Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.Cl[C:9]1[CH:14]=[C:13]([C:15]([N:17]([CH3:19])[CH3:18])=[O:16])[CH:12]=[C:11]([CH3:20])[N:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:27](=[NH:40])([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:28]1([C:27](=[N:40][C:9]2[CH:14]=[C:13]([C:15]([N:17]([CH3:19])[CH3:18])=[O:16])[CH:12]=[C:11]([CH3:20])[N:10]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Cc1cc(C(=O)N(C)C)cc(Cl)n1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: Cc1cc(C(=O)N(C)C)cc(N=C(c2ccccc2)c2ccccc2)n1
Temperature: 80 °C

Procedure:
Dioxane (2.7 mL), 2-chloro-N,N,6-trimethylpyridine-4-carboxamide trifluoroacetate (250 mg, 0.80 mmol), and cesium carbonate (782 mg, 2.40 mmol) were added to benzophenone imine (0.134 mL, 0.80 mmol) in a scintillation vial. The vial was purged and flushed with argon 3 times before adding Xantphos (69 mg, 0.12 mmol) and Pd2(dba)3 (73 mg, 0.080 mmol). The vial was purged and flushed with argon 3 times before sealing the system and heating to 80° C. for 10 hours. The reaction mixture was cooled to room temperature, and purified directly by silica gel chromatography (10-80% acetone/hexanes, linear gradient) to afford 2-[(diphenylmethylidene)amino]-N,N,6-trimethylpyridine-4-carboxamide. The isolated material was diluted with DCM (1 mL) and TFA (1 mL). The reaction mixture was stirred at room temperature for 2 hours, and then directly purified by reverse phase HPLC (5-30% acetonitrile/water with 0.1% TFA, linear gradient) to afford 2-amino-N,N,6-trimethylpyridine-4-carboxamide TFA salt. MS ESI calc'd. for C9H14N3O [M+H]+ 180. found 180. 1H NMR (500 MHz, CDCl3) δ 7.09 (s, 1H), 7.03 (s, 1H), 3.06 (s, 3H), 2.91 (s, 3H), 2.52 (s, 3H).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=3)[CH:9]=2)[N:4]([S:22]([C:25]2[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH:3]=1.CC1(C)C(C)(C)OB([C:40]2[CH:41]=[N:42][N:43]([CH2:45][C:46]3[CH:47]=[C:48]([CH:51]=[CH:52][CH:53]=3)[C:49]#[N:50])[CH:44]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].COCCOC.O>[C:49]([C:48]1[CH:47]=[C:46]([CH:53]=[CH:52][CH:51]=1)[CH2:45][N:43]1[CH:44]=[C:40]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:12]=[C:13]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=4)[CH:9]=3)[N:4]([S:22]([C:25]3[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[CH:3]=2)[CH:41]=[N:42]1)#[N:50]
Reactant: CC1(C)OB(c2cnn(Cc3cccc(C#N)c3)c2)OC1(C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4cccc(NS(C)(=O)=O)c4)cnc32)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(C#N)c4)c3)c3cc(-c4cccc(NS(C)(=O)=O)c4)cnc32)cc1
Yield: 41.3 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, N-(3-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)methanesulfonamide (Intermediate 9) (200 mg, 0.35 mmol) was coupled with 3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)benzonitrile (Intermediate 14) (119.8 mg, 0.38 mmol) in sodium carbonate (111 mg, 1.05 mmol), PdCl2(dppf) (12.8 mg, 0.017 mmol) and DME/water (2/1 ml) to afford 90 mg (30% yield) of the pure product after column purification using 50% ethyl acetate in hexane as eluent.
Reaction SMILES: [F:1][C:2]([F:12])([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][N:6]=1)[CH2:3]O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:37]I>CC#N.C1(C)C=CC=CC=1>[F:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][N:6]=1)([F:12])[CH2:3][I:37]
Reactant: Cc1ccc(C(F)(F)CO)nc1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CC#N
Product: Cc1ccc(C(F)(F)CI)nc1
Temperature: 90 °C
Yield: 32 %

Procedure:
2,2-Difluoro-2-(5-methyl-pyridin-2-yl)-ethanol (8.5 g, 0.05 mol), as prepared in the previous step, was dissolved into toluene:CH3CN (98 mL, 2:1) and cooled to 0° C. To this solution was added PPh3 (19.3 g, 0.074 mol, 1.5×), imidazole (6.7 g, 0.098 mol, 2×) and I2 (18.7 g, 0.074 mol, 1.5×). The reaction was heated to 90° C., then was cooled to RT and concentrated in vacuo to afford a thick amber oil. Purification via flash chromatography (CH2Cl2) afforded the product as a clear oil (4.6 g, 0.016 mol, 33% yield). 1H NMR (300 Hz, CDCl3) δ 8.48 (s, 1H), 7.61 (m, 1H), 3.92 (t, J=14.7 Hz), 2.41 (s, 3H); LC/MS (m/z) [M+1]+ 284.1 (calculated for C8H9F2IN, 284.07).
Reaction SMILES: Cl.[Cl-].[NH2:3][C:4]1[C:9]([CH2:10][N+:11]2[CH:20]=[CH:19][C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[CH:12]=2)=[CH:8][N:7]=[C:6]([CH3:21])[N:5]=1.[BH4-].[Na+]>CO>[CH2:12]1[C:13]2[CH2:14][CH2:15][CH2:16][CH2:17][C:18]=2[CH2:19][CH2:20][N:11]1[CH2:10][C:9]1[C:4]([NH2:3])=[N:5][C:6]([CH3:21])=[N:7][CH:8]=1
Reactant: Cc1ncc(C[n+]2ccc3c(c2)CCCC3)c(N)n1
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: CO
Product: Cc1ncc(CN2CCC3=C(CCCC3)C2)c(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
A solution of 9.81 g (0.030 mol) of 2-(4-amino-2-methyl-pyrimidin-5-ylmethyl)-5,6,7,8-tetrahydro-isoquinolinium chloride hydrochloride in 50 ml of methanol was treated portionwise at 10° with 3.5 g (0.092 mol) of sodium borohydride. The mixture was stirred at room temperature for 1 hour and completely freed from the solvents. The residue was partitioned between ethyl acetate and water, extracted and recrystallized from petroleum ether. 5.7 g (74%) of 5-(3,4,5,6,7,8-hexahydro-1H-isoquinolin-2-ylmethyl)-2-methyl-pyrimidin-4-ylamine were obtained as white crystals; m.p. 137°-139° (dec.).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.FC(F)(F)C1C=C(C(F)(F)F)C=CC=1CN1C2C(=CC(C=C3S[C:53]([N:55]4[CH2:60][CH2:59][NH:58][C@@H:57]([C:61](NC)=[O:62])[CH2:56]4)=NC3=O)=CC=2)C=N1>>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:58]4[CH2:59][CH2:60][N:55]([CH3:53])[CH2:56][C@@H:57]4[CH2:61][OH:62])=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: CNC(=O)[C@H]1CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)CCN1
Product: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)[C@@H](CO)C1

Procedure:
5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[(2R)-2-(hydroxymethyl)-4-methylpiperazin-1-yl]-1,3-thiazol-4(5H)-one was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and (2R) (4-Methyl-piperazin-2-yl)-methanol following General Procedure C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH:9]=[N:10][CH2:11][C:12]2[C:13]([NH2:19])=[N:14][C:15]([CH3:18])=[N:16][CH:17]=2)=[CH:4][N:3]=1.CC1N=C(N)C(CO)=CN=1>>[CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][NH:10][CH2:11][C:12]2[C:13]([NH2:19])=[N:14][C:15]([CH3:18])=[N:16][CH:17]=2)=[CH:4][N:3]=1
Reactant: Cc1ncc(C=NCc2cnc(C)nc2N)c(N)n1
Agent: Cc1ncc(CO)c(N)n1
Product: Cc1ncc(CNCc2cnc(C)nc2N)c(N)n1

Procedure:
And, neither 2-methyl-4-amino-5-pyrimidylmethylidene-(2-methyl-4-amino-5-pyrimidylmethyl)amine nor 2-methyl-4-amino-5-hydroxylmethylpyrimidine was detected.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:16](=[O:25])[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:8][C@H:7]([NH:26][C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:6]1=[O:35].CO.O.O[Li].O>C1COCC1>[O:35]=[C:6]1[N:5]([CH2:4][C:3]([OH:36])=[O:2])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:16](=[O:25])[CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:8][CH:7]1[NH:26][C:27](=[O:34])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COC(=O)CN1C(=O)[C@@H](NC(=O)c2ccccc2)CN(C(=O)CCc2ccccc2)c2ccccc21
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)CN1C(=O)C(NC(=O)c2ccccc2)CN(C(=O)CCc2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 64 h
Yield: 19 %

Procedure:
(3S)-2-Oxo-3-benzoylamino-5-(3-phenylpropionyl)-2,3,4,5-tetrahydro-1H-1,5-benzo diazepine-1-acetic acid methyl ester (602a; 1.25 g, 2.57 mmol) was dissolved in 11 ml of THF, MeOH and H2O (5:5:1) and treated with LiOH.H2O (42 mg, 0.62 mmol) stirred at RT for 64 h. The reaction was concentrated in vacuo, diluted with H2O and acidified with aq. 1N HCl to give 230 mg of 603a as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OB(O)O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Br[C:14]([C:16]([F:19])([F:18])[F:17])=[CH2:15].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:14]([C:16]([F:19])([F:18])[F:17])=[CH2:15])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: C=C(Br)C(F)(F)F
Reactant: OB(O)Oc1cc(Cl)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Temperature: 25 °C
Yield: 88.2 %

Procedure:
In a solution of 25.0 g of 3,5-dichlorophenyl boric acid in 200 mL of tetrahydrofuran and 100 mL of water, 27.5 g of 2-bromo-3,3,3-trifluoropropene, 38.0 g of potassium carbonate and 1.84 g of dichlorobis(triphenylphosphine) palladium (II) were added, and stirred under reflux with heat for 3 hours. After the completion of the reaction, the reaction mixture was left and cooled to room temperature, 500 mL of ice water was added, and extracted with ethyl acetate (500 mL×1). The organic phase was washed with water, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with hexane to obtain 25.7 g of the aimed product as colorless oily substance.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8](OCC)=[O:9])[CH2:4][CH2:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].N#N>CCOCC>[CH2:1]=[C:2]1[CH2:7][CH2:6][CH:5]([CH2:8][OH:9])[CH2:4][CH2:3]1
Reactant: C=C1CCC(C(=O)OCC)CC1
Agent: N#N
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: C=C1CCC(CO)CC1
Reaction time: 0.08 h

Procedure:
To a solution of ethyl 4-methylenecyclohexanecarboxylate (2 g, 11.89 mmol) in ether (40 mL) was added LAH (0.5 g, 13.17 mmol) portionwise under N2. The reaction mixture was refluxed for 1 h and was quenched by addition of 1 mL of EtOAc carefully and refluxed for 10 min. The reaction mixture was cooled down and added 3 mL of 1 N NaOH and stirred for 5 min, filtered off the solid and washed with ether. The filtration was washed with water, brine, dried (MgSO4), and removed the solvent to afford (4-methylenecyclohexyl)methanol.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1COCC1>[C:12]1([NH:11][C:2]2[CH:10]=[CH:9][C:5]3[NH:6][CH:7]=[N:8][C:4]=3[CH:3]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Brc1ccc2nc[nH]c2c1
Reactant: Nc1ccccc1
Agent: [Pd]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: c1ccc(Nc2ccc3[nH]cnc3c2)cc1

Procedure:
The compound was synthesized starting from 5-bromobenzimidazole (1.0 g; 5 mmol; 1 eq.), aniline (559 mg; 0.547 ml; 6 mmol; 1.2 eq.), lithiumbis(trimethylsilyl)amide 1M in THF (11 ml; 11 mmol; 2.2 eq.), 2-dicyclohexylphos-phino-2″-(N,N-dimethylamino)biphenyl) (45 mg; 0.12 mmol; 0.024 eq.; 2.4 mol %), Pd2 dba3 (45 mg; 0.05 mmol; 0.01 eq.; 1 mol %) and THF (5 ml) according to method 1; Yield: 0.565 g (54.1%); MS m/z: 210.2 [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 6.72-6.75 (m, 1H); 6.94-6.96 (m, 1H); 7.00-7.02 (m, 2H); 7.16-7.19 (m, 2H); 7.25 (br s, 1H); 7.47 (d, 1H, 3J=8.5 Hz); 7.98 (br s, 1H); 8.04 (s, 1H); 12.13 (br s, 1H); HPLC (METHOD [A]): rt 10.62 min (87.0%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20](O)=[O:21])[C:14](=[O:23])[C@@H:13]2[CH3:24])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:25][C:26]1([OH:32])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]([N:29]3[CH2:30][CH2:31][C:26]([OH:32])([CH3:25])[CH2:27][CH2:28]3)=[O:21])[C:14](=[O:23])[C@@H:13]2[CH3:24])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C[C@H]1C(=O)N(CCC(=O)O)CCN1C(=O)Nc1ccc(Cl)c(Cl)c1
Reactant: CC1(O)CCNCC1
Product: C[C@H]1C(=O)N(CCC(=O)N2CCC(C)(O)CC2)CCN1C(=O)Nc1ccc(Cl)c(Cl)c1
Yield: 51 %

Procedure:
In analogy to the procedure described in Example 15, 3-[(S)-4-(3,4-dichloro-phenylcarbamoyl)-3-methyl-2-oxo-piperazin-1-yl]-propionic acid (intermediate 12) and 4-methyl-piperidin-4-ol gave the titled compound in 51% yield as off-white solid. MS: 471.2 (MH+, 2Cl).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@@H:27]4[CH2:31][CH2:30][NH:29][CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1.C([O:35][C@@H:36]([CH3:40])[C:37](Cl)=[O:38])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@@H:27]4[CH2:31][CH2:30][N:29]([C:37](=[O:38])[C@@H:36]([OH:35])[CH3:40])[CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1CCNC1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1CCN(C(=O)[C@H](C)O)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-fluorophenyl]-6-methyl-N-[(3R)-pyrrolidin-3-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f15) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[C:12]1([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1.C1C=CC=CC=1.C(N(CC)CC)C.CCCCCC>[C:2]([N:21]1[CH2:22][CH2:23][N:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:19][CH2:20]1)([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCN(c2ccccc2)CC1
Reaction time: 2 h

Procedure:
A solution of 4.4 g of benzyl chloroformate in toluene is added to a solution comprising 4.05 g of N-phenylpiperazine in 50 cm3 of benzene and 2.5 g of triethylamine, at a temperature between +5° C. and +10° C. The whole is allowed to return to ambient temperature and agitated for 2 hours. The triethylamine chloride is filtered off and evaporated to dryness. An oily residue is obtained which is solidified in n-hexane and 7.1 g of expected product is recovered.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:39])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:35])([CH3:34])[CH:32]=[CH2:33])[NH:17][CH:16]2[C:36](O)=[O:37])[CH:12]=[CH:13][CH:14]=1.[CH3:40][C:41]1([CH3:49])[O:45][C@@H:44]([CH2:46][CH2:47][NH2:48])[CH2:43][O:42]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:40][C:41]1([CH3:49])[O:45][C@@H:44]([CH2:46][CH2:47][NH:48][C:36]([CH:16]2[CH:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=3[F:39])[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:35])([CH3:34])[CH:32]=[CH2:33])[NH:17]2)=[O:37])[CH2:43][O:42]1
Reactant: CC1(C)OC[C@H](CCN)O1
Reactant: C=CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: C=CC(C)(C)CC1NC(C(=O)NCC[C@H]2COC(C)(C)O2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 80 %

Procedure:
In a manner similar to the method described in Example 42c, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-but-3-enyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 80c (1.0 g, 1.69 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.73 g, 5.0 mmol), HATU (1.15 g, 3 mmol) and iPr2NEt (1.46 mL, 8.4 mmol) in CH2Cl2 at room temperature for 20 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-but-3-enyl)-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethyl]-amide as a white solid (0.82 g, 80%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH3:9].C([Li])CCC.CN(C)[CH:17]=[O:18]>O1CCCC1.CCCCCC>[F:8][C:6]1[CH:5]=[CH:4][C:3]([CH3:9])=[C:2]([CH:7]=1)[CH:17]=[O:18]
Reactant: Cc1ccc(F)cc1Br
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(F)cc1C=O
Temperature: 0 °C
Yield: 98.4 %

Procedure:
A solution of 2-bromo-4-fluorotoluene (16.0 g) in anhydrous tetrahydrofuran was treated dropwise at −78° C. with a 1.6 M solution of butyllithium in hexane (55.5 ml). At the same temperature, the mixture was stirred and treated dropwise with a solution of dimethylformamide (6.8 g) in tetrahydrofuran (20 ml). After being allowed to warm to 0° C., the reaction mixture was combined with ice-water. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed successively with water and saturated brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 5-fluoro-2-methylbenzaldehyde (11.5 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:14]=[O:15])=[CH:4][NH:5][C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[CH3:33][S:34]([C:37]1[CH:38]=[C:39]([S:43](Cl)(=[O:45])=[O:44])[CH:40]=[CH:41][CH:42]=1)(=[O:36])=[O:35]>O1CCCC1.C(=O)([O-])O.[Na+]>[Cl:1][C:2]1[C:3]([CH:14]=[O:15])=[CH:4][N:5]([S:43]([C:39]2[CH:40]=[CH:41][CH:42]=[C:37]([S:34]([CH3:33])(=[O:36])=[O:35])[CH:38]=2)(=[O:45])=[O:44])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=Cc1c[nH]c(-c2cccnc2F)c1Cl
Reactant: CS(=O)(=O)c1cccc(S(=O)(=O)Cl)c1
Agent: C1COCCOCCOCCOCCO1
Agent: O=C([O-])O
Agent: [H-]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cccc(S(=O)(=O)n2cc(C=O)c(Cl)c2-c2cccnc2F)c1
Reaction time: 0.08 h
Yield: 56.8 %

Procedure:
To a solution of 4-chloro-5-(2-fluoropyridin-3-yl)-1H-pyrrole-3-carbaldehyde (250 mg) in tetrahydrofuran (25 mL) was added sodium hydride (60% in oil, 89 mg) at room temperature and the mixture was stirred for 5 min. 15-Crown-5 (490 mg) was added dropwise, and the mixture was stirred for 5 min. 3-(Methylsulfonyl)benzenesulfonyl chloride (426 mg) was added, and the mixture was further stirred for 1 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:1) to give the title compound as a pale-yellow oil (yield 280 mg, 57%).
Reaction SMILES: O.C[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20]C)[CH:16]=3)[C:11]=2[O:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]=[CH:30][C:31]([OH:33])=[O:32])=[CH:25][CH:24]=2)=[CH:6][CH:5]=1.B(Br)(Br)Br>ClCCl>[OH:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([OH:20])[CH:16]=3)[C:11]=2[O:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]=[CH:30][C:31]([OH:33])=[O:32])=[CH:25][CH:24]=2)=[CH:8][CH:9]=1
Reactant: COc1ccc(-c2ccc3cc(OC)ccc3c2Oc2ccc(C=CC(=O)O)cc2)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=C(O)C=Cc1ccc(Oc2c(-c3ccc(O)cc3)ccc3cc(O)ccc23)cc1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A solution was prepared of 658 mg (1.54 mmol) of 3-[4-((2-(4-methoxyphenyl)-6-methoxynaphth-1-yl)oxy)phenyl]propenoic acid hydrate in 10 mL of dichloromethane. The solution was cooled to 5° C. and 0.44 mL (4.7 mmol) of BBr3 was added. The reaction was allowed to proceed for one hour at 0° C. under a nitrogen atmosphere. The reaction was quenched by pouring into water and extracting three times with ethyl acetate. The combined ethyl acetate extracts were washed with water, brine, dried with Na2SO4, and evaporated to an oily, red solid. The product was purified by chromatography on a silica gel column eluted with MeOH--CHCl3 (1:99) (v/v). This yielded 489 mg of the title compound as a yellow, amorphous solid, mp 150-153° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:5]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([CH3:20])[CH:19]=2)[C:6]2[N:7]([C:9]([CH2:12][CH3:13])=[CH:10][CH:11]=2)[N:8]=1.[C:30](O)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[C:30]([NH:1][CH2:2][C:3]1[C:4]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:5]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([CH3:20])[CH:19]=2)[C:6]2[N:7]([C:9]([CH2:12][CH3:13])=[CH:10][CH:11]=2)[N:8]=1)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCOC(=O)CCCCc1c(CN)nn2c(CC)ccc2c1-c1cncc(C)c1
Reactant: O=C(O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCc1c(CNC(=O)c2ccccc2)nn2c(CC)ccc2c1-c1cncc(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.3 %

Procedure:
A mixture of ethyl 5-[2-(aminomethyl)-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate (75 mg), benzoic acid (27.9 mg), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (54.7 mg) and 1-hydroxybenotriazole (38.5 mg) in dimethylformamide (2 mL) was stirred at ambient temperature for 2 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with saturated sodium bicarbonate solution, water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by preparative silica gel column chromatography eluting with a mixture of chloroform and methanol (20:1) to give ethyl 5-[2-[(benzoylamino)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate as yellow oil (60 mg).