Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[O:7][C:8]1[CH:9]=[C:10]([CH2:14]O)[CH:11]=[CH:12][CH:13]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:28]=[N+:29]=[N-:30].[Na+]>ClCCl.O>[N:28]([CH2:14][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[O:7][C:2]1[N:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[N+:29]=[N-:30]
Reactant: OCc1cccc(Oc2ncccn2)c1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: [N-]=[N+]=NCc1cccc(Oc2ncccn2)c1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 86.1 %

Procedure:
To a mixture of 3-(pyrimidin-2-yloxy)-phenyl-methanol (500 mg, 2.47 mmol) and triethylamine (625 μL, 4.5 mmol) in dichloromethane (40 mL) was added MsCl (2.33 uL, 3.0 mmol) at 0° C. The reaction was kept at 0° C. for 15 min. Removal of the solvent, the residue was dissolved in N,N-dimethylformamide (30 mL) and then treated with sodium azide (803 mg, 12.4 mmol). The reaction mixture was heated at 80° C. for 4 hr. The reaction mixture was poured into water, and extracted with ethyl acetate (2×). The solvent was removed, and the resulting residue was chromatographered using hexane/ethyl acetate (2:1) to give the title compound (483 mg, 86%). MS (DCI/NH3) m/z 228 (M+1)+. 1H NMR (500 MHz, DMSO-d6) δ ppm 4.49 (s, 2H) 7.19 (dd, J=8.11, 2.18 Hz, 1H) 7.21 (t, J=1.87 Hz, 1H) 7.26 (d, J=7.18 Hz, 1H) 7.27 (t, J=4.68 Hz, 1H) 7.47 (t, J=7.80 Hz, 1H) 8.64 (s, 1H) 8.65 (s, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Li]CCCC.[O:11]1[C:15]2([CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]2)[O:14][CH2:13][CH2:12]1>C1COCC1>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:18]1([OH:21])[CH2:19][CH2:20][C:15]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:16][CH2:17]1
Reactant: c1cscn1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2nccs2)CCC2(CC1)OCCO2
Temperature: -10 °C
Reaction time: 0.67 h
Yield: 85.5 %

Procedure:
Thiazole (25.0 mL, 352 mmol) was diluted with THF (300 mL) and cooled to −78° C. n-BuLi (220 mL, 352 mmol) was added at such a rate that the internal temperature did not exceed −65 C. A yellow slurry formed and the addition took 40 min. The reaction was aged for 20 min then 1,4-dioxaspiro[4.5]decan-8-one (50 g, 320 mmol) was added as a solution in THF (420 mL) dropwise via addition funnel. After 2 h, the reaction was quenched with water, the cooling bath removed and the mixture stirred until the internal temperature reached 0° C. The mixture was diluted with EtOAc and the layers were separated followed by extraction of the aqueous portion with EtOAc. The combined organics were dried with MgSO4, filtered, and concentrated to a viscous orange oil. EtOAc was added and concentrated to 100 mL. Hexanes was added dropwise via an addition funnel. The mixture was stirred for 1 h then cooled to −10° C. and filtered. The white cake was washed with hexanes (2×) then dried under a nitrogen bag to afford 8-(1,3-thiazol-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol (66 g, 85%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[CH:5]=[CH:6][C:7]=1Cl.[O:12]1[CH2:17][CH2:16][N:15]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[N:21]1[CH2:22][CH2:23][CH:18]([N:15]2[CH2:16][CH2:17][O:12][CH2:13][CH2:14]2)[CH2:19][CH2:20]1)[NH2:9]
Reactant: O=[N+]([O-])c1ccc(Cl)c(Br)c1
Reactant: C1CC(N2CCOCC2)CCN1
Product: Nc1ccc(N2CCC(N3CCOCC3)CC2)c(Br)c1

Procedure:
By the reaction and treatment in the same manner as in Starting Material Synthesis Example 40 using 3-bromo-4-chloronitrobenzene and 4-morpholinopiperidine, the title compound was obtained, melting point: 215–217° C.
Reaction SMILES: [C:1]1([CH:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:18]3[C:19]([OH:29])=[CH:20][C:21]4[O:25][C:24](=[O:26])[N:23]([CH3:27])[C:22]=4[CH:28]=3)(O)[C:9]2=[O:30])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N1C2C(=CC=CC=2)C(C2C(O)=CC3N(C)C(=O)COC=3C=2)(O)C1=O)(C1C=CC=CC=1)C1C=CC=CC=1>>[C:31]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:18]3[C:19]([OH:29])=[CH:20][C:21]4[O:25][C:24](=[O:26])[N:23]([CH3:27])[C:22]=4[CH:28]=3)[C:9]2=[O:30])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: Cn1c(=O)oc2cc(O)c(C3(O)C(=O)N(C(c4ccccc4)c4ccccc4)c4ccccc43)cc21
Agent: CN1C(=O)COc2cc(C3(O)C(=O)N(C(c4ccccc4)c4ccccc4)c4ccccc43)c(O)cc21
Product: Cn1c(=O)oc2cc(O)c(C3C(=O)N(C(c4ccccc4)c4ccccc4)c4ccccc43)cc21

Procedure:
Following the procedure as described in PREPARATION 17B, and making non-critical variations using 5-[1-(diphenylmethyl)-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl]-6-hydroxy-3-methyl-1,3-benzoxazol-2(3H)-one to replace 7-(1-benzhydryl-3-hydroxy-2-oxoindolin-3-yl)-6-hydroxy-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one, 5-[1-(diphenylmethyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-6-hydroxy-3-methyl-1,3-benzoxazol-2(3H)-one was obtained (73%) as a pale pink solid: MS (ES+) m/z 463.4 (M+1).
Reaction SMILES: [CH3:1]/[CH:2]=[C:3]1\[C@H:4]2[CH:11]=[C:10]([CH3:12])[CH2:9][C@@:8]\1([NH2:13])[C:7]1[CH:14]=[CH:15][C:16]([NH:18][C:6]=1[CH2:5]2)=[O:17].C(N(CC)CC)C.[C:26](Cl)(=[O:30])[O:27][CH2:28][CH3:29]>C1COCC1>[CH2:28]([O:27][C:26]([NH:13][C@@:8]12[C:7]3[CH:14]=[CH:15][C:16](=[O:17])[NH:18][C:6]=3[CH2:5][C@@H:4](/[C:3]/1=[CH:2]\[CH3:1])[CH:11]=[C:10]([CH3:12])[CH2:9]2)=[O:30])[CH3:29]
Reactant: CCOC(=O)Cl
Reactant: C/C=C1\[C@H]2C=C(C)C[C@@]1(N)c1ccc(=O)[nH]c1C2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C/C=C1\[C@H]2C=C(C)C[C@]1(NC(=O)OCC)c1ccc(=O)[nH]c1C2
Temperature: 0 °C
Yield: 61.7 %

Procedure:
Dissolved 10 mg huperzine A and 10 mg triethylamine in 5 mL dry THF; cooled the solution down to 0° C.; added ethyl chlorocarbonate (6 mg) and stirred the resultant reaction mixture for 4 hours; filtered to remove solid residues; after concentrating the filtrate, purified on prep TLC (chloroform:methanol=9:1) to yield 8 mg of pure title compound. MS: 315 (M+1).
Reaction SMILES: C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.Br[C:15]1[CH:16]=[CH:17][C:18]2[N:23]([CH:24]3[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25]3)[CH2:22][CH2:21][S:20][C:19]=2[CH:36]=1.CCCC[N+:41](CCCC)(CCCC)CCCC.[F-]>C1COCC1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.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]>[NH2:41][C:15]1[CH:16]=[CH:17][C:18]2[N:23]([CH:24]3[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25]3)[CH2:22][CH2:21][S:20][C:19]=2[CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCSc3cc(Br)ccc32)C1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
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: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(N2CCSc3cc(N)ccc32)C1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 83 %

Procedure:
Tris(dibenzylideneacetone)dipalladium(0) (0.056 g, 0.062 mmol) in THF (3 mL) was treated with tri-tert-butylphosphine 10% wt in hexanes (0.748 mL, 0.247 mmol) and was stirred vigorously under argon atmosphere for 10 minutes. tert-Butyl 3-(7-bromo-2H-benzo[b][1,4]thiazin-4(3H)-yl)pyrrolidine-1-carboxylate (0.49 g, 1.233 mmol) in THF (9 mL) and 1M LiHMDS in THF (3.70 mL, 3.70 mmol) were added to the mixture. The reaction was sealed, placed in a preheated oil bath, and refluxed at 100° C. The solution was cooled to room temperature, treated with 1M TBAF in THF (8 mL), and was stirred for 40 minutes. The mixture was concentrated and treated with 1N NaOH (50 mL). The mixture was transferred to a separatory funnel, diluted with water (50 mL), and extracted with EtOAc (2×50 mL). The organic phase was washed with brine (50 mL) and dried (Na2SO4). The crude material was subject to flash chromatography on silica gel (25-70% EtOAc/hexanes). The collected fractions were concentrated to give a clear brown oil (0.34 g, 83%). 1H NMR (CDCl3) δ 6.64 (d, J=8.7 Hz, 1H), 6.48 (s, 1H), 6.39 (brs, 1H), 4.08-4.02 (m, 1H), 3.70-3.07 (m, 6H), 3.09-3.07 (m, 2H), 2.08-1.92 (m, 2H), 1.46 (s, 9H); ESI-MS (m/z, %): 338, 336 (MH+, 40), 282, 280 (100).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:20][C:21]1[CH2:26][CH2:25][CH2:24][C:23](=[O:27])[CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH2:28]1[O:38][C:31]2([CH2:36][CH2:35][C:34](=[O:37])[CH2:33][CH2:32]2)[O:30][CH2:29]1.[Cl-].[NH4+]>O1CCCC1.ClCCl>[CH2:13]([O:20][C:21]1[CH2:26][CH2:25][CH:24]([C:34]2([OH:37])[CH2:35][CH2:36][C:31]3([O:38][CH2:28][CH2:29][O:30]3)[CH2:32][CH2:33]2)[C:23](=[O:27])[CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1C=C(OCc2ccccc2)CCC1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C1C=C(OCc2ccccc2)CCC1C1(O)CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 0.58 h
Yield: 88.2 %

Procedure:
To a flask equipped with magnetic stirrer was added tetrahydrofuran (600 ml) and diisopropylamine (38.1 ml, 272 mmol). The stirred solution was cooled to −78° C. and n-butyl lithium (113.4 ml, 272 mmol, 2.4 M in hexanes) was added dropwise via syringe. The resulting yellow solution was stirred for 35 min at −78° C., then 3-(benzyloxy)-2-cyclohexen-1-one (50.0 g, 248 mmol) was added as a solution in tetrahydrofuran (100 ml). The solution was stirred for 1 hr prior to the addition of cyclohexane-1,4-dione monoethylene ketal (38.7 g, 248 mmol) as a solution in anhydrous tetrahydrofuran (100 ml). The solution was stirred for 2 hr at −78° C., then allowed to warm slowly to room temperature over 1 hr. Saturated aqueous ammonium chloride (80 ml) was added, followed by dichloromethane (700 ml) and the mixture stirred until no solids remained. The layers were separated and the aqueous phase extracted with dichloromethane (2×100 ml). The combined organic layers were washed with brine (50 ml), dried over magnesium sulfate, then concentrated in vacuo. Trituration of the resulting solid with methanol afforded the title compound (78.4 g, 88%). m/z (ES+) 359 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][C:14]=1[Cl:15])[N:11](S(C1C=CC(C)=CC=1)(=O)=O)[C:10]1[C:9]([C:31]([F:34])([F:33])[F:32])([O:26][Si](C)(C)C)[C:8]([F:36])([F:35])[CH2:7][CH2:6][C:5]2=1.[OH-].[K+].CCO>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][C:14]=1[Cl:15])[NH:11][C:10]1[C:9]([C:31]([F:32])([F:33])[F:34])([OH:26])[C:8]([F:35])([F:36])[CH2:7][CH2:6][C:5]2=1
Reactant: Cc1ccc(S(=O)(=O)n2c3c(c4cc(Cl)c(Cl)cc42)CCC(F)(F)C3(O[Si](C)(C)C)C(F)(F)F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: OC1(C(F)(F)F)c2[nH]c3cc(Cl)c(Cl)cc3c2CCC1(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 34.7 %

Procedure:
To a solution of 6,7-dichloro-2,2-difluoro-9-tosyl-1-(trifluoromethyl)-1-(trimethylsilyloxy)-2,3,4,9-tetrahydro-1H-carbazole (0.090 g, 0.2 mmol) in THF (5 mL), cooled to 0° C., KOH (0.064 g, 1.0 mmol) in H2O (2 mL), was added and the reaction mixture was slowly cooled to room temperature and stirred for an additional 30 min EtOH (2 mL) was added to the reaction mixture and stirred at 80° C. for 4 h, diluted with water (20 mL) and extracted with EtOAc (3×30 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to give the crude compound which was purified by column chromatography [EtOAc-hexane (3:17) as eluant] to give the title compound (0.025 g, 31%). 1H NMR (500 MHz, CDCl3, in ppm) 8.26 (bs, 1H), 7.63 (s, 1H), 7.52 (s, 1H), 3.31 (d, J=3.5 Hz, 1H), 2.97-2.94 (m, 2H), 2.61-2.52 (m, 2H).
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[S:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[CH:14]=2)[CH2:11][N:10]([CH:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH3:23])[CH2:9]1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[S:17]1[C:13]([CH:12]2[CH2:11][N:10]([CH:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH3:23])[CH2:9][CH:8]2[C:6]([OH:7])=[O:5])=[CH:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]1=2
Reactant: CC(c1ccccc1)N1CC(C(=O)OC(C)(C)C)C(c2cc3ccccc3s2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(c1ccccc1)N1CC(C(=O)O)C(c2cc3ccccc3s2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product from step b) (2.0 g, 0.0077 mol) was dissolved in 20 mL dichloromethane and was treated with 10 mL of TFA and stirred for 2 hours at room temperature. The solvent was evaporated in vacuo to give the crude subtitle compound that was used in the next step without further purification. MS calculated for C21H21NO2S +H: 352, observed: 352.
Reaction SMILES: O.[C:2]1([CH2:8][C:9](=O)[C:10]([O-:12])=[O:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].Cl.[Cl:16][C:17]1[CH:18]=[C:19]([NH:24][NH2:25])[CH:20]=[CH:21][C:22]=1[Cl:23].C(O)C>O>[Cl:16][C:17]1[CH:18]=[C:19]([NH:24][N:25]=[C:9]([CH2:8][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:10]([OH:12])=[O:11])[CH:20]=[CH:21][C:22]=1[Cl:23]
Reactant: NNc1ccc(Cl)c(Cl)c1
Reactant: O=C([O-])C(=O)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(O)C(Cc1ccccc1)=NNc1ccc(Cl)c(Cl)c1

Procedure:
Add 21.0 g of sodium β-phenylpyruvate monohydrate and 21.3 g of 3,4-dichlorophenylhydrazine hydrochloride to 300 ml of ethanol and reflux the resulting mixture for 30 minutes. Cool, add water, collect and dry the solid to yield phenylpyruvic acid 3,4-dichlorophenylhydrazone, m.p. 166°-167°.
Reaction SMILES: [CH2:1]([C:3]1[C:4](F)=[C:5]([N+:17]([O-:19])=[O:18])[CH:6]=[C:7]([F:16])[C:8]=1[N:9]1[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]1)[CH3:2].[F-].[K+].[CH:23]1([NH2:26])[CH2:25][CH2:24]1>C(OCC)(=O)C>[CH:23]1([NH:26][C:4]2[C:5]([N+:17]([O-:19])=[O:18])=[CH:6][C:7]([F:16])=[C:8]([N:9]3[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]3)[C:3]=2[CH2:1][CH3:2])[CH2:25][CH2:24]1
Reactant: NC1CC1
Reactant: CCc1c(F)c([N+](=O)[O-])cc(F)c1N1CCN(C)CC1
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCc1c(NC2CC2)c([N+](=O)[O-])cc(F)c1N1CCN(C)CC1
Reaction time: 1.5 h

Procedure:
To 3-ethyl-2,5-difluoro-4-(4-methyl-1-piperazinyl)nitrobenzene (1.12 g) are added potassium fluoride (0.24 g), N,N-dimethylsulfoxide (3.5 ml) and cyclopropylamine (0.4 ml), and the mixture is stirred at 80° to 85° C. for 1.5 hour. The reaction mixture is diluted with ethyl acetate, and the organic layer is washed with water and aqueous saturated sodium chloride and dried over magnesium sulfate and then concentrated under reduced pressure to give N-cyclopropyl-2-ethyl-3-(4-methyl-1-piperazinyl)-4-fluoro-6-nitroaniline (1.00 g), as viscous oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[H-].[Na+].[CH3:14][O:15][CH2:16]Cl.O>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([O:11][CH2:14][O:15][CH3:16])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COCOc1ccc([N+](=O)[O-])c(F)c1
Reaction time: 0.5 h
Yield: 64 %

Procedure:
To a solution of 3-fluoro-4-nitrophenol (120 g) in N,N-dimethylformamide (500 mL) was added sodium hydride (oily, 60%) (22 g) under ice-cooling, and the mixture was stirred for 30 min. To the reaction solution was added chloromethyl methyl ether (64 mL) and the mixture was stirred for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was subjected to basic column chromatography (ethyl acetate) to give the title compound (98 g, yield 64%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[C:3]([C:18]([O:21]COC)([CH3:20])[CH3:19])=[C:4]([B:9]2[O:13]C(C)(C)C(C)(C)O2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.Cl>>[F:1][C:2]1[C:3]2[C:18]([CH3:19])([CH3:20])[O:21][B:9]([OH:13])[C:4]=2[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: COCOC(C)(C)c1c(F)cc(C)cc1B1OC(C)(C)C(C)(C)O1
Agent: Cl
Product: Cc1cc(F)c2c(c1)B(O)OC2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.5 %

Procedure:
The crude 2-(3-fluoro-2-(2-(methoxymethoxy)propan-2-yl)-5-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was mixed with 25 ml of 6N HCl and the reaction mixture was stirred at rt overnight. The reaction was monitored by LC-MS. The reaction solution was extracted with EtOAc, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE-EA (5:1 to 2:1) to give 4-fluoro-3,3,6-trimethylbenzo[c][1,2]oxaborol-1(3H)-ol (3.5 g, 52.5% yield) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.17 (s, 1H), 7.30 (s, 1H), 7.08 (d, J=11.2 Hz, 1H), 2.34 (s, 3H), 1.49 (s, 6H) ppm.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:10]=[C:9]([CH2:11][NH2:12])[N:8]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=2)[N:7]=1)([CH3:5])([CH3:4])[CH3:3].[F:24][C:25]1[CH:26]=[C:27]([CH:36]([CH3:40])[C:37](O)=[O:38])[CH:28]=[CH:29][C:30]=1[CH2:31][O:32][CH2:33][CH2:34][OH:35].C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1.CN(C=O)C>[C:2]([C:6]1[CH:10]=[C:9]([CH2:11][NH:12][C:37](=[O:38])[CH:36]([C:27]2[CH:28]=[CH:29][C:30]([CH2:31][O:32][CH2:33][CH2:34][OH:35])=[C:25]([F:24])[CH:26]=2)[CH3:40])[N:8]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:22])([F:23])[F:21])[CH:14]=2)[N:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C(=O)O)c1ccc(COCCO)c(F)c1
Reactant: CC(C)(C)c1cc(CN)n(-c2cccc(OC(F)(F)F)c2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C(=O)NCc1cc(C(C)(C)C)nn1-c1cccc(OC(F)(F)F)c1)c1ccc(COCCO)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.8 %

Procedure:
To a stirred solution of (3-tert-butyl-1-(3-(trifluoromethoxy)phenyl)-1H-pyrazol-5-yl)methanamine hydrochloride (119 mg, 0.351 mmol, 1 eq) in THF/DMF (1/20, v/v, 3 mL) was added 2-(3-fluoro-4-((2-hydroxyethoxy)methyl)phenyl)propanoic acid (84 mg, 0.35 mmol, 1 equiv.), HOBt (49 mg. 0.35 mmol, 1 equiv.), TBTU (112 mg, 0.351 mmo, 1 equiv.) and DIPEA (0.234 mL, 178 mg, 1.40 mmol, 4 equiv.) and the mixture was stirred for at room temperature overnight. The reaction mixture was evaporated and the residue was purified by column chromatography (EtOAc/cyclohexane (1:2) as eluent) to give N-((3-tert-butyl-1-(3-(trifluoromethoxy)phenyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-((2-hydroxyethoxy)methyl)phenyl)propanamide (137 mg, 73%).
Reaction SMILES: [F:1][CH:2]([F:37])[O:3][CH2:4][C@H:5]([NH:27][C:28](=[O:36])[CH2:29][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)[C:6]([NH:8][C@@H:9]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:10]([O:12]CC1C=CC=CC=1)=[O:11])=[O:7]>C1COCC1.[Pd]>[F:37][CH:2]([F:1])[O:3][CH2:4][C@H:5]([NH:27][C:28](=[O:36])[CH2:29][N:30]1[CH2:31][CH2:32][O:33][CH2:34][CH2:35]1)[C:6]([NH:8][C@@H:9]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:10]([OH:12])=[O:11])=[O:7]
Reactant: O=C(CN1CCOCC1)N[C@@H](COC(F)F)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C(CN1CCOCC1)N[C@@H](COC(F)F)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 1 h

Procedure:
A stirred solution of benzyl (2S)-2-[[(2S)-3-(difluoromethoxy)-2-[(2-morpholinoacetyl)amino]propanoyl]amino]-3-phenyl-propanoate (1.54 g, 2.96 mmol) in THF (10 mL) was treated with palladium (10 wt. % on activated carbon) (157 mg, 0.148 mmol) and stirred under an atmosphere of hydrogen, balloon pressure, for 1 h. The mixture was then filtered through a pad of Celite™ and concentrated in vacuo giving the compound of Formula XVIII(a) (1.27 g, quantitative yield) as colourless foam. 1H NMR (CDCl3, 400 MHz): δ (ppm) 8.09 (m, 1H), 7.24-7.05 (m, 5H), 6.10 (t, J=74 Hz, 1H), 5.6 (brs, 1H), 4.70-4.60 (m, 2H), 4.15-4.01 (m, 1H), 3.95-3.85 (m, 1H), 3.70-3.55 (m, 4H), 3.25-2.90 (m, 4H), 2.65-2.50 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:13])=[CH:4][C:3]=1[O:14][CH3:15].Cl[C:17]([O:19][CH3:20])=[O:18].C(N(CC)CC)C>O1CCCC1>[CH3:20][O:19][C:17]([O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:13])=[CH:4][C:3]=1[O:14][CH3:15])=[O:18]
Reactant: COC(=O)Cl
Reactant: COc1cc(OC)c2ccccc2c1O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)Oc1c(OC)cc(OC)c2ccccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1.27 g of 1-hydroxy-2,4-dimethoxynaphthalene, prepared as shown in Preparations 7 and 8, in 50 ml of tetrahydrofuran was added 0.694 g of methyl chloroformate followed by 0.743 g of triethylamine. The mixture was stirred at room temperature for 16 hours, filtered, then the solvent removed under reduced pressure. The residue was dissolved in diethyl ether, washed with dilute hydrochloric acid and dried over anhydrous sodium sulfate. The ether was removed under reduced pressure and the residue chromatographed on silica gel, eluting with a 1:1 mixture of methylene chloride and hexane, to give 1-methoxycarbonyloxy-2,4-dimethoxynaphthalene, m.p. 128°-129° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:26][CH2:27]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:25])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:34]1([C:40]2([C:46]([NH2:48])=[O:47])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:26][CH2:27][N:43]3[CH2:42][CH2:41][C:40]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)([C:46]([NH2:48])=[O:47])[CH2:45][CH2:44]3)[CH2:13][CH2:12][N:11]([C:14](=[O:25])[C:15]3[CH:16]=[C:17]([O:23][CH3:24])[CH:18]=[C:19]([O:21][CH3:22])[CH:20]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Reactant: COc1cc(OC)cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)c1
Agent: Cl
Product: COc1cc(OC)cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)c1

Procedure:
The method of example 3.3 was used with 2-[3-(3,4-dichloro-phenyl)-1-(3,5-dimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (0.96 mmol) and 4-phenylpiperidine-4-carboxylic acid amide hydrochloride (1.06 mmol) to prepare the title compound. Chromatography on silica gel eluting sequentially with ethyl acetate, 6% methanol in dichloromethane, and then 10% methanol in dichloromethane gave the title compound: Rf =0.55 (silica gel, 10% methanol in dichloromethane).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:10](=[O:22])[CH2:11][CH2:12][N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:7]=[CH:8][CH:9]=1.[CH3:23]I>C1COCC1>[Cl:3][C:4]1[CH:5]=[C:6]([C:10](=[O:22])[CH:11]([CH3:23])[CH2:12][N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])[CH:7]=[CH:8][CH:9]=1
Reactant: CN(CCC(=O)c1cccc(Cl)c1)C(=O)OC(C)(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(CN(C)C(=O)OC(C)(C)C)C(=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.5 %

Procedure:
To NaH (680 mg, 1.7 mmol) in THF (10 mL) was added tert-butyl 3-(3-chlorophenyl)-3-oxopropyl(methyl)carbamate (2.4 g, 8.5 mmol) in THF (5 mL) at 0° C. over 3 min. After a few minutes THF (100 mL) was added. And an additional 10 min, CH3I (1.32 g, 9.3 mmol) was added drop wise. The mixture was stirred for 16 h at room temperature. Then the mixture was quenched with NH4Cl and 1N HCl was added until pH=4 was reached. The mixture was extracted with ethyl acetate. The organic layers was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by chromatography to give the product (2.0 g, 79%).