Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9](Cl)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[NH:29]1[CH:33]=[CH:32][N:31]=[CH:30]1>C(#N)C>[N:29]1([C:2]2([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:9]([N:29]3[CH:33]=[CH:32][N:31]=[CH:30]3)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:8]3[C:3]2=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:33]=[CH:32][N:31]=[CH:30]1
Reactant: c1c[nH]cn1
Reactant: ClC1(c2ccccc2)c2ccccc2C(Cl)(c2ccccc2)c2ccccc21
Solvent: CC#N
Product: c1ccc(C2(n3ccnc3)c3ccccc3C(c3ccccc3)(n3ccnc3)c3ccccc32)cc1
Yield: 53.8 %

Procedure:
15 g (0.04 mol) of 9,10-dichloro-9,10-dihydro-9,10-diphenyl-anthracene and 17.7 g (0.24 mol) of imidazole in 250 ml of absolute acetonitrile are heated under reflux for 6 hours. Thereafter, the solvent is distilled off in vacuo and the residue is taken up in 500 ml of methylene chloride. The methylene chloride solution is washed twice with 500 ml of water each time and the organic phase is separated off, dried over sodium sulphate and concentrated by distilling off the solvent in vacuo. The residue is heated in 300 ml of methanol and filtered. The filtrate is concentrated and the oil which remains is triturated with 50 ml of diisopropyl ether, whereupon it crystallises. 10 g (54% of theory) of 9,10-diimidazol-1-yl-9,10-dihydro-9,10-diphenyl-anthracene of melting point 258°-260° C. are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:17]=1[CH:18]=[O:19].[CH2:25]([Mg]Br)[CH3:26].O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:17]=1[CH:18]([OH:19])[CH2:25][CH3:26]
Reactant: COc1cc2nccc(Oc3ccc(C)cc3C=O)c2cc1OC
Reactant: CC[Mg]Br
Solvent: O
Solvent: C1CCOC1
Product: CCC(O)c1cc(C)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
Under an argon atmosphere, 2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-methylbenzaldehyde (intermediate 1) (81.6 mg) was dissolved in tetrahydrofuran (3 ml), and the solution was then cooled to −78° C. A 0.96 M tetrahydrofuran solution (0.4 ml) of ethylmagnesium bromide was added dropwise thereto, and the mixture was stirred at −78° C. for 30 min. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure. The residue was purified by thin layer chromatography using acetone-hexane to give the title compound (41 mg, yield 46%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[C:13]([OH:15])[C:12]2[C:7](=[CH:8][C:9]([O:16][CH3:17])=[CH:10][CH:11]=2)[N:6]=1)=O.O.[NH2:19][NH2:20]>CO>[OH:15][C:13]1[C:12]2[C:7](=[CH:8][C:9]([O:16][CH3:17])=[CH:10][CH:11]=2)[N:6]=[C:5]([C:3]([NH:19][NH2:20])=[O:2])[CH:14]=1
Reactant: COC(=O)c1cc(O)c2ccc(OC)cc2n1
Reactant: NN
Solvent: O
Solvent: CO
Product: COc1ccc2c(O)cc(C(=O)NN)nc2c1
Yield: 80 %

Procedure:
To a solution of 4-hydroxy-7-methoxy-quinoline-2-carboxylic acid methyl ester (2.0 g, 8.58 mmol) in methanol (85 mL) was added hydrazine mono hydrate (1.7 g, 34.3 mmol) and the mixture was refluxed for 6 hours. The crude reaction mixture was concentrated in vacuo and the residue was taken up in methanol and poured onto an ice/water mixture (800 mL). A white precipitate formed, which was collected by filtration and washed with cold water. The filter cake was then dried on house vacuum by passing air through in sintered glass funnel, and then dried on vacuum oven at 45° C. overnight to afford 4-hydroxy-7-methoxy-quinoline-2-carboxylic acid hydrazide (1.6 g, 80% yield). 1H NMR (DMSO-d6, 300 MHz) δ 11.57 (s, 1H), 10.28 (s, 1H), 7.95 (d, 1H), 7.43 (d, 1H), 7.01-6.91 (m, 1H), 6.54 (s, 1H), 4.72 (br s, 2H), 3.82 (s, 3H). LCMS found 234.18 [M+H]+.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][C:14]1[O:18][N:17]=[C:16]([C:19]([OH:21])=O)[CH:15]=1.Cl.[CH2:23]([O:25][C:26](=[O:30])[C@H:27]([CH3:29])[NH2:28])[CH3:24]>O1CCCC1>[CH2:23]([O:25][C:26](=[O:30])[C@H:27]([CH3:29])[NH:28][C:19]([C:16]1[CH:15]=[C:14]([CH3:13])[O:18][N:17]=1)=[O:21])[CH3:24]
Reactant: CCOC(=O)[C@H](C)N
Reactant: Cc1cc(C(=O)O)no1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](C)NC(=O)c1cc(C)on1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
8.2 g of 1,1'-carbonyldiimidazole (CDI) was added to a mixture of 6.35 g of 1B and 75 ml of dry tetrahydrofuran (THF) and the mixture was stirred for 2 hours at room temperature. Then 7.5 g of alanine ethyl ester hydrochloride was added, the mixture was stirred overnight, filtered, and the filtrate was stripped of solvent. The residue was dissolved in 100 ml of a 9:1 v:v mixture of methylene chloride and ethyl acetate, the solution was filtered through silica gel, the gel was washed with 900 ml of the same solvent, then the combined filtrate and washings was stripped of solvent. The residue was a yellow oil that crystallized on standing. The crystals were washed with pentane and dried, to give N-(5-methyl-3-isoxazolylcarbonyl)alanine ethyl ester (1C), as a solid, m.p.: 65°-66° C. 1C was converted to the corresponding acid (1D, a solid, m.p.: 148°-150° C.) in the manner that 1A was converted to 1B.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=[S:17])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Br[CH:20]1[CH2:25][CH2:24][CH2:23][CH:22]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:21]1=O>C(O)C>[CH2:29]([O:28][C:26]([CH:22]1[C:21]2[N:18]=[C:16]([NH:15][C:5]3[CH:6]=[CH:7][C:8]([N:9]4[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]4)=[C:3]([O:2][CH3:1])[CH:4]=3)[S:17][C:20]=2[CH2:25][CH2:24][CH2:23]1)=[O:27])[CH3:30]
Reactant: CCOC(=O)C1CCCC(Br)C1=O
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Solvent: CCO
Product: CCOC(=O)C1CCCc2sc(Nc3ccc(-n4cnc(C)c4)c(OC)c3)nc21
Temperature: 25 °C
Yield: 87.3 %

Procedure:
A suspension of [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (131 mg, 0.50 mmol) and of 2-bromo-6-(carbethoxy)-cyclohexanone (137 mg, 0.55 mmol) in ethanol (5 mL) was stirred at room temperature for 2 days and then heated to reflux under an atmosphere of nitrogen over night. After cooling to room temperature the solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using dichloromethane/methanol (19:1 v/v) as eluent to yield the title compound (180 mg, 87%) as a white solid. MS ISP (m/e): 413.3 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=10.28 (s, 1H), 7.66 (d, 1H), 7.64 (s, 1H), 7.21 (d, 1H), 7.11 (d, 1H), 7.01 (s, 1H), 4.10 (q, 2H), 3.76 (s, 3H), 3.66 (m, 1H), 2.62 (m, 2H), 2.14 (s, 3H), 1.68-2.09 (m, 4H), 1.19 (t, 3H).
Reaction SMILES: [H-].[Na+].[CH:3]1([C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][N:9]=2)=[O:7])[CH2:5][CH2:4]1.[S:17](Cl)([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18]>CN(C=O)C>[CH:3]1([C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([S:17]([C:20]3[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[N:9]=2)=[O:7])[CH2:4][CH2:5]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(c1n[nH]c2ncccc12)C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2nc(C(=O)C3CC3)c3cccnc32)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.7 %

Procedure:
NaH (0.030 g, 0.75 mmol) was added to cyclopropyl(1H-pyrazolo[3,4-b]pyridin-3-yl)methanone (100 mg, 0.534 mmol) in DMF (2 mL) at 0° C. After 10 minutes, tosyl chloride (0.13 g, 0.69 mmol) was added, and the reaction mixture was allowed to warm to room temperature. The reaction mixture was stirred at room temperature for 16 hours and then quenched with ice and water. The mixture was extracted with EtOAc (3×10 mL) and dried over sodium sulfate. Column chromatography afforded cyclopropyl(1-tosyl-1H-pyrazolo[3,4-b]pyridin-3-yl)methanone (127 mg, 70%) as an oil, which crystallized upon standing.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[N:4][C:3]=1[CH3:10].C1C(=O)N([Br:18])C(=O)C1>>[Br:18][CH2:10][C:3]1[C:2]([CH3:1])=[N:7][C:6]([CH3:8])=[C:5]([CH3:9])[N:4]=1
Reactant: Cc1nc(C)c(C)nc1C
Reactant: O=C1CCC(=O)N1Br
Product: Cc1nc(C)c(CBr)nc1C

Procedure:
Dehydrated tetramethylpyrazine is dissolved into an organic solvent and then NBS is added at a mole ratio of tetramethylpyrazine to NBS=1:(0.5-0.7). The reaction liquid is then refluxed to react for 10-12 h. 2-bromomethyl-3,5,6-trimethyl pyrazine is obtained as a pale-red half-oily substance after post-treatment purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[O:8][C:9]3[C:14]([CH2:15][C:5]2=[C:4]([NH2:19])[C:3]=1[C:20]#[N:21])=[CH:13][C:12]([N+:16]([O-])=O)=[CH:11][CH:10]=3>CN(C=O)C.[Pd]>[NH2:1][C:2]1[N:7]=[C:6]2[O:8][C:9]3[C:14]([CH2:15][C:5]2=[C:4]([NH2:19])[C:3]=1[C:20]#[N:21])=[CH:13][C:12]([NH2:16])=[CH:11][CH:10]=3
Reactant: N#Cc1c(N)nc2c(c1N)Cc1cc([N+](=O)[O-])ccc1O2
Agent: [Pd]
Solvent: CN(C)C=O
Product: N#Cc1c(N)nc2c(c1N)Cc1cc(N)ccc1O2
Yield: 79 %

Procedure:
A mixture of 2,4-diamino-7-nitro-5H-chromeno[2,3-b]pyridine-3-carbonitrile, produced as described above, (0.55 mmol, 155 mg) and Pd/C (35 mg, 10% on activated carbon) in DMF (15 mL) was stirred under an atmosphere of hydrogen (balloon) for 3.5 hours. The catalyst was removed by filtration using a plug of celite. The filtrated was concentrated in vacuo and the residue was triturated with methanol to give 2,4,7-triamino-5H-chromeno[2,3-b]pyridine-3-carbonitrile as a grey solid (109 mg, 79% yield). 1H NMR (300 MHz, DMSO-d6): δ 6.72 (d, J=8.0 Hz, 1H), 6.39-6.5(m, 4H), 6.25 (s, 2H), 3.52 (s, 2H); m/z 254 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:16][CH:17]([N:19]([CH:24]([CH3:26])[CH3:25])[C:20](=[O:23])[CH2:21]Br)[CH3:18]>>[CH:17]([N:19]([CH:24]([CH3:26])[CH3:25])[C:20](=[O:23])[CH2:21][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)([CH3:18])[CH3:16]
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: CC(C)N(C(=O)CBr)C(C)C
Product: CC(C)N(C(=O)COc1ccc(-c2ccc(C#N)cc2)cc1)C(C)C
Yield: 89.3 %

Procedure:
The product was prepared as in Example 2, Stage A starting with 780 mg of 4'-hydroxy-(4-biphenyl carbonitrile) (Aldrich) and 1.33 g of N,N-bis(1-methylethyl)-2-bromo-acetamide (Preparation 8) to obtain 1.2 g of the expected product.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([CH3:10])[C:5]([CH3:9])=[N+:6]([O-])[CH:7]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:16]>ClCCl>[Br:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([CH3:10])[C:5]([CH2:9][OH:16])=[N:6][CH:7]=1
Reactant: COc1c(Br)c[n+]([O-])c(C)c1C
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: COc1c(Br)cnc(CO)c1C
Reaction time: 8 h

Procedure:
5-Bromo-4-methoxy-2,3-dimethylpyridine 1-oxide (4.91 g) was dissolved in dichloromethane (60 ml), and trifluoroacetic anhydride (20 ml) was then added to the solution at room temperature. The resulting mixture was stirred overnight. Thereafter, the reaction solution was concentrated, and the concentrated solution was then dissolved in methanol (50 ml). The resulting mixture was stirred at 50° C. for 1 hour. The reaction solution was concentrated. The residue was dissolved in dichloromethane, and was then washed with a saturated sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate, and the filtrate was then concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate), so as to obtain the title compound (3.43 g) as a solid.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O-:19])=[O:18])=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Na+].C(O)C.S(O[CH:35]([CH3:41])[C:36]([O:38][CH2:39][CH3:40])=[O:37])(C1C=CC(C)=CC=1)(=O)=O>O>[CH:1]1([CH2:7][CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19][CH:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH3:41])=[O:18])=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C(C)OS(=O)(=O)c1ccc(C)cc1
Reactant: O=C([O-])Cc1ccc(NCCC2CCCCC2)cc1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(C)OC(=O)Cc1ccc(NCCC2CCCCC2)cc1

Procedure:
To a warm mixture of 7 g. sodium 4-(2-cyclohexylethylamino)phenylacetate in 100 ml. ethanol is added 4.7 g. ethyl 2-tosyloxypropionate. After 17 hours at reflux, the cooled solution is diluted with an equal volume of water and the resultant precipitate is filtered. After washing with cold ethanol and drying, the product is crystallized from acetonitrile to yield 1-(ethoxycarbonyl)ethyl 4-(2-cyclohexylethylamino)phenylacetate as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1.[Br:13]Br>C(O)(=O)C>[Br:13][C:4]1[CH:5]=[C:6]([NH:9][C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: BrBr
Reactant: COc1ccc(NC(C)=O)cc1
Solvent: CC(=O)O
Product: COc1ccc(NC(C)=O)cc1Br
Temperature: 65 °C
Yield: 45.1 %

Procedure:
To a solution of N-(4-methoxyphenyl)acetamide II (7.50 g, 45.40 mmol) in acetic acid (50 mL) was added a solution of Br2 (4.70 mL, 90.80 mmol) in acetic acid (10.0 mL). The resulting reaction mixture was then heated to 65° C. for 4 h. After the completion of the reaction (TLC monitoring), acetic acid was distilled off, cooled the residue to 0° C. and then basified with aqueous NH3 till pH 12 followed by extraction with EtOAc (2×500.0 mL). The combined organics was washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude residue was purified over silica gel (60-120 M, 25-30% EtOAc-Hexane) to obtain the desired product (5.0 g, 45%). 1H NMR (400 MHz, DMSO-d6): δ 2.0 (s, 3H), 3.79 (s, 3H), 7.06 (d, J=8.80 Hz, 1H), 7.44 (dd, J=2.40 and 8.80 Hz, 1H), 7.91 (d, J=2.40 Hz, 1H) and 9.92 (br s, 1H). MS: 244.15 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10](=[O:15])[C:9]=2[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.[CH3:34][C:35](OC(C)=O)=[O:36]>C(Cl)Cl.O>[CH3:14][C:11]1([CH3:13])[O:12][C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:35](=[O:36])[CH3:34])=[CH:3][CH:4]=2)=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[CH:18][CH:17]=2)[C:10]1=[O:15]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)OC(c2ccc(N)cc2)=C(c2ccc(OCc3ccc4ccccc4n3)cc2)C1=O
Solvent: ClCCl
Solvent: O
Product: CC(=O)Nc1ccc(C2=C(c3ccc(OCc4ccc5ccccc5n4)cc3)C(=O)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 26.1 %

Procedure:
To a stirred solution of 5-(4-aminophenyl)-2,2-dimethyl-4-(4-(quinolin-2-ylmethoxy)phenyl)furan-3(2H)-one (0.07 g, 0.16 mmol) in DCM (5 mL) were added Ac2O (0.018 mL, 0.19 mmol) and TEA (0.04 mL, 0.32 mmol) at 0° C. under N2 atmosphere. The reaction mixture was stirred at RT for 14 h. The reaction mixture was diluted with water and extracted with DCM (2×15 mL). Combined organic layers were washed with water (2×5 mL), brine and dried over anhydrous Na2SO4. After filtration and evaporation, the crude material was purified by silica gel column chromatography to afford N-(4-(5,5-dimethyl-4-oxo-3-(4-(quinolin-2-ylmethoxy)phenyl)-4,5-dihydrofuran-2-yl)phenyl)acetamide (20 mg, 26%), as an off white solid. 1H NMR (500 MHz, CDCl3): δ 8.22 (d, J=8.5 Hz, 1 H), 8.08 (d, J=7.9 Hz, 1H), 7.84 (d, J=8.4 Hz, 1 H), 7.74 (t, J=8.2 Hz, 1 H), 7.68 (d, J=8.2 Hz, 1 H), 7.64 (d, J=8.2 Hz, 2 H), 7.56 (t, J=8.5 Hz, 1 H), 7.48 (d, J=7.4 Hz, 2 H), 7.22 (d, J=7.5 Hz, 2 H), 7.08 (d, J=8.9 Hz, 2H), 5.42 (s, 2 H), 2.22 (s, 3 H), 1.58 (s, 6 H). MS: [M+Na]: m/z=501.3, [M+H]: m/z=479.3. HPLC: 95.9% (RT-2.32 min), Column: Acquity BEH—C-18, 50×2.1 mm, 1.7 um. Mobile Phase: 0.025% TFA in Water (A), ACN (B), Flow rate: 0.5 ml/min (Gradient).
Reaction SMILES: [CH2:1]([O:3][C:4]1([C:11]([OH:13])=[O:12])[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C.O>[CH2:1]([O:3][C:4]1([C:11]([O:13][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:12])[CH2:5][CH2:6][C:7](=[O:10])[CH2:8][CH2:9]1)[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC1(C(=O)O)CCC(=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC1(C(=O)OCc2ccccc2)CCC(=O)CC1
Temperature: 60 °C
Yield: 78.2 %

Procedure:
To a solution of 1-ethoxy-4-oxocyclohexanecarboxylic acid (0.777 g, 4.17 mmol) in DMF (15 mL) was added potassium carbonate (1.153 g, 8.35 mmol) followed by benzyl bromide (0.546 mL, 4.59 mmol). The mixture was heated at 60° C. for 18 h, then cooled to rt. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (2×30 mL). The organic layers were washed with water (3×30 mL), then with brine and dried over magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography using a 0-25% ethyl acetate in hexanes gradient and a 24 g silica gel column to give benzyl 1-ethoxy-4-oxocyclohexanecarboxylate (0.9 g, 3.26 mmol, 78% yield) as a light-yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ=7.40-7.32 (m, 5H), 5.21 (s, 2H), 3.48 (q, J=6.9 Hz, 2H), 2.65-2.54 (m, 2H), 2.39-2.27 (m, 4H), 2.20-2.09 (m, 2H), 1.24 (t, J=7.0 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:9]([OH:16])[CH2:10][NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])([CH3:4])([CH3:3])[CH3:2].[CH3:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([S:35](Cl)(=[O:37])=[O:36])[CH:33]=2)[NH:28][N:27]=1.C([O-])(O)=O.[Na+].CCCCCC>ClCCl>[C:1]([O:5][C:6](=[O:24])[NH:7][CH:8]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH:9]([OH:16])[CH2:10][N:11]([CH2:12][CH:13]([CH3:14])[CH3:15])[S:35]([C:32]1[CH:33]=[C:34]2[C:29](=[CH:30][CH:31]=1)[NH:28][N:27]=[C:26]2[CH3:25])(=[O:37])=[O:36])([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1n[nH]c2ccc(S(=O)(=O)Cl)cc12
Reactant: CC(C)CNCC(O)C(Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: ClCCl
Product: Cc1n[nH]c2ccc(S(=O)(=O)N(CC(C)C)CC(O)C(Cc3ccccc3)NC(=O)OC(C)(C)C)cc12
Reaction time: 8 h
Yield: 99.5 %

Procedure:
To (1-Benzyl-2-hydroxy-3-isobutylamino-propyl)-carbamic acid tert-butyl ester 15 (60 mg, 0.18 mmol) and 3-methyl-1H-indazole-5-sulfonyl chloride (50 mg, 0.22 mmol) in 2 mL dichloromethane was added a 70 ul solution of a saturated NaHCO3 and 30 mg NaHCO3 and stirred overnight. The product was purified by preparative TLC using 1:1 ethyl acetate:hexane to give 95 mg product (99% yield). MS 531 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[C:12]([F:21])[CH:11]=1)=[O:8].[NH:24]1[CH2:28][CH2:27][C@@H:26]([OH:29])[CH2:25]1>>[Br:1][C:2]1[C:3]([N:24]2[CH2:28][CH2:27][C@@H:26]([OH:29])[CH2:25]2)=[N:4][CH:5]=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[C:12]([F:21])[CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(SC(F)(F)F)c(F)c1)c1cnc(Cl)c(Br)c1
Reactant: O[C@@H]1CCNC1
Product: O=C(Nc1ccc(SC(F)(F)F)c(F)c1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 9.2 using 5-bromo-6-chloro-N-(3-fluoro-4-((trifluoromethyl)thio)phenyl)nicotinamide (Stage 15.3) and (R)-pyrrolidin-3-ol to afford an off-white crystalline solid. HPLC (Condition 4) tR=6.11 min, UPLC-MS (Condition 3) tR=1.23 min, m/z=480.1 [M+H]+.
Reaction SMILES: C(O[CH:4]([O:25]CC)[C:5]#[C:6][C:7]([CH:15]([CH3:24])[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[Cl:23])([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)O)C.C(=O)(O)[O-:29].[Na+]>S(=O)(=O)(O)O>[Cl:23][C:17]1[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=1[CH:15]([C:7]1([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[C:6](=[O:29])[CH:5]=[CH:4][O:25]1)[CH3:24]
Reactant: CCOC(C#CC(O)(c1cccnc1)C(C)c1ccc(Cl)cc1Cl)OCC
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(c1ccc(Cl)cc1Cl)C1(c2cccnc2)OC=CC1=O
Temperature: 25 °C

Procedure:
A solution of 1 g of α-(3,3-diethoxy-1-propynyl)-α-(2,4-dichloro-α-methylbenzyl)-3-pyridinemethanol in 30 ml of 4N sulphuric acid is heated at 120° C. for 1.5 hours while stirring and the reaction mixture is subsequently left to cool to room temperature, neutralized with solid sodium bicarbonate and extracted with methylene chloride. The organic phase is washed three times with saturated aqueous sodium chloride solution and evaporated under reduced pressure. Thereafter, the residue is subjected to a column chromatography on silica gel using methylene chloride/ethyl acetate (4:1) as the eluent and it is recrystallized from n-hexane. In this manner there is obtained 0.4 g of 2-(2,4-dichloro-α-methylbenzyl)-2-(3-pyridyl)-3(2H)-furanone, m.p. 111°-111.5° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:8][CH2:7]2)(=[O:3])[CH3:2].[Br:18]CC(C1C=C2C(=CC=1)CCC2)=O>>[Br:18][CH2:2][C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:8][CH2:7]2)=[O:3]
Reactant: CCOC(=O)N1CCc2cc(C(C)=O)ccc21
Reactant: O=C(CBr)c1ccc2c(c1)CCC2
Product: CCOC(=O)N1CCc2cc(C(=O)CBr)ccc21

Procedure:
*5-bromoacetyl-1-ethoxycarbonyl-2,3-dihydro-1H-indole was prepared from 5-acetyl-1-ethoxycarbonyl-2,3-dihydro-1H-indole (Y. Ishihara et al., J.Chem.. Soc. Perkin Trans.1, 1992, 3401) according to the procedure for preparing 5-bromoacetylindan described in Example 11.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:36]=[CH:35][C:8]([CH2:9][NH:10][C:11]([C:13]2[C:14](=[O:34])[N:15]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)[C:16]([CH3:23])=[C:17]([C:19]([NH:21][NH2:22])=[O:20])[CH:18]=2)=[O:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:37]([N:39]=[C:40]=[O:41])[CH3:38]>O1CCOCC1>[CH2:37]([NH:39][C:40]([NH:22][NH:21][C:19]([C:17]1[CH:18]=[C:13]([C:11]([NH:10][CH2:9][C:8]2[CH:35]=[CH:36][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)=[O:12])[C:14](=[O:34])[N:15]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:33])[F:32])[CH:25]=2)[C:16]=1[CH3:23])=[O:20])=[O:41])[CH3:38]
Reactant: Cc1c(C(=O)NN)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: CCN=C=O
Solvent: C1COCCO1
Product: CCNC(=O)NNC(=O)c1cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n(-c2cccc(C(F)(F)F)c2)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.3 %

Procedure:
To 5-hydrazinocarbonyl-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylic acid 4-methanesulfonyl-benzylamide (0.030 g, 0.057 mmol) in 1,4-dioxane (10 ml) was added ethyl isocyanate (0.016 g, 0.23 mmol) and the mixture was stirred at room temperature for 1 h. The mixture was evaporated and the residue was purified by preparative HPLC giving 0.015 g (44%) of the title compound.
Reaction SMILES: [Na].Cl[C:3]1[N:4]=[N:5][C:6]([S:9][CH2:10][CH:11]=[CH2:12])=[CH:7][CH:8]=1.[CH2:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([O:20][C:3]1[N:4]=[N:5][C:6]([S:9][CH2:10][CH:11]=[CH2:12])=[CH:7][CH:8]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCc1ccccc1
Reactant: C=CCSc1ccc(Cl)nn1
Agent: [Na]
Product: C=CCSc1ccc(OCc2ccccc2)nn1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
0.11 g(0.005 mol) of metallic sodium was dissolved in 20 ml of dry benzylalcohol. To the resulting solution was added 0.93 g(0.005 mol) of 3-chloro-6-allylthiopyridazine and then the reaction solution was stirred for 2 hours at 80±5° C. To remove the excessive benzylalcohol and the insoluble material (NaCl), the reaction mixture was purified with silica gel column chromatography (eluent: n-hexane/ethyl acetate=40/1, v/v) to obtain the title compound as a needle crystal.