Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:38]/[O:39][C:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])([CH3:42])[CH3:41])/[C:8]([NH:10][C@@H:11]2[C:36](=[O:37])[N:13]3[C:14]([C:20]([O:22][CH:23]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:21])=[C:15]([CH2:18]Cl)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.[I-:50].[Na+].P([O-])([O-])([O-])=O.C(OCC)(=O)C>C1(C)C=CC=CC=1.[Cl-].C(C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC)(=O)CCCCCCC.O>[NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:38]/[O:39][C:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])([CH3:42])[CH3:41])/[C:8]([NH:10][C@@H:11]2[C:36](=[O:37])[N:13]3[C:14]([C:20]([O:22][CH:23]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:21])=[C:15]([CH2:18][I:50])[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)c1nsc(N)n1
Reactant: [I-]
Agent: CCCCCCCC(=O)C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CS[C@H]12)c1nsc(N)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.9 %

Procedure:
To a solution of benzhydryl 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino)acetamido]-3-chloromethyl-3-cephem-4-carboxylate (60 g) in toluene (600 ml) were added a solution of sodiumiodide (61.8 g) in 0.05 mol phosphate buffer (pH 7, 500 ml) and tricaprylylmethylammonium chloride (6.67 g). The mixture was stirred at room temperature for 15 hours. The reaction mixture was added to a mixture of ethyl acetate and water. The organic layer was washed with water and brine, and then dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated to 255 g under reduced pressure. The concentrate was poured into diisopropyl ether (2 L). The resulting precipitate was collected by filtration and dried to give benzhydryl 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino)acetamido]-3-iodomethyl-3-cephem-4-carboxylate (59.4 g).
Reaction SMILES: [O:1]1[C:9]2[CH:8]([OH:10])[CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=[CH:2]1.[Br:11][C:12]1[C:13]([Cl:19])=[C:14](F)[CH:15]=[CH:16][CH:17]=1>>[Br:11][C:12]1[C:13]([Cl:19])=[C:14]([O:10][CH:8]2[CH2:7][NH:6][CH2:5][C:4]3[CH:3]=[CH:2][O:1][C:9]2=3)[CH:15]=[CH:16][CH:17]=1
Reactant: OC1CNCc2ccoc21
Reactant: Fc1cccc(Br)c1Cl
Product: Clc1c(Br)cccc1OC1CNCc2ccoc21

Procedure:
The same method as in Example 1 was conducted using 4,5,6,7-tetrahydrofuro[3,2-c]pyridin-7-ol (Reference Example 33) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3-bromo-2-chloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [O:1]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9]([OH:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+]([O-])(O)=O.[O:19]([CH2:23][CH2:24][NH2:25])[N+:20]([O-:22])=[O:21].C(OC(C)C)(C)C>>[O:19]([CH2:23][CH2:24][NH:25][C:9](=[O:11])[CH:8]([O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:12]([CH3:14])[CH3:13])[N+:20]([O-:22])=[O:21]
Reactant: NCCO[N+](=O)[O-]
Reactant: CC(C)C(Oc1ccccc1)C(=O)O
Solvent: O=[N+]([O-])O
Solvent: CC(C)OC(C)C
Product: CC(C)C(Oc1ccccc1)C(=O)NCCO[N+](=O)[O-]
Yield: 68.9 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.47 g of 2-phenoxy-3-methylbutyric acid and 0.40 g of 2-nitroxyethylamine nitrate, 0.46 g of the title compound was obtained as colorless powdery crystals (solvent for recrystallization; diisopropyl ether).
Reaction SMILES: [CH2:1]([O:3][C:4](OCC)([O:8][CH2:9][CH3:10])[CH:5]([CH3:7])[CH3:6])[CH3:2].CC(C)([O-])C.[Al+3].CC(C)([O-])C.CC(C)([O-])C>C(O)(C)(C)C>[CH2:1]([O:3][C:4]([O:8][CH2:9][CH3:10])=[C:5]([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(OCC)(OCC)C(C)C
Agent: CC(C)(C)[O-]
Agent: [Al+3]
Solvent: CC(C)(C)O
Product: CCOC(OCC)=C(C)C
Yield: 59.9 %

Procedure:
A mixture of 1,1,1-triethoxyisobutane (27.5 g, 0.14 mol) and aluminium t-butoxide (30 g, 0.12 mol) was heated at 170° C. for 1 hour during which time t-butanol distilled off. The residue was distilled at 100°-130° C. (atomosphere pressure) to afford 12.1 g (58%) of 1,1-diethoxy-2,2-dimethylethylene (Formula III: R2 =R3 =CH3 ;R4 =R5 =OC2H5), as a clear oil.
Reaction SMILES: Cl[CH:2](Cl)[C:3]([OH:5])=[O:4].[H-].[Na+].[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([OH:26])=[C:15]([C:17]([CH3:25])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[OH:18])[CH:16]=1>O1CCOCC1>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]2[O:26][CH:2]([C:3]([OH:5])=[O:4])[O:18][C:17]([CH3:25])([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:15]=2[CH:16]=1
Reactant: O=C(O)C(Cl)Cl
Reactant: COc1ccc(O)c(C(C)(O)c2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc2c(c1)C(C)(c1ccccc1)OC(C(=O)O)O2
Temperature: 90 °C
Yield: 112.7 %

Procedure:
A solution of 17 g of dichloroacetic acid in 180 ml of dioxane was added dropwise with stirring to a suspension of 14.9 g of sodium hydride as 50% oil suspension, 1.1 g of dibenzo-18-courone-6 and 160 ml of dioxane and then a solution of 21.5 g of the product of Step A in 220 ml of dioxane was added. The reaction mixture was heated at 90° C. for 3 hours, was cooled and was poured into ice. The aqueous phase was washed with 300 ml of ether, was acidified with 30 ml of concentrated hydrochloric acid and was extracted 3 times with 200 ml of ether. The ether phase was washed twice with 100 ml of water and was extracted twice with 250 ml of aqueous 5% sodium bicarbonate solution. The aqueous phase was washed with 100 ml of ether, acidified with 40 ml of concentrated hydrochloric acid and was extracted 3 times with 250 ml of ether. The combined organic phases were washed with water until the water was neutral, dried over magnesium sulfate and evaporated under reduced pressure to obtain 29.8 g of raw 6-methoxy-4-methyl-4-phenyl-[4H]-1,3-benzodioxin-2-carboxylic acid (mixture of 2 diastereoisomeric racemates).
Reaction SMILES: CN(C)C=O.[NH:6]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)[CH2:8][CH2:7]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][CH2:32][CH2:33][OH:34]>O.C(Cl)(Cl)Cl>[OH:34][CH2:33][CH2:32][CH2:31][N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]#[N:21])=[CH:22][CH:23]=2)[CH2:8][CH2:7]1
Reactant: OCCCBr
Reactant: N#Cc1ccc(OCCCC2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: N#Cc1ccc(OCCCC2CCN(CCCO)CC2)cc1
Reaction time: 0.25 h

Procedure:
To an N,N-dimethylformamide (70 mL) solution of 9.81 g of 4-[3-(4-piperidinyl)propoxy]benzonitrile were added 8.02 g of potassium carbonate and 2.62 mL of 3-bromo-1-propanol at room temperature, which was then stirred at the same temperature for 2 hours and 15 minutes. Thereto was added 2.62 mL of 3-bromo-1-propanol, which was then stirred at the same temperature for 1 hour and 45 minutes. Chloroform and water were added to the reaction mixture. The organic layer was separated, washed sequentially with a 1 mol/L sodium hydroxide aqueous solution and a saturated sodium chloride aqueous solution, and then dried with anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The resultant residue was purified using silica gel column chromatography (eluent; chloroform:methanol=4:1) to provide 4.28 g of 4-{3-[1-(3-hydroxypropyl)-4-piperidinyl]propoxy}benzonitrile as white solid form.
Reaction SMILES: [CH2:1]([C:5]1[NH:14][C:13](=[O:15])[C:12]2[C:7](=[CH:8][C:9]([C:16]([O:18]C)=[O:17])=[CH:10][CH:11]=2)[N:6]=1)[CH:2]([CH3:4])[CH3:3].[OH-].[K+].O>O.O1CCOCC1>[CH2:1]([C:5]1[NH:14][C:13](=[O:15])[C:12]2[C:7](=[CH:8][C:9]([C:16]([OH:18])=[O:17])=[CH:10][CH:11]=2)[N:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)c1ccc2c(=O)[nH]c(CC(C)C)nc2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)Cc1nc2cc(C(=O)O)ccc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of methyl 2-isobutyl-4-oxo-3,4-dihydroquinazoline-7-carboxylate (55.8 mg, 0.21 mmol), KOH (0.3 g, 5.3 mmol) in water/dioxane (2 mL/5 mL) was stirred at room temperature for 1 h. The reaction mixture was poured into water (50 mL) and the solution was adjusted to pH to 4-5. The mixture was extracted with ethyl acetate (3×20 mL) and dried over Na2SO4. After filtration and concentration, the residue was purified by silica gel chromatography to give the desired product. MS (ESI): 246 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][NH:15]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Mg]Br)C.[CH3:22][C:23]1([CH3:31])[C:25]([CH3:27])([CH3:26])[CH:24]1[C:28](Cl)=[O:29]>ClCCl.[Cl-].[Zn+2].[Cl-]>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([C:28]([CH:24]3[C:25]([CH3:27])([CH3:26])[C:23]3([CH3:31])[CH3:22])=[O:29])=[CH:14][NH:15]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Reactant: c1ccc(COc2ccc3cc[nH]c3c2)cc1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CC1(C)C(C(=O)c2c[nH]c3cc(OCc4ccccc4)ccc23)C1(C)C
Yield: 64.4 %

Procedure:
A mixture of 6-benzyloxyindole (Lancaster, 2.0 g, 9.0 mmol), ethylmagnesium bromide (1.0 M solution in THF, 11 mL, 11 mmol), zinc chloride (1.0 M solution in Et2O, 11 mL, 11 mmol) and the product of Example 1A (13.4 mmol) in 30 mL of dichloromethane was processed as described in Example 1B to provide the title compound (2.0 g, 5.8 mmol, 64% yield). MS (DCI/NH3) m/z 348 (M+H)+.
Reaction SMILES: [C:1]([O:10]CC)(=O)[C:2]#[C:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl.[CH3:14][N:15](C)[NH2:16].[OH-].[Na+].CCOC(C)=O>CCO.O>[OH:10][C:1]1[CH:2]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:15]([CH3:14])[N:16]=1
Reactant: CN(C)N
Reactant: CCOC(=O)C#CC(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1cc(O)nn1C
Temperature: 20 °C
Reaction time: 1 h
Yield: 17 %

Procedure:
To a solution of diethyl but-2-ynedioate (100 g, 0.588 mol) in a mixture of EtOH (600 mL) and water (600 mL) was added a solution of 1,1-dimethylhydrazine hydrochloride (68 g, 0.705 mol) and NaOH (28.2 g, 0.705 mol) in water (150 mL) dropwise at 0° C. over a period of 20 min. The mixture was stirred at 0° C. for 30 min and 20° C. for 60 min. To the reaction mixture was added EtOAc (800 mL) and stirred. The mixture was separated and the aqueous layer was concentrated. The residue was dissolved in 1N HCl (1 L) and stirred at rt for 90 min. CH2Cl2 (500 mL) was added and the mixture stirred, separated and the aqueous layer was concentrated. The residue was purified by chromatography (petroleum ether/EtOAc 10:1-3:1) to give the title compound (17 g, 17% yield) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[CH:17][C:16]([O:19][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(O)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(O[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 123.5 %

Procedure:
To a solution of (R)-tert Butoxycarbonylamino-(4-hydroxy-phenyl)-acetic acid (2.54 g, 9.55 mmol) in DMF (5 mL) was added imidazole (1.43 g, 21 mmol) followed by t-butyldimethylsilyl chloride (1.58 g, 10.5 mmol). The resulting mixture was stirred at rt for overnight. Additional t-butyldimethylsilyl chloride (1.43 g, 9.55 mmol) was added and let the reaction continue for another hour. The reaction mixture was diluted with EtOAc and washed with H2O three times and concentrated. To the residue was added aqueous 1N NaOH and then acidified with concentrated HCl. The resulting mixture was extracted with EtOAc three times. The combined organic layer was dried (MgSO4) and concentrated to provide the titled compound (4.5 g).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([OH:16])([CH3:15])[CH3:14])[C:7](=[O:17])[C:6]3([CH3:22])[CH2:18][O:19][CH2:20][CH2:21][N:5]3[C:4]=2[N:3]=1.[CH3:23][NH:24][C:25]([NH:27][C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][CH:29]=1)=[O:26].C([O-])(O)=O.[Na+]>O1CCOCC1.C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[OH:16][C:13]([CH3:15])([CH3:14])[CH2:12][N:8]1[C:7](=[O:17])[C:6]2([CH3:22])[CH2:18][O:19][CH2:20][CH2:21][N:5]2[C:4]2[N:3]=[C:2]([C:31]3[CH:30]=[CH:29][C:28]([NH:27][C:25]([NH:24][CH3:23])=[O:26])=[CH:33][CH:32]=3)[N:11]=[CH:10][C:9]1=2
Reactant: CNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CC(C)(O)CN1C(=O)C2(C)COCCN2c2nc(Cl)ncc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CNC(=O)Nc1ccc(-c2ncc3c(n2)N2CCOCC2(C)C(=O)N3CC(C)(C)O)cc1
Yield: 18.5 %

Procedure:
A mixture of 2-chloro-5-(2-hydroxy-2-methylpropyl)-6a-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (84.9 mg, 0.260 mmol), 1-methyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)phenyl]-urea (143 mg, 0.520 mmol), saturated aqueous NaHCO3 (1 ml) and PdCl2(dppf) (17.0 mg, 0.021 mmol) in 1,4-dioxane (2 ml) was irradiated in the microwave at 110° C. for 30 minutes The reaction mixture was diluted with THF and passed through 0.45 μM PTFE syringe filter (washed with small amount of MeOH). The filtrate was purified by preparative HPLC (eluting with a gradient of 20-20% ACN (containing 0.035% TFA) in water (containing 0.05% TFA) using a Sunfire Prep 5 μm C18, 75×30 mm column). The fractions containing the desired product were combined and were evaporated under reduced pressure. Then NaHCO3 aqueous solution was added (in order to adjust the pH to basic) and extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo to afford a crude solid. The solid was triturated with hexane/ethyl acetate (3:1), collected by filtration, rinsed with hexane/ethyl acetate (3:1) and dried to afford the title compound (21.1 mg, 0.048 mmol, 18.4% yield) as a pale beige solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.14 (s, 3 H) 1.15 (s, 3 H) 1.35 (s, 3 H) 2.66 (d, J=4.55 Hz, 3 H) 3.19-3.33 (m, 1 H) 3.52-3.80 (m, 3 H) 3.94-4.11 (m, 3 H) 4.12-4.22 (m, 1 H) 4.67 (s, 1 H) 6.00-6.10 (m, 1 H) 7.48 (d, J=8.84 Hz, 2 H) 8.17 (d, J=8.84 Hz, 2 H) 8.58 (s, 1 H) 8.68 (s, 1 H). MS [M+H] found 441.
Reaction SMILES: [C:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][CH:9]=[CH:10][C:11](OCC)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C.O>ClCCl>[C:16]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH:9]=[CH:10][CH2:11][OH:12])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)C=CCC(c1ccccc1)c1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: O
Product: OCC=CCC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2.22 mg (7.92 mmol) of ethyl 5,5-diphenyl-2-pentenoate was dissolved in 30 ml of dichloromethane. 16.1 ml (15.1 mmol) of diisobutylaluminum hydride (0.94 mol/L: hexane solution) was added to the obtained solution under cooling with ice, and they were stirred at room temperature for 2 days. Water was added to the reaction mixture and they were stirred under cooling with ice. The precipitate thus formed was filtered through Celite. The precipitate was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by the silica gel chromatography (hexane/ethyl acetate=3/1 to 1/1) to obtain the title compound.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[CH:10][N:9]([C:12]3[N:34]=[CH:33][CH:32]=[CH:31][C:13]=3[C:14]([NH:16][CH:17]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)[CH:18]([OH:22])[C:19]([OH:21])=O)=[O:15])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:36][O:37][NH2:38]>>[F:30][C:26]1[CH:25]=[C:24]([CH2:23][CH:17]([NH:16][C:14](=[O:15])[C:13]2[CH:31]=[CH:32][CH:33]=[N:34][C:12]=2[N:9]2[CH:10]=[CH:11][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8]2)[CH:18]([OH:22])[C:19]([NH:38][O:37][CH3:36])=[O:21])[CH:29]=[CH:28][CH:27]=1
Reactant: CON
Reactant: O=C(NC(Cc1cccc(F)c1)C(O)C(=O)O)c1cccnc1-n1ccc(-c2ccccc2)n1
Agent: Cl
Product: CONC(=O)C(O)C(Cc1cccc(F)c1)NC(=O)c1cccnc1-n1ccc(-c2ccccc2)n1

Procedure:
The reaction was carried out in analogy to reaction step 1.3 by reacting 3-(2-(3-phenyl-1H-pyrazol-1-yl)nicotinamido)-2-hydroxy-4-(3-fluorophenyl)-butanoic acid with O-methylhydroxylamine hydrochloride. ESI-MS [M+H]+: 490.2
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:13][C:12]2[C:14]([OH:21])=[CH:15][CH:16]=[C:17]([C:18]([OH:20])=[O:19])[C:11]=2[N:10]=1.O=S(Cl)Cl.[CH3:26]O>>[CH3:26][O:19][C:18]([C:17]1[C:11]2[N:10]=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])[NH:13][C:12]=2[C:14]([OH:21])=[CH:15][CH:16]=1)=[O:20]
Reactant: O=C(O)c1ccc(O)c2[nH]c(-c3ccc(F)cc3F)nc12
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(O)c2[nH]c(-c3ccc(F)cc3F)nc12
Temperature: 25 °C
Yield: 84 %

Procedure:
2-(2,4-difluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid (1.70 mg, 5.86 mmol) obtained in step 3 was dissolved in methanol, SOCl2 (8.2 ml, 112 mmol) was added dropwise thereto and refluxed for 15 hours. The resulting solution was cooled to room temperature, concentrated under a reduced pressure to remove methanol, and the residue was neutralized with NaHCO3. Then, the neutralized residue was extracted with ethyl acetate and concentrated under a reduced pressure to obtain a residue which was purified by silica gel chromatography to obtain the title compound (1.50 mg, 1.64 mmol) in a yield of 84%.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N+]([O-])=O)=[CH:4][C:3]=1[S:11]([OH:14])(=[O:13])=[O:12].OC1C2C(=C(S(O)(=O)=O)C([NH2:26])=CC=2)C=C(S(O)(=O)=O)C=1>O>[S:11]([OH:14])(=[O:13])([C:3]1[CH:4]=[CH:5][C:6]([NH2:26])=[CH:7][CH:2]=1)=[O:12]
Reactant: Nc1ccc([N+](=O)[O-])cc1S(=O)(=O)O
Reactant: Nc1ccc2c(O)cc(S(=O)(=O)O)cc2c1S(=O)(=O)O
Solvent: O
Product: Nc1ccc(S(=O)(=O)O)cc1
Reaction time: 1 h

Procedure:
2-Amino-5-nitro-benzenesulfonic acid is diazotized and coupled neutrally to I acid. 43 mmol of this dye are dissolved in 200 ml water and indirectly diazotized. After stirring for 1 hour, the excess nitrous acid is removed with amidosulfonic acid and a solution of 43 mmol 4-hy-droxy-7-aminonaphthalene-2,8-disulfonic acid in 200 ml water is added. Coupling is completed overnight at pH 8-9, the dye is filtered under suction and the sulfo group is split off by boiling for 12 h in a 1:1 mixture of water and N-methyl pyrrolidone containing 60 ml concentrated hydrochloric acid. This dye is diazdtized and added dropwise to a solution in 100 ml water of 7.2 mmol of a dye obtained by acidic coupling of p-sulfanilic acid onto 4-amino-5-hydroxynaphthalene-1,3-disulfonic acid. After stirring overnight, the dye is precipitated by addition of acetone, optionally dissolved and allowed to crystallize once more and then washed with aqueous acetone. 0.1 g dye are dissolved in 9.9 g polyvinyl alcohol (PVAL) (Mowiol®28-99, a product of Hoechst AG) and 190 ml water and a 500μ thick layer is cast from this solution. After evaporation of the water, an approx. 50μ thick dark-blue film is obtained. The film is stretched by 500% at 130° C. The value is 15.3 at 650 nm. If the following acids are used instead of 4-amino-5-hydroxynaphthalene-,1, 3-disulfonic acid, the following results are obtained:
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:5](=[O:14])[NH:6][CH2:7][C:8]([CH3:13])([CH3:12])[CH2:9][C:10]=2[N:11]=1.CC1(C)C(C)(C)OB([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].P(C(C)(C)C)(C(C)(C)C)C(C)(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH3:12][C:8]1([CH3:13])[CH2:7][NH:6][C:5](=[O:14])[C:4]2[S:3][C:2]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)=[N:11][C:10]=2[CH2:9]1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Reactant: CC1(C)CNC(=O)c2sc(Br)nc2C1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC1(C)CNC(=O)c2sc(-c3ccncc3)nc2C1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
2-bromo-5,6,7,8-tetrahydro-7,7-dimethylthiazolo[5,4-c]azepin-4-one (200 mg, 1.0 Eq.), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (224 mg, 1.5 Eq.), Pd(DBA)2 (42 mg, 0.1 Eq.) and sodium carbonate (2M aq., 1090 μl, 3.0 Eq.) were suspended/dissolved in dioxane (4 mL). The system was degassed using vacuum/N2 cycles three times. P(tBu)3 (42 mg, 0.1 Eq.) was then added and the reaction mixture stirred at 80° C. overnight. The reaction mixture was allowed to cool to room temperature. The reaction mixture was partitioned in EtOAc/H2O and filtered through celite, which was washed copiously with EtOAc/H2O. The filtrate was partitioned and the aqueous was extracted with EtOAc (3×20 mL). The combined organics were washed with sat. aq. Na2CO3 (1×20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by column chromatography (5% MeOH/95% EtOAc, followed by recrystallization from EtOAc/Hexanes gave the title compound was isolated as a brown powder (19.6 mg, 10% yield); 1H NMR (DMSO D6) 1.0 (6H, s), 3.0 (4H, m), 7.7-7.8 (2H, d), 8.3 (1H, br m), 8.7-8.8 (2H, d); LC/MS M+1 (obs.) 274.60; LC/MS M−1 (obs.) 272.80.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:19]O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([O:6][CH3:19])=[O:5]
Reactant: CO
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(S(C)(=O)=O)ccc1Cl
Temperature: 25 °C
Reaction time: 72 h

Procedure:
2-chloro-5-(methylsulfonyl)benzoic acid (4 g, 0.016 mol) was dissolved in MeOH (10 ml) and thionyl chloride (1 ml) was added. The reaction was stirred for 72 h at RT. Solvents were evaporated and crude solid was dissolved in DCM and washed with saturated aqueous solution of NaHCO3. The organic solvent was dried (Na2SO4) and evaporated to obtain 0.88 g of the title compound as white solid.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[NH:13][C:14]1[N:15]=[C:16]([CH3:29])[C:17]2[CH2:23][CH2:22][CH2:21][N:20]([CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[C:18]=2[N:19]=1.I[CH2:31][CH3:32]>CN(C)C=O>[Br:3][C:4]1[CH:9]=[C:8]([CH:10]([CH3:11])[CH3:12])[CH:7]=[CH:6][C:5]=1[N:13]([CH2:31][CH3:32])[C:14]1[N:15]=[C:16]([CH3:29])[C:17]2[CH2:23][CH2:22][CH2:21][N:20]([CH:24]([CH2:25][CH3:26])[CH2:27][CH3:28])[C:18]=2[N:19]=1
Reactant: CCC(CC)N1CCCc2c(C)nc(Nc3ccc(C(C)C)cc3Br)nc21
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(CC)N1CCCc2c(C)nc(N(CC)c3ccc(C(C)C)cc3Br)nc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
To a vigorously stirred suspension of sodium hydride (0.004 g, 0.17 mmol) in N,N-dimethylformamide (0.5 mL) under nitrogen was added a solution of (2-bromo-4-isopropyl-phenyl)-[8-(1-ethyl-propyl)-4-methyl-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-2-yl]-amine (XIV; 0.056 g, 0.13 mmol) in N,N-dimethylformamide (0.5 mL). After 30 minutes at room temperature, iodoethane (0.026 g, 0.17 mmol) was added, and the resulting mixture was stirred at room temperature for 14 hours. The reaction mixture was then poured onto water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined extracts were washed with brine (10 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The yellow oil so obtained was chromatographed over silica gel, eluting with a gradient of 20 to 50% ethyl acetate in hexane, to afford 116 as a pale yellow oil (0.040 g, 67%). ESIMS m/z 459 (M+H).