Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:53])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33]4[NH:34][C:35]([CH:38]([NH:41][C:42](=[O:52])[CH:43]([NH:47][C:48]([O:50][CH3:51])=[O:49])[CH:44]([CH3:46])[CH3:45])[CH2:39]O)=[N:36][CH:37]=4)=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].O1CCNC1.[CH:59]1([CH:62]2CN[C@H](C(O)=O)C2)[CH2:61][CH2:60]1.Cl>O1CCOCC1>[CH3:51][O:50][C:48](=[O:49])[NH:47][CH:43]([C:42]([N:41]1[CH:38]([C:35]2[NH:34][C:33]([C:30]3[CH:29]=[CH:28][C:27]([C:24]4[CH:23]=[CH:22][C:21]([C:18]5[NH:17][C:16]([CH:12]6[CH2:13][CH2:14][CH2:15][N:11]6[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:53])[CH:6]([CH3:8])[CH3:7])=[N:20][CH:19]=5)=[CH:26][CH:25]=4)=[CH:32][CH:31]=3)=[CH:37][N:36]=2)[CH2:39][C:59]2([CH2:61][CH2:60]2)[CH2:62]1)=[O:52])[CH:44]([CH3:46])[CH3:45]
Reactant: O=C(O)[C@@H]1CC(C2CC2)CN1
Reactant: COC(=O)NC(C(=O)NC(CO)c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CCCN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)[nH]1)C(C)C
Agent: C1COCN1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CC6(CC6)CN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)[nH]1)C(C)C

Procedure:
(Example DW) was prepared in a similar fashion to (1-{2-[5-(4′-{2-[2-Hydroxy-1-(2-methoxycarbonylamino-3-methyl-butyrylamino)-ethyl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester, replacing the oxazolidine derived carboxylic acid with the corresponding 4-cyclopropyl-proline derivative and using HCl in dioxane for the Boc deprotection.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH3:12])=[CH:4][C:3]=1F.[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:17][CH2:16]1.C([O-])(O)=O.[Na+]>CS(C)=O>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[N:24]1[CH2:23][CH2:22][CH:21]([N:18]2[CH2:17][CH2:16][N:15]([CH3:14])[CH2:20][CH2:19]2)[CH2:26][CH2:25]1
Reactant: CN1CCN(C2CCNCC2)CC1
Reactant: COc1cc(F)c(F)cc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)c(F)cc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
1,2-Difluoro-4-methoxy-5-nitrobenzene (INTERMEDIATE 52) (1.0 g, 5.3 mmol) and 1-methyl-4-(piperidin-4-yl)piperazine (1.066 g, 5.8 mmol) were added in a 50 mL round-bottomed flask. DMSO (6 mL) was added. The reaction was stirred at 90° C. for 1 h. After it was cooled to RT, sat. NaHCO3 (20 mL) was added. After the mixture was stirred at RT for 10 min, filtration afforded the title product as an orange solid (1.7 g, 90% yield).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].C(N(CC)C(C)C)(C)C.[C:17]([O:21][C:22]([N:24]1[C@@H:29]([C@@H:30]([OH:41])[C@@H:31]([NH2:40])[CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([OH:39])[CH:34]=2)[CH2:28][O:27][C@@H:26]([O:42][CH2:43][C:44]([CH3:47])([CH3:46])[CH3:45])[C@@H:25]1[CH3:48])=[O:23])([CH3:20])([CH3:19])[CH3:18]>C(OCC)(=O)C>[C:17]([O:21][C:22]([N:24]1[CH:29]([C@@H:30]([OH:41])[C@@H:31]([NH:40][C:1](=[O:3])[CH3:2])[CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([OH:39])[CH:34]=2)[CH2:28][O:27][C@@H:26]([O:42][CH2:43][C:44]([CH3:47])([CH3:46])[CH3:45])[C@@H:25]1[CH3:48])=[O:23])([CH3:19])([CH3:18])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H]1[C@H](OCC(C)(C)C)OC[C@H]([C@@H](O)[C@@H](N)Cc2cccc(O)c2)N1C(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(=O)N[C@@H](Cc1cccc(O)c1)[C@H](O)C1CO[C@@H](OCC(C)(C)C)[C@H](C)N1C(=O)OC(C)(C)C
Reaction time: 2.5 h
Yield: 34.7 %

Procedure:
Add acetic anhydride (320 μL, 3.4 mmol) and N,N-diisopropylethylamine (590 μL, 3.4 mmol) to a solution of 5-(R)-[2-(S)-amino-1-(S)-hydroxy-3-(3-hydroxyphenyl)-propyl]-2-(R)-(2,2-dimethylpropoxy)-3-(S)-methylmorpholine-4-carboxylic acid tert-butyl ester (770 mg, 1.70 mmol). Stir for 2.5 hours. Dilute with ethyl acetate, wash with 1 N hydrochloric acid (twice), saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dry (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 20:80 to 25:75 ethyl acetate:hexanes) to give the desired compound (292 mg).
Reaction SMILES: [F:1][CH:2]([F:11])[C:3]([CH:8]([F:10])[F:9])([OH:7])[C:4](O)=[O:5].C(C1NC=CN=1)(C1NC=CN=1)=O.[NH2:24][C:25]1[CH:38]=[CH:37][C:28]([C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:30])=[CH:27][CH:26]=1>O1CCCC1>[C:31]1([C:29]([C:28]2[CH:27]=[CH:26][C:25]([NH:24][C:4](=[O:5])[C:3]([OH:7])([CH:8]([F:10])[F:9])[CH:2]([F:11])[F:1])=[CH:38][CH:37]=2)=[O:30])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C(O)C(O)(C(F)F)C(F)F
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: O=C(c1ccccc1)c1ccc(NC(=O)C(O)(C(F)F)C(F)F)cc1
Yield: 25 %

Procedure:
To a solution of 2,2,-bis-difluoromethyl-2-hydroxy-acetic acid (1.76 g, 10 mmole) in tetrahydrofuran(40 ml) was added carbonyl diimidazole (0.81 g, 5 mmole). The flask was placed in a sonic bath and the reaction sonicated for 20 minutes followed by addition of 4-aminobenzophenone. The reaction was sonicated for 18 hours. The reaction mixture was filtered and the filtrate evaporated to dryness. The recovered pasty solid was washed with ether and the combined ether washings evaporated. The recovered solid was crystallized from ethyl acetate/hexane to give the title compound (0.89 g, 25%) as yellow crystals; mp 139°-142° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][OH:22])[CH2:17][CH2:16]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:12][C:11]([F:14])([F:13])[C:8]1[N:6]2[N:7]=[C:2]([N:15]3[CH2:20][CH2:19][CH:18]([CH2:21][OH:22])[CH2:17][CH2:16]3)[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: OCC1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: OCC1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Yield: 88.7 %

Procedure:
A stirred solution of 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (5.56 g, 25 mmol), piperidin-4-ylmethanol (3.17 g, 27.50 mmol) and DIPEA (5.66 mL, 32.50 mmol) in DMF (50 mL) was heated at 70° C. for 1 hour. The solution was evaporated and partitioned between DCM and 1M aqueous K2CO3. The organic phase was washed with brine, dried over MgSO4, evaporated and triturated with ether. The precipitate was collected by filtration, washed with ether and dried under vacuum to afford [1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]methanol (6.68 g, 89%) as a cream crystalline solid.
Reaction SMILES: [H-].[Na+].O[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17]Cl>CN(C)C=O>[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: COCCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOCc1ccc(C=O)cc1
Reaction time: 1 h
Yield: 92.7 %

Procedure:
Sodium hydride (2.4 g (60%), 60 mmol) was added to 4-hydroxybenzaldehyde (6.0 g, 50 mmol) in N, N-dimethylformamide (100 mL). The suspension was stirred for 1 hour and then treated with 2-methoxyethoxymethyl chloride (6.8 mL, 60 mmol), and allowed to stir an additional 16 hours. The reaction was then partitioned between water and ether:ethyl acetate (1:1). The organics were then washed with water (4×), dried (potassium carbonate), and concentrated. The crude materials were then purified by silica gel chromatography (hexanes:ethyl acetate) to afford the title compound (9.0 g).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:11][CH2:12][CH3:13])[CH2:5][C:6]([O:8]CC)=[O:7])[CH3:2].[OH-].[Na+].Cl.CCOC(C)=O>O>[CH2:12]([O:11][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][C:6]([OH:8])=[O:7])[CH3:13]
Reactant: CCOC(=O)CC(OCC)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(CC(=O)O)OCC
Temperature: 0 °C
Yield: 95.6 %

Procedure:
A solution of ethyl 3,3-diethoxypropanoate (4.2 g, 22.0 mmol, 1 eq) and NaOH (1.1 g, 28 mmol, 1.3 eq) in water (8 mL) was heated in a 110° C. oil bath for 1.25 h. The reaction was then cooled to 0° C. and was stirred with concentrated HCl (2.3 mL) and EtOAc (20 mL). The organic layer was saved, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and evaporated to afford 3,3-diethoxypropanoic acid (3.41 g, 96% yield) as an orange oil, which was used in the next step without any further purification.
Reaction SMILES: [ClH:1].[NH2:2][N:3]=[CH:4][NH:5][NH:6][CH2:7][C:8]([OH:10])=[O:9].[CH2:11](O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[ClH:1].[C:12]1([CH2:11][O:9][C:8](=[O:10])[CH2:7][NH:6][NH:5][CH:4]=[N:3][NH2:2])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NN=CNNCC(=O)O
Reactant: OCc1ccccc1
Agent: Cl
Product: NN=CNNCC(=O)OCc1ccccc1
Yield: 82 %

Procedure:
HCl (g) was bubbled through a suspension of [2-(aminoiminomethyl)hydrazino]-acetic acid (2.00 g, 15.2 mmol) in benzyl alcohol (30 mL). The reaction was stirred for about an hour until everything was in solution. The crude product was precipitated out by adding Et2O. This material was recrystallized from MeOH/EtOAc to yield [2-(aminoiminomethyl)hydrazino] acetic acid phenylmethyl ester monohydrochloride (3.20 g, 82%) as a white crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:3]=1[NH:4][CH:5]1[C:9]([C:10]#[N:11])=[CH:8][S:7][CH2:6]1.S(Cl)(Cl)(=O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:3]=1[NH:4][C:5]1[C:9]([C:10]#[N:11])=[CH:8][S:7][CH:6]=1
Reactant: N#CC1=CSCC1Nc1c(Cl)cccc1Cl
Solvent: ClCCl
Solvent: O=S(=O)(Cl)Cl
Product: N#Cc1cscc1Nc1c(Cl)cccc1Cl
Yield: 75 %

Procedure:
A solution of 0.27 part of 3-(2',6'-dichloro-anilino)-4-cyanodihydrothiophene in 15 parts by volume of dry methylene chloride is added, in the course of 30 minutes, to a solution of 0.12 part by volume of sulfuryl chloride in 15 parts by volume of dry methylene chloride at 0° C. The end product is isolated from the reaction mixture by the method described in Example 1c. 0.20 (75% of theory) of 3-(2',6'-dichloroanilino)-4-cyanothiophene of melting point 105°-108° C. are obtained.
Reaction SMILES: [C:1]1([C:11](Cl)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:21][C:22]([C:24]1[C:29]([NH2:30])=[CH:28][C:27]2[O:31][CH2:32][O:33][C:26]=2[CH:25]=1)=[O:23]>C1(C)C=CC=CC=1>[C:22]([C:24]1[C:29]([NH:30][C:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)=[O:12])=[CH:28][C:27]2[O:31][CH2:32][O:33][C:26]=2[CH:25]=1)(=[O:23])[CH3:21]
Reactant: CC(=O)c1cc2c(cc1N)OCO2
Reactant: O=C(Cl)c1cccc2ccccc12
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(=O)c1cc2c(cc1NC(=O)c1cccc3ccccc13)OCO2
Temperature: 20 °C
Reaction time: 24 h

Procedure:
Into solutions of 149 (5.0 mmol) in 200 mL of dry toluene were added triethylamine (4 mL) and 2-amino-4,5-methylenedioxy acetophenone (148) (5 mmol). The mixtures were stirred at 20±2° C. for 24 h and then evaporated. The residues were washed with acetone and EtOH and then recrystallized from acetone or EtOH to form 150. Obtained as a grayish-white solid; mp 143-144° C.; ESI-MS (Positive mode): m/z 334 [M+H]+; 1H-NMR (400 MHz, DMSO-d6, δ): 2.59 (3H, s), 6.20 (2H, s), 7.60-7.68 (4H, m), 7.87 (1H, d, J=7.2 Hz), 8.05-8.07 (1H, m), 8.15 (1H, d, J=8.0 Hz), 8.33-8.38 (2H, m), 12.52 (1H, s); IR (KBr): 1647, 1672 (C═O) cm−1.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17]([N:21]1[CH2:26][CH2:25][S:24][CH2:23][CH2:22]1)=[N:16][N:15]=[CH:14]2.[OH:27]OS([O-])=O.[K+]>CO.O>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17]([N:21]1[CH2:26][CH2:25][S:24](=[O:27])[CH2:23][CH2:22]1)=[N:16][N:15]=[CH:14]2
Reactant: O=S([O-])OO
Reactant: Cc1ccc(C(N)=O)cc1-c1ccc2c(N3CCSCC3)nncc2c1
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1ccc(C(N)=O)cc1-c1ccc2c(N3CCS(=O)CC3)nncc2c1
Temperature: 25 °C

Procedure:
A mixture of 4-methyl-3-[1-(thiomorpholin-4-yl)phthalazin-6-yl]benzamide (0.6 mmol) (Method A) in 10 mL methanol/H2O (8:2) was stirred at RT was treated with oxone® monopersulfate compound (1 mmol). The mixture was stirred at 0° C.-50° C. over 1h. The mixture was quenched with 20 mL sat. N2SO3, extracted with dichloromethane (3×50 mL). The combined organic layers were dried over anhydrous Na2SO4, concentrated in vacuo and purified by silica gel chromatography eluting with 1-5% 2 M ammonia methanol in dichloromethane to give the title compound. Found MS(ES+): 381(M+H)+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([O:22][CH3:23])=[O:21]>CC(C)=O>[CH3:23][O:22][C:20](=[O:21])[CH2:19][O:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:8][CH:7]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(C(F)(F)F)cc1

Procedure:
A mixture of 4-trifluoromethyl-phenol (10.000 g; 61.687 mmol), potassium carbonate (9.377 g; 67.856 mmol), and methyl bromoacetate (5.67 ml; 61.687 mmol) in acetone (250 ml) was heated at reflux for 1 h30. Filtration, concentration to dryness under reduced pressure, and purification by FC (DCM) afforded (4-trifluoromethyl-phenoxy)-acetic acid methyl ester as a colorless oil (14.100 g; 98%). LC-MS: tR=0.95 min.; [M+H]+: no ionisation.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[Cl:16][C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1.CN([CH:26]=[O:27])C>C1COCC1>[Cl:16][C:17]1[C:22]([CH:26]=[O:27])=[N:21][CH:20]=[CH:19][N:18]=1
Reactant: CN(C)C=O
Reactant: Clc1cnccn1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1nccnc1Cl
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
A flame dried and cooled 100 mL round bottom flask was charged with 2,2,6,6-tetramethylpiperidine (2.5 mL, 14.96 mmol) and anhydrous THF (25 mL) under a nitrogen atmosphere. The contents were cooled to −78° C. and n-butyllithium (2.5 M in hexane, 5.7 mL, ˜14.28 mmol) was added dropwise over a 5 minute period. The reaction mixture was stirred at −78° C. for 5 minutes, bought to 0° C. and stirred at 0° C. for 25 minutes. The reaction mixture was recooled to −78° C. and 2-chloropyrazine (0.78 g, 1 mL, 6.8 mmol) was added over a 3 minute period. After 30 minutes at −78° C., anhydrous DMF (0.99 mL, 13.6 mmol) was added over 3 minutes and the contents stirred at −78° C. for a further 30 minutes. The reaction mixture was bought to 0° C., stirred at 0° C. for 15 minutes, recooled to −78° C. and quenched by the addition of acetic acid (4 mL) in THF (10 mL). The reaction mixture was stirred at room temperature for 10 minutes and partitioned between ethyl acetate (60 mL) and brine (30 mL). The ethyl acetate layer is separated, dried over sodium sulfate, concentrated under reduced pressure and purified by silica gel flash chromatography using dichloromethane and ethyl acetate (9.5:0.5, 400 mL) to yield the title compound a (950 mg). 1H-NMR of the compound was consistent with the desired structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[N:12][C:11](=[S:14])[NH:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[Na].Br[CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>CS(C)=O.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[N:12][C:11]([S:14][CH:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:23])=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: S=c1ncn(-c2ccc(Cl)c(Cl)c2)[nH]1
Reactant: CCOC(=O)C(C)Br
Agent: [Na]
Solvent: CCO
Solvent: CS(C)=O
Product: CCOC(=O)C(C)Sc1ncn(-c2ccc(Cl)c(Cl)c2)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
An 11.5 g portion of 1-(3,4-dichlorophenyl)3-thiono-1,2,4-1H-triazole was dissolved in 100 ml of dry dimethylsulfoxide, and was added to 1.1 g of sodium dissolved in 50 ml of absolute ethanol. The mixture was warmed at 60°-80° for 1 hour, and then 8.5 g of ethyl 2-bromopropionate was added and the mixture was held at 100°-110° for 2 hours. It was then cooled and poured over ice-water, and the aqueous mixture was extracted with dichloromethane. The organic layer was washed with brine, and was dried over magnesium sulfate. The solvent was removed under vacuum, and the residue was purified by chromatography, eluting with 2:1 hexane:ethyl acetate. The product-containing fractions were combined and evaporated under vacuum to obtain 11 g of the desired product.
Reaction SMILES: [F:1][C:2]1[C:3](I)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:17][CH:16]=[N:15][C:14]=1[CH3:18].C([O-])([O-])=O.[Na+].[Na+].[NH2:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1.CN(C=O)C>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.COCCOC>[NH2:26][C:27]1[CH:32]=[C:31]([C:3]2[C:2]([F:1])=[CH:10][CH:9]=[C:8]3[C:4]=2/[C:5](=[CH:12]/[C:13]2[NH:17][CH:16]=[N:15][C:14]=2[CH3:18])/[C:6](=[O:11])[NH:7]3)[CH:30]=[CH:29][CH:28]=1
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: Nc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COCCOC
Product: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(-c3cccc(N)c3)c21

Procedure:
A solution of (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (50 mg, 0.135 mmol) (Starting Material 11), 2M aqueous Na2CO3 solution (0.14 mL), (Ph3P)2PdCl2 (11 mg, 0.0135 mmol) and 3-aminobenzeneboronic acid (52.5 mg, 0.339 mmol) (Lancaster) in a 1:4 mixture of DMF:1,2-dimethoxyethane (5 mL) was heated at 104° C. for 4 days. The reaction mixture was concentrated and the crude material was purified by C18 reverse phase chromatography to give (Z)-4-(3-Aminophenyl)-1,3-dihydro-5-fluoro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one. (Yield 18 mg, 40%).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([OH:9])[C:6]([CH3:10])=[C:5]([CH3:11])[C:3]=1[OH:4].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19](O)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:15][CH:14]=1>B(F)(F)F.CCOCC.C1(C)C=CC=CC=1>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:8]2[C:7](=[O:9])[C:6]([CH3:10])=[C:5]([CH3:11])[C:3](=[O:4])[C:2]=2[CH3:1])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:15][CH:14]=1
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: O=C(O)CCCCCC(O)c1ccc(Cl)cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC1=C(C)C(=O)C(C(CCCCCC(=O)O)c2ccc(Cl)cc2)=C(C)C1=O
Temperature: 60 °C
Yield: 78.2 %

Procedure:
Toluene (15 ml) was added to 0.76 g (5.0 mmole) of 2,5,6-trimethylhydroquinone and 1.28 g (5.0 mmole) of 7-(4-chlorophenyl)-7-hydroxyheptanoic acid, and the mixture was warmed at 60° C. and stirred. 0.19 ml (5.0×0.3 mmole) of boron trifluoride ethyl etherate was added to the mixture, followed by stirring at 60° C. for 15 hours. After the conclusion of the reaction, a large amount of the toluene was distilled off, and the residue was dissolved in tetrahydrofuran (20 ml). An aqueous solution (10 ml) of ferric chloride (2.7 g, 10.0 mmole was added to the solution, followed by stirring at room temperature for 20 minutes. The tetrahydrofuran was distilled off, and ethyl acetate was added to the residue to extract the reaction product. The organic layer was separated out, washed with aqueous sodium chloride solution and dried (magnesium sulfate). The ethyl acetate solution was chromatographed on a short silica gel (10 g) column, and elution was performed with ethyl acetate. The fractions containing the object compound were collected and concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate/isopropyl ether to give 1.52 g (78%) of 7-(4-chlorophenyl)-7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)heptanoic acid.
Reaction SMILES: [Na].[C:2]([C:5]1[N:10]=[C:9]([P:11]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([OH:29])=[O:28])[N:22]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([OH:20])=[O:19])[N:13]=2)[CH:8]=[CH:7][CH:6]=1)([OH:4])=[O:3].C([O-])(=O)C.[Gd+3:34].C([O-])(=O)C.C([O-])(=O)C>O>[Gd:34].[C:27]([C:23]1[N:22]=[C:21]([P:11]([C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:2]([OH:4])=[O:3])[N:10]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([OH:20])=[O:19])[N:13]=2)[CH:26]=[CH:25][CH:24]=1)([OH:29])=[O:28]
Reactant: [Gd+3]
Agent: CC(=O)[O-]
Agent: O=C(O)c1cccc(P(c2cccc(C(=O)O)n2)c2cccc(C(=O)O)n2)n1
Agent: [Na]
Solvent: O
Product: [Gd]
Temperature: 90 °C

Procedure:
A reaction flask was equipped with a reflux condenser, agitator, addition funnel, nitrogen source and heating bath. The tris(6-carboxy-2-pyridyl)phosphine sodium salt (310 mg, 0.67 mmol, MW 463) from Example 9 was dissolved warm demineralized water (10 mL) and the resultant solution was filtered and charged to reaction flask. Gadolinium (III) acetate (260 mg, 0.64 mmol, MW 406 for tetrahydrate, 1 equiv) was dissolved in warm demineralized water (10 mL) and the resultant solution was filtered and charged to the addition funnel. The bath was heated to 90° C. and the gadolinium acetate solution was added dropwise with agitation over 30 min. Once the addition was complete, the reaction was cooled to ambient temperature and the white solids were isolated by filtration and washed with demineralized water. The solids were dried in vacuo to afford 130 mg of white solids (369 mg theoretical yield for anhydrous complex, 93% by HPLC area%/o), and having the structural formula shown below: ##STR14##
Reaction SMILES: [C:1]([C:4]1[CH2:5][O:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[Br:14]Br.C(=O)([O-])[O-].[K+].[K+]>C(OCC)C.CO>[Br:14][CH2:2][C:1]([C:4]1[CH2:5][O:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:3]
Reactant: CC(=O)C1=Cc2ccccc2OC1
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CO
Product: O=C(CBr)C1=Cc2ccccc2OC1
Reaction time: 2 h

Procedure:
3-Acetyl-2H-chromene (0.2 mole) is dissolved in diethyl ether (250 ml) and methanol (10 ml). The solution is cooled to 0°-5° C. Bromine (0.21 mole) is added dropwise thereto, with stirring. The resulting material is left aside 2 hours at room temperature. Anhydrous potassium carbonate (25 g) is then added and the material is evaporated to dryness. The pasty residue is placed in a flask with 600 ml hexane, and is refluxed for 1 hour. The reaction mixture is decanted hot, allowed to cool, and the organic solution is placed in the freezer. Brown-yellow crystals having a sufficient purity for the next step separate out. After two recrystallizations from hexane, a sample gives long pale yellow needles, M.p.=87° C.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]1(=[O:15])[O:14][C:12](=[O:13])[CH:11]=[CH:10]1>N(C(C)(C)C#N)=NC(C)(C)C#N.C1(C)C=CC=CC=1>[CH:1]([C:10]1=[CH:11][C:12]([O:14][C:9]1=[O:15])=[O:13])=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=Cc1ccccc1
Reactant: O=C1C=CC(=O)O1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Cc1ccccc1
Product: O=C1C=C(C=Cc2ccccc2)C(=O)O1
Temperature: 90 °C
Yield: 98.4 %

Procedure:
A flask similar to that used in Example A was charged with 156.0 g of styrene, 147.0 g of maleic anhydride, 2.0 g of azobisisobutyronitrile and 2,400 ml of toluene. The mixture was heated at 90° C. for 1 hour while agitated under a nitrogen atmosphere so as to carry out the required reaction. After the reaction, the reaction mixture was condensed and petroleum ether about 10 times as much as the condensed mixture by volume was added to the condensed reaction mixture so as to precipitate the resultant cooligomer. The cooligomer thus obtained was washed with 500 g of petroleum ether three times and, then, dried, thereby obtaining 295 g of styrene-maleic anhydride cooligomer having a number average molecular weight of 8,500.