Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8](Br)[CH:7]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:21][Si:22]([C:25]#[CH:26])([CH3:24])[CH3:23].C(OCC)(=O)C>CCCCCC.[Cu]I.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>[CH:1]([O:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:26]#[C:25][Si:22]([CH3:24])([CH3:23])[CH3:21])[CH:7]=1)([CH3:3])[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)OC(=O)c1cccc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)OC(=O)c1cccc(C#C[Si](C)(C)C)c1
Yield: 93.4 %

Procedure:
Following General Procedure D and using 3-bromo-benzoic acid isopropyl ester (Intermediate 135, 1.25 g, 5.14 mmol), triethyl amine (12 mL), copper(I)iodide (0.078 g, 0.41 mmol), trimethylsilyl acetylene (4 mL, 28.16 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.288 g, 0.41 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 3% ethyl acetate in hexane as the eluent, the title compound (1.25 g, 94%) was obtained as an orange oil.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][C@H:34]5[CH2:38][CH2:37][NH:36][CH2:35]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)S(O[CH2:45][C:46]([F:49])([F:48])[F:47])(=O)=O.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][C@H:34]5[CH2:38][CH2:37][N:36]([CH2:45][C:46]([F:49])([F:48])[F:47])[CH2:35]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1O[C@H]1CCNC1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1O[C@H]1CCN(CC(F)(F)F)C1
Yield: 47.3 %

Procedure:
The title compound was prepared as described in Example 103C using (S)-1-(5-tert-butylisoxazol-3-yl)-3-{3-[6-methoxy-7-(pyrrolidin-3-yloxy)quinazolin-4-yloxy]phenyl}urea (0.198 g, 0.38 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.139 g, 0.6 mmol), and N,N-diisopropylethylamine (0.5 mL) in CH2Cl2 (10 mL) at 40° C. for 3 hours, which was purified by silica gel chromatography with 70-85% EtOAc/hexane as eluants to afford (S)-1-(5-tert-butylisoxazol-3-yl)-3-(3-{6-methoxy-7-[1-(2,2,2-trifluoroethyl)pyrrolidin-3-yloxy]quinazolin-4-yloxy}phenyl)urea as solid (0.108 g, 47%). 1H NMR (300 MHz, CDCl3) δ 9.4 (s, 1H), 8.62 (s, 1H), 7.93 (s, 1H), 7.65 (t, 1H), 7.54 (s, 1H), 7.39 (t, 1H), 7.32 (m, 1H), 7.20 (s, 1H), 7.01 (d, 1H), 5.89 (s, 1H), 5.06 (m, 1H), 4.03 (s, 3H), 3.41 (m, 1H), 3.18 (q, 2H), 2.9-3.08 (m, 3H), 2.44 (m, 1H), 2.2 (m, 1H), 1.33 (s, 9H); LC-MS (ESI) m/z 601 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12]2[CH2:11][S:10][N:9]=[C:8]([N:13](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[C:7]3=[N:28][N:29]([CH2:31][C:32]4[C:37]([CH3:38])=[C:36]([O:39][CH3:40])[C:35]([CH3:41])=[CH:34][N:33]=4)[N:30]=[C:5]([C:6]=23)[CH:4]=1.N1C=CC=CC=1.[C:48](OC(=O)C)(=[O:50])[CH3:49]>ClCCl>[NH2:13][C:8]1[C:7]2[C:6]3[C:5](=[N:30][N:29]([CH2:31][C:32]4[C:37]([CH3:38])=[C:36]([O:39][CH3:40])[C:35]([CH3:41])=[CH:34][N:33]=4)[N:28]=2)[CH:4]=[C:3]([CH2:2][NH:1][C:48](=[O:50])[CH3:49])[C:12]=3[CH2:11][S:10][N:9]=1
Reactant: COc1c(C)cnc(Cn2nc3cc(CN)c4c-3c(n2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4)c1C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1c(C)cnc(Cn2nc3cc(CNC(C)=O)c4c-3c(n2)C(N)=NSC4)c1C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture composed of di-tert-butyl {8-(aminomethyl)-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-2,7-dihydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-4-yl}imidodicarbonate of Example 112 (20 mg), pyridine (8.3 μl), acetic anhydride (5 μl) and dichloromethane (0.5 ml) was stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure. Dichloromethane (2 ml) and trifluoroacetic acid (0.5 ml) were added to the resulting residue, and the mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure. A saturated sodium bicarbonate solution was placed into the resulting residue, followed by extraction with chloroform. The organic layer was dried over sodium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel thin-layer chromatography (chloroform-methanol) to obtain the title compound (3.7 mg) as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:16]1[CH2:21][CH2:20][C:19]([CH3:23])([CH3:22])[CH2:18][CH:17]=1.[K+].[C:25]([C:27]1[N:28]=[C:29]([C:40]([O-])=[O:41])[N:30]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:31]=1)#[N:26]>>[C:14]([C:8]1([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:40]([C:29]3[N:30]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:31]=[C:27]([C:25]#[N:26])[N:28]=3)=[O:41])=[C:3]([C:16]3[CH2:21][CH2:20][C:19]([CH3:23])([CH3:22])[CH2:18][CH:17]=3)[CH:4]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1)#[N:15]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: CC1(C)CC=C(c2cc(C3(C#N)CCCCC3)ccc2N)CC1
Agent: [K+]
Product: CC1(C)CC=C(c2cc(C3(C#N)CCCCC3)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1

Procedure:
The title compound was prepared from 1-[4-amino-3-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-cyclohexanecarbonitrile (as prepared in the previous step) and 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 1, step (d)) according to the procedure of Example 1, step (f). Mass spectrum (ESI, m/z): Calcd. for C32H43N5O2Si, 558.3 (M+H). found 557.8.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=1)[CH3:3].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[BH4-].[Na+]>N1C=CC=CC=1.CO>[CH3:13][O:12][C:6]1[CH:5]=[C:4]([CH:2]([CH3:3])[NH:1][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]=[CH:8][C:7]=1[O:10][CH3:11]
Reactant: O=Cc1ccccc1
Reactant: COc1ccc(C(C)N)cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CO
Product: COc1ccc(C(C)NCc2ccccc2)cc1OC
Reaction time: 48 h
Yield: 100 %

Procedure:
A mixture containing 18.1 g of 1-amino-1-(3,4-dimethoxyphenyl)-ethane (J. Chem. Soc. 1963, 4289), 10,6 g of benzaldehyde and 1 drop of pyridine in 100 ml of methanol is let stand at 20° C. for 2 days, then 3.8 g of sodium borohydride are added during 30 minutes and stirred for additional 3 hours. After evaporation of the solvent, the residue is diluted with water, extracted with chloroform, the organic phase is dried and evaporated to give 27.1 g of the crude title compound, which can directly be used in the process described in Example 6.
Reaction SMILES: Br.Br.Br.[NH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)[CH2:15][CH2:14]2)=[O:12])[N:9]=1.[Br:26][C:27]1[S:31][C:30]([C:32](O)=[O:33])=[CH:29][CH:28]=1>>[CH3:25][N:22]1[CH2:23][CH2:24][CH:19]([N:16]2[CH2:15][CH2:14][N:13]([C:11](=[O:12])[CH2:10][C:8]3[N:9]=[C:5]([NH:4][C:32]([C:30]4[S:31][C:27]([Br:26])=[CH:28][CH:29]=4)=[O:33])[S:6][CH:7]=3)[CH2:18][CH2:17]2)[CH2:20][CH2:21]1
Reactant: CN1CCC(N2CCN(C(=O)Cc3csc(N)n3)CC2)CC1
Reactant: O=C(O)c1ccc(Br)s1
Agent: Br
Product: CN1CCC(N2CCN(C(=O)Cc3csc(NC(=O)c4ccc(Br)s4)n3)CC2)CC1

Procedure:
47.3 Using general procedure D, 2-(2-amino-thiazol-4-yl)-1-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-ethanone trihydrobromide was coupled with 5-bromothiophene-2-carboxylic acid to give 5-bromo-thiophene-2-carboxylic acid (4-{2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-amide. Yellow solid. MS 514.3 ([M+H]+)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[C:10]([OH:11])=[C:9]([C:12]([OH:14])=O)[CH:8]=[N:7][C:6]=12.[C:15]1([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.C(OCC)(=O)C.Cl>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[C:10]([OH:11])=[C:9]([C:12]([N:24]3[CH2:25][CH2:26][CH:21]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:22][CH2:23]3)=[O:14])[CH:8]=[N:7][C:6]=12
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: O=C(O)c1cnc2c(Br)cnn2c1O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(c1cnc2c(Br)cnn2c1O)N1CCC(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 78.3 %

Procedure:
3-Bromo-7-hydroxypyrazolo[1,5-a]pyrimidine-6-carboxylic acid (6.3 g, 24.5 mmol) obtained in step 1 and 4-phenylpiperidine (7.9 g, 49.0 mmol) were suspended in methylene chloride (120 mL), triethylamine (13.7 ml, 98.1 mmol) and 50% 1-propylphosphonic acid anhydride cyclic trimer-ethyl acetate solution (6.0 g, 49.0 mmol) were added at 0° C., and the mixture was stirred at 0° C. for 2 hr. 4-Phenylpiperidine (7.9 g, 49.0 mmol), triethylamine (13.7 mL, 98.1 mmol) and 50% 1-propylphosphonic acid anhydride cyclic trimer-ethyl acetate solution (6.0 g, 49.0 mmol) were added to the reaction mixture, and the mixture was further stirred at 0° C. for 2 hr. 2 mol/L Hydrochloric acid (100 mL) was added to the reaction mixture, the organic layer and the aqueous layer were separated, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 2 mol/L Hydrochloric acid (100 mL) was added to the residue, and the mixture was stirred at 30° C. for 2 hr. The precipitate was collected by filtration, and washed with water (100 mL) to give the title compound (7.7 g, 78%).
Reaction SMILES: C(N(CC)[CH2:4][C:5]#[C:6][CH:7]([O:13][C:14](=[O:16])[CH3:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])C.N#C[Br:21]>CCOCC>[Br:21][CH2:4][C:5]#[C:6][CH:7]([O:13][C:14](=[O:16])[CH3:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCC(C#CCN(CC)CC)OC(C)=O
Reactant: N#CBr
Solvent: CCOCC
Product: CCCCCC(C#CCBr)OC(C)=O
Reaction time: 18 h

Procedure:
A solution of 1-diethylamino-4-acetoxy-2-nonyne (50.6 g., 0.20 mole) and cyanogen bromide (21.2 g., 0.20 mole) in ether (250 ml.) is allowed to stand at 25°-27° for 18 hours. The ether solution is washed with 5% hydrochloric acid solution, water, and brine and dried over sodium sulfate. The ether is evaporated and the residual oil distilled. After a forerun of diethylcyanamide, there is collected 34.1 g. (65%) of 1-bromo-4-acetoxy-2-nonyne, b.p. 97°-105°/0.2 mm.
Reaction SMILES: [F:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[C:4]([CH:6]=[C:7](F)[CH:8]=1)[NH2:5].C([O-])([O-])=O.[Cs+].[Cs+].[OH:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1.O>CS(C)=O>[NH2:5][C:4]1[CH:6]=[C:7]([O:19][C:20]2[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=2)[CH:8]=[C:2]([F:1])[C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: Nc1cc(F)cc(F)c1[N+](=O)[O-]
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1cc(Oc2ccc(C=O)cc2)cc(F)c1[N+](=O)[O-]
Yield: 84.4 %

Procedure:
A solution of 3,5-difluoro-2-nitroaniline (0.400 g, 2.30 mmol), Cs2CO3 (1.87 g, 5.74 mmol), and 4-hydroxybenzaldehyde (0.309 g, 2.53 mmol) in dimethylsulfoxide (5 mL) was heated at 80 degrees Centigrade for 2 hours and then cooled. Water was added and the organics extracted using ethyl acetate (2×50 mL). The combined organics were washed once in brine and dried (Na2SO4), filtered and concentrated. Chromatography on silica gel using a gradient of 20%-60% ethyl acetate/hexanes eluted the product to give 0.536 g of 4-[(3-amino-5-fluoro-4-nitrophenyl)oxy]benzaldehyde as a yellow solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][CH:9]1[CH2:21][O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:24])C1C=CC=CC=1.[ClH:30]>C(O)C.[Pd]>[ClH:30].[N:25]1([C:23]([O:22][CH2:21][CH:9]2[CH2:10][NH:11][CH2:12][CH2:13][NH:8]2)=[O:24])[CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: O=C(OCC1CN(Cc2ccccc2)CCN1Cc1ccccc1)N1CCCC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: O=C(OCC1CNCCN1)N1CCCC1
Yield: 98.3 %

Procedure:
1.48 g (3.7 mmol) of 1,4-dibenzyl-2-(1′-pyrrolidinocarbonyloxymethyl)piperazine are dissolved in 40 ml of absolute ethanol and 1 ml of 12N HCl in a 100 ml ground-necked round-bottomed flask. About 100 mg of palladium (10%) on charcoal are added thereto. The mixture is then placed under a hydrogen atmosphere, vigorously stirred and gentle heating is applied (40° C.). When the initial product has disappeared (the reaction program is monitored by thin-layer chromatography eluted with an MeOH/CH2Cl2 mixture (5/95 v/v), after neutralization of an aliquot with a few grains of NaHCO3), the solution is filtered on paper and the catalyst is rinsed several times with ethanol and water. The solvents are then evaporated off under vacuum. 1.04 g of 2-(1′-pyrrolidinocarbonyloxymethyl)piperazine hydrochloride are thus obtained and used in the following step without further purification. Yield: 98.3%. Rf=0.4 (80/20/2 v/v/v CHCl3/MeOH/NH4OH).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[S:11]([O-:14])(=[O:13])=[O:12].[Na+:15].[C:16]1([OH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[O:22]([C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[S:11]([O-:14])(=[O:13])=[O:12])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Na+:15]
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)[O-])c(Cl)c1
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccc(S(=O)(=O)[O-])c(Oc2ccccc2)c1

Procedure:
The synthesis of (A) was carried out as follows. First, sodium 2-chloro-4-nitrobenzenesulfonate and phenol were reacted in water in the presence of a base, to obtain sodium 2-phenoxy-4-nitrobenzenesulfonate. This was reacted with POCl3 /DMAC to produce the sulfonyl chloride form, and then the sulfonyl chloride was reacted with the ethyl ester of glycine, to obtain the carboxylic acid ethyl form of (A). Then it was hydrolyzed followed by reaction with SOCl2 in benzene, and then the benzene was distilled off, so that (A) was obtained in the form of crystals.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:17][S:18]C)[C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])(=O)C>O.N>[SH:18][CH2:17][CH:6]([CH2:5][S:4][CH3:1])[C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8]
Reactant: CSCC(CSC(C)=O)C(=O)N1CCC[C@H]1C(=O)O
Agent: N
Solvent: O
Product: CSCC(CS)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
1-[3-(acetylthio)-2-(methylthiomethyl)propanoyl]-L-proline (1.2 g.) is dissolved in a mixture of water (12 ml.) and concentrated ammonia (12 ml.) under a blanket of argon. After twenty minutes, the reaction mixture is acidified and extracted with ethyl acetate. The organic layer is dried and concentrated to dryness to yield 1-([3-mercapto-2-(methylthiomethyl)propanoyl]-L-proline.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:14][CH3:15])=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Na+].Cl>O1CCCC1>[Cl:1][C:2]1[C:3]([O:14][CH3:15])=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Cl)c(OC)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(OC)c(C(=O)O)cc1Cl
Reaction time: 4 h

Procedure:
A 0.56 g portion of methyl 5-chloro-2,4-dimethoxybenzoate was dissolved in 5 ml of tetrahydrofuran, and 10 ml of 2N sodium hydroxide aqueous solution was added, followed by 4 hours of heating under reflux. After completion of the reaction, the reaction solution was poured into 1N hydrochloric acid aqueous solution, and the thus precipitated product of interest was collected by filtration, washed with water and then dried under a reduced pressure to give 0.45 g of 5-chloro-2,4-dimethoxybenzoic acid.
Reaction SMILES: CN(C)C(OC(C)(C)C)N(C)C.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:14][CH3:15].[CH3:20][N:21]([CH:23]=O)[CH3:22]>>[CH3:22][N:21]([CH3:20])/[CH:23]=[C:14](\[CH3:15])/[C:13]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CN(C)C=O
Reactant: CCOC(=O)CC
Agent: CN(C)C(OC(C)(C)C)N(C)C
Product: CCOC(=O)/C(C)=C/N(C)C
Yield: 30 %

Procedure:
A solution of N,N,N′,N′-tetramethyl-1-[(2-methylpropan-2-yl)oxy]methanediamine (2.47 g, 14.19 mmol), ethyl propionate (2.17 g, 21.27 mmol) and DMF (2 mL) in a sealed tube was heated to 90° C. for 24 h. Then extracted with ethyl acetate, collected the organic phase and washed with water, brine and dried with anhydrous sodium sulfate. Organic phase was concentrated and purified by silica gel chromatograph to give 0.68 g of the title compound (30%). 1H NMR (400 MHz, CDCl3): δ 1.24 (3H, t, J=7.2 Hz), 1.95 (3H, s), 3.00 (6H, s), 4.11 (2H, q, J=7.2 Hz), 7.28 (1H, s). [M+H] Calc'd for C8H15NO2, 158. Found, 158.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[N+:16]([O-])=O.[H][H]>[Pd].C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][C:3]=1[NH2:16]
Reactant: Cc1ccc(C=Cc2ccccc2)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(CCc2ccccc2)cc1N

Procedure:
A mixture of the product from Example 241A (0.166 g, 0.694 mmol) and 10% palladium on charcoal (18.4 mg, 0.025 eq), in ethanol (10 mL) was stirred under one atmosphere of hydrogen for 16 hours. The reaction mixture was then filtered through Celite and the solvent evaporated under reduced pressure to provide the title compound as a slightly red oil (0.141 g, 96% yield).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([C:14]1([CH3:22])[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:23].[Cl:24][C:25]1[CH:26]=[C:27]([N:32]=[C:33]=[O:34])[CH:28]=[CH:29][C:30]=1[CH3:31].C(N(CC)CC)C.Cl>C1COCC1>[Cl:24][C:25]1[CH:26]=[C:27]([NH:32][C:33]([NH:2][CH2:3][C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[C:9](=[O:13])[N:8]([C:14]2([CH3:22])[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]2=[O:21])[C:7]3=[O:23])=[O:34])[CH:28]=[CH:29][C:30]=1[CH3:31]
Reactant: CC1(N2C(=O)c3ccc(CN)cc3C2=O)CCC(=O)NC1=O
Reactant: Cc1ccc(N=C=O)cc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)NCc2ccc3c(c2)C(=O)N(C2(C)CCC(=O)NC2=O)C3=O)cc1Cl
Reaction time: 2 h
Yield: 56.9 %

Procedure:
To a stirred mixture of 5-aminomethyl-2-(3-methyl-2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.50 g, 1.50 mmol) and 3-chloro-4-methyl-phenyl isocyanate (0.25 g, 1.50 mmol) in THF (25 mL), was added triethylamine (0.42 mL, 3.00 mmol) at room temperature under nitrogen. After 2 h, 2% aq. HCl (75 mL) was added. The product was extracted with EtOAc (75 mL) and the organic layer was separated and washed with water (2×75 mL), dried (MgSO4) and concentrated in vacuo to give 1-(3-chloro-4-methyl-phenyl)-3-[2-(3-methyl-2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (0.40 g, 58% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 50/50 CH3CN/0.1% H3PO4, 4.37 min (98.73%); mp: 232-234° C.; 1H NMR (DMSO-d6) δ 1.89 (s, 3H), 1.98-2.13 (m, 1H), 2.23 (s, 3H), 2.52-2.79 (m, 3H), 4.44 (d, J=6.0 Hz, 2H), 6.89 (t, J=5.9 Hz, 1H), 7.08-7.21 (m, 2H), 7.64 (d, J=1.9 Hz, 1H), 7.72-7.88 (m, 3H), 8.82 (s, 1H), 11.01 (s, 1H); 13C NMR (DMSO-d6) δ 18.74, 21.02, 28.58, 29.11, 442.65, 58.76, 116.53, 117.74, 121.37, 123.13, 127.53, 129.49, 131.02, 131.37, 132.97, 133.21, 139.49, 148.47, 155.10, 167.77, 167.93, 172.13, 172.21; LCMS: MH=469/471; Anal Calcd for C23H21ClN4O5: C, 58.91; H, 4.51; N, 11.95. Found: C, 58.63; H, 4.40; N, 11.82.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH2:10][CH2:11][C:12]1([CH2:19][S:20]([N:23]2[CH2:28][CH2:27][CH:26]([O:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][N:31]=3)[CH2:25][CH2:24]2)(=[O:22])=[O:21])[NH:16][C:15](=[O:17])[NH:14][C:13]1=[O:18].[CH3:37]CN(C(C)C)C(C)C.[S:46](Cl)(Cl)(=[O:48])=[O:47]>C(Cl)Cl>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([O:29][CH:26]2[CH2:27][CH2:28][N:23]([S:20]([CH2:19][C:12]3([CH2:11][CH2:10][CH2:9][NH:8][S:46]([CH3:37])(=[O:48])=[O:47])[C:13](=[O:18])[NH:14][C:15](=[O:17])[NH:16]3)(=[O:21])=[O:22])[CH2:24][CH2:25]2)=[N:31][CH:32]=1
Reactant: NCCCC1(CS(=O)(=O)N2CCC(Oc3ccc(Cl)cn3)CC2)NC(=O)NC1=O
Reactant: CCN(C(C)C)C(C)C
Reactant: O=S(=O)(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)NCCCC1(CS(=O)(=O)N2CCC(Oc3ccc(Cl)cn3)CC2)NC(=O)NC1=O

Procedure:
5-(3-Aminopropyl)-5-[({4-[(5-chloropyridin-2-yl)oxy]piperidin-1-yl}sulfonyl)methyl]imidazolidine-2,4-dione trifluoroacetic acid (100 mg, 0.18 mmol) was slurried in 2 mL DCM. DIPEA (62 μL, 0.36 mmol) was added and the slurry was stirred for some minutes. Sulfonylchloride (16 μL, 0.18 mmol) was added and the reaction was stirred at rt over night. The crude product was purified by preparative HPLC.
Reaction SMILES: C([O:5][C:6](=[O:27])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:11][C:10]=1[O:25][CH3:26])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:26][O:25][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17](=[O:24])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:13]=[CH:14][C:9]=1[CH:8]=[CH:7][C:6]([OH:27])=[O:5]
Reactant: COc1cc(C=CC(=O)c2ccccc2)ccc1C=CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C=CC(=O)c2ccccc2)ccc1C=CC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.8 %

Procedure:
3-[2-methoxy-4-(3-oxo-3-phenyl-propenyl)-phenyl]-acrylic acid tert-butyl ester (635 mg, 1.74 mmol) was dissolved in DCM (12 ml) and TFA (3 ml) was added to the resulting solution. After stirring for 2 h at room temperature the solvent was removed under vacuo giving 541 mg of 3-[2-methoxy-4-(3-oxo-3-phenyl-propenyl)-phenyl]-acrylic acid as yellow powder.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]#[N:20])=[N:17][CH:18]=1.C(N(CC)CC)C>ClCCl>[CH:12]([C:13]1[CH:14]=[CH:15][C:16]([C:19]#[N:20])=[N:17][CH:18]=1)=[O:11]
Reactant: N#Cc1ccc(CO)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc(C=O)cn1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
1.04 g (8.2 mmol) oxalylchloride are dissolved in 8 ml dichloromethane. At −78° C., 1.28 g (16.4 mmol) dimethylsulfoxide are added dropwise. The solution is stirred at −78° C. for 20 minutes, then 1 g (7.46 mmol) of the compound of Example 2A, dissolved in 7 ml dichloromethane, is added, and stirring at −78° C. is continued for another 2 hours. 3.4 g (33.6 mmol) triethylamine are then added dropwise, and after warming up to room temperature, the mixture is purified by column chromatography (silica, eluent: cyclohexane to cyclohexane/ethyl acetate 2:1).