Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][C:15]([N:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][O:25][CH2:26][CH2:27][OH:28])[CH2:19][CH2:18]2)=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[C:1]1([S:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][C:15]([N:17]2[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][C:36](=[O:43])[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:21][CH2:22]2)=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(Nc1ccccc1Sc1ccccc1)N1CCN(CCOCCO)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(OCCOCCN1CCN(C(=O)Nc2ccccc2Sc2ccccc2)CC1)c1ccccc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
4-[2-(2-hydroxyethoxy)-ethyl]-piperazine-carboxylic acid (2-phenylsulfanyl-phenyl)-amide (4 g, 10 mmol), triethylamine (2 ml, 15 mmol) and toluene (50 ml) were charged into a reaction flask. Benzoyl chloride (1.7 g, 12 mmol) in toluene (5 ml) was added at 0-10° C. The mixture was stirred for 16 h at 20° C. Cold water (50 ml) and 1 M NaOH (100 ml) were added. The mixture was stirred for 20 min. The water phase was separated. The organic phase was washed with saturated NaCl solution (25 ml) and evaporated in vacuo. The yield of benzoic acid 2-{2-[4-(2-phenylsulfanyl-phenylcarbamoyl)piperazin-1-yl]-ethoxy}-ethyl ester was 4.91 g.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]1([CH2:13][O:14][C:15]2[CH:23]=[CH:22][C:21]([S:24]([N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)(=[O:26])=[O:25])=[CH:20][C:16]=2[C:17]([OH:19])=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([NH2:39])[CH:34]=1.C(N(C(C)C)CC)(C)C>ClCCl>[C:7]1([CH2:13][O:14][C:15]2[CH:23]=[CH:22][C:21]([S:24]([N:27]3[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]3)(=[O:25])=[O:26])=[CH:20][C:16]=2[C:17]([NH:39][C:35]2[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=2)=[O:19])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O)c1cc(S(=O)(=O)N2CCCCC2)ccc1OCc1ccccc1
Reactant: Nc1cccnc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccnc1)c1cc(S(=O)(=O)N2CCCCC2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Oxalyl chloride (0.05 ml, 0.59 mmol) in dichloromethane (5 ml) was added dropwise over 1 min to a stirred solution of 2-[(phenylmethyl)oxy]-5-(1-piperidinylsulfonyl)benzoic acid (may be prepared as described in Description 69; 220 mg, 0.59 mmol) in dichloromethane (5 ml) at 0° C. The reaction mixture was stirred at 25° C. for 0.5 h, and then concentrated under reduced pressure to give crude acyl chloride. A solution of this crude acyl chloride in dichloromethane (5 ml) was added dropwise over 5 min to a stirred solution of 3-pyridinamine (55.1 mg, 0.59 mmol) and diisopropylethylamine (0.10 ml, 0.59 mmol) in dichloromethane (20 ml) under nitrogen at 0° C. The reaction mixture was stirred at 25° C. for 1 h. The organic phase was washed with water (25 ml) three times, saturated brine (10 ml) two times, dried over sodium sulfate, and evaporated in vacuo to give crude product as a orange oil. The product was crystallized from methanol to yield the title compound as a white solid. 125 mg.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([CH:14]([CH2:20][CH:21]=[CH2:22])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23]([Li])(C)(C)C.IC>C1COCC1.CCCCCC>[C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14]([CH3:23])([CH2:20][CH:21]=[CH2:22])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [Li]C(C)(C)C
Reactant: C=CCC(C(=O)OCC)c1csc(NC(=O)OC(C)(C)C)n1
Solvent: C1CCOC1
Solvent: CI
Solvent: CCCCCC
Product: C=CCC(C)(C(=O)OCC)c1csc(NC(=O)OC(C)(C)C)n1
Temperature: -78 °C
Reaction time: 2 h
Yield: 15.7 %

Procedure:
A solution of 5.0 g (15 mmol) of Ethyl 2-(2-tert-butoxycarbonylaminothiazol-yl)-4-pentenoate (Intermediate 34) in 100 mL of THF at −78° C. was treated with 25 mL (43 mmol) of 1.7 M t-butyl lithium in hexane for 30 min. To the resulting red solution was added a neat solution of 2.82 g (20 mmol) of iodomethane. The reaction was stirred at −78° C. for 2 h and then warmed to 0° C. and stirred for 0.5 h. The reaction was quenched with 10 g of citric acid in 100 mL of water. The mixture was stirred overnight, evaporated to remove THF and extracted with CH2Cl2 (2×100 mL). The combined organic phases were washed with brine and dried over Na2SO4 and concentrtaed in vacuo. MPLC using 1:9 v/v EtOAc/hexanes as the eluant afforded 0.8 g of the title compound as an oil. 1H NMR (300 MHz, CDCl3): δ 1.15–1.22 (m, 3H), 1.42–1.67 (d, 12H), 2.67–2.76 (m, 2H), 4.09–4.17 (m, 2H), 5.00–5.10 (m, 2H), 5.50–5.65 (m, 1H), 6.63 (1, 1H), 7.91 (wide, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.Br[CH2:21][C:22]1[CH:27]=[C:26]([Cl:28])[N:25]=[C:24]([Cl:29])[CH:23]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:21][C:22]3[CH:27]=[C:26]([Cl:28])[N:25]=[C:24]([Cl:29])[CH:23]=3)([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: COc1cccc(C2C(=O)Nc3cc(Cl)ccc32)c1
Reactant: Clc1cc(CBr)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COc1cccc(C2(Cc3cc(Cl)nc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)c1
Temperature: 60 °C

Procedure:
A mixture of rac-3-(3-methoxy-phenyl)-6-chloro-1,3-dihydro-indol-2-one (82 mg, 0.3 mmol) (from Example 6b supra), 4-bromomethyl-2,6-dichloro-pyridine (85.3 mg, 0.35 mmol) (Maybridge), potassium iodide (59.2 mg, 0.35 mmol) and potassium carbonate (89.2 mg, 0.645 mmol) in acetone (3 mL) was heated at 60° C. for 3 hours in a capped pressure tube. After cooling, mixture was diluted with ethyl acetate and extracted with water and brine. Aqueous layers were back washed with ethyl acetate. Organic layers were combined, dried (Na2SO4), filtered and concentrated. Residue was recrystallized from dichloromethane-hexanes to give rac-6-chloro-3-(2,6-dichloro-pyridin-4-ylmethyl)-3-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one as a light brown solid. (Yield 60 mg, 45%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH2:7].C(N(CC)CC)C.[CH3:15][O:16][C:17]1[CH:26]=[CH:25][C:20]([CH2:21][N:22]=[C:23]=[S:24])=[CH:19][CH:18]=1>CN(C)C=O.C(OCC)(=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:23]([NH:22][CH2:21][C:20]1[CH:25]=[CH:26][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1)=[S:24]
Reactant: COc1ccc(CN=C=S)cc1
Reactant: NCc1ccco1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(CNC(=S)NCc2ccco2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.5 %

Procedure:
Furan-2-ylmethylamine (190 mg) was dissolved in dimethylformamide (5 ml) and to the solution were added triethylamine (200 mg) and 4-methoxybenzylisothiocyanate (360 mg), followed by stirring at room temperature for 24 hours. Then, the resulting mixture was diluted with ethyl acetate, washed with water, dried, and concentrated under reduced pressure. The residue was purified by column-chromatography (hexane/ethyl acetate=1/1) to yield the compound 16-1 (0.5 g, 90%) as a liquid.
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[Cl:14][C:15]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:16]=1[O:17][CH2:18][CH2:19][CH2:20][OH:21].C(O)(C)C>CC(C)=O>[Cl:14][C:15]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:16]=1[O:17][CH2:18][CH2:19][C:20]([OH:3])=[O:21]
Reactant: OCCCOc1ccc(Cl)cc1Cl
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: O=C(O)CCOc1ccc(Cl)cc1Cl
Yield: 91.5 %

Procedure:
Jones reagent (2.3M, 0.283L, 0.650 mol, CrO3 /H2SO4) is added to a solution of 3-(2,4-dichlorophenoxy)-1-propanol (71.87 g, 0.325 mol) in acetone while maintaining the temperature of the reaction mixture below 40° C. After the addition is complete, isopropanol is added and the reaction mixture is filtered through diatomaceous earth. The filtrate is concentrated in vacuo to give a blue-green solid which is partitioned between ether and water. The organic phase is separated, washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo to obtain the title product as a yellow solid (69.87 g, mp 93°-95° C.).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[CH2:23]([O:22][C:20]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:21])[CH3:24]
Reactant: CCOC(=O)Cl
Reactant: CCN1CC=C(c2c[nH]c3ccc(N)nc23)CC1
Product: CCOC(=O)Nc1ccc2[nH]cc(C3=CCN(CC)CC3)c2n1

Procedure:
Beginning with 0.015 gm (0.062 mMol) 5-amino-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[3,2-b]pyridine and 0.006 mL (0.068 mMol) ethyl chloroformate, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]=[C:10]([C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[O:11][C:7]=2[C:6](F)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[C:4]=1[CH3:25])#[N:2].C(N(CC)CC)C.[CH3:33][N:34](C)[C@H:35]1[CH2:39][CH2:38][NH:37][CH2:36]1>CS(C)=O>[C:1]([C:3]1[C:8]2[N:9]=[C:10]([C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[O:11][C:7]=2[C:6]([N:37]2[CH2:38][CH2:39][C@H:35]([NH:34][CH3:33])[CH2:36]2)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[C:4]=1[CH3:25])#[N:2]
Reactant: CN(C)[C@H]1CCNC1
Reactant: Cc1c(-c2cccc(F)c2)c(F)c2oc(C(=O)N(C)C)nc2c1C#N
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN[C@H]1CCN(c2c(-c3cccc(F)c3)c(C)c(C#N)c3nc(C(=O)N(C)C)oc23)C1
Temperature: 150 °C
Reaction time: 1 h

Procedure:
4-Cyano-7-fluoro-6-(3-fluorophenyl)-N,N,5-trimethyl-1,3-benzoxazole-2-carboxamide (I-184) (75 mg, 0.22 mmol) was dissolved in dimethyl sulfoxide (3.5 ml), then at room temperature, triethylamine (40 μl, 0.29 mmol) was added. The solution was heated at 150° C., a solution of (3S)-3-(dimethylamino)pyrrolidine (30 μl, 0.29 mmol) dissolved in dimethyl sulfoxide (1 ml) was added all at a time. The solution was stirred under nitrogen atmosphere at the same temperature for 1 hour. After cooling to room temperature, the solvent was evaporated away under reduced pressure. The residue was fractionated with chloroform and an aft aqueous saturated sodium hydrogencarbonate solution. The aqueous layer was further extracted twice with chloroform. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away under reduced pressure, and the resulting residue was purified first by preparative TLC (eluent, chloroform:methanol=9:1) to obtain a roughly-purified form (54 mg). This was further purified by preparative TLC (eluent, chloroform:7 N ammonia-containing methanol solution=95:5), then recrystallized from diisopropyl ether to obtain the entitled compound (12 tag, 13%) as a white solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].OS(O)(=O)=O.O.[CH3:17]O>>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH3:17])=[O:6]
Reactant: CO
Reactant: O=C(O)c1cccc(I)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1cccc(I)c1
Temperature: 25 °C

Procedure:
To a solution of 3-iodobenzoic acid (50.0 g, 0.202 mol) in methanol (300.0 ml) was added H2SO4 (1.0 ml). The reaction mixture was heated to reflux. After reflux 24 h, heating was stopped. The reaction mixture was cooled to room temperature. Water (400.0 ml) was added, the product was extracted with ethyl acetate (2×300.0 ml). The organic layer was washed with 20% of NaHCO3 water solution and followed with water. After removal of ethyl acetate, the crude product was purified by recrystallization from ethanol/water. Final white pure product was obtained in 51.0 g (96.5%) after dry under vacuum. 1H NMR (400 MHz, CDCl3, δ): 8.35 (t, J=1.6 Hz, 1H), 7.97 (dt, J1=8.4 Hz, J2=1.6 Hz, 1H), 7.85 (dt, J1=8.4 Hz, J2=1.6 Hz, 1H), 7.14 (t, J=8.4 Hz, 1H), 3.89 (s, 3H, OCH3). 13C NMR (100 MHz, CDCl3, δ): 165.56, 141.70, 138.42, 131.93, 130.03, 128.70, 93.76, 52.38.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][CH2:17][NH:18]C(=O)OC(C)(C)C)[CH:11]=2)=[CH:6][CH:5]=1)=[O:3].FC(F)(F)C(O)=O.C([O-])([O-])=O.[K+].[K+].C(Cl)(Cl)Cl>C(Cl)Cl>[NH2:18][CH2:17][CH2:16][C:12]1[CH:11]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([C:2]([NH2:1])=[O:3])=[CH:5][CH:6]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)NCCc1cccc(-c2ccc(C(N)=O)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: NCCc1cccc(-c2ccc(C(N)=O)cc2)c1

Procedure:
To a solution of 1,1-dimethylethyl {2-[4′-(aminocarbonyl)-3-biphenylyl]ethyl}-carbamate (1.81 g, 0.005 mol) in CH2Cl2 (50 mL) at room temperature was added trifluoroacetic acid (15 mL) in one portion. After 1 hr the mixture was cooled in an ice bath and 1M K2CO3 (200 mL) and chloroform were added. The aqueous phase was extracted several times with mixtures of ethyl acetate, dichloromethane and chloroform. Residual solids were collected by filtration, affording the title compound as a white solid; LC/MS (method A) 1.04 min; m/z 241 (M+H). Combined organic extracts were dried over Na2SO4 and concentrated in vacuo affording an additional batch of the title compound (combined with the solid collected above). This product was used without further purification.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][NH2:12])=[CH:9][C:4]=2[O:3][CH2:2]1.[Cl:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1)[O:20][CH2:19][CH2:18][CH:17]2[C:34]([O:36][CH2:37][CH3:38])=[O:35].Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][NH:12][C:29]([C:28]3[CH:27]=[CH:26][C:25]([O:24][C:23]4[CH:22]=[C:21]5[C:16]([CH:17]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:18][CH2:19][O:20]5)=[CH:15][C:14]=4[Cl:13])=[CH:33][CH:32]=3)=[O:30])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc5c(c4)OCO5)cc3)c(Cl)cc21
Reaction time: 16 h
Yield: 93.2 %

Procedure:
2-(Benzo[d][1,3]dioxol-5-yl)ethanamine (32.9 mg, 0.199 mmol) in DMF (0.1 M) was treated sequentially with 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation 1) (1327 μL, 0.133 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (30.5 mg, 0.159 mmol), and 1-hydroxy-7-azabenzotriazole (5.42 mg, 0.0398 mmol) at ambient temperature. After 16 hours, the reaction was applied directly to a silica gel column and eluted with a gradient (20% to 80%) of ethyl acetate-hexanes to provide the title compound (65 mg, 0.124 mmol, 93.5% yield) as a white solid.
Reaction SMILES: S(=O)(=O)(O)O.C(OS(C1C=CC=CC=1)(=O)=O)CCCCCCCCCCC.C([NH3+])(C)C.C[C:33]1[CH:38]=[CH:37][C:36]2[NH:39][C:40]3[C:45]([C:46](=[O:47])[C:35]=2[CH:34]=1)=[CH:44][C:43]1[NH:48][C:49]2[CH:56]=[CH:55][C:54](C)=[CH:53][C:50]=2[C:51](=[O:52])[C:42]=1[CH:41]=3>>[CH:54]1[CH:53]=[C:50]2[C:51]([C:42]3[C:43]([NH:48][C:49]2=[CH:56][CH:55]=1)=[CH:44][C:45]1[C:46]([C:35]2[C:36]([NH:39][C:40]=1[CH:41]=3)=[CH:37][CH:38]=[CH:33][CH:34]=2)=[O:47])=[O:52]
Reactant: Cc1ccc2[nH]c3cc4c(=O)c5cc(C)ccc5[nH]c4cc3c(=O)c2c1
Agent: CC(C)[NH3+]
Agent: CCCCCCCCCCCCOS(=O)(=O)c1ccccc1
Agent: O=S(=O)(O)O
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12

Procedure:
A suitable vessel is charged with 8182 kg of 1.5% sulfuric acid, 68.2 kg of isopropylammoniumdodecylbenzene sulfonate and 4909 kg of mill powder from above. The mixture is heated near its boiling point for 3 hours after which the pigmentary solid solution of 2,9-dimethylquinacridone and quinacridone is isolated in a suitable filtration device and washed free of acid and salts. The resulting water wet pigment may be either dried as such or further treated depending on the desired end use.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH:23]=O>>[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH2:23][NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=Cc1cccs1
Product: CN1CCC(c2c[nH]c3ccc(NCc4cccs4)nc23)CC1

Procedure:
Beginning with 0.25 gm (1.09 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.20 mL (2.17 mMol) thiophene-2-carboxaldehyde, the title compound was prepared essentially as described in Example 2.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](Cl)=[O:27]>C1COCC1>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:26]([C:22]3[O:21][CH:25]=[CH:24][CH:23]=3)=[O:27])[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: O=C(Cl)c1ccco1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Solvent: C1CCOC1
Product: O=C1CCC(N2C(=O)c3cccc(NC(=O)c4ccco4)c3C2=O)C(=O)N1
Yield: 88.5 %

Procedure:
To a stirred suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.55 g, 2.0 mmol) in THF (30 ml) was added furan-2-carbonyl chloride (0.52 g, 4.0 mmol). The mixture was heated to reflux for 18 hours. To the reaction mixture was added additional furan-2-carbonyl chloride (0.26 g, 2 mmol). The mixture was heated to reflux for an additional 8 hours. The solvent was evaporated in vacuo and the resulting solid was slurried in diethyl ether (20 ml) and filtered to give 0.65 g (88%) of product as an off-white solid: mp 299–301° C.; 1H NMR (DMSO-d6) δ 11.19 (s, 1H), 10.37 (s, 1H), 8.68 (dd, J=1.4 and 8.4 Hz, 1H), 8.06 (s, 1H), 7.90 (t, J=8.1 Hz, 1H), 7.65 (d, J=7.3 Hz, 1H), 7.39 (d, J=3.5 Hz, 1H), 6.79 (dd, J=1.5 and 3.2 Hz, 1H), 5.19 (dd, J=5.1 and 12.5 Hz, 1H), 2.98–2.84 (m, 1H), 2.67–2.49(m, 2H), 2.13–2.08 (m, 1H); 13C NMR (DMSO-d6) δ 172.66, 169.62, 168.44, 166.59, 155.71, 146.80, 146.34, 136.55, 136.23, 136.12, 131.30, 124.86, 118.54, 116.64, 113.06, 48.98, 30.90, 22.01; Anal. Calcd. For C18H13N3O6: C, 58.86; H. 3.57; N, 11.44. Found: C, 58.69; H, 3.54; N, 11.41.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:36])[C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:13]=[C:12]([OH:35])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:37][CH2:38][CH2:39][CH2:40]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C=O)C>[C:1]1([CH2:7][O:8][C:9](=[O:36])[C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:13]=[C:12]([O:35][CH2:40][CH2:39][CH2:38][Br:37])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(O)cc(C(=O)OCc2ccccc2)c1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCBr)cc(C(=O)OCc2ccccc2)c1
Yield: 79.5 %

Procedure:
A mixture of 5.0 g (0.01 mol) of 3-hydroxy-5-(octadecyloxy)benzoic acid phenylmethyl ester, 10.2 ml (0.1 mol) of 1,3-dibromopropane and 7.0 g (0.05 mol) of potassium carbonate in 75 ml of acetone and 15 ml of DMF wasstirred at reflux for 22 hours. The reaction mixture was filtered and the filtrate was concentrated at reduced pressure to an oil. Purification by HPLC using 5% ethyl acetate-hexane gave 4.91 g (79% yield, mp 57°-58°) of 3-(3-bromopropoxy)-5-(octadecyloxy)benzoic acid phenylmethyl ester. The structure was confirmed by the nmr spectrum.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][CH:20]=2)=[CH:14][CH:13]=1)=S.C1([N:39]=[C:40]=[N:41]C2CCCCC2)CCCCC1.C(N(C(C)C)CC)(C)C.N#CN>C(Cl)Cl.C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][CH:20]=2)=[CH:14][CH:13]=1)=[N:41][C:40]#[N:39]
Reactant: COc1cc2nccc(Oc3ccc(NC(=S)Nc4ccccc4F)cc3)c2cc1OC
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: N#CN
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2nccc(Oc3ccc(NC(=NC#N)Nc4ccccc4F)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
N-(2-Fluorophenyl)-N'-(4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}thiourea (42 mg) obtained in Example 167, dicyclohexylcarbodiimide (37 mg) and a catalytic amount of diisopropylethyl amine were dissolved in methylene chloride (10 ml). To this solution, a solution of cyanamide (20 mg) in THF (1 ml) was added, and the admixture was stirred at room temperature overnight. After removing the solvent by distillation, the resulting residue was purified by column chromatography on silica gel eluting with chloroform/methanol (100/1) to obtain 41 mg of the title compound (yield: 99%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([C:9]([NH2:12])([CH3:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:21][CH2:22][C:23](Cl)=[O:24].Cl>ClCCl.O>[Cl:21][CH2:22][C:23]([NH:12][C:9]([CH3:11])([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:13])([F:14])[F:1])[CH:4]=1)[CH3:10])=[O:24]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(N)c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(NC(=O)CCl)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.5 g (12.3 mmol) of the compound from Example 1A and 1.70 g (12.3 mmol) of potassium carbonate are placed in 30 ml dichloromethane and slowly treated at RT with a solution of 1.46 g (12.9 mmol) of chloroacetyl chloride in 5 ml dichloromethane. The mixture is stirred for 3 hrs at RT and then treated with 150 ml water and slowly with 30 ml 1 N hydrochloric acid. It is extracted three times with dichloromethane. The combined organic phases are dried over magnesium sulphate and freed of solvent on the rotary evaporator. 2.65 g (77% of theory) of the title compound are thus obtained.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:13])=[CH:7][C:8](=[O:12])[S:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:21]([O:23][C:24](=[O:29])[CH2:25][N:26]=[C:27]=[O:28])[CH3:22].Cl>ClCCl>[CH2:21]([O:23][C:24](=[O:29])[CH2:25][NH:26][C:27]([C:7]1[C:8](=[O:12])[S:9][C:10]2[C:5]([C:6]=1[OH:13])=[CH:4][CH:3]=[C:2]([F:1])[CH:11]=2)=[O:28])[CH3:22]
Reactant: O=c1cc(O)c2ccc(F)cc2s1
Reactant: CCOC(=O)CN=C=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)c1c(O)c2ccc(F)cc2sc1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 27.1 %

Procedure:
7-Fluoro-4-hydroxy-thiochromen-2-one (2.0 g, 10.2 mmol) was dissolved in a mixture of triethylamine (1.7 mL, 12.23 mmol) and dichloromethane (50 mL). Isocyanato-acetic acid ethyl ester (1.4 mL, 12.23 mmol) was added to the solution and the reaction stirred overnight (18 h) at ambient temperature. The reaction mixture was acidified to pH 3 using 1N HCl and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, and the crude residue purified by silica gel chromatography (10%-40% ethyl acetate in hexanes) to provide [(7-fluoro-4-hydroxy-2-oxo-2H-thiochromene-3-carbonyl)-amino]-acetic acid ethyl ester (900 mg, 30%). MS ESI(−) m/e: 324.117 (M−1).