Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[N:8][C:7]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]4[C:23]([CH3:28])=[N:24][O:25][C:26]=4[CH3:27])=[CH:16][CH:15]=3)(=[O:13])=[O:12])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[C:29](N=C(N(C)C)N(C)C)([CH3:32])([CH3:31])[CH3:30].BrCC(C)C>C(#N)C>[CH:1]1([C:4]2[N:9]=[N:8][C:7]([N:10]([CH2:30][CH:29]([CH3:32])[CH3:31])[S:11]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]4[C:23]([CH3:28])=[N:24][O:25][C:26]=4[CH3:27])=[CH:18][CH:19]=3)(=[O:12])=[O:13])=[CH:6][CH:5]=2)[CH2:2][CH2:3]1
Reactant: CN(C)C(=NC(C)(C)C)N(C)C
Reactant: Cc1noc(C)c1COc1ccc(S(=O)(=O)Nc2ccc(C3CC3)nn2)cc1
Solvent: CC(C)CBr
Solvent: CC#N
Product: Cc1noc(C)c1COc1ccc(S(=O)(=O)N(CC(C)C)c2ccc(C3CC3)nn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 4.8 %

Procedure:
To a solution of N-(6-cyclopropylpyridazin-3-yl)-4-((3,5-dimethylisoxazol-4-yl)methoxy)benzenesulfonamide (51 mg, 0.127 mmol) in acetonitrile (0.1 mL) stirred at room temperature, was added 2-(tert-butyl)-1,1,3,3-tetramethylguanidine (0.051 mL, 0.255 mmol). The mixture was stirred at room temperature for 1 hour, then 1-bromo-2-methylpropane (0.028 mL, 0.255 mmol) added. The reaction was then heated by microwaves to 150° C., for 30 minutes. After cooling the solvent was removed under a stream of nitrogen and the crude sample purified by mass directed autoprep (formic acid modifier) to give the title product (2.8 mg). LCMS (2 min, formic) Rt 1.21 min, m/z (ES+) 457 (M+H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-])=O.C(=O)([O-])[O-].[K+].[K+].[CH2:26]([NH2:29])[CH2:27][CH3:28].[H][H]>C(O)C.[C].[Pd].O>[CH2:26]([NH:29][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[NH2:17])[CH2:27][CH3:28]
Reactant: CCCN
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1F
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCCNc1ccc(-c2nc3ccccc3o2)cc1N
Temperature: 25 °C
Reaction time: 14 h
Yield: 49 %

Procedure:
To a suspension of 2-(4-fluoro-3-nitrophenyl)benzoxazole (see Working Example 15-2) (300 mg, 1.16 mmol) in ethanol (5 mL) was added potassium carbonate (176 mg, 1.28 mmol) and aqueous n-propylamine (82.4 mg, 1.39 mmol), and this was heated to reflux for 2.5 hours. After the reaction was complete, this was cooled to room temperature, water was added, and the precipitated crystals were filtered, washed with water and then dried. To a tetrahydrofuran solution (7 mL) of the crystals obtained was added 10% palladium-carbon (100 mg). A hydrogen atmosphere was substituted in the flask, and this was stirred at room temperature for 14 hours. After the reaction was complete, this was filtered through Celite and the filtrate was concentrated. The residue obtained was purified by silica gel column chromatography to yield the title compound (152 mg, 49% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[OH:19].C(N(CC)C(C)C)(C)C.C(OCC)(=O)C>CN(C)C=O>[NH2:1][C:2]1[CH:7]=[C:6]([O:19][C:11]2[CH:12]=[CH:13][C:14]([N+:16]([O-:18])=[O:17])=[CH:15][C:10]=2[Cl:9])[N:5]=[CH:4][N:3]=1
Reactant: Nc1cc(Cl)ncn1
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cc(Oc2ccc([N+](=O)[O-])cc2Cl)ncn1
Temperature: 160 °C
Reaction time: 8 h
Yield: 17.2 %

Procedure:
4-Amino-6-chloropyrimidine (648 mg) was dissolved in N,N-dimethylformamide (5 ml), and 2-chloro-4-nitrophenol (1.736 g) and N,N-diisopropylethylamine (3.48 ml) were added thereto, followed by stirring at 160° C. overnight. The reaction mixture was cooled down to room temperature, and partitioned between ethyl acetate and a 1 N aqueous solution of sodium hydroxide. The organic layer was washed with a 1 N aqueous solution of sodium hydroxide and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reducer pressure to give a residue, to which ethyl acetate (10 ml) was then added to precipitate crystals. The crystals were filtered and dried under aeration to provide the titled compound (230 mg, 17%) as pale yellow crystals.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:11][CH3:12])[C:4]1[O:8][C:7](O)=[CH:6][C:5]=1C.[OH-].[Na+].[CH2:15]([CH:17]1[O:19][CH2:18]1)Cl.C([C:22](C)=[O:23])C>>[CH3:12][O:11][CH:3]([O:2][CH3:1])[C:4]1[O:8][C:7]([CH2:22][O:23][CH2:15][CH:17]2[O:19][CH2:18]2)=[CH:6][CH:5]=1
Reactant: ClCC1CO1
Reactant: CCC(C)=O
Reactant: COC(OC)c1oc(O)cc1C
Agent: [Na+]
Agent: [OH-]
Product: COC(OC)c1ccc(COCC2CO2)o1
Reaction time: 0.5 h

Procedure:
5-Glycidoxymethyl furfuraldehyde dimethyl acetal was prepared by adding a total of 6.0 g (0.035 mole) of 5-hydroxy-methyl furfuraldehyde dimethyl acetal (HMFA) to 1.54 g sodium hydroxide (0.038 mole) in a 100 ml round bottom flask equipped with magnetic stir bar, reflux condenser, and nitrogen inlet. After stirring for 30 min., 3.89 g (0.042 mole) of epichlorohydrin in 50 ml. of methyl ethyl ketone was added quickly, and the reaction mixture was allowed to reflux overnight under an inert (nitrogen) atmosphere. The mixture was then cooled, filtered, and the solvent removed under vacuum. The resulting oil was mixed with 250 ml of toluene and the toluene was distilled off at atmospheric pressure to remove any residual epichlorohydrin. The sample was freed of toluene by subjecting it to high vacuum overnight.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:16]([O:18][C:19]([C:21]1[C:22](=[O:41])[C:23]2[CH:28]=[N:27][C:26](S(C)(=O)=O)=[N:25][C:24]=2[N:33]([CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[CH:34]=1)=[O:20])[CH3:17]>>[CH2:16]([O:18][C:19]([C:21]1[C:22](=[O:41])[C:23]2[CH:28]=[N:27][C:26]([NH:15][C:12]3[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:10][CH:11]=3)=[N:25][C:24]=2[N:33]([CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[CH:34]=1)=[O:20])[CH3:17]
Reactant: CCOC(=O)c1cn(C2CCCCC2)c2nc(S(C)(=O)=O)ncc2c1=O
Reactant: Nc1ccc(CCN2CCOCC2)cc1
Product: CCOC(=O)c1cn(C2CCCCC2)c2nc(Nc3ccc(CCN4CCOCC4)cc3)ncc2c1=O

Procedure:
Using the procedure outlined in Example 1(g) the title compound was prepared from 4-(2-morpholin-4-yl-ethyl)-phenylamine (from Example 27(A), 54 mg, 0.26 mmol) and 8-cyclohexyl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 17(e) above, 100 mg, 0.26 mmol). The title compound was obtained as a white solid (77 mg, 59%). 1H NMR (400 MHz, CDCl3) δ (ppm): 9.28 (s, 1H), 8.46 (s, 1H), 7.98 (br, 1H), 7.50 (d, J=8.5 Hz, 2H), 7.17 (d, J=8.5 Hz, 2H), 5.04 (m, 1H), 4.32 (q, J=7.1 Hz, 2H), 3.67 (t, J=4.6 Hz, 4H), 2.76 (m, 2H), 2.54 (m, 2H), 2.47 (m, 4H), 1.99 (m, 4H), 1.78 (m, 1H), 1.61 (m, 2H), 1.46 (m, 2H), 1.34 (t, J=7.1 Hz, 3H), 1.23 (m, 1H).
Reaction SMILES: COC(=O)CC[C:6]1(C)[CH2:17][CH2:16][CH2:15][CH2:14][C:7]21C(=O)CCC2=O.CO[C:22](=O)[CH2:23][CH2:24][C:25]1(CCC)[CH2:36][CH2:35][CH2:34]CC21C(=O)CCC2=O.[O:41]=[C:42]1[CH2:47][CH2:46][CH2:45][CH2:44][C:43]1([CH2:52][CH2:53][CH3:54])[CH2:48][C:49](O)=O>>[C:35]1([C:34]([C:6]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:7]=2)=[CH:49][CH2:48][C:43]2([CH2:52][CH2:53][CH3:54])[CH2:44][CH2:45][CH2:46][CH2:47][C:42]2=[O:41])[CH:22]=[CH:23][CH:24]=[CH:25][CH:36]=1
Reactant: CCCC1(CCC(=O)OC)CCCCC12C(=O)CCC2=O
Reactant: COC(=O)CCC1(C)CCCCC12C(=O)CCC2=O
Reactant: CCCC1(CC(=O)O)CCCCC1=O
Product: CCCC1(CC=C(c2ccccc2)c2ccccc2)CCCCC1=O

Procedure:
Again in the same manner but replacing 6-methyl-1,4-dioxospiro[4.5]decane-6-propionic acid methyl ester with an equivalent amount of 6-propyl-1,4-dioxospiro[4.5]decane-6-propionic acid methyl ester, described in Example 7, 2-oxo-1-propylcyclohexaneacetic acid, νmaxCHCl3 1775, 1710 cm-1, is obtained via the respective intermediates, α,α-diphenyl-6-propyl-1,6-dioxaspiro[4.5]decane-6-propanol, νmaxCHCl3 3620, 3480, 1175, 1130, 1110, 1062 cm-1 , and 2-(3,3-diphenylallyl)-2-propylcyclohexanone, nmr (CDCl3) δ 0.85 (m, 3H), 6.0 (t, 1H), 7.3 (m, 10H).
Reaction SMILES: [N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=[O:11])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:12]Br>Br>[BrH:12].[Br:12][CH:7]1[CH2:8][CH2:9][C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]1=[O:11]
Reactant: O=C1CCCc2ncccc21
Reactant: BrBr
Agent: Br
Product: O=C1c2cccnc2CCC1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 159.7 %

Procedure:
To a warm solution of 5.00 g (33.52 mmol) of 7,8-dihydro-5(6H)-quinolinone, prepared in Example 1, in 25 ml of 48% hydrobromic acid, was added dropwise 6.0 g (37.54 mmol) of bromine. The solution was stirred at room temperature for 1 hour, then concentrated to a yellow-white solide. Recrystallization from absolute ethanol afforded 9.20 g (88.5%) of 6-bromo-7,8-dihydro-5(6H)-quinolinone hydrobromide as a white solid; mp 187°-189° C. (dec.).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]2[N:15]=[C:16](Cl)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:26])(=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:28][CH2:29][CH2:30][NH2:31]>>[CH2:1]([NH:8][C:9]1[C:14]2[N:15]=[C:16]([NH:31][CH2:30][CH2:29][OH:28])[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:26])(=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S1(=O)CCN(c2nc(Cl)nc3c(NCc4ccccc4)ncnc23)CC1
Reactant: NCCO
Product: O=S1(=O)CCN(c2nc(NCCO)nc3c(NCc4ccccc4)ncnc23)CC1

Procedure:
This compound was prepared analogous to Example 2 from 8-benzylamino-2-chloro-4-(1,1-dioxido-thiomorpholino)pyrimido[5,4-d]pyrimidine (melting point: 213°-215° C.) and 2-hydroxyethyl-amine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH:22]=[C:21](OS(C(F)(F)F)(=O)=O)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH:20]=[C:21]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc([N+](=O)[O-])cn2)CC1
Temperature: 80 °C
Yield: 74.5 %

Procedure:
A solution of 202 mg (0.994 mmol) 2-bromo-5-nitropyridine in 4 mL of toluene and 2 mL of EtOH was treated with 338 mg (1.09 mmol) 4-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (Synthesis, 993, (1991)) and 1.49 mL (2.981 mmol) 2 M aqueous Na2CO3. The mixture was degassed via sonication, placed under argon, treated with 80.3 mg (0.00700 mmol) Pd(PPh3)4 and heated to 80° C. for 4 h. The mixture was diluted with EtOAc and washed with water. The organic layer was dried over MgSO4 and concentrated in vacuo. The resulting residue was chromatographed on a 50-g silica Varian MegaBond Elut column with 10-25% EtOAc-hexane to afford 226 mg (75%) of the title compound as a light yellow solid: Mass spectrum (ESI, m/z): Calcd. for C15H19N3O4, 306.1 (M+H). found 305.7.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([NH:13][CH2:14][CH2:15][C:16]#[N:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C[Si]([N:53]=[N+:54]=[N-:55])(C)C>C1COCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[N:13]([CH2:14][CH2:15][C:16]#[N:17])[N:55]=[N:54][N:53]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)NCCC(=O)NCCC#N
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCc1nnnn1CCC#N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 3-(t-butoxycarbonylamino)-N-(2-cyanoethyl)propionamide (4.6 mmol) in THF (40 mL) under nitrogen is added triphenylphosphine (4.6 mmol). The solution is cooled to 0° and treated with diethyl azodicarboxylate (DEAD, 2.4 mmol) followed by trimethylsilyl azide (2.4 mmol). The solution is warmed up to room temperature and stirred for 18 hours. One additional equivalent of triphenyl phosphine (4.6 mmol), DEAD (2.4 mmol) and trimethylsilyl azide (2.4 mmol) are added and stirring is continued for 3 days. The solution is cooled to 0°. Ceric ammonium nitrate (0.2 L; 10% aqueous solution) is added dropwise. After 20 minutes of stirring, extraction is carried out with methylene chloride. The organic extract is dried over anhydrous sodium sulfate, then concentrated in vacuo. The residue is purified by chromatography to give 3-[5-(2-t-butoxycarbonylamino-ethyl)-tetrazol-1-yl]propionitrile.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:8]=2[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([Cl:21])[CH:3]=1.[B-](F)(F)(F)F.C1C=CN=CC=1.C1C=CN=CC=1.[IH2+:39]>ClCCl.C(OCC)(=O)C>[NH2:1][C:2]1[C:20]([I:39])=[CH:19][C:5]([O:6][C:7]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:8]=2[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([Cl:21])[CH:3]=1
Reactant: [IH2+]
Reactant: CCOC(=O)c1ccc(F)cc1Oc1ccc(N)cc1Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc(F)cc1Oc1cc(I)c(N)cc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of EXAMPLE 242A (8.15 g) in dichloromethane (60 mL) was added bis(pyridine)iodonium tetrafluoroborate (9.79 g). The mixture was stirred at room temperature for 4 hours. The mixture was diluted with ethyl acetate (200 mL) and washed with aqueous Na2S2O3, water, brine and dried over Na_SO4. The mixture was filtered, and the solvent was evaporated and the residue was loaded on a column and eluted with 10% ethyl acetate in hexane to give the pure product.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C@@H:7]2[CH2:12][CH2:11][CH2:10][N:9]([CH2:13][C@@H:14]3[CH2:19][CH2:18][O:17][CH2:16][C@H:15]3[NH2:20])[CH2:8]2)=[CH:4][CH:3]=1.C1([O:29][C:30](=O)[NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]3[N:42]([CH3:43])[N:41]=[N:40][N:39]=3)[CH:33]=2)C=CC=CC=1>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@@H:7]2[CH2:12][CH2:11][CH2:10][N:9]([CH2:13][C@@H:14]3[CH2:19][CH2:18][O:17][CH2:16][C@H:15]3[NH:20][C:30]([NH:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]4[N:42]([CH3:43])[N:41]=[N:40][N:39]=4)[CH:33]=3)=[O:29])[CH2:8]2)=[CH:21][CH:22]=1
Reactant: Cn1nnnc1-c1cccc(NC(=O)Oc2ccccc2)c1
Reactant: N[C@@H]1COCC[C@H]1CN1CCC[C@@H](Cc2ccc(F)cc2)C1
Solvent: CC#N
Product: Cn1nnnc1-c1cccc(NC(=O)N[C@@H]2COCC[C@H]2CN2CCC[C@@H](Cc3ccc(F)cc3)C2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 22 %

Procedure:
(3S,4S)-4-[(S)-3-(4-Fluoro-benzyl)-piperidin-1-ylmethyl]-tetrahydro-pyran-3-ylamine (44 mg, 143 μmol) and [3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-carbamic acid phenyl ester (47 mg, 158 μmol) were dissolved in acetonitrile (1 mL) and the mixture was stirred at room temperature. After 24 h, the mixture was concentrated, dissolved in ethyl acetate, washed with water, dried (Na2SO4) and concentrated. The residue was purified by reverse phase high pressure liquid chromatography (C18, 10-100% acetonitrile in water, containing 0.05% trifluoroacetic acid), then by flash column chromatography (5% methanol in dichloromethane, containing 0.5% ammonium hydroxide) to provide the product as a glass (16 mg, 23%).
Reaction SMILES: [OH:1][Li].O.OO.C([C@H]1COC(=O)N1C(=O)[C@@H:20]([C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[CH2:21][N:22]([CH:30]([CH3:32])[CH3:31])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])C1C=CC=CC=1.[O-]S([O-])=O.[Na+].[Na+].C1[CH2:51][O:50]CC1>O>[C:25]([O:24][C:23]([N:22]([CH:30]([CH3:31])[CH3:32])[CH2:21][C@H:20]([C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:51]([OH:50])=[O:1])=[O:29])([CH3:27])([CH3:28])[CH3:26]
Reactant: CC(C)N(C[C@@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Reactant: C1CCOC1
Reactant: [Li]O
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Product: CC(C)N(C[C@@H](C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
LiOH—H2O (168 mg, 4.00 mmol) was added to a stirring solution of THF (30 mL) and water (15 mL) at room temperature until it was dissolved. The mixture was treated with hydrogen peroxide (658 uL of a 35% wt. solution in water, 8.00 mmol) and allowed to stir at room temperature for 10 minutes. The reaction was cooled to 0° C. in an ice bath, and the tert-butyl (S)-3-((S)-4-benzyl-2-oxooxazolidin-3-yl)-2-(4-chlorophenyl) -3-oxopropyl(isopropyl)carbamate (1.00 g, 2.00 mmol) was added dropwise via addition funnel as a solution in THF (15 mL) over a 10 minutes. The mixture was allowed to stir overnight at room temperature to completion by LCMS analysis of the crude. The reaction was cooled to 0° C., and then treated with 1M Na2SO3 (9.00 mL) solution via addition funnel over a ten minute period. After the addition was complete, the mixture was allowed to warm to room temperature for 10 minutes. The mixture was concentrated to remove the THF, and then diluted with water. The aqueous layer washed twice with ethyl acetate (discarded). The aqueous layer was partitioned with ethyl acetate, then treated dropwise while stirring with 1M HCl until pH 2-3 was attained. The aqueous layer was extracted twice with ethyl acetate, and the organics were combined. The organic washed with brine, separated, dried over MgSO4, filtered, and concentrated in vacuo. The colorless oil product was dried under high vacuum for one hour to afford (S)-3-(tert-butoxycarbonyl(isopropyl)amino) -2-(4-chlorophenyl)propanoic acid as a viscous oil/foam (685 mg, 100%). LC/MS (APCI+) m/z 242.1 [M-Boc]+.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)([O-:3])=[O:2].[CH3:17][C:18]1[C:19]([NH2:23])=[N:20][O:21][N:22]=1.C(N(CC)CC)C.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:17][C:18]1[C:19]([NH:23][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:11]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:12][C:4]=2[N+:1]([O-:3])=[O:2])=[N:20][O:21][N:22]=1
Reactant: Cc1nonc1N
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c([N+](=O)[O-])c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nonc1NC(=O)c1ccc(S(C)(=O)=O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 30 h

Procedure:
495 mg (2.02 mmol) of 2-nitro-4-methylsulfonylbenzoic acid and 200 mg (2.02 mmol) of 4-methyl-1,2,5-oxadiazol-3-ylamine are dissolved at room temperature (RT) in 5 ml of CH2Cl2 and treated with 0.28 ml (2.02 mmol) of triethylamine, 49 mg (0.40 mmol) of 4-dimethylaminopyridine (DMAP) and 1.93 g (3.03 mmol) of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50% solution in THF). The reaction mixture is stirred for 30 h at RT and subsequently washed twice with in each case 5 ml of water. The organic phase is dried over Na2SO4 and evaporated. The residue is purified by column chromatography (silica gel, heptane/ethyl acetate). Yield 350 mg (53%).
Reaction SMILES: Br[C:2]1[C:3]2[CH:4]=[C:5]3[CH:14]([CH2:15][C:16]([OH:18])=[O:17])[CH2:13][CH2:12][N:6]3[C:7]=2[CH:8]=[C:9]([F:11])[CH:10]=1.[CH3:19][Mg+].[Br-].[Li]CCCC.[CH3:27][S:28]SC.Cl>C1COCC1>[F:11][C:9]1[CH:10]=[C:2]([S:28][CH3:27])[C:3]2[CH:4]=[C:5]3[CH:14]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][N:6]3[C:7]=2[CH:8]=1
Reactant: O=C(O)CC1CCn2c1cc1c(Br)cc(F)cc12
Reactant: CSSC
Reactant: C[Mg+]
Agent: Cl
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)CC1CCn2c1cc1c(SC)cc(F)cc12
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 99.6 %

Procedure:
To a solution of (+/−)-(8-bromo-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid (Example 7A, Step 1, 400 mg, 1.3 mmol) in THF (10 mL) at −78° C. was added 3M MeMgBr (1.5 mmol) followed by the addition of n-BuLi (2.6 mmol, 1.6M solution). The reaction mixture was stirred at −78° C. for 5 minutes and an excess of methyl disulfide (300 mg) was added. The reaction mixture was warmed to r.t. and stirred for 15 minutes and 1N HCl was added. The phases were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated. The residue was dissolved in THF and the solution was cooled to 0° C. and treated with an excess of CH2N2. The reaction mixture was stirred for 5 minutes and the solvent removed to give 380 mg of the title compound as a pale yellow syrup used as such.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.CCN(CC)CC.[CH2:14]([O:21][CH2:22][C:23](Cl)=[O:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>C(Cl)Cl>[CH2:14]([O:21][CH2:22][C:23]([N:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1)=[O:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OC1CCNC1
Reactant: O=C(Cl)COCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(COCc1ccccc1)N1CCC(O)C1
Reaction time: 3.5 h
Yield: 98.1 %

Procedure:
A solution of 4.4 mL (52.93 mmol) 3-pyrrolidinol in 250 mL CH2Cl2 at 0° C. was added 8.4 mL (60.26 mmol) NEt3 and 8.2 mL (51.97 mmol) benzyloxyacetyl chloride. The reaction was stirred for 3.5 h and then poured into 400 mL H2O. The reaction was extracted with CH2Cl2, dried over MgSO4, filtered and rotary evaporated to yield 12.0 g (98%) of N-(benzyloxyacetyl)-3-pyrrolidinol as a yellow oil.
Reaction SMILES: [C:1]([NH:4][N:5]=[C:6]([C:15]#[N:16])[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1)(=[NH:3])[NH2:2].C([OH:20])CC>CS(C)=O>[NH2:3][C:1]1[N:4]=[N:5][C:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=2)=[C:15]([NH2:16])[N:2]=1.[Cl:14][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][C:10]=1[Cl:13])[C:6]([C:15]#[N:16])=[O:20]
Reactant: CCCO
Reactant: N#CC(=NNC(=N)N)c1ccc(Cl)c(Cl)c1
Solvent: CS(C)=O
Product: N#CC(=O)c1ccc(Cl)c(Cl)c1
Product: Nc1nnc(-c2ccc(Cl)c(Cl)c2)c(N)n1

Procedure:
The title compound was prepared as in Example 2(a) from 3,4-dichlorobenzoyl cyanide amidinohydrazone obtained in Example 5. The solvent for the ring closure was a mixture of 1-propanol and dimethyl sulfoxide (11). Total yield (from 3,4-dichlorobenzoyl cyanide): 76%; m.p. 222-224° C. (uncorrected).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]=[C:10]([NH:20][C:21](=[O:24])[CH2:22]Cl)[CH:9]=1)(=[O:3])[CH3:2].[F:25][C:26]1[CH:38]=[CH:37][C:29]([CH2:30][CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:28][CH:27]=1.CCOC(C)=O>CC(O)C>[C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]=[C:10]([NH:20][C:21](=[O:24])[CH2:22][N:34]2[CH2:35][CH2:36][CH:31]([CH2:30][C:29]3[CH:28]=[CH:27][C:26]([F:25])=[CH:38][CH:37]=3)[CH2:32][CH2:33]2)[CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCCNc1cc(NC(=O)CCl)nc(-c2ccccc2)n1
Reactant: Fc1ccc(CC2CCNCC2)cc1
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CC(=O)NCCNc1cc(NC(=O)CN2CCC(Cc3ccc(F)cc3)CC2)nc(-c2ccccc2)n1

Procedure:
This compound was prepared from chloroacetamide 6 (77 mg; 0.221 mmol) and 4-(4-fluorobenzyl)-piperidine (7.9) (47 mg; 0.24 mmol) in a manner analogous to 8.8 yielding a white crystalline solid (80.5 mg; 72%) after silica gel chromatography (12-8:1 EtOAc:i-PrOH). LC (method B) tR=13.1 min; 1H NMR (200 MHz, CDCl3) δ 9.51 (brs, 1H), 8.37 (m, 2H), 7.48 (m, 3H), 7.22 (s, 1H), 7.11 (m, 2H), 6.98 (m, 2H), 6.58 (brs, 1H), 5.45 (brt, J=5.4 Hz, 1H), 3.68 (m, 2H), 3.53 (m, 2H), 3.11 (s, 2H), 2.89 (m, 2H), 2.57 (m, 2H), 2.20 (m, 2H), 1.86 (s, 3H), 1.80-1.30 (m, 5H); ESIMS 505.0 (42) [MH+], 253.1 (100).