Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][NH:11][CH:12]=2)=[CH:4][CH:3]=1.IC.[C:15](=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH3:15])[CH:12]=2)=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Brc1ccc(-c2c[nH]cn2)cc1
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: C1CCOC1
Product: Cn1cnc(-c2ccc(Br)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To a solution of Step 1 product (3.1 g, 13.90 mmol) in 50 mL of THF was added iodomethane (1.74 mL, 27.8 mmol) and cesium carbonate (5.43 g, 16.68 mmol). The reaction was stirred at rt overnight. EtOAc (150 mL) was added to the reaction, and the mixture was washed with water (2 times) and brine, dried over MgSO4, and concentrated to dryness. The residue was purified by silica column (10-80% EtOAc in hexanes) to give 2.8 g (yield 85%) 4-(4-bromophenyl)-1-methyl-1H-imidazole. LCMS: [M+1]+=237.
Reaction SMILES: CS[C:3]1[S:4][C:5](=[CH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][N:14]=[CH:13]3)[C:6](=[O:8])[N:7]=1.[S:20]1[CH:24]=[CH:23][N:22]=[C:21]1[NH2:25].CCN(C(C)C)C(C)C>>[N:16]1[C:17]2[C:12](=[CH:11][C:10](/[CH:9]=[C:5]3/[C:6](=[O:8])[N:7]=[C:3]([NH:25][C:21]4[S:20][CH:24]=[CH:23][N:22]=4)[S:4]/3)=[CH:19][CH:18]=2)[CH:13]=[N:14][CH:15]=1
Reactant: Nc1nccs1
Reactant: CSC1=NC(=O)C(=Cc2ccc3ncncc3c2)S1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(Nc2nccs2)S/C1=C\c1ccc2ncncc2c1

Procedure:
Similar procedure as described in example 1d was used, starting from 2-methylsulfanyl-5-quinazolin-6-ylmethylene-thiazol-4-one, thiazol-2-ylamine and DIEA to give 5-[1-quinazolin-6-yl-meth-(Z)-ylidene]-2-(thiazol-2-ylamino)-thiazol-4-one: LC-MS m/e observed. LC-MS m/e 340 (MH+).
Reaction SMILES: [C:1]([N:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2)#[N:2].[O-]Cl.[Na+].[OH:21]S([O-])(=O)=O.[Na+]>C(Cl)Cl>[C:1]([N:3]1[C:4]2[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=2[C:6](=[O:21])[CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=2)#[N:2]
Reactant: N#CN1c2ccccc2CCc2ccccc21
Reactant: O=S(=O)([O-])O
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: N#CN1c2ccccc2CC(=O)c2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
20 g (85 mmols) of (I) are dissolved in 120 ml of CH2Cl2. The solution is cooled to 0° C. and added with 0.24 g of 2,2,6,6-tetramethylpiperidine nitroxide, then with 180 ml of 1.4M NaClO, adjusted to pH 8.3 with a NaHSO4 saturated solution. The mixture is left for 1 hour at 0° C., then warmed to 20° C. for 4 hours. The organic phase is separated and washed with 50 ml of water, dried with 2 g of Na2SO4 and solvent is evaporated off. The residue is taken up with 50 ml of acetone and kept at 0° C. for 2 hours. The mixture is filtered, washed with 50 ml of cold acetone, dried at 60° C. for 4 hours to obtain 17 g of 5-cyano-10-oxo-10,11-dihydro-5H-dibenz[b,f]azepine (VII), m.p. 153-4° C., with 98.5% purity by HPLC (85% yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[N:12][C:13]([CH2:16]Cl)=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C([O-])(O)=O.[Na+]>C(#N)C.O.C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[N:12][C:13]([CH2:16][N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1ccc(CCl)nc1
Reactant: C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)NCc1ccc(CN2CCCCC2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.8 %

Procedure:
Add 3-(tert-butoxycarbonylamino-methyl)-6-chloromethyl-pyridine (500 mg, 1.95 mmol) to a solution of piperidine (0.58 mL, 5.84 mmol) and saturated aqueous NaHCO3 (2.5 mL) in acetonitrile (15 mL). Stir the mixture at room temperature overnight. Dilute the mixture with water (20 mL) and DCM (25 mL), separate the layers and extract the aqueous layer with DCM (3×20 mL). Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel (80 g pre-packed cartridge) eluting with hexane/EtOAc (1:0 to 1:1 gradient over 60 min, 80 mL/min) to obtain the desired intermediate as a colorless oil (547 mg, 92%). MS (APCI+) m/z: 306 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].[Br:9]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:9][C:2]1([CH3:1])[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1CCCCC1=O
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(Br)CCCCC1=O
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of 15 g (0.134 mol) of 2-methyl-1-cyclohexanone (7) and 23.84 g (0.134 mol) of N-bromosuccinimide in 150 mL of carbon tetrachloride was stirred and heated to reflux for 12 h under argon. The mixture was cooled to room temperature, filtered through Celite to remove succinimide and the filter cake was washed with 150 mL of ether. The filtrate was concentrated to give 25.6 g (100% yield) of 2-bromo-2-methyl-1-cyclohexanone. 1H NMR δ 3.21 (td, J=16 Hz, 8 Hz, 1 H, CH--CO), 2.36 (m, 2 H), 2.06 (m, 2 H), 1.82 (s, 3 H, Me), 1.77 (m, 2 H), 1.62 (m, 1 H).
Reaction SMILES: C([O:8][C:9](=[O:43])[C@@H:10]([NH:21][C:22]([C@@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][N:25]1[S:30]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=1)(=[O:32])=[O:31])=[O:23])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:20][CH:18]([C:15]1[CH:14]=[CH:13][C:12]([CH2:11][C@H:10]([NH:21][C:22]([C@@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][N:25]2[S:30]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:41])([F:42])[F:40])[CH:34]=2)(=[O:32])=[O:31])=[O:23])[C:9]([OH:43])=[O:8])=[CH:17][CH:16]=1)[CH3:19]
Reactant: [H][H]
Reactant: CC(=O)c1ccc(C[C@H](NC(=O)[C@@H]2CCCCN2S(=O)(=O)c2cccc(C(F)(F)F)c2)C(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: CC(O)c1ccc(C[C@H](NC(=O)[C@@H]2CCCCN2S(=O)(=O)c2cccc(C(F)(F)F)c2)C(=O)O)cc1
Yield: 100 %

Procedure:
To 0.15 g (0.24 mmol) of (S)-3-(4-acetyl-phenyl)-2-{[(S)-1-(3-trifluoromethyl-benzenesulfonyl)-piperidine-2-carbonyl]-amino}-propionic acid benzyl ester in 30 ml of methanol was added 0.030 g of 10% palladium on carbon. The resulting suspension was stirred under 50 psi of hydrogen for 2 hours, after which the suspension was filtered and the filtrate was concentrated to provide 0.12 g (0.24 mmol) of the title compound which was used without further purification. The 300 MHz 1H NMR was consistent with the structure. LCMS (M+Na): m/z 551, retention time 3.05 min.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.ClCCl.Cl.CN(C)CCCN=C=NCC.[CH:27]1([CH2:32][CH2:33][NH2:34])[CH2:31][CH2:30][CH2:29][CH2:28]1>CN(C=O)C>[CH:27]1([CH2:32][CH2:33][NH:34][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([CH3:11])=[C:2]([I:1])[CH:3]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: NCCC1CCCC1
Reactant: Cc1ccc(C(=O)O)cc1I
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NCCC2CCCC2)cc1I
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a round-bottomed flask was charged 3-iodo-4-methylbenzoic acid (1.4 g, 5.4 mmol), dicloromethane (4 ml), and DMF (2 ml). This mixture was cooled to 0° C. and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.2 g, 6.3 mmol) was added. The reaction mixture was stirred for 10 min before 2-cyclopentylethanamine (0.47 g, 4.2 mmol) was introduced. The reaction mixture was stirred at 0° C. for 1 h, then at RT under N2 for 16 h. The reaction was partitioned between DCM (60 ml) and brine (50 mL). The aqueous layer was back exacted with DCM (4×20 mL) and the combined DCM layer was dried (Na2SO4) and concentrated. The crude product was dissolved in DCM and purified by chromatography through a Redi-sep pre-packed silica gel column (330 g), eluting with a gradient of 5% to 15% EtOAc in hexane, to provide N-(2-cyclopentylethyl)-3-iodo-4-methylbenzamide as a white solid. MS (ESI, pos. ion) m/z: 358.1 (M+1).
Reaction SMILES: [S:1]1[CH2:7][CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[Br:21][C:22]1[CH:23]=[C:24]2[C:28](=[C:29]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:30]=1)[NH:27][CH:26]=[CH:25]2.C([SiH](CC)CC)C>ClCCl>[Br:21][C:22]1[CH:23]=[C:24]2[C:28](=[C:29]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:30]=1)[NH:27][CH:26]=[C:25]2[CH:4]1[CH2:5][CH2:6][CH2:7][S:1][CH2:2][CH2:3]1
Reactant: O=C1CCCSCC1
Reactant: CCOC(=O)c1cc(Br)cc2cc[nH]c12
Agent: CC[SiH](CC)CC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cc(Br)cc2c(C3CCCSCC3)c[nH]c12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 4-thiepanone (900 mg, 6.9 mmol, 1.1 eq) in dry dichloromethane (30 mL) was added activated molecular sieves (4 Å, beads, spatula tip full) and the solution was cooled to 0° C. using an ice water bath. Trimethylsilyl trifluoromethanesulfonate (1.25 mL, 6.9 mmol, 1.1 eq) was added dropwise to the ketone solution, followed by the dropwise addition of ethyl 5-bromo-1H-indole-7-carboxylate (1.69 g, 6.3 mmol, 1 eq) as a solution in dichloromethane (10 mL). The reaction mixture was stirred at rt for 2 h, then warmed to 35° C. for 45 minutes. The deep red reaction mixture was cooled to 0° C. and triethylsilane (2 mL, 12.6 mmol, 2 eq) was added. The mixture was warmed to rt for 30 minutes, then was quenched by the addition of saturated aq. sodium bicarbonate. The aqueous layer was extracted with dichloromethane (2×50 mL), and the combined organic extracts were dried over sodium sulfate, filtered through a thin pad of silica gel (to remove baseline impurities), eluting with 50% ethyl acetate in hexanes, and concentrated to afford the crude product as a yellow residue. The crude material was purified by Isco Combiflash, eluting with 0-30% ethyl acetate in hexanes (120 gram column). The title compound was obtained as a yellow residue (540 mg, 24%).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][N:5]([S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[C@@H:4]([CH2:17][OH:18])[CH2:3]1.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.Cl>N1C=CC=CC=1>[C:13]1([CH3:16])[CH:14]=[CH:15][C:10]([S:7]([N:5]2[CH2:6][C@@H:2]([O:1][S:25]([C:22]3[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=3)(=[O:27])=[O:26])[CH2:3][C@@H:4]2[CH2:17][O:18][S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])(=[O:9])=[O:8])=[CH:11][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)N2CC(O)C[C@@H]2CO)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H]2C[C@H](OS(=O)(=O)c3ccc(C)cc3)CN2S(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 10 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
To an ice-cold solution of 219.2 g (0.808 mole) of 2R, 4S-1-(4-toluenesulfonyl)-2-hydroxymethyl-4-hydroxy-pyrrolidine (6) in 1 L of pyridine were added 539.2 g (2.828 mole) of 4-toluenesulfonyl chloride in one portion. The temperature rose to 50° C. The mixture was cooled at 10° C. and kept for 2 hours at this temperature and then at room temperature overnight. The mixture was pured into 5 L of 2.4N hydrochloric acid. After cooling, a precipitate was collected, washed with cold water, dried under reduced pressure. This presicpitate was taken up with 1 L of ethanol, filtered and washed with cold ethanol, dried under reduce pressure to give 406 g (86%) of the titled compound. M.P. =134° C. [α]D =+57.13° (c=1.9, acetone).
Reaction SMILES: C[CH:2](C)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[N+]([C:19]1C=CC(O)=CC=1)([O-])=O.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[CH3:19][CH:3]([CH3:2])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(C)CCCCCCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: CC(C)CCCCCCCCC(=O)O
Reaction time: 12 h

Procedure:
To 11-methyldodecanoic acid (400 mg) and para-nitrophenol (260 mg) dissolved in N,N-dimethylformamide (DMF, 30 ml) was added N,N'-dicyclohexylcarbodiimide (385 mg), and the- mixture was stirred for 12 hours. The reaction mixture was filtered and concentrated to give the active ester of 10-methylundecanoic acid. To the active ester (620 mg), after having been dissolved in DMF, were added 6-(4'-N-glycyl-spicaminyl-amino)purine hydrochloride (710 mg) and triethylamine (2.0 ml), and the mixture was stirred for 12 hours. The solvent was removed by distillation, and the residue was subjected to chromatography on a silica gel column with eluent systems of chloroform-methanol (from 7:1 to 5:1) to give SPK251 in the yield of 236 mg.
Reaction SMILES: N[CH2:2][CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH2:11][N:10]([C:13]2[C:18]([Cl:19])=[CH:17][N:16]=[CH:15][C:14]=2[Cl:20])[CH2:9][CH2:8]1)=[O:6].[CH:21]1([CH:27]=O)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.[C:29]([BH3-])#[N:30].[Na+]>CO>[CH:21]1([CH2:27][N:30]([CH2:29][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH2:2][CH2:3][NH:4][C:5]([CH:7]2[CH2:8][CH2:9][N:10]([C:13]3[C:14]([Cl:20])=[CH:15][N:16]=[CH:17][C:18]=3[Cl:19])[CH2:11][CH2:12]2)=[O:6])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=CC1CCCCC1
Reactant: NCCNC(=O)C1CCN(c2c(Cl)cncc2Cl)CC1
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: O=C(NCCN(CC1CCCCC1)CC1CCCCC1)C1CCN(c2c(Cl)cncc2Cl)CC1
Reaction time: 0.5 h
Yield: 87 %

Procedure:
To a solution of N-(2-aminoethyl)-1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide E13 (20 mg, 0.060 mmol) in MeOH (2 mL) was added cyclohexanecarbaldehyde (23 μL, 0.19 mmol). After stirring for 30 min, sodium cyanoborohydride (12 mg, 0.19 mmol) was added and the mixture was stirred for a further 16 h. The solvent was removed under reduced pressure, the residue was dissolved in EtOAc (20 mL), washed with a saturated solution of sodium hydrogencarbonate (25 mL), brine (25 mL), dried (MgSO4) and the solvent was removed under reduced pressure. The crude product was purified by preparative tlc on silica gel (CH2Cl2, MeOH, 9:1) to furnish the title compound as a white solid (28 mg, 87%), m.p. 236-238° C.; umax (CHCl3)/cm−1 2926, 2852, 1656, 1510, 1384, 1099; m/z (ESI) C27H42Cl2N4O requires 509.2808, found [M+H]+ 509.2808.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([F:19])[CH:18]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH2:15])[CH:13]=2)[CH:8]=[CH:7]1.[N+:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29]Cl)([O-:22])=[O:21]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([F:19])[CH:18]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH2:15])[CH:13]=2)[C:8]([S:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N+:20]([O-:22])=[O:21])=[CH:7]1
Reactant: Nc1ccc2ccn(Cc3cc(F)cc(F)c3)c2c1
Reactant: O=[N+]([O-])c1ccccc1SCl
Solvent: ClCCl
Product: Nc1ccc2c(Sc3ccccc3[N+](=O)[O-])cn(Cc3cc(F)cc(F)c3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28 %

Procedure:
To a solution of 1-(3,5-Difluoro-benzyl)-1H-indol-6-ylamine (25 mg, 0.1 mmol) in DCM (4 mL) was added 2-nitrobenzenesulfenyl chloride. The resulting yellow solution was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo and purified over a SiO2 column (heptane/ethyl acetate 9:1) to give the title compound as an orange solid (11.6 mg, yield=28%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7].[CH2:13](I)[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:13]([O:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7])[CH3:14]
Reactant: COC(=O)c1ccc(O)cc1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(C(=O)OC)c(O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.9 %

Procedure:
Methyl 4-hydroxysalicylate (10.0 g, 59.5 mmol) was dissolved in DMF. Ethyl iodide (9.74 g, 62.4 mmol) was added, followed by potassium carbonate (8.63 g, 62.4 mmol), and the reaction mixture was stirred under N2 at room temperature for 18 h. The reaction mixture was concentrated in vacuo to remove the majority of the DMF, and the residue taken up in EtOAc, and washed with water (2×), dried, and concentrated in vacuo to give an off-white solid. Recrystallization from hexane gave 6.41 g, (54.9%) of methyl 4-ethoxysalicylate as an off-white solid.
Reaction SMILES: [OH-:1].[Na+].[S:3]([N:13]1[CH2:16][C:15]([CH2:19][OH:20])([CH2:17][OH:18])[CH2:14]1)([C:6]1[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].BrBr.[OH2:23]>[Ni](Cl)Cl>[S:3]([N:13]1[CH2:14][C:15]([C:19]([OH:23])=[O:20])([C:17]([OH:1])=[O:18])[CH2:16]1)([C:6]1[CH:7]=[CH:8][C:9]([CH3:10])=[CH:11][CH:12]=1)(=[O:4])=[O:5]
Reactant: Cc1ccc(S(=O)(=O)N2CC(CO)(CO)C2)cc1
Reactant: [OH-]
Reactant: O
Agent: Cl[Ni]Cl
Agent: BrBr
Agent: [Na+]
Product: Cc1ccc(S(=O)(=O)N2CC(C(=O)O)(C(=O)O)C2)cc1

Procedure:
Sodium hydroxide (6.3 g) was dissolved in water (50 ml) and nickel chloride (1 g) and N-tosyl-3,3-bis(hydroxymethyl) azetidine (4.4 g) were added. Bromine (9.6 g) was added over 6 hours to the green suspension with vigorous stirring and cooling. The mixture was stirred overnight and the last traces of nickel peroxide destroyed with sodium sulphite. The green precipitate was filtered off and the clear filtrate acidified to pH 1 with hydrochloric acid. Ether extraction yielded the desired product, N-tosylazetidine-3,3-dicarboxylic acid.
Reaction SMILES: [CH:1]([N:4]1[C:8](=[O:9])[CH:7]([CH2:10][C:11]([OH:13])=O)[S:6][CH:5]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:3])[CH3:2].[NH:20]1[CH2:25][CH2:24][CH:23]([N:26]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[NH:28][C:27]2=[O:35])[CH2:22][CH2:21]1.[CH3:36]CN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CC#N>[CH:1]([N:4]1[C:8](=[O:9])[CH:7]([CH2:10][C:11]([N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[CH2:36][C:30]4[C:29](=[CH:34][CH:33]=[CH:32][CH:31]=4)[NH:28][C:27]3=[O:35])[CH2:22][CH2:21]2)=[O:13])[S:6][CH:5]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:2])[CH3:3]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)N1C(=O)C(CC(=O)O)SC1c1ccccc1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CN(C)C=O
Product: CC(C)N1C(=O)C(CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)SC1c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(3-isopropyl-4-oxo-2-phenylthiazolidin-5-yl)acetic acid (0.2 mmol, 56 mg), 1-(piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (0.15 mmol, 33 mg) and DIPEA (0.375 mmol, 65.3 μl) in 4:1 CH3CN:DMF (0.5 ml) was added HATU (0.18 mmol, 68 mg) and the reaction mixture was stirred at room temperature for 16 h. Purification by preparative reverse phase HPLC using 10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA) gave the title compound. LC/MS (10% to 99%): M/Z (M+H)+ (obs)=493.5; tR=3.1. 1H NMR (400 MHz, CDCl3) δ 7.31-7.25 (m, 5H), 7.14-7.10 (m, 1H), 7.05 (s, 1H), 7.00 (m, 1H), 6.93-6.89 (m, 1H), 6.62 (d, J=7.8 Hz, 1H), 5.56 (m, 1H), 4.72 (m, 1H), 4.47-4.41 (m, 2H), 4.27-4.19 (m, 2H), 4.02-3.96 (m, 1H), 3.87 (m, 1H), 3.36-3.29 (m, 1H), 3.13-3.10 (m, 1H), 2.70 (m, 2H), 1.70-1.60 (m, 3H), 1.20 (dd, J=2.0, 6.9 Hz, 3H), 0.94 (m, 3H).
Reaction SMILES: C([O:3][C:4](=[O:20])[C:5]([C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=1)=[CH:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)C.C[O-].[Na+].O.[OH-].[Na+]>CO>[Br:19][C:16]1[CH:15]=[CH:14][C:13](/[C:5](=[CH:6]\[CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)/[C:4]([OH:20])=[O:3])=[CH:18][CH:17]=1
Reactant: CCOC(=O)C(=CC1CCCCC1)c1ccc(Br)cc1
Agent: C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)/C(=C/C1CCCCC1)c1ccc(Br)cc1
Temperature: 50 °C
Reaction time: 72 h
Yield: 63.9 %

Procedure:
Dissolve E/Z mixture of 2-(4-bromo-phenyl)-3-cyclohexyl-acrylic acid ethyl ester (158.9 g, 472 mmol) in methanol (800 mL) and add the solution to sodium methoxide in methanol (222 mL, 30%). Stir the reaction mixture at 50° C. for 72 h. Add water (17 mL) and 5 N aqueous sodium hydroxide solution (10 mL) and stir at 50° C. until all methyl ester is hydrolyzed (1-4,days). Add water and evaporate the methanol; Add ether (300 mL) and water (200 mL) and adjust the pH to a value of 1 with 1 N HCl. Separate the layers and extract the aqueous layer with ether. Dry the combined organic layers organic phase over sodium sulfate, filter and concentrate. Recrystallization of the residue in EtOAc affords the title compound as a white solid (93.3 g). MS (m/e): 309 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[C:8]([CH2:11][C:12]3[C:13]([CH2:24][CH2:25][CH2:26][CH3:27])=[N:14][N:15]([CH2:19][C:20]([F:23])([F:22])[F:21])[C:16]=3[CH:17]=[O:18])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]1[NH:38][N:37]=[N:36][N:35]=1.CC(=CC)C.Cl([O-])=[O:45].[Na+].P([O-])(O)(O)=O.[Na+]>C1COCC1.C(O)(C)(C)C.O>[Br:1][C:2]1[C:6]2[CH:7]=[C:8]([CH2:11][C:12]3[C:13]([CH2:24][CH2:25][CH2:26][CH3:27])=[N:14][N:15]([CH2:19][C:20]([F:22])([F:21])[F:23])[C:16]=3[C:17]([OH:45])=[O:18])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]1[NH:38][N:37]=[N:36][N:35]=1
Reactant: CCCCc1nn(CC(F)(F)F)c(C=O)c1Cc1ccc2oc(-c3ccccc3-c3nnn[nH]3)c(Br)c2c1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)(C)O
Product: CCCCc1nn(CC(F)(F)F)c(C(=O)O)c1Cc1ccc2oc(-c3ccccc3-c3nnn[nH]3)c(Br)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.9 %

Procedure:
A solution of the product of Example 6 (0.3 g) and 2-methyl-but-2-ene (2M in THF; 4 ml) in a mixture of THF (14 ml) and t-butanol (14 ml) was treated with a solution of sodium chlorite (80% tech. 0.55 g), and sodium dihydrogenorthophosphate (0.65 g) in water (10 ml). The mixture was stirred at ambient temperature for 2 h. The solvent was removed in vacuo and the aqueous residue acidified (pH 4.5) with hydrochloric acid (2M). The product was extracted with a mixture of dichloromethane:ethyl acetate (1:1; 25 ml) and the organic extract dried and evaporated in vacuo. The residue was crystallized from methyl acetate/hexane to give the title compound as a white solid (0.2 g), m.p. 216°-220°.
Reaction SMILES: O=[C:2]1[C:11]2[C:10]([C:12](OCC)=O)=[CH:9][CH:8]=[CH:7][C:6]=2[NH:5][CH:4]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[CH:3]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[OH2:29].[NH2:30][NH2:31]>CO>[C:23]1([CH:3]2[C:2]3=[N:30][NH:31][C:12](=[O:29])[C:10]4[CH:9]=[CH:8][CH:7]=[C:6]([C:11]=43)[NH:5][CH:4]2[C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1ccccc1)C(c1ccncc1)N2
Reactant: NN
Solvent: CO
Product: O=c1[nH]nc2c3c(cccc13)NC(c1ccncc1)C2c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
A mixture of ethyl 4-oxo-3-phenyl-2-(pyridin-4-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate (340 mg) in 85% hydrazine monohydrate (6 mL) and methanol (3 mL) was stirred at room temperature for 2 h. After the evaporation of the solvent, water was added. Filtered and washed the cake by water (5 mL) then ethyl acetate to obtain a white solid. The solid was dried in vacuum at 50° C. to obtain 9-phenyl-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (150 mg, yield: 48%). 1H-NMR (400 MHz, DMSO-d) δ (ppm): 4.38-4.40 (d, J=7.6 Hz, 1H), 4.84-7.86 (d, J=8.0 Hz, 1H), 7.15-7.25 (m, 6H), 7.30-7.31 (m, 2H), 7.39-7.41 (d, J=7.6 Hz, 1H), 7.51-7.52 (s, 1H), 7.59-7.62 (t, J=8.0 Hz, 1H), 8.43-8.44 (d, J=6.0 Hz, 2H) 12.19 (s, 1H); LC-MS (ESI) m/z: 341 (M+1)+.