Azzindani/Open_Reaction_Data huggingface dataset:
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:38]=[CH:37][C:24]([C:25]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35]Br)=[CH:29][CH:28]=2)=[O:26])=[C:23]([OH:39])[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:38]=[CH:37][C:24]([C:25]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][O:1][C:2]4[CH:3]=[CH:4][C:5]([C:8]5[S:9][C:10]6[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=6[N:12]=5)=[CH:6][CH:7]=4)=[CH:29][CH:28]=3)=[O:26])=[C:23]([OH:39])[CH:22]=2)=[CH:7][CH:6]=1
Reactant: O=C(c1ccc(OCCBr)cc1)c1ccc(OCCBr)cc1O
Reactant: Oc1ccc(-c2nc3ccccc3s2)cc1
Product: O=C(c1ccc(OCCOc2ccc(-c3nc4ccccc4s3)cc2)cc1)c1ccc(OCCOc2ccc(-c3nc4ccccc4s3)cc2)cc1O

Procedure:
A hot solution of 16 g. of zinc o-aminophenylmercaptide and 125 g. of 4-hydroxybenzaldehyde in 1 liter of acetic acid was treated with hydrogen sulfide for 2 hours, filtered hot, diluted with an equal volume of water and cooled. 2-(4-Hydroxyphenyl)benzothiazole (47% yield, m.p. 227°-229°) was obtained. The 2-(4-hydroxyphenyl)benzothiazole was reacted with 4,4'-bis(2-bromoethoxy)-2-hydroxybenzophenone as in Example 1 to produce Compound V.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:5]=[N:6][C:7]=1[Cl:8].[NH2:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[NH2:23][C:24]1[CH:29]=[C:28]([C:2]2[CH:3]=[C:4]([O:9][CH2:10][C@H:11]3[CH2:15][CH2:14][CH2:13][N:12]3[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:5]=[N:6][C:7]=2[Cl:8])[CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cnc(Cl)c(Br)c1
Reactant: Nc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cnc(Cl)c(-c2cccc(N)c2)c1
Yield: 29.8 %

Procedure:
To a solution of 5-bromo-6-chloro-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridine from Example 69a (520 mg, 1.33 mmol) and 3-aminophenylboronic acid (310 mg, 2.0 mmol) in toluene (8mL) was added Pd(0) (50 mg) and Na2CO3 (2.5 mL of a 2M solution), and the mixture was heated at reflux for 16 hours. The solvent was removed under vacuum, and the residue was purified by chromatography on a silica gel column, eluting with chloroform:ether 100:5-100:4 to afford 160 mg of the title compound. MS (DCI/NH3) m/z 404 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ1.44 (s, 9H), 1.88 (m, 1H), 2.03 (m, 2H), 3.37 (m, 2H), 3.76 (m, 2H), 4.16 (m, 2H), 6.75 (m, 2H), 6.82 (m, 1H), 7.22 (m, 2H), 8.08 (m, 1H).
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][C:9]2[CH:10]=[C:11]([S:15]([NH2:18])(=[O:17])=[O:16])[O:12][C:13]=2[CH3:14])=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[CH3:34][O:35][CH2:36][CH2:37][C:38](O)=[O:39].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[CH3:34][O:35][CH2:36][CH2:37][C:38]([NH:18][S:15]([C:11]1[O:12][C:13]([CH3:14])=[C:9]([CH2:8][O:7][C:4]2[CH:3]=[CH:2][C:1]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:6][CH:5]=2)[CH:10]=1)(=[O:17])=[O:16])=[O:39]
Reactant: COCCC(=O)O
Reactant: Cc1oc(S(N)(=O)=O)cc1COc1ccc(-c2ccccc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCC(=O)NS(=O)(=O)c1cc(COc2ccc(-c3ccccc3)cc2)c(C)o1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 4-(biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulphonic acid amide (45) (50 mg, 0.146 mmoles) in N,N-dimethylformamide (4.0 ml) was added diisopropylethylamine (85 μl, 0.480 mmoles) then a solution of 3-methoxypropionic acid (14 μl, 0.146 mmoles) in N,N-dimethylformamide (1.0 ml). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (61 mg, 0.160 mmoles) in N,N-dimethylformamide (1.0 ml) was added and the solution stirred at room temperature for 16 hours. The reaction mixture was concentrated in-vacuo, and the residue was purified by HPLC to give compound 65 as as a white solid (42 mg). LC/MS System A: Rt=3.80 mins, m/z (ES−)=428 ((M−H) for C22H23NO6S).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][CH2:29][CH2:30][NH2:31]>CS(C)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:31][CH2:30][CH2:29][NH:28][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:16][CH2:17]1
Reactant: NCCNc1ccccn1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: CS(C)=O
Product: Nc1c(F)c(NCCNc2ccccn2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 75.4 %

Procedure:
A solution of 7 (270 mg, 0.91 mmol) and N-2-pyridinyl-1,2-ethanediamine (250 mg, 1.82 mmol) in DMSO (7 mL) was stirred at 80° C. for 1 h. The reaction mixture was cooled and freeze-dried overnight. The crude product was taken up in methanol (75 mL) and the resulting precipitate was removed by filtration, washed with cold methanol and dried to yield 8 (285 mg, 75%) as a yellow solid.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:7][CH:6]([CH2:8][OH:9])[CH2:5][CH:4]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH3:2].[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[CH2:1]([CH:3]1[CH2:7][CH:6]([CH2:8][O:9][S:18]([CH3:17])(=[O:20])=[O:19])[CH2:5][CH:4]1[C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCC1CC(CO)CC1C(=O)OC(C)(C)C
Solvent: ClCCl
Product: CCC1CC(COS(C)(=O)=O)CC1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
To a solution of tert-butyl 2-ethyl-4-(hydroxymethyl)cyclopentanecarboxylate (0.220 g, 0.964 mmol) in DCM (5 mL) was added TEA (0.16 mL, 1.15 mmol) and methanesulfonyl chloride (0.083 mL, 1.06 mmol) at about 0° C. The reaction mixture was allowed to warm to about 25° C. and stirred at about 25° C. for about 16 h. The reaction mixture was partitioned between water (20 mL) and DCM (20 mL). The aqueous solution was washed with DCM (2×20 mL). The combined organic extracts were dried over anhydrous MgSO4, filtered, and concd under reduced pressure to give tert-butyl 2-ethyl-4-((methylsulfonyloxy)methyl)cyclopentanecarboxylate (0.295 g, 100%): LC/MS (Table 1, Method b) Rt=2.55 min; MS m/z: 307 (M+H)+.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([OH:13])=O)[C:5]=2[O:4][CH2:3][CH2:2]1.[NH2:14][CH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1.O>O1CCCC1>[N:19]1[CH:20]=[CH:21][C:16]([CH2:15][NH:14][C:11]([C:10]2[C:5]3[O:4][CH2:3][CH2:2][O:1][C:6]=3[CH:7]=[CH:8][CH:9]=2)=[O:13])=[CH:17][CH:18]=1
Reactant: NCc1ccncc1
Reactant: O=C(O)c1cccc2c1OCCO2
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCc1ccncc1)c1cccc2c1OCCO2
Temperature: 60 °C
Yield: 72.1 %

Procedure:
N,N′-Carbonyidiimidazole (1.62 g, 10 mmol) was added to a stirred solution of 2,3-dihydrobenzo[1,4]dioxine-5-carboxylic acid(1.64 g, 10 mmol) in tetrahydrofuran (25 mL) and the resulting solution was heated at 60° C. for 15 minutes. The solution was cooled to room temperature and -4-(aminomethyl)pyridine (1.08 g, 10 mmol) was added. The reaction mixture was heated at 60° C. for 2 hours, cooled, poured into water, and extracted 3 times with ethyl acetate. The combined ethyl acetate extract was dried (Na2SO4) and evaporated in vacuo to a crystalline residue which was triturated with water, filtered, and dried in vacuo to give 2,3-dihydrobenzo[1,4]dioxine-5-carboxylic acid (pyridin-4-ylmethyl)amide as a white solid (1.95 g, 72%); m.p. 120-121° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13]I)[N:12]=2)=[CH:4][CH:3]=1.[N-:15]=[N+:16]=[N-:17].[Na+]>CN(C=O)C.CCOC(C)=O>[N:15]([CH2:13][C:11]1[N:12]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[O:9][CH:10]=1)=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: Fc1ccc(-c2nc(CI)co2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NCc1coc(-c2ccc(F)cc2)n1
Temperature: 70 °C
Yield: 84.5 %

Procedure:
A solution of 2-(4-fluorophenyl)-4-(iodomethyl)oxazole (1.2 g, 3.96 mmol) in dry DMF (10 mL) was added sodium azide (515 mg, 7.9 mmol) and the reaction mixture was heated to 70° C. for 8 h. The reaction mixture was allowed to cool down to room temperature and diluted with EtOAc. The mixture was extracted with EtOAc and the combined extracts were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford 4-(azidomethyl)-2-(4-fluorophenyl)oxazole (0.73 g, yield 85%) as a pale orange liquid, which was carried through without further purification. 1H NMR (400 MHz, CDCl3) δ 8.04-8.01 (m, 2H), 7.67 (s, 1H), 7.16-7.12 (m, 2H), 4.34 (s, 2H). MS (ESI) m/z: Calculated for C10H7FN4O: 218.06. found: 219.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:48]=[CH:47][C:5]([CH2:6][N:7]2[C:16](=[O:17])[C:15]([C:18]3[NH:23][C:22]4[S:24][CH:25]=[C:26]([CH2:27][NH:28][S:29]([NH:32]C(=O)OCC5C=CC=CC=5)(=[O:31])=[O:30])[C:21]=4[S:20](=[O:44])(=[O:43])[N:19]=3)=[C:14]([OH:45])[C@H:13]3[C@@H:8]2[C@H:9]2[CH2:46][C@@H:12]3[CH2:11][CH2:10]2)=[CH:4][CH:3]=1>CO.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:16](=[O:17])[C:15]([C:18]3[NH:23][C:22]4[S:24][CH:25]=[C:26]([CH2:27][NH:28][S:29]([NH2:32])(=[O:31])=[O:30])[C:21]=4[S:20](=[O:43])(=[O:44])[N:19]=3)=[C:14]([OH:45])[C@H:13]3[C@@H:8]2[C@H:9]2[CH2:46][C@@H:12]3[CH2:11][CH2:10]2)=[CH:47][CH:48]=1
Reactant: O=C(NS(=O)(=O)NCc1csc2c1S(=O)(=O)N=C(C1=C(O)[C@@H]3[C@H]4CC[C@H](C4)[C@@H]3N(Cc3ccc(F)cc3)C1=O)N2)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NS(=O)(=O)NCc1csc2c1S(=O)(=O)N=C(C1=C(O)[C@@H]3[C@H]4CC[C@H](C4)[C@@H]3N(Cc3ccc(F)cc3)C1=O)N2
Reaction time: 8 h
Yield: 88.2 %

Procedure:
To a solution of benzyl (N-{3-[(1R,2S,7R,8S)-3-(4-fluoro-benzyl)-6-hydroxy-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-7-ylmethyl}amino)sulfonylcarbamate (120 mg, 0.17 mmol) in methanol (20 mL) was added 10% palladium on carbon (60 mg). The mixture was degassed and stirred under an atmosphere of hydrogen gas (balloon) overnight. The resulting mixture was filtered through a pad of Celite. The organic was concentrated in vacuo. The residue was purified via flash column chromatography (Teledyne Isco RediSep column; 0-3% methanol in dichloromethane) to afford the desired product, N-{3-[(1R,2S,7R,8S)-3-(4-fluoro-benzyl)-6-hydroxy-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-7-ylmethyl}-sulfamide (89 mg, 0.15 mmol, 88%), as a white solid. 1H NMR (400 MHz, CDCl3) δ: 1.19-1.79 (6H, m), 2.57-2.58 (1H, m), 2.83-2.88 (2H, m), 3.49 (1H, d, J=9.6 Hz), 4.22 (1H, d, J=15.6 Hz), 4.48 (2H, d, J=6.4 Hz), 4.55 (2H, bs), 5.16 (1H, d, J=14.8 Hz), 5.29-5.32 (1H, m), 7.03-7.07 (3H, m), 7.19-7.22 (2H, m). LC-MS (ESI) calculated for C23H24FN5O6S3 581.66. found 582.2 [M+H+].
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([NH2:17])[CH3:16])=[CH:11][CH:10]=1.[CH3:18][C:19]1[C:24]([Cl:25])=[C:23](Cl)[N:22]2[N:27]=[CH:28][N:29]=[C:21]2[N:20]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[Cl:25][C:24]1[C:19]([CH3:18])=[N:20][C:21]2[N:22]([N:27]=[CH:28][N:29]=2)[C:23]=1[NH:17][C@H:15]([C:12]1[CH:13]=[CH:14][C:9]([F:8])=[CH:10][CH:11]=1)[CH3:16]
Reactant: C[C@H](N)c1ccc(F)cc1
Reactant: Cc1nc2ncnn2c(Cl)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1nc2ncnn2c(N[C@@H](C)c2ccc(F)cc2)c1Cl

Procedure:
0.300 g (3.0 mmol) Triethylamine, a spatula tip of tetrabutylammonium iodide and 0.514 g (3.7 mmol) of (S)-1-(4-fluorophenyl)-ethylamine were added successively to a solution of 0.500 g (2.5 mmol) of 5-methyl-6,7-dichloro-[1,2,4]triazolo[1,5-a]pyrimidine in 10 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 with water. The organic phase was separated, dried and the solvent was evaporated under reduced pressure. Treatment of the resulting residue with hexane yielded 0.520 g (1.7 mmol, 68% of theory) of the title compound having a melting point of 103-104° C.
Reaction SMILES: [C:1]1([CH2:17][NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH2:25])[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.Br[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[B:34]1[O:39]CCC[O:35]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:17]([N:25]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[B:34]([OH:35])[OH:39])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][N:18]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[B:34]([OH:39])[OH:35])[CH2:17][C:1]1[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1)[C:1]1[CH:14]=[CH:15][CH:4]=[CH:3][CH:2]=1
Reactant: BrCc1ccccc1B1OCCCO1
Reactant: NCCCCCCNCc1ccc2ccc3cccc4ccc1c2c34
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OB(O)c1ccccc1CN(CCCCCCN(Cc1ccccc1B(O)O)Cc1ccc2ccc3cccc4ccc1c2c34)Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.4 %

Procedure:
A solution of N-pyren-1-ylmethyl-hexane-1,6-diamine (291 mg, 0.69 mmol), 2-(2-bromomethyl-phenyl)-[1,3,2]dioxaborinane (422 mg, 1.66 mmol), and potassium carbonate (380 mg, 2.76 mmol) in dry acetonitril (10 ml) was heated at reflux for 20 hours under nitrogen atmosphere. The solvent was removed under vacuum, the residue was dissolved in chloroform and washed with water. The solvent was dried over magnesium sulphate and removed under vacuum. The residue was dissolved in THF (10 ml). Water (10 ml) was added to the THF solution, and the solution was stirred at room temperature for 3 hours. Organic phase was extracted with chloroform, washed with water, and dried over magnesium sulphate. The solvent was removed under vacuum. The residue was reprecipitated from chloroform with n-hexane to give a white yellow powder (172 mg, 35%). 1H NMR (CDCl3) δ/ppm 1.25-1.48 (8H, m, (CH2)4), 2.25 (2H, t, BnNCH2), 2.48 (2H, t, PyCNCH2), 3.45 (2H, s, PhB(OH)CH2NBn), 3.58 (2H, s, PhB(OH)CH2NCPy), 3.85 (2H, s, PhCH2), 4.21 (2H, s, PyCH2), 7.02-7.41 and 7.88-8.19 (22H m, Ar-H), 8.86 (4H, bs, BOH). 13C NMR (CDCl3) δ/ppm 51.69, 52.99, 54.42, 56.42, 57.11, 61.03, 61.86, 67.85, 122.90, 124.55, 124.99, 125.79, 127.31, 128.28, 128.57, 129.43, 130.00, 130.55, 136.32, 141.56; Found: C, 76.56; H, 6.69; N, 3.80, C44H46B2N2O4 requires C, 76.76; H, 6.73 N, 4.07%; m/z (FAB) 1230 ([M+H+4(3-HOCH2C6H4NO2)-4(H2O)]+, 100%); mp. 165-168° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=13)[C:6]([CH2:13][CH3:14])=[C:5]2[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1.C([Li])(C)(C)C.CN(C)[C:30](=[O:45])[C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:33][CH:32]=1>>[CH2:38]([O:37][C:34]1[CH:33]=[CH:32][C:31]([C:30]([C:2]2[CH:3]=[C:4]3[N:12]4[C:7](=[CH:8][CH:9]=[CH:10][C:11]=24)[C:6]([CH2:13][CH3:14])=[C:5]3[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[O:45])=[CH:36][CH:35]=1)[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: CN(C)C(=O)c1ccc(OCc2ccccc2)cc1
Reactant: CCc1c(-c2ccc(OC)cc2)c2cc(Br)c3cccc1n32
Agent: [Li]C(C)(C)C
Product: CCc1c(-c2ccc(OC)cc2)c2cc(C(=O)c3ccc(OCc4ccccc4)cc3)c3cccc1n32
Yield: 14 %

Procedure:
4-Bromo-1-ethyl-2-(4-methoxyphenyl)pyrrolo[2,1,5-cd]indolizine, prepared in example 75, step 2, was reacted with t-butyllithium and N,N-dimethyl 4-benzyloxybenzamide by the general synthetic principles outlined in example 75, to afford 4-(4-benzyloxybenzoyl)-1-ethyl-2-(4-methoxyphenyl)pyrrolo[2,1,5-cd]indolizine in 14% yield. MS(SP): m/z 485 (M+). 1H--NMR (CDCl3, 200 MHz) δ: 1.48 (t, 3 H); 3.21 (q, 2 H); 3.90 (s, 3 H); 5.17 (s, 2 H); 7.03-7.12 (m,4 H); 7.30-7.50 (m, 5 H); 7.70 (d, 2 H); 7.80-8.01 (m, 5 H); 8.39 (dd, 1 H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[N:28]=[C:27]([C:29](O)=[O:30])[CH:26]=[CH:25][CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[Br:34][C:35]1[CH:36]=[C:37]([CH2:42][NH2:43])[CH:38]=[CH:39][C:40]=1[Cl:41].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl>[Br:34][C:35]1[CH:36]=[C:37]([CH2:42][NH:43][C:29]([C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([C:21]([NH:20][CH2:19][C:10]3[C:11]([NH:12][CH:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[C:6]4[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]4=[N:8][C:9]=3[CH2:32][CH3:33])=[O:22])[N:28]=2)=[O:30])[CH:38]=[CH:39][C:40]=1[Cl:41]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)n1
Reactant: NCc1ccc(Cl)c(Br)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(Cl)c(Br)c2)n1
Temperature: 25 °C
Yield: 76 %

Procedure:
A mixture of 6-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-2-pyridinecarboxylic acid (1,000 mg, 2.210 mmol), 1-(3-bromo-4-chlorophenyl)methanamine (487 mg, 2.210 mmol), HBTU (1,006 mg, 2.65 mmol) and Et3N (1.540 mL, 11.05 mmol) in DCM was stirred at room temperature over the weekend. The reaction was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were washed with brine and then concentrated under vacuum to give the crude residue. It was then purified with flash chromatography eluting with 0 to 100% ethyl acetate in hexane (product came out at 100% ethyl acetate in hexane). The product fractions were combined to give N-[(3-bromo-4-chlorophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-pyridinedicarboxamide (1,100 mg, 41%). LC-MS m/z 654.4 (M+H)+, 0.93 min (ret time).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[C:28]([NH2:31])(=[O:30])[CH3:29]>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:31][C:28](=[O:30])[CH3:29])=[CH:3][C:4]=2[S:24]([CH3:27])(=[O:26])=[O:25])=[O:9])[CH2:11][CH2:12]1
Reactant: CC(N)=O
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Product: CC(=O)Nc1ccc(C(=O)N2CCN(c3ccc(C)cc3C)CC2)c(S(C)(=O)=O)c1
Yield: 10.8 %

Procedure:
Using (4-bromo-2-methanesulfonylphenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (526 mg) described in Preparation Example 110 and acetamide (75.7 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (54 mg) was obtained.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][CH:12]=1.[OH-].[Na+].O>CO>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1
Reactant: COC(=O)c1ccc(Cc2nc3ccccc3[nH]2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(Cc2nc3ccccc3[nH]2)cc1
Temperature: 65 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
A solution of methyl 4-((1H-benzo[d]imidazol-2-yl)methyl)benzoate (5 g, 0.019 mol) in methanol was treated with sodium hydroxide (1.50 g, 0.037 mol) and water, heated to 65° C., stirred for 3 h and concentrated under reduced pressure. The resultant residue was dissolved in water and acidified with concentrated HCl. The resultant precipitate was removed by filtration and dried under vacuum overnight to provide 4-((1H-benzo[d]imidazol-2-yl)methyl)benzoic acid (82.0%). 1H NMR-(400 MHz, DSMO-d6): 7.96 (d, J=8 Hz, 2H), 7.91 (m, J=9 Hz, 2H), 7.60 (d, J=8 Hz, 2H), 7.52 (m, J=6 Hz, 2H), 4.65 (s, 2H). LCMS (ESI+) 253 (M+H). A portion of 4-((1H-benzo[d]imidazol-2-yl)methyl)benzoic acid (5.0 g, 0.020 mol) was dissolved in dichloromethane, cooled to 0° C., treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.50 g, 0.023 mol), 1-hydroxybenzotriazole (HOBT) (3.21 g, 0.024 mol), and diisopropylethylamine (6.41 g, 0.049 mol), stirred at room temperature for 30 min, cooled to 0° C., treated with a solution of 3-pyrrolidinol (1.89 g, 0.021 mol) in dichloromethane, stirred at room temperature for 24 h and diluted with water. The phases were separated and the organic phase was washed sequentially with saturated aqueous NaHCO3, saturated aqueous NaCl, dried over sodium sulfate and concentrated to dryness under reduced pressure to provide [4-(1H-benzoimidazol-2-ylmethyl)-phenyl]-(3-hydroxy-pyrrolidin-1-yl)-methanone (34%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): 7.47 (s, 4H), 7.38 (d, J=7.6 Hz, 2H), 4.87 (s, J=4.2 Hz, 1H), 4.21 (d, 2H), 3.48 (m, 4 H), 1.85 (m, 2H). LCMS (ESI+) 322 (M+H).
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([O:18][CH3:19])=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[C:8]([CH3:21])([CH3:20])[CH2:7][CH2:6]1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH3:28][NH:29][CH3:30]>O1CCCC1.O>[CH3:20][C:8]1([CH3:21])[C:9]2[C:14](=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11]([O:18][CH3:19])[CH:10]=2)[N:5]([C:3](=[O:4])[CH2:2][N:29]([CH3:30])[CH3:28])[CH2:6][CH2:7]1
Reactant: CNC
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)CBr)CCC2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)CN(C)C)CCC2(C)C

Procedure:
A solution of 1-(bromoacetyl)-4,4-dimethyl-6-(methyloxy)-7-nitro-1,2,3,4-tetrahydroquinoline (1.0 g, 2.8 mmol) in tetrahydrofuran (35 mL) was treated with potassium carbonate (1.3 g, 9.4 mmol) and dimethyl amine (10 mL, 20 mmol, 2 M in THF, Aldrich). The mixture was heated in sealed tube at 55° C. for 1h, cooled, diluted with water, and extracted with ethyl acetate. The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated to give {2-[4,4-dimethyl-6-(methyloxy)-7-nitro-3,4-dihydro-1(2H)-quinolinyl]-2-oxoethyl}dimethylamine which was taken directly to the next step. ESIMS (M+H)+=322.
Reaction SMILES: Br[CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:15]1([N:21]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:22][C:23]([N:25]([CH3:31])[C@@H:26]2[CH2:30][CH2:29][NH:28][CH2:27]2)=[O:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CC(=O)CC>[CH:2]([N:28]1[CH2:29][CH2:30][C@@H:26]([N:25]([CH3:31])[C:23](=[O:24])[CH2:22][N:21]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:27]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: CN(C(=O)CN(c1ccccc1)c1ccccc1)[C@@H]1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CN(C(=O)CN(c1ccccc1)c1ccccc1)[C@@H]1CCN(C(c2ccccc2)c2ccccc2)C1

Procedure:
To a solution of bromodiphenylmethane (0.3 g, 1.23 mmol) in butanone (10 ml) was added (R)-2-diphenylamino-N-methyl-N-pyrrolidin-3-yl-acetamide (0.46 g, 1.5 mmol), K2CO3 (0.17 g, 1.23 mmol) and KI (0.2 g, 1.23 mmol). The mixture was heated under reflux for 18 hours, then filtered and the solvent was removed in vacuo. The residue was dissolved in CH2Cl2, (50 ml) and washed with water (10 ml). Drying over MgSO4 and removal of solvent under reduced pressure followed by column chromatography using Hex:EtOAc (3:1) gave the desired product.