Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[C:9]([F:43])[C:10]([CH3:42])=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([NH:21][CH2:22][C:23](C)([CH3:25])[CH3:24])=[O:20])=[CH:15][C:14]=3[O:27][CH2:28][CH2:29]CC(NNC(OC(C)(C)C)=O)=O)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[CH:44]1([NH:47][C:48](=O)C2C=C(F)C(C)=C(B3OC(C)(C)C(C)(C)O3)C=2)CC1.C(=O)([O-])O.[Na+]>CC(O)C.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>[CH:1]1([NH:4][C:5]([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([NH:21][CH2:22][CH:23]4[CH2:24][CH2:25]4)=[O:20])=[CH:15][C:14]=3[O:27][CH2:28][CH2:29][N:47]([CH3:48])[CH3:44])[C:10]([CH3:42])=[C:9]([F:43])[CH:8]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)NCC(C)(C)C)cc1OCCCC(=O)NNC(=O)OC(C)(C)C
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: CC(C)O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)NCC2CC2)cc1OCCN(C)C

Procedure:
N-Cyclopropylmethyl-3-[2-(dimethylarnino)ethoxy]4-iodobenzamide (Intermediate 1) (42 mg), N-cyclopropyl-5-fluoro-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (38 mg), tetrakis(triphenylphosphine)palladium (2 mg) and aqueous sodiumhydrogen carbonate (1M, 0.3 ml) were reacted in propan-2-ol (2 ml) at 9° C. for 20 hours. The solvent was evaporated under vacuum and the residue purified by bond-elut (silica, 10 g) eluting with a methanol/chloroform gradient (1-10% methanol) to give, after evaporation of the solvents, N3-cyclopropyl-N4′-(cyclopropylmethyl)-2′-[2-(dimethylamino)ethoxy]-5-fluoro-6-methyl-1,1 ′-biphenyl-3,4′-dicarboxamide.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.OS(O)(=O)=O>O>[F:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][O:15][CH2:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2ccc(F)cc2)CC1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(COCC2CCNCC2)cc1
Reaction time: 2 h

Procedure:
To a solution of 0.89 g (2.35 mmol) of 1-t-butoxycarbonyl-4-(4-fluorobenzyloxymethyl)piperidine in 8 mL of H2O at rt was added 2 mL of TFA and the reaction mixture was stirred for 2 h. To the reaction mixture was added 50 mL of 0.5N H2SO4. After stirring vigorously for 5 min, the mixture was was washed with CH2Cl2. The aqueous fraction was made basic with solid K2CO3 and extracted with CH2Cl2. The combined organic fractions were washed with sat'd NaCl solution, dried over MgSO4 and filtered. The filtrate was concentrated to give the title compound.
Reaction SMILES: [F:1][C:2](=[C:6]([F:8])[F:7])[CH2:3][CH2:4][NH2:5].[O:9]=[C:10]1[NH:14][N:13]=[CH:12][CH:11]1[CH:15]=O>C(O)C>[F:1][C:2](=[C:6]([F:8])[F:7])[CH2:3][CH2:4][NH:5][CH:15]=[C:11]1[CH:12]=[N:13][NH:14][C:10]1=[O:9]
Reactant: O=CC1C=NNC1=O
Reactant: NCCC(F)=C(F)F
Solvent: CCO
Product: O=C1NN=CC1=CNCCC(F)=C(F)F
Yield: 68 %

Procedure:
A solution of 3,4,4-trifluoro-3-butene-1-amine (2.25 g, 0.018 mole) and 4,5-dihydro-5-oxo-1H-pyrazole-4-carboxaldehyde (1.12 g 0.01 mole) in absolute ethanol (30 mL) is heated at reflux for 15 min. The solution is concentrated and the residue is recrystallized from ether/dichloromethane to give 1.49 g of the title compound as an yellow solid, a 68% yield. m.p. 126°-130° C.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)=O.[C:16](=O)([O-])[O-].[K+].[K+].O>CO>[C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[CH:16]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: [K+]
Solvent: O
Solvent: CO
Product: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 4-formylpiperidine-1-carboxylate (2.2 g, 10.4 mmol) and potassium carbonate (2.9 g, 20.8 mmol) in methanol (100 mL) was added Example 21A (2.0 g, 10.4 mmol) in methanol (20 mL) and the mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with ethyl acetate (twice). The combined organic layers were washed with brine and concentrated. Purification by flash chromatography on silica gel (Teledyne CombiFlash Rf, 1:5 ethyl acetate/hexane) gave the title compound. MS (DCI/NH3) m/z 210 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7](O)[N:6]=1)=[O:4].P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:7]1[N:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)c1cccc(O)n1
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cccc(Cl)n1
Temperature: 110 °C
Reaction time: 0.25 h
Yield: 61 %

Procedure:
To 6-hydroxy-pyridine-2-carboxylic acid methyl ester (10.0 g, 71.9 mmol) was added phosphorus oxychloride (138 mL). The mixture was heated in an oil bath at 110° C. for 14 h and the excess phosphorus oxychloride was removed in vacuo. The resulting residue was cooled in an ice bath and anhydrous methanol (146 mL) was slowly added. After 15 min, half of the methanol was removed in vacuo and water (208 mL) was added. The solution was cooled in an ice bath and the precipitate was collected. The solid was dissolved in ethyl acetate and this organic phase was washed with water and then a saturated sodium bicarbonate solution. The combined aqueous layers were extracted with ethyl acetate and diethyl ether. The organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo generating 7.47 g (61% yield, 43.5 mmol) of the title compound.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:21]=[CH:20][C:19]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:11]=3[CH:10]=2)O1.Br[C:40]1[CH:41]=[C:42]([C:47]2[O:48][C:49]([C:52]3[CH:57]=[CH:56][C:55]([O:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])=[CH:54][CH:53]=3)=[N:50][N:51]=2)[CH:43]=[C:44](Br)[CH:45]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[CH2:22]([C:12]1([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:13]2[CH:14]=[C:15]([C:40]3[CH:41]=[C:42]([C:47]4[O:48][C:49]([C:52]5[CH:57]=[CH:56][C:55]([O:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])=[CH:54][CH:53]=5)=[N:50][N:51]=4)[CH:43]=[C:44]([C:9]4[CH:21]=[CH:20][C:19]5[C:18]6[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=6)[C:12]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:11]=5[CH:10]=4)[CH:45]=3)[CH:16]=[CH:17][C:18]=2[C:19]2[C:11]1=[CH:10][CH:9]=[CH:21][CH:20]=2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCC1(CCCCCCCC)c2ccccc2-c2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Reactant: CCCCCCCCOc1ccc(-c2nnc(-c3cc(Br)cc(Br)c3)o2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCCCCOc1ccc(-c2nnc(-c3cc(-c4ccc5c(c4)C(CCCCCCCC)(CCCCCCCC)c4ccccc4-5)cc(-c4ccc5c(c4)C(CCCCCCCC)(CCCCCCCC)c4ccccc4-5)c3)o2)cc1
Temperature: 80 °C
Yield: 74.7 %

Procedure:
Into a flask was introduced 2.8 mL of toluene, 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9,9-dioctylfluorene (0.80 g, 1.5 mmol), 2-(3,5-dibromophenyl)-5-[4-(octyloxy)phenyl]-1,3,4-oxadiazole from Example 7 (0.375 g, 0.7 mmole), Aliqua™ 336 (0.15 g, 0.4 mmol) and 1.4 mL of aqueous 2M Na2CO3. This was N2 purged for 1 h. The flask was heated to about 80° C. and tetrakistriphenylphosphine palladium (0) (12 mg, 0.01 mmol) then added under a nitrogen purge. The content of the flask was refluxed for 21 hrs. The reaction flask was allowed to cool to RT and about 5 mL water added and the organic layer separated. The aqueous layer was extracted with 3×15 mL ether. The organic layers were combined and washed successively with saturated NaCl twice and then dried over MgSO4. Concentration gave an oil that was purified by flash chromatography (eluent: 10% ethyl acetate in hexane) and dried as an oil under vacuum for 30 minutes to give 0.59 grams of 2-[3,5-Bis-(9,9-dioctyl-9H-fluoren-2-yl)-phenyl]-5-(4-octyloxy-phenyl)-[1,3,4]oxadiazole.
Reaction SMILES: [CH:1]1[C:18]2=[C:19]3[C:8]([C:9]4[C:20]5[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=5)[CH:12]=[CH:11][CH:10]=4)=[CH:7][CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.[C:21]1(=[O:27])[O:26][C:24](=[O:25])[CH2:23][CH2:22]1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[O:27]=[C:21]([C:16]1[C:17]2=[C:20]3[C:9]([C:8]4[C:19]5[C:4](=[CH:3][CH:2]=[CH:1][C:18]2=5)[CH:5]=[CH:6][CH:7]=4)=[CH:10][CH:11]=[CH:12][C:13]3=[CH:14][CH:15]=1)[CH2:22][CH2:23][C:24]([OH:26])=[O:25]
Reactant: c1cc2cccc3c4cccc5cccc(c(c1)c23)c54
Reactant: O=C1CCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(O)CCC(=O)c1ccc2cccc3c4cccc5cccc(c1c23)c54
Temperature: 25 °C
Reaction time: 13 h
Yield: 100.2 %

Procedure:
The perylene 71 (5.01 g, 19.8 mmol) and 4.34 g (43.4 mmol) of succinic anhydride were put into a 500-ml three-inlet flask, and a nitrogen substitution was performed. The substance obtained here was immersed in an ice bath. After 16.3 g (122 mmol) of aluminum chloride dispersed in 200 ml of methylene chloride was slowly dripped onto the substance, the reaction container was removed from the ice bath, and the substance was stirred at room temperature for 13 hours. After the reaction was completed, 40 ml of cooled 2M hydrochloric acid was added, followed by 30-minute stirring. The solid substance obtained here was collected by filtration. This solid substance was dispersed in 100 ml of xylene, and was heated to 140° C., to extract the impurities. After the substance was cooled slowly back to room temperature, the solid substance was collected by filtration, and was dried under reduced pressure, to obtain 6.99 g of the brownish solid substance 72.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][CH:3]=1.[Li]CCCC.[O:14]1[C:18]2([CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]2)[O:17][CH2:16][CH2:15]1.C[Si](Cl)(C)C>C1COCC1>[I:8][C:5]1[CH:6]=[CH:7][C:2]([C:21]2([OH:24])[CH2:22][CH2:23][C:18]3([O:17][CH2:16][CH2:15][O:14]3)[CH2:19][CH2:20]2)=[CH:3][CH:4]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Ic1ccc(I)cc1
Agent: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2ccc(I)cc2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.6 %

Procedure:
To a solution of 1,4 diiodobenzene (16.5 g, 50 mmol) in THF (350 mL) at −78° C. was added n-BuLi (2.5 M, 24 mL) over 1 hour. After being stirred for an additional 30 minutes, a solution of 1,4-dioxa-spiro[4.5]decan-8-one (7.8 g, 50 mmol) in THF (30 mL) was added in and the resulting mixture was sired for 3 hours. To the mixture was added TMSCl (5.4 g, 50 mmol) and the resulting mixture was allowed to warm to rt and stirred at rt for 18 hours. The reaction mixture was neutralized to pH 6.0, and extracted with ethyl acetate (3×50 mL). The organic extracts were combined, washed with saline solution (2×50 mL), dried over sodium sulfate, concentrated in vacuo. The residue was chromatographed on silica gel, eluting with hexane/ethyl acetate (95/5 to 100/0). The appropriate fractions were combined to give 8-(4-Iodo-phenyl)-1,4-dioxa-spiro[4.5]decan-8-ol (12 g, 66.6%) with LCMS: 361.2 (M+H+, 100%) and {[8-(4-iodophenyl)-1,4-dioxaspiro[4.5]dec-8-yl]oxy}(trimethyl)silane (6 g, 27%) with LCMS: 433.1 (M+H+, 100%).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH2:27]([NH2:31])[CH2:28][CH2:29][CH3:30]>C(#N)C>[CH3:26][S:23]([C:20]1[CH:21]=[CH:22][C:16]2[O:15][CH2:14][CH:13]([CH2:12][NH:31][CH2:27][CH2:28][CH2:29][CH3:30])[O:18][C:17]=2[CH:19]=1)(=[O:24])=[O:25]
Reactant: CCCCN
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3ccc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: CCCCNCC1COc2ccc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 25 using [7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.018 g, 0.046 mmol), butan-1-amine (0.5 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 299 (M+, 6), 256 (5), 87 (6), 86 (bp), 70 (5).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[CH:16]([CH3:17])[CH2:15][N:14]([C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:13][CH2:12][C:11]=2[N:24]=1.O.C([O-])([O-])=O.[K+].[K+]>OS(O)(=O)=O>[CH3:5][O:6][C:7]1[C:8]([N+:1]([O-:4])=[O:2])=[CH:9][C:10]2[CH:16]([CH3:17])[CH2:15][N:14]([C:18](=[O:23])[C:19]([F:22])([F:20])[F:21])[CH2:13][CH2:12][C:11]=2[N:24]=1
Reactant: COc1ccc2c(n1)CCN(C(=O)C(F)(F)F)CC2C
Reactant: O=[N+]([O-])O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: COc1nc2c(cc1[N+](=O)[O-])C(C)CN(C(=O)C(F)(F)F)CC2
Temperature: 25 °C
Yield: 77 %

Procedure:
Nitric Acid (200 μl) was added dropwise to a stirred solution of 2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (174 mg, 604 μmol) in H2SO4 (1.5 ml). The reaction mixture was added into cold water after 3 d of stirring at room temperature. K2CO3 was added to neutralize the mixture to pH=8. After extraction with EtOAc, the organic layer was dried over Na2SO4, concentrated in vacuo and purified by column chromatography to give 155 mg (77%) of 2-methoxy-5-methyl-3-nitro-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. MS (ESI) m/z 334. After treatment of 2-methoxy-5-methyl-3-nitro-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (30.0 mg, 90.0 μmol) with K2CO3 (30 mg), methanol (1 ml) and H2O (0.2 ml) at 60° C. for 10 minutes, the reaction was quenched with sat. aq. NH4Cl and extracted with DCM. The organic layer was dried over Na2SO4, concentrated in vacuo and purified by column chromatography to give 21 mg (99%) of 2-methoxy-5-methyl-3-nitro-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. 1H-NMR (CDCl3) δ 8.10 (s, 1H), 4.09 (s, 3H), 3.25 (m, 2H), 3.10 (m, 3H), 2.93 (dd, 1H), 2.72 (dd, 1H), 1.39 (d, 3H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[C:18](OC)[CH:17]=[CH:16][C:4]=1[C:5]([NH:7][C@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].[CH3:22][O:23]C1C=CC(OC)=CC=1C(O)=O>>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:17]([O:23][CH3:22])=[CH:16][C:4]=1[C:5]([NH:7][C@H:8]1[CH:13]2[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]2)[CH2:9]1)=[O:6]
Reactant: COc1ccc(OC)c(C(=O)O)c1
Reactant: COc1ccc(C(=O)N[C@@H]2CN3CCC2CC3)c(OC)c1
Product: COc1ccc(OC)c(C(=O)N[C@@H]2CN3CCC2CC3)c1

Procedure:
Title compound was synthesized according to the procedure used in the synthesis of Compound 88S using 2,5-dimethoxybenzoic acid in place of 2,4-dimethoxybenzoic acid. 1H NMR (400 MHz, Acetone-D4) δ (ppm): 7.61 (m, J=4 Hz, 1H), 7.11 (s, 1H), 7.07 (m, J=4 Hz, 1H), 4.07 (m, 1H), 4.00 (s, 3H), 3.80 (s, 3H), 3.34 (s, 3H), 2.89-2.82 (m, 4H), 2.62 (m, 1H), 1.98 (m, 1H), 1.84 (m, 1H), 1.84 (m, 2H), 1.52 (m, 1H). C16H22N2O3=290.16 LCMS (M+H): m/z 291
Reaction SMILES: [CH2:1]([C:13]1[CH:17]=[C:16]([C:18](O)=[O:19])[O:15][N:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+]>O1CCCC1>[CH2:1]([C:13]1[CH:17]=[C:16]([CH2:18][OH:19])[O:15][N:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCc1cc(C(=O)O)on1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCc1cc(CO)on1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred, chilled (+3° C.) solution of 3-dodecyl -5-isoxazole carboxylic acid (24.27 g, 0.08625 mol) and triethylamine (12.0 mL, 0.0861 mol) in dry tetrahydrofuran (600 mL) under nitrogen was added in one portion a chilled (+3° C.) solution of ethyl chloroformate (8.25 mL, 0.0863 mol) in dry tetrahydrofuran (30 mL). A white precipitate formed immediately. The suspension was stirred for 1.25 hours before sodium borohydride (6.54 g, 0.173 mol) was added in portions over 10 minutes. The mixture was stirred for 1.5 hours while warming to room temperature. The mixture was rechilled and carefully quenched with water (350 mL). The organic layer was diluted with dichloromethane. The aqueous layer was washed with THF-CH2Cl2. The organic solutions were combined, dried (Na2SO4), and rotoevaporated. The residue was chromatographed on silica gel (1.5 kg, 70-230 mesh) using petroleum ether-acetone (9:1, 20×1 L) eluent. Fractions 10 to 14 were rotoevaporated from dichloromethane and dried in vacuo to give a white solid; yield 11.1 g (48%); mp 57°-59° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[CH3:11][C:12]1[NH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][C:17]([C:21]#[N:22])=[CH:16][CH:15]=2.C(=O)([O-])[O-].[K+].[K+]>O>[CH:8]([C:20]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:21]#[N:22])[CH:18]=2)[NH:13][C:12]=1[CH3:11])=[O:9]
Reactant: Cc1cc2cc(C#N)ccc2[nH]1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cc1[nH]c2ccc(C#N)cc2c1C=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Under ice-cooling, 1.3 ml of phosphorus oxychloride was added to 7 ml of N,N-dimethylformamide at an inner temperature of from 10 to 20° C., followed by stirring at room temperature for 15 minutes. Under ice-cooling, 9 ml of an N,N-dimethylformamide solution of 2-methyl-1H-indole-5-carbonitrile was added to this solution at an inner temperature of from 10 to 20° C., followed by overnight stirring at room temperature. A 64 ml portion of water was added thereto at 0° C. and the pH was adjusted to 8 with potassium carbonate, followed by 2.5 hours of stirring at room temperature. The thus precipitated solid was collected by filtration, washed with water and then dried at 80° C. under a reduced pressure to obtain 1.73 g of 3-formyl-2-methyl-1H-indole-5-carbonitrile as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:12]([OH:14])=O)[C:10]=1[F:11])[NH:7][CH:6]=[CH:5]2.[C:15]([C:19]1[CH:38]=[CH:37][C:22]([CH2:23][NH:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:15]([C:19]1[CH:38]=[CH:37][C:22]([CH2:23][N:24]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=2)[C:12]([C:9]2[C:10]([F:11])=[C:2]([F:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:14])=[CH:21][CH:20]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: O=C(O)c1c(F)c(F)cc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2cccc(C(F)(F)F)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CN(CCc2cccc(C(F)(F)F)c2)C(=O)c2c(F)c(F)cc3cc[nH]c23)cc1
Temperature: 25 °C
Yield: 37.9 %

Procedure:
87 mg (0.44 mol) of 5,6-difluoro-1H-indol-7-carboxylic acid, 134 mg (0.40 mmol) of (4-tert-butyl-benzyl)-[2-(3-trifluoromethyl-phenyl)-ethyl]-amine and 84 mg (0.44 mmol) of EDC.HCl were dissolved in 4 ml DCM. The reaction mixture was stirred at rt over night. The solvent was evaporated and the residue was purified by column chromatography (20 g silica gel; heptane/EtOAc 4:1) to yield 78 mg (38%) product as a colorless viscous oil. MS (ISP) 515.3 (M+H)+.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH3:6][C:7]([CH3:16])=[CH:8][CH2:9][C@@H:10]1O[C@@:11]1([CH:14]=[CH2:15])[CH3:13]>>[CH3:6][C:7]([CH3:16])=[CH:8][CH:9]([OH:2])/[CH:10]=[C:11](/[CH:14]=[CH2:15])\[CH3:13]
Reactant: O=S(=O)(O)O
Reactant: C=C[C@@]1(C)O[C@H]1CC=C(C)C
Product: C=C/C(C)=C/C(O)C=C(C)C
Reaction time: 1 h
Yield: 70 %

Procedure:
To 500 ml. of 50% aqueous sulphuric acid acid cooled between -5° and 0° were added dropwise 75 g. of transepoxyocimene prepared according to the description of paragraph (a) above. The mixture was vigorously stirred for one hour wile the temperature was allowed to slowly rise to 20-25°. It was extracted with methylene chloride, the extract was washed several times with water, with a saturated aqueous solution of sodium carbonate and finally with water. The extract was dried, concentrated and distilled. Thus secondary trans-ocimenol was obtained with a yield of 70-80%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:19]3[O:20][CH:21]=[CH:22][CH:23]=3)=[C:11]([CH2:13][C:14]([O:16]CC)=[O:15])[N:12]=2)=[CH:4][CH:3]=1.CO.[OH-].[Na+]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:19]3[O:20][CH:21]=[CH:22][CH:23]=3)=[C:11]([CH2:13][C:14]([OH:16])=[O:15])[N:12]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1nc(-c2ccc(F)cc2)oc1-c1ccco1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)Cc1nc(-c2ccc(F)cc2)oc1-c1ccco1
Yield: 87.8 %

Procedure:
5.0 g of ethyl 2-[2-(4-fluorophenyl)-5-(2-furyl)-4-oxazolyl]acetate, 70 ml of methanol, 10 ml of water and 1.5 g of sodium hydroxide are treated in the same manner as described in Example 16. 4.0 g of 2-[2-(4-fluorophenyl)-5-(2-furyl)-4-oxazolyl]acetic acid are thereby obtained. Yield: 87.7%
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][Br:9])[CH:5]=[CH:4][N:3]=1.[Cl:10]C1C=C(C)N=CN=1>>[Br:9][CH2:8][C:6]1[CH:5]=[C:4]([Cl:10])[N:3]=[CH:2][N:7]=1
Reactant: Cc1cc(Cl)ncn1
Reactant: BrCc1ccnc(Br)n1
Product: Clc1cc(CBr)ncn1

Procedure:
Prepared according to the same procedure as 2-bromo-4-(bromomethyl)pyrimidine, starting with 4-chloro-6-methylpyrimidine. 1H NMR (500 MHz, DMSO-d6) δ 9.07 (s, 1H), 7.91 (d, J=0.9 Hz, 1H), 4.66 (s, 2H), Mass spec.: 208.9 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([CH2:10][CH2:11][CH2:12]Cl)=[O:9].[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([CH2:10][CH2:11][CH2:12][N:28]1[CH2:29][CH2:30][CH:25]([C:21]2[CH:20]=[C:19]([NH:18][C:16](=[O:17])[CH:15]([CH3:14])[CH3:31])[CH:24]=[CH:23][CH:22]=2)[CH2:26][CH2:27]1)=[O:9]
Reactant: O=S(CCCCl)c1ccccc1Br
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCS(=O)c3ccccc3Br)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 1-bromo-2-[(3-chloropropyl)sulfinyl]benzene and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: Anal. Calcd for C24H31BrN2O2S+0.3CHCl3: ESMS m/e: 491.0 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9](O)=[N:8][C:7]3[CH:13]=[CH:14][CH:15]=[N:16][C:6]2=3)[CH2:3][CH2:2]1.P(Br)(Br)([Br:19])=O.C(=O)([O-])[O-].[Na+].[Na+]>ClC(Cl)C>[Br:19][C:9]1[C:10](=[O:11])[N:5]([CH2:4][CH:1]2[CH2:3][CH2:2]2)[C:6]2[N:16]=[CH:15][CH:14]=[CH:13][C:7]=2[N:8]=1
Reactant: O=c1c(O)nc2cccnc2n1CC1CC1
Reactant: O=P(Br)(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: O=c1c(Br)nc2cccnc2n1CC1CC1
Yield: 66.5 %

Procedure:
700 mg (3.22 mM) of 4-(cyclopropylmethyl)-2-hydroxypyrido[2,3-b]pyrazin-3(4H)-one and 972.3 mg (3.22 mM) of phosphorus oxybromide at 95% in 10 ml of dichloroethane were refluxed for 16H under stirring. The reaction mixture was then basified with an aqueous solution of sodium carbonate and the aqueous layer was extracted with dichloromethane. The organic layer was separated, washed with water, dried on anhydrous sodium sulfate and the solvent was removed under vacuum. The compound was further purified by silica gel column chromatography, using dichloromethane as eluant, to give, after evaporation, 650 mg of 2-bromo-4-(cyclopropylmethyl)pyrido[2,3-b]pyrazin-3(4H)-one as a white solid. Yield: 66.5%.