Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[CH3:12][O:13][CH:14]([O:22][CH3:23])[C:15](=O)[CH2:16][C:17]([O:19][CH3:20])=[O:18].N1CCCCC1.[NH2:30]/[C:31](/[CH3:37])=[CH:32]\[C:33]([O:35][CH3:36])=[O:34]>C1C=CC=CC=1.C(O)(=O)C>[CH3:37][C:31]1[NH:30][C:15]([CH:14]([O:22][CH3:23])[O:13][CH3:12])=[C:16]([C:17]([O:19][CH3:20])=[O:18])[CH:7]([C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:32]=1[C:33]([O:35][CH3:36])=[O:34]
Reactant: COC(=O)CC(=O)C(OC)OC
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: COC(=O)/C=C(/C)N
Solvent: c1ccccc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: COC(=O)C1=C(C)NC(C(OC)OC)=C(C(=O)OC)C1c1cccc([N+](=O)[O-])c1
Yield: 51.5 %

Procedure:
To a mixture of 3-nitrobenzaldehyde (7.56 g), methyl 4,4-dimethoxyacetoacetate (9.69 g) and acetic acid (600 mg) in benzene (25 ml) was added portionwise each one fifth portion of piperidine (851 mg) in benzene (5 ml) for each 20 minutes interval and the mixture was heated to reflux for 4 hours under azeotropic dehydration. After cooling, the reaction mixture was diluted with benzene (50 ml), washed twice with diluted aqueous sodium bicarbonate solution, and in turn, with water and saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated to dryness under reduced pressure to give crude reddish brown oily methyl(3-nitrobenzylidene)-4,4-dimethylacetoacetate (17.82 g) which was used in the following reaction without any further purification. A mixture of above oil (17.82 g) and methyl 3-aminocrotonate (6.33 g) was heated at 60° to 65° C. for 4.5 hours, at 100° to 105° C. for 8 hours and 45 minutes. The reaction mixture was chromatographed on a column of silica-gel (440 g) and eluted with a mixture of benzene and ethyl acetate (10:1, v/v) to give crystalline product (10.46 g) of dimethyl 2-methyl-4-(3-nitrophenyl)-6-dimethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate. Thus obtained crystals (720 mg) were recrystallized from diisopropyl ether (10 ml) to give pure specimen (560 mg), mp 99° to 100° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][OH:11])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[H-].[Na+].Cl[C:15]1[CH:16]=[C:17]2[N:24]([CH3:25])[CH2:23][CH2:22][N:18]2[C:19](=[O:21])[N:20]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:9])[C:7]=1[F:8])[CH2:10][O:11][C:15]1[CH:16]=[C:17]2[N:24]([CH3:25])[CH2:23][CH2:22][N:18]2[C:19](=[O:21])[N:20]=1
Reactant: OCc1cc(F)c(F)c(Cl)c1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCn2c1cc(OCc1cc(F)c(F)c(Cl)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using (3-chloro-4,5-difluorophen-yl)methanol (192 mg, 1.078 mmol) in DMF (4 mL), sodium hydride (129 mg, 3.23 mmol) and 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (200 mg, 1.078 mmol).
Reaction SMILES: [CH3:1][I:2].[CH:3]1([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19]([CH:21]3[C:34]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[O:28][C:27]4[C:22]3=[CH:23][CH:24]=[CH:25][CH:26]=4)=[O:20])[CH2:14][CH2:13]2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1>>[I-:2].[CH:3]1([CH2:11][N+:12]2([CH3:1])[CH2:13][CH2:14][CH:15]([NH:18][C:19]([CH:21]3[C:34]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[O:28][C:27]4[C:22]3=[CH:23][CH:24]=[CH:25][CH:26]=4)=[O:20])[CH2:16][CH2:17]2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: O=C(NC1CCN(CC2CCCCCCC2)CC1)C1c2ccccc2Oc2ccccc21
Reactant: CI
Product: C[N+]1(CC2CCCCCCC2)CCC(NC(=O)C2c3ccccc3Oc3ccccc32)CC1
Product: [I-]
Temperature: 25 °C
Reaction time: 19 h

Procedure:
1 ml of methyl iodide was added to 9 mg of N-[1-(cyclooctylmethyl)piperidin-4-yl]xanthene-9-carboxamide, followed by stirring for 19 hours at room temperature. Methyl iodide was distilled off under reduced pressure, and 12 mg of the title compound as a pale yellow solid was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](O)=[C:7]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.O(Br)[Br:24].[P+5].[OH-].[Na+]>C(Cl)(Cl)Cl.C(N(CC)CC)C.O>[Br:24][C:6]1[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=[CH:8][C:7]=1[S:12]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13]
Reactant: BrOBr
Reactant: O=S(=O)(c1ccc(Cl)cc1)c1cnc2cc(Cl)ccc2c1O
Agent: [Na+]
Agent: [OH-]
Agent: [P+5]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: O=S(=O)(c1ccc(Cl)cc1)c1cnc2cc(Cl)ccc2c1Br
Yield: 76.5 %

Procedure:
A mixture of 7-chloro-3-(4-chloro-benzenesulfonyl)-quinolin-4-ol (0.5 g, 1.41 mmol) and phosphorus(V) oxybromide (1.2 g, 4.2 mmol) in chloroform (30 ml) and triethylamine (1 ml) was refluxed for 6 hours. The reaction mixture was diluted with water (30 ml) and the pH was adjusted to 10 with aqueous sodium hydroxide solution. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. The obtained crude product was purified by crystallization from diethyl ether to obtain 0.45 g of the title compound in 77% yield.
Reaction SMILES: C(O[N:5]1[N:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:15]=[CH2:16])[CH:11]=2)[C:6]1=[O:17])(=O)C.C(C1C=C2C(=CC=1)C(=O)NN=C2)=C.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40]>CN(C=O)C>[O:17]=[C:6]1[C:7]2[C:12](=[CH:11][C:10]([CH:15]=[CH2:16])=[CH:9][CH:8]=2)[CH:13]=[N:14][N:5]1[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40]
Reactant: C=Cc1ccc2c(=O)n(OC(C)=O)ncc2c1
Reactant: CCOC(=O)CBr
Agent: C=Cc1ccc2c(=O)[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=Cc1ccc2c(=O)n(CC(=O)OCC)ncc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
Ethyl-2-(1-oxo-6-vinylphthalazine-2(1H)-yl acetate (BI24): To a stirred solution of 6-vinylphthalazine-1(2H)-one (0.5 g, 2.90 mmol) in DMF (5.0 mL) was added Cs2CO3 (0.94 g, 2.90 mmol) and the reaction was stirred for 10 min Ethyl bromoacetate (0.48 g, 2.90 mmol) was added to the reaction mixture at ambient temperature and the reaction was stirred for 8 h at ambient temperature. The reaction mixture was diluted and extracted with EtOAc, and the EtOAc layer was washed with water and brine solution (2×). The separated EtOAc layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude product. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 25% EtOAc/petroleum ether) to afford the title compound as a brown solid (0.34 g, 45%): 1H NMR (400 MHz, DMSO-d6) δ 8.45 (m, 1H), 8.24 (m, 1H), 8.04 (m, 2H), 7.01 (m, 1H), 6.17 (d, J=2.1 Hz, 1H), 5.56 (d, J=10.8 Hz, 1H), 4.92 (s, 2H), 4.19 (m, 2H), 1.23 (m, 3H). ESIMS m/z 259.10 ([M+H]+); IR (thin film) 1750, 1660 cm−1.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([NH:5][CH2:6][C:7]1[C:8]([CH3:17])=[C:9]([C:13]([CH3:16])=[CH:14][CH:15]=1)[C:10](O)=[O:11])=[O:4].C(Cl)(=O)C(Cl)=O.[NH3:26]>C1COCC1>[F:1][C:2]([F:19])([F:18])[C:3]([NH:5][CH2:6][C:7]1[C:8]([CH3:17])=[C:9]([C:13]([CH3:16])=[CH:14][CH:15]=1)[C:10]([NH2:26])=[O:11])=[O:4]
Reactant: N
Reactant: Cc1ccc(CNC(=O)C(F)(F)F)c(C)c1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: Cc1ccc(CNC(=O)C(F)(F)F)c(C)c1C(N)=O

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-26 by using 3((2,2,2-trifluoroacetamido)methyl)-2,6-dimethylbenzoic acid (1.0 g), oxalyl chloride (1.0 mL), THF (50 mL) and ammonia gas to afford 0.800 g of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][CH2:9][NH:8][CH2:7][C:6]=2[CH:12]=1.CCN(CC)CC.[C:20](OC(=O)C)(=[O:22])[CH3:21]>C1COCC1>[C:20]([CH:9]1[NH:8][CH2:7][C:6]2[CH:12]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[NH:11][CH2:10]1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: Clc1ccc2c(c1)CNCCN2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)C1CNc2ccc(Cl)cc2CN1
Temperature: 25 °C
Yield: 22.6 %

Procedure:
7-chloro-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine (12.5 mmol) was dissolved in a mixture of THF (100 mL), Et3N (19.1 mmol) and acetic anhydride (12.4 mmol). The reaction mixture was heated under reflux for 18 h, cooled to room temperature and partitioned between H2O and EtOAc. The aqueous phase was extracted again 2× with EtOAc and the combined organic layers were dried over MgSO4, filtered and concentrated to a yellow, oily solid. The crude material was purified by column chromatography on silia eluting with EtOAc to yield 3-acetyl-7-chloro-1,2,3,5-tetrahydro-4H-[1,4]benzodiazepine (2.8 mmol, 22%) as a clear oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH2:10].[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][C:14]=1[CH3:22].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:17](=[O:18])[C:16]1[CH:20]=[CH:21][C:13]([Br:12])=[C:14]([CH3:22])[CH:15]=1
Reactant: COC(=O)c1ccccc1N
Reactant: Cc1cc(C(=O)Cl)ccc1Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccccc1NC(=O)c1ccc(Br)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To 2-amino-benzoic acid methyl ester (3.1 g) in dichloromethane (31 mL) was slowly added 4-bromo-3-methyl-benzoyl chloride [21900-25-4] (4.8 g) and triethylamine (3.1 mL). The reaction mixture was then stirred at room temperature for 1 hour. After such time, the reaction mixture was further diluted with dichloromethane (50 mL) and washed with water. The combined aqueous phase was further extracted with dichloromethane. All combined organic phases were then dried over sodium sulfate and concentrated in vacuo. The residue was then recrystallised from ethanol to give 2-(4-bromo-3-methyl-benzoylamino)-benzoic acid methyl ester (6.14 g) as white crystals, m.p.=123° C. MS (m/e): 348.3 (M+H+, 100%).
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:15][CH2:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cccc([N+](=O)[O-])c1CBr
Temperature: 25 °C
Yield: 88.3 %

Procedure:
A suspension containing 98 g (0.5 mol) of methyl 2-methyl-3-nitrobenzoate, 100 g (0.56 mol) of N-bromosuccinimide and 1 g of benzoyl peroxide in carbon tetrachloride (800 ml), was refluxed for 3 days under irradiation with 500W. The suspension was cooled to room temperature and subjected to filtration, whereupon the filtrate was concentrated. To the residue, ethyl ether (200 ml) and IPE (200 ml) were added, whereupon the formed crystals were collected by filtration to obtain 121 g (yield: 88.3%) of the desired product. Melting point: 65°-67° C.
Reaction SMILES: C([O:4][P:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[C:22]([C:24](=[O:31])[NH:25][C:26]3[S:27][CH:28]=[CH:29][N:30]=3)[CH:21]=[C:20]([S:32][C:33]3[N:34]([CH3:38])[CH:35]=[CH:36][N:37]=3)[CH:19]=2)=[CH:13][CH:12]=1)(=[O:10])[O:6]C(C)C)(C)C.[Br:39][Si](C)(C)C>C(Cl)Cl>[BrH:39].[CH3:38][N:34]1[CH:35]=[CH:36][N:37]=[C:33]1[S:32][C:20]1[CH:19]=[C:18]([CH:23]=[C:22]([C:24](=[O:31])[NH:25][C:26]2[S:27][CH:28]=[CH:29][N:30]=2)[CH:21]=1)[O:17][C:14]1[CH:15]=[CH:16][C:11]([P:5](=[O:4])([OH:6])[OH:10])=[CH:12][CH:13]=1
Reactant: C[Si](C)(C)Br
Reactant: CC(C)OP(=O)(OC(C)C)c1ccc(Oc2cc(Sc3nccn3C)cc(C(=O)Nc3nccs3)c2)cc1
Solvent: ClCCl
Product: Br
Product: Cn1ccnc1Sc1cc(Oc2ccc(P(=O)(O)O)cc2)cc(C(=O)Nc2nccs2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.7 %

Procedure:
In a manner similar to Example 1, a mixture of {4-[3-(1-methyl-1H-imidazol-2-ylsulfanyl)-5-(thiazol-2-ylcarbamoyl)-phenoxy]-phenyl}-phosphonic acid diisopropyl ester (58 mg, 0.10 mmol) and bromotrimethylsilane (0.27 mL, 2.03 mmol) in 2 mL CH2Cl2 was stirred for 16 h at rt. The solvent evaporated, the residue dissolved in CH3CN and then the solvent evaporated, and the residue sonicated in a mixture of 1 mL CH3CN and 0.1 mL water. The resulting white solid was collected by filtration and dried under high vacuum to provide 30 mg (61%) of the title compound. 1H NMR (500 MHz, DMSO-d6): δ 3.84 (s, 3H), 7.14 (dd, 2H, J=8, 3 Hz), 7.30 (d, 1H, J=4 Hz), 7.38 (br s, 1H), 7.55 (d, 1H, J=4 Hz), 7.72 (d, 1H, J=1 Hz), 7.72 (dd, 2H, J=12, 8 Hz), 7.76 (br s, 1H), 7.80 (t, 111, J=2 Hz), 7.88 (d, 1H, 1=1 Hz); LCMS (m/z): 489.5 [C20H17N4O5PS2+H]+. Anal. calcd. for (C20H17N4O5PS2+1.5HBr+1.5H2O): C, 37.72; H, 3.40; N, 8.80. Found: C, 37.94; H, 3.44; N, 8.58.
Reaction SMILES: CC1C=CC(C[S:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=CC=1.[CH3:16][C:17]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[C:18]=1[CH2:19]Cl.CC[O-].[Na+].SCC(OCC)=O>C(O)C>[CH3:16][C:17]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[C:18]=1[CH2:19][S:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)CSCc1ccc(C)cc1
Reactant: Cc1cc(C)c(CCl)c(C)c1
Agent: CCOC(=O)CS
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CSCc1c(C)cc(C)cc1C

Procedure:
The procedure is as in Example 29 for the preparation of ethyl (4-methylbenzylthio)acetate, starting with 2,4,6-trimethylbenzyl chloride (10.25 g), a 2M ethanolic solution of sodium ethylate (32.5 cc) and ethyl 2-mercaptoacetate (7.1 g) in ethanol (150 cc). Ethyl (2,4,6-trimethylbenzylthio)acetate (11 g) is thereby obtained, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: [OH-:1].C([N+]([CH2:15][CH2:16][CH2:17][CH3:18])(CCCC)CCCC)CCC>C(#N)C>[C:15]1([OH:1])[C:16]2[C:17]3[C:18](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:18]=2[CH:17]=[CH:16][CH:15]=1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: [OH-]
Solvent: CC#N
Product: Oc1cccc2c1-c1ccccc1-2

Procedure:
Diacyl biphenyl XIX is treated with a reducing agent (e.g., tetrabutylammonium hydroxide)in an organic solvent (e.g., acetonitrile) to form a biphenyl enol ##STR28##
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[OH:10].C(N(CC)CC)C.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].[OH-].[Na+]>O1CCCC1.CCCCCCC>[C:21]([Si:18]([O:10][C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[F:1])([CH3:20])[CH3:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: COc1ccc(F)c(O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: COc1ccc(F)c(O[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.7 %

Procedure:
To a flask, 2-fluoro-5-methoxyphenol (6.00 g, 42 mmol), triethylamine (5.77 g, 57 mmol), and tetrahydrofuran (36.0 mL) were added, and the resulting mixture was cooled in an ice water bath under nitrogen atmosphere. To the solution, a solution of tert-butyldimethylsilyl chloride (6.89 g, 44 mmol) in tetrahydrofuran (30.0 mL) was added dropwise, and the resulting mixture was stirred overnight at room temperature. To the reaction mixture, heptane and a 2 N aqueous sodium hydroxide solution were added, and the resulting mixture was extracted. The organic layer was washed with water, and concentrated under reduced pressure to obtain the captioned compound (10.2 g) as a light brownish-red oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH:13]([C:17]3[N:18]=[C:19]([C:22]([F:25])([F:24])[F:23])[S:20][CH:21]=3)[CH2:12]2)=[CH:5][CH:4]=1.Br.C(=O)([O-])[O-].[K+].[K+].BrC[C:35]([O:37][CH3:38])=[O:36]>CC(C)=O>[C:35]([CH2:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH:13]([C:17]3[N:18]=[C:19]([C:22]([F:25])([F:24])[F:23])[S:20][CH:21]=3)[CH2:12]2)=[CH:5][CH:4]=1)([O:37][CH3:38])=[O:36]
Reactant: COC(=O)CBr
Reactant: COc1ccc(CCN2CCOC(c3csc(C(F)(F)F)n3)C2)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(CCN2CCOC(c3csc(C(F)(F)F)n3)C2)cc1

Procedure:
0.6 g (1.6 mmol) of N-[2-(4-Methoxyphenyl)ethyl]-2-(2-trifluoromethyl-thiazol-4-yl)morpholine are heated on a steam bath with 6 ml of 48% strength aqueous hydrobromic acid for 3 hours. The mixture is then concentrated, toluene is added, and the mixture is again evaporated to dryness. The foamy residue is boiled under reflux in 15 ml of acetone with 1.2 g (8.7 mmol) of potassium carbonate and 0.3 ml (1.65 mmol) of methyl bromoacetate for 1 hour. The mixture is then filtered, the filtrate is concentrated, and the residue is purified on a silica gel column using toluene/acetone =4:1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.[Br:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17](Br)[CH:18]=1.C(=O)(O)[O-].[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:12][C:13]1[CH:18]=[C:17]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH:16]=[CH:15][CH:14]=1
Reactant: Brc1cccc(Br)c1
Reactant: COc1ccccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccccc1-c1cccc(Br)c1
Reaction time: 8 h
Yield: 190.7 %

Procedure:
A mixture of 2-methoxyphenylboronic acid (4.3 g, 28.3 mmol), 3,5-dibromobenzene (20 g, 85.5 mmol, 3 equiv.) and bis(triphenylphosphine)palladium(II) dichloride (100 mg) in ethyleneglycol dimethylether (25 mL) and a solution of sodium bicarbonate (8.2 g, 0.098 mol) in water (140 mL) were kept at reflux under nitrogen with good stirring overnight. After cooling, the reaction mixture was partitioned between ethyl acetate (600 mL) and water (300 mL). The organic phase was washed with water (2×300 mL), dried over sodium sulfate and filtered. The solvent was removed in vacuo and the crude product was purified by chromatography on silica (150 g) with heptane (6 L) to afford pure 21 (14.2 g, 58%).
Reaction SMILES: [C:1](#[N:3])[CH3:2].[Li+].CCC[CH2-].[F:9][C:10]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:11]=1[C:12](OC)=[O:13].Cl>O1CCCC1>[F:9][C:10]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:11]=1[C:12](=[O:13])[CH2:2][C:1]#[N:3]
Reactant: COC(=O)c1ccc(OC)cc1F
Reactant: CC#N
Agent: Cl
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)CC#N)c(F)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
To a solution of 4.4 g (108.6 mmol, 5.7 ml) of acetonitrile diluted in 50 ml of anhydrous tetrahydrofuran are added dropwise at −78° C. under argon 27.1 ml of a N-butyllithium solution (2.5M in hexane, 67.8 mmol), the reaction mixture is stirred 30 min at −78° C., then 5 g (27.15 mmol) of methyl 2-fluoro-4-methoxybenzoate diluted in 30 ml of tetrahydrofuran are added dropwise at −78° C. to the reaction mixture. This mixture is stirred 2 h at −78° C., then a 1M hydrochloric acid solution is added, and the product is extracted several times with ethyl acetate. The organic phases are combined, dried over magnesium sulfate and concentrated. The solid is triturated in 15 ml of methanol to yield 4.4 g (84%) of 3-(2-fluoro-4-methoxyphenyl)-3-oxopropanenitrile in beige solid form.
Reaction SMILES: [N+:1]([CH:4]([N+:6]([O-:8])=[O:7])[CH3:5])([O-:3])=[O:2].[OH-].[K+].[C:11]([O:15][CH:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:17][CH3:18])(=[O:14])[CH:12]=[CH2:13].CO>O>[N+:1]([C:4]([N+:6]([O-:8])=[O:7])([CH3:5])[CH2:13][CH2:12][C:11]([O:15][CH:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:17][CH3:18])=[O:14])([O-:3])=[O:2]
Reactant: C=CC(=O)OC(CC)CCCCC
Reactant: CC([N+](=O)[O-])[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCC(CC)OC(=O)CCC(C)([N+](=O)[O-])[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h
Yield: 80.5 %

Procedure:
Dinitroethane (2.4 g, 0.02 mol) and potassium hydroxide (1.2 g, 0.22 mol) were dissolved in 50 mL of water to form a first solution. 50 mL of water was added to the first solution to dissolve a salt remaining in the first solution to form a second solution. Octane-3-yl acrylate (8.3 mL, 0.05 mol) was mixed with 50 mL of methanol, and then the mixture was slowly added to the second solution to form a third solution. The third solution was stirred at room temperature for 5 hours. The reaction product was extracted by diethyl ether, and was then distilled under reduced pressure to obtain yellow liquid octane-3-yl 4,4-dinitropentanoate (4.9 g, yield: 80%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Br:9])[CH:3]=1.C([Li])CCC.[F:15][C:16]([F:24])([F:23])[C:17]([C:19]([F:22])([F:21])[F:20])=[O:18].Cl>CCCCCC.C(OCC)C>[F:15][C:16]([F:24])([F:23])[C:17]([C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Br:9])[CH:3]=1)([OH:18])[C:19]([F:22])([F:21])[F:20]
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: Brc1cc(Br)cc(Br)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: OC(c1cc(Br)cc(Br)c1)(C(F)(F)F)C(F)(F)F
Temperature: -78 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
Under nitrogen atmosphere, a 500 mL glass flask was charged with 30.0 g (95.0 mmol) of 1,3,5-tribromobenzene and 400 mL of diethyl ether, followed by cooling to −78° C. At −78° C., 60 mL of a 1.6M solution containing 96.0 mmol of n-butyllithium in hexane was added dropwise by spending 1 hr, followed by aging at −78° C. for 1 hr. After confirming lithiation by gas chromatography, 16.6 g (100.0 mmol) of hexafluoroacetone was bubbled at −78° C., followed by stirring for 1 hr. After stirring, the reaction liquid was added to 400 mL of 2N hydrochloric acid to separate it into an organic layer and an aqueous layer. The aqueous layer was extracted with 100 mL of isopropyl ether. The combined organic layer was dried with anhydrous magnesium sulfate, followed by concentration with an evaporator and then solid distillation, thereby obtaining 23.0 g of 1-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-3,5-dibromobenzene (yield: 60%) represented by the following formula.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1.[O-:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14].[C:20]1([I+]C2C=CC=CC=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(OCC)C>O.C([O-])(=O)C1C=CC=CC=1.[Cu+2].C([O-])(=O)C1C=CC=CC=1>[O-:15][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:14])=[O:12].[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S+:6]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: c1csc(Sc2cccs2)c1
Reactant: c1ccc([I+]c2ccccc2)cc1
Agent: [Cu+2]
Agent: O=C([O-])c1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: O
Solvent: CCOCC
Product: c1ccc([S+](c2cccs2)c2cccs2)cc1
Reaction time: 24 h
Yield: 77 %

Procedure:
Di-(2-thienyl)sulfide (2.1 g, 0.0104 mole), diphenyliodonium triflate (5.8 g, 0.0135 mole) and copper benzoate (0.08 g, 0.003 mole) are heated without solvent for 3 hours at 120-145° C. under a nitrogen atmosphere. After cooling down, 75 ml ethyl ether was added and the mixture vigorously stirred overnight to achieve solidification. Filtration and washing with ethyl ether yielded a brown solid, which was dissolved in hot water, the solution filtered and the water removed in vacuo. The resulting white solid was stirred in 50 ml ethyl ether for 24 hours, the mixture filtered and the residue washed with ethyl ether, yielding 3.4 g (78%) of the title compound, di(2-thienyl)phenylsulfonium triflate. The structure was confirmed by 1H/13C NMR spectroscopy.