Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](C1C=CC(CO[C:12](=O)[CH2:13][C:14](=[O:35])[CH2:15][C@:16]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])([NH2:27])[C:17]([O:19]CC2C=CC=CC=2)=[O:18])=CC=1)([O-])=O.C([O-])([O-])=O.[Na+].[Na+].I[CH2:44][CH2:45][CH2:46][CH2:47]I>CN(C=O)C>[C:28]([C@:16]([NH2:27])([CH2:15][C:14](=[O:35])[CH2:13][CH:12]1[CH2:47][CH2:46][CH2:45][CH2:44]1)[C:17]([OH:19])=[O:18])([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29]
Reactant: CC(C)(C)OC(=O)[C@](N)(CC(=O)CC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)OCc1ccccc1
Reactant: ICCCCI
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@](N)(CC(=O)CC1CCCC1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 149.6 %

Procedure:
Boc-2(S)-amino-4-keto-1,6-hexanedioic acid 1-benzyl ester 6-(4-nitrophenyl)methyl ester (4.8 g, 9.6 mmol) was dissolved in DMF (100 mL). Na2CO3 (4.07 g, 38.4 mmol) and 1,4-diiodobutane (3.59 g, 11.6 mmol) were added to the solution. The mixture was stirred 18 h at room temperature and then heated at 50° for 3 h. Evaporation of the solvent, dissolution of the resulting residue with EtOAc, washing of the resulting solution with 1N aqueous HCl and water, followed by drying (MgSO4) and evaporation gave a crude product. The crude product was purified by chromatography {SiO2, eluent: hexane-EtOAc (4:1)} to give the corresponding benzyl ester of the title compound (4.3 g). The benzyl ester was subjected to hydrogenolysis {20% Pd(OH2)/C in MeOH, 18 h} and worked up (see section (d) of example 8 hereinafter) to give the title compound (140 mg). NMR and mass spectrum of the product were in agreement with the expected structure.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[C:10]([S:13][CH3:14])[CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:15].[C:16]([O:20][C:21]([NH:23][C:24]([CH3:30])([CH3:29])[CH2:25][C:26](O)=[O:27])=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([NH:23][C:24]([CH3:30])([CH3:29])[CH2:25][C:26]([NH:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[C:10]([S:13][CH3:14])[CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:15])=[O:27])=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CSc1ccc2c(c1)CCC(N)C(=O)N2
Reactant: CC(C)(CC(=O)O)NC(=O)OC(C)(C)C
Product: CSc1ccc2c(c1)CCC(NC(=O)CC(C)(C)NC(=O)OC(C)(C)C)C(=O)N2

Procedure:
Prepared from the intermediate obtained in Step D and 3-t-butoxycarbonylamino-3-methyl-butanoic acid (Example 31, Step E) by the procedure described in Example 1, Step F. 1H NMR (200MHz,CDCl3): 1.33 (s,6H), 1.40 (s,9H), 1.91 (m,1H), 2.4-3.0 (m,5H), 2.48 (s,3H), 4.50 (m,1H), 5.22 (br, s1H), 6.68 (d,7Hz,1H), 6.90 (d,8Hz,1H), 7.11 (m,2H), 7.66 (br, s,1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[K+]>C1COCC1>[NH2:15][CH2:14][C:11]1[CH:10]=[CH:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)=[CH:13][CH:12]=1
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: NCc1ccc(-c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4′-Hydroxy-biphenyl-4-carbonitrile (10.00 g, 51.2 mmol) in 150 mL of anhydrous THF was added under nitrogen dropwise over 30 minutes to a suspension of LAH (2.91 g, 76.7 mmol) in 200 mL of anhydrous THF at room temperature. After the addition the reaction was refluxed for 20 h (overnight). In the following order 2.91 mL of water, 2.91 mL of 15% KOH and 8.73 mL of water were added dropwise. The reaction was stirred for 30 minutes at room temperature. The solid was removed by filtration and dried under reduced pressure to give a yellow solid which was used in the next step without additional purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=2[O:22][CH3:23])[CH:17]=O)=[CH:5][CH:4]=1.[NH2:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[NH2:34])[C:28]([OH:30])=[O:29]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]([C:17]3[NH:34][C:33]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=4[N:24]=3)[CH:19]=[CH:20][C:21]=2[O:22][CH3:23])=[CH:5][CH:4]=1
Reactant: Nc1ccc(C(=O)O)cc1N
Reactant: COc1ccc(CCCCOc2cc(C=O)ccc2OC)cc1
Product: COc1ccc(CCCCOc2cc(-c3nc4cc(C(=O)O)ccc4[nH]3)ccc2OC)cc1
Yield: 35.2 %

Procedure:
3-(4-(4-Methoxyphenyl)-butoxy)-4-methoxybenzaldehyde (2.8 g) and 3,4-diaminobenzoic acid (1.4 g) were heated to about 120° C. over 1 hour. The resulting residue was chromatographed on a 5×10 cm pad of silica gel eluting with ether to give 1.4 g of a beige solid which was recrystallized from 20 ml of methanol. M.P. 167°-169° C. MS m/e 450 (M+ +1). Elemental analysis calculated for C26H28 O5N2 : C, 69.62; H, 6.29; N, 6.24. Found: C, 69.72; H. 6.70; N, 5.75.
Reaction SMILES: Br[CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:29])[CH2:11][N:12]2[C:17](=[O:18])[CH:16]=[C:15]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][N:22]=3)[CH:14]=[N:13]2)=[C:6]([CH3:30])[CH:5]=1)[CH3:3].[CH3:31][NH:32][CH3:33]>C(Cl)Cl>[CH3:31][N:32]([CH3:33])[CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:29])[CH2:11][N:12]2[C:17](=[O:18])[CH:16]=[C:15]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][N:22]=3)[CH:14]=[N:13]2)=[C:6]([CH3:30])[CH:5]=1)[CH3:3]
Reactant: CNC
Reactant: COc1ccc(COc2cnn(CC(=O)c3ccc(C(C)Br)cc3C)c(=O)c2)nc1
Solvent: ClCCl
Product: COc1ccc(COc2cnn(CC(=O)c3ccc(C(C)N(C)C)cc3C)c(=O)c2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-{2-[4-(1-Bromo-ethyl)-2-methyl-phenyl]-2-oxo-ethyl}-5-(5-methoxy-pyridin-2-ylmethoxy)-2H-pyridazin-3-one (preparation 10d, 1.55 g, 3.28 mmol) in CH2Cl2 (5 mL) is added a solution of dimethylamine (2 M in THF, 4.9 mL, 9.8 mmol). The reaction mixture is stirred overnight at room temperature. After dilution with CH2Cl2, the mixture is washed with aqueous NaHCO3 solution. The organic layer is dried over MgSO4 and evaporated under reduced pressure. The crude product is purified via reverse phase HPLC chromatography (Phenomenex Gemini C18, gradient 30%→95% methanol in water+0.1% NH4OH, 120 mL/min).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][CH:16]1[C:24]2[C:19](=[CH:20][C:21]([CH2:25][C:26]3[CH:27]=[C:28]([CH2:36][OH:37])[CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=3)=[CH:22][CH:23]=2)[CH2:18][CH2:17]1.[F:38][C:39]([F:49])([F:48])[C:40]1[C:41]([CH:46]=O)=[N:42][CH:43]=[CH:44][CH:45]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:35][C:32]([F:33])([F:34])[C:30]1[CH:29]=[C:28]([CH2:36][OH:37])[CH:27]=[C:26]([CH2:25][C:21]2[CH:20]=[C:19]3[C:24](=[CH:23][CH:22]=2)[CH:16]([NH:15][CH2:46][C:41]2[C:40]([C:39]([F:48])([F:38])[F:49])=[CH:45][CH:44]=[CH:43][N:42]=2)[CH2:17][CH2:18]3)[CH:31]=1
Reactant: O=Cc1ncccc1C(F)(F)F
Reactant: NC1CCc2cc(Cc3cc(CO)cc(C(F)(F)F)c3)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: OCc1cc(Cc2ccc3c(c2)CCC3NCc2ncccc2C(F)(F)F)cc(C(F)(F)F)c1
Yield: 45.7 %

Procedure:
Sodium triacetoxyborohydride (40 mg, 0.19 mmol) was added to a solution of (3-((1-amino-2,3-dihydro-1H-inden-5-yl)methyl)-5-(trifluoromethyl)phenyl)methanol (30 mg, 0.093) and 3-trifluoromethyl-2-formylpyridine (15 mg, 0.086 mmol) in DCM (1 mL). The reaction was stirred at rt for 24 h before aq. sat. NaHCO3 (2 mL) was added to the mixture was filtered over a phase separator. The organic filtrate was evaporated to dryness in a Genevac. The crude material was purified by prep. LCMS to afford the title compound (18.9 mg, 42.1%). MS (ESI): m/z [M+H]+ 481.2
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9](=[O:18])[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH2:11])[CH:5]=[CH:4][C:3]=1[O:19][CH3:20]>S(=O)(=O)(O)O>[C:12]1([CH:10]2[CH2:11][C:5]3[C:6](=[C:7]([Cl:8])[C:2]([Cl:1])=[C:3]([O:19][CH3:20])[CH:4]=3)[C:9]2=[O:18])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C=C(C(=O)c1ccc(OC)c(Cl)c1Cl)c1ccccc1
Agent: O=S(=O)(O)O
Product: COc1cc2c(c(Cl)c1Cl)C(=O)C(c1ccccc1)C2
Temperature: 0 °C

Procedure:
2,3-Dichloro-4-(2-phenylacryloyl)anisole (7.4 g., 0.024 mole) is added portionwise to cold, concentrated sulfuric acid (150 ml.) with stirring. The reaction mixture is stirred in an ice bath for 2 hours, then added dropwise to ice-water to precipitate 3.91 g. of 2-phenyl-5-methoxy-6,7-dichloro-1-indanone which melts at 193°-195° C. upon crystallization from benzene:cyclohexane, 1:2.
Reaction SMILES: C[O:2][C:3]([CH:5]([O:10][CH:11]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:12]1[CH:32]=[CH:31][C:15]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)=[O:17])=[CH:14][CH:13]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])=[O:4].CO.[OH-].[K+:42]>C1COCC1>[K+:42].[C:27]([O:26][C:24]([N:21]1[CH2:22][CH2:23][N:18]([C:16]([C:15]2[CH:31]=[CH:32][C:12]([CH:11]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[O:10][CH:5]([CH2:6][CH:7]([CH3:8])[CH3:9])[C:3]([O-:4])=[O:2])=[CH:13][CH:14]=2)=[O:17])[CH2:19][CH2:20]1)=[O:25])([CH3:29])([CH3:30])[CH3:28]
Reactant: COC(=O)C(CC(C)C)OC(c1ccccc1)c1ccc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)CC(OC(c1ccccc1)c1ccc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc1)C(=O)[O-]
Temperature: 70 °C

Procedure:
To a solution of tert-butyl 4-{4-[[1-(methoxycarbonyl)-3-methylbutoxy](phenyl)methyl]benzoyl}piperazine-1-carboxylate from step 3 (0.6 g, 1.1 mmol) in THF (6.5 mL) was added methanol (2.2 mL) and 1.0N aqueous potassium hydroxide solution (2.2 mL, 2.2 mmol). The mixture was heated at 70° C. for 20 minutes and then cooled down to room temperature. The crude mixture was evaporated under reduced pressure and co-evaporated twice with toluene. The solid residue obtained was used as such in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11](OCC)=[O:12])=[C:5]([N+:16]([O-])=O)[CH:4]=1>C(O)(=O)C.[Fe]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6]([CH:9]=[CH:10][C:11](=[O:12])[NH:16]2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)/C=C/c1ccc(OC)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: COc1ccc2ccc(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 93.8 %

Procedure:
(E)-Ethyl 3-(4-methoxy-2-nitrophenyl)acrylate (20.00 g, 80 mmol) and iron powder (3.39 mL, 478 mmol) were mixed in acetic acid (300 mL). The reaction mixture was stirred at room temperature for 4 days. The reaction mixture was filtered through CELITE™. The filtrate was partitioned between ethyl acetate and saturated sodium bicarbonate. The aqueous layer was separated and extracted once more with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated. The resulting crude product was diluted with dichloromethane and filtered. The filtrate was diluted with hexanes and partially concentrated. The resulting precipitate was filtered off to yield 7-methoxyquinolin-2(1H)-one (13.16 g, 75 mmol, 94% yield) as a light yellow solid.
Reaction SMILES: [P:1]([O:5][C:6]1[C:7]([O:9][C@H:10]([C@H:13]([CH2:15][OH:16])[OH:14])[C:11]=1[O-:12])=[O:8])([OH:4])([OH:3])=[O:2].[OH-].[Mg+2:18].[OH-]>>[P:1]([O:5][C:6]1[C:7]([O:9][C@H:10]([C@H:13]([CH2:15][OH:16])[OH:14])[C:11]=1[O-:12])=[O:8])([O-:4])([O-:3])=[O:2].[Mg+2:18].[O:8]=[C:7]1[O:9][C@H:10]([C@H:13]([CH2:15][OH:16])[OH:14])[C:11]([O-:12])=[C:6]1[O:5][P:1]([O-:4])([O-:3])=[O:2].[Mg+2:18].[Mg+2:18]
Reactant: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1OP(=O)(O)O
Agent: [Mg+2]
Agent: [OH-]
Product: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1OP(=O)([O-])[O-]
Reaction time: 2 h

Procedure:
The remainder (247 ml) of the reaction mixture which had been analyzed by uv and HPLC, was passed through a column of strongly acidic cation exchange resin (600 ml) in the hydrogen ion form. The column was washed until the total effluent was 2000 ml. The absorbance of the column effluent at pH 10 and 264 nm showed a 93.4% recovery (53.1 mmoles) of the theoretical amount (57 mmoles) of L-ascorbate 2-phosphate expected for stoichiometric 2-phosphorylation of IAA. The column effluent (which was at pH 1.0), was allowed to stand 2 hr. at 25° C., and solid magnesium hydroxide (about 11 g) was added to adjust the pH to about 9.0. The mixture was then allowed to stand overnight at 5° C., and was filtered. Recovery of L-ascorbate 2-phosphate in the filtrate was 91.7%. The filtrate was next concentrated under reduced pressure to a volume of 50 ml, and the concentrate added to absolute ethanol (300 ml). The precipitated magnesium L-ascorbate 2-phosphate was collected by centrifugation and was washed with 95% ethanol (2×100 ml). High pressure liquid chromatographic examination of the ethanol washings showed that magnesium bis-(L-ascorbyl) 2,2'-phosphate was concentrated in the ethanolic washings, and that the solid residue contained only traces of the bis compound. The insoluble material was dried under vacuum to give 19.5 g of practically pure magnesium L-ascorbate 2-phosphate as a freeflowing powder (approximately 86% yield).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][N:7]([CH3:63])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:59]([CH3:62])[CH2:60][CH3:61])[C@H:24]([O:57][CH3:58])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:55][CH3:56])[C@@H:34]([CH3:54])[C:35]([NH:37][C@H:38](/[CH:46]=[CH:47]/[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])(O)=[O:2].Cl.[O:65]=[C:66]1[CH:70]=[CH:69][C:68](=[O:71])[N:67]1[CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][C:77]([NH:79][NH2:80])=[O:78]>>[O:71]=[C:68]1[CH:69]=[CH:70][C:66](=[O:65])[N:67]1[CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][C:77]([NH:79][NH:80][C:1](=[O:2])[CH2:4][CH2:5][CH2:6][N:7]([CH3:63])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:59]([CH3:62])[CH2:60][CH3:61])[C@H:24]([O:57][CH3:58])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:55][CH3:56])[C@@H:34]([CH3:54])[C:35]([NH:37][C@H:38](/[CH:46]=[CH:47]/[C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)[CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:17])[CH3:18])=[O:13])[CH:9]([CH3:11])[CH3:10])=[O:78]
Reactant: NNC(=O)CCCCCN1C(=O)C=CC1=O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](/C=C/c1ccccc1)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Agent: Cl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](/C=C/c1ccccc1)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)NNC(=O)CCCCCN1C(=O)C=CC1=O)C(C)C

Procedure:
8 mg (9.1 mmol) of N-(3-carboxypropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S,3E)-1,4-diphenylbut-3-en-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide and 7.2 mg (27.4 mmol) of 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanehydrazide hydrochloride were coupled and worked up in analogy to Intermediate 157. 8.2 mg (82% of theory) of the title compound were obtained as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH2:9][C:10]([C:12]2[C:13]([CH3:20])=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:29][OH:30].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH2:9]/[C:10](/[C:12]2[C:13]([CH3:20])=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[N:29]\[OH:30])=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1cc(=O)n(C)cc1C(=O)CC(c1ccc(Br)cc1)c1ccccc1C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(=O)n(C)cc1/C(CC(c1ccc(Br)cc1)c1ccccc1C)=N/O

Procedure:
In analogy to example 151, step 3, 5-[3-(4-bromo-phenyl)-3-o-tolyl-propionyl]-1,4-dimethyl-1H-pyridin-2-one was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound as a colorless solid, MS (ESI+): m/z=439.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.Br[CH2:10][CH:11]=O>C(O)CCC>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:10]=[CH:11][N:1]=2)[N:4]=1
Reactant: O=CCBr
Reactant: Nc1ccc(Cl)nn1
Solvent: CCCCO
Product: Clc1ccc2nccn2n1
Temperature: 0 °C
Yield: 38.7 %

Procedure:
3-Amino-6-chloro pyridazine (1.5 g, 0.0116 mol) was dissolved in n-butanol (12 ml), cooled to 0° C. and bromoacetaldehyde (2.8 g, 0.023 mol) was added. The reaction was refluxed for 20 hrs and n-butanol was removed under reduced pressure. To the reaction mixture, water was added and extracted with EtOAc (5×20 ml). The combined organic layers were dried (Na2SO4), concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/hexane) to afford 6-Chloro-imidazo[1,2-b]pyridazine (4) (690 mg, yield=40%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21](I)[S:22][C:13]=12.[CH:24]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)=[O:25]>COCCOC.C(=O)(O)[O-].[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>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21]([C:30]3[CH:29]=[CH:28][CH:27]=[C:26]([CH:24]=[O:25])[CH:31]=3)[S:22][C:13]=12
Reactant: COc1cc(Nc2c(C#N)cnc3cc(I)sc23)c(Cl)cc1Cl
Reactant: O=Cc1cccc(B(O)O)c1
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
Product: COc1cc(Nc2c(C#N)cnc3cc(-c4cccc(C=O)c4)sc23)c(Cl)cc1Cl
Temperature: 25 °C
Yield: 13 %

Procedure:
A mixture of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-iodothieno[3,2-b]pyridine-6-carbonitrile (500 mg, 1.05 mmol), 3-formylphenylboronic acid (330 mg, 2.2 mmol) and 65 mg of tetrakis(triphenylphosphine)palladium(0) in 70 mL of ethylene glycol dimethyl ether and 40 mL of saturated aqueous sodium bicarbonate is heated at reflux for 1.5 hours. The reaction mixture is cooled to room temperature and partitioned between water and ethyl acetate. The organic layer is washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 1:1 hexane:ethyl acetate. The fractions containing product are combined and concentrated in vacuo. The residue is recrystallized from ethyl acetate to provide 62 mg of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(3-formylphenyl)thieno[3,2-b]pyridine-6-carbonitrile as yellow crystals, mp 262–263° C.; 1H NMR (DMSO-d6) δ 3.86 (s, 3H), 7.39 (s, 1H), 7.69–7.82 (m, 2H), 7.98 (s, 1H), 8.03–8.14 (m, 2H), 8.23 (s, 1H), 8.64 (s, 1H), 9.80 (s, 1H), 10.08 (s, 1H); MS 452.0, 453.9 (M−H)−.
Reaction SMILES: [CH2:1]1[O:7][C@H:6]([C@@H:8]([CH2:10][OH:11])[OH:9])[C@H:4]([OH:5])[C@H:2]1[OH:3].OC[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.S(=O)(=O)(O)O.CC1(C)O[C@]2(OC[C@@H]3OC(C)(C)O[C@@H]3C2=O)CO1.C1O[C@@H]([C@H](CO)O)[C@@H](O)[C@@H]1O.C(O)[C@H]([C@@H]([C@H]([C@H](CO)O)O)O)O.[BH4-].[Na+].O=C[C@H]([C@@H]([C@H]([C@H](CO)O)O)O)O>>[CH2:1]1[O:7][CH:6]([CH:8]([CH2:10][OH:11])[OH:9])[CH:4]([OH:5])[CH:2]1[OH:3]
Reactant: OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O
Agent: CC1(C)O[C@H]2CO[C@@]3(COC(C)(C)O3)C(=O)[C@H]2O1
Agent: O=C[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)CO
Agent: O=S(=O)(O)O
Product: OCC(O)C1OCC(O)C1O

Procedure:
1,4-Anhydro-D-glucitol may be prepared using the procedure disclosed in Acta Chem. Scand., B35, 441-449 (1981), whereby D-sorbitol is heated with an aqueous mineral acid such as sulfuric acid. The L-enantiomer, 1,4-anhydro-L-glucitol, may be prepared from L-glucitol by an analogous procedure. L-glucitol may be prepared by sodium borohydride reduction of L-glucose. The D and L enantiomers may simply be combined to form a 1,4-anhydro-DL-glucitol mixture.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[C:7]([C:9]1[CH:10]=C([CH:15]=[C:16]([O:18][C:19]([F:22])([F:21])[F:20])[CH:17]=1)C(O)=O)#[N:8]>CN(C=O)C>[C:7]([C:9]1[CH:10]=[C:1]([CH:15]=[C:16]([O:18][C:19]([F:20])([F:22])[F:21])[CH:17]=1)[C:2]([Cl:4])=[O:3])#[N:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: N#Cc1cc(OC(F)(F)F)cc(C(=O)O)c1
Solvent: CN(C)C=O
Product: N#Cc1cc(OC(F)(F)F)cc(C(=O)Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Oxalyl chloride (2.0 M in DCM, 0.636 mL, 1.272 mmol) was added to neat 3-cyano-5-(trifluoromethoxy)benzoic acid (98 mg, 0.424 mmol) and one drop of DMF was added. The reaction mixture was stirred at room temperature for 30 min and then concentrated under reduced pressure.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].Br[CH2:7][CH2:8][CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]>>[Si:11]([O:10][CH2:9][CH2:8][CH2:7][NH:5][CH2:1][CH2:2][CH2:3][CH3:4])([C:14]([CH3:15])([CH3:16])[CH3:17])([CH3:13])[CH3:12]
Reactant: CCCCN
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Product: CCCCNCCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Butan-1-amine (8 mL) was added to (3-bromopropoxy)(tert-butyl)dimethylsilane (0.8 g) and the resulting mixture stirred overnight at RT. The volatiles were removed by concentration under reduced pressure and the residue was partitioned between saturated sodium bicarbonate solution (20 mL) and ethyl acetate (25 mL). The phases were separated and the aqueous phase was extracted with more ethyl acetate (2×25 mL). The combined organic phases were washed with brine (25 mL), dried over sodium sulphate, filtered and evaporated to give the titled compound as a clear oil. Yield 0.75 g.
Reaction SMILES: CC([N:5]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2S[CH:17]=[CH:18][CH:19]=2)=[CH:11][C:10]=1[NH:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][NH:30][C:31]([O:33][CH2:34][C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)=[O:32])=[CH:25][CH:24]=1)=[O:22])C(=O)[O-])(C)C.[C:41](O)([C:43](F)(F)F)=O>C(Cl)Cl>[N:37]1[CH:38]=[CH:39][CH:40]=[C:35]([CH2:34][O:33][C:31](=[O:32])[NH:30][CH2:29][C:26]2[CH:27]=[CH:28][C:23]([C:21]([NH:20][C:10]3[CH:11]=[C:12]([C:15]4[CH:43]=[CH:41][CH:17]=[CH:18][CH:19]=4)[CH:13]=[CH:14][C:9]=3[NH2:5])=[O:22])=[CH:24][CH:25]=2)[CH:36]=1
Reactant: CC(C)(C)N(C(=O)[O-])c1ccc(-c2cccs2)cc1NC(=O)c1ccc(CNC(=O)OCc2cccnc2)cc1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(-c2ccccc2)cc1NC(=O)c1ccc(CNC(=O)OCc2cccnc2)cc1
Reaction time: 1 h

Procedure:
1,1-dimethylethyl[2-[({4-[({[(pyridin-3-ylmethyl)oxy]carbonyl}amino)methyl]phenyl}carbonyl)amino]-4-(2-thienyl)phenyl]carbamate (10.5 g, 19 mmol) was taken up in DCM (208 mL)/TFA (41.7 mL). After 1 hour, the solvent was removed in vacuo, saturated NaHCO3 was added and the products extracted into EtOAc (×2). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo to give pyridin-3-ylmethyl[(4-{[(4-aminobiphenyl-3-yl)amino]carbonyl}phenyl)methyl]carbamate as a tan solid. 1H NMR (d6-DMSO, 600 MHz) δ 9.69 (s, 1H), 8.57 (s, 1H), 8.51 (dd, J=4.8 and 1.8 Hz, 1H), 7.94 (m, 3H), 7.77 (d, J=7.8 Hz, 1H), 7.53 (d, J=7.8 Hz, 2H), 7.50 (d, J=1.8 Hz, 1H), 7.37 (m, 5H), 7.31 (dd, J=8.4 and 1.8 Hz, 1H), 7.22 (t, J=7.8 Hz, 1H), 6.84 (d, J=8.4 Hz, 1H), 5.08 (br s, 4H), 4.26 (d, J=6.0 Hz, 2H). MS: cal'd 453 (MH+), exp 453 (MH+).