Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[C:8]1(=[O:13])[CH2:12][CH2:11][CH2:10][CH2:9]1.[Li]CCCC.C(N(C(C)C)CC)(C)C>C1COCC1>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1([OH:13])[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=C1CCCC1
Reactant: Brc1cccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: OC1(c2ccncc2Br)CCCC1
Yield: 33.8 %

Procedure:
Using analogous reaction condition and reagents as described in Example 20 for the preparation of I-20a above, 3-bromo pyridine solution (1.0 g, 6.36 mmol) was reacted with cyclopentanone solution (0.6 mL, 7.0 mmol) in dry THF (6 mL), n-BuLi solution (4.0 mL, 7.6 mmol) and diisopropylethyl amine (1.0 mL, 7.0 mmol) in dry THF (6 mL) to afford the crude product. The crude was purified by column chromatography on silica gel (20% ethyl acetate in hexane) afforded 520 mg of the product (34% yield).
Reaction SMILES: [N+:1]1([O-])[CH:2]=[CH:3][C:4]2[C:9]=1[NH:8][CH:7]=[CH:6][CH:5]=2.CS([Cl:15])(=O)=O.[OH-].[Na+]>CN(C=O)C>[Cl:15][C:5]1[CH:6]=[CH:7][N:8]=[C:9]2[NH:1][CH:2]=[CH:3][C:4]=12
Reactant: CS(=O)(=O)Cl
Reactant: [O-][n+]1ccc2ccc[nH]c1-2
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Clc1ccnc2[nH]ccc12
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 70 %

Procedure:
7-Azaindole N-oxide (43.6 g, 325 mmol) was dissolved in anhydrous DMF (280 mL), and methanesulfonyl chloride (d=1.477, 80 mL, 1.03 mol) was dropwise added thereto under an argon atmosphere. The resulting mixture was stirred at 70° C. for 90 minutes. The reaction content was poured onto ice (1 kg) and was neutralized with a 5 N sodium hydroxide solution (400 mL). The precipitated solid was collected by filtration under reduced pressure, washed with iced-water, and dried under reduced pressure using an oil pump to give 34.7 g of 4-chloro-1H-pyrrolo[2,3-b]pyridine (yield: 70%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C@@H:8]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C@H:9]([OH:20])[CH2:10][NH:11][CH2:12][C:13]([CH3:19])([CH3:18])[CH2:14][CH2:15][C:16]#[N:17])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[O:38]1[C:42]2[CH:43]=[CH:44][C:45]([S:47](Cl)(=[O:49])=[O:48])=[CH:46][C:41]=2[O:40][CH2:39]1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:28])[NH:7][C@@H:8]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C@H:9]([OH:20])[CH2:10][N:11]([S:47]([C:45]1[CH:44]=[CH:43][C:42]2[O:38][CH2:39][O:40][C:41]=2[CH:46]=1)(=[O:48])=[O:49])[CH2:12][C:13]([CH3:19])([CH3:18])[CH2:14][CH2:15][C:16]#[N:17])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OCO2
Reactant: CC(C)(CCC#N)CNC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(CCC#N)CN(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)S(=O)(=O)c1ccc2c(c1)OCO2
Yield: 57.9 %

Procedure:
[(1S,2R)-1-Benzyl-3-(4-cyano-2,2-dimethyl-butylamino)-2-hydroxy-propyl]-carbamic acid tert-butyl ester (0.099 g, 0.25 mmol) was dissolved in CH2Cl2 and treated with diisopropylethylamine (0.066 ml, 0.38 mmol) and Benzo[1,3]dioxole-5-sulfonyl chloride (0.067 g, 0.31 mmol) at ambient temperature under argon with stirring. After 15 h the reaction mixture was concentrated in vacuo, taken up in EtOAc, washed with sat. aq. NaHCO3, and brine. The organic phase was dried over MgSO4, filtered and solvent removed in vacuo. Purification by column chromatography (1% MeOH in CH2Cl2) gave 0.083 g of a white solid. MS (ES): 574 (M+1).
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].[CH2:6]([O:8][C:9]([C:11]1([CH2:21]Br)[CH2:20][CH2:19][C:14]2([O:18][CH2:17][CH2:16][O:15]2)[CH2:13][CH2:12]1)=[O:10])[CH3:7].O>CN(C=O)C>[CH2:6]([O:8][C:9]([C:11]1([CH2:21][S:3][C:1](=[O:4])[CH3:2])[CH2:20][CH2:19][C:14]2([O:15][CH2:16][CH2:17][O:18]2)[CH2:13][CH2:12]1)=[O:10])[CH3:7]
Reactant: CCOC(=O)C1(CBr)CCC2(CC1)OCCO2
Reactant: CC([O-])=S
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(CSC(C)=O)CCC2(CC1)OCCO2
Temperature: 80 °C
Yield: 101.6 %

Procedure:
Potassium thioacetate (1.0 g) was added to a solution of 8-bromomethyl-1,4-dioxa-spiro[4.5]decane-8-carboxylic acid ethyl ester (1.0 g) in DMF (30 ml) and the solution was heated at 80° C. for 4 h. The mixture was then added to water (100 ml) and extracted with ether. The solvent was washed with water, bicarbonate solution and brine, then dried (MgSO4) and evaporated to give the title compound (1.0 g) as colourless oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[N:15][NH:16][CH:17]=3)[N:10]3[CH:18]=[CH:19][N:20]=[C:9]3[CH:8]=2)[CH:4]=[N:3]1.[CH2:21]1[C:24]2([CH2:27][CH2:26][CH2:25]2)[CH2:23][C:22]1=[CH:28][C:29]#[N:30].N1CCCN2CCCCCC=12>CC#N>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[N:15][N:16]([C:22]4([CH2:28][C:29]#[N:30])[CH2:23][C:24]5([CH2:27][CH2:26][CH2:25]5)[CH2:21]4)[CH:17]=3)[N:10]3[CH:18]=[CH:19][N:20]=[C:9]3[CH:8]=2)[CH:4]=[N:3]1
Reactant: N#CC=C1CC2(CCC2)C1
Reactant: Cn1cc(-c2cc3nccn3c(-c3cn[nH]c3)n2)cn1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CC5(CCC5)C4)c3)n2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.3 %

Procedure:
7-(1-Methyl-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (Preparation K-1; 0.050 g, 0.189 mmol), 2-(spiro[3.3]heptan-2-ylidene)acetonitrile (0.050 g, 0.377 mmol) and 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (0.014 mL, 0.094 mmol) were suspended in MeCN (3 mL) and stirred at ambient temperature overnight. The reaction mixture was concentrated under reduced pressure and the crude material purified by flash column chromatography, eluting with 1-4% (9:1 MeOH:NH4OH)/DCM to provide 2-(2-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)spiro[3.3]heptan-2-yl)acetonitrile (0.032 g, 0.080 mmol, 42% yield). MS (apci) m/z=399.2 (M+H).
Reaction SMILES: C([Cl:4])(=O)C.C(OC([N:12]1[CH2:17][CH2:16][S:15](=[O:19])(=[O:18])[CH:14]([C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][CH:21]=2)[CH2:13]1)=O)(C)(C)C>C(O)C>[ClH:4].[I:26][C:23]1[CH:22]=[CH:21][C:20]([CH:14]2[S:15](=[O:19])(=[O:18])[CH2:16][CH2:17][NH:12][CH2:13]2)=[CH:25][CH:24]=1
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCS(=O)(=O)C(c2ccc(I)cc2)C1
Solvent: CCO
Product: Cl
Product: O=S1(=O)CCNCC1c1ccc(I)cc1
Temperature: 55 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
Acetyl chloride (2.8 mL, 39.4 mmol) was added to ethanol (35 mL). The resulting solution was added to 2-(4-Iodo-phenyl)-1,1-dioxo-1λ6-thiomorpholine-4-carboxylic acid tert-butyl ester (2.16 g; 4.94 mmol), at RT. The resulting mixture was stirred at 55° C. for 2 hours, and subsequently, at RT overnight. The resulting suspension was concentrated in vacuo, and treated with iPr2O. The formed precipitate was collected by filtration and dried in vacuo to afford 2-(4-iodo-phenyl)-thiomorpholine 1,1-dioxide hydrochloride (1.78 g).
Reaction SMILES: C(OC([NH:8][CH:9]1[C:46](=[O:47])[N:11]2[C:12]([C:30]([O:32][CH:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])=[C:13]([C:16]3[C:19](=[O:20])[C:18](=[O:21])[C:17]=3[O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:14][S:15][C@H:10]12)=O)(C)(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(#N)C>[NH2:8][CH:9]1[C:46](=[O:47])[N:11]2[C:12]([C:30]([O:32][CH:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[O:31])=[C:13]([C:16]3[C:19](=[O:20])[C:18](=[O:21])[C:17]=3[O:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:14][S:15][C@H:10]12
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3c(OCc4ccccc4)c(=O)c3=O)CS[C@H]12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: O
Product: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3c(OCc4ccccc4)c(=O)c3=O)CS[C@H]12

Procedure:
Diphenylmethyl 7-(t-butoxycarbonylamino)-3-(2-benzyloxy-3,4-dioxo-1-cyclobutenyl)-3-cephem-4-carboxylate was deprotected with a solution of pTSOH·H2O in acetonitrile as described in the preceding experiment to provide the title compound which was directly used in the next step.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[O:8])[CH:2]=1.[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH-].[Pb+2].[OH-]>[Pt].CN(C)C=O>[CH2:9]([NH:16][C:7](=[O:8])[C:3]1[CH:4]=[CH:5][CH:6]=[N:1][CH:2]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCc1ccccc1
Reactant: O=Cc1cccnc1
Agent: [Pt]
Agent: [OH-]
Agent: [Pb+2]
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1)c1cccnc1
Yield: 23 %

Procedure:
In the same flask as in Example 1 were charged 2 g of pyridine-3-aldehyde, 5 g of benzylamine, 40 g of N,N-dimethylformamide and 3 g of a catalyst in which 5 percent by weight of platinum metal together with lead hydroxide with an atomic ratio of Pt to Pb being 1 to 1 had been supported on alumina. The reaction was conducted at a reaction temperature of 25° C. by introducing air into the flask at a rate of 6 l/hour for 2 hours to give nicotinic acid benzylamide at a yield of 23%.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][C:12]=2[CH:21]2[C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:25]([CH3:31])[NH:24][C:23]([CH3:32])=[C:22]2[C:33]([O:35][CH3:36])=[O:34])C(=O)C2=CC=CC=C12.O.NN>C(O)C>[NH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:18])=[O:19])=[CH:13][C:12]=1[CH:21]1[C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:25]([CH3:31])[NH:24][C:23]([CH3:32])=[C:22]1[C:33]([O:35][CH3:36])=[O:34]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cc(S(C)(=O)=O)ccc1OCCCCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cc(S(C)(=O)=O)ccc1OCCCCN
Yield: 48.2 %

Procedure:
A solution of 6.9 g of dimethyl 4-[2-(4-phthalimidobutoxy)-5-methylsulfonylphenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate and 5.9 g of hydrazine monohydrate in 170 ml of % ethanol(water: 5%) was refluxed under heating for 6 hours. After cooling, the reaction solution was concentrated under reduced pressure. The residue was extracted with chloroform, and the extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Crude crystals thus obtained were recrystallized from chloroform-ether to give 2.6 g of dimethyl 4-[2-(4-aminobutoxy)-5-methylsulfonylphenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:17]#[N:18])[C:5]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[F-:19].[K+].C(OCC)(=O)C.O>CS(C)=O>[C:17]([C:4]1[C:5]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=[C:2]([F:19])[N:3]=1)#[N:18]
Reactant: N#Cc1nc(Br)cnc1NC(=O)c1ccccc1
Reactant: [F-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1nc(F)cnc1NC(=O)c1ccccc1
Temperature: 112.5 °C
Reaction time: 1 h
Yield: 13.7 %

Procedure:
In 86 mL of dimethyl sulfoxide was dissolved 4.3 g of N-(5-bromo-3-cyano-2-pyrazinyl)benzamide. After adding 8.3 g of potassium fluoride, the mixture thus obtained was stirred at 110-115° C. for one hour. The reaction mixture was returned to room temperature, a mixture of 100 mL of ethyl acetate and 200 mL of water was added, and the organic layer was separated. The organic layer thus obtained was washed successively with water and saturated aqueous solution of sodium chloride, treated with active charcoal and dried on anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent: toluene:ethyl acetate=5:1] to obtain 0.47 g of N-(3-cyano-5-fluoro-2-pyrazinyl)benzamide as a white-colored solid product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[C@@H:4]1[C@H:8](O)[CH2:7][CH2:6][NH:5]1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P([N:58]=[N+:59]=[N-:60])(C2C=CC=CC=2)=O)C=CC=CC=1>>[CH3:1][O:2][C:3](=[O:10])[C@@H:4]1[CH:8]([N:58]=[N+:59]=[N-:60])[CH2:7][CH2:6][NH:5]1
Reactant: COC(=O)[C@H]1NCC[C@H]1O
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)[C@H]1NCCC1N=[N+]=[N-]

Procedure:
Reaction of cis-3-hydroxyproline methyl ester with DIAD, triphenylphosphine and diphenylphosphoryl azide provides the desired 3-azido proline methyl ester. Transformation is typically carried out at low temperatures, e.g., 0° C., and after the addition, the reaction is allowed to warm to ambient temperature, e.g., about 25° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH2:9])=[C:7]([O:10][CH3:11])[N:6]=[C:5]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:18]=3)[CH2:13]2)[N:4]=1.N1C=CC=CC=1.[C:32]([CH2:36][C:37](Cl)=[O:38])([CH3:35])([CH3:34])[CH3:33]>ClCCl>[CH3:1][O:2][C:3]1[C:8]([NH:9][C:37](=[O:38])[CH2:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[C:7]([O:10][CH3:11])[N:6]=[C:5]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:22]([F:24])([F:25])[F:23])[CH:18]=3)[CH2:13]2)[N:4]=1
Reactant: CC(C)(C)CC(=O)Cl
Reactant: COc1nc(N2CCc3cc(C(F)(F)F)ccc3C2)nc(OC)c1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1nc(N2CCc3cc(C(F)(F)F)ccc3C2)nc(OC)c1NC(=O)CC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To a mixture of 5c (0.69 g, 1.96 mmol) and pyridine (0.156 g, 2.0 mmol) in dichloromethane (20 ml) was added tert-butylacetyl chloride (0.269 g, 2.0 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was washed with brine and extracted with ethyl acetate. The organic layer was dried over MgSO4, concentrated and chromatographed to yield the title compound (0.657 g, 1.45 mmol, 72%). 1H NMR (CDCl3, 400 MHz) δ 1.10 (s, 9H), 2.20 (s, 2H), 2.95 (t, J=5.8 Hz, 2H), 3.92 (s, 6H), 4.04 (t, J=5.8 Hz, 2H), 4.92 (s, 2H), 6.18 (s, 1H), 7.29 (d, J=7.8 Hz, 1H), 7.42 (s, 1H), 7.44 (d, J=7.8 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9](=O)[CH2:8][CH:7]1[CH3:21])=[O:5])[CH3:2].Cl.[NH2:23][OH:24].C([O-])(=O)C.[Na+].O>C(O)C>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9](=[N:23][OH:24])[CH2:8][CH:7]1[CH3:21])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2cc(OC)c(OC)cc2C(=O)CC1C
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)N1c2cc(OC)c(OC)cc2C(=NO)CC1C
Reaction time: 0.17 h
Yield: 116.8 %

Procedure:
A stirred solution of 6,7-dimethoxy-2-methyl-4-oxo-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (10.0 g, 34.1 mmol), hydroxylamine hydrochloride (7.1 g, 102 mmol), and sodium acetate (7.0 g, 85 mmol) in ethanol (50 mL) was heated at reflux for 2 h. Water (50 mL) was added, and the volatiles were removed in vacuo. Ethyl acetate (175 mL) was added, and the mixture was stirred vigorously for 10 min. The aqueous phase was separated and extracted with ethyl acetate (2×60 mL). The combined organic layers were washed with brine (25 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound as a white foam (12.28 g, ca. 100%). 1H NMR (CDCl3) δ 1.1 (d, 3H), 1.32 (t, 3H), 2.77 (dd, 1H), 3.07 (dd, 1H), 3.89 (s, 6H), 4.2-4.4 (m, 2H), 5.0 (m, 1H), 7.18 (s, 1H), 7.26 (s, 1H).
Reaction SMILES: C[C:2]1[C:3]2[C:22](=[O:23])CCC=2N(S(C2C=CC(C)=CC=2)(=O)=O)[C:6]=1C(O)=O.O=C1C2[CH:31]=[C:30]([C:33]([O:35][CH3:36])=O)NC=2CC1.BrC1C=C(C=CC=1)C[Mg]Br.Br[C:48]1[CH:49]=[C:50]([CH:74]=[CH:75][CH:76]=1)/[CH:51]=[C:52]1\[CH2:53][CH2:54][C:55]2[N:56]([S:64]([C:67]3[CH:73]=[CH:72][C:70]([CH3:71])=[CH:69][CH:68]=3)(=[O:66])=[O:65])[C:57]([C:60]([O:62][CH3:63])=[O:61])=[CH:58][C:59]\1=2.O1C=CC=C1B(O)O>>[O:23]1[CH:22]=[CH:3][CH:2]=[C:6]1[C:48]1[CH:49]=[C:50]([CH:74]=[CH:75][CH:76]=1)[CH2:51][CH:52]1[C:59]2[CH:58]=[C:57]([C:60]([O:62][CH3:63])=[O:61])[NH:56][C:55]=2[CH2:54][CH2:53]1.[O:35]1[CH:33]=[CH:30][CH:31]=[C:36]1[C:48]1[CH:49]=[C:50]([CH:74]=[CH:75][CH:76]=1)/[CH:51]=[C:52]1\[CH2:53][CH2:54][C:55]2[N:56]([S:64]([C:67]3[CH:68]=[CH:69][C:70]([CH3:71])=[CH:72][CH:73]=3)(=[O:66])=[O:65])[C:57]([C:60]([O:62][CH3:63])=[O:61])=[CH:58][C:59]\1=2
Reactant: COC(=O)c1cc2c([nH]1)CCC2=O
Reactant: Cc1ccc(S(=O)(=O)n2c3c(c(C)c2C(=O)O)C(=O)CC3)cc1
Reactant: COC(=O)c1cc2c(n1S(=O)(=O)c1ccc(C)cc1)CC/C2=C\c1cccc(Br)c1
Agent: Br[Mg]Cc1cccc(Br)c1
Agent: OB(O)c1ccco1
Product: COC(=O)c1cc2c([nH]1)CCC2Cc1cccc(-c2ccco2)c1
Product: COC(=O)c1cc2c(n1S(=O)(=O)c1ccc(C)cc1)CC/C2=C\c1cccc(-c2ccco2)c1

Procedure:
The title compound was synthesized in four steps. First, tosyl protected methyl 4-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (methyl 4-oxo-1-tosyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate) (1.50 g, 8.37 mmol) was reacted with 3-bromobenzylmagnesium bromide (15 mL, 3.75 mmol) according to General Procedure 3 to give exo olefin-containing compound (E)-methyl 4-(3-bromobenzylidene)-1-tosyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate, followed by coupling with furan-2-boronic acid (0.138 g, 1.23 mmol) according to General Procedure 9.1 to give (E)-methyl 4-(3-(furan-2-yl)benzylidene)-1-tosyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate, then tosyl deprotection according to General Procedure 10.1 to give (E)-methyl 4-(3-(furan-2-yl)benzylidene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate. Hydrogenation of (E)-methyl 4-(3-(furan-2-yl)benzylidene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate according to General Procedure 6, then purification by column (Isco CombiFlash) eluting with a gradient of 0-25% EtOAc/heptane afforded the title compound: 0.024 g.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.[N+:12]([O-])(O)=O>[Pd].CO>[NH2:12][C:3]1[C:2]([CH3:1])=[CH:11][C:6]2[NH:7][C:8](=[O:10])[O:9][C:5]=2[CH:4]=1
Reactant: Cc1ccc2oc(=O)[nH]c2c1
Reactant: O=[N+]([O-])O
Agent: [Pd]
Solvent: CO
Product: Cc1cc2[nH]c(=O)oc2cc1N
Temperature: 50 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
5-Methyl-3H-benzoxazol-2-one (1.10 g, 7.38 mmol) added to stirring Nitric acid (6.00 mL, 143 mmol). After stirring 1 h, the mixture was heated at 50° C. for 4 h, cooled and then poured into 100 mL ice and allowed to stand overnight to melt. The yellow solids were collected by filtration, washing with water. The crude nitro product was hydrogenated (25 psi) over 10% Palladium on Carbon (50% Wet) (0.240 g, 0.113 mmol) in Methanol (30.0 mL) for 3 h. The mixture was filtered through Celite and rinsed with MeOH (50 mL). After conc. in vacuo, 6-Amino-5-methyl-3H-benzoxazol-2-one (0.765 g; Yield=63.2%) was isolated as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]([CH2:12][CH2:13][NH2:14])[CH2:8][CH2:9]2)=[CH:5][CH:4]=1.[C:15](O)(=O)[C@H:16]([C@@H:18]([C:20](O)=[O:21])O)O.C(N)(=O)CCC.CCCC(Cl)=O>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]([CH2:12][CH2:13][NH:14][C:20](=[O:21])[CH2:18][CH2:16][CH3:15])[CH2:8][CH2:9]2)=[CH:5][CH:4]=1
Reactant: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Reactant: COc1ccc2c(c1)CCC2CCN
Agent: CCCC(=O)Cl
Agent: CCCC(N)=O
Product: CCCC(=O)NCCC1CCc2cc(OC)ccc21

Procedure:
N-[2-(2-,3-dihydro-6-methoxy-1H-inden-3-yl)ethyl]amine was resolved with D-tartaric acid using the resolution technique described. The 1:1 amine: D-tartaric acid complex was shown to have an enantiomeric excess of ≤90 by 1H NMR. The resolved amine was converted into the butanamide using n-butyryl chloride according to General Procedure A. The resulting white solid was purified by recrytallization from EtOAc/Hexane and shown to be product. m.p. 79°-80° C.; 1H NMR (300 MHz, CDCl3) δ7.08 (d, J=8Hz, 1H), 6.72-6.67 (M, 2H), 5.57 (bs, 1H), 3.76 (s, 3H), 3.86-3.66 (bm, 2H), 3.08 (bm, 1H), 2.89-2.69 (bm, 2H), 2.35-2.27 (m, 1H), 2.13 (t, J=7.5 Hz, 2H), 2.06-2.00 (m, 2H), 1.7-1.5 (bm, 4H), 0.92 (t, J=7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ172.0, 158.8, 148.11, 135.8, 124.9, 112.27, 109.18, 55.48, 42.67, 38.71, 37.98, 34.83, 32.47, 30.55, 19.21, 13.76; IR (KBr) 1632, 1546, 1290 cm-1 ; MS (DCI) 276m/e (MH); Analysis calc'd for C16H21NO1 : C, 78.97; H, 8.70; N, 5.76; found: C, 78.73; H, 8.90; N, 5.76.Analysis calc'd for C16H23N1O2 : C, 73.53; H, 8.87; N, 5.36; found: C, 73.47; H, 8.77; N, 5.13; [α] (25° C., 589 nm, CHCl3)=-5.26
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][N:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][CH2:30][C@@H:3]12.[CH3:31][CH:32]([NH2:34])[CH3:33].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:32]([NH:34][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH2:12][C:9]3[CH:10]=[N:11][C:5]4[N:4]5[CH2:28][CH2:29][CH2:30][C@H:3]5[C:2](=[O:1])[NH:7][C:6]=4[CH:8]=3)[CH2:18][CH2:17]2)=[N:20][CH:21]=1)([CH3:33])[CH3:31]
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)nc1
Reactant: CC(C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.8 %

Procedure:
(S)-6-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinic acid (87.0 mg, 0.213 mmol) and propan-2-amine (18.89 mg, 0.319 mmol) were suspended in DMF (1 ml) and treated with DIPEA (0.186 ml, 1.065 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (162 mg, 0.426 mmol). The reaction mixture was stirred at room temperature for 3 h and purified using HPLC (10-95% acetonitrile in water, NH4HCO3 buffered) to afford (S)—N-isopropyl-6-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinamide (62.1 mg, 0.138 mmol, 64.9% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.13 (d, J=6.57 Hz, 6 H) 1.84-2.01 (m, 3 H) 2.12-2.22 (m, 1 H) 2.41 (d, J=4.29 Hz, 4H) 3.36-3.47 (m, 1H) 3.49-3.64 (m, 5 H) 3.95-4.10 (m, 2 H) 6.81 (d, J=8.84 Hz, 1 H) 6.99 (d, J=2.02 Hz, 1 H) 7.61 (d, J=1.77 Hz, 1 H) 7.94 (dd, J=9.09, 2.53 Hz, 1H) 7.97 (d, J=7.83 Hz, 1 H) 8.57 (d, J=2.53 Hz, 1 H) 10.44 (s, 1 H); [M+H] calc'd for C24H31N7O2, 450; found, 450.
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-])=O)[CH3:2].[CH:18]([Mg]Br)=[CH2:19].[Cl-].[NH4+]>O1CCCC1>[CH2:1]([N:3]([CH2:16][CH3:17])[C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:7]=1[NH:12][CH:19]=[CH:18]2)[CH3:2]
Reactant: CCN(CC)C(=O)Cc1ccccc1[N+](=O)[O-]
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCN(CC)C(=O)Cc1cccc2cc[nH]c12
Temperature: -70 °C
Reaction time: 5 h
Yield: 5 %

Procedure:
N,N-Diethyl-2-(2-nitrophenyl)acetamide (87.2 g, 0.369 mol) is dissolved in tetrahydrofuran (1.5L), and the mixture is cooled to −70° C. To the mixture is added dropwise a 1M solution of vinylmagnesium bromide in tetrahydrofuran (1.11 L, 1.11 mol). After the addition, the mixture is stirred at −50° C. for additional 5 hours. The reaction solution is poured into an aqueous ammonium chloride solution, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The resulting residue is purified by silica gel column chromatography (chloroform, hexane/ethyl acetate=4/1) to give the title compound (4.02 g, yield: 5%).