Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([Cl:11])=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([O:22][CH3:23])[CH:16]=1.C(N(CC)CC)C>CN(C=O)C.O>[Cl:11][C:10]1[C:3]2[C:2]([NH:12][CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([O:22][CH3:23])[CH:16]=3)=[N:7][CH:6]=[N:5][C:4]=2[S:8][CH:9]=1
Reactant: COc1cc(CCN)ccc1O
Reactant: Clc1csc2ncnc(Cl)c12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(CCNc2ncnc3scc(Cl)c23)ccc1O
Yield: 76 %

Procedure:
A solution of 4,5-dichlorothieno[2,3-d]pyrimidine (2.0 g, 9.8 mmol), 4-(2-aminoethyl)-2-methoxyphenol (1.8 g, 10.7 mmol) and triethylamine (1.2 g, 11.8 mmol) in DMF (15 mL) was stirred overnight. The solution was diluted with H2O and the product collected by filtration yielding an off white powder, 2.5 g, 7.4 mmol, 76 percent yield.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([N:12]1[C:16]2[C:17](=[O:22])[N:18]([CH3:21])[N:19]=[CH:20][C:15]=2[N:14]=[C:13]1[N:23]1[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]1)[C:9]#[C:10][CH3:11]>ClCCl>[CH2:8]([N:12]1[C:16]2[C:17](=[O:22])[N:18]([CH3:21])[N:19]=[CH:20][C:15]=2[N:14]=[C:13]1[N:23]1[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]1)[C:9]#[C:10][CH3:11]
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2cnn(C)c(=O)c21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC#CCn1c(N2CCNCC2)nc2cnn(C)c(=O)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.8 %

Procedure:
200 ml of trifluoroacetic acid was added to 200 ml of a dichloromethane solution containing 54.3 g of t-butyl 4-[1-(2-butynyl)-6-methyl-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]piperazine-1-carboxylate, and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, the residue was dissolved in 500 ml of ethyl acetate. 1 L of 10% aqueous sodium bicarbonate solution was gradually added. Then, 1 L of ethyl acetate and 500 ml of a 5N aqueous sodium hydroxide solution were added to the solution. The organic layer was separated. Then, the aqueous layer was extracted five times with 1 L of dichloromethane. The organic layers were combined together, washed with 500 ml of an aqueous solution of 2N sodium hydroxide, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give 30.5 g of the crystalline title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:11]=[C:12]([C:17]2([C:32]([F:35])([F:34])[F:33])[O:21][N:20]=[C:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[C:24]([CH3:31])[CH:23]=3)[CH2:18]2)[CH:13]=[C:14]([Cl:16])[CH:15]=1>N1C=CC=CC=1>[Br:8][C:5]1[CH:4]=[N:3][C:2]([NH:1][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([C:19]3[CH2:18][C:17]([C:12]4[CH:13]=[C:14]([Cl:16])[CH:15]=[C:10]([Cl:9])[CH:11]=4)([C:32]([F:35])([F:34])[F:33])[O:21][N:20]=3)=[CH:23][C:24]=2[CH3:31])=[N:7][CH:6]=1
Reactant: Nc1ncc(Br)cn1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Cl
Solvent: c1ccncc1
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Nc1ncc(Br)cn1
Yield: 70 %

Procedure:
In a solution of 2.87 g of 2-amino-5-bromopyrimidine in 40 mL of pyridine, 6.00 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methylbenzoyl-chloride synthesized in Step 4 of Synthetic Example 1 was added at room temperature with stirring, and stirred at the same temperature for 2 days. The solvent was distilled off under reduced pressure, the residue was dissolved in 30 mL of 1,4-dioxane, a solution of 3.09 g of potassium hydroxide in 30 mL of water was added and stirred at room temperature for 3 hours. After the completion of the reaction, 20 mL of hydrochloric acid was added in the reaction mixture under cooling with ice and with stirring, extracted with ethyl acetate (50 mL×1), the organic phese was washed with 50 mL of 3N hydrochloric acid, and dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with neutral alumina column chromatography that was eluated with chloroform to obtain 5.52 g of the aimed product as white crystal.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH:3]([OH:8])[C:4]([F:7])([F:6])[F:5].ClC(Cl)(O[C:15](=[O:21])OC(Cl)(Cl)Cl)Cl.C(N(CC)C(C)C)(C)C.[CH3:32][CH:33]1[CH2:38][NH:37][CH2:36][CH2:35][N:34]1[CH2:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[CH:42][CH:41]=1>O.C(#N)C>[CH3:32][CH:33]1[N:34]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)=[CH:42][CH:41]=2)[CH2:35][CH2:36][N:37]([C:15]([O:8][CH:3]([C:4]([F:7])([F:6])[F:5])[C:2]([F:10])([F:9])[F:1])=[O:21])[CH2:38]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OC(C(F)(F)F)C(F)(F)F
Reactant: CC1CNCCN1Cc1ccc(-c2ccccc2)cc1
Solvent: O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC1CN(C(=O)OC(C(F)(F)F)C(F)(F)F)CCN1Cc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.1 %

Procedure:
A 50 mL round-bottom flask was charged with 1,1,1,3,3,3-hexafluoropropan-2-ol (168 mg, 1.00 mmol, 1.00 equiv), triphosgene (99.0 mg, 0.330 mmol, 0.33 equiv), and acetonitrile (10 mL). N,N-diisopropylethylamine (471 mg, 3.64 mmol, 3.65 equiv) was added dropwise. The mixture was stirred at room temperature for 2 hours. 2-Methyl-1-[(4-phenylphenyl)methyl]piperazine (266 mg, 1.00 mmol, 1.00 equiv) was added. The resulting solution was stirred for 2 hours at room temperature and diluted with water (20 mL). The resulting solution was extracted with dichloromethane (3×20 mL) and the organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/3). The product (208 mg) was purified by preparative HPLC using the following gradient conditions: 20% CH3CN/80% Phase A increasing to 80% CH3CN over 10 min, then to 100% CH3CN over 0.1 min, holding at 100% CH3CN for 1.9 min, then reducing to 20% CH3CN over 0.1 min, and holding at 20% for 1.9 min, on a Waters 2767-5 Chromatograph. Column: Xbridge Prep C18, 19*150 mm 5 um; Mobile phase: Phase A: aqueous NH4HCO3 (0.05%); Phase B: CH3CN; Detector, UV220 & 254 nm. Purification resulted in 91.3 mg (20% yield) of 1,1,1,3,3,3-hexafluoropropan-2-yl 3-methyl-4-[(4-phenylphenyl)methyl]piperazine-1-carboxylate as colorless oil. 1H NMR 400 MHz (CDCl3) δ 7.54-7.62 (m, 4H), 7.33-7.49 (m, 5H), 5.75-5.80 (m, 1H), 3.98-4.23 (m, 1H), 3.75-3.86 (m, 2H), 3.01-3.48 (m, 3H), 2.62-2.77 (m, 2H), 2.20-2.27 (m, 1H), 1.19 (br, 3H). LCMS (ESI, m/z): 461 [M+H]+.
Reaction SMILES: [Cl-:1].[Al+3].[Cl-].[Cl-].[Cl:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10](Cl)=[O:11].[CH:13]1[C:26]2[C:17](=[CH:18][C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[Cl:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([C:16]1[C:17]2[C:26](=[CH:25][C:24]3[C:19]([CH:18]=2)=[CH:20][CH:21]=[CH:22][C:23]=3[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][Cl:1])[CH:13]=[CH:14][CH:15]=1)=[O:11]
Reactant: [Cl-]
Reactant: c1ccc2cc3ccccc3cc2c1
Reactant: O=C(Cl)CCCCCl
Agent: [Al+3]
Solvent: ClCCl
Product: O=C(CCCCCl)c1cccc2cc3c(C(=O)CCCCCl)cccc3cc12
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 97.7 %

Procedure:
To a mixture of 226 g of aluminum chloride (0.17 mole), 280 g of 5-chlorovaleryl chloride (1.18 mole), and 5 liters of methylene chloride is added 100 g (0.56 mole) of anthracene contained in 1 liter of methylene chloride. The mixture is stirred for 1.5 hours and added to 2 liters of an ice-water mixture. The organic layer is separated and stirred with 2 liters of a saturated aqueous sodium bicarbonate solution for 16 hours. The organic phase is separated, dried and evaporated in vacuo to give a residue, which when crystallized from benzene yields 69 g of the desired product, 1,5-bis(5-chlorovaleryl)anthracene. Recrystallization from ethyl cellosolve and again from benzene results in a product having bright yellow needles and having a m.p. of 146°-8° C.
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14](S(C3C=CC(C)=CC=3)(=O)=O)[CH:13]=2)[CH2:4]1.[OH-].[Na+].O>CC(C)=O.CO>[NH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([C@H:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C@H:3]([NH:2][CH3:1])[CH2:4]2)=[CH:13]1
Reactant: CN[C@@H]1C[C@@H](c2cn(S(=O)(=O)c3ccc(C)cc3)c3ccccc23)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Solvent: CO
Product: CN[C@@H]1C[C@@H](c2c[nH]c3ccccc23)c2ccccc21
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
Dimethylbromoborane (1.77 mL, 1.05 equiv) (Synthesized according to Nöth, H., Vahrenkamp, H. Journal of Organometallic Chemistry 11(1968), 399-405) was added to 3-((1R,3R)-3-azido-indan-1-yl)-1-(toluene-4-sulfonyl)-1H-indole (17.3 mmol ) in 100 mL 1,2-dichloro-ethane under argon at 0° C. The reaction mixture was warmed to room temperature and stirred 2.5 hours. 1 mL Ethanol was added. The reaction mixture was extracted with ethyl acetate and 0.5N aqueous NaOH. The organic phase was washed with brine, dried over MgSO4, concentrated in vacuo to give methyl-{(1R,3R)-3-[1-(toluene-4-sulfonyl)-1H-indol-3-yl]-indan-1-yl}-amine after flash chromatography (ethyl acetate, methanol, triethylamine, silica gel). Methyl-{(1R,3R)-3-[1-(toluene-4-sulfonyl)-1H-indol-3-yl]-indan-1-yl}-amine was dissolved in 8 mL acetone and 20 mL methanol. 8 mL 28% Aqueous NaOH was added and the reaction mixture was stirred in two portions at 120° C. for 10 minutes under microwave irradiation using the Emry Optimizer™ instrument. The reaction mixture was poured into 250 mL water and a precipitate was formed. Recrystallization gave 2.15 g [(1R,3R)-3-(1H-indol-3-yl)-indan-1-yl]-methyl-amine.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH2:19]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCCc2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1CCCc2ccc(OCc3ccccc3)cc21
Reaction time: 3 h

Procedure:
7-Benzyloxy-3,4-dihydro-1(2H)naphthalenone was prepared by treating 7-hydroxy-1-tetralone (5.91 g, 36.4 mmol) and caesium carbonate (13 g, 40.0 mmol) in dry DMF (100 ml) and under N2 with benzylbromide (6.22 g, 4.33 ml, 36.4 mmol). The reaction was stirred for 3 h and the mixture then filtered and the filtrate concentrated in vacuo. The oily residue was partitioned between ethyl acetate (200 ml) and brine (200 ml), the organic layer separated, dried (MgSO4) and concentrated in vacuo. Trituration of the resultant solid with diethylether-hexane (1:1, 200 ml) gave the desired compound as a white solid (6.57 g) m.p. 86-87°. MS (EI, 60 V) 252 (M+, 100%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[NH:15][C:16](=[O:27])[C:17]2[N:22]([CH3:23])[N:21]=[C:20]([CH2:24][CH2:25][CH3:26])[C:18]=2[N:19]=1)[CH3:6].O>S(=O)(=O)(O)O>[CH2:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:1]([O-:4])=[O:2])=[CH:10][C:9]=1[C:14]1[NH:15][C:16](=[O:27])[C:17]2[N:22]([CH3:23])[N:21]=[C:20]([CH2:24][CH2:25][CH3:26])[C:18]=2[N:19]=1)[CH3:6]
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3ccccc3OCC)nc12
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3cc([N+](=O)[O-])ccc3OCC)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 61 %

Procedure:
Concentrated nitric acid (0.5 ml) was added dropwise to a stirred solution of 5-(2-ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one (2.0 g, 0.0064 mol) in concentrated sulphuric acid (10 ml) at 0° C., an the resulting orange solution was stirred at room temperature for 18 hours. The reaction solution was then added dropwise to stirred ice and water (200 g) and the solid precipitate collected by filtration. This solid was then dissolved in dichloromethane (50 ml) and the solution washed successively with brine (2×30 ml) and water (30 ml), dried (Na2SO4) and evaporated under vacuum to give a yellow solid. Crystallisation from acetronitrile gave the title compound as yellow needles (1.40 g, 61%), m.p. 214°-216° C. Found: C,57.36; H,5.21; N,19.49. C17H19N5O4 requires C,57.13; H,5.36; N,19.60%.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].ClC1C=CC=C(C(OO)=O)C=1.C[Si]([C:31]#[N:32])(C)C>>[C:31]([C:11]1[CH:10]=[CH:15][CH:14]=[CH:13][N:12]=1)#[N:32].[CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:31]#[N:32])=[N:12][CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: CCOP(=O)(Cc1cccnc1)OCC
Reactant: C[Si](C)(C)C#N
Agent: O=C(OO)c1cccc(Cl)c1
Product: CCOP(=O)(Cc1ccc(C#N)nc1)OCC
Product: N#Cc1ccccn1

Procedure:
Treatment of 3-(diethylphosphonomethyl)pyridine (Biochemistry 19, 3400) with m-chloroperbenzoic acid followed by trimethylsilyl cyanide gives both 3-diethylphosphonomethyl)-2-cyanopyridine and 5-(diethylphosphonomethyl)-2-cyanopyridine, the starting materials for compounds under (a) and (b).
Reaction SMILES: [O-2].[Ca+2].[O:3]([CH2:10][C:11]([NH:13][CH:14]1[C:36](=[O:37])[N:16]2[CH:17]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=3)=[O:24])[C:18]([CH3:22])([CH3:21])[S:19](=[O:20])[C@H:15]12)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1OC1C>C1(C)C=CC=CC=1>[O:3]([CH2:10][C:11]([NH:13][CH:14]1[C:36](=[O:37])[N:16]2[CH:17]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=3)=[O:24])[C:18](=[CH2:21])[CH2:22][S:19](=[O:20])[C@H:15]12)=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC1(C)C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2S1=O
Agent: CC1CO1
Agent: [Ca+2]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: C=C1CS(=O)[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 46.9 %

Procedure:
To a 200 gallon glass-lined still were added 400 liters of binary-dried toluene. To the toluene then were added 14.6 kg. of calcium oxide, 14.6 kg. of p-nitrobenzyl 6-phenoxyacetamido-2,2-dimethylpenam-3-carboxylate-1-oxide, and 6.67 kg. of N-chlorophthaimide. The mixture was heated to 100° C., and 11.68 liters of propylene oxide were added over a 4 minute period. The mixture was refluxed at a temperature of 102°-103° C. for about 90 minutes and then was concentrated over a period of about 45 minutes. About 71 liters of material were removed, and the temperature of the mixture rose from about 103° C. to about 110°-111° C. The mixture then was cooled to about 95° C. and was filtered into a mixture of 7.3 liters of stannic chloride in 108 liters of toluene, the total having been cooled to -6° C. Upon completion of the filtration, an additional 30 liters of toluene were added to facilitate complete transfer of the mixture. The mixture then was allowed to stir overnight at a temperature of from about 17°-20° C. The resulting solid was collected by filtration and was dissolved in 73 liters of acetone. To the acetone solution then were added 146 liters of ethyl acetate followed by 292 liters of water. The mixture was stirred for 5 minutes and then was separated. The organic layer was concentrated in vacuo to about 135 liters, cooled to 0°-5° C., and maintained at that temperature overnight. The resulting mixture was filtered, and the collected solid was washed with 25 liters of ethyl acetate and dried at 50° C. to obtain 6.8 kg. (46.9%) of the title compound.
Reaction SMILES: [CH:1]1([OH:5])[CH2:4][CH2:3][CH2:2]1.CN(C=O)C.[H-].[Na+].[Br:13][C:14]1[C:19]([O:20][CH3:21])=[CH:18][C:17]([CH2:22]Cl)=[CH:16][C:15]=1[O:24][CH3:25]>C(OCC)(=O)C.O>[Br:13][C:14]1[C:19]([O:20][CH3:21])=[CH:18][C:17]([CH2:22][O:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)=[CH:16][C:15]=1[O:24][CH3:25]
Reactant: COc1cc(CCl)cc(OC)c1Br
Reactant: OC1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(COC2CCC2)cc(OC)c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
To a mixture of cyclobutyl alcohol (4.16 g, 57.7 mmol) and DMF (30 mL) was added sodium hydride (60% dispersion in oil: 2.31 g, 57.7 mmol) while cooling on ice, and the mixture was stirred at room temperature for 1 hour. To this mixture was slowly added dropwise a mixture of 2-bromo-5-(chloromethyl)-1,3-dimethoxybenzene (2.47 g, 9.3 mmol) and DMF (30 mL), and the resulting mixture was stirred at room temperature for 1 hour. Water was added to the mixture while cooling on ice, and then ethyl acetate was added. After thoroughly shaking the mixture, the organic layer was separated and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The mixture was filtered, and then the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (mixture of n-heptane and ethyl acetate: n-heptane/ethyl acetate=4/1) to obtain the title compound (2.39 g, 7.94 mmol).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]=[C:10]=[S:11].[CH2:12]([NH:14][CH2:15][C:16](O)=[O:17])[CH3:13].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[C:16](=[O:17])[CH2:15][N:14]([CH2:12][CH3:13])[C:10]1=[S:11]
Reactant: CCNCC(=O)O
Reactant: Cc1ccc(C)c(N=C=S)c1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCN1CC(=O)N(c2cc(C)ccc2C)C1=S
Yield: 42.7 %

Procedure:
The title compound was prepared by the procedure described in Example 16 using 16.3 g of 2,5-dimethylphenyl-isothiocyanate, 18.4 g of N-ethyl glycine, 20.2 g of triethyl amine, and 250 mL of chloroform. Crystallization from ethyl acetate afforded the title compound (10.6 g) as an off-white solid, m.p. 176°-178° C. Anal. Calcd. for. C13H16N2O S: C,62.87; H, 6.49; N, 11.28. Found: C, 62.70; H, 6.46; N, 11.27. Mass spectrum (EI, M.+) m/z 248.
Reaction SMILES: [Cl:1]CC([NH:5][CH2:6][C:7]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:10]=[C:9]([S:17]([N:20]=CN(C)C)(=[O:19])=[O:18])[C:8]=1[OH:25])=O>C(O)C.Cl>[ClH:1].[NH2:5][CH2:6][C:7]1[CH:12]=[C:11]([C:13]([CH3:15])([CH3:16])[CH3:14])[CH:10]=[C:9]([S:17](=[O:18])(=[O:19])[NH2:20])[C:8]=1[OH:25]
Reactant: CN(C)C=NS(=O)(=O)c1cc(C(C)(C)C)cc(CNC(=O)CCl)c1O
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1cc(CN)c(O)c(S(N)(=O)=O)c1

Procedure:
3 g (0.008 mole) of 2-chloro-N-[5-(1,1-dimethylethyl)-3 -dimethylaminomethyleneaminosulfonyl-2-hydroxybenzyl]-acetamide in a mixture of 30 ml of ethanol and 3 ml of concentrated hydrochloric acid are heated under reflux for 2 hours. The solvent is removed in vacuo and the residue is crystallized from methanol/ether.
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][C:6]1[CH:7]=[C:8]([CH2:13][C@@H:14]([OH:18])[C:15]([OH:17])=[O:16])[CH:9]=[CH:10][C:11]=1[Br:12].[CH3:19][CH2:20]O>>[Br:5][C:6]1[CH:7]=[C:8]([CH2:13][C@@H:14]([OH:18])[C:15]([O:17][CH2:19][CH3:20])=[O:16])[CH:9]=[CH:10][C:11]=1[Br:12]
Reactant: O=C(O)[C@H](O)Cc1ccc(Br)c(Br)c1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)[C@H](O)Cc1ccc(Br)c(Br)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
0.8 mL (10.9 mmol) thionyl chloride were added dropwise to a solution of 3.2 g (9.9 mmol) of (R)-3-(3,4-dibromo-phenyl)-2-hydroxy-propionic acid in 40 mL dry EtOH cooled to 0° C. and the reaction mixture was stirred for 1 h at RT. The reaction solution was evaporated down i.vac. the residue combined with 30 mL DCM and filtered to remove the insoluble precipitate. After the solvent had been eliminated the product was obtained as a viscous oil, which was further reacted without purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([CH2:11][CH2:12][CH3:13])[CH:10]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[CH2:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH2:12][CH3:13])[N:8]([CH2:21][C:22]([N:24]2[CH2:25][CH2:26][N:27]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH2:28][CH2:29]2)=[O:23])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCCc1cc(C(=O)OCC)[nH]n1
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCCc1cc(C(=O)OCC)nn1CC(=O)N1CCN(c2ccc(F)cc2)CC1

Procedure:
Protocol T was followed using 5-Propyl-2H-pyrazole-3-carboxylic acid ethyl ester, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1/1) afforded the title compound as white solid. 1H NMR (400 MHz, CDCl3): 6.94-7.0 (m, 2H), 6.82-6.90 (dd, 2H), 6.2 (s, 1H), 5.06 (s, 2H), 4.34-4.40 (q, 2H), 3.62-3.8 (m, 4H), 3.02-3.12 (m, 4H), 2.54-2.60 (t, 2H), 1.64-1.78 (m, 2H), 1.34-1.38 (t, 3H), 0.98-1.4 (t, 3H). 13C NMR (400 MHz, CDCl3): 165, 160, 156.4, 152.2, 146.6, 132.8, 118.4, 118.2, 115.8, 115.4, 113.2, 61, 53, 50.6, 50.2, 45.2, 42, 28, 21.8, 14.2, 14.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][CH:10]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[Se].C(N=C=[Se:41])C1C=CC=CC=1>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][N:9]=[C:10]=[Se:41])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CNCCc1ccccc1
Reactant: [Se]=C=NCc1ccccc1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Se]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: [Se]=C=NCCc1ccccc1
Yield: 95 %

Procedure:
(AS3.091) A mixture of phenylethylformamide (g, 1.5 mmol), triethylamine (6.4 mmol), 4 Å molecular sieves (g), triphosgene (0.8 mmol), and selenium powder (3.0 mmol) in CH2Cl2 was refluxed and worked up as mentioned for 2a. The crude residue thus obtained was purified by silica gel column chromatography (EtOAc/hexanes 2:98) to give 0.96 g (95%) of 2b as an oil. 1H NMR (CDCl3) δ 3.03 (t, 2H, J=6.9 Hz), 3.81 (t, 2H, J=6.9 Hz) 7.20-7.38 (m, 5H); HRMS (EI) calcd for C9H9NSe, 210.9895. found, 210.9892.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9](OC)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:13][C:14]1[CH:30]=[CH:29][C:17]([O:18][CH2:19][CH2:20][NH:21]C(=O)OC(C)(C)C)=[C:16]([C:31]2[N:35]([CH3:36])[N:34]=[CH:33][C:32]=2[Cl:37])[CH:15]=1.CN([C:41]([O:45]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.Cl>ClCCl>[NH2:21][CH2:20][CH2:19][O:18][C:17]1[CH:29]=[CH:30][C:14]([NH:13][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([O:45][CH3:41])[C:2]=2[F:1])=[CH:15][C:16]=1[C:31]1[N:35]([CH3:36])[N:34]=[CH:33][C:32]=1[Cl:37]
Reactant: Cn1ncc(Cl)c1-c1cc(N)ccc1OCCNC(=O)OC(C)(C)C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1ccc(C(=O)O)c(F)c1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(C(=O)Nc2ccc(OCCN)c(-c3c(Cl)cnn3C)c2)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-fluoro-4-methoxybenzoic acid (92.8 mg, 545 μmol), tert-butyl 2-(4-amino-2-(4-chloro-1-methyl-1H-pyrazol-5-yl)phenoxy)ethylcarbamate (200 mg, 545 μmol), HATU (207 mg, 545 μmol) and triethylamine (76.0 μL, 545 μmol) in dichloromethane was stirred at room temperature overnight. The reaction was diluted with dichloromethane and washed with water. The organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated. To the crude product was added 2M HCl (5 eq.). The mixture was stirred at room temperature overnight. The mixture was concentrated and the title compound was obtained as a yellow oil. LCMS m/z (%)=419 (M+H, 35Cl, 100), 421 (M+H, 37Cl, 40).