Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C@@H:11]([CH3:14])[C@@H:10]([N:15]([CH3:25])[C:16]2[C:17]3[CH:24]=[CH:23][NH:22][C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:9]1)C1C=CC=CC=1.Cl>C(O)C>[CH3:25][N:15]([C@@H:10]1[C@H:11]([CH3:14])[CH2:12][CH2:13][NH:8][CH2:9]1)[C:16]1[C:17]2[CH:24]=[CH:23][NH:22][C:18]=2[N:19]=[CH:20][N:21]=1
Reactant: C[C@@H]1CCN(Cc2ccccc2)C[C@@H]1N(C)c1ncnc2[nH]ccc12
Agent: Cl
Solvent: CCO
Product: C[C@@H]1CCNC[C@@H]1N(C)c1ncnc2[nH]ccc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 89.3 %

Procedure:
To the product from Method A (0.7 grams, 2.19 mmol) dissolved in 15 mL of ethanol was added 1.5 mL of 2 N hydrochloric acid and the reaction mixture degassed by nitrogen purge. To the reaction mixture was then added 0.5 grams of 20% palladium hydroxide on carbon (50% water) (Aldrich) and the resulting mixture shaken (Parr-Shaker) under a 50 psi atmosphere of hydrogen at room temperature for 2 days. The Celite filtered reaction mixture was concentrated to dryness in vacuo and the residue purified by flash chromatography (silica; 5% methanol in dichoromethane) affording 0.48 grams (90%) of the title compound. LRMS: 246.1 (M+1).
Reaction SMILES: Cl.[NH:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)[C:3]([NH2:5])=[NH:4].[C:15]([O:19][C:20](=[O:41])[CH2:21][C@@:22]1([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[O:26][N:25]=[C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=2)[CH2:23]1)([CH3:18])([CH3:17])[CH3:16].N1C=CC=CC=1.CC(N(C)C)=O>O>[C:15]([O:19][C:20](=[O:41])[CH2:21][C@@:22]1([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[O:26][N:25]=[C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][C:10](=[O:11])[C:9]3[CH:8]=[CH:7][C:6]([NH:2][C:3]([NH2:5])=[NH:4])=[CH:14][CH:13]=3)[CH:28]=2)[CH2:23]1)([CH3:17])([CH3:18])[CH3:16]
Reactant: N=C(N)Nc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)C[C@]1(C(=O)OC(C)(C)C)CC(c2cccc(O)c2)=NO1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)C[C@]1(C(=O)OC(C)(C)C)CC(c2cccc(OC(=O)c3ccc(NC(=N)N)cc3)c2)=NO1
Reaction time: 3 h
Yield: 56.4 %

Procedure:
4-Carbamimidamidobenzoyl chloride hydrochloride (2.158 g) was added to a mixture of tert-butyl (5S)-5-(2-tert-butoxy-2-oxoethyl)-3-(3-hydroxyphenyl)-4,5-dihydro-1,2-oxazole-5-carboxylate (1.74 g), pyridine (2.2 mL), and DMA (2.2 mL) at 50 C, and the obtained mixture was stirred at 50 C for 3 hours. Further, 4-carbamimidamidobenzoyl chloride hydrochloride (2.158 g), DMA (1.1 mL), and pyridine (1.1 mL) were added thereto, and the obtained mixture was stirred at 50 C for 2 hours. To the reaction mixture, water was added, followed by extraction with ethyl acetate and ethyl acetate/THF (1/1). The extract was washed with brine and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate, subsequently acetonitrile/acetic acid), and then, the obtained fraction was concentrated under reduced pressure. The residue was added to a saturated aqueous solution of sodium bicarbonate, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (1.40 g).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C[O:12][C:13]([C:15]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([Cl:24])[CH:22]=2)[N:17]([S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])[C:16]=1[CH2:34][N:35]([CH2:46][C:47]#[N:48])S(C1C=CC(C)=CC=1)(=O)=O)=O>C1COCC1>[C:28]1([S:25]([N:17]2[C:16]3[CH:34]=[N:35][C:46]([C:47]#[N:48])=[C:13]([OH:12])[C:15]=3[C:23]3[CH:22]=[C:21]([Cl:24])[CH:20]=[N:19][C:18]2=3)(=[O:27])=[O:26])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COC(=O)c1c(CN(CC#N)S(=O)(=O)c2ccc(C)cc2)n(S(=O)(=O)c2ccccc2)c2ncc(Cl)cc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ncc2c(c1O)c1cc(Cl)cnc1n2S(=O)(=O)c1ccccc1
Temperature: -10 °C
Yield: 27.7 %

Procedure:
Lithium bis(trimethylsilyl)amide (220 mL of a 1N solution in THF, 220 mmol) was added dropwise to a cooled (−78° C.) suspension of 1-benzenesulfonyl-5-chloro-2-{[cyanomethyl-(toluene-4-sulfonyl)amino]methyl}-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid methyl ester (39.6 g, 69.1 mmol) in dry THF (350 mL). The reaction mixture was allowed to slowly warm to −10° C. then slowly quenched into cold 1M hydrochloric acid. The layers were separated and the aqueous layer further extracted with THF. The combined organic layer was washed with brine, dried (Na2SO4), filtered and evaporated. The resultant residue was triturated with methanol then acetone and air dried to afford the title compound as a tan solid (7.37 g, 27%). LCMS (Method B): RT=5.11 min, M+H+=385/387. 1H NMR (400 MHz, DMSO-d6): 9.23 (s, 1H), 8.76 (d, J=2.4 Hz, 1H), 8.69 (d, J=2.4 Hz, 1H), 8.19-8.19 (m, 2H), 7.75-7.75 (m, 1H), 7.62-7.61 (m, 2H).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[CH2:14][CH2:15][OH:16].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH2:14][CH2:15][OH:16])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: OCCCl
Reactant: Oc1ccc(-n2ccnc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: OCCOc1ccc(-n2ccnc2)cc1
Yield: 49.9 %

Procedure:
A stirred mixture of 8.0 g (0.050 mole) of 4(1H-imidazol-1-yl)phenol, 13.5 ml (0.20 mole) of 2-chloroethanol and 28 g (0.2 mole) of potassium carbonate in 200 ml of methyl ethyl ketone was heated at reflux, filtered, and concentrated to obtain 5.1 g of 2-[4-(1H-imidazol-1-yl)phenoxy]ethanol (50%). This alcohol (0.25 mole) and 5.2 g (0.030 mole) of sulfamic acid phenyl ester (Example 33) in 100 ml of dioxane was heated at reflux for 20 minutes, concentrated and the residual solid triturated in acetone. The triturant was acidified with an anhydrous solution of hydrogen chloride in isopropyl alcohol and the solid hydrochloride collected by filtration. The product was recrystallized from isopropyl alcohol-isopropyl ether to yield 4.26 g of solid, monohydrochloride, mp 156°-157° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[C:5]2=[N:6][CH:7]=1.[CH3:21][Mg]Br.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:21][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[C:5]2=[N:6][CH:7]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Br)cnc21
Reactant: C[Mg]Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: Cc1ccccc1
Product: Cc1cnc2c(ccn2[Si](C(C)C)(C(C)C)C(C)C)c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To PdCl2(dppf) (0.04 g, 0.05 mmol) in toluene (10.0 mL) under an atmosphere of nitrogen were added 5-bromo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (2, 0.3 g, 0.8 mmol, prepared as described in Example 4, 1.0 mL in toluene) and methylmagnesium bromide (1.0 M in tetrahydrofuran, 3.0 mL, 3.0 mmol). The reaction was stirred 90° C. for 2 hours and then allowed to reach to room temperature. The reaction was poured into citric acid (0.1 M in water) and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 50% ethyl acetate in hexane to give the compound (12, 0.16 g 60.0%). MS (ESI) [M+H+]+=289.4.
Reaction SMILES: [Si]([O:8][C@H:9]([C:47]1[CH:48]=[CH:49][C:50]([OH:58])=[C:51]([NH:53][S:54]([CH3:57])(=[O:56])=[O:55])[CH:52]=1)[CH2:10][NH:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([C@@H:31]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:32][CH2:33][N:34]([CH:38]([CH3:40])[CH3:39])[CH:35]([CH3:37])[CH3:36])[CH:25]=2)=[CH:16][CH:15]=1)(C(C)(C)C)(C)C.CCN(CC)CC.F.F.F>O1CCCC1.CO>[CH:38]([N:34]([CH:35]([CH3:37])[CH3:36])[CH2:33][CH2:32][C@@H:31]([C:26]1[CH:25]=[C:24]([CH2:23][CH2:22][CH2:21][O:20][C:17]2[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]([C:47]3[CH:48]=[CH:49][C:50]([OH:58])=[C:51]([NH:53][S:54]([CH3:57])(=[O:56])=[O:55])[CH:52]=3)[OH:8])=[CH:15][CH:16]=2)[CH:29]=[CH:28][C:27]=1[OH:30])[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)([CH3:39])[CH3:40]
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCCOc2ccc(CCNC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(O)c(NS(C)(=O)=O)c3)cc2)ccc1O)C(C)C
Agent: F
Solvent: CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCCOc2ccc(CCNC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)cc2)ccc1O)C(C)C
Reaction time: 24 h

Procedure:
N-{5-[(1R)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-({2-[4-(3-{3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-hydroxyphenyl}propoxy)phenyl]ethyl}amino)ethyl]-2-hydroxyphenyl}methanesulfonamide (Preparation 10, 98 mg, 0.11 mmol) was dissolved in tetrahydrofuran (4 ml) and methanol (2 ml) and triethylaminetrihydrofluoride (95 ul, 0.58 mmol) was added in one portion at room temperature. The reaction was stirred for 24 hours and the solvent removed under reduced pressure, the residue was dissolved in methanol (10 ml) and 880 ammonia (1 ml) and the solvent removed under reduced pressure to yield an off white solid. The solid was dissolved in methanol (1 ml) and precipitated with an excess of diisopropylether, the solid was collected by filtration to furnish the title compound as a white solid, 16 mg.
Reaction SMILES: [F:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[Si:11]([O:28][CH2:29][CH2:30][C:31]1[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=1[NH2:33])([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>S(Cl)(Cl)=O.C(Cl)Cl>[Si:11]([O:28][CH2:29][CH2:30][C:31]1[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=1[NH:33][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[N:10][C:2]=1[F:1])([C:24]([CH3:27])([CH3:25])[CH3:26])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)c1cccnc1F
Reactant: CC(C)(C)[Si](OCCc1ccccc1N)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(C)(C)[Si](OCCc1ccccc1NC(=O)c1cccnc1F)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.1 %

Procedure:
A mixture of 2-fluoronicotinic acid (Aldrich, 0.42 g, 2.9 mmol) in thionyl chloride (15 mL) was refluxed for two hours before being concentrated in vacuo to a residue which was used without further purification. The residue was dissolved in anhydrous DCM (5 mL) then added dropwise to a 0° C. solution of 2-(2-(tert-butyldiphenylsilyloxy)ethyl)aniline (1.10 g, 2.9 mmol) and TEA (0.43 mL, 3.1 mmol) in anhydrous DCM (15 mL). The reaction was then stirred at ambient temperature for 16 hours before being quenched with water then stirred for an additional thirty minutes. The layers were separated and the aqueous layer extracted with DCM. The combined organic layers were washed sequentially with water, saturated aqueous NaHCO3, and brine before being dried over anhydrous MgSO4, and then concentrated in vacuo. The resultant residue was purified by silica gel flash chromatography, eluting with 4:1 hexane/EtOAc, to afford the desired compound as a white solid (1.1 g, 72%). 1H NMR (DMSO-d6) δ 9.93 (s, 1H), 8.41 (d, 1H, J=4.4 Hz), 8.22 (t, 1H, J=7.6 Hz), 7.27-7.60 (m, 15H), 3.84 (t, 2H, J=6.7 Hz), 2.98 (t, 2H, J=6.7 Hz), 0.92 (s, 9H); HRMS(ESI+), 499.2217 (M+H)+ calc, 499.2230 (M+H)+ found.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[C:17]([C:22](=[O:31])[NH:23][CH2:24][C:25](=[O:30])[NH:26][CH:27]([CH3:29])[CH3:28])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:33][O:34][C:35]1[CH:36]=[C:37]([CH:43]=[CH:44][CH:45]=1)[C:38](=N)OCC>CCO>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:16]=[C:17]3[C:18](=[CH:19][CH:20]=2)[N:21]=[C:38]([C:37]2[CH:43]=[CH:44][CH:45]=[C:35]([O:34][CH3:33])[CH:36]=2)[N:23]([CH2:24][C:25](=[O:30])[NH:26][CH:27]([CH3:28])[CH3:29])[C:22]3=[O:31])[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)NC(=O)CNC(=O)c1cc(N2CCCN(C(=O)OC(C)(C)C)CC2)ccc1N
Reactant: CCOC(=N)c1cccc(OC)c1
Agent: Cl
Solvent: CCO
Product: COc1cccc(-c2nc3ccc(N4CCCN(C(=O)OC(C)(C)C)CC4)cc3c(=O)n2CC(=O)NC(C)C)c1
Yield: 13 %

Procedure:
A mixture of 4-{4-Amino-3-[(isopropylcarbamoylmethyl)carbamoyl]phenyl}perhydro-1,4-diazepine-1-carboxylic acid tert-butyl ester (INTERMEDIATE V.2) (300 mg, 0.69 mmol) and ethyl 3-methoxybenzimidate hydrochloride (INTERMEDIATE II.2) (298 mg, 1.38 mmol) in EtOH (6 mL) was heated at reflux temperature for 16 h. The reaction mixture was cooled, filtered and the filtrate concentrated in vacuo. The crude residue was purified by preparative HPLC to afford 4-[3-(isopropylcarbamoylmethyl)-2-(3-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl]perhydro-1,4-diazepine-1-carboxylic acid tert-butyl ester (INTERMEDIATE VII.1) (50 mg, 0.09 mmol, 13%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH3:15][C:16]1[C:17]([C:21]2[C:30]3[N:29]=[CH:28][CH:27]=[N:26][C:25]=3[C:24]([C:31](O)=[O:32])=[CH:23][CH:22]=2)=[CH:18][S:19][CH:20]=1>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([NH:14][C:31]([C:24]3[C:25]4[N:26]=[CH:27][CH:28]=[N:29][C:30]=4[C:21]([C:17]4[C:16]([CH3:15])=[CH:20][S:19][CH:18]=4)=[CH:22][CH:23]=3)=[O:32])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: Cc1cscc1-c1ccc(C(=O)O)c2nccnc12
Reactant: CN1CCN(c2ccc(N)cn2)CC1
Product: Cc1cscc1-c1ccc(C(=O)Nc2ccc(N3CCN(C)CC3)nc2)c2nccnc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but stirring the reaction mixture for 20 h at rt, using 6-(4-methylpiperazin-1-yl)-pyridin-3-ylamine (prepared as described in Example 33 but using N-methyl-piperazine in Step 33.2) and 8-(4-methyl-thiophen-3-yl)-quinoxaline-5-carboxylic acid (Example 67). Title compound: ESI-MS: 445.0 [M+H]+; tR=3.42 min (System 1).
Reaction SMILES: C(N(CC)CC)C.Br[C:9]1[N:14]=[C:13]([O:15][CH3:16])[C:12]([N:17]2[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]2)=[CH:11][CH:10]=1.[C:23]([NH2:27])(=[O:26])[CH:24]=[CH2:25]>CN(C)C=O.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].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:16][O:15][C:13]1[N:14]=[C:9](/[CH:25]=[CH:24]/[C:23]([NH2:27])=[O:26])[CH:10]=[CH:11][C:12]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1
Reactant: C=CC(N)=O
Reactant: COc1nc(Br)ccc1-n1cnc(C)c1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1nc(/C=C/C(N)=O)ccc1-n1cnc(C)c1
Temperature: 100 °C
Reaction time: 0.83 h
Yield: 89.5 %

Procedure:
Triethylamine (52 ml) was added to a suspension of 6-bromo-2-methoxy-3-(4-methyl-1H-imidazol-1-yl)pyridine (49.8 g), tris(dibenzylideneacetone)dipalladium (0) (5.11 g), tri-o-tolylphosphine (3.41 g) and acrylamide (14.5 g) in N,N-dimethyl formamide (260 ml). The reaction solution was stirred at 100° C. for 50 minutes. The reaction solution was returned to room temperature and then filtered through celite. The filter cake was sequentially washed with N,N-dimethylformamide, methanol, a 50% N,N-dimethylformamide solution and N,N-dimethylformamide. The resulting filtrate was filtered through celite again, and the filtrate was concentrated under reduced pressure. Toluene was added to the residue, and the reaction solution was concentrated again. Toluene and a saturated sodium bicarbonate solution were added to the resulting residue, and the insoluble matter was collected by filtration. The resulting powder was dried under reduced pressure to obtain 42.96 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]([S:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)([CH3:14])[CH3:13])[CH2:11][O:10]1.[NH:25]1[CH:29]=[N:28][CH:27]=[N:26]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:10])([C:12]([S:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)([CH3:14])[CH3:13])[CH2:11][N:25]1[CH:29]=[N:28][CH:27]=[N:26]1
Reactant: COc1ccc(CSC(C)(C)C2(c3ccc(F)cc3F)CO2)cc1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CSC(C)(C)C(O)(Cn2cncn2)c2ccc(F)cc2F)cc1
Temperature: 105 °C
Reaction time: 17 h
Yield: 94.3 %

Procedure:
A mixture of 64.0 g (182 mmol) of (-)-2-(2,4-difluorophenyl)-2-(1-((4-methoxyphenyl)methylthio)-1-methylethyl)oxirane, 25.1 g (364 mmol) of 1,2,4-triazole, 50.3 g (364 mmol) of potassium carbonate, and 910 ml of DMF was stirred at 105° C. for 17 hours. After allowing the mixture to cool, the solvent was removed by distillation under reduced pressure, and to the residue were added dichloromethane and water. The organic layer was separated, washed with a saturated sodium chloride aqueous solution, and dried. The solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography using a mixed solvent of chloroform and methanol (30:1) as an eluent. The solvent was removed by distillation under reduced pressure to obtain 72.0 g (94%) of (+)-2-(2,4-difluorophenyl)-3-((4-methoxyphenyl)methylthio)-3-methyl-1-(1H-1,2,4-triazol-1-yl)butan-2-ol as a pale yellow oily substance.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:12]([Cl:13])=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[C:6]([OH:14])[CH:5]=1.Cl[CH2:16][CH2:17][S:18][CH3:19]>CN(C)C=O>[NH2:3][C:4]1[C:12]([Cl:13])=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[C:6]([O:14][CH2:16][CH2:17][S:18][CH3:19])[CH:5]=1
Reactant: CSCCCl
Reactant: Nc1cc(O)c(C(=O)O)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCCOc1cc(N)c(Cl)cc1C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57.3 %

Procedure:
A cooled (5° C.) suspension of 60% sodium hydride oil dispersion (0.52 g, 13 mmole) in anhydrous dimethylformamide (15 ml) under nitrogen was treated in portions with 4-amino-5-chloro-2-hydroxybenzoic acid (0.94 g, 5 mmoles) stirred for 15 minutes at 25° C., treated with (2-chloroethyl)methyl sulfide (1.66 g, 15 mmoles), and heated to 100°±5° C. for 18 hours. The solution was cooled, concentrated in vacuo to remove most of the dimethylformamide and water (25 ml) was added. The aqueous solution was extracted with ether (2×25 ml), and the combined extracts were dried (MgSO4), concentrated in vacuo, taken up in 50% aqueous ethanol (50 ml), treated with potassium hydroxide (5.0 g), and refluxed for one hour. The mixture was concentrated to remove most of the ethanol, diluted with water to 75 ml total volume, extracted with ether (2×35 ml), and acidified to pH 3 with concentrated HCl. The resultant precipitate was filtered, washed with water, air dried, and recrystallized from ethyl acetate to yield 0.75 g (57%) of fine voluminous white needles, mp 137.5°-139.5° C.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].BrC[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([O:31][CH3:32])=[CH:23][CH:22]=1>CN(C=O)C>[CH3:32][O:31][C:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: COc1ccc(CBr)c2ccccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CN(C)C=O
Product: COc1cccc2ccccc12

Procedure:
In analogy with Example 44, the title compound is obtained from 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-[(4-methoxy-1-naphthyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide in abs. DMF using TBAF. [The starting compound for preparing the naphthylmethyl substituent, 1-bromomethyl-4-methoxynaphthalene, is obtained from 1-methoxynaphthalene (Fluka, Buchs, Switzerland) by brominating with I2 /Br2 in CHCl3, reacting the resulting bromide by means of a Grignard reaction and working up with CO2 to form the corresponding acid; reaction of the latter with lithium aluminium hydride to form 1-hydroxymethyl-4-methoxynaphthalene (reduction); and reaction of the latter with PBr3, thereby yielding the desired starting material (see Can. J. Chem. 59, 2629 (1981))].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Ca+2].[Cl-].[BH4-].[Na+]>C(O)C.C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:12][OH:13])[CH:14]=[CH:15][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cccc(OCc2ccccc2)c1
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: C1CCOC1
Product: OCc1cccc(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 15 h
Yield: 81.7 %

Procedure:
The intermediate 33 (8.2 mmols) and calcium chloride (16.4 mmols) were dissolved in 55 mL of anhydrous ethanol and 27 mLs of THF. The solution was next cooled to 0° C. and sodium borohydride (16.4 mmols) was added slowly over several minutes to the reaction vessel. Upon warming to ambient temperature, the mixture was allowed to stir for an additional 15 hours. After this time, the flask was again cooled to 0° C. and the excess sodium borohydride was quenched with the addition of 5 mLs of 1N HCl. The aqueous layer was extracted with four 20 mL portions of EtOAc; the organic layers were then combined, washed with 10 mLs of brine and dried with MgSO4. After evaporation, the crude organic material was purified by flash chromatography and 6.7 mmols of the title product was recovered. 1H NMR (300 MHz, CDCl3) δ 7.49-7.24 (m, 5H), 7.06-6.88 (m, 2H), 5.08 (s, 21-1), 4.66 (s, 2H), 1.78 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 129.88, 128.83, 128.21, 127.72, 119.60, 114.35, 113.45, 70.17, 65.46.
Reaction SMILES: [CH3:1][N:2]([CH2:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([C:30]([O:32]C)=O)[C:26]([O:28]C)=[O:27])=[CH:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].C(=O)([O-])[O-].[Na+].[Na+].Cl.[NH2:41][OH:42].Cl>O1CCCC1.CO>[OH:42][NH:41][C:30](=[O:32])[CH:25]([CH2:24][C:21]1[CH:20]=[CH:19][C:18]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([CH2:11][N:2]([CH3:1])[C:3]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[O:4])[CH:13]=2)=[CH:23][CH:22]=1)[C:26]([OH:28])=[O:27]
Reactant: NO
Reactant: COC(=O)C(Cc1ccc(-c2cccc(CN(C)C(=O)c3ccccc3)c2)cc1)C(=O)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CN(Cc1cccc(-c2ccc(CC(C(=O)O)C(=O)NO)cc2)c1)C(=O)c1ccccc1
Temperature: 60 °C
Yield: 69.4 %

Procedure:
A mixture of 130 mg (0.3 mmol) of dimethyl 2-(3′{[methyl-(1-phenylmethanoyl)amino]methyl}biphenyl-4-ylmethyl)malonate (prepared in Example 15(b)), 2 ml of methanol, 2 ml of tetrahydrofuran, 480 mg of sodium carbonate (4.5 mmol) and 200 mg (1.5 mmol) of hydroxylamine hydrochloride is heated at 60° C. for 18 hours. The reaction medium is neutralized to pH 6-7 with hydrochloric acid solution and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and evaporated. The residue obtained is purified by chromatography on a column of silica, eluted with a mixture of heptane and ethyl acetate (75/25). 90 mg (72%) of the desired product, with a melting point of 60° C., are obtained.