Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([N:18]1[CH2:22][C@@H:21]([C:23]2[CH:27]=[CH:26][S:25][CH:24]=2)[C@H:20]([CH2:28][OH:29])[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl.CCOCC.O>[CH2:11]([N:18]1[CH2:22][C@@H:21]([C:23]2[CH:27]=[CH:26][S:25][CH:24]=2)[C@H:20]([CH:28]=[O:29])[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OC[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccsc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=C[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccsc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A solution of 2.04 mL (23.4 mmol) of oxalyl chloride in 40 mL of dry CH2Cl2 was cooled to −78° C. under nitrogen. To this was added 3.32 mL (46.8 mmol) of DMSO and the mixture was stirred at −78° C. for 15 min. A solution of 3.2 g (11.7 mmol) of 1-benzyl-3-(S)-hydroxymethyl-4-(R)-(3-thienyl)pyrrolidine in 20 mL of dry CH2Cl2 was added and the mixture was stirred at −78° C. for 15 min. Then 8.15 mL (58.5 mmol) of triethylamine were added and the solution was allowed to warm to room temperature over 1 h. The reaction mixture was diluted with 400 mL of ether, poured onto 200 mL of water and the layers were separated. The aqueous layer was washed with ether and the combined organic extracts were washed with saturated NaHCO3 solution and brine. The organic fraction was dried over Na2SO4, filtered, and concentrated to afford the title compound, which was used directly in the next step.
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]#[N:17])=[CH:13][CH:14]=2)[C:9]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[N:8]1>O1CCCC1.Cl>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[C:12]([C:16]#[N:17])[CH:11]=3)[NH:7][N:8]=2)[CH:19]=1
Reactant: N#Cc1ccc2c(c1)c(-c1cccnc1)nn2C1CCCCO1
Agent: Cl
Solvent: C1CCOC1
Product: N#Cc1ccc2[nH]nc(-c3cccnc3)c2c1
Yield: 64.5 %

Procedure:
The title compound was prepared by hydrolyzing 1-perhydro-2H-pyran-2-yl-3-(3-pyridyl)-1H-indazole-5-carbonitrile (0.147 g, 0.48 mmol) in a mixture of 5 mL of tetrahydrofuran and 5 mL of aqueous hydrogen chloride (6.0N) at room temperature for 12 hours, and reflux temperature for 6 hours. The compound was successfully purified by column chromatography (SiO2, 50% ethyl acetate in hexanes). (0.068 g, 64.5% yield): ES-MS (m/z) 221 [M+1]+.
Reaction SMILES: C([Li])CCC.[F:6][C:7](=[C:16]([F:18])[F:17])[CH2:8][CH2:9][S:10][C:11]1[O:12][CH:13]=[CH:14][N:15]=1.[CH3:19][O:20][CH2:21]Br.[Cl-].[NH4+]>CCOCC>[CH3:19][O:20][CH2:21][C:13]1[O:12][C:11]([S:10][CH2:9][CH2:8][C:7]([F:6])=[C:16]([F:17])[F:18])=[N:15][CH:14]=1
Reactant: FC(F)=C(F)CCSc1ncco1
Reactant: COCBr
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: COCc1cnc(SCCC(F)=C(F)F)o1
Reaction time: 1 h
Yield: 13.2 %

Procedure:
10.40 ml of n-butyl lithium (1.6 M n-hexane solution) were slowly added dropwise to a solution of 3.14 g of 2-(3,4,4-trifluoro-3-butenylthio)oxazole in 40 ml of ether at −70° C. After stirring for 1 hour, a solution of 2.06 g bromomethyl methyl ether in 10 ml ether was added dropwise. After bringing the mixture back to room temperature and stirring for 1 hour, 50 ml of saturated solution of ammonium chloride was added to separate it into an ether layer and an aqueous layer. The aqueous layer was further extracted with ether and together with the separated ether layer it was washed with a saturated sodium chloride water and dried with anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was treated by column chromatography to obtain 0.5 g of 5-methoxymethyl-2-(3,4,4-trifluoro-3-butenylthio)oxazole (yield 13%). n20D=1.4705.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[N:4]([CH3:6])[CH3:5].[Li]C(C)(C)C.CCCCC.CN([CH:25]=[O:26])C>CCOCC>[CH3:5][N:4]([CH3:6])[C:3]1[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:2]=1[CH:25]=[O:26]
Reactant: Cc1cccc(Br)c1N(C)C
Reactant: CN(C)C=O
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: CCOCC
Product: Cc1cccc(C=O)c1N(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of Compound 150 (0.17 g, 0.81 mmol) in Et2O (5.0 mL) at −78° C. under Argon atmosphere was added dropwise a solution of 1.7M t-BuLi in pentane (1.0 mL, 1.79 mmol), and the reaction was stirred for 1 h. DMF (0.25 mL, 3.24 mmol) was added, and the cooling bath was removed. After 1h15, the reaction was cooled to 0° C., and saturated NH4Cl was added. The mixture was extracted with EtOAc, washed with brine, dried over MgSO4, and filtered. The solvent was removed, and the residue was purified by silica gel flash chromatography with EtOAc (15%) and hexanes (85%) as eluent to produce Compound 151 as a yellow oil.
Reaction SMILES: [C:1]([NH:9][CH2:10][CH:11]1[C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:19][CH2:18][CH2:17][C:12]21[O:16][CH2:15][CH2:14][O:13]2)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH2:1]([NH:9][CH2:10][CH:11]1[C:20]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:19][CH2:18][CH2:17][C:12]21[O:13][CH2:14][CH2:15][O:16]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCC1C2(CCCC1(c1ccccc1)c1ccccc1)OCCO2)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(CNCC2C3(CCCC2(c2ccccc2)c2ccccc2)OCCO3)cc1
Yield: 84.2 %

Procedure:
A solution of (RS)-6-benzamidomethyl-7,7-diphenyl-1,4-dioxaspiro[4.5]decane (8.1 g) in anhydrous tetrahydrofuran (150 cc) is added dropwise, in the course of 1 hour 30 minutes and while the temperature of the reaction mixture is maintained at +5° C., to a suspension, cooled to +5° C. of lithium aluminum hydride (1.9 g) in anhydrous tetrahydrofuran (60 cc), and the mixture is then brought to reflux for 24 hours. The reaction mixture is then cooled to +5° C., treated with distilled water (2.1 cc), then with 5N aqueous sodium hydroxide solution (1.9 cc) and then with distilled water (5.8 cc), filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel with a slight excess pressure of nitrogen (0.04-0.063 mm, diameter 5 cm, height 29 cm), eluting with ethyl acetate and collecting 120-cc fractions. Fractions 3 to 12 are combined and concentrated to dryness under reduced pressure (2.7 kPa). (RS)-6-Benzylaminomethyl-7,7-diphenyl-1,4-dioxaspiro[4.5]decane (6.6 g) is obtained in the form of a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[S:9](Cl)(=[O:11])=[O:10].[Br:13][C:14]1[CH:15]=[C:16]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22]1[CH:21]([NH2:27])[CH2:20][CH2:19][CH2:18][C:17]2=1>>[Br:13][C:14]1[CH:15]=[C:16]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22]1[CH:21]([NH:27][S:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])(=[O:11])=[O:10])[CH2:20][CH2:19][CH2:18][C:17]2=1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Product: O=S(=O)(NC1CCCc2c1[nH]c1ccc(Br)cc21)c1c(F)cccc1F

Procedure:
N-(6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2,6-difluorobenzenesulfonamide was prepared from 2,6-difluorobenzenesulfonylchloride and 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine in a similar manner as described above to give a white solid: 1H-NMR (CDCl3): δ 8.60 (s, 1H), 7.48-7.58 (m, 2H), 7.24 (dd, 1H), 7.18 (d, 1H), 7.04 (t, 1H), 5.31 (m, 1H), 4.73 (m, 1H), 2.62 (m, 2H), 1.7-2.1 (m, 4H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[C:28](=[O:29])[CH:27]=[C:26]([CH2:30][OH:31])[O:25][CH:24]=1)=[CH:13][CH:12]=[C:11]([C:32]([F:35])([F:34])[F:33])[CH:10]=2)=[O:5])[CH3:2].C(N(CC)CC)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[C:28](=[O:29])[CH:27]=[C:26]([CH2:30][O:31][S:44]([CH3:43])(=[O:46])=[O:45])[O:25][CH:24]=1)=[CH:13][CH:12]=[C:11]([C:32]([F:34])([F:33])[F:35])[CH:10]=2)=[O:5])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1OCCCCCOc1coc(CO)cc1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1OCCCCCOc1coc(COS(C)(=O)=O)cc1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a solution of 4-[5-(6-hydroxymethyl-4-oxo-4H-pyran-3-yloxy)-pentyloxy]-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester 13 (330 mg, 0.67 mmol) in CH2Cl2 (15 mL) was added at 0° C. triethylamine (37 μL, 0.26 mmol), methanesulfonyl chloride (62 μL, 0.80 mmol). The solution was stirred at RT for 1 h. Dichloromethane (50 mL) was added and the solution was washed with water (2×100 mL), dried over MgSO4, filtered and evaporated. The crude product was purified by column chromatography on silica using as eluent CH2Cl2:MeOH=95:15. (5-(5-(6-(Trifluoromethyl)quinolin-4-yloxy)pentyloxy)-4-oxo-4H-pyran-2-yl)methylmethanesulfonate 18 was obtained (246 mg, 65% yield) as a pale yellow oil.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1)=O.C1(P(=[CH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O>[C:36]([O:35][C:33](=[O:34])/[CH:32]=[CH:1]/[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1)([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc(C=O)nc1
Solvent: O
Product: COC(=O)c1ccc(/C=C/C(=O)OC(C)(C)C)nc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
Methyl 6-formylnicotinate (1.0 g, 6.06 mmol) and tert-butyl (triphenylphosphoranylidene)acetate (2.73 g, 7.27 mmol) were put in suspension in water (50 mL) and stirred at 90° C. for 2 h. The reaction mixture was cooled to room temperature and concentrated under pressure. The residue was triturated in ethyl acetate and filtered. The filtrate was concentrated and purified by flash chromatography using hexanes-ethyl acetate 10% to give (E)-methyl 6-(3-(tert-butoxy)-3-oxoprop-1-en-1-yl)nicotinate. MS (APCI) 264 (M+). (E)-methyl 6-(3-(tert-butoxy)-3-oxoprop-1-en-1-yl)nicotinate was dissolved in ethanol in the presence of 50 mg Pd/C, 10% and stirred under hydrogen balloon overnight to give 6-2(tert-butoxycarbonyl-ethyl)nicotinic methyl ester. LCMS: 266 (M+)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:22][S:23]([C:26]3[C:31](F)=[CH:30][CH:29]=C[C:27]=3F)(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1.ClC1N=C(C2SC(C(C)C)=NC=2C2C=C(C=CC=2)N)C=C[N:36]=1.N1C=CC=C(S(Cl)(=O)=O)C=1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:14])[CH3:15])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:22][S:23]([C:26]3[CH:27]=[N:36][CH:29]=[CH:30][CH:31]=3)(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)c1nc(-c2cccc(N)c2)c(-c2ccnc(Cl)n2)s1
Reactant: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Agent: O=S(=O)(Cl)c1cccnc1
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3cccnc3)c2)c(-c2ccnc(Cl)n2)s1
Yield: 72 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-[5-(2-Chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]aniline (3 g, 9.1 mmol) and pyridine-3-sulfonyl chloride (1.93 g, 10.9 mmol) the title compound was obtained (3.1 g, 72% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.57-10.63 (br, 1H), 8.84 (d, J=2.2 Hz, 1H), 8.74-8.78 (m, 1H), 8.50 (d, J=5.3 Hz, 1H), 8.07-8.12 (m, 1H), 7.55-7.59 (m, 1H), 7.31-7.37 (m, 1H), 7.17-7.28 (m, 3H), 6.92 (d, J=5.3 Hz, 1H), 3.24-3.34 (m, 1H), 1.34 (d, J=6.8 Hz, 6H). MS (ES+): 472 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](OC)=[O:16])=[N:8][C:4]=2[CH:3]=1.[NH2:21][OH:22].[OH-].[K+]>C1COCC1>[Br:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([NH:21][OH:22])=[O:16])[NH:8][C:4]=2[CH:3]=1
Reactant: COC(=O)CCCCCCc1nc2cc(Br)ccc2[nH]1
Reactant: NO
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(CCCCCCc1nc2ccc(Br)cc2[nH]1)NO
Temperature: 0 °C
Reaction time: 2 h
Yield: 52.8 %

Procedure:
To a solution of methyl 7-(5-bromo-1H-benzimidazol-2-yl)heptanoate (100 mg, 0.295 mmol) in THF at 0° C. was added 50% hydroxylamine solution (0.17 mL, 2.70 mmol). To this was added KOH (0.74 mL, 1M in MeOH, 0.74 mmol) dropwise. The reaction was stirred at 0° C. for 2 hr, briefly concentrated and neutralized by adding 1 N HCl solution until pH was 7. The light yellow precipitate was collected by filtration and pump-dried to give 7-(6-bromo-1H-benzimidazol-2-yl)-N-hydroxy heptanamide 15 (53 mg). The filtrate was extracted with ethyl acetate, dried and concentrated. The residue was purified by column to give another portion of the desired product 15 (16 mg). LCMS (M+1 @retention time): 340@1.283 min (LC conditions: 1. Column: YMC, C-18 ODS, 50×4.6 mm 0.5 u; 2. Mobile phase: A 0.05% TFA in water and B 0.05% TFA in acetonitrile; 3. Flow rate 1.2 mL/min; Gradient program: 20% B to 100% B in 3 min).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[BrH:17].BrBr.S([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C.C(Cl)Cl>[Br:17][CH:9]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[O:16]
Reactant: O=C(Cc1ccccc1)c1ccc(F)cc1
Reactant: Br
Agent: BrBr
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(c1ccc(F)cc1)C(Br)c1ccccc1
Temperature: 19 °C
Reaction time: 0.08 h

Procedure:
Methylene chloride (1 L) is taken in a 4 necked RB flask equipped with mechanical strring rod, pressure equalization funnel and a CaCl2 guard tube. 100 g (0.466 mol) of 1-(4-Fluorophenyl)-2-phenyl ethanone is introduced in to the above flask and stirred for 5 minutes to obtain a clear solution.2 ml of a 30% hydrobromic acid in acetic acid is then added, followed by gradual addition of a cold solution of bromine (73 g, 0.456 mole) in 200 ml of methylene chloride at 26±2° C. Bromine solution is added in such a manner that it is consumed instantly as indicated by colouration of reaction mixture. After addition of bromine solution the reaction mixture is cooled to 19±1° C., treated with 5% aqueous sodium sulphite (200 ml) and stirred for about lhr at 21.5±3.5° C. The organic layer is then separated and is subjected to the above operation twice with 5% aqueous sodium sulphite (2×200 ml). The organic layer is then stirred with 5% aqueous sodium bicarbonate (200 ml) for about 1 hr at 21.5±3.5° C. and separated. The organic layer is finally stirred with 5% aqueous sodium chloride(200 ml) and separated. The organic layer is dried over sodium sulphate and filtered. Methylene chloride is removed by distillation and the syrup thus obtained solidified on standing in to a pale orange coloured solid. Yield 129 g (94.8%)
Reaction SMILES: C([O:3][C:4](=[O:21])[CH:5]([CH3:20])[C:6]1[CH:18]=[CH:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:19])[CH:14]=3)[NH:9][C:8]=2[CH:7]=1)C.[OH-].[K+].CO>O>[OH:19][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]1[CH:7]=[C:6]([CH:5]([CH3:20])[C:4]([OH:21])=[O:3])[CH:18]=[CH:17][C:16]2=1
Reactant: CCOC(=O)C(C)c1ccc2c(c1)[nH]c1ccc(O)cc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C(=O)O)c1ccc2c(c1)[nH]c1ccc(O)cc12
Yield: 48.5 %

Procedure:
A mixture consisting of 6-hydroxy-α-methyl carbazole-2-acetic acid ethyl ester (5.0 g, 0.021 mol), potassium hydroxide (5.0 g, 0.089 mol), methanol (300 mL), and water (20 mL) is refluxed for 15 hours. The reaction mixture is cooled concentrated and acidified with a 1:1 solution of concentrated HCl and water to pH 1. The aqueous layer is extracted with ether (4×300 mL), washed with water (200 mL), brine (200 mL), dried over MgSO4, filtered and concentrated to give 2.6 g of product as a foam.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=3[F:17])=[C:7]([C:18]([NH:20][CH3:21])=[O:19])[C:6]=2[CH:22]=1.[C:28]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[C:3]([N:23]([CH3:28])[S:24]([CH3:27])(=[O:25])=[O:26])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=3[F:17])=[C:7]([C:18]([NH:20][CH3:21])=[O:19])[C:6]=2[CH:22]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2F)oc2cc(NS(C)(=O)=O)c(Br)cc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CNC(=O)c1c(-c2ccc(F)cc2F)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Temperature: 80 °C
Reaction time: 3 h
Yield: 18.1 %

Procedure:
To a solution of 5-bromo-2-(2,4-difluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (653 mg, 1.38 mmol), K2CO3 (406 mg, 2.94 mmol) in DMF (10 mL) was added MeI (519 mg, 3.66 mmol), then the mixture was stirred at 80° C. After 3 hours, the solvent was removed by vacuum, the mixture was washed with H2O (20 mL) and extract with dichloromethane (50 mL*3), dried over Na2SO4 and concentrated to provide 5-bromo-2-(2,4-difluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (118 mg, yield: 25%). 1H-NMR (CDCl3, 400 MHz) 8.24 (s, 1H), 7.69˜7.75 (m, 2H), 7.05˜7.10 (m, 1H), 6.98˜7.03 (m, 1H), 5.64 (d, J=3.0 Hz, 1H), 3.09 (s, 3H), 2.97 (s, 3H), 2.95 (s, 3H). MS (M+H)+: 473/475.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:4]=1[CH2:5][NH:6][C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][N:13]=2)[CH2:8]1.[CH3:24][Si:25]([C:28]#[CH:29])([CH3:27])[CH3:26]>ClCCl.C(N(CC)CC)C.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.[Cu]I>[Cl:2][C:3]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:4]=1[CH2:5][NH:6][C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:29]#[C:28][Si:25]([CH3:27])([CH3:26])[CH3:24])=[CH:14][N:13]=2)[CH2:8]1
Reactant: C#C[Si](C)(C)C
Reactant: Clc1ccc(CN[C@H]2CCN(c3ccc(I)cn3)C2)c(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc(N2CC[C@H](NCc3ccc(Cl)cc3Cl)C2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
Dissolve (S)-(2,4-dichlorobenzyl)-[1-(5-iodopyridin-2-yl)-pyrrolidin-3-yl]-amine hydrochloride (250 mg, 0.52 mmol) in dichloromethane (15 mL) and triethylamine (10 mL). Add trans-dichlorobis(triphenylphosphine)palladium (II) (24 mg, 0.034 mmol), copper (I) iodide (6 mg, 0.032 mmol) and (trimethylsilyl)acetylene (370 μL, 2.62 mmol). Stir the mixture at room temperature for 1 h, filter through a pad of Celite®, concentrate and chromatograph on silica gel, eluting with a gradient of 20:80 to 1:1 ethyl acetate:hexanes, to give (S)-(2,4-dichlorobenzyl)-[1-(5-trimethylsilanylethynyl-pyridin-2-yl)-pyrrolidin-3-yl]-amine as a yellow oil (190 mg, 88%). MS (ES): m/z=418 [M+H].
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:15]2[CH:16]=[CH:17][C:18]([N:21]3[CH2:27][CH2:26][CH2:25][N:24]([C:28]4[CH:33]=[CH:32][C:31]([C:34]5[CH:39]=[C:38]([C:40](OC)=[O:41])[CH:37]=[C:36]([C:44](OC)=[O:45])[CH:35]=5)=[CH:30][N:29]=4)[CH2:23][CH2:22]3)=[N:19][CH:20]=2)[CH:8]=[C:9]([C:11](OC)=[O:12])[CH:10]=1)=O.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.CO.Cl.[OH-].[Na+]>O1CCCC1.[Cl-].[Na+].O>[OH:41][CH2:40][C:38]1[CH:39]=[C:34]([C:31]2[CH:32]=[CH:33][C:28]([N:24]3[CH2:25][CH2:26][CH2:27][N:21]([C:18]4[CH:17]=[CH:16][C:15]([C:7]5[CH:6]=[C:5]([CH2:3][OH:2])[CH:10]=[C:9]([CH2:11][OH:12])[CH:8]=5)=[CH:20][N:19]=4)[CH2:22][CH2:23]3)=[N:29][CH:30]=2)[CH:35]=[C:36]([CH2:44][OH:45])[CH:37]=1
Reactant: COC(=O)c1cc(C(=O)OC)cc(-c2ccc(N3CCCN(c4ccc(-c5cc(C(=O)OC)cc(C(=O)OC)c5)cn4)CC3)nc2)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: OCc1cc(CO)cc(-c2ccc(N3CCCN(c4ccc(-c5cc(CO)cc(CO)c5)cn4)CC3)nc2)c1
Temperature: -20 °C
Reaction time: 1 h
Yield: 52.8 %

Procedure:
Under nitrogen, a solution of 1,4-bis[5-[3,5-bis(methoxycarbonyl)phenyl]-2-pyridyl]hexahydro-1,4-diazepine (17.0 mg, 0.0266 mmol), which had been synthesized in Example 20, in anhydrous tetrahydrofuran (1.0 mL) was cooled to −20° C. To the resulting solution was added a 1.0 M solution of diisobutylaluminum hydride in toluene (0.40 mL, 0.40 mmol), and the resulting mixture was stirred for 1 hour. Methanol (0.2 mL, 4.9 mmol) was added to the mixture, and the bath was removed, then 0.50 M hydrochloric acid (1.0 mL, 0.50 mmol) was added. The mixture was stirred at room temperature for 1 hour, and a 1.0 M aqueous sodium hydroxide (1.0 mL, 1.0 mmol) and brine were added. The resulting mixture was extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography on silica gel to yield the title compound as a colorless amorphous powder (7.4 mg, yield: 53%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.C(N(CC)C(C)C)C.Cl.[CH3:20][NH:21][O:22][CH3:23]>ClCCl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:21]([CH3:20])[O:22][CH3:23])=[O:7])=[CH:9][CH:10]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: CNOC
Agent: CCN(CC)C(C)C
Agent: Cl
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 89.6 %

Procedure:
To a solution of 6-chloronicotinoyl chloride (2 g, 11.4 mmol) and diethylisopropylamine (5 mL, 28.5 mmol) in dichloromethane (100 mL) was added N,O-dimethylhyroxylamine hydrochloride (1.22 g, 12.5 mmol) at 0° C. The solution was allowed to warm to room temperature then was stirred for 48 hours. The mixture was washed with 20% aqueous citric acid (2×100 mL), 1N aqueous sodium hydroxide (2×100 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to afford 6-chloro-N-methyl-N-(methyloxy)pyridine-3-carboxamide (2.05 g, 92% yield) as a yellow oil. 1H NMR (400 MHz, d6-DMSO): 8.65 (d, 1H), 8.08 (dd, 1H), 7.63 (d, 1H), 3.67 (s, 3H), 3.30 (s, 3H); MS (EI) for C8H9ClN2O2: 201 (MH+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[CH2:30]([O:32][C:33](=[O:41])[C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1)[CH3:31].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC(C)=O>[CH2:30]([O:32][C:33](=[O:41])[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]=2[O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:36][CH:35]=1)[CH3:31]
Reactant: BrCCCCCCc1cccc(OCc2ccccc2)c1OCc1ccccc1
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1ccc(OCCCCCCc2cccc(OCc3ccccc3)c2OCc2ccccc2)cc1
Yield: 80.6 %

Procedure:
A mixture of 2.4 g (5.3 mmole) of 1-(6-bromohexyl)-2,3-bis-(phenylmethoxy)benzene, 0.88 g (5.3 mmole) of 4-hydroxybenzoic acid ethyl ester, 2.5 g (18 mmole) of potassium carbonate and 0.8 g (5.3 mmole) of sodium iodide in 40 mL of acetone was stirred at reflux for 22 hours. Workup as in Example 16 and recrystallization of the crude product from ethyl acetate-hexane gave 2.3 g, mp 63°-65° (81% yield) of 4-[6-[2,3-bis(phenylmethoxy)phenyl]hexyloxy]benzoic acid ethyl ester.