Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]([S:15][C:16]([F:19])([F:18])[F:17])=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[C:6]=1[Br:7].ClC1C=C(C=CC=1)C(OO)=[O:25]>C(Cl)(Cl)Cl>[Br:1][C:2]1[NH:3][C:4]([S:15]([C:16]([F:19])([F:18])[F:17])=[O:25])=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[C:6]=1[Br:7]
Reactant: FC(F)(F)Sc1[nH]c(Br)c(Br)c1-c1ccc(Cl)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: O=S(c1[nH]c(Br)c(Br)c1-c1ccc(Cl)cc1)C(F)(F)F
Temperature: 0 °C
Yield: 38.5 %

Procedure:
A solution of 2,3-dibromo-4-(p-chlorophenyl)-5-[(trifluoromethyl)thio]pyrrole (1.0 g, 0.0023 mol) in chloroform (10 mL) is treated with 3-chloroperoxybenzoic acid (0.4 g, 60%, 0.0023 mol) with stirring at 0° C., warmed to room temperature with stirring for two hours, washed with saturated sodium metabisulfite solution, saturated sodium hydrogen carbonate solution, water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a yellow syrup. Flash chromatography of the syrup using silica gel and a 1:4 ethyl acetate/hexanes solution gives the title product as a yellow solid (0.4 g, mp 165.5°-167.5° C.) which is identified by 1NHMR, 19FNMR and 13CNMR spectral analyses.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:19])[C:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:12][CH:13]=2)=[CH:4][N:3]=1.[CH3:20][C:21]1[N:25]=[CH:24][N:23]([C:26]2[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=2[CH:28]=O)[N:22]=1.OOS([O-])=O.[K+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C.O>[C:15]([N:14]1[C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=3)=[CH:9][C:10]=2[N:19]=[C:28]1[C:27]1[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=1[N:23]1[CH:24]=[N:25][C:21]([CH3:20])=[N:22]1)([CH3:16])([CH3:18])[CH3:17]
Reactant: Cc1ncn(-c2ccccc2C=O)n1
Reactant: CC(C)(C)Nc1ccc(-c2cnc(N)nc2)cc1N
Agent: O=S([O-])([O-])=S
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ncn(-c2ccccc2-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)n1
Reaction time: 1 h
Yield: 31 %

Procedure:
To a solution of 4-(2-amino-pyrimidin-5-yl)-N1-tert-butyl-benzene-1,2-diamine (50 mg, 0.19 mmol) in DMF (5 mL) is added 2-(3-methyl-1,2,4-triazol-1-yl)-benzaldehyde (44 mg, 0.23 mmol) at room temperature. Oxone (119 mg, 0.19 mmol) in H2O (1 mL) is added and the solution stirred for 1 hour. Saturated sodium thiosulfate solution (5 mL) is added and the mixture is extracted with EtOAc (3×10 mL) and H2O (10 mL). The combined organic layer is dried with (MgSO4), filtered and concentrated. The residue is purified by silica gel flash column chromatography eluting with 10% MeOH in CH2Cl2 to afford the title compound (25 mg, 30%) as a white solid. LCMS (ESMS): m/z 425.20 (M++1)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[C:6]([OH:9])[C:7]=1[F:8].C([O-])([O-])=O.[K+].[K+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.N(CC)CC>CCOC(C)=O.O.CN(C=O)C>[CH2:23]([O:9][C:6]1[CH:5]=[C:4]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=[C:2]([F:1])[C:7]=1[F:8])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)CCc1cc(O)c(F)c(F)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1cc(F)c(F)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 138.3 %

Procedure:
A solution of DMF (21 mL), ethyl 3-(3,4-difluoro-5-hydroxyphenyl)propanoate (2.46 g, 0.0107 mol), and K2CO3 (1.92 g, 0.0139 mol) were combined at 0° C. under N2. After 10 min, benzyl bromide (1.65 mL, 0.0139 mol) was added dropwise. The solution was allowed to warm to room temperature. After 16 h, H2O (50 mL), Et2NH (2 eq) and EtOAc (50 mL) were added and the organic layer isolated. The aqueous layer was washed with EtOAc (2×) and the combined organic fractions were washed with 1M HCl (2×), sat. aq. NaHCO3 (2×), dried, and concentrated. The crude product was purified by flash chromatography (gradient 100% hexanes-60% EtOAc/hexanes) to afford 4.74 g of product as an oil (86%).
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16])C.[NH2:20][C:21]1[CH:28]=[C:27]([Br:29])[CH:26]=[CH:25][C:22]=1[CH:23]=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:29][C:27]1[CH:28]=[C:21]2[C:22]([CH:23]=[C:5]([N:6]3[C:7](=[O:16])[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:14]3=[O:15])[CH:4]=[N:20]2)=[CH:25][CH:26]=1
Reactant: CCOC(CN1C(=O)c2ccccc2C1=O)OCC
Reactant: Nc1cc(Br)ccc1C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1c1cnc2cc(Br)ccc2c1
Yield: 45.3 %

Procedure:
A mixture of 2-(2,2-diethoxyethyl)isoindoline-1,3-dione (3.16 g, 12.00 mmol), 2-amino-4-bromobenzaldehyde (2 g, 10.00 mmol) and p-toluenesulfonic acid monohydrate (1.902 g, 10.00 mmol) in toluene (60 mL) was heated under reflux using Dean-Stark apparatus overnight. A very dark/black solid precipitated overnight and was collected, washed with toluene and hexanes, then dissolved in chloroform fortified with DMF. The mixture was washed with aq. NaHCO3 solution (×2), ensuring any precipitate was dissolved in additional chloroform during separation. The organic layer was dried (sodium sulfate) and evaporated onto silica gel. Purification by flash chromatography (0-2% methanol in dichloromethane) afforded the title compound (1.6 g, 45%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.05 (d, 1 H), 8.57 (d, J=2.3 Hz, 1 H), 8.35 (d, J=1.8 Hz, 1 H), 8.11 (d, J=8.6 Hz, 1 H), 8.09-8.02 (m, 2 H), 8.02-7.93 (m, 2 H), 7.87 (dd, J=1.9, 8.7 Hz, 1 H).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C@@H:7]1[N:12]([C:13](=O)[CH2:14][C@@H:15]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][C:26]=2[S:35]([C:38]([F:41])([F:40])[F:39])(=[O:37])=[O:36])[CH2:16][S:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:11][CH2:10][O:9][CH2:8]1)[CH2:4][CH3:5])[CH3:2].C1COCC1.Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.CO>[CH2:1]([N:3]([CH2:6][C@@H:7]1[N:12]([CH2:13][CH2:14][C@@H:15]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:32])=[O:33])=[CH:27][C:26]=2[S:35]([C:38]([F:40])([F:39])[F:41])(=[O:37])=[O:36])[CH2:16][S:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:11][CH2:10][O:9][CH2:8]1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)C[C@H]1COCCN1C(=O)C[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCN(CC)C[C@H]1COCCN1CC[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 37 %

Procedure:
A mixture of 4-((R)-4-((S)-3-((diethylamino)methyl)morpholino)-4-oxo-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide (INTERMEDIATE 87, 360 mg, 0.55 mmol) and 1 M borane-tetrahydrofuran complex in THF (1191 μl, 1.19 mmol) was stirred at room temperature for 16 hours. The reaction mixture was treated carefully with MeOH (5 ml) and concentrated HCl (1 ml). The mixture was heated at 80° C. for 3 hours, cooled to r.t, and the pH was adjusted to pH 10 with 4 N aqueous sodium carbonate. The mixture was diluted with ethyl acetate (300 ml), washed successively with water (150 ml) and brine (150 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (ISCO, eluting with 0→20% MeOH/DCM over 15 minutes) to give the title product (130 mg, yield: 37%).
Reaction SMILES: [CH2:1]1[C:10](=[O:11])[CH2:9][C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.C(=O)=O.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[C:41]([Cl:46])[CH:40]=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[Cl:45][C:42]1[CH:43]=[C:44]([CH:9]2[C:8]3[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:2][CH2:1][C:10]2=[O:11])[CH:39]=[CH:40][C:41]=1[Cl:46]
Reactant: O=C1CCc2ccccc2C1
Reactant: Clc1ccc(Br)cc1Cl
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: Cc1ccccc1
Product: O=C1CCc2ccccc2C1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 73 %

Procedure:
To a stirring solution of β-tetralone (34) (1.00 g, 6.84 mmol) and pd(dba)2 (39 mg, 1 mol%) in toluene was added t-Bu3P (228 uL, 10 wt % in hexanes, 1.1%). The solution was chilled (dry-ice bath) before adding LiHMDS (7.5 mL, 1M in hexanes, 1.1 eq) followed by 1-bromo-3,4-dichlorobenzene (1 mL, 1.1 eq). The solution was then allowed to warm to ambient temperature and heated under microwave radiation for 5 minutes (maximum temperature 140° C.). After cooling, the reaction was quenched with aqueous ammonium chloride and extracted with MTBE. The organic layer was dried with sodium sulfate, filtered through celite, and evaporated. The crude oil was separated on silic gel to give the title compound (1.45 g, 73%) as a slight brown oil. This material was assayed as 90% pure. TLC Rf (25% EA/Hex)=0.42. GCMS Rt=13.21 min m/z=290 (M+). 1H NMR (CDCl3, δ): 7.37 (d, J=8.3 Hz, 1H), 7.3-7.2 (m, 3H), 7.17 (d, J=2.1 Hz, 1H), 6.9 (m, 2H), 4.68 (s, 1H), 3.1 (m, 2H), 2.7 (m, 2H). 13C NMR (CDCl3, δ): 208.4, 137.7, 136.7, 135.3, 132.7, 131.5, 130.7, 130.5, 129.2, 128.2, 128.1, 127.7, 127.3, 58.6, 37.1, 28.0.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[CH:5]=[C:4]([CH3:16])[N:3]=1.[B-](F)(F)(F)[F:18].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.C(#N)C>CO>[F:18][C:5]1[C:6]2[C:11](=[CH:10][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:7]=2)[C:2]([OH:1])=[N:3][C:4]=1[CH3:16]
Reactant: F[B-](F)(F)F
Reactant: COC(=O)c1ccc2cc(C)nc(O)c2c1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Solvent: CO
Product: COC(=O)c1ccc2c(F)c(C)nc(O)c2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 42.3 %

Procedure:
A mixture of methyl 1-hydroxy-3-methylisoquinoline-7-carboxylate (120 mg), Selectfluor (registered trademark) (215 mg), acetonitrile (2 mL), and methanol (2 mL) was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted with water. Then, the precipitate was collected by filtration to obtain methyl 4-fluoro-1-hydroxy-3-methylisoquinoline-7-carboxylate (55 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:14])=[C:4]([F:13])[CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH2:8][CH2:7]2.C(=O)([O-])[O-].[Cs+].[Cs+].[CH:21](I)([CH3:23])[CH3:22]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:3]([O:14][CH:21]([CH3:23])[CH3:22])=[C:4]([F:13])[CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH2:8][CH2:7]2
Reactant: O=C1NCCc2cc(F)c(O)c(Cl)c21
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)Oc1c(F)cc2c(c1Cl)C(=O)NCC2
Temperature: 25 °C
Reaction time: 20 h
Yield: 39.6 %

Procedure:
To a solution of 8-chloro-6-fluoro-7-hydroxy-3,4-dihydroisoquinolin-1(2H)-one (Cpd O, 131 mg, 0.607 mmol) in DMF (3.0 mL) was added cesium carbonate (0.210 g, 0.645 mmol) and iso-propyl iodide (0.0850 mL, 0.850 mmol). The reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was diluted with EtOAc and washed with water (2×) and brine. The organic layer was concentrated under vacuum and the residue was purified by column chromatography (40-100% EtOAc/heptane) to give the title compound (Cpd P, 62 mg, 40%) as a white solid. MS 258 [M+H].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[SH:12])[NH:5][C:6](=[O:8])[CH3:7].[CH2:13](OC=C(C#N)C#N)C>CC(O)=O>[C:6]([NH:5][C:4]1[CH:9]=[CH:10][C:11]2[S:12][CH:13]=[N:1][C:2]=2[CH:3]=1)(=[O:8])[CH3:7]
Reactant: CCOC=C(C#N)C#N
Reactant: CC(=O)Nc1ccc(S)c(N)c1
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc2scnc2c1
Temperature: 125 °C
Yield: 17 %

Procedure:
To a solution of intermediate 3′-amino-4′-mercaptoacetanilide in HOAc (50 mL) was added ethoxymethylene malononitrile (1.95 g, 16 mmol) and the resulting mixture was refluxed at 125° C. for 5 h. After cooling, the product mixture was concentrated under reduced pressure, and the residue was partitioned between satd aqueous NaHCO3 and EtOAc. The aqueous phase was extracted with EtOAc, and the combined extracts were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography on silica gel, eluting with EtOAc-Hex (0:100 to 50:50) to give the title compound (508 mg, 17%) as a yellow solid. 1H-NMR (DMSO-d6): δ 9.35 (1H, s), 8.53(1H, s), 8.10 (1H, d), 7.63 (1H, d), 2.15 (3H, s).
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH:11]([C@@H:14]1[N:19]([C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21])[CH2:18][CH2:17][C:16]([C:26]2[N:27]=[C:28]([SH:31])[S:29][CH:30]=2)=[CH:15]1)([CH3:13])[CH3:12].O(P(OC1C=CC=CC=1)O[C:41]1[C@H:47]([CH3:48])[C@H:46]2[N:43]([C:44](=[O:56])[C@@H:45]2[C@H:49]([O:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[CH3:50])[C:42]=1[C:57]([O:59][CH2:60][CH:61]=[CH2:62])=[O:58])C1C=CC=CC=1.C(#N)C>C1COCC1>[CH2:23]([O:22][C:20]([N:19]1[C@@H:14]([CH:11]([CH3:13])[CH3:12])[CH:15]=[C:16]([C:26]2[N:27]=[C:28]([S:31][C:41]3[C@H:47]([CH3:48])[C@H:46]4[N:43]([C:44](=[O:56])[C@@H:45]4[C@H:49]([O:51][Si:52]([CH3:53])([CH3:54])[CH3:55])[CH3:50])[C:42]=3[C:57]([O:59][CH2:60][CH:61]=[CH2:62])=[O:58])[S:29][CH:30]=2)[CH2:17][CH2:18]1)=[O:21])[CH:24]=[CH2:25]
Reactant: C=CCOC(=O)N1CCC(c2csc(S)n2)=C[C@@H]1C(C)C
Reactant: C=CCOC(=O)C1=C(OP(Oc2ccccc2)Oc2ccccc2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C)C(=O)N12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CC#N
Solvent: C1CCOC1
Product: C=CCOC(=O)C1=C(Sc2nc(C3=C[C@H](C(C)C)N(C(=O)OCC=C)CC3)cs2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C)C(=O)N12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 61 %

Procedure:
A solution of lithium hexamethyldisilazide in THF (1M, 0.62 ml, 0.62 mmol) was added at 0–5° C. to a solution of allyl (6S)-6-isopropyl-4-(2-mercapto-1,3-thiazol-4-yl)-3,6-dihydro-1(2 H)-pyridinecarboxylate (202 mg, 0.62 mmol) in THF (11.0 ml) and the mixture was stirred for 15 minutes. To the reaction solution was added at 0° C. a solution of allyl (4R,5R,6S)-3-[(diphenoxyphosphino)oxy]-4-methyl-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate in acetonitrile (30%, 2.37 g, 1.2 mmol) and the solution was allowed to stand in a refrigerator for 16 hours. To the reaction solution was added ice water and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After removal of the solvent in vacuo, the residue was purified with silica gel chromatography (hexane/ethyl acetate: 1/5→1/3) to give allyl (4R,5S,6S)-3-[(4-{(6S)-1-[(allyloxy)carbonyl]-6-isopropyl-1,2,3,6-tetrahydro-4-pyridinyl}-1,3-thiazol-2-yl)sulfanyl]-4-methyl-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.24 g, 61%).
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[Br:7][C:8]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:9]=1[CH:10]=[O:11].Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.[I-].[I-].[Zn+2]>[NH2:6][CH2:5][CH:10]([C:9]1[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:8]=1[Br:7])[OH:11]
Reactant: O=Cc1ccc(F)cc1Br
Reactant: C[Si](C)(C)C#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: ClCCl
Product: NCC(O)c1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.7 %

Procedure:
Add trimethylsilyl cyanide (1.01 mL, 7.39 mmol) and zinc diiodide (0.11 g, 0.37 mmol) to a solution of 2-bromo-4-fluorobenzaldehyde (1.5 g, 7.39 mmol) in DCM (10 mL). Stir the mixture overnight at RT. Remove the solvent. Dissolve the residue in THF (5 mL) and cool at 0° C. Add borane-THF complex (11.1 mL, 11.1 mmol). Stir the mixture at RT for 3 h. Add 1 M HCl slowly and stir for 15 min. Adjust the pH to basic with saturated sodium carbonate. Extract with DCM. Dry it over sodium sulfate and concentrate to give the title compound as a colorless oil (1.5 g, 86%). MS (ES) m/z 235 [M+1]+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:22])=[N:12][CH:13]=[C:14]([C:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH:21]=2)[N:15]=1.Cl[C:24](=[O:31])[CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28].C(N(CC)CC)C>C(Cl)Cl>[NH2:22][C:11]1[N:12]=[CH:13][C:14]([C:16]2[CH2:17][CH2:18][N:19]([C:24](=[O:31])[CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH2:20][CH:21]=2)=[N:15][C:10]=1[C:2]1[NH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=1
Reactant: Nc1ncc(C2=CCNCC2)nc1-c1nc2ccccc2[nH]1
Reactant: COC(=O)CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCC(=O)N1CC=C(c2cnc(N)c(-c3nc4ccccc4[nH]3)n2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(1H-benzimidazol-2-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrazin-2-amine (50 mg, 0.12 mmol) in DCM (2 mL) at 0° C. was added methyl 4-chloro-4-oxo-butanoate (19 mg, 15 μL, 0.12 mmol) followed by the addition of triethylamine (50 mg, 69 μL, 0.5 mmol). The reaction mixture was stirred at room temperature for 2 h and then partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc, dried (MgSO4), filtered and concentrated. The crude material was dissolved in DMSO and purified by reverse phase HPLC using 1-99% MeOH in H2O to obtain methyl 4-(4-(5-amino-6-(1H-benzo[d]imidazol-2-yl)pyrazin-2-yl)-5,6-dihydropyridin-1(2H)-yl)-4-oxobutanoate, which was re-dissolved in THF (1.0 mL), treated with NaOH (996 μL of 2.5 M, 2.5 mmol) and stirred for 18 h at room temperature. The reaction mixture was then acidified with conc. HCl till pH7 and extracted with DCM. The organic layer was dried (MgSO4), filtered and concentrated. The crude material was purified via reverse phase HPLC using 1-99% MeOH in H2O (0.05% HCl modifier) to obtain 4-(4-(5-amino-6-(1H-benzo[d]imidazol-2-yl)pyrazin-2-yl)-5,6-dihydropyridin-1(2H)-yl)-4-oxobutanoic acid (5 mg, 11%). 1H NMR (400 MHz, MeOD) δ 8.24 (s, 1H), 7.66 (d, J=4.1 Hz, 2H), 7.27 (dd, J=6.0, 3.1 Hz, 2H), 6.68 (d, J=7.9 Hz, 1H), 4.34 (s, 1H), 4.27 (s, 1H), 3.84 (t, J=5.6 Hz, 2H), 2.85 (s, 1H), 2.80-2.65 (m, 3H), 2.56-2.47 (m, 2H). LC/MS m/z 393.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[N:3]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1F)[C:15]#[N:16].C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C.CN(C)C=O>[NH2:1][C:2]1[N:6]([C:19]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=2[F:11])[N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[N:3]=1
Reactant: Nc1nc(C(F)(F)F)n[nH]1
Reactant: N#Cc1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(-n2nc(C(F)(F)F)nc2N)c(F)c1
Temperature: 60 °C
Reaction time: 6 h
Yield: 58.6 %

Procedure:
In a 50-ml eggplant flask provided with a magnetic stirrer were placed 3.04 g (20 mmol) of 5-amino-3-trifluoromethyl-1H-1,2,4-triazole, 3.06 g (22 mmol) of 3,4-difluorobenzonitrile, 2.76 g (20 mmol) of potassium carbonate and then 10 ml of N,N-dimethylformamide. The mixture was stirred at 60° C. for 6 hours. Thereto were added 50 ml of ethyl acetate and 50 ml of water to give rise to phase separation. The aqueous phase was extracted with 50 mol of ethyl acetate. The ethyl acetate phase was washed with water and then with a saturated aqueous sodium chloride solution. The ethyl acetate phase was dried over anhydrous sodium sulfate and then subjected to vacuum distillation to distil off ethyl acetate. To the residue was added 5 ml of toluene. The mixture was stirred with heating, cooled and then filtered to obtain 3.18 g of a crystal. Yield: 58.6%
Reaction SMILES: [F:1][C@H:2]1[C@H:6]([OH:7])[CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)=[O:9])[CH2:3]1.C(Cl)Cl.[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>CN(C1C=CN=CC=1)C.O>[F:1][C@H:2]1[C@H:6]([O:7][S:32]([C:29]2[CH:30]=[CH:31][C:26]([CH3:25])=[CH:27][CH:28]=2)(=[O:34])=[O:33])[CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)=[O:9])[CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(OCc1ccc2ccccc2c1)N1C[C@@H](O)[C@H](F)C1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)O[C@@H]2CN(C(=O)OCc3ccc4ccccc4c3)C[C@H]2F)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 44.1 %

Procedure:
A flask was charged with (trans)-naphthalen-2-ylmethyl 3-fluoro-4-hydroxypyrrolidine-1-carboxylate (237 mg, 0.819 mmol), TEA (0.343 ml, 2.458mmol) and DMAP (10.0 mg, 0.082 mmol) in DCM (4.3 ml, 0.86 mmol). The reaction mixture was cooled to 0° C., and 4-methylbenzene-1-sulfonyl chloride (234 mg, 1.23 mmol) was added. The reaction was warmed to ambient temperature and stirred for 3 hours. The reaction was diluted with water and extracted with DCM. The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography, eluting with 0-5% MeOH in DCM to give the product as an oil (160 mg, 44% yield).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:12][C:13]([CH3:18])=[CH:14][C:15](Cl)=[O:16].C(N(CC)CC)C>C(OCC)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:11][C:15](=[O:16])[CH:14]=[C:13]([CH3:18])[CH3:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: CC(C)=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)=CC(=O)Oc1ccc(C(C)(C)C)cc1
Temperature: 25 °C

Procedure:
To a chilled solution of 4-tert-butylphenol (15 g, 100 mmol) and 11.12 mL of 3-methylbut-2-enoyl chloride in 200 mL of diethyl ether at 0° C. was added 13.9 mL of triethylamine by addition funnel. The reaction mixture was warmed to room temperature and stirred until TLC indicated the reaction was complete. The reaction mixture was then filtered through diatomaceous earth, and the diethyl ether layer was washed two times with water, washed with brine, dried over magnesium sulfate, and concentrated in vacuo to leave 23 g of 3-methylbut-2-enoic acid 4-tert-butylphenyl ester as a brown oil that partially crystallized upon standing.
Reaction SMILES: N[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].N([O-])=O.[Na+].[ClH:16]>O1CCOCC1.O>[Cl:16][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11]
Reactant: Cl
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cccc(O)c1Cl
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
2-Amino-3-nitrophenol 2b1 (5 g; 32.4 mmol) was dissolved in concentrated HCl (75 ml_) and 1,4-dioxane (14.7 ml_). The mixture was heated to 70° C. until most of the solids were in solution. The reaction mixture was cooled to 0° C. (ice bath), and sodium nitrite (2.23 g; 32.3 mmol) in H2O (5.4 mL) was added over a period of 3 hours to the brown solution. The temperature was maintained below 10° C. during the addition and the stirring was continued for an additional 15 min. at 0° C. This diazonium intermediate was poured into a solution of Cu(I)Cl(3.8 g; 38.9 mmol) in H2O (18.5 mL) and cone. HCl (18.5 mL) at 0° C. The reaction was stirred for 15 min. at 0° C., warmed to 60° C., and stirred for an additional 15 min. The reaction mixture was then brought to room temperature, and left to stir overnight. The reaction mixture was transferred to a separatory funnel and extracted with ether (3×150 mL). The organic layers were combined, washed with brine (1×), dried (Na2SO4), filtered and concentrated to afford the crude product (5.83 g) as a red-brown oil. The crude material was purified by flash column chromatography (1:25 ultra pure silica gel, 230-400 mesh, 40-60 mm, 60 angstroms; 3:1 hexane/EtOAc as the solvent) to afford pure 2-chloro-3-nitrophenol 2c1 (48%; 2.7 g) as an orange solid. MS 171.8 (MH)+: Homogeneity by HPLC (TFA) @ 220 nm: 96%.