Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)([OH:17])[CH:10]([N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)[CH3:11])=[CH:5][CH:4]=1.[H-].[Na+].[C:32](Cl)(=[O:34])[CH3:33]>CN(C)C=O.O>[C:32]([O:17][C:9]([C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:28])[F:29])=[CH:4][CH:5]=1)([C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:20][CH:19]=1)[CH:10]([N:12]1[CH:16]=[N:15][CH:14]=[N:13]1)[CH3:11])(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: CC(n1cncn1)C(O)(c1ccc(C(F)(F)F)cc1)c1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OC(c1ccc(C(F)(F)F)cc1)(c1ccc(C(F)(F)F)cc1)C(C)n1cncn1
Yield: 29.1 %

Procedure:
1,1-Bis-(4-trifluoromethylphenyl)-2-(1,2,4-1H-triazol-1-yl)propan-1-ol (0.5 g) was added carefully to a suspension of sodium hydride (60 mg, freed from dispersion in oil by washing with hexane) in dry dimethylformamide (20 cm3) under a nitrogen atmosphere. After stirring the mixture for 2 hours acetyl chloride (0.1 g) was added and after a further 2 hours the mixture was diluted with water and extracted with chloroform. The chloroform layer was separated, washed with water, dried over anhydrous magnesium sulphate, and concentrated by evaporation of the solvent under reduced pressure to yield a residual oil which was purified by hplc and which solidified on trituration with petroleum ether (boiling range 60°-80° C.) to yield 1,1-bis(4-trifluoromethylphenyl)-2-(1,2,4-1H-triazol-1-yl)propyl acetate (160 mg).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C[Si]([C:25]#[CH:26])(C)C.CCN(CC)CC>[Cu]I.CN(C=O)C>[C:25]([C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1)#[CH:26]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(I)cc2)CC1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C#Cc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 95.8 %

Procedure:
A microwave vial was charged with tert-butyl 4-(4-iodophenyl)piperazine-1-carboxylate (300 mg, 0.773 mmol), trimethylsilylacetylene (0.22 mL, 1.54 mmol), NEt3 (3.0 mL), DMF (1.5 mL), CuI (15 mg, 0.080 mmol), and PdCl2 (PPh3)2 (27 mg, 0.039 mmol). The vial was capped and heated in the microwave at 100° C. for 1 h. After removing the NEt3 in vacuo, the residue was extracted with EtOAc (15 mL). The organic layer was then washed with NaHCO3 (sat.) (5 mL), H2O (5 mL), brine (5 mL) and then dried over MgSO4. The solvent was removed and then the material was dissolved into MeOH (4 mL) and THF (2 mL). K2CO3 (1.0 mL of a 1M solution) was added and the reaction stirred for 3 h. The solvent was removed and the residue extracted with EtOAc (15 mL). The organic layer was washed with brine (5 mL) and then dried over MgSO4. The solvent was removed and the product dried under high vacuum to give the title compound as a brown solid (212 mg, 96%); MS ESI 287.0 [M+H]+, calcd for [C17H22N2O2+H]+ 287.18.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([NH2:13])=[O:12])=[CH:5][CH:4]=1.Cl[CH:17]([C:23]([CH3:25])=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[CH2:21]([O:20][C:18]([C:17]1[O:12][C:11]([CH2:10][CH2:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:14])([F:15])[F:1])=[CH:8][CH:7]=2)=[N:13][C:23]=1[CH3:25])=[O:19])[CH3:22]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: NC(=O)CCc1ccc(C(F)(F)F)cc1
Product: CCOC(=O)c1oc(CCc2ccc(C(F)(F)F)cc2)nc1C
Temperature: 150 °C
Reaction time: 8 h

Procedure:
18.6 g 3-(4-Trifluoromethyl-phenyl)-propionamide and 42.8 ml ethyl 2-chloroacetoacetate were mixed and stirred at 150° C. for eight hours. Excess ethyl 2-chloroacetoacetate was removed in vacuo (oil pump) and the residue purified by chromatography on silica gel with the eluent petroleum benzene:ethyl acetate=3:1 to obtain 13.75 g 4-methyl-2-[2-(4-trifluoromethyl-phenyl)-ethyl]-oxazole-5-carboxylic acid ethyl ester as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:7]3[CH2:15][CH:10]([C:11](=O)[C:12]=2[CH:13]=1)[CH:9]=[CH:8]3.[OH-].[K+].O.NN>C(O)CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:7]3[CH2:15][CH:10]([CH2:11][C:12]=2[CH:13]=1)[CH:9]=[CH:8]3
Reactant: COc1ccc2c(c1)C(=O)C1C=CC2C1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: COc1ccc2c(c1)CC1C=CC2C1
Temperature: 25 °C

Procedure:
5-Methoxytricyclo[7.2.1.02,7]dodeca-2(7),3,5,10-tetraene-8-one (9.41 g, 47 mmol) and pulverized potassium hydroxide (KOH) (6.17 g, 110 mmol) were warmed in ethylene glycol (50 mL) until solution occurred. The mixture was cooled to rt, treated with hydrazine hydrate (6 mL, 190 mmol) and heated to reflux for 2 hours. The reflux condenser was replaced with a distilling head and distillates were collected from 120-190° C. The distillates were diluted with H2O (100 mL) and extracted with EtOAc (4×40 mL). The organic layer was washed with H2O (4×30 mL), brine (25 mL), dried (MgSO4), filtered and concentrated to an oil (8.2 g, 94%). (TLC 25% EtOAc/hexanes Rf 0.68). 1H NMR (CDCl3) δ 6.92 (d, J=8.0 Hz, 1H), 6.88 (m, 2H), 6.25 (dd, J=5.1, 2.5 Hz, 1H), 5.79 (dd, J=5.1, 2.4 Hz, 1H), 3.77 (s, 3H), 3.31 (br s, 1H), 3.01-2.94 (2H), 2.56 (d, J=16.5 Hz, 1H), 2.22 (m, 1H), 1.85 (d, J=10.0 Hz, 1H). GCMS m/e 186 (M+).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[F:10][B-:11]([F:14])([F:13])[F:12].[H+]>ClCCl.C(OCC)C>[F:10][B-:11]([F:14])([F:13])[F:12].[NH+:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1
Reactant: c1ccc2[nH]cnc2c1
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CCOCC
Solvent: ClCCl
Product: c1ccc2[nH+]c[nH]c2c1
Temperature: 0 °C

Procedure:
To a solution of benzimidazole (10 g, 84.6 mmol) in dichloromethane (30 mL) is added dropwise tetrafluoroboric acid as its etherate (85%, HBF4 by volume, Aldrich Chemicals Co.) with stirring at 0° C. The reaction mixture is diluted with diethylether (100 mL) to precipitate the title compound. The title compound is filtered, washed with ether and recrystallized from ether.
Reaction SMILES: C1(C[O:8][C:9]2[CH:19]=[CH:18][C:12]3[C:13](=[O:17])[CH:14]=[CH:15][O:16][C:11]=3[C:10]=2[CH2:20]/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)C=CC=CC=1.CO.[H][H]>[Pd].C(OCC)(=O)C>[OH:8][C:9]1[CH:19]=[CH:18][C:12]2[C:13](=[O:17])[CH2:14][CH2:15][O:16][C:11]=2[C:10]=1[CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=c1ccoc2c(C/C=C/c3ccccc3)c(OCc3ccccc3)ccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C1CCOc2c1ccc(O)c2CCCc1ccccc1
Yield: 228.9 %

Procedure:
A mixture of 6.1 g (16.6 mmol) of (E)-7-(phenylmethoxy)-8-(3-phenyl-2-propenyl)-4H-1-benzopyran-4-one from the preceding example, 1 g of 10% palladium on carbon, 100 mL of methanol, and 300 mL of ethyl acetate was stirred at room temperature, in an atmosphere of hydrogen until approximately one third of the theoretical volume of hydrogen gas was taken up. The catalyst was filtered with suction and the filtrate concentrated in vacuo. The residue was dissolved in 150 mL of methanol and 0.5 g of Raney nickel was added. The hydrogenation was continued with careful monitoring by TLC analysis. When the reduction was essentially complete, the catalyst was filtered with suction and the filtrate concentrated in vacuo. The solid residue (4.75 g) was combined with 6.4 g from another experiment (23.9 mmol scale) and chromatographed on silica gel. Elution with hexane-ethyl acetate mixtures afforded 10.73 g (93.9%) of the title compound as a colorless solid, mp 110°-112° C.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9]B(O)O)=[CH:5][CH:4]=1)=[O:2].C(N(CC)CC)C.[CH3:20][O:21][C:22](=[O:34])[C:23]1[CH:28]=[C:27](O)[CH:26]=[C:25]([O:30][CH:31]([CH3:33])[CH3:32])[CH:24]=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:20][O:21][C:22](=[O:34])[C:23]1[CH:24]=[C:25]([O:30][CH:31]([CH3:32])[CH3:33])[CH:26]=[C:27]([O:9][C:6]2[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=2)[CH:28]=1
Reactant: COC(=O)c1cc(O)cc(OC(C)C)c1
Reactant: O=Cc1ccc(OB(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(Oc2ccc(C=O)cc2)cc(OC(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.2 %

Procedure:
After adding 1.05 g of molecular sieves 4 A, 1.00 g (6.70 mol) of p-formylphenylboric acid, 605 mg (3.30 mol) of copper (II) acetate and 2.32 ml (16.6 mol) of triethylamine to a solution of 700 mg (3.30 mmol) of the obtained phenol compound in methylene chloride (30 ml), the mixture was stirred at room temperature overnight under a oxygen atmosphere. The reaction mixture was filtered and then concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:acetic acid ethyl ester=5:1) to obtain 593 mg of 3-(4-formylphenoxy)-5-isopropoxybenzoic acid methyl ester (yield: 57%) as a colorless oil.
Reaction SMILES: [H-].[Na+].F[C:4]1[C:11]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10][C:7]([CH:8]=[O:9])=[C:6]([N+:19]([O-:21])=[O:20])[CH:5]=1.[CH2:22]([OH:24])[CH3:23]>>[CH2:22]([O:24][C:4]1[C:11]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10][C:7]([CH:8]=[O:9])=[C:6]([N+:19]([O-:21])=[O:20])[CH:5]=1)[CH3:23]
Reactant: O=Cc1cc(Oc2ccccc2)c(F)cc1[N+](=O)[O-]
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Product: CCOc1cc([N+](=O)[O-])c(C=O)cc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
NaH (60%, 400 mg, 10 mmol) was added to ethanol (10 mL) and stirred at room temperature for 30 min. Then, 4-fluoro-2-nitro-5-phenoxy-benzaldehyde (520 mg, 2 mmol) was added. The resulting mixture was stirred at room temperature overnight and ten concentrated. The resulting crude mixture was purified by chromatography (silica gel, 20-50% methylene chloride in heptane) to yield a slightly yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](\[CH:13]([CH3:17])[C:14]([OH:16])=O)/[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.O>FC(F)(F)S(O)(=O)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[CH:8]=[C:9]([C:10]([OH:12])=[O:11])[C:13]([CH3:17])=[C:14]2[OH:16]
Reactant: CC(C(=O)O)/C(=C\c1ccc(F)cc1)C(=O)O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O
Product: Cc1c(C(=O)O)cc2ccc(F)cc2c1O
Yield: 107.8 %

Procedure:
A solution of 2-[1-(4-fluoro-phenyl)-meth-(E)-ylidene]-3-methyl succinic acid (28 g, 118 mmol) in trifluoromethanesulfonic acid (140 mL) was stirred at room temperature for 16 h. The resulting mixture was carefully poured into ice cooled water with continuous stirring to give a solid precipitate, which was filtered, washed with water and dried in vacuo to yield 6-fluoro-4-hydroxy-3-methyl-naphthalene-2-carboxylic acid (28 g, >100% crude) as yellow solid. This crude product was used in the next step without further purification. MS calcd. for C12H8FO3 [(M−H)−] 219, obsd. 218.9.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([N:9]([O:11][CH3:12])[CH3:10])=[O:8])[NH:4][N:3]=1.[CH3:13][C:14](=O)[CH2:15][CH2:16][C:17](=O)[CH3:18]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH3:18][C:17]1[N:1]([C:2]2[CH:6]=[C:5]([C:7]([N:9]([O:11][CH3:12])[CH3:10])=[O:8])[NH:4][N:3]=2)[C:14]([CH3:13])=[CH:15][CH:16]=1
Reactant: CC(=O)CCC(C)=O
Reactant: CON(C)C(=O)c1cc(N)n[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CON(C)C(=O)c1cc(-n2c(C)ccc2C)n[nH]1
Temperature: 25 °C
Yield: 64.7 %

Procedure:
A 250-mL round-bottomed flask equipped with a magnetic stirrer and a Dean-Stark trap was charged with 150b (11.0 g, 1.0 eq., 64.7 mmol), hexane-2,5-dione (11.1 g, 1.5 eq., 97.2 mmol), p-toluenesulfonic acid monohydrate (558 mg, 0.05 eq., 3.24 mmol), and toluene (100 mL). The reaction mixture was refluxed overnight. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica-gel column chromatography eluting with 1:2 petroleum ether/ethyl acetate to afford 150c (10.4 g, 65%) as a white solid. MS-ESI: [M+H]+ 249.0
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:25]([O:32][C:33]1[C:34]([O:56][CH2:57][C:58](O)=[O:59])=[C:35]([C:51]([O:53][CH2:54][CH3:55])=[O:52])[N:36]([C:43]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=2)[C:37]=1[C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CCN(C(C)C)C(C)C.[NH4+:70].[Cl-]>C1COCC1>[NH2:70][C:58](=[O:59])[CH2:57][O:56][C:34]1[C:33]([O:32][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[C:37]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[N:36]([C:43]2[CH:44]=[CH:45][C:46]([O:49][CH3:50])=[CH:47][CH:48]=2)[C:35]=1[C:51]([O:53][CH2:54][CH3:55])=[O:52]
Reactant: [NH4+]
Reactant: CCOC(=O)c1c(OCC(=O)O)c(OCc2ccccc2)c(C(=O)OCC)n1-c1ccc(OC)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1c(OCC(N)=O)c(OCc2ccccc2)c(C(=O)OCC)n1-c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 66.5 %

Procedure:
HATU (153 mg, 0.40 mmol) was added to a stirred solution 2-((4-(benzyloxy)-2,5-bis(ethoxycarbonyl)-1-(4-methoxyphenyl)-1H-pyrrol-3-yl)oxy)acetic acid (24) (100 mg, 0.20 mmol), DIPEA (176 μL, 1.00 mmol), and NH4Cl (53.8 mg, 1.00 mmol) in THF (2 mL) at 0° C. The reaction mixture was stirred at 0° C. for 20 min and then at RT for 2 h volatiles were removed in vacuo, dissolved in EtOAc (30 mL) and washed with 1 M HCl (3×30 mL), sat. NaHCO3 (aq.) (3×30 mL) and brine (30 mL), dried (MgSO4), filtered and solvents removed in vacuo to give a yellow oil. The product was purified by silica gel chromatography (12 g, 0-100% EtOAc in isohexane) to afford diethyl 3-(2-amino-2-oxoethoxy)-4-(benzyloxy)-1-(4-methoxyphenyl)-1H-pyrrole-2,5-dicarboxylate (25) (66 mg, 66%) as a white solid: m/z 497 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 7.58 (br s, 1H), 7.51 (br s, 1H), 7.49-7.44 (m, 2H), 7.43-7.33 (m, 3H), 7.17-7.09 (m, 2H), 6.95-6.86 (m, 2H), 5.10 (s, 2H), 4.46 (s, 2H), 4.00 (q, J=7.1 Hz, 2H), 3.98 (q, J=7.1 Hz, 2H), 3.79 (s, 3H), 0.97 (t, J=7.1 Hz, 3H), 0.96 (t, J=7.1 Hz, 3H).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[Si:10]([O:17][C@H:18]1[CH2:27][C:26]([CH3:29])([CH3:28])[CH2:25][C:24]2[N:23]=[C:22]([CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[C:21]([C@H:35]([C:37]3[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=3)O)=[C:20]([CH:47]3[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]3)[C:19]1=2)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Si:10]([O:17][C@H:18]1[CH2:27][C:26]([CH3:29])([CH3:28])[CH2:25][C:24]2[N:23]=[C:22]([CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[C:21]([C@@H:35]([F:7])[C:37]3[CH:38]=[CH:39][C:40]([C:43]([F:44])([F:46])[F:45])=[CH:41][CH:42]=3)=[C:20]([CH:47]3[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52]3)[C:19]1=2)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC1(C)Cc2nc(C3CCCC3)c([C@@H](O)c3ccc(C(F)(F)F)cc3)c(C3CCCCC3)c2[C@@H](O[Si](C)(C)C(C)(C)C)C1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC1(C)Cc2nc(C3CCCC3)c([C@@H](F)c3ccc(C(F)(F)F)cc3)c(C3CCCCC3)c2[C@@H](O[Si](C)(C)C(C)(C)C)C1
Reaction time: 1 h

Procedure:
At −55° C. and under argon, 3.21 ml of diethylaminosulphur trifluoride (24.3 mmol, 1.5 eq.) are added dropwise to a solution of 9.96 g (16.2 mmol) of the compound from Example 5A in 300 ml of dry toluene. The mixture is stirred at this temperature for 1 h and then at room temperature for a further 2 h. For work-up, 120 ml of a saturated sodium bicarbonate solution are added carefully. The mixture is extracted three times in total with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product is purified by filtration through silica gel (mobile phase: cyclohexane/ethyl acetate 9:1).
Reaction SMILES: C(N(CC)CC)C.[C:8]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1)([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[CH:23]1[C:35]2[CH:34]([CH2:36][O:37][C:38](Cl)=[O:39])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]=2[CH:26]=[CH:25][CH:24]=1>CC#N>[C:11]([O:10][C:8]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:38]([O:37][CH2:36][CH:34]2[C:33]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:27]3[C:35]2=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:39])=[CH:20][CH:21]=1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.6 %

Procedure:
Triethylamine (7.36 mL, 52.82 mmol, 1.1 eq) is added at 0° C. to a stirred solution of N—BOC-1,4-phenylene diamine (10.00 g, 48.02 mmol, 1.0 eq) in CH3CN (240 mL), followed by 9-fluorenylmethyloxycarbonyl chloride (14.90 g, 57.62 mmol, 1.2 eq). The resulting mixture is allowed to warm to room temperature. After 4 hours stirring at room temperature, the reaction mixture is filtered to afford 20.60 g of the crude product as a white powder which is used in the next step without any further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][O:13][CH2:14][C:15]#[CH:16])=[N:4][N:3]=1.[NH2:17][C:18]1[CH:32]=[CH:31][C:21]2[N:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:23]=[N:24][C:20]=2[CH:19]=1>CC(O)C>[C:25]1([N:22]2[C:21]3[CH:31]=[CH:32][C:18]([NH:17][C:2]4[C:11]5[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=5)[C:5]([CH2:12][O:13][CH2:14][C:15]#[CH:16])=[N:4][N:3]=4)=[CH:19][C:20]=3[N:24]=[CH:23]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C#CCOCc1nnc(Cl)c2ccccc12
Reactant: Nc1ccc2c(c1)ncn2-c1ccccc1
Solvent: CC(C)O
Product: C#CCOCc1nnc(Nc2ccc3c(c2)ncn3-c2ccccc2)c2ccccc12
Yield: 28.2 %

Procedure:
A solution of 1-chloro-4-(prop-2-ynyloxy)methylphthalazine (3) (20 mg, 0.09 mmol) and 5-amino-1-phenylbenzimidazole (15 mg, 0.07 mmol) in i-PrOH (2 mL) is stirred at 95° C. under argon for 2.5 h. The reaction mixture is concentrated, quenched with sat. NaHCO3 (10 mL), and extracted with CHCl3 (60 mL). The extract is washed (brine) and dried. After solvent removal at reduced pressure, the residue is purified on silica gel (0:1:2 to 1:25:0 methanol/ethyl acetate/hexane) to give 8 mg (27%) of BI-3035 as a light-brown solid, mp 89-91° C. IR 3321, 2927, 1496 cm−1; 1H NMR (CDCl3) δ 2.60 (t, J=2.4 Hz, 1H, CH≡C—CH2O), 4.98 (s, 2H, CH2), 5.36 (d, J=2.4 Hz, CH≡CCH2O), 6.94 (dd, J=8.7, 2.1 Hz, 1H, 6-BenzimidH), 7.27 (d, J=2.1 Hz, 1H, 4-BenzimidH), 7.41 (d, J=8.7 Hz, 1H, 7-BenzimidH), 7.41-7.63 (m, 5H, PhH), 7.90-8.02 (m, 2H, 6,7-PhthH), 8.06 (s, 1H, 2-BenzimidH), 8.14 (m, 1H, 5-PhthH), 8.35 (m, 1H, 8-PhthH).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[C@H:4]([C:20]([OH:22])=O)[CH2:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:35][C@H:36]1[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37]1>C(#N)C>[C:44]([O:43][C:41]([N:38]1[CH2:39][CH2:40][C@H:36]([NH:35][C:20](=[O:22])[C@@H:4]2[CH2:3][CH:2]([OH:1])[CH2:6][N:5]2[C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)=[O:8])[CH2:37]1)=[O:42])([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: O=C(O)[C@@H]1CC(O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)[C@@H]2CC(O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.6 %

Procedure:
To a solution of 4-hydroxy-1-(4-nitrobenzyloxycarbonyl)-L-proline (1.79 g) in anhydrous acetonitrile (30 ml), N,N,-carbonyldiimidazole (981 mg) was added at room temperature, followed by stirring at room temperature for one hour. To the reaction mixture, a solution of (3S)-3-amino-1-(tert-butoxycarbonyl)pyrrolidine (1.02 g) in anhydrous acetonitrile (20 ml) was added under ice cooling. The resulting mixture was stirred at room temperature for 6 hours. The reaction mixture was purified in a similar manner to that described in Referential Example 1-(1), whereby 1.22 g of (3S)-1-(tert-butoxycarbonyl)-3-[1-(4-nitrobenzyloxycarbonyl)-4-hydroxy-L-prolylamino]pyrrolidine were obtained as an amorphous substance.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH2:20][NH2:21])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:15]=[CH:14][C:13]([Cl:12])=[CH:18][CH:17]=1)[CH:22]1[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1)=[O:6]
Reactant: NCC(c1ccc(Cl)cc1)C1CCOCC1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: O=C(NCC(c1ccc(Cl)cc1)C1CCOCC1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and 2-(4-chlorophenyl)-2-(tetrahydro-2H-pyran-4-yl)ethanamine. LCMS (MH+): m/z=412.1, tR (minutes, Method G)=2.49
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH2:12]([O:14][C:15]([CH:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29](O)=[O:30])=[CH:25][CH:24]=2)[CH2:19][CH2:18]1)=[O:16])[CH3:13].CCN=C=NCCCN(C)C>C(Cl)Cl>[CH2:12]([O:14][C:15]([CH:17]1[CH2:18][CH2:19][N:20]([C:23]2[CH:24]=[CH:25][C:26]([C:29](=[O:30])[NH:8][C:7]3[CH:9]=[CH:10][CH:11]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=3)=[CH:27][CH:28]=2)[CH2:21][CH2:22]1)=[O:16])[CH3:13]
Reactant: CCOC(=O)C1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: CC(C)(C)c1cccc(N)c1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3cccc(C(C)(C)C)c3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
A mixture of 3-tert-butyl aniline (54 mg, 0.36 mmol), 1-(4-carboxy-phenyl)-piperidine-4-carboxylic acid ethyl ester (100 mg, 0.36 mmol) and EDCI (200 mg, 1.08 mmol) in CH2Cl2 was stirred at room temperature overnight. Next morning the reaction mixture was partitioned between EtOAc and water. The organic layer was separated dried over Na2SO4, filtered and concentrated. The residue was purified on a silica gel column with 20-50% Et2O in hexanes gradient to afford the product (31 mg; Yield: 21%). HRMS m/z calcd for C25H32N2O3 [M+H]+: 409.2486. Found: 409.2484.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[N:5]([CH:13]1[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]1=[O:20])[C:6]([CH3:12])=[N:7]2.[C:22](Cl)(=[O:29])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>O1CCCC1>[O:20]=[C:14]1[CH:13]([N:5]2[C:4](=[O:21])[C:3]3[C:8](=[CH:9][CH:10]=[CH:11][C:2]=3[NH:1][C:22](=[O:29])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[N:7]=[C:6]2[CH3:12])[CH2:18][CH2:17][C:16](=[O:19])[NH:15]1
Reactant: Cc1nc2cccc(N)c2c(=O)n1C1CCC(=O)NC1=O
Reactant: CCCCCCC(=O)Cl
Solvent: C1CCOC1
Product: CCCCCCC(=O)Nc1cccc2nc(C)n(C3CCC(=O)NC3=O)c(=O)c12
Temperature: 80 °C
Yield: 18.8 %

Procedure:
To a stirred mixture of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione (0.49 g, 1.6 mmol) in tetrahydrofuran (10 mL), was added heptanoyl chloride (0.88 mL, 5.7 mmol) and heated at 80° C. for two hours. The mixture was quenched with a few drops of methanol. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give heptanoic acid [3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-yl]-amide as a white solid (120 mg, 18% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 7.12 min (95.5%); mp, 230-232° C.; 1HNMR (DMSO-d6) δ 0.86 (t, J=7 Hz, 3H, CH3), 1.24-1.36 (m, 6H, 3CH2), 1.56-1.65 (m, 2H, CH2), 2.18-2.23 (m, 1H, CHH), 2.40 (t, J=7 Hz, 2H, CH2), 2.59-2.88 (m, 6H, CHCH2, CH3), 5.32 (dd, J=6, 11 Hz, 1H, CH), 7.26-8.55 (m, 3H, Ar), 11.09 (s, 1H, NH), 11.74 (s, 1H, NH); 13C NMR (DMSO-d6) δ 13.87, 20.65, 21.89, 23.35, 24.66, 28.05, 30.60, 30.95, 37.64, 56.73, 107.43, 115.12, 120.32, 135.63, 139.85, 147.86, 154.71, 163.07, 169.28, 171.51, 172.57. LCMS MH=399; Anal Calcd For C21H26N4O4+0.3H2O: C, 62.45; H, 6.64; N, 13.87. Found: C, 62.28; H, 6.66; N, 13.61.