Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.O1CCOCC1.[C:8]([NH:16][C:17]1[S:18][CH2:19][C@@H:20]2[CH2:26][C@H:25]([CH2:27][F:28])[O:24][CH2:23][C@:21]2([C:29]2[C:30]([F:45])=[CH:31][C:32]([F:44])=[C:33]([CH:43]=2)[CH2:34][NH:35]C(=O)OC(C)(C)C)[N:22]=1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[NH2:35][CH2:34][C:33]1[C:32]([F:44])=[CH:31][C:30]([F:45])=[C:29]([C@:21]23[CH2:23][O:24][C@@H:25]([CH2:27][F:28])[CH2:26][C@H:20]2[CH2:19][S:18][C:17]([NH:16][C:8](=[O:15])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[N:22]3)[CH:43]=1
Reactant: CC(C)(C)OC(=O)NCc1cc([C@]23CO[C@@H](CF)C[C@H]2CSC(NC(=O)c2ccccc2)=N3)c(F)cc1F
Agent: Cl
Solvent: C1COCCO1
Product: NCc1cc([C@]23CO[C@@H](CF)C[C@H]2CSC(NC(=O)c2ccccc2)=N3)c(F)cc1F
Reaction time: 8 h
Yield: 88.3 %

Procedure:
A solution of hydrogen chloride in dioxane (4.0 M, 10 mL, 41 mmol) was added to tert-butyl {5-[(4aR,6R,8aS)-2-(benzoylamino)-6-(fluoromethyl)-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-2,4-difluorobenzyl}carbamate (C25) (0.8277 g, 1.506 mmol) at room temperature. The reaction mixture was stirred overnight and then concentrated under reduced pressure to yield a brown solid. The solid was partitioned between a 1:1 solution of ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate (100 mL). The organics were separated and the aqueous layer was extracted further with ethyl acetate (2×100 mL). The combined organics were then washed with brine (200 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to yield the product as a brown solid (0.598 g), which was taken directly to the following step. LCMS m/z 450 [M+H+]. 1H NMR (400 MHz, CD3OD), characteristic peaks: δ 8.11-8.13 (m, 2H), 7.44-7.57 (m, 3H), 7.09 (dd, J=12.3, 9.6 Hz, 1H), 4.49-4.51 (m, 1H), 4.37-4.39 (m, 1H), 3.20-3.23 (m, 1H), 3.01 (dd, J=13.0, 4.2 Hz, 1H), 2.77 (dd, J=13.0, 2.8 Hz, 1H), 1.89 (m, 1H), 1.70 (ddd, J=13.4, 4.1, 2.2 Hz, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH:20]=[O:21])=[C:12]2Cl)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH:20]=[O:21])=[C:12]2[N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(-n2c(Cl)c(C=O)c3ccccc32)cc1
Reactant: C1CCNCC1
Product: CC(C)(C)c1ccc(-n2c(N3CCCCC3)c(C=O)c3ccccc32)cc1
Yield: 87 %

Procedure:
1-(4-tert-Butylphenyl)-2-chloro-1H-indole-3-carboxaldehyde is reacted with piperidine as described in Step 2 of Example 29 to afford 1-(4-tert-butylphenyl)-2-piperidin-1-yl-1H-indole-3-carboxaldehyde (87% yield) as an off-white solid. TLC (silica gel, heptane-30% ethyl acetate); Rf 0.23; ESI/MS 361 (M+H); RT 4.48 min; NMR 10.14 (1H, s); 8.11 (1H, d, J=6 Hz); 7.66 (2H, d); 7.46 (2H, d); 7.16 (2H, m); 6.91 (1H, d, J=9 Hz); 3.27 (4H, m); 1.46 (6H, m); 1.36 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[NH:10][C:11](=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15]Cl.CC(C)([O-])C.[K+].[I-].[Na+]>C(O)(C)(C)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=[O:17]
Reactant: Cc1cc(C)c(NC(=O)CCCCCl)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: Cc1cc(C)c(N2CCCCC2=O)c(Cl)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 100.5 %

Procedure:
5-Chloropentanoic acid (2-chloro-4,6-dimethylphenyl)amide (21.7 g), potassium t-butoxide (9.34 g), and sodium iodide (1.2 g) were combined in 200 mL t-butanol and the mixture was stirred in a 60° C. oil bath for 3 h. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was washed with additional ethyl acetate. The organic phases were washed with brine, dried with magnesium sulfate, and concentrated to give 18.9 g of 1-(2-chloro-4,6-dimethylphenyl)piperidin-2-one as a solid, mp. 107.7–108.7° C.
Reaction SMILES: [Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)C=CC=CC=1.C([Li])CCC.[CH3:37][O:38][C:39]1[CH:40]=[C:41]([CH:44]=[C:45]([O:47][CH3:48])[CH:46]=1)[CH:42]=O>CCOCC>[CH3:48][O:47][C:45]1[CH:44]=[C:41]([CH:42]=[CH:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:40]=[C:39]([O:38][CH3:37])[CH:46]=1
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: c1ccc(OCCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1cc(C=CCCCOc2ccccc2)cc(OC)c1
Yield: 60 %

Procedure:
The triphenyl(4-phenoxybutyl)phosphonium bromide was converted to an ylide using n-butyllithium and refluxing with 3,5-dimethoxybenzaldehyde in ether for 3 hours gave 1-(3,5-dimethoxyphenyl)-5-phenoxy-1-pentene as a 2:1 mixture of E:Z isomers. Purification was by column chromatography and gave a 60% yield. Subsequently, hydrogenation of 1-(3,5-dimethyoxypheny)-5-phenoxy-1-pentene over palladium on carbon (10%) under 50 psi of hydrogen gas resulted in the quantitative reduction of the pentene carbon-carbon double bond in to yield 1-(3,5-dimethoxyphenyl)-5-phenoxy-1-pentane. This phenoxy-1-pentane was then contacted with boron tribromide in benzene for 72 hours at 25° C. to deprotect the methoxy groups of the compound and substitute the phenoxy moiety with bromide to form 5'-bromo olivetol. After purification, an 80% yield was achieved.
Reaction SMILES: [OH-].[K+].[CH2:3]([C:5]1([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:15][CH:14]=2)[CH2:9][O:8]C(=O)[NH:6]1)[CH3:4].[ClH:30]>O.CO.O1CCCC1.CCOCC>[ClH:30].[NH2:6][C:5]([CH2:3][CH3:4])([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:15][CH:14]=1)[CH2:9][OH:8]
Reactant: CCC1(CCc2ccc(OCCCCc3ccccc3)cc2)COC(=O)N1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: CO
Product: CCC(N)(CO)CCc1ccc(OCCCCc2ccccc2)cc1

Procedure:
A solution of potassium hydroxide (5.8 g) in water (20 ml) was added to a solution of 4-ethyl-4-(2-(4-(4-phenylbutyloxy)phenyl)ethyl)oxazolidin-2-one (3.0 g) in methanol (60 ml) and tetrahydrofuran (50 ml). The mixture was refluxed under heating for 18.5 hours while stirring. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure to give a pale brown, oily substance. The oily substance was subjected to silica gel column chromatography (eluent; ethyl acetate then methanol) and the solvent was distilled away to give a pale brown residue. The obtained residue was dissolved in methanol and thereto was added a 1M solution of hydrochloric acid in ether. The solution was concentrated under reduced pressure, and the obtained crude crystals were recrystallized from isopropyl ether and hexane to give the subject compound (0.63 g) as white crystals, melting at 101-103° C.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([I:10])[CH:5]=1.[C:12](Cl)(=O)[CH3:13]>N1C=CC=CC=1.C(OCC)(=O)C>[I:10][C:6]1[CH:5]=[C:4]([C:3]2[N:11]=[C:12]([CH3:13])[O:1][N:2]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: NC(=NO)c1cccc(I)c1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1nc(-c2cccc(I)c2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.5 %

Procedure:
N′-Hydroxy-3-iodobenzamidine (1.80 g, 6.87 mmol) obtained in Step 1 was dissolved in pyridine (14 mL), and the mixture was stirred at room temperature for 1 hour after adding acetyl chloride (0.551 mL, 6.87 mmol). The mixture was cooled to room temperature after further stirring at 90° C. for 4 hours. After diluting the mixture with ethyl acetate, the organic layer was washed with 1 mol/L hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained upon concentration under reduced pressure was then purified by silica gel column chromatography to give 3-(3-iodophenyl)-5-methyl-1,2,4-oxadiazole (756 mg, 39%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([CH3:27])([C:21]3[NH:22][CH:23]=[C:24]([CH3:26])[N:25]=3)[CH3:20])[CH:17]=2)[NH:12][C:11]=1[C:28]1[CH:33]=[C:32]([CH3:34])[CH:31]=[C:30]([CH3:35])[CH:29]=1)(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>>[CH3:35][C:30]1[CH:29]=[C:28]([C:11]2[NH:12][C:13]3[C:18]([C:10]=2[CH2:9][CH2:8][NH2:7])=[CH:17][C:16]([C:19]([CH3:27])([C:21]2[NH:22][CH:23]=[C:24]([CH3:26])[N:25]=2)[CH3:20])=[CH:15][CH:14]=3)[CH:33]=[C:32]([CH3:34])[CH:31]=1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)c4nc(C)c[nH]4)cc3c2CCNC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)c4nc(C)c[nH]4)cc3c2CCN)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.6 %

Procedure:
To a solution of (2-{2-(3,5-dimethylphenyl)-5-[1-methyl-1-(4-methyl-1H-imidazol-2-yl)ethyl]-1H-indol-3-yl}ethyl)carbamic acid tert-butyl ester (353 mg in 8 mL methylene chloride) at 0° C. was added 0.56 mL anisole followed by 2.5 mL trifluoroacetic acid and the mixture stirred at room temperature. After 2 hours, the mixture was concentrated in vacuo and the residual acid removed by azeotrope with toluene. The residue was solvated in methylene chloride and washed sequentially with 0.5N sodium hydroxide and brine. Purification of the concentrate by preparative tlc on silica gel (methylene chloride:methanol:ammonium hydroxide, 80:20:0.25) to give the title compound (198 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])[CH:5]=[CH:6][CH:7]=1.[CH3:19][C:20](C)([O-:22])[CH3:21].[K+].C(C1OC1)Br>CC(N(C)C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH2:19][CH:20]2[CH2:21][O:22]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[O-]
Reactant: Oc1ccccc1CCCCc1cccc(Cl)c1
Agent: BrCC1CO1
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Clc1cccc(CCCCc2ccccc2OCC2CO2)c1
Yield: 86.5 %

Procedure:
Following a procedure similar to that described in Example 1(a), 800 mg of 2-[4-(3-chlorophenyl)butyl]phenol (prepared as described in Preparation 17), 344 mg of potassium t-butoxide and 835 mg of epibromohydrin were reacted in 20 ml of dimethylacetamide. The crude product, extracted as described in Example 1(a), was purified as described in Example 1(a), to give 840 mg (yield 86%) of the title compound as a colorless oil.
Reaction SMILES: C(N(CC)CC)C.[CH2:8](Cl)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl:16][SiH:17]([Cl:19])[Cl:18]>>[CH2:8]([Si:17]([Cl:19])([Cl:18])[Cl:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: ClCc1ccccc1
Reactant: Cl[SiH](Cl)Cl
Solvent: CCN(CC)CC
Product: Cl[Si](Cl)(Cl)Cc1ccccc1
Yield: 46.1 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.051 g (0.5 mmol) of triethylamine, 0.63 g (5.0 mmol) of benzyl chloride, and 3.41 g (25.2 mmol) of trichlorosilane were reacted at 150° C. for 18 hrs. The resulting mixture was distilled to give 0.52 g of benzyltrichlorosilane (yield; 47%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH2:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[F:19])=[CH:4][N:3]=1.C([Li])CCC.[C:25]([Si:29]([O:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([N:39]=[C:40]=[O:41])[CH2:35][CH2:34]1)([CH3:31])[CH3:30])([CH3:28])([CH3:27])[CH3:26]>O1CCCC1.C(OCC)(=O)C>[C:25]([Si:29]([CH3:31])([CH3:30])[O:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([N:39]2[C:6]3=[N:7][C:2]([Cl:1])=[N:3][CH:4]=[C:5]3[CH2:9][N:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=3[F:19])[C:40]2=[O:41])[CH2:35][CH2:34]1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](N=C=O)CC1
Reactant: COc1ccc(NCc2cnc(Cl)nc2Cl)c(F)c1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(N2Cc3cnc(Cl)nc3N([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)CC3)C2=O)c(F)c1
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
To a solution of (2,4-dichloro-pyrimidin-5-yl-methyl)-(2-fluoro-4-methoxy-phenyl)amine (1.1 g, 3.64 mmol) (from Example 17a supra) in tetrahydrofuran (50 mL) at −78° C. was added n-butyllithium (2.5 M in hexanes, 1.75 mL, 4.37 mmol) (Aldrich). After stirring at −78° C. for 40 minutes, tert-butyl-(trans-4-isocyanato-cyclohexyloxy)-dimethyl-silane (1.12 g, 4.37 mmol) (from Example 17b supra) was added. The mixture was stirred at −70° C. for 1 hour and then at room temperature for 3 hours. It was diluted with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with ethyl acetate-hexanes (3:7 then 2:3) to give 1-[trans-4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-7-chloro-3-(2-fluoro-4-methoxy-phenyl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one. (Yield 0.60 g, 33%).
Reaction SMILES: C([O:5][C:6]([NH:8][NH:9][C:10]([C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1[F:19])=[NH:11])=O)(C)(C)C.[CH2:20](OC(=O)C=O)C>C1(C)C=CC=CC=1>[F:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([F:18])[C:12]=1[C:10]1[N:11]=[CH:20][C:6](=[O:5])[NH:8][N:9]=1
Reactant: CCOC(=O)C=O
Reactant: CC(C)(C)OC(=O)NNC(=N)c1c(F)cccc1F
Solvent: Cc1ccccc1
Product: O=c1cnc(-c2c(F)cccc2F)n[nH]1
Reaction time: 5 h

Procedure:
At room temperature, 30 g of N′-[(2,6-difluorophenyl)-imino-methyl]-hydrazinecarboxylic acid tert-butyl ester and 23.8 g of glyoxylic acid ethyl ester are stirred in 500 ml of toluene at 70° C. for 4 hours. The reaction mixture is then concentrated, 200 ml of formic acid are added and stirring is continued at room temperature for 5 hours. The reaction mixture is concentrated, and the residue is taken up in 300 ml of ethanol and boiled under reflux for 6 h. After concentration of the reaction mixture and recrystallisation from ethyl acetate there is obtained 3-(2,6-difluorophenyl)-[1,2,4]triazin-6(1H)-one having a melting point of 219-226° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9](=O)[C:10]([NH2:19])([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=1)[CH3:11].[O-]S([O-])(=O)=O.[Na+].[Na+].[H][H]>C1COCC1>[NH2:19][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=1)([CH3:11])[CH2:9][OH:8]
Reactant: [H][H]
Reactant: COC(=O)C(C)(N)c1cccc(Br)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(N)(CO)c1cccc(Br)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 85.1 %

Procedure:
Lithium aluminium hydride (1 M in THF; 22 mL, 22 mmol) was added dropwise to a stirred solution of rac-2-amino-2-(3-bromo-phenyl)-propionic acid methyl ester (7.5 g, 29.1 mmol) in THF (200 mL) at −15° C. The mixture was left warming up slowly to 0° C. during 1 hour. Then more THF (150 mL) was added and sat. Na2SO4 was added dropwise until no more hydrogen was formed. Then anhydrous Na2SO4 was added and left stirring overnight at room temperature. The mixture was filtered over diatomaceous earth, rinsed with THF and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel; 7 M solution of ammonia in methanol in DCM 0/100 to 3/97). The desired fractions were collected and concentrated in vacuo to yield rac-2-amino-2-(3-bromo-phenyl)-propan-1-ol (5.70 g, 85% yield) as an oil.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[C:9]([C:18]([O:20][CH3:21])=[O:19])[N:10](C(OC(C)(C)C)=O)[C:6]=2[CH:5]=[CH:4][N:3]=1.[F:22][C:23]1[CH:28]=[C:27]([Sn](CCCC)(CCCC)CCCC)[CH:26]=[CH:25][N:24]=1.[F-].[Cs+]>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.O1CCOCC1>[F:22][C:23]1[CH:28]=[C:27]([C:2]2[C:7]3[CH:8]=[C:9]([C:18]([O:20][CH3:21])=[O:19])[NH:10][C:6]=3[CH:5]=[CH:4][N:3]=2)[CH:26]=[CH:25][N:24]=1
Reactant: COC(=O)c1cc2c(Cl)nccc2n1C(=O)OC(C)(C)C
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(F)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: COC(=O)c1cc2c(-c3ccnc(F)c3)nccc2[nH]1
Temperature: 100 °C
Yield: 76.7 %

Procedure:
1-Tert-butyl 2-methyl 4-chloro-1H-pyrrolo[3,2-c]pyridine-1,2-dicarboxylate (100 mg, 0.322 mmole), 2-fluoro-4-(tributylstannyl)pyridine (162 mg, 0.418 mmole), CsF (108 mg, 0.708 mmole), and bis(tri-t-butylphosphine)palladium(0) (16 mg, 0.031 mmole) were combined in a screw cap vial. To this was added 1,4-dioxane (1 mL). N2 was bubbled through the mixture for 10 seconds. The vial was capped then heated to 100° C. After 6 hr was cooled to RT, diluted with EtOAc, filtered through a pad of Celite washing with EtOAc, and concentrated. The residue was taken up in 2 mL CH2Cl2. To this was added 2 mL TFA. After 2 hr the mixture was concentrated. The residue was taken up in saturated NaHCO3 and extracted with CH2Cl2 (3×). The combined organic layers were dried (MgSO4), filtered, and concentrated. Flash column chromatography (Biotage-SNAP-10 g SiO2, 70% EtOAc/hexanes) gave the title compound (67 mg, 77%) as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 9.23 (bs, 1 H); 8.56 (d, J=5.8 Hz, 1 H); 8.40 (d, J=5.2 Hz, 1 H); 7.82-7.79 (m, 1 H); 7.56 (s, 1 H); 7.50 (dd, J=2.0, 1.1 Hz, 1 H); 7.43 (dd, J=5.8, 1.1 Hz, 1 H); 4.00 (s, 3 H).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)C.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[C:10]1([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][OH:3])=[CH:12][CH:11]=1
Reactant: CCOC(=O)COc1ccc(-c2ccccc2)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: OCCOc1ccc(-c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of (Biphenyl-4-yloxy)-acetic acid ethyl ester (0.63 g, 2.46 mmol) in dry toluene (15 mL) at −78° C. was added DIBAL-H 1M in toluene (4.92 mL, 4.92 mmol). The solution was stirred at −78° C. for 1 hour, warmed to room temperature and quenched with mixture of a solution of sodium tartrate in water and ethyl acetate for 1 hour. The layers were separated and the aqueous phase further extracted with ethyl acetate. The combined organic layers were dried (MgSO4), concentrated under vacuum and the residue purified bu column chromatography (silica gel, hexanes/Ethyl acetate 4:1, Rf0.1), 48%. 1H-NMR (CDCl3, 200.15 MHz): 7.58–7.26 (m, 8H); 7.00 (d, 2H, J=8.6), 4.14 (t, 2H, J=4.6), 4.02–3.98 (m, 2H); 2.04 (t, 1H, J=5.4).
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH:7]([O:16][Si](C)(C)C)[CH2:8][P:9]([CH2:14][CH3:15])(=[O:13])[O:10]CC)C(=O)C2=CC=CC=C12.[ClH:27]>>[ClH:27].[NH2:5][CH2:6][CH:7]([OH:16])[CH2:8][P:9]([CH2:14][CH3:15])(=[O:10])[OH:13]
Reactant: CCOP(=O)(CC)CC(CN1C(=O)c2ccccc2C1=O)O[Si](C)(C)C
Agent: Cl
Product: CCP(=O)(O)CC(O)CN
Temperature: 25 °C

Procedure:
A solution of 6.4 g of ethyl 3-phthalimido-2-trimethylsilyloxy-propyl(ethyl)phosphinate in 100 ml of concentrated aqueous hydrochloric acid is heated to reflux for 20 hours. After this time the suspension is cooled to room temperature and filtered. The filtrate is evaporated to dryness, the resulting semi-solid is co-evaporated with water (5×50 ml) and absolute ethanol (5×100 ml) and the white solid is dried in high vacuum overnight. Crystallisation from absolute ethanol/acetone affords 3-amino-2-hydroxy-propyl(ethyl)phosphinic acid hydrochloride, m.p. 114°-115°.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:42]=[C:41]([Cl:43])[CH:40]=[CH:39][C:9]=2[O:10][C:11]2[C:16]([F:17])=[CH:15][C:14]([S:18]([N:21](CC3C=CC(OC)=CC=3OC)[C:22]3[S:26][N:25]=[CH:24][N:23]=3)(=[O:20])=[O:19])=[C:13]([F:38])[CH:12]=2)[CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Cl[CH2:50][CH:51]=O>C(O)C.O.ClCCl>[Cl:43][C:41]1[CH:40]=[CH:39][C:9]([O:10][C:11]2[C:16]([F:17])=[CH:15][C:14]([S:18]([NH:21][C:22]3[S:26][N:25]=[CH:24][N:23]=3)(=[O:19])=[O:20])=[C:13]([F:38])[CH:12]=2)=[C:8]([C:6]2[N:7]3[CH:50]=[CH:51][N:1]=[C:2]3[CH:3]=[CH:4][CH:5]=2)[CH:42]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(Oc3ccc(Cl)cc3-c3cccc(N)n3)cc2F)c(OC)c1
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: O=S(=O)(Nc1ncns1)c1cc(F)c(Oc2ccc(Cl)cc2-c2cccc3nccn23)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 43 %

Procedure:
To a stirred solution of 4-(2-(6-aminopyridin-2-yl)-4-chlorophenoxy)-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (2.43 g, 3.75 mmol) in ethanol (75 mL) and water (9 mL) was added sodium bicarbonate (0.41 g, 4.9 mmol) and chloroacetaldehyde (50% w/w in water, 0.63 mL, 4.9 mmol) at ambient temperature. The mixture was heated at reflux for 16 h, allowed to cool to ambient temperature and diluted with dichloromethane (200 mL) and water (20 mL). The organic layer washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in dichloromethane (50 mL) and trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred for 5 h at ambient temperature and concentrated in vacuo. The residue was purified by column chromatography eluting with a 0-10% gradient of methanol in ethyl acetate to afford 4-(4-chloro-2-(imidazo[1,2-a]pyridin-5-yl)phenoxy)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide as a pale yellow solid in 43% yield (0.84 g): 1H NMR (300 MHz, DMSO-d6) δ8.14 (s, 1H), 7.93 (d, J=1.5 Hz, 2H), 7.87-7.78 (m, 2H), 7.76-7.66 (m, 2H), 7.62-7.52 (m, 1H), 7.42-7.30 (m, 3H); MS (ES+) m/z 519.8 (M+1), 521.8 (M+1).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][O:5][C@@H:4]2[C@H:7]([O:10][C:11]3[N:12](COCC[Si](C)(C)C)[C:13]4[C:14]([N:28]=3)=[N:15][C:16]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=3)=[C:17]([Cl:19])[CH:18]=4)[CH2:8][O:9][C@H:3]12.C(O)=O.OS([O-])(=O)=O.[K+].[OH-].[Na+].Cl>>[OH:1][C@@H:2]1[CH2:6][O:5][C@@H:4]2[C@H:7]([O:10][C:11]3[NH:12][C:13]4[C:14]([N:28]=3)=[N:15][C:16]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=3)=[C:17]([Cl:19])[CH:18]=4)[CH2:8][O:9][C@H:3]12
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2nc(-c3ccc(C#N)cc3)c(Cl)cc21
Agent: Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O=CO
Product: N#Cc1ccc(-c2nc3nc(O[C@@H]4CO[C@H]5[C@@H]4OC[C@H]5O)[nH]c3cc2Cl)cc1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A flask was charged with 4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-1-(2-trimethylsilylethoxymethyl)-imidazo[4,5-b]pyridin-5-yl]benzonitrile (209.8 mg, 0.397 mmol), formic acid (3.6 ml, 94 mmol), and saturated aqueous KHSO4 (0.4 ml). The reaction mixture was heated to 40° C. for 16 h. Then the reaction mixture was cooled to room temperature before being cooled to 0° C. in an ice bath. A 50% weight solution of aqueous NaOH (5.3 ml, 200.7 mmol) was added to the reaction mixture, which solidified after being removed from the ice bath and was allowed to warm to room temperature. The reaction mixture was diluted with THF (2.0 ml) and water (10.0 ml) to give a hazy biphasic mixture with a pH of 14 that was stirred at room temperature for 30 min. The pH was adjusted to 5 by the addition of 2 N aqueous HCl. The reaction mixture was partitioned between EtOAc (50 ml) and water (20 ml). The aqueous layer was extracted with EtOAc (2×50 ml). The organic layers were combined, washed with brine (1×30 ml), dried over Na2SO4, filtered, and evaporated under reduced pressure to give a light pink residue. This material was purified by preparative HPLC reverse phase (C-18), using a 30×150 mm Sunfire™ column and eluting with a 20%-100% acetonitrile/water+0.05% TFA gradient, followed by a 100% acetonitrile+0.05% TFA flush. The product fractions were combined, evaporated under reduced pressure, and lyophilized from ethanol and benzene to give the title compound as a white solid. LC-MS: calculated for C19H15ClN4O4 398.08 observed m/e: 399.09 (M+H)+ (Rt 1.07/2 min); 1H NMR δ (ppm) (CD3OD): 7.84 (s, 1H), 7.84 (qt, J=8.3 Hz, 4H), 5.54 (qt, J=5.3 Hz, 1H), 4.96 (t, J=5.2 Hz, 1H), 4.46 (t, J=5.0 Hz, 1H), 4.25-4.30 (m, 1H), 4.16 (dd, J=5.6 Hz, J=10.2, 1H), 4.11 (dd, J=4.7 Hz, J=10.2 Hz, 1H), 3.89 (dd, J=7.0 Hz, J=8.1 Hz, 1H), 3.59 (t, J=8.6 Hz, 1H).