Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2](O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.P(Br)(Br)[Br:11]>C(Cl)(Cl)Cl>[Br:11][CH:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:1]
Reactant: CC(O)c1ccccc1
Reactant: BrP(Br)Br
Solvent: ClC(Cl)Cl
Product: CC(Br)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.4 %

Procedure:
To a solution of DL-sec-phenethyl alcohol (1.81 ml, 15 mmol) in chloroform (20 ml) was added phosphorus tribromide (15.75 ml, 15.75 mmol) dropwise at room temperature. The mixture was stirred at room temperature for 18 hours, poured into wet ice, washed with brine (4×), dried (MgSO4), then evaporated to dryness to yield 2.62 g of the title compound.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([N+:17]([O-])=O)[C:10]([F:16])=[C:11]([F:15])[C:12]=3[CH3:14])[C:7](=[O:20])[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1>[Ni].C(O)(=O)C>[NH2:17][C:9]1[C:10]([F:16])=[C:11]([F:15])[C:12]([CH3:14])=[C:13]2[C:8]=1[C:7](=[O:20])[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5][N:4]2[CH:1]1[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(C)c(F)c(F)c([N+](=O)[O-])c2c1=O
Agent: [Ni]
Solvent: CC(=O)O
Product: CCOC(=O)c1cn(C2CC2)c2c(C)c(F)c(F)c(N)c2c1=O
Reaction time: 1.5 h
Yield: 87.4 %

Procedure:
A suspension of 18.5 g of ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-5-nitro-4-oxoquinoline-3-carboxylate, 10 ml of Raney nickel in 300 ml of acetic acid was hydrogenated at room temperature for 1.5 hours under atmospheric pressure. The catalyst was filtered off and resulting filtrate was evaporated. To this residue, 150 ml of 10% aqueous potassium carbonate was added and the mixture was extracted with methylene chloride. The combined organic extracts were dried and evaporated to give 14.8 g of the desired compound as slightly yellow crystals, which was recrystallized from acetonitrile to give slightly yellow needles, m.p. 182.5°-185.5° C.
Reaction SMILES: C[O:2][C:3](=[O:24])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:15](=[O:23])[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1.[OH-].[Na+]>CO.C1COCC1>[Cl:14][C:10]1[CH:9]=[C:8]2[C:13]([C:5]([CH2:4][C:3]([OH:24])=[O:2])=[C:6]([C:15](=[O:23])[C:16]3[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[NH:7]2)=[CH:12][CH:11]=1
Reactant: COC(=O)Cc1c(C(=O)c2ccc(Cl)cc2)[nH]c2cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)Cc1c(C(=O)c2ccc(Cl)cc2)[nH]c2cc(Cl)ccc12
Temperature: 80 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
A mixture of methyl[6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetate (Example 8, 1.80 g) and 2N aqueous NaOH (7.5 ml) in MeOH-THF (10 ml-10 ml) was stirred at 80° C. for 1 h. The mixture was cooled and concentrated. The residue was dissolved in water (150 ml) and washed with diethyl ether (50 ml). The aqueous layer was acidified with 2N aqueous HCl (10 ml), and extracted with ethyl acetate (100 ml×2). The combined organic extracts were washed with brine (50 ml), dried (MgSO4), and concentrated. The residual solids were recrystalized from toluene to afford 1.58 g (91%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10][CH2:9]2)[CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[P:28](Cl)([O:33][CH2:34][CH3:35])([O:30][CH2:31][CH3:32])=[O:29].[Cl-].[NH4+]>C1COCC1>[CH2:31]([O:30][P:28]([CH2:17][S:14]([N:11]1[CH2:12][CH2:13][N:8]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=2)[CH2:9][CH2:10]1)(=[O:16])=[O:15])([O:33][CH2:34][CH3:35])=[O:29])[CH3:32]
Reactant: Cc1ccnc(N2CCN(S(C)(=O)=O)CC2)c1
Reactant: CCOP(=O)(Cl)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOP(=O)(CS(=O)(=O)N1CCN(c2cc(C)ccn2)CC1)OCC
Temperature: -78 °C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
1-(4-Methyl-2-pyridyl)-4-methylsulfonyl-piperazine (1.16 g, 4.54 mmol) was dissolved in anhydrous THF (80 ml) and cooled under nitrogen to −78° C. Lithium bis(trimethylsilyl)amide (1M in THF, 14 ml, 14 mmol) was added dropwise and the mixture was stirred at −78° C. for one hour. Diethyl chlorophosphate (3.1 g, 18 mmol) was added dropwise and stirring was continued for one hour at −78° C., after which the mixture was allowed to reach room temperature over three hours. A saturated solution of ammonium chloride was added and the mixture was extracted with DCM (3×), the combined organic layers were dried (sodium sulfate), concentrated under reduced pressure and the residue was purified by column chromatography (silica, gradient from 0 to 6% methanol in DCM) to give 1.44 g of a light-brown oil (3.68 mmol, yield 81%) MS (ESI) m/z=392.1 [M+1]+.
Reaction SMILES: [C:1]([C:3]1[CH2:8][CH2:7][CH:6]=[CH:5][CH:4]=1)#[N:2].[C:9]1(=[O:15])[NH:13][C:12](=[O:14])[CH:11]=[CH:10]1.C(C1C=C(O)C(=CC=1)O)(C)(C)C>CN(C)C=O>[C:1]([C:3]12[CH2:8][CH2:7][CH:6]([CH:5]=[CH:4]1)[CH:11]1[CH:10]2[C:9](=[O:15])[NH:13][C:12]1=[O:14])#[N:2]
Reactant: O=C1C=CC(=O)N1
Reactant: N#CC1=CC=CCC1
Agent: CC(C)(C)c1ccc(O)c(O)c1
Solvent: CN(C)C=O
Product: N#CC12C=CC(CC1)C1C(=O)NC(=O)C12

Procedure:
59 g (0.56 mol) of 1-cyano-cyclohexa-1,3-diene are heated at 150° C. with 54 g (0.56 mol) of maleimide and 5 g of 4-(tert-butyl)-pyrocatechol in 1000 ml of dimethylformamide for 8 hours. The mixture is concentrated, the residue is stirred with water and toluene and the product which has crystallized is filtered off with suction, washed with isopropanol and dried in air.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:17])=[C:4]([NH:10][C:11]2C=CC=CC=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].Cl.NC1C2CCCCC=2C(C#N)=CC=1.N(C1C2CCCCC=2C(C#N)=CC=1)=C=[O:34]>>[Cl:1][C:2]1[C:3]([CH3:17])=[C:4]([N:10]=[C:11]=[O:34])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1c(Nc2ccccc2)ccc(C#N)c1Cl
Reactant: N#Cc1ccc(N=C=O)c2c1CCCC2
Agent: Cl
Agent: N#Cc1ccc(N)c2c1CCCC2
Product: Cc1c(N=C=O)ccc(C#N)c1Cl

Procedure:
The title compound was prepared from compound 23D in a manner similar to that described in Experiments 2D to 2E.
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14](Cl)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]([F:29])([F:28])[C:21]1[N:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1.I.O>O1CCOCC1>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([NH:27][C:24]3[CH:25]=[N:26][C:21]([C:20]([F:29])([F:19])[F:28])=[CH:22][CH:23]=3)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(C(F)(F)F)nc1
Reactant: Clc1ncnc2c1CCN(Cc1ccccc1)C2
Agent: I
Solvent: O
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc(Nc2ncnc3c2CCN(Cc2ccccc2)C3)cn1
Temperature: 130 °C
Yield: 95 %

Procedure:
7-Benzyl-4-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (0.5 g, 1.93 mmol) was dissolved in anhydrous dioxane (3 mL) and 6-Trifluoromethylpyridin-3-ylamine was added (469 mg, 2.9 mmol), followed by HI/H2O (0.3 mL, 47%). The mixture was heated at 130° C. for 600 s in a Personal Chemistry microwave. The solvents were removed under vacuum and the residue was dissolved in ethyl acetate and washed with sat. NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and evaporated to give the product as an orange solid (700 mg, 95% crude). The crude product was used for the subsequent step.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[C:8]2[NH:13][C:14]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:15]=1[C:16]([O:18]C)=[O:17].[OH-].[Na+]>CO>[F:26][C:2]([F:1])([F:25])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[C:8]2[NH:13][C:14]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:15]=1[C:16]([OH:18])=[O:17]
Reactant: COC(=O)c1cc(F)ccc1Nc1ccnc2c(C(F)(F)F)cccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(F)ccc1Nc1ccnc2c(C(F)(F)F)cccc12
Temperature: 60 °C
Yield: 90.4 %

Procedure:
A mixture of 1.45 g of the product of Example 11, 4 ml of 2 N sodium hydroxide solution and 21 ml of methanol was refluxed and the methanol was evaporated. 25 ml of water were added to the mixture and the solution was filtered through asbestos. The solution was heated to 60° C. and was acidified with concentrated hydrochloric acid. The resulting suspension was cooled and filtered and the recovered precipitate was washed with water and dried to obtain 1.26 g of 2-(8-trifluoromethyl-4-quinolinylamino)-5-fluoro-benzoic acid melting at 265°±3° C.
Reaction SMILES: [CH2:1]([C:3]1([C:8]2[S:12][C:11]([CH2:13][OH:14])=[CH:10][CH:9]=2)[O:7][CH2:6][CH2:5][O:4]1)[CH3:2].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].[Cl-].[NH4+]>ClCCl>[CH3:22][S:23]([O:14][CH2:13][C:11]1[S:12][C:8]([C:3]2([CH2:1][CH3:2])[O:4][CH2:5][CH2:6][O:7]2)=[CH:9][CH:10]=1)(=[O:25])=[O:24]
Reactant: CCC1(c2ccc(CO)s2)OCCO1
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC1(c2ccc(COS(C)(=O)=O)s2)OCCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
9.25 g (43.2 mmol) of [5-(2-ethyl-[1,3]dioxolan-2-yl)-2-thienyl]methanol are dissolved in 500 mL of dichloromethane and cooled to 0° C. 9.0 mL (64.7 mmol) of triethylamine are added, followed by 3.5 mL of methylsulphonyl chloride (45.3 mmol). After stirring for 1 hour, the reaction medium is treated with ammonium chloride solution and extracted with dichloromethane. The organic phases are combined, dried and concentrated under reduced pressure. A brown oil is obtained (m=9.28 g; Y=75%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:22])([CH3:21])[C:6]=2[CH:23]=1.[C:24]([O:28][C:29](=[O:34])[NH:30][CH2:31][CH2:32]O)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([O:28][C:29](=[O:34])[NH:30][CH2:31][CH2:32][O:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:21])([CH3:22])[C:6]=2[CH:23]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Product: CC(C)(C)OC(=O)NCCOc1ccc2c(c1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O

Procedure:
Under the same conditions as the method for synthesizing Compound A7-1, the title compound was prepared from Compound A6 and (2-hydroxy-ethyl)-carbamic acid tert-butyl ester.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:1][C:2]2[S:3][C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:6]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)c1sc(N)nc1-c1ccccc1
Product: CCOC(=O)c1sc(NS(=O)(=O)c2ccc(Cl)cc2)nc1-c1ccccc1

Procedure:
The title compound was prepared from ethyl 2-amino-4-phenylthiazole-5-carboxylate and 4-chlorobenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (61.7 mg) with purity >90%. LCMS (pos) m/z 423.0.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:38])[O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:25])[S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:26]1[S:27][CH:28]([CH2:31][N:32]3[CH2:37][CH2:36][S:35][CH2:34][CH2:33]3)[CH2:29][N:30]=1)=[CH:9]2.ClC1C=CC=C(C(OO)=[O:47])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl.C(OCC)(=O)C>[CH3:1][O:2][CH2:3][C@H:4]([CH3:38])[O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:25])[S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:26]1[S:27][CH:28]([CH2:31][N:32]3[CH2:37][CH2:36][S:35](=[O:47])[CH2:34][CH2:33]3)[CH2:29][N:30]=1)=[CH:9]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC[C@H](C)Oc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=NCC(CN4CCSCC4)S3)cc2c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=NCC(CN4CCS(=O)CC4)S3)cc2c1
Reaction time: 0.5 h
Yield: 68.3 %

Procedure:
To a solution of N-{5-[(1S)-2-methoxy-1-methylethoxy]-2-[5-(thiomorpholinomethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-methylpyridine-2-sulfonamide (80 mg) in dichloromethane (2 mL) was added m-chloroperbenzoic acid (16 mg) under ice-cooling, and the mixture was stirred for 30 min. Aqueous sodium thiosulfate solution was added, and the mixture was diluted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized (acetone-hexane-diisopropyl ether) to give the title compound (37.5 mg, yield 46%) as a colorless solid. melting point 175-176° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH:15][C:16]([C:18]1[S:28][C:27]2[N:29]3[C:20](=[CH:21][N:22]=[C:23]3[CH:24]=[CH:25][CH:26]=2)[CH:19]=1)=[O:17])=O)(C)(C)C.[ClH:30]>C(O)C>[ClH:30].[ClH:30].[NH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH:15][C:16]([C:18]1[S:28][C:27]2[N:29]3[C:20](=[CH:21][N:22]=[C:23]3[CH:24]=[CH:25][CH:26]=2)[CH:19]=1)=[O:17]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CNC(=O)C1=Cc2cnc3cccc(n23)S1
Agent: Cl
Solvent: CCO
Product: O=C(NCC1CCCCN1)C1=Cc2cnc3cccc(n23)S1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
While 3.605 g (16.519 mM) of 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid and 2.09 g (18.2 mM) of N-hydroxysuccinimide were stirred together in 100 ml of acetonitrile, 3.48 g (18.2 mM) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added and the mixture was stirred at room temperature for 2 hours. To this reaction mixture was added 3.45 ml (24.8 mM) of triethylamine as well as 2.83 g (24.8 mM) of 2-aminomethylpiperidine and the mixture was stirred at room temperature for one hour. Then, 5.41 g (24.8 mM) of di-tert-butyl dicarbonate was added and the mixture was stirred at room temperature for another hour. This reaction mixture was poured in aqueous solution of sodium hydrogen carbonate and extracted with 3 portions of ethyl acetate. The organic layers were pooled and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate to ethyl acetate-methanol=9/1) to provide crude N-[1-(tert-butoxycarbonyl)piperidin-2-ylmethyl]-5-thia-1,8b-diazaacenaphthylene-4-carboxamide. To this crude N-[1-(tert-butoxycarbonyl)piperidin-2-ylmethyl)-5-thia-1,8b-diazaacenaphthylene-4-carboxamide was added 5 ml of concentrated hydrochloric acid and the mixture was stirred at room temperature for 0.5 hour. After addition of ethanol, the mixture was stirred and the resulting precipitate was recovered and rinsed serially with ethanol and diethyl ether to provide the title compound.
Reaction SMILES: O[C:2]1([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:32][CH:31]=2)[C:6]2[C:7]([CH3:27])=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4][C:3]1([CH3:29])[CH3:28]>C(O)C>[CH3:28][C:3]1([CH3:29])[CH:2]([C:30]2[CH:31]=[CH:32][C:33]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)=[CH:34][CH:35]=2)[C:6]2[C:7]([CH3:27])=[C:8]([N:13]3[CH2:14][CH2:15][N:16]([C:19]4[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=4)[CH2:17][CH2:18]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4]1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(O)(c3ccc(-c5ccccc5)cc3)C(C)(C)O4)CC2)cc1
Solvent: CCO
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(c3ccc(-c5ccccc5)cc3)C(C)(C)O4)CC2)cc1
Yield: 82 %

Procedure:
Using 1-(3-hydroxy-2,2,4,6,7-pentamethyl-3-(1,1′-biphenyl-4-yl)-2,3-dihydro-1-benzofuran-5-yl)-4-(4-methoxyphenyl)piperazine obtained in Example 35, the title compound was synthesized in the same manner as in Example 46. Yield 82%. mp. 147–148° C. (ethanol).
Reaction SMILES: [OH-].[Na+].[NH:3]1[CH2:10][CH2:9][CH2:8][C@H:4]1[C:5]([OH:7])=[O:6].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20](Cl)=[O:21])=[CH:15][CH:14]=1.Cl>O.CC(C)=O>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([N:3]2[CH2:10][CH2:9][CH2:8][C@H:4]2[C:5]([OH:7])=[O:6])=[O:21])=[CH:15][CH:14]=1
Reactant: COc1ccc(CC(=O)Cl)cc1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(CC(=O)N2CCC[C@H]2C(=O)O)cc1
Temperature: 0 °C
Yield: 68 %

Procedure:
5M Aqueous sodium hydroxide solution (26 ml) was added to a solution of (S)-proline (582 g) in water (3.5 L) and acetone (3.5 L). The mixture was treated with ice (3.5 kg), cooled in an ice/acetone bath, treated over a one hour period with a solution of 4-methoxyphenylacetyl chloride (944 g) in acetone (1.75 L) with vigorous stirring and the simultaneous addition of sufficient 5M aqueous sodium hydroxide solution in order to keep the pH within the range 9.5-9.7. The reaction was stirred for 30 minutes, treated with concentrated hydrochloric acid (6 ml) and partially evaporated under reduced pressure to remove the majority of the acetone. The residue was treated with ice (2 kg), concentrated hydrochloric acid (750 ml) and the mixture stirred at room temperature for one hour. The resulting precipitate was collected, washed with water and recrystallised from toluene/ethanol to give the desired product as a colourless solid (905 g, 75%), m.p. 138°-139° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:18]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][C:21]=2[Cl:27])=[C:17]([F:28])[C:8]2[N:9]=[CH:10][N:11]([CH2:12][CH2:13][C:14](O)=[O:15])[C:7]=2[CH:6]=1)=[O:4].[CH:29]1[CH:30]=CC2N(O)N=[N:35][C:33]=2[CH:34]=1.O.CCN(CC)CC.N1CCCC1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.CCOC(C)=O.O>[CH3:1][O:2][C:3]([C:5]1[C:18]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][C:21]=2[Cl:27])=[C:17]([F:28])[C:8]2[N:9]=[CH:10][N:11]([CH2:12][CH2:13][C:14](=[O:15])[N:35]3[CH2:30][CH2:29][CH2:34][CH2:33]3)[C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2c(ncn2CCC(=O)O)c(F)c1Nc1ccc(Br)cc1Cl
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCNC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2c(ncn2CCC(=O)N2CCCC2)c(F)c1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.1 %

Procedure:
To solution of 6-(4-bromo-2-chloro-phenylamino)-3-(2-carboxy-ethyl)-7-fluoro-3H-benzoimidazole-5-carboxylic acid methyl ester (60 mg, 0.13 mmol) in DMF (1.8 mL) is added HOBt-H2O (24 mg, 0.16 mmol), Et3N (0.043 mL, 0.31 mmol), pyrrolidine (0.011 mL, 0.13 mmol), and EDCl (34 mg, 0.18 mmol) at rt. The resulting yellow solution is stirred 16 hours at rt. The reaction mixture is diluted with EtOAc and water, washed with sat'd aq NH4Cl, brine, sat'd aq NaHCO3, and brine. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo to give a crude material which is purified by flash chromatography (3% MeOH in CH2Cl2) to afford 45 mg (67%) of the desired product: MS APCI (+) m/z 523, 525 (M+, Br pattern) detected.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH:17]=[CH:18][C:19]([O:21][CH3:22])=[O:20])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][NH:33][C:32](=[O:36])[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].CC(C)([O-])C.[K+]>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH:17]([N:33]2[CH2:34][CH2:35][N:30]([C:28]([O:27][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:29])[CH2:31][C:32]2=[O:36])[CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: COC(=O)C=CC1CCN(C(=O)OCc2ccccc2)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)CC(C1CCN(C(=O)OCc2ccccc2)CC1)N1CCN(C(=O)OC(C)(C)C)CC1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 59.9 %

Procedure:
To a solution of methyl 3-(1-benzyloxycarbonylpiperidin-4-yl)acrylate (5.55 g) and 4-(tert-butoxycarbonyl)-2-piperazinone (3.66 g) in tetrahydrofuran (50 ml) was added potassium tert-butoxide (0.56 g), and the mixture was stirred under nitrogen atmosphere at room temperature for 3 days. The reaction solution was diluted with ethyl acetate (50 ml), washed with 0.5N hydrochloric acid and saturated brine, dried and concentrated, and the residue was purified with silica gel column chromatography (eluent:acetone/hexane=1/2) to give colorless amorphous of methyl 3-(1-benzyloxycarbonylpiperidin-4-yl)-3-[4-(tert-butoxycarbonyl)-2-oxopiperazine-1-yl]propionate (5.51 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:21][C:22]([C:24]2[C:25]([OH:35])=[N:26][C:27]([N:30]3[CH:34]=[CH:33][CH:32]=[N:31]3)=[N:28][CH:29]=2)=[O:23])[C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:20])(=[O:19])[O:16]CC)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([NH:21][C:22]([C:24]2[C:25]([OH:35])=[N:26][C:27]([N:30]3[CH:34]=[CH:33][CH:32]=[N:31]3)=[N:28][CH:29]=2)=[O:23])[C:9]2[CH:10]=[CH:11][C:12]([P:15]([CH3:20])(=[O:16])[OH:19])=[CH:13][CH:14]=2)=[CH:6][CH:7]=1
Reactant: CCOP(C)(=O)c1ccc([C@H](NC(=O)c2cnc(-n3cccn3)nc2O)c2ccc(F)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CP(=O)(O)c1ccc([C@H](NC(=O)c2cnc(-n3cccn3)nc2O)c2ccc(F)cc2)cc1
Temperature: 80 °C

Procedure:
Ethyl 4-((R)-(4-fluorophenyl)(4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxamido)methyl)phenyl(methyl)phosphinate, 18-f, (7 g, 14 mmol) was dissolved in 50 ml of dioxane and treated with 5 ml of 3N NaOH. The mixture was heated at 80° C. for one hour. Then the mixture was concentrated under vacuum. The residue was diluted with water and washed with ethyl acetate. The aqueous layer was acidified with conc. HCl to pH=1 and the expected product crashed out (9.2 g of crude). The product can be further purified via prep-HPLC give 4 g of title product, 18-1, (Y=61%). 1H NMR (300 MHz, DMSO-d6): δ 10.32 (br, 1H), 8.62 (s, 1H), 8.43 (s, 1H), 8.05 (s, 1H), 7.46 (m, 2H), 7.37 (m, 4H), 7.20 (m, 2H), 6.72 (s, 1H), 6.33 (d, 1H), 1.50 (d, 3H). (M+H)+=468.1.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]([CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[C:21]([OH:23])=O)=[CH:16][CH:15]=2)[C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.S(Cl)(C)(=O)=O.[C:41]1([CH3:51])[CH:46]=[CH:45][C:44]([S:47]([NH2:50])(=[O:49])=[O:48])=[CH:43][CH:42]=1>C1COCC1.CN(C1C=CN=CC=1)C.O.C(O)(=O)C>[C:41]1([CH3:51])[CH:42]=[CH:43][C:44]([S:47]([NH:50][C:21](=[O:23])[CH:20]([C:17]2[CH:18]=[CH:19][C:14]([CH2:13][N:6]3[C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=[C:5]3[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:15][CH:16]=2)[CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)(=[O:48])=[O:49])=[CH:45][CH:46]=1
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(C(C(=O)O)C2CCCC2)cc1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(C(C(=O)NS(=O)(=O)c2ccc(C)cc2)C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1.2 g (2.6 mmol) of the compound from Example II are dissolved in 30 ml of THF, then 0.72 mol (5.2 mmol) of triethylamine, 0.23 ml (2.9 mmol) of mesyl chloride, 320 mg (2.6 mmol) of DMAP and 535 mg (3.1 mmol) of 4-tolylsulphonamide in 10 ml of THF are added successively at 0° C. The mixture is stirred at 25° C. for 20 h, 0.4 ml of glacial acetic acid and 30 ml of water are added, the mixture is extracted three times with 30 ml of ethyl acetate, the organic is phase is concentrated and the residue is chromatographed on silica gel 60 using dichloromethane/methanol (100:2).
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[N:10]=[CH:9]N(C(OC(C)(C)C)=O)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH3:19][N:20]([CH:22]([C:28](OCC)=O)[C:23](OCC)=O)[CH3:21].C(N(C(C(OCC)=O)C(OCC)=O)CCC)CC>>[CH3:19][N:20]([CH3:21])[CH:22]1[CH2:28][C:7]2[C:11]3=[C:3]([CH2:2][CH2:9][N:10]3[CH2:23]1)[CH:4]=[CH:5][CH:6]=2
Reactant: CCOC(=O)C(C(=O)OCC)N(C)C
Reactant: CC(C)(C)OC(=O)n1cnc2c(CBr)cccc21
Agent: CCCN(CCC)C(C(=O)OCC)C(=O)OCC
Product: CN(C)C1Cc2cccc3c2N(CC3)C1

Procedure:
This compound was prepared by following the procedure of Example 18, but substituting t-butyl 2,3-dihydro-7-(bromomethyl)-1H-indole-1-carboxylate for t-butyl 4-(bromomethyl)-1H-benzimidazole-1-carboxylate and diethyl (dimethylamino)malonate for diethyl (dipropylamino)malonate.