Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:18][CH2:17][S:16](=[O:20])(=[O:19])[CH2:15]1.[O:21]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:19]=[S:16]1(=[O:20])[CH2:17][CH2:18][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:23]4[CH:24]=[CH:25][O:21][CH:22]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:15]1
Reactant: OB(O)c1ccoc1
Reactant: NC(=O)c1cc(Br)cc2c(C3CCS(=O)(=O)C3)c[nH]c12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)c1cc(-c2ccoc2)cc2c(C3CCS(=O)(=O)C3)c[nH]c12
Temperature: 100 °C
Yield: 35.3 %

Procedure:
5-bromo-3-(1,1-dioxidotetrahydro-3-thienyl)-1H-indole-7-carboxamide (0.050 g, 0.140 mmol) and 3-furanylboronic acid (0.020 g, 0.182 mmol) was dissolved in a 6:1 solution of 1,4 dioxane/water in a 20 mL microwave reaction vessel. Potassium carbonate (0.097 g, 0.70 mmol) was added and the solution was degassed with Argon. PdCl2(dppf) (0.017 g, 0.024 mmol) was added and the reaction was heated in a microwave at 100° C. for 10 min. The solution was passed through a StratoSphere SPE PL-Thiol MP SPE column to remove palladium and purified on Gilson preparative HPLC using Acetonitrile/0.1% NH4OH/H20. The desired fractions were concentrated, giving 0.017 g (36%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:30][OH:31])[CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([N:21]([CH3:29])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClS([N:36]=[C:37]=[O:38])(=O)=O.O>C(Cl)Cl>[C:37]([O:31][CH2:30][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([N:21]([CH3:29])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)(=[O:38])[NH2:36]
Reactant: CN(C(=O)OC(C)(C)C)c1ccc2onc(OCC(CO)NC(=O)OC(C)(C)C)c2c1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CN(C(=O)OC(C)(C)C)c1ccc2onc(OCC(COC(N)=O)NC(=O)OC(C)(C)C)c2c1

Procedure:
To a solution of 0.11 g of 3-(2-tert-butoxycarbonylamino-3-hydroxypropoxy)-5-(N-methyl-N-tert-butoxycarbonylamino)-1,2-benzoisoxazole in 5 ml of methylene chloride is added 0.10 g of chlorosulfonyl isocyanate at -45° to -40° C., and the temperature is elevated to 0° C., after which they are subjected to reaction at the same temperature for one hour. To the reaction mixture is added 10 ml of water and they are subjected to reaction at 20°-25° C. for one hour, after which the organic layer is separated. The separated organic layer is dried over anhydrous magnesium sulfate and the solvent is then removed by distillation under reduced pressure, to obtain 0.10 g of yellow, oily 3-(3-carbamoyloxy-2-tert-butoxycarbonylaminopropoxy)-5-(N-methyl-N-tert-butoxycarbonylamino)-1,2-benzoisoxazole.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([N:22]4[CH2:27][CH2:26][CH2:25][CH:24]([C:28]([O:30]CC)=[O:29])[CH2:23]4)=[O:21])=[C:14]([Cl:33])[C:13]=3[Cl:34])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[OH-].[K+].[OH-].[Na+]>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([N:22]4[CH2:27][CH2:26][CH2:25][CH:24]([C:28]([OH:30])=[O:29])[CH2:23]4)=[O:21])=[C:14]([Cl:33])[C:13]=3[Cl:34])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C1CCCN(C(=O)/C=C/c2ccc(Sc3ccc4c(c3)OCCO4)c(Cl)c2Cl)C1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C1CCCN(C(=O)/C=C/c2ccc(Sc3ccc4c(c3)OCCO4)c(Cl)c2Cl)C1

Procedure:
The title compound was prepared by the procedures described in Example 155, substituting the ethyl ester from Example 137 with the ethyl ester from Example 327, and KOH with NaOH, providing a white solid. 1H NMR (CDCl3, 300 MHz) δ 1.70-2.0 (m, 2H), 2.0-2.20 (m, 1H), 2.54-2.68 (m, 1H), 3.03-3.46 (m, 2H), 3.80-4.11 (m, 2H), 4.27-4.40 (m, 4H), 4.50-4.70 (m, 1H), 6.60 (d, J=8.9 Hz, 1H), 6.79 (d, J=15.3 Hz, 1H), 6.94 (d, J=8.5 Hz, 1H), 7.03 (dd, J=2.1, 8.5 Hz, 1H), 7.08 (d, J=2.1 Hz, 1H), 7.30 (d, J=8.9 Hz, 1H), 7.93 (d, J=15.3 Hz, 1H). MS (ESI+) (M−2H)− at m/z 492, 494, 496. Anal. Calcd for C23H21Cl2NO5S.0.73H2O: C, 54.43; H, 4.46; N, 2.76. Found: C, 54.43; H, 4.39; N, 2.49.
Reaction SMILES: Br[C:2]1[C:6]2=[N:7][C:8]([N:13]([CH2:16][CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:14][CH3:15])=[C:9]([C:11]#[N:12])[CH:10]=[C:5]2[N:4]([CH3:22])[CH:3]=1.[CH3:23][Mg]Br.O>C1COCC1>[CH:17]1([CH2:16][N:13]([C:8]2[N:7]=[C:6]3[C:2]([CH3:23])=[CH:3][N:4]([CH3:22])[C:5]3=[CH:10][C:9]=2[C:11]#[N:12])[CH2:14][CH3:15])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: C[Mg]Br
Reactant: CCN(CC1CCCC1)c1nc2c(Br)cn(C)c2cc1C#N
Solvent: O
Solvent: C1CCOC1
Product: CCN(CC1CCCC1)c1nc2c(C)cn(C)c2cc1C#N
Temperature: 75 °C
Reaction time: 22 h

Procedure:
A mixture of 3-bromo-5-[N-(cyclopentylmethyl)-N-ethylamino]-1-methyl-1H-pyrrolo[3,2-b]pyridine-6-carbonitrile (1.05 g, 2.91 mmol) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (II) dichloromethane complex (PdCl2(dppf)-CH2Cl2, 0.24 g, 0.29 mmol) in THF (20 mL) is treated with methylmagnesium bromide (0.93 M in THF, 7.8 mL) at 0° C. The reaction mixture is stirred at 75° C. for 22 hours. After cooling to room temperature, H2O is added, and the reaction mixture is extracted with EtOAc. The organic layer is washed with sat. NaHCO3 and brine, dried over sodium sulfate and concentrated. The residue is purified by silica-gel column chromatography to give 5-[N-(cyclopentylmethyl)-N-ethylamino]-1,3-dimethyl-1H-pyrrolo[3,2-b]pyridine-6-carbonitrile as a colorless oil.
Reaction SMILES: C([NH:7][C:8]1[C:13]([CH:14]=[O:15])=[CH:12][CH:11]=[CH:10][N:9]=1)(=O)C(C)(C)C.C([O-])([O-])=O.[K+].[K+]>Cl>[NH2:7][C:8]1[C:13]([CH:14]=[O:15])=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: CC(C)(C)C(=O)Nc1ncccc1C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Nc1ncccc1C=O
Temperature: 25 °C
Yield: 96.5 %

Procedure:
Crude 2-(pivaloylamino)-3-pyridinecarboxaldehyde (from step b, 43 g) was dissolved in 3 M HCl (500 mL), and the solution was heated to reflux. After 18 hr the mixture was cooled to RT, and the pH was carefully adjusted to 7 using solid K2CO3. The aqueous solution was extracted with EtOAc (3×500 mL). The combined organic layers were dried (MgSO4)and concentrated to give the title compound (24.57 g, 101%) as a reddish brown solid: 1H NMR (300 MHz, CDCl3) δ 9.85 (s, 1H), 8.24 (m. 1 H), 7.80 (m, 1H), 6.90 (br s, 2H), 6.74 (m, 2H); MS (ES) m/e 123 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)O)=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]([O:22][Si](C)(C)C)=[C:19]([CH3:21])[CH3:20].C([O-])([O-])=O.[K+].[K+]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:16][O:17][C:18](=[O:22])[C:19]([CH3:21])([CH3:20])[CH:7]([C:5]1[S:6][C:2]([Br:1])=[CH:3][CH:4]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1
Reactant: COC(O[Si](C)(C)C)=C(C)C
Reactant: OC(c1cccc(F)c1)c1ccc(Br)s1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)C(C)(C)C(c1cccc(F)c1)c1ccc(Br)s1
Temperature: 0 °C
Reaction time: 3 h
Yield: 87.5 %

Procedure:
To a solution of (5-bromo-thiophen-2-yl)-(3-fluoro-phenyl)-methanol (3.40 mmol) and (1-methoxy-2-methyl-propenyloxy)-trimethyl-silane (3.45 ml, 17 mmol) in dichloromethane (10 ml) at 0° C. was added a solution of titanium tetrachloride in dichloromethane (1M solution, 7.4 ml, 7.4 mmol) slowly. After being stirred at 0° C. for 10 minutes and room temperature for 3 hours, the reaction mixture was poured onto an iced aqueous K2CO3. The solution was extracted with dichloromethane. The organic layer was washed, dried (MgSO4) and concentrated to give 3-(5-bromo-thiophen-2-yl)-3-(3-fluoro-phenyl)-2,2-dimethyl-propionic acid methyl ester as a viscous yellow oil (1.104 g, 87.5% yield). LC/MS (m/z) 393.13 [(M+23)+]; HPLC Rt: 3.883 min.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=1)[CH2:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1.CO.[Cl-].[NH4+]>O1CCCC1.O>[F:7][C:8]1[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=1)[CH2:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1
Reactant: N#Cc1ccc(OCc2cccc(F)c2)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: NCc1ccc(OCc2cccc(F)c2)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 935.1 %

Procedure:
Next, to a solution of lithium aluminum hydride (1.25 g, 133.0 mmol) in tetrahydrofuran (15 mL) was added a solution of 4-(3-fluorobenzyloxy)-benzonitrile (218 mg, 0.615 mmol) in tetrahydrofuran (12 mL) on an ice bath, and the solution was stirred at room temperature for 19 hours. A mixture solvent of methanol and water (9:1) was added to the reaction solution, an aqueous solution of saturated ammonium chloride was further added, and the solution was stirred on an ice bath for 30 minutes. This solution was filtered through Celite pad, and insoluble matter was removed. The filtrate was partitioned, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated, and the title compound (1.33 g, 44%) was obtained as a yellow solid. This was used in the next reaction without further purification.
Reaction SMILES: C[O-].[Na+].Cl.[NH2:5][C:6]([NH2:8])=[NH:7].O1CCCC1.Cl.[Cl:15][C:16]([C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]([C:27]2[C:36]3[C:31](=[C:32]([C:37]([F:40])([F:39])[F:38])[CH:33]=[CH:34][CH:35]=3)[N:30]=[CH:29][CH:28]=2)[CH:19]=1)=[O:17]>CO.ClCCl>[ClH:15].[NH:7]([C:16]([C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]([C:27]2[C:36]3[C:31](=[C:32]([C:37]([F:39])([F:38])[F:40])[CH:33]=[CH:34][CH:35]=3)[N:30]=[CH:29][CH:28]=2)[CH:19]=1)=[O:17])[C:6]([NH2:8])=[NH:5]
Reactant: O=C(Cl)c1cn(-c2ccnc3c(C(F)(F)F)cccc23)c2ccccc12
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: N=C(N)NC(=O)c1cn(-c2ccnc3c(C(F)(F)F)cccc23)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
20 cm3 of methanol and 14 cm3 (7 mmol) of a 0.5M solution of sodium methoxide in methanol are added to 0.67 g (7 mmol) of guanidine hydrochloride under an argon atmosphere. After stirring at a temperature in the region of 25° C. for 1 hour, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) and the residue is three times successively dissolved in 20 cm3 of dichloromethane and evaporated to dryness under reduced pressure (2.7 kPa). 30 cm3 of tetrahydrofuran and 0.525 g (1.4 mmol) of 3-chlorocarbonyl-1-(8-(trifluoromethyl)quinol-4-yl)-1H-indole hydrochloride, suspended in 30 cm3 of dichloromethane, are subsequently added thereto under an argon atmosphere. After stirring at a temperature in the region of 20° C. for 16 hours, the reaction mixture is concentrated to give a solid which is purified by flash chromatography [eluent: ethyl acetate/methanol (9/1 and then 8/2 by volume)]. After concentrating the fractions to dryness under reduced pressure (2.7 kPa), the product obtained is triturated in 20 cm3 of diisopropyl ether and filtered off, resulting in 0.14 g of 3-guanidinocarbonyl-1-(8-(trifluoromethyl)quinol-4-yl)-1H-indole hydrochloride in the form of a white powder melting at 212° C. Mass spectrum (EI): m/e 397 (M+•), m/e 339 (base peak).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][N:21]=[CH:20]4)[N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].Br[CH2:27][C:28]([CH3:35])([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[N:22]([CH2:27][C:28]([CH3:35])([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:21]=[CH:20]4)[N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)Oc1ncc(-c2nc(-c3ccc4[nH]ncc4c3)no2)cc1Cl
Reactant: CCOC(=O)C(C)(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Cn1ncc2cc(-c3noc(-c4cnc(OC(C)C)c(Cl)c4)n3)ccc21
Temperature: 80 °C
Reaction time: 48 h
Yield: 22 %

Procedure:
A mixture of 5-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indazole (D110) (335 mg, 0.94 mmol), ethyl 3-bromo-2,2-dimethylpropanoate (D98) (197 mg, 0.94 mmol) and K2CO3 (130 mg, 0.94 mmol) in DMF (5 ml) was stirred at 80° C. for 48 hours. The reaction mixture was then cooled to room temperature and partitioned between EtOAc and water (30 ml). The organic phase was separated, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel [20% ethyl acetate/cyclohexane] gave the title compound (100 mg, 22%) as a colourless solid. MS (ES) C24H26ClN5O4 requires 483, found 484 [M+H]+
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:36])[CH2:7][CH:8]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)[O:23][C:24]=2[CH3:25])=[CH:14][CH:13]=1)[C:9]#[C:10][CH3:11])C.Cl>C(O)C.O>[CH3:25][C:24]1[O:23][C:22]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:34])([F:33])[F:35])=[CH:28][CH:27]=2)=[N:21][C:20]=1[CH2:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([CH:8]([C:9]#[C:10][CH3:11])[CH2:7][C:6]([OH:36])=[O:5])=[CH:17][CH:16]=1
Reactant: CC#CC(CC(=O)OCC)c1ccc(OCc2nc(-c3ccc(C(F)(F)F)cc3)oc2C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC#CC(CC(=O)O)c1ccc(OCc2nc(-c3ccc(C(F)(F)F)cc3)oc2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
2N KOH(aq) was added to a solution of 18.3 (304 mg, 0.65 mmol) in ethanol (5 mL). The reaction was stirred at room temperature overnight and then taken up in copious water. The aqueous solution was adjusted to pH=2.0 with 1N HCl(aq) and extracted with ethyl acetate (2×25 mL). The combined organic layers were washed with water, followed by brine. The solvent was removed under reduced pressure and the resulting residue was purified via radial chromatography (40% ethyl acetate in Hexanes+0.1% AcOH) to yield 150 mg (52%) of compound 18 as a glass. LC/MSD m/e: 444.0 (M+H); 1H NMR (400 MHz) (acetone) ∂ 8.21 (2H, m), 7.89 (2H, d, J=8.0 Hz), 7.38 (2H, m), 7.03 (2H, m), 5.06 (2H, s), 4.06 (1H, m), 2.70 (2H, m), 2.52 (3H, s), 1.81 (3H, s).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[C:20]([S:21](=[O:28])(=[O:27])[NH:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+]>>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[C:20]([S:21](=[O:28])(=[O:27])[NH:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:7][CH:6]=1
Reactant: CCCCNc1cc(C(=O)O)cc(S(=O)(=O)NCCCC)c1Sc1ccc(NC(C)=O)cc1
Agent: [Na+]
Agent: [OH-]
Product: CCCCNc1cc(C(=O)O)cc(S(=O)(=O)NCCCC)c1Sc1ccc(N)cc1
Temperature: 25 °C

Procedure:
The mixture of 5.1 g of 4-(4-acetamidophenylmercapto)-3-n-butylamino-5-n-butylsulfamoyl benzoic acid and 75 ml of 2N aqueous sodium hydroxide is refluxed for 2 hours under nitrogen and filtered after cooling to room temperature. The filtrate is acidified with glacial acetic acid to pH=4, the precipitate filtered off and recrystallized several times from aqueous ethanol. It is dissolved in the minimum amount of 2N aqueous sodium hydroxide, chromatographed on silica gel and the column eluted with ethyl acetate-methanol-saturated aqueous amonia (65: 25: 10), to yield the 4-(4-amino-phenylmercapto)-3-n-butylamino-5-n-butylsulfamoylbenzoic acid of the formula ##SPC17##
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([C:9]2[S:13][C:12]([NH2:14])=[N:11][C:10]=2[C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)=[O:8])[CH2:3][CH2:2]1.C(N(CC)CC)C.[Br:27][CH2:28][C:29](Br)=[O:30].O>CN(C1C=CN=CC=1)C.C1COCC1>[Br:27][CH2:28][C:29]([NH:14][C:12]1[S:13][C:9]([C:7]([CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[O:8])=[C:10]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[N:11]=1)=[O:30]
Reactant: Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1
Reactant: O=C(Br)CBr
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: O=C(CBr)Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.6 %

Procedure:
Compound 454 (1.39 g, 5.00 mmol), triethylamine (3.06 mL, 22.0 mmol) and DMAP (61.0 mg, 0.500 mmol) were suspended in THF (30 mL), and bromoacetyl bromide (1.64 mL, 20.0 mmol) was added dropwise thereto at 0° C., followed by stirring at room temperature for 2 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (chloroform:methanol=99:1), followed by reslurrying with diethyl ether to afford the entitled Compound 531 (1.59 g, 80%) as a pale brown solid.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][C:16]3=[O:21])=[CH:11][CH:10]=2)[CH2:4]1.[CH:22](O)=[O:23]>O>[O:8]=[C:6]1[N:5]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][C:16]3=[O:21])=[CH:11][CH:10]=2)[CH2:4][C@H:3]([CH2:2][NH:1][CH:22]=[O:23])[O:7]1
Reactant: O=CO
Reactant: NC[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1
Solvent: O
Product: O=CNC[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1
Temperature: 115 °C

Procedure:
In a four neck round bottom flask charged 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one free base (50 g) toluene (350 ml) and formic acid (21.63 g). Reaction mass then heated azeotropically to 110-120° C. employing dean-stark apparatus for 3 to 4 h. (water removed azeotropically) Reaction mass is cooled to 25 to 30° C. Obtained solid is filtered off and washed by toluene.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([NH2:13])=[CH:8][N:7]=1.C(Cl)Cl.[CH3:17][CH2:18][OH:19]>>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([NH:13][C:18](=[O:19])[CH3:17])=[CH:8][N:7]=1
Reactant: Cc1cc(C2OCCO2)ncc1N
Reactant: CCO
Solvent: ClCCl
Product: CC(=O)Nc1cnc(C2OCCO2)cc1C

Procedure:
2-(1,3-Dioxolanyl)-4-methyl-5-acetylaminopyridine was prepared from 2-(1,3-dioxolanyl)-4-methyl-5-aminopyridine by the procedure employed for the synthesis of Example XIV. Yield: 0.5 g (82%); mp 98°-99° C.; TLC, Rf 0.65 (CH2Cl2 /EtOH, 10:1, v/v); 1H NMR (90 MHz, CDCl3) δ 2.08 (s, 3H, COCH3), 2.15 (s, 3H, 4-CH3), 4.05 (m, 4H, CH2CH2), 5.72 (s, 1H, 2-CH), 7.30 (s, 1H, 3-H), 8.05 (br s, 1H, NH, D2O exchangeable), 8.58 (s, 1H, 6-H). Anal. (C11H14N2O3) C, H, N.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7]([CH3:28])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[NH:20][C:19]3[CH:21]([CH2:25][CH2:26]O)[NH:22][C:23](=[O:24])[C:18]=3[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2].CS(Cl)(=O)=O.[N-:34]=[N+:35]=[N-:36].[Na+]>C(Cl)Cl.CCOC(C)=O>[N:34]([CH2:26][CH2:25][CH:21]1[C:19]2[NH:20][C:16]([C:13]3[CH:12]=[CH:11][CH:10]=[C:9]4[C:14]=3[N:15]=[C:6]([NH:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:7]([CH3:28])=[N:8]4)=[CH:17][C:18]=2[C:23](=[O:24])[NH:22]1)=[N+:35]=[N-:36]
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)C(CCO)NC4=O)c2nc1NC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1nc2cccc(-c3cc4c([nH]3)C(CCN=[N+]=[N-])NC4=O)c2nc1NC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.5 %

Procedure:
To a suspension of 2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-6-(2-hydroxyethyl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (462) (149 mg, 0.39 mmol) in 5 mL of DCM at 0° C. was added TEA (0.27 mL, 1.96 mmol) followed by methanesulfonyl chloride (33.4 μL, 0.43 mmol). It was stirred at 0° C. for 30 min, diluted with 30 mL of DCM, washed sequentially with 5 mL of water, 5 mL of sat NaHCO3 and 5 mL of brine. The DCM solution was dried over Na2SO4 and concentrated. The brown residue was dissolved in 1 mL of DMF and treated with sodium azide (80 mg, 1.24 mmol). The mixture was heated in an oil bath at 70° C. for 45 min. It was diluted with EtOAc (50 mL) and filtered. The filtrate was washed with 2×5 mL of water. The EtOAc solution was concentrated and purified on a silica gel column (2-8% MeOH in DCM) to give 6-(2-azidoethyl)-2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (463a, 97 mg, 0.24 mmol, 61% yield). m/z (ESI, +ve) 405 (M+H)+. To a solution of 6-(2-azidoethyl)-2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-5,6-dihydropyrrolo[3,4-b]pyrrolo-4(1H)-one (463a, 97 mg, 0.24 mmol) in 3 mL of THF and water (43.2 μl, 2.39 mmol) at RT was added trimethylphosphine (0.36 mL of 1 M in THF, 0.36 mmol). It was stirred at RT for 30 min, then diluted with 50 mL of EtOAc, and washed with 5 mL of water. The organic layer was concentrated and the residue was purified on a silica gel column (5% MeOH in DCM followed by 5% of 2 M NH3 in MeOH in DCM) to provide 6-(2-aminoethyl)-2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (463) (68 mg, 0.18 mmol, 75% yield) as a brown amorphous solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.81 (1H, dd, J=7.4, 1.4 Hz), 7.71 (1H, s), 7.57-7.67 (1H, m), 7.35 (1H, t, J=7.7 Hz), 6.84 (1H, s), 5.99 (1H, s), 4.57 (1H, dd, J=8.4, 4.1 Hz), 3.41 (3H, br.), 2.64-2.77 (2H, m), 2.56 (3H, s), 1.92 (1H, dd, J=13.3, 4.3 Hz), 1.57-1.65 (1H, m), 1.55 (9H, s). m/z 379.1 (ESI, +ve) (M+H)+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[C:21]([NH:23][C:24](=O)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][N:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=4)[CH2:32][CH2:31]3)[CH:22]=1)[N:19]=[CH:18][CH:17]=[C:16]2[CH3:43].[OH-].[Na+]>O1CCCC1.O>[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][N:30]3[CH2:31][CH2:32][N:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=4)[CH2:34][CH2:35]3)[CH:22]=1)[N:19]=[CH:18][CH:17]=[C:16]2[CH3:43]
Reactant: COc1cc(NC(=O)CCCCCN2CCN(c3ccccn3)CC2)c2nccc(C)c2c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(NCCCCCCN2CCN(c3ccccn3)CC2)c2nccc(C)c2c1
Yield: 66.3 %

Procedure:
A cold (-40°) slurry of 1.7 g (0.0127 mole) of anhydrous aluminum chloride in 50 ml of tetrahydrofuran was added to an equally cold suspension of 1.35 g (0.0355 mole) of lithium aluminum hydride in 30 ml of tetrahydrofuran. The mixture was stirred and allowed to warm to -10°. A solution of 3.3 g (0.0073 mole) of N-(6-methoxy-4-methyl-8-quinolinyl)-6-[4-(2-pyridinyl)-1-piperazinyl]hexanamide, 0.2 hydrate in 100 ml of tetrahydrofuran was added to the mixture dropwise, with stirring. The mixture was stirred for 3 hr, treated with 6.5 ml of 30% sodium hydroxide solution and with enough water to clarify the supernatant, and filtered through Supercel. The filtrate was concentrated in vacuo to remove most of the tetrahydrofuran, diluted with dichloromethane, washed with water, dried and concentrated to dryness. Recrystallization of the residue from 2-propanol afforded 2.1 g (66%) of the title compound, mp 78°-81° .