Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[CH3:27][C:28]1(C)C(C)(C)OB(C=C)O1.C([O-])([O-])=O.[Na+].[Na+].CO.C(Cl)Cl>O1CCOCC1.O.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>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([CH:27]=[CH2:28])[CH:3]=1)=[O:15]
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)nc3c2cnn3C(C)C)c(=O)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: C=Cc1cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c2cnn(C(C)C)c2n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
A solution of 6-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1 g, 2.39 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.442 g, 2.87 mmol) and Pd(PPh3)4 (0.276 g, 0.238 mmol) in 1,4-dioxane (10 mL) was purged with argon for 10 min. Then, solution of Na2CO3 (0.91 g, 8.58 mmol) in water (4.3 mL) was added to it and again argon was purged through it for 10 min. The reaction mixture was stirred at 100° C. for 1 h. After completion of the reaction, water was added to it and extraction was carried out using 20% MeOH/DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give desired product (0.8 g, 91.6%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[CH:9]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O)(C)(C)C.[CH3:21][Mg]Br>O1CCCC1>[CH3:21][C:10]1([OH:14])[CH2:11][CH2:12][CH2:13][NH:8][CH:9]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C[Mg]Br
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1c1ccccc1
Solvent: C1CCOC1
Product: CC1(O)CCCNC1c1ccccc1

Procedure:
A solution of 1-t-butoxycarbonyl-2-phenyl-piperidin-3-one (0.57 g, Example 48a)in 5 ml anhydrous tetrahydrofuran at -78° C. was treated with methyl magnesium bromide (1.6 ml of 1.5M solution in toluene-THF). The reaction was partitioned between saturated ammonium chloride-diethyl ether, the organic phase dried and evaporated in vacuo. The residue was chromatographed using 20% ethyl acetate in hexane as eluant to give 1-t-butoxycarbonyl, 3-methyl-2-phenyl piperidin-3-ol as a crystalline solid, m.p.=95°-97° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[N:18][CH:19]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=3)[CH:21]=1)[CH2:10][C:9]2([CH3:33])[CH3:32])=[O:5])C.Cl>C(O)C.O1CCCC1.[OH-].[Na+].O>[C:28]([C:25]1[CH:24]=[CH:23][C:22]([C:20]2[CH:21]=[C:16]([CH:11]3[CH2:10][C:9]([CH3:33])([CH3:32])[C:8]4[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=4)[NH:12]3)[CH:17]=[N:18][CH:19]=2)=[CH:27][CH:26]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cncc(-c3ccc(C(C)(C)C)cc3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1ccc(-c2cncc(C3CC(C)(C)c4cc(C(=O)O)ccc4N3)c2)cc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 91.2 %

Procedure:
A mixture of 2-[5-(4-tert-butyl-phenyl)-pyridin-3-yl]-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (1.0 g, 2.3 mmol) in ethanol (10 mL) and tetrahydrofuran (50 mL), 30% sodium hydroxide in water (10 mL). The reaction mixture was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-[5-(4-tert-butyl-phenyl)-pyridin-3-yl]-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (0.87 g, 90%) as a white solid which was used for next step without further purification: MS (ESI) M+1=415.3.
Reaction SMILES: Br.[Br:2][C:3]1[N:4]=[C:5]([CH3:11])[NH:6][C:7]=1[C:8](=O)[CH3:9].C(=O)(O)[O-].[Na+].CC(C)=O.[C:21]([NH:24][C:25]([NH2:27])=[S:26])(=[NH:23])[NH2:22]>O>[BrH:2].[NH:24]([C:25]1[S:26][CH:9]=[C:8]([C:7]2[N:6]=[C:5]([CH3:11])[NH:4][CH:3]=2)[N:27]=1)[C:21]([NH2:23])=[NH:22]
Reactant: CC(=O)c1[nH]c(C)nc1Br
Reactant: N=C(N)NC(N)=S
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1nc(-c2csc(NC(=N)N)n2)c[nH]1
Yield: 79.3 %

Procedure:
2.8 g (9.86 mmol) of 4-bromo-acetyl-2-methylimidazole hydrobromide was dissolved in 10 ml water. Saturated sodium bicarbonate solution was added to pH 10 and the resultant solid was collected by filtration and washed with 15 ml water. The dried free base was heated at reflux in 50 ml acetone. To the refluxing clear acetone solution was added 1.2 g (9.86 mmol) of amidinothiourea. Solution occurred immediately and within a minute a solid began to form. After one hour reflux the slurry was cooled and the solid was collected by filtration and was washed with acetone followed by ether to give 2.37 g (79%) of the title compound, M.P. 158° (dec.); nmr (DMSO-d6) (delta): 7.71 (s shoulder on broad s, 1H); 7.56 (broad s, 4H); 4.32 (s, 1H); 2.51 (s, 3H).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Br:14])(=O)=O.[C:15]1([CH2:21][NH2:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].O1CCCC1>O.C(OCC)(=O)C>[CH2:21]([NH:22][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Br:14])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CS(=O)(=O)OCCc1ccccc1Br
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Brc1ccccc1CCNCc1ccccc1
Reaction time: 0.08 h
Yield: 235.9 %

Procedure:
3.18 g of 2-(2-bromophenyl)ethyl methanesulfonate, 6.2 g of 1-phenylmethanamine, 7.87 g of potassium carbonate and 65 cm3 of tetrahydrofuran are stirred under an inert atmosphere for 16 h under the reflux of the solvent. The reaction mixture is cooled to a temperature close to 20° C., then in ice. 100 cm3 of ethyl acetate and 200 cm3 of water are then added thereto. Stirring is continued for 5 min. The aqueous phase is extracted using ethyl acetate. The organic phases are combined, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated using a rotary evaporator under reduced pressure (5 kPa). The 7.8 g of brown oil obtained are purified by flash chromatography over silica (column: 400 g; particle size: 15-40 μm; eluent: 100% dichloromethane to 90% dichloromethane/10% methanol gradient). After concentrating the fractions under reduced pressure, 2.49 g of N-benzyl-2-(2-bromophenyl)ethanamine are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:10]=1)[C:5]([OH:7])=[O:6].[H-].[Na+].[CH2:19](Br)[CH:20]=[CH2:21].O.[OH-].[Li+]>CN(C=O)C.O>[CH2:21]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:10]=1)[C:5]([OH:7])=[O:6])[CH:20]=[CH2:19]
Reactant: O=C(O)c1cc(O)cc(N2CCCC2=O)c1
Reactant: C=CCBr
Agent: [H-]
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1cc(C(=O)O)cc(N2CCCC2=O)c1
Temperature: 60 °C
Reaction time: 96 h

Procedure:
To the solution of 1.57 g (7.1 mmol) 3-hydroxy-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid in 5 ml DMF are added 1.02 g (21.3 mmol, 3 eq) 50% sodium hydride in oil. After gas evolution stops 2.53 ml (28.4 mmol, 4 eq) allylbromide are added and the reaction mixture is stirred 4 days at 60° C. The reaction is diluted with water and extracted with EtOAc. The organic layer is dried over sodium sulfate and the solvent is evaporated at reduced pressure. The resulting ester is redissolved in 40 ml MeOH and 0.347 g (8.2 mmol, 1.2 eq) lithiumhydroxide monohydrate are added. The reaction is stirred at rt for 48 h. After evaporation of part of the solvent at reduced pressure the reaction is taken into water and washed with EtOAc. The aqueous layer is acidified with potassium hydrogensulfate and extracted with EtOAc. Drying over sodium sulfate and evaporation of the solvent at reduced pressure gives the product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:14][CH2:13][CH2:12][CH:11]2[CH3:15])=[C:6]([CH:9]=1)[CH:7]=[O:8].[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:14][CH2:13][CH2:12][CH:11]2[CH3:15])=[C:6]([CH2:7][OH:8])[CH:9]=1
Reactant: CC1CCCN1c1ccc(Br)cc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC1CCCN1c1ccc(Br)cc1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
To a solution of 5-bromo-2-(2-methylpyrrolidin-1-yl)benzaldehyde (17 g, 63.4 mmol) in methanol (150 mL) under nitrogen was added sodium borohydride (2.41 g, 63.4 mmol) at 0° C. in portions. The reaction mixture was stirred at RT for 1 hour, then evaporated to remove methanol. The resulting crude was taken up with water (250 mL) and extracted with EtOAc (150 mL). The organic layer was washed with water, then dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as a yellow oil (16 g, 93%). 1H NMR (DMSO-d6, 400 MHz) δ 7.53 (1H, d), 7.27 (1H, d), 6.87 (1H, d), 5.22 (1H, t), 4.42 (2H, m), 3.56 (1H, m), 3.36 (1H, m), 2.70 (1H, m), 2.49 (1H, m) 2.09 (1H, m), 1.83 (1H, m), 1.73 (1H, m), 1.47 (1H, m), 0.90 (3H, d).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[Br:23][C:24]1[CH:25]=[N:26][C:27]2[N:28]([N:30]=[C:31]([C:33]([OH:35])=O)[CH:32]=2)[CH:29]=1.[N:36]1[C:41]2[CH2:42][CH2:43][NH:44][CH2:45][CH2:46][C:40]=2[CH:39]=[CH:38][CH:37]=1>CN(C=O)C>[Br:23][C:24]1[CH:25]=[N:26][C:27]2[N:28]([N:30]=[C:31]([C:33]([N:44]3[CH2:45][CH2:46][C:40]4[CH:39]=[CH:38][CH:37]=[N:36][C:41]=4[CH2:42][CH2:43]3)=[O:35])[CH:32]=2)[CH:29]=1
Reactant: c1cnc2c(c1)CCNCC2
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: O=C(c1cc2ncc(Br)cn2n1)N1CCc2cccnc2CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
73 mg (0.23 mmol) TBTU was added to 50 mg (0.21 mmol) 6-Bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid, 31 mg (0.21 mmol) 6,7,8,9-Tetrahydro-5H-pyrido[2,3-d]azepine and 90 μL (0.64 mmol) TEA in 1.5 mL DMF and stirred at RT overnight. The reaction mixture was purified by HPLC chromatography and lyophilized. Yield: 22 mg (29% of theory). ESI-MS: m/z=372 (M+H)+; Rt(HPLC): 0.81 min. (Method J).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH:15]=[O:16])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[CH:20]=[N:21][C:22]2[C:27]([C:28]=1[CH:29]=[O:30])=[N:26][C:25]([O:31][CH3:32])=[CH:24][CH:23]=2.N1CCC[C@H]1C(O)=O.C(OCC)(=O)C>CS(C)=O.O>[C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([CH:14]([CH:15]=[O:16])[CH:29]([C:28]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([O:31][CH3:32])[N:26]=3)[N:21]=[CH:20][C:19]=2[Cl:18])[OH:30])[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Reactant: COc1ccc2ncc(Cl)c(C=O)c2n1
Agent: O=C(O)[C@@H]1CCCN1
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc2ncc(Cl)c(C(O)C(C=O)[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c2n1

Procedure:
A solution of [trans-4-(2-oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (3.1 g, 25.1 mmol, 1.0 eq), 3-chloro-6-methoxy-[1,5]naphthyridine-4-carbaldehyde (5.6 g, 25.1 mmol, 1.0 eq) and L-proline (1.16 mg, 10.1 mmol, 0.4 eq) in dimethyl sulfoxide (100 mL) and water (15 mL) is stirred at room temperature for 16 hours. The reaction mixture is then extracted with ethyl acetate (500 mL) and water (500 mL). The organic layer is washed with brine (300 mL), dried over magnesium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel, eluent: ethyl acetate:petroleum ether, 1:1, v/v) to afford {trans-4-[2-(3-chloro-6-methoxy-[1,5]naphthyridin-4-yl)-1-formyl-2-hydroxy-ethyl]-cyclohexyl}-carbamic acid tert-butyl ester as a light yellow solid (4.5 g, 39% yield).
Reaction SMILES: [CH3:1][Si:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][OH:5].C(Cl)CCl.CCN(CC)CC.[OH:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][C:29](O)=[O:30])=[CH:22][CH:21]=1>C1COCC1.CN(C1C=CN=CC=1)C>[OH:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][CH2:28][C:29]([O:5][CH2:4][CH2:3][Si:2]([CH3:7])([CH3:6])[CH3:1])=[O:30])=[CH:24][CH:25]=1
Reactant: O=C(O)CCCc1ccc(O)cc1
Reactant: C[Si](C)(C)CCO
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: C[Si](C)(C)CCOC(=O)CCCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.6 %

Procedure:
To a stirred solution of 2-(trimethylsilyl) ethanol (0.56 mL, 3.91 mmol) in THF (1 mL) at rt under nitrogen, was added 4-DMAP (113 mg, 0.92 mmol) followed by EDC (177 mg, 0.92 mmol). After about 1 minute Et3N (170 μL, 1.22 mmol) was added, drop-wise followed by 4-(4-hydroxyphenyl)butanoic acid (150 mg, 0.83 mmol) in THF (4 mL) and the mixture stirred at rt for 18 hours. The mixture was then partitioned between Et2O (25 mL) and aqueous HCl (2M, 30 mL) and the layers separated. The aqueous layer was re-extracted with Et2O (20 mL) and the combined organic layer washed with brine (50 mL), dried (MgSO4) and concentrated under vacuum to give a ‘chalk-white’ milky oil. Purification by SPE (silica, 5 g Cartridge) eluting with cyclohexane:EtOAc (gradient 25:1 to 1:2) afforded the title compound (55 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[C:12]1[CH2:13][CH2:14][NH:15][CH2:16][CH:17]=1.[O:18]1[CH2:20][C@H:19]1[CH2:21][O:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[CH:26][NH:27]2>CO.CS(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[C:12]1[CH2:13][CH2:14][N:15]([CH2:20][C@H:19]([OH:18])[CH2:21][O:22][C:23]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:24]=2[CH:25]=[CH:26][NH:27]3)[CH2:16][CH:17]=1
Reactant: COc1ccc2[nH]cc(C3=CCNCC3)c2c1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Solvent: CO
Solvent: CS(C)=O
Product: COc1ccc2[nH]cc(C3=CCN(C[C@H](O)COc4cccc5[nH]ccc45)CC3)c2c1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 193 from 5-methoxy-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.70 g, 3.1 mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.58 g, 3.1 mmol). The product was isolated as a yellow foam. Yield 245 mg (19%). mp 105°-110° C. FDMS m/e=417 (M+ of free base). α[D]589 =+7.52 (c=1.01, methanol/dimethylsulfoxide).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:18])[CH2:13][CH2:14][C:15]([OH:17])=O)=[CH:8][CH:7]=1)(=[O:4])=[O:3].ClC(OCC(C)C)=O.[CH2:27]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]([OH:37])[CH3:36])[CH3:28].Cl>C1COCC1.C(N(CC)CC)C>[CH2:27]([N:29]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]([OH:37])[CH3:36])[C:15](=[O:17])[CH2:14][CH2:13][C:12](=[O:18])[C:9]1[CH:8]=[CH:7][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:11][CH:10]=1)[CH3:28]
Reactant: CS(=O)(=O)Nc1ccc(C(=O)CCC(=O)O)cc1
Reactant: CCNCCCCCC(C)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN(CCCCCC(C)O)C(=O)CCC(=O)c1ccc(NS(C)(=O)=O)cc1
Temperature: -8 °C
Reaction time: 1.5 h
Yield: 48.5 %

Procedure:
A stirred solution of 4-((methanesulfonyl)amino)-γ-oxobenzenebutanoic acid (as described in EP 164 865) (0.49 g, 1.8 mmol) in THF (15 ml), under nitrogen, was treated with triethylamine (0.28 ml), cooled to -8° C. and treated during 5 minutes with isobutyl chloroformate (0.26 ml, 2.04 mmol). This mixture was kept at -5° to -8° C. for 90 minutes and then treated during 30 minutes with a solution of the product from Step III (0.31 g, 1.95 mmol) and triethyl amine (0.28 ml) in THF (10 ml). The mixture was kept at -8° C. for 2 hours and then poured into 1N HCl (19.2 ml). The product was extracted with EtOAc; the extract was washed successively with water, aqueous NaHCO3, water and brine; dried (MgSO4) and concentrated. The residue was crystallized frown EtOAc-hexane to give 0.36 g (48.6%) of N-ethyl-N-(6-hydroxyheptyl)-γ-oxo-4-((methanesulfonyl)amino)benzenebutanamide, mp 78°-80° C.
Reaction SMILES: S(Cl)(C1C=CC(C)=CC=1)(=O)=O.[F:12][C:13]1[CH:14]=[C:15]([CH2:20][CH2:21][CH2:22]O)[CH:16]=[C:17]([F:19])[CH:18]=1.[N-:24]=[N+:25]=[N-:26].[Na+]>N1C=CC=CC=1.O>[F:12][C:13]1[CH:14]=[C:15]([CH2:20][CH2:21][CH2:22][N:24]=[N+:25]=[N-:26])[CH:16]=[C:17]([F:19])[CH:18]=1
Reactant: [N-]=[N+]=[N-]
Reactant: OCCCc1cc(F)cc(F)c1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: [N-]=[N+]=NCCCc1cc(F)cc(F)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.5 %

Procedure:
Tosyl chloride (0.0814 mol) was added to a cooled (0°) solution of 3-(3,5-difluorophenyl)propanol (0.0407 mol) in pyridine (75 ml). The reaction was stirred 2 hours at 25°, then it was poured into ice/water and extracted into ethyl ether. The ethereal extracts were washed with 3N aqueous hydrogen chloride and water, then were dried over sodium sulfate and concentrated. The residue was dissolved in dimethylformamide (75 ml) and sodium azide (0.0814 mol) was added. The reaction was stirred 8 hours, then was diluted with water and extracted into ethyl acetate. The organic extract was washed with 3N aqueous hydrogen chloride and water, then dried over sodium sulfate and concentrated to yield 6.7 g (64%) of an oily product.
Reaction SMILES: C([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1[S:19]([NH2:22])(=[O:21])=[O:20])C1C=CC=CC=1.[H][H]>CO.[Pd]>[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:16])[F:18])=[CH:11][C:10]=1[S:19]([NH2:22])(=[O:21])=[O:20]
Reactant: [H][H]
Reactant: NS(=O)(=O)c1cc(C(F)(F)F)ccc1NCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(C(F)(F)F)cc1S(N)(=O)=O
Yield: 94.2 %

Procedure:
A solution of 2-benzylamino-5-trifluoromethylbenzenesulfonamide (7.3 g) in methanol (80 mL) was supplemented with 10% Pd/C (0.73 g) and submitted to hydrogen under pressure (4 bars) during 90 min. at room temperature. The insoluble material was removed by filtration and the filtrate was concentrated to dryness. The residue was crystallized in methanol-water to give the title compound (yield: 5 g); m.p. 142-143° C.
Reaction SMILES: [CH2:1]1[C:6]2([C:16](=[O:17])[NH:15][C:14](=[O:18])[C:8]3([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+].[CH2:21](Br)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>CO.CN(C=O)C.CCOCC>[CH2:38]([N:15]1[C:16](=[O:17])[C:6]2([CH2:5][CH2:4][CH2:3][CH2:2][CH2:1]2)[NH:7][C:8]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[C:14]1=[O:18])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH3:21]
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: O=C1NC(=O)C2(CCCCC2)NC12CCCCC2
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCN1C(=O)C2(CCCCC2)NC2(CCCCC2)C1=O
Temperature: 75 °C
Reaction time: 3 h

Procedure:
To a solution of 10.0 g. (0.04 moles) of 7,15-diazadispiro [5,1,5,3] hexadecane-14,16-dione in 150 ml of anhydrous methanol in a 500 ml flask was added 2.6 g. of 86% KOH (0.04 moles) and the mixture was shaken until solution was obtained. The reaction mixture was then evaporated to dryness under reduced pressure. The residue was transferred to a 300 ml 3-necked flask equipped with a stirrer, thermometer, condenser with drying tube, dropping funnel and nitrogen inlet with the aid of a small amount of dry DMF. To the potassium imide salt, under a nitrogen atmosphere, was added 150 ml of dry DMF. To the stirred solution was added dropwise a solution of 13.3 g. (0.04 moles) of n-octadecyl bromide in 50 ml of DMF. The reaction mixture was heated slowly to 75°C and held at that temperature for 3 hours. The reaction mixture was cooled and allowed to stand at room temperature overnight. The reaction mixture was then taken up in 500 ml ether, the ether solution washed well with water, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue, which crystallized on standing, was recrystallized from methanol yielding 14.3 g. of white needles as the product, m.p. 39°-40°C.
Reaction SMILES: [F-].[K+].CN1CCCC1.[F:9][C:10]([Si](C)(C)C)([F:12])[F:11].[Cl:17][C:18]1[CH:23]=[C:22](I)[C:21]([Cl:25])=[CH:20][N:19]=1.N>[Cu](I)I>[Cl:17][C:18]1[CH:23]=[C:22]([C:10]([F:12])([F:11])[F:9])[C:21]([Cl:25])=[CH:20][N:19]=1
Reactant: Clc1cc(I)c(Cl)cn1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: I[Cu]I
Agent: CN1CCCC1
Agent: N
Product: FC(F)(F)c1cc(Cl)ncc1Cl
Reaction time: 0.33 h
Yield: 63.4 %

Procedure:
Copper iodide (1.67 g) and potassium fluoride (0.51 g) were subjected to a reduced pressure (1 Torr) using a vacuum pump, and were heated with a heat gun for 20 minutes while stirring slowly. Under the argon atmosphere, 14 ml of N-methylpyrrolidine and 1.25 g of trifluoromethyltrimethylsilane were added, and a temperature was elevated to 50° C. over 20 minutes. After further stirring for 30 minutes, 2 g of 2,5-dichloro-4-iodopyridine was added, and the mixture was stirred for 20 hours. After allowing to cool, the reaction solution was poured into a 12% aqueous ammonia solution, the resultant solution was extracted with diethyl ether three times, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 1 g of 2,5-dichloro-4-trifluoromethylpyridine.
Reaction SMILES: [CH2:1]([CH:4]([CH2:12][CH2:13][CH3:14])[C:5]([O:7][CH2:8][CH2:9][CH2:10][OH:11])=[O:6])[CH2:2][CH3:3].CC(C)=[O:17].OS(O)(=O)=O.O=[Cr](=O)=O.CC(O)C>CC(C)=O.S(=O)(=O)(O)O.O.[O-2].[O-2].[O-2].[Cr+6]>[CH2:12]([CH:4]([CH2:1][CH2:2][CH3:3])[C:5]([O:7][CH2:8][CH2:9][C:10]([OH:17])=[O:11])=[O:6])[CH2:13][CH3:14]
Reactant: CC(C)=O
Reactant: CCCC(CCC)C(=O)OCCCO
Agent: O=[Cr](=O)=O
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)O
Product: CCCC(CCC)C(=O)OCCC(=O)O

Procedure:
3-hydroxypropyl 2-propylpentanoate (2.08 g, 10.3 mmol) was dissolved in 120 ml of acetone. 3.1 ml of a solution of Jones Reagent (prepared by dissolving 26.72 g of chromium trioxide in 23 ml of concentrated sulfuric acid, and then diluting the mixture to 100 ml with water) was added. Propan-2-ol (5 ml) was added to the reaction mixture which was filtered through a pad of celite. The filtrate was washed with 0.01 M HCl solution (3×50 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product (2.05 g, 9.5 mmol, 92%) was used in the next step without any further purification.