Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl.[N:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([CH2:38][NH:39][C:40]2[CH:44]=[CH:43][S:42][C:41]=2[C:45](O)=[O:46])=[CH:30][CH:29]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[N:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([CH2:38][NH:39][C:40]2[CH:44]=[CH:43][S:42][C:41]=2[C:45]([NH:1][C:2]2[CH:10]=[C:9]3[C:5]([CH2:6][CH2:7][N:8]3[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][CH:3]=2)=[O:46])=[CH:30][CH:29]=1
Reactant: O=C(O)c1sccc1NCc1ccnc2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(N)cc21
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCc2ccc(NC(=O)c3sccc3NCc3ccnc4ccccc34)cc21
Temperature: 25 °C

Procedure:
To a solution of tert-butyl 6-aminoindoline-1-carboxylate (3.2 g, 13.68 mmol) in CH2Cl2 (135 mL) was added iPr2NEt (14 mL), 3-[(quinolin-4-ylmethyl)amino]thiophene-2-carboxylic acid hydrochloride (5.27 g, 16.42 mmol), EDC (3.93 g, 20.5 mmol), DMAP (0.81 g, 6.63 mmol), and HOAt (5.5 mL. 0.5M in DMF). The resulting mixture was then heated to reflux under N2 atmosphere. After 8 h the reaction was cooled to rt and then washed with 50% NaCl solution. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to yield a residue that was purified by silica gel chromatography (80% EtOAc in Hexanes 100% EtOAc) to yield tert-butyl 6-({[3-[(quinolin-4-ylmethyl)amino]thien-2-yl]carbonyl}amino)indoline-1-carboxylate as a yellow solid. MS (ES+): m/z 501 [M+1]. 1H NMR (d6-DMSO, 400 MHz): δ1.48 (s, 9H), 2.99 (t, J=8.4 Hz, 2H), 3.90 (t, J=8.4 Hz, 2H), 5.06 (d, J=6.0 Hz, 2H), 6.78 (brs, 1H), 7.07 (d, J=8.4 Hz, 1H), 7.40 (d, J=4.4 Hz, 1H), 7.56 (d, J=5.6 Hz, 1H), 7.66 (t, J=6.8 Hz, 1H), 7.78 (t, J=6.8 Hz, 1H), 8.04 (m, 2H), 8.21 (d, J=8.0 Hz, 1H), 8.82 (d, J=4.4 Hz, 1H), 9.35 (s, 1H).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][O:6][C:7]([CH3:25])([CH3:24])[CH2:8][N:9](CC1C=CC=CC=1)CC1C=CC=CC=1)C>CCO.[OH-].[OH-].[Pd+2]>[CH3:24][C:7]1([CH3:25])[CH2:8][NH:9][C:4](=[O:3])[CH2:5][O:6]1
Reactant: CCOC(=O)COC(C)(C)CN(Cc1ccccc1)Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)CNC(=O)CO1
Yield: 60 %

Procedure:
(2-Dibenzylamino-1,1-dimethyl-ethoxy)-acetic acid ethyl ester (Example 172, step 1) was hydrogenated in EtOH with Pd(OH)2 for 16 hours at 60° C. The desired 6,6-dimethyl-morpholin-3-one (585 mg, 60% purity, quant.) was obtained as a colorless liquid, MS: m/e=129 (M+H+) and used in the next step without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7](Br)[S:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=1)=[O:4].[CH3:18][CH2:19][OH:20]>>[Cl:16][C:12]1[CH:11]=[C:10]([C:9]2[S:8][C:7]([O:20][CH2:19][CH3:18])=[N:6][C:5]=2[C:3]([OH:2])=[O:4])[CH:15]=[CH:14][CH:13]=1
Reactant: CCO
Reactant: COC(=O)c1nc(Br)sc1-c1cccc(Cl)c1
Product: CCOc1nc(C(=O)O)c(-c2cccc(Cl)c2)s1

Procedure:
prepared by reaction of 2-bromo-5-(3-chloro-phenyl)-thiazole-4-carboxylic acid methyl ester with EtOH. LC-MS: tR=0.98 min; [M+H]+=284.0.
Reaction SMILES: [NH2:1][C:2](=[O:45])[CH2:3][N:4]([CH3:44])[C:5](=[O:43])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N:12]2[C:20]3[C:15](=[C:16]([NH:22][CH2:23][C:24]([OH:42])([C:38]([F:41])([F:40])[F:39])[CH2:25][C:26]([C:29]4[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=4[O:36]C)([CH3:28])[CH3:27])[CH:17]=[C:18]([CH3:21])[CH:19]=3)[CH:14]=[N:13]2)[CH:7]=1.C(=O)=O.CC(C)=O.B(Br)(Br)Br>ClCCl>[NH2:1][C:2](=[O:45])[CH2:3][N:4]([CH3:44])[C:5](=[O:43])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N:12]2[C:20]3[C:15](=[C:16]([NH:22][CH2:23][C:24]([OH:42])([C:38]([F:39])([F:40])[F:41])[CH2:25][C:26]([C:29]4[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=4[OH:36])([CH3:28])[CH3:27])[CH:17]=[C:18]([CH3:21])[CH:19]=3)[CH:14]=[N:13]2)[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1cccc(C(=O)N(C)CC(N)=O)c1)C(F)(F)F
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: Cc1cc(NCC(O)(CC(C)(C)c2cc(F)ccc2O)C(F)(F)F)c2cnn(-c3cccc(C(=O)N(C)CC(N)=O)c3)c2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 31.9 %

Procedure:
N-(2-Amino-2-oxoethyl)-3-(4-{[4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazol-1-yl)-N-methylbenzamide (55.1 mg, 0.0875 mmol) was dissolved in anhydrous dichloromethane (0.2 mL) and cooled to −78° C. (cardice/acetone bath) under nitrogen. Boron tribromide (1.0M in dichloromethane) (0.435 mL, 0.435 mmol) was then added portionwise and after 5 minutes the mixture was allowed to warm to room temperature. The reaction was stirred at room temperature for 6 hours, re-cooled to −78° C. and quenched with methanol (1 mL). The reaction was warmed to room temperature when more dichloromethane (1 mL) and aqueous saturated sodium hydrogen carbonate solution (2 mL) were added and the mixture stirred vigorously and then poured onto a hydrophobic frit and the dichloromethane layer collected and evaporated in vacuo. This crude product was purified by mass-directed autopreparation (System B). Product containing fractions were combined and partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The aqueous layer was re-extracted twice more with dichloromethane and the combined organic extracts were washed successively water and brine, dried through a hydrophobic frit and evaporated in vacuo to give the title compound (17.2 mg).
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Cl:11])=[CH:4][N:3]=1.[O:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[OH:21])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([O:21][C:15]2[C:14]([O:12][CH3:13])=[CH:19][CH:18]=[CH:17][C:16]=2[F:20])=[N:3][CH:4]=1
Reactant: O=[N+]([O-])c1cc(Cl)cnc1Br
Reactant: COc1cccc(F)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(F)c1Oc1ncc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of 2-bromo-5-chloro-3-nitropyridine (2.37 g, 10 mmol) was dissolved in 40 mL DMF was added of 2-methoxyl-6-fluorophenol (1.7 g 11.9 mmol) was added into the solution followed by potassium carbonate (2.76, 20 mmol). The mixture was stirred at room temperature for 5 h, then poured into ice water (200 mL). The precipitate was filtered and dried under high vacuum to provide 5-chloro-2-(2-fluoro-6-methoxy-phenoxy)-3-nitro-pyridine.
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][CH2:7][NH:6][C:5]1=[N:9][C:10]1[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Br:17])[C:2]#[CH:3].Cl.N1CCNC1>C(O)C>[Br:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([F:16])[C:10]=1[N:9]1[C:2](=[CH2:3])[CH2:1][N:4]2[CH2:8][CH2:7][N:6]=[C:5]12
Reactant: C#CCN1CCNC1=Nc1c(F)cccc1Br
Agent: C1CNCN1
Agent: Cl
Solvent: CCO
Product: C=C1CN2CCN=C2N1c1c(F)cccc1Br

Procedure:
A quantity of 8.9 gm of 1-propargyl-2-(2-bromo-6-fluorophenylimino)-imidazolidine was refluxed in 60 ml of absolute ethanol for about 11 hours. Then the solvent was eliminated in vacuo, and the remaining residue was dissolved in dilute (approximately 1N) hydrochloric acid. The imidazolidine derivative used (identified by thin layer chromatography) was then eliminated by fractional extraction with ethyl acetate at increasing pH values (rendered alkaline with 2N NaOH). As soon as the starting imidazolidine has been quantitatively removed, the imidazo[1,2-a]imidazole derivative according to the invention was extracted as the pH values increased still further (carefully rendered alkaline with 2N NaOH in stages). After being checked by thin layer chromatography, the individual extracts were combined and dried over anhydrous calcium sulfate, and the solvent was eliminated in vacuo.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([CH:17]2[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:20](=[O:28])[NH:19][CH2:18]2)=[O:16])[CH2:11][CH2:10]1.[H-].[Na+].[F:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[S:39](Cl)(=[O:41])=[O:40]>>[F:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[S:39]([N:19]1[CH2:18][CH:17]([C:15]([N:12]2[CH2:13][CH2:14][N:9]([C:3]3[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=3[CH3:1])[CH2:10][CH2:11]2)=[O:16])[N:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:20]1=[O:28])(=[O:41])=[O:40]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CNC(=O)N3c3ccccc3)CC2)c1
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4ccc(F)cc4F)C(=O)N3c3ccccc3)CC2)c1

Procedure:
In analogy to example 33, (RS)-5-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-1-phenyl-imidazolidin-2-one (example 33, step 1) was reacted with sodium hydride and 2,4-difluorobenzenesulfonyl chloride to give the title compound as a colorless solid. MS: 555.2 ([M+H]+)
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][C:9]1([CH2:23][CH2:24][OH:25])[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:16][C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2.Cl>N1C=CC=CC=1>[CH3:1][S:2]([O:25][CH2:24][CH2:23][C:9]1([CH2:8][CH2:7][O:6][S:2]([CH3:1])(=[O:4])=[O:3])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=2[O:16][C:17]2[C:22]1=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:4])=[O:3]
Reactant: OCCC1(CCO)c2ccccc2Oc2ccccc21
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCC1(CCOS(C)(=O)=O)c2ccccc2Oc2ccccc21
Temperature: 0 °C
Reaction time: 20 h

Procedure:
A mixture of 9,9-bis(2'-vinyloxyethyl)xanthene (57 g.) (prepared as in Example 2), water (400 ml.) and concentrated hydrochloric acid (15 ml.) is heated on the steambath with vigorous stirring for 5 hours. The cooled mixture is extracted three times with ether and the combined extracts are dried over MgSO4 and evaporated to dryness. The solid residue is recrystallised from chloroform-light petroleum (b.p. 60°-80° C.) to give 9,9-bis(2'-hydroxyethyl)xanthene, m.p. 144°-145° C. Methanesulphonyl chloride (588 mg.) is added dropwise over 5 minutes at 5° C. to a solution of 9,9-bis(2'-hydroxyethyl)xanthene (0.54 g.) in dry pyridine (5 ml.) with stirring. The mixture is allowed to stand at room temperature for 20 hours and is then poured into a mixture of 3 N hydrochloric acid (20 ml.) and ice (10 g.), and the resulting mixture is extracted with ethyl acetate. The ethyl acetate extract is washed with 3 N hydrochloric acid and water, dried over MgSO4, and evaporated to dryness. The solid residue is recrystallised from acetone-light petroleum (b.p. 60°-80° C.) to give 9,9-bis(2'-methanesulphonyloxyethyl)-xanthene, m.p. 121°-122° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[C-]#N.[K+].C[N:13]([CH:15]=[O:16])C>O>[Cl:8][C:4]1[N:3]=[C:2]([C:15]([NH2:13])=[O:16])[CH:7]=[N:6][CH:5]=1
Reactant: Clc1cncc(Cl)n1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [K+]
Solvent: O
Product: NC(=O)c1cncc(Cl)n1
Temperature: 100 °C
Reaction time: 3 h
Yield: 32 %

Procedure:
To a solution of 2,6-dichloropyrazine (50 mg, 0.34 mmol) in DMF (1 mL) was added a solution of potassium cyanide (24 mg, 0.37 mmol) in H2O (1 mL). After stirring for 3 h at 100° C., the reaction mixture was cooled to r.t., poured into H2O (10 mL) and extracted with EtOAc three times. The combined organic layer was dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel, EtOAc:Hexane, 3:7) to give 15 mg of the desired product. Yield: 32%.
Reaction SMILES: [CH3:1][C:2]1[O:10][C@@H:9]2[C@@H:4]([C@@H:5]([O:20][C:21]([CH3:23])=[O:22])[C@H:6]([O:16][C:17]([CH3:19])=[O:18])[C@@H:7]([CH2:11][O:12][C:13]([CH3:15])=[O:14])[O:8]2)[N:3]=1.[CH2:24]([O:31][C:32](=[O:35])[CH2:33][OH:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(Cl)(Cl)Cl.[Fe](Cl)(Cl)Cl>[CH2:24]([O:31][C:32](=[O:35])[CH2:33][O:34][C@@H:9]1[O:8][C@H:7]([CH2:11][O:12][C:13](=[O:14])[CH3:15])[C@@H:6]([O:16][C:17](=[O:18])[CH3:19])[C@H:5]([O:20][C:21](=[O:22])[CH3:23])[C@H:4]1[NH:3][C:2](=[O:10])[CH3:1])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(CO)OCc1ccccc1
Reactant: CC(=O)OC[C@H]1O[C@@H]2OC(C)=N[C@@H]2[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl[Fe](Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(=O)N[C@H]1[C@H](OCC(=O)OCc2ccccc2)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 21 h

Procedure:
A solution of 600 mg (1.82 mmol) of 2-methyl-(3,4,6-tri-O-acetyl-1,2-dideoxy-α-D-glucopyrano)-[2,1-d]-2-oxazoline of the formula ##STR13## [prepared according to V. K. Srivastava, Carbohydrate Research 103, 286 (1982)]and 605 mg (3.64 mmol) of glycolic acid benzyl ester in 6 ml of methylene chloride is added to a solution of 300 mg (1.85 mmol) of iron(III) chloride (anhydrous) in 6 ml of absolute methylene chloride and the whole is stirred for 21 hours at 22°. 8 ml of cold, saturated sodium bicarbonate solution are added and the mixture is diluted with 100 ml of chloroform and filtered until clear. The organic phase of the filtrate yields, after drying over magnesium sulphate and concentration by evaporation, a yellow oil which is purified by digesting an ethyl acetate solution with hexane and by chromatography on silica gel. 2-(2-acetylamino-3,4,6-tri-O-acetyl-2-deoxy-β-D-glucopyranosyloxy)-acetic acid benzyl ester is obtained in the form of a colourless powder.
Reaction SMILES: C(N(CC)CC)C.[C:8]([C@@H:12]1[CH2:17][CH2:16][C@H:15]([NH2:18])[CH2:14][CH2:13]1)([CH3:11])([CH3:10])[CH3:9].[F:19][CH:20]([C:22]1[C:27]([Cl:28])=[C:26](Cl)[N:25]2[N:30]=[CH:31][N:32]=[C:24]2[N:23]=1)[CH3:21]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[C:8]([C@@H:12]1[CH2:13][CH2:14][C@H:15]([NH:18][C:26]2[N:25]3[N:30]=[CH:31][N:32]=[C:24]3[N:23]=[C:22]([CH:20]([F:19])[CH3:21])[C:27]=2[Cl:28])[CH2:16][CH2:17]1)([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(F)c1nc2ncnn2c(Cl)c1Cl
Reactant: CC(C)(C)[C@H]1CC[C@@H](N)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(F)c1nc2ncnn2c(N[C@H]2CC[C@@H](C(C)(C)C)CC2)c1Cl

Procedure:
0.220 g (2.2 mmol) Triethylamine, a spatula tip of tetrabutylammonium iodide and 0.340 g (2.2 mmol) of cis-4-tert-butylcyclohexylamine were added successively to a solution of 0.470 g (2.0 mmol) of 5-(1-fluoroethyl)-6,7-dichloro-[1,2,4]triazolo[1,5-a]pyrimidine in 15 ml of toluene under stirring. The reaction mixture was heated at reflux for 5 hours and then stirred for another 12 hours at room temperature. The solvent was evaporated under reduced pressure and dichloromethane was added to the resulting residue. The resulting reaction mixture was washed with 2N hydrochloric acid and water. The organic phase was separated, dried and the solvent was evaporated under reduced pressure. Treatment of the resulting residue with hexane yielded 0.540 g (1.5 mmol, 76% of theory) of the title compound having a melting point of 138-139° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:13][C:14]1[O:15][CH:16]=[C:17]([C:19](O)=[O:20])[N:18]=1.C(N(CC)CC)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[Li+].[OH-]>C(Cl)Cl.O>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:19]([C:17]3[N:18]=[C:14]([CH3:13])[O:15][CH:16]=3)=[O:20])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: Cc1nc(C(=O)O)co1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)co1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56 %

Procedure:
A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.869 mmol, Example 1, Step H), 2-methyloxazole-4-carboxylic acid (276 mg, 2.17 mmol), triethylamine (606 μL, 4.35 mmol), and BOP-Cl (203 mg, 2.17 mmol) in CH2Cl2 (10 mL) was stirred at room temperature for 4 hours. Next, 2M LiOH. H2O (3 mL) was added, and after 30 minutes water (10 mL) was added. The solid formed was filtered, washed with water (2×5 mL) and dried to provide N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methyloxazole-4-carboxamide (165 mg, 56% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 12.15 (s, 1H), 9.68 (s, 1H), 8.63 (s, 1H), 8.37 (d, 1H), 7.67 (s, 1H), 2.52 (s, 3H); LCMS (APCI+) m/z 338.9, 341.0 (M+H)+, Retention time=3.21 minutes (Method 2).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[NH:9][C:8]2=[O:18])[CH2:3][CH2:2]1.[Cl:19][C:20]1[C:28]2[NH:27][N:26]=[CH:25][C:24]=2[C:23]2[CH2:29][N:30]([CH2:55][C:56]([CH3:59])([CH3:58])[CH3:57])[C:31](=[O:54])[C@H:32]([CH2:34][C:35](=[O:53])N3CCC(N4CC5C(=CC=CC=5)NC4=O)CC3)[CH2:33][C:22]=2[CH:21]=1>>[Cl:19][C:20]1[C:28]2[NH:27][N:26]=[CH:25][C:24]=2[C:23]2[CH2:29][N:30]([CH2:55][C:56]([CH3:59])([CH3:58])[CH3:57])[C:31](=[O:54])[C@H:32]([CH2:34][C:35](=[O:53])[N:1]3[CH2:2][CH2:3][CH:4]([N:7]4[CH:11]=[C:10]([C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=5)[NH:9][C:8]4=[O:18])[CH2:5][CH2:6]3)[CH2:33][C:22]=2[CH:21]=1
Reactant: O=c1[nH]c(-c2ccccn2)cn1C1CCNCC1
Reactant: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Product: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(n3cc(-c4ccccn4)[nH]c3=O)CC2)C1=O
Yield: 37 %

Procedure:
Title compound was prepared from 1-(piperidin-4-yl)-4-(pyridine-2-yl)-1H-imidazol-2(3H)-one in a manner analogous to the preparation of 4-Chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one. Material was obtained as white solid in 37% yield. MS m/e (M+H)+=590.2. 1H NMR (500 MHz, DMSO-D6): δ=13.54 (s, 1H), 10.69 (d, 1H), 8.45 (s, 1H), 8.37 (s, 1H), 7.74 (s, 1H), 7.54 (d, J=8.24, 1H), 7.33 (d, J=4.88, 1H), 7.25 (s, 1H), 7.15 (dd, J1=6.71, J2=5.19, 1H), 5.37 (d, J=117.09, 1H), 4.63 (d, J=15.87, 1H), 4.50 (s, 1H), 4.12 (m, 2H), 3.87 (m, 1H), 3.56 (dd, J1=28.69, J2=13.43, 1H), 3.18 (t, J=13.73, 1H), 3.10 (d, J=14.65, 1H), 3.01 (m, 2H), 2.88 (t, J=15.26, 1H), 2.66 (m, 1H), 2.35 (d, J=14.95, 1H), 1.84 (m, 3H), 1.57 (m, 1H), 0.73 (d, J=16.17, 9H).
Reaction SMILES: [N:1]1[C:6]2[CH:7]=[CH:8][S:9][C:5]=2[C:4]([C:10]([OH:12])=O)=[N:3][CH:2]=1.[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1)([O-:15])=[O:14].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>ClCCl>[N+:13]([C:16]1[CH:17]=[CH:18][C:19]([CH2:20][NH:21][C:10]([C:4]2[C:5]3[S:9][CH:8]=[CH:7][C:6]=3[N:1]=[CH:2][N:3]=2)=[O:12])=[CH:22][CH:23]=1)([O-:15])=[O:14]
Reactant: O=C(O)c1ncnc2ccsc12
Reactant: NCc1ccc([N+](=O)[O-])cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: O=C(NCc1ccc([N+](=O)[O-])cc1)c1ncnc2ccsc12

Procedure:
To a solution of compound 7.2 (1.0 mmol) and 4-nitrobenzyl amine (1.0 mmol) in dichloromethane (5.0 mL) is added TEA (3.0 equivalents) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (“HATU”; 1.1 equivalents). After completion of the reaction, the reaction is partitioned between EtOAc and water. The organic layer is separated, washed with 0.5 N HCl, saturated sodium bicarbonate, brine and dried. Purification by flash column chromatography on silica gel provides thieno[3,2-d]pyrimidine-4-carboxylic acid 4-nitro-benzylamide (compound 7.3).
Reaction SMILES: [C:1]1([N:7]2[C:19]3[CH:18]=[CH:17][C:16]([C:20]4[CH:21]=[CH:22][C:23]5[NH:24][C:25]6[C:30]([C:31]=5[CH:32]=4)=[CH:29][CH:28]=[CH:27][CH:26]=6)=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:33][C:34]1[CH:39]=[CH:38][C:37](I)=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+].S(=O)(O)[O-].[Na+]>[Cu].C1(C)C=CC=CC=1.ClC1C=CC=CC=1Cl>[Br:33][C:34]1[CH:39]=[CH:38][C:37]([N:24]2[C:23]3[CH:22]=[CH:21][C:20]([C:16]4[CH:17]=[CH:18][C:19]5[N:7]([C:1]6[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=6)[C:8]6[C:13]([C:14]=5[CH:15]=4)=[CH:12][CH:11]=[CH:10][CH:9]=6)=[CH:32][C:31]=3[C:30]3[C:25]2=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:36][CH:35]=1
Reactant: c1ccc(-n2c3ccccc3c3cc(-c4ccc5[nH]c6ccccc6c5c4)ccc32)cc1
Reactant: Brc1ccc(I)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: O=S([O-])O
Solvent: Cc1ccccc1
Solvent: Clc1ccccc1Cl
Product: Brc1ccc(-n2c3ccccc3c3cc(-c4ccc5c(c4)c4ccccc4n5-c4ccccc4)ccc32)cc1
Temperature: 170 °C
Reaction time: 19.5 h
Yield: 97.2 %

Procedure:
9-Phenyl-9H,9′H-[3,3′]bicarbazolyl (12.9 g), 4-bromo-iodobenzene (13.4 g), a copper powder (0.64 g), potassium carbonate (8.34 g), sodium bisulfite (0.49 g), and orthodichlorobenzene (50 ml) were added to a nitrogen-substituted reaction vessel, heated, and stirred at 170° C. for 19.5 hours. The mixture was cooled to 90° C., and dissolved after adding toluene (200 ml). After removing the insolubles by filtration, the filtrate was concentrated under reduced pressure, and crystallized from methanol (50 ml) to obtain a white powder of 9-(4-bromophenyl)-9′-phenyl-9H,9′H-[3,3′]bicarbazolyl (17.30 g; yield 97%).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[NH:12][CH:11]=[C:10]([CH:13]=[O:14])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[F:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39](Cl)(=[O:41])=[O:40]>O1CCCC1.[Cl-].[Na+].O>[F:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39]([N:12]1[C:8]([C:7]2[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:9][C:10]([CH:13]=[O:14])=[CH:11]1)(=[O:41])=[O:40]
Reactant: O=Cc1c[nH]c(-c2cccnc2F)c1
Reactant: O=S(=O)(Cl)c1ccccc1F
Agent: C1COCCOCCOCCOCCO1
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cc(-c2cccnc2F)n(S(=O)(=O)c2ccccc2F)c1
Reaction time: 0.17 h
Yield: 81.9 %

Procedure:
To a solution of 5-(2-fluoropyridin-3-yl)-1H-pyrrole-3-carbaldehyde (80 mg) in tetrahydrofuran (8 mL) was added sodium hydride (60% in oil, 34 mg) at room temperature, and the mixture was stirred for 10 min. 15-Crown-5 (186 mg) was added dropwise, and the mixture was stirred for 5 min. 2-Fluorobenzenesulfonyl chloride (123 mg) was added, and the mixture was further stirred for 1 hr. The reaction mixture was diluted with saturated brine, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→1:1) to give the title compound as a colorless oil (yield 120 mg, 82%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29](O)=[O:30].Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:29]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=2)=[O:30])=[CH:20][CH:21]=1
Reactant: O=C(O)c1ccccn1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4ccccn4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 19 h
Yield: 56.1 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (50 mg) and commercially available picolinic acid (42 mg) were dissolved in N,N-dimethylformamide (2 ml), 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (123 mg) was added, and the admixture was stirred at room temperature for 19 hours. The reaction mixture was then purified in the same manner as described in Example 51 to obtain 38 mg of the title compound (yield: 56%).
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]([OH:18])=O)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:19]([OH:21])=[O:20]>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]2[C:16]([O:21][C:19](=[O:20])[C:7]3[C:8]=2[C:3]=1[CH:4]=[CH:5][CH:6]=3)=[O:18]
Reactant: O=C(O)c1cccc2c(Cl)c3ccccc3c(C(=O)O)c12
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)c2c3ccccc3c(Cl)c3cccc1c23
Temperature: 25 °C
Yield: 61.2 %

Procedure:
A suspension of 1.45 g (4.8 mmol) of 10-chloranthracene-1,9-dicarboxylic acid in 50 ml of acetic anhydride was heated under reflux for 4 hours and then cooled to room temperature. The yellow precipitate that formed was collected by filtration, washed with cold methanol and dried to give 0.83 g (61%) of the title compound, m.p. 269°-271° C.