Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]2[N:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:11]([CH2:12][C:13]=1[C:14]1[S:15][C:16]([CH2:20][CH2:21][OH:22])=[C:17]([CH3:19])[N:18]=1)[CH2:10][N:9]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:8]2)=[O:5])C.[OH-].[Na+].Cl.N1C=CN=C1.[CH3:46][C:47]([Si:50](Cl)([CH3:52])[CH3:51])([CH3:49])[CH3:48].[NH4+].[Cl-].C([O-])([O-])=O.[K+].[K+]>CCO.CCOC(C)=O.C1COCC1.O.CO>[C:34]([O:33][C:31]([N:9]1[CH2:8][CH:7]2[N:23]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[CH:11]([CH2:12][C:13]([C:14]3[S:15][C:16]([CH2:20][CH2:21][O:22][Si:50]([C:47]([CH3:49])([CH3:48])[CH3:46])([CH3:52])[CH3:51])=[C:17]([CH3:19])[N:18]=3)=[C:6]2[C:4]([OH:3])=[O:5])[CH2:10]1)=[O:32])([CH3:35])([CH3:37])[CH3:36]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)C1=C(c2nc(C)c(CCO)s2)CC2CN(C(=O)OC(C)(C)C)CC1N2C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CO
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1nc(C2=C(C(=O)O)C3CN(C(=O)OC(C)(C)C)CC(C2)N3C(=O)OC(C)(C)C)sc1CCO[Si](C)(C)C(C)(C)C
Temperature: 80 °C
Reaction time: 2 h
Yield: 123.8 %

Procedure:
A mixture of compound C1 (8.37 g, 13.6 mmol) in EtOH (88 mL) and aq. 1M NaOH (88 mL) was stirred at 80° C. for 2 h. The mixture was allowed to cool to rt, and was then diluted with EtOAc (500 mL). This mixture was acidified with aq. 1M HCl (110 mL) until a pH between 3 and 4 was obtained. The layers were separated, then the aq. phase was extracted with EtOAc. The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. The crude product was dissolved in DMF (175 mL). Imidazole (5.43 g, 79.7 mmol)) and TBDMS-Cl (7.74 g, 51.3 mmol) were added. The mixture was stirred overnight. Aq. sat. NH4Cl (500 mL) was added and the resulting suspension was extracted with heptane (3×800 mL). The combined org. extracts were dried over MgSO4, filtered, and concentrated to yield a yellow oil. This crude product was dissolved in THF (130 mL), MeOH (44 mL) and H2O (44 mL), and K2CO3 (0.95 g) was added. The mixture was stirred at rt for 2.5 h and was concentrated to half under reduced pressure. The residue was then diluted with Et2O (800 mL) to produce a clear yellow sol. This yellow sol. was washed with aq. sat. NH4Cl (500 mL). The aq. phase was extracted with Et2O (2×800 mL), and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. The crude title product (10.5 g, quantitative yield) was used without further purification. LC-MS: tR=1.19 min, ES+: 624.27.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[S:22](=[O:32])(=[O:31])[N:23]([CH3:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:6]1[CH3:33].[OH-].[Na+].Cl>O1CCCC1>[F:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([CH2:4][C:3]([OH:34])=[O:2])[C:6]([CH3:33])=[C:7]2[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22](=[O:32])(=[O:31])[N:23]([CH3:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)N(C)c2ccccc2)c2cc(F)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(Cc2ccccc2S(=O)(=O)N(C)c2ccccc2)c2cc(F)ccc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 15 h
Yield: 85.5 %

Procedure:
A mixture of {5-fluoro-2-methyl-3-[2-(methylphenylsulfamoyl)benzyl]indol-1-yl}acetic acid methyl ester (0.10 g) and tetrahydrofuran (0.5 mL) was treated with 2.0 M aqueous sodium hydroxide solution (2.0 mL), and the resulting mixture was stirred at room temperature for 15 hours. The mixture was acidified by the addition of 2.0 M aqueous hydrochloric acid solution and concentrated under reduced pressure. The residue was purified by preparative reverse-phase HPLC, eluting with a mixture of acetonitrile and water (2:3 to 1:9 by volume) to afford the title compound as pale yellow solid (0.083 g).
Reaction SMILES: C(O[C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)(C)(C)C.[Li]C(C)(C)C.[C:21]([N:25]=[C:26]=[O:27])([CH3:24])([CH3:23])[CH3:22]>C1COCC1>[C:21]([N:25]1[C:26](=[O:27])[C:9]2[C:8](=[CH:13][CH:12]=[C:11]([Cl:14])[CH:10]=2)[NH:7][C:6]1=[O:15])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)N=C=O
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)n1c(=O)[nH]c2ccc(Cl)cc2c1=O
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 99.7 %

Procedure:
To a room temperature solution of 4-chloro-phenylamine (5.0 g, 39.19 mmol) was added di-tert-butyl dicarbonate (9.41 g, 43.11 mmol) portion-wise. The solution was heated to reflux, stirred for 2 hrs, cooled, concentrated, and dissolved in diethylether. The solution was washed with water, sodium bicarbonate and brine, dried over MgSO4, filtered, and concentrated to provide (4-chloro-phenyl)-carbamic acid tert-butyl ester (8.5 g) as a white solid, which was used with no further purification. To a −78° C. solution of (4-chloro-phenyl)-carbamic acid t-butyl ester (5.046, 23.30 mmol) in THF (232 mL) was added 32.9 mL of t-BuLi (1.7 M in pentane, 55.92 mmol) via cannula. The solution was stirred 10 min, warmed to −20° C. and stirred 2 hours further. To the −20° C. red solution was added t-butyl isocyanate (3.33 mL, 29.13 mmol). The solution was stirred at −20° C. for 1 hr, warmed to room temperature, stirred 2 hrs, then heated to reflux and stirred for 12 hrs. The reaction was cooled to room temperature, concentrated and dissolved in diethylether. The solution was washed with water, sodium bicarbonate and brine, dried over MgSO4, filtered, and concentrated to provide 5.87 g of white solid (100%). 1H NMR (300 MHz, CDCl3) δ ppm 1.76 (s, 9H), 6.91 (d, J=8.6 Hz, 1H), 7.48 (dd, J=2.2, 8.5 Hz, 1H), 7.97 (d, J=2.3 Hz, 1H), 9.22 (br s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]3[N:14]=[C:15]([NH:22][C:23]4[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=4)[C:26]#[N:27])[C:16]4[C:21]([C:12]3=[N:11][N:10]=2)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:5][CH:4]=1.[N-:31]=[N+:32]=[N-:33].[Na+].Cl.C(N(CC)CC)C.O>CN1CCCC1=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:13]3[N:14]=[C:15]([NH:22][C:23]4[CH:30]=[CH:29][CH:28]=[C:25]([C:26]5[N:31]=[N:32][NH:33][N:27]=5)[CH:24]=4)[C:16]4[C:21]([C:12]3=[N:11][N:10]=2)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nnc3c4ccccc4c(Nc4cccc(C#N)c4)nn23)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(-c2nnc3c4ccccc4c(Nc4cccc(-c5nn[nH]n5)c4)nn23)cc1
Temperature: 100 °C
Reaction time: 48 h
Yield: 53.7 %

Procedure:
To a suspension of 3-[3-(4-methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-benzonitrile (compound T1) (5.0 g, 12.7 mmol) in N-methylpyrrolidinone (80 mL) are added sodium azide (2.90 g, 44.6 mmol) and triethyl amine hydrochloride (6.14 g, 44.6 mmol). The mixture is stirred at 100° C. for 2 days. Upon cooling, water (400 mL) is added to the reaction mixture and the resulting precipitate is filtered. The solid is washed successively with MeOH, AcOEt, a saturated solution of NH4Cl and water. The residue is dried azeotropically with toluene to yield 2.97 g (54%) of the title compound as light brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[C:12](OC(=O)C)(=[O:14])[CH3:13].CO>O1CCCC1>[C:12]([NH:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11])(=[O:14])[CH3:13]
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: CC(=O)OC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)Nc1cc([N+](=O)[O-])ccc1O
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
2-Amino-4-nitrophenol (10 g, 0.065 mol) was dissolved in tetrahydrofuran (100 ml) and, after cooling to 0° C., acetic anhydride (12.24 ml, 0.130 mol) was added dropwise, followed by stirring at room temperature for 2 h. Thereafter, methanol (10 ml) was added to the reaction mixture, which was then stirred at room temperature for 30 min and, thereafter, the solvent was evaporated and the resulting residue was diluted with diethyl ether and filtered. The solvent was evaporated off the filtrate and the resulting solids were dried to yield the end compound 2-acetamido-4-nitrophenol (12.21 g) as a pale brown solid mass.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:29][CH2:30][CH:31]2[CH2:33][CH2:32]2)=[C:6]([C:8]2[C:9]3[CH:18]=[CH:17][N:16](S(C4C=CC(C)=CC=4)(=O)=O)[C:10]=3[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1.[B-](F)(F)(F)[CH2:35][N:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1.[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].[OH-].[Na+]>O1CCOCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH:31]1([CH2:30][O:29][C:5]2[CH:4]=[CH:3][C:2]([CH2:35][N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)=[CH:7][C:6]=2[C:8]2[C:9]3[CH:18]=[CH:17][NH:16][C:10]=3[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH2:33][CH2:32]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4cc(Br)ccc4OCC4CC4)cn(C)c(=O)c32)cc1
Reactant: F[B-](F)(F)CN1CCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2cc(CN3CCCC3)ccc2OCC2CC2)c2cc[nH]c2c1=O
Temperature: 140 °C
Yield: 11.2 %

Procedure:
A mixture of Example 314b (100 mg, 0.190 mmol), potassium trifluoro(pyrrolidin-1-ylmethyl)borate (36.2 mg, 0.190 mmol), palladium(II) acetate (2.55 mg, 0.011 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (10.85 mg, 0.023 mmol), and cesium carbonate (185 mg, 0.569 mmol) in 4 mL dioxane/water (9:1) was purged with nitrogen gas and then heated under microwave conditions (Biotage Initiator) at 140° C. for 40 minutes. The reaction mixture was then treated with 2 mL of 4 N NaOH and heated in a microwave oven (Biotage Initiator) at 100° C. for 30 minutes. Water was added. The mixture was extracted with ethyl acetate, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated and the residue was purified by flash chromatography (silica gel, 2-14% methanol/dichloromethane gradient) to give the title compound (8.0 mg, 11% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 11.93 (s, 1H), 7.29-7.17 (m, 4H), 7.00 (d, J=8.4 Hz, 1H), 6.11 (dd, J=2.6, 2.2 Hz, 1H), 3.81 (d, J=6.7 Hz, 2H), 3.56 (s, 3H), 3.53 (s, 2H), 2.43 (s, 4H), 1.68 (s, 4H), 1.13-0.98 (m, 1H), 0.48-0.36 (m, 2H), 0.26-0.16 (m, 2H). MS (ESI+) m/z 378.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:12]3[CH:23]=[CH:24][CH:25]=[CH:26][C:11]=3[S:10]2)=[CH:5][CH:4]=1.[N+:27]([C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32](Cl)=[O:33])([O-:29])=[O:28]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([O:16][C:32](=[O:33])[C:31]3[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=3[N+:27]([O-:29])=[O:28])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:12]3[CH:23]=[CH:24][CH:25]=[CH:26][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Solvent: c1ccncc1
Product: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2OC(=O)c2ccccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
1.2 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are dissolved in 10 ml of pyridine, and 0.66 g of 2-nitrobenzoyl chloride is added thereto. The mixture is stirred at room temperature for 2 hours. After the reaction, the mixture is poured into ice-water. The crystalline precipitates are collected by filtration and then recrystallized from a mixture of ethyl acetate and n-hexane. 1.41 g of (±)-cis-2-(4-methoxyphenyl)-3-(2-nitrobenzoyloxy)-5-[2-(dimethylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are thereby obtained as colorless needles. Yield: 84%.
Reaction SMILES: ON=[CH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14])=[O:5].S(=O)(=O)(O)[OH:17]>>[N+:13]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[NH:6][C:4](=[O:5])[C:3]2=[O:17])([O-:15])=[O:14]
Reactant: O=S(=O)(O)O
Reactant: O=C(C=NO)Nc1ccccc1[N+](=O)[O-]
Product: O=C1Nc2c(cccc2[N+](=O)[O-])C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Hydroxyimino-N-(2-nitro-phenyl)-acetamide (15 g, 72 mmol) was carefully added in small portions to a stirred solution of preheated (90° C.) conc. sulphuric acid (45 mL) over a period of 30 min and the resulting mixture was stirred for another 2 h at the same temperature. It was then cooled to room temperature, poured into crushed ice, the precipitated products was collected by filtrations. The collected precipitated products were washed with water and dried in a vacuum oven to get a brick red colour powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=1[CH:20]=[O:21].Br[CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26].[I-].[Na+].[In]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=1[CH:20]([OH:21])[C:25]([CH3:27])([CH3:26])[CH:24]=[CH2:23]
Reactant: CC(C)=CCBr
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C=O)c1
Agent: [I-]
Agent: [In]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CC(C)(C)C(O)c1cc(C(=O)OC)ccc1-c1cc(OC)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a mixture of T29.3 (0.38 g, 1.3 mmol), 1-bromo-3-methylbut-2-ene (commercially available from Aldrich) (0.31 mL, 2.6 mmol) and sodium iodide (0.40 g, 2.6 mmol) in DMF (8 mL), was added indium (0.30 g, 2.6 mmol). The resulting mixture was stirred at room temperature for 1 hour and then additional 1-bromo-3-methylbut-2-ene (100 mg) and indium (100 mg) were added and the mixture was stirred at room temperature for one more hour. The reaction was quenched with water (20 mL) and extracted with EtOAc (200 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate, and filtered. After removing solvent, the residue was purified by flash chromatography (silica gel, 1:4 EtOAc/hexane) and gave product (T29.4), in 94% yield.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([OH:5])=O.[CH2:10]([O:17][NH:18][C:19]1[CH:29]=[CH:28][CH:27]=[CH:26][C:20]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N1C=CC=CC=1.O=P(Cl)(Cl)Cl>C(#N)C.C(Cl)Cl>[CH2:10]([O:17][N:18]([C:19]1[CH:29]=[CH:28][CH:27]=[CH:26][C:20]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:3](=[O:5])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)CC(=O)O
Reactant: CCOC(=O)c1ccccc1NOCc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)CC(=O)N(OCc1ccccc1)c1ccccc1C(=O)OCC
Temperature: 5 °C
Reaction time: 0.38 h
Yield: 79 %

Procedure:
To a stirring solution of ethyl hydrogen malonate (0.6 g, 4.54 mmol) and ethyl 2-(benzyloxyamino)benzoate (1.12 g, 4.13 mmol) in acetonitrile (10 mL) was added pyridine (1.3 g, 16.51 mmol) and reaction mixture was cooled to 0-10° C. To this was added POCl3 (0.423 mL, 4.54 mmol), at 0-10° C. in 15-30 min. and stirring continued for 1 h. Reaction mixture was diluted with DCM and washed with water. Organic layer was separated and distilled out to get crude product which was column purified using 15% EtOAC in hexane to get titled compound in 79% yield.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([CH2:33]O)[CH:32]=1)[C:27]([OH:29])=[O:28])([CH3:23])([CH3:22])[CH3:21].Br[N:36]1[C:40](=O)[CH2:39][CH2:38][C:37]1=O.N1CCCC1>CC(C)=O.O.CCOC(C)=O>[C:20]([C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([CH2:33][N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)[CH:32]=1)[C:27]([OH:29])=[O:28])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)c1cc(CO)cc(C(=O)O)c1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC(C)=O
Solvent: C1CCNC1
Product: CC(C)(C)c1cc(CN2CCCC2)cc(C(=O)O)c1
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 6 %

Procedure:
To a solution of triphenylphosphine (1.2 g, 0.0048 mol) and 3-tert-butyl-5-(hydroxymethyl)benzoic acid (1.0 g, 0.0048 mol) in acetone (20 mL) at −18° C. was added N-bromosuccinimide (0.85 g, 0.0048 mol) portionwise over 2 minutes. After 5 minutes, pyrrolidine (0.96 mL, 0.012 mol) was added. The reaction mixture was heated at 80° C. overnight. EtOAc and water were added to the reaction mixture. The phases were separated and the organic solution was washed with 1M NaOH, 1M HCl, and brine, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography to give 3-tert-butyl-5-(pyrrolidin-1-ylmethyl)benzoic acid (6%). LCMS ES+ 262, ES− 260.
Reaction SMILES: [CH3:1][CH:2]([C@H:4]([NH:8][C:9]([O:11]C(C)(C)C)=O)[C:5]([OH:7])=[O:6])[CH3:3].C1CCC(N=C=NC2CCCCC2)CC1.C(O)(C(F)(F)F)=O.[CH3:38][CH:39]([C@H:41]([NH2:60])C(OCCOCN1C2NC(N)=NC(=O)C=2N=C1)=O)[CH3:40]>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:38][CH:39]([C@H:41]([NH2:60])[C:9]([NH:8][C@H:4]([C:5]([OH:7])=[O:6])[CH:2]([CH3:1])[CH3:3])=[O:11])[CH3:40]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)[C@H](N)C(=O)OCCOCn1cnc2c(=O)nc(N)[nH]c21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](N)C(=O)N[C@H](C(=O)O)C(C)C

Procedure:
Boc-VAL, DCC, DMF, 0° C., 1 hr, ii) DMAP, DMF, 18 hrs, rt iii) TFA, 0° C., 30 min, iv) Boc-Val, DCC, DMF, 0° C., 1 hr, v) TEA, rt, vi) adding Boc-Val amino acid anhydride (step iv) to the neutralized Val-ACV (step v), 5 hrs, rt, vii) TFA, 0° C., 30 min.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]2[C:13]3[C:18]([O:19][CH2:20][C:3]=12)=[CH:17][C:16]([OH:21])=[CH:15][CH:14]=3.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>>[OH:21][C:16]1[CH:17]=[C:18]2[O:19][CH2:20][C:3]3[C:4](=[N:5][C:6]4[C:11]([C:2]=3[C:27]3[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=4)[C:13]2=[CH:14][CH:15]=1
Reactant: Oc1ccc2c(c1)OCc1c-2nc2ccc(O)cc2c1Br
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2c3c(nc4ccc(O)cc24)-c2ccc(O)cc2OC3)cc1
Yield: 84 %

Procedure:
This compound was prepared from 7-bromo-3,9-dihydroxy-6H-chromeno[4,3-b]quinoline (7) using 4-methoxyphenylboronic acid according to method M. Yellow powder; Yield: 84%; mp 195° C. (dec.); 1H-NMR (400 MHz, DMSOd-6) δ 3.87 (s, 3H), 5.03 (s, 2H), 6.36 (d, J=2.2 Hz, 1H), 6.60 (dd, J=8.5, 2.5 Hz, 1H), 6.73 (d, J=8.6 2.6 Hz, 1H), 7.16 (d, J=8.6 Hz, 2H), 7.24 (dd, J=9.0, 2.6 Hz, 1H), 7.30 (d, J=8.6 Hz, 2H), 7.89 (d, J=9.0 Hz, 1H), 8.15 (d, J=8.6 Hz, 1H), 9.80 (s, 1H), 9.98 (s, 1H); MS (ESI) m/z 370 ([M−H]−), 372 ([M+H]+); HRMS (ESI+) calcd for C23H17NO4 372.1230 ([M+H]+). Found: 372.1226.
Reaction SMILES: Cl[O-].[Na+].[Br-].[Na+].[OH-].[Na+].[Cl:8][C:9]1[C:10]([F:21])=[C:11]([CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1)[CH:12]=[O:13].S([O-])([O-])=[O:23].[Na+].[Na+].Cl>O.CC1CCCCC1>[Cl:8][C:9]1[C:10]([F:21])=[C:11]([CH:14]=[C:15]([C:17]([F:19])([F:20])[F:18])[CH:16]=1)[C:12]([OH:23])=[O:13]
Reactant: O=S([O-])[O-]
Reactant: O=Cc1cc(C(F)(F)F)cc(Cl)c1F
Agent: Cl
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CC1CCCCC1
Product: O=C(O)c1cc(C(F)(F)F)cc(Cl)c1F
Temperature: 50 °C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
To an aqueous solution of sodium hypochlorite (15.3 ml, 25.7 mmol, 1.2 equiv.) and sodium bromide (2.6 g, 25.7 mmol, 1.2 equiv.) in sodium hydroxide solution (47%, 2.73 ml, 32.12 mmol, 1.50 equiv.) and water (12.5 ml) was added slowly (during 25 min) at 50° C. 3-chloro-2-fluoro-5-trifluoromethyl-benzaldehyde (5.0 g, 21.4 mmol). The reaction mixture was stirred at 50° C. for 60 min, cooled to ambient temperature and quenched upon addition of aqueous sodium sulfite solution (20%, 16.2 ml, 25.7 mmol, 1.2 equiv.) to give a light turbid suspension and stirred for 1 h. The suspension was stirred for 15 min, treated with HCl (37%, 4.0 ml, 47.3 mmol, 2.21 equiv.) adjusting the pH to 1, whereupon a white precipitate formed. This precipitate was extracted with TMBE (30 ml), the organic phase was washed with brine (30 ml), whereas the aqueous phase was washed with TBME (30 ml). The combined organic phases were dried over sodium sulfate, filtered and the solvent was removed under vacuum to give the crude product as light yellow solid (5.12 g, 98.6% yield). The crude product was dissolved in hot methylcyclohexane (25 ml), and the solution was cooled to ambient temperature, whereupon white crystals precipitated. The crystals were filtered off with suction on a funnel with a fritted disk, washed with methylcyclohexane (5 ml) dried under vacuum until weight constancy to give the title compound as white crystals (4.27 g, 81.6% yield).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([N:18](C)[C:19](=O)C(F)(F)F)[C@H:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=3)[CH2:13]2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO.O>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([NH:18][CH3:19])[C@H:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=3)[CH2:13]2)=[O:11])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(C(=O)N2CC[C@@H](N(C)C(=O)C(F)(F)F)[C@H](c3ccc(Cl)c(Cl)c3)C2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CN[C@@H]1CCN(C(=O)C2CCN(C(C)=O)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 50 °C
Reaction time: 24 h
Yield: 56 %

Procedure:
To a mixture of the compound (0.66 g) obtained in step 4 in methanol (6.5 mL) and water (1.3 mL) was added potassium carbonate (0.35 g) at room temperature, and the mixture was stirred at 50° C. for 24 hr. Furthermore, potassium carbonate (1.70 g) was added, and the mixture was stirred at 50° C. for 6 days. The organic solvent was evaporated under reduced pressure, and the residue was poured into saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer was washed with brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH Chromatorex) (solvent gradient; 0→9% methanol/ethyl acetate) to give the title compound (0.30 g, 58%) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][NH:5][C:6](=O)[C:7]=1[NH:8][C:9](=O)[CH3:10].P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:6]1[N:5]=[CH:4][N:3]=[C:2]2[C:7]=1[N:8]=[C:9]([CH3:10])[NH:1]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)Nc1c(N)nc[nH]c1=O
Product: Cc1nc2c(Cl)ncnc2[nH]1
Yield: 6 %

Procedure:
A solution of N-(4-amino-6-oxo-1,6-dihydropyrimidin-5-yl)acetamide (330 mg, 1.92 mmol, 1.00 equiv, 98%) in phosphorus oxychloride (5 mL) was refluxed overnight. The resulting mixture was concentrated under vacuum. The residue was redissolved in 10 mL of ethyl acetate, washed with 10 mL of saturated aqueous sodium bicarbonate solution, 1×10 mL of water and 1×10 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give 20 mg (6%) of 6-chloro-8-methyl-9H-purine as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([CH:6]=[CH:7][CH2:8]Cl)=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][C:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:21]=2[N:22]=1.C(=O)([O-])[O-].[K+].[K+].CCOCC>C(#N)C>[NH2:12][C:13]1[S:14][C:15]2[CH2:16][CH2:17][N:18]([CH2:8][CH:7]=[CH:6][C:5]3[CH:10]=[CH:11][C:2]([CH3:1])=[CH:3][CH:4]=3)[CH2:19][CH2:20][C:21]=2[N:22]=1
Reactant: Cc1ccc(C=CCCl)cc1
Reactant: Nc1nc2c(s1)CCNCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: Cc1ccc(C=CCN2CCc3nc(N)sc3CC2)cc1
Yield: 33 %

Procedure:
Prepared from 4-methyl-cinnamyl chloride and 1 equivalent of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine in acetonitrile in the presence of 1 equivalent of potassium carbonate for 40 minutes at 80° C. Yield: 33% of theory, Melting point: 126°-30° C. (ether).