Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Mg]Cl.[CH:4]([S:7]([N:10]1[C:14]2[CH:15]=[C:16]([C:19](=[O:28])[C:20]3[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=3[F:27])[CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[NH2:29])(=[O:9])=[O:8])([CH3:6])[CH3:5]>O1CCCC1>[NH2:29][C:11]1[N:10]([S:7]([CH:4]([CH3:6])[CH3:5])(=[O:8])=[O:9])[C:14]2[CH:15]=[C:16]([C:19]([C:20]3[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=3[F:27])([CH3:1])[OH:28])[CH:17]=[CH:18][C:13]=2[N:12]=1
Reactant: CC(C)S(=O)(=O)n1c(N)nc2ccc(C(=O)c3cc(F)ccc3F)cc21
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)n1c(N)nc2ccc(C(C)(O)c3cc(F)ccc3F)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.5 %

Procedure:
Methyl magnesium chloride (929 mL, 2.79 mol, 3M in tetrahydrofuran) was added slowly over 30 minutes to a solution of 1-isopropylsulfonyl-2-amino-6-(2,5-difluorobenzoyl)benzimidazole (352.7 g, 0.929 mol) in tetrahydrofuran while maintaining the temperature between -20° C. and -30° C. When the addition was complete, the reaction mixture was warmed slowly to room temperature over 2 hours. Additional 3M methyl magnesium chloride (186 mL, followed by 46.5 mL) was added until less than 1% ketone starting material remained by HPLC analysis. The reaction was quenched by the sequential addition of ethyl acetate (4.2 L) and 1N hydrochloric acid (4.2 L) and the mixture stirred for 1 hour. The phases were separated and the aqueous phase extracted with ethyl acetate (2.0 L). The combined organic fractions were washed with brine (4.0 L) and dried over magnesium sulfate. After filtration, removal of the solvent by rotary evaporation afforded 373 g of the title compound as a beige foam (93% purity, 94% yield).
Reaction SMILES: FC(F)(F)[C:3]1[CH:4]=[C:5]([N+:16]([O-])=O)[CH:6]=[CH:7][C:8]=1[S:9][C:10]1[CH:15]=[CH:14]N=CC=1.SC1C=C[N:25]=[CH:24][CH:23]=1.FC1C=CC([N+]([O-])=O)=CC=1C(F)(F)F.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOCC.O>[N:25]1[CH:24]=[CH:23][CH:14]=[CH:15][C:10]=1[S:9][C:8]1[CH:3]=[CH:4][C:5]([NH2:16])=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Sc2ccncc2)c(C(F)(F)F)c1
Reactant: Sc1ccncc1
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: Nc1ccc(Sc2ccccn2)cc1
Yield: 54 %

Procedure:
3-(Trifluoromethyl)-4-(4-pyridinylthio)nitrobenzene: A solution of 4-mercaptopyridine (2.8 g, 24 mmoles), 2-fluoro-5-nitrobenzotrifluoride (5 g, 23.5 mmoles), and potassium carbonate (6.1 g, 44.3 mmoles) in anhydrous DMF (80 mL) was stirred at room temperature and under argon overnight. TLC showed complete reaction. The mixture was diluted with Et2O (100 mL) and water (100 mL) and the aqueous layer was back-extracted with Et2O (2×100 mL). The organic layers were washed with a saturated NaCl solution (100 mL), dried (MgSO4), and concentrated under reduced pressure. The solid residue was triturated with Et2O to afford the desired product as a tan solid (3.8 g, 54%): TLC (30% EtOAc/70% hexane) Rf 0.06; 1H-NMR (DMSO-d6) δ 7.33 (dd, J=1.2, 4.2 Hz, 2H), 7.78 (d, J=8.7 Hz, 1H), 8.46 (dd, J=2.4, 8.7 Hz, 1H), 8.54-8.56 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[CH:19]([N:22]([CH:37]([CH3:39])[CH3:38])[CH2:23][CH2:24][NH:25][C:26]([C:28]1[C:32]([CH3:33])=[C:31]([CH:34]=O)[NH:30][C:29]=1[CH3:36])=[O:27])([CH3:21])[CH3:20]>C(O)C.N1CCCCC1>[CH:37]([N:22]([CH:19]([CH3:21])[CH3:20])[CH2:23][CH2:24][NH:25][C:26]([C:28]1[C:32]([CH3:33])=[C:31]([CH:34]=[C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[CH:17][C:9]=3[C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[NH:13][C:12]2=[O:18])[NH:30][C:29]=1[CH3:36])=[O:27])([CH3:38])[CH3:39]
Reactant: COc1cccc(-c2cccc3c2CC(=O)N3)c1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN(C(C)C)C(C)C
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1cccc(-c2cccc3c2C(=Cc2[nH]c(C)c(C(=O)NCCN(C(C)C)C(C)C)c2C)C(=O)N3)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 73.8 %

Procedure:
To a solution of 4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diisopropylamino-ethyl)-amide (73 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. The reaction solution was evaporated, and purified on a silica gel column eluting with MeOH—CH2Cl2 5:95 to provide pure product 5-[4-(3-methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diisopropylamino-ethyl)-amide as a yellow solid (95 mg, 79%).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:7]([OH:9])=[O:8])=[CH:5][CH:6]=1.C(Cl)(Cl)Cl.BrBr.C(=O)([O-])[O-:17].[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl.[W]>[CH:1]([C:2]1[S:3][C:4]([C:7]([OH:9])=[O:8])=[CH:5][CH:6]=1)=[O:17]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(C(=O)O)s1
Agent: [W]
Agent: BrBr
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=Cc1ccc(C(=O)O)s1

Procedure:
2-Methyl thiophen-5-carboxylic acid was dissolved in carbon tetrachloride (150 ml.) and chloroform (10 ml.) and AZDN (0.5g.) was added. The mixture was refluxed over a 150 watt tungsten spotlight. Two molar equivalents of bromine as a 30% v/v solution in carbon tetrachloride were slowly added. A precipitate was formed but the mixture continued to take up bromine. After the addition of the two molar equivalents, solvent was boiled off until the volume was 100 ml. and the product treated with sodium carbonate solution with gentle heating for two hours to obtain 2-formyl thiophen-5-carboxylic acid in the form of a yellow solid after acidification, extraction and removal of the solvent.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]3[S:26][C:25]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)=[N:24][C:23]=3[CH2:34][CH:35](OC)OC)=[O:21])=[CH:15][C:14]=2[O:40][CH3:41])[CH2:9]1)=O)(C)(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[NH:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:35]=[CH:34][C:23]4[N:24]=[C:25]([C:27]5[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=5)[S:26][C:22]=4[C:20]3=[O:21])=[CH:15][C:14]=2[O:40][CH3:41])[CH2:9]1
Reactant: COc1cc(NC(=O)c2sc(-c3ccc(Cl)cc3)nc2CC(OC)OC)ccc1OC1CN(C(=O)OC(C)(C)C)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(-n2ccc3nc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OC1CNC1
Temperature: 95 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
Dissolve 3-(4-{[2-(4-chloro-phenyl)-4-(2,2-dimethoxy-ethyl)-thiazole-5-carbonyl]-amino}-2-methoxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (18.9 g, 31.28 mmol) and p-toluenesulfonic acid monohydrate (19.7 g, 103.56 mmol) in dry toluene (460 mL) and stir mechanically at 95° C. overnight. Cool the reaction mixture and add 1 N NaOH. Stir the mixture vigorously at room temperature for one hour. Extract the aqueous layer with CH2Cl2 (2×700 mL). Combine the organic portions, wash with brine (700 mL), dry over MgSO4, and filter. Concentrate the filtrate in vacuo to give 13.0 g (85%) of 5-[4-(azetidin-3-yloxy)-3-methoxy-phenyl]-2-(4-chloro-phenyl)-5H-thiazolo[5,4-c]pyridin-4-one. ES/MS m/z 440.0 (35Cl) [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].[S:11]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17]O)=[CH:12]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:17][CH2:16][C:13]1[CH:14]=[CH:15][S:11][CH:12]=1)[C:5]#[N:6]
Reactant: OCCc1ccsc1
Reactant: N#Cc1ccc(O)c(Br)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: N#Cc1ccc(OCCc2ccsc2)c(Br)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a solution of 3-bromo-4-hydroxybenzonitrile (15.0 g) in THF (100 mL) was added 2-(3-thienyl)ethanol (7.94 mL) and triphenyl phosphine (19.84 g). The reaction was cooled to 0° C. and diethylazodicarboxylate (11.92 mL) was added dropwise. The reaction was stirred at room temperature for 16 h. The solvent was then reduced in vacuo and the residue redissolved in diethyl ether (100 mL) The mixture was stirred at 0° C. for 10 min and then filtered. The filtrate was washed with aqueous sodium carbonate solution (80 mL), 1 M aqueous hydrochloric acid (80 mL) and brine (80 mL), dried (MgSO4), reduced in vacuo and purified on silica to give 3-bromo-4-(2-thiophen-3-yl-ethoxy)-benzonitrile.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:22])=[C:5]([C:18]([O:20][CH3:21])=[O:19])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].[CH2:23]([Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:24]=[CH2:25].B(F)(F)F.CCOCC>C(Cl)(Cl)Cl>[CH3:22][C:4]12[CH2:25][CH:24]([CH2:23][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:7]([C:8]([O:10][CH3:11])=[O:9])([CH:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:5]1[C:18]([O:20][CH3:21])=[O:19])[C:2]([CH3:1])=[N:3]2
Reactant: C=CC[Si](C)(C)C
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1ccccc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: COC(=O)C1C(c2ccccc2)C2(C(=O)OC)C(C)=NC1(C)CC2C[Si](C)(C)C
Reaction time: 4 h

Procedure:
To 1.0 g (3.3 mmol) dimethyl 2,6-dimethyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylate (1) [B. Loev. et al., J. Med. Chem., 17, 956 (1974)] in 50 ml chloroform cooled in an ice-bath to 0°-5° there was added 7.5 g (66 mmol) commercially obtained allyltrimethylsilane (2) followed by 1.41 g (10 mmol) boron trifluoride etherate added dropwise via syringe. The reaction mixture was then stirred for 4 hours at 0°-10° and quenched by addition of saturated aqueous NaHCO3 solution. After the addition of 50 ml Et2O, the organic phase was separated, washed with brine and dried. Solvent removal left an oil that was purified by column chromatograhy on silica gel eluting with 7% isopropanol/hexane to give pure 3 as of oil, which crystallized after standing, mp. 152°-155°, formula: C23H33NO4Si; m.w., 415.606. mmr (CDCl3) δ 0.78(9H, s), 0.27(1H, dd), 0.47(1H, dd), 0.83(1H, dd), 1.57(3H, s), 2.46(1H, dd), 2.55(3H, s), 2.60(1H, dd), 2.76(1H, m), 3.58(3H, s), 3.74(1H, d), 3.79(3H, s), 7.16(2H, dd), 7.30(3H, m).
Reaction SMILES: [H-].[Na+].CS(C)=O.[I-].[CH3:8][S+](C)C.[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[O:17]>O.O1CCCC1>[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]1[O:17][CH2:8]1
Reactant: C[S+](C)C
Reactant: O=Cc1cccc(Cl)c1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Clc1cccc(C2CO2)c1
Reaction time: 0.25 h

Procedure:
A mixture of 42.0 g. of 57% sodium hydride dispersed in oil and 700 ml. of dimethyl sulfoxide is stirred at 70°-75° C. for one to one and one-half hours. The solution is diluted with 700 ml. of dry tetrahydrofuran and cooled to 0° C., under nitrogen. A 200 g. (1.0 mole) sample of trimethylsulfonium iodide is added in portions, maintaining the temperature between 0°-5° C. The mixture is stirred for 15 minutes and then a solution of 70.4 g. (0.50 mole) of m-chlorobenzaldehyde in 300 ml. of dry tetrahydrofuran is added dropwise. The resulting mixture is stirred at room temperature for four hours, poured into water and extracted with ether. The extract is washed with brine, dried and evaporated in vacuo to leave m-chlorostyrene oxide.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12](F)[N:11]=1.[H-].[Na+].O>CN(C=O)C>[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:8][CH2:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[N:11]=1
Reactant: Fc1cccc(F)n1
Reactant: OCC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1cccc(OCC2CCOCC2)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 74.8 %

Procedure:
To a solution of tetrahydro-2H-pyran-4-yl methanol (1.00 g) and 2,6-difluoropyridine (1.19 g) in DMF (10 mL) was added 60% sodium hydride (410 mg), and the mixture was stirred at 80° C. for 8 hours. Water (50 mL) was added dropwise to the reaction mixture, followed by extraction with ethyl acetate (100 mL). The organic layer was washed sequentially with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=80/20) to obtain 2-fluoro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridine (1.36 g).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7]([OH:9])=[O:8].[CH2:16](I)[CH3:17].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][C:2]1[O:3][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7]([O:9][CH2:16][CH3:17])=[O:8]
Reactant: CCI
Reactant: Cc1oc(-c2ccccc2)cc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.1 %

Procedure:
A suspension of 2-methyl-5-phenyl-3-furancarboxylic acid (5.0 g), ethyl iodide (4.7 g) and potassium carbonate (3.5 g) in N,N-dimethylformamide (50 mL) was stirred at room temperature for 4 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (5.7 g, 100%) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:13])[CH:12]=1)[CH:5]=[CH:6][C:7]([OH:9])=[O:8]>C1COCC1.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][CH2:6][C:7]([OH:9])=[O:8])[CH:10]=[C:11]([F:13])[CH:12]=1
Reactant: O=C(O)C=Cc1cc(F)cc(F)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C(O)CCc1cc(F)cc(F)c1
Yield: 108.6 %

Procedure:
According to the literature (Kruse et al., J. Med. Chem. (1987), 30, 486-494), a solution of 3,5-difluorocinnamic acid (9.94 g, 53.9 mmol) in THF (100 ml) was hydrogenated over 10% Pd/C (1.50 g) at 50 psi of H2 pressure for 5 h at RT. The mixture was filtered and concentrated under reduced pressure to yield the 3-(3,5-difluoro-phenyl)propionic acid (10.9 g, 100%). Oxalyl chloride (13 ml, 150 mmol) was slowly added to a solution of the acid (10.9 g, 53.9 mmol) in THF (220 ml) at 23° C., followed by the addition of a catalytic amount of DMF (1 drop). After 90 min at RT, the volatiles were removed under reduced pressure and the resulting residue was twice coevaporated with dry benzene to yield 3-(3,5-difluorophenyl)-propionyl chloride as a yellow oil (11.91 g, 100%). The acid chloride was used in the ensuing step without further purification. The acylation was carried out in analogy to the literature (Pettit et al. Synthesis (1996), 719-725). A solution of (S)-(−)-4-isopropyl-2-oxazolidinone (6.46 g, 50 mmol) in THF (150 ml) was stirred under argon and cooled to −78° C. n-BuLi (2.45 M in hexanes, 20.8 ml, 50.96 mmol) was added dropwise, followed by a solution of the previously prepared 3-(3,5-difluorophenyl)-propionyl chloride in THF (8 ml). After warming the reaction to 23° C. over 15 h, the reaction was quenched with saturated aq. NH4Cl (30 ml), followed by removal of the volatiles in vacuo. The slurry was extracted with CH2Cl2 (2×), and the combined organic layers washed with 1M NaOH (2×) and brine, dried (Na2SO4) and concentrated in vacuo. Purification of the residue by chromatography over silica gel (15→30% EtOAc/hexanes) gave the product (14.27 g, 48 mmol, 96%). 1H NMR (400 MHz, CDCl3) δ 6.73 (m, 2H), 6.59 (m, 1H), 4.37 (m, 1H), 4.17-4.25 (m, 2H), 3.24 (m, 1H), 3.16 (m, 1H), 2.93 (m, 2H), 2.30 (m, 1H), 0.86 (d, 3H, J=6.8 Hz), 0.80 (d, 3H, J=6.8 Hz); LCMS (Conditions A): tR=4.47 min: 595 (2M+H)+, 298 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([C:11](Cl)=[O:12])[C:8]([Br:14])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Cl-].[Al+3].[Cl-].[Cl-].[C:19]1([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[C:9]([C:11]([C:22]2[CH:23]=[CH:24][C:19]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:20][CH:21]=2)=[O:12])[C:8]([Br:14])=[CH:7][C:3]=1[C:4]([C:22]1[CH:21]=[CH:20][C:19]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:24][CH:23]=1)=[O:5]
Reactant: CCCCCCCCCCc1ccccc1
Reactant: O=C(Cl)c1cc(Br)c(C(=O)Cl)cc1Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCCCCCCCc1ccc(C(=O)c2cc(Br)c(C(=O)c3ccc(CCCCCCCCCC)cc3)cc2Br)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
Compound 7 (19.2 g, 0.059 mol) was dissolved in 100 mL of dry CH2Cl2, and aluminum chloride (16.6 g, 0.12 mol) was added. The reaction turned orange and some precipitate formed. The reaction was cooled to 0° C., and phenyldecane (45.3 g, 0.21 mol) in 50 mL of dry CH2Cl2 was added through an additional funnel. The reaction was stirred at room temperature under nitrogen overnight. The reaction was quenched carefully with 1 N HCl, extracted with CH2Cl2, and the combined organic phase was dried over MgSO4. The crude product was obtained as off-white solid and was recrystallized from acetone to give 31.8 g of pure product as white crystals at 74% yield. 1H NMR (CDCl3) δ (ppm): 0.88 (t, J=6.7 Hz, 6H), 1.26-1.32 (m, 28H), 1.62-1.67 (m, 4H), 2.69 (t, J=7.6 Hz, 4H), 7.32 (d, J=7.9 Hz, 4H), 7.58 (s, 2H), 7.76 (d, J=7.9 Hz, 4H). Mp 128-129° C.
Reaction SMILES: O[CH2:2][CH:3]([C:7]1[N:16]=[C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[CH3:24])[CH:14]=[C:13]2[C:8]=1[CH:9]=[C:10]([NH:25][C:26]([CH:28]1[CH2:30][CH2:29]1)=[O:27])[N:11]=[CH:12]2)[CH2:4][CH2:5][OH:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.C(OCC)(=O)C>[F:23][C:21]1[CH:20]=[CH:19][C:18]([CH3:24])=[C:17]([C:15]2[CH:14]=[C:13]3[C:8]([CH:9]=[C:10]([NH:25][C:26]([CH:28]4[CH2:30][CH2:29]4)=[O:27])[N:11]=[CH:12]3)=[C:7]([CH:3]3[CH2:4][CH2:5][O:6][CH2:2]3)[N:16]=2)[CH:22]=1
Reactant: Cc1ccc(F)cc1-c1cc2cnc(NC(=O)C3CC3)cc2c(C(CO)CCO)n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(F)cc1-c1cc2cnc(NC(=O)C3CC3)cc2c(C2CCOC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.5 %

Procedure:
To a solution of N-(5-(1,4-dihydroxybutan-2-yl)-7-(5-fluoro-2-methylphenyl)-2,6-naphthyridin-3-yl)cyclopropanecarboxamide (45 mg, 0.1 mmol) in tetrahydrofuran (1 mL) was added triphenylphosphine (61 mg, 0.23 mmol) followed by diisopropyl azodicarboxylate (0.028 mL, 0.14 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 4 g, ISCO, 0-60% ethyl acetate in heptane) and then repurified by reverse phase HPLC (5-85% acetonitrile in water with 0.1% formic acid over 14 min) to afford the title compound as an off-white solid (10 mg, 20% over two steps). 1H NMR (400 MHz, DMSO) δ 11.18 (s, 1H), 9.30 (s, 1H), 8.83 (s, 1H), 8.03 (s, 1H), 7.41-7.31 (m, 2H), 7.19 (td, J=8.5, 2.8 Hz, 1H), 4.31-4.23 (m, 1H), 4.20 (t, J=7.7 Hz, 1H), 4.00-3.95 (m, 1H), 3.94-3.86 (m, 2H), 2.42-2.35 (m, 5H), 2.10 (m, 1H), 0.95-0.82 (m, 4H). LCMS (Method E): RT=5.416 min, M+H+=392.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:18]1[S:19][CH2:20][C@@H:21]([CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[N:22]=1)=[CH:5]2.[N:31]1([CH2:36][C:37](O)=[O:38])[CH:35]=[N:34][N:33]=[N:32]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:18]1[S:19][CH2:20][C@@H:21]([CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][N:28]([C:37](=[O:38])[CH2:36][N:31]4[CH:35]=[N:34][N:33]=[N:32]4)[CH2:27][CH2:26]3)[N:22]=1)=[CH:5]2
Reactant: O=C(O)Cn1cnnn1
Reactant: Clc1cc(NC2CCOCC2)c2[nH]c(C3=N[C@H](CCN4CCNCC4)CS3)cc2c1
Product: O=C(Cn1cnnn1)N1CCN(CC[C@@H]2CSC(c3cc4cc(Cl)cc(NC5CCOCC5)c4[nH]3)=N2)CC1
Yield: 48 %

Procedure:
The compound (61 mg, 0.14 mmol) prepared in Example 117 and 1H-tetrazole-1-acetic acid instead of glycolic acid were reacted according to the same procedure as Example 118 to give the title compound (31 mg, Yield 48%).
Reaction SMILES: CO[C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:5]=1.[C:17]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:19])[CH3:18].[Li]>>[C:21]([O:20][C:17](=[O:19])[CH2:18][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:5]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(=O)OC(C)(C)C
Reactant: COC(=O)c1cccc(-c2ccccn2)c1
Agent: [Li]
Product: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccccn2)c1

Procedure:
The title compond was prepared from 3-pyridin-2-yl-benzoic acid methyl ester [CAS-No. 98061-20-2] (9.42 g, 44.18 mmol) by treatment with lithium tert-butyl acetate according to general procedure K (method b). Obtained as a yellow oil (8.35 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[Cl:25][C:26]1[CH:27]=[C:28]([OH:32])[CH:29]=[CH:30][CH:31]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:32][C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([Cl:25])[CH:27]=3)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: Oc1cccc(Cl)c1
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Product: CC(NC(=O)c1coc(Oc2cccc(Cl)c2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 29.3 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with 3-chlorophenol (34 mg, 0.26 mmol) to give the title compound (18 mg, 29%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: C[Si](C)(C)CC[O:5][C:6](=[O:46])[CH:7]([CH2:33][CH:34]=[CH:35][CH2:36][P:37]([O:40][CH:41]([C:43]([OH:45])=[O:44])[CH3:42])([OH:39])=[O:38])[CH2:8][C:9]([CH3:32])=[CH:10][CH2:11][C:12]1[C:13]([O:25]CC[Si](C)(C)C)=[C:14]2[C:18](=[C:19]([CH3:23])[C:20]=1[O:21][CH3:22])[CH2:17][O:16][C:15]2=[O:24].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:43]([CH:41]([O:40][P:37]([CH2:36][CH:35]=[CH:34][CH2:33][CH:7]([CH2:8][C:9]([CH3:32])=[CH:10][CH2:11][C:12]1[C:13]([OH:25])=[C:14]2[C:18](=[C:19]([CH3:23])[C:20]=1[O:21][CH3:22])[CH2:17][O:16][C:15]2=[O:24])[C:6]([OH:46])=[O:5])([OH:39])=[O:38])[CH3:42])([OH:45])=[O:44]
Reactant: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)CC(CC=CCP(=O)(O)OC(C)C(=O)O)C(=O)OCC[Si](C)(C)C)C(=O)OC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1c(C)c2c(c(O)c1CC=C(C)CC(CC=CCP(=O)(O)OC(C)C(=O)O)C(=O)O)C(=O)OC2
Reaction time: 16 h

Procedure:
A solution of crude 2-{4-[(1-carboxy-ethoxy)-hydroxy-phosphoryl]-but-2-enyl}-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoic acid 2-trimethylsilanyl-ethyl ester (AC-2101-59) and tetrabutylammonium fluoride in THF (1M, 54 μL, 0.054 mmol) was stirred with THF (1 mL) for 2 hours at ambient temperature, when more tetrabutylammonium fluoride in THF (54 μL, 0.054 mmol) was added. The reaction was stirred for an additional 16 hours, by which time the reaction was complete. The reaction mixture was concentrated in vacuo and the product was purified by RP HPLC using a Phenomenex Synergi 5μ Hydro RP 80A column (50×21.2 mm) with eluents of H2O, 0.1% TFA-CH3CN, 0.1% TFA to provide the product (8.0 mg) as a clear oil. 1H NMR (300 MHz, CDCl3) δ 1.51 (d, 3H, J=7 Hz), 1.79 (s, 3H), 2.05-2.40 (m, 4H), 2.11 (s, 3H), 2.49-2.71 (m, 3H), 3.38 (d, 2H, J=6 Hz), 3.76 (s, 3H), 4.85 (br s, 1H), 5.20 (s, 2H), 5.21-5.30 (m, 1H), 5.33-5.63 (m, 2H) ppm; 31P (121.4 MHz, CDCl3) δ 27.7 ppm; MS (m/z) 525.2 [M−H]−.