Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[N:10][C:5]2=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:14][C:15]1[CH:25]=[CH:24][C:18]2[N:19]=[C:20]([S:22][CH3:23])[S:21][C:17]=2[CH:16]=1.O>CN(C=O)C>[Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:14][C:15]3[CH:25]=[CH:24][C:18]4[N:19]=[C:20]([S:22][CH3:23])[S:21][C:17]=4[CH:16]=3)[CH:9]=[N:10][C:5]2=[CH:4][CH:3]=1
Reactant: Brc1ccc2nc[nH]c2n1
Reactant: CSc1nc2ccc(CCl)cc2s1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nc2ccc(Cn3cnc4ccc(Br)nc43)cc2s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51.6 %

Procedure:
To a stirred solution of 5-bromo-3H-imidazo[4,5-b]pyridine (1 g, 5.05 mmol) from Step 2 of this Example in anhydrous DMF (25 mL) at 0° C. was added in one portion sodium hydride (60% dispersion in mineral oil, 222 mg 5.56 mmol), and the mixture was stirred at 0° C. for 30 min. To the reaction mixture was added a solution of 6-(chloromethyl)-2-(methylthio)benzo[d]thiazole (1.39 g, 6.06 mmol) from Step 4 of Example 36 in DMF (5 mL). The mixture was allowed to warm to rt and stirred for a further 15 h. To the reaction mixture was added water (300 mL) and the mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with water and then brine. The organic layer was separated, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 100% DCM, followed by 1% MeOH in DCM to afford 6-((5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]thiazole (1.02 g, 52%) as a white solid. The regiochemistry of the alkylation was determined by 2-dimensional nuclear Overhauser effect (NOE) experiment. 1H NMR (300 MHz, DMSO-d6) δ 8.65 (s, 1H), 8.09 (d, J=8.3 Hz, 1H), 7.96 (d, J=0.9 Hz, 1H), 7.83 (d, J=8.3 Hz, 1H), 7.49 (d, J=8.3 Hz, 1H), 7.43 (dd, J=1.5, 8.3 Hz, 1H), 5.60 (s, 2H), 2.77 (s, 3H). LCMS (ESI) m/z 391 and 393 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@@H:9]([CH2:13][CH3:14])[C:10](O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN([C:25]([O:29][N:30]1N=NC2C=CC=C[C:31]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.Cl.CNOC>ClCCl>[CH2:1]([N:8]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@@H:9]([CH2:13][CH3:14])[C:10]([N:30]([O:29][CH3:25])[CH3:31])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC[C@@H](C(=O)O)N(Cc1ccccc1)Cc1ccccc1
Agent: CNOC
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC[C@@H](C(=O)N(C)OC)N(Cc1ccccc1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Under an atmosphere of argon, (S)-2-(dibenzylamino)butanoic acid (27 g, 80.0 mmol, Eq: 1.00) was combined with dichloromethane (250 ml) to give a white suspension. At 0° C., TBTU (36.0 g, 112 mmol, Eq: 1.4) was added. The reaction was stirred for 2 h at 0° C. Then N-methylmorpholine (24.3 g, 26.4 ml, 240 mmol, Eq: 3) and N,O-dimethylhydroxylamine hydrochloride (19.5 g, 200 mmol, Eq: 2.5) were added. The reaction was stirred overnight at RT. The reaction mixture was extracted with water (2×75 ml) and brine (50 ml). The organic layers were dried over Na2SO4 and concentrated in vacuo. The residual solvent was removed under vacuum. The title compound was obtained as a light yellow oil (35.5 g, 95.1%, MS (m/e)=327.3 [M+H+]).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O>>[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1F
Reactant: Brc1ccc2cc[nH]c2c1
Product: Fc1ccccc1-c1ccc2cc[nH]c2c1

Procedure:
Prepared by Procedure I and Scheme T using 6-bromo-1H-indole and 2-fluorophenylboronic acid: ESMS m/e: 211.9 (M+H)+.
Reaction SMILES: [P:1]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])([O:21][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][CH2:38][CH3:39])[O:2]CCCCCCCCCCCCCCCCCC.[C:59]([C:63]1[C:68]([OH:69])=[C:67]([CH3:70])[C:66]([CH2:71]Cl)=[C:65]([CH3:73])[CH:64]=1)([CH3:62])([CH3:61])[CH3:60]>>[C:59]([C:63]1[CH:64]=[C:65]([CH3:73])[C:66]([CH2:71][P:1](=[O:2])([O:21][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][CH2:38][CH3:39])[O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])=[C:67]([CH3:70])[C:68]=1[OH:69])([CH3:62])([CH3:61])[CH3:60]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C)c1CCl
Reactant: CCCCCCCCCCCCCCCCCCOP(OCCCCCCCCCCCCCCCCCC)OCCCCCCCCCCCCCCCCCC
Product: CCCCCCCCCCCCCCCCCCOP(=O)(Cc1c(C)cc(C(C)(C)C)c(O)c1C)OCCCCCCCCCCCCCCCCCC

Procedure:
21.7 Grams of trioctadecyl phosphite and 5.75 grams 6-tert.-butyl-3-chloromethyl-2,4-dimethylphenol was stirred together as a melt at 110° to 120° for 2 hours and at 120° to 125° for 7 hours. The reaction mixture was dissolved in 100 ml. of toluene and the colorless, slightly turbid solution was successively washed with 3 N aqueous hydrochloric acid, water, 2 N aqueous sodium carbonate solution and water until the wash waters were neutral. After drying over anhydrous sodium sulfate and filtering free of drying agent, the clear filtrate was concentrated by distillation of the solvent at reduced pressures. The residual oil was topped in the "ASCO 50" Rota-Film Molecular Still at a wall temperature of 210° to 215° and a pressure of 1 to 5 microns. After crystallization from methylethyl ketone, the desired product was obtained as white crystals melting at 70° to 72.5°. (compound 4)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=2)[NH2:19])[CH:5]=[CH:4][N:3]=1.[CH:23]1([S:26](Cl)(=[O:28])=[O:27])[CH2:25][CH2:24]1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:19][S:26]([CH:23]3[CH2:25][CH2:24]3)(=[O:28])=[O:27])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)c1nc(-c2cccc(N)c2)c(-c2ccnc(Cl)n2)s1
Reactant: O=S(=O)(Cl)C1CC1
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)C3CC3)c2)c(-c2ccnc(Cl)n2)s1
Yield: 94.4 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]aniline (1.0 g, 3.03 mmol) and cyclopropanesulfonyl chloride (465 mg, 3.32 mmol) the title compound of Step A was obtained (1.24 g, 94.4% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.30 (d, J=5.3 Hz, 1H), 7.36-7.42 (m, 2H), 7.29-7.36 (m, 2H), 7.01 (d, J=5.3 Hz, 1H), 6.91-6.93 (br, 1H), 3.29-3.40 (m, 1H), 2.46-2.53 (m, 1H), 1.44 (d, J=7.0 Hz, 6H), 1.12-1.18 (m, 2H), 093-1.01 (m, 2H). MS (ES+): 435 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([NH:14][C:15](=[O:27])[C:16]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([CH3:18])[CH3:17])[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][N:29]1[CH2:33][C@H:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@:31]2([CH2:44][CH2:43][CH2:42][NH:41][CH2:40]2)[C:30]1=[O:45].CN1C[C@@H](C2C=CC=CC=2)[C@@]2(CCCNC2)C1=O.CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C=O)C>[CH2:1]([O:8][CH2:9][C@@H:10]([NH:14][C:15](=[O:27])[C:16]([NH:19][C:20](=[O:21])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])([CH3:18])[CH3:17])[C:11]([N:41]1[CH2:42][CH2:43][CH2:44][C:31]2([C:30](=[O:45])[N:29]([CH3:28])[CH2:33][CH:32]2[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:40]1)=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1C[C@H](c2ccccc2)[C@]2(CCCNC2)C1=O
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](COCc1ccccc1)C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN1C[C@@H](c2ccccc2)[C@@]2(CCCNC2)C1=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CC(c2ccccc2)C2(CCCN(C(=O)[C@@H](COCc3ccccc3)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture comprising (R)-3-(benzyloxy)-2-(2-(tert-butoxycarbonylamino)-2-methyl propanamido)propanoic acid (Intermediate 3A) (800 mg, 2.103 mmol) and a racemic mixture of (4R,5S)-2-Methyl-4-phenyl-2,7-diazaspiro[4.5]decan-1-one and (4S,5R)-2-Methyl-4-phenyl-2,7-diazaspiro[4.5]decan-1-one (Intermediate 1A) (514 mg, 2.103 mmol) in DMF (10 ml) was treated with DIPEA (1.102 ml, 6.31 mmol) and ®T3P (amide coupling agent 50% in DMF, 2.455 ml, 4.21 mmol) and stirred at RT for 1 hour. The resulting mixture was concentrated in vacuo and the residue was suspended in water (50 ml) and extracted with EtOAc (2×100 ml). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. Purification by chromatography on silica eluting with 0-100% EtOAc in iso-hexane afforded the title compound as a white foam.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14](I)=[C:15]([NH:17][C:18](=[O:20])[CH3:19])[N:16]=3)[N:13]=2)=[CH:4][C:3]=1[NH:22][S:23]([CH3:26])(=[O:25])=[O:24].CS(C)=O.[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:36]4[CH:35]=[CH:34][CH:33]=[C:32]([F:31])[CH:37]=4)=[C:15]([NH:17][C:18](=[O:20])[CH3:19])[N:16]=3)[N:13]=2)=[CH:4][C:3]=1[NH:22][S:23]([CH3:26])(=[O:25])=[O:24]
Reactant: CC(=O)Nc1nc2ccc(-c3cnc(Cl)c(NS(C)(=O)=O)c3)nn2c1I
Reactant: OB(O)c1cccc(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)Nc1nc2ccc(-c3cnc(Cl)c(NS(C)(=O)=O)c3)nn2c1-c1cccc(F)c1
Temperature: 90 °C
Reaction time: 0.67 h
Yield: 76.7 %

Procedure:
To a 10 mL round-bottomed flask was added N-(6-(6-chloro-5-(methylsulfonamido)pyridin-3-yl)-3-iodoimidazo[1,2-b]pyridazin-2-yl)acetamide (Example 21) (0.0820 g, 0.162 mmol), DMSO (2.50 mL, 35.2 mmol), 3-fluorophenylboronic acid (0.0272 g, 0.194 mmol, Aldrich, St. Louis, Mo.), and sodium carbonate (0.405 mL, 0.809 mmol, 2 M). The mixture was carefully evacuated and backfilled with N2. To the mixture was added trans-dichlorobis(triphenylphosphine)palladium(II) (0.011 g, 0.0162 mmol, Strem Chemical, Inc., Newburyport, Mass.). Again, the mixture was carefully evacuated and backfilled with N2. The mixture was stirred at 90° C. for 40 min, allowed to cool to rt. and then directly purified by preparative HPLC (Phenomenex Gemini 5 micron (Phenomenex, Torrance, Calif.), C18, 100×30 mm, 5 to 75% CH3CN(0.1% TFA)/H2O(0.1% TFA) over 20 min then 100% CH3CN(0.1% TFA) for 3 minutes at 20 mL/min) with the fractions containing suspected product concentrated to afford the title compound as a yellow solid (0.059 g, 62%). MS (ESI, positive ion) m/z: 475 (M−TFA+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.04 (s, 3H), 3.20 (s, 3H), 7.25-7.28 (m, 1H), 7.53-7.60 (m, 1H), 7.70-7.75 (m, 1H), 7.77-7.81 (m, 1H), 8.02 (d, J=9.6 Hz, 1H), 8.32 (d, J=9.6 Hz, 1H), 8.52 (d, J=2.2 Hz, 1H), 8.95 (d, J=2.2 Hz, 1H), 9.92 (s, 1H), 10.24 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[F:56][C:57]([F:61])([F:60])[CH2:58][NH2:59]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:59][CH2:58][C:57]([F:61])([F:60])[F:56])=[O:21])=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1onc(-c2cccc(Cl)c2)c1COc1ccc(C(=O)O)cn1
Reactant: NCC(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1onc(-c2cccc(Cl)c2)c1COc1ccc(C(=O)NCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.2 %

Procedure:
To a solution of 6-[3-(3-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (69 mg, 0.2 mmol) in DMF (300 μL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (71 mg, 0.22 mmol), N,N-diisopropyl ethyl amine (171 μL, 1.0 mmol) and 2,2,2-trifluoroethylamine (17.3 μL, 0.22 mmol). The resulting reaction mixture was stirred for 1 h at room temperature. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (30 mg, 35%) as a white solid. MS: m/e=426.1 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:19])[C:6]1[CH:11]=[CH:10][CH:9]=[N:8][C:7]=1[N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1.[N+:20]([O-])([OH:22])=[O:21].C(OC(=O)C)(=O)C.C(=O)([O-])O.[Na+]>C(#N)C>[O:1]([CH2:2][CH2:3][NH:4][C:5](=[O:19])[C:6]1[CH:11]=[CH:10][CH:9]=[N:8][C:7]=1[N:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]1)[N+:20]([O-:22])=[O:21]
Reactant: O=[N+]([O-])O
Reactant: CN1CCN(c2ncccc2C(=O)NCCO)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC#N
Product: CN1CCN(c2ncccc2C(=O)NCCO[N+](=O)[O-])CC1
Reaction time: 4 h

Procedure:
To a solution of 1.27 g of compound 7 prepared in Examples 2-10 in 13 ml of acetonitrile was added dropwise a mixture of 2.0 g of fuming nitric acid and 1.4 g of acetic anhydride while maintaining the temperature below -10° C. The mixture was stirred for 4 hours, then poured into an aqueous sodium hydrogen carbonate solution and extracted with methylene chloride. The extract was washed twice with water and once with a saturated aqueous saline solution, dried over anhydrous magnesium sulfate and concentrated to give N-(2-nitroxyethyl)-2-(4-methyl-1-piperazinyl)nicotinamide (compound 17). The product was dissolved in ethanol, and to the solution was added under ice-cooling hydrogen chloride-saturated ethanol. The hydrochloride thus formed was recrystallized from ethanol to give 1.32 g of N-(2-nitroxyethyl)-2-(4-methyl-1-piperazinyl) nicotinamide dihydrochloride (compound 18)(yield 66%).
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]1[C:18]2([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15](Br)[CH:16]=2)[NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:25]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)([O-:27])=[O:26]>>[CH2:1]([O:8][N:9]=[C:10]1[C:18]2([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([N+:25]([O-:27])=[O:26])[CH:33]=3)[CH:16]=2)[NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: Brc1ccc2c(c1)C1(CCCCC1)C(=NOCc1ccccc1)N2
Product: O=[N+]([O-])c1cccc(-c2ccc3c(c2)C2(CCCCC2)C(=NOCc2ccccc2)N3)c1
Yield: 53.8 %

Procedure:
Prepared from 5′-bromospiro{cyclohexane-1,3′-[3H]indol}-2′(1′H)-one 2′(O-benzyloxime) (1.0 g, 2.6 mmol) and 3-Nitrophenyl boronic acid (0.86 g, 5.2 mmol) according to Example 45 procedure A. Purification by flash silica gel chromatography (eluant: 10:0.5 hexane:ethyl acetate) afforded the desired compound (0.60 g, 1.4 mmol, 55%) as a viscous oil. 1H NMR (500 MHz, DMSO-d6) δ 1.42–1.82 (8H, m), 2.02–2.04 (2H, q), 5.01 (2H, s), 6.88 (1H, d), 7.28–7.71 (8H, m), 8.08–8.13 (2H, m), 8.38 (1H, d), 9.69 (1H, s); MS (ESI(−ve)) m/z 426 (M−H)−.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:15](OCC)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]1=[O:25])(=O)C.[CH2:26]([N:33]([CH2:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1)[CH3:34])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([N:33]([CH2:35][C:36]1[CH:37]=[CH:38][C:39]([NH:40]/[C:15](=[C:6]2\[C:5](=[O:25])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=3)/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:41][CH:42]=1)[CH3:34])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CN(Cc1ccccc1)Cc1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(OC)ccc21)c1ccccc1
Product: COc1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN(C)Cc2ccccc2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-6-methoxy-2-indolinone and 4-[(N-benzyl-N-methyl-amino)-methyl]-aniline
Reaction SMILES: [C:1]1([CH3:22])[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:13]([NH2:14])=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[CH:3][CH:2]=1.[CH2:23](OC=C(C#N)C#N)C>C(O)(C)C>[C:1]1([CH3:22])[CH:2]=[CH:3][C:4]([N:7]2[C:8]3=[N:9][CH:10]=[CH:11][C:12]([C:15]4[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=4)=[C:13]3[N:14]=[CH:23]2)=[CH:5][CH:6]=1
Reactant: Cc1ccc(Nc2nccc(-c3ccc(C)cc3)c2N)cc1
Reactant: CCOC=C(C#N)C#N
Solvent: CC(C)O
Product: Cc1ccc(-c2ccnc3c2ncn3-c2ccc(C)cc2)cc1
Yield: 84 %

Procedure:
0.70 mol of N2,4-dip-tolylpyridine-2,3-diamine and 2.56 mol of 2-(ethoxymethylene)malonnitrile were added in 10 ml of isopropanol, and refluxed for 6 hours. The solution was removed and was purified by using column chromatography to thereby produce a solid crystalline product at a yield of 84%.
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: CN(C)c1cccc2cccc(N(C)C)c12
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
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: C1COCC1.[NH2:6][C:7]1[C:12]2=[C:13]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][C:30]=4[F:39])=[O:27])=[C:21]([F:40])[CH:20]=3)[C:14]([CH2:16][O:17][CH3:18])=[CH:15][N:11]2[N:10]=[CH:9][N:8]=1.[Br:41]N1C(C)(C)C(=O)N(Br)C1=O.[O-]S([O-])=O.[Na+].[Na+]>CCOC(C)=O>[NH2:6][C:7]1[C:12]2=[C:13]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:34]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:32]=[CH:31][C:30]=4[F:39])=[O:27])=[C:21]([F:40])[CH:20]=3)[C:14]([CH2:16][O:17][CH3:18])=[C:15]([Br:41])[N:11]2[N:10]=[CH:9][N:8]=1
Reactant: COCc1cn2ncnc(N)c2c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)c(F)c1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCc1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)c(F)c2)c2c(N)ncnn2c1Br
Temperature: -40 °C
Reaction time: 1 h
Yield: 107 %

Procedure:
To a solution of THF (500 mL) was added 1-{4-[4-amino-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea (2.29 g, 4.65 mmol). The solution was cooled to −40° C. and then 1,3-dibromo-5,5-dimethylhydantoin (665 mg, 2.33 mmol) was added in two batches 20 min apart. The reaction was stirred at −40° C. for 1 h and then allowed to warm to rt over the following 2 h. Aq saturated Na2SO3 was added to the reaction followed by EtOAc. The layers were separated and the aqueous layer was back extracted with EtOAc. The organic layer was washed with 1N NaOH and water, dried (Na2SO4), filtered and evaporated to yield 2.83 g crude (107%) of the desired product. MS [M+H]+=571; LCMS RT=3.54.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[CH2:15](Cl)[C:16]#[C:17][CH2:18][CH3:19]>>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:15][C:16]#[C:17][CH2:18][CH3:19])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)CSc1ccc(O)cc1
Reactant: CCC#CCCl
Product: CCC#CCOc1ccc(SCC(=O)OCC)cc1

Procedure:
(4-Pent-2-ynyloxy-phenylsulfanyl)-acetic acid ethyl ester was prepared according to the general method as outlined in Example 1 (Step 2). Starting from (4-hydroxy-phenylsulfanyl)-acetic acid ethyl ester (5 g, 30 mmol) and 2-pentynyl chloride (3.7 g, 36.6 mmol) 7.15 g of the product isolated. Yield 7.15 g (86%); brown oil; MS: 278 EI (M+H)+
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br)[C:8]2=[O:32])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[P:33]([O:42]C(C)C)([O:38]C(C)C)[O:34][CH:35]([CH3:37])[CH3:36].[C:46]1(C)[C:47](C)=CC=C[CH:51]=1>>[PH:33](=[O:34])([OH:42])[OH:38].[CH:35]([CH:30]([CH:46]([CH3:47])[CH3:51])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][N:9]1[C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]1=[O:32])([CH3:37])[CH3:36]
Reactant: CC(C)OP(OC(C)C)OC(C)C
Reactant: Cc1ccccc1C
Reactant: O=c1n(CCCCCCCBr)c(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1
Product: CC(C)C(CCCCCCn1c(-c2ccccc2)c(-c2ccccc2)n(-c2ccccc2)c1=O)C(C)C
Product: O=[PH](O)O

Procedure:
A solution of 1,4,5-triphenyl-3-(7-bromoheptyl)-imidazol-2-one (1.47 g) and triisopropyl phosphite (3.12 g) in xylene (15 ml) was heated at reflux temperature for 48 hours. The solution was evaporated to an oil and chromatographed on silica gel (ethyl acetate/ethanol). The resulting oil was taken up in diethyl ether, filtered and evaporated to the titled compound as a clear oil (0.33 g; 19%) Found: C, 70.02; H, 7.53; N, 5.19%; C34H43N2O4P+1.5% H2O; Requires: C, 69.99; H, 7.60; N, 4.80%.