Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]([CH:14]2[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]2)[C:7](=[O:21])[C:6]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:25][C:24]=1[F:37])[CH2:2][CH2:3][CH3:4].O1CCCC1.[BH4-].[Na+]>CO>[CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]([C@H:14]2[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]2)[C:7](=[O:21])[C:6]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:25][C:24]=1[F:37])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](O)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 4′-{[7-butyl-5-oxo-4-(4-oxocyclohexyl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile (2.61 g), tetrahydrofuran (10 mL) and methanol (10 mL) was added sodium borohydride (0.15 g) at 0° C., and the mixture was stirred at room temperature for 1 hr. After evaporation of the solvent under reduced pressure, the residue was extracted with water and ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless oil (2.14 g, 82%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH:9]([NH:12][C:13]3[O:14][CH2:15][C:16]4[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:17]=4[N:18]=3)[CH2:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH:24]1([S:27](Cl)(=[O:29])=[O:28])[CH2:26][CH2:25]1>>[CH3:1][O:2][C:3]1[C:8]2[CH:9]([NH:12][C:13]3[O:14][CH2:15][C:16]4[CH:22]=[C:21]([NH:23][S:27]([CH:24]5[CH2:26][CH2:25]5)(=[O:29])=[O:28])[CH:20]=[CH:19][C:17]=4[N:18]=3)[CH2:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1C(NC1=Nc3ccc(N)cc3CO1)CO2
Reactant: O=S(=O)(Cl)C1CC1
Product: COc1cccc2c1C(NC1=Nc3ccc(NS(=O)(=O)C4CC4)cc3CO1)CO2
Yield: 42.4 %

Procedure:
Prepared from rac-N2-(4-methoxy-2,3-dihydro-benzofuran-3-yl)-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 6) (150 mg, 0.482 mmol) and cyclopropanesulfonyl chloride (75 mg, 0.53 mmol) according to the procedure described for Example 27. Obtained the title compound as an off-white solid (85 mg, 43%), MS (ISP) m/e=416.1 [(M+H)+].
Reaction SMILES: [C:1]1([C:11]([OH:13])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(Cl)CCl.C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:36][NH:37][O:38][CH3:39]>CN(C)C=O>[CH3:36][N:37]([C:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)=[O:13])[O:38][CH3:39]
Reactant: CNOC
Reactant: O=C(O)c1cccc2ccccc12
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CON(C)C(=O)c1cccc2ccccc12
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 7.5 %

Procedure:
3.44 g(20 mmol) of 1-naphthoic acid was dissolved in 20 ml of dimethylformamide, and then 4.6 g(24 mmol) of EDC, 2.02 g(20 mmol) of triethylamine and 3.24 g(24 mmol) of HOBT were added thereto. The resulting mixture was stirred at 0° C. for 5 minutes. To the reaction solution was added 1.85 g(20 mmol) of N,O-dimethylhydroxylamine hydrochloride, which was then stirred at room temperature for 5 hours. The solvent was removed under reduced pressure and then 100 ml of saturated potassium carbonate solution was added to the residue. The resulting solution was extracted with ethyl acetate. Then, the organic layer was washed sequencially with 1N aqueous hydrochloric acid solution, aqueous sodium chloride solution and water, dried over anhydrous sodium sulfate and concentrated to give 3.04 g(1.50 mmol) of the title compound.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:28])[CH2:13][NH:14][C:15](=[O:27])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]2[CH2:26][CH2:25][NH:24][CH2:23]2)[CH:17]=1.C=O.[BH3-][C:32]#N.[Na+].CC(O)=O>CO>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:28])[CH2:13][NH:14][C:15](=[O:27])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]2[CH2:26][CH2:25][N:24]([CH3:32])[CH2:23]2)[CH:17]=1
Reactant: [BH3-]C#N
Reactant: O=C(NCC(O)CN1CCc2ccccc2C1)c1cccc(C2CCNC2)c1
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN1CCC(c2cccc(C(=O)NCC(O)CN3CCc4ccccc4C3)c2)C1
Yield: 14.2 %

Procedure:
To a solution of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-(pyrrolidin-3-yl)benzamide (200 mg, 0.53 mmol) in MeOH (4 ml) was added HCHO (31.9 mg, 1.05 mmol) and NaBH3CN (66.1 mg, 1.05 mmol) at 29° C. The mixture was then added AcOH (0.5 ml) at 29° C. and stirred for 16 h. The mixture was purified by prep-HPLC to give the title compound (29.6 mg, Yield 14.3%). 1H NMR (CD3OD, 400 MHz): δ 8.52 (brs, 2H), 7.88 (s, 1H), 7.78 (d, J=7.7 Hz, 1H), 7.53-7.60 (m, 1H), 7.43-7.52 (m, 1H), 7.22-7.33 (m, 3H), 7.15-7.21 (m, 1H), 4.36 (s, 3H), 3.78 (brs, 2H), 3.46-3.67 (m, 6H), 3.41 (brs, 1H), 3.07-3.19 (m, 3H), 3.01 (s, 3H), 2.50-2.64 (m, 1H), 2.19-2.34 (m, 1H). LCMS (m/z): 394.2 (M+1).
Reaction SMILES: F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[C:47]([OH:55])(=O)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.C(N(C(C)C)C(C)C)C.[CH3:65][C@:66]12[C:74]([CH3:76])([CH3:75])[C@H:70]([NH:71][CH2:72][CH2:73]1)[CH2:69][C:68]1[C:77]([OH:81])=[CH:78][CH:79]=[CH:80][C:67]2=1>ClCCl.CN(C=O)C>[OH:81][C:77]1[C:68]2[CH2:69][C@@H:70]3[C:74]([CH3:76])([CH3:75])[C@:66]([CH3:65])([C:67]=2[CH:80]=[CH:79][CH:78]=1)[CH2:73][CH2:72][N:71]3[C:47]([C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)=[O:55]
Reactant: CC1(C)[C@H]2Cc3c(O)cccc3[C@]1(C)CCN2
Reactant: O=C(O)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1(C)[C@H]2Cc3c(O)cccc3[C@]1(C)CCN2C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (155 mg; alternatively, N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate may be used) is added to a solution of benzoic acid (60 mg) and ethyldiisopropylamine (0.25 mL) in dichloromethane (1 mL; DMF may be used as well). The resulting solution is stirred at ambient temperature for 15 min before it is cooled in an ice bath. (2R,6S)-6,11,11-Trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-10-ol (0.10 g) is added and the solution is warmed to room temperature and stirred overnight. The mixture is concentrated under reduced pressure and the residue is purified by HPLC on reversed phase (H2O/MeCN) to give the product as a beige solid.
Reaction SMILES: [N:1]1([CH2:8][C:9]([C:11]2[CH:22]=[CH:21][C:14]([O:15][CH2:16][C:17]([O:19]C)=[O:18])=[CH:13][CH:12]=2)=[O:10])[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].Cl.[Cl:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>O.O1CCOCC1>[ClH:24].[N:28]1[CH:29]=[CH:30][C:25]([N:4]2[CH2:5][CH2:6][N:1]([CH2:8][C:9]([C:11]3[CH:22]=[CH:21][C:14]([O:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][CH:12]=3)=[O:10])[C:2](=[O:7])[CH2:3]2)=[CH:26][CH:27]=1
Reactant: Clc1ccncc1
Reactant: COC(=O)COc1ccc(C(=O)CN2CCNCC2=O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)COc1ccc(C(=O)CN2CCN(c3ccncc3)CC2=O)cc1
Yield: 40.7 %

Procedure:
A solution of methyl 4-[2-(piperazin-2-one-1-yl)acetyl]phenoxyacetate (0.347 g), 4-chloropyridine hydrochloride (0.19 g) and triethylamine (0.178 g) in water (8 ml) and dioxan (1 ml) was heated on a steam bath for 2 hours and then evaporated to dryness. The residue was triturated with water (2 ml) and filtered. The solid thus obtained was recrystallised from water to give the title compound (0.187 g), m.p. 275°-277° C.; NMR(d6DMSO δ8.33(2H,d), 8.0(2H,d), 7.21(2H,d), 7.1(2H,d), 4.97(2H,s), 4.81(2H,s), 3.94(2H,m), 3.59(2H,m); m/e 370(M+H)+ ; calculated for C19H20N3O5Cl. 0.75 H2O: C, 54.4; H, 5.0; N, 10.0. Found: C, 54.5; H, 5.3; N, 9.5%.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8]C)=[C:6]([F:10])[CH:5]=[CH:4][C:3]=1[CH:11]([NH:26][C:27]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:28]=1[CH:29]=[CH:30][C:31]([CH3:37])=[N:32]2)[C:12]([CH2:18][S:19][C:20]1[N:21]([CH3:25])[CH:22]=[CH:23][N:24]=1)([C:14]([F:17])([F:16])[F:15])[OH:13].B(Br)(Br)Br>ClCCl>[F:1][C:2]1[C:7]([OH:8])=[C:6]([F:10])[CH:5]=[CH:4][C:3]=1[CH:11]([NH:26][C:27]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:28]=1[CH:29]=[CH:30][C:31]([CH3:37])=[N:32]2)[C:12]([CH2:18][S:19][C:20]1[N:21]([CH3:25])[CH:22]=[CH:23][N:24]=1)([C:14]([F:17])([F:16])[F:15])[OH:13]
Reactant: COc1c(F)ccc(C(Nc2cccc3nc(C)ccc23)C(O)(CSc2nccn2C)C(F)(F)F)c1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ccc2c(NC(c3ccc(F)c(O)c3F)C(O)(CSc3nccn3C)C(F)(F)F)cccc2n1
Reaction time: 22 h

Procedure:
Analogously to example 10 39 mg 2,4-Difluoro-α-{[(1-methylimidazol-2-yl)sulfanyl]methyl}-3-methoxy-β-[(2-methylquinolin-5-yl)amino]-α-(trifluoromethyl)-benzeneethanol in 3.5 ml dichloromethane are treated with 0.7 ml of a 1 M solution of boron tribromide in dichloromethane at −10° C. The typical work up after 22 hours at room temperature and preparative thin layer chromatography on silica gel (acetone in hexane 50%) yields 4 mg of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][N:12]([CH3:14])[CH3:13])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([NH2:24])[N:19]=1>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][N:12]([CH3:14])[CH3:13])=[N:7][N:8]2[C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH2:24])[N:19]=2)=[CH:4][CH:3]=1
Reactant: Nc1nccc(Cl)n1
Reactant: CN(C)Cc1n[nH]c2cc(Br)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)Cc1nn(-c2ccnc(N)n2)c2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of (6-Bromo-1H-indazol-3-ylmethyl)-dimethyl-amine (523 mg, 2.05 mmol) in DMF (8 mL) was added NaH (60% oil dispersion) (132 mg, 3.29 mmol) at 0° C. The reaction mixture was allowed to warm up to RT and was stirred for 15 min. A solution of 4-chloropyrimidin-2-amine (533 mg, 4.11 mmol) in DMF (3 mL) was added slowly. The resulting mixture was stirred at 60° C. for 18 hr. When the reaction mixture was partitioned between EtOAc (25 mL) and water (10 mL), precipitation occurred. The solid was collected by suction filtration and was washed with EtOAc to give the title compound: 1H NMR (500 MHz, DMSO) δ 2.22 (6H, s), 3.81 (2H, s), 7.04 (1H, d, J=5.52 Hz), 7.06-7.19 (2H, m), 7.50 (1H, m, J=8.51 Hz), 7.92 (1H, d, J=8.51 Hz), 8.27 (1H, d, J=5.52 Hz), 9.11 (1H, d, J=1.26 Hz); LC-MS: m/z=+348.9 (M+H)+.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.CN([CH:16]=[O:17])C.O>CCOCC>[F:6][C:7]1[C:8]([CH:16]=[O:17])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: Fc1cccnc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: O=Cc1ncccc1F
Temperature: -20 °C
Reaction time: 1 h
Yield: 11.1 %

Procedure:
n-Butyl lithium (1.6 M in hexanes, 6.86 mL, 11.0 mmol) was added to a stirred solution of 1,4-diazobicyclo[2.2.2]-octane (1.23 g, 11.0 mmol) in dry Et2O (55 mL) at −78° C. under N2. The reaction was warmed to −20° C. and stirred for 1 h. The reaction was cooled to −78° C. and a solution of 3-fluoropyridine (1.07 g, 11.0 mmol) in Et2O (5.5 mL) was added dropwise via cannula. The reaction was warmed to −60° C. and stirred for 1 h after which time a yellow precipitate appeared. DMF (803 mg, 847 μL, 12.1 mmol) was added dropwise and the reaction was gradually warmed to −20° C. over 4 h. Water (20 mL) was added and the mixture was extracted with Et2O (3×40 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 25×160 mm, 0-60% EtOAc in hexanes gradient) to afford 3-fluoropyridine-2-carbaldehyde (152.3 mg, 11%). Rf=0.23 (20% EtOAc/hexanes). LCMS calc.=126.0; found=125.9 (M+1)+. 1H NMR (500 MHz, CDCl3): δ 10.14 (d, J=2.4 Hz, 1H); 8.57 (m, 1H); 7.57-7.53 (m, 2H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:3]1[CH3:14].[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[C:15]([NH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:3]1[CH3:14])(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: CC1C(N)CCN1Cc1ccccc1
Product: CC(=O)NC1CCN(Cc2ccccc2)C1C

Procedure:
3-Amino-1-benzyl-2-methylpyrrolidine [Japanese Laid-Open Patent Publication No. 22699/1980] was allowed to react with acetic anhydride to give 3-acetylamino-1-benzyl-2-methylpyrrolidine, m.p. 51°-54° C. This compound was hydrogenated catalytically in the presence of 5% palladium-carbon to give 3-acetylamino-2-methylpyrrolidine as an oil.
Reaction SMILES: [CH2:1]1[O:11][C:10]2[C:3](=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=O)[O:2]1.[CH3:12][O:13][C:14](=[O:19])[CH2:15][N:16]=[N+:17]=[N-:18].C[O-].[Na+]>CO>[N:16]([C:15](=[CH:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:10]2[O:11][CH2:1][O:2][C:3]=12)[C:14]([O:13][CH3:12])=[O:19])=[N+:17]=[N-:18]
Reactant: O=Cc1cccc2c1OCO2
Reactant: COC(=O)CN=[N+]=[N-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(=Cc1cccc2c1OCO2)N=[N+]=[N-]
Reaction time: 3 h

Procedure:
A solution of 2,3-methylenedioxy benzaldehyde (15.76 g, 104 mmol) and methylazidoacetate (48.38 g, 419 mmol) in methanol was cooled to −15° C. using an ice/acetone bath. The resulting solution was then treated over one hour with sodium methoxide (96 ml) at a rate that maintained the temperature below −10° C. After 3 hours, the solution was stored at 5° C. for two days to give crystalline material which was filtered off and washed with hexane.
Reaction SMILES: [C:1]([O:14][C@H:15]([CH2:61][O:62][C:63](=[O:75])[CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH3:74])[CH2:16][S:17][CH2:18][C@H:19]([NH:43][C:44]([O:46][CH2:47][CH:48]1[C:60]2[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=2[C:54]2[C:49]1=[CH:50][CH:51]=[CH:52][CH:53]=2)=[O:45])[C:20](=[O:42])[NH:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][CH2:33][NH:34]C(=O)OC(C)(C)C)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>C(O)(C(F)(F)F)=O.C(Cl)Cl.C(Cl)Cl>[C:63]([O:62][CH2:61][C@@H:15]([O:14][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:16][S:17][CH2:18][C@H:19]([NH:43][C:44]([O:46][CH2:47][CH:48]1[C:60]2[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=2[C:54]2[C:49]1=[CH:50][CH:51]=[CH:52][CH:53]=2)=[O:45])[C:20](=[O:42])[NH:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][CH2:33][NH2:34])(=[O:75])[CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH3:74]
Reactant: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCCOCCCCOCCCNC(=O)OC(C)(C)C)OC(=O)CCCCCCCCCCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCCOCCCCOCCCN)OC(=O)CCCCCCCCCCC

Procedure:
(20R,24R)-20-(((9H-fluoren-9-yl)methoxy)carbonylamino)-2,2-dimethyl-4,19-dioxo-3,9,14-trioxa-22-thia-5,18-diazapentacosane-24,25-diyl didodecanoate was stirred in 30% TFA/DCM for 4 hours at room temperature. The reaction was then diluted with DCM and washed with 1M citric acid (pH3). The organics were then dried over anhydrous Na2SO4, filtered and concentrated to afford (2R,6R)-6-(((9H-fluoren-9-yl)methoxy)carbonylamino)-20-amino-7-oxo-12,17-dioxa-4-thia-8-azaicosane-1,2-diyl didodecanoate.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:19]([OH:22])[C:20]#[CH:21])=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1>ClCCl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([C:19](=[O:22])[C:20]#[CH:21])=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C#CC(O)c1c(-c2cccc(OC)c2)nc2c(Cl)cccn12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: C#CC(=O)c1c(-c2cccc(OC)c2)nc2c(Cl)cccn12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.7 %

Procedure:
To a solution of 1-[8-chloro-2-(3-methoxyphenyl)imidazo[1,2-α]pyridin-3-yl]-2-propyn-1-ol (870 mg, 2.78 mmol) in dichloromethane (150 mL) was added manganese dioxide (9.6 g, 111 mmol) and the resulting suspension was stirred at room temperature for 1.5 hours. The mixture was filtered through Celite. The filtrate was concentrated in vacuo to give 1-[8-chloro-2-(3-methoxyphenyl)imidazo[1,2-α]pyridin-3-yl]-2-propyn-1-one (680 mg, 78%) as a golden foam. 1H NMR (CDCl3): δ 9.66 (d, 1 H), 7.65 (d, 1 H), 7.34 (t, 1 H), 7.28–7.22 (m, 2 H), 7.10 (t, 1 H), 7.02 (m, 1 H), 3.86 (s, 3 H), 2.86 (s, 1 H); MS m/z 311 (M+1).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[NH:5][C:6]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])=[C:7]([CH3:9])[N:8]=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>O1CCCC1>[CH3:16][S:17]([N:5]1[C:6]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])=[C:7]([CH3:9])[N:8]=[C:4]1[Br:3])(=[O:19])=[O:18]
Reactant: Cc1nc(Br)[nH]c1C(=O)OC(C)C
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(Br)n(S(C)(=O)=O)c1C(=O)OC(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
To a suspension of 195 milligrams (mg) (8.13 mM) of sodium hydride in 20 ml of anhydrous tetrahydrofuran was added, in portions, 2 g (8.13 mM) of the isopropyl 2-bromo-4-methyl-5-imidazolecarboxylate. The resulting suspension was cooled to 0° C. and 931 mg (8.13 mM) of methanesulfonyl chloride was added dropwise. The reaction mixture was stirred overnight at room temperature. The precipitated sodium chloride was removed by filtration and concentration of the filtrate in vacuo gave 2.4 g of desired product, isopropyl N-methylsulfonyl-2-bromo-4-methyl-5-imidazolecarboxylate as a yellow oil (93% yield).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([C:11]#[N:12])=[C:9]([O:13][C:14]3[CH:15]=[CH:16][C:17]([F:34])=[C:18]([NH:20][C:21](=[O:33])[CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)[CH:19]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.N1C=CC=CC=1.[CH:41]1([C:44](Cl)=[O:45])[CH2:43][CH2:42]1.O>CN(C)C(=O)C>[C:11]([C:10]1[C:4]2[S:3][C:2]([NH:1][C:44]([CH:41]3[CH2:43][CH2:42]3)=[O:45])=[N:6][C:5]=2[CH:7]=[CH:8][C:9]=1[O:13][C:14]1[CH:15]=[CH:16][C:17]([F:34])=[C:18]([NH:20][C:21](=[O:33])[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:30])[F:31])[CH:24]=2)[CH:19]=1)#[N:12]
Reactant: N#Cc1c(Oc2ccc(F)c(NC(=O)Cc3cccc(C(F)(F)F)c3)c2)ccc2nc(N)sc12
Reactant: O=C(Cl)C1CC1
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Solvent: O
Product: N#Cc1c(Oc2ccc(F)c(NC(=O)Cc3cccc(C(F)(F)F)c3)c2)ccc2nc(NC(=O)C3CC3)sc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
To a solution of N-{5-[(2-amino-7-cyano-1,3-benzothiazol-6-yl)oxy]-2-fluorophenyl}-2-[3-(trifluoromethyl)phenyl]acetamide (980 mg, 2.01 mmol) in N,N-dimethylacetamide (8 mL) were added pyridine (242 μL, 3.02 mmol) and cyclopropanecarbonyl chloride (255 μL, 2.81 mmol), and the mixture was stirred at room temperature for 2 hr. Cyclopropanecarbonyl chloride (255 μL, 2.81 mmol) was added to the reaction mixture, and the mixture was further stirred at room temperature for 2 hr. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL). The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution (20 mL) and saturated brine (20 mL), and dried over anhydrous magnesium sulfate. Insoluble material was filtered off, the filtrate was purified by basic silica gel column chromatography (eluate: ethyl acetate), and the obtained solution was concentrated under reduced pressure. A pale-brown oil residue was crystallized from ethanol/water (1/1) to give the title compound (1.06 g, 95%) as a white powder.
Reaction SMILES: [F:1][C:2]([F:50])([F:49])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[CH:39]=[CH:38][C:37]([C:40]([O:42]C)=[O:41])=[CH:36][C:35]=5[CH3:44])[CH:29]=[CH:30][C:31]=4[O:32][CH3:33])=[CH:24][CH:23]=[C:22]([CH:45]([CH3:47])[CH3:46])[N:21]=3)[C@H:14]2[CH3:48])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.O.[OH-].[Li+].Cl>O1CCOCC1.O>[F:50][C:2]([F:1])([F:49])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[CH:39]=[CH:38][C:37]([C:40]([OH:42])=[O:41])=[CH:36][C:35]=5[CH3:44])[CH:29]=[CH:30][C:31]=4[O:32][CH3:33])=[CH:24][CH:23]=[C:22]([CH:45]([CH3:47])[CH3:46])[N:21]=3)[C@H:14]2[CH3:48])[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(C)C)nc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2ccc(C(=O)O)cc2C)cc1-c1ccc(C(C)C)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reaction time: 72 h
Yield: 59.1 %

Procedure:
To a solution of methyl 3′-[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-isopropylpyridin-3-yl]-4′-methoxy-2-methylbiphenyl-4-carboxylate (102 mg, 0.146 mmol) in 1,4-dioxane (3 mL) was added a solution of lithium hydroxide monohydrate (27 mg, 0.643 mmol) in water (1.8 mL). The reaction was stirred for 3 days. The crude mixture was acidified with HCl (aq, 1N, 1 mL). The crude product was purified by reverse-phase prep-HPLC (Kromasil 100-5C18, 100×21.1 mm) eluting with a MeCN (0.1% TFA, v/v)/H10 (0.1% TFA, v/v) gradient mixture. Two peaks were recorded in the prep-LC chromatogram representing the desired acid (60 A %, the faster eluting peak) and the starting ester. Corresponding fractions were pooled and evaporated in vacuo to aqueous mixtures. The resulting mixtures were extracted with EtOAc. The separated organic phases were back washed with water, separated, dried over Na2SO4, filtered and evaporated to afford 3′-[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-isopropylpyridin-3-yl]-4′-methoxy-2-methylbiphenyl-4-carboxylic acid (59.27 mg) as a glass and the recovered starting ester. LCMS calc.=686.22; found=687.44 (M+1)+. 1H NMR signals are doubled because of atropoisomerism. 1H NMR (CDCl3, 500 MHz) 8.13 (d, J=8 Hz, 1H), 8.02-7.95 (m, 1H), 7.94-7.88 (m, 1H), 7.85 (s, 1H), 7.70-7.62 (m, 3H), 7.49 (d, J=8.5 Hz, 1H), 7.38 (s, 0.5H), 7.35-7.28 (m, 1H), 7.20-7.10 (m, 1.5H), 5.67 (d, J=7 Hz, 0.7H), 5.58 (d, J=8.0 Hz, 0.3H), 5.05 (d, J=16 Hz, 0.3H), 4.75 (d, J=16 Hz, 0.7H), 4.67 (d, J=16 Hz, 0.7H), 4.60 (d, J=16 Hz, 0.3H), 4.40-4.32 (m, 1H), 3.92 (s, 0.9H), 3.88 (s, 2.1H), 3.74-3.60 (m, 1H), 2.39 (s, 2.1H), 2.35 (s, 0.9H), 1.46 (s, 3H), 1.45 (s, 3H), 0.73 (d, J=6.5 Hz, 2.1H), 0.65 (d, J=5.5 Hz, 0.9H).
Reaction SMILES: [CH:1]1([C:4]2[CH:8]=[C:7]([CH:9]3[CH2:11][CH2:10]3)[N:6]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14]C=3F)[N:5]=2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].ClC1C=CC([N+]([O-])=O)=C[N:30]=1>CS(C)=O>[CH:1]1([C:4]2[CH:8]=[C:7]([CH:9]3[CH2:10][CH2:11]3)[N:6]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:30]=3)[N:5]=2)[CH2:2][CH2:3]1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: O=[N+]([O-])c1ccc(-n2nc(C3CC3)cc2C2CC2)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(-n2nc(C3CC3)cc2C2CC2)nc1
Reaction time: 2 h
Yield: 20.7 %

Procedure:
A solution of intermediate 3 (8.0 g, 54.05 mmol) and K2CO3 (27.96 g, 202.6 mmol) in DMSO (60 mL) was heated at 110° C. under nitrogen for 0.5 h. To the mixture, 2-chloro-5-nitro pyridine (12.8 g, 80.75 mmol) was added and stirred at the same temperature for 2 h. Work-up (H2O/AcOEt) and purification afforded the title compound (3.03 g). 1H-NMR (δ ppm, CDCl3, 400 MHz): 9.24 (d, J 2.6, 1H), 8.51 (dd, J 2.6, 9.9, 1H), 8.10 (d, J 9.2, 1H), 5.72 (s, 1H), 2.90-2.75 (m, 1H), 1.99-1.90 (m, 1H), 1.06-0.93 (m, 4H), 0.82-0.64 (m, 4H).