Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([NH:13][C:14]2[CH:15]=[C:16]([CH:22]=[CH:23][C:24]=2[CH:25]=O)[C:17]([O:19][CH2:20]C)=[O:18])=O)=[CH:5][CH:4]=1)#[N:2].[NH3:27]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:27]=[CH:25][C:24]3[C:14](=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:22][CH:23]=3)[N:13]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N
Reactant: CCOC(=O)c1ccc(C=O)c(NC(=O)CCc2ccc(C#N)cc2)c1
Product: COC(=O)c1ccc2cnc(CCc3ccc(C#N)cc3)nc2c1

Procedure:
0.6 g (1.8 mmol) of ethyl 3-[3-(4-cyanophenyl)propionylamino]-4-formylbenzoate and 10 mL of methanolic ammonia solution were agitated in a pressure vessel for 36 hours. Then the solvent was distilled off, the residue was chromatographed on silica gel and eluted with methylene chloride containing 0 to 1% methanol. Yield: 0.35 g (62% of theory); Rf value: 0.38 (silica gel, ethyl acetate/cyclohexane=1:1).
Reaction SMILES: [C:1]1([C:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COC(OC)[N:19]([CH3:21])C.[NH2:24]N>>[C:1]1([C:7]2[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:21][NH:19][N:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(OC)N(C)C
Reactant: NN
Reactant: O=C(Cc1ccccc1)c1ccccc1
Product: c1ccc(-c2c[nH]nc2-c2ccccc2)cc1
Temperature: 120 °C
Yield: 92.9 %

Procedure:
A mixture of deoxybenzoin (50 g, 0.255 mole) and N,N-dimethylformamide dimethyl acetal (37.9 g, 42.5 ml, 0.32 mole) was stirred at 120° C. under an atmosphere of nitrogen. After 30 minutes the heating source was removed and hydrazine (24 g, 24 ml, 0.75 mole) added dropwise to the hot mixture. After completing the addition, the mixture was poured onto water (600 ml) and a solid filtered off and air dried to afford 3,4-diphenyl-1H-pyrazole (52.18 g, 92%) which was used without further purification. An analytical sample was prepared by recrystallization from ethanol; m.p.=150°-152° C. (lit. m.p.=154°-155° C.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[C:10]1\[CH:11]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:12]2[CH:17]([C:18]\1=[O:19])C1CC2C=C1.C1(=O)OC(=O)C=C1.C[Al](Cl)Cl>ClCCl>[CH3:1][O:2][C:3](=[O:29])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[C:10]1\[CH:11]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:12]=[CH:17][C:18]\1=[O:19].[CH3:1][O:2][C:3](=[O:29])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[C:10]1/[CH:11]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:12]=[CH:17][C:18]/1=[O:19]
Reactant: CCCCCCCCC1/C(=C\CCCCCC(=O)OC)C(=O)C2C3C=CC(C3)C12
Agent: C[Al](Cl)Cl
Agent: O=C1C=CC(=O)O1
Solvent: ClCCl
Product: CCCCCCCCC1C=CC(=O)/C1=C/CCCCCC(=O)OC
Product: CCCCCCCCC1C=CC(=O)/C1=C\CCCCCC(=O)OC
Temperature: 50 °C
Yield: 17 %
Yield: 69 %

Procedure:
Under nitrogen in oven dried glassware, a mixture of 7 (200 mg, 0.50 mmol, 1 eq.) and maleic anhydride (245 mg, 2.50 mmol, 5 eq.) in dichloromethane (20 cm3) was treated with a 1 M solution of MeAlCl2 in hexanes (0.5 cm3, 0.50 mmol, 1 eq.) and heated to 50° C. (oil bath temperature) for 6 hours. The reaction mixture was cooled to room temperature and silica (ca. 2 g) was added. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (Hex-EtOAc; 4:1) affording the title compound (8) (115 mg, 69%) and its cis-isomer (9) (28 mg, 17%) both as clear liquids. 7-[2-Octyl-5-oxocyclopent-3-en-(E)-ylidene]heptanoic acid methyl ester (8): Rf=0.2 (Hex-EtOAc; 3:1); δH (400 MHz, CDCl3) 0.88 (3H, t, J 6.5 Hz, CH3), 1.21-1.34 (12H, m, CH2), 1.34-1.42 (2H, m, CH2), 1.46-1.54 (1H, m, CHAHB), 1.52 (2H, pent, J 7.5 Hz, CH2), 1.65 (2H, pent, J 7.5 Hz, CH2), 1.76-1.86 (1H, m, CHAHB), 2.18-2.32 (2H, m, 6-CH2), 2.31 (2H, t, J 7.5 Hz, 2-CH2), 3.44-3.49 (1H, m, 2-CH), 3.66 (3H, s, CH3), 6.32 (1H, dd, J 2.0, 6.0 Hz, 4-CH), 6.53 (1H, t, J 7.5 Hz, 7-CH), 7.50-7.57 (1H, m, 3-CH); δC (100 MHz, CDCl3) 14.0, 22.6, 24.7, 25.9, 28.3, 28.85, 28.9, 29.2, 29.4, 29.7, 31.8, 32.5, 33.9, 43.3, 51.4, 134.8, 135.1, 138.1, 164.9, 174.0, 196.9; m/z (CI) 352 (MNH4+, 5%), 335 (MH+, 100%); Found C, 75.33; H, 10.35%, C21H34O3 requires C, 75.40; H, 10.26%. 7-[2-Octyl-5-oxocyclopent-3-en-(Z)-ylidene]heptanoic acid methyl ester (9): Rf=0.25 (Hex-EtOAc; 3:1); δH (400 MHz, CDCl3) 0.88 (3H, t, J 6.5 Hz, CH3), 1.19-1.32 (20H, m, CH2), 2.29 (2H, t, J 7.5 Hz, 2-CH2), 2.80 (2H, q, J 7.5 Hz, 6-CH2), 3.23-3.28 (1H, m, 2-CH), 3.67 (3H, s, CH3), 5.99 (1H, t, J 7.5 Hz, 7-CH), 6.26 (1H, dd, J 2.0, 6.0 Hz, 4-CH), 7.42 (1H, dd, J 2.5, 6.0 Hz, 3-CH); δC (100 MHz, CDCl3) 14.1, 22.6, 24.8, 26.4, 27.0, 28.8, 29.0, 29.2, 29.4, 29.8, 31.8, 33.6, 34.0, 45.5, 51.4, 136.3, 137.1, 139.8, 160.3, 174.1, 198.2; m/z (CI) 352 (MNH4+, 10%), 335 (MH+, 100%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[C:16]([C:18]1[CH:19]=[CH:20][C:21]([F:31])=[C:22]([NH:24][C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH:23]=1)#[CH:17]>C1COCC1.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.[Cu]I>[Cl:1][C:2]1[N:7]=[C:6]([C:17]#[C:16][C:18]2[CH:19]=[CH:20][C:21]([F:31])=[C:22]([NH:24][C:25](=[O:30])[C:26]([F:27])([F:28])[F:29])[CH:23]=2)[CH:5]=[CH:4][N:3]=1
Reactant: C#Cc1ccc(F)c(NC(=O)C(F)(F)F)c1
Reactant: Clc1ccnc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(C#Cc2ccnc(Cl)n2)ccc1F)C(F)(F)F
Yield: 49.3 %

Procedure:
To an oven-dried flask under N2 was added 2,4-dichloropyrimidine (520 mg, 3.49 mmol), anhydrous degassed THF (100 mL), dichlorobis(triphenylphosphine)-palladium(II) (62 mg, 0.09 mmol), copper(I) iodide (10 mg, 0.05 mmol), and triethylamine (718 mg, 7.10 mmol). After heating the reaction at 60° C. for 30 min, N-(5-ethynyl-2-fluorophenyl)-2,2,2-trifluoroacetamide (410 mg, 1.77 mmol) was added dropwise as a solution in THF (10 mL) and the resulting mixture was allowed to heat overnight. The crude reaction mixture was adsorbed to silica gel and purified by column chromatography (5-50% EtOAc in hexanes) to afford the desired product (300 mg, 49%) as an off white solid. ESIMS (M+H)+=344.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:22])[CH:6]=1)[CH3:2].Br[C:25]1[CH:26]=[N:27][N:28]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)[CH:29]=1>>[CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:25]3[CH:26]=[N:27][N:28]([C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)[CH:29]=3)[C:13]=2[CH3:22])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Reactant: Cc1ccc(-n2cc(Br)cn2)cc1
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3cnn(-c4ccc(C)cc4)c3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: 3-(6-Chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid ethyl ester and 4-bromo-1-p-tolyl-1H-pyrazole.
Reaction SMILES: [N:1]([CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][NH:9][C:8](=[O:12])[C:7]1=[O:13])=[N+:2]=[N-:3].[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=[CH:21][C:22]([O:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH:15]=1.N12CCCN=C1CCCCC2>CN(C)C=O>[N:1]([CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH:20]([C:16]2[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=2)[CH2:21][C:22]([O:24][CH:25]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:23])[C:8](=[O:12])[C:7]1=[O:13])=[N+:2]=[N-:3]
Reactant: O=C(C=Cc1cccnc1)OC(c1ccccc1)c1ccccc1
Reactant: [N-]=[N+]=NCCN1CCNC(=O)C1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCN1CCN(C(CC(=O)OC(c2ccccc2)c2ccccc2)c2cccnc2)C(=O)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 52.2 %

Procedure:
A mixture of 0.5 g of 1-(2-azidoethyl)-2,3-dioxopiperazine, 1.72 g of diphenylmethyl 3-(3-pyridyl)-acrylate, 0.2 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene and 2.5 ml of N,N-dimethylformamide was stirred at room temperature for 12 hours. The solvent was distilled off under reduced pressure, after which 30 ml of ethyl acetate and 20 ml of water were added to the resulting residue and the pH was adjusted to 6 with 2N hydrochloric acid. The organic layer was separated and the aqueous layer was extracted with 30 ml of ethyl acetate. The combined organic layer was washed with 20 ml of water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent; chloroform: methanol=20:1) to obtain 0.71 g of diphenylmethyl 3-[4-(2-azidoethyl)-2,3-dioxopiperazin-1-yl]-3-(pyridin-3-yl)propionate as a light-brown oil.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7](=[O:27])[N:8]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[CH:9]=[C:10](B3OC(C)(C)C(C)(C)O3)[C:5]=2[NH:4][N:3]=1.Cl[C:29]1[N:34]=[CH:33][CH:32]=[CH:31][N:30]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(O)C>[NH2:1][C:2]1[C:6]2[C:7](=[O:27])[N:8]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[CH:9]=[C:10]([C:29]3[N:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[C:5]=2[NH:4][N:3]=1
Reactant: Clc1ncccn1
Reactant: CC1(C)OB(c2cn(-c3ccccc3Cl)c(=O)c3c(N)n[nH]c23)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Nc1n[nH]c2c(-c3ncccn3)cn(-c3ccccc3Cl)c(=O)c12
Temperature: 120 °C
Reaction time: 8 h
Yield: 19.4 %

Procedure:
A mixture of 3-amino-7-bromo-5-(2-chlorophenyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one obtained in Step B of Example 18 (200 mg), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (179 mg), (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (21.6 mg), potassium acetate (116 mg) and N,N-dimethylformamide (3.0 mL) was stirred overnight at 110° C. under argon atmosphere. The reaction mixture was cooled to room temperature, water was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 3-amino-5-(2-chlorophenyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one (277 mg). A mixture of 3-amino-5-(2-chlorophenyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one (277 mg), 2-chloropyrimidine (131 mg), tripotassium phosphate (365 mg), tetrakis(triphenylphosphine)palladium(0) (99.0 mg), toluene (5.0 mL), ethanol (1.0 mL) and water (1.0 mL) was stirred overnight at 120° C. under argon atmosphere. The reaction mixture was cooled to room temperature, water was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (basic silica gel, methanol/ethyl acetate) to give the title compound (47.0 mg).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([I:11])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1.[N+:21]([C:24]1[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=1)([O-:23])=[O:22].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([O:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([N+:21]([O-:23])=[O:22])[CH:25]=2)[C:5]2[C:10]([I:11])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)nc(Cl)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc(I)c2c(Oc3cccc([N+](=O)[O-])c3)nc(Cl)nc21
Temperature: 60 °C

Procedure:
To a reaction vial was added 2,4-dichloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (3.50 g, 7.9 mmol), as prepared in Example 5, step 1, 3-nitrophenol (1.1 g, 7.9 mmol), DMF (26 mL) and K2CO3 (2.18 g, 16 mmol, 2 mol eq). The reaction mixture was stirred and heated to 60° C. (block temperature) for 1 hr. The volatiles were removed and water (30 mL) was added. Ethyl acetate (120 mL) was added and the organic layer was separated, washed with water (20 mL), brine (20 mL), dried over Na2SO4 and evaporated to give crude product (TLC: Rf 0.6 (major) and 0.4 (minor) in 20% ethyl acetate-80% heptane). The product was purified on silica to give a light yellow oil, which solidified to a light yellow solid (3.65 g, 85% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.28-8.31 (m, 1H) 8.26 (d, J=8.06 Hz, 1H) 8.02 (s, 1H) 7.90-7.94 (m, 1H) 7.83-7.89 (m, 1H) 5.60 (s, 2H) 3.53-3.67 (m, 2H) 0.84-0.99 (m, 2H) 0.00 (s, 9H). m/z (APCI+) for C18H20ClIN4O4Si 547.0 (M+H)+.
Reaction SMILES: C(OC[C:6]([C@:8]1([OH:30])[C@:24]2([CH3:25])[C@H:11]([C@H:12]3[C@:21]([F:27])([C@@H:22]([OH:26])[CH2:23]2)[C@:20]2([CH3:28])[C:15](=[CH:16][C:17](=[O:29])[CH2:18][CH2:19]2)[CH2:14][CH2:13]3)[CH2:10][CH2:9]1)=[O:7])(=O)C.[OH-].[Na+].Cl.I(O)(O)(O)(O)(O)=[O:35]>CO.O>[F:27][C@@:21]12[C@:20]3([CH3:28])[C:15](=[CH:16][C:17](=[O:29])[CH2:18][CH2:19]3)[CH2:14][CH2:13][C@H:12]1[C@H:11]1[C@@:24]([CH3:25])([C@@:8]([OH:30])([C:6]([OH:35])=[O:7])[CH2:9][CH2:10]1)[CH2:23][C@@H:22]2[OH:26]
Reactant: CC(=O)OCC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Reactant: [O-][I+](O)(O)(O)(O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3CC[C@](O)(C(=O)O)[C@@]3(C)C[C@H](O)[C@@]12F
Reaction time: 0.17 h
Yield: 101.1 %

Procedure:
In a 1000 mL round-bottomed flask was suspended 2-((8S,9R,10S,11S,13S,14S,17R)-9-fluoro-11,17-dihydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl acetate (Fludrocortisone-21-acetate, 22.8 g, 53.97 mmol) in MeOH (200 mL) and the suspension was degassed with nitrogen. 2M sodium hydroxide (40.5 mL, 80.95 mmol) was added to the solution and the mixture was stirred for 10 minutes. To the solution was added 4M HCl (20 ml, 80 mmol) and MeOH was removed in vacuo. The obtained residue was dissolved in THF (200 ml), a solution of orthoperiodic acid (15.99 g, 70.16 mmol) in water (40 ml) was added at room temperature and the obtained mixture was stirred for 1 hour. 100 ml of water was added and the organic solvent was removed in vacuo. An additional 100 ml of water was added to the aqueous residue and the obtained solid was collected by filtration, was washed with water (2×200 ml) and was air dried on the sinter, followed by drying in vacuo to yield 20 g of the desired compound as an off-white solid. APCI-MS m/z: 367 [MH+].
Reaction SMILES: C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:38][O:39][CH2:40][C:41]1[CH:46]=[CH:45][C:44]([CH2:47][CH2:48][OH:49])=[CH:43][CH:42]=1.O[C:51]1[CH:64]=[CH:63][C:54]([CH2:55][CH:56]([CH2:61][CH3:62])[C:57]([O:59][CH3:60])=[O:58])=[CH:53][CH:52]=1>ClCCl.C(OCC)(=O)C>[CH3:38][O:39][CH2:40][C:41]1[CH:46]=[CH:45][C:44]([CH2:47][CH2:48][O:49][C:51]2[CH:64]=[CH:63][C:54]([CH2:55][CH:56]([CH2:61][CH3:62])[C:57]([O:59][CH3:60])=[O:58])=[CH:53][CH:52]=2)=[CH:43][CH:42]=1
Reactant: CCC(Cc1ccc(O)cc1)C(=O)OC
Reactant: COCc1ccc(CCO)cc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCC(Cc1ccc(OCCc2ccc(COC)cc2)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 23.2 %

Procedure:
ADDP (1,23 g, 4,89 mmole) and triphenylphosphine (1,03 g, 3,92 mmole) were added to a solution of 2-[4-(methoxymethyl)phenyl]ethanol (0,54 g, 3,26 mmole) and methyl 2-(4-hydroxybenzyl)butanoate (0,68 g, 3,26 mmole) in dry dichloromethane (10 ml) under argon. After 5 minutes, more dichloromethane (10 ml) was added. The reaction mixture was stirred at room temperature for 5.5 hours and then filtered. Purification by chromatography on silica gel using heptan:ethyl acetate (1:1) as eluent gave a mixture of product and starting material wich was dissolved in ethyl acetate and washed 3 times with 1 N sodium hydroxide. The organic phase was washed with brine, dried (sodium sulphate), filtered and solvent was evaporated to give 0,27 g (yield 60%) of the desired product.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH:9]([CH3:20])[C:10]([N:12]1[C@H:16]([C:17]([OH:19])=[O:18])[CH2:15][S:14][CH2:13]1)=[O:11].[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([O-:28])=[S:27])=[CH:24][C:23]=1[S:31](=[O:34])(=[O:33])[NH2:32].[K+].[CH:36]1([NH:42][CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>O>[CH:43]1([NH:42][CH:36]2[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]2)[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]1.[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([S:27][CH2:8][C@@H:9]([CH3:20])[C:10]([N:12]2[C@H:16]([C:17]([OH:19])=[O:18])[CH2:15][S:14][CH2:13]2)=[O:11])=[O:28])=[CH:24][C:23]=1[S:31](=[O:34])(=[O:33])[NH2:32]
Reactant: NS(=O)(=O)c1cc(C([O-])=S)ccc1Cl
Reactant: CC(CBr)C(=O)N1CSC[C@H]1C(=O)O
Agent: C1CCC(NC2CCCCC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C[C@H](CSC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1)C(=O)N1CSC[C@H]1C(=O)O

Procedure:
A solution of 1.4 g of potassium carbonate in 30 ml of water is added to 2.8 g of 3-(3-bromo-2-methylpropionyl)-4(R)-thiazolidinecarboxylic acid whereupon 3 g of potassium 4-chloro-3-sulfamoyl-thiobenzoate is added slowly under ice-cooling and stirring, and the resulting mixture is stirred at room temperature for 4 hours. The reaction mixture is then treated in an analogous manner of Example 1, and the oily residue thus obtained is converted in a conventional manner into the dicyclohexylamine salt. Thus is obtained dicyclohexylamine salt of 3-[3-(4-chloro-3-sulfamoylbenzoylthio)-2(S)-methylpropionyl]-4(R)-thiazolidinecarboxylic acid as white crystalline powder, melting at 173°-176° C. (recrystallized twice from isopropanol).
Reaction SMILES: [CH2:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH2:4][CH2:3][CH:2]1[NH2:14].[C:15]1([CH2:21][C:22](Cl)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>O1CCCC1>[C:15]1([CH2:21][C:22]([NH:14][C:2]2[CH:3]=[CH:4][C:5]3[O:6][C:7]4[CH2:13][CH2:12][CH2:11][CH2:10][C:8]=4[C:9]=3[CH:1]=2)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NC1CCc2oc3ccccc3c2C1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)Nc1ccc2oc3c(c2c1)CCCC3
Yield: 55.9 %

Procedure:
Following the procedure of Example 1, tetrahydro-dibenzofuran-2-ylamine (0.78 g, 4.1 mmol), phenylacetyl chloride (1.1 mL, 8.2 mmol), and triethylamine (1.8 mL, 13 mmol) in tetrahydrofuran (10 mL) provided 2-phenyl-N-(6,7,8,9-tetrahydro-dibenzofuran-2-yl)-acetamide (0.70 g). Mp 180-181° C.; Anal. Calcd. for C20H19NO2: C, 78.66; H, 6.27; N, 4.59; Found: C, 78.53; H, 6.13; N, 4.75.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[Cs+].[Cs+].[NH:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)=[O:17].F[C:26]1[C:31]([CH:32]2[CH2:38][CH2:37]N[C:35](=O)[CH2:34][CH2:33]2)=[CH:30][CH:29]=[CH:28][N:27]=1>CN1C(=O)CCC1>[NH:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][C:26]2[C:31]([CH:32]3[CH2:33][CH2:34][CH2:35][C:1](=[O:4])[CH2:37][CH2:38]3)=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:20][CH:19]=1)=[O:17]
Reactant: O=C([O-])[O-]
Reactant: O=C1CCC(c2cccnc2F)CCN1
Reactant: O=C(c1ccc(O)cc1)c1nc2ccccc2[nH]1
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: O=C1CCCC(c2cccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)CC1
Temperature: 140 °C

Procedure:
A mixture of cesium carbonate (0.24 g, 0.72 mmol), (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (0.17 g, 0.72 mmol), and 5-(2-fluoropyridin-3-yl)azepan-2-one (0.050 g, 0.24 mmol) in NMP (0.25 mL) under argon was heated to 140° C. for 36 h. After cooling to room temperature, the mixture was partitioned between ethyl acetate and water. The layers were separated and the organic layer was washed with water several times, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by reversed phase HPLC, and the resulting oil was dissolved in DCM and washed with saturated aqueous sodium bicarbonate (2×), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give 4-(2-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyridin-3-yl)cycloheptanone. MS (ESI, pos. ion) m/z: 427.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: Cl.[CH3:2][Si:3]([C:6]#[C:7][C:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH:13]=1)([CH3:5])[CH3:4].[CH3:14][C@@:15]1([CH2:22][S:23](Cl)(=[O:25])=[O:24])[C:19](=[O:20])[NH:18][C:17](=[O:21])[NH:16]1.C(N(C(C)C)C(C)C)C>C1COCC1>[CH3:14][C@:15]1([CH2:22][S:23]([N:11]2[CH2:10][CH:9]=[C:8]([C:7]#[C:6][Si:3]([CH3:4])([CH3:5])[CH3:2])[CH2:13][CH2:12]2)(=[O:25])=[O:24])[NH:16][C:17](=[O:21])[NH:18][C:19]1=[O:20]
Reactant: C[C@]1(CS(=O)(=O)Cl)NC(=O)NC1=O
Reactant: C[Si](C)(C)C#CC1=CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[C@]1(CS(=O)(=O)N2CC=C(C#C[Si](C)(C)C)CC2)NC(=O)NC1=O
Temperature: -10 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
4-[(Trimethylsilyl)ethynyl]-1,2,3,6-tetrahydropyridine hydrochloride (3.43 g, 15.9 mmol) was stirred in THF (100 mL) with [(4S)-4-methyl-2,5-dioxoimidazolidin -4-yl]methanesulfonyl chloride (3.39 g, 15 mmol) and cooled in an ice salt bath (temperature about −10° C.). N-Ethyldiisopropylamine (5.13 mL, 30 mmol) in THF (100 mL) was added dropwise over 2 hours and the mixture stirred a further 2 hours. The reaction mixture was washed with water, the aqueous layer extracted into EtOAc (×2), the organic phases combined, washed with 2M HCl (×2), saturated bicarbonate solution (x2), followed by brine, dried (sodium sulphate) and evaporated to give the crude product (5.06 g). This was used without further purification.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([C:8]2[CH:9]=[CH:10][C:11]([N+:15]([O-])=O)=[C:12]([CH:14]=2)[NH2:13])[CH2:5][C@@H:4]([CH3:18])[O:3]1>[Pd].C(OCC)(=O)C.CO>[NH2:13][C:12]1[CH:14]=[C:8]([N:6]2[CH2:5][C@@H:4]([CH3:18])[O:3][C@@H:2]([CH3:1])[CH2:7]2)[CH:9]=[CH:10][C:11]=1[NH2:15]
Reactant: C[C@@H]1CN(c2ccc([N+](=O)[O-])c(N)c2)C[C@H](C)O1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: C[C@@H]1CN(c2ccc(N)c(N)c2)C[C@H](C)O1
Reaction time: 25 h
Yield: 97 %

Procedure:
To a solution of 5-(cis-2′,6′-dimethylmorpholino)-2-nitroaniline (1.26 g, 5.03 mmol) in 4:1 ethyl acetate/methanol (75 ml) was added 5% palladium on carbon (0.24 g) and the reaction mixture stirred under an atmosphere of hydrogen for 25 h. The reaction mixture was then filtered through celite, the filtered solid washed with methanol, and the combined filtrate and washings concentrated in vacuo to give crude 2-amino-4-(cis-2′,6′-dimethylmorpholino)aniline (1.08 g, 97%) which was used immediately in the next step.