Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[O:18][CH3:19].C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.C1(C)C=CC=CC=1.[Cu]Br>[CH3:19][O:18][C:10]1[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=1[N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: CN1CCNCC1
Reactant: COc1cc([N+](=O)[O-])ccc1Br
Agent: [Cu]Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COc1cc([N+](=O)[O-])ccc1N1CCN(C)CC1
Temperature: 100 °C
Yield: 14.8 %

Procedure:
A mixture of N-methylpiperazine (216 mg, 2.15 mmol), 2-bromo-5-nitroanisole (1 g, 4.3 mmol), potassium carbonate (447 mg, 3.23 mmol), copper (I) bromide (86.6 mg, 0.30 mmol) in pyridine (0.5 ml) and toluene (2 ml) was heated at 100° C. overnight. After cooling, the mixture was partitioned between water and ether and the aqueous phase was further extracted with ethyl acetate. The combined organic phases were dried (Na2SO4) and evaporated under reduced pressure, to give the crude product. This was purified by chromatography on silica gel, eluting with methanol and dichloromethane, to give the title compound (D34) as a yellow/brown oil (80 mg, 15%) MH+=252.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].C([O-])([O-])=O.[Na+].[Na+].[N+:12]([C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[C:16]=1[C:17](O)=[O:18])([O-:14])=[O:13]>[N+](C1C=CC=C([N+]([O-])=O)C=1C(Cl)=O)([O-])=O>[N+:12]([C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[C:16]=1[C:17]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:18])([O-:14])=[O:13]
Reactant: NCC(=O)O
Reactant: O=C(O)c1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: O=C(Cl)c1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1c([N+](=O)[O-])cccc1[N+](=O)[O-]

Procedure:
The reaction of 2,6-dinitrobenzoyl chloride (prepared from 2,6-dinitrobenzoic acid, 1.2 g and SOCl2, 20 mL) with glycine (530 mg, 7.075 mmol) in the presence of Na2CO3 (749 mg, 7.075 mmol) as described in intermediate 2 gave the title compound as an off-white color solid (1.2 g, 80%), mp 210-212° C. 1H NMR (400 MHz, DMSO-d6): δ 12.76 (1H, s), 9.22 (1H, t, J=5.0 Hz), 8.45 (2H, d, J=8.4 Hz), 7.93 (1H, t, J=8.4 Hz), 3.98 (2H, d, J=5.2 Hz); LC-MS (negative ion mode): m/z 268 (M−H)−.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[O:13]1[CH2:18][CH2:17][N:16]([CH2:19]/[CH:20]=[CH:21]/[CH2:22][OH:23])[CH2:15][CH2:14]1.[Cl:24][C:25]1[CH:44]=[CH:43][C:28]([NH:29][C:30]2[C:39]3[C:34](=[CH:35][C:36](O)=[C:37]([O:40][CH3:41])[CH:38]=3)[N:33]=[CH:32][N:31]=2)=[C:27]([F:45])[CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[ClH:24].[Cl:24][C:25]1[CH:44]=[CH:43][C:28]([NH:29][C:30]2[C:39]3[C:34](=[CH:35][C:36]([O:23][CH2:22]/[CH:21]=[CH:20]/[CH2:19][N:16]4[CH2:17][CH2:18][O:13][CH2:14][CH2:15]4)=[C:37]([O:40][CH3:41])[CH:38]=3)[N:33]=[CH:32][N:31]=2)=[C:27]([F:45])[CH:26]=1
Reactant: OC/C=C/CN1CCOCC1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OC/C=C/CN1CCOCC1
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.7 %

Procedure:
Diethyl azodicarboxylate (325 μl, 2 mmol) was added dropwise to a mixture of (E)4 morpholinobut-2-en-1-ol (151 mg, 0.96 mmol), (J. Med. Chem. 1972, 15, 110-112), 4-(4chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (220 mg, 0.688 mol), (prepared as described for the starting material in Example 2), and triphenylphosphine (541 mg, 2 mmol) in methylene chloride (4 ml). The mixture was stirred for 30 minutes at ambient temperature, and further (E)4-morpholinobut-2-en-1-ol (10 mg, 0.06 mmol), triphenylphosphine (36 mg, 0.137 mol) and diethyl azodicarboxylate (22 μl, 0.14 mmol) were added. The mixture was stirred for 20 minutes and the volatiles were removed by evaporation. The residue was purified by column chromatography on silica eluting with methylene chloride/methanol (92/8). The purified solid was dissolved in methylene chloride and 2M ethereal hydrogen chloride (3 ml) was added. The volatiles were removed by evaporation and the solid was triturated with ether, collected by filtration, washed with ether and dried under vacuum to give (E)-4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(4-morpholinobut-2-en-1-yloxy)quinazoline hydrochloride (165 mg, 45%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:9]=1)=[O:6].[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:29]([NH:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:9]=1)=[O:6])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CS(=O)(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1N
Product: CS(=O)(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1NC(=O)c1ccccc1
Yield: 45.4 %

Procedure:
3-Amino-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide (30 mg, 0.072 mmol) was reacted with benzoyl chloride (9 μl, 0.079 mmol) via procedure V to afford 17 mg of 3-benzamido-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide as a white solid. MS (Q1) 520 (M)+.
Reaction SMILES: CS(O[CH:6]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2([CH3:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=1)[C:7]([O:9]CC)=O)(=O)=O.[NH2:28][C:29](N)=[S:30].C([OH:34])C.Cl>O>[CH3:27][C:21]1([CH2:20][O:19][C:16]2[CH:15]=[CH:14][C:13]([CH2:12][CH:6]3[S:30][C:29](=[O:34])[NH:28][C:7]3=[O:9])=[CH:18][CH:17]=2)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: CCOC(=O)C(Cc1ccc(OCC2(C)CCCCC2)cc1)OS(C)(=O)=O
Reactant: CCO
Reactant: NC(N)=S
Agent: Cl
Solvent: O
Product: CC1(COc2ccc(CC3SC(=O)NC3=O)cc2)CCCCC1

Procedure:
2.0 g Of ethyl 2-methanesulfonyloxy-3-[4-(1-methylcyclohexylmethyloxy)phenyl]propionate and 760 mg. of thiourea are added to 20 ml of ethanol. The mixture is refluxed for 2 hours. To the mixture is added 10 ml of hydrochloric acid, and the mixture is further refluxed for 16 hours. After cooling, water is added to the mixture. The mixture is subjected to extraction with ethyl acetate. The extract is washed with water and dried. The ethyl acetate is distilled off to give 1.4 g of 5-[4-(1-methylcyclohexylmethyloxy)benzyl]thiazolidine-2,4-dione. Crystallization from 85% ethanol gives crystals melting at 130°-131° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:15]([O:17][CH3:18])=[O:16])[C:8](=[CH:13][CH:14]=1)[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2].[N+:19]([O-])([OH:21])=[O:20]>C(Cl)Cl>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:15]([O:17][CH3:18])=[O:16])[C:8](=[CH:13][C:14]=1[N+:19]([O-:21])=[O:20])[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(NC(C)=O)cc1C(=O)OC
Reactant: O=[N+]([O-])O
Solvent: ClCCl
Product: COC(=O)c1cc(NC(C)=O)c([N+](=O)[O-])cc1C(=O)OC
Reaction time: 2.5 h

Procedure:
Dimethyl 4-acetamidophthalate (100.4 g, 0.400 mol) is added to fuming nitric acid (90%, 600 mL) at 0° C. to 5° C. When the addition is completed (0.5 hour), the mixture is stirred 2.5 hours at 0° C. to 10° C., combined with cold methylene chloride and shaken with crushed ice. The aqueous layer is separated and extracted further with methylene chloride. The combined organic layers are washed with ice water, sodium bicarbonate solution and cold water, dried (MgSO4) and concentrated in vacuo to give a solid residue. The residue is recrystallized twice from methanol to afford the title product I as orange-brown needles, mp 119°-120° C. The original mother liquor is concentrated in vacuo, and the residue is recrystallized several times from carbon tetrachloride to afford the title compound II as light yellow needles, mp 124°-125° C. The yield of compound I is 38.9 g (32.9%), and the yield of compound II is 33.1 g (28.1%).
Reaction SMILES: [O:1]1[C@H:5]2[O:6][CH2:7][CH2:8][C@H:4]2[C@@H:3]([O:9][C:10]([NH:12][C@H:13]([C@H:28]([OH:47])[CH2:29][N:30]([S:35]([C:38]2[CH:46]=[CH:45][C:41]3[O:42][CH2:43][O:44][C:40]=3[CH:39]=2)(=[O:37])=[O:36])[CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:14][C:15]2[CH:27]=[CH:26][C:18]([O:19][CH2:20][CH2:21][CH2:22][C:23](O)=[O:24])=[CH:17][CH:16]=2)=[O:11])[CH2:2]1.C([N:51](CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)O.N>CN(C=O)C.CO>[NH2:51][C:23](=[O:24])[CH2:22][CH2:21][CH2:20][O:19][C:18]1[CH:26]=[CH:27][C:15]([CH2:14][C@H:13]([NH:12][C:10](=[O:11])[O:9][C@@H:3]2[C@H:4]3[C@H:5]([O:6][CH2:7][CH2:8]3)[O:1][CH2:2]2)[C@H:28]([OH:47])[CH2:29][N:30]([S:35]([C:38]2[CH:46]=[CH:45][C:41]3[O:42][CH2:43][O:44][C:40]=3[CH:39]=2)(=[O:37])=[O:36])[CH2:31][CH:32]([CH3:33])[CH3:34])=[CH:16][CH:17]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCCC(=O)O)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Agent: CN(C)C(O)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCCC(N)=O)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 43.9 %

Procedure:
A solution of 25 mg (0.037 mmol) of 4-(4-{(2S,3R)-2-({[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl}amino)-4-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-3-hydroxybutyl}phenoxy)butanoic acid and 19 μL (0.11 mmol) of N,N-diisopropylethylamine in 1 mL of anhydrous DMF was treated with 28 mg (0.074 mmol) of O-(7-azabenzotriazol-* 1-yl) 1,1,3,3-tetramethyluronium hexafluorophosphate (HATU). The resulting solution was stirred at RT for 15 minutes and was then treated with 0.5 mL of 2M NH3 in MeOH. After 20 minutes TLC indicated the reaction to be complete. The solution was concentrated to dryness at reduced pressure and the residue subjected to flash chromatography (SiO2, 95:5 CH2Cl2/2M NH3 in MeOH) to afford 11 mg (44%) of the desired compound as a white powder. 1H NMR (CDCl3): 7.30 (d, 1H), 7.14 (s, 1H), 7.07 (d, 2H), 6.85 (d 2H), 6.75 (d, 2H), 6.05 (s, 2H), 5.60 (d, 1H), 5.56-5.34 (m, 2H), 4.97 (m, 2H), 3.94 (m, 3H), 3.78 (m, 3H), 3.66 (m, 2H), 3.09 (m, 1H), 3.00-2.64 (m, 7H), 2.40 (t, 2H), 2.08 (m, 2H), 1.80 (m, 1H), 1.61 (m, 1H), 1.48 (m, 1H), 0.90 (d, 3H), 0.82 (d, 3H). MS(ESI): 678(M+H).
Reaction SMILES: [ClH:1].Cl.[CH3:3][C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12]1[CH2:16][CH2:15][CH2:14][N:13]=1.[CH2:17]([OH:21])[CH2:18][CH2:19][OH:20].[CH2:22]([O:24]CC)C>>[ClH:1].[CH3:3][C:4]1[CH:9]=[C:8]([NH:10][C:22]([O:20][CH2:19][CH2:18][CH2:17][OH:21])=[O:24])[CH:7]=[CH:6][C:5]=1[NH:11][C:12]1[CH2:16][CH2:15][CH2:14][N:13]=1
Reactant: Cc1cc(N)ccc1NC1=NCCC1
Reactant: OCCCO
Reactant: CCOCC
Agent: Cl
Product: Cc1cc(NC(=O)OCCCO)ccc1NC1=NCCC1

Procedure:
The title compound was prepared by the general method of Example 25 using the product compound of Example 9 and 1,3-propanediol. The reaction mixture was treated with an eight-fold quantity of diethyl ether, in which the product was not soluble. The oily product was triturated with several portions of ether until solid. The crude solid was stirred as a suspension in a small amount of 1:1 ethanol/methanol, and then collected by filtration. Drying in a high vacuum over 5A molecular sieves produced the desired compound as the hydrochloride salt.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:6]2[S:14][CH:13]=[C:12]([CH3:15])[C:7]=2[N:8]=[C:9](Cl)[N:10]=1)[CH:2]=[CH2:3].[CH3:16][O:17][CH2:18][CH2:19][NH2:20].C(=O)([O-])O.[Na+]>>[CH2:1]([NH:4][C:5]1[C:6]2[S:14][CH:13]=[C:12]([CH3:15])[C:7]=2[N:8]=[C:9]([NH:20][CH2:19][CH2:18][O:17][CH3:16])[N:10]=1)[CH:2]=[CH2:3]
Reactant: COCCN
Reactant: C=CCNc1nc(Cl)nc2c(C)csc12
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCNc1nc(NCCOC)nc2c(C)csc12
Yield: 82 %

Procedure:
287 mg (1.2 mmol) of 4-allylamino-2-chloro-7-methylthieno[3,2-d]pyrimidine and 1.44 mg (19.2 mmol) of 2-methoxyethylamine were heated in a sealed tube at 160° C. for 16 hours. After completion of the reaction, the reaction mixture was allowed to resume room temperature, followed by adding a saturated aqueous sodium hydrogen carbonate solution thereto and extraction with ethyl acetate (50 ml×2). After the organic layer was washed with brine and dried over anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/4) to give 274 mg (yield: 82.3%) of the title compound.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][CH2:6][CH2:7][N:8]([CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:28]([Cl:29])=[C:27]3[C:22]([CH:23]=[CH:24][CH:25]=[CH:26]3)=[N:21]2)=[CH:16][CH:15]=1)[CH3:9])C.[OH-].[Na+]>>[ClH:29].[Cl:29][C:28]1[N:20]([C:17]2[CH:16]=[CH:15][C:14]([O:13][CH2:12][CH2:11][CH2:10][N:8]([CH3:9])[CH2:7][CH2:6][CH2:5][C:4]([OH:30])=[O:3])=[CH:19][CH:18]=2)[N:21]=[C:22]2[C:27]=1[CH:26]=[CH:25][CH:24]=[CH:23]2
Reactant: CCOC(=O)CCCN(C)CCCOc1ccc(-n2nc3ccccc3c2Cl)cc1
Agent: [Na+]
Agent: [OH-]
Product: CN(CCCOc1ccc(-n2nc3ccccc3c2Cl)cc1)CCCC(=O)O
Product: Cl
Yield: 48.9 %

Procedure:
The title compound was prepared from the product of step 1 (0.1 g, 0.28 mmol) and NaOH (50% in water, 0.080 g, 1.0 mmol) using the procedure of step 2 of the Example 3 to provide the title compound (30 mg, 30%)as a hydrochloride salt. 1H NMR (400 MHz, DMSO) δ 7.68-7.62 (m, 4H), 7.43-7.38 (m, 1H), 7.28 (d, J=8.8 Hz, 2H), 7.17 (m, 1H), 7.05 (d, J=8.8 Hz, 2H), 4.23 (t, J=5 Hz, 2H), 3.33 (br t, J=8.8 Hz, 2H), 3.17 (br t, J=8 Hz, 2H), 2.86 (s, 3H), 2.53 (t, J=6.4 Hz, 2H), 2.45 (m, 2H), 2.15 (m, 2H) LC/MS (APCI) m/z: 98%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7](OS(C2C=CC(C)=CC=2)(=O)=O)=[C:6]([NH:21][C:22](=[O:24])[CH3:23])[CH:5]=1.[CH:26]#[C:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>CCCCCCC.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([C:26]#[C:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[C:6]([NH:21][C:22](=[O:24])[CH3:23])[CH:5]=1
Reactant: C#CCCCCC
Reactant: COC(=O)c1ccc(OS(=O)(=O)c2ccc(C)cc2)c(NC(C)=O)c1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCCCCC#Cc1ccc(C(=O)OC)cc1NC(C)=O

Procedure:
This product was prepared from 3-acetylamino-4-(toluene-4-sulfonyloxy)-benzoic acid methyl ester and 1-heptyne following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane/EtOAc 8:2; yield (80 mg, 55%); 1H NMR δ (CDCl3): 8.96 (d, J=1.51 Hz, 1H), 7.92 (br s, 1H), 7.66 (dd, J=1.57, J=8.33 Hz, 1H), 7.38 (d, J=8.15 Hz, 1H), 3.89 (s, 3H), 2.53 (t, J=7.09 Hz, 2H), 2.21 (s, 3H), 1.63 (p, J=7.16 Hz, 2H), 1.48-1.3 (m, 4H), 0.92 (t, J=7.26 Hz, 3H); LCMS m/z: 287.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH2:3][CH2:4][CH:5]([NH:14][C:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13].C(O)C>P(Cl)(Cl)(Cl)=O.CCOCC>[ClH:13].[Cl:13][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[CH2:6][CH:5]([CH2:4][CH2:3][N:2]([CH3:23])[CH3:1])[N:14]=[C:15]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CN(C)CCC(Cc1ccccc1Cl)NC(=O)c1ccccc1
Solvent: CCO
Solvent: CCOCC
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)CCC1Cc2c(Cl)cccc2C(c2ccccc2)=N1
Product: Cl
Reaction time: 12 h

Procedure:
A suspension of 32 g of 1-dimethylamino 3-benzamido 4-orthochlorophenyl butane [(XI), code number 57] in 350 ml of phosphorous oxychloride were brought to 100° C. for 12 hours. Then the solvent is evaporated, the residue taken up in water, basified with concentrated aqueous NaOH, extracted with methylene chloride, filtered, the filtrate evaporated and the product obtained chromatographed on an alumina column (elution by means of methylene chloride). Then the product obtained is dissolved in ether, hydrochloric ethanol is added and the precipitate formed is filtered.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C:21]2[CH2:22][CH2:23][N:24]([CH2:26][C:27]#[CH:28])[CH2:25][C:20]=2[C:5]2[C:6]([OH:19])=[CH:7][C:8]([CH:10]([CH:12]([CH3:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:11])=[CH:9][C:4]=2[O:3]1.C1(N=C=NC2CCCCC2)CCCCC1.Cl.[N:46]1([CH2:52][CH2:53][CH2:54][C:55](O)=[O:56])[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1.CO.C(Cl)(Cl)[Cl:61]>C(Cl)Cl.C(Cl)Cl.C1CCCCC1>[ClH:61].[CH3:29][C:2]1([CH3:1])[C:21]2[CH2:22][CH2:23][N:24]([CH2:26][C:27]#[CH:28])[CH2:25][C:20]=2[C:5]2[C:6]([O:19][C:55](=[O:56])[CH2:54][CH2:53][CH2:52][N:46]3[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]3)=[CH:7][C:8]([CH:10]([CH:12]([CH3:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:11])=[CH:9][C:4]=2[O:3]1
Reactant: ClC(Cl)Cl
Reactant: C#CCN1CCC2=C(C1)c1c(O)cc(C(C)C(C)CCCCC)cc1OC2(C)C
Reactant: O=C(O)CCCN1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: C1CCCCC1
Solvent: ClCCl
Solvent: CO
Product: C#CCN1CCC2=C(C1)c1c(OC(=O)CCCN3CCCCC3)cc(C(C)C(C)CCCCC)cc1OC2(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The preparation of this compound was repeated by combining equimolar quantities of 5,5-dimethyl-10-hydroxy-8-(3-methyl-2-octyl)-2-(2-propynyl)-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-d]pyridine, dicyclohexylcarbodiimide and γ-piperidinobutyric acid hydrochloride in methylene chloride. After stirring for about 16 hours at room temperature, the reaction mixture was cooled, and the by-product of dicyclohexylurea was removed by suction filtration. The mother liquor was evaporated to give a light yellow residue which was dissolved in a methylene chloride/cyclohexane mixture and stored in the cold for 16 hours. A small quantity of additional dicyclohexylurea was removed by filtration, and the solvents were distilled off using a rotary evaporator. The residue which remained was dried in vacuo and crystallized from a mixture of methylene chloride and diethyl ether to give a colorless solid, m.p. 108°-111° C. Thin layer chromatography (10% MeOH/CHCl3) indicated the compound to be pure; the nuclear magnetic resonance and infrared spectra of the material were consistent with the desired product.
Reaction SMILES: [CH:1](=[C:8]1[CH2:13][C:12](=[O:14])[O:11][C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][NH2:23])=[CH:17][CH:16]=1>C(Cl)Cl>[CH2:22]([NH:23][C:12]([CH2:13][C:8](=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]([OH:11])=[O:10])=[O:14])[CH2:21][C:18]1[CH:19]=[CH:20][CH:15]=[CH:16][CH:17]=1
Reactant: NCCc1ccccc1
Reactant: O=C1CC(=Cc2ccccc2)C(=O)O1
Solvent: ClCCl
Product: O=C(CC(=Cc1ccccc1)C(=O)O)NCCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
226 mg (1.2 mmol) of benzalsuccinic acid anhydride were treated in 20 ml of methylene chloride with 0.15 ml of 2-phenethylamine and subsequently stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and the residue was chromatographed on silica gel, to obtain 260 mg (70%) of α-[(phenethylcarbamoyl)methyl]cinnamic acid, MS: 309 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[CH2:15][C:14](=[O:16])[NH:13][NH:12]2)=[O:10])=[C:4]([C:17](=[O:24])[NH:18][CH:19]([CH:21]2[CH2:23][CH2:22]2)[CH3:20])[CH:3]=1.Cl[C:26]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][N:27]=1.[H-].[Na+].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[N:12]([C:26]3[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][N:27]=3)[N:13]=[C:14]([OH:16])[CH2:15]2)=[O:10])=[C:4]([C:17](=[O:24])[NH:18][CH:19]([CH:21]2[CH2:22][CH2:23]2)[CH3:20])[CH:3]=1
Reactant: CC(NC(=O)c1cc(Cl)ccc1NC(=O)C1CC(=O)NN1)C1CC1
Reactant: Clc1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(NC(=O)c1cc(Cl)ccc1NC(=O)C1CC(O)=NN1c1ncccc1Cl)C1CC1
Temperature: 70 °C
Reaction time: 7 h
Yield: 87.3 %

Procedure:
1.0 g of N-(4-chloro-2-(1-cyclopropylethylcarbamoyl)phenyl)-5-oxopyrazolidine-3-carboxamide was dissolved in 10 ml of N,N-dimethylformamide, 460 mg of 2,3-dichloropyridine was added and then 350 mg of sodium hydride was added, followed by stirring for about 7 hours at about 70° C. in nitrogen atmosphere, and the reaction liquid was stood to cool. Water was added to the reaction liquid and stirred, followed by extraction with ethyl acetate, and the obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate/methanol=9/1) to obtain 1.15 g of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][SH:5].B(F)(F)F.CCOCC.[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1(O)[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]1>C(O)(=O)C>[ClH:1].[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][S:5][C:26]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[F:19])[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]1
Reactant: CN1CCC(O)(c2ccccc2F)CC1
Reactant: SCc1ccccc1Cl
Agent: FB(F)F
Solvent: CC(=O)O
Solvent: CCOCC
Product: CN1CCC(SCc2ccccc2Cl)(c2ccccc2F)CC1
Product: Cl
Reaction time: 20 h

Procedure:
59.7 g of 2-chlorobenzylmercaptan, followed by 55 ml of boron trifluoride etherate are added to 25 g of 4-(2-fluorophenyl)-4-hydroxy-1-methylpiperidine of Example 1a in 55 ml of acetic acid. The reaction is stirred at 55°-65° C. for 20 hours. The excess acid is removed under reduced pressure at 80°-100° C. The oily residue is then equilibrated with 200 ml of 2 N hydrochloric acid and 200 ml of ether. The ether, and two more 125 ml portions of ether, is decanted off. The oil and water mixture is diluted to 650 ml volume with water and is stored at 0° C. for about three days to produce crystals. The mixture is diluted and filtered. The precipitate is washed with water and ether, and dried. The solid is recrystallized (acetone:ether) to a broad melting (122°-129° C.) solid. A portion of the solid is placed in water, basified with 10% aqueous NaOH, extracted into ether, washed, dried and treated with ethereal hydrogen chloride to give a white powder. The powder is recrystallized from acetone-ether to give a white crystalline solid, m.p. 173°-175° C. of 4-(2-chlorobenzylthio)-4-(2-fluorophenyl)-1-methylpiperidine hydrochloride.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[C:21](Cl)=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:23]1[CH2:28][CH2:27][CH:26]([CH2:29][OH:30])[CH2:25][CH2:24]1.CCN(CC)CC>CS(C)=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[C:21]([N:23]3[CH2:28][CH2:27][CH:26]([CH2:29][OH:30])[CH2:25][CH2:24]3)=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OCC1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CC(c2nc3ccccc3nc2Cl)C1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(c2nc3ccccc3nc2N2CCC(CO)CC2)C1
Temperature: 140 °C
Yield: 84 %

Procedure:
To a solution of 3-(3-chloro-quinoxalin-2-yl)-azetidine-1-carboxylic acid tert-butyl ester (46) (638 mg, 2 mmol, Preparation 14) and piperidin-4-yl-methanol (253 mg, 2.2 mmol) in DMSO (10 mL) was added Et3N (404 mg, 4 mmol). The reaction mixture was stirred at 140° C. in microwave heating for 4 h. The reaction mixture was diluted with water, extracted with EtOAc (30 mL×3). The combined organic extracts were washed with water (30 mL) and brine (30 mL), dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel to give (47) (670 mg, 1.68 mmol, yield 84.15%). ESI-MS (M+1): 399 calc. for C17H22N4O 398.