Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.P(Cl)(Cl)([Cl:9])=O.[F:12][C:13]1[CH:14]=[C:15]([N+:20]([O-:22])=[O:21])[C:16](O)=[N:17][CH:18]=1.O>C(OCC)(=O)C>[Cl:9][C:16]1[C:15]([N+:20]([O-:22])=[O:21])=[CH:14][C:13]([F:12])=[CH:18][N:17]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cc(F)cnc1O
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: O
Product: O=[N+]([O-])c1cc(F)cnc1Cl
Temperature: 100 °C
Reaction time: 8 h
Yield: 48.4 %

Procedure:
To a mixture of phosphorus pentachloride (9.41 g, 45.2 mmol) and phosphorus oxychloride (4.2 mL, 45.1 mmol) at 60° C. was added in portions 5-fluro-2-hydroxy-3-nitropyridine (6.5 g, 41.1 mmol). The mixture was stirred in an oil bath at 100° C. under nitrogen overnight, cooled to room temperature and poured into ice/water. After addition of more water and ethyl acetate, the mixture was filtered through Celite® to remove dark insoluble material. The organic phase was washed with brine, filtered again to remove more dark material, dried over MgSO4 and concentrated. The residue was subjected to flash chromatography on silica gel using chlorform as eluant. Fractions containing the title compound were combined and concentrated to provide a yellow oil (3.51 g, 48%) which solidified on standing at 5° C. overnight.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:12]([O-:14])=[O:13])=[C:7]([CH:11]=1)[C:8](O)=[O:9]>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:12]([O-:14])=[O:13])=[C:7]([CH2:8][OH:9])[CH:11]=1
Reactant: COc1ccc([N+](=O)[O-])c(C(=O)O)c1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc([N+](=O)[O-])c(CO)c1
Yield: 9.8 %

Procedure:
To the solution of 5-methoxy-2-nitrobenzoic acid (20 g, 1.0 mol) in THF (100 mL) was added BH3 (1.0 M in THF, 30.4 mL, 3.0 eq) at 0° C. The mixture was refluxed for 3 h, diluted with water (200 mL) and extracted with DCM (100 ml*3). The combined organic lays were dried over MgSO4, evaporated to afford (5-methoxy-2-nitrophenyl)methanol (18 g, yield: 97%), as a white solid. 1HNMR (400 MHz, DMSO-d6) δ: 8.13 (d, J=6.4 Hz, 1H), 7.34 (d, J=6.4 Hz, 1H), 7.02 (s, 1H), 5.60˜5.58 (m, 1H), 4.84 (d, J=8.0 Hz, 2H), 3.89 (s, 3H); ESI-MS: m/z 184.1 ([M+1]+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:22][C:23](O)=[O:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(Cl)(Cl)=O.C(N(CC)CC)C.O>ClC(Cl)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH2:22][C:23]2=[O:24])[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2OCC(=O)O)CC1
Solvent: O
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(N2C(=O)COc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 57.4 %

Procedure:
1-(tert-Butoxycarbonyl)-4-[(2-carboxymethoxyphenyl)amino]piperidine (351 mg) was dissolved in dichloroethane (7 ml), added with thionyl chloride (73 μl) and stirred at room temperature for 1.5 hours. The reaction mixture was added with triethylamine (0.28 ml) and further stirred at 40° C. for 2 hours. The reaction mixture was added with water (10 ml) and extracted twice with ethyl acetate (10 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate=2:1) to obtain 191 mg of the title compound. Yield: 57%.
Reaction SMILES: [BH4-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([C:12](=[O:14])[CH3:13])[CH:9]=[CH:10][CH:11]=1)([O-:5])=[O:4]>C(O)C.C(=O)([O-])[O-].[K+].[K+]>[N+:3]([C:6]1[CH:7]=[C:8]([CH:12]([OH:14])[CH3:13])[CH:9]=[CH:10][CH:11]=1)([O-:5])=[O:4]
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [K+]
Solvent: CCO
Product: CC(O)c1cccc([N+](=O)[O-])c1
Yield: 86.7 %

Procedure:
A solution of sodium borohydride (0.4 g, 10 mmol) in ethanol (10 ml) was treated with m-nitroacetophenone (3.3 g, 20 mmol) at 20° C. for 20 mins. The solution was the diluted with aqueous potassium carbonate and extracted with chloroform. The extracts were dried (magnesium sulphate) and evaporated in vacuo to give 1-(m-nitrophenyl)ethanol as an oil (2.9 g, 90%);
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[C:14]([O:15][CH3:16])=[CH:13][C:12]([CH3:17])=[CH:11][C:10]=2[O:18][CH3:19])[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]=2[N:4]([CH3:24])[C:3]1=[O:25].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH:53]1[C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[CH:55]=[C:54]1[C:62](O)=[O:63].C(N(CC)CC)C>CN(C)C=O.O>[CH3:19][O:18][C:10]1[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([O:15][CH3:16])[C:9]=1[C:7]1[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]=2[N:4]([CH3:24])[C:3](=[O:25])[CH:2]([NH:1][C:62]([C:54]2[NH:53][C:61]3[C:56]([CH:55]=2)=[CH:57][CH:58]=[CH:59][CH:60]=3)=[O:63])[N:8]=1
Reactant: COc1cc(C)cc(OC)c1C1=NC(N)C(=O)N(C)c2ccccc21
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc(C)cc(OC)c1C1=NC(NC(=O)c2cc3ccccc3[nH]2)C(=O)N(C)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of 0.38 g of the laevorotatory enantiomer of 3-amino-1,3-dihydro-5-(2,6-dimethoxy-4-methylphenyl)-1-methyl-1,4-benzodiazepin-2-one in 10 ml of dimethylformamide, cooled to 50° C., are added 0.52 g of BOP and 0.19 g of indole-2-carboxylic acid, followed by 0.23 ml of triethylamine. The reaction mixture is stirred overnight at room temperature and is then poured into water and extracted with ethyl acetate, dried over sodium sulphate and evaporated to dryness. The product is purified by chromatography on a column of silica gel (eluent: dichlormethane/methanol: 95/5). The fractions of pure product are evaporated to dryness and the residue is crystallized from isopropyl ether. White crystals of (-)-N-[2,3-dihydro-5-(2,6-dimethoxy-4-methylphenyl)-1-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-1H-indol-2-carboxamide are obtained, melting at 135° C.; Yield=81%; [α]D20 =-408 (c=0.35 in 1N HCl/CH3OH-50/50).
Reaction SMILES: CI.CCCCCC.CC(C)=O.[CH2:13]([O:20][C:21]1[C:22]([C:29]([O:31]C)=[O:30])=[N:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O[Li].O>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[CH2:13]([O:20][C:21]1[C:22]([C:29]([OH:31])=[O:30])=[N:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)c1nc(OC)ccc1OCc1ccccc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Agent: [Li]O
Solvent: O
Solvent: Cc1ccccc1
Solvent: CI
Product: COc1ccc(OCc2ccccc2)c(C(=O)O)n1
Temperature: 60 °C

Procedure:
To a stirred solution of this compound (10.25 g) in toluene (125 mL), warmed in an oil bath at 60° C. was added silver carbonate (16.6 g), then methyl iodide (8.52 g). The resulting mixture was stirred and heated for 3 hours at 60° C. After cooling, the mixture was filtered through Celite® and the solvent evaporated to give a yellow oil. Silica gel chromatography (4:1 hexane/acetone) gave a nearly colorless oil, whose 1H-NMR and MS data were consistent with methyl 3-benzyloxy-6-methoxypicolinate. Hydrolysis of this ester to the title acid 18 was accomplished with LiOH.H2O as described above for related esters.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:5])[CH3:2].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.O.[CH:69]([O-:71])=[O:70].[Li+].[Cl-].[Li+].C(N(CC)C(C)C)(C)C.C(OC(=O)C)(=O)C>C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C)C=O>[CH3:2][CH2:1][O:3][C:4]([C:6]1[N:7]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:69]([OH:71])=[O:70])=[CH:10][CH:9]=2)=[O:5]
Reactant: O=C[O-]
Reactant: CCOC(=O)c1cc2cc(Br)ccc2n1S(=O)(=O)c1ccc(C)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)OC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)c1cc2cc(C(=O)O)ccc2n1S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 5-bromo-1-(toluene-4-sulfonyl)-1H-indole-2-carboxylic acid ethyl ester (948.4 mg, 2.24 mmol), Tris(dibenzylideneacetone)dipalladium (0) (0.112 mmol, 103 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (0.225 mmol, 130 mg), lithium formate monohydrate (5.6 mmol, 394 mg), lithium chloride (286 mg, 6.75 mmol), and anhydrous N,N-dimethylformamide (DMF) (5.9 ml) was evacuated, and backfilled with argon. Then, N,N-diisopropylethyl amine (4.5 mmol, 0.78 ml) and acetic anhydride (4.5 mmol, 0.43 ml) were added to the mixture, and deaeration and argon replacement was performed again. The reaction container was placed in a reaction device preheated at 80° C. and the reaction mixture was stirred for 20 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and an aqueous solution of 1 M hydrochloric acid, and filtered through Celite. The resulting filtrate was washed with 1 M hydrochloric acid, water, and a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1 to 1/3, and finally ethyl acetate/methanol=15/1) to give 1-(toluene-4-sulfonyl)-1H-indole-2,5-dicarboxylic acid 2-ethyl ester as a yellow amorphous material (930 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:17][CH3:18])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([O:14]C)=[O:13])[CH:8]=[C:7]2[OH:16].CO.C1COCC1.[Li+].[OH-]>O>[Cl:1][C:2]1[C:3]([O:17][CH3:18])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([OH:14])=[O:13])[CH:8]=[C:7]2[OH:16]
Reactant: COC(=O)c1cc(O)c2ccc(OC)c(Cl)c2n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc2c(O)cc(C(=O)O)nc2c1Cl
Temperature: 25 °C
Yield: 93.5 %

Procedure:
To a solution of methyl 8-chloro-4-hydroxy-7-methoxyquinoline-2-carboxylate (36.5 g, 0.145 mol) in a mixture of 1:1 of MeOH: THF (160 mL total) was added a solution of LiOH (30.5 g, 0.725 mol) in H2O (80 mL). The mixture was stirred at room temperature for an hour when LCMS analysis showed complete conversion to the carboxylic acid. The reaction was worked up by removal of the volatiles and adjusting the pH of the solution to 6 using aqueous 6N HCl. The resulted gummy residue was filtered and dried on the lypholizer for 2 days to provide 34.4 g (99.6%) of the product as a white solid. EI MS (m/z) 253.9 [M+H].
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[O:7])=[CH:15][CH:16]=1
Reactant: Cc1ccc(C(=O)c2ccc(F)cc2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(c1ccc(F)cc1)c1ccc(CBr)cc1
Yield: 43 %

Procedure:
A mixture of 2.0 g (9.9 mmol) of 4-methyl-4′-fluorobenzophenone, 1.524 g (9.9 mmol) of recrystallized N-bromosuccinimide, 170 mg benzoyl peroxide, and 20 mL CCl4 was refluxed under argon for 3 hours. The hot solution was filtered through a glass sintered filter and rinsed with 20 mL of hot CCl4 until the crystals became colorless. The crystals were washed with 6 mL of cold CCl4 and the solution was concentrated under reduced vacuum. The crude product was recrystallized from hexane and dried under vacuum. The resultant yield was 43%. Rf=0.25 (ethyl Acetate/hexane; 15:85). 1H-NMR: δ 7.85 (dd, aromatic, 2H), 7.75 (d, aromatic, 2H), 7.51 (d, aromatic, 2H), 7.17 (dd, aromatic, 2H), 4.52 (s, methyl, 3H). 13C-NMR: δ 195.0 (carbonyl); 166.5, 164.5, 142.5, 138.5, 133.4, 130.4, 129.2, 115.8, 115.5 (aromatic); 31.1 (alkyl).
Reaction SMILES: [C:1]([O:9][CH:10]([C:16](=[O:18])[CH3:17])[C:11](=[O:15])[CH:12]=[CH:13]O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)CC.C(O)(=O)C(O)=O.Cl.S(=O)(=O)(O)O>C(O)(=O)C.C(O)=O>[C:1]([O:9][C:10]1[C:11](=[O:15])[CH:12]=[CH:13][O:18][C:16]=1[CH3:17])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)C(OC(=O)c1ccccc1)C(=O)C=CO
Agent: Cl
Agent: O=C(O)C(=O)O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: CCC(=O)O
Solvent: O=CO
Product: Cc1occc(=O)c1OC(=O)c1ccccc1

Procedure:
said 4-benzoyloxy-1-hydroxy-1-hexene-3,5-dione is heated in an acid chosen from the group consisting of formic acid, acetic acid, propionic acid, oxalic acid, dilute hydrochloric acid and dilute sulfuric acid to form 3-benzoyloxy-2-methyl-4-pyrone, and,
Reaction SMILES: [O-]CC.[Na+].[C:5]([O:14][CH2:15][CH3:16])(=[O:13])/[CH:6]=[CH:7]\[C:8]([O:10]CC)=O.[NH:17]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[NH2:18]>C(O)C>[O:10]=[C:8]1[NH:18][N:17]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:6]([C:5]([O:14][CH2:15][CH3:16])=[O:13])[CH2:7]1
Reactant: NNc1cccnc1
Reactant: CCOC(=O)/C=C\C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1CC(=O)NN1c1cccnc1

Procedure:
In a preferred reaction, sodium ethoxide in an anhydrous ethanol are introduced into a reaction vessel and 3-hydrazinopyridine•dihydrochloride is added. The mixture is stirred and diethyl maleate is added. The mixture is heated at about 60° C. until most of the 3-hydrazinopyridine has reacted. The mixture is allowed to cool and the excess base is neutralized with acid. The crude ethyl 5-oxo-2-(pyridin-3-yl)pyrazolidine-3-carboxylate (10a) is conveniently isolated and purified by standard techniques.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[N-:9]=[N+:10]=[N-:11].[Na+]>C(O)C>[N:9]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8])=[N+:10]=[N-:11]
Reactant: [N-]=[N+]=[N-]
Reactant: OCCCCCCBr
Agent: [Na+]
Solvent: CCO
Product: [N-]=[N+]=NCCCCCCO
Yield: 88 %

Procedure:
A solution of 6-bromo-1-hexanol (3.6 g, 20 mmol) and sodium azide (2.6 g, 40 mmol) in 95% ethanol (50 mL) was heated with stirring to reflux for 12 hours. The mixture was filtered, and the filtrate concentrated by rotary evaporation. The residue was dissolved in ether (250 mL) and washed three times with water. The ether layer was dried over anhydrous MgSO4, and concentrated by rotary evaporation to give the desired product as a colorless liquid in 88% yield: 1H NMR (CDCl3, 400 MHz): δ (CHCl3 7.26 ppm) 3.65-3.62 (t, J=6.52 Hz, 2H), 3.28-3.24 (t, J=6.88 Hz, 2H), 1.60 (m, 4H), 1.40 (m, 4H); 13C NMR (CDCl3, 100 MHz): δ (ppm) 62.7, 51.3, 32.5, 28.8, 26.5, 25.3.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[NH2:10][OH:11]>CCO>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[N:10][OH:11])[NH2:7])=[CH:4][CH:3]=1
Reactant: NO
Reactant: N#Cc1ccc(Cl)cc1
Solvent: CCO
Product: NC(=NO)c1ccc(Cl)cc1
Yield: 76.2 %

Procedure:
A solution of 4-chlorobenzonitrile (1 g, 7.23 mmol) and hydroxylamine (50% in water, 0.67 cm3, 10.9 mmol, 1.5 eq) in EtOH (12.5 cm3) was stirred under reflux for 48 hours. The solvent was removed under reduced pressure and the residue was washed with CH2Cl2 (10 cm3) to give the product 4-chloro-N′-hydroxybenzimidamide (0.94 g, 76%) as a white solid, mp 133-135° C.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([OH:23])[CH:19]=2)[CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O.CN(C)C=O>[CH2:1]([O:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([OH:23])[CH:19]=2)[CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: Oc1ccc2cc(O)ccc2c1
Reactant: CCCCCCCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCOc1ccc2cc(O)ccc2c1
Temperature: 130 °C
Reaction time: 2 h

Procedure:
Decyl monobromide (7.0 g), 2,6-dihydroxynaphthalene (5.0 g) and anhydrous potassium carbonate (4.0 g) were added to 100 ml of dimethylformamide. After stirring at 130° C. for 2 hours, the reaction solution was poured into water. Dilute hydrochloric acid was added to neutralize the solution, which was extracted with diethyl ether. The extract was distilled to remove the solvent to obtain the titled compound as residue (8.0 g).
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][CH:10]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:8])=[CH:5][C:4]=1[F:19])#[N:2].CC1C=C2N=C3C(=NC(NC3=O)=O)N(C[C@H](O)[C@H](O)[C@H](O)CO)C2=CC=1C.C(O)C.[H][H]>C(O)(=O)C.O>[NH2:2][CH2:1][C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][CH:10]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:8])=[CH:5][C:4]=1[F:19]
Reactant: [H][H]
Reactant: N#Cc1ccc(C(=O)NC2CCCCCC2)cc1F
Agent: Cc1cc2nc3c(=O)[nH]c(=O)nc-3n(C[C@H](O)[C@H](O)[C@H](O)CO)c2cc1C
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: NCc1ccc(C(=O)NC2CCCCCC2)cc1F
Reaction time: 0.5 h

Procedure:
Add 4-cyano-N-cycloheptyl-3-fluoro-benzamide (0.86 g, 3.3 mmol), 10% NYC (Degussa type E101, 250 mg), ethanol (25 mL), water (9 mL) and acetic acid (1 mL) to a pressure vessel under a nitrogen atmosphere. Pressurize the vessel to 50 psi with hydrogen, and stir the mixture for 0.5 h. Filter the mixture through Celite® and wash the cake with warm ethanol followed by dichloromethane under a nitrogen atmosphere. Concentrate the filtrate in vacuo to obtain the title compound as the acetic acid salt. Use SCX chromatography to obtain the title compound (805 mg, 92%). MS (ES+) m/z: 265.3 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[NH:10]1[CH:14]=[CH:13][N:12]=[CH:11]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:3][CH:4]=1
Reactant: COc1ccc(Br)cc1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(-n2ccnc2)cc1
Yield: 49.9 %

Procedure:
A mixture of 37.4 g (0.20 mole) of 4-bromoanisole, 170 g (0.25 mole) of imidazole, 26 g (0.2 mole) of potassium carbonate, and 1.2 g of cuprous bromide in 150 ml of N-methylprryolidinone was heated at reflux under a blanket of nitrogen for 4 hr. The mixture filtered and concentrated to remove the solvent. The residue was partioned between dilute sodium hydroxide solution and methylene chloride. After filtration, the organic fraction was chromatographed. The desired fractions were concentrated and the crystalline residue was recrystallized from toluene/cyclohexane to give 17.4 g (50%) of the title compound as white plates, mp 63.0-64.0° C.
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.[NH:67]1[C:71](=[O:72])[CH2:70][CH2:69][C@H:68]1[C:73]([OH:75])=[O:74]>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.[NH:67]1[C:71](=[O:72])[CH2:70][CH2:69][C@H:68]1[C:73]([O-:75])=[O:74]
Reactant: O=C1CC[C@@H](C(=O)O)N1
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: O=C1CC[C@@H](C(=O)[O-])N1
Reaction time: 0.12 h

Procedure:
Amphotericin B methyl ester (9.36 g, 0.01 Mol) is added in portions to a solution of pyroglutamic acid (1.30 g, 0.01 Mol) in 500 ml of water and stirred until dissolution (5-10 minutes). The clear solution is thereafter lyopholized. The resulting product is found to be very soluble in water (more than 10% soluble at RT).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]#[CH:18])=[CH:11][CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[NH2:20][S:21]([C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[CH3:31])[NH2:27])(=[O:23])=[O:22].FC(F)(F)C(O)=O.CC(O)C>Cl>[NH2:20][S:21]([C:24]1[CH:25]=[C:26]([NH:27][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]#[CH:18])=[CH:11][CH:10]=3)[C:5]([F:19])=[CH:4][N:3]=2)[CH:28]=[CH:29][C:30]=1[CH3:31])(=[O:22])=[O:23]
Reactant: C#CCOc1ccc(Nc2nc(Cl)ncc2F)cc1
Reactant: Cc1ccc(N)cc1S(N)(=O)=O
Agent: Cl
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: C#CCOc1ccc(Nc2nc(Nc3ccc(C)c(S(N)(=O)=O)c3)ncc2F)cc1
Temperature: 100 °C

Procedure:
2-Chloro-5-fluoro-N4-[4-(prop-2-ynyloxy)phenyl]-4-pyrimidineamine (0.514 g, 1.85 mmol), 3-(aminosulfonyl)-4-methylaniline (0.689 g, 3.70 mmol), and trifluoroacetic acid (0.186 mL, 2.41 mmol) were combined with iPrOH (6.0 mL) in a sealed vial and heated at 100° C. for 3 h. The reaction mixture was cooled to room temperature and diluted with 1N HCl (80 mL). N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine VI-53) was isolated as a white solid by suction filtration (0.703 g). 1H NMR (DMSO-d6): δ 10.08 (bs, 2H), 8.19 (d, J=4.5 Hz, 1H), 7.89 (s, 1H), 7.74 (dd, J=2.4 and 8.4 Hz, 1H), 7.58 (d, J=8.7 Hz, 2H), 7.32 (bs, 2H), 7.23 (d, J=8.4 Hz, 1H), 6.97 (d, J=8.4 Hz, 2H), 4.79 (d, J=2.1 Hz, 2H), 3.59-3.55 (m, 1H), 2.53 (s, 3H); LCMS: purity: 97%; MS (m/e): 428 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH:18]([C:20](=[O:22])[CH3:21])[CH3:19])[C:4]2[C:9]([C:10]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[BH4-].[Na+]>O1CCCC1>[OH:22][CH:20]([CH3:21])[CH:18]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[C:2]1[CH3:1])[CH3:19]
Reactant: CC(=O)C(C)n1c(C)c(C(=O)OC(C)(C)C)c2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(C(=O)OC(C)(C)C)c2ccccc2n1C(C)C(C)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
To a mixture of tert-butyl 2-methyl-1-(3-oxobutan-2-yl)-1H-indole-3-carboxylate (120 mg, 0.39 mmol) in tetrahydrofuran (3 mL) was added sodium borohydride (79 mg, 2.08 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched by adding water (3 ml) and extracted with ethyl acetate (20 mL×4). The combined organic layers was dried over sodium sulfate and concentrate to afford tert-butyl 1-(3-hydroxybutan-2-yl)-2-methyl-1H-indole-3-carboxylate (110 mg, yield: 93%) as a yellow oil. LRMS (M+H+) m/z: calcd 303.17. found 304.