Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:15])=O.CN(C=O)C>C(Cl)Cl>[OH:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C(=O)O)c(O)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(C(=O)Cl)c(O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-hydroxy-4-methoxybenzoic acid (20 g, 118.9 mmol) in 500 mL CH2Cl2 was added thionyl chloride (21.2 g, 178.4 mmol), followed by 0.4 mL DMF. After stirring at rt for 8 h, the reaction mixture was concentrated to a white solid (azeotroped twice from benzene). This material was used as is in the next step.
Reaction SMILES: [CH2:1]([O:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([O:29][CH2:30][CH2:31][CH2:32][O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:28]=1)[C:23]([OH:25])=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH:40]([CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43].C(N(CC)CC)C>S(Cl)(Cl)=O.C1(C)C=CC=CC=1.C1COCC1>[CH2:45]([O:44][C:42](=[O:43])[CH2:41][N:40]([CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])[C:23](=[O:25])[C:22]1[CH:21]=[C:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:28]=[C:27]([O:29][CH2:30][CH2:31][CH2:32][O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:26]=1)[CH3:46]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(OCCCOc2ccccc2)cc(C(=O)O)c1
Reactant: CCOC(=O)CNCC(=O)OCC
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCOc2ccccc2)cc(C(=O)N(CC(=O)OCC)CC(=O)OCC)c1
Yield: 91.1 %

Procedure:
A solution of 1.0 g (1.85 mmol) of 3-(octadecyloxy)-5-(3-phenoxypropoxy)benzoic acid in 10 ml of thionyl chloride and 4 ml of toluene was stirred at reflux for 4.5 hours. The mixture was concentrated at reduced pressure, the residual acid chloride was dissolved in 10 ml of anhydrous THF and added dropwise to a solution of 0.44 g (2.3 mmol) of diethyl iminodiacetate and 0.8 ml (5.8 mmol) of triethylamine in 20 ml of THF with stirring. The reaction mixture was stirred at room temperature for 16 hours and then was concentrated at reduced pressure to yield an oil. Purification by HPLC using 20% ethyl acetate-hexane to give 1.2 g of N-(2-ethoxy-2-oxoethyl)-N-[3-[3-(phenoxy)propoxyl]-5-(octadecyloxy)benzoyl] glycine ethyl ester as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[Cl:9].[C:10]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[C:13]([O:12][C:10]([N:17]1[CH2:22][CH2:21][N:20]([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=2[Cl:9])[CH2:19][CH2:18]1)=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: Cc1ccc(Br)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(Cl)c1
Yield: 97.8 %

Procedure:
A mixture of 4-bromo-3-chlorotoluene (2.1 g), Boc-piperazine (1.9 g), palladium acetate (112 mg), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (312 mg), sodium tert-butoxide (1.4 g) and toluene (20 mL) was refluxed for 5 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform) to give 4-(2-chloro-4-methylphenyl)piperazine-1-carboxylic acid tert-butyl ester (3.1 g). To a mixture of 4-(2-chloro-4-methylphenyl)piperazine-1-carboxylic acid tert-butyl ester (932 mg), 2,4,6-trivinylcyclotriboroxane pyridine complex (1 g), palladium acetate (74 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (271 mg) and potassium fluoride (697 mg) was added tetrahydrofuran (4 mL), and the mixture was refluxed for 8 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform) to give 4-(4-methyl-2-vinylphenyl)piperazine-1-carboxylic acid tert-butyl ester (0.9 g). 4-(4-Methyl-2-vinylphenyl)piperazine-1-carboxylic acid tert-butyl ester (0.9 g) was dissolve in chloroform (2 mL), 4N hydrogen chloride/ethyl acetate (1 mL) was added, and the mixture was stirred at room temperature for 3 hr. 1N aqueous sodium hydroxide solution (8 mL) was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated to give 1-(4-methyl-2-vinylphenyl)piperazine (606 mg). 1-(4-Methyl-2-vinylphenyl)piperazine (606 mg) was dissolved in tetrahydrofuran (8 mL), 4-iodobenzoyl chloride (1.1 g) and 1N aqueous sodium hydroxide solution (4 mL) were added, and the mixture was stirred at room temperature overnight. The mixture was extracted with ethyl acetate, washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform) to give the title compound (1 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[CH:13]1([N:17]2[CH2:22][CH2:21][CH:20](O)[CH2:19][CH2:18]2)[CH2:16][CH2:15][CH2:14]1>O1CCCC1.N(C(OCC)=O)=NC(OCC)=O>[CH:13]1([N:17]2[CH2:22][CH2:21][CH:20]([O:1][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]4)[CH2:19][CH2:18]2)[CH2:16][CH2:15][CH2:14]1
Reactant: O=C1CCc2cc(O)ccc2N1
Reactant: OC1CCN(C2CCC2)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Product: O=C1CCc2cc(OC3CCN(C4CCC4)CC3)ccc2N1
Temperature: 25 °C
Reaction time: 40 h
Yield: 25 %

Procedure:
Under a nitrogen atmosphere, to a solution of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (5.00 g) and N-cyclobutyl-4-hydroxypiperidine (which can be synthesized as described in WO2005/108384) (7.10 g) in tetrahydrofuran (50 mL), diethyl azodicarboxylate (40% in toluene, 16.7 mL) was added dropwise under ice cooling. After completion of the dropwise addition, the reaction mixture was warmed to room temperature and stirred for 40 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluting solvent: chloroform/methanol=95/5) to give the titled compound (2.30 g, 25%) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:34])=[C:4]([C@H:8]([NH:10][C:11]([C@@H:13]2[CH2:18][C@@H:17]3[C@@H:15]([CH2:16]3)[N:14]2[C:19](=[O:33])[CH2:20][N:21]2[C:25]3=[CH:26][N:27]=[CH:28][CH:29]=[C:24]3[C:23]([C:30]([NH2:32])=[O:31])=[N:22]2)=[O:12])[CH3:9])[CH:5]=[CH:6][CH:7]=1.ClC1C=C(C=CC=1)C(OO)=[O:40]>C(O)(=O)C>[C:30]([C:23]1[C:24]2[C:25](=[CH:26][N+:27]([O-:40])=[CH:28][CH:29]=2)[N:21]([CH2:20][C:19]([N:14]2[C@H:13]([C:11](=[O:12])[NH:10][C@@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:34])[CH3:9])[CH2:18][C@@H:17]3[C@H:15]2[CH2:16]3)=[O:33])[N:22]=1)(=[O:31])[NH2:32]
Reactant: C[C@@H](NC(=O)[C@@H]1C[C@H]2C[C@H]2N1C(=O)Cn1nc(C(N)=O)c2ccncc21)c1cccc(Cl)c1F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CC(=O)O
Product: C[C@@H](NC(=O)[C@@H]1C[C@H]2C[C@H]2N1C(=O)Cn1nc(C(N)=O)c2cc[n+]([O-])cc21)c1cccc(Cl)c1F
Temperature: 55 °C
Reaction time: 18 h

Procedure:
To a solution of 1-(2-((1R,3S,5R)-3-((R)-1-(3-chloro-2-fluorophenyl)ethylcarbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (Example 702, 150 mg, 0.31 mmol) in acetic acid (4 mL) was added 3-chlorobenzoperoxoic acid (85 mg, 0.50 mmol) at 55° C. The reaction mixture was stirred at 55° C. for 18 h and then cooled to RT. Volatiles were evaporated and the residue was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30×100 mm, flow: 40 mL/min, eluent: 5-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA) to afford the title compound as a white solid. MS: 501 [M+H]+; tR (HPLC conditions c): 3.64 min.
Reaction SMILES: [I:1][C:2]1[S:10][C:9]2[C:8]([C:11]#[N:12])=[CH:7][N:6]=[C:5]([NH:13]CC3C=CC(OC)=CC=3)[C:4]=2[CH:3]=1.[OH:23]S(O)(=O)=O>>[NH2:13][C:5]1[C:4]2[CH:3]=[C:2]([I:1])[S:10][C:9]=2[C:8]([C:11]([NH2:12])=[O:23])=[CH:7][N:6]=1
Reactant: O=S(=O)(O)O
Reactant: COc1ccc(CNc2ncc(C#N)c3sc(I)cc23)cc1
Product: NC(=O)c1cnc(N)c2cc(I)sc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 2-iodo-4-(4-methoxy-benzylamino)-thieno[3,2-c]pyridine-7-carbonitrile 27 (3.88 g, 9.21 mmol) was added conc. H2SO4 (9.75 mL). The reaction was stirred for 1 h at room temperature, then quenched by the addition of ice (20 g). The filtered precipitate was washed with H2O, then suspended in 30% MeOH—CH2Cl2 (30 mL). Triethylamine was added dropwise until the solids dissolved. The solution was purified by silica gel column chromatography (eluent: 10 to 20% MeOH in CH2Cl2 with 1% NH4OH additive) to yield 2.6 g of 28. 1H NMR (400 MHz, d6-DMSO) δ 8.46 (s, 1H), 7.94 (m, 2H), 7.31 (bs, 1H), 7.18 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[CH:18]=[C:19]([C:23](=[O:25])[CH3:24])[CH:20]=[CH:21][CH:22]=3)(=[O:16])=[O:15])[C@H:10]([CH3:26])[CH2:9]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[Si]([C:35]([F:38])([F:37])[F:36])(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C([O-])(O)=O.[Na+]>[F:36][C:35]([F:38])([F:37])[C:23]([C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([S:14]([N:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=3[C:27]([F:30])([F:29])[F:28])[CH2:9][C@H:10]2[CH3:26])(=[O:16])=[O:15])[CH:18]=1)([OH:25])[CH3:24]
Reactant: CC(=O)c1cccc(S(=O)(=O)N2CCN(c3ccc(F)cc3C(F)(F)F)C[C@H]2C)c1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Product: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1cccc(C(C)(O)C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 64.4 %

Procedure:
To a solution of (3R)-1-[4-fluoro-2-(trifluoromethyl)phenyl]-3-methylpiperazine (2.5 g, 9.53 mmol) in DCM (50 mL) at 0° C. was added 3-acetyl benzenelsulfonyl chloride (2.08 g, 9.53 mmol) and DIPEA (3.32 mL, 19.06 mmol). The resultant mixture was stirred at room temperature overnight, then washed with H2O first, the aqueous layer was extracted with DCM (2×50 mL). The combined organic layer was dried over Na2SO4. The crude product was purified on SiO2 gel column eluted with 30-40% EtOAc in hexanes to give 1-[3-({(2R)4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}sulfonyl)phenyl]ethanone as an off white solid (3.7 g, 90%). Step 3: To 1-[3-({(2R)4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}sulfonyl)phenyl]ethanone (3.7 g, 8.33 mmol) was added TMS-CF3 (50 mL, 25 mmol, 0.5 M in THF) at room temperature. This was cooled down to 0° C. in an ice bath, then TBAF (8.33 mL, 8.33 mmol, 1.0 M in THF) was added slowly. The resultant mixture was stirred at 0° C. for 30 min, then stirred at room temperature for 5 hours. The resultant mixture was diluted with saturated NaHCO3 (40 mL), washed with DCM (100 mL). This was separated, the organic layer washed with saturated brine, dried over Na2SO4. The crude product was purified on SiO2 gel column eluted with 30-50% EtOAc in Hexanes first, then purified again on SiO2 gel column eluted with 2.5% MeOH in DCM to give 1,1,1-trifluoro-2-[3-({(2R)4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}sulfonyl)phenyl]propan-2-ol as a white solid (2.76 g, 64%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=O)(=[O:4])=[O:3].ON1C2C=CC=CC=2N=N1.[CH3:24][C:25]([CH3:46])([CH3:45])[CH2:26][CH2:27][NH:28][C:29](=[O:44])[C@H:30]([CH3:43])[CH2:31][C@H:32]([OH:42])[C@@H:33]([NH2:41])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C=O)C>[CH2:34]([C@H:33]([NH:41][C:8](=[O:10])[C:7]1[CH:11]=[CH:12][CH:13]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=1)[C@@H:32]([OH:42])[CH2:31][C@H:30]([C:29](=[O:44])[NH:28][CH2:27][CH2:26][C:25]([CH3:24])([CH3:45])[CH3:46])[CH3:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: C[C@H](C[C@H](O)[C@@H](N)Cc1ccccc1)C(=O)NCCC(C)(C)C
Reactant: CS(=O)(=O)c1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cccc(S(C)(=O)=O)c1)C(=O)NCCC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.2 %

Procedure:
To a solution of 3-methanesulfonyl benzoic acid (77 mg, 0.39 mmol) and 1-hydroxybenzotriazole (52 mg, 0.39 mmol) in 2:1 dichloromethane/DMF (3.0 ml) was added (2R,4S,5S)-5-amino-4-hydroxy-2-methyl-6-phenylhexanoic acid (3,3-dimethylbutyl)-amide (D2) (100 mg, 0.32 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (86 mg, 0.45 mmol). The resulting solution was stirred at room temperature overnight and then evaporated to dryness. The residue was partitioned between ethyl acetate and 1M hydrochloric acid. The organic phase was separated and washed with further 1M hydrochloric acid, dil. aq. NaHCO3 and brine. It was dried over MgSO4, filtered and evaporated to afford the crude product which was triturated with ether to afford the title compound (63 mg, 39%).
Reaction SMILES: [Br-].[OH:2][C:3]1[CH:28]=[CH:27][CH:26]=[CH:25][C:4]=1[CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[O:29]=[C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32](=[O:39])[N:31]1[CH2:40][CH2:41][CH2:42][C:43]1[CH:44]=[C:45]([CH:48]=[CH:49][CH:50]=1)[CH:46]=O>>[OH:2][C:3]1[CH:28]=[CH:27][CH:26]=[CH:25][C:4]=1/[CH:5]=[CH:46]/[C:45]1[CH:44]=[C:43]([CH2:42][CH2:41][CH2:40][N:31]2[C:32](=[O:39])[C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:30]2=[O:29])[CH:50]=[CH:49][CH:48]=1
Reactant: Oc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1
Agent: [Br-]
Product: O=C1c2ccccc2C(=O)N1CCCc1cccc(/C=C/c2ccccc2O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Hydroxybenzyltriphenylphosphonium bromide was coupled with phthalimide 29 according to the method used in Example 45 except that the reaction was stirred at room temperature overnight. The reaction mixture was then concentrated under reduced pressure and partitioned between EtOAc and water. The combined organics were washed with saturated aqueous NH4Cl and water, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (5 to 60% EtOAc-hexanes gradient) gave (E)-2-(3-(3-(2-hydroxystyryl)phenyl)propyl)isoindoline-1,3-dione as a light yellow foam. Yield (0.165 g, 43%): 1H NMR (400 MHz, DMSO-d6) δ 9.69 (s, 1H), 7.78-7.84 (m, 4H), 7.53 (dd, J=8.0, 1.6 Hz, 1H), 7.28-7.38 (m, 3H), 7.22 (t, J=8.4 Hz, 1H), 7.05-7.14 (m, 3H), 6.76-6.86 (m, 2H), 3.61 (t, J=6.8 Hz, 2H), 2.63 (t, J=7.2 Hz, 2H), 1.89-1.97 (m, 2H).
Reaction SMILES: C(N1CCC(C2C=CC(N[C:17]3[C:18]4[N:19]([CH:33]=[CH:34][N:35]=4)[C:20]([C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][CH:31]=4)[C:28](=[O:32])[NH:27][CH2:26]5)=[CH:21][N:22]=3)=CC=2)CC1)(C)C.[CH:36]([N:39]1[CH2:44][CH2:43][N:42]([C:45]2[CH:50]=[CH:49][C:48]([NH2:51])=[CH:47][C:46]=2[C:52]([F:55])([F:54])[F:53])[CH2:41][CH2:40]1)([CH3:38])[CH3:37]>>[CH:36]([N:39]1[CH2:40][CH2:41][N:42]([C:45]2[CH:50]=[CH:49][C:48]([NH:51][C:17]3[C:18]4[N:19]([CH:33]=[CH:34][N:35]=4)[C:20]([C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][CH:31]=4)[C:28](=[O:32])[NH:27][CH2:26]5)=[CH:21][N:22]=3)=[CH:47][C:46]=2[C:52]([F:55])([F:54])[F:53])[CH2:43][CH2:44]1)([CH3:38])[CH3:37]
Reactant: CC(C)N1CCN(c2ccc(N)cc2C(F)(F)F)CC1
Reactant: CC(C)N1CCC(c2ccc(Nc3ncc(-c4ccc5c(c4)CNC5=O)n4ccnc34)cc2)CC1
Product: CC(C)N1CCN(c2ccc(Nc3ncc(-c4ccc5c(c4)CNC5=O)n4ccnc34)cc2C(F)(F)F)CC1

Procedure:
This compound may be prepared using the methods as described for Compound 206, using 4-(4-isopropylpiperazin-1-yl)-3-(trifluoromethyl)phenylamine in Step 3. LCMS: Rt=0.98 min (95%), m/z 536 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][S:9]([C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([OH:17])=O)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:45]1[NH:50][CH2:49][CH2:48][N:47]2[CH2:51][CH2:52][CH2:53][C@@H:46]12>CN(C)C(=O)C.CC1CCCO1>[F:1][C:2]1[CH:3]=[C:4]([NH:8][S:9]([C:12]2[CH:20]=[CH:19][CH:18]=[C:14]([C:15]([N:50]3[CH2:49][CH2:48][N:47]4[CH2:51][CH2:52][CH2:53][C@H:46]4[CH2:45]3)=[O:17])[CH:13]=2)(=[O:10])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(S(=O)(=O)Nc2cccc(F)c2)c1
Reactant: C1C[C@H]2CNCCN2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC1CCCO1
Solvent: CC(=O)N(C)C
Product: O=C(c1cccc(S(=O)(=O)Nc2cccc(F)c2)c1)N1CCN2CCC[C@H]2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-{[(3-fluorophenyl)amino]sulfonyl}benzoic acid (0.9 g, 3.05 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (1.27 g, 3.35 mmol) in N,N-dimethylacetamide (6.4 mL) and 2-methyltetrahydrofuran (15 mL) was added (S)-octahydropyrrolo[1,2-a]pyrazine (0.55 g, 4.33 mmol) in 2-methyltetrahydrofuran (4 mL). The reaction was stirred at ambient temperature overnight and then diluted with 2-methyltetrahydrofuran (15 mL). The organic solution was washed with 6% NaHCO3/6% NaCl (10 mL), and the aqueous layer was extracted with 2-methyltetrahydrofuran (15 mL). The combined organic layers were washed with 6% NaHCO3/6% NaCl (10 mL), saturated NaCl (2×10 mL, 2×20 mL) and 1:1 saturated NaCl/water (2×20 mL), and then concentrated. The residue was concentrated from ethanol (2×10 mL) to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([N:22]2[C:30]3[CH:29]=[C:28]4[C:31]5([CH2:37][O:38][C:27]4=[CH:26][C:25]=3[CH2:24][CH2:23]2)[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]5)=[O:21])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:46][CH2:47][OH:48]>C(O)C>[OH:48][CH2:47][CH2:46][N:34]1[CH2:33][CH2:32][C:31]2([C:28]3[C:27](=[CH:26][C:25]4[CH2:24][CH2:23][N:22]([C:20]([C:17]5[CH:16]=[CH:15][C:14]([C:3]6[CH:4]=[CH:5][C:6]([C:8]7[O:9][C:10]([CH3:13])=[N:11][N:12]=7)=[CH:7][C:2]=6[CH3:1])=[CH:19][CH:18]=5)=[O:21])[C:30]=4[CH:29]=3)[O:38][CH2:37]2)[CH2:36][CH2:35]1
Reactant: OCCBr
Reactant: Cc1nnc(-c2ccc(-c3ccc(C(=O)N4CCc5cc6c(cc54)C4(CCNCC4)CO6)cc3)c(C)c2)o1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1nnc(-c2ccc(-c3ccc(C(=O)N4CCc5cc6c(cc54)C4(CCN(CCO)CC4)CO6)cc3)c(C)c2)o1
Yield: 56.4 %

Procedure:
A stirred solution of 5-(2'-methyl-4'-(5-methyl-1,3,4-oxadiazol-2-yl)biphenyl-4-carbonyl)-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (E17 in WO 96/19477, 1.5 g, 2.9 mmole) in ethanol (30 ml) was treated with sodium carbonate (1.2 g, 11.6 mmole) and 2-bromoethanol (0.41 ml, 5.8 mmole) and heated under reflux for 20 hours. The reaction mixture was concentrated in vacuo and the residue treated with water (10 ml) and extracted with chloroform. The extract was dried (Na2SO4), concentrated in vacuo and the residue chromatographed on silica gel eluting with 0-6% methanol/chloroforn to afford the title compound as a yellow solid (0.9 g, 56%). This was converted to its hydrochloride salt and crystallised from acetone m.p. >250° C.
Reaction SMILES: [C:1]1([C:7]2[C:16]([N:17]3[CH2:22][CH2:21][CH:20]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:19][CH2:18]3)=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:30]([O:32]C)=[O:31])[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:36]I>O1CCCC1>[CH3:36][N:23]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:20]1[CH2:19][CH2:18][N:17]([C:16]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:8][C:9]3[C:14]([N:15]=2)=[CH:13][C:12]([C:30]([OH:32])=[O:31])=[CH:11][CH:10]=3)[CH2:22][CH2:21]1
Reactant: CI
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCC(Nc4ccccc4)CC3)nc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(c1ccccc1)C1CCN(c2nc3cc(C(=O)O)ccc3nc2-c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 10.1 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 2-phenyl-3-(4-(phenylamino)piperidin-1-yl)quinoxaline-6-carboxylate (297.4 mg, 0.68 mmol, 1.00 equiv) in tetrahydrofuran (16 mL). Then sodium hydride (163 mg, 6.79 mmol, 10.00 equiv) and CH3I (964 mg, 6.79 mmol, 10.00 equiv) was added. The resulting solution was stirred for 2 days at room temperature. The reaction was then quenched by the addition of water. The resulting aqueous solution was extracted with 5×30 mL of dichloromethane. The organic layers were combined and concentrated under vacuum. The crude product (150 mg) was purified by Prep-HPLC with the following conditions (AGILENT Pre-HPLC (UV-Directed): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (25% CH3CN up to 60% in 6 min, up to 100% in 1 min); Detector, UV 254 nm 30 mg of product was obtained. This resulted in 30 mg (10%) of 3-(4-(methyl(phenyl)amino)piperidin-1-yl)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: C([O:8][C:9]1[C:13]([O:14]CC2C=CC=CC=2)=[C:12]([C:22](=[O:26])[N:23]([CH3:25])[CH3:24])[N:11]([C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)[C:10]=1[C:34]([O:36][CH2:37][CH3:38])=[O:35])C1C=CC=CC=1>CO.[Pd]>[CH3:25][N:23]([CH3:24])[C:22]([C:12]1[N:11]([C:27]2[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=2)[C:10]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:9]([OH:8])[C:13]=1[OH:14])=[O:26]
Reactant: CCOC(=O)c1c(OCc2ccccc2)c(OCc2ccccc2)c(C(=O)N(C)C)n1-c1ccc(O)cc1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1c(O)c(O)c(C(=O)N(C)C)n1-c1ccc(O)cc1
Yield: 54.8 %

Procedure:
A solution of ethyl 3,4-bis(benzyloxy)-5-(dimethylcarbamoyl)-1-(4-hydroxyphenyl)-1H-pyrrole-2-carboxylate (36) (30 mg, 0.06 mmol) in MeOH (2 mL) was passed through a Thales ‘H-cube’ cartridge (10% Pd/C) at a flow rate of 1 mL/min at 25° C. under H2 (full H2 mode). The output was concentrated in vacuo, and a solid was collected by filtration after trituration with isohexane to afford ethyl 5-(dimethylcarbamoyl)-3,4-dihydroxy-1-(4-hydroxyphenyl)-1H-pyrrole-2-carboxylate (UL1-100) (11 mg, 56%) as a yellow solid: m/z 335 (M+H)+ (ES+), 333 (M−H)− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 9.50 (s, 1H), 8.54 (s, 1H), 8.42 (s, 1H), 6.94-6.86 (m, 2H), 6.69-6.62 (m, 2H), 3.99 (q, J=7.0 Hz, 2H), 2.81 (br s, 6H), 0.98 (t J=7.0 Hz, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.Cl[C:10]1[N:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:18]=[C:14]2[N:13]=[C:12]([S:25][CH3:26])[N:11]=1>>[NH:6]1[CH:5]=[C:4]([CH2:3][CH2:2][NH:1][C:10]2[N:15]3[N:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:18]=[C:14]3[N:13]=[C:12]([S:25][CH3:26])[N:11]=2)[N:8]=[CH:7]1
Reactant: CSc1nc(Cl)n2nc(-c3ccccc3)cc2n1
Reactant: NCCc1c[nH]cn1
Product: CSc1nc(NCCc2c[nH]cn2)n2nc(-c3ccccc3)cc2n1

Procedure:
4-[4-imidazolylethylamino]-2-methylthio-7-phenylpyrazolo[1,5-a]-1,3,5-triazine is prepared from histamine and 4-chloro-2-methylthio-7-phenylpyrazolo[1,5-a]-1,3,5-triazine according to conventional methods.