Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][CH:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:11][CH2:12][CH2:13][Cl:14]>CC(C)=O>[Cl:14][CH2:13][CH2:12][CH2:11][N:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH:8]=[O:9]
Reactant: O=CNc1ccccc1
Reactant: ClCCCBr
Solvent: CC(C)=O
Product: O=CN(CCCCl)c1ccccc1
Yield: 85.4 %

Procedure:
To a mixture of phenylformamide (49.6 g, 410 mmol), 1-bromo-3-chloropropane (75.4 g, 490 mmol) in acetone (400 mL) was added CsCO3 (156.4 g, 480 mmol) and the resulting mixture was stirred at reflux temperature for 14 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Ethyl acetate (400 mL) and water (150 mL) were added to the residue and the organic layer was washed with brine (150 nL), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane-ethyl acetate, 1/0 to 10/3, v/v) to give 3-chloropropyl(phenyl)formamide (69.1 g, 350 mmol) as pale yellow oil. Yield: 85%. To a solution of this pale yellow oil (36.2 g, 180 mmol) in 2-propanol (140 mL) was added conc. HCl (25 mL) and the mixture was stirred at 70° C. for 3 hours. The reaction mixture was cooled to r.t. and diisopropyl ether (140 mL), was added. The resulting mixture was allowed to stand at r.t. for 12 hours, that led precipitation of crystals. The crystals were collected by filtration and washed with diisopropyl ether (10 mL×2) to give N-(3-chloropropyl)aniline hydrochloride (13.7 g, 57 mmol) as colorless needles. The combined filtrates were concentrated under reduced pressure and recrystallized from diisopropyl ether-2-propanol (1/2, v/v) to give N-(3-chloropropyl) aniline hydrochloride (19.5 g, 81 mmol). Yield: 76%. From N-(3-chloropropyl)aniline hydrochloride (5.0 g, 21 mmol), using a similar procedure to that described for reference example 57, the title compound (7.0 g, 19 mmol) was obtained as colorless crystals. Yield: 90%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:7]=2)[CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: Fc1ccc2[nH]ncc2c1
Product: CCOC(=O)Cn1cc2cc(F)ccc2n1

Procedure:
The title compound was prepared according to the method described for Preparation 93 using 5-fluoro-1H-indazole and ethyl bromoacetate to afford the title compound as an off-white solid in 27% yield, 130 mg.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([CH2:14][O:15]C(=O)C)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:25](I)[CH2:26][CH:27]([CH3:29])[CH3:28].C(Cl)(=O)C>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([CH2:14][OH:15])[N:10]([CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: CC(C)CCI
Reactant: COC(=O)c1cccc2[nH]c(COC(C)=O)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CC(=O)Cl
Product: COC(=O)c1cccc2c1nc(CO)n2CCC(C)C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-acetoxymethyl-1H-benzoimidazole-4-carboxylic acid methyl ester (2.09 g, 8.42 mmol) and cesium carbonate (4.1 g, 12.6 mmol) in DMF (15 mL) at ambient temperature was added isoamyl iodide (1.34 mL, 10.1 mmol). The mixture was stirred overnight and DMF was removed in vacuo. The residue was suspended in water and extracted with ethyl acetate (twice), the combined organic phases were washed with brine, dried (MgSO4) and concentrated. The residue (2-acetoxymethyl-1-(3-methyl-butyl)-1H-benzoimidazole-4-carboxylic acid methyl ester) was dissolved in methanol (20 mL) and cooled to 0° C., followed by the addition of acetyl chloride (6.0 mL, 84 mmol) and slowly allowed to reach room temperature. After stirring for 3 hrs the volatiles were removed in vacuo and the residue triturated in ethyl acetate to afford 2-hydroxymethyl-1-(3-methyl-butyl)-1H-benzoimidazole-4-carboxylic acid methyl ester after filtration (1.98 g, 85% over 2 steps) as a white solid. 1H NMR Analysis of the crude acetate indicated that the desired N-1 regioisomer was contaminated with the N-3 isomer (ca. 15%), which was efficiently eliminated by the ethyl acetate wash (<2%). The 1H NMR spectral data of the regioisomeric impurity 2-acetoxymethyl-3-(3-methyl-butyl)-3H-benzoimidazole-4-carboxylic acid methyl ester matched those of an authentic sample prepared via an independent route.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:28])([F:27])[O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[NH:14][C:13]2=[O:26])=[CH:8][CH:7]=1.Cl[CH2:30][O:31][CH2:32][CH3:33]>CN(C)C=O>[CH2:32]([O:31][CH2:30][N:14]1[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])=[CH:16][C:17](=[O:18])[N:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][C:4]([F:3])([F:27])[F:28])=[CH:7][CH:8]=2)[C:13]1=[O:26])[CH3:33]
Reactant: CCOCCl
Reactant: O=c1cc(-c2ccccc2Cl)[nH]c(=O)n1-c1ccc(OC(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCn1c(-c2ccccc2Cl)cc(=O)n(-c2ccc(OC(F)(F)F)cc2)c1=O
Temperature: 0 °C
Yield: 73.1 %

Procedure:
0.5 g of sodium hydride (purity: 55%) was added to 50 ml of dimethylformamide, and then 3.8 g of 3-(4-trifluoromethoxyphenyl)-6-(2-chlorophenyl)-2,4(1H,3H)-pyrimidinedione was added to the solution with stirring at 0° C. The resulting solution was stirred at room temperature for 15 minutes, then added dropwise with 1.3 g of chloromethylethyl ether and further stirred at room temperature for 3 hours. The reaction mixture was added into 200 ml of ice water and extracted with 200 ml of ethyl acetate. The organic layer was washed with water and dried, and then the solvent was distilled away under reduced pressure to obtain 3.8 g of a crude product. This crude product was recrystallized from diisopropyl ether to obtain 3.2 g of the objective compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH3:20])[NH:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1.[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH3:20])[N:11]([C:28](=[O:29])[NH:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2n[nH]c(-c3ccccc3C)n2)c1
Reactant: O=C=Nc1ccccc1
Solvent: CC#N
Product: COc1cccc(-c2nc(-c3ccccc3C)n(C(=O)Nc3ccccc3)n2)c1
Reaction time: 8 h

Procedure:
A solution of 0.53 g (0.002 mole) of 3-(3-methoxyphenyl)-5-(2-methylphenyl)-1H-1,2,4-triazole and 0.22 ml. (0.002 mole) of phenylisocyanate in 5 ml of acetonitrile was strred for 7 hours at room temperature and, subsequently, it was left standing overnight. The solvent was evaporated off and the obtained residue was firts taken up with hexane, then, after separating the liquid and the solid phase by decantation, it was recrystallized from acetonitrile. Yield: 0.25 g of the title compund. M.p. 123°-125° C. Δ δ=-0.18.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].ClCCl.Cl[C:9]([CH3:17])([CH2:11][CH2:12][C:13](Cl)([CH3:15])[CH3:14])[CH3:10].[C:18]1([OH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>[Cl-].[Cl-].C>[CH3:10][C:9]1([CH3:17])[CH2:11][CH2:12][C:13]([CH3:15])([CH3:14])[C:22]2[CH:23]=[C:18]([OH:24])[CH:19]=[CH:20][C:21]1=2
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Reactant: Oc1ccccc1
Agent: C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc(O)ccc21
Temperature: 35 °C
Yield: 90.8 %

Procedure:
To a mixture of aluminum trichloride (3.0 g, 22.5 mmol), dichloromethane (50 ml) and 2,5-dichloro-2,5-dimethylhexane (15.0 g, 81.9 mmol) is added dropwise into a solution of phenol (7.7 g, 81.90 mmol) in 50 ml of methane dichloride, then the reaction mixture is heated for 4 hours at 35° C. After cooled, the reaction mixture is poured into ice (200 g) and extracted with ether (3×80 ml). The organic phase is washed with 10% NaHCO3 solution (2×150 ml), dried over MgSO4 and evaporated to give a crude product, which is crystallized from ethanol to give the title compound (15.20 g, 84%).
Reaction SMILES: CCCCCCC.[N+:8]([CH2:11][C@:12]1([CH2:19][C:20]([O:22]CC)=[O:21])[CH2:18][C@@H:17]2[C@H:13]1[CH2:14][CH2:15][CH2:16]2)([O-:10])=[O:9].O1CCCC1.[OH-].[Na+]>O>[N+:8]([CH2:11][C@:12]1([CH2:19][C:20]([OH:22])=[O:21])[CH2:18][C@@H:17]2[C@H:13]1[CH2:14][CH2:15][CH2:16]2)([O-:10])=[O:9]
Reactant: CCOC(=O)C[C@@]1(C[N+](=O)[O-])C[C@H]2CCC[C@H]21
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C[C@@]1(C[N+](=O)[O-])C[C@H]2CCC[C@H]21
Reaction time: 16 h
Yield: 96.9 %

Procedure:
The n-heptane from the organic solution of the nitro ester of Example 7 (1.08 Kg; 4.49 mol) was replaced with tetrahydrofuran by azeotropic distillation at atmospheric pressure and constant volume. The solution was cooled to +25° C. and a solution of sodium hydroxide (0.359 Kg; 8.98 mol) in demineralised water (4.5 L) was added and the reaction stirred for 16 hours. n-Heptane (4.5 L) was added and the phases were separated. The aqueous phase was adjusted to pH 2–4 by the addition of concentrated hydrochloric acid (0.8 L) giving a suspension. The aqueous phase was extracted with ethyl acetate (9.6 L) to give the title product (0.928 Kg) in 97% yield as an organic solution which is used directly in the next step.
Reaction SMILES: C(N(CC)CC)C.[N:8]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:9]=[O:10].[OH:17][C:18]1[C:23](=[O:24])[CH:22]=[CH:21][N:20]([CH3:25])[C:19]=1[CH3:26]>C(#N)C.C(Cl)Cl>[CH2:15]([O:14][C:12]([CH2:11][NH:8][C:9]([O:17][C:18]1[C:23](=[O:24])[CH:22]=[CH:21][N:20]([CH3:25])[C:19]=1[CH3:26])=[O:10])=[O:13])[CH3:16]
Reactant: Cc1c(O)c(=O)ccn1C
Reactant: CCOC(=O)CN=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)CNC(=O)Oc1c(C)n(C)ccc1=O
Reaction time: 0.25 h

Procedure:
With stirring, 1.4 ml of triethylamine 1.7 ml of ethyl isocyanatoacetate are added at room temperature to a suspension of 1.39 g of 3-hydroxy-1,2-dimethyl-4(1H)-pyridinone in 100 ml of acetonitrile and 100 ml of methylene chloride, followed by the addition of 1.7 ml of ethyl isocyanatoacetate. The ensuing reaction is slightly exothermic. The solution that forms after about 15 minutes is concentrated by evaporation under reduced pressure after a further 45 minutes. The residue is dried under a high vacuum and crystallized from a mixture of methylene chloride and ethyl acetate. The crude crystalline product is taken up in 10 ml of methanol, insoluble material is removed by filtration, and the filtrate is concentrated by evaporation under reduced pressure. The residue is crystallised from a mixture of methylene chloride/ethyl acetate, affording 3-(ethoxycarbonylmethylaminocarbonyloxy)-1,2-dimethyl-4(1H)-pyridinone with a melting point of 132°-135° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[N:8]3[CH2:11][CH2:12][NH:13][C:7]3([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH2:6][N:5]2[CH:21]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>COCCOC.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.O>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:7]23[NH:13][CH2:12][CH2:11][N:8]2[C:9](=[O:10])[C:4]2[N:5]([CH:21]=[C:2]([C:24]4[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=4)[CH:3]=2)[CH2:6]3)=[CH:15][CH:16]=1
Reactant: O=C1c2cc(Br)cn2CC2(c3ccc(Cl)cc3)NCCN12
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: O=C1c2cc(-c3cccnc3)cn2CC2(c3ccc(Cl)cc3)NCCN12
Temperature: 150 °C
Yield: 39.2 %

Procedure:
7-bromo-10a-(4-chlorophenyl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (50 mg, 0.14 mmol), pyridine-3-boronic acid (18.5 mg, 0.15 mmol), dichlorobis(triphenylphosphine)palladium(II) (1.9 mg, 2.7 μmol) and sodium carbonate (22 mg, 0.21 mmol) were suspended in a mixture of 1,2-dimethoxyethane (1.4 mL), ethanol (200 μL) and water (300 μL). The reaction vessel was flushed with argon, sealed and heated in a microwave reactor at 150° C. for 10 min. After this time water (50 mL) was added and the mixture extracted with CH2Cl2. The organic layer was separated, dried (MgSO4) and concentrated in vacuo to give a crude mixture. This mixture was purified by flash chromatography (Biotage SP4, 12 g cartridge, 0-10% MeOH gradient in CH2Cl2) to give 10a-(4-chlorophenyl)-7-(pyridin-3-yl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one as a white solid (20 mg, 40% yield). 1H NMR (400 MHz, d6-acetone): δ 3.30-3.31 (m, 1H), 3.33-3.40 (m, 1H), 3.43-3.50 (m, 1H). 3.75 (dt, 1H, J 10.8, 8.0 Hz), 4.46 (d, 1H, J 12.4 Hz), 4.74 (d, 1H, J 12.4 Hz), 7.14 (d, 1H, J 1.8 Hz), 7.23 (d, 1H, J 1.8 Hz), 7.27 (ddd, 1H, J 8.0, 4.8, 0.9 Hz), 7.32-7.36 (m, 2H), 7.40-7.44 (m, 2H), 7.85 (ddd, 1H, J 7.9, 2.4, 1.7 Hz), 8.34 (dd, 1H, J 4.7, 1.6 Hz), 8.75 (dd, 1H, J 2.4, 0.8 Hz).
Reaction SMILES: Cl.O[CH2:3][C@H:4]1[N:14]2[C:15]3[N:6]([C:7](=[O:17])[CH2:8][CH2:9][C:10]=3[CH:11]=[CH:12][C:13]2=[O:16])[CH2:5]1.C(N(CC)CC)C.CS(Cl)(=O)=O.CS([O-])(=O)=O.[F:35][C:36]([F:47])([F:46])[C:37]([NH:39][CH2:40][C@@H:41]1[CH2:45][CH2:44][NH:43][CH2:42]1)=[O:38]>C(Cl)Cl>[O:16]=[C:13]1[CH:12]=[CH:11][C:10]2[CH2:9][CH2:8][C:7](=[O:17])[N:6]3[CH2:5][C@@H:4]([CH2:3][N:43]4[CH2:44][CH2:45][C@@H:41]([CH2:40][NH:39][C:37](=[O:38])[C:36]([F:46])([F:47])[F:35])[CH2:42]4)[N:14]1[C:15]=23
Reactant: O=C1CCc2ccc(=O)n3c2N1C[C@H]3CO
Reactant: O=C(NC[C@@H]1CCNC1)C(F)(F)F
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCc2ccc(=O)n3c2N1C[C@H]3CN1CC[C@@H](CNC(=O)C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.9 %

Procedure:
To a 100 mL round-bottomed flask was added (1S)-1-(hydroxymethyl)-1,2,5,6-tetrahydro-4H,9H-imidazo[1,2,3-ij]-1,8-naphthyridine-4,9-dione HCl (for a preparation see Example 47(c)) (350 mg, 1.589 mmol), triethylamine (0.266 ml, 1.907 mmol) in DCM (20 ml) 0° C. to give a orange solution. Methane sulfonylchloride (0.135 ml, 1.748 mmol) was added and the reaction was allowed to warm to rt and stir for 1 h. LCMS indicated that the methanesulfonate had formed. The reaction was diluted with DCM (100 mL) and washed with 2×25 mL of a saturated aqueous NaHCO3 solution. The organic phase was separated and dried over Na2SO4. The solution was concentrated under vacuum, diluted with acetonitrile (20.00 ml) and pyridine (0.500 ml) was added. 2,2,2-trifluoro-N-[(3R)-3-pyrrolidinylmethyl]acetamide (550 mg, 2.364 mmol) was added and the reaction was heated to 80° C. and stirred for 25 h. LCMS indicated a complete reaction. The reaction was cooled to rt and concentrated under vacuum. The reaction mixture was diluted with DCM (100 mL) and washed with 25 mL of a saturated NaHCO3 solution. The organic phase was separated and dried over Na2SO4. The crude product was purified on silica eluting with 0-15% MeOH/DCM to give product (240 mg, 0.602 mmol, 37.9% yield) as a pale yellow oil.
Reaction SMILES: C([C:4]1[S:8][C:7]2[S:9][C:10]([C:12]([C:14]3[CH:15]=[C:16]([CH:20]([CH2:24][CH3:25])[C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:11][C:6]=2[CH:5]=1)(O)=O.Cl.C(#N)C>N1C2C(=CC=CC=2)C=CC=1.[Cu]>[S:9]1[C:7]2[S:8][CH:4]=[CH:5][C:6]=2[CH:11]=[C:10]1[C:12]([C:14]1[CH:15]=[C:16]([CH:20]([CH2:24][CH3:25])[C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=1)=[O:13]
Reactant: CCC(C(=O)O)c1cccc(C(=O)c2cc3cc(C(=O)O)sc3s2)c1
Agent: [Cu]
Agent: Cl
Solvent: c1ccc2ncccc2c1
Solvent: CC#N
Product: CCC(C(=O)O)c1cccc(C(=O)c2cc3ccsc3s2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 56.7 %

Procedure:
2-{3-(5-Carboxy-thieno[2,3-b]thien-2-yl)carbonyl-phenyl}butyric acid (15.6 g) and copper powder (1 g) are suspended in quinoline (150 cc) and heated at 195°-200° C. for 20 minutes, and then at the boil for 10 minutes. After cooling, ice (300 g) and a 12 N concentrated aqueous solution of hydrogen chloride (100 cc) are added to the reaction mixture, which is extracted three times with methylene chloride (total 600 cc). The combined methylene chloride solutions are washed three times with distilled water (total 300 cc), and then extracted twice with a 2 N aqueous solution of sodium hydroxide (total 400 cc) and three times with distilled water (total 600 cc). The combined aqueous alkaline phases are acidified to pH 1 by the addition of a 12 N concentrated aqueous solution of hydrogen chloride and extracted three times with methylene chloride (total 450 cc). The combined methylene chloride solutions are washed three times with distilled water (total 300 cc), dried over anhydrous sodium sulphate in the presence of decolourizing charcoal (5 g), filtered and evaporated. The residue obtained (9.3 g) is dissolved in boiling acetonitrile (70 cc). After cooling, starting the crystallization and standing for one hour at 4° C., the resulting crystals are filtered off, washed once with iced acetonitrile (15 cc) and dried under reduced pressure (20 mm Hg) at a temperature of about 20° C., in the presence of potassium hydroxide pellets. Crude 2-{3-(thieno[2,3-b]thien-2-yl)carbonyl-phenyl}butyric acid (7.8 g), melting at 143° C., is thus obtained.
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].CCN(C(C)C)C(C)C.Br[CH:15]1[CH2:19][CH2:18][O:17][C:16]1=[O:20]>C1COCC1>[OH:4][CH2:3][CH2:2][S:1][CH:15]1[CH2:19][CH2:18][O:17][C:16]1=[O:20]
Reactant: OCCS
Reactant: O=C1OCCC1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C1OCCC1SCCO
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-mercapto-ethanol (2560 μmol) in THF (4 ml) were added DIEA (1.1 eq) and 3-bromo-dihydro-furan-2-one (1 eq). The reaction mixture was stirred at RT for 4 hours. The precipitate was filtered and the solvent was removed under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[CH:4][CH:3]=1.[Br:10][C:11]1[N:16]=[C:15]([C:17](O)=[O:18])[C:14]([O:20][CH3:21])=[CH:13][CH:12]=1.C(N(CC)CC)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C(Cl)Cl.O>[Br:10][C:11]1[N:16]=[C:15]([C:17]([NH:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:18])[C:14]([O:20][CH3:21])=[CH:13][CH:12]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: COc1ccc(Br)nc1C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Br)nc1C(=O)NCc1ccc(Cl)cc1
Yield: 84.8 %

Procedure:
To a solution of (4-chlorophenyl)methanamine (610 mg, 4.31 mmol), 6-bromo-3-methoxypicolinic acid (1.0 g, 4.31 mmol) and triethylamine (1.31 g, 12.9 mmol) in DCM (10 mL) was added dropwise T3P (2.74 g, 8.61 mmol) at 0° C. Five minutes later, TLC indicated the reaction was complete, and the mixture was suspended in water and extracted with DCM. The organic phase was washed with brine, dried over sodium sulfate and concentrated in vacuo to give the crude 6-bromo-N-(4-chlorobenzyl)-3-methoxypicolinamide (1.3 g, yield: 87%) without further purification. 1H-NMR (DMSO-d6, 400 MHz) δ 8.98 (t, J=6.0 Hz, 1H), 7.69 (d, J=8.8 Hz, 1H), 7.58 (d, J=8.8 Hz, 1H), 7.39˜7.43 (m, 2H), 7.33 (d, J=8.4 Hz, 2H), 4.22 (d, J=6.4 Hz, 2H), 3.84 (s, 3H). MS (M+H)+: 355/357.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH:11]=[CH:10][N:9]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]2=[N:7][CH:8]=1.[CH:21]([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.CI>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([CH3:21])[N:9]([S:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)(=[O:14])=[O:13])[C:6]2=[N:7][CH:8]=1
Reactant: CC(C)[N-]C(C)C
Reactant: COc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Solvent: CC(C)NC(C)C
Product: COc1cnc2c(c1)cc(C)n2S(=O)(=O)c1ccccc1
Temperature: -25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
A solution of 5-methoxy-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (900 mg, 3.12 mmol) in THF (22.5 ml) was added dropwise to a solution of lithium diisopropylamide (prepared from nBu-Li (2.5M in hexane); 2.5 ml) and diisopropylamine (874 μl) in THF (13.5 ml)) cooled at −25° C. and the mixture was stirred for 30 minutes. Methyl iodide (215 μl, 3.44 mmol) in THF (9 ml) was then added dropwise and the mixture was stirred for 10 minutes at −25° C., left to warm up to ambient temperature and stirred for 15 minutes. The mixture was then poured onto ice/water. The mixture was then extracted with ethyl acetate. The organic layer was separated, washed with water, brine, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography, eluting with ethyl acetate/petroleum ether (20/80 followed by 30/70). The fractions containing the expected product were combined and evaporated to give 5-methoxy-2-methyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (805 mg, 85%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:7]([C:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)=[O:8].CN(C)C=O.Br[CH2:30][C:31]1[C:36]([F:37])=[CH:35][CH:34]=[CH:33][N:32]=1>C(#N)C>[CH3:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:7]([C:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:30][C:31]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][N:32]=2)[CH:10]=1)=[O:8]
Reactant: Fc1cccnc1CBr
Reactant: Cc1ccc(C(=O)c2c[nH]c3ccccc3c2=O)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)c2cn(Cc3ncccc3F)c3ccccc3c2=O)cc1C

Procedure:
Compound 4ll was prepared following the procedure outlined in Step 3 of Example 1 using 26 mg (0.65 mmol) of sodium hydride (60%), 138.6 mg (0.50 mmol) of 3-(3,4-Dimethyl-benzoyl)-2,3-dihydro-1H-quinolin-4-one 3a, 3 mL of anhydrous dimethylformamide, and 123.5 mg (0.65 mmol) of 2-bromomethyl-3-fluoro-pyridine. The crude product was purified by flash chromatography to yield 96 mg of 4ll as a colorless solid: LC-MSD, m/z for C24H19FN2O2, [M+H]+=387.5, [M+2H]+=388.5; Reverse phase HPLC (gradient acetonitrile 0.1% TFA 20-95% in 4 min) retention time=2.192 min; 1H NMR (400 MHz, CDCl3/HCl): δ 2.30 (d, 6H), 5.56 (s, 2H), 7.17 (d, 1H), 7.31 (m, 1H), 7.38 (t, 1H), 7.46 (t, 1H), 7.56-7.70 (m, 4H), 8.35-8.42 (m, 2H), 8.42-8.47 (m, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].Cl.[CH3:17]O>>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:17])=[O:14]
Reactant: NCCCCCCCCCCCC(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)CCCCCCCCCCCN
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
To a suspension of 12-aminododecanoic acid (5.00 g, 23.3 mmol) in anhydrous MeOH (90 mL) was introduced hydrogen chloride gas for 25 minutes, during which time the suspension became clear. The solution was then stirred at room temperature for 3 hours and the solvent was removed in vacuo. The white solid residue was dissolved in H2O. Solid NaHCO3 was added to neutralize the solution to pH 8-9. The white precipitates thus formed were collected by vacuum filtration (5.20 g) (Yield: 98%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:31]=[CH:30][C:11]([C:12]([NH:14][C:15]3[C:16]4[CH:22]=[C:21]([C:23]([O:25]C(C)(C)C)=[O:24])[S:20][C:17]=4[NH:18][N:19]=3)=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[ClH:32]>O1CCOCC1>[ClH:32].[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([NH:14][C:15]3[C:16]4[CH:22]=[C:21]([C:23]([OH:25])=[O:24])[S:20][C:17]=4[NH:18][N:19]=3)=[O:13])=[CH:30][CH:31]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4sc(C(=O)OC(C)(C)C)cc34)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4sc(C(=O)O)cc34)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of tert-butyl 3-{[4-(4-methylpiperazin-1-yl)benzoyl]amino}-1H-thieno[2,3-c]pyrazole-5-carboxylate (0.50 g, 1.1 mmol) in hydrochloric acid 4M in dioxane (15 mL) was stirred for 16 hours at room temperature. Afterward, volatiles were removed by evaporation under reduced pressure and the residue was triturated with ethyl ether to give 0.496 g of the title compound as a white solid.