Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH3:7])[CH:4]=[O:5])[CH3:2].S(=O)(O)[O-].[Na+].S(=O)(O)[O-].[C-:17]#[N:18].[Na+]>C(Cl)Cl.O>[C:17]([CH:4]([OH:5])[CH:3]([CH2:6][CH3:7])[CH2:1][CH3:2])#[N:18]
Reactant: [C-]#N
Reactant: CCC(C=O)CC
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCC(CC)C(O)C#N
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 2-ethyl butyraldehyde (6 g, 60 mmol) in CH2Cl2 (75 mL) was stirred vigorously with a solution of sodium bisulfite (9.4 g, 90 mmol) in water (35 mL). The thick precipitate which had formed was collected by filtration and washed with CH2Cl2 and dried in vacuo. The bisulfite adduct (10 g, 49 mmol) was dissolved in water (60 mL) and to the solution was added sodium cyanide (3.6 g, 73 mmol). The resulting solution was stirred at ambient temperature for 48 h. The mixture was extracted with ether (2×100 mL) and the combined extracts were dried (MgSO4), filtered, and the solvent was removed in vacuo. The residue was purified by flash silica gel column chromatography using a gradient elution of 10%, 12.5%, 15% EtOAc in hexanes. The product-containing fractions were combined to give 1-cyano-2-ethylbutanol as a liquid after removal of the solvents in vacuo (5.0 g; TLC Rf=0.4 (9:1 hexanes:EtOAc); 400 MHz 1H NMR, CDCl3, 4.51 ppm (dd, 1H), 2.45 ppm (d, 1H), 1.4-1.7 ppm (overlapping m, 5H), 0.98 ppm (overlapping t, 6H)).
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[C:13](=[O:14])[NH:12][C:11]([S:15][CH3:16])=[C:10]2[C:17]#[N:18])=[CH:5][CH:4]=1.[H-].[Na+].[CH3:28][N:29]([CH3:34])[CH2:30][CH2:31][CH2:32]Cl>O1CCOCC1>[CH3:25][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[C:13](=[O:14])[N:12]([CH2:32][CH2:31][CH2:30][N:29]([CH3:34])[CH3:28])[C:11]([S:15][CH3:16])=[C:10]2[C:17]#[N:18])=[CH:5][CH:4]=1
Reactant: CSC1=C(C#N)C(c2ccc(N(C)C)cc2)(c2cccnc2)C(=O)N1
Reactant: CN(C)CCCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CSC1=C(C#N)C(c2ccc(N(C)C)cc2)(c2cccnc2)C(=O)N1CCCN(C)C
Yield: 41.4 %

Procedure:
A suspension of 3.5 g 4-(4-dimethylaminophenyl)-2-methylthio-5-oxo-4-(3-pyridyl)-2-pyrroline-3-carbonitrile and 0.3 g sodium hydride (80% in white oil) is refluxed for one hour. One then adds dropwise thereto, within ten minutes, a solution of 1.3 g 3-dimethylaminopropyl chloride in 25 ml abs. dioxan and further boils for six hours. After cooling, the reaction mixture is filtered, the solvent is removed on a Rotavapor and the residue is chromatographed on silica gel with chloroform+methanol 10+1 as elution agent. After crystallization of the main fraction from isopropanol, one obtains 1.8 g of colorless crystals of mp 90°-91° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[N:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)=[C:13]=[S:14].CC(O)C>O>[CH3:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([N:12]2[C:4]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:3][N:2]=[C:13]2[SH:14])=[CH:20][CH:19]=1
Reactant: NCC(=O)c1ccccc1
Reactant: COc1ccc(N=C=S)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: COc1ccc(-n2c(-c3ccccc3)cnc2S)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
A mixture of 17.5 parts of 2-amino-1-phenylethanone hydrochloride, 16.5 parts of 1-isothiocyanato-4-methoxybenzene, 10 parts of sodium hydrogen carbon and 200 parts of 2-propanol is stirred first for 30 minutes at room temperature and further for 2 hours at reflux temperature. The reaction mixture is poured onto 500 parts of water. The product is filtered off and stirred and refluxed for 1 hour with 240 parts of hydrochloric acid solution 10%. After cooling, the product is filtered off, washed with water and 2-propanol, and dried, yielding 25.3 parts (90%) of 1-(4-methoxyphenyl)-5-phenyl-1H-imidazole-2-thiol; mp. 267.4° C.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[N:15]1([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Reactant: C1COCCN1
Product: Nc1nnc(N2CCOCC2)c(-c2ccccc2)n1
Yield: 24.3 %

Procedure:
6-(Morpholin-4-yl)-5-phenyl-1,2,4-triazin-3-amine (50 mg, 20%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.21 g, 0.80 mmol) and morpholine (0.126 g, 1.44 mmol) according to the general procedure of Example 2.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=2)[C:7]([CH:10]=O)=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].C(C1N(CC2C=CC(C(OCC)=O)=CC=2Cl)C(C=O)=CN=1)CCC.[S:47]1[CH:51]=[CH:50][CH:49]=[C:48]1[CH2:52][CH2:53][C:54]([O:56]C(C)(C)C)=[O:55].C(C1N(CC2C=CC=CC=2Cl)C(/C(/C)=C(\C2C=CN=CC=2)/C(O)=O)=CN=1)CCC.FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=2)[C:7](/[CH:10]=[C:53](\[CH2:52][C:48]2[S:47][CH:51]=[CH:50][CH:49]=2)/[C:54]([OH:56])=[O:55])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(C=O)n1Cc1ccc(C(=O)OC)cc1
Reactant: CC(C)(C)OC(=O)CCc1cccs1
Agent: CCCCc1ncc(/C(C)=C(/C(=O)O)c2ccncc2)n1Cc1ccccc1Cl
Agent: CCCCc1ncc(C=O)n1Cc1ccc(C(=O)OCC)cc1Cl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1ncc(/C=C(\Cc2cccs2)C(=O)O)n1Cc1ccc(C(=O)OC)cc1

Procedure:
The title compound was prepared using 2-n-butyl-1-[(4carbomethoxyphenyl)methyl]imidazole-5-aldehyde (prepared by the method described for the preparation of 2-n-butyl-1-[(4-carboethoxy-2-chlorophenyl)methyl]imidazole-5-aldehyde in Example 42) and t-butyl 3-(2-thienyl)-propanoate by the procedure of Example 1 (iv, Method B), except, instead of basic hydrolysis, trifluoroacetic acid hydrolysis of the t-butyl ester was employed; mp 217°-220° C.
Reaction SMILES: C([O:4][CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:7](=O)[O:6]1)(=O)C.[H][H]>[Pd].CO>[C:5]1([C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:7][O:6]1)=[O:4]
Reactant: CC(=O)OC1OC(=O)c2ccccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C1OCc2ccccc21
Temperature: 35 °C
Reaction time: 3 h

Procedure:
In the manner described in Example 1, the autoclave is filled with 86.4 g of 3-acetoxyphthalide, 400 ml of methanol and 10 g of palladium-on-charcoal catalyst (Pd content 5 wt%), raised to 10 bars with hydrogen, and slowly heated to 35° C. The consumed hydrogen is first replaced by addition in the range up to 10 bars, and then again in the range up to 20 bars and after the reaction rate has decreased. After 3 hours the pressure remains constant. The catalyst is filtered off and the remaining solution is concentrated at 70° C. and 20 Torr in a rotary thin film evaporator. The residue, still smelling slightly of acetic acid, is fractionally distilled between 99° and 103° C. at 0.5 Torr, and the distillate is recrystallized from water. 54 g (90.05% of the theory) of phthalide of a melting point of 72.5° C. is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[N:19]=3)[N:16]=[C:15]([C:25](O)=[O:26])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C([N:49]3[CH2:53][C:52](=[O:54])[NH:51][CH2:50]3)=O)C=2)C=C(F)C=1.Cl.N1C=CNC1=O>>[Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[N:19]=3)[N:16]=[C:15]([C:25]([N:49]3[CH2:53][C:52](=[O:54])[NH:51][CH2:50]3)=[O:26])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:11])([F:10])[F:12])[CH:7]=1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccccn3)n2)CN1
Reactant: O=C(O)c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2cccc(Cl)n2)n1
Agent: Cl
Agent: O=c1[nH]cc[nH]1
Product: O=C1CN(C(=O)c2cc(-c3cc(Br)cc(OC(F)(F)F)c3)n(-c3cccc(Cl)n3)n2)CN1

Procedure:
75 mg (0.16 mmol) of the compound of Example 38A is reacted analogously to the synthesis of the compound of Example 1 with 22 mg (0.18 mmol) of 4-imidazolinone-hydrochloride. 65 mg (75% of theory) of the title compound is obtained.
Reaction SMILES: Cl[S:2]([C:5]1[C:6](=[O:22])[C:7]2[C:15](=[CH:16][CH:17]=1)[C:14]1[C:9](=[CH:10][C:11]([S:18](Cl)(=[O:20])=[O:19])=[CH:12][CH:13]=1)[CH:8]=2)(=[O:4])=[O:3].C(=O)(O)[O-].[Na+:27].S([O-])([O-])=O.[Na+:32].[Na+]>O>[Na:27][S:2]([C:5]1[C:6](=[O:22])[C:7]2[C:15](=[CH:16][CH:17]=1)[C:14]1[C:9](=[CH:10][C:11]([S:18]([Na:32])(=[O:20])=[O:19])=[CH:12][CH:13]=1)[CH:8]=2)(=[O:4])=[O:3]
Reactant: O=C1C2=Cc3cc(S(=O)(=O)Cl)ccc3C2=CC=C1S(=O)(=O)Cl
Reactant: [Na+]
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Solvent: O
Product: O=C1C2=Cc3cc(S(=O)(=O)[Na])ccc3C2=CC=C1S(=O)(=O)[Na]

Procedure:
Also, for example, 2,7-bis(chlorosulfonyl)fluorenone can be mixed with a heated solution of sodium bicarbonate and sodium sulfite in water to yield 2,7-bis(sodiosulfonyl)fluorenone, which can be refluxed with n-butyl iodide in ethanol to yield 2,7-bis(n-butylsulfonyl)fluorenone, which in turn can be refluxed with malononitrile in methanol in the presence of piperidine to yield 2,7-bis(n-butylsulfonyl)-9-(dicyanomethylene)fluorene.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=2[C:18]#[N:19])=[CH:6][C:5]([NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])=[C:4]([F:27])[CH:3]=1.O1CCCC1>C(O)(=O)C>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:7]2[C:2]([Cl:1])=[CH:3][C:4]([F:27])=[C:5]([NH:20][C:21](=[O:26])[C:22]([F:23])([F:24])[F:25])[CH:6]=2)=[C:10]([C:18]#[N:19])[CH:11]=1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Oc1cc(NC(=O)C(F)(F)F)c(F)cc1Cl
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: N#Cc1cc(N)ccc1Oc1cc(NC(=O)C(F)(F)F)c(F)cc1Cl
Temperature: 60 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
To a solution of N-[4-chloro-5-(2-cyano-4-nitrophenoxy)-2-fluorophenyl]-2,2,2-trifluoroacetamide (16.0 g, 39.6 mmol) in acetic acid (850 ml)/tetrahydrofuran (500 mL) was added reduced iron (11.1 g, 198 mmol), and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was cooled to room temperature, insoluble material was filtered off through a pad of celite, and washed with acetic acid. The filtrate and washings were combined and the mixture was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (900 mL)/tetrahydrofuran (100 mL), washed successively with saturated aqueous sodium hydrogen carbonate solution (500 mL) and saturated brine (500 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=10/90→50/50), and the obtained solution was concentrated under reduced pressure to give the title compound (12.2 g, 82%) as a white powder.
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]=[C:18]=[O:19]>>[OH:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:18]([NH:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[Br:10])=[O:19]
Reactant: Nc1ccc(F)cc1O
Reactant: O=C=Nc1ccccc1Br
Product: O=C(Nc1ccc(F)cc1O)Nc1ccccc1Br

Procedure:
The urea was prepared from 2-hydroxy 4-fluoro aniline(254 mg, 2 mmol) and 2-bromophenylisocyanate by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane(173 mg, 26%). EI-MS m/z 325 (M+H)+.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:7][C:6]=2[C:5]([CH3:12])=[N:4]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:20][CH2:21][CH2:22][Cl:23]>CC(C)=O>[Cl:23][CH2:22][CH2:21][CH2:20][N:8]1[CH2:9][CH2:10][C:11]2[N:3]([CH3:2])[N:4]=[C:5]([CH3:12])[C:6]=2[CH2:7]1
Reactant: ClCCCBr
Reactant: Cc1nn(C)c2c1CNCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1nn(C)c2c1CN(CCCCl)CC2
Yield: 49.8 %

Procedure:
To a mixture of 1,3-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine hydrochloride (2.00 g, 13.22 mmol, 1.0 eq) and K2CO3 (5.47 g, 39.66 mmol, 3.0 eq) in 40 mL of acetone was added 1-bromo-3-chloropropane (4.16 g, 26.44 mmol, 2.0 eq) at room temperature. The reaction mixture was heated to reflux for 5.0 h and filtered. The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (eluting agent: 100:1 (v/v) DCM/MeOH) to give the title compound as yellow oil (1.50 g, 51.02%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 228.73 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[C:23]3[C:18](=[C:19]([CH2:24][S:25][CH3:26])[CH:20]=[CH:21][CH:22]=3)[N:17]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:16]=2)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[CH2:34](OC(=O)C(C)C(C1C2C(=C(CSC)C=CC=2)N(C(OC(C)(C)C)=O)C=1)C1C=CC(C(F)(F)F)=CC=1)C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[C:23]3[C:18](=[C:19]([CH2:24][S:25][CH3:26])[CH:20]=[CH:21][CH:22]=3)[N:17]([C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[CH:16]=2)[CH:9]([CH3:34])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(c1ccc(Cl)cc1)c1cn(C(=O)OC(C)(C)C)c2c(CSC)cccc12
Reactant: CCOC(=O)C(C)C(c1ccc(C(F)(F)F)cc1)c1cn(C(=O)OC(C)(C)C)c2c(CSC)cccc12
Product: CCOC(=O)C(C)C(c1ccc(Cl)cc1)c1cn(C(=O)OC(C)(C)C)c2c(CSC)cccc12

Procedure:
The title compound was prepared starting from 1.62 g (91% purity, 3.01 mmol) of the compound from Example 30A in analogy to the synthesis of the compound from Example 27A. 0.89 g (59% of theory) of the title compound was obtained as mixture of diastereomers.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[CH2:3]1.[Br:38][C:39]1[C:44]([N+:45]([O-:47])=[O:46])=[CH:43][CH:42]=[CH:41][C:40]=1[CH2:48]Br>>[Br:38][C:39]1[C:44]([N+:45]([O-:47])=[O:46])=[CH:43][CH:42]=[CH:41][C:40]=1[CH2:48][O:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:29])[CH2:3]1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2O)cc1
Reactant: O=[N+]([O-])c1cccc(CBr)c1Br
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2cccc([N+](=O)[O-])c2Br)cc1

Procedure:
Analogously to Method D, 1.30 g of benzyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]-phenyl}piperidine-1-carboxylate (Example 10f) and 1.0 g of 2-bromo-1-bromomethyl-3-nitrobenzene are reacted. The title compound is obtained as a yellowish oil. Rf=0.29 (1:1 EtOAc-heptane); Rt=6.12.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:25][C:26]([CH3:32])=[CH:27][C:28]=1[C:29](O)=[O:30])(=[O:12])=[O:11].[N:33]1([CH2:38][CH2:39][CH2:40][NH2:41])[CH2:37][CH2:36][CH2:35][CH2:34]1>>[N:33]1([CH2:38][CH2:39][CH2:40][NH:41][C:29]([C:28]2[CH:27]=[C:26]([CH3:32])[NH:25][C:24]=2/[CH:23]=[C:16]2\[C:17](=[O:22])[NH:18][C:19]3[C:15]\2=[CH:14][C:13]([S:10]([CH2:9][C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])(=[O:12])=[O:11])=[CH:21][CH:20]=3)=[O:30])[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: NCCCN1CCCC1
Reactant: Cc1cc(C(=O)O)c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)[nH]1
Product: Cc1cc(C(=O)NCCCN2CCCC2)c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)[nH]1

Procedure:
2-[5-(2,6-Dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid was coupled with 3-pyrrolidin-1-yl-propylamine to give the titled compound.
Reaction SMILES: [OH-].[K+].C([O:5][C:6]([C:8]1[CH:9]=[C:10]([NH:14][C:15](=[O:38])[NH:16][CH2:17][C:18]([N:20]2[CH:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:30][CH2:29][CH:21]2[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:19])[CH:11]=[CH:12][CH:13]=1)=[O:7])C>O.CO>[C:25]([O:24][C:22]([CH:21]1[CH2:29][CH2:30][CH:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:20]1[C:18](=[O:19])[CH2:17][NH:16][C:15](=[O:38])[NH:14][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[C:6]([OH:7])=[O:5])=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: CCOC(=O)c1cccc(NC(=O)NCC(=O)N2C(C(=O)OC(C)(C)C)CCC2c2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)C1CCC(c2ccccc2)N1C(=O)CNC(=O)Nc1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.6 %

Procedure:
0.9 g of potassium hydroxide dissolved in 60 cm3 of distilled water is added to a solution of 8 g of tert-butyl (2RS,5SR)-1-{2-[3-(3-ethoxycarbonylphenyl)ureido]acetyl}-5-phenylprolinate in 120 cm3 of methanol. The reaction mixture is stirred for 3 hours at a temperature in the vicinity of 25° C. then concentrated to 50 cm3 under reduced pressure. The solution obtained is diluted with 30 cm3 of water, washed with 2 times 50 cm3 of ethyl acetate, acidified to a pH of 2 with a 4N aqueous hydrochloric acid solution and extracted with 3 times 100 cm3 of dichloromethane. The organic phases are combined, washed with 2 times 50 cm3 of water, dried over magnesium sulphate and concentrated to dryness under reduced pressure at a temperature in the vicinity of 40° C. The crude product obtained is purified by chromatography on silica [eluent: dichloromethane/methanol (90/10 by volume)]. The fractions containing the expected product are combined and concentrated to dryness under reduced pressure. After recrystallization in ethyl acetate, 4.5 g of (2RS,5SR)-3-{3-[2-(2-tert-butyoxycarbonyl-5-phenyl-1-pyrrolidinyl)-2-oxoethyl]ureido}benzoic acid, melting at 236° C., are obtained.
Reaction SMILES: [OH:1][NH:2][C:3]([CH3:10])([C:5]([NH:8][OH:9])([CH3:7])[CH3:6])[CH3:4].[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1>CO>[OH:1][N:2]1[C:3]([CH3:10])([CH3:4])[C:5]([CH3:7])([CH3:6])[N:8]([OH:9])[CH:17]1[C:16]1[CH:19]=[CH:20][C:13]([O:12][CH3:11])=[CH:14][CH:15]=1
Reactant: CC(C)(NO)C(C)(C)NO
Reactant: COc1ccc(C=O)cc1
Solvent: CO
Product: COc1ccc(C2N(O)C(C)(C)C(C)(C)N2O)cc1
Yield: 34 %

Procedure:
A solution of 2,3-bis(hydroxylamino)-2,3-dimethylbutane (1.3 g, 8.8 mmol) and 4-methoxy-benzaldehyde (1.2 g, 8.8 mmol) in methanol (10 mL) was stirred at room temperature until reactants disappeared as TLC indicated. 1,3-Dihydroxy-2-(4-methoxyphenyl)-4,4,5,5-tetramethylimidazolidine was obtained by filtration, the filtrate was evaporated under reduced pressure to obtain the second crop of the title compound. The combined compound was then washed with petroleum ether and used for the next reaction (0.8 g, 34% yield). 1HNMR (400 MHz, DMSO): δ 7.63 (s, 1H), 7.32 (d, 1H, J=6.8), 6.87 (d, 1H, J=5.8), 4.42 (s, 1H), 3.72 (s, 3H), 1.06 (s, 3H), 1.02 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.Br[CH:12]([CH2:18][CH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[C:13]([O:15][CH2:16][CH3:17])=[O:14].O1CCC(C=CC(OCC)=O)CC1.C(=O)([O-])[O-].[K+].[K+]>O.CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH:12]([CH2:18][CH:19]1[CH2:20][CH2:21][O:22][CH2:23][CH2:24]1)[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)C(Br)CC1CCOCC1
Reactant: Brc1cccc2[nH]ncc12
Agent: CCOC(=O)C=CC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(CC1CCOCC1)n1ncc2c(Br)cccc21
Yield: 53.4 %

Procedure:
A mixture of 4-bromo-1H-indazole (3.00 g), a 1:1 mixture (6.73 g) of ethyl 2-bromo-3-(tetrahydro-2H-pyran-4-yl)propanoate and ethyl 3-(tetrahydro-2H-pyran-4-yl)-2-propenoate, potassium carbonate (2.1 g) and N,N-dimethylformamide (20 mL) was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to give the title compound (3.10 g) as a yellow oil from the fraction eluted with ethyl acetate-hexane (1:4, volume ratio). MS: 383 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6](=[O:24])[CH:5]2[C:25]1[C:34]([OH:35])=[CH:33][C:28]2[O:29][CH2:30][CH2:31][O:32][C:27]=2[CH:26]=1.[C:36]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6](=[O:24])[C:5]12[C:25]2[C:34](=[CH:33][C:28]3[O:29][CH2:30][CH2:31][O:32][C:27]=3[CH:26]=2)[O:35][CH2:36]1
Reactant: O=C1C(c2cc3c(cc2O)OCCO3)c2cc(Br)ccc2N1C(c1ccccc1)c1ccccc1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccc(Br)cc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 5-bromo-1-(diphenylmethyl)-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 5′-bromo-1′-(diphenylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (76%) as a colorless solid: MS (ES+) m/z 539.9 (M+1), 541.1 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([F:12])=[C:6]([OH:11])[C:7]([F:10])=[CH:8][CH:9]=1)[CH3:2].[CH2:13]([O:15][C:16](=[O:20])[C:17]#[C:18][CH3:19])[CH3:14].N12CCCN=C1CCCCC2>O1CCCC1>[CH2:13]([O:15][C:16](=[O:20])/[CH:17]=[C:18](/[O:11][C:6]1[C:7]([F:10])=[CH:8][CH:9]=[C:4]([O:3][CH2:1][CH3:2])[C:5]=1[F:12])\[CH3:19])[CH3:14]
Reactant: CCOc1ccc(F)c(O)c1F
Reactant: CC#CC(=O)OCC
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)/C=C(\C)Oc1c(F)ccc(OCC)c1F
Yield: 67.4 %

Procedure:
To a stirred mixture of 3-ethoxy-2,6-difluoro-phenol (4.26 g, 0.024 mol) and ethyl-2-butynoate (5.48 g, 0.049 mol) in tetrahydrofuran (30 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (3.73 g, 0.025 mol) slowly. After addition was complete the mixture was stirred at reflux for 6 h. Upon completion of the reaction the tetrahydrofuran was removed in vacuo and the residue was diluted in diethyl ether and washed first with 1N aqueous hydrochloric acid, then 10% aqueous sodium hydroxide solution, a saturated sodium chloride solution and dried over magnesium sulfate. The crude product was purified by ISCO column chromatography (Teledyne Isco RediSep Flash Column 120 g, 0% to 20% ethyl acetate/hexanes) which afforded (E)-3-(3-ethoxy-2,6-difluoro-phenoxy)-but-2-enoic acid ethyl ester (4.63 g, 66%) as a white crystalline solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:9]=[C:10]([B:14]2[O:22][C:19]([CH3:21])([CH3:20])[C:16]([CH3:18])([CH3:17])[O:15]2)[CH:11]=[CH:12][CH:13]=1.[CH3:23][O:24][CH2:25][CH2:26]Br>CN(C=O)C>[CH3:23][O:24][CH2:25][CH2:26][O:7][C:8]1[CH:9]=[C:10]([B:14]2[O:22][C:19]([CH3:21])([CH3:20])[C:16]([CH3:17])([CH3:18])[O:15]2)[CH:11]=[CH:12][CH:13]=1
Reactant: COCCBr
Reactant: CC1(C)OB(c2cccc(O)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Temperature: 100 °C
Yield: 86.9 %

Procedure:
Potassium carbonate (1.88 g, 13.65 mmol) was added to a solution of −3-hydroxyphenylboronic acid pinacol ester (Apollo, 1.0 g, 4.55 mmol) in DMF (10 mL). 2-Bromoethyl methyl ether (0.41 mL, 5.46 mmol) was added and the reaction mixture was heated to 100° C. for 1 hr. The reaction mixture was allowed to cool and then partitioned between ethyl acetate (50 mL), and water (150 mL). The phases were separated and the organic phase was washed with brine (150 mL), dried over anhydrous sodium sulphate, filtered and the filtrate solvents removed in vacuo, to afford the title product as a light-brown oil (1.1 g) which was used without further purification.