Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:6]2([C:12]3[C:24]4[CH2:23][C:22]5[C:17](=[CH:18][C:19]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:20][CH:21]=5)[C:16]=4[CH:15]=[C:14]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:13]=3)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[Li]CCCC.Cl[Si:39]([CH3:42])([CH3:41])[CH3:40]>C1COCC1>[CH3:40][Si:39]([CH3:42])([CH3:41])[C:3]1[CH:4]=[CH:5][CH:1]([C:6]2([C:12]3[C:24]4[CH2:23][C:22]5[C:17](=[CH:18][C:19]([C:25]([CH3:26])([CH3:28])[CH3:27])=[CH:20][CH:21]=5)[C:16]=4[CH:15]=[C:14]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:13]=3)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH:2]=1
Reactant: C[Si](C)(C)Cl
Reactant: CC(C)(C)c1ccc2c(c1)-c1cc(C(C)(C)C)cc(C3(C4C=CC=C4)CCCCC3)c1C2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc2c(c1)-c1cc(C(C)(C)C)cc(C3(C4C=CC([Si](C)(C)C)=C4)CCCCC3)c1C2
Yield: 45.8 %

Procedure:
In a 30 ml Schlenk flask purged with nitrogen, 0.86 g (2.02 mmol, 1 eq) of 1-(cyclopentadienyl)-1-(3,6-di-tert-butylfluorenyl)cyclohexane was placed at room temperature. Then, 12 ml of dehydrated THF was added, and the mixture was stirred by a magnetic stirrer to give a solution. The solution was cooled with an ice bath (colorless transparent solution). To the solution, 1.4 ml (2.28 mmol, 1.13 eq) of n-BuLi (hexane solution) was dropwise added. Then, the ice bath was removed, and the solution was stirred at room temperature for 19 hours. The solution was cooled with an ice bath, and to the solution, 1.6 ml (12.6 mmol, 6.24 eq) of chlorotrimethylsilane was dropwise added by a syringe. The ice bath was removed, and the solution was stirred at room temperature for 4 hours. The resulting yellow solution was poured into 50 ml of a diluted hydrochloric acid solution to perform quenching. After the soluble component was extracted with 70 ml of diethyl ether, the organic phase was washed with 50 ml of a saturated saline solution. The organic phase was dried over MgSO4 then the MgSO4 was filtered off, and from the filtrate the solvent was vacuum distilled off by a rotary evaporator to obtain a yellow amorphous product. The amorphous product was purified by silica gel column chromatography (developing solution: hexane) to obtain 0.46 g a white amorphous product (yield: 46%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:10]Br>CC(O)=O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([Br:10])=[CH:4][N:3]=1
Reactant: BrBr
Reactant: N#Cc1cccnc1N
Solvent: CC(=O)O
Product: N#Cc1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-aminopyridine-3-carbonitrile 1 (0.56 g, 4.6 mmol) was dissolved in 10 mL HOAc, to which one equivalent of Na2CO2 was added. Then, 1.1 equivalent of Br2 was added dropwise and reaction mixture was stirred at room temperature for 30 minutes. Orange precipitation was formed and filtered off to obtain the desired compound 2 in quantitative yield. The compound was carried on without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH:5]2[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[C:30]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH:31]=[CH:32][CH:33]=2)O1>C(OCC)(=O)C.CCCCCC>[Cl:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[O:12][CH:5]1[C:4]2[C:9](=[N:10][CH:11]=[C:2]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([N:34]4[CH2:35][CH2:36][O:37][CH2:38][CH2:39]4)[CH:29]=3)[CH:3]=2)[NH:8][CH2:7][CH2:6]1
Reactant: CC1(C)OB(c2cccc(N3CCOCC3)c2)OC1(C)C
Reactant: Clc1cccc(OC2CCNc3ncc(Br)cc32)c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Clc1cccc(OC2CCNc3ncc(-c4cccc(N5CCOCC5)c4)cc32)c1
Yield: 49 %

Procedure:
6-Bromo-4-(3-chlorophenoxy)-1,2,3,4-tetrahydro-[1,8]naphthyridine (20 mg) was reacted with 4-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]morpholine (23.9 mg) as in General Procedure 13. Silica gel chromatography using a gradient of 0-100% ethyl acetate/hexane as the eluting solvent gave the title compound as a yellow foam (49% yield). LCMS: m/z=422.18 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.00-2.11 (m, 1H), 2.22-2.26 (m, 1H), 3.19 (t, J=4.8 Hz, 4H), 3.40-3.45 (m, 1H), 3.58-3.64 (m, 1H), 3.88 (t, J=4.8 Hz, 4H), 5.14 (bs, 1H), 5.37 (t, J=1.0 Hz, 1H), 6.82-6.92 (m, 2H), 6.92 (s, 1H), 6.95-7.02 (m, 2H), 7.03-7.08 (m, 1H), 7.20-7.33 (m, 2H), 7.55 (d, J=1.9 Hz, 1H), 8.27 (d, J=2.1 Hz, 1H).
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:10])[CH2:8][NH2:9])([CH3:5])([CH3:4])[CH3:3].[CH2:11]([O:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:21][CH:22]=2)[C:17]([CH3:31])=[N:16][C:15]=1[C:32](O)=[O:33])[CH3:12]>>[C:2]([O:6][C:7](=[O:10])[CH2:8][NH:9][C:32]([C:15]1[N:16]=[C:17]([CH3:31])[C:18]2[C:23]([C:14]=1[O:13][CH2:11][CH3:12])=[CH:22][CH:21]=[C:20]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:19]=2)=[O:33])([CH3:5])([CH3:4])[CH3:3]
Reactant: CCOc1c(C(=O)O)nc(C)c2cc(Oc3ccccc3)ccc12
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Product: CCOc1c(C(=O)NCC(=O)OC(C)(C)C)nc(C)c2cc(Oc3ccccc3)ccc12

Procedure:
Synthesized from glycine tert-butyl ester hydrochloride and 4-ethoxy-1-methyl-7-phenoxy-isoquinoline-3-carboxylic acid in analogy to Example D-78 c); MS-(+)-ion: M+1=437.1.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]2[C:12](=[O:18])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[O:19][CH3:20])[C:5](=[O:21])[C:4]=2[CH:3]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24].O>N1C=CC=CC=1>[CH3:17][O:16][C:14]1[C:13]2[C:12](=[O:18])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[O:19][CH3:20])[C:5](=[O:21])[C:4]=2[CH:3]=[C:2]([NH:1][S:23]([CH3:22])(=[O:25])=[O:24])[CH:15]=1
Reactant: COc1cccc2c1C(=O)c1c(OC)cc(N)cc1C2=O
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: COc1cccc2c1C(=O)c1c(OC)cc(NS(C)(=O)=O)cc1C2=O
Temperature: 90 °C

Procedure:
2-Amino-9,10-dihydro-4,5-dimethoxy-9,10-dioxoanthracene (1.5 g) was dissolved in dry pyridine (30 ml) and freshly distilled methanesulphonyl chloride (0.61 g) slowly added. The mixture was heated to 90° C. for 3 hours under an atmosphere of nitrogen before being allowed to cool to room temperature. The mixture was then poured into water (150 ml), generating a brown precipitate. The solid was collected by filtration and dried in vacuo over silica gel to yield N-(4,5-dimethoxy-9,10-dihydro-9,10-dioxoanthracen-2-yl)methanesulphonamide at 94% purity (HPLC) as brown lustrous crystals. To improve purity, the crystals were dissolved in 2N sodium hydroxide solution, washed with CHCl3, and filtered to remove any remaining solid residue.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10]C)=O)=[N:6][C:5]([Cl:12])=[CH:4][N:3]=1.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>CO>[NH2:1][C:2]1[C:7]([C:8]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:10])=[N:6][C:5]([Cl:12])=[CH:4][N:3]=1
Reactant: C1CCNC1
Reactant: COC(=O)c1nc(Cl)cnc1N
Solvent: CO
Product: Nc1ncc(Cl)nc1C(=O)N1CCCC1

Procedure:
Methyl 2-amino-5-chloropyrazine-3-carboxylate was treated as described in Example 1 with 25 ml. of pyrrolidine in 100 ml. of methanol. Crystallization from ether yielded 7 g. (72%) of the above-named product with m.p. 90°-95°. Recrystallization from 2-propanol gave pale yellow needles with m.p. 95°-97°.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:6][CH2:5][C:4]([CH3:8])([CH3:7])[C:3]1=[O:9].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C>O1CCCC1>[CH3:1][C:2]1([CH3:10])[CH2:6][CH2:5][C:4]([CH3:8])([CH3:7])[CH:3]1[OH:9]
Reactant: CC1(C)CCC(C)(C)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(C)CCC(C)(C)C1O
Yield: 81.5 %

Procedure:
To a magnetically stirred solution of 10 g (0.071 mol) 2,2,5,5-tetramethylcyclopentanone in 75 ml of dry tetrahydrofuran at 0° C. under argon is added 2.69 g (0.071 mol) of lithium aluminum hydride. When the reduction was complete, ethyl acetate was introduced dropwise to destroy unreacted lithium aluminum hydride. 25 mls of water is then added, followed by 300 mls of diethyl ether. The organic phase is washed with 100 mls of water, and dried over MgSO4. Filtration followed by evaporation afforded 8.23 g of 2,2,5,5-tetramethylcyclopentanol.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O[N:30]1[C:34](=[O:35])[C:33]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]2[C:31]1=[O:40].N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[O:9]=[C:5]1[CH2:6][CH2:7][CH2:8][N:4]1[CH2:3][CH2:2][O:1][N:30]1[C:34](=[O:35])[C:33]2[C:32](=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:31]1=[O:40]
Reactant: O=C1CCCN1CCO
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1CCCN1CCON1C(=O)c2ccccc2C1=O
Reaction time: 4 h
Yield: 57 %

Procedure:
1-(2-Hydroxy-ethyl)-pyrrolidin-2-one (1.00 g, 7.74 mmol, commercial product), PPh3 (2.07 g, 7.90 mmol), N-hydroxy-phthalimide (1.29 g, 7.90 mmol), and diisopropyl azodicarboxylate (1.60 g, 7.90 mmol) were added to anhydrous THF at 0° C. under a nitrogen atmosphere, and the mixture was stirred. After 4 hours, the reaction mixture was purified by silica gel chromatography to give 2-(2-(2-oxo-pyrrolidin-1-yl)-ethoxy)-isoindol-1,3-dione (1.21 g).
Reaction SMILES: [Na].Cl.[C:3]([NH2:9])(=[NH:8])[CH2:4][CH2:5][CH2:6][CH3:7].[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]=[C:18]=[O:19]>CC(C)=O>[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17][C:18]([NH:8][C:3](=[NH:9])[CH2:4][CH2:5][CH2:6][CH3:7])=[O:19]
Reactant: CCCCC(=N)N
Reactant: O=C=Nc1ccccc1Cl
Agent: Cl
Agent: [Na]
Solvent: CC(C)=O
Product: CCCCC(=N)NC(=O)Nc1ccccc1Cl

Procedure:
Following a procedure similar to that described in Example 1 but using 2.3 g. sodium in 250 ml. dry acetone, 13.6 g. valeramidine hydrochloride, and 15.3 g. 2-chlorophenyl isocyanate in 100 ml. dry acetone, there was obtained after recrystallization from isopropyl alcohol-ether 15.4 g. of the hydrochloride of 1-(2-chloropheyl)-3-(pentanimidoyl)yrea; m.p. 132°-134°C.
Reaction SMILES: [F:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:43][C:44]1[CH:45]=[CH:46][C:47]([Cl:66])=[C:48]([C:50]2[N:51]=[C:52]3[N:57]=[CH:56][C:55]([NH:58][C:59](=[O:64])[O:60][CH:61]([CH3:63])[CH3:62])=[CH:54][N:53]3[CH:65]=2)[CH:49]=1>CN(C=O)C>[Cl:66][C:47]1[CH:46]=[CH:45][C:44]([NH:43][C:7]([C:5]2[O:6][C:2]([F:1])=[CH:3][CH:4]=2)=[O:9])=[CH:49][C:48]=1[C:50]1[N:51]=[C:52]2[N:57]=[CH:56][C:55]([NH:58][C:59](=[O:64])[O:60][CH:61]([CH3:62])[CH3:63])=[CH:54][N:53]2[CH:65]=1
Reactant: O=C(O)c1ccc(F)o1
Reactant: CC(C)OC(=O)Nc1cnc2nc(-c3cc(N)ccc3Cl)cn2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)OC(=O)Nc1cnc2nc(-c3cc(NC(=O)c4ccc(F)o4)ccc3Cl)cn2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 40 mL vial isopropyl (2-(5-amino-2-chlorophenyl)imidazo[1,2-a]pyrimidin-6-yl)carbamate (I-9) (30 mg, 0.09 mmol) was dissolved in DMF (Volume: 0.3 mL). 5-fluorofuran-2-carboxylic acid (11 mg, 0.09 mmol) was then added to the reaction mixture followed by HATU (65.98 mg, 0.17 mmol) and (iPr)2NEt (0.043 mL, 0.26 mmol). The reaction was stirred at rt for 8 hrs. The reaction was monitored was LCMS which indicated the reaction was complete with a new peak of desired mass was observed (M+H=468.1). The reaction mixture was quenched with water and extracted with ethyl acetate (3×5 mL). Combined all organics, dried over sodium sulfate and concentrated under reduce pressure. The crude reaction purified by reverse phase HPLC yeild 2-(2-chloro-5-(5-fluorofuran-2-carboxamido)phenyl)imidazo[1,2-a]pyrimidin-6-yl)carbamate (1). The TFA salt was neutralized to a free base by a HCO3 column. 1H NMR (400 MHz, DMSO) δ 10.41 (s, 1H), 10.01 (s, 1H), 9.31 (s, 1H), 8.69 (s, 1H), 8.61 (d, J=2.7, 1H), 8.51 (d, J=2.7, 1H), 7.87 (dd, J=2.7, 8.8, 1H), 7.53 (d, J=8.7, 1H), 7.47 (t, J=3.6, 1H), 6.11 (dd, J=3.7, 7.1, 1H), 5.03-4.85 (m, 1H), 1.29 (d, J=6.2, 6H). M/Z=(458.1M+1). RT=1.64 min.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]2)[CH:7]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>CO.ClCCl>[CH3:14][CH:11]1[CH2:12][CH2:13][N:8]([C:6]2[CH:7]=[C:2]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH:3]=[CH:4][C:5]=2[N+:15]([O-:17])=[O:16])[CH2:9][CH2:10]1
Reactant: CC1CCN(c2cc(Cl)ccc2[N+](=O)[O-])CC1
Reactant: C1CNCCN1
Solvent: ClCCl
Solvent: CO
Product: CC1CCN(c2cc(N3CCNCC3)ccc2[N+](=O)[O-])CC1
Yield: 94 %

Procedure:
The procedure of Example 4, step (b) was followed using 460 mg (1.81 mmol) of 1-(5-chloro-2-nitro-phenyl)-4-methyl-piperidine (as prepared in the Example 12, step (a)) and 3.12 g (36.2 mmol) of piperazine for 24 h to afford, after chromatography on a 20-g silica SPE column with 0-10% MeOH-dichloromethane, 518 mg (94%) of the title compound as an orange resin: Mass spectrum (ESI, m/z): Calcd. for C16H24N4O2, 305.2 (M+H), found 305.1.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Cl:15][C:16]1[C:17]2[C:24]([I:25])=[CH:23][NH:22][C:18]=2[N:19]=[CH:20][N:21]=1.[C:26]([N:33]1[CH2:37][CH2:36][C@@H:35](O)[CH2:34]1)([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Cl:15][C:16]1[C:17]2[C:24]([I:25])=[CH:23][N:22]([C@H:36]3[CH2:35][CH2:34][N:33]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:37]3)[C:18]=2[N:19]=[CH:20][N:21]=1
Reactant: Clc1ncnc2[nH]cc(I)c12
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](n2cc(I)c3c(Cl)ncnc32)C1
Reaction time: 1 h
Yield: 64.8 %

Procedure:
DIAD (1.41 ml) was added to a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (1.00 g), (R)—N-Boc-3-pyrrolidinol (1.01 g), and triphenylphosphine (1.88 g) in tetrahydrofuran (40 ml), and the reaction mixture was stirred for 1 hour. The reaction mixture was concentrated and washed with ethyl acetate to obtain the title compound as a white solid (1.04 g). Physical properties: m/z [M+H]+ 448.9
Reaction SMILES: Br[C:2]1[CH:13]=[C:12]([O:14][C@@H:15]([C@H:17]2[CH2:21][NH:20][C:19](=[O:22])[CH2:18]2)[CH3:16])[C:5]2[N:6]([CH:9]3[CH2:11][CH2:10]3)[CH:7]=[N:8][C:4]=2[CH:3]=1.C([Sn](CCCC)(CCCC)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)CCC>O1CCOCC1>[CH:9]1([N:6]2[C:5]3[C:12]([O:14][C@@H:15]([C@H:17]4[CH2:21][NH:20][C:19](=[O:22])[CH2:18]4)[CH3:16])=[CH:13][C:2]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[CH:3][C:4]=3[N:8]=[CH:7]2)[CH2:11][CH2:10]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: C[C@@H](Oc1cc(Br)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Solvent: C1COCCO1
Product: C[C@@H](Oc1cc(-c2ccccn2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Temperature: 130 °C
Yield: 18.1 %

Procedure:
Into a microwave-tube, a mixture of (R)-4-((R)-1-((5-bromo-1-cyclopropyl-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one: (100.0 mg, 0.275 mmol), 2-(tributylstannyl)pyridine (152.0 mg, 0.412 mmol) Bis(triphenylphosphine)palladium(II) dichloride (28.9 mg, 0.04 mmol) and dioxane (8 mL). The reaction mixture was placed in the microwave reactor and heated at 130° C. for 30 min. Quenched with saturated KF, extracted with EtOAc (3×30 ml). The combined organic layers were washed with water (2×5 mL), concentrated, and purified by flash chromatography (100% EtOAc to 20% MeOH/EtOAc) to give 18.0 mg (18.1%) of (R)-4-((R)-1-((1-cyclopropyl-5-(pyridin-2-yl)-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one. 1H NMR (300 MHz, DMSO-d6) δ 8.65 (d, J=7.5 Hz 1H), 8.127 (s, 1H), 8.04 (d, J=9.6 Hz 1H), 7.90-7.81 (m, 2H), 7.62 (d, J=0.9 Hz 1H), 7.60 (s, 1H), 7.324-7.283 (m, 1H), 4.856-4.815 (m, 1H), 3.742-3.695 (m, 1H), 3.41 (t, J=9.5 Hz, 1H), 3.21 (dd, J=6.3, 6.9 Hz, 1H), 2.862-2.811 (m, 1H), 2.426-2.24 (m, 2H), 1.33 (d, J=6.6 Hz, 3H), 1.266-1.016 (m, 4H). LCMS-ESI+ (m/z): [M+H]+ calcd C21H22N4O2:362.17; found 363.1.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[CH3:9][S:10]([NH:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)(=[O:12])=[O:11].C([O-])([O-])=O.[Na+].[Na+].COCCOC>C(OCC)(=O)C.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>[Cl:1][C:2]1[N:3]=[N:4][C:5]([C:17]2[CH:16]=[CH:15][C:14]([NH:13][S:10]([CH3:9])(=[O:11])=[O:12])=[CH:19][CH:18]=2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: CS(=O)(=O)Nc1ccc(B(O)O)cc1
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: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CS(=O)(=O)Nc1ccc(-c2ccc(Cl)nn2)cc1

Procedure:
To a round bottom flask was added 3,6-dichloropyridazine (20.1 mmole), 4-(methylsulfonylamino)phenylboronic acid (20.1 mmole), tetrakis(triphenylphosphine)palladium (1.00 mmole), 2M Na2CO3 (30 mL), and 1,2-dimethoxyethane (120 mL). The resulting reaction mixture was heated at 85 C for 22 hours. The reaction mixture was diluted with ethyl acetate and filtered through celite. The filtrate was washed with water. The organic extract was dried over Na2SO4 and evaporated in vacuo. The crude residue was purified by biotage column chromatography eluting with 4:1 ethyl acetate to hexane mixture to afford N-(4-(6-chloropyridazin-3-yl)phenyl)methanesulfonamide.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[CH:28]=[CH:27][C:11]([CH2:12][N:13]2[C:17]3=[N:18][C:19]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:21]=[C:16]3[N:15]=[C:14]2[CH3:26])=[C:10]([Cl:29])[CH:9]=1)=[O:6].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:29][C:10]1[CH:9]=[C:8]([N:7]2[CH2:2][CH2:3][CH2:4][C:5]2=[O:6])[CH:28]=[CH:27][C:11]=1[CH2:12][N:13]1[C:17]2=[N:18][C:19]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:21]=[C:16]2[N:15]=[C:14]1[CH3:26]
Reactant: COC(=O)c1ccc2nc(C)n(Cc3ccc(NC(=O)CCCBr)cc3Cl)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc2nc(C)n(Cc3ccc(N4CCCC4=O)cc3Cl)c2n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 66.5 %

Procedure:
Methyl 3-(4-((4-bromobutyryl)amino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (425 mg) was dissolved in N,N-dimethylformamide (5 ml) and potassium carbonate (245 mg) was added, which was followed by stirring at 60° C. for 2 hr. Water was added to the reaction mixture under ice-cooling and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Ethanol (10 ml) was added to the residue, and the mixture was heated and allowed to cool. The precipitated crystals were collected by filtration and dried under reduced pressure with heating to give methyl 3-(2-chloro-4-(2-oxotetrahydro-1H-pyrrol-1-yl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (235 mg) as pale-yellow crystals.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])[CH2:2][CH3:3].[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[C:15]([N:10]1[C:11]2[C:7](=[CH:6][C:5]([C:1](=[O:4])[CH2:2][CH3:3])=[CH:13][CH:12]=2)[CH2:8][C:9]1=[O:14])(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: CCC(=O)c1ccc2c(c1)CC(=O)N2
Product: CCC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O

Procedure:
Prepared from 5-propionyl-2-indolinone and acetic anhydride
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[NH:5][C:4](=[O:13])[CH:3]=1.[F:14][C:15]1[CH:31]=[CH:30][C:18]([CH2:19][N:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28]Cl)[CH2:22][CH2:21]2)=[CH:17][CH:16]=1>>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:28][CH2:27][CH2:26][N:23]3[CH2:24][CH2:25][N:20]([CH2:19][C:18]4[CH:17]=[CH:16][C:15]([F:14])=[CH:31][CH:30]=4)[CH2:21][CH2:22]3)[CH:10]=2)[NH:5][C:4](=[O:13])[CH:3]=1
Reactant: Fc1ccc(CN2CCN(CCCCl)CC2)cc1
Reactant: Cc1cc(=O)[nH]c2ccc(O)cc12
Product: Cc1cc(=O)[nH]c2ccc(OCCCN3CCN(Cc4ccc(F)cc4)CC3)cc12

Procedure:
In a manner analogous to that described in Example 5, by the appropriate reaction of 4-methyl-6-hydroxy-2-oxo-1,2-dihydroquinoline with 3-[4-(4-fluorobenzyl)-piperazin-1-yl]-propyl chloride, there is obtained 4-methyl-6-{3-[4-(4-fluorobenzyl)-piperazin-1-yl]-propoxy}-2-oxo-1,2-dihydroquinoline which, after recrystallization from ethanol, melts at 178°-180° C.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=[CH:12][C:10]=3[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH3:23]O>>[C:1]1([C:7]2[O:8][C:9]3[C:15]([C:16]([O:18][CH3:23])=[O:17])=[CH:14][CH:13]=[CH:12][C:10]=3[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cccc2cc(-c3ccccc3)oc12
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc2cc(-c3ccccc3)oc12

Procedure:
7.0 g of 2-phenylbenzofuran-7-carboxylic acid are dissolved in 70 ml of methanol, and 6.4 ml of thionyl chloride are added dropwise thereto at 0° C. The mixture is refluxed for 1 hour and evaporated to remove solvent. The residue is dissolved in ethyl acetate, and the solution is washed with water, dried and evaporated to remove solvent. The residue is recrystallized from n-hexane to give 7.04 g of methyl 2-phenylbenzofuran-7-carboxylate as colorless needles.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].C([O-])([O-])=O.[K+].[K+].[CH:19]1[CH:24]=[CH:23][C:22]([CH2:25]Br)=[CH:21][CH:20]=1>CN(C=O)C>[CH2:25]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([CH3:1])=[CH:10][CH:9]=2)[C:5](=[O:12])[C:6]1=[O:11])[C:22]1[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)C(=O)C(=O)N2Cc1ccccc1
Temperature: 75 °C
Reaction time: 0.08 h

Procedure:
To a mixture of 5-methylisatin (8.05 g, 50 mmol) and K2CO3 (8.16 g, 60 mmol) in DMF (100 mL) was added BnBr (6.5 mL, 55 mmol) dropwise over 2 min. After addition, the resulting mixture was heated in an oil bath at 75° C. for 1.5 h. After cooling to rt, the reaction mixture was poured onto ice/cold water (250 mL), rinsed with H2O (50 mL) and stirred for 5 min. The resulting precipitates were collected by suction filtration and air dried to give 1-benzyl-5-methylisatin as dark red solid. MS ESI 252.0 [M+H]+, calcd for [C16H13NO2+H]+ 252.1. 1-Benzyl-5-methylisatin was suspended in DMSO (100 mL) and cooled to 0° C. Hydrazine hydrate (5 mL) was added dropwise over 5 min. After addition, the resulting clear red solution was heated at 120° C. for 2 h then 140° C. for 5 h. After cooling to rt, it was poured into a 1 L Erlenmeyer flask, rinsed with H2O (50 mL) and ice was added until a total volume about 300 mL. 2 M HCl (50 mL) was added and the mixture was extracted with EtOAc (200 mL×2, then 100 mL), and the organic layer was dried (Na2SO4). Removal of solvents followed by drying under high vacuum for 2 days gave the title compound as a dark red solid (12.53 g, quantitative yield over 2 steps, contained some DMSO residue). 1H NMR (400 MHz, CDCl3) δ 7.35-7.29 (m, 5H), 7.09 (s, 1H), 6.97 (d, J=7.6 Hz, 1H), 6.61 (d, J=8.0 Hz, 1H), 4.91 (s, 2H), 3.60 (s, 2H), 2.31 (s, 3H); MS ESI 238.0 [M+H]+, calcd for [C16H15NO+H]+ 238.1.