Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=O.C(N(CC)CC)C.[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[C:20]#[CH:21])[CH3:17].O.[NH2:26][NH2:27]>O1CCOCC1.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.[Cu](I)I>[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[C:20]1[NH:27][N:26]=[C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[CH:21]=1)[CH3:17]
Reactant: C#CC(OCC)OCC
Reactant: O=C(Cl)c1cccs1
Reactant: NN
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(OCC)c1cc(-c2cccs2)n[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.3 %

Procedure:
A solution of 2-thiophenecarbonyl chloride (3.0 g, 23.41 mmol) in anhydrous dioxane (60 mL) was bubbled with argon for 10 minutes. Triethylamine (9.80 mL, 70.22 mmol) was added and the bubbling was maintained for 5 minutes. Bis(triphenylphosphine)palladium(II) dichloride (657 mg, 0.94 mmol), copper iodide (356 mg, 1.87 mmol) and 3,3-diethoxy-1-propyne (3.36 mL, 23.41 mmol) were added, and the reaction mixture was stirred for 2 hours at room temperature, under argon atmosphere. The solution was filtered and water (50 mL) was added to the filtrate. Layers were separated and the aqueous layer was extracted with dichloromethane (2×50 mL). The combined organic layers were washed with a saturated solution of sodium hydrogenocarbonate (50 mL), dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in ethanol (200 mL) and hydrazine hydrate (2.51 g, 35.10 mmol) was added. The reaction mixture was stirred overnight and concentrated in vacuo. The residue was dissolved in ethyl acetate (40 mL) and successively washed with water (40 mL) and brine (40 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to provide 5-(diethoxymethyl)-3-(thiophen-2-yl)-1H-pyrazole (34a) (4.39 g, 17.40 mmol, 74%) which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([N:8]([O:10][CH3:11])[CH3:9])=[O:7])=[CH:4][C:3]=1[OH:14].[CH:15](I)([CH3:17])[CH3:16].C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C>C(Cl)Cl.O>[F:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([N:8]([O:10][CH3:11])[CH3:9])=[O:7])=[CH:4][C:3]=1[O:14][CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)I
Reactant: CON(C)C(=O)c1ccc(F)c(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(F)c(OC(C)C)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
A 2 L round bottom flask equipped with a mechanical stirrer, a N2 inlet, a condenser and a temperature controller, was charged 4-fluoro-3-hydroxy-N-methoxy-N-methylbenzamide (99.6 g, 0.5 mol), isopropyl iodide (110.5 g, 0.65 mol) and Cs2CO3 (195.5 g) and DMF (300 mL). The reaction mixture was heated at 50° C. for 3 h. Isopropyl iodide (17.0 g, 0.1 mol) was added and the reaction was heated at 50° C. for 12 h. The reaction mixture was allowed to cool to rt and water (1 L) and CH2Cl2 (500 mL) were added. The reaction mixture was stirred at rt for 0.5 h, and the organic phase was separated. The aqueous layer was extracted with CH2Cl2 (3×500 mL). The combined organic extracts were washed with water (2×1 L), brine (1 L), dried over MgSO4, filtered and concentrated in vacuo at 40° C. for 18 h to give 4-fluoro-3-isopropoxy-N-methoxy-N-methlbenzamide as an off-white solid (120.0 g, 100%).
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([OH:15])=[O:14])[CH:9]=[CH:10][CH:11]=1.[C:16](=O)(O)[O-].[Na+]>CO>[CH3:16][O:14][C:13](=[O:15])[CH2:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([NH2:5])[CH:7]=1
Reactant: Nc1cccc(CC(=O)O)c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1cccc(N)c1

Procedure:
Methanol (20 mL) was cooled to −10 degrees under an atmosphere of argon. To the solvent was added dropwise thionyl chloride (4.31 mL) and a solution of 3-aminophenylacetic acid (3.00 g) in methanol (25 mL) and the mixture was stirred at −10˜0 degrees for 1 hour. To the reaction mixture was added saturated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, and then concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:1) to give the title compound (3.90 g) having the following physical data.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:12]([S:13]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:22][N:23](C)[C:24](=O)[O:25][C:26]([CH3:29])(C)C)[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:32]([O:35]CC)(=[O:34])[CH3:33].Cl.C([OH:41])C>>[C:26]([OH:25])(=[O:41])/[CH:29]=[CH:33]/[C:32]([OH:35])=[O:34].[Cl:1][C:2]1[C:7]([C:8]2[N:12]([S:13]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)(=[O:14])=[O:15])[CH:11]=[C:10]([CH2:22][NH:23][CH3:24])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CCO
Reactant: CCOC(C)=O
Reactant: CN(Cc1cc(-c2cccnc2Cl)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Agent: Cl
Product: CNCc1cc(-c2cccnc2Cl)n(S(=O)(=O)c2cccnc2)c1
Product: O=C(O)/C=C/C(=O)O
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
tert-Butyl {[5-(2-chloropyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (280 mg) was dissolved in ethanol (10 mL), a 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL) was added and the mixture was stirred at 70° C. for 30 min. The reaction mixture was concentrated under reduced pressure, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (10 mL), a solution of fumaric acid (116 mg) in methanol (3 mL) was added, and the obtained crystals were collected by filtration to give the title compound as colorless crystals (yield 197 mg, 68%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].[Cl-].Cl[C:13](=[N+:15]([CH3:17])[CH3:16])Cl>C(Cl)Cl>[CH3:13][N:15]([CH3:17])[C:16]1[O:10][C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=2[N:1]=1
Reactant: C[N+](C)=C(Cl)Cl
Reactant: N#Cc1ccc(O)c(N)c1
Agent: [Cl-]
Solvent: ClCCl
Product: CN(C)c1nc2cc(C#N)ccc2o1

Procedure:
A mixture of 3-Amino-4-hydroxybenzonitrile (2 g, 14.9 mmol) and dichloromethylenedimethylammonium chloride (phosgene iminium chloride, 2.42 g, 14.9 mmol) in 50 mL of dry CH2Cl2 was refluxed for 6 h. After cooling the solution was extracted with EtOAc, washed with NaHCO3, brine and dried (MgSO4). The residue was crystallized in MeOH yielding 2.51 g (90%) of the title compound as a white solid. M.p.: 198-200° C., 1H NMR (CD3OD) δ 7.61 (d, 1H, J=2.8 Hz, H-4), 7.36-7.32 (m, 2H, H-6, H-7), 3.28 (s, 6H, CH3×2); 13C NMR (CD3OD) δ 164.4 (C-2), 152.2 (C-7a), 145.0 (C-3a), 125.4 (C-6), 120.0 (CN), 119.9 (C-4), 109.8 (C-7), 108.0 (C-5), 38.2 (CH3).
Reaction SMILES: Cl.[C:2]([CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)=[O:13])[CH2:8][CH2:7]1)(=[O:4])[CH3:3].[BH4-].[Na+].Cl>CO>[OH:4][CH:2]([CH3:3])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)=[O:13])[CH2:8][CH2:7]1
Reactant: CC(=O)CN1CCN(C(=O)c2ccc3c(c2)CCC(=O)N3)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)CN1CCN(C(=O)c2ccc3c(c2)CCC(=O)N3)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.76 Grams of 6-(4-acetylmethyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyril monohydrochloride was dissolved in 50 ml of methanol, under ice-cooled condition, 0.44 g of sodium borohydride (NaBH4) was added slowly and then stirred at a room temperature for 1 hour. After the reaction was completed, a concentrated hydrochloric acid was added to ajust the pH of the reaction mixture to about pH 1, then most portion of the solvent was removed by distillation under a reduced pressure and the residue was extracted with 1N--NaOH-chloroform. The organic layer was washed with water and dried with anhydrous sodium sulfate, then the solvent was removed by distillation. The residue obtained was treated by means of a column chromatography and recrystallized from ethanol to obtain 2.26 g of 6-[4-(2-hydroxypropyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril. Colorless flake-like crystals. Melting point: 156°-157.5° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]4[C:30]([CH3:31])=[C:29]([C:32]([O:34]CC)=[CH2:33])[C:28](=[O:37])[N:27]([CH:38]5[CH2:42][CH2:41][CH2:40][CH2:39]5)[C:25]=4[N:26]=3)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(Cl)Cl.C(OCC)C>[C:32]([C:29]1[C:28](=[O:37])[N:27]([CH:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)[C:25]2[N:26]=[C:21]([NH:20][C:17]3[CH:18]=[CH:19][C:14]([N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[CH:15][N:16]=3)[N:22]=[CH:23][C:24]=2[C:30]=1[CH3:31])(=[O:34])[CH3:33]
Reactant: C=C(OCC)c1c(C)c2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)c1c(C)c2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 114.4 %

Procedure:
Hydrogen chloride gas was bubbled into an ice-bath cooled solution of 4-{6-[8-cyclopentyl-6-(1-ethoxy-vinyl)-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-pyridin-3-yl}-piperazine-1-carboxylic acid tert-butyl ester (4.50 g, 0.00783 mol, prepared as in Example 35) in DCM (100 mL). The resulting suspension was stoppered and stirred at room temperature overnight, then diluted with diethyl ether (200 mL). The solid was collected by filtration, washed with diethyl ether, and dried to give the hydrochloride salt of 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one as a yellow solid (4.01 g, 92%). mp 200° C. HPLC, C18 reverse phase, 10–95% gradient of 0.1% TFA/CH3CN in 0.1% TFA/H2O during 22 minutes: 99.0% at 11.04 minutes. MS (APCI); M++1: Calc'd, 448.2, Found, 448.3. Anal. Calc'd for C24H29N7O2.2.4 H2O.1.85HCl: C, 51.64; H, 6.44; N, 17.56, Cl (total), 11.75. Found: C, 51.31; H, 6.41; N, 17.20; Cl (total), 12.11.
Reaction SMILES: [Na+:1].[CH3:2][C:3]1([CH2:28][CH2:29][CH2:30][S:31]([OH:34])(=[O:33])=[O:32])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N+:5]([CH2:12][CH2:13][CH2:14][S:15]([OH:18])(=[O:17])=[O:16])=[C:4]1/[CH:19]=[CH:20]/NC1C=CC=CC=1.[I-].[C:36]([CH2:39][CH2:40][CH2:41][C:42]1([CH3:54])[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[N+:44]([CH2:51][CH3:52])=[C:43]1[CH3:53])([OH:38])=[O:37].N1C=CC=CC=1>C(O)(=O)C.C(OC(=O)C)(=O)C>[Na+:1].[C:36]([CH2:39][CH2:40][CH2:41][C:42]1([CH3:54])[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[N:44]([CH2:51][CH3:52])/[C:43]/1=[CH:53]/[CH:20]=[CH:19]/[C:4]1[C:3]([CH3:2])([CH2:28][CH2:29][CH2:30][S:31]([OH:34])(=[O:32])=[O:33])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N+:5]=1[CH2:12][CH2:13][CH2:14][S:15]([OH:18])(=[O:16])=[O:17])([OH:38])=[O:37]
Reactant: CC[N+]1=C(C)C(C)(CCCC(=O)O)c2ccccc21
Reactant: CC1(CCCS(=O)(=O)O)C(/C=C/Nc2ccccc2)=[N+](CCCS(=O)(=O)O)c2ccccc21
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCN1/C(=C/C=C/C2=[N+](CCCS(=O)(=O)O)c3ccccc3C2(C)CCCS(=O)(=O)O)C(C)(CCCC(=O)O)c2ccccc21

Procedure:
500 mg (1 mmol) 1-ethyl-3-methyl-2-((E)-2-phenylamino-vinyl)-5-sulfo-3-(3-sulfo-propyl)-3H-indolium sodium salt 8 and 387 mg (1 mmol) 3-(3-carboxypropyl)-2,3-dimethyl-1-ethyl-3H-indolium iodide salt 3 are dissolved in a mixture of 10 ml acetic acid and 10 ml acetic anhydride. Subsequently, 5 ml of pyridine is added. The solution is stirred under reflux for 15 minutes.
Reaction SMILES: [C:1]([N:9](C)[C@H:10]([C:18]([OH:20])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(C1C=CC=CC=1)=O.[H][H]>C(O)(=O)C.Cl.[C].[Pd]>[NH:9]([CH3:1])[C@H:10]([C:18]([OH:20])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: [H][H]
Reactant: CN(C(=O)c1ccccc1)[C@@H](Cc1ccccc1)C(=O)O
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Product: CN[C@@H](Cc1ccccc1)C(=O)O

Procedure:
A 12.66 g portion of the BzMePhe was dissolved in 120 ml of acetic acid and 47 ml of HCl, and the solution was subjected to hydrogen catalytic reduction (room temperature, 8 hours) with addition of 5.0 g of 10% palladium-carbon catalyst. After separating off the catalyst by filtration, the filtrate was concentrated in vacuo, and the concentrate was recrystallized from ethanol (50 ml)-ether (500 ml) to give 7.93 g of MePhe, yeild 94.1%. M.p. 225° C.
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][O:7][C:8](=[NH:10])[NH2:9].C[O:12][C:13](=N)N.C[NH+]([CH2:19][C:20](CN(C)C)=[CH:21][NH+](C)C)C.C(OC(C)C)(=O)C.C(=O)(O)[O-].[K+]>O>[CH3:6][O:7][C:8]1[N:9]=[CH:21][C:20]([CH:13]=[O:12])=[CH:19][N:10]=1
Reactant: CN(C)CC(=C[NH+](C)C)C[NH+](C)C
Reactant: COC(=N)N
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: CC(=O)OC(C)C
Product: COc1ncc(C=O)cn1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To a stirred slurry of O-methylisourea hemisulfate (1.08 g, 4.13 mmol), vinamidinium salt (3.00 g, 8.26 mmol), 1-methylethyl acetate (16.0 mL, 137 mmol) was added a solution of potassium bicarbonate (1.17 g, 11.6 mmol) in water (5.0 mL) over a 10 minutes period. After completion of the addition the resulting reaction mixture was stirred at room temperature for 40 hours. The mixture was diluted with water (20 mL) and extracted with EtOAc (2×25 mL). The combined organic layers were dried over sodium sulfate and concentrated to yield a white solid.
Reaction SMILES: C([C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#N.[CH3:9][Mg]Br.C(Cl)(Cl)Cl.[CH3:16][OH:17]>C1COCC1.O>[N:4]1[CH:5]=[CH:6][CH:7]=[N:8][C:3]=1[C:16](=[O:17])[CH3:9]
Reactant: N#Cc1ncccn1
Reactant: C[Mg]Br
Reactant: CO
Solvent: C1CCOC1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(=O)c1ncccn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
A solution of 2-cyano-pyrimidine (10.0 g, 95.2 mmol) in THF (100 mL) was cooled to −5° C. and treated with a 3 M solution of methyl magnesium bromide in THF (38.0 mL, 98.4 mmol). The reaction was stirred at 0° C. for two hours until completion was observed by TLC (chloroform/methanol, 9:1). The reaction mixture was poured in water; the pH was adjusted to 5-6 and the aqueous layer was extracted with ethyl acetate (3×150 mL). The combined organic layers were concentrated under reduced pressure and the crude compound was purified by column chromatography, eluting with chloroform to afford the target compound (6.5 g, 48%).
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]=[C:16]=[O:17])=[CH:11][CH:10]=1.[CH3:18][O:19][C:20]([C:22]1[O:38][C:25]2=[N:26][CH:27]=[CH:28][C:29]([O:30][C:31]3[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=3)=[C:24]2[CH:23]=1)=[O:21]>C(#N)C>[CH3:18][O:19][C:20]([C:22]1[O:38][C:25]2=[N:26][CH:27]=[CH:28][C:29]([O:30][C:31]3[CH:36]=[CH:35][C:34]([NH:37][C:16]([NH:15][C:12]4[CH:13]=[CH:14][C:9]([F:8])=[CH:10][CH:11]=4)=[O:17])=[CH:33][CH:32]=3)=[C:24]2[CH:23]=1)=[O:21]
Reactant: COC(=O)c1cc2c(Oc3ccc(N)cc3)ccnc2o1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: CC#N
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ccnc2o1

Procedure:
After adding toluene (1 ml), acetonitrile (0.5 ml) and 4-fluorophenyl isocyanate (0.02 ml) to 4-(4-aminophenoxy)furo[2,3-b]pyridine-2-carboxylic acid methyl ester (28 mg), the mixture was heated to reflux for 30 minutes. After cooling, the precipitated crystals were filtered off and washed with toluene to obtain the title compound (24 mg) as light yellow crystals.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].IC.[OH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18][C:19](=[O:21])[CH3:20])=[CH:12][CH:11]=1>C(O)C.C(OCC)(=O)C>[CH3:1][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][NH:18][C:19](=[O:21])[CH3:20])=[CH:14][CH:15]=1
Reactant: CC(=O)NCCc1ccc(O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CCO
Product: COc1ccc(CCNC(C)=O)cc1
Yield: 61 %

Procedure:
Potassium carbonate (3.5 g, 25.5 mol) and iodomethane(2.0 ml, 31.9 mmol) was added to a solution of N-(4-hydroxyphenylethyl)acetamide (4.4 g, 24.6 mmol) in ethanol(2.4 ml), which was then refluxed for 12 hours. The resulting solid was filtered and washed with ethanol. The filtrate was concentrated to give oily residue, which was diluted with ethyl acetate and washed with water. The separated organic layer was concentrated and the resulting solid was suspended in ethylether, filtered, and dried to give 2.9 g of the titled compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:16]=2[C:17](Cl)=[O:18])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O.[NH2:26][NH2:27].NN>ClCCl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:16]=2[C:17]([NH:26][NH2:27])=[O:18])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)Cl)cc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)NN)cc1
Temperature: -10 °C
Yield: 85 %

Procedure:
The crude 2-(4-tert-butyl-benzenesulfonylamino)-5-chlorobenzoyl chloride was dissolved in dichloromethane (300 mL) and transferred to an addition funnel. Hydrazine hydrate (212 mL, 4.35 mol), dissolved in 1.2 L dichloromethane in a 4 L Erlenmeyer flask, was cooled to −10° C. in a dry ice-acetone bath and the acyl chloride solution was added in a slow stream to the stirring hydrazine solution over a 15 minute period. The cold bath was subsequently removed following the addition and LCMS analysis at 15 minutes indicated the reaction was complete. The resultant reaction mixture was quenched with water (500 mL), resulting in a voluminous white precipitate that was collected by vacuum filtration. The precipitate was slurried in 800 mL ethyl acetate and acetic acid was added while stirring until a homogeneous solution was formed. The solution was transferred to a separatory funnel and extracted with 3×100 mL of water. The aqueous phases were discarded and the organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo to produce 4-tert-butyl-N-(4-chloro-2-hydrazinocarbonyl-phenyl)benzenesulfonamide (71 g) in an 85% yield: HPLC retention time 2.49 minutes; MS (ES) M+H expected 382.0, found 382.0.
Reaction SMILES: Cl.[NH2:2][CH2:3][C@@H:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[OH:5].[Cl:13][C:14]1[CH:19]=[C:18](Cl)[N:17]=[CH:16][N:15]=1.C([O-])(O)=O.[Na+].O>O1CCOCC1>[Cl:13][C:14]1[N:15]=[CH:16][N:17]=[C:18]([NH:2][CH2:3][C@@H:4]([C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=2)[OH:5])[CH:19]=1
Reactant: NC[C@H](O)c1ccc(F)cc1
Reactant: Clc1cc(Cl)ncn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O[C@@H](CNc1cc(Cl)ncn1)c1ccc(F)cc1
Temperature: 100 °C
Yield: 65.4 %

Procedure:
A suspension of (R)-2-amino-1-(4-fluoro-phenyl)-ethanol hydrochloride (500 mg, 2.61 mmol), 4,6-dichloropyrimidine (353 mg, 2.37 mmol), and NaHCO3 (1.39 g, 16.6 mmol) in dioxane (10 mL) was heated in a 100° C. bath for 19 h and cooled to rt. Water (10 mL) was added, and the mixture, containing solid, was extracted with CH2Cl2 (3×10 mL). The combined organic extracts were dried (MgSO4) and concentrated. The residue was purified (FCC) to give the title compound as a white solid (415 mg, 59%) in 90% enantiomeric excess (Chiralcel AD-H column, supercritical CO2).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[C:13](Cl)[C:12]([C:19](OCC)=O)=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].CS(Cl)(=O)=O.[N:32]1C=CC=CC=1>O1CCCC1.CO.O>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[CH:13][C:12]([C:19]#[N:32])=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1cc2c(nc1Cl)CCN(C(=O)OC(C)(C)C)C2
Reactant: c1ccncc1
Agent: CS(=O)(=O)Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2ncc(C#N)cc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product from Step A above in 6 mL of 3:2:1 tetrahydrofuran/methanol/water was added lithium hydroxide monohydrate (0.23 g, 5.58 mmol). The mixture was allowed to stir overnight and the volatiles were removed under reduced pressure. Additional water was added, and the solution was acidified with citric acid monohydrate. The resultant precipitate was collected, washed with water, and dried in vacuo. To an ice-cold solution of this intermediate (1.0 g, 3.6 mmol) in 32 mL of pyridine was added methanesulfonyl chloride (0.41 g, 3.6 mmol) dropwise, and the resultant mixture was allowed to stir for one hour. Dry ammonia gas was bubbled into the reaction mixture for 2 minutes. The excess ammonia was then removed under reduced pressure, and the solution was cooled again in ice and treated with methanesulfonyl chloride (3.43 g, 30.0 mmol). The resultant mixture was allowed to warm to room temperature overnight. The reaction was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and 1N hydrochloric acid. The product was extracted with ethyl acetate, and the combined extracts were dried over magnesium sulfate and concentrated under reduced pressure. The resultant crystalline solid was triturated with ether, and the precipitate was collected to afford the title compound as a light orange powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].CC1C(Cl)=CC=CC=1N>>[C:3]1([CH2:8][C:9]([OH:11])=[O:10])[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1
Reactant: O=C(O)Cc1ccccc1Br
Agent: Cc1c(N)cccc1Cl
Product: O=C(O)Cc1ccccc1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 2-methyl-3-chloroaniline to yield 2-[2-methyl-3-chlorophenyl)amino]phenylacetic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23].[CH:31]([S:39](Cl)(=[O:41])=[O:40])=[CH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[C:33]1(/[CH:32]=[CH:31]/[S:39]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]3)=[CH:4][C:3]=2[NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=S(=O)(Cl)C=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)c(NS(=O)(=O)c3ccccc3)c2)CC1
Product: O=S(=O)(/C=C/c1ccccc1)Nc1ccc(N2CCNCC2)cc1NS(=O)(=O)c1ccccc1

Procedure:
N-[2-({[(E)-2-Phenylethenyl]sulfonyl}amino)-5-(1-piperazinyl)phenyl]benzenesulfonamide was synthesized from N-{2-amino-5-(4-t-butyloxycarbonyl-piperazinyl)-phenyl}benzenesulfonamide and β-styrenesulfonylchloride (48 mg, 0.239 mmol according to general method 3 to give before Boc-deprotection 160 mg of a purple solid. MS (posES-FIA) m/z=Found: 499.2. Calcd 499.14. 1H-NMR δ 8.26 (d, 1H), 8.04 (d, 1H), 7.75-7.38 (m, 8H), 7.22 (d, 1H, J=15.4 Hz), 7.16 (d, 1H), 6.97 (d, 1H), J=15.4 Hz), 6.78 (dd, 1H), 6.68 (d, 1H), 3.68 (app t, 2H), 3.39 (app t, 2H), 3.28-3.21 (m, 4H),