Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Li+].[Cl:3][C:4]1[CH:5]=[C:6]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH:7]=[C:8]([Cl:10])[CH:9]=1.[CH3:17][C:18]1[CH:19]=[C:20]([C:29](=[O:31])[CH3:30])[S:21][C:22]=1[C:23]#[C:24][Si:25]([CH3:28])([CH3:27])[CH3:26].CC(OC)(C)C>C1COCC1>[Cl:3][C:4]1[CH:5]=[C:6]([C:11]([OH:16])([C:12]([F:13])([F:14])[F:15])[CH2:30][C:29]([C:20]2[S:21][C:22]([C:23]#[C:24][Si:25]([CH3:28])([CH3:26])[CH3:27])=[C:18]([CH3:17])[CH:19]=2)=[O:31])[CH:7]=[C:8]([Cl:10])[CH:9]=1
Reactant: O=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: CC(=O)c1cc(C)c(C#C[Si](C)(C)C)s1
Agent: [H-]
Agent: [Li+]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: Cc1cc(C(=O)CC(O)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)sc1C#C[Si](C)(C)C
Reaction time: 0.5 h
Yield: 56.1 %

Procedure:
LiH (1.72 g) is added to a solution of 3′,5′-dichloro-2,2,2-trifluoroacetophenone (26.6 g) and 1-(4-methyl-5-trimethylsilanylethynyl-thiophen-2-yl)-ethanone (18.2 g) in THF (100 ml). After 30 minutes at 60° C. MTBE is added (200 ml) and the reaction mixture is poured onto water (30 ml) at 5° C. The organic phase is extracted with water and a saturated aqueous solution of NaCl, dried over Na2SO4 and concentrated in vacuo to yield 3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-3-hydroxy-1-(4-methyl-5-trimethylsilanylethynyl-thiophen-2-yl)-butan-1-one (20.7 g). The crude product is used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=O.[CH3:13][NH:14][C@H:15]1[CH2:34][N:19]2[C:20]3[C:25]([C:26]([CH2:27][C:28]([O:30]CCC)=[O:29])=[C:18]2[CH2:17][CH2:16]1)=[CH:24][CH:23]=[CH:22][CH:21]=3>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([N:14]([CH3:13])[C@H:15]1[CH2:34][N:19]2[C:20]3[C:25]([C:26]([CH2:27][C:28]([OH:30])=[O:29])=[C:18]2[CH2:17][CH2:16]1)=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:12]
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Reactant: O=C(O)Cc1ccc(F)cc1Br
Product: CN(C(=O)Cc1ccc(F)cc1Br)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from (2-bromo-4-fluorophenyl)acetic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 473.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[CH:18][CH2:19][CH3:20])[C:15]([OH:17])=O)[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CS(Cl)(=O)=O.[NH2:26][C@@H:27]1[C:56](=[O:57])[N:29]2[C:30]([C:40]([O:42][CH:43]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:41])=[C:31]([CH2:34][O:35][C:36](=[O:39])[NH:37][CH3:38])[CH2:32][S:33][C@H:28]12.CN1CCOCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl.C(N(CC)CC)C>[C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[CH:18][CH2:19][CH3:20])[C:15]([NH:26][C@@H:27]2[C:56](=[O:57])[N:29]3[C:30]([C:40]([O:42][CH:43]([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)=[O:41])=[C:31]([CH2:34][O:35][C:36](=[O:39])[NH:37][CH3:38])[CH2:32][S:33][C@H:28]23)=[O:17])[N:13]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CNC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CCC=C(C(=O)O)c1csc(NC(=O)OC(C)(C)C)n1
Agent: CS(=O)(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CCN(CC)CC
Product: CCC=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COC(=O)NC)CS[C@H]12)c1csc(NC(=O)OC(C)(C)C)n1
Temperature: -65 °C
Reaction time: 3 h
Yield: 85.3 %

Procedure:
To a solution of 2-(2-tert-butoxycarbonylaminothiazol-4-yl)-2-pentenoic acid (1.49 g) in dichloromethane (60 ml) are added triethylamine (0.83 ml) and methanesulfonyl chloride (0.4 ml) at -65° C., and the mixture is stirred for 3 hours at -65° C. To the mixture is added diphenylmethyl 7β-amino-3-methylcarbamoyloxymethyl-3-cephem-4-carboxylate (2.26 g) and N-methylmorpholine (0.55 ml) in dichloromethane (60 ml). After 2 hours, the reaction mixture is neutralized with 10% citric acid, washed with water, dried, and concentrated to give diphenylmethyl 7β-[2-(2-tert-butoxycarbonylaminothiazol-4-yl)-2-pentenoylamino]-3-methylcarbamoyloxymethyl-3-cephem-4-carboxylate (3.12 g). Yield: 85%.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.[NH2:10][CH2:11][C@@H:12]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>CN(C)C=O.C(N(C(C)C)CC)(C)C>[CH3:30][C:27]([O:26][C:24](=[O:25])[C@H:12]([CH2:11][NH:10][C:2]1[C:7]([CH3:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1)[NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)[C@H](CN)NC(=O)OCc1ccccc1
Reactant: Cc1c(Cl)ncnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c(Cl)ncnc1NC[C@H](NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 120 °C
Yield: 53.5 %

Procedure:
A mixture of 325 mg (2 mmoles) of 4,6-dichloro-5-methyl-pyrimidine (marketed by SPECS), 600 mg (2 mmoles) of (1,1-dimethylethyl) 3-amino-N-[(phenylmethoxy)carbonyl]alaninate (prepared according to J. Med. Chem. (2001), 44(8), 1158-1176) in 3 ml of dimethylformamide and 3 ml of diisopropylethylamine is heated at 120° C. overnight. The reaction medium is concentrated to dryness under vacuum and the residue is taken up in a mixture of water, ethyl acetate and a saturated solution of sodium bicarbonate. The organic phase is separated and the aqueous phase reextracted with ethyl acetate. The combined organic phases are dried over magnesium sulphate then the solvent is evaporated off under vacuum. The residue is chromatographed on silicagel eluting with a gradient of heptane (100%) to a mixture of heptane-ethyl acetate (50-50). 450 mg (Yield=53%) of expected product is obtained in the form of an oil.
Reaction SMILES: [OH:1][CH:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[C:5](=[O:19])[N:4]([C:20]2[CH2:21][O:22][C:23](=[O:26])[C:24]=2[CH3:25])[CH2:3]1.I[CH3:28].[Al]>C(#N)C.[Ag]=O>[CH3:28][O:1][CH:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:8][CH2:7]2)[C:5](=[O:19])[N:4]([C:20]2[CH2:21][O:22][C:23](=[O:26])[C:24]=2[CH3:25])[CH2:3]1
Reactant: CC1=C(N2CC(O)C3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)COC1=O
Reactant: CI
Agent: O=[Ag]
Agent: [Al]
Solvent: CC#N
Product: COC1CN(C2=C(C)C(=O)OC2)C(=O)C12CCN(C(=O)OC(C)(C)C)CC2
Temperature: 58 °C
Reaction time: 15 h

Procedure:
To a solution of tert-butyl 4-hydroxy-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (100 mg, 0.273 mmol) in acetonitrile (1 mL) was added iodomethane (171 μL, 2.73 mmol) and silver oxide (69.6 mg, 0.300 mmol). The vial was sealed, wrapped with aluminum foil, and stirred at 58° C. for 15 h. The reaction mixture was filtered through CELITE®, concentrated to give the crude product, which was purified by column chromatography (0-10% MeOH/DCM) to afford the title compound as a mixture of enantiomers. LC/MS: [(M+1)]+=381. The racemic mixture was separated by SFC-HPLC, using the following conditions: chiralcel AD-H, 2×25 cm, 15% MeOH, 60 mL/min to afford faster eluting Enantiomer A: LC/MS: [(M+1)]+=381; and slower eluting Enantiomer B: LC/MS: [(M+1)]+=381
Reaction SMILES: [CH:1]([N:4]([CH:19]([CH3:21])[CH3:20])[C:5]([C:7]1[CH:12]=[CH:11][N:10]=[C:9]([O:13][CH2:14][CH3:15])[C:8]=1B(O)O)=[O:6])([CH3:3])[CH3:2].I[C:23]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:24]=1[NH2:25].C(=O)([O-])[O-].[Na+].[Na+]>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>[NH2:25][C:24]1[CH:23]=[CH:29][C:28]([F:30])=[CH:27][C:26]=1[C:8]1[C:9]([O:13][CH2:14][CH3:15])=[N:10][CH:11]=[CH:12][C:7]=1[C:5]([N:4]([CH:19]([CH3:21])[CH3:20])[CH:1]([CH3:3])[CH3:2])=[O:6]
Reactant: CCOc1nccc(C(=O)N(C(C)C)C(C)C)c1B(O)O
Reactant: Nc1ccc(F)cc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1nccc(C(=O)N(C(C)C)C(C)C)c1-c1cc(F)ccc1N
Temperature: 100 °C

Procedure:
To a solution of {4-[(diisopropylamino)carbonyl]-2-ethoxypyridin-3-yl}boronic acid (8.19 g, 27.8 mmol) in THF (45 mL), were added 2-iodo-4-fluoro-aniline (3 g, 12.7 mmol), sodium carbonate (2.0 M, 10 mL), and tetrakis(triphenylphosphine)palladium (2.93 g, 2.53 mmol). The solution was degassed by bubbling nitrogen through the flask and subsequently heated to 100° C. for 2 hr. The solution was cooled and worked up with EtOAc and water, dried over MgSO4, filtered, and concentrated. Column chromatography on silica gel (100% hexanes to 100% EtOAc) provided the title product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:17])[CH:15]=[CH2:16])=[CH:4][CH:3]=1.[CH2:18]([O:20][C:21]([C:23]1([C:26]2[CH:31]=[CH:30][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:28][CH:27]=2)[CH2:25][CH2:24]1)=[O:22])[CH3:19]>>[CH2:18]([O:20][C:21]([C:23]1([C:26]2[CH:31]=[CH:30][C:29]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:17])[CH:15]=[CH2:16])=[CH:4][CH:3]=3)=[CH:28][CH:27]=2)[CH2:24][CH2:25]1)=[O:22])[CH3:19]
Reactant: C=CC(O)c1c(C)noc1-c1ccc(Br)cc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: C=CC(O)c1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)OCC)CC3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-prop-2-en-1-ol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: S(=O)(=O)(O)O.[P:6]([CH2:10][N:11](CC(O)=O)[CH2:12][C:13]([OH:15])=[O:14])([OH:9])([OH:8])=[O:7].OO>O>[P:6]([CH2:10][NH:11][CH2:12][C:13]([OH:15])=[O:14])([OH:9])([OH:8])=[O:7]
Reactant: O=C(O)CN(CC(=O)O)CP(=O)(O)O
Agent: O=S(=O)(O)O
Agent: OO
Solvent: O
Product: O=C(O)CNCP(=O)(O)O
Temperature: 80 °C

Procedure:
Thirty-nine parts of water and 39 parts of concentrated sulfuric acid were charged into a suitable reaction vessel and then 20 parts of N-(phosphonomethyl) iminodiacetic acid added. The mixture was heated to 80°C. and then 277 parts of a 35% hydrogen peroxide solution was added over a period of from 61/2 to 7 hours while maintaining the temperature at 77°-81°C. During the addition of the hydrogen peroxide, additional N-(phosphonomethyl) iminodiacetic acid was added in 20 part increments over a 4 hour period. When visual observation showed the reaction mass was clear, that is, it contained no suspended solids, a sample was taken for nuclear magnetic resonance spectra analysis. The reaction was then continued to be heated at 80°C. with stirring until nuclear magnetic resonance spectra analysis showed that the reaction was essentially complete. The mixture was then cooled at 0°C. overnight, centrifuged, washed with a small amount of water and dried under vacuum to yield approximately 100 parts of N-phosphonomethyl glycine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[C:13](=[CH:21]O)[C:14](=O)[CH2:15]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[NH2:24][C:25]([NH2:27])=[NH:26]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[C:13]2[CH:21]=[N:24][C:25]([NH2:27])=[N:26][C:14]=2[CH2:15]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: N=C(N)N
Reactant: O=C1CC2CCCC(C1=CO)N2S(=O)(=O)c1ccc(Cl)cc1
Agent: Cl
Product: Nc1ncc2c(n1)CC1CCCC2N1S(=O)(=O)c1ccc(Cl)cc1

Procedure:
Prepared as described in Example 5 using 9-(4-chlorophenylsulfonyl)-2-(hydroxymethylene)-9-azabicyclo[3.3.1]nonan-3-one which was prepared as described in Example 34 and guanidine hydrochloride. See also: Hasan, Mashooda; Rashid, Naghmana; Khan, Khalid Mohammed; Snatzke, Guenther; Duddeck, Helmut; Voelter, Wolfgang Liebigs Annalen 1995, (5), 889-96.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[N:6]([C:7]2[S:8][C:9]3[CH:15]=[C:14]([C:16]#[N:17])[CH:13]=[CH:12][C:10]=3[N:11]=2)[C@@H:5]2[CH2:18][CH2:19][CH2:20][CH2:21][C@H:4]2[O:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][C:2]1([CH3:22])[N:6]([C:7]2[S:8][C:9]3[CH:15]=[C:14]([CH2:16][NH2:17])[CH:13]=[CH:12][C:10]=3[N:11]=2)[C@@H:5]2[CH2:18][CH2:19][CH2:20][CH2:21][C@H:4]2[O:3]1
Reactant: CC1(C)O[C@@H]2CCCC[C@H]2N1c1nc2ccc(C#N)cc2s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)O[C@@H]2CCCC[C@H]2N1c1nc2ccc(CN)cc2s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 93.3 %

Procedure:
To a stirred mixture of 2-((3aR,7aR)-2,2-dimethylhexahydrobenzo[d]oxazol-3(2H)-yl)benzo[d]thiazole-6-carbonitrile (260 mg, 0.8 mmol) from Step 3 of this Example in THF (10 mL) at 0° C. was added LAH (3.3 mL of a 1M solution in THF, 3.3 mmol). The mixture was allowed to warm slowly to rt and stirred for 15 h. The mixture was again cooled to 0° C. and Na2SO4.10H2O was added slowly. The mixture was stirred for 2 h, filtered, and the filtrate was concentrated under reduced pressure to afford (2-((3aR,7aR)-2,2-dimethylhexahydrobenzo[d]oxazol-3(2H)-yl)benzo[d]thiazol-6-yl)methanamine (237 mg). The material was used in the next step without further purification. LCMS (ESI) m/z 318 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1/[CH:10]=[CH:11]\[C:12]([O:14][CH2:15][CH3:16])=[O:13].S(NN)(C1C=CC(C)=CC=1)(=O)=O.CC([O-])=O.[Na+].COCCOC>O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)/C=C\c1ccc(O)c(Cl)c1Cl
Agent: CC(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)NN)cc1
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)CCc1ccc(O)c(Cl)c1Cl
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed ethyl (2Z)-3-(2,3-dichloro-4-hydroxyphenyl)prop-2-enoate (270 mg, 1.03 mmol, 1.00 equiv), TsNHNH2 (193 mg, 1.04 mmol, 1.00 equiv), NaOAc (424 mg, 5.17 mmol, 5.00 equiv), ethylene glycol dimethyl ether (10 mL), water (1 mL). The resulting solution was stirred overnight at 80° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:3). This resulted in 150 mg (52%) of ethyl 3-(2,3-dichloro-4-hydroxyphenyl)propanoate as a red solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]([CH2:17]Cl)[C:9]2[C:4](=[CH:5][C:6]([Cl:21])=[C:7]([O:19][CH3:20])[CH:8]=2)[N:3]=1.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(OCC)(=O)C>O>[Cl:1][C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]([CH2:17][N:26]2[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]2)[C:9]2[C:4](=[CH:5][C:6]([Cl:21])=[C:7]([O:19][CH3:20])[CH:8]=2)[N:3]=1
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1c(Cl)nc2cc(Cl)c(OC)cc2c1CCl
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1c(Cl)nc2cc(Cl)c(OC)cc2c1CN1CCN(C)CC1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 81.2 %

Procedure:
A mixture of ethyl 2,7-dichloro-4-(chloromethyl)-6-methoxy-3-quinolinecarboxylate (6.9 g, 20 mmol) and N-methylpiperazine (9 ml, 80 mmol) is heated to 60° C. for 30 min. The reaction mass is diluted with water and extraction is carried out with ethyl acetate. After decanting, the organic phase is washed with water, followed by drying over magnesium sulphate, filtering and evaporating under reduced pressure. The residue is taken up in water, agitated for 15 minutes, filtered, washed with water and dried under vacuum. The residue is purified by column chromatography (SiO2, MeOH/CH2Cl2: 5/95 to 8/92). 6.7 g of product, a beige solid, is obtained.
Reaction SMILES: [Cl-].[F:2][C:3]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:4]=1[O:5][CH2:6][C@@H:7]([OH:11])[C@@H:8]([NH3+:10])[CH3:9].[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:32]3[C:27](=[CH:28][C:29](I)=[CH:30][CH:31]=3)[CH:26]=[N:25]2)=[CH:20][CH:19]=1>>[F:2][C:3]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:4]=1[O:5][CH2:6][C@@H:7]([O:11][C:29]1[CH:28]=[C:27]2[C:32](=[CH:31][CH:30]=1)[N:24]([C:21]1[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=1)[N:25]=[CH:26]2)[C@@H:8]([NH2:10])[CH3:9]
Reactant: C[C@H]([NH3+])[C@H](O)COc1ccc(F)cc1F
Reactant: Fc1ccc(-n2ncc3cc(I)ccc32)cc1
Agent: [Cl-]
Product: C[C@H](N)[C@@H](COc1ccc(F)cc1F)Oc1ccc2c(cnn2-c2ccc(F)cc2)c1

Procedure:
Prepared as described in Example 1a from (2S,3S)-4-(2,4-difluorophenoxy)-3-hydroxybutan-2-aminium chloride (290 mg, 1.14 mmol) and 1-(4-fluorophenyl)-5-iodo-1H-indazole (464 mg, 1.37 mmol). Yield: 90 mg (18%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21](Br)[CH:20]=2)([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([F:18])[F:17])=[CH:11][CH:10]=2)[N:3]=1.C(COC)OC.[CH:32]1(/[CH:35]=[CH:36]/B2OC(C)(C)C(C)(C)O2)[CH2:34][CH2:33]1.C([O-])([O-])=O.[Na+].[Na+]>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.O>[NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21](/[CH:36]=[CH:35]/[CH:32]3[CH2:34][CH2:33]3)[CH:20]=2)([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([F:18])[F:17])=[CH:11][CH:10]=2)[N:3]=1
Reactant: CC1(C)OB(/C=C/C2CC2)OC1(C)C
Reactant: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(Br)c2)N=C1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(/C=C/C3CC3)c2)N=C1N
Reaction time: 15 h
Yield: 68.5 %

Procedure:
A mixture of 2-amino-5-(3-bromophenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one (150 g, 0.36 mmol), dimethoxyethane, 2-[(E)-2-cyclopropylvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (105 mg) and Na2CO3 (2 M, 2.5 mL) was degassed under argon for 5 minutes and treated with tetrakis(triphenylphosphine)palladium(0) (21 mg, 0.018 mmol). The reaction mixture was stirred for 15 hour, poured into water and extracted with ethyl acetate. The extracts were combined, dried over MgSO4 and concentrated in vacuo. Purification of the resultant residue by ICSO (EtOAc/MeOH 10/1) gave the title product as a white solid (98 mg), identified by NMR and mass spectral analyses.
Reaction SMILES: [K].C(OC([C:8]1[CH2:9][N:10]([C:15]2[O:16][C:17]([CH3:20])=[N:18][N:19]=2)[CH2:11][CH2:12][C:13]=1[OH:14])=O)C=C.C(N(CC)CC)C.C(O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>Cl.O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:20][C:17]1[O:16][C:15]([N:10]2[CH2:9][CH2:8][C:13](=[O:14])[CH2:12][CH2:11]2)=[N:19][N:18]=1
Reactant: C=CCOC(=O)C1=C(O)CCN(c2nnc(C)o2)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O=CO
Solvent: C1CCOC1
Product: Cc1nnc(N2CCC(=O)CC2)o1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
4-Hydroxy-1-(5-methyl-[1,3,4]oxadiazol-2-yl)-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid allyl ester potassium salt (163 mg, 0.54 mmol) was dissolved in little 25% aqueous HCl solution and the solvent was removed under reduced pressure. The residue was evaporated twice with toluene/tetrahydrofurane. The residue was suspended in tetrahydrofurane (0.26 mL). To a solution of triethyl amine (263 L, 1.88 mmol) and formic acid (42 L, 1.08 mmol) in tetrahydrofurane (0.51 mL) was added under nitrogen and stirring a solution of palladium (II) acetate (3.0 mg, 0.013 mmol) and triphenylphosphine (7.3 mg, 0.027 mmol) in tetrahydrofurane (0.77 mL). After stirring for 5 minutes at room temperature the prepared catalyst solution was added to the suspension. The reaction was stirred at room temperature for 1 hour, poured onto water and extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The title compound was obtained as a yellow viscous oil (54 mg, 55%).
Reaction SMILES: Cl[C:2]([CH3:21])([CH3:20])[CH:3]([N:18]=[O:19])[CH2:4][O:5][CH2:6][CH:7]([OH:17])[CH2:8][N:9]1[CH:13]=[CH:12][N:11]=[C:10]1[N+:14]([O-:16])=[O:15].[NH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]([CH3:34])([CH3:33])[C:28](=[N:31][OH:32])[CH2:29]C.C(N(C(C)C)CC)(C)C>C(#N)C>[CH3:20][C:2]([CH3:21])([NH:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]([CH3:34])([CH3:33])[C:28](=[N:31][OH:32])[CH3:29])[C:3](=[N:18][OH:19])[CH2:4][O:5][CH2:6][CH:7]([OH:17])[CH2:8][N:9]1[CH:13]=[CH:12][N:11]=[C:10]1[N+:14]([O-:16])=[O:15]
Reactant: CC(C)(Cl)C(COCC(O)Cn1ccnc1[N+](=O)[O-])N=O
Reactant: CCC(=NO)C(C)(C)NCCCN
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(=NO)C(C)(C)NCCCNC(C)(C)C(COCC(O)Cn1ccnc1[N+](=O)[O-])=NO
Temperature: 40 °C

Procedure:
A slurry of 3-chloro-1-[2-hydroxy-3-(2-nitro-1H-imidazol-1-yl)propoxy]-3-methyl-2-nitrosobutane (3.2 g, 0.01 mol) in acetonitrile (35 mL) was maintained at 40° C. for 30 minutes. To this slurry was added a solution of N-(3-aminopropyl)-1-amino-1,1-dimethyl-2-butanoneoxime (1.73 g, 0.01 mol) in acetonitrile (10 mL) and diisopropylethylamine (1.5 g, 0.012 mol) and the mixture was maintained at 40° C. for 48 hrs. The solid which formed was filtered and the acetonitrile solution was evaporated on a rotary evaporator to give a green viscous oil which was dried under vacuum. The foamy solid obtained was triturated with acetonitrile to afford a thick oil which solidified on standing. This was purified by column chromatography (CH2Cl2:CH3OH, 7:3, 50:50)). The fractions containing the product were collected and evaporated to give an oil which was dried under vacuum and triturated with acetonitrile to give a white solid. It was recrystallized from ethyl acetate to yield the title product. Yield: 1.2 g (26%). mp: 134-35° C. MS: (M+H)+=458+. 1H NMR (DMSO) δ 1.05 and 1.16 [s, 12H, C(CH3)2], 1.38 (m, 2H, NHCH2CH2CH2NH), 1.72 (s, 3H, CH3), 2.2 (m, 2H, NHCH2CH2CH2NH), 3.38 (m, 4H, CH2OCH2CHOH), 3.8 (m, 2H, OCH2CHOH), 4.28 and 4.6 (m, 3H, CHOHCH2N<), 7.12 and 7.58 (8, 2H, imi H), 10.4 and 10.85 (s, 2H, NOH). Anal. Calcd for C19H35N7O6: C, 49.88; H, 7.71; N, 21.43. Found: C, 49.80; H, 7.79; N, 21.47.
Reaction SMILES: Br[C:2]1[CH:12]=[C:11]([CH3:13])[C:5]([O:6][CH2:7][C:8](=[O:10])[CH3:9])=[C:4]([CH3:14])[CH:3]=1.[CH:15]([C:18]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21])([CH3:17])[CH3:16]>>[CH:15]([C:18]1[CH:27]=[C:26]([C:2]2[CH:12]=[C:11]([CH3:13])[C:5]([O:6][CH2:7][C:8](=[O:10])[CH3:9])=[C:4]([CH3:14])[CH:3]=2)[CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21])([CH3:17])[CH3:16]
Reactant: CC(=O)COc1c(C)cc(Br)cc1C
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1C(C)C
Product: COC(=O)c1ccc(-c2cc(C)c(OCC(C)=O)c(C)c2)cc1C(C)C

Procedure:
The title compound was prepared according to procedures analogous to those as described in Reference Example 31 by using 1-(4-bromo-2,6-dimethylphenoxy)propan-2-one and methyl 2-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6]2.C=O.[OH-].[K+].[CH3:17]CCCCC>C(O)C.[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Fe].C(OC(=O)C)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH:7]([CH3:17])[CH2:6]2
Reactant: CCCCCC
Reactant: COc1ccc2c(c1)CCC2=O
Agent: [Fe]
Agent: C=O
Agent: [C-]#[O+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)CC(C)C2=O
Yield: 44 %

Procedure:
5-Methoxy indanone was treated with aqueous formaldehyde in the presence of iron pentacarbonyl and KOH in ethanol according to G. Cainelli et. al., Tetrahedron Letters 27, 2491 (1973). After chromatography (hexane:ethylacetate=7:3) over SiO2, a 44% yield of white crystals was obtained (m.p. 73-76° C.).
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH3:9].[OH:10][C:11]1[CH:16]=[CH:15][C:14]([SH:17])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:10][C:11]1[CH:16]=[CH:15][C:14]([S:17][CH2:2][CH2:3][CH:4]2[CH2:8][CH2:7][CH2:6][N:5]2[CH3:9])=[CH:13][CH:12]=1
Reactant: Oc1ccc(S)cc1
Reactant: CN1CCCC1CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CCCC1CCSc1ccc(O)cc1
Yield: 44.3 %

Procedure:
2-(2-Chloroethyl)-1-methylpyrrolidine (2.0 g, 13.5 mmole), 4-hydroxythiophenol (1.7 g, 13.5 mmole), potassium carbonate (18.7 g, 135.4 mmole) and DMF (26 mL) were combined, yielding 1.42 g (5.98 mmole, 44%) of the desired compound.