Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:10][C:9]2[NH:8][C:7]([C:11]([O:13]CC)=[O:12])=[C:6]([CH2:16][CH3:17])[C:5]=2[C:4](=[O:18])[CH2:3]1.[OH-].[K+].C(O)(=O)C>CCO.O>[CH3:19][C:2]1([CH3:1])[CH2:10][C:9]2[NH:8][C:7]([C:11]([OH:13])=[O:12])=[C:6]([CH2:16][CH3:17])[C:5]=2[C:4](=[O:18])[CH2:3]1
Reactant: CCOC(=O)c1[nH]c2c(c1CC)C(=O)CC(C)(C)C2
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CCc1c(C(=O)O)[nH]c2c1C(=O)CC(C)(C)C2
Temperature: 60 °C
Yield: 85 %

Procedure:
A solution of ethyl 6,6-dimethyl-3-ethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate (5.4 g, 0.02 mol) and KOH (2.9 g, 0.05 mol) in EtOH (25 mL) and water (7.5 mL) was heated at reflux for 6 h. The mixture was cooled to 60° C., and neutralized by the addition of acetic acid. Water (80 mL) was added and the cream precipitate collected by filtration. The precipitate was washed with EtOH and hexane then dried under vacuum at 50° C. The acid (4 g, 83%) was isolated as a cream solid, and used without further purification. mp>198° C. 1H NMR (360 MHz, d6-DMSO δ 1.00 (6H,s), 1.04 (3H,t,J=7.3 Hz), 2.22 (2H,s), 2.62 (2H,s), 2.98 (2H,q,J=7.3 Hz), 11.72 (1H, br s). C13H17NO3. O.4(H2O) requires: C, 64.39; H, 7.40; N, 5.73%. Found:C, 64.38, H, 7.30; N, 5.70%. MS(ES+) 236 (M+1).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:27][CH3:28])=[C:10]([CH2:19][NH:20][C:21](=[O:26])[CH2:22][C:23](O)=[O:24])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:29][N:30]1[CH2:35][CH2:34][CH:33]([CH2:36][C:37]2[CH:38]=[C:39]([C:43]3[CH:48]=[CH:47][CH:46]=[C:45]([CH2:49][NH2:50])[CH:44]=3)[CH:40]=[CH:41][CH:42]=2)[CH2:32][CH2:31]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CCOC(C)=O.ClCCl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:27][CH3:28])=[C:10]([CH2:19][NH:20][C:21](=[O:26])[CH2:22][C:23]([NH:50][CH2:49][C:45]3[CH:44]=[C:43]([C:39]4[CH:40]=[CH:41][CH:42]=[C:37]([CH2:36][CH:33]5[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]5)[CH:38]=4)[CH:48]=[CH:47][CH:46]=3)=[O:24])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)O
Reactant: CN1CCC(Cc2cccc(-c3cccc(CN)c3)c2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)NCc1cccc(-c2cccc(CC3CCN(C)CC3)c2)c1
Yield: 46.7 %

Procedure:
A mixture of 3-({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-3-oxopropanoic acid (77 mg, 0.198 mmol), (({3′-[(1-methyl-4-piperidinyl)methyl]-3-biphenylyl}methyl)amine (64.1 mg, 0.218 mmol), HATU (90 mg, 0.238 mmol), triethylamine (0.080 mL, 0.574 mmol) and dichloromethane (DCM) (3 mL) was stirred overnight at room temperature. The reaction was diluted with EtOAc; washed in turn with saturated aqueous NaHCO3, then saturated aqueous NaCl. The organic phase was dried (Na2SO4) and evaporated to a residue (185 mg). The residue was purified on a Gilson HPLC on RP column using a CH3CN—H2O (0.1% TFA) gradient [10-80%]. Fractions containing the desired product were combined and reduced to a small volume, and then treated with saturated aqueous NaHCO3. The mixture was extracted with EtOAc (2×); the combined extracts were washed with saturated aqueous NaCl and dried (Na2SO4), then solvent was evaporated of to give a glassy solid (61.6 mg). LC-MS m/z 666.6 (M+H)+, 0.75 min (ret time).
Reaction SMILES: [CH2:1]([O:15][C:16]1[O:20][C:19]([C:21]([OH:23])=O)=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH3:14].[CH3:24]COCC.C[Li].[Cl-].[NH4+]>C(O)(=O)C>[CH2:1]([O:15][C:16]1[O:20][C:19]([C:21]([CH3:24])=[O:23])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH3:14]
Reactant: CCOCC
Reactant: CC/C=C\CCCCCCCCCCOc1ccc(C(=O)O)o1
Agent: [Cl-]
Agent: [Li]C
Agent: [NH4+]
Solvent: CC(=O)O
Product: CC/C=C\CCCCCCCCCCOc1ccc(C(C)=O)o1
Temperature: 25 °C

Procedure:
A mixture of 4.2 g (0.013 mole) of cis-5-(11-tetradecenyloxy)furan-2-carboxylic acid and 50 ml of anhydrous ether was stirred at room temperature and 20.2 ml (0.0313 mole) of methyllithium (1.55 molar in hexane) added over 15 minutes. The mixture was stirred at room temperature for 3 hours and poured into saturated ammonium chloride solution. About 10 ml of glacial acetic acid was added and the phases separated. The ether layer was washed with water and evaporated to dryness to give a light yellow semisolid residue which was recrystallized twice from methanol to give methyl cis-5-(11-tetradecenyloxy)-2-furyl ketone, M.P. 3638° C.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[CH:8]=[CH:7][C:6]3[C:12]([C:16]([O:18]CC)=O)=[N:13][N:14]([CH3:15])[C:5]=3[C:4]=2[N:3]=1.C[N:22](C)C=O.[NH4+].[OH-]>CO>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[CH:8]=[CH:7][C:6]3[C:12]([C:16]([NH2:22])=[O:18])=[N:13][N:14]([CH3:15])[C:5]=3[C:4]=2[N:3]=1
Reactant: CCOC(=O)c1nn(C)c2c1ccc1cnc(N)nc12
Reactant: CN(C)C=O
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: Cn1nc(C(N)=O)c2ccc3cnc(N)nc3c21
Temperature: 65 °C
Yield: 50 %

Procedure:
2.5 g of ethyl 8-amino-1-methyl-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate (9.16 mmol) were dissolved in 40 mL of methanol, 40 mL of dimethylformamide and 50 mL of NH4OH 30% mixture. The mixture was maintained at 65° C. under stirring for a day. The solvent was then evaporated to dryness, the residue redissolved with dichloromethane and washed with water. The organic layer was dried over Na2SO4 and evaporated. The crude was triturated with diethyl ether and the product collected by filtration (50% yield).
Reaction SMILES: [C:1]([C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[O:7][CH:8]1[CH2:11][N:10]([C:12](=[O:18])[C:13]([O:15]CC)=[O:14])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>C(O)C>[C:1]([C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[O:7][CH:8]1[CH2:9][N:10]([C:12](=[O:18])[C:13]([OH:15])=[O:14])[CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(=O)N1CC(Oc2ccccc2C(C)(C)C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)c1ccccc1OC1CN(C(=O)C(=O)O)C1
Temperature: 0 °C
Yield: 64.8 %

Procedure:
To a stirred solution of ethyl 2-(3-(2-tert-butylphenoxy)azetidin-1-yl)-2-oxoacetate (1.65 g, 5.40 mmol) in ethanol (60.0 ml) was added lithium hydroxide (16.2 mL of 1.0 M solution in water, 16.2 mmol) at room temperature. After 1 h the reaction mixture was concentrated under reduced pressure, the resulting residue was diluted with water, cooled to 0° C., adjusted to about pH 1 with 1.0 N hydrochloric acid and the resulting solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was recrystallized from heptane/ethyl acetate to provide 2-(3-(2-tert-butylphenoxy)azetidin-1-yl)-2-oxoacetic acid (0.97 g, 65%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=1.[CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]([CH3:31])[CH3:30])[C:24]=1[N:32]=[C:33]=[O:34])([CH3:22])[CH3:21]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][N:10]([C:11]1[CH:12]=[CH:13][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:15][CH:16]=1)[C:33]([NH:32][C:24]1[C:23]([CH:20]([CH3:21])[CH3:22])=[CH:28][CH:27]=[CH:26][C:25]=1[CH:29]([CH3:31])[CH3:30])=[O:34]
Reactant: CC(C)c1ccc(NCc2ccc(Cl)cc2Cl)cc1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Product: CC(C)c1ccc(N(Cc2ccc(Cl)cc2Cl)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1
Yield: 9.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 2 using [(2,4-dichlorophenyl)methyl](4-isopropylphenyl)amine (2.7 g) and 2,6-diisopropylphenyl isocyanate (2.1 g) as starting materials, N-[(2,4-dichlorophenyl)methyl]-N′-(2,6-diisopropylphenyl)-N-(4-isopropylphenyl)urea (0.43 g) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=3)[CH2:11][CH2:10][CH:9]2[C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.[Cl-].[NH4+]>C(O)C.C1COCC1.O.[Fe]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=3)[CH2:11][CH2:10][CH:9]2[C:22]2[CH:23]=[CH:24][C:25]([NH2:28])=[CH:26][CH:27]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(C2CCC(c3ccc([N+](=O)[O-])cc3)N2c2ccc(F)cc2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Nc1ccc(C2CCC(c3ccc(N)cc3)N2c2ccc(F)cc2)cc1
Temperature: 80 °C
Reaction time: 0.75 h

Procedure:
To a solution of the product from Example 1D (0.501 g, 1.23 mmol) in ethanol (5 ml) and THF (5.00 ml) was added iron powder (0.412 g, 7.38 mmol) and a solution of ammonium chloride (0.197 g, 3.69 mmol) in water (1.0 ml). The resulting mixture was stirred at 80° C. for 45 min. The mixture was cooled, filtered through celite, washed with ethanol, and concentrated in vacuo. The crude product was purified by chromatography on silica gel using a solvent gradient of 0-100% ethyl acetate in hexanes to give the title compound as a mixture of cis and trans isomers (0.135 gm, 32%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:12]2[C:7](=[C:8]([CH3:13])[CH:9]=[CH:10][CH:11]=2)[C:6]([O:14][CH2:15][O:16][CH3:17])=[C:5]([O:18][CH3:19])[CH:4]=1>[O-2].[O-2].[Mn+4].ClCCl>[CH3:19][O:18][C:5]1[CH:4]=[C:3]([CH:2]=[O:1])[C:12]2[C:7]([C:6]=1[O:14][CH2:15][O:16][CH3:17])=[C:8]([CH3:13])[CH:9]=[CH:10][CH:11]=2
Reactant: COCOc1c(OC)cc(CO)c2cccc(C)c12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COCOc1c(OC)cc(C=O)c2cccc(C)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
37 g of manganese dioxide was added to a dichloromethane (150 ml) solution of 1-hydroxymethyl-3-methoxy-4-methoxymethoxy-5-methylnaphthalene and agitated at room temperature overnight. The reaction suspension was filtered through Celite and the resultant filtrate was concentrated under reduced pressure, followed by purification by silica gel column chromatography (5% ethyl acetate/hexane) to obtain 3.8 g of the captioned compound as light yellowish brown crystals.
Reaction SMILES: [CH2:1]1[O:12][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH3:13][CH:14]([CH2:17][CH2:18][NH2:19])[CH2:15][NH2:16]>>[CH3:13][CH:14]([CH2:17][CH2:18][NH:19][CH2:1][CH:2]([OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:15][NH:16][CH2:1][CH:2]([OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CC(CN)CCN
Reactant: CCCCCCCCCC1CO1
Product: CCCCCCCCCC(O)CNCCC(C)CNCC(O)CCCCCCCCC

Procedure:
Condensation of 1-undecene oxide and 2-methyl-1,4-butanediamine affords N,N'-(2-methyl-1,4-butylene)-bis[2-hydroxyundecylamine] (I: R = CH3 (CH2)8, R' = H, X = CH2CH(CH3)CH2CH2, Z = H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[ClH:6].[N:7]1([C:13]2[CH:14]=[N:15][C:16](O)=[N:17][CH:18]=2)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.CCN(C1C=CC=CC=1)CC.C(=O)([O-])O.[Na+]>C(#N)C.C(Cl)(Cl)Cl>[Cl:6][C:16]1[N:15]=[CH:14][C:13]([N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[CH:18][N:17]=1
Reactant: Oc1ncc(N2CCOCC2)cn1
Reactant: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1ncc(N2CCOCC2)cn1
Temperature: 25 °C
Yield: 67 %

Procedure:
Phosphoryl chloride (16 ml) was added to a solution of 5-morpholin-4-yl-pyrimidin-2-ol hydrochloride (7.49 g) and diethylaniline (11 ml) in acetonitrile (150 ml) over 10 minutes and the mixture was heated to reflux for 7.5 hours. The reaction mixture was cooled to room temperature, and added to a mixture of a saturated sodium hydrogen carbonate aq. solution and chloroform. The organic layer was washed with a saturated brine, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography (silica gel; hexane:ethyl acetate=4:1→1:1) to give the titled compound (4.6 g). MS (m/z): 200/202 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[C:16](I)[C:17]=1[O:18][CH3:19])[CH2:6][C:7]1[C:8]([NH2:14])=[N:9][C:10]([NH2:13])=[N:11][CH:12]=1.[C:21]([C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=1)#[CH:22].C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O.[Cu]I.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[C:16]([C:22]#[C:21][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)[C:17]=1[O:18][CH3:19])[CH2:6][C:7]1[C:8]([NH2:14])=[N:9][C:10]([NH2:13])=[N:11][CH:12]=1
Reactant: COc1cc(Cc2cnc(N)nc2N)cc(I)c1OC
Reactant: C#Cc1ccc2ccccc2c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(Cc2cnc(N)nc2N)cc(C#Cc2ccc3ccccc3c2)c1OC
Temperature: 25 °C
Yield: 57.8 %

Procedure:
A mixture of 197 mg of 5-(3,4-dimethoxy-5-iodo-benzyl)pyrimidine-2,4-diamine, 155 mg of 2-ethynyl-naphthalene (Bull. Soc. Chim. Fr. [3], 7, 648, (1892)), 108 mg of potassium carbonate, 14 mg of triphenylphosphine and 5 mg of copper(I) iodide in 2 ml of dimethylformamide is heated at 100° for 4 hrs. The reaction mixture is cooled to room temperature, poured into 50 ml of water and extracted three times with 50 ml of methylene chloride each time. The organic phases are washed with 50 ml of water, dried over magnesium sulphate and concentrated. The crude product is recrystallized from ethyl acetate/n-hexane. 121 mg (58%) of 5-[3,4-dimethoxy-5-(naphthalen-2-ylethynyl)-benzyl]-pyrimidine-2,4-diamine are obtained as a yellowish solid. M.p. 152°-155°.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([O:19][CH3:20])[N:12]=2)=[CH:6][CH:5]=1.[CH3:21]I>>[I:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]([CH3:21])[C:11]2[N:12]=[C:13]([O:19][CH3:20])[CH:14]=[C:15]([O:17][CH3:18])[N:16]=2)=[CH:8][CH:9]=1
Reactant: CI
Reactant: COc1cc(OC)nc(Nc2ccc(I)cc2)n1
Agent: [H-]
Agent: [Na+]
Product: COc1cc(OC)nc(N(C)c2ccc(I)cc2)n1

Procedure:
In the same manner as in Reference Example 24-(1), 4-iodoaniline (220 mg) and 2-chloro-4,6-dimethoxypyrimidine (200 mg) were reacted in the presence of sodium hydride to obtain N-(4-iodophenyl)-4,6-dimethoxypyrimidin-2-amine (141 mg). (2) In the same manner as in Reference Example 24-(2), sodium hydride (16 mg), N-(4-iodophenyl)-4,6-dimethoxypyrimidin-2-amine (140 mg) and methyl iodide (0.024 ml) were reacted to obtain N-(4-iodophenyl)-4,6-dimethoxy-N-methylpyrimidin-2-amine (118 mg).
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[OH-].[K+].C(O[C@@H:13]1[C@H:18]2[C@H:19]3[C@H:29]([CH2:30][CH2:31][C@:16]2([CH3:17])[C:15](=[O:34])[CH2:14]1)[C@:27]1([CH3:28])[C:22]([CH:23]=[C:24]([O:32][CH3:33])[CH2:25][CH2:26]1)=[CH:21][CH2:20]3)(=O)C.O>CS(C)=O>[CH2:2]1[C@@H:14]2[C:15](=[O:34])[C@:16]3([CH2:31][CH2:30][C@H:29]4[C@@H:19]([CH2:20][CH:21]=[C:22]5[C@:27]4([CH3:28])[CH2:26][CH2:25][C:24]([O:32][CH3:33])=[CH:23]5)[C@@H:18]3[C@H:13]12)[CH3:17]
Reactant: C[S+](C)(C)=O
Reactant: COC1=CC2=CC[C@H]3[C@@H]4[C@@H](OC(C)=O)CC(=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)CC1
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COC1=CC2=CC[C@H]3[C@@H]4[C@@H]5C[C@@H]5C(=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)CC1
Temperature: 27.5 °C
Reaction time: 1 h

Procedure:
12.96 kg of trimethylsulfoxonium iodide is dissolved in 180 l of dimethyl sulfoxide under nitrogen bubbling and vigorous stirring and at 25-30° C. 5.51 kg of potassium hydroxide is added to the solution. Stirring is continued for 1 hour, then 16.22 kg of 15α-acetoxy-3-methoxyandrosta-3,5-diene-17-one is added, the reaction mixture is stirred at 25-30° C. until the reaction is complete (about 6 hours). The solution is added slowly to 900 l of water, the precipitate obtained is stirred for 30 minutes until it is dense, filtered by centrifuge, washed with portions of water until is neutral and dried in vacuo to constant weight at a temperature below 40° C. and the crude tide compound is crystallized from methanol.
Reaction SMILES: [C:1]1(/[C:7](/[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[C:8](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)\[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:28]([C:31]1[CH:32]=[C:33]([S:37]([NH2:40])(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=1)([O-:30])=[O:29]>>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:40][S:37]([C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([N+:28]([O-:30])=[O:29])[CH:32]=3)(=[O:38])=[O:39])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NS(=O)(=O)c1cccc([N+](=O)[O-])c1
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)c2cccc([N+](=O)[O-])c2)cc1)c1ccccc1

Procedure:
Prepared by coupling 1a and 3-nitrobenzenesulfonamide in accordance with Procedure 1, Method A described hereinabove. Yield (14%); 1H NMR (d6-DMSO) δ 8.59 (t, J=2.2 Hz, 1H), 8.47 (d, J=7.0 Hz, 1H), 8.30 (d, J=7.7 Hz, 1H) 7.87 (t, J=8.1 Hz, 1H), 7.38–7.07 (m, 13H), 6.83 (d, J=8.4 Hz, 2H), 6.38 (d, J=15.7 Hz, 1H), 2.35 (q, J=7.4 Hz, 2H), 0.81 (t, J=7.4 Hz, 3H); APcI m/z: 537 (M−H−).
Reaction SMILES: [C:1]([N:11]1[CH2:16][CH2:15][N:14](C=O)[CH2:13][CH2:12]1)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(Cl)(Cl)Cl>[C:1]([N:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]1)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=CN1CCN(C(=O)C=Cc2ccccc2)CC1
Solvent: ClC(Cl)Cl
Product: O=C(C=Cc1ccccc1)N1CCNCC1

Procedure:
1-Cinnamoyl-4-formylpiperazine (1.22 g) was dissolved in chloroform (8 mL), and the atmosphere was purged with nitrogen. Under stirring of the solution in an ice-water bath, a liquid mixture (concentrated hydrochloric acid:methanol=1:4) (5 mL) was added thereto. The mixture was stirred at room temperature for 20 hours and 30 minutes and in a 60° C.-water bath for one hour. Further, under stirring of the mixture in an ice-water bath, the same liquid mixture as described above (concentrated hydrochloric acid—methanol mixture) (4 mL) was added thereto, and the resultant mixture was stirred in a water bath for 6 hours at 60° C. The solvents were removed under reduced pressure, and water was added to the residue, followed by extraction with ethyl acetate. The ethyl acetate layer was removed, and pH of the water layer was adjusted to 8 to 9 with saturated sodium hydrogencarbonate solution, followed by extraction twice with chloroform. The chloroform layers were combined and dried over sodium sulfate anhydrate. The solvent was removed under reduced pressure, to thereby yield 1.14 g of the product of interest as a colorless oil. The product was employed in the next step in a crude form.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([O:11][C:12](=[O:27])[NH:13][C:14]2[C:15]([CH3:26])=[N:16][O:17][C:18]=2[C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=2)[CH3:10])=[CH:5][CH:4]=1.[CH2:28]([O:30][C:31]([C:33]1([C:36]2[CH:41]=[CH:40][C:39](B3OC(C)(C)C(C)(C)O3)=[CH:38][CH:37]=2)[CH2:35][CH2:34]1)=[O:32])[CH3:29]>>[CH2:28]([O:30][C:31]([C:33]1([C:36]2[CH:41]=[CH:40][C:39]([C:22]3[CH:23]=[CH:24][C:19]([C:18]4[O:17][N:16]=[C:15]([CH3:26])[C:14]=4[NH:13][C:12]([O:11][C@@H:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[CH3:10])=[O:27])=[CH:20][CH:21]=3)=[CH:38][CH:37]=2)[CH2:34][CH2:35]1)=[O:32])[CH3:29]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: COc1ccc([C@@H](C)OC(=O)Nc2c(C)noc2-c2ccc(Br)cc2)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)O[C@H](C)c4ccc(OC)cc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 6, Step 3 using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(4-methoxy-phenyl)-ethyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].Cl.[F:9][C:10]1[CH:11]=[CH:12][C:13]([N+:24]([O-:26])=[O:25])=[C:14]([CH:23]=1)[O:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([NH2:22])[CH2:18][CH2:17]1.C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.S([O-])(O)(=O)=O.[K+]>[F:9][C:10]1[CH:11]=[CH:12][C:13]([N+:24]([O-:26])=[O:25])=[C:14]([CH:23]=1)[O:15][C@H:16]1[CH2:17][CH2:18][C@H:19]([NH:22][C:1](=[O:3])[CH3:2])[CH2:20][CH2:21]1
Reactant: CC(=O)OC(C)=O
Reactant: N[C@H]1CC[C@H](Oc2cc(F)ccc2[N+](=O)[O-])CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N[C@H]1CC[C@H](Oc2cc(F)ccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
166 μl acetic anhydride were added to a mixture of 0.341 g trans-4-(5-fluoro-2-nitrophenoxy)-cyclohexylamine hydrochloride and 327 μl triethylamine in 5 ml methylene chloride. The reaction mixture was stirred at rt overnight. The mixture was diluted with methylene chloride and 10% aq. potassium hydrogensulfate and 10% aq.potassium carbonate. Then the mixture was passed through a hydrophobic frit and the solvent was evaporated.
Reaction SMILES: N1C=CC=CC=1.[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1.[OH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]1[N:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:28]=[N:27][N:26]=1>ClCCl>[S:13]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]1[N:29]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:28]=[N:27][N:26]=1)([C:10]1[CH:11]=[CH:12][C:7]([CH3:17])=[CH:8][CH:9]=1)(=[O:15])=[O:14]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCCCOc1nnnn1-c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCCCOc2nnnn2-c2ccccc2)cc1
Reaction time: 6 h
Yield: 54 %

Procedure:
0.5 g of pyridine and 0.31 g of p-toluenesulfonyl chloride were added to a solution of 0.4 g of the compound obtained in Example 1a in dichloromethane (10 ml) and the mixture was stirred for 6 hours. The organic layer was washed with 10% aqueous citric acid and then with water and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane) to obtain 0.35 g of the title compound (yield: 54%).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])C.Cl[CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=2)[CH:20]=[CH:19][CH:18]=1>>[CH3:28][O:27][C:24]1[CH:25]=[C:26]2[C:21]([CH:20]=[CH:19][CH:18]=[C:17]2[CH2:16][N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:14]=[C:6]2[C:4]([OH:3])=[O:5])=[CH:22][CH:23]=1
Reactant: COc1ccc2cccc(CCl)c2c1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Product: COc1ccc2cccc(Cn3c(C(=O)O)cc4ccccc43)c2c1

Procedure:
Using general procedure B, 1H-indole-2-carboxylic acid ethyl ester was coupled with 1-chloromethyl-7-methoxy-naphthalene (Lit. 12) and the product obtained was hydrolyzed to give the title compound as a white solid. MS: 330.1 ([M−H]−).
Reaction SMILES: C1C2=CC=CC=C2C1.[Br:9]Br.[Br:11][C:12]1[CH:19]=[CH:18][CH:17]=[C:14]2[CH2:15][CH2:16][C:13]=12>>[Br:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:14][C:13]=1[CH2:16][CH2:15][Br:9]
Reactant: Brc1cccc2c1CC2
Reactant: BrBr
Agent: c1ccc2c(c1)CC2
Product: BrCCc1ccccc1Br

Procedure:
The four-membered ring of benzocyclobutenes is known to open at elevated temperature to form a very reactive diene which rapidly dimerizes and polymerizes. Molecules containing two or more benzocyclobutene groups are therefore useful as heat-curable thermosetting resins. Also, elastomers or thermoplastics containing benzocyclobutene substituents crosslink on heating. One of the easiest and most useful methods of functionalizing the benzocyclobutene molecule for subsequent production of resins or functionalized polymers is halogenation of the aromatic ring. Bromination with aqueous bromine, for example, can yield 4-bromobenzocyclobutene in over 75% yield. However, a significant proportion of the starting benzocyclobutene (10-15%) reacts with bromine by addition and opening of the four-membered ring to form 1-bromo-2-(2-bromoethyl)benzene.