Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:36])[C@H:17]([NH:26][C@H:27]([C:32]([O:34][CH3:35])=[O:33])[CH2:28][CH:29]([CH3:31])[CH3:30])[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[F:25])C1C=CC=CC=1>[Pd].C(OCC)(=O)C>[F:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[C@@H:17]([NH:26][C@H:27]([C:32]([O:34][CH3:35])=[O:33])[CH2:28][CH:29]([CH3:30])[CH3:31])[C:16]([NH:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[OH:8])=[O:36]
Reactant: COC(=O)[C@H](CC(C)C)N[C@@H](C(=O)Nc1ccccc1OCc1ccccc1)c1ccc(F)cc1F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CC(C)C)N[C@@H](C(=O)Nc1ccccc1O)c1ccc(F)cc1F
Reaction time: 3 h
Yield: 92.4 %

Procedure:
A mixture of palladium on carbon (10%, 300 mg), methyl N-[(1R)-2-{[2-(benzyloxy)phenyl]amino}-1-(2,4-difluorophenyl)-2-oxoethyl]-L-leucinate (2.88 g) and ethyl acetate (30 ml) was stirred under a hydrogen atmosphere for 3 hours. The reaction was then filtered through Celite and the filter pad was washed with further portions of ethyl acetate. The combined organic fractions were evaporated to give methyl N-{(1R)-1-(2,4-difluorophenyl)-2-[(2-hydroxyphenyl)amino]-2-oxoethyl}-L-leucinate (2.179 g).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.[CH2:13]([N:20]1[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH2:13]([N:20]1[CH2:24][CH2:23][CH:22]([O:25][C:2]2[N:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=2)[CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: OC1CCN(Cc2ccccc2)C1
Reactant: COc1nc(Br)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1nc(OC2CCN(Cc3ccccc3)C2)ccc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 4 h
Yield: 17.9 %

Procedure:
A mixture of 6-bromo-2-methoxy-3-nitropyridine (1.5 g, 6.44 mmol), 1-benzyl-pyrrolidin-3-ol (1.14 g, 6.44 mmol) and K2CO3 (0.89 g, 6.44 mmol) in dimethylformamide (DMF) (20 ml) was stirred at room temperature for 24 h and at 40° C. for 4 h. After evaporation of the solvent under reduced pressure the residue was purified by silica gel chromatography with dichloromethane/methanol (10:0; 9:1; 7:3; 0:10) as eluent to provide 380 mg (18.1%) of the product.
Reaction SMILES: [O:1]=[C:2]1[NH:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([CH:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)=[CH:7][CH:8]=2)[NH:3]1.FC(F)(F)C(O)=O>>[NH:15]1[CH2:14][CH2:13][CH:12]([C:6]2[CH:5]=[C:4]3[C:9]([CH2:10][NH:11][C:2](=[O:1])[NH:3]3)=[CH:8][CH:7]=2)[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc3c(c2)NC(=O)NC3)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCc2ccc(C3CCNCC3)cc2N1
Yield: 95 %

Procedure:
Following the same procedure adopted for the synthesis of 5, treatment of compound 23 with trifluoroacetic acid afforded the title compound 6 as a dark brown gum (95%). IR (KBr) νmax. cm−1: 3271 (NH), 3032 (Ar—H), 1688 (C═O), 1610, 1515, 1412 (C═C). 1H NMR (500 MHz, CDCl3) δ=1.71 (m, 2H, CH2); 1.85 (m, 2H, CH2); 2.75 (m, 1H, CH); 2.95 (m, 2H, CH2); 3.32 (m, 2H, CH2); 5.23 (s, 2H, CH2); 6.82 (d, 1H, J=8.2 Hz, aromatic H); 7.02 (s, 1H, aromatic H); 7.09 (d, 1H, J=8.1 Hz, aromatic H); 8.61 (br. s, 1H, NH); 8.87 (br. s, 1H, NH); 10.11 (s, 1H, NH); 13C NMR (125.7 MHz, CDCl3) δ=29.51 (CH2), 38.34 (CH), 43.54 (CH2), 67.61 (CH2), 113.81 (aromatic-C), 118.68 (aromatic-C), 122.45 (aromatic-C), 126.84 (aromatic-C), 134.96 (aromatic-C), 138.77 (aromatic-C), 151.86 (C═O). Calculated (%) for C18H17F3N3O2 (328.13); C, 52.17; H, 5.25; N, 12.17. found (%); C, 52.08; H, 5.33; N, 12.07.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[CH2:9]=[CH:10][CH:11]=[CH2:12]>>[CH2:12]([C:2]1[CH:1]=[C:6]([OH:7])[CH:5]=[CH:4][C:3]=1[CH3:8])[CH2:11][CH:10]=[CH2:9]
Reactant: C=CC=C
Reactant: Cc1ccc(O)cc1
Product: C=CCCc1cc(O)ccc1C

Procedure:
As shown in Reaction Scheme 2, para-cresol (p-CH3C6H4OH) is reacted with butadiene (C4H6) to form 3-(but-3-enyl)-4-methylphenol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl.[NH:10]([C:17]1[C:22]([Br:23])=[CH:21][N:20]=[C:19](Cl)[N:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)CCC>[NH:10]([C:17]1[C:22]([Br:23])=[CH:21][N:20]=[C:19]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)[N:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccc(O)cc1
Reactant: Clc1ncc(Br)c(Nc2ccccc2)n1
Agent: Cl
Solvent: CCCCO
Product: Oc1ccc(Nc2ncc(Br)c(Nc3ccccc3)n2)cc1
Temperature: 100 °C
Yield: 31.5 %

Procedure:
4-Aminophenol (0.73 g, 7.8 mmol) and concentrated hydrochloric acid (1.30 ml, 7.1 mmol) were added to 4-anilino-5-bromo-2-chloropyrimidine (Method 1; 3.0 g, 7.1 mmol) in n-butanol (30 ml), and the mixture was heated at 100° C. for 12 hours. The solid which precipitated out on cooling was filtered off and washed with n-butanol and diethyl ether to give the product (0.80 g, 32%). MS (MH+): 357, 359.
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1[C:21]([O:23][CH3:24])=[O:22]>ClCCl>[CH3:24][O:23][C:21]([CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][N:15]1[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1)=[O:22]
Reactant: COC(=O)C1CCCCN1
Reactant: COC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Solvent: ClCCl
Product: COC(=O)c1cnc(N2CCCCC2C(=O)OC)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 98.9 %

Procedure:
Methyl 6-chloro-5-nitronicotinate (2.0 g, 9.23 mmol) was added to methyl piperidine-2-carboxylate (5.2 g, 36.92 mmol) while stirring at room temperature. The viscous yellow reaction was heated to 90° C. for one h and then allowed to cool back to room temperature. The reaction was diluted with dichloromethane (20 mL) and purified via column chromatography (220 g SiO2, 20-30% gradient, ethyl acetate in hexanes) to yield the title compound (2.95 g, 99% yield) as a yellow oil. [M+H] calc'd for C14H17N3O6, 324. found, 324.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:18])[NH:15][CH2:16][CH2:17][C:12]=3[C:11]([C:19]([F:22])([F:21])[F:20])=[N:10]2)=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:26][C:27]([O:29][CH3:30])=[O:28]>CN(C)C=O>[CH3:30][O:29][C:27](=[O:28])[CH2:26][N:15]1[CH2:16][CH2:17][C:12]2[C:11]([C:19]([F:22])([F:20])[F:21])=[N:10][N:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[C:13]=2[C:14]1=[O:18]
Reactant: COC(=O)CBr
Reactant: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)NCC3)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CN1CCc2c(C(F)(F)F)nn(-c3ccc(OC)cc3)c2C1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 73.9 %

Procedure:
Part D: 1-(4-Methoxy-phenyl)-3-trifluoromethyl-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one (1.0 g, 3.213 mmol) was dissolved in N,N-dimethylformamide (20 mL) and cooled to 0° C. Sodium hydride (60%, 0.321 g, 8.032 mmol) was added followed by methyl bromoacetate (0.608 mL, 6.425 mmol). The reaction was stirred at rt overnight. The reaction was quenched with 1N hydrochloric acid (100 mL), extracted with ethyl acetate (3×100 mL), washed with water (2×100 mL), washed with brine (1×100 mL), dried over MgSO4, concentrated, and purified by flash chromatography using 0–100% ethyl acetate/hexanes gradient as the eluent to afford the title compound (0.91 g, 74%): 1H NMR (CDCl3) δ 7.45 (d, j=8.8 Hz, 2H), 6.96 (d, j=9.2 Hz, 2H), 4.25 (s, 2H), 3.84 (s, 3H), 3.78 (t, j=7.0 Hz, 2H), 3.75 (m, 3H), 3.02 (t, j=6.8 Hz, 2H) ppm.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C@@H:18]3[NH:22][C:21](=[O:23])[CH2:20][CH2:19]3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH2:29]([O:36][C:37](Cl)=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1>[CH2:29]([O:36][C:37]([NH:22][C@@H:18]([C:9]1[O:10][C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=1)[CH2:19][CH2:20][CH2:21][OH:23])=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C1CC[C@H](c2nc(-c3ccccc3)c(-c3ccccc3)o2)N1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(N[C@H](CCCO)c1nc(-c2ccccc2)c(-c2ccccc2)o1)OCc1ccccc1
Reaction time: 1 h

Procedure:
To a solution of (5R)-5-(4,5-diphenyloxazol-2-yl)pyrrolidin-2-one (12 g) in tetrahydrofuran (THF) (200 ml) were added butyllithium (26 ml, 1.6N solution in hexane) and benzyloxycarbonyl chloride (6.8 ml) at -78° C. under N2. The mixture was stirred for 1 hour at the same temperature and partitioned between ethyl acetate and water. The organic layer was washed with 1N-HCl, water, sat. NaHCO3 and brine. The dried solvent was evaporated in vacuo, the residue was dissolved in THF (200 ml), and 1N-NaOH (87 ml) was added at 0° C. After being stirred for 12 hours at room temperature, the solvent was evaporated in vacuo. After the residue was partitioned between hexane and water, aqueous layer was adjusted to pH=2 and extracted with ethyl acetate. The organic layer was washed with water, sat. NaHCO3 and brine. The dried solvent was evaporated in vacuo and the residue was dissolved in THF (200 ml). To the solution were added triethylamine (9.0 ml) and ethyl chloroformate (5.0 ml) at ±5° C. under N2 and the mixture was stirred for 1 hour at the same temperature. After the filtration, the solution was dropwise added to the solution of NaBH4 (3.2 g) in a mixture of THF (100 ml) and water (100 ml) at 0° C. and stirred for 1 hour. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with 1N-HCl, sat. NaHCO3 and brine. The dried solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel to give (1R)-N-benzyloxycarbonyl-4-hydroxy-1-(4,5-diphenyloxazol-2-yl)butylamine (13 g). MS (m/z): 443 (M+ +1) IR (Neat): 3300, 1700 cm-1NMR (CDCl3, δ): 1.6-2.2 (4H, m), 3.68 (2H, m), 5.10-5.2 (1H, m), 5.14 (2H, s), 5.73 (1H, d, J=10.0 Hz), 7.2-7.7 (10H, m)
Reaction SMILES: [ClH:1].[CH3:2][NH:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[CH2:15](O)[CH3:16]>>[ClH:1].[CH3:2][NH:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:15][CH3:16])=[O:8]
Reactant: CCO
Reactant: CNCCCC(=O)O
Agent: Cl
Agent: O=S(=O)(O)O
Product: CCOC(=O)CCCNC
Temperature: 90 °C
Reaction time: 1 h

Procedure:
2.00 g (13.0 mmol) of 4-(methylamino)butanoic acid hydrochloride was dissolved in 40 mL of ethanol and 69 μL (1.30 mmol) of concentrated sulfuric acid was added thereto, followed by stirring of the mixture at 90° C. for 1 hour. The solvent was distilled off under reduced pressure, followed by azeotropy with toluene. 3.02 g of the obtained residue was used for the subsequent reaction as such.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9](Cl)=[O:10].[CH3:15][N:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21]([OH:23])=[O:22]>ClCCCl>[CH3:15][N:16]1[CH:20]=[C:19]([C:9](=[O:10])[C:8]2[CH:12]=[CH:13][CH:14]=[C:6]([Cl:5])[CH:7]=2)[CH:18]=[C:17]1[C:21]([OH:23])=[O:22]
Reactant: Cn1cccc1C(=O)O
Reactant: O=C(Cl)c1cccc(Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cn1cc(C(=O)c2cccc(Cl)c2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.9 %

Procedure:
As a modification, the acid is prepared in the following manner: 26.7 g aluminium chloride are added to a solution of 17.7 g 3-chlorobenzoic acid chloride in 300 ml 1,2-dichloroethane. At about 0° C., a solution of 12.5 g 1-methylpyrrole-2-carboxylic acid in 200 ml 1,2-dichloroethane is added portionwise. After stirring for 3 hours at room temperature, the mixture is poured over ice. The resulting precipitate is recrystallized from 250 ml 2-butanone, to give 20 g of the pure acid, m.p.=214° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH:9]=1)([CH2:6][CH3:7])[CH2:4][OH:5].[CH2:26](Br)[C:27]#[CH:28]>>[CH2:28]([O:5][CH2:4][C:3]([O:2][CH3:1])([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH:9]=1)[CH2:6][CH3:7])[C:27]#[CH:26]
Reactant: CCC(CO)(OC)c1cccc(OCc2ccc3ccccc3c2)c1
Reactant: C#CCBr
Product: C#CCOCC(CC)(OC)c1cccc(OCc2ccc3ccccc3c2)c1
Yield: 92 %

Procedure:
Using the procedure described in Example 8, 2-methoxy-2-[3-(naphth-2-ylmethoxy)phenyl]butan-1-ol (Example 6) with reacted with prop-2-ynyl bromide to give 2-methoxy-2-[3-(naphth-2-ylmethoxy)phenyl]but-1-yl prop-2-ynyl ether in 92% yield, m.p. 54° C.
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]([CH2:8][NH:9][C:10](=O)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl-:20]>S(Cl)(Cl)=O>[N+:1]([C:4]1[CH:19]=[CH:18][C:7]([CH2:8][N:9]=[C:10]([Cl:20])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(NCc1ccc([N+](=O)[O-])cc1)c1ccccc1
Reactant: [Cl-]
Solvent: O=S(Cl)Cl
Product: O=[N+]([O-])c1ccc(CN=C(Cl)c2ccccc2)cc1
Yield: 85 %

Procedure:
A solution of 3.7 mmol of N-(p-nitrobenzyl)-benzamide in thionyl chloride was refluxed under an inert atmosphere for 30 minutes and after cooling, the excess thionyl chloride was removed under vacuum to leave a solid residue. The residue was crystallized from dry cyclohexane under dry nitrogen (Note: the subsequent filtration had to be done under dry nitrogen also to obtain an 85% yield of the purified imidoyl--chloride melting at 71° to 73° C. (Lit. m.pt. 73--4 Huisgen et al--Loc. cit) which was used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[CH2:5][C:6]3[CH2:10][N:9]([C@@H:11]([CH2:15][CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)[C:12](O)=[O:13])[C:8](=[O:22])[C:7]=3[O:23][C:24]=2[CH:25]=[CH:26][CH:27]=1.C(Cl)(=O)C(Cl)=O.[Cl:34][C:35]1[CH:36]=[CH:37][C:38]([NH2:41])=[N:39][CH:40]=1>C(Cl)Cl.O>[Cl:34][C:35]1[CH:36]=[CH:37][C:38]([NH:41][C:12](=[O:13])[C@@H:11]([N:9]2[CH2:10][C:6]3[CH2:5][C:4]4[C:3]([O:2][CH3:1])=[CH:27][CH:26]=[CH:25][C:24]=4[O:23][C:7]=3[C:8]2=[O:22])[CH2:15][CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[N:39][CH:40]=1
Reactant: COc1cccc2c1CC1=C(O2)C(=O)N([C@@H](CC2CCCCC2)C(=O)O)C1
Reactant: Nc1ccc(Cl)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Product: COc1cccc2c1CC1=C(O2)C(=O)N([C@@H](CC2CCCCC2)C(=O)Nc2ccc(Cl)cn2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22 %

Procedure:
A solution of (S)-2-(8-methoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-3-cyclohexyl-propionic acid (200 mg, 0.64 mmol) (from Example 7, Step 2c), in methylene chloride (10 mL) was treated with oxalyl chloride (0.07 mL, 0.64 mmol) at 0° C. The mixture was warmed to 25° C. and stirred for additional 2 hours. Then, the reaction mixture was cooled to 0° C., and N,N′-diisopropylethyl amine (0.34 mL, 1.92 mmol) and commercially available 5-chloro-pyridin-2-ylamine (83 mg, 0.64 mmol), were added. The reaction mixture was stirred for 16 hours at 25° C. The reaction mixture was diluted with water and extracted with ethyl acetate (2×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue, upon silica gel flash chromatography using hexane-ethyl acetate gradiant elution, afforded (S)—N-(5-chloro-pyridin-2-yl)-3-cyclohexyl-2-(8-methoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-propionamide (68 mg, 26.3%), as a white solid. 1H NMR (DMSO-d6) δ: 11.07 (s, 1H), 8.39 (s, 1H), 8.04 (d, J=8.8 Hz, 1H), 7.90 (d, J=8.8 Hz, 1H), 7.22 (t, J=8.3 Hz, 1H), 6.77 (d, J=8.3 Hz, 1H), 6.68 (d, J=8.3 Hz, 1H), 5.07 (d, J=5.9 Hz, 1H), 4.37 (d, J=18.6 Hz, 1H), 4.03 (d, J=19.1 Hz, 1H), 3.82 (s, 3H), 3.55 (s, 2H), 1.48-2.00 (m, 7H), 0.85-1.32 (m, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH:7]=[CH:8][O:9][C:4]=2[CH:3]=1.[OH:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[OH:22])[CH:17]=O.Cl.CO>O>[OH:13][C:14]1[CH:15]=[C:16]([CH:17]=[C:8]2[CH2:7][C:6](=[O:10])[C:5]3[CH:11]=[CH:12][C:2]([OH:1])=[CH:3][C:4]=3[O:9]2)[CH:19]=[CH:20][C:21]=1[OH:22]
Reactant: O=c1ccoc2cc(O)ccc12
Reactant: O=Cc1ccc(O)c(O)c1
Agent: Cl
Solvent: O
Solvent: CO
Product: O=C1CC(=Cc2ccc(O)c(O)c2)Oc2cc(O)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.6 %

Procedure:
After 7-hydroxy-4(4H)-benzopyranone 0.5 g and 3,4-dihydroxybenzaldehyde 0.42 g were added to a mixture of concentrated hydrochloric acid 25 ml and methanol 35 ml, the mixture was refluxed for 2.5 hours and cooled to room temperature, and water 250 ml was added. The mixture was allowed to stand for 18 hours and the precipitated crystals were filtered. The crystals were dried over phosphorous pentoxide for four hours under reduced pressure to obtain the desired compound 0.61 g.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[S:15](Cl)([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)(=[O:17])=[O:16].CCN(CC)CC>C(Cl)Cl>[S:15]([O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)(=[O:17])=[O:16]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
A mixture of tert-butyl 4-hydroxypiperidine-1-carboxylate (5.00 g, 24.80 mmol, 1 eq), TsCl (5.70 g, 29.80 mmol, 1.2 eq) and Et3N (10.7 mL, 74.40 mmol, 3 eq) in 100 mL of anhydrous CH2Cl2 was stirred for 8 h at room temperature. The resulted mixture was washed with brine (30 mL) and water (30 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (5:1 (v/v) PE/EtOAc) to afford the title compound as a white solid (5.50 g, 68.00%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 356.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:12]=[CH:11][NH:10][N:9]=1.[Cl:13]Cl>C(O)(=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([Cl:13])=[CH:11][NH:10][N:9]=1
Reactant: ClCl
Reactant: Clc1ccccc1-c1cc[nH]n1
Solvent: CC(=O)O
Solvent: ClCCl
Product: Clc1ccccc1-c1n[nH]cc1Cl
Temperature: 25 °C
Yield: 44.5 %

Procedure:
6.8 g (0.038 mol ) of 3-(2'-chlorophenyl)-1H-pyrazole, prepared as in Example 9, are dissolved, at temperature and with stirring, in 30 ml of acetic acid. 2.9 g (0.0409 mol) of chlorine are then introduced into the reaction mixture. Stirring is maintained for 1 hour at room temperature and then the acetic acid is driven off under reduced pressure. The residue is taken up in methylene chloride and this organic solution is washed with an aqueous bicarbonate solution, then with water and then dried over Na2SO4 before being concentrated to dryness. The residue is chromatographed on a silica column (eluent: heptane/ethyl acetate 60/40). 3.6 g of 3-(2'-chlorophenyl)-4-chloro-1H-pyrazole (compound 96) are obtained, which is of honey-like consistency (yield 44%).
Reaction SMILES: C([O-])(=[O:3])C.[K+].Cl[C:7]1[N:12]=[N:11][C:10]([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[CH2:25][CH2:24][C:23]4[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:22]=4[NH:21][C:20]3=[O:32])[CH2:15][CH2:14]2)=[CH:9][C:8]=1[C:33]([C:35]1[CH:44]=[C:43]([CH3:45])[C:38]2[NH:39][C:40](=[O:42])[O:41][C:37]=2[CH:36]=1)=[O:34]>C(O)(=O)C>[CH3:31][O:30][C:27]1[CH:28]=[CH:29][C:22]2[NH:21][C:20](=[O:32])[N:19]([CH:16]3[CH2:15][CH2:14][N:13]([C:10]4[N:11]=[N:12][C:7](=[O:3])[CH:8]([C:33]([C:35]5[CH:44]=[C:43]([CH3:45])[C:38]6[NH:39][C:40](=[O:42])[O:41][C:37]=6[CH:36]=5)=[O:34])[CH:9]=4)[CH2:18][CH2:17]3)[CH2:25][CH2:24][C:23]=2[CH:26]=1
Reactant: CC(=O)[O-]
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5[nH]c(=O)oc5c4)c(Cl)nn3)CC1)C(=O)N2
Agent: [K+]
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CCN(C1CCN(C3=CC(C(=O)c4cc(C)c5[nH]c(=O)oc5c4)C(=O)N=N3)CC1)C(=O)N2
Reaction time: 7 h

Procedure:
0.10 g (1.0 mmol) potassium acetate were added to 0.13 g (0.20 mmol) 3-{1-[6-chloro-5-(4-methyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-pyridazin-3-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one (mixture) in 3 mL acetic acid and the mixture was boiled under a nitrogen atmosphere for 7 h. Then the reaction mixture was evaporated down and the residue was triturated with water, suction filtered and dried. The residue was purified by preparative HPLC-MS. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: [CH2:1](P(=O)(OCC)OCC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.[CH2:24]([N:31]1[C:39]2[C:34](=[CH:35][C:36]([O:40][CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][O:42]3)=[CH:37][CH:38]=2)[C:33]([CH:47]=O)=[C:32]1[CH:49]([CH3:51])[CH3:50])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1.CCOC(C)=O>[CH2:24]([N:31]1[C:39]2[C:34](=[CH:35][C:36]([O:40][CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][O:42]3)=[CH:37][CH:38]=2)[C:33](/[CH:47]=[CH:1]/[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:32]1[CH:49]([CH3:51])[CH3:50])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(C)c1c(C=O)c2cc(OC3CCCCO3)ccc2n1Cc1ccccc1
Reactant: CCOP(=O)(Cc1ccccc1)OCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)c1c(/C=C/c2ccccc2)c2cc(OC3CCCCO3)ccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a −78° C. solution of diethyl benzylphoshonate (91 mg, 0.4 mmol) in THF (5 mL) was added a 2 M solution of LDA and THF (0.2 mL, 0.4 mmol), and the solution was warmed to RT over 20 min. A solution of 1-benzyl-2-isopropyl-5-(tetrahydropyran-2-yloxy)-1H-indole-3-carboxaldehyde (Compound 13, 100 mg, 0.27 mmol) and THF (2 mL) was added, and the solution was stirred for 1 h at ambient temperature. The solution was diluted with EtOAc (50 mL), and washed with brine (10 mL), and dried (Na2SO4), and the solvent was removed under vacuum. Silica gel flash chromatography using 20% EtOAc in hexane gave (E)-1-benzyl-2-isopropyl-3-(2-phenylethen-1-yl)-5-(tetrahydropyran-2-yloxy)-1H-indole (Compound 26) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH2:21]([N:23]1[CH2:28][CH2:27][CH:26]([CH2:29][CH2:30][NH2:31])[CH2:25][CH2:24]1)[CH3:22]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:31][CH2:30][CH2:29][CH:26]2[CH2:25][CH2:24][N:23]([CH2:21][CH3:22])[CH2:28][CH2:27]2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: CCN1CCC(CCN)CC1
Product: CCN1CCC(CCNC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)CC1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and 2-(1-ethylpiperidin-4-yl)ethanamine (15.6 mg, 0.12 mmol). The title compound was obtained as a solid (26.1 mg, 53% yield). MS m/z: 489.06, 491.06 [M+H]+.
Reaction SMILES: [H-].[Na+].C1(S([CH2:12][CH2:13][CH2:14][CH:15]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C:16]2=O)(=O)=O)C=CC=CC=1>CS(C)=O>[C:15]12[CH2:14][CH2:13][CH:12]=[C:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]=2
Reactant: O=C1CCCCCCCCCCC1CCCS(=O)(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: C1=C2CCC=C2CCCCCCCCC1
Yield: 79.8 %

Procedure:
0.144 g (6 mmole) of NaH and 10 ml of DMSO were first heated at 80° for 30 min. Once the hydrogen evolution was terminated, 0.728 g (2 mmole) of 2-(3-phenylsulfonyl-prop-1-yl)-cyclododecanone were added to the above mixture and the resulting reaction mixture further heated at 100° for 4 hours. After the treatmments of extraction and distillation mentioned hereinabove, there were isolated 0.326 g (80% yield) of the desired compound.