Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([CH3:15])[CH:3]=1.[Br:16][C:17]1[N:22]=[C:21]([CH:23](O)[CH2:24][O:25][CH2:26][CH3:27])[CH:20]=[CH:19][CH:18]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[Br:16][C:17]1[N:22]=[C:21]([CH:23]([S:1][C:2]2[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([CH3:15])[CH:3]=2)[CH2:24][O:25][CH2:26][CH3:27])[CH:20]=[CH:19][CH:18]=1
Reactant: CCOCC(O)c1cccc(Br)n1
Reactant: CCOC(=O)COc1ccc(S)cc1C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOCC(Sc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(Br)n1
Temperature: 25 °C

Procedure:
A solution of (ethyl [(4-mercapto-2-methylphenyl)oxy]acetate) (386 mg, 1.71 mmol), 1-(6-bromo-2-pyridinyl)-2-(ethyloxy)ethanol (352 mg, 1.43 mmol) and PPh3 (450 mg, 1.72 mmol) in DCM (17 mL) at 0° C. under nitrogen was stirred for 10 mins and then treated drop-wise with DIAD (0.34 mL, 1.73 mmol). The resulting mixture was then stirred, with slow warming to ambient temperature over 18 h. The mixture was then reduced under vacuum and the resulting yellow oil purified by SPE (silica, 20 g cartridge), eluting with cyclohexane:EtOAc (gradient 15:1 to 5:1). Further purification using the OPTIX-SPE (C18 cartridge, 50 g) eluting with 60-80% MeCN (+0.05% HCOOH) in H2O (+0.01% HCOOH) over 56 mins afforded the title compound as an oil (232 mg).
Reaction SMILES: CO.[NH2:3][C:4]1[C:9]([F:10])=[C:8]([Br:11])[C:7](Cl)=[C:6]([NH:13][C:14]([CH3:21])([CH3:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[N:5]=1>[Pd].C(N(CC)CC)C>[NH2:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([NH:13][C:14]([CH3:21])([CH3:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[N:5]=1.[NH2:3][C:4]1[C:9]([F:10])=[C:8]([Br:11])[CH:7]=[C:6]([NH:13][C:14]([CH3:21])([CH3:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[N:5]=1
Reactant: CC(C)(C)CC(C)(C)Nc1nc(N)c(F)c(Br)c1Cl
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)CC(C)(C)Nc1cc(Br)c(F)c(N)n1
Product: CC(C)(C)CC(C)(C)Nc1ccc(F)c(N)n1
Reaction time: 39 h

Procedure:
To 10 ml of methanol were added 1.6 g of 2-amino-4-bromo-5-chloro-3-fluoro-6-(1,1,3,3-tetramethylbutylamino)pyridine together with 0.47 g of triethylamine and 0.09 g of 10% palladium on carbon, and the mixture was hydrogenated at room temperature for 39 hours. The catalyst was separated by filtration, and the solvent and the like were distilled off under reduced pressure. To the residue was added 50 ml of chloroform, and the mixture was washed with 50 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to chromatography (silica gel, 25 g; eluent: chloroform) to obtain 0.75 g of 2-amino-3-fluoro-6-(1,1,3,3-tetramethylbutylamino)pyridine as a pale brown oil, and 0.2 g of 2-amino-4-bromo-3-fluoro-6-(1,1,3,3-tetramethylbutylamino)pyridine as a brown oil.
Reaction SMILES: ClC1C=CC([C:8]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[O:9])=CC=1.[Cl:18]C1C=CC(CC(O)=O)=CC=1>S(Cl)(Cl)=O>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][C:8]([Cl:18])=[O:9])=[CH:12][CH:13]=1
Reactant: O=C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Solvent: O=S(Cl)Cl
Product: O=C(Cl)Cc1ccc(Cl)cc1

Procedure:
4,4'-Dichlorodeoxybenzoin can be prepared by heating 4-chlorophenylacetic acid (85g) in thionyl chloride (59.5g) under reflux for 2.5 hours to yield 4-chlorophenylacetyl chloride (45.5g) which is subsequently dissolved in chlorobenzene (30g) and added dropwise with cooling to a stirred aluminium chloride (73g). The resultant mixture is cooled and stirred for a further 0.5 hours and then heated at 100° for one hour. The mixture was again cooled and poured into a mixture of conc. hyrochloric acid (200ml) and ice (1 liter) precipitate on standing crude 4,4'-dichlorodeoxybenzoin which on recrystallisation from methanol has a melting point of 115°-116°.
Reaction SMILES: [CH:1]1([C:4]2[CH:16]=[CH:15][C:7]([O:8][CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[Br:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][N:19]=1>>[Br:17][C:18]1[N:19]=[CH:20][C:21]([C:22]([N:12]2[CH2:13][CH2:14][CH:9]([O:8][C:7]3[CH:15]=[CH:16][C:4]([CH:1]4[CH2:2][CH2:3]4)=[CH:5][CH:6]=3)[CH2:10][CH2:11]2)=[O:23])=[CH:25][CH:26]=1
Reactant: O=C(O)c1ccc(Br)nc1
Reactant: c1cc(C2CC2)ccc1OC1CCNCC1
Product: O=C(c1ccc(Br)nc1)N1CCC(Oc2ccc(C3CC3)cc2)CC1
Yield: 100.7 %

Procedure:
To a mixture of 1-Boc-4-(4-bromophenoxy)piperidine (5 g), dichlorobis(tricyclohexylphosphine)palladium(II) (725 mg), tripotassium phosphate (14.9 g) and cyclopropylboronic acid (1.81 g) was added toluene (70 mL), and the mixture was stirred with heating under reflux for 7 hr. The reaction mixture was cooled, water was added, and the insoluble material was collected by filtration. The filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography to give 4-(4-cyclopropylphenoxy)piperidine-1-carboxylic acid tert-butyl ester. The obtained 4-(4-cyclopropylphenoxy)piperidine-1-carboxylic acid tert-butyl ester was dissolved in ethyl acetate (3 mL), 4N hydrogen chloride/ethyl acetate (7 mL) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was washed with ethyl acetate. To the obtained aqueous layer was added 1N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated to give 4-(4-cyclopropylphenoxy)piperidine (2.49 g). Using the obtained 4-(4-cyclopropylphenoxy)piperidine (1.4 g) and 6-bromonicotinic acid (1.2 g) and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (2.4 g) was obtained.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH2:9]([O:11][C:12]([C:14]1[CH:19]=[CH:18][C:17](=[O:20])[NH:16][C:15]=1[CH3:21])=[O:13])[CH3:10].O>C(#N)C>[CH2:9]([O:11][C:12]([C:14]1[CH:19]=[C:18]([I:1])[C:17](=[O:20])[NH:16][C:15]=1[CH3:21])=[O:13])[CH3:10]
Reactant: CCOC(=O)c1ccc(=O)[nH]c1C
Reactant: O=C1CCC(=O)N1I
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1cc(I)c(=O)[nH]c1C
Temperature: 95 °C

Procedure:
N-Iodosuccinimide (40 g, 180 mmol) was added to a suspension of intermediate (5b), 2-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid ethyl ester (18.1 g, 100 mmol) in acetonitrile (400 mL), under a nitrogen atmosphere. The resulting suspension was heated at 95° C. for 5 hours to give an initial orange solution. An off-white precipitate slowly formed. The resulting suspension was allowed to cool and was poured into water (1200 mL) to give an off-white precipitate. The separated by filtration and the solids washed with water (500 mL) to give an off-white powder. The solids were dried in vacuo (60° C.) to give the product as an off-white powder, 28.3 g (92%)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:37]=1)[N:7]=[C:8]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:9][C:10]([C:12](=[O:28])[N:13]([CH2:17][CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:14][CH2:15][CH3:16])=[CH:11]2.Br[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[CH2:45][C:46]([O:48][CH2:49][CH:50]([CH3:52])[CH3:51])=[O:47].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:32]([O:31][C:30]([NH:29][C:8]1[CH2:9][C:10]([C:12](=[O:28])[N:13]([CH2:17][CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:25])[CH3:26])([CH3:22])[CH3:23])[CH2:14][CH2:15][CH3:16])=[CH:11][C:5]2[CH:4]=[CH:3][C:2]([C:43]3[CH:42]=[CH:41][C:40]([CH2:45][C:46]([O:48][CH2:49][CH:50]([CH3:52])[CH3:51])=[O:47])=[CH:39][CH:44]=3)=[CH:37][C:6]=2[N:7]=1)=[O:36])([CH3:34])([CH3:35])[CH3:33]
Reactant: CCCN(CCCO[Si](C)(C)C(C)(C)C)C(=O)C1=Cc2ccc(Br)cc2N=C(NC(=O)OC(C)(C)C)C1
Reactant: CC(C)COC(=O)Cc1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCN(CCCO[Si](C)(C)C(C)(C)C)C(=O)C1=Cc2ccc(-c3ccc(CC(=O)OCC(C)C)cc3)cc2N=C(NC(=O)OC(C)(C)C)C1
Temperature: 100 °C

Procedure:
tert-butyl (1E,4E)-8-bromo-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-3H-benzo[b]azepin-2-ylcarbamate, isobutyl 2-(2-bromophenyl)acetate (1.5 equiv), tetrakis(triphenylphosphine)palladium(0), 2M aqueous potassium carbonate (3 equiv) were combined in 2 mls of acetonitrile in a microwave reaction vial. This mixture was heated in a microwave to 100° C. for 30 minutes. The mixture was then diluted with EtOAc, washed twice with brine, dried over sodium sulfate, and concentrated under reduced pressure. Preparative thin layer chromatography (2×0.5 mm plates, 7% MeOH/DCM) afforded isobutyl 2-(4-((1E,4E)-2-(tert-butoxycarbonylamino)-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)phenyl)acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=2[F:18])[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.Cl[C:27](OC1C=CC=CC=1)=[O:28].[NH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>O1CCCC1>[F:18][C:10]1[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=1[O:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:1][C:27]([N:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[O:28])[CH:7]=1
Reactant: C1CCNCC1
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ncn1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ncn1)N1CCCCC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 63.5 %

Procedure:
4-Amino-6-(2-fluoro-4-nitrophenoxy)pyrimidine (300 mg) was dissolved in tetrahydrofuran (5 ml) under a nitrogen atmosphere, and then triethylamine (0.335 ml) and phenyl chloroformate (0.301 ml) were added dropwise thereto while cooling in an ice bath, followed by stirring at room temperature for 45 min. To the reaction mixture was added piperidine (0.446 ml), followed by stirring at room temperature for 45 min. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of ammonium chloride. The organic layer was washed with a saturated aqueous solution of ammonium chloride, a 1 N aqueous solution of sodium hydroxide, water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (eluent; hexane:ethyl acetate=3:2). Fractions containing the target compound was concentrated under a reduced pressure, and dried in vacuum to provide the titled compound (275.4 mg, 63.5%) as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[NH:15][C:16]([CH3:18])=[CH:17][C:10]=12.[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33](O)=[O:34])[C:28]2=[O:36])=[CH:23][CH:22]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([NH:19][C:33]([C:29]2[C:28](=[O:36])[N:27]([C:24]3[CH:23]=[CH:22][C:21]([F:20])=[CH:26][CH:25]=3)[CH:32]=[CH:31][CH:30]=2)=[O:34])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[NH:15][C:16]([CH3:18])=[CH:17][C:10]=12
Reactant: Cc1cc2c(Oc3ccc(N)cc3F)ccnc2[nH]1
Reactant: O=C(O)c1cccn(-c2ccc(F)cc2)c1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc2c(Oc3ccc(NC(=O)c4cccn(-c5ccc(F)cc5)c4=O)cc3F)ccnc2[nH]1
Temperature: 25 °C
Yield: 25.2 %

Procedure:
A mixture of 3-fluoro-4-(2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yloxy)benzenamine (17 mg, 0.066 mmol), 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (20 mg, 0.086 mmol) in DMF (0.5 mL) was stirred with BOP reagent (50 mg, 0.11 mmol) and triethylamine (0.01 mL) at 50° C. for 1 h. The reaction mixture was cooled to room temperature and diluted with water. The precipitate was collected and washed with water. The crude product was purified by preparative HPLC and the appropriate fractions were collected, neutralized and concentrated in vacuo to give the title compound (7.85 mg, 25%) as a solid. 1H NMR (DMSO-d6) δ 12.07 (s, 1H), 11.56 (s, 1H), 8.49 (d, 1H, J=6.2 Hz), 8.12 (d, 1H, J=6.2 Hz), 7.98 (dd, 1H, J=10.4, 2.6 Hz), 7.95 (d, 1H, J=5.5 Hz), 7.61 (m, 2H), 7.43 (m, 3H), 7.29 (t, 1H, J=8.40 Hz), 6.72 (t, 1H, J=6.2 Hz), 6.36 (d, 1H, J=5.5 Hz), 5.88 (s, 1H), 2.32 (s, 3H); MS(ESI+) m/z 473 (M+H)+.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.C(OC(=O)C)=O.[NH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]2[CH2:31][CH2:30][N:29]([C:32]3[N:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[CH2:28][CH2:27]2)=[CH:21][CH:20]=1>C(Cl)Cl>[N:33]1[CH:34]=[CH:35][CH:36]=[N:37][C:32]=1[N:29]1[CH2:30][CH2:31][N:26]([CH2:25][C:22]2[CH:23]=[CH:24][C:19]([CH2:18][NH:17][CH:5]=[O:7])=[CH:20][CH:21]=2)[CH2:27][CH2:28]1
Reactant: NCc1ccc(CN2CCN(c3ncccn3)CC2)cc1
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)OC=O
Solvent: ClCCl
Solvent: O=CO
Product: O=CNCc1ccc(CN2CCN(c3ncccn3)CC2)cc1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
A mixture of acetic anhydride (0.30 ml) and formic acid (0.13 ml) was stirred at 50-60° C. for 1 hr. To the obtained acetic formic anhydride was added a solution of 2-(4-(4-(aminomethyl)phenylmethyl)piperazin-1-yl)pyrimidin (0.42 g) in methylene chloride (10 ml) under ice-cooling and the mixture was stirred at 5-10° C. for 2 hr. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (developing solvent; chloroform:methanol=9:1) to give a yellow oil. (0.46 g). The obtained yellow oil was crystallized from ethyl acetate/diisopropyl ether to give the title compound (0.45 g) as pale-yellow crystals, m.p.=97-98° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1>O1CCOCC1>[N:14]1([C:2]2[C:11]3[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:13])[CH:3]=2)[CH:18]=[CH:17][N:16]=[CH:15]1
Reactant: Cc1cc(Cl)c2cccc(O)c2n1
Reactant: c1c[nH]cn1
Solvent: C1COCCO1
Product: Cc1cc(-n2ccnc2)c2cccc(O)c2n1

Procedure:
A mixture of 4-chloro-2-methyl-quinolin-8-ol (2.0 g, 10 mmol) and imidazole (3.53 g, 51.8 mmol) in dioxane (20 mL) was heated to reflux for 28 h. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (elution with DCM/methanol 10:1) to give the title compound. MS (m/z): 226.3 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:29])[N:9]([C:13]3[CH:18]=[CH:17][C:16]([C@H:19]4[CH2:24][CH2:23][C@H:22]([CH2:25][C:26]([OH:28])=O)[CH2:21][CH2:20]4)=[CH:15][CH:14]=3)[CH2:10][CH2:11][O:12][C:6]=2[N:5]=[CH:4][N:3]=1.C[NH:31][SH:32](=[O:34])=[O:33].[CH:35]1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CCOC(C)=O>[NH2:1][C:2]1[C:7]2[C:8](=[O:29])[N:9]([C:13]3[CH:18]=[CH:17][C:16]([C@H:19]4[CH2:24][CH2:23][C@H:22]([CH2:25][C:26]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[O:28])[CH2:21][CH2:20]4)=[CH:15][CH:14]=3)[CH2:10][CH2:11][O:12][C:6]=2[N:5]=[CH:4][N:3]=1
Reactant: On1nnc2ccccc21
Reactant: Nc1ncnc2c1C(=O)N(c1ccc([C@H]3CC[C@H](CC(=O)O)CC3)cc1)CCO2
Reactant: CN[SH](=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)NC(=O)C[C@H]1CC[C@H](c2ccc(N3CCOc4ncnc(N)c4C3=O)cc2)CC1
Reaction time: 18 h

Procedure:
To a stirred solution of {trans-4-[4-(4-amino-5-oxo-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-6(5H)-yl)phenyl]cyclohexyl}acetic acid (50 mg, 0.13 mmol), from Example 2, N-methylsulfonamide (30 mg, 0.32 mmol) were added HOBT (29 mg, 0.19 mmol), EDCl (30 mg, 0.32 mmol) and TEA (19.1 mg, 0.19 mmol). After 18 hours, the reaction mixture was diluted into EtOAc, washed with water, dried over sodium sulfate and concentrated in vacuo. Reverse-phase chromatography afforded the desired product as a white solid, 5.3 mg. 1H NMR (400 MHz, DMSO-d6): δ 8.17 (s, 1H), 7.64 (br s, 2H) 7.20 (s, 4H), 4.58 (m, 2H), 3.92 (m, 2H), 3.20 (s, 3H), 2.42 (m, 1H), 2.17 (m, 2H), 1.73 (m, 5H), 1.40 (m, 2H), 1.05 m, 2H). m/z=474.4 (M+1). IC50 44.5 nM (range 34.2-75.0 nM).
Reaction SMILES: C([O:8][C:9]([N:11]([CH3:14])[NH:12][CH3:13])=O)C1C=CC=CC=1.ClC(OC(Cl)(Cl)Cl)=O.[CH3:23][NH:24][CH3:25].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:23][N:24]([CH3:25])[C:9]([N:11]([CH3:14])[NH:12][CH3:13])=[O:8]
Reactant: CNN(C)C(=O)OCc1ccccc1
Reactant: CNC
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CNN(C)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.9 %

Procedure:
To a solution of N-benzyloxycarbonyl-N,N'-dimethylhydrazine (1.6 g) in toluene (30 ml) was added trichloromethyl chloroformate (0.553 ml). After the solution was refluxed for 30 minutes, dimethylamine (672 mg) and triethylamine (2.0 g) was added thereto at 0° C. The reaction mixture was stirred at ambient temperature for 2 hours. After evaporation of the solvent, the residue was dissolved in ethyl acetate (50 ml). The solution was washed with 5% hydrochloric acid, 1M sodium bicarbonate solution and water successively, and dried over magnesium sulfate. After evaporation of the solvent, the residue was dissolved in methanol (20 ml) and water (20 ml). The solution was hydrogenated over 10% palladium on carbon (100 mg) at 3 atmospheric pressure of hydrogen for 1 hour. The solution was filtered and concentrated in vacuo to give N-(N,N-dimethylcarbamoyl)-N,N'-dimethylhydrazine (820 mg) as an oil.
Reaction SMILES: [CH:1]([CH:4]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[C:5](Cl)=[O:6])([CH3:3])[CH3:2]>C(Cl)Cl.C(N(CC)CC)C.CCCCCCC>[Cl:14][C:11]1[CH:10]=[CH:9][C:8]([C:4]([CH:1]([CH3:3])[CH3:2])=[C:5]=[O:6])=[CH:13][CH:12]=1
Reactant: CC(C)C(C(=O)Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCCCCCC
Product: CC(C)C(=C=O)c1ccc(Cl)cc1
Reaction time: 18 h
Yield: 41.6 %

Procedure:
To a solution of 2.31 g of isopropyl(4-chlorophenyl)acetyl chloride in 10 ml of methylene chloride was added in one portion 1.5 g of triethylamine. After 18 hours, 15 ml of heptane was added to the mixture and the triethylamine hydrochloride was removed by filtration. The filtrate was stripped and 10 ml of heptane was added and the resulting mixture was filtered and stripped to give a yellow residue, which was dissolved in 5 ml heptane for GLC analysis. The resulting solution was distilled through a Bantam-ware short-neck head from an oil bath at 125°-150° C. and head temperature of 110°-100° C. at 0.2-0.05 mm to give 0.95 g of distillate and 0.81 g of gum. The distillate was crystallized twice from 2 volumes of hexane at -80° C. The solid was melted and stripped to about 40° C. at 0.5 mm to give 0.42 g of the desired product as a yellow liquid.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:11]([OH:13])=O)[C@H:7]([CH2:9][CH3:10])[CH3:8])=[O:4].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[S:28]1[CH:32]=[CH:31][N:30]=[C:29]1[C:33]1[CH:38]=[CH:37][C:36]([CH2:39][N:40]([NH2:64])[CH2:41][C@H:42]([OH:63])[C@@H:43]([NH:51][C:52](=[O:62])[C@H:53]([CH:59]([CH3:61])[CH3:60])[NH:54][C:55]([O:57][CH3:58])=[O:56])[CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[CH:35][CH:34]=1>CN(C=O)C>[S:28]1[CH:32]=[CH:31][N:30]=[C:29]1[C:33]1[CH:34]=[CH:35][C:36]([CH2:39][N:40]([NH:64][C:11](=[O:13])[C@H:6]([C@H:7]([CH2:9][CH3:10])[CH3:8])[NH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:41][C@H:42]([OH:63])[C@@H:43]([NH:51][C:52](=[O:62])[C@H:53]([CH:59]([CH3:61])[CH3:60])[NH:54][C:55]([O:57][CH3:58])=[O:56])[CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[CH:37][CH:38]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2nccs2)cc1)C(C)C
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)NN(Cc1ccc(-c2nccs2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)C

Procedure:
Analogously to Example 7, 106 mg (0.56 mmol) of N-methoxycarbonyl-(L)-iso-leucine, 201 mg (1.05 mmol) of EDC and 95 mg (0.7 mmol) of HOBT in 4.6 ml of DMF and 293 μl (2.1 mmol) of TEA are reacted with 0.35 mmol of 1-[4-(thiazol-2-yl)-phenyl]-4(S)-hydroxy-2-amino-5 (S)-N-(N-methoxycarbonyl-(L)-valyl)amino-6-phenyl-2-azahexane to form the title compound: m.p: 227°-229° C.; HPLC20-100 : tRet =14.5; FAB MS (M+H)+ =697.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:18][Si:19]([CH2:24][CH3:25])([CH2:22][CH3:23])[CH2:20][CH3:21])[CH2:16]I)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:26][C@H:27]([CH3:47])[CH2:28][C:29]1[C:37]2[C:32](=[C:33]([O:38][CH2:39][C:40]([N:42]([CH2:45][CH3:46])[CH2:43][CH3:44])=[O:41])[CH:34]=[CH:35][CH:36]=2)[NH:31][CH:30]=1.CCN(C(C)C)C(C)C>O1CCCC1.C(Cl)(Cl)Cl>[NH3:26].[Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:18][Si:19]([CH2:24][CH3:25])([CH2:22][CH3:23])[CH2:20][CH3:21])[CH2:16][NH:26][C@H:27]([CH3:47])[CH2:28][C:29]2[C:37]3[C:32](=[C:33]([O:38][CH2:39][C:40]([N:42]([CH2:43][CH3:44])[CH2:45][CH3:46])=[O:41])[CH:34]=[CH:35][CH:36]=3)[NH:31][CH:30]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCN(CC)C(=O)COc1cccc2c(C[C@@H](C)N)c[nH]c12
Reactant: CC[Si](CC)(CC)O[C@@H](CI)c1ccc(O[Si](C)(C)C(C)(C)C)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCN(CC)C(=O)COc1cccc2c(C[C@@H](C)NC[C@H](O[Si](CC)(CC)CC)c3ccc(O[Si](C)(C)C(C)(C)C)cc3)c[nH]c12
Product: N
Temperature: 110 °C
Reaction time: 10 h
Yield: 48.4 %

Procedure:
(R)-1-(tert-Butyldimethylsilyloxy)-4-(2-iodo-1-triethylsilyloxy-ethyl)benzene (J. Org. Chem., vol. 56, p. 442 (1991)) (65 mg, 0.13 mmol) and (R)-2-[3-(2-aminopropyl)-1H-indol-7-yloxyl]-N,N-diethylacetamide (80 mg, 0.26 mmol) and iPr2NEt (115 μL) are dissolved in tetrahydrofuran (2 mL), and the mixture is stirred at 110° C. for 10 hours. After cooling, the mixture is concentrated and the residue is purified by silica gel column chromatography (chloroform→a saturated ammonia solution in chloroform) to give the desired 2-[3-((2R)-2-{2-[4-(tert-butyl-dimethylsilyloxy)phenyl]-(2R)-2-(triethylsilyloxy)ethylamino}propyl)-1H-indol-7-yloxy]-N,N-diethylacetamide (42 mg, yield: 48%).