Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12[C:14](=[O:15])[O:13][C:11](=[O:12])[C:9]3=[C:10]1[C:5](=[CH:6][CH:7]=[CH:8]3)[CH:4]=[CH:3][CH:2]=2.P([O-])([O-])([O-])=O.[OH:21][NH3+:22].O[NH3+].O[NH3+]>O>[OH:21][N:22]=[C:14]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]([OH:13])=[O:12])[CH:4]=[CH:3][CH:2]=1)[OH:15]
Reactant: [NH3+]O
Reactant: O=C1OC(=O)c2cccc3cccc1c23
Agent: O=P([O-])([O-])[O-]
Solvent: O
Product: O=C(O)c1cccc2cccc(C(O)=NO)c12

Procedure:
1.98 g (10.0 mmol) of 1,8-naphthalenedicarboxylic anhydride and 0.985 g (5.00 mmol) of hydroxylammonium phosphate were reacted with 2 ml of water analogously to Example 7 for 6 hours at a bath temperature of 130° C. Following cooling, the pale brown reaction mixture was digested with water, and the solid was filtered off with suction and dried. The yield was 1.89 g (89%).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]#[N:21])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N)(=[S:24])C.Cl.O1CCOCC1>C(Cl)(Cl)Cl>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][C:20](=[S:24])[NH2:21])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1csc(-c2cc3cc(CC#N)ccc3o2)n1
Reactant: CC(N)=S
Agent: Cl
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1csc(-c2cc3cc(CC(N)=S)ccc3o2)n1

Procedure:
A mixture of 4-tert-butyl-2-[5-(cyanomethyl)benzofuran-2-yl]thiazole (1.31 g) and thioacetamide in a mixture of 4N-hydrogen chloride of 1,4-dioxane (4 ml) and chloroform was stirred under reflux for 30 minutes and removed the solvent at the same temperature. The residue was washed with water to give crude 4-tert-butyl-2-[5-(thiocarbamoylmethyl)-benzofuran-2-yl]thiazole (1.23 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=O)=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Mg]Br.Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[CH2:6][CH:7]=1
Reactant: O=C1CCc2ccc(Cl)cc21
Reactant: COc1ccccc1[Mg]Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1ccccc1C1=CCc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Under an argon atmosphere, a solution of 12.80 g of 6-chloroindan-1-one (73.45 mol) from Example 16A in 60 ml of THF is added drop wise to 88 ml of a 1 M solution of 2-methoxyphenylmagnesium bromide in THF (88.0 mol) at 0° C. The reaction mixture is stirred at room temperature for 1.5 h and 200 ml of 1 N hydrochloric acid are added for working up. The mixture is extracted three times with ethyl acetate, the combined organic phases are dried over sodium sulphate, and the solvent is removed in a rotary evaporator. The residue is dissolved in 400 ml of dichloromethane, mixed with 0.10 g of 4-toluenesulphonic acid monohydrate (0.53 mol) and stirred at room temperature for 16 h. The reaction mixture is washed with saturated sodium bicarbonate solution and saturated sodium chloride solution and dried over sodium sulphate. The solvent is removed in a rotary evaporator, and the residue is purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 150:1). 12.02 g (61% of theory) of the title compound are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[C:12]([S:15][CH2:16][CH:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:18](Cl)=[O:19])(=[O:14])[CH3:13]>C(=O)([O-])O.[Na+].O.O1CCCC1>[C:12]([S:15][CH2:16][CH:17]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:18]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6])=[O:19])(=[O:14])[CH3:13]
Reactant: Cc1ccc(C(=O)O)cc1N
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)SCC(Cc1ccccc1)C(=O)Nc1cc(C(=O)O)ccc1C
Yield: 52.4 %

Procedure:
3-Amino-4-methylbenzoic acid (1.5 g) is dissolved in a solution of sodium hydrogen carbonate (1.68 g) in water (25 ml), and to the mixture is added dropwise a solution of 2-acetylthiomethyl-3-phenylpropionyl chloride (2.86 g) in tetrahydrofuran (8 ml) with vigorously stirring, and the mixture is stirred at room temperature for 3 hours. Tetrahydrofuran is distilled off at a low temperature under reduced pressure, and the residue is washed with diethyl ether and acidified with hydrochloric acid, and the resulting oily substance is extracted with ethyl acetate. The extract is washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and then the solvent is distilled off under reduced pressure. The oily residue is purified by a medium pressure column chromatography with CHP-20P (eluant, water-acetonitrile). The fractions containing the desired compound are collected, and acetonitrile is distilled off under reduced pressure, and the precipitated crystals are separated by filtration to give the title compound (1.93 g).
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:13][C:12]1=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[CH3:24][O:25][CH:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)[CH2:28][CH2:27]1>CN(C=O)C>[CH3:24][O:25][CH:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]2[CH:34]=[CH:35][C:36]([NH:37]/[C:4](=[C:11]3\[C:12](=[O:23])[NH:13][C:14]4[C:15]\3=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=4)/[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:38][CH:39]=2)[CH2:28][CH2:27]1
Reactant: COC1CCN(Cc2ccc(N)cc2)CC1
Reactant: CCOC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccccc1
Solvent: CN(C)C=O
Product: COC1CCN(Cc2ccc(N/C(=C3\C(=O)Nc4ccc([N+](=O)[O-])cc43)c3ccccc3)cc2)CC1

Procedure:
Prepared analogously to Example 89 from 3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-(4-methoxypiperidinomethyl)-aniline in DMF.
Reaction SMILES: [H-].[Na+].[O:3]([C:10]1[C:15]([O:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][C:21]=2[OH:26])=[CH:14][CH:13]=[CH:12][N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.COC[O:30][CH2:31][CH2:32]Br.C(Cl)(Cl)Cl>CN(C=O)C>[O:3]([C:10]1[C:15]([O:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][C:21]=2[O:26][CH2:32][CH2:31][OH:30])=[CH:14][CH:13]=[CH:12][N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COCOCCBr
Reactant: Oc1cnccc1CCCOc1cccnc1Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: OCCOc1cnccc1CCCOc1cccnc1Oc1ccccc1
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% in mineral oil, 0.08 g, 2.0 mmol) is suspended in DMF (5 ml), and thereto is added 2-phenoxy-3-[3-(3-hydroxypyridin-4-yl)propoxy]pyridine (0.20 g, 0.62 mmol) obtained in Example 30 at room temperature, and the mixture is stirred for 30 minutes. To the mixture is added 2-methoxymethoxyethyl bromide (0.32 g, 2.0 mmol) under ice-cooling, and the mixture is stirred at 50° C. for 30 minutes. To the reaction solution is added chloroform (100 ml), and the mixture is washed with a saturated brine (50 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the residue are added ethanol (20 ml) and a 35% aqueous hydrochloric acid solution (2 ml), and the mixture is stirred at 60° C. for 30 minutes. The pH value of the reaction solution is adjusted to pH 10 with a saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with chloroform (50 ml×2), washed with a saturated brine (50 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: chloroform/methanol) to give 2-phenoxy-3-[3-(3-(2-hydroxyethoxy)pyridin-4-yl)propoxy]pyridine, which is further treated with fumaric acid to give the title compound (0.17 g), m.p. 129-132° C. (recrystallized from ethanol/isopropyl ether).
Reaction SMILES: [C:1]([C:4]([CH2:21][C:22]#[C:23][CH:24]([O:30]C(=O)C)[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])C(OCC)=O)(=[O:3])[CH3:2].[OH-].[Na+]>O.CO>[C:1]([CH:4]([CH2:21][C:22]#[C:23][CH:24]([OH:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])(=[O:3])[CH3:2]
Reactant: CCCCCC(C#CCC(CCCCCCC(=O)OCC)(C(C)=O)C(=O)OCC)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCC(O)C#CCC(CCCCCCC(=O)O)C(C)=O
Yield: 36.1 %

Procedure:
A solution of diethyl 2-acetyl-2-(4-acetoxy-2-nonyn-1-yl)azelate (59.7 g., 0.128 mole) and sodium hydroxide (30 g., 0.75 mole) in water (200 ml.) and methanol (800 ml.) is heated at 60° for 16 hours. Most of the methanol is then distilled at reduced pressure and the residue is dissolved in water. The solution is acidified to Congo Red with hydrochloric acid and the oily product taken up in ether and dried over sodium sulfate. Evaporation of the ether leaves 41.1 g. of the crude product as a redish viscous oil. The product is purified by chromatography on 650 g. of silica gel with 2% methanol in chloroform as eluant. Fifteen grams of pure 8-acetyl-12-hydroxy-10-heptadecynoic acid is obtained as a yellow viscous oil; pmr (CDCl3) δ 0.90 (3H,t), 2.20 (3H,s CH3CO), 4.37 (1H,t HCO).
Reaction SMILES: [C:1]1([CH3:23])[CH:6]=[CH:5][C:4]([C:7]2[S:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]=2[C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[CH:3][CH:2]=1.C1C(=O)N([Br:31])C(=O)C1.O>C1COCC1>[Br:31][C:13]1[CH:14]=[CH:15][C:9]2[C:8]([C:16]3[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=3)=[C:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:23])=[CH:2][CH:3]=3)[S:11][C:10]=2[CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2sc3ccccc3c2-c2ccc(C)cc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2sc3cc(Br)ccc3c2-c2ccc(C)cc2)cc1
Reaction time: 6 h
Yield: 80.5 %

Procedure:
2.5 g (1 eq, 7.9 mmol) of 2,3-di-p-tolyl-benzo[b]thiophene and 14 g (10 eq, 79 mmol) of NBS were dissolved in 200 ml of THF in a 500 ml-round-bottomed flask and stirred for 6 hours. 50 ml of water was added to the solution to terminate the reaction, and the organic phase was extracted using brine and methylene chloride. The extracted organic phase was dried using anhydrous magnesium sulfate and filtered to remove the solvent. A resulting solid was recrystallized using methylene chloride and hexane, dissolved in a small amount of THF, and separated using column chromatography (silica and hexane) to obtain 2.5 g (71%) of a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:12][C:13]1[C:18]([O:19][CH3:20])=[N:17][C:16]([CH3:21])=[CH:15][N:14]=1.N1C=CC=CC=1>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[C:7]([S:8]([NH:12][C:13]2[C:18]([O:19][CH3:20])=[N:17][C:16]([CH3:21])=[CH:15][N:14]=2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: COc1nc(C)cnc1N
Reactant: O=S(=O)(Cl)c1cccnc1Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1nc(C)cnc1NS(=O)(=O)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 29.9 %

Procedure:
4-Dimethylaminopyridine (0.1 g) was added to a solution of 2-chloropyridine-3-sulphonyl chloride (1.06 g), 2-amino-3-methoxy-5-methylpyrazine (0.695 g) and pyridine (0.424 ml) in dichloromethane (5 ml) and the mixture was stirred at ambient temperature for 18 hours. The solution was then transferred to a silica gel Mega Bond Elut column. Elution with 0-40% ethyl acetate/hexane gave 2-chloro-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (0.47 g) as an oil; 1H NMR (d6-DMSO): 2.3 (s, 3H), 3.9 (s, 3H), 7.5 (s, 1H), 7.65 (dd, 1H), 8.45 (dd, 1H), 8.7 (dd, 1H); mass spectrum (+ve CI): 315 (M+H)+.
Reaction SMILES: CC(O)(C)[C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH3:13])=[CH:7][CH:6]=1.[H-].[Na+].O>C1(C)C=CC=CC=1>[CH2:11]([C:8]1[CH:7]=[CH:6][C:5]([C:4]#[CH:3])=[CH:10][CH:9]=1)[CH2:12][CH3:13]
Reactant: CCCc1ccc(C#CC(C)(C)O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: C#Cc1ccc(CCC)cc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 68 %

Procedure:
3-Methyl-1-(4'-propylphenyl)-1-butyne-3-ol (33 g) was dissolved in toluene (320 ml) under nitrogen atmosphere, and then sodium hydride (60% in 2 g of paraffin liquid) was added thereto. The mixture was stirred at 60° C. for 6 hours. The reaction solution was poured into water (300 ml), and then extracted with chloroform, followed by washing with water three times. After distilling off toluene and chloroform, the resultant was distilled under reduced pressure (b.p. 60° to 63° C./4 mmHg) to give 4-propylphenylacetylene (16 g).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]=[CH:10][CH:11]1[O:20][CH:14]2[O:15]C(C)(C)[O:17][CH:13]2[CH2:12]1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].Cl.CC(C)=O.C([O-])(O)=O.[Na+]>CC#N>[CH2:1]([O:3][P:4]([CH:9]=[CH:10][CH:11]1[CH2:12][CH:13]([OH:17])[CH:14]([OH:15])[O:20]1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(C=CC1CC2OC(C)(C)OC2O1)OCC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CC#N
Product: CCOP(=O)(C=CC1CC(O)C(O)O1)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 111.8 %

Procedure:
Compound 9.6 (3.6 g, 11.76 mmol) in MeCN (40 mL) was treated with 1 N HCl (10 mL) and stirred at 50° C. for 5 h with slow distillation of residual acetone. The solution was cooled to ambient temperature and treated with NaHCO3 (1.0 g) then concentrated in vacuo. The residue was lyophilized overnight and MeOH (20 mL) was added and the solution was filtered. The solution was then co-evaporated with MeCN to afford crude compound 9.7 (3.5 g, >100% yield).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH2:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[C:20]([C:22](OCC)=[O:23])[N:21]=2)[CH:18]=1>>[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[C:20]([C:22]([NH:11][CH2:10][C:7]3[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=3)=[O:23])[N:21]=2)[CH:18]=1
Reactant: CC(C)c1ccc(CN)cc1
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Product: CC(C)c1ccc(CNC(=O)c2cn3cc(Br)ccc3n2)cc1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate I, using (4-isopropylphenyl)methanamine and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)=[CH:10][C:9]=1[N+:19]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:15]=[CH:16][CH:17]=[CH:18]2)=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-n2cccc2)cc1[N+](=O)[O-]
Agent: [Pd]
Product: CC(C)(C)OC(=O)Nc1ccc(-n2cccc2)cc1N

Procedure:
The title compound was prepared from (2-nitro-4-pyrrol-1-yl-phenyl)-carbamic acid tert-butyl ester (Example A11) by hydrogenation with 5% Pd/C according to the general procedure J (method a). Obtained as a white solid (9.06 g).
Reaction SMILES: CC([O-])(C)C.[K+].Cl[C:8]1[N:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:9]=1[C:10]([NH:12][C:13](=[NH:26])[CH2:14][O:15][CH2:16][CH2:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[F:25])=[O:11]>CS(C)=O>[Cl:31][C:28]1[CH:29]=[N:30][C:8]2[N:26]=[C:13]([CH2:14][O:15][CH2:16][CH2:17][C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[F:25])[NH:12][C:10](=[O:11])[C:9]=2[CH:27]=1
Reactant: N=C(COCCc1cc(F)ccc1F)NC(=O)c1cc(Cl)cnc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=c1[nH]c(COCCc2cc(F)ccc2F)nc2ncc(Cl)cc12
Temperature: 50 °C
Reaction time: 1 h
Yield: 9200 %

Procedure:
KOtBu (28 mg, 250 μmol) was added at ambient temperature to a solution of 2,5-dichloro-N-{2-[2-(2,5-difluoro-phenyl)-ethoxy]-1-imino-ethyl}-nicotinamide (97 mg, 250 μmol) in DMSO (1 ml). The solution was stirred for 1 h at 50° C., cooled to ambient temperature, KOtBu (28 mg, 250 μmol) was added and the reaction solution was stirred at 50° C. for 14 h. The mixture was poured onto isopropyl acetate/ice water 1/1. The layers were separated and the aqueous layer was extracted two times with isopropyl acetate. The combined extracts were washed three times with brine and dried over sodium sulfate. The solvent was removed under reduced pressure to leave a yellow solid which was recrystallized from dichloromethane/heptane to give 6-chloro-2-[2-(2,5-difluoro-phenyl)-ethoxymethyl]-3H-pyrido[2,3-d]pyrimidin-4-one (8 mg, 23 mmol; 9%) as yellow crystals. MS: m/e=352.3 [M+H+].
Reaction SMILES: [O:1]([CH2:8][CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[CH3:17][CH:18]([CH3:40])[C@@H:19](OS(C)(=O)=O)[C:20]([NH:22][C@H:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)[CH3:24])=[O:21].O>C1COCC1>[CH3:17][CH:18]([CH3:40])[C@@H:19]([O:10][CH2:9][CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:20]([NH:22][C@H:23]([C:25]1[CH:26]=[CH:27][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:33][CH:34]=1)[CH3:24])=[O:21]
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H](OS(C)(=O)=O)C(C)C)cc1
Reactant: OCCOc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H](OCCOc2ccccc2)C(C)C)cc1
Reaction time: 0.5 h
Yield: 59.6 %

Procedure:
Under a nitrogen atmosphere, 2-phenoxyethanol (17.3 mL, 138 mmol) in THF (450 mL) is cooled to 5° C. using an ice water bath and treated dropwise over 5 min with a 1M solution of potassium tert-butoxide in THF (138 mL, 138 mmol). The mixture is stirred for 30 min, and methyl 4-[(1S)-1-[[(2R)-3-methyl-2-methylsulfonyloxy-butanoyl]amino]ethyl]benzoate (45 g, 126 mmol) is added in one portion. The mixture is stirred to room temperature for 1 h, and water (300 mL) is added. The layers are separated, and the aqueous layer is extracted with ethyl acetate (100 mL). The combined organic layers are washed with brine, dried over MgSO4, filtered, and concentrated. The crude material is purified using silica gel column chromatography (750 g cartridge; 20 to 60% ethyl acetate in heptane) to provide the title compound as a white solid (30 g, 60%). MS (m/z): 400.4 (M+1).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.CC(N)(C)C[C:22]1[CH:27]=[CH:26][C:25]([NH:28][S:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)(=[O:31])=[O:30])=[CH:24][CH:23]=1>C(O)C>[OH:1][C@@H:2]([CH2:3][N:11]([C:22]1[CH:23]=[CH:24][C:25]([NH:28][S:29]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)(=[O:30])=[O:31])=[CH:26][CH:27]=1)[CH2:10][CH:18]([CH3:6])[CH3:17])[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(N)Cc1ccc(NS(=O)(=O)c2ccccc2)cc1
Reactant: c1ccc2c(c1)[nH]c1cccc(OC[C@@H]3CO3)c12
Solvent: CCO
Product: CC(C)CN(C[C@H](O)COc1cccc2[nH]c3ccccc3c12)c1ccc(NS(=O)(=O)c2ccccc2)cc1
Yield: 134.6 %

Procedure:
A solution of (S)-4-(oxiranylmethoxy)-9H-carbazole (1.0 g, 4.18 mmol) and N-(4-[2-methyl-2-aminopropyl]phenyl) benzenesulfonamide (1.9 g, 6.24 mmol) in absolute ethanol (100 mL) was refluxed for 18 h. The solvent was removed under vacuum and the residue was purified by column chromatography eluting with chloroform:methanol (95:5). Concentration of the appropriate fractions provided 1.53 g (69%) of the desired product. MS (FD) m/e 544.3 (MH+); Anal. Calcd. for C31H33N3O4S: C, 68.48; H, 6.12. N, 7.73. Found: C, 68.49; H, 6.02; N, 7.53.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[F:11].[C-:12]#[N:13].[Na+]>C(O)C.O>[F:11][C:4]1[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][C:12]#[N:13]
Reactant: COc1cccc(CCl)c1F
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1cccc(CC#N)c1F
Temperature: 70 °C
Yield: 82.3 %

Procedure:
To a solution of 1-(chloromethyl)-2-fluoro-3-methoxybenzene (8.6 g, 49.3 mmol) in ethanol (60 mL) and water (10 mL), sodium cyanide (4.8 g, 98.5 mmol) was added. The resulting solution was heated at 70° C. for 16 h. After cooling to room temperature, the solution was poured into water (200 mL) and extracted with ethyl acetate (2×200 mL). The combined organic layers were washed (brine), dried (Na2SO4), and concentrated in vacuo to give the title compound (6.7 g). 1H NMR (CDCl3): δ 7.13-7.07 (m, 1H), 7.02-6.92 (m, 2H), 3.89 (s, 3H), 3.81 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[CH2:10][CH2:11][OH:12].[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>C(Cl)(Cl)Cl>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[CH2:10][CH2:11][O:12][S:27]([C:24]1[CH:25]=[CH:26][C:21]([CH3:31])=[CH:22][CH:23]=1)(=[O:29])=[O:28]
Reactant: COc1ccccc1C(CCO)c1ccccc1OC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Product: COc1ccccc1C(CCOS(=O)(=O)c1ccc(C)cc1)c1ccccc1OC
Temperature: 0 °C

Procedure:
The propanol (XVII) of Example 3b) (35 g, 0.128 mol) in 100 ml chloroform containing 30 ml pyridine was cooled to about -10° and then treated with p-toluene sulphonyl chloride (29 g, 0.15 mol). After standing in the cooler (about +5° C.) overnight, the mixture was poured into ice-water, the organic phase was washed with water and cold 2N HCl, dried, and the solvent was distilled off at <50° C., giving a crude oil in quantitative yield. Recrystallization from IPE gave white crystals of low and indefinite m.p.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[C:8]([OH:10])=[O:9]>C(O)(=O)C>[Br:1][C:11]1[C:12]([O:16][CH3:17])=[C:13]([O:14][CH3:15])[C:5]([O:4][CH3:3])=[CH:6][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: BrBr
Reactant: COc1cc(C(=O)O)cc(OC)c1OC
Solvent: CC(=O)O
Product: COc1cc(C(=O)O)c(Br)c(OC)c1OC
Temperature: 0 °C

Procedure:
A solution of bromine (100 mmol) in 100 mL of acetic acid is added dropwise to a solution of 3,4,5-trimethoxybenzoic acid (100 mmol) in 100 mL of acetic acid cooled by an ice water bath. After the red color of the resulting mixture is discharged, the mixture is poured onto 500 g of crushed ice. The resulting solid is collected by filtration, dried over P2O5 in vacuo, and recrystallized from Et2O to give the product as a pale yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.Cl.O1CCOCC1>C(O)(=O)C.O1CCOCC1.[Zn]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:13][CH:14]=1
Reactant: O=C(O)C=Cc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: Nc1ccc(C=CC(=O)O)cc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 322.6 %

Procedure:
Cycloartenyl ester of p-nitro cinnamic acid (160.0 g, 0.266 mole) prepared according to the procedure of Example 101 was suspended in a mixture of acetic acid (1.5 l) and dioxane (1.5 l). To the suspension were added 6N-HCl-dioxane (95 ml) and zinc powder (80 g) and the mixture was stirred at 40° C. for 3 hours. After the reaction, zinc powder was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was extracted with chloroform. The extracts were washed successively with water and saturated aqueous NaHCO3, then dried, and concentrated under reduced pressure. The residual crystals were recrystallized from chloroform-ethanol (1:5, v/v), giving cycloartenyl ester of p-aminocinnamic acid (140.0 g), in a 92.0% yield. m.p. 185°-187° C.