Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH:15]([F:17])[F:16])[NH:13][C:12](=O)[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19].C(OCC)(=O)C.Cl>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH:15]([F:17])[F:16])[NH:13][C:12](=[S:19])[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C1COCC(c2cccc(Br)c2)(C(F)F)N1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: FC(F)C1(c2cccc(Br)c2)COCC(=S)N1

Procedure:
5-(3-Bromo-phenyl)-5-difluoromethyl-morpholin-3-one (6.10 g, 19.93 mmol) was dissolved in 63 ml dry pyridine, and P2S5 (5.32 g, 23.91 mmol) was added. The mixture was heated to 80° V for 2 hrs. After completion, the mixture was put between ethyl acetate and 1H HCl solution. Phases were separated and the organic phase was washed with 1 N HCl, saturated NaHCO3 solution and brine. The organic phases were combined, dried over Na2SO4 and concentrated under reduced pressure to yield the title compound as off-white solid. 1H-NMR (360 MHz, DMSO-d6): 8.60 (s, 1H, NH), 7.80-7.35 (m, 4H), 6.54 (t, 1H, CHF2), 4.45 (m, 2H), 4.28 (d, 1H), 4.12 (d, 1H); MS: 322 [(M+H)+].
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C@@H:13]([C:30](=[O:42])[NH:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([CH:39]([CH3:41])[CH3:40])=[CH:35][CH:34]=3)[CH2:12]2)=[N:9][CH:10]=1)=[O:4].[OH-].[Na+].Cl>O1CCCC1.CO>[CH:39]([C:36]1[CH:35]=[CH:34][C:33]([CH2:32][NH:31][C:30]([C@@H:13]2[N:14]([S:17]([C:20]3[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=3)(=[O:19])=[O:18])[CH2:15][CH2:16][N:11]([C:8]3[CH:7]=[N:6][C:5]([C:3]([OH:4])=[O:2])=[CH:10][N:9]=3)[CH2:12]2)=[O:42])=[CH:38][CH:37]=1)([CH3:41])[CH3:40]
Reactant: COC(=O)c1cnc(N2CCN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)[C@@H](C(=O)NCc3ccc(C(C)C)cc3)C2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1ccc(CNC(=O)[C@H]2CN(c3cnc(C(=O)O)cn3)CCN2S(=O)(=O)c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Yield: 83.3 %

Procedure:
To a mixed solution of the compound (75 mg) obtained in Example 8 in tetrahydrofuran (400 μl) and methanol (400 μl) was added, with stirring at room temperature, 2N aqueous sodium hydroxide solution (186 μl). After stirring at room temperature for 30 min, 2N aqueous hydrochloric acid solution (186 μl) was added, and the mixture was concentrated under reduced pressure. Methanol and water were added to the residue, and the mixture was stirred at room temperature. The precipitated crystals were collected by filtration, and dried to give the title compound (61 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:15]([F:18])([F:17])[F:16])=[CH:5][C:6]([N+:12]([O-])=O)=[C:7]([CH2:9][C:10]#N)[CH:8]=1>C(O)C.O.C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][C:4]=1[C:15]([F:18])([F:17])[F:16])[NH:12][CH:10]=[CH:9]2
Reactant: COc1cc(CC#N)c([N+](=O)[O-])cc1C(F)(F)F
Agent: [Pd]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: COc1cc2cc[nH]c2cc1C(F)(F)F
Yield: 96.1 %

Procedure:
(5-Methoxy-2-nitro-4-trifluoromethylphenyl)acetonitrile (D9) (85 g, 0.327 mol) in ethanol/water (9:1, 1.6 l) and glacial acetic acid (16 ml) was hydrogenated over 10% palladium on carbon (50 g) at 50 psi for 0.5 h at room temperature. The reaction mixture was filtered and evaporated in vacuo. The residue was partitioned between aqueous K2CO3 (1 l) and dichloromethane (2×1 l) and the combined organic extract was dried (Na2SO4) and evaporated to afford the title indole (67.63 g, 96%) as a grey solid.
Reaction SMILES: O.O.P([O-])(O)(O)=O.[Na+].[Na+].P([O-])(O)(O)=O.[CH2:15]([O:17][C:18]([C@@H:20]([NH:29][C@H:30]([C:32]([OH:34])=[O:33])[CH3:31])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:19])[CH3:16].Cl[C:36](Cl)([O:38]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1>O.ClCCl>[CH3:16][CH2:15][O:17][C:18]([CH:20]([N:29]1[C:36](=[O:38])[O:34][C:32](=[O:33])[CH:30]1[CH3:31])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:19]
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C(CCc1ccccc1)N1C(=O)OC(=O)C1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Disodium dihydrogen phosphate dihydrate (177 gms; 0.994 moles) was dissolved in water (300 ml) at 35° C. and cooled to ambient temperature. Dichloromethane (250 ml) was charged and stirred for 15 mins. N-[1-(S)-ethoxy carbonyl-3-phenyl propyl]-L-alanine (106 gms; 0.381 moles) was added to the above solution and the reaction mass was cooled to 15° C. Solution of triphosgene (52.8 gms; 0.177 moles) dissolved dichloromethane (40 ml) was added dropwise to the reaction mass in 40 mins at 15-20° C. The reaction mass was further stirred for 30 min. Pyridine (0.5 ml; 0.006 moles) was added and the reaction mass was stirred for 1 hr at 15-20° C. The reaction mass was settled and layers were separated. Organic layer was washed with 2N HCl till the neutral pH obtained. The organic layer was further washed with water and dried over sodium sulphate. The solvent was evaporated to residue (110 gms).
Reaction SMILES: C([C@@H:4]([C@@H:20]([OH:29])/[CH:21]=[CH:22]/[C:23]1C=CC=CC=1)[C:5]([N:7]1[C@H:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10]O[C:8]1=[O:19])=[O:6])C=C.[C:30]1(C)C=CC=CC=1>Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1>[CH2:12]([C@H:11]1[N:7]([C:5]([C@H:4]2[CH2:23][CH:22]=[CH:21][C@@H:20]2[OH:29])=[O:6])[C:8](=[O:19])[CH2:30][CH2:10]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1ccccc1
Reactant: C=CC[C@H](C(=O)N1C(=O)OC[C@H]1Cc1ccccc1)[C@@H](O)/C=C/c1ccccc1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Product: O=C1CC[C@@H](Cc2ccccc2)N1C(=O)[C@H]1CC=C[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
A solution of (R)-3-((2S,3S,E)-2-allyl-3-hydroxy-5-phenylpent-4-enoyl)-4-benzyloxazolidin-2-one (50 g, 128 mmol) and Grubbs 2nd generation catalyst (5.4 g, 6.4 mmol) in toluene (300 mL) was degassed with nitrogen three times, and stirred at room temperature overnight. The reaction mixture was then concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:4) to afford the title compound (32 g, 87%) as a dark brown oil, which solidified upon standing. MS (ES+) C17H19NO3 requires: 285, found: 270 [M+H−H2O]+.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9](O)(O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].[C:14]1([S:20][CH3:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O>[CH3:21][S:20][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:9]1[C:10](=[O:11])[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[C:7]1=[O:8]
Reactant: CSc1ccccc1
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CSc1ccccc1C1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 13.3 %

Procedure:
Ninhydrin (0.10 g, 0.56 mmols) and thioanisole (0.07 mL, 0.56 mmols) were dissolved in trifluoroacetic acid (3 mL) and was stirred for 90 min at room temperature. The reaction mixture was neutralization with an aqueous sodium bicarbonate solution and was extracted with ethylacetate and was purified by silica gel column chromatography to afford the title compound (20 mg, 13%).
Reaction SMILES: Cl[CH:2]([OH:4])[CH3:3].[O:5]1[CH:10]=[CH:9][CH2:8][CH2:7][CH2:6]1.C(Cl)[Cl:12]>>[Cl:12][CH2:3][CH2:2][O:4][CH:10]1[CH2:9][CH2:8][CH2:7][CH2:6][O:5]1
Reactant: ClCCl
Reactant: C1=COCCC1
Reactant: CC(O)Cl
Product: ClCCOC1CCCCO1
Temperature: 0 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
1-Chloro ethanol (8.06 g, 100 mmol) was dissolved in dry CH2Cl2 (100 ml ) and cooled to 0° C. in an ice bath under argon. To this stirred solution was added dihydropyran (12.6 g, 150 mmol) followed by pyridinium -p-toluene -4-sulfonate (1.25 g, 5 mmol) and the stirring continued for overnight. The reaction mixture was evaporated to dryness and dissolved in EtOAc (200 ml). The EtOAC extract was washed with 5% NaHCO3 solution (100 ml), water (100 ml) and brine (100 ml). The organic extract was dried and evaporated to dryness. The crude material was purified by flash chromatography over silica gel using hexane→CH2Cl2 as the eluent. The pure fractions collected together and evaporated to give 11 g (67%) of pure product.
Reaction SMILES: CC(CC(O)=O)=O.[CH3:8][C:9]1[N:18]=[C:17]([N:19]2[CH2:25][C:24]3[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][C:23]=3[O:22][CH2:21][CH2:20]2)[C:16]2[CH2:15][C:14]([CH3:34])([CH3:33])[CH2:13][CH2:12][C:11]=2[N:10]=1.[NH2:35][C:36]1[C:41]([S:42]([NH:45][CH2:46][CH:47]2[CH2:52][CH2:51][N:50]([CH3:53])[CH2:49][CH2:48]2)(=[O:44])=[O:43])=[CH:40][C:39](Br)=[CH:38][N:37]=1>>[NH2:35][C:36]1[C:41]([S:42]([NH:45][CH2:46][CH:47]2[CH2:48][CH2:49][N:50]([CH3:53])[CH2:51][CH2:52]2)(=[O:44])=[O:43])=[CH:40][C:39]([C:27]2[CH:28]=[CH:29][C:23]3[O:22][CH2:21][CH2:20][N:19]([C:17]4[C:16]5[CH2:15][C:14]([CH3:34])([CH3:33])[CH2:13][CH2:12][C:11]=5[N:10]=[C:9]([CH3:8])[N:18]=4)[CH2:25][C:24]=3[CH:26]=2)=[CH:38][N:37]=1
Reactant: Cc1nc2c(c(N3CCOc4ccc(B(O)O)cc4C3)n1)CC(C)(C)CC2
Reactant: CN1CCC(CNS(=O)(=O)c2cc(Br)cnc2N)CC1
Agent: CC(=O)CC(=O)O
Product: Cc1nc2c(c(N3CCOc4ccc(-c5cnc(N)c(S(=O)(=O)NCC6CCN(C)CC6)c5)cc4C3)n1)CC(C)(C)CC2

Procedure:
Prepared as a diacetate salt according to the method of example 5 by using [4-(2,6,6-trimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]boronic acid (reagent preparation 23) and 2-amino-5-bromo-N-((1-methylpiperidin-4-yl)methyl)pyridine-3-sulfonamide (reagent preparation 25) in step 1. 1H NMR (400 MHz, DMSO-d6) δ 8.51 (d, 1H), 8.05 (d, 1H), 7.60 (d, 1H), 7.45 (dd, 1H), 7.03 (d, 1H), 6.67 (br s, 2H), 4.57 (s, 2H), 4.30-4.24 (m, 2H), 3.86-3.79 (m, 2H), 2.70-2.61 (m, 6H), 2.40 (s, 2H), 2.33 (s, 3H), 2.08 (s, 3H), 1.87 (s, 6H), 1.69 (t, 2H), 1.62-1.50 (m, 4H), 1.32-1.19 (m, 1H), 1.08-0.95 (m, 2H), 0.84 (s, 6H); MS (EI) for C32H43N7O3S: 606 (MH+).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)Br.CC#N.[CH2:28]([O:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42]CO)=[C:38]([N+:45]([O-:47])=[O:46])[CH:37]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CCOC(C)=O.CCCCCC>[CH2:28]([O:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH2:20][Br:24])=[C:38]([N+:45]([O-:47])=[O:46])[CH:37]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: BrC(Br)(Br)Br
Reactant: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1CCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1CCBr
Reaction time: 8 h
Yield: 97.3 %

Procedure:
Triphenylphosphine (1.92 g, 7.33 mmol), CBr4 (7.28 g, 21.96 mmol), and dry CH3CN (16.6 mL) were added to a round bottom flask containing 2-(4-benzyloxy-2-nitrophenyl)ethanol (1.00 g, 3.66 mmol). A red solution resulted which was allowed to stir overnight under a positive pressure of nitrogen. The solution was checked by TLC (20% EtOAc/hexane) and concentrated down on a rotoevaporator. The excess CBr4 was removed by vacuum kugelrohr distillation (60° C., 0.25 mmHg). Column chromatography (SiO2, 10% EtOAc/5% CHCl3/85% petroleum ether gradient elution) afforded 2-(4-benzyloxy-2-nitrophenyl)ethyl bromide as a brownish solid (1.33 g, 3.56 mmol, 92%). Mp 30-34° C.; TLC (20% EtOAc/hexane) Rf=0.48; 1H-NMR (CDCl3, 500 MHz) 7.52 (d, 2.5, 1H), 7.34 (m, 5H), 7.24 (d, 8.5, 1H), 7.11 (dd, 2.5, 8.5, 1H), 5.04 (s, 2H), 3.57 (t, 7.0, 2H), 3.30 (t, 7.0, 2H); 13C-NMR (CDCl3, 125 MHz) 158.0, 149.4, 135.6, 133.8, 128.7, 128.4, 127.5, 125.8, 120. 5, 110.8, 70.6, 35.9, 32.0; IR (neat) 3070, 3027, 2919, 2855, 1618, 1570, 1526, 1499, 1451, 1408, 1381, 1343, 1289, 1262, 1240, 1149, 1025, 842, 804, 733, 695; EI-MS m/z (relative intensity) 335 (M+, 9); isotope pattern of M+ and M++2 agrees with the presence of one bromine atom. Accurate mass (EI-MS) for C15H14NO3Br: calcd. 335.0157, obsd. 335.0160.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[NH:10][S:11]([C:14]1[CH:15]=[C:16]([CH:23]=C)[C:17]2[O:21][CH:20]=[CH:19][C:18]=2[CH:22]=1)(=[O:13])=[O:12].N1C(C)=CC=CC=1C.I([O-])(=O)(=O)=[O:34].[Na+].Cl>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[CH:23]([C:16]1[C:17]2[O:21][CH:20]=[CH:19][C:18]=2[CH:22]=[C:14]([S:11]([NH:10][C:4]2[CH:5]=[C:6]([CH3:9])[CH:7]=[CH:8][C:3]=2[O:2][CH3:1])(=[O:12])=[O:13])[CH:15]=1)=[O:34]
Reactant: C=Cc1cc(S(=O)(=O)Nc2cc(C)ccc2OC)cc2ccoc12
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: Cc1cccc(C)n1
Solvent: O
Product: COc1ccc(C)cc1NS(=O)(=O)c1cc(C=O)c2occc2c1
Reaction time: 1.5 h
Yield: 98.3 %

Procedure:
Osmium tetroxide (84 mg, 0.33 mmol) was added to a solution of N-(2-methoxy-5-methylphenyl)-7-vinyl-1-benzofuran-5-sulfonamide (1.25 g, 3.3 mmol; Intermediate 61) and lutidine (0.71 g, 6.6 mmol) in dioxane (30 mL). A solution of sodium periodate (2.82 g, 13.2 mmol) in water (10 mL) was added under stirring. After 90 min, aqueous HCl (2 M; 40 mL) was added to give a clear solution. Addition of water (200 mL) gave a precipitate that was collected by filtration. This material was washed with water and dried to give 1.12 g (88%) of the title product. 1H NMR (400 MHz, CDCl3) δ 2.27 (s, 3H), 3.55 (s, 3H), 6.57 (d, 1H), 6.80-6.85 (m, 1H), 6.92 (d, 1H), 7.02 (br s, 1H), 7.38 (d, 1H), 7.85 (d, 1H), 8.22 (d, 1H), 8.28 (d, 1H), 10.38 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:5]=1[C:6]([OH:8])=O)([O-:3])=[O:2].[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN1C(=O)CCC1.CCN(C(C)C)C(C)C.C(OCC)(=O)C>[CH2:14]([NH:21][C:6](=[O:8])[C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1cccc([N+](=O)[O-])c1C(=O)O
Reactant: NCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1cccc([N+](=O)[O-])c1C(=O)NCc1ccccc1
Reaction time: 1 h
Yield: 75.5 %

Procedure:
2-Nitro-6-methylbenzoic acid (0.91 g) and benzylamine (0.53 g) were dissolved in NMP (5 mL) and DIPEA (3 mL). HATU (1.9 g) was added and the mixture was stirred for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with 1N hydrochloric acid, saturated aqueous sodium bicarbonate and then brine. The organic solution was dried with magnesium sulfate, filtered and the solvent was removed under vacuum to give a light brown oil (1.01 g) that crystallized on standing.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][OH:5].Cl[CH2:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([F:15])[C:9]=1[O:16][CH3:17]>>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][CH2:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([F:15])[C:9]=1[O:16][CH3:17]
Reactant: COc1c(F)cc(F)cc1CCl
Reactant: OCCCCl
Product: COc1c(F)cc(F)cc1COCCCCl

Procedure:
In an analogous manner to that described in (δ) 1-chloromethyl-3,5-difluoro-2-methoxy-benzene was reacted with 1-chloro-3-propanol to yield 1-(3-chloro-propoxymethyl)-3,5-difluoro-2-methoxy-benzene as a colorless liquid; MS: 250 (M)+.
Reaction SMILES: [F:1][C:2]1[C:3]([N:14]=P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:4](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][C:37]=1[N:43]=[C:44]=O.[F:46][C:47]1[CH:52]=[CH:51][C:50]([N:53]2[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]2)=[CH:49][CH:48]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[N:14]=[C:44]([N:56]1[CH2:55][CH2:54][N:53]([C:50]3[CH:49]=[CH:48][C:47]([F:46])=[CH:52][CH:51]=3)[CH2:58][CH2:57]1)[N:43]([C:37]1[C:36]([O:35][CH3:34])=[CH:41][CH:40]=[C:39]([Cl:42])[CH:38]=1)[CH:8]2[CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)/C=C/c1cccc(F)c1N=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(Cl)cc1N=C=O
Reactant: Fc1ccc(N2CCNCC2)cc1
Product: COC(=O)CC1c2cccc(F)c2N=C(N2CCN(c3ccc(F)cc3)CC2)N1c1cc(Cl)ccc1OC

Procedure:
Starting with 1.0 g (2.2 mmol) of the iminophosphorane from Example 10A, 423 mg (2.31 mmol) of 2-methoxy-5-chlorophenyl isocyanate and 396 mg (2.2 mmol) of 4-fluorophenylpiperazine, 621 mg (52% of theory) of product are obtained after purification by preparative HPLC.
Reaction SMILES: [NH2:1][C@@H:2]([C:4]1[N:5]([CH2:25][CH3:26])[C:6]([O:9][C:10]2[CH:11]=[C:12]([N:16]3[CH2:21][CH2:20][N:19]([C:22](=[O:24])[CH3:23])[CH2:18][CH2:17]3)[CH:13]=[CH:14][CH:15]=2)=[N:7][N:8]=1)[CH3:3].Cl.C(N(CC)CC)C.[Cl:35][C:36]1[CH:37]=[C:38]([S:43](Cl)(=[O:45])=[O:44])[CH:39]=[CH:40][C:41]=1[Cl:42].C([O-])([O-])=O.[K+].[K+]>O>[C:22]([N:19]1[CH2:18][CH2:17][N:16]([C:12]2[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=2)[O:9][C:6]2[N:5]([CH2:25][CH3:26])[C:4]([C@H:2]([NH:1][S:43]([C:38]3[CH:39]=[CH:40][C:41]([Cl:42])=[C:36]([Cl:35])[CH:37]=3)(=[O:45])=[O:44])[CH3:3])=[N:8][N:7]=2)[CH2:21][CH2:20]1)(=[O:24])[CH3:23]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CCn1c(Oc2cccc(N3CCN(C(C)=O)CC3)c2)nnc1[C@@H](C)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCN(CC)CC
Product: CCn1c(Oc2cccc(N3CCN(C(C)=O)CC3)c2)nnc1[C@@H](C)NS(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Water was added to a mixture (307 mg) of 1-(4-[3-[5-((R)-1-aminoethyl)-4-ethyl-4H-[1,2,4]triazol-3-yloxy]-phenyl]-piperazin-1-yl)-ethanone obtained in Example 27-(2) and triethylamine hydrochloride, 3,4-dichlorobenzenesulfonyl chloride (0.13 ml), and K2CO3 (355 mg). The mixture was stirred at room temperature for 15 hours. The precipitated solid was filtered and purified by column chromatography (NH SiO2, MeOH/CHCl3=1/50) to give the titled compound (Compound 697) (117 mg, colorless syrup).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12]([C:14]4[O:18][N:17]=[C:16]([O:19][CH2:20][C@@H:21]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH3:22])[CH:15]=4)=[N:11][C:10]=3[CH:31]=2)[CH2:3][CH2:2]1.[CH2:32]([Li])CCC.IC.Cl>C1COCC1.CCCCCC>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12]([C:14]4[O:18][N:17]=[C:16]([O:19][CH2:20][C@@H:21]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:29])[CH3:28])[CH3:22])[C:15]=4[CH3:32])=[N:11][C:10]=3[CH:31]=2)[CH2:2][CH2:3]1
Reactant: [Li]CCCC
Reactant: C[C@@H](COc1cc(-c2nc3cc(OCC4CC4)ccc3o2)on1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCCCCC
Solvent: CI
Solvent: C1CCOC1
Product: Cc1c(OC[C@H](C)NC(=O)OC(C)(C)C)noc1-c1nc2cc(OCC3CC3)ccc2o1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
Under an argon atmosphere, to a solution of tert-butyl [(1S)-2-({5-[5-(cyclopropylmethoxy)-1,3-benzoxazol-2-yl]isoxazol-3-yl}oxy)-1-methylethyl]carbamate (644 mg) in THF (15 mL) was added dropwise a hexane solution (1.6 M, 2.156 mL) of n-butyllithium at −78° C., and the mixture was stirred at −78° C. for 20 min. To the reaction mixture was added iodomethane (0.140 mL), and the mixture was stirred at −78° C. for 15 min, and then at 0° C. for 1 hr. The reaction mixture was neutralized with 1M hydrochloric acid, and extracted with ethyl acetate. The combined organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (46.0 mg).
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([OH:15])(=O)[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1.C1(C)C=CC=CC=1>N1C=CC=CC=1>[C:5]([Cl:3])(=[O:15])[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=Cc1ccc(C(=O)O)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: O=Cc1ccc(C(=O)Cl)cc1
Temperature: 25 °C

Procedure:
The title substance was synthesized as follows: 300 ml of thionyl chloride was dropped into a mixture of 358 g of commercially available terephthalaldehydic acid with 700 ml of toluene and 2 g of pyridine, and the solution was heated under reflux slowly until a homogeneous reaction solution was obtained. After the solution was cooled to room temperature, unreacted thionyl chloride and toluene as a solvent were distilled off in vacuum. Terephthalaldehydic acid chloride (b.p. 133°-135° C./15 Torr) was obtained by the vacuum distillation of the remaining reaction product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:14][C:15]1[CH:29]=[CH:28][CH:27]=[CH:26][C:16]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24]O)=[CH:20][CH:19]=1.C1(C)C(O)=CC=CC=1.BrC1C=CC(C=O)=CC=1>>[CH3:14][C:15]1[CH:29]=[CH:28][CH:27]=[CH:26][C:16]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=2)=[CH:20][CH:19]=1
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: Cc1ccccc1Oc1ccc(CO)cc1
Agent: Cc1ccccc1O
Agent: O=Cc1ccc(Br)cc1
Product: COC(=O)CCc1ccc(OCc2ccc(Oc3ccccc3C)cc2)cc1

Procedure:
The title compound was synthesized in the same manner as in Example 277 from methyl 3-(4-hydroxyphenyl)propanoate and [4-(2-methylphenoxy)phenyl]methanol (synthesized in the same manner as in Reference Example 201 from o-cresol and 4-bromobenzaldehyde (mixture with side product)) (preparative HPLC (gradient cycle A) was used for purification). colorless crystals (yield 56%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C@@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[C@H:10]([CH2:25]O)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:35][S:36](Cl)(=O)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:27])[NH:7][C@@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[C@H:10]([CH2:25][S:36][CH3:35])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)[C@H](CO)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSC[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
(1R,3R,4S)-(4-Benzyloxycarbonylamino-3-hydroxymethylcyclohexyl)carbamic acid tert-butyl ester (1.0 g) was dissolved in CH2Cl2 (120 ml) and cooled to 0° C. prior to the addition of Et3N (0.5 mL) and methanesulfonyl chloride (0.55 mL). This mixture was warmed to RT and was stirred for 3 h. The CH2Cl2 was removed and EtOAc was added along with water. The organic layer was dried, filtered, and concentrated. This solid was dissolved in DMF (15 mL) and HMPA (2 mL) prior to the addition of NaSMe (1.1 g) and 18-crown-6 (500 mg). After 18 h, additional HMPA (0.5 mL) was added. After another 3 h, water was added and the solution was extracted with EtOAc. The organic layer was dried, filtered, and concentrated. Flash chromatography of the resulting residue gave (1R,3R,4S)-(4-benzyloxycarbonylamino-3-(methyl)thiomethylcyclohexyl)carbamic acid tert-butyl ester (1.1 g). MS found: (M+H)+=409.2.