Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:49][CH:50]2[CH2:54][CH2:53][CH2:52][CH2:51]2)[C:40]([NH:42][C:43]2[CH:47]=[CH:46][N:45]([CH3:48])[N:44]=2)=[O:41])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[CH3:55][C:56]([CH3:65])=[CH:57]CN1C=CC(N)=N1.N1C(C)=CC=CC=1C>C(Cl)Cl.C(OCC)(=O)C>[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:49][CH:50]2[CH2:51][CH2:52][CH2:53][CH2:54]2)[C:40]([NH:42][C:43]2[CH:47]=[CH:46][N:45]([CH2:48][CH:55]=[C:56]([CH3:65])[CH3:57])[N:44]=2)=[O:41])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36]
Reactant: CC(C)=CCn1ccc(N)n1
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)=CCn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 0 °C
Yield: 38.9 %

Procedure:
Triphenylphosphine (224 mg, 0.85 mmol) was dissolved in methylene chloride (3 mL) and cooled to 0° C. To this solution was added N-bromosuccinimide (172 mg, 0.97 mmol) and was stirred at 0° C. until it was completely dissolved and became light purple in color. The 2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1; 188 mg, 0.57 mmol) was then added and it was stirred at 0° C. for 20 min and then warmed to 25° C. and stirred for another 30 min. After such time 1-(3-methyl-but-2-enyl)-1H-pyrazol-3-ylamine (86 mg, 0.57 mmol) and 2,6-lutidine (198 μL, 1.71 mmol) were added and the reaction was stirred at 25° C. for 16 h. The reaction was then diluted with ethyl acetate (50 mL), washed with water (2×15 mL), saturated aqueous brine solution (1×15 mL), dried over magnesium sulfate and concentrated in vacuo to give an orange oil. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 20% ethyl acetate/hexanes to 100% ethyl acetate/hexanes) followed by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% ethyl acetate/methylene chloride to 20% ethyl acetate/methylene chloride) afforded 2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(3-methyl-but-2-enyl)-1H-pyrazol-3-yl]-propionamide (103 mg 39%) as an off white powder: ESI-LRMS m/e calcd for C23H30ClN3O3S [M+] 463.17, found 464.23 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.06-1.23 (m, 2H, CH2), 1.46-1.93 (m, 8H, 4×CH2), 1.76 (s, 3H, CH3), 1.80 (s, 3H, CH3), 2.05-2.35 (m, 1H, CH), 3.28 (s, 3H, SO2CH3), 3.53 (t, J=7.6 Hz, 1H, CH), 4.59 (d, J=7.1 Hz, 2H, NCH2), 531-5.43 (m, 1H, vinylic), 6.66 (d, J=2.3 Hz, 1H, Ar), 7.27 (d, J=2.3 Hz, 1H, Ar), 7.46 (dd, Jo=8.1, Jm=1.7 Hz. 1H, Ar), 7.59 (d, Jm=1.7 Hz, 1H, Ar), 7.83 (s, 1H, NH), 8.10 (d, Jo=8.1 Hz, 1H, Ar).
Reaction SMILES: [CH2:1]([N:4]1[C:11]([NH2:12])=[C:10]([NH2:13])[C:8](=[O:9])[N:7]([CH2:14][CH2:15][CH3:16])[C:5]1=[O:6])[CH2:2][CH3:3].[CH:17]12[CH2:23][CH:20]([CH2:21][CH2:22]1)[CH2:19][CH:18]2[C:24](O)=[O:25]>>[NH2:12][C:11]1[N:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:6])[N:7]([CH2:14][CH2:15][CH3:16])[C:8](=[O:9])[C:10]=1[NH:13][C:24]([CH:18]1[CH2:19][CH:20]2[CH2:23][CH:17]1[CH2:22][CH2:21]2)=[O:25]
Reactant: O=C(O)C1CC2CCC1C2
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Product: CCCn1c(N)c(NC(=O)C2CC3CCC2C3)c(=O)n(CCC)c1=O
Yield: 93 %

Procedure:
The substantially same operations as in Example 1 were repeated using 3.0g (13.3 mmol) of 1,3-dipropyl-5,6-diaminouracil and 2.61g (18.6 mmol) of bicyclo[2.2.1]heptane-2-carboxylic acid to afford 4.31g (yield: 93%) of amorphous 6-amino-5-(bicyclo[2.2.1]heptan-2-yl)carbonylamino-1,3-dipropyluracil.
Reaction SMILES: [C:1]12([C:11]3[CH:22]=[CH:21][C:14]([O:15][CH:16]=[CH:17][C:18](O)=[O:19])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:23][O:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH2:32])[CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:23][O:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:18](=[O:19])/[CH:17]=[CH:16]/[O:15][C:14]2[CH:13]=[CH:12][C:11]([C:1]34[CH2:10][CH:5]5[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]5)[CH2:2]3)[CH2:8]4)=[CH:22][CH:21]=2)[CH:27]=1
Reactant: O=C(O)C=COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reactant: COC(=O)c1cccc(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(NC(=O)/C=C/Oc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 10 %

Procedure:
3-(4-Adamantan-1-yl-phenoxy)-acrylic acid (110.6 mg, 0.5 mmol), 3-aminobenzoic acid methyl ester (151.2 mg, 1.0 mmol) and HATU (143.8 mg, 0.75 mmol) were mixed in 5 ml of DMF, to which DIPEA (0.13 ml, 0.75 mmol) was added, followed by stirring for 12 hours at room temperature. The reaction mixture was extracted with ethylacetate and 10% HCl, thereafter the organic layer was washed with NaCl solution and water, dried over anhydrous MgSO4, and concentrated. The residue was purified by silcagel column chromatography (n-Hexane:EtOAc=10:1) to give the target compound as a white solid (21.5 mg, yield: 10.6%).
Reaction SMILES: [C:1]([CH2:9][C:10]#[N:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:13]1([CH3:21])[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][NH2:20]>CO>[C:2]1([C:1]2[CH:9]=[C:10]([NH2:11])[N:19]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH3:21])[N:20]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCC(=O)c1ccccc1
Reactant: Cc1ccccc1NN
Agent: Cl
Solvent: CO
Product: Cc1ccccc1-n1nc(-c2ccccc2)cc1N
Temperature: 120 °C
Yield: 45.7 %

Procedure:
Benzoylacetonitrile (500 mg, 3.44 mmol) and o-tolylhydrazine hydrochloride (574 mg, 3.61 mmol) were placed in a microwave vial and dissolved in methanol (1.7 mL). The reaction vessel was sealed, placed in a microwave oven and heated at 120° C. for 1 hour. After this period, the reaction mixture was concentrated onto silica gel and purified by flash chromatography (0-50% ethyl acetate/hexanes gradient) to afford the desired intermediate, 5-phenyl-2-o-tolyl-2H-pyrazol-3-ylamine (392 mg). LC/MS: Calc. C16H15N3 249.13 amu; Obs. [M+H]+=250.2 amu.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([Li])CCC.[CH2:17](Br)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].O>CCOCC.CCCCCC>[CH2:1]([C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCBr
Reactant: Cc1ccc2ccccc2n1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: CCOCC
Product: CCCCCCCc1ccc2ccccc2n1
Temperature: 25 °C
Yield: 78.1 %

Procedure:
A solution of 25 g of 2-methylquinoline in 40 ml of ether was added slowly to a mixture of 70 ml of a 1.6M solution of n-butyllithium in hexane and 40 ml of diethyl ether. The reaction mixture was stirred at room temperature, then it was cooled to about 5° C. and a solution of 28.9 g of n-hexyl bromide in 10 ml of ether was slowly added. The reaction mixture was then warmed to room temperature and stirred at room temperature for 2 hours. For working-up, the reaction mixture was added to 500 ml of water and extracted with ether. The organic phase was washed with slightly acidified water, dried and evaporated. The crude product obtained was purified by chromatography on a silica gel column using dichloromethane as the eluent. 31 g of oily crude 2-n-heptylquinoline were obtained.
Reaction SMILES: BrBr.[Br:3][C:4]1[C:9]([F:10])=[C:8]([F:11])[C:7]([F:12])=[C:6]([F:13])[C:5]=1Br>>[Br:3][C:4]1[C:9]([F:10])=[C:8]([F:11])[C:7]([F:12])=[C:6]([F:13])[CH:5]=1
Reactant: Fc1c(F)c(F)c(Br)c(Br)c1F
Agent: BrBr
Product: Fc1cc(Br)c(F)c(F)c1F

Procedure:
A residue of 3.9 g consisting of bromine and dibromotetrafluorobenzene remains in the boiler in a ratio of about 1:1. The calculated yield to bromotetrafluorobenzene with respect to the distillate is 33.4%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][C:15]=3[CH:16]=[O:17])[N:7]([CH3:18])[C:6]=2[CH:19]=1.C[Mg+].[Br-].[CH2:23](OCC)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][C:15]=3[CH:16]([OH:17])[CH3:23])[N:7]([CH3:18])[C:6]=2[CH:19]=1
Reactant: Cn1c(-c2cnccc2C=O)nc2ccc(Cl)cc21
Reactant: CCOCC
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(O)c1ccncc1-c1nc2ccc(Cl)cc2n1C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(6-chloro-1-methyl-1H-benzoimidazol-2-yl)-pyridine-4-carbaldehyde (75 mg, 0.276 mmol) in THF (4 mL) at −78° C. was added 3 M MeMgBr in diethyl ether (0.138 mL, 0.414 mmol) and the mixture was stirred at −78° C. for 0.5 hr. The reaction was quenched with water (0.5 mL) and the mixture was warmed to room temperature. It was concentrated in vacuo. The crude was taken up in MeOH (5 mL) and purified on RP-HPLC using RP18 column and gradient 0.1% aqueous NH4OH in acetonitrile, followed with a second purification by silica gel flash chromatography DCM-MeOH (9:1) to afford 1-[3-(6-chloro-1-methyl-1H-benzoimidazol-2-yl)-pyridin-4-yl]-ethanol. 1H NMR (400 MHz, MeOD) δ ppm 1.34 (d, J=6.6 Hz, 3H), 3.73 (s, 3H), 4.81-4.86 (m, 1H), 7.38 (dd, J=8.6, 2.0 Hz, 1H), 7.72 (d, J=9.1 Hz, 1H), 7.73 (d, J=2.0 Hz, 1H), 7.86 (d, J=5.3 Hz, 1H), 8.63 (s, 1H), 8.79 (d, J=5.3 Hz, 1H); HRMS: (ESI) ink 288.0894 [(M+H)+ Calcd for C15H14ClN3O 288.0904].
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8](OCCCN3CCCC3)=[C:9](OC)[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].OC1C=CC2C3C(=CC=CC=3)NC=2C=1>CN(C=O)C>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:2]=[N:3][CH:4]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCC1
Agent: O=C([O-])[O-]
Agent: Oc1ccc2c(c1)[nH]c1ccccc12
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc2ncncc2c1
Temperature: 100 °C
Yield: 76.8 %

Procedure:
To a solution of 4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (100 mg, 0.31 mmol), (prepared as described for the starting material in Example 9), in DMF (10 ml) was added potassium carbonate (124 mg, 0.9 mmol, 3eq.) followed by 2-hydroxycarbazole (66 mg, 0.36 mmol, 1.2eq.) and the reaction heated at 100° C. for 4 hours. The DMF was removed in vacuo, the residue dissolved in dichloromethane and placed onto a 2 g SCX ion-exchange column. Elution with dichloromethane, followed by 20% methanol/dichloromethane then 20% methanol/dichloromethane+3% ammonium hydroxide, gave the crude product as a brown solid. Further purification by silica bond elut chromatography eluting with dichloromethane to 15% methanol/dichloromethane+1% ammonium hydroxide, followed by trituration with ether gave 4-(9H-carbazol-2-yloxy)-6-methoxy-7–3-(pyrrolidin-1-yl)propoxy)quinazoline (31 mg, 22%) as a white solid.
Reaction SMILES: C(O[C:4]1([C:15]([F:18])([F:17])[F:16])[CH:6]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:5]1)C.[O:19]1[CH2:24][CH2:23][NH:22][C:21]2[CH:25]=[CH:26][CH:27]=[CH:28][C:20]1=2>FC(F)(F)C(O)C(F)(F)F>[CH2:7]([CH:6]1[C:4]([C:15]([F:16])([F:17])[F:18])([OH:5])[C:25]2[C:21]3=[C:20]([O:19][CH2:24][CH2:23][N:22]13)[CH:28]=[CH:27][CH:26]=2)[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCOC1(C(F)(F)F)OC1CCc1ccccc1
Reactant: c1ccc2c(c1)NCCO2
Solvent: OC(C(F)(F)F)C(F)(F)F
Product: OC1(C(F)(F)F)c2cccc3c2N(CCO3)C1CCc1ccccc1

Procedure:
A solution of 2-ethoxy-3-phenethyl-2-(trifluoromethyl)oxirane (340 mg, 1.3 mmol) and 3,4-dihydro-2H-benzo[b][1,4]oxazine (177 mg, 1.3 mmol) in hexafluoroisopropanol was stirred at room temperature overnight. The solvent was evaporated and the residue purified by reverse-phase HPLC (CH3CN/0.1% trifluoroacetic acid) to yield 5-phenethyl-6-(trifluoromethyl)-2,3,5,6-tetrahydro-[1,4]oxazino[2,3,4-hi]indol-6-ol as a solid (MS m/z 350 MH+).
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH:29]1[CH2:34][CH2:33][CH2:32][C@@H:31]([NH:35]C(=O)OCC2C=CC=CC=2)[CH2:30]1>>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:14]2[CH:15]=[C:16]3[C:8]([C:6]4[N:7]=[C:2]([N:29]5[CH2:34][CH2:33][CH2:32][C@@H:31]([NH2:35])[CH2:30]5)[CH:3]=[CH:4][CH:5]=4)=[N:9][NH:10][C:11]3=[CH:12][N:13]=2)[CH:18]=1
Reactant: Fc1cccc(-c2nn(C3CCCCO3)c3cnc(-c4cccnc4)cc23)n1
Reactant: O=C(N[C@@H]1CCCNC1)OCc1ccccc1
Product: N[C@@H]1CCCN(c2cccc(-c3n[nH]c4cnc(-c5cccnc5)cc34)n2)C1
Yield: 15 %

Procedure:
Following the procedure of Example 144, 3-(6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine and (R)-benzyl piperidin-3-ylcarbamate were reacted to give 17 mg of 149 (15% over two steps). ESI MS m/z 372.1 (M+1). 1H NMR (400 MHz, DMSO): 14.24 (s, 1H), 9.49 (s, 1H), 9.30 (s, 1H), 9.10 (d, J=8.3 Hz, 1H), 9.06 (s, 1H), 8.36 (s, 3H), 8.21-8.12 (m, 1H), 7.78-7.72 (m, 1H), 7.56 (d, J=7.4 Hz, 1H), 6.99 (d, J=8.5 Hz, 1H), 4.49 (d, J=11.3 Hz, 2H), 3.53-3.44 (m, 3H), 3.35 (m, 1H), 3.22 (d, J=9.2 Hz, 1H), 2.10 (m, 1H), 1.95 (m, 1H)
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[CH:10][NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N([Br:19])C(=O)C1.O>CN(C=O)C>[Br:19][C:11]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][NH:9][CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc(-c2cc[nH]n2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Brc1c[nH]nc1-c1ccccc1
Yield: 92.5 %

Procedure:
A solution of 3-phenyl-1H-pyrazole (4.08 g, 28.3 mmol) and NBS (5.04 g, 28.3 mmol) in DMF (40 mL) was stirred for 1 h at room temperature. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was recrystallized from hexane/AcOEt to give the title compound (5.84 g, 93% yield) as a white solid: mp 114-116° C.; NMR (300 MHz, CDCl3): δ ppm 7.39-7.50 (31-1, m), 7.64 (1H, s), 7.77 (2H, d, J=6.8 Hz), 10.73 (1H, brs).
Reaction SMILES: FC(F)(F)C([O-])=O.[C:8]([C:11]1[C:12]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:13][N:14]([C:16]2([CH2:22][C:23]#[N:24])[CH2:21][CH2:20][NH2+:19][CH2:18][CH2:17]2)[CH:15]=1)(=[O:10])[NH2:9].[CH:32]1([C:35](O)=[O:36])[CH2:34][CH2:33]1.CCN(C(C)C)C(C)C.O1P(=O)OP(=O)OP1=O>CN(C=O)C.CS(C)=O>[C:23]([CH2:22][C:16]1([N:14]2[CH:15]=[C:11]([C:8]([NH2:9])=[O:10])[C:12]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:13]2)[CH2:21][CH2:20][N:19]([C:35]([CH:32]2[CH2:34][CH2:33]2)=[O:36])[CH2:18][CH2:17]1)#[N:24]
Reactant: O=C(O)C1CC1
Reactant: N#CCC1(n2cc(C(N)=O)c(Nc3ccccc3)n2)CC[NH2+]CC1
Agent: O=C([O-])C(F)(F)F
Agent: O=[PH]1O[PH](=O)O[PH](=O)O1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: N#CCC1(n2cc(C(N)=O)c(Nc3ccccc3)n2)CCN(C(=O)C2CC2)CC1
Temperature: 40 °C
Reaction time: 16 h

Procedure:
4-[4-Carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidinium trifluoroacetate (Intermediate #38-1) (20 mg, 0.05 mmol) was diluted with DMF (0.5 mL) and treated with cyclopropanecarboxylic acid (5 mg, 0.06 mmol), DIPEA (0.020 mL, 0.12 mmol) and 1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (0.040 mL, 0.060 mmol). The reaction mixture was heated to 40° C. and allowed to stir for 16 hours. The mixture was then cooled to ambient temperature, diluted with DMSO (1.0 mL), and purified by reverse-phase preparative HPLC (using a gradient elution of 5-95% MeCN/water, with 0.1% v/v NH4OH modifier). Desired fractions were identified, combined and concentrated in vacuo to afford the title compound, Example #34-1. 1H NMR (600 MHz, DMSO-d6): δ 9.09-9.00 (m, 1H), 8.50 (s, 1H), 7.55 (s, 1H), 7.48 (d, J=7.7 Hz, 2H), 7.26-7.17 (m, 2H), 7.15 (s, 1H), 6.80 (m, 1H), 4.09-3.90 (m, 2H), 3.18 (s, 2H), 2.47 (s, 2H), 2.35 (s, 2H), 2.07-1.97 (m, 2H), 1.95-1.87 (m, 1H), 0.74-0.62 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[N+:25]([C:28]1[CH:29]=[C:30]([OH:34])[CH:31]=[CH:32][CH:33]=1)([O-:27])=[O:26]>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:34][C:30]3[CH:31]=[CH:32][CH:33]=[C:28]([N+:25]([O-:27])=[O:26])[CH:29]=3)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Product: CC(NC(=O)c1coc(Oc2cccc([N+](=O)[O-])c2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 49.4 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with 3-nitrophenol (36 mg, 0.26 mmol) to give the title compound (31 mg, 49%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: C(O)(=[O:4])CC.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C([N:25]([CH2:28]C)[CH2:26][CH3:27])C.[NH2:30][C:31]1[S:32][C:33]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[C:34]([CH3:41])[C:35]=1[C:36]([O:38][CH2:39][CH3:40])=[O:37]>C1(C)C=CC=CC=1.[Cl-].[Na+].O>[CH2:45]([O:44][C:42]([C:33]1[S:32][C:31]([NH:30][C:28]([NH:25][CH2:26][CH3:27])=[O:4])=[C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:34]=1[CH3:41])=[O:43])[CH3:46]
Reactant: CCOC(=O)c1sc(N)c(C(=O)OCC)c1C
Reactant: CCN(CC)CC
Reactant: CCC(=O)O
Agent: [Cl-]
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCNC(=O)Nc1sc(C(=O)OCC)c(C)c1C(=O)OCC

Procedure:
A mixture of propionic acid (0.8 ml, 10 mol), diphenylphosphoryl azide (2.22 ml, 10.3 mmol) and triethylamine (1.39 ml, 10 mmol) in toluene (15 ml) was refluxed for 90 minutes. The mixture was then cooled to below 40° C., and a solution of ethyl 2-amino-5-(ethoxycarbonyl)-4-methylthiophene-3-carboxylate (1.76 g, 6.85 mmol) in toluene (10 ml) was added, the mixture refluxed for 24 hours. The reaction mixture was diluted with brine, and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. Solvent was removed under reduced pressure, and the residue purified by column chromatography, eluting with ethyl acetate/hexane 1:6 to 1:4, to provide ethyl 5-(ethoxycarbonyl)-2-[(ethylamino)carbonylamino]-4-methylthiophene-3-carboxylate. The structure was confirmed by 1H NMR and mass spectrometry.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[N:32][N:31]=[N:30]2)=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:12][CH2:13]OS(C)(=O)=O)[CH2:8]1)=[O:6].I.[CH2:35]([N:39]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=[C:40]1[NH:48][CH:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1)[CH2:36][CH:37]=[CH2:38]>>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[N:32][N:31]=[N:30]2)=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:52]2[CH2:53][CH2:54][CH:49]([NH:48][C:40]3[N:39]([CH2:35][CH2:36][CH:37]=[CH2:38])[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=4[N:41]=3)[CH2:50][CH2:51]2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:8]1)=[O:6]
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCOS(C)(=O)=O)(c2ccccc2)C1
Reactant: C=CCCn1c(NC2CCNCC2)nc2ccccc21
Agent: I
Product: C=CCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(-n5cnnn5)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 99.1 using 1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (prepared from (−)-3-(2-hydroxyethyl)-3-phenylpyrrolidine (R,R)-di-p-anisoyltartaric acid salt) and (1-(but-3-en-1-yl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine hydriodic acid salt to give the title compound.
Reaction SMILES: [F:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7](=[O:40])[C:8]([N:10]([CH3:39])[C:11]23[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]2)[CH2:14][N:13]2[C:20](=[O:38])[C:21]([O:29]C(C4C=CC=CC=4)=O)=[C:22]([C:24]([O:26]CC)=O)[N:23]=[C:12]32)=[O:9])[CH2:3]1.CNC.CO.[F:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:53][NH2:54])=[CH:49][CH:48]=1.C(N(CC)CC)C>C(O)C>[F:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:53][NH:54][C:24]([C:22]2[N:23]=[C:12]3[C:11]4([N:10]([C:8](=[O:9])[C:7]([N:4]5[CH2:5][CH2:6][C@@H:2]([F:1])[CH2:3]5)=[O:40])[CH3:39])[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19]4)[CH2:14][N:13]3[C:20](=[O:38])[C:21]=2[OH:29])=[O:26])=[CH:49][CH:48]=1
Reactant: NCc1ccc(F)cc1
Reactant: CCOC(=O)c1nc2n(c(=O)c1OC(=O)c1ccccc1)CC1CCC2(N(C)C(=O)C(=O)N2CC[C@@H](F)C2)CC1
Agent: CNC
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(C(=O)C(=O)N1CC[C@@H](F)C1)C12CCC(CC1)Cn1c2nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Temperature: 90 °C
Yield: 51 %

Procedure:
To a mixture of ethyl 10-((((3R)-3-fluoro-1-pyrrolidinyl)(oxo)acetyl)(methyl)amino)-4-oxo-3-((phenylcarbonyl)oxy)-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxylat (35 mg, 0.063 mmol) in ethanol (2 mL) was added 2M dimethylamine in methanol (0.063 mL, 0.126 mmol) and the resulting mixture was heated at 50° C. for 1 h. (4-Fluorophenyl)methanamine (0.036 mL, 0.316 mmol) followed by triethylamine (0.044 mL, 0.316 mmol) were added and the mixture heated at 90° C. for 18 h. The reaction mixture was then cooled, concentrated and purified by preparative HPLC to afford the title compound (17 mg, 51% yield) as an off-white solid. 1H NMR (500 MHz, CDCl3) δ: 11.96 (1 H, brs), 9.45 (1 H, brs), 7.34-7.40 (2H, m), 6.97 (2 H, t, J=8.70 Hz), 5.32-5.39 (0.5 H, m), 5.20-5.29 (0.5 H, m), 4.76-4.86 (1 H, m), 4.56-4.67 (1 H, m), 4.40-4.52 (1 H, m), 3.86-3.93 (0.5 H, m), 3.74-3.82 (0.5 H, m), 3.34-3.71 (6 H, m), 3.03 (1.2 H, s), 3.02 (1.8 H, s), 2.49 (1 H, brs), 2.29-2.41 (1 H, m), 1.99-2.09 (4 H, m), 1.76-1.83 (2 H, m), 1.44-1.51 (1 H, m). LCMS (M+H)=530.61. HPLC purity: >95%.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([C@@H:20]([N:22]3[CH2:27][CH2:26][C@:25]([CH2:34][C:35]([OH:38])([CH3:37])[CH3:36])([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[O:24][C:23]3=[O:39])[CH3:21])=[CH:16][CH:15]=2)[N:9]=1)=[O:7])C.Cl>CO>[OH:38][C:35]([CH3:36])([CH3:37])[CH2:34][C@@:25]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:24][C:23](=[O:39])[N:22]([C@H:20]([C:17]2[CH:18]=[CH:19][C:14]([C:10]3[N:9]=[C:8]([C:6]([OH:7])=[O:5])[CH:13]=[CH:12][CH:11]=3)=[CH:15][CH:16]=2)[CH3:21])[CH2:27][CH2:26]1
Reactant: CCOC(=O)c1cccc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@@H](c1ccc(-c2cccc(C(=O)O)n2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4 M aqueous NaOH solution (0.80 mL) was added to a solution of 6-(4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-pyridine-2-carboxylic acid ethyl ester (0.55 g) in methanol (3 mL) and the resulting solution was stirred at room temperature overnight. Then, the solution was acidified using 1 M hydrochloric acid and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine and dried (MgSO4). The solvent was evaporated to give the title compound. Yield: 0.49 g (95% of theory); Mass spectrum (ESI−): m/z=473 [M−H]−.