Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[F:27][C:28]([F:39])([F:38])[C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:33](=[O:34])[C:32]5[CH:36]=[CH:37][C:29]([C:28]([F:27])([F:38])[F:39])=[CH:30][CH:31]=5)[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1)c1ccc(C(F)(F)F)cc1

Procedure:
The title compound, off-white solid (99 mg, 79%), MS (ISP) m/z=501.2 [(M+H)+], mp 228° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydro chloride (intermediate B) (100 mg, 0.25 mmol) and 4-trifluoromethyl-benzoic acid.
Reaction SMILES: Br[CH:2]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:17][C:18]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:19]=1[C:20](=[S:22])[NH2:21]>CO>[CH2:10]([C:2]1[S:22][C:20]([C:19]2[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:18]=2[F:17])=[N:21][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)C(=O)C(Br)Cc1ccccc1
Reactant: NC(=S)c1cc(F)ccc1F
Solvent: CO
Product: CCOC(=O)c1nc(-c2cc(F)ccc2F)sc1Cc1ccccc1
Yield: 60.4 %

Procedure:
To a solution of ethyl 3-bromo-2-oxo-4-phenylbutanoate (13.8 g, 48.4 mmol) in MeOH (161 mL) was slowly added 2,5-difluorobenzothioamide (8.38 g, 48.4 mmol) at room temperature. The reaction mixture was then refluxed for overnight. After cooled down, white precipitate was filtered, washed by cold ethanol and dried. A mixture of methyl 5-benzyl-2-(2,5-difluorophenyl)thiazole-4-carboxylate and ethyl 5-benzyl-2-(2,5-difluorophenyl)thiazole-4-carboxylate (10.5 g, 61%) was obtained as white solid. LC/MS (uplc): MW 346.1, 1.21 min for methyl ester; 360.1, 1.27 min for ethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[CH3:11].[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:16]2[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH2:15]2)=[O:7])=[CH:4][C:3]=1[CH3:11]
Reactant: CN1CCNCC1
Reactant: Cc1cc(C(=O)Cl)ccc1Br
Solvent: Cc1ccccc1
Product: Cc1cc(C(=O)N2CCN(C)CC2)ccc1Br
Reaction time: 8 h
Yield: 33.6 %

Procedure:
To a solution of 4-bromo-3-methylbenzoyl chloride (0.5 g, 2 mmol) in toluene (6 mL) was added N-methylpiperazine (0.5 mL, 4 mmol, 2 equiv.). The resulting mixture was stirred overnight, The precipitate was filtered and the filtrate was concentrated under reduced pressure. The residue was taken into ethyl acetate and washed with water. The organic layer was dried over sodium sulfate, concentrated under reduced pressure to give 0.2 g (34% yield) of intermediate 11.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:18])=[C:6]([C:8](=[O:17])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[CH:7]=1.[C:19](OC(=O)CC)(=O)[CH2:20][CH3:21].Cl>C(N(CC)CC)C>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:18][C:19]([CH2:20][CH3:21])=[C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])[C:8]2=[O:17]
Reactant: CCC(=O)OC(=O)CC
Reactant: O=C(Cc1ccccc1F)c1cc(Br)ccc1O
Agent: Cl
Solvent: CCN(CC)CC
Product: CCc1oc2ccc(Br)cc2c(=O)c1-c1ccccc1F
Temperature: 25 °C
Yield: 64.9 %

Procedure:
Intermediate 23 (1.1 g, 3.55 mmoles) was taken in a RB flask and to this triethylamine (10 ml) and propionic anhydride (1.44 g, 11.13 mmoles) were added and the mixture was refluxed for 22 h. After cooling to RT, the reaction mixture was acidified by the addition of 1N HCl solution, extracted with ethyl acetate, washed with sodium bicarbonate solution, dried with sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to afford the title compound as off-white solid (0.800 g, 65% yield). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 8.10(d, J=2.5 Hz, 1H), 8.00(dd, J=9.0,2.5 Hz, 1H), 7.71(d, J=9.0 Hz, 1H), 7.51(m, 1H),7.36(m, 3H), 2.54(m, 2H), 1.19(t, J=7.6 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9](Br)=[N:8][C:7]=1[CH2:12][N:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])[CH3:2].[O:31]1[C:35]2[CH:36]=[CH:37][C:38](B(O)O)=[CH:39][C:34]=2[CH2:33][CH2:32]1>>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:38]2[CH:37]=[CH:36][C:35]3[O:31][CH2:32][CH2:33][C:34]=3[CH:39]=2)=[N:8][C:7]=1[CH2:12][N:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])[CH3:2]
Reactant: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(Br)sc1C(=O)OCC
Reactant: OB(O)c1ccc2c(c1)CCO2
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(-c2ccc3c(c2)CCO3)sc1C(=O)OCC

Procedure:
Prepared from 2-bromo-4-{[(2,4-dimethoxy-benzyl)-ethoxycarbonylmethyl-amino]-methyl}-thiazole-5-carboxylic acid ethy ester, example 81(b), and 2,3-dihydro-1-benzofuran-5-yl-boronic acid under conditions analogous to experimental example 81(c). MS: (+) m/z 541.4 (M+1).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][N:6]([C:24]2[CH:25]=[C:26]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=3)[CH:27]=[CH:28][CH:29]=2)[S:7]([C:10]2[CH:22]=[CH:21][C:13]([O:14][CH2:15][C:16]([O:18]CC)=[O:17])=[C:12]([CH3:23])[CH:11]=2)(=[O:9])=[O:8])[CH2:3][CH2:2]1.[OH-].[Na+]>CO.C1COCC1>[CH:1]1([CH2:4][CH2:5][N:6]([C:24]2[CH:25]=[C:26]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:37])[F:38])=[CH:32][CH:31]=3)[CH:27]=[CH:28][CH:29]=2)[S:7]([C:10]2[CH:22]=[CH:21][C:13]([O:14][CH2:15][C:16]([OH:18])=[O:17])=[C:12]([CH3:23])[CH:11]=2)(=[O:9])=[O:8])[CH2:2][CH2:3]1
Reactant: CCOC(=O)COc1ccc(S(=O)(=O)N(CCC2CC2)c2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(S(=O)(=O)N(CCC2CC2)c2cccc(-c3ccc(C(F)(F)F)cc3)c2)ccc1OCC(=O)O
Yield: 43.1 %

Procedure:
To a solution of ethyl [4-({(2-cyclopropylethyl)[4′-(trifluoromethyl)-1,1′-biphenyl-3-yl]amino}sulfonyl)-2-methylphenoxy]acetate (156 mg, 0.28 mmol) in MeOH (2 mL) and THF (2 mL) at room temperature was added 2M NaOH aq. (1 mL, 2 mmol). The resultant mixture was stirred for 2 h. The solvents were removed in vacuo and the residue was partitioned between EtOAc (2×20 mL) and 2M HCl (20 mL). The organic solution was dried (MgSO4) and the solvent was removed in vacuo. Purification by SPE (5 g aminopropyl cartridge), loading crude material in CH2Cl2 and then washing with MeOH, prior to eluting with 5% NH3 in MeOH. The 5% NH3 in MeOH extract was concentrated in vacuo and the residue was partitioned between CH2Cl2 (20 mL) and 2M HCl (2 mL). The organic solution was dried (MgSO4) and the solvent was removed in vacuo affording the title compound as a white solid (64.4 mg).
Reaction SMILES: [CH2:1]([N:4]=[C:5]([NH2:19])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]#[N:18])[N:8]=1)[CH2:2][CH3:3].S(=O)(=O)(O)[OH:21].N>>[CH2:1]([N:4]=[C:5]([NH2:19])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([NH2:18])=[O:21])[N:8]=1)[CH2:2][CH3:3]
Reactant: O=S(=O)(O)O
Reactant: CCCN=C(N)Nc1ccnc(CCCCC#N)n1
Agent: N
Product: CCCN=C(N)Nc1ccnc(CCCCC(N)=O)n1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A mixture of 5-(4-[2-propylguanidino]pyrimid-2-yl)valeronitrile (0.25 g.) and concentrated sulphuric acid (2 ml.) was stirred at ambient temperature for 3.5 hours. The reaction mixture was cooled in an ice bath and basified by careful dropwise addition of concentrated aqueous ammonia (s.g. 0.880). The resulting white precipitate was collected, washed with water and allowed to dry. The solid was purified by medium pressure chromatography on silica gel using CHCl3 /MeOH/aqueous ammonia (s.g. 0.880) 8:2:0.3 v/v/v as eluant to give 5-(4-[2-propylguanidino]pyrimid-2-yl)valeramide (0.15 g.), m.p. 212°-214°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]=[C:21]=[S:22]>CCOCC>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21]([N:10]1[CH2:9][CH2:8][N:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)[CH2:12][CH2:11]1)=[S:22]
Reactant: S=C=Nc1ccccc1Cl
Reactant: c1cnc(N2CCNCC2)cn1
Solvent: CCOCC
Product: S=C(Nc1ccccc1Cl)N1CCN(c2cnccn2)CC1
Reaction time: 0.5 h

Procedure:
To a solution of 4.92 g. of 1-(2-pyrazinyl)piperazine in 50 ml. of anhydrous ether is added dropwise a solution of 5.08 g. of 2-chlorophenyl isothiocyanate in 50 ml. of anhydrous ether over 5 minutes. The mixture isstirred for 30 minutes and the resulting solid is collected. This solid is recrystallized from 430 ml. of ethanol giving 7.41 g. of the desired product, m.p. 167°-169° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]2[S:13][CH:12]=[N:11][CH:10]=2)[CH:3]=1.Cl[C:15]1[N:16]=[CH:17][C:18]2[CH:23]=[C:22]([C:24]3[CH2:25][CH2:26][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:28][CH:29]=3)[NH:21][C:19]=2[N:20]=1>C(O)CCC>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:17]2[C:18]3[CH:23]=[C:22]([C:24]4[CH2:25][CH2:26][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:28][CH:29]=4)[NH:21][C:19]=3[N:20]=[CH:15][N:16]=2)=[CH:3][C:4]=1[C:9]1[S:13][CH:12]=[N:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3cnc(Cl)nc3[nH]2)CC1
Reactant: Nc1ccc(O)c(-c2cncs2)c1
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Nc4ccc(O)c(-c5cncs5)c4)ncnc3[nH]2)CC1
Temperature: 120 °C
Reaction time: 14 h

Procedure:
4-Amino-2-thiazol-5-ylphenol (70.0 mg, 0.364 mmol) was added to a solution of tert-butyl 4-(chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (192 mg, 0.546 mol) in n-butanol (2.0 mL). The reaction was stirred at 120° C. for 14 h. The solvent was removed and the residue was dissolved in DMF. The DMF solution was filtered and purified by HPLC to give the title compound. 1H-NMR (DMSO-d6, 400 MHz): δ=1.43 (s, 9H), 2.46 (m, 2H), 3.56 (t, J=5.6 Hz, 2H), 4.04 (s, 2H), 6.38 (s, br, 1H), 6.70 (s, 1H), 6.97 (d, J=8.8 Hz, 1H), 7.70 (dd, J=2.4, 8.8 Hz, 1H), 8.07 (d, J=2.4 Hz, 1H), 8.22 (s, 1H), 8.32 (s, 1H), 9.05 (s, 1H), 9.23 (s, 1H), 10.25 (s, br, 1H), 11.88 (s, 1H). MS (ES+): m/z 490.94 (MH+). HPLC: tR=2.51 min (ZQ2000, polar—5 min).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[CH2:22]([O:21][CH:18]1[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCC(OCc2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(COC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
Trifluoroacetic acid (5 ml) was added to a solution of 1-(tert-butoxycarbonyl)-4-benzyloxypiperidine (2.08 g, 7.14 mmol) in dichloromethane (20 ml) and the solution stirred for 30 minutes at room temperature under nitrogen. The solution was concentrated in vacuo, the residue was redissolved in dichloromethane (20 ml) and treated with trifluoroacetic acid (20 ml). The solution was stirred for 30 minutes, partially evaporated and poured into saturated aqueous potassium carbonate solution (50 ml). The mixture was diluted with water (50 ml) and extracted with dichloromethane (2×100 ml). The combined extracts were dried (MgSO4) and concentrated in vacuo to give crude 4-benzyloxypiperidine (1.29 g), as an amber oil. A portion of this material (0.59 g, 3.08 mmol) was dissolved in dimethylformamide (15 ml). Potassium carbonate (0.85 g, 6.15 mmol) and 2-(chloromethyl) benzimidazole (0.46 g, 2.76 mmol) were added to the solution and the mixture stirred at room temperature, under nitrogen, overnight. The reaction mixture was poured into water (150 ml) and extracted with ethyl acetate (2×100 ml). The extracts were washed with brine (100 ml), combined, dried (MgSO4) and the residue after evaporation purified by flash chromatography, eluting with 7.5% methanol in dichloromethane, to give the title compound (0.26 g, 30%) as a pale yellow solid. Recrystallisation from ethyl acetate afforded very pale yellow needles, m.p. 190.5°-191° C.; (Found: C, 74.83; H, 7.17; N, 13.00. C20H23N3O requires C, 74.74; H, 7.21; N, 13.07%); δH (DMSO-d6) 1.56 (2H, m, piperidinyl H), 1.88 (2H, m, piperidinyl H), 2.21 (2H, m, piperidinyl H), 2.74 (2H, m, piperidinyl H), 3.40 (1H, m, piperidinyl CH-O), 3.69 (2H, s, CH2N), 4.49 (2H, s, OCH2Ph), 7.12 (2H, m, ArH), 7.27 (5H, m, ArH), 7.48 (2H, br s, ArH), and 12.23 (1H, br s, NH); m/z (CI+, NH3) 322 (M+H)+.
Reaction SMILES: [C:1](=O)([S:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][C@H:13]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:14]([N:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH3:17])=[O:15])[CH:7]=1)[CH3:2].[OH-].[K+].C([N:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:42]([CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])=C1CBr)(=O)C.Cl>C(O)C>[C:30]([O:29][C:27]([NH:26][C@H:13]([C:14]([N:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[CH3:17])=[O:15])[CH2:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[CH2:5][CH2:4][S:3][CH2:1][C:2]1[NH:40][C:48]2[C:43]([C:42]=1[CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])=[CH:44][CH:45]=[CH:46][CH:47]=2)=[O:28])([CH3:31])([CH3:33])[CH3:32]
Reactant: CCOC(=O)Cc1c(CBr)n(C(C)=O)c2ccccc12
Reactant: COc1ccc(N(C)C(=O)[C@H](Cc2cccc(CCSC(C)=O)c2)NC(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)Cc1c(CSCCc2cccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)c3ccc(OC)cc3)c2)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 52.3 %

Procedure:
To a solution of (S)—S-3-(2-(tert-butoxycarbonylamino)-3-((4-methoxyphenyl)(methyl)amino)-3-oxopropyl)phenethyl ethanethioate (2.8 g, 5.74 mmol) in ethanol (20 ml) was added potassium hydroxide (0.64 g, 11.4 mmol). After 10 minutes, ethyl 2-(1-acetyl-2-(bromomethyl)-1H-indol-3-yl)acetate (2.2 g, 6.47 mmol) was added to the solution. The reaction was stirred for 2 hours at room temperature. The reaction was neutralized with 1N (aq) HCl and then extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was introduced to a silica gel loading column and purified by column chromatography (3-6% MeOH/DCM) to provide the desired product (2.0 g, 3.0 mmol), 52.3%. MS (m/z) 660 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH:13]([NH:21][C:22](=[O:24])[CH3:23])[CH2:14][N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[CH:7][C:5]=2[N:6]=1.C(N(CC)CC)C.[CH:32]1[C:44]2[CH2:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:36]=2[CH:35]=[CH:34][C:33]=1[N:45]=[C:46]=[O:47]>O1CCCC1>[CH:32]1[C:44]2[CH2:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:36]=2[CH:35]=[CH:34][C:33]=1[NH:45][C:46]([N:18]1[CH2:17][CH2:16][N:15]([CH2:14][CH:13]([NH:21][C:22](=[O:24])[CH3:23])[CH2:12][O:11][C:8]2[CH:9]=[CH:10][C:4]3[S:3][C:2]([CH3:1])=[N:6][C:5]=3[CH:7]=2)[CH2:20][CH2:19]1)=[O:47]
Reactant: O=C=Nc1ccc2c(c1)Cc1ccccc1-2
Reactant: CC(=O)NC(COc1ccc2sc(C)nc2c1)CN1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NC(COc1ccc2sc(C)nc2c1)CN1CCN(C(=O)Nc2ccc3c(c2)Cc2ccccc2-3)CC1
Temperature: 55 °C
Reaction time: 4 h
Yield: 44 %

Procedure:
To a solution of N-[2-(2-methylbenzothiazol-5-yloxy)-1-(piperazinylmethyl)ethyl]-acetamide (18.4 mg) in tetrahydrofuran (1 ml) was added triethylamine (25.6 μl) and 2-fluorenyl isocyanate (9.5 mg). The reaction mixture was stirred at 55° C. for 4 hours, producing a white precipitate. The precipitate was filtered off, and solvent removed from the filtrate under reduced pressure. The residue was purified by thin layer chromatography, developing with 4% methanol/methylene chloride, to provide N-{2-[4-(N-fluoren-2-ylcarbamoyl)piperazinyl]-1-[(2-methylbenzothiazol-5-yloxy)methyl]ethyl}acetamide (11.2 mg), a compound of Formula I.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:16](=[O:22])[CH2:17][C:18](=[O:21])[CH2:19][CH3:20])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.C(N(CC)CC)C.S([N:34]=[N+:35]=[N-])(C)(=O)=O.[OH-].[Na+]>ClCCl>[CH3:1][O:2][C:3]1([C:16](=[O:22])[C:17](=[N+:34]=[N-:35])[C:18](=[O:21])[CH2:19][CH3:20])[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH2:7][CH2:8]1
Reactant: CS(=O)(=O)N=[N+]=[N-]
Reactant: CCC(=O)CC(=O)C1(OC)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)C(=[N+]=[N-])C(=O)C1(OC)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 70.8 %

Procedure:
To a solution of tert-butyl 4-methoxy-4-(1,3-dioxopent-1-yl)piperidine-1-carboxylate (0.227 g, 0.724 mmol) from Step C in dichloromethane (10 mL) was added triethylamine (0.101 mL, 0.724 mmol). Next, a solution of mesyl azide (0.087 g, 0.724 mmol) in dichloromethane (1 mL) was added. The reaction mixture was stirred for 3.5 h at room temperature. Additional mesyl azide (0.026 g, 0.217 mmol) was added. After 2 h, the reaction mixture was diluted with dichloromethane, poured into 1N sodium hydroxide solution, and extracted three times with dichloromethane. The organic layers were combined, washed with saturated sodium chloride, dried over sodium sulfite, filtered, and concentrated. The residue was purified by flash chromatography eluting with 5% ethyl acetate/dichloromethane to afford the title compound (0.174 g). MS/EI (acetonitrile/water): m/z 362 (M+Na) retention time=3.37 min.
Reaction SMILES: [I:1][C:2]1[C:6]2[C:7]([O:11][CH3:12])=[N:8][CH:9]=[CH:10][C:5]=2[NH:4][CH:3]=1.[H-].[Na+].CC1C=CC(S(O[C@H:26]2[CH2:31][CH2:30][C@H:29]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH2:28][CH2:27]2)(=O)=O)=CC=1>CN(C=O)C>[Si:33]([O:32][C@@H:29]1[CH2:28][CH2:27][C@H:26]([N:4]2[C:5]3[CH:10]=[CH:9][N:8]=[C:7]([O:11][CH3:12])[C:6]=3[C:2]([I:1])=[CH:3]2)[CH2:31][CH2:30]1)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]
Reactant: COc1nccc2[nH]cc(I)c12
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CC[C@H](O[Si](C)(C)C(C)(C)C)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nccc2c1c(I)cn2[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-iodo-4-methoxy-1H-pyrrolo[3,2-c]pyridine (0.100 g) in DMF (5 mL) was added sodium hydride (60% dispersion in mineral oil, 36.5 mg), and the mixture was stirred at room temperature for 1 hr. trans-4-((tert-Butyl(dimethyl)silyl)oxy)cyclohexyl 4-methylbenzenesulfonate (351 mg) was added thereto, and the mixture was stirred overnight at room temperature. The reaction mixture was extracted with water and ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (100 mg).
Reaction SMILES: Br.[NH2:2][CH:3]([CH3:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.C(=O)(O)[O-].[Na+].O.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(OCC)(=O)C>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:2][CH:3]([CH3:12])[CH2:4][C:5]2[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: CC(N)Cc1ccc(O)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(Cc1ccc(O)cc1)NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.8 %

Procedure:
A mixture of 2.32 g of 4-(2-aminopropyl)phenol hydrobromide, 4.2 g of sodium bicarbonate, 50 ml of water, 100 ml of ethyl acetate and 2.11 g of 4-chlorophenylsulfonyl chloride is stirred at room temperature for 3 hours. After the reaction, the ethyl acetate layer is separated therefrom, dried and evaporated to remove the solvent. 3.25 g of 4-[2-(4-chlorophenyl)sulfonylaminopropyl)phenol are obtained as brown oil.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH:11]1([Mg]Br)[CH2:13][CH2:12]1.ClCCl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1(C)C=CC=CC=1>[CH:11]1([C:2]2[C:3]3[CH:10]=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:13][CH2:12]1
Reactant: Br[Mg]C1CC1
Reactant: Clc1ncnc2[nH]ccc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: c1nc(C2CC2)c2cc[nH]c2n1
Temperature: 60 °C
Yield: 99.4 %

Procedure:
4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (9, 0.452 g, 2.94 mmol), cyclopropylmagnesium bromide (17, 31.4 mL, 0.50 M in tetrahydrofuran, 15.7 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) 1:1 complex with dichloromethane (0.240 g, 0.294 mmol) are combined with 15.4 mL of toluene. The reaction is heated at 60° C. overnight, then quenched with 1 M aqueous hydrochloric acid to pH 4 and filtered through a bed of celite. The layers of the filtrate are separated and the aqueous layer extracted with ethyl acetate. The combined organic layers are washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with ethyl acetate and hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (18, 0.465 g). MS (ESI) [M+H+]+=160.1. This is reacted similarly to steps 2 and 3 of Scheme 4 to provide the desired compound 19.
Reaction SMILES: C([O:3][C:4](=[O:35])[C:5]([CH3:34])([O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][NH:19][C:18](=[O:21])[N:17]2[CH3:22])=[CH:9][CH:8]=1)C.[H-].[Na+].[C:38]([C:42]1[CH:49]=[CH:48][C:45]([CH2:46]Br)=[CH:44][CH:43]=1)([CH3:41])([CH3:40])[CH3:39]>CN(C=O)C.CCOCC.Cl>[C:38]([C:42]1[CH:43]=[CH:44][C:45]([CH2:46][N:19]2[CH2:20][CH:16]([CH2:15][CH2:14][O:13][C:10]3[CH:11]=[CH:12][C:7]([CH2:6][C:5]([CH3:34])([O:23][C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:33])[F:32])=[CH:26][CH:25]=4)[C:4]([OH:3])=[O:35])=[CH:8][CH:9]=3)[N:17]([CH3:22])[C:18]2=[O:21])=[CH:48][CH:49]=1)([CH3:41])([CH3:39])[CH3:40]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CNC(=O)N2C)cc1)Oc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)c1ccc(CBr)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CN1C(=O)N(Cc2ccc(C(C)(C)C)cc2)CC1CCOc1ccc(CC(C)(Oc2ccc(C(F)(F)F)cc2)C(=O)O)cc1
Reaction time: 0.33 h
Yield: 40 %

Procedure:
To a mixture of 80 mg of 2-Methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-(4-trifluoromethyl-phenoxy)-propionic acid ethyl ester in 5 mL of dry DMF at 0° C. under an atmosphere of nitrogen, 16 mg of NaH (0.40 mmol) is added. The resulting solution is allowed to stand at r.t. for 20 minute Then 0.07 mL of 4-tert-butylbenzyl bromide is added and resulting mixture is allowed to stand at r.t. for overnight. Reaction mixture is diluted with Et2O and 1N HCl. Organic layer is then washed with 1N HCl. (2×10 mL), brine (2×10 mL), dried over Na2SO4, filtered and concentrated under vacuum. The crude material is in 5 mL of EtOH and 0.5 mL of 5N NaOH. The mixture is heated to reflux for 1 h. The organic solvent is then removed under vacuum and residue is dissolved in CH2Cl2 and 1N HCl. Aqueous layer is washed with CH2Cl2 (2×10 mL). Combined organic layer is dried over Na2SO4, filtered and concentrated under vacuum. The crude material is purified by MS/LC to give 40 mg (40%) of the title product. 1H NMR (400 MHz, CDCl3): δ 7.51 (d, 2H, J=8.8 Hz), 7.38-7.32 (m, 2H), 7.16 (t, 4H, J=8.8 Hz), 6.95 (d, 2H, J=8.8 Hz), 6.76 (d, 2H, J=8.8 Hz), 4.37, 4.28 (ABq, 2H, J=14.8 Hz), 4.24 (bs, 1H), 3.97 (t, 2H, J=6.0 Hz), 3.74-3.67 (m, 1H), 3.44 (t, 1H, J=9.2 Hz), 3.31, 3.16 (ABq, 2H, J=13.8 Hz), 3.07 (t, 1H, J=9.2 Hz), 2.85 (s, 3H), 2.27-2.18 (m, 1H), 1.98-1.89 (m, 1H), 1.50 (s, 3H), 1.29 (s, 9H). HRMS (ES+) m/z exact mass calcd for C34H40N2O5F3 (m+1) 613.2889, found 613.2872.