Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[CH:7][C:6]([N+:13]([O-:15])=[O:14])=[C:5]2Cl.CCN(C(C)C)C(C)C.[NH2:26][C@H:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][C@@H:28]1[F:40].CCOC(C)=O.CCCCCC>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[CH:7][C:6]([N+:13]([O-:15])=[O:14])=[C:5]2[NH:26][C@H:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])[CH2:29][C@@H:28]1[F:40]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)[C@@H](F)C1
Reactant: O=[N+]([O-])c1cnc2cc(F)c(Br)cc2c1Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2c([N+](=O)[O-])cnc3cc(F)c(Br)cc23)[C@@H](F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 972.1 %

Procedure:
6-Bromo-4-chloro-7-fluoro-3-nitroquinoline (17.5 g, 0.0057 mol) was taken in dry DMF (200 mL) under N2 atmosphere. DIPEA (14.8 g, 0.114 mol) and (3S,4S)-tert-butyl 4-amino-3-fluoropiperidine-1-carboxylate (12.5 g, 0.057 mol) in dry DMF (50 mL) was added sequentially at RT. The resulting mixture was stirred for overnight at RT. The reaction was monitored by TLC (30% EtOAc/Hexane), after completion of reaction, the reaction mixture poured into ice water and extracted with EtOAc (3×200 mL). The combined EtOAc layers were washed with brine solution and water, dried over sodium sulphate. The organic layer was evaporated under vacuum and the residue was purified by column chromatography on silica gel (10-50% EtOAc-Hexane) to afford the (3S,4S)-tert-butyl 4-((6-bromo-7-fluoro-3-nitroquinolin-4-yl)amino)-3-fluoropiperidine-1-carboxylate, 1 (27 g, 956% yield). 1HNMR (CDCl3, 400 MHz): δ 9.37 (s, 1H) 8.83-8.81 (d, 1H) 8.48-8.46 (d, 1H) 7.74-7.71 (d, 1H), 4-58-4.40 (m, 2H), 4.19-4.12 (m, 2H), 2.95-2.87 (m, 2H) 2.27-2.23 (m, 1H) 1.79-1.66 (m, 1H), 1.47 (s, 9H); LCMS: 98.84%, (M+2) 488.7; HPLC: 99.47%.
Reaction SMILES: Br[CH:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[OH:22][C:23]([CH3:33])([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:24][CH2:25][NH2:26].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[OH:22][C:23]([CH3:33])([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:24][CH2:25][NH:26][CH:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(Br)CCCCCCCOC1CCCCO1
Reactant: CCCCCCC(C)(O)CCN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCCC(C)(O)CCNC(CCCCCCCOC1CCCCO1)C(=O)OCC
Yield: 40.5 %

Procedure:
Ethyl 2-bromo-9-tetrahydropyranyloxy-nonanoate (2.5 g) and 3-hydroxy-3-methylnonylamine (2.2 g) were refluxed together in dry ethanol (50 ml) containing sodium carbonate (726 mg) overnight. The ethanol was evaporated in vacuo and the residue was partitioned between ether and brine. The ether solution was washed with brine, dried and evaporated in vacuo. The resulting yellow gum was chromatographed on silica gel (100 g) using chloroform as eluant to give ethyl 2-(3'-hydroxy-3'-methyl-n-nonyl)amino-9-tetrahydropyranyloxy-nonanoate (1.27 g) as a colourless gum.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:12]1[C:17]([S:18]([N:21]2[CH2:42][CH2:41][C:24]3([C:28](=[O:29])[N:27]([C:30]4[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=4)[CH2:26][CH2:25]3)[CH2:23][CH2:22]2)(=[O:20])=[O:19])=[CH:16][CH:15]=[CH:14][N:13]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:3]([O:10][C:12]1[C:17]([S:18]([N:21]2[CH2:22][CH2:23][C:24]3([C:28](=[O:29])[N:27]([C:30]4[CH:31]=[CH:32][C:33]([O:36][C:37]([F:38])([F:39])[F:40])=[CH:34][CH:35]=4)[CH2:26][CH2:25]3)[CH2:41][CH2:42]2)(=[O:20])=[O:19])=[CH:16][CH:15]=[CH:14][N:13]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1cccnc1Cl)CC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1cccnc1OCc1ccccc1)CC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
To a suspension of NaH (12 mg, 0.31 mmol) in DMF (2 mL) at 0° C. was added benzyl alcohol (25 uL, 0.25 mmol) and the mixture was stirred for 30 min at 0° C. A solution of 8-(2-chloro-pyridine-3-sulfonyl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 188, 100 mg, 0.20 mmol) in DMF (500 uL) was added drop-wise and the reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo to give the crude residue which was purified by flash column chromatography (1:2 AcOEt/heptane) which afforded the desired product as a colourless solid (100 mg, 87%). MS (ESI): 562.3 (MH+).
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>O1CCOCC1>[O:1]([CH2:8][CH2:9][CH2:10][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CNCCN1
Reactant: BrCCCOc1ccccc1
Solvent: C1COCCO1
Product: c1ccc(OCCCN2CCNCC2)cc1
Yield: 97 %

Procedure:
15.1 g of phenoxypropyl bromide and 60 g of piperazine were dissolved in 150 ml of dioxane, and the solution was heated at 80°-90° C. for 1 hour. The precipitated crystals were removed by filtration, and the filtrate was then concentrated. Afterward, the resultant residue was dissolved in chloroform and then washed with water. Chloroform was distilled off to obtain 15 g of 1-(3-phenoxypropyl)piperazine.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]N)=[CH:5][CH:4]=1)#[N:2].[Mn]([O-])(=O)(=O)=[O:12].[K+].S(=O)(=O)(O)O>O>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:12])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(CN)cc1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: N#Cc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 26 %

Procedure:
13.2 g of p-cyanobenzylamine was added dropwise to 200 ml of water and 15.8 g of potassium permanganate with vigorous stirring at room temperature over 20 minutes. The mixture was adjusted to pH 1 by sulfuric acid and stirred at room temperature for 5 hours. The p-cyanobenzaldehyde obtained had a yield of 26% (on a basis of cyanobenzylamine compound, hereafter the same) determined by the analysis of high performance liquid chromatography.
Reaction SMILES: CC(C)([O-])C.[Na+].Cl[C:8]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.Cl>C([O-])(=O)C.C([O-])(=O)C.[Pd+2].O1CCOCC1>[F:22][C:19]1[CH:20]=[CH:21][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][C:9]=2[CH:18]=1
Reactant: Fc1ccc(Nc2cc(F)ccc2Cl)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: Fc1ccc2c(c1)[nH]c1ccc(F)cc12
Temperature: 110 °C
Reaction time: 20 h
Yield: 16.5 %

Procedure:
A mixture of sodium tert-butoxide (11.429 g, 118.9 mmol), 2-chloro-5-fluoro-N-(4-fluorophenyl)aniline (5.700 g, 23.8 mmol) and anhydrous 1,4-dioxane (120 mL) was degassed and back-filled with argon. Tri-tert-butylphosphonium tetrafluoroborate (0.483 g, 1.7 mmol) and palladium diacetate (0.267 g, 1.2 mmol) were added and the mixture was stirred in an oil bath at 110° C. for 20 hrs. After cooling to room temperature, the mixture was treated with 2M aqueous hydrochloric acid (90 mL) and extracted with methylene chloride (3×50 mL). The combined organic layers were washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (20-50% methylene chloride/hexanes). The solids were rinsed with hexanes and dried to afford the pure compound as a white powder (0.80 g, 17%). 1H NMR (300 MHz, CDCl3) δ 8.05 (br s, 1H), 7.94 (dd, 1H, J=8.7, 5.7 Hz), 7.67 (dd, 1H, J=8.7, 2.7 Hz), 7.35 (dd, 1H, J=9.0, 4.5 Hz), 7.14 (td, 1H, J=9.0, 2.7 Hz), 7.11 (dd, 1H, J=9.3, 2.4 Hz), 6.98 (ddd, 1H, J=9.3, 8.4, 2.4 Hz).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:3]=1[CH2:4][C@H:5]1[CH2:10][C@H:9]([C:11]2[O:15][NH:14][C:13](=[O:16])[CH:12]=2)[CH2:8][CH2:7][N:6]1C(OC)=O.Br>>[F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:3]=1[CH2:4][C@H:5]1[CH2:10][C@H:9]([C:11]2[O:15][NH:14][C:13](=[O:16])[CH:12]=2)[CH2:8][CH2:7][NH:6]1
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1c(F)cccc1F
Agent: Br
Product: O=c1cc([C@@H]2CCN[C@@H](Cc3c(F)cccc3F)C2)o[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 1.7 %

Procedure:
Trans-methyl 2-(2,6-difluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.329 g, 0.93 mmol) was dissolved in hydrogen bromide (33% in acetic acid, 7.5 mL, 42.82 mmol) and the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-(trans-2-(2,6-difluorobenzyl)piperidin-4-yl)isoxazol-3(2H)-one (4.6 mg, 1.7%). HRMS Calculated for [C15H16F2N2O2+H]+: 295.1258. Found: 295.1257
Reaction SMILES: [CH3:1][Si:2]([NH-:5])([CH3:4])[CH3:3].[CH3:6][Si:7]([NH-])([CH3:9])[CH3:8].[Li+:11].[Li+].COC1[C@@H](O)[C@@H]2[C@@]3(N(CCC4C2=CC2OCOC=2C=4)CCC3)C=1.C(OC(=O)C)(=O)C>O1CCCC1.C([Li])CCC>[CH3:1][Si:2]([N-:5][Si:7]([CH3:9])([CH3:8])[CH3:6])([CH3:4])[CH3:3].[Li+:11]
Reactant: C[Si](C)(C)[NH-]
Agent: COC1=C[C@]23CCCN2CCc2cc4c(cc2[C@@H]3[C@@H]1O)OCO4
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: C[Si](C)(C)[N-][Si](C)(C)C
Reaction time: 0.08 h

Procedure:
A commercial solution of lithium bis-(trimethylsilylamide) 1M in tetrahydrofurane (0.95 ml, 0.95 mmol) was added to a stirred solution of (−)-cephalotaxine (200 mg, 0.63 mmol) in anhydrous tetrahydrofurane at −40° C. After stirring for 5 minutes, acetic anhydride (90 μl, 0.95 mmol) was added, and the reaction mixture was treated like method above-mentioned in 1°). The product thus obtained showed identical characteristics to this obtained above in butyllithium method.
Reaction SMILES: FC(F)(F)C(O)=O.CC([O:12][C:13](=[O:23])[CH2:14][N:15]1[CH2:20][C:19](=[O:21])[NH:18][CH2:17][C:16]1=[O:22])(C)C>C1(OC)C=CC=CC=1>[O:22]=[C:16]1[CH2:17][NH:18][C:19](=[O:21])[CH2:20][N:15]1[CH2:14][C:13]([OH:23])=[O:12]
Reactant: CC(C)(C)OC(=O)CN1CC(=O)NCC1=O
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CN1CC(=O)NCC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 50 ml round bottom flask 5.0 ml of 70% trifluoroacetic acid acid was added to 2,5-dioxo-1-piperazineacetic acid 1,1-dimethylethyl ester (1.0 g) dissolved in anisole (1 ml). The reaction was stirred at room temperature. The progress of the reaction was monitored by thin layer chromatography. The deprotection rection was sufficiently complete after one hour.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([NH2:8])=[CH:6][C:5]([CH3:9])=[N:4]1)[CH3:2].[CH2:10]([O:12][C:13](=[O:24])[C:14](=[CH:20]OCC)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:11]>C(O)C>[CH2:10]([O:12][C:13](=[O:24])[C:14](=[CH:20][NH:8][C:7]1[N:3]([CH2:1][CH3:2])[N:4]=[C:5]([CH3:9])[CH:6]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:11]
Reactant: CCn1nc(C)cc1N
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)C(=CNc1cc(C)nn1CC)C(=O)OCC

Procedure:
12.5 g of 1-ethyl-3-methyl-5-aminopyrazole (0.1 mol) and 21.6 g of ethoxymethylene malonic acid diethyl ester (0.1 mol) are heated to 120° (bath temperature) for 2 hours with stirring. The ethanol formed by this reaction is removed by means of a water aspirator. Vacuum distillation (b.p. 0.05 152°-153°) yields 24.0 g (81.5% of theory) of a quickly crystallizing oil, [[(1-ethyl-3-methyl-5-pyrazolyl)-amino]methylene]malonic acid diethyl ester, m.p. 60°-67°. The product, recrystallized from ligroin (90°-100°), melts at 69°-70°.
Reaction SMILES: N([O-])=O.[Na+].Cl.[CH2:6]([C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[CH3:22][CH:23](C(C)=O)[C:24]([O:26][CH2:27][CH3:28])=[O:25].[OH-].[K+].[Cl-].[NH4+]>O.CCO>[CH2:27]([O:26][C:24]([C:23]1[C:16]2[C:17](=[CH:19][CH:20]=[C:14]([CH2:6][CH2:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:15]=2)[NH:18][CH:22]=1)=[O:25])[CH3:28]
Reactant: Nc1ccc(CCc2ccccc2)cc1
Reactant: CCOC(=O)C(C)C(C)=O
Agent: Cl
Agent: O=N[O-]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c[nH]c2ccc(CCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Solid NaNO2 (0.35 g, 5 mmol) was added to a suspension of the p-phenethylaniline hydrochloride (1.1 g, 5 mmol) and concentrated HCl (2 ml) in H2O (3 ml) under an icewater bath. The solution was kept at -5° C. with stirring while ethyl 2-methylacetoacetate (0.72 g, 5 mmol)in EtOH 95% (5 ml) was treated at -10° C. with a solution of 50% KOH (1.7 ml) followed at once by ice (10 g). The diazo-solution was then added immediately, stirred at room temperature for 20 min, and extracted with Et2O (2×20 ml). The combined Et2O portions were dried (MgSO4) and the solvent was removed under reduced pressure to give a red oil which was taken up in anhydrous EtOH (10 ml), and dry hydrogen chloride gas was passed through the solution until ammonium chloride was precipitated. The mixture was heated at reflux for 20 min, and then stirred at room temperature for 2 h. The suspension was poured into ice water (100 ml) and extracted with Et2O (2×30 ml). The combined Et2O portions were dried (MgSO4) and the solvent was removed under reduced pressure to give a solid which was recrystallized from EtOH 95% to provide 3-ethyloxycarbonyl-5-(2-phenylethyl)indole.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[Br:10][C:11]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:12]=1[C:13](O)=[O:14].[CH3:21][NH:22][O:23][CH3:24].Cl.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.O>[Br:10][C:11]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:12]=1[C:13]([N:22]([O:23][CH3:24])[CH3:21])=[O:14]
Reactant: CNOC
Reactant: O=C(O)c1cc(Cl)ccc1Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1cc(Cl)ccc1Br
Reaction time: 3 h

Procedure:
N,N-diisopropylethylamine (1.10 mL, 6.36 mmol) was added to a stirred solution of 2-bromo-5-chlorobenzoic acid (0.500 g, 2.12 mmol), N,O-dimethylhydroxyl-amine.HCl (0.310 g, 3.18 mmol), and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluoro-phosphate (1.21 g, 3.18 mmol) in N,N-dimethylformamide (8.5 mL) at ambient temperature. After 3 h, the reaction mixture was poured into water and extracted three times with ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium bicarbonate, brine, dried (MgSO4) and concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel (gradient elution; 0-25% ethyl acetate/hexanes as eluent) gave the title compound as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][C@H:12]2[C@:16]([OH:18])([CH3:17])[CH:15]([OH:19])[O:14][C@@H:13]2[CH2:20][O:21][Si:22]([C:35]([CH3:38])([CH3:37])[CH3:36])([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CO[C:41](OC)([CH3:43])[CH3:42].CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][C@H:12]2[C@@:16]3([CH3:17])[O:18][C:41]([CH3:43])([CH3:42])[O:19][CH:15]3[O:14][C@@H:13]2[CH2:20][O:21][Si:22]([C:35]([CH3:38])([CH3:37])[CH3:36])([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: COC(C)(C)OC
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)OC(O)[C@]2(C)O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)O[C@@H]2[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)OC3OC(C)(C)O[C@@]32C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
To a mixture of compounds (2R,3R,4R)-2-((tert-butyldiphenylsilyloxy)methyl)-4,5-dihydroxy-4-methyl-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (from step 3) (58 g, 0.104 mol), 2,2-dimethoxy propane (25.7 mL, 0.209 mol) in 500 mL of anhydrous CH2Cl2 at 0° C., PTSA was added and stirred at room temperature for 2 h. The reaction mixture was poured into saturated NaHCO3 solution and organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. Purified by column chromatography using hexane and ethyl acetate as a gradient mixture to give 57.2 g of the title compound (92% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[BH4-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH2:7][OH:8]
Reactant: O=Cc1cc(Br)ccc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCc1cc(Br)ccc1F
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 97.7 %

Procedure:
To a solution of 5-bromo-2-fluoro-benzaldehyde (6.10 g, 30.0 mmol) in 30 mL of THF at 0° C. is added 5 mL of sodium borohydride (2.0M solution in triglyme, 10.0 mmol). The reaction mixture is stirred at 0° C. for 25 min and then quenched by the addition of 1N HCl. The mixture is diluted with EtOAc and the layers are separated. The organic layer is washed with H2O and saturated NaCl. The organic layer is dried over MgSO4, filtered and concentrated. The crude product is purified by column chromatography eluting with 15% EtOAc/hexanes to afford the title compound (6.00 g, 29.3 mmol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[NH:10][C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)=[C:12]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[N:20]=[CH:19][CH:18]=[CH:17]4)[N:13]=2)=[CH:4][C:3]=1[OH:31].Br[CH2:33][CH2:34][NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39].C([O-])([O-])=O.[K+].[K+]>CC(C)=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[NH:10][C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)=[C:12]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[N:20]=[CH:19][CH:18]=[CH:17]4)[N:13]=2)=[CH:4][C:3]=1[O:31][CH2:33][CH2:34][NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39]
Reactant: Cc1cccc(-c2[nH]c(Cc3ccc(F)c(O)c3)nc2-c2ccc3ncccc3c2)n1
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1cccc(-c2[nH]c(Cc3ccc(F)c(OCCNC(=O)OC(C)(C)C)c3)nc2-c2ccc3ncccc3c2)n1
Temperature: 60 °C
Reaction time: 20 h
Yield: 91.4 %

Procedure:
To a stirred solution of 2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenol (Example 81) (100 mg, 0.244 mmol) in acetone (5 mL) were added tert-butyl 2-bromoethylcarbamate (109 mg, 0.488 mmol) and K2CO3 (67 mg, 0.488 mmol) and the mixture was stirred at 60° C. for 20 hours. The reaction mixture was cooled to room temperature, diluted with H2O (20 mL), and extracted with CH2Cl2 (5 mL, 3 times). The organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by MPLC on NH silica gel (MeOH:CH2Cl2=1:50 (v/v)) to give tert-butyl 2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenoxy)ethylcarbamate (123.5 mg, 91%). This compound was dissolved in CH2Cl2 (5 mL), and p-anisole (224 uL, 2.23 mmol) and trifluoroacetic acid (1 mL) were added. The mixture was stirred for 1 hour, then concentrated, diluted with H2O (10 mL), and neutralized by addition of aqueous NH4OH solution to pH 7˜8. The aqueous solution was saturated with NH4Cl solid, extracted with CH2Cl2 (5 mL, 3 times), and then the organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by MPLC on NH silica gel (MeOH:CH2Cl2=3:100 (v/v)) to afford the title compound (70.2 mg, 69%). 1H NMR (300 MHz, CDCl3) δ 2.50 (3H, s), 3.09 (2H, t), 4.04 (2H, t), 4.16 (2H, s), 6.85-6.90 (1H, m), 6.95-7.07 (3H, m), 7.24 (1H, s), 7.36 (1H, d), 7.41 (1H, dd), 7.97 (1H, dd), 8.09-8.18 (3H, m), 8.92 (1H, dd), 10.40 (1H, bs). MS (ESI) m/z 454 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]([N:15]3[CH2:20][CH2:19][CH2:18][CH:17]([OH:21])[CH2:16]3)=[O:14])[N:12]=2)=[C:4]([NH:22][CH:23]([CH3:25])[CH3:24])[CH:3]=1.[S:26]1[C:30]2[CH:31]=[C:32]([NH2:35])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1.C([O-])([O-])=O.[Na+].[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[S:26]1[C:30]2[CH:31]=[C:32]([NH:35][C:2]3[N:7]=[CH:6][C:5]([C:8]4[S:9][CH:10]=[C:11]([C:13]([N:15]5[CH2:20][CH2:19][CH2:18][CH:17]([OH:21])[CH2:16]5)=[O:14])[N:12]=4)=[C:4]([NH:22][CH:23]([CH3:25])[CH3:24])[CH:3]=3)[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1
Reactant: CC(C)Nc1cc(Cl)ncc1-c1nc(C(=O)N2CCCC(O)C2)cs1
Reactant: Nc1ccc2ncsc2c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)Nc1cc(Nc2ccc3ncsc3c2)ncc1-c1nc(C(=O)N2CCCC(O)C2)cs1
Temperature: 115 °C

Procedure:
(2-(6-chloro-4-(isopropylamino)pyridin-3-yl)thiazol-4-yl)(3-hydroxypiperidin-1-yl)methanone (24a) (100 mg, 0.263 mmol) was dissolved in 1,4-Dioxane (10 mL): H2O (2 mL), to it benzo[d]thiazol-6-amine (0.263 mmol), Na2CO3 (1.05 mmol) and xanthphos (0.105 mmol) were added and degassed for 10 min. Pd2(dba)3 (0.105 mmol) was added and degassed once again for 15 min and heated at 115° C., overnight. The reaction mass was filtered through celite and concentrated to remove solvent. The crude material obtained was purified by column chromatography through silica gel and MeOH: CHCl3 as eluent. The material obtained was further purified by prep. HPLC to obtain the title compound, (2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)thiazol-4-yl)(3-hydroxypiperidin-1-yl)methanone. 1H NMR: 400 MHz, CD3OD: δ 0.87-0.94 (m, 1H), 1.31-1.36 (m, 6H), 1.62-0.00 (m, 2H), 1.92-2.03 (m, 2H), 3.42-3.43 (m, 1H), 3.75-3.98 (m, 4H), 6.16 (s, 1H), 7.54 (dd, J=2.00, 8.80 Hz, 1H), 7.79 (bs, 1H), 7.91 (s, 1H), 7.97 (d, J=8.80 Hz, 1H), 8.43 (d, J=2.40 Hz, 1H), 8.45 (s, 1H), 9.07 (s, 1H). LC/MS: Ascentis Express C18, 5×2.1 mm-2.7 μm; Solvent A=2% ACN: 98% H2O: 10 mM NH4COOH; Solvent B=98% ACN: 2% H2O: 10 mM NH4COOH; gradient 0-100% B over 3 min; retention time: 1.754 min; LCMS (ES-API), m/z 495.2 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H2O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H2O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min run time); Flow rate: 1.0 μL/min; Retention time: 5.431 min; Purity: 96.29%.