Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=1)[C:16]([O:18]C)=[O:17])[C:7]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:6]2.[OH-].[Na+].Cl>O1CCCC1CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=1)[C:16]([OH:18])=[O:17])[C:7]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:6]2
Reactant: COC(=O)c1cccc(Cn2c(-c3ccccc3)cc3cc(OC)ccc32)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: OCC1CCCO1
Product: COc1ccc2c(c1)cc(-c1ccccc1)n2Cc1cccc(C(=O)O)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
To a solution of methyl 3-(5-methoxy-2-phenylindol-1-ylmethyl)benzoate (48.6 mg) in tetrahydrofuran-methanol (7/3, 1.1 mL) was added 2 mol/L aqueous sodium hydroxide solution (0.196 mL) at room temperature, and the mixture was stirred at 60° C. for 2 hours. 1 mol/L Hydrochloric acid (10 mL) was added to the reaction mixture at room temperature and this resulting mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (44.7 mg).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=1.O.[NH2:32][NH2:33]>CN(C=O)C>[N+:27]([C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[CH2:20][C:19]1[C:3]2[C:4](=[O:18])[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:33][N:32]=1)([O-:29])=[O:28]
Reactant: O=C(Cc1cccc([N+](=O)[O-])c1)c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Reactant: NN
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2c(Cc3cccc([N+](=O)[O-])c3)n[nH]c2c2cccnc2n1-c1ccccc1
Yield: 70.4 %

Procedure:
To a suspension of 4-hydroxy-3-[1-oxo-2-(3-nitrophenyl)ethyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (568 mg, 1.42 mmol, prepared in Synthetic Example 19) in DMF (14 ml) was added hydrazine monohydrate (80%, 203 μl, 5.07 mmol, 3.6 eq.), and the mixture was treated in the same manner as in Example 24 to give 3-(3-nitrobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (397 mg, 71%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:12]=[CH:11][C:10]2[NH:9][C:8]3[CH2:13][CH2:14][NH:15][C:16](=[O:17])[C:7]=3[C:6]=2[CH:5]=1.[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CO>CN(C=O)C.C(Cl)Cl>[F:3][C:4]1[CH:12]=[CH:11][C:10]2[N:9]([S:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:26])=[O:25])[C:8]3[CH2:13][CH2:14][NH:15][C:16](=[O:17])[C:7]=3[C:6]=2[CH:5]=1
Reactant: O=C1NCCc2[nH]c3ccc(F)cc3c21
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: O=C1NCCc2c1c1cc(F)ccc1n2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 53.6 %

Procedure:
60% NaH (196 mg, 8.16 mmol) was added to a stirred solution of 8-fluoro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one (500 mg, 2.44 mmol) in DMF (20 mL) at −10° C. and stirred for 10 minutes at room temperature. This was followed by the addition of benzene sulfonyl chloride (517 mg, 2.92 mmol) at 0° C. and the resulting reaction mass was stirred at room temperature for 5 minutes. The reaction was monitored by TLC (5% methanol in DCM). The reaction mass was quenched with ice and extracted using ethyl acetate. The organic layer was washed with water, brine solution, dried over Na2SO4 and concentrated to afford the crude product. Purification by column chromatography on silica gel (0.5% methanol in DCM) afforded 450 mg of the product (53.6% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:32])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][C:21]([O:29][CH3:30])=[C:22]([O:27][CH3:28])[C:23]=3Br)[C:18]2=[O:31])=[CH:12][CH:11]=1.[C:33]1(B(O)O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C(OCC)(=O)C.C1(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)C=CC=CC=1>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:32])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][C:21]([O:29][CH3:30])=[C:22]([O:27][CH3:28])[C:23]=3[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:18]2=[O:31])=[CH:12][CH:11]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1cc2c(c(Br)c1OC)CN(Cc1ccc(C(=O)Nc3ccccc3N)cc1)C2=O
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc2c(c(-c3ccccc3)c1OC)CN(Cc1ccc(C(=O)Nc3ccccc3N)cc1)C2=O
Yield: 92.9 %

Procedure:
N-(2-aminophenyl)-4-((4-bromo-5,6-dimethoxy-1-oxoisoindolin-2-yl)methyl)benzamide (60 mg, 0.12 mmol) in Example 1, phenyl boronic acid (22 mg, 0.18 mmol, 1.5 equiv.), tetrakis(triphenyl-phosphino)palladium (8.4 mg, 0.0073 mmol, 6 mol %) and sodium carbonate (38 mg, 0.36 mmol, 3 equiv.) were dissolved in a mixture of dioxane and the distilled water (mixture ratio=4:1 (v/v), 5.0 mL) and the resulting solution was reacted at 150° C. under microwave for 15 mins. The resulting material thus obtained was diluted with ethyl acetate (EtOAc), dried over anhydrous MgSO4, and filtered with Celite. The filtrates were distilled under a reduced pressure to remove the solvent and the resulting residue was subjected to a silica gel column chromatography (EtOAc) to obtain the title compound (55 mg, 92%).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:32](=[O:33])[N:13]3[CH:14]([C:19]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=4)=[O:20])[CH:15](O)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS(C)=O.[C:38]([O:41][C:42](=O)C)(=[O:40])[CH3:39].O>C(OCC)(=O)C>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:32](=[O:33])[N:13]3[CH:14]([C:19]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=4)=[O:20])[C:15](=[CH:42][O:41][C:38](=[O:40])[CH3:39])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(O)CS[C@H]12
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)OC=C1CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4-Nitrobenzyl 7-(2-phenylacetamido)-3-hydroxycepham-4-carboxylate (1.5 g.) was added to a solution of dimethylsulfoxide (15 ml.) and acetic anhydride (15 ml.), and stirred at room temperature for 5 hours. After adding the resultant mixture into water, ethyl acetate was added to the solution, adjusted to pH 7.5 and stirred for an hour. The ethyl acetate layer was separated, washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was subjected to column chromatography on silica gel with a solution of diisopropyl ether and ethyl acetate (5:1) to give 4-nitrobenzyl 7-(2-phenylacetamido)-3-acetoxymethylenecepham-4-carboxylate (660 mg.).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:14](=[O:15])[C:13]3[C:8]4[C:9](=[CH:16][C:17]5[O:21][CH2:20][O:19][C:18]=5[C:7]=4[C:5]=2[CH:6]=1)[CH:10]=[CH:11][N:12]=3.[I:22][CH3:23]>C(Cl)(Cl)Cl>[CH3:23][N+:12]1[CH:11]=[CH:10][C:9]2[C:8]3=[C:7]([C:18]4[O:19][CH2:20][O:21][C:17]=4[CH:16]=2)[C:5]2[C:4]([C:14](=[O:15])[C:13]=13)=[CH:3][CH:2]=[CH:1][CH:6]=2.[I-:22]
Reactant: O=C1c2ccccc2-c2c3c(cc4ccnc1c24)OCO3
Reactant: CI
Solvent: ClC(Cl)Cl
Product: C[n+]1ccc2cc3c(c4c2c1C(=O)c1ccccc1-4)OCO3
Product: [I-]

Procedure:
Liriodenine methiodide was prepared from the liriodenine isolated in accordance with Example 1. A 2.71 gm sample of liriodenine was reflexed in 30 ml of chloroform and then 10 ml of iodomethane was added. After 24 hours at reflux, the solution was cooled, excess iodomethane removed, and the red crystals filtered. Crystallization from methanol yielded 2.24 gm liriodenine methiodide, mp 235 d.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:9]2[CH2:19][OH:20])=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.[Si:32](Cl)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:9]2[CH2:19][O:20][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])=[CH:21][CH:22]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(Cn2cc(-c3ccccc3)nc2CO)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(Cn2cc(-c3ccccc3)nc2CO[Si](C)(C)C(C)(C)C)cc1
Yield: 90 %

Procedure:
Treat a solution of 1-(4-methoxybenzyl)-2-hydroxymethyl-4-phenylimidazole (1.68 g, 5.71 mmol) in CH2Cl2 (35 mL) with N,N-diisopropylethylamine (3.2 mL, 18.4 mmol) and tert-butyldimethylsilyl chloride (TBSCl) (1.46 g, 9.69 mmol) at room temperature for 60 hours. Quench with H2O (40 mL), extract with CH2Cl2 (100 mL), dry (Na2SO4), and concentrate in vacuo. Purify the residue by flash chromatography (SiO2, hexane/EtOAc 20:1→9:1) to provide 2.09 g (90% yield). MS (ES+): m/z=409 (M+H)+
Reaction SMILES: [C:1]([C:3]1[O:4][C:5]2[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:6]=2[C:7](=[O:9])[CH:8]=1)#[N:2].[Cl:15][CH2:16][CH2:17][CH2:18]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([C:3]1[O:4][C:5]2[CH:13]=[C:12]([O:14][CH2:18][CH2:17][CH2:16][Cl:15])[CH:11]=[CH:10][C:6]=2[C:7](=[O:9])[CH:8]=1)#[N:2]
Reactant: ClCCCBr
Reactant: N#Cc1cc(=O)c2ccc(O)cc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1cc(=O)c2ccc(OCCCCl)cc2o1
Yield: 51 %

Procedure:
A mixture of 2.43 g (13 mmol) of 2-cyano-7- hydroxy-4-oxo-4H-1-benzopyran, 2.04 g (13 mmol) of 3-chlorobromopropane and 1.80 g (13 mmol) of potassium carbonate was refluxed in 250 ml dry acetone overnight with heating. After evaporating to dryness, the residue was extracted with chloroform (3×100 ml), and dried with sodium sulfate. The chloroform solution was evaporated to one-third of the original volume to which was added n-hexane. The white precipitate was collected by filtration, washed with n-hexane and dried in vacuum to obtain 2-cyano-7-(3-chloropropyloxy)-4-oxo-4H-1-benzopyran (yield 51%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[CH2:12][C:13]#[N:14].[OH-:15].[Na+].OO>CO.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:10])([F:11])[F:9])[C:3]=1[CH2:12][C:13]([NH2:14])=[O:15]
Reactant: [OH-]
Reactant: N#CCc1c(F)cccc1C(F)(F)F
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CO
Product: NC(=O)Cc1c(F)cccc1C(F)(F)F
Temperature: 40 °C

Procedure:
20 g (98.5 mmol) of 2-fluoro-6-trifluoromethyl-phenyl-acetonitrile is dissolved in 150 ml of methanol. It is adjusted to pH 10 with sodium hydroxide solution and heated to 40° C. Then, 15 ml (132.3 mmol) of hydrogen peroxide (30%) is instilled, diluted with 25 ml of water, and the pH is kept between 9-10 by simultaneous addition of sodium hydroxide solution. A solid precipitates with foaming. After completion of the addition, it is stirred for 30 more minutes, allowed to cool off, suctioned off from the solid, washed with water and dried in a vacuum. The title compound is obtained in crystalline form.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1(/[CH:35]=[C:36](\[C:40]2[CH:45]=[CH:44][C:43]([S:46]([CH3:49])(=[O:48])=[O:47])=[CH:42][CH:41]=2)/[C:37]([OH:39])=O)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:50][C:51]1[S:52][CH:53]=[CH:54][N:55]=1>C(Cl)Cl>[CH:28]1(/[CH:35]=[C:36](\[C:40]2[CH:45]=[CH:44][C:43]([S:46]([CH3:49])(=[O:48])=[O:47])=[CH:42][CH:41]=2)/[C:37]([NH:50][C:51]2[S:52][CH:53]=[CH:54][N:55]=2)=[O:39])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: CS(=O)(=O)c1ccc(/C(=C\C2CCCCCC2)C(=O)O)cc1
Reactant: Nc1nccs1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(/C(=C\C2CCCCCC2)C(=O)Nc2nccs2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 43.3 %

Procedure:
A solution of triphenylphosphine (8.08 g, 30.8 mmol) in methylene chloride (100 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (5.48 g, 30.8 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with a solution of (E)-3-cycloheptyl-2-(4-(methanesulfonyl)-phenyl)-acrylic acid (4.97 g, 15.41 mmol) in methylene chloride (20 mL). The clear solution was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 1.5 h. The reaction mixture was then treated with 2-aminothiazole (4.63 g, 46.23 mmol), and the resulting suspension was stirred for 2 d at 25° C. The reaction mixture was then concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (250 mL) and a 1N aqueous hydrochloric acid solution (150 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×150 mL). The combined organic extracts were successively washed with a saturated aqueous sodium bicarbonate solution (1×250 mL) and a saturated aqueous sodium chloride solution (1×200 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 5/1 to 3/2 hexanes/ethyl acetate) afforded (E)-3-cycloheptyl-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-acrylamide (2.7 g, 43%) as an amorphous solid. This compound was dissolved in acetonitrile (˜55 mL) and stored overnight at 25° C. The solids were collected by filtration and washed with acetonitrile (5 mL) to obtain (E)-3-cycloheptyl-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-acrylamide (2.1 g, 33%) as a crystalline solid: mp 163-165° C.; EI-HRMS m/e calcd for C20H24N2O3S2 (M+) 404.1253, found 404.1251.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4](=[O:10])[CH2:5][CH2:6][C:7]([OH:9])=[O:8].[CH3:11]O>Cl>[ClH:1].[NH2:2][CH2:3][C:4](=[O:10])[CH2:5][CH2:6][C:7]([O:9][CH3:11])=[O:8]
Reactant: NCC(=O)CCC(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)CCC(=O)CN
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a 500 ml glass reactor containing 200 ml methanol, was added 1 gram 5-amino-levulinic acid hydrochloride and 1 drop conc. HCl. The reaction mixture was then stirred overnight at 60° C. The progress of the esterification was followed by 1H-NMR. Excess methanol was removed by distillation, and the product further dried, under vacuum at 30-40° C., giving methyl 5-aminolevulinate hydrochloride. The structure was confirmed by 1H-NMR in DMSO-d6.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([OH:16])=O)[CH2:9]2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:59][N:60]1[C:64]([NH2:65])=[CH:63][CH:62]=[N:61]1>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:65][C:64]3[N:60]([CH3:59])[N:61]=[CH:62][CH:63]=3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)[N:3]=1
Reactant: Cn1nccc1N
Reactant: N#Cc1ccc(-c2cc(N3CCC[C@H](C(=O)O)C3)nc(N)n2)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1nccc1NC(=O)[C@H]1CCCN(c2cc(-c3ccc(C#N)c(F)c3)nc(N)n2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97.5 %

Procedure:
To a solution of (3S)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-3-piperidinecarboxylic acid (150 mg, 0.439 mmol) and HATU (201 mg, 0.527 mmol) in DMF (3 mL) was added Hunig's base (0.15 mL, 0.88 mmol), and the mixture was stirred at room temperature for 15 minutes. 1-Methyl-1H-pyrazol-5-amine (51 mg, 0.53 mmol) was added, and the reaction mixture was stirred at room temperature for 0.5 hours. LCMS showed the reaction was completed. The reaction was poured onto water, and EtOAc was added to extract the product. The product stayed in the EtOAc layer. The organic solution was concentrated to dryness to give the title compound (180 mg) as a yellow solid. LC-MS (ES) m/z=421 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][NH:5][CH2:6][C:7]1[CH:8]=[C:9]([C:13]2[O:14][C:15]3[C:21]([C:22](OC)=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)[CH:10]=[CH:11][CH:12]=1.O.[NH4+:28]>C(O)C>[CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][NH:5][CH2:6][C:7]1[CH:8]=[C:9]([C:13]2[O:14][C:15]3[C:21]([C:22]([NH2:28])=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: COC(=O)c1cccc2nc(-c3cccc(CNCCN(C)C)c3)oc12
Reactant: [NH4+]
Solvent: CCO
Solvent: O
Product: CN(C)CCNCc1cccc(-c2nc3cccc(C(N)=O)c3o2)c1
Temperature: 30 °C
Reaction time: 1 h
Yield: 10.6 %

Procedure:
Methyl 2-(3-((2-(dimethylamino)ethylamino)methyl)phenyl)benzo[d]oxazole-7-carboxylate (100 mg, 0.28 mmol) and ammonium water (58.8 mg, 1.68 mmol) were added to ethanol (30 mL) and the mixture was stirred at 30° C. for 1 hr. Evaporation under reduced pressure and purification with pre-HPLC gave 2-(3-((2-(dimethylamino)ethylamino)methyl)phenyl)benzo[d]oxazole-7-carboxamide (10.0 mg, yield 11%). 1H-NMR (400 MHz, DMSO-d6) δ 2.85 (s, 6H), 3.37-3.42 (d, J=20 Hz, 4H), 4.36 (s, 2H), 7.48-7.52 (t, J=8 Hz, 1H), 7.71-7.97 (m, 6H), 8.35-8.37 (d, J=8 Hz, 1H), 8.43 (s, 1H); LC-MS (ESI) m/z 339 [M+1]+.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]=[CH:9][CH3:10].B(F)(F)F>F>[CH:9]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[OH:7])([CH3:10])[CH3:8]
Reactant: C=CC
Reactant: Oc1ccccc1
Agent: F
Agent: FB(F)F
Product: CC(C)c1ccccc1O
Reaction time: 0.25 h
Yield: 59 %

Procedure:
9.4 g (0.1 mol) phenol is dissolved in 100 ml of anhydrous hydrogen fluoride and while keeping the solution at about 0° C., 2 g (0.05 mol) propylene was introduced and stirring continued for 15 minutes. The reaction mixture is then saturated with boron trifluoride and heated to 100° C. for 30 minutes. After workup, 59% isopropylphenol is obtained, containing 99% meta isomer, together with 31% phenol and some diisopropylphenols.
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C@H:6]([C:13]2[CH:14]=[CH:15][C:16]([Cl:20])=[C:17]([Cl:19])[CH:18]=2)[CH2:5][CH2:4]1.[C:21]([OH:26])(=[O:25])[C@H:22]([CH3:24])[OH:23]>C(O)(C)C.C(OCC)(=O)C>[CH3:1][NH:2][C@@H:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C@H:6]([C:13]2[CH:14]=[CH:15][C:16]([Cl:20])=[C:17]([Cl:19])[CH:18]=2)[CH2:5][CH2:4]1.[C:21]([O-:26])(=[O:25])[C@H:22]([CH3:24])[OH:23]
Reactant: C[C@H](O)C(=O)O
Agent: CN[C@H]1CC[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: C[C@H](O)C(=O)[O-]
Temperature: 40 °C

Procedure:
Sertraline base (10 g)was dissolved in isopropanol (150 mL) in a 500 mL round bottom flask and the solution was heated to 40° C. L-Lactic acid (3.4 g) was separately dissolved in ethyl acetate (25 mL). The L-lactic acid solution was added in small portions to the solution in the round bottom flask which was constantly stirred with a magnetic stirrer. The reaction mixture was stirred at 40° C. for 4 hours after the addition of the L-lactic acid solution was complete. The reaction mixture was then allowed to cool to room temperature and the solids were filtered. The solids were washed with 50 mL of hexane and then dried under vacuum at 40° C. for 48 hours. The dried solid was identified as the L-lactate salt of sertraline. The yield was calculated to be 94%. mp 153° C.
Reaction SMILES: C1CO[C:8]23OCCO[C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([CH2:16]/[C:17](=[N:28]\[O:29][CH2:30][CH3:31])/[CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1.C([C@@H]1C2[C@](C)(CCC(=[O:52])C2)[C@@H]2[C@H]([C@H]3[C@@](CC2)(C)C(=O)CC3)C1)#N>>[CH2:30]([O:29]/[N:28]=[C:17]1\[CH2:16][C@@H:15]2[C@@H:25]([C@:23]3([CH3:24])[CH:18]\1[CH2:19][C:20](=[O:52])[CH2:21][CH2:22]3)[CH2:26][CH2:27][C@@:4]1([CH3:5])[C@H:6]2[CH2:7][CH2:8][C:3]1=[O:2])[CH3:31]
Reactant: CCO/N=C1\C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC24OCCOC23OCCO4)[C@@]2(C)CCCCC12
Reactant: C[C@]12CCC(=O)CC1[C@@H](C#N)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Product: CCO/N=C1\C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Yield: 100 %

Procedure:
The title compound II-av was prepared in 100% yield from 3,3:17,17-bis(ethylendioxy)-6(E)-ethoxyiminoandrostane by the procedure described above for the preparation of 6α-cyanoandrostane-3,17-dione (II-ac, Prepn. 3). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 4.03 (2H, q), 3.40 (1H, dd), 2.70-1.12 (19H, m), 1.20 (3H, t), 1.01 (3H, s), 0.87 (3H, s).
Reaction SMILES: CN1CCCC1=O.[C:8]([OH:14])(=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:27][C:28](=[N:58]O)[C:29]1[CH:57]=[CH:56][C:32]([O:33][CH2:34][CH2:35][CH2:36][CH:37]2[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][CH2:45][O:46][C:47]3[CH:55]=[CH:54][C:50]([C:51]([NH2:53])=[O:52])=[CH:49][CH:48]=3)[CH2:39][CH2:38]2)=[CH:31][CH:30]=1>O.C(OCC)(=O)C>[NH2:58][C:28](=[N:27][O:13][C:8](=[O:14])[C:9]([CH3:12])([CH3:11])[CH3:10])[C:29]1[CH:57]=[CH:56][C:32]([O:33][CH2:34][CH2:35][CH2:36][CH:37]2[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][CH2:45][O:46][C:47]3[CH:48]=[CH:49][C:50]([C:51]([NH2:53])=[O:52])=[CH:54][CH:55]=3)[CH2:39][CH2:38]2)=[CH:31][CH:30]=1
Reactant: NC(=O)c1ccc(OCCCN2CCC(CCCOc3ccc(C(N)=NO)cc3)CC2)cc1
Reactant: CC(C)(C)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)C(=O)ON=C(N)c1ccc(OCCCC2CCN(CCCOc3ccc(C(N)=O)cc3)CC2)cc1
Reaction time: 0.33 h
Yield: 68.4 %

Procedure:
To an N-methyl-2-pyrrolidone (10 mL) solution of 0.47 g of pivalic acid was added 0.76 g of 1,1′-carbonyldiimidazole at room temperature, which was then stirred at the same temperature for 1 hour and 20 minutes. An N-methyl-2-pyrrolidone (10 mL) solution of 1.00 g of 4-{3-[4-(3-{4-[amino(hydroxyimino)methyl]phenoxy}propyl)-1-piperidinyl]propoxy}benzamide=oxime was added to the mixture at room temperature, which was then stirred at the same temperature for 2 hours. The reaction mixture was added a mixture of ethyl acetate and water. The precipitate was collected by filtration and washed with ethyl acetate to provide 0.81 g of 4-{3-[4-(3-{4-[amino(2,2-dimethylpropionyloxyimino)methyl]phenoxy}propyl)-1-piperidinyl]propoxy}benzamide=O-(2,2-dimethylpropionyl)oxime as white solid form.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[C:10]2[C:5](=[CH:6][C:7]([N:11]3[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]4[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=4)[C:12]3=[O:26])=[CH:8][CH:9]=2)[NH:4][CH2:3]1.C(O)(=O)C(O)=O.CS(O[CH:39]1[CH2:42][N:41]([CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)[CH2:40]1)(=O)=O>>[CH:43]1([N:41]2[CH2:42][CH:39]([N:4]3[C:5]4[C:10](=[CH:9][CH:8]=[C:7]([N:11]5[C:15](=[O:16])[C:14]([CH3:17])([CH3:18])[N:13]([CH2:19][C:20]6[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=6)[C:12]5=[O:26])[CH:6]=4)[C:2]([CH3:27])([CH3:1])[CH2:3]3)[CH2:40]2)[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1
Reactant: CS(=O)(=O)OC1CN(C2CCCCC2)C1
Reactant: CC1(C)CNc2cc(N3C(=O)N(Cc4ccncc4)C(C)(C)C3=O)ccc21
Agent: O=C(O)C(=O)O
Product: CC1(C)CN(C2CN(C3CCCCC3)C2)c2cc(N3C(=O)N(Cc4ccncc4)C(C)(C)C3=O)ccc21

Procedure:
prepared as described for example 96 by reaction of 3-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-5,5-dimethyl-1-pyridin-4-ylmethylimidazolidine-2,4-dione with 1-cyclohexylazetidin-3-yl methanesulphonate oxalate