Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.Br[CH:3]([C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O-])(=[O:20])C.[K+].O>C(OC(=O)C)(=O)C>[OH:20][CH:3]([C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)[O-]
Reactant: O=C(c1cccnc1)C(Br)c1ccccc1
Agent: Br
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: O=C(c1cccnc1)C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.3 %

Procedure:
Alternatively, a mixture of 20.0 g (56.0 mmoles) of 3-pyridyl α-bromobenzyl ketone hydrobromide and 24.0 g (0.24 mole) of potassium acetate in 100 ml of acetic anhydride was stirred overnight at room temperature. The reaction mixture was poured into water and the product extracted into ether. The combined ether layers were washed with water and then 10% aqueous sodium bicarbonate solution. The ether layer was dried over potassium carbonate and evaporated. A solution of the residue in 140 ml of 1 N aqueous hydrochloric acid was heated at reflux for 30 minutes and after cooling made basic with solid sodium carbonate. The product was extracted into ether and the combined ether extracts evaporated, after drying over anhydrous potassium carbonate, to give 8.15 g of 3-pyridyl α-hydroxybenzyl ketone.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10](Cl)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([NH2:30])[CH:21]=[CH:22][C:23]=1[C:24]1[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=1>ClCCl.C(OCC)(=O)C>[CH2:1]([C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH:30][C:20]2[CH:21]=[CH:22][C:23]([C:24]3[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=3)=[C:18]([O:17][CH3:16])[CH:19]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(Cc2ccccc2)nc(Cl)n1
Reactant: COc1cc(N)ccc1-c1cnn(C)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc(Nc2nc(C)cc(Cc3ccccc3)n2)ccc1-c1cnn(C)c1
Yield: 22.2 %

Procedure:
The title compound was prepared from 4-benzyl-2-chloro-6-methyl-pyrimidine (119 mg, 0.54 mmol) and 3-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-phenylamine (100 mg, 0.49 mmol) using in analogous manner the procedure described in example 206c). Column chromatography (25 g silica, dichloromethane/ethyl acetate 0-25% v/v) afforded the title compound (42 mg, 22%) as a light yellow viscous oil. MS ISP (m/e): 386.2 [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.82 (s, 1H), 7.76 (m, 2H), 7.39 (d, 1H), 7.29 (m, 5H), 7.08 (s, 1H), 6.98 (dd, 1H), 6.44 (s, 1H), 3.96 (s, 2H), 3.93 (s, 3H), 3.86 (s, 3H), 2.35 (s, 3H).
Reaction SMILES: C(O)=O.[CH3:4][C:5](=[CH2:8])[CH:6]=O.[NH2:9][C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]>C(O)(C)C>[CH3:8][C:5]1[CH:4]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:9][CH:6]=1
Reactant: CCOC(=O)C=C(N)C(=O)OCC
Reactant: C=C(C)C=O
Solvent: O=CO
Solvent: CC(C)O
Product: CCOC(=O)c1cc(C)cnc1C(=O)OCC
Temperature: 70 °C
Yield: 50 %

Procedure:
Isopropyl alcohol 675 ml and 90% formic acid 61.5 g (1.20 mol) were placed in 1 liter four-neck flask equipped with a reflux condenser. After heating the content to 70° C., 2-methyl-2-propenal 84.3 g (1.20 mol) and ethyl β-amino-β-ethoxycarbonylacrylate 150 g (0.801 mol) were simultaneously added dropwise thereto over a period of 1 hour with air-bubbling and refluxed for 10 hours. After removing isopropyl alcohol, 400 ml of water was added thereto and neutralized with sodium bicarbonate. After standing at 65°-67° C., separated oil layer was concentrated under reduced pressure to obtain 200 g of oily substance, which was distilled under reduced pressure to give 95 g of 5-methyl-2,3-diethoxycarbonylpyridine.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH2:12])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.[CH:13]1([C:16](Cl)=[O:17])[CH2:15][CH2:14]1.O>N1C=CC=CC=1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:16]([CH:13]3[CH2:15][CH2:14]3)=[O:17])[N:8]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1cc2ccc(Br)cc2cn1
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1cc2ccc(Br)cc2cn1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
To a cold solution (below 0° C.) of 7-bromoisoquinolin-3-amine (20 g, 0.09 mol) in pyridine (150 mL) was added cyclopropanecarbonyl chloride (11.2 g, 0.108 mol) dropwise. The mixture was stirred at room temperature overnight. After water (500 mL) was added, the reaction mixture was stirred for 30 min. Solid was collected by filtration and washed with water to give the desired product (21 g, 80.4%). LCMS (ESI): RT (Min)=1.009, M+H+=290.7, method=A. 1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 9.10 (s, 1H), 8.44 (s, 1H), 8.30 (s, 1H), 7.22 (d, J=8.8 Hz, 1H), 7.67 (d, J=8.8 Hz, 1H), 2.02-2.10 (m, 1H), 0.84-0.79 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:10](O)([C:12]([F:15])([F:14])[F:13])=O.Cl>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:10]([C:12]([F:15])([F:14])[F:13])=[N:9][C:4]=2[CH:3]=1
Reactant: Nc1ccc(Br)cc1N
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Product: FC(F)(F)c1nc2cc(Br)ccc2[nH]1
Yield: 61.3 %

Procedure:
A mixture of 4-bromobenzene-1,2-diamine (3.0 g, 16.0 mmol), TFA (9.5 mL, 128.3 mmol) and aq. HCl (3 M, 32 mL) was heated to reflux overnight. The reaction mixture was concentrated and purified by column chromatography to afford the titled compound (2.60 g, 60%). LCMS: 265.0 [M+1]+. 1HNMR (400 MHz, DMSO-d6): δ 7.52 (dd, J=8.8 Hz, 1.2 Hz, 1H), 7.69 (d, J=8.4 Hz, 1H), 7.95 (s, 1H), 14.20 (br, 1H).
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11](F)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:19]([OH:25])[CH:20]=[CH:21][CH:22]=[CH:23][CH3:24]>CN(C=O)C>[CH2:19]([O:25][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:7][CH2:6][CH:5]=[CH:4][CH:3]=[CH:2][CH3:16])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1)[CH:20]=[CH:21][CH:22]=[CH:23][CH3:24]
Reactant: CC=CC=CCO
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC=CC=CCOc1ccc(C(=O)c2ccc(OCC=CC=CC)cc2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 50.3 %

Procedure:
4,4′-Difluorobenzophenone (34) (4.8 grams, 22 mmol) was dissolved in anhydrous DMF (1 liter), NaH (95%; 5.6 grams, 220 mmol) was added and the solution was cooled to 0° C. 2,4-Hexadienol (5.8 mL, 51 mmol) was slowly added to the solution and the reaction mixture was allowed to warm to room temperature with stirring under argon overnight. The reaction mixture was concentrated in vacuo, dissolved in dichloromethane, and washed with water. The organic phase was dried (MgSO4) and concentrated and purified by column chromatography (silica gel; hexane/CH2Cl2, ⅓) to afford 2.07 grams (25%) of compound 35 as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 1.73 (d, J=6.6 Hz, 6 H), 4.68 (d, J=6.0 Hz, 4 H), 5.69-5.84 (m, 4 H), 6.05-6.19 (m, 2 H), 6.31-6.45 (m, 2 H), 7.08 (d, J=9.0 Hz, 4 H), 7.68 (d, J=10.2 Hz, 4 H).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]([F:37])([F:36])[C:21]1[CH:35]=[CH:34][CH:33]=[CH:32][C:22]=1[CH:23](O)[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1.C(N1CC(OC(C2C=CC(Cl)=CC=2)C2C=CC(Cl)=CC=2Cl)C1)(C1C=CC=CC=1)C1C=CC=CC=1>>[CH:1]([N:14]1[CH2:17][CH:16]([O:18][CH:23]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[C:22]2[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=2[C:20]([F:37])([F:36])[F:19])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: OC(c1ccc(F)cc1)c1ccccc1C(F)(F)F
Agent: Clc1ccc(C(OC2CN(C(c3ccccc3)c3ccccc3)C2)c2ccc(Cl)cc2Cl)cc1
Product: Fc1ccc(C(OC2CN(C(c3ccccc3)c3ccccc3)C2)c2ccccc2C(F)(F)F)cc1

Procedure:
This material was prepared from 1-benzhydryl-3-azetidinol (1) (7.5 mmol) and 2-(trifluoromethyl)-4′-fluorobenzhydrol (160) (15 mmol) using the procedure described for compound (3). After basic aqueous workup, the crude product was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1([CH2:21][CH3:22])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[C:8](=O)[CH2:7][O:6]1)=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:18][CH3:19].Cl.[NH2:25][OH:26].N1C=CC=CC=1>O>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1([CH2:21][CH3:22])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[C:8](=[N:25][OH:26])[CH2:7][O:6]1)=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:18][CH3:19]
Reactant: CCc1cccc2c3c([nH]c12)C(CC)(CC(=O)OC)OCC3=O
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCc1cccc2c3c([nH]c12)C(CC)(CC(=O)OC)OCC3=NO

Procedure:
The ester of Example 4, Step B (0.5 g, 1.6 mmol), hydroxylamine hydrochloride (0.17 g, 2.4 mmol), and 25 ml pyridine were refluxed for 3.5 h. The reaction mixture was poured into water, extracted with CHCl3. The organic phase was then washed with 1.0N HCl, water, dilute NaHCO3, water, and brine, dried (MgSO4) and evaporated to yield a crude solid which was purified by filtration through a pad of silica gel and celite. The product, 0.33 g was isolated as a solid, m. p. 188°-190° C.
Reaction SMILES: N1C2C(=CC=CC=2)C=C1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:13][CH:12]=1.[I:23]Cl>>[NH2:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:15][C:16]=1[I:23]
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: ClI
Agent: c1ccc2[nH]ccc2c1
Product: CCOC(=O)Cc1ccc(N)c(I)c1

Procedure:
Generally, Scheme 1 illustrates a synthetic route to the indole-containing fused ring compounds of the present invention. An ethyl 2-(4-aminophenyl)acetate is iodinated with a reagent such as, for example, iodine monochloride, to afford the corresponding ethyl 2-(4-amino-3-iodophenyl)acetate. This amine is treated with a 3-oxoacetate to produce the desired ethyl 3-(phenylamino)but-2-enoate. Formation of the indole is then achieved upon treatment with a catalyst, such as, for example, palladium acetate. The resulting ethyl 2-[3-(ethoxycarbonyl)indol-5-yl]acetate is saponified with a base such as potassium hydroxide to afford the 2-[3-(ethoxycarbonyl)indol-5-yl]acetic acid. The acid is subsequently converted to the amide by treatment with an amine and a suitable coupling agent, such as, for example, N,N′-carbonyldiimidazole or dicyclohexylcarbodiimide. Cyclization of the amide (e.g., in the presence of phosphorous oxychloride via the Bischler-Napieralske reaction) affords the dihydroisoquinoline, which is then treated with, for example, oxomethyl 2,2-dimethylpropanoate to produce the corresponding trihydroisoquinoline-2-carbaldehyde-ene. This compound is further cyclized and subsequently reduced to form the 6,11,12,13,12a,6a-hexahydroisoquinolino[2,1-b]pyrrolo[2,3-h]isoquinoline. The R4 group (as found in Formula I) can be present on the starting ethyl 2-(4-aminophenyl)acetate or introduced at various steps of the scheme (such as depicted in Scheme 1), depending on the nature of the group. The indole nitrogen can also be alkylated with various procedures known in the art.
Reaction SMILES: [Br:1]Br.[CH3:3][CH:4]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[CH2:5]1.O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:1][C:11]1[CH:10]=[CH:9][C:7]2[O:8][CH:4]([CH3:3])[CH2:5][C:6]=2[CH:12]=1
Reactant: BrBr
Reactant: CC1Cc2ccccc2O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC1Cc2cc(Br)ccc2O1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 215 ml of bromine in 450 ml of methylene chloride is added dropwise over 21/2 hours to an ice-cooled mixture of 562.3 g of 2,3-dihydro-2-methylbenzo[b]furan, 1600 ml of methylene chloride, 1600 ml of water and 352.5 g of sodium bicarbonate. After the mixture has been stirred for another 11/2 hours at the same temperature, the aqueous phase is separated and extracted with two 300 ml portions of methylene chloride. The combined organic phases are washed with 2×250 ml of water, dried over sodium sulfate and concentrated. After removal of all constituents having a boiling point below 99° C. under a pressure of 8 mbar, there are obtained 750.7 g of 5-bromo-2,3-dihydro-2-methylbenzo[b]furan as residue.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([CH3:7])[CH2:5][OH:6].Cl[C:10]1[C:15]([C:16]#[N:17])=[CH:14][N:13]=[CH:12][N:11]=1>C1COCC1>[F:3][C:4]([F:8])([CH3:7])[CH2:5][O:6][C:10]1[C:15]([C:16]#[N:17])=[CH:14][N:13]=[CH:12][N:11]=1
Reactant: N#Cc1cncnc1Cl
Reactant: CC(F)(F)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(F)(F)COc1ncncc1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.2 %

Procedure:
To a suspension of sodium hydride (60% dispersed in mineral oil, 1.84 g, 46 mmol) in THF (30.0 mL) was added 2,2-difluoropropan-1-ol (4.42 g, 46.0 mmol) at 0° C. The resulting mixture was stirred at room temperature for 1 h, then 4-chloropyrimidine-5-carbonitrile (6 g, 43.2 mmol) was added in portions at 0° C. After addition, the reaction mixture was stirred at room temperature for 30 min. The reaction was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to give a crude product, which was purified by silica gel column chromatography (10% ethyl acetate in petroleum ether) to afford the title compound (4.40 g, 22.1 mmol, 51% yield) as a yellow solid. MS (ESI) m/z 200.0 [M+H]+.
Reaction SMILES: OCCN1CCN(CC(NC2C(SC)=NC(C)=CC=2SC)=O)CC1.O[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]([NH:37][C:38]2[C:39]([N:50]3[CH2:54][CH2:53][CH2:52][CH2:51]3)=[N:40][C:41]([CH3:49])=[CH:42][C:43]=2[N:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)=[O:36])[CH2:30][CH2:29]1.SC1NC2C=CC=CC=2N=1.[SH:65][C:66]1[O:67][C:68]2[C:74]([C:75]([F:78])([F:77])[F:76])=[CH:73][CH:72]=[CH:71][C:69]=2[N:70]=1>>[F:76][C:75]([F:78])([F:77])[C:74]1[C:68]2[O:67][C:66]([S:65][CH2:26][CH2:27][N:28]3[CH2:29][CH2:30][N:31]([CH2:34][C:35]([NH:37][C:38]4[C:39]([N:50]5[CH2:51][CH2:52][CH2:53][CH2:54]5)=[N:40][C:41]([CH3:49])=[CH:42][C:43]=4[N:44]4[CH2:45][CH2:46][CH2:47][CH2:48]4)=[O:36])[CH2:32][CH2:33]3)=[N:70][C:69]=2[CH:71]=[CH:72][CH:73]=1
Reactant: Cc1cc(N2CCCC2)c(NC(=O)CN2CCN(CCO)CC2)c(N2CCCC2)n1
Reactant: FC(F)(F)c1cccc2nc(S)oc12
Agent: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCO)CC1
Agent: Sc1nc2ccccc2[nH]1
Product: Cc1cc(N2CCCC2)c(NC(=O)CN2CCN(CCSc3nc4cccc(C(F)(F)F)c4o3)CC2)c(N2CCCC2)n1

Procedure:
The reaction and treatments of Example 12 were repeated, except that 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamide was replaced by 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(pyrrolidin-1-yl)-6-methylpyridin-3-yl]acetamide, and 2-mercaptobenzimidazole was replaced by 2-mercapto-7-trifluoromethylbenzoxazole, to thereby yield the title compound as a pale yellow oil.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:10])[CH:3]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[F:10][C:4]1[CH:3]=[C:2]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: O=Cc1ccc(Br)cc1F
Reactant: OB(O)c1ccccc1
Product: O=Cc1ccc(-c2ccccc2)cc1F

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 2 using 4-bromo-2-fluoro-benzaldehyde instead of tert-butyl N-(4-bromobenzyl)carbamate and phenylboronic acid instead of 3-benzyloxyphenylboronic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:13]2[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[NH:15][C:14]2=[O:21])[CH:5]=[CH:6][C:7]=1[S:8][C:9]([F:12])([F:11])[F:10].[H-].[Na+].[Cl:24][C:25]1[CH:30]=[C:29]([CH2:31]Cl)[CH:28]=[CH:27][N:26]=1>CN(C)C=O>[NH2:1][C:2]1[CH:3]=[C:4]([N:13]2[C:17](=[O:18])[C:16]([CH3:19])([CH3:20])[N:15]([CH2:31][C:29]3[CH:28]=[CH:27][N:26]=[C:25]([Cl:24])[CH:30]=3)[C:14]2=[O:21])[CH:5]=[CH:6][C:7]=1[S:8][C:9]([F:12])([F:10])[F:11]
Reactant: CC1(C)NC(=O)N(c2ccc(SC(F)(F)F)c(N)c2)C1=O
Reactant: ClCc1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)C(=O)N(c2ccc(SC(F)(F)F)c(N)c2)C(=O)N1Cc1ccnc(Cl)c1
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 89.7 %

Procedure:
To a solution of 0.4 g of 3-{3-amino-4-[(trifluoro-methyl)thio]phenyl}-5,5-dimethylimidazolidine-2,4-dione obtained in stage c) below in 20 mL of dimethylformamide are added, under argon, 53 mg of 60% sodium hydride and stirring is continued for 20 minutes at room temperature. To this solution are added 2.85 g of 2-chloro-4chloromethylpyridine obtained in stage b) of Example 3 dissolved in 5 mL of dimethylformamide, and the reaction mixture is then heated at 70° C. for 3.5 hours and then poured into 100 mL of ice-water and extracted with three times 100 mL of ethyl acetate. The combined organic phases are dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue is taken up in 100 mL of diethyl ether, washed with water, dried over magnesium sulphate, filtered and concentrated under vacuum to give 500 mg of 3-{3-amino-4-[(trifluoromethyl)thio]phenyl}-1-[(2-chloropyridin-4-yl)methyl]-5,5-dimethylimidazolidine-2,4-dione, the characteristics of which are as follows:
Reaction SMILES: Cl[CH:2]([C:13](=O)[CH3:14])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[O:4].[CH2:16]([SH:19])[CH2:17][SH:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3]([C:2]2[S:18][CH2:17][CH2:16][S:19][C:13]=2[CH3:14])=[O:4])=[CH:7][CH:8]=1
Reactant: CC(=O)C(Cl)C(=O)Nc1ccc(Cl)cc1
Reactant: SCCS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC1=C(C(=O)Nc2ccc(Cl)cc2)SCCS1
Yield: 84 %

Procedure:
2-Chloro-N-(4-chlorophenyl)-3-oxobutanamide (24.7 g, 0.1 mole), 1,2-ethanedithiol (9.4 g, 0.1 mole) and a small amount of p-toluenesulfonic acid were heated under reflux in benzene (150 ml), using a Dean-Stark trap to remove water (1.9 ml collected). The reaction mixture was filtered, treated with triethylamine (8 ml), and refluxed for a further 30 minutes. The mixture was then washed with water, dilute hydrochloric acid, and water. Evaporation of the benzene gave a white solid, which was recrystallized from absolute ethanol. The product melted at 115°-117° C. (24 g, 84% yield).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:5]=1[CH2:6][NH2:7].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[N:23][N:22]=1>CC(O)(C)C>[CH3:2][O:3][C:4]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:5]=1[CH2:6][NH:7][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[N:23][N:22]=1
Reactant: Clc1nnc(-c2ccccc2)c2ccccc12
Reactant: COc1ccc(CN)c(OC)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)(C)O
Product: COc1ccc(CNc2nnc(-c3ccccc3)c3ccccc23)c(OC)c1
Temperature: 25 °C

Procedure:
In a nitrogen purged 75 mL sealed tube, dissolved 2,4-dimethoxybenzylamine hydrochloride (2.54 g, 12.5 mmol), cesium carbonate (4.06 g, 12.5 mmol) in tBuOH (15 mL). Added 1-chloro-4-phenylphthalazine (2.0 g, 8.31 mmol)and the tube was stirred at 100° C. for 17 h. The tube was cooled to RT, and the mixture was concentrated in vacuo. Dissolved the crude material in DCM, and filtered the solution to remove cesium carbonate. Performed silica gel chromatography using 0-100% EtOAc/Hex and concentrated to yield N-(2,4-dimethoxybenzyl)-4-phenylphthalazin-1-amine as orange oil. MS [M+H]=372; Calc'd 371.4 for C23H21N3O2.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Cl:6][C:7]([Cl:12])([Cl:11])[C:8](Cl)=[O:9]>CCOCC>[Cl:6][C:7]([Cl:12])([Cl:11])[C:8]([C:2]1[NH:1][CH:5]=[CH:4][CH:3]=1)=[O:9]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: c1cc[nH]c1
Solvent: CCOCC
Product: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Yield: 85 %

Procedure:
The strategy for the synthesis of polymer 8 is outlined in SCHEME 1. Pyrrole was treated with trichloroacetyl chloride in ether to give compound 1 in 85% yield. The methyl ester of this compound (2) was formed by reacting compound 1 with sodium methoxide in refluxing methanol, achieving yields of 71%.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:37])[CH:4]=[C:5]([CH2:8][N:9]2[CH2:13][CH2:12][N:11]([S:14]([NH:17][C:18]([N:20]3[CH2:23][C@H:22]([NH:24]C(=O)OCC4C=CC=CC=4)[C:21]3=[O:35])=[O:19])(=[O:16])=[O:15])[C:10]2=[O:36])[NH:6][CH:7]=1.C1(SC)C=CC=CC=1.[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49]>>[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49].[NH2:24][C@H:22]1[CH2:23][N:20]([C:18]([NH:17][S:14]([N:11]2[CH2:12][CH2:13][N:9]([CH2:8][C:5]3[NH:6][CH:7]=[C:2]([OH:1])[C:3](=[O:37])[CH:4]=3)[C:10]2=[O:36])(=[O:16])=[O:15])=[O:19])[C:21]1=[O:35]
Reactant: O=C(N[C@H]1CN(C(=O)NS(=O)(=O)N2CCN(Cc3cc(=O)c(O)c[nH]3)C2=O)C1=O)OCc1ccccc1
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CN(C(=O)NS(=O)(=O)N2CCN(Cc3cc(=O)c(O)c[nH]3)C2=O)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-[1-[[[[3-[(1,4-Dihydro-5-hydroxy-4-oxo-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester (0.50 g, 0.93 mmol) was added to a mixture of 0.5 ml of thioanisole and 2 ml of trifluoroacetic acid . The solution was stirred overnight at room temperature and evaporated in vacuo. The residue was triturated with ether, filtered off by suction, and dried in vacuo, yielding 0.49 g of the title compound, melting point 155° C.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:7][N:6]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.O>O1CCCC1>[C:19]([O:18][C:16]([N:6]1[CH2:7][C@H:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:9][C@H:5]1[CH2:3][OH:2])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: COC(=O)[C@@H]1C[C@@H](c2ccccc2)CN1C(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](c2ccccc2)C[C@H]1CO
Reaction time: 14 h

Procedure:
4.2 g of (2S,4S)-4-Phenyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (13.75 mmol) in 30 ml tetrahydrofuran were slowly added to a suspension of 0.27 g of lithium aluminium hydride in 50 ml tetrahydrofurane. Stirring was continued for 5 h at 0-5° C. and for 14 h at room temperature. For workup, a mixture of tetrahydrofurane/water (1:1) was slowly added to the reaction mixture at 0° C. The solvent was then evaporated under reduced pressure, water was added and the pH was adjusted to about 5 with 20% aqueous citric acid. The aqueous phase was extracted four times with ethyl acetate, the organic layers were combined, dried over magnesium sulphate, filtered, and the solvent was removed under reduced pressure to yield 3.85 of product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH2:12][CH2:13][OH:14])=[C:6]([CH:9]=1)[CH:7]=O.[Cl:15][C:16]1[CH:24]=[C:23]2[C:19]([CH2:20][C:21](=[O:25])[NH:22]2)=[CH:18][CH:17]=1.N1CCCC1>CO>[Cl:15][C:16]1[CH:24]=[C:23]2[C:19](/[C:20](=[CH:7]/[C:6]3[CH:9]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:10][CH2:11][CH2:12][CH2:13][OH:14])/[C:21](=[O:25])[NH:22]2)=[CH:18][CH:17]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: O=Cc1cc(Cl)ccc1OCCCO
Solvent: C1CCNC1
Solvent: CO
Product: O=C1Nc2cc(Cl)ccc2/C1=C/c1cc(Cl)ccc1OCCCO
Temperature: 70 °C
Yield: 87.6 %

Procedure:
5-Chloro-2-(3-hydroxy-1-propoxy)-benzaldehyde (8 g, 37 mmol) and 6-chlorooxindole (6.2 g, 37 mmol) were mixed in anhydrous methanol (20 mL). Then pyrrolidine (3 mL, 37 mmol) was added slowly at r.t. The mixture was heated to 70° C. for 3 h and cooled to room temperature. The precipitate was collected by filtration to give title compound as a yellow solid (Yield: 11.8 g).