Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[CH:5][C:4](=[O:7])[N:3]1[CH2:8][C:9]([OH:11])=O.S(Cl)([Cl:14])=O>>[O:1]=[C:2]1[CH:6]=[CH:5][C:4](=[O:7])[N:3]1[CH2:8][C:9]([Cl:14])=[O:11]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CN1C(=O)C=CC1=O
Product: O=C(Cl)CN1C(=O)C=CC1=O

Procedure:
A suspension of 2,5-dihydro-2,5-dioxopyrrol-1-ylacetic acid (821 mg) in thionyl chloride (15.9 ml) was heated under reflux for 0.5 hours and the excess thionyl chloride was removed under vacuum. The residue was evaporated twice with dry toluene to afford 2,5-dihydro-2,5-dioxopyrrol-1-ylacetyl chloride [(5) where m=1] as a colourless, readily hydrolysed liquid. (The compound has been prepared previously by a less convenient route5). The crude acid chloride was dissolved in dry ether (25 ml) and added dropwise to an ice-cold solution of the hydrazinecarboxylate [(4) where n=1, 1.30 g] and triethylamine (588 mg) in dry ether (25 ml). The mixture was stirred in an ice bath for 1 hour then diluted with ethyl acetate and washed with water, dilute HCl, saturated NaHCO3 and brine, dried and evaporated. The residue was crystallised from ethyl acetate--petroleum ether to give the compound (6) as colourless plates (1.67 g; 82%) m.p. 157°-9° C. (Found: C, 53.1; H, 6.7; N, 10.8. C17H25N3O7 requires C, 53.25; H, 6.6; N, 11.0%).
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][CH2:9][C:10]2[C:11]([CH3:16])=[N:12][O:13][C:14]=2[CH3:15])=[O:7])=[CH:4][C:3]=1[F:19].[CH2:20]([N:22]([CH2:38][CH3:39])[C:23](=[O:37])[CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[CH3:21].C([O-])([O-])=O.[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:38]([N:22]([CH2:20][CH3:21])[C:23]([CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[N:25]1[CH2:26][CH2:27][N:28]([C:2]2[CH:18]=[CH:17][C:5]([C:6]([NH:8][CH2:9][C:10]3[C:11]([CH3:16])=[N:12][O:13][C:14]=3[CH3:15])=[O:7])=[CH:4][C:3]=2[F:19])[CH2:29][CH2:30]1)=[O:37])[CH3:39]
Reactant: CCN(CC)C(=O)C(c1ccccc1)N1CCNCC1
Reactant: Cc1noc(C)c1CNC(=O)c1ccc(Br)c(F)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCN(CC)C(=O)C(c1ccccc1)N1CCN(c2ccc(C(=O)NCc3c(C)noc3C)cc2F)CC1
Temperature: 100 °C
Reaction time: 16 h
Yield: 57.5 %

Procedure:
A mixture of 4-bromo-N-(3,5-dimethyl-isoxazol-4-ylmethyl)-3-fluoro-benzamide (0.31 mmol), N,N-diethyl-2-phenyl-2-piperazin-1-yl-acetamide (0.20 mmol), Cs2CO3 (1.2 mmol), Pd2(dba)3 (0.0030 mmol), and BINAP (0.0120 mmol) in toluene (2.0 mL) was stirred at 100° C. for 16 h. The mixture was cooled to rt and purified by PTLC to provide the title compound (60 mg, 58%). MS (ESI): mass calcd. for C29H36FN5O3, 521.28. m/z found, 522.4 [M+H]+. 1H NMR (CDCl3): 7.50-7.25 (m, 7H), 6.82 (t, J=8.5, 1H), 6.51 (t, J=5.2, 1H), 4.31 (d, J=5.3, 2H), 4.22 (s, 1H), 3.48-3.36 (m, 2H), 3.30-3.10 (m, 6H), 2.73-2.60 (m, 4H), 2.36 (s, 3H), 2.21 (s, 3H), 1.12-1.02 (m, 6H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[NH2:9][CH2:10][CH:11]1[CH2:14][N:13]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([N:26]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:28]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:27]3)(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[O:16])[CH2:12]1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:8][C:5]1[CH:6]=[CH:7][C:2]([NH:9][CH2:10][CH:11]2[CH2:12][N:13]([C:15]([C:17]3[CH:18]=[CH:19][C:20]([S:23]([N:26]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[C:28]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)=[CH:27]4)(=[O:25])=[O:24])=[CH:21][CH:22]=3)=[O:16])[CH2:14]2)=[CH:3][CH:4]=1
Reactant: Fc1ccc(Br)cc1
Reactant: NCC1CN(C(=O)c2ccc(S(=O)(=O)n3cc(-c4ccccc4)c4ccccc43)cc2)C1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: O=C(c1ccc(S(=O)(=O)n2cc(-c3ccccc3)c3ccccc32)cc1)N1CC(CNc2ccc(F)cc2)C1
Temperature: 100 °C
Yield: 18.2 %

Procedure:
Add 1-bromo-4-fluorobenzene (220 μL, 350 mg, 2.0 mmol, 2.0 equiv) to a mixture of (3-aminomethyl-azetidin-1-yl)-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanone (446 mg, 1.00 mmol, 1 equiv), tris(dibenzylideneacetone)dipalladium(0) (23 mg, 0.025 mmol, 0.025 equiv), 2-(di-tert-butylphosphino)biphenyl (15 mg, 0.057 mmol, 0.050 equiv), and sodium tert-butoxide (120 mg, 1.2 mmol, 1.2 equiv) in anhydr toluene (4 mL) and heat at 100° C. for 19 h. After cooling, transfer the reaction mixture through a 0.45-μm filter disc to a column of silica gel (125 mm×25 mm dia.) and elute (10-100% EtOAc/hex) to yield 98 mg (18%) of [3-[(4-fluoro-phenylamino)-methyl]-azetidin-1-yl]-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanone as a light-yellow foam. 1H NMR indicated pure desired product. MS (m/e): 540.07 (M+1); 538.19 (M−1).
Reaction SMILES: [CH:1]1([C:7]2[C:13]3[C:14]([CH3:18])=[C:15]([CH3:17])[S:16][C:12]=3[N:11]3[C:19]([CH3:22])=[N:20][N:21]=[C:10]3[CH:9]([CH2:23][C:24]([OH:26])=O)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:27]([N:29](CC)CC)C.C(Cl)(=O)C(C)(C)C.CN>O.O1CCCC1.CN(C)C=O>[CH3:27][NH:29][C:24](=[O:26])[CH2:23][CH:9]1[N:8]=[C:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:13]2[C:14]([CH3:18])=[C:15]([CH3:17])[S:16][C:12]=2[N:11]2[C:19]([CH3:22])=[N:20][N:21]=[C:10]12
Reactant: CCN(CC)CC
Reactant: Cc1sc2c(c1C)C(C1CCCCC1)=NC(CC(=O)O)c1nnc(C)n1-2
Agent: CC(C)(C)C(=O)Cl
Agent: CN
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)CC1N=C(C2CCCCC2)c2c(sc(C)c2C)-n2c(C)nnc21
Temperature: -5 °C
Reaction time: 2 h

Procedure:
(±)-4-Cyclohexyl-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-acetic acid (0.54 g) and triethylamine (0.22 ml) are added to a mixed solvent of dimethylformamide (20 ml) and tetrahydrofuran (10 ml). The mixture is cooled to -5° C. and pivaloyl chloride (0.18 ml) is dropwise added at said temperature. Ten minutes later, a 40% aqueous solution (2 ml) of methylamine is dropwise added at said temperature and the mixture is stirred at room temperature for 2 hours. Water is added to the reaction mixture, and the mixture is extracted with ethyl acetate, washed with water and dried over anhydrous magnesium sulfate. The solvent is distilled away under reduced pressure and the residue is recrystallized from ethyl acetate to give (±)-N-methyl-4-cyclohexyl-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-acetamide, melting point 228°-231° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]([CH2:15]Cl)[C:6]1[C:11]([CH2:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:14])=[O:4].[Cl:17][C:18]1[C:19]([CH3:24])=[N:20][NH:21][C:22]=1[CH3:23]>COCCOC>[Cl:1][CH2:2][C:3]([N:5]([CH2:15][N:20]1[C:19]([CH3:24])=[C:18]([Cl:17])[C:22]([CH3:23])=[N:21]1)[C:6]1[C:11]([CH2:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:14])=[O:4]
Reactant: Cc1n[nH]c(C)c1Cl
Reactant: CCc1cccc(C)c1N(CCl)C(=O)CCl
Solvent: COCCOC
Product: CCc1cccc(C)c1N(Cn1nc(C)c(Cl)c1C)C(=O)CCl
Temperature: 0 °C

Procedure:
21.4 parts by weight of 2-chloro-2'-methyl-6'-ethyl-N-chloromethyl acetanilide and 20.2 parts by weight of 4-chloro-3,5-dimethylpyrazole are refluxed for 10 hours in 100 parts by volume of glycol dimethyl ether. After cooling the mixture to 0° C., it is filtered, and the filtrate, concentrated to 23.8 parts by weight, is filtered with 600 parts by volume of chloroform through 50 parts by weight of silica gel. From the concentrated chloroform filtrate there is isolated 20.4 parts by weight of 2-chloro-2'-methyl-6'-ethyl-N-(4-chloro-3,5-dimethylpyrazol-1-yl-methyl)-acetanilide as an oil which completely crystallizes upon milling with 50 ml of petroleum ether (m.p. 66° C. from petroleum ether).
Reaction SMILES: [NH3:1].Cl[C:3]([CH:5]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:4]>C(Cl)Cl>[NH2:1][C:3]([CH:5]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:4]
Reactant: CCOC(=O)C(CCCCCc1ccc(Cl)cc1)C(=O)Cl
Reactant: N
Solvent: ClCCl
Product: CCOC(=O)C(CCCCCc1ccc(Cl)cc1)C(N)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A saturated solution of gaseous ammonia in 25 ml of methylene chloride is added drop by drop at -10° C. to a solution of 5.6 (17 mmol) of ethyl 2-(chlorocarbonyl)-7-(4-chlorophenyl)heptanoate in 50 ml of methylene chloride. The mixture is stirred for 30 minutes at room temperature, suction filtered from the ammonium chloride, the filtrate is washed with water, and dried and concentrated. The concentrate is chromatographed on silica gel with a mixture of toluene and dioxane (5:1). 3.6 g (68% of theory) is obtained of ethyl 2-(aminocarbonyl)-7-(4-chlorophenyl)heptanoate, M.P. 110°-111° C.
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].[NH:39]1[CH2:43][CH2:42][C@@H:41]([OH:44])[CH2:40]1.CS(C)(=O)=O>O1CCOCC1>[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][NH:24][C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14]([N:39]3[CH2:43][CH2:42][C@@H:41]([OH:44])[CH2:40]3)[N:13]=2)[CH2:6]1)(=[O:3])=[O:4]
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cnc(S(C)(=O)=O)nc3N[C@H]3CCCN(S(C)(=O)=O)C3)cnc21
Reactant: O[C@@H]1CCNC1
Agent: CS(C)(=O)=O
Solvent: C1COCCO1
Product: CS(=O)(=O)N1CCC[C@@H](Nc2nc(N3CC[C@@H](O)C3)ncc2-c2cnc3[nH]ccc3n2)C1

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, (R)-pyrrolidin-3-ol was used to displace the methylsulfone similar to examples above and the de-protection step was similar to step 5, Example 76, to give (R)-1-[4-((R)-1-methanesulfonyl-piperidin-3-ylamino)-5-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-pyrimidin-2-yl]-pyrrolidin-3-ol. MS: (ES+): 459
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([F:29])[CH:20]=2)([N:16]=[C:17]=S)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[N:30]([CH2:33][C:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:35])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:16][C:17]2[O:35][C:34]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:33][N:30]=2)([C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([F:29])[CH:20]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1
Reactant: [N-]=[N+]=NCC(=O)c1ccccc1
Reactant: Fc1cc(C(F)(F)F)cc(C(Cc2ccccc2)(N=C=S)c2ccc(Cl)cn2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Fc1cc(C(F)(F)F)cc(C(Cc2ccccc2)(Nc2ncc(-c3ccccc3)o2)c2ccc(Cl)cn2)c1
Temperature: 90 °C
Yield: 12 %

Procedure:
5-chloro-2-(1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-isothiocyanato-2-phenylethyl)pyridine (0.047 g, 0.108 mmol) in dioxane (3 mL) in a two drum vial was added 2-azido-1-phenylethanone (21 mg, 0.129 mmol) and solid bound triphenylphosphine (100 mg, 0.162 mmol). The reaction was heated at 90° C. for 1 hour. The reaction was concentrated and the crude mixture was purified by preparative HPLC (phenominex C18 column, 21×100 mm, 5μ) using MeOH/H2O (0.1% TFA) to give N-(1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)-5-phenyloxazol-2-amine as a yellow solid (7 mg, 12% yield). LCMS: 4.1 min [M+1] 538.2 (4 min gradient, MeOH/H2O 0.1% TFA); 1H NMR (400 MHz, CDCl3) δ ppm 3.97-4.02 (m, 1H), 4.06-4.13 (m, 1H), 6.52 (d, J=7.58 Hz, 2H), 7.09 (t, J=7.46 Hz, 2H), 7.15 (s, 1H), 7.17 (dd, J=6.36, 1.71 Hz, 3H), 7.23 (d, J=8.56 Hz, 1H), 7.30-7.40 (m, 5H), 7.68-7.73 (m, 2H), 8.50 (d, J=2.20 Hz, 1H).
Reaction SMILES: [NH:1]1CCC(C(N)=O)CC1.[CH:10]([C:12]1[CH:45]=[CH:44][C:15]([C:16]([CH2:18][NH:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([O:28][C:29](=[O:43])[NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:24][CH2:23]2)=[O:17])=[CH:14][CH:13]=1)=[O:11].[O-]S([O-])(=O)=O.[Na+].[Na+].CC(O)=O>CC(O)C>[C:10]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([CH2:18][NH:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([O:28][C:29](=[O:43])[NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH2:24][CH2:23]2)=[O:17])=[CH:44][CH:45]=1)(=[O:11])[NH2:1]
Reactant: O=Cc1ccc(C(=O)CNCCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)cc1
Reactant: NC(=O)C1CCNCC1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CC(=O)O
Product: NC(=O)c1ccc(C(=O)CNCCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)cc1
Temperature: 30 °C

Procedure:
Isonipecotamide (15.4, 120 mmol, 2.0 eq.) and IPA (200 mL) were added to the solution of biphenyl-2-yl-carbamic acid 1-{2-[(4-formylbenzoyl)methylamino]ethyl}piperidin-4-yl ester from the previous step. Liquid (200 mL) was distilled off and additional IPA (400 mL) was added under reduced pressure at 60° C. Liquid (400 mL) was distilled off over a period of 1.5 hours and additional IPA (600 mL) was added. Liquid (100 mL) was distilled off and the remaining solution was cooled to 30° C. to yield a hazy white mixture, which was then added to Na2SO4 (18 g). The flask was rinsed with IPA (100 mL) and added to the solution. The resulting mixture was cooled to room temperature and AcOH (20 mL, 360 mmol, 6.0 eq.) was added. The mixture was cooled to 18° C. with an ice bath and NaHB(OAc)3 (38.2 g, 180 mmol, 3.0 eq.) was added over 5 minutes. The mixture was allowed to warm up to 25° C. and was maintained at that temperature for 2 hours. Solvent was removed under reduced pressure, and the remaining material was used directly in the next step.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:6]([OH:54])([CH3:53])[CH2:7][CH2:8][CH:9]([O:47][CH:48]([O:50][CH2:51][CH3:52])[CH3:49])[CH2:10][C:11]([O:13][CH:14](/[C:19](/[CH3:46])=[CH:20]/[CH:21]=[CH:22]/[C:23]([O:40][CH:41]([O:43][CH2:44][CH3:45])[CH3:42])([CH3:39])[CH2:24][CH:25]2[O:38][CH:26]2[CH:27]([CH3:37])[CH:28]([O:31][CH:32]([O:34][CH2:35][CH3:36])[CH3:33])[CH2:29][CH3:30])[CH:15]([CH3:18])[CH:16]=[CH:17]1)=[O:12])(=[O:3])[CH3:2].[CH3:55]N(C1C2C(=CC=CC=2N(C)C)C=CC=1)C.FC(F)(F)S(OC)(=O)=O>C1(C)C=CC=CC=1>[C:1]([O:4][CH:5]1[C:6]([O:54][CH3:55])([CH3:53])[CH2:7][CH2:8][CH:9]([O:47][CH:48]([O:50][CH2:51][CH3:52])[CH3:49])[CH2:10][C:11]([O:13][CH:14](/[C:19](/[CH3:46])=[CH:20]/[CH:21]=[CH:22]/[C:23]([O:40][CH:41]([O:43][CH2:44][CH3:45])[CH3:42])([CH3:39])[CH2:24][CH:25]2[O:38][CH:26]2[CH:27]([CH3:37])[CH:28]([O:31][CH:32]([O:34][CH2:35][CH3:36])[CH3:33])[CH2:29][CH3:30])[CH:15]([CH3:18])[CH:16]=[CH:17]1)=[O:12])(=[O:3])[CH3:2]
Reactant: CCOC(C)OC1CCC(C)(O)C(OC(C)=O)C=CC(C)C(/C(C)=C/C=C/C(C)(CC2OC2C(C)C(CC)OC(C)OCC)OC(C)OCC)OC(=O)C1
Reactant: CN(C)c1cccc2cccc(N(C)C)c12
Agent: CCOC(C)OC1CCC(C)(O)C(OC(C)=O)/C=C/C(C)C(/C(C)=C/C=C/C(C)(CC2OC2C(C)C(CC)OC(C)OCC)OC(C)OCC)OC(=O)C1
Agent: CCOC(C)OC1CCC(C)(OC)C(OC(C)=O)/C=C/C(C)C(/C(C)=C/C=C/C(C)(CC2OC2C(C)C(CC)OC(C)OCC)OC(C)OCC)OC(=O)C1
Agent: COS(=O)(=O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CCOC(C)OC1CCC(C)(OC)C(OC(C)=O)C=CC(C)C(/C(C)=C/C=C/C(C)(CC2OC2C(C)C(CC)OC(C)OCC)OC(C)OCC)OC(=O)C1
Temperature: 65 °C
Reaction time: 11 h

Procedure:
(8E,12E,14E)-7-Acetoxy-3,16,21-tris(1-ethoxyethoxy)-6-hydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide (34 mg, 44 μmol) obtained in Example 3 and 1,8-bis(N,N-dimethylamino)naphthalene (57 mg, 266 μmol) were dissolved in toluene (2 mL). Methyl trifluoromethanesulfonate (22 mg, 133 μmol) was added to this solution, and the reaction mixture was stirred at 65° C. for 11 hours. After removing the precipitate by filtration, the reaction mixture was diluted with ethyl acetate, and an aqueous solution of ammonium chloride was added, followed by vigorous stirring for 5 minutes. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography (Kanto silica gel 60N spherical, neutral, 40 to 100 μm; hexane:ethyl acetate=1:1) to give (8E,12E,14E)-7-acetoxy-3,16,21-tris(1-ethoxyethoxy)-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide (14 mg) as a colorless oil.
Reaction SMILES: [CH3:1][O:2]/[CH:3]=[CH:4]/[C:5]#[CH:6].[CH2:7]([SnH:11]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9][CH3:10].N(C(C)(C)C#N)=NC(C)(C)C#N>>[CH2:16]([Sn:11]([CH2:7][CH2:8][CH2:9][CH3:10])([CH2:12][CH2:13][CH2:14][CH3:15])/[CH:6]=[CH:5]/[CH:4]=[CH:3]/[O:2][CH3:1])[CH2:17][CH2:18][CH3:19]
Reactant: C#C/C=C/OC
Reactant: CCCC[SnH](CCCC)CCCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCCC[Sn](/C=C/C=C/OC)(CCCC)CCCC

Procedure:
Scheme D shows a method of preparing an aldehyde which may be used in Scheme A. 1-Methoxy-1E-buten-3-yne is reacted with tributylstannane in the presence of catylytic 2,2'-azobisisobutyronitrile (AIBN) to give tributyl(4-methoxy-1E,3E-butadienyl)stannane which is then reacted with butyllithium followed by coupling with an appropriate aldehyde (XVIII). The alcohol-formed is reacted with toluene sulfonic acid (TSOH) to give the desired aldehyde (V).
Reaction SMILES: [CH3:1][C:2]([CH2:10][CH3:11])([CH2:6][C:7]([OH:9])=O)[C:3]([OH:5])=O.[N+:12]([C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18])([O-:14])=[O:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[N+:12]([C:15]1[CH:16]=[C:17]([N:18]2[C:7](=[O:9])[CH2:6][C:2]([CH3:1])([CH2:10][CH3:11])[C:3]2=[O:5])[CH:19]=[CH:20][CH:21]=1)([O-:14])=[O:13]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: CCC(C)(CC(=O)O)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: CCC1(C)CC(=O)N(c2cccc([N+](=O)[O-])c2)C1=O

Procedure:
Sixty-four g. of 2-methyl-2-ethylsuccinic acid was combined with 55.2 g. of m-nitro aniline in 250 ml. of xylene. One-half g. of p-toluene sulfonic acid was added and the mixture heated to reflux under a modified Dean Stark apparatus. After 15-16 ml. of water was removed, the mixture was cooled and the product recovered by filtration. Yield was 78 g. of a product having a m.p. of 88°-89° C. The product was identified as the title compound by analysis of infrared spectra.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([O:17][CH3:18])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.C(OC([N:26]1[CH2:31][CH2:30][CH:29]([N:32]2[CH2:36][CH2:35][NH:34][C:33]2=[O:37])[CH2:28][CH2:27]1)=O)(C)(C)C.[ClH:38]>>[ClH:38].[CH3:18][O:17][C:6]1[C:5]2[C:9](=[CH:10][C:2]([N:34]3[CH2:35][CH2:36][N:32]([CH:29]4[CH2:28][CH2:27][NH:26][CH2:31][CH2:30]4)[C:33]3=[O:37])=[CH:3][CH:4]=2)[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]=1
Reactant: COc1nn(-c2ccccc2)c2cc(Br)ccc12
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCNC2=O)CC1
Agent: Cl
Product: COc1nn(-c2ccccc2)c2cc(N3CCN(C4CCNCC4)C3=O)ccc12

Procedure:
The title compound was prepared according to the procedure as described in Example 57 reacting 6-bromo-3-methoxy-1-phenyl-1H-indazole and 4-(2-oxo-imidazolidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester, followed by de-protection with HCl.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)(=[O:15])=[O:14])[CH:11]=[C:10]([CH:23]=[O:24])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[Cu][C:26]#[N:27].O.C(OCC)(=O)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[F:22][C:18]1[CH:17]=[C:16]([S:13]([N:12]2[CH:11]=[C:10]([CH:23]=[O:24])[CH:9]=[C:8]2[C:7]2[C:2]([C:26]#[N:27])=[N:3][CH:4]=[CH:5][CH:6]=2)(=[O:15])=[O:14])[CH:21]=[CH:20][CH:19]=1
Reactant: N#C[Cu]
Reactant: O=Cc1cc(-c2cccnc2Cl)n(S(=O)(=O)c2cccc(F)c2)c1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1ncccc1-c1cc(C=O)cn1S(=O)(=O)c1cccc(F)c1
Yield: 17.1 %

Procedure:
5-(2-Chloropyridin-3-yl)-1-[(3-fluorophenyl)sulfonyl]-1H-pyrrole-3-carbaldehyde (420 mg), copper (I) cyanide (516 mg), tris(dibenzylideneacetone)dipalladium (0) (53 mg) and 1,1′-bis(diphenylphosphino)ferrocene (96 mg) were mixed in 1,4-dioxane (20 mL), and the mixture was heated under reflux for 3 hr. The reaction mixture was cooled to around room temperature, copper (I) cyanide (516 mg), tris(dibenzylideneacetone)dipalladium (0) (53 mg) and 1,1′-bis(diphenylphosphino)ferrocene (96 mg) were added and the mixture was heated under reflux for 60 hr. The reaction mixture was allowed to cool, water and ethyl acetate were added and the mixture was filtered. The obtained ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:3→3:2) to give the title compound as a colorless oil (yield 70 mg, 17%).
Reaction SMILES: C(OCC[CH:6]([C:29]([OH:31])=[O:30])[N:7]([C:19](OCC1C=CC=CC=1)=O)[CH2:8][P:9]([S:15][CH2:16][CH:17]=[CH2:18])([S:11][CH2:12][CH:13]=[CH2:14])=[O:10])C.Br.[CH3:33][CH2:34][O:35][CH2:36]C>C(O)(=O)C>[CH2:34]([O:35][CH2:36][CH2:19][N:7]([CH2:8][P:9]([S:11][CH2:12][CH:13]=[CH2:14])([S:15][CH2:16][CH:17]=[CH2:18])=[O:10])[CH2:6][C:29]([OH:31])=[O:30])[CH3:33]
Reactant: C=CCSP(=O)(CN(C(=O)OCc1ccccc1)C(CCOCC)C(=O)O)SCC=C
Reactant: CCOCC
Agent: Br
Solvent: CC(=O)O
Product: C=CCSP(=O)(CN(CCOCC)CC(=O)O)SCC=C

Procedure:
Ethoxyethyl N-carbobenzoxy-N-[bis(allylthio)phosphinylmethyl]glycine (4.8 g., 0.01 mole) was reacted with 32% hydrogen bromide (15 ml) in glacial acetic acid at 0° C. Ether was added and the oily precipitate was isolated by decanting the ether layer. The oil was washed with ether twice, then suspended in benzene and treated with propylene oxide. Concentration of the solution in vacuo yielded ethoxyethyl N-[bis(allylthio)phosphinylmethyl]glycine as an oil, ND22 =1.5163.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Br:14]Br>C(O)(=O)C>[Br:14][C:5]1[CH:6]=[C:7]([O:8][CH3:9])[C:2]([OH:1])=[CH:3][C:4]=1[CH2:10][C:11]([OH:13])=[O:12]
Reactant: COc1ccc(CC(=O)O)cc1O
Reactant: BrBr
Solvent: CC(=O)O
Product: COc1cc(Br)c(CC(=O)O)cc1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 3-hydroxy-4-methoxy-phenyl acetic acid (8 g) in 150 ml acetic acid was added drop wise 2.48 ml bromine. The mixture was stirred 18 hours at room temperature under nitrogen. The solvent was then removed in vacuo and the residue was triturated with toluene, filtered, washed with toluene then hexane to yield 11.1 g (2-bromo-5-hydroxy-4-methoxy-phenyl)-acetic acid a solid.