Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH:3]=1.[CH3:16][S:17]([NH2:20])(=[O:19])=[O:18].Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:20][S:17]([CH3:16])(=[O:19])=[O:18])=[O:7])=[C:4]([CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH:3]=1
Reactant: CC(C)CCc1cc(Br)ccc1C(=O)O
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)CCc1cc(Br)ccc1C(=O)NS(C)(=O)=O
Temperature: 30 °C
Reaction time: 16 h
Yield: 93.5 %

Procedure:
To a suspension of 4-bromo-2-(3-methylbutyl)benzoic acid (1.3 g) and methanesulfonamide (365 mg) in N,N-dimethylformamide (12 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (735 mg) and 4-dimethylaminopyridine (469 mg), and stirred at 30° C. for 16 hours. The mixture was diluted with ethyl acetate, washed with 1N aqueous hydrochloride solution, water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=2/1) to give 4-bromo-2-(3-methylbutyl)-N-(methylsulfonyl)benzamide (1.25 g).
Reaction SMILES: [CH3:1][N:2](C(OC(C)(C)C)=O)[CH:3]([CH2:5]/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([NH:15][C:16](=[O:18])[CH3:17])[CH:9]=1)[CH3:4].Br>>[CH3:1][NH:2][CH:3]([CH2:5]/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([NH:15][C:16](=[O:18])[CH3:17])[CH:9]=1)[CH3:4]
Reactant: CC(=O)Nc1cc(/C=C/CC(C)N(C)C(=O)OC(C)(C)C)ccc1C
Agent: Br
Product: CNC(C)C/C=C/c1ccc(C)c(NC(C)=O)c1
Temperature: 0 °C
Yield: 99.8 %

Procedure:
A solution of (4E)-N-methyl-N-(tert-butoxycarbonyl)-5-(3-acetamido-4-methylphenyl)-4-penten-2-amine (0.90 g, 2.60 mmol) and aqueous hydrobromic acid (50%, 25 mL) was stirred at 0° C. to ambient temperature for ˜16 h. The reaction mixture was extracted with chloroform (40 mL). The aqueous layer was cooled to 0° C., basified with aqueous sodium hydroxide solution to pH 8-9, and extracted with chloroform (4×50 mL). The combined extracts were dried over sodium sulfate, filtered and concentrated on a rotary evaporator to yield 0.639 g (94.6%) of a colorless oil.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:17])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>N1C=CC=CC=1>[I:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:17][C:18](=[O:20])[CH3:19])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: OC(Cc1ccc(I)cc1)c1ccc(I)cc1
Solvent: c1ccncc1
Product: CC(=O)OC(Cc1ccc(I)cc1)c1ccc(I)cc1
Reaction time: 48 h

Procedure:
1 ,2-di(p-bromophenyl)-hydroxyethane (17.8 g, 0.05 mol), potassium iodide (165 g), copper (I) iodide (95 g) and hexamethylphosphoramide (200 mL) was stirred at 150-160° C. for 48 h and then cooled. Work-up was as described in Example IV to provide a light yellow solid (10 g), which was the expected 1,2-di(p-iodophenyl)-1-hydroxyethane. A portion of this compound (7.2 g, 0.016 mol), acetic anhydride (16 mL), pyridine (16 mL) were heated at 60° C. for 30 min, followed by standing for 2 days. The resulting solution was worked up as in Example IlIl to provide an oil which solidified upon standing. The solid was crystallized from hexanes to provide the title compound as a light yellow solid (4.3 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[CH:10][N:9]=2)[CH:5]=[CH:4][CH:3]=1.C1C(=O)N([Cl:23])C(=O)C1>CC(O)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:23][C:5]1[C:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[CH:10][N:9]=2)=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cnc(-c2cccc(Cl)n2)c(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: Cc1cnc(-c2nc(Cl)ccc2Cl)c(C)c1
Temperature: 120 °C
Reaction time: 20 h
Yield: 69.2 %

Procedure:
A mixture of 6′-chloro-3,5-dimethyl-2,2′-bipyridine (300 mg, 1.37 mmol), NCS (202 mg, 1.51 mmol), and Pd(OAc)2 (31.4 mg, 0.137 mmol) in AcOH (9.15 mL) was heated to 120° C. in a sealed microwave vial using an oil bath. After 20 h, the reaction was removed from heat and concentrated. Took up the residue in EtOAc, filtered off the solid through a glass fiber filter, and washed with 1:1 EtOAc/heptane. The filtrate was concentrated and purified on Biotage 25S column, eluting with 0-25% EtOAc/heptane to get 240 mg (69%) of the title compound as an off-white solid. m/z (APCI+) for C12H10N2Cl2 253.00 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.33 (s, 1 H) 8.16 (d, J=8.59 Hz, 1 H) 7.66 (d, J=8.59 Hz, 1 H) 7.61 (s, 1 H) 2.34 (s, 3 H) 2.08 (s, 3 H).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[N:21]=1>Cl>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[N:21]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cccc(Br)n1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Agent: Cl
Product: COc1cccc(NCCCOc2cccc(CN3CCCCC3)c2)n1
Reaction time: 5 h
Yield: 23 %

Procedure:
3-[3-(Piperidinomethyl)phenoxy]propylamine (14.90 g) and 2-bromo-6-methoxypyridine (5.64 g) were heated with stirring in an oil bath at 165°-170° C. for 5 hours. The reaction mixture was cooled, dissolved in dilute hydrochloric acid to pH 3-4, washed with ether (5 times), taken to pH 9-10 with dilute sodium hydroxide, extracted into ether (5 times). The pH was adjusted after each extraction. The latter ether extracts were combined, dried (MgSO4), evaporated under reduced pressure, and subjected to medium pressure chromatography on silica using ethyl acetate as eluant, to yield the title compound as an oil (2.45 g). This was treated with maleic acid in ethanol to give 2-[3-[3-(piperidinomethyl)phenoxy]propylamino]-6-methoxypyridine dimaleate (2.71 g), m.p. 114.5°-115° C.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH2:6]([O:8][C:9](=[O:16])[CH2:10][C:11](=[O:15])[CH:12]([CH3:14])[CH3:13])[CH3:7]>ClCCl>[CH2:6]([O:8][C:9](=[O:16])[CH:10]([Cl:4])[C:11](=[O:15])[CH:12]([CH3:13])[CH3:14])[CH3:7]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)CC(=O)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C(Cl)C(=O)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 1M solution of sulfuryl chloride in dichloromethane (25 mL, 25 mmol) was added to a solution of 4-methyl-3-oxopentanoic acid ethyl ester (3.95 g, 25 mmol) in dichloromethane (15 mL) cooled in a water bath. The solution was stirred at room temperature for 2 h and then the reaction mixture was washed with water (2×20 mL). Each of the aqueous layers was extracted with dichloromethane and the combined organic layers were dried (MgSO4), filtered and evaporated to give 2-chloro-4-methyl-3-oxopentanoic acid ethyl ester (5.0 g, 104% of the theoretical amount). This was used directly in the next step without purification.
Reaction SMILES: [C:1]([CH:4]([CH2:16][CH2:17][CH2:18][CH:19]1[O:21][CH2:20]1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])(=[O:3])[CH3:2].[C:22]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23].[OH-].[Na+]>O.O1CCCC1>[C:1]([CH:4]([CH2:16][CH2:17][CH2:18][CH:19]([OH:21])[CH2:20][O:32][C:29]1[CH:30]=[CH:31][C:26]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:27][CH:28]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[CH3:2]
Reactant: CCOC(=O)CCCCCCC(CCCC1CO1)C(C)=O
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)C(CCCCCCC(=O)O)CCCC(O)COc1ccc(C(C)(C)C)cc1
Reaction time: 1 h

Procedure:
A mixture of ethyl 8-acetyl-12,13-epoxytridecanoate (14.9 g., 0.05 mole), 4-tert-butylphenol (11.2 g., 0.075 mole), sodium hydroxide (7.0 g., 0.175 mole), water (30 ml.) and tetrahydrofuran (200 ml.) is stirred 4 hours at 40°-45°, 17 hours at 25° and one hour on the steam bath letting the tetrahydrofuran slowly boil away. The residue is treated with water and extracted with ether. The aqueous solution is acidified with hydrochloric acid. The oily product is taken up in ether. The ether is evaporated and the residue treated with a solution of 16.8 g. sodium bicarbonate in 275 ml. of water. The resulting solution is extracted twice with ether to remove the excess weakly acidic phenol. The aqueous solution is acidified, the product taken up in ether, washed with water and dried over sodium sulfate. The ether is evaporated leaving 10.2 g. of the crude title compound as a yellow viscous oil.
Reaction SMILES: S(O[CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)[CH2:17][CH2:16]1)(C1C=CC(C)=CC=1)(=O)=O.[N:30]1(C(C)CC2CCN(C3C=CC(N)=CC=3)CC2)[CH:34]=[CH:33][N:32]=[N:31]1>>[N:30]1([CH2:12][CH2:13][CH2:14][CH:15]2[CH2:16][CH2:17][N:18]([C:21]3[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=3)[CH2:19][CH2:20]2)[CH:34]=[CH:33][N:32]=[N:31]1
Reactant: Cc1ccc(S(=O)(=O)OCCCC2CCN(c3ccc([N+](=O)[O-])cc3)CC2)cc1
Reactant: CC(CC1CCN(c2ccc(N)cc2)CC1)n1ccnn1
Product: O=[N+]([O-])c1ccc(N2CCC(CCCn3ccnn3)CC2)cc1

Procedure:
Following the procedure of Example 7(1), the 4-tosyloxypropyl-N-(4-nitrophenyl)piperidine obtained in Example 11(2) was used instead of 4-tosyloxyethyl-N-(4-nitrophenyl)piperidine, thereby obtaining 4-[2-(1,2,3-triazol-1-yl)-propyl]-N-(4-aminophenyl)piperidine (69%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9](Br)[CH:8]=2)=[O:4].C([O-])(=O)C.[K+].Br[C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][N:32]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][N:32]=1)[CH:8]=2)=[O:4]
Reactant: Fc1ccc(Br)nc1
Reactant: COC(=O)c1cc2ccc(Br)cc2n1S(=O)(=O)c1ccc(C)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1cc2ccc(-c3ccc(F)cn3)cc2n1S(=O)(=O)c1ccc(C)cc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
6-Bromo-1-(toluene-4-sulfonyl)-1H-indole-2-carboxylic acid methyl ester (202.0 mg, 0.495 mmol), dichlorobis(triphenylphosphine)palladium (II) (35.6 mg, 0.051 mmol), bis(pinacol)diborane (189.3 mg, 0.745 mmol), potassium acetate (147.3 mg, 1.51 mmol), and dioxane (1.6 ml) were mixed. The air was replaced three times with argon under reduced pressure. The mixture was microwaved at 120° C. for 30 minutes. Dichlorobis(triphenylphosphine)palladium (II) (35.6 mg, 0.051 mmol) and 2-bromo-5-fluoro-pyridine (206.9 mg, 1.48 mmol) were added to the reaction mixture. After deaeration, the air was replaced three times with argon. This was heated and stirred at 100° C. for three hours. The reaction mixture was extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and concentration was performed. Then, the residue obtained by concentration under reduced pressure was purified by amino gel column chromatography (n-hexane/ethyl acetate=7/100 to 63/100). Thus, 6-(5-fluoro-pyridin-2-yl)-1-(toluene-4-sulfonyl)-1H-indole-2-carboxylic acid methyl ester was obtained as a pale yellow amorphous material (150.5 mg, yield of 72%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:11][CH2:10][NH:9][C:8]2=[O:12])[CH:2]=1.Br[C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH2:23][CH3:24])[CH:18]=[CH:17]2.N[C@@H]1CCCC[C@H]1N.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH2:23]([N:19]1[C:20]2[C:16](=[CH:15][C:14]([N:9]3[CH2:10][CH2:11][N:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[C:8]3=[O:12])=[CH:22][CH:21]=2)[CH:17]=[CH:18]1)[CH3:24]
Reactant: CCn1ccc2cc(Br)ccc21
Reactant: O=C1NCCN1c1cccnc1
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCn1ccc2cc(N3CCN(c4cccnc4)C3=O)ccc21
Yield: 49.3 %

Procedure:
Using the same reaction conditions as in Example 1, 1-pyridin-3-yl-imidazolidin-2-one (I-1b: 200 mg, 1.226 mmol) was reacted with 5-bromo-1-ethyl-1H-indole (274 mg, 1.226 mmol), 1,4-dioxane (10 mL), copper iodide (23.3 mg, 0.1226 mmol), trans-1,2-diamino cyclohexane (20.99 mg, 1.839 mmol) and potassium carbonate (338 mg, 2.452 mmol) to afford the crude product. Purification by column chromatography on silica gel (30% ethylacetate in hexane), afforded 185 mg of the product (49.33% yield).
Reaction SMILES: [CH2:1]1[NH:6][C:4](=[O:5])[NH:3][CH2:2]1.[F:7][C:8]1[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>>[F:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([N:3]2[CH2:2][CH2:1][NH:6][C:4]2=[O:5])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: O=C1NCCN1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Product: O=C1NCCN1S(=O)(=O)c1ccc(F)cc1

Procedure:
A mixture of 17.2 g of ethyleneurea and 19.5 g of p-fluorobenzene sulphonyl chloride is heated at 110° for 3 1/2 hrs. The residue is recrystallized from a mixture of methanol and water to afford 1-(4-fluorophenylsulphonyl)-2-oxo-tetrahydroimidazole which melts at 183°-185°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[C:14]([F:15])=[C:13]([OH:16])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:17])[CH:11]=2)[C:6]=1Br>CO.[Pd]>[CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[C:14]([F:15])=[C:13]([OH:16])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:17])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1c(F)c(O)c2cc(F)ccc2c1Br
Agent: [Pd]
Solvent: CO
Product: COC(=O)Cc1cc2ccc(F)cc2c(O)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
To a solution of (1-bromo-3,6-difluoro-4-hydroxy-naphthalen-2-yl)-acetic acid methyl ester (50 mg, 0.152 mmol) in methanol was added 10% palladium on carbon (10 mg). After being stirred at room temperature under a hydrogen atmosphere overnight, the resulting mixture was filtered. The filtrate was concentrated in vacuo to afford (3,6-difluoro-4-hydroxy-naphthalen-2-yl)-acetic acid methyl ester (25 mg, 65%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Br:9])[CH:3]=1.[CH3:10][N:11](C=O)C.[Cu]C#N>N1C=CC=CC=1>[Br:9][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([F:8])[CH:5]=1)[C:10]#[N:11]
Reactant: CN(C)C=O
Reactant: Fc1cc(Br)cc(Br)c1
Agent: N#C[Cu]
Solvent: c1ccncc1
Product: N#Cc1cc(F)cc(Br)c1
Temperature: 25 °C
Yield: 35 %

Procedure:
A 250-mL round-bottom flask equipped with a magnetic stir bar was charged with 1,3-dibromo-5-fluorobenzene (7.70 g, 30.3 mmol), DMF (45 mL), pyridine (4.9 mL), and copper (I) cyanide (2.72 g, 30.3 mmol) under nitrogen. A reflux condenser was attached to the flask. The green, cloudy mixture was stirred at reflux for 3 h. Once lower Rf impurities were observed, the reaction was allowed to cool to room temperature. The reaction was quenched with 30 mL of ether, and a precipitate formed in the dark solution. The precipitate was gravity-filtered though Celite. The filtrate was rinsed three times with ether (100 mL/50 g bromide). The isolated solution was added to a separatory funnel. The organic layer was washed with a 2:1 mixture of water and concentrated ammonium hydroxide (30 mL), followed by saturated ammonium chloride solution (2×30 mL) and saturated sodium bicarbonate (30 mL). The aqueous layers were extracted with ether (3×40 mL). The organic layers were combined and dried over anhydrous sodium sulfate. The product was purified by flash column chomatography to yield 3-bromo-5-fluorobenzonitrile (2.10 g, 35%). 1H NMR (400 MHz, CDCl3) δ 7.62 (s, 1H), 7.54-7.50 (m, 1H), 7.35-7.32 (m, 1H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]([Br:24])[CH:17]=[C:18]3[C:23]=2[N:22]=[CH:21][CH:20]=[CH:19]3)[CH2:10][CH2:9]1)C1C=CC=CC=1.ClCCOC(Cl)=O.ClC(OC=C)=O.O>ClC(Cl)C>[Br:24][C:16]1[CH:17]=[C:18]2[C:23](=[C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH:15]=1)[N:22]=[CH:21][CH:20]=[CH:19]2
Reactant: Brc1cc(N2CCN(Cc3ccccc3)CC2)c2ncccc2c1
Agent: C=COC(=O)Cl
Agent: O=C(Cl)OCCCl
Solvent: CC(Cl)Cl
Solvent: O
Product: Brc1cc(N2CCNCC2)c2ncccc2c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
To a solution of 8-(4-benzyl-piperazin-1-yl)-6-bromo-quinoline (1.6 g, 4.2 mmol) in dichloroethane (50 mL) under a N2 atmosphere was added chloroethylchloroformate (1.26 mL, 12.6 mmol) and the reaction mixture was heated at 80° C. for 4 hours, and at ambient temperature overnight. No reaction was observed by TLC, therefore vinyl chloroformate (0.35 mL, 6.3 mmol) was added and the reaction was heated at 80° C. for another 4 hours. The cooled reaction was poured into H2O and extracted into CH2Cl2 (2×100 mL) and EtOAc (100 mL). The organic fractions were combined, dried over Na2SO4, and left in EtOAc overnight. The organic layer was concentrated and purified by column chromatography (10%MeOH/CH2Cl2+NH4OH) affording 1.03 g (84%) of a brown foam. MS (+) APCI m/z 292 [M+H]+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:35][CH2:34][CH2:33][CH:32]2[C:36]2[CH:37]=[C:38]([C:53](O)=[O:54])[CH:39]=[C:40]3[C:45]=2[O:44][C:43]([N:46]2[CH2:51][CH2:50][O:49][CH2:48][CH2:47]2)=[CH:42][C:41]3=[O:52])[CH:27]=[C:28]([F:30])[CH:29]=1.CCN(C(C)C)C(C)C.Cl.[NH:66]1[CH2:71][CH2:70][S:69](=[O:72])[CH2:68][CH2:67]1>C(Cl)Cl>[F:30][C:28]1[CH:27]=[C:26]([N:31]2[CH2:35][CH2:34][CH2:33][CH:32]2[C:36]2[CH:37]=[C:38]([C:53]([N:66]3[CH2:71][CH2:70][S:69](=[O:72])[CH2:68][CH2:67]3)=[O:54])[CH:39]=[C:40]3[C:45]=2[O:44][C:43]([N:46]2[CH2:51][CH2:50][O:49][CH2:48][CH2:47]2)=[CH:42][C:41]3=[O:52])[CH:25]=[C:24]([F:23])[CH:29]=1
Reactant: O=C(O)c1cc(C2CCCN2c2cc(F)cc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1
Reactant: O=S1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1cc(C2CCCN2c2cc(F)cc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1)N1CCS(=O)CC1
Reaction time: 2.5 h
Yield: 57.8 %

Procedure:
TBTU (176 mg, 0.55 mmol) was added in one portion to a stirred solution of 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (125 mg, 0.27 mmol) and DIPEA (0.286 mL, 1.64 mmol) at room temperature and stirred for 2.5 h. Thiomorpholine 1-oxide hydrochloride (85 mg, 0.55 mmol) was added to the reaction mixture and stirring was continued for 3 h. The reaction mixture was diluted with DCM, washed with water, brine, dried over MgSO4 and concentrated. The residue was purified by preparative HPLC. The fractions were evaporated to dryness, the residue was dissolved in DCM, dried over MgSO4 and concentrated. The remaining solid was triturated with diethyl ether, filtered, washed with diethyl ether and dried under vacuum at 50° C. to afford 8-[1-(3,5-difluorophenyl)pyrrolidin-2-yl]-2-morpholino-6-(1-oxo-1,4-thiazinane-4-carbonyl)chromen-4-one (87 mg, 57%) as a pale beige solid.
Reaction SMILES: [CH2:1]([O:15][C:16]1[O:20][C:19]([C:21]([O:23][CH2:24][CH2:25]Br)=[O:22])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH3:27][NH:28][CH3:29]>C1COCC1>[CH2:1]([O:15][C:16]1[O:20][C:19]([C:21]([O:23][CH2:24][CH2:25][N:28]([CH3:29])[CH3:27])=[O:22])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)OCCBr)o1
Reactant: CNC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)OCCN(C)C)o1
Temperature: 25 °C
Reaction time: 12 h
Yield: 71 %

Procedure:
To a solution of 2-bromoethyl 5-(tetradecyloxy)furan-2-carboxylate (0.186 g, 0.43 mmol) (prepared in Example 5) in THF at 0° C. was added dimethylamine (1 mL of a 2M solution in THF, 2.15 mmol) with stirring. The solution was allowed to warm to room temperature and stirring was continued for 12 hrs at which time the reaction was concentrated to dryness. The crude material was purified by flash chromatography eluting with ethyl acetate in hexanes (5-35%) to yield 0.121 g (71%) of the title compound as a waxy, colourless solid. MS (m/z, ES+): 396.29 (M+1, 100%); 1H NMR (400 MHz, DMSO-d6) δ: 7.2 (d, 1H), 5.6 (d, 1H), 4.23 (t, 2H), 4.13 (t, 2H), 2.53 (t, 2H), 2.18 (s, 6H), 1.7 (p, 2H), 1.2-1.5 (m, 22H), 0.85 (t, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[F:26][C:27]([F:49])([F:48])[C:28]1[CH:33]=[CH:32][C:31]([S:34]([N:37]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39]([CH:46]=O)=[CH:38]2)(=[O:36])=[O:35])=[CH:30][CH:29]=1.N1CCCCC1>CO>[OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])/[C:7](=[CH:46]/[C:39]3[C:40]4[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=4)[N:37]([S:34]([C:31]4[CH:32]=[CH:33][C:28]([C:27]([F:49])([F:26])[F:48])=[CH:29][CH:30]=4)(=[O:36])=[O:35])[CH:38]=3)/[O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Reactant: O=Cc1cn(S(=O)(=O)c2ccc(C(F)(F)F)cc2)c2ccccc12
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2cn(S(=O)(=O)c4ccc(C(F)(F)F)cc4)c4ccccc24)C3=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.1 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.0500 g, 0.144 mmol) obtained in Example A16, Step 1 in methanol (0.6 mL) was added with 1-[4-(trifluoromethyl)phenylsulfonyl]-1H-indole-3-carboxaldehyde (0.0509 g, 0.144 mmol) and piperidine (0.00123 g, 0.0144 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was added with methanol (1 mL), and the solid was suspended in methanol and thereby washed to obtain tert-butyl (Z)-4-([6-hydroxy-3-oxo-2-({1-[4-(trifluoromethyl)phenylsulfonyl]-1H-indol-3-yl}methylene)-2,3-dihydrobenzofuran-7-yl]methyl)piperazine-1-carboxylate (0.0759 g, 77%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:11][CH:12]2[CH2:17][CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13]2)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1.Cl.CO>O1CCOCC1>[ClH:1].[Cl:1][C:2]1[N:3]=[C:4]([NH:11][CH:12]2[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]2)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(Nc2nc(Cl)nc3c2SCC3)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Clc1nc2c(c(NC3CCCNC3)n1)SCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 180.4 %

Procedure:
1.77 g (4.8 mmol) of tert-butyl 3-(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamino)piperidin-1-carboxylate (V) is placed in 21.5 mL of a 4% hydrochloric acid solution in dioxane, and methanol is added. The solution is stirred for 0.5 hours at ambient temperature, whereupon a precipitate is formed. This is suction filtered, washed with diethyl ether, and dried. 1.33 g of product (VI) (91%) is obtained.