Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[O:15][CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[C:6]1=[O:27])[CH2:2][CH2:3][CH3:4].[BH4-].[Na+].O>CO>[CH2:1]([C:5]1([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[O:15][CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH:6]1[OH:27])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(CCCC)CCc2c(OCc3ccc4ccccc4n3)cccc2C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCC1(CCCC)CCc2c(OCc3ccc4ccccc4n3)cccc2C1O

Procedure:
To a solution of 2,2-dibutyl-3,4-dihydro-5-(2-quinolylmethoxy)-1(2H)-naphthalenone (500 Mg) in methanol (20 ml) was added sodium borohydride (68 mg) with stirring in an ice bath. The mixture was stirred for half an hour in an ice bath and then sodium borohydride (136 mg) was added thereto at the same temperature. The solution was stirred for 1.5 hours at ambient temperature, followed by the addition of sodium borohydride (68 mg). The mixture was stirred at ambient temperature for half an hour and then poured into water with stirring in an ice bath. The separated solid was collected by filtration, washed with water (50 ml), dried, and recrystallized from methanol to yield 2,2-dibutyl-5-(2-quinolylmethoxy)-1,2,3,4-tetrahydro-1-naphthol (388 mg). mp: 122°-123° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH2:10][OH:11])=[CH:4][CH:3]=1.[C:12]1(C=CCO)C=CC=CC=1.N>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:12][C@H:9]2[CH2:10][OH:11])=[CH:6][CH:7]=1
Reactant: OC/C=C/c1ccc(Br)cc1
Reactant: OCC=Cc1ccccc1
Agent: N
Product: OC[C@@H]1C[C@H]1c1ccc(Br)cc1

Procedure:
The title compound was prepared by the method of A. B. Charette and H. Lebel (Organic Synthesis, 1998, 76, 86-96) substituting trans-3-(4-Bromophenyl)prop-2-en-1-ol (the product from Example 1A) for 3-Phenyl-prop-2-en-1-ol. 1H NMR (300 MHz, CDCl3): δ 0.92-1.0 (m, 2H), 1.45-1.48 (m, 2H), 1.76-1.85 (m, 1H), 3.61 (d, J=7.5 Hz, 2H), 6.95 (d, J=9 Hz, 2H), 7.37 (d, J=9 Hz, 2H). MS (DCl—NH3) m/z 228 (M+H)+.
Reaction SMILES: [ClH:1].[CH2:2]([N:4]([C:11]1[CH:16]=[C:15]([CH3:17])[N:14]=[C:13](OCC)[CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:3].C(=O)([O-])[O-].[Na+].[Na+].Cl.[CH2:28]([CH2:30][NH2:31])[OH:29]>O.C(OCC)(=O)C>[ClH:1].[CH2:2]([N:4]([C:11]1[CH:16]=[C:15]([CH3:17])[N:14]=[C:13]([NH:31][CH2:30][CH2:28][OH:29])[CH:12]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH3:3]
Reactant: NCCO
Reactant: CCOc1cc(N(CC)c2ccccc2)cc(C)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCN(c1ccccc1)c1cc(C)nc(NCCO)c1
Yield: 24 %

Procedure:
4-(N-ethylanilino)-2-ethoxy-6-methylpyridine hydrochloride (0.584 g, 2 mM) in ethanolamine (5 ml) was heated under argon at 180° C. for 24 hours. The solution was cooled, diluted with water (50 ml), basified with aqueous sodium carbonate solution and extracted with methylene chloride (4×10 ml). The organic extracts were combined, dried (MgSO4) and evaporated to give a gum. This gum was triturated with ether to give, 4-(N-ethylanilino)-2-hydroxy-6-methylpyridine as a white solid (0.05 g) which was collected by filtration. The filtrate was evaporated and the residue was purified by flash column chromatography, eluting successively with methanol/methylene chloride (1:19 v/v), methanol/methylene chloride, (1:9 v/v/) and methanol/methylene chloride/0.88d aqueous NH4OH (20:80:1 v/v) to give a gum. This gum was dissolved in ethyl acetate and treated with etheral hydrogen chloride to give a gum which solidified on standing. The solid was washed with ether to give 4-(N-ethylanilino)-2-(2-hydroxyethylamino)-6-methylpyridine hydrochloride (0.15 g, 24% yield); m.p. 190° C.; microanalysis, found C, 62.2; H, 7.5; N, 13.7%; C16H22N3OCl requires: C, 62.4; H, 7.15; N, 13.6%; NMR: 1.1-1.2 (3H, t, CH3), 2.23(3H, s, CH3), 3.2-3.32(2H, q, CH2), 3.5-3.6(2H, t, CH2), 3.7-3.85(2H, q, CH2), 5.7(1H, s, CH), 5.9(1H, s, CH), 7.2-7.6(5H, complex, aromatic), 4.7-5.1(1H, broad, OH), 12.4(1H, NH).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].Cl[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)[N:16]=1>CN(C)C=O.[Cu]I>[S:24]1[CH:25]=[CH:26][CH:27]=[C:23]1[CH2:22][O:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=2)[N:16]=1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: Clc1cccc(OCc2cccs2)n1
Agent: [Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(Oc2cccc(OCc3cccs3)n2)c1

Procedure:
To a solution containing meta-trifluoromethylphenol (3.62 g, 0.0045×5.0 mol), sodium hydride (0.36 g, (Ca.60% in mineral oil), 0.0045×2.0 mol) and CuI (0.42 g, 0.0045×0.5 mol) in dimethylformamide, 2-chloro-6-(2-thienylmethyloxy)pyridine (1.0 g, 0.0045 mol) was added and the resultant solution was refluxed for about 3 hours. Additional sodium hydride (0.36 g, (60% in mineral oil), 0.0045×2.0 mol) was added thereto and the resultant solution was refluxed for another about 1 hour, thereafter the reaction solution was partitioned between ethyl acetate and aqueous saturated sodium hydrogen carbonate. The obtained organic layer was washed with aqueous saturated sodium chloride, dried over anhydrous sodium sulfate and thereafter, concentrated and purified on a silica gel column to obtain the end product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([Cl:20])=[CH:14][C:13]=2[F:21])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8].S(=O)(=O)(O)O.[N+:27]([O-])([OH:29])=[O:28]>>[Cl:1][C:2]1[C:3]([C:12]2[C:13]([F:21])=[CH:14][C:15]([Cl:20])=[C:16]([O:18][CH3:19])[C:17]=2[N+:27]([O-:29])=[O:28])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:8])([F:10])[F:9]
Reactant: COc1cc(-c2nn(C)c(C(F)(F)F)c2Cl)c(F)cc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COc1c(Cl)cc(F)c(-c2nn(C)c(C(F)(F)F)c2Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Chloro-3-(4-chloro-2-fluoro-5-methoxyphenyl)-1-methyl-5-trifluoromethyl-1H-pyrazole (1.2 g, 3.5 mmol) was slurried with 4 ml of conc. sulfuric acid and was slowly added to a stirred 4 ml of conc. sulfuric acid-con. nitric acid (9:1) at −15° C. Solution was allowed to stir at ambient temperature for 2 hr and then added to ice water. Extraction with ethyl acetate and removal of the solvent afforded a crude product which was chromatographed on silica gel. Elution of the column with hexane-methylene chloride (4:6) furnished the title compound (0.72 g).
Reaction SMILES: O.[C:2]1([C:8]([CH:10]=[O:11])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>ClC(Cl)C.[Ti](Cl)(Cl)(Cl)Cl>[CH2:12]([C:18]1[CH:19]=[CH:20][C:21]([CH:10]([OH:11])[C:8](=[O:9])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:22][CH:23]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: O=CC(=O)c1ccccc1
Reactant: CCCCCCc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: CC(Cl)Cl
Product: CCCCCCc1ccc(C(O)C(=O)c2ccccc2)cc1

Procedure:
Phenylglyoxal monohydrate (304 mg, 2 mM) and n-hexylbenzene (0.76 ml, 4 mM) were dissolved in dichloroethane (3 ml), titanium tetrachloride (0.33 ml, 3 mM) was added, and reacted at room temperature for 1 hour. Using the same procedure as in Example 1, 4'-n-hexylbenzoin was obtained as crystal (352.8 mg, 59.4% yield).
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[Cl:14]>C(#N)C>[Cl:14][C:6]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=1[NH:2][NH2:3]
Reactant: NN
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Solvent: O
Solvent: CC#N
Product: NNc1ccc([N+](=O)[O-])cc1Cl
Temperature: 25 °C

Procedure:
59 g of hydrazine hydrate was dissolved in 712 ml of acetonitrile at room temperature under an atmosphere of nitrogen. A solution obtained by dissolving 46.3 g of 1,2-dichloro-4-nitrobenzene in 71 g of acetonitrile was added dropwisely to the obtained solution. After the addition had been completed, the obtained mixture was subjected to reflux by heat for 4 hours, and the reaction solution was concentrated. 500 g of water was added to the concentrate, and the produced crystals were filtered off. 200 g of acetonitrile was then added to the crystals, and the obtained mixture was subjected to reflux by heat for 30 minutes and then cooled with ice to room temperature. The produced crystals were filtered off (yield: 27 g).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1)(=[O:8])[CH3:7].O>CC(C)=O>[N:1]1([S:16]([C:13]2[CH:12]=[CH:11][C:10]([NH:9][C:6](=[O:8])[CH3:7])=[CH:15][CH:14]=2)(=[O:18])=[O:17])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: C1CCNC1
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)Nc1ccc(S(=O)(=O)N2CCCC2)cc1
Temperature: 0 °C
Yield: 46.4 %

Procedure:
(prepared according to an analogous procedure described in U.S. Pat. No. 5,755,873) Step A: Pyrrolidine (16 ml, 0.1925 mol) was dissolved in acetone (40 ml) and cooled to 0° C.; 4-acetylaminobenzenesulfonyl chloride (15 g, 0.065 mol) was added over 10 min. Additional acetone (13 ml) was added and the mixture was heated at reflux for 2 h. After cooling to rt, the mixture was added to water (350 ml) and the resulting precipitate collected by filtration, the precipitate was washed with water until the washings were at pH 7. The solid was dried under vacuum to give 8.1 g of N-[4-(pyrrolidine-1-sulfonyl)phenyl]acetamide. Step B: The compound from step A (8.1 g) was suspended in water (37.5 ml) and treated with concentrated HCl (19 ml). The mixture was heated at reflux for 1 h. After cooling to rt, NH4OH (23 ml) was added with stirring. The resulting precipitate was collected by filtration and washed with water until the washings were pH 7. The solid was dried to give 6.0 g of 4-(pyrrolidine-1-sulfonyl)phenylamine. 1H NMR (DMSO) δ 7.40 (d, J=8.8 Hz, 2H), 6.62 (d, J=8.8 Hz, 2H), 6.02 (s, 2H), 3.03 (m, 4H), 1.61 (m, 4H).
Reaction SMILES: S(O[CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])(C1C=CC(C)=CC=1)(=O)=O.[C:30]1(=[O:40])[NH:34][C:33](=[O:35])[C:32]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:31]12.[K].O>CN(C=O)C>[O:35]=[C:33]1[C:32]2[C:31](=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:30](=[O:40])[N:34]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOCCOCCC(=O)OC(C)(C)C)cc1
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCOCCOCCOCCN1C(=O)c2ccccc2C1=O
Temperature: 100 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of tert-butyl 3-(2-(2-(2-(tosyloxy)ethoxy)ethoxy)ethoxy)propanoate (13.4 g, 30.98 mmol, 1.00 equiv) in anhydrous DMF (100 mL) followed by potassium phthalimide (7.5 g, 40.49 mmol, 1.31 equiv). The resulting solution was heated to 100° C. and stirred for 3 h. The reaction progress was monitored by LCMS. The DMF was removed under vacuum to afford a brown oil residue. To the residue was added 200 mL water and the mixture was extracted with 3×50 mL of ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After evaporation of solvent, The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0˜1:3). The solvent was removed from fractions containing phthalimide and the residue was washed with 20% ethyl acetate/petroleum ether to yield 10.1 g (78%) of tert-butyl 3-(2-(2-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)ethoxy)ethoxy)propanoate as pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]12[O:16][CH2:15][CH2:14][CH2:13][O:12]1.[OH-].[CH2:18]([N+:25](C)(C)C)[C:19]1C=CC=C[CH:20]=1.C(#N)C=C>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:20][CH2:19][C:18]#[N:25])[C:6](=[O:11])[C:5]12[O:16][CH2:15][CH2:14][CH2:13][O:12]1
Reactant: O=C1Nc2ccc(Br)cc2C12OCCCO2
Reactant: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C=CC#N
Product: N#CCCN1C(=O)C2(OCCCO2)c2cc(Br)ccc21
Temperature: 52 °C
Yield: 711.1 %

Procedure:
At room temperature, to a solution of 5′-bromospiro[1,3-dioxane-2,3′-indol]-2′(1′H)-one (2.50 g, 8.80 mmol) in N,N dimethylformamide (39 mL) was added benzyltrimethylammonium hydroxide (40% aq. solution, 0.347 mL, 0.88 mmol, 0.1 mole % ) followed by the dropwise addition of acrylonitrile (1.16 mL, 17.6 mmol, 2 eq). The reaction mixture was heated at 52° C. for 2 hr., cooled to room temperature, quenched with H2O (400 mL) and extracted with Et2O (3×). The combined organic extracts were dried and concentrated. The crude product was purified on Biotage KP silica gel eluting with 96/4 CH2Cl2/CH3CN to give the title compound as a yellow solid (2.11 g, 71% ). NMR (300 Mz, DMSO-d6): consistent; MS: (API-ES+) m/z 361 [M+Na].
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[C@@H:20]([OH:31])[CH2:21][C@@H:22]([C:27]([OH:30])([CH3:29])[CH3:28])[C:23]([NH:25][CH3:26])=[O:24])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[O:7])(C)(C)C.[O:39]1[CH2:44][CH2:43][N:42]([CH2:45][C:46]([NH:48][C@H:49](C(O)=O)[CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[O:47])[CH2:41][CH2:40]1.P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>>[O:39]1[CH2:40][CH2:41][N:42]([CH2:45][C:46]([NH:48][C@H:49]([C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:32][CH:33]2[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]2)[C@@H:20]([OH:31])[CH2:21][C@@H:22]([C:27]([OH:30])([CH3:29])[CH3:28])[C:23]([NH:25][CH3:26])=[O:24])=[O:17])[CH2:10][C:11]2[N:12]=[CH:13][S:14][CH:15]=2)=[O:7])[CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[O:47])[CH2:43][CH2:44]1
Reactant: CNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C)C(C)(C)O
Reactant: O=C(CN1CCOCC1)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Product: CNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)CN1CCOCC1)C(C)(C)O
Yield: 77 %

Procedure:
A procedure similar to that described in Example 2 was repeated, except that 100 mg (0.18 mmoles) of (2S, 4S, 5S)-5-[N-(t-butoxycarbonyl) 3-(4-thiazolyl)-L-alanyl]amino-6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-methylethyl)-N-methylhexanamide [prepared as described in Example 9(a)], 58 mg (0.20 mmoles) of N-morpholinoacetyl-L-phenylalanine, 0.03 ml (0.20 mmoles) of diethyl cyanophosphate, and 0.08 ml (0.57 mmoles) of triethylamine were used, to obtain 101 mg (yield 77%) of the title compound as a white amorphous substance.
Reaction SMILES: [NH3:1].[CH3:2][C:3]1[CH:17]=[CH:16][C:6]([S:7][C:8]2[CH:15]=[CH:14][C:11]([CH2:12]Br)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.O>CO>[CH3:2][C:3]1[CH:17]=[CH:16][C:6]([S:7][C:8]2[CH:15]=[CH:14][C:11]([CH2:12][NH2:1])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: Cc1ccc(Sc2ccc(CBr)cc2)cc1
Reactant: N
Solvent: O
Solvent: CO
Product: Cc1ccc(Sc2ccc(CN)cc2)cc1
Reaction time: 96 h
Yield: 53 %

Procedure:
To a stirred mixture of 28% aq NH3 (40 ml) and methanol (200 ml) was added dropwise a solution (20 ml) of 4-(4-methylthiophenoxy)benzylbromide (5.00 g, 16.2 mM) in methanol at room temperature, and the mixture was stirred for 4 days at the same temperature. To the mixture was added water (100 ml), and the mixture was concentrated in vacuo. The residue was diluted with chloroform, and the mixture was washed with water and brine, dried with sodium sulfate, and concentrated in vacuo. The residue was chromatographed over alumina to give 4-(4-methylthiophenoxy)benzylamine (2.11 g, 53%) as colorless crystals, m.p. 61.8° C.
Reaction SMILES: [NH2:1][C@H](C(O)=O)CCCC.ON1C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1.Cl.Cl.N[C@@H:38]([CH2:50][CH:51]1[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]1)[C@@H:39]([OH:49])[CH:40]([OH:48])[CH2:41][N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1>CN(C=O)C.C(N(CC)CC)C>[NH2:1][CH:41]([N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1)[CH:40]([OH:48])[CH:39]([OH:49])[CH2:38][CH2:50][CH:51]1[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]1
Reactant: N[C@@H](CC1CCCCC1)[C@@H](O)C(O)CN1CCOCC1
Reactant: CCCC[C@H](N)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(C(O)C(O)CCC1CCCCC1)N1CCOCC1
Temperature: 0 °C

Procedure:
50 mg of L-N-[(2S or R)-3-(2-hydroxyethyl)sulfonyl-2-(1-naphthylmethyl)propionyl]norleucine was dissolved in 0.2 ml of dry DMF, and 28.2 mg of 1-hydroxybenzotriazole and 33.2 mg of DCC were added thereto at 0° C. under stirring. Then, 55.2 mg of (2RS,3R,4S)-4-amino-5-cyclohexyl-1-morpholino-2,3-pentanediol dihydrochloride was dissolved in 0.2 ml of dry DMF, and 31.1 mg of triethylamine was added thereto for neutralization. This mixture was added to the previous reaction solution, and the mixture was stirred at 0° C. for two hours and at room temperature overnight. The precipitated dicyclohexyl urea was removed by filtration, and the filtrate was diluted with 10 ml of ethyl acetate. The ethyl acetate layer was washed sequentially with a 4% sodium hydrogencarbonate aqueous solution, with water and with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Then, the solvent was distilled off. The residue was purified by silica gel column chromatography (chlorofrom/methanol= 20/1) to obtain 20.1 mg of (2S,3R,4S)-4-{L-N-[(2S or R)-3-(2-hydroxyethyl)sulfonyl-2-(1-naphthylmethyl)propionyl]norleucy}amino-5-cyclohexyl-1-morpholino-2,3-pentanediol as colorless solid.
Reaction SMILES: [N+:1]([CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O)([O-:3])=[O:2].O.[CH3:12][NH:13][CH3:14]>CO>[CH3:12][N:13]([CH3:14])[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][N+:1]([O-:3])=[O:2]
Reactant: COC(=O)CCC[N+](=O)[O-]
Reactant: CNC
Solvent: CO
Solvent: O
Product: CN(C)C(=O)CCC[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 90.9 %

Procedure:
To a solution of methyl 4-nitrobutyrate (1.0 g, 6.80 mmol) in methanol (10 ml) was added 40% dimethylamine water solution (12.5 ml, 102 mmol). The solution was stirred at room temperature for 48 h, concentrated by vacuum, and diluted with ethyl acetate (20 ml). The organic layer was dried and evaporated. The residue was purified by flash chromatography over silica gel (Hexane-EtOAc, 1:1) to give the title product (0.99 g, 91%). 1H NMR (CDCl3): 4.53 (t, J=6.6 Hz, 2H), 3.02-2.94 (m, 6H), 2.48-2.43 (m, 2H), 2.36-2.31 (m, 2H).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][C@@H:14]([CH3:19])[C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH2:20][C:21]1([CH2:27][C:28]([NH2:30])=[O:29])[CH2:24][S:23](=[O:26])(=[O:25])[CH2:22]1>>[NH2:30][C:28](=[O:29])[CH2:27][C:21]1([NH:20][C:10]([C:7]2[CH:6]=[C:5]([O:13][C@@H:14]([CH3:19])[C:15]([F:18])([F:17])[F:16])[C:4]([CH:1]3[CH2:2][CH2:3]3)=[CH:9][N:8]=2)=[O:12])[CH2:22][S:23](=[O:25])(=[O:26])[CH2:24]1
Reactant: C[C@H](Oc1cc(C(=O)O)ncc1C1CC1)C(F)(F)F
Reactant: NC(=O)CC1(N)CS(=O)(=O)C1
Product: C[C@H](Oc1cc(C(=O)NC2(CC(N)=O)CS(=O)(=O)C2)ncc1C1CC1)C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-Cyclopropyl-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridine-2-carboxylic acid (example 68a) and 2-(3-amino-1,1-dioxo-thietan-3-yl)acetamide (example 160d) as starting materials and isolated (19.3 mg, 28%); MS (ESI, m/z): 436.3 (M+H+).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8]Cl.[Cl:10][C:11]1[CH:12]=[C:13]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][C:27]=3[O:29][CH2:30][C@@H:31]([NH:33][C:34](=[O:36])[CH3:35])[CH3:32])[N:22]=[CH:21][N:20]=2)[CH:14]=[CH:15][C:16]=1[OH:17]>>[Cl:10][C:11]1[CH:12]=[C:13]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][C:27]=3[O:29][CH2:30][C@@H:31]([NH:33][C:34](=[O:36])[CH3:35])[CH3:32])[N:22]=[CH:21][N:20]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=1
Reactant: CC(=O)N[C@@H](C)COc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Reactant: ClCc1ccccn1
Agent: Cl
Product: CC(=O)N[C@@H](C)COc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 63 %

Procedure:
The procedure described in Example 3 was repeated using picolyl chloride hydrochloride and N-[(1S)-2-({4-[(3-chloro-4-hydroxyphenyl)amino]quinazolin-5-yl}oxy)-1-methylethyl]acetamide to give the title compound in 63% yield; NMR spectrum (DMSO-d6) 1.21 (s, 3H), 1.73 (s, 3H), 4.12-4.30 (m, 2H), 4.33-4.43 (m, 1H), 5.29 (s, 2H), 7.15-7.25 (m, 2H), 7.35 (t, 2H), 7.51-7.59 (m, 2H), 7.72 (t, 1H), 7.87 (t, 1H), 7.99 (s, 1H), 8.14 (d, 1H), 8.48 (s, 1H), 8.59 (d, 1H), 9.80 (s, 1H); Mass spectrum MH+ 478.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[F:25][C:26]([F:36])([F:35])[C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[F:25][C:26]([F:35])([F:36])[C:27]1[CH:34]=[CH:33][C:30]([CH2:31][N:15]2[C:14](=[O:17])[N:11]3[N:12]=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[C:9]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)[C:10]3=[N:16]2)=[CH:29][CH:28]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1n(Cc2ccc(C(F)(F)F)cc2)nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Temperature: 90 °C
Yield: 27.7 %

Procedure:
A solution of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (300 mg, 0.84 mmol), prepared as described in Example 1, 4-(trifluoromethyl)benzyl bromide (200 mg, 0.84 mmol) and K2CO3 (290 mg, 2.1 mmol) in DMF (10 ml), was heated at 90° C. for 2 hours. After this time, the reaction mixture was cooled to RT and diluted with ethyl acetate. The resultant solution was then washed with water. The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by preparative HPLC to give the title compound, 2-(4-(trifluoromethyl)benzyl)-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (120 mg, 28%) as a yellow solid. MS M+H=515; 1H NMR (CDCl3) δ 8.19 (1H), 7.60 (2H), 7.50 (2H), 7.34 (4H), 7.28 (2H), 7.10 (2H), 5.27 (2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[C:17]#[CH:18])([CH3:4])([CH3:3])[CH3:2].Br[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][C:26]=1[CH3:27]>>[C:1]([O:5][C:6](=[O:19])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[C:17]#[C:18][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][C:26]=1[CH3:27])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccncc1Br
Reactant: C#Cc1cc(C#N)ccc1OCC(=O)OC(C)(C)C
Product: Cc1ccncc1C#Cc1cc(C#N)ccc1OCC(=O)OC(C)(C)C

Procedure:
Following the general method as outlined in Intermediate 20, starting from tert-butyl(4-cyano-2-ethynylphenoxy)acetate (Intermediate 46) and 3-bromo-4-methylpyridine (53), the title compound was obtained as a dark orange sticky solid after purification by flash column chromatography, eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10].[O:15]1[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl>[O:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1[O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][P:7](=[O:14])([O:8][CH2:9][CH3:10])[O:11][CH2:12][CH3:13]
Reactant: CCOP(=O)(CCCCCO)OCC
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOP(=O)(CCCCCOC1CCCCO1)OCC

Procedure:
A solution of 66.9 g (0.298 mol) of diethyl 5-hydroxypentylphosphonate, 32.6 g (0.38 mol) of 3,4-dihydropyran and 1 g (0.004 mol) of pyridinium toluene-4-sulfonate in 800 ml of dichloromethane was heated under reflux for 16 hours. The solution was washed with water and saturated sodium hydrogen carbonate solution, dried over sodium sulfate and distilled in a bulb tube.