Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[CH2:13]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([CH2:29][C:30]([OH:32])=[O:31])[CH:27]=2)[CH:22]=[CH:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:20]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([CH2:29][C:30]([OH:32])=[O:31])[CH:27]=3)[CH:22]=[CH:21]2)=[CH:5][CH:4]=1.[CH2:13]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([CH2:29][C:30]([OH:32])=[O:31])[CH:27]=2)[CH:22]=[CH:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: FC(F)(F)c1ccc(CCl)cc1
Agent: O=C(O)Cc1ccc2ccn(Cc3ccccc3)c2c1
Product: O=C(O)Cc1ccc2ccn(Cc3ccc(C(F)(F)F)cc3)c2c1

Procedure:
The titled compound (33 mg) as a white solid was prepared from the compound [4-6] obtained in the process (6) of Example 4 (100 mg) and 4-(trifluoromethyl)benzyl chloride according to the method of the process (7) of Example 4.
Reaction SMILES: C([O:5][CH:6](OCCCC)[C@H:7]([CH2:34][CH2:35][CH2:36][NH:37][C:38](=[NH:40])[NH2:39])[NH:8][C:9](=[O:33])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:32])[C@@H:16]1[CH2:20][CH2:19][C:18](=[O:21])[N:17]1C(OCC1C=CC=CC=1)=O)CCC.[H][H]>CO.[Pd]>[NH:17]1[C:18](=[O:21])[CH2:19][CH2:20][C@H:16]1[C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[C:9]([NH:8][C@H:7]([CH:6]=[O:5])[CH2:34][CH2:35][CH2:36][NH:37][C:38](=[NH:39])[NH2:40])=[O:33])=[O:32]
Reactant: [H][H]
Reactant: CCCCOC(OCCCC)[C@H](CCCNC(=N)N)NC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: N=C(N)NCCC[C@@H](C=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCC(=O)N1
Yield: 87.3 %

Procedure:
After N-benzyloxycarbonyl-L-pyroglutamyl-L-prolyl-L-argininal 1/2 sulfate (0.055 g, 0.10 mmol) was dissolved in 85% methanol (25 ml), a small amount of palladium black (1 g) was added to the solution followed by catalytic hydrogenation at room temperature for an hour in a hydrogen flow. After completion of the reaction, the catalyst was filtered off and the filtrate was concentrated. The residue was dissolved in a small amount of methanol and the solution was poured onto an excess of dry ether. The precipitated crystals were filtered to give 0.032 g (77%) of L-pyroglutamyl-L-prolyl-L-argininal.1/2 sulfate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.[C:13]([C:19]([O:21][CH3:22])=[O:20])#[C:14][C:15]([O:17][CH3:18])=[O:16].C(OCC)(=O)C>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]23[O:9][CH:10]([CH:11]=[CH:12]2)[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]3[C:19]([O:21][CH3:22])=[O:20])=[CH:6][CH:7]=1
Reactant: Clc1ccc(-c2ccco2)cc1
Reactant: COC(=O)C#CC(=O)OC
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C1=C(C(=O)OC)C2(c3ccc(Cl)cc3)C=CC1O2
Reaction time: 8 h

Procedure:
A mixture of 2-(4-chlorophenyl)furan (prepared according to A.W. Johnson, J. of Chem. Soc. 1946, p 895-99) (0.105 g), and dimethyl acetylenedicarboxylate (0.07 mL) in distilled water (0.25 mL) was placed in a closed vial and subjected to ultrasonic vibration overnight. The reaction temperature at the end of the reaction was between 40 and 50° C. After cooling the Diels-Alder adduct was isolated by extraction with ethyl acetate. The ethyl acetate extract was dried (Na2SO4) and evaporated to dryness in-vacuo to provide almost pure product which was further purified by chromatography on silica gel using 5-10% acetone in n-hexane. The title compound (0.16 g) m.p. 84° C. was isolated from some of the combined fractions: PMR δH (CDCl3): 3.7(s,3H), 3.84 (s, 3H), 5.76 (d, 1H, J=1.2Hz), 7.58-7.29 (m, 5H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.Cl.[NH2:32][CH2:33][C:34]([NH2:36])=[O:35].C(N(CC)CC)C>ClCCl>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([NH:32][CH2:33][C:34]([NH2:36])=[O:35])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: NCC(N)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)CNC(=O)CNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
N-benzyloxycarbonylglycine (3 g, 14.4 mmole) were dissolved in 200 mL of dichloromethane and 4.5 g (21.6 mmole) of DCC were added. The mixture was stirred at room temperature for 2 hours, the insoluble materials were removed and 3.2 g (28.8 mmole) of glycinamide hydrochloride and 2.93 g (28.8 mmole) of TEA (triethylamine) were added to the filtrate. The reaction was stirred for 24 hours at room temperature, the insoluble materials were filtered and the filtrate was evaporated to dryness in vacuum. The residue was recrystallized from distilled water to get a pure product 1.9 g (7.2 mmole), yield of 50%.
Reaction SMILES: C(Cl)(Cl)=O.[NH2:5][C:6]1[S:7][CH:8]=[C:9]([CH3:21])[C:10]=1[S:11]([NH:14][C:15]([NH:17][CH:18]([CH3:20])[CH3:19])=S)(=[O:13])=[O:12].C(N(CC)CC)C.C(OCC)(=O)C>C1(C)C=CC=CC=1.C1COCC1>[CH:18]([NH:17][C:15]1[NH:5][C:6]2[S:7][CH:8]=[C:9]([CH3:21])[C:10]=2[S:11](=[O:13])(=[O:12])[N:14]=1)([CH3:20])[CH3:19]
Reactant: Cc1csc(N)c1S(=O)(=O)NC(=S)NC(C)C
Agent: O=C(Cl)Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1csc2c1S(=O)(=O)N=C(NC(C)C)N2
Temperature: 0 °C
Yield: 44.7 %

Procedure:
A 20% solution of phosgene in toluene (715 μl) was added to a stirred and cooled solution of N-(2-amino-4-methyl-3-thienylsulfonyl)-N′-isopropylthiourea (0.22 g) and triethylamine (313 μl) in dry THF (5 ml) the temperature being kept below 5° C. After stirring for 1.5 h the mixture was evaporated and triturated with 10 ml of water. The precipitate was collected by filtration and dried to give 0.14 g of crude product. The crystals were heated at 70° C. with 5 ml of ethyl acetate and the resulting mixture was cooled to 0° C. for 10 min and then filtered. The filter cake was rinsed with a minute amount of ethyl acetate and dried to give 0.087 g (yield 45%) of the title compound as tan crystals; m.p. 152-154° C.; 1H-NMR (DMSO-d6): δ(ppm): 7.10 (br d, 1 H, NH), 6.61 (s, 1 H, N(4)H), 6.52 (s, 1 H, C(6)H), 3.89 (m, 1 H, CH), 2.32 (s, 3 H, CH3), 1.18 (d, 6 H, CH3).
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:32]#[N:33])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:21]=[CH:22][C:23]3[O:27][C:26]([N:28]([CH3:30])[CH3:29])=[N:25][C:24]=3[CH:31]=1)[CH:12]=2)=[O:7])CCC.[NH2:34][CH2:35][C:36]([OH:38])=[O:37].C[O-].[Na+].CO>>[C:32]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([O:19][C:20]3[CH:21]=[CH:22][C:23]4[O:27][C:26]([N:28]([CH3:30])[CH3:29])=[N:25][C:24]=4[CH:31]=3)[CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([NH:34][CH2:35][C:36]([OH:38])=[O:37])=[O:7])[N:9]=1)#[N:33]
Reactant: NCC(=O)O
Reactant: CCCCOC(=O)c1nc(C#N)c2cc(Oc3ccc4oc(N(C)C)nc4c3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CN(C)c1nc2cc(Oc3ccc4c(O)c(C(=O)NCC(=O)O)nc(C#N)c4c3)ccc2o1
Temperature: 25 °C
Yield: 67.1 %

Procedure:
A mixture of 1-cyano-7-(2-dimethylamino-benzooxazol-5-yloxy)-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (37 mg, 0.08 mmol), glycine (126 mg, 1.68 mmol) and 0.5 M sodium methoxide/methanol (3.2 mL) was refluxed for twenty-five hours before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (20 mL) and extracted with dichloromethane (2×25 mL). The remaining aqueous layer was acidified to pH=3 with 1N HCl (2.4 mL). The white precipitate was filtered, washed with water and dried in vacuo to give the title compound as a white solid (24 mg): MS: (+) m/z 448.27 (M+1).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][CH:5]([C:8]#[N:9])[C:6]#[N:7].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:19][C:20]1[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=1>CN(C)C=O>[F:29][C:26]([F:27])([F:28])[C:23]1[N:22]=[CH:21][C:20]([CH2:19][C:5]([CH2:4][CH2:3][C:2]([F:10])([F:11])[F:1])([C:8]#[N:9])[C:6]#[N:7])=[CH:25][CH:24]=1
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: FC(F)(F)c1ccc(CCl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1ccc(C(F)(F)F)nc1
Yield: 79.1 %

Procedure:
By using (3,3,3-trifluoropropyl)malononitrile (83 mg), N,N-dimethylformamide (10 ml), potassium carbonate (71 mg) and 3-(chloromethyl)-6-(trifluoromethyl)pyridine (100 mg) according to the similar method described in Production Example 4 was obtained 130 mg of 2-((6-(trifluoromethyl)-3-pyridyl)methyl)-2-(3,3,3-trifluoropropyl)malononitrile represented by the following formula (hereinafter referred to as the present invention compound (9)).
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:10])=[O:9])C.[OH-].[Na+].O>C(O)C>[C:11]1([S:8]([NH:7][CH2:6][CH2:5][C:4]([OH:17])=[O:3])(=[O:10])=[O:9])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)CCNS(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CCNS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Next, to a solution of 3-benzenesulfonylaminopropionic acid ethyl ester (340 mg, 1.32 mmol) in ethanol (15 mL) is added aqueous 1M NaOH (4 mL, 4.0 mmol) and the mixture is stirred at room temperature for 4 hours. The mixture is poured into water and is extracted with ether. The aqueous phase is acidified with aqueous 1M HCl and the solution is lyophilized to give 3-benzenesulfonylaminopropionic acid.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C@:6]23[CH2:41][CH2:40][C@@H:39]([C:42]([CH3:44])=[CH2:43])[C@@H:7]2[C@@H:8]2[C@@:21]([CH3:24])([CH2:22][CH2:23]3)[C@@:20]3([CH3:25])[C@@H:11]([C@:12]4([CH3:38])[C@@H:17]([CH2:18][CH2:19]3)[C:16]([CH3:27])([CH3:26])[C:15]([C:28]3[CH:37]=[CH:36][C:31]([C:32]([O:34]C)=[O:33])=[CH:30][CH:29]=3)=[CH:14][CH2:13]4)[CH2:10][CH2:9]2)[CH2:3][CH2:2]1.[OH-].[Na+]>O1CCOCC1>[CH:1]1([CH2:4][NH:5][C@:6]23[CH2:41][CH2:40][C@@H:39]([C:42]([CH3:44])=[CH2:43])[C@@H:7]2[C@@H:8]2[C@@:21]([CH3:24])([CH2:22][CH2:23]3)[C@@:20]3([CH3:25])[C@@H:11]([C@:12]4([CH3:38])[C@@H:17]([CH2:18][CH2:19]3)[C:16]([CH3:26])([CH3:27])[C:15]([C:28]3[CH:37]=[CH:36][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=3)=[CH:14][CH2:13]4)[CH2:10][CH2:9]2)[CH2:3][CH2:2]1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCC3CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(NCC3CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 65 °C
Reaction time: 2 h
Yield: 27 %

Procedure:
To a cloudy mixture of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(cyclopropylmethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (0.024 g, 0.040 mmol) in 1,4-dioxane (1.5 mL) was added NaOH (1N) (0.5 mL, 0.5 mmol). The mixture was heated to 65° C. After two hours, the mixture was cooled to rt and stirred at rt overnight. The mixture was filtered through plug of glass wool and was purified by prep HPLC to afford the title compound (0.007 g, 10.79 μmol, 26.9% yield) as a white film. LCMS: m/e 584.6 (M+H)+, 1.83 min (method 2). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.00 (2H, d, J=8.0 Hz), 7.21 (2H, d, J=8.0 Hz), 5.31 (1H, d, J=5.0 Hz), 4.75 (1H, d, J=1.5 Hz), 4.61 (1H, s), 2.76 (1H, td, J=10.9, 5.6 Hz), 2.62 (1H, dd, J=11.2, 6.1 Hz), 2.23 (1H, dd, J=11.5, 7.8 Hz), 1.97-2.16 (3H, m), 1.82-1.95 (2H, m), 1.70 (3H, s), 1.16 (3H, s), 1.01 (3H, s), 1.00 (3H, s), 0.96 (3H, s), 0.95 (3H, s), 0.80-1.77 (19H, m), 0.48-0.58 (2H, m), 0.09-0.24 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].Cl[C:11](Cl)([O:13]C(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][N:5]=[C:11]=[O:13]
Reactant: NCc1ccccc1Cl
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C=NCc1ccccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 232.7 %

Procedure:
To a solution of 2-chlorobenzylamine (1.0 g, 7.06 mmol) in a mixture of CH2Cl2 and H2O (10 mL/10 mL), triphosgene (838 mg, 2.82 mmol) and NaHCO3 (1.78 g, 21.2 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. Then the reaction mixture was partitioned between CH2Cl2 and water. The combined organic layers are dried over MgSO4 and filtered. The solvent was evaporated to give the desired product (1.1 g, 93%). EI-MS m/z 168.7 (M+).
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[C:9]([CH3:31])[C:8]=1[F:32].Cl.Cl.[NH2:35][CH:36]1[CH2:39][NH:38][CH2:37]1.CN1CCCC1>C(O)C>[NH2:35][CH:36]1[CH2:39][N:38]([C:20]2[C:21]([Cl:23])=[C:22]3[C:17]([C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14][N:13]3[C:11]3[C:10]([F:30])=[C:9]([CH3:31])[C:8]([F:32])=[C:7]([NH2:6])[N:12]=3)=[CH:18][C:19]=2[F:25])[CH2:37]1
Reactant: NC1CNC1
Reactant: Cc1c(F)c(N)nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c1F
Agent: CN1CCCC1
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: Cc1c(F)c(N)nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(N)C4)c(Cl)c32)c1F
Temperature: 90 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
To 280 mg of N,N-dimethylformamide were added 50 mg of 1-(6-amino-3,5-difluoro-4-methylpyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 40 mg of 3-aminoazetidine dihydrochloride, and 120 mg of N-methylpyrrolidine, and the mixture was stirred at 90° C. for 1 hour. After adding 0.4 ml of ethanol, the mixture was allowed to cool. The precipitate was collected by filtration, and washed with ethanol and diisopropylether successively to obtain 45 mg of the title compound as a colorless powder.
Reaction SMILES: FC(F)(F)C(O)=O.CC([N:12]([CH:16]1[CH2:21][CH2:20][N:19]([C:22]2[C:23]3[C:30]([CH3:31])=[CH:29][NH:28][C:24]=3[N:25]=[CH:26][N:27]=2)[CH2:18][CH2:17]1)C(=O)[O-])(C)C>>[CH3:31][C:30]1[C:23]2[C:22]([N:19]3[CH2:20][CH2:21][CH:16]([NH2:12])[CH2:17][CH2:18]3)=[N:27][CH:26]=[N:25][C:24]=2[NH:28][CH:29]=1
Reactant: Cc1c[nH]c2ncnc(N3CCC(N(C(=O)[O-])C(C)(C)C)CC3)c12
Solvent: O=C(O)C(F)(F)F
Product: Cc1c[nH]c2ncnc(N3CCC(N)CC3)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (TFA) (5 ml) was added to a solution of 1,1-dimethylethyl[1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]carbamate D10 (580 mg, 1.313 mmol). The mixture was stirred at room temperature during one hour. The solvent was evaporated and purified using and SCX cartridge (5 g). The cartridge was washed sequentially with MeOH and then Ammonia in MeOH (0.5M and 1M). The washings with Ammonia in methanol 0.5M and 1M were combined and evaporated to give D11a (280 mg) as a white solid. LCMS [M+H]+232@0.36 mins (2 minute run).
Reaction SMILES: Cl[C:2]1[C:3]2[S:10][C:9]([I:11])=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:12]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCCl>[CH2:12]([N:19]1[CH2:24][CH2:23][N:22]([C:6]2[N:7]=[CH:2][C:3]3[S:10][C:9]([I:11])=[CH:8][C:4]=3[N:5]=2)[CH2:21][CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Clc1ncnc2cc(I)sc12
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: ClCCCl
Product: Ic1cc2nc(N3CCN(Cc4ccccc4)CC3)ncc2s1
Yield: 88.2 %

Procedure:
To a solution of 4-chloro-6-iodothieno[3,2-d]pyrimidine (0.5 g, 1.7 mmol) in DCE (5 mL)/TEA (1 mL) was added 1-Benzyl-piperazine (0.3 g, 1.69 mmol). The mixture was refluxed for 1 hour. The solvent was removed and the residue was subject to chromatography on silica gel to afford (4-Benzyl-piperazin-1-yl)-6-iodothieno[3,2-d]pyrimidine (0.65 g, 88%). 1H NMR (CDCl3, 400 Hz) δ 8.47 (s, 1H) 7.60 (s, 1H), 7.35-7.23 (m, 5H), 3.95-3.92 (m, 4H), 3.51 (s, 2H), 2.59-2.54 (m, 4H). MS (ESI+) [M+H]+ 437.
Reaction SMILES: [H-].[OH-].[Li+].C[O:5][C:6](=[O:39])[CH:7]([NH:12][C:13]([C:15]1[N:16]=[N:17][C:18]([N:21]2[CH2:26][CH2:25][N:24]([C:27](=[O:38])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:37])([F:36])[F:35])[CH2:23][CH2:22]2)=[CH:19][CH:20]=1)=[O:14])[CH2:8][CH:9]([CH3:11])[CH3:10]>O1CCCC1.O>[CH3:10][CH:9]([CH3:11])[CH2:8][CH:7]([NH:12][C:13]([C:15]1[N:16]=[N:17][C:18]([N:21]2[CH2:22][CH2:23][N:24]([C:27](=[O:38])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:37])([F:36])[F:35])[CH2:25][CH2:26]2)=[CH:19][CH:20]=1)=[O:14])[C:6]([OH:39])=[O:5]
Reactant: COC(=O)C(CC(C)C)NC(=O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Agent: [H-]
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CC(NC(=O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.4 %

Procedure:
Lithium hydroxide monohydride (25 mg, 0.595 mmol) was added to a solution of 4-methyl-2-({6-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]pyridazine-3-carbonyl}-amino)pentanoic acid methyl ester (130 mg, 0.256 mmol) in tetrahydrofuran (3 mL) and water (1.5 mL), the reaction mixture was stirred at ambient temperature for 3 hours, THE was removed by evaporation, the residue was adjusted with 5% citric acid to pH about 6, and diluted with ethyl acetate, washed with water and brine, dried (Na2SO4) and concentrated to afford 4-methyl-2-({6-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]pyridazine-3-carbonyl}amino)pentanoic acid (94 mg, 74%). 1H NMR (400 MHz, CDCl3) δ 8.17, 8.02, 7.78, 7.66-7.53, 7.38, 6.99, 6.72, 4.88-4.73, 4.25-3.60, 3.44-3.21, 1.79-1.06, 1.33-1.19, 1.03, 0.99.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:11]=[CH:10][S:9][C:8]=1Br.[CH3:13][Sn:14](Cl)([CH3:16])[CH3:15]>O1CCCC1>[CH3:13][Sn:14]([CH3:16])([CH3:15])[C:8]1[S:9][C:10]([Sn:14]([CH3:16])([CH3:15])[CH3:13])=[CH:11][CH:7]=1
Reactant: Brc1ccsc1Br
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Sn](C)(C)c1ccc([Sn](C)(C)C)s1
Reaction time: 0.5 h
Yield: 61 %

Procedure:
After 18.4 mL (30 mmol) of n-butyl lithium solution (n-BuLi, 1.63M in hexane) was added to a solution of 3.0 g (12.4 mmol) dibromothiophene in tetrahydrofuran (50 mL) at −50° C. under nitrogen atmosphere, the reaction was allowed to proceed for 30 minutes. To the mixture was added 5 g of trimethylstannyl chloride (SnMe3Cl, 25 mmol) and the reaction was continued at −50° C. for about 4˜5 hours. Next, the aqueous layer and organic layer were separated. The obtained organic layer was dried over a drying agent, and then solvents were removed. The resulting crude product was recrystallized from ether twice to afford 3.1 g (yield: 60%) of the title compound as a white crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1=[O:18])[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.[Cl:48][C:49]1[CH:60]=[CH:59][C:52]2[NH:53][C:54]([C@@H:56]([NH2:58])[CH3:57])=[N:55][C:51]=2[CH:50]=1>CN(C=O)C>[Cl:48][C:49]1[CH:60]=[CH:59][C:52]2[NH:53][C:54]([C@@H:56]([NH:58][C:6](=[O:8])[C:5]3[CH:9]=[CH:10][C:11]([N:12]4[CH2:17][CH2:16][CH2:15][CH2:14][C:13]4=[O:18])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH3:57])=[N:55][C:51]=2[CH:50]=1
Reactant: COc1cc(C(=O)O)ccc1N1CCCCC1=O
Reactant: C[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N[C@@H](C)c2nc3cc(Cl)ccc3[nH]2)ccc1N1CCCCC1=O

Procedure:
Prepared analogously to Example 1f from 3-methoxy-4-(piperidin-2-on-1-yl)-benzoic acid, TBTU, NMM and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethylamine in DMF and subsequent purification by preparative HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]1[NH:14][CH2:13][CH2:12][NH:11]1.[H-].[Na+].Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]1[NH:11][CH2:12][CH2:13][N:14]1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: Clc1ccc(N=C2NCCN2)c(Cl)c1
Reactant: CCOC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)N1CCNC1=Nc1ccc(Cl)cc1Cl
Temperature: 0 °C

Procedure:
A mixture of 2-(2,4-dichlorophenylimino)imidazolidine (9.2 g.), sodium hydride (1.3 g. as 80% dispersion in oil) and tetrahydrofuran (65 ml.) was stirred and heated under reflux for 1 hour. The mixture was cooled and a solution of ethyl chloroformate (4.8 g.) in tetrahydrofuran (20 ml.) was added dropwise. The mixture was then stirred and heated under reflux for a further three hours. The mixture was cooled and then poured onto an ice-water mixture to give a solid which was dried over phosphorus pentoxide. Recrystallisation with charcoal from isopropanol gave 2-(2,4-dichlorophenylimino)-1-ethoxycarbonylimidazolidine, m.p. 138°-139° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]([CH3:9])[C:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:13][CH:12]=2)=[C:5]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[N:4]=1.CS(O)(=O)=O.S(Cl)(Cl)=O.[CH3:36][N:37]([CH3:43])[CH2:38][CH2:39][CH2:40][CH2:41]O.CN(C)C>C(#N)C.C(OCC)(=O)C>[NH2:2][C:3]1[N:8]=[C:7]([CH3:9])[C:6]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([CH2:17][C:18]([O:20][CH2:41][CH2:40][CH2:39][CH2:38][N:37]([CH3:43])[CH3:36])=[O:19])=[CH:15][CH:16]=2)=[C:5]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[N:4]=1
Reactant: CN(C)CCCCO
Reactant: CCCCCNc1nc(N)nc(C)c1Cc1ccc(CC(=O)O)cc1
Agent: CN(C)C
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O=S(Cl)Cl
Product: CCCCCNc1nc(N)nc(C)c1Cc1ccc(CC(=O)OCCCCN(C)C)cc1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
The solution of the product from step (vi) (2.00 g, 5.28 mmol) and methanesulfonic acid (1.52 g, 15.8 mmol) in acetonitrile (16.0 g) was cooled to 20° C. and thionyl chloride (0.94 g, 7.92 mmol) was slowly added to the solution. After the mixture was stirred at 20° C. for 30 minutes, 4-dimethylamino-1-butanol (1.11 g, 9.50 mmol) was slowly added to the mixture. The mixture was heated to 40° C. and stirred at the temperature for 5 hours. After the reaction mixture was cooled to 20° C., ethyl acetate (18.0 g) and 25% aq. trimethylamine (18.0 g) was slowly added to the mixture. The organic layer was separated and washed respectively with 5% aq. NH4Cl (20.0 g), 1% aq. NaCl (20.0 g) and water (20.0 g). The solution of the subtitle compound was used in the next step without concentration.
Reaction SMILES: CS[C:3](=[N:12][CH2:13][Si](C)(C)C)[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[C:6]([Cl:11])[CH:5]=1.[Cl:18][C:19]1[CH:24]=[C:23]([C:25]([C:27](F)(F)F)=[CH2:26])[CH:22]=[C:21]([Cl:31])[CH:20]=1.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]2[CH2:27][C:25]([C:23]3[CH:22]=[C:21]([Cl:31])[CH:20]=[C:19]([Cl:18])[CH:24]=3)([CH3:26])[CH2:13][N:12]=2)=[CH:5][C:6]=1[Cl:11]
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: CSC(=NC[Si](C)(C)C)c1ccc(Br)c(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(c2cc(Cl)cc(Cl)c2)CN=C(c2ccc(Br)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 114.8 %

Procedure:
To a solution of 4-bromo-3-chloro-N-trimethylsilanylmethyl-thiobenzimidic acid methyl ester (Example I14) (1.83 g) and 1,3-dichloro-5-(1-trifluoromethyl-vinyl)-benzene (see WO 2007125984) (1.38 g) in THF (25 ml) was added at −5° C. tetrabutylammonium fluoride trihydrate (TBAF) (0.41 g) dissolved in THF (15 ml). The reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture concentrated and the residue was purified by chromatography on silica gel (eluent: ethyl acetate/heptanes 1:6) to give 5-(4-bromo-3-chloro-phenyl)-3-(3,5-dichloro-phenyl)-3-methyl-3,4-dihydro-2H-pyrrole (2.50 g). 1H-NMR (400 MHz, CDCl3): 7.95-7.25 (m, 6H), 4.88 (d, 1H), 4.42 (d, 1H), 3.75 (d, 1H), 3.40 (d, 1H) ppm.