Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][C@@H:5]([CH2:7][Si](C)(C)C)[N:4]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[C@H:3]1[CH3:22].CC(C)([O-])C.[K+].C1OCCOCCOCCOCCOCCOC1.O>CS(C)=O>[OH:1][C@H:2]1[CH2:6][C@@H:5]([CH3:7])[N:4]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[C@H:3]1[CH3:22]
Reactant: C[C@H]1[C@@H](O)C[C@@H](C[Si](C)(C)C)N1C(=O)OCc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C[C@@H]1C[C@H](O)[C@H](C)N1C(=O)OCc1ccccc1
Temperature: 100 °C
Reaction time: 17 h
Yield: 65.1 %

Procedure:
To a solution (12 mL) of benzyl (2S,3S,5S)-3-hydroxy-2-methyl-5-[(trimethylsilyl)methyl]pyrrolidine-1-carboxylate (222 mg) synthesized according to the method described in Journal of Organic Chemistry, vol. 59, pages 1958-1960 (1994), potassium tert-butoxide (130 mg) and 18-crown-6-ether (53 mg) in DMSO was added water (0.6 mL), and the mixture was stirred at 100° C. for 17 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=50/1→2/3) to give the title compound as colorless oil (yield: 112 mg, yield: 65%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[NH:12][CH2:13][C:14]([O:16]CC)=[O:15].[Li+].[OH-].CO.Cl>C1COCC1>[F:20][C:2]([F:1])([F:19])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[NH:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: CCOC(=O)CNc1n[nH]c2ccc(C(F)(F)F)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CNc1n[nH]c2ccc(C(F)(F)F)cc12
Reaction time: 2 h

Procedure:
Preparation I6, Step 3: A sample of ethyl 2-(5-(trifluoromethyl)-1H-indazol-3-ylamino)acetate (75 mg) was dissolved in THF (6 mL). The resulting solution was charged successively with an aqueous solution of LiOH (12.5 mg in 2 mL water) and methanol (2 mL). The reaction mixture was stirred for 2 h before being acidified with 1N HCl and extracted with EtOAc. The organic extracts were combined, washed with water and brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure to afford 2-(5-(trifluoromethyl)-1H-indazol-3-ylamino)acetic acid. MS found: (M+H)+=260.22.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:23]2[CH:22]=[CH:21][C:20]([CH3:25])([CH3:24])[C:19]=2[CH2:18][CH2:17][NH:16]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:20]([CH3:25])([CH3:24])[CH:21]=[CH:22][C:23]=4[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCC2=C1C=CC2(C)C
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: CC1C2=C(CCN1C(=O)c1cc3ncc(Cl)cn3n1)C(C)(C)C=C2

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1,5,5-trimethyl-2,3,4,5-tetrahydro-1H-[2]pyrindine to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH2:8]O)[CH:7]=1.O=S(Cl)[Cl:14]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:7]=1)[CH2:8][Cl:14]
Reactant: COc1ccc(F)cc1CO
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccc(F)cc1CCl
Temperature: 25 °C
Yield: 61 %

Procedure:
Neat (5-Fluoro-2-methoxy-phenyl)-methanol (19.587 g, 1 equiv.) is added to neat SOCl2 (42.2 mL, 4.6 equiv.) at −78° C. under a nitrogen atmosphere and the solution is then allowed to warm to room temperature and stirred until evolution of gas ceases. An equivalent volume of anhydrous toluene is added to the flask and the solution heated to 60° C. On cooling, the reaction solution is poured onto ice water. The toluene layer is separated and dried (MgSO4) and the solvent removed under reduced pressure. The crude material is sublimed (60-80° C./0.05 mBarr) to give the title compound as a white solid (13.40 g, 61%). MW 174.60; C8H8ClFO; 1H NMR (CDCl3): 3.87 (s, 3H), 4.60 (s, 2H), 6.79-7.20 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([O:14][CH2:15][C:16]3([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[CH2:12][F:13])[CH:10]=1)[NH:7][N:6]=[CH:5]2.[OH-].[Na+].C(O)C.C1C(=O)N([Cl:48])C(=O)C1>>[Cl:48][C:5]1[C:4]2[C:8](=[C:9]([C@H:11]([O:14][CH2:15][C:16]3([C:29]4[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=4)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[CH2:12][F:13])[CH:10]=[C:2]([Cl:1])[CH:3]=2)[NH:7][N:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COC(CF)c2cc(Cl)cc3cn[nH]c23)(c2ccc(F)cc2)CC1
Reactant: O=C1CCC(=O)N1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(CO[C@H](CF)c2cc(Cl)cc3c(Cl)n[nH]c23)(c2ccc(F)cc2)CC1
Reaction time: 2 h
Yield: 74.8 %

Procedure:
To a solution of tert-butyl 4-((1-(5-chloro-1H-indazol-7-yl)-2-fluoroethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (90 mg, 0.178 mmol) and sodium hydroxide (4N in water) (0.056 mL, 0.222 mmol) in ethanol (1.7 mL, 29.1 mmol) at 0 C was added NCS (47.5 mg, 0.356 mmol), it was stirred at 0 C for 2 h when most S.M. converted to product. The reaction was treated with 0.03 ml of 4 N NaOH, 1 eq. of NCS and was stirred at 0 C for another 2 h., there is still some unreacted SM by TLC. The reaction was quenched by addition of aqueous ammonia and diluted with Et2O. The organic layer was washed with water (2×) then brine, dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel column chromatography (25% EtOAc/Hex) to give title compound (72 mg, 74.9% yield) as clear oil. 1H-NMR (CDCl3, 500 MHz) δ 7.57 (d, J=1.83, 1H), 7.28-7.25 (m, 2H), 7.09-7.06 (m, 3H), 4.6-4.4 (m, 3H), 3.77-3.6 (m, 2H), 3.51 (d, J=9.16 Hz, 1H), 3.39 (d, J=9.16 Hz, 1H), 3.08-2.95 (m, 2H), 2.27 (m, 1H), 2.05 (m, 1H), 1.86 (m, 1H), 1.74 (m, 1H), 1.43 (s, 9H); 13C-NMR (CDCl3, 126 MHz) δ 161.8 (d, J=247.6 Hz), 154.9, 137.8, 137.6, 134.4, 128.73, 127.67, 126.7, 122.2, 121.8, 119.0, 115.9, 115.8, 85.7, 84.3, 81.1, 80.9, 79.7, 42.5, 41.4, 32.4, 32.1, 31.7, 28.5, 22.7, 14.2. LC/MS (HPLC method 3): tR=4.12 min, 540.1(MH)+.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3]([NH2:5])=[S:4].[CH:7]([O:20][C:21]([C:23]1[N:24]2[CH:27]([S:28][CH2:29][C:30]=1[CH:31]=[CH:32]N(C)C)[CH:26]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:25]2=[O:44])=[O:22])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH:7]([O:20][C:21]([C:23]1[N:24]2[CH:27]([S:28][CH2:29][C:30]=1[C:31]1[S:4][C:3]([N:2]([CH3:6])[CH3:1])=[N:5][CH:32]=1)[CH:26]([NH:36][C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[C:25]2=[O:44])=[O:22])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CN(C)C(N)=S
Reactant: CN(C)C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)OC(C)(C)C)C2SC1
Product: CN(C)c1ncc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)OC(C)(C)C)C3SC2)s1
Yield: 58.3 %

Procedure:
The working method of Example 2 is followed, but replacing the thiourea by N,N-dimethylthiourea (5.25 g) and starting with 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-(2-dimethylamino-vinyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (E-form) (21.4 g). The product obtained is chromatographed on a column (diameter: 4.5 cm) containing silica gel (0.2-0.06 mm)(500 cc), elution being carried out with methylene chloride (5 liters) and then with mixtures of methylene chloride and ethyl acetate, namely 99:1 by volume (5 liters) followed by 97:3 by volume (7.5 liters), and 500 cc fractions being collected; fractions 13 to 34 are concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 30° C. The residue is triturated with isopropyl ether (100 cc) and 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-(2-dimethylamino-thiazol-5-yl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (13.8 g) is obtained in the form of a yellow solid.
Reaction SMILES: Cl.[F:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].[F:14][C:15]([F:23])([F:22])[C:16]1([C:19](O)=[O:20])[CH2:18][CH2:17]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][C:19]([C:16]2([C:15]([F:23])([F:22])[F:14])[CH2:18][CH2:17]2)=[O:20])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12]
Reactant: NCc1ccc(F)c([N+](=O)[O-])c1
Reactant: O=C(O)C1(C(F)(F)F)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(F)c([N+](=O)[O-])c1)C1(C(F)(F)F)CC1

Procedure:
The sub-title compound was prepared in analogy to the procedure in Example 94, step (c) using 4-fluoro-3-nitro-benzylamine hydrochloride (3.0 g; 14.5 mmol), 1-(trifluoromethyl)-cyclopropanecarboxylic acid (2.5 g; 16.0 mmol), HBTU (6.07 g; 16.0 mmol), TEA (5.88 g; 58.1 mmol) and DMF (50 mL).
Reaction SMILES: Cl[C:2]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:3].[NH2:9][CH:10]1[N:14]=[C:13]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[CH:21]=[C:12]2[S:11]1.N1C=CC=CC=1>C(Cl)Cl>[S:11]1[C:12]2=[CH:21][C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:13]2=[N:14][CH:10]1[NH:9][C:2](=[O:3])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(=O)Cl
Reactant: NC1N=C2C(=Cc3ccccc32)S1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C(=O)NC1N=C2C(=Cc3ccccc32)S1
Reaction time: 8 h
Yield: 61.9 %

Procedure:
4.2 g (0.031 mole) of ethyl chloroformylformate were added dropwise at room temperature to a solution of 5.2 g (0.028 mole) of 2-amino indeno[1,2-d]thiazole in 250 ml of methylene chloride/2.5 ml of pyridine. The reaction mixture was stirred overnight, after which it was washed with water and dried over Na2SO4, the solvent was distilled off and the residue was recrystallized from acetone to give 5.0 g (62%) of a product of melting point 226°-228° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]([CH3:29])([O:6][C:7]1[CH:8]=[C:9]([C:13]2[C:22]([CH3:24])([CH3:23])[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:25]([O:27][CH3:28])=[O:26])[CH:19]=3)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH3:5]>CO.O1CCCC1.[Pd]>[CH3:1][O:2][C:3](=[O:30])[C:4]([CH3:29])([O:6][C:7]1[CH:8]=[C:9]([CH:13]2[C:22]([CH3:24])([CH3:23])[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:25]([O:27][CH3:28])=[O:26])[CH:19]=3)[NH:14]2)[CH:10]=[CH:11][CH:12]=1)[CH3:5]
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(OC(C)(C)C(=O)OC)c1)=N2
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(OC(C)(C)C(=O)OC)c1)N2
Reaction time: 13 h
Yield: 93.7 %

Procedure:
To a solution of methyl 2-(3-(1-methoxy-2-methyl-1-oxopropan-2-yloxy)phenyl)-3,3-dimethyl-3,4-dihydroquinoline-6-carboxylate (230 mg, 0.56 mmol) in methanol (5 mL) and tetrahydrofuran (5 mL) was added 10% Pd/C (100 mg). The mixture was hydrogenated by H2 balloon for 13 h. Pd/C was removed by filtration. The filtrate was concentrated to afford 216 mg of methyl 2-(3-(1-methoxy-2-methyl-1-oxopropan-2-yloxy)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as syrup. (Yield: 93%).
Reaction SMILES: Cl.CN.[CH2:4]([N:6](CC)CC)C.[Cl:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([C:18](Cl)=[O:19])[CH:13]=1>C(Cl)Cl>[Cl:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([C:18]([NH:6][CH3:4])=[O:19])[CH:13]=1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1cc(Cl)ccn1
Agent: CN
Agent: Cl
Solvent: ClCCl
Product: CNC(=O)c1cc(Cl)ccn1
Reaction time: 8 h
Yield: 52.4 %

Procedure:
To a solution of methylamine hydrochloride (2.057 g, 30.5 mmol) and triethylamine (14.16 ml, 102 mmol) in DCM (30 ml) at 0° C., was added 4-chloropyridine-2-carbonyl chloride (3.575 g, 20.31 mmol) in DCM (20 ml). The resulting black suspension was allowed to reach room temperature and stirred overnight. The mixture was concentrated under reduced pressure and dissolved in ethyl acetate. Water was added and the layers were separated. The aqueous layer was extracted with ethyl acetate (3×), the combined organic layers were washed with water (3×) and brine, dried with Na2SO4 and concentrated under reduced pressure. The residue was purified with column chromatography (20-50% ethyl acetate in n-heptane) to give 2.04 gram of a yellow oil (10.64 mmol, 52%). MS (ESI) m/z=170.0 [M+1]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3](/[CH:6]=[CH:7]/[C:8]([OH:10])=[O:9])=[CH:2]1.[H][H]>[Pd].C(OCC)(=O)C>[O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])[CH2:2]1
Reactant: O=C(O)/C=C/c1ccoc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(O)CCC1CCOC1
Yield: 95.4 %

Procedure:
A solution of (2E)-3-(3-furanyl)-2-propenoic acid (4.75 g, 34.4 mmol) and 10% palladium on carbon (0.366 g, 3.44 mmol) in ethyl acetate (100 ml) was hydrogentated at atmospheric pressure and room temperature for 72 hours. Hydrogen uptake ˜1.4 L (expected 2.4 L). The catalyst was filtered through Celite and concentrated in vacuo to give a brown oil. Analysis by 1H-NMR showed that the some material still contained the furan ring. Hydrogenation was continued under the same conditions with fresh catalyst for a further 24 hours with additional hydrogen uptake of 400 ml. The catalyst was filtered through Celite and the filtrate concentrated in vacuo to afford the title compound as a colourless oil (4.73 g).
Reaction SMILES: [OH:1][C:2]([CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:22])[CH2:13][CH2:14][CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:8][CH:7]=1)=O>CCOCC>[OH:1][CH2:2][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([CH:12]([CH3:22])[CH2:13][CH2:14][CH2:15][CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[CH:10][CH:11]=1
Reactant: CC(CCCC1CCCCC1)c1ccc(CCC(=O)O)cc1
Solvent: CCOCC
Product: CC(CCCC1CCCCC1)c1ccc(CCCO)cc1

Procedure:
Next, 0.82 g of Li[AlH4 ] was added to 50 ml of dried (C2H5)2O, and the resulting mixture was stirred. Thereto was gradually added 5 g of 4-[p-(2-hydroxycarbonylethyl)phenyl]pentylcyclohexane. Thereafter the thus obtained mixture was stirred for 5 hours, and filtered. The (C2H5)2O was distilled off from the filtrate, and the residue was recrystallized from n--C6H14 to obtain 4-[p-(3-hydroxypropyl)phenyl]pentylcyclohexane. The melting point of this compound was 70.7° to 72.5° C. To a mixture of 3.6 g of SOCl2, one drop of pyridine and 50 ml of benzene was added 4.3 g of the 4-[p-(3-hydroxypropyl)phenyl]pentylcyclohexane obtained above, and the resulting mixture was refluxed for 5 hours. Thereafter, the surplus SOCl2 was distilled off to obtain 4-[p-(3-chloropropyl)phenyl]pentylcyclohexane. The melting point of this compound was 70.7° to 72.5° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[S:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:5]2=[C:4]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:3]=1>C(O)(=O)C.[Zn]>[F:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:5]3[C:6](=[N:7][CH:2]=[CH:3][C:4]=3[NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[S:8][CH:9]=2)=[CH:16][CH:15]=1
Reactant: Fc1ccc(-c2csc3nc(Cl)cc(NCc4ccccn4)c23)cc1
Agent: [Zn]
Solvent: CC(=O)O
Product: Fc1ccc(-c2csc3nccc(NCc4ccccn4)c23)cc1

Procedure:
[6-Chloro-3-(4-fluoro-phenyl)-thieno[2,3-b]pyridin-4-yl]-pyridin-2-ylmethyl-amine (40 mg, 0.1 mmol) was dissolved in acetic acid (3 ml). Zinc powder (71 mg, 1 mmol) was added and the mixture refluxed for 6 hr. On cooling, the mixture was filtered through celite and the solids washed with further portions of acetic acid (3×5 ml). The acetic acid extracts were neutralized with saturated sodium bicarbonate solution and extracted with DCM (2×50ml). The extracts were combined, dried over sodium sulfate and concentrated. The residue was purified on silica (ethyl actetate/hexane 20-40%) to give [3-(4-fluoro-phenyl)-thieno[2,3-b]pyridin-4-yl]-pyridin-2-ylmethyl-amine as a white solid. Yield=5.5 mg (15.2%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH:5]=[C:4]([CH3:16])[N:3]=1.[H][H]>[Pt].C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:11][CH2:12][CH:13]([CH3:14])[CH3:15])[CH:5]=[C:4]([CH3:16])[N:3]=1
Reactant: Cc1cc(NCC(C)C)c([N+](=O)[O-])c(Cl)n1
Reactant: [H][H]
Agent: [Pt]
Solvent: Cc1ccccc1
Product: Cc1cc(NCC(C)C)c(N)c(Cl)n1

Procedure:
2-Chloro-N-(2-methylpropyl)-6-methyl-3-nitropyridin-4-amine (5.00 g) from Part A, toluene (100 ml), and 5% platinum on carbon (3.5 g) were added to a Parr shaker and placed on a hydrogenator at a hydrogen pressure of 345 kPa for 4 hours. The reaction, monitored by HPLC, was complete, and the resulting reaction mixture was filtered through a fluted filter paper and then through a folded No.2 Whatman filter. The solvent was removed from the filtrate under reduced pressure, and the resulting oil (4.14 g) was carried on to the next step.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:12][C:13](=[O:15])[CH3:14])([CH3:11])[CH3:10])=[CH:4][C:3]=1[N+:16]([O-])=O.C(N(CC)CC)C>C(O)C.[Pd]>[NH2:16][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([NH:12][C:13](=[O:15])[CH3:14])([CH3:11])[CH3:10])[CH:6]=[CH:7][CH:2]=1
Reactant: CC(=O)NC(C)(C)Cc1ccc(Br)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=O)NC(C)(C)Cc1cccc(N)c1
Reaction time: 6 h
Yield: 74.9 %

Procedure:
A solution of 3.5 g (11 mmol) of N-[2-(4-bromo-3-nitrophenyl)-1,1-dimethyl-ethyl]acetamide in 60 ml of ethanol was treated with 3 ml (22 mmol) of triethylamine and 500 mg of 10% palladium on charcoal. The mixture was hydrogenated at atmospheric pressure for 6 hours, filtered and evaporated. The residue was partitioned between 60 ml of ethyl acetate and 60 ml of saturated aqueous sodium bicarbonate. The organic phase was dried over magnesium sulfate, filtered and evaporated to give 1.7 g (75%) of N-[2-(3-aminophenyl)-1,1-dimethyl-ethyl]-acetamide as an orange gum. [Mass spectrum (ESI) MH+ =207].
Reaction SMILES: Cl.[CH3:2][O:3][CH:4]1[CH2:8][C@@H:7]([NH2:9])[C@H:6]([NH2:10])[CH2:5]1.C(N(CC)CC)C.[Cl:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([C:28](OC1C=CC([N+]([O-])=O)=CC=1)=[O:29])=[CH:22]2>CN(C)C=O>[CH3:2][O:3][CH:4]1[CH2:8][C@@H:7]([NH:9][C:28]([C:23]2[NH:24][C:25]3[C:21]([CH:22]=2)=[CH:20][C:19]([Cl:18])=[CH:27][CH:26]=3)=[O:29])[C@H:6]([NH2:10])[CH2:5]1
Reactant: COC1C[C@@H](N)[C@H](N)C1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)c1cc2cc(Cl)ccc2[nH]1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC1C[C@@H](N)[C@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)C1
Temperature: 25 °C
Reaction time: 96 h
Yield: 34.3 %

Procedure:
(1R*,2R*)-4-Methoxy-1,2-cyclopentanediamine hydrochloride (470 mg) was suspended in N,N-dimethylformamide (5 ml), and triethylamine (0.966 ml) and p-nitrophenyl 5-chloroindole-2-carboxylate (805 mg) were added to stir the mixture at room temperature for 4 days. The solvent was distilled off under reduced pressure, and a saturated aqueous solution of sodium hydrogencarbonate and dichloromethane were added to the residue to conduct liquid separation. The resultant organic layers was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (methanol:dichloromethane=1:9) to obtain (1R*,2R*)-4-methoxy-N1-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclopentanediamine (mixture of stereoisomers at 4-position) (268 mg) as yellow powder.
Reaction SMILES: [H-].[Na+].C(O)C.[C:6]([O:14]CC)(=[O:13])[CH2:7][C:8](OCC)=O.[Br:17][C:18]1[CH:25]=[CH:24][C:21](CBr)=[CH:20][CH:19]=1>C1COCC1>[Br:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:8][CH2:7][C:6]([OH:14])=[O:13])=[CH:20][CH:19]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 10.9 %

Procedure:
Sodium hydride (60% dispersion in oil; 4 g) was added portionwise to an ethanol (100 ml) solution of diethyl malonate (16 g) under ice-cooling. The reaction mixture was stirred at room temperature for 10 minutes, to which was added dropwise a THF (50 ml) solution of p-bromobenzylbromide (12 g) at room temperature. The reaction mixture was stirred at room temperature for 2 hours, and concentrated. Acetic acid (200 ml) and6N hydrochloric acid (100 ml) were added to the residue. The reaction mixture was stirred under heating at 90° C. for 18 hours, and concentrated. Water was added to the residue, which was extracted with ethyl acetate. The organic layer was washed with water, then dried and concentrated. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/1), which was recrystallized from IPE to obtain the entitled compound (1.2 g).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1Cl)=[O:13])[CH2:8]2.[CH3:26][CH:27]1[CH2:31][CH2:30][CH2:29][NH:28]1>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1[N:28]1[CH2:29][CH2:30][CH2:31][CH:27]1[CH3:26])=[O:13])[CH2:8]2
Reactant: CC1CCCN1
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1Cl
Product: CC1CCCN1c1c(C(=O)NC2C3CC4CC(C3)CC2C4)cnn1-c1ccccc1

Procedure:
5-(2-Methyl-pyrrolidin- 1-y1)-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide was prepared using Procedure A from 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Intermediate 3) and 2-methylpyrrolidine. Mass spectrum (ES) MH+=405.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[C:3]=1[C:14]([OH:16])=O.Cl.C(N=C=NCCCN(C)C)C.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>ClCCl>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[C:3]=1[C:14]([N:40]1[CH2:39][CH2:38][N:37]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[O:30][CH3:29])[CH2:42][CH2:41]1)=[O:16]
Reactant: COc1ccccc1N1CCNCC1
Reactant: Nc1onc(-c2ccccc2Cl)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1ccccc1N1CCN(C(=O)c2c(-c3ccccc3Cl)noc2N)CC1
Yield: 69 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-amino-3-(2-chlorophenyl)isoxazol-4-carboxylic acid (440 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(2-methoxyphenyl)piperazine (354 mg, 1.84 mmol), a white solid required compound (523 mg, 1.27 mmol, 69%) was obtained.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:11][C:6]=1[C:7]([O:9]C)=O.[NH2:23][CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][NH:26]1.O>C1(C)C=CC=CC=1>[CH:13]1[C:12]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:11][C:6]([C:7]([NH:23][CH2:24][CH:25]2[NH:26][CH2:27][CH2:28][CH2:29][CH2:30]2)=[O:9])=[C:5]([O:4][CH2:3][C:2]([F:1])([F:22])[F:21])[CH:14]=1
Reactant: COC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Reactant: NCC1CCCCN1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(NCC1CCCCN1)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Temperature: 25 °C
Yield: 87.1 %

Procedure:
A mixture of methyl 2,5-bis(2,2,2-trifluoroethoxy)benzoate (1.5 g), 2-(aminomethyl)piperidine (0.62 g) in toluene (3 ml) was stirred at reflux for 10 hours. After cooling to room temperature, water (10 ml) was added and two layers solution were separated. The aqueous layer was extracted with toluene (2×10 ml) and the combined organic layers were washed with water (3×10 ml). The organic layer was concentrated under reduced pressure to give Flecainide free base as a white solid (1.63 g, 85%).