Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])/[CH:4]=[CH:5]/[C:6]1[CH:14]=[CH:13][C:12]2[C:8](=[CH:9][N:10]([CH3:15])[N:11]=2)[C:7]=1[C:16]([O:18][CH3:19])=[O:17]>CO.[C].[Pd]>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][C:6]1[CH:14]=[CH:13][C:12]2[C:8](=[CH:9][N:10]([CH3:15])[N:11]=2)[C:7]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)/C=C/c1ccc2nn(C)cc2c1C(=O)OC
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1ccc2nn(C)cc2c1C(=O)OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 79.1 %

Procedure:
To a solution of methyl 5-[(1E)-3-methoxy-3-oxoprop-1-en-1-yl]-2-methyl-2H-indazole-4-carboxylate (1.02 g, 3.72 mmol) in methanol (40 mL) was added palladium-carbon powder (100 mg), and the mixture was stirred under a hydrogen atmosphere at room temperature for 12 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (813 mg, yield 79%).
Reaction SMILES: [F:1][C:2]1([F:27])[CH:7]([NH:8][C:9]2[N:26]=[C:12]3[C:13]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[C:18]=4[F:25])=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)[CH2:6][CH2:5][NH:4][CH2:3]1.Cl[C:29]1[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31][N:30]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1>[F:27][C:2]1([F:1])[CH:7]([NH:8][C:9]2[N:26]=[C:12]3[C:13]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[C:18]=4[F:25])=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)[CH2:6][CH2:5][N:4]([C:29]2[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31][N:30]=2)[CH2:3]1
Reactant: Fc1ccc(-c2cccn3nc(NC4CCNCC4(F)F)nc23)c(F)c1F
Reactant: Cc1cc(Cl)ncn1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1cc(N2CCC(Nc3nc4c(-c5ccc(F)c(F)c5F)cccn4n3)C(F)(F)C2)ncn1
Temperature: 150 °C

Procedure:
A solution of N-(3,3-difluoropiperidin-4-yl)-8-(2,3,4-trifluorophenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (75 mg, 196 μmol), 4-chloro-6-methylpyrimidine (27.7 mg, 215 μmol) and N,N-diisopropylethylamine (37.9 mg, 49.9 μL, 293 μmol) in dioxane (4 mL) was heated to 150° C. in the microwave for 1 hour. Further 4-chloro-6-methylpyrimidine (27.7 mg, 215 μmol) and N,N-diisopropylethylamine (37.9 mg, 49.9 μL, 293 μmol) were added and heated to 150° C. in the microwave for another hour. Further 4-chloro-6-methylpyrimidine (27.7 mg, 215 μmol) and N,N-diisopropylethylamine (37.9 mg, 49.9 μL, 293 μmol) were added and heated to 110° C. for 12 hours. The crude material was directly purified by flash chromatography (silica gel, 70 g, 0% to 15% MeOH/NH4OH (9:1) in dichloromethane). The title compound was obtained as light yellow foam (25 mg, 22%). MS ISP (m/e): 476.1 (100) [(M+H)+].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][NH:13][CH2:14]C)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:16]1[CH2:20][CH2:19][C:18](=O)[CH2:17]1.C(N(C(C)C)CC)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][N:13]([CH3:14])[CH:18]2[CH2:19][CH2:20][O:16][CH2:17]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCOC1
Reactant: CCNCC1CN(C(=O)OC(C)(C)C)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(CC1CN(C(=O)OC(C)(C)C)C1)C1CCOC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
A mixture of 3-ethylaminomethyl-azetidine-1-carboxylic acid tert-butyl ester (200 mg, 1.0 mmol), dihydrofuran-3-one (0.155 mL, 2.0 mmol), diisopropylethylamine (0.347 mL, 2.0 mmol) and 4 Å molecular sieves (600 mg) in DCM (10 mL) was stirred at RT for 30 min. Sodium triacetoxyborohydride (424 mg, 2 mmol) was added and the resulting reaction mixture was stirred at RT under nitrogen atmosphere for 60 h. The suspension was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 5:95) to afford the title compound as a colourless oil (257 mg, 95%). 1H NMR (400 MHz, CDCl3): δ 4.04-3.92 (3H, m), 3.83 (1H, dd, J=8.89, 6.90 Hz), 3.75 (1H, q, J=8.07 Hz), 3.64 (1H, dd, J=8.87, 6.21 Hz), 3.56-3.55 (2H, m), 3.14 (1H, m), 2.67-2.66 (2H, m), 2.51 (1H, dd, J=12.33, 7.20 Hz), 2.17 (3H, s), 2.05 (1H, s), 1.89-1.79 (1H, m), 1.44 (9H, s).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[C:14]([CH3:21])[CH:13]=2)[CH2:8]1.[H][H]>CO.C(Cl)Cl.[Pd]>[CH3:21][C:14]1[CH:13]=[C:12]([N:9]2[CH2:10][CH2:11][CH:7]([N:3]3[CH2:4][CH2:5][CH2:6][C@H:2]3[CH3:1])[CH2:8]2)[CH:17]=[CH:16][C:15]=1[NH2:18]
Reactant: Cc1cc(N2CCC(N3CCC[C@H]3C)C2)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(N2CCC(N3CCC[C@H]3C)C2)ccc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A solution of 2-(2R)-methyl-1′-(3-methyl-4-nitro-phenyl)-[1,3′]bipyrrolidinyl (2 g, 6.9 mmol) in MeOH (15 mL) was de-aerated and nitrogen was introduced. To this solution was added Pd—C (10%, 0.20 g). The nitrogen was replaced with hydrogen and the mixture was stirred under H2 atmosphere at r.t. overnight. TLC (10% MeOH in DCM) and LC/MS showed the reaction was complete. The mixture was passed through a celite pad, rinsed with methanol. The filtrate was concentrated to dryness, and further dried under high vacuum to yield the title compound as a reddish brown liquid after drying under high vacuum, 2.02 g (100% yield). This material is used in the next step without further purification. MS: 260 (M+H+).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[C@H:9]([O:16][Si](C(C)C)(C(C)C)C(C)C)[CH2:8][CH2:7][C@H:6]1[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=1[F:34])(=[O:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1>[C:1]([O:4][C@@H:5]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[C@H:9]([OH:16])[CH2:8][CH2:7][C@H:6]1[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=1[F:34])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1c2cccnc2[C@H](O[Si](C(C)C)(C(C)C)C(C)C)CC[C@H]1c1cccc(F)c1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(=O)O[C@@H]1c2cccnc2[C@H](O)CC[C@H]1c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
In a 100 mL round-bottom flask was dissolved (5S,6S,9R)-6-(2,3-difluorophenyl)-9-(triisopropylsilyloxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-yl acetate (1098 mg, 2.243 mmol) (azeotroped with dry benzene) in tetrahydrofuran (20 mL) to give a colorless solution. TBAF (2.69 mL, 2.69 mmol) was added, and the resulting light yellow solution was stirred at room temperature for 2 h (8:30 am). LCMS indicated complete conversion. Tetrahydrofuran was removed in vacuo and the residue was diluted with water and ethyl acetate. The layers were separated. The organic layer was washed with brine, dried, and concentrated to give a colorless oil. Purification by FCC up to 70% ethyl acetate/hexane afforded the desired product (648 mg, 87% for 2 steps) as a colorless oil. MS(ESI)[M+H+]=334.21; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.47 (dd, J=4.78, 1.51 Hz, 1H) 7.69 (d, J=7.30 Hz, 1H) 7.28 (dd, J=7.81, 5.04 Hz, 1H) 6.94-7.10 (m, 3H) 6.20 (d, J=10.32 Hz, 1H) 5.95 (br. s., 1H) 4.95 (dd, J=11.21, 1.64 Hz, 1H) 3.16-3.31 (m, 1H) 2.27-2.41 (m, 2H) 2.06-2.19 (m, 1H) 1.80 (s, 3H) 1.48-1.63 (m, 1H); 13C NMR (101 MHz, CHLOROFORM-d) δ ppm 168.96 (s, 1C) 157.96 (s, 1C) 149.66-151.75 (d, J=12.6 and 199 Hz, 1C) 147.21-149.29 (d, J=13 and 198 Hz, 1C) 146.00 (s, 2C) 133.43 (s, 1C) 132.23 (d, J=11.56 Hz, 1C) 131.99 (s, 2C) 123.90-124.24 (m, 2C) 122.89 (br. s., 1C) 122.66 (s, 2C) 115.36 (d, J=16.95 Hz, 2C) 72.77 (s, 2C) 71.14 (s, 3C) 42.12 (br. s., 1C) 35.66 (s, 2C) 32.68 (s, 2C) 20.28 (s, 2C); 19F NMR (376 MHz, CHLOROFORM-d) δ ppm −138.20-−137.93 (m, 1F) −143.38-−143.16 (m, 1F).
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[C:34](Cl)(=[O:38])[CH2:35][CH2:36][CH3:37]>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:34](=[O:38])[CH2:35][CH2:36][CH3:37])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: CCCC(=O)Cl
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCCC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.33 h
Yield: 62 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.62 g, 4.08 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.85 mmol) in CH3CN (50 mL). After stirring for 20 min, butyryl chloride (0.24 g, 2.22 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 mL). The CH2Cl2 solution was washed with H2O (30 mL), brine (30 mL) and dried (MgSO4). The solvent was removed in vacuo and residue was purified by chromatography (SiO2, CH2Cl2:EtOAc 1:1) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}butanamide (0.41 g, 62%) as a white solid. mp 121-123° C.; 1H NMR (DMSO-d6) δ 11.14 (s, 1H), 8.44 (t, J=5.55 Hz, 1H), 7.87-7.66 (m, 3H), 5.19-5.12 (dd, J=5.1 and 12.4 Hz, 1H), 4.72 (d, J=5.6 Hz, 2H), 2.96-2.85 (m, 1H), 2.63-2.51 (m, 2H), 2.17 (t, J=7.2 Hz, 2H), 2.08-2.04 (m, 1H), 1.63-1.51 (m, 2H), 0.87 (t, J=7.3 Hz, 3H); 13C NMR (DMSO-d6) δ 172.71, 172.47, 169.77, 167.46, 166.92, 139.53, 134.68, 133.11, 131.49, 127.04, 121.77, 48.84, 37.55, 37.16, 30.91, 21.96, 18.60, 13.63; Anal. Calcd. For C18H19N3O5: C, 60.50; H, 5.36; N, 11.76. Found: C, 60.46; H, 5.36; N, 11.59.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11].[N:25]([CH2:32][CH2:33][OH:34])([CH2:29][CH2:30][OH:31])[CH2:26][CH2:27][OH:28]>C(COC)OC>[Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([O-:12])=[O:11].[OH:28][CH2:27][CH2:26][NH+:25]([CH2:32][CH2:33][OH:34])[CH2:29][CH2:30][OH:31]
Reactant: OCCN(CCO)CCO
Reactant: O=C(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Solvent: COCCOC
Product: O=C([O-])c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Product: OCC[NH+](CCO)CCO
Temperature: 25 °C

Procedure:
5-(2-Chloro-4-trifluoromethylphenoxy)-2-nitrobenzoic acid (3.0 g, 0.0083 mole) is dissolved in glyme (20 ml) and a solution of triethanolamine (1.35 g, 0.0091 mole) in glyme (5 ml) is added rapidly while stirring at room temperature. After stirring for a few hours the solvent is removed in vacuo, the product is triturated repeatedly with petroleum ether (bp 30°-60° C.) and dried to a weight of 2.5 g. Anal. Calcd. for C20H22ClF3N2O8 : C, 47.02; H, 4.34; Cl, 6.39; N, 5.48; F, 11.15. Found: C, 47.08; H, 4.78; Cl, 6.48; N, 5.21; F, 10.16.
Reaction SMILES: [NH2:1][CH:2]([C:9]([OH:11])=[O:10])[CH2:3][CH2:4][S:5](=[O:8])([OH:7])=[O:6].[CH2:12]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH3:13].[CH3:19][Si:20]([CH3:23])([CH3:22])Cl>C1C=CC=CC=1>[CH2:12]([NH+:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH3:13].[CH3:19][Si:20]([CH3:23])([CH3:22])[NH:1][CH:2]([C:9]([O:11][Si:20]([CH3:23])([CH3:22])[CH3:19])=[O:10])[CH2:3][CH2:4][S:5](=[O:7])([OH:8])=[O:6]
Reactant: CCN(CC)CC
Reactant: C[Si](C)(C)Cl
Reactant: NC(CCS(=O)(=O)O)C(=O)O
Solvent: c1ccccc1
Product: CC[NH+](CC)CC
Product: C[Si](C)(C)NC(CCS(=O)(=O)O)C(=O)O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 42 h
Yield: 78 %

Procedure:
A suspension of D,L-homocysteic acid (915 mg, 5 mmoles) in dry benzene (25 ml) is treated with triethylamine (2 g, 20 mmoles) and trimethylchlorosilane (2.5 ml, 2.16 g, 20 mmoles). After being stirred at room temperature for 42 hr, the mixture is quickly suction filtered to remove the triethylamine hydrochloride, and the filtrate is evaporated to dryness under reduced pressure to obtain N,O-bis(trimethylsilyl)-D,L-homocysteic acid triethylammonium salt as a pale amber-colored oil or soft semisolid (1.93 g, 90 percent yield). This product is kept protected from atmospheric moisture and used without further purification in the next step.
Reaction SMILES: [C:1]1([CH3:52])[CH:6]=[CH:5][C:4]([S:7]([NH:10][CH2:11][CH2:12][CH2:13][N:14]([S:42]([C:45]2[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=2)(=[O:44])=[O:43])[CH2:15][CH2:16][N:17]([S:32]([C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=2)(=[O:34])=[O:33])[CH2:18][CH2:19][CH2:20][NH:21][S:22]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)(=[O:24])=[O:23])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[H-].[Na+].[OH2:55].C[N:57]([CH3:60])[CH:58]=O>>[C:1]1([CH3:52])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:12][CH2:13][N:14]([S:42]([C:45]3[CH:46]=[CH:47][C:48]([CH3:51])=[CH:49][CH:50]=3)(=[O:43])=[O:55])[CH2:15][CH2:60][N:57]([S:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:52])=[CH:2][CH:3]=3)(=[O:8])=[O:9])[CH2:58][CH2:16][N:17]([S:32]([C:35]3[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][CH:40]=3)(=[O:34])=[O:33])[CH2:18][CH2:19][N:21]([S:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[CH2:20][CH2:19][CH2:18][N:17]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:33])=[O:34])[CH2:16][CH2:15][N:14]([S:42]([C:45]3[CH:46]=[CH:47][C:48]([CH3:51])=[CH:49][CH:50]=3)(=[O:44])=[O:43])[CH2:13][CH2:12][CH2:11]2)(=[O:8])=[O:9])=[CH:3][CH:2]=1
Reactant: CN(C)C=O
Reactant: O
Reactant: Cc1ccc(S(=O)(=O)NCCCN(CCN(CCCNS(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)cc1
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(S(=O)(=O)N2CCCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CCCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Subsequently, 126 g (0.16 mol) of 1,5,8,12-Tetrakis(p-tolylsulfonyl)-1,5,8,12-tetraazadodecane was dissolved in 1500 ml of anhydrous dimethylform amide and then, 7.2 g (0.3 mol) of NaH was slowly added thereto in a nitrogen atmosphere. The mixture was heated for 30 minutes at a temperature of 80° C. 500 ml of dimethylform amide solution in which 129.5 g (0.16 mol) of the 3,6,9-Tris(p-tolylsulfonyl)-3,6,9-triazaundecane-1,11-dimethanesulfonate was dissolved was slowly added to the mixture at a temperature of 80° C. and then left to sit for 30 minutes. The reaction solution was cooled to room temperature, and also, cooled using iced water, and a filtered precipitate was recrystallized with acetone to produce 1,5,8,12,15,18,21-Heptakis(p-tolylsulfonyl)-1,5,8,12,15,18,21-heptaazacyclotricosane.
Reaction SMILES: O.[C:2]([OH:6])(=[O:5])[CH:3]=O.[CH2:7]([SH:11])[CH2:8][CH2:9][SH:10].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[S:10]1[CH2:9][CH2:8][CH2:7][S:11][CH:3]1[C:2]([OH:6])=[O:5]
Reactant: SCCCS
Reactant: O=CC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)C1SCCCS1
Temperature: 25 °C

Procedure:
9.20 g (100 mmol) of glyoxalic acid monohydrate, 11.1 ml (110 mmol) of 1,3-propanedithiol and 1.72 g (10.0 mmol) of para-toluenesulphonic acid were heated in 200 ml of toluene under reflux for 3 h. The reaction mixture was cooled to RT and extracted three times with 100 ml of saturated aqueous sodium bicarbonate solution. The combined aqueous phases were washed with 200 ml of diethyl ether, acidified with aqueous hydrochloric acid (6N) and extracted four times with 200 ml of ethyl acetate. The combined organic phases were dried over magnesium sulphate and filtered, and the solvent was removed under reduced pressure. The residue was used for the next step without further purification. Yield: 8.0 g (47% of theory)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([CH3:10])[CH2:6][CH2:7][CH2:8][NH2:9].CO[C:13]1[C:22](=[O:23])[C:17]2[N:18]=[C:19]([CH3:21])[S:20][C:16]=2[C:15](=[O:24])[CH:14]=1>C(O)C>[CH3:10][N:5]([CH2:6][CH2:7][CH2:8][NH:9][C:13]1[C:22](=[O:23])[C:17]2[N:18]=[C:19]([CH3:21])[S:20][C:16]=2[C:15](=[O:24])[CH:14]=1)[CH2:4][CH2:3][CH2:2][NH:1][C:13]1[C:22](=[O:23])[C:17]2[N:18]=[C:19]([CH3:21])[S:20][C:16]=2[C:15](=[O:24])[CH:14]=1
Reactant: CN(CCCN)CCCN
Reactant: COC1=CC(=O)c2sc(C)nc2C1=O
Solvent: CCO
Product: Cc1nc2c(s1)C(=O)C=C(NCCCN(C)CCCNC1=CC(=O)c3sc(C)nc3C1=O)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 12.6 %

Procedure:
83.4 mg (0.57 mmol; 0.6 equivalents) of N-(3-aminopropyl)-N-methylpropane-1,3-diamine are added to 200 mg (0.95 mmol) of 5-methoxy-2-methyl-4,7-dioxobenzothiazole in solution in 15 ml of anhydrous ethanol. The reaction mixture is stirred at 60° C. for 2 hours, then the solvent is evaporated off under reduced pressure. The residue is purified on a silica column (eluent: methanol at 3% in dichloromethane) and 30 mg (yield=36%) of expected product is obtained in the form of a red powder. Melting point: 94-96° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10]Br)=[CH:4][CH:3]=1.C([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)=O>CC(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:4][CH:3]=1
Reactant: O=CN1CCNCC1
Reactant: BrCCOc1ccc(Br)cc1
Solvent: CC(C)O
Product: Brc1ccc(OCCN2CCNCC2)cc1
Yield: 70.1 %

Procedure:
A mixture of 56.0 g (0.2 moles) of 2-bromoethyl p-bromophenyl ether and 45.6 g (0.4 moles) of 1-formylpiperazine in 500 ml of 2-propanol was heated at reflux for 18 hours. The mixture was cooled and filtered. The filter was washed with 2-propanol and the filtrate was evaporated to an oil in vacuo. Water was added and the oil was extracted three times with about 200 ml of chloroform. The extracts were combined, dried over magnesium sulfate and filtered. The filtrate was evaporated to an oil to which 250 ml of 5N sodium hydroxide was added. The mixture was refluxed for 18 hours, cooled and extracted three times with about 200 ml of chloroform. The extracts were combined, dried over magnesium sulfate and evaporated to an oil. The oil was distilled, bp 125°-128° C./0.05 mm of mercury, and gave 40 g of 1-[2-(4-bromophenoxy)ethyl]-piperazine as a yellowing oil.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:11])[C@H:8]([CH3:10])[NH2:9])([CH3:5])([CH3:4])[CH3:3].[CH3:12][CH:13]([C@H:15]([NH:26]C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C:16](ON1C(=O)CCC1=O)=[O:17])[CH3:14].CCN(C(C)C)C(C)C>ClCCl>[NH2:26][C@@H:15]([CH:13]([CH3:14])[CH3:12])[C:16]([NH:9][C@@H:8]([CH3:10])[C:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:11])=[O:17]
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Reactant: CC(C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)ON1C(=O)CCC1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)[C@H](N)C(=O)N[C@@H](C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of the alanine-O-tert-butyl ester hydrogen chloride salt (98) (500 mg, 2.76 mmol) in dichloromethane (5 mL) was added Fmoc-val-OSu (99) (1.09 g, 2.51 mmol). DIPEA (0.96 ml, 5.5 mmol) was added and the reaction mixture was allowed to stir at an ambient temperature for 16 h. The mixture was poured into dichloromethane (100 mL) and washed with 1N HCl (50 mL) and water (50 mL) before being dried over magnesium sulfate. The material was chromatographed on a 2 mm radial chromatotron plate eluting with 1 to 5% methanol/dichloromethane gradient and product containing fractions were combined and concentrated. The resulting residue was dissolved in dichloromethane (16 mL) and piperidine (4 mL) was added. The mixture was stirred for 10 min before being concentrated under reduced pressure. The resulting residue was chromatographed on a 2 mm plate eluting first with ammonia-saturated dichloromethane followed by 5% methanol in ammonia-saturated dichloromethane to give 494 mg (2.02 mmol, 81% for two steps) of 97: 1H-NMR (400 MHz, CDCl3) δ 7.78 (bs, 1H), 4.47 (m, 1H), 3.30 (d, 1H), 2.30 (m, 1H), 1.38 (d, 3H), 1.47 (s, 9H), 1.00 (d, J=7.0 Hz, 3H), 0.84 (d, J=6.9 Hz, 3H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:13]1[CH2:18][CH:17]=[CH:16][CH2:15][CH2:14]1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][C:10]([N:13]2[CH2:14][CH:15]=[CH:16][CH2:17][CH2:18]2)=[O:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CCCc1ccccc1
Reactant: C1=CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CCCc1ccccc1)N1CC=CCC1
Yield: 83 %

Procedure:
5 mmol of 4-phenyl butyric acid, 5 mmol of 1,2,3,6-tetrahydropyridine, and 6 mmol of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were mixed with 20 ml of methylene chloride. The mixture was reacted for 2 hours at room temperature with stirring. The reaction mixture was washed with 5% hydrochloric acid, 2% sodium hydroxide, and brine. The organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel to obtain 950 mg of colorless crystals of N-(4-phenylbutanoyl)-1,2,3,6-tetrahydropyridine (yield: 83%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].O.C([O-])(=O)C.[Na+].[N:17]#[C:18]Br>C(O)(=O)C>[OH2:6].[C:18]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])#[N:17]
Reactant: Nc1cccc(C(=O)O)c1
Reactant: N#CBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: N#CNc1cccc(C(=O)O)c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 174.9 %

Procedure:
To a 3-aminobenzoic acid (Aldrich, 9.05 g, 66 mmol) in acetic acid:water (70 mL, 1:1) was added sodium acetate (8.12 g, 99 mmol) and the mixture was cooled in an ice-water bath. Cyanogen bromide (8.38 g, 79.2 mmol) was added in two batches in 10 min and the stirring was continued for 18 h at room temperature. The reaction mixture was poured into 350 g of an ice-water mixture with stirring. The precipitate was collected through filtration, washed with cold water (about 70 mL), dried in air, and crystallized from methanol-water. The white solid was separated through filtration, dried in air followed by drying in a pistol at toluene reflux in vacuo to give 10.40 g (95%) of the title compound, mp 238°-240° C.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH2:17]O)[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=2)[N:5]=[N:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:38]N1C(=O)CCC1=O>C(Cl)Cl.C(OCC)(=O)C>[Br:38][CH2:17][C:9]1[CH:8]=[C:7]([N:6]2[C:2]([CH3:1])=[N:3][N:4]=[N:5]2)[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nnnn1-c1cc(CO)cc(C(F)(F)F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1nnnn1-c1cc(CBr)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
(3-(5-Methyl-1H-tetrazol-1-yl)-5-(trifluoromethyl)phenyl)methanol (110 mg, 0.46 mmol) and triphenylphosphine (240 mg, 0.93 mmol) were combined in methylene chloride (4 mL) and cooled to 0° C. N-Bromosuccinimide (171 mg, 0.96 mmol) was introduced in portions and the reaction allowed to warm to room temperature. After 16 h, the reaction mixture was diluted with ethyl acetate, washed with concentrated sodium bicarbonate (2×), brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (20% ethyl acetate/hexanes) gave 120 mg (82%). LC/MS (HPLC method 3): tR=2.30 min, 323.01 (MH)+.
Reaction SMILES: Br[Si](C)(C)C.C([O:8][P:9]([C:14]1[C:15](=[O:30])[NH:16][C:17]2[C:22]([CH:23]=1)=[CH:21][C:20]([N:24]1[CH:28]=[CH:27][CH:26]=[CH:25]1)=[C:19]([Cl:29])[CH:18]=2)(=[O:13])[O:10]CC)C>C(Cl)Cl>[Cl:29][C:19]1[CH:18]=[C:17]2[C:22]([CH:23]=[C:14]([P:9](=[O:8])([OH:10])[OH:13])[C:15](=[O:30])[NH:16]2)=[CH:21][C:20]=1[N:24]1[CH:25]=[CH:26][CH:27]=[CH:28]1
Reactant: CCOP(=O)(OCC)c1cc2cc(-n3cccc3)c(Cl)cc2[nH]c1=O
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: O=c1[nH]c2cc(Cl)c(-n3cccc3)cc2cc1P(=O)(O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3.37 ml (25.5 mmol) of bromotrimethylsilane are added to a solution of the compound obtained in Example 27 (1.62 g, 4.25 mmol) in 30 ml of CH2Cl2, and the solution is stirred for 4 hours 30 minutes at room temperature. Evaporation to dryness is carried out, and the residue is taken up in methanol. After complete dissolution, a precipitate is observed to form, and stirring is carried out for 10 minutes at room temperature. Filtration and then rinsing with a small amount of methanol and then ether are carried out to obtain the title product.