Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]2[NH:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:27][CH2:26][CH:25]([NH:28]C(=O)OC(C)(C)C)[CH2:24]2)=[N:21][CH:22]=1.[Cl:36][C:37]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[C:39]([F:52])[C:38]=1[OH:53]>>[NH2:28][CH:25]1[CH2:26][CH2:27][N:23]([C:20]2[N:21]=[CH:22][C:17]([NH:16][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:41]5[CH:40]=[C:39]([F:52])[C:38]([OH:53])=[C:37]([Cl:36])[CH:42]=5)[CH:3]=4)[N:8]=[CH:7][C:6]=3[C:12](=[O:15])[CH2:13][CH3:14])=[CH:18][CH:19]=2)[CH2:24]1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CCC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(N2CCC(NC(=O)OC(C)(C)C)C2)nc1
Product: CCC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1Nc1ccc(N2CCC(N)C2)nc1
Yield: 37.3 %

Procedure:
Following general procedure D, tert-butyl 1-(5-(6-bromo-3-propionylquinolin-4-ylamino) pyridin-2-yl)pyrrolidin-3-ylcarbamate (100 mg, 0.18 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (76 mg, 0.28 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (34 mg, 37% over two steps) as a yellow solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.29 (s, 1H), 8.29-8.18 (m, 2H), 8.06-7.99 (m, 2H), 7.82 (dd, J=9.1, 2.6 Hz, 1H), 7.16-7.10 (m, 1H), 7.07 (s, 1H), 6.97 (d, J=9.1 Hz, 1H), 4.17-4.08 (m, 1H), 4.06-3.98 (m, 1H), 3.90-3.81 (m, 1H), 3.79-3.70 (m, 2H), 3.27-3.19 (m, 2H), 2.64-2.53 (m, 1H), 2.35-2.25 (m, 1H), 1.26 (t, J=7.1 Hz, 3H); ESI MS m/z 506 [C27H25ClFN5O2+H]+; HPLC>99% (AUC), tR=10.75 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[N:7][C:6]=1Cl)[CH3:2].[CH3:14][S:15][C:16]1[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[N:7][C:6]=1[O:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([S:15][CH3:14])[CH:17]=1)[CH3:2]
Reactant: CSc1cccc(O)c1
Reactant: CCOC(=O)c1cc(F)cnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(F)cnc1Oc1cccc(SC)c1
Temperature: 100 °C
Reaction time: 48 h

Procedure:
A solution of ethyl-2-chloro-5-fluoro-nicotinoate (J. Med. Chem., 1993, 36(18), 2676–88) (29 g, 0.143 mol) and 3-methylsulphanyl-phenol (WO 98/45268, pg. 68, preparation 61) (20 g, 0.143 mol) in dioxane (300 mL) was treated with caesium carbonate (46.5 g, 0.143 mol) at room temperature. The reaction mixture was heated to 100° C. and stirred for 48 hours. The reaction mixture was concentrated in vacuo and the residue taken up in water (600 mL) and extracted with ethyl acetate (3×250 mL). The organics were combined, washed with brine (200 mL), dried over magnesium sulphate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane:toluene (99.75:0.25 to 99.5:0.5) to yield the title product as a yellow oil, 27.1 g.
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[C:3]([C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])=[O:4].C(O)(C)(C)C.CC(C)([O-])C.[K+].Br[CH:27]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:28]([O:30][CH2:31][CH3:32])=[O:29]>C(O)C>[CH2:31]([O:30][C:28]([C:27]1([C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:3]([OH:4])([CH:2]([CH3:1])[CH3:14])[C:5]2[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:7](=[O:8])[O:9]1)=[O:29])[CH3:32]
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: CC(C)C(=O)c1ccccc1C(=O)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC(C)(C)O
Product: CCOC(=O)C1(C(=O)OCC)OC(=O)c2ccccc2C1(O)C(C)C
Reaction time: 0.17 h
Yield: 94.2 %

Procedure:
A stirred mixture of 2-(2-methylpropanoyl)benzoic acid (44.27 g) and tert-butanol (300 ml) was treated portionwise with potassium tert-butoxide (28.14 g) over 5 minutes at room temperature and the reaction mixture stirred for a further 10 minutes and then treated dropwise over 10 minutes with a solution of diethyl bromomalonate (55.1 g) in ethanol (200 ml). The stirred mixture was refluxed for 18 hours and then evaporated to dryness. The residue was treated with diethyl ether (400 ml) and washed with water (400 ml). The aqueous phase was re-extracted with diethyl ether (200 ml) and the combined ethereal extracts washed with water (200 ml), saturated aqueous sodium hydrogen carbonate solution (200 ml) and water (200 ml), dried over magnesium sulphate and evaporated to give crude 3,3-bis(ethoxycarbonyl)-4-hydroxy-4-isopropyl-3,4-dihydroisocoumarin (76 g) as an amber oil.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[C:9](Cl)(=[O:27])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25]>>[C:9]([OH:27])(=[O:2])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25].[C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2]
Reactant: CC(C)CCCCCCCCCCCCCCC(=O)Cl
Agent: Oc1ccc(O)cc1
Product: CC(C)CCCCCCCCCCCCCCC(=O)O

Procedure:
According to the same procedure as described in Preparation 1, hydroquinone and isostearoyl chloride (prepared by chlorination of isostearic acid with thionyl chloride) were reacted and the reaction mixture was extracted with ethyl acetate. The extract was washed with water and the solvent was removed. The resulting residue was thoroughly washed with water to remove unreacted hydroquinone and concentrated on a water bath at 70° C. under the reduced pressure of 1 mmHg to give hydroquinone monoisostearate.
Reaction SMILES: [NH:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].[CH3:10][Si](C)(C)N[Si](C)(C)C.C[Si](Cl)(C)C.CI>C(O)(=O)C>[CH3:10][N:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Agent: C[Si](C)(C)Cl
Solvent: CI
Solvent: CC(=O)O
Product: Cc1cn(C)c(=O)[nH]c1=O
Temperature: 60 °C
Reaction time: 17 h

Procedure:
Thymine (2.0 g, 16 mmol), hexamethyl-disilazane (32 mL) and trimethyl silylchloride (4.1 mL) were added in 100 mL mad apple-type flask with a magnetic stirrer and allowed to stir for 17 hr. at 140° C. until the reaction solution became transparent. After the reaction solution was cooled to 60° C., the solution was added with methyl-iodide (10 mL) and was allowed to stir for 29 hr. at 60° C. Then, the reaction solution was added with 6 N aqueous acetic acid solution (6 mL×10) and subjected to evaporation under reduced pressure. The residues were dissolved by the addition of 2-propanol and insolubles were filtered out. The filtrate was added with ethanol-water mixture. The object was recrystallized in ethanol-water mixture to give white solids (1.6 g, yield, 72%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:39])([CH3:38])[CH2:12][C:13]([OH:37])([C:33]([F:36])([F:35])[F:34])[CH2:14][C:15]#[C:16][C:17]2[C:22]([NH:23]C(=O)C(F)(F)F)=[CH:21][N:20]=[C:19]([CH:30]([CH3:32])[CH3:31])[N:18]=2)[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.CN(C)C(=N)N(C)C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:38])([CH3:39])[CH2:12][C:13]([CH2:14][C:15]2[NH:23][C:22]3[CH:21]=[N:20][C:19]([CH:30]([CH3:32])[CH3:31])=[N:18][C:17]=3[CH:16]=2)([OH:37])[C:33]([F:36])([F:35])[F:34])[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1
Reactant: CC(C)c1ncc(NC(=O)C(F)(F)F)c(C#CCC(O)(CC(C)(C)c2cc(Cl)cc3c2OCC3)C(F)(F)F)n1
Agent: CN(C)C(=N)N(C)C
Solvent: C1COCCO1
Product: CC(C)c1ncc2[nH]c(CC(O)(CC(C)(C)c3cc(Cl)cc4c3OCC4)C(F)(F)F)cc2n1
Temperature: 100 °C
Yield: 52 %

Procedure:
To a solution of N-{4-[6-(5-chloro-2,3-dihydrobenzofuran-7-yl)-4-hydroxy-6-methyl-4-trifluoromethylhept-1-ynyl]-2-isopropylpyrimidin-5-yl}-2,2,2-trifluoroacetamide (58 mg, 0.1 mmol) in 1 mL of anhydrous dioxane was added tetramethylguanidine (0.05 mL, 0.4 mmol) and the reaction mixture stirred and heated in oil bath maintained at 100° C. for 1 hour. Purification by preparative TLC over silica gel eluting with 5% methanol in dichloromethane provided the title compound as a light cream colored solid, (25 mg, 52% yield) M+H=482.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]5[S:23][C:24]([F:28])=[C:25](F)[CH:26]=5)=[CH:16][C:15]4=[O:29])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[Br:30]C1C=C(COC2C=CN(C3C=CC4N=C(C5CC5)N(C)C=4C=3)C(=O)C=2)SC=1>>[Br:30][C:25]1[CH:26]=[C:22]([CH2:21][O:20][C:17]2[CH:18]=[CH:19][N:14]([C:11]3[CH:12]=[CH:13][C:6]4[N:5]=[C:4]([CH:1]5[CH2:3][CH2:2]5)[N:8]([CH3:9])[C:7]=4[CH:10]=3)[C:15](=[O:29])[CH:16]=2)[S:23][C:24]=1[F:28]
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4cc(F)c(F)s4)cc3=O)cc21
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4cc(Br)cs4)cc3=O)cc21
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4cc(Br)c(F)s4)cc3=O)cc21

Procedure:
A mixture of the title compound, 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-((4,5-difluoro-2-thienyl)methoxy)pyridin-2(1H)-one and 4-((4-bromo-2-thienyl)methoxy)-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one obtained in step D in example 219 was subjected to HPLC separation (C18, mobile phase: H2O/CH3CN (0.1% TFA included)). The solution was neutralized with saturated Na2CO3 solution and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO4, filtered through a plug of silica gel, and concentrated in vacuo. The residual solid was recrystallized from EtOH to give the title compound (10.0 mg) as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:21])=[C:16](F)[C:17]=2[F:19])[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]1.Br.Br.[C:28]12[CH2:35][NH:34][CH2:33][C:32]=1[CH2:31][NH:30][CH2:29]2.N12CCCN=C1CCCCC2>C(#N)C>[C:28]12[CH2:35][NH:34][CH2:33][C:32]=1[CH2:31][N:30]([C:7]1[C:2]([F:1])=[C:3]3[C:4]([C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10][N:9]3[C:18]3[CH:13]=[CH:14][C:15]([F:21])=[CH:16][C:17]=3[F:19])=[CH:5][C:6]=1[F:8])[CH2:29]2
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(F)c(F)c(F)cc2c1=O
Reactant: C1NCC2=C1CNC2
Agent: Br
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(F)c(N3CC4=C(CNC4)C3)c(F)cc2c1=O
Reaction time: 8 h
Yield: 74.5 %

Procedure:
1-(2,4-Difluorophenyl)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.07 g), 3,7-diazabicyclo [3.3.0] oct-1(5)-ene dihydrobromide (1 g) and 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU, 2 ml) were dissolved in acetonitrile (30 ml) and refluxed for 7 hours. The reaction mixture was kept overnight at room temperature and the produced precipitate was filtered and then suspended in methanol (10 ml) and sonicated for 30 minutes. The insoluble product was collected by filtration to give the title compound (1 g, yield 74%).
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[C:15]2[O:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:12]([CH3:22])[C:11](=[O:23])[C:10]=2[CH:9]=[CH:8][CH:7]=1)(=[O:5])[CH3:4]>C(Cl)(Cl)Cl>[Br:1][CH2:4][C:3]([C:6]1[C:15]2[O:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:12]([CH3:22])[C:11](=[O:23])[C:10]=2[CH:9]=[CH:8][CH:7]=1)=[O:5]
Reactant: CC(=O)c1cccc2c(=O)c(C)c(-c3ccccc3)oc12
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: Cc1c(-c2ccccc2)oc2c(C(=O)CBr)cccc2c1=O
Reaction time: 1 h
Yield: 63.9 %

Procedure:
A solution of 11.2 g of bromine in 250 ml of chloroform was added, over a period of two hours at 20°-25° C., to a solution of 19.5 g of the Intermediate V in 700 ml of chloroform. After stirring for 1 hour at 20°-25° C., the solution was washed with 400 ml of 2N aqueous sodium hydroxide solution and then repeatedly with water, dried with anhydrous sodium sulfate and stripped in vacuo. The crude product was treated with diethyl ether, collected by suction filtration and crystallized from acetone, yielding 16 g of the title compound, m.p 134°-135° C.
Reaction SMILES: CCN=C=NCCCN(C)C.[C:12]([O:16][C:17]([N:19]1[CH2:22][CH:21]([NH2:23])[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].[F:24][C:25]1[CH:26]=[C:27]([C:38]([F:41])([F:40])[F:39])[CH:28]=[C:29]([CH:37]=1)[C:30]([NH:32][CH2:33][C:34](O)=[O:35])=[O:31]>>[C:12]([O:16][C:17]([N:19]1[CH2:22][CH:21]([NH:23][C:34](=[O:35])[CH2:33][NH:32][C:30](=[O:31])[C:29]2[CH:37]=[C:25]([F:24])[CH:26]=[C:27]([C:38]([F:39])([F:41])[F:40])[CH:28]=2)[CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: O=C(O)CNC(=O)c1cc(F)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Agent: CCN=C=NCCCN(C)C
Product: CC(C)(C)OC(=O)N1CC(NC(=O)CNC(=O)c2cc(F)cc(C(F)(F)F)c2)C1

Procedure:
The title compounds were prepared as white solids from EDCI coupling between 3-amino-azetidine-1-carboxylic acid tert-butyl ester (AstaTech) and (5-fluoro-3-trifluoromethyl-benzoylamino)-acetic acid (prepared by the method similar to Ingersoll, A. W. et. al., Organic Syntheses 1932, XII, 40-2) using the procedure described in Step C of Example 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]2([CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)=O)[CH2:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1>C1COCC1.[Ti](Cl)(Cl)(Cl)Cl.[Zn]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][C:10]3([CH2:14][C:15]=2[C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[CH2:13][CH2:12][CH2:11]3)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(C(=O)CC2(CC(=O)c3ccc(F)cc3)CCC2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(C2=C(c3ccc(F)cc3)CC3(CCC3)C2)cc1
Temperature: 25 °C
Yield: 76.4 %

Procedure:
Under nitrogen, 16.3 mL (149 mmol) of titanium(IV) chloride was slowly added to a suspension of 19.5 g (298 mmol) of zinc dust in 500 mL of anhydrous THF at -78° C. The resulting mixture was allowed to warm to ambient temperature and then to stir at reflux for 45 minutes. The reaction was cooled to ambient temperature prior to the addition of 19.27 g (49.6 mmol) of neat 1-(4-fluorophenyl)-2-[1-[2-[4-(methysulfonyl)phenyl]-2-oxoethyl]cyclobutan-1-yl]ethan-1-one (prepared in Step 6) by syringe. The reaction was allowed to stir at ambient temperature overnight, filtered through celite, and concentrated in vacuo. The residue was partitioned between ethyl acetate and water; the ethyl acetate phase was washed with brine, dried (MgSO4), and concentrated in vacuo. Purification by silica gel chromatography (Waters Prep-500A) with ethyl acetate/hexane (20:80) gave 13.5 g (76%) of 6-(4-fluorophenyl)-7-[4-(methylsulfonyl)phenyl]spiro[ 3.4]oct-6-ene as a colorless solid: mp 123-124° C.; NMR (CDCl3) δ 1.85-1.98 (m, 2H), 2.08 (t, J=7 Hz, 4H), 2.98 (s, 4H), 3.04 (s, 3H), 6.92 (t, J=9 Hz, 7.05-7.13 (m, 2H), 7.30 (t, J=8HZ, 2H), 7.75 (t, J=8 Hz, 2H). MS (FAB) m/e 357 (M+H). Anal. Calc'd for C21H21FO2S: C, 70.76; H, 5.94; F, 5.53; S, 8.99. Found: C, 70.76; H, 6.10; F, 5.20; S, 8.96.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16](OC)=[CH:15][C:14]=3OC)[C:10](=[O:23])[C@@H:9](CC(O)=O)[O:8][C@H:7]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3Cl)[C:6]=2[CH:35]=1.[OH-:36].[Na+].Cl>CO>[CH2:12]([N:11]1[C:5]2[CH:4]=[CH:3][CH:2]=[CH:35][C:6]=2[C@H:7]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:8][C@H:9]([CH2:5][CH2:6][C:7]([OH:8])=[O:36])[C:10]1=[O:23])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: [OH-]
Reactant: COc1ccc(CN2C(=O)[C@@H](CC(=O)O)O[C@H](c3ccccc3Cl)c3cc(Cl)ccc32)c(OC)c1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C(O)CC[C@H]1O[C@@H](c2ccccc2)c2ccccc2N(Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 20 ml of methanol was dissolved 0.5 g of ethyl ester of cis-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionic acid obtained in Example 8. To the solution was added 7 ml of 1N sodium hydroxide, and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was acidified with 100 ml of 1N hydrochloric acid, which was subjected to extraction with 150 ml of ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate. Then the solvent was distilled off under reduced pressure to leave 0.46 g of cis-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionic acid as plates, m.p. 112°-114° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:9]2)=[CH:4][CH:3]=1.C[O:24][C:25](=[O:36])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH2:33][CH2:34]Cl>>[Cl:1][C:2]1[S:6][C:5]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH:17]3[CH2:22][CH2:21][N:20]([CH2:34][CH2:33][O:32][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[C:25]([OH:36])=[O:24])[CH2:19][CH2:18]3)=[CH:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(Cn2cc(C3CCNCC3)c3ccccc32)s1
Reactant: COC(=O)c1ccccc1OCCCl
Product: O=C(O)c1ccccc1OCCN1CCC(c2cn(Cc3ccc(Cl)s3)c3ccccc23)CC1

Procedure:
This compound was prepared following the procedure described in example 13 (part D), starting with 4.21 mmol (13 mmol) of 1-(5-chloro-thiophen-2-ylmethyl)-3-piperidin-4-yl-1H-indole and 3.6 g (17 mmol) of of 2-(2-chloro-ethoxy)-benzoic acid methyl ester. After the standard work-up, 2.47 g of the corresponding acid was obtained. The crude mixture was purified by flash chromatography over silica gel affording 1.2 g (17% of yield) of the pure acid.
Reaction SMILES: [CH2:1]([C:3]1([CH2:32][CH3:33])[C:6](=[O:7])[N:5]([C:8]([NH:10][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH2:12][CH2:13][CH3:14])=[O:9])[CH:4]1[O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=1)[CH3:2].CN(C)C=O.C(Cl)(=O)C([Cl:42])=O>C(Cl)Cl>[CH2:1]([C:3]1([CH2:32][CH3:33])[C:6](=[O:7])[N:5]([C:8]([NH:10][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH2:12][CH2:13][CH3:14])=[O:9])[CH:4]1[O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([Cl:42])=[O:28])=[CH:25][CH:24]=1)[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCC(NC(=O)N1C(=O)C(CC)(CC)C1Oc1ccc(C(=O)O)cc1)c1ccc(C)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCC(NC(=O)N1C(=O)C(CC)(CC)C1Oc1ccc(C(=O)Cl)cc1)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.150 g of [S-(R*,S*)] 4-((3,3-diethyl-1-(((1-(4-methylphenyl)butyl)amino)-carbonyl)-4-oxo-2-azetidinyl)oxy)benzoic acid in 5 ml methylene chloride containing a catalytic amount of dimethylformamide is added 0.5 ml of oxalyl chloride. The mixture is stirred at room temperature for 30 minutes and then concentrated in vacuo to yield (S-(R*,S*))-4-((3,3-diethyl-1-((1-(4-methyl-phenyl)-butylamino)carbonyl)-4-oxo-2-azetidinyl)oxy)-benzoyl chloride.
Reaction SMILES: CCCCCC.C([Li])CCC.[S:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH:14]=[CH:13]1.[Br:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([O:32][CH3:33])=[C:24]([CH:34]=[O:35])[CH:23]=1.[Cl-].[NH4+]>C1COCC1>[S:12]1[C:13]([CH:34]([C:24]2[CH:23]=[C:22]([Br:21])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]=2[O:32][CH3:33])[OH:35])=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]1=2
Reactant: COc1c(C=O)cc(Br)c2ccccc12
Reactant: c1ccc2sccc2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1c(C(O)c2cc3ccccc3s2)cc(Br)c2ccccc12
Reaction time: 0.17 h
Yield: 82.9 %

Procedure:
In a nitrogen stream, an n-butyllithium hexane solution (1.6 M, 6.2 ml, 9.90 mmol) was added dropwise to a solution of benzothiophene (1.33 g, 9.90 mmol) in THF (20 ml) at −78° C. and the reaction mixture was stirred at the same temperature for 10 minutes. To this mixture, a solution of 4-bromo-1-methoxynaphthalene-2-carbaldehyde (2.5 g, 9.43 mmol) in THF (30 ml) was added dropwise at −78° C. The reaction mixture was stirred at the same temperature for two hours, and then a saturated ammonium chloride aqueous solution was added thereto and the mixture was extracted with ether. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:4)] to obtain the title compound (3.12 g, 83%).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[N:9]=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=3)[C:11]3[N:16]=[CH:15][S:14][C:12]=3[N:13]=2)[CH2:4]1.[O:28]=[C:29]1[NH:33][C:32]2[CH:34]=[CH:35][C:36]([C:38](O)=[O:39])=[CH:37][C:31]=2[NH:30]1.CCN=C=NCCCN(C)C.CN1C=CN=C1>C(Cl)Cl>[CH3:27][O:26][C:20]1[CH:19]=[C:18]([NH:17][C:10]2[C:11]3[N:16]=[CH:15][S:14][C:12]=3[N:13]=[C:8]([N:5]3[CH2:6][CH2:7][CH:3]([NH:2][C:38]([C:36]4[CH:35]=[CH:34][C:32]5[NH:33][C:29](=[O:28])[NH:30][C:31]=5[CH:37]=4)=[O:39])[CH2:4]3)[N:9]=2)[CH:23]=[CH:22][C:21]=1[O:24][CH3:25]
Reactant: O=C(O)c1ccc2[nH]c(=O)[nH]c2c1
Reactant: COc1ccc(Nc2nc(N3CCC(N)C3)nc3scnc23)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Cn1ccnc1
Solvent: ClCCl
Product: COc1ccc(Nc2nc(N3CCC(NC(=O)c4ccc5[nH]c(=O)[nH]c5c4)C3)nc3scnc23)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.2 %

Procedure:
A mixture of 5-(3-aminopyrrolidin-1-yl)-N-(3,4-dimethoxyphenyl)thiazolo[5,4-d]pyrimidin-7-amine hydrochloride (100 mg, 0.245 mmol), 2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylic acid (48 mg, 0.27 mmol), EDCI (97 mg, 0.49 mmol) and N-methylimidazole (60 mg, 0.735 mmol) in 10 mL of DCM was stirred at room temperature for 16 hours. The mixture was washed with water (5 mL), The organic layer was dried over Na2SO4. After filtration and concentration, the residue was purified by column chromatography on silica gel eluting with a mixture of CH2Cl2 and methanol (100:1: to 20:1, V/V) to give N-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide (25 mg, 19%) as white solid. 1H NMR (300 MHz, DMSO): δ 9.57 (s, 1H), 8.81 (s, 1H), 8.475-8.46 (m, 1H), 8.27-8.25 (m, 2H), 7.60-7.25 (m, 2H), 6.92 (d, 1H, J=8.7 Hz), 6.47-6.39 (m, 3H), 4.54-4.52 (m, 1H), 3.76-3.58 (m, 10H), 2.27-2.05 (m, 2H). LC-MS: 247 [M/2+H]+, 493 [M+H]+, 491 [M−H]−, tR=1.22 min. HPLC: 95.20% at 214 nm, 95.06% at 254 nm, tR=5.64 min.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:28])[CH:11]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1)[CH2:12][C:13]([O:15]C(C)(C)C)=[O:14]>ClCCl>[CH3:8][O:9][C:10](=[O:28])[CH:11]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1)[CH2:12][C:13]([OH:15])=[O:14]
Reactant: COC(=O)C(CC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(CC(=O)O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trifluoroacetic acid (100 ml) was added to a mixture of 2-(3,4-dichloro-phenyl)-succinic acid 4-tert-butyl ester 1-methyl ester (23.64 g, 0.071 mol) and dichloromethane (100 ml). The reaction mixture was stirred at room temperature for 3 hours then concentrated in vacuo. The crude mixture was kept under vacuo for several hours before being used without further purification in the next step.). 1H NMR (400 MHz, DMSO-d6) δ 2.66 (1H, dd), 3.01 (1H, dd), 3.59 (3H, s), 4.08 (1H, m), 7.30 (1H, m), 7.56–7.61 (2H, m); MS (ES+): m/e=277.1 (100%), 279.1 (65%), 281.0 (10%); MS (ES−): m/e=275.1 (50%), 277.1 (30%), 279.1 (5%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([OH:22])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][C:11]=1[Cl:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCOCC1.[O-2].[O-2].[Mn+4]>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:22])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][C:11]=1[Cl:23])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)CC(O)c1ccc(CNC(=O)OC(C)(C)C)c(Cl)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: CC(C)(C)CC(=O)c1ccc(CNC(=O)OC(C)(C)C)c(Cl)c1
Temperature: 70 °C
Yield: 75.6 %

Procedure:
Add manganese dioxide (7.276 g, 83.7 mmol) to a solution of N-(tert-butoxycarbonyl)-2-chloro-4-(1-hydroxy-3,3-dimethyl-butyl)-benzylamine (1.819 g, 5.3 mmol) in anhydrous 1,4-dioxane (75 mL) at room temperature. Heat the mixture at 70° C. overnight. Filter the reaction mixture over Celite® and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (85:15) to obtain the desired intermediate as a yellow oil (1.362 g, 76%).