Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:7]2)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[Cl:19][CH2:20][C:21](Cl)=[O:22]>C(OCC)(=O)C>[Cl:19][CH2:20][C:21]([CH:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH2:7][NH:8]1)=[O:22]
Reactant: O=C(Cl)CCl
Reactant: O=[N+]([O-])c1ccc2c(c1)CNC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: O=C(CCl)C1NCc2cc([N+](=O)[O-])ccc21
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a suspension in which 42.8 g of 5-nitroisoindoline had been added to an aqueous potassium carbonate solution (108 g of potassium carbonate, 200 ml of water) was added dropwise 200 ml of an ethyl acetate solution containing 31.2 ml of chloroacetyl chloride at 0° C. over 1 hour. The mixture was further stirred at 0° C. for 45 minutes and precipitates were collected by filtration. The obtained solid was treated with activated carbon in ethyl acetate and recrystallized to obtain 2-chloroacetyl-5-nitroisoindoline. (2) In 10 ml of N,N-dimethylformamide were stirred 1.21 g of the compound obtained in the above (1), 1.07 g of N-tert-butoxycarbonyl-trans-1,4-cyclohexanediamine and 1.39 g of potassium carbonate at room temperature for 20 hours. The reaction mixture was poured into water and precipitated solids were collected by filtration, washed with water, dried, and purified by silica gel column chromatography (solvent, chloroform-methanol=98:2 to 95:5) to obtain N-tert-butoxycarbonyl-trans-4-[(5-nitro-2-isoindolinyl)-carbonylmethylamino]cyclohexylamine. In 3 ml of trifluoroacetic acid was dissolved 284 mg of this compound and the solution was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was made basic by 10% sodium hydroxide and extracted with chloroform. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain trans-4-[(5-nitro-2-isoindolinyl)carbonylmethylaminolcyclohexylamine (Reference Example 10-1 in Table 11).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=2[CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[N:28]([CH:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)[N:27]=[C:26]([C:35]#[C:36][C:37]([O:39]CC)=[O:38])[CH:25]=3)=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[Li+].[OH-]>CO.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=2[CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[N:28]([CH:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)[N:27]=[C:26]([C:35]#[C:36][C:37]([OH:39])=[O:38])[CH:25]=3)=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C#Cc1cc(-c2ccc(OCc3cc(OC)ccc3-c3ccc(Cl)cc3)cc2)n(C2CCCCC2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(-c2ccc(Cl)cc2)c(COc2ccc(-c3cc(C#CC(=O)O)nn3C3CCCCC3)cc2)c1

Procedure:
Ester 7.6 (55 mg, 0.097 mmol) was stirred with 1N LiOH (1 ml) in 4 ml of MeOH/THF (1:3) at rt for 24 h, concentrated, and partitioned between Et2O and H2O. The organic phase was extracted with 0.1 N NaOH (2×), and the combined aqueous extracts were acidified with conc. HCl, and extracted with EtOAc (3×). The combined organic extracts were washed with H2O, brine, and dried (Na2SO4). The crude mixture was purified by semi-preparative HPLC (gradient elution: 70 to 100% CH3CN/H2O+0.1% TFA) to give 7.7, 52 mg (100%). HRMS (ESI) calc'd for C32H30ClN2O4 514.1894, found 541.1913 (MH+); 1H NMR (300 MHz, CDCl3) δ 7.39–7.17 (m, 8H), 7.00–6.94 (m, 3H), 6.51 (s, 1H), 4.95 (s, 2H), 4.14–4.05 (m, 1H), 3.88 (s, 3H), 2.08–1.96 (m, 2H), 1.90–1.86 (m, 4H), 1.26 (br s, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[NH2:12][C:13](N)=[O:14]>O>[Br:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:5])[NH:12][C:13](=[O:14])[NH:1]2)=[CH:7][CH:8]=1
Reactant: Nc1cc(Br)ccc1C(=O)O
Reactant: NC(N)=O
Solvent: O
Product: O=c1[nH]c(=O)c2ccc(Br)cc2[nH]1
Temperature: 195 °C
Reaction time: 3 h
Yield: 89.6 %

Procedure:
To a 250 mL round bottom flask, 2-amino-4-bromo-benzoic acid (10 g, 0.0463 mol) and urea (27.78 g, 0.4629 mol) were added. The reaction mixture was stirred at 195° C. for 3 hours. The reaction mixture was allowed to cool to 80° C. and water was added. The aqueous reaction mixture was stirred at 80° C. for 5-10 minutes then allowed to reach room temperature. The solid was filtered, dried and azeotroped with toluene to afford the title compound (10 g, 90%). This material was taken to the next step without further purification.
Reaction SMILES: C([O-])(O)=O.[Na+].[CH3:6][O:7][CH2:8][CH2:9][O:10][CH2:11][C:12]([C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23])([CH3:14])[CH3:13].[C:25](Cl)(=[O:27])[CH3:26].O>ClCCl>[CH3:6][O:7][CH2:8][CH2:9][O:10][CH2:11][C:12]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:25](=[O:27])[CH3:26])=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23])([CH3:14])[CH3:13]
Reactant: COCCOCC(C)(C)c1ccc(N)cc1[N+](=O)[O-]
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COCCOCC(C)(C)c1ccc(NC(C)=O)cc1[N+](=O)[O-]
Temperature: 15 °C
Reaction time: 8 h
Yield: 80.6 %

Procedure:
To a suspension of NaHCO3 (10 g, 0.1 mol) in dichloromethane (50 mL) was added 4-[2-(2-methoxy-ethoxy)-1,1-dimethyl-ethyl]-3-nitro-phenylamine (5 g, 30 mmol) and acetyl chloride (3 mL, 20 mmol) at 0-5° C. The mixture was stirred overnight at 15° C. and then poured into water (200 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (50 mL×2). The combined organic layers were washed with water and brine, dried over Na2SO4, and concentrated to dryness to give N-{4-[2-(2-methoxy-ethoxy)-1,1-dimethyl-ethyl]-3-nitro-phenyl}-acetamide (5.0 g, 87%).
Reaction SMILES: C(N(C(C)C)C(C)C)C.[CH2:10](Br)[CH2:11][CH2:12][CH3:13].[NH2:15][CH2:16][C:17]1[O:21][N:20]=[C:19]([C:22]2[N:23]=[CH:24][N:25]3[C:31]4[CH:32]=[CH:33][S:34][C:30]=4[C:29](=[O:35])[N:28]([CH3:36])[CH2:27][C:26]=23)[N:18]=1>CN(C)C=O>[CH2:10]([NH:15][CH2:16][C:17]1[O:21][N:20]=[C:19]([C:22]2[N:23]=[CH:24][N:25]3[C:31]4[CH:32]=[CH:33][S:34][C:30]=4[C:29](=[O:35])[N:28]([CH3:36])[CH2:27][C:26]=23)[N:18]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CN1Cc2c(-c3noc(CN)n3)ncn2-c2ccsc2C1=O
Reactant: CCCCBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCNCc1nc(-c2ncn3c2CN(C)C(=O)c2sccc2-3)no1
Reaction time: 1 h
Yield: 49 %

Procedure:
1.17 ml (6.8 mmol) of N-ethyldiisopropylamine and 0.55 ml (5.1 mmol) of butyl bromide were added to a solution of 0.54 g (1.7 mmol) of 3-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepin-6-one in 20 ml of dimethylformamide and the mixture was stirred at 70° for 1 hour. The reaction solution was subsequently evaporated, whereupon the residue was partitioned between methylene chloride and 2N sodium carbonate solution. The aqueous phase was washed three times with methylene chloride. The organic phases were dried with magnesium sulfate, filtered and evaporated. The residue obtained was chromatographed (silica gel, methylene chloride/methanol/aqueous ammonia 110:10:1). There were obtained 310 mg (47%) of 3-(5-butylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepin-6-one as a colourless foam, Rf=0.73 (silica gel, methylene chloride/methanol/aqueous ammonia 110:10:1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1.C([N-]C(C)C)(C)C.[Li+].CON(C)[C:19](=[O:21])[CH3:20]>O1CCCC1>[N:5]1[CH:6]=[CH:7][C:2]([CH2:1][C:19](=[O:21])[CH3:20])=[N:3][CH:4]=1
Reactant: Cc1ccncn1
Reactant: CON(C)C(C)=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)Cc1ccncn1
Temperature: -78 °C

Procedure:
4-Methylpyrimidine (2 g) was stirred in dry tetrahydrofuran (65 ml) under argon and the solution was cooled to −78° C. Lithium diisopropylamide (13.8 ml, 2M solution) was added dropwise over 20 minutes and stirring was continued at −78° C. for 1.5 h before dropwise addition of N-methoxy-N-methylacetamide (2.49 ml). The reaction mixture was stirred at −78° C. for a further 40 minutes before allowing to warm to room temperature over 1.25 h, then partitioned between saturated aqueous sodium carbonate and ethyl acetate. The layers were separated and the aqueous phase further extracted with ethyl acetate. The combined extracts were washed with brine, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography on silica gel eluting with 40-50% ethyl acetate in hexane to give an oil which crystallised on standing (0.70 g, 24%).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH3:4][C:5]1[CH:9]([Si:10](Cl)([CH3:12])[CH3:11])[C:8]([CH3:14])=[C:7]([CH3:15])[C:6]=1[CH3:16].C1COCC1>>[CH3:1][N:2]([C:9]1([SiH:10]([CH3:12])[CH3:11])[C:8]([CH3:14])=[C:7]([CH3:15])[C:6]([CH3:16])=[C:5]1[CH3:4])[CH3:3]
Reactant: CNC
Reactant: CC1=C(C)C([Si](C)(C)Cl)C(C)=C1C
Solvent: C1CCOC1
Product: CC1=C(C)C(N(C)C)([SiH](C)C)C(C)=C1C
Temperature: 15 °C
Reaction time: 16 h

Procedure:
A 250 ml roundboftom flask equipped with a condenser, stirrer, thermometer and dropping funnel with nitrogen inlet was charged with 100 ml of dimethylamine solution (2.0 M in THF, 0.20 mol) and cooled to 15° C. A solution of tetramethylcyclopentadienyl-dimethylsilylchloride in THF (10.1 g in 30 ml THF, 47 mmol) was added and the solution stirred for 16 hours allowing the temperature of the reaction mixture to rise to room temperature. A precipitate was filtered off and the solvent evaporated. The remaining residue was distilled at sub-atmospheric pressure (2.6 mbar) at 80-81° C. to obtain N,N-dimethylamino-dimethylsilyl-tetramethylcyclopentadiene (4.2 g). The product was characterized by GC, GC-MS, 13C and 1H NMR.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[C:4]([N+:13]([O-])=O)[CH:3]=1.[H][H]>CO.[Pd]>[NH2:13][C:4]1[CH:3]=[C:2]([F:1])[C:11]([F:12])=[CH:10][C:5]=1[C:6]([NH:8][CH3:9])=[O:7]
Reactant: CNC(=O)c1cc(F)c(F)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CNC(=O)c1cc(F)c(F)cc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4,5-difluoro-N-methyl-2-nitrobenzamide (1.33 g, 6.15 mmol) in methanol (50 mL) was added Pd/C (10% Pd in carbon, 200 mg, 15 wt %) under argon. A hydrogen balloon was used as hydrogen source. The reaction was stirred at room temperature overnight. The mixture was filtered through celite and the celite pad was washed several times. The solvent was removed the crude was purified by silica gel chromatography to obtain the desired product (quantitative yield).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](OCC)=[O:13])=[C:5]2[NH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:27]#[N:28])([CH3:26])[CH3:25])=[CH:20][CH:19]=1.C(O)C.[BH4-].[Na+]>ClCCl>[Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([CH2:12][OH:13])=[C:5]2[NH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([CH3:26])([CH3:25])[C:27]#[N:28])=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(C(C)(C)C#N)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C#N)c1ccc(Nc2c(CO)cnc3ccc(Cl)nc23)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Ethyl 6-chloro-4-((4-(2-cyanopropan-2-yl)phenyl)amino)-1,5-naphthyridine-3-carboxylate (8.1 g, 20.5 mmol) was added to a mixed solvent of ethanol (120 mL) and dichloromethane (12 mL), to the system added sodium borohydride (5.4 g, 143 mmol) in batches, stirred at room temperature for 24 h, ethanol was removed under reduced pressure, adjusted pH of the solution to be neutral with 1 N dilute hydrochloric acid and extracted with 200 mL of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting 9.0 g of a crude solid was used directly in the next step.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[N:6][C:5]=1[CH:12]=[CH2:13].[NH3:15]>CO>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:4]2[C:3](=[O:2])[NH:15][CH2:13][CH2:12][C:5]=2[N:6]=1
Reactant: N
Reactant: C=Cc1nc(OC)ccc1C(=O)OC
Solvent: CO
Product: COc1ccc2c(n1)CCNC2=O
Temperature: 100 °C
Reaction time: 24 h
Yield: 63 %

Procedure:
A mixture of 6-methoxy-2-vinyl-nicotinic acid methyl ester (130 g, 674 mmol) in 7M solution of NH3 in MeOH (500 mL) was added to a sealed vessel. The mixture was stirred at 100° C. for 24 h. The solvent was evaporated in vacuo. The crude product was diluted with MeOH and the mixture was stirred at rt. The solid was filtered and dried in vacuo to yield 2-methoxy-7,8-dihydro-1,6-naphthyridin-5(6H)-one (75 g, 63%) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14]C(=O)C)[CH2:6][CH2:7][C:8](Cl)=[O:9].[NH2:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([OH:24])=[O:23]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[OH:14])[CH2:6][CH2:7][C:8]([NH:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([OH:24])=[O:23])=[O:9]
Reactant: COc1cc(CCC(=O)Cl)ccc1OC(C)=O
Reactant: Nc1cccc(C(=O)O)c1
Product: COc1cc(CCC(=O)Nc2cccc(C(=O)O)c2)ccc1O

Procedure:
In a similar manner except that 3-methoxy-4-acetoxyhydrocinnamoyl chloride was used in place of the 4-acetoxycinnamoyl chloride used in Example 1 for reaction with 3-aminobenzoic acid and the reaction product was hydrolyzed, 3-(3'-methoxy-4'-hydroxyhydrocinnamoyl amino)benzoic acid was obtained. After recrystallization from an aqueous alcohol, this product had a melting point of 218'220°C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[N:6][CH:7]=1.Cl[C:26]1[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=1>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][CH:18]2[CH2:19][CH2:20][N:21]([C:26]3[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=3)[CH2:22][CH2:23]2)=[N:6][CH:7]=1
Reactant: O=C(Nc1ccc(Cl)cn1)c1ccccc1NCC1CCNCC1
Reactant: Cc1cc(Cl)ccn1
Solvent: CCO
Product: Cc1cc(N2CCC(CNc3ccccc3C(=O)Nc3ccc(Cl)cn3)CC2)ccn1
Yield: 66 %

Procedure:
To a solution of N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.130 g, 0.38 mmol) in ethanol (10 mL) was added 4-chloro-2-picoline (0.1 mL). The reaction mixture was heated in a sealed tube for 24 hours. The reaction mixture was concentrated and the residue was purified by RPHPLC. The pure product containing fractions were combined and lyophilized to give 155 mg (66%) of a tan powder.
Reaction SMILES: [ClH:1].[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C:11]1[CH:34]=[CH:33][C:14]([CH2:15][O:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][O:22][CH2:23][C:24]#[C:25][C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)=[CH:13][CH:12]=1>CO.[Pd]>[ClH:1].[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C:11]1[CH:34]=[CH:33][C:14]([CH2:15][O:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=2)=[CH:13][CH:12]=1
Reactant: Cc1ccc(C#CCOCCNCCOCc2ccc(-c3nc4ccccc4o3)cc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Cc1ccc(CCCOCCNCCOCc2ccc(-c3nc4ccccc4o3)cc2)cc1
Reaction time: 0.33 h

Procedure:
N-[2-(4-(benzoxazol-2-yl)benzyloxy)ethyl]-2-[3-(4-methylphenyl)prop-2-ynyloxy]ethanamine hydrochloride (125 mg) is dissolved in MeOH (12 ml) in an argon atmosphere and then 27 mg Pd/C catalyst is added. H2 is bubbled into the reaction mixture for 1 minute and stirred under H2 for 20 minutes. The mixture is purged with argon and filtered through celite and washed with MeOH and THF. Several drops of HCl/EtOH are added until acidic and the mixture concentrated to dryness to obtain N-[2-(4-(benzoxazol-2-yl)benzyloxy)ethyl]-2-[3-(4-methyl-phenyl)propoxy]ethanamine hydrochloride as a white solid. (m.p. 138°-139° C.).
Reaction SMILES: NN.[N+:3]([C:6]1[CH:7]=[C:8]([C:15]2[CH:16]=[N:17][CH:18]=[N:19][CH:20]=2)[C:9]2[O:13][CH:12]=[CH:11][C:10]=2[CH:14]=1)([O-])=O>C(O)C.C1COCC1.[Ni]>[N:17]1[CH:16]=[C:15]([C:8]2[C:9]3[O:13][CH:12]=[CH:11][C:10]=3[CH:14]=[C:6]([NH2:3])[CH:7]=2)[CH:20]=[N:19][CH:18]=1
Reactant: O=[N+]([O-])c1cc(-c2cncnc2)c2occc2c1
Agent: [Ni]
Agent: NN
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1cc(-c2cncnc2)c2occc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.3 %

Procedure:
Raney-nickel (slurry in ethanol; 2 mL) and hydrazine (0.378 g, 7.55 mmol) were added to 5-(5-nitro-1-benzofuran-7-yl)pyrimidine (0.455 g, 1.87 mmol, Intermediate 17) in ethanol/THF (100 mL:25 mL). The mixture was stirred at room temperature for 3 h, filtered through Celite and concentrated in vacuo to afford 0.317 g (80%) of the title compound as a yellow solid. HPLC 100%, RT: 0.957 min (System A; 10-97% over 3 min). 1H NMR (270 MHz, methanol-d4) δ ppm 6.77 (d, J=2.23 Hz, 1H) 7.05 (q, J=2.23 Hz, 2H) 7.76 (d, J=2.23 Hz, 1H) 9.14 (s, 1H) 9.26 (s, 2H). LC-MS 212 (M+H)+.
Reaction SMILES: [CH:1]1([C:4](Cl)=O)[CH2:3][CH2:2]1.[K].[CH3:8][O:9][C:10]1[CH:11]=[C:12]([C:16]2([CH2:22][CH2:23][NH2:24])[CH2:21][CH2:20][CH2:19][CH:18]=[CH:17]2)[CH:13]=[CH:14][CH:15]=1>C(Cl)Cl.CCOCC>[CH:1]1([CH2:4][NH:24][CH2:23][CH2:22][C:16]2([C:12]3[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH3:8])[CH:11]=3)[CH2:21][CH2:20][CH2:19][CH:18]=[CH:17]2)[CH2:3][CH2:2]1
Reactant: COc1cccc(C2(CCN)C=CCCC2)c1
Reactant: O=C(Cl)C1CC1
Agent: [K]
Solvent: CCOCC
Solvent: ClCCl
Product: COc1cccc(C2(CCNCC3CC3)C=CCCC2)c1

Procedure:
3.45 g of cyclopropanecarboxylic acid chloride are placed in 50 ml of methylene chloride, whereafter 5.0 g of potassium carbnate are added, and then a solution of 7.0 g of 1-(m-methoxyphenyl)-2-cyclohexene-1-ethylamine in 10 ml of methylene chloride is added dropwise while stirring. The mixture is stirred at room temperature overnight and subsequently at reflux for 30 minutes and cooled. Then, the precipitate is removed by filtration under suction, the filtrate is evaporated, and the oil obtained is taken up in ether. The ethereal solution is washed with 1 N hydrochloric acid and subsequently with water, dried over magnesium sulfate and evaporated, and N-[2-[1-(m-methoxyphenyl)-2-cyclohexen-1-yl]ethyl]-cyclopropanecarboxamide remains as the residue. 6.5 g of this compound, dissolved in 30 ml of absolute tetrahydrofuran, are added dropwise to a dispersion of 6 g of lithium aluminum hydride in 100 ml of absolute tetrahydrofuran. The mixture is boiled at reflux for 3 hours, cooled and worked-up in the usual manner, and there is obtained N-(cyclopropylmethyl)-1-(m-methoxyphenyl)-2-cyclohexene-1-ethylamine, the hydrochloride of which melts at 141°-142° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([NH:11][C:12](=[O:17])[CH2:13][CH2:14][CH2:15]Cl)[CH:7]=[CH:8][C:9]=1[F:10]>C1COCC1>[Br:3][C:4]1[CH:5]=[C:6]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:17])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: O=C(CCCCl)Nc1ccc(F)c(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CCCN1c1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
60% Sodium hydride in oil dispersion (1.2 g, 29.88 mmol) was added portionwise over 5 mins to an ice-cooled, stirred solution of N-(3-bromo-4-fluoro-phenyl)-4-chloro-butanamide (which may be prepared as described in Description 57) (8 g, 27.16 mmol) in dry THF (150 mL) under N2. After cooling for a further 5 mins the cooling bath was removed and the mixture stirred at ambient temp for 2 hours. The reaction mixture was then treated with AcOH (1 ml) by dropwise addition. The mixture was evaporated and the residue partitioned between DCM (150 ml) and water (150 ml). The latter was re-extracted with DCM (50 ml) and the combined organic extracts dried (MgSO4) and evaporated to a white solid. The solid was dissolved in refluxing Et2O (65 ml) and the solution diluted with iso-hexane (240 ml) and left to stand for 1 hour. The crystalline solid was filtered and dried. The filtrate was concentrated to approx 50 ml volume and a 2nd crop of crystals was collected and dried. The combined mass gave N-(3-bromo-4-fluoro-phenyl)pyrrolidin-2-one (D58) (6.03 g);
Reaction SMILES: [Na+].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([C:11]([O-:13])=O)=[N:8][C:7]=2[CH:14]=1.[C:15]([O:19][C:20](=[O:42])[C@@H:21]([NH:25][S:26]([C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=2)=[CH:31][CH:30]=1)(=[O:28])=[O:27])[CH:22]([CH3:24])[CH3:23])([CH3:18])([CH3:17])[CH3:16].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>[Cl-].[Na+].O.CN(C=O)C>[C:15]([O:19][C:20](=[O:42])[C@@H:21]([NH:25][S:26]([C:29]1[CH:30]=[CH:31][C:32]([C:35]2[CH:36]=[CH:37][C:38]([NH:41][C:11]([C:9]3[S:10][C:6]4[CH:5]=[CH:4][C:3]([Cl:2])=[CH:14][C:7]=4[N:8]=3)=[O:13])=[CH:39][CH:40]=2)=[CH:33][CH:34]=1)(=[O:28])=[O:27])[CH:22]([CH3:24])[CH3:23])([CH3:17])([CH3:18])[CH3:16]
Reactant: O=C([O-])c1nc2cc(Cl)ccc2s1
Reactant: CC(C)[C@H](NS(=O)(=O)c1ccc(-c2ccc(N)cc2)cc1)C(=O)OC(C)(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3nc4cc(Cl)ccc4s3)cc2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.4 %

Procedure:
To 5-chloro-benzothiazole-2-carboxylic acid sodium salt (150 mg, 0.64 mmol) was added (S)-2-(4′-amino-biphenyl-4-sulfonylamino)-3-methyl-butyric acid tert-butyl ester (310 mg, 1.2 eq), BOP (340 mg, 1.2 eq), N,N-diisopropylethylamine (99 mg, 1.2 eq) and 4 mL of DMF. The mixture was stirred at room temperature overnight. The reaction mixture was poured into brine, and extracted with ethyl acetate. The combined organic solution was washed with brine and water. Removal of solvent gave the crude product, which was purified by column chromatography on silica gel to give 136 mg of (S)-3-methyl-2-{4′-[(5-chloro-benzothiazole-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-butyric acid tert-butyl ester was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9](F)=[CH:8][CH:7]=1)=[O:5].[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>O>[Cl:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)=[CH:8][CH:7]=1)=[O:5]
Reactant: O=C(c1ccc(F)cc1)c1cc(Cl)ccc1Cl
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C(c1ccc(-n2ccnc2)cc1)c1cc(Cl)ccc1Cl
Temperature: 110 °C
Yield: 87.3 %

Procedure:
150.7 g (0.560 mol) of 2,5-dichloro-4′-fluorobenzophenone, 114.4 g (1.68 mol) of imidazole, 100.6 g (0.728 mol) of potassium carbonate, and 840 mL of N,N-dimethyl acetamide were weighed in a 2 L three-necked flask equipped with a stirrer, thermometer, cooling pipe, and nitrogen inlet tube. The reaction solution was heated to 110° C. using an oil bath for 2 hours under a nitrogen atmosphere. After confirming the disappearance of raw materials by way of thin-layer chromatography, the reaction liquid was allowed to cool to room temperature. Thereafter, the reaction liquid was gradually added to 3 L of water, the product was solidified and filtered. The product obtained by filtering was dissolved in THF (1.2 L), toluene (4 L) was added, and the mixture was washed with a sodium chloride solution till the aqueous layer became neutral. The organic layer was dried using magnesium sulfate, and then the solvent was removed by an evaporator. The approximate yield amount was 180 g. The crude product was subjected to a recrystallization separating operation using a mixed solvent of 1 L toluene and 20 mL methanol heated at 80° C. to obtain 155 g of a white solid at a yield of 87%.