Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[N:6]([C:11]2[CH:12]=[C:13]([Cl:19])[C:14](=[O:18])[N:15]([CH3:17])[CH:16]=2)[C:7](=[O:10])[C:8]=1O)(=O)[CH3:2].[NH:27]([C:29]1[C:30]([O:35][CH3:36])=[N:31][CH:32]=[CH:33][CH:34]=1)[NH2:28].S(=O)(=O)(O)N.CC(O)=O>CCO>[Cl:19][C:13]1[C:14](=[O:18])[N:15]([CH3:17])[CH:16]=[C:11]([N:6]2[CH:5]([C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)[C:4]3[C:1]([CH3:2])=[N:28][N:27]([C:29]4[C:30]([O:35][CH3:36])=[N:31][CH:32]=[CH:33][CH:34]=4)[C:8]=3[C:7]2=[O:10])[CH:12]=1
Reactant: COc1ncccc1NN
Reactant: CC(=O)C1=C(O)C(=O)N(c2cc(Cl)c(=O)n(C)c2)C1c1ccc(Cl)cc1
Agent: NS(=O)(=O)O
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ncccc1-n1nc(C)c2c1C(=O)N(c1cc(Cl)c(=O)n(C)c1)C2c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 4.1 %

Procedure:
To a stirred solution of 5-(3-acetyl-2-(4-chlorophenyl)-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrol-1-yl)-3-chloro-1-methylpyridin-2(1H)-one (Step 57.1) (250 mg, 0.636 mmol) and TEA (0.115 ml, 0.827 mmol) in EtOH (2 ml) was added 3-hydrazinyl-2-methoxypyridine (Step 71.1) (115 mg, 0.827 mmol) and the reaction mixture was stirred 1 hr at 90° C. Sulfamic acid (93 mg, 0.954 mmol) and AcOH (2 ml) was added and the reaction mixture was stirred 3 hr at 115° C. The reaction mixture was concentrated under reduced pressure, quenched with a saturated aq. NaHCO3 solution and extracted with CH2Cl2. The combined organic layers were dried over Na2SO4 and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with EtOAC. The residue was further purified by SFC (column Propyl-pyridyl-urea, gradient 13-18% in 6 min_total 11 min) and triturated in hexane/Et2O (2:1) to afford the title product (13 mg, 0.026 mmol, 4% yield) as white solid. tR: 4.55 min (HPLC 1); tR: 1.04 min (LC-MS 2); ESI-MS: 496 [M+H]+ (LC-MS 2); Rf=0.41 (EtOAc); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.02 (s, 3H) 3.43 (s, 3H) 3.89 (s, 3H) 6.24 (s, 1H) 7.15-7.22 (m, 1H) 7.32-7.37 (m, 2H) 7.40-7.45 (m, 2H) 7.88-7.96 (m, 3H) 8.28-8.33 (m, 1H).
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([N:10]2[CH2:15][CH2:14][O:13][C:12]3[CH:16]=[CH:17][C:18]([NH2:20])=[N:19][C:11]2=3)(=[O:9])=[O:8])[CH:2]=1.[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:24]=1[C:25](Cl)=[O:26].C([O-])(O)=O.[Na+]>O1CCOCC1.O>[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:24]=1[C:25]([NH:20][C:18]1[CH:17]=[CH:16][C:12]2[O:13][CH2:14][CH2:15][N:10]([S:7]([C:3]3[CH:2]=[C:1]([CH3:21])[CH:6]=[CH:5][CH:4]=3)(=[O:9])=[O:8])[C:11]=2[N:19]=1)=[O:26]
Reactant: Cc1cccc(S(=O)(=O)N2CCOc3ccc(N)nc32)c1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccc(S(=O)(=O)N2CCOc3ccc(NC(=O)c4c(Cl)cccc4Cl)nc32)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
4-(Toluene-3-sulfonyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-ylamine (20 mg, 0.065 mmol) was dissolved in p-dioxane (0.400 mL) and water (0.100 mL), followed by 2,6-dichlorobenzoyl chloride (21 μL, 0.098 mmol) and NaHCO3 (11 mg, 0.13 mmol). The resulting mixture was stirred at room temperature for 15 hours, concentrated under vacuum, and purified by HPLC to give 2,6-dichloro-N-[4-(toluene-3-sulfonyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl]-benzamide. LCMS (ESI): calc. C21H17Cl2N3O4S=477; obs. M+H=478.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH:4]=[CH:3][C:2]1=[O:8].N1CCC=CCC1=O.[H-].[Na+].[CH2:19](Br)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>C1COCC1.O>[CH2:30]([N:1]1[CH2:7][CH2:6][CH:5]=[CH:4][CH2:3][C:2]1=[O:8])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19]
Reactant: O=C1C=CCCCN1
Reactant: CCCCCCCCCCCCBr
Agent: O=C1CC=CCCN1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCCN1CCC=CCC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 11.4 g (0.102 mol) of a mixture of azacyclohept-3-ene-2-one and azacyclohept-4-ene-2-one (Example 3-C) in THF was added dropwise to a suspension of 4.8 g (107 mmol) of sodium hydride (50% oil dispersion) in THF. The mixture was stirred at room temperature for 1 hour, 25.4 g (0.102 mol) of dodecyl bromide was added, and the solution was refluxed for 5 hours. The mixture was cooled, water was added, and the solvent was removed in vacuo. The residue was dissolved in CH2Cl2, washed with water, the organic phase dried over MgSO4 and concentrated in vacuo to yield an oil which was Kugelrohr distilled to give 15.5 g of a crude product. This material was subjected to flash chromatography (silica gel; 9:1 petroleum ether/ether V/V) to give 1-dodecylazacyclohept-4-ene-2-one, Rf =0.45; GC retention time 7.4 min. GC conditions identical to Example 3-D.
Reaction SMILES: [Li]CCCC.C1(NC(C)C)CCCCC1.[C:16]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])[CH3:17].[Cl:24][CH2:25]/[CH:26]=[CH:27]\[CH2:28]Cl>C1COCC1.Cl>[Cl:24][CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:17][C:16]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: ClC/C=C\CCl
Reactant: CC(=O)OC(C)(C)C
Agent: CC(C)NC1CCCCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC/C=C\CCl
Reaction time: 0.08 h

Procedure:
n-BuLi (1.6M, 6 ml) was added over 5 min. to a stirred, cooled (-10°) solution of cyclohexylisopropylamine (1.64 ml) in dry THF (10 ml) under nitrogen. After 5 min., the solution was cooled to -78° and 15 min. later tert-butyl acetate (1.35 ml) was added over 5 min. After 20 min. cis-1,4-dichloro-2-butene (4 ml) was added and the mixture was allowed to warm to 10° over 4 h. The mixture was diluted with 1N HCl (25 ml) and extracted with ER (2×30 ml). The combined extracts were successively washed with 1N HCl (20 ml), brine (20 ml) and 8% NaHCO3 solution (20 ml) then dried and evaporated. The excess of dichloromethane was removed in vacuo and the residue was purified by chromatography (A) using PE, followed by 1:1 CH2Cl2 -PE increasing to CH2Cl2 as eluant to give the title compound as an oil (0.66 g)
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][N:24](COCC[Si](C)(C)C)[C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14](S(C)(=O)=O)[N:13]=2)[CH2:6]1)(=[O:4])=[O:3].[CH3:39][N:40]([CH3:47])[CH:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1.CS(C)(=O)=O>O1CCOCC1>[CH3:39][N:40]([CH3:47])[CH:41]1[CH2:46][CH2:45][N:44]([C:14]2[N:13]=[C:12]([NH:11][C@H:7]3[CH2:8][CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6]3)[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][NH:24][C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=2)[CH2:43][CH2:42]1
Reactant: CN(C)C1CCNCC1
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cnc(S(C)(=O)=O)nc3N[C@H]3CCCN(S(C)(=O)=O)C3)cnc21
Agent: CS(C)(=O)=O
Solvent: C1COCCO1
Product: CN(C)C1CCN(c2ncc(-c3cnc4[nH]ccc4n3)c(N[C@H]3CCCN(S(C)(=O)=O)C3)n2)CC1

Procedure:
In a dioxane solution of ((S)-1-methanesulfonyl-piperidin-3-yl)-{2-methanesulfonyl-5-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyrimidin-4-yl}-amine derived from Example 84, step 1, dimethylpiperidin-4-ylamine was used to displace the methylsulfone similar to examples above and the de-protection step was similar to step 5, Example 76, to give [2-(4-dimethylamino-piperidin-1-yl)-5-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-pyrimidin-4-yl]-((S)-1-methanesulfonyl-piperidin-3-yl)-amine. MS: (ES+): 500.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][NH:11]3)=[CH:4][C:3]=2[O:2]1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[CH2:39]([O:46][C:47](Cl)=[O:48])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>ClCCl>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:47]([O:46][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:48])=[CH:4][C:3]=2[O:2]1
Reactant: c1ccc2c3c([nH]c2c1)C(c1ccc2c(c1)OCO2)NCC3
Reactant: O=C(Cl)OCc1ccccc1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCc2c([nH]c3ccccc23)C1c1ccc2c(c1)OCO2
Reaction time: 16 h

Procedure:
To a solution of 1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline (9.11 g, 31.1 mmol) (prepared according to the process as disclosed in WO97/43287, Intermediate 7, page 24) in dry dichloromethane (100 mL) were added triethylamine (8.80 mL, 63.1 mmol) and dimethylaminopyridine (5 mg), followed by the dropwise addition of benzylchloroformate (4.60 mL, 30.6 mmol) over a period of 30 min. The reaction mixture was stirred for 16 h, transferred to a separatory funnel, washed with 2N HCl, brine, dried over anhydrous magnesium sulfate and concentration in vacuo. Flash chromatography yielded the product as a white solid.
Reaction SMILES: [SH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:17]12([C:27]3[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=3[O:36][CH3:37])[C:30](Cl)=[O:31])[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[CH2:18]1)[CH2:24]2>ClCCl>[C:17]12([C:27]3[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=3[O:36][CH3:37])[C:30]([S:1][C:2]3[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=3)=[O:31])[CH2:18][CH:19]3[CH2:25][CH:23]([CH2:22][CH:21]([CH2:20]3)[CH2:26]1)[CH2:24]2
Reactant: COc1ccc(C(=O)Cl)cc1C12CC3CC(CC(C3)C1)C2
Reactant: O=C(O)c1ccc(S)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(C(=O)Sc2ccc(C(=O)O)cc2)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
In a round bottom flask, there are introduced 1.7 g (11 mmoles) of 4-mercaptobenzoic acid and 20 ml of pyridine. There is then slowly added a solution of 3.4 g (11.17 mmoles) of 3-(1-adamantyl)-4-methoxybenzoic acid chloride in 50 ml of dichloromethane. The reaction mixture is o stirred at ambient temperature for 8 hours, evaporated to dryness, taken up in 100 ml of water and acidified to pH 5 with 1N HCl. The solid is filtered, washed with water and dried at 60° C. under a vacuum, then recrystallized in dioxan. 3.3 g (75% yield) of 4-[3-(1-adamantyl)-4-methoxybenzoylthio] benzoic acid having a melting point of 264° C. are obtained.
Reaction SMILES: Cl.Cl.[C:3]1([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][CH:19]3[O:24][CH2:23][CH2:22][NH:21][CH2:20]3)=[O:16])[CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C=O.O.[C:28](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[C:3]1([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][CH:19]3[O:24][CH2:23][CH2:22][N:21]([CH3:28])[CH2:20]3)=[O:16])[CH2:11][CH2:10]2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=C(OCC1CNCCO1)N1CCN(c2ccccc2)CC1
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN1CCOC(COC(=O)N2CCN(c3ccccc3)CC2)C1
Reaction time: 2 h
Yield: 89 %

Procedure:
Morpholin-2-ylmethyl 4-phenylpiperazine-1-carboxylate (non-HCl salt of Example 10; 1.00 g, 3.27 mmol) and 37% formaldehyde in water (1.97 g, 1.82 mL, 65.5 mmol) were dissolved in MeOH (20 mL) at room temperature followed by addition of sodium triacetoxyborohydride (2.78 g, 13.1 mmol) portionwise over 5 minutes. The reaction mixture was stirred for 2 h. The reaction mixture was quenched by the addition of saturated aq Na2CO3 solution. The solvents were removed in vacuo and the residual aqueous phase was loaded onto an Isolute HM-N 20 mL cartridge. The desired product was eluted with DCM (200 mL) and the solvent removed in vacuo to give (4-methylmorpholin-2-yl)methyl 4-phenylpiperazine-1-carboxylate (0.93 g, 88.9%) as a colourless gum.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[O:11])[CH2:2]1.[H-].[Na+].CS(O[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23][CH2:22]1)(=O)=O.COC1C=C2C(C=CC(=O)N2CCN2CCC(NC(=O)OC(C)(C)C)CC2)=CC=1>ClCCl.CO>[O:11]=[C:3]1[N:4]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([NH:27][C:28](=[O:29])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:23][CH2:22]2)[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:1][CH2:2]1
Reactant: O=C1COc2ccccc2N1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Agent: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(CCN2C(=O)COc3ccccc32)CC1
Yield: 63 %

Procedure:
2H-1,4-Benzoxazin-3(4H)-one (298 mg, 2.0 mmol) was deprotonated with sodium hydride and alkylated with 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate (Intermediate 6) (2.0 mmol) as described for Intermediate 2. Chromatography on silica gel with dichloromethane/methanol (20:1) gave the product in 63% yield as a yellow gum.
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][CH2:6][C:5](=O)[C:4]=2[CH:3]=[CH:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:20])=CC=1.C([O-])(O)=O.[Na+]>C1COCC1>[NH:1]1[C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[S:20])[C:4]=2[CH:3]=[CH:2]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1CCCc2[nH]ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: S=C1CCCc2[nH]ccc21
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 86.3 %

Procedure:
To a solution of 1,5,6,7-tetrahydro-indol-4-one (4.51 g, 33.36 mmol) in dry THF (300 mL) was added Lawesson's reagent (3.495 g, 33.36 mmol) at 0° C. as a solid, in portions. The reaction mixture was warmed to RT and stirred for 35 min. The reaction mixture was then poured into saturated NaHCO3, the product extracted into Et2O, dried over MgSO4, filtered, evaporated, and dried under vacuum overnight. The product was purified by filtration through SiO2 using 30% EtOAc/hexane, evaporated to dryness, and dried under vacuum for 1 h to provide 1,5,6,7-tetrahydro-indole-4-thione (4.354 g, 86.3% yield).
Reaction SMILES: [N:1]1([CH:7]=[N:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[OH:15])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:23][N:24]([CH3:28])[C:25](Cl)=[O:26]>O1CCCC1>[CH3:23][N:24]([CH3:28])[C:25]([O:15][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:9]=1[N:8]=[CH:7][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:26]
Reactant: Oc1cnccc1N=CN1CCOCC1
Reactant: CN(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)C(=O)Oc1cnccc1N=CN1CCOCC1

Procedure:
A mixture prepared from 4-[[(4-morpholinyl)methylene]amino]-3-pyridinol (3.04 g), triethylamine (3.19 mL), dimethylcarbamyl chloride (2.04 mL) and tetrahydrofuran (121 mL) was refluxed for 1 hour, cooled, poured directly onto a silica column and eluted successively with ethyl acetate and 5% Et3N/ethyl acetate. Recrystallization from ethyl acetate (50 mL) and drying under high vacuum and refluxing acetone overnight yielded 3.04 g of fluffy needles, m.p. 127°-129° C.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:19](=[O:20])[C:15]3([CH2:18][CH2:17][CH2:16]3)[NH:14][C:13]2=[O:21])=[CH:8][C:7]=1[C:22]([F:25])([F:24])[F:23])([O-:5])=[O:4].CS(O[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][S:40][CH2:41][CH2:42][CH2:43][C:44]([F:50])([F:49])[C:45]([F:48])([F:47])[F:46])(=O)=O.O>CN(C=O)C>[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:19](=[O:20])[C:15]3([CH2:16][CH2:17][CH2:18]3)[N:14]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][S:40][CH2:41][CH2:42][CH2:43][C:44]([F:50])([F:49])[C:45]([F:46])([F:47])[F:48])[C:13]2=[O:21])=[CH:8][C:7]=1[C:22]([F:25])([F:24])[F:23])([O-:5])=[O:4]
Reactant: O=C1NC2(CCC2)C(=O)N1c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Reactant: CS(=O)(=O)OCCCCCCCCCSCCCC(F)(F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)C2(CCC2)N1CCCCCCCCCSCCCC(F)(F)C(F)(F)F
Temperature: 23 °C
Yield: 33 %

Procedure:
NaH (to 60%) (44 mg, 1.1 mmole) is added under argon to a solution of 7-[4-nitro-3-(trifluoromethyl)phenyl]-5,7-diazaspiro[3.4]octane-6,8-dione (329 mg, 1 mmole) in anhydrous DMF (9 ml). A release of gas accompanies the change in colour of the reaction medium which becomes orange. Stirring is maintained for 1 hour at 23° C. before adding 9-[(4,4,5,5,5-pentafluoropentyl)-thio]nonyl methanesulphonate (prepared according to an experimental protocol described in WO 2005077968) (332 mg, 0.8 mmole). After reaction for 15 hours, the reaction medium is poured into water (25 ml) and extracted with AcOEt (2×25 ml). The organic phases are combined and washed successively with water (25 ml) and salt water (25 ml). After drying over Na2SO4, the organic solution is filtered and concentrated under vacuum. The evaporation residue is purified on an RP18 silica column (eluent: ACN/H2O: 8/2 to 100). The expected compound is obtained in the form of a colourless oil with a yield of 33% (214 mg).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.CC(C[AlH]CC(C)C)C.I[C:20]1[CH:21]=[C:22]([CH:28]=[CH:29][CH:30]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24]>O1CCCC1.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>[CH3:9][C:6]1[CH:7]=[CH:8][C:3]([C:20]2[CH:30]=[CH:29][CH:28]=[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:21]=2)=[CH:4][CH:5]=1
Reactant: Cc1ccc(Br)cc1
Reactant: CCOC(=O)c1cccc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)C[AlH]CC(C)C
Agent: [Mg]
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(-c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.2 %

Procedure:
Magnesium (1.6 g) and p-bromotoluene (10.26 g) in 60 ml of tetrahydrofuran were stirred and warmed until the reaction commenced. When the exothermic reaction had finished, the mixture was refluxed overnight. In a separate flask, 4 ml of DIBAL (1M in toluene) was added to a suspension of bis(triphenylphosphine)palladium(II) chloride (1.4 g) in 100 ml of tetrahydrofuran, followed by ethyl 3-iodobenzoate (11.04 g). To this mixture, the magnesium reagent prepared above was added dropwise, causing an exothermic reaction. The reaction mixture was stirred overnight at room temperature, and then quenched by addition of dilute hydrochloric acid. The mixture was extracted with ether, and the organic layer washed with water, and then saturated brine. The organic layer was separated, dried over sodium sulfate, the solvent evaporated under reduced pressure, and the residue chromatographed on silica gel, eluting with 5% ethyl acetate in heptane, to yield 5.69 g of ethyl 4'-methylbiphenyl-3-carboxylate, a compound of Formula (17), as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[Cl:12][C:13]1[CH:14]=[C:15]([NH:23][C:24](OC2C=CC=CC=2)=[O:25])[C:16](=[CH:21][CH:22]=1)[C:17](OC)=[O:18]>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[C:17](=[O:18])[C:16]2[C:15](=[CH:14][C:13]([Cl:12])=[CH:22][CH:21]=2)[NH:23][C:24]1=[O:25])(=[O:9])=[O:10]
Reactant: COC(=O)c1ccc(Cl)cc1NC(=O)Oc1ccccc1
Reactant: Nc1ccccc1S(N)(=O)=O
Product: Nc1ccccc1S(=O)(=O)n1c(=O)[nH]c2cc(Cl)ccc2c1=O
Yield: 58 %

Procedure:
2.7 g (15.7 mmol) of 2-aminobenzenesulfonamide and 4.8 g (15.7 mmol) of methyl 4-chloro-2-N-phenoxycarbonylanthranilate were treated in the same way as Preparation Example 1 to obtain 3.2 g (yield 58%: 3 steps) of the above-identified compound. Properties: colorless crystal, Melting point: >200° C. (decomposition), PMR (δ ppm, DMSO-d6): 6.46 (2H, s), 6.65 (1H, t), 6.81 (1H, d), 7.12 (1H, s), 7.23 (1H, d), 7.34 (1H, t), 7.76 (1H, d), 7.86 (1H, d).
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[NH:4][C:3]1=[O:14].C(N(CC)CC)C.[CH:22]1([C:27](Cl)=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23]1>CN(C=O)C>[O:9]=[C:8]1[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[NH:4][C:3](=[O:14])[CH:2]1[NH:1][C:27]([CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:28]
Reactant: O=C(Cl)C1CCCC1
Reactant: NC1C(=O)Nc2ccccc2NC1=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NC1C(=O)Nc2ccccc2NC1=O)C1CCCC1
Reaction time: 8 h
Yield: 87 %

Procedure:
Combine 3-amino-1H-1,5-benzodiazepine-2,4-(3H, 5H)-dione (7.0 g, 36.6 mmol) and triethyl amine (4.07 g, 40.3 mmol) in 120 mL DMF and add dropwise cyclopentanecarbonyl chloride (5.34 g, 40.3 mmol) at RT. After stirring overnight, remove DMF under reduced pressure, suspend the residue in a mixed solvent (CHCl3/i-PrOH=3/1, 400 mL). Collect an off-white solid via suction filtration to give the title compound. Wash the filtrate with NaHCO3 (sat.2×100 mL) and dry with Na2SO4. Concentrate the the solvent to give second crop of title compound, total 9.13 g, yield 87%: 1H NMR (300 MHz, DMSO-d6): 10.70 (s, 2H), 8.11 (d, 1H, J=7.8 Hz), 7.24–7.15 (m, 4H), 4.73 (d, 1H, J=7.5 Hz), 2.96–2.87 (m, 1H), 1.74–1.45 (m, 8H).
Reaction SMILES: [ClH:1].[CH2:2]([O:9][C:10](=[O:13])[CH2:11][NH2:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:14]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[ClH:1].[CH2:2]([O:9][C:10](=[O:13])[CH2:11][NH:12][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1CCCCC1
Reactant: NCC(=O)OCc1ccccc1
Agent: Cl
Product: O=C(CNC1CCCCC1)OCc1ccccc1

Procedure:
Following the procedure as described in Example 26, STEP A, glycine benzylester hydrochloride was reacted with cyclohexanone to yield cyclohexylamino-acetic acid benzyl ester hydrochloride as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[C:5]([O:7][CH3:8])=[O:6].[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21]>C(NC(C)C)(C)C.C(OCC)(=O)C.[Cu]I>[N:14]1([C:12]([C:11]2[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=2[C:24]#[C:23][Si:20]([CH3:22])([CH3:21])[CH3:19])=[O:13])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COC(=O)c1ccc(C(=O)N2CCCC2)c(Br)c1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: COC(=O)c1ccc(C(=O)N2CCCC2)c(C#C[Si](C)(C)C)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
18 g (57.7 mmol) of methyl 3-bromo-4-(pyrrolidin-1-ylcarbonyl)benzoate is placed under a nitrogen atmosphere together with 6.66 g (5.77 mmol) of tetrakis-triphenylphosphinepalladium(0) and 0.439 g (2.31 mmol) of copper(1) iodide in 150 mL of N,N-diisopropylamine, the mixture is heated to 80° C. and 16.6 mL (115 mmol) trimethylsilylethyne is added. The reaction mixture is stirred for 8 hours at 80° C. and then for 16 hours at ambient temperature. Then volatile constituents are eliminated in vacuo, the residue is taken up in ethyl acetate, insoluble matter is filtered off, and the solvent is eliminated in vacuo. The residue is purified by chromatography on silica gel (gradient: dichloromethane/ethanol 100:0□95:5). Yield: 7.7 g (41%); Rf value: 0.44 (silica gel; dichloromethane/ethanol=95:5); C18H23NO3Si (329.48); mass spectrum: (M+H)+=330.
Reaction SMILES: [OH:1][CH2:2]/[CH:3]=[C:4](/[CH3:23])\[CH2:5][CH2:6]/[CH:7]=[C:8](\[CH3:22])/[CH2:9][CH2:10][C:11](=[O:21])[CH:12]([CH3:20])[CH2:13][S:14][CH2:15][C:16]([O:18][CH3:19])=[O:17].N1C=CC=CC=1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>C(Cl)Cl>[C:30]([O:1][CH2:2]/[CH:3]=[C:4](/[CH3:23])\[CH2:5][CH2:6]/[CH:7]=[C:8](\[CH3:22])/[CH2:9][CH2:10][C:11](=[O:21])[CH:12]([CH3:20])[CH2:13][S:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])(=[O:32])[CH3:31]
Reactant: COC(=O)CSCC(C)C(=O)CC/C(C)=C/CC/C(C)=C\CO
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)CSCC(C)C(=O)CC/C(C)=C/CC/C(C)=C\COC(C)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 300 mg (0.00088 mol) of methyl [[(6E, 10Z)-12-hydroxy-2,6,10-trimethyl-3-oxo-6,10-dodecadienyl]thio]acetate in 5 ml of methylene chloride is treated with 0.5 ml of pyridine and 0.4 ml of acetic anhydride. The solution is stirred at room temperature for 18 hours under argon. After removing the solvent the residue is taken up three times in toluene and freed from solvent each time on a rotary evaporator. The residue is chromatographed on silica gel with ether. There is obtained (2Z,6E)-12-[[(methoxycarbonyl)methyl]thio]-3,7,11-trimethyl-10-oxo-2,6-dodecadienyl acetate which exhibits the following bands in the IR spectrum: 1710 cm-1, 1657 cm-1, 1552 cm-1, 1445 cm-1, 1375 cm-1, 1290 cm-1, 1235 cm-1.