Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:8]([O:9][CH2:10][C:11]2[C:12]([C:17]3[N:21]([CH:22]([CH3:24])[CH3:23])[N:20]=[CH:19][CH:18]=3)=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:7][N:6]=[CH:5][C:4]=1[OH:25]>CC#N.O=[Mn]=O>[OH:25][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([O:9][CH2:10][C:11]2[C:12]([C:17]3[N:21]([CH:22]([CH3:24])[CH3:23])[N:20]=[CH:19][CH:18]=3)=[N:13][CH:14]=[CH:15][CH:16]=2)[C:3]=1[CH:2]=[O:1]
Reactant: CC(C)n1nccc1-c1ncccc1COc1cncc(O)c1CO
Agent: O=[Mn]=O
Solvent: CC#N
Product: CC(C)n1nccc1-c1ncccc1COc1cncc(O)c1C=O
Temperature: 46 °C

Procedure:
To 4-(hydroxymethyl)-5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)pyridin-3-ol (26 mg, 0.076 mmol, 1 eq.) in CH3CN (10 mL) was added MnO2 (66 mg, 0.76 mmol, 10 eq.). The mixture was heated to 46° C. with stirring O/N, cooled to rt, filtered, and concentrated to give 3-hydroxy-5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 11.06 (s, 1H), 10.35 (s, 1H), 8.70 (dd, J=4.7, 1.5 Hz, 1H), 8.11 (s, 1H), 7.89 (dd, J=7.9, 1.1 Hz, 1H), 7.80 (s, 1H), 7.53 (d, J=1.8 Hz, 1H), 7.36 (dd, J=7.9, 4.8 Hz, 1H), 6.27 (d, J=1.8 Hz, 1H), 5.14 (s, 2H), 4.61 (sep, J=6.6 Hz, 1H), 1.41 (d, 1=6.6 Hz, 6H). LRMS (M+H+) m/z 339.1
Reaction SMILES: C(Cl)(Cl)=O.[N+]([C:8]1[NH:9][CH:10]=[CH:11][N:12]=1)([O-])=O.C(N(CC)CC)C.O[CH2:21][N:22]1[CH2:26][CH:25]([C:27]2[CH:32]=[C:31]([F:33])[C:30]([F:34])=[C:29]([F:35])[CH:28]=2)[CH2:24][C:23]1=[O:36].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1>[F:33][C:31]1[CH:32]=[C:27]([CH:25]2[CH2:26][N:22]([CH2:21][N:9]3[CH:10]=[CH:11][N:12]=[CH:8]3)[C:23](=[O:36])[CH2:24]2)[CH:28]=[C:29]([F:35])[C:30]=1[F:34]
Reactant: O=[N+]([O-])c1ncc[nH]1
Reactant: O=C1CC(c2cc(F)c(F)c(F)c2)CN1CO
Agent: O=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1CC(c2cc(F)c(F)c(F)c2)CN1Cn1ccnc1
Reaction time: 0.5 h

Procedure:
In a 100 ml three necked flask fitted with a magnetic stirrer, under inert atmosphere, phosgene (20 wt % in toluene, 0.95 eq, 2.02 mmol, 1 g) was added dropwise at room temperature to a solution of 2-nitroimidazole (2.5 eq, 5.1 mmol, 0.577 g) and triethylamine (3 eq, 6.1 mmol, 0.628 g, 0.85 ml) in THF (30 ml). After 0.5 h, 1-hydroxymethyl-4-(3,4,5-trifluoro-phenyl)-pyrrolidin-2-one a23 (1 eq, 2.1 mmol, 0.5 g) in THF (5 ml) was added dropwise at room temperature. After 4 h, the crude mixture was pored into a mixture of ice-cooled saturated sodium carbonate. After extraction (AcOEt), drying of the cumulated organic layers (MgSO4), filtration and evaporation of the solvents, the crude mixture was purified by flash chromatography on silicagel (dichloromethane/methanol: 98/2 (v/v)) to give, after recrystallization in AcOEt, 1-(2-nitro-imidazol-1-ylmethyl)-4-(3,4,5-trifluoro-phenyl)-pyrrolidin-2-one 40 (138 mg, 20.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([O:13][CH2:14]/[CH:15]=[C:16](\[Sn](CCCC)(CCCC)CCCC)/[CH3:17])=[N:9]2)=[CH:4][CH:3]=1.[I:31]I>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([O:13][CH2:14]/[CH:15]=[C:16](\[I:31])/[CH3:17])=[N:9]2)=[CH:4][CH:3]=1
Reactant: II
Reactant: CCCC[Sn](CCCC)(CCCC)/C(C)=C\COc1ccn(-c2ccc(Cl)cc2)n1
Solvent: ClCCl
Product: C/C(I)=C/COc1ccn(-c2ccc(Cl)cc2)n1
Reaction time: 3 h

Procedure:
To 10.0 g (18.6 mmol) 1-(4-chloro-phenyl)-3-((Z)-3-tributylstannanyl-but-2-enyloxy)-1H-pyrazole in 100 ml methylene chloride have been added 4.7 g (18.6 mmol) iodine at ambient temperature with stirring which was continued for 3 h. After removal of the solvents in vacuo the crude product was dissolved in 200 ml MTBE. 100 ml 20% aqueous potassium fluoride solution have been added and the mixture was stirred for 2 h at ambient temperature. The aqueous layer was separated and extracted with 20 ml methyl-tert.-butyl ether twice. The combined organic phases have been washed twice with 20 ml of water each, dried with sodium sulfate, and the solvents were removed in vacuo. The crude product (7.2 g) has been purified by chromatography on 50 g silica with methyl-tert.-butylether/hexane (1:20). Yield 5.9 g, melting point 75-77° C.
Reaction SMILES: Br[C:2]1[C:3]([O:31][CH3:32])=[CH:4][C:5]2[CH2:6][CH2:7][N:8]3[C:14]4[C:15](=[O:25])[N:16]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:17][CH2:18][O:19][CH2:20][C:13]=4[C:12]([C:26]4[S:30][CH:29]=[N:28][CH:27]=4)=[C:9]3[C:10]=2[CH:11]=1.C([Sn](CCCC)(CCCC)[C:38]1[S:42][CH:41]=[N:40][CH:39]=1)CCC>C1(C)C=CC=CC=1.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>[C:21]([N:16]1[C:15](=[O:25])[C:14]2[N:8]3[CH2:7][CH2:6][C:5]4[CH:4]=[C:3]([O:31][CH3:32])[C:2]([C:38]5[S:42][CH:41]=[N:40][CH:39]=5)=[CH:11][C:10]=4[C:9]3=[C:12]([C:26]3[S:30][CH:29]=[N:28][CH:27]=3)[C:13]=2[CH2:20][O:19][CH2:18][CH2:17]1)([CH3:22])([CH3:24])[CH3:23]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncs1
Reactant: COc1cc2c(cc1Br)-c1c(-c3cncs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCOC3
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1-c1cncs1)-c1c(-c3cncs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCOC3
Yield: 76.9 %

Procedure:
A degassed solution of 40 mg of 11i, 45 mg of 5-tributylstannyl thiazole and 15 mg of Pd(PPh3)4 in 3 ml of toluene was heated at 110° C. during 5 hr. The reaction mixture was concentrated and the residue was chromatographed over silica gel, using a gradient of toluene/acetone as eluent. The isolated product was treated with diethyl ether, to provide 31 mg of 11l as white crystalline material; Mp: 254-255° C.; Rf 0.30 (heptane/acetone 1/1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([F:12])=[C:7]([OH:13])[CH:6]=[CH:5]2.B([C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1)(O)O>>[F:12][C:8]1[C:7]([OH:13])=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[CH:11][C:2]([C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1)=[CH:3]2
Reactant: Oc1ccc2cc(Br)ccc2c1F
Reactant: O=C(O)c1ccc(B(O)O)cc1
Product: O=C(O)c1ccc(-c2ccc3c(F)c(O)ccc3c2)cc1

Procedure:
Followed the coupling procedure described in Example 29 starting from 6-bromo-1-fluoronaphthalen-2-ol (Intermediate 13) and 4-boronobenzoic acid. 1H-NMR (DMSO-d6, 300 MHz, TMS): δ 13.04 (b, 1H), 10.23 (b, 1H), 8.29 (s, 1H), 7.91-8.01 (m, 7H), 7.74 (d, 1H). MS (ESI): m/z=281.26 [M−1]−.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=[O:10])[CH2:5][C:6]([O:8][CH3:9])=[O:7].[CH3:11][O:12][CH2:13][C:14](Cl)=[O:15]>>[CH3:9][O:8][C:6](=[O:7])[CH:5]([C:14](=[O:15])[CH2:13][O:12][CH3:11])[C:4](=[O:10])[CH2:3][O:2][CH3:1]
Reactant: COCC(=O)Cl
Reactant: COCC(=O)CC(=O)OC
Product: COCC(=O)C(C(=O)COC)C(=O)OC

Procedure:
In analogy to the procedures described for intermediates 1A-E, the title compound has been obtained by i) condensation of methyl 4-methoxyacetoacetate with methoxyacetyl chloride to give 4-methoxy-2-(2-methoxy-acetyl)-3-oxo-butyric acid methyl ester; ii) methylation of 4-methoxy-2-(2-methoxy-acetyl)-3-oxo-butyric acid methyl ester with methyl trifluoromethanesulfonate to give (E and/or Z)-3,4-dimethoxy-2-(2-methoxy-acetyl)-but-2-enoic acid methyl ester; iii) condensation of (E and/or Z)-3,4-dimethoxy-2-(2-methoxy-acetyl)-but-2-enoic acid methyl ester with (3-bromo-phenyl)-hydrazine to give 1-(3-bromo-phenyl)-3,5-bis-methoxymethyl-1H-pyrazole-4-carboxylic acid methyl ester; iv) reaction of 1-(3-bromo-phenyl)-3,5-bis-methoxymethyl-1H-pyrazole-4-carboxylic acid methyl ester with (E)-2-(4-chlorophenyl)vinyl boronic acid to give 1-{3-[(E)-2-(4-chloro-phenyl)-vinyl]-phenyl}-3,5-bis-methoxymethyl-1H-pyrazole-4-carboxylic acid methyl ester; v) saponification of 1-{3-[(E)-2-(4-chloro-phenyl)-vinyl]-phenyl}-3,5-bis-methoxymethyl-1H-pyrazole-4-carboxylic acid methyl ester to give the title compound as light brown solid. MS: 411.2 ([M−H]−, 1 Cl).
Reaction SMILES: [OH-].[Na+].[F:3][CH:4]([F:22])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([O:19]C)=[O:18])=[CH:13][C:12]=1[CH3:21]>CCO>[F:3][CH:4]([F:22])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][C:12]=1[CH3:21]
Reactant: COC(=O)c1ccc(-c2ccccc2C(F)F)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C(=O)O)ccc1-c1ccccc1C(F)F
Temperature: 70 °C
Yield: 97.2 %

Procedure:
A 5 N aqueous solution of NaOH (1.5 mL, 7.5 mmol) was added into a solution of methyl 2′-(difluoromethyl)-2-methylbiphenyl-4-carboxylate (1.4 g, 5.1 mmol) in EtOH (15 mL). The resulting mixture was heated at 70° C. for 1 hour, and then evaporated. The residue was taken up with water (25 mL) and a 5N aqueous solution of HCl (3 mL), and then extracted with MTBE (2×50 mL). The organic layers were washed with brine (25 mL), combined, dried (MgSO4) and concentrated reduced pressure to give the title compound as a white powder (1.3 g, 93%). HPLC (Method A) Rt 4.2 min (purity: 98.9%). LC/MS (Method B): 261.1 (M−H)−. 1H NMR (DMSO-d6, 300 MHz) δ 13.1 (s, 1H), 7.90 (s, 1H), 7.82 (dd, J=7.9, 1.4 Hz, 1H), 7.74 (m, 1H), 7.66-7.55 (m, 2H), 7.26 (m, 2H), 6.55 (t, J=55 Hz, 1H), 2.05 (s, 3H).
Reaction SMILES: [CH2:1]1[CH2:11]CN2[C:4](=[N:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][CH2:2]1.[CH3:12][N:13]([CH:15]=[O:16])[CH3:14]>CC(=O)OCC.O>[CH2:11]=[C:1]1[C:2]2=[CH:3][CH:4]=[N:5][C:6]3[CH:7]=[CH:8][C:15](=[O:16])[N:13]([C:14]=32)[CH2:12]1
Reactant: C1CCC2=NCCCN2CC1
Reactant: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: C=C1Cn2c(=O)ccc3nccc1c32
Yield: 72 %

Procedure:
A solution of intermediate BD.v (1.03 g) in DMF (10 mL) was stirred at rt in the presence of DBU (1.12 mL) for 2 h. The reaction mixture was diluted with EA and water. The aq. layer was extracted with EA (2×100 mL) and DCM/MeOH (3×50 mL; 9:1). The combined org. layers were sequentially washed with water and brine and dried over MgSO4. The solvent was evaporated under reduced pressure, affording a yellow solid (490 mg; 72% yield).
Reaction SMILES: N[C@H](C(O)=O)C.C(O)=O.C(N(CC)CC)C.[CH2:17]([N:24]=[C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH:26]1[CH3:35])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>ClCCl.CCCCCC.C(OCC)(=O)C>[CH2:17]([NH:24][C@@H:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][C@@H:26]1[CH3:35])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC1CCc2ccccc2C1=NCc1ccccc1
Agent: C[C@H](N)C(=O)O
Solvent: CCCCCC
Solvent: O=CO
Solvent: CCOC(C)=O
Product: C[C@H]1CCc2ccccc2[C@H]1NCc1ccccc1
Reaction time: 0.33 h
Yield: 79.8 %

Procedure:
3 mg (4.7 μmol) of the catalyst from example Ala are dissolved in 1 ml of a mixture of formic acid and triethylamine (5:2 v/v) and stirred for 20 min. A solution of 350 mg (1.141 mmol) of racemic N-benzyl-(2-methyl-3,4-dihydro-2H-naphth-1-ylidene)amine in 1.7 ml of dichloromethane is then added and the mixture is stirred at room temperature for 5 days. After removal of the solvent, the dissolution in 5 ml of methanol, treatment with approx. 200 mg of potassium hydroxide and admixing with 10 ml of water at room temperature, extraction is effected three times with in each case 15 ml of dichloromethane and the organic phase is dried over sodium sulfate. After removal of the solvent and column chromatography (20:1 hexane/ethyl acetate), 229 mg (65% yield) of (1S,2S)-N-benzyl-(2-methyl-1,2,3,4-tetrahydronaphth-1-yl)amine are obtained as a light yellow oil.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5]N(C=O)C.[Br:10][C:11]1[CH:20]=[C:19]([Br:21])[CH:18]=[C:17]2[C:12]=1[CH:13]=[CH:14][CH:15]=[C:16]2[C:22](Cl)=[O:23].Cl.COCN>C(N(CC)CC)C>[C:22]([C:16]1[C:17]2[C:12](=[C:11]([Br:10])[CH:20]=[C:19]([Br:21])[CH:18]=2)[CH:13]=[CH:14][CH:15]=1)(=[O:23])[CH3:5]
Reactant: CN(C)C=O
Reactant: O=C(Cl)c1cccc2c(Br)cc(Br)cc12
Agent: COCN
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)c1cccc2c(Br)cc(Br)cc12

Procedure:
The 1-acetyl-5,7-dibromonaphthalene used in the foregoing procedure was prepared by dibromination of benz[cd]-indol-2(1H)-one with bromine in glacial acetic acid to give 41 g of 6,8-dibromobenz[cd]indol-2(1H)-one, m.p. 259°-260° C. The latter (12.8 g) was heated under reflux for one hour in two liters of 5% potassium hydroxide, the reaction mixture was cooled, filtered and then treated with 2.8 g of a solution of sodium nitrite in 50 ml of water. The resulting solution, cooled to 0° C., was added dropwise to 800 ml of a 40% solution of sulfuric acid while maintaining the temperature at -5° C. The reaction mixture was stirred for one hour, then poured slowly into a solution of 140 g of sodium hypophosphite in 800 ml of water at 0° C. with stirring. The solid which separated was collected by filtration and dissolved in 3 liters of 2% sodium carbonate solution, and the resulting solution was filtered, acidified with concentrated hydrochloric acid and the mixture extracted with ethyl acetate. The combined organic extracts were dried and taken to dryness to give 8 g of 5,7-dibromo-1-naphthalenecarboxylic acid which was heated with thionyl chloride in the presence of a small amount of DMF. The resulting crude 5,7-dibromo-1-naphthalenecarboxylic acid chloride, together with 6.0 g of methoxymethylamine hydrochloride in 750 ml of MDC, was treated dropwise at 0° C. with 60 ml of triethylamine in 250 ml of MDC. The reaction mixture was filtered, the filtrate was taken to dryness, and the resulting residue (12.0 g) was dissolved in THF and treated at 0° C. with stirring with a solution of 29.5 ml of 3M methyl magnesium bromide. The reaction mixture was stirred for ten minutes, quenched with water, taken to dryness and the residue partitioned between ethyl acetate and water. The mixture was filtered, the organic extracts were separated, dried and taken to dryness to give 9.9 g of 1-acetyl-5,7-dibromonaphthalene.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].[CH3:28]I>CN(C=O)C>[CH3:28][O:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CI
Reactant: COC(=O)c1ccc(OC2CCCN(C(=O)OC(C)(C)C)C2)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC2CCCN(C(=O)OC(C)(C)C)C2)cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl 2-hydroxy-4-(1-tert-butyloxycarbonyl-3-piperidinyloxy)benzoate from Step 2 above (1.50 g, 4.27 mmol) in DMF (40 mL) under N2 was added NaH (246 mg, 6.41 mmol). The reaction mixture was cooled, then CH3I (0.53 mL, 8.54 mmol) was added via syringe. The reaction mixture was warmed to ambient temperature and stirred for 2 hours. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and aqueous NaHCO3. The ethyl acetate layer was dried (MgSO4), filtered, and evaporated under reduced pressure. The residue was purified using pressurized silica gel column chromatography, eluting with 20% ethyl acetate in hexanes. Methyl 2-methoxy-4-(1-tert-butyloxycarbonyl-3-piperidinyloxy)benzoate was obtained as a colorless oil which crystallized on standing overnight.
Reaction SMILES: C([O:5][C:6](=[O:33])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[C:23](=[O:24])[CH:22]=[C:21]3[C:16]([CH:17]=[C:18]([C:25]#[C:26][CH2:27][N:28]4[CH:32]=[CH:31][N:30]=[CH:29]4)[CH:19]=[CH:20]3)=[CH:15]2)=[CH:9][CH:8]=1)(C)(C)C.FC(F)(F)C(O)=O>>[N:28]1([CH2:27][C:26]#[C:25][C:18]2[CH:19]=[CH:20][C:21]3[C:16]([CH:17]=2)=[CH:15][N:14]([CH2:13][C:10]2[CH:11]=[CH:12][C:7]([C:6]([OH:33])=[O:5])=[CH:8][CH:9]=2)[C:23](=[O:24])[CH:22]=3)[CH:32]=[CH:31][N:30]=[CH:29]1
Reactant: CC(C)(C)OC(=O)c1ccc(Cn2cc3cc(C#CCn4ccnc4)ccc3cc2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(Cn2cc3cc(C#CCn4ccnc4)ccc3cc2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-[7-(3-imidazol-1-ylprop-1-ynyl)-3-oxo-2H-isoquinolin-2-ylmethyl]benzoic acid tert-butyl ester (0.38 g, 0.86 mmol, Example 13A) is treated with trifluoroacetic acid (6 mL) and stirred at room temperature for 30 minutes. The reaction mixture is evaporated to dryness, triturated with ethyl acetate, the solid is collected by filtration, washed with water, washed with ethyl acetate, and dried under house vacuum. This will afford the desired product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=[O:9])[CH3:8])[N:2]=1.[BH4-].[Na+]>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([OH:9])[CH3:8])[N:2]=1
Reactant: CC(=O)c1cccnn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1cccnn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
To 1-pyridazin-3-yl-ethanone (1.4 g, 11.2 mmol) in methanol (112 mL) add sodium borohydride (0.85 g, 22.5 mmol) at 0° C. and stir for 1 h at ambient temperature. Evaporate the mixture and purify by chromatography on silica gel eluting with EtOAc:hexane (1:1 to 1:0) and methanol:EtOAc (0:1 to 1:9) to obtain the title compound (1.3 g, 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[CH3:17].[NH2:18][C:19]1[C:23]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[CH:25]=2)=[CH:22][NH:21][N:20]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:20]3[N:21]=[CH:22][C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[CH:25]=4)=[C:19]3[N:18]=2)=[CH:4][C:3]=1[CH3:17]
Reactant: Cc1cc(-c2c[nH]nc2N)ccn1
Reactant: Cc1cc(C(=O)CC(=O)C(F)(F)F)ccc1Cl
Product: Cc1cc(-c2cnn3c(C(F)(F)F)cc(-c4ccc(Cl)c(C)c4)nc23)ccn1
Yield: 48.2 %

Procedure:
Reaction of 1-(4-chloro-3-methyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (132 mg, 0.5 mmol), prepared from commercially available 4-chloro-3-methyl-acetophenone according to general procedure A, and 3-amino-4-(2-methyl-4-pyridinyl)-pyrazole [see part synthesis of amino-pyrazole derivatives] (87 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (97 mg, 48%). MS (ISP) 403.5 [(M+H)+]; mp 240° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[N:11]([CH2:14][CH2:15][CH2:16][F:17])[N:10]=[N:9]2)=[C:4]([F:18])[CH:3]=1.[N+:19]([O-])([OH:21])=[O:20].OS(O)(=O)=O>>[OH:1][C:2]1[C:7]([N+:19]([O-:21])=[O:20])=[CH:6][C:5]([N:8]2[C:12](=[O:13])[N:11]([CH2:14][CH2:15][CH2:16][F:17])[N:10]=[N:9]2)=[C:4]([F:18])[CH:3]=1
Reactant: O=c1n(CCCF)nnn1-c1ccc(O)cc1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=c1n(CCCF)nnn1-c1cc([N+](=O)[O-])c(O)cc1F

Procedure:
From 4-hydroxy-2-fluoroaniline there is produced (in the manner described in published PCT International Application No. WO 85/01939 published May 9, 1985) 1-(4-hydroxy-2-fluorophenyl)-1,4-dihydro-4-(3-fluoropropyl) -5H-tetrazol-5-one. The latter is the nitrated by treatment with a mixture of HNO3 and H2SO4 to form 1-(4-hydroxy-2-fluoro-5-nitrophenyl)-1,4-dihydro-4-(3-fluoropropyl)-5H-tetrazol-5-one. The latter is then dissolved in N,N-dimethylformamide ("DMF") and mixed with a dispersion of NaH in DMF, after which a solution of ethyl bromoacetate is added, resulting in a reaction yielding 1-(4-carboethoxy-methoxy-2-fluoro-5-nitrophenyl)-1,4-dihydro-4-(3-fluoropropyl)-5H-tetrazol-5-one. The latter is then dissolved in acetic acid and then added to a hot suspension of iron powder in acetic acid and reacted at elevated temperature (e.g. 80°-90° C.) for about an hour to form 1-(7-fluoro-2H-1,4-benzoxazin-3(4H)-one-6-yl)1,4-dihydro-4-(3-fluoropropyl)-5H-tetrazol-5-one. The latter is then dissolved in DMF and added to a suspension of NaH in DMF and warmed to, e.g 50° C. Then a solution of 1-iodopropane in DMF is added and the mixture allowed to react to form 1-[7-fluoro-4-propyl-2H-1,4-benzoxazin-3(4H)-on-6-yl]-1,4-dihydro-4-(3-fluoropropyl)-5H-tetrazol-5-one.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10](=O)[CH2:11][C:12]([O:14]CC)=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:18]([C:21]1[CH:31]=[CH:30][C:24]([C:25]([NH:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=1)=[N+:19]=[N-:20].[O-]CC.[Na+].O>C(O)C>[CH2:28]([NH:27][C:25]([C:24]1[CH:30]=[CH:31][C:21]([N:18]2[C:10]([CH2:9][CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[C:11]([C:12]([OH:14])=[O:13])[N:20]=[N:19]2)=[CH:22][CH:23]=1)=[O:26])[CH3:29]
Reactant: CCNC(=O)c1ccc(N=[N+]=[N-])cc1
Reactant: CCOC(=O)CC(=O)CCCc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CCCc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 10.5 h
Yield: 92.6 %

Procedure:
Ethyl 6-phenyl-3-oxohexanoate (1.11 g, 4.73 mmol, 1.25 eq.) obtained in Example 100a) and 4-azido-N-ethylbenzamide (0.719 g, 3.78 mmol) were dissolved in ethanol (20 ml), sodium ethoxide (357 mg, 4.73 mmol, 1.25 eq.) was added, and the mixture was stirred at room temperature for 30 min and at 60° C. for 10.5 hr. Water (20 ml) was added to the reaction mixture, ethanol was evaporated, and the residue was diluted with 2% aqueous sodium carbonate solution (20 ml) and washed with ethyl acetate-hexane (2:1, 50 ml). The organic layer was extracted with 2% aqueous sodium carbonate solution (20 ml). The aqueous layers were combined, acidified (pH<3) with 6N hydrochloric acid and stood still at 0° C. The precipitate was collected by filtration, washed with ice-cold water and dried to give the title compound as a pale-yellow powder (1.32 g, 3.50 mmol, 92.6%).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:11]2[NH:10][CH:9]=[C:8]3[C:14](=[O:23])[N:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:16]=[C:7]3[C:6]=2[CH:5]=1)([O-:3])=[O:2].[Cl:24]C1C=CC(NN)=CC=1>>[Cl:24][C:20]1[CH:21]=[CH:22][C:17]([N:15]2[C:14](=[O:23])[C:8]3=[CH:9][NH:10][C:11]4[CH:12]=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=4[C:7]3=[N:16]2)=[CH:18][CH:19]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: O=c1c2c[nH]c3ccc([N+](=O)[O-])cc3c-2nn1-c1ccccc1
Product: O=c1c2c[nH]c3ccc([N+](=O)[O-])cc3c-2nn1-c1ccc(Cl)cc1

Procedure:
The title compound was prepared following the procedure described for 5a using 4-chlorophenylhydrazine instead of phenylhydrazine. 1H-NMR (DMSO-d6) δ (ppm): 7.50 (2H, d, J=8.91 Hz), 7.90 (1H, d, J=8.91 Hz), 8.29 (2H, d, J=8.91 Hz), 8.48 (1H, dd, J=8.91, 2.38 Hz), 8.88 (1H, s), 8.91 (1H, d, J=2.67 Hz). m/z 341.8 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][CH2:8][C:9]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:10]=1[CH2:16][NH:17][C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6](=[O:24])[CH2:7][CH2:8][C:9]1[CH:14]=[C:13]([O:15][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:12]=[CH:11][C:10]=1[CH2:16][NH:17][C:18]([O:20][CH:21]([CH3:22])[CH3:23])=[O:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CC(C)OC(=O)NCc1ccc(O)cc1CCC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)OC(=O)NCc1ccc(OCc2ccccc2)cc1CCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-[5-hydroxy-2-(isopropoxycarbonylamino-methyl)-phenyl]-propionic acid tert-butyl ester (14.8 mmol) in DMF (100 mL) was added Cs2CO3 (29.6 mmol) and benzyl bromide (16.3 mmol). The reaction mixture was stirred overnight at ambient temperature and diluted with EtOAc (200 mL). The mixture was washed with brine (100 mL) and water (100 mL). The organic layer was dried (Na2SO4) and concentrated to a yellow oil (6.8 g). MS [ES] m/z 428 (M+H)+.