Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[CH2:3][CH2:4][C:5]1[N:6]=[C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[NH:8][CH:9]=1.[OH-].[K+].Cl.Cl[CH2:29][CH2:30][N:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>CS(C)=O.C(OCC)(=O)C>[N:31]1([CH2:30][CH2:29][N:8]2[CH:9]=[C:5]([CH2:4][CH2:3][C:2]([F:23])([F:1])[F:24])[N:6]=[C:7]2[CH:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:14][CH2:15]2)[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(CCC(F)(F)F)c[nH]2)CC1
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(CCC(F)(F)F)cn2CCN2CCCC2)CC1
Temperature: 50 °C
Yield: 25.1 %

Procedure:
Combine tert-butyl 4-(4-(3,3,3-trifluoropropyl)-1H-imidazol-2-yl)piperidine-1-carboxylate (2.27 g, 6.53 mmol), potassium hydroxide (1.20 g, 3.3 eq) (freshly powdered), and 1-(2-chloroethyl)pyrrolidine hydrochloride (1.34 g, 1.2 eq) in dimethyl sulfoxide (100 mL). Heat the reaction mixture at 50° C. overnight, then allow to cool to room temperature. Dilute with ethyl acetate. Wash with water followed by saturated aqueous sodium chloride. Dry the organics over anhydrous sodium sulfate, filter, and concentrate in vacuo. Purify by silica gel chromatography, eluting with 4:1 dichloromethane:isopropyl alcohol, to give tert-butyl 4-(1-(2-(pyrrolidin-1-yl)ethyl)-4-(3,3,3-trifluoropropyl)-1H-imidazol-2-yl)piperidine-1-carboxylate as a thick yellow oil (0.73 g, 25%). MS (ES) m/z=445 [M]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]2=[N:8][CH:9]=[C:10]([O:12]C)[N:11]=[C:6]2[CH:5]=[CH:4][N:3]=1.B(Br)(Br)Br.ClCCl>ClCCCl>[Cl:1][C:2]1[C:7]2=[N:8][CH:9]=[C:10]([OH:12])[N:11]=[C:6]2[CH:5]=[CH:4][N:3]=1
Reactant: COc1cnc2c(Cl)nccc2n1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: ClCCCl
Product: Oc1cnc2c(Cl)nccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 153.8 %

Procedure:
A pressure-resistant vessel was charged with 5-chloro-2-methoxypyrido[3,4-b]pyrazine (5.0 g, 26 mmol) and DCE (25 mL). To this was added a 1M solution of boron tribromide in dichloromethane (82 mL, 82 mmol) slowly via syringe. The vessel was sealed, and the reaction was stirred at ambient temperature overnight. After 16 hours, the reaction was quenched by slow addition of the reaction mixture into a beaker containing methanol (100 mL) and ice. The resulting yellow solution was concentrated to a tan slurry, which was triturated with ethyl acetate (50 mL). The off-white precipitate was collected by vacuum filtration, washed with ethyl acetate, and dried in vacuo to provide the title compound (7.2 g, 40 mmol, 155% yield) along with some bromide salts. LC/MS (ESI+) m/z: 182.1 (M+H+).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:35][C:36]1[S:37][CH:38]=[C:39]([CH2:41][CH2:42]O)[N:40]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:42][CH2:41][C:39]3[N:40]=[C:36]([CH3:35])[S:37][CH:38]=3)=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([OH:9])=[O:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(O)cc2)c1N1CCC(C)(C)CC1
Reactant: Cc1nc(CCO)cs1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(CCOc2ccc(-c3c(C)nc(C)c([C@H](OC(C)(C)C)C(=O)O)c3N3CCC(C)(C)CC3)cc2)cs1
Reaction time: 18 h
Yield: 64.2 %

Procedure:
To a stirred solution of (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-hydroxyphenyl)-2,6-dimethylpyridin-3-yl)acetate (25 mg, 0.053 mmol), 2-(2-methylthiazol-4-yl)ethanol (22.92 mg, 0.160 mmol) and Ph3P-resin (69.7 mg, 0.267 mmol) in THF (2 mL) was added DEAD (0.025 mL, 0.160 mmol) at rt. After 18 h, mixture was filtered to remove polymer, concentrated and treated with 1N NaOH (1.067 mL, 1.067 mmol) in MeOH (1 mL) at 75° C. for 16 h. Mixture was then cooled and purified by prep-HPLC to afford (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(4-(2-(2-methylthiazol-4-yl)ethoxy)phenyl)pyridin-3-yl)acetic acid (19.4 mg, 0.034 mmol, 64.3% yield). 1H NMR (500 MHz, DMSO-d6) δ 7.26-7.18 (m, 2H), 7.08-6.97 (m, 3H), 5.83 (s, 1H), 4.41-4.28 (m, 2H), 3.40-3.30 (m, 2H), 3.14 (t, J=6.4 Hz, 2H), 2.80 (t, J=12.1 Hz, 1H), 2.64 (s, 3H), 2.43 (s, 3H), 2.17 (d, J=11.0 Hz, 1H), 2.06 (s, 3H), 1.99-1.93 (m, 1H), 1.49 (br. s., 1H), 1.30 (br. s., 1H), 1.18 (d, J=11.4 Hz, 1H), 1.13 (s, 9H), 1.03 (d, J=10.6 Hz, 1H), 0.85 (br. s., 3H), 0.61 (br. s., 3H). LCMS (M+H)=566.6.
Reaction SMILES: C([NH:3][C:4]1[S:5][C:6]([Br:35])=[C:7]([C:9](=[N:32][O:33][CH3:34])[C:10]([NH:12][CH:13]2[C:30](=[O:31])[N:15]3[C:16]([C:27]([OH:29])=[O:28])=[C:17]([CH2:20][S:21][C:22]4[S:23][CH:24]=[N:25][N:26]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.[ClH:36]>>[ClH:36].[NH2:3][C:4]1[S:5][C:6]([Br:35])=[C:7]([C:9](=[N:32][O:33][CH3:34])[C:10]([NH:12][CH:13]2[C:30](=[O:31])[N:15]3[C:16]([C:27]([OH:29])=[O:28])=[C:17]([CH2:20][S:21][C:22]4[S:23][CH:24]=[N:25][N:26]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1nc(NC=O)sc1Br
Agent: Cl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1nc(N)sc1Br

Procedure:
7-[2-(2-Formamido-5-bromothiazol-4-yl)-2-methoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer, 1.2 g.) was treated with conc. hydrochloric acid (2 ml.) in a similar manner to that of Example 1-(2) to give 7-[2-(2-amino-5-bromothiazol-4-yl)-2-methoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid hydrochloride (syn isomer, 1.2 g.).
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:14]=[C:13]2[N:15]([CH:27]([CH2:32][O:33][CH2:34][CH3:35])[CH2:28][O:29][CH2:30][CH3:31])[C:16](=[O:26])[N:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[CH2:18][C:12]2=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:44])C=1>ClCCl>[CH2:1]([S:8]([C:9]1[N:14]=[C:13]2[N:15]([CH:27]([CH2:32][O:33][CH2:34][CH3:35])[CH2:28][O:29][CH2:30][CH3:31])[C:16](=[O:26])[N:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[CH2:18][C:12]2=[CH:11][N:10]=1)=[O:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOCC(COCC)N1C(=O)N(c2ccccc2Cl)Cc2cnc(SCc3ccccc3)nc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOCC(COCC)N1C(=O)N(c2ccccc2Cl)Cc2cnc(S(=O)Cc3ccccc3)nc21
Reaction time: 1 h

Procedure:
A suspension of 7-benzylthio-3-(2-chlorophenyl)-1-(2-ethoxy-1-ethoxymethylethyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (566 mg, 1.1 mmol) in dichloromethane (5 mL) was cooled in an ice bath and 3-chloroperbenzoic acid was added. The reaction mixture was stirred for 1 hour, concentrated in vacuo, and the residue was purified by column chromatography on silica gel using 98:2 dichloromethane/methanol. The column fractions containing product were combined and concentrated in vacuo to yield 425 mg of 7-benzylsulfinyl-3-(2-chlorophenyl)-1-(2-ethoxy-1-ethoxymethylethyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([OH:42])=O)[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[NH2:49][C:50]1[S:51][CH:52]=[C:53]([CH3:55])[N:54]=1.N1C=CC=CC=1>C(Cl)Cl.O>[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([NH:49][C:50]2[S:51][CH:52]=[C:53]([CH3:55])[N:54]=2)=[O:42])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:36])=[O:37]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Reactant: Cc1csc(N)n1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: Cc1csc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 0 °C
Yield: 45.3 %

Procedure:
A solution of triphenylphosphine (238 mg, 0.91 mmol) in methylene chloride (6 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (183 mg, 1.03 mmol). The reaction mixture was stirred at 0° C. until it became homogeneous. The resulting light purple reaction mixture was then treated with 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 137, 200 mg, 0.61 mmol). The reaction mixture was stirred at 0° C. for 20 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-amino-4-methylthiazole (104 mg, 0.91 mmol) and pyridine (0.15 mL, 1.82 mmol), and the resulting reaction mixture was stirred at 25° C. for 16 h. The reaction was then diluted with water (15 mL) and then extracted with methylene chloride (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 70/30 hexanes/ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(4-methyl-thiazol-2-yl)-propionamide (118 mg, 46%) as an off-white foam: [α]23589=−44.4° (c=0.024, chloroform); EI-HRMS m/e calcd for C19H23ClN2O3S2(M+) 426.0838, found 426.0837.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:6]=[CH:5][C:4]=1[N+:17]([O-])=O>CO.[Pd]>[CH3:16][S:13]([CH2:12][CH2:11][CH2:10][O:9][C:7]1[CH:6]=[CH:5][C:4]([NH2:17])=[C:3]([O:2][CH3:1])[CH:8]=1)(=[O:14])=[O:15]
Reactant: COc1cc(OCCCS(C)(=O)=O)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COc1cc(OCCCS(C)(=O)=O)ccc1N
Reaction time: 0.5 h
Yield: 115.7 %

Procedure:
Step C A suspension of 2-methoxy-4-(3-(methylsulfonyl)propoxy)-1-nitrobenzene (0.4 g, 1.6 mmol) and Pd/C (Aldrich, 10%, 0.1 g) in methanol (15 mL) was vigorously shaken in a Parr under atmosphere of H2 (50 psi) for 0.5 h. The mixture was filtered through a short pad of celite. The filtrate was concentrated to give 4-(3-methanesulfonyl-propoxy)-2-methoxy-phenylamine as a black oil (0.48 g, 92%).
Reaction SMILES: [O:1]=[C:2]1[CH:7]([N:8]2C(=O)C3C(=CC=CC=3NC=O)N=C2C)[CH2:6][CH2:5][C:4](=[O:23])[NH:3]1.[CH3:24][C:25]1O[C:27](=[O:38])[C:28]2[C:34]([N+:35]([O-:37])=[O:36])=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=1.NC1CCC(=O)NC1=O>>[CH3:24][C:25]1[N:8]([CH:7]2[CH2:6][CH2:5][C:4](=[O:23])[NH:3][C:2]2=[O:1])[C:27](=[O:38])[C:28]2[C:29](=[CH:31][CH:32]=[CH:33][C:34]=2[N+:35]([O-:37])=[O:36])[N:30]=1
Reactant: Cc1nc2cccc(NC=O)c2c(=O)n1C1CCC(=O)NC1=O
Reactant: Cc1nc2cccc([N+](=O)[O-])c2c(=O)o1
Agent: NC1CCC(=O)NC1=O
Product: Cc1nc2cccc([N+](=O)[O-])c2c(=O)n1C1CCC(=O)NC1=O

Procedure:
In another embodiment, provided herein is a method for preparing 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or polymorph thereof; comprising the steps of (a) reacting 2-amino-6-nitrobenzoic acid with an activated acetic acid in a solvent to form 2-methyl-5-nitro-4H-benzo[d][1,3]oxazin-4-one; (b) reacting 2-methyl-5-nitro-4H-benzo[d][1,3]oxazin-4-one with 3-aminopiperidine-2,6-dione or a salt thereof in a solvent to form 3-(2-methyl-5-nitro-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione; (c) reducing 3-(2-methyl-5-nitro-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione in a solvent in the presence of formic acid to form N-(3-(2,6-dioxopiperidin-3-yl)-2-methyl-4-oxo-3,4-dihydroquinazolin-5-yl)formamide; and (d) hydrolyzing N-(3-(2,6-dioxopiperidin-3-yl)-2-methyl-4-oxo-3,4-dihydroquinazolin-5-yl)formamide in a solvent to form 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or polymorph thereof; wherein steps (a), (b), (c), and (d) are each as described herein elsewhere.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:10]1[CH:18]=[C:17]([F:19])[CH:16]=[C:15]2[C:11]=1[CH:12]=[CH:13][NH:14]2.[CH3:20][CH:21]([N:23]1[C:27]([C:28]([NH:30][C:31]2[C:32]3[C:36]([CH:37]=[C:38](B4OC(C)(C)CC(C)(C)O4)[CH:39]=2)=[N:35][N:34](C2CCCCO2)[CH:33]=3)=[O:29])=[CH:26][CH:25]=[N:24]1)[CH3:22].O>O1CCOCC1.CO>[F:19][C:17]1[CH:16]=[C:15]2[C:11]([CH:12]=[CH:13][NH:14]2)=[C:10]([C:38]2[CH:37]=[C:36]3[C:32]([CH:33]=[N:34][NH:35]3)=[C:31]([NH:30][C:28]([C:27]3[N:23]([CH:21]([CH3:22])[CH3:20])[N:24]=[CH:25][CH:26]=3)=[O:29])[CH:39]=2)[CH:18]=1
Reactant: CC(C)n1nccc1C(=O)Nc1cc(B2OC(C)(C)CC(C)(C)O2)cc2nn(C3CCCCO3)cc12
Reactant: Fc1cc(Br)c2cc[nH]c2c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: CC(C)n1nccc1C(=O)Nc1cc(-c2cc(F)cc3[nH]ccc23)cc2[nH]ncc12
Temperature: 120 °C

Procedure:
A microwave vial was charged with Solvias catalyst (8 mg), tripotassium phosphate (90 mg) and 4-bromo-6-fluoro-1H-indole (available from Sinova, 33 mg). 1-(1-Methylethyl)-N-[2-(tetrahydro-2H-pyran-2-yl)-6-(4,4,6,6-tetramethyl-1,3,2-dioxaborinan-2-yl)-2H-indazol-4-yl]-1H-pyrazole-5-carboxamide (70 mg) in 1,4-dioxane (0.5 ml) was added followed by water (0.1 ml). The mixture was heated under microwave irradiation at 120° C. for 10 min. The mixture was passed through a silica cartridge which had been preconditioned with methanol, washed through with methanol, then dried under a stream of nitrogen. The residue was subjected to a DCM/water wash and then dried under a stream of nitrogen. The residue was dissolved in DMSO:methanol (1 ml, 1:1, v/v) and purified by MDAP (method A). Appropriate fractions were evaporated under a stream of nitrogen. The residues were dissolved in a minimum amount of methanol, a few drops of 2M HCl (aq) were added and the reactions were left to stand briefly at room temperature. The reactions were combined then passed through an aminopropyl cartridge preconditioned with methanol and dried. Purification was carried out using the following system:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][CH:11]1[CH2:19][CH2:18][CH:17]2[CH:13]([CH2:14][N:15]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]2)[CH2:12]1.CCN(CC)CC>CCO>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][CH:11]2[CH2:19][CH2:18][CH:17]3[CH:13]([CH2:14][N:15]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]3)[CH2:12]2)[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC2CCC(N)CC2C1
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC2CCC(Nc3nc(Cl)ncc3Cl)CC2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 126.3 %

Procedure:
To a solution of 2,4,5-trichloropyrimidine (0.60 g, 3.27 mmol) and tert-butyl 5-aminohexahydro-1H-isoindole-2(3H)-carboxylate (2.79 g, 11.61 mmol) in EtOH (10 mL) was added Et3N (1.30 g, 12.84 mmol). After addition, the reaction mixture was stirred at rt overnight and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/5) to give the title compound as a pale yellow solid (1.60 g, 100%).
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([OH:3])=[O:2].[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21](=[O:28])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:15][CH:14]=1.N1CCCCC1>C1C=CC=CC=1>[CH2:26]([O:25][C:23]([C:22]([C:21](=[O:28])[CH2:20][CH2:19][C:16]1[CH:15]=[CH:14][C:13]([F:12])=[CH:18][CH:17]=1)=[CH:8][C:7]1[CH:10]=[CH:11][C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH:6]=1)=[O:24])[CH3:27]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)CC(=O)CCc1ccc(F)cc1
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: CCOC(=O)C(=Cc1ccc(C(=O)O)cc1)C(=O)CCc1ccc(F)cc1
Yield: 25.4 %

Procedure:
A mixture of 4-carboxybenzaldehyde (2.07 g, 13.81 mmol), ethyl 5-(4-fluorophenyl)-3-oxopentanoate (3.29 g, 13.81 mmol) and piperidine (0.25 mL, 2.53 mmol) in benzene (60 mL) was heated at reflux overnight under Dean-Stark conditions. The reaction mixture was concentrated and the crude material was dissolved in EtOAc. The EtOAc solution was washed with 0.1 M HCl and brine and then dried, filtered, and concentrated. Recrystallization of the resulting material from EtOAc/hexanes produced the title compound as a yellow solid (1.3 g, 3.51 mmol, 25%): 1H NMR (400 MHz, CDCl3) δ 8.09 (d, 2H, J=8), 7.98 (d, 2H, J=8), 7.70 (s, 1H), 7.60 (s, 1H), 7.49 (d, 2H, J=8), 7.32 (d, 2H, J=8), 7.16 (dd, 2H, J=8, 6), 7.07 (dd, 2H, J=8, 6), 6.97 (t, 2H, J˜9), 6.91 (t, 2H, J˜9), 4.29 (q, 2H, J=7), 4.27 (q, 2H, J=7), 3.03 (m, 2H), 2.99 (m, 2H), 2.90 (m, 2H), 2.84 (m, 2H), 1.29 (t, 3H, J=7), 1.23 (t, 3H, J=7) ppm (carboxyl proton not found).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([F:12])[C:6]([F:11])=[C:7]([CH:10]=1)[C:8]#[N:9].Cl.[CH3:14][NH:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>>[C:8]([C:7]1[CH:10]=[C:3]([CH:4]=[C:5]([F:12])[C:6]=1[F:11])[CH2:2][N:15]([CH3:14])[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])#[N:9]
Reactant: N#Cc1cc(CBr)cc(F)c1F
Reactant: CNCC(=O)OC(C)(C)C
Agent: Cl
Product: CN(CC(=O)OC(C)(C)C)Cc1cc(F)c(F)c(C#N)c1

Procedure:
The title compound was prepared following general procedure 10, starting from 5-(bromomethyl)-2,3-difluorobenzonitrile and tert-butyl N-methylglycinate hydrochloride. It was obtained as a yellow oil (618 mg, 88%). HPLC (Method A) Rt 2.75 (Purity: 97%).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[CH:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:35][N:36]1[C:44]2[C:39](=[CH:40][CH:41]=[C:42](B(O)O)[CH:43]=2)[CH:38]=[N:37]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([C:42]4[CH:43]=[C:44]5[C:39]([CH:38]=[N:37][N:36]5[CH3:35])=[CH:40][CH:41]=4)[CH:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)c3)sc2c1-c1ccc(Cl)cc1
Reactant: Cn1ncc2ccc(B(O)O)cc21
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: C1COCCO1
Product: Cc1cc2nc(-c3ccnc(-c4ccc5cnn(C)c5c4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 110 °C

Procedure:
The reaction mixture of (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (20 mg, 0.039 mmol), 1-methyl-1H-indazole-6-boronic acid (10.3 mg, 0.058 mmol), 2N K2CO3 (100 μL, 0.19 mmol), Pd(PPh3)4 (4.3 mg, 0.004 mmol) in dioxane (1.5 mL) in sealed tube was heated at 110° C. for 2 h. After the starting material consumed, the reaction was cooled down, to the mixture was added MeOH, excess NaOH, the reaction mixture was heated at 45° C. overnight. Then the reaction mixture was neutralized by acetic acid, concentrated down, then treated by MeOH, and purified by reverse phase HPLC, eluting by 0-100% acetonitrile in H2O with 0.1% TFA to give the product. LCMS-ESI+: calc'd for C33H29ClN4O3S: 597.2 (M+H+); Found: 597.2 (M+H+). 1H NMR (400 MHz, CD3OD): δ 8.78 (d, J=2.6 Hz, 1H), 8.60 (s, 1H), 8.26 (s, 1H), 8.06 (s, 1H), 8.03-7.82 (m, 4H), 7.71-7.69 (m, 1H), 7.61-7.60 (m, 3H), 5.28 (s, 1H), 4.16 (s, 3H), 2.64 (s, 3H), 0.98 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[CH2:11][C:10](=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.[C:16]([O-])(=[O:18])[CH3:17].[Na+].C(OCC)(=O)C.O>C(OC(=O)C)(=O)C>[C:16]([CH:11]1[C:12](=[O:14])[CH2:13][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:9][C:10]1=[O:15])(=[O:18])[CH3:17]
Reactant: CC(=O)[O-]
Reactant: O=C1CC(=O)CC(c2ccc(F)cc2)C1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)C1C(=O)CC(c2ccc(F)cc2)CC1=O
Temperature: 120 °C

Procedure:
5-(4-Fluorophenyl)cyclohexane-1,3-dione (500 mg, 2.4 mmol) and sodium acetate (200 mg, 2.4 mmol) were dissolved in acetic anhydride (5 ml) and heated in a sealed tube at 120° C. for 16 h. The reaction mixture was then allowed to cool to ambient temperature whereupon ethyl acetate (20 ml) and water (10 ml) were added. The organic phase was collected and washed 3 times with a saturated solution of sodium bicarbonate (3×15 ml). The organic phase was dried with MgSO4 and filtered. The solvent was removed under reduced pressure. The title compound was purified by column chromatography using ethyl acetate/heptane (1/3) as the eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([OH:15])=O)[O:10][C:11]=1[CH3:12].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=1)[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=2)[CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])=[O:15])[O:10][C:11]=1[CH3:12]
Reactant: Cc1oc(C(=O)O)cc1-c1c(Cl)cnn1C
Reactant: N[C@@H](Cc1cccc(F)c1)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cc1oc(C(=O)N[C@@H](Cc2cccc(F)c2)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Cl)cnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.9 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylic acid (244 mg, 0.95 mmol), 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (320 mg, 0.95 mmol) [prepared according to the procedure of Preparation 6, except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-3-fluoro-L-phenylalanine (5.0 g, 17.8 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (533 mg, 1.14 mmol) in chloroform (9 mL). DIEA (830 μL, 4.75 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (242 mg, 0.465 mmol, 49%): LC-MS (ES) m/z=521 (M+H)+.