Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:7])([OH:6])[C:3](O)=[O:4].[NH2:8][C@H:9]([C:11]([N:13]1[C:19](=[O:20])[CH:18]([CH3:21])[C:17]2[CH:22]=[CH:23][CH:24]=[CH:25][C:16]=2[C:15]2[C:26]([NH2:30])=[CH:27][CH:28]=[CH:29][C:14]1=2)=[O:12])[CH3:10]>>[OH:6][C:2]([CH3:7])([CH3:1])[C:3]([NH:8][C@H:9]([C:11]([N:13]1[C:19](=[O:20])[CH:18]([CH3:21])[C:17]2[CH:22]=[CH:23][CH:24]=[CH:25][C:16]=2[C:15]2[C:26]([NH2:30])=[CH:27][CH:28]=[CH:29][C:14]1=2)=[O:12])[CH3:10])=[O:4]
Reactant: CC(C)(O)C(=O)O
Reactant: CC1C(=O)N(C(=O)[C@H](C)N)c2cccc(N)c2-c2ccccc21
Product: CC1C(=O)N(C(=O)[C@H](C)NC(=O)C(C)(C)O)c2cccc(N)c2-c2ccccc21

Procedure:
Following General procedure D above using 2-methyllactic acid (Aldrich) and 5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, as described in Example 7-B, the title compound was prepared. The product was purified by flash chromatography CHCl3/MeOH (98:2) to yield the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:16]=2)([CH3:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][C:3]=1[C:26]([CH3:29])([CH3:28])[CH3:27].[C:30]1(C)[CH:35]=CC(S(O)(=O)=O)=[CH:32][CH:31]=1>C1(C)C=CC=CC=1>[CH2:35]([O:12][C:11](=[O:13])[CH2:10][CH2:9][C:8]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:16]=1)([C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:4]=1)[CH3:14])[CH2:30][CH2:31][CH3:32]
Reactant: CC(C)(C)c1cc(C(C)(CCC(=O)O)c2ccc(O)c(C(C)(C)C)c2)ccc1O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCOC(=O)CCC(C)(c1ccc(O)c(C(C)(C)C)c1)c1ccc(O)c(C(C)(C)C)c1

Procedure:
39.8 g of 4,4-bis(4'-hydroxy-3'-tert.-butyl-phenyl) pentanoic acid were dissolved in 222 g of n-bitanol and 228 g of toluene and 1 g of p-toluene-sulfonic acid was added as an esterification catalyst. Azeotropic distillation was continued until no more water distilled over. After toluene and butanol had been distilled off, a resin-like residue was obtained. After recrystallization from hexane, the 4,4-bis(4'-hydroxy-3'-tert.-butyl-phenyl)pentanoic acid n-butyl ester was obtained as a white crystallized substance.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][N:32]([CH3:34])[CH3:33])[CH:26]=4)[N:19]=3)=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[S:35]1[CH:39]=[CH:38][CH:37]=[C:36]1[CH2:40][C:41](Cl)=[O:42]>C1COCC1.CCOC(C)=O>[CH3:33][N:32]([CH2:31][C:27]1[CH:26]=[C:25]([NH:24][C:20]2[N:19]=[C:18]([C:17]3[C:9]([C:4]4[CH:5]=[CH:6][C:7]([F:8])=[C:2]([NH:1][C:41](=[O:42])[CH2:40][C:36]5[S:35][CH:39]=[CH:38][CH:37]=5)[CH:3]=4)=[N:10][N:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=34)[CH:23]=[CH:22][N:21]=2)[CH:30]=[CH:29][CH:28]=1)[CH3:34]
Reactant: CN(C)Cc1cccc(Nc2nccc(-c3c(-c4ccc(F)c(N)c4)nn4ccccc34)n2)c1
Reactant: O=C(Cl)Cc1cccs1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)Cc1cccc(Nc2nccc(-c3c(-c4ccc(F)c(NC(=O)Cc5cccs5)c4)nn4ccccc34)n2)c1
Reaction time: 20 h
Yield: 77.2 %

Procedure:
To a stirred solution of 4-[2-(3-amino-4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-{3-[(dimethylamino)methyl]phenyl}-2-pyrimidinamine (58 mg, 0.13 mmol) in THF (3 mL) was added TEA (27 μL, 0.19 mmol) and 2-thiopheneacetyl chloride (17 μL, 0.13 mmol). After 20 h, the reaction mixture was diluted with EtOAc (20 mL), adsorbed onto silica gel, and purified by column chromatography to give the title compound (58 mg, 77% yield). 1H NMR (400 MHz, d6-DMSO) 610.15 (s, 1H), 9.54 (s, 1H), 8.83 (d, J=7.0 Hz, 1H), 8.48 (d, J=8.8 Hz, 1H), 8.26-8.29 (m, 2H), 7.69 (s, 1H), 7.63 (d, J=8.2 Hz, 1H), 7.47 (t, J=7.9 Hz, 1H), 7.36-7.39 (m, 2H), 7.18 (t, J=7.8 Hz, 1H), 7.13 (t, J=6.9 Hz), 6.96-6.98 (m, 2H), 6.87 (d, J=7.1 Hz, 1H), 6.52 (d, J=5.3 Hz, 1H), 3.99 (s, 2H), 3.32 (s, 2H), 2.15 (s, 6H). ES-LC/MS m/z=578 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([C:17]([OH:19])=O)[O:13][CH2:12][C:11]=2[S:10][C:9]=1[NH2:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.[NH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.N1C(C)=CC=CC=1C>ClCCl>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([C:17](=[O:19])[NH:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[O:13][CH2:12][C:11]=2[S:10][C:9]=1[NH2:20])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CC(C(=O)O)OC2
Reactant: Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1c(N)sc2c1CC(C(=O)Nc1ccccc1)OC2
Reaction time: 72 h
Yield: 43.9 %

Procedure:
To a solution of the above 2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3,5-dicarboxylic acid 3-tert-butyl ester (94 mg, 0.31 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (72 mg, 0.37 mmol) in distilled dichloromethane (4 ml) under nitrogen was added aniline (321 μl, 0.34 mmol) followed by 2,6-lutidine (0.11 ml, 0.93 mmol). The reaction was stirred for 72 hours, concentrated in vacuo and reconstituted in ethyl acetate (30 ml). The organic layer was washed with 1% hydrochloric acid (10 ml), saturated sodium bicarbonate (10 ml), brine (10 ml), dried (Na2SO4), filtered, and the solvent evaporated in vacuo to give 51 mg (45%) of 2-amino-5-phenylcarbamoyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as a solid.
Reaction SMILES: C(C1(O[Si](C)(C)C)[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1)#N.Cl.[C:21]([OH:24])(=[O:23])[CH3:22]>>[CH3:14][O:13][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[CH:22]([C:21]([OH:24])=[O:23])[CH2:4][CH2:5][CH2:6]2
Reactant: COc1ccc2c(c1)CCCC2(C#N)O[Si](C)(C)C
Reactant: CC(=O)O
Agent: Cl
Product: COc1ccc2c(c1)CCCC2C(=O)O
Temperature: 25 °C

Procedure:
As described with reference to Reaction Scheme I, compounds of Formula 2 can be converted to the intermediates of Formula 3 according to the procedure described by Belletire, et al. [Synthetic Commun., 12(10), 763-770 (1982)]. For example, to a 250 ml single neck round bottom reaction flask equipped with a magnetic stirrer, reflux condenser and nitrogen inlet, is added 6.0 g (21.79 mmol) of 1-cyano-1-trimethylsiloxy-6-methoxy-1,2,3,4-tetrahydronaphthalene. In one portion, 20.0 g (88.6 mmol) stannous chloride decahydrate followed by 20 ml glacial acetic acid and 20 ml concentrated hydrochloric acid is added. The reaction apparatus is immediately flushed with nitrogen and plunged into a preheated (140° C.) oil bath. With vigorous stirring the reaction mixture is heated at reflux for 65 hours, cooled to room temperature, diluted with 250 ml chloroform, the layers separated, and the aqueous layer again extracted with chloroform. The combined organic layers are extracted three times with 2N aqueous KOH, and the combined basic aqueous layers back-extracted with ether. The basic aqueous layer is acidified with ice-bath cooling, extracted three times with chloroform, the organic layers dried over magnesium sulfate, filtered, and the volatiles removed to give 6-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid, an intermediate of Formula 3, as a crystalline solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[S:9][C:10]([C:13]([F:16])([F:15])[F:14])=[N:11][N:12]=2)[CH2:3][CH2:2]1.[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:21]Br.C(N(C(C)C)CC)(C)C>C(#N)C.ClCCl>[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:21][N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[S:9][C:10]([C:13]([F:16])([F:14])[F:15])=[N:11][N:12]=2)[CH2:3][CH2:2]1
Reactant: Fc1ccc(CBr)cc1F
Reactant: FC(F)(F)c1nnc(NC2CCNCC2)s1
Solvent: ClCCl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(CN2CCC(Nc3nnc(C(F)(F)F)s3)CC2)cc1F
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 79.3 %

Procedure:
A mixture of piperidin-4-yl-(5-trifluoromethyl-[1,3,4]thiadiazol-2-yl)-amine (D4) (0.040 g, 0.16 mmol), 3,4-difluorobenzyl bromide (0.024 ml, 0.19 mmol) and diisopropylethylamine (0.042 ml, 0.24 mmol) in acetonitrile (3 ml) was stirred at 100° C. for 5 min., under microwave irradiation. After cooling to room temperature, the reaction mixture was diluted with dichloromethane and extracted with a 10% solution of ammonium chloride (25 ml). The organic layer was separated, dried (Na2SO4) and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel; 0-3% ammonia in methanol (7M)/dichloromethane) to yield E5 (0.048 g, 80%) as a solid. C15H15F5N4S requires 378. Found 379 (MH+).
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[S:11][CH:12]=[CH:13][CH:14]=3)[N:7]=[C:6]([OH:15])[CH:5]=2)[CH2:3][CH2:2]1.[S:16]([Cl:20])(=O)(=[O:18])[OH:17]>>[CH:1]1([C:4]2[CH:5]=[C:6]([OH:15])[N:7]=[C:8]([C:10]3[S:11][C:12]([S:16]([Cl:20])(=[O:18])=[O:17])=[CH:13][CH:14]=3)[N:9]=2)[CH2:3][CH2:2]1
Reactant: O=S(=O)(O)Cl
Reactant: Oc1cc(C2CC2)nc(-c2cccs2)n1
Product: O=S(=O)(Cl)c1ccc(-c2nc(O)cc(C3CC3)n2)s1
Temperature: 0 °C

Procedure:
6-Cyclopropyl-2-(thiophen-2-yl)pyrimidin-4-ol (2.5 g, 11.46 mmol) in sulfurochloridic acid (30 mL) was stirred at rt for 7 days. The solution was poured into ice-water while stirring vigorously. The mixture was maintained below 25° C. during the quenching, the reaction mixture was extracted with EA (3) and the combined organic layers were washed (cold water), dried (Na2SO4) and concentrated to provide the crude product 5-(4-cyclopropyl-6-hydroxypyrimidin-2-yl)thiophene-2-sulfonyl chloride which is used for the subsequent step without further purification. LC-MS (m/z)=316.1 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:6]([O:12][CH3:13])=[CH:5][C:4]=1[N:14]1[CH2:19][CH2:18][CH:17]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:16][CH2:15]1.CCOC(C)=O>CCO.[Pt]>[N:20]1([CH:17]2[CH2:16][CH2:15][N:14]([C:4]3[C:3]([O:2][CH3:1])=[CH:8][C:7]([NH2:9])=[C:6]([O:12][CH3:13])[CH:5]=3)[CH2:19][CH2:18]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: COc1cc([N+](=O)[O-])c(OC)cc1N1CCC(N2CCCCC2)CC1
Agent: [Pt]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc(N2CCC(N3CCCCC3)CC2)c(OC)cc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1′-[2,5-Bis(methyloxy)-4-nitrophenyl]-1,4′-bipiperidine (3.0 g, 8.6 mmol) was taken up in EtOH (50 mL) and EtOAc was added to help with solubility. The catalyst, 5% sulfided platinum on carbon (300 mg) was added. The reaction was placed on a Fischer-Porter Hydrogenator under 50 psi of H2 gas and was allowed to stir at rt overnight. The catalyst was filtered off and the filtrate was concentrated in vacuo to give the title compound of step B without further purification (2.72 g, 99%). 1H NMR (400 MHz, DMSO-d6) δ ppm 6.42 (s, 1H), 6.28 (s, 1H), 4.31 (s, 2H), 3.63 (s, 3H), 3.61 (s, 3H), 3.15 (d, J=11.4 Hz, 2H), 2.38-2.47 (m, 6H), 2.20 (t, J=11.5 Hz, 1H), 1.67 (d, J=11.7 Hz, 2H), 1.41-1.53 (m, 6H), 1.34 (d, J=4.8 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[N:7][C:8]3[C:13]([N:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>C(O)(=O)C>[C:16]([NH:1][C:2]1[C:15]2[C:6](=[N:7][C:8]3[C:13]([N:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc2nc3ccccc3nc12
Solvent: CC(=O)O
Product: CC(=O)Nc1cccc2nc3ccccc3nc12

Procedure:
Scheme 8 provides a synthetic route to a 1-acetamido-N-ethyl phenazine derivative (35). A 3-amino-catechol hydrochloride (30) is reacted with silver oxide and anhydrous sodium sulfate in ethyl acetate to give 3-amino-1,2-quinone (31), which is further reacted in situ with ortho phenylenediamine (32) to give 1-amino phenazine (33). The amino phenazine (33) is acetylated with acetic anhydride in acetic acid to give 1-acetamido phenazine (34). The resulting 1-acetamido phenazine is reacted with diethyl sulfate in the presence of potassium carbonate to give N-ethyl-1-acetamido-phenazine (35)
Reaction SMILES: [F:1][CH2:2][CH:3]([N:8]1[C:12](=[O:13])[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]2[C:9]1=[O:18])[CH2:4][C:5]([CH3:7])=[CH2:6].[Br:19]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[F:1][CH2:2][CH:3]([N:8]1[C:12](=[O:13])[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]2[C:9]1=[O:18])[CH2:4][C:5](=[CH2:7])[CH2:6][Br:19]
Reactant: C=C(C)CC(CF)N1C(=O)c2ccccc2C1=O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: C=C(CBr)CC(CF)N1C(=O)c2ccccc2C1=O

Procedure:
A mixture of 1-fluoro-2-phthalimido-4-methyl-4-pentene (28.3 g, 115 mmoles) prepared as in step B above, N-bromosuccinimide (20.4 g, 115 mmoles), carbontetrachloride (300 mL), and a few mgs of benzoyl peroxide is heated under strong reflux (325 W lamp) during 7.5 hours. After cooling and filtration, the solution is washed with water (100 mL, 3 times), dried over magnesium sulfate and concentrated. The oily residue (quantitative), consisting mainly of the title compound plus some 1-fluoro-2-phthalimido-4-methyl-5-bromo-3-pentene, is used for the next step without further purification.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].S(Cl)([Cl:19])=O>N1C=CC=CC=1>[CH2:1]([O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([Cl:19])=[O:13])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: O=S(Cl)Cl
Reactant: C=CCCCCOc1ccc(C(=O)O)cc1
Solvent: c1ccncc1
Product: C=CCCCCOc1ccc(C(=O)Cl)cc1

Procedure:
The 4-(5-hexenyloxy)benzoic acid 10 g (0.046 mol) was reflux with thionyl chloride (5.4 mL, 0.069 mol) and several drops of pyridine for 8 hours. The excess thionyl chloride was removed in vacuo leaving 4-(5-hexenyl-oxy)benzoyl chloride as a clear liquid at 25° C. This acid chloride was used without further purification.
Reaction SMILES: O[CH:2]([CH3:28])[CH2:3][NH:4][C:5](=[O:27])[CH2:6][N:7]1[C:25](=[O:26])[N:10]2[CH:11]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH:13]=[CH:14][C:9]2=[N:8]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.O>C1COCC1>[CH3:28][C:2]1[O:27][C:5]([CH2:6][N:7]2[C:25](=[O:26])[N:10]3[CH:11]=[C:12]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=4)[CH:13]=[CH:14][C:9]3=[N:8]2)=[N:4][CH:3]=1
Reactant: CC(O)CNC(=O)Cn1nc2ccc(-c3ccc(C(F)(F)F)cc3)cn2c1=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: Cc1cnc(Cn2nc3ccc(-c4ccc(C(F)(F)F)cc4)cn3c2=O)o1
Reaction time: 1 h
Yield: 101.2 %

Procedure:
N-(2-Hydroxypropyl)-2-(3-oxo-6-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)acetamide (30.0 mg, 0.0761 mmol) was treated with Dess-Martin periodinane (64.6 mg, 0.1522 mmol, 2.0 equiv.) in THF (2 mL) at room temperature in a 50 mL round bottomed flask. After stirring for 1 h, water (30 mL) was added and the whole was extracted with EtOAc (30 mL×3). Combined organic layers were washed with sat. Na2S2O3 aq. solution (30 mL), sat. NaHCO3 aq. solution (30 mL) and brine (30 mL) successively. The organic layer was dried over Na2SO4. The solvent was removed under a reduced pressure to give the desired product as colorless crystals (2-(3-oxo-6-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)-N-(2-oxopropyl)acetamide, 30.3 mg, 0.077 mmol, >99%). LCMS (EI: 70 eV) 415 (M++Na), 393 (M++1).
Reaction SMILES: O.[OH-].[Li+:3].[N:4]1([C:10]2[N:11]=[C:12]([CH2:17][C:18]([O:20]CC)=[O:19])[NH:13][C:14](=[O:16])[CH:15]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1>CO>[N:4]1([C:10]2[N:11]=[C:12]([CH2:17][C:18]([O-:20])=[O:19])[NH:13][C:14](=[O:16])[CH:15]=2)[CH2:5][CH2:6][O:7][CH2:8][CH2:9]1.[Li+:3]
Reactant: CCOC(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Temperature: 25 °C
Reaction time: 48 h
Yield: 94.3 %

Procedure:
7.5 ml of water and 197 mg of lithium hydroxide are added to a solution of 2 g of ethyl [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 1 of Example 1 in 75 ml of methanol. After stirring for 48 hours at ambient temperature, the reaction mixture is concentrated under reduced pressure. 50 ml of water are added. The aqueous phase is then washed with ethyl acetate and then lyophilized. 1.73 g of lithium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate are obtained in the form of a white solid, the characteristics of which are similar to the product of stage 2.
Reaction SMILES: Cl.[CH2:2]1[C:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[S:10][C:6]=2[CH2:5][CH2:4][NH:3]1.Cl[CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24].C([O-])([O-])=O.[Na+].[Na+]>CC(C)CC(=O)C>[CH2:2]1[C:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[S:10][C:6]=2[CH2:5][CH2:4][N:3]1[CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)NCCCCCl
Reactant: c1ccc2c3c(sc2c1)CCNC3
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: CC(C)(C)OC(=O)NCCCCN1CCc2sc3ccccc3c2C1
Temperature: 25 °C

Procedure:
A mixture of 1,2,3,4-tetrahydro[1]benzothieno[3,2-c]pyridine HCl (1:1) (0.02 mol), 1,1-dimethylethyl (4-chlorobutyl)carbamate (0.044 mol), Na2CO3 (0.05 mol) and KI (catalytic quantity) in 4-methyl-2-pentanone (200 ml) was stirred and refluxed overnight, then cooled to room temperature and the solvent was evaporated. The residue was washed with water and extracted with CH2Cl2. The separated organic layer was dried, filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 90/10). The desired fractions were collected and the solvent was evaporated, yielding 1,1-dimethylethyl [4-(3,4-dihydro[1]benzothieno[3,2-c]pyridine-2(1H)-yl)butyl]carbamate (intern 1).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][C:9]2[CH:10]=[C:11]3[N:16]([CH:17]=2)[N:15]=[CH:14][N:13]=[C:12]3[NH2:18])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:19]N1C(C)(C)C(=O)N(Br)C1=O>CN(C=O)C>[Br:19][C:17]1[N:16]2[C:11]([C:12]([NH2:18])=[N:13][CH:14]=[N:15]2)=[CH:10][C:9]=1[CH2:8][CH2:7][CH2:6][N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1ncnn2cc(CCCN3CCCC3)cc12
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: CN(C)C=O
Product: Nc1ncnn2c(Br)c(CCCN3CCCC3)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.1 %

Procedure:
To a solution of the compound (257 mg, 1.05 mmol) prepared in Example 12 in DMF (8 mL) at −78° C. was added 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (150 mg, 0.52 mmol) portion wise over a period of 5 minutes. The reaction was stirred for 30 minutes and was allowed to warm to room temperature, and stirred overnight. DMF was removed under vacuum, and the crude solid was extracted with DCM/sodium hydroxide (1N) solution. The organic layer was dried, concentrated, and the crude product was purified by prep HPLC. The pure fractions were concentrated, extracted with saturated sodium bicarbonated/DCM, and the organic layer was dried sodium sulfate, filtered and concentrated to obtain the title compound (135 mg) having the following physical data.
Reaction SMILES: Br.[CH3:2][N:3]1[C:7]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19]Br)[CH:14]=2)=[N:6][C:5]([NH2:21])=[N:4]1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C(O)C>[CH3:2][N:3]1[C:7]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:14]=2)=[N:6][C:5]([NH2:21])=[N:4]1
Reactant: Cn1nc(N)nc1NCCCOc1cccc(CBr)c1
Reactant: C1CCNCC1
Agent: Br
Solvent: CCO
Product: Cn1nc(N)nc1NCCCOc1cccc(CN2CCCCC2)c1
Yield: 89.7 %

Procedure:
1-Methyl-N5 -[3-[3-(bromomethyl)phenoxy]propyl]-1H-1,2,4-triazole-3,5-diamine, hydrobromide (0.3 g) was dissolved in ethanol (5 ml) and treated with piperidine (0.3 g) at room temperature. The solvent was evaporated in vacuo and the residue triturated with ethyl acetate to afford the title compound as a white crystalline solid (0.22 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.CO>CO>[F:24][C:21]([F:22])([F:23])[O:20][C:17]1[CH:18]=[CH:19][C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OC(F)(F)F)cc2)CC1
Agent: Cl
Solvent: CO
Product: FC(F)(F)Oc1ccc(C2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 114.2 %

Procedure:
4-(4-(trifluoromethoxy)phenyl)piperidine-1-formic acid tert-butyl ester (1.73 g, 5 mmol) was dissolved in methanol (15 mL), added HCl/MeOH saturated solution (15 mL), stirred for 3 h at room temperature, removed solvents under reduced pressure, residuals were washed by ethyl ether to give 1.4 g white solid, ie 4-(4-(trifluoromethoxy)phenyl)piperidine hydrochloride, yield was 100%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C@H:8]([CH2:12][N:13]=[N+]=[N-])[CH:9]([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].[N+:17]([C:20]1[CH:30]=[CH:29][C:23]([CH2:24][O:25][C:26](Cl)=[O:27])=[CH:22][CH:21]=1)([O-:19])=[O:18].C(N(CC)CC)C>CO.[Pd]>[N+:17]([C:20]1[CH:21]=[CH:22][C:23]([CH2:24][O:25][C:26](=[O:27])[NH:13][CH2:12][C@@H:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:16])[CH:9]([CH3:11])[CH3:10])=[CH:29][CH:30]=1)([O-:19])=[O:18]
Reactant: CC(C)[C@@H](CN=[N+]=[N-])NC(=O)OC(C)(C)C
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)[C@@H](CNC(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
A solution of ((1S)-1-azidomethyl-2methylpropyl)-carbamic acid t-butyl ester (3.26 g, 13.3 mmol) (obtained as described in Reference Example 61(2)) in methanol (160 ml) was subjected to catalytic hydrogenation in the presence of 10% palladium on charcoal (3.26 g) at room temperature for 1 hour. After checking the completion of the reaction, the reaction mixture was filtered in order to remove the catalyst and the filtrate concentrated under reduced pressure. To a solution of the obtained crude product in methylene chloride (160 ml) were added chloroformic acid p-nitrobenzyl ester (4.31 g, 20.0 mmol) and triethylamine (2.80 ml, 20.0 mmol) in an ice bath, and then the mixture was stirred at room temperature overnight. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The obtained organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (8:1→1:1) as the eluant to afford ((2S)-2-t-butoxycarbonylamino-3-methylbutyl)carbamic acid p-nitrobenzyl ester (3.13 mg, yield 62%) as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(O)(C(F)(F)F)=O.ClC(Cl)C>ClCCl>[Cl:1][C:2]1[C:3]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncccc2Cl)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Product: Clc1cccnc1N1CCNCC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a clear solution of tert-butyl 4-(3-chloropyridin-2-yl)piperazine-1-carboxylate in anhydrous dichloromethane (25 mL) was added TFA (25 mL) dropwise. The yellow solution was stirred at room temperature for 2.5 hour. Reaction was complete as determined by TLC. TFA was azeotropped with dichloroethane to give 1-(3-chloropyridin-2-yl)piperazine in quantitative yield (1.265 g).