Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([O:40][CH2:41][CH2:42][S:43][CH3:44])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:45][CH3:46])=[O:5])[CH3:2].ClC1C=CC=C(C(OO)=[O:55])C=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:29]=[C:28]([C:36]([F:37])([F:38])[F:39])[CH:27]=3)[C:22]([O:40][CH2:41][CH2:42][S:43]([CH3:44])=[O:55])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:45][CH3:46])=[O:5])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(OCCSC)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(OCCS(C)=O)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.4 %

Procedure:
(2R*,4S*)-4-{[3,5-Bis(trifluoromethyl)benzyl]-[5-(2-methylsulfanyl-ethoxy)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (150 mg) is dissolved in chloroform (1 ml), then thereto is added m-chloroperbenzoic acid (60 mg) is added thereto, and the mixture is stirred at room temperature for 2 hours. After addition of a saturated aqueous sodium hydrogen carbonate solution, the reaction mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; chloroform:methanol=19:1) to give (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-methylsulfinylethoxy)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (125 mg). MS (m/z): 690 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][C:15](B4OC(C)(C)C(C)(C)O4)=[C:16]([F:19])[CH:17]=3)[CH2:12][N:11]([CH3:29])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:31]1[N:32]=[N:33][C:34]([O:37][CH:38]([F:40])[F:39])=[CH:35][CH:36]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([C:31]4[N:32]=[N:33][C:34]([O:37][CH:38]([F:40])[F:39])=[CH:35][CH:36]=4)=[C:16]([F:19])[CH:17]=3)[CH2:12][N:11]([CH3:29])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: FC(F)Oc1ccc(Cl)nn1
Reactant: CN1Cc2cc(B3OC(C)(C)C(C)(C)O3)c(F)cc2C(c2ccc(Cl)c(Cl)c2)C1
Product: CN1Cc2cc(-c3ccc(OC(F)F)nn3)c(F)cc2C(c2ccc(Cl)c(Cl)c2)C1
Yield: 66 %

Procedure:
A procedure similar to the one in Step A of Example 29 was used to couple (+)-4-(3,4-dichlorophenyl)-6-fluoro-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline with 3-chloro-6-(difluoromethoxy)pyridazine. (+)-4-(3,4-Dichlorophenyl)-7-(6-(difluoromethoxy)pyridazin-3-yl)-6-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinoline was obtained in 66% yield as a brown oil: ESI MS m/z 454 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[CH2:13]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)[CH2:14][CH3:15]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[S:22]([C:19]2[CH:20]=[CH:21][C:16]([CH2:13][CH2:14][CH3:15])=[CH:17][CH:18]=2)(=[O:24])=[O:23])=[CH:6][CH:7]=1
Reactant: Fc1ccc(C2CCCN2)cc1
Reactant: CCCc1ccc(S(=O)(=O)Cl)cc1
Product: CCCc1ccc(S(=O)(=O)N2CCCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, colorless oil, MS: m/e=347 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and 4-propyl-benzenesulfonyl chloride.
Reaction SMILES: NC(N)=O.[I:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[CH2:13]([N:15]=[C:16]=[O:17])[CH3:14]>N1C=CC=CC=1>[CH2:13]([NH:15][C:16]([NH:12][C:9]1[CH:8]=[CH:7][C:6]([I:5])=[CH:11][N:10]=1)=[O:17])[CH3:14]
Reactant: CCN=C=O
Reactant: Nc1ccc(I)cn1
Agent: NC(N)=O
Solvent: c1ccncc1
Product: CCNC(=O)Nc1ccc(I)cn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 92.3 %

Procedure:
Step-1. 5-tributylstannanyl-pyridin-2-yl)-urea. (85) To 5-iodo-pyridin-2-ylamine (0.5 g, 2.27 mmol) in pyridine (2.5 mL) was added ethylisocyanate (0.24 g, 3.4 mmol)). The reaction mixture was stirred at room temperature for 72 h, concentrated. Water (40 mL) was added, stirred for 0.5 h, filtered, washed with water, dried to afford 0.61 g (92%) of 1-ethyl-3-(5-iodo-pyridin-2-yl)-urea, MR-66, as white solid. To MR-66 (0.5 g, 1.72 mmol) and bis-tributyltin (5.6 g, 9.64 mmol) in dioxane (25 mL) was added bis-triphenylphosphine palladium dichloride (0.28 g, 0.4 nmol). Ar gas was bubbled through the stirred reaction for 5 min. The reaction was stirred at 90° C. under Ar for 20 h. The reaction was cooled to room temperature, concentrated. The residue was purified by silica gel column chromatography using 30% ethyl acetate in hexanes to afford 0.41 g (53%) of (85) as viscous liquid.
Reaction SMILES: [C:1]([CH2:6][S:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18])([O:3][CH2:4][CH3:5])=[O:2].ClC1C=CC=C(C(OO)=[O:30])C=1>C(Cl)Cl>[C:1]([CH2:6][S:7]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:30])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)CSc1c(C(=O)OCC)[nH]c2ccccc12
Solvent: ClCCl
Product: CCOC(=O)CS(=O)c1c(C(=O)OCC)[nH]c2ccccc12

Procedure:
3-[(Carbethoxymethyl)thio]-2-carbethoxyindole is treated with m-chloroperbenzoic acid (1 eq.) in methylene chloride at 0° C. The reaction is followed by TLC. After starting material is consumed the reaction mixture is washed with sat. NaHCO3 and sat. NaCl. The organic layer is dried. 3-[(Carbethoxymethyl)sulfinyl]-2-carbethoxyindole may be isolated by flash column chromatography followed by recrystallization.
Reaction SMILES: [O:1]([CH2:8][CH:9]([CH:11]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][NH:12]1)[OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18](OC(=O)C)(=O)[CH3:19]>>[CH2:18]([N:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:11]1[CH:9]([CH2:8][O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[OH:10])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: OC(COc1ccccc1)C1CCCCCN1
Product: CCN1CCCCCC1C(O)COc1ccccc1

Procedure:
The free base of the title compound is prepared by reacting α-phenoxymethyl-2-homopiperidinemethanol with acetic anhydride and following the procedure of Example 12.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([Cl:16])[N:14]=3)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[F:17][C:18]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:19]=1[CH2:20][CH2:21]Br>>[F:17][C:18]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:19]=1[CH2:20][CH2:21][N:1]1[CH2:2][CH2:3][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([Cl:16])[N:14]=3)[CH2:9][CH2:8]2)[CH2:5][CH2:6]1
Reactant: Fc1ccc(CCBr)c(F)c1
Reactant: Clc1ccc2c(n1)N(C1CCNCC1)CC2
Product: Fc1ccc(CCN2CCC(N3CCc4ccc(Cl)nc43)CC2)c(F)c1
Yield: 7.8 %

Procedure:
1-(Piperidin-4-yl)-6-chloro-7-azaindoline (0.5 g) and 2,4-difluorophenethyl bromide (0.43 g) were treated as in Example 2 to give the hydrochloride (74 mg) of the title compound as a brown powder (yield: 7.8%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:30])[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([CH2:25][NH:26][CH2:27][CH2:28][CH3:29])[CH:19]=2)[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:31]#[C:32]Br>C(O)C>[CH2:1]([O:8][C:9](=[O:30])[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:19]=[C:20]3[C:21](=[CH:22][CH:23]=2)[N:24]=[C:32]([NH2:31])[N:26]([CH2:27][CH2:28][CH3:29])[CH2:25]3)[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCNCc1cc(Oc2cccc(NC(=O)OCc3ccccc3)c2)ccc1N
Reactant: N#CBr
Solvent: CCO
Product: CCCN1Cc2cc(Oc3cccc(NC(=O)OCc4ccccc4)c3)ccc2N=C1N
Temperature: 25 °C

Procedure:
A mixture of [3-(4-Amino-3-propylaminomethyl-phenoxy)-phenyl]-carbamic acid benzyl ester (0.032 mol) and cyanogen bromide (0.035 mol) in ethanol (250 mL) was stirred and refluxed for 2 hours, then the reaction mixture was cooled to room temperature and the solvent was evaporated. The residue was converted into its free base with a NaOH solution and the resulting mixture was extracted with CH2Cl2. The organic layer was separated and the solvent was evaporated, then the residue was stirred in diisopropyl ether, filtered off and dried under vacuum to yield the title compound as a solid.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([O:8][C:9]2[C:14]([CH:15](C)C)=C(S([O-])(=O)=O)C=CC=2C)=[CH:6][CH:5]=1)([O-:3])=[O:2].[K].[C:26]1(=[O:36])[NH:30][C:29](=[O:31])[C:28]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]12>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH:14]([N:30]2[C:29](=[O:31])[C:28]3=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]3[C:26]2=[O:36])[CH3:15])=[CH:23][CH:24]=1)([O-:3])=[O:2]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1ccc(S(=O)(=O)[O-])c(C(C)C)c1Oc1ccc([N+](=O)[O-])cc1
Agent: [K]
Solvent: CN(C)C=O
Product: CC(COc1ccc([N+](=O)[O-])cc1)N1C(=O)c2ccccc2C1=O
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A mixture consisting of 77 g of 2-(4-nitrophenoxy)-1-methylethyl-p-toluenesulfonate, 45 g of potassium salt of phthalimide and N,N-dimethylformamide was heated at 110° C. for 3 hr. with stirring. The reaction mixture was extracted with ethyl acetate; the extract was washed consecutively with water and saturated saline, and dried with anhydrous sodium sulfate. The solvent was thereafter distilled off under reduced pressure; the residue was dissolved in ethanol and left standing overnight in refrigirator. Crystals thus isolated were filtered off, dried, and yielded 38.5 g of N-{2-(4-nitrophenoxy)-1-methylethyl}phthalimide in crystalline form.
Reaction SMILES: Br[CH2:2][CH2:3][NH:4][C:5](=[O:9])[O:6][CH2:7][CH3:8].[NH:10]1[CH2:15][CH2:14][CH:13]([N:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[NH:18][C:17]2=[O:25])[CH2:12][CH2:11]1.C(=O)([O-])O.[Na+]>C(O)C>[O:25]=[C:17]1[N:16]([CH:13]2[CH2:12][CH2:11][N:10]([CH2:2][CH2:3][NH:4][C:5](=[O:9])[O:6][CH2:7][CH3:8])[CH2:15][CH2:14]2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[NH:18]1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: CCOC(=O)NCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)NCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1

Procedure:
A mixture of 12.94 parts of ethyl (2-bromoethyl)carbamate, 13.51 parts of 1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, 10.1 parts of sodium hydrogen carbonate and 160 parts of ethanol is stirred and refluxed overnight. The reaction mixture is cooled, filtered over hyflo and the filtrate is evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane, 10% of methanol and one drop of ammonium hydroxide, as eluent. The pure fractions are collected and the eluent is evaporated, yielding 4.4 parts of ethyl 2-[4-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]ethylcarbamate as a residue.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([Cl:22])=[CH:7][C:8]([Cl:21])=[C:9]([N:11]2[C:19](=[O:20])[N:14]3[CH2:15][CH2:16][CH2:17][CH2:18][C:13]3=[N:12]2)[CH:10]=1)(=[O:3])[CH3:2].[Br:23]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[C:1]([O:4][C:5]1[C:6]([Cl:22])=[CH:7][C:8]([Cl:21])=[C:9]([N:11]2[C:19](=[O:20])[N:14]3[CH2:15][CH2:16][CH2:17][CH:18]([Br:23])[C:13]3=[N:12]2)[CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(-n2nc3n(c2=O)CCCC3)c(Cl)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)Oc1cc(-n2nc3n(c2=O)CCCC3Br)c(Cl)cc1Cl
Temperature: 25 °C
Yield: 93.6 %

Procedure:
To a solution of 3.55 g (10.4 mmol) of 5,6,7,8-tetrahydro-2-(5-acetyloxy-2,4-dichlorophenyl)-1,2,4-triazolo[4,3-α]pyridin-3(2H)-one in 100 mL of carbon tetrachloride was added 2.03 g (11.4 mmol) of N-bromosuccinimide at room temperature. The mixture was warmed under reflux by irradiating with a sun lamp for 3h. The mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel, eluting with a 1:1 v:v mixture of ethyl acetate and n-hexane to give 4.10 g of the title product of Step 1 as a white solid, m.p.: 75°-83° C.; 1H NMR (CDCl3, 300 MHz) δ 7.6 (s,1H), 7.35 (s,1H), 5.25 (m,1H), 4.0 (m,1H), 3.6 (m,1H), 2.75 (s,3H), 2.5-1.9 (m,4H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][S:9]([CH2:12][CH2:13][OH:14])(=[O:11])=[O:10])[CH:5]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][C@@H:16]2[CH3:21])[N:3]=1.CC1(C)C(C)(C)OB([C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.COCCOC.O.C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:34][C:33]1[CH:35]=[CH:36][C:30]([C:2]2[N:7]=[C:6]([CH2:8][S:9]([CH2:12][CH2:13][OH:14])(=[O:11])=[O:10])[CH:5]=[C:4]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][C@@H:16]3[CH3:21])[N:3]=2)=[CH:31][CH:32]=1
Reactant: C[C@H]1COCCN1c1cc(CS(=O)(=O)CCO)nc(Cl)n1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: C[C@H]1COCCN1c1cc(CS(=O)(=O)CCO)nc(-c2ccc(N)cc2)n1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
trans-Dichlorobis(triphenylphosphine)palladium (II) (0.013 g, 0.02 mmol) was added to 2-[[2-chloro-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-4-yl]methylsulfonyl]ethanol (0.122 g, 0.36 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.119 g, 0.54 mmol) and sodium carbonate (0.908 mL, 1.82 mmol) in 18% DMF in a mixture of DME:water:ethanol (7:3:2) (10 mL) at RT under nitrogen. The resulting solution was stirred at 80° C. for 2 hours. The reaction was cooled and partitioned between ethyl acetate and water. The reaction mixture was extracted with ethyl acetate twice and the combined organics dried (MgSO4) filtered and concentrated in vacuo to give the desired (0.143 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH:15]([CH2:21][CH2:22][OH:23])[CH2:16][CH2:17][O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH:15]([CH2:21][CH2:22][O:23][S:32]([CH3:31])(=[O:34])=[O:33])[CH2:16][CH2:17][O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1cccc(F)c1)c1ccc2c(c1)OCCC2CCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCC1CCOc2cc(S(=O)(=O)c3cccc(F)c3)ccc21
Reaction time: 2 h

Procedure:
A solution of 2-[7-(3-Fluoro-benzenesulfonyl)-chroman-4-yl]-ethanol (1.35 g, 4.01 mmol) in CH2Cl2 (40 ml) was cooled to 0° C. Et3N (4.06 g, 40.2 mmol) was added at 0° C. followed by methanesulfonylchloride (0.91 g, 8.00 mmol). The reaction mixture was stirred in an ice bath for 2 hours, then diluted with CH2Cl2, washed with brine, dried with MgSO4, filtered and concentrated to give AN oil residue. The residue was purified with flash chromatography to give methanesulfonic acid 2-[7-(3-fluoro-benzenesulfonyl)-chroman-4-yl]-ethyl ester as a clear oil: 1.35 g; MS: 415.2 (M+H)+, 829.2 (2M+H)+.
Reaction SMILES: [CH2:1]([N:5]([S:19]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[C@H:6]([C:16]([OH:18])=[O:17])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:15])[CH2:13]I)[CH:2]([CH3:4])[CH3:3].CCN(CCO)CC.[CH2:37]([NH2:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH3:28][C:25]1[CH:26]=[CH:27][C:22]([S:19]([N:5]([C@H:6]([C:16]([OH:18])=[O:17])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([CH2:13][NH:44][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:15])[CH2:1][CH:2]([CH3:4])[CH3:3])(=[O:21])=[O:20])=[CH:23][CH:24]=1
Reactant: NCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)CI)C(=O)O)cc1
Agent: CCN(CC)CCO
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)CNCc2ccccc2)C(=O)O)cc1

Procedure:
The title compound was prepared from Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-Nε-iodoacetyl-L-lysine (200 mg, 0.38 mmol, example 105, step B) by following the indications of general procedure H using DEEA (0.20 mL, 1.10 mmol) and benzylamine (320 mg, 2.99 mmol). The crude material was purified by preparative HPLC. The product was isolated as a solid (137 mg, 71% yield).
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH:13]2[O:14][CH2:15][CH:16]([OH:17])[CH:12]2[O:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[Na].I[CH3:21]>C(#N)C>[CH2:1]([O:8][CH:9]1[CH2:10][O:11][CH:12]2[CH:16]([O:17][CH3:21])[CH2:15][O:14][CH:13]12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: OC1COC2C(OCc3ccccc3)COC12
Agent: O[Na]
Solvent: CC#N
Product: COC1COC2C(OCc3ccccc3)COC12
Temperature: 45 °C
Yield: 92.1 %

Procedure:
To a solution of 6-(benzyloxy)hexahydrofuro[3,2-b]furan-3-ol (8.1 g, 34 mmol) in acetonitrile (100 mL) was added hydroxyl sodium (4.12 g, 103 mmol) and iodomethane (9.76 g, 68.8 mmol). The reaction was heated to 45° C. for 8 h and concentrated in vacuo. The residue was diluted with EtOAc (500 mL) and filtered. The filtrate was washed with H2O (50 mL×3), dried with Na2SO4 filtered and concentrated in vacuo to give the title compound as yellow oil (7.84 g, 91.4%).
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6](Br)[CH:5]=1.[F:14][C:15]([F:26])([F:25])[C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1>>[CH3:11][O:10][C:7]1[C:6]([C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([C:15]([F:26])([F:25])[F:14])[CH:21]=2)=[CH:5][C:4]([C:3]([OH:2])=[O:13])=[CH:9][CH:8]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(OC)c(Br)c1
Product: COc1ccc(C(=O)O)cc1-c1cccc(C(F)(F)F)c1

Procedure:
3-bromo-4-methoxybenzoic acid methyl ester was coupled to 3-trifluoromethyl-phenylboronic acid in analogy to step 3 of example 92, and the obtained ester intermediate was hydrolyzed in analogy to step 4 of example 1 to yield 6-methoxy-3′-trifluoromethyl-biphenyl-3-carboxylic acid. This intermediate was coupled to the compound of step 1 of example 361 in analogy to step 1 of example 3, and the obtained ester intermediate was hydrolyzed in analogy to step 4 of example 1 to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[OH:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([NH:26][NH2:27])=[O:25])=[CH:22][CH:21]=1.ClC1C(C)=C(N[C@H]([C@@H](O)C)C(NNC(=O)C2C=CC=CC=2)=O)C=CC=1C#N>CO.CCOC(C)=O>[Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12]([NH:27][NH:26][C:24](=[O:25])[C:23]2[CH:28]=[CH:29][C:20]([OH:19])=[CH:21][CH:22]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1c(N[C@@H](C(=O)O)[C@H](C)O)ccc(C#N)c1Cl
Reactant: NNC(=O)c1ccc(O)cc1
Agent: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccccc2)[C@H](C)O)ccc(C#N)c1Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(O)cc2)[C@H](C)O)ccc(C#N)c1Cl

Procedure:
(2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (intermediate 1a) (534 mg, 1.9 mmol) and 4-hydroxy-benzohydrazide (304 mg, 2.0 mmol) were coupled similarly to the procedure described for the preparation of intermediate 1b. After column chromatography (3% methanol/EtOAc) the title compound was isolated as a white solid (490 mg, 61%). 1H NMR (500 MHz, acetone-d6, δ in ppm) 9.76 (br s, 1H), 9.49 (br s, 1H), 9.15 (br s, 1H), 7.83 (AA′XX′, =8.8 Hz, 2H), 7.46 (d, J=8.6 Hz, 1H), 6.89 (AA′XX′, J=8.8 Hz, 2H), 6.64 (d, J=8.7 Hz, 1H), 5.53 (d, J=7.2 Hz, 1H), 5.01 (br s, 1H), 4.39 (m, 1H), 4.11 (dd, J=3.0, 6.4 Hz, 1H), 2.33 (s, 3H), 1.33 (d, J=6.5 Hz, 3H).
Reaction SMILES: [C:1](O)(=[O:4])[CH2:2][CH3:3].C1C=NC2N(O)N=NC=2C=1.[CH3:16][O:17][C:18]1[CH:34]=[CH:33][C:21]([CH2:22][N:23]2[CH:28]=[C:27]([Br:29])[C:26]([CH3:30])=[C:25]([NH2:31])[C:24]2=[O:32])=[CH:20][CH:19]=1.C(Cl)CCl>C(Cl)Cl.CN(C=O)C>[C:1]([NH:31][C:25]1[C:24](=[O:32])[N:23]([CH2:22][C:21]2[CH:33]=[CH:34][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[CH:28]=[C:27]([Br:29])[C:26]=1[CH3:30])(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)O
Reactant: COc1ccc(Cn2cc(Br)c(C)c(N)c2=O)cc1
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCC(=O)Nc1c(C)c(Br)cn(Cc2ccc(OC)cc2)c1=O
Reaction time: 8 h
Yield: 44.3 %

Procedure:
To a solution of 2-(S)-tbutoxycarbonylamino-3-[4′-(1″-tbutoxycarbonyl-1″-methyl)ethyl]benzene]propanoic acid (3.20 g, 7.88 mmol) in methylene chloride (20 ml,) and DMF (5 mL) at 0° C. were added HOAT (1.07 g) and 1-(4-methoxybenzyl)-5-bromo-4-methyl-3-amino-2-pyridone (2.80 g, 8.67 mmol). EDC (1.66 g) and TMP (1.04 mL) were added, and the mixture was stirred coming to rt overnight. The methylene chloride was evaporated and DMF (25 mL) was added. Additional EDC (0.80 ;), HOAT (0.50 g) and TMP (0.5 mL) were added. After 3 hours the mixture was diluted with ethyl acetate, and washed with 1N HCl, aqueous sodium bicarbonate and brine. The organic phase was dried (MgSO4), filtered and evaporated. Chromatography of the residue over silica gel (ethyl acetate/hexane 1/3) gave 1-[2′-(S)-tbutoxycarbonylamino-)′-[4″-(1′″-tbutoxycarbonyl-1′″-methyl)ethyl]benzene]propanoylamino-5-bromo-1-(4-methoxybenzyl)-4-methyl-2-pyridone (2.48 g, 3.49 mmol, 44%).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[S:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].Cl.CN(C)CCCN=C=NCC.[CH3:32][C@@H:33]1[CH2:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[NH:34]1>CN(C=O)C.N1C=CC=CC=1>[CH3:32][C@@H:33]1[CH2:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]1[C:16](=[O:18])[CH2:15][C:3]1[N:2]([CH3:1])[C:7](=[S:8])[CH:6]=[C:5]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[N:4]=1
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=S
Reactant: C[C@@H]1Cc2ccccc2N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: C[C@@H]1Cc2ccccc2N1C(=O)Cc1nc(N2CCOCC2)cc(=S)n1C

Procedure:
The product is prepared by following the procedure described in example 4e (step 4e) using 250 mg of sodium (1-methyl-4-morpholin-4-yl-6-thioxo-1,6-dihydropyrimidin-2-yl)acetate in 6 ml of DMF and 6 ml of pyridine are added 512 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride and 126 mg of (R)-2-methyl-2,3-dihydro-1H-indole (which can be prepared according to Krasnov, V. P. et al. (Mendeleev Commun. 2002, 12(1), 27-28)).
Reaction SMILES: [CH2:1]([S:3]([C:5]1[O:6][C:7]2[C:12]([C:13](=[O:23])[C:14]=1[CH2:15][O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1)=[CH:11][CH:10]=[CH:9][CH:8]=2)=O)[CH3:2].[C:24]([C:28]1[CH:35]=[CH:34]C(CS)=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25]>C(#N)C>[C:24]([C:28]1[CH:35]=[CH:34][C:2]([CH2:1][S:3][C:5]2[O:6][C:7]3[C:12]([C:13](=[O:23])[C:14]=2[CH2:15][O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)c1ccc(CS)cc1
Reactant: CCS(=O)c1oc2ccccc2c(=O)c1COC1CCCCO1
Solvent: CC#N
Product: CC(C)(C)c1ccc(CSc2oc3ccccc3c(=O)c2COC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
Into a 25 mL round bottom flask is introduced 2-ethylsulfinyl-3-((2-tetrahydropyranyloxy)methyl) chromen-4-one (5 g, 14.87 mmol). Acetonitrile is then added to it followed by 4-tertbutylbenzyl mercaptan (74.3 mmol). The reaction mixture is stirred for 10 hours at room temperature after which the solvent is removed in vacuo. The crude residue obtained is purified by silica gel chromatography (ethyl acetate:hexanes) to obtain the product.