Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:30]([CH3:31])=[CH:29][C:14]2[N:15]=[C:16]([N:18]3[CH2:22][CH2:21][CH:20](C4C=CC=CC=4)[CH2:19]3)[S:17][C:13]=2[C:12]=1[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-:39].[Na+]>CO>[C:1]([O:5][C@@H:6]([C:11]1[C:30]([CH3:31])=[CH:29][C:14]2[N:15]=[C:16]([N:18]3[CH2:22][CH2:21][CH:20]([O:39][C:11]4[CH:30]=[CH:29][CH:14]=[CH:13][CH:12]=4)[CH2:19]3)[S:17][C:13]=2[C:12]=1[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:7]([OH:9])=[O:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: [OH-]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(N3CCC(c4ccccc4)C3)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Solvent: CO
Product: Cc1cc2nc(N3CCC(Oc4ccccc4)C3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
To a solution of (2S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(3-phenylpyrrolidin-1-yl)benzo[d]thiazol-6-yl)acetate (29.3 mg, 0.653 mmol) in CH3OH (1 mL) was added NaOH (1N, 1 mL, 1 mmol), the resulting mixture was heated at 50 C for 10 hr. The mixture was acidified to pH 3 and evaporated to a small volume, and the residue was partitioned between CH2Cl2 and brine. The organic layer was separated, dried, filtered and evaporated to dryness. The residue was purified on TLC (50% EtOAc/Hex) to give (2S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(3-phenoxypyrrolidin-1-yl)benzo[d]thiazol-6-yl)acetic acid. LCMS-ESI+: calc'd for C30H32ClN2O3S: 534.2, 536.2 (M+H+); found: 535.2, 537.2 (M+H+). 1H-NMR: 400 MHz, (CD3OD) δ: 7.63 (dd, J=2.0, 7.2 Hz, 1H), 7.49-7.52 (m, 3H), 7.30-7.34 (m, 5H), 7.24 (m, 1H), 5.13 (s, 1H), 3.94 (m, 1H), 3.70 (m, 1H), 3.52-3.63 (m, 4H), 2.48 (s, 3H), 2.46 (m, 1H), 2.20 (m, 1H), 0.94 (s, 9H).
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2.[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([F:24])=[CH:19][N:18]=1.C(N(C(C)C)CC)(C)C>>[Cl:16][C:17]1[N:22]=[C:21]([NH:2][CH:3]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:9]3[C:4]2=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:20]([F:24])=[CH:19][N:18]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: NC1c2ccccc2-c2ccccc21
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cnc(Cl)nc1NC1c2ccccc2-c2ccccc21

Procedure:
In like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro 4-pyrimidineamine, 9-aminofluorene hydrochloride and 2,4-dichloro-5-fluoropyrimidine with added diisopropylethylamine were reacted to produce 2-chloro-N-(fluoren-9-yl)-5-fluoro-4-pyrimidineamine. 1H NMR (CDCl3): δ 7.97 (d, 1H, J=2.3 Hz), 7.73 (d, 2H, J=7.6 Hz), 7.59 (d, 2H, J=7.6 Hz), 7.44 (t, 2H, J=7.6 Hz), 7.32 (app t, 2H, J=7.6 Hz), 6.50 (d, 1H, J=8.8 Hz), 5.45 (d, 1H, J=8.4 Hz).
Reaction SMILES: C([N:8]1[C@H:12]([C:13]#[CH:14])[CH2:11][C@@H:10]([OH:15])[CH2:9]1)(OC(C)(C)C)=O.[C:16]([C:19]1[CH:20]=[C:21](/[CH:24]=[C:25]2\[C:26](=[O:36])[NH:27][C:28]3[C:33]\2=[C:32](I)[C:31]([F:35])=[CH:30][CH:29]=3)[NH:22][CH:23]=1)(=[O:18])[CH3:17]>CN(C=O)C.CCN(CC)CC.CCOC(C)=O.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.[Cu]I>[C:16]([C:19]1[CH:20]=[C:21](/[CH:24]=[C:25]2\[C:26](=[O:36])[NH:27][C:28]3[C:33]\2=[C:32]([C:14]#[C:13][C@@H:12]2[CH2:11][C@@H:10]([OH:15])[CH2:9][NH:8]2)[C:31]([F:35])=[CH:30][CH:29]=3)[NH:22][CH:23]=1)(=[O:18])[CH3:17]
Reactant: C#C[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: CC(=O)c1c[nH]c(/C=C2\C(=O)Nc3ccc(F)c(I)c32)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)c1c[nH]c(/C=C2\C(=O)Nc3ccc(F)c(C#C[C@@H]4C[C@@H](O)CN4)c32)c1
Reaction time: 2 h

Procedure:
Using Method C above, (3R,5S)-N-Boc-3-Hydroxy-5-ethynyl-pyrrolidine (240 mg, 1.13 mmol) (Example 99C above) was coupled with (Z)-3-[(4-acetyl-1H-pyrrol-2-yl)methylene]-1,3-dihydro-5-fluoro-4-iodo-2H-indol-2-one (150 mg, 0.38 mmol) (Example 90B) using (Ph3P)4Pd (43 mg, 0.04 mmol) and a catalylic amount of CuI in a mixture of DMF (5 mL) and Et3N (5 mL) as solvent at 80° C. for 5 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4, concentrated and the residue was chromatographed on a silica gel column with a 0-100% EtOAc in hexanes gradient. The resulting intermediate was dissolved in 6 mL of a 50% trifluoroacetic acid in CH2Cl2 solution that contained 0.4 mL of H2O at 0° C. and stirred for 2 hrs. Upon completion, the solution was poured in ammonium hydroxide and extracted with a 5:1 (V/V) mixture of EtOAc and DMF. The organic layer was dried over Na2SO4 and concentrated. (Z)-3-[(4-Acetyl-1H-pyrrol-2-yl)methylene]-1,3-dihydro-5-fluoro-4-[(2S,4R)-(4-hydroxy-pyrrolidin-2-yl)ethynyl]-2H-indol-2-one was obtained after silica gel column chromatography with a 0-10% MeOH in CH2Cl2 gradient and trituration with CH2Cl2. (Yield 50 mg, 35%).
Reaction SMILES: [CH2:1]([NH:5][C:6]([O:8][CH2:9][C:10]([O:12]C)=[O:11])=[O:7])[CH2:2][CH2:3][CH3:4]>[OH-].[Na+]>[CH2:1]([NH:5][C:6]([O:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)OCC(=O)OC
Agent: [Na+]
Agent: [OH-]
Product: CCCCNC(=O)OCC(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The ester oil from Part (1) (1.82 g, 9.6 mmol) was treated with 2N NaOH (20 ml). The heterogeneous mixture was stirred vigorously at room temperature and became homogeneous in about 30 minutes. After stirring 4 hours, the reaction was washed with ether (2×30 ml) and the ether washes were reextracted with 2N NaOH solution (10 ml). The combined aqueous layers were acidified to pH 1 with concentrated HCl and the product was extracted into ether (2×30 ml). The combined ether extracts were washed with saturated NaCl solution (2×20 ml), dried (MgSO4) and freed of solvent in vacuo. The crude solid obtained (1.48 g) was recrystallized from benzene to give title acid (1.11 g, 6.3 mmol, 66%) as colorless crystals, m.p. 83°-84°.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:19])[NH:12][NH:13][C:14](OCC)=[O:15])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[OH-].[K+]>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:11](=[O:19])[NH:12][NH:13][C:14]2=[O:15])=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)NNC(=O)Nc1ccc(C(C)=O)cc1
Agent: [K+]
Agent: [OH-]
Product: CC(=O)c1ccc(-n2c(=O)[nH][nH]c2=O)cc1
Temperature: 25 °C

Procedure:
p-Acetyl-4-phenyl-1-carbethoxysemicarbazide 1 (15 g, 56 mmol) was heated with aqueous 4 M KOH solution (28 mL, 112 mmol) at 70° C. for about 2 h. Leftover granular solid was filtered off using a sintered filter funnel. Filtrate was cooled to room temperature and acidified with concentrated HCl. The precipitate formed was filtered and dried in vacuum oven to give p-acetyl-4-phenylurazole 2 as light yellow solid (12.4 g, 85%). 1H NMR (400 MHz, DMSO-d6): s=1.65 (s, 3H), 6.70 (d, 2H), 7.10 (d, 2H), 9.50 (s, 2H). (Synthesis adopted from: Organic Syntheses, Coll. Vol. 6, p. 936 (1988); Vol. 51, p. 121 (1971). 4-PHENYL-1,2,4-TRIAZOLINE-3,5-DIONE). In various aspects, the values of each of the components used in this example can be increased or decreased by an amount in the range of from about 5% to about 20%, for example, each component can be used in an amount that is from 5% less to 5% more than the value used in this example, each component can be used in an amount that is from 10% less to 10% more than the value used in this example, each component can be used in an amount that is from 15% less to 15% more than the value used in this example, or each component can be used in an amount that is from 20% less to 20% more than the value used in this example. In various aspects, the values can be varied by about plus or minus 5% to 20%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[N:5]=[C:4](NC2CCCCCC2)[N:3]=1.[Cl:26]C1N=C(NC2C=CC(OC)=C(Cl)C=2)N=C(NC2C=CC(OCC)=C(Cl)C=2)N=1>>[Cl:17][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[N:5]=[C:4]([Cl:26])[N:3]=[C:2]([Cl:1])[N:7]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Reactant: CCOc1ccc(Nc2nc(Cl)nc(Nc3ccc(OC)c(Cl)c3)n2)cc1Cl
Product: COc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1Cl

Procedure:
A 1 kg campaign was conducted to develop a process which avoids multiple column purifications and employs a suitable recrystallisation method to produce compound 137. This scheme was stabilized for the campaign, however the scale up of compound 133 by one pot synthesis resulted in the formation of an impurity, which was carried over to the final step and was difficult to remove. The impurity was isolated and characterized to be 6-chloro-N-(3-chloro-4-methoxyphenyl)-N′-(3-chloro-4-ethoxyphenyl)[1,3,5]triazine-2,4-diamine. To avoid the impurity, the single pot reaction was avoided and compound 101 was isolated and purified by recrystallisation in ethylacetate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](O)([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O>C1C=CC=CC=1.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]=[C:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc3ccccc3n2)CC1
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55.3 %

Procedure:
4-Hydroxy-4-quinolin-2-yl-piperidine-1-carboxylic acid tert-butyl ester (3.16 g, 9.61 mmol) and (methoxycarbonylsulfamoyl)triethylammonium hydroxide, inner salt (5.00 g, 20.98 mmol) in benzene (60 mL) under N2 were refluxed for 3 hours. The solution was cooled to ambient temperature, diluted with water (50 mL) and the resulting mixture was stirred at ambient temperature for 10 minutes. The benzene layer was separated, washed with brine, dried over magnesium sulfate and concentrated onto silica gel; flash chromatography using an ethyl acetate/hexanes gradient gave 4-quinolin-2-yl-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.65 g, 55%) as a yellow oil. 1H NMR CDCl3 δ 8.09 (d, J=9 Hz, 1H), 8.03 (d, J=8 Hz, 1H), 7.76 (d, J=8 Hz, 1H), 7.70-7.63 (m, 1H), 7.56 (d, J=9 Hz, 1H), 7.51-7.44 (m, 1H), 6.69-6.63 (m, 1H), 4.21-4.14 (m, 2H), 3.68 (t, J=6 Hz, 1H), 2.87-2.80 (m, 2H), 1.48 (s, 9H).
Reaction SMILES: [CH:1](=[N:8][OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:10]#[C:11][CH:12]([OH:15])[CH2:13][CH3:14].Cl[O-].[Na+]>ClCCl>[OH:15][CH:12]([C:11]1[O:9][N:8]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=1)[CH2:13][CH3:14]
Reactant: ON=Cc1ccccc1
Reactant: C#CC(O)CC
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: CCC(O)c1cc(-c2ccccc2)no1

Procedure:
In 12.5 ml of dichloromethane, were dissolved 2.5 g (20.7 mmol) of benzaldoxime and 2.1 g (25.0 mmol) of 1-pentyne-3-ol. Under ice cooling, 14.5 g of a 12.0% aqueous solution of sodium hypochlorite were added dropwise to the solution. After completion of the dropwise addition, they were reacted at room temperature for 3 hours, followed by the extraction of the organic layer with dichloromethane. The extract was washed with water and the resulting organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by chromatography on a silica gel column (eluent: chloroform), whereby the target compound, namely, 5-(1-hyroxypropyl)-3-phenylisooxazole was obtained as crystals.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1([CH3:32])[CH2:9][CH2:8][CH2:7][N:6]([C:10]2[C:30]([F:31])=[CH:29][C:13]3[C:14]4[C:15](=[O:28])[C:16]([C:23]([O:25]CC)=[O:24])=[CH:17][N:18]([CH3:22])[C:19]=4[CH:20]=[N:21][C:12]=3[CH:11]=2)[CH2:5]1.Cl>C(O)C.O>[CH3:3][C:4]1([CH3:32])[CH2:9][CH2:8][CH2:7][N:6]([C:10]2[C:30]([F:31])=[CH:29][C:13]3[C:14]4[C:15](=[O:28])[C:16]([C:23]([OH:25])=[O:24])=[CH:17][N:18]([CH3:22])[C:19]=4[CH:20]=[N:21][C:12]=3[CH:11]=2)[CH2:5]1
Reactant: CCOC(=O)c1cn(C)c2cnc3cc(N4CCCC(C)(C)C4)c(F)cc3c2c1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1cc(C(=O)O)c(=O)c2c3cc(F)c(N4CCCC(C)(C)C4)cc3ncc21
Temperature: 100 °C
Yield: 81.6 %

Procedure:
1.4 cm3 of 1 N aqueous potassium hydroxide was added, with stirring, to a suspension of 0.5 g of ethyl 8-(3,3-dimethylpiperidin-1-yl)-9-fluoro-4-methyl-1-oxo-1,4-dihydrobenzo[f][1,7]naphthyridine-2-carboxylate in 15 cm3 of ethanol and 15 cm3 of water. The mixture was heated at about 100° C. for one hour. The suspension obtained was acidified by addition of 1.4 cm3 of 1 N aqueous hydrochloric acid. After cooling, the precipitate was dewatered, washed three times with 10 cm3 of water, three times with 10 cm3 of ethanol, and three times with 10 cm3 of ether. The solid was dried at about 80° C. at 1 kPa for 4 hours. 0.38 g of 8-(3,3-dimethylpiperidin-1-yl)-9-fluoro-4-methyl-1-oxo-1,4-dihydrobenzo[f][1,7]naphthyridine-2-carboxylic acid was obtained in the form of a yellow solid, which melted with decomposition at about 286-7° C.
Reaction SMILES: [Br:1][CH:2]1[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]2[C:5]([NH:7][C:8](=[O:9])[CH:3]12)=[O:6].N1C=CC=CC=1.[Br:20][C:21]1[CH:29]=[C:28]([Br:30])[CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>C1C=CC=CC=1>[Br:20][C:21]1[CH:29]=[C:28]([Br:30])[CH:27]=[CH:26][C:22]=1[C:23]([N:7]1[C:8](=[O:9])[CH:3]2[CH:2]([Br:1])[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]2[C:5]1=[O:6])=[O:24]
Reactant: O=C1NC(=O)C2C1CCC(Br)C2Br
Reactant: O=C(Cl)c1ccc(Br)cc1Br
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: O=C(c1ccc(Br)cc1Br)N1C(=O)C2CCC(Br)C(Br)C2C1=O
Temperature: 25 °C

Procedure:
3,4-Dibromohexahydrophthalimide (0.10 mole), benzene (300 ml) and pyridine (0.11 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2,4-Dibromobenzoyl chloride (0.10 mole) is then added dropwise to the flask with stirring at room temperature. After the addition is completed the reaction mixture is heated at reflux with continued stirring for a period of about 1 hour. After this time the reaction mixture is filtered and the filtrate is washed with water. The washed filtrate is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(2,4-dibromobenzoyl)-3,4-dibromohexahydrophthalimide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C@H:10]([CH3:18])[NH:9]2)=[CH:4][CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C@H:10]([CH3:18])[N:9]2[C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)=[O:28])=[CH:4][CH:3]=1
Reactant: C[C@H]1Cc2ccccc2[C@@H](c2ccc(Br)cc2)N1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: ClCCl
Product: C[C@H]1Cc2ccccc2[C@@H](c2ccc(Br)cc2)N1C(=O)Nc1ccc(F)cc1
Reaction time: 4 h

Procedure:
To a solution of (1R,3S)-1-(4-bromophenyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline (48.5 mg, 160 μmol) in CH2Cl2 (1.0 mL) at RT was added 1-fluoro-4-isocyanatobenzene (28.9 μL, 249 μmol). The reaction was stirred 4 h and directly purified by reverse phase HPLC to give (1R,3S)-1-(4-bromophenyl)-N-(4-fluorophenyl)-3-methyl-3,4-dihydroisoquinoline-2(1H)-carboxamide as a white solid. MS (ESI pos. ion) m/z: 439, 441 (M+1).
Reaction SMILES: [C:1]([C:5]1[C:10]2[CH2:11][C:12]([CH3:17])([C:14]([OH:16])=[O:15])[O:13][C:9]=2[CH:8]=[C:7]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=1[O:22][Si](C)(C)C)([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:1]([C:5]1[C:10]2[CH2:11][C:12]([CH3:17])([C:14]([OH:16])=[O:15])[O:13][C:9]=2[CH:8]=[C:7]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=1[OH:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C(=O)O)Cc2c(cc(C(C)(C)C)c(O[Si](C)(C)C)c2C(C)(C)C)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC1(C(=O)O)Cc2c(cc(C(C)(C)C)c(O)c2C(C)(C)C)O1
Reaction time: 1 h
Yield: 91 %

Procedure:
Under a nitrogen atmosphere, a solution of 0.19 g of 4,6-di-t-butyl-2-methyl-5-trimethylsilyloxy-2,3-dihydrobenzofuran-2-carboxylic acid in 1 ml of THF was cooled to 0° C. and 1 ml of tetra-n-butylammonium fluoride (1.0 mmol/ml THF solution) was added dropwise to this solution and the mixture was stirred for 1 hour. After the reaction was quenched by adding a saturated aqueous ammonium chloride solution, the mixture was extracted with water and diethyl ether, and the combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated to give 0.14 g of 4,6-di-t-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran-2-carboxylic acid as a colorless solid (yield 91%).
Reaction SMILES: Cl.Cl.Cl.S1C(C2C=CN=C([NH:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)N=2)=CC2C=CC=CC1=2.Cl[C:31]1[N:36]=[C:35]([C:37]2[S:41][C:40]3[C:42]([O:46][CH3:47])=[CH:43][CH:44]=[CH:45][C:39]=3[CH:38]=2)[C:34]([Cl:48])=[CH:33][N:32]=1.NCCCN1CCN(C)CC1>>[Cl:48][C:34]1[C:35]([C:37]2[S:41][C:40]3[C:42]([O:46][CH3:47])=[CH:43][CH:44]=[CH:45][C:39]=3[CH:38]=2)=[N:36][C:31]([NH:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]2)=[N:32][CH:33]=1
Reactant: COc1cccc2cc(-c3nc(Cl)ncc3Cl)sc12
Reactant: CN1CCN(CCCNc2nccc(-c3cc4ccccc4s3)n2)CC1
Agent: CN1CCN(CCCN)CC1
Agent: Cl
Product: COc1cccc2cc(-c3nc(NCCCN4CCN(C)CC4)ncc3Cl)sc12

Procedure:
Using the method of [4-(benzo[b]thiophen-2-yl)-pyrimidin-2-yl]-[3-(4-methylpiperazin-1-yl)-propyl]-amine tri-hydrochloride, the title compound is prepared from 2,5-dichloro-4-(7-methoxybenzo[b]thiophen-2-yl)-pyrimidine and 1-(3-aminopropyl)-4-methylpiperazine and isolated as a yellowish solid. ES+(m/z) 432(35Cl) and 434(37Cl) [M+H].
Reaction SMILES: C([N:5]1[C:34](=[O:35])[N:8]2[CH:9]=[C:10]([C:17]3[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=3)[C:20]([NH:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:21])[N:11]=[C:12]([NH:13][CH:14]([CH3:16])[CH3:15])[C:7]2=[N:6]1)(C)(C)C.B(Br)(Br)Br>ClC(Cl)C>[CH:14]([NH:13][C:12]1[C:7]2[N:8]([C:34](=[O:35])[NH:5][N:6]=2)[CH:9]=[C:10]([C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:21])[N:11]=1)([CH3:16])[CH3:15]
Reactant: CC(C)Nc1nc(-c2cccc(C(=O)NCCc3ccccc3)c2)cn2c(=O)n(C(C)(C)C)nc12
Agent: BrB(Br)Br
Solvent: CC(Cl)Cl
Product: CC(C)Nc1nc(-c2cccc(C(=O)NCCc3ccccc3)c2)cn2c(=O)[nH]nc12
Temperature: 25 °C

Procedure:
A solution of 32 mg of the product of Step B and 251 mg of boron tribromide in dichloroethane (2.0 mL) was heated in a sealed tube at 125° C. After two h, the reaction was cooled to ambient temperature and the excess reagent carefully quenched by the addition of water. The resulting mixture was extracted with EtOAc and the organic layer washed with sat. sodium chloride, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to afford the title compound as a tan solid. MS (M+H+)=417.4.
Reaction SMILES: [CH:1]([C:3]1[C:8](=[O:9])[C:7]2[CH:10]=[C:11]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:12]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][C:6]=2[O:5][CH:4]=1)=[O:2].[CH3:26][Mg]I>>[OH:2][CH:1]([C:3]1[C:8](=[O:9])[C:7]2[CH:10]=[C:11]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:12]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][C:6]=2[O:5][CH:4]=1)[CH3:26]
Reactant: C[Mg]I
Reactant: CS(=O)(=O)Nc1cc2occ(C=O)c(=O)c2cc1Oc1ccccc1
Product: CC(O)c1coc2cc(NS(C)(=O)=O)c(Oc3ccccc3)cc2c1=O

Procedure:
3-Formyl-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one was reacted with methylmagnesium iodide to obtain 3-(1-hydroxyethyl)-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one.
Reaction SMILES: [CH3:1][C@@H:2]1[C@@H:41]([OH:42])[C@@H:40]([CH3:43])[C@H:39]([CH3:44])[O:38][C:36](=[O:37])[CH2:35][C@H:34]([OH:45])[CH2:33][C@H:32]([OH:46])[CH2:31][CH2:30][C@@H:29]([OH:47])[C@H:28]([OH:48])[CH2:27][C@H:26]([OH:49])[CH2:25][C@@:23]2([OH:50])[O:24][C@H:19]([C@H:20]([C:52]([O:54][CH3:55])=[O:53])[C@@H:21]([OH:51])[CH2:22]2)[CH2:18][C@@H:17]([O:56][C@@H:57]2[O:62][C@H:61]([CH3:63])[C@@H:60]([OH:64])[C@H:59]([NH2:65])[C@@H:58]2[OH:66])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=[CH:3]1.[NH2:67][C@H:68]([C:73]([OH:75])=[O:74])[CH2:69][C:70]([OH:72])=[O:71]>O>[CH3:1][C@@H:2]1[C@@H:41]([OH:42])[C@@H:40]([CH3:43])[C@H:39]([CH3:44])[O:38][C:36](=[O:37])[CH2:35][C@H:34]([OH:45])[CH2:33][C@H:32]([OH:46])[CH2:31][CH2:30][C@@H:29]([OH:47])[C@H:28]([OH:48])[CH2:27][C@H:26]([OH:49])[CH2:25][C@@:23]2([OH:50])[O:24][C@H:19]([C@H:20]([C:52]([O:54][CH3:55])=[O:53])[C@@H:21]([OH:51])[CH2:22]2)[CH2:18][C@@H:17]([O:56][C@@H:57]2[O:62][C@H:61]([CH3:63])[C@@H:60]([OH:64])[C@H:59]([NH2:65])[C@@H:58]2[OH:66])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=[CH:3]1.[NH2:67][C@H:68]([C:73]([O-:75])=[O:74])[CH2:69][C:70]([O-:72])=[O:71]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: COC(=O)[C@H]1[C@@H]2C[C@@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@H](N)[C@@H]3O)/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@@H]1O)O2
Agent: COC(=O)[C@H]1[C@@H]2C[C@@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@H](N)[C@@H]3O)C=CC=CC=CC=CC=CC=CC=C[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@@H]1O)O2
Solvent: O
Product: N[C@@H](CC(=O)[O-])C(=O)[O-]
Reaction time: 1 h

Procedure:
Amphotericin B methyl ester (9.36 g, 0.01 Mol) is added in portions to a solution of L-aspartic acid (0.73 g, 0.0055 Mol) in 500 ml of water and stirred until dissolution (1 hour). The clear solution is thereafter freeze-dried. The product when dissolved in water (1%) has a pH of 6.25 and a solubility of greater than 10% at RT.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[C:4]([Cl:14])[N:3]=1.Cl.[F:16][C:17]1([F:22])[CH2:21][CH2:20][NH:19][CH2:18]1.CN1C(=O)CCC1.CCN(C(C)C)C(C)C>>[Cl:14][C:4]1[CH:5]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=[C:2]([N:19]2[CH2:20][CH2:21][C:17]([F:22])([F:16])[CH2:18]2)[N:3]=1
Reactant: FC1(F)CCNC1
Reactant: Clc1cc(-c2cccnc2)cc(Cl)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: FC1(F)CCN(c2cc(-c3cccnc3)cc(Cl)n2)C1
Temperature: 140 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2,6-dichloro-4-(3-pyridyl)pyridine (48 mg, 0.21327 mmol) and 3,3-difluoropyrrolidine hydrochloride (153 mg, 5.0 equiv., 1.0663 mmol) in NMP (1.0 mL, 10 mmol) in a microwave vial was added DIPEA (0.26 mL, 7.0 equiv., 1.4929 mmol), and the reaction was maintained at 140° C. for 60 min then at 150° C. for 20 min in the microwave machine, while LCMS indicated the conversion was more than 95%. The crude was used without further treatment. LCMS: m/z 296 (M+H).