Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([O:10][Si](C)(C)C)[C:8]#N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].BrC[C:27]1[CH:28]=[C:29]([F:36])[C:30]([S:34][CH3:35])=[C:31]([F:33])[CH:32]=1.Cl>C1COCC1>[F:36][C:29]1[CH:28]=[C:27]([CH2:8][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:10])[CH:32]=[C:31]([F:33])[C:30]=1[S:34][CH3:35]
Reactant: C[Si](C)(C)OC(C#N)c1ccccc1
Reactant: CSc1c(F)cc(CBr)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1c(F)cc(CC(=O)c2ccccc2)cc1F
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 68.1 %

Procedure:
To a solution of phenyl[(trimethylsilyl)-oxy]aceto-nitrile (13.7 g, 60.7 mmol) in anhydrous THF (140 mL) cooled in a dry ice/acetone bath, was added a THF solution of lithium bis(trimethylsilyl)amide (62 mL 1.0M) slowly over 15 minutes. The reaction mixture was stirred for 45 minutes cooling at −78° C., then a solution of 5-(bromomethyl)-1,3-difluoro-2-(methylthio)benzene (14.7 g, 58 mmol) in anhydrous THF (20 mL) was added over 10 minutes. The reaction mixture was allowed to warm to room temperature, and stirred for 18 hours. To this mixture was added 5% HCl (300 mL) and the mixture stirred for one hour. The resulting oil was extracted with ethyl acetate (1×400 mL, 2×100 mL). To the combined extracts was added 5% sodium hydroxide (200 mL), and the mixture stirred for one hour. Additional water (200 mL) was added, the organic phase was separated, and the aqueous phase extracted with ethyl acetate (2×150 mL). The combined extracts were dried using magnesium sulfate, and concentrated. Chromatography on silica gel with 15% dichloromethane in hexanes initially and eluting the product with 30% gave 2-[3,5-difluoro-4-(methylthio)phenyl]-1-phenylethanone as light yellow solid (11.0 g, 68%). MP 71.8-71.9° C. 1H NMR (CDCl3/400 MHz) 7.96-7.99 (m, 2H), 7.57-7.61 (m, 1H), 7.24-7.50 (m, 2H), 6.80-6.85 (m, 2H), 4.24 (s, 2H), 2.42 (s, 3H). HRMS m/z 279.0667 (M+H+, calcd 279.0655). Anal. Calcd for C15H12F2OS: C, 64.73; H, 4.35. Found: C, 64.70; H, 4.38.
Reaction SMILES: C(O[C:6]([NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])[CH:17]=2)[CH:12]=[CH:11][CH:10]=1)=O)(C)(C)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:25][O:24][CH2:23][CH2:22][O:21][CH2:20][O:19][C:16]1[CH:17]=[C:18]2[C:13]([CH:12]=[CH:11][CH:10]=[C:9]2[NH:8][CH3:6])=[CH:14][CH:15]=1
Reactant: COCCOCOc1ccc2cccc(NC(=O)OC(C)(C)C)c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNc1cccc2ccc(OCOCCOC)cc12
Temperature: 65 °C
Reaction time: 1.17 h

Procedure:
A mixture of 1-(tert-butoxycarbonylamino)-7-[(2-methoxyethoxy)methoxy]naphthalene, as described above in Step A, (1.59 g, 4.58 mmol) and LAH (11.4 mL of a 1.0 M solution in THF, 11.4 mmol) in dry THF (100 mL) was heated to 65° C., under argon. After 70 min, the reaction mixture was cooled to ambient temperature and quenched with saturated aqueous NH4Cl (5 mL). Most of the THF was removed by concentration under reduced pressure, and the residual mixture was partitioned between water (500 mL) and CH2Cl2 (250 mL). The aqueous layer was extracted further with CH2Cl2 (250 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with hexane −25% EtOAc to yield the titled product.
Reaction SMILES: Cl([O-])=[O:2].[Na+].[Cl:5][C:6]1[N:7]=[C:8]([NH:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[S:9][C:10]=1[CH:11]=[O:12]>O.C(#N)C.CC(O)(C)C.CC(=CC)C>[C:14]([NH:13][C:8]1[S:9][C:10]([C:11]([OH:2])=[O:12])=[C:6]([Cl:5])[N:7]=1)(=[O:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1sc(NC(=O)c2ccccc2)nc1Cl
Agent: CC=C(C)C
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: CC#N
Product: O=C(Nc1nc(Cl)c(C(=O)O)s1)c1ccccc1
Reaction time: 1 h
Yield: 17 %

Procedure:
A solution of sodium chlorite (2.20 g, 19.40 mmol) and NaH2PO4 (2.32 g, 19.10 mmol) in water (10 mL) was added to a mixture of N-(4-chloro-5-formylthiazol-2-yl)benzamide (0.52 g, 1.95 mmol) in acetonitrile (20 mL), t-BuOH (20 mL) and 2-methyl-2-butene (4 mL) at 0° C. The mixture was stirred for 1 h, then extracted with chloroform, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give the crude product in 17% yield (0.097 g), which was used for next step without purification; MS (ES+) m/z 283.3 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:43])[C:3]1[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH3:42])[C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[C:15]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28](C)[C:29](=O)OC(C)(C)C)[N:14]=2)[CH2:8][CH2:7]1.FC(F)(F)C(O)=O>ClCCl>[CH3:43][N:2]([CH3:1])[C:3]1[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH3:42])[C:4]=1[CH2:5][N:6]1[CH2:7][CH2:8][CH:9]([NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[C:15]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][CH3:29])[N:14]=2)[CH2:10][CH2:11]1
Reactant: COc1cccc(N(C)C)c1CN1CCC(Nc2nc(NCCCCN(C)C(=O)OC(C)(C)C)nc3ccccc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCCCCNc1nc(NC2CCN(Cc3c(OC)cccc3N(C)C)CC2)c2ccccc2n1

Procedure:
A solution of Compound 101 (39 mg, 0.07 mmol) and trifluoroacetic acid (0.2 ml, 0.35 mmol) in dichloromethane (3 mL) was stirred at room temperature for 2 h. The product (Compound 102) was purified by basic alumina flash column chromatography using 3% MeOH and 97% CH2Cl2 solution as eluent.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[C:7]([O:16][CH3:17])[CH:8]=[C:9]([C:12]([O:14]C)=O)[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([Mg]Br)=[CH:21][CH:20]=1>O1CCCC1>[Br:1][C:2]1[C:11]2[C:6](=[C:7]([O:16][CH3:17])[CH:8]=[C:9]([C:12]([C:22]3[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=3)([C:22]3[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=3)[OH:14])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: COC(=O)c1cc(OC)c2nccc(Br)c2c1
Solvent: C1CCOC1
Product: COc1cc(C(O)(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc2c(Br)ccnc12
Reaction time: 3 h

Procedure:
Into a 1000-mL 3-necked round-bottom flask, was placed methyl 4-bromo-8-methoxyquinoline-6-carboxylate (13 g, 43.90 mmol, 1.00 equip), tetrahydrofuran (500 mL), and (4-chlorophenyl)magnesium bromide (220 mL, 5.00 equip). The resulting solution was stirred for 3 hr at reflux temperature. The reaction was then quenched by the addition of water (400 mL). The resulting solution was extracted with ethyl acetate (3×300 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (2:1) to yield (4-bromo-8-methoxyquinolin-6-yl)bis(4-chlorophenyl)methanol as a yellow solid. LCMS (ES, m/z) 490 [M+H]+
Reaction SMILES: [C:1]1([CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+](C1C=CC=CC=1[Se]C#N)([O-])=O.C(P(CCCC)CCCC)CCC>C1COCC1>[C:1]1([CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH:12]=[CH2:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCOCCc1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: N#C[Se]c1ccccc1[N+](=O)[O-]
Solvent: C1CCOC1
Product: C=CCCOCCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
To a solution of 4-[2-phenylethoxy]butanol (3.16 g) and 2-nitrophenyl selenocyanate (4.0 g) in THF (50 ml) under argon was added tributylphosphine (4.5 ml) in THF (2 ml) dropwise over 30 min. After a further 2 hours at room temperature the solvent was removed under reduced pressure. A further 50 ml of THF was added and the mixture cooled to 0° at which point H2O2 (17 ml, 30% aqueous v/v) was added to the stirred solution over 1 hour. The mixture was allowed to warm to room temperature and stirring continued overnight. The solvent was removed under reduced pressure and the residue taken up in ether, washed with 1 molar aqueous hydrochloric acid, sodium bicarbonate solution and brine. The solution was dried, filtered and the solvent removed under reduced pressure to yield a yellow oil which was purified by chromatography using diethyl ether in petroleum ether (bp 60°-80°) as eluant to yield the subtitled compound (2.63 g, 92%).
Reaction SMILES: [CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=2[C@@H:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[O:11][C@H:10]([CH2:27][OH:28])[C:9]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=[O:32].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=2[C@@H:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[O:11][C@H:10]([C:27]([OH:32])=[O:28])[C:9]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1[C@@H](CO)O[C@H](c2ccccc2Cl)c2cc(Cl)ccc2N1Cc1ccccc1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: O=C(O)[C@H]1O[C@H](c2ccccc2Cl)c2cc(Cl)ccc2N(Cc2ccccc2)C1=O
Temperature: 25 °C

Procedure:
In 20 ml of acetone was dissolved 0.5 g of trans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-methanol obtained in Example 46. To the solution was added dropwise, while stirring at room temperature, 0.5 ml of a Jones reagent. The reaction mixture was stirred for one hour at room temperature, which was then concentrated under reduced pressure The concentrate was subjected to extraction with ethyl acetate. The organic layer was washed with water and dried, then the solvent was distilled off under reduced pressure. From the residue was obtained 0.23 g of trans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-carboxylic acid as white crystals, m.p.177°-178 C.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[CH:4]([C:5](=[O:22])[CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:21])[CH2:3]1.[CH2:23]([O:30][C:31]([NH:33][CH2:34][C:35]([CH3:40])([CH3:39])[C:36](O)=[O:37])=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:39][C:35]([CH3:40])([CH2:34][NH:33][C:31]([O:30][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:32])[C:36]([O:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[CH:4]([C:5](=[O:22])[CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:21])[CH2:3]1)=[O:37]
Reactant: C[C@]12CC[C@H](O)CC1C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: CC(C)(CNC(=O)OCc1ccccc1)C(=O)O
Product: CC(C)(CNC(=O)OCc1ccccc1)C(=O)O[C@H]1CC[C@@]2(C)C(C1)C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 92.3 %

Procedure:
Following the procedure described in Prepn. 68 and starting from 3β-hydroxyandrostane-6,17-dione (Prepn. 68, 0.50 g) and 3-(benzyloxycarbonylamino)-2,2-dimethylpropanoic acid (0.41 g), after purification by flash chromatography (SiO2; EtOAc:n-hexane 6:4) to give 3β-[(2,2-dimethyl)-3-(carbobenzyloxyamino)propionyloxy]-androstane-6,17-dione (0.81 g, 90%) was obtained. 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 7.34 (5H, m), 5.07 (2H, s), 7.01 (1H, m), 4.57 (1H, m), 2.50-1.10 (22H, m), 1.10 (6H, s), 0.78 (3H, s), 0.70 (3H, s).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9](=[O:33])[N:10]([S:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([C:24](=[O:32])[C:25]3[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=3)[CH2:19][CH2:18]4)(=[O:14])=[O:13])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[Cl:40][CH2:41][C:42](Cl)=[O:43]>ClCCl>[C:1]1([C:7]2[NH:8][C:9](=[O:33])[N:10]([S:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([C:24](=[O:32])[C:25]3[CH:26]=[CH:27][C:28]([NH:31][C:42](=[O:43])[CH2:41][Cl:40])=[CH:29][CH:30]=3)[CH2:19][CH2:18]4)(=[O:13])=[O:14])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(C(=O)N2CCc3cc(S(=O)(=O)n4cc(-c5ccccc5)[nH]c4=O)ccc32)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(CCl)Nc1ccc(C(=O)N2CCc3cc(S(=O)(=O)n4cc(-c5ccccc5)[nH]c4=O)ccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.7 %

Procedure:
4-Phenyl-1-[N-(4-aminobenzoyl)indoline-5-sulfonyl]-2-imidazolone (150 mg, 0.3 mmol) prepared in Example 10 was dissolved in 10 m of dichloromethane. Pyridine (73 μ, 0.9 mmol) and chloroacetylchloride (36 μ, 0.45 mmol) were added thereto one after another, and then the reaction mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. After stirring, the reaction mixture was diluted with 30 m of dichloromethane, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1, v/v) to afford 130 mg of the title compound as a white solid.
Reaction SMILES: B(Br)(Br)Br.[Br:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH:10]=[CH:9]2.C(OCC)C.O>C(Cl)Cl>[Br:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH:10]=[CH:9]2
Reactant: COc1ccc(S(=O)(=O)c2ccc3cc(Br)ccc3c2)cc1
Agent: BrB(Br)Br
Solvent: CCOCC
Solvent: O
Solvent: ClCCl
Product: O=S(=O)(c1ccc(O)cc1)c1ccc2cc(Br)ccc2c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 88.4 %

Procedure:
A 1M solution of boron tribromide in methylene chloride (9.65 ml) was slowly added to a stirred, cooled (−78° C.), methylene chloride (25 ml) solution of a portion (1.21 g) of the anisole derivative so obtained. The mixture was stirred for 20 hours at ambient temperature, then cooled to −10° C., diethyl ether (4 ml) slowly added, and stirring continued for 10 minutes. Water (25 ml) was added and the mixture extracted with ethyl acetate (2×25 ml). The combined organic extracts were washed with water, dried (MgSO4) and evaporated. Trituration of the residue under ether gave 4-(6-bromonaphth-2-ylsulphonyl)phenol (1.03 g), m.p. 178-180° C.;
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:15]([NH:16][CH:17]([CH3:19])[CH3:18])[C:14]([CH2:20][CH2:21][CH3:22])=[N:13][C:7]=3[C:8]([NH2:12])=[N:9][C:10]=2[CH:11]=1.[N:23]1([C:29]([C:31]2[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=2)=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[Na+].[Na+].O>C(O)CC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:17]([NH:16][N:15]1[C:6]2[C:5]3[CH:4]=[CH:3][C:2]([C:35]4[CH:34]=[CH:33][CH:32]=[C:31]([C:29]([N:23]5[CH2:28][CH2:27][O:26][CH2:25][CH2:24]5)=[O:30])[CH:36]=4)=[CH:11][C:10]=3[N:9]=[C:8]([NH2:12])[C:7]=2[N:13]=[C:14]1[CH2:20][CH2:21][CH3:22])([CH3:19])[CH3:18]
Reactant: CCCc1nc2c(N)nc3cc(Br)ccc3c2n1NC(C)C
Reactant: O=C(c1cccc(B(O)O)c1)N1CCOCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCCO
Product: CCCc1nc2c(N)nc3cc(-c4cccc(C(=O)N5CCOCC5)c4)ccc3c2n1NC(C)C
Temperature: 100 °C
Reaction time: 16 h
Yield: 52.4 %

Procedure:
A suspension of 7-bromo-N1-isopropyl-2-propyl-1H-imidazo[4,5-c]quinoline-1,4-diamine (1.00 g, 2.76 mmol) in 20 mL of 1-propanol was treated with the 3-(morpholine-4-carbonyl)phenylboronic acid (0.715 g, 3.04 mmol). The headspace of the flask was purged and back-filled with nitrogen (3×). The reaction mixture was then treated with triphenylphosphine (11 mg, 0.041 mmol), sodium carbonate (1.66 mL, 3.31 mmol, 2 M solution in H2O), H2O (2 mL), and palladium (II) acetate (3.1 mg, 0.014 mmol). Again the headspace of the flask was purged and back filled with nitrogen (3×). The reaction mixture was heated to 100° C. After 16 h, the reaction mixture was concentrated under reduced pressure to yield a brown solid. The solid was partitioned between CHCl3 (45 mL) and H2O (15 mL) and separated. The organic portion was washed again with H2O (15 mL) and brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a tan solid. The solid was purified by chromatography (SiO2, 95:5 CHCl3: MeOH) to yield a light yellow foam. The foam was crystallized from 1:1 acetonitrile (MeCN):MeOH to give N1-isopropyl-7-[3-(morpholin-4-ylcarbonyl)phenyl]-2-propyl-1H-imidazo[4,5-c]quinoline-1,4-diamine (0.683 g) as light yellow crystals. mp 274–276° C.; 1H NMR (300 MHz, DMSO-d6, 350 K) δ 8.56 (d, J=8.5 Hz, 1H), 7.86–7.81 (m, 2H), 7.74 (s, 1H), 7.57–7.52 (m, 2H), 7.38 (d, J=7.6 Hz, 1H), 6.81 (s, 1H), 6.21 (s, 2H), 3.65–3.62 (m, 4H), 3.58–3.54 (m, 5H), 2.93 (t, J=7.5 Hz, 2H), 1.96–1.83 (m, 2H), 1.07–1.02 (m, 9H); 13C NMR (75 MHz, DMSO-d6, 350 K) δ 169.5, 154.9, 152.3, 145.4, 141.1, 137.8, 136.9, 132.8, 129.4, 128.1, 126.1, 125.5, 124.6, 124.1, 122.0, 119.9, 114.7, 66.5, 51.4, 45.4, 28.3, 20.9, 20.6, 14.1; MS (APCI) m/z 473 (M+H)+; Anal. Calcd for C27H32N6O2: C, 68.62; H, 6.83; N, 17.78; Found: C, 68.73; H, 6.71; N, 17.85.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)([CH3:17])[CH3:16])=[CH:11][CH:10]=1.C(N(CC)CC)C.Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>C(OCC)C>[CH2:36]([O:35][C:33]([NH:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)([CH3:17])[CH3:16])=[CH:11][CH:10]=1)=[O:34])[CH3:37]
Reactant: CCOC(=O)Cl
Reactant: CC(C)(c1ccc(F)cc1)c1ccc(OC[C@H]2CCC[C@H]2N)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)N[C@@H]1CCC[C@@H]1COc1ccc(C(C)(C)c2ccc(F)cc2)cc1

Procedure:
To a solution of (±) cis -1-amino-2-[4-(1-(4-fluorophenyl)-1-methylethyl)phenoxymethyl] cyclopentane (0.58 g, 1.77 mmol) in dry diethyl ether (30 ml) containing triethylamine (0.49 ml, 3.54 mmol) was added a solution of ethyl chloroformate (0.29 g, 2.66 mmol) in diethyl ether (5 ml). The reaction was worked up as described in Preparation 8, and the resulting yellow oil (0.62 g) was used directly in the next stage.
Reaction SMILES: Cl.[OH:2][C:3]1[C:4]2[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=2[C:6]2[C@H:7]([CH2:13][Cl:14])[CH2:8][N:9](N)[C:10]=2[CH:11]=1.[CH3:19][S:20][S:21][CH2:22][CH2:23][C:24]([NH:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31]([C:36](O)=[O:37])=[CH:30]2)=[O:25].C(Cl)CCl>CC(N(C)C)=O>[Cl:14][CH2:13][C@H:7]1[C:6]2[C:5]3[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=3[C:3]([OH:2])=[CH:11][C:10]=2[N:9]([C:36]([C:31]2[NH:32][C:33]3[C:29]([CH:30]=2)=[CH:28][C:27]([NH:26][C:24](=[O:25])[CH2:23][CH2:22][S:21][S:20][CH3:19])=[CH:35][CH:34]=3)=[O:37])[CH2:8]1
Reactant: CSSCCC(=O)Nc1ccc2[nH]c(C(=O)O)cc2c1
Reactant: NN1C[C@@H](CCl)c2c1cc(O)c1ccccc21
Agent: Cl
Solvent: ClCCCl
Solvent: CC(=O)N(C)C
Product: CSSCCC(=O)Nc1ccc2[nH]c(C(=O)N3C[C@@H](CCl)c4c3cc(O)c3ccccc43)cc2c1

Procedure:
To a solution of 5-hydroxy-3-amino-1-[S]-(chloromethyl)-1,2-dihydro-3H-benz(e)indole, hydrochloride salt (155 mg, 0.57 mmol) and 5-(3-(methyl-disulfanyl)propanamido)-1H-indole-2-carboxylic acid (170 mg, 0.55 mmol) in 7.0 ml of DMA was added EDC (300 mg, 1.56 mmol) under Ar. After stirred over night, the mixture was evaporated to dryness, purified by SiO2 chromatography (20% to 40% THF in toluene) and crystallized with THF/Toluene/Hexane to afford 218 mg (76%) of DC101SMe. 1H NMR (DMF-d7) 11.63 (s, 1H), 10.56 (s, 1H), 9.95 (s, 1H), 8.23 (s, 2H), 7.93 (d, 1H, J=8.3 Hz), 7.56 (dd, 1H, J=2.0, 8.1 Hz), 7.52 (s, 1H), 7.47 (dd, 1H, J=1.9, 8.9 Hz), 7.41 (d, 1H, J=1.7 Hz), 7.25 (d, 1H, J=1.7 Hz), 4.88 (dd, 1H, J=8.7, 11.0 Hz), 4.73 (dd, 1H, J=2.3, 10.9 Hz), 4.31 (m, 1H), 4.12 (dd, 1H, J=3.1, 11.0 Hz), 3.95 (dd, 1H, J=8.4, 11.2 Hz), 3.21 (t, 2H, J=7.1 Hz), 2.71 (t, 2H, J=7.1 Hz), 2.45 (s, 3H); 13C NMR 169.54, 161.06, 155.36, 134.21, 133.39, 132.54, 131.05, 128.39, 127.99, 123.98, 123.74, 123.46, 123.31, 118.88, 115.99, 112.87, 112.31, 106.40, 101.33, 55.93, 48.10, 42.61, 36.92, 30.81, 25.34. MS m/z+548.2 (M+Na), 550.2 (M+2+Na).
Reaction SMILES: [OH-].[Li+].O.C([O:6][P:7]([CH2:16][C@@H:17]([OH:29])[CH2:18][NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=1)([CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])=[O:8])C.P(=O)(O)(O)O>C(O)C>[Cl:28][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[Cl:27])[CH2:20][NH:19][CH2:18][C@H:17]([OH:29])[CH2:16][P:7]([CH:9]([O:10][CH2:11][CH3:12])[O:13][CH2:14][CH3:15])(=[O:6])[OH:8]
Reactant: CCOC(OCC)P(=O)(C[C@@H](O)CNCc1ccc(Cl)c(Cl)c1)OCC
Agent: O=P(O)(O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(OCC)P(=O)(O)C[C@@H](O)CNCc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.254 g of lithium hydroxide and 6 ml of water are added to a solution of 2.26 g of 3-[N-(3,4-dichlorobenzyl)amino]-2(S)-hydroxy-propyl(diethoxymethyl)phosphinic acid ethyl ester in 3 ml of ethanol and the mixture is stirred at 60° for 24 hours. The mixture is allowed to cool to room temperature, adjusted to pH 7 with aqueous phosphoric acid and concentrated to dryness by evaporation. The evaporation residue is made into a slurry in hot methanol and filtered. The filtrate is concentrated to dryness by evaporation and the glassy evaporation residue is taken up in a small amount of ethanol. The pH value is adjusted to pH 1 with ethanolic hydrochloric acid and the solvent is removed. Crystallisation from acetonitrile yields 3-[N-(3,4-dichlorobenzyl)amino]-2(S)-hydroxy-propyl(diethoxymethyl)phosphinic acid; [α]20D =-10.8°±1.7° (c=0.595 in methanol); 1H-NMR (CD3OD): δ=7.76 (1H, m), 7.61 (1H, m), 7.45 (1H, m), 4.47 (1H, d), 4.29 (1H, m), 4.20 (2H, m), 3.80 (2H, m), 3.69 (2H, m), 3.25 (1H, dd), 3.02 (1H, d, d), 2.04 (1H, dd), 1.87 (1H, d, d); 1.20 (6H, t).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH2:6][NH2:7].CN1CCOCC1.[CH3:23][O:24][C:25]1[N:30]=[CH:29][C:28]([CH:31]=[CH:32][C:33](O)=[O:34])=[C:27]([C:36]([F:39])([F:38])[F:37])[CH:26]=1.O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>C1COCC1>[F:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH2:6][NH:7][C:33](=[O:34])[CH:32]=[CH:31][C:28]1[CH:29]=[N:30][C:25]([O:24][CH3:23])=[CH:26][C:27]=1[C:36]([F:38])([F:37])[F:39]
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Reactant: COc1cc(C(F)(F)F)c(C=CC(=O)O)cn1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COc1cc(C(F)(F)F)c(C=CC(=O)NCc2ccc(NS(C)(=O)=O)c(F)c2)cn1
Reaction time: 0.08 h
Yield: 51.6 %

Procedure:
To a suspension of 3-fluoro-4-methansulfonylaminobenzylamine hydrochloride (40 mg, 0.16 mmol) in THF (4 mL) was added N-methylmorpholine (26 μL, 0.24 mmol). After stirring for 5 minutes, 3-[6-methoxy-4-(trifluoromethyl)pyridin-3-yl]acrylic acid (32 mg, 0.13 mmol) dissolved in THF (3 mL) and 4-(4,6-dimethoxy[1,3,5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMTMM, 43 mg, 0.16 mmol) were added. The mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was diluted with EtOAc and water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by recrystallization from EtOAc/hexane to give N-(3-fluoro-4-methanesulfonylaminobenzyl)-3-(6-methoxy-4-trifluoromethylpyridin-3-yl)acrylamide (30 mg, 42.7%) as a solid.