Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([OH:12])=[C:7]([Cl:13])[CH:6]=1)(=[O:3])[CH3:2].[OH-].[K+].[F:16][C:17]([F:24])([F:23])[C:18]([F:22])=[C:19]([F:21])[F:20]>CN(C)C=O>[C:1]([NH:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([O:12][C:19]([F:21])([F:20])[CH:18]([F:22])[C:17]([F:24])([F:23])[F:16])=[C:7]([Cl:13])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(Cl)c(O)cc1Cl
Reactant: FC(F)=C(F)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(Cl)c(OC(F)(F)C(F)C(F)(F)F)cc1Cl
Temperature: 70 °C
Reaction time: 20 h

Procedure:
47 g of 4-acetylamino-2,5-dichlorophenol together with 154 g of 90% potassium hydroxide solution and 130 ml of dimethylformamide are stirred in an autoclave. 75.8 g of hexafluoropropylene are then pressed into the closed autoclave. The mixture is stirred for 20 hours at 70° C. under the pressure existing in the autoclave. After cooling, the mixture is concentrated by rotary evaporation and the residue is dissolved in methylene chloride. The resultant solution is washed with water, dried over Na2SO4 and concentrated. The crude product obtained as residue is chromatographed through a column of silica gel (length: 1 m; diameter: 10 cm) eluted with an 11:1 mixture of toluene and acetone, affording 4-acetylamino-2,5-dichloro-1-(1,1,2,3,3,3-hexafluoropropyloxy)benzene in the form of pale yellow crystals (m.p.: 93°-95° C.), 26 g of which are kept for 10 hours under reflux with 110 ml of ethanol and 35.6 ml of 37% hydrochloric acid. The reaction mixture is then concentrated, diluted with ice/water and made weakly alkaline. The product is extracted from the mixture with methylene chloride. The organic extract phase is washed with water, dried over Na2SO4 and concentrated. The residue is purified by distillation, thus affording the title compound of the formula ##STR12## as a colourless liquid with a boiling point of 81°-83° C./0.05 torr.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:21]=1)=[CH:5]2.[CH2:30]([S:32](Cl)(=[O:34])=[O:33])[CH3:31]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][N:27]([S:32]([CH2:30][CH3:31])(=[O:34])=[O:33])[CH2:26][CH2:25]3)[N:21]=1)=[CH:5]2
Reactant: CCS(=O)(=O)Cl
Reactant: Clc1cc(NC2CCCC2)c2[nH]c(C3=N[C@H](CCN4CCNCC4)CS3)cc2c1
Product: CCS(=O)(=O)N1CCN(CC[C@@H]2CSC(c3cc4cc(Cl)cc(NC5CCCC5)c4[nH]3)=N2)CC1

Procedure:
{5-Chloro-2-[(R)-4-(2-piperazin-1-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-cyclopentyl-amine prepared in Example 160 and ethylsulfonylchloride were reacted according to the same procedure as Step B of Preparation 29 to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[OH:8].[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1>[C:22]([O:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[O:8][C:14](=[O:15])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(C=Cc1cc(O)c(O)c([N+](=O)[O-])c1)c1ccccc1
Solvent: C1CCOC1
Product: O=C(C=Cc1cc(OC(=O)c2ccccc2)c(OC(=O)c2ccccc2)c([N+](=O)[O-])c1)c1ccccc1

Procedure:
1.0 g of the product obtained in Example 8 and 2.0 ml of benzoylchloride were dissolved in 5 ml of tetrahydrofuran. Tetrahydrofuran was distilled off to a great extend and the residue was refluxed for 2 h. After cooling ether was added to the mixture and the product was filtered and triturated with ethylmethylketone. Yield 0.50 g (29%), m.p. 206°-210° C.
Reaction SMILES: [Cl:1][CH:2]1[N:5]([CH:6]([C:23]([CH3:25])=[CH2:24])[C:7]([O:9][CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[C:4](=[O:26])[CH:3]1[NH:27][C:28](=[O:37])[CH2:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(OC)=O.[Cl:42]OC(C)(C)C>C(OCC)(=O)C>[Cl:1][CH:2]1[N:5]([CH:6]([C:23]([CH2:25][Cl:42])=[CH2:24])[C:7]([O:9][CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[C:4](=[O:26])[CH:3]1[NH:27][C:28](=[O:37])[CH2:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: C=C(C)C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1Cl
Reactant: CC(C)(C)OCl
Solvent: COC=O
Solvent: CCOC(C)=O
Product: C=C(CCl)C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 5.18 g. portion of diphenylmethyl 2-(4-chloro-3-phenoxyacetamido-2-oxo-1-azetidinyl)-3-methyl-3-butenoate was dissolved in 200 ml. of methyl formate, and 1.71 ml. of t-butyl hypochlorite was added. The mixture was stirred at room temperature for 16 hours. It was then evaporated under vacuum to obtain a white foam, which was taken up in ethyl acetate and washed three times with water. The organic layer was then decolorized with activated carbon, dried over magnesium sulfate, and evaporated to a white foam. The foam was taken up in 100 ml. of dry diethyl ether, from which 1.12 g. of the desired product was obtained in crystalline form. The product was analyzed by infrared in chloroform, showing maxima at 1795, 1745 and 1695 cm-1 ; a second spectrum in methanol showed maxima at 1775, 1740 and 1695 cm-1. NMR analysis on a 100 megacycle instrument in CDCl3 showed the following 6 values. 4.24(s); 4.63(s); 5.73(center of q); 6.2(d); 5.09(s); 5.33(s); 5.5(s)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)=[O:6].C([O:27][C:28]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)=[O:29])C.COCCOC.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[CH3:24][O:23][C:22]1[CH:21]=[CH:20][C:4]([C:5](=[O:6])[NH:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:10][CH:9]=2)=[CH:3][C:2]=1[C:33]1[CH:34]=[CH:35][C:30]([C:28]([OH:29])=[O:27])=[CH:31][CH:32]=1
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Reactant: COc1ccc(C(=O)Nc2ccc(N3CCOCC3)cc2)cc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(C(=O)Nc2ccc(N3CCOCC3)cc2)cc1-c1ccc(C(=O)O)cc1

Procedure:
A mixture of 3-Bromo-4-methoxy-N-(4-morpholin-4-yl-phenyl)-benzamide (788 mg) and 4-(ethoxycarbonyl)-phenyl boronic acid (564 mg) in 2:1 DME:water (15 ml) containing cesium carbonate (1.31 g) and tetrakis(triphenylphosphine)palladium0 (232 mg) was heated to reflux for 18 h.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].Cl[CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[CH2:19][CH2:18]1.Cl>>[CH3:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[N:20]1[CH2:19][CH2:18][N:17]([CH2:16][CH2:15][CH2:14][O:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH2:4][CH2:5][CH2:6][C:7]3=[O:12])[CH2:22][CH2:21]1
Reactant: O=C1CCCc2c(O)cccc21
Reactant: Cc1ccccc1N1CCN(CCCCl)CC1
Agent: Cl
Product: Cc1ccccc1N1CCN(CCCOc2cccc3c2CCCC3=O)CC1
Yield: 73.4 %

Procedure:
from 5-hydroxy-1-oxotetraline and 1-(3-chloropropyl)-4 -(2-methylphenyl)-piperazine; yield 73.4% of theory; m.p. of the hydrochloride (recrystallized from water) 243°-245°C;
Reaction SMILES: COC1C=CC(CN2CCN(CC3N=CC([NH:21][C:22]([C:24]4[CH:25]=[CH:26][C:27]([C:34]5[C:39]([Cl:40])=[C:38]([O:41][CH3:42])[CH:37]=[C:36]([O:43][CH3:44])[C:35]=5[Cl:45])=[C:28]5[C:33]=4[N:32]=[CH:31][CH:30]=[CH:29]5)=[O:23])=CC=3)CC2)=CC=1.N[C:49]1[N:54]=[CH:53][C:52]([CH2:55][N:56]([CH3:62])[CH2:57][CH2:58][N:59]([CH3:61])[CH3:60])=[CH:51][CH:50]=1>C(Cl)Cl.CO>[CH3:60][N:59]([CH3:61])[CH2:58][CH2:57][N:56]([CH2:55][C:52]1[CH:51]=[CH:50][C:49]([NH:21][C:22]([C:24]2[CH:25]=[CH:26][C:27]([C:34]3[C:39]([Cl:40])=[C:38]([O:41][CH3:42])[CH:37]=[C:36]([O:43][CH3:44])[C:35]=3[Cl:45])=[C:28]3[C:33]=2[N:32]=[CH:31][CH:30]=[CH:29]3)=[O:23])=[N:54][CH:53]=1)[CH3:62]
Reactant: COc1ccc(CN2CCN(Cc3ccc(NC(=O)c4ccc(-c5c(Cl)c(OC)cc(OC)c5Cl)c5cccnc45)cn3)CC2)cc1
Reactant: CN(C)CCN(C)Cc1ccc(N)nc1
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN(C)CCN(C)C)cn3)c3ncccc23)c1Cl
Temperature: 25 °C
Reaction time: 14 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 5-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid (6-piperazin-1-ylmethyl-pyridin-3-yl)-amide (Example 170), N-(6-amino-pyridin-3-ylmethyl)-N,N′,N′-trimethyl-ethane-1,2-diamine (prepared as described in Example 26 but using N,N,N′-trimethyl-ethane-1,2-diamine in Step 26.2), and stirring the reaction mixture for 14 h at rt. Title compound: ESI-MS: 568.0 [M+H]+; TLC: Rf=0.15 (DCM/MeOH, 9:1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:6]([O:8][CH3:9])=[O:7])#[CH:2].I[C:15]1[CH:16]=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2.C(N(C(C)C)CC)(C)C>CN(C=O)C.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>[CH3:13][C:12]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:1]#[C:2][C:15]1[CH:16]=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2
Reactant: C#Cc1cc(C(=O)OC)ccc1C
Reactant: Ic1cnc2ccccc2c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C)c(C#Cc2cnc3ccccc3c2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of methyl 3-ethynyl-4-methylbenzoate (0.341 g, 2 mmol), 3-iodoquinoline (0.5 g, 2 mmol), Pd(PPh3)4 (0.11 g, 0.01 mmol), CuI (0.179 g, 0.1 mmol) and diisopropylethylamine (0.5 ml, 3 mmol) in DMF (15 ml) was stirred at ambient temperature for 12 hrs under an atmosphere of nitrogen. The reaction mixture was concentrated and the crude product was purified by flash chromatography on silica gel (elution with 10% ethyl acetate in n-hexane) to provide methyl 4-methyl-3-[(quinolin-3-yl)ethynyl]benzoate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[OH:9]O>C(O)(=O)C.O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N+:3]=1[O-:9]
Reactant: OO
Reactant: Cc1ccc(C)nc1
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(C)[n+]([O-])c1
Temperature: 90 °C
Reaction time: 48 h

Procedure:
A mixture of 2,5-dimethylpyridine (12.5 g, 0.12 mol) and 30% hydrogen peroxide (30 mL) in acetic acid (25 mL) was stirred at 90° C. for 48 h. The reaction mixture was diluted with water (50 mL) and concentrated to a volume of approximately 25 mL. The concentrated solution was neutralized with solid sodium carbonate, extracted with DCM (100 mL×3), dried with anhydrous sodium sulfate, and concentrated to give 14.4 g of the product as a yellow oil. MS (ESI): m/z 124.1 [M+H]+.
Reaction SMILES: [F:1][CH2:2][C@@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:4].[Cl:11][S:12](O)(=[O:14])=[O:13].P(Cl)(Cl)(Cl)(Cl)Cl>ClCCl>[F:1][CH2:2][C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([S:12]([Cl:11])(=[O:14])=[O:13])=[CH:7][CH:6]=1)[CH3:4]
Reactant: O=S(=O)(O)Cl
Reactant: C[C@@H](CF)c1ccccc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: C[C@@H](CF)c1ccc(S(=O)(=O)Cl)cc1
Temperature: 2.5 °C
Reaction time: 0.33 h
Yield: 11.7 %

Procedure:
1.3 g of ((R)-2-fluoro-1-methyl-ethyl)-benzene (9.4 mmol) were dissolved in 50 ml of dichloromethane. At 0-5° C., 1.1 g of chlorosulfonic acid (9.4 mmol), dissolved in 10 ml of dichloromethane were added dropwise. The reaction mixture was stirred for 20 min at 0-5° C. and then added to a solution of 2.15 g of phosphorous pentachloride dissolved in 40 ml of dichloromethane. The reaction mixture was stirred for 30 min at 0-5° C. and 1 h at room temperature. The solvent was evaporated, 100 ml of diethyl ether were added, the mixture was washed once with 150 ml of water, and the organic layer was dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The crude product was purified via silica gel chromatography with n-heptane-dichloromethane (1:1) as eluent to give 0.261 g of the title compound.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][C:6]1[NH:11][C:10]2[S:12][CH:13]=[C:14]([CH2:15][O:16][CH2:17][O:18][CH3:19])[C:9]=2[S:8](=[O:21])(=[O:20])[N:7]=1)C.O.[OH-].[Li+]>O1CCCC1.O>[CH3:19][O:18][CH2:17][O:16][CH2:15][C:14]1[C:9]2[S:8](=[O:21])(=[O:20])[N:7]=[C:6]([CH2:5][C:4]([OH:22])=[O:3])[NH:11][C:10]=2[S:12][CH:13]=1
Reactant: CCOC(=O)CC1=NS(=O)(=O)c2c(COCOC)csc2N1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COCOCc1csc2c1S(=O)(=O)N=C(CC(=O)O)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.1 %

Procedure:
To a solution of (7-methoxymethoxymethyl-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-3-yl)-acetic acid ethyl ester (0.54 g, 1.55 mmol) in tetrahydrofuran (5 mL) and water (5 mL) was added lithium hydroxide monohydrate (0.33 g, 7.75 mmol). The reaction was stirred at 25° C. for 1 h before it was cooled to 0° C. The reaction was quenched via the addition of 6.0 M aqueous hydrochloric acid solution until a pH of 1-2 was reached. The resulting mixture was extracted with ethyl acetate (3×10 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo to afford the crude product, (7-methoxymethoxymethyl-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-3-yl)-acetic acid (0.39 g, 1.21 mmol, 78%), which was used in the next step without further purification.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:18]2[NH:22][C:21]([C:23](=[S:25])[NH2:24])=[C:20]([CH3:26])[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:28][CH:29](OCC)OCC>CN(C)C(=O)C.C(OCC)(=O)C>[CH:1]1([CH2:6][CH:7]([C:18]2[NH:22][C:21]([C:23]3[S:25][CH:28]=[CH:29][N:24]=3)=[C:20]([CH3:26])[CH:19]=2)[C:8]2[CH:9]=[CH:10][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][CH:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(C(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)[nH]c1C(N)=S
Reactant: CCOC(CBr)OCC
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Cc1cc(C(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)[nH]c1-c1nccs1
Temperature: 60 °C
Reaction time: 2 h
Yield: 47.1 %

Procedure:
To a solution (3 mL) of 5-{2-cyclopentyl-1-[4-(methylsulfonyl)phenyl]ethyl}-3-methyl-1H-pyrrole-2-carbothioamide (120 mg) in N,N-dimethylacetamide was added 2-bromo-1,1-diethoxyethane (125 mg), and the mixture was stirred at 60° C. for 2 hr, then at 100° C. for 4 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (60 mg, yield 47%) was obtained as colorless amorphous crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). MS: 415 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([C:11](=O)[CH2:12][CH3:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[ClH:15].[NH2:16]O>N1C=CC=CC=1>[ClH:15].[CH3:1][C:2]1[CH:10]=[C:9]([CH:11]([NH2:16])[CH2:12][CH3:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: NO
Reactant: CCC(=O)c1ccc(C(=O)O)c(C)c1
Agent: Cl
Solvent: c1ccncc1
Product: CCC(N)c1ccc(C(=O)O)c(C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.4 %

Procedure:
To a mixture of methyl 4-propionyl benzoic acid (0.50 g) and pyridine (5.0 mL) was added hydroxylamine hydrochloride (0.54 g) under ice-cooling, followed by stirring at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, to the residue were added ethyl acetate and a 10% aqueous citric acid solution and the aqueous layer was extracted with ethyl acetate. The organic layer was combined, and washed with a 10% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution, water, and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and to the residue was added ethanol (15 mL). To the reaction mixture were added a suspension of Raney nickel (2.0 mL) in ethanol (15 mL), and concentrated aqueous ammonia (3.0 mL), followed by stirring at room temperature for 14 hours under a hydrogen atmosphere of 3 atm. The insoluble materials in the reaction mixture were separated by filtration through Celite, and the filtrate was concentrated under reduced pressure. To the residue was added diethyl ether (10 mL), and a 4 M-hydrogen chloride/dioxane solution (1.0 mL) was added thereto under ice-cooling. The precipitated crystal was collected by filtration and washed with diethyl ether to obtain methyl 4-(1-amino propyl)benzoic acid hydrochloride (0.51 g).
Reaction SMILES: [CH:1]1([CH2:4][C:5]([OH:7])=O)[CH2:3][CH2:2]1.Cl.C[O:10][C:11](=[O:15])[C@H:12]([CH3:14])[NH2:13]>>[CH:1]1([CH2:4][C:5]([NH:13][C@H:12]([C:11]([OH:15])=[O:10])[CH3:14])=[O:7])[CH2:2][CH2:3]1
Reactant: COC(=O)[C@H](C)N
Reactant: O=C(O)CC1CC1
Agent: Cl
Product: C[C@H](NC(=O)CC1CC1)C(=O)O

Procedure:
Following General Procedure A above using cyclopropylacetic acid (Aldrich) and L-alanine methyl ester hydrochloride (Sigma), the title compound was prepared as an oil. The reaction was monitored by tlc on silica gel (Rf=0.15 in 25% ethyl acetate/hexanes) and purification was by flash column chromatography using 25% ethyl acetate/hexanes as the eluant.
Reaction SMILES: [C:1]1([CH:7]2[CH:12]([CH3:13])[CH:11]([NH:14][C:15](=[O:27])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:10]([CH3:28])[CH:9]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC1(C)O[O:37]1>CC(C)=O>[OH:37][N:8]1[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:12]([CH3:13])[CH:11]([NH:14][C:15](=[O:27])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:10]([CH3:28])[CH:9]1[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC1(C)OO1
Reactant: CCCCCCCCCCCC(=O)NC1C(C)C(c2ccccc2)NC(c2ccccc2)C1C
Solvent: CC(C)=O
Product: CCCCCCCCCCCC(=O)NC1C(C)C(c2ccccc2)N(O)C(c2ccccc2)C1C

Procedure:
Following the general procedure of Example 2 and using 8.56 g (18.5 mmol) of N-(2,6-diphenyl-3,5-dimethylpiperidin-4-yl)lauramide, prepared in Example 11, and 462 ml of a 0.04 molar solution of dimethyldioxirane (18.5 mmol) in acetone, the title compound is isolated in a yield of 7.37 g (70%) after purification by LC (silica gel; ethyl acetate:hexanes) as a white solid melting at 58°-62° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[C:11]1([CH2:17][CH2:18][CH2:19]Br)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].CC(C)=O>O>[C:11]1([CH2:17][CH2:18][CH2:19][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: BrCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)c1ccc(OCCCc2ccccc2)cc1
Reaction time: 8 h
Yield: 58.1 %

Procedure:
A mixture of 68.1 g (0.5 mole) of 4'-hydroxyacetophenone, 100.3 g (0.5 mole) of 3-phenylpropyl bromide, 69.0 g (0.5 mole) of potassium carbonate and 500 ml of anhydrous acetone is refluxed with stirring for 8 hours. After adding 1 liter of water the product is extracted into ether, the extract is washed with water and 2 N sodium carbonate solution and dried over anhydrous sodium sulfate and the solvent is evaporated. The resulting oil (125.8 g) begins to crystallize and yields after two recrystallizations from ether-hexane and ether, respectively, 73.9 g (58% yield) of the desired product, M.P. 80°-81°.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1.[H-].[Na+].[N+:18]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1)([O-:20])=[O:19].O>C1COCC1>[N+:18]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25][O:1][C:2]2[CH:15]=[CH:14][C:13]3[S:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[NH:5][C:4]=3[CH:3]=2)=[CH:23][CH:22]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: Oc1ccc2c(c1)Nc1ccccc1S2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc(COc2ccc3c(c2)Nc2ccccc2S3)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 37 %

Procedure:
1.08 g (5 mmol) of 2-hydroxy-10H-phenothiazine (J. Med. Chem. (1992) 35, 716) is dissolved, under argon atmosphere, in 20 ml anhydrous THF in a flask. The solution is then cooled down to 0° C. and 0.22 g (5.5 mmol) of NaH (60%) is added by portions. After agitation for 15 minutes, 1.2 g (5.5 mmol) of 4-nitrobenzyl bromide is added by portions and the reaction mixture is agitated for 15 hours at 20° C. before being poured into 50 ml of ice-cooled water. The product is extracted twice with 25 ml CH2Cl2 and the organic solution is washed successively with 25 ml of water and 25 ml of salt water. After drying over MgSO4, filtration and concentration under vacuum, the evaporation residue is purified on a silica column (eluent: CH2Cl2/EtOH: 99/1 to 98/2). After concentration of the purest fractions, a maroon solid is obtained, which is recrystallized using isopropyl acetate. A maroon solid is finally obtained with a yield of 37%.
Reaction SMILES: N1C=CN=C1.[I:6]I.[Si:8]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]O)([C:21]([CH3:24])([CH3:23])[CH3:22])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[C:21]([Si:8]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][I:6])([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:23])([CH3:24])[CH3:22]
Reactant: CC(C)(C)[Si](OCCCCCO)(c1ccccc1)c1ccccc1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)[Si](OCCCCCI)(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 0.1 %

Procedure:
Imidazole (310 mg, 4.40 mmol), iodine (440 mg, 3.5 mmol), and a solution of 2 (1 g, 2.98 mmol) in CH2Cl2 (2 mL) were added sequentially to a 0° C. solution of PPh3 (450 mg, 3.5 mmol) in CH2Cl2 (15 mL) and kept in the dark. After 2 h, the reaction mixture was quenched by adding 20% aq. Na2S2O3 (5 mL). The aqueous layer was extracted with CH2Cl2 (2×50 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na2SO4, and the solvent was removed in vacuo. The residue was purified by careful column chromatography using 5% EtOAC/hexane to afford iodide 3 (1.25 mg, 92%). TLC: 10% EtOAc/hexane, Rf˜0.85; 1H NMR (CDCl3, 400 MHz) δ 7.67-7.62 (m, 4H), 7.45-7.35 (m, 6H), 3.67 (t, 2H, J=6.0 Hz), 3.41 (t, 2H, J=6.7 Hz), 2.03-1.93 (m, 2H), 1.72-1.64 (m, 4H), 1.04 (s, 9H).
Reaction SMILES: [N:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([NH:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]=1[OH:15])=[N+:2]=[N-:3].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([NH:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[N+:2]=[N-:3]
Reactant: BrCc1ccccc1
Reactant: CCNC(=O)c1ccc(N=[N+]=[N-])c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(N=[N+]=[N-])c(OCc2ccccc2)c1
Temperature: 55 °C
Reaction time: 3.5 h
Yield: 97 %

Procedure:
To a solution of 4-azido-N-ethyl-3-hydroxybenzamide (3.44 g) obtained in Example 133b) in DMF (50 ml) were added benzyl bromide (2.4 ml) and potassium carbonate (2.76 g), and the reaction mixture was stirred at 55° C. for 3.5 hr. The reaction mixture was allowed to cool to room temperature, water was added and the resulting precipitate was collected by filtration and washed with water to give the title compound as a brown powder (4.81 g, 97%).