Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][CH2:11][C:12]1[CH:16]=[C:15]([CH3:17])[O:14][N:13]=1.CCOCC>CN(C=O)C>[Br:1][C:16]1[C:12]([CH2:11][O:10][CH3:9])=[N:13][O:14][C:15]=1[CH3:17]
Reactant: COCc1cc(C)on1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COCc1noc(C)c1Br
Temperature: 60 °C
Yield: 92.5 %

Procedure:
N-bromosuccinimide (590 mg, 3.31 mmol) was added to 3-methoxymethyl-5-methyisoxazole (351 mg, 2.76 mmol) in DMF (3.5 mL) at room temperature under nitrogen. The reaction was heated at 60° C. for 15 h then allowed to cool to room temperature. Ether (50 mL) was added to the reaction mixture, then washed with water (3×10 mL), saturated aqueous sodium hydrogen carbonate (10 mL), and brine (10 mL). The organic layer was dried over magnesium sulfate, filtered, and evaporated to provide 526 mg (92% yield) of 4-bromo-3-methoxymethyl-5-methylisoxazole as a clear liquid which was used in the next step without further purification: 1H NMR (300 MHz, CDCl3) δ ppm 4.50 (s, 2H), 3.41 (s, 3H), 2.43 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16](C(O)=O)=[C:15]3[N:10]([N:11]=[C:12]([O:20][CH3:21])[CH:13]=[CH:14]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C1C(=O)N([Br:29])C(=O)C1>CN(C=O)C.C(OCC)(=O)C>[Br:29][C:16]1[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[N:9][N:10]2[C:15]=1[CH:14]=[CH:13][C:12]([O:20][CH3:21])=[N:11]2
Reactant: COc1ccc2c(C(=O)O)c(-c3cccc(F)c3)nn2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2c(Br)c(-c3cccc(F)c3)nn2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 2-(3-fluoro-phenyl)-6-methoxy-pyrazolo[1,5-b]pyridazine-3-carboxylic acid (2.0 g) in anhydrous DMF (20 ml) was added n-bromosuccinimide (1.78 g) and the resulting solution stirred at ambient temperature for 3 hours. The reaction mixture was diluted with ethyl acetate (800 ml) and washed sequentially with water (10×100 ml) and sat. brine (25 ml), dried (Na2SO4), and concentrated to give the title compound as a buff solid (2.1 g, 93%).
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)=[CH:4][N:3]=[CH:2]1.[Li]CCCC.[C:17](Cl)(=[O:29])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>C1COCC1.CCOC(C)=O.[Cl-].[Cl-].[Zn+2]>[N:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:5]1[O:1][C:2]([C:17](=[O:29])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[N:3][CH:4]=1
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: c1ccc(-c2cnco2)nc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCC(=O)c1ncc(-c2ccccn2)o1
Reaction time: 0.33 h
Yield: 52.9 %

Procedure:
(185) A solution of 2-(oxazol-5-yl)pyridine (102 mg, 0.70 mmol) in anhydrous THF (5 mL) cooled to −75° C. under N2 was treated with n-BuLi (2.5 M in hexanes, 1.1 equiv, 0.77 mmol, 0.31 mL), and stirred for 20 min. ZnCl2 (0.5 M in THF, 2.0 equiv, 1.40 mmol, 2.8 mL) was added at −75° C., and stirred for 45 min at 0° C. Cul (1.0 equiv, 0.70 mmol, 133 mg) was added, and the solution was stirred for 10 min at 0° C. Lauroyl chloride (2 equiv, 1.4 mmol, 306 mg, 0.32 mL) was added and the solution was stirred for 1 h at 0° C. The reaction was diluted with EtOAc (10 mL), and washed with 15% aqueous NH4OH (1×10 mL), H2O (1×10 mL), and saturated aqueous NaCl (1×10 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. Flash chromatography (SiO2, 2.5 cm×17.5 cm, 20% EtOAc-hexanes) afforded 1-(5-(pyridin-2-yl)oxazol-2-yl)dodecan-1-one (185) (122 mg, 0.37 mmol, 53% yield) as an off-white powder: mp 73-74° C.; 1H NMR (CDCl3, 250 MHz) d 8.65 (br d, J=4.0 Hz, 1H), 7.89-7.75 (m, 3H), 7.34-7.25 (m, 1H), 3.09 (t, J =7.7 Hz, 2H), 1.83-1.69 (m, 2H), 1.41-1.19 (m, 16H), 0.86 (br t, J=7.0 Hz, 3H); 13C NMR (CDCl3, 62.5 MHz) d 188.6, 153.2, 150.1 (2C), 146.3, 137.1, 126.8, 124.1, 120.3, 39.1, 31.9, 29.6 (2C), 29.4, 29.3, 29.2 (2C), 24.0, 22.7, 14.1; IR (KBr) umax 2929, 2857, 1704, 1609, 1415, 1378 cm−1; MALDI-FTMS (DHB) m/z 329.2214 (C20H28N2O2+H+ requires 329.2223).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[N:9]=[C:10]([CH2:13][O:14][C:15]2[C:16]([F:25])=[C:17]([C:21]([F:24])=[CH:22][CH:23]=2)[C:18]([NH2:20])=O)[S:11][CH:12]=1.C(N(CC)CC)C>CN(C=O)C>[Br:7][C:8]1[N:9]=[C:10]([CH2:13][O:14][C:15]2[C:16]([F:25])=[C:17]([C:21]([F:24])=[CH:22][CH:23]=2)[C:18]#[N:20])[S:11][CH:12]=1
Reactant: NC(=O)c1c(F)ccc(OCc2nc(Br)cs2)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1c(F)ccc(OCc2nc(Br)cs2)c1F
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 70.2 %

Procedure:
To an ice cold solution of DMF (0.20 ml) and acetonotrile (5 ml) was added oxalyl chloride (45 μL, 0.52 mmol) dropwise while maintaining the temperature to 0° C. The reaction mixture was stirred at 0° C. for 40 min followed by addition of a solution of 3-((4-bromothiazol-2-yl)methoxy)-2,6-difluorobenzamide (0.15 g, 0.43 mmol) in DMF (2 ml). The resulting reaction mixture was stirred at 0° C. 40 min and then allowed to come to room temperature. After completion of reaction (10 min, TLC monitoring), triethyl amine (100 μL, 0.86 mmol) was added dropwise. The reaction mass was concentrated in vaccuo followed by addition of water (50 ml) and extraction with ethyl acetate (3×75 ml). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified over silica gel (60-120 M, 20% EtOAc-Hexane) to get the desired product (0.10 g, 71%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([OH:8])[CH:7]=1.F[C:14]1[CH:19]=[CH:18][C:17]([S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:16][C:15]=1[C:29]([F:32])([F:31])[F:30]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([O:8][C:14]2[CH:19]=[CH:18][C:17]([S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:21])=[O:22])=[CH:16][C:15]=2[C:29]([F:32])([F:31])[F:30])[CH:7]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc(F)c(C(F)(F)F)c1
Reactant: O=C(O)Cc1cc(O)cc(Cl)c1
Product: O=C(O)Cc1cc(Cl)cc(Oc2ccc(S(=O)(=O)c3ccccc3)cc2C(F)(F)F)c1

Procedure:
The title compound was prepared as described in example 2 step (iii) but instead using the product from example 18 step (iv) and the product from step (i).
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]([O:8][C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:5][CH2:6][CH3:7].CS(C)=O.O.Cl.[CH3:34][CH2:35]OCC>>[C:10]1([C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:8][CH:4]([CH2:5][CH2:6][CH3:7])[CH2:3][CH2:2][C:34]#[CH:35])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCCC(CCCl)OC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOCC
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Product: C#CCCC(CCC)OC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
To a stirred solution of 32.2 g. (85 mmoles) of 1-chloro-3-triphenylmethoxyhexane (Example 906) in 25 ml. of dimethylsulfoxide (DMSO) is added a solution of 9.4 g. (102 mmoles) of lithium acetylide-ethylene diamine complex in 60 ml. of DMSO during 10 minutes while maintaining a temperature of 25°-30° C. After 3.5 hours the mixture is diluted with ether and treated successively with water and 4N hydrochloric acid while cooling in an ice bath. The phases are separated, and the aqueous phase is extracted with ether-petroleum ether. The combined extracts are washed successively with water and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. The product is then purified by column chromatography of the residue on Florisil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[S:7])=[CH:4][CH:3]=1.[F:12][CH:13]([F:23])[O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=O.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[S:7][CH:17]([C:16]3[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=3[O:14][CH:13]([F:12])[F:23])[NH:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1OC(F)F
Reactant: NNC(=S)c1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: FC(F)Oc1ccccc1C1NN=C(c2ccc(Cl)cc2)S1
Reaction time: 0.17 h

Procedure:
To a heterogeneous mixture of 4-chloro-thiobenzoic acid hydrazide (0.107 mmol) in CH2Cl2 (1 mL) is added 2-difluoromethoxy-benzaldehyde (0.128 mmol) and DIEA (0.128 mmol). After 10 minutes the mixture become homogenous and the reaction is complete by TLC and LCMS to give 5-(4-chloro-phenyl)-2-(2-difluoromethoxy-phenyl)-2,3-dihydro-[1,3,4]thiadiazole which is used in the next step without evaporation of the solvent.
Reaction SMILES: C[O-].[Na+].[CH2:4]1[O:14][C:13]2[C:6](=[CH:7][C:8]([NH2:15])=[C:9]([CH:12]=2)[CH:10]=O)[O:5]1.[C:16]([CH2:18][C:19]([NH2:21])=[O:20])#[N:17]>CO>[CH2:4]1[O:5][C:6]2[CH:7]=[C:8]3[C:9]([CH:10]=[C:18]([C:19]([NH2:21])=[O:20])[C:16]([NH2:17])=[N:15]3)=[CH:12][C:13]=2[O:14]1
Reactant: N#CCC(N)=O
Reactant: Nc1cc2c(cc1C=O)OCO2
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1cc2cc3c(cc2nc1N)OCO3
Yield: 89.3 %

Procedure:
To sodium methoxide (1.90 g., 0.03 mole) in methanol (50 ml.) is added 4,5-methylenedioxy-2-aminobenzaldehyde (5.0 g., 0.03 mole) and 2-cyanoacetamide (2.50 g., 0.03 mole). The mixture is heated to reflux for 15 minutes and then cooled in an ice bath. The bright yellow solid is filtered off and recrystallized from acetic acid to give 6.18 g. (89.3%) of the desired product. M.P. 308° C. (dec.). (m/e = 231)
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][C:16]=4[CH:6]2[CH2:5][CH:4]([C:18]([OH:20])=[O:19])[CH2:3]1)[NH:11][CH:10]=3.[OH-].[K+].CN(C=O)C.[C:28]1(C)[CH:33]=[CH:32]C(S(OC(CC)CC)(=O)=O)=[CH:30][CH:29]=1>O>[CH2:29]([CH:28]([N:11]1[C:12]2[C:17]3[C:9]([CH2:8][C@@H:7]4[C@@H:6]([C:16]=3[CH:15]=[CH:14][CH:13]=2)[CH2:5][CH:4]([C:18]([OH:20])=[O:19])[CH2:3][N:2]4[CH3:1])=[CH:10]1)[CH2:33][CH3:32])[CH3:30]
Reactant: CN1CC(C(=O)O)CC2c3cccc4[nH]cc(c34)CC21
Reactant: CCC(CC)OS(=O)(=O)c1ccc(C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(CC)n1cc2c3c(cccc31)[C@H]1CC(C(=O)O)CN(C)[C@@H]1C2
Yield: 59.8 %

Procedure:
A 250 ml, three-neck round bottom flask was charged with 10.0 g (33.9 mmol) of 92% pure 9,10-dihydrolysergic acid, 10.3 g (158 mmol) of 86% pure powdered potassium hydroxide and 75 ml of DMF. The mixture was stirred until the solid constituents were completely dissolved, and 17.9 g (73.9 mmol) of p-toluenesulfonic acid, 1-ethylpropyl ester was added. The reaction mixture was stirred at room temperature overnight and 300 ml of deionized water was added. The mixture was filtered, and 1N hydrochloric acid was added to the filtrate until the pH was adjusted to approximately 6.5. The precipitated solid was collected by vacuum filtration and rinsed with water to provide 6.9 g of 1-(1-ethylpropyl)-6-methylergoline-8-carboxylic acid. The identity of the solid was determined by thin layer chromatography employing chloroform:methanol:acetic acid (18:6:1, v:v:v) as the solvent system as compared to an authentic reference standard. The products obtained from Example 1 and Example 2 were combined to provide 7.6 g of solid, which was recrystallized from methanol to provide 2.1 g of the desired product following drying of the solid in vacuo. The purity of the product was 95.6% as determined by HPLC as compared to an authentic reference standard.
Reaction SMILES: [Br:1]Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:22]([N:41]1[C:45]([CH2:46][CH2:47][CH2:48]O)=[N:44][CH:43]=[N:42]1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>ClCCl>[Br:1][CH2:48][CH2:47][CH2:46][C:45]1[N:41]([C:22]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:42]=[CH:43][N:44]=1
Reactant: BrBr
Reactant: OCCCc1ncnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: BrCCCc1ncnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -5 °C
Yield: 43.3 %

Procedure:
A solution of bromine (5.6 g) in dichloromethane (15 ml) was added dropwise to a stirred solution of triphenylphosphine (9.2 g) in dichloromethane (100 ml) cooled to -5° C. The mixture was stirred for a further ten minutes at 0° C., then treated portionwise with a solution of the above alcohol (6.9 g) and triethylamine (4.9 ml) in dichloromethane (30 ml) again maintaining the temperature below 0° C. The solution was stirred for a further ten minutes, filtered through a bed of silica, then chromatographed on silica, using dichloromethane-ether (25:1) as eluant, to give 1-bromo-3(1-trityl-1,2,4-triazol-5-yl)propane (3.5 g, m.p. 146°-149° C.). NMR (CDCl3): δ1.8(2H,m), 2.15(2H,t), 3.2(2H,t), 7.1-7.3(15H,m), 7.9(1H,s). 13C NMR was used to confirm the position of the trityl substituent.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][C:12]([NH:14][C@H:15]2[CH2:20][C:19]3[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([OH:27])=[O:26])[C:18]=3[O:17][B:16]2[OH:28])=[O:13])[CH2:7][CH2:6]1.C(O)(=O)C.[CH3:33][C:34]([CH3:36])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[OH:28][B:16]1[C@@H:15]([NH:14][C:12](=[O:13])[CH2:11][C@H:8]2[CH2:9][CH2:10][C@H:5]([NH:4][CH2:3][CH2:2][NH:1][CH:34]([CH3:36])[CH3:33])[CH2:6][CH2:7]2)[CH2:20][C:19]2[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([OH:27])=[O:26])[C:18]=2[O:17]1
Reactant: CC(C)=O
Reactant: NCCN[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)NCCN[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid from Example 15 (92 mg) in MeOH (2 mL) was added TEA (70 μL), acetic acid (30 μL), acetone (0.1 mL) and sodium triacetoxyborohydride (212 mg). The reaction mixture was stirred overnight at RT. Solvent was removed and the product was purified using reverse phase HPLC to afford the titled compound. ESI-MS m/z 432 (MH)+.
Reaction SMILES: [OH:1]S(O)(=O)=O.[C:6]([NH:9][C:10]12[CH2:19][C:14]3([CH3:20])[CH2:15][CH:16]([CH2:18][C:12]([CH3:21])([CH2:13]3)[CH2:11]1)[CH2:17]2)(=[O:8])[CH3:7]>>[C:6]([NH:9][C:10]12[CH2:19][C:14]3([CH3:20])[CH2:15][C:16]([OH:1])([CH2:18][C:12]([CH3:21])([CH2:13]3)[CH2:11]1)[CH2:17]2)(=[O:8])[CH3:7]
Reactant: O=S(=O)(O)O
Reactant: CC(=O)NC12CC3CC(C)(CC(C)(C3)C1)C2
Product: CC(=O)NC12CC3(C)CC(C)(CC(O)(C3)C1)C2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Fuming H2SO4 (3 mL) was added to 1-acetamido-3,5-dimethyladamantane (0.2 g) at 0° C. under nitrogen and the reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was poured onto ice (10 g) and the product was extracted with ether (10 mL×4). The combined ether solution was washed with brine (10 mL) and water (10 mL). The solution was dried using sodium sulfate. The solvent was removed in vacuo and, after crystallization on standing, 70 mg of white product was obtained. Pure product was obtained by recrystallization in ether. 1H NMR (DMSO-d6, ppm): 7.30 (brs, 1H, NH), 4.37 (brs, 1 H, OH), 1.72 (s, 3 H, COCH3), 1.65 (s, 2 H), 1.47 (s, 4 H), 1.24-1.14 (dd, 4 H, J=11.2, 23.9 Hz), 0.99 (s, 2 H), 0.82 (s, 6 H, 2×CH3). m.p. 194-195° C. Anal. (C14H23NO2), C. H. N.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:7](Cl)=O)=[CH:3][CH:2]=1.[CH2:16]([N:18]([CH2:23][CH3:24])[C:19](=[O:22])[CH:20]=C)[CH3:17]>>[CH2:16]([N:18]([CH2:23][CH3:24])[C:19](=[O:22])[CH:20]=[CH:7][C:4]1[CH:5]=[CH:6][C:1]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:2][CH:3]=1)[CH3:17]
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: C=CC(=O)N(CC)CC
Product: CCN(CC)C(=O)C=Cc1ccc(-c2ccccc2)cc1
Temperature: 120 °C
Reaction time: 0.83 h

Procedure:
This compound is prepared from 10.83 g (50 millimols) of biphenyl-4-carboxylic acid chloride and 7.94 g (62.5 millimols) of N,N-diethylacrylamide, the mixture being stirred for 50 minutes at 120° C. The crude product is extracted, in a Soxhlet extractor, with 125 ml of n-hexane, and is recrystallised once from diethyl ether. 8.5 g (15% of theory) of pale yellow crystals, melting point 113.3° C., are obtained. Analysis for C10H21NO: calculated C 81.72%, H 7.53%, N 5.02%; found C 81.44%, H 7.50%, N 4.91%.
Reaction SMILES: [N:1]1([C:7](=[O:29])[CH2:8][CH2:9][CH:10]=[CH:11][CH2:12][CH:13]=[CH:14][CH2:15][CH:16]=[CH:17][CH2:18][CH:19]=[CH:20][CH2:21][CH:22]=[CH:23][CH2:24][CH:25]=[CH:26][CH2:27][CH3:28])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:30](O)(=[O:38])[C:31]1[C:32](=[CH:34][CH:35]=[CH:36][CH:37]=1)[OH:33].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC#N>[OH:33][C:32]1[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=1[C:30]([N:4]1[CH2:5][CH2:6][N:1]([C:7](=[O:29])[CH2:8][CH2:9][CH:10]=[CH:11][CH2:12][CH:13]=[CH:14][CH2:15][CH:16]=[CH:17][CH2:18][CH:19]=[CH:20][CH2:21][CH:22]=[CH:23][CH2:24][CH:25]=[CH:26][CH2:27][CH3:28])[CH2:2][CH2:3]1)=[O:38]
Reactant: CCC=CCC=CCC=CCC=CCC=CCC=CCCC(=O)N1CCNCC1
Reactant: O=C(O)c1ccccc1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCC=CCC=CCC=CCC=CCC=CCC=CCCC(=O)N1CCN(C(=O)c2ccccc2O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.7 %

Procedure:
To a mixture of 1-(piperazin-1-yl)docosa-4,7,10,13,16,19-hexaen-1-one (1.17 g, 2.95 mmol), salicylic acid (0.61 g, 4.43 mmol) and Et3N (0.89 g, 8.85 mmol) in CH3CN (10 mL) was added HATU (1.68 g, 4.43 mmol). The mixture was stirred (RT, 16 h). The solvent was removed under reduced pressure and the residue was extracted with EtOAc (4×50 mL). The combined organic layers were washed successively with 1N aqueous HCl, water, 5% NaHCO3 and water, and dried over MgSO4. The solvent was removed under reduced pressure. Purification of the crude product by prep-HPLC afforded 1-(4-(2-hydroxybenzoyl)piperazin-1-yl)docosa-4,7,10,13,16,19-hexaen-1-one (300 mg, 19.6%) as a light yellow oil. Mass calculated for C33H44N2O3=516.71; found: [M+H]+ 517.6.
Reaction SMILES: [SH2:1].CC([O-])(C)C.[K+].F[C:9]1[C:10]([S:15]([NH2:18])(=[O:17])=[O:16])=[N:11][CH:12]=[CH:13][CH:14]=1>CN(C)C=O>[SH:1][C:9]1[C:10]([S:15]([NH2:18])(=[O:17])=[O:16])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: NS(=O)(=O)c1ncccc1F
Reactant: S
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ncccc1S
Reaction time: 2 h

Procedure:
1.06 g of hydrogen sulfide are passed at a temperature of +16° to +20° C. under a nitrogen atmosphere into a mixture of 6.88 g of potassium tert-butylate and 5 g of 3-fluoropyridin-2-ylsulfonamide in 90 ml of dimethylformamide. After the mixture has been stirred for 41/2 hours at a temperature of +50° C., 0.32 g of potassium tert-butylate are added and 0.1 g of hydrogen sulfide is passed in. After the reaction mixture has been stirred for 2 hours at a temperature of +50° C., it is concentrated in vacuo at a temperature of +75° C. The resulting oily residue is triturated with 135 ml of cold 0.75N sulfuric acid. After the residue has been filtered and washed with a little water, the resulting product is dried in vacuo over phosphorus pentoxide. This gives 3.58 g of 3-mercaptopyridin-2-ylsulfonamide of a melting point of +102 to +104° C.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:12]([C:31]2[CH:36]=[C:35]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([CH2:44][CH3:45])=[CH:40][CH:39]=3)[C:34]([Cl:46])=[C:33](Br)[C:32]=2[O:48][CH2:49][CH2:50]Cl)[O:11][C@@H:10]1[CH2:52][O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC>C1COCC1>[Cl:46][C:34]1[C:33]2[CH2:50][CH2:49][O:48][C:32]=2[C:31]([CH:12]2[C@H:13]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@@H:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@H:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C@@H:10]([CH2:52][O:53][CH2:54][C:55]3[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=3)[O:11]2)=[CH:36][C:35]=1[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][CH3:45])=[CH:40][CH:39]=1
Reactant: CCc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(OCCCl)c(Br)c2Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2Cl)CCO3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the intermediate 34 (1.18 g, 1.30 mmol) in anhydrous THF (15 mL) was added dropwise n-BuLi (2.5M in hexane, 0.78 mL, 1.94 mmol) at −78° C. under nitrogen atmosphere. The mixture was slowly warmed up to rt and stirred overnight. The reaction mixture was quenched with 1M HCl solution (10 mL) and extracted with EtOAc (50 mL). The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to provide the crude intermediate 35, which was used without further purification (1.03 g, 1.30 mmol, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]#[N:29])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH:21]3[CH2:26][O:25][CH2:24][CH2:23][O:22]3)[C:17](O)=[O:18])[C:10](=[O:27])[CH:9]=2)[CH:7]=1.[NH2:30][C:31]1[CH:43]=[CH:42][C:34]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:33][CH:32]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]#[N:29])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH:21]3[CH2:26][O:25][CH2:24][CH2:23][O:22]3)[C:17]([NH:30][C:31]3[CH:43]=[CH:42][C:34]([C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])=[CH:33][CH:32]=3)=[O:18])[C:10](=[O:27])[CH:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: COc1cn(C(CC2COCCO2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Product: COc1cn(C(CC2COCCO2)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
132 mg (purity 60%, 0.19 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1,4-dioxan-2-yl)propanoic acid (mixture of racemic diastereomers) and 40 mg (0.21 mmol, 1.1 eq.) of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 106 mg (94% of theory)
Reaction SMILES: C(O)(C(F)(F)F)=O.[OH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18](=[O:27])[N:19]([CH3:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:13][CH:12]=1.[N:28]1([C:33]2[CH:38]=[CH:37][C:36](O)=[CH:35][CH:34]=2)[CH:32]=[CH:31][N:30]=[CH:29]1>>[N:28]1([C:33]2[CH:38]=[CH:37][C:36]([O:8][CH2:9][CH2:10][C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18](=[O:27])[N:19]([CH3:26])[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:15][CH:16]=3)=[CH:35][CH:34]=2)[CH:32]=[CH:31][N:30]=[CH:29]1
Reactant: CN(C(=O)Oc1ccc(CCO)cc1)c1ccccc1
Reactant: Oc1ccc(-n2ccnc2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)Oc1ccc(CCOc2ccc(-n3ccnc3)cc2)cc1)c1ccccc1
Yield: 62 %

Procedure:
The title compound was prepared as its TFA salt in 62% yield as an oil using methyl-phenyl-carbamic acid 4-(2-hydroxy-ethyl)-phenyl ester and 4-imidazol-1-yl-phenol.
Reaction SMILES: CS([O-])(=O)=O.[C:6]1(=[O:13])[O:12][C:10](=[O:11])[CH2:9][O:8][CH2:7]1.[NH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20]>>[OH:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:10](=[O:11])[CH2:9][O:8][CH2:7][C:6]([OH:12])=[O:13]
Reactant: O=C1COCC(=O)O1
Reactant: NCCCCCO
Agent: CS(=O)(=O)[O-]
Product: O=C(O)COCC(=O)NCCCCCO

Procedure:
methanesulfonate by the following sequence of steps: (a) by reacting diglycolic anhydride and 5-aminopentanol to produce [2-(5-hydroxypentyl)amino-2-oxoethoxy]acetic acid, (b) heating to cyclize the latter to obtain 4-(5-hydroxypentyl)-b 3,5-dioxomorpholine, (c) esterifying the latter with methanesulfonyl chloride to produce 5-(3,5-dioxomorpholino)pentyl methanesulfonate and (d) reacting the mesylate with 2-benzhydrylpiperidine.