Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[B-](F)(F)F.C([O+](CC)CC)C.[CH3:13][N:14]([CH3:24])[C:15]1[CH:20]=[CH:19][C:18]([C:21](=O)[CH3:22])=[CH:17][CH:16]=1.[Cl-:25].[NH2:26][N+:27]1[CH:31]=[CH:30][N:29]([NH2:32])[C:28]=1[CH2:33][CH3:34].CO>C(Cl)Cl>[Cl-:25].[NH2:26][N:27]1[CH:31]=[CH:30][N+:29]([N:32]=[C:21]([CH3:22])[C:18]2[CH:19]=[CH:20][C:15]([N:14]([CH3:24])[CH3:13])=[CH:16][CH:17]=2)=[C:28]1[CH2:33][CH3:34]
Reactant: CCc1n(N)cc[n+]1N
Reactant: CC(=O)c1ccc(N(C)C)cc1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Agent: [Cl-]
Solvent: CO
Solvent: ClCCl
Product: CCc1n(N)cc[n+]1N=C(C)c1ccc(N(C)C)cc1

Procedure:
380 mg (2 mmol) of triethyloxonium tetrafluoroborate are dissolved in 15 ml of methylene chloride. 326 mg (2 mmol) of p-dimethylaminoacetophenone are added thereto at -15°. After 5 minutes there are added thereto at the same temperature 162 mg (1 mmol) of 1,3-diamino-2-ethyl-imidazolium chloride and the mixture is stirred at -10° for 1 hour and at 0° for 2 hours. After the addition of a small amount of methanol the mixture is evaporated and the residue is placed on a column loaded with 10 g of silica gel. The product is eluted with chloroform/methanol (87:13 parts by weight) and crystallized using ether. The crystallizate is dissolved in 80 ml of water, placed on a column loaded with ion exchanger Amberlite IRA 400 (chloride) and elution is carried out with water. The eluate is evaporated and the residue is crystallized from ethanol/water. There is obtained 3-amino-1-[[p-(dimethylamino)-α-methylbenzylidene]amino]-2 -ethylimidazolium chloride of melting point 223°-225°.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]3[C:20]4[CH2:21][O:22][C:23]5[CH:24]=[C:25]([CH2:29][OH:30])[CH:26]=[CH:27][C:28]=5[C:19]=4[O:18][N:17]=3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]3[C:20]4[CH2:21][O:22][C:23]5[CH:24]=[C:25]([CH:29]=[O:30])[CH:26]=[CH:27][C:28]=5[C:19]=4[O:18][N:17]=3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCc1ccc2c(c1)OCc1c(-c3onc(-c4ccccc4)c3C(F)(F)F)noc1-2
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=Cc1ccc2c(c1)OCc1c(-c3onc(-c4ccccc4)c3C(F)(F)F)noc1-2
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of (3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4H-chromeno[3,4-d]isoxazol-7-yl)methanol (Preparation 60H, 0.027 g, 0.065 mmol) in dichloromethane (2.0 mL) at room temperature was added Dess-Martin Periodinane (0.030 g, 0.072 mmol). The reaction mixture was stirred for 30 min. The reaction was quenched with a 1:1 mixture of saturated aqueous sodium thiosulfate and saturated aqueous sodium bicarbonate (˜2.0 mL), extracted with dichloromethane (2×), and the combined organic layers were dried over anhydrous sodium sulfate and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to afford 3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4H-chromeno[3,4-d]isoxazole-7-carbaldehyde (0.027 g, 0.065 mmol, 100% yield) as a white solid. The product had an HPLC ret. time=3.31 min.−Column: Chromolith SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13](=[O:20])[C:14]3[S:19][CH:18]=[CH:17][C:15]=3[N:16]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[C:25]#[N:26].C[Si](C)(C)[N-][Si](C)(C)C.[K+].C1(C)C=CC=CC=1.[NH4+].[Cl-]>C(OCC)(=O)C.C1COCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([NH:16][C:15]2[CH:17]=[CH:18][S:19][C:14]=2[C:13]([NH:21][C:22]2[CH:29]=[CH:28][CH:27]=[C:24]([C:25]#[N:26])[CH:23]=2)=[O:20])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(-c2nc3ccsc3c(=O)o2)cc1
Reactant: N#Cc1cccc(N)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(C(=O)Nc2ccsc2C(=O)Nc2cccc(C#N)c2)cc1
Reaction time: 0.25 h
Yield: 102.7 %

Procedure:
To a mixture of 2-(4-t-butylphenyl)-4H-thieno[3,2-d]-[1,3]oxazin-4-one (400 mg, 1.4 mmol), 3-aminobenzonitrile (165 mg, 1.4 mmol) and THF (5 mL) was added 0.5 M potassium hexamethyldisilazide in toluene (3.08 mL, 1.54 mmol) and stirred for 15 min. The reaction was added NH4Cl and ethyl acetate. The organic layer was washed with water (3×) and brine, MgSO4 dried and concentrated. The residue was chromatographed (20% THF/hexanes) to give the title compound as a solid (580 mg, 51%); 1.37 (s, 9H), 7.47 (m, 4H), 7.57 (d, 2H, J=8.4 HZ); 7.68 (m, 1H), 7.98 (d, 2H, J=8.4 Hz); 8.20 (s, 1H); 8.42 (d, 1H, J=5.7 Hz); 11.80 (s, 1H); MS(FD): 403.
Reaction SMILES: C[O:2][C:3]([CH2:5][N:6]1[C:14]2[C:9](=[N:10][CH:11]=[N:12][C:13]=2[NH2:15])[N:8]=[CH:7]1)=O.O.[BH4-].[Na+].Cl>C1COCC1>[OH:2][CH2:3][CH2:5][N:6]1[C:14]2[C:9](=[N:10][CH:11]=[N:12][C:13]=2[NH2:15])[N:8]=[CH:7]1
Reactant: COC(=O)Cn1cnc2ncnc(N)c21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ncnc2ncn(CCO)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.1 %

Procedure:
To a stirred solution containing 16 (0.207 g, 0.999 mmol) and water (0.50 mL) in THF (12 mL) was added NaBH4 (0.38 g, 10.0 mmol). After stirring for 4 h at 25° C., the reaction mixture was neutralized to pH=7.0 by use of 10% HCl aqueous solution. Solvent was evaporated under reduced pressure and the residue was purified by column chromatography (EtOAc/hexanes=9:1) to give 18 (0.10 g, 0.55 mmol) in 55% yield: mp 132-133° C.; Rf(hexanes/EtOAc=1:2) 0.09; UV (EtOH) λmax 265 (ε 14,110); 1H NMR (CD3OD) δ 3.68 (t, J=5.9 Hz, 2 H, CH2O), 3.66 (t, J=5.9 Hz, 2 H, CH2N), 8.34 (s, 1 H, HC2), 8.68 (s, 1 H, HC8); MS m/z 179 (M+). Anal (C7H9N5O) C, H, N; calcd (%): 46.92, 5.06, 39.08; found (%): 47.01, 5.12, 39.11.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][CH2:24]I)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.Cl.[F:27][C@H:28]1[CH2:32][CH2:31][NH:30][CH2:29]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][CH2:24][N:30]3[CH2:31][CH2:32][C@H:28]([F:27])[CH2:29]3)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12
Reactant: Clc1c(-c2ccccc2)nnc2c1c(-c1ccccc1)nn2CCI
Reactant: F[C@H]1CCNC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: F[C@H]1CCN(CCn2nc(-c3ccccc3)c3c(Cl)c(-c4ccccc4)nnc32)C1
Reaction time: 48 h
Yield: 29.6 %

Procedure:
A solution of 4-chloro-1-(2-iodoethyl)-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine (90 mg, 0.2 mmol) in dry CH2Cl2 (2 mL) was added to (S)-3-fluoropyrrolidine hydrochloride (126 mg, 1 mmol), DIPEA (0.21 mL, 1.2 mmol) was added and the reaction stirred for 2 days. Further CH2Cl2 (3 mL), (S)-3-fluoropyrrolidine hydrochloride (126 mg, 1 mmol) and DIPEA (0.21 mL, 1.2 mmol) was added and the reaction stirred for an additional 7 days. The resultant residue was purified using chromatography (silica gel, gradient 20 to 100% ethyl acetate/isohexane), followed by preparative HPLC to provide Compound IIt as a white solid (25 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:7]([OH:13])=[C:6]([F:14])[C:5]=1[F:15]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([OH:13])=[C:6]([F:14])[C:5]=1[F:15]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(O)c(F)c1F
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(N)c(O)c(F)c1F
Yield: 99.5 %

Procedure:
A solution of 2,3-difluoro-4-hydroxy-5-nitro-benzoic acid methyl ester (2.2 g, 9.4 mmol) in methanol (100 mL) was stirred under atmospheric hydrogen at ambient temperature in the presence of 10% palladium on charcoal (0.8 g) for 3 hours. The mixture was filtered and the filtrate was evaporated in vacuo to give the title compound (1.9 g, 100%) as a colourless solid.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[C:7]1([P:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[OH:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1(C)C=CC=CC=1>[O:5]=[C:4]1[CH2:3][CH:2]([CH2:1][P:13](=[O:14])([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:6]1
Reactant: C=C1CC(=O)O1
Reactant: OP(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: O=C1CC(CP(=O)(c2ccccc2)c2ccccc2)O1

Procedure:
A mixture of 4.2 parts of diketene, 10.1 parts of diphenylphosphinous acid, 2.3 parts of bis-(t-butylcyclohexyl)-perdicarbonate and 70 parts of toluene was stirred by a stream of nitrogen in a quartz apparatus at room temperature while being irradiated by UV light from a medium pressure mercury lamp. After three hours irradiation, the reaction mixture was filtered, and the filtrate evaporated. The semi-crystalline residue was triturated with a little toluene, and the crystals collected on a filter and washed with toluene. Crystallisation from toluene gave colourless crystals of (2-oxo-4-oxetanylmethyl)-diphenylphosphine oxide which melted at 154°-155° C. and had the following elemental analysis by weight.
Reaction SMILES: C(Cl)(Cl)Cl.C([O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[C:19]([F:23])=[C:18]([C:24]([O:26][C@@H:27]([C:32]([F:35])([F:34])[F:33])[CH2:28][CH2:29][CH2:30][CH3:31])=[O:25])[CH2:17][CH2:16]2)C1C=CC=CC=1.I[Si](C)(C)C>CO>[OH:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[C:19]([F:23])=[C:18]([C:24]([O:26][C@@H:27]([C:32]([F:33])([F:34])[F:35])[CH2:28][CH2:29][CH2:30][CH3:31])=[O:25])[CH2:17][CH2:16]2
Reactant: CCCC[C@@H](OC(=O)C1=C(F)c2ccc(OCc3ccccc3)cc2CC1)C(F)(F)F
Agent: C[Si](C)(C)I
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCC[C@@H](OC(=O)C1=C(F)c2ccc(O)cc2CC1)C(F)(F)F
Yield: 36.5 %

Procedure:
To 3.1 ml of a chloroform solution of 0.82 g (1.9 mmol) of the (R)1-trifluoromethylpentyl 6-benzyloxy-1-fluoro-3,4-dihydro-2-naphthalenecarboxylate obtained in the third step was dropwise added 134 μl (0.95 mmol) of iodotrimethylsilane, and they were reacted at room temperature for 30 minutes in a nitrogen atmosphere with stirring. Then, 10 ml of methanol was added to terminate the reaction. The reaction mixture was separated by column chromatography, to obtain 0.24 g of (R)1-trifluoromethylpentyl 6-hydroxy-1-fluoro-3,4-dihydro-2-naphthalenecarboxylate (yield: 37%). The 1H-NMR data of this compound are described below.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([C@@H:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:51][CH2:52][C:53]1[C:54]([OH:61])=[N:55][C:56]([CH3:60])=[CH:57][C:58]=1[CH3:59]>ClCCl.O>[OH:61][C:54]1[C:53]([CH2:52][NH:51][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][C:9]([C@@H:11]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH3:12])=[CH:10][C:2]=2[CH3:1])=[C:58]([CH3:59])[CH:57]=[C:56]([CH3:60])[N:55]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: Cc1cc([C@H](C)Oc2ccccc2)ccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc([C@H](C)Oc3ccccc3)cc2C)c(O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.1 %

Procedure:
To a solution of (S)-2-methyl-4-(1-phenoxyethyl)benzoic acid (5.3 g, 19.5 mmol) in dichloromethane (100 mL) was added 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (11.1 g, 29.3 mmol) and triethylamine (8.6 mL, 62.2 mmol). The mixture was stirred at room temperature for 30 minutes. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (3.15 g, 21 mmol) was added and the mixture was stirred at room temperature for 12 hours. The mixture was poured into water (100 mL) and extracted with dichloromethane (50 mL*2). The combined organic phase was separated, dried by sodium sulphate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel, methanol/dichloromethane=1:10) to give (S)—N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-2-methyl-4-(1-phenoxyethyl)benzamide (Compound I-55) as a white solid (4.5 g, 59%). LRMS (M+H+) m/z: calcd 390.19. found 390. HPLC purity (214 nm): 100%. 1H NMR (300 MHz, CD3OD): δ 7.28-7.22 (m, 3H), 7.12-7.09 (m, 2H), 6.83-6.79 (m, 3H), 6.10 (s, 1H), 5.36-5.34 (m, 1H), 4.44 (s, 2H), 2.36 (s, 3H), 2.33 (s, 3H), 2.23 (s, 3H), 1.57 (d, J=6.6 Hz, 3H).
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([C:6]([C:8]2[CH:9]=[CH:10][C:11]([O:16][CH2:17][C:18]([OH:20])=[O:19])=[C:12]([Cl:15])[C:13]=2[Cl:14])=[O:7])[S:4][CH:5]=1.[NH2:21][CH:22]([CH2:26][CH2:27][CH2:28][NH2:29])[C:23]([OH:25])=[O:24]>C(O)C>[Cl:15][C:12]1[C:13]([Cl:14])=[C:8]([C:6]([C:3]2[S:4][CH:5]=[CH:1][CH:2]=2)=[O:7])[CH:9]=[CH:10][C:11]=1[O:16][CH2:17][C:18]([OH:20])=[O:19].[NH2:21][C@H:22]([C:23]([OH:25])=[O:24])[CH2:26][CH2:27][CH2:28][NH2:29]
Reactant: NCCCC(N)C(=O)O
Agent: O=C(O)COc1ccc(C(=O)c2cccs2)c(Cl)c1Cl
Solvent: CCO
Product: NCCC[C@H](N)C(=O)O

Procedure:
Using the method of Example 1, this salt was obtained at an 85% yield by reacting 13.6 g tienilic acid and 6 g 2,5-diaminopentanoic acid in ethanol. M.Pt: 230° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[C:22](Br)[CH:23]=[CH:24][CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.CCOC(C)=O.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]>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[C:22]([N:37]5[CH2:42][CH2:41][O:40][CH2:39][CH2:38]5)[CH:23]=[CH:24][CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(Br)cccc4c3=O)cc2)CCC1
Reactant: C1COCCN1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(N5CCOCC5)cccc4c3=O)cc2)CCC1
Temperature: 150 °C
Yield: 69.6 %

Procedure:
{1-[4-(8-bromo-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (50 mg, 0.091 mmol), morpholine (10 μL, 0.11 mmol), tris(dibenzylideneacetone)dipalladium(0) (5 mg, 0.005 mmol), (S)-BINAP (9 mg, 0.015 mmol) and cesium carbonate (42 mg, 0.127 mmol) were suspended in toluene (1 mL) in a microwave vial. The vial was sealed, evacuated and flushed twice with nitrogen. The reaction mixture was heated in a microwave at 150° C. for 1 h. Further morpholine (10 μL, 0.11 mmol), tris(dibenzylideneacetone)dipalladium(0) (5 mg, 0.005 mmol), (S)-BINAP (9 mg, 0.015 mmol) and cesium carbonate (42 mg, 0.127 mmol) were added to the vial and the resultant mixture was heated in a microwave at 150° C. for 1.5 h. Further morpholine (10 μL, 0.11 mmol), tris(dibenzylideneacetone)dipalladium(0) (5 mg, 0.005 mmol), (S)-BINAP (9 mg, 0.015 mmol) and cesium carbonate (42 mg, 0.127 mmol) were added to the vial and the resultant mixture was heated in a microwave at 150° C. for 1 h. The reaction mixture was diluted with EtOAc, washed with water, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 100% ethyl acetate in DCM) to afford the title compound as a pale yellow solid (35 mg, 70%). LCMS (Method G): RT=4.33 min, [M+H]+=553.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1>C1COCC1.[Rh]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)C=Cc1ccc(F)cc1
Agent: [Rh]
Solvent: C1CCOC1
Product: O=C(O)CCc1ccc(F)cc1

Procedure:
3-(4-Fluoro-phenyl)-acrylic acid (25.00 g, 151.00 mmol) in THF was mixed with Rh/Al2O3 (1.00 g) and hydrogenated for 14 hours. The reaction mixture was filtered through celite and the filtrate was concentrated to give 3-(4-fluoro-phenyl)-propionic acid. 3-(4-fluoro-phenyl)-propionic acid was then reacted with SOCl2 (16.50 mL, 0.23 mol) and AlCl3 (22.00 g, 0.16 mol) according to the protocols as outlined in general procedure C to afford the title compound.
Reaction SMILES: N(OC(C)(C)C)=O.[CH3:8][C:9]1[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:10]=1N.[CH3:17][S:18]SC>[Cu]>[CH3:8][C:9]1[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:10]=1[S:18][CH3:17]
Reactant: Cc1cccc(N)c1C
Reactant: CSSC
Agent: [Cu]
Agent: CC(C)(C)ON=O
Product: CSc1cccc(C)c1C
Temperature: 77.5 °C
Reaction time: 1.5 h

Procedure:
355 g (3.44 mol) of tert-butyl nitrite and 250 g of copper powder (3.9 mol) are initially charged in 1250 ml of dimethyl disulfide, and a solution of 250 g (2.07 mol) of 2,3-dimethylaniline in 1000 ml of dimethyl disulfide is added dropwise at 50-52° C. The mixture is subsequently stirred at 75-80° C. for 1.5 hours. For work-up, the mixture is cooled, filtered off with suction through kieselguhr, and the filtrate is washed with saturated aqueous NaHCO3 solution. For the purification of the product, the organic phase is separated by distillation. Initially, excess dimethyl disulfide is removed at atmospheric pressure. 1446 g of dimethyl disulfide (purity >97% according to GC) are recovered. The residue is then subjected to fractional distillation under reduced pressure (0.1 mbar).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([N:22]2[CH2:27][CH2:26][C:25]([F:29])([F:28])[CH2:24][CH2:23]2)[CH2:20][NH2:21])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([N:22]1[CH2:23][CH2:24][C:25]([F:29])([F:28])[CH2:26][CH2:27]1)[C:16]1[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: NCC(c1ccc(F)cc1)N1CCC(F)(F)CC1
Product: O=C(NCC(c1ccc(F)cc1)N1CCC(F)(F)CC1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and 2-(4-fluoro-phenyl)-2-(4,4-difluoro-piperidin-1-yl)-ethylamine.
Reaction SMILES: C[O:2][C:3]1[N:8]=[N:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[BrH:15]>>[BrH:15].[OH:2][C:3]1[N:8]=[N:7][C:6]([N:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N2CCNCC2)nn1
Agent: Br
Product: Oc1ccc(N2CCNCC2)nn1
Reaction time: 8 h

Procedure:
4-(6-Methoxypyridazin-3-yl)piperazine (7.2 g) (J. Med. Chem. 1963, 5, 541) in 48% hydrobromic acid (140 ml) was heated at 110°-120° for 11/2 hours, left at room temperature overnight, then heated at 120° for a further 1 hour. The solvent was evaporated in vacuo and the residue treated twice with isopropanol and evaporated to dryness. The resulting solid was triturated with diethyl ether, filtered and washed with ether to give 4-(6-hydroxypyridazin-3-yl)piperazine, hydrobromide (11.2 g). A sample re-crystallized from ethanol had m.p. 289°-291°.
Reaction SMILES: [C:1]1([CH:7]2[C:14](=[O:15])[N:13]3[CH:8]2[CH2:9][CH2:10][CH2:11][CH2:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:17][OH:18]>>[CH3:17][O:18][C:14]([CH:7]([CH:8]1[NH:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:15]
Reactant: CO
Reactant: O=C1C(c2ccccc2)C2CCCCN12
Agent: Cl
Product: COC(=O)C(c1ccccc1)C1CCCCN1

Procedure:
reacting the 7-phenyl-1-azabicyclo[4.2.0]octan-8-one obtained in step (i) with a solution of hydrogen chloride in methanol to give methylphenidate;
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.[CH3:12][C:13]([CH3:15])=O>[Pd].C(O)C>[CH:13]([N:1]1[CH2:2][CH2:3][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10][CH2:11]1)([CH3:15])[CH3:12]
Reactant: CC(C)=O
Reactant: CCOC(=O)C1CCNCC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1CCN(C(C)C)CC1
Temperature: 35 °C

Procedure:
An autoclave was charged with ethyl isonipecotate (50 g, 318.0 mmol), 10% Pd/C (5 g, 10 wt %), acetone (450 mL, 6.13 mol) and ethanol (100 mL). The autoclave was pressurized to 4.1 bar with H2, and the slurry was heated to 35° C. After 14 h the mixture was filtered, rinsed with acetone, and was concentrated to remove excess acetone. The crude material was taken on without any purification:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:15]2[O:14][C:13]3[C:16]([CH:23]=[O:24])=[C:17]([O:21][CH3:22])[CH:18]=[C:19]([CH3:20])[C:12]=3[C:11](=[O:25])[O:10][C:9]=2[C:8]([CH3:26])=[C:7]([O:27][CH3:28])[CH:6]=1)=[O:4].Cl.O1CC[CH2:32][CH2:31]1>>[CH3:1][O:2][C:3]([C:5]1[C:15]2[O:14][C:13]3[C:16]([CH:23]([OH:24])[CH2:31][CH3:32])=[C:17]([O:21][CH3:22])[CH:18]=[C:19]([CH3:20])[C:12]=3[C:11](=[O:25])[O:10][C:9]=2[C:8]([CH3:26])=[C:7]([O:27][CH3:28])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(OC)c(C)c2c1Oc1c(C=O)c(OC)cc(C)c1C(=O)O2
Reactant: C1CCOC1
Agent: Cl
Product: CCC(O)c1c(OC)cc(C)c2c1Oc1c(C(=O)OC)cc(OC)c(C)c1OC2=O
Reaction time: 1 h

Procedure:
The compound from Example 3 (0.15 mmol) was dissolved in absolute tetrahydrofuran. A solution of 2M Grignard reagent (0.7 ml, 1.4 mmol) in tetrahydrofuran was added under ice bath. The mixture was stirred for 1 h. Upon completion, 2 ml of 1N hydrochloric acid was added, and the mixture was extracted with methylene chloride. The organic layer was subsequently washed with water and saturated brine, dried over anhydrous MgSO4, filtered and evaporated by a rotatory evaporator. After chromatographic purification on silica, the title compound was obtained.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[C:19]([C:21]([OH:23])=O)[CH:18]=[CH:17][N:16]2[CH:24]=1.[NH2:25][CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>>[N:29]1[CH:30]=[CH:31][CH:32]=[C:27]([CH2:26][NH:25][C:21]([C:19]2[CH:18]=[CH:17][N:16]3[CH:24]=[C:13]([C:3]4[C:4]([C:7]5[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=5)=[N:5][O:6][C:2]=4[CH3:1])[N:14]=[C:15]3[CH:20]=2)=[O:23])[CH:28]=1
Reactant: NCc1cccnc1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2ccc(C(=O)O)cc2n1
Product: Cc1onc(-c2ccccc2)c1-c1cn2ccc(C(=O)NCc3cccnc3)cc2n1
Yield: 66 %

Procedure:
As described for Example 11b, 2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridine-7-carboxylic acid (64 mg, 0.2 mmol) was converted, using 3-(aminomethyl)pyridine instead of aminomethylcyclopropane, to the title compound (54 mg, 66%) which was obtained as a light yellow foam. MS: m/e=410.3 [M+H]+.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH3:4].[Br:6][C:7]1[C:8]([CH3:14])=[C:9]([NH2:13])[CH:10]=[CH:11][CH:12]=1.BrC1C(C)=C(C=CC=1)NCCC>>[Br:6][C:7]1[C:8]([CH3:14])=[C:9]([CH:10]=[CH:11][CH:12]=1)[NH:13][CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: CCCC=O
Reactant: Cc1c(N)cccc1Br
Agent: CCCNc1cccc(Br)c1C
Product: CCCCNc1cccc(Br)c1C

Procedure:
Prepared from butyraldehyde and 3-bromo-2-methylphenylamine using the procedure described Intermediate 56.