Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][PH:2](=[O:6])[O:3][CH2:4][CH3:5].C[Si](N[Si](C)(C)C)(C)C.[F:16][C:17](=[CH:23][CH3:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(Cl)Cl>[CH2:4]([O:3][P:2]([CH:23]([CH3:24])[CH:17]([F:16])[C:18]([O:20][CH2:21][CH3:22])=[O:19])([CH3:1])=[O:6])[CH3:5]
Reactant: CC=C(F)C(=O)OCC
Reactant: CCO[PH](C)=O
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: ClCCl
Product: CCOC(=O)C(F)C(C)P(C)(=O)OCC
Temperature: 25 °C
Reaction time: 96 h
Yield: 40.2 %

Procedure:
A mixture of ethyl (methyl)phosphinate (3.2 g, 30 mmol) and 1, 1,1,3,3,3-hexamethyldisilazane (4.8 g, 30 mmol) was heated to reflux for 2 h under an argon atmosphere. The mixture was cooled to room temperature and a diastereomeric mixture of ethyl 2-fluorobut-2-enoate (4.0 g, 30 mmol) was added. The reagents were heated to 70° C. for three days and then at room temperature for 4 days under an argon atmosphere. The mixture was diluted with methylene chloride (200 mL). The solution was washed with 1 N HCl (200 mL) and the aqueous solution extracted with methylene chloride (200 mL). The combined organic solutions were washed with saturated sodium chloride, dried over MgSO4, filtered and evaporated. The residue was purified by chromatography on a wet-packed silica gel column eluting with methylene chloride/methanol (99:1-97:3). The appropriate fractions were combined and evaporated to give 2.9 g (40%) of ethyl 3-[ethoxy(methyl)phosphoryl]-2-fluorobutanoate as a clear oil. 1H NMR (400 MHz, CDCl3) δ4.8-5.6 (m, 1H), 4.2-4.4 (m, 2H), 4.0-4.2 (m, 2H), 2.4-2.6 (m, 1H), 1.1-1.5 (m, 12H).
Reaction SMILES: [O:1]1[CH2:12][C@@H:2]1[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:13]([NH2:16])[CH:14]=[CH2:15]>>[CH2:13]([NH:16][CH2:12][C@@H:2]([OH:1])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:14]=[CH2:15]
Reactant: c1ccc(COC[C@H]2CO2)cc1
Reactant: C=CCN
Product: C=CCNC[C@@H](O)COCc1ccccc1
Temperature: 50 °C
Reaction time: 20 h
Yield: 100 %

Procedure:
A 22 L reactor was charged with (2R)-benzyl 2-epoxypropyl ether (0.7692 kg, 4.684 mol) T-internal 18-19C. Allylamine (3800 mL, 51 mol) was added at 18-19° C. and resultant mixture was heated to 50° C. After 20 h, the mixture was concentrated, azeotroped with MTBE (4 L×3) to give (R)-1-(allylamino)-3-(benzyloxy)propan-2-ol, 7 (ca. 1037 g, 4.684 mol, 100% yield assumed) as colorless oil.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH:5]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1)[CH2:6][NH:7][C:8]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)=[O:9])C.[OH-].[Na+]>C(O)C>[CH3:30][O:29][C:23]1[CH:22]=[C:21]([CH:5]([CH2:6][NH:7][C:8]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)=[O:9])[C:4]([OH:31])=[O:3])[CH:26]=[CH:25][C:24]=1[O:27][CH3:28]
Reactant: CCOC(=O)C(CNC(=O)Cc1ccc(OC)c(OC)c1)c1ccc(OC)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(CC(=O)NCC(C(=O)O)c2ccc(OC)c(OC)c2)cc1OC
Yield: 63.4 %

Procedure:
A mixture of 18.4 g of 2-(3,4-dimethoxyphenyl)-3-{{[(3,4-dimethoxyphenyl)methyl]carbonyl}amino}propanoic acid ethyl ester, 50 ml of ethanol, and 65 ml of 10% sodium hydroxide was refluxed for 2 hours, concentrated to remove ethanol, and diluted with water. The aqueous layer was washed with ethyl acetate, acidified with excess 6N hydrochloric acid, and the product was extracted with ethyl acetate, dried, and evaporated. Trituration of the residue with ether provided 10.9 g of insoluble 2-(3,4-dimethoxyphenyl)3-{{[(3,4-dimethoxyphenyl)methyl]carbonyl}amino}propanoic acid, mp 151°-153°. Crystallization from ethyl acetate gave the analytical sample, mp 150°-152°.
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[C:7]([C:8](Cl)=[O:9])=[CH:6][N:5]([CH3:11])[N:4]=1.[CH:13]1([CH:23]2[CH2:25][CH2:24]2)[CH2:15][CH:14]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH2:22]>C1(C)C=CC=CC=1>[CH:13]1([CH:23]2[CH2:25][CH2:24]2)[CH2:15][CH:14]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:8]([C:7]1[C:3]([CH:2]([F:12])[F:1])=[N:4][N:5]([CH3:11])[CH:6]=1)=[O:9]
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Reactant: Nc1ccccc1C1CC1C1CC1
Solvent: Cc1ccccc1
Product: Cn1cc(C(=O)Nc2ccccc2C2CC2C2CC2)c(C(F)F)n1
Temperature: 85 °C
Reaction time: 0.75 h

Procedure:
16.7 g (0.086 mol, 98% pure) of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride were dissolved at 25° C. in 48.0 g of toluene. The solution was evacuated to 400 mbar and heated to 85° C. Subsequently, within 45 min, 15.0 g (0.087 mol) of 2-bicyclopropyl-2-ylphenylamine, dissolved in 51.6 g of toluene, were metered in and the reaction mixture was stirred for another 1 h. After venting and cooling to 25° C., the mixture was stirred overnight. Subsequently, the mixture was concentrated under reduced pressure and dried. The yield was 27.3 g (96%).
Reaction SMILES: F[C:2]1[C:7]2[N:8]=[CH:9][N:10]([C@@H:11]3[CH2:15][C@H:14]([OH:16])[CH:13]=[CH:12]3)[C:6]=2[C:5]([F:17])=[CH:4][N:3]=1.[NH3:18]>>[NH2:18][C:2]1[C:7]2[N:8]=[CH:9][N:10]([C@@H:11]3[CH2:15][C@H:14]([OH:16])[CH:13]=[CH:12]3)[C:6]=2[C:5]([F:17])=[CH:4][N:3]=1
Reactant: O[C@@H]1C=C[C@H](n2cnc3c(F)ncc(F)c32)C1
Reactant: N
Product: Nc1ncc(F)c2c1ncn2[C@H]1C=C[C@@H](O)C1
Temperature: 100 °C

Procedure:
Liquid ammonia (100 mL) was added to (1S,4R)-4-(4,7-difluoro-1H-imidazo[4,5-c]pyridin-1-yl)cyclopent-2-enol (3-2) (220 mg, 0.6 mmol, 1 equiv). The resulting solution was heated in a high pressure vessel to 100° C. for 3 days. The mixture was then concentrated and purified via reverse phase chromatography (5-95% CH3CN/water with 0.1% TFA modifier) to yield (1S,4R)-4-(4-amino-7-fluoro-1H-imidazo[4,5-c]pyridin-1-yl)cyclopent-2-enol (3-3) as a white solid. LRMS m/z (M+H) 235.0 found, 235.1 required.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([N:21]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=3)[OH:22])=[O:20])=[CH:14][CH:13]=1)[CH:7]=[CH:6]2.[C:34](OC(=O)C)(=[O:36])[CH3:35]>>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([N:21]([OH:22])[C:19](=[O:20])[NH:18][C:15]2[CH:14]=[CH:13][C:12]([N:8]3[C:9]4[C:5](=[CH:4][C:3]([NH:2][C:34](=[O:36])[CH3:35])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)=[CH:17][CH:16]=2)=[CH:24][C:25]=1[C:30]([F:33])([F:32])[F:31]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2c(ccn2-c2ccc(NC(=O)N(O)c3ccc(Cl)c(C(F)(F)F)c3)cc2)c1
Agent: Cl
Product: CC(=O)Nc1ccc2c(ccn2-c2ccc(NC(=O)N(O)c3ccc(Cl)c(C(F)(F)F)c3)cc2)c1

Procedure:
The title compound can be synthesized from 1-[4-(5-aminoindol-1-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)-3-hydroxyurea hydrochloride and acetic anhydride by using the same techniques as in Example 41.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10]/[C:11](=[C:18]2\[C:19](=[O:30])[NH:20][C:21]3[C:26]\2=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.[CH:31](=O)[CH2:32][CH3:33].C([BH3-])#N.[Na+]>CO>[CH2:31]([NH:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10]/[C:11](=[C:18]2\[C:19](=[O:30])[NH:20][C:21]3[C:26]\2=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)/[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:8][CH:9]=1)[CH2:32][CH3:33]
Reactant: NCc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1
Reactant: CCC=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCNCc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 159 from (Z)-3-[1-(4-aminomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone-hydrochloride, propionaldehyde and sodium cyanoborohydride in methanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:14])[CH:10]2[CH3:13])=[CH:5][CH:4]=1.Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:14])[C:10]2([CH3:13])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5][CH:4]=1
Reactant: CCOC(=O)CBr
Reactant: COc1ccc2c(c1)C(C)C(=O)CC2
Product: CCOC(=O)CC1(C)C(=O)CCc2ccc(OC)cc21

Procedure:
The compound 3,4-dihydro-7-methoxy-1-methyl-2(1H)-naphthalenone (VIIIb) (28.23 g, 148 mmol) was reacted with ethyl bromoacetate by the method of Example 5 to yield 36.0 g (88%) (IXb) b.p. 138°-140°/0.1 mm Hg; IR (neat) 1740 cm-1 (unresolved ketone and ester bands); NMR δ, 1.05 and 3.93 (triplet and quartet for CO2CH2CH3), 1.37 (s, 3, CH3), 3.80 (s, 3, OCH3), 6.6-7.3 (m, 3, ArH). The distillate crystallized on standing. A sample recrystallized from ethanol melted at 55°-55.55°.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.[CH3:12][S:13][CH3:14].ClN1C(=O)CCC1=O>C(Cl)Cl>[CH3:12][S:13]([CH3:14])=[N:1][C:2]1[N:3]=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([O:8][CH3:9])[N:7]=1
Reactant: COc1cc(OC)nc(N)n1
Reactant: CSC
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: COc1cc(OC)nc(N=S(C)C)n1
Temperature: -20 °C
Reaction time: 2 h
Yield: 27.9 %

Procedure:
To a solution of 15.5 g (0.10 mole) of 2-amino-4,6-dimethoxypyrimidine and 8 ml (0.109 mole) of methylsulfide in 100 ml of methylene chloride at -20° C. was added dropwise a solution of 13.3 g (0.10 mole) of N-chlorosuccinimide in 300 ml of methylene chloride. After addition, the resulting solution stirred at -20° C. for 2 hours and then warmed up to room temperature. The solution was stirred at room temperature for another hour. The solution was washed with 400 ml of 2.5% sodium hydroxide aqueous solution and then 400 ml of water. The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure. The residue was washed with ethyl ether, and dried under vacuum at ambient temperature to afford 6 g of the title compound as a solid, m.p. 102°-103° C. (dec.).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2B(O)O)[CH:4]=[CH:3][CH:2]=1.Br[C:15]1[CH:16]=[CH:17][C:18]([CH3:40])=[C:19]([NH:21][C:22](=[O:39])[CH2:23][O:24][CH2:25][C:26]([NH:28][C:29]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:30]=2[C:31]([OH:33])=[O:32])=[O:27])[CH:20]=1>>[Cl:38][C:35]1[CH:36]=[CH:37][C:29]([NH:28][C:26](=[O:27])[CH2:25][O:24][CH2:23][C:22]([NH:21][C:19]2[CH:20]=[C:15]([C:9]3[CH:8]=[CH:7][CH:6]=[C:5]4[C:10]=3[N:1]=[CH:2][CH:3]=[CH:4]4)[CH:16]=[CH:17][C:18]=2[CH3:40])=[O:39])=[C:30]([CH:34]=1)[C:31]([OH:33])=[O:32]
Reactant: Cc1ccc(Br)cc1NC(=O)COCC(=O)Nc1ccc(Cl)cc1C(=O)O
Reactant: OB(O)c1cccc2cccnc12
Product: Cc1ccc(-c2cccc3cccnc23)cc1NC(=O)COCC(=O)Nc1ccc(Cl)cc1C(=O)O

Procedure:
Using the same method as in Example 19-(ii), 8-quinoline boronic acid was reacted with the 2-[((2-[(5-bromo-2-methylphenyl)amino]-2-oxoethoxy)acetyl)amino]-5-chlorobenzoic acid.methyl ester obtained in Example 38-(i) to give 5-chloro-2-([(2-([2-methyl-5-(quinolin-8-yl)phenyl]amino)-2-oxoethoxy)acetyl]amino)benzoic acid.methyl ester (yield: 53%).
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][C:4]#[CH:5].[CH:7](/Br)=[CH:8]\[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(NCC)C>[C:9]1(/[CH:8]=[CH:7]/[C:5]#[C:4][CH2:3][CH2:2][CH2:1][OH:6])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Br/C=C/c1ccccc1
Reactant: C#CCCCO
Solvent: CCNCC
Product: OCCCC#C/C=C/c1ccccc1
Reaction time: 16 h
Yield: 87.1 %

Procedure:
Cuprous iodide (0.4 g, 2.1 mmol) and bis-triphenylphosphine palladium (II) chloride (0.8 g, 1.14 mmol) were added to a solution of pent-4-yn-1-ol (16 g, 193 mmol) (Jones, Eglinton, and Whiting, Org. Syn. Coll., 4, 755, (1963)) and E-styryl bromide (34.34 g, 188 mmol) (Feurerstein and Heimann, Ber., 34, 1468 (1901)) in anhydrous diethylamine (250 m). The whole was stirred under an atmosphere of dry nitrogen with the exclusion of moisture and light for 16 hours. The diethylamine was removed at reduced pressure and the residue diluted with water (500 ml). The aqueous mixture was extracted with ether. The ethereal extracts were passed down a column composed of silica (100 g), Celite (trade name, from Koch-light Ltd) (100 g) and activated charcoal (20 g) at 3 psi (21 KPa) pressure. The column was washed with ether (200 ml) and the combined organic extracts dried over anhydrous magensium sulphate. Removal of solvents gave 30.5 g of 7-phenyl-hept-4-yn-6E-en-1-ol as a pale brown oil. The material was not purified further.
Reaction SMILES: [Br:1][C:2]([OH:12])([CH3:11])[CH2:3][CH2:4][CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].N1C=CN=C1>CN(C=O)C.CN(C1C=CN=CC=1)C>[Br:1][C:2]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])([CH3:11])[CH2:3][CH2:4][CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(O)(Br)CCC1CCC(=O)N1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(Br)(CCC1CCC(=O)N1)O[Si](C)(C)C(C)(C)C
Reaction time: 24 h
Yield: 98.4 %

Procedure:
To a solution of 5-(3-bromo-3-hydroxy-butyl)-pyrrolidin-2-one (6.76 g, 21.6 mmol) in DMF (86 mL) was added tert-butyldimethylsilyl chloride (3.59 g, 23.8 mmol) followed by imidazole (2.95 g, 43.3 mmol) and DMAP (264 mg, 2.16 mmol). The reaction was stirred for 24 h and was quenched with saturated aqueous ammonium chloride. The aqueous solution was washed with EtOAc (3×) and the combined organic extracts were dried (MgSO4), filtered, and concentrated. Purification by medium pressure chromatography using a solvent gradient (CH2Cl2 to 1% MeOH in CH2Cl2 to 3% MeOH in CH2Cl2 to 5% MeOH in CH2Cl2 to 8% MeOH in CH2Cl2) provided 5-[3-bromo-3-(tert-butyl-dimethyl-silanyloxy)-butyl]-pyrrolidin-2-one (7.45 g). 1H NMR (CDCl3) δ7.30 (m, 2H), 7.12 (m, 1H), 7.04 (m, 1H), 5.71 (m, 1H), 3.81 (m, 1H), 3.56 (m, 1H), 2.66 (m, 2H), 2.32-2.17 (m, 3H), 1.70-1.35 (m, 5H), 0.82 (s, 9H), −0.06 (d, 3H), −0.24 (d, 3H); MS 426.2, 428.2 (M+).
Reaction SMILES: Br/[CH:2]=[CH:3]/[C@H:4]([OH:14])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.C(NCC)C.[CH:20](/[C@H:26]1[O:30][C:29]([CH3:32])([CH3:31])[O:28][C@H:27]1[CH2:33][O:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])=[CH:21]\[CH:22]=[CH:23]\[C:24]#[CH:25]>C1COCC1.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>[OH:14][C@H:4]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)/[CH:3]=[CH:2]/[C:25]#[C:24]/[CH:23]=[CH:22]/[CH:21]=[CH:20]/[C@H:26]1[O:30][C:29]([CH3:32])([CH3:31])[O:28][C@H:27]1[CH2:33][O:34][CH2:35][C:36]([O:38][CH3:39])=[O:37]
Reactant: O[C@@H](/C=C/Br)COc1ccc(F)cc1
Reactant: C#C/C=C/C=C/[C@H]1OC(C)(C)O[C@H]1COCC(=O)OC
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCNCC
Product: COC(=O)COC[C@@H]1OC(C)(C)O[C@@H]1/C=C/C=C/C#C/C=C/[C@H](O)COc1ccc(F)cc1
Reaction time: 4 h
Yield: 79.6 %

Procedure:
In a flame dried flask, a solution of (1E,3S)-1-bromo-4-(4-fluorophenoxy)-3-hydroxy-1-butene (0.84 g, 3 mmol), tetrakis(triphenylphosphine)palladium(0) (0.13 g, 0.2 mmol) and copper(I) iodide (60 mg, 0.3 mmol) in THF (50 mL) and diethylamine (5 mL, 48 mmol) was carefully deoxygenated by bubbling in argon gas for 45 minutes. The reaction was stirred as a solution of 2-[[(4S,5R)-5-[(1E,3E)-1,3-hexadien-5-ynyl]-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy]ethanoic acid, methyl ester, (0.9 g, 3.2 mmol) in THF (50 mL), which had been deoxygenated by bubbling in argon for 45 minutes, was added. After about 4 hours, the reaction was complete. The reaction mixture was diluted with hexane and filtered through a pad of silica gel and the silica gel was eluted with ether. The combined filtrates were concentrated to give an oil. Purification by chromatography using a 20-75% gradient of ether in hexane gave 1.1 g of 2-[[(4S,5R)-5-[(1E,3E,7E,9S)-9-hydroxy-10-(4-fluorophenoxy)-1,3,7-decatrien-5-ynyl]-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy]ethanoic acid, methyl ester, a compound of formula (EE), as an oil; 1H NMR (CDCl3) δ 1.37 (s, 3H), 1.5 (s, 3H), 3.52 (m, 2H), 3.75 (s, 3H), 3.83 (m, 2H), 4.13 (m, 2H), 4.44 (m, 1H), 5.74 (m, 1H), 5.76 (m, 2H), 6.05 (m, 1H), 6.17 (m, 1H), 6.29 (m, 1H), 6.58 (dd, 1H), 6.88 (m, 4H) ppm.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]([C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=2)[N:9]=1.S(=O)(=O)(O)O.[CH2:34](O)[CH3:35]>>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]([C:20]2[CH:21]=[CH:22][C:23]([C:24]([O:26][CH2:34][CH3:35])=[O:25])=[CH:27][CH:28]=2)[N:9]=1
Reactant: CCO
Reactant: O=C(O)c1ccc(-n2nc(-c3ccccc3O)nc2-c2ccccc2O)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(-n2nc(-c3ccccc3O)nc2-c2ccccc2O)cc1

Procedure:
10 g of 4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid (Example 5) and 0.5 ml of sulfuric acid are boiled under reflux for 20 h in 200 ml of ethanol. The crystals precipitating on cooling are crystallized from isopropanol/water. After drying, ethyl 4-[3,5-bis(2-hydroxy-phenyl)-[1,2,4]triazol-1-yl]benzoate is obtained as colorless crystals of m.p. 148-149° C.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]12[CH2:12][CH2:11][C:8]([C:13]([O:15][CH3:16])=[O:14])([CH2:9][CH2:10]1)[CH2:7][CH2:6]2)=O.C(Cl)(=O)C(Cl)=O.CN(C=O)C.[F:28][C:29]([F:42])([F:41])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]1NN=[N:38][N:37]=1>C(Cl)Cl>[CH3:1][N:2]1[C:36]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[C:29]([F:28])([F:42])[F:41])=[N:37][N:38]=[C:3]1[C:5]12[CH2:12][CH2:11][C:8]([C:13]([O:15][CH3:16])=[O:14])([CH2:9][CH2:10]1)[CH2:7][CH2:6]2
Reactant: CNC(=O)C12CCC(C(=O)OC)(CC1)CC2
Reactant: FC(F)(F)c1ccccc1-c1nnn[nH]1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)C12CCC(c3nnc(-c4ccccc4C(F)(F)F)n3C)(CC1)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Carboxylate 1-B (2.76 g, 12.3 mmol) was dissolved in methylene chloride (100 ml). Oxalyl chloride (2.0 M, 15.3 ml) was added to the resulting solution followed by DMF (0.19 ml, 2.45 mmol). The reaction mixture was then stirred at room temperature under a nitrogen atmosphere for 2 hours before it was concentrated and stripped from toluene 3 times. The residue was redissolved in toluene (100 ml), treated with 5-[2-(trifluoromethyl)phenyl]-1H-tetrazole (3.15 g, 14.7 mmol) and heated at 100° C. under nitrogen for 12 hours. The product, 1,2,4-triazole 1-C, which precipitated out of reaction mixture as the HCl salt, was dissolved in methylene chloride, washed twice with saturated aqueous sodium bicarbonate solution, dried (MgSO4) and stripped to yield 1-C as a white solid. MS (ESI+)=394.2 (M+1); 1H NMR (500 MHz, CDCl3): δ 2.00 (6H, m), 2.18 (6H, m), 3.48 (3H, s), 3.72 (3H, s), 7.51 (1H, m), 7.71 (2H, m), 7.85 (1H, m) ppm.
Reaction SMILES: [C:1]1([CH:7]2[O:12][CH2:11][CH:10]([C:13]([OH:15])=O)[CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.C(N(CC)C(C)C)(C)C.Cl.Cl.[N:50]1([C:56]2[CH:61]=[CH:60][C:59]([N:62]3[CH2:66][C@H:65]([CH2:67][O:68][C:69]4[CH:73]=[CH:72][O:71][N:70]=4)[O:64][C:63]3=[O:74])=[CH:58][C:57]=2[F:75])[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1>ClCCl>[C:1]1([CH:7]2[O:8][CH2:9][CH:10]([C:13]([N:53]3[CH2:52][CH2:51][N:50]([C:56]4[CH:61]=[CH:60][C:59]([N:62]5[CH2:66][C@H:65]([CH2:67][O:68][C:69]6[CH:73]=[CH:72][O:71][N:70]=6)[O:64][C:63]5=[O:74])=[CH:58][C:57]=4[F:75])[CH2:55][CH2:54]3)=[O:15])[CH2:11][O:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1O[C@@H](COc2ccon2)CN1c1ccc(N2CCNCC2)c(F)c1
Reactant: O=C(O)C1COC(c2ccccc2)OC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(C1COC(c2ccccc2)OC1)N1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)CC1
Reaction time: 1 h
Yield: 70 %

Procedure:
To a stirred solution of 2-phenyl-1,3-dioxan-5-ylcarboxylic acid (478 mg, 2.3 mmol) and N-hydroxysuccinimide (291 mg, 2.5 mmol) in anhydrous dichloromethane (25 ml) at 0° was added dicyclohexylcarbodiimide (522 mg, 2.5 mmol). After sitting 1 hour at 0°, N,N-diisopropylethylamine (623 mg, 4.8 mmol) was added, followed by 3-(4-(piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one dihydrochloride (1 g, 2.3 mmol) in portions over 5 minutes. The temperature was allowed to rise to ambient, and stirring continued for 3 hours. Solid was filtered off, washed with dichloromethane (2×20 ml), and the combined organics evaporated to dryness. The residue was purified by chromatography on a 20 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 10% MeOH in dichloromethane. Relevant fractions were combined and evaporated to give the required product (890 mg) as a mixture of cis and trans isomers.
Reaction SMILES: [ClH:1].[OH:2][CH2:3][CH2:4][NH:5][N:6]=[CH:7][NH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1.Cl.[C:19]([C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[C:28]([CH2:32][C:33](=[O:35])[NH2:34])=[C:27](O)[CH:26]=[CH:25]2)(=[NH:21])[NH2:20].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[ClH:1].[ClH:1].[OH:2][CH2:3][CH2:4][NH:5][N:6]=[CH:7][NH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([O:15][C:27]2[CH:26]=[CH:25][C:24]3[C:29](=[CH:30][CH:31]=[C:22]([C:19](=[NH:20])[NH2:21])[CH:23]=3)[C:28]=2[CH2:32][C:33](=[O:35])[NH2:34])=[O:14])=[CH:11][CH:10]=1
Reactant: O=C(O)c1ccc(NC=NNCCO)cc1
Reactant: N=C(N)c1ccc2c(CC(N)=O)c(O)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: N=C(N)c1ccc2c(CC(N)=O)c(OC(=O)c3ccc(NC=NNCCO)cc3)ccc2c1
Reaction time: 2 h
Yield: 114.3 %

Procedure:
20 Milliliters of 20% hydrous pyridine was added to 1.02 g of 4-[(2-hydroxyethyl)aminoiminomethylamino]benzoic acid.hydrochloride, 1.0 g of 6-amidino-1-carbamoylmethyl-2-naphthol.hydrochloride, 884 mg of DCC and 43.6 mg of DMAP, followed by stirring for 2 hours under cooling with ice and then 24 hours at room temperature. Thereafter, the same procedure as in Example 1 was carried out to obtain 1.17 g of the desired product.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]([CH2:31][C:32]1[CH:33]=[C:34]([CH:36]=[CH:37][CH:38]=1)[NH2:35])[CH3:30]>>[CH3:30][N:29]([CH2:31][C:32]1[CH:33]=[C:34]([CH:36]=[CH:37][CH:38]=1)[NH:35]/[C:17](=[C:6]1\[C:5](=[O:27])[NH:4][C:12]2[C:7]\1=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)/[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH3:28]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21)c1ccccc1
Reactant: CN(C)Cc1cccc(N)c1
Product: COc1cc2c(cc1OC)/C(=C(/Nc1cccc(CN(C)C)c1)c1ccccc1)C(=O)N2

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone and 3-(dimethylaminomethyl)-aniline
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[Cl:30][C:31]1[CH:36]=[C:35](B(O)O)[CH:34]=[CH:33][N:32]=1>>[Cl:30][C:31]1[CH:36]=[C:35]([N:11]2[C:12]3[C:17](=[CH:16][C:15]([O:19][CH:20]4[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]4)=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][C:2]([F:1])([F:29])[CH2:3][CH2:4]2)=[O:9])[CH:34]=[CH:33][N:32]=1
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2ccnc(Cl)c2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 6, the title compound was synthesized from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (intermediate 1) and 2-chloropyridine-4-boronic acid. The title compound was obtained in 10% yield as light yellow foam. MS (m/e): 517.2 (MH+, 100%).