Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([O:13][CH:14]3[CH2:18][CH:17]([C:19]([OH:21])=O)[CH:16]([C:22](=[O:34])[NH:23][C:24]4([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:26][CH:25]4[CH:27]=[CH2:28])[CH2:15]3)[CH:10]=[C:9]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:41][NH:42][CH:43]=[CH:44][CH2:45][CH2:46][CH2:47][CH3:48].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:32]([O:31][C:29]([C:24]1([NH:23][C:22]([CH:16]2[CH2:15][CH:14]([O:13][C:11]3[CH:10]=[C:9]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:8]=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:12]=3)[CH2:18][CH:17]2[C:19](=[O:21])[N:42]([CH2:43][CH2:44][CH2:45][CH2:46][CH:47]=[CH2:48])[CH3:41])=[O:34])[CH2:26][CH:25]1[CH:27]=[CH2:28])=[O:30])[CH3:33]
Reactant: CCCCC=CNC
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc(-c3ccccc3)n2)CC1C(=O)O)C(=O)OCC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: C=CCCCCN(C)C(=O)C1CC(Oc2cc(-c3ccccc3)nc(-c3ccccc3)n2)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Yield: 94.2 %

Procedure:
The acid 17c (1.2 g, 2 mmol) was reacted with N-methylhexeneamine (340 mg, 3.0 mmol) DIEA (1.29 g, 10.0 mmol) and HATU (1.1 g, 3 mmol) in dry DMF (30 ml) according to the procedure described in Example 13 step c. Purification by column chromatography on silica gel gave the title compound (1.2 g, 93%), (M+H)+637.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21](=[O:26])[CH2:20][CH2:19]3)[CH2:12][CH2:11]1)=[O:9].[C:32](Cl)(=[O:34])[CH3:33]>CN(C)C=O>[C:32]([N:22]1[C:23]2[C:18](=[CH:17][C:16]([N:13]3[CH2:12][CH2:11][N:10]([C:8](=[O:9])[C:7]4[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:5]([O:4][CH3:3])[CH:6]=4)[CH2:15][CH2:14]3)=[CH:25][CH:24]=2)[CH2:19][CH2:20][C:21]1=[O:26])(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: COc1ccc(C(=O)N2CCN(c3ccc4c(c3)CCC(=O)N4)CC2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N2CCN(c3ccc4c(c3)CCC(=O)N4C(C)=O)CC2)cc1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% in oil, 263 mg) was suspended in dimethylformamide (DMF) (30 ml). To the suspension was added 6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril (2 g) and the mixture was stirred at 70° to 80° C. for 30 minutes. After cooling, to the mixture was added slowly acetyl chloride (0.43 m/g) with stirring and under ice-cooling, and the mixture was stirred at the same temperature for 5 minutes. After completion of reaction, the reaction mixture was poured into ice-water and extracted with chloroform. The chloroform layer was washed successively with water and saturated saline solution and dried over magnesium sulfate. The chloroform extract was evaporated under reduced pressure. The resultant residue was purified by silica-gel column chromatography (eluent:dichloromethane:methanol=100:1) and recrystallized from a mixture of dichloromethane and diethyl ether to give 1-acetyl-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril (700 mg).
Reaction SMILES: [CH2:1]1[CH:8]2[N:4]([C:5](=[O:9])[CH2:6][CH2:7]2)[C:3](=[O:10])[CH2:2]1.Cl.[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][OH:18])=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][O:18][C:5](=[O:9])[CH2:6][CH2:7][CH:8]2[CH2:1][CH2:2][C:3](=[O:10])[NH:4]2)=[CH:15][CH:14]=1
Reactant: O=C1CCC2CCC(=O)N12
Reactant: OCc1ccc(Cl)cc1
Agent: Cl
Product: O=C1CCC(CCC(=O)OCc2ccc(Cl)cc2)N1
Temperature: 100 °C

Procedure:
Five grams of dihydro-1H-pyrrolizine-3,5(2H,6H) -dione (III) are dissolved in 31 g of p-chlorobenzyl alcohol and 0.2 ml of concentrated hydrochloric acid is added. The solution is heated at 100° C. for 65 hours. The mixture is cooled and chromatographed over silica gel in dichloromethane. The starting p-chlorobenzyl alcohol is eluted with dichloromethane and the product is eluted with 2.5% methanol in dichloromethane. The eluate containing the product is concentrated at reduce pressure and the residual oil solidifies upon standing. The solid is recrystallized from toluene diethyl ether to yield 5-oxo-2-pyrrolidinepropanoic acid p-chlorobenzyl ester with a melting point of 63°-64° C.
Reaction SMILES: [Cs+].[Cl:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:4]=1[C:5]([O-:7])=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:20][N:21]1[C:25](=[O:26])[CH:24]([CH2:27][CH2:28][CH3:29])[N:23]([CH2:30][CH3:31])[S:22]1(=[O:33])=[O:32]>CO.CN(C=O)C>[Cl:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:4]=1[C:5]([O:7][CH2:20][N:21]1[C:25](=[O:26])[CH:24]([CH2:27][CH2:28][CH3:29])[N:23]([CH2:30][CH3:31])[S:22]1(=[O:32])=[O:33])=[O:6]
Reactant: CCCC1C(=O)N(CCl)S(=O)(=O)N1CC
Reactant: O=C([O-])c1c(Cl)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCCC1C(=O)N(COC(=O)c2c(Cl)cccc2Cl)S(=O)(=O)N1CC
Temperature: 0 °C
Yield: 80 %

Procedure:
A mixture of 2,6-dichlorobenzoic acid cesium salt (prepared from 0.42 g of the acid and cesium carbonate (0.36 g) in methanol followed by removal of methanol and drying in vacuo) and 2-chloromethyl-4-propyl-5-ethyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (0.5 g) in DMF was allowed to react at 90°-100° C. for 2 hours, and then cooled. The mixture was diluted with ice/water, extracted with ether/ethyl acetate, and the organic layer was washed with water, brine, and dried. The organic solution was concentrated in vacuo and the residue was purified by flash chromatography to afford 0.64 g (80%) of 2-(2,6-dichloro-phenylcarbonyloxymethyl)-4-propyl-5-ethyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula I: Ar=2,6-Cl2 -phenyl; R1 =H; R2 =propyl; R3 =ethyl) as an oil.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]2[CH:12]=[C:11]([C:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=O)[CH:10]=[CH:9][N:8]2[C:20]=1[CH2:21][CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1>COCCOC>[C:1]([C:5]1[N:6]=[C:7]2[CH:12]=[C:11]([C:13](=[S:37])[N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:10]=[CH:9][N:8]2[C:20]=1[CH2:21][CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)C(=O)c1ccn2c(CC3CCOCC3)c(C(C)(C)C)nc2c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: COCCOC
Product: CCN(CC)C(=S)c1ccn2c(CC3CCOCC3)c(C(C)(C)C)nc2c1
Reaction time: 1 h
Yield: 62.5 %

Procedure:
Compound 2 (60.0 mg, 0.160 mmol) obtained in Example 2 was dissolved in DME (1.0 mL). To this was added Lawesson's reagent (71.0 mg, 0.170 mmol), and then the mixture was stirred under ref lux for 1 hour. The solvent was evaporated off in vacuo and the residue was purified by column chromatography (hexane/ethyl acetate=50/50). The resulting crude crystals were reslurried with hexane to give the title compound (40.0 mg, 0.100 mmol, yield 65%).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([OH:19])[CH2:16][CH:15]2[C:20](=[O:29])[N:21]([CH2:23][CH2:24][CH2:25][CH2:26][CH:27]=[CH2:28])[CH3:22])=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])C.[Li+].[OH-].Cl>CN(C=O)C>[CH2:23]([N:21]([CH3:22])[C:20]([CH:15]1[CH2:16][CH:17]([OH:19])[CH2:18][CH:14]1[C:12]([NH:11][C:6]1([C:4]([OH:5])=[O:3])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:13])=[O:29])[CH2:24][CH2:25][CH2:26][CH:27]=[CH2:28]
Reactant: C=CCCCCN(C)C(=O)C1CC(O)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: C=CCCCCN(C)C(=O)C1CC(O)CC1C(=O)NC1(C(=O)O)CC1C=C
Temperature: 40 °C
Yield: 89.5 %

Procedure:
Compound 1c (493 mg, 1.21 mmol) was dissolved in DMF (1 ml) and transferred to a 20 ml microwave reaction vessel. Then, aqueous LiOH (2 M, 10.5 ml) and a stirbar were added. The reaction vessel was sealed and the immiscible slurry was shaken vigorously before insertion in the microwave cavity. The reaction was irradiated for 30 min to 130° C. The reaction mixture was cooled to 40° C. and the clear solution acidified to pH 2 with aqueous HCl (1 M, 24 ml) and extracted 3 times with EtOAc (20 ml). The pooled organic layers were washed with brine, dried (MgSO4) and filtered. The solvent was evaporated in vacuo to afford the title compound (410 mg, 90%). LC/MS >95%, m/z (ESI+)=379(MH+).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5]Br.[H-].[Na+].[CH:9]1[C:21]2[NH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1>CN(C=O)C>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][N:20]1[C:21]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=2[C:14]2[C:19]1=[CH:18][CH:17]=[CH:16][CH:15]=2
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: BrCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: BrCCCCn1c2ccccc2c2ccccc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 61.8 %

Procedure:
1,4-Dibromobutane (640.2 g, 30 mol) and sodium hydride (30.1 g, 0.60 mol, 55%) were mixed in 500 mL of DMF under an argon atmosphere. Carbazole (100.0 g, 0.60 mol) was slowly added and the reaction mixture was stirred for 6 hours at room temperature. DMF was removed by vacuum distillation. Then, 9-(4-bromobutyl)-9H-carbazole was purified in a fresh column. The resulting product was purified by silica gel column chromatography (eluent: ethyl acetate:hexane=1:50 v/v) to yield 112 g (62%) of 9-(4-bromobutyl)-9H-carbazole (Compound 8).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:16]=[CH:15][C:14]2[C:13](=[O:17])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:18])[C:5]=2[CH:4]=1.[N-:19]=[N+:20]=[N-:21].[Na+].O>CN(C)C=O>[N:19]([CH2:2][C:3]1[CH:16]=[CH:15][C:14]2[C:13](=[O:17])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:18])[C:5]=2[CH:4]=1)=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1c2ccccc2C(=O)c2cc(CCl)ccc21
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1ccc2c(c1)C(=O)c1ccccc1C2=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
10 g (0.039 mole) of 2-chloromethylanthraquinone [prepared according to G. Izoret, Ann. Chim., 7, 180 (1962)] are dissolved in 50 ml of N,N-dimethylformamide (DMF), and 2.53 g (0.039 mole) of sodium azide are added, with stirring. After 1 hour, the temperature is increased to 50° C. and the mixture is stirred at this temperature for 10 hours. 250 ml of water are added and the precipitate is filtered off. 9.5 g (92.3% of theory) of 2-azidomethyl-anthraquinone are obtained; melting point: 130° C. (decomposition).
Reaction SMILES: [I-].[Na+].[CH:3]([NH:5][C:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:7][C:8](=C)[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:4].O>C(COC)OC.[Zn]>[CH:3]([NH:5][C:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:7]=[CH:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:4]
Reactant: C=C(CCC(=O)OCC)CC(NC=O)(C(=O)OCC)C(=O)OCC
Agent: [I-]
Agent: [Na+]
Agent: [Zn]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)CCC=CC(NC=O)(C(=O)OCC)C(=O)OCC
Reaction time: 2 h
Yield: 69.5 %

Procedure:
4.2 g of sodium iodide and 3.7 g of zinc were added to a solution of 2.4 g of the product A of Step C of Example 1 and the reaction medium in dimethoxyethane was refluxed in the presence of water with stirring for 2 hours. 50 ml of water were added and after filtration, extraction was carried out with methylene chloride. The extracts were dried and evaporated to dryness under reduced pressure to obtain 2.3 g of crude product which was chromatographed on silica. Elution with a cyclohexane ethyl acetate mixture (5-5) yielded 1.6 g of the expected product.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.[CH3:19][CH2:20][O:21][C:22]([CH2:24][CH:25]1[C:30](=O)[CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:23]>>[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[C:26]3[CH:25]([CH2:24][C:22]([O:21][CH2:20][CH3:19])=[O:23])[CH2:30][CH2:29][CH2:28][C:27]=3[C:15]3[C:10]2=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=3)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CC1CCCCC1=O
Reactant: NN(Cc1ccc(Cl)cc1)c1ccc(F)cc1
Agent: Cl
Product: CCOC(=O)CC1CCCc2c1n(Cc1ccc(Cl)cc1)c1ccc(F)cc21
Yield: 57.8 %

Procedure:
To 3.50 g of 1-(4-chlorobenzyl)-1-(4-fluorophenyl)hydrazine hydrochloride in 70 cc of iso-propan. (was added 2.23 g of ethyl 2-cyclohexanone acetate. The reaction was refluxed under nitrogen for 16 hours. The resulting reaction mixture was then evaporated to dryness and the residue suspended in ether. The solid material was then filtered. The ether filtrate was washed with water, dried and evaporated. The resulting syrup was chromatographed on silica gel to give 2.8 g (42%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[NH:4][CH:5]([C:9]([N:11]1[CH:15]([C:16]2[NH:17][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=3)[N:20]=2)[CH2:14][N:13]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:35][O:36][C:37](=[O:70])[NH:38][CH:39]([C:43]([N:45]1[CH2:49][CH2:48][CH2:47][CH:46]1[C:50]1[NH:51][CH:52]=[C:53]([C:55]2[CH:60]=[CH:59][C:58](B3OC(C)(C)C(C)(C)O3)=[CH:57][CH:56]=2)[N:54]=1)=[O:44])[CH:40]([CH3:42])[CH3:41].C(=O)([O-])[O-].[K+].[K+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:1][O:2][C:3](=[O:34])[NH:4][CH:5]([C:9]([N:11]1[CH:15]([C:16]2[NH:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:58]4[CH:59]=[CH:60][C:55]([C:53]5[NH:54][C:50]([CH:46]6[CH2:47][CH2:48][CH2:49][N:45]6[C:43](=[O:44])[CH:39]([NH:38][C:37]([O:36][CH3:35])=[O:70])[CH:40]([CH3:42])[CH3:41])=[N:51][CH:52]=5)=[CH:56][CH:57]=4)=[CH:23][CH:22]=3)=[CH:18][N:17]=2)[CH2:14][N:13]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CN(c2ccccc2)CC1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)N1CCCC1c1nc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c[nH]1)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CN(c6ccccc6)CN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)[nH]1)C(C)C
Temperature: 120 °C
Yield: 8.7 %

Procedure:
{1-[4-(4-Bromo-phenyl)-1′-phenyl-1′,2′,4′,5′-tetrahydro-1H-[2,4′]biimidazolyl-3′-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (40 mg, 0.076 mmol) was combined with [2-Methyl-1-(2-{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (37.6 mg, 0.076 mmol) under an argon atmosphere. Potassium carbonate (20.9 mg, 0.152 mmol) and Pd(PPh3)4 (8.7 mg, 0.0076 mmol) were added, followed by DME (1.8 mL) and water (0.3 mL). The mixture was heated under microwave conditions for 20 minutes at 120° C. All volatiles were removed in vacuo and the crude material was dissolved in DMF and purified via RP-HPLC (eluent: water/MeCN w 0.1% TFA) to yield the product {1-[5-(4′-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1′-phenyl-1′,2′,4′,5′-tetrahydro-1H-[2,4]biimidazolyl-3′-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (5.4 mg): LCMS-ESI+: calc'd for C45H53N9O6: 815.9 (M+). Found: 816.5 (M+H+); 1H-NMR: 300 MHz, (MeOH-d4) δ: 7.89-7.86 (m, 10H), 7.35 (m, 2H), 7.18 (m, 1H), 6.94 (m, 2H), 5.67 (m, 1H), 5.37 (m, 1H), 5.25 (m, 1H), 5.12 (m, 1H), 4.31-4.08 (m, 3H), 4.01-3.79 (m, 3H), 3.67 (s, 3H), 3.66 (s, 3H), 2.58 (m, 1H), 2.29-1.99 (m, 5H), 0.99-0.89 (m, 12H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:10]2[S:11][C:12]([C:14]([O:16]C(C)(C)C)=[O:15])=[CH:13][C:9]=2[C:8]([NH:21][C:22](=[O:32])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N+:29]([O-:31])=[O:30])=[N:7]1)=[O:5])[CH3:2]>OC(C(F)(F)F)=O.ClCCl>[CH2:1]([O:3][C:4]([N:6]1[C:10]2[S:11][C:12]([C:14]([OH:16])=[O:15])=[CH:13][C:9]=2[C:8]([NH:21][C:22](=[O:32])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N+:29]([O-:31])=[O:30])=[N:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)n1nc(NC(=O)c2ccccc2[N+](=O)[O-])c2cc(C(=O)OC(C)(C)C)sc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)n1nc(NC(=O)c2ccccc2[N+](=O)[O-])c2cc(C(=O)O)sc21
Reaction time: 1 h
Yield: 85.8 %

Procedure:
To a solution of 5.380 g of 3-(2-Nitro-benzoylamino)-thieno[2,3-c]pyrazole-1,5-dicarboxylic acid 5-tert-butyl ester 1-ethyl ester in 25 mL of dichloromethane TFA (25 mL) is slowly added at room temperature. After stirring for 1 hour the reaction mixture is dried up. The colourless solid is taken up with ethyl ether and filtered affording 4.052 g (86%) of the titled compound.
Reaction SMILES: [CH3:1][S:2]Cl.[NH2:4][C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([CH2:13][CH2:14][CH2:15][CH3:16])=[C:10]([C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][N:29]([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:30][CH2:31][CH2:32][CH3:33])=[CH:21][CH:20]=3)=[O:18])[C:9]=2[CH:38]=1.C[O-].[Na+].O>CO>[CH2:13]([C:11]1[O:12][C:8]2[CH:7]=[CH:6][C:5]([NH:4][S:2][CH3:1])=[CH:38][C:9]=2[C:10]=1[C:17]([C:19]1[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH2:27][CH2:28][N:29]([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:34][CH2:35][CH2:36][CH3:37])=[CH:23][CH:24]=1)=[O:18])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1oc2ccc(N)cc2c1C(=O)c1ccc(OCCCN(CCCC)CCCC)cc1
Reactant: CSCl
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCc1oc2ccc(NSC)cc2c1C(=O)c1ccc(OCCCN(CCCC)CCCC)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.1 %

Procedure:
1.98 g of methanesulfenyl chloride (II) (0.024 mol, 1.2 eq; freshly prepared as described in the above mentioned literature), 9.57 g of (5-amino-2-butyl-benzofuran-3-yl)-[4-(3-dibutylamino-propoxy)-phenyl]-methanone (III) (0.02 mol, 1 eq) and 10 mL of 1.5 M sodium methylate methanolic solution were added into a flask and the mixture was diluted with 50 mL of methanol. The reaction mixture was stirred for 3 hours at room temperature. After the reaction was complete (followed by HPLC) the mixture was poured into 150 mL of water. The product was extracted with 2×60 mL of dichloromethane. The organic phase was washed with 50 mL of aq. NaHCO3 solution and then with 50 mL of water. The solvent was evaporated and the product was purified by column chromatography (column: spheric silica (60 Å); eluent: toluene:MTBE:methanol=50:40:10) to obtain 9.14 g of compound (IV) (87%) as a light yellow oil.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]3[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=3)[C:14]([NH:16][CH3:17])=[O:15])=[CH:10][C:5]2=[N:4][CH:3]=1.[N:21]1([C:26]2[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=2)[CH:25]=[CH:24][CH:23]=[N:22]1.O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH3:17][NH:16][C:14](=[O:15])[C:13]1[CH:18]=[CH:19][CH:20]=[C:11]([C:9]2[CH:8]=[CH:7][N:6]3[C:2]([C:30]4[CH:29]=[CH:28][CH:27]=[C:26]([N:21]5[CH:25]=[CH:24][CH:23]=[N:22]5)[CH:31]=4)=[CH:3][N:4]=[C:5]3[CH:10]=2)[CH:12]=1
Reactant: CNC(=O)c1cccc(-c2ccn3c(Br)cnc3c2)c1
Reactant: OB(O)c1cccc(-n2cccn2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CNC(=O)c1cccc(-c2ccn3c(-c4cccc(-n5cccn5)c4)cnc3c2)c1

Procedure:
3-(3-Bromo-imidazo[1,2-a]pyridine-7-yl)-N-methyl-benzamide (Intermediate EA) (1 eq, 0.303 mmol, 100 mg) and 3-(1H-pyrazolyl)-phenylboronic acid (1.3 eq, 0.394 mmol, 74 mg) are dissolved in DME (3 ml) and water (0.8 ml) and Na2CO3 (3 eq, 0.909 mmol, 96.3 mg) is added. PdCl2(PPh3)2 (0.05 eq, 0.015 mmol, 10.6 mg) is added and the reaction mixture is heated using microwave radiation at 120° C. for 10 min. At the completion of this time the solvent is removed in vacuo and the reaction mixture is purified by flash column chromatography eluting with 9:1 DCM/MeOH to yield N-methyl-3-[3-(3-pyrazol-1-yl-phenyl)-imidazo[1,2-a]pyridin-7-yl]-benzamide as a light brown solid; [M+H]+=395
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:16])[CH2:14][OH:15].N1C=CN=C1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].C([O-])(O)=O.[Na+]>CN(C=O)C>[Si:22]([O:15][CH2:14][C:13]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[Cl:1])=[N:10][C:9]([Cl:12])=[CH:8][CH:7]=2)=[O:16])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: O=C(CO)c1cnc2ccc(Cl)nc2c1Cl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC(=O)c1cnc2ccc(Cl)nc2c1Cl
Reaction time: 3 h
Yield: 46.9 %

Procedure:
To a solution of 1-(4,6-dichloro-1,5-naphthyridin-3-yl)-2-hydroxyethanone (128 mg, 0.5 mmol) in DMF (5 mL) was added imidazole (68 mg, 1.0 mmol) and tert-butyldimethylsilyl chloride (90 mg, 0.6 mmol) at 0° C. The mixture was stirred for 3 h, poured into NaHCO3 (saturated), and extracted with ethyl acetate. The organic layer was dried over Na2SO4, concentrated, and purified by chromatography to afford product (87 mg, 47%) as a light yellow oil: ESI MS m/z 371 [M+H]+.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.[OH-].[Na+]>>[CH2:1]([O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=2)=[CH:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: CCCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
n-Octyl bromide (0.102 mol) is added to a solution of 4-(4-hydroxyphenyl)benzoic acid (0.102 mol) and 2.5N sodium hydroxide (0.102 mol) and the mixture stirred at 70° C. for a period of 18 hours. The reaction mixture is allowed to cool and then acidified to pH 3 and partitioned between ethyl acetate and water. The organic phase is washed with water and brine and the solvent then removed to obtain the 4′-n-octyloxy[1,1′-biphenyl]-4-ylcarboxylic acid, C21H23O3, M.W. 326.4.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=O)[CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=4)[N:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[OH-].[Na+]>O1CCCC1>[CH3:30][O:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][C:25]=1[O:31][CH3:32])[N:22]=[CH:21][CH:20]=[C:19]2[O:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH2:9][NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)=[CH:13][CH:14]=1
Reactant: COc1cc2nccc(Oc3ccc(OCC(=O)Nc4cccc(C)c4)cc3)c2cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(OCCNc4cccc(C)c4)cc3)c2cc1OC
Yield: 45.7 %

Procedure:
N1-(3-Methylphenyl)-2-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenoxy}acetamide (70 mg) was dissolved in tetrahydrofuran (10 ml) to prepare a solution. A borane-tetrahydrofuran complex (1.0 M solution: 0.78 ml) was then added to the solution, and the mixture was heated under reflux overnight. 1 N Hydrochloric acid was added thereto, and the mixture was further heated under reflux for 30 min. A 5% aqueous sodium hydroxide solution was added to the reaction solution, the mixture was extracted with chloroform, and the extract was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography using chloroform/methanol for development to give the title compound (31 mg, yield 46%).