Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:47])[CH:5]=[C:6]([Cl:46])[C:7]=1[CH2:8][C@H:9]([O:20][C:21]([C@@H:23]1[CH2:27][CH2:26][CH2:25][N:24]1[S:28]([C:31]1[CH:36]=[CH:35][C:34]([CH2:37][NH:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[F:45])=[CH:33][CH:32]=1)(=[O:30])=[O:29])=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1.Cl.[C:49](Cl)(=[O:59])[O:50][C@@H:51]1[CH:56]2[CH2:57][CH2:58][N:53]([CH2:54][CH2:55]2)[CH2:52]1.N1C=CC=CC=1>C(#N)C>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:47])[CH:5]=[C:6]([Cl:46])[C:7]=1[CH2:8][C@H:9]([O:20][C:21]([C@@H:23]1[CH2:27][CH2:26][CH2:25][N:24]1[S:28]([C:31]1[CH:36]=[CH:35][C:34]([CH2:37][N:38]([C:49]([O:50][C@@H:51]2[CH:56]3[CH2:57][CH2:58][N:53]([CH2:54][CH2:55]3)[CH2:52]2)=[O:59])[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[F:45])=[CH:33][CH:32]=1)(=[O:29])=[O:30])=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1
Reactant: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)[C@@H]2CCCN2S(=O)(=O)c2ccc(CNc3ccccc3F)cc2)cc1OC
Reactant: O=C(Cl)O[C@H]1CN2CCC1CC2
Agent: Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)[C@@H]2CCCN2S(=O)(=O)c2ccc(CN(C(=O)O[C@H]3CN4CCC3CC4)c3ccccc3F)cc2)cc1OC
Temperature: 80 °C
Yield: 16.3 %

Procedure:
To a stirred solution of [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl](2S)-1-[4-[(2-fluoroanilino)methyl]phenyl]sulfonylpyrrolidine-2-carboxylate (105 mg, 0.15 mmol) in acetonitrile (3.2 mL) was added (R)-quinuclidin-3-yl carbonochloridate hydrochloride (131 mg, 0.6 mmol) and pyridine (0.12 mL), and the mixture was heated to 80° C. in a microwave for 6 minutes. Further (R)-quinuclidin-3-yl carbonochloridate hydrochloride (34 mg, 0.15 mmol) was added, and the mixture was heated to 80° C. in a microwave for 6 minutes. The solvent was removed in vacuo and the mixture was partitioned between ethyl acetate (10 mL) and water (10 mL). The layers were separated and the water was removed in vacuo. Purification of the residue from the aqueous layer was achieved by preparative HPLC to afford the title compound as a white solid (21 mg, 16%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C@H:4]([CH2:13][OH:14])[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].N1C=CC=CC=1.[C:22](Cl)([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>C(Cl)Cl>[CH2:25]([O:24][C:22]([O:14][CH2:13][C@H:4]([NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7])[C:3]([O:2][CH3:1])=[O:15])=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)[C@H](CO)NC(=O)OC(C)(C)C
Reactant: O=C(Cl)OCc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@H](COC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.4 %

Procedure:
A solution of N-(tert-butoxycarbonyl)-L-serine methyl ester (25.0 g, 114 mmol) in DCM (570 mL) was cooled to −50° C. Pyridine (23.0 mL, 285 mmol) was added. CBZ-Cl (18.9 mL, 125 mmol) was added dropwise over 1 hour. The reaction mixture was warmed to ambient temperature and stirred overnight. The reaction mixture was then diluted with DCM, washed with 10% citric acid and brine, dried and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (5:1 hexanes/EtOAc) to give (S)-methyl 3-(benzyloxycarbonyloxy)-2-(tert-butoxycarbonylamino)propanoate (36.0 g, 89%).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][O:20][CH2:21][CH2:22][N:23]([CH3:30])[C:24]1[S:25][C:26]([NH2:29])=[CH:27][N:28]=1>>[CH3:19][O:20][CH2:21][CH2:22][N:23]([CH3:30])[C:24]1[S:25][C:26]([NH:29][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:27][N:28]=1
Reactant: COCCN(C)c1ncc(N)s1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Product: COCCN(C)c1ncc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)s1

Procedure:
With a procedure similar to example 16 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {2-[(2-methoxy-ethyl)-methyl-amino]-thiazol-5-yl}-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and N2-(2-methoxy-ethyl)-N2-methyl-thiazole-2,5-diamine. LCMS calcd for C18H17F3N4O3S (m/e) 426, obsd 427 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:13][CH2:12][NH:11][C:10]2=[CH:14][N+:15]([O-:17])=[O:16])=[CH:4][N:3]=1.[CH:18](=[O:24])[CH2:19][CH2:20][CH2:21][CH:22]=O.Cl>C(#N)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][N:9]2[C:10]3=[C:14]([N+:15]([O-:17])=[O:16])[CH:22]4[O:24][CH:18]([N:11]3[CH2:12][CH2:13]2)[CH2:19][CH2:20][CH2:21]4)=[CH:6][CH:7]=1
Reactant: O=CCCCC=O
Reactant: O=[N+]([O-])C=C1NCCN1Cc1ccc(Cl)nc1
Agent: Cl
Solvent: CC#N
Product: O=[N+]([O-])C1=C2N(Cc3ccc(Cl)nc3)CCN2C2CCCC1O2
Temperature: 25 °C
Yield: 86 %

Procedure:
To a 50 ml round bottom flask was added 1.27 g (0.005 mol) 2-chloro-5-((2-(nitromethylene)imidazolidin-1-yl)methyl)pyridine, 30 ml acetonitrile, 3 ml 25% glutaraldehyde aqueous solution and catalytic concentrated HCl. The reaction was stirred at r.t. and monitored by TLC. After completion, the mixture was evaporated to remove solvent and purified by column chromatography to afford final product as faint yellow powder with 86% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([OH:19])=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:23])[C:6]=2[CH:24]=1.CO.N1C=CC=C[CH:28]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([O:19][CH3:28])=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:23])[C:6]=2[CH:24]=1
Reactant: Cc1c(S(=O)(=O)Nc2cccc(C(=O)O)c2)sc2ccc(Br)cc12
Reactant: c1ccncc1
Solvent: CO
Product: COC(=O)c1cccc(NS(=O)(=O)c2sc3ccc(Br)cc3c2C)c1
Yield: 47 %

Procedure:
The product was prepared from 3-{[(5-bromo-3-methyl-1-benzothien-2-yl)sulfonyl]-amino}benzoic acid (20.4 mg, 0.048 mmol) (Example 41) and MeOH (50 μL, 1.23 mmol) according to the General Procedure 8, described in Example 119, using different amounts of pyridine (7.5 μL, 0.092 mmol) and a slightly modified reaction volume (0.80 mL). The title compound was obtained in 47% yield (9.9 mg). 1H NMR (500 MHz, CDCl3) δ ppm 2.44 (s, 3H) 3.87 (s, 3 H) 6.94 (s, 1 H) 7.36 (dd, J=8.10, 7.66 Hz, 1 H) 7.41 (ddd, J=8.10, 2.35, 1.26 Hz, 1 H) 7.57 (dd, J=8.63, 1.86 Hz, 1 H) 7.66 (dd, J=8.63, 0.54 Hz, 1 H) 7.73 (dd, J=2.35, 1.51 Hz, 1 H) 7.84 (ddd, J=7.66, 1.51, 1.26 Hz, 1 H) 7.87 (dd, J=1.86, 0.54 Hz, 1 H). MS (ESI+) m/z 440 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=O)[CH2:4][C:5](OCC)=[O:6].[NH2:13][NH2:14].O.[ClH:16]>C(O)C>[ClH:16].[OH:6][C:5]1[NH:14][N:13]=[C:3]([C:2]([F:12])([F:11])[F:1])[CH:4]=1
Reactant: NN
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: Cl
Solvent: CCO
Solvent: O
Product: Oc1cc(C(F)(F)F)n[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.9 %

Procedure:
Ethyl 4,4,4-trifluoroacetoacetate (18.4 g (0.1 mol)) was dissolved in 20 mL of ethanol. The resulting solution was cooled to 10° C. or less with stirring, and 6.0 g (0.12 mol) of hydrazine was added dropwise thereto over 0.5 hours. After the dropwise addition, the solution was stirred at room temperature for 1 hour and subsequently at the reflux temperature for 5 hours. When the reaction was completed, the reaction solution was cooled to room temperature, and 100 mL of water and 20.6 g (0.2 mol) of 35% hydrochloric acid were added thereto. The produced crystal was collected by filtration, washed twice with 10 mL of water and dried by a hot air drier to obtain 12.8 g (yield: 68.1%) of the title compound as a white crystal.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:11]([CH3:13])[CH3:12])=[N:5][NH:6]2.[BH:14]([OH:16])[OH:15]>>[CH:11]([C:4]1[C:3]2[C:2]([B:14]([OH:16])[OH:15])=[CH:10][CH:9]=[CH:8][C:7]=2[NH:6][N:5]=1)([CH3:13])[CH3:12]
Reactant: OBO
Reactant: CC(C)c1n[nH]c2cccc(Br)c12
Product: CC(C)c1n[nH]c2cccc(B(O)O)c12

Procedure:
4-Bromo-3-isopropyl-1H-indazole is converted to the corresponding boronic acid following analogous procedures to that given in the preceding example. 1H NMR (CD3OD) 7.44(d, 1H), 7.32 (t, 1H), 7.05 (d, 1H), 3.56 (m, 1H), 1.38 (d, 6H). LCMS (m/z): 205.45 (MH)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8](Cl)=[N:9][N:10]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].[C:18]1([SH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC#N>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([S:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:9][N:10]=1)=[O:5])[CH3:2]
Reactant: Sc1ccccc1
Reactant: CCOC(=O)c1nnc(Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1nnc(Sc2ccccc2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
To a solution of 5-chloro-[1,3,4]thiadiazole-2-carboxylic acid ethyl ester (1.0 g, 5.2 mmol, 1 eq), and K2CO3 (1.44 g, 104 mmol, 2 eq) in CH3CN (50 mL), thiophenol (0.53 mL, 5.2 mmol, 1 eq) is added. The reaction is stirred overnight at room temperature. The reaction is filtered to remove the salts, and the filtrate is washed with CH3CN. The solvents are removed under reduced pressure, and the product is recrystallized from EtOH to give 5-phenylsulfanyl-[1,3,4]thiadiazole-2-carboxylic acid ethyl ester (1.03 g, 74%). MS (ESD for C11H10N2O2S2 m/z 267.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([OH:9])=[CH:7][CH:6]=[C:5](/[CH:10]=[CH:11]/[C:12]([CH2:14][C:15](/[CH:17]=[CH:18]/[C:19]2[CH:27]=[C:24]([O:25][CH3:26])[C:22]([OH:23])=[CH:21][CH:20]=2)=[O:16])=[O:13])[CH:4]=1.[C:28](O)(=[O:50])/[CH:29]=[CH:30]\[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=[CH:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl.O>[C:28]([O:9][C:8]1[CH:7]=[CH:6][C:5]([CH:10]=[CH:11][C:12](=[O:13])[CH2:14][C:15](=[O:16])[CH:17]=[CH:18][C:19]2[CH:20]=[CH:21][C:22]([OH:23])=[C:24]([O:25][CH3:26])[CH:27]=2)=[CH:4][C:3]=1[O:2][CH3:1])(=[O:50])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=[CH:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49]
Reactant: COc1cc(/C=C/C(=O)CC(=O)/C=C/c2ccc(O)c(OC)c2)ccc1O
Reactant: CCCCCCCCCC=CC=CC=CC=CC=C/C=C\C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCCC=CC=CC=CC=CC=CC=CC(=O)Oc1ccc(C=CC(=O)CC(=O)C=Cc2ccc(O)c(OC)c2)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.5 %

Procedure:
To a solution of curcumin (300 mg, 0.81 mmol), cis-docosahexaenoic acid (275 mg, 0.83 mmol) and catalytic amount of 4-(dimethylamino)pyridine in DCM (10 mL) was added a solution of N,N′-dicyclohexylcarbodiimide (252 mg, 1.2 mmol) in DCM (5 mL) for 5 min at ice cold temperature. The mixture was stirred at rt for 16 h and diluted with water. DCM layer was separated and the aqueous layer was extracted with DCM (3×100 mL). The combined DCM layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and the residue was chromatographed over silica gel column using hexane-ethyl acetate mixture (90:10) as an eluent to give the product as oil (250 mg, 45%). IR (neat) νmax 3015, 2960, 2930, 1761, 1631, 1593, 1269, 1120, 1031, 972 cm−1; 1H NMR (CDCl3) δ 7.61 (1H, d, J=16.0 Hz, H-1), 7.60 (1H, d, J=15.6 Hz, H-7), 7.03-7.16 (5H, m, H-2′, 2″, 5′, 6′, 6″), 6.93 (1H, d, J=8.4 Hz, H-5″), 6.55 (1H, d, J=16 Hz, H-2), 6.49 (1H, d, J=16 Hz, H-6), 5.89 (1H, br s, Ar—OH), 5.83 (1H, s, H-4), 5.38-5.39 (12H, m, H-4′″, 5′″, 7′″, 8′″, 10′″, 11′″, 13′″, 14′″, 16′″, 17′″, 19′″, 20′″), 3.95 (3H, s, Ar—OCH3), 3.87 (3H, s, Ar—OCH3), 2.84-2.86 (10H, m, H-6′″, 9′″, 12′″, 15′″, 18′″), 2.58-2.66 (2H, m, H-2″), 2.22-2.23 (2H, m, H-21″), 2.05-2.09 (2H, m, H-3′″), 0.97 (3H, t, J=7.4 Hz, H-22′″); LCMS (ESI, negative ion mode): m/z 677 (M-H)−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:10][CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>CN(C=O)C.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]([S:19]([C:16]3[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=3)(=[O:21])=[O:20])[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Brc1cnc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3ncc(Br)cc32)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
To a solution of 6-bromo-1H-pyrrolo[3,2-b]pyridine (4.0 g, 20.3 mmol) in DMF (40 mL) at 0° C. was added sodium hydride (893 mg, 22.33 mmol). The reaction mixture was stirred at 0° C. for 30 minutes. Next, p-toluensulfonyl chloride (4.64 g, 24.26 mmol) was added, and the reaction mixture was stirred for 1 hour while warming to RT. The reaction mixture was subsequently diluted with DCM (300 mL) and washed with brine. The combined organic layers were dried over MgSO4, concentrated in vacuo, and purified by silica gel chromatography (1% to 2% MeOH/DCM) to give the title compound as a white solid (6.87 g, 96%). 1H NMR (500 MHz, CDCl3) δ ppm 8.58 (d, 1H, J=2.0 Hz), 8.43 (d, 1H, J=2.0 Hz), 7.74-7.78 (m, 3H), 7.29 (d, 2H, J=8.0 Hz), 6.83 (d, 1H, J=4.0 Hz), 2.38 (s, 3H); ESI-MS m/z [M+H]+ calc'd for C14H11BrN2O2S, 351, 353; found 351, 353.
Reaction SMILES: [C:1]1([P:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:8]2[N:13]=[C:12]([C:14]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH3:15])[CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:34]O>ClCCl>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:14]([C:12]1[N:13]=[C:8]([P:7](=[O:34])([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:9]=[CH:10][CH:11]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)[CH3:15]
Reactant: OO
Reactant: CC(c1ccccn1)(c1ccccn1)c1cccc(P(c2ccccc2)c2ccccc2)n1
Solvent: ClCCl
Product: CC(c1ccccn1)(c1ccccn1)c1cccc(P(=O)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6.7 g of 2,2′-(1-(6-(diphenylphosphino)pyridin-2-yl)ethane-1,1-diyl)dipyridine were dissolved in 25 ml of dichloromethane and ice-bath cooled. 1.8 ml of hydrogen peroxide (35 wt % in water) were added drop wise and the mixture was stirred overnight at room temperature. The reaction was quenched with 20 ml of saturated ammonium chloride solution and the aqueous layer was extracted three times with dichloromethane. The combined organic layers were washed with brine and dried with magnesium sulphate. The solvent was removed under reduced pressure until the residue starts to foam. The residue crystallised from diethyl ether. After drying in high vacuum 5.1 g (74%) of an off-white solid were obtained. The compound was further purified by gradient sublimation.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][O:12][CH2:13][C:14](Cl)=[O:15]>N1C=CC=CC=1>[CH3:11][O:12][CH2:13][C:14]([NH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1)=[O:15]
Reactant: Nc1nc2ccccc2s1
Reactant: COCC(=O)Cl
Solvent: c1ccncc1
Product: COCC(=O)Nc1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Aminobenzothiazole (4.5 g) is dissolved in pyridine (100 ml) and thereto is added dropwise methoxyacetyl chloride (3.0 ml) at room temperature. After the mixture is stirred at room temperature for 2 hours, the solvent is distilled off. The resulting oil is dissolved in chloroform and the organic layer is washed with water and then with a saturated saline. The organic layer is dried over anhydrous sodium sulfate and the solvent is distilled off. The resulting solids are recrystallized from ethanol/water to give the title compound (5.2 g) having the following physical properties.
Reaction SMILES: [CH3:1][NH:2][C:3]([CH:5]1[CH2:10][NH:9][CH2:8][CH2:7][NH:6]1)=[O:4].Cl[CH2:12][C:13]([NH:15][C:16]1[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][C:17]=1[Cl:24])=[O:14].C(N(CC)CC)C>COCCO>[CH3:1][NH:2][C:3]([CH:5]1[NH:6][CH2:7][CH2:8][N:9]([CH2:12][C:13]([NH:15][C:16]2[C:17]([Cl:24])=[CH:18][C:19]([Cl:23])=[CH:20][C:21]=2[Cl:22])=[O:14])[CH2:10]1)=[O:4]
Reactant: O=C(CCl)Nc1c(Cl)cc(Cl)cc1Cl
Reactant: CNC(=O)C1CNCCN1
Solvent: COCCO
Solvent: CCN(CC)CC
Product: CNC(=O)C1CN(CC(=O)Nc2c(Cl)cc(Cl)cc2Cl)CCN1
Temperature: 60 °C
Reaction time: 3 h
Yield: 24.4 %

Procedure:
A mixture of 15.33 parts of N-methyl-2-piperazinecarboxamide, 27.2 parts of 2-chloro-N-(2,4,6-trichlorophenyl)acetamide, 9.8 parts of N,N-diethylethanamine and 300 parts of 2-methoxyethanol was stirred for 3 hours at 60° C. The reaction mixture was evaporated. The residue was taken up in a small amount of water and treated with sodium carbonate. The product was extracted three times with dichloromethane. The combined extracts were dried, filtered and evaporated. The residue was crystallized from acetonitrile. The product was filtered off (the filtrate was set aside) and dried, yielding a first fraction of 9.27 parts (24.4%) of 3-[(methylamino)carbonyl]-N-(2,4,6-trichlorophenyl)-1-piperazineacetamide. The filtrate, which was set aside (see above) was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and 2-propanol (90:10 by volume) as eluent. The desired fraction was collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding a second fraction of 5.93 parts (15.6%) of 3-[(methylamino)carbonyl]-N-(2,4,6-trichlorophenyl)-1-piperazineacetamide; mp. 168.9° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18](O)[CH2:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[CH:14][CH:13]=1.Cl>>[C:8]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:1][CH:18]([C:15]1[CH:14]=[CH:13][C:12]([Cl:11])=[CH:17][CH:16]=1)[CH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1)(=[O:10])[CH3:9]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(O)c3ccc(Cl)cc3)CC2)c1
Reactant: CC(=O)c1cccc(O)c1
Agent: Cl
Product: CC(=O)c1cccc(OC(CCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccc(Cl)cc2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 1-(3-hydroxyphenyl)ethanone and N-(3-{1-[5-(4-chlorophenyl)-5-hydroxypentyl]-4-piperidinyl}phenyl)-2-methylpropanamide: 1H NMR (400 MHz, CDCl3), HCl salt δ 8.05 (s, br, 1H), 7.74-6.88 (m, 12H), 5.27-5.16 (m, 1H), 3.69-3.52 (m, br, 2H), 3.10-2.81 (br, 2H), 2.81-2.57 (m, br, 4H), 2.54 (s, 3H), 2.52-2.40 (m, br, 2H), 2.05-1.80 (m, br, 6H), 1.66-1.42 (m, br, 2H), 1.25 (d, 6H, J=6.8 Hz); Anal. Calc. for C34H42Cl2N2O3.0.5CH2Cl2.1.0H2O: C, 63.46; H, 6.91; N, 4.30. Found: C, 63.46; H, 7.09; N, 4.00. ESMS m/e: 561.1 (M+H)+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]([F:41])([F:40])[C:27]1[C:35]2[CH2:34][CH2:33][CH2:32][CH2:31][C:30]=2[N:29]([CH2:36][C:37]([OH:39])=O)[N:28]=1.CCN(C(C)C)C(C)C.[C:51]1([CH2:57][CH:58]([C:60]2[N:64]([C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)[N:63]=[N:62][CH:61]=2)[NH2:59])[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>CN(C=O)C>[C:51]1([CH2:57][CH:58]([NH:59][C:37](=[O:39])[CH2:36][N:29]2[C:30]3[CH2:31][CH2:32][CH2:33][CH2:34][C:35]=3[C:27]([C:26]([F:25])([F:41])[F:40])=[N:28]2)[C:60]2[N:64]([C:65]3[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=3)[N:63]=[N:62][CH:61]=2)[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: O=C(O)Cn1nc(C(F)(F)F)c2c1CCCC2
Reactant: NC(Cc1ccccc1)c1cnnn1-c1ccccc1
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: CN(C)C=O
Product: O=C(Cn1nc(C(F)(F)F)c2c1CCCC2)NC(Cc1ccccc1)c1cnnn1-c1ccccc1
Reaction time: 0.17 h

Procedure:
HATU (40 mg, 0.105 mmol) was added to a solution of 2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acid (25.0 mg, 0.1 mmol) and DIPEA (0.02 mL, 0.12 mmol) in DMF (0.3 mL). After 10 minutes, 9D (26.5 mg, 0.1 mmol) in 0.2 mL of DMF was added to the reaction. The reaction was stirred for 2 hours. LC/MS shows desired product with a small amount of acid. Purified reaction mixture on prep reverse phase HPLC using 20-80% B over 20 min. (A=0.1% TFA/H2O; B=0.1% TFA/Acetonitrile). Combined pure fractions as determined by LC/MS and lyophilized to provide the desired compound. 1H NMR (400 MHz, DMSO) δ 9.02 (d, J=7.9 Hz, 1H), 7.96 (s, 1H), 7.58-7.42 (m, 3H), 7.30-7.18 (m, 2H), 7.18-7.06 (m, 3H), 7.00-6.86 (m, 2H), 5.06 (q, J=7.6 Hz, 1H), 4.74-4.61 (m, 2H), 2.98 (td, J=13.6, 6.4 Hz, 2H), 2.43 (s, 2H), 2.37-2.17 (m, 2H), 1.61 (d, J=5.9 Hz, 4H). MS (m/z) 495 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([F:11])[CH:5]=1)=[O:3].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].O1CCCC1.[CH2:27]([O:29][CH:30]([O:36][CH2:37][CH3:38])[C:31](OCC)=[O:32])[CH3:28].Cl>O1CCCC1>[F:11][C:6]1[CH:5]=[C:4]([C:2](=[O:3])[CH2:1][C:31](=[O:32])[CH:30]([O:36][CH2:37][CH3:38])[O:29][CH2:27][CH3:28])[CH:9]=[C:8]([F:10])[CH:7]=1
Reactant: CCOC(=O)C(OCC)OCC
Reactant: CC(=O)c1cc(F)cc(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(OCC)C(=O)CC(=O)c1cc(F)cc(F)c1
Reaction time: 1 h

Procedure:
At −78° C., a tetrahydrofuran (20 ml) solution of 3,5-difluoroacetophenone (8.86 g) was added to a tetrahydrofuran (180 ml) solution of 1 N lithium hexamethyldisilazide/tetrahydrofuran solution (68 ml), and stirred at the same temperature for 1 hour. At −78° C., ethyl diethoxyacetate (12.2 ml) was added to the reaction liquid, and stirred overnight at room temperature. At 0° C., 2 N hydrochloric acid (60 ml) was added to the reaction liquid, and extracted with ethyl acetate. The extract was washed with saturated saline water, dried with anhydrous magnesium sulfate, and the solvent was evaporated off to obtain the entitled compound (16.5 g).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:7]([O:35][CH3:36])=[C:8]([C:13]([CH2:16][S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3/[CH:26]=[CH:27]\[CH2:28][N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)(=[O:19])=[O:18])=[CH:14][CH:15]=2)[C:9]([O:11]C)=[O:10])=[CH:2]1.O.[OH-].[Li+]>O.O1CCOCC1>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:7]([O:35][CH3:36])=[C:8]([C:13]([CH2:16][S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3/[CH:26]=[CH:27]\[CH2:28][N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)(=[O:19])=[O:18])=[CH:14][CH:15]=2)[C:9]([OH:11])=[O:10])=[CH:2]1
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2/C=C\CN2CCCCC2)ccc(-c2ccoc2)c1OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1c(-c2ccoc2)ccc(CS(=O)(=O)c2ccccc2/C=C\CN2CCCCC2)c1C(=O)O
Temperature: 65 °C

Procedure:
(Z)-Methyl 3-(furan-3-yl)-2-methoxy-6-((2-(3-(piperidin-1-yl)prop-1-enyl)benzenesulfonyl)methyl)benzoate (Intermediate 198, 0.069 g) was added to a solution of lithium hydroxide monohydrate (0.051 g) in water (0.7 ml) and dioxane (3 ml) and the resultant mixture was stirred and heated at 65° C. for 4 days. After cooling, the mixture was diluted with water and washed with diethyl ether. The aqueous layer was acidified with 1M HCl and extracted with ethyl acetate, washed with brine, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by HPLC (C6 phenyl column) eluting with 1:1 methanol:water containing 0.1% formic acid to give (Z)-3-(Furan-3-yl)-2-methoxy-6-((2-(3-(piperidin-1-yl)prop-1-enyl)benzenesulfonyl)methyl)benzoic acid as a white solid.