Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:22]4[CH:27]=[CH:26][N:25]=[C:24](NC(C)C)[CH:23]=4)=[N:15][N:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:32]C1C=C(C2C(C3C=CN=C(S(C)=O)N=3)=C3C=CC=CN3N=2)C=CN=1>>[CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:22]4[CH:27]=[CH:26][N:25]=[C:24]([F:32])[CH:23]=4)=[N:15][N:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)Nc1cc(-c2nn3ccccc3c2-c2ccnc(NC3CCCC3)n2)ccn1
Reactant: CS(=O)c1nccc(-c2c(-c3ccnc(F)c3)nn3ccccc23)n1
Product: Fc1cc(-c2nn3ccccc3c2-c2ccnc(NC3CCCC3)n2)ccn1
Product: NC1CCCC1

Procedure:
N-Cyclopentyl-4-{2-[2-(isopropylamino)-4-pyridinyl]pyrazolo[1,5-a]pyridin-3-yl}-2-pyrimidinamine. In a similar manner as described in example 17 from 2-(2-fluoro-4-pyridinyl)-3-[2-(methylsulfinyl)-4-pyrimidinyl]pyrazolo[1,5-a]pyridine (410 mg, 1.16 mmol) and cyclopentylamine (4 mL, 40.5 mmol) was formed crude N-cyclopentyl-4-[2-(2-fluoro-4-pyridinyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine (385 mg), of which 260 mg (0.694 mmol) was dissolved in isopropylamine (3 mL, 35.2 mmol) and heated at 150° C. in a steel bomb for 16 hours. The reaction mixture was cooled and the excess isopropylamine was removed under a stream of nitrogen to provide N-cyclopentyl-4-{2-[2-(isopropylamino)-4-pyridinyl]pyrazolo[1,5-a]pyridin-3-yl}-2-pyrimidinamine (170 mg, 52% for 2 step procedure) as a beige solid. 1H NMR (CDCl3) δ 8.50 (d, 1H), 8.41 (d, 1H), 8.13–8.08 (m, 2H), 7.32 (t, 1H), 6.92 (t, 1H), 6.80 (d, 1H), 6.62 (s, 1H), 6.47 (d, 1H), 5.26 (d, 1H), 4.63 (d, 1H), 4.34 (m, 1H), 3.85 (m, 1H), 2.11–2.04 (m, 2H), 1.79–1.51 (m, 6H), 1.22 (d, 6H); MS m/z 414 (M+1).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][C@@H:13]([CH2:15]I)[O:12][C:11](=[O:17])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC[O:20][C:21]([CH3:23])=[O:22].O>CC(O)=O.CC([O-])=O.[Ag+]>[C:21]([O:22][CH2:15][C@@H:13]1[CH2:14][C@@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:10][C:11](=[O:17])[O:12]1)(=[O:20])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC(=O)O[C@H](CI)C1
Reactant: CCOC(C)=O
Agent: [Ag+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)OC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Yield: 92.6 %

Procedure:
To a solution of (4R,6S)-4-(tert-butyldimethylsilyloxy)-6-(iodomethyl)-tetrahydropyran-2-one (40.00 g, 108.0 mmol) in AcOH (660 mL), AgOAc (20.03 g, 118.8 mmol) is added. The resultant mixture is then heated at 125° C. for 6 hours. The reaction mixture is filtered through diatomite filter medium (Celite®). The obtained filtrate is evaporated to afford the residue. To this residue, EtOAc (500 mL) and water (600 mL) are added. The organic layer is separated and the aqueous layer is washed again with EtOAc (5×150 mL). The combined organic layers are washed with water (4×300 mL), brine (5×300 mL) and dried over anhydrous MgSO4, filtered and concentrated under the reduced pressure to afford 30.28 g (92.6%) of ((2S,4R)-4-(tert-butyldimethylsilyloxy)-6-oxo-tetrahydro-2H-pyran-2-yl)methyl acetate as yellow oil (HPLC purity 98%).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:16]=2[CH2:15][C@H:14]([NH:17][C:18](=[O:20])[CH3:19])[CH2:13][CH2:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:29](Br)[CH3:30]>CC(C)=O.C(OCC)(=O)C.CCCCCC>[CH2:29]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:16]=2[CH2:15][C@H:14]([NH:17][C:18](=[O:20])[CH3:19])[CH2:13][CH2:12]3)[CH2:2][CH2:3]1)[CH3:30]
Reactant: CC(=O)N[C@@H]1CCc2cccc(N3CCNCC3)c2C1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCN1CCN(c2cccc3c2C[C@H](NC(C)=O)CC3)CC1
Yield: 78 %

Procedure:
To a mixture of (R)-N-[8-(piperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]acetamide (100 mg, 0.37 mmol), potassium carbonate (76 mg, 0.54 mmol) and potassium iodide (15 mg, 0.10 mmol) in acetone (20 mL) was added ethyl bromide (56 μL, 0.74 mmol) added and the reaction mixture was vigorously stirred over night. The reaction was filtered and the solvent was evaporated in vacuo. The residue was purified on a silica gel column using chloroform/methanol/concentrated ammonium hydroxide (95:5:0.5) as the eluent. This gave 87 mg (78% yield) of the title compound as an oil which was crystallized from ethyl acetate/hexane. Yield: 55 mg (50%) as white crystals: mp 142-143° C.; [α]21D +27° (c 0.50, chloroform); EIMS (70 eV) m/z (relative intensity) 301 (100, M+).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([C:7](=[O:9])[CH3:8])=[CH:3][CH:2]=1.[Br-:11].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl.CO>[Br:11][CH2:8][C:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=1)=[O:9]
Reactant: CC(=O)c1ccc(C)cc1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc(C(=O)CBr)cc1
Yield: 83.5 %

Procedure:
To a solution of 1-p-tolyl-ethanone (0.5 g, 4.16 mmol) in dichloromethane-methanol (50 ml-20 mL) was added tetrabutylammonium tribromide (2.2 g, 4.58 mmol) at room temperature. The mixture was stirred until the orange color faded. The solvent was then distilled under reduced pressure and the resulting precipitate was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated in vacuo to give a residue which was purified by flash column chromatography to yield the desired product 2-bromo-1-p-tolyl-1-ethanone (0.74 g, 84%). 1H NMR (300 MHz, DMSO-d6) δ 2.39 (s, 3H), 4.89 (s, 2H), 7.37 (d, 2H), 7.89 (d, 2H); ESI-MS (MH+): 213 and 215.
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([S:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:9])=[O:8])=[CH:3][CH:2]=1.Br[CH2:18][CH2:19][C:20](C)=[CH2:21]>>[CH2:14]([O:13][C:11](=[O:12])[CH:10]([S:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:16])=[CH:6][CH:5]=1)(=[O:9])=[O:8])[CH2:18][CH:19]=[CH:20][CH3:21])[CH3:15]
Reactant: C=C(C)CCBr
Reactant: CCOC(=O)CS(=O)(=O)c1ccc(C)cc1
Product: CC=CCC(C(=O)OCC)S(=O)(=O)c1ccc(C)cc1

Procedure:
5-Methyl-2-(3-methyl-but-2-enyl)-2-(toluene-4-sulfonyl-hex-4-enoic acid ethyl ester was prepared according to general method as outlined in example 9. Starting from ethyl α-(p-tolylsulfonyl)acetate (2.9g, 10.9 mmol and 4-bromo-2-methyl butene (3.42g, 23 mmol). Yield 4.6g; tan oil; MS 379.2 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:6]([OH:13])=[C:5]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:4]=1.[CH3:18][CH:19]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1)[CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23]>O1CCCC1>[C:9]([C:7]1[CH:8]=[C:3]([CH2:2][NH:32][C:29]2[CH:28]=[CH:27][C:26]([NH:25][CH:19]([CH3:18])[CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:31][CH:30]=2)[CH:4]=[C:5]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:6]=1[OH:13])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)c1cc(CBr)cc(C(C)(C)C)c1O
Reactant: CC(C)CCC(C)Nc1ccc(N)cc1
Solvent: C1CCOC1
Product: CC(C)CCC(C)Nc1ccc(NCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc1

Procedure:
4Bromomethyl-2,6-di-tert-butyl-phenol (2.42 g, 0.008 mole) was dissolved in 50 mL of dry tetrahydrofuran. In a separate conical flask N(1,4-Dimethyl-pentyl)-benzene-1,4-diamine (3.28 g, 0.016 mole) was dissolved in 25 mL of tetrahydrofuran and solution was transferred to a cylindrical funnel with pressure equalizing tube. Three-necked round-bottom flask containing solution of 4-Bromomethyl-2,6-di-tert-butyl-phenol was kept in oil-bath at temperature 85° C. Solution in the flask was continuously stirred with the help of magnetic stirrer. N(1,4-Dimethyl-pentyl)-benzene-1,4diamine solution was added drop-by-drop, from funnel to the flask in acidic medium for a span of 4-5 hours till all the solution was poured out. The reaction was terminated after that and the final reaction mixture was allowed to attain room temperature. Product was separated by solvent evaporation. The product was purified using silica gel column chromatography. Product was identified by 1H-NMR. The yield of 2,6-di-tert-butyl-4-{[4-(1,4-dimethyl-pentylamino)-phenylamino)methyl}-phenol is 2. 29 g (67%).
Reaction SMILES: FC(F)(F)C(O)=O.O.C(OC([N:16]1[CH2:19][CH2:18][C@@H:17]1[CH2:20][O:21][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][C@@H:35]([O:43][CH3:44])[CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:29]=2)[CH:27]=1)=O)(C)(C)C>C(Cl)Cl>[NH:16]1[CH2:19][CH2:18][C@H:17]1[CH2:20][O:21][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][C@H:35]([O:43][CH3:44])[CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:29]=2)[CH:27]=1
Reactant: CO[C@@H](Cc1ccccc1)Cc1cccc(-c2cncc(OC[C@H]3CCN3C(=O)OC(C)(C)C)c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CO[C@H](Cc1ccccc1)Cc1cccc(-c2cncc(OC[C@@H]3CCN3)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.9 %

Procedure:
Trifluoroacetic acid (1.6 mL) and water (0.16 mL) were added to 8 mL of CH2Cl2. This mixture was added to 3-[[1-(tert-butoxycarbonyl)-2(R)-azetidinyl]methoxy]-5-[3-(2(S)-methoxy-3-phenylpropyl)phenyl]pyridine (470 mg, 0.96 mmol) at 0° C. under N2. The solution was stirred overnight at room temperature. After concentration in vacuo, the crude product (300 mg) was purified by preparative HPLC (column: SunFire Prep C18, 150×19, 5 μm; UV detection, at 254 nm; mobile phase: A, water with 0.05% CF3COOH; B, CH3CN; 18-40% B in A in 6 min, 40-100% in 1 min). The product-containing eluate was partially evaporated under reduced pressure (bath 30° C.) to remove CH3CN. The pH of the residue was adjusted to 8.0 with saturated aqueous NaHCO3 solution, and the product was extracted into EtOAc (3×60 mL). The combined organic phases were washed with brine and dried over Na2SO4. After filtration and concentration, the free amine (175 mg, 47%) was obtained as a colorless oil. LC-MS (ESI) m/z 389 (M+H+).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH2:7]([C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1)[CH2:8][CH3:9].Cl[C:20]1[C:25]([S:26]([N:29]([C:39]([O:41][CH2:42][CH:43]([CH3:45])[CH3:44])=[O:40])[C:30]2[C:35]([O:36][CH3:37])=[N:34][C:33]([CH3:38])=[CH:32][N:31]=2)(=[O:28])=[O:27])=[CH:24][CH:23]=[CH:22][N:21]=1.C(O)C>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH2:42]([O:41][C:39]([N:29]([C:30]1[C:35]([O:36][CH3:37])=[N:34][C:33]([CH3:38])=[CH:32][N:31]=1)[S:26]([C:25]1[C:20]([C:13]2[CH:14]=[CH:15][C:10]([CH2:7][CH2:8][CH3:9])=[CH:11][CH:12]=2)=[N:21][CH:22]=[CH:23][CH:24]=1)(=[O:28])=[O:27])=[O:40])[CH:43]([CH3:45])[CH3:44]
Reactant: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1Cl
Reactant: CCCc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCCc1ccc(-c2ncccc2S(=O)(=O)N(C(=O)OCC(C)C)c2ncc(C)nc2OC)cc1
Temperature: 80 °C
Yield: 76.4 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0) (60 mg) was added to a deoxygenated solution of sodium carbonate (212 mg), 4-propylphenylboronic acid (328 mg) and 2-chloro-N-(isobutoxycarbonyl)-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (828 mg) in a mixture of water (5 ml), ethanol (8 ml) and toluene (16 ml). The mixture was stirred and heated under argon at 80° C. for 17 hours and then allowed to cool to ambient temperature. Ice water (25 g) was added and the reaction extracted with ethyl acetate (3×50 ml). The combined organic layers were dried (MgSO4) and evaporated to afford an amber oil. This was purified by chromatography on a silica gel Mega Bond Elut column, eluting with 20% ethyl acetate/isohexane to give N-(isobutoxycarbonyl)-2-(4-propylphenyl)-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (760 mg) as a solid, mass spectrum (+ve ESP): 499 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:18]2[CH2:24][C:23](=O)[O:22][C:20](=[O:21])[CH2:19]2)[CH:14]=[CH:15][C:16]=1[Cl:17]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:23]([CH2:24][CH:18]([C:13]3[CH:14]=[CH:15][C:16]([Cl:17])=[C:11]([Cl:10])[CH:12]=3)[CH2:19][C:20]([OH:22])=[O:21])[NH:9][C:4]=2[CH:3]=1.[ClH:1]
Reactant: O=C1CC(c2ccc(Cl)c(Cl)c2)CC(=O)O1
Reactant: Nc1ccc(Cl)cc1N
Product: Cl
Product: O=C(O)CC(Cc1nc2ccc(Cl)cc2[nH]1)c1ccc(Cl)c(Cl)c1

Procedure:
By a procedure similar to that of example 1.4, starting from 4-chloro-1,2-phenylenediamine and 3-(3,4-dichlorophenyl)glutaric anhydride, 4-(5-chloro-2-benzimidazolyl)-3-(3,4-dichlorophenyl)butanoic acid•HCl was obtained as off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7]([NH2:16])([C:13]([OH:15])=[O:14])[CH2:8]2.C(N(CC)CC)C.[C:24](=O)([O:40]N1C(=O)CCC1=O)[O:25][CH2:26][CH:27]1[C:39]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2>C(#N)C.O>[C:24]([CH:8]1[C:9]2[C:4](=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:6][C:7]1([NH2:16])[C:13]([OH:15])=[O:14])([O:25][CH2:26][CH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:34]2[C:39]1=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:40]
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: COc1cccc2c1CCC(N)(C(=O)O)C2
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cccc2c1CCC(N)(C(=O)O)C2C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 30 h
Yield: 71 %

Procedure:
A mixture of racemic 5-methoxy-2-aminotetraline-2-carboxylic acid (prepared according to Obrecht, D. et. al. Helv. Chim Acta. 1992, 75, 1666) (802 mg, 3.62 mmole), triethylamine (0.62 ml, 4.45 mmole), 9-fluorenylmethyl succinimidyl carbonate (Fmoc-OSu, 1.47 g, 4.36 mmole) in acetonitrile (25 ml) and water (25 ml) was stirred at room temperature for 30 hours. TLC analysis of the reaction indicated the presence of starting material amino acid. 9-fluorenylmethyl succinimidyl carbonate (370 mg) and triethylamine (0.6 ml) were added and the mixture was stirred at room temperature for another 24 hours. The reaction mixture was concentrated in vacuo to remove most of the acetonitrile, acidified to pH 3 with 10% aqueous citric acid solution, and the white emulsion was extracted three times with ethyl acetate. The combined organic layers were washed with water, brine and dried over magnesium sulfate. Filtration and concentration gave a crude oil which was purified by column chromatography (eluted with 1→3→5→10% methanol/methylene chloride) to give racemic Fmoc-5-methoxy-2-aminotetraline-2-carboxylic acid (1.14 g, 71% yield) as an off-white solid. HRMS (FAB): C27H26NO5 (M+H) calc. 444.1812; observed: 444.1814.
Reaction SMILES: O[C:2]1[C:3]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[N:6][N:7]=1.[NH2:15][CH:16]1[CH:21]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]1>>[F:31][C:28]([F:29])([F:30])[C:25]1[CH:24]=[CH:23][C:22]([CH:21]2[CH2:20][CH2:19][NH:18][CH2:17][CH:16]2[NH:15][C:2]2[C:3]3[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[N:6][N:7]=2)=[CH:27][CH:26]=1
Reactant: NC(=O)c1cccc2c(O)nnnc12
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(F)(F)F)cc2)C(N)C1
Product: NC(=O)c1cccc2c(NC3CNCCC3c3ccc(C(F)(F)F)cc3)nnnc12

Procedure:
Compound 22 was prepared following general synthesis scheme 9 wherein 4-hydroxybenzo[d][1,2,3]triazine-8-carboxylic acid amide was reacted with tert-butyl 3-amino-4-(4-(trifluoromethyl)phenyl)piperidine-1-carboxylate to give the title compound. LC-MS [417 (M+H)], 1H NMR (400 MHz, DMSO-d6) δ 9.21 (s, 1H), 9.04-8.92 (m, 1H), 8.61-8.43 (m, 3H), 8.11-7.92 (m, 2H), 7.72 (d, 1H), 7.64-7.46 (m, 5H), 5.58-5.44 (m, 1H), 3.71-3.44 (m, 4H), 3.30-3.09 (m, 1H), 2.81-2.60 (m, 1H), 2.08 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:47]([F:48])=[CH:46][CH:45]=[C:44]([F:49])[C:4]=2[S:5][C:6]=1[C:7]([N:9]([CH2:25][C:26]1[CH:27]=[C:28]([C:34]2[CH:39]=[CH:38][C:37]([S:40](=[O:43])(=[O:42])[NH2:41])=[CH:36][CH:35]=2)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH:10]1[CH2:15][CH2:14][CH:13]([N:16](C)[C:17](=O)OC(C)(C)C)[CH2:12][CH2:11]1)=[O:8].CC(OC)(C)C>C(Cl)Cl>[ClH:1].[CH3:33][O:32][C:31]1[CH:30]=[CH:29][C:28]([C:34]2[CH:39]=[CH:38][C:37]([S:40](=[O:43])(=[O:42])[NH2:41])=[CH:36][CH:35]=2)=[CH:27][C:26]=1[CH2:25][N:9]([CH:10]1[CH2:15][CH2:14][CH:13]([NH:16][CH3:17])[CH2:12][CH2:11]1)[C:7]([C:6]1[S:5][C:4]2[C:44]([F:49])=[CH:45][CH:46]=[C:47]([F:48])[C:3]=2[C:2]=1[Cl:1])=[O:8]
Reactant: COc1ccc(-c2ccc(S(N)(=O)=O)cc2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: CNC1CCC(N(Cc2cc(-c3ccc(S(N)(=O)=O)cc3)ccc2OC)C(=O)c2sc3c(F)ccc(F)c3c2Cl)CC1
Product: Cl

Procedure:
tert-Butyl carbamate 217 (100 mg, 0.14 mmol) is deprotected using Method F. The isolated salt is then dissolved in the minimum amount of DCM and added dropwise to cold (0° C.) TBME (25 mL). The resultant pale yellow precipitate is isolated by filtration, washed with TBME (10 mL) and diethyl ether (10 mL) and dried to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH2:8][C:9]2[N:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]3=[N:11][C:10]=2[CH2:18][NH:19][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])[CH:7]=1.C(N(CC)CC)C.[Cl:33][C:34]1[C:42]([O:43][CH3:44])=[C:41]([O:45][CH3:46])[CH:40]=[CH:39][C:35]=1[C:36](Cl)=[O:37]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH2:8][C:9]2[N:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]3=[N:11][C:10]=2[CH2:18][N:19]([CH2:20][CH2:21][CH:22]([CH3:23])[CH3:24])[C:36]([C:35]2[CH:39]=[CH:40][C:41]([O:45][CH3:46])=[C:42]([O:43][CH3:44])[C:34]=2[Cl:33])=[O:37])[CH:7]=1
Reactant: CC(C)CCNCc1nc2ccccn2c1Cc1cc(Br)ccc1O
Reactant: COc1ccc(C(=O)Cl)c(Cl)c1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)N(CCC(C)C)Cc2nc3ccccn3c2Cc2cc(Br)ccc2O)c(Cl)c1OC
Temperature: 45 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
A solution of 90 mg (0.25 mmol) ({3-[(5-bromo-2-hydroxyphenyl)methyl](imidazolo[1,2-a]pyridin-2-yl)}methyl)(3-methylbutyl)amine in 4 mL dichloromethane at 0° C. is treated with triethylamine 50 mg (0.50 mmol) and then 2-chloro-3,4-dimethoxybenzoylchloride 110 mg (0.50 mmol). The solution is stirred overnight and the volatiles removed by rotary evaporation. The residue is dissolved in 4 mL methanol and treated with 2 mL 1M sodium hydroxide. The solution is heated to 45° C. for 1 hr and the volatiles removed by rotary evaporation. The mixture is acidified with 1M hydrochloric acid, extracted with 3×5 mL ethyl acetate and the combined extracts washed with 5 mL brine. The combined extract is dried over anhydrous MgSO4 and the solvent removed in vacuo to yield 120 mg (80%) N-({3-[(5-bromo-2-hydroxyphenyl)methyl](imidazolo[1,2-a]pyridin-2-yl)}methyl)(2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)carboxamide. Mass Spec m/z (M++1) 602.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[S:3]Cl.[NH:7]1[CH:11]=[CH:10][CH:9]=[CH:8]1.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14]C=1>C(=O)=O.C(Cl)(Cl)Cl.[Fe]>[F:1][C:2]([F:6])([F:5])[S:3][C:8]1[NH:7][C:11]([S:3][C:2]([F:6])([F:5])[F:1])=[CH:10][CH:9]=1.[F:1][C:2]([F:6])([F:5])[S:3][C:17]1[NH:12][CH:14]=[C:15]([S:3][C:2]([F:6])([F:5])[F:1])[CH:16]=1
Reactant: FC(F)(F)SCl
Reactant: c1ccncc1
Reactant: c1cc[nH]c1
Agent: [Fe]
Agent: O=C=O
Solvent: ClC(Cl)Cl
Product: FC(F)(F)Sc1c[nH]c(SC(F)(F)F)c1
Product: FC(F)(F)Sc1ccc(SC(F)(F)F)[nH]1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
25 g of trifluoromethanesulfenyl chloride was condensed in a pressured bottle in dry ice and 2.34 g of pyrrole in 40 ml of anhydrous chloroform, 12.1 g of pyridine and 0.8 g of iron powder were added. The mixture was then stirred at room temperature for 3 days. It was then filtered to remove insoluble materials. The mixture was washed with water, diluted hydrochloric acid and water again. After evaporation of the solvent, the residue was distilled under vacuum, giving 4.2 g of 2,5-bis(trifluoromethylthio)pyrrole and 3.5 g 2,4-bis(trifluoromethylthio)pyrrole. The total yield was 82%.
Reaction SMILES: O[Li].O.C[O:5][C:6]([C:8]1[CH:9]=[C:10]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=2[F:29])[CH:11]=[C:12]([C:14]2[N:15]([CH:19]([CH3:21])[CH3:20])[N:16]=[CH:17][CH:18]=2)[CH:13]=1)=[O:7]>O.C1COCC1>[F:29][C:23]1[CH:24]=[C:25]([CH3:28])[CH:26]=[CH:27][C:22]=1[C:10]1[CH:11]=[C:12]([C:14]2[N:15]([CH:19]([CH3:21])[CH3:20])[N:16]=[CH:17][CH:18]=2)[CH:13]=[C:8]([C:6]([OH:7])=[O:5])[CH:9]=1
Reactant: COC(=O)c1cc(-c2ccc(C)cc2F)cc(-c2ccnn2C(C)C)c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)O)cc(-c3ccnn3C(C)C)c2)c(F)c1
Temperature: 25 °C
Yield: 92.8 %

Procedure:
A solution of LiOH hydrate (82 mg, 1.94 mmol) in H2O (7 mL) was added dropwise to a solution of 2′-fluoro-5-(2-isopropyl-2H-pyrazol-3-yl)-4′-methyl-biphenyl-3-carboxylic acid methyl ester (524 mg, 1.49 mmol) in THF (4 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred until the reaction solution turned into clear. Solvent was removed under vacuum and the resulting aqueous solution was acidified by 10% HCl to pH=6˜7. The resulting precipitate was collected and dried to afford 2′-fluoro-5-(2-isopropyl-2H-pyrazol-3-yl)-4′-methyl-biphenyl-3-carboxylic acid (468 mg, 93%).
Reaction SMILES: [NH4+:1].[OH-].[C:3]([O:7][C:8]([NH:10][C:11]1[S:12][CH:13]=[C:14](/[C:16](=[N:37]/[O:38][C:39]2([C:42]([O:44][CH:45]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)=[O:43])[CH2:41][CH2:40]2)/[C:17]([NH:19][C@@H:20]2[C:23](=[O:24])[NH:22][C@@H:21]2[CH2:25][N:26]2[N:30]=[C:29]([CH2:31]OS(C)(=O)=O)[CH:28]=[N:27]2)=[O:18])[N:15]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>CCO.C1COCC1.C(Cl)Cl>[NH2:1][CH2:31][C:29]1[CH:28]=[N:27][N:26]([CH2:25][C@@H:21]2[C@H:20]([NH:19][C:17](=[O:18])/[C:16](=[N:37]\[O:38][C:39]3([C:42]([O:44][CH:45]([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)[C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)=[O:43])[CH2:41][CH2:40]3)/[C:14]3[N:15]=[C:11]([NH:10][C:8]([O:7][C:3]([CH3:5])([CH3:4])[CH3:6])=[O:9])[S:12][CH:13]=3)[C:23](=[O:24])[NH:22]2)[N:30]=1
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N[C@@H]2Cn2ncc(COS(C)(=O)=O)n2)cs1
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N[C@@H]2Cn2ncc(CN)n2)cs1
Temperature: -5 °C
Reaction time: 12 h
Yield: 49 %

Procedure:
To a solution of aq. NH4OH (2 mL, 28-30% wt) in EtOH (2 mL, ratio:1) and THF (2 mL, ratio:1) was added a solution of benzhydryl 1-(((Z)-(1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-(((2R,3S)-2-((4-(((methylsulfonyl)oxy)methyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)cyclopropanecarboxylate (190 mg, 0.24 mmol) in THF (1 mL) at −5° C. dropwise. After stirring at −5° C. for 1 h and rt for 12 h, the reaction mixture was diluted with 40 mL of DCM and washed with 10 mL of aq. saturated NaHCO3 (aq), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified via silica gel chromatography (MeOH-DCM, 5-10%) to afford the title compound (120 mg, 49%). LCMS: Rt=0.87 min, m/z=716.4 (M+1) Method 2m_acidic.