Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Br:10][C:11]1[N:12]([CH3:20])[C:13]([Br:19])=[C:14]([Br:18])[C:15]=1[C:16]#[N:17].[SH2:21]>N1C=CC=CC=1>[Br:10][C:11]1[N:12]([CH3:20])[C:13]([Br:19])=[C:14]([Br:18])[C:15]=1[C:16](=[S:21])[NH2:17]
Reactant: Cn1c(Br)c(Br)c(C#N)c1Br
Reactant: S
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Br)c(Br)c(C(N)=S)c1Br
Temperature: 25 °C
Reaction time: 120 h

Procedure:
Diisopropylethylamine (1.1 mL, 6 mmol), 2,4,5-tribromo-1-methylpyrrole-3-carbonitrile (2.16 g, 6 mmol) and pyridine (10 mL) are added to condensed hydrogen sulfide in a pressure tube at -78° C. The tube is sealed and the reaction mixture is stirred for 5 days at room temperature. The reaction mixture is then concentrated in vacuo to obtain a residue. Chromatography of the residue using silica gel and a 4:1 hexanes/ethyl acetate mixture gives the title product as a yellow solid (0.47 g, mp 100.5°-102° C. dec.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][NH:9][C:10](=[O:36])[CH2:11][C:12]([NH:14][CH2:15][C:16]2[C:17]([NH:29][CH:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[C:18]3[CH:26]=[N:25][N:24]([CH2:27][CH3:28])[C:19]3=[N:20][C:21]=2[CH2:22][CH3:23])=[O:13])[CH:5]=[CH:6][CH:7]=1.[CH:37]([C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[CH:43][CH:44]=1)=[O:38].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:27]([N:24]1[C:19]2=[N:20][C:21]([CH2:22][CH3:23])=[C:16]([CH2:15][NH:14][C:12](=[O:13])[CH2:11][C:10]([NH:9][CH2:8][C:4]3[CH:3]=[C:2]([C:43]4[CH:42]=[CH:41][CH:40]=[C:39]([CH:37]=[O:38])[CH:44]=4)[CH:7]=[CH:6][CH:5]=3)=[O:36])[C:17]([NH:29][CH:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[C:18]2[CH:26]=[N:25]1)[CH3:28]
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)NCc1cccc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)NCc1cccc(-c2cccc(C=O)c2)c1
Temperature: 130 °C
Yield: 70.7 %

Procedure:
To N-[(3-bromophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}propanediamide (1.356 g, 2.432 mmol) was added (3-formylphenyl)boronic acid (0.401 g, 2.68 mmol) followed by K2CO3 (1.008 g, 7.30 mmol) and PdCl2(dppf) (0.071 g, 0.097 mmol) in 1,4-dioxane (14.95 mL) and water (4.98 mL). The mixture was heated under microwave for 15 min at 130° C. The solvent was removed by Glas-Col and DCM was added. The crude product was filtered through sintered glass funnel. Then the solid was washed with water and DCM to afford 1.0023 g (70.7%) of the title compound. LC-MS (M+H)+ 583.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl.CN(C)CCCN=C=NCC.[N:27]1([S:33]([C:36]2[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=2)[C:39](O)=[O:40])(=[O:35])=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C(OCC)(=O)C.CN(C=O)C>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:39](=[O:40])[C:38]2[CH:42]=[CH:43][CH:44]=[C:36]([S:33]([N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)(=[O:35])=[O:34])[CH:37]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(Nc1ccc(F)cc1)c1cccc(S(=O)(=O)N2CCCCC2)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 65.1 %

Procedure:
4-Fluoroaniline (41 mg), pyridine (0.06 mL) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (107 mg) were added in that order to a DMF (2.0 mL) solution of 3-(piperidin-1-ylsulfonyl)benzoic acid (100 mg), and stirred at room temperature for 14 hours. Ethyl acetate was added to the reaction liquid, washed twice with 2 M hydrochloric acid, and dried with sodium sulfate. The drying agent was removed through filtration, and the solvent was evaporated off. The residue was purified through silica gel column chromatography (ethyl acetate/hexane=from 5% to 50%, gradient) to give the entitled compound (87 mg, 65%) as a white crystal.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].[Li+].CC([N-]C(C)C)C.[CH2:17]([O:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>C1COCC1>[CH2:7]([O:6][C:1](=[O:5])[C:2]([CH3:4])([CH3:3])[CH:29]([C:28]1[CH:27]=[CH:26][C:25]([O:24][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:32][CH:31]=1)[OH:30])[CH3:8]
Reactant: CCOC(=O)C(C)C
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)C(O)c1ccc(OCc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 67.3 %

Procedure:
Ethyl isobutyrate (2.5 mL, 18.42 mmol) was dissolved in THF (8 mL), and the solution was cooled to −78° C. LDA (9.2 mL, 18.42 mmol) was added thereto, and the mixture was stirred at the corresponding temperature for 2 hours. After 4-benzyloxy-benzaldehyde (1.7 g, 8.01 mmol) obtained in Step A was added thereto at −78° C., the mixture was heated to room temperature, and then stirred for 2 days. The reactant was added with water, and then extracted with EtOAc. The organic layer was concentrated under reduced pressure. The residue was purified by column chromatography (eluent, EtOAc/Hex=1/5) to obtain the title compound (1.77 g, 67%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])[CH2:15][NH2:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.O.[OH-].[Na+].Cl[C:34]([O:36][CH3:37])=[O:35]>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])[CH2:15][NH:16][C:34]([O:36][CH3:37])=[O:35])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(C(CN)c2ccc(F)cc2F)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)NCC(c1ccc(F)cc1F)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
To 4-[2-Amino-1-(2,4-difluoro-phenyl)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester (209) (0.38 g, 1.13 mmol) in a 1:1 mixture of THF/H2O (30 mL) was added NaOH (0.05 g, 1.24 mmol) and methyl chloroformate (0.11 g, 1.13 mmol ). The reaction was allowed to stir at room temperature for 2 h. The reaction mixture was then diluted with EtOAc (200 mL) and washed with H2O (100 mL) and brine (100 mL). The organic phase was concentrated to dryness. The crude material was purified by chromatography (silica gel 60 mesh, eluting with 50% hexanes/50% EtOAc) yielding 0.23 g (50%) pure product.
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[CH:23]=[CH:22][C:9]([O:10][CH:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][CH:7]=1)(=[O:5])[CH3:4].C(OC(C)(C)C)(=O)C>C1C=CC=CC=1>[Br:1][CH2:4][C:3]([C:6]1[CH:23]=[CH:22][C:9]([O:10][CH:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][CH:7]=1)=[O:5]
Reactant: BrBr
Reactant: CCOC(=O)C(Oc1ccc(C(C)=O)cc1)C(=O)OCC
Solvent: c1ccccc1
Solvent: CC(=O)OC(C)(C)C
Product: CCOC(=O)C(Oc1ccc(C(=O)CBr)cc1)C(=O)OCC
Reaction time: 0.5 h

Procedure:
A solution of bromine (5.4g.) in benzene (50ml.) was added dropwise over 1 hour to a stirred solution of diethyl 4-acetylphenoxymalonate (10.0g.) and t-butyl acetate (3.95g.) in benzene (200ml.). The solution was stirred for 30 minutes, washed with N-sodium bicarbonate solution (1 × 30ml.), water (3 × 40ml.), dried and evaporated. The residue was chromatographed on silica to give diethyl 4-(bromoacetyl)phenoxymalonate, m.p. 55°-58° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][C:10]([CH:18]([CH3:20])[CH3:19])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.CO.[OH-].[Na+]>O>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]([CH:18]([CH3:20])[CH3:19])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(C(C)C)nn1-c1ncccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)c1cc(C(=O)O)n(-c2ncccc2Cl)n1
Yield: 100.2 %

Procedure:
A mixture of 1.07 g of ethyl 1-(3-chloro-2-pyridinyl)-3-isopropyl-1H-pyrazole-5-carboxylate, 15 ml of methanol and 15 ml of a 2N aqueous sodium hydroxide solution was heated to reflux for 1.5 hours. After the reaction mixture was allowed to cool, water was poured and the mixture was washed with methyl t-butyl ether two times. The aqueous layer was adjusted to around pH 3 by an addition of 2N hydrochloric acid, and then extracted with methyl t-butyl ether three times. The combined organic layer was washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 0.97 g of 1-(3-chloro-2-pyridinyl)-3-isopropyl-1H-pyrazole-5-carboxylic acid of the formula:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[CH2:10]([O:17][C:18]1[C:23](=[O:24])[CH:22]=[CH:21]O[C:19]=1[CH3:25])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.NCCC(O)=O>>[CH2:10]([O:17][C:18]1[C:23](=[O:24])[CH:22]=[CH:21][N:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])[C:19]=1[CH3:25])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCCCCCC(=O)O
Reactant: Cc1occc(=O)c1OCc1ccccc1
Agent: NCCC(=O)O
Product: Cc1c(OCc2ccccc2)c(=O)ccn1CCCCCC(=O)O
Yield: 70 %

Procedure:
6-Aminocaproic acid is reacted with 3-benzyloxy-2-methyl-4-pyrone in an exactly analogous procedure to that described in Example 2 for the reaction of the latter compound with β-alanine to give 3-benzyloxy-1-(5'-carboxypentyl)-2-methylpyrid-4-one in 70% yield, this compound being obtained after recrystallisation from ethanol/acetone (1:1 v/v) as white crystals, m.p. 145°-147° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[N:5]([OH:10])[C:4]([CH3:12])([CH3:11])[CH2:3]1.OO.Cl.[C:16]([OH:20])([CH3:19])([CH3:18])[CH3:17]>O>[OH:1][CH:2]1[CH2:7][C:6]([CH3:8])([CH3:9])[N:5]([O:10][CH2:17][C:16]([OH:20])([CH3:19])[CH3:18])[C:4]([CH3:12])([CH3:11])[CH2:3]1
Reactant: CC(C)(C)O
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Agent: Cl
Agent: OO
Solvent: O
Product: CC(C)(O)CON1C(C)(C)CC(O)CC1(C)C
Temperature: 45 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
A solution of 17.2 g (100 mmol) of 4-hydroxy-1-oxyl-2,2,6,6-tetramethylpiperidine dissolved in 50 mL of water and a solution of 25.3 g (0.37 mol) of 50% aqueous hydrogen peroxide are added simultaneously over 3-3.5 hours at 40° C. to a mixture of 0.27 g (1.0 mmol) of ferric chloride hexahydrate, 25 mL of water, 1.1 mL of 37% hydrochloric acid and 200 mL of tert-butyl alcohol. About two hours into the addition, 0.5 mL of 37% hydrochloric acid is added to the reaction mixture. After the peroxide addition is complete, 1.2 mL of 37% hydrochloric acid is added and the reaction mixture is heated at 40-50° C. for 3.5 hours. The reaction mixture is stirred overnight at room temperature. The reaction is completed by adding two portions of 0.3 mL of 37% hydrochloric acid while heating the reaction mixture at 45° C. for 5.5 hours. Work-up is done as in Example 20 and affords 21.5 g (88% yield) of the title compound as a white solid. Gas chromatography shows the product has a purity greater than 96%.
Reaction SMILES: [CH2:1]([N:5]1[C:10]2=[N:11][N:12]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[CH:24][CH:23]=3)[C:13]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:9]2[C:8](=S)[N:7]([CH3:35])[C:6]1=[O:36])[CH:2]([CH3:4])[CH3:3].[CH3:37][NH2:38]>C1COCC1.Cl[Hg]Cl>[CH2:1]([N:5]1[C:10]2=[N:11][N:12]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[CH:24][CH:23]=3)[C:13]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:9]2[C:8](=[N:38][CH3:37])[N:7]([CH3:35])[C:6]1=[O:36])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cn1c(=O)n(C)c(=S)c2c(Nc3ccccc3)n(Cc3ccc(-c4ccccn4)cc3)nc21
Reactant: CN
Agent: Cl[Hg]Cl
Solvent: C1CCOC1
Product: CN=c1c2c(Nc3ccccc3)n(Cc3ccc(-c4ccccn4)cc3)nc2n(CC(C)C)c(=O)n1C
Temperature: 110 °C

Procedure:
7-Isobutyl-5-methyl-3-(phenylamino)-2-(4-(pyridin-2-yl)benzyl)-4-thioxo-4,5-dihydro-2H-pyrazolo[3,4-d]pyrimidin-6(7H)-one (15 mg, 0.030 mmol) and HgCl2 (16.4 mg, 0.060 mmol) are suspended in THF, and then 2.0 M methylamine solution in THF (240 μL, 0.12 mmol) is added. The reaction mixture is heated in a Biotage microwave at 110° C. for 5 hours. After routine workup, the mixture is purified by a semi-preparative HPLC to give pure product as white solids. MS (ESI) m/z 494.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]([Cl:6])([Cl:5])[C:3]#[N:4].[ClH:7]>>[Cl:1][C:2]([Cl:6])([Cl:5])[C:3]1[N:4]=[C:3]([C:2]([Cl:1])([Cl:7])[Cl:7])[N:4]=[C:3]([C:2]([Cl:6])([Cl:5])[Cl:1])[N:4]=1
Reactant: Cl
Reactant: N#CC(Cl)(Cl)Cl
Product: ClC(Cl)(Cl)c1nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Aluminum bromide (0.5 g, 0.0019 mol) was added to a solution of the compound 5a (4.4 g, 0.019 mol) obtained in the above (1) dissolved in trichloroacetonitrile (43 g, 0.298 mol). Dry hydrogen chloride gas was passed through the reaction mixture at −10° C. for 2 hours. Then, the mixture was stirred at room temperature for one day. Trichloroacetonitrile was removed under reduced pressure. The residue was purified by a column (hexane/ethyl acetate=9/1). As a result, the mixture of 2,4-trichloromethyl-(2′-acetylbiphenyl)-6-triazine (5b) and 2,4,6-tris(trichloromethyl)-1,3,5-triazine was obtained. These two products were not separated since they have similar solubility in any solvent.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:7]=[C:8]([CH:16]=[CH:17][C:18]=1[C:19]([NH2:21])=[O:20])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].N1C=CC=CC=1>O1CCCC1>[C:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:16]=[CH:17][C:18]=1[C:19]([NH2:21])=[O:20])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)c1ccc(C(N)=O)c(N)c1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(C(=O)OC(C)(C)C)ccc1C(N)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 157.2 %

Procedure:
Acetyl chloride (50 uL, 0.32 mmol) was added to a solution of 1,1-dimethylethyl 3-amino-4-(aminocarbonyl)benzoate (126 mg, 0.53 mmol) and pyridine (52 uL, 0.64 mmol) in tetrahydrofuran (3 mL) at 0° C., and the resulting mixture was stirred at 0° C. for one hour. The mixture was quenched with ice-water (10 mL) and extracted ethyl acetate (3×10 mL). The combined extract was washed with 15 mL, each of 5% aqueous citric acid, saturated aqueous sodium bicarbonate, and brine solutions then dried over sodium sulfate, filtered and concentrated to give the 1,1-dimethylethyl 3-(acetylamino)-4-(aminocarbonyl)benzoate (140 mg, 94% yield). MS (EI) for C14H18N2O4: 279 (MH+).
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:26])[CH:6]=[CH:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH:12]=[CH:11]2>O1CCOCC1>[C:20]1([S:17]([N:13]2[C:14]3[C:10](=[CH:9][C:8]([CH:7]=[CH:6][C:5]([OH:26])=[O:4])=[CH:16][CH:15]=3)[CH:11]=[CH:12]2)(=[O:19])=[O:18])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)C=Cc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)C=Cc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Temperature: 40 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
1M LiOH aqueous solution (11.72 ml, 11.72 mmol) was added to a solution of 7 (2.00 g, 5.86 mmol) in dioxane (20 mL). The reaction mixture was stirred at 40° C. overnight and was then concentrated under reduced pressure. The residue was dissolved in water. Then concentrated HCl was added to the solution to reach acidic pH to give the precipitation, which was dried by vacuum to afford 8 (1.72 g) as a white solid. 1H NMR (500 MHz, CDCl3): δ6.39 (d, J=16.1 Hz, 1H), 6.71 (d, J=3.6 Hz, 1H), 7.45-7.48 (m, 2H), 7.52 (dd, J=8.7, 1.4 Hz, 1H), 7.55-7.58 (m, 1H), 7.61 (d, J=3.7 Hz, 1H), 7.67-7.72 (m, 2H), 7.89 (d, J=8.9 Hz, 2H), 7.96 (d, J=8.7 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:15]([O:17]CC)=[O:16])=[C:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:6]=1.O1CC[CH2:22][CH2:21]1.[OH-].[Li+].O.Cl>CO>[CH2:21]([SH:3]1[C:4]([C:15]([OH:17])=[O:16])=[C:5]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=2)[N:6]=[C:2]1[Br:1])[CH3:22]
Reactant: C1CCOC1
Reactant: CCOC(=O)c1sc(Br)nc1Cc1ccc(Cl)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC[SH]1C(Br)=NC(Cc2ccc(Cl)cc2)=C1C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In a 100 mL round bottomed flask were placed ethyl 2-bromo-4-(4-chlorobenzyl)-1,3-thiazole-5-carboxylate (955 mg, 2.65 mmol) and tetrahydrofuran (50 mL, 600 mmol). To this solution was added a freshly prepared aqueous solution of lithium hydroxide [(lithium hydroxide.H2O (177 mg, 4.22 mmol) and water (15 mL, 830 mmol)). The mixture was stirred for 4 h at rt then MeOH (20 mL) was added and the mixture was refluxed for 3 h. The mixture was allowed to cool to rt and then acidified by the addition of 1.0N HCl aq (4.5 mL). The mixture was stirred for 1 h at rt. The mixture was then concentrated under reduced pressure until reduced to ca 5 mL volume. EtOAc (50 mL) was added and the mixture was washed with water (50 mL), then brine (50 mL), then was dried over anhydrous MgSO4. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure. The residual yellow crystalline solid was used in the next step without further purification. LC/MS (FA) ES+ 332.
Reaction SMILES: C(O)C.C(Cl)(=O)C.[CH3:8][O:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([C@@H:18]([NH:20][C:21]([C@H:23]2[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25][N:24]2C(OC(C)(C)C)=O)=[O:22])[CH3:19])=[CH:14][CH:13]=1)=[O:11]>C(OCC)(=O)C>[CH2:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:32][C@H:23]([C:21]([NH:20][C@H:18]([C:15]2[CH:14]=[CH:13][C:12]([C:10]([O:9][CH3:8])=[O:11])=[CH:17][CH:16]=2)[CH3:19])=[O:22])[NH:24]1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2Cc3ccccc3CN2C(=O)OC(C)(C)C)cc1
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CC(=O)Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2Cc3ccccc3CN2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
Cool a mixture of ethyl acetate (214 mL) and ethanol (87.6 mL, 1.51 mol) to 0° C., and then add acetyl chloride (97.4 mL, 1.37 mol) in a dropwise fashion. Stir the mixture for 30 minutes while allowing it to warm to room temperature. Add a solution of tert-butyl (3R)-3-[[(1S)-1-(4-methoxycarbonylphenyl)ethyl]carbamoyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (60 g, 137 mmol) in ethyl acetate (480 mL), and then stir the resulting mixture at 40° C. overnight. Cool the mixture to room temperature, then isolate the resulting precipitate by filtration, and dry under reduced pressure. Add water (300 mL) to the solid, and then add a 32% aqueous ammonia solution until the pH of the mixture reaches 10. Isolate the suspended solids by filtration, then dry them in a vacuum oven at 45° C. overnight to furnish the title compound as a white solid (44 g, 95% yield). Mass spectrum (m/z): 339 ([M+H]+), 677 ([2M+H]+), 699 ([2M+Na]+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[N:14]=[C:13]2[C:9]([NH:10][CH:11]=[N:12]2)=[C:8]([NH2:15])[N:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:23][CH2:24][CH2:25][P:26](=[O:33])([O:30][CH2:31][CH3:32])[O:27][CH2:28][CH3:29]>CN(C=O)C>[CH2:31]([O:30][P:26]([CH2:25][CH2:24][CH2:23][N:12]1[CH:11]=[N:10][C:9]2[C:13]1=[N:14][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[N:7][C:8]=2[NH2:15])(=[O:33])[O:27][CH2:28][CH3:29])[CH3:32]
Reactant: COCCOc1nc(N)c2[nH]cnc2n1
Reactant: CCOP(=O)(CCCBr)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOP(=O)(CCCn1cnc2c(N)nc(OCCOC)nc21)OCC
Temperature: 70 °C
Reaction time: 1 h
Yield: 78.8 %

Procedure:
To a suspension of 2-(2-methoxyethoxy)adenine Compound (15) (200 mg, 0.96 mmol) in DMF (5 ml) was added K2CO3 (132 mg 0.96 mmol). Then diethyl (3-bromopropyl)phosphonate (265 μl, 1.44 mmol) was added. The reaction mixture was stirred at 70° C. for 1 h, and the solvent was removed under vacuum. The residue was dissolved in DCM and washed with brine. The aqueous phase was extracted again with DCM. The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting using a linear gradient of 0-10% MeOH in DCM) to give 293 mg of Compound (19). 1H NMR (CDCl3) δ 1.10-1.16 (m, 6H), δ 1.52-1.59 (m, 2H), δ 1.90-2.09 (m, 2H), δ 3.25 (s, 3H), δ 3.51-3.57 (m, 2H), δ 3.89-3.92 (m, 4H), δ 4.04 (t, 2H), δ 4.28 (t, 2H), δ 6.60 (M, 2H), δ 7.53 (s, 1H); MS: 388.1 (M+H)+, 386.0 (M−1).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1)#[N:2].C[O:12][C:13](=O)[C:14]1[C:19]([I:20])=[CH:18][C:17]([F:21])=[CH:16][C:15]=1[CH2:22]Br.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[F:21][C:17]1[CH:16]=[C:15]2[C:14](=[C:19]([I:20])[CH:18]=1)[C:13](=[O:12])[N:2]([CH2:1][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)[CH2:22]2
Reactant: COC(=O)c1c(I)cc(F)cc1CBr
Reactant: N#Cc1ccc(CN)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: N#Cc1ccc(CN2Cc3cc(F)cc(I)c3C2=O)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 40.8 %

Procedure:
A mixture of 4-cyano-benzyl amine (0.218 g, 1.3 mmol), 2-bromomethyl-4-fluoro-6-iodo-benzoic acid methyl ester (0.374 g, 1.0 mmol), and K2CO3 (0.277 g, 2 mmol) in toluene (4 mL) was heated with stirring at 100° C. for 2 h. The resulting mixture was filtered and concentrated. Silica gel column chromatography using 30% ethyl acetate in hexane afforded 5-fluoro-7-iodo-2-(4-cyano-benzyl)-2,3-dihydro-isoindol-1-one (0.160 g, 41%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.19 (s, 2H), 4.83 (s, 2H), 7.13 (d, 1H), 7.42 (d, 2H), 7.64 (m, 3H). GC-MS: m/z 392 (M)4.
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:11]2[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=2)[N:4]=[C:5]2[C:10]=1[CH:9]=[CH:8][CH:7]=[CH:6]2.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[N:3]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[N:4]=[C:5]2[C:10]=1[CH:9]=[CH:8][CH:7]=[CH:6]2
Reactant: COc1ccc(-n2nc3ccccc3c2Cl)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(-n2nc3ccccc3c2Cl)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
To a solution of product from step 3 (5.0 g, 19.3 mmol) in CH2Cl2 (100 mL) was added boron tribromide (14.53 g, 58 mmol) at −78° C. over 5 min. The reaction mixture was stirred at −78° C. for 1 h, and then at room temperature for 18 h. The reaction was quenched with saturated aqueous NaHCO3 at 0° C., the product was collected on a filter, and washed with water. After dried under vacuum, the title compound (4.7 g, 99%) was obtained; MS (ESI+) m/z 245 (M+1, 100).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[NH2:6][C:7]1[N:16]=[C:15]([C:17]([N:19]2[CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20]2)=[O:18])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:28]3[CH:33]=[C:32]([F:34])[C:31]([F:35])=[CH:30][C:29]=3[CH2:36][OH:37])[CH:13]=2)[N:8]=1.C(OCC)(=O)C.O>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:1]([O:37][CH2:36][C:29]1[CH:30]=[C:31]([F:35])[C:32]([F:34])=[CH:33][C:28]=1[C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH2:6])[N:16]=[C:15]2[C:17]([N:19]1[CH2:20][C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:27]1)=[O:18])(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)Cl
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3cc(F)c(F)cc3CO)ccc2n1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCC(=O)OCc1cc(F)c(F)cc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
33 μl of propionyl chloride are added to a solution of 150 mg of [2-amino-6-(4,5-difluoro-2-hydroxymethylphenyl)quinazolin-4-yl]-(1,3-dihydroisoindol-2-yl)methanone and 2 mg of 4-(dimethylamino)pyridine (DMAP) in 5 ml of dimethylformamide, and the mixture is stirred at 80° C. for 16 h. 8 ml of ethyl acetate and 8 ml of water are added, the organic phase is separated off and evaporated to dryness in vacuo. The residue is dissolved in 1 ml of dimethyl sulfoxide and purified by chromatography (reversed phase HPLC).