Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17](Cl)[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[NH3:22]>O1CCOCC1>[NH2:22][C:17]1[CH:16]=[C:15]([C:13]2[CH:12]=[CH:11][N:10]=[C:9]([NH:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:14]=2)[CH:20]=[CH:19][N:18]=1
Reactant: Clc1cccc(Nc2nccc(-c3ccnc(Cl)c3)n2)c1
Reactant: N
Solvent: C1COCCO1
Product: Nc1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1
Temperature: 200 °C

Procedure:
A suspension of (3-chloro-phenyl)-[4-(2-chloro-pyridin-4-yl)-pyrimidin-2-yl]-amine (10.0 g, 0.03 mol) in dioxane (150 ml) and ammonia (20 g) is heated in an autoclave at 200° C. for 48 hours. The reaction mixture is partitioned between ethyl acetate and water. The organic phase is evaporated under reduced pressure and the product is purified by chromatography on silicagel.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[C:7]([OH:14])[N:8]=[CH:9]2)([O-:3])=[O:2].[C:15](O)(=[O:17])[CH3:16].N1C=CC=CC=1>C(OC(=O)C)(=O)C>[C:15]([O:14][C:7]1[N:8]=[CH:9][C:10]2[C:5]([CH:6]=1)=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=[CH:12][CH:11]=2)(=[O:17])[CH3:16]
Reactant: CC(=O)O
Reactant: O=[N+]([O-])c1cccc2cnc(O)cc12
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1cc2c([N+](=O)[O-])cccc2cn1
Temperature: 120 °C

Procedure:
5-Nitro-3-isoquinolinol (3.40 g, 17.9 mmol) in acetic anhydride (40 mL) was treated with acetic acid (5 mL) and pyridine (5 mL) and heated at 120° C. for 2 hours. The mixture was cooled to room temperature and concentrated under reduced pressure to provide the title compound which was used in the next step without further purification. MS (ESI+) m/z 233 (M+H)+; MS (ESI−) m/z 231 (M−H)−; 1H NMR (DMSO, 300 MHz) isomers δ 2.39 (s, 3H), 7.88 (m, 1H), 8.27 (m, 1H), 8.50 (m, 1H), 8.65, 8.74 (d, J 7.8, 1H), 9.47, 9.55 (s, 1H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH3:16])=[CH:8]1.[OH-].[Na+].CN([CH:22]=[O:23])C>O>[CH3:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH3:16])=[C:8]1[CH:22]=[O:23]
Reactant: Cc1cn(C)c2ccccc12
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1c(C=O)n(C)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a stirred solution of phosphorus oxychloride (7.0 mL, 75 mmole) in DMF (25 mL) was added dropwise a solution of 1,3-dimethylindole (12.0 g, 83 mmole) in dry DMF (6.0 mL). The reaction was stirred at RT for 2 hr then was poured onto ice. The mixture was basified with a solution of NaOH (13.2 g, 330 mmole) in H2O (44 mL), then was extracted with Et2O (2×50 mL). The combined organic layers were washed with brine, dried (MgSO4), and concentrated under vacuum. Flash chromatography on silica gel (10% ethyl acetate/hexanes) gave the title compound (13.03 g, 91%) as an off-white solid: LCMS (ES) m/e 174.2 (M+H)+; 1H NMR (400 MHz, CDCl3) δ 10.16 (s, 1 H), 7.68 (d, J=8.1 Hz, 1 H), 7.42 (t, 1 H), 7.32 (d, J=8.5 Hz, 1 H), 7.15 (t, 1 H), 4.04 (s, 3 H), 2.63 (s, 3 H).
Reaction SMILES: [CH3:1][P:2]1(=[O:7])[CH2:6][CH2:5][CH:4]=[CH:3]1.O=O.[CH3:10][O:11][P:12]([CH3:14])[OH:13]>>[CH3:10][O:11][P:12]([CH:3]1[CH2:4][CH2:5][CH2:6][P:2]1([CH3:1])=[O:7])([CH3:14])=[O:13]
Reactant: CP1(=O)C=CCC1
Reactant: COP(C)O
Agent: O=O
Product: COP(C)(=O)C1CCCP1(C)=O
Reaction time: 1.5 h
Yield: 277.5 %

Procedure:
6 g of t-butyl peroctoate in 30 g of methane phosphonous acid methyl ester and 116 g of 1-methyl-1-oxophospholine are added dropwise to 282 g of oxygen-free methane phosphonous acid methyl ester at 120° C with stirring. The reaction time is 90 minutes. Excess methane phosphonous acid methyl ester and a small quantity of 1-methyl-oxophospholine are distilled off. The residue, consisting of 205 g of 1-methyl-1-oxophospholanylmethyl phosphinic acid methyl ester, is purified by distillation under vacuum (bp 1mm :210° to 220° C) to yield 186 g of pure product which solidifies very slowly to stellate crystals which begin to reliquefy at 70° C. Acid saponification leads to isomeric 1-methyl-1-oxophospholanyl-methyl phosphinic acids of the idealized constitution: ##STR16##
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Br[CH2:15][CH2:16][CH2:17][Cl:18].C(N(CC)CC)C>O1CCCC1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:15][CH2:16][CH2:17][Cl:18])[CH2:10][CH2:9]1
Reactant: ClCCCBr
Reactant: Cc1ccccc1N1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccccc1N1CCN(CCCCl)CC1
Yield: 64.7 %

Procedure:
A mixture of 35.2 g (0.2 mole) of 1-(2-methyl-phenyl)-piperazine, 31.4 g (0.2 mole) of 1-bromo-3-chloropropane, 40.4 g (0.4 mole) of triethylamine and 100 ml of tetrahydrofurane is refluxed for five hours. After cooling it is filtered, the filtrate is concentrated and the residue is fractionally distilled under vacuum. There are obtained 32.7 g of 3-[4-(2-methyl-phenyl)-piperazino]-propyl chloride (65% of theory) of boiling point 138°-140° C/0.1 mm Hg.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])[CH:3]=1.[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)([O-:16])=[O:15].C(OCC)(=O)C.[OH-].[Na+]>ClC1C=CC=CC=1>[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([O:23][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])[CH:3]=2)=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: CC(C)OC(=O)c1cc(Cl)ccn1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: Clc1ccccc1
Product: CC(C)OC(=O)c1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1
Temperature: 120 °C
Reaction time: 23 h
Yield: 45.3 %

Procedure:
2-Propyl 4-chloropyridine-2-carboxylate (3.13 g) was dissolved in chlorobenzene (9.5 ml). 4-Nitrophenol (3.28 g) was added thereto, followed by stirring at 120° C. for 23 hr. 4-Nitrophenol (1.09 g) was added thereto, followed by stirring at 120° C. for 3 hr. The reaction mixture was allowed to cool down to room temperature. Ethyl acetate (50 ml) and a 1N aqueous solution of sodium hydroxide (50 ml) were added to the reaction mixture and stirred. Insoluble matter was precipitated, which was dissolved by addition of THF (50 ml). The organic layer was separated, washed with a 1N aqueous solution of sodium hydroxide (50 ml×3) and brine (50 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=2:1 to 1:1). Fractions containing the target compound were concentrated under reduced pressure, and dried under reduced pressure to provide the titled compound as pale brown crystals (2.147 g, 45%).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=2)=[O:12])=[CH:5][CH:4]=1.[N:25]#[C:26][NH2:27].C(OCC)C>C(O)C>[ClH:1].[NH:2]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=2)=[O:12])=[CH:7][CH:8]=1)[C:26]([NH2:27])=[NH:25]
Reactant: CCOC(=O)c1ccc(OC(=O)CCc2ccc(N)cc2)cc1
Reactant: N#CN
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)c1ccc(OC(=O)CCc2ccc(NC(=N)N)cc2)cc1

Procedure:
In 200 ml of ethanol were dissolved 28.6 g of the p-ethoxycarbonylphenyl β-(p-aminophenyl)-propionate hydrochloride obtained and 4.2 g of cyanamide, and the solution was subjected to reaction at 70° C. for 5 hours. After the reaction, the solvent was removed by distillation under reduced pressure to obtain an oily product, to which a mixture consisting of ethanol and diethyl ether was added and the solution was cooled, upon which crystals precipitated. The crystals were collected by filtration and recrystallized from an ethanol-diethyl ether mixture to obtain p-ethoxycarbonylphenyl β-(p-guanidinophenyl)propionate hydrochloride in the form of colorless crystals. Yield: 25.1 g (78%); melting point: 125°-127° C.; IR (cm-1): 3500-2550, 1750, 1708, 1670, 1599; MS: M+= m/e 355 (M.W. - HCl).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[N:5]=[CH:4][N:3]=1.[N+:18]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)([O-])=O.C(N(C(C)C)CC)(C)C>CC(O)C>[N+:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][C:6]2[N:5]=[CH:4][N:3]=[C:2]([NH:18][C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[CH:7]=2)=[CH:10][CH:11]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccc(Oc2cc(Cl)ncn2)cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(Oc2cc(Nc3ccc(O)cc3)ncn2)cc1
Temperature: 85 °C
Reaction time: 18 h

Procedure:
4-Chloro-6-(4nitro-phenoxy)pyrimidine (Stage 22.5; 3 g, 11.9 mmol), 4-nitrophenol (1.95 g, 17.9 mmol), and diisopropylethylamine (DIPEA) (3.04 ml, 179 mmol) dissolved in 2-propanol (50 ml) are stirred at 85° C. for 18 h. After concentrating the reaction mixture under reduced pressure, the product precipitates as a colorless fine solid: M+H=245.0; 1H-NMR (400 MHz, DMSO-d6): 9.40/9.25 (s/s, 2H, NH/OH), 8.28 (d, 7.5 Hz, 2H, phenyl-NO2), 8.26 (s, 1H, pyrimidinyl), 7.40 (d, 7.5 Hz, 2H, phenyl-NO2), 7.24 (d, 8.0 Hz, 2H, phenyl-OH), 6.77 (d, 8.0 Hz, 2H, phenyl-OH), 6.15 (s, 1H, pyrimidinyl); Rf (AcOEt/hexane=2:1): 0.48.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:14][CH:13]([CH2:15][OH:16])[CH2:12][C:11]2=[O:17])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:18]1(O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:14][CH:13]([CH2:15][O:16][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:12][C:11]2=[O:17])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(N2CC(CO)CC2=O)cc1F
Reactant: Oc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(N2CC(COc3ccccc3)CC2=O)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(3-fluoro-4-methoxyphenyl)-4-(hydroxymethyl)pyrrolidin-2-one (Step 2, 1.0 g, 4.18 mmol), phenol (0.786 g, 8.36 mmol) and PPh3 (2.41 g, 9.2 mmol) in 50 mL of CH2Cl2 at 0° C. was added DIAD (1.65 mL, 9.2 mmol) slowly via a syringe. The reaction was warmed to RT and stirred overnight. The mixture was concentrated in vacuo and the residue was purified by chromatography (hexanes to 50% EtOAc/hexanes) to give the title compound as a white solid. MS (ESI pos. ion) m/z: 316.2 (M+H). Calc'd Exact Mass for C18H18FNO3: 315.34.
Reaction SMILES: [Cl:1][C:2]([F:27])([F:26])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:25])[C:12]2[CH:17]=[C:16](I)[C:15]([N:19]3[CH2:22][C:21]([OH:24])([CH3:23])[CH2:20]3)=[N:14][CH:13]=2)=[CH:6][CH:5]=1.[F:28][C:29]1[CH:30]=[N:31][NH:32][C:33]=1[Sn](CCCC)(CCCC)CCCC>>[Cl:1][C:2]([F:27])([F:26])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:25])[C:12]2[CH:17]=[C:16]([C:33]3[NH:32][N:31]=[CH:30][C:29]=3[F:28])[C:15]([N:19]3[CH2:22][C:21]([OH:24])([CH3:23])[CH2:20]3)=[N:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: CC1(O)CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cc2I)C1
Reactant: CCCC[Sn](CCCC)(CCCC)c1[nH]ncc1F
Product: CC1(O)CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cc2-c2[nH]ncc2F)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 92 using N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxy-3-methylazetidin-1-yl)-5-iodonicotinamide (Stage 90.1) and 4-fluoro-5-(tributylstannyl)-1H-pyrazole to afford a white solid. HPLC (Condition 7) tR=5.813 min, UPLC-MS (Condition 8) tR=0.98 min, m/z=468.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.34 (s, 3H) 3.54-3.74 (m, 4H) 5.49 (s, 1H) 7.34 (d, J=8.60 Hz, 2H) 7.58-7.71+7.94-8.01 (m, 1H) 7.83-7.92 (m, 2H) 8.05 (br. s, 1H) 8.78 (br. s, 1H) 10.23 (s, 1H) 13.03 (br.s, 1H).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][OH:10]>>[C:1]1([C:2]2[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][O:10]1)=[O:8]
Reactant: OCc1ccccc1
Reactant: CO
Product: O=C1OCc2ccccc21

Procedure:
The procedure described in method F is repeated, except that the methanol is replaced by 50 ml of benzyl alcohol, affording a phthalide compound of the formula ##STR19## melting point 183°-184° C.
Reaction SMILES: [CH:1](I)([CH3:3])[CH3:2].[NH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:8][CH2:7]1.C(N(C(C)C)CC)(C)C>C1COCC1>[CH:1]([NH:5][CH:6]1[CH2:11][CH2:10][CH:9]([CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])[CH2:8][CH2:7]1)([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCC1CCC(N)CC1
Reactant: CC(C)I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)NC1CCC(CNC(=O)OC(C)(C)C)CC1
Temperature: 40 °C
Reaction time: 24 h
Yield: 22 %

Procedure:
Isopropyl iodide (2 equivalents) was added dropwise to a suspension of tert-butyl N-[4-aminocyclohexyl]methyl-carbamate (1 equivalent) and diisopropylethyl amine (3 equivalents) in THF. The resulting mixture was stirred for 1 day. TLC analysis showed some starting amine. Additional isopropyl iodide (1 equivalent) and diisopropylethyl amine (3 equivalents) were added to the reaction mixture and heated at 40° C. for 1 day. The reaction mixture was concentrated and chromatrographed to give tert-butyl N-[4-(isopropylamino)cyclohexyl]methylcarbamate: 22% yield, 271 (ESMS, MH+); 1H NMR (CDCl3) δ 4.65 (broad, 1H), 2.91 (m, 3H), 2.42 (m, 1H), 1.80 (ABm, 4H), 1.38 (s, 9H), 0.98 (d, 6H, J=6.3 Hz), 1.32–0.85 (m, 5H).
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([O:14]C2CCCCO2)[CH:11]=[CH:12][CH:13]=1.[Br:21]CCBr>O1CCCC1.Cl>[Br:21][C:9]1[C:8]([O:7][CH3:6])=[CH:13][CH:12]=[CH:11][C:10]=1[OH:14]
Reactant: BrCCBr
Reactant: COc1cccc(OC2CCCCO2)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc(O)c1Br
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 30 %

Procedure:
33 mL (52.8 mMol) n-butyllithium (1.6 M in hexane)were added dropwise to a solution 10 gm (48.1 mMol) tetrahydropyran-2-yl 3-methoxyphenyl ether in 100 mL tetrahydrofuran over 15 minutes. After stirring for 2.5 hours at room temperature, the reaction mixture was cooled to 0° C. and then 4.6 mL (53.2 mMol) 1,2-dibromoethane were added dropwise. The reaction mixture was then allowed to stir at room temperature for about 14 hours. The reaction mixture was then diluted with 50 mL 1 N hydrochloric acid and was stirred for 1 hour. The aqueous phase was extracted with three 100 mL portions of diethyl ether. The organic phases were combined and extracted well with 5 N sodium hydroxide. These basic aqueous extracts were combined and cooled in an ice/water bath. The pH of this aqueous solution was adjusted to about 1 with 5 N hydrochloric acid and then extracted with three 100 mL portions of diethyl ether. These ether extracts were combined and washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography, eluting with a gradient of hexane containing from 0 to 10% ethyl acetate. Fractions containing the desired compound were combined and concentrated under reduced pressure to provide 2.91 gm (30%) of a residue which crystallized upon standing.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([NH:6][C:7]1[CH:12]=[C:11]([Sn](C)(C)C)[N:10]=[CH:9][N:8]=1)[CH3:5].[Cl:17][C:18]1[N:23]=[C:22](Cl)[CH:21]=[CH:20][N:19]=1>CN1CCCC1=O.O.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:17][C:18]1[N:23]=[C:22]([C:11]2[CH:12]=[C:7]([NH:6][CH:4]([CH3:5])[CH2:3][O:2][CH3:1])[N:8]=[CH:9][N:10]=2)[CH:21]=[CH:20][N:19]=1
Reactant: COCC(C)Nc1cc([Sn](C)(C)C)ncn1
Reactant: Clc1ccnc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CN1CCCC1=O
Solvent: O
Product: COCC(C)Nc1cc(-c2ccnc(Cl)n2)ncn1
Temperature: 25 °C

Procedure:
To a solution of N-(2-methoxy-1-methylethyl)-6-(trimethylstannyl)-4-pyrimidinamine (i.e., the product of Step B) (0.5 g, 1.51 mmol), 2,4-dichloropyrimidine (0.22 g, 1.51 mmol) and copper iodide (12 mg, 0.061 mmol) in N-methylpyrrolidinone (12 mL) under a nitrogen atmosphere was added bis(triphenylphosphine)palladium(II) dichloride (53 mg, 0.076 mmol). The resulting mixture was stirred at reflux for 2 h. After cooling to room temperature, the solution was diluted with water and extracted with diethyl ether 3 times. The organic layers were combined and washed three times with water, then dried and concentrated. The residue was purified on silica gel using a gradient of 100% hexanes to 40% ethyl acetate in hexanes to afford 270 mg of title compound as a solid.
Reaction SMILES: CO.C(=O)([O-])[O-].[K+].[K+].C([O:12][CH2:13][C:14](=[O:35])[C@@H:15]1[C@:32]2([CH3:33])[C@H:18]([C@H:19]3[C@H:29]([CH2:30][CH2:31]2)[C@:27]2([CH3:28])[C:22](=[CH:23][C:24](=[O:34])[CH2:25][CH2:26]2)[CH:21]=[CH:20]3)[CH2:17][CH2:16]1)(=O)C.[CH3:36][C:37]([SH:39])=[O:38]>C(Cl)Cl>[C:37]([S:39][C@@H:20]1[CH2:21][C:22]2[C@:27]([CH3:28])([CH2:26][CH2:25][C:24](=[O:34])[CH:23]=2)[C@@H:29]2[C@@H:19]1[C@H:18]1[C@:32]([CH3:33])([CH2:31][CH2:30]2)[C@@H:15]([C:14](=[O:35])[CH2:13][OH:12])[CH2:16][CH2:17]1)(=[O:38])[CH3:36]
Reactant: CC(=O)OCC(=O)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(=O)S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: CC(=O)S[C@@H]1CC2=CC(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(=O)CO)CC[C@H]3[C@H]12

Procedure:
The product of Example 3 was hydrolyzed by treating 0.5 g of the 21-acetoxy derivative in 8 ml methylene chloride with 10 ml methanol and 4 ml 0.2M aqueous potassium carbonate at room temperature under nitrogen for 30 minutes. The hydrolyzed product was extracted with methylene chloride, washed with water, dried and evaporated. A sample obtained by preparative high performance liquid chromatography showed M+ =404 daltons. An identical product was obtained by a different synthetic route involving alkaline hydrolysis of 21-acetoxy-4,6-pregnadiene-3,20-dione to the C-21-alcohol, followed by reaction with ethanethiolic acid.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:15]3[CH:14]=[C:13]([C:16]4[C:21]([Cl:22])=[CH:20][N:19]=[C:18](Cl)[N:17]=4)[S:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][C:34]([CH2:39][CH2:40][CH2:41][NH2:42])([CH2:37][CH3:38])[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][C:34]([CH2:39][CH2:40][CH2:41][NH:42][C:18]2[N:17]=[C:16]([C:13]3[S:12][C:11]4[CH:10]=[CH:9][CH:8]=[C:7]([C:5](=[O:6])[NH:4][CH:1]5[CH2:3][CH2:2]5)[C:15]=4[CH:14]=3)[C:21]([Cl:22])=[CH:20][N:19]=2)([CH2:37][CH3:38])[CH2:33][CH2:32]1)=[O:30])([CH3:25])([CH3:27])[CH3:26]
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(Cl)ncc3Cl)cc12
Reactant: CCC1(CCCN)CCN(C(=O)OC(C)(C)C)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCC1(CCCNc2ncc(Cl)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 90 °C
Yield: 66.7 %

Procedure:
A stirred mixture of 2-(2,5-dichloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid cyclopropylamide (180 mg, 0.494 mmol), 4-(3-aminopropyl)-4-ethylpiperidine-1-carboxylic acid tert-butyl ester (200 mg, 0.741 mmol) and diisopropylethylamine (128 mg, 0.988 mmol) in 1,4-dioxane (3 mL) is heated at 90° C. under nitrogen for 18 hours. At room temperature the mixture is concentrated and the crude product is chromatographed on silica gel, eluting with 3% 2 M NH3/MeOH in dichloromethane, to give 197 mg of 4-{3-[5-chloro-4-(4-cyclopropylcarbamoylbenzo[b]thiophen-2-yl)-pyrimidin-2-ylamino]-propyl}-4-ethylpiperidine-1-carboxylic acid tert-butyl ester. The intermediate is then subject to deprotection by dissolving the material (197 mg, 0.329 mmol) in MeOH (25 mL) and dichloromethane (12 mL) and bubbling anhydrous hydrogen chloride gas for 5 minutes. The hot, yellow solution is allowed to sit at room temperature for 2 hours, then concentrated to give the title compound as a yellow solid (184 mg, 98% yield). ES+(m/z) 498 (35Cl) and 500 (37Cl) [M(free base)+H].
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C@H:7]([NH2:13])[C:8]2([CH3:12])[CH2:11][O:10][CH2:9]2)=[CH:4][CH:3]=1.[OH:14][C:15]1[C:29]([NH:30][C:31]2[C:34](=O)[C:33](=[O:36])[C:32]=2[O:37]C)=[CH:28][CH:27]=[CH:26][C:16]=1[C:17]([CH2:19][NH:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[O:18]>CO>[OH:14][C:15]1[C:29]([NH:30][C:31]2[C:32](=[O:37])[C:33](=[O:36])[C:34]=2[NH:13][C@@H:7]([C:5]2[O:6][C:2]([CH3:1])=[CH:3][CH:4]=2)[C:8]2([CH3:12])[CH2:9][O:10][CH2:11]2)=[CH:28][CH:27]=[CH:26][C:16]=1[C:17]([CH2:19][NH:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[O:18]
Reactant: COC(=O)CNCC(=O)c1cccc(Nc2c(OC)c(=O)c2=O)c1O
Reactant: Cc1ccc([C@H](N)C2(C)COC2)o1
Solvent: CO
Product: COC(=O)CNCC(=O)c1cccc(Nc2c(N[C@@H](c3ccc(C)o3)C3(C)COC3)c(=O)c2=O)c1O
Temperature: 60 °C
Yield: 78 %

Procedure:
A mixture of 371 mg (2.07 mmol, 1.2 eq) of C—(R)-(5-methylfuran-2-yl)-C-(3-methyloxetan-3-yl)methylamine (prepared in EXAMPLE 50, steps 1 to 4) and 600 mg (1.7 mmol, 1 eq) of methyl {[2-hydroxy-3-(2-methoxy-3,4-dioxocyclobut-1-enylamino)benzoyl]methylamino}acetate in 24 ml of methanol was heated at 60° C. for 16 hours. The methanol was evaporated off and the residue was chromatographed on silica gel, eluent dichloromethane/ethyl acetate (75/25). The paste obtained was crystallized from diethyl ether and heptane and dried under vacuum at 40° C. 660 mg of methyl {[2-hydroxy-3-(2-{[(R)-(5-methylfuran-2-yl)-(3-methyloxetan-3-yl)methyl]amino}-3,4-dioxocyclobut-1-enylamino)benzoyl]methylamino}acetate were obtained in the form of a pale yellow solid. Yield=76%.
Reaction SMILES: [CH:1]1([CH2:7][C:8]([OH:10])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:11][O:12][C:13](=[O:28])[C@H:14]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH:15][C:16](=[O:20])[C@H:17]([CH3:19])[NH2:18].C(N[C@H](C(O)=O)C)(OC(C)(C)C)=O.Cl.COC(=O)[C@H](CC1C=CC=CC=1)N>>[CH3:11][O:12][C:13](=[O:28])[C@H:14]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH:15][C:16](=[O:20])[C@H:17]([CH3:19])[NH:18][C:8](=[O:10])[CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)CC1CCCCC1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)N
Agent: COC(=O)[C@@H](N)Cc1ccccc1
Agent: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)CC1CCCCC1

Procedure:
Following General Procedure U and using cyclohexylacetic acid (Aldrich) and N-(L-alaninyl)-L-phenylalanine methyl ester prepared by coupling N-BOC-L-alanine (Bachem) with L-phenylalanine methyl ester hydrochloride (Bachem) using General Procedure U, followed by removal of the BOC-group using General Procedure Y), the title compound was prepared as a solid (mp=156-158° C.). The reaction was monitored by tlc (Rf=0.25 in 1:1 EtOAc/hexanes).