Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH:14]=[O:15])=[CH:8][CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2].[CH2:16]=[O:17].[Br-].C(C1SC2C=CC=CC=2[NH+]=1)C.C(N(CC)CC)C>C(O)C>[OH:17][CH2:16][C:14](=[O:15])[CH2:13][CH2:12][C:9]1[CH:10]=[CH:11][C:6]([C:1]([O:3][CH2:4][CH3:5])=[O:2])=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1ccc(CCC=O)cc1
Reactant: C=O
Agent: CCc1[nH+]c2ccccc2s1
Agent: [Br-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(CCC(=O)CO)cc1

Procedure:
A mixture of 1.1 g (5 mmol) of 3-(4-carbethoxyphenyl)propanal and 150 mg (5 mmol) of paraformaldehyde in 10 mL of ethanol, together with 230 mg (0.9 mmol) of ethyl benzothiazolium bromide and 90 mg (0.9 mmol) of triethylamine, is heated at about 70° C. for 16 hours. The reaction mixture is concentrated in vacuo and the product further purified by chromatography on silica gel, eluting with 15:85 ethyl acetate:hexane, to yield ethyl 4-(4-hydroxy-3-oxobutyl)benzoate as a colorless oil which solidifies upon standing; m.p. 51°-52° C. Anal. calcd for C13H16O4 : C, 66.09; H 6.83. Found: C, 66.29; H, 6.70.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:19]([N:20]4[CH2:24][CH2:23][CH2:22][C@@H:21]4[CH2:25][O:26][CH3:27])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:28]([O:30]C)=[O:29])[CH:16]=4)[N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-].[Na+]>CO.O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:19]([N:20]4[CH2:24][CH2:23][CH2:22][C@@H:21]4[CH2:25][O:26][CH3:27])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:28]([OH:30])=[O:29])[CH:16]=4)[N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: COC[C@H]1CCCN1c1nc2cc(C(=O)OC)ccc2nc1-c1ccc2[nH]ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC[C@H]1CCCN1c1nc2cc(C(=O)O)ccc2nc1-c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.4 %

Procedure:
To a solution of methyl 2-(1H-indol-5-yl)-3-[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]quinoxaline-6-carboxylate (200 mg, 0.48 mmol) in methanol (35.0 mL) and water (1.0 mL) was added sodium hydroxide (76.9 mg, 1.92 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water (30.0 mL), adjusted pH to 4 with HCl (3N) to give the precipitate, which was collected by filtration to afford 2-(1H-indol-5-yl)-3-[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]quinoxaline-6-carboxylic acid (80 mg, 41%).
Reaction SMILES: [C:1]([C:3]([C:20](=[O:28])[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:14][C:15]([O:17]CC)=[O:16])[CH:6]=1)#[N:2].[OH-].[Na+]>C1COCC1.O>[C:1](/[C:3](/[C:20](=[O:28])[NH:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[CH:4]\[C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:14][C:15]([OH:17])=[O:16])[CH:6]=1)#[N:2]
Reactant: CCOC(=O)Cn1cc(C=C(C#N)C(=O)Nc2ccccc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#C/C(=C\c1cn(CC(=O)O)c2ccccc12)C(=O)Nc1ccccc1

Procedure:
A stirred solution of crude ethyl [3-(2-cyano-2-phenylcarbamoyl-vinyl)-indol-1-yl]-acetate (0.079 mmol) in THF (0.8 ml) is treated with 0.2N aqueous NaOH (0.4 ml, 0.08 mmol) at rt for 10 min. The yellow reaction mixture is diluted with water (2 ml) and washed twice with diethyl ether (2 ml). The aqueous phase is acidified to pH 1 by adding conc. HCl and extracted with dichloromethane. The solvent is evaporated and the residue is recrystallized from acetonitrile yielding pure title compound.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][N:12]([CH:15]([CH3:17])[CH3:16])[CH2:11][CH2:10]1)=O)(C)(C)C>C(O)C>[ClH:1].[CH:15]([N:12]1[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]1)([CH3:17])[CH3:16]
Reactant: CC(C)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCO
Product: CC(C)N1CCNCC1
Yield: 41 %

Procedure:
1M HCl in ethanol (40 mL) was added to 1-isopropylpiperazine-4-carboxylic acid tert-butyl ester (2.253 g) obtained from Referential Example 94, and the resultant mixture was stirred at room temperature for 17 hours, and then refluxed under heat for 1 hour. The solvent was evaporated under reduced pressure. Ethanol was added to the residue, and the insoluble solid was recovered by filtration, to thereby give the title compound (824 mg, 41%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)[C:7](=[O:25])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]([OH:23])=O)=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:24])=[CH:10][CH:9]=2)=[O:4].[N:37]1([CH2:43][CH2:44][CH2:45][NH2:46])[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.Cl.C(N=C=NCCCN(C)C)C.O.OC1C2N=NNC=2C=CC=1>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)[C:7](=[O:25])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:23])[NH:46][CH2:45][CH2:44][CH2:43][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:24])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(-c2ccc(C(=O)O)cc2)c2cc(Cl)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1
Reactant: NCCCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CC#N
Product: COC(=O)c1c(-c2ccc(C(=O)NCCCN3CCOCC3)cc2)c2cc(Cl)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1

Procedure:
To a solution (2 ml) of 4-(4-carboxyphenyl)-6-chloro-2-(4-methanesulfonylbenzyl)-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (100 mg) and 3-morpholin-4-ylpropylamine (31 μl) in acetonitrile were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (69 mg) and 4-hydroxybenzotriazole monohydrate (38 mg) at room temperature with stirring, and the mixture was stirred at room temperature for 12 hrs. The solvent was removed under reduced pressure, and the residue was partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was dried and concentrated to dryness. The residue was purified by silica gel column chromatography (ethyl acetate/methanol=10/1) to give the title compound (93 mg) as colorless crystals.
Reaction SMILES: ClCCC[O:5][P:6]1[CH2:10][CH:9]=[C:8]([CH3:11])[CH2:7]1.[CH2:12](O)[CH2:13][OH:14].C(Br)C>ClCCCl>[OH:14][CH2:13][CH2:12][P:6]1(=[O:5])[CH2:10][CH2:9][C:8]([CH3:11])=[CH:7]1
Reactant: OCCO
Reactant: CC1=CCP(OCCCCl)C1
Solvent: CCBr
Solvent: ClCCCl
Product: CC1=CP(=O)(CCO)CC1
Reaction time: 0.08 h

Procedure:
To a solution of 14.7 g. (0.076 mole) of 1-(chloropropoxy)-3-methyl-3-phospholene in 50 ml. of 1,2-dichloroethane was added, with stirring, over a period of 5 minutes, a total of 14.14 g. (0.23 mole) of ethylene glycol. The resulting solution was cloudy. Ethyl bromide (1.66 g.) was added and the mixture was heated under reflux for 1 hour. At the end of this time the solvent and other volatile materials were removed by evaporation and the residue was distilled under reduced pressure. There was thus obtained 1.3 g. (10.6% theoretical yield) of a mixture of the 2- and 3-isomers of 1-(2-hydroxyethyl)-3-methylphospholene-1-oxide in the form of a liquid having a boiling point of 125° - 150° C at 0.2 mm. of mercury. A glassy residue remained in the distillation flask and was believed to be 1,1'-ethylenebis-(3-methylphospholene-1-oxide).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[NH:5][CH:6]=[O:7].Br[CH2:13][CH2:14][CH2:15][Cl:16].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[N:5]([CH2:13][CH2:14][CH2:15][Cl:16])[CH:6]=[O:7]
Reactant: ClCCCBr
Reactant: O=CNc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: O=CN(CCCCl)c1ccc(Cl)c(Cl)c1
Yield: 76.9 %

Procedure:
To the mixture of 3,4-dichloro-N-formylaniline (133.0 g, 700 mmol), 1-bromo-3-chloropropane (132.3 g, 840 mmol) and acetone (700 mL) was added cesium carbonate (273.7 g, 840 mmol), and the mixture was stirred for under reflux. The reaction mixture was concentrated under reduced pressure, and to the concentrate was added ethyl acetate (500 mL). The organic layer was washed with water (300 mL) and saturated sodium chloride solution (100 mL×3), successively, dried over magnesium sulfate and concentrated under reduced pressure. The concentrate was subjected to column chromatography (silica gel 500 g×2, hexane/ethyl acetate=1/0 to 9/1 to 4/1), and the desired fraction was concentrated under reduced pressure to give the titled compound (143.5 g, 538 mmol, Yield 77%) as pale yellow oily substance.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][N:17]1[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1>[CH2:22]([N:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]1[CH2:15][N:10]1[CH:11]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[CH:9]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: c1ccc(-c2c[nH]cn2)cc1
Reactant: BrCC1CCCCN1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ccc(CN2CCCCC2Cn2cnc(-c3ccccc3)c2)cc1
Reaction time: 16 h
Yield: 24.1 %

Procedure:
4-Phenylimidazole (1.3 g) was treated with sodium hydride (0.6 g 50% in oil) in dry tetrahydrofuran (80 ml). When gas evolution had ceased, 2-bromomethyl-N-benzylpiperidine (2.5 g) in tetrahydrofuran (30 ml) was added. The mixture was stirred for 16 h, solvent removed at reduced pressure and treated with ice/water (1:1, 100 ml). The mixture was extracted with dichloromethane (2×), the combined organic phase washed with water, solvent removed at reduced pressure and the residue column chromatographed (silica gel, 0.5→9.5% dichloromethane/methanol). Appropriate fractions were combined to give the title compound 0.72 g.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[O:22][CH2:21][C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)[CH3:2].[Sn](Cl)(Cl)(Cl)Cl.[CH3:28][CH:29]([CH2:35][CH2:36][CH2:37][CH:38]([CH3:50])[CH2:39][CH2:40][CH2:41][CH:42]([CH3:49])[CH2:43][CH2:44][CH2:45][CH:46]([CH3:48])[CH3:47])[CH2:30][CH2:31]CCO.O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:8]([O:7][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:16]([O:17][C:18](=[O:20])[CH3:19])[CH2:21][O:22][C@H:5]1[O:4][CH2:1][CH2:2][CH2:31][CH2:30][CH:29]([CH3:28])[CH2:35][CH2:36][CH2:37][CH:38]([CH3:50])[CH2:39][CH2:40][CH2:41][CH:42]([CH3:49])[CH2:43][CH2:44][CH2:45][CH:46]([CH3:48])[CH3:47])(=[O:10])[CH3:9]
Reactant: CC(C)CCCC(C)CCCC(C)CCCC(C)CCCCO
Reactant: CC(=O)O[C@@H]1OC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OCCCCC(C)CCCC(C)CCCC(C)CCCC(C)C)OC[C@H]1OC(C)=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 15.9 %

Procedure:
Under an argon atmosphere, 318 mg of β-xylose tetraacetate was dissolved in 6 ml of dry methylene chloride, and the solution was cooled to 0° C. A solution of 0.12 ml of tin tetrachloride dissolved in 1 ml of methylene chloride was added dropwise thereto, the mixture was agitated at room temperature for 20 minutes, and then cooled to −10° C. A solution of 326.6 mg of 5,9,13,17-tetramethyloctadecanol in 1 ml of methylene chloride was added dropwise thereto, and the mixture was agitated for 4 hours. A sodium bicarbonate water was added to the reaction solution and extraction was carried out 3 times with methylene chloride. The extract was washed with water and dried over anhydrous sodium sulfate. After the filtration, the resultant was concentrated, and the concentrate was purified by column chromatography to obtain 93 mg of 1-O-(5,9,13,17-tetramethyloctadecyl)-β-D-xylopyranoside triacetate.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[Cl:14][C:15]1[CH:20]=[C:19]([C:21](=O)[CH2:22][CH2:23][C:24](=O)[CH3:25])[CH:18]=[CH:17][N:16]=1.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:14][C:15]1[CH:20]=[C:19]([C:21]2[N:2]([CH2:3][C:4]([O:6][CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[O:5])[C:24]([CH3:25])=[CH:23][CH:22]=2)[CH:18]=[CH:17][N:16]=1
Reactant: NCC(=O)OCc1ccccc1
Reactant: CC(=O)CCC(=O)c1ccnc(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(-c2ccnc(Cl)c2)n1CC(=O)OCc1ccccc1
Temperature: 65 °C
Reaction time: 14 h

Procedure:
A slurry of benzyl 2-aminoacetate hydrochloride (922 mg, 4.57 mmol), 1-(2-chloropyridin-4-yl)pentane-1,4-dione (968 mg, 4.57 mmol), and solid sodium bicarbonate (961 mg, 11.4 mmol) in dichloromethane (15.2 mL) was heated to 45° C. for 14 hours. A significant amount of starting material was observed after 14 hours by LC/MS, so the reaction was heated to 65° C. The reaction was allowed to stir (with occasional monitoring by LCMS) at this temperature for 11 days. The reaction was then allowed to cool down to room temperature and poured onto water and extracted with dichloromethane (3×50 mL), dried (sodium sulfate), filtered, and concentrated to a dark orange residue. Purification was achieved by column chromatography (Luknova 80 g, 20 mL/min) using 5 to 45% ethyl acetate in hexanes over 60 minutes. The product, benzyl 2-(2-(2-chloropyridin-4-yl)-5-methyl-1H-pyrrol-1-yl)acetate was isolated as a light orange oil (890 mg, 2.61 mmol, 57% yield). 1H NMR (400 MHz, CDCl3): δ (ppm) 8.23 (d, 1H), 7.36-7.40 (m, 5H), 7.21 (m, 1H), 7.02 (dd, 1H), 6.37 (d, 1H), 6.07 (d, 1H), 5.25 (s, 2H), 4.64 (s, 2H), 2.22 (s, 3H).
Reaction SMILES: [Zn](CC)[CH2:2][CH3:3].[CH:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O>C1(C)C=CC=CC=1>[OH:13][CH:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:2][CH3:3]
Reactant: CC[Zn]CC
Reactant: O=Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(O)c1ccccc1
Reaction time: 0.5 h
Yield: 31.4 %

Procedure:
(+)-Me-IAN amine (19.0 mg, 66.8 μmol) was dissolved in toluene (0.85 mL) in a 10 mL flask. Et2Zn (1.22 mL, 1.1 M in toluene, 1.34 mmol) was added in one portion via syringe. Immediately, a clear red-orange solution formed. After stirring for 30 min., benzaldehyde (0.068 mL, 0.669 mmol) was added. This addition immediately lightened the solution to a pale orange-yellow. After 19 h, the solution returned to its red-orange color. Water was added and the mixture was extracted three times with CH2Cl2. The combined organic phases were dried over MgSO4, filtered, and concentrated iii vacuo. Purification of the crude product via flash column chromatography on silica gel gave 1-hydroxy-1-phenylpropane as a light yellow liquid (28.6 mg, 31.4%). HPLC analysis of the product (OD column, 1.0 mL/min, 2% iPrOH in hexanes) gave 85.2% ee (retention time of major peak=13.7 min, retention time of minor peak=16.3 min) and a decrease in the ee of (+)-Me-IAN amine (from 99% to 93.2% ee).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][C:18]([S:22]([N:25](CC3C=CC(OC)=CC=3)[C:26]3[S:30][N:29]=[CH:28][N:27]=3)(=[O:24])=[O:23])=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:4][C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][C:18]([S:22]([NH:25][C:26]3[S:30][N:29]=[CH:28][N:27]=3)(=[O:23])=[O:24])=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4Br)nccc3c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(Nc1ncns1)c1ccc2c(-c3ccc(C(F)(F)F)cc3Br)nccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(2-bromo-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide (INTERMEDIATE DD, 100 mg, 0.157 mmol) in DCM (1574 μl) was added TFA (60.6 μl, 0.787 mmol). The mixture was stirred at room temperature. After 2 h, LC/MS showed mainly the desired product. The reaction mixture was concentrated and dissolved in 3 ml of DMSO. This solution was injected onto the reverse phase HPLC (Xbridge 10 μm, C18, 19×100 mm column eluting with 0.1% NH4OH in ACN and water as the mobile phase) ultimately affording 1-(2-bromo-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide (10.6 mg, 0.021 mmol). MS (ESI): 514.8 [M+H]+; 1H NMR (500 MHz, DMSO-d6) δ ppm 7.68 (d, J=8.87 Hz, 1H), 7.76 (d, J=7.80 Hz, 1H), 7.90-7.98 (m, 2H), 8.22-8.26 (m, 2H), 8.48 (s, 1H), 8.65 (m, 1H), 8.76 (d, J=5.66 Hz, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([CH:8]=[C:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH:13]=[CH:12][C:11]3[CH:20]=[CH:21][CH:22]=[CH:23][C:10]2=3)=[CH:6][CH:5]=1)([O-])=O.Cl.[OH-].[Na+]>[Fe].CN(C)C=O>[NH2:1][C:4]1[CH:25]=[CH:24][C:7]([CH:8]=[C:9]2[C:10]3[CH:23]=[CH:22][CH:21]=[CH:20][C:11]=3[CH:12]=[CH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]2=3)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(C=C2c3ccccc3C=Cc3ccccc32)cc1
Agent: [Fe]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ccc(C=C2c3ccccc3C=Cc3ccccc32)cc1
Temperature: 70 °C
Yield: 92.6 %

Procedure:
10.0 g (30.7 m moles) of 5-(4-nitrobenzylidene)-5H-dibenzo[a,d]cycloheptene, 8.0 g (143 m moles) of reductive iron powder, and 2.70 ml (30.6 m moles) of concentrated hydrochloric acid (d: 1.18, 35%) were added to 150 ml of N,N-dimethyl formamide, and the mixture was heated at an inside temperature of about 70° C., and stirred at that temperature with heating for 3 hours. After the end of reaction, the mixture was cooled over an ice-water bath, admixed with about 12.4 ml of an aqueous 10% NaOH solution, stirred and subjected to filtration by suction. The filtrate was poured into about 1l of an aqueous saturated NaCl solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was removed therefrom under reduced pressure. The residue was admixed with methanol, and the precipitated crystal was recovered therefrom by filtration. The thus obtained crystal was recrystallized from methanol, whereby 8.41 g of 5-(4-aminobenzylidene)-5H-dibenzo[ a,d]cycloheptene was obtained (yield: 92.7%). The melting point was 119°-120.0° C. Elemental analysis as C22H17N was as follows:
Reaction SMILES: [CH:1]1[C:16]2[C:17]3[C:4]([C:5](=O)[O:6][C:7](=[O:18])[C:8]=3[CH:9]=[C:10]3[C:15]=2[O:14][CH2:13][O:12][CH2:11]3)=[CH:3][CH:2]=1.Cl.[NH2:21][OH:22].O>N1C=CC=CC=1>[OH:22][N:21]1[C:5](=[O:6])[C:4]2=[CH:3][CH:2]=[CH:1][C:16]3[C:17]2=[C:8]([CH:9]=[C:10]2[C:15]=3[O:14][CH2:13][O:12][CH2:11]2)[C:7]1=[O:18]
Reactant: NO
Reactant: O=C1OC(=O)c2cc3c(c4cccc1c24)OCOC3
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=C1c2cccc3c4c(cc(c23)C(=O)N1O)COCO4
Yield: 57.9 %

Procedure:
To a solution of 310 mg (1.21 mmol) of 8H-5,9,11-trioxabenzo[de]anthracene-4,6-dione (from Example T3) in 4 mL pyridine was added 260 mg (3.74 mmol) of hydroxylamine hydrochloride and the reaction mixture refluxed for 2 hours and poured into 50 mL water while hot. The precipitate was isolated, washed with water, and dried to yield 190 mg of the title compound, mp 314-315° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:14]([CH3:15])[C:13]2[C:12]([F:16])=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:17][C:18]1[CH:23]=[CH:22][C:21]([Si](C)(C)C)=[CH:20][C:19]=1[F:28])=[O:5])[CH3:2].[I:29]Cl>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:14]([CH3:15])[C:13]2[C:12]([F:16])=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:17][C:18]1[CH:23]=[CH:22][C:21]([I:29])=[CH:20][C:19]=1[F:28])=[O:5])[CH3:2]
Reactant: ClI
Reactant: CCOC(=O)c1c(Nc2ccc([Si](C)(C)C)cc2F)c2cncc(F)c2n1C
Solvent: ClCCl
Product: CCOC(=O)c1c(Nc2ccc(I)cc2F)c2cncc(F)c2n1C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
To a cooled (0° C.) solution of 7-fluoro-3-(2-fluoro-4-trimethylsilanyl-phenylamino)-1-methyl-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (1.0 g, 2.48 mmol) in DCM (25 mL) was added iodine monochloride (1M in DCM, 4.96 mmol, 4.96 mL) dropwise. The mixture was stirred cold for 30 minutes then quenched by the addition of a saturated solution of sodium thiosulphate. The organic layer was separated, washed with a saturated solution of sodium thiosulphate, then dried (Na2SO4), filtered and evaporated to give a residue. The residue was triturated with diethyl ether to provide the title compound as a beige solid (805 mg, 71%). LCMS (method B): RT=3.52 min, M+H+ 458.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.Cl[CH:19]([CH:22]([C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[N:30]=[CH:29][CH:28]=[CH:27]2)[CH3:23])[CH:20]=O.C(N(CC)CC)C>C(O)(C)C>[N:30]1[C:31]2[C:26](=[CH:25][C:24]([CH:22]([C:19]3[N:3]4[N:4]=[C:5]([C:8]5[CH:9]=[CH:10][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:16][CH:17]=5)[CH:6]=[N:7][C:2]4=[N:1][CH:20]=3)[CH3:23])=[CH:33][CH:32]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: CC(c1ccc2ncccc2c1)C(Cl)C=O
Reactant: COC(=O)c1ccc(-c2cnc(N)nn2)cc1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: COC(=O)c1ccc(-c2cnc3ncc(C(C)c4ccc5ncccc5c4)n3n2)cc1
Temperature: 110 °C
Yield: 22.5 %

Procedure:
A mixture of methyl 4-(3-amino-1,2,4-triazin-6-yl)benzoate (50 mg, 0.217 mmol) and 2-chloro-3-quinolin-6-ylbutanal (61 mg, 0.26 mmol) in isopropyl alcohol (3.0 mL) was heated at 110° C. for 48 h. The mixture was adjusted to pH 9 by adding triethylamine. The volatiles were removed under reduced pressure and the residue was purified by chromatography on silica gel with EtOAc in methylene chloride (0-60%) to afford the desired product (0.020 g, 22%). LCMS: (M+H)=410.0.
Reaction SMILES: [Br-:1].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[CH3:34][C:35]([C:37]1[CH:38]=[CH:39][C:40]([OH:43])=[CH:41][CH:42]=1)=[O:36]>O1CCCC1>[Br:1][CH2:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=1)=[O:36]
Reactant: [Br-]
Reactant: CC(=O)c1ccc(O)cc1
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: O=C(CBr)c1ccc(O)cc1
Reaction time: 3 h
Yield: 53.9 %

Procedure:
Phenyltrimethylammonium tribromide (276 g, 734 mmol) was added to a suspension of 4-hydroxyacetophenone (100 g, 734 mmol) in tetrahydrofuran (1000 ml) at room temperature. After stirring for 3 hours, the resulting suspension was filtered, and the filtrate was concentrated under reduced pressure. The residue was washed with diisopropyl ether to afford 2-bromo-1-(4-hydroxyphenyl)-ethan-1-one (85 g, 54%) as white crystals.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([SH:15])=[CH:11][C:10]=1[CH:16]([CH3:18])[CH3:17].[CH3:19][C:20]1[CH:21]=[C:22]([O:28][CH3:29])[CH:23]=[C:24]([CH3:27])[C:25]=1I.C(OCC)(=O)C>C1(C)C=CC=CC=1.[I].[Cu]>[CH3:19][C:20]1[CH:21]=[C:22]([O:28][CH3:29])[CH:23]=[C:24]([CH3:27])[C:25]=1[S:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH3:7])=[C:10]([CH:16]([CH3:18])[CH3:17])[CH:11]=1
Reactant: COc1ccc(S)cc1C(C)C
Reactant: COc1cc(C)c(I)c(C)c1
Agent: [Cu]
Agent: CC(C)(C)[O-]
Agent: [I]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1cc(C)c(Sc2ccc(OC)c(C(C)C)c2)c(C)c1
Yield: 49 %

Procedure:
Copper iodine (70 mg, 0.37 mmol), neocuprinine (80 mg, 0.37 mmol) and potassium t-butoxide (470 mg, 4.05 mmol) were added in this order to a solution of 4-methoxy-3-iso-propyl-thiophenol (U.S. Pat. No. 6,747,048 B2, 600 mg, 2.3 mmol) and 3,5-dimethyl-4-iodoanisole (678 mg, 3.72 mmol) in toluene (10 mL). After refluxing overnight, the cooled reaction mixture was poured into ethyl acetate (50 mL) and washed twice with 1 N HCl then brine. The organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane/ethyl acetate 100:0 to 40:1) to give 3,5-dimethyl-4-(3′-iso-propyl-4′-methoxyphenylsulfanyl)anisole (0.358 g, 49%); 1H NMR (200 MHz, DMSO-d6): δ 6.87-6.80(m, 4H), 6.56(m, 1H), 3.76(s, 3H), 3.71(s, 3H), 3.15(m, 1H), 2.34(s, 6H), 1.06(d, 6H, J=7 Hz); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=25% ethyl acetate in hexane; Rf=0.36