Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][CH2:10][C:11]([C:13]2[S:14][C:15]([CH2:24][CH3:25])=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:17]=2)=[O:12])=[CH:4][C:3]=1[CH3:26].Cl[CH2:28][C@@H:29]([OH:32])[CH2:30][OH:31]>CC(O)C.[OH-].[Na+].O>[OH:32][C@@H:29]([CH2:30][OH:31])[CH2:28][O:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][CH2:10][C:11]([C:13]2[S:14][C:15]([CH2:24][CH3:25])=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:17]=2)=[O:12])=[CH:4][C:3]=1[CH3:26]
Reactant: CCc1sc(C(=O)CCc2cc(C)c(O)c(C)c2)cc1-c1ccccc1
Reactant: OC[C@H](O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CCc1sc(C(=O)CCc2cc(C)c(OC[C@@H](O)CO)c(C)c2)cc1-c1ccccc1
Temperature: 70 °C
Reaction time: 15 h
Yield: 22.3 %

Procedure:
A solution of 3-(4-hydroxy-3,5-dimethyl-phenyl)-1-(5-ethyl-4-phenyl-thiophen-2-yl)-propan-1-one (52 mg, 0.143 mmol) in 2-propanol (1 mL) and 3 N aq. NaOH (0.3 mL) is treated with (S)-3-chloro-propane-1,2-diol (79 mg, 0.71 mmol) and the mixture is stirred at 70° C. for 15 h. The reaction mixture is diluted with water and extracted with DCM. The solvent of the organic extract is evaporated and the crude product is purified on prep. TLC plates with heptane:EA 1:3 to give 3-[4-((S)-2,3-dihydroxy-propoxy)-3,5-dimethyl-phenyl]-1-(5-ethyl-4-phenyl-thiophen-2-yl)-propan-1-one (14 mg) as a colourless resin; LC-MS: tR=1.03 min, [M+1]+=439.25; 1H NMR (CDCl3): δ 7.58 (s, 1H), 7.45-7.30 (m, 5H), 6.88 (s, 2H), 4.11-4.04 (m, 1H), 3.87-3.80 (m, 4H), 3.67-3.60 (m, 2H), 3.60-3.56 (m, 1H), 3.48-3.40 (m, 1H), 3.20-3.10 (m, 2H), 2.98-2.87 (m, 4H), 2.25 (s, 6H), 1.30 (t, J=7.6 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[N:14]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:15]([O:17][C@H:18]4[C@H:22]5[O:23][CH2:24][C@@H:25]([OH:26])[C@H:21]5[O:20][CH2:19]4)=[N:16][C:11]3=[CH:10][C:9]=2[Cl:35])=[CH:4][CH:3]=1.[NH:36]1[CH2:41][CH2:40][CH:39]([NH:42][C:43](=[O:50])[O:44][CH:45]2[CH2:49][CH2:48][CH2:47][CH2:46]2)[CH2:38][CH2:37]1>>[Cl:35][C:9]1[CH:10]=[C:11]2[N:16]=[C:15]([O:17][C@@H:18]3[CH2:19][O:20][C@@H:21]4[C@H:25]([OH:26])[CH2:24][O:23][C@H:22]34)[N:14]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:12]2=[N:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([N:36]2[CH2:37][CH2:38][CH:39]([NH:42][C:43](=[O:50])[O:44][CH:45]3[CH2:49][CH2:48][CH2:47][CH2:46]3)[CH2:40][CH2:41]2)=[CH:3][CH:4]=1
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2cc(Cl)c(-c3ccc(Br)cc3)nc21
Reactant: O=C(NC1CCNCC1)OC1CCCC1
Product: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2cc(Cl)c(-c3ccc(N4CCC(NC(=O)OC5CCCC5)CC4)cc3)nc21

Procedure:
The title compound is prepared from (3R,3aR,6R,6aR)-6-(5-(4-bromophenyl)-6-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-2-yloxy)hexahydrofuro[3,2-b]furan-3-ol and cyclopentyl piperidin-4-ylcarbamate following a procedure analogous to that described for Intermediate 23. LC (method 1): tR=1.09 min; Mass spectrum (ESI+): m/z=714 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH2:44]([O:46][C:47](=[O:55])[CH2:48][C:49]1[N:50]=[C:51]([NH2:54])[S:52][CH:53]=1)[CH3:45].C(N(CC)C(C)C)(C)C.Cl>CN(C)C=O>[CH2:44]([O:46][C:47](=[O:55])[CH2:48][C:49]1[N:50]=[C:51]([NH:54][C:8](=[O:10])[CH:7]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[S:52][CH:53]=1)[CH3:45]
Reactant: O=C(O)C(CC1CCCC1)c1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)Cc1csc(N)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cc1csc(NC(=O)C(CC2CCCC2)c2ccc([N+](=O)[O-])cc2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 16.2 %

Procedure:
A solution of 3-cyclopentyl-2-(4-nitro-phenyl)-propionic acid (prepared in Example 22A, 263.0 mg, 1.0 mmol) in N,N-dimethylformamide (10 mL) was treated with O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (379 mg, 1.0 mmol), (2-amino-thiazol-4-yl)-acetic acid ethyl ester (279 mg, 1.5 mmol) and N,N-diisopropylethylamine (0.34 mL, 2.0 mmol). The reaction mixture was stirred at 25° C. for 5 h. The reaction mixture was then poured into a 2 N aqueous hydrochloric acid solution (25 mL) and extracted with ethyl acetate (3×25 mL). The organic layers were combined and washed with water (1×75 mL), a saturated aqueous sodium bicarbonate solution (1×75 mL), a saturated aqueous sodium chloride solution (3×75 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 70/30 hexanes/ethyl acetate) afforded {2-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-thiazol-4-yl}-acetic acid ethyl ester (70.0 mg, 39.4%) as a pale yellow oil: FAB-HRMS m/e calcd for C21H25N3O5S (M+H)+ 432.1593, found 432.1595.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:11])[CH3:10])C.S(=O)(=O)(O)O>O>[C:9]([NH:8][CH2:7][CH2:6][CH2:5][CH:4]=[O:3])(=[O:11])[CH3:10]
Reactant: CCOC(CCCNC(C)=O)OCC
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)NCCCC=O

Procedure:
Dissolve 5 gms. of 4-acetamidobutyraldehyde diethyl acetal in 75 ml. of distilled water and 5 ml. of 1 N sulfuric acid. Allow the solution to stand at room temperature until the hydrolysis is complete as determined by thin layer chromatography. Neutralize the solution with sodium bicarbonate, then saturate the solution with sodium chloride and extract with chloroform. Distill the combined chloroform extracts to a residue comprising 4-acetamidobutyraldehyde, which can be used without further purification in the following procedure.
Reaction SMILES: [Cl:1][C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[O:10]1[C:12]2([CH2:17][CH2:16][N:15]([C:18](=[O:33])[CH2:19][N:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)[CH2:14][CH2:13]2)[CH2:11]1.C(=O)([O-])O.[Na+]>C(O)C>[Cl:1][C:2]1[N:3]([CH2:11][C:12]2([OH:10])[CH2:13][CH2:14][N:15]([C:18](=[O:33])[CH2:19][N:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:22][CH2:21]3)[CH2:16][CH2:17]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(=O)N2CCC3(CC2)CO3)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(CC(=O)N2CCC(O)(Cn3cc([N+](=O)[O-])nc3Cl)CC2)CC1
Yield: 60.5 %

Procedure:
2-Chloro-4-nitro-1H-imidazole (1.29 g, 8.76 mmol), tert-butyl 4-{2-(1-oxa-6-azaspiro[2,5]octan-6-yl)-2-oxoethyl}piperazine-1-carboxylate (2.97 g, 8.76 mmol) and sodium hydrogencarbonate (809 mg, 9.64 mmol) in ethanol (10 ml) was stirred under reflux for 5 hours. The reaction mixture was concentrated under reduced pressure, and a saturated sodium hydrogencarbonate solution was added. The solution was extracted with methylene chloride. The organic phase was dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=100/1) to afford tert-butyl 4-{2-[4-(2-chloro-4-nitroimidazol-1-ylmethyl)-4-hydroxypiperidin-1-yl]-2-oxoethyl}piperazine-1-carboxylate (2.58 g, yield 61%) as a yellow oil.
Reaction SMILES: Cl.N(OCCC(C)C)=O.[CH2:10]([O:17][C:18]([NH:20][C@H:21]([C:24]([NH:26][C@H:27]([C:36]([N:38]=[N+]=[N-])=[O:37])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)=[O:25])[CH2:22][OH:23])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl.[CH3:42][O:43][C:44](=[O:55])[C@H:45]([CH2:51][CH:52]([CH3:54])[CH3:53])[NH:46][C:47](=[O:50])[CH2:48]N>O1CCCC1.C(N(CC)CC)C.CN(C)C=O>[CH3:42][O:43][C:44](=[O:55])[C@H:45]([CH2:51][CH:52]([CH3:53])[CH3:54])[NH:46][C:47](=[O:50])[CH2:48][NH:38][C:36](=[O:37])[C@H:27]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)[NH:26][C:24](=[O:25])[C@H:21]([CH2:22][OH:23])[NH:20][C:18]([O:17][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:19]
Reactant: [N-]=[N+]=NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)CN
Agent: CC(C)CCON=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Temperature: -60 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 7.49 g. of N-benzyloxycarbonyl-L-seryl-L-tyrosyl hydrazide [this compound is reported in Helv. Chim. Acta, 41, 1852 (1958)] in 50 ml. of N,N-dimethylformamide, cooled to -30° C., is first added 16.9 ml. of 3.607 N hydrogen chloride in tetrahydrofuran and then 2.7 ml. of isoamyl nitrite, and the resulting mixture is stirred at -30° C. for 30 minutes. The mixture, which contains N-benzyloxycarbonyl-L-seryl-L-tyrosyl azide, is next cooled to -60° C., and to it are added first 8.57 ml. of triethylamine, then 4.297 g. of glycyl-L-leucine methyl ester hydrochloride and finally 2.52 ml. more of triethylamine. The stirred mixture is allowed to warm to 0° C. during one hour and is stirred at 0° C. for one hour and kept at -5° C. for 48 hours. It is then filtered, and the filtrate is evaporated under reduced pressure at 40°-50° C. The gummy residue is partitioned between dilute hydrochloric acid and ethyl acetate, and the organic layer is separated, washed with saturated aqueous sodium bicarbonate and with saturated aqueous sodium chloride, dried, and evaporated to give a solid residue of N-benzyloxycarbonyl-L-seryl-L-tyrosylglycyl-L-leucine methyl ester; m.p. 166°-167° C., following two crystallizations from ethyl acetate-ether; [α]D25 -25.4° (2% in N,N-dimethylformamide); [α]D25 -38.2° (2.09% in methanol).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[S:3]([C:6]1[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][C:10]([O:12]CC)=O)(=[O:5])=[O:4].[NH2:20][CH2:21][CH:22]([OH:33])[CH2:23][N:24]1[CH2:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25]1>CCO>[CH3:19][N:2]([CH3:1])[S:3]([C:6]1[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][C:10]([NH:20][CH2:21][CH:22]([OH:33])[CH2:23][N:24]1[CH2:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25]1)=[O:12])(=[O:4])=[O:5]
Reactant: CCOC(=O)COc1ccccc1S(=O)(=O)N(C)C
Reactant: NCC(O)CN1Cc2ccccc2C1
Solvent: CCO
Product: CN(C)S(=O)(=O)c1ccccc1OCC(=O)NCC(O)CN1Cc2ccccc2C1
Temperature: 120 °C
Yield: 13 %

Procedure:
To a solution of ethyl 2-(2-(N,N-dimethylsulfamoyl)phenoxy)acetate (100 mg, 0.35 mmol) in EtOH (1 mL) was added 1-amino-3-(isoindolin-2-yl)propan-2-ol (66.8 mg, 0.35 mmol). The reaction mixture was heated under microwave conditions at 120° C. for 0.5 h. The material was concentrated and purified by preparative HPLC purification. (20 mg, yield 13%) MS (ESI+) e/z: 434.1 [M+1]+. 1H NMR (MeOD, 400 MHz), δ ppm: 7.85 (dd, J=7.78, 1.51 Hz, 1H), 7.70-7.61 (m, 1H), 7.27-7.16 (m, 6H), 4.75 (s, 2H), 4.05-3.91 (m, 5H), 3.55 (dd, J=13.68, 4.89 Hz, 1H), 3.40-3.35 (m, 1H), 2.92-2.77 (m, 8H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[C:26]([F:29])([F:28])[F:27])=[O:9])=[CH:4][CH:3]=1.[OH-].[NH4+:31]>O>[NH2:31][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[C:26]([F:27])([F:28])[F:29])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(F)cc1)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Product: Nc1ccc(C(=O)c2cnc3c(C(F)(F)F)cccc3c2-c2ccccc2)cc1
Temperature: 150 °C

Procedure:
(4-Fluorophenyl)[4-phenyl-8-(trifluoromethyl)quinolin-3-yl]methanone (0.631 g, 1.60 mmol) and ammonium hydroxide (9 mL) are heated in a steel pressure vessel at 150° C. overnight. The cooled reaction is poured into water, extracted with methylene chloride, and concentrated in vacuo. The resulting solid into DMSO (2 mL) and ammonium hydroxide (8 mL) is heated in the steel bomb at 150° C. overnight and worked up as above. The product is purified by chromatography eluting with 30:70 ethyl acetate:hexane to yield the title compound as a solid (0.344 g). MS (ESI) m/z 393; HRMS: calcd for C23H15F3N2O—H, 391.10582; found (ESI, [M−H]−), 391.1054.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[H-].[Na+].[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14](Cl)[N:13]=1>CN(C=O)C>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[N:13]=1
Reactant: Fc1ccccc1S
Reactant: Clc1cccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccccc1Sc1cccc(Cl)n1
Temperature: 70 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
2-Fluorothiophenol (Aldrich, St. Louis, Mo., Cat. No. 275379; 1.6 mL, 15 mmol) was dissolved in DMF (10 mL), and then NaH (0.45 g, 19 mmol) was added slowly to the mixture. After 1 hour, 2,6-dichloropyridine (Aldrich, St. Louis, Mo., Cat. No. 073707; 2.00 g, 14 mmol) was added and the mixture was heated in a pre-heated (70° C.) bath, and allowed to stir under inert atmosphere for 3 hours. The mixture was quenched with 1N NaOH and diluted with DCM. The organic layer was extracted with 4:1 DCM/MeOH (3×25 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by ISCO Silica-Gel Chromatography (Teledyne ISCO, Lincoln, Nebr.) on a 120 gm column eluting with a solvent gradient of 1-30% DCM/Hexanes over 35 minutes to give 2-chloro-6-(2-fluorophenylthio)pyridine (1.13 g, 35% yield) as colorless oil. MS (ESI pos. ion) m/z: 240 (MH+). Calculated exact mass for C11H7ClFNS: 239.
Reaction SMILES: [F:1][C:2]1C(F)=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:9]1([NH:37][C:38]([NH:40][C:41](=[O:48])[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[S:39])[C@H:13]([CH2:14]O)[C@@H:12]([CH2:16][O:17][C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:11][CH2:10]1.N1C=CC=CC=1.F[C:56]([F:69])(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[NH4+].[Cl-]>C(Cl)Cl.O>[F:1][C:2]1[C:56]([F:69])=[CH:6][CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:10][O:11][C@H:12]([CH2:16][O:17][C:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:13]1[CH2:14][S:39][C:38]([NH:40][C:41](=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[N:37]2
Reactant: O=C(NC(=S)N[C@@]1(c2cccc(F)c2F)CO[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@H]1CO)c1ccccc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: O=C(NC1=N[C@@]2(c3cccc(F)c3F)CO[C@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@H]2CS1)c1ccccc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 101.7 %

Procedure:
To a solution of N-(((3S,4R,5S)-3-(2,3-difluorophenyl)-4-(hydroxymethyl)-5-((trityloxy)methyl)tetrahydrofuran-3-yl)carbamothioyl)benzamide (34.0 g, 0.0511 mol, 1.0 equiv.) in CH2Cl2 (204 mL) at −20° C., pyridine (10.3 ml, 0.128 mol, 2.50 equiv.) was added. A solution of trifluoromethanesulfonic anhydride (9.46 mL, 0.0563 mol, 1.10 equiv.) in CH2Cl2 (34 mL) was then added over 12 min while maintaining temperature below −17° C. The reaction was stirred for 30 min at −20° C. then allowed to warm up slowly to 5° C. Sat aq. NH4Cl (85 mL) and water (32 mL) were added. The aqueous layer was then extracted with CH2Cl2 (68 mL). The organic phase was concentrated under reduced pressure providing title compound (33.6 g) as an orange foam.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1.[OH:19][C@@H:20]1[CH2:24][O:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21]1.[H-].[Na+].O>C1COCC1>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=[C:2]([O:19][C@@H:20]2[CH2:24][O:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21]2)[CH:7]=1
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)CO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@H](Oc2cc(Cl)nc(SCc3cccc(F)c3F)n2)CO1
Temperature: 60 °C

Procedure:
To a stirred solution of 4,6-Dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine (the product of Example 1, step ii) (0.25 g) and 1,1-dimethylethyl (S)-4-hydroxyisoxazolidine-2-carboxylate (0.16 g) in dry THF (5 mL) was added 60% Sodium hydride (0.034 g) over 5 min. The reaction mixture was stirred and heated at 60° C. for 7 days, H2O was added and the solvents were partially evaporated. The residue was extracted with EtOAc which was washed with H2O, dried (MgSO4) and the solvent evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with Et2O/iso-hexane (1:9) to give the subtitle compound as a gum. Yield: 0.15 g.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][CH2:15][CH:16]([NH:30][CH2:31][C:32]([O:34]C)=[O:33])[CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH-].[K+]>O1CCCC1>[F:1][C:2]([F:36])([F:37])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][CH2:15][CH:16]([NH:30][CH2:31][C:32]([OH:34])=[O:33])[CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COC(=O)CNC(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CNC(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(c1ccccc1)c1ccccc1

Procedure:
To a solution of 1-((3,5-bis (trifiuoromethyl)phenyl)methyloxy)-2-(N-((carbomethoxy) methyl)amino)-3,3-diphenylpropane (Example 1g, 2.38 g) in tetrahydrofuran (25 ml) was added 1M-potassium hydroxide solution (25 ml) and the mixture heated to reflux for 16 hours. The solvent was removed by evaporation and 1M-hydrochloric acid was added to an aqueous solution of the residue until pH=2. The gum which formed was recrystallised from aqueous ethanol to give N-(1-((3,5-bis(trifiuoromethyl) phenyl)methyloxy)-3,3- diphenylprop-2-yl)glycine mp 116°-119° C.; m/e (CI+) 512 (M+H), (CI-) 511 (M). Found: C, 60.06; H, 4.55; N, 2.66; C26H23NO3F6.0.5(H2O) requires C, 60.00; H, 4.64; N, 2.69%.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](Cl)=[O:8])(=[O:4])=[O:3].[CH2:14]([NH:21][C:22]([C:24]1[S:28][C:27]([NH2:29])=[N:26][C:25]=1[CH3:30])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([NH:21][C:22]([C:24]1[S:28][C:27]([NH:29][C:7](=[O:8])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[S:2]([CH3:1])(=[O:4])=[O:3])=[N:26][C:25]=1[CH3:30])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Reactant: CS(=O)(=O)c1ccccc1C(=O)Cl
Product: Cc1nc(NC(=O)c2ccccc2S(C)(=O)=O)sc1C(=O)NCc1ccccc1
Yield: 9 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 2-methanesulfonylbenzoyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 9% yield; m.p. 239-242° C.; 1H NMR (DMSO-d6, 300 MHz) δ 8.64 (t, J=5.8 Hz, 1H), 8.59 (s, 1H), 8.35 (d, J=7.8 Hz, 1H), 8.13 (d, J=7.8 Hz, 1H), 7.80 (t, J=7.8 Hz, 1H), 7.33-7.19 (m, 6H), 4.38 (d, J=5.8 Hz, 2H), 3.26 (s, 3H), 2.51 (s, 3H); MS (ES+) m/z 430.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CCN(C(C)C)C(C)C>C(#N)C>[C:26]([N:15]1[CH2:16][CH2:17][N:12]([C:6]2([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)[C:5]3[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=3)[NH:8][C:7]2=[O:11])[CH2:13][CH2:14]1)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(c1ccccc1)N1CCN(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.7 %

Procedure:
The mixture of rac-6-chloro-3-(3-chloro-benzyl)-3-piperazin-1-yl-1,3-dihydro-indol-2-one (100 mg, 0.266 mmol), benzoyl chloride (37 mg, 0.266 mmol) and DIPEA (34 mg, 0.266 mmol) in acetonitrile (3 mL) was stirred at room temperature for overnight. Then the mixture was concentrated and the residue was purified with preparative HPLC to give 29 mg of rac-3-(4-benzoyl-piperazin-1-yl)-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one as a light orange solid. MS m/z 480 (M+H)+.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH:13]2[C:14]([O:47]C(OCC)C)([CH3:46])[CH2:15][CH2:16][CH:17]([OH:45])[CH2:18][C:19]([O:21][CH:22](/[C:27](/[CH3:44])=[CH:28]/[CH:29]=[CH:30]/[C:31]([OH:43])([CH3:42])[CH2:32][CH:33]3[O:41][CH:34]3[CH:35]([CH3:40])[CH:36]([OH:39])[CH2:37][CH3:38])[CH:23]([CH3:26])[CH:24]=[CH:25]2)=[O:20])=[O:11])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.CC(O)(C)C>O1CCCC1>[CH2:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][CH:13]2[C:14]([OH:47])([CH3:46])[CH2:15][CH2:16][CH:17]([OH:45])[CH2:18][C:19]([O:21][CH:22](/[C:27](/[CH3:44])=[CH:28]/[CH:29]=[CH:30]/[C:31]([OH:43])([CH3:42])[CH2:32][CH:33]3[O:41][CH:34]3[CH:35]([CH3:40])[CH:36]([OH:39])[CH2:37][CH3:38])[CH:23]([CH3:26])[CH:24]=[CH:25]2)=[O:20])=[O:11])[CH2:8][CH2:9]1)[CH:2]=[CH2:3]
Reactant: C=CCN1CCN(C(=O)OC2C=CC(C)C(/C(C)=C/C=C/C(C)(O)CC3OC3C(C)C(O)CC)OC(=O)CC(O)CCC2(C)OC(C)OCC)CC1
Agent: C=CCN1CCN(C(=O)OC2/C=C/C(C)C(/C(C)=C/C=C/C(C)(O)CC3OC3C(C)C(O)CC)OC(=O)CC(O)CCC2(C)O)CC1
Agent: C=CCN1CCN(C(=O)OC2/C=C/C(C)C(/C(C)=C/C=C/C(C)(O)CC3OC3C(C)C(O)CC)OC(=O)CC(O)CCC2(C)OC(C)OCC)CC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: C=CCN1CCN(C(=O)OC2C=CC(C)C(/C(C)=C/C=C/C(C)(O)CC3OC3C(C)C(O)CC)OC(=O)CC(O)CCC2(C)O)CC1

Procedure:
To Compound 46 (8E,12E,14E)-7-((4-allylpiperazin-1-yl)carbonyl)oxy-6-(1-ethoxyethoxy)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide (8.7 mg, 12 μmol) obtained in Example 46 was added a solution of pyridinium p-toluenesulfonate (3.3 mg, 13 μmol) in a mixture of tetrahydrofuran:2-methyl-2-propanol=1:1 (1 mL) at room temperature, and the reaction mixture was stirred at the same temperature for 17 hours. The reaction mixture was concentrated. The resulting residue was purified by thin layer chromatography (Fuji Silysia, NH Silica gel Plate; methanol:dichloromethane=5:95) to give the title compound (5.5 mg, 70%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH2:20][C:21]1([CH3:26])[O:25][CH2:24][CH2:23][O:22]1)[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=[C:5]1[CH2:17][CH2:18][CH3:19].C1C=C(Cl)C=C(C(OO)=[O:36])C=1>>[CH3:27][C:2]([CH3:1])([CH2:20][C:21]1([CH3:26])[O:25][CH2:24][CH2:23][O:22]1)[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N+:9]([O-:36])=[CH:8][C:7]=2[N:6]=[C:5]1[CH2:17][CH2:18][CH3:19]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCc1nc2cnc3ccccc3c2n1CC(C)(C)CC1(C)OCCO1
Product: CCCc1nc2c[n+]([O-])c3ccccc3c2n1CC(C)(C)CC1(C)OCCO1

Procedure:
The general method described in Steps 9 and 10 of Example 1 was used to aminate 1-[2,2-dimethyl-3-(2-methyl-[1,3]dioxolan-2-yl)propyl]-2-propyl-1H-imidazo[4,5-c]quinoline (3.10 g, 8.44 mmol) by reaction with m-CPBA (3.70 g) to provide 1-[2,2-dimethyl-3-(2-methyl-[1,3]dioxolan-2-yl)propyl]-5-oxido-2-propyl-1H-imidazo[4,5-c]quinoline followed by reaction with p-toluenesulfonyl chloride (2.80 g, 14.7 mmol) and ammonium hydroxide solution (100 mL) to provide 1-[2,2-dimethyl-3-(2-methyl-[1,3]dioxolan-2-yl)propyl]-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine as off-white needles after recrystallization from aqueous methanol, mp 186-188° C.