Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]([C:16]1[C:21]([F:22])=[C:20]([C:23]2[C:24](=[O:37])[N:25]([CH3:36])[C:26]3[C:31]([CH:32]=2)=[CH:30][N:29]=[C:28]([NH:33][CH2:34][CH3:35])[CH:27]=3)[C:19]([F:38])=[CH:18][N:17]=1)C(OC(C)(C)C)=O)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][C:16]1[C:21]([F:22])=[C:20]([C:23]2[C:24](=[O:37])[N:25]([CH3:36])[C:26]3[C:31]([CH:32]=2)=[CH:30][N:29]=[C:28]([NH:33][CH2:34][CH3:35])[CH:27]=3)[C:19]([F:38])=[CH:18][N:17]=1
Reactant: CCNc1cc2c(cn1)cc(-c1c(F)cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1F)c(=O)n2C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCNc1cc2c(cn1)cc(-c1c(F)cnc(N)c1F)c(=O)n2C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(2-(N,N-bis-(t-butoxycarbonyl)amino)-3,5-difluoropyridin-4-yl)-7-(ethylamino)-1-methyl-1,6-naphthyridin-2(1H)-one (32 mg) in DCM (10 mL) was added trifluoroacetic acid (5 mL). The mixture was stirred at room temperature for 1 h. The solvent was removed and the residue was partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic phase was washed with brine and was then dried over sodium sulfate, filtered, and concentrated. The residue was chromatographed on silica gel (3% methanol in dichloromethane eluant) to provide the title compound. MS (m/z) 332.1 (M+1).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]=[O:11].C1COCC1.[BH4-].[Na+]>CO>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][OH:11]
Reactant: O=Cc1cc2ccccc2o1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: OCc1cc2ccccc2o1
Temperature: 25 °C

Procedure:
To benzofuran-2-carbaldehyde (4 g, 27.4 mmol, 1 eq.), THF (50 mL) and methanol (50 mL) were added, under argon, and the reaction was cooled using an ice-salt bath. Then sodium borohydride (3.11 g, 82.1 mmol, 3 eq.) was added in several portions, and the reaction was allowed to warm slowly to room temperature for 1 hour. After work-up, benzofuran-2-yl-methanol was obtained in quantitative yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.6 (d, J=5.8 Hz, 2 H) 5.5 (t, J=5.9 Hz, 1 H) 6.8 (s, 1 H) 7.3 (m, 2 H) 7.6 (m, 2 H).
Reaction SMILES: [Br-].C([N+:9]12[CH2:17][C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])([CH2:14][CH2:15][CH2:16]1)[CH2:12][CH2:11][CH2:10]2)C1C=CC=CC=1.CCO>[Pd].[C].C(Cl)(Cl)Cl>[N:9]12[CH2:17][C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])([CH2:14][CH2:15][CH2:16]1)[CH2:12][CH2:11][CH2:10]2
Reactant: CCOC(=O)C12CCC[N+](Cc3ccccc3)(CCC1)C2
Agent: [Pd]
Agent: [Br-]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C12CCCN(CCC1)C2
Temperature: 25 °C
Yield: 75.3 %

Procedure:
A mixture of 1-benzyl-5-(ethoxycarbonyl)-1-azoniabicyclo[3.3.1]nonane bromide (932 mg), 10% Pd/Carbon with a 50% hydration (25 mg), and EtOH (15 mL) was stirred at room temperature under a hydrogen atmosphere of 3 atm. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to obtain a colorless solid. To this solid were added CHCl3 and a saturated aqueous NaHCO3 solution, and the organic layer was separated. Furthermore, the aqueous layer was extracted with CHCl3. The organic layer was collected, dried over MgSO4, and then concentrated under reduced pressure to obtain ethyl 1-azabicyclo[3.3.1]nonane-5-carboxylate (376 mg).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4](=O)[CH2:5][CH2:6][C:7]([OH:9])=[O:8].[CH3:11][C:12]1([CH3:20])[CH2:17][C:16](=[O:18])[CH2:15][C:14](=O)[CH2:13]1.C([O-])(=O)C.[Na+]>O>[CH3:11][C:12]1([CH3:20])[CH2:13][C:14]2[NH:2][CH:3]=[C:4]([CH2:5][CH2:6][C:7]([OH:9])=[O:8])[C:15]=2[C:16](=[O:18])[CH2:17]1
Reactant: NCC(=O)CCC(=O)O
Reactant: CC1(C)CC(=O)CC(=O)C1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC1(C)CC(=O)c2c(CCC(=O)O)c[nH]c2C1
Temperature: 110 °C
Yield: 68 %

Procedure:
A mixture of 5-aminolevulinic acid hydrochloride (1.68 g, 10 mmol), 5,5-dimethyl-1,3-cyclohexandione (1.4 g, 10 mmol) and sodium acetate (1.64 g, 20 mmol) in water (10 mL) was heated to at 110° C. for 4 hours and then cooled. The resulting solid was collected by vacuum filtration, washed with 30% ethanol in water and dried under vacuum to give 1.6 g (68% yield) of 3-(6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-3-yl)-propionic acid. 1H-NMR (360 MHz, dimethylsulfoxide-d6) δ 11.89 (br s, 1H, COOH), 10.94 (br s, 1H, NH), 6.45 (d, 1H), 2.76 (t, 2H, CH2), 2.57 (s, 2H, CH2), 2.44 (t, 2H, CH2), 2.16 (s, 2H, CH2), 0.99 (s, 6H, 2×CH3). MS m/z 235 [M+].
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[C:10]=2[F:19])[CH2:5][CH2:4]1)[CH3:2].Cl>[Pd].CO>[F:19][C:10]1[C:11]([C:15]([F:16])([F:17])[F:18])=[CH:12][CH:13]=[CH:14][C:9]=1[CH:6]1[CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5]1
Reactant: CCN1CC=C(c2cccc(C(F)(F)F)c2F)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCN1CCC(c2cccc(C(F)(F)F)c2F)CC1

Procedure:
Preparation according to Example 2: 1-ethyl-4-[2-fluoro-3-(trifluoromethyl)phenyl]-1,2,3,6-tetrahydropyridine (3.1 g, 11.3 mmol), palladium on carbon (0.3 g), hydrochloric acid (1.5 ml, conc), methanol (30 ml). Yield: 2.3 g (74%). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 235-237° C. MS m/z (relative intensity, 70 eV) 275 (M+, 12), 261 (16), 260 (bp), 177 (10) 84 (13).
Reaction SMILES: Cl[C:2]1[C:7]2=[C:8]([Cl:11])[CH:9]=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.[F:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[OH:22].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:11][C:8]1[CH:9]=[CH:10][N:6]2[C:7]=1[C:2]([O:22][C:14]1[CH:15]=[CH:16][C:17]([N+:19]([O-:21])=[O:20])=[CH:18][C:13]=1[F:12])=[N:3][CH:4]=[N:5]2
Reactant: Clc1ccn2ncnc(Cl)c12
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ncnn3ccc(Cl)c23)c(F)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 71.5 %

Procedure:
A mixture of 4,5-dichloropyrrolo[2,1-f][1,2,4]triazine (3.73 g, 19.8 mmol), 2-fluoro-4-nitrophenol (3.43 g, 21.8 mmol) and potassium carbonate (5.47 g, 39.6 mmol) in DMF (100 mL) was stirred at 60° C. for 1 h. After cooling to rt, the reaction was filtered through a short plug of silica gel with ethyl acetate and then concentrated in vacuo. The crude product was purified by recrystallization from ethyl acetate/hexanes (1:1) to give the title compound (4.37 g, 71%) as a white solid. 1H NMR (CDCl3) δ 8.22–8.17 (m, 2H), 7.92 (s, 1H), 7.77 (d, 1H, J=2.8 Hz), 7.58 (t, 1H, J=7.2 Hz), 6.87 (d, 1H, J=3.2 Hz); MS(ESI+) m/z 309.3 (M+H)+.
Reaction SMILES: [Cl-].[F:2][C:3]([F:35])([F:34])[O:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([CH2:12][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:7]([CH3:32])[C:6]=1[CH3:33].C([Li])CCC.[CH2:41]([O:43][C:44](=[O:55])/[CH:45]=[C:46](\[CH3:54])/[CH:47]=[CH:48]/[CH:49]=[C:50](\[CH3:53])/[CH:51]=O)[CH3:42].O>C1COCC1>[CH2:41]([O:43][C:44](=[O:55])/[CH:45]=[C:46](\[CH3:54])/[CH:47]=[CH:48]/[CH:49]=[C:50](\[CH3:53])/[CH:51]=[CH:12]/[C:8]1[C:9]([CH3:11])=[CH:10][C:5]([O:4][C:3]([F:2])([F:34])[F:35])=[C:6]([CH3:33])[C:7]=1[CH3:32])[CH3:42]
Reactant: Cc1cc(OC(F)(F)F)c(C)c(C)c1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)/C=C(C)/C=C/C=C(\C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(C)/C=C/C=C(C)/C=C/c1c(C)cc(OC(F)(F)F)c(C)c1C
Temperature: 45 °C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
A suspension of 12.2 g (24 mmol) of (4-trifluoromethoxy-2,3,6-trimethylphenyl)methyltriphenylphosphonium chloride in 490 ml of dry THF was cooled to 45° C. and treated rapidly (over ~5 minutes) with 11.1 ml (25.5 mmol) of n-butyl lithium (2.3M in hexane) at -35° to -45° C. The reaction mixture was maintained at that temperature for 15 minutes, allowed to warm slowly to -25° C. at which time it became a slightly turbid orange solution. The mixture was cooled to -45° to -50° C. and 7.0 g (33 mmol) of ethyl-(2E,4E,6E)-3,7-dimethyl-8-oxo-octatrienoate in 50 ml of dry THF was added rapidly. The orange color disappeared; the reaction mixture was stirred at -25° C. for 2 hours, then allowed to warm to 0° C. over 1 hour and maintained at that temperature for 2 hours. The mixture was then poured into 1 liter of cold water and extracted with 250-ml portions of hexane. The organic phase was combined, washed successively with 500 ml of cold water, 2×500 ml of a 60% by volume methanol-water solution, and 500 ml of saturated NaCl solution, dried (MgSO4), filtered and concentrated. The resulting yellow oil was purified by HPLC (2 silica gel columns, 2% ethyl acetate in hexane as elutant) to give 5.79 g of ethyl-(2E,4E,6E,8E)-3,7-dimethyl-9-[2,3,6-trimethyl-4-(trifluoromethoxy)phenyl]-nonatetraenoate; mp 47°-49° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7].C(=O)([O-])[O-].[K+].[K+].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].[I-].[K+]>C(#N)C>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7])[CH3:20]
Reactant: CCOC(=O)CBr
Reactant: O=Cc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)Cn1ccnc1C=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
To a solution of 1H-imidazole-2-carbaldehyde (4.47 g) in acetonitrile (80 ml) were added potassium carbonate (12.93 g), ethyl bromoacetate (6.2 ml) and potassium iodide (7.78 g) at room temperature. The mixture was stirred at 50° C. for 1 hour. After cooling to room temperature, the mixture was filtered to remove the precipitates. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography using dichloromethane and methanol (99:1 to 96:4) as eluents to afford the title compound (5.23 g, yield: 62%) as a brown oil.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([NH:6][C:7]([NH:9][C:10]2[CH:15]=[C:14]([C:16]3[C:17](=[O:29])[N:18]([CH2:27][CH3:28])[C:19]4[C:24]([CH:25]=3)=[CH:23][N:22]=[C:21](Cl)[CH:20]=4)[C:13]([CH3:30])=[CH:12][C:11]=2[F:31])=[O:8])[C:3]2[CH:32]=[CH:33][CH:34]=[CH:35][C:2]1=2.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:42][N:43]([CH3:47])[C:44]([NH2:46])=[O:45].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[S:1]1[CH:5]=[C:4]([NH:6][C:7](=[O:8])[NH:9][C:10]2[C:11]([F:31])=[CH:12][C:13]([CH3:30])=[C:14]([C:16]3[C:17](=[O:29])[N:18]([CH2:27][CH3:28])[C:19]4[C:24]([CH:25]=3)=[CH:23][N:22]=[C:21]([NH:46][C:44](=[O:45])[N:43]([CH3:47])[CH3:42])[CH:20]=4)[CH:15]=2)[C:3]2[CH:32]=[CH:33][CH:34]=[CH:35][C:2]1=2
Reactant: CCn1c(=O)c(-c2cc(NC(=O)Nc3csc4ccccc34)c(F)cc2C)cc2cnc(Cl)cc21
Reactant: CN(C)C(N)=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3csc4ccccc34)c(F)cc2C)cc2cnc(NC(=O)N(C)C)cc21
Temperature: 100 °C
Yield: 9.9 %

Procedure:
A mixture of 1-(benzo[b]thiophen-3-yl)-3-(5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)urea (0.23 g, 0.454 mmol), Cs2CO3 (0.443 g, 1.361 mmol), N,N-dimethylurea (0.200 g, 2.268 mmol) and Xantphos (0.079 g, 0.136 mmol) in dioxane (10 mL) was sparged with Ar, treated with Pd2(dba)3 (0.062 g, 0.068 mmol), sparged again with Ar and heated at 100° C. overnight. The mixture was cooled to RT, the solids removed via filtration and rinsed with water and EtOAc. The layers of the filtrate were separated, the organic layer washed with brine, dried over Na2SO4 and concentrated to dryness. The material was treated with DCM, the solid removed via filtration and the filtrate purified via silica gel chromatography (EtOAc/Hex) to afford 3-(3-(5-(3-(benzo[b]thiophen-3-yl)ureido)-4-fluoro-2-methylphenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-1,1-dimethylurea (25 mg, 9% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.34 (s, 1H), 9.13 (s, 1H), 8.79 (s, 1H), 8.60 (s, 1H), 8.03 (d, J=8.4 Hz, 1H), 7.97 (s, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.83 (m, 2H), 7.62 (s, 1H), 7.45-7.40 (m, 1H), 7.36 (t, J=7.5 Hz, 1H), 7.15 (d, J=12.3 Hz, 1H), 4.14 (d, J=8.0 Hz, 2H), 2.93 (s, 3H), 1.20 (m, 3H); MS (ESI) m/z: 559.2 [M+H]+.
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[C:5]([O:7][CH3:8])=[O:6].C(N(CC)CC)C.[CH2:16]([NH:23][CH2:24][CH2:25][NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[CH2:16]([N:23]1[CH2:24][CH2:25][N:26]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:2][CH:3]1[CH2:4][C:5]([O:7][CH3:8])=[O:6])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)/C=C/CBr
Reactant: c1ccc(CNCCNCc2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)CC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.2 %

Procedure:
Methyl 4-bromocrotonate (Aldrich, 5.53 mL, 40 mmol) was added dropwise with stirring to an ice-cooled solution of triethylamine (11.15 mL, 80 mmol) and N,N′-dibenzylethylenediamine (Aldrich, 9.67 mL, 40 mmol) in toluene (200 mL). The solution was stirred with ice cooling for 1 hour, then allowed to warm gradually to room temperature and stirred 25 hours longer. The mixture was filtered through a pad of diatomaceous earth with an ethyl acetate (20 mL) rinse. The filtrate was concentrated to an oil, which was mixed with 10% aqueous HCl (240 mL). After 5 minutes, the mixture was filtered and the cake was rinsed with water (2×10 mL). The filtrate was washed with ethyl acetate (2×80 mL) and the aqueous phase was made basic (pH˜9-10) by portionwise addition of solid K2CO3 (26 g), then 25% aqueous NaOH (10 mL). The turbid mixture was extracted with ethyl acetate (3×120 mL) and the combined extracts were washed with brine (100 mL), dried (MgSO4) and concentrated under vacuum to leave the title compound as an oil (9.78 g): 1H NMR (300 MHz, CDCl3) δ ppm 2.30-2.47 (m, 4H), 2.49-2.73 (m, 4H), 3.06-3.18 (m, 1H), 3.43 (d, J=13.2 Hz, 2H), 3.53 (d, J=13.2 Hz, 1H), 3.60 (s, 3H), 3.76 (d, J=13.6 Hz, 1H), 7.14-7.36 (m, 10H); MS (DCI) m/z 339 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:13][C:14]1([OH:20])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([N:17]2[CH2:18][CH2:19][C:14]([OH:20])([CH3:13])[CH2:15][CH2:16]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(O)CCNCC1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC1(O)CCN(C2CN(C(=O)OC(C)(C)C)C2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 54.4 %

Procedure:
A 50 mL round-bottomed flask was charged with a solution of 3-oxoazetidine-1-carboxylic acid tert-butyl ester (0.57 g, 3.33 mmol), 4-methylpiperidin-4-ol (0.46 g, 3.99 mmol) and 4 Å molecular sieves (3.34 g) in DCE (20 mL) The reaction mixture was stirred for 6 h at room temperature. Sodium triacetoxyborohydride (1.41 g, 6.66 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The suspension was filtered through Celite and the solution was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, EtOAc:cyclohexane, 0:100 to 100:0) to give 3-(4-Hydroxy-4-methylpiperidin-1-yl)azetidine-1-carboxylic acid tert-butyl ester as a colourless oil (0.49 g, 55%). 1H NMR (CDCl3, 400 MHz) δ 3.93 (dd, J=8.7, 7.17 Hz, 2H); 3.82 (dd, J=8.7, 5.5 Hz, 2H); 3.15-3.07 (m, 1H); 2.58-2.44 (m, 2H); 2.27 (td, J=11.0, 3.5 Hz, 2H); 1.77-1.54 (m, 4H); 1.42 (s, 9H); 1.26 (t, J=6.7 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:11]([CH3:13])([OH:12])[CH:10]([O:14][C:15]2[CH2:19][CH2:18][C:17](=[O:20])[CH:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:21](OC)=[O:22])[CH:8]=2)[O:3]1.[CH3:26][NH:27][CH3:28]>>[CH3:1][C:2]1([CH3:25])[C:11]([CH3:13])([OH:12])[CH:10]([O:14][C:15]2[CH2:19][CH2:18][C:17](=[O:20])[CH:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:21]([N:27]([CH3:28])[CH3:26])=[O:22])[CH:8]=2)[O:3]1
Reactant: CNC
Reactant: COC(=O)c1ccc2c(c1)C(OC1=CC(=O)CC1)C(C)(O)C(C)(C)O2
Product: CN(C)C(=O)c1ccc2c(c1)C(OC1=CC(=O)CC1)C(C)(O)C(C)(C)O2

Procedure:
A solution of 3.46 g of 2,2,3-trimethyl-4-(3-oxo-1-cyclopenten-1-yloxy)-6-methoxycarbonyl-3-chromanol in 100 ml of 33% ethanolic dimethylamine solution is heated to 100° in an autoclave for 10 days. The mixture is cooled, worked up in a customary manner and gives 2,2,3-trimethyl-4-(3-oxo-1-cyclopenten-1-yloxy)-6-dimethylaminocarbonyl-3-chromanol.
Reaction SMILES: C=[C:2]1[CH2:5][N:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]1=[O:12].[O:13]=[O+][O-].O=O.CSC>C(OCC)(=O)C.O>[C:6]1([N:4]2[CH2:5][C:2](=[O:13])[C:3]2=[O:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=[O+][O-]
Reactant: C=C1CN(c2ccccc2)C1=O
Agent: O=O
Solvent: CSC
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1CN(c2ccccc2)C1=O
Temperature: -70 °C
Reaction time: 1.5 h

Procedure:
800 mg (5 mmol) methylene-1-phenyl-azetidine-2-one were dissolved in 50 ml of ethyl acetate and cooled to -70° C. For 15 min ozone was passed through the solution and then oxygen for 1 hour. Then 0.5 ml dimethylsulfide were added, and the solution was stirred for 1.5 hour at -70° C. The temperature was raised to 0° C., and 25 ml of water were added. After 5 min the organic phase was separated and extracted with each of 50 ml of sodium thiosulfate solution and 50 ml of ferrous sulfate solution and then dried over magnesium sulfate. The solvent was evaporated and the residue purified by chromatography over silica gel (eluent: benzene). Yield: 114 mg (14.5%) M.p. 115°-117° C. IR(KBr): 1822, 1757 cm-1
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[CH3:14][C:15]1[C:20]([F:21])=[C:19](F)[N:18]=[C:17]([F:23])[C:16]=1[F:24]>CN(C=O)C.C(#N)C>[CH3:14][C:15]1[C:20]([F:21])=[C:19]([O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=2)[N:18]=[C:17]([F:23])[C:16]=1[F:24]
Reactant: Cc1c(F)c(F)nc(F)c1F
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: Cc1c(F)c(F)nc(Oc2cccc(C(F)(F)F)c2)c1F
Temperature: 75 °C
Reaction time: 16 h
Yield: 76 %

Procedure:
To a solution of 3-trifluoromethyl phenol (13.2 ml, 0.11 mol) in anhydrous DMF (200 ml) is added sodium hydride (4.8 g, 60 %, 0.12 mol). After 30 min at ambient temperature the solution is added to another solution of 4-methyl-2,3,5,6-tetrafluoropyridine (16.5 g, 0.1 mol) in anhydrous acetonitrile (700 ml) at 50° C. during 3 hours. The resulting mixture is then stirred for 1 hour at 50° C. and 16 hours at 75° C. The solvents are removed in vacuo and to the residue is added ethyl acetate/pentane (1000 ml, 1/1 by volume). The mixture is washed twice with 2M NaOH and 5 times with water. After drying and evaporation of the organic layer, the residue is purified by vacuum destillation. One obtains a colorless oil (23.3 g, 76 mmol, 76 % yield, bp. 76 ° C. at 0.025 mbar) of 4-methyl-2,3,5-trifluoro-6-(3-trifluoromethylphenoxy)pyridine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]#[N:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Br[CH:14]([CH3:16])[CH3:15].[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[CH:14]([CH:10]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=1)[C:11]#[N:12])([CH3:16])[CH3:15]
Reactant: CC(C)Br
Reactant: COc1ccc(CC#N)cc1F
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(C(C#N)C(C)C)cc1F
Yield: 82.3 %

Procedure:
A mixture of 3-fluoro-4-methoxyphenylacetonitrile (30 g, 0.18 mol), 2-bromopropane (27.7 g, 0.225 mol), benzyltriethylammonium chloride (2.3 g, 0.01 mol) and sodium hydroxide solution (50%, 66 ml) is heated at 55° for 1 hour and cooled. The mixture is diluted with water, extracted with ether, washed with water, 1 NHCl, water, and dried (Na2SO4). Evaporation gives the product as a brown oil (30.7 g). NMR spectrum shows the benzylic proton as a doublet at 3.6 δ.
Reaction SMILES: Br[C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[N:7]=[C:6]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[C:5]=2[S:4][CH:3]=1.[N:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>>[N:26]1[CH:31]=[CH:30][C:29]([C:2]2[C:10]3[C:9](=[O:11])[N:8]([CH2:12][CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=4)[N:7]=[C:6]([C:20]4[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=4)[C:5]=3[S:4][CH:3]=2)=[CH:28][CH:27]=1
Reactant: OB(O)c1ccncc1
Reactant: O=c1c2c(Br)csc2c(-c2ccncc2)nn1CCc1ccccn1
Product: O=c1c2c(-c3ccncc3)csc2c(-c2ccncc2)nn1CCc1ccccn1
Yield: 75.2 %

Procedure:
The title compound was prepared in analogy to the process described in Example 3.5 starting from 3-bromo-7-pyridin-4-yl-5-[2-(pyridin-2-yl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one and pyridine-4-ylboronic acid. Yield: 75.2%.
Reaction SMILES: [CH3:1][CH:2]([O:6][C:7](=[O:25])[C:8]1[CH:13]=[CH:12][C:11]([O:14]C(OCC2C=CC=CC=2)=O)=[CH:10][CH:9]=1)[CH2:3][CH2:4][CH3:5].[H][H]>C(OCC)(=O)C.[C].[Pd]>[CH3:1][CH:2]([O:6][C:7](=[O:25])[C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCC(C)OC(=O)c1ccc(OC(=O)OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCC(C)OC(=O)c1ccc(O)cc1
Yield: 89 %

Procedure:
A solution of 10 m moles of the above 4-carbobenzoxyoxybenzoic acid 1-methylbutyl ester, 0.5 g of palladium carbon (5% catalyst) in 40 ml of ethyl acetate was reacted for four hours in an atmosphere of hydrogen gas. After the reaction, palladium carbon was filtered out using a membrane filter, and the filtrate was concentrated and purified by column chromatography to obtain 1.9 g of 4-hydroxybenzoic acid 1-methylbutyl ester. (yield: 89%)
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[CH:24]=[CH:23][C:6]([CH2:7][CH:8]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1.Cl>C(OCC)C.[BH4-].[Zn+2].[BH4-]>[F:25][CH:2]([F:1])[C:3]1[CH:24]=[CH:23][C:6]([CH2:7][CH:8]([CH:14]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[OH:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(Cc1ccc(C(F)F)cc1)C(=O)c1ccc(F)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Zn+2]
Solvent: CCOCC
Product: CCOC(=O)C(Cc1ccc(C(F)F)cc1)C(O)c1ccc(F)cc1
Reaction time: 2 h

Procedure:
While stirring zinc chloride (2.17 g, 16.0 mmol) in diethyl ether (50 ml), sodium borohydride (1.21 g, 31.9 mmol) as added at room temperature and the mixture was stirred as it was for 2 hrs. The insoluble material of the mixture was removed by filtration (washed with diethyl ether) to give a solution of zinc borohydride in diethyl ether. To the obtained solution was added a solution of ethyl 2-[4-(difluoromethyl)benzyl]-3-(4-fluorophenyl)-3-oxopropionate (2.794 g, 7.975 mmol) in diethyl ether (30 ml) at room temperature and the mixture was stirred as it was for 2 hrs. To the reaction solution was added dilute hydrochloric acid by small portions to decompose excess zinc borohydride and the mixture was extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane/ethyl acetate=6/1−3/1) to give the objective substance.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[C:4](=[O:14])[CH2:3]1>CO.[Pd]>[NH2:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[C:2]([CH3:1])([CH3:15])[CH2:3][C:4]2=[O:14]
Reactant: CC1(C)CC(=O)c2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CO
Product: CC1(C)CC(=O)c2cc(N)ccc21
Reaction time: 4 h
Yield: 1029.8 %

Procedure:
A solution of 1,1-dimethyl-5-nitro-indan-3-one (6.5 g, 3.17 mmoles, prepared according to part D of Example 1) in methanol (150 ml) containing 5% palladium on carbon (0.75 g) was stirred under hydrogen gas at 15 psi for four hours. The catalyst was filtered and the methanol was recovered under vacuum to obtain a green solid (5.72 g). The reaction product was used in the next step without further purification. 1H NMR (CDCl3) δ 7.26 (d, J=8.20 Hz, 1H), 6.95 (m, 2H), 3.82 (broad s, 2H), 2.55 (s, 2H), 1.36 (s, 6H); 13C NMR (CDCl3) δ 206.25, 154.53, 146.05, 136.27, 124.04, 123.03, 107.14, 53.41, 37.74, 30.04.