Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:9]=[C:10]([C:14]2[N:22]([CH2:23][C:24]([OH:26])=O)[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)[CH:11]=[CH:12][CH:13]=1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.C(N(CC)CC)C>CN(C)C=O>[Cl:7][C:8]1[CH:9]=[C:10]([C:14]2[N:22]([CH2:23][C:24]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[O:26])[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: Nc1ccccn1
Reactant: O=C(O)Cn1c(-c2cccc(Cl)c2)nc2cccnc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Cn1c(-c2cccc(Cl)c2)nc2cccnc21)Nc1ccccn1
Temperature: 0 °C
Yield: 15.8 %

Procedure:
Under a nitrogen atmosphere, oxalyl chloride (2.38 g, 0.019 mole) was added slowly dropwise to a stirred and chilled (15°-20° C.) solution of 2-(3-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.70 g, 0.016 mole) in 50 ml of dimethylformamide. The reaction mixture was stirred at ambient temperature for 1/2 hr., then warmed to 60°-65° C. for 5 hrs. This acylchloride solution was added dropwise under nitrogen to a stirred and chilled (15°-20° C.) solution of 2-aminopyridine (1.76 g, 0.019 mole), triethylamine (1.89 g, 0.019 mole), and 30 ml of dimethylformamide. The reaction mixture was stirred at room temperature over the weekend. The reaction mixture was poured into 400 ml of ice water and extracted with ethyl acetate (3×). The ethyl acetate layers were washed with 5% potassium hydroxide (2×50 ml), water (2×50 ml), dried, and filtered. The residue was treated with isopropyl alcohol and excess ethereal hydrogen chloride to give solid which was recrystallized twice from isopropyl alcohol-isopropyl ether and once from isopropyl alcohol. The solid was collected by filtration, washed with cold isopropyl alcohol, then isopropyl alcohol-water, and dried under high vacuum for 2 days to give 0.92 g (15.8%) of title compound, mp 165°-66° C.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[CH2:29][CH2:30][NH2:31].[BH4-].[Na+]>CO>[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[CH2:29][CH2:30][NH:31][CH2:1][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1
Reactant: NCCc1ccc(F)cc1F
Reactant: COc1cc(C=O)ccc1Oc1ccc(C(N)=O)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(CNCCc2ccc(F)cc2F)ccc1Oc1ccc(C(N)=O)cn1
Reaction time: 8 h

Procedure:
Place 6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B) (0.300 g, 1.10 mmol), 2-(2,4-difluorophenyl)ethylamine (0.343 g, 2.184 mmol) and 3 Å molecular sieves in a vial. Add methanol (4.4 mL), cap and stir overnight. Add NaBH4 (ca. 3-5 eq in two portions) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 2% to 20% (2.0 M NH3 in methanol) in ethyl acetate to give 6-(4-{[2-(2,4-difluorophenyl)ethylamino]methyl}-2-methoxyphenoxy)nicotinamide. Dissolve the compound in methanol (5.0 mL) and add 1 equivalent of 0.50 M methanesulfonic acid in dichloromethane. Stir the solution for a short time before concentrating to give the title compound: TOF MS ES+ 414.2 (M+H)+, HRMS calcd for C22H22N3O3F, 414.1629 (M+H)+, found 414.1613, time 0.52 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.14% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18 min], tR=11.6 min, 100% purity.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([S:7](O)(=[O:9])=[O:8])=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:19])=O>>[C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([S:7]([Cl:19])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: O=S(=O)(O)c1ccc(-c2ccccc2)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1

Procedure:
4-Biphenylsulfonic acid (3.0 g, 12.8 mmol) was heated at 70° C. with phosphorus oxychloride (1.30 ml, 14.0 mol) for 2 h. Excess phosphorus oxychloride was removed under reduced pressure. The residue was decomposed with ice water and extracted with ethyl acetate. The extract was washed with 5% sodium bicarbonate solution, dried over anhydrous magnesium sulfate and concentrated to yield 2.9 crude 4-biphenylsulfonyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[Br:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:21])=[C:17]([CH:20]=1)[CH:18]=O>>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:21])=[C:17]([CH2:18][C:10]2[S:9][C:8]3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=3[CH:11]=2)[CH:20]=1
Reactant: O=Cc1cc(Br)ccc1Cl
Reactant: COc1cccc2ccsc12
Product: COc1cccc2cc(Cc3cc(Br)ccc3Cl)sc12

Procedure:
7-Methoxybenzo[b]thiophene (see WO 02/094262) and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1) were treated in a manner similar to Reference Example 9 to give the target compound. APCI-Mass m/Z 367/369 (M+H).
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][NH:3]1.[I:12]N1C(=O)CCC1=O>C(Cl)Cl>[I:12][C:5]1[CH:6]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:2](=[O:1])[NH:3][CH:4]=1
Reactant: COC(=O)c1ccc[nH]c1=O
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Product: COC(=O)c1cc(I)c[nH]c1=O
Yield: 46.7 %

Procedure:
A solution containing 19.48 g of methyl 2-oxo-1,2-dihydro-3-pyridinecarboxylate and 36.15 g of N-iodosuccinimide in 500 ml of anhydrous methylene chloride is heated at reflux under a nitrogen atmosphere in the dark for 48 hours. The reaction mixture is concentrated to 150 ml under reduced pressure and the solid which forms is collected by filtration and washed with small portions of cold methylene chloride and benzene to give 16.59 g (47%) of methyl 5-iodo-2-oxo-1,2-dihydro-3-pyridinecarboxylate as a pale yellowish solid. This material is sufficiently pure for the next reaction; its properties upon recrystallization from ethyl acetate are as follows: m.p. 190°-192° C.; NMR (DMSO-d6, 300 MHz) delta 3.71 (s, 3H), 7.93 (d, 1H, J=2.26 Hz), 8.10 (d, 1H, J=2.26 Hz), IR (KBr) 2500-3050 (broad), 1725, 1630, 1585, 1475, 1425, 1320, 1260, 1235, 1180, 1150, 1105, 1065, 965, 875 and 800 cm-1 ; M/S (279, M+), 247, 127 and 93. Anal. Calcd. for C7H6INO3 : C, 30.13; H, 2.17; I, 45.48; N, 5.02. Found: C, 30.24; H, 2.22; I, 45.55: N, 4.87. The filtrate is evaporated and the residue dissolved in 500 ml of methylene chloride. The organic solution is extracted with a 10% sodium thiosulfate solution, washed with a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solution is concentrated under reduced pressure and the residue triturated with ethyl acetate and filtered to yield an additional 5.49 g (15%) of methyl 5-iodo-2-oxo-1,2-dihydro-3-pyridinecarboxylate.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[CH2:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[C:13]1([CH2:12][O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[C:7](=[O:11])[CH2:6][CH2:5]3)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1CCc2cc(O)ccc21
Reactant: OCc1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: O=C1CCc2cc(OCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.4 %

Procedure:
To a solution of 5-hydroxyindanone (1.0 g, 6.2 mmol), benzyl alcohol (0.65 g, 5.6 mmol) and tributylphosphine (1.7 g, 8.4 mmol) in tetrahydrofuran (30 mL) was added 1,1′-(azodicarbonyl)dipiperidine (2.1 g, 8.4 mmol), and the mixture was stirred at room temperature for 16 hrs. Insoluble material was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10:1) to give the title compound (1.3 g, yield 97%) as a powder.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]([CH3:17])([CH3:16])[O:7][C:6]=2[C:5]([C:18](=[O:20])[CH3:19])=[C:4]([OH:21])[CH:3]=1.[C:22](OCC)(=O)[C:23]([O:25]CC)=[O:24].[Na].Cl>C(O)C>[C:23]([C:22]1[O:21][C:4]2[CH:3]=[C:2]([CH3:1])[C:11]3[C:10]4[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=4[C:8]([CH3:17])([CH3:16])[O:7][C:6]=3[C:5]=2[C:18](=[O:20])[CH:19]=1)([OH:25])=[O:24]
Reactant: CC(=O)c1c(O)cc(C)c2c1OC(C)(C)c1ccccc1-2
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: Cc1cc2oc(C(=O)O)cc(=O)c2c2c1-c1ccccc1C(C)(C)O2
Temperature: 10 °C

Procedure:
A solution of 1.2 gm (4.3 millimols) of 1-methyl-3-hydroxy-4-acetyl-6,6-dimethyl-6H-dibenzo-[b,d]-pyran and 1.2 gm (8.3 millimols) of diethyl oxalate in 10 ml of ethanol was poured at 40° C into a solution of 1.03 gm (45 millimols) of sodium in 20 ml of ethanol. The mixture was refluxed for 1 hour, cooled to 10° C and acidified with 2 N hydrochloric acid. The raw reaction product was extracted twice with 15 ml of ether each, the combined extracts were dried, and the solvent was evaporated. The orange residue was refluxed for 13/4hours in 18.2 ml of a mixture of acetic acid and hydrochloric acid (1.2 : 1), the reaction mixture was then cooled, and the precipitate formed thereby was recrystallized from ethanol. 1.1 gm (77% of theory) of the compound named in the heading, m.p. 231°-232° C, were obtained.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:22])[C:12]([CH3:21])([S:14][CH2:15][CH:16]2[CH2:20][CH2:19][NH:18][CH2:17]2)[CH3:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C1COCC1>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:22])[C:12]([SH:14]([CH2:15][CH:16]2[CH2:20][CH2:19][NH:18][CH2:17]2)[S:33]([CH3:32])(=[O:35])=[O:34])([CH3:13])[CH3:21])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(SCC1CCNC1)C(=O)Nc1cc(C(C)(C)C)on1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1cc(NC(=O)C(C)(C)[SH](CC2CCNC2)S(C)(=O)=O)no1
Temperature: 90 °C
Yield: 79.7 %

Procedure:
To a solution of 172 mg (0.52 mmol) of N-(5-tert-butyl-isoxazol-3-yl)-2-methyl-2-(pyrrolidin-3-ylmethylsulfanyl)-propionamide (prepared according to Method I, step 1) and 0.18 mL (1.04 mmol) of N,N-diisopropylethylamine in THF were added 0.16 mL (2.11 mmol) of methanesulfonyl chloride. The reaction was heated within a microwave to 90° C. for 0.5 h. The mixture was concentrated under reduced pressure. The residue was dissolved in DCM (5 mL) and washed with saturated aqueous NaHCO3 solution (5 mL). The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to afford 168 mg of N-(5-tert-butyl-isoxazol-3-yl)-2-(1-methanesulfonyl-pyrrolidin-3-ylmethylsulfanyl)-2-methyl-propionamide, which was used in the next step without further purification.
Reaction SMILES: P(Br)(Br)[Br:2].[O:5]([C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14]O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O>O1CCOCC1>[O:5]([C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][Br:2])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OCc1ccccc1Oc1ccccc1
Reactant: BrP(Br)Br
Solvent: O
Solvent: C1COCCO1
Product: BrCc1ccccc1Oc1ccccc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 89.4 %

Procedure:
Phosphorus tribromide (5.5 ml, 57.1 mmol) was added dropwise over a period of 10 min to a solution of 2-phenoxybenzylalcohol (4.08 g, 20.4 mmol) in dioxane (165 ml). The reaction mixture was stirred for 40 min. Another portion of phosphorus tribromide (5.5 ml, 57.1 mmol) was added. The reaction mixture was stirred for 56 hours at room temperature. It was cooled to 0° C. Water (45 ml) was added carefully. The reaction mixture was stirred for 30 min at room temperature. The mixture was extracted with ethyl acetate (100 ml). The ethyl acetate phase was washed with 1 N hydrochloric acid. The combined aqueous layers were extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous soludtion of sodium hydrogen carbonate (100 ml) and dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (90 g), using ethyl acetate/heptane (1:3) as eluent, to give 4.80 g of 2-phenoxybenzyl bromide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:9][O:8][B:7]([OH:10])[C:6]=2[CH:11]=1.[NH:12]1[C:20]2[C:15](=[CH:16][C:17]([S:21](Cl)(=[O:23])=[O:22])=[CH:18][CH:19]=2)[CH:14]=[N:13]1.O>N1C=CC=CC=1>[OH:10][B:7]1[C:6]2[CH:11]=[C:2]([NH:1][S:21]([C:17]3[CH:16]=[C:15]4[C:20](=[CH:19][CH:18]=3)[NH:12][N:13]=[CH:14]4)(=[O:23])=[O:22])[CH:3]=[CH:4][C:5]=2[CH2:9][O:8]1
Reactant: O=S(=O)(Cl)c1ccc2[nH]ncc2c1
Reactant: Nc1ccc2c(c1)B(O)OC2
Solvent: c1ccncc1
Solvent: O
Product: O=S(=O)(Nc1ccc2c(c1)B(O)OC2)c1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-amino-3H-benzo[c][1,2]oxaborol-1-ol (0.385 g, 2.07 mmol) in anhydrous pyridine (30 mL) at 5° C. was added 1H-indazole-5-sulfonyl chloride (0.45 g, 2.07 mmol) and the resulting orange solution stirred at room temperature for 0.5 h. The reaction was warmed to 50° C. for 2 h and then the pyridine was removed under reduced pressure to afford a sticky residue. This was treated with water (40 mL) and sonicated for 5 h at 70° C. The fine precipitate that formed was collected by filtration, washed with water and dried in vacuo generating 0.402 g (59%) of the title compound as a yellowish orange solid. mp 222° C.; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.21 (s, 1H), 9.19 (s, 1H), 8.24 (s, 2H), 7.67 (s, 2H), 7.48 (d, J=1.2 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 7.17 (dd, J=8.2, 2.0 Hz, 1H), 4.84 (s, 2H); MS (ESI) m/z=330 (M+1, positive); HPLC purity: 97.30% (MaxPlot 200-400 nm), 97.30% (220 nm).
Reaction SMILES: CO[C:3]1[CH:27]=[CH:26][C:25]2[C:9]3[N:10]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:11]4[NH:12][CH2:13][CH2:14][CH2:15][C:16]=4[C:17](=[O:18])[C:8]=3[CH2:7][CH2:6][C:5]=2[CH:4]=1.[C:28](Cl)(=[O:30])[CH3:29].C(N(CC)CC)C>C(Cl)Cl>[C:28]([N:12]1[C:11]2[N:10]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]3[C:25]4[CH:26]=[CH:27][CH:3]=[CH:4][C:5]=4[CH2:6][CH2:7][C:8]=3[C:17](=[O:18])[C:16]=2[CH2:15][CH2:14][CH2:13]1)(=[O:30])[CH3:29]
Reactant: COc1ccc2c(c1)CCc1c-2n(-c2ccccc2)c2c(c1=O)CCCN2
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCCc2c1n(-c1ccccc1)c1c(c2=O)CCc2ccccc2-1

Procedure:
Treat 5,6,8,9,10,11-hexahydro-3-methoxy-12-phenyl-naphtho[1,2-b] [1,8]naphthyridin-7(12H)-one (10 mmoles) with equimolar amounts of acetyl chloride and triethylamine dissolved in CH2Cl2 (10 ml) at 0°-25° C. for 3 days. Wash the resulting solution with aqueous NaHCO3 solution and with water, and dry the organic solution. Evaporate the CH2Cl2, and chromatograph the residue on silica gel. Elute the N-acetylated product with 2% MeOH in CHCl3, and crystallize it from isopropyl acetate/disopropyl ether to provide 11-acetyl-5,6,8,9,10,11-hexahydro-12-phenyl-naphtho[1,2-b] [1,8]naphthyridin-7(12H)-one, m.p. 178.5°-182° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][C:7]([O:9]C)=O)[CH2:2]1.[NH2:11][NH2:12].O>CO>[O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][C:7]([NH:11][NH2:12])=[O:9])[CH2:2]1
Reactant: NN
Reactant: COC(=O)CC1CCOC1
Solvent: O
Solvent: CO
Product: NNC(=O)CC1CCOC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a round-bottom flask was added a solution of methyl 2-(tetrahydrofuran-3-yl)acetate (compound 130.3, 1.50 g, 10.4 mmol, 1.00 equiv) and NH2NH2. H2O (1.04 g, 20.8 mmol, 2.00 equiv) in methanol (15 mL). The resulting mixture was stiffed overnight at 80° C. in an oil bath. After cooling to ambient temperature, the mixture was concentrated in vacuo to yield 1.20 g (80%) of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13](=[O:22])[C:14]3[CH:19]=[CH:18][C:17]([CH2:20][NH2:21])=[CH:16][CH:15]=3)[S:11][C:7]=2[C:6]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:5][CH:4]=1.[CH3:29][O:30][CH2:31][CH2:32][C:33](Cl)=[O:34]>>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13](=[O:22])[C:14]3[CH:19]=[CH:18][C:17]([CH2:20][NH:21][C:33](=[O:34])[CH2:32][CH2:31][O:30][CH3:29])=[CH:16][CH:15]=3)[S:11][C:7]=2[C:6]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:5][CH:4]=1
Reactant: COCCC(=O)Cl
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(CN)cc3)nc12
Product: COCCC(=O)NCc1ccc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)cc1

Procedure:
Using N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4-aminomethyl-benzamide and 3-methoxy-propionyl chloride, the title compound was prepared as white crystals (44% yield). MS: m/e=485(M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:9][C:10]([F:13])([F:12])[F:11])[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].O>C1(C)C=CC=CC=1>[CH2:24]([O:23][C:21](=[O:22])[NH:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][C:4]=1[O:9][C:10]([F:11])([F:12])[F:13])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc(Br)cc1OC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(Br)cc1OC(F)(F)F)OCc1ccccc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 76 %

Procedure:
4-Bromo-2-(trifluoromethoxy)aniline (1.0 g, 3.9 mmol) was dissolved in dry toluene (25 mL), sodium carbonate (0.621 g, 5.86 mmol) and benzyl chloroformate (0.669 mL, 4.69 mmol) was added and the mixture stirred under nitrogen at room temperature for 22 hours. The reaction was then heated to 80° C. and stirred at this. temperature for 17 hours and then heated further to reflux and stirred for 22 hours. Water (100 mL) was added to the coiled mixture, the aqueous phase separated and washed with ethyl acetate (2×100 mL). The combined organic extracts were washed with 0.5 M aq. citric acid (70 mL), water (70 mL), brine (70 mL), dried (MgSO4), filtered and concentrated in vacuo to give a pink solid. The crude material was purified by silica gel chromatography (40 g Si cartridge, 0-20% EtOAc in 40-60° C. petroleum benzine) to give the title compound (I46) (1.153 g, 76% yield) as a white solid; 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J=8.7 Hz, 1H), 7.44-7.36 (m, 7H), 6.95 (s, 1H), 5.22 (s, 2H). LCMS Method C: rt 6.67 min; m/z 389.9 [M−H]−.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[N:4]=1)#[N:2].[C:16](OC)(=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[SH:19].C(N(CC)CC)C>C1(C)C=CC=CC=1>[N:13]1[CH:14]=[CH:15][C:10]([S:9][C:5]2[N:4]=[C:3]([C:1]3[S:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[C:16](=[O:24])[N:2]=3)[CH:8]=[CH:7][CH:6]=2)=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccccc1S
Reactant: N#Cc1cccc(Sc2ccncc2)n1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=c1nc(-c2cccc(Sc3ccncc3)n2)sc2ccccc12
Yield: 2.1 %

Procedure:
2-Cyano-6-(4-pyridylthio)pyridine (1.54 g, 7.22 mmol) and methyl thiosalicylate (1.34 g, 7.94 mmol) were dissolved in toluene (50 ml), and triethylamine (1.52 ml, 10.83 mmol) was added thereto. The mixture was refluxed for 18 hrs. The solvent was evaporated, and the residue was recrystallized from ethanol to give the titled compound (0.053 g, 2%) as pale yellow crystals.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][C:10]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[C:11]([I:14])[CH:12]=2)[O:7][C:6]=1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].Br[CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39]>CC(C)=O>[CH3:41][O:40][C:38](=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34][N:15]([C:10]1[N:9]=[C:8]2[O:7][C:6]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[C:5]([C:3](=[O:4])[NH:2][CH3:1])[C:13]2=[CH:12][C:11]=1[I:14])[S:16]([CH3:19])(=[O:18])=[O:17]
Reactant: COC(=O)CCCCBr
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(NS(C)(=O)=O)c(I)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(N(CCCCC(=O)OC)S(C)(=O)=O)c(I)cc12
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To 2-(4-Fluoro-phenyl)-5-iodo-6-methanesulfonylamino-furo[2,3-b]pyridine-3-carboxylic acid methylamide (300 mg, 0.613 mmol), K2CO3 (169 mg, 1.226 mmol), KI (1018 mg, 6.13 mmol), and methyl 5-bromopentanoate (250 μl, 1.747 mmol) is added acetone (3066 μl) and the reaction mixture is stirred at 60° C. overnight. The acetone is removed under N2 and the mixture is taken up in 2 mL 1:1:1 DMF/H2O/ACN and filtered with a 0.45μ PTFE filter. Purification is achieved by reverse phase HPLC with a C8 column with 40-80% MeOH (0.1% TFA)/H2O (0.1% TFA). MS (ESI) m/z 604.0 (M+1). Retention time=1.48 min, Method A. 1H NMR (400 MHz, CDCl3 d ppm 8.77 (s, 1H), 7.96 (t, 2H), 7.19-7.36 (m, 2H), 5.80 (br s, 1H), 3.68 (t, 2H), 3.54 (s, 3H), 3.14 (s, 3H), 2.97 (d, 3H), 2.29 (t, 2H), 1.69-1.79 (m, 2H), 1.42 (s, 2H)
Reaction SMILES: [CH3:1][C:2]([Si:5]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[O:6][CH2:7][CH:8]([OH:14])[CH:9]([OH:13])[CH2:10][CH:11]=[CH2:12])([CH3:4])[CH3:3].C(=O)(O)[O-].[Na+].[I:32]I>C(OCC)C.O>[CH3:4][C:2]([Si:5]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[O:6][CH2:7][C@H:8]1[O:14][C@H:11]([CH2:12][I:32])[CH2:10][C@H:9]1[OH:13])([CH3:1])[CH3:3]
Reactant: C=CCC(O)C(O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: II
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)[Si](OC[C@H]1O[C@H](CI)C[C@H]1O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 76.3 %

Procedure:
A 0° C. solution of 14.67 g of product from Example 274 in 200 ml of 3:1 diethyl ether/water is treated with 4.99 g of sodium bicarbonate and 15.07 g of iodine. The reaction minute is stirred vigorously for 24 hours at room temperature, quenched with 15 ml of saturated sodium sulfite, and diluted with 100 ml of water. the reaction minute is extracted with diethyl ether, dried, concentrated in vacuo, and purified by chromatography (silica gel: 0-10% ethyl acetate/hexane) to give 15.0 g of the desired product.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH3:11])=[CH:8][C:7]([C:12]([OH:14])=[O:13])=[CH:6][CH:5]=2.Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2([C:26]([O:28][CH3:29])=[O:27])[CH2:25][CH2:24]2)=[CH:19][CH:18]=1.[H-].[Na+].Cl>CN(C=O)C.C(OCC)(=O)C>[CH3:29][O:28][C:26]([C:23]1([C:20]2[CH:19]=[CH:18][C:17]([CH2:16][N:3]3[C:4]4[C:9](=[CH:8][C:7]([C:12]([OH:14])=[O:13])=[CH:6][CH:5]=4)[C:10]([CH3:11])=[C:2]3[CH3:1])=[CH:22][CH:21]=2)[CH2:25][CH2:24]1)=[O:27]
Reactant: Cc1[nH]c2ccc(C(=O)O)cc2c1C
Reactant: COC(=O)C1(c2ccc(CBr)cc2)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C1(c2ccc(Cn3c(C)c(C)c4cc(C(=O)O)ccc43)cc2)CC1
Reaction time: 8 h
Yield: 41.6 %

Procedure:
To a solution of 2,3-dimethyl-1H-indole-5-carboxylic acid (500 mg, 2.3 mmol) in anhydrous DMF (20 mL) was added methyl 1-(4-(bromomethyl)phenyl)cyclopropanecarboxylate (620 mg) followed by NaH (230 mg). The resulting solution was allowed to stir overnight under argon atmosphere. The remaining NaH was hydrolyzed by the careful addition of a 0.5 N HCl solution. The mixture was diluted with ethyl acetate, washed with a 0.5 N HCl solution and brine, dried on MgSO4, and concentrated. The crude residue was purified by chromatography on silica gel (Hexane/Ethyl acetate 5/5) to afford an orange powder (361 mg). ESI-MS (m/z): 378 [MH]+