 520.1.\
Reaction SMILES: [C:1]([C:5]1[NH:6][CH:7]=[C:8]([CH:10]=O)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[NH:13][NH2:14]>C(O)C>[CH2:17]([O:16][C:12](=[O:15])[NH:13][N:14]=[CH:10][C:8]1[N:9]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[NH:6][CH:7]=1)[CH3:18]
Reactant: CCOC(=O)NN
Reactant: CC(C)(C)c1nc(C=O)c[nH]1
Solvent: CCO
Product: CCOC(=O)NN=Cc1c[nH]c(C(C)(C)C)n1

Procedure:
A 7.6 gm. portion of 2-tert-butyl-4-imidazolecarboxaldehyde and 5.2 gm. of ethyl carbazate in 100 ml. of ethanol are reacted as described in Example 32 giving the desired product, m.p. 194°-197° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:12]=[N:13][C:14]([Cl:17])=[CH:15][CH:16]=1)=[O:10].[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]([C:11]2[CH:12]=[N:13][C:14]([Cl:17])=[CH:15][CH:16]=2)=[O:10])(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccc(Cl)nc1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccc(Cl)nc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-Amino-5-chloro-phenyl)-(6-chloro-pyridin-3-yl)-methanone and 4-tert-butyl-benzenesulfonyl chloride and purified by HPLC. 1H NMR: δ 1.21 (s, 9H), 7.30 (d, J=2.4 Hz, 1H), 7.33 (d, J=6.6 Hz, 2H), 7.43 (d, J=8.0 Hz, 1H), 7.52 & 7.55 (dd, J=8.8 Hz, 2.8 Hz, 1H), 7.60 (d, J=7.0 Hz, 1H), 7.79 (m, 3H), 8.27 (d, J=2.0 Hz, 1H), 9.73 (s, 1H). MS: M/z 463.0 (M++1).
Reaction SMILES: C(OC([NH:8][CH:9]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]=2[N:11]([CH2:27][C:28]2[C:33](C(O)=O)=[CH:32][CH:31]=[CH:30][N:29]=2)[C:10]1=[O:37])=O)(C)(C)C.O.ON1C2C=CC=C[C:43]=2N=N1.[OH-].[NH4+].N1C(=O)C=NC=C2C=CC=CC=12>O1CCCC1>[NH2:8][CH:9]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]=2[N:11]([CH2:27][C:28]2[CH:33]=[C:32]([CH3:43])[CH:31]=[CH:30][N:29]=2)[C:10]1=[O:37]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)NC1N=C(c2ccccc2F)c2ccccc2N(Cc2ncccc2C(=O)O)C1=O
Agent: O=c1cncc2ccccc2n1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccnc(CN2C(=O)C(N)N=C(c3ccccc3F)c3ccccc32)c1
Reaction time: 2 h

Procedure:
A solution of (3RS)-3-tert-butoxycarbonylamino-2,3-dihydro-5-(2-fluorophenyl)-1-(3-hydroxycarbonylpyridin-2-yl) methyl-1H-1,4-benzodiazepin-2-one (0.71 g) in tetrahydrofuran (20 ml) was treated with dicyclohexylcalbodiimide (0.29 g) and 1-hydroxybenzotriazole monohydrate (0.215 g) at room temperature. The mixture was stirred for 2 hours at the same condition. To the mixture was added dropwise a solution of ammonium hydroxide (28% ammonia in water, 0.359 g) in tetrahydrofuran (1 ml) at ambient temperature under stirring. The mixture was stirred overnight at ambient temperature. The resultant mixture was concentrated in vacuo, and the residue was taken up with ethyl acetate. The organic layer was washed with a brine and dried over sodium sulfate. Filtration and evaporation gave a crude product. The crude product was purified by column chromatography on silica gel with a mixture of chloroform and methanol to afford (3RS)-1-(3-aminocarbonylpyridin-2-yl)methyl-3-tert-butoxycarbonyl-amino-2,3-dihydro-5-(2-fluorophenyl)-1H,-1,4-benzodiazepin-2-one (0.32 g) as a yellow form.
Reaction SMILES: [N:1]1([CH2:10][C:11]([OH:13])=O)[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].Cl.[N+:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24]([N:27]1[CH2:32][CH2:31][NH:30][CH:29]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:28]1=[O:39])(=[O:26])=[O:25])([O-:17])=[O:16].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[N+:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24]([N:27]1[CH2:32][CH2:31][N:30]([C:11](=[O:13])[CH2:10][N:1]2[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]2=[O:3])[CH:29]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:28]1=[O:39])(=[O:25])=[O:26])([O-:17])=[O:16]
Reactant: Cc1cn(CC(=O)O)c(=O)[nH]c1=O
Reactant: O=C1C(c2ccccc2)NCCN1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cn(CC(=O)N2CCN(S(=O)(=O)c3ccccc3[N+](=O)[O-])C(=O)C2c2ccccc2)c(=O)[nH]c1=O
Reaction time: 27 h
Yield: 43.3 %

Procedure:
To a solution of (thymin-1-yl)-acetic acid (13 mg, 0.071 mmol), 1-(2-nitro-benzenesulfonyl)-3-phenyl-piperazin-2-one HCl salt (28 mg, 0.070 mmol), and PyBOP (40 mg, 0.077 mmol) in DMF (0.3 mL) was added N,N-diisopropylethylamine (0.018 mL) at room temperature. After stirring for additional 27 h, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography to give the titled compound (16 mg, 43%). 1H NMR (500 MHz; DMSO-d6) δ 11.33 (s, 1H), 8.36 (d, 1H), 8.13 (d, 1H), 8.05˜7.94 (m, 3H), 7.39˜7.29 (m, 5H), 5.93 (s, 1H), 4.87 (d, 1H), 4.67 (d, 1H), 4.22˜4.16 (m, 2H), 3.96 (m, 1H), 3.78 (m, 1H), 1.74 (s, 3H).
Reaction SMILES: ClC1N=C(NC2C=C(OC(C)C)NN=2)C([N+]([O-])=O)=CN=1.[Cl:21][C:22]1[N:27]=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:25]([N+:33]([O-:35])=[O:34])=[C:24](Cl)[N:23]=1.[CH3:37][C:38]1[NH:42][N:41]=[C:40]([NH2:43])[CH:39]=1>>[Cl:21][C:22]1[N:27]=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:25]([N+:33]([O-:35])=[O:34])=[C:24]([NH:43][C:40]2[CH:39]=[C:38]([CH3:37])[NH:42][N:41]=2)[N:23]=1
Reactant: CCOC(=O)c1nc(Cl)nc(Cl)c1[N+](=O)[O-]
Reactant: Cc1cc(N)n[nH]1
Agent: CC(C)Oc1cc(Nc2nc(Cl)ncc2[N+](=O)[O-])n[nH]1
Product: CCOC(=O)c1nc(Cl)nc(Nc2cc(C)[nH]n2)c1[N+](=O)[O-]

Procedure:
The title compound was prepared using a procedure similar to the one described for the synthesis of Intermediate 30 using ethyl 2,6-dichloro-5-nitropyrimidine-4-carboxylate and 5-methyl-1H-pyrazol-3-amine as the starting materials. LCMS: 327 [M+1].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:10])=[C:6]([CH2:8]O)[CH:7]=1.O=S(Cl)[Cl:13]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:10])=[C:6]([CH2:8][Cl:13])[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cc(Br)ccc1I
Solvent: ClCCl
Product: ClCc1cc(Br)ccc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.5 %

Procedure:
To a solution of (5-bromo-2-iodophenyl)methanol (1.4 g, 4.5 mmol) in DCM (20 mL) was added SOCl2 (3.2 g, 26.9 mmol) at 0° C., and the reaction was stirred at rt overnight. The solution was concentrated, and the residue was purified silica gel chromatography (PE) to give 1.2 g (81%) of the title compound as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]4[C@@H:18]([CH2:26]O)[O:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[CH3:65][NH:66][S:67]([C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][C:71]=1[N+:76]([O-:78])=[O:77])(=[O:69])=[O:68]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:24])([CH3:25])[O:23][C@@H:19]4[C@@H:18]([CH2:26][N:66]([CH3:65])[S:67]([C:70]4[CH:75]=[CH:74][CH:73]=[CH:72][C:71]=4[N+:76]([O-:78])=[O:77])(=[O:68])=[O:69])[O:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1
Reactant: CNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CO)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CN(C)S(=O)(=O)c3ccccc3[N+](=O)[O-])[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 37.6 %

Procedure:
A solution of ((3aR,4R,6R,6aR)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol (1.52 g, 3.33 mmol) and triphenylphosphine (1.92 g, 7.32 mmol) in tetrahydrofuran (25 mL) was cooled at 0° C. and treated dropwise with diethyl azodicarboxylate (1.26 mL, 7.99 mmol). The now yellow solution was treated dropwise with a solution of N-methyl-2-nitrobenzenesulfonamide (1.01 g, 4.66 mmol) in tetrahydrofuran (9.9 mL, 120 mmol) over ˜5 minutes and the solution was allowed to stir and slowly warm up to room temperature. After 24 h at room temperature, HPLC indicated that the starting material had been consumed. The reaction mixture was partially concentrated and the solution was purified by flash chromatography (175 g silica gel, 60-90% EA/hept) to yield the title compound (0.82 g, 38%) as a light yellow glass: MS (ESI+) for C30H34N6O9S m/z 655.3 (M+H)+; (ESI−) for C30H34N6O9S m/z 653.3 (M−H)−; HPLC purity 68% (ret. time, 3.94 min).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[C:10]1(=[O:15])[O:14][CH2:13][CH2:12][CH2:11]1.C[O-].[Na+]>>[OH:15][CH2:10][CH2:11][CH2:12][C:13](=[O:14])[CH2:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccccc1
Reactant: O=C1CCCO1
Agent: C[O-]
Agent: [Na+]
Product: O=C(CCCO)CC(=O)c1ccccc1

Procedure:
60.0 g of acetophenone, 47.4 g of butyrolactone and 99.0 g of sodium methylate (30% solution in methanol) are reacted in the same manner as described in Example 8. After working up as described in Example 8, the product precipitates from the mother solution after several hours. The precipitate is isolated by filtration, washed with water and dried to constant weight under vacuum at ca. 30° C.