Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2]([CH3:14])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)=O.Cl.NC1[N:18]=[CH:19][NH:20][C:21]=1[C:22]([NH2:24])=[O:23].C(=O)(O)[O-].[Na+]>C(O)(=O)C>[CH3:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[N:18]3[CH:19]=[N:20][C:21]([C:22]([NH2:24])=[O:23])=[C:14]3[N:2]=[CH:3][CH:4]=2)=[CH:12][CH:11]=1
Reactant: NC(=O)c1[nH]cnc1N
Reactant: Cc1ccc(C(=O)C=CN(C)C)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1ccc(-c2ccnc3c(C(N)=O)ncn23)cc1
Yield: 69 %

Procedure:
A mixture of 15.0 g of 3-dimethylamino-4'-methylacrylophenone (prepared as described in Example 11) and 10.0 g of 4-amino-5-imidazolecarboxamide hydrochloride in 150 ml of glacial acetic acid was stirred and heated at reflux for 4 hours. The mixture was evaporated in vacuo to give a yellow crystalline solid. The solid was treated with saturated sodium bicarbonate solution and was collected by filtration, and then it was recrystallized from acetonitrile to give 10.7 g of the desired product as yellow crystals, mp 263°-266° C.
Reaction SMILES: O[CH:2]([CH3:8])[C:3]#[C:4][C:5](=[O:7])[CH3:6].Br.[CH2:10]([S:16][C:17](=[NH:19])[NH2:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(N(CC)CC)C>C1COCC1>[CH2:10]([S:16][C:17]1[N:19]=[C:4]([CH:5]([OH:7])[CH3:6])[CH:3]=[C:2]([CH3:8])[N:18]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCSC(=N)N
Reactant: CC(=O)C#CC(C)O
Agent: Br
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCSc1nc(C)cc(C(C)O)n1
Reaction time: 3 h
Yield: 61.1 %

Procedure:
5-Hydroxy-hex-3-yn-2-one (2 g, 18 mmol) and 2-hexyl-isothiourea hydrobromide (5.2 g, 21 mmol) were dissolved in THF (10 mL). Then the triethylamine (5.5 mL, 40 mmol) was added and stirring continued for 3 h. The reaction was slightly exothermic. The mixture was extracted with AcOEt and sat. NH4Cl solution. The crude product was purified by chromatography on silica gel with a heptane/AcOEt gradient. One obtained 2.8 g (61%) of a light yellow oil. MS: m/z=254 (M)
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([NH:10][C:11]2[N:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([O:21]C(C)(C)C)=[O:20])=[CH:13][CH:12]=2)=[O:9])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([NH:10][C:11]2[N:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20])=[CH:13][CH:12]=2)=[O:9])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(NC(=O)CN2CCOCC2)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)/C=C/c1ccc(NC(=O)CN2CCOCC2)nc1
Reaction time: 16 h
Yield: 86.9 %

Procedure:
A solution of 58c (550 mg, 1.58 mmol) in CH2Cl2(10 ml) was treated with trifluoro acetic acid (1.22 ml) at 20-35° C. for 2 h. The progress of the reaction was monitored by TLC. After 16 h of stirring, the clear solution was concentrated under vacuum and the resultant solid was washed with diethyl ether to get the desired compound as a creamy white solid (400 mg, 87%). MS (ES) m/e 290.1 (M−H)+.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][N:26]=4)[N:21]=[CH:20][N:19]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:28][O-:29].[Na+].O>CS(C)=O>[CH3:28][O:29][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][N:26]=4)[N:21]=[CH:20][N:19]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cccc(Oc2ccc(CCNc3ncnc4nccnc34)cc2)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cccc(Oc2ccc(CCNc3ncnc4nccnc34)cc2)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 67.5 %

Procedure:
{2-[4-(6-Fluoropyridin-2-yloxy)-phenyl]-ethyl}-pteridin-4-ylamine (200 mg, 0.55 mmol) was dissolved in 4 mL dry DMSO and treated with sodium methoxide (300 mg, 5.5 mmol, 10 eq) and stirred for 20 h at 25° C. The mixture was poured into H2O (15 mL) and extracted with CH2Cl2 (2×25 ml). The pooled CH2Cl2 extracts were washed with H2O and brine, dried (Na2SO4), filtered, and evaporated. The gummy residue was dissolved in a minimum quantity of CH2Cl2 and treated with hexane to precipitate the product as a solid that was collected by suction filtration, washed with hexane and dried in vacuo to afford {2-[4-(6-methoxypyridin-2-yloxy)-phenyl]-ethyl}-pteridin-4-yl-amine (139 mg) as a tan solid: mp 152-153° C.; 1H NMR (DMSO-d6) δ 9.09 (s, 1H), 9.00 (t, J=5.9 Hz, 1H), 8.82 (s, 1H), 8.63 (s, 1H), 7.70 (t, J=8.0 Hz, 1H), 7.30 (d, J=8.3 Hz, 2H), 7.05 (d, J=8.4 Hz, 2H), 6.51 (d, J=8.0 Hz, 2H), 6.36 (d, J=7.7 Hz, 2H), 3.83 (m, 2H), 3.65 (s, 3H), 3.00 (m, 2H); ESIMS m/z 375 ([M+H]+).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[CH:5][C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:3]1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([S:24](Cl)(=[O:26])=[O:25])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]>N1C=CC=CC=1>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([S:24]([NH:7][C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:5]=2)(=[O:25])=[O:26])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: Cn1nc(-c2ccccc2)cc1N
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2cc(-c3ccccc3)nn2C)cc1OC
Temperature: 25 °C
Reaction time: 22 h
Yield: 93.7 %

Procedure:
To a solution of 1-methyl-3-phenyl-pyrazol-5-amine (346 mg, 2 mmol) in 10 mL of dry pyridine was added 529 mg (2.23 mmol) of 3,4-dimethoxybenzenesulfonyl chloride. The solution was stirred at room temperature under Argon. After 22 h, the pyridine was removed in vacuo and flashed off with toluene. The crude base soluble material (1M NaOH) weighed 1.1 g. The crude product was taken up in EtOAc and extracted with 1M NaOH and H2O alternately. The basic aqueous phase was made acidic with 1M HCl, extracted with EtOAc, washed with water, dried and evaporated in vacuo to give a cream colored solid (0.70 g) which was taken up in 5 mL of hot EtOH, diluted with 5 mL of H2O and seeded to give 473 mg of a solid with mp 163-165° C. after drying in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][N:11]3[C:17]=2[CH2:18][C:19]2[N:23]=[C:22]([C:24]([O:26]CC)=O)[O:21][N:20]=2)=[CH:4][CH:3]=1.[NH2:29][OH:30].Cl.C([O-])([O-])=O.[K+].[K+]>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][N:11]3[C:17]=2[CH2:18][C:19]2[N:23]=[C:22]([C:24]([NH:29][OH:30])=[O:26])[O:21][N:20]=2)=[CH:6][CH:7]=1
Reactant: NO
Reactant: CCOC(=O)c1nc(Cc2c(-c3ccc(Cl)cc3)nc3ccc(F)cn23)no1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C(NO)c1nc(Cc2c(-c3ccc(Cl)cc3)nc3ccc(F)cn23)no1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.9 %

Procedure:
To a solution of ethyl 3-((2-(4-chlorophenyl)-6-fluoroimidazo[1,2-a]pyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carboxylate (0.125 mmol, 50.0 mg) in EtOH (10 mL) was added NH2OH.HCl (0.75 mmol, 52.1 mg) and K2CO3 (0.375 mmol, 51.8 mg) at r.t. The reaction mixture was stirred for 30 mins at r.t., and filtered. The filtrate was concentrated under reduced pressure, to give the title product (30 mg, 60.0%), as a white solid. m/e+=388 (M+H+). 1H NMR (300 MHz, in DMSO-d6): δ 12.14 (1H, D, brd, OH), δ 9.87 (1H, D, brd, NH), δ 8.69-8.68 (1H, D, dd, J=5.2, 2.4 Hz, ArH), δ 7.81-7.79 (2H, D, d, J=8.4 Hz, ArH), δ 7.74-7.71 (1H, D, dd, J=9.6, 5.2 Hz, ArH), δ 7.55-7.53 (2H, D, d, J=8.4 Hz, ArH), δ 7.47-7.41 (1H, D, m, ArH), and δ 4.73 (2H, D, s, CH2).
Reaction SMILES: [OH:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[OH:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:17][CH3:18])=[O:5]
Reactant: CCO
Reactant: O=C(O)c1cccc(O)c1O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cccc(O)c1O
Yield: 100 %

Procedure:
To a solution of 2,3-dihydroxybenzoic acid (25 g) in ethanol (320 ml) was added concentrated sulfuric acid (1.8 ml), and the mixture was heated under reflux for one day. The reaction mixture was concentrated, poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to normal phase chromatography (elution solvent ethyl acetate) to give the title compound (30 g, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH3:14])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1>C1COCC1.CCN(CC)CC>[C:4]([C:3]1[CH:7]=[C:8]([O:11][CH2:12][CH2:13][CH3:14])[CH:9]=[CH:10][C:2]=1[NH:1][C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1)(=[O:5])[NH2:6]
Reactant: O=C(Cl)c1cccnc1
Reactant: CCCOc1ccc(N)c(C(N)=O)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCOc1ccc(NC(=O)c2cccnc2)c(C(N)=O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
To a solution of 2-amino-5-propoxy-benzamide (760 mg, 3.91 mmol) in THF (15 mL) and Et3N (1 mL) was added nicotinoyl chloride (607 mg, 4.30 mmol) in anhydrous THF (15 min) dropwise. The resulting mixture was stirred at room temperature for 3 h. After the reaction was completed, the volatiles were removed. The residue was washed with H2O (10 mL). The pH was adjusted to approximately 5 by adding dilute HCl (2N in water). The resulting solid was collected and dried in vacuo to give 1.00 g of iii-a as a pale yellow solid (89.0%). LCMS m/z=300.1 (M+1) (Method B) (retention time=1.60 min).
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9]([O:12][NH:13]C(=O)OC(C)(C)C)(=[O:11])=[O:10]>FC(F)(F)C(O)=O>[C:1]1([CH3:21])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9]([O:12][NH2:13])(=[O:11])=[O:10]
Reactant: Cc1cc(C)c(S(=O)(=O)ONC(=O)OC(C)(C)C)c(C)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Temperature: 0 °C

Procedure:
A solution of tert-butyl mesitylsulfonyloxycarbamate (3 g, 9.5 mmol) in trifluoroacetic acid (7 mL) was stirred at 10° C. for 40 min, then poured into ice/water (10 mL) and the resulting solid was collected by filtration. The solid was dissolved in DCM (12 mL), dried over Na2SO4, and filtered. The solution containing O-(mesitylsulfonyl)hydroxylamine was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@@:5]2([N:22]=1)[C:18]1[CH:17]=[C:16]([OH:19])[CH:15]=[C:14]([F:20])[C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8](Br)=[CH:9][CH:10]=1.[N:23]1[CH:28]=[C:27](B(O)O)[CH:26]=[N:25][CH:24]=1.CN(C=O)C.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[NH2:1][C:2]1[O:3][CH2:4][C@@:5]2([N:22]=1)[C:18]1[CH:17]=[C:16]([OH:19])[CH:15]=[C:14]([F:20])[C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([C:27]2[CH:28]=[N:23][CH:24]=[N:25][CH:26]=2)=[CH:9][CH:10]=1
Reactant: NC1=N[C@@]2(CO1)c1cc(Br)ccc1Oc1c(F)cc(O)cc12
Reactant: OB(O)c1cncnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: NC1=N[C@@]2(CO1)c1cc(-c3cncnc3)ccc1Oc1c(F)cc(O)cc12
Temperature: 85 °C
Reaction time: 2.5 h

Procedure:
A 25 ml RB flask was charged with (S)-2-amino-7′-bromo-4′-fluoro-5H-spiro[oxazole-4,9′-xanthen]-2′-ol (629 mg, 1.723 mmol), tetrakis(triphenylphosphine)palladium(0) (199 mg, 0.172 mmol), and pyrimidin-5-ylboronic acid (320 mg, 2.58 mmol). DMF (8613 μL) and sodium carbonate (2 M solution) (2584 μL, 5.17 mmol) were added and the mixture was stirred at 85° C. for 2.5 hrs The mixture was cooled to room temperature, water (˜5 ml) was added and stirring was continued for 10 min. The precipitate was filtered out, washed with water (3×5 mL), 1:1 i-PrOH/water to remove color and dried in vacuo to afford (S)-2-amino-4′-fluoro-7′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthen]-2′-ol as yellow solid.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:12]([CH2:13][NH2:14])=[CH:11][CH:10]=[C:9]([C:15]([F:18])([F:17])[F:16])[N:8]=2)[CH:2]=1.[F:20][C:21]1[CH:22]=[C:23]([CH:33]([CH3:37])[C:34](O)=[O:35])[CH:24]=[CH:25][C:26]=1[CH2:27][NH:28][S:29]([CH3:32])(=[O:31])=[O:30].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>O1CCCC1>[F:20][C:21]1[CH:22]=[C:23]([CH:33]([CH3:37])[C:34]([NH:14][CH2:13][C:12]2[C:7]([C:3]3[CH:2]=[C:1]([CH3:19])[CH:6]=[CH:5][CH:4]=3)=[N:8][C:9]([C:15]([F:16])([F:18])[F:17])=[CH:10][CH:11]=2)=[O:35])[CH:24]=[CH:25][C:26]=1[CH2:27][NH:28][S:29]([CH3:32])(=[O:31])=[O:30]
Reactant: CC(C(=O)O)c1ccc(CNS(C)(=O)=O)c(F)c1
Reactant: Cc1cccc(-c2nc(C(F)(F)F)ccc2CN)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)C(C)c2ccc(CNS(C)(=O)=O)c(F)c2)c1
Reaction time: 48 h
Yield: 0 %

Procedure:
To a stirred solution of (2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methanamine (3.5 g, 13.143 mmol) and 2-(3-fluoro-4-(methylsulfonamidomethyl)phenyl)propanoic acid (5.415 g, 19.715 mmol) in tetrahydrofuran (102 mL) was added 1-hydroxybenzotriazolhydrate (1.834 mL, 13.143 mmol), O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (4.213 g, 13.143 mmol) and N-ethyldiisopropylamine (6.676 mL, 39.429 mmol). The reaction mixture was stirred for 48 h. The reaction mixture was concentrated under reduced pressure and the solid obtained was purified by column chromatography (silica gel: 100-200 mesh, eluent: ethyl acetate/cyclohexane 2:1) to afford a white solid (2.65 mg, 32%).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[N-:10]=[N+:11]=[N-:12].[Na+].O>CS(C)=O>[N:10]([C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)=[N+:11]=[N-:12]
Reactant: [N-]=[N+]=[N-]
Reactant: O=Cc1ccc(F)cc1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: [N-]=[N+]=Nc1ccc(C=O)cc1
Temperature: 105 °C

Procedure:
50 g 4-fluoro benzaldehyde and 50 g sodium azide were dispersed in 150 ml dry dimethyl sulfoxide. Subsequently, the mixture was heated for 3 hours at 105° C. while nitrogen was introduced. The mixture was poured into 200 ml water, and the solution extracted with 200 ml dichloro methane (three times). Then the solvent was distilled off by means of a vacuum rotation vaporizer. 53 g of a liquid remained having infrared (IR) and nuclear magnetic resonance (NMR) spectra consistent with the 4-azido benzaldehyde structure.
Reaction SMILES: [C:1]1([NH2:15])[N:2]=[C:3]([NH2:14])[N:4]=[C:5]2[C:10]=1[C:9]1[CH:11]=[CH:12][NH:13][C:8]=1[CH:7]=[CH:6]2.CN(C)C=O.[H-].[Na+].F[C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=1>C(O)(=O)C>[C:28]([C:27]1[CH:30]=[CH:31][C:24]([N:13]2[C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[C:1]([NH2:15])[N:2]=[C:3]([NH2:14])[N:4]=4)[C:9]=3[CH:11]=[CH:12]2)=[CH:25][CH:26]=1)#[N:29]
Reactant: Nc1nc(N)c2c(ccc3[nH]ccc32)n1
Reactant: N#Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: N#Cc1ccc(-n2ccc3c4c(N)nc(N)nc4ccc32)cc1

Procedure:
A solution of 15.94 g. 7H-pyrrolo[3,2-f]quinazoline-1,3-diamine in 800 ml. dry dimethylformamide is stirred, under nitrogen, with 4.61 g. ca. 50% sodium hydride-mineral oil dispersion for 1.5 hours. Addition of 10.66 g. 4-fluorobenzonitrile is followed by heating of the reaction mixture at 95° for 6 hours. Glacial acetic acid (40 ml.) is added and the solvent is removed in vacuo. The residue is stirred thoroughly with excess aqueous potassium carbonate solution, collected, washed with water and dried. Two recrystallizations of the crude product from dimethylformamide, followed by washing with a small amount of dimethylformamide, with methanol and thorough drying, yield the title compound, m.p. 344° (dec.), NMR (dDMSO): δ 7.17 (doublet, J=9Hz, 5 or 6H), 7.42 (doublet, J=3Hz, 9H), 7.76-7.95 (four protons multiplet, 5 or 6H, 8H and two protons meta to the cyano group), 8.09 (two proton doublet, J= 8Hz, two protons ortho to the cyano group) p.p.m.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][C:8]=1[O:16][CH3:17])=[O:5].CN(C)C=O.C(Cl)(=O)C([Cl:31])=O>ClCCl>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([Cl:31])=[O:12])=[CH:9][C:8]=1[O:16][CH3:17])=[O:5]
Reactant: COc1cc(C(=O)O)ccc1NC(=O)c1cc(F)ccc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(C(=O)Cl)ccc1NC(=O)c1cc(F)ccc1Cl
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
35 (152 g, 0.45 mol, 1 equiv.) was suspended in dichloromethane (1.5 L) and dimethylformamide (1 mL) was added. Oxalyl chloride (71.6 g, 0.56 mol, 1.2 equiv.) was added drop-wise over 30 minutes at 0° C. After addition, the cold bath was removed and the reaction mixture was further stirred at room temperature for 3.5 h. The solvent and any unreacted oxalyl chloride were evaporated to yield a white solid, which was further dried on a rotary evaporator under vacuum at 40° C. overnight to yield dry 4-(2-chloro-5-fluoro-benzoylamino)-3-methoxy-benzoyl chloride 36 as a white solid. 1H NMR (400 MHz, CDCl3) δ: 8.97 (s, 1H), 8.71 (d, 1H), 7.91 (dd, 1H), 7.60 (d, 1H), 7.57 (dd, 1H), 7.47 (dd, 1H), 7.21-7.15 (m, 1H), 3.99 (s, 3H). MS (ES) m/z 339.9 (MH)+.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH2:8][CH2:9][CH2:10][OH:11])=[C:6]([O:12][Si](C(C)(C)C)(C)C)[C:5]([Cl:20])=[C:4]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Br:1][C:2]1[C:7]([CH2:8][CH2:9][CH2:10][OH:11])=[C:6]([OH:12])[C:5]([Cl:20])=[C:4]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)[CH:3]=1
Reactant: COc1ccc(Cc2cc(Br)c(CCCO)c(O[Si](C)(C)C(C)(C)C)c2Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(Cc2cc(Br)c(CCCO)c(O)c2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
To a solution of alcohol 187 (1.73 g, 3.46 mmol) in THF (28 mL) was added TBAF (1M in THF, 7.0 mL, 6.92 mmol) at 0° C. The mixture was stirred for 1 hr at rt. The mixture was extracted with EtOAc/aq. sat'd NH4Cl solution (500 mL/50 mL). The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the product 188 (1.19 g, 89%).
Reaction SMILES: [ClH:1].[N:2]1[CH:7]=[CH:6][CH:5]=[N:4][C:3]=1[NH:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([NH:15]C(=O)OC(C)(C)C)[CH2:11][CH2:10]1>>[ClH:1].[N:2]1[CH:7]=[CH:6][CH:5]=[N:4][C:3]=1[NH:8][C@H:9]1[CH2:14][CH2:13][C@@H:12]([NH2:15])[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](Nc2ncccn2)CC1
Agent: Cl
Product: N[C@H]1CC[C@@H](Nc2ncccn2)CC1
Reaction time: 0.5 h

Procedure:
As shown in step 5-ii of Scheme 5, HCl (3 mL, 4M in THF, 12 mmol) was added to compound 1010. The mixture was stirred for 30 min and concentrated under reduced pressure to produce (cis)-N1-(pyrimidin-2-yl)cyclohexane-1,4-diamine hydrochloride (compound 1011). This material was used in subsequent reactions as is without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[I:14]I>C(Cl)Cl.O>[I:14][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: Cc1ccc(N)cc1
Reactant: II
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(N)c(I)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.9 %

Procedure:
To a stirred solution of p-toluidine (50 g, 467 mmol) in methylene chloride (250 mL) was added a solution of sodium bicarbonate (47 g, 560 mmol) in water (750 mL). Then it was added iodine (118.6 g, 467 mmol) in small portions and the mixture was stirred for 16 h at room temperature. The reaction was quenched with saturated NaHSO3 and the product was extracted with methylene chloride. The methylene chloride layer was washed with brine, dried over Na2SO4, and evaporated in vacuum to give the crude product (100 g, yield 92%). 1H NMR (300 MHz, CDCl3): δ 7.46 (s, 1H), 7.13-6.95 (d, 1H), 6.68-6.64 (d, 1H), 4.00 (br, 2H), 2.21 (s, 3H). MS: m/z 234 [M+1]+.
Reaction SMILES: C([O:8][C:9](=[O:38])[CH2:10][C@@H:11]([N:24]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH3:37])=[CH:31][CH:30]=2)=[CH:25]1)[C:12]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][CH3:22])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])C1C=CC=CC=1>CO.CCOC(C)=O>[CH3:18][C:16]([CH3:17])([CH3:19])[C@H:15]([NH:14][C:12](=[O:13])[C@H:11]([N:24]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH3:37])=[CH:31][CH:30]=2)=[CH:25]1)[CH2:10][C:9]([OH:38])=[O:8])[C:20](=[O:23])[NH:21][CH3:22]
Reactant: CCCc1ccc(-c2ccn([C@H](CC(=O)OCc3ccccc3)C(=O)N[C@H](C(=O)NC)C(C)(C)C)c2)cc1
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCc1ccc(-c2ccn([C@H](CC(=O)O)C(=O)N[C@H](C(=O)NC)C(C)(C)C)c2)cc1
Yield: 91 %

Procedure:
According to the procedure described in Example 1(a), N-[2,2-dimethyl-1(S)-(methylcarbamoyl)propyl]-3(R)-[3-(4-propylphenyl)-1H-pyrrol-1-yl]succinamic acid benzyl ester in MeOH and EtOAc was hydrogenolyzed to provide 30 mg(91%) of N-[2,2-dimethyl-1(S)-(methylcarbamoyl)propyl]-3(R)-[3-(4-propylphenyl)-1H-pyrrol-1-yl]succinamic acid as a yellow powder, mp 104-6° C. 1H NMR (CD3OD): ∂ 7.95 (bs, 1H), 7.60 (bs, 1H), 7.48 (d, 2H, J=7.5 Hz), 7.16 (bs, 1H), 7.08 (d, 2H, J=7.5 Hz), 6.86 (bs, 1H), 6.42 (bs, 1H), 5.34 (t, 1H, J=7.0 Hz), 4.15 (bd, 1H, J=5.9 Hz), 2.83 (dd, 1H, J=6.2, 16.0 Hz), 2.62 (s, 3H), 2.60-2.50 (m, 2H), 1.7-1.58 (m, 2H), 0.95 (s, 9H). IR (KBr): 3300, 2960, 1642, 1560, 1195, 775 cm−1. HRFABMS: Calculated for C24H33N3O4Cs (M+Cs+): 560.1525. Found: 560.1509. Anal. Calculated for C24H33N3O4.0.3 EtOAc: C, 66.67; H, 7.86; N, 9.26. Found: C, 66.93; H, 7.78; N, 8.89.
Reaction SMILES: [C:1]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:4])[CH2:2][CH3:3].[C:11](OCC)(=O)CC(C)=O>>[CH3:11][CH:5]([C:1](=[O:4])[CH2:2][CH3:3])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)CC(C)=O
Reactant: CCOC(=O)CC(=O)CC
Product: CCOC(=O)C(C)C(=O)CC
Yield: 45 %

Procedure:
The target product was prepared following the procedure as described in step 1) of Preparation Example 3, except for that ethyl propionylacetate was used to replace for ethyl acetoacetate. Yield 45%.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][NH:7][C:8](=[O:18])[C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH3:16])=[C:11]([NH2:17])[CH:10]=1)=[O:4].P(Cl)(Cl)(Cl)=O.[C:24]([C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=O)=[CH:28][CH:27]=1)#[N:25]>C(OCC)(=O)C>[C:24]([C:26]1[CH:34]=[CH:33][C:29]([C:30]2[N:15]([CH3:16])[C:12]3[CH:13]=[CH:14][C:9]([C:8]([NH:7][CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])=[O:18])=[CH:10][C:11]=3[N:17]=2)=[CH:28][CH:27]=1)#[N:25]
Reactant: CNc1ccc(C(=O)NCCC(=O)OC)cc1N
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)CCNC(=O)c1ccc2c(c1)nc(-c1ccc(C#N)cc1)n2C
Temperature: 90 °C

Procedure:
4.7 g of 3-amino-4-methylamino-benzoic acid-[N-(2-methoxycarbonyl-ethyl)-amide] are first stirred at ambient temperature with 40 ml of phosphorusoxychloride, then 3.1 g of 4-cyano-benzoylchloride are added and the mixture is heated to 90° C. for 8 hours. The phosphorusoxychloride is distilled off in vacuo, the residue is stirred into 500 ml of water at 30° C. and neutralised by the addition of sodium bicarbonate in batches. The precipitate is suction filtered and extracted with ethyl acetate. The ethyl acetate phases are evaporated down, the residue is combined with the precipitate and purified by chromatography on silica gel (eluant:ethyl acetate/ethanol=100:1 to 100:5). The product obtained is decocted with ethyl acetate for final purification. Yield: 1,86 g (27% of theory), Rf value: 0.51 (silica gel; ethyl acetate/ethanol=9:1)