Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[Cl-].[CH3:16][CH:17]1[CH2:21][CH2:20][C:19](=[O:22])[N:18]1[NH3+:23]>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:23][N:18]2[C:19](=[O:22])[CH2:20][CH2:21][CH:17]2[CH3:16])[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1
Reactant: COC(=O)CC(=O)c1ccc(F)cc1
Reactant: CC1CCC(=O)N1[NH3+]
Agent: [Cl-]
Solvent: c1ccncc1
Product: COC(=O)CC(=NN1C(=O)CCC1C)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 93.1 %

Procedure:
A mixture of 7.50 g (38.2 mmol) of methyl 3-(4-fluorophenyl)-3-oxopropanoate and 11.5 g (76.5 mmol) of 2-methyl-5-oxopyrrolidin-1-aminium chloride in 50 ml of pyridine is stirred at room temperature for 72 h. The reaction mixture is concentrated under reduced pressure. Purification by column chromatography on silica gel (cyclohexane/ethyl acetate) gives 10.4 g (93%) of the desired product as a mixture of isomers; log P(HCOOH): 2.13 and 2.45; 1H-NMR (ppm): δ (DMSO-d6)=1.16-1.19 (m, 3H), 1.58-1.62 (m, 2H), 2.20-2.22 (m, 1H), 2.36-2.41 (m, 1H), 3.54 (s, 2.25H), 3.64 (s, 0.75H), 3.80 (d, 1H), 3.90 (d, 1H), 3.80 (q, 1H), 7.24 (t, 0.6H), 7.29 (t, 1.4H), 7.44-7.47 (m, 0.6H), 7.89-7.92 (m, 1.4H); LC-MS: m/z=293 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1([CH2:8][C:9]([O:11]CC)=O)[CH2:5][S:4](=[O:7])(=[O:6])[CH2:3]1.CO.[CH3:16][NH2:17]>>[NH2:1][C:2]1([CH2:8][C:9]([NH:17][CH3:16])=[O:11])[CH2:5][S:4](=[O:7])(=[O:6])[CH2:3]1
Reactant: CN
Reactant: CCOC(=O)CC1(N)CS(=O)(=O)C1
Solvent: CO
Product: CNC(=O)CC1(N)CS(=O)(=O)C1
Temperature: 45 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
ethyl 2-(3-amino-1,1-dioxo-thietan-3-yl)acetate (example 160c, 548 mg, 2.64 mmole) was dissolved in a solution 2.0M of methylamine in methanol (19.8 mL, 39.7 mmole) and the reaction mixture was stirred at 45° C. overnight. Removal of volatiles in vacuo yielded the title compound (505 mg, 99%) as crude light brown oil which was used without any further purification; MS (ESI, m/z): 193.1 (M+H+).
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[CH:9]([C:12]1[CH:13]=[CH:14][C:15]([S:18](Cl)(=[O:20])=[O:19])=[N:16][CH:17]=1)([CH3:11])[CH3:10]>>[C:1]1([CH3:8])[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][S:18]([C:15]2[CH:14]=[CH:13][C:12]([CH:9]([CH3:11])[CH3:10])=[CH:17][N:16]=2)(=[O:19])=[O:20])[CH:2]=1
Reactant: Cc1cccc(N)c1
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)nc1
Product: Cc1cccc(NS(=O)(=O)c2ccc(C(C)C)cn2)c1

Procedure:
prepared by reaction of m-tolylamine with 5-isopropyl-pyridine-2-sulfonyl chloride
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:6]=[C:7]([I:9])[CH:8]=1)#[N:2].[H-].[Na+].[C:16](OC(=O)C)(=[O:18])[CH3:17]>CN(C)C=O>[C:16]([NH:13][S:10]([C:5]1[CH:6]=[C:7]([I:9])[CH:8]=[C:3]([C:1]#[N:2])[CH:4]=1)(=[O:12])=[O:11])(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1cc(I)cc(S(N)(=O)=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)NS(=O)(=O)c1cc(I)cc(C#N)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 3.08 g. (10 mmoles) of 3-cyano-5-iodobenzenesulfonamide in 30 ml. of dimethylformamide is treated with 420 mg. (10 mmoles) of 57% sodium hydride emulsion. When the initial reaction subsides, the mixture is heated in a warm water bath for one hour. 2.8 Ml. (30 mmoles) of acetic anhydride is added and the solution becomes cloudy. The mixture is stirred for one hour and poured into an ice water mixture. After 30 minutes of stirring, the precipitate is filtered, washed with water, methanol and ether affording 2.97 g. (85%) of N-acetyl-3-cyano-5-iodobenzenesulfonamide melting point 249° to 251°C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2.[F:16][C:17]1[CH:18]=[C:19]([C:32]2[C:33]([C:38]#[N:39])=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:20]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:22]=1>>[F:16][C:17]1[CH:18]=[C:19]([C:32]2[C:33]([C:38]#[N:39])=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:20]=[C:21]([C:2]2[C:3]3[C:8](=[N:7][C:6]([C:12]([F:15])([F:14])[F:13])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:22]=1
Reactant: CC1(C)OB(c2cc(F)cc(-c3ccccc3C#N)c2)OC1(C)C
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2n1
Product: N#Cc1ccccc1-c1cc(F)cc(-c2ccnc3nc(C(F)(F)F)ccc23)c1
Yield: 34.7 %

Procedure:
5-Chloro-2-trifluoromethyl[1,8]naphthyridine (50 mg, 0.22 mmol) was coupled to 3′-fluoro-5′-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile (90 mg, 0.28 mmol) as described in Example 7 part g), affording 3′-fluoro-5′-(7-trifluoromethyl[1,8]naphthyridin-4-yl)biphenyl-2-carbonitrile (30 mg, 35%). δH (360 MHz, CDCl3) 7.32-7.36 (1H, m), 7.41-7.44 (1H, m), 7.50-7.59 (3H, m), 7.64 (1H, d, J 4.6), 7.72 (1H, td, J 7.7 and 1.4), 7.85 (1H, dd, J 7.7 and 0.7), 7.90 (1H, d, J 8.8), 8.75 (1H, d, J 8.8), 9.30 (1H, d, J 4.2). m/z (ES+) 394 [MH]+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Cl[C:12]1[N:20]=[C:19]2[C:15]([N:16]=[C:17]([CH2:22][N:23]3[CH2:28][CH2:27][CH:26]([C:29]4([OH:33])[CH2:32][O:31][CH2:30]4)[CH2:25][CH2:24]3)[N:18]2[CH3:21])=[C:14]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[N:13]=1>>[CH3:21][N:18]1[C:17]([CH2:22][N:23]2[CH2:24][CH2:25][CH:26]([C:29]3([OH:33])[CH2:32][O:31][CH2:30]3)[CH2:27][CH2:28]2)=[N:16][C:15]2[C:19]1=[N:20][C:12]([N:3]1[C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=[C:2]1[CH3:1])=[N:13][C:14]=2[N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1
Reactant: Cc1nc2ccccc2[nH]1
Reactant: Cn1c(CN2CCC(C3(O)COC3)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C4(O)COC4)CC3)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, 2-methylbenzimidazole and 3-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)oxetan-3-ol were reacted to give 257. LCMS m/z: 519.3 (MH+)
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][N:18]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[NH:20][C:19]3=[O:27])[CH2:11][CH2:10]2)=[C:4]([N+:28]([O-])=O)[CH:3]=1.[H][H]>[Pd].CO>[NH2:28][C:4]1[CH:3]=[CH:2][CH:7]=[CH:6][C:5]=1[NH:8][CH:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][N:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[NH:20][C:19]2=[O:27])[CH2:13][CH2:14]1
Reactant: O=c1[nH]c2ccccc2n1CCCN1CCC(Nc2ccc(Cl)cc2[N+](=O)[O-])CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1ccccc1NC1CCN(CCCn2c(=O)[nH]c3ccccc32)CC1
Yield: 100 %

Procedure:
A mixture of 21.5 parts of 1-[3-{4-[(4-chloro-2-nitrophenyl)amino]-1-piperidinyl}propyl]-1,3-dihydro-2H-benzimidazol-2-one and 240 parts of methanol is hydrogenated at normal pressure and at room temperature with 10 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated, yielding 18.5 parts (100%) of 1-[3-{4-[(2-aminophenyl)amino]-1-piperidinyl}-propyl]-1,3-dihydro-2H-benzimidazol-2-one as a residue.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:12][CH2:11][CH:10](O)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].COCCN(S(F)(F)[F:25])CCOC>C(Cl)Cl>[F:25][C@@H:10]1[CH2:11][CH2:12][C@H:8]([NH:7][C:6](=[O:14])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCC(O)C1
Reactant: COCCN(CCOC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](F)C1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To a solution of (3-hydroxycyclopentyl)-carbamic acid tert-butyl ester (prepared as described in Tetrahedron 1999, 55, 10815-10834) (1 eq) in DCM (1 M) at −10° C. was added [bis(2-methoxyethyl)amino]sulfur trifluoride (1 eq). The reaction mixture was stirred at −10° C. for 15 min, then the reaction mixture was diluted with DCM, washed with sat. aq. NaHCO3 solution, and back-extracted with DCM (3×). The collected organic phases were dried (Na2SO4), and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford tert-butyl cis-3-fluorocyclopentylcarbamate, MS (ES) C10H18FNO2 requires: 203 found: 204 (M+H)+. A solution of this intermediate in DCM/TFA (1:1, 0.24 M) was stirred at RT for 30 min and then concentrated under reduced pressure. The resulting crude was used as such in the next step without further purification. MS (ES) C5H10FN requires: 103 found: 104 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:20]=[CH:21][C:22]=3[CH3:23])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.[CH:24]([NH2:27])([CH3:26])[CH3:25]>C(#N)C.ClCCl>[CH:24]([NH:27][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:20]=[CH:21][C:22]=3[CH3:23])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1)([CH3:26])[CH3:25]
Reactant: CC(C)N
Reactant: CCOC(=O)c1ccc(C)c(-c2ccc3c(Cl)nncc3c2)c1
Solvent: ClCCl
Solvent: CC#N
Product: CCOC(=O)c1ccc(C)c(-c2ccc3c(NC(C)C)nncc3c2)c1
Temperature: 140 °C

Procedure:
Ethyl 3-(1-chlorophthalazin-6-yl)-4-methylbenzoate (1.4 g) in acetonitrile (10 mL) was treated with isopropylamine (8 mL, 89 mmol). The mixture was stirred at 140° C. (sealed tube) for 15 h. The mixture was dissolved in 100 mL dichloromethane and was washed with water (20 mL), brine (20 mL), then dried over anhydrous Na2SO4, concentrated in vacuo, and purified by column chromatography eluting with 50% ethyl acetate/DCM to give ethyl 3-(1-(isopropylamino)phthalazin-6-yl)-4-methylbenzoate as a white solid.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]([O:14]C)=[CH:4][CH:3]=1.[CH3:16][S-:17].[Na+]>CN(C)C=O>[CH3:16][S:17][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]([OH:14])=[CH:4][CH:3]=1
Reactant: C[S-]
Reactant: COc1ccc(F)nc1-c1ccccn1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ccc(O)c(-c2ccccn2)n1
Temperature: 160 °C
Reaction time: 8 h
Yield: 46.8 %

Procedure:
6-Fluoro-3-methoxy-[2,2′]bipyridine (12 mg) and sodium thiomethoxide (41 mg) were suspended in N,N-dimethylformamide (1.5 ml), and the suspension was stirred at 160° C. overnight. The reaction solution was cooled to room temperature, the reaction solution was then filtered, and the solvent was removed from the filtrate by distillation under the reduced pressure. The residue was purified by thin layer chromatography using acetone-chloroform to give 6-methylsulfanyl-[2,2′]bipyridin-3-ol (6 mg, yield 47%).
Reaction SMILES: [B-](F)(F)(F)F.CN(C(O[N:14]1[C:19](=O)[CH2:18][CH2:17][C:15]1=O)=[N+](C)C)C.[OH:21][CH:22]([C:24]1[CH:25]=[C:26]([C:41](O)=[O:42])[CH:27]=[C:28]2[C:33]=1[O:32][C:31]([N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)=[CH:30][C:29]2=[O:40])[CH3:23].C(N(C(C)C)C(C)C)C.N1CCCC1>C(Cl)Cl>[OH:21][CH:22]([C:24]1[CH:25]=[C:26]([C:41]([N:14]2[CH2:15][CH2:17][CH2:18][CH2:19]2)=[O:42])[CH:27]=[C:28]2[C:33]=1[O:32][C:31]([N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)=[CH:30][C:29]2=[O:40])[CH3:23]
Reactant: CC(O)c1cc(C(=O)O)cc2c(=O)cc(N3CCOCC3)oc12
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: C1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(O)c1cc(C(=O)N2CCCC2)cc2c(=O)cc(N3CCOCC3)oc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 80.5 %

Procedure:
2-(2,5-dioxopyrrolidin-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (3.34 g, 11.09 mmol) at 25° C. was added portionwise to 8-(1-hydroxyethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (1.77 g, 5.54 mmol) and N-ethyl-N-isopropylpropan-2-amine (2.028 mL, 11.64 mmol) suspended in DCM (15 mL) under nitrogen. The resulting mixture was stirred at 25° C. for 5 hrs. Pyrrolidine (1.388 mL, 16.63 mmol) was then added the mixture and the resulting mixture was stirred at 25° C. overnight. The mixture was poured onto a silica gel column and purified by flash chromatography eluting with 2 to 7% methanolic ammonia (7 N) in DCM. The solvent was evaporated to dryness, the residue was triturated in ethylacetate (10 mL), collected by filtration and dried to afford 8-(1-hydroxyethyl)-2-morpholino-6-(pyrrolidine-1-carbonyl)-4H-chromen-4-one (1.66 g, 80%) as a beige solid. Mass Spectrum: M+H+ 373.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@H:8]([NH2:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[C:11]([O:15][C:16](=[O:19])[CH:17]=[CH2:18])([CH3:14])([CH3:13])[CH3:12]>C(O)C>[C:11]([O:15][C:16](=[O:19])[CH2:17][CH2:18][NH:10][C@H:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[CH3:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: C[C@H](N)c1cccc(Br)c1
Solvent: CCO
Product: C[C@H](NCCC(=O)OC(C)(C)C)c1cccc(Br)c1

Procedure:
A solution of (S)-1-(3-bromo-phenyl)-ethylamine (0.3 g, 1.5 mmol) and acrylic acid tert-butyl ester (0.19 g, 1.50 mmol) in ethanol (1.3 mL) was stirred at 55° C. for 2.5 hours. The solvent was concentrated and the crude residue was purified by chromatography on silica gel (heptane/EtOAc).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][C:16]([O:25][CH3:26])=[CH:17][C:18]=3[O:23][CH3:24])[N:13]=2)=[CH:7][C:6]=1[CH3:27].[CH2:28]([N:31]=[C:32]=[O:33])[CH2:29][CH3:30]>C1COCC1>[CH2:28]([NH:31][C:32](=[O:33])[O:1][CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][C:16]([O:25][CH3:26])=[CH:17][C:18]=3[O:23][CH3:24])[N:13]=2)=[CH:7][C:6]=1[CH3:27])[CH2:29][CH3:30]
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCO)c(C)c3)nc2c1
Reactant: CCCN=C=O
Solvent: C1CCOC1
Product: CCCNC(=O)OCCOc1c(C)cc(-c2nc3cc(OC)cc(OC)c3c(=O)[nH]2)cc1C
Temperature: 70 °C
Reaction time: 16 h
Yield: 40.4 %

Procedure:
A mixture of the compound of Example 20 (0.070 g, 0.19 mmol), propyl isocyanate (0.088 mL, 0.94 mmol), and TEA (0.14 g, 1.1 mmol) in THF (4.0 mL) was stirred at 70° C. for 16 h. The mixture was filtered, washed with THF, and the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with saturated aqueous sodium bicarbonate (50 mL), dried and the solvent was removed under reduced pressure. The resulting solid was chromatographed on silica gel to yield 2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethyl-phenoxy)ethyl propylcarbamate (0.035 g, 41%) as an off-white solid: Selected data: 1H NMR (300 MHz, DMSO-d6) δ 11.82 (s, 1H), 7.90 (s, 2H), 7.23 (t, J=5.27 Hz, 1H), 6.74 (d, J=2.32 Hz, 1H), 6.52 (d, J=2.31 Hz, 1H), 4.27 (t, J=4.29 Hz, 2H), 3.99 (t, J=4.29 Hz, 2H), 3.89 (s, 3H), 3.84 (s, 3H), 3.02-2.86 (m, 2H), 2.29 (s, 6H), 1.50-1.30 (m, 2H), 0.84 (t, J=7.33 Hz, 3H); MS (APCI) m/z 456 [M+H]+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[N:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:42]([O:49][C:50](=[O:71])[C@@:51]([CH2:69][OH:70])([CH3:68])[CH2:52][C@H:53]([NH2:67])[CH2:54][C:55]1[CH:60]=[CH:59][C:58]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[CH:57][CH:56]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CN(C=O)C>[CH2:42]([O:49][C:50](=[O:71])[C@@:51]([CH2:69][OH:70])([CH3:68])[CH2:52][C@H:53]([NH:67][C:6]([C:4]1[NH:3][N:2]=[N:1][CH:5]=1)=[O:8])[CH2:54][C:55]1[CH:56]=[CH:57][C:58]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[CH:59][CH:60]=1)[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: C[C@@](CO)(C[C@H](N)Cc1ccc(-c2ccccc2)cc1)C(=O)OCc1ccccc1
Reactant: O=C(O)c1c[nH]nn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@](CO)(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 21.7 %

Procedure:
1,2,3-Triazole-4-carboxylic acid (14 mg, 124 μmol), DIPEA (86.3 μL, 496 μmol) and HATU (47.1 mg, 124 μmol) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. This was then combined with (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid benzyl ester (50 mg, 120 μmol). The resulting mixture was stirred for 15 minutes and the reaction was quenched with AcOH. The product purified by preparative HPLC and lyophilized to yield the title compound (13 mg; purity 95%). MS m/z [M+H]+ calc'd for C29H30N4O4, 499.23. found 499.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]([O:8][CH3:9])=[CH:6][S:5][CH:4]=1.C1(C)C=CC=CC=1.[CH2:17](O)[C@@H:18](O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]CC.N#N>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>[CH2:17]([CH:1]1[O:2][C:3]2=[CH:4][S:5][CH:6]=[C:7]2[O:8][CH2:9]1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: COc1cscc1OC
Reactant: CCCCCCCCCC[C@H](O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N#N
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCC1COc2cscc2O1
Yield: 68.8 %

Procedure:
A solution of 3,4-dimethoxythiophene (1.90 g), toluene (30 ml), (S)-1,2-dodecanediol (2.50 g) and p-toluenesulfonic acid monohydrate (100 mg) was heated at 95° C., continuously leading a N2-stream over the solution. After 24 h the reaction mixture was poured into ethyl acetate, washed with NaHCO3 and the organic phase was concentrated. Subsequent filtration over SiO2 using n-hexane/CH2Cl2 (98/2) as eluant resulted in pure product (2.40 g).
Reaction SMILES: [C:1]([C:3]1[C:4]([OH:11])=[N:5][C:6]([CH3:10])=[CH:7][C:8]=1[CH3:9])#[N:2].[Br:12]N1C(=O)CCC1=O>CN(C)C=O.O>[Br:12][C:7]1[C:8]([CH3:9])=[C:3]([C:1]#[N:2])[C:4]([OH:11])=[N:5][C:6]=1[CH3:10]
Reactant: Cc1cc(C)c(C#N)c(O)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(O)c(C#N)c(C)c1Br
Temperature: 25 °C
Reaction time: 72 h
Yield: 97.8 %

Procedure:
Under a nitrogen atmosphere, a stirred solution of 14.9 grams (0.10 mole) of 3-cyano-2-hydroxy-4,6-dimethylpyridine is cooled in an ice bath, and a solution of 18.1 grams (0.10 mole) of N-bromosuccinimide in 50 mL of N,N-dimethylformamide is added dropwise during a 15 minute period. Upon completion of addition, the reaction mixture is stirred at ambient temperature for about 72 hours. After this time, the reaction mixture is diluted to 1000 mL with water and filtered to collect a solid. The solid is dried under vacuum at about 60° C., yielding 22.2 grams of 5-bromo-3-cyano- 2-hydroxy-4,6-dimethylpyridine, mp 254°-262° C. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][O:7][CH:8]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.Cl.[NH2:19][CH2:20][C:21]#[N:22].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][CH:8]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:9]([NH:22][CH2:21][C:20]#[N:19])=[O:11])=[CH:16][CH:17]=1
Reactant: N#CCN
Reactant: CC(C)CC(OCc1ccc(Br)cc1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)CC(OCc1ccc(Br)cc1)C(=O)NCC#N
Reaction time: 0.02 h

Procedure:
To a solution of 2-[(4-bromobenzyl)oxy]4-methylpentanoic acid in DMF (15 mL) was added aminoacetonitrile hydrochloride (1.9 g, 20.6 mmoles) and HATU (5 g, 13.3 mmoles). After stirring for one minute, triethylamine (5.3 mL, 38.3 mmoles) was added in one portion. The reaction was stirred overnight, diluted with ethyl acetate and water. The organic phase was separated and washed twice with 1.2 N hydrochloric acid, brine and dried over magnesium sulfate. After concentration under reduced pressure, 2-[(4-bromobenzyl)oxy]-N-(cyanomethyl)-4-methylpentanamide was obtained.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([N:13]2[CH2:18][CH2:17][CH:16]([O:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([F:27])[CH:21]=3)[CH2:15][CH2:14]2)[CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[NH:8]1[CH2:12][CH2:11][CH:10]([N:13]2[CH2:14][CH2:15][CH:16]([O:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([F:27])[CH:21]=3)[CH2:17][CH2:18]2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC(Oc3ccc(F)c(F)c3)CC2)C1
Agent: Cl
Solvent: C1COCCO1
Product: Fc1ccc(OC2CCN(C3CCNC3)CC2)cc1F
Reaction time: 3 h

Procedure:
The product of Step c was dissolved in dioxane (10 ml) and HCl (6N) (10 ml) was added and the reaction stirred for 3 hrs. Organic solvent was evaporated and aqueous NaOH (2M) added. The product was extracted with ethyl acetate, the combined organic extracts dried with Na2SO4 and concentrated to give the sub-title product as an oil (0.54 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.[CH3:9][C:10]1[S:11][CH:12]=[C:13]([C:15]#[C:16][Si](C)(C)C)[N:14]=1.C(N(CC)CC)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:16]#[C:15][C:13]2[N:14]=[C:10]([CH3:9])[S:11][CH:12]=2)=[CH:4][N:3]=1
Reactant: Cc1nc(C#C[Si](C)(C)C)cs1
Reactant: Clc1ccc(I)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCN(CC)CC
Product: Cc1nc(C#Cc2ccc(Cl)nc2)cs1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
2-Chloro-5-iodopyridine (40 mmol, 10.0 g), 2-methyl-4-[(trimethylsilyl)ethynyl]-1,3-thiazole (40 mmol, 7.8 g), dichlorobis(triphenylphosphine)palladium(II) (2 mmol, 1.4 g), copper(I) iodide (4 mmol, 760 mg) and triethylamine (200 mmol, 28 mL) were added to deoxygenated DMF (200 mL) at room temperature. The reaction was then warmed to 60° C. and tetrabutylammonium fluoride (40 mmol, 40 mL of 1.0 M solution in THF) was added dropwise via syringe. Stirring continued for 2.5 hrs and the reaction contents were then poured in to a separatory funnel and partitioned with 1:1 hexanes:EtOAc (1000 mL) and water (500 mL). The organic layer was then washed with 5 portions of 5% NaCl (250 mL each). The combined aqueous layers were back-extracted with 1:1 hexanes:EtOAc (500 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was chromatographed on SiO2, eluting with 1:1 EtOAc:hexanes to afford 2-chloro-5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine as a tan solid. 1H-NMR (CDCl3, 300 MHz) δ 8.57 (s, 1H), 7.77 (d, 1H), 7.45 (s, 1H), 7.32 (d, 1H), 2.75 (s, 3H). MS (ESI) 235.2 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[C:17]([F:32])=[C:18]([NH:22][S:23]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1.[CH2:33]([NH2:37])[CH:34]([CH3:36])[CH3:35]>>[F:32][C:17]1[C:16]([C:9]2[N:10]=[C:11]([CH:13]([CH3:15])[CH3:14])[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:37][CH2:33][CH:34]([CH3:36])[CH3:35])[N:7]=2)=[CH:21][CH:20]=[CH:19][C:18]=1[NH:22][S:23]([C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)(=[O:25])=[O:24]
Reactant: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3cccnc3)c2F)c(-c2ccnc(Cl)n2)s1
Reactant: CC(C)CN
Product: CC(C)CNc1nccc(-c2sc(C(C)C)nc2-c2cccc(NS(=O)(=O)c3cccnc3)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 18, Step B using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-pyridinesulfonamide (150 mg, 0.306 mmol) and isobutylamine (0.307 mL, 3.06 mmol). the title compound was obtained as a white solid (105 mg, 65% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.53 (s, 1H), 8.83 (d, J=2.2 Hz, 1H), 8.73 (dd, J=4.8, 1.0 Hz, 1H), 8.03-8.13 (m, 1H), 7.99 (d, J=5.1 Hz, 1H), 7.53 (dd, J=8.1, 4.9 Hz, 1H), 7.31-7.41 (m, 1H), 7.09-7.33 (m, 3H), 5.67-5.93 (m, 1H), 3.14-3.25 (m, 1H), 2.84-3.09 (m, 2H), 1.69-1.87 (m, 1H), 1.30 (d, J=6.9 Hz, 6H), 0.81 (d, J=5.3 Hz, 6H). MS (ESI): 527.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[CH:6]=[CH:5][C:4]=1[CH2:17][OH:18]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[CH:6]=[CH:5][C:4]=1[CH:17]=[O:18]
Reactant: COc1cc(CN2CCN(C)CC2)ccc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: COc1cc(CN2CCN(C)CC2)ccc1C=O
Temperature: 55 °C
Reaction time: 13 h
Yield: 99 %

Procedure:
To 220 mL of a solution of 22.2 g of [2-methoxy-4-[(4-methylpiperazin-1-yl)methyl]phenyl]methanol in CHCl3 was added 61.8 g of manganese dioxide, and the mixture was stirred at 55° C. for 13 hours. The reaction mixture was allowed to stand to cool. After insoluble matter was filtered off, the mother liquor was concentrated to give 21.8 g of the title compound (99% yield).