Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[N:3](C)[C:4]([C@H:6]1[CH2:11][CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7]1)=O.B1(C)O[C:26]([C:34]2[CH:39]=[CH:38]C=CC=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@@H]2N1CCC2.[NH:41]1[CH:45]=[CH:44][N:43]=N1.N1C=NN=N1>>[CH:26]1[C:28]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:38]=[CH:39][C:34]=1[C@@H:4]([N:3]1[N:43]=[CH:44][CH:45]=[N:41]1)[C@H:6]1[CH2:11][CH2:10][CH2:9][NH:8][CH2:7]1
Reactant: c1c[nH]nn1
Reactant: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Reactant: CON(C)C(=O)[C@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: c1nnn[nH]1
Product: c1ccc2cc([C@H]([C@H]3CCCNC3)n3nccn3)ccc2c1

Procedure:
The procedure given in Example 1 was followed using tert-butyl (3S)-3-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate was used instead of tert-butyl (3R)-3-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate. As a reducing agent, (R)-2-methyl-CBS-oxazaborolidine was used instead of (S)-2-methyl-CBS-oxazaborolidine. And 1H-[1,2,3]-triazole was used as a reactant, instead of 1H-tetrazole, to give (3S)-3-[(S)-naphthalen-2-yl(2H-1,2,3-triazol-2-yl)methyl]piperidine.
Reaction SMILES: Br.[OH:2][C:3]1[CH:12]=[CH:11][C:6]([CH2:7][CH:8]([NH2:10])[CH3:9])=[CH:5][CH:4]=1.O.[C:14](OC(=O)C)(=[O:16])[CH3:15].[OH-].[Na+].[C:23](OCC)(=[O:25])[CH3:24]>>[C:14]([O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8]([NH:10][C:23](=[O:25])[CH3:24])[CH3:9])=[CH:11][CH:12]=1)(=[O:16])[CH3:15]
Reactant: CCOC(C)=O
Reactant: CC(=O)OC(C)=O
Reactant: CC(N)Cc1ccc(O)cc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)NC(C)Cc1ccc(OC(C)=O)cc1
Temperature: 5 °C
Reaction time: 4 h

Procedure:
In a 1-l. flask, flushed with nitrogen and provided with a stirrer, thermometer, two dropping funnels, and a nitrogen inlet tube was placed a solution of 46.4 g. (0.2 moles) of rac. 4-hydroxy-alpha-methylphenethylamine hydrobromide in 100 ml. of water. The flask was cooled in an ice bath, and when the temperature reached 5° C., 40 ml. of acetic anhydride (0.395 moles) and 440 ml. of 2N NaOH were added simultaneously from the two dropping funnels at approximately equivalent rates, maintaining the temperature below 5° C. An oil gradually separated during the addition, and the mixture was stirred for another 4 hours at 5° C., then allowed to come to room temperature overnight. The oil that had solidified to a mass of crystals was recovered by filtration. After washing with water the solid was dried in vacuo over KOH and CaCl2. Yield, 32 g. of mp. 92°-93.5°. An analytical sample was obtained by recrystallization from ethyl acetate-- 30°-60° C. petroleum ether; mp. 97.5° - 99° C.
Reaction SMILES: C1([O:4][S:5](=[O:8])(=[O:7])[NH2:6])CC1.[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16]>>[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:6][S:5](=[O:8])(=[O:7])[O-:4].[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][S:5](=[O:7])(=[O:4])[NH2:6]
Reactant: NS(=O)(=O)OC1CC1
Reactant: Oc1ccccc1Cl
Product: NS(=O)(=O)Oc1ccccc1Cl
Product: O=S(=O)([O-])Nc1ccccc1Cl

Procedure:
2-Chlorophenylsulfamate was synthesized according to the method presented in the synthesis of Sulfamic acid cyclopropyl ester in Example 1 with the exception of utilizing 2-chlorophenol to obtain sulfamic acid 2-chloro-phenyl ester.
Reaction SMILES: [NH:1]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:2]([C:20](O)=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10].[CH3:30]CN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.[N:46]1([O:55][P+](N(C)C)(N(C)C)N(C)C)[C:50]2C=CC=CC=2N=N1>CN(C=O)C>[NH:1]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[C@H:2]([C:20]([N:46]([O:55][CH3:30])[CH3:50])=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:10])=[O:11]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CON(C)C(=O)[C@H](CCCNC(=N)NS(=O)(=O)c1ccc(C)cc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 10 h
Yield: 70 %

Procedure:
To a suspension of Boc-Arg(Tos)-OH (2 g, 4.7 mmol) in DMF (20 mL) at 0° C. is added MeNHOMeHCl (1 g, 10.3 mmol), DIEA (6 mL) and BOP (2.5 g, 5.6 mmol). The solution is stirred at 0° C. for 10 hours. DMF is evaporated by vacuum. The oily residue is dissolved in EtOAc (200 mL) and water (20 mL). The organic layer is washed with sat. NaHCO3, water (20 mL), 1 M HCl (10 mL) and sat. NaCl (2 X 20 mL). The organic layer is dried over MgSO4, filtered and evaporated to give a suspension. The suspension is filtered, washed with cold EtOAc (10 mL) and dried to give Boc-Arg(Tos)-N(Me)OMe, shown above, (1.5 g, 70% yield). FAB-MS (M+H)+=472
Reaction SMILES: N1C=CC=CC=1.[C:7]1(=[O:13])[O:12][C:10](=[O:11])[CH:9]=[CH:8]1.[CH2:14]([NH2:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].Cl>ClCCl>[CH2:14]([NH:26][C:7](=[O:13])/[CH:8]=[CH:9]\[C:10]([OH:12])=[O:11])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCN
Reactant: O=C1C=CC(=O)O1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCNC(=O)/C=C\C(=O)O
Temperature: 25 °C
Yield: 96.5 %

Procedure:
30 g of pyridine are added to a solution of 83 g of maleic anhydride in 700 ml of dichloromethane at room temperature. A solution of 122 g of n-dodecyl-amine and 70 g of pyridine in 800 ml of dichloro-methane is then added dropwise in 15 min, during which the temperature rises to 39° C. The mixture is then refluxed for 30 min, cooled to 25° C. and 210 ml of 32% by weight aqueous hydrochloric acid are cautiously added. The aqueous phase is separated off at 35° C., and the organic phase is washed three times with 200 ml of water each time at 35° C., dried over sodium sulfate and crystallized at 10° C. 180 g (96%) of N-dodecylmaleamic acid are obtained in the form of colorless waxy crystals. The product is pure by NMR and gives a clear solution in dilute sodium hydroxide solution.
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:36])/[CH:12]=[CH:13]/[CH:14]=[C:15]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)=CC=1)([O-])=O.[N:37]1[CH:42]=[CH:41][CH:40]=[C:39]([CH2:43][CH2:44][CH2:45][CH2:46][NH2:47])[CH:38]=1>O1CCCC1>[F:24][C:22]([F:25])([F:23])[C:18]1[CH:17]=[C:16]([C:15]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:35])[F:34])[CH:27]=2)=[CH:14]/[CH:13]=[CH:12]/[C:11]([NH:47][CH2:46][CH2:45][CH2:44][CH2:43][C:39]2[CH:38]=[N:37][CH:42]=[CH:41][CH:40]=2)=[O:36])[CH:21]=[CH:20][CH:19]=1
Reactant: NCCCCc1cccnc1
Reactant: O=C(/C=C/C=C(c1cccc(C(F)(F)F)c1)c1cccc(C(F)(F)F)c1)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: O=C(/C=C/C=C(c1cccc(C(F)(F)F)c1)c1cccc(C(F)(F)F)c1)NCCCCc1cccnc1
Yield: 65.2 %

Procedure:
As in Example 134, a solution of (E)-5,5-bis[3-(trifluoromethyl)phenyl]-2,4-pentadienoic acid 4-nitrophenyl ester (4.8 g) and 3-pyridinebutanamine (1.5 g) in tetrahydrofuran (20 mL) was stirred for 2 hours at room temperature and was then worked up in the usual manner. The crude product was purified by HPLC (ethyl acetate) and then crystallized from ether-hexane to afford 3.2 g of (E)-5,5-bis[3-(trifluoromethyl)phenyl]-N-[4-(3-pyridinyl)butyl]-2,4-pentadienamide mp 89°-90° C. Anal Calculated for C28H24F6N2O : C, 64.86; H, 4.67; F, 21.98; N, 5.40 Found: C, 64.82; H, 4.72; F, 22.19; N, 5.38.
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[F:21][C:22]([F:35])([F:34])[C:23]1[CH:24]=[C:25]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[NH2:26]>ClCCl.N1C=CC=CC=1>[F:21][C:22]([F:34])([F:35])[C:23]1[CH:24]=[C:25]([NH:26][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:26][C:25]2[CH:27]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:29]=[C:23]([C:22]([F:21])([F:34])[F:35])[CH:24]=2)=[O:13])[CH:27]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:29]=1
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1SSc1ccccc1C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 8 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (2.00 g, 5.83 mmol) in 50 mL of dichloromethane and 3,5-bis(trifluoromethyl)aniline (2.66 g, 11.6 mmol) in 21 mL of pyridine. The crude product was recrystallized from ethyl acetate-hexanes (1:9) to yield 0.34 g of the title compound, mp 213-214° C.
Reaction SMILES: [Mg].Br[C:3]1[C:8]([CH3:9])=[C:7]([O:10][CH3:11])[C:6]([CH3:12])=[C:5]([CH3:13])[C:4]=1[O:14][CH3:15].[C:16]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)(=[O:23])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].O>O1CCCC1>[CH3:15][O:14][C:4]1[C:5]([CH3:13])=[C:6]([CH3:12])[C:7]([O:10][CH3:11])=[C:8]([CH3:9])[C:3]=1[C:16]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)([OH:23])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCC(=O)c1cccnc1
Reactant: COc1c(C)c(C)c(OC)c(Br)c1C
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCC(O)(c1cccnc1)c1c(C)c(OC)c(C)c(C)c1OC
Yield: 39.3 %

Procedure:
A Grignard reagent was prepared from 693 mg (28.3 g atom) of magnesium, 7.6 g (29.3 mmol) of 1-bromo-2,5-dimethoxy-3,4,6-trimethylbenzene and tetrahydrofuran at 65° C. and cooled to 0° C., to which a solution of 3.75 g (21.9 mmol) of 3-heptanoylpyridine in 10 ml of tetrahydrofuran was added dropwise. After completion of the addition, the reaction mixture was stirred at room temperature for 1 hour, to which water was added and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was purified with silica gel column chromatography (isopropyl ether) and recrystallized from hexane, to give 3.2 g (39%) of 1-(2,5-dimethoxy-3,4,6-trimethylphenyl)-1-(3-pyridyl)heptanol. m.p. 109°-110° C.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:48])[C:29]2[CH:34]=[CH:33][C:32]([CH:35]([O:42][CH2:43][CH2:44][N:45]([CH3:47])[CH3:46])[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:31][CH:30]=2)[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9](OC3C=CC=CC=3)[C:8]=2[N:22]=1)[CH2:2][CH2:3][CH3:4].C([O-])(=O)C.[NH4+:53].[OH-].[Na+]>O>[NH2:53][C:9]1[C:8]2[N:22]=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:6]([CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:48])[C:29]3[CH:34]=[CH:33][C:32]([CH:35]([O:42][CH2:43][CH2:44][N:45]([CH3:46])[CH3:47])[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[CH:31][CH:30]=3)[C:7]=2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=1
Reactant: CCCCc1nc2c(Oc3ccccc3)nc(C)c(C)c2n1CCCCNC(=O)c1ccc(C(OCCN(C)C)c2ccccc2)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCc1nc2c(N)nc(C)c(C)c2n1CCCCNC(=O)c1ccc(C(OCCN(C)C)c2ccccc2)cc1
Temperature: 150 °C
Yield: 15.3 %

Procedure:
N-[4-(2-Butyl-6,7-dimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl)butyl]-4-[[2-(dimethylamino)ethoxy](phenyl)methyl]benzamide (101 mg, 0.16 mmol) and ammonium acetate (1.1 g) were placed into a pressure tube along with a stir bar. The tube was sealed and heated at 150° C. for 16 hours. The reaction was cooled to room temperature and diluted with water. The resulting cloudy aqueous mixture was made basic with 10% aqueous sodium hydroxide and extracted with chloroform (3×25 mL). The combined organic fractions were washed with water followed by brine, dried (Na2SO4), decanted and evaporated to provide a yellow oil. Purification by flash column chromatography (silica gel, 95:5 dichloromethane/methanol gradient to 9:1 dichloromethane/methanol and finally 94:5:1 dichloromethane/methanol/triethylamine) provided 14 mg of N-[4-(4-amino-2-butyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)butyl]-4-[[2-(dimethylamino)ethoxy](phenyl)methyl]benzamide as a yellow oil. 1H-NMR (500 MHz, DMSO-d6) δ 8.41 (t, J=5.5 Hz, 1H), 7.76 (d, J=8.3 Hz, 2H); 7.43 (d, J=8.3, 2H), 7.37-7.31 (m, 4H), 7.26-7.22 (m, 1H), 5.84 (bs, 2H), 5.52 (s, 1H), 4.42 (t, J=7.7 Hz, 2H), 3.49 (t, J=5.8 Hz, 2H), 3.29 (dd, J=6.4, 12.4 Hz, 2H), 2.76 (t, J=7.7 Hz, 2H), 2.58 (t, J=5.7 Hz, 2H), 2.32 (s, 3H), 2.27 (s, 3H), 2.22 (s, 6H), 1.73-1.65 (m, 4H), 1.61-1.55 (m, 2H), 1.35 (sextet, J=7.4 Hz, 2H), 0.86 (t, J=7.4 Hz, 3H); 13C-NMR (125 MHz, DMSO-d6) δ 165.9, 153.0, 148.1, 145.4, 142.0, 138.6, 133.5, 128.23, 127.4, 127.3, 127.1, 126.4, 126.1, 124.5, 103.0, 82.0, 66.3, 58.0, 45.2, 43.6, 38.4, 29.3, 28.8, 26.1, 26.0, 21.7, 21.0, 13.6, 12.2. HRMS(CI) m/e 571.3763 (M+H), (571.3761 calcd for C34H47N6O2, M+H).
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C@@H:21]3[O:26][C:25]4[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=4[O:23][CH2:22]3)=[CH:17][CH:16]=2)[CH2:12][CH3:13])=[CH:6][CH:5]=1.O[Li].O.CO.O>C(O)(=O)C>[O:26]1[C:25]2[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=2[O:23][CH2:22][C@@H:21]1[C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:11]([CH2:10][C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:31])=[O:2])=[CH:9][CH:8]=2)[CH2:12][CH3:13])=[CH:16][CH:17]=1
Reactant: CCN(Cc1ccc(C(=O)OC)cc1)Cc1ccc([C@H]2COc3ccccc3O2)cc1
Agent: [Li]O
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CCN(Cc1ccc(C(=O)O)cc1)Cc1ccc([C@H]2COc3ccccc3O2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-({[(S)-4-(2,3-dihydro-benzo[1,4]dioxin-2-yl)-benzyl]-ethyl-amino}-methyl)-benzoic acid methyl ester (65 mg, 0.16 mmol), LiOH.H2O (23 mg, 0.55 mmol), MeOH (5 mL) and water (0.5 mL) is stirred at room temperature for 16 h. The reaction mixture is neutralized with acetic acid and concentrated. The residue is diluted with water and DCM, phases are separated, the organic layer is dried over Na2SO4, filtered and concentrated. The residue is purified by flash chromatography eluting with a gradient of 0-10% MeOH in DCM to give the title compound.
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[CH3:9][CH:10]=O.CCOC(C1CC(C(OCC)=O)=C(C)NC=1C)=O.N1C=CC=CC=1>CO.C(Cl)Cl>[CH2:9]([CH:2]1[C:3](=[O:7])[CH2:4][CH2:5][CH2:6][C:1]1=[O:8])[CH3:10]
Reactant: O=C1CCCC(=O)C1
Reactant: CC=O
Agent: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Solvent: c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: CCC1C(=O)CCCC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
1,3-Cyclohexanedione (10 g, 89.2 mmol), 40% aqueous CH3CHO (49.4 g, 445.9 mmol) were dissolved in methanol (40 mL) followed by addition of Hantzsch ester (22.7 g, 89.2 mmol) and pyridine (2.1 g, 18.74 mmol) under nitrogen. The resulting light yellow mixture was stirred at room temperature overnight, then concentrated to give crude product that was re-slurried in a mixture of CH2Cl2 (40 mL) and hexanes (60 mL) to furnish 2-ethyl-1,3-cyclohexanedione (8.6 g, 69%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH2:8])=[O:7].[Cl:9][CH2:10][C:11]([CH2:13]Cl)=O>>[Cl:9][CH2:10][C:11]1[N:8]=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[O:7][CH:13]=1
Reactant: NC(=O)c1ccco1
Reactant: O=C(CCl)CCl
Product: ClCc1coc(-c2ccco2)n1
Yield: 47 %

Procedure:
In substantially the same manner as in Reference Example 47, 2-furancarboxamide was aollowed to react with 1,3-dichloroacetone to give 4-chloromethyl-2-(2-furyl)oxazole. The yield was 47%. Oily substance.
Reaction SMILES: Cl[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=1[C:8]#[N:9].[Se-2:10].[Na+].[Na+].Cl[CH2:14][C:15]#[N:16].[OH-].[Na+]>>[NH2:9][C:8]1[C:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C:2]=2[Se:10][C:14]=1[C:15]#[N:16]
Reactant: N#CC1=C(Cl)CCCC1
Reactant: N#CCCl
Reactant: [Se-2]
Agent: [Na+]
Agent: [OH-]
Product: N#Cc1[se]c2c(c1N)CCCC2

Procedure:
The 3-amino-4,5,6,7-tetrahydrobenzo[1,2-b]selenophene-2-carbonitrile is prepared starting from 2-chlorocyclohex-1-enecarbonitrile, sodium selenide and chloroacetonitrile, which on treatment with aqueous sodium hydroxide gave the corresponding amide in good yield. Diazotization of the amine with sodium nitrite followed by treatment with iodomethane in presence of a base gave the required 3-methyl-6,7,8,9-tetrahydrobenzo[1,2-b]1,2,3-triazino-[4,5-d]-selenophen-4-one (compound 14).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:13][CH2:12][C@H:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23]Cl.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][N:17]1[CH2:16][CH2:15][N:14]([C@H:11]2[CH2:10][CH2:9][C@@H:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:13][CH2:12]2)[CH2:19][CH2:18]1
Reactant: ClCc1ccccc1Cl
Reactant: Fc1ccc([C@H]2CC[C@@H](N3CCNCC3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc([C@H]2CC[C@@H](N3CCN(Cc4ccccc4Cl)CC3)CC2)cc1

Procedure:
The title compound was prepared by refluxing cis 1-[4-(4-fluorophenyl)-1-cyclohexyl]piperazine (0.35 g, 1.3 mmole) and 2-chlorobenzyl chloride (0.21 g, 1.3 mmole) in acetonitrile with excess potassium carbonate for 18 hr. The solvent was removed in vacuo and the crude material recrystallized from 2-propyl acetate to give the product (85%, mp: 86°-87° C.). Calc'd for C23H28ClFN2.0.4H2O: C, 70.09%; H, 7.37%; N, 7.11%. Found: C, 70.12%; H, 7.52%; N, 7.07%.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C:9]1[CH:10]=[C:11]([CH:29]=[CH:30][CH:31]=1)[CH2:12][S:13][C:14]1[CH:15]=[C:16]([NH:20][C:21]2[C:26]([Cl:27])=[CH:25][N:24]=[C:23](Cl)[N:22]=2)[CH:17]=[CH:18][CH:19]=1.Cl>COCCO.C(O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:27][C:26]1[CH:25]=[N:24][C:23]2[NH:8][C:9]3[CH:31]=[CH:30][CH:29]=[C:11]([CH:10]=3)[CH2:12][S:13][C:14]3[CH:15]=[C:16]([NH:20][C:21]=1[N:22]=2)[CH:17]=[CH:18][CH:19]=3
Reactant: Nc1cccc(CSc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Agent: Cl
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Solvent: COCCO
Product: Clc1cnc2nc1Nc1cccc(c1)SCc1cccc(c1)N2
Temperature: 150 °C
Yield: 27.6 %

Procedure:
A solution of N-{3-[(3-aminobenzyl)thio]phenyl}-2,5-dichloropyrimidin-4-amine trifluoroacetate (33 mg, 67 μmol) in 2-methoxyethanol (6.6 mL) was treated with 3.5 M HCl in ethanol (3 mL) and heated in the microwave at 150° C. for 5 min. The reaction mixture was degassed to remove the HCl and concentrated to a crude residue. This material was purified by preparative LCMS to give the desired product (8.4 mg, 27%) as a TFA salt. LCMS for C17H14ClN4S (M+H)+: m/z=341.0. 1H NMR (300 MHz, DMSO-d6): δ 9.59 (s, 1H), 9.20 (s, 1H), 8.17 (s, 2H), 7.93 (s, 1H), 7.21-7.15 (m, 3H), 7.08-7.05 (m, 1H), 7.00-6.97 (m, 1H), 6.91-6.88 (m, 1H), 4.03 (s, 2H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([O:15][CH3:16])[CH:14]=1)[C:8]([O:10]C)=O.[CH:17]([O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:23][CH:22]=1)([CH3:19])[CH3:18].C(O)(=O)C>C1(C)C=CC=CC=1.O>[CH3:16][O:15][C:13]1[CH:12]=[C:7]([C:8](=[O:10])[CH:27]([C:24]2[CH:25]=[CH:26][C:21]([O:20][CH:17]([CH3:19])[CH3:18])=[CH:22][CH:23]=2)[C:28]([O:30][CH3:31])=[O:29])[CH:6]=[C:5]([O:4][CH3:3])[CH:14]=1
Reactant: COC(=O)Cc1ccc(OC(C)C)cc1
Reactant: COC(=O)c1cc(OC)cc(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)C(C(=O)c1cc(OC)cc(OC)c1)c1ccc(OC(C)C)cc1
Temperature: 2.5 °C

Procedure:
14.4 g of 60% sodium hydride in mineral oil (0.36 mol) which are washed with 2 times 50 ml of toluene are introduced into a three-necked round-bottomed flask. 90 ml of toluene and 28.3 g of methyl 3,5-dimethoxybenzoate (0.144 mol) are then introduced. The mixture is brought to reflux and a solution of 30 g of methyl p-isopropyloxyphenylacetate (0.144 mol) dissolved in 95 ml of toluene is added over 10 h. The mixture is maintained at reflux for 2 h. It is cooled to a temperature of 0-5° C. and a solution of glacial acetic acid (22.5 g, i.e. 0.374 mol) in 25 ml of toluene is added slowly. Then, at ambient temperature, 135 ml of water are added slowly.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[NH:5][C:4](=[CH:14][C:15]([O:17][CH2:18][CH3:19])=O)[CH2:3]1.[N:20]([O-])=[O:21].[Na+].[OH2:24]>C(O)(=O)C>[CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]=[C:4]([C:14](=[O:24])[C:15](=[N:20][OH:21])[O:17][CH2:18][CH3:19])[CH2:3]1
Reactant: O=N[O-]
Reactant: O
Reactant: CCOC(=O)C=C1CN(C)C(=O)c2ccccc2N1
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=NO)C(=O)C1=Nc2ccccc2C(=O)N(C)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
32.2 g (0.124 mol) of ethyl (1,3,4,5-tetrahydro-4-methyl-5-oxo-2H-1,4-benzodiazepin-2-ylidene)acetate are dissolved in 300 ml of acetic acid and treated at room temperature with 12.8 g (0.186 mol) of sodium nitrite. The mixture is stirred at room temperature for a further 10 minutes, then poured into 1 liter of water and extracted three times with 200 ml of chloroform each time. The combined chloroform phases are washed with 100 ml of water, dried over magnesium sulphate and evaporated. The residue is recrystallised from ethyl acetate. There is obtained ethyl 4,5-dihydro-4-methyl-5-oxo-3H-1,4-benzodiazepine-2-glyoxylate α-oxime of melting point 173°-174° C.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH3:12][OH:13]>>[C:4]([O:13][CH3:12])(=[O:5])[C:3]1[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:1]([OH:6])=[O:11]
Reactant: CO
Reactant: O=C1OC(=O)c2ccccc21
Product: COC(=O)c1ccccc1C(=O)O

Procedure:
Methanol (300 ml) was added in a single portion to 148 g (1.00 mole) of phthalic anhydride and the resulting suspension was stirred and heated at reflux for 36 hours; solution occurred during heating. The solvent was removed and the product was recrystallized from a mixture of ethyl acetate and hexane to afford 114.6 g of the title compound (Lit.: Beilstein, 9,797-mp 82.5°, 84°).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][C:3]=1[C:13](=[O:31])[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38]([OH:41])(=[O:40])=O)=[CH:34][CH:33]=1.[CH2:43]([CH2:45][NH2:46])O.C1(C)C=CC=CC=1>O>[C:32]1([CH3:42])[CH:33]=[CH:34][C:35]([S:38]([O:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([O:12][CH2:43][CH2:45][NH2:46])=[CH:4][C:3]=2[C:13](=[O:31])[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])(=[O:40])=[O:41])=[CH:36][CH:37]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCCCCCCCCCCCCCCCNC(=O)c1cc(O)c2ccccc2c1O
Reactant: NCCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCNC(=O)c1cc(OCCN)c2ccccc2c1OS(=O)(=O)c1ccc(C)cc1
Yield: 52.9 %

Procedure:
To a mixture of 128 g of 1,4-dihydroxy-2-hexadecylcarbamoylnaphthalene, 285 g of p-toluenesulfonic acid and 73 g of ethanolamine was added 300 ml of toluene. The resulting mixture was heated under reflux for about 2 hours under nitrogen atmosphere, during which water was removed by a water separator. Toluene was then evaporated off under reduced pressure and 1.5 l of water was added into the residue. Precipitated crystals were collected and recrystallized from ethyl acetate to give 99 g of 4-(2-aminoethyloxy)-2-hexadecylcarbamoyl-1-naphthol p-toluenesulfonate. Yield: 51%. M.P.: 140°-146° C.
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:24]([OH:26])=O)[NH:16]C(OC(C)(C)C)=O)=O)C1C=CC=CC=1.[CH2:27]([S:29]([Cl:32])(=[O:31])=[O:30])[CH3:28].[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>>[ClH:32].[NH2:16][C@H:15]([C:24](=[O:26])[N:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1)[CH2:14][CH2:13][CH2:12][NH:11][S:29]([CH2:27][CH3:28])(=[O:31])=[O:30]
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: CCS(=O)(=O)Cl
Product: CCS(=O)(=O)NCCC[C@H](N)C(=O)N1CCCC1
Product: Cl

Procedure:
Starting from (S)-N5-(benzyloxycarbonyl)-N2-(tert-butyloxycarbonyl)-ornithine, ethanesulphonyl chloride and pyrrolidine, the expected product is obtained according to the procedure described in Example 3.