Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]2[NH:26][CH:25]([C:27]([OH:29])=O)[CH2:24][S:23]2)[CH:17]=1.ON1C2C=CC=CC=2N=N1.[CH2:40]([NH2:59])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58]>O1CCCC1.C(OCC)(=O)C>[CH2:40]([NH:59][C:27]([CH:25]1[CH2:24][S:23][CH:22]([C:18]2[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=2)[NH:26]1)=[O:29])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58]
Reactant: CCCCCCCCCCCCCCCCCCCN
Reactant: O=C(O)C1CSC(c2cccnc2)N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCCCCNC(=O)C1CSC(c2cccnc2)N1
Reaction time: 1 h
Yield: 21.9 %

Procedure:
A solution of 500 mg of dicyclohexylcarbodiimide in 3 ml of tetrahydrofuran was added dropwise to a mixture of 510 mg of 2-(3-pyridyl)thiazolidine-4-carboxylic acid, 490 mg of 1-hydroxybenzotriazole, 680 mg of nonadecylamine and 12 ml of tetrahydrofuran with ice cooling, and the resulting mixture was stirred with ice cooling for 1 hour and then at room temperature for 12 hours. The reaction mixture was diluted with 30 ml of ethyl acetate, and the insoluble matter was filtered off. The filtrate was washed in sequence with saturated aqueous solution of sodium hydrogen carbonate, water and saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate) and recrystallized from ethyl acetate to give 250 mg of N-nonadecyl-2-(3-pyridyl)thiazolidine-4-carboxamide. Melting point 108°-110° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][S:15]([C:12]2[CH:13]=[CH:14][C:9]([CH3:19])=[CH:10][CH:11]=2)(=[O:17])=[O:16])[CH2:3][CH2:2]1
Reactant: OCC1CCOCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC2CCOCC2)cc1
Reaction time: 8 h
Yield: 75.1 %

Procedure:
At room temperature, a mixture of (tetrahydro-pyran-4-yl)-methanol (2.4 g, 20.7 mmol), p-toluenesulfonyl chloride (6.73 g, 35.4 mmol), triethylamine (6.6 mL, 47.6 mmol) and DMAP (0.288 g, 2.36 mmol) in DCM (50 mL) was stirred overnight. The solution was washed with water and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography to give the title compound as an oil (4.2 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(=O)([O-])[O-:13].[Na+].[Na+].BrN1C(C)(C)C(=O)N(Br)C1=O>CC(CC(C)C)C#N.C1CCCCC1>[CH:11](=[O:13])[C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(C)cc1OC
Agent: CC(C)CC(C)C#N
Agent: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: [Na+]
Solvent: C1CCCCC1
Product: COc1ccc(C=O)cc1OC
Temperature: 25 °C
Yield: 110.4 %

Procedure:
In a 5 L flask equipped with mechanical stirrer and reflux condenser were placed 100.0 g (0.657 mol) of 3.4-dimethoxytoluene, 2.64 L of cyclohexane (0.25 M), and 104.5 g (0.986 mol) of anhydrous sodium carbonate. The apparatus was flushed with argon. The mixture was stirred and heated to reflux while continuing to sweep argon gently over the solution. A mixture of 197.28 g of 1,3-dibromo-5,5-dimethylhydantoin (DBDMH, 0.69 mol, 1.05 eq.) and 4.08 g 2,2'-azobis- 2,4-dimethylpentanenitrile (VAZO-52, 0.016 mol, 0.025 eq.) were gradually added through a funnel to the solution over a period of 120 minutes. After addition of the mixture was complete, the reaction mixture was allowed to stir for another thirty minutes at reflux. The solution was allowed to cool to room temperature and the solids was removed by vacuum filtration. The receiver flask contained 122.0 g of sodium carbonate monohydrate. The cyclohexane was removed in vacuo. To the residue was added 600 mL of water and 600 mL of tetrahydrofuran. The solution was mechanically stirred and heated to reflux for two hours. After cooling, the tetrahydrofuran was removed in vacuo. The aqueous solution was extracted three times with 200 mL of methyl tert-butyl ether. The organic extract was dried with anhydrous magnesium sulfate. After removing the magnesium sulfate by vacuum filtration through a fritted funnel, the methyl tert-butyl ether was removed in vacuo to provide 120.6 g of crude veratraldehyde (0.725 mol, 110.4% yield) that was shown to be 74.9% pure by GC and 77.4% pure by HPLC. The product was purified by bulb-to-bulb distillation to provide 72.2 g of veratraldehyde (0.434 mol, 66.1% yield, 94.1% pure by GC, 97.2% pure by HPLC). The distilled material was dissolved in 1.5 volumes (108 mL) of toluene and 1.5 volumes of cyclohexane and allowed to sit overnight in a freezer. The crystals were collected the following morning by vacuum filtration. The filter cake was washed liberally with cyclohexane. After drying in vacuo, 53.7 g (0.323 mol, 49.2% yield, 100.0% pure by HPLC, 99.2% pure by GC) of white crystalline veratraldehyde was collected.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]3[C:19]([O:25][CH3:26])=[CH:20][C:21]([C:23]#N)=[CH:22][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[PH2]([O-])=[O:28].[Na+].C(O)(=O)C>[Ni].N1C=CC=CC=1>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]3[C:19]([O:25][CH3:26])=[CH:20][C:21]([CH:23]=[O:28])=[CH:22][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: O=[PH2][O-]
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(C#N)cc(OC)c21
Agent: [Ni]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(C=O)cc(OC)c21
Temperature: 60 °C
Reaction time: 6 h
Yield: 68.3 %

Procedure:
A mixture of 480 mg (1.37 mmol) 2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carbonitrile (example 32), 15 mg Raney-Nickel (in water), 967 mg (11.0 mmol) sodium hypophosphite (in 10 ml water), 10 ml acetic acid and 20 ml pyridine is stirred for 6 h at 60° C. The catalyst is filtered off and the filtrate is poured on water and extracted (3×) with ethyl acetate. The combined organic layers are washed with water (2×) and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane:EtOAc=1:1) to afford 330 mg of the title compound as a white crystalline solid.
Reaction SMILES: [N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:38]=[CH:37][C:14]([C:15]([C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:27][CH3:28])=[CH:24][CH:25]=4)[CH:20]=[CH:19][C:18]=3OS(C(F)(F)F)(=O)=O)=[O:16])=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:40]1[C:45]([F:46])=[C:44]([F:47])[CH:43]=[CH:42][C:41]=1[F:48].OC1C=C2C(=CC=1)C(C(C1C=CC(OCCN3CCCCC3)=CC=1)=O)=C(C1C=C(F)C=C(F)C=1F)C=C2>>[N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([C:15]([C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:27][CH3:28])=[CH:24][CH:25]=4)[CH:20]=[CH:19][C:18]=3[C:40]3[C:41]([F:48])=[CH:42][CH:43]=[C:44]([F:47])[C:45]=3[F:46])=[O:16])=[CH:37][CH:38]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Reactant: Fc1ccc(F)c(Br)c1F
Agent: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2cc(F)cc(F)c2F)ccc2cc(O)ccc12
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCCC4)cc3)c(-c3c(F)ccc(F)c3F)ccc2c1
Yield: 46.3 %

Procedure:
Couple trifluoromethanesulfonic acid 1-[4-(2-azepan-1-yl-ethoxy)-benzoyl]-6-methoxynaphthalen-2-yl ester (1.48 g, 2.67 mmol) with 2-bromo-1,3,4-trifluoro-benzene (1.13 g, 5.35 mmol) in a procedure similar to the preparation of [6-hydroxy-2-(2,3,5-trifluoro-phenyl)-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone to give 660 mg (46%) of the title compound: mass spectrum (ion spray): m/z=534.4 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:25]([CH3:27])[CH3:26])[CH:19]=1.[Cl:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([F:44])[C:30]=1[OH:45]>>[Cl:28][C:29]1[CH:34]=[C:33]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:5]3[NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:25]([CH3:27])[CH3:26])[CH:19]=2)[CH:32]=[C:31]([F:44])[C:30]=1[OH:45]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CN(C)Cc1cccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)c1
Product: CN(C)Cc1cccc(Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(F)c(O)c(Cl)c4)cc23)c1
Yield: 71.9 %

Procedure:
Following general procedure D, (6-bromo-4-(3-((dimethylamino)methyl)phenylamino)quinoline-3-yl)(cyclopropyl)methanone (100 mg, 0.23 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (93 mg, 0.34 mmol) to afford the desired product (81 mg, 72%) as a yellow-green solid. 1H NMR (300 MHz, MeOD+TFA-d) δ 9.44 (s, 1H), 8.25 (dd, J=8.9, 1.9 Hz, 1H), 8.09-7.95 (m, 2H), 7.79-7.54 (m, 4H), 7.19 (dd, J=11.5, 2.3 Hz, 1H), 7.06 (s, 1H), 4.38 (s, 2H), 2.91-2.82 (m, 1H), 2.83 (s, 6H), 1.23-1.14 (m, 4H); ESI MS m/z 490 [C29H25ClFN3O2+H]+; HPLC 97.3% (AUC), tR=11.07 min.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N-:22]=[N+:23]=[N-:24].[Na+]>>[N:22]([C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)=[N+:23]=[N-:24]
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: COc1ccc(N(C)c2nc(N=[N+]=[N-])nc3ccccc23)cc1

Procedure:
The title compound was prepared from (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (150 mg, 0.5 mmol), sodium azide (97.5 mg, 1.5 mmol) in 5 mL of solvent (THF:MeOH:water=0.3:1:1) by a procedure similar to that of example 120 (4%). 1H NMR (CDCl3): 8.45 (d, J=8.4 Hz, 1H), 7.78-7.72 (m, 1H), 7.27-7.22 (m, 2H), 7.19-7.14 (m, 2H), 6.95 (d, J=8.7 Hz, 2H), 3.86 (s, 3H), 3.69 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH2:11][C:12]([OH:14])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH3:28][O:29][NH2:30]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH2:11][C:12]([NH:30][O:29][CH3:28])=[O:14]
Reactant: O=C(O)Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: CON
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CONC(=O)Cc1cc([N+](=O)[O-])ccc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 69 %

Procedure:
2-(2-Chloro-5-nitrophenyl)acetic acid (49.9 mmol) and CDI (59.9 mmol) were dissolved in DMF (300 mL) to give a yellow solution. O-Methylhydroxylamine hydrochloride (59.9 mmol) was added. The mixture was stirred at room temperature for 4 h. The reaction mixture was then concentrated under reduced pressure to approximately 50 mL and diluted with 300 mL of ethyl acetate. The organic layer was washed twice with 250 mL of water. The aqueous layer was then saturated with brine and back-extracted with ethyl acetate. The organic layers were combined and subsequently washed with 300 mL of 1 M aq. HCl, 300 mL of sat. aq. NaHCO3, and 300 mL of brine. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give 2-(2-chloro-5-nitrophenyl)-N-methoxyacetamide as a solid (69%).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].C(O[CH:12]=[CH:13][C:14]#[N:15])C>C(O)CCCC>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[N:1]1[C:14]([NH2:15])=[CH:13][CH:12]=[N:2]1
Reactant: NNc1ccccn1
Reactant: CCOC=CC#N
Solvent: CCCCCO
Product: Nc1ccnn1-c1ccccn1

Procedure:
A solution of 2-hydrazinopyridine (38.9 g, 453 mmol) was slowly added to a solution of 3-ethoxyacrylonitrile (31.5 g, 324 mmol) in pentanol (155 ml). The reaction mixture was brought to reflux for 5 h. 2-Hydrazinopyridine (10.6 g, 97 mmol) was again added and the reaction was allowed to continue to reflux for 4 h. The progress of the reaction is observed by TLC and, when the reaction is complete, the mixture is concentrated under reduced pressure until the excess hydrazinopyridine has precipitated. The filtrate was purified by column chromatography to give 2-pyridin-2-yl-2H-pyrazol-3-ylamine in the form of a white solid (2.75 g, 5.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(N(CC)CC)C.[C:16](Cl)(=[O:19])[CH2:17][CH3:18]>ClCCl>[C:16]([O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:19])[CH2:17][CH3:18]
Reactant: CCC(=O)Cl
Reactant: Oc1ccccc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)Oc1ccccc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
A solution, cooled to 10° C., of 2-chlorophenol (100 g, 0.778 mol) in 250 ml of dichloromethane is slowly admixed with triethylamine (120.7 ml). A solution of 60.7 ml of propionyl chloride in 60 ml of dichloromethane is added slowly dropwise to this mixture over the course of an hour. Following the addition of the propionyl chloride, the mixture is allowed to come slowly to room temperature and is stirred at room temperature for a total of five hours. Following removal of the triethylammonium chloride by filtration, the filtrate is diluted with 100 ml of dichloromethane and washed with 0.1 N hydrochloric acid (500 ml), 0.1 M aqueous sodium hydroxide solution (500 ml) and water (500 ml). The organic phase is dried over sodium sulphate (100 g) for three hours. After the drying agent has been removed by filtration, the solvent is removed on a rotary evaporator. Distillation of the oily yellow residue under reduced pressure gives 129.2 g (90% yield) of 2-chlorophenyl propionate as a colourless liquid (bp 90-93° C./0.3 mm).
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:16][C:17]1[CH:18]=[C:19]([OH:24])[CH:20]=[CH:21][C:22]=1[F:23]>>[N+:13]([C:10]1[CH:11]=[CH:12][C:2]([O:24][C:19]2[CH:20]=[CH:21][C:22]([F:23])=[C:17]([F:16])[CH:18]=2)=[C:3]([CH:9]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])([O-:15])=[O:14]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: Oc1ccc(F)c(F)c1
Product: CCOC(=O)c1cc([N+](=O)[O-])ccc1Oc1ccc(F)c(F)c1
Yield: 94.7 %

Procedure:
Using the method described in Example 21.2, ethyl 2-chloro-5-nitrobenzoate (0.6 g) and 3,4-difluorophenol (0.34 g) were combined to provide 0.8 g of the title compound as an oil.
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][CH:9]=[C:8]2[CH:4]([C:5](=[O:12])[O:6][C:7]2=[O:11])[CH2:3]1.[C:13]([O:21][CH3:22])(=[O:20])/[CH:14]=[CH:15]\[C:16]([O:18][CH3:19])=[O:17].C(OC)(=O)/C=C/C(OC)=O>>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[O:6][C:5]2=[O:12].[C:13]([O:21][CH3:22])(=[O:20])[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17]
Reactant: CC1CC=C2C(=O)OC(=O)C2C1
Reactant: COC(=O)/C=C\C(=O)OC
Agent: COC(=O)/C=C/C(=O)OC
Product: COC(=O)CCC(=O)OC
Product: Cc1ccc2c(c1)C(=O)OC2=O

Procedure:
10 ml/hour of a solution of 1 mol of 5-methyl-tetrahydroisobenzofuran-1,3-dione and 2 mol of dimethyl maleate were pumped at 200° C. into the top of a trickle-phase reactor filled with 100 ml of catalyst in tablet form (5% by weight palladium-on-aluminium oxide). The conversion of the dimethyl maleate after passage through the reactor was 100%. No dimethyl fumarate could be detected in the product mixture leaving the reactor. 5-Methylisobenzofuran-1,3-dione and dimethyl succinate had been formed with selectivities of over 95% and over 97% respectively. The conversion of the dehydrogenation was 99.8%. The catalyst showed no signs of deactivation after 500 hours of operation.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([C:15]=2[C:16]([C:18]2[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=2[C:20]([OH:22])=[O:21])=O)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:27][N:28]([CH3:38])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]([CH3:37])[CH3:36])[CH:30]=1.C(OC(=O)C)(=O)C.Cl>>[CH3:36][N:35]([CH3:37])[C:31]1[CH:30]=[C:29]([N:28]([CH3:38])[CH3:27])[CH:34]=[CH:33][C:32]=1[C:16]1([C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:18]2[C:19](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:20](=[O:21])[O:22]1
Reactant: CN(C)c1cccc(N(C)C)c1
Reactant: O=C(O)c1ccccc1C(=O)c1c(-c2ccccc2)[nH]c2ccccc12
Agent: Cl
Solvent: CC(=O)OC(C)=O
Product: CN(C)c1ccc(C2(c3c(-c4ccccc4)[nH]c4ccccc34)OC(=O)c3ccccc32)c(N(C)C)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 4.82 g (0.014 mole) of the 2-[(2-phenyl-3-indolyl)carbonyl]benzoic acid from part A above, 3.60 g (0.02 mole) of N,N,N',N'-tetramethyl-m-phenylenediamine, and five ml of acetic anhydride was slowly heated until a purple color formed and maintained at this temperature for approximately two hours. After cooling to room temperature, sufficient 3 N hydrochloric acid was added to the mixture to effect solution and stirring was continued for approximately 1.5 hours. The resulting solution was filtered and the pH adjusted to five by the addition of sodium acetate. The precipitate which separated from the solution was collected by filtration and dried to obtain 3-[2,4-bis(dimethylamino)phenyl]-3-(2-phenyl-3-indolyl)phthalide (Formula III: R0 =R1 =R2 =R3 =R6 =Y1 =H; R=CH3 ; R4 =N(CH3)2 ; R5 =C6H5). After recrystallization from toluene and hexane, the off white-colored solid melted at 153°-155° C. Significant infrared maxima were observed at 3380 cm-1 (NH; m) and 1750 cm-1 (C=O; s). The nuclear magnetic resonance spectrum was consistent with the structure. A toluene solution of this product spotted on silica gel developed an intense grape-red-colored image.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[N:18]=3)[C:10]3[N:11]([CH:13]=[CH:14][N:15]=3)[N:12]=2)[CH2:3]1.C[O:28][C:29]([C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=1)=[O:30].CCN=C=NCCCN(C)C.C(N(CC)CC)C.CN1C=CN=C1>ClCCl>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:9]2[C:10]3[N:11]([CH:13]=[CH:14][N:15]=3)[N:12]=[C:7]([N:4]3[CH2:5][CH2:6][CH:2]([NH:1][C:35]([C:34]4[CH:38]=[CH:39][C:31]([C:29]([OH:30])=[O:28])=[CH:32][CH:33]=4)=[O:36])[CH2:3]3)[CH:8]=2)=[N:18][C:19]=1[O:25][CH3:26]
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Reactant: COc1ccc(Nc2cc(N3CCC(N)C3)nn3ccnc23)nc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cn1ccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Nc2cc(N3CCC(NC(=O)c4ccc(C(=O)O)cc4)C3)nn3ccnc23)nc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.9 %

Procedure:
A mixture of 6-(3-aminopyrrolidin-1-yl)-N-(5,6-dimethoxypyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (180 mg, 0.51 mmol), 4-(methoxycarbonyl)benzoic acid (92 mg, 0.51 mmol), EDCI (389 mg, 2.0 mmol), triethylamine (103 mg, 1.02 mmol) and 1-methyl-1H-imidazole (167 mg, 2.0 mmol) in dichloromethane (10 mL) was stirred at room temperature for 16 h. The residue was concentrated and purified by chromatography (silica gel, 200-300 mesh, dichloromethane:MeOH=20:1) to give 4-(1-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-ylcarbamoyl)benzoic acid (100 mg, 38%) as a brown liquid. LC-MS: 518 [M+1]+, tR=1.327 min.
Reaction SMILES: C[O:2][C:3](=[O:25])[C@H:4]([NH:8][S:9]([C:12]1[CH:24]=[CH:23][C:15]2[N:16]=[C:17]([S:19][CH2:20][CH2:21][CH3:22])S[C:14]=2[CH:13]=1)(=[O:11])=[O:10])[CH:5]([CH3:7])[CH3:6].[Li+].[OH-:27]>C1COCC1.O>[CH3:6][CH:5]([CH3:7])[C@@H:4]([NH:8][S:9]([C:12]1[CH:24]=[CH:23][C:15]2[N:16]=[C:17]([S:19][CH2:20][CH2:21][CH3:22])[O:27][C:14]=2[CH:13]=1)(=[O:11])=[O:10])[C:3]([OH:2])=[O:25]
Reactant: CCCSc1nc2ccc(S(=O)(=O)N[C@@H](C(=O)OC)C(C)C)cc2s1
Reactant: [OH-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCCSc1nc2ccc(S(=O)(=O)N[C@@H](C(=O)O)C(C)C)cc2o1

Procedure:
(2R)-3-methyl-2-[(2-propylthiobenzthiazol-6-sulfonyl)amino]butanoic acid methylester (0.19 g, 0.48 mmol) was dissolved in THF/H2O (2 mL/2 mL), and LiOH (0.10 g, 5 equi.) was added. After reflux for 6 hours, the reaction solution was distilled under reduced pressure and treated with 1N HCl. The product was extracted with ethylacetate (10 mL). The separated organic phase was washed with NaCl solution, dried over MgSO4, distilled under reduced pressure and dried under vacuum to prepare the titled compound, (2R)-3-methyl-2-[(2-propylthiobenzoxazol-6-sulfonyl)amino]butanoic acid (0.14 g, 77%).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[CH3:3].Cl[CH2:19][CH2:20][CH2:21]Br.C([O-])([O-])=O.[K+].[K+].[CH:29]([NH2:32])([CH3:31])[CH3:30]>CN(C=O)C>[CH3:3][N:2]([CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:19][CH2:20][CH2:21][NH:32][CH:29]([CH3:31])[CH3:30])=[CH:13][CH:12]=2)[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1)[CH3:1]
Reactant: CN(C)CC1(c2ccc(O)cc2)CCOCC1
Reactant: ClCCCBr
Reactant: CC(C)N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)NCCCOc1ccc(C2(CN(C)C)CCOCC2)cc1

Procedure:
4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (730 mg, 3.10 mmol), 3-chloro-1-bromopropane (980 mg, 6.20 mmol), DMF (10 ml) and K2CO3 (1.72 g, 12.40 mmol) were reacted together according to general procedure B. Purification by chromatography on silica, eluant DCM:MeOH (20:1) provided a mixture of bromo and chloro phenoxy ether (250 mg) which was used in the next stage. The mixture (250 mg) was refluxed with isopropyl amine (34° C.) (10 ml, 40 vol) for 7 days. The reaction was concentrated in vacuo and partitioned between 2M NaOH (10 ml) and DCM (10 ml). The aqueous phase was extracted with DCM (3×10 mL). The combined DCM layers were dried over MgSO4, filtered, washed with DCM and concentrated in vacuo. Purification by chromatography on silica, eluant DCM:MeOH:NH3 (95:5:0) increasing gradually to DCM:MeOH:NH3 (90:9:1) gave the title compound as a pale yellow solid (180 mg, 17% over the 2 steps). 1H NMR (400 MHz, CDCl3) δ7.20 (d, 2H), 6.88 (d, 2H), 4.03 (t, 2H), 3.75 (dt, 2H), 3.59-3.50 (m, 2H), 2.89-2.76 (m, 3H), 2.40 (s, 2H), 2.15-2.05 (m, 2H), 2.03-1.93 (m, 2H), 1.96 (s, 6H), 1.88 (ddd, 2H), 1.49 (br s, 1H), 1.07 (d, 6H).
Reaction SMILES: [C:1]([C:3]1[C:16]2[S:15](=[O:18])(=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:19])[C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2].[N-:20]=[N+:21]=[N-:22].[Na+].Cl>CS(C)=O>[NH:20]1[C:1]([C:3]2[C:16]3[S:15](=[O:17])(=[O:18])[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[C:8](=[O:19])[C:7]=3[CH:6]=[CH:5][CH:4]=2)=[N:2][N:22]=[N:21]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cccc2c1S(=O)(=O)c1ccccc1C2=O
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C1c2ccccc2S(=O)(=O)c2c1cccc2-c1nnn[nH]1

Procedure:
4-Cyanothioxanthone-10,10-dioxide (1.35g), sodium azide (0.39g) ammonium chloride (0.32g) and dimethylsulphoxide were heated together at 125°- 130° C. for 6.5 hr. The mixture was cooled, poured into dilute hydrochloric acid and the precipitated product filtered off. It was warmed with 1% sodium bicarbonate solution, filtered, and the filtrate acidified with dilute hydrochloric acid. 4-(5-Tetrazolyl)thioxanthone-10,10-dioxide was filtered off and recrystallised from acetic acid, m.p. 271° C. with decomposition. Found: C 53.50%; H 2.70%; N 18.04%. C14H8N4O3S requires C 53.85%; H 2.58%; N 17.95%.