Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([O:9][CH3:10])[C:2](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O:3][CH3:4].[Li]CCCC.CN(OC)[C:18](=[O:25])[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1>O1CCCC1>[CH3:4][O:3][C:2]1[C:1]([O:9][CH3:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C:18]([C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)=[O:25]
Reactant: COc1ccccc1OC
Reactant: CON(C)C(=O)c1ccncc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc(C(=O)c2ccncc2)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
A solution of veratrole (8.04 g, 58.2 mmol) in tetrahydrofuran (50 mL) is treated with BuLi (26 mL, 2.5 M in hexane, 65 mmol) at −70° C. After the addition is complete, the reaction mixture is permitted to warm to room temperature and stirred for 2 hours. The mixture is re-cooled to −70° C. and treated with a solution of N-methyl-N-methoxyisonicotinamide (19) (9.15 g, 55.1 mmol) in tetrahydrofuran (30 mL). The resulting slurry is permitted to slowly warm to room temperature over an hour period. When the reaction mixture reaches 0° C. it becomes homogeneous. After 3 hours at room temperature, the reaction is quenched with 10% AcOH (aqueous, 100 mL). After stirring for 45 minutes, the tetrahydrofuran is removed at reduced pressure and the residue is diluted with toluene (150 mL). After neutralization with NHCO3, the phases are separated and the organic phase is submitted to a normal workup to provide an oil. Kugelrohr distillation provides the title compound (12) as a dark oil (12.77 g, 95% yield); b.p. 130-150° C./0.05 mm Hg.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:31]=[C:32]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH:33]=1)[C:12]([C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]([CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:15]=1)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:44]([C:48]1[CH:55]=[CH:54][C:51]([CH2:52]Cl)=[CH:50][CH:49]=1)[CH:45]([CH3:47])[CH3:46].Cl>CN(C)C=O.C(OCC)(=O)C>[CH2:44]([C:48]1[CH:55]=[CH:54][C:51]([CH2:52][N:34]([C:32]2[CH:31]=[C:11]([CH:10]=[C:9]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:52][C:51]3[CH:54]=[CH:55][C:48]([CH2:44][CH:45]([CH3:47])[CH3:46])=[CH:49][CH:50]=3)[CH:33]=2)[C:12]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:15]=2)=[O:13])[C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])=[CH:50][CH:49]=1)[CH:45]([CH3:47])[CH3:46]
Reactant: CCOC(=O)CCCn1cc(C(=O)c2cc(NC(=O)OC(C)(C)C)cc(NC(=O)OC(C)(C)C)c2)c2ccccc21
Reactant: CC(C)Cc1ccc(CCl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCn1cc(C(=O)c2cc(N(Cc3ccc(CC(C)C)cc3)C(=O)OC(C)(C)C)cc(N(Cc3ccc(CC(C)C)cc3)C(=O)OC(C)(C)C)c2)c2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 34.1 %

Procedure:
A solution of ethyl 4-[3-[3,5-bis[tertbutoxycarbonylamino)benzoyl]indol-1-yl]butyrate (300 mg) in N,N-dimethylformamide (5 ml) was added to a suspension of sodium hydride (60% dispersion in mineral oil, 54 mg) in N,N-dimethylformamide (5 ml) at 0° C. The mixture was stirred at 0° C. for 30 minutes, and a solution of 4-isobutylbenzyl chloride (388 mg) in N,N-dimethylformamide (5 ml) was added at 0° C. The reaction mixture was stirred at 0° C. for 3 hours, and poured into a mixture of 0.1N hydrochloric acid and ethyl acetate. The organic layer was separated, washed with water, aqueous solution of sodium bicarbonate and brine in successively. After dryness over magnesium sulfate and evaporation of the solvent, the residue was chromatographed on silica gel (25 g) eluting with a mixture of ethyl acetate and hexane (1:4) to give ethyl 4-[3-[3,5-bis[N-(4-isobutylbenzyl)-N-tert-butoxycarbonyl- amino]benzoyl]indol-1-yl]butyrate (155 mg) as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:26]([O:28][CH3:29])=[O:27])=[N:11][N:12]2[CH:17]([CH2:18]OS(C)(=O)=O)[CH2:16][N:15]([CH3:24])[C:14](=[O:25])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1CCCCC1>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:10]([C:26]([O:28][CH3:29])=[O:27])=[N:11][N:12]2[C:17]([CH3:18])=[CH:16][N:15]([CH3:24])[C:14](=[O:25])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(C)CC2COS(C)(=O)=O
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: COC(=O)c1nn2c(C)cn(C)c(=O)c2c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 3-benzyloxy-5-methyl-7-methylsulfonyloxymethyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (57 mg, 0.14 mmol) in anhydrous DMF under an atmosphere of nitrogen was added piperidine (133 μL, 1.35 mmol). The reaction was stirred at room temperature for 2 hours, heated to 50° C. for 2 hours, and stirred at room temperature overnight. Purification by reverse phase chromatography on a C-18 column using a gradient elution of 95-5% H2O (0.1% TFA)/CH3CN (0.1% TFA) and collection and concentration of the appropriate fractions afforded the title product. ES MS (M+H)=328.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]([CH3:19])[C:9]2=[O:20])=[CH:4][C:3]=1I.[C:22]([O:26][CH2:27][C:28]([F:31])([F:30])[F:29])(=[O:25])[CH:23]=[CH2:24].C([O-])(=O)C.[Na+].O>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]([CH3:19])[C:9]2=[O:20])=[CH:4][C:3]=1[CH:24]=[CH:23][C:22]([O:26][CH2:27][C:28]([F:31])([F:30])[F:29])=[O:25]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c(I)c2)c1=O
Reactant: C=CC(=O)OCC(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c(C=CC(=O)OCC(F)(F)F)c2)c1=O
Temperature: 120 °C
Reaction time: 4 h

Procedure:
A suspension of 5.0 g of 3-[4-chloro-3-iodophenyl]-2,4-dioxo-1-methyl-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine, 2.0 g of 2,2,2-trifluoroethyl acrylate, 0.5 mg of palladium acetate and 1.1 g of sodium acetate in 50 ml of dimethylformamide was stirred for 4 hours at 120° C., after which further palladium acetate and 2,2,2-trifluoromethyl acrylate were added and stirring was continued for a further 2 hours at 120° C. The cooled reaction mixture was added to 200 ml of water and the precipitate was isolated, washed with petroleum ether and dried under greatly reduced pressure.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:33][C:34]3[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[C:37]([NH2:44])=[C:36]([Cl:45])[CH:35]=3)[C:19](=[O:32])[N:20]3[CH2:25][CH2:24][N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH2:22][CH2:21]3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:46]=[CH:47][CH:48]=[CH:49][C:4]=2[NH:3]1.C([O-])([O-])=O.[K+].[K+].Br[C:57]([CH3:64])([CH3:63])[C:58]([O:60][CH2:61][CH3:62])=[O:59]>CN(C=O)C>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:33][C:34]3[CH:39]=[C:38]([C:40]([F:41])([F:43])[F:42])[C:37]([NH2:44])=[C:36]([Cl:45])[CH:35]=3)[C:19]([N:20]3[CH2:21][CH2:22][N:23]([CH:26]4[CH2:31][CH2:30][N:29]([C:57]([C:58]([O:60][CH2:61][CH3:62])=[O:59])([CH3:64])[CH3:63])[CH2:28][CH2:27]4)[CH2:24][CH2:25]3)=[O:32])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:46]=[CH:47][CH:48]=[CH:49][C:4]=2[NH:3]1
Reactant: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCNCC3)CC2)cc1C(F)(F)F
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)N1CCC(N2CCN(C(=O)[C@@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
A mixture of 140 mg (0.20 mmol) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-ethyl 4-(2-oxo -1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 29a), 60.8 mg (0.44 mmol) K2CO3 and 45 μL (0.30 mmol) ethyl 2-bromo-2-methyl-propionate in 1.8 mL DMF was shaken at 50° C. for 12 h and then for 48 h at RT. The precipitate was filtered off and the filtrate was purified by HPLC without working up; the fractions containing the product were combined, evaporated down i. vac., the residue was made alkaline with saturated NaHCO3 solution, the precipitate was suction filtered, washed with 20 mL water and dried at 40° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:13]=2)[NH:8][C:7]=1[CH3:20])[CH3:2].[H-].[Na+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:13]=2)[N:8]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:7]=1[CH3:20])[CH3:2]
Reactant: CCOC(=O)Cc1c(C)[nH]c2ccc(C(=O)OCC)cc12
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)Cc1c(C)n(Cc2ccccc2)c2ccc(C(=O)OCC)cc12
Yield: 56.2 %

Procedure:
Using the procedure described in Example 2, Part B, 2.18 g (7.5 mmol) of 5-ethoxycarbonyl-2-methyl-1H-indole-3-acetic acid ethyl ester was reacted with 320 mg (8 mmol) of 60% NaH/mineral oil and 1.0 mL (8.4 mmol) of benzyl bromide to give after silica chromatography (25% ether/hexane→50% ether/hexane) 1.6 g (56%) of 5-ethoxycarbonyl-2-methyl-1-(phenylmethyl)-1H-indole-3-acetic acid ethyl ester.
Reaction SMILES: O=[C:2]([CH2:8][C:9](=O)[C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].CCN(CC)CC.[ClH:24].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][NH2:34])=[CH:29][CH:28]=1>CO>[ClH:24].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:9]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)=[CH:8][C:2]([CH2:3][CH2:4][C:5]([OH:7])=[O:6])=[N:34]2)=[CH:29][CH:28]=1
Reactant: O=C(O)CCC(=O)CC(=O)c1cccnc1
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1ccc(-n2nc(CCC(=O)O)cc2-c2cccnc2)cc1
Yield: 52 %

Procedure:
Compound 29 (2.21 g, 10 mM) in methanol (150 ml) containing Et3N (2 ml) was treated with 4-methoxyphenylhydrazine hydrochloride (1.85 g, 10.6 mM) at RT for 4 hr. The solvent was removed in vacuo and the residue was partitioned between 5% NaOH and Et2O. The basic aqueous layer was separated and acidified with 10% HCl to pH 2. Saturated brine was added and the aqueous layer was exhaustively extracted with CH2Cl2. The combined CH2Cl2 layers were concentrated to give the title compound 31 as a tan crystalline solid (Recry. Acetone, 1.87 g, 52%) mp=226°-228° C., MS, m/e 323 (M+).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:6][O:5][C:4]([C:7]2[C:8]([C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:21])=[CH:9][C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)=[N:11][CH:12]=2)=[N:3]1.Cl.[OH-:30].[Na+]>O1CCCC1>[NH2:3][C:2]([CH3:1])([CH3:28])[CH2:6][O:5][C:4](=[O:30])[C:7]1[C:8]([C:20](=[O:21])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:9][C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[N:11][CH:12]=1
Reactant: [OH-]
Reactant: CN1CCN(c2cc(C(=O)c3ccccc3)c(C3=NC(C)(C)CO3)cn2)CC1
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCN(c2cc(C(=O)c3ccccc3)c(C(=O)OCC(C)(C)N)cn2)CC1
Temperature: 50 °C

Procedure:
To a solution of 1.13 g (3 mmol) [5-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-2-(4-methyl-piperazin-1-yl)-pyridin-4-yl]-phenyl-methanone in 30 ml tetrahydrofuran were added 3 ml of 2 N aqueous hydrochloric acid and the reaction mixture was heated at 50° C. for 18 h. After cooling to room temperature, 1 N sodium hydroxide solution was added to adjust pH 11 and the mixture was extracted with ethyl acetate. The organic layer was dried (magnesium sulfate) and evaporated to yield 1.18 g (quantitative) of the product as yellow oil.
Reaction SMILES: Br[C:2]1[CH2:6][O:5][C:4](=[O:7])[CH:3]=1.CCN(C(C)C)C(C)C.[CH2:17]1[C:22]2([CH2:27][CH2:26][CH2:25][NH:24][CH2:23]2)[CH2:21][CH2:20][N:19]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:18]1>C1COCC1>[O:7]=[C:4]1[O:5][CH2:6][C:2]([N:24]2[CH2:25][CH2:26][CH2:27][C:22]3([CH2:17][CH2:18][N:19]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:20][CH2:21]3)[CH2:23]2)=[CH:3]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCNC2)CC1
Reactant: O=C1C=C(Br)CO1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CCCN(C3=CC(=O)OC3)C2)CC1
Temperature: 76 °C
Reaction time: 8 h

Procedure:
To commercially available 4-bromofuran-2(5H)-one (128 mg, 0.786 mmol) in THF (4 mL) was added Hunig's Base (275 μL, 1.57 mmol) and tert-butyl 3,8-diazaspiro[5,5]undecane-3-carboxylate (200 mg, 0.786 mmol). The reaction mixture was stirred at 76° C. overnight, concentrated and purified by column chromatography (0-10% MeOH in DCM) to afford the title compound. LCMS: [(M+1)]+=337
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]N)=[CH:5][CH:4]=1)#[N:2].[Mn]([O-])(=O)(=O)=[O:12].[K+].S(=O)(=O)(O)O>O>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:12])=[CH:5][CH:4]=1)#[N:2]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: N#Cc1ccc(CN)cc1
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: N#Cc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 26 %

Procedure:
13.2 g of p-cyanobenzylamine was added dropwise to 200 ml of water and 15.8 g of potassium permanganate with vigorous stirring at room temperature over 20 minutes. The mixture was adjusted to pH 1 by sulfuric acid and stirred at room temperature for 5 hours. The p-cyanobenzaldehyde obtained had a yield of 26% (on a basis of cyanobenzylamine compound, hereafter the same) determined by the analysis of high performance liquid chromatography.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:23])[C:10](=[O:22])[CH2:11][C@:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=2)([CH3:14])[N:13]=1)(C)(C)C.[C:25](O)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=1>>[NH2:7][C:8]1[N:9]([CH3:23])[C:10](=[O:22])[CH2:11][C@:12]([C:15]2[CH:16]=[C:17]([NH:21][C:25](=[O:32])[C:26]3[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=3)[CH:18]=[CH:19][CH:20]=2)([CH3:14])[N:13]=1
Reactant: O=C(O)c1cccnc1
Reactant: CN1C(=O)C[C@@](C)(c2cccc(N)c2)N=C1NC(=O)OC(C)(C)C
Product: CN1C(=O)C[C@@](C)(c2cccc(NC(=O)c3cccnc3)c2)N=C1N

Procedure:
The coupling of [(S)-4-(3-amino-phenyl)-1,4-dimethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester from experiment F1 and nicotinic acid followed by deprotection of the intermediate yielded the title compound as a colourless solid. MS (ESI): m/z=338.4 [ M+H]+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][C:3]=1[N:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18](=[O:23])[C:17]([C:24](N(OC)C)=[O:25])=[N:16]1.[CH3:30][Mg+].[Br-]>C1COCC1>[C:24]([C:17]1[C:18](=[O:23])[C:19]([O:21][CH3:22])=[CH:20][N:15]([C:3]2[CH:4]=[CH:5][C:6]([N:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[C:7]([F:8])[C:2]=2[F:1])[N:16]=1)(=[O:25])[CH3:30]
Reactant: COc1cn(-c2ccc(N3CCOCC3)c(F)c2F)nc(C(=O)N(C)OC)c1=O
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cn(-c2ccc(N3CCOCC3)c(F)c2F)nc(C(C)=O)c1=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
A solution of 1-(2,3-difluoro-4-morpholin-4-ylphenyl)-N,5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (1.1 g, 2.6 mmol) in THF (25 mL) was added dropwise to MeMgBr (1.0 M in THF, 11 mL, 11 mmol) at −78° C. under N2. The mixture was stirred at −78° C. for 1 h. The reaction was quenched with 1 M HCl aqueous solution (11 mL) at −78° C. The mixture warmed up to room temperature, diluted with AcOEt, and washed with brine. The organic layer was dried over MgSO4, and concentrated under reduced pressure. The residue was recrystallized from iPr2O/AcOEt to give the title compound (870 mg, 92% yield) as a pale yellow solid: 1H NMR (300 MHz, DMSO-d6): δ ppm 2.49 (3H, s), 2.90-3.28 (4H, m), 3.64-4.01 (7H, m), 7.05 (1H, td, J=8.9, 2.3 Hz), 7.53 (1H, td, J=8.6, 2.5 Hz), 8.50 (1H, d, J=1.9 Hz). LC-MS (ESI) m/z 366 [M+H]+.
Reaction SMILES: [N:1]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:9]2[CH:4]([NH:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>C1COCC1>[N:1]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:9]2[CH:4]([N:5]([C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[CH2:6][CH2:7][CH2:8]2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC2NCCCC21
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2C1CCCN2C(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
The product of Step 4 (HOAc salt; 3.49 g, 12.2 mmol) was added to a flask, followed by THF (55 mL). Aqueous sodium carbonate (2M; 30.5 mL, 60.9 mmol) was added, and the resulting biphasic mixture was cooled to 0° C. Benzyl chloroformate (2.61 mL, 18.3 mmol) was added and the reaction mixture was allowed to stir while the bath naturally warmed to ambient temperature. After 30 minutes the reaction mixture was partitioned between EtOAc and water (100 mL each) and the layers were separated. The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo to a crude oil that was purified by column chromatography on silica gel eluting with EtOAc/hexane (5-30%) (TLC was visualized with CAM staining) to afford the title product as a colorless oil. LRMS calc'd for C20H28N2O4Na [M+Na]+, 383; found 383. 1H NMR (500 MHz, CDCl3) δ 7.39-7.30 (br m, 5H), 5.15 (br s, 2H), 4.70-4.45 (br m, 1H), 4.15-3.95 (br m, 1H), 3.82-3.62 (br d, 1H), 3.50-3.21 (br m, 2H), 2.79 (br pentet, 1H), 2.30-1.90 (br m, 3H), 1.72-1.58 (br m, 1H), 1.45 (s, 9H), 1.40 (br m, 1H), 1.28-1.14 (br m, 1H).
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([CH:15]=[O:16])[CH:9]=[CH:8]2>CC(O)=O>[Br:1][C:6]1[C:5]([O:4][CH3:3])=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][C:10]([CH:15]=[O:16])=[CH:11]2
Reactant: BrBr
Reactant: COc1ccc2cc(C=O)ccc2c1
Solvent: CC(=O)O
Product: COc1ccc2cc(C=O)ccc2c1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
Bromine (556 μL, 10.8 mL) in 10 mL of glacial HOAc was added under nitrogen dropwise over 1 h to a solution of 6-methoxy-naphthalene-2-carbaldehyde (2.01 g, 10.8 mmol) in 25 mL of glacial HOAc at room temperature. After the addition the reaction was stirred at room temperature for 2 h. The solid was collected by filtration, rinsed with glacial HOAc and dried under reduced pressure to give 5-bromo-6-methoxy-naphthalene-2-carbaldehyde (2.27 g, 79%) as a tan solid, mp 148-150° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:37][N:38]([CH3:69])[NH:39][C:40]([C:42]1([CH2:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[CH2:47][CH2:46][N:45]([C:48](=[O:61])[CH:49]([NH2:60])[CH2:50][C:51]2[C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[NH:53][CH:52]=2)[CH2:44][CH2:43]1)=[O:41].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([C:10](=[O:12])[NH:60][CH:49]([CH2:50][C:51]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[NH:53][CH:52]=1)[C:48]([N:45]1[CH2:44][CH2:43][C:42]([CH2:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)([C:40]([NH:39][N:38]([CH3:69])[CH3:37])=[O:41])[CH2:47][CH2:46]1)=[O:61])([CH3:14])[CH3:13])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)NC(=O)C1(Cc2ccccc2)CCN(C(=O)C(N)Cc2c[nH]c3ccccc23)CC1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)NC(=O)C1(Cc2ccccc2)CCN(C(=O)C(Cc2c[nH]c3ccccc23)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)CC1
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
To a solution of 2-tert-butoxycarbonylamino-2-methylpropionic acid (0.18 g, 0.88 mmol) in methylene chloride (10 ml) was added 1-hydroxy-7-azabenzotriazole (0.12 mg, 0.88 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.12 g, 0.88 mmol) and the mixture was stirred for 30 min. Then 1-(2-amino-3-(1H-indol-3-yl)propionyl)-4-benzylpiperidine-4-carboxylic acid N′,N′-dimethylhydrazide (0.46 g, 0.73 mmol) and diisopropylethylamine (0.50 ml, 2.92 mmol) was added and the mixture was stirred overnight. Methylene chloride (100 ml) was added and the mixture was washed with saturated aqueous sodium hydrogencarbonate (20 ml), water (20 ml), dried (MgSO4), filtered and concentrated in vacuo. The obtained oil was chromatographed on silica (40 g) with methylene chloride/(10% ammonia in methanol) (9:1) to give 0.31 g of (1-(2-(4-benzyl-4-(N′,N′-dimethylhydrazinocarbonyl)piperidine-1-yl)-1-(1H-indol-3-ylmethyl)-2-oxoethylcarbamoyl)-1-methylethyl)carbamic acid tert-butyl ester as a colorless oil.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=[O:14])=[N:10][CH:9]=2)[CH2:4][CH2:3]1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[F:35][C:32]([F:33])([F:34])[C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[C:25]([NH:24][CH2:23][C:21]([NH:20][CH:18]1[CH2:19][N:16]([CH:2]2[CH2:7][CH2:6][CH:5]([C:8]3[S:12][C:11]([C:13]([OH:15])=[O:14])=[N:10][CH:9]=3)[CH2:4][CH2:3]2)[CH2:17]1)=[O:22])=[O:36]
Reactant: O=C1CCC(c2cnc(C(=O)O)s2)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(c3cnc(C(=O)O)s3)CC2)C1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 5-(4-oxo-cyclohexyl)-thiazole-2-carboxylic acid (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step F of Example 1.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[S:10][C:9]([C:11](Cl)=[O:12])=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>C(Cl)Cl>[Cl:1][C:2]1[C:3]2[S:10][C:9]([C:11]([NH:14][CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:12])=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=C(Cl)c1cc2ncnc(Cl)c2s1
Reactant: NCCN1CCOCC1
Solvent: ClCCl
Product: O=C(NCCN1CCOCC1)c1cc2ncnc(Cl)c2s1
Temperature: 25 °C
Reaction time: 14 h
Yield: 65.2 %

Procedure:
To a stirred solution of 22 (500 mg, 2.15 mmol) in anhydrous DCM (20 mL) at 0° C. under nitrogen was added 4-(2-aminoethyl)-morpholine (307 mg, 2.36 mmol). The reaction mixture was allowed to warm to the room temperature over 3 hours and was stirred for additional 14 hours, treated with saturated aqueous solution of NHCO3 and extracted with DCM. The organic layer was dried over Na2SO4, filtered, and concentrated. The residues was purified by flash chromatography on silica gel (eluents MeOH-DCM, 5:95, then 1:9) to afford the title compound 23 (458 mg, 65% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ(ppm): 9.13 (t, J=5.6 Hz, 1H), 9.08 (s, 1H), 8.32 (s, 1H), 3.60-3.54 (m, 4H), 3.44 (q, J=6.8 Hz, 2H), 2.54-2.48 (m, 2H), 2.46-2.40 (m, 4H).