Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=[O:13].Cl.[CH:15]([N:18]([CH:22]([CH3:24])[CH3:23])[CH2:19][CH2:20]Cl)([CH3:17])[CH3:16].[H-].[Na+]>CN(C)C=O>[CH:15]([N:18]([CH:22]([CH3:24])[CH3:23])[CH2:19][CH2:20][N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[C:6](=[O:13])[C:7]1=[O:12])([CH3:17])[CH3:16]
Reactant: COc1ccc2c(c1)C(=O)C(=O)N2
Reactant: CC(C)N(CCCl)C(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C(=O)C(=O)N2CCN(C(C)C)C(C)C
Temperature: 80 °C
Yield: 64.6 %

Procedure:
To a solution of 3.00 g of 5-methoxyisatin and 3.39 g of 2-diisopropylaminoethyl chloride hydrochloride in 50 ml of dry N,N-dimethylformamide was added 1.36 g of sodium hydride (60% dispersion in mineral oil) with stirring under ice-cooling. The mixture was stirred for 1 hour at room temperature and then heated at 80° C. for 13 hours. The reaction mixture was concentrated under reduced pressure, and water was added to the residue. The mixture was extracted with ethyl acetate and the ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel flash column chromatography (eluent: chloroform) and recrystallized from hexane to obtain 3.33 g of 1-(2-diisopropylaminoethyl)-5-methoxyisatin having a melting point of 81°-82.5° C.
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].[H-].[Na+].Cl[C:8]1[C:9]2[CH:18]=[CH:17][N:16]([C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3[CH3:27])[C:10]=2[C:11](=[O:15])[N:12]([CH3:14])[N:13]=1>CN(C=O)C.O>[CH:2]([O:4][C:8]1[C:9]2[CH:18]=[CH:17][N:16]([C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3[CH3:27])[C:10]=2[C:11](=[O:15])[N:12]([CH3:14])[N:13]=1)([CH3:3])[CH3:1]
Reactant: Cc1cc(C)c(-n2ccc3c(Cl)nn(C)c(=O)c32)c(C)c1
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)c(-n2ccc3c(OC(C)C)nn(C)c(=O)c32)c(C)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
To a solution of 2-propanol (0.026 ml, 0.60 mmol) in DMF (1 ml) was added sodium hydride (60% in oil, 24 mg, 0.60 mmol). The mixture was stirred for 10 min before addition of 4-chloro-1-mesityl-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one (45.3 mg, 0.15 mmol). The mixture was stirred at 60° C. for 1 hour, then diluted with water (30 ml) and extracted with ethyl acetate (50 ml). The extract was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (5:1) to give 28.3 mg (58%) of the title compound as crystals.
Reaction SMILES: [CH:1]([CH:3]([C:6]#[C:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:4][NH2:5])=[CH2:2].Cl[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[CH:17][N:16]=1.C(N(CC)CC)C.CN(C=O)C>O>[CH:1]([CH:3]([C:6]#[C:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:4][NH:5][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[CH:17][N:16]=1)=[CH2:2]
Reactant: C=CC(C#Cc1ccccc1)CN
Reactant: Clc1ncnc2ccccc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: C=CC(C#Cc1ccccc1)CNc1ncnc2ccccc12
Temperature: 80 °C
Reaction time: 5 h
Yield: 82.5 %

Procedure:
550 mg of 2-vinyl-4-phenyl-3-butynylamine, 500 mg of 4-chloroquinazoline, and 636 μl of triethylamine were added to 15 ml of DMF, and the obtained mixture was then stirred at 80° C. for 5 hours. Thereafter, the reaction solution was cooled, and 20 ml of water was then added thereto, followed by extraction with 50 ml of ethyl acetate twice. The organic layer was washed with 50 ml of a saturated brine twice, and it was then dried over sodium sulfate. The sodium sulfate was filtrated, and the organic layer was then concentrated. The residue was purified using an automated flash chromatography instrument (manufactured by Biotage AB; Isolera™), so as to obtain 750 mg of a product of interest.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([C:17]([O:19]C)=[O:18])=[CH:12][CH:11]=3)[CH2:3]1.[OH-].[Na+].Cl>CO.O>[OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([C:17]([OH:19])=[O:18])=[CH:12][CH:11]=3)[CH2:3]1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CC[C@H](O)C3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(N3CC[C@H](O)C3)nc2c1

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of (S)-methyl 3-(3-hydroxypyrrolidin-1-yl)-2-phenylquinoxaline-6-carboxylate (170 mg, 0.49 mmol, 1.00 equiv) in methanol (20 mL). This was followed by the dropwise addition of a solution of sodium hydroxide (97.4 mg, 2.44 mmol, 5.00 equiv) in water (2.5 mL) with stirring. The resulting solution was stirred overnight at 50° C. in an oil bath. The pH value of the solution was adjusted to 3-4 with 1N hydrogen chloride. The resulting solid was collected by filtration and washed with water and methanol. The solid was dried in an oven. This resulted in 40 mg (25%) of (S)-3-(3-hydroxypyrrolidin-1-yl)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[CH3:9][O-].[Na+]>[Cl-].C1([N+](C)(C)C)C=CC=CC=1.CN(C)C=O>[CH3:9][O:1][C:2]1[CH:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: C[O-]
Reactant: Cc1ccc(O)cn1
Agent: C[N+](C)(C)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-hydroxy-6-methylpyridine (2.5 g), sodium methoxide (1.36 g) and phenyltrimethylammonium chloride (4.33 g) in dry dimethylformamide (25 ml) was heated at reflux under argon for 2.5 h. The mixture was allowed to cool then stirred at room temperature overnight. Insoluble material was removed by filtration and washed with ethanol. The filtrate was acidified with 6M hydrochloric acid and the solvent was removed in vacuo. The residue was then diluted with water, basified with 2M sodium hydroxide and extracted with ether. The combined extracts were washed with brine, dried (MgSO4), filtered and evaporated. The crude product was purified by column chromatography on silica gel eluting with 3% ethyl acetate in hexane (1.55 g, 55%).
Reaction SMILES: CN(C)C=O.CS(O[CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:18]=[C:19]([CH3:34])[N:20]([CH2:24][C:25]3[S:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=3)[C:21](=[O:23])[N:22]=2)[CH2:13][CH2:12]1)(=O)=O.[Br:35][C:36]1[CH:37]=[N:38][NH:39][CH:40]=1.C(=O)([O-])[O-].[K+].[K+]>O>[Br:35][C:36]1[CH:37]=[N:38][N:39]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:18]=[C:19]([CH3:34])[N:20]([CH2:24][C:25]4[S:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=4)[C:21](=[O:23])[N:22]=3)[CH2:13][CH2:12]2)[CH:40]=1
Reactant: Brc1cn[nH]c1
Reactant: Cc1nc(N2CCC(OS(C)(=O)=O)CC2)nc(=O)n1Cc1ccc(C(F)(F)F)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(N2CCC(n3cc(Br)cn3)CC2)nc(=O)n1Cc1ccc(C(F)(F)F)s1
Yield: 48.5 %

Procedure:
To an N,N-dimethylformamide solution (1.0 mL) of 1-(6-methyl-4-oxo-5-{[5-(trifluoromethyl)thiophen-2-yl]methyl}-4,5-dihydro-1,3,5-triazin-2-yl)piperidin-4-yl methanesulfonate (45.2 mg, 0.100 mmol) synthesized in Reference Synthesis Example 349, 4-bromo-1H-pyrazole (29.4 mg, 0.200 mmol) and potassium carbonate (27.6 mg, 0.200 mmol) were added and the resultant mixture was stirred at 100° C. for 1 hour. After the completion of the reaction, to the reaction solution, water was added and extraction with ethyl acetate from the reaction solution was performed. The organic layer was dried over anhydrous sodium sulfate and was concentrated under reduced pressure and the resultant residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (24.4 mg, yield: 48%).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:23])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]4[CH:17]=[C:18]([Br:22])[N:19]=[C:20](Br)[C:15]4=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[NH2:24][CH2:25][CH2:26][CH2:27][OH:28].C1(C)C=CC=CC=1>CN(C)C=O>[Br:22][C:18]1[N:19]=[C:20]([NH:24][CH2:25][CH2:26][CH2:27][OH:28])[C:15]2[N:16]([C:12]([C:9]3[CH:10]=[CH:11][C:6]([C:5]([NH:4][CH:1]4[CH2:2][CH2:3]4)=[O:23])=[CH:7][CH:8]=3)=[CH:13][N:14]=2)[CH:17]=1
Reactant: NCCCO
Reactant: O=C(NC1CC1)c1ccc(-c2cnc3c(Br)nc(Br)cn23)cc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(NC1CC1)c1ccc(-c2cnc3c(NCCCO)nc(Br)cn23)cc1
Temperature: 40 °C
Reaction time: 6 h
Yield: 92 %

Procedure:
To a solution of 500 mg (1.15 mmol) N-cyclopropyl-4-(6,8-dibromoimidazo[1,2-a]pyrazin-3-yl)benzamide which was prepared according to intermediate example 1b in 15 mL N,N-dimethylformamide were added 261 μL 3-aminopropan-1-ol and the mixture was stirred at 40° C. for 6 hours. Toluene was added and the solvents removed. The residue was purified by chromatography to give 453 mg (92%) of the title compound.
Reaction SMILES: Cl.[F:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.[C:17]([O:21][C:22](=[O:33])[NH:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([CH2:30][CH:31]=O)[CH2:26][CH2:25]1)([CH3:20])([CH3:19])[CH3:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:17]([O:21][C:22](=[O:33])[NH:23][C@H:24]1[CH2:25][CH2:26][C@H:27]([CH2:30][CH2:31][N:12]2[CH2:13][CH2:14][CH:9]([C:7](=[O:8])[C:6]3[CH:5]=[CH:4][C:3]([F:2])=[CH:16][CH:15]=3)[CH2:10][CH2:11]2)[CH2:28][CH2:29]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCC(C(=O)c3ccc(F)cc3)CC2)CC1
Reaction time: 12 h

Procedure:
A mixture of 4-(4-fluorobenzoyl)piperidine hydrochloride (0.850 g, 3.4 mmol), trans-[4-(2-Oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (0.926 g, 4 mmol), in dichloromethane (10 mL) was stirred for 2 hours at room temperature and sodium triacetoxyborohydride (1.33 g, 6 mmol) was added and the resulting solution was stirred for 12 hours until the TLC indicated completion of the reaction. The mixture was filtrated and concentrated to dryness and purified with column chromatography on silica gel using CH2Cl2—CH2Cl2/MeOH (1-9:1). The product fractions were concentrated to give 1.4 g (3.25 mmol, 93.2% yield) of a light yellow solid. MS (m/e): 433.4 (M+H+).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[N:17]=[CH:16][N:15]=1.[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[N:32]([CH3:33])[N:31]=[CH:30][C:29]=2[CH:34]=[O:35])=[CH:24][CH:23]=1>O1CCCC1>[Cl:13][C:14]1[C:19]([CH:34]([C:29]2[CH:30]=[N:31][N:32]([CH3:33])[C:28]=2[C:25]2[CH:26]=[CH:27][C:22]([CH3:21])=[CH:23][CH:24]=2)[OH:35])=[C:18]([Cl:20])[N:17]=[CH:16][N:15]=1
Reactant: Cc1ccc(-c2c(C=O)cnn2C)cc1
Reactant: Clc1cc(Cl)ncn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cc1ccc(-c2c(C(O)c3c(Cl)ncnc3Cl)cnn2C)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (2.5 M in hexanes, 240 mL, 0.60 mol) was added drop-wise to a solution of diisopropylamine (85.2 mL, 0.60 mol) in tetrahydrofuran (600 mL) at −78° C. After the reaction had stirred for 30 minutes at −78° C., a solution of 4,6-dichloropyrimidine (89.4 g, 0.600 mol) in tetrahydrofuran (600 mL) was added drop-wise at about −90° C., and stirring was continued for 1 hour. To this mixture was added drop-wise a solution of 5-(4-methylphenyl)-1-methyl-1H-pyrazole-4-carbaldehyde (C3) (60.0 g, 300 mmol) in tetrahydrofuran (600 mL) at about −90° C. After completion of the addition, the reaction mixture was stirred at this temperature for 2 hours. The reaction mixture was quenched with acetic acid (60 g); the mixture was warmed to room temperature, and then concentrated under reduced pressure to remove tetrahydrofuran. The residue was dissolved in ethyl acetate (2 L) and washed with saturated aqueous sodium bicarbonate solution (1 L). The organic layer was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, and concentrated in vacuo. Recrystallization from ethyl acetate yielded the product as a white solid. Yield: 82.0 g, 235 mmol, 78%. 1H NMR (400 MHz, CDCl3) δ 2.39 (s, 3H), 3.72 (s, 3H), 6.26 (s, 1H), 7.17 (br AB quartet, JAB=8 Hz, ΔνAB=32 Hz, 4H), 7.66 (s, 1H), 8.55 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:14])[NH:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(=O)([O-])[O-].[Ag+2].C1(C)C=CC=CC=1>[CH2:15]([O:14][C:3]1[C:2]([Br:1])=[N:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][N:4]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: O=c1[nH]cc(-c2ccccc2)nc1Br
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Brc1nc(-c2ccccc2)cnc1OCc1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 3-bromo-5-phenylpyrazin-2(1H)-one (0.16 g), silver carbonate (0.18 g), benzyl bromide (0.080 mL) and toluene (6.0 mL) was heated under reflux for 3 hr. The reaction mixture was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.21 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH2:12][CH2:13][CH3:14])[C:6](=[O:15])[CH2:5]2.[C:16]([O:20][C:21](=[O:27])[NH:22][CH2:23][C@H:24]1[CH2:26][O:25]1)([CH3:19])([CH3:18])[CH3:17].FC(F)(F)S([O-])(=O)=O.[Li+]>C(#N)C.C(OCC)(=O)C>[C:16]([O:20][C:21](=[O:27])[NH:22][CH2:23][C@H:24]([OH:25])[CH2:26][NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH2:12][CH2:13][CH3:14])[C:6](=[O:15])[CH2:5]2)([CH3:18])([CH3:17])[CH3:19]
Reactant: CCCN1C(=O)Cc2cc(N)cc(F)c21
Reactant: CC(C)(C)OC(=O)NC[C@H]1CO1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Li+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCN1C(=O)Cc2cc(NC[C@@H](O)CNC(=O)OC(C)(C)C)cc(F)c21

Procedure:
5-Amino-7-fluoro-1-propyl-1,3-dihydro-indol-2-one (0.500 g, 2.40 mmol), (S)-oxiranylmethyl-carbamic acid tert-butyl ester (0.417 g, 2.40 mmol) and lithium trifluoromethanesulfonate (0.368 g, 2.40 mmol) in acetonitrile (8 ml) are heated at 90° C. for 8 hours. The reaction mixture is diluted with ethyl acetate, washed with water and brine, dried (Na2SO4) and evaporated. Final purification by flash chromatography (70% Ethyl acetate/hexane) gives the title compound as a yellow solid. HPLC r.t. 4.30 min; MS for C19H28FN3O4 m/z 382.3 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[C:5]([O:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[C:20](O)=[O:21])[CH:17]=[CH:16][S:15]3)[CH:7]=[CH:8][CH:9]=1.[NH2:30][C:31]1[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][N:32]=1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C1COCC1.CN(C=O)C>[C:35]([C:34]1[CH:37]=[CH:38][C:31]([NH:30][C:20]([C:19]2[N:18]3[C:14]([S:15][CH:16]=[CH:17]3)=[N:13][C:12]=2/[CH:11]=[CH:10]/[C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH:2]([F:1])[F:29])[C:5]=2[O:23][CH2:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:21])=[N:32][CH:33]=1)#[N:36]
Reactant: CC(C)(C)COc1c(/C=C/c2nc3sccn3c2C(=O)O)cccc1OC(F)F
Reactant: N#Cc1ccc(N)nc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)COc1c(/C=C/c2nc3sccn3c2C(=O)Nc2ccc(C#N)cn2)cccc1OC(F)F

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 7A (80 mg, 0.189 mmol) with 6-aminonicotinonitrile (27 mg, 0.226 mmol) in the presence of EDCI hydrochloride (72 mg, 0.378 mmol), DMAP (22 mg, 0.189 mmol) in a mixture of THF and DMF (1:1, 4 mL) to give 25 mg of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.03 (s, 9H), 3.56 (s, 2H), 7.17 (t, J=74.1 Hz, 1H), 7.19-7.25 (m, 2H), 7.42-7.50 (m, 2H), 7.55-7.62 (m, 1H), 7.82 (d, J=15.6 Hz, 1H), 8.02-8.08 (m, 1H), 8.18-8.24 (m, 1H), 8.28-8.35 (m, 1H), 8.83-8.90 (m, 1H), 11.39 (br s, 1H); APCI-MS (m/z) 524.25 (MH)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[C@@H:7]([NH2:13])[C@@H:8]([OH:12])[CH:9]([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:22]([O:29][C:30](ON1C(=O)CCC1=O)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:22]([O:29][C:30]([NH:13][C@@H:7]([C@@H:8]([OH:12])[CH:9]([CH3:10])[CH3:11])[C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:14])=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CC(C)[C@H](O)[C@H](N)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[C@H](O)[C@H](NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 96.3 %

Procedure:
A solution of (2S,3S)-2-amino-3-hydroxy-4-methyl-pentanoic acid tert-butyl ester (297 mg, 1.37 mmol) and triethylamine (139 mg, 1.37 mmol) in anhydrous methylene chloride (2 ml) was cooled to 0° C. under a nitrogen atmosphere. To this solution was added N-(benzyloxycarbonyloxy)-succinimide (343 mg, 1.37 mmol). The resulting mixture was warmed to room temperature and stirred for 15 hours. The reaction mixture was partitioned between ether and water. The organic layer was washed with cold 1N hydrochloric acid and saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated in vacuo, to provide tert-butyl (2S,3S)-2-{[(benzyloxy)carbonyl]-amino}-3-hydroxy-4-methylpentanoate (445 mg, 96%) as a yellow oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:22]([NH:24][NH:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].[C:34]([O:38][C:39]([NH:41][CH2:42][CH2:43][C:44](O)=[O:45])=[O:40])([CH3:37])([CH3:36])[CH3:35].Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(OCC)(=O)C>[C:34]([O:38][C:39]([NH:41][CH2:42][CH2:43][C:44]([N:25]([CH2:26][CH:27]([CH3:28])[CH3:29])[NH:24][C:22](=[O:23])[C@@H:21]([C@@H:11]([C:9](=[O:10])[NH:8][O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:30][CH:31]([CH3:33])[CH3:32])=[O:45])=[O:40])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)CNNC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)CCNC(=O)OC(C)(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.2 %

Procedure:
A solution of 0.459 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)-carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide in 5 ml of dimethylformamide was cooled to 0° C. and treated with 0.378 g of N-tert.-butoxycarbonyl-β-alanine and 0.383 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodimide hydrochloride. The mixture was stirred at room temperature for 16 hours and diluted with ethyl acetate. The solution was washed in succession with water, 5% citric acid solution and water, dried over anhydrous magnesium sulphate and evaporated. Chromatography on silica gel using ethyl acetate/hexane (1:1) for the elution followed by evaporation gave 0.48 g of (E)-2′-(N-tert.-butoxycarbonyl-β-alanyl)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)-carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide in the form of a white foam.
Reaction SMILES: [NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@H:2]([C:11]([OH:13])=O)[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[NH2:39][C@H:40]([C:48]([NH2:50])=[O:49])[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C1COCC1.CN(C=O)C.O.C(OCC)(=O)C>[NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@H:2]([C:11]([NH:39][C@H:40]([C:48]([NH2:50])=[O:49])[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:13])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:7])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: NC(=O)[C@@H](N)Cc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(N)=O
Temperature: 25 °C
Reaction time: 0.07 h
Yield: 89.2 %

Procedure:
To a -10° C. solution of Cbz-Asp(O-t-Bu) (2.5 g, 4.95 mmol) in THF (40 mL) were added NMM (0.52 g, 5.18 mmol) followed by isobutylchloroformate (0.705 g, 5.16 mmol) to form a white precipitate. The suspension was stirred for 4 minutes and a solution of Phe-NH2 (0.81 g, 4.94 mmol) in DMF (10 mL) and water (5 mL) were added. The solution was stirred at -15° C. for additional 10 minutes then allowed to warm to ambient temperature. After 6 hours, the solution was diluted with ethyl acetate, washed with 1M HCl, saturated bicarbonate solution and brine. After drying over anhydrous sodium sulfate, the solvent was removed in vacuo to yield 2.07 g (89% yield) of the title compound as a white solid which was recrystallied from ethyl acetate. MS(FAB+) m/e 470 (M+H+). 1H NMR (300 MHz,CDCl3) δ1.41 (s, 9H), 2.67 (dd, J=6 and 15 Hz, 1H), 2.80 (dd, 1H), 3.03-3.22 (m, 2H), 4.42 (m, 2H), 4.64 (m, 2H), 5.17 (dd, 2H), 7.15-7.40 (m, 10H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:4][C:3]=1[C:15]([CH:18]1[CH2:20][CH2:19]1)([OH:17])[CH3:16].[C:21](N1C=CN=C1)(N1C=CN=C1)=[O:22]>>[Cl:14][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]3[NH:1][C:21](=[O:22])[O:17][C:15]([CH:18]4[CH2:20][CH2:19]4)([CH3:16])[C:3]=3[CH:4]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: CC(O)(c1cc(-c2cccc(Cl)c2)ccc1N)C1CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Product: CC1(C2CC2)OC(=O)Nc2ccc(-c3cccc(Cl)c3)cc21

Procedure:
The title compound was prepared from 1-(4-amino-3′-chloro-biphenyl-3-yl)-1-cyclopropyl-ethanol and 1,1′carbonyldiimidazole according to Procedure C. Off-white solid: mp 158-159° C.; 1H-NMR (DMSO-d6) δ 10.3 (s, 1H), 7.74 (t, 1H, J=1.71 Hz), 7.67-7.57 (m, 3H), 7.47 (t, 1H, J=7.88 Hz), 7.39 (d, 1H, J=8.1 Hz), 6.95 (d, 1H, J=8.12 Hz), 1.7 (s, 3H), 1.45 (m, 1H), 0.48 (m, 2H), 0.28 (m, 2H); MS (APCI) m/z 314 ([M+H]+, 100%); Anal. Calc. For C18H16ClNO2: C, 68.9; H, 5.14; N, 4.46. Found: C, 68.13; H, 5.01; N, 4.36.
Reaction SMILES: O[C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]#[N:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[N:5]=[CH:4][N:3]=1.O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]#[N:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[N:5]=[CH:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1ccc2c(c1)[nH]c1ncnc(O)c12
Product: N#Cc1ccc2c(c1)[nH]c1ncnc(Cl)c12
Temperature: 25 °C

Procedure:
A solution of 4-hydroxy-9H-pyrimido[4,5-b]indole-7-carbonitrile (215 mg, 1.02 mmol) in 5 mL POCl3 (5 mL) was heated at 100° C. for 18 hours. Upon cooling to room temperature the reaction mixture was evaporated to dryness and the residue treated with saturated sodium bicarbonate solution and ethyl acetate. The organic phase was dried over sodium sulphate and concentrated to the title compound as an orange solid. LC-MS (1) Rt 1.66 min; (100% UV), m/z (ES−) 227/229. The product was used without further purification.