Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][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:5].F[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23].C(=O)(O)[O-].[Na+].O>CN(C=O)C>[C:11]([O:10][C:8]([NH:7][C@@H:3]([CH2:2][NH:1][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23])[C:4]([OH:6])=[O:5])=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CC(C)(C)OC(=O)N[C@@H](CN)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CNc1ccccc1[N+](=O)[O-])C(=O)O
Temperature: 80 °C
Yield: 62.8 %

Procedure:
To a solution of (S)-3-amino-2-tert-butoxycarbonylamino-propionic acid (Aldrich) (5 g, 24.48 mmol) in DMF (75 mL) was added 1-fluoro-2-nitro-benzene (2.92 mL, 26.93 mmol) and sodium bicarbonate (6.17 g, 73.44 mmol) at RT and the resulting mixture was heated at 80° C. for 18 h under nitrogen atmosphere. Water was added and the aqueous layer was washed with ethyl acetate. The pH of the aqueous solution was adjusted to 3 with the addition of 10% aqueous sodium bisulfate solution and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated under reduced pressure to give crude mass which was triturated with hexanes to afford (S)-2-tert-butoxycarbonylamino-3-(2-nitro-phenylamino)-propionic acid (5 g, 63%) as an orange yellow solid. LC-MS: 326.2 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[Li]CCCC.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:24]([CH:25]=[O:26])=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[S:22][N:21]=2)=[CH:16][CH:15]=1>CCOCC.C1COCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:24]([CH:25]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)[OH:26])=[C:23]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[S:22][N:21]=2)=[CH:18][CH:19]=1
Reactant: Brc1cccnc1
Reactant: O=Cc1c(-c2ccc(Cl)cc2)nsc1-c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC(c1cccnc1)c1c(-c2ccc(Cl)cc2)nsc1-c1ccccc1
Reaction time: 0.25 h
Yield: 105.5 %

Procedure:
A solution of 3-bromopyridine (103 mg) in 2.5 ml of ether is cooled to −78° C. under N2 and to this is added drop-wise a BuLi solution (0.375 ml, 1.6 M in hex). After stirring for 15 min, a solution of 15 (150 mg) in THF is added drop-wise. Stirring is continued for 20 min at −78° C., the red colored reaction mixture is quenched with water (5 ml) and the cooling bath is removed. Water (25 ml) and EtOAc (30 ml) are added. After washing, the layers are separated, the organic layer is washed with brine, dried and concentrated to afford an orange foam (200 mg). The material is purified by flash column chromatography (2% MeOH in CH2Cl2). Desired compound 16 is obtained as white foam showing the expected mass in LCMS (M+1:379 and its isotopes at 380; 381 and 382).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:24])[CH:5]=[C:6]2[C:14]=1[NH:13][C:12]1[C:11]([C:20]([F:23])([F:22])[F:21])([O:15][Si](C)(C)C)[CH2:10][CH2:9][CH2:8][C:7]2=1.[OH-].[K+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([F:24])[CH:5]=[C:6]2[C:14]=1[NH:13][C:12]1[C:11]([C:20]([F:23])([F:21])[F:22])([OH:15])[CH2:10][CH2:9][CH2:8][C:7]2=1
Reactant: C[Si](C)(C)OC1(C(F)(F)F)CCCc2c1[nH]c1c(Cl)cc(F)cc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: OC1(C(F)(F)F)CCCc2c1[nH]c1c(Cl)cc(F)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
8-Chloro-6-fluoro-1-(trifluoromethyl)-1-(trimethylsilyloxy)-2,3,4,9-tetrahydro-1H-carbazole (0.1 g, 0.26 mmol) was dissolved in THF (10 mL) and KOH (0.073 g, 1.3 mmol), in water (2 mL), was added. The reaction mixture was stirred at room temperature for 2 h, diluted with water (25 mL) and extracted with EtOAc (2×25 mL). The combined organic extracts were dried over Na2SO4, concentrated in vacuo to give the crude compound which was purified by silica gel chromatography [EtOAc-hexane (1:4) as eluant] to provide the title compound (0.02 g, 24%) (HPLC 96%). 1H NMR (500 MHz, CDCl3, δ in ppm) 8.27 (bs, 1H), 7.12-7.11 (d, J=9.0 Hz, 1H), 7.08-7.0 (d, J=8.5 Hz, 1H), 2.82-2.77 (m, 1H), 2.71-2.65 (m, 1H), 2.49 (s, 1H), 2.29-2.23 (m, 1H), 2.12-2.09 (m, 1H), 2.05-2.02 (m, 2H).
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[N:17]=[C:16]4[C:12]([N:13]=[C:14]([CH:19]=[O:20])[N:15]4[CH3:18])=[C:11]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:10]=3)[C:7]3[CH:27]=[CH:28][CH:29]=[CH:30][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[OH-:31].[Na+]>CCO.O.[N+]([O-])([O-])=O.[Ag+]>[CH:1]1([C:4]2[N:8]([C:9]3[N:17]=[C:16]4[C:12]([N:13]=[C:14]([C:19]([OH:31])=[O:20])[N:15]4[CH3:18])=[C:11]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:10]=3)[C:7]3[CH:27]=[CH:28][CH:29]=[CH:30][C:6]=3[N:5]=2)[CH2:3][CH2:2]1
Reactant: [OH-]
Reactant: Cn1c(C=O)nc2c(N3CCOCC3)nc(-n3c(C4CC4)nc4ccccc43)nc21
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cn1c(C(=O)O)nc2c(N3CCOCC3)nc(-n3c(C4CC4)nc4ccccc43)nc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.8 %

Procedure:
To a suspension of 2-(2-cyclopropylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (500 mg, 1.24 mmol) in EtOH (16 mL) was added AgNO3 (265 mg, 1.56 mmol) followed by a solution of NaOH (302 mg, 7.5 mmol) in H2O (5 mL). The resulting black suspension was allowed to stir at r.t. for 30 min then filtered through Celite® and the resulting filtrate concentrated in vacuo. The resulting residue was dissolved in H2O and basified by the addition of aq. NaOH. The aqueous phase was extracted with DCM then acidified to pH 2 with HCl. The aqueous phase was concentrated in vacuo to half volume then cooled on ice. The resulting precipitate was collected by filtration and dried in vacuo affording the title compound (280 mg, 55%). 1H NMR (DMSO, 400 MHz): δ 8.12-8.11 (1 H, m), 7.72-7.68 (1 H, m), 7.44-7.43 (2 H, m), 4.60 (4 H, brd s), 4.04 (3 H, s), 3.90-3.70 (4 H, m), 3.06-3.00 (1 H, m), 1.33-1.31 (4 H, m)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:13]3[C:14]([CH:17]=[O:18])=[CH:15][N:16]=[C:12]3[CH2:11][CH2:10]2)=[CH:5][C:4]=1[F:19])#[N:2].CC(=CC)C.Cl([O-])=[O:26].[Na+].O.P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C.O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:13]3[C:14]([C:17]([OH:26])=[O:18])=[CH:15][N:16]=[C:12]3[CH2:11][CH2:10]2)=[CH:5][C:4]=1[F:19])#[N:2]
Reactant: N#Cc1ccc(C2CCc3ncc(C=O)n32)cc1F
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: N#Cc1ccc(C2CCc3ncc(C(=O)O)n32)cc1F
Reaction time: 16 h

Procedure:
To a solution of aldehyde from Step L (990 mg, 3.88 mmol) in tert-butanol (20 mL)/2-methyl-2-butene (2 mL) was added a solution of sodium chlorite (421 mg, 4.65 mmol) and sodium dihydrogenphosphate monohydrate (642 mg, 4.65 mmol) in H2O (4 mL). The reaction mixture was stirred for 16 hours and the precipitate filtered to yield the title product as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.Cl.[NH2:12][OH:13].C(N(CC)CC)C>CO>[NH2:1][C:2]1[C:3]([C:9](=[N:12][OH:13])[NH2:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: N#Cc1nc(Br)cnc1N
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: NC(=NO)c1nc(Br)cnc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.1 %

Procedure:
A solution of 3-amino-6-bromo-pyrazine-2-carbonitrile (1 g, 5.025 mmol) in MeOH (20 mL) was cooled to 0° C. and treated with hydroxylamine hydrochloride (349.2 mg, 5.025 mmol) and triethylamine (508.5 mg, 700.4 μL, 5.025 mmol) and the reaction allowed to warm to ambient temperature. After a period of 2 hours a precipitate was observed which was filtered off. The resultant filtrate was evaporated to dryness and triturated with MeOH to furnish further product as a beige solid (771 mg, 78% Yield).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:17][CH2:16][CH2:15][C@@:14]2([CH3:18])[C@H:10]1[CH2:11][CH2:12][C@@H:13]2[C@H:19]([CH3:22])[CH2:20][OH:21])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C[N+]1([O-])CCOCC1.[CH3:31][Si:32]([CH3:50])([CH3:49])[O:33][C:34]([CH3:48])([CH3:47])[C@H:35]([CH3:46])[CH2:36]S(C1C=CC=CC=1)(=O)=O>ClCCl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Si:1]([O:8][C@H:9]1[CH2:17][CH2:16][CH2:15][C@@:14]2([CH3:18])[C@H:10]1[CH2:11][CH2:12][C@@H:13]2[C@@H:19]([CH:20]([OH:21])[CH2:36][C@@H:35]([CH3:46])[C:34]([CH3:48])([O:33][Si:32]([CH3:50])([CH3:31])[CH3:49])[CH3:47])[CH3:22])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@H](CS(=O)(=O)c1ccccc1)C(C)(C)O[Si](C)(C)C
Reactant: C[C@H](CO)[C@H]1CC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: C[C@H](C(O)C[C@@H](C)C(C)(C)O[Si](C)(C)C)[C@H]1CC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound of Example 10E (200 mg, 0.61 mmol) was dissolved in 2 mL of dichloromethane; 100 mg of 4 Å molecular sieves were added, followed by 15 mg of tetrapropylammonium perruthenate and 75 mg of 4-methylmorpholine N-oxide. The mixture was stirred for 2 hours at ambient temperature, and then filtered through diatomaceous earth to removed solids. The crude product was purified by silica gel chromatography using an Analogix IntelliFlash™ 40, eluting with a gradient of 5% to 30% ethyl acetate in hexanes. The compound of Example 10C (200 mg, 0.63 mmol) was combined with this aldehyde according to the coupling procedure described by Kutner et al. in J. Org. Chem. 1988, 53, 3450-3457. The named product, the result of desulfurization without elimination, was isolated after chromatographic purification using an Analogix Intelliflash 280™, eluting with a gradient of 0% to 50% ethyl acetate in hexanes.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH:11]1[CH2:17][CH:16]2[N:18]([CH3:19])[CH:13]([CH2:14][CH2:15]2)[CH2:12]1)=O.[ClH:20].[NH2:21][OH:22].C([O-])(=O)C.[NH4+]>C(O)C.O>[ClH:20].[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[C:9](/[CH:11]1[CH2:17][CH:16]2[N:18]([CH3:19])[CH:13]([CH2:14][CH2:15]2)[CH2:12]1)=[N:21]\[OH:22]
Reactant: CN1C2CCC1CC(C(=O)c1ccc(F)cc1F)C2
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CN1C2CCC1CC(/C(=N/O)c1ccc(F)cc1F)C2

Procedure:
A mixture of (2,4-difluorophenyl)(8-methyl-8-azabicyclo[3.2.1 ]octan-3-yl)methanone (20 g), hydroxylamine hydrochloride (10.6 g) and ammonium acetate (18.7 g) was heated in 67.5 ml of refluxing ethanol-water (3.2 mixture) for 19 hours. The mixture was concentrated to approximately half of its original volume, and the precipitated solid (21.3 g) was collected.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI>O1CCCC1>[C:1]([O:5][C:6](=[O:20])[NH:7][CH:8]1[C:14](=[O:15])[N:13]([CH3:21])[C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[NH:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CNc2ccccc2NC1=O
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CN1C(=O)C(NC(=O)OC(C)(C)C)CNc2ccccc21
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
To a solution of 5.0 g (18 mmol) (S)-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-carbamic acid tert-butyl ester in 80 ml of tetrahydrofuran at −75° C. 18 ml (18 mmol) of lithium bis(trimethylsilyl)amide solution (1M in tetrahydrofurane) was added. After stirring for 30 min at −75° C. the mixture was allowed to reach room temperature and 3.07 g (21.6 mmol) of methyl iodide was added. The mixture was stirred for 2.5 hours at room temperature and concentrated in vacuo. The residue was distributed between 1M NaHSO4 solution and ethyl acetate. The combined organic layers were reextracted with water and dried (MgSO4) to yield 4.95 g (94%) of (1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-carbamic acid tert-butyl ester as a white foam.
Reaction SMILES: [OH:1][C:2]1([CH2:15][O:16][C:17]2[CH:26]=[CH:25][C:20]([C:21](OC)=[O:22])=[CH:19][CH:18]=2)[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[NH2:27][CH2:28][CH2:29][OH:30]>O>[OH:30][CH2:29][CH2:28][NH:27][C:21](=[O:22])[C:20]1[CH:19]=[CH:18][C:17]([O:16][CH2:15][C:2]2([OH:1])[CH2:3][CH2:4][N:5]([CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:6][CH2:7]2)=[CH:26][CH:25]=1
Reactant: NCCO
Reactant: COC(=O)c1ccc(OCC2(O)CCN(Cc3ccccc3)CC2)cc1
Solvent: O
Product: O=C(NCCO)c1ccc(OCC2(O)CCN(Cc3ccccc3)CC2)cc1
Temperature: 145 °C
Reaction time: 4 h
Yield: 69.3 %

Procedure:
A mixture of 10.7 parts of methyl 4-[[4-hydroxy-1-(phenylmethyl)-4-piperidinyl]methoxy]benzoate and 8 parts of 2-aminoethanol was stirred for 4 hours in an oil bath at 145° C. After cooling, the reaction mixture was poured into water. The oil was decanted, washed twice with water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from a mixture of 2,2-oxybispropane and 2-propanol. The product was filtered off and dried yielding 8 parts (69.3%) of N-(2-hydroxyethyl)-4-[[4-hydroxy-1-(phenylmethyl)-4-piperidinyl]methoxy]benzamide; mp. 161.1° C. (int. 80).
Reaction SMILES: [CH2:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH:2]1[O:4][CH2:3]1.C(O)=[O:11].[OH-].[Na+]>O>[C:6]([O:5][CH2:1][CH:2]([OH:4])[CH2:3][OH:11])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OCC1CO1
Reactant: O=CO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)OCC(O)CO
Yield: 54 %

Procedure:
Compound 17 was prepared by the method described by Montanari and Tundo (Montanari, F. and Tundo, P., J. Org. Chem. 1982, 47, 1298). tert-Butyl glycidyl ether (Aldrich), (141 ml, 1.0 mol.) was added dropwise to 99% formic acid (83 ml, 2.2 mol). The reaction mixture was stirred and the temperature was maintained below 30° C. The mixture was stirred at room temperature for 12 hours. A solution of sodium hydroxide (100 g, 2.5 mol.) in 125 ml of water was added slowly, keeping the temperature below 40° C. The organic fraction was separated and the aqueous phase was extracted several times with dichloromethane. The combined organic fractions were dried (MgSO4) and evaporated and the oily residue was distilled under vacuum to give 17 (75 g, 54%) as a colorless oil: (bpt. 55°-60° C., 0.015 torr): IR 3400 (OH) cm-1 ; 1H-NMR (CDCl3) d (ppm) 3.25-4.0 (m, 7H), 1.2 (s, 9H); 13C-NMR (CDCl3) d (ppm) 73.5, 70.5, 64.4, 63.6, and 27.16. Mass spectrosocopy, m/e: 148 M+ base peak (Scheme 3). ##STR5##
Reaction SMILES: [C:1]1([NH:7][C:8]2[N:9]=[C:10]([OH:26])[C:11]3[N:12]=[CH:13][N:14]([C:24]=3[N:25]=2)[C@@H:15]2[O:23][C@H:20]([CH2:21][OH:22])[C@@H:18]([OH:19])[C@H:16]2[OH:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[C:31](=[O:33])[CH3:32])(=O)C>N1C=CC=CC=1>[C:1]1([NH:7][C:8]2[N:9]=[C:10]([OH:26])[C:11]3[N:12]=[CH:13][N:14]([C:24]=3[N:25]=2)[C@@H:15]2[O:23][C@H:20]([CH2:21][O:22][C:31](=[O:33])[CH3:32])[C@@H:18]([O:19][C:18](=[O:19])[CH3:20])[C@H:16]2[O:17][C:16](=[O:17])[CH3:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)OC(C)=O
Reactant: OC[C@H]1O[C@@H](n2cnc3c(O)nc(Nc4ccccc4)nc32)[C@H](O)[C@@H]1O
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(O)nc(Nc4ccccc4)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 3 h

Procedure:
In 100 parts by volume of pyridine is suspended 10 parts by weight of 2-phenylaminoinosine and 50 parts by weight of acetic anhydride is added dropwise. The mixture is stirred for 3 hours, at the end of which time it is concentrated under reduced pressure. The residue is recrystallized from 5 parts by volume of methanol. The procedure gives 2 parts by weight of 2-phenylamino-2',3',5'-tri-O-acetylinosine in the form of colorless flocs.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:28])[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][N:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[Cl:31][C:32]1[S:33][C:34]([S:38](Cl)(=[O:40])=[O:39])=[CH:35][C:36]=1[Cl:37]>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:37][C:36]1[CH:35]=[C:34]([S:38]([NH:1][C:2]2[CH:30]=[CH:29][C:5]3[NH:6][C:7]([C:12]4[C:13](=[O:28])[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:15]5[C:20]([C:21]=4[OH:22])=[CH:19][CH:18]=[CH:17][N:16]=5)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=3[CH:3]=2)(=[O:40])=[O:39])[S:33][C:32]=1[Cl:31]
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(N)ccc3N2)c(O)c2cccnc21
Reactant: O=S(=O)(Cl)c1cc(Cl)c(Cl)s1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NS(=O)(=O)c4cc(Cl)c(Cl)s4)ccc3N2)c(O)c2cccnc21
Temperature: 100 °C
Yield: 49 %

Procedure:
To the product of Example 205 (0.020 g, 0.047 mmol) in pyridine (0.2 mL) was added 2,3-dichlorothiophene-5-sulfonyl chloride (0.015 g, 0.056 mmol). The reaction mixture was heated in a microwave reactor at 100° C. for 15 minutes. The reaction was diluted with ethyl acetate (40 mL), washed with 1 N hydrochloric acid, water, and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was chromatographed on silica gel eluting with 99:1 dichloromethane:methanol to give the title compound (14.8 mg, 50%). 1H NMR (300 MHz, DMSO-d6) δ 0.98 (d, J=6.25 Hz, 6 H) 1.56 (m, 2 H) 1.69 (m, 1 H) 4.47 (m, 2 H) 7.50 (m, 2 H) 7.56 (s, 1 H) 7.71 (d, J=8.82 Hz, 1 H) 7.76 (s, 1 H) 8.55 (dd, J=7.91, 2.02 Hz, 1 H) 8.88 (dd, J=4.60, 1.65 Hz, 1 H) 11.28 (s, 1 H) 14.19 (br s, 1 H). MS (ESI−) m/z 640 (M−H)−.
Reaction SMILES: [C:1]([CH2:9][CH2:10][C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=O)OCC.[NH:27]([CH2:31][CH2:32][OH:33])[CH2:28][CH2:29][OH:30]>C1C=CC=CC=1>[OH:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][OH:33])[C:11](=[O:13])[CH2:10][CH2:9][C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCNCCO
Reactant: O=C(O)CCC(=O)c1ccccc1
Agent: CCOC(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(CCC(=O)N(CCO)CCO)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension is prepared containing 17.8 grams (0.1 mole)-β-benzoyl-propionic acid in 500 ml of anhydrous benzene; then are added in this order and at room temperature 10.5 grams triethylamine, 15 grams ethyl chlorocarbonate and 21 grams (0.2 moles) diethanolamine. The suspension is stirred for over two hours, always at room temperature, and it is then filtered to remove the triethylamine hydrochloride. The liquid is concentrated, at reduced pressure, to about half of the initial volume and it is left to rest about 12 hours at 5°-10° C. temperature. The crystallized solid is filtered, vacuum dried at reduced pressure, about 40° C., and is recrystallized from ethanol. 17.5 grams of N,N-bis(2- hydroxy-ethyl)-β-benzoyl-propionamide with m.p. 98° C. are obtained.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[C:11]([C:20]([C:22]3[CH:23]=[N:24][C:25](Cl)=[CH:26][CH:27]=3)=[O:21])=[CH:10]2)[CH:5]=[CH:4][CH:3]=1.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[C:11]([C:20]([C:22]3[CH:23]=[N:24][C:25]([N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:26][CH:27]=3)=[O:21])=[CH:10]2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)nc1)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Reactant: C1CCNC1
Solvent: C1CCOC1
Product: O=C(c1ccc(N2CCCC2)nc1)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O

Procedure:
Experimental conditions analogous to those described for Example 141, from 103 mg (0.23 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-3-(6-chloro-pyridine-3-carbonyl)-1H-quinolin-4-one and 0.5 mL pyrrolidine in 2 mL THF. Yield: 50 mg of a yellow powder. LC-MSD, m/z for C25H21BrN4O2 [M+H]+=489.0, 491.0; HPLC retention time: 1.1 min.
Reaction SMILES: [C:1]([C:5]1[CH:18]=[C:17]([CH3:19])[C:8]([CH2:9][CH:10](C(O)=O)[C:11]([OH:13])=[O:12])=[C:7]([CH3:20])[C:6]=1[OH:21])([CH3:4])([CH3:3])[CH3:2].C(=O)=O.C(=O)(O)[O-].[Na+]>O.CCCCCC>[C:1]([C:5]1[CH:18]=[C:17]([CH3:19])[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[C:7]([CH3:20])[C:6]=1[OH:21])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C)c1CC(C(=O)O)C(=O)O
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Product: Cc1cc(C(C)(C)C)c(O)c(C)c1CCC(=O)O

Procedure:
17.9 grams of the compound of Example 16 was stirred together with white oil at 165° to 180° for two hours until little CO2 evolution could be detected. The reaction mixture was cooled to 50° and stirred thoroughly together with 5.2 grams of sodium bicarbonate dissolved in 100 ml of water until no foaming took place and all solids had dissolved. The reaction mixture was diluted with 50 ml of n-hexane and the upper organic phase separated from the lower aqueous phase. The organic phase was washed with water, the wash water being combined with the aqueous phase. The combined aqueous phase was then washed with n-hexane, clarified by filtration through filtercel, and added dropwise to about 150 ml of cold 6 N aqueous hydrochloric acid so that a granular off-white precipitate was obtained. The product was used as such after drying in the vacuum oven at 60° and 3 mm Hg. overnight.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([CH3:11])=[CH:4][C:3]=1[CH3:12].[CH:13]([Mg]Br)=[CH2:14].O>C1COCC1>[Br:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([CH3:11])=[C:6]2[C:7]=1[CH:13]=[CH:14][NH:8]2
Reactant: Cc1cc(C)c([N+](=O)[O-])cc1Br
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C)c2[nH]ccc2c1Br
Temperature: -40 °C
Reaction time: 4 h
Yield: 31.5 %

Procedure:
To a solution of 1-bromo-2,4-dimethyl-5-nitro-benzene (7.5 g, 32.6 mmol) in THF (100 mL) at −78° C. was added vinylmagnesium bromide (110 mL of 1.0 M solution in THF, 1.1 mol) dropwise. The reaction was allowed to warm slowly to −40° C. then stirred for 4 h. Water was added, and the reaction mixture allowed to warm slowly to rt and extracted with EtOAc. The organic phase was then dried over Na2SO4 and concentrated to give 4-bromo-5,7-dimethylindole (2.3 g) which was used in the subsequent step without purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[C:5](=O)[CH2:6][C:7]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[C:13]1[N:19]([CH3:32])[C:20](=[O:31])[C:21]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[Cl:30])=[CH:22][C:12]2=1)=O)[CH3:2].C(O)(=O)C(O)=O.[CH2:41]([NH:43][NH2:44])[CH3:42]>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13]2[N:19]([CH3:32])[C:20](=[O:31])[C:21]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=4[Cl:30])=[CH:22][C:12]3=2)[N:43]([CH2:41][CH3:42])[N:44]=1)=[O:34])[CH3:2]
Reactant: CCNN
Reactant: CCOC(=O)C(=O)CC(=O)c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3Cl)c(=O)n(C)c1n2C
Agent: O=C(O)C(=O)O
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)n(CC)n1

Procedure:
930 mg (1.85 mmol) of compound A 4-[3-(2,4-dichlorophenyl)-1,9-dimethyl-2-oxo-2,9-dihydro-1H-pyrido[2,3-b]indol-6-yl]-2,4-dioxobutyric acid ethyl ester are dissolved in 20 ml of absolute ethanol. 583 mg (5.56 mmol) of ethylhydrazine oxalate are added and the mixture is refluxed overnight. The reaction medium is evaporated to dryness and the residue is triturated in a saturated K2CO3 solution. The product is filtered and washed with water. Purification is carried out on a silica column, elution being carried out with EtOAc.