Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14](=[O:34])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][S:22][C:23]2[NH:27][C:26]3[CH:28]=[CH:29][C:30]([O:32][CH3:33])=[CH:31][C:25]=3[N:24]=2)=[CH:17][CH:16]=1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14](=[O:34])[C:15]1[CH:16]=[CH:17][C:18]([CH2:21][S:22][C:23]2[NH:27][C:26]3[CH:28]=[CH:29][C:30]([O:32][CH3:33])=[CH:31][C:25]=3[N:24]=2)=[CH:19][CH:20]=1
Reactant: COc1ccc2[nH]c(SCc3ccc(C(=O)Nc4ccccc4O[Si](C)(C)C(C)(C)C)cc3)nc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc2[nH]c(SCc3ccc(C(=O)Nc4ccccc4O)cc3)nc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.7 %

Procedure:
To a stirred solution of compound 198 (313 mg, 0.600 mmol) in THF (15 ml) was added TBAF 1M in THF (1.20 ml, 1.20 mmol). The reaction mixture was stirred 16 h at room temperature. The solvent was evaporated and the residue was dissolved in EtOAc, washed with sat. NH4Cl and brine, dried over anhydrous MgSO4, filtered and concentrated to afford the title compound 199 (150 mg, 61% yield) as a white powder. 1H NMR (DMSO-d6) δ (ppm): 9.72 (bs, 1H), 9.49 (bs, 1H), 7.90 (d, J=8.1 Hz, 2H), 7.63 (d, J=8.1 Hz, 1H), 7.58 (d, J=8.8 Hz, 2H), 7.51 (d, J=9.5 Hz, 1H), 7.08-6.89 (m, 4H), 6.81 (dd, J=7.0, 7.0 Hz, 1H), 4.76 (s, 2H), 3.81 (s, 3 H). m/z: 406.2 (MH+).
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl:23][C:24]1[CH:25]=[C:26]([C:30]([NH2:33])([CH3:32])[CH3:31])[CH:27]=[CH:28][CH:29]=1>>[Cl:23][C:24]1[CH:25]=[C:26]([C:30]([NH:33][CH2:19][C:18]2[CH:21]=[CH:22][C:15]([C:14]#[C:13][C:10]3[CH:11]=[CH:12][C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:8][CH:9]=3)=[CH:16][CH:17]=2)([CH3:31])[CH3:32])[CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(N)c1cccc(Cl)c1
Reactant: CCCCCCc1ccc(C#Cc2ccc(C=O)cc2)cc1
Product: CCCCCCc1ccc(C#Cc2ccc(CNC(C)(C)c3cccc(Cl)c3)cc2)cc1
Yield: 80 %

Procedure:
The same procedure as employed in the preparation of Example 226 (step a) but using 4-[(4-hexylphenyl)ethynyl]benzaldehyde and 1-(3-chlorophenyl)-1-methylethylamine gave the title compound as a brown oil (80%). HPLC (Condition A), Rt: 4.73 min (HPLC purity: 98.7%).
Reaction SMILES: [N:1]1([CH2:10][O:11][C:12]2[CH:33]=[CH:32][C:15]([CH2:16][N:17]3[CH:21]=[C:20]([CH2:22][CH2:23][C:24]([O:26]CC)=[O:25])[C:19]([O:29][CH2:30][CH3:31])=[N:18]3)=[CH:14][CH:13]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[N:1]1([CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([CH2:16][N:17]3[CH:21]=[C:20]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])[C:19]([O:29][CH2:30][CH3:31])=[N:18]3)=[CH:32][CH:33]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCn3nnc4ccccc43)cc2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1nn(Cc2ccc(OCn3nnc4ccccc43)cc2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.2 %

Procedure:
After a mixture of ethyl 3-[1-[4-(1H-benzotriazol-1-ylmethoxy)benzyl]-3-ethoxy-1H-pyrazol-4-yl]propionate (652 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 3 hours, 1N hydrochloric acid (3 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[1-[4-(1H-benzotriazol-1-ylmethoxy)benzyl]-3-ethoxy-1H-pyrazol-4-yl]propionic acid (576 mg, yield: 94%). This was recrystallized from ethanol-hexane. Melting point: 136–137° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([NH:12][NH:13][C:14](=[O:16])[CH3:15])=O)=[CH:6][CH:5]=1>O=P(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:16][C:14]([CH3:15])=[N:13][N:12]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C(=O)NNC(C)=O)cc1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc(-c2nnc(C)o2)cc1
Yield: 75.92 %

Procedure:
Oxalyl chloride (1.05 g, 8.3 mmol) was added to a stirred solution of terephthalic acid monomethyl ester (1 g, 5.55 mmol) in DCM (12 mL) and stirring was continued at ambient temperature for 4 hr. The reaction mixture was concentrated under reduced pressure to afford the residue. The residue was dissolved in DCM (4 mL) and to the resulting solution was added, acetic acid hydrazide (490 mg, 6.66 mmol), Et3N (670 mg, 6.66 mmol) and stirring was continued at temperature overnight. The reaction mixture was diluted with water and extracted with ethylacetate, dried over sodium sulfate and concentrated under reduced pressure to afford 1 g (76.39% Yield) of 4-(N′-acetyl-hydrazinocarbonyl)-benzoic acid methyl ester. A stirred solution of 4-(N′-acetyl-hydrazinocarbonyl)-benzoic acid methyl ester (500 mg, 5.55 mmol) in POCl3 (12 mL) was heated at 100° C. for 3 hr. The reaction mixture was concentrated under reduced pressure to afford the residue. The residue was diluted with cold water, extracted with ethyl acetate, washed the organic layer with sodium bicarbonate solution, saturated brine solution and dried over sodium sulfate. The organic layer was concentrated under reduced pressure to 350 mg (75.92% Yield) of afford 4-(5-methyl-[1,3,4]oxadiazol-2-yl)-benzoic acid methyl ester. LiOH.H2O (330 mg, 8 mmol) was added to a solution of 4-(5-methyl-[1,3,4]oxadiazol-2-yl)-benzoic acid methyl ester (350 mg, 1.6 mmol) in the mixture of methanol (4 mL), THF (10 mL) and H2O (4 mL). The resulting reaction mixture was stirred at ambient temperature for 2 hrs. The reaction mixture was concentrated The residue was diluted with water, acidified with aqueous citric acid solution, extracted with ethyl acetate and dried over sodium sulfate. The organic layer was concentrated under reduced pressure to afford 280 mg (87.46% Yield) of 4-(5-methyl-[1,3,4]oxadiazol-2-yl)-benzoic acid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:15]([O:17]C)=[O:16])[S:10][C:11]=2[CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=[N:3]1.[Br:19]N1C(=O)CCC1=O.[OH-].[Na+]>O1CCCC1>[Br:19][C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[C:7]1[CH:8]=[C:9]([C:15]([OH:17])=[O:16])[S:10][C:11]=1[CH2:12][CH2:13][CH3:14]
Reactant: CCCc1sc(C(=O)OC)cc1-c1ccnn1C
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCc1sc(C(=O)O)cc1-c1c(Br)cnn1C
Temperature: 70 °C
Reaction time: 12 h
Yield: 50 %

Procedure:
A solution of methyl 4-(1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylate (714 mg, 2.70 mmol)[prepared in Example 112] and N-bromosuccinimide (481 mg, 2.70 mmol) in tetrahydrofuran (12 ml) was stirred in a sealed tube for 1 h at 70° C. The reaction mixture was divided and half of the solution was treated with 6N sodium hydroxide (2.251 ml, 13.51 mmol). The reaction mixture stirred at 70° C. in a sealed tube for 12 h and was partitioned between H2O-DCM. The pH of the aqueous phase was adjusted to ˜4 and washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and used directly affording 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylic acid (445 mg, 1.35 mmol, 50% yield): LCMS (ES) m/e 329, 331 (M, M+2)+.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4](Br)=[CH:5][CH:6]=1.C([Li])CCC.[C:13](=[O:15])=[O:14]>C1COCC1>[Br:1][C:2]1[S:3][C:4]([C:13]([OH:15])=[O:14])=[CH:5][CH:6]=1
Reactant: Brc1ccc(Br)s1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Br)s1
Temperature: -78 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
THF (50 mL) was added via cannula to a flame-dried 100 mL Schlenk flask. 2,5-dibromothiophene (10 mmol, 2.42 g) was added via syringe. Reaction vessel was cooled to −78° C. and n-butyllithium (1.61M solution in hexanes, 11 mmol, 6.8 mL) was added dropwise over 5 minutes. The solution was allowed to stir at −78° C. for 1 hr. Dry ice (approx. 50 g) was added to the reaction mixture, and was allowed to stir and return to room temperature for 18 hrs. under nitrogen. The light gray suspension was filtered and the white solid was stirred in 2M HCl for 1 hr. The suspension was filtered to yield a white solid (5.7 mmol, 1.2 g, 57%). 1H NMR (400 MHz, CDCl3) δ: 11.45 (br s, 1H), 7.64 (d, 1H, J=4.0 Hz), 7.11 (dd, 1H, J=4.0 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:13](O)[CH2:14][OH:15].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCC2(CC1)OCCO2

Procedure:
4-Oxo-cyclohexanecarboxylic acid ethyl ester (52.8 g, 0.31 mol, Merck, order no. 814249, ethylene glycol (67.4 g, 1.08 mol) and p-toluenesulfonic acid (0.7 g) in toluene (160 ml) were stirred at RT for 20 h, the reaction solution was poured into diethyl ether (300 ml) and the mixture was washed with water, sodium bicarbonate solution and sodium chloride solution. The solution was dried (Na2SO4) and concentrated i. vac. and the colourless liquid which remained was processed further without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][N:3]=1.CC(C)([O-])C.[K+].Br[C:16]1[C:17]([CH3:25])=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[N:20][CH:21]=1>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:16]2[CH:21]=[N:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=2[CH3:25])[CH:5]=[CH:4][N:3]=1
Reactant: Oc1ccnc(Cl)c1
Reactant: Cc1cc([N+](=O)[O-])ncc1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc([N+](=O)[O-])ncc1Oc1ccnc(Cl)c1
Temperature: 65 °C
Reaction time: 24 h
Yield: 17.8 %

Procedure:
2-Chloro-4-hydroxypyridine (0.239 g, 1.843 mmol) was dissolved in DMF (18.43 ml) and potassium t-butoxide (0.290 g, 2.58 mmol) was added. The solution was degassed for several minutes, and then 5-bromo-4-methyl-2-nitropyridine (0.4 g, 1.843 mmol) was added. The mixture was heated at 65° C. for 70 hours under argon and then at 80° C. for 24 hours. The reaction mixture was cooled to RT, diluted with ethyl acetate (150 mL), washed with water (75 mL), 10% aqueous LiCl (2×75 mL), saturated aqueous bicarbonate (75 mL) and brine (75 mL), dried (MgSO4), evaporated and purified via silica gel chromatography (ethyl acetate/hexanes) to yield 2-chloro-4-(4-methyl-6-nitropyridin-3-yloxy)pyridine as a yellow solid (0.087 g, 18% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.49 (s, 1H), 8.47 (s, 1H), 8.35 (d, 1H), 7.24 (d, 1H), 7.12 (dd, 1H), 2.31 (s, 3H); MS (ESI) m/z: 266.0 (M+H+).
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C@H:3]([N:28]1[CH2:32][CH2:31][C@H:30]([NH:33]C(=O)OC(C)(C)C)[CH2:29]1)[C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][C:17]([O:24][CH2:25][CH2:26][OH:27])=[C:18]([F:23])[CH:19]=4)[N:14]=3)=[N:11][N:12]=2)[CH:9]=1>C(O)(C(F)(F)F)=O>[NH2:33][C@H:30]1[CH2:31][CH2:32][N:28]([C@H:3]([C:4]2[CH:5]=[CH:6][C:7]3[N:8]([C:10]([C:13]4[CH:22]=[CH:21][C:20]5[C:15](=[CH:16][C:17]([O:24][CH2:25][CH2:26][OH:27])=[C:18]([F:23])[CH:19]=5)[N:14]=4)=[N:11][N:12]=3)[CH:9]=2)[C:2]([F:41])([F:1])[F:42])[CH2:29]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN([C@H](c2ccc3nnc(-c4ccc5cc(F)c(OCCO)cc5n4)n3c2)C(F)(F)F)C1
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CCN([C@H](c2ccc3nnc(-c4ccc5cc(F)c(OCCO)cc5n4)n3c2)C(F)(F)F)C1
Yield: 77 %

Procedure:
tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(3-(6-fluoro-7-(2-hydroxyethoxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (200 mg, 0.339 mmol) was stirred in TFA (3 mL) for 1 hour and then concentrated. The residue was dissolved in minimum methanol and added dropwise to a 4N HCl in ether solution. The resulting solid was filtered and dried to yield 2-(2-(6-((R)-1-((S)-3-aminopyrrolidin-1-yl)-2,2,2-trifluoroethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoro quinolin-7-yloxy)ethanol (128 mg, 77.1% yield) hydrochloride as an off-white solid. LCMS APCI (+) m/z 491 (M+H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([C:6]([O:8][CH3:9])=[O:7])[CH2:2]1.[Br:10]N1C(=O)CCC1=O.O>C1COCC1>[Br:10][C:3]1([C:6]([O:8][CH3:9])=[O:7])[CH2:4][CH2:5][O:1][CH2:2]1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C1CCOC1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C1(Br)CCOC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
5.0 g (38.419 mmol) of methyl tetrahydrofuran-3-carboxylate (Journal of Organic Chemistry; 1996; 2690) were dissolved in 200 ml of THF and cooled to −78° C., and 76.83 ml (76.83 mmol) of bis(trimethylsilyl)lithium amide (1 M in THF) were then added. After 30 min at −78° C., 10.26 g (57.63 mmol) of N-bromosuccinimide, suspended in 50 ml of THF, were added slowly. The mixture was then allowed to warm to RT overnight. Water was added, and the mixture was extracted with ethyl acetate. The phases were separated and the aqueous phase was extracted two more times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution and then dried with sodium sulphate, filtered and concentrated. The crude product was purified by chromatography on silica gel (mobile phase:dichloromethane). This gave 491 mg (6% of theory) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.Br[CH2:18][CH2:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([Cl:27])=[N:25][CH:26]=1>>[Cl:27][C:24]1[N:25]=[CH:26][C:21]([O:20][CH2:19][CH2:18][N:3]2[C:4]3[C:9](=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=3)[CH:10]=[C:2]2[CH3:1])=[CH:22][CH:23]=1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: Clc1ccc(OCCBr)cn1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1CCOc1ccc(Cl)nc1

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 120) and 5-[(2-bromoethyl)oxy]-2-chloropyridine: MS (ES) m/z 380 (M+1) and 382 (M+1, isotope).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:26][C@H:27]3[CH2:31][CH2:30][CH2:29][N:28]3C(OC(C)(C)C)=O)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=4[F:25])=[CH:13][CH:12]=3)[C:3]=12.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>ClCCl>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[F:25][C:19]1[C:20]([F:24])=[CH:21][CH:22]=[CH:23][C:18]=1[O:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:3]3[C:4](=[N:5][CH:6]=[N:7][C:2]=3[NH2:1])[N:8]([CH2:26][C@H:27]3[CH2:31][CH2:30][CH2:29][NH:28]3)[N:9]=2)=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3cccc(F)c3F)cc2)c2c(N)ncnc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncnc2c1c(-c1ccc(Oc3cccc(F)c3F)cc1)nn2C[C@H]1CCCN1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46 %

Procedure:
Into a 100 mL, round-bottom flask, was placed a solution of tert-butyl (2R)-2-([4-amino-3-[4-(2,3-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)-pyrrolidine-1-carboxylate (350 mg, 0.67 mmol, 1.00 equiv) in dichloromethane (10 mL). Trifluoroacetic acid (2 mL) dropwise with stirring and the resulting solution was stirred for 3 h at 25° C. The resulting mixture was concentrated under vacuum to give 200 mg (46%) of 3-[4-(2,3-difluorophenoxy)phenyl]-1-[(2R)-pyrrolidin-2-ylmethyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine bis(trifluoroacetic acid) salt as a brown solid.
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[C@H:9]2[O:10][CH2:11][C@@H:12]([OH:13])[C@H:8]2[O:7][C@H:4]1[O:5][CH3:6].N1C=CC=CC=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[CH3:1][O:2][C@@H:3]1[C@H:9]2[O:10][CH2:11][C@@H:12]([O:13][S:21]([CH3:20])(=[O:23])=[O:22])[C@H:8]2[O:7][C@H:4]1[O:5][CH3:6]
Reactant: CO[C@@H]1O[C@H]2[C@H](OC[C@H]2O)[C@H]1OC
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CO[C@@H]1O[C@H]2[C@H](OC[C@H]2OS(C)(=O)=O)[C@H]1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Methyl 3,6-anhydro-2-O-methyl-β-D-glucofuranoside (420 mg, 2.6 mmol) was dissolved in dichloromethane (10 mL) and pyridine (0.36 mL, 3.7 mmol) at 0° C. Methanesulfonyl chloride (0.14 mL, 3.1 mmol) was added and the resulting mixture was stirred at 0° C. for 1 hour then at room temperature for 2 hours. The reaction mixture was washed with water and saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and concentrated to give methyl 3,6-anhydro-2-O -methyl-5-O-(methylsulfonyl)-β-D-glucofuranoside as a colorless oil, 669 mg, 95% yield, which was used without further purification.
Reaction SMILES: C([Mg]Br)C.[Cl:5][C:6]1[N:20]=[CH:19][C:9]2[C:10]3[N:11]([CH:15]=[C:16](I)[N:17]=3)[CH2:12][CH2:13][O:14][C:8]=2[CH:7]=1.CN(C)[CH:23]=[O:24]>O1CCCC1>[Cl:5][C:6]1[N:20]=[CH:19][C:9]2[C:10]3[N:11]([CH:15]=[C:16]([CH:23]=[O:24])[N:17]=3)[CH2:12][CH2:13][O:14][C:8]=2[CH:7]=1
Reactant: Clc1cc2c(cn1)-c1nc(I)cn1CCO2
Reactant: CN(C)C=O
Agent: CC[Mg]Br
Solvent: C1CCOC1
Product: O=Cc1cn2c(n1)-c1cnc(Cl)cc1OCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.5 %

Procedure:
Ethylmagnesium bromide (3.0 M in Et2O, 100 mmol, 33.3 mL) was added dropwise to a solution of 9-chloro-2-iodo-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepine (10.0 g, 28.8 mmol) in tetrahydrofuran (173 mL) at −20° C. The mixture was maintained at this temperature 20 min and then allowed to warm to ambient temperature for a 1 hr period. At this point, the reaction was re-cooled to −20° C. and N,N-dimethylformamide (8.9 mL, 115 mmol) was added to the mixture. Stirring was continued for 16 h before quenching with saturated aqueous ammonium chloride solution (220 mL) and further dilution with EtOAc (250 mL). The phases were separated and the aqueous layer was extracted twice with EtOAc. The combined organic portions were washed once with brine, dried over MgSO4, filtered and concentrated in vacuo. This provided 7.08 g (98% yield) of 9-chloro-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepine-2-carbaldehyde as a yellow solid in >95% purity as determined by analytical HPLC. MS (ESI+): m/z 249.8 (M+H+), calc. 249.65
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH2:9]([O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CS(C)=O.C1COCC1>[CH2:9]([O:16][C:17]1[CH:18]=[CH:19][C:20]([CH:21]2[CH2:4][O:22]2)=[CH:23][CH:24]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: c1ccc(COc2ccc(C3CO3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
NaH (60%, 0.5 g, 23.6 mmol) was diluted in DMSO (50 mL) and stirred for 30 min at rt under nitrogen. Trimethylsulfoxonium iodide (7.8 g, 35.37 mmol) was added in portions at 0° C. The reaction mixture was stirred for 1 h. Then a solution of 4-benzyloxybenzaldehyde (5 g, 23.58 mmol) in THF (15 mL) was added. The reaction solution was stirred at rt for 3 h. The reaction mixture was poured into ice-water and extracted with ether. The organic layer was dried over Na2SO4 and concentrated to give 2-(4-(benzyloxy)phenyl)oxirane, which was used for the next step without further purification.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[CH:10]=2)[CH:5]=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB([C:25]2[CH:43]=[CH:42][C:28]([O:29][C@@H:30]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31]3)=[CH:27][CH:26]=2)O1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1>[CH:14]1([C:12]([NH:11][C:9]2[CH:10]=[C:3]3[C:2]([C:25]4[CH:43]=[CH:42][C:28]([O:29][C@@H:30]5[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])[CH2:31]5)=[CH:27][CH:26]=4)=[CH:7][CH:6]=[CH:5][N:4]3[N:8]=2)=[O:13])[CH2:16][CH2:15]1
Reactant: O=C(Nc1cc2c(Br)cccn2n1)C1CC1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC[C@@H](Oc2ccc(-c3cccn4nc(NC(=O)C5CC5)cc34)cc2)C1
Temperature: 25 °C

Procedure:
N-(4-Bromopyrazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide (265 mg, 0.95 mmol), (R)-tert-butyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyrrolidine-1-carboxylate (442 mg, 1.14 mmol), PdCl2dppf (39 mg, 0.047 mmol) and Na2CO3 (501 mg, 4.73 mmol) were stirred in 1,4-dioxane (15 ml) and water (3 ml) and heated at 100° C. for 2 h. The reaction mixture was cooled to room temperature and filtered through celite. The residue was partitioned between EtOAc and water and the aqueous phase was extracted with EtOAc. The combined organics were dried (MgSO4), filtered and concentrated in vacuo to give (R)-tert-Butyl 3-(4-(2-(cyclopropanecarboxamido)pyrazolo[1,5-a]pyridin-4-yl)phenoxy)pyrrolidine-1-carboxylate as a brown oil which was used in the next step without further purification.
Reaction SMILES: C(OC(C1C=C([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][S:19][CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:14][CH:13]=2)C=CC=1)=O)C.[CH2:29]([O:31][C:32]([C:34]1[CH:39]=[CH:38][C:37](C2C=CC=C(CSCCO)C=2)=[CH:36][CH:35]=1)=[O:33])[CH3:30].C1(O)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:29]([O:31][C:32]([C:34]1[CH:39]=[CH:38][C:37]([C:13]2[CH:12]=[CH:17][CH:16]=[C:15]([CH2:18][S:19][CH2:20][CH2:21][O:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:14]=2)=[CH:36][CH:35]=1)=[O:33])[CH3:30]
Reactant: CCOC(=O)c1ccc(-c2cccc(CSCCO)c2)cc1
Reactant: CCOC(=O)c1cccc(-c2ccc(CSCCOc3ccccc3)cc2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Oc1ccccc1
Product: CCOC(=O)c1ccc(-c2cccc(CSCCOc3ccccc3)c2)cc1

Procedure:
3′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid ethyl ester was synthesized as described for 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethyl ester. 3′-(2-Hydroxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid ethyl ester (1.95 g, 6.16 mmol, 1 eq.) in anhydrous THF was treated with phenol (0.75 g, 8.01 mmol, 1.3 eq.), triphenylphosphine (2.10 g, 8.01 mmol, 1.3 eq.), and diisopropyl azidocarboxylate (1.62 g, 8.01 mmol, 1.3 eq.). When complete, the reaction was worked up as described leaving an orange oil.
Reaction SMILES: [Cl:1][C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:13][S:14]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)(=[O:16])=[O:15].N1C=CC=CC=1>C(Cl)Cl>[CH3:13][S:14]([N:17]1[CH2:22][CH2:21][N:20]([C:2]([Cl:1])=[O:4])[CH2:19][CH2:18]1)(=[O:16])=[O:15]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CS(=O)(=O)N1CCNCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(C(=O)Cl)CC1
Temperature: 25 °C
Yield: 159.4 %

Procedure:
To a stirred solution of carbonic acid ditrichloromethyl ester (triphosgene) (1.81 g, 6.09 mmol) in CH2Cl2 (30 ml) at 0° C., was added a solution of 1-methanesulfonyl-piperazine (2.0 g, 12.2 mmol) and pyridine (1.08 ml, 13.4 mmol) in CH2Cl2 (5 ml) over 30 minutes. The temperature was raised to RT, and stirring was continued over night. The organic phase was washed with H2O, dried over Na2SO4. Purification by flash chromatography (SiO2, EtOAc) yielded 2.20 g (79%) of the title compound as white solid.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([N:11]2[CH2:16][CH2:15][NH:14][C@H:13]([CH3:17])[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Br[C:19]1C=CC2OCCC=2C=1>>[O:9]1[C:8]2[CH:7]=[CH:6][C:5]([N:11]3[CH2:16][CH2:15][NH:14][C@H:13]([CH3:17])[CH2:12]3)=[CH:4][C:3]=2[CH2:19][CH2:10]1
Reactant: COc1ccc(N2CCN[C@H](C)C2)cc1OC
Reactant: Brc1ccc2c(c1)CCO2
Product: C[C@@H]1CN(c2ccc3c(c2)CCO3)CCN1

Procedure:
The title compound was prepared following the procedure of Intermediate 25, but starting from 5-bromo-2,3-dihydrobenzo[b]furan. Purification by flash chromatography (CHCl3/MeOH) gave the title compound as a brown oil. M+(ESI): 219.2. HPLC (Condition A), Rt: 1.3 min (HPLC purity: 99.9%).