Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH3:13][CH:14]([CH3:34])[CH2:15][C:16]1([CH2:30][C:31](O)=[O:32])[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]1=[O:29].O.[OH:36][N:37]1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.NO>C(Cl)Cl.CN(C=O)C>[OH:36][NH:37][C:31](=[O:32])[CH2:30][C:16]1([CH2:15][CH:14]([CH3:34])[CH3:13])[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]1=[O:29]
Reactant: On1nnc2ccccc21
Reactant: CC(C)CC1(CC(=O)O)CCN(CCc2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)CC1(CC(=O)NO)CCN(CCc2ccccc2)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 30.9 %

Procedure:
Solid 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 451 mg, 2.35 mmol) is added to a solution of 3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetic acid (595 mg, 1.96 mmol), 1-hydroxybenzotriazole hydrate (HOBT, 281 mg, 2.08 mmol) and 4-methylmorpholine (0.26 mL, 2.4 mmol) in CH2Cl2 (19 mL) and DMF (4 mL) at 0° C. The solution is stirred at 0° C. for 1 hour, and then a near solution of hydroxylamine hydrochloride (204 mg, 2.94 mmol) and 4-methylmorpholine (0.32 mL, 2.9 mmol) in DMF (2.7 mL) is added. After stirring at room temperature overnight, the mixture is concentrated under high vacuum, and purified by column chromatography (3% MeOH/CH2Cl2). Crystallization from Et2O/hexane provided 193 mg (31%) of the title compound as a white solid (mp 123°-124° C.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:23]=[C:11]3[N:12]=[C:13]([Cl:22])[CH:14]=[C:15]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[N:10]3[N:9]=2)=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[N:43]1([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>C1(C)C=CC=CC=1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[C:52]([O:51][C:49]([N:43]1[CH2:48][CH2:47][N:46]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:23]=[C:11]4[N:12]=[C:13]([Cl:22])[CH:14]=[C:15]([N:16]5[CH2:21][CH2:20][O:19][CH2:18][CH2:17]5)[N:10]4[N:9]=3)=[CH:4][CH:3]=2)[CH2:45][CH2:44]1)=[O:50])([CH3:55])([CH3:53])[CH3:54]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1cc(N2CCOCC2)n2nc(-c3ccc(Br)cc3)cc2n1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cc4nc(Cl)cc(N5CCOCC5)n4n3)cc2)CC1
Yield: 56.9 %

Procedure:
There was dissolved, in toluene (3 mL), 2-(4-bromo-phenyl)-5-chloro-7-morpholin-4-yl-pyrazolo[1,5-a]pyrimidine (56.2 mg, 0.143 mM) in an argon gas atmosphere, then there were added, to the resulting solution, a solution of sodium t-butoxide (20.6 mg, 0.215 mM), tris(dibenzylidene acetone) di-palladium (7.2 mg, 0.0079 mM) and tri-t-butyl phosphine (4.7 μL, 0.023 mM) in toluene (0.30 mL) and t-butyl 1-piperazine carboxylate (39.9 mg, 0.215 mM) and the resulting mixture was stirred at 90° C. for 30 minutes. This reaction liquid was diluted with a saturated aqueous common salt solution and then extracted with ethyl acetate. The extracts thus obtained were combined, dried over anhydrous sodium sulfate, then the solvent was distilled off and the resulting residue was purified by the silica gel column chromatography (ethyl acetate/hexane=1:3) to thus give the title compound (40.5 mg, yield: 57%).
Reaction SMILES: [C:1]([C:3]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)(=[O:17])=[O:16])=[C:6]([CH3:23])[N:5]([CH2:24][C:25]([O:27]CC)=[O:26])[C:4]=1[CH:30]1[CH2:32][CH2:31]1)#[N:2].O.[OH-].[Li+]>>[C:1]([C:3]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)(=[O:17])=[O:16])=[C:6]([CH3:23])[N:5]([CH2:24][C:25]([OH:27])=[O:26])[C:4]=1[CH:30]1[CH2:31][CH2:32]1)#[N:2]
Reactant: CCOC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)N2CCCC2)c(C#N)c1C1CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: Cc1c(Cc2ccccc2S(=O)(=O)N2CCCC2)c(C#N)c(C2CC2)n1CC(=O)O
Yield: 95.1 %

Procedure:
was followed using ethyl 2-(3-cyano-2-cyclopropyl-5-methyl-4-(2-(pyrrolidin-1-ylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetate (65.4 mg, 0.144 mmol) and lithium hydroxide hydrate (12.05 mg, 0.287 mmol) to afford 2-(3-cyano-2-cyclopropyl-5-methyl-4-(2-(pyrrolidin-1-ylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetic acid as a white solid (58.5 mg, 0.137 mmol, 95% yield). 1H NMR (400 MHz, CDCl3) δ (ppm) 7.94 (d, 1H), 7.43 (dd, 1H), 7.32 (dd, 1H), 7.08 (d, 1H), 4.69 (s, 2H), 4.26 (s, 2H), 3.31-3.35 (m, 4H), 1.90-1.95 (m, 7H), 1.65 (m, 1H), 0.86-0.97 (m, 4H).
Reaction SMILES: C1(C(=[N:14][CH2:15][C:16]([CH3:27])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17]([O:19]C)=[O:18])C2C=CC=CC=2)C=CC=CC=1.[ClH:28]>>[ClH:28].[NH2:14][CH2:15][C:16]([CH3:27])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:17]([OH:19])=[O:18]
Reactant: COC(=O)C(C)(CN=C(c1ccccc1)c1ccccc1)c1ccccc1
Agent: Cl
Product: CC(CN)(C(=O)O)c1ccccc1

Procedure:
A mixture of methyl 3-(diphenylmethyleneamino)-2-methyl-2-phenylpropanoate (E321) and 6 N HCl was refluxed overnight. The solution was cooled and evaporated to give 3-amino-2-methyl-2-phenylpropanoic acid hydrochloride (E322).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:30])[NH:13][C:14](=[O:29])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][C:21]([N+:25]([O-:27])=[O:26])=[CH:22][CH:23]=3)[N:18]([CH3:28])[CH:17]=2)=[CH:3]1.[CH2:31]=[O:32]>O>[OH:32][CH2:31][N:13]1[C:14](=[O:29])[C:15]([C:16]2[C:24]3[C:19](=[CH:20][C:21]([N+:25]([O-:27])=[O:26])=[CH:22][CH:23]=3)[N:18]([CH3:28])[CH:17]=2)=[C:11]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=2)[C:12]1=[O:30]
Reactant: C=O
Reactant: Cn1cc(C2=C(c3cn(C)c4cc([N+](=O)[O-])ccc34)C(=O)NC2=O)c2ccccc21
Solvent: O
Product: Cn1cc(C2=C(c3cn(C)c4cc([N+](=O)[O-])ccc34)C(=O)N(CO)C2=O)c2ccccc21
Reaction time: 14 h

Procedure:
A suspension consisting of 0.5 g (1.25 mmole) of 3-(1-methyl-3-indolyl)-4-(1-methyl-6-nitro-3-indolyl)-1H-pyrrole-2,5-dione (See Davis U.S. Pat. No. 5,057,614), 4.0 ml of formaldehyde solution (37% w/w), and 2.0 ml of water was heated to 125° C. with stirring and with a reflux condensed attached for 14 hours. The reaction mixture was cooled and diluted with water. The red solid was filtered, washed with water and dried. The solid was purified by chromatography using silica gel and a mixture of EtOAc/Hexane as elutant to afford 1-hydroxymethyl-3-(1-methyl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)-pyrrole-2,5-dione (mp=209-211° C.).
Reaction SMILES: Cl.[N+:2]([O:5][CH2:6][CH2:7][CH2:8][O:9][C:10](=[O:21])[C@H:11]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[NH2:12])([O-:4])=[O:3].[C:22]([O:26][C:27](=[O:48])[C@@H:28]1[CH2:32][CH2:31][CH2:30][N:29]1[C:33](=[O:47])[C@H:34](OS(C1C=CC(C)=CC=1)(=O)=O)[CH3:35])([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C>CN(C=O)C.CCOCC>[C:22]([O:26][C:27](=[O:48])[C@@H:28]1[CH2:32][CH2:31][CH2:30][N:29]1[C:33](=[O:47])[C@H:34]([CH3:35])[NH:12][C@H:11]([C:10]([O:9][CH2:8][CH2:7][CH2:6][O:5][N+:2]([O-:4])=[O:3])=[O:21])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:24])([CH3:23])[CH3:25]
Reactant: Cc1ccc(S(=O)(=O)O[C@H](C)C(=O)N2CCC[C@H]2C(=O)OC(C)(C)C)cc1
Reactant: N[C@@H](CCc1ccccc1)C(=O)OCCCO[N+](=O)[O-]
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C[C@H](N[C@@H](CCc1ccccc1)C(=O)OCCCO[N+](=O)[O-])C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 46.2 %

Procedure:
Homophenylalanine 3-nitrooxypropyl ester hydrochloride (3.85 g, 12.1 mmol) and N-[(2R)-2-(4-toluenesulfonyloxy) propionyl]-L-proline t-butyl ester (6.40 g, 16.1 mmol) were dissolved in DMF (15 mL) and triethylamine (3.9 mL, 28 mmol) was added to the solution. The reaction was stirred at room temperature for 48 hours, then N-[(2R)-2-(4-toluenesulfonyloxy)propionyl]-L-proline t-butyl ester (3.21 g, 8.1 mmol) was added again and the reaction stirred for further 48 hours. The reaction mixture was diluted with Et2O (100 mL), washed with brine (3×50 mL) dried over Na2SO4 and concentrated. The crude material was purified by flash chromatography (CHCl3/EtOAc 2:1) affording N-[(1S)-1-(3-nitrooxypropoxycarbonyl)-3-phenylpropyl]-L-alanyl-L-proline t-butyl ester as a clear oil (2.84 g, 46%). The product was dissolved in CH3CN (20 mL), maleic acid was added (0.69 g, 5.9 mmol) and the solvent was removed. The crude material was crystallised from EtOAc/iPr2O affording N-[(1S)-1-(3-nitrooxypropoxycarbonyl)-3-phenylpropyl]-L-alanyl-L-proline t-butyl ester hydrogen maleate as a white powder (2.27 g, 30%, 98%).
Reaction SMILES: C(O[N:5]1[C:10]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[CH:17][CH2:16][CH2:15]3)=[CH:9][CH:8]=[C:7]([NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)=[O:24])[CH2:6]1)(=O)C.C(=O)([O-])[O-:37].[K+].[K+]>C(O)C>[C:18]1(=[O:37])[C:19]2[C:14](=[CH:13][C:12]([O:11][C:10]3[N:5]=[CH:6][C:7]([NH:22][C:23]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=4)=[O:24])=[CH:8][CH:9]=3)=[CH:21][CH:20]=2)[CH2:15][CH2:16][CH2:17]1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)ON1CC(NC(=O)Nc2ccc(C(F)(F)F)cc2)=CC=C1Oc1ccc2c(c1)CCC=C2
Agent: [K+]
Solvent: CCO
Product: O=C(Nc1ccc(C(F)(F)F)cc1)Nc1ccc(Oc2ccc3c(c2)CCCC3=O)nc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 70.9 %

Procedure:
To a solution of N1-{1-acetoxy-6-[(3,4-dihydronaphthalene-6-yl)oxy]pyridine-3-yl}-N3-[4-(trifluoromethyl)phenyl]urea (450 mg) in ethanol (20 ml), 980 mg of potassium carbonate was added and the mixture was stirred at room temperature for 40 minutes. After the reaction mixture was filtered and concentrated, the residue was dissolved in ethyl acetate and the solution was washed with water. After drying over anhydrous magnesium sulfate, the solvent was distilled off. The residue was washed with ether to obtain 290 mg of the titled compound as a white powder.
Reaction SMILES: [Cl-].[NH4+].[CH3:3][C:4]1[C:9]([N+:10]([O-])=O)=[CH:8][CH:7]=[C:6]([N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[N:5]=1>C(OCC)(=O)C.[Zn]>[CH3:3][C:4]1[C:9]([NH2:10])=[CH:8][CH:7]=[C:6]([N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[N:5]=1
Reactant: Cc1nc(-n2cncn2)ccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCOC(C)=O
Product: Cc1nc(-n2cncn2)ccc1N
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 75.3 %

Procedure:
A mixture of zinc (Aldrich, <10 micron; 798 mg, 12.2 mmol) in aqueous ammonium chloride (2 M; 6.1 mL, 12.2 mmol) was cooled to 0° C. using an ice-water bath, and stirred at this temperature for 15 min. A solution of 2-methyl-3-nitro-6-[1,2,4]triazol-1-yl-pyridine (500 mg, 2.44 mmol) in ethyl acetate (8 mL) was added and the mixture was stirred at 0° C. for 1 h and then at room temperature overnight. The mixture was then filtered through Celite™ to remove zinc dust, and the Celite™ was washed with ethyl acetate and methanol. Water and ethyl acetate were added to the filtrate and the mixture was shaken and then filtered to remove some solid material between the two layers. The aqueous layer was extracted twice with ethyl acetate and the combined organic layers were evaporated to dryness under high vacuum to give 2-methyl-6-[1,2,4]triazol-1-yl-pyridin-3-ylamine (322 mg, 75%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 2.30 (s, 3H), 5.37 (s, 2H), 7.11 (d, 1H, J=8.4 Hz), 7.38 (d, 1H, J=8.4 Hz), 8.13 (s, 1H), 9.03 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:9](=[C:10]([O:23][CH3:24])[C:11](=[O:22])[N:12]([CH3:21])[C:13]=3[C:17]([O:19]C)=[O:18])[C:8]2=[O:25])=[CH:4][CH:3]=1.[Li+].[OH-]>CO.O>[F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:9](=[C:10]([O:23][CH3:24])[C:11](=[O:22])[N:12]([CH3:21])[C:13]=3[C:17]([OH:19])=[O:18])[C:8]2=[O:25])=[CH:4][CH:3]=1
Reactant: COC(=O)c1c2c(c(OC)c(=O)n1C)C(=O)N(Cc1ccc(F)cc1)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1c2c(c(C(=O)O)n(C)c1=O)CCN(Cc1ccc(F)cc1)C2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 6-(4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate (0.575 g, 1.536 mmol) in methanol was added LiOH (0.11 g, 4.61 mmol) in water. The reaction mixture was heated to reflux. After 0.5 hours, the product mixture cooled to room temperature and concentrated under vacuum. The residual material was partitioned between EtOAc and 1 N HCl. The organic extract was washed with brine, dried with Na2SO4, filtered, and concentrated under vacuum to provide the title compound.
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]([NH:17][C:18]([NH2:20])=[O:19])=[C:10]([C:12](OCC)=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>CO>[C:1]1([C:7]2[S:8][C:9]3[N:17]=[C:18]([OH:19])[N:20]=[C:12]([OH:13])[C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1nc(-c2ccccc2)sc1NC(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Oc1nc(O)c2nc(-c3ccccc3)sc2n1
Temperature: 25 °C

Procedure:
Ethyl 2-phenyl-5-ureidothiazole-4-carboxylate 63 (x mg, x eq) was suspended in methanol (5 ml) and treated with 1.5 M NaOH (1 ml). Reaction mixture was heated to reflux for 90 minutes. Reaction mixture was allowed to cool down to room temperature, and was acidified with 6N HCl up to pH 3. Solid was filtered and dried at 95° C. under high vacuum for 24 h to yield 2-phenylthiazolo[5,4-d]pyrimidine-5,7-diol 64 as a beige solid which was used in the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)([CH3:12])[C:7](=[O:20])[C:6]([C:21](OCC)=[O:22])=[C:5]2[OH:26].Cl.[C:28]([O:32][C:33](=[O:36])[CH2:34][NH2:35])([CH3:31])([CH3:30])[CH3:29].CCN(C(C)C)C(C)C>O1CCOCC1.O>[Cl:19][C:16]1[CH:15]=[C:14]2[C:13](=[CH:18][CH:17]=1)[C:8]([C:9]1[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=1)([CH3:12])[C:7](=[O:20])[C:6]([C:5]([NH:35][CH2:34][C:33]([O:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:36])=[O:26])=[C:21]2[OH:22]
Reactant: CCOC(=O)C1=C(O)c2cc(Cl)ccc2C(C)(c2ccc(Cl)cc2)C1=O
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(Cl)ccc2C(C)(c2ccc(Cl)cc2)C1=O
Temperature: 120 °C
Reaction time: 3 h
Yield: 73.1 %

Procedure:
A solution of ethyl 6-chloro-1-(4-chlorophenyl)-4-hydroxy-1-methyl-2-oxo-naphthalene-3-carboxylate (0.998 g, 2.55 mmol), glycine tert-butyl ester hydrochloride (0.513 g, 3.06 mmol), and DIPEA (0.889 mL, 5.10 mmol) in 1,4-dioxane (15 mL) in a 75 mL sealed vessel was stirred at 120° C. for 3 hours. The solution was diluted with deionized water (75 mL) and extracted with DCM (2×50 mL). The combined organic layers were then washed with brine (50 mL), dried over MgSO4, and concentrated in vacuo to give 1.42 g crude product. The crude product was purified by flash column chromatography (silica, 0-25% DCM in hexane) to give the title compound (0.888 g). MS m/e=420 (M+H-tBu)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[CH:4]([NH:8][C:9](=[O:35])[CH:10]([NH:27][C:28]([O:30]C(C)(C)C)=O)[CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)=[CH:16][CH:15]=1)[CH:5]([CH3:7])[CH3:6].O.CCN(C(C)C)C(C)C.ClC(OC1C=CC=CC=1)=O>C(O)(C(F)(F)F)=O.O1CCOCC1.CN(C=O)C>[CH3:1][O:2][C:3](=[O:36])[CH:4]([N:8]1[C:9](=[O:35])[CH:10]([CH2:11][O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[CH:18][CH:19]=2)[NH:27][C:28]1=[O:30])[CH:5]([CH3:6])[CH3:7]
Reactant: COC(=O)C(NC(=O)C(COCc1ccc(-c2cccc(F)c2)cc1)NC(=O)OC(C)(C)C)C(C)C
Agent: O=C(Cl)Oc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COC(=O)C(C(C)C)N1C(=O)NC(COCc2ccc(-c3cccc(F)c3)cc2)C1=O
Reaction time: 2 h
Yield: 53.9 %

Procedure:
The compound obtained in step a above (20a) (813 mg, 1.619 mmol) was stirred in TFA (4 mL) at 0° C. for 5 h, then concentrated under vacuum. The residue was diluted with CH2Cl2, washed with saturated NaHCO3 and brine, dried over anhydrous Na2SO4 and concentrated which gave the crude product. The obtained crude product was stirred in dioxane (9 mL) and water (1 mL) at 0° C. DIEA (610 mg, 4.86 mmol) and phenyl chloroformate (379 mg, 2.429 mmol) were added, and the mixture was stirred for 2 h. The solvent was removed under vacuum; the residue was diluted with EtOAc and washed with brine. The combined organic layers were dried and concentrated to give a yellow oil. The obtained oil was then stirred with DIEA (610 mg, 4.86 mmol) in DMF (10 mL) for 24 h. After general workup, the crude product was purified by silica gel column chromatography which gave the title compound as a white solid (374 mg, 54% yield).
Reaction SMILES: [CH2:1]([N:5]1[C:13]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[N:12][C:11]2[C:6]1=[N:7][C:8]([C:26]1[CH:27]=[N:28][C:29]([NH2:32])=[N:30][CH:31]=1)=[N:9][C:10]=2[N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[CH:2]([CH3:4])[CH3:3].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[OH:55][C@@H:56]([CH3:61])[CH2:57][C:58](O)=[O:59]>CN(C)C=O>[NH2:32][C:29]1[N:30]=[CH:31][C:26]([C:8]2[N:7]=[C:6]3[C:11]([N:12]=[C:13]([N:14]4[CH2:19][CH2:18][N:17]([C:58](=[O:59])[CH2:57][C@@H:56]([OH:55])[CH3:61])[CH2:16][CH2:15]4)[N:5]3[CH2:1][CH:2]([CH3:4])[CH3:3])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)=[CH:27][N:28]=1
Reactant: CC(C)Cn1c(N2CCNCC2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Reactant: C[C@H](O)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)Cn1c(N2CCN(C(=O)C[C@H](C)O)CC2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Reaction time: 16 h
Yield: 56 %

Procedure:
5-(9-Isobutyl-6-morpholin-4-yl-8-piperazin-1-yl-9H-purin-2-yl)pyrimidin-2-amine (150 mg, 0.33 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (128 mg, 0.67 mmol), 1-hydroxybenzotriazole (45 mg, 0.33 mmol), and (S)-3-hydroxybutyric acid (70 mg, 0.67 mmol) were dissolved in dimethylformamide (5 ml) and the resulting mixture was stirred for 16 hours. The solvent was evaporated under reduced pressure and then the residue was purified by preparative HPLC (column, NOMURA Develosil Combi-RP-5; mobile phase, acetonitrile/water/formic acid) to give the title compound (97 mg, 56%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]([CH3:15])[C:4]=1[C:5]([O:7][CH3:8])=[O:6].C1C(=O)N([Br:23])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:23][CH2:15][C:9]1[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=[C:3]([O:2][CH3:1])[C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1c(C)cc(OC)cc1OC
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(CBr)cc(OC)cc1OC
Yield: 82.1 %

Procedure:
Dissolve compound 3 (10 g, 0.0476 mol) in 50 ml carbon tetrachloride, heat to reflux under nitrogen protection, add portion wise a mixture of NBS (8.5 g, 0.0476 mol) and BPO (0.11 g, 0.476 mmol), after finishing the addition, reflux to react for 1 h. Then stop the reaction, cool and filter the mixture, spin-dry filtrate to obtain a pale yellow solid, re-crystallize from ethanol to obtain 11.3 g white solid (82%). 1H-NMR (400M, CDCl3) δ (ppm): 3.85 (s, 3H), 3.93 (s, 3H), 3.96 (s, 3H), 4.66 (s, 2H), 6.47 (s, 1H), 6.74 (s, 1H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[C:10]([C:18]([O:20]CC)=[O:19])=[C:9]1[CH:23]([CH3:25])[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CCO.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[C:10]([C:18]([OH:20])=[O:19])=[C:9]1[CH:23]([CH3:25])[CH3:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(C(C)C)n(Cc2ccccc2)c2ccc(O)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)c1c(C(=O)O)c2cc(O)ccc2n1Cc1ccccc1

Procedure:
General Procedure E. A solution of ethyl 1-benzyl-5-hydroxy-2-isopropyl-1H-indole-3-carboxylate (Compound 1, 1.1 g, 3.3 mmol) and NaOH (2.6 g, 65 mmol) in EtOH (20 ml) and H2O (10 ml) was heated to 100° C. for 16 h. The solvent was removed and the residue was treated with cold 6 M HCl (10.8 ml) and filtered. The resulting solid was washed with H2O (×3) and was taken in Et2O (∴3) to yield 1-benzyl-5-hydroxy-2-isopropyl-1H-indole-3-carboxylic acid (Compound 28) as a brown solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O)[C:7](=O)[CH3:8])=[O:5])[CH3:2].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:12](=[O:14])[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:7]=1[CH3:8])=[O:5])[CH3:2]
Reactant: CCOC(=O)C(C(C)=O)c1ccccc1C(=O)O
Reactant: Nc1ccccc1
Product: CCOC(=O)c1c(C)n(-c2ccccc2)c(=O)c2ccccc12
Temperature: 150 °C
Yield: 93.1 %

Procedure:
A mixture of 2-(1-ethoxycarbonyl-2-oxo-propyl)-benzoic acid (7.6 g, 30.4 mmol) and aniline (10 ml, 108 mmol) was flushed with argon, sealed in the Emrys process vial and heated at 150° C. for 15 min under microwave irradiation. The volatiles were removed in vacuo and the obtained residue was partitioned between ethyl acetate (100 ml) and 2M HCl (100 ml). The organic layer was washed with brine (2×20 ml), dried (Na2SO4) and evaporated to give 8.7 g of brown oil that solidified. The obtained crude product was of ca. 90% purity according to 1H NMR and can be used in the next step without further purification. Alternatively, the crude product was dissolved in hot ethyl acetate (20 ml), precipitated with heptane (60 ml), allowed to cool, filtered and washed with diethyl ether to give 4.2 g of a pale-brown crystalline solid, yield 45%. LC-MS (m/z) 308.2 (MH+); tR=1.43. 1H NMR (500 MHz, DMSO-d6): 1.34 (t, 3H), 1.97 (s, 3H), 4.41 (q, 2H), 7.38 (d, 2H), 7.51 (t, 1H), 7.56 (t (overlapping m), 3H), 7.62 (d, 1H), 7.8 (t, 1H), 8.22 (d, 1H).
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[O:14])[C:5]1=[O:23])([CH3:3])[CH3:2].[C:24]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])(=[O:27])[CH:25]=[CH2:26]>C1COCC1.C([O-])(O)=O.[Na+]>[CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13]([NH:15][CH2:16][CH:17]2[CH2:18][CH2:19][N:20]([CH2:26][CH2:25][C:24]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21][CH2:22]2)=[O:14])[C:5]1=[O:23])([CH3:3])[CH3:2]
Reactant: CC(C)n1c(=O)n(C(=O)NCC2CCNCC2)c2ccccc21
Reactant: C=CC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)n1c(=O)n(C(=O)NCC2CCN(CCC(=O)OC(C)(C)C)CC2)c2ccccc21
Yield: 15.8 %

Procedure:
A mixture of 3-isopropyl-2-oxo-N-(piperidin-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide (0.50 g, 1.58 mmol, Step 2), tert-butyl acrylate (0.340 mL, 2.37 mmol) and iPrNEt (0.275 mL, 2.37 mmol) in THF (20 mL) was refluxed for 18 h. After cooling, the reaction mixture was diluted with sat. NaHCO3 aq. (100 mL), extracted with CH2Cl2 (100 mL) for three times. The combined extracts were dried over Na2SO4, filtered and concentrated. The residue was chromatographed on a column of silica gel eluted with MeOH/CH2Cl2 (1:20→1:10) and then NH-silica gel eluted with EtOAc/hexane (1:5→1:2) to give 0.111 g (16%) of title compound as colorless syrup.