Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[Cl:5][CH2:6][S:7](Br)(=[O:9])=[O:8]>ClCCl>[CH:1]([NH:4][S:7]([CH2:6][Cl:5])(=[O:9])=[O:8])([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: O=S(=O)(Br)CCl
Solvent: ClCCl
Product: CC(C)NS(=O)(=O)CCl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 11.8 g (0.2 mol) sample of isopropylamine was added dropwise to a cooled (-60° C.) solution of 19.3 g (0.1 mol) chloromethanesulfonyl bromide in 200 ml dichloromethane. The reaction was then allowed to warm to about 25° C. and stirred about 16 hours. The reaction mixture was then filtered, washed with water, dried over magnesium sulfate and evaporated to give crude N-isopropyl chloromethanesulfonamide.
Reaction SMILES: [NH2:1][C:2](=[C:10]([C:15](=O)[CH:16]([CH3:18])[CH3:17])[C:11]([O:13][CH3:14])=[O:12])[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.[N:20]#[C:21][NH2:22].C(OCC)(=O)C>O>[NH2:22][C:21]1[N:1]=[C:2]([C:3]2[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=2)[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:15]([CH:16]([CH3:18])[CH3:17])[N:20]=1
Reactant: N#CN
Reactant: COC(=O)C(C(=O)C(C)C)=C(N)c1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1c(-c2ccc(F)cc2)nc(N)nc1C(C)C
Temperature: 25 °C
Reaction time: 17 h
Yield: 8.4 %

Procedure:
A suspension of 1.33 g of methyl 2-[1-amino-1-(4-fluorophenyl)methylene]-4-methyl-3-oxopentanoate (5.00 mmol) in 4.20 g of 50% strength aqueous cyanamide solution (50.0 mmol) was heated to reflux. After 17 h, it was cooled to room temperature and treated with ethyl acetate (5 ml) and water (5 ml). The undissolved solid was filtered off. The organic phase was separated off and the aqueous phase was extracted with ethyl acetate (2×5 ml). The combined organic phases were dried over magnesium sulphate and concentrated in vacuo. The crude product (0.97 g) was purified by flash chromatography on silica gel (eluent: methylene chloride). 121.6 mg of methyl 2-amino-4-(4-fluorophenyl)-6-isopropylpyrimidine-5-carboxylate were obtained in the form of a colourless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[CH3:11][S-:12].[Na+].O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[S:12][CH3:11])[CH:5]=[O:6]
Reactant: O=Cc1ccc(F)c(Cl)c1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ccc(C=O)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.1 %

Procedure:
A solution of 3-chloro-4-fluorobenzaldehyde (50.0 g) in N,N-dimethylformamide (350 mL) was cooled to −10° C., and sodium methanethiolate (25 g) was added. The reaction solution was warmed to room temperature, and stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to give the title compound (33.6 g, yield 59%) as colorless crystals. The mother liquor was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=5:95-30:70, volume ratio) and recrystallized from hexane-ethyl acetate to give the title compound (12.3 g, yield 21%) as colorless crystals. melting point 58-59° C.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:18]2[CH:22]=[C:21]([C:23]3[C:24]4[CH:31]=[CH:30][N:29]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:25]=4[N:26]=[CH:27][N:28]=3)[CH:20]=[N:19]2)[CH2:7][N:6]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][CH:9]=2)[CH2:5]1)#[N:2].[OH-].[Li+]>O1CCCC1.O>[C:1]([CH2:3][C:4]1([N:18]2[CH:22]=[C:21]([C:23]3[C:24]4[CH:31]=[CH:30][N:29]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:37])([CH3:39])[CH3:38])[C:25]=4[N:26]=[CH:27][N:28]=3)[CH:20]=[N:19]2)[CH2:5][N:6]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([OH:14])=[O:13])=[CH:16][CH:17]=2)[CH2:7]1)#[N:2]
Reactant: COC(=O)c1ccc(N2CC(CC#N)(n3cc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(c5ccc(C(=O)O)cc5)C4)c3)ncnc21
Temperature: 35 °C
Reaction time: 46 h

Procedure:
To a solution of methyl 4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)-ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}benzoate (0.9 g, 2 mmol) in tetrahydrofuran (8 mL) was added a solution of lithium hydroxide (0.16 g, 6.7 mmol) in water (7.4 mL). The reaction mixture was then stirred at 35° C. The progress of reaction was monitored by LC/MS. After 46 hours, LC/MS data indicated that the main component of the reaction was the desired product LCMS m/z=530.2. The reaction mixture was diluted with water (5 mL), pH was adjusted to ˜4 with 1N HCl, and was extracted with ethyl acetate. Organic fraction was then washed water (1×), brine (1×), dried over sodium sulfate and then concentrated in-vacuo. The crude product was purified by flash chromatography on a silica gel column with methanol in methylene chloride to give the desired product (0.450 g, 50%). LCMS (M+H)+: m/z=530.2.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[C:8]3[CH2:31][S:30][CH2:29][CH2:28][C:9]=3[N:10]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH:24]=[C:23]([CH3:25])[N:22]=[CH:21]4)=[C:16]([O:26][CH3:27])[CH:15]=3)[N:12]=2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:42])C=1.C([O-])(O)=O.[Na+].O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[C:8]3[CH2:31][S:30](=[O:42])[CH2:29][CH2:28][C:9]=3[N:10]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH:24]=[C:23]([CH3:25])[N:22]=[CH:21]4)=[C:16]([O:26][CH3:27])[CH:15]=3)[N:12]=2)=[CH:32][CH:33]=1
Reactant: COc1cc(Nc2nc3c(c(Cc4ccc(F)cc4)n2)CSCC3)ccc1-n1cnc(C)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1cc(Nc2nc3c(c(Cc4ccc(F)cc4)n2)CS(=O)CC3)ccc1-n1cnc(C)c1
Yield: 18.7 %

Procedure:
4-(4-Fluorobenzyl)-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-2-amine (254 mg, 0.55 mmol) and meta-chloroperbenzoic acid (95 mg, 0.55 mmol) was slurrified in DCM (4 mL). Saturated NaHCO3 and water were added to the reaction mixture, the organic phase was separated and the solvent was evaporated. The crude product was purified on preparative HPLC yielding 4-(4-fluorobenzyl)-N-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-2-amine 6-oxide (49.0 mg, 18%).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.I[CH3:18]>O1CCCC1.O>[CH3:18][O:3][CH:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (1.19 g, 60% in mineral oil, 29.7 mmol) was added portionwise to a cooled (10° C.) solution of tert-butyl 4-hydroxy-1-piperidinecarboxylate (Bioorg. Med. Chem. Lett. 10; 24; 2000; 2815) in tetrahydrofuran (80 mL), and the suspension stirred at room temperature for 1 hour. Iodomethane (1.85 mL, 29.7 mmol) was added, and the reaction stirred at 50° C. for 20 hours. The mixture was diluted with water (50 mL), extracted with ethyl acetate (2×150 mL) and the combined organic extracts washed with saturated sodium bicarbonate solution (50 mL), dried (MgSO4) and evaporated under reduced pressure, to afford the title compound as a golden oil, 5.24 g.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@H:4]([N:7]2[C:11]3=[C:12]4[S:18][CH:17]=[CH:16][C:13]4=[N:14][CH:15]=[C:10]3[N:9]=[C:8]2[C@H:19]([OH:21])[CH3:20])[CH2:3]1.C(N(CC)C(C)C)(C)C.[C:31](#[N:35])[CH2:32][CH2:33][CH3:34]>C(#N)C>[OH:21][C@@H:19]([C:8]1[N:7]([C@H:4]2[CH2:5][CH2:6][N:2]([CH2:34][CH2:33][CH2:32][C:31]#[N:35])[CH2:3]2)[C:11]2=[C:12]3[S:18][CH:17]=[CH:16][C:13]3=[N:14][CH:15]=[C:10]2[N:9]=1)[CH3:20]
Reactant: CCCC#N
Reactant: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CCNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CCN(CCCC#N)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 38 %

Procedure:
To a mixture of (1R)-1-{1-[(3S)-pyrrolidin-3-yl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}ethanol hydrochloride (15 mg, 0.046 mmol) and N,N-diisopropylethylamine (24 μL, 0.14 mmol) in acetonitrile (0.2 mL) was added butanenitrile, 4-bromo- (5.1 μL, 0.051 mmol). The resulting mixture was stirred at rt for 4 h. The mixture was diluted and purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give 6.3 mg (38%) of the desired product. LCMS calculated for C18H22N5OS (M+H)+: m/z=356.2. Found: 356.0.
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:8]=[N:9][N:10]([CH3:15])[C:11]=2[C:12]([OH:14])=O)=[O:6])[CH2:4][CH2:3][CH2:2]1.[F:16][C:17]1[CH:18]=[C:19]([C:23]2[N:24]=[C:25]3[CH:30]=[C:29]([NH2:31])[N:28]=[CH:27][N:26]3[CH:32]=2)[CH:20]=[CH:21][CH:22]=1>>[F:16][C:17]1[CH:18]=[C:19]([C:23]2[N:24]=[C:27]3[N:28]=[C:29]([NH:31][C:12]([C:11]4[N:10]([CH3:15])[N:9]=[CH:8][C:7]=4[C:5]([N:1]4[CH2:2][CH2:3][CH2:4]4)=[O:6])=[O:14])[CH:30]=[CH:25][N:26]3[CH:32]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: Cn1ncc(C(=O)N2CCC2)c1C(=O)O
Reactant: Nc1cc2nc(-c3cccc(F)c3)cn2cn1
Product: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1ccn2cc(-c3cccc(F)c3)nc2n1

Procedure:
The title compound was prepared in analogy to example 82 from 4-(azetidine-1-carbonyl)-1-methyl-1H-pyrazole-5-carboxylic acid (91.7 mg, 438 μmol) and 2-(3-fluorophenyl)imidazo[1,2-c]pyrimidin-7-amine (100 mg, 438 μmol). Yellow solid (6.5 mg, 3.5%). MS (m/z)=420.1 [M+H+].
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[C:15](#[N:18])[CH2:16][OH:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[N+:12]([C:3]1[CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[C:6]([Cl:8])=[CH:7][C:2]=1[O:17][CH2:16][C:15]#[N:18])([O-:14])=[O:13]
Reactant: N#CCO
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCOc1cc(Cl)c([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 58.5 %

Procedure:
A solution of 1,5-dichloro-2,4-dinitrobenzene (5.0 g), glycolonitrile (1.81 g) and anhydrous potassium carbonate (2.19 g) in dimethylformamide (20 g) was stirred at 25° to 30° C. for 24 hours. After completion of the reaction, the reaction mixture was diluted with water (200 ml) and extracted with ethyl acetate (200 ml). The organic layer was washed with water, dried over magnesium sulfate and concentrated. The precipitated crystals were collected by filtration and washed with ether to give crude crystals (4.16 g), which were recrystallized from methanol to give 2,4-dinitro-5-chlorophenoxyacetonitrile (3.18 g; yield, 58.5%). M.P., 117°-118° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[C:8](=[O:13])[CH2:7][CH2:6][CH2:5]2.[N:14]1([CH2:19][CH2:20]O)[CH:18]=[CH:17][N:16]=[CH:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.CCOC(C)=O>[N:14]1([CH2:19][CH2:20][O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[CH3:12])[C:8](=[O:13])[CH2:7][CH2:6][CH2:5]3)[CH:18]=[CH:17][N:16]=[CH:15]1
Reactant: OCCn1ccnc1
Reactant: Cc1cc2c(cc1O)CCCC2=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc2c(cc1OCCn1ccnc1)CCCC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.9 %

Procedure:
Under N2, a solution of 2.08 g (11.8 mmol) of 6-hydroxy-7-methyl-1,2,3,4-tetrahydro-1-naphthalenone in 25 mL of THF was treated with 1.46 g (13.9 mmol) of 2-(1H-1-imidazolyl)-1-ethanol and 3.1 g (11.8 mmol) of triphenylphosphine. The solution was cooled in ice and treated with a solution of 1.9 mL (11.8 mmol) of diethyl azodicarboxylate in 5 mL of THF. The solution was allowed to stir at room temperature overnight. The mixture was diluted with EtOAc and washed twice with H2O, twice with saturated NaHCO3, then with saturated NaCl. Drying over MgSO4 and removal of the solvent under pressure left the crude product. Chromatography on silica gel, eluting with CHCl3/MeOH (95/5) gave the product which was recrystallized from EtOAc/hexane to give 1.05 g (32.9% yield) of the product as a tan solid, mp 118-120° C. The structure was confirmed by NMR and mass spectroscopy. MS m/z 271 (M+H+).
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]1[C:8]([CH3:9])=[C:7]([C:10]([O:12]CC)=[O:11])[C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:5]1[C:21]([O:23]CC)=[O:22]>O.C(O)C>[CH3:3][N:4]1[C:8]([CH3:9])=[C:7]([C:10]([OH:12])=[O:11])[C:6]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[C:5]1[C:21]([OH:23])=[O:22]
Reactant: CCOC(=O)c1c(-c2ccccc2)c(C(=O)OCC)n(C)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(C(=O)O)c(-c2ccccc2)c(C(=O)O)n1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
A solution of sodium hydroxide (101 g, 2.53 mol) in water (340 mL) was added to a solution of diethyl 1,5-dimethyl-3-phenyl-pyrrole-2,4-dicarboxylate (80 g, 0.25 mol) in ethanol (340 mL) and heated at reflux for 15 h. Ethanol was removed under reduced pressure and the residue diluted with water (200 mL) and chilled to 0° C. Concentrated hydrochloric acid (˜150 mL) was slowly added to adjust pH to ˜2, while maintaining temperature below 10° C. and the mixture was stirred for 30 min. The precipitated solid was filtered, washed with water (100 mL) and petroleum ether (200 mL) and dried under vacuum at 60° C. to afford 1,5-dimethyl-3-phenyl-pyrrole-2,4-dicarboxylic acid (60 g, 91%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][S:22](Cl)(=[O:24])=[O:23])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+].[F-:27]>CC(C)=O.C(OCC)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][S:22]([F:27])(=[O:24])=[O:23])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)CCCCCCCc1ccc(OCc2ccccc2)cc1
Reactant: [F-]
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: O=S(=O)(F)CCCCCCCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 93.3 %

Procedure:
To a stirred solution of 12.1 (0.345 g, 0.9 mmol) in dry acetone (20 mL), was added anhydrous NH4F (0.066 g, 1.8 mmol) and the mixture refluxed for 2 hours. The reaction mixture was cooled to room temperature, the solvent was evaporated, and the residue obtained was dissolved in diethyl ether (20 mL). The ethereal solution was successively washed with water and brine, dried (MgSO4) and concentrated under reduced pressure. Purification by flash column chromatography on silica gel (20% diethyl ether-hexane) afforded 13.1 (0.306 g, 93% yield) as a white solid (m p 35-38° C.).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Cl:8][C:9]1[CH:28]=[CH:27][C:12]([CH2:13][C:14]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH:15]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[OH:16])=[CH:11][CH:10]=1>N1C=CC=CC=1>[C:1]([O:16][CH:15]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C:14]([CH2:13][C:12]1[CH:11]=[CH:10][C:9]([Cl:8])=[CH:28][CH:27]=1)([CH2:23][CH3:24])[CH2:25][CH3:26])(=[O:3])[CH3:2]
Reactant: CCC(CC)(Cc1ccc(Cl)cc1)C(O)c1cccnc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCC(CC)(Cc1ccc(Cl)cc1)C(OC(C)=O)c1cccnc1
Temperature: 80 °C

Procedure:
10.2 g (0.10 mol) of acetic anhydride are added dropwise to a solution of 12.1 g (0.04 mol) of 2-(4-chlorobenzyl)-2-ethyl-1-(3-pyridyl)-1-butanol in 50 ml of pyridine at room temperature, and the mixture is then heated at 80° C. for 8 h. The reaction mixture is concentrated, the residue is taken up in 200 ml of dichloromethane, and the solution is washed with saturated NaHCO3 solution and then with water. The organic phase is dried and concentrated, and the remaining black oil is purified on silica gel (mobile phase: 5:1 cyclohexane/ethyl acetate). 11.2 g (81% of theory) of the title compound are obtained as a viscous yellow oil. 1H-NMR (CDCl3): δ=8.60(2-Hpy), 8.52(6-Hpy), 7.65(4-Hpy), 7.30(5-Hpy), 7.25(2Hm), 7.05(2Ho), 5.62(CHOAc), 2.68(CH2Ar), 2.08(COCH3), 1.45(CH2), 1.30(CH2), 0.95(CH3), 0.83(CH3).
Reaction SMILES: C[Si]([N:5]=[N+:6]=[N-:7])(C)C.[N:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:33]=[CH:32][C:19]([O:20][CH2:21][C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=3)=[CH:18][CH:17]=2)=[CH:10][CH:9]=1>>[N:8]1[CH:9]=[CH:10][C:11]([C:14]2[NH:7][N:6]=[N:5][C:15]=2[C:16]2[CH:17]=[CH:18][C:19]([O:20][CH2:21][C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=3)=[CH:32][CH:33]=2)=[CH:12][CH:13]=1
Reactant: C(#Cc1ccc(OCc2ccc3ccccc3n2)cc1)c1ccncc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Product: c1ccc2nc(COc3ccc(-c4nn[nH]c4-c4ccncc4)cc3)ccc2c1
Temperature: 150 °C
Yield: 85.2 %

Procedure:
Trimethylsilylazide (730 mg, 6.4 mmol) and 2-((4-(2-(pyridin-4-yl)ethynyl)phenoxy)methyl)quinoline (360 mg) were combined in a screw cap sealed tube and heated behind a safety shield in a 150° C. bath for 72 h. The mixture was concentrated and the yellow residue triturated with ether (2×10 mL) leaving a yellow solid (346 mg) which was chromatographed on silica eluted with a gradient of 0.5%-2% methanol in dichloromethane giving a yellow solid (210 mg, 52%). 1H NMR (CDCl3 with a drop of CD3OD, 400 mHz) 68.54 (d, 2H, J=6.2 Hz), 8.23 (d, 1H, J=8.7 Hz), 8.07 (d, 1H, J=8.7 Hz), 7.84 (d, 1H, J=7.9 Hz), 7.74 (ddd, 1H, J=8.4, 7, 1 Hz), 7.69 (d, 1H, J=8.7 Hz), 7.63 (d, 2H, J=6.2 Hz), 7.56 (ddd, 1H), 7.41 (m, 2H), 7.09 (m, 2H), 5.41 (s, 2H). MS (AP+) m/e 380 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16](=[O:20])[C:17](Cl)=[O:18])=[CH:8]2)=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH2:28][O:27][C:26](=[O:29])[CH:25]=1.O>O1CCCC1>[O:29]=[C:26]1[O:27][CH2:28][C:24]([NH:23][C:17](=[O:18])[C:16]([C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:7]([CH2:6][C:5]3[CH:21]=[CH:22][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:8]=2)=[O:20])=[CH:25]1
Reactant: NC1=CC(=O)OC1
Reactant: O=C(Cl)C(=O)c1cn(Cc2ccc(Cl)cc2)c2ccccc12
Solvent: C1CCOC1
Solvent: O
Product: O=C1C=C(NC(=O)C(=O)c2cn(Cc3ccc(Cl)cc3)c3ccccc23)CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.5 %

Procedure:
A solution of 2-(1-(4-chlorobenzyl)-1H-indol-3-yl)-2-oxo-acetyl chloride (0.45 g) and 4-amino-5H-furan-2-one (0.30 g) in dry tetrahydrofuran (10 ml) is refluxed for 2 h. After cooling at room temperature, the reaction mixture is poured into water (200 ml) and the resulting suspension is left under stirring for 1 h. The solid is filtered off and resuspended in methanol (4.3 ml) under stirring for 1 h, then collected by filtration to give N-(5-oxo-2,5-dihydrofuran-3-yl)-2-(1-(4-chlorobenzyl)-1H-indol-3-yl)-2-oxo-acetamide (0.27 g).
Reaction SMILES: Br[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[N:11]([C:14]3[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=3[CH3:21])[C:12](=[O:13])[C:4]=2[CH:3]=1.[C:29]([C:31]1[CH:32]=[CH:33][C:34]([O:40][CH3:41])=[C:35](B(O)O)[CH:36]=1)#[N:30].[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1.O>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:20][C:18]1[CH:17]=[CH:16][C:15]([CH3:21])=[C:14]([N:11]2[C:12](=[O:13])[C:4]3[CH:3]=[C:2]([C:33]4[CH:32]=[C:31]([CH:36]=[CH:35][C:34]=4[O:40][CH3:41])[C:29]#[N:30])[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]=3[CH:10]2[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH:19]=1
Reactant: COc1ccc(C#N)cc1B(O)O
Reactant: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(C#N)cc1-c1cc2c(n1C(C)C)C(c1ccc(Cl)cc1)N(c1cc(Cl)ccc1C)C2=O
Temperature: 100 °C

Procedure:
A degassed mixture of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one (Intermediate B) (0.337 mmol), 5-cyano-2-methoxyphenylboronic acid [612833-37-1] (0.675 mmol), Pd(PPh3)4 (0.067 mmol) and K3PO4 (1.350 mmol) in 2:1 dioxane/H2O (4.5 mL) was heated at 100° C. for 4 h. After cooling to rt, the reaction mixture was diluted with H2O and extracted with EtOAc (3×). The combined organic phases were dried (Na2SO4) and concentrated. The residue was dissolved in CH2Cl2 and filtered through a PL-thiol MP SPE cartridge (StratoSpheres), washing through with additional CH2Cl2. The filtrate was re-concentrated and the residue purified using a RediSep® silica gel column to afford the title compound as a yellow solid. tR: 5.43 min (HPLC 1); ESI-MS: tR=1.37 min, [M+H]+ 530/532/534 (LC-MS 1); TLC: Rf=0.29 (1:1 EtOAc/heptanes); 1H-NMR (d6-DMSO, 600 MHz): 8.15 (br s, 1H), 7.95 (m, 1H), 7.77 (m, 2H), 7.37 (m, 2H), 7.31 (d, 1H), 7.24 (m, 1H), 7.15 (m, 1H), 7.10 (m, 1H), 6.51 (s, 1H), 6.31 (s, 1H), 3.85 (m, 1H), 3.85 (s, 3H), 1.91 (s, 3H), 1.29 (m, 3H), 0.46 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19](Cl)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[N:12]=[CH:11][C:10]2=[O:23])=[C:4]([O:24][CH3:25])[CH:3]=1.ClCCl.[NH2:29][C:30]1[CH:34]=[CH:33][O:32][N:31]=1>N1C=CC=CC=1>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:29][C:30]4[CH:34]=[CH:33][O:32][N:31]=4)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[N:12]=[CH:11][C:10]2=[O:23])=[C:4]([O:24][CH3:25])[CH:3]=1
Reactant: Nc1ccon1
Reactant: COc1cc(Br)c(F)cc1-n1c(=O)cnc2cc(S(=O)(=O)Cl)ccc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(Br)c(F)cc1-n1c(=O)cnc2cc(S(=O)(=O)Nc3ccon3)ccc21
Reaction time: 2 h
Yield: 82.1 %

Procedure:
A RBF was charged with 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-6-sulfonyl chloride (512.8 mg, 1.031 mmol), dichloromethane (1718 μl), and 3-aminoisoxazole (114 μl, 1.546 mmol) to give a thick suspension. Pyridine (3437 μl) was added relatively quickly, leading to thinner suspension. After 2 h, the mixture was concentrated in vacuo. The residue was partitioned between EtOAc and 2N aq. HCl. The layers were separated, and the aq. layer was extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (50-g SNAP Ultra column, 0-50% 3:1 EtOAc/EtOH in heptane with 10% DCM) to give 1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoxaline-6-sulfonamide (419.2 mg, 0.846 mmol, 82% yield) as a white foam. 1H NMR (400 MHz, DMSO-d6) δ=11.74 (br. s., 1H), 8.74 (d, J=1.9 Hz, 1H), 8.47 (s, 1H), 8.29 (d, J=2.2 Hz, 1H), 7.90 (dd, J=2.2, 8.9 Hz, 1H), 7.72 (d, J=6.1 Hz, 1H), 7.62 (d, J=8.4 Hz, 1H), 6.98 (d, J=8.8 Hz, 1H), 6.48 (d, J=1.9 Hz, 1H), 3.74-3.71 (m, 3H), 3.32 (s, 3H). m/z (ESI) 495.0 (M+H)+.