Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:12]([NH2:15])(=[O:14])=[O:13])[CH:5]=[C:6]([CH:10]=[O:11])[C:7]=1[O:8][CH3:9].[C:16]([C:18]1[CH:19]=[CH:20][C:21]([O:27][CH3:28])=[C:22](B(O)O)[CH:23]=1)#[N:17]>>[C:16]([C:18]1[CH:19]=[CH:20][C:21]([O:27][CH3:28])=[C:22]([C:2]2[C:7]([O:8][CH3:9])=[C:6]([CH:10]=[O:11])[CH:5]=[C:4]([S:12]([NH2:15])(=[O:14])=[O:13])[CH:3]=2)[CH:23]=1)#[N:17]
Reactant: COc1ccc(C#N)cc1B(O)O
Reactant: COc1c(Br)cc(S(N)(=O)=O)cc1C=O
Product: COc1ccc(C#N)cc1-c1cc(S(N)(=O)=O)cc(C=O)c1OC

Procedure:
Proceeding as in Reference 19, but substituting 3-bromo-5-formyl-4-methoxy-benzenesulfonamide and 5-cyano-2-methoxy-benzeneboronic acid, gave 5′-cyano-5-formyl-6,2′-dimethoxybiphenyl-3-sulfonamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([NH:11]C(=O)C(F)(F)F)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1>C([O-])([O-])=O.[K+].[K+]>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([NH2:11])=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1
Reactant: O=C(Nc1c([N+](=O)[O-])cc(F)cc1[N+](=O)[O-])C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Nc1c([N+](=O)[O-])cc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 52.2 %

Procedure:
A solution of 4-fluoro-2,6-dinitro-(trifluoroacetamido)benzene (297 mg, 1.00 mmol) in 10% K2CO3 (10 mL) was refluxed for 1 h, then cooled to room temperature to give yellow crystals. It was filtered and washed with cold water (2×1 mL), affording 105 mg (52%) of the title compound. 1H NMR (DMSO-d6): δ8.254 (s, 2H), 8.460 (d, 2H, J=8.4).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:15])[N:10]=[N:11][C:12]=1[CH2:13][OH:14].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([O:15][S:22]([C:19]2[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=2)(=[O:24])=[O:23])=[N:10][NH:11][C:12]=1[CH2:13][OH:14]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1N=NC(CO)=C1c1ccccc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Oc2n[nH]c(CO)c2-c2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 47.4 %

Procedure:
To a suspension of 4-(2-fluorophenyl)-5-(hydroxymethyl)pyrazol-3-one (28.7 g, 0.138 mol) in dry dichloromethane (300 ml) was added p-toluenesulfonyl chloride (28.9 g, 0.152 mol) followed by triethylamine (21.2 ml, 0.152 mol) dropwise. The solution was stirred at room temperature for 2 days. Dichloromethane (300 ml) was then added to dilute and the solution was washed with brine (300 ml), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography with 0%→40% ethyl acetate/dichloromethane as eluent to give the title compound (23.7 g). Data for the title compound: 1H NMR (360 MHz, DMSO) δ 2.34 (3H, s), 4.66 (2H, s), 6.94 (1H, t), 7.06 (3H, m), 7.17-7.25 (2H, m), 7.51 (2H, d); MS (ES+) m/e 362 [MH]+.
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:4]([OH:6])=O.Cl.[NH:16]1[CH2:19][CH:18]([C:20]#[N:21])[CH2:17]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:11]([O:10][C:8](=[O:9])[NH:7][C@@H:3]([C:4]([N:16]1[CH2:19][CH:18]([C:20]#[N:21])[CH2:17]1)=[O:6])[CH2:2][CH3:1])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N#CC1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CC(C#N)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 77.9 %

Procedure:
In a round-bottomed flask Boc-D-2-aminobutyric acid (400 mg, 1.97 mmol) and azetidine-3-carbonitrile hydrochloride (373 mg, 3.15 mmol) were dissolved in DMF (9 ml). N,N-Diisopropylethylamine (1.0 ml, 5.73 mmol) was added followed by HATU (823 mg, 2.16 mmol). The reaction mixture was stirred at room temperature for 48 h then quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated to provide 410 mg (70%) of [(R)-1-(3-cyano-azetidine-1-carbonyl)-propyl]-carbamic acid tert-butyl ester as an off-white solid.
Reaction SMILES: [CH:1]1([CH:4]([C:6]2[S:7][CH:8]=[CH:9][CH:10]=2)O)[CH2:3][CH2:2]1.[BrH:11]>>[Br:11][CH2:3][CH2:2]/[CH:1]=[CH:4]/[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1
Reactant: OC(c1cccs1)C1CC1
Reactant: Br
Product: BrCC/C=C/c1cccs1
Reaction time: 2 h

Procedure:
At 5° to 10° C., 225 g (1.46 mol) of cyclopropyl-2-thienylcarbinol was dripped over a period of 1 hour into 972ml of 48% strength hydrobromic acid. The mixture was kept for 2 hours at room temperature, after which the organic phase was separated off and the aqueous solution was extracted three times, each time with 300 ml of dichloromethane. The combined organic phases were washed neutral with dilute sodium hydroxide solution and water, dried over magnesium sulfate and evaporated down under reduced pressure. There was obtained 322 g (94%,corrected) of crude bromide (GC: 92%). 1H-NMR (250 MHZ, CDCl3): δ=2.65-2.80 (m, 2H), 3.46 (t,2H), 5.90-6.10 (m, 1H), 6.61 (d, 1H), 6.80-7.00 (m, 2H), 7.14 (d, 1H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4].[CH3:12][S-:13].[Na+]>O1CCCC1.C(OCC)C>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][S:13][CH3:12])=[CH:6][CH:7]=1
Reactant: C[S-]
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CSCC(=O)c1ccc(Cl)cc1
Reaction time: 1 h
Yield: 86.9 %

Procedure:
To a suspension of 2-bromo-1-(4-chlorophenyl)ethanone (1, 20 g, 86 mmol) in tetrahydrofuran (250 ml) was added sodium methanethiolate (7.2 g, 103 mmol) in tetrahydrofuran (250 ml) at −40° C. and the mixture was stirred for 1 hour. The mixture was diluted with diethyl ether and filtered off, and the filtrate was washed with brine. The solvent was evaporated off under the reduced pressure, and the residue was subjected to silica gel column chromatography (Biotage) to obtain 15 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][NH:11][N:12]1[C:20]2[C:15](=[CH:16][C:17]([OH:21])=[CH:18][CH:19]=2)[CH:14]=[CH:13]1.C(=O)([O-])[O-].[K+].[K+].[CH3:28][N:29]=[C:30]=[O:31]>C1COCC1>[CH3:28][NH:29][C:30](=[O:31])[O:21][C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][CH:18]=1)[N:12]([NH:11][CH2:10][CH2:9][CH2:8][C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[F:1])[CH:13]=[CH:14]2
Reactant: Oc1ccc2c(ccn2NCCCc2ccncc2F)c1
Reactant: CN=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CNC(=O)Oc1ccc2c(ccn2NCCCc2ccncc2F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-[(3-fluoro-4-pyridinyl)propylamino]-1H-indol-5-ol (2.5 g) in 50 ml THF was added potassium carbonate (1.2 g), followed by methyl isocyanate (0.53 ml). After stirring at ambient temperature for three hours, the mixture was filtered, and the filtrate was concentrated to give a solid, 3.0 g, m.p. 165°-166° C. This material was eluted on a silica gel column with ethyl acetate/dichloromethane (1:1) via HPLC. The desired fractions were combined and concentrated to give a solid, 2.7 g, m.p. 177°-178° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7]([S:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)=[C:8]([CH3:20])[N:9]2[CH2:14][C:15]([O:17]CC)=[O:16])(=[O:3])[CH3:2].[OH-].[Na+].CC(CC(C)=O)C>C(O)CC>[C:1]([NH:4][CH:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]1=[C:7]([S:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[CH:8]([CH3:20])[N:9]2[CH2:14][C:15]([OH:17])=[O:16])(=[O:3])[CH3:2]
Reactant: CCOC(=O)Cn1c(C)c(Sc2ccc(Cl)cc2)c2c(NC(C)=O)cccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCCO
Solvent: CC(=O)CC(C)C
Product: CC(=O)NC1C=CC=C2C1=C(Sc1ccc(Cl)cc1)C(C)N2CC(=O)O
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To a stirred slurry of ethyl [4-acetylamino-3-(4-chlorophenylsulfanyl)-2-methyl-1H-indol-1-yl]acetate (3.16 kg, 3.05 kg corrected for assay, 7.3 moles) in 1-propanol (15.3 L) was added aqueous NaOH (1M, 15.3 L). The mixture was then heated at 70° C. for 2 h, cooled to 40° C. then MIBK (30.5 L) was added and the mixture reheated to 80° C. Approximately 20% of the resulting biphasic mixture was removed from the reaction vessel to be processed separately. To the remainder, aqueous hydrochloric acid (1M, 13.4 L) was added to the solution over a period of 45 mins then the resulting slurry was cooled to 15° C. over 1 h and stirring continued at this temperature for a further 30 mins. The solid product was collected by filtration, washed with water (2×9.8 L) followed by EtOAc (7.3 L) then dried on the filter for 10 mins then in vacuo at 45° C. to give the title compound as a solid; 2.15 kg; assay by 1H NMR: 99.4% w/w; 2.14 kg corrected for assay (94%); purity: 99.5 area % by HPLC; m/z: 389 (MH+); 1H NMR: 1.86 (3H, s), 2.34 (3H, s), 5.11 (2H, s), 6.97-7.00 (2H, d), 7.08-7.11 (1H, m), 7.27-7.30 (3H, m), 7.47-7.50 (1H, d), 9.50 (1H, br s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13](=[O:29])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=1)=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=[CH:6]2.[F:38][C:39]1[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=1B(O)O.[F-].[Cs+]>>[F:38][C:39]1[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=1[C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]=1[C:13]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:16][CH:15]=1)=[O:29]
Reactant: OB(O)c1cccc(F)c1F
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Agent: [Cs+]
Agent: [F-]
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3cccc(F)c3F)ccc2c1
Temperature: 85 °C
Yield: 70.1 %

Procedure:
Charge a flask with trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (2.0 g, 3.7 mmol), 2,3 difluorophenyl boronic acid (1.17 g, 7.4 mmol) palladium dichloride bis(triphenylphosphine) (518 mg, 0.74 mmol) and cesium fluoride (5.06 g, 33.3 mmol) and add 250 mL degassed acetonitrile. Heat the mixture at 85° C. for two hours, cool the reaction and filter off any solids. Purify on an SCX column eluting with 2N ammonia/methanol. Purify further on a silica gel column eluting with a 0-10% methanol/methylene chloride gradient to give 1.3 g (70%) of the title compound: 1H-NMR (CD3OD, 400 MHz) δ7.92 (d, J=8.8 Hz, 1H); 7.54 (dd, J=8.4, 4.0 Hz, 3H); 7.43 (dd, J=8.4, 1.6 Hz, 1H); 7.31 (d, J=2.8 Hz, 1H); 7.09 (dd, J=9.2, 2.4 Hz, 1H); 7.05-6.92 (m, 3H); 6.79 (d, J=8.8 Hz, 2H); 4.10 (t, J=5.6 Hz, 2H); 3.93 (s, 3H); 2.73 (t, J=5.2 Hz, 2H); 2.50-2.50 (m, 4H); 1.62-1.57 (m, 4H); 1.48-1.43 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8](I)[C:7]4[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1.[S:21]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22]1>>[OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8]([C:23]4[CH:24]=[CH:25][S:21][CH:22]=4)[C:7]4[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1
Reactant: OB(O)c1ccsc1
Reactant: O=C1NC(=O)c2c1c(I)cc1[nH]c3ccc(O)cc3c21
Product: O=C1NC(=O)c2c1c(-c1ccsc1)cc1[nH]c3ccc(O)cc3c21
Yield: 74 %

Procedure:
The reaction of 9-hydroxy-4-iodopyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione, prepared as in example 7, with 3-thienylboronic acid according to the procedure described in example 8 gave 9-hydroxy-4-(3-thienyl)pyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (12) (I, Ar=3-thienyl) in a 74% yield; mp 247° C. (dec). 1H NMR δ [(CD3)2SO] 11.73 (br s, 1H), 11.05 (br s, 1H), 9.24 (s, 1H), 9.15 (s, 1H), 8.34 (d, J=2.4 Hz, 1H), 7.92 (dd, J=5.0, 2.7 Hz, 1H), 7.70 (s, 1H), 7.61 (dd, J=5.0, 2.7 Hz, 1H), 7.51 (dd, J=5.0, 0.9 Hz, 1H), 7.42 (d, J=8.7 Hz, 1H), 7.06 (dd, J=8.7, 2.4 Hz, 1H). Found: C, 61.05; H, 2.96; N, 7.60. C18H10N2SO3,H2O requires C, 61.36; H, 3.43; N, 7.95.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9](Cl)[C:8]([C:12]([N:14]([CH2:32][CH:33]([CH3:35])[CH3:34])[C@@H:15]2[CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][C@H:17]([C:28]([O:30][CH3:31])=[O:29])[CH2:16]2)=[O:13])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:45][S:46][CH2:47][CH2:48][CH2:49][NH2:50].C(=O)([O-])O.[Na+]>CN(C=O)C>[C:1]([C:5]1[N:10]=[C:9]([NH:50][CH2:49][CH2:48][CH2:47][S:46][CH3:45])[C:8]([C:12]([N:14]([CH2:32][CH:33]([CH3:34])[CH3:35])[C@@H:15]2[CH2:20][NH:19][CH2:18][C@H:17]([C:28]([O:30][CH3:31])=[O:29])[CH2:16]2)=[O:13])=[CH:7][N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CSCCCN
Reactant: COC(=O)[C@@H]1C[C@H](N(CC(C)C)C(=O)c2cnc(C(C)(C)C)nc2Cl)CN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1CNC[C@@H](N(CC(C)C)C(=O)c2cnc(C(C)(C)C)nc2NCCCSC)C1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 1-tert-butyl 3-methyl (3R*,5S*)-5-{[(2-tert-butyl-4-chloropyrimidin-5-yl)carbonyl](isobutyl)amino}piperidine-1,3-dicarboxylate (51.1% mg) and diisopropylethylamine (38 mg) in DMF (0.5 ml) was added a solution of 3-methylthiopropylamine (21 mg) in DMF (0.5 ml), and the mixture was stirred at 80° C. overnight. To the reaction mixture was added 2% aqueous sodium hydrogen carbonate and the mixture was extracted with ethyl acetate, and the extract was concentrated by a nitrogen gas blower. The residue was purified by reversed-phase preparative HPLC, and the object fraction was concentrated by a nitrogen gas blower. The residue was dissolved in trifluoroacetic acid/acetonitrile solution (20% (V/V), 1.0 ml), and the mixture was stirred at room temperature for 6 hr. The reaction mixture was concentrated by a nitrogen gas blower. The residue was neutralized with triethylamine (1 ml), saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The extract was concentrated by a nitrogen gas blower. The residue was purified by reversed-phase preparative HPLC, and the object fraction was concentrated by a nitrogen gas blower to give the object compound (6.4 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[CH2:20]([NH2:22])[CH3:21]>CO>[C:8]1([C:5]2[N:6]=[CH:7][C:2]([NH:22][CH2:20][CH3:21])=[N:3][C:4]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Clc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Reactant: CCN
Solvent: CO
Product: CCNc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Temperature: 90 °C
Reaction time: 17.5 h

Procedure:
1.00 g of 2-chloro-5,6-diphenylpyrazine was added to 18.7 ml of 2M ethylamine in methanol and the mixture was reacted in a sealed tube at 80° C. for 16 hours. After cooling, 12 ml of a 2M ethylaminemethanol solution was further added, followed by continuous stirring in the sealed tube at 90° C. for 17.5 hours and further stirring at room temperature for 46 hours. After the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography to obtain 531 mg of the desired compound as a pale yellow crystal having a melting point of 121 to 123° C.
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH:22][C:23]([C:25]4[CH:30]=[CH:29][C:28]([C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=5[NH2:38])=[CH:27][CH:26]=4)=[O:24])(=[O:21])=[O:20])=[CH:15][C:14]=3[N+:39]([O-:41])=[O:40])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Cl[C:43]([O:45][CH3:46])=[O:44].C(N(CC)C(C)C)(C)C.Cl>CN(C1C=CN=CC=1)C.ClCCl>[C:1]12([CH2:11][NH:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH:22][C:23]([C:25]4[CH:30]=[CH:29][C:28]([C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=5[NH:38][C:43]([O:45][CH3:46])=[O:44])=[CH:27][CH:26]=4)=[O:24])(=[O:21])=[O:20])=[CH:15][C:14]=3[N+:39]([O-:41])=[O:40])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: COC(=O)Cl
Reactant: Nc1cc(F)ccc1-c1ccc(C(=O)NS(=O)(=O)c2ccc(NCC34CC5CC(CC(C5)C3)C4)c([N+](=O)[O-])c2)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Nc1cc(F)ccc1-c1ccc(C(=O)NS(=O)(=O)c2ccc(NCC34CC5CC(CC(C5)C3)C4)c([N+](=O)[O-])c2)cc1

Procedure:
A room temperature solution of Example 43B (30 mg, 0.051 mmol), methyl chloroformate (0.05 mL, 0.65 mmol), N,N-diisopropylethylamine (0.1 mL, 0.57 mmol) and DMAP (3 mg, 0.02 mmol) in dichloromethane (1 mL) was stirred for 16 hours, treated with 4M HCl (0.3 mL), and concentrated. The concentrate was purified by flash column chromatography on silica gel with 50-100% ethyl acetate/hexanes to provide the desired product. MS (ESI(−)) m/e 635 (M−H)−; 1H NMR (400 MHz, DMSO-d6) δ 8.89 (br s, 1H), 8.65 (d, 1H), 8.56 (t, 1H), 7.92 (, 3H), 7.43 (d, 2H), 7.35 (m, 3H), 7.12 (dt, 1H), 3.50 (s, 3H), 3.18 (d, 2H), 1.98 (m, 3H), 1.72-1.55 (m, 12H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:7]=2[F:15])[CH2:3][CH2:2]1>CO.[C].[Pd]>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:7]=2[F:15])[CH2:2][CH2:3]1
Reactant: O=[N+]([O-])c1ccc(OCC2CC2)c(F)c1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(OCC2CC2)c(F)c1
Reaction time: 3 h
Yield: 96.8 %

Procedure:
A suspension of 1-(cyclopropylmethoxy)-2-fluoro-4-nitrobenzene (18.3 g) and 5% palladium carbon (containing water (50%), 1.84 g) in methanol (289 mL) was stirred for 3 hr under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (15.2 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][S:17](Cl)(=[O:19])=[O:18].C(OCC)C>N1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[O:15][S:17]([CH3:16])(=[O:19])=[O:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@@H]1O
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@@H]1OS(C)(=O)=O
Reaction time: 5 h
Yield: 71.6 %

Procedure:
(1S,2S)-2-tert-Butoxycarbonylamino-1-cyclohexanol (646 mg) was dissolved in pyridine (4 ml), methane-sulfonyl chloride (378 mg) was added with ice cooling, and the mixture was stirred for 5 hours. After diethyl ether was added to the reaction mixture and washed 5 times with water, the resultant organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (630 mg) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH:4]=[C:5]([C:11]([CH2:13][O:14][CH2:15][CH2:16][N:17]1[C:21](=[O:22])[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:27])=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[CH2:32]([O:34][C:35](=[O:40])/[CH:36]=[C:37](\[NH2:39])/[CH3:38])[CH3:33]>CC(O)C>[Cl:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH:4]1[C:36]([C:35]([O:34][CH2:32][CH3:33])=[O:40])=[C:37]([CH3:38])[NH:39][C:11]([CH2:13][O:14][CH2:15][CH2:16][N:17]2[C:21](=[O:22])[C:20]3[C:19](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:18]2=[O:27])=[C:5]1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)/C=C(/C)N
Reactant: CCOC(=O)C(=Cc1ccccc1Cl)C(=O)COCCN1C(=O)c2ccccc2C1=O
Solvent: CC(C)O
Product: CCOC(=O)C1=C(C)NC(COCCN2C(=O)c3ccccc3C2=O)=C(C(=O)OCC)C1c1ccccc1Cl
Temperature: 15 °C
Reaction time: 20 h

Procedure:
116.7 g of ethyl 2-(o-chlorobenzylidene)-4-(2-phthalimidoethoxy)acetoacetate was dissolved in 120 ml of 2-propanol at 80° C. 31.2 g of ethyl-3-aminocrotonate was added and the mixture was heated at the same temperature for 16 hours. The mixture was evaporated to dryness. The residue was dissolved in 180 ml of glacial acetic acid at 80° C. The mixture was cooled to 15° C. and stirred at the same temperature for 20 hours. The solid was filtered off and washed with 92 ml of glacial acetic acid. The solid was dissolved in 75 ml of ethanol at 80° C. The solution was cooled to 20° C. and the suspension was agitated for 2 h. The solid was filtered off, washed with 25 ml of ethanol. The wet product was recrystallized from 60 ml of ethyl acetate. Yield: 43.6 g (30%) of the product, purity (HPLC, IN) −98.4%; m.p. 142.5-144° C.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].[CH:11]1([C:14](=O)[CH2:15][CH2:16][C:17](O)=[O:18])[CH2:13][CH2:12]1>C1(C)C=CC=CC=1.CCOC(C)=O>[CH:11]1([C@@:14]23[CH2:15][CH2:16][C:17](=[O:18])[N:1]2[C@@H:2]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:3][O:4]3)[CH2:13][CH2:12]1
Reactant: N[C@H](CO)c1ccccc1
Reactant: O=C(O)CCC(=O)C1CC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1CC[C@@]2(C3CC3)OC[C@H](c3ccccc3)N12
Temperature: 25 °C
Yield: 75.4 %

Procedure:
A mixture of (S)-2-amino-2-phenylethanol (2.28 g, 16.6 mmol) and 4-cyclopropyl-4-oxobutanoic acid (1.97 g, 13.8 mmol) in toluene (35 mL) was heated at reflux for about 6 h. The reaction mixture was cooled to room temperature and diluted with EtOAc, washed with aqueous HCl (1.0 N), saturated NaHCO3, brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified on a Biotage silica gel column eluting with heptane/EtOAc (3:2) to afford (3S,7aS)-7a-cyclopropyl-3-phenyltetrahydropyrrolo[2,1-b]oxazol-5(6H)-one (2.54 g, 10.4 mmol) as a bright yellow needle-like solid. RP-HPLC (Table 1, Method a) Rt 1.77 min; m/z: (M+H)+ 244.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:31])=[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[CH:17]=[C:16]4[C:28](O)=[O:29])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[NH:32]1[CH2:36][CH2:35][C@@H:34]([NH2:37])[CH2:33]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:37][C@@H:34]1[CH2:35][CH2:36][N:32]([C:28]([C:16]2[C:15]3[C:20](=[CH:21][CH:22]=[C:13]([C:11]4[CH:12]=[C:7]([CH:8]=[CH:9][C:10]=4[CH3:31])[C:5]([NH:4][CH:1]4[CH2:2][CH2:3]4)=[O:6])[CH:14]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[CH:17]=2)=[O:29])[CH2:33]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C(=O)O)c2c1
Reactant: N[C@@H]1CCNC1
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: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C(=O)N3CC[C@@H](N)C3)c2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of the product of step v) (100 mg), (R)-pyrrolidin-3-amine (20 mg) and N,N-diisopropylethylamine (0.13 mL) in DMF (2 mL) was added HATU (140 mg) and the reaction stirred at room temperature for 10 minutes. The reaction mixture was filtered and purified by HPLC to yield the title compound as a solid (65 mg).
Reaction SMILES: [CH2:1]1[C:10](=[O:11])[CH2:9][C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.[Li+].CC([N-]C(C)C)C.Br[CH2:21][C:22]([O:24][CH3:25])=[O:23]>C1COCC1>[CH3:25][O:24][C:22](=[O:23])[CH2:21][CH:9]1[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2][CH2:1][C:10]1=[O:11]
Reactant: O=C1CCc2ccccc2C1
Reactant: COC(=O)CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)CC1C(=O)CCc2ccccc21
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
A three-neck, round-bottomed flask equipped with a dropping funnel and a septum, was charged with 6.6 mL (50 mmol) of beta-tetralone and 100 mL of THF under a nitrogen atmosphere. The solution was cooled to -30° C. and 36.6 mL (55 mmol) of LDA (1.5M in cyclohexane) was added dropwise. The solution was stirred for 30 minutes and warmed to 0° C. To this solution, 5.7 mL (60 mmol) of methyl bromoacetate was added. The solution was stirred at 0° C. for 1 h. The reaction was quenched with 3N HCl until pH of the mixture was <3. THF was removed in vacuo and the concentrate was extracted with methylene chloride (2×500 mL). The organic layer was washed with brine, dried (MgSO4), filtered and concentrated in vacuo to give a yellow oil. This oil was purified by liquid chromatography on 560 g silica gel 60 (230°-400 m), eluting with hexane-ethyl acetate (4:1) and collecting 40 mL fractions. Fractions homogeneous by TLC were combined and concentrated in vacuo. The resulting oil needed the second chromatography to afford 8.22 g (75.4%) of >95% pure product as a near colorless oil.