Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:24]=[N:23][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:9](=[O:10])[C:4]=2[C:3]=1[CH:25]([C:27]1[CH:32]=[CH:31]C(Cl)=CC=1)[OH:26].[Li+].[CH3:35]C([N-]C(C)C)C.CC(C)CC=O>C1COCC1.C(Cl)Cl.O>[Br:1][C:2]1[CH:24]=[N:23][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:9](=[O:10])[C:4]=2[C:3]=1[CH:25]([OH:26])[CH2:27][CH:32]([CH3:35])[CH3:31]
Reactant: CC(C)[N-]C(C)C
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(Cl)cc3)c(Br)cnc21
Agent: CC(C)CC=O
Agent: [Li+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CC(O)c1c(Br)cnc2c1c(=O)n(CCCOC1CCCCO1)c(=O)n2C
Temperature: -78 °C
Reaction time: 1 h
Yield: 17.8 %

Procedure:
To a solution of 6-bromo-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (See Compound 20, step 4, 300 mg, 0.753 mmol) in THF (10 mL) at −78° C. was added LDA (1.8M in THF, 2.1 mL, 3.765 mmol) dropwise. The reaction was stirred at −78° C. for 1 h then 3-methylbutanal (129.8 mg, 1.506 mmol) in THF (2 mL) was added. The reaction was stirred at −78° C. for 30 min then diluted with DCM (10 mL) and water (10 mL). The organic layer was dried over Na2SO4, and concentrated to a residue which was purified by chromatography eluted with PE/EA (10:1) to give 6-bromo-5-(1-hydroxy-3-methylbutyl)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (65 mg, 17.8% yield) as a solid. LCMS: [M+-THP-OH] 382 and TR=2.155 min.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[NH:20][N:19]=[C:18]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[F:52][C:53]1[CH:54]=[CH:55][C:56]([C:66]([F:69])([F:68])[F:67])=[C:57]([NH:59][CH:60]2[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]2)[CH:58]=1>CN(C=O)C.O>[F:52][C:53]1[CH:54]=[CH:55][C:56]([C:66]([F:69])([F:67])[F:68])=[C:57]([NH:59][CH:60]2[CH2:61][CH2:62][N:63]([C:25](=[O:27])[CH2:24][NH:23][C:21]([C:18]3[CH:17]=[C:16]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)[NH:20][N:19]=3)=[O:22])[CH2:64][CH2:65]2)[CH:58]=1
Reactant: Fc1ccc(C(F)(F)F)c(NC2CCNCC2)c1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCC(Nc2cc(F)ccc2C(F)(F)F)CC1)c1cc(-c2ccccc2)[nH]n1
Reaction time: 8 h
Yield: 44.4 %

Procedure:
DIPEA (232 mg, 1.8 mmol) was added to a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (148 mg, 0.6 mmol) in DMF (2 mL) followed by HOBt (95 mg, 0.7 mmol) and EDCI.HCl (137 mg, 0.7 mmol). After 2 minutes (5-fluoro-2-trifluoromethyl-phenyl)-piperidin-4-yl-amine dihydrochloride (prepared according to the method used for the synthesis of Intermediate 3) (150 mg, 0.6 mmol) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, extracted with ethyl acetate and dried over sodium sulfate. The organic layer was concentrated under reduced pressure. Purification by column chromatography (using 60-120 silica gel and 5% MeoH in CHCl3 as eluent) afforded 129 mg (44.4% Yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(5-fluoro-2-trifluoromethyl-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 490.18, 95.08%. 1H NMR (300 MHz, DMSO-d6): δ13.8 (s, 1H), 8.0 (bs, 1H), 7.8 (d, 2H), 7.5 (t, 4H), 7.1 (bs, 1H), 6.8 (d, 1H), 6.5 (t, 1H), 5.0 (d, 1H), 4.4 (d, 1H), 4.3 (d, 2H), 3.8 (m, 2H), 3.7 (m, 2H), 3.2 (t, 1H), 2.8 (t, 1H), 2.0 (m, 2H), 1.5 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+]([O-])=O)[CH:6]=1)[CH3:3].C[N:15](CC1C=CC=CC=1[N+]([O-])=O)C.CN(CC1C=C(C=CC=1)N)C.CN(CC1C=CC=CC=1N)C>>[CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:15])=[CH:7][CH:6]=1)[CH3:3]
Reactant: CN(C)Cc1ccccc1[N+](=O)[O-]
Reactant: CN(C)Cc1cccc([N+](=O)[O-])c1
Agent: CN(C)Cc1cccc(N)c1
Agent: CN(C)Cc1ccccc1N
Product: CN(C)Cc1ccc(N)cc1

Procedure:
By using N,N-dimethyl-3-nitrobenzylamine or N,N-dimethyl-2-nitrobenzylamine in place of N,N-dimethyl-4-nitrobenzylamine, 3-dimethylaminomethylaniline and 2-dimethylaminomethylaniline are obtained, respectively.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[O:3][CH2:2]1.C([Li])(CC)C.C(O[B:19]1[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]1)(C)C>O1CCCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([B:19]3[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]3)[C:4]=2[O:3][CH2:2]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: c1ccc2c(c1)OCO2
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CC1(C)OB(c2cccc3c2OCO3)OC1(C)C
Temperature: -108 °C
Reaction time: 2 h
Yield: 34.5 %

Procedure:
Benzo[d][1,3]dioxole (3.05 g, 25 mmol) was dissolved in tetrahydrofuran (50 mL) and cooled to −108° C. utilizing a tetrahydrofuran/liquid nitrogen bath. sec-Butyllithium (1.4 M in cyclohexane; 19.64 mL, 27.5 mmol) was added dropwise, keeping the temperature below −100° C. The reaction mixture was then stirred at temperatures between −100° C. and −108° C. for 2 h to ensure complete deprotonation. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.65 g, 25.00 mmol) was then added to the reaction mixture dropwise, keeping the temperature below −100° C. The reaction mixture was then allowed to warm to room temperature and partitioned between diethyl ether and water. The organic phase was extracted with water once again and the aqueous phases combined and acidified to pH 4 with HCl. The product was extracted with diethyl ether and the organic phase was dried and concentrated under vacuum. The product was purified by flash chromatography (silica gel) to provide the title compound as a white solid (2.14 g, 34.5%): 1H NMR (300 MHz, CDCl3) δ 7.21 (dd, J=7.6, 1.4 Hz, 1H), 6.90 (dd, J=7.7, 1.5 Hz, 1H), 6.82 (t, J=7.6 Hz, 1H), 6.02 (s, 2H), 1.36 (s, 12H); EIMS m/z 248.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16](C(O)=O)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[Br:25]N1C(=O)CCC1=O.O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([Br:25])=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1c(-c2ccc(F)cc2)nn2ccccc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(-c2nn3ccccc3c2Br)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-(4-fluorophenyl)-pyrazolo[1,5-a]pyridine-3-carboxylic acid (0.96 g, 3.75 mmol) in dry DMF (10 mL) was added sodium bicarbonate (0.95 g, 11.3 mmol) followed by N-bromosuccinimide (0.667 g, 3.75 mmol) and the mixture was stirred at room temperature under a nitrogen atmosphere for about 90 min. The mixture was poured into water (300 mL) and the resulting solid was collected by filtration and washed with water. The solid was dissolved in 10:1 chloroform:methanol (10 mL) and filtered through a pad (0.5 cm) of silica gel using 10:1 chloroform:methanol as eluent. The filtrate was evaporated to leave the title compound as a tan solid, 0.87 g (80%). 1H NMR (d6-DMSO) δ 8.7 (d, 1H, J=6.9 Hz), 8.02 (dd, 2H, J=8.7, 5.7 Hz), 7.61 (d, 1H, J=8.4 Hz), 7.40 (t, 1H, J=6 Hz), 7.38 (t, 2H, J=9 Hz), 7.04 (t, 1H, J=6.9 Hz). MS (+ve ion electrospray) 293 (100), (MH+).
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[Cl:9][C:10]1[CH:24]=[CH:23][C:13]([O:14][CH:15]([F:22])[C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:12][CH:11]=1>CS(C)=O.C1COCC1>[C:17]([C:16]1([CH:15]([O:14][C:13]2[CH:12]=[CH:11][C:10]([Cl:9])=[CH:24][CH:23]=2)[F:22])[CH2:2][O:21]1)([CH3:19])([CH3:20])[CH3:18]
Reactant: C[S+](C)(C)=O
Reactant: CC(C)(C)C(=O)C(F)Oc1ccc(Cl)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC(C)(C)C1(C(F)Oc2ccc(Cl)cc2)CO1

Procedure:
43 g of trimethyloxosulfonium iodide were added in portions to a dispersion of 5.28 g of 80% sodium hydride in 300 ml of absolute DMSO under a nitrogen atmosphere, while stirring. When the exothermic reaction had subsided, the mixture was stirred for a further 1 h, a solution of 40 g of 1-(4-chlorophenoxy)-3,3-dimethyl-1-fluoro-2-butanone in 100 ml of THF was then added dropwise at RT and the mixture was stirred at RT for a further 2 h. The reaction solution was then poured onto ice-water and extracted several times with diethyl ether. The combined extracts were washed with water, dried over sodium sulfate and filtered and the filtrate was concentrated. Yield of crude product: 41.5 g in the form of a yellow-brown oil, which can be either purified by column chromatography or further processed without purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[C@@H:14]3[CH2:15][C@@H:11]([CH:12]=[CH:13]3)[C@@H:10]2[C:16]([NH2:18])=[O:17])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:22]=[N:23][N:24]([C@H:26]2[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27]2)[CH:25]=1>CC(O)C>[Cl:19][C:5]1[C:6]([NH:8][C@@H:9]2[C@@H:14]3[CH2:15][C@@H:11]([CH:12]=[CH:13]3)[C@@H:10]2[C:16]([NH2:18])=[O:17])=[N:7][C:2]([NH:20][C:21]2[CH:22]=[N:23][N:24]([C@H:26]3[CH2:30][CH2:29][NH:28][CH2:27]3)[CH:25]=2)=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](n2cc(N)cn2)C1
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Solvent: CC(C)O
Product: NC(=O)[C@@H]1[C@H](Nc2nc(Nc3cnn([C@H]4CCNC4)c3)ncc2Cl)[C@H]2C=C[C@@H]1C2
Temperature: 85 °C
Reaction time: 0.25 h

Procedure:
(+)-(1S,2S,3R,4R)-3-(2,5-Dichloropyrimidin-4-ylamino)bicyclo[2.2.1]hept-5-ene-2-carboxamide (75 mg, 0.25 mmol) and (S)-tert-butyl 3-(4-amino-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate (63 mg, 0.25 mmol) were combined with 2-propanol (2.4 ml) in a sealed tube and the mixture was heated to 85° C. for 4 hours. The reaction mixture was concentrated to dryness, then treated with 5 mL TFA and stirred for 15 minutes. The mixture was again concentrated to dryness, the residue was dissolved in CH2Cl2, and the mixture was treated with aqueous saturated NaHCO3. The layers were separated and the aqueous layer was further extracted 3× with ethyl acetate. The extracts were dried (Na2SO4) and concentrated, then purified by flash chromatography yielding the desired product. 1H NMR (300 MHz, DMSO-D6) ppm 1.41 (d, J=7.8 Hz, 1H) 1.92-2.04 (m, 1H) 2.07-2.21 (m, 2H) 2.52-2.56 (m, 1H) 2.71-2.91 (m, 3H) 2.93 (d, J=5.4 Hz, 1H) 2.95-3.03 (m, 1H) 3.12 (dd, J=11.5, 7.12 Hz, 1H) 4.13 (t, J=7.5 Hz, 1H) 4.65-4.77 (m, 1H) 6.25-6.40 (m, 2H) 7.25 (s, 1H) 7.51 (s, 1H) 7.61-7.84 (m, 3H) 7.89 (s, 1H) 9.10 (s, 1H); MS (ESI(+)) m/e 415 (M+H)+.
Reaction SMILES: [O-][CH2:2][CH3:3].[Na+].Cl.[C:6]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)(=[NH:8])[NH2:7].[CH:15]([CH:17]([CH:23]=O)[C:18]([O:20]CC)=[O:19])=O>C(O)C>[CH2:2]([C:15]1[C:17]([C:18]([OH:20])=[O:19])=[CH:23][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[N:8]=1)[CH3:3]
Reactant: CC[O-]
Reactant: CCOC(=O)C(C=O)C=O
Reactant: N=C(N)c1ccncc1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCc1nc(-c2ccncc2)ncc1C(=O)O
Yield: 14.6 %

Procedure:
Sodium ethoxide (590 mg) was dissolved in anhydrous ethanol (50 ml) at room temperature. To the resulting solution, 4-amidinopyridine hydrochloride (1.31 g) was added, followed by the dropwise addition of a solution of ethyl 2,2-diformylacetate (1.20 g) in anhydrous ethanol (50 ml). The resulting mixture was heated under reflux for 6 hours. To the residue obtained by distilling off the solvent under reduced pressure, dichloromethane and water were added. The organic layer thus separated was dried over anhydrous sodium sulfate. After the solvent was concentrated under reduced pressure, the residue was crystallized in ethanol, whereby the title compound (279 mg, 15%) was obtained as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[O:6]/[C:5]/2=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([C:20]([N:22]2[CH2:27][CH2:26][CH:25]([O:28][CH3:29])[CH2:24][CH2:23]2)=[O:21])[CH:14]=1.CN(C)C=O.O.[NH2:36][NH2:37]>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:6])[NH:37][N:36]=[C:5]2[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([C:20]([N:22]2[CH2:27][CH2:26][CH:25]([O:28][CH3:29])[CH2:24][CH2:23]2)=[O:21])[CH:14]=1
Reactant: NN
Reactant: COC1CCN(C(=O)c2cc(/C=C3\OC(=O)c4ccc(Cl)cc43)ccc2F)CC1
Solvent: O
Solvent: CN(C)C=O
Product: COC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccc(Cl)cc34)ccc2F)CC1
Temperature: 105 °C
Reaction time: 1 h
Yield: 23.3 %

Procedure:
(Z)-5-chloro-3-(4-fluoro-3-(4-methoxypiperidine-1-carbonyl)benzylidene)isobenzofuran-1 (3H)-one (66) (53 mg, 0.13 mmol) was suspended in water (1.5 mL) and N,N-dimethylformamide (0.5 mL) and treated with Hydrazine monohydrate (35 μl, 0.72 mmol). The resulting mixture was stirred at 105° C. for 1 hour. The reaction mixture was cooled and diluted with water (˜5 mL) and mixture extracted with DCM (2×5 mL). Combined organics were evaporated to dryness to afford the crude product, which was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and acetonitrile as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired material as a white solid (13 mg, 24% yield); 1H NMR (400.132 MHz, DMSO) δ 1.28-1.38 (1H, m), 1.40-1.50 (1H, m), 1.49-1.76 (1H, m), 1.83-1.91 (1H, m), 3.01-3.09 (1H, m), 3.25 (3H, s), 3.26-3.37 (2H, m), 3.40-3.46 (1H, m), 3.88-3.96 (1H, m), 4.34 (2H, s), 7.22 (1H, t), 7.35-7.42 (2H, m), 7.87 (1H, dd), 8.02 (1H, d), 8.26 (1H, d), 12.68 (1H, s); m/z (LC-MS, ESI+), RT=2.24 (M+H 430.6).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.Br[C:14]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([C:14]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:15]=3[C:16]([OH:18])=[O:17])=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1ccc(Br)c(C(=O)O)c1
Reactant: O=C(O)c1ccc2c(c1)OCO2
Product: COc1ccc(C(=O)c2ccc3c(c2)OCO3)c(C(=O)O)c1

Procedure:
This compound is obtained according to the procedure described in 1.1. by reacting 1,3-benzodioxole-5-carboxylic acid and 2-bromo-5-methoxybenzoic acid after halogen-lithium exchange. It is used in crude form in the following reaction.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:11]=[CH:10][C:9]3[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:8]=3[CH:7]([C:17]3[C:18](=[O:25])[NH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=3)[C:5]=2[N:6]=1.[CH:26]1([NH2:30])[CH2:29][CH2:28][CH2:27]1>O1CCOCC1>[Cl:16][C:13]1[CH:14]=[CH:15][C:8]2[CH:7]([C:17]3[C:18](=[O:25])[NH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=3)[C:5]3[N:6]=[C:2]([NH:30][CH:26]4[CH2:29][CH2:28][CH2:27]4)[S:3][C:4]=3[CH:11]=[CH:10][C:9]=2[CH:12]=1
Reactant: Cn1cc(C2c3ccc(Cl)cc3C=Cc3sc(Cl)nc32)c(=O)[nH]c1=O
Reactant: NC1CCC1
Solvent: C1COCCO1
Product: Cn1cc(C2c3ccc(Cl)cc3C=Cc3sc(NC4CCC4)nc32)c(=O)[nH]c1=O
Temperature: 60 °C

Procedure:
A mixture of the product from example 44 step (viii) (0.25 g) and cyclobutylamine (0.54 ml) in dry 1,4-dioxane (3 ml) were heated at 60° C. for 34 h. The solvent was removed under reduced pressure and the residue partitioned between water and ethyl acetate. The organic extracts were dried (MgSO4) and evaporated under reduced pressure.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:33]3[N:37]([CH2:38][CH2:39][CH2:40][CH3:41])[C:36]4[CH:42]=[CH:43][CH:44]=[CH:45][C:35]=4[N:34]=3)[CH:31]=[CH:32][C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][CH:15]=2)[C:7]2[CH:29]=[C:30]([C:33]3[N:37]([CH2:38][CH2:39][CH2:40][CH3:41])[C:36]4[CH:42]=[CH:43][CH:44]=[CH:45][C:35]=4[N:34]=3)[CH:31]=[CH:32][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCCn1c(-c2ccc3nc(CCC)n(Cc4ccc(-c5ccccc5C(=O)OC(C)(C)C)cc4)c3c2)nc2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCn1c(-c2ccc3nc(CCC)n(Cc4ccc(-c5ccccc5C(=O)O)cc4)c3c2)nc2ccccc21

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[(2-n-propyl-6-(1-butyl-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [C:1](#[N:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:11][C:12]1[NH:16][N:15]=[C:14]([NH2:17])[CH:13]=1.[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH3:11][C:12]1[NH:16][N:15]=[C:14]([NH:17][C:3]2[CH:2]=[C:1]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:10]=[C:1]([CH:2]=[CH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[N:10]=2)[CH:13]=1
Reactant: N#CC=Cc1ccccc1
Reactant: C1CCNC1
Reactant: Cc1cc(N)n[nH]1
Product: Cc1cc(Nc2cc(N3CCCC3)nc(C=Cc3ccccc3)n2)n[nH]1

Procedure:
Example 76 was synthesized via Scheme 6 according to the general scheme provided above with the appropriate starting materials cinnamonitrile, 5-methyl-1H-pyrazole-3-amine, and pyrrolidine. Structure of the target was confirmed by 1H-NMR. The 1H-NMR is attached.
Reaction SMILES: [OH-].[Na+].[C:3]1([S+:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH:22][CH2:23][C:24]([F:30])([F:29])[S:25]([OH:28])(=[O:27])=[O:26].Br[CH2:32][C:33](=[CH2:41])[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]>C(#N)C>[C:16]1([S+:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1.[C:37]([O:36][C:34]([C:33](=[CH2:32])[CH2:41][O:22][CH2:23][C:24]([F:30])([F:29])[S:25]([OH:28])(=[O:27])=[O:26])=[O:35])([CH3:40])([CH3:39])[CH3:38]
Reactant: O=S(=O)(O)C(F)(F)CO
Reactant: C=C(CBr)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: C=C(COCC(F)(F)S(=O)(=O)O)C(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 61 %

Procedure:
In a 100-ml flask, 31 g of an aqueous solution of 5 mass % sodium hydroxide was placed. The solution was cooled, with stirring, by immersing the flask in an ice water bath. Then, 15.0 g of 2-hydroxy-1,1-difluoroethanesulfonic acid triphenylsulfonium (purity: 95%, 0.035 mol) was gradually added to the solution. The solution was returned to room temperature and stirred for 30 minutes. The solution was again cooled by immersing the flask in the ice water bath. After that, a solution of 6.5 g of tert-butyl 2-bromomethylacrylate (0.029 mol) in 10 g of acetonitrile was dropped into the above solution. The mixed solution was further stirred for 1.5 hours at room temperature. The thus-obtained reaction solution was separated into upper and lower layers. The lower layer was mixed with 20 g of chloroform and washed three times with 24 g of water. The resulting solution was solidified by concentration under reduced pressure. The solid product was dissolved in 10 g of methyl ethyl ketone at 40° C. Into the product solution, 25 g of diisopropyl ether was slowly dropped. The product solution was then stirred for 1 hour at room temperature. After confirming the deposition of a crystalline substance, the crystalline substance was filtered out and dried under reduced pressure. With this, 10 g of the target compound (PAG-1) was obtained as a white solid substance (purity: 99%, yield: 88%).
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][C:6]1[N:11]=[C:10]([Cl:12])[C:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20]O)=[CH:16][C:15]=2[O:22][CH3:23])=[C:8]([CH3:24])[N:7]=1>C(Cl)Cl>[Cl:12][C:10]1[C:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][Cl:3])=[CH:16][C:15]=2[O:22][CH3:23])=[C:8]([CH3:24])[N:7]=[C:6]([NH2:5])[N:11]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc(CO)ccc1Cc1c(C)nc(N)nc1Cl
Solvent: ClCCl
Product: COc1cc(CCl)ccc1Cc1c(C)nc(N)nc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (0.12 mL) was added to a solution of the product from step (i) (0.39 g) in DCM (10 mL) at 0° C. The reaction mixture was stirred at rt for 1 h and then the solvent was evaporated under reduced pressure to give the subtitle compound (0.40 g) which was used without purification.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11](=[O:14])[CH2:12][NH2:13].[CH:15](=O)[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1.S([O-])([O-])(=O)=O.[Na+].[Na+]>ClCCl>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16](/[CH:15]=[N:13]/[CH2:12][C:11]([O:10][CH3:9])=[O:14])=[CH:17][CH:18]=1
Reactant: COC(=O)CN
Reactant: COc1ccc(C=O)cc1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C/N=C/c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (4.6 mL, 33 mmol) and glycine methyl ester hydrochloride (3.8 g, 30.26 mmol) were successively added to a solution of p-anisaldehyde (2.0 g, 14.7 mmol) in dichloromethane (150 mL) at 0° C. Sodium sulfate (10 g) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was then filtered and concentrated to dryness. The resulting residue was portioned in ethyl acetate and filtered in order to remove the triethylamine salts. The title compound was obtained as a pale yellow solid (4.43 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:11][CH2:12][CH3:13])=[N:4][NH:5][C:6]=1[C:7]([F:10])([F:9])[F:8].C([O-])([O-])=O.[K+].[K+].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][N:30]([C:33](=[O:35])[CH3:34])[CH2:29][CH2:28]2)=[CH:23][C:22]=1[O:36][CH3:37].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([CH2:11][CH2:12][CH3:13])=[N:4][N:5]([CH2:34][C:33]([N:30]2[CH2:29][CH2:28][N:27]([C:24]3[CH:25]=[CH:26][C:21]([Cl:20])=[C:22]([O:36][CH3:37])[CH:23]=3)[CH2:32][CH2:31]2)=[O:35])[C:6]=1[C:7]([F:8])([F:10])[F:9]
Reactant: CCCc1n[nH]c(C(F)(F)F)c1Cl
Reactant: COc1cc(N2CCN(C(C)=O)CC2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCc1nn(CC(=O)N2CCN(c3ccc(Cl)c(OC)c3)CC2)c(C(F)(F)F)c1Cl

Procedure:
Protocol T was followed using 4-Chloro-3-n-propyl-5-trifluoromethyl-1-H-pyrazol, K2CO3, 1-[4-(4-Chloro-3-methoxyphenyl)-piperazine-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=3/7, Rf=0.78) afforded the title compound as white solid. 1H NMR (400 MHz, CDCl3); 7.22–7.24 (d, 2H), 6.42–6.48 (m, 2H), 5.7 (s, 2H), 3.8 (s, 3H), 3.72–3.78 (m, 4H), 3.22–3.42 (m, 4H), 2.66–2.72 (t, 2H), 1.58–1.68 (m, 2H), 0.98–1.02 (t, 3H). 13C NMR (400 MHz, CDCl3): 164, 154.8, 150.5, 130, 109.8, 102.2, 56.4, 52.8, 50, 49.8, 45.2, 42.6, 26, 21.8, 14.