Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:10])=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.Cl.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].[CH3:21][C:22]1[C:27]([CH:28]=O)=[CH:26][N:25]=[C:24]([NH:30][CH2:31][CH2:32][CH2:33][CH:34]2[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]2)[N:23]=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:28]([C:27]3[C:22]([CH3:21])=[N:23][C:24]([NH:30][CH2:31][CH2:32][CH2:33][CH:34]4[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]4)=[N:25][CH:26]=3)=[N:9][C:4]=2[C:3]=1[CH3:10]
Reactant: Cc1nc(NCCCC2CCN(C)CC2)ncc1C=O
Reactant: Cc1c(F)ccc(N)c1N
Agent: Cl
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(NCCCC2CCN(C)CC2)ncc1-c1nc2c(C)c(F)ccc2[nH]1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a 2 L Erlenmeyer flask were added 4-fluoro-3-methyl-benzene-1,2-diamine.HCl (46.32 g, 262.3 mmol), Na2S2O5 (64.82 g, 341.0 mmol), and 4-methyl-2-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrimidine-5-carbaldehyde (72.5 g, 262.3 mmol) in DMF (725 L). To the resultant mixture was then added triethylamine (36.6 mL, 262.3 mmol), and the reaction was warmed on a hot plate with stirring to 90° C. and held at this temperature for 2 hours. The resultant mixture was then concentrated to near dryness and partitioned between dichloromethane (1 L) and 1 N NaOH (1 L). After separation of the layers, the aqueous layer was extracted a second time with dichloromethane (1 L). The combined organic layers were then washed with saturated aqueous NaHCO3 (1.6 L). The organics were then extracted with a 1 M mono/dibasic phosphate buffer (pH 5.62, 1.23 L. The aqueous layer was then basified with 50% NaOH (80 mL) to pH 10.8. The resultant heterogeneous layer was then extracted with dichloromethane (1.5 L and 500 mL), and the combined organics were concentrated to yield the title compound.
Reaction SMILES: C([O:8][CH2:9][C@H:10]([O:23][CH2:24][P:25]([O:30][CH2:31][CH3:32])([O:27][CH2:28][CH3:29])=[O:26])[CH2:11][O:12][N:13]1[CH:21]=[N:20][C:19]2[C:14]1=[N:15][CH:16]=[N:17][C:18]=2[NH2:22])C1C=CC=CC=1>ClCCl.FC(F)(F)C(O)=O.N.[Pd]>[CH2:31]([O:30][P:25]([CH2:24][O:23][C@@H:10]([CH2:9][OH:8])[CH2:11][O:12][N:13]1[CH:21]=[N:20][C:19]2[C:14]1=[N:15][CH:16]=[N:17][C:18]=2[NH2:22])([O:27][CH2:28][CH3:29])=[O:26])[CH3:32]
Reactant: CCOP(=O)(CO[C@@H](COCc1ccccc1)COn1cnc2c(N)ncnc21)OCC
Agent: [Pd]
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOP(=O)(CO[C@@H](CO)COn1cnc2c(N)ncnc21)OCC
Reaction time: 5 h

Procedure:
10% Pd-C (50 mg) was added to a solution of (S)-9-[3-benzyloxy-2-(diethoxyphosphorylmethoxy)propoxy]adenine (0.21 g, 0.45 mmol) in dichloromethane (5 ml) and trifluoroacetic acid (lml) and the mixture hydrogenated at atmospheric pressure and ambient temperature for 5 hours. The mixture was filtered, the filtrate evaporated and the residue obtained dissolved in ethanolic ammonia solution (5 ml). After 15 minutes the solvent was evaporated and the residue chromatographed on silica gel using dichloromethane/methanol 90:10 as eluant. T.l.c. examination of the product indicated traces of a non UV absorbing impurity which was removed by prep. t.l.c. using dichloromethane/methanol 88:12 as eluant. (S)-9-[2-(diethoxyphosphorylmethoxy)3-hydroxypropoxy]adenine was obtained as a colourless gum (0.11 g, 65%). 1H NMR: δH [(CD3)2SO] 1.23 (6H, t, J=7 Hz, (OCH2CH3)2), 3.5-3.65 (2H, m, CH2OH), 3.75-3.85 (1H, m, CH), 3.98-4.15 (6H, m, OCH2P, (OCH2CH3)2), 4.38 (1H, dd, J=6.6 Hz, J=11.3 Hz, NOCHB), 4.54 (1H, dd, J=3 Hz, J=11.3 Hz, NOCHA), 4.88 (1H, t, J=5.5 Hz, D2O exchangeable OH), 7.38 (2H, br.s, D2O exchangeable NH2), 8.15 (1H, s, H-2 or H-8), 8.43 (1H, s, H-2 or H-8). m/z: (FAB+, thioglycerol matrix) 376 (MH+).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=[O:18])=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[CH:8]2.C1C=C(Cl)C=C(C(OO)=[O:27])C=1>C(Cl)Cl>[CH3:1][S:2]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([CH:17]=[O:18])=[C:11]2[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]2)=[O:27]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1c2ccccc2c(C=O)c2ccccc12
Solvent: ClCCl
Product: CS(=O)c1c2ccccc2c(C=O)c2ccccc12
Temperature: 25 °C
Yield: 94 %

Procedure:
A 1 L round bottom flask fitted with addition funnel and stirring bar was charged with 10-methylthio-9-anthracenecarbaldehyde (example 6A, 12.0 g, 48 mmol) and 450 mL of CH2Cl2. The resulting solution was cooled to 5° with an ice bath. A solution of MCPBA (Aldrich (85%), 9.64 g, 48 mmol) in 350 mL of CH2Cl2 was then added dropwise to the flask over 1 h. The reaction mixture was allowed to warm to RT over 1 h and then was washed with 5% NaHCO3 solution (2×500 mL), dried (Na2SO4), filtered, concentrated to 500 mL, and passed through SiO2 (250 g) using PhCH3 (5 L) eluting solvent. The desired material was then eluted from the SiO2 using EtOAc (2 L) as the eluting solvent. The solvent volume was reduced to 100 mL and then diluted to 700 mL with hexane. The resulting yellow solid was filtered and dried at 50° to give 11.98 g (94% of 10-methylsulfinyl-9-anthracenecarbaldehyde mp 182°-184°, (C, H, S).
Reaction SMILES: Cl[C:2]1[CH:14]=[CH:13][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[O:7])=[CH:4][N:3]=1.[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:35])[C:24]2[CH:29]=[CH:28][N:27]=[C:26]([N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[CH:25]=2)=[CH:18][C:17]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:10]1([CH2:9][NH:8][C:6]([C:5]2[CH:13]=[CH:14][C:2]([C:17]3[CH:18]=[C:19]([NH:22][C:23](=[O:35])[C:24]4[CH:29]=[CH:28][N:27]=[C:26]([N:30]5[CH2:31][CH2:32][CH2:33][CH2:34]5)[CH:25]=4)[CH:20]=[CH:21][C:16]=3[CH3:15])=[N:3][CH:4]=2)=[O:7])[CH2:12][CH2:11]1
Reactant: O=C(NCC1CC1)c1ccc(Cl)nc1
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCCC3)c2)cc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2ccnc(N3CCCC3)c2)cc1-c1ccc(C(=O)NCC2CC2)cn1
Yield: 59.3 %

Procedure:
6-Chloro-N-cyclopropylmethylnicotinamide (Intermediate 1) (25 mg, 0.098 mmol) and N-[4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-2-pyrrolidin-1-yl-isonicotinamide (Intermediate 18) (30 mg, 0.074 mmol), aqueous sodium carbonate (2N, 0.5 ml) and tetrakis(triphenylphosphine)palladium (4 mg) were heated at 80° C. in DMF (1 ml) for 18 hours. The reaction was absorbed onto silica, applied to a bond-elut (10 g, silica) and eluted with an ethylacetate/cyclohexane (0 to 100%), then acetone and methanol. The solvent was evaporated from the product fractions under vacuum and the residue triturated with ether to give N-(3-[5-(cyclopropylmethyl-carbamoyl)-pyridin-2-yl]-4-methyl-phenyl)-2-pyrrolidin-1-yl-isonicotinamide as a white solid (20 mg). LCMS: retention time 2.42 min, MH− 456. NMR: δH [2H6]-DMSO 10.32, (1H, s), 9.09, (1H, s), 8.82, (1H, t), 8.28, (1H, m), 8.19, (1H, m), 7.85, (1H, t), 7.76, (1H, m), 7.64, (1H, m), 7.31, (1H, m), 6.98, (1H, m), 6.88, (1H, s), 3.43, (4H, m), 3.18, (2H, m), 2.31, (3H, s), 1.95, (4H, m), 1.07, (1H, m), 0.45, (2H, m), 0.25, (2H, m).
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:26])[CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)=[CH:6][CH:5]=1.[CH:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(OCC)C.C(OCC)(=O)C>[ClH:1].[ClH:1].[CH2:27]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:26])[CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)=[CH:6][CH:5]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1ccc(NC(=O)CN2CCC(Cc3ccccc3)CC2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=C(CN1CCC(Cc2ccccc2)CC1)Nc1ccc(NCc2ccccc2)cc1

Procedure:
The title compound is prepared from N-(4-amino-phenyl)-2-(4-benzyl-piperidin-1-yl)-acetamide dihydrochloride (Example 174) and benzaldehyde according to the method described in Example 177. Melting Point: 147° C. (dec.) (diethylether-ethyl acetate)
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1.C(Cl)(=O)C([Cl:25])=O>CN(C)C=O.C(Cl)Cl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([Cl:25])=[O:18])=[CH:15][CH:14]=1
Reactant: O=C(O)c1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(OCc2ccc3ccccc3n2)cc1

Procedure:
1.28 g of 4-(quinolin-2-ylmethoxy)benzoic acid, in 4.6 ml of oxalyl chloride and 3 drops of dimethylformamide are combined in 50 ml of methylene chloride. The mixture is refluxed for 30 minutes and then concentrated in vacuo to give 4-(quinolin-2-ylmethoxy)benzoyl chloride.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][O:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]=[CH:26][N:25]=3)=[CH:17][CH:16]=2)(=O)=O)=CC=1.[F-:35].[K+].C1N2CCOCCOCCN(CCOCCOCC2)CCOCCOC1.C1COCC1>O>[F:35][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][O:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]=[CH:26][N:25]=2)=[CH:17][CH:16]=1
Reactant: [F-]
Reactant: Cc1ccc(S(=O)(=O)OCCCCc2ccc(CCOc3ncnc4ccccc34)cc2)cc1
Agent: C1COCCN2CCOCCOCCN(CCO1)CCOCCOCC2
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: FCCCCc1ccc(CCOc2ncnc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-(2-(4-(4-p-toluenesulfonyloxybutyl)phenyl)ethoxy)quinazoline (0.3 g, 0.63 mmol) is added to a solution of potassium fluoride/kryptofix 222 in 5 ml THF (1:1 ratio, 3.15 mmol each). After stirring at room temperature for 15 minutes the solution is then refluxed for 20 minutes. It is then cooled and water is added to it. The solution is then extracted in dichloromethane and washed with water and dried. The crude product is purified by silica gel flash chromatography (ethyl acetate/hexanes) to afford the product.
Reaction SMILES: CCO.C([Cl:7])(=O)C.[CH3:8][C:9]([C:12]1[O:16][C:15]([CH2:17][S:18][C:19]2[S:23][C:22]([NH:24][C:25]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[O:26])=[N:21][CH:20]=2)=[N:14][CH:13]=1)([CH3:11])[CH3:10]>O>[ClH:7].[CH3:11][C:9]([C:12]1[O:16][C:15]([CH2:17][S:18][C:19]2[S:23][C:22]([NH:24][C:25]([CH:27]3[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]3)=[O:26])=[N:21][CH:20]=2)=[N:14][CH:13]=1)([CH3:8])[CH3:10]
Reactant: CC(=O)Cl
Agent: CC(C)(C)c1cnc(CSc2cnc(NC(=O)C3CCNCC3)s2)o1
Solvent: CCO
Solvent: O
Product: Cl
Temperature: 25 °C

Procedure:
To a solution of 40 mL of absolute EtOH cooled in an ice-bath was added acetyl chloride (0.28 mL, 3.9 mmol) dropwise. The reaction mixture was allowed to warm to room temperature over 30 min then N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]-thio]-2-thiazolyl]-4-piperidinecarboxamide (1.50 g, 3.94 mmol, 1 eq) was introduced in one portion with stirring to give a thick slurry. Water (˜4 mL) was added until homogeneous then concentrated in vacuo to give a crude pale yellow solid. The crude material was recrystallized (aq EtOH) to afford the title compound (70%) as a white solid, mp 256-258°.
Reaction SMILES: [S:1]([O:21][CH2:22][CH3:23])([O:3][CH2:4][C:5]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH3:6])=[O:2].[OH2:24]>CC#N.C(Cl)Cl>[S:1]([O:21][CH2:22][CH3:23])([O:3][CH2:4][C:5]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH3:6])(=[O:24])=[O:2]
Reactant: O
Reactant: CCCCCCOC(C)(COS(=O)OCC)OCCCCCC
Solvent: ClCCl
Solvent: CC#N
Product: CCCCCCOC(C)(COS(=O)(=O)OCC)OCCCCCC
Temperature: 23 °C
Reaction time: 5 h
Yield: 91 %

Procedure:
To a solution of sulfite 6 (24.5 g, 69.5 mmol) in MeCN (200 mL), CH2Cl2 (200 mL) and water (300 mL) is added NaIO4 (29.7 g, 139.0 mmol) and RuCl3 (10 mg, 0.05 mmol). The mixture is stirred at 23° C. for 5 hours. The mixture is filtered through Celite and extracted with CH2Cl2 (2×200 mL). The combined organic layers are washed with saturated NaHCO3 (100 mL), brine (100 mL) and dried over anhydrous sodium sulfate. The solvent is removed and the residue is purified by silica gel chromatography (1→10% ethyl acetate/hexane) to give 2,2-bis(hexyloxy)propanyl ethyl sulfate 7 (23.3 g, 91%) as a colorless oil: Rf (15% EtOAc/hexane)=0.41; IR (thin film, cm−1) 2931, 2860, 1737, 1467, 1403, 1380, 1196, 1179, 1012, 925, 858; 1H NMR (600 MHz, CDCl3) δ 4.34 (q, J=7.2 Hz, 2H), 4.09 (s, 2H), 3.43 (ddd, J=9.0, 7.2, 6.6 Hz, 2H), 3.38 (ddd, J=9.0, 7.2, 6.6 Hz, 2H), 1.51 (m, 4H), 1.40 (t, J=7.2 Hz, 3H), 1.37 (s, 3H), 1.34-1.24 (m, 12H), 0.86 (t, J=7.2 Hz, 6H); 13C NMR (150 MHz, CDCl3) δ 98.2, 72.4, 69.7, 60.9, 31.6, 29.8, 25.9, 22.6, 20.8, 14.5, 14.0.
Reaction SMILES: [Cl:1][C:2]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[CH2:6][CH2:5]1)=[O:3].[CH3:17]C1C(C)=CC=CC=1N1CCNCC1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1>ClCCl>[Cl:1][C:2]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:17])[C:11]=2[CH3:16])[CH2:6][CH2:5]1)=[O:3]
Reactant: Cc1ccccc1N1CCN(C(=O)Cl)CC1
Reactant: Cc1cccc(N2CCNCC2)c1C
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cccc(N2CCN(C(=O)Cl)CC2)c1C
Yield: 78 %

Procedure:
1-chlorocarbonyl-4-(2,3-dimethylphenyl)piperazine Compound 40A is prepared according to the procedure described for compound 15A, using the following reactants: 1-(2,3-dimethylphenyl)piperazine (3.94 g, 20.7 mmol); triphosgene (2.05 g, 6.9 mmol); pyridine (1.68 ml, 21 mmol); dichloromethane (150 ml).
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9](O)=[O:10])=[CH:3][CH:2]=1.O=S(Cl)[Cl:20]>>[C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]([Cl:20])=[O:10])=[CH:3][CH:2]=1
Reactant: O=C(O)CCc1ccc(-c2ccccc2)cc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)CCc1ccc(-c2ccccc2)cc1
Temperature: 85 °C
Yield: 101 %

Procedure:
A mixture of 3-(4-biphenylyl)propionic acid (5 g, 22.10 mmol) and SOCl2 (4.03 ml, 55.2 mmol) is refluxed under nitrogen at 85° C. for 1.5 hour. The reaction mixture is concentrated under reduced pressure to give 3-(biphenyl-4-yl)propanoyl chloride (5.46 g). The material is used in the next step without further purification.
Reaction SMILES: C([O:8][C:9](=[O:38])[CH2:10][C@@H:11]([N:24]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH3:37])=[CH:31][CH:30]=2)=[CH:25]1)[C:12]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][CH3:22])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])C1C=CC=CC=1>CO.CCOC(C)=O>[CH3:18][C:16]([CH3:17])([CH3:19])[C@H:15]([NH:14][C:12](=[O:13])[C@H:11]([N:24]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH3:37])=[CH:31][CH:30]=2)=[CH:25]1)[CH2:10][C:9]([OH:38])=[O:8])[C:20](=[O:23])[NH:21][CH3:22]
Reactant: CCCc1ccc(-c2ccn([C@H](CC(=O)OCc3ccccc3)C(=O)N[C@H](C(=O)NC)C(C)(C)C)c2)cc1
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCc1ccc(-c2ccn([C@H](CC(=O)O)C(=O)N[C@H](C(=O)NC)C(C)(C)C)c2)cc1
Yield: 91 %

Procedure:
According to the procedure described in Example 1(a), N-[2,2-dimethyl-1(S)-(methylcarbamoyl)propyl]-3(R)-[3-(4-propylphenyl)-1H-pyrrol-1-yl]succinamic acid benzyl ester in MeOH and EtOAc was hydrogenolyzed to provide 30 mg(91%) of N-[2,2-dimethyl-1(S)-(methylcarbamoyl)propyl]-3(R)-[3-(4-propylphenyl)-1H-pyrrol-1-yl]succinamic acid as a yellow powder, mp 104-6° C. 1H NMR (CD3OD): ∂ 7.95 (bs, 1H), 7.60 (bs, 1H), 7.48 (d, 2H, J=7.5 Hz), 7.16 (bs, 1H), 7.08 (d, 2H, J=7.5 Hz), 6.86 (bs, 1H), 6.42 (bs, 1H), 5.34 (t, 1H, J=7.0 Hz), 4.15 (bd, 1H, J=5.9 Hz), 2.83 (dd, 1H, J=6.2, 16.0 Hz), 2.62 (s, 3H), 2.60-2.50 (m, 2H), 1.7-1.58 (m, 2H), 0.95 (s, 9H). IR (KBr): 3300, 2960, 1642, 1560, 1195, 775 cm−1. HRFABMS: Calculated for C24H33N3O4Cs (M+Cs+): 560.1525. Found: 560.1509. Anal. Calculated for C24H33N3O4.0.3 EtOAc: C, 66.67; H, 7.86; N, 9.26. Found: C, 66.93; H, 7.78; N, 8.89.
Reaction SMILES: O=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]2[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:4]=2[NH:3]1.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:2]1=[N:3][C:4]2[CH:16]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=[CH:13][C:5]=2[O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]1=2
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc2c(c1)NC(=O)c1ccccc1O2
Product: COC(=O)c1ccc2c(c1)N=C(Cl)c1ccccc1O2
Temperature: 100 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
Compound 548 (1.00 g, 3.71 mmol)) was suspended in POCl3 (20 mL). The reaction mixture was stirred at 100° C. for 3 h. POCl3 was removed on rotovap. The crude product was dissolved in ethyl acetate and washed with 2M Na2CO3 solution then with NaHCO3 saturated solution and finally with brine. The organic layer was separated and dried with Na2SO4, filtered and concentrated via rotary evaporation to afford compound 549 (1.069 g, 100%) as a orange solid that was taken on without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[C:5]([CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:6].C([NH:24][C@H:25]([CH:29]=O)[CH:26]([CH3:28])[CH3:27])(OC(C)(C)C)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[NH2:24][CH:25]([CH:26]([CH3:28])[CH3:27])[CH2:29][N:10]1[CH2:9][CH2:8][CH:7]([C:5]([C:4]2[CH:13]=[CH:14][C:15]([Cl:16])=[C:2]([Cl:1])[CH:3]=2)=[O:6])[CH2:12][CH2:11]1
Reactant: CC(C)[C@@H](C=O)NC(=O)OC(C)(C)C
Reactant: O=C(c1ccc(Cl)c(Cl)c1)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)C(N)CN1CCC(C(=O)c2ccc(Cl)c(Cl)c2)CC1
Reaction time: 24 h
Yield: 86.3 %

Procedure:
A mixture of 4-(3,4-dichlorobenzoyl)piperidine (1.28 g, 4.96 mmol) (see., Boswell et. al., J. Med. Chem., 21, 136, (1977)) and DL-N-BOC-Valinal (1.33 g, 6.6 mmol) (see., Stanfield et. al., J. Org. Chem., 46(23), 4797, (1981)) in dichloromethane (150 mL) was treated with sodium triacetoxyborohydride (1.36 g, 6.4 mmol). The reaction mixture was stirred under nitrogen for 1 day, then directly purified by filtration through a pad of silica gel by elution with hexanes and ethyl acetate. The organics were removed and the resultant oil (2.1 g) was dissolved in dichloromethane (22 mL) and treated with trifluoroacetic acid (8 mL). After stirring under nitrogen for 1 h, the solvent was removed in vacuo. The residue was treated with aqueous sodium bicarbonate until basic and the product was extracted into chloroform. The organic layer was dried with magnesium sulfate, filtered and concentrated to give [1-(2-amino-3-methylbutyl)piperidin-4-yl]-(3,4-dichlorophenyl)methanone (1.47 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([C:10]2[NH:14][CH:13]=[C:12]([S:15](Cl)(=[O:17])=[O:16])[CH:11]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:19]([NH:26][S:15]([C:12]1[CH:11]=[C:10]([C:8]([C:7]2[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=2)=[O:9])[NH:14][CH:13]=1)(=[O:17])=[O:16])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(c1cc(S(=O)(=O)Cl)c[nH]1)c1cccnc1Cl
Reactant: NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1cc(S(=O)(=O)NCc2ccccc2)c[nH]1)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 5-(2-chloro-pyridine-3-carbonyl)-1H-pyrrole-3-sulfonyl chloride (500 mg, 1.64 mmol) (from Example 17), benzylamine (351.5 mg, 3.28 mmol) and triethylamine (1 mL) in DCM (5 mL) was stirred at room temperature for 4 hours. The reaction was diluted with DCM, washed with water, dried and concentrated. The residue was purified on a silica gel column to give 5-(2-chloro-pyridine-3-carbonyl)1H-pyrrole-3-sulfonic acid benzylamide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])/[CH:4]=[CH:5]\[C:6]([OH:8])=[O:7].[NH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:9])[CH2:4][C@@H:5]([C:6]([OH:8])=[O:7])[NH:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COC(=O)/C=C\C(=O)O
Reactant: NCCCN1CCCCC1
Solvent: CCN(CC)CC
Product: COC(=O)C[C@H](NCCCN1CCCCC1)C(=O)O

Procedure:
In a manner analogous to that described in Example 1, 28.6 g (0.2 mol+10% excess) of maleic acid-monomethyl ester, 40 ml of triethylamine and 88.4 g (0.2 mol) of N-(3'-aminopropyl)-piperidine are reacted and the reaction product is purified. The yield is 36.7 g (67.4% of theory) and the melting point of the product obtained is 172°-173° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][S:8]([CH3:11])(=[O:10])=[O:9])(=O)=O.[NH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:32])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)=[CH:18][C:17]=1[C:33]1[N:37]([CH3:38])[N:36]=[CH:35][CH:34]=1>CN(C=O)C>[CH3:11][S:8]([CH2:7][CH2:6][NH:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:32])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)=[CH:18][C:17]=1[C:33]1[N:37]([CH3:38])[N:36]=[CH:35][CH:34]=1)(=[O:10])=[O:9]
Reactant: CS(=O)(=O)CCOS(C)(=O)=O
Reactant: COc1cccc(C(=O)Nc2ccc(OCCN)c(-c3ccnn3C)c2)c1
Solvent: CN(C)C=O
Product: COc1cccc(C(=O)Nc2ccc(OCCNCCS(C)(=O)=O)c(-c3ccnn3C)c2)c1
Temperature: 150 °C
Yield: 18.5 %

Procedure:
A mixture of 2-(methylsulfonyl)ethyl methanesulfonate (16.6 mg, 81.9 μmol) and N-(4-(2-aminoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-methoxybenzamide (30 mg, 81.9 μmol) in DMF was heated to 150° C. for 1 hour under microwave irradiation in a heavy-walled sealed tube. The crude product was purified by HPLC. The proper fractions were collected and lyophilized to afford the title compound as a yellow solid in 18.5% yield. LCMS m/z (%)=473 (M+H, 100).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CN1CCCC1.C(N(C(C)C)CC)(C)C>CCOC(C)=O>[N+:10]([C:7]1[CH:8]=[CH:9][C:2]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:3]([CH:6]=1)[C:4]#[N:5])([O-:12])=[O:11]
Reactant: Nc1ccccc1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Agent: CN1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: N#Cc1cc([N+](=O)[O-])ccc1Nc1ccccc1
Yield: 88 %

Procedure:
2-Chloro-5-nitrobenzonitrile (Aldrich) (3.64 grams (hereinafter “g”), 20 millimoles (hereinafter “mmol”), aniline (2 milliliter (hereinafter “mL”), 22 mmol), N-methylpyrollidine (10 mL) and diisopropylethylamine (4 mL) were combined and heated to 120° under Ar for 18 hours (hereinafter “h”), cooled, poured into EtOAc (150 mL), washed with H2O (3×50 mL) and saturated aqueous (hereinafter “satd. aq.) NaCl (50 mL), dried (Na2SO4), concentrated, and the residue was triturated with hexane, filtered and the solid was washed with hexane and dried in vacuo to afford 4.23 g (88%) of the title compound as a light green solid. 1H NMR (400) MHz, δ: 8.45 (finely split doublet, 1), 8.19 (dd, 1), 7.48 (m,3), 7.28 (d,2), 7.06 (d, 1), 6.96 (br s,1).