Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][N:3]=1.[CH:28]1[C:36](Br)=[CH:35][N:34]2[C:30](=[N:31][CH:32]=[CH:33]2)[CH:29]=1.COC1C2C=CNC=2N=C(N)[N:41]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[NH2:41][C:32]1[N:31]=[C:30]2[CH:29]=[CH:28][C:36]([C:5]3[CH:6]=[C:7]([NH:8][S:9]([C:12]4[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=4)(=[O:10])=[O:11])[C:2]([Cl:1])=[N:3][CH:4]=3)=[CH:35][N:34]2[CH:33]=1
Reactant: COc1nc(N)nc2[nH]ccc12
Reactant: Brc1ccc2nccn2c1
Reactant: CC1(C)OB(c2cnc(Cl)c(NS(=O)(=O)c3ccc(F)cc3)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Nc1cn2cc(-c3cnc(Cl)c(NS(=O)(=O)c4ccc(F)cc4)c3)ccc2n1
Temperature: 95 °C
Reaction time: 3 h
Yield: 22.3 %

Procedure:
To a 10 mL round-bottomed flask was added N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-4-fluorobenzenesulfonamide (0.150 g, 0.363 mmol) (Step 2, Example 48), 6-bromoH-imidazo[1,2-a]pyridin-2-amine (0.0700 g, 0.330 mmol) (Step 4, Example 28), DMSO (3.00 mL), and sodium carbonate (0.990 mL, 1.98 mmol, 2 M). The mixture was carefully evacuated and backfilled with N2. To the mixture was added trans-dichlorobis(triphenylphosphine)palladium(II) (0.0232 g, 0.0330 mmol, Strem Chemical, Inc., Newburyport, Mass.). Again, the mixture was carefully evacuated and backfilled with N2. The mixture was stirred at 95° C. for 3 h. After cooling to rt, the mixture was poured into pH 4.8 buffer (3 M sodium acetate solution pH adjusted to 4.8, Teknova, Hollister, Mass.) diluted with water. The solution was filtered and the filtercake was washed with water and then 50% CH2Cl2/hexane. The aqueous washings were extracted with 25% iPrOH/CHCl3 and the extracts were combined with the filtercake. The combined material was concentrated to remove all of the solvents and the residue was taken up in MeOH/CH2Cl2 and concentrated onto silica. Purification by silica gel chromatography (2.0 to 9.0% MeOH/CH2Cl2) afforded the title compound as a yellow solid (0.0307 g, 22%). MS (ESI, positive ion) m/z: 418 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.08 (s, 1H), 7.34 (br s, 3H), 7.38-7.44 (m, 3H), 7.60 (br s, 2H), 7.78-7.84 (m, 3H), 7.97 (d, J=2.2 Hz, 1H), 8.49 (d, J=2.0 Hz, 1H), 8.77 (s, 1H).
Reaction SMILES: C(N(C(C)C)CC)(C)C.CS(Cl)(=O)=O.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([N:24]2[CH2:28][CH2:27][CH2:26][C@H:25]2[CH2:29]O)=[O:23])=[CH:18][CH:17]=1.[N-:31]=[N+:32]=[N-:33].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[N:31]([CH2:29][C@@H:25]1[CH2:26][CH2:27][CH2:28][N:24]1[C:22]([C:19]1[CH:20]=[CH:21][C:16]([Br:15])=[CH:17][CH:18]=1)=[O:23])=[N+:32]=[N-:33]
Reactant: O=C(c1ccc(Br)cc1)N1CCC[C@H]1CO
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: [N-]=[N+]=NC[C@@H]1CCCN1C(=O)c1ccc(Br)cc1
Reaction time: 2 h
Yield: 44.8 %

Procedure:
Diisopropylethylamine (0.36 ml, 2.1 mmol) and 0.15 ml (1.9 mmol) of methanesulfonyl chloride were added under ice cooling to a solution of 397 mg (1.4 mmol) of (S)-(4-bromophenyl)(2-(hydroxymethyl)pyrrolidin-1-yl)methanone synthesized in the same manner as in step (i) of Reference Example 8 in methylene chloride (15 ml) solution, and the mixture was stirred for 2 hr. The reaction solution was diluted with 45 ml of ethyl acetate and was washed with a saturated aqueous ammonium chloride solution. The aqueous layer was extracted twice with 5 ml of ethyl acetate. The organic layers were combined and were washed with 25% brine. The organic layer was dried over anhydrous sodium sulfate and was filtered. The filtrate was concentrated under the reduced pressure, and the residue was dissolved in 10 ml of N,N-dimethylformamide. Sodium azide (146 mg, 2.2 mmol) was added to the solution, and the mixture was stirred at 50° C. for 5 hr. The reaction solution was diluted with 20 ml of ethyl acetate, and the diluted solution was washed five times with 10 ml of 12.5% brine. The organic layer was dried over anhydrous sodium sulfate and was filtered, and the filtrate was concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=2:1) to give 194 mg (yield 45%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[S:12]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)(=[O:14])=[O:13].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:42][C:43]1[CH:44]=[C:45]([C@H:49]([NH2:51])[CH3:50])[CH:46]=[CH:47][CH:48]=1>CN(C=O)C.CCOC(C)=O.O>[Cl:42][C:43]1[CH:44]=[C:45]([C@H:49]([NH:51][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4]([S:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)(=[O:14])=[O:13])[CH:5]=2)[CH3:50])[CH:46]=[CH:47][CH:48]=1
Reactant: COc1ccc(C(=O)O)cc1S(=O)(=O)N1CCOCC1
Reactant: C[C@@H](N)c1cccc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N[C@H](C)c2cccc(Cl)c2)cc1S(=O)(=O)N1CCOCC1
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
To a solution of 4-methoxy-3-(morpholinosulfonyl)benzoic acid 42 (0.824 g, 2.73 mmol) in DMF (6 mL) was added EDCI (0.686 g, 3.58 mmol) and HOBT (0.536 g, 3.50 mmol), the solution was stirred for 30 min and (R)-1-(3-chlorophenyl)ethanamine (0.673 g, 4.32 mmol) was added. The reaction mixture was stirred at room temperature for 16 h and diluted with EtOAc and water. The organic phase was washed with water (2×), brine (1×), dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel (eluted with 60% to 100% EtOAc in hexanes) gave (R)—N-(1-(3-chlorophenyl)ethyl)-4-methoxy-3-(morpholinosulfonyl)benzamide 43 (1.14 g, 95.0% yield) as a white solid. Mass spectrum: calculated for C20H23ClN2O5S 438.1. found 439.1 (M++1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.[NH2:12][CH2:13][CH:14]([OH:16])[CH3:15].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.O.C(N(CC)CC)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH:12][CH2:13][CH:14]([OH:16])[CH3:15])=[O:7]
Reactant: CC(O)CN
Reactant: Cc1ccc(C(=O)O)cc1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc(C(=O)NCC(C)O)cc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 91 %

Procedure:
To 30 ml of a solution of 5.00 g of 3,4-dimethylbenzoic acid and 2.75 g of 1-amino-2-propanol in N,N-dimethylformamide, 4.95 g of 1-hydroxybenzotriazole, 6.96 ml of triethylamine and 7.02 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added sequentially, and stirred for 15 hours at room temperature. After addition of water, the reaction solution was extracted with ethyl acetate, washed with 10% hydrochloric acid, ice-cold water and aqueous solution of saturated sodium hydrogen carbonate sequentially, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to provide 6.28 g of the objective compound as colorless crystals. M.p. 77–78° C.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=2)[C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>C(OCC)(=O)C.CO.[Pd]>[NH2:23][C:20]1[CH:19]=[CH:18][C:17]([CH:7]([CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:9])=[CH:22][CH:21]=1
Reactant: O=C(Nc1ccccn1)C(CC1CCCC1)c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc(C(CC2CCCC2)C(=O)Nc2ccccn2)cc1
Yield: 85 %

Procedure:
A mixture of 3-cyclopentyl-2-(4-nitro-phenyl)-N-pyridin-2-yl-propionamide (130 mg, 0.38 mmol) in ethyl acetate (50 mL) and methanol (5 mL) was treated with a catalytic amount of 10% palladium on activated carbon (50 mg). The resulting mixture was shaken at 25° C. under 60 psi of hydrogen gas in a Parr apparatus for 24 h. At this time, the catalyst was removed by filtration through a plug of celite. The filtrate was concentrated in vacuo to afford 2-(4-amino-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide (99.9 mg, 84.3%) as a tan oil: EI-HRMS m/e calcd for C19H23N3O (M+) 309.1834, found 309.1849.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][C:7]([OH:9])=O)(=[O:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[CH2:24]([C@@H:31]1[CH2:35][O:34][C:33](=[O:36])[NH:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[Li]CCCC.[Li]>O1CCCC1.C(OCC)(=O)C>[CH2:24]([C@@H:31]1[CH2:35][O:34][C:33](=[O:36])[N:32]1[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][C:1](=[O:3])[CH3:2])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Reactant: CC(=O)CCCC(=O)O
Agent: CC(C)(C)C(=O)Cl
Agent: [Li]
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)CCCC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 4-acetylbutyric acid (1-7) (25.0 g, 192 mmol), triethylamine (29.5 ml, 211 mmol) in tetrahydrofuran (500 mL) at −78° C. was added pivaloyl chloride (26.0 ml, 211 mmol). After 20 min, the mixture was warmed to 0° C. for 1.0 h and then recooled to −78° C. To a stirred solution of (R)-(−)-4-benzyl-2-oxazolidinone (37.4 g, 211 mmol) in tetrahydrofuran (500 ml) at −78° C. was added nBuLi (84.5 ml, 211 mmol, 2.5M in hexanes) dropwise over 10 minutes. After 20 minutes, the lithium reagent was transferred to the mixed anhydride via cannula. After 10 minutes, the reaction was warmed to 0° C. for 1.0 h. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The reaction mixture was filtered and concentrated at reduced pressure to give 2-1 as a solid which was triturated with ethyl ether and filtered to give a white solid.
Reaction SMILES: [C:1]([O:9][C@H:10]1[C@H:14]([OH:15])[CH2:13][N:12]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[C@H:11]1[CH2:26][F:27])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(Cl)(Cl)C(=N)O[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.FC(F)(F)S(O)(=O)=O.C(=O)([O-])O.[Na+]>C(Cl)Cl.C1CCCCC1.C(OCC)(=O)C>[C:1]([O:9][C@H:10]1[C@@H:14]([O:15][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:13][N:12]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[C@H:11]1[CH2:26][F:27])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O[C@H]1[C@H](O)CN(C(=O)OCc2ccccc2)[C@H]1CF)c1ccccc1
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: O=C(O[C@H]1[C@@H](OCc2ccccc2)CN(C(=O)OCc2ccccc2)[C@H]1CF)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
The compound (344 mg, 0.92 mmol) synthesized in Example 10 (10a) was dissolved in methylene chloride:cyclohexane (1:2, 10 mL) and benzyl trichloroacetoimidate (0.68 mL, 3.68 mmol) and trifluoromethane sulfonic acid (16 μL, 0.18 mmol) were added thereto, followed by stirring of the mixture at room temperature for 4 hours. After saturated aqueous sodium hydrogencarbonate (1 mL) was added to the reaction mixture at 0° C. and the mixture was diluted with ethyl acetate (20 mL), the mixture was washed with water (20 mL) and saturated brine (20 mL) and dried with anhydrous sodium sulfate, followed by distilling off of the solvent under reduced pressure. The residue was purified using silica gel flash column chromatography (hexane:ethyl acetate, 8:1-5:1, V/V) to obtain a colorless oil (307 mg, 68%).
Reaction SMILES: C[Si](C#C[C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=1)(C)C.CO.C(=O)([O-])[O-].[K+].[K+].O1CC[CH2:24][CH2:23]1>>[C:23]([NH:13][C:10]1[CH:9]=[CH:8][CH:7]=[CH:12][N:11]=1)#[CH:24]
Reactant: C[Si](C)(C)C#Cc1ccc(N)nc1
Reactant: C1CCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#CNc1ccccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a solution of 5-trimethylsilanylethynyl-pyridin-2-ylamine (26 mg, 137 μmol) described in Manufacturing Example 28-1-2 in tetrahydrofuran (1 mL) and methanol (1 mL) was added potassium carbonate (37.9 mg, 274 μmol) at room temperature, which was stirred for 1 hour at room temperature. The reaction solution was partitioned into water and ethyl acetate at 0° C. The organic layer was washed with saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (16 mg, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:12]([NH:13][CH3:14])[CH2:11][N:10]([C:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][N:24]=4)[CH2:19][CH2:18]3)=[O:16])[CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:39]([O:41][CH2:42][CH3:43])=[O:40]>ClCCl>[CH2:42]([O:41][C:39](=[O:40])[N:13]([C@H:12]1[C@H:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:9][N:10]([C:15]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][N:24]=3)[CH2:19][CH2:18]2)=[O:16])[CH2:11]1)[CH3:14])[CH3:43]
Reactant: CN[C@@H]1CN(C(=O)C2CCN(c3ccc(C#N)cn3)CC2)C[C@H]1c1ccc(Cl)cc1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N(C)[C@@H]1CN(C(=O)C2CCN(c3ccc(C#N)cn3)CC2)C[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.6 %

Procedure:
To a solution of 4-[(3R,4S)-3-(4-Chloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carbonitrile (30 mg, 0.07 mmol) in dichloromethane (1 mL) were added triethylamine (13 uL, 0.09 mmol) and ethyl chloroformate (9 uL, 0.09 mmol) and the reaction mixture was stirred at ambient temperature for 3 h. After concentration it was purified by chromatography affording the title compound (20 mg, 57%) as a colorless foam. MS m/e: 496.4 [M]+.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:6]2)[NH2:2].CCN(C(C)C)[CH:23]([CH3:25])[CH3:24].CN(C=[O:33])C>>[O:13]=[C:8]1[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:6][C:5]2[N:4]=[C:3]([NH:1][NH:2][C:24](=[O:33])[CH2:23][CH3:25])[CH:12]=[CH:11][C:10]=2[NH:9]1
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(C)C=O
Reactant: NNc1ccc2[nH]c(=O)c(-c3ccccc3)cc2n1
Product: CCC(=O)NNc1ccc2[nH]c(=O)c(-c3ccccc3)cc2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 6-hydrazino-3-phenyl-1,5-naphthyridin-2(1H)-one (7-2) (70 mg, 0.277 mmol) and DIPEA (0.2 mL, 1.15 mmol) in DMF (3 mL) was stirred at room temperature for 0.5 hours. The solvent was removed under reduced pressure to give N′-(6-oxo-7-phenyl-5,6-dihydro-1,5-naphthyridin-2-yl)propanohydrazide (7-3) as yellow solid.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[H][H].[CH3:13][CH:14]([C:16]1[N:17]=[C:18]([C:24]2[C:29](F)=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:31])[O:19][C:20]=1[O:21][CH2:22][CH3:23])[CH3:15]>CN(C=O)C>[CH3:13][CH:14]([C:16]1[N:17]=[C:18]([C:24]2[C:25]([Cl:31])=[CH:26][CH:27]=[CH:28][C:29]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[O:19][C:20]=1[O:21][CH2:22][CH3:23])[CH3:15]
Reactant: CCOc1oc(-c2c(F)cccc2Cl)nc1C(C)C
Reactant: OCc1ccccc1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1oc(-c2c(Cl)cccc2OCc2ccccc2)nc1C(C)C
Temperature: 70 °C
Reaction time: 5 h

Procedure:
To 20 ml DMF solution containing 0.39 g benzyl alcohol, was added 60% sodium hydride in an amount of 0.16 g. After the end of hydrogen gas generation, DMF solution containing 1.0 g 4-(2-propyl)-5-ethoxy-2-(chloro-6-fluorophenyl)oxazole was added to the solution while keeping at -10° C. The solution reacted was heated up to 70° C. and then stirred for 5 hours. After completing the reaction, the solution reacted was poured into ice water and then extracted with ethyl acetate. The organic layer obtained was washed with water and saturated saline solution in turn, then dried by using anhydrous magnesium sulfate, and the solvent used was removed by distillation under reduced pressure. The residue obtained was purified by using silica gel column chromatography, affording the objective substance in an amount of 0.82 g.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:17]O>>[Br:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: CO
Reactant: O=C(O)c1ccc(Br)cc1Br
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(Br)cc1Br
Temperature: 25 °C

Procedure:
A solution of 2,4-dibromobenzoic acid (52.0 g, 176 mmol, 1.00 equiv, 95%) and sulfuric acid (20 mL) in methanol (400 mL) was stirred at 90° C. overnight. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was diluted with 500 mL of ethyl acetate and washed with 3×100 mL of H2O followed by 1×100 mL of NaHCO3 (aq., sat. Note: gas evolution occurs). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. This resulted in 45.0 g (78%) of methyl 2,4-dibromobenzoate as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1.FC(F)(F)C(=N[Si](C)(C)C)O[Si](C)(C)C.[Si](S(C(F)(F)F)(=O)=O)(C)(C)C.C(O[C@@H:43]1[O:65][C@H:64]([CH2:66][O:67]C(=O)C2C=CC=CC=2)[C@@H:54]([O:55]C(=O)C2C=CC=CC=2)[C@H:44]1[O:45]C(=O)C1C=CC=CC=1)(=O)C>C(#N)C>[Cl:1][C:2]1[N:3]([C@@H:43]2[O:65][C@H:64]([CH2:66][OH:67])[C@@H:54]([OH:55])[C@H:44]2[OH:45])[C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1
Reactant: Clc1nc2cc(Cl)c(Cl)cc2[nH]1
Reactant: CC(=O)O[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: C[Si](C)(C)N=C(O[Si](C)(C)C)C(F)(F)F
Agent: C[Si](C)(C)S(=O)(=O)C(F)(F)F
Solvent: CC#N
Product: OC[C@H]1O[C@@H](n2c(Cl)nc3cc(Cl)c(Cl)cc32)[C@H](O)[C@@H]1O
Temperature: 75 °C
Reaction time: 0.75 h

Procedure:
2,5,6-Trichlorobenzimidazole (700 mg, 0.0032 moles) was dissolved in acetonitrile and BSTFA (1 ml, 0.0038 moles) was added. The mixture was heated at 75° C. for 20 minutes. TMSTf (1 ml, 0.0051 moles) and 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (1.9 g, 0.0038 moles) were added while heating was continued for 45 min. The acetonitrile was removed under reduced pressure and the protected nucleoside was separated on a silica column, eluting with chloroform. The benzoyl protecting groups were removed by overnight treatment at room temperature with methanolic ammonia. The nucleoside was separated on a column using 50% EtOAc/hexane and then 10% MeOH/CHCl3. The isolated compound was recrystallized from methanol. Yield: (74%); MP: 185°-186° C.; TLC (10% MeOH/CHCl3): Rf=0.20; 1H NMR (DMSO-d6) δ3.68 ppm (q, 2H), 4.00 (d, 1H), 4.12 (t, 1H), 4.40 (q, 1H), 5.28 (d, 1H), 5.41 (t, 1H), 5.49 (d, 1H), 5.57 (d, 1H), 7.96 (s, 1H), 8.55 (s, 1H); 13C NMR (DMSO-d6, Broad band decoupling): d 61.08 ppm, 69.80, 71.70, 86.47, 89.16, 114.93, 120.04, 125.77, 125.97, 132.30, 140.96, 142.16; MS (Fast Atom Bombardment): m/e (M+ 6) 359, (M+ 4) 357, (M+ 2) 355, (M+) 353, 319, 285, 263, 221, 187, 177, 133, 115, 103, 97, 85.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][C:18]2[N:23]=[CH:22][N:21]=[C:20]([NH:24][CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[CH:19]=2)=[CH:4][CH:3]=1.Cl[C:31]1C=CC(C2N=C3C=CC=CN3C=2CC2C=C(Cl)N=CN=2)=CC=1.CN1CCNCC1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][C:18]2[CH:19]=[C:20]([N:24]3[CH2:31][CH2:29][N:27]([CH3:28])[CH2:26][CH2:25]3)[N:21]=[CH:22][N:23]=2)=[CH:6][CH:7]=1
Reactant: CN(C)CCNc1cc(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)ncn1
Reactant: Clc1ccc(-c2nc3ccccn3c2Cc2cc(Cl)ncn2)cc1
Agent: CN1CCNCC1
Product: CN1CCN(c2cc(Cc3c(-c4ccc(Cl)cc4)nc4ccccn34)ncn2)CC1

Procedure:
The title compound was prepared according to Method D and the experimental for compound 243 from 2-(4-chlorophenyl)-3-((6-chloropyrimidin-4-yl)methyl)imidazo[1,2-a]pyridine and 1-methylpiperazine. (59 mg, 45%) m/e+=419 (M+H+). 1H-NMR (400 MHz, CDCl3, δ): 8.57 (s, 1H), 7.93 (d, 1H, D, J=7.0 Hz), 7.73 (d, 2H, D, J=8.4 Hz), 7.67 (d, 1H, D, J=8.8 Hz), 7.42 (d, 2H, D, J=8.8 Hz), 7.25 (t, 1H, D, J=7.7 Hz), 6.81 (t, 1H, D, 7.7 Hz), 6.05 (s, 1H), 4.39 (s, 2H), 3.48 (m, 4H), 2.37 (m, 4H), 2.28 (s, 3H).
Reaction SMILES: Br[C:2]1[C:6]([CH3:7])=[C:5](I)[S:4][C:3]=1[CH:9]1[O:13]CCO1.[Cl:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][C:20]=1[O:21]C.C[O:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[Cl:14][C:15]1[CH:16]=[C:17]([C:5]2[S:4][C:3]([CH:9]=[O:13])=[C:2]([C:31]3[CH:32]=[CH:33][C:28]([OH:27])=[CH:29][CH:30]=3)[C:6]=2[CH3:7])[CH:18]=[CH:19][C:20]=1[OH:21]
Reactant: COc1ccc(B(O)O)cc1
Reactant: COc1ccc(B(O)O)cc1Cl
Reactant: Cc1c(I)sc(C2OCCO2)c1Br
Product: Cc1c(-c2ccc(O)c(Cl)c2)sc(C=O)c1-c1ccc(O)cc1
Yield: 75 %

Procedure:
Starting from 2-(3-bromo-5-iodo-4-methylthien-2-yl)-1,3-dioxolane (2.5 g, 6.7 mmol) and 3-chloro-4-methoxyphenylboronic acid (1.5 g, 8.0 mmol) in place of 4-methoxyphenylboronic acid (Step 1), and substituting 4-methoxyphenylboronic acid in place of 3-methoxyphenylboronic acid (Step 2), the title compound (0.41 g, 75%) was synthesized in essentially the same manner as described in Example 1.
Reaction SMILES: CO[C:3]1[C:4]2[C:9]([N:10]=[C:11]3[C:16]=1[C:15]1[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=1[CH2:13][CH2:12]3)=[CH:8][CH:7]=[CH:6][C:5]=2[C:21](OC)=[O:22].O.[NH2:26][NH2:27].C(OCC)(=O)C.O>CC(N(C)C)=O.[Cl-].[Na+].O>[N:26]1[NH:27][C:21](=[O:22])[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[C:3]=1[C:16]1[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[CH2:13][CH2:12][C:11]=1[NH:10]3
Reactant: NN
Reactant: COC(=O)c1cccc2nc3c(c(OC)c12)-c1ccccc1CC3
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: O=c1[nH]nc2c3c(cccc13)NC1=C2c2ccccc2CC1
Temperature: 130 °C
Yield: 39 %

Procedure:
A mixture of methyl 12-methoxy-5,6-dihydrobenzo[a]acridine-11-carboxylate (20 mg, 0.06 mmol) and hydrazine hydrate (0.5 mL) in DMA (0.8 mL) was heated at 130° C. for 4 h. The reaction mixture was cooled, treated with ethyl acetate (0.5 mL), water (1 mL) and brine (1 mL). The resulting precipitate was collected by filtration, dissolved in a mixture of methanol:dichloromethane (1:8, 10 mL), dried over Na2SO4, filtered, concentrated, chromatographed on silica gel using gradint eluant of 0-3.2% methanol in dichloromethane to give the desired compound as a yellow solid (7 mg, 39%). 1H NMR (DMSO-d6) δ11.85 (s, 1H), 10.88 (s, 1H), 8.77-8.78 (m, 1H), 7.66-7.68 (m, 1H), 7.56-7.57 (m, 1H), 7.35-7.37 (m, 1H), 7.19-7.20 (m, 2H), 7.09-7.11 (m, 1H), 2.83-2.85 (m, 2H), 2.66-2.69 (m, 2H). MS (ESI) m/e [M+1]+288.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:26]=[CH:27][CH:28]=2)[CH:12]=[C:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)=[N:6][CH:7]=1.[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32].C1(C)C=CC=CC=1>C(Cl)Cl>[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32].[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:28]=[CH:27][CH:26]=[C:11]([CH:12]=[C:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]3)[CH:10]=2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ccc(Br)cn3)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: Brc1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Reaction time: 2 h

Procedure:
tert-Butyl 4-(3-(5-bromopyridin-2-yloxy)benzylidene)piperidine-1-carboxylate (1.36 g, 3.05 mmol) from Step 4 was dissolved in CH2Cl2 (15 mL) and treated with trifluoroacetic acid (6 mL). After 2 h, toluene was added and the reaction was concentrated in vacuo. After evaporating again from toluene, the residue was dried in vacuo to afford the title compound (2.08 g, quantitative yield based on 3 eq trifluoroacetic acid) as an orange oil. This material was dissolved in acetonitrile (0.33 mmol/mL) and used in the next step.