Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C@H:13]2[CH2:19][C:20]2[N:21]=[N:22][N:23]([C@@H:25]([C:27]3[CH:32]=[CH:31][C:30]([CH2:33][OH:34])=[CH:29][CH:28]=3)[CH3:26])[CH:24]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].CO>C(Cl)Cl.O=[Mn]=O>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C@H:13]2[CH2:19][C:20]2[N:21]=[N:22][N:23]([C@@H:25]([C:27]3[CH:28]=[CH:29][C:30]([CH:33]=[O:34])=[CH:31][CH:32]=3)[CH3:26])[CH:24]=2)(=[O:10])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C[C@H](c1ccc(CO)cc1)n1cc(C[C@@H]2C(=O)NC=CN2S(=O)(=O)c2ccc(Cl)c(Cl)c2)nn1
Agent: O=[Mn]=O
Solvent: CO
Solvent: ClCCl
Product: C[C@H](c1ccc(C=O)cc1)n1cc(C[C@@H]2C(=O)NC=CN2S(=O)(=O)c2ccc(Cl)c(Cl)c2)nn1
Reaction time: 1.5 h

Procedure:
To a solution of (R)-4-(3,4-dichlorobenzenesulfonyl)-3-((1-((R)-1-(4-(hydroxymethyl)-phenyl)ethyl)-1H-1,2,3-triazol-4-yl)methyl)-3,4-dihydropyrazin-2(1H)-one (0.461 g, 0.882 mmol) in CH2Cl2 (100 mL) was added MnO2 (1.92 g, 22.1 mmol). After 1.5 h, MeOH (20 mL) was added. After the reaction mixture had stirred for 15 min, it was filtered through Celite and the solid was washed with CH2Cl2/MeOH (10/1). The solvent was removed under reduced pressure and dried in vacuo to yield the title compound.
Reaction SMILES: [Na].[C:2]([NH:5][CH:6]([C:12]#[N:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3].Br[CH:15]1[CH2:22][C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2>C(O)C>[C:2]([NH:5][C:6]([CH:15]1[CH2:22][C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:12]#[N:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3]
Reactant: CCOC(=O)C(C#N)NC(C)=O
Reactant: BrC1Cc2ccccc21
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C#N)(NC(C)=O)C1Cc2ccccc21
Reaction time: 0.33 h
Yield: 95.2 %

Procedure:
Sodium (464 mg, 20.2 mmol, 1.2 eq.) was allowed to react with absolute ethanol (40 mL, 0.42 M); to the resulting mixture was added ethyl 2-(acetylamino)-2-cyanoacetate (3.44 g, 20.2 mmol, 1.2 eq.). After 20 minutes at 60° C., 7-bromobicyclo[4.2.0]octa-1,3,5-triene (3.092 g, 16.89 mmol, 1 eq.) was added and the reaction mixture was heated at reflux overnight, then filtered and concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give a dark oil, which was purified by silica gel chromatography (Gradient: 0% to 50% ethyl acetate in heptane) to give #99 (4.38 g) as a yellow gum. LC-MS: m/z 273.2 [M+H+], retention time=2.36 minutes.
Reaction SMILES: Br[C@@H:2]([CH2:8][N:9]([CH2:19][C@@H:20](Br)[C:21]([O:23][CH2:24][CH3:25])=[O:22])[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:12])=[O:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1(C)C=CC=CC=1>[CH2:27]([N:34]1[C@H:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:8][N:9]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH2:19][C@@H:20]1[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)[C@H](Br)CN(C[C@H](Br)C(=O)OCC)S(=O)(=O)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@H]1CN(S(=O)(=O)c2ccccc2)C[C@@H](C(=O)OCC)N1Cc1ccccc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 59.9 %

Procedure:
To a solution of 112b (20 g, 38.8 mmol) in toluene (100 ml) was added BnNH2 (12.48 g, 116.5 mmol). The reaction mixture was stirred at 90° C. for 3 h. Then the mixture was purified through a silica gel column eluting with PE:EA=50:1 to 10:1 to give 112c as a white crystal (10.7 g, 60%) MS: [M+H]+: 461
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[O:47]1[CH2:52][CH2:51][N:50]([C:53]([C:55]2[N:56]=[C:57]([C:64]([F:67])([F:66])[F:65])[N:58]3[CH2:63][CH2:62][NH:61][CH2:60][C:59]=23)=[O:54])[CH2:49][CH2:48]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([N:61]1[CH2:62][CH2:63][N:58]2[C:57]([C:64]([F:66])([F:67])[F:65])=[N:56][C:55]([C:53]([N:50]3[CH2:51][CH2:52][O:47][CH2:48][CH2:49]3)=[O:54])=[C:59]2[CH2:60]1)=[O:5]
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: O=C(c1nc(C(F)(F)F)n2c1CNCC2)N1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[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: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCn2c(C(F)(F)F)nc(C(=O)N3CCOCC3)c2C1
Reaction time: 12 h
Yield: 19.7 %

Procedure:
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (390 mg, 1.30 mmol) was dissolved in 10 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (983 mg, 2.60 mmol), crude morpholino-[3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl]methanone 20d (400 mg, 1.30 mmol) and N, N-diisopropylethylamine (0.7 mL, 3.90 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 4-[[4-fluoro-3-[1-(morpholine-4-carbonyl)-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carbonyl]phenyl]methyl]-2H-phthalazin-1-one 20 (150 mg, yield 20.0%) as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([F:58])[C:5]([S:52]([CH:55]2[CH2:57][CH2:56]2)(=[O:54])=[O:53])=[C:6]([CH2:8][N:9]([CH3:51])[C:10]([CH:12]([NH:24][C:25]2[CH:26]=[C:27]3[C:32](=[C:33]([F:35])[CH:34]=2)[C:31]([N:36]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[N:30][CH:29]=[CH:28]3)[C:13]2[CH:18]=[CH:17][C:16]([C@@H:19]([CH3:22])[CH2:20][OH:21])=[C:15]([CH3:23])[CH:14]=2)=[O:11])[CH:7]=1.[C:59](Cl)(Cl)=[O:60]>C(#N)C.ClCCl>[C:39]([O:38][C:37]([N:36]([C:31]1[C:32]2[C:27](=[CH:26][C:25]([NH:24][C@H:12]3[C:10](=[O:11])[N:9]([CH3:51])[CH2:8][C:6]4[CH:7]=[C:2]([CH:3]=[C:4]([F:58])[C:5]=4[S:52]([CH:55]4[CH2:57][CH2:56]4)(=[O:53])=[O:54])[NH:1][C:59](=[O:60])[O:21][CH2:20][C@H:19]([CH3:22])[C:16]4[CH:17]=[CH:18][C:13]3=[CH:14][C:15]=4[CH3:23])=[CH:34][C:33]=2[F:35])[CH:28]=[CH:29][N:30]=1)[C:44](=[O:45])[O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:43])([CH3:41])([CH3:40])[CH3:42]
Reactant: Cc1cc(C(Nc2cc(F)c3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)C(=O)N(C)Cc2cc(N)cc(F)c2S(=O)(=O)C2CC2)ccc1[C@@H](C)CO
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: CC#N
Product: Cc1cc2ccc1[C@@H](C)COC(=O)Nc1cc(F)c(S(=O)(=O)C3CC3)c(c1)CN(C)C(=O)[C@@H]2Nc1cc(F)c2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc2c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 25.8 %

Procedure:
A solution of 11F (163 mg, 0.198 mmol) in acetonitrile (3 mL) and dichloromethane (6 mL) was cooled to 0° C. To this solution was added phosgene (20% in toluene) (0.108 mL, 0.218 mmol). The mixture was stirred at 0° C. for 5 min, and rt for 1 h. The mixture was bubbled with Ar for 10 min to remove excess phosgene. The resulting solution was added dropwise over 3 h via a syringe pump into a solution of TEA (0.276 mL, 1.978 mmol) in CH2Cl2 (260 mL) at rt. The solution was stirred for 16 h. Solvent was removed and the crude product was purified by flash chromatography to give a mixture of diastereoisomers (102 mg, 60.7% yield). The diastereoisomers were separated by a prep chiral HPLC equipped with an IA column to give 11G (43 mg, 0.051 mmol, 43.0% yield). MS (ESI) m/z: 850.1 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2O)=[N:13][C:14]=1[CH2:15][CH3:16].BrC1N=C(CC)C(NC2C3C(=CC=CC=3)[O:43]CC2)=NC=1CC>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][CH:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[O:43][CH2:20][CH2:19]2)=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: CCc1nc(NC2CCOc3ccccc32)c(CC)nc1Br
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1NC1CCOc2ccccc21

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting 5-bromo-N-(3,4-dihydro-2H-chromen-4-yl)-3,6-diethylpyrazin-2-amine, ethylene glycol dimethyl ether and tetrakis(triphenylphosphine) palladium and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ); 7.51, 7.36–7.23, 6.98–6.90, 5.37, 4.69, 4.32, 2.66, 2.51, 2.31, 1.29–1.17; HRMS (EI) calcd for C23H23Cl2N3O 427.1218, found 427.1224.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:7][CH2:6]1)=[O:4].C1(C)C=CC=CC=1.C[O-].[Na+]>COC(C)(C)C>[CH2:11]([C@H:8]1[CH2:9][CH2:10][C@H:5]([C:3]([OH:4])=[O:2])[CH2:6][CH2:7]1)[CH:12]([CH3:14])[CH3:13]
Reactant: COC(=O)[C@H]1CC[C@H](CC(C)C)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: COC(C)(C)C
Product: CC(C)C[C@H]1CC[C@H](C(=O)O)CC1
Temperature: 25 °C

Procedure:
A 2-necked round bottom flask, which had been dried and cooled under argon, was charged with cis/trans-4-isobutyl-cyclohexanecarboxylic acid methyl ester (7:3) (0.5 g, 2.5 mmol), dry toluene (10 ml) and sodium methoxide (0.41 g, 7.6 mmol). The reaction mixture was heated at reflux for 96 h. After cooling to room temperature the mixture was diluted with tert-butyl methyl ether (100 ml) and washed with ice-cold aqueous hydrochloric acid solution (pH 1). The aqueous layer was extracted with one 50-ml portion of tert-butyl methyl ether. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a (15:85) cis/trans mixture. MS m/e: 183 ([M−H]−)
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:24])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10]([NH:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:24]
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)NOCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCCCCC(=O)NOCc1ccccc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
N-(benzyloxy)-6-(BOC-amino)hexanamide (5.65 g, 16.8 mmol) was dissolved in methylene chloride (40 mL), and the resulting solution thus obtained was cooled at 0° C. The trifluoroacetic acid (2.5 mL, 34 mmol, 2.0 eq.) was added thereto slowly and stirred at room temperature for 24 hrs. The reaction proceeded until no starting material was detectable by TLC. The resulting reaction mixture thus obtained was distilled under a reduced pressure to remove the solvent and thus obtained the title compound quantitatively.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(NC(C)C)(C)C.Br[C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35](=[O:37])[CH3:36])=[CH:30][CH:29]=1.[C:38]([C:40]1[CH:45]=[CH:44][C:43]([CH2:46][C:47]([NH:49][NH:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])=[O:48])=[CH:42][CH:41]=1)#[CH:39]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[C:35]([NH:34][C:31]1[CH:32]=[CH:33][C:28]([C:39]#[C:38][C:40]2[CH:41]=[CH:42][C:43]([CH2:46][C:47]([NH:49][NH:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])=[O:48])=[CH:44][CH:45]=2)=[CH:29][CH:30]=1)(=[O:37])[CH3:36]
Reactant: C#Cc1ccc(CC(=O)NNC(=O)OC(C)(C)C)cc1
Reactant: CC(=O)Nc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CC(C)NC(C)C
Product: CC(=O)Nc1ccc(C#Cc2ccc(CC(=O)NNC(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 20.2 %

Procedure:
Palladium (II) acetate (2.5 mg, 0.011 mmol) and triphenylphosphine (11 mg, 0.044 mmol) were added to diisopropylamine (4 ml), and the mixture was stirred at room temperature for 20 mins. N-(4-Bromophenyl)acetamide (78 mg, 0.365 mmol) and tert-butyl 2-[(4-ethynylphenyl)acetyl]hydrazinecarboxylate (100 mg, 0.365 mmol) were added, and the mixture was stirred at 70° C. for 2 hrs. Anhydrous acetonitrile (2 ml) was added, and the mixture was further stirred at 70° C. for 1 hr. The reaction mixture was cooled and concentrated. The residue was purified by silica gel column chromatography (dichloromethane:methanol=97:3) to give tert-butyl 2-({4-[(4-acetamidophenyl)ethynyl]phenyl}acetyl)hydrazinecarboxylate (30 mg, yield 20%).
Reaction SMILES: [SH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.Cl[CH2:13][C:14]1[NH:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1>>[N:15]1[C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[NH:18][C:14]=1[CH2:13][S:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: Sc1ncnc2ccccc12
Reactant: ClCc1nc2ccccc2[nH]1
Product: c1ccc2[nH]c(CSc3ncnc4ccccc34)nc2c1
Yield: 56.5 %

Procedure:
The title compound(2.5 g) was prepared from 4-mercaptoquinazoline(6.0 g) and 2-chloromethylbenzimidazole (2.52 g).
Reaction SMILES: Cl[C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[F:13][C:14]1[C:19]([F:20])=[CH:18][C:17]([F:21])=[C:16]([F:22])[C:15]=1[SH:23]>>[N+:10]([C:3]1[CH:4]=[C:5]([C:7](=[O:9])[CH3:8])[S:6][C:2]=1[S:23][C:15]1[C:14]([F:13])=[C:19]([F:20])[CH:18]=[C:17]([F:21])[C:16]=1[F:22])([O-:12])=[O:11]
Reactant: CC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Reactant: Fc1cc(F)c(F)c(S)c1F
Product: CC(=O)c1cc([N+](=O)[O-])c(Sc2c(F)c(F)cc(F)c2F)s1
Yield: 17.4 %

Procedure:
Prepared by a similar procedure to that described for example 18 from the 1-(5-chloro-4-nitro-2-thienyl)ethanone (200 mg, 0.98 mmol) and 2,3,5,6-tetrafluorobenzenethiol (178 mg, 0.98 mmol) to afford the title product as a solid (60 mg, 18% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.54 (1H, s), 8.41 (1H, m). MS m/z: 349.75 [M+H]+.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:11][C:12](=[O:31])[NH:13][C:14]([CH3:30])([CH3:29])[CH2:15][N:16]([C:25](=[O:28])[CH2:26]Br)[C:17]1[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=1[F:24])([CH3:10])([CH3:9])[CH3:8].C(O)(=O)C>O1CCCC1>[C:7]([O:11][C:12]([N:13]1[CH2:26][C:25](=[O:28])[N:16]([C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])[CH2:15][C:14]1([CH3:30])[CH3:29])=[O:31])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(CN(C(=O)CBr)c1c(F)cccc1F)NC(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(=O)N(c2c(F)cccc2F)CC1(C)C
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
A solution of 2.05 g of potassium t-butoxide (18.3 mmol) in tetrahydrofuran (120 ml) was added to a solution of 5.14 g of {2-[(2-bromoacetyl)-(2,6-difluorophenyl)amino]-1,1-dimethylethyl}carbamic acid t-butyl ester obtained in Example (60b) (12.2 mmol) in tetrahydrofuran (120 ml) under a nitrogen atmosphere and under cooling in a dry ice-acetone bath over 30 minutes, and the mixture was stirred at the same temperature for 30 minutes. 0.33 ml of acetic acid (6.10 mmol) was added to the reaction mixture. After returning to room temperature, the solvent was evaporated under reduced pressure. The residue was diluted with water, followed by extraction with ethyl acetate. Then, the organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:hexane/ethyl acetate=3/1) to obtain 3.43 g of the title compound (yield: 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][C:37]=1[C:46]1([C:52]([NH2:54])=[O:53])[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:49]3[CH2:48][CH2:47][C:46]([C:37]4[CH:38]=[CH:39][C:40]5[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=5)[CH:36]=4)([C:52]([NH2:54])=[O:53])[CH2:51][CH2:50]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC(=O)C1(c2ccc3ccccc3c2)CCNCC1
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Agent: Cl
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccc5ccccc5c4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.3 using 2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (5 mmol) and 4-(naphth-2-yl)-piperidine-4-carboxylic acid amide hydrochloride (7.5 mmol, 1.5 eq.). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]3[C:15]([NH2:16])=[N:14][NH:13][C:9]3=[N:10]2)=[CH:5][CH:4]=1.Cl.Cl[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.[H-].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]3[C:15]([NH2:16])=[N:14][N:13]([CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[C:9]3=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2cc3c(N)n[nH]c3nc2c1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2cc3c(N)nn(CCN4CCOCC4)c3nc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.2 %

Procedure:
A mixture of 17.1 g 7-methoxy-1H-pyrazolo[3,4-b]quinolin-3-amine (Example 3d), 15.25 g 4-(2-chloroethyl)morpholine hydrochloride, 7.2 g sodium hydride and 500 ml dimethylformamide was stirred at room temperature for about 16 hours. The solvent was then removed by evaporation, and the residue dissolved in 1N hydrochloric acid and extracted with ethyl acetate. The aqueous layer was made basic with carbonate to pH 8 and extracted with chloroform. The chloroform extracts were washed with water, dried over magnesium sulfate and passed through a silica gel pad. The pad was eluted with warm ethyl acetate, the product isolated and recrystallized from ethyl acetate to give 9.2 g 7-methoxy-1-[2-(4-morpholinyl)ethyl]-1H-pyrazolo[3,4-b]quinolin-3-amine, orange solid, m.p. 166°-168° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C:13]2([OH:27])[C:17]3=[C:18]([F:26])[CH:19]=[N:20][C:21]4[CH:22]=[CH:23][C:24](=[O:25])[N:15]([C:16]=43)[CH2:14]2)(=O)=O)=CC=1.[O:28]1[C:37]2[CH:36]=[C:35]([CH2:38][N:39]([CH:47]3[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]3)[C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[N:34]=[CH:33][C:32]=2[O:31][CH2:30][CH2:29]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[O:28]1[C:37]2[CH:36]=[C:35]([CH2:38][N:39]([CH:47]3[CH2:52][CH2:51][N:50]([CH2:12][C:13]4([OH:27])[C:17]5=[C:18]([F:26])[CH:19]=[N:20][C:21]6[CH:22]=[CH:23][C:24](=[O:25])[N:15]([C:16]=65)[CH2:14]4)[CH2:49][CH2:48]3)[C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[N:34]=[CH:33][C:32]=2[O:31][CH2:30][CH2:29]1
Reactant: Cc1ccc(S(=O)(=O)OCC2(O)Cn3c(=O)ccc4ncc(F)c2c43)cc1
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCN(CC2(O)Cn3c(=O)ccc4ncc(F)c2c43)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of [(4R/S)-3-fluoro-4-hydroxy-7-oxo-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-4-yl]methyl 4-methylbenzenesulfonate (100 mg, 0.25 mmol), 1,1-dimethylethyl (2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-4-piperidinylcarbamate (84 mg, 0.24 mmol) (for a synthesis, see WO2004058144, Example 99(h)), sodium carbonate (77 mg, 0.7 mmol) and ethanol (2.5 ml) was stirred at room temperature overnight then evaporated under vacuum. The residue was treated with water and the mixture extracted twice with dichloromethane. The combined organic extracts were dried over magnesium sulphate and evaporated under vacuum. The residue was chromatographed on silica eluting with 0-100% ethyl acetate in dichloromethane then 0-10% methanol in ethyl acetate affording a yellow oil (88 mg, 64%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)=[CH:12][CH:11]=2)=[O:9])=[N:6][CH:7]=1.[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26]O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][O:1][C:2]1[CH:3]=[N:4][C:5]([C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)=[CH:14][CH:15]=2)=[O:9])=[N:6][CH:7]=1
Reactant: CN(C)CCO
Reactant: O=C(c1ccc(OC2CCCCO2)cc1)c1ncc(O)cn1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C)CCOc1cnc(C(=O)c2ccc(OC3CCCCO3)cc2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a mixture of (5-hydroxypyrimidin-2-yl)(4-(tetrahydro-2H-pyran-2-yloxy) phenyl)methanone (300 mg, 1 mmol), 2-(dimethylamino)ethanol (180 mg, 2 mmol) and PPh3 (524 mg, 2 mmol) in 50 mL of THF was added DIAD (404 mg, 2 mmol) dropwise and the mixture was stirred overnight at rt. The mixture was concentrated and purified by flash chromatography to give the product (297 mg, 80% yield)
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=1.C([O-])(=O)C.[NH4+]>>[Cl:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:27]([C:23]3[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: O=Cc1cccnc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4cccnc4)nc23)[C@H]2C=C[C@@H]1C2
Yield: 5.6 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (75 mg, 0.26 mmol), 3-Pyridinecarboxaldehyde (26.4 uL, 0.281 mmol), and Ammonium acetate (39.4 mg, 0.511 mmol) were reacted to produce 5.5 mg (6%) of the title compound. (300 MHz, DMSO-d6) 13.50 (s, 1H), 9.31 (s, 1H), 8.66 (d, J=5 Hz, 1H), 8.45 (d, J=8 Hz, 1H), 7.99 (s, 1H), 7.78 (s, 1H), 7.59 (q, J=13 Hz, 6 Hz, 1H), 7.29 (d, J=8 Hz, 1H), 7.24 (s, 1H), 6.42 (m, 1H), 6.37 (m, 1H), 5.18 (t, J=17 Hz, 8.5 Hz, 1H), 2.90 (s, 1H), 2.80 (s, 1H), 2.63 (d, J=8 Hz, 1H), 2.24 (d, J=8 Hz, 1H), 1.38 (d, J=8 Hz, 1H). MS=381 (M+H), HPLC: 1.69 min. (G Method)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][N:6]=1)=[O:4].FC(F)(F)C(OC1C(OC(=O)C(F)(F)F)=C([I:25])C=CC=1)=O.II.S(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([I:25])[CH:12]=2)[NH:7][N:6]=1)=[O:4]
Reactant: O=C(Oc1cccc(I)c1OC(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1n[nH]c2ccccc12
Agent: II
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1n[nH]c2ccc(I)cc12
Yield: 35.1 %

Procedure:
A solution of Example 271A (300 mg; 1.7 mmol), bis(trifluoroacetoxy)iodobenzene (800 mg; 1.9 mmol), and iodine (253 mg; 1.0 mmol) in CH2Cl2 (10 mL) was stirred overnight at r.t., and treated with sodium bisulfite (aq). The precipitate was collected, rinsed with water and hexane, and dried under vacuum to provide the desired product (180 mg; 36%).