Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].[CH:23]1([CH2:29][N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[K+].[Br-]>>[Cl:18][C:17]1[C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:33]3[CH2:34][CH2:35][N:30]([CH2:29][CH:23]4[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]4)[CH2:31][CH2:32]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:16]=1
Reactant: O=C(Cl)Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1
Reactant: C1CCC(CN2CCNCC2)CC1
Agent: [Br-]
Agent: [K+]
Product: O=C(Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)N1CCN(CC2CCCCC2)CC1

Procedure:
The hydrochloride of the title compound was prepared from 4-(3-chloro-5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-cyclohexylmethyl-piperazine, yield 76%. White crystals, m.p. 265-266° C.; IR (KBr): ν 1732 (C═O) cm−1.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].ClCCl.[CH2:9]([C@H:12]1[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([CH2:26][OH:27])[CH2:22][CH2:21]2)[CH2:14][CH2:13]1)[CH2:10][CH3:11].Cl>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[CH3:1][S:2]([O:27][CH2:26][C@H:23]1[CH2:22][CH2:21][C@H:20]([CH2:19][CH2:18][C@H:15]2[CH2:16][CH2:17][C@H:12]([CH2:9][CH2:10][CH3:11])[CH2:13][CH2:14]2)[CH2:25][CH2:24]1)(=[O:4])=[O:3]
Reactant: CCC[C@H]1CC[C@H](CC[C@H]2CC[C@H](CO)CC2)CC1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC[C@H]1CC[C@H](CC[C@H]2CC[C@H](COS(C)(=O)=O)CC2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methanesulfonyl chloride (15.0 mL) was added by titration under water-cooling conditions to dichloromethane solution (200 mL) of trans-4-(2-(trans-4-propylcyclohexyl)ethyl)cyclohexyl methanol (47.3 g), and then pyridine (17.0 mL) was also added by titration, with the temperature maintained. After being cooled down to room temperature, 4-(N,N-dimethylamino)pyridine (2.6 g) was added, and the resultant was stirred continuously at room temperature for 16 hours. After the reaction was halted by adding 3M hydrochloric acid to a reaction solution, an organic layer was separated and extracted from a water layer by using dichloromethane. The thus collected organic layer was washed by using 3M hydrochloric acid, water, a saturated sodium bicarbonate aqueous solution and brine in that order, and dried with anhydrous magnesium sulphate. Solvents were removed by distillation to obtain a slightly yellow solid. The thus obtained solid was purified by column chromatography (alumina, toluene) and also subjected to recrystallization (toluene/hexane), thereby obtaining a colourless scaly crystal of 51.5 g.
Reaction SMILES: [C:1]([Si:5]([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:12]([S:19]C#N)=[CH:11][C:10]=1[CH3:22])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].SC[C@H]([C@@H](CS)O)O.OP([O-])([O-])=O.[K+].[K+]>CCO>[C:15]([C:13]1[CH:14]=[C:9]([O:8][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:6])[CH3:7])[C:10]([CH3:22])=[CH:11][C:12]=1[SH:19])([CH3:18])([CH3:17])[CH3:16]
Reactant: Cc1cc(SC#N)c(C(C)(C)C)cc1O[Si](C)(C)C(C)(C)C
Agent: O=P([O-])([O-])O
Agent: O[C@H](CS)[C@H](O)CS
Agent: [K+]
Solvent: CCO
Product: Cc1cc(S)c(C(C)(C)C)cc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C

Procedure:
A solution of 3.02 g (9.00 mmol) of tert-butyl-(5-tert-butyl-2-methyl-4-thiocyanato-phenoxy)-dimethyl-silane (prepared in Example HHH), 2.3 g (12 mmol) of dithiothreitol, EtOH (20 mL), and 0.02M potassium dibasic phosphate buffer (10 mL) was heated to 50° C. overnight. The mixture was cooled to room temperature, diluted with hexanes and washed with H2O. The organic layer was then dried (Na2SO4) and the solvent removed in vacuo to yield the title compound. 1H NMR (CDCl3) δ 0.20 (s, 6 H), 1.00 (s, 9 H), 1.44 (s, 9 H), 2.10 (s, 3 H), 3.42 (s, 1 H), 6.80 (s, 1 H), 7.04 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[C:10](=[O:18])[CH2:9]2)=[CH:4][CH:3]=1.[OH:19][C:20]1C=C2C(C(C3C=CC=CC=3)CC2=O)=C[CH:21]=1>>[C:20]([O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH2:9][C:10]2=[O:18])(=[O:19])[CH3:21]
Reactant: O=C1CC(c2ccc(F)cc2)c2ccc(O)cc21
Reactant: O=C1CC(c2ccccc2)c2ccc(O)cc21
Product: CC(=O)Oc1ccc2c(c1)C(=O)CC2c1ccc(F)cc1
Reaction time: 2 h
Yield: 99 %

Procedure:
The procedure of Step 3 of Example 1 was repeated except for using 3-(4-fluorophenyl)-2,3-dihydro-6-hydroxyinden-1-one obtained in Step 2 as a starting material instead of 2,3-dihydro-6-hydroxy-3-phenylinden-1-one and being stirred for 2 h to obtain the title compound (99%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([N+:16]([O-])=O)[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4]>CO.[Pd]>[NH2:16][C:13]1[CH:14]=[CH:15][C:8]2[CH2:7][CH2:6][N:5]([C:3](=[O:4])[C:2]([F:20])([F:1])[F:19])[CH2:11][CH2:10][C:9]=2[CH:12]=1
Reactant: O=C(N1CCc2ccc([N+](=O)[O-])cc2CC1)C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
To a suspension of 2,2,2-trifluoro-1-(7-nitro-1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)ethanone (1.1 mmol) in MeOH (5 mL) was added 10% Pd/C and the mixture was stirred at RT under H2 (1 atm) for 24 h. After filtration, the filtrate was concentrated to afford 1-(7-amino-1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-2,2,2-trifluoroethanone (0.27 g, 95% yield). LC-MS (EI) m/z: 259.0 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[CH:15]=[C:16]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])[CH:17]=[C:18]([C:20](=[O:28])[C:21]3[CH:26]=[CH:25][C:24](F)=[CH:23][CH:22]=3)[CH:19]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:34](=O)([O-])[O-:35].[K+].[K+].O>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[CH:15]=[C:16]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])[CH:17]=[C:18]([C:20](=[O:28])[C:21]3[CH:26]=[CH:25][C:24]([O:35][CH3:34])=[CH:23][CH:22]=3)[CH:19]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)CCc1cc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc(C(=O)c2ccc(F)cc2)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1ccc(C(=O)c2cc(CCNS(=O)(=O)c3ccc(Cl)cc3)cc(CCC(=O)O)c2)cc1
Yield: 85.9 %

Procedure:
A mixture of 3-[2-[(4-chlorophenyl)sulphonylamino]ethyl]-5-(4-fluorobenzoyl)benzenepropanoic acid (0.25 g) and potassium carbonate (0.212 g) in anhydrous methanol (5.0 ml) was heated under reflux for 18 hours. Additional potassium carbonate (0.212 g) was added and the mixture was heated under reflux for a further 20 hours and then cooled. Water (15 ml) was added and the solution was evaporated to about 10 ml and then acidified with 2N hydrochloric acid. The mixture was extracted several times with ethyl acetate and the combined extracts were washed with water and dried (MgSO4). Evaporation of the solvent gave the title compound as a glass (0.22 g). Found: C,60.25; H,4.92; N,2.51. C25H24ClNO6S requires C,59.81; H,4.82; N,2.79%.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[C:11]([CH3:13])[C:10]([I:14])=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6])[CH3:2].[OH-].[Na+]>CO.O>[CH2:1]([C:3]1[CH:12]=[C:11]([CH3:13])[C:10]([I:14])=[CH:9][C:4]=1[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCc1cc(C)c(I)cc1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCc1cc(C)c(I)cc1C(=O)O
Temperature: 40 °C
Reaction time: 12 h

Procedure:
To a round-bottom flask, was added a solution of methyl 2-ethyl-5-iodo-4-methylbenzoate (compound 211.2, 10.0 g, 32.9 mmol, 1.00 equiv) in methanol (40 mL). A solution of NaOH (5.26 g, 132 mmol, 4.00 equiv) in water (20 mL) was added dropwise. After stirring for 12 h at 40° C., the organic solvent was removed under reduced pressure. The pH of the remaining aqueous phase was adjusted to 4 with hydrogen chloride (aq., 6 M), then extracted with 2×100 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. This resulted in 9.30 g (97%) of 2-ethyl-5-iodo-4-methylbenzoic acid as a white solid.
Reaction SMILES: [CH:1]1([CH:7]=[C:8]2[NH:12][C:11](=[O:13])[N:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:9]2=[O:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:22](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C.O>[CH:1]1([CH:7]=[C:8]2[N:12]([CH3:22])[C:11](=[O:13])[N:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:9]2=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1NC(=CC2CCCCC2)C(=O)N1c1ccccc1F
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(=O)N(c2ccccc2F)C(=O)C1=CC1CCCCC1
Yield: 80.5 %

Procedure:
The 5-cyclohexylmethylene-3-(2-fluorophenyl)-imidazolidine-2,4-dione (2.25 g, 7.81 mmol), cesium carbonate (2.6 g, 8.0 mmol) and methyl iodide (1.66 g, 11.7 mmol) were stirred overnight in DMF (25 mL). The solution was diluted with water and extracted with ethyl acetate (3×). The combined extracts were washed with brine (saturated, 2×), dried (over MgSO4), filtered and concentrated. Purification by column chromatography afforded 1.9 grams of 5-cyclohexylmethylene-3-(2-fluorophenyl)-1-methylimidazolidine-2,4-dione, a white solid, m.p. 131°-137° C.
Reaction SMILES: Br[C:2]1[C:3]([CH3:12])=[N:4][C:5]([O:10][CH3:11])=[C:6]([CH2:8][CH3:9])[CH:7]=1.[CH3:13][C:14]1([CH3:21])[C:18]([CH3:20])([CH3:19])[O:17][BH:16][O:15]1.C(N(CC)CC)C>O1CCOCC1.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:8]([C:6]1[C:5]([O:10][CH3:11])=[N:4][C:3]([CH3:12])=[C:2]([B:16]2[O:17][C:18]([CH3:20])([CH3:19])[C:14]([CH3:21])([CH3:13])[O:15]2)[CH:7]=1)[CH3:9]
Reactant: CCc1cc(Br)c(C)nc1OC
Reactant: CC1(C)OBOC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCc1cc(B2OC(C)(C)C(C)(C)O2)c(C)nc1OC
Temperature: 90 °C
Reaction time: 18 h
Yield: 71.7 %

Procedure:
3-Bromo-5-ethyl-6-methoxy-2-methylpyridine (11.51 g, 50 mmol), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (8.31 g, 64.95 mmol) and triethylamine (21.84 ml, 164.4 mmol) were dissolved under argon in 100 ml of dioxane and then 1,1′bis(diphenylphosphino)ferrocenepalladium(II) chloride (1.94 g, 2.65 mmol) was added. The mixture was stirred at 90° C. for 18 h, cooled and diluted with ethyl acetate, and filtered through silica gel. The solution was cooled to 0° C., mixed with water and extracted twice with ethyl acetate. The dried and concentrated organic phase was chromatographed on silica gel dried at 45° C. in a vacuum drying oven. A pale beige solid (9.94 g, 72%) was obtained.
Reaction SMILES: [CH2:1]([O:15][C:16]1[O:20][C:19]([C:21]([OH:23])=[O:22])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH3:24][CH:25](O)[CH3:26]>>[CH2:1]([O:15][C:16]1[O:20][C:19]([C:21]([O:23][CH:25]([CH3:26])[CH3:24])=[O:22])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CC(C)O
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)o1
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)OC(C)C)o1

Procedure:
The title compound was prepared as described in Example 1 starting from 0.228 g (0.7 mmol) of 5-(tetradecyloxy)furan-2-carboxylic acid and 0.161 mL (2.1 mmol) of 2-propanol. MS (m/z, ES+): 366.30 (M+, 100%); 1H NMR (400 MHz, DMSO-d6) δ: 7.2 (d, 1H), 5.6 (d, 1H), 5.0 (p, 1H), 4.1 (t, 2H), 1.7 (p, 2H), 1.3-1.4 (m, 2H), 1.23 (d, 6H), 1.2 (s, 20H), 0.85 (t, 3H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([S:11]([N:14]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:17][C:16]([CH:25]=O)=[CH:15]2)(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].CO.[CH3:29][NH2:30].[BH4-].[Na+].[ClH:33].C(=O)([O-])O.[Na+]>CO>[ClH:33].[CH3:29][NH:30][CH2:25][C:16]1[CH:17]=[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:14]([S:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=2)(=[O:13])=[O:12])[CH:15]=1
Reactant: CN
Reactant: CS(=O)(=O)c1cccc(S(=O)(=O)n2cc(C=O)cc2-c2ccccc2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Product: CNCc1cc(-c2ccccc2)n(S(=O)(=O)c2cccc(S(C)(=O)=O)c2)c1
Reaction time: 0.5 h
Yield: 83 %

Procedure:
1-{[3-(Methylsulfonyl)phenyl]sulfonyl}-5-phenyl-1H-pyrrole-3-carbaldehyde (160 mg) was dissolved in methanol (20 mL), 40% methylamine methanol solution (160 mg) was added at room temperature, and the mixture was stirred for 30 min. Sodium borohydride (32 mg) was added at room temperature, and the mixture was stirred for 10 min. 1 mol/L Hydrochloric acid (20 mL) was added, and the mixture was stirred for 5 min. The reaction mixture was alkalized with a saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in methanol (5 mL), a 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL) was added, and the mixture was concentrated under reduced pressure. The residue was crystallized from tetrahydrofuran to give the title compound as colorless crystals (yield 150 mg, 83%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][C:16]=2[CH2:24][S:25][CH2:26][C:27]([F:30])([F:29])[F:28])[CH:7]=1)[CH3:2].CN(C)N.C>CCO>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH2:24][S:25][CH2:26][C:27]([F:28])([F:29])[F:30])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc([N+](=O)[O-])cc2CSCC(F)(F)F)c1
Agent: C
Agent: CN(C)N
Solvent: CCO
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(N)cc2CSCC(F)(F)F)c1

Procedure:
A solution of {4-methoxy-3-[4-nitro-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-phenyl}-acetic acid ethyl ester (1.46 g, 3.18 mmol), ferric chloride (0.026 g, 0.16 mmol), 1,1-dimethylhydrazine (1.69 mL, 22.27 mmol), and DARCO (0.300 g) in EtOH (30 mL) was stirred overnight at 65° C. The mixture was partitioned between EtOAc and H2O and extracted three times with EtOAc. The combined organic layers were washed with H2O and brine, and then dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (EtOAc in hexanes gradient) to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19](N(OC)C)=[O:20])=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:6][N:7]=1.[CH3:25][Mg+].[Br-]>C1COCC1>[NH2:1][C:2]1[C:3]([C:19](=[O:20])[CH3:25])=[N:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([S:14]([CH2:17][CH3:18])(=[O:15])=[O:16])[CH2:12][CH2:13]2)=[CH:6][N:7]=1
Reactant: CCS(=O)(=O)N1CCN(c2cnc(N)c(C(=O)N(C)OC)n2)CC1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CCS(=O)(=O)N1CCN(c2cnc(N)c(C(C)=O)n2)CC1
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 67.5 %

Procedure:
3-amino-6-(4-(ethylsulfonyl)piperazin-1-yl)-N-methoxy-N-methylpyrazine-2-carboxamide (864 mg, 2.411 mmol) was dissolved in THF (10 mL) and cooled to −20° C. under nitrogen. MeMgBr (2.411 mL of 3 M, 7.233 mmol) was added dropwise and the reaction was left to stir at this temperature for 15 minutes after which time the reaction was allowed to slowly warm to ambient temperature. A further MeMgBr (803.7 μL of 3 M, 2.411 mmol) was added and analysis showed after 10 minutes showed no SM remaining. The mixture was quenched with 10 mL 1M HCl, stirred for 5 mins and then extracted with EtOAc (3×), dried (MgSO4), filtered and the solvent removed in vacuo to give the product as an orange solid (510 mg, 68% Yield). 1H NMR (400.0 MHz, DMSO) d 1.23 (t, 3H), 2.54 (s, 3H), 3.11 (q, 2H), 3.30-3.32 (m, 4H), 3.47-3.49 (m, 4H), 7.42 (br s, 2H) and 8.34 (s, 1H) ppm; MS (ES+) 314.0
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[CH3:13][O:14][C:15](=[O:26])[CH:16]([NH2:25])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>>[CH3:13][O:14][C:15](=[O:26])[C@@H:16]([NH:25][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[OH:11])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=1
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: COC(=O)C(N)Cc1ccc(Br)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1cc(Cl)ccc1O

Procedure:
5-Chloro-2-hydroxy-benzoic acid (2.5 g, 28.97 mmol) was coupled with 2-amino-3-(4-bromo-phenyl)-propionic acid methyl ester hydrochloride (4.26 g, 28.96 mmol) with HBTU (6.59 g, 34.76 mmol) and diisopropylethylamine (8 ml, 86.9 mmol) as per general procedure A to yield the corresponding 3-(4-bromo-phenyl)-(2S)-(5-chloro-2-hydroxy-benzoylamino)-propionic acid methyl ester.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=1[CH3:32]>>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([NH:24][C:1]([C:4]23[CH2:5][CH2:6][C:7]([NH:12][CH2:13][C:14]([N:16]4[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]4[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]2)[CH2:10][CH2:11]3)=[O:3])=[C:26]([CH3:32])[CH:27]=1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: Cc1cc(Cl)ccc1N
Product: Cc1cc(Cl)ccc1NC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C#N)(CC1)CC2
Yield: 24.3 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 2-amino-5-chlorotoluene (48.2 mg) were used to obtain (2S,4S)-1-[[N-[4-[N-(4-chloro-2-methylphenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (16.8 mg).
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:8][C:9]1([CH3:19])[C:14](=[O:15])[O:13][CH2:12][C:11]([CH3:18])([CH2:16][OH:17])[NH:10]1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:8][C:9]1([CH3:19])[C:14](=[O:15])[O:13][CH2:12][C:11]([CH3:18])([CH2:16][O:17][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])[NH:10]1
Reactant: CC1(CO)COC(=O)C(C)(C)N1
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(COC(=O)C(C)(C)C)COC(=O)C(C)(C)N1
Reaction time: 16 h

Procedure:
A solution of 2.63g (0.021 mol) of pivaloyl chloride is added dropwise to a solution of 3.5 g (0.02 mol) of 3,3,5-trimethyl-5-hydroxymethylmorpholin-2-one (prepared in accordance with J. T. Lai.: Synthesis 122 (1984)) and 0.lg of 4-dimethylaminopyridine in 20 ml of dichloromethane at 15° C. After stirring for 16 hours, another 0.75 ml of pivaloyl chloride is added and the reaction mixture is stirred for 24 hours.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1C(C2NC=CN=2)=CN=C(CCN)N=1.Cl[C:24]1[N:29]=[C:28]([O:30][CH3:31])[C:27]([C:32]#[N:33])=[CH:26][CH:25]=1.[Cl:34][C:35]1[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:36]=1[C:42]1[C:47]([C:48]2[NH:49][CH:50]=[CH:51][N:52]=2)=[CH:46][N:45]=[C:44]([NH:53][CH2:54][CH2:55][NH:56]C2C=CC([N+]([O-])=O)=C(OC)N=2)[N:43]=1>>[Cl:34][C:35]1[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:36]=1[C:42]1[C:47]([C:48]2[NH:52][CH:51]=[CH:50][N:49]=2)=[CH:46][N:45]=[C:44]([NH:53][CH2:54][CH2:55][NH:56][C:24]2[N:29]=[C:28]([O:30][CH3:31])[C:27]([C:32]#[N:33])=[CH:26][CH:25]=2)[N:43]=1
Reactant: COc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Reactant: COc1nc(Cl)ccc1C#N
Agent: NCCc1ncc(-c2ncc[nH]2)c(-c2ccc(Cl)cc2Cl)n1
Product: COc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1C#N

Procedure:
6-[(2-{[4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]amino)ethyl)amino]-2-methoxypyridine-3-carbonitrile was prepared from [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-ylethylamine and 6-chloro-2-methoxypyridine-3-carbonitrile in accordance with the procedure described above for the preparation of [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(6-methoxy-5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([N:10](C)[C:11]1[N:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]3[C:23](=[C:24]([C:26]([NH2:28])=[O:27])[CH:25]=2)[NH:22][CH:21]=[C:20]3[CH:29]2[CH2:34][CH2:33][N:32]([S:35]([CH2:38][CH3:39])(=[O:37])=[O:36])[CH2:31][CH2:30]2)=[CH:13][CH:12]=1)[CH3:9].[CH3:41]NC>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:38]([S:35]([N:32]1[CH2:31][CH2:30][CH:29]([C:20]2[C:19]3[C:23](=[C:24]([C:26]([NH2:28])=[O:27])[CH:25]=[C:17]([C:14]4[CH:15]=[N:16][C:11]([NH:10][CH:8]([CH3:41])[CH3:9])=[CH:12][CH:13]=4)[CH:18]=3)[NH:22][CH:21]=2)[CH2:34][CH2:33]1)(=[O:36])=[O:37])[CH3:39]
Reactant: CNC
Reactant: CCN(C)c1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cn1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(NC(C)C)nc4)cc23)CC1
Yield: 14.5 %

Procedure:
The title compound was prepared according to the general procedure of 5-{6-[ethyl(methyl)amino]-3-pyridinyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting 2-propanamine (64.3 mg, 1 mmol) for dimethylamine to afford 9.8 mg of the title compound (14.5%).
Reaction SMILES: C([O:9][CH2:10][C:11]1[CH:16]=[C:15]([CH2:17][NH:18][C:19]2[CH:20]=[C:21]([C:26]3[CH:31]=[CH:30][C:29]([C:32](=[O:35])[CH2:33][CH3:34])=[CH:28][C:27]=3[CH3:36])[C:22]([CH3:25])=[CH:23][CH:24]=2)[CH:14]=[CH:13][C:12]=1[CH2:37][O:38]C(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(=O)([O-])[O-].[K+].[K+]>[OH:9][CH2:10][C:11]1[CH:16]=[C:15]([CH:14]=[CH:13][C:12]=1[CH2:37][OH:38])[CH2:17][NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([C:26]2[CH:31]=[CH:30][C:29]([C:32](=[O:35])[CH2:33][CH3:34])=[CH:28][C:27]=2[CH3:36])[CH:20]=1
Reactant: CCC(=O)c1ccc(-c2cc(NCc3ccc(COC(=O)c4ccccc4)c(COC(=O)c4ccccc4)c3)ccc2C)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCC(=O)c1ccc(-c2cc(NCc3ccc(CO)c(CO)c3)ccc2C)c(C)c1
Reaction time: 1 h

Procedure:
800 mg (1.3 mmol) of 2-benzoyloxymethyl-5-[(6,2′-dimethyl-4′-propionylbiphenyl-3-ylamino)methyl]benzyl benzoate are dissolved in methanolic 2% potassium carbonate solution and the medium is stirred for 1 hour. After water/dichloromethane extraction, the residue obtained is purified by chromatography on silica gel (eluent: 30 heptane/70 ethyl acetate). A yellow oil is obtained (m=470 mg, Y=88%).
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[F:6][C:7]([F:25])([F:24])[C:8]([N:10]([CH2:17][P:18]([O:22]Cl)([O:20]Cl)=[O:19])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:9]>CCOCC>[F:6][C:7]([F:25])([F:24])[C:8]([N:10]([CH2:17][P:18]([OH:22])([O:20][N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:1][CH2:2][CH2:3][CH3:4])=[O:19])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:9]
Reactant: CCOC(=O)CN(CP(=O)(OCl)OCl)C(=O)C(F)(F)F
Reactant: CCCCN
Solvent: CCOCC
Product: CCCCN(CCCC)OP(=O)(O)CN(CC(=O)OCC)C(=O)C(F)(F)F
Reaction time: 2 h
Yield: 78.5 %

Procedure:
To a solution of n-butylamine (3.1 g, 0.0423 mole) in 40 ml. of ether was added dropwise with stirring ethyl N-trifluoroacetyl-N-(dichlorophosphonomethyl)glycinate (3.3 g, 0.01 mole) in 50 ml. of ether. The reaction mixture was stirred for 21/2 hours, then filtered and the filtrate was concentrated in vacuo to give a light yellow viscous oil. This oil was dissolved in petroleum ether, washed three times with water, dried over MgSO4, and concentrated in vacuo to give 3.3 g of ethyl N-trifluoroacetyl-N-(dibutylaminophosphonomethyl)glycinate, ND =1.4429.