Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[CH:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([OH:16])=[O:15])[CH:12]=2)[C:7](=[O:17])[NH:6][C:5]1=[O:18].[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)[CH2:22][CH2:21]1>CN(C)C=O>[CH3:19][N:20]1[CH2:21][CH2:22][N:23]([C:26]2[CH:31]=[CH:30][C:29]([NH:32]/[CH:3]=[C:4]3\[C:5](=[O:18])[NH:6][C:7](=[O:17])[C:8]4[C:13]\3=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=4)=[CH:28][CH:27]=2)[CH2:24][CH2:25]1
Reactant: COC=C1C(=O)NC(=O)c2ccc(C(=O)O)cc21
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(C(=O)O)cc43)cc2)CC1
Temperature: 100 °C
Yield: 64.9 %

Procedure:
A mixture of 4-methoxymethylene-1,3-dioxo-1,2,3,4-tetrahydro-isoquinoline-6-carboxylic acid (90 mg, 0.364 mmol), 4-(4-methyl-piperazin-1-yl)-phenylamine (69.6 mg, 0.364 mmol) in 1 mL of N,N-dimethylformamide is heated at 100° C. for 1 h. After cooling in the refrigerator, the precipitate is collected, and washed with ether to give 96 mg (65%) of yellow solid mp 278-280° C.; HRMS (ESI) m/z calcd for C22H22N4O4 407.17139. found 407.17128 (M+H)+1, Analysis for C22H22N4O4, Calcd: C, 63.60; H, 5.58; N, 13.49. Found: C, 63.67; H, 5.98; N, 13.20.
Reaction SMILES: [CH2:1]([O:3][C:4]1[O:9][C:8](=[O:10])[C:7]2[C:11]([CH3:15])=[CH:12][CH:13]=[CH:14][C:6]=2[N:5]=1)[CH3:2].[O:16]1C2C=CC=CC=2CC(=O)N1>>[CH2:1]([O:3][C:4]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:7]=1[C:8]([OH:16])=[O:10])=[O:9])[CH3:2]
Reactant: CCOc1nc2cccc(C)c2c(=O)o1
Reactant: O=C1Cc2ccccc2ON1
Product: CCOC(=O)Nc1cccc(C)c1C(=O)O

Procedure:
By following the procedure of Part A, but replacing 2-ethoxy-5-methyl-4H-3,1-benzoxazin-4-one with the appropriate benzoxazinone prepared in Preparation III, the following compounds of Formula I are prepared:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]=O)[C:6](=[CH:10][CH:11]=1)[C:7]([OH:9])=[O:8].[S:14]1[CH2:20][C:18](=[O:19])[NH:17][C:15]1=[S:16].C(O)(=O)C.C([O-])(=O)C.[Na+]>O>[C:7]([C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH:12]=[C:20]1[S:14][C:15](=[S:16])[NH:17][C:18]1=[O:19])([OH:9])=[O:8]
Reactant: O=C1CSC(=S)N1
Reactant: COc1ccc(C(=O)O)c(C=O)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(C(=O)O)c(C=C2SC(=S)NC2=O)c1

Procedure:
To a stirred hot solution of 4.23 g. (23.5 mM) of 4-methoxyphthalaldehydic acid and 3.13 g. (23.5 mM) of rhodanine in 16.5 ml. of acetic acid is added 6.33 g. (77.2 mM) of anhydrous sodium acetate. The resulting hot solution is refluxed for 0.5 hour, whereupon a solid yellow mass forms. The mixture is cooled, poured into water, to yield 5-(2-carboxy-5-methoxybenzylidene)rhodanine.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4](S([O-])(=O)=O)=[CH:3][CH:2]=1.[Na+:17].[OH-:18].[Na+]>>[C:11]1([C:1]2[CH:6]=[CH:5][C:4]([O-:18])=[CH:3][CH:2]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Na+:17]
Reactant: [OH-]
Reactant: O=S(=O)([O-])c1ccc(-c2ccccc2)cc1
Agent: [Na+]
Product: [O-]c1ccc(-c2ccccc2)cc1

Procedure:
Sodium biphenyl-4-sulfonate is reacted with about 70% strength by weight NaOH to give sodium 4-phenylphenolate (about 320° C.; 16-26 bar), with the molar ratio of NaOH to biphenyl-4-sulfonate having to be about 10:1. The reaction mixture is diluted to a content of about 12% by weight of 4-hydroxybiphenyl by direct expansion at 320° C. to a water reservoir or by pumping water into the reaction mixture after prior cooling to 200° C. The resulting alkaline 4-hydroxybiphenyl sodium salt suspension is metered into a water reservoir simultaneously with roughly 50% strength by weight H2SO4 at 90° C. and a pH of 5.5. The resulting aqueous Na2SO3 /NaHSO3 -containing 4-hydroxybiphenyl suspension having a content of about 4.3% by weight of 4-hydroxybiphenyl is then heated at 130°-135° C. and about 2 bar for about 2 h, stirred cold at 10 K/h to 100° C. and then further to 60° C. The highly readily filtering coarsely crystalline product is isolated at 60° C. via a glass sinter vacuum filter and washed with water. A virtually colorless flowable non-thixotropic substantially Na2SO4 -free product having a drastically decreased water content of 10-20% by weight is obtained, in comparison with the highly thixotropic product containing 65-70% by weight of H2O obtained without the heating according to the invention.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O-].[Na+].Cl[C:12]1[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[N:13]=1>>[CH3:18][C:16]1[CH:17]=[C:12]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:13]=[C:14]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[N:15]=1
Reactant: Cc1ccc(-c2nc(C)cc(Cl)n2)cc1
Reactant: Oc1ccccc1
Agent: C[O-]
Agent: [Na+]
Product: Cc1ccc(-c2nc(C)cc(Oc3ccccc3)n2)cc1
Temperature: 160 °C
Reaction time: 3 h
Yield: 86.7 %

Procedure:
A mixture of 250 g of phenol and 29.7 g of sodium methylate is heated to an interval temperature of 160° C. while simultaneously distilling off methanol. The melt obtained is cooled to 120° C., then 109 g of 4-chloro-6-methyl-2-p-tolylpyrimidine are added and the mixture is stirred for 3 hours at 120° C. After cooling, excess phenol is removed with steam, and the residue is filtered with suction, washed with water and dried. Recrystallisation from methanol yields 119.4 g (86.5% of theory) of 4-methyl-6-phenoxy-2-p-tolylpyrimidine with a melting point of 90°-91° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[O-:21][C:22]#[N:23].[Na+]>>[C:22]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1)(=[O:21])[NH2:23]
Reactant: N#C[O-]
Reactant: COC(=O)[C@H](C)c1ccc(N)cc1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](C)c1ccc(NC(N)=O)cc1
Temperature: 25 °C
Yield: 55 %

Procedure:
To a solution of methyl (2R)-2-(4-aminophenyl)propanoate (3.0 g, 18.1 mmol) in toluene (50 ml) conc. H2SO4 (0.47 ml, 50 mmol) was slowly added. Then sodium cyanate (1.88 g, 28 mmol) was added to the suspension and the reaction mixture refluxed for 24 h. After cooling at room temperature, the mixture was washed with a saturated aqueous solution of NH4Cl (2×30 ml), dried over anhydrous Na2SO4 and evaporated under vacuum to give a crude that, after purification by flash chromatography (n-hexane/EtOAc 1:1) afforded the methyl (2R)-2-[4-(carbamoylamino)phenyl]propanoate (2.07 g, 9.95 mmol) as white solid (55%). 1H-NMR (CDCl3): δ 9.35 (bs, 1H, CONH), 7.45 (d, 2H, J=7 Hz), 7.25 (d, 2H, J=7 Hz), 6.55 (bs, 2H, CONH2), 3.75 (m, 1H), 1.50 (d, 3H, J=7 Hz).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C>[CH2:14]([O:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.8 %

Procedure:
To a suspension of NaH (0.395 g, 9.87 mmol, 60% in mineral oil) in DMF (20 mL) was added methyl 3-hydroxybenzoate (1.0 g, 6.58 mmol). After stirring for 15 min at room temperature, benzyl bromide (1.1 g, 6.58 mmol) was added. After stirring at room temperature for 3 h, the solution was partitioned between ethyl acetate and water. The organic layer was washed with water (2×75 mL), saturated aqueous sodium bicarbonate, and brine, then dried (MgSO4), filtered and concentrated to yield an off-white solid (1.013 g, 4.2 mmol). 1H NMR (400 MHz, CDCl3) δ 7.67 (m, 2H), 7.48-7.34 (m. 6H), 7.19 (m, 1H), 5.12 (s, 2H), 3.95 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([I:8])[C:3]=1[CH2:9][OH:10].[H-].[Na+].[CH2:13](Br)[CH:14]=[CH2:15]>C1COCC1>[CH2:15]([O:10][CH2:9][C:3]1[C:4]([I:8])=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[CH:14]=[CH2:13]
Reactant: OCc1c(F)cccc1I
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOCc1c(F)cccc1I
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (2-fluoro-6-iodophenyl)methanol (10 mmol) in 50 mL of THF was added NaH (12 mmol) in small portions at room temperature. After the addition, allylbromide (12 mmol) was added slowly via syringe. The reaction mixture was stirred 16 hours at room temperature. The resulting white heterogeneous mixture was quenched with water and then diluted with 100 mL of Et2O, followed by washing with water and brine. The organic layer was dried over MgSO4 and then concentrated to dryness in vacuo to offer 2.8 g of the title compound.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7]2[N:16]=[C:15]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH2:2]1.N1C=CC=CC=1.[C:36]1([CH2:42][C:43](Cl)=[O:44])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[C:36]1([CH2:42][C:43]([N:1]2[CH2:5][CH2:4][C@H:3]([NH:6][C:7]3[N:16]=[C:15]([N:17]4[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]4)[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[N:8]=3)[CH2:2]2)=[O:44])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(N[C@H]3CCNC3)nc3ccccc23)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCN(c2nc(N[C@H]3CCN(C(=O)Cc4ccccc4)C3)nc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.7 %

Procedure:
To a mixture of t-butyl 4-(2-((S)-pyrrolidin-3-ylamino)quinazolin-4-yl)piperazine-1-carboxylate (0.15 g), pyridine (60 mg), and chloroform was added phenylacetic acid chloride (87 mg), and the mixture was stirred at room temperature for 16 h. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate, the mixture was extracted with chloroform, and the organic layer was dried with anhydrous magnesium sulfate. The desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (NH silica gel, hexane/ethyl acetate=2:1−ethyl acetate) to obtain t-butyl 4-(2-((S)-1-(2-phenylethanoyl)pyrrolidin-3-ylamino)quinazolin-4-yl)piperazine-1-carboxylate (0.12 g). (2) To t-butyl 4-(2-((S)-1-(2-phenylethanoyl)pyrrolidin-3-ylamino)quinazolin-4-yl)piperazine-1-carboxylate (0.12 g) was added a mixed solution (7.5 mL) of chloroform and trifluoroacetic acid (10:1), and the mixture was stirred overnight at room temperature. To the reaction mixture was added 1 M aqueous sodium hydroxide, the mixture was extracted with chloroform, and the organic layer was dried with anhydrous magnesium sulfate. The desiccant was removed by filtration, then the solvent was evaporated, and the residue was purified by preparative TLC to obtain title compound (69 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([Sn](CCCC)(CCCC)CCCC)=[N:7][N:8]2[CH2:11][CH3:12])=[CH:4][CH:3]=1.[C:26]([CH:28]1[CH2:31][N:30]([C:32](=[O:56])[C@H:33]([NH:35][C:36]([C:38]2[C:46]3[C:41](=[N:42][CH:43]=[C:44](Br)[N:45]=3)[N:40]([CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[CH:39]=2)=[O:37])[CH3:34])[CH2:29]1)#[N:27]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[C:26]([CH:28]1[CH2:29][N:30]([C:32](=[O:56])[C@H:33]([NH:35][C:36]([C:38]2[C:46]3[C:41](=[N:42][CH:43]=[C:44]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=5)[N:8]([CH2:11][CH3:12])[N:7]=4)[N:45]=3)[N:40]([CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[CH:39]=2)=[O:37])[CH3:34])[CH2:31]1)#[N:27]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(CC)c2cc(Cl)ccc12
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(=O)N1CC(C#N)C1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCn1nc(-c2cnc3c(n2)c(C(=O)N[C@H](C)C(=O)N2CC(C#N)C2)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Temperature: 80 °C
Yield: 102.8 %

Procedure:
To a solution of 6-chloro-1-ethyl-3-tributylstannyl-1H-indazole (125 mg, 0.27 mmol) and 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (125 mg, 0.25 mmol) in DMF (1.5 mL) were added Pd(PPh3)4 (14 mg, 0.012 mmol) and copper(I) iodide (9 mg, 0.05 mmol). The yellow reaction mixture was purged with argon then heated at 80° C. for 0.5 h then cooled to room temperature, quenched with sat NH4Cl and extracted with EtOAc (2×). The combined organics were washed with sat LiCl and brine then dried over MgSO4 and concentrated. The crude residue was purified by silica gel chromatography with 50% to 100% EtOAc/heptane to isolate 156 mg of 2-(6-chloro-1-ethyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a viscous colorless oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([N:10]2[CH2:14][CH2:13][N:12]=[C:11]2SC)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:17][N:18]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[N:18]1([N:17]2[C:2]3[N:3]=[CH:4][CH:5]=[CH:6][C:7]=3[C:8](=[O:9])[N:10]3[CH2:14][CH2:13][N:12]=[C:11]23)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: NN1CCCCCC1
Reactant: CSC1=NCCN1C(=O)c1cccnc1Cl
Product: O=C1c2cccnc2N(N2CCCCCC2)C2=NCCN12
Temperature: 160 °C
Yield: 66.3 %

Procedure:
A mixture of 10.0 g (39.1 mmoles) of the product of Example 12 and 12.5 g (0.109 mole) of N-aminohomopiperidine was heated at 160° C. for 1 hour. Excess N-aminohomopiperidine was removed by Kugelrohr distillation and the residue was partitioned between methylene chloride and water. The organic layer was dried (sodium sulfate) and concentrated leaving 7.40 g of 10-(hexahydro-1H-azepin-1yl)-2,10-dihydroimidazo[1,2-a]pyrido[2,3-d]pyrimidin-5(3H)-one; melting point 217°-219° C. Total yield 66%.
Reaction SMILES: [Cl-].[OH:2][CH:3]([CH2:38][NH:39]C(OC(C)(C)C)=O)[CH2:4][N+:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][C:13]2[CH2:20][S:19][C@H:18]3[N:15]([C:16](=[O:34])[C@H:17]3[NH:21][C:22](=[O:33])[CH2:23][S:24][C:25]3[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=3[Cl:32])[C:14]=2[C:35]([OH:37])=[O:36])=[CH:7][CH:6]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl-:31].[OH:2][CH:3]([CH2:38][NH2:39])[CH2:4][N+:5]1[CH:6]=[CH:7][C:8]([S:11][CH2:12][C:13]2[CH2:20][S:19][C@H:18]3[N:15]([C:16](=[O:34])[C@H:17]3[NH:21][C:22](=[O:33])[CH2:23][S:24][C:25]3[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=3[Cl:32])[C:14]=2[C:35]([OH:37])=[O:36])=[CH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)NCC(O)C[n+]1ccc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)CSc4cc(Cl)ccc4Cl)[C@H]3SC2)cc1
Agent: [Cl-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: NCC(O)C[n+]1ccc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)CSc4cc(Cl)ccc4Cl)[C@H]3SC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 127.2 %

Procedure:
A slurry of 1-(2-hydroxy-3-t-butoxycarbonylamino-1-propyl)-4-[[(6R)trans-2-carboxy-8-oxo-7-[(2,5- dichlorophenylthio)acetamido]-5- thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridinium chloride (1.19 g, 1.58 mmol) in methylene chloride (22 mL) was cooled to 0° C. Anisole (3.4 mL) was added followed by trifluoroacetic acid (11 mL). The mixture was stirred for 30 min at 0° C. and 30 min at rt. The reaction mixture was concentrated in vacuo. The residue was stirred with ether until a yellow powder resulted. This solid was collected by filtration washing with ether. The crude product was stirred with ether (20 mL) for 45 min, and then the solid was collected by filtration. This was followed by similar treatments with acetone (1×10 mL) and then ether (1×20 mL). The final filtration gave 655 mg (54%) of the title compound as a yellow solid. 1H NMR (300 MHz, DMSO) δ2.80 (t, J=10, 1H), 3.06 (d, J=11, 1H), 3.31-3.44 (m, 1H), 3.60 (d, J=18, 1H), 3.90 (s, 2H), 4.10 (br s, 1H), 4.34-4.42 (m, 3H), 4.66 (d, J=12, 1H), 5.02 (d, J=5, 1H), 5.56 (t, J=6, 1H), 6.5-7.0 (br s, 1H), 7.21 (dd, J=2, 8, 1H), 7.41-7.46 (m, 2H), 8.12 (m, 2H), 8.30 (br s, 3H), 8.68 (m, 2H), 9.28 (m, 1H); MS (FIA) m/e 615 (MH+); Anal. calcd for C24H24 N4O5S3Cl2.HCl. HO2CCF3 : C, 40.71; H, 3.55; N, 7.30. Found: C, 40.70; H, 3.52; 7.38.
Reaction SMILES: CO[C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH2:19][CH2:20][CH2:21][CH3:22])=[N:14][O:15][C:16]=2[CH2:17][OH:18])=[N:6][CH:5]=1.[CH:24]([NH2:27])([CH3:26])[CH3:25].N12CCCNC1=NCCC2.ClCCl>C1(C)C=CC=CC=1>[CH2:19]([C:13]1[C:12]([CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([NH:27][CH:24]([CH3:26])[CH3:25])=[O:23])=[CH:5][N:6]=2)=[C:16]([CH2:17][OH:18])[O:15][N:14]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCc1noc(CO)c1COc1ccc(C(=O)OC)cn1
Reactant: CC(C)N
Agent: C1CN=C2NCCCN2C1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCCc1noc(CO)c1COc1ccc(C(=O)NC(C)C)cn1
Temperature: 50 °C
Reaction time: 84 h
Yield: 16.7 %

Procedure:
To a solution of 6-[3-butyl-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (100 mg, 0.31 mmol) in toluene (1 mL) was added isopropylamine (55 mg, 0.93 mmol) and 1,5,7-triazabicyclo[4.4.0]dec-5-ene (26 mg, 0.19 mmol). The reaction mixture was stirred for 3.5 days at 50° C. A further portion of isopropylamine was added and the reaction was heated at 50° C. for an additional 3.5 days. Dichloromethane (40 mL) was added and the reaction mixture was concentrated in vacuo onto silica gel and purified by chromatography (silica, dichloromethane:methanol 1:0 to 9:1) to afford the title compound (18 mg, 17%) as a colorless oil. MS: m/e=348.3 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[Cl-].[O:12]([C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=1)[CH:22]=[N+:23]([CH3:25])[CH3:24])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O(C1C=C(C=CC=1)C=O)C1C=CC=CC=1.CNC>>[CH3:24][N:23]([CH3:25])[CH:22]([C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[CH:3]=1)[C:21]1[CH:26]=[CH:27][CH:28]=[C:19]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:20]=1
Reactant: C[N+](C)=Cc1cccc(Oc2ccccc2)c1
Reactant: Cn1ccc2ccccc21
Agent: CNC
Agent: O=Cc1cccc(Oc2ccccc2)c1
Agent: [Cl-]
Product: CN(C)C(c1cccc(Oc2ccccc2)c1)c1cn(C)c2ccccc12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1-methyl-1H-indole and (3-phenoxy-benzylidene)-dimethylammonium chloride, which had been prepared in accordance with example 44 from 3-phenoxy-benzaldehyde and dimethylamine.
Reaction SMILES: C[O-].[Na+].[C:4]([NH:7][NH2:8])([NH2:6])=[NH:5].Cl.[Si]([O:17][CH2:18][C@@H:19]([N:28]1[CH:32]=[C:31]([C:33](OC)=O)[N:30]=[CH:29]1)[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(C(C)(C)C)(C)C>CO>[NH2:5][C:4]1[NH:7][N:8]=[C:33]([C:31]2[N:30]=[CH:29][N:28]([C@@H:19]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:18][OH:17])[CH:32]=2)[N:6]=1
Reactant: COC(=O)c1cn([C@@H](CCc2ccccc2)CO[Si](C)(C)C(C)(C)C)cn1
Reactant: N=C(N)NN
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Nc1nc(-c2cn([C@H](CO)CCc3ccccc3)cn2)n[nH]1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 35.8 %

Procedure:
A solution of 28% NaOMe in methanol (772 mg) was added to an ice cooled solution of aminoguanidine hydrochloride (332 mg) in methanol (5 ml). After 10 minutes, methyl (S)-1-[1-(tert-butyldimethylsilyloxy)-4-phenyl-2-butyl]-imidazole-4-carboxylate (obtained in Example 6) (389 mg) in methanol (2 ml) was added to the mixture and the resulting mixture was stirred at reflux for 22 hours. After cooling, the insoluble material was removed and then the filtrate was evaporated. The residue was diluted with water and the solution was acidified to pH 4 with 6N HClaq. The resulting mixture was washed with CHCl3. The aqueous layer was purified by HP-20 (50 cc) column chromatography eluting with water/2-propanol (9:1) and lyophilized to give (S)-2-[4-(5-amino-1,2,4-triazol-3-yl)-1-imidazolyl]-4-phenylbutan-1-ol (107 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[CH2:6]=[C:7]1[O:11][C:9](=[O:10])[CH2:8]1>O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:9](=[O:10])[CH2:8][C:7](=[O:11])[CH3:6]
Reactant: COCCN
Reactant: C=C1CC(=O)O1
Solvent: C1CCOC1
Product: COCCNC(=O)CC(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
33 ml (0.38 mol) methoxyethylamine were added dropwise to a solution of 30 g of diketene (0.36 mol) in 300 ml tetrahydrofuran at −5 to 0° C. After 1 h stirring at 0° C. no more starting material was detected by thin layer chromatography. The reaction mixture was evaporated and the residue purified by column chromatography. This gave 47.15 g (0.30 mol, 83% yield) of a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([C@H:13]([CH3:20])[C:14]([NH:16][CH:17]1[CH2:19][CH2:18]1)=[O:15])[C:7]2=[O:12].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C@H:28]([CH3:32])[C:29](O)=[O:30])=[CH:24][CH:23]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CN(C)C=O>C(Cl)Cl>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C@H:28]([CH3:32])[C:29]([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][N:6]([C@H:13]([CH3:20])[C:14]([NH:16][CH:17]2[CH2:19][CH2:18]2)=[O:15])[C:7]3=[O:12])=[O:30])=[CH:26][CH:27]=1
Reactant: C[C@H](C(=O)O)c1ccc(Cl)cc1
Reactant: C[C@H](C(=O)NC1CC1)n1ccc2c(N)cccc2c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](C(=O)Nc1cccc2c(=O)n([C@H](C)C(=O)NC3CC3)ccc12)c1ccc(Cl)cc1

Procedure:
(R)-2-(5-Amino-1-oxoisoquinolin-2(1H)-yl)-N-cyclopropylpropanamide (0.2 g, 0.0007 mol), (S)-2-(4-chlorophenyl)propanoic acid (0.16 g, 0.00088 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.33 g, 0.00088 mol), N,N-diisopropylethylamine (0.4 g, 0.003 mol) were stirred in N,N-dimethylformamide (3 mL, 0.04 mol) at room temperature over a weekend. The reaction mixture was diluted with CH2Cl2 (100 mL), washed with NaHCO3 (20 mL×3), dried over Na2SO4, purified via flash chromatography (12 g of silica gel, 0-90% EtOAc/Hexane) and then prep. HPLC gave a white solid. 1H NMR δ (CDCl3) δ: 8.23 (d, J=8.5 Hz, 1H), 7.95 (d, J=7.9 Hz, 1H), 7.52-7.39 (m, 5H), 7.22 (d, J=7.6 Hz, 1H), 7.09 (br, 1H), 6.44 (br, 1H), 6.06-6.03 (m, 1H), 5.58 (q, J=7.0 Hz, 1H), 3.83 (q, J=6.7 Hz, 1H), 2.63 (br, 1H), 1.64 (d, J=7.2 Hz, 3H), 1.56 (d, J=5.2 Hz, 3H), 0.78-0.67 (m, 2H), 0.51-0.40 (m, 2H). MS m/z 438.3 (M+H)+.
Reaction SMILES: [Cl:1]/[C:2](/[C:12]([F:15])([F:14])[F:13])=[CH:3]\[C@@H:4]1[C@H:6]([C:7]([OH:9])=[O:8])[C:5]1([CH3:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+].[Cl:22][C:23]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:24]=1[CH2:25]Br.CC(C)=O>C(OCC)C>[Cl:1]/[C:2](/[C:12]([F:13])([F:14])[F:15])=[CH:3]\[C@@H:4]1[C@H:6]([C:7]([O:9][CH2:25][C:24]2[CH:27]=[CH:28][C:29]([F:31])=[CH:30][C:23]=2[Cl:22])=[O:8])[C:5]1([CH3:11])[CH3:10]
Reactant: Fc1ccc(CBr)c(Cl)c1
Reactant: CC1(C)[C@H](/C=C(\Cl)C(F)(F)F)[C@@H]1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: CC1(C)[C@H](/C=C(\Cl)C(F)(F)F)[C@@H]1C(=O)OCc1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.1 %

Procedure:
A mixture of (±)-cis-3-(Z-2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-2,2-dimethylcyclopropane carboxylic acid (1.20 g), anhydrous potassium carbonate (2.0 g), 2-chloro-4-fluorobenzyl bromide (1.10 g), and dry acetone (30 ml) was stirred for a period of 2 hours at the ambient temperature (ca 25° C.) and kept at that temperature for a further 18 hours. After diluting the mixture with diethyl ether (300 ml) the resultant mixture was washed with dilute aqueous sodium carbonate solution and dried over anhydrous magnesium sulphate. The solvents were evaporated and the residual oil purified by preparative thick layer chromatography using silica gel plates and chloroform eluent, to give 2-chloro-4-fluorobenzyl(±)-cis-3-(Z-2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-2,2-dimethylcyclopropane carboxylate (1.31 g) as a colourless oil.