Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][O:11][CH2:12][CH2:13]Cl.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:10][O:11][CH2:12][CH2:13][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: COCCCl
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1ccc(C=O)cc1
Temperature: 60 °C
Yield: 47.9 %

Procedure:
4-Hydroxybenzaldehyde (300 g) and 2-chloroethyl methyl ether (279 g) were dissolved in DMF (3 L) and potassium carbonate (408 g) was added. The mixture was stirred with heating at 60° C. for 16 hr. After the reaction, the reaction mixture was poured into water and liberated oil was extracted with ethyl acetate. The organic layer was washed with 1N aqueous sodium hydroxide solution and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate. After drying, the residue was concentrated under reduced pressure to give 4-(2-methoxyethoxy)benzaldehyde as an oil (212 g).
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH3:10])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[C:11](Cl)(=O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]CC>O1CCCC1>[O:6]=[C:5]([CH2:7][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:4][C:3]([O:9][CH3:10])=[O:8]
Reactant: CCCCCCCC(=O)Cl
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCC(=O)CC(=O)OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
A dry tetrahydrofuran suspension (4 l) containing 440 g (11 mol) of 60% sodium hydride was cooled to 0° C., and 1.8 l of a tetrahydrofuran solution of 1.161 kg (10 mol) of methyl acetoacetate was added thereto dropwise, followed by stirring at room temperature for 1 hour. To the reaction mixture was added dropwise 1.789 kg (11 mol) of octanoyl chloride at 0 to 5° C., followed by stirring at room temperature overnight. After confirming disappearance of the octanoyl chloride by thin layer chromatography (TLC), tetrahydrofuran was evaporated, and the residue was poured into ice-water and extracted with 8 l of ethyl acetate. Ethyl acetate was evaporated, and the residue was poured into a mixture of 400 g of a 28% methanol solution of sodium methoxide and 1.2 e of methanol and heated at 60 to 65° C. for 6 hours while stirring to conduct deacylation. The product was cooled with ice, adjusted to pH 5 with a 10% sulfuric acid aqueous solution, and extracted with ethyl acetate. The ethyl acetate layer was washed successively with a 5% sodium carbonate aqueous solution and a saturated sodium chloride aqueous solution. The ethyl acetate was evaporated, and the concentrated residue was distilled under reduced pressure to give 1.10 kg (5.5 mol; yield: 50%) of methyl 3-oxodecanoate (boiling point: 121° C./5 mmHg).
Reaction SMILES: Cl[CH:2]([C:8](=O)[CH:9]([CH3:11])[CH3:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(O)C.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C@H:23]2[NH:27][C:26](=[S:28])[NH:25][C@:24]2([C:30]2[CH:31]=[N:32][C:33]([Cl:36])=[CH:34][CH:35]=2)[CH3:29])=[CH:19][C:18]=1[F:37]>C(OCC)(=O)C>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C@H:23]2[N:27]3[C:26]([S:28][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:8]3[CH:9]([CH3:11])[CH3:10])=[N:25][C@:24]2([C:30]2[CH:31]=[N:32][C:33]([Cl:36])=[CH:34][CH:35]=2)[CH3:29])=[CH:19][C:18]=1[F:37]
Reactant: C[C@@]1(c2ccc(Cl)nc2)NC(=S)N[C@@H]1c1ccc(Cl)c(F)c1
Reactant: CCOC(=O)C(Cl)C(=O)C(C)C
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)C1=C(C(C)C)N2C(=N[C@@](C)(c3ccc(Cl)nc3)[C@H]2c2ccc(Cl)c(F)c2)S1
Yield: 76.5 %

Procedure:
Ethyl 2-chloro-4-methyl-3-oxopentanoate (1.36 g, 7.09 mmol) was added to an ethanol (20 ml) solution of the compound (1.94 g, 5.45 mmol) obtained in Step 11 above at room temperature and the resulting mixture was heated to reflux for 16 hours. The reaction mixture was returned to room temperature and the reaction solvent was evaporated under reduced pressure. The residue obtained was diluted with ethyl acetate and the organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue obtained was purified by silica gel column chromatography [n-hexane:ethyl acetate=3:1 (v/v)] to give the title compound (2.06 g, 76%) as a colorless solid.
Reaction SMILES: [C:1]1([C:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd].C(O)C>[C:29]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[CH2:13][CH2:14]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: C(=C(c1ccccc1)c1ccccc1)C1CCN(CCCCCCCCc2cccnc2)CC1
Agent: [Pd]
Solvent: CCO
Product: c1ccc(C(CC2CCN(CCCCCCCCc3cccnc3)CC2)c2ccccc2)cc1
Yield: 81.8 %

Procedure:
The title compound was prepared by the hydrogenation of 7.3 g of 3-[8-[4-(2,2-diphenylethenyl)-1-piperidinyl]octyl]pyridine at ambient conditions using 100 mL of ethanol and 1.5 g of 10% palladium on carbon catalyst. After filtration and evaporation, the residue was crystallized from hexane to give 6.0 g (82%) of 3-[8-[4-(2,2-diphenylethyl)-1-piperidinyl]octyl]pyridine, mp 68°-70° C. Analysis Calculated for C32H42N2 : C, 84.53: H, 9.31; N, 6.16. Found: C, 84.68; H, 9.15; N, 6.12. The fumarate salt was crystallized from acetone, mp 110°-111° C. Analysis Calculated for C32H42N2.C4H4O4 : C, 75.76; H, 8.12; N, 4.91. Found: C, 75.59; H, 8.00; N, 4.83.
Reaction SMILES: C(OC([NH:8][CH:9]([C:14]([CH3:18])([CH3:17])[CH:15]=[CH2:16])[C:10]([O:12][CH3:13])=[O:11])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][CH:9]([C:14]([CH3:18])([CH3:17])[CH:15]=[CH2:16])[C:10]([O:12][CH3:13])=[O:11]
Reactant: C=CC(C)(C)C(NC(=O)OC(C)(C)C)C(=O)OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CC(C)(C)C(N)C(=O)OC
Reaction time: 2 h
Yield: 75.8 %

Procedure:
To a solution of methyl 2(R/S)-(tert-butoxycarbonyl)amino-3,3-dimethyl-4-pentenoate (4.97 g, 19.3 mmol) in 50 mL of dichloromethane at 0° C. was added 16.5 mL of trifluoroacetic acid. After 2 hours, the solution was concentrated and the residue was dissolved in 100 mL of dichloromethane and washed with sat. aq. sodium bicarbonate (50 mL). The organic layer was dried over sodium sulfate and concentrated to give methyl 2(R/S)-amino-3,3-dimethyl-4-pentenoate (2.30 g), which was dissolved in 50 mL of dichloromethane and cooled to 0° C. Triethylamine (8.1 mL, 58 mmol) was added, followed by addition of 4-(4-fluorophenoxy)benzenesulfonyl chloride (6.71 g, 21.3 mmol). The reaction was allowed to warm to room temperature and stirred for 18 hours and then washed 3 N hydrochloric acid (125 mL), dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel, eluting with 20% ethyl acetate in hexane, to yield 4.41 g (61%) of methyl 2(R/S)-[4-(4-fluorophenoxy)benzenesulfonyl]amino-3,3-dimethyl-4-pentenoate as a white solid.
Reaction SMILES: C[O:2][C:3]([CH:5]([OH:23])[C@H:6]1[O:10][C@@H:9]([N:11]2[C:20]3[N:19]=[CH:18][N:17]=[C:15]([NH2:16])[C:14]=3[N:13]=[CH:12]2)[C@H:8]([OH:21])[C@@H:7]1[OH:22])=O.[C:24]([NH2:28])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([NH:28][C:3]([CH:5]([OH:23])[C@H:6]1[O:10][C@@H:9]([N:11]2[C:20]3[N:19]=[CH:18][N:17]=[C:15]([NH2:16])[C:14]=3[N:13]=[CH:12]2)[C@H:8]([OH:21])[C@@H:7]1[OH:22])=[O:2])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)N
Reactant: COC(=O)C(O)[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O
Product: CC(C)(C)NC(=O)C(O)[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O
Reaction time: 16 h
Yield: 38 %

Procedure:
5 g of adenosine-5'-carboxylic acid methyl ester are heated together with 100 ml of tert.-butylamine on a streambath until a clear solution is obtained and thereafter the reaction mixture is left to stand for 16 hours at ambient temperature. Excess tert.-butylamine is then distilled off and the residue is mixed with methanol, again evaporated to dryness and the solid residue, after slurrying in cold methanol is filtered off with suction. After recrystallizing twice from a little methanol, there are obtained 2.15 g (38% of theory) of adenosine-5'-carboxylic acid N-tert.-butylamide, which melts, with decomposition, at 279°-280° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[Sn](CCCC)(CCCC)CCCC.C([Li])CCC.[C:24]1([CH2:30][C:31]([NH:33][CH:34]2[C:65](=[O:66])[N:36]3[C:37]([C:49]([O:51][CH:52]([C:59]4[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=4)[C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)=[O:50])=[C:38](OS(C(F)(F)F)(=O)=O)[CH2:39][S:40][C@H:35]23)=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[O-]S(C(F)(F)F)(=O)=O>C1COCC1.CCCCCC.CSC.CN1CCCC1=O.[Cu]Br.[Cu](Br)Br>[C:24]1([CH2:30][C:31]([NH:33][C@@H:34]2[C:65](=[O:66])[N:36]3[CH:37]([C:49]([O:51][CH:52]([C:53]4[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=4)[C:59]4[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=4)=[O:50])[C:38]([CH:2]4[CH2:3][CH2:4][CH2:5][O:1]4)=[CH:39][S:40][C@H:35]23)=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(OS(=O)(=O)C(F)(F)F)CS[C@H]12
Reactant: CCCC[Sn](CCCC)(CCCC)C1CCCO1
Agent: Br[Cu]Br
Agent: [Cu]Br
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: C1CCOC1
Solvent: CSC
Solvent: CN1CCCC1=O
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(C3CCCO3)=CS[C@H]12
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A solution of (tetrahydrofuran-2-yl)tri-n-butylstannane (J. S. Sawyer, A. Kucerovy, T. L. MacDonald, and G. J. McGarvey, J. Amer. Chem. Soc., 1988, 110, 842) (3.0 g, 8.30 mmol) in THF (20 ml) was cooled to -78° C. n-Butyl lithium (6.23 ml of a 1.6M solution in hexane, 9.97 mmol) was then added and the solution was stirred for 15 min. at -78° C. A second flask containing copper (I) bromide.dimethylsulphide complex (0.854 g, 4.14 mmol) suspended in a mixture of dimethyl sulphide (15 ml) and THF (30 ml) was then cooled to -78° C. The α-lithiotetrahydrofuran species was transferred via a cannula to the suspension of copper bromide at -78° C. The red-brown homogeneous solution was stirred for 30 min. at -78° C. A third flask containing a solution of diphenylmethyl 7-phenylacetamido-3-triflyloxyceph-3-em-4-carboxylate (V. Farina, S. R. Baker, and S. I. Hanck, J. Org. Chem., 1989, 54, 4962) (1.9 g, 3.0 mmol) in a mixture of N-methylpyrrolidinone (20 ml) and THF (50 ml) was then cooled to -18° C. The cuprate species was transferred via a cannula to the solution of triflate at -78° C. The reaction mixture was stirred for 1 h at -78° C. then quenched by the addition of saturated aq. ammonium chloride (30 ml). The resulting mixture was allowed to warm to room temperature then diluted with water (100 ml) and extracted with ethyl acetate (100 ml, 30 ml). The combined organic phases were washed with water, brine, then dried over magnesium sulphate. After removal of the solvents under reduced pressure the crude reaction product was purified by flash chromatography on silica gel using 10-30% ethyl acetate/methylene dichloride as eluent. After elution of the 3-n-butylcephem, the title compound was obtained as a mixture of diastereoisomers of the Δ2 and Δ3 cephems (1.014 g, 61%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][C@H:6]([CH3:13])[CH2:5]2.[CH2:14](N(CC)CC)[CH3:15].C([B-](F)(F)F)=C.[K+]>CCO.C(Cl)(Cl)Cl>[CH:14]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][CH:6]([CH3:13])[CH2:5]2)=[CH2:15]
Reactant: C[C@@H]1Cc2cc(Br)ccc2C(=O)O1
Reactant: CCN(CC)CC
Agent: C=C[B-](F)(F)F
Agent: [K+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: C=Cc1ccc2c(c1)CC(C)OC2=O
Temperature: 100 °C

Procedure:
A solution of (3R)-6-bromo-3-methyl-3,4-dihydro-1H-isochromen-1-one (2.4 g, 9.96 mmol) and triethylamine (2.78 ml, 19.91 mmol) in EtOH (39.8 ml) was added to a microwave vial containing Cl2Pd(dppf)2-DCM (0.406 g, 0.498 mmol) and potassium vinyltrifluoroborate (2,000 g, 14.93 mmol). The contents of the vial were heated to 100° C. for 1 hour after which the mixture was cooled, diluted with chloroform (50 mL) and washed with aqueous ammonium chloride (25 mL). The organic layer was then dried over magnesium sulfate, filtered and the solvent was evaporated under reduced pressure. MPLC purification (15-60% EtOAc/Hex) gave 6-ethenyl-3-methyl-3,4-dihydro-1H-isochromen-1-one. 1H NMR (500 MHz; CDCl3): 8.07 (d, J=8.0 Hz, 1H), 7.44 (dd, J=1.2, 7.1 Hz, 1H), 7.26 (s, 1H), 6.75 (dd, J=10.8, 17.6 Hz, 1H), 5.90 (d, J=17.6 Hz, 1H), 5.44 (d, J=11 Hz, 1H), 4.75 (m, 1H), 2.96 (m, 2H), 1.54 (d, J=6.1 Hz, 3H); LC/MS (M+H)+189;
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1>C(O)(=O)C>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:17])=[O:16])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2ccc(C(=O)O)cc2)cc1
Solvent: CC(=O)O
Product: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Temperature: 0 °C

Procedure:
A stirred mixture of compound 2 (27.00 g, 0.118 mol) and hydronbromic acid (48% w/v, 350 ml) in glacial acetic acid (600 ml) was heated under reflux for 6 h. The cooled solution was poured into an ice/water mixture (1 l) and the resulting white precipitate was filtered off and washed with water until acid-free. Recrystallisation from glacial acetic acid afforded white crystals which were dried over potassium hydroxide in vacuo.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:3]=1.[OH:24][C:25]1[CH:34]=[C:33]2[C:28]([CH:29]=[CH:30][CH:31]=[N:32]2)=[CH:27][CH:26]=1.[H-].[Na+]>CN(C=O)C>[C:8]1([C:5]2[N:6]=[N:7][C:2]([O:24][C:25]3[CH:34]=[C:33]4[C:28]([CH:29]=[CH:30][CH:31]=[N:32]4)=[CH:27][CH:26]=3)=[CH:3][C:4]=2[C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)nnc2-c2ccccc2)cc1
Reactant: Oc1ccc2cccnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(-c2cc(Oc3ccc4cccnc4c3)nnc2-c2ccccc2)cc1
Temperature: 50 °C
Reaction time: 15 h

Procedure:
To a solution of 6-chloro-3-phenyl-4-(4-trifluoromethyl-phenyl)-pyridazine, (Example 13(e)), (106 mg, 0.3 mmol) and 7-hydroxyquinoline (55 mg, 0.4 mmol, Acros) in DMF (2.5 mL) was added NaH (22 mg, 0.6 mmol, 60% suspension in mineral oil, Aldrich) and the mixture was stired at room temperature for 15 h. The reaction mixture was then heated at 50° C. for another 28 h, allowed to cool to room temperature and the solvent removed in vacuum. The residue was partitioned between EtOAc/H2O and the aqueous layer was extracted with EtOAc. The combined organic layers were evaporated onto SiO2 and purified by flash silica gel chromatography with EtOAc/hexanes (0:1→3:7) as eluant to give the title compound as an off-white amorphous solid. Mp: 178–183° C. MS (ESI, pos ion.) m/z: 444 (M+1).
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]2)[CH:7]=[CH:6][C:5]=1[N+:17]([O-:19])=[O:18].Cl.O>CC(C)=O>[OH:16][CH:13]1[CH2:12][CH2:11][N:10]([C:8]2[CH:7]=[CH:6][C:5]([N+:17]([O-:19])=[O:18])=[C:4]([CH:9]=2)[CH:3]=[O:2])[CH2:15][CH2:14]1
Reactant: COC(OC)c1cc(N2CCC(O)CC2)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: O=Cc1cc(N2CCC(O)CC2)ccc1[N+](=O)[O-]
Yield: 96.4 %

Procedure:
To a solution of 4.3 g of 5-(4-hydroxypiperidino)-2-nitrobenzaldehyde dimethylacetal in 40 ml of acetone was added 40 ml of 2N hydrochloric acid. After refluxing for 15 min, the reaction mixture was poured into water, and extracted with ethyl acetate. The extract was washed with water, dried, and evaporated under a reduced pressure to give 3.5 g of 5-(4-hydroxypiperidino)-2-nitrobenzaldehyde.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH3:15])[N:8]=1.[OH-].[Na+]>S(=O)(=O)(O)O>[Br:6][C:7]1[C:12]([N+:1]([O-:4])=[O:2])=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH3:15])[N:8]=1
Reactant: O=[N+]([O-])[O-]
Reactant: CCOc1cccc(Br)n1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [Na+]
Product: CCOc1ccc([N+](=O)[O-])c(Br)n1
Temperature: 25 °C
Yield: 72 %

Procedure:
Potassium nitrate (0.625 g) was added with stirring to a solution of the compound prepared in Example 278 (0.500 g) in sulfuric acid (2.47 mL) at 0° C. The mixture was allowed to warm up to room temperature and then heated slowly to 75° C. After heating for 2 hours, the mixture was cooled to room temperature, poured into ice, pH adjusted to 4 with 10% aqueous sodium hydroxide, and the precipitated to obtain the title compound (0.440 g) having the following physical data.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[CH2:5]([O:7][C:8]([N:10]1[CH2:19][CH2:18][C:17]2[N:16]=[CH:15][C:14]([C:20]([O-:22])=O)=[C:13]([OH:23])[C:12]=2[CH2:11]1)=[O:9])[CH3:6]>>[CH2:5]([O:7][C:8]([N:10]1[CH2:19][CH2:18][C:17]2[N:16]=[CH:15][C:14]([C:20](=[O:22])[NH:4][CH2:1][CH2:2][CH3:3])=[C:13]([OH:23])[C:12]=2[CH2:11]1)=[O:9])[CH3:6]
Reactant: CCCN
Reactant: CCOC(=O)N1CCc2ncc(C(=O)[O-])c(O)c2C1
Product: CCCNC(=O)c1cnc2c(c1O)CN(C(=O)OCC)CC2

Procedure:
Reaction of N-propylamine with 6-ethoxycarbonyl-4-hydroxy-5,6,7,8-tetrahydro[1,6]naphthyridine-3carboxylate yields 6-ethoxycarbonyl-4-hydroxy-5,6,7,8-tetrahydro-3-(N-propylcarbamoyl)[1,6]-naphthyridine, mp 99°-201°.
Reaction SMILES: [C:1]1([P:7]([Cl:9])Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([C:12]1[CH:17]=[CH:16][C:15]([N+]#N)=[CH:14][CH:13]=1)#[N:11].F[B-](F)(F)F.[Al]>>[C:10]([C:12]1[CH:17]=[CH:16][C:15]([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[Cl:9])=[CH:14][CH:13]=1)#[N:11]
Reactant: N#Cc1ccc([N+]#N)cc1
Reactant: ClP(Cl)c1ccccc1
Agent: F[B-](F)(F)F
Agent: [Al]
Product: N#Cc1ccc(P(Cl)c2ccccc2)cc1
Yield: 47 %

Procedure:
In this process, the reaction product of phenyldichlorophosphine and p-cyanophenyl-diazonium-tetrafluoroborate has to be subjected to a reduction with aluminum in order to obtain the p-cyanophenyl-phenylchlorophosphine. The yield is 47 % of the theoretical yield. This process can be carried out only with difficulty on a large scale, and the formation of large amounts of fluorine containing waste secondary products creates the problem of the pollution-free destruction thereof.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)=[C:6]2[C:11]=1[CH:10]([C:12]([O:14]CC)=[O:13])[N:9]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:8][CH2:7]2.[OH-].[K+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)=[C:6]2[C:11]=1[CH:10]([C:12]([OH:14])=[O:13])[N:9]([S:17]([C:20]1[CH:21]=[CH:22][C:23]([O:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[CH:24][CH:25]=1)(=[O:19])=[O:18])[CH2:8][CH2:7]2
Reactant: CCOC(=O)C1c2c(Br)ccc(OCCN3CCCCC3)c2CCN1S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1c2c(Br)ccc(OCCN3CCCCC3)c2CCN1S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
0.25 g (0.38 mmol) of ethyl 8-bromo-2-[4-(4-fluorophenoxy)benzenesulfonyl]-5-(2-piperidin-1-ylethoxy)-1,2,3,4-tetrahydroisoquinoline-1-carboxylate are mixed with 2 ml of 2 N KOH in 7 ml of methanol and stirred at room temperature. After two hours, a further 2 ml of 2 N KOH are added, and stirring is continued for one hour. For workup, the methanol is removed in a rotary evaporator and the aqueous residue is adjusted to a pH of 6-7 with 2 N HCl. The precipitate is filtered off with suction and dried to afford 0.13 g of the desired carboxylic acid.
Reaction SMILES: C(=O)(O)[O-:2].[Na+].Cl.NCCS.[C:11]([O:15][C:16](=[O:28])[NH:17][C@@H:18]([C:25](F)=[O:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:14])([CH3:13])[CH3:12]>O.C(Cl)Cl>[C:11]([O:15][C:16]([NH:17][C@H:18]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:25]([OH:2])=[O:26])=[O:28])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C([O-])O
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)F)c1ccccc1
Agent: Cl
Agent: NCCS
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a 50 mL round-bottom flask charged with a solution of sodium bicarbonate (78.0 mg, 0.93 mmol) in 4.5 mL water was added 2-aminoethanethiol hydrochloride (56.6 mg, 0.50 mmol). To this stirring solution was added dropwise over 60 seconds a solution of 25j (114.8 mg, 0.45 mmol) in 4.5 mL CH2Cl2. The reaction was vigorously stirred for 25 minutes at room temperature, then extracted twice with fresh CH2Cl2. The combined CH2Cl2 extracts were washed once with 5% aqueous HCl, once with 10% aqueous sodium bicarbonate, then once with water. The organic fraction was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 132.3 mg (86% from 24j) of 26j as an off-white paste.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:23][C:24]5([CH2:27][NH:28]C(=O)OC(C)(C)C)[CH2:26][CH2:25]5)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[ClH:36]>O1CCOCC1>[ClH:36].[NH2:28][CH2:27][C:24]1([NH:23][C:21]([C:20]2[C:14]3[C:15](=[N:16][CH:17]=[C:12]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=5)[N:8]([CH3:11])[N:7]=4)[N:13]=3)[NH:18][CH:19]=2)=[O:22])[CH2:25][CH2:26]1
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)NC4(CNC(=O)OC(C)(C)C)CC4)c3n2)c2ccc(F)cc21
Agent: Cl
Solvent: C1COCCO1
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC4(CN)CC4)c3n2)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 15.8 %

Procedure:
tert-Butyl (1-(2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamido)cyclopropyl)methylcarbamate (95 mg, 0.20 mmol) was dissolved in 20 mL of a saturated solution of HCl (g) in dioxane and the solution was stirred at room temperature for 3 hours. The solvent was evaporated at 40° C. under reduced pressure and the residue was triturated with ethyl acetate (10 mL) then decanted and dried to give N-(1-(aminomethyl)cyclopropyl)-2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide hydrochloride (13 mg, 15.8%) as a pale yellow solid. MS: (M+H)+=380.1; 1H NMR (300 MHz, CD3OD): δ 9.18 (s, 1H), 8.43-8.41 (m, 2H), 7.45 (d, 1H, J=9.3 Hz), 7.19 (s, 1H), 4.17 (s, 3H), 3.32 (s, 2H), 1.25 (s, 4H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[Br-].[CH3:19][N:20]1[CH2:24][CH2:23][CH:22]([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:21]1=[O:44].C(N(CC)CC)C>C(O)C>[CH3:19][N:20]1[CH2:24][CH2:23][C:22](=[CH:8][C:7]2[CH:6]=[C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])[C:12]([OH:13])=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:10]=2)[C:21]1=[O:44]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: CN1CCC([P+](c2ccccc2)(c2ccccc2)c2ccccc2)C1=O
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN1CCC(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Yield: 61.9 %

Procedure:
1.2 g of 3,5-di-tert-butyl-4-hydroxybenzaldehyde, 2.5 g of (N-methyl-2-pyrrolidone-3-yl)triphenylphosphonium bromide and 1.0 ml of triethylamine were heated under reflux in ethanol for two hours. After distilling the ethanol off, the residue was dissolved in chloroform, washed with water followed by a saturated saline solution and dried over anhydrous magnesium sulfate. After distilling the chloroform off, the residue was subjected to column chromatography with the use of silica gel and benzene/acetone and recrystallized from a mixture of ethyl acetate and hexane to give 1.0 g of the title compound.