Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:17])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH:14]([CH3:16])[CH3:15])[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1.[N+](C1C=CC(C(O)C(N(C)C)CO)=CC=1)([O-])=O>C1(C)C=CC=CC=1>[F:1][CH:2]([F:17])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C@H:10]([CH:14]([CH3:15])[CH3:16])[C:11]([OH:13])=[O:12])=[CH:8][CH:9]=1
Reactant: CC(C)C(C(=O)O)c1ccc(OC(F)F)cc1
Agent: CN(C)C(CO)C(O)c1ccc([N+](=O)[O-])cc1
Solvent: Cc1ccccc1
Product: CC(C)[C@H](C(=O)O)c1ccc(OC(F)F)cc1
Temperature: 25 °C
Yield: 43.5 %

Procedure:
Dissolve 50 g of 2-(4-difluoromethoxyphenyl)-3-methylbutyric acid in 130 g of toluene and to this solution is added 0.24 mole of resolving agent 1-(4-nitrophenyl)-2-dimethylamino-1,3-propanediol. Heat the solution with stirring under reflux for 6 hours, then cool, filter, and transfer the resulting solids to 48.7 g of 15% hydrochloric acid. Heat the mixture with stirring at 40° C. for 2 hours and then allow the mixture to cool to room temperature. The resulting mixture is extracted with benzene 2-3 times, and the solvent benzene is then removed by distillation to give 21.75 g (yield: 43.5%) of (S)-2-(4-difluoromethoxyphenyl)-3-methylbutyric acid.
Reaction SMILES: P(Br)(Br)([Br:3])=O.O[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]3[C:21](=[C:22]([P:24](=[O:31])([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27])[CH:23]=2)[N:20]=[C:19]([CH3:32])[CH:18]=[CH:17]3)=[CH:10][CH:9]=1.O>C(Cl)Cl.CN(C=O)C>[Br:3][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]3[C:21](=[C:22]([P:24](=[O:31])([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27])[CH:23]=2)[N:20]=[C:19]([CH3:32])[CH:18]=[CH:17]3)=[CH:10][CH:9]=1
Reactant: O=P(Br)(Br)Br
Reactant: CCOP(=O)(OCC)c1cc(-c2ccc(CO)cc2)cc2ccc(C)nc12
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CCOP(=O)(OCC)c1cc(-c2ccc(CBr)cc2)cc2ccc(C)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
To a solution of POBr3 (150 mg, 0.39 mmol) in CH2Cl2 (4 mL) and DMF (2 mL) was added the product of step 2 (150 mg, 0.39 mmol). The mixture was stirred at r.t. for 0.5 h. H2O was added and the mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried (anhyd. MgSO4) and concentrated in vacuo. The residue was purified by chromatography on silica gel to give 159 mg (91%) of the title compound.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[C:6]([NH:10][CH2:11][O:12][S:13]([CH2:16][CH2:17][CH3:18])(=[O:15])=[O:14])(=[O:9])[CH:7]=[CH2:8].[Na:19].S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].C(OCCOCC1OC1)C1OC1.[OH-].[Na+:45]>O>[C:1]([O-:5])(=[O:4])[CH:2]=[CH2:3].[Na+:45].[C:6]([NH:10][CH2:11][O:12][S:13]([CH2:16][CH2:17][CH3:18])(=[O:15])=[O:14])(=[O:9])[CH:7]=[CH2:8].[Na:19]
Reactant: C=CC(=O)O
Agent: C(COCC1CO1)OCC1CO1
Agent: C=CC(=O)NCOS(=O)(=O)CCC
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Solvent: O
Product: C=CC(=O)[O-]

Procedure:
51.1 g of acrylic acid was diluted with 22.6 g of water and neutralized with 75.0 g of a 30 wt. % aqueous sodium hydroxide solution under cooling. Thereafter, 143.3 of a 40 wt. % aqueous sodium acrylamidomethylpropanesulfonate solution was added thereto, and then 7.9 g of a 5.2 wt. % aqueous potassium persulfate solution and 0.082 g of epoxy bifunctional cross linking agent (ethylene glycol diglycidyl ether) were added thereto to prepare a homogeneous solution as the aqueous monomer/initiator solution. Thereafter, the same procedure as that of Example 18 was repeated, thereby providing 131.5 g of a sodium acrylate/sodium acrylamidomethylpropanesulfonate copolymer. The resultant polymer was in the form of distorted granular particles having an average diameter of 580 μm and a bulk density of 0.44 g/ml. The measurement was conducted on the resultant polymer particles in the same manner as that of Example 4. The results are given in Table 2.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]([OH:18])=[O:17])=[CH:5]2.[OH-].[Na+:27]>C(O)C>[Cl:1][C:2]1[C:3]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]([F:15])([F:13])[F:14])[C:6]([C:16]([O-:18])=[O:17])=[CH:5]2.[Na+:27]
Reactant: O=C(O)C1=Cc2c(ccc(Cl)c2Oc2ccccc2)OC1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C([O-])C1=Cc2c(ccc(Cl)c2Oc2ccccc2)OC1C(F)(F)F

Procedure:
A solution of 110 mg (0.297 mmole) of 6-chloro-5-phenoxy-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid in 3.0 mL of ethanol was treated with 2.94 mL of 0.1008N NaOH. The resultant mixture was lyophilized to provide 116 mg (quant.) of an off-white solid: 1H NMR (CD3OD/400 MHz) 5.90 (q, 1H, J=7.2 Hz), 6.81 (d, 2H, J=8.3 Hz), 6.93 (d, 1H, J=8.9 Hz) 7.05 (t, 1H, J=7.5 Hz), 7.32 (t, 2H, J=8.6 Hz), 7.42 (d, 1H, J=8.9 H), 7.56 (s, 1H); MS (ES+) 371 (M+1, 100).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]([NH2:17])=[O:16].[N:18]1[CH:23]=[CH:22][CH:21]=[N:20][C:19]=1[O:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1.[BH4-].[Na+]>CCO.N1CCCCC1>[Cl:14][C:10]1[CH:9]=[C:8]([NH:7][C:4]2[C:3]([C:15]([NH2:17])=[O:16])=[C:2]([NH:1][CH2:29][C:28]3[CH:27]=[CH:26][C:25]([O:24][C:19]4[N:18]=[CH:23][CH:22]=[CH:21][N:20]=4)=[CH:32][CH:31]=3)[NH:6][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N
Reactant: O=Cc1ccc(Oc2ncccn2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCNCC1
Solvent: CCO
Product: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1NCc1ccc(Oc2ncccn2)cc1
Yield: 17.9 %

Procedure:
5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carboxamide (100 mg) was then suspended in EtOH (4 mL) and 4-(pyrimidin-2-yloxy)benzaldehyde (80 mg, 1 eq.) and piperidine (1 drop) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain product as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr (104 mg, 60% yield). Resulting imine (104 mg) was suspended in 5 mL MeOH and sodium borohydride (10 eq, 100 mg) was added. HPLC confirmed reaction was complete (absence of imine). After completion (1 hr), precipitate was filtered to obtain D32 as a light yellow powder. Product was washed with deionized water to remove excess sodium borohydride. Product was allowed to dry under vacuum for 18 hrs. 31 mg (30% yield) of final product was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[Br:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1.N1CCCCC1.C1(O)C=CC=CC=1>CO>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:16])[C:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:22][C:21]2[CH:24]=[CH:25][C:18]([Br:17])=[CH:19][CH:20]=2)=[CH:6][CH:7]=1
Reactant: O=C(Cc1ccccc1)c1ccc(O)cc1
Reactant: O=Cc1ccc(Br)cc1
Solvent: CO
Solvent: Oc1ccccc1
Solvent: C1CCNCC1
Product: O=C(C(=Cc1ccc(Br)cc1)c1ccccc1)c1ccc(O)cc1
Yield: 36.3 %

Procedure:
8.02 g (0.0378 mole) of 1-(4-hydroxyphenyl)-2-phenylethanone, 7.0 g (0.0378 mole) of 4-bromobenzaldehyde, 3.01 g (0.0353 mole) of piperidine and 16.5 ml of methanol was treated or mentioned under Example IA to give 13 g (74%) of crude product. 12.5 g (0.027 mole) of this phenol was refluxed with 120 ml and worked up as in Example IB. Recrystallization from methanol gave 5.2 g (51%) of the product.
Reaction SMILES: [NH2:1][C:2]1([O:11][CH:10]=[CH:9][CH2:8]1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[OH-].[Na+].[C:14]([O:18][C:19](ON=C(C1C=CC=CC=1)C#N)=[O:20])([CH3:17])([CH3:16])[CH3:15]>O1CCOCC1.O>[C:14]([O:18][C:19]([NH:1][C:2]1([O:11][CH:10]=[CH:9][CH2:8]1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6])=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: NC1(CCC(=O)O)CC=CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1(CCC(=O)O)CC=CO1

Procedure:
5.0 pts. by wt. of 2-amino-furfurylacetic acid (Rohm and Haas, Netherlands Application 66,07754) in 100 pts. by vol. of 80 percent strength aqueous dioxane are brought to pH with 4 N sodium hydroxide solution. 8.0 pts. by wt. of 2-(t-butoxycarbonyloxyimino)-2-phenylacetonitrile are added and the mixture is warmed to 70° for 2 hrs. During this time, the above pH is maintained by adding 4 N sodium hydroxide solution. Thereafter, 80 pts. by vol. of water are added, the dioxane is stripped off and the reaction mixture is extracted several times with ethyl acetate. The aqueous phase is brought to pH 4 with 10 percent strength citric acid, and is saturated with sodium chloride and extracted by shaking with ethyl acetate. The ethyl acetate phases are dried over sodium sulphate and concentrated. The residue is recrystallized from a little abs. carbon tetrachloride. 4.3 pts. by wt. of 2-t-butoxycarbonylamino-furfurylacetic acid of melting point 99°-101° are obtained.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([S:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[N:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH:18]O>C(O)(=O)C>[NH2:1][C:2]1[S:6][C:5]([S:7]([C:8]([CH3:11])([CH3:9])[CH3:10])=[O:18])=[N:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)Sc1nc(-c2ccccc2)c(N)s1
Reactant: OO
Solvent: CC(=O)O
Product: CC(C)(C)S(=O)c1nc(-c2ccccc2)c(N)s1

Procedure:
To 5-amino-2-(tert-butylsulfanyl)-4-phenylthiazole (102 mg, 385 μmol) in acetic acid (5.0 ml) was added aqueous hydrogen peroxide (218 μl, 30% wt, 1.9 mmol) dropwise at ambient temperature. After 5 hr the mixture was partitioned between dichloromethane (50 ml) and water (50 ml). The aqueous phase was separated and extracted with dichloromethane (20 ml). The combined organic phases were washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, filtered and concentrated in vacuo to yield essentially pure 5-amino-2-(tert-butylsulfinyl)-4-phenylthiazole (110 mg, quant.).
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][C:4]([C:7]([C@H:9]2[CH2:11][C@H:10]2[C:12](O)=[O:13])=O)=[CH:3][CH:2]=1.O.[NH2:17][NH2:18]>C(O)C>[C:1]1([CH3:15])[CH:6]=[CH:5][C:4]([C:7]2[CH:9]3[CH:10]([C:12](=[O:13])[NH:17][N:18]=2)[CH2:11]3)=[CH:3][CH:2]=1
Reactant: NN
Reactant: Cc1ccc(C(=O)[C@H]2C[C@H]2C(=O)O)cc1
Solvent: O
Solvent: CCO
Product: Cc1ccc(C2=NNC(=O)C3CC23)cc1
Yield: 79.8 %

Procedure:
5.5 g (26.9 millimoles) of cis-2-(p-toluoyl)-cyclopropanecarboxylic acid, 1.5 g (30.0 millimoles) of hydrazine hydrate and 100 ml of ethanol are refluxed for 6 hours. The mixture is then concentrated and the residue is recrystallized from ethyl acetate. 4.3 g (80% of theory) of 2-(p-tolyl)-3,4-diaza-bicyclo[4.1.0]-hept-2-en-5-one are obtained as colorless crystals of melting point 162°-163.5° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]([OH:14])=O)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.S(Cl)([Cl:17])=O>>[Cl:1][C:2]1[C:3]([C:12]([Cl:17])=[O:14])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ncc(C(F)(F)F)cc1Cl
Product: O=C(Cl)c1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
89.3 g of 3-chloro-5-trifluoromethyl-2-pyridinecarboxylic acid (Example P3) are slowly heated to reflux with 60 ml of thionyl chloride and the mixture is then stirred at that temperature for 4 hours, after which it is cooled to 25° C. and concentrated to dryness in vacuo. Twice, toluene is added and the mixture is again concentrated to dryness. 94.0 g of the desired product are obtained in the form of a yellow residue.
Reaction SMILES: CC(C)(O[C:5](=O)[N:6](C)[O:7][CH2:8][CH:9]([CH3:18])[O:10][C:11](=[O:17])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])C>C(O)(C(F)(F)F)=O>[CH3:5][NH:6][O:7][CH2:8][CH:9]([O:10][C:11](=[O:17])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH3:18]
Reactant: CC(CON(C)C(=O)OC(C)(C)C)OC(=O)CCC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CNOCC(C)OC(=O)CCC(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2,2,5,8-Tetramethyl-4,10-dioxo-3,6,9-trioxa-5-azatridecan-13-oic acid (227 mg, 0.744 mmol) was dissolved in 4 mL TFA. The reaction mixture was stirred at room temperature for 4 h and concentrated. The crude product was purified by silica gel flash column chromatography using 12% MeOH/dichloromethane as eluent. The desired product was obtained as a colorless gel (30 mg, 0.146 mmol, 20%). 1H NMR (CD3OD, 300 MHz): δ (ppm) 1.17 (d, 3 H, J=6.6 Hz), 2.58 (s, 3 H), 2.61 (s, 3 H), 3.66 (d, 2 H, J=5.4 Hz), 5.10-5.16 (m, 1 H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Si:7]([O:24][C@H:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C@H:28]([NH:35]C(=O)C(F)(F)F)[CH2:27][CH2:26]1)([C:20]([CH3:23])([CH3:22])[CH3:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O.CO.CCOC(C)=O>[Si:7]([O:24][C@H:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C@H:28]([NH2:35])[CH2:27][CH2:26]1)([C:20]([CH3:22])([CH3:23])[CH3:21])([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)[Si](O[C@@H]1CC[C@@H](NC(=O)C(F)(F)F)c2ccccc21)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)[Si](O[C@@H]1CC[C@@H](N)c2ccccc21)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
Potassium carbonate (8.3 g) in water (16 mL) was added to a solution of N-((1R,4R)-4-(tert-butyldiphenylsilyloxy)-1,2,3,4-tetrahydronaphthalen-1-yl)-2,2,2-trifluoroacetamide (4 g) in MeOH (160 mL). The reaction mixture was stirred at room temp overnight then diluted with EtOAc (150 mL), and after separation, the aqueous phase was extracted several times with EtOAc. The organic phase was dried over MgSO4 and concentrated in vacuo to afford 3.1 g of the title compound, whose purity was good enough to use crude. 1H-NMR (300 MHz, CDCl3) □ 7.7 (d, 2H), 7.6 (d, 2H), 7.4 (m, 7H), 7.2 (m, 3H), 4.8 (t, 1H), 4.2 (t, 1H), 3.8 (broad s, 2H), 2.4 (m, 1H), 1.8 (m, 2H), 1.6 (m, 1H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=2)=[CH:6][CH:7]=1
Reactant: O=C(COc1ccc(O)cc1)Nc1ccc(Br)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Oc1ccc(OCCNc2ccc(Br)cc2)cc1
Yield: 12 %

Procedure:
Compound 7b (80 mg, 0.25 mmol) was dissolved in THF (5 ml). LiAlH4 (30 mg, 0.5 mmol) was added portionwise and the reaction was refluxed for 6 hrs. The reaction was quenched slowly with water, 10% sodium hydroxide, and then water again. The aqueous layer was extracted with EtOAc (2×50 mL). The organic was concentrated to yield compound 7 (10 mg, 0.03 mmol, 13% yield). 1H NMR (CDCl3, 400 MHz) δ 7.29 (m, 2H), 6.80 (q, 4H), 6.56 (d, 2H), 4.81 (broad s, 1H), 4.13 (t, 2H), 3.47 (t, 2H); HRMS (ESI, positive) m/z calcd. for C14H14BrNO2 [M+H]+: 308.0286, found: 308.0261.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([SH:11])[CH:7]=[CH:8][C:9]=1[CH3:10].I[CH:13]([CH3:15])[CH3:14]>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]([S:11][CH:13]([CH3:15])[CH3:14])[CH:7]=[CH:8][C:9]=1[CH3:10]
Reactant: CC(C)I
Reactant: Cc1ccc(S)cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(SC(C)C)cc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred suspension of NaH (40 mg) in anhydrous DMF (5 mL) was treated with a solution of 3-bromo-4-methylbenzenethiol (200 mg) in anhydrous DMF (3 ml). The reaction mixture was stirred for 30 minutes at RT, then 2-iodo propane (0.14 ml) was added to the reaction mixture and the reaction mixture was heated to 55° C. for 3 hours. The reaction mixture was quenched with ice and extracted with diethylether. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (Silica gel), eluting with hexane, to give the title compounds.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:27])[CH2:9][N:10]2[C:14](=[O:15])[C:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)([CH2:16][CH2:17][CH3:18])[N:12]=[C:11]2[CH3:26])=[C:4]([F:28])[CH:3]=1.[N:29]([C:32]1[C:33]([CH3:38])=[N:34][O:35][C:36]=1[CH3:37])=[C:30]=[O:31]>>[CH3:38][C:33]1[C:32]([NH:29][C:30]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:27])[CH2:9][N:10]3[C:14](=[O:15])[C:13]([C:19]4[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=4)([CH2:16][CH2:17][CH3:18])[N:12]=[C:11]3[CH3:26])=[C:4]([F:28])[CH:3]=2)=[O:31])=[C:36]([CH3:37])[O:35][N:34]=1
Reactant: CCCC1(c2ccc(F)cc2)N=C(C)N(CC(=O)c2ccc(N)cc2F)C1=O
Reactant: Cc1noc(C)c1N=C=O
Product: CCCC1(c2ccc(F)cc2)N=C(C)N(CC(=O)c2ccc(NC(=O)Nc3c(C)noc3C)cc2F)C1=O

Procedure:
Synthesis in analogy to Example 7 and Example 10 starting from (+/−)-3-[2-(4-amino-2-fluoro-phenyl)-2-oxo-ethyl]-5-(4-fluoro-phenyl)-2-methyl-5-propyl-3,5-dihydro-imidazol-4-one and 4-isocyanato-3,5-dimethyl-isoxazole to yield (+/−)-1-(3,5-dimethyl-isoxazol-4-yl)-3-(3-fluoro-4-{2-[4-(4-fluoro-phenyl)-2-methyl-5-oxo-4-propyl-4,5-dihydro-imidazol-1-yl]-acetyl}-phenyl)-urea. The compound is suspended in a 1 molar aqueous sodium hydroxide solution. Subsequently iodomethane (1 equivalent) and tetrabutyl ammonium chloride (1 equivalent) are added and the mixture is stirred for 18 hours at room temperature. Subsequently the product is extracted with dichloromethane and subjected to preparative LC purification (method 3) to yield (+/−)-1-(3,5-dimethyl-isoxazol-4-yl)-3-(3-fluoro-4-{2-[4-(4-fluoro-phenyl)-2-methyl-5-oxo-4-propyl-4,5-dihydro-imidazol-1-yl]-acetyl}-phenyl)-1,3-dimethyl-urea LC/MS at 254 nm; [M+H] 552; Rt 3.502 min.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([Br:9])=[CH:4][C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([CH:14]2[NH:1][C:2]3[C:7]([Br:8])=[CH:6][C:5]([Br:9])=[CH:4][C:3]=3[S:10](=[O:12])(=[O:11])[NH:13]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1c(Br)cc(Br)cc1S(N)(=O)=O
Product: O=S1(=O)NC(c2ccccc2)Nc2c(Br)cc(Br)cc21

Procedure:
2-Amino-3,5-dibromobenzenesulfonamide (see compound 125) was transformed by Method G (using benzaldehyde). M.p. 186-189° C.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[CH2:6][C:7]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1)=[C:8]2[C:12]([O:14]CC=C)=[O:13])[CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(C(CCCC)C([O-])=O)C.[Na+:55].C(OCC)(=O)C>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.CCCCCC>[OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[CH2:6][C:7]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1)=[C:8]2[C:12]([O-:14])=[O:13])[CH3:3].[Na+:55]
Reactant: C=CCOC(=O)C1=C(c2cccc(OC)c2)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCCC(CC)C(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cccc(C2=C(C(=O)[O-])N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 23 %

Procedure:
Allyl (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(3-methoxyphenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (1.37 g, 3.99 mmol) prepared by Reference Example 3, triphenylphosphine (52 mg), and tetrakis(triphenylphosphine)palladium(0) (0.23 g, 0.2 mmol) were dissolved in THF (20 ml), and thereto was added at 0° C. sodium 2-ethylhexanoate in ethyl acetate (0.5 M, 8.0 ml, 4.0 mmol), followed by stirring for 1 hour. Thereto was added hexane (30 ml) and the resulting white crystals were filtered under a nitrogen atmosphere, washed with hexane, dried at room temperature in vacuo to give a crude product. The product was dissolved in a small amount of ice-water, and purified with C18 reverse column chromatography (filler: Akosil 40C18 (Wako Pure Chemical Ind.); mobile phase; 0˜5%THF/ice-cooled ion-exchange water). The fractions containing the object compound were combined and THF therein was removed at room temperature in vacuo under stirring for 1 hour. The residue was lyophilized to give sodium (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(3-methoxyphenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (297 mg, yield 23%).
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=O.[F:8][C:9]([F:35])([F:34])[C:10]1[CH:11]=[C:12]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:13][O:14][CH2:15][C:16]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([OH:20])[CH2:17][CH2:18][NH2:19].C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCCl.CN(C)C1C=CN=CC=1>[F:8][C:9]([F:34])([F:35])[C:10]1[CH:11]=[C:12]([CH:27]=[C:28]([C:30]([F:32])([F:31])[F:33])[CH:29]=1)[CH2:13][O:14][CH2:15][C:16]([OH:20])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:17][CH2:18][NH:19][C:2](=[O:1])[C:4]([F:7])([F:6])[F:5]
Reactant: O=C(O)C(F)(F)F
Reactant: NCCC(O)(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=C(NCCC(O)(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(3,5-bis(trifluoromethyl)benzyloxy)-4-amino-2-phenylbutan-2-ol TFA salt (37 mg, 0.071 mmol) was dissolved in 1,2-dichloroethane (0.6 ml). Triethylamine (0.040 ml, 0.29 mmol) was added to the solution, and followed by addition of trifluoroacetic anhydride (0.013 ml, 0.091 mmol) and catalytic amount of 4-dimethylaminopyridine. After stirred overnight at room temperature, the reaction mixture was concentrated, and the residue was purified by flash chromatography on silica gel to give the desired trifluoroacetamide. 1H NMR (300 MHz, Acetone) δ ppm 8.27 (s, 1 H) 7.95 (s, 2 H) 7.94 (s, 1 H) 7.54–7.61 (m, 2 H) 7.31–7.40 (m, 2 H) 7.23–7.31 (m, 1 H) 4.72–4.84 (m, 2 H) 4.69 (s, 1 H) 3.73–3.84 (m, 2 H) 3.29–3.43 (m, 1 H) 3.19 (ddd, J=19.39, 8.05, 5.86 Hz, 1 H) 2.27 (ddd, J=8.60, 6.40, 4.39 Hz, 2 H); LRMS [ESI, MNa+] m/z calcd for C21H18NO3F9Na 526.10, found 525.97.
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][N:7]1[C:12](=[O:13])[CH:11]=[N:10][C:9]2[CH:14]=[CH:15][C:16]([N:18]3[CH:22]=[N:21][CH:20]=[N:19]3)=[N:17][C:8]1=2.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+].[OH-].[Na+]>C(OCC)(=O)C.O>[O:13]=[C:12]1[N:7]([CH2:6][CH:2]=[O:1])[C:8]2[N:17]=[C:16]([N:18]3[CH:22]=[N:21][CH:20]=[N:19]3)[CH:15]=[CH:14][C:9]=2[N:10]=[CH:11]1
Reactant: O=c1cnc2ccc(-n3cncn3)nc2n1CC1OCCO1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=CCn1c(=O)cnc2ccc(-n3cncn3)nc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 143.5 %

Procedure:
To 98 mg of 4-(1,3-dioxolan-2-ylmethyl)-6-(1H-1,2,4-triazol-1-yl)pyrido(2,3-b)pyrazin-3(4H)-one, 3 mL of an 80% aqueous trifluoroacetic acid solution was added, and the mixture was stirred at room temperature for 6 hours 30 minutes. Thereto were added water and ethyl acetate, and the mixture was neutralized with a saturated aqueous sodium hydrogen carbonate solution and an aqueous sodium hydroxide solution. The organic layer was separated, and sodium chloride was added to the aqueous layer, and the mixture was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 0.12 g of (3-oxo-6-(1H-1,2,4-triazol-1-yl)pyrido(2,3-b)pyrazin-4(3H)-yl)acetaldehyde as a light red solid.