Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:25]1([N:30]2[CH2:40][C:39]([CH3:42])([CH3:41])[C:38](=[O:43])[N:37]([CH3:44])[C:36]3[C:31]2=[N:32][C:33]([NH:45][C:46]2[CH:54]=[CH:53][C:49]([C:50](O)=[O:51])=[CH:48][C:47]=2[O:55][CH3:56])=[N:34][CH:35]=3)[CH2:29][CH2:28][CH2:27][CH2:26]1.CCN(C(C)C)C(C)C.[NH2:66][CH:67]1[CH2:72][CH2:71][N:70]([CH2:73][CH2:74][O:75][CH3:76])[CH2:69][CH2:68]1>CC(N(C)C)=O>[CH:25]1([N:30]2[CH2:40][C:39]([CH3:41])([CH3:42])[C:38](=[O:43])[N:37]([CH3:44])[C:36]3[C:31]2=[N:32][C:33]([NH:45][C:46]2[CH:54]=[CH:53][C:49]([C:50]([NH:66][CH:67]4[CH2:72][CH2:71][N:70]([CH2:73][CH2:74][O:75][CH3:76])[CH2:69][CH2:68]4)=[O:51])=[CH:48][C:47]=2[O:55][CH3:56])=[N:34][CH:35]=3)[CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: COCCN1CCC(N)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COCCN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC(C)(C)C(=O)N4C)c(OC)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of HATU (126 mg, 0.33 mmol) in DMA (5 mL) was added to a mixture of 4-[(2-cyclopentyl-4,4,6-trimethyl-5-oxo-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-10-yl)amino]-3-methoxy-benzoic acid (Example 242 132 mg, 0.3 mmol), DIPEA (261 uL, 1.5 mmol) and 4-amino N-(2-methoxyethyl)piperidine (60 mg, 0.375) in DMA (5 mL). The resulting mixture was stirred at room temperature for 2 hours, then partially purified by SCX. The compound was retrieved from the SCX column using 7N ammonia in methanol, then concentrated in vacuo, and further purified by column chromatography, eluting with 0-10% ammonia (7N in methanol) in DCM. The pure material was recovered as an orange oil, which foamed and solidified under high vacuum. Trituration under ether gave a pale yellow amorphous solid. (55 mg, 32%)
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].C(O[CH:17](OCC)[N:18]([CH3:20])[CH3:19])C>CN(C=O)C>[CH3:17][N:18]([CH3:20])[CH:19]=[C:8]([N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]1=[O:1])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(OCC)N(C)C
Reactant: CCOC(=O)Cn1ccccc1=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(=CN(C)C)n1ccccc1=O
Yield: 84.5 %

Procedure:
Combined ethyl 2-(2-oxopyridin-1(2H)-yl)acetate (500 mg, 2.76 mmol), 1,1-diethoxy-N,N-dimethylmethanamine (2031 mg, 13.80 mmol) and DMF (2 mL) and heated at 100° C. for 15 h. The reaction mixture was diluted with xylenes and concentrated onto Celite® then purified on a 30 g NH silica column (Moritex) eluted with 0 to 100% EtOAc in hexanes to give the title compound (551 mg, 85% yield) as a light yellow solid. MS m/z 237 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13 (br. s., 3H) 2.77 (br. s., 6H) 3.94-4.08 (m, 2H) 6.17 (td, J=6.7, 1.3 Hz, 1H) 6.36 (dt, J=9.0, 1.1 Hz, 1H) 7.35-7.45 (m, 2H) 7.47 (s, 1H).
Reaction SMILES: [CH2:1]([N:15]([CH3:17])[CH3:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(#N)C.[CH2:21]([Br:24])[CH:22]=[CH2:23]>>[Br-:24].[CH2:1]([N+:15]([CH2:23][CH:22]=[CH2:21])([CH3:17])[CH3:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: C=CCBr
Reactant: CCCCCCCCCCCCCCN(C)C
Solvent: CC#N
Product: C=CC[N+](C)(C)CCCCCCCCCCCCCC
Product: [Br-]
Temperature: 61 °C

Procedure:
The procedure is as described in Example 1, but the following are added successively to the flask with stirring: 157.4 g (0.65 mol) of N-tetradecyl-N,N-dimethylamine, 240.0 g (5.85 mol) of acetonitrile and 82.6 g (0.683 mol) of allyl bromide. The contents of the flask warm up without external heating to 61° C. in the course of 20 minutes. The flask is then heated again to 70° C. by means of the external heating and kept at this temperature with stirring for 1 hour and then cooled to room temperature, and an amine conversion of 99.7% is determined in a sample of the contents of the flask by a residual amine determination. Working-up is carried out as described in Example 1. The N-tetradecyl-N-allyl-N,N-dimethylammonium bromide (3) thus obtained is used for the viscosity determinations described below. The following contents are determined analytically:
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[NH2:12][CH2:13][CH2:14][OH:15]>CS(C)=O>[NH2:1][C:2]1[N:3]=[C:4]([NH:12][CH2:13][CH2:14][OH:15])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: NCCO
Solvent: CS(C)=O
Product: Nc1nc(NCCO)ccc1[N+](=O)[O-]

Procedure:
2-[(6-Amino-5-nitropyridin-2-yl)amino]ethanol (Example 48A) is prepared in analogy to Example 36A from 2-amino-6-chloro-3-nitropyridine (400 mg, 2.3 mmol) and 2-aminoethanol (282 mg, 4.6 mmol) in DMSO (110° C., 4 h). Removal of the solvent results in a crude product which is precipitated from dichloromethane. The product is filtered off with suction and dried. 283 mg (62% of theory) of the product are obtained.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[C:13]([F:21])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[C:13]([F:21])[CH:12]=2)[C:3]([OH:22])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(C(F)(F)F)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C(CC1CCCC1)c1ccc(C(F)(F)F)c(F)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 64.1 %

Procedure:
A solution of 3-cyclopentyl-2-(3-fluoro-4-trifluoromethyl-phenyl)-propionic acid methyl ester (1.80 g, 5.69 mmol) in tetrahydrofuran (15 mL) was treated with a 0.8M aqueous lithium hydroxide solution (7.1 mL, 5.69 mmol). The reaction mixture was stirred at 25° C. for 15 h. The reaction mixture was concentrated in vacuo. The resulting residue was diluted with ethyl acetate (100 mL) and then washed with a 5% aqueous hydrochloric acid solution and a saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 2/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3-fluoro-4-trifluoromethyl-phenyl)-propionic acid (1.11 g, 64%) as a white solid: mp 93-95° C.; FAB-HRMS m/e calcd for C15H16F4O2 (M+H)+305.1165, found 305.1175.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([F:11])[N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.CCN(C(C)C)C(C)C.[CH3:21][C:22]1[N:27]=[CH:26][C:25]([CH2:28][NH2:29])=[CH:24][CH:23]=1>CCCCO>[F:11][C:9]1[N:8]=[C:7]2[C:3]([N:4]=[CH:5][NH:6]2)=[C:2]([NH:29][CH2:28][C:25]2[CH:26]=[N:27][C:22]([CH3:21])=[CH:23][CH:24]=2)[N:10]=1
Reactant: Fc1nc(Cl)c2[nH]cnc2n1
Reactant: Cc1ccc(CN)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1ccc(CNc2nc(F)nc3[nH]cnc23)cn1
Reaction time: 1 h

Procedure:
To a stirred solution of 6-chloro-2-fluoropurine (0.4 g, 2.3 mmol) in n-BuOH (50 ml) under an argon atmosphere at 0° C., was added DIEA (2.5 ml, 14.7 mmol) followed by (6-methylpyridin-3-yl)methanamine (0.36 g, 2.95 mmol). The reaction mixture was stirred at this temperature for 1 h and then allowed to return to room temperature and stirred for 4 h, it was still seen incomplete, hence heated the reaction to 100° C. and left at that temperature for 8 h. The solvent was evaporated in vacuo and the residue was purified by gradient column chromatography on silica gel, eluted with CHCl3:MeOH (100:0→90:10), to afford the product as a white solid; Yield: 0.38 g (65%) δH CDCl3, 250 MHz) 2.44 (3 H, s, CH3), 3.66-3.57 (2 H, m, NHCH2), 4.63 (1H, s, br, NH), 7.25 (1 H, d, J 7.5, ArH), 7.71 (1 H, dd, J 2.5, 7.5, ArH), 8.14 (1 H, s, ArH), 8.49 (1 H, s, ArH), 9.07 (1 H, s, br, NH); δC (CDCl3, 250 MHz) 159.12 (C), 158.62 (C), 157.61 (C), 155.56 (C), 147.44 (CH), 146.99 (CH), 136.32 (C), 123.05 (2×CH), 119.42 (C), 41.64 (CH2), 18.47 (CH3); m/z 259.2 (M+H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:26][C:27]1[C:36]2[C:31](=[CH:32][C:33]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][C:35]=2[CH3:37])[N:30]=[CH:29][CH:28]=1.S(Cl)(Cl)(=O)=O>C1COCC1>[Cl:26][C:27]1[C:36]2[C:31](=[CH:32][C:33]([S:38]([N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:15][CH:14]=3)[C:9]3[S:10][CH:11]=[CH:12][N:13]=3)(=[O:39])=[O:40])=[CH:34][C:35]=2[CH3:37])[N:30]=[CH:29][CH:28]=1
Reactant: COc1ccc(CNc2nccs2)cc1
Reactant: Cc1cc(S(=O)(=O)Cl)cc2nccc(Cl)c12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O=S(=O)(Cl)Cl
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2cc(C)c3c(Cl)ccnc3c2)cc1
Reaction time: 0.25 h

Procedure:
To a flask containing ice cold suspension of N-(4-methoxybenzyl)thiazol-2-amine (25.1 mg, 0.114 mmol) in THF (418 μl) was added lithium bis(trimethylsilyl)amide (1M in THF) (120 μl, 0.120 mmol) dropwise over 10 min. The mixture was stirred for 15 min prior to the drop wise addition of a solution of 4-chloro-5-methylquinoline-7-sulfonyl chloride (30 mg, 0.109 mmol) in THF (0.6 ml). After 30 min LC/MS indicated desired product and methanolysis of the sulfonyl chloride (about 1:1). Additional solid N-(4-methoxybenzyl)thiazol-2-amine (25.1 mg, 0.114 mmol) was added with stirring at room temperature. After 15 min, no further conversion had occurred. Additional LHMDS (0.5 eq) was added after cooling back to 0° C. and stirring continued. After 20 min, LC/MS indicated consumption of sulfonyl chloride (methanolysis) with product visible as a minor species. To the orange/brown solution was added acetic acid (300 μl) and the mixture dried under reduced pressure. The crude material was purified with a 25 g (25 μm spherical) silica column ramping EtOAc in heptane (0-50%, 5% DCM throughout) to provide 4-chloro-N-(4-methoxybenzyl)-5-methyl-N-(thiazol-2-yl)quinoline-7-sulfonamide (6 mg, 0.013 mmol, 12.01% yield) as a white solid. m/z (ESI) 460.3 (M+H)+.
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][NH2:11])[CH3:4].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[S:24][C:23]([S:25](Cl)(=[O:27])=[O:26])=[N:22][N:21]=2)=[C:16]([N+:29]([O-:31])=[O:30])[CH:15]=1>>[CH2:3]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][NH:11][S:25]([C:23]1[S:24][C:20]([C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][C:16]=2[N+:29]([O-:31])=[O:30])=[N:21][N:22]=1)(=[O:27])=[O:26])[CH3:4]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1-c1nnc(S(=O)(=O)Cl)s1
Reactant: CCOC(=O)CNCCN
Agent: Cl
Product: CCOC(=O)CNCCNS(=O)(=O)c1nnc(-c2ccc(Cl)cc2[N+](=O)[O-])s1

Procedure:
The title compound was synthesized by the reaction of N-(2-aminoethyl)-glycine ethyl ester 2HCl with 5-(4-chloro-2-nitrophenyl)-1,3,4-thiadiazole-2-sulfonyl chloride as per the procedure of example 1. 1H NMR (500 MHz; DMSO-d6) δ 8.40 (d, 1H), 8.05 (dd, 1H), 8.02 (d, 1H) 4.07 (q, 2H), 3.30 (s, 2H), 3.19 (t, 2H), 2.67 (t, 2H), 1.18 (t, 3H).
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([S:14]([N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=4)[CH2:19][CH2:18]3)(=[O:16])=[O:15])[CH:11]=2)[CH2:6]1.[Li+].[OH-]>C1COCC1>[F:32][C:29]([F:30])([F:31])[C:26]1[CH:27]=[CH:28][C:23]([N:20]2[CH2:19][CH2:18][N:17]([S:14]([C:10]3[CH:11]=[C:12]4[C:7](=[CH:8][CH:9]=3)[CH2:6][CH:5]([CH2:4][C:3]([OH:33])=[O:2])[CH2:13]4)(=[O:15])=[O:16])[CH2:22][CH2:21]2)=[CH:24][CH:25]=1
Reactant: COC(=O)CC1Cc2ccc(S(=O)(=O)N3CCN(c4ccc(C(F)(F)F)cc4)CC3)cc2C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CC1Cc2ccc(S(=O)(=O)N3CCN(c4ccc(C(F)(F)F)cc4)CC3)cc2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.6 %

Procedure:
{5-[4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indan-2-yl}-acetic acid methyl ester (118 mg, 0.245 mmol) was dissolved in THF (10 mL). To this solution was added 1M LiOH (5 mL) and was stirred at room temperature for 3 h. TLC indicated that the reaction was complete. The reaction mixture was then quenched with Dowex 50WX4-50 until neutral and then filtered to afford pure {5-[4-(4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indan-2-yl}-acetic acid (112 mg, 98%) as a white solid. The product can be further purified by silica gel flash column chromatography (dichloromethane/MeOH/AcOH 95:5:0.1). 1H NMR (400 MHz, MeOH-d4) 7.60 (s, 1H), 7.56 (d, 1H), 7.45 (d, 2H), 7.41 (d, 1H), 7.00 (d, 2H), 3.32 (m, 4H), 3.22 (m, 2H), 3.17 (m, 4H), 2.88 (m, 1H), 2.72 (m, 2H), 2.47 (d, 2H); LCMS: 468.8 (M+1)+.
Reaction SMILES: [C:1]([O:7][CH2:8][CH2:9][N:10]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[CH3:11])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[N+:20]([C:23]1[CH:24]=[C:25]([CH:38]=[CH:39][CH:40]=1)[CH:26]=[C:27]([C:35]([CH3:37])=O)[C:28]([O:30][CH2:31][CH:32]1[CH2:34][CH2:33]1)=[O:29])([O-:22])=[O:21].[NH3:41]>C(O)C>[CH3:5][C:3]1[NH:41][C:35]([CH3:37])=[C:27]([C:28]([O:30][CH2:31][CH:32]2[CH2:34][CH2:33]2)=[O:29])[CH:26]([C:25]2[CH:38]=[CH:39][CH:40]=[C:23]([N+:20]([O-:22])=[O:21])[CH:24]=2)[C:2]=1[C:1]([O:7][CH2:8][CH2:9][N:10]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[CH3:11])=[O:6]
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)OCC1CC1
Reactant: N
Reactant: CC(=O)CC(=O)OCCN(C)Cc1ccc(Cl)cc1
Solvent: CCO
Product: CC1=C(C(=O)OCCN(C)Cc2ccc(Cl)cc2)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OCC2CC2)=C(C)N1
Reaction time: 7 h
Yield: 56.3 %

Procedure:
A mixture of 10.0 g (35 mmol) of 2-[N-(4-chlorobenzyl)-N-methylamino]-ethyl acetoacetate, 10.2 g (35 mmol) of cyclopropylmethyl 2-(3-nitrobenzylidene)acetoacetate, 2.9 ml of 28% aqueous ammonia and 50 ml of ethanol was stirred at the reflux temperature for 7 hours, and then the solvent was removed under reduced pressure. The residue was chromatographed on silica gel column and crystallized from methanol to afford 3-[2-[N-(4-chlorobenzyl)-N-methylamino]ethyl] 5-cyclopropylmethyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate (11.0 g, 56.3%) as yellow crystals.
Reaction SMILES: [OH:1][C:2]([CH3:9])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].CC1C=CC(S(O)(=O)=O)=CC=1.N1C=CC=CC=1.[O:27]1[CH:32]=[CH:31][CH2:30][CH2:29][CH2:28]1.C(OCC)C>ClCCl>[CH3:8][C:2]([O:1][CH:28]1[CH2:29][CH2:30][CH2:31][CH2:32][O:27]1)([CH3:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(C)(C)O
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCOC(=O)C(C)(C)OC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
To a solution of ethyl 2-hydroxy-2-methylpropanoate (5.20 mL, 38.06 mmol) in dichloromethane (100 mL) were sequentially added pyridine 4-methylbenzenesulfonate (1.0 g, 3.80 mmol) and 3,4-dihydro-2H-pyran (5.20 ml, 57.0 mmol). The resulting mixture was stirred at room temperature overnight. Ethyl ether was added (600 mL) and the resulting organic layer was washed with brine (3×100 ml), dried over anhydrous sodium sulphate and the solvent removed under reduced pressure to give the title compound (7.85 g, 95%).
Reaction SMILES: [C:1]1([P:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:16](=O)/[CH:17]=[CH:18]/[CH2:19][CH2:20][CH3:21].[C:23]1([CH3:32])[CH:28]=[CH:27][C:26]([S:29]([OH:31])=[O:30])=[CH:25][CH:24]=1>>[C:1]1([P:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])[NH:8][CH:16]([S:29]([C:26]2[CH:27]=[CH:28][C:23]([CH3:32])=[CH:24][CH:25]=2)(=[O:31])=[O:30])/[CH:17]=[CH:18]/[CH2:19][CH2:20][CH3:21])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)O)cc1
Reactant: NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCC/C=C/C=O
Product: CCC/C=C/C(NP(=O)(c1ccccc1)c1ccccc1)S(=O)(=O)c1ccc(C)cc1

Procedure:
The title compound is synthesized following a previously reported procedure7 from P,P-diphenylphosphinic amide (2.17 g, 10.0 mmol, 1.00 equiv.), (E)-hex-2-enal (2.31 mL, 20.0 mmol, 2.00 equiv.), and p-toluenesulfinic acid (2.34 g, 15.0 mmol, 1.50 equiv.) to obtain S5 as white solid (3.22 g, 7.10 mmol, 71% yield). M.p.=138-139° C. IR (neat): 3177 (w, br), 2959 (w), 2933 (w), 2870 (w), 1661 (m), 1596 (w), 1437 (m), 1300 (m), 1281 (m), 1214 (m), 1185 (s), 1170 (m), 1138 (m), 1125 (s), 1106 (m), 1083 (m), 955 (m), 894 (m), 752 (m), 726 (s), 693 (s), 662 (m), 583 (s), 568 (m), 536 (s) cm−1; 1H NMR (400 MHz, CDCl3): δ 7.79-7.71 (4H, m), 7.59 (2H, d, J=8.4 Hz), 7.59-7.54 (2H, m), 7.50-7.43 (4H, m), 7.23 (2H, d, J=8.0 Hz), 5.90 (1H, ddd, J=13.6, 11.6, 9.6 Hz), 5.31 (1H, t, J=10.0 Hz), 4.73 (1H, dd, J=14.0, 10.4 Hz), 3.28 (1H, app td, J=10.8, 3.6 Hz), 2.42 (3H, s), 1.97-1.88 (1H, m), 1.52-1.32 (2H, m), 1.20-1.10 (1H, m), 0.82 (3H, t, J=7.2 Hz); 13C NMR (100 MHz, CDCl3): δ 144.3, 134.7, 132.8, 132.6 (d, J=2.9 Hz), 132.5 (d, J=2.9 Hz), 132.2 (d, J=10.1 Hz), 131.9 (d, J=10.1 Hz), 131.4 (d, J=128.0 Hz), 131.1 (d, J=128.0 Hz), 129.6, 129.2, 128.9 (d, J=12.9 Hz), 128.9 (d, J=13.0 Hz), 101.9 (d, J=9.9 Hz), 67.6, 29.7, 21.8, 20.0, 13.7.
Reaction SMILES: Cl.[NH:2]1[CH:6]=[C:5]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16](=[O:20])[CH2:15][CH2:14][CH2:13]3)[N:4]=[CH:3]1.[CH3:21][C:22]1[S:26][C:25]([CH:27]=O)=[CH:24][CH:23]=1>[OH-].[K+].CCO>[NH:2]1[CH:6]=[C:5]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16](=[O:20])[C:15](=[CH:27][C:25]2[S:26][C:22]([CH3:21])=[CH:23][CH:24]=2)[CH2:14][CH2:13]3)[N:4]=[CH:3]1
Reactant: Cc1ccc(C=O)s1
Reactant: O=C1CCCc2cc(OCCc3c[nH]cn3)ccc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(C=C2CCc3cc(OCCc4c[nH]cn4)ccc3C2=O)s1
Yield: 53.1 %

Procedure:
According to the method of Example 34, 6-[2-(1H-imidazole-4-yl)-ethoxy]-3,4-dihydro-2H-naphthalen-1-one, monohydrochloride (0.313 g, 1.07 mmol) was reacted with 5-methyl-2-thiophene carboxaldehyde (0.142 g, 1.13 mmol) in 5 mL of 4% KOH in EtOH overnight to afford 0.207 g (44%) of the title compound as a bright orange solid, mp 69-70° C.: CI-MS m/e 364 (M+), 365 (M+ +1).
Reaction SMILES: CO[C:3]([C:5]1[CH:14]=[CH:13][C:12]2[CH2:11][CH2:10][CH:9]([NH2:15])[CH2:8][C:7]=2[CH:6]=1)=[O:4].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.[OH:27][NH2:28].[OH-].[K+]>ClCCl>[OH:27][NH:28][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[CH2:11][CH2:10][CH:9]([NH:15][S:23]([C:20]3[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=3)(=[O:25])=[O:24])[CH2:8][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)CC(N)CC2
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: NO
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(NO)c1ccc2c(c1)CC(NS(=O)(=O)c1ccc(Cl)cc1)CC2

Procedure:
The title compound was prepared in two steps according to Scheme 6 by (1) treating amine VII with 4-chlorobenzenesulfonyl chloride and TEA in dichloromethane, and (2) treating the ester intermediate with aqueous HONH2 and KOH. MS: calc'd (MH+) 381, exp (MH+) 381. 1H NMR (CD3OD, 400 MHz), 7.90 (d, 2H, J=8.4 Hz), 7.60 (d, 2H, J=8.4 Hz), 7.47 (d, 1H, J=8.0 Hz), 7.37 (s, 1H), 7.15 (d, 1H, J=8.0 Hz), 3.55 (m, 1H), 2.95 (m, 2H), 2.82 (m, 1H), 2.69 (m, 1H), 1.95 (m, 1H) 1.73 (m, 1H).
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:8]=[C:9]3[C:14](=[N:15][C:16]=2[CH:17]([O:20][CH3:21])[O:18][CH3:19])[NH:13][CH2:12][CH2:11][CH2:10]3)[CH2:3][CH2:2]1.[H][H]>C1COCC1.CO.[Pd]>[CH3:21][O:20][CH:17]([O:18][CH3:19])[C:16]1[N:15]=[C:14]2[C:9]([CH2:10][CH2:11][CH2:12][NH:13]2)=[CH:8][C:7]=1[CH:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1
Reactant: COC(OC)c1nc2c(cc1C1=CCOCC1)CCCN2
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(OC)c1nc2c(cc1C1CCOCC1)CCCN2
Temperature: 25 °C
Reaction time: 56 h

Procedure:
A suspension of 10% Pd on carbon (0.34 g) in a solution of 6-(3,6-dihydro-2H-pyran-4-yl)-7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (intermediate 313, 0.94 g, 3.24 mmol) in THF (60 ml) and MeOH (20 ml) was stirred under an atmosphere of hydrogen at room temperature for 56 h, at which point 1 equivalent of hydrogen had been consumed. The reaction mixture was flushed with argon, filtered and evaporated to give the title compound as a beige solid. (UPLC-MS 3) tR 0.54 min; ESI-MS 293.3 [M+H]+.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:22](Cl)(=[O:25])[CH2:23][CH3:24]>C(Cl)Cl>[C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][N:15]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[C:22](=[O:25])[CH2:23][CH3:24])[CH2:9]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCCC(CNc2cccnc2)C1
Reactant: CCC(=O)Cl
Solvent: ClCCl
Product: CCC(=O)N(CC1CCCN(C(=O)OC(C)(C)C)C1)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To a solution of N-(1-Boc-piperidin-3-ylmethyl)-N-(pyridin-3-yl)amine 17 (100 mg, 0.34 mmol) and piperidinomethyl polystyrene resin (100 mg) in 1 mL of dry CH2Cl2 was added propionyl chloride (30 μL, 1 eq.) at room temperature. After being shaken at room temperature overnight, the reaction mixture was passed through an aminopropyl NH2 cartridge and washed with CH2Cl2. Removal of CH2Cl2 afforded N-(1-Boc-piperidin-3-ylmethyl)-N-(pyridin-3-yl)propionamide 18 (85 mg, 71%). LRMS 248 (M-100)+.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[N+](C1C=CC([O:32][C:33](=O)[C@H:34]([CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=CC=1)([O-])=O.O>CN(C)C=O>[F:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:33](=[O:32])[CH:34]([NH:35][C:36](=[O:37])[O:38][C:39]([CH3:40])([CH3:41])[CH3:42])[CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(=O)N1CCN(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.2 %

Procedure:
To a solution of 1-(4-fluorophenyl)piperazine dihydrochloride (2.53 g, 10 mmol) in N,N-dimethylformamide (40 ml) were added triethylamine (2.8 ml, 20 mmol) and N-tert butoxycarbonylphenylalanine p-nitrophenyl ester (2.65 g, 10 mmol) in the order mentioned, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into cold water and extracted with ethyl acetate. The extract was washed with 1 w/v % aqueous ammonia, saturated brine, 0.1N hydrochloric acid, saturated brine, saturated aqueous sodium hydrogencarbonate solution, and saturated brine in the order mentioned, and the organic layer was dried over anhydrous magnesium sulfate and further concentrated under reduced pressure. The residue was purified by silica gel column chromatography using chloroform-methanol (50:1, v/v) to give 1,1-dimethylethyl 2-(4-(4-fluorophenyl)-1-piperazinyl)-2-oxo-1-(phenylmethyl)ethylcarbamate (2.7 g, 92.2%) as colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(N(CC)CC)C>C(#N)C>[Br:1][C:2]1[C:3]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: Cc1ccc(Br)c(Cl)n1
Reactant: C1CNCCN1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(Br)c(N2CCNCC2)n1
Reaction time: 0.5 h
Yield: 20.3 %

Procedure:
A solution of 3-bromo-2-chloro-6-picoline (0.2 g), piperazine (0.083 g) and triethylamine (0.096 g) in acetonitrile (5 ml) was heated in the microwave apparatus: 30 min at 120° C. followed by 60 min at 150° C. and 30 min at 170° C. The mixture was concentrated and the product was purified by chromatography (SiO2, CH2Cl2=>CH2Cl2/CH3OH 4:1) to give 1-(3-bromo-6-methyl-pyridin-2-yl)-piperazine (0.05 g) as a light yellow solid.