Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:21]=1[C:27]1[CH:32]=[CH:31][C:30](C(O)=O)=[CH:29][CH:28]=1.[NH2:36][CH2:37][CH:38]([OH:49])[CH2:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=1>>[CH3:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([CH3:19])[C:21]=1[C:27]1[CH:28]=[CH:29][C:30]([C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:36][CH2:37][CH:38]([OH:49])[CH2:39][O:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)=[O:18])=[O:7])=[CH:31][CH:32]=1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: Cc1cccc(C)c1-c1ccc(C(=O)O)cc1
Reactant: COc1ccc(OCC(O)CN)cc1
Product: CON=C1C[C@@H](C(=O)NCC(O)COc2ccc(OC)cc2)N(C(=O)c2ccc(-c3c(C)cccc3C)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′,6′-dimethyl[1,1′-biphenyl]-4-carboxylic acid, and (2RS)-1-amino-3-(4-methoxyphenoxy)-2-propanol, the title compound was obtained in 87% purity by HPLC. MS(ESI+): m/z=546.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[S:9][CH2:8][C:7](=O)[CH2:6]2.[CH2:14]([NH:17][CH2:18][CH2:19][C:20](OC)=[O:21])[CH2:15][CH3:16].FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[S:9][CH2:8][C:7]3[N:17]([CH2:14][CH2:15][CH3:16])[CH2:18][CH2:19][C:20](=[O:21])[C:6]=3[C:5]=2[CH:4]=1
Reactant: CCCNCCC(=O)OC
Reactant: COc1ccc2c(c1)CC(=O)CS2
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CCCN1CCC(=O)C2=C1CSc1ccc(OC)cc12

Procedure:
A mixture of 7.5 g 6-methoxythiochroman-3-one [J. Org. Chem. 34, 1566 (1969)], 5.8 g of methyl 3-(propylamino)-propionate and 0.8 ml of trifluoroacetic acid in 80 ml of toluene is heated under reflux for 22 hours in a Dean Stark apparatus. Additional 0.8 ml portions of trifluoroacetic acid are added after 2, 5, and 16 hours. The solvent is removed, the residue is taken up in ether and the product is extracted with 3N hydrochloric acid. After neutralization the aqueous layers are extracted with ethyl acetate, the organic layer is dried and the solvent is removed. The product crystallized from a small volume of methanol to afford 9-methoxy-4-propyl-1,2,3,5-tetrahydro-4H-[1]-benzothiopyrano[3,4-b]pyridine-1-one, melting point 108°-110°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][CH:10](OCC)OCC)[CH:3]=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[CH:10]=[CH:9][O:8][C:4]=2[CH:3]=1
Reactant: CCOC(COc1cccc(Br)c1)OCC
Solvent: Cc1ccccc1
Product: Brc1ccc2ccoc2c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a solution of the acetal 1-2 in toluene (200 mL) was added polyphosphoric acid (20 g). The biphasic mixture was heated to 100° C. and stirred at this temperature for 4 h. The mixture was cooled to room temperature, poured onto ice, and extracted with Et2O (2×200 mL). The combined organic extracts were washed with saturated aq. NaHCO3 and brine. The solution was dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (100% hexanes) to give the product 1-3 as a yellow oil. TLC Rf=0.3 (100% hexanes). 1H NMR (300 MHz, CDCl3) δ 7.68 (s, 1H), 7.60 (d, 1H, J=2.1 Hz), 7.46 (d, 1H, J=8.4 Hz), 7.36 (dd, 1H, J=8.1, 1.5 Hz), 6.75 (dd, 1H, J=7.1, 0.9 Hz).
Reaction SMILES: N1C2C(=CC=CC=2)C=CC=1.[H][H].[CH2:13]([O:15][C:16](=[O:22])[CH2:17][CH:18]([NH2:21])[C:19]#[CH:20])[CH3:14]>CCO.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[CH2:13]([O:15][C:16](=[O:22])[CH2:17][CH:18]([NH2:21])[CH:19]=[CH2:20])[CH3:14]
Reactant: C#CC(N)CC(=O)OCC
Reactant: [H][H]
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CCO
Solvent: c1ccc2ncccc2c1
Product: C=CC(N)CC(=O)OCC
Reaction time: 2.5 h
Yield: 185.1 %

Procedure:
A mixture of 5% Pd/BaSO4 (0.025 g) and quinoline (0.30 mL) was stirred under a ballon of hydrogen for 30 minutes. 3-Amino-pent-4-ynoic acid ethyl ester 17-1 (1.77 g, 10.0 mmol) in EtOH (15 mL) was added and the solution stirred for an additional 2.5 hours. The solution was filtered through a pad of celite and concentrated in vacuo to provide 2.65 g of crude product 19-1.
Reaction SMILES: [N:1]([C:4]1[CH:24]=[CH:23][C:7]([O:8][C:9]2[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([S:21][CH3:22])[N:16]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:6][CH:5]=1)=[C:2]=S.C1CCC(N=C=NC2CCCCC2)CC1.[F:40][C:41]1[CH:42]=[C:43]([NH2:49])[C:44]([NH2:48])=[CH:45][C:46]=1[F:47].C1COCC1>C(Cl)Cl>[F:40][C:41]1[C:46]([F:47])=[CH:45][C:44]2[NH:48][C:2]([NH:1][C:4]3[CH:24]=[CH:23][C:7]([O:8][C:9]4[C:14]([C:15]5[CH:20]=[CH:19][N:18]=[C:17]([S:21][CH3:22])[N:16]=5)=[CH:13][CH:12]=[CH:11][N:10]=4)=[CH:6][CH:5]=3)=[N:49][C:43]=2[CH:42]=1
Reactant: Nc1cc(F)c(F)cc1N
Reactant: CSc1nccc(-c2cccnc2Oc2ccc(N=C=S)cc2)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CSc1nccc(-c2cccnc2Oc2ccc(Nc3nc4cc(F)c(F)cc4[nH]3)cc2)n1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A resealable pressure vial, under nitrogen, was charged with 4-(2-(4-isothiocyanatophenoxy)pyridin-3-yl)-2-(methylthio)pyrimidine (1.12 g, 3.18 mmol), PS-DCC (1.27 mmol/g polymer supported cyclohexyl carbodiimide) (7.50 g, 9.53 mmol), 4,5-difluorobenzene-1,2-diamine (0.69 g, 4.77 mmol), and THF (45 ml, 0.07 M). The vessel was sealed and the reaction mixture stirred at 70° C. for 4 h. The reaction mixture was cooled to RT, diluted with DCM, and filtered over celite. The filtrate was concentrated to afford yellow residue, which was triturated with DCM, filtered, and dried under high vacuum to afford 5,6-difluoro-N-(4-(3-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine as a tan solid. MS m/z=463.1 [M+H]+. Calc'd for C23H16F2N6OS: 462.48.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:4]=1[NH2:5])[CH3:2].N1C=CC=CC=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[CH2:1]([C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:4]=1[NH:5][S:20]([CH3:19])(=[O:22])=[O:21])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCc1ccc([N+](=O)[O-])cc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCc1ccc([N+](=O)[O-])cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
To a solution of 2-ethyl-5-nitroaniline (200 mg, 1.20 mmol) in DCM (5 mL) was added pyridine (0.195 mL, 2.41 mmol) and methanesulfonyl chloride (0.11 mL, 1.44 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with DCM, washed with water and brine and dried to give Intermediate 78A (290 mg, 99%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.35 (1H, d, J=2.26 Hz), 8.04 (1H, dd, J=8.53, 2.26 Hz), 7.44 (1H, d, J=8.53 Hz), 6.59 (1H, br. s.), 3.15 (3H, s), 2.76 (2H, q, J=7.53 Hz), 1.32 (3H, t, J=7.53 Hz).
Reaction SMILES: [CH3:1][CH:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[F:15][C:16]([F:26])([F:25])[C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br>C1COCC1>[CH3:1][C:2]([CH2:20][C:19]1[CH:22]=[CH:23][CH:24]=[C:17]([C:16]([F:15])([F:25])[F:26])[CH:18]=1)([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(Cc1cccc(C(F)(F)F)c1)C(=O)OCC

Procedure:
Diethyl 2-methylmalonate was converted, in THF, into the anion using 1 eq. of sodium hydride and alkylated with 1.05 eq. of 3-trifluoromethylbenzyl bromide. After working up in the standard manner, diethyl 2-methyl-2-(3-trifluoromethylbenzyl)malonate was obtained. Colorless oil, MS (ES):333 (M+1)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].C1(C)C=CC=CC=1.C([Li])(C)(C)C.CN(C)[CH:30]=[O:31]>O.C(OCC)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:30]=[O:31])[C:3]=1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)Nc1ccccc1F
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Nc1c(F)cccc1C=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl 2-fluorophenylcarbamate (42.7 g, 202 mmol) was concentrated from toluene in vacuo (3×) to remove any traces of water. The resulting residue was dissolved in tetrahydrofuran (600 mL), and cooled to −78° C. To this was added tert-butyllithium (1.7 M in pentane, 285 mL, 485 mmol) in dropwise fashion. After addition was complete, the reaction was stirred at −78° C. for 30 minutes. The solution was allowed to gradually warm to −20° C. before re-cooling to −78° C. To this was added dimethylformamide (46.9 mL, 606 mmol). The reaction was allowed to gradually warm to room temperature overnight. The reaction was poured into a separatory funnel containing diethyl ether and water. The organics were washed with water (3×) and concentrated. The combined aqueous washes were neutralized with 1 M potassium bisulfate and extracted with diethyl ether. The ethereal layers were combined with the other organics, washed with water, then brine, dried over magnesium sulfate, and concentrated to give 48.1 g (100%) as a yellow oil which was used without further purification. 1H-NMR (CDCl3, 500 MHz) δ 1.50 (s, 9H), 7.27 (m, 1H), 7.35 (m, 1H), 7.56 (d, J=7.6 Hz, 1H), 7.85 (bs, 1H), 9.99 (d, J=1.2 Hz, 1H). Mass spec.: 262.16 (MNa)+.
Reaction SMILES: ClCCOC1C=C(C=CC=1)C#N.Cl[CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[C:21]#[N:22].N1C=NC(S)=N1.[F:32][C:33]([F:41])([F:40])[C:34]1[NH:38][N:37]=[C:36]([SH:39])[N:35]=1>>[F:32][C:33]([F:41])([F:40])[C:34]1[NH:38][N:37]=[C:36]([S:39][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=2)[C:21]#[N:22])[N:35]=1
Reactant: FC(F)(F)c1nc(S)n[nH]1
Reactant: N#Cc1cccc(OCCCCl)c1
Agent: N#Cc1cccc(OCCCl)c1
Agent: Sc1nc[nH]n1
Product: N#Cc1cccc(OCCCSc2n[nH]c(C(F)(F)F)n2)c1

Procedure:
By a method similar to that in Reference Example 2, and using, instead of 3-[(2-chloroethyl)oxy]benzonitrile, 3-[(3-chloropropyl)oxy]benzonitrile obtained in Reference Example 4 and using, instead of 1H-1,2,4-triazole-3-thiol, 5-(trifluoromethyl)-1H-1,2,4-triazole-3-thiol, the title compound was obtained as a yellow oil (1.25 g, 64%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:11]2([C:31]([F:34])([F:33])[F:32])[O:15][N:14]=[C:13]([C:16]3[CH:29]=[CH:28][C:19]([C:20]([NH:22][CH:23]4[CH2:27][CH2:26][CH2:25][O:24]4)=[O:21])=[C:18]([CH3:30])[CH:17]=3)[CH2:12]2)[CH:7]=[C:8]([Cl:10])[CH:9]=1.Cl[C:36]([O:38][CH3:39])=[O:37]>O1CCCC1.O>[Cl:3][C:4]1[CH:5]=[C:6]([C:11]2([C:31]([F:33])([F:32])[F:34])[O:15][N:14]=[C:13]([C:16]3[CH:29]=[CH:28][C:19]([C:20]([N:22]([CH:23]4[CH2:27][CH2:26][CH2:25][O:24]4)[C:36](=[O:37])[O:38][CH3:39])=[O:21])=[C:18]([CH3:30])[CH:17]=3)[CH2:12]2)[CH:7]=[C:8]([Cl:10])[CH:9]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NC1CCCO1
Reactant: COC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)N(C(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C)C1CCCO1
Yield: 23.7 %

Procedure:
In a suspension of 0.07 g of 55% oily sodium hydride in 10 mL of tetrahydrofuran, a solution of 0.49 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-2-methyl-N-(2-tetrahydrofuranyl)benzoic acid amide in 5 mL of tetrahydrofuran was added dropwise under cooling with ice and with stirring. After the completion of the addition dropwise, it was stirred at room temperature for 10 minutes. Then, 0.15 g of methyl chloroformate was added, and continued to stir at the same temperature further for 15 hours. After the completion of the reaction, the reaction was poured in 10 mL of water, extracted with ethyl acetate (20 mL×2), the organic phase was dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (2:3) to obtain 0.13 g of the aimed product as colorless resinous substance.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5](=[O:9])[O:6][C:7]=1[CH3:8].[I-].[Na+].C(O)=[O:13].C>ClCCl.O.C(N(CC)CC)C>[OH:13][CH2:2][C:3]1[O:4][C:5](=[O:9])[O:6][C:7]=1[CH3:8]
Reactant: Cc1oc(=O)oc1CCl
Reactant: O=CO
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1oc(=O)oc1CO
Temperature: 12.5 °C
Reaction time: 5.5 h

Procedure:
4-Chloromethyl-5-methyl-1,3-dioxol-2-one (25 g) was dissolved in dichloromethane (250 ml) at 20-25° C., sodium iodide (2.5 g) and formic acid (22 g) was added at 20-25° C. Resulting mixture was cooled to 10-15° C. and triethyl amine (46.8 g) was added at 10-15° C. in 20-25 minutes. Resulting mixture was stirred for 5.0-6.0 hrs at 40-45° C., cooled to 20-25° C. and added DM water (250 ml). Organic layer was separated and washed with brine solution, and distilled out. Residue was dissolved in methanol (300 ml), methanolic HCl was added drop wise and resulting mixture was stirred for 1 hrs at 60-65° C. Active charcoal (1 g) was added to the reaction mass and stirred for 20-25 minutes at 50-55° C. Reaction mass was filtered through hyflo bed and bed was washed by MeOH (12 ml). The filtrate was evaporated under vacuum at 40-45° C. Obtained product was diluted with ethyl acetate (75 ml) and evaporated under vacuum to remove methanol content. (Yield: 0.67 g; 76.5%)
Reaction SMILES: [Na].O[CH:3]=[CH:4][C:5]#[N:6].Cl.[CH2:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(#N)C>[CH2:8]([NH:15][CH:3]=[CH:4][C:5]#[N:6])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: N#CC=CO
Reactant: NCc1ccccc1
Agent: Cl
Agent: [Na]
Solvent: CC#N
Product: N#CC=CNCc1ccccc1
Yield: 57.1 %

Procedure:
32.5 g (0.25 mol) of sodium-3-hydroxyacrylonitrile (content 70%) and 43.1 g (0.3 mol) of benzylamine hydrochloride are refluxed for 5 h in 150 ml of acetonitrile. After removal of the solid by filtration and withdrawal of the solvent, the product was dissolved in chloroform and washed with water. Subsequent vacuum distillation yielded 22.6 g of 3-benzylaminoacrylonitrile (57.1%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[N+:13]([O-])=O>C1COCC1.CCO.[Pd]>[NH2:13][C:3]1[CH:4]=[C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[CH:6]=[CH:7][C:2]=1[OH:1]
Reactant: CC(C(=O)O)c1ccc(O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C(=O)O)c1ccc(O)c(N)c1
Reaction time: 3 h

Procedure:
A mixture of (1) (810 mg, 1 mmol) in THF (20 ml) and EtOH (20 ml) is slowly added to 10% Pd/C (90 mg) at room temperature. The reaction mixture is hydrogenated for 3 h with H2 balloon at 45 psi. The mixture is filtered through celite pad and washed with EtOH. The filtrate is concentrated in vacuo.
Reaction SMILES: [C:1](O)(=O)C.C(N)=N.C([O-])(=O)C.COCCO.[NH2:17][C:18]1[CH:46]=[CH:45][CH:44]=[CH:43][C:19]=1[NH:20][C:21]1[CH:33]=[CH:32][C:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[C:23]([NH:34][C:35](=[O:42])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:22]=1>O.C(OCC)(=O)C>[C:35]([NH:34][C:23]1[CH:22]=[C:21]([N:20]2[C:19]3[CH:43]=[CH:44][CH:45]=[CH:46][C:18]=3[N:17]=[CH:1]2)[CH:33]=[CH:32][C:24]=1[C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])(=[O:42])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)c1ccc(Nc2ccccc2N)cc1NC(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: N=CN
Solvent: COCCO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(-n2cnc3ccccc32)cc1NC(=O)c1ccccc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 79.8 %

Procedure:
28 mg of formamidine acetate was acetate to 1.0 mL of ethylene glycol monomethyl ether solution containing 44 mg of tert-butyl 4-(2-aminoanilino)-2-(benzamido)benzoate at room temperature and stirred at 80° C. for 3 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and water were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [PSQ100B (spherical) manufactured by Fuji Silysia Chemical Ltd., eluent; hexane:ethyl acetate=1:1] to obtain 36 mg of tert-butyl 2-(benzamido)-4-(1H-benzimidazol-1-yl)benzoate as pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=O)[CH2:7]Br)=[CH:4][CH:3]=1.[C:12]([NH2:15])(=[O:14])[CH3:13]>>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[N:15]=[C:12]([CH3:13])[O:14][CH:7]=2)=[CH:4][CH:3]=1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: CC(N)=O
Product: Cc1nc(-c2ccc(Br)cc2)co1
Reaction time: 2.5 h
Yield: 22.5 %

Procedure:
4-Bromophenacyl bromide (21.3 g) and acetamide (11.3 g) were heated together at 130° C. under argon. After 2.5 h the reaction mixture was allowed to cool, and partitioned between water (150 ml) and Et2O (150 ml). The organic phase was washed with aqueous NaOH (0.5N), aqueous HCl (0.5M) and saturated aqueous NaCl solution (100 ml of each), dried (MgSO4) and evaporated to give a brown solid which was recrystallised from hexanes to give the title compound (D14) as an orange solid (4.1 g). LCMS electrospray (+ve) 239 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([CH2:18][N:19]2[CH2:24][CH2:23][N:22]([C:25](OCC=C)=O)[CH:21]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:20]2)[CH:15]=[C:14]2[C:9]=1[CH2:10][NH:11][C:12](=[O:46])[N:13]2[C:38]1[C:43]([Cl:44])=[CH:42][CH:41]=[CH:40][C:39]=1[Cl:45].O.[CH2:48]([SnH](CCCC)CCCC)[CH2:49]CC>C(Cl)Cl.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>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([CH2:18][N:19]2[CH2:24][CH2:23][NH:22][CH:21]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:20]2)[CH:15]=[C:14]2[C:9]=1[CH2:10][NH:11][C:12](=[O:46])[N:13]2[C:38]1[C:43]([Cl:44])=[CH:42][CH:41]=[CH:40][C:39]=1[Cl:45].[CH2:25]([N:22]1[CH2:23][CH2:24][N:19]([CH2:18][C:16]2[CH:15]=[C:14]3[C:9]([CH2:10][NH:11][C:12](=[O:46])[N:13]3[C:38]3[C:43]([Cl:44])=[CH:42][CH:41]=[CH:40][C:39]=3[Cl:45])=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH:17]=2)[CH2:20][CH:21]1[C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])[CH:48]=[CH2:49]
Reactant: C=CCOC(=O)N1CCN(Cc2cc(-c3ccccc3Cl)c3c(c2)N(c2c(Cl)cccc2Cl)C(=O)NC3)CC1C(=O)OC(C)(C)C
Reactant: CCCC[SnH](CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: O
Product: C=CCN1CCN(Cc2cc(-c3ccccc3Cl)c3c(c2)N(c2c(Cl)cccc2Cl)C(=O)NC3)CC1C(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)C1CN(Cc2cc(-c3ccccc3Cl)c3c(c2)N(c2c(Cl)cccc2Cl)C(=O)NC3)CCN1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 1-allyl 2-tert-butyl 4-{[5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl]methyl}piperazine-1,2-dicarboxylate (EXAMPLE AAA10, STEP A, 200 mg, 0.29 mmol) and dichlorobis(triphenylphosphine)palladium(II) (10.2 mg, 0.0146 mL) in methylene chloride (3 mL) was added water (30 μL). To this mixture was added tributyltin hydride (94 μL, 0.348 mmol) rapidly. The mixture was stirred at rt for 5 h, diluted with methylene chloride, washed with water and brine, and dried over anhydrous sodium sulfate. Removal of the solvent and subsequent purification by preparative thin layer chromatography using 5% of 2N ammonium in methanol/methylene chloride as eluent provided tert-butyl 4-{[5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl]methyl}piperazine-2-carboxylate and tert-butyl 1-allyl-4-{[5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl]methyl}piperazine-2-carboxylate.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:33]2[NH:37][CH:36]=[C:35]([C:38]([O-:40])=[O:39])[CH:34]=2)O1.[CH3:42]C1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:11]([O:10][C:9]([N:8]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=1)[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:33]2[NH:37][CH:36]=[C:35]([C:38]([O:40][CH3:42])=[O:39])[CH:34]=2)[CH:7]=1)=[O:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC1(C)OB(c2cc(C(=O)[O-])c[nH]2)OC1(C)C
Reactant: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Reactant: CC(C)(C)OC(=O)N(c1cccc([N+](=O)[O-])c1)c1ccnc(Cl)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COC(=O)c1c[nH]c(-c2cc(N(C(=O)OC(C)(C)C)c3cccc([N+](=O)[O-])c3)ccn2)c1
Temperature: 105 °C
Reaction time: 18 h
Yield: 543.8 %

Procedure:
A mixture of tert-Butyl 2-chloropyridin-4-yl(3-nitrophenyl)carbamate (3.65 g, 10.43 mmol), methyl-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-3-carboxylate (5.48 g, 21.82 mmol), xantphos (0.72 g, 1.25 mmol) and Pd2 dba3 (0.72 g, 0.79 mmol) was added to a thick walled reaction vessel and purged with N2. A solution of 2M K2CO3 (8.76 mL) was added, followed by dioxane (67 mL). The reaction vessel was sealed and the mixture stirred at 105° C. for 18 h. The reaction vessel was cooled to rt and the mixture was filtered over celite, washing with EtOAc. The filtrate was concentrated to afford a dark oil, which was purified via column chromatography eluting with 30-50% EtOAc/hexanes to afford methyl 5-(4-(tert-butoxycarbonyl(3-nitrophenyl)amino)pyridine-2-yl)-1H-pyrrole-3-carboxylate (2.98 g, 65% yield) as an orange oil.
Reaction SMILES: [C:1]([C:3]1[C:8]([O:9][CH:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)=[CH:7][C:6](=[O:23])[N:5]([C:24]2[CH:25]=[N:26][C:27]([C:30]#[N:31])=[CH:28][CH:29]=2)[N:4]=1)#[N:2].[ClH:32].O1CCOCC1.CCOCC>C(Cl)Cl>[ClH:32].[C:30]([C:27]1[N:26]=[CH:25][C:24]([N:5]2[C:6](=[O:23])[CH:7]=[C:8]([O:9][CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:3]([C:1]#[N:2])=[N:4]2)=[CH:29][CH:28]=1)#[N:31]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(C#N)nc3)nc2C#N)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCOCC
Product: N#Cc1ccc(-n2nc(C#N)c(OC3CCNCC3)cc2=O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirring solution of tert-butyl 4-(3-cyano-1-(6-cyanopyridin-3-yl)-6-oxo-1,6-dihydropyridazin-4-yloxy)piperidine-1-carboxylate (22 mg, 0.050 mmol) in DCM (3 mL) at room temperature under argon was added 4 M HCl in dioxane (0.375 mL, 1.5 mmol). The reaction mixture was stirred at room temperature overnight. Et2O (10 mL) was added to the reaction mixture. The solid product was collected by filtration and further washed with ether (2 mL×2). After drying under vacuum for 2 hours, 17.3 mg (100%) of 1-(6-cyanopyridin-3-yl)-6-oxo-4-(piperidin-4-yloxy)-1,6-dihydropyridazine-3-carbonitrile HCl salt was obtained as an off-white solid. MS (ESI) 323 (M+H).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH:10][C:11](=[O:21])[C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[C:24](Cl)(Cl)=[O:25].[H][H]>CCO.[Pd]>[N+:18]([C:15]1[CH:14]=[CH:13][C:12]([C:11]2[O:21][C:24](=[O:25])[N:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:22])([F:23])[F:1])=[CH:8][CH:7]=3)[N:10]=2)=[CH:17][CH:16]=1)([O-:20])=[O:19]
Reactant: O=C(NNc1ccc(C(F)(F)F)cc1)c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Reactant: O=C(Cl)Cl
Agent: [Pd]
Solvent: CCO
Product: O=c1oc(-c2ccc([N+](=O)[O-])cc2)nn1-c1ccc(C(F)(F)F)cc1

Procedure:
5-(4-Nitrophenyl)-3-(4-trifluoromethylphenyl) 3H-[1,3,4]oxadiazole-2-one was prepared by treating the corresponding 4-nitrobenzoic acid N′-(4-trifluoromethylphenyl)hydrazide with phosgene, using conditions described by Reimlinger et al. in Chem. Ber. 1970, 103, 1934. The nitro group was then reduced to the amine by treatment with hydrogen and Pd/C in EtOH: mp 160-163° C.; 1H NMR (400 MHz, CDCl3) δ 8.1 (d, J=8.4 Hz, 2H), 7.75 (m, 4H), 6.75 (d, J=8.4 Hz, 2H), 4.1 (br s, 2H); MS m/z 322.6 (MAI).