Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@@H:5]([C:7]1[N:12]=[C:11]([N:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][C:17]([S:23](=[O:28])(=[O:27])[N:24]([CH3:26])[CH3:25])=[CH:18][CH:19]=3)[CH2:14]2)[CH:10]=[CH:9][N:8]=1)[CH3:6])(=O)C.O.[OH-].[Li+]>CO.O>[CH3:26][N:24]([CH3:25])[S:23]([C:17]1[CH:16]=[C:15]2[C:20]([CH2:21][CH2:22][N:13]([C:11]3[CH:10]=[CH:9][N:8]=[C:7]([C@H:5]([OH:4])[CH3:6])[N:12]=3)[CH2:14]2)=[CH:19][CH:18]=1)(=[O:28])=[O:27]
Reactant: CC(=O)O[C@H](C)c1nccc(N2CCc3ccc(S(=O)(=O)N(C)C)cc3C2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@@H](O)c1nccc(N2CCc3ccc(S(=O)(=O)N(C)C)cc3C2)n1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 31 %

Procedure:
To a solution of (R)-1-[4-(7-dimethylsulfamoyl-3,4-dihydro-1H-isoquinolin-2-yl)-pyrimidin-2-yl]-ethyl acetate (prepared according to the method of Example 247, Step C, 326 mg, 0.81 mmol) in a 4:1 mixture of methanol/water (8 mL) was added lithium hydroxide hydrate (170 mg, 4.0 mmol). This mixture was stirred at room temperature for 50 min, concentrated, re-suspended in water, and extracted with 10% isopropanol/chloroform (3×). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (1% methanol/chloroform) to give a white foam which was further purified by recrystallization from ether/methanol to give 90 mg (31%) of the title compound as a white solid. mp: 120.5-122° C.; 1H NMR (CDCl3, 300 MHz) δ 8.24 (d, 1H), 7.62-7.59 (c, 2H), 7.35 (d, 1H), 6.44 (d, 1H), 4.83 (s, 2H), 4.73 (q, 1H), 4.34 (br s, 1H), 3.93-3.85 (c, 2H), 3.03 (t, 2H), 2.71 (s, 6H), 1.52 (d, 3H); MS (TS) 363 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:11](=[O:12])[N:10]([C:13]3[S:14][C:15]([C:19](O)=[O:20])=[C:16]([CH3:18])[N:17]=3)[CH:9]=[N:8]2)=[CH:4][CH:3]=1.O[N:25]1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[Cl-].[NH4+]>CN(C)C=O>[F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:11](=[O:12])[N:10]([C:13]3[S:14][C:15]([C:19]([NH2:25])=[O:20])=[C:16]([CH3:18])[N:17]=3)[CH:9]=[N:8]2)=[CH:4][CH:3]=1
Reactant: On1nnc2ccccc21
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(N)=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 77.1 %

Procedure:
To a solution of 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylic acid (0.35 g, 1.05 mmol) in anhydrous N,N-dimethylformamide (10.0 mL) was added 1-hydroxybenzotriazole (0.28 g, 2.09 mmol), 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (0.80 g, 2.09 mmol), N,N-diisopropylethylamine (1.09 mL, 6.28 mmol) and ammonium chloride (0.22 g, 4.19 mmol). The resulting solution was stirred at ambient temperature for 72 h and concentrated in vacuo. The residue was suspended in saturated aqueous sodium bicarbonate solution (100 mL). The crude product was filtered and washed with water (50 mL). The crude solid was recrystallized in ethanol to afford the title compound as an off-white solid (0.27 g, 73%): mp 232-233° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.75 (s, 1H), 7.64 (br, 2H), 7.40-7.36 (m, 2H), 7.22-7.16 (m, 2H), 5.00 (s, 2H), 2.55 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 162.7, 161.69 (d, 1JC-F=243.5 Hz), 151.3, 150.9, 149.7, 132.2 (d, 4JC-F=3.0 Hz), 132.0, 129.9 (d, 3JC-F=8.4 Hz), 123.0, 115.4 (d, 2JC-F=21.5 Hz), 47.7, 16.8; MS (ES+) m/z 334.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6]([Cl:9])[CH:5]=[C:4]([CH3:10])[CH:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:25][CH:24]2[N:26]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:20]([CH2:21][C:22]([C:50]3[S:54][C:53]([O:55][CH2:56][CH2:57]O)=[N:52][CH:51]=3)=[C:23]2[C:34](=[O:49])[N:35]([CH:46]2[CH2:48][CH2:47]2)[CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[C:38]=2[CH3:45])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].P(CCCC)(CCCC)CCCC>C1(C)C=CC=CC=1.CCOCC>[C:11]([O:15][C:16]([N:18]1[CH2:25][CH:24]2[N:26]([C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[CH:20]([CH2:21][C:22]([C:50]3[S:54][C:53]([O:55][CH2:56][CH2:57][O:8][C:7]4[C:2]([Cl:1])=[CH:3][C:4]([CH3:10])=[CH:5][C:6]=4[Cl:9])=[N:52][CH:51]=3)=[C:23]2[C:34](=[O:49])[N:35]([CH:46]2[CH2:47][CH2:48]2)[CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[C:38]=2[CH3:45])[CH2:19]1)=[O:17])([CH3:12])([CH3:13])[CH3:14]
Reactant: COc1cccc(CN(C(=O)C2=C(c3cnc(OCCO)s3)CC3CN(C(=O)OC(C)(C)C)CC2N3C(=O)OC(C)(C)C)C2CC2)c1C
Reactant: Cc1cc(Cl)c(O)c(Cl)c1
Agent: CCCCP(CCCC)CCCC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COc1cccc(CN(C(=O)C2=C(c3cnc(OCCOc4c(Cl)cc(C)cc4Cl)s3)CC3CN(C(=O)OC(C)(C)C)CC2N3C(=O)OC(C)(C)C)C2CC2)c1C
Temperature: 80 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
A sol. of 2,6-dichloro-p-cresol (0.55 mmol; 97 mg) in toluene (4.8 mL) was treated with compound E9 (0.37 mmol; 250 mg) followed by azodicarboxylic dipiperidide (0.73 mmol; 184 mg) and PBu3 (1.28 mmol; 0.27 mL). The reaction mixture was stirred at 80° C. After 1 h, the reaction mixture was allowed to cool to rt, diluted with Et2O (50 mL), filtrated, and the filtrate was washed with NaOH 1M (50 mL) and brine (50 mL). The org. extract was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 30:70) yielded the title compound (0.23 g, 76%). LC-MS: tR=1.25 min; ES+: 843.29.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21]([C:23]#[C:24][C:25]3[CH:26]=[N:27][NH:28][CH:29]=3)[S:22][C:13]=12.Cl.Cl[CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21]([C:23]#[C:24][C:25]3[CH:29]=[N:28][N:27]([CH2:32][CH2:33][N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)[CH:26]=3)[S:22][C:13]=12
Reactant: COc1cc(Nc2c(C#N)cnc3cc(C#Cc4cn[nH]c4)sc23)c(Cl)cc1Cl
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(Nc2c(C#N)cnc3cc(C#Cc4cnn(CCN5CCOCC5)c4)sc23)c(Cl)cc1Cl
Temperature: 50 °C
Yield: 69.5 %

Procedure:
A mixture of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(1H-pyrazol-4-ylethynyl)thieno[3,2-b]pyridine-6-carbonitrile (57 mg, 0.13 mmol), 4-(2-chloroethyl)morpholine hydrochloride (24 mg, 0.13 mmol), and cesium carbonate (42 mg, 0.13 mmol) in 1 mL of dimethylformamide is heated at 50° C. overnight. The mixture is cooled to room temperature and then added to water. The resulting precipitate is collected by filtration. The collected solid is purified by flash column chromatography, eluting with 1:7 methanol:ethyl acetate to provide 50 mg of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{[1-(2-morpholin-4-ylethyl)-1H-pyrazol-4-yl]ethynyl}thieno[3,2-b]pyridine-6-carbonitrile as a yellow solid, mp greater than 200° C.; 1H NMR (DMSO-d6) δ 2.44 (br s, 4H), 2.62 (t, 2H), 3.53 (br s, 4H), 3.81 (s, 3H), 4.23 (br s, 2H), 6.77 (s, 1H), 7.57 (s, 1H), 7.71 (s, 1H), 7.80 (br, 1H), 8.24 (br, 1H), 8.37 (s, 1H), 13.36 (br s, 1H); MS 553.1 (M+H)+.
Reaction SMILES: C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)[OH:4].[Na+].[Na+].[Na+].[C:17]([OH:38])(=[O:37])[CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33]CCC>C(O)C>[OH:4][CH:28]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:27]=[CH:26][CH:25]=[CH:24][CH2:23][CH:22]=[CH:21][CH2:20][CH2:19][CH2:18][C:17]([OH:38])=[O:37]
Reactant: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)O
Reactant: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCC(O)C=CC=CCC=CCCCC(=O)O
Reaction time: 0.17 h

Procedure:
Eight ml of blood was gathered from the abdominal aorta of a rat (JcI : Wistar, male, 12-15 weeks age) subjected to abdominal incision under anesthesia by the use of 3.2 % sodium citrate (1 volume of sodium citrate solution to 9 volume of whole blood). The blood was centrifuged at 800 rpm for 10 minutes at room temperature to gather PRP (platelet rich plasma), and the residual blood was further centrifuged at 3000 rpm for 10 minutes to gather PPP (platelet poor plasma). The platelet number in PRP was measured and the PRP was adjusted by diluting with PPP so that the concentration of platelet was one million/μl. To 0.25 ml of the PRP, 125 μg of arachidonic acid and the test compound (the final concentration of 100 μM, 10 μM, 1 μM and 0.1 μM) were added, and the mixture was incubated at 37° C. for 15 minutes. After the reaction, 1.1 ml of ethanol was added, well shaken and centrifuged at 2000 rpm for 10 minutes to separate the supernatant. To 1 ml of the supernatant 1 ml of water was added and subjected to high performance liquid chromatography to determine HHT. The absorption at 240 nm due to HHT was measured by an ultraviolet absorption monitor. The inhibition rate of HHT formation calculated from the peak area is shown in Table 2.
Reaction SMILES: [OH:1][C:2]1[C:11]2[N:10]=[C:9]([NH:12][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=3)[N:8]3[CH2:21][CH2:22][N:23]=[C:7]3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[O:24]=[S:25]1(=[O:35])[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33]O)[CH2:27][CH2:26]1>>[O:35]=[S:25]1(=[O:24])[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][O:1][C:2]2[C:11]3[N:10]=[C:9]([NH:12][C:13](=[O:20])[C:14]4[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=4)[N:8]4[CH2:21][CH2:22][N:23]=[C:7]4[C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:27][CH2:26]1
Reactant: O=C(NC1=Nc2c(O)cccc2C2=NCCN12)c1cccnc1
Reactant: O=S1(=O)CCN(CCCO)CC1
Product: O=C(NC1=Nc2c(OCCCN3CCS(=O)(=O)CC3)cccc2C2=NCCN12)c1cccnc1

Procedure:
The procedure used for the preparation of Example 4 was used to prepare the title compound from N-(7-hydroxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide (Intermediate C) and 3-(1,1-dioxidothiomorpholin-4-yl)propan-1-ol. High vacuum drying at 60° C. gave the title compound (105 mg, 45%): HPLC MS RT=1.16 min, MH+=483.2; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 2.32-2.33 (2H, m), 3.53-3.58 (2H, m), 3.66 (4H, bs), 3.87 (4H, bs), 4.27-4.40 (2H, m), 4.58-4.65 (2H, m), 7.60 (1H, t), 7.70 (1H, d), 7.93 (1H, dd), 8.89 (1H, d), 8.99 (1H, dd), 9.50 (1H, s).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]4[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=4)=[C:14]([O:28][CH3:29])[CH:13]=3)[C:5]2=[N:6][CH:7]=1.[Cu][C:31]#[N:32]>CN(C)C=O>[CH3:29][O:28][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[O:18][CH2:19][C:20]1[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)[CH2:11][N:8]1[C:5]2=[N:6][CH:7]=[C:2]([C:31]#[N:32])[CH:3]=[C:4]2[N:10]=[CH:9]1
Reactant: COc1ccc(COc2ccc(Cn3cnc4cc(I)cnc43)cc2OC)cn1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: COc1ccc(COc2ccc(Cn3cnc4cc(C#N)cnc43)cc2OC)cn1
Temperature: 150 °C
Reaction time: 5 h
Yield: 66.3 %

Procedure:
To a stirred solution of 6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine (1.00 g, 1.99 mmol) in N,N-dimethylformamide (15 mL) was added copper(I) cyanide (0.53 g, 6.00 mmol). The mixture was heated to 150° C. After 5 h, the mixture was allowed to cool to room temperature and was concentrated. The residue was purified by silica gel chromatography (2% methanol/dichloromethane elute) to give 0.53 g (66%) of 3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile as a yellow solid.
Reaction SMILES: [CH2:1]([C:3]1([C:40]2[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=2)[CH:12]([CH2:13]CCCCCCCCC(CCCCCCC(F)(F)C(F)(F)F)C(O)=O)[C:11]2[C:6](=[CH:7][C:8]([OH:39])=[CH:9][CH:10]=2)[O:5][CH2:4]1)[CH3:2].[F:47][C:48]([F:71])([C:67]([F:70])([F:69])[F:68])[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH:54]([CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH:65]=[CH2:66])[C:55]([O:57]CC)=[O:56]>>[CH2:1]([C:3]1([C:40]2[CH:41]=[CH:42][C:43]([OH:46])=[CH:44][CH:45]=2)[CH:12]([CH2:13][CH2:66][CH2:65][CH2:64][CH2:63][CH2:62][CH2:61][CH2:60][CH:54]([CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][C:48]([F:47])([F:71])[C:67]([F:68])([F:69])[F:70])[C:55]([OH:57])=[O:56])[C:11]2[C:6](=[CH:7][C:8]([OH:39])=[CH:9][CH:10]=2)[O:5][CH2:4]1)[CH3:2]
Reactant: C=CCCCCCC(CCCCCC(F)(F)C(F)(F)F)C(=O)OCC
Reactant: CCC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCCC(CCCCCCC(F)(F)C(F)(F)F)C(=O)O
Product: CCC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCC(CCCCCC(F)(F)C(F)(F)F)C(=O)O

Procedure:
Starting with the allyl compound prepared in Example 21 and the ethyl 2-(6,6,7,7,7-pentafluoroheptyl)-8-nonenoate prepared in Example 11, the same procedure as shown in Example 21 was repeated to give 10-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)chroman-4-yl]-2-(6,6,7,7,7-pentafluoroheptyl)decanoic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)([CH:10]2[CH2:15][CH2:14][N:13](CC3C=CC=CC=3)[CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1>C(O)C.[Pd]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:23]2[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:6][CH:7]=1
Reactant: Cc1ccc(C(O)(c2ccc(C)cc2)C2CCN(Cc3ccccc3)CC2)cc1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(C(O)(c2ccc(C)cc2)C2CCNCC2)cc1
Yield: 59.9 %

Procedure:
A solution of 38.5 g (0.1 mole) of α,α-bis(4-methylphenyl)-1-(phenylmethyl)-4-piperidinemethanol in 500 ml of absolute ethanol was hydrogenated at 50 psi and 60° C. over 1 tsp of 5% palladium on carbon in a Parr apparatus for 3 days. The cooled mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure to give a glass as residue. The glass was crystallized from 2-propanol to yield 17.7 g (60%) of the title compound as a white solid, mp 150°-153° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[C:10]2[C:15](=O)[C:14](=[CH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[CH2:13][S:12][CH2:11]2)=[CH:5][CH:4]=1.[CH2:26]([NH:29][NH2:30])[CH2:27][CH3:28]>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[NH:30][N:29]([CH2:26][CH2:27][CH3:28])[C:15]3[C:14](=[CH:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)[CH2:13][S:12][CH2:11][C:10]2=3)=[CH:5][CH:4]=1
Reactant: COc1ccc(C=C2CSCC(=Cc3ccc(OC)cc3)C2=O)cc1
Reactant: CCCNN
Solvent: CO
Product: CCCN1NC(c2ccc(OC)cc2)C2=C1C(=Cc1ccc(OC)cc1)CSC2
Reaction time: 8 h

Procedure:
A mixture of tetrahydro-3,5-bis-(4-methoxyphenyl-methylene)-4H-thiopyran-4-one (6 g, 17 mmole) and propylhydrazine (1.4 g, 19 mmole) in methanol (250 ml) is heated at reflux temperature for 4.5 hours. After the reaction mixture is left at room temperature overnight, yellow solids precipitate out and are collectd by filtration. The crude product is applied to a Al2O3 column (Activity I, neutral). The major product is eluted with 10-20% ethyl acetate/acetic acid. Continued elution with 10-60% CHCl3 /hexane yields the title compound. Recrystallization from acetone/hexane gives 0.65 g of final product in crystalline form (99% pure), m.p. 131.5°-133.5°.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[F:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:11]=1[C:12]#[N:13].[C:20](=[O:22])=[O:21]>C1COCC1>[C:12]([C:11]1[C:10]([F:9])=[C:17]([CH:16]=[CH:15][C:14]=1[O:18][CH3:19])[C:20]([OH:22])=[O:21])#[N:13]
Reactant: COc1cccc(F)c1C#N
Reactant: O=C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)O)c(F)c1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a stirred lithium diisopropylamide solution (1.8M in heptane/THF/ethylbenzene, 44.1 mL, 79.4 mmol) at −50° C. was added a solution of 2-fluoro-6-methoxybenzonitrile (10 g, 66.16 mmol) in THF (80 mL) slowly and stirring was continued at that temperature for 1 h. The reaction mixture was poured onto a stirred slurry of dry ice in dry THF (100 mL). After the mixture had warmed up to room temperature, it was concentrated to about 50 mL, diluted with 6 N HCl (200 mL), extracted with dichloromethane, dried with sodium sulfate, concentrated, and dried in vacuo to give 3-cyano2-fluoro-4-methoxybenzoic acid (12.9 g, 100%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.Br[CH2:18][CH2:19][O:20][C:21]1[CH:34]=[CH:33][C:24]([C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:26])=[C:23]([OH:35])[CH:22]=1>>[S:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=[C:8]1[C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:18][CH2:19][O:20][C:21]2[CH:34]=[CH:33][C:24]([C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:26])=[C:23]([OH:35])[CH:22]=2)=[CH:7][CH:6]=1
Reactant: Oc1ccc(-c2nc3ccccc3s2)cc1
Reactant: O=C(c1ccccc1)c1ccc(OCCBr)cc1O
Product: O=C(c1ccccc1)c1ccc(OCCOc2ccc(-c3nc4ccccc4s3)cc2)cc1O

Procedure:
A hot solution of 16 g. of zinc, o-aminophenylmercaptide and 12.5 g. of p-hydroxybenzaldehyde in 1 l. of acetic acid was treated with hydrogen sulfide for two hours, filtered hot, diluted with an equal volume of water and cooled. 2-(p-Hydroxyphenyl)benzothiazole (47% yield, m.p. 227°-229° F.) was obtained. The 2-(p-hydroxyphenyl)benzothiazole was reacted with 4-(2-bromoethoxy)-2-hydroxybenzophenone as in Example 1 to produce 4-{2-[4-(2-benzothiazolyl)phenoxy]ethoxy}-2-hydroxybenzophenone.
Reaction SMILES: COCCCNS(C1C=CC(NC2CC(C(OC)=O)=C(NC3C=CC(S(=O)(=O)NCCCOC)=CC=3)CC=2C(OC)=O)=CC=1)(=O)=O.[NH:47]([C:54]1[CH2:62][C:61]([C:63](O)=[O:64])=[C:60]([NH:66][C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[CH2:59][C:55]=1[C:56](O)=[O:57])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>>[CH:70]1[CH:71]=[C:72]2[C:63]([C:61]3[C:60]([NH:66][C:67]2=[CH:68][CH:69]=1)=[CH:59][C:55]1[C:56]([C:53]2[C:48]([NH:47][C:54]=1[CH:62]=3)=[CH:49][CH:50]=[CH:51][CH:52]=2)=[O:57])=[O:64]
Reactant: O=C(O)C1=C(Nc2ccccc2)CC(C(=O)O)=C(Nc2ccccc2)C1
Agent: COCCCNS(=O)(=O)c1ccc(NC2=C(C(=O)OC)CC(Nc3ccc(S(=O)(=O)NCCCOC)cc3)=C(C(=O)OC)C2)cc1
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12
Temperature: 85 °C
Reaction time: 1 h

Procedure:
To 320 g of polyphosphoric acid (116.5% phosphoric acid) was sequentially added 6.8 g of 2,5-bis[4-(3-methoxypropylsulfamoyl)anilino]-1,4-cyclohexadiene-1,4-dicarboxylic acid, dimethyl ester and 64 g of 2,5-dianilino-3,6-dihydroterephthalic acid over a period of 45 minutes, the temperature being maintained below 110° C. The reaction mixture was stirred at 100° to 110° C. for one hour and then allowed to cool to 85° C., after which the phosphoric acid concentration was reduced to 85% by the slow addition of chilled water. The mixture was stirred at 85° to 90° C. for 30 minutes, then slowly poured into 1200 ml of ice/water and stirred at less than 30° C. for an additional hour. The solid component was collected by filtration and washed with water. The resultant wet presscake was reslurried in 181.3 g of methanol and 73.9 g of water and stirred until uniform. After 37.3 g of 50% aqueous sodium hydroxide was added, the slurry was stirred at less than 35° C. for one hour. The slurry was then heated to 60° C., diluted with 12.6 g of water, and heated at reflux for 30 minutes. After the slurry was allowed to cool to 60° C., 37.3 g of 92% sodium 3-nitrobenzenesulfonate and 31.6 g of water were added sequentially. After ten minutes, the slurry was heated at 88° C. for 15 hours. Upon being cooled to room temperature, the solid component was isolated by filtration and washed with water. The wet presscake cake was reslurried in 357.1 g of methanol and 357.1 g of water (which includes the amount of water in the presscake). When the slurry became uniform, 95.2 g of 50% aqueous sodium hydroxide and an additional 60.0 g of 92% sodium 3-nitrobenzenesulfonate were added. The resultant slurry was heated in a sealed system at 115° to 120° C. for six hours. Upon being cooled to room temperature, the solid component was isolated by filtration and washed with water. The wet presscake cake was dried to give 41.0 g of gamma quinacridone.
Reaction SMILES: [CH3:1][N:2]([CH2:16][CH2:17][OH:18])[C:3](=[O:15])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:19]1([CH3:28])[CH:24]=[CH:23][C:22]([C:25](Cl)=[O:26])=[CH:21][CH:20]=1>>[CH3:1][N:2]([CH2:16][CH2:17][O:18][C:25]([C:22]1[CH:23]=[CH:24][C:19]([CH3:28])=[CH:20][CH:21]=1)=[O:26])[C:3](=[O:15])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CCCCCCCCCCCC(=O)N(C)CCO
Product: CCCCCCCCCCCC(=O)N(C)CCOC(=O)c1ccc(C)cc1

Procedure:
N-methyl-N-(2-p-toluoyloxyetyl)lauramide was prepared by the procedure of example 1 from 26 gms. (0.1 mole) of N-methyl-N-(2-hydroxyethyl)lauramide and 15 gms. (0.1 mole) of p-toluoyl chloride. The structure of the final product was characterized on the basis of IR and NMR spectral analyses as described in example 1.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N:12]=[CH:13][N:14](C)C.Cl.[CH:18]([O:21]N)([CH3:20])[CH3:19].C(N(CC)CC)C.C1(C)C=CC=CC=1>C(O)C>[CH:18]([O:21][N:14]1[C:2]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:5]=[CH:4][C:3]=2[N:12]=[CH:13]1)([CH3:20])[CH3:19]
Reactant: CC(C)ON
Reactant: CN(C)C=Nc1cnc2ccccc2c1Cl
Agent: Cl
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)On1cnc2cnc3ccccc3c21
Reaction time: 5 h
Yield: 78.1 %

Procedure:
A solution of N′-(4-chloroquinolin-3-yl)-N,N-dimethylimidoformamide (9.3 g, 0.040 mol) and O-isopropylhydroxylamine hydrochloride (5.0 g, 45 mmol) in ethanol (150 mL) was heated at reflux overnight. An analysis by LC/MS indicated the reaction was incomplete, and triethylamine (2.0 mL) was added. The reaction was heated at reflux for three hours and found to be incomplete. The ethanol was removed under reduced pressure, and toluene (150 mL) was added. The reaction was heated at reflux overnight but was found again to be incomplete. The toluene was removed under reduced pressure, and ethanol (150 mL) and additional O-isopropylhydroxylamine hydrochloride (1.0 g, 9.0 mmol) were added. The reaction was heated at reflux over night with additional O-isopropylhydroxylamine hydrochloride (0.5 g) added after three hours and again (0.4 g) after five hours. The work-up and purification procedures described in Part C of Example 19 were followed with the modification that chromatographic purification was carried out eluting with 5% methanol in dichloromethane containing 3 mL of aqueous ammonium hydroxide per liter of eluent. 1-Isopropoxy-1H-imidazo[4,5-c]quinoline (7.1 g) was obtained as a light red solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH3:10])[CH:6]=[C:5]([CH2:11][CH3:12])[C:4]=1[C:13]1[C:14](=[O:26])[N:15]([CH3:25])[N:16]=[C:17]([C:21]([F:24])([F:23])[F:22])[C:18]=1[S:19][CH3:20])[CH3:2].C(=O)([O-])[OH:28].[Na+].ClC1C=C(C=CC=1)C(O)=O.S([O-])([O-])=O.[Na+].[Na+]>O.C(Cl)(Cl)Cl>[CH2:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH3:10])[CH:6]=[C:5]([CH2:11][CH3:12])[C:4]=1[C:13]1[C:14](=[O:26])[N:15]([CH3:25])[N:16]=[C:17]([C:21]([F:24])([F:23])[F:22])[C:18]=1[S:19]([CH3:20])=[O:28])[CH3:2]
Reactant: CCc1cc(CC)c(-c2c(SC)c(C(F)(F)F)nn(C)c2=O)c(CC)c1
Reactant: O=C([O-])O
Agent: O=C(O)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCc1cc(CC)c(-c2c(S(C)=O)c(C(F)(F)F)nn(C)c2=O)c(CC)c1
Yield: 97.3 %

Procedure:
To a 100 ml volume four-necked flask, 4-(2,4,6-triethylphenyl)-2-methyl-5-methylsulfanyl-6-trifluoromethyl-2,3-dihydro-3-pyridazinone ((2-46)-(1)-40) (0.683 g) and chloroform (24 ml) were added at room temperature, and stirred. Sodium hydrogen carbonate (0.597 g), and meta-chlorobenzoic acid (0.615 g) was added and the resulting mixture was stirred at room temperature for 4 hours. Then, the reaction mixture was poured into water (30 ml), added sodium sulfite (0.4 g), and extracted with t-butyl methyl ether (30 ml) 4 times. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and subjected to silica gel column chromatography (hexane: ethyl acetate=5:1 to hexane: ethyl acetate=1:1) to give 0.692 g of 4-(2,4,6-triethylphenyl)-2-methyl-5-methylsulfinyl-6-trifluoromethyl-2,3-dihydro-3-pyridazinone ((2-49)-(1)-40).