Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:13]3[N:14]=[C:15]([NH2:17])[N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][N:25]=2)[CH2:20][CH2:19]1>>[CH:1]1([NH:7][C:8]2[N:13]3[N:14]=[C:15]([NH:17][C:28](=[O:29])[C:27]4[CH:31]=[CH:32][C:24]([N:21]5[CH2:20][CH2:19][O:18][CH2:23][CH2:22]5)=[N:25][CH:26]=4)[N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1nc2cccc(NC3CCCCC3)n2n1
Reactant: O=C(Cl)c1ccc(N2CCOCC2)nc1
Product: O=C(Nc1nc2cccc(NC3CCCCC3)n2n1)c1ccc(N2CCOCC2)nc1

Procedure:
The title compound was prepared following procedure described for intermediate B1, but starting from N5-cyclohexyl[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine ((A9), 174 mg; 0.75 mmol; 1.0 eq.) and 6-morpholinonicotinoyl chloride (255 mg; 1.12 mmol; 1.5 eq.) as a white solid (15 mg, 5%). HPLC, Rt: 2.83 min. (purity 99.0%). LC/MS, M+(ESI): 422.2, M−(ESI): 420.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]2[C:15](=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[O:18][CH3:19])[C:8]([CH2:24][C:25](O)=[O:26])([CH2:20][C:21](O)=[O:22])[C:7]=2[CH:6]=[CH:5][CH:4]=1.B#B.O>O1CCCC1>[OH:26][CH2:25][CH2:24][C:8]1([CH2:20][CH2:21][OH:22])[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[C:14]=2[CH2:15][C:16]2[C:7]1=[CH:6][CH:5]=[CH:4][C:3]=2[O:2][CH3:1]
Reactant: COc1cccc2c1C(=O)c1c(OC)cccc1C2(CC(=O)O)CC(=O)O
Agent: B#B
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc2c1Cc1c(OC)cccc1C2(CCO)CCO

Procedure:
To 4,5-dimethoxy-10-oxo-9,10-dihydroanthracene-9,9-diacetic acid (9.9 g.) in dry tetrahydrofuran (300 ml.) is added with stirring, in an atmosphere of nitrogen, diborane in tetrahydrofuran (1M, 100 ml.). The reaction mixture is refluxed for 72 hours, cooled, and water (100 ml.) is added. The tetrahydrofuran is evaporated and the remaining suspension is filtered, the residue is washed successively with aqueous sodium bicarbonate, water, a little isopropanol, and petroleum ether (b.p. 60°-80°C.) to give 9,9-di-(2-hydroxyethyl)-4,5-dimethoxy-9,10-dihydroanthracene, m.p. 193°-196°C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[S:20](Cl)(=[O:22])=[O:21]>>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[S:20]([NH:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])(=[O:22])=[O:21]
Reactant: Nc1cc(I)ccc1C(=O)O
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Product: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1c(F)cccc1F

Procedure:
2-Amino-4-iodo-benzoic acid was sulfonylated with 2,6-difluorobenzenesulfonyl chloride as in EXAMPLE 1, Part A. 1H NMR (500 MHz, CD3OD): 8.05 (d, J=1.6, 1H), 7.72 (d, J=8.4, 1H), 7.68-7.60 (m, 1H), 7.48 (dd, J=8.4, 1.6, 1H), 7.16-7.09 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[N:11]=1.[Cl:17][C:18]([Cl:25])([Cl:24])[CH2:19]C(=N)OC>C(O)(=O)C.O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[C:19]([C:18]([Cl:25])([Cl:24])[Cl:17])[N:9]([C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[N:11]=3)[C:3]=2[CH:4]=1
Reactant: COC(=N)CC(Cl)(Cl)Cl
Reactant: Nc1nccc(Nc2cc(Br)ccc2N)n1
Solvent: CC(=O)O
Solvent: O
Product: Nc1nccc(-n2c(C(Cl)(Cl)Cl)nc3ccc(Br)cc32)n1
Yield: 81.2 %

Procedure:
To a solution of 4-N-(2-amino-5-bromophenyl)pyrimidine-2,4-diamine (16.5 g, 58.90 mmol) in acetic acid (55 mL) was added methyl 2,2,2-trichloroethanecarboximidate (11 g, 62.35 mmol) dropwise with stirring. The reaction mixture was stirred at room temperature for 3 hr and then at 45° C. overnight. The resulting solution was diluted with 100 mL of water and the precipitate was collected by filtration. The solid was dried in a vacuum oven to give 19.5 g (81%) of 4-[6-bromo-2-(trichloromethyl)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine as a light brown solid: 1H NMR (300 MHz, DMSO) delta 8.58 (d, J=4.8 Hz, 1H), 7.68 (t, J=4.5 Hz, 1H), 7.61-7.58 (m, 2H), 7.21 (s, 2H), 7.01 (d, J=5.1 Hz, 3H); LC-MS: m/z=+408 (M+H)+.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[CH2:28][S:29][CH2:30][CH2:31][C:32]([OH:35])([CH3:34])[CH3:33])[CH2:12][C@@H:11]([O:36][Si](C(C)(C)C)(C)C)[CH2:10]1)(C(C)(C)C)(C)C.O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[OH:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[CH2:28][S:29][CH2:30][CH2:31][C:32]([OH:35])([CH3:34])[CH3:33])[CH2:12][C@@H:11]([OH:36])[CH2:10]1
Reactant: CC(C)(O)CCSC[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(O)CCSC[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 83.9 %

Procedure:
To a solution of 1α,3β-bis(tert-butyldimethylsilyloxy)-17β-(3-hydroxy-3-methylbutylthiomethyl)androsta-5,7-diene (130 mg, 0.215 mmol) in tetrahydrofuran (1 ml), was added a 1M tetra-n-butylammonium fluoride tetrahydrofuran solution (2.15 ml, 2.15 mmol), followed by reflux under heating for 5 hours. The reaction mixture was returned to room temperature, diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to remove the solvent. The thus obtained residue was purified by preparative thin layer chromatography (3 sheets (each 0.5 mm thickness), dichloromethane:ethanol=9:1, developed once) to give the titled compound (75.9 mg, 84%) as a white solid.
Reaction SMILES: ClC1C(C2C=CC(Cl)=C(SCC#C)C=2)=NC=C(C(F)(F)F)C=1.[Cl:23][C:24]1[C:25]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([SH:41])[CH:35]=2)=[N:26][CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1.Br[CH:43]([CH3:49])[C:44]([O:46][CH2:47][CH3:48])=[O:45]>COC(C)(C)C>[Cl:23][C:24]1[C:25]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([S:41][CH:43]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH3:49])[CH:35]=2)=[N:26][CH:27]=[C:28]([C:30]([F:32])([F:33])[F:31])[CH:29]=1
Reactant: FC(F)(F)c1cnc(-c2ccc(Cl)c(S)c2)c(Cl)c1
Reactant: CCOC(=O)C(C)Br
Agent: C#CCSc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Solvent: COC(C)(C)C
Product: CCOC(=O)C(C)Sc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Yield: 92.3 %

Procedure:
In a preparation similar to that described above for 3-chloro-2-[4-chloro-3-(2-propynylthio)phenyl]-5-trifluoromethylpyridine, reaction of 2.0 g of 3-chloro-2-(4-chloro-3-mercaptophenyl)-5-trifluoromethylpyridine with 1.11 g of ethyl 2-bromopropionate and extraction of the product with tert-butyl methyl ether afforded 2.4 g (92%) of a colorless oil.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[NH:5][CH:6]=1.[N+:19]([O-])([OH:21])=[O:20].S(=O)(=O)(O)O>O>[Br:1][C:2]1[N:3]=[C:4]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:9][C:8]=2[Cl:18])[NH:5][C:6]=1[N+:19]([O-:21])=[O:20]
Reactant: FC(F)(F)c1cc(Cl)c(-c2nc(Br)c[nH]2)c(Cl)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1[nH]c(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1Br
Temperature: 70 °C

Procedure:
A mixture of 4-bromo-2-(2,6-dichloro-4-trifluoromethylphenyl)-imidazole (0.9 g, 0.025 mol), nitric acid (70% w /w, 1 ml) and sulphuric acid (98% w /w, 1 ml) was stirred and heated at 70° C. for 7.5 hours. After cooling it was added to a mixture of ice and water (50 ml). The precipitated solid was filtered off and purified by mplc on silica eluted with a mixture of ethyl acetate and petroleum spirit (b.p. 60°-80° C.) (1:5) to give 4-bromo-2-(2,6-dichloro-4-trifluoromethylphenyl)-5-nitro-imidazole (0.2 g), m.p. 292°-293° C., as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([NH:11][C:12](=[O:25])/[CH:13]=[CH:14]/[C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[C:5]([C:26]([O:28]C)=[O:27])[CH:4]=1.[OH-].[Na+]>CO>[C:26]([C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[CH:7][C:6]=1[NH:11][C:12](=[O:25])/[CH:13]=[CH:14]/[C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)([OH:28])=[O:27]
Reactant: COC(=O)c1cc(OC)c(OC)cc1NC(=O)/C=C/c1ccc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(NC(=O)/C=C/c2ccc3ccccc3c2)c(C(=O)O)cc1OC

Procedure:
Prepared analogously to Example 2 from trans-3-(naphth-2-yl)-acrylic acid-N-(4,5-dimethoxy-2-methoxycarbonyl-phenyl)-amide and sodium hydroxide solution in methanol.
Reaction SMILES: [I-].[CH2:2]([O:4][C:5]([C:7]1[NH:11][CH:10]=[C:9]([CH2:12][N+](C)(C)C)[CH:8]=1)=[O:6])[CH3:3].[C-:17]#[N:18].[Na+]>C(O)C>[C:17]([CH2:12][C:9]1[CH:8]=[C:7]([C:5]([O:4][CH2:2][CH3:3])=[O:6])[NH:11][CH:10]=1)#[N:18]
Reactant: [C-]#N
Reactant: CCOC(=O)c1cc(C[N+](C)(C)C)c[nH]1
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc(CC#N)c[nH]1

Procedure:
A solution of the product obtained in Step E and sodium cyanide (0.225 g) in ethanol is heated at reflux for 72 hours. After evaporation to dryness, the residue is taken up in a mixture of CH2Cl2/water. The aqueous phase is extracted three times with CH2Cl2. The organic phases are combined. The organic phase is dried over magnesium sulphate, filtered and evaporated to dryness to yield the title product which is used directly in the next Step.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=2[CH3:21])=[C:4]([CH:9]=[CH:10][C:11]=1[F:12])[C:5]([NH:7][NH2:8])=[O:6].[C:22](=S)=[S:23].[OH-].[K+].Cl>CCO.CCOC(C)=O.O>[F:1][C:2]1[C:3]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=2[CH3:21])=[C:4]([C:5]2[O:6][C:22]([SH:23])=[N:8][N:7]=2)[CH:9]=[CH:10][C:11]=1[F:12]
Reactant: Cc1cc(I)ccc1Nc1c(C(=O)NN)ccc(F)c1F
Reactant: S=C=S
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: Cc1cc(I)ccc1Nc1c(-c2nnc(S)o2)ccc(F)c1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 51.3 %

Procedure:
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid hydrazide (170 mg, 0.42 mmol) was suspended in 7 mL of absolute EtOH and cooled to 0° C. Carbon disulfide (74 mg, 0.97 mmol) was added followed by 24 mg (0.42 mmol) of powdered KOH. The reaction was stirred for 1 h at 0° C., 1 h at rt, and refluxed for 3 h to afford a homogeneous reaction. The reaction was cooled to rt. at which point a ppt formed. Water was added and the reaction diluted with 5 mL of EtOAc. 1N HCl was added to acidify the aqueous layer (pH=2). The aqueous layer was extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4 and concentrated to obtain 96 mg (51%) of 5-[3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]oxadiazole-2-thiol as a yellow powder. M.p.=231.8-232.8° C. 1H NMR (400 MHz, CDCl3) δ7.62 (m, 2H), 7.47 (s, 1H), 7.30 (complex m, 2H), 6.44 (dd, J=8.0, 4.5 Hz, 1H), 2.19 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([O:20][Si](C(C)C)(C(C)C)C(C)C)=[CH:15][C:14]=2[F:31])[CH3:12])=[CH:6][C:5]=1[CH3:32].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>C1COCC1>[CH3:1][O:2][C:3](=[O:33])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([OH:20])=[CH:15][C:14]=2[F:31])[CH3:12])=[CH:6][C:5]=1[CH3:32]
Reactant: COC(=O)c1ccc(CN(C)c2c(C)cc(O[Si](C(C)C)(C(C)C)C(C)C)cc2F)cc1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CN(C)c2c(C)cc(O)cc2F)cc1C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 76.1 %

Procedure:
A mixture of 4-{[(2-fluoro-6-methyl-4-triisopropylsilanyloxy-phenyl)-methyl-amino]-methyl}-2-methyl-benzoic acid methyl ester (457 mg, 0.965 mmol) and tetrabutylammonium fluoride (2.0 mL of 1M in THF, 2.0 mmol) in THF (10 mL) is stirred at 0° C. for 20 minutes and then 2.0 mL of 1M HCl is added and the mixture is concentrated. The residue is portioned between ethyl acetate and brine. The layers are separated and the brine layer is extracted with ethyl acetate. The combined ethyl acetate layers are dried (MgSO4) and concentrated. The residue is purified on 40 g silica with ethyl acetate in heptane gradient (10% to 70%) to provide 233 mg (76%) of the titled compound as a glass. LC-ES/MS m/e 318.2 (M+1).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]([CH:19]2[CH2:22][CH2:21][CH2:20]2)[C:16]([CH:23]2[CH2:25][CH2:24]2)=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])C1C=CC=CC=1.[H][H]>[C].[Pd].CO>[CH:19]1([C:17]2[C:16]([CH:23]3[CH2:24][CH2:25]3)=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([OH:8])[CH:18]=2)[CH2:22][CH2:21][CH2:20]1
Reactant: COC(=O)c1cc(C2CC2)c(C2CCC2)cc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(C2CC2)c(C2CCC2)cc1O
Yield: 96.4 %

Procedure:
A methanol (100 mL) solution of methyl 2-(benzyloxy)-4-cyclobutyl-5-cyclopropylbenzoate (8.5 g) was deaerated for 20 minutes in a nitrogen stream. Then, 10% palladium carbon (containing 55% water, 1.1 g) was added thereto, and the mixture was stirred at room temperature for 3 hours in a hydrogen atmosphere. The reaction mixture was filtered through celite, and the solvent was distilled off under reduced pressure to obtain the title compound (6.0 g).
Reaction SMILES: [F:1][CH:2]([F:19])[C:3]1[CH:4]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:6]=[CH:7][C:8]=1[F:9].[Cl:20][C:21]1[C:22]([CH3:32])=[C:23]([N:27]2[CH:31]=[CH:30][N:29]=[CH:28]2)[N:24]=[N:25][CH:26]=1>>[ClH:20].[F:19][CH:2]([F:1])[C:3]1[CH:4]=[C:5]([C:21]2[C:22]([CH3:32])=[C:23]([N:27]3[CH:31]=[CH:30][N:29]=[CH:28]3)[N:24]=[N:25][CH:26]=2)[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: Cc1c(Cl)cnnc1-n1ccnc1
Reactant: CC1(C)OB(c2ccc(F)c(C(F)F)c2)OC1(C)C
Product: Cc1c(-c2ccc(F)c(C(F)F)c2)cnnc1-n1ccnc1
Product: Cl

Procedure:
The title compound, MS: m/e=305.2 (M+H+), was prepared from 2-(3-difluoromethyl-4-fluoro-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and 5-chloro-3-imidazol-1-yl-methyl-pyridazine.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][CH:4]([CH:10]1[NH:14]C(=O)N[C:11]1=[O:16])[CH2:5][C:6]([F:9])([F:8])[F:7].[OH-:19].[Na+]>>[F:1][C:2]([F:18])([F:17])[CH2:3][CH:4]([CH2:5][C:6]([F:9])([F:8])[F:7])[CH:10]([C:11]([OH:19])=[O:16])[NH2:14]
Reactant: [OH-]
Reactant: O=C1NC(=O)C(C(CC(F)(F)F)CC(F)(F)F)N1
Agent: [Na+]
Product: NC(C(=O)O)C(CC(F)(F)F)CC(F)(F)F

Procedure:
5-(3,3,3-Trifluoro-1-(2,2,2-trifluoroethyl)propyl)imidazolidine-2,4-dione (1.0 g, 3.59 mmol) was dissolved in a 10 mL solution of aqueous NaOH (0.575 g in 10 mL H2O, 14.38 mmol). The solution was divided in 2 special vessels for microwave technology. The solution was heated by microwave in sealed vessels for 1 h. Microwave conditions: 15 min at about 100% power, 150° C., 50 psi, then 5 min at rest, 0% power. The sequence was repeated until the reaction was done. Water and ammonia were removed from the reaction mixture in vacuo and the resulting crude 5,5,5-trifluoro-3-(2,2,2-trifluoroethyl)-dl-norvaline (0.92 g, 100%) and NaOH mixture was used in the next reaction without further purification. Mass Spectrum (+ESI): 254 (M+H)+.
Reaction SMILES: C([O:3][P:4]([CH:9]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][S:28][C:29](=[O:31])[CH3:30])=[CH:21][N:20]=1)[P:10](=[O:17])([O:14]CC)[O:11]CC)(=[O:8])[O:5]CC)C>O>[C:29]([S:28][CH2:27][CH2:26][CH2:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][CH:9]([P:10](=[O:11])([OH:17])[OH:14])[P:4](=[O:3])([OH:5])[OH:8])=[N:20][CH:21]=1)(=[O:31])[CH3:30]
Reactant: CCOP(=O)(OCC)C(Nc1ccc(CCCSC(C)=O)cn1)P(=O)(OCC)OCC
Solvent: O
Product: CC(=O)SCCCc1ccc(NC(P(=O)(O)O)P(=O)(O)O)nc1

Procedure:
[(5-(3-Acetylthiopropyl)-2-pyridinyl)aminomethylene]-bis[phosphonic acid] is prepared by heating [(5-(3-acetylthiopropyl)-2-pyridinyl)aminomethylene]bis[phosphonic acid] tetraethyl ester [prepared as described in Example A (part III) hereinbefore] at reflux in distilled water for 18 hours under an atmosphere of argon. The reaction mixture is concentrated under reduced pressure and the product is obtained by recrystallization from water and isopropanol.
Reaction SMILES: [P:1]([O-:40])([O:36][CH2:37][CH2:38]Br)([O:3][CH2:4][CH:5]([O:24][C:25]1[CH:29]=[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:27][N:26]=1)[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:2].[N:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[P:1]([O-:40])([O:36][CH2:37][CH2:38][N+:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([O:3][CH2:4][CH:5]([O:24][C:25]1[CH:29]=[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:27][N:26]=1)[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:2]
Reactant: CCCCCCCCCCCCCCCCOCC(COP(=O)([O-])OCCBr)Oc1cc(-c2ccccc2)on1
Reactant: c1ccncc1
Product: CCCCCCCCCCCCCCCCOCC(COP(=O)([O-])OCC[n+]1ccccc1)Oc1cc(-c2ccccc2)on1

Procedure:
0.875 g of the crude (2RS)-3-hexadecyloxy-2-(5-phenyl-3-isoxazolyloxy)propyl 2-bromoethyl phosphate obtained as described in the first part of Example 7 was reacted with pyridine in a similar manner to that described in Example 3 to afford 0.507 g of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]([N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16]C[CH2:14]1)=[O:12].CNC1C(C)=CC=CC=1>CCCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[C:6]([C:11]([N:13]([CH3:14])[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:16])=[O:12])=[CH:7][N:8]=[CH:9][CH:10]=1
Reactant: O=C(c1cnccc1Oc1cc(Cl)ccc1Cl)N1CCCc2ccccc21
Agent: CNc1ccccc1C
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Cc1ccccc1N(C)C(=O)c1cnccc1Oc1cc(Cl)ccc1Cl

Procedure:
The title compound was prepared in analogy to Example 1, from 4-(2,5-dichloro-phenoxy)-nicotinic acid (Example 1, intermediate) and N-methyl-o-toluidine (commercially available; CAS RN 611-21-2) and using a gradient of n-heptane:ethyl acetate (100:0 to 40:60). The compound was further purified through a second preparative HPLC chromatography (Phenomenex Gemini column) using a gradient of acetonitrile:water (containing 0.05% formic acid) (10:90 to 98:2). White solid (35%). MS (ESI): m/z=387.066 [M+H]+.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH3:7][O:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([CH:16]=O)=[CH:12][CH:11]=1.CCCCCC>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH:16]([C:13]1[CH:14]=[CH:15][C:10]([C:9]([O:8][CH3:7])=[O:18])=[CH:11][CH:12]=1)=[CH2:1]
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=Cc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 76.2 %

Procedure:
To a slurry of methyltriphenylphosphonium bromide (10.88 g, 30.46 mmol, 1 eq.) and potassium tert-butoxide (31 mL, 1 M solution in THF, 30.46 mmol, 1 eq.) in THF is added methyl-4-formylbenzoate (5.0 g, 30.46 mmol, 1 eq.). The bright yellow reaction mixture is stirred at room temperature for 5 hrs. Hexane is added and after stirring for 10 minutes, the mixture is filtered and washed twice with hexanes. Solvent is removed in vacuum and the crude oily residue is purified by silica gel chromatography (0-14% ethyl acetate/hexanes) to give 3.76 g of a white oily solid, methyl 4-vinylbenzoate (23.21 mmol, 76.2% yield). 1H NMR (300 MHz, CDCl3): δ 7.99 (2H, d, J=9 Hz), 7.45 (2H, d, J=9 Hz), 6.76 (1H, dd, J=17, 11 Hz), 5.86 (1H, d, J=17 Hz), 5.37 (1H, d, J=11 Hz), 3.91 (3H, s).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9](=[O:40])[C@H:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([C:26]#[C:27][Si](C)(C)C)[N:24]=3)[N:19]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:18]=2)=[O:16])[CH:11]2[CH2:13][CH2:12]2)[CH2:5][CH2:4]1)#[N:2].C([O-])([O-])=O.[K+].[K+]>CO>[C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9](=[O:40])[C@H:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([C:26]#[CH:27])[N:24]=3)[N:19]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:37])([CH3:39])[CH3:38])[CH:18]=2)=[O:16])[CH:11]2[CH2:12][CH2:13]2)[CH2:5][CH2:4]1)#[N:2]
Reactant: C[Si](C)(C)C#Cc1cnc2c(n1)c(C(=O)N[C@@H](C(=O)N1CCC(C#N)CC1)C1CC1)cn2COCC[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cnc2c(n1)c(C(=O)N[C@@H](C(=O)N1CCC(C#N)CC1)C1CC1)cn2COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
To a solution of 5-(2-trimethylsilanyl-ethoxymethyl)-2-trimethylsilanylethynyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide (400 mg, 0.69 mmol) in MeOH (8 mL) at room temp was added K2CO3 (10 mg, 0.072 mmol). The reaction mixture was stirred at room temp for 30 min then concentrated. The residue was dissolved in CH2Cl2 and washed with water. The organic layer was dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (50% to 100% EtOAc/hexanes) to afford 310 mg (89%) of 2-ethynyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide as a light brown foamy solid. NMR showed a trace of 5-Cl pyrrolopyrazine present.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][N:20]4[C:28]5[C:23](=[CH:24][C:25]([C:29]([O:31]C)=[O:30])=[CH:26][CH:27]=5)[C:22]([C:33]#[N:34])=[CH:21]4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O.Cl>CO>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][N:20]4[C:28]5[C:23](=[CH:24][C:25]([C:29]([OH:31])=[O:30])=[CH:26][CH:27]=5)[C:22]([C:33]#[N:34])=[CH:21]4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc2c(c1)c(C#N)cn2Cc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)c1csc(-c2cc3cc(Cn4cc(C#N)c5cc(C(=O)O)ccc54)ccc3o2)n1

Procedure:
A mixture of methyl 1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}-3-cyanoindole-5-carboxylate (1.09 g) and sodium hydroxide (1.5 g) in a mixed solvent of water (15 ml) and methanol (30 ml) was stirred under reflux for 2 hours. After cooling, the mixture was made acidic with diluted hydrochloric acid, and the resulting precipitates were collected by filtration and washed with water to give 1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}-3-cyanoindole-5-carboxylic acid. Borane-methyl sulfide complex (2.0M) in tetrahydrofuran (1.4 ml) was added to a mixture of the acid obtained above in tetrahydrofuran (25 ml) and the mixture was stirred at room temperature for 1 day. After addition of methanol to mixture, the resulting mixture was evaporated under reduced pressure. The residue was partitioned between diluted hydrochloric acid and ethyl acetate. The ethyl acetate layer was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel and eluted with a mixture of toluene and ethyl acetate. The fractions containing the objective compounds were combined and concentrated under reduced pressure to give 1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}-5-(hydroxymethyl)indole-3-carbonitrile (0.87 g).