Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1.Br[CH2:46][C:47]1[CH:48]=[CH:49][C:50]([NH:53][C:54](=[O:60])[O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[N:51][CH:52]=1.BrCC1OC(C(F)(F)F)=CC=1>>[O:22]=[C:2]1[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]1[CH2:46][C:47]1[CH:48]=[CH:49][C:50]([NH:53][C:54](=[O:60])[O:55][C:56]([CH3:58])([CH3:57])[CH3:59])=[N:51][CH:52]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CBr)cn1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: CC(C)(C)OC(=O)Nc1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)cn1

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and tert-butyl [5-(bromomethyl)pyridin-2-yl]carbamate to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, tert-butyl {5-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridin-2-yl}carbamate was obtained (74%) as a colorless solid: mp 238-239° C.; 1H NMR (300 MHz, DMSO-d6) δ9.81 (s, 1H), 8.30-8.27 (m, 1H), 7.79-7.73 (m, 1H), 7.73-7.66 (m, 1H), 7.31-7.24 (m, 1H), 7.20-7.14 (m, 1H), 7.12-6.99 (m, 2H), 6.52 (s, 1H), 6.06 (s, 1H), 4.89 (ABq, J=22.9, 15.5 Hz, 2H), 4.74 (ABq, J=44.4, 9.3 Hz, 2H), 4.23-4.05 (m, 4H), 1.45 (s, 9H); 13C NMR (75 MHz, DMSO-d6) δ 176.7, 154.6, 152.6, 151.8, 146.9, 144.1, 141.8, 137.8, 137.2, 131.6, 128.7, 126.2, 123.6, 123.1, 121.1, 112.2, 110.8, 109.3, 98.8, 79.5, 79.3, 64.1, 63.5, 57.2, 27.9; MS (ES+) m/z 502.1 (M+1).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10]/[CH:11]=[CH:12]/[C:13]1[CH:14]=[CH:15][C:16](/[C:21](/[C:40]2[CH:45]=[CH:44][C:43]([C:46]([CH3:49])([CH3:48])[CH3:47])=[CH:42][CH:41]=2)=[CH:22]/[C@@H:23]2[N:27]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:30]=3[O:37][CH3:38])[C:26](=[O:39])[CH2:25][CH2:24]2)=[N:17][C:18]=1[O:19][CH3:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H][H]>CO.C(OCC)(=O)C.[Pd].[Br-].[Zn+2].[Br-]>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16](/[C:21](/[C:40]2[CH:41]=[CH:42][C:43]([C:46]([CH3:49])([CH3:48])[CH3:47])=[CH:44][CH:45]=2)=[CH:22]/[C@@H:23]2[N:27]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:30]=3[O:37][CH3:38])[C:26](=[O:39])[CH2:25][CH2:24]2)=[N:17][C:18]=1[O:19][CH3:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(/C=C/CCO[Si](C)(C)C(C)(C)C)c(OC)n2)c(OC)c1
Agent: [Pd]
Agent: [Br-]
Agent: [Zn+2]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(CCCCO[Si](C)(C)C(C)(C)C)c(OC)n2)c(OC)c1
Yield: 61.8 %

Procedure:
10% palladium-activated carbon (50 mg) and zinc(II) bromide (25 mg) were added to a solution of (5R)-5-[(E)-2-{5-[(1E)-4-{[tert-butyl(dimethyl)silyl]oxy}but-1-en-1-yl]-6-methoxypyridin-2-yl}-2-(4-tert-butylphenyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one (226 mg) in methanol (5 mL), and the mixture was stirred at room temperature for five hours in a hydrogen atmosphere. The reaction solution was diluted with ethyl acetate and filtered through celite. The filtrate was sequentially washed with water and brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3→1:9) to give (5R)-5-[(E)-2-[5-(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)-6-methoxypyridin-2-yl]-2-(4-tert-butylphenyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one as a colorless oil (140 mg, 62%).
Reaction SMILES: [CH2:1]([NH:3][CH:4]1[CH2:13][CH2:12][C:7]2([O:11][CH2:10][CH2:9][O:8]2)[CH2:6][CH2:5]1)[CH3:2].[CH2:14]([O:21][C:22](Cl)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[CH2:1]([N:3]([CH:4]1[CH2:13][CH2:12][C:7]2([O:8][CH2:9][CH2:10][O:11]2)[CH2:6][CH2:5]1)[C:22](=[O:23])[O:21][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:2]
Reactant: CCNC1CCC2(CC1)OCCO2
Reactant: O=C(Cl)OCc1ccccc1
Solvent: C1CCOC1
Product: CCN(C(=O)OCc1ccccc1)C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of N-ethyl-1,4-dioxaspiro[4.5]decan-8-amine (1.8 g, 9.9 mmol) from above step a in THF is treated with TEA (1.4, 9.9 mmol) and benzyloxycarbonyl chloride (1.4 mL, 9.9 mmol). The mixture was stirred for 18 h at room temperature. THF was removed under vacuum and the residue was taken EtOAc and washed with 10% citric acid, saturated NaHCO3, and saturated NaCl. The solution was dried over Na2SO4 and evaporated under vacuum. The residue was purified by silica column chromatography to give the title compound.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][NH:13][C:12](=[O:16])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[CH2:18][CH:19]1[CH2:21][CH2:20]1>CN(C)C(=O)C.O>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([CH2:18][CH:19]2[CH2:21][CH2:20]2)[C:12](=[O:16])[CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: BrCC1CC1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCN(CC2CC2)C(=O)C1
Reaction time: 18 h
Yield: 99.9 %

Procedure:
Sodium hydride (60% dispersion in oil) (0.40 g, 10.0 mmol) was added portionwise over 10 min to a solution of 3-oxopiperazine-1-carboxylic acid tert-butyl ester (1.00 g, 5.0 mmol) in N,N-dimethylacetamide (10 ml). The mixture was stirred for 30 min before addition of bromomethylcyclopropane (1.45 ml, 15.0 mmol) and then stirred for a further 18 h. The mixture was diluted with water (100 ml) and extracted with EtOAc (2×100 ml). The combined organic extracts were washed with brine (50 ml), dried over MgSO4 and evaporated to give 4-cyclopropylmethyl-3-oxopiperazine-1-carboxylic acid tert-butyl ester (1.27 g, 100%) as a yellow oil. This oil was dissolved in dichloromethane and hydrogen chloride bubbled through the reaction (2×10 min). The solvent was evaporated to give 1-cyclopropylmethylpiperazin-2-one.HCl (0.95 g, 100%) as a white solid.
Reaction SMILES: O[Li].O.[C:4]([O:8][C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[N:25]=[C:24]([CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH2:34][C:35]([O:37]C)=[O:36])[C:23]([C:39]([F:42])([F:41])[F:40])=[CH:22][N:21]=2)=[CH:15][CH:14]=1)=[O:10])([CH3:7])([CH3:6])[CH3:5]>CO.O.C1COCC1>[C:4]([O:8][C:9]([NH:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]2[N:25]=[C:24]([CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH2:34][C:35]([OH:37])=[O:36])[C:23]([C:39]([F:41])([F:42])[F:40])=[CH:22][N:21]=2)=[CH:17][CH:18]=1)=[O:10])([CH3:7])([CH3:5])[CH3:6]
Reactant: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(CNC(=O)OC(C)(C)C)cc2)ncc1C(F)(F)F
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1ccc(Nc2ncc(C(F)(F)F)c(CCc3ccccc3CC(=O)O)n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
LiOH.H2O (94 mg, 2.2 mmol) was added to a solution of methyl 2-(2-(2-(2-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetate (A14) (306 mg, 0.562 mmol) in MeOH (1 mL), water (1 mL) and THF (10 mL) and the resulting mixture was stirred at room temperature overnight. The volatiles were removed in vacuo and the resultant oil partitioned between EtOAc (150 mL) and 2 M aqueous NaOH (100 mL). The organic layer was separated, washed with water (2×100 mL), brine (50 mL) and dried over MgSO4. The volatiles were removed in vacuo to yield the title compound A15 as a yellow oil (0.25 g, 83%); LCMS-A: rt 6.267 min; m/z 531 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[S:6][CH:7]=[C:8]([CH:9]([P:23]([CH3:26])(=[O:25])[OH:24])[C:10](=[O:22])[NH:11][CH:12]=[CH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=3)[C:4]=2[CH:3]=1.[CH2:29]([N:31]([CH2:36][CH3:37])[C:32](=[O:35])[CH2:33]O)[CH3:30].CC1C=C(C)C(S(N2N=C([N+]([O-])=O)N=C2)(=O)=O)=C(C)C=1>N1C=CC=CC=1>[CH2:29]([N:31]([CH2:36][CH3:37])[C:32]([CH2:33][O:25][P:23]([CH:9]([C:8]1[C:4]2[CH:3]=[C:2]([Cl:1])[CH:28]=[CH:27][C:5]=2[S:6][CH:7]=1)[C:10](=[O:22])[NH:11][CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=1)([CH3:26])=[O:24])=[O:35])[CH3:30]
Reactant: CCN(CC)C(=O)CO
Reactant: CP(=O)(O)C(C(=O)NC=Cc1ccc(F)c(F)c1)c1csc2ccc(Cl)cc12
Agent: Cc1cc(C)c(S(=O)(=O)n2cnc([N+](=O)[O-])n2)c(C)c1
Solvent: c1ccncc1
Product: CCN(CC)C(=O)COP(C)(=O)C(C(=O)NC=Cc1ccc(F)c(F)c1)c1csc2ccc(Cl)cc12
Yield: 44.3 %

Procedure:
Using the procedure described in Example 47, Compound 17 (0.25 g, 0.57 mmol), N,N-diethyl-2-hydroxyacetamide (0.37 g, 2.86 mmol), and MSNT (0.25 g, 0.86 mmol) in pyridine (5 ml) yielded 0.14 g of Compound 185, as a white powder (˜3:1 mixture of diastereomers). HPLC: 4.03 min (24%), 4.11 min (76%); MS (ES) m/z 555 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:17]=[C:16]4[C:18]([C:21]([OH:23])=O)=[CH:19][NH:20][C:15]4=[N:14][CH:13]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[NH2:24][C:25]1([CH2:28][OH:29])[CH2:27][CH2:26]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>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:17]=[C:16]4[C:18]([C:21]([NH:24][C:25]5([CH2:28][OH:29])[CH2:27][CH2:26]5)=[O:23])=[CH:19][NH:20][C:15]4=[N:14][CH:13]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: NC1(CO)CC1
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(F)cc21
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: Cn1nc(-c2cnc3[nH]cc(C(=O)NC4(CO)CC4)c3n2)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 4.7 %

Procedure:
A mixture of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (70 mg, 0.225 mmol), (1-aminocyclopropyl)methanol (30 mg, 0.337 mmol), HATU (171 mg, 0.45 mmol) and DIEA (58 mg, 0.45 mmol) in DMF (3 mL) was stirred at 25° C. for 16 hours. Then the mixture was filtered and the cake was washed with MeOH. The crude product was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions were: 55% acetonitrile/45% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 80% acetonitrile/20% water (0.1% trifluoroacetic acid, v/v) in a linear fashion after 9 min.) to give 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-N-(1-(hydroxymethyl)cyclopropyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (4 mg, 5%). MS: (M+H)+=381; 1H NMR (300 MHz, DMSO): δ 12.88 (s, 1H), 9.12 (s, 1H), 8.71 (s, 1H), 8.60-8.55 (m, 1H), 8.46 (s, 1H), 7.72 (dd, 1H, J=9.6, 2.1 Hz), 7.28-7.21 (m, 1H), 4.17 (s, 3H), 3.60 (s, 2H), 0.96-0.85 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.Br[CH2:21][C:22]1[C:31]2[O:30][C:29]([C:32]#[N:33])=[CH:28][C:27](=[O:34])[C:26]=2[CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OC(=O)C)C>[C:32]([C:29]1[O:30][C:31]2[C:22]([CH2:21][O:1][C:2]3[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]4[CH:17]=[CH:16][C:15]5[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=5)[N:9]=4)=[CH:18][CH:19]=3)=[CH:23][CH:24]=[CH:25][C:26]=2[C:27](=[O:34])[CH:28]=1)#[N:33]
Reactant: N#Cc1cc(=O)c2cccc(CBr)c2o1
Reactant: Oc1ccc(OCc2ccc3ccccc3n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cc(=O)c2cccc(COc3ccc(OCc4ccc5ccccc5n4)cc3)c2o1
Yield: 27.4 %

Procedure:
1.0 g of 2-(4-hydroxyphenoxy)methylquinoline, 1.0 g of 8-bromomethyl-2-cyano-4-oxo-4H-1-benzopyran and 0.5 g of potassium carbonate are stirred at room temperature in 5 ml of dimethylformamide for 2 days. The reaction mixture is diluted with ethylacetate, filtered and concentrated. The residue is chromatographed on silica gel to give 0.45 g of 2-cyano-8-(4-(quinolin-2-ylmethoxy)phenoxymethyl)-4-oxo-4H-1-benzopyran.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:9]=[C:8](Cl)[CH:7]=[C:6]([Cl:11])[N:5]=1.[C:12]([O:16][C@@H:17]([C@H:19]1[CH2:23][O:22][C:21](=[O:24])[NH:20]1)[CH3:18])([CH3:15])([CH3:14])[CH3:13].CCOC(C)=O.CCCCCCC>CN(C=O)C.CCOC(C)=O>[C:12]([O:16][C@@H:17]([C@H:19]1[CH2:23][O:22][C:21](=[O:24])[N:20]1[C:8]1[CH:7]=[C:6]([Cl:11])[N:5]=[C:4]([Cl:3])[N:9]=1)[CH3:18])([CH3:13])([CH3:14])[CH3:15]
Reactant: C[C@@H](OC(C)(C)C)[C@H]1COC(=O)N1
Reactant: Clc1cc(Cl)nc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: C[C@@H](OC(C)(C)C)[C@H]1COC(=O)N1c1cc(Cl)nc(Cl)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 65.3 %

Procedure:
To a round bottom flask was added NaH (0.54 g, 13.5 mmol, 57% dispersion in mineral oil) to a solution of 2,4,6-trichloropyrimidine (1.22 ml, 10.6 mmol) and (R)-4-((R)-1-(tert-butoxy)ethyl)oxazolidin-2-one (1.8 g, 9.61 mmol) in DMF (32 mL) at 0° C. (ice bath) under a bubbler. The yellow suspension was then stirred at 0° C. for 15 min and then the ice bath was removed and reaction mixture allowed to stir 1 hr at room temperature. Reaction mixture was diluted with EtOAc and then carefully quenched with brine. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 0 to 100%) provided (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2,6-dichloropyrimidin-4-yl)oxazolidin-2-one (2.1 g, 6.28 mmol, 65% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.04 (d, J=6.55 Hz, 3H) 1.26 (s, 9H) 4.38-4.48 (m, 2H) 4.64-4.75 (m, 2H) 8.22 (s, 1H). LCMS m/z 334.1 (M+H)+, Rt 1.10 min.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:7]2[C:12]([N:13]=[C:14]3[C:19]=1[CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4].[CH2:20]([O:22][C:23](=[O:27])[C@H:24]([CH3:26])[NH2:25])[CH3:21].C(Cl)(Cl)Cl>O>[CH2:20]([O:22][C:23](=[O:27])[C@H:24]([CH3:26])[NH:25][CH2:2][C:3]([NH:5][C:6]1[C:7]2[C:12]([N:13]=[C:14]3[C:19]=1[CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4])[CH3:21]
Reactant: CCOC(=O)[C@H](C)N
Reactant: O=C(CCl)Nc1c2c(nc3ccccc13)CCCC2
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)[C@H](C)NCC(=O)Nc1c2c(nc3ccccc13)CCCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
To 5 g of 9-chloroacetylamino-1,2,3,4-tetrahydroacridine, was added 22 g of L-alanine ethyl ester and the reaction was continued for 30 minutes at 100° C. After cooled to room temperature, the reaction mixture was added with 100 ml of chloroform and 100 ml of water and stirred. The chloroform layer was dried over anhydrous sodium sulfate and purified by silica gel column chromatography (chloroform-methanol), followed by recrystallization from chloroform-n-hexane to obtain 5.9 g of the titled compound having the melting point of 101° to 102° C.
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.Cl.[NH2:24][CH:25]1[CH2:30][NH:29][C:28](=[O:31])[CH2:27][CH2:26]1.CCN(C(C)C)C(C)C>>[CH3:22][C:3]1[C:2]([NH:24][CH:25]2[CH2:26][CH2:27][C:28](=[O:31])[NH:29][CH2:30]2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]2[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=2)[N:4]=1
Reactant: NC1CCC(=O)NC1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC1CCC(=O)NC1
Temperature: 100 °C
Yield: 33 %

Procedure:
Prepared similarly to that described in Example 131 using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 48 mg, 0.162 mmol), rac-5-aminopiperidin-2-one hydrochloride (48.8 mg, 0.324 mmol, Advanced ChemBlocks, Inc., Burlingame, Calif.), and DIPEA (141 μl, 0.810 mmol), heating at 100° C. for 1.5 h. Purification by silica gel (100% DCM to 20% MeOH/DCM) provided rac-2-(2-methyl-3-((6-oxopiperidin-3-yl)amino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (33% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.93-2.07 (m, 1H) 2.14-2.23 (m, 1H) 2.31-2.41 (m, 1H) 2.58 (s, 3H) 2.83-2.90 (m, 2H) 3.23-3.29 (m, 1H) 3.44 (td, J=6.85, 2.15 Hz, 2H) 3.51-3.59 (m, 1H) 4.39-4.51 (m, 1H) 6.94 (br. s., 1H) 7.00 (d, J=6.65 Hz, 1H) 7.13 (s, 1H) 7.37 (t, J=7.82 Hz, 1H) 7.50 (d, J=2.15 Hz, 1H) 7.61 (d, J=7.04 Hz, 1H) 7.89 (d, J=7.63 Hz, 1H) 11.90 (br. s., 1H). MS (ESI, pos. ion) m/z: 391.3 (M+1).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C:19]2([CH2:21][CH2:20]2)[C@H:18]2[C@@H:11]([O:12][Si:13]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[O:14][Si:15]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[O:16][CH2:17]2)[C@H:10]1O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(S(F)(F)[F:41])CC)C>C(Cl)Cl>[CH2:1]([O:8][C@H:9]1[C:19]2([CH2:21][CH2:20]2)[C@H:18]2[C@@H:11]([O:12][Si:13]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[O:14][Si:15]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[O:16][CH2:17]2)[C@@H:10]1[F:41])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)[Si]1(C(C)C)OC[C@@H]2[C@@H](O[Si](C(C)C)(C(C)C)O1)[C@@H](O)[C@@H](OCc1ccccc1)C21CC1
Solvent: ClCCl
Product: CC(C)[Si]1(C(C)C)OC[C@@H]2[C@@H](O[Si](C(C)C)(C(C)C)O1)[C@H](F)[C@@H](OCc1ccccc1)C21CC1
Yield: 45.9 %

Procedure:
To a solution of alcohol 25 (5.1 g, 10.7 mmol) in anhydrous CH2Cl2, (diethylamino) sulfur trifluoride (DAST) (9.3 ml, 70.5 mmol) was added slowly at room temperature. The reaction mixture was quenched with iced H2O after 20 min. The organic layer was collected and the aqueous phase was extracted with dichloromethane. The organic layer was then combined, dried over Na2SO4 and the volatiles removed under reduced pressure. The crude residue was purified by flash silica gel column chromatography (1% EtOAc/Hexane) to give 26 (2.5 g, 49%). [α]24D −98.08° (c 0.51, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.39-7.26 (m, 5H), 4.92 (ddd, J=6.0, 7.5 & 5.5 Hz, 1H), 4.78 (d, J=11.5 Hz, 1H), 4.65 (d, J=11.5 Hz, 1H), 4.31-4.26 (m, 1H), 4.23-4.16 (m, 1H), 4.01-3.92 (m, 2H), 2.70 (m, 1H) 1.08-0.94 (m, 28H), 0.72 (m, 1H), 0.68-0.43 (m, 2H), 0.28 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 142.6 (d, J=9.2 Hz), 141.8, 137.9, 128.4, 112.7, 103.4 (d, J=189.0 Hz), 80.4 (d, J=21.3 Hz), 73.8 (d, J=19.8 Hz), 71.3, 61.6, 48.8 (d, J=5.3 Hz), 29.4, 24.5, 17.5, 17.4, 17.3, 17.2, 17.1, 17.0, 16.9, 16.8, 13.4, 13.3, 12.7, 12.5, 7.9; HR-MS Calcd. For (C27H45FO4Si2+H)+ 509.2840. found 509.2923.
Reaction SMILES: ClC1C(Cl)=C(C=O)C=CC=1OCCCC(O)=O.[N+](CCC)([O-])=O.[Cl:24][C:25]1[C:38]([Cl:39])=[C:37]([CH:40]=O)[CH:36]=[CH:35][C:26]=1[O:27][C:28]1([C:32]([OH:34])=[O:33])[CH2:31][CH2:30][CH2:29]1.[N+:42]([CH2:45][CH2:46][CH2:47][CH3:48])([O-:44])=[O:43]>>[Cl:24][C:25]1[C:38]([Cl:39])=[C:37](/[CH:40]=[C:45](/[N+:42]([O-:44])=[O:43])\[CH2:46][CH2:47][CH3:48])[CH:36]=[CH:35][C:26]=1[O:27][C:28]1([C:32]([OH:34])=[O:33])[CH2:29][CH2:30][CH2:31]1
Reactant: CCCC[N+](=O)[O-]
Reactant: O=Cc1ccc(OC2(C(=O)O)CCC2)c(Cl)c1Cl
Agent: O=Cc1ccc(OCCCC(=O)O)c(Cl)c1Cl
Solvent: CCC[N+](=O)[O-]
Product: CCC/C(=C\c1ccc(OC2(C(=O)O)CCC2)c(Cl)c1Cl)[N+](=O)[O-]

Procedure:
By following substantially the same procedure described in Example 1, Step B except that the 4-(2,3-dichloro-4-formylphenoxy)butyric acid and 1-nitropropane are replaced by equimolar quantities of 1-(2,3-dichloro-4-formylphenoxy)cyclobutane-1-carboxylic acid (See Example 6, Step A) and 1-nitrobutane and there is obtained (E)-1-[2,3-dichloro-4-(2-nitro-l-pentenyl)phenoxy]cyclobutane-1-carboxylic acid
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:30]=[CH:31][C:32]=3[CH3:33])[C:22]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:37].[CH3:38][C:39]([NH:42][CH2:43][CH2:44][CH2:45][NH2:46])([CH3:41])[CH3:40]>>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:46][CH2:45][CH2:44][CH2:43][NH:42][C:39]([CH3:41])([CH3:40])[CH3:38])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:30]=[CH:31][C:32]=3[CH3:33])[C:22]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:37]
Reactant: Cc1ccc(C(=O)Nc2nccs2)cc1-c1nc(S(C)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: CC(C)(C)NCCCN
Product: Cc1ccc(C(=O)Nc2nccs2)cc1-c1nc(NCCCNC(C)(C)C)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
The title compound was prepared from 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methyl-N-1,3-thiazol-2-ylbenzamide and N-(1,1-dimethylethyl)-1,3-propanediamine by following the procedures in Example 79c. LC-MS m/z 604 (M+H)+; 1H-NMR (MeOD) 1.09 (m, 9 H), 1.70 (m, 2 H), 2.33 (m, 3 H), 2.47 (m, 1 H), 2.66 (m, 1 H), 3.13 (m, 1 H), 3.47 (m, 1 H), 6.36 (d, J=8.8 Hz, 1 H), 7.10 (m, 1 H), 7.23 (m, 2 H), 7.47 (m, 2 H), 7.58 (m, 2 H), 8.04 (m, 1 H), 8.13 (d, J=7.6 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:23])[C:9]2[CH:22]=[CH:21][C:12]3[N:13]([CH3:20])[C:14]([NH:16][CH:17]([CH3:19])[CH3:18])=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH2:24][C:25]1[CH:26]=[C:27]([S:31]([NH2:34])(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1>>[ClH:1].[CH:17]([NH:16][C:14]1[N:13]([CH3:20])[C:12]2[CH:21]=[CH:22][C:9]([N:8]([CH3:23])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:24][C:25]4[CH:26]=[C:27]([S:31]([NH2:34])(=[O:32])=[O:33])[CH:28]=[CH:29][CH:30]=4)[N:7]=3)=[CH:10][C:11]=2[N:15]=1)([CH3:19])[CH3:18]
Reactant: CC(C)Nc1nc2cc(N(C)c3ccnc(Cl)n3)ccc2n1C
Reactant: Nc1cccc(S(N)(=O)=O)c1
Product: CC(C)Nc1nc2cc(N(C)c3ccnc(Nc4cccc(S(N)(=O)=O)c4)n3)ccc2n1C
Product: Cl

Procedure:
The title compound was prepared following the procedure of example 1 with N5-(2-chloropyrimidin-4-yl)-N2-isopropyl-N5,1-dimethyl-1H-benzimidazole-2,5-diamine (83 mg, 0.25 mmol) and 3-amino-benzenesulfonamide (43 mg, 0.25 mmol) as a white solid (59 mg, 47%). 1H NMR (300 MHz, d6-DMSO) δ 11.03 (s, 1H), 8.94 (d, J=8.1 Hz, 1H), 8.35 (s, 1H), 7.97 (d, J=7.2 Hz, 1H), 7.71 (d, J=7.2 Hz, 1H), 7.66 (d, J=8.4 Hz, 1H), 7.48-7.57 (m, 3H), 7.40 (s, 1H), 7.33 (dd, J=8.4 and 1.5 Hz, 1H), 5.90 (s, 1H), 4.12 (m, 1H), 3.70 (s, 3H), 3.54 (s, 3H), 1.33 (d, J=6.3 Hz, 6H) ppm. MS (ESI) m/z=467 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][CH2:9][C:10]1[N:21](S(C2C=CC=CC=2)(=O)=O)[C:13]2=[N:14][CH:15]=[C:16]([N+:18]([O-:20])=[O:19])[CH:17]=[C:12]2[CH:11]=1.C(OCC)(=O)C>CO.O>[CH3:7][O:8][CH2:9][C:10]1[NH:21][C:13]2=[N:14][CH:15]=[C:16]([N+:18]([O-:20])=[O:19])[CH:17]=[C:12]2[CH:11]=1
Reactant: COCc1cc2cc([N+](=O)[O-])cnc2n1S(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: COCc1cc2cc([N+](=O)[O-])cnc2[nH]1
Temperature: 60 °C
Yield: 106.6 %

Procedure:
Potassium carbonate (0.306 g, 2.22 mmol) was added to a solution of 2-(methoxymethyl)-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.11 g, 0.317 mmol) in methanol (3.3 mL) and water (0.9 mL). The reaction mixture was heated at 60° C. for 90 minutes. The reaction mixture was then cooled down. The mixture was treated with water and ethyl acetate, and the layers were separated. The organic layers were washed twice with water, dried over sodium sulfate, filtered, and evaporated to afford 2-(methoxymethyl)-5-nitro-1H-pyrrolo[2,3-b]pyridine (70 mg, quantitative yield).