Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:41][C:42]3[CH:47]=[C:46]([CH3:48])[C:45]([OH:49])=[C:44]([CH3:50])[CH:43]=3)[C:19]([N:21]3[CH2:26][CH2:25][N:24]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:51]=[CH:52][CH:53]=[CH:54][C:4]=2[NH:3]1.[Li+].[OH-]>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:41][C:42]3[CH:47]=[C:46]([CH3:48])[C:45]([OH:49])=[C:44]([CH3:50])[CH:43]=3)[C:19]([N:21]3[CH2:26][CH2:25][N:24]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37])[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:51]=[CH:52][CH:53]=[CH:54][C:4]=2[NH:3]1
Reactant: CCOC(=O)CCCN1CCC(N2CCN(C(=O)[C@@H](Cc3cc(C)c(O)c(C)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Agent: [Li+]
Agent: [OH-]
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCN(CCCC(=O)O)CC3)CC2)cc(C)c1O

Procedure:
Prepared analogously to Example 8.1 from 50 mg (0.07 mmol) (R)-2-{4-[1-(3-ethoxycarbonyl-propyl)-piperidin-4-yl]-piperazin-1-yl}-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 2.6 mg (0.11 mmol) LiOH.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[C:6](=[O:16])[NH:5]2.[CH3:17][O:18][C:19]([C:21]1(OC)[CH2:25][CH2:24][CH:23](OC)O1)=[O:20].C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:17][O:18][C:19]([C:21]1[N:1]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[C:6](=[O:16])[NH:5]3)[CH:23]=[CH:24][CH:25]=1)=[O:20]
Reactant: COC(=O)C1(OC)CCC(OC)O1
Reactant: Nc1cc2[nH]c(=O)c(=O)[nH]c2cc1[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1cccn1-c1cc2[nH]c(=O)c(=O)[nH]c2cc1[N+](=O)[O-]

Procedure:
7 g (27.1 mmol) of 6-amino-7-nitro-2,3(1H,4H)-quinoxalinedione, 5.1 g (27.1mmol) of 2-methoxycarbonyl-2,5-dimethoxytetrahydrofuran and 4.5 g (54.2 mmol) of sodium acetate in 500 ml of glacial acetic acid were refluxed for one hour. The reaction mixture was concentrated and then the crude product was purified by column chromatography on silica gel (mobile phase: toluene/acetone/glacial acetic acid=10/10/1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH:4]([NH:20]C(OC(C)(C)C)=O)[CH2:5][S:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)=O.FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][O:2][C:3]([CH:4]1[CH2:5][S:6][CH2:7][CH:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=2)[NH:20]1)=[O:28]
Reactant: COC(=O)C(CSCC(=O)c1ccc(OC)c(OC)c1)NC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1CSCC(c2ccc(OC)c(OC)c2)N1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To an ice chilled solution of 2-tert-butoxycarbonylamino-3-[2-(3,4-dimethoxy-phenyl)-2-oxo-ethylsulfanyl]-propionic acid methyl ester (2.00 g, 9.34 mmol, 1.0 equivalents) in dichloromethane (9 ml) was added trifluoroacetic acid (9 ml). The reaction solution was stirred on ice for 4 hours. The solution was concentrated, coevaporated with toluene. The residue was dissolved in dichloromethane (30 ml) and chilled on ice. To this was added sodium triacetoxyborohydride (2.97 g, 14.02 mmol, 1.5 equivalents) followed by dichloromethane (7 ml). The reaction was stirred 18 hours at room temperature. Saturated sodium bicarbonate was added, and the reaction mixture was extracted with dichloromethane. The dichloromethane extracts were dried with MgSO4, filtered and concentrated. 5-(3,4-Dimethoxy-phenyl)-thiomorpholine-3-carboxylic acid methyl ester was obtained as an oil (1.63 g, 59% yield). Analysis H1 NMR (400 MHz, CDCl3): 6.92 (2H, m), 6.83 (1H, d), 3.95 (3H, s), 3.93 (3H, s), 3.87 (2H, m), 3.85 (3H, s), 2.77 (3H, m), 2.42 (1H, m). MS (LC-MC): Calculated for C14H19NO4S 297.10, found 298.17.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:15])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:7]=1[CH3:8].Cl[C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][CH:18]=1>CN(C1C=CN=CC=1)C.ClC1C=CC=CC=1Cl>[CH3:1][C:2]1[CH:3]=[C:4]([O:15][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=3)[N:20]=[CH:19][CH:18]=2)[C:5]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[N:6][C:7]=1[CH3:8]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Cc1cc(O)c(-c2ccccc2)nc1C
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cc(C)c(C)nc3-c3ccccc3)c2cc1OC
Temperature: 140 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
1,2-Dichlorobenzene (4.5 ml) was added to 5,6-dimethyl-2-phenyl-pyridin-3-ol (267 mg), 4-chloro-6,7-dimethoxyquinoline (100 mg), and 4-(N,N-dimethylamino)pyridine (164 mg), and the mixture was stirred at 140° C. for 8 hr. The reaction solution was cooled to room temperature, and the solvent was then removed by distillation under the reduced pressure. Water was added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using hexane-acetone to give the title compound (159 mg, yield 92%).
Reaction SMILES: N(C(OC(C)(C)C)=O)CC(NCC(NCC(N[C@H](C(O)=O)CC1C=CC=CC=1)=O)=O)=O.ON1C(=O)CCC1=O.C1CCC(N=C=NC2CCCCC2)CC1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OC(=O)CCCCN)C1C=CC=CC=1.[NH:81]([C:119]([O:121][C:122]([CH3:125])([CH3:124])[CH3:123])=[O:120])[CH2:82][C:83]([NH:85][CH2:86][C:87]([NH:89][CH2:90][C:91]([NH:93][C@H:94]([C:102]([NH:104][CH2:105][CH2:106][CH2:107][CH2:108][C:109]([O:111]CC1C=CC=CC=1)=[O:110])=[O:103])[CH2:95][C:96]1[CH:101]=[CH:100][CH:99]=[CH:98][CH:97]=1)=[O:92])=[O:88])=[O:84]>CN(C=O)C.CO.O.[Pd].C(N(CC)CC)C>[NH:81]([C:119]([O:121][C:122]([CH3:125])([CH3:124])[CH3:123])=[O:120])[CH2:82][C:83]([NH:85][CH2:86][C:87]([NH:89][CH2:90][C:91]([NH:93][C@H:94]([C:102]([NH:104][CH2:105][CH2:106][CH2:107][CH2:108][C:109]([OH:111])=[O:110])=[O:103])[CH2:95][C:96]1[CH:101]=[CH:100][CH:99]=[CH:98][CH:97]=1)=[O:92])=[O:88])=[O:84]
Reactant: CC(C)(C)OC(=O)NCC(=O)NCC(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NCCCCC(=O)OCc1ccccc1
Agent: [Pd]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)(C)OC(=O)NCC(=O)NCC(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCC(=O)NCC(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NCCCCC(=O)O
Reaction time: 0.5 h

Procedure:
Boc-Gly-Gly-Gly-Phe-OH (575 mg) (SEQ ID NO. 8), HOSu (182 mg), and DCC (326 mg) were dissolved in DMF (20 ml), and the mixture was stirred for 30 minutes. The solution was added with a solution of p-toluenesulfonic acid salt of 5-aminopentanoic acid benzyl ester (500 mg) and triethylamine (0.184 ml) dissolved in DMF (10 ml), and the mixture was stirred for 3 days at room temperature. The reaction mixture was concentrated, and the residue was purified by column chromatography (CH2Cl2:MeOH=20:1) to obtain 380 mg of Boc-Gly-Gly-Gly-Phe-NH—(CH2)4—COOBzl (Bzl represents benzyl group) (SEQ ID NO. 8). The Boc-Gly-Gly-Gly-Phe-NH—(CH2)4—COOBzl (SEQ ID NO. 8) (380 mg) was dissolved in methanol containing 50% of water (20 ml), and the solution was added with 5% Pd—C (water content; 50%, 300 mg) and stirred overnight under hydrogen at ordinary pressure. The catalyst in the reaction mixture was removed by filtration, and the filtrate was concentrated to dryness to obtain Boc-Gly-Gly-Gly-Phe-NH—(CH2)4—COOH (SEQ ID NO. 8) (330 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH:12]2[CH2:17][CH2:16][N:15]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:24][S:25]([C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=1)(=[O:27])=[O:26]>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH:12]2[CH2:13][CH2:14][N:15]([CH:18]3[CH2:23][CH2:22][N:21]([C:32]([C:31]4[CH:30]=[CH:29][C:28]([S:25]([CH3:24])(=[O:27])=[O:26])=[CH:36][CH:35]=4)=[O:33])[CH2:20][CH2:19]3)[CH2:16][CH2:17]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=S(=O)(c1ccc(Cl)c(Cl)c1)C1CCN(C2CCNCC2)CC1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Product: CS(=O)(=O)c1ccc(C(=O)N2CCC(N3CCC(S(=O)(=O)c4ccc(Cl)c(Cl)c4)CC3)CC2)cc1

Procedure:
The product of step 5 was coupled to 4-methanesulfonyl-benzoic acid following the procedure of Example 2 step c.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([NH:33][C:34](=O)[CH2:35][O:36][C:37]3[CH:42]=[CH:41][C:40]([CH2:43][CH:44]4[S:48][C:47](=[O:49])[NH:46][C:45]4=[O:50])=[CH:39][CH:38]=3)=[C:22]([N:24](C)[C:25](=O)OC(C)(C)C)[CH:23]=2)=[CH:11][CH:10]=1)=O)(C)(C)C>FC(F)(F)C(O)=O>[NH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]3[N:33]=[C:34]([CH2:35][O:36][C:37]4[CH:42]=[CH:41][C:40]([CH2:43][CH:44]5[S:48][C:47](=[O:49])[NH:46][C:45]5=[O:50])=[CH:39][CH:38]=4)[N:24]([CH3:25])[C:22]=3[CH:23]=2)=[CH:13][CH:14]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(OCCc2ccc(NC(=O)OC(C)(C)C)cc2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(OCCc3ccc(N)cc3)cc21
Yield: 72.5 %

Procedure:
A solution of t-butyl N-[5-[2-(4-t-butoxycarbonylaminophenyl)ethoxy]-2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]phenyl]-N-methylcarbamate (18.2 g) in trifluoroacetic acid (100 ml) was stirred at 70° C. for 3.5 hours. The reaction mixture was concentrated, diluted with water, neutralized with sodium bicarbonate and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated. The residue was chromatographed on a silica gel column using ethyl acetate as the eluant to afford the desired compound (9.2 g, mp 184-188° C.).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.O=[CH:16][CH2:17][O:18][C:19]1[CH:32]=[CH:31][C:22]([CH2:23][CH:24]2[S:28][C:27](=[O:29])[NH:26][C:25]2=[O:30])=[CH:21][CH:20]=1.II.C(O)C>COCCOC.C(O)(=O)C>[C:9]1([N:8]2[C:3]3=[N:4][CH:5]=[CH:6][CH:7]=[C:2]3[N:1]=[C:16]2[CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:23][CH:24]3[S:28][C:27](=[O:29])[NH:26][C:25]3=[O:30])=[CH:31][CH:32]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=CCOc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: Nc1cccnc1Nc1ccccc1
Agent: II
Solvent: CC(=O)O
Solvent: COCCOC
Solvent: CCO
Product: O=C1NC(=O)C(Cc2ccc(OCc3nc4cccnc4n3-c3ccccc3)cc2)S1
Yield: 6.2 %

Procedure:
A procedure similar to that described in Example 18 was repeated, except that 2.78 g of 3-amino-2-phenylaminopyridine (prepared as described in Preparation 84), 3.98 g of 5-[4-(2-oxoethoxy)benzyl)thiazolidine-2,4-dione (prepared as described in Preparation 47), 4.9 g of iodine, 6 ml of ethanol, 6 ml of acetic acid and 50 ml of 1,2-dimethoxyethane were used. After working up the product as described in Example 18, the resulting crude product was purified by column chromatography through silica gel, using a 1:2 by volume mixture of hexane and ethyl acetate as the eluent, to give 400 mg of the title compound, melting at 88-91° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][C:5]=1[NH:15][C:16](=[O:23])[O:17][CH2:18][CH:19]1[CH2:22][NH:21][CH2:20]1)([O-:3])=[O:2].[C:24](OC(=O)C)(=[O:26])[CH3:25]>ClCCl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][C:5]=1[NH:15][C:16](=[O:23])[O:17][CH2:18][CH:19]1[CH2:20][N:21]([C:24](=[O:26])[CH3:25])[CH2:22]1)([O-:3])=[O:2]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(Nc1cc(-c2cccs2)ccc1[N+](=O)[O-])OCC1CNC1
Solvent: ClCCl
Product: CC(=O)N1CC(COC(=O)Nc2cc(-c3cccs3)ccc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.6 %

Procedure:
To a solution of azetidin-3-ylmethyl (2-nitro-5-(thiophen-2-yl)phenyl)carbamate (0.35 g, 1.05 mmol, 1 eq.) in dichloromethane (10 mL) was added TEA (0.22 mL, 1.57 mmol, 1.5 eq.) and acetic anhydride (0.11 mL, 1.15 mmol, 1.1 eq.) at 0° C. The reaction was warmed to room temperature and stirred for 1 h. The reaction was diluted with dichloromethane. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 4% MeOH/CH2Cl2) to obtain (1-acetylazetidin-3-yl)methyl (2-nitro-5-(thiophen-2-yl)phenyl)carbamate (0.31 g, 79% yield).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][N:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2.Cl.[NH2:21][OH:22].C[O-].[Na+].CO.C([O-])(O)=O.[Na+]>CN(C=O)C.C(OCC)(=O)C.O>[CH:17]1[C:18]2[N:6]([CH2:5][CH2:4][C:3]([NH:21][OH:22])=[O:2])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13]=2[CH:14]=[CH:15][CH:16]=1
Reactant: COC(=O)CCn1c2ccccc2c2ccccc21
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(CCn1c2ccccc2c2ccccc21)NO
Temperature: 25 °C
Reaction time: 24 h
Yield: 46.7 %

Procedure:
3-Carbazol-9-yl-propionic acid methyl ester (22) (0.50 g, 1.97 mmol) and hydroxylamine hydrochloride (0.82 g, 12 mmol) were placed under argon and dissolved in DMF (8 mL). To it was added a 25% sodium methoxide solution in methanol (3.4 g, 16 mmol) which resulted in immediate precipitation of a white solid. The reaction was stirred for 24 h at room temperature after which was taken up in ethyl acetate (20 mL), water (10 mL) and of saturated aqueous NaHCO3 (10 mL). The organic layer was isolated and the aqueous layer was further extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine (10 mL), dried (Na2SO4) and concentrated in vacuo. The crude extract was purified by HPLC to yield the title compound (234 mg, 47%) as a white solid. 1H NMR (400 MHz, DMSO): δ 10.46 (s, 1H), 8.75 (s, 1H), 8.14 (d, 2H, J=7.7 Hz), 7.60 (d, 2H, J=8.0 Hz), 7.45 (t, 2H, J=7.2 Hz), 7.20 (t, 2H, J=7.6 Hz), 4.61 (t, 2H, J=6.8 Hz), 2.48 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 169.2, 140.2, 126.2, 122.6, 120.6, 119.3, 109.8, 39.3, 32.3. ESI-MS (m/z): [M+H]+ 254.1. Analytical HPLC: Purity=97%, tR=5.62 min, Method A.
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[N:9]1([S:14]([N:17]2[CH:21]=[CH:20][N+](C)=[CH:18]2)(=[O:16])=[O:15])[CH:13]=[CH:12][N:11]=[CH:10]1.CN[C:25]1[CH:30]=CC=[CH:27][CH:26]=1>CC#N>[CH3:18][N:17]([C:21]1[CH:20]=[CH:27][CH:26]=[CH:25][CH:30]=1)[S:14]([N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1)(=[O:15])=[O:16]
Reactant: C[n+]1ccn(S(=O)(=O)n2ccnc2)c1
Reactant: CNc1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CC#N
Product: CN(c1ccccc1)S(=O)(=O)n1ccnc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-(1H-imidazol-1-ylsulfonyl)-3-methyl-1H-imidazol-3-ium trifluoromethanesulfonate (3 g, 8.3 mmol) in dry CH3CN (dried over MgSO4) was added N-methylaniline (740 mg, 6.9 mmol) under nitrogen. The mixture was stirred at room temperature for 16 h. After the solvent was removed, the residue was extracted with EtOAc (50 mL×3). The organic layer was washed with brine (50 mL) and water (50 mL). After the solvent was removed, the residue was purified by column chromatography (eluting with 30˜60% EtOAc) to give the title compound, which was used in next step without further purification (1 g, 51%). LCMS (ESI): m/z 237.9 [M+H+].
Reaction SMILES: [CH:1]1([N:7]([CH3:17])[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:28][CH2:29][CH3:30])(=[O:27])=[O:26])=[CH:21][CH:20]=1>CO>[CH:1]1([N:7]([CH3:17])[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([S:25]([NH:28][CH2:29][CH3:30])(=[O:27])=[O:26])=[CH:21][CH:20]=3)=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(c1cc(C(=O)O)ncn1)C1CCCCC1
Reactant: CCNS(=O)(=O)c1ccc(N)cc1
Solvent: CO
Product: CCNS(=O)(=O)c1ccc(NC(=O)c2cc(N(C)C3CCCCC3)ncn2)cc1

Procedure:
Following the general method as outlined in Example 1, starting from 6-[cyclohexyl(methyl)amino]pyrimidine-4-carboxylic acid (Intermediate 10) and 4-amino-N-ethyl-benzenesulfonamide (Oakwood), the title compound was obtained as a white solid after trituration in methanol.
Reaction SMILES: Br[Zn][CH2:3][CH2:4][CH2:5][C:6]#[N:7].Cl[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:29])[C:15]=2[NH:19][C:20](=[O:28])[CH2:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[N:10]=1>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.[Cl-].[NH4+]>[Cl:29][C:14]1[C:15]([NH:19][C:20](=[O:28])[CH2:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH2:3][CH2:4][CH2:5][C:6]#[N:7])[CH:18]=[CH:17]2
Reactant: N#CCCC[Zn]Br
Reactant: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(Cl)ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Product: N#CCCCc1ccc2c(NC(=O)CC3CCCCC3)c(Cl)ccc2n1
Temperature: 25 °C

Procedure:
Bromo(3-cyanopropyl)-zinc (30 mL, 0.5 M in tetrahydrofuran) and tetrakis(triphenylphosphine)palladium(0) (86 mg) were added to N-(2,6-dichloro-5-quinolinyl)-cyclohexaneacetamide (Example 1(a)) (500 mg). The reaction mixture was heated to reflux for 30 minutes. The mixture was cooled to room temperature and then poured into aqueous saturated ammonium chloride solution (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried, filtered and evaporated. Purification (SiO2, methanol:dichloromethane 3:97 as eluant) gave the sub-title compound as a solid (490 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].[CH2:32]([C:34]1[CH:35]=[C:36]([OH:40])[CH:37]=[CH:38][CH:39]=1)[CH3:33].C([O-])([O-])=O.[K+].[K+].[I-].[Na+]>CS(C)=O>[CH2:32]([C:34]1[CH:35]=[C:36]([O:40][CH2:2][CH2:3][CH2:4][S:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[C:22]4[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH:21]=4)[NH:16][CH:15]=3)[CH2:10][CH2:9]2)(=[O:7])=[O:6])[CH:37]=[CH:38][CH:39]=1)[CH3:33]
Reactant: CCc1cccc(O)c1
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCc1cccc(OCCCS(=O)(=O)N2CCC(c3c[nH]c4c(C(N)=O)cc(-c5ccccc5)cc34)CC2)c1
Temperature: 80 °C
Yield: 18.3 %

Procedure:
To a solution of 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-phenyl-1H-indole-7-carboxamide (23.0 mg, 0.05 mmol) in DMSO (1.0 mL), were added 3-ethylphenol (122.0 mg, 0.5 mmol), K2CO3 (35.0 mg, 0.25 mmol) and sodium iodide (1.0 mg). The reaction solution was heated to 80° C. overnight. After which time the reaction mixture was filtered and purified by reverse phase HPLC (water/CH3CN, 0.1% TFA 10-90%) to give the title compound (5 mg, 18%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].Cl[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=1>>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[C:5]#[N:6])=[N:12][CH:13]=1
Reactant: N#Cc1cccc(O)c1
Reactant: Clc1ccc(Cl)nc1
Product: N#Cc1cccc(Oc2ccc(Cl)cn2)c1

Procedure:
3-Hydroxy-benzonitrile was reacted with 2,5-dichloro-pyridine according to the method of Example 78A to provide the title compound. MS (DCI/NH3) m/z 231 (M)+, 233 (M+2)+.
Reaction SMILES: I[C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)=[C:4]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[CH:3]=1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=[NH:98])(C1C=CC=CC=1)C1C=CC=CC=1.Cl.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:98][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)=[C:4]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[CH:3]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: Cc1ccccc1-c1cc(I)ncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: Cc1ccccc1-c1cc(N)ncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 150 °C
Reaction time: 0.17 h
Yield: 34.1 %

Procedure:
N-(6-Iodo-4-o-tolylpyridin-3-yl)-N-methyl-3,5-bis(trifluoromethyl)benzamide (60 mg, 0.11 mmol), sodium tert-butoxide (31 mg, 0.32 mmol), palladium acetate (2.4 mg, 0.011 mmol, CAS RN 3375-31-3) and BINAP (19.9 mg; 0.032 mmol, CAS RN 76189-55-4) were dissolved in toluene (4 mL) and stirred under an argon atmosphere for 10 min. Benzophenone imine (38 mg, 0.21 mmol, CAS RN 1013-88-3) was added and the reaction mixture was sealed and heated to 150° C. by microwave irradiation for 30 minutes. The reaction mixture was cooled, unsealed and 200 μL of 1M aqueous HCl was added. After stirring for 1 h, the reaction mixture was neutralized with saturated aqueous NaHCO3 solution and extracted three times with EtOAc. The combined organic layers were washed with brine and dried over MgSO4. Filtration followed by removal of volatiles under reduced pressure afforded a brown solid. Column chromatography on silica gel (50% EtOAc in n-hexane) afforded the title compound as a yellow solid (17 mg, 35%). MS (ESI): m/z=453.9 [M+H]+.
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH2:16]([C:20]1[N:21]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[C:22]([CH2:25][CH2:26]O)=[CH:23][N:24]=1)[CH2:17][CH2:18][CH3:19].C(N(C(C)C)CC)(C)C.[CH3:45][O:46][C:47](=[O:57])[C@H:48]([CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[NH2:49]>C(Cl)Cl>[CH3:45][O:46][C:47](=[O:57])[C@H:48]([CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[NH:49][CH2:26][CH2:25][C:22]1[N:21]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[C:20]([CH2:16][CH2:17][CH2:18][CH3:19])=[N:24][CH:23]=1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: CCCCc1ncc(CCO)n1Cc1ccccc1Cl
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCc1ncc(CCN[C@@H](Cc2ccccc2)C(=O)OC)n1Cc1ccccc1Cl
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 64.6 %

Procedure:
A solution of trifluoromethanesulfonic anhydride (0.954 g, 3.38 mmol) in methylene chloride (5 ml) was cooled to -78° C. under nitrogen, and a solution of 2-n-butyl-1-(2-chlorophenyl)methyl-5-(2-hydroxyethyl)-1H-imidazole (0.9 g, 3.07 mmol), diisopropylethylamine (0.44 g. 3.38 mmol) and methylene chloride (10 ml) was added dropwise. The mixture was stirred at -78° C. for an additional 15 minutes, then a solution of the free base of phenylalanine methyl ester (prepared from 1.33 q (6.15 mmol) of the hydrochloride salt) in methylene chloride (10 ml) was added. This mixture was stirred for 2 hours at -78° C. and an additional 18 hours at ambient temperature. The reaction mixture was washed with water, dried and concentrated and the crude product was flash chromatographed with 5% methanol in ethyl acetate to yield 0.9 g (65%) of N-[2-{1-[(2 chlorophenyl)methyl]-2-n-butyl-1H-imidazol-5-yl}ethyl ]phenylalanine methyl ester.