Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][CH:21]=[CH:20]3)=[CH:11][CH:10]=1.[BH3-]C#N.[Na+].C([O-])(O)=O.[Na+]>CC(O)=O>[F:27][C:2]([F:1])([F:26])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][CH2:21][CH2:20]3)=[CH:13][CH:14]=1
Reactant: FC(F)(F)c1ccccc1-c1ccc(CCc2ccc3[nH]ccc3c2)cc1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: FC(F)(F)c1ccccc1-c1ccc(CCc2ccc3c(c2)CCN3)cc1
Reaction time: 1 h
Yield: 75.4 %

Procedure:
The product of Step C (0.24 g, 0.65 mmol) was dissolved in AcOH (2 ml) and NaCNBH3 (0.082 g, 1.3 mmol) was added in portions. The mixture was stirred for 1 h and then poured into an aqueous solution of NaHCO3 and extracted with EtOAc (50 ml). The organic layer was separated, dried over MgSO4 and filtered. The filtrate was evaporated to dryness and the residue was purified by FCC (SiO2) to give the desired product (0.18 g, 75%), as pale paste. 1H-NMR (CDCl3) 2.81-2.94 (m, 4H); 3.0 (tr, 2H, J=7.22 Hz); 3.54 (tr, 2H, J=8.35 Hz); 6.58 (d, 1H, J=7.83 Hz); 6.84 (d, 1H, J=7.82 Hz); 6.9 (b, 1H); 7.17-7.21 (m, 3H); 7.31-7.35 (m, 2H); 7.43 (tr, 1H, J=7.65 Hz); 7.54 (tr, 1H, J=7.37 Hz); 7.72 (d, 1H, J=7.78 Hz).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH2:7]/[N:8]=[CH:9]/[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:19]=[C:20](/[CH:24]=[C:25](/[C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)\[C:26]#[N:27])[CH:21]=[CH:22][CH:23]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:24]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([Cl:17])[CH:19]=2)[C:25]([C:28]2[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=2)([C:26]#[N:27])[CH:9]([CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)[NH:8]1)=[O:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C/N=C/C1CCCCC1
Reactant: N#C/C(=C\c1cccc(Cl)c1)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C1NC(C2CCCCC2)C(C#N)(c2ccc(Cl)cc2)C1c1cccc(Cl)c1
Yield: 37.3 %

Procedure:
In a manner similar to the method described in Example 1c, {[1-cyclohexyl-meth-(E)-ylidene]-amino}-acetic acid tert-butyl ester prepared in Example 50a (1.2 g, 5.3 mmol) was reacted with (Z)-3-(3-chloro-phenyl)-2-(4-chloro-phenyl)-acrylonitrile (1 g, 3.7 mmol) prepared in Example 1b, AgF (1.5 g, 12 mmol), and triethylamine (2 g, 20 mmol) in dichloromethane (100 mL) at room temperature for 20 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-cyclohexyl-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (0.69 g, 38%).
Reaction SMILES: [Cl-].[Cl-].[Ca+2].FC1C=CC(N)=C(N)C=1.[F:13][C:14]1[C:20]([F:21])=[CH:19][C:17]([NH2:18])=[C:16]([N+:22]([O-])=O)[CH:15]=1>CCO.O.[Zn]>[F:13][C:14]1[C:20]([F:21])=[CH:19][C:17]([NH2:18])=[C:16]([NH2:22])[CH:15]=1
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Agent: Nc1ccc(F)cc1N
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: Nc1cc(F)c(F)cc1N

Procedure:
4,5-Difluoro-1,2-diaminobenzene was prepared using an adaptation of the method of Tsuji et al., (Tsuji, Y. et al., J. Org. Chem. 55:580 (1990)). Zn powder (942 mg, 14.4 mmol), CaCl2 (94.4 mg), H2O (1.0 mL) and 4.0 mL EtOH were combined and brought to reflux as described for 4-fluoro-1,2-diaminobenzene (see Example 11) and to this mixture was added slowly dropwise a solution of 4,5-difluoro-2-nitroaniline (200 mg, 1.15 mmol) in 2 mL EtOH. Analysis and workup were as described for 4-fluoro-1,2-diaminobenzene (Example 11) except that the reaction was dissolved in 5 mL H2O and the solution extracted with 3×10 mL Et2O. The organic layers were combined and treated with activated charcoal, dried (MgSO4) and filtered through a pad of Celite. The solvent was evaporated at reduced pressure to yield 111.5 mg (67.3%) of a brown crystalline solid. 1H NMR (CDCl3) δ3.34 (br s, 4H, NH2), 6.53 (t, 2H, ArH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].C([Li])CCCCC.[Cl:16][CH2:17][C:18](Cl)=[O:19]>[Cl-].[Zn+2].[Cl-].[Cu]Cl.C1COCC1>[Cl:16][CH2:17][C:18]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[F:8])=[O:19]
Reactant: Fc1ccccc1F
Reactant: O=C(Cl)CCl
Agent: Cl[Cu]
Agent: [Cl-]
Agent: [Li]CCCCCC
Solvent: C1CCOC1
Product: O=C(CCl)c1cccc(F)c1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
To a 5 L 4-necked round bottom flask was charged 1,2-difluorobenzene (130.0 g) and dry THF (1.3 L). This solution was cooled to <−60 while stirring under nitrogen. To this was added n-hexyllithium (455 mL of 2.5 M/hexane) dropwise such that T<−60 (˜15 minute addition). The solution quickly turned into a stirrable slurry, which was aged for 1 hour cold. To this was added zinc chloride (2.3 L of 0.5 M/THF) such that T<−60 and the slurry quickly became a homogeneous solution. This was warmed to 0° C. followed by the addition of copper(I) chloride (11.3 g) and chloroacetyl chloride (142 g) such that T<5° C. The reaction was assayed after 20 minutes and judged complete by HPLC. The reaction was quenched with 1N HCl (2 L) and then the two phase system was transferred to a separatory funnel and diluted with IPAc (2 L). The aqueous was cut and the organic washed again with 1N HCl (2 L) followed by 1N NH4OH (2×2 L) and finally with water (2 L). The organic was concentrated to an oil. Assay yield=78%. The oil is then diluted with heptane (800 mL—does not all go into solution) and stirred while cooling to −30° C. During cooling the oil turns over to a crystalline solid. The slurry is aged 1 hour at −30° C., filtered and washed with cold heptane. Desired product isolated in 71% yield (154 g).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[C:4]([F:25])[CH:3]=1.[O:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31].C(=O)([O-])[O-].[K+].[K+].CNCCNC>[Cu]I.O.C1(C)C=CC=CC=1>[CH3:23][C:22]1[C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:9]([C:5]3[C:6]([F:8])=[CH:7][C:2]([N:28]4[CH2:29][CH2:30][O:26][C:27]4=[O:31])=[CH:3][C:4]=3[F:25])=[O:10])[CH2:12][CH2:13]2)=[N:18][CH:19]=[C:20]([CH3:24])[CH:21]=1
Reactant: O=C1NCCO1
Reactant: Cc1cnc(N2CCN(C(=O)c3c(F)cc(Br)cc3F)CC2)c(C)c1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cnc(N2CCN(C(=O)c3c(F)cc(N4CCOC4=O)cc3F)CC2)c(C)c1
Yield: 55.1 %

Procedure:
To a mixture of (4-bromo-2,6-difluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (410 mg) described in Preparation Example 60, oxazolidin-2-one (87 mg), potassium carbonate (277 mg) and copper (I) iodide (95.8 mg) were added toluene (1 mL) and N,N′-dimethylethylenediamine (101 μL), and the mixture was refluxed for 8 hr. Water was added to the reaction mixture, the mixture was extracted with chloroform, and the solvent was evaporated. The residue was purified by column chromatography (chloroform:methanol) to give the title compound (229.3 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[C@@H:15]1(N)[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]1N.CC(C)([O-])C.[Na+]>O1CCOCC1.[Cu](I)I>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][N:14]=2)=[CH:6][CH:7]=1
Reactant: Brc1ccc(Nc2ncccn2)cc1
Reactant: N[C@@H]1CCCC[C@H]1N
Agent: I[Cu]I
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Brc1ccc(N(c2ccccc2)c2ncccn2)cc1
Temperature: 110 °C
Reaction time: 22 h

Procedure:
Under an argon atmosphere, a suspension of N-(4-bromophenyl)pyrimidin-2-amine (250 mg), copper iodide (1.9 mg), trans-1,2-cyclohexanediamine (0.015 ml) and sodium-tert-butoxide (144 mg) in dioxane (1 ml) was stirred at 110° C. for 22 hours in a pressure-resistant test tube. The reaction solution was filtered and the filtrate was concentrated. The residue was purified by thin layer chromatography (silica gel, mobile phase: chloroform/ethyl acetate=5/1) to obtain N-(4-bromophenyl)-N-phenylpyrimidin-2-amine (56 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[C:7]([CH3:34])([CH3:33])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([C:22]([O:24]CC2C=CC=CC=2)=[O:23])=[C:18]([F:32])[CH:17]=1)([CH3:4])([CH3:3])[CH3:2]>O.O1CCCC1.[C].[Pd]>[C:1]([O:5][C:6](=[O:35])[C:7]([CH3:34])([CH3:33])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([C:22]([OH:24])=[O:23])=[C:18]([F:32])[CH:17]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C(C)(C)COc1ccccc1-c1ccc(C(=O)OCc2ccccc2)c(F)c1
Agent: [Pd]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C)(C)COc1ccccc1-c1ccc(C(=O)O)c(F)c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 68.8 %

Procedure:
To a mixed solvent solution of benzyl 2′-(3-tert-butoxy-2,2-dimethyl-3-oxopropoxy)-3-fluorobiphenyl-4-carboxylate (15.0 g) in water (75 ml) and tetrahydrofuran (300 ml) was added 10% palladium carbon (4.50 g), followed by stirring at room temperature for 7 hours under a hydrogen atmosphere. The reaction solution was filtered through Celite, and washed with methanol, and then the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 2′-(3-tert-butoxy-2,2-dimethyl-3-oxopropoxy)-3-fluorobiphenyl-4-carboxylic acid (8.38 g).
Reaction SMILES: [CH3:1][NH:2][CH3:3].Br[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)=[O:7]>C(Cl)Cl>[CH3:1][N:2]([CH3:3])[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)=[O:7]
Reactant: CNC
Reactant: O=C(CBr)c1ccc(Cl)cc1
Solvent: ClCCl
Product: CN(C)CC(=O)c1ccc(Cl)cc1
Temperature: 20 °C
Yield: 99 %

Procedure:
To 66 g (1460 mmole) of anhydrous dimethylamine in 200 ml of methylene chloride and cooled to -30° C. was added a solution of 155 g (664 mmole) of 2-bromo-4'-chloroacetophenone in 200 ml of methylene chloride. After the addition was complete the reaction was allowed to warm to 20° C. Concentration in vacuo, partitioning between diethyl ether and 1M aqueous sodium hydroxide, washing with brine, drying over anhydrous magnesium sulfate, and reconcentration in vacuo gives 130 g of the title compound, an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[N:15]([CH2:19][CH2:20][O:21][CH3:22])[C:16]([CH3:18])=[N:17][C:13]=2[CH:12]=[C:11]([C:23]([OH:25])=O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:27][NH:28][CH3:29].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[CH2:1]([O:8][C:9]1[C:14]2[N:15]([CH2:19][CH2:20][O:21][CH3:22])[C:16]([CH3:18])=[N:17][C:13]=2[CH:12]=[C:11]([C:23]([N:28]([CH3:29])[CH3:27])=[O:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCn1c(C)nc2cc(C(=O)O)cc(OCc3ccccc3)c21
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCn1c(C)nc2cc(C(=O)N(C)C)cc(OCc3ccccc3)c21
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.2 %

Procedure:
A mixture of 7-(benzyloxy)-1-(2-methoxyethyl)-2-methyl-1H-benzimidazole-5-carboxylic acid (520 mg, 1.53 mmol, Step 5 of Example 1), dimethylamine hydrochloride (374 mg, 4.58 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (498 mg, 2.60 mmol), 1-hydroxybenzotriazole hydrate (413 mg, 3.06 mmol), and triethylamine (0.64 mL, 4.58 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 1 day. The mixture was poured onto water, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane/methanol (10:1) to afford the title compound as a white solid (524 mg, 93%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:14]2[CH:15]=[N:16][C:17]([N:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)=[N:18][CH:19]=2)([CH3:13])[C:9](OC)=[O:10])=[CH:4][CH:3]=1.[Li+].[BH4-]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:14]2[CH:15]=[N:16][C:17]([N:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)=[N:18][CH:19]=2)([CH3:13])[CH2:9][OH:10])=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(c1ccc(F)cc1)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(C(C)(CO)c3ccc(F)cc3)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
To a mixture of tert-butyl 4-(5-(2-(4-fluorophenyl)-1-methoxy-1-oxopropan-2-yl)pyrimidin-2-yl)piperazine-1-carboxylate (0.4 g, 0.9 mmol) in THF (10 mL) was added LiBH4 (40 mg, 1.8 mmol). After stirred at RT for 2 h, the reaction was quenched by aq. NH4Cl and extracted with EA. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was passed a column (silica gel, PE:EA=1:1) to afford the title compound (225 mg, 60%) as a yellow solid. MS (ES+) C22H29FN4O3 requires: 416. found: 417 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][N:12]=1)[C:7]([OH:9])=O)[CH3:2].C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[CH:26]([NH:29][CH:30]([CH3:32])[CH3:31])([CH3:28])[CH3:27].C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][N:12]=1)[C:7]([N:29]([CH:30]([CH3:32])[CH3:31])[CH:26]([CH3:28])[CH3:27])=[O:9])[CH3:2]
Reactant: CC(C)NC(C)C
Reactant: CCOc1cc(C(=O)O)ccn1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)N(C(C)C)C(C)C)ccn1
Reaction time: 2 h

Procedure:
To a solution of 2-ethoxyisonicotinic acid (20 g, 120 mmol) in CH2Cl2 (500 mL) was added oxalyl chloride (10.4 mL) followed by one drop of DMF. The solution was stirred for 2 hr then triethylamine (33.4 mL, 239 mmol) and diisopropyl amine (25 mL, 179 mmol) were added dropwise. The solution was allowed to stir for 12 hr then worked up with CH2Cl2 and sat. NaHCO3. The crude mixture was purified by silica gel chromatography (100% hexanes to 100% EtOAc) to afford the title compound.
Reaction SMILES: C([Zn]CC)C.C(OC(=O)CC)(=O)CC.C1(=O)CCCC=C1.S(=O)(=O)(O)O.C([O:31][C:32]1[CH2:37][CH2:36][CH2:35][CH:34]([CH2:38][CH3:39])[CH:33]=1)(=O)CC>C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Cu+2].C1(C)C=CC=CC=1>[CH2:38]([CH:34]1[CH2:35][CH2:36][CH2:37][C:32](=[O:31])[CH2:33]1)[CH3:39]
Reactant: CCC(=O)OC1=CC(CC)CCC1
Agent: [Cu+2]
Agent: CCC(=O)OC(=O)CC
Agent: CC[Zn]CC
Solvent: Cc1ccccc1
Product: CCC1CCCC(=O)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 75 %

Procedure:
Placed in a 50-mL four-necked flask equipped with a stirrer, thermometer and dropping funnel were 36.2 mg (0.1 mmol) of Cu(OTf)2, 10 g of toluene and 87.1 mg (0.2 mmol) of the ligand, and the inner atmosphere was replaced with nitrogen. After replacement with nitrogen, the mixture was stirred at 25° C. for 20 min. Then, 16 mL (17.6 mmol) of a toluene solution (1.1 mol/L) of diethylzinc was added to the mixture at 25° C., followed by further stirring for 10 min. The mixture was then cooled to −17° C., followed by addition of 1.43 g (11 mmol) of propionic anhydride, and 0.96 g (10 mmol) of 2-cyclohexenone was added dropwise to the mixture over the period of 1 hour. After completion of the dropwise addition, stirring was continued at the same temperature for 6 hours. After the reaction was completed, 34.5 g of a 5% aqueous sulfuric acid solution as cooled to 0° C. was added to the reaction solution for quenching. After separation, the organic layer was washed (5 times), and the resultant organic layer was concentrated under reduced pressure to give 1.58 g of a crude product. The crude product was purified by silica-gel column chromatography to produce 1.37 g (7.5 mmol), 75% yield, of 3-ethyl-1-cyclohexene-1-yl propionate. A portion of the compound was hydrolyzed by the conventional method to give 3-ethylcyclohexanone, which was then subjected to determination of optical purity and identified as the (R) isomer with 34.0% ee of optical purity.
Reaction SMILES: C(#N)C.C(=O)([O-])[O-].[Na+].[Na+].[NH2:10][C:11]1[CH:16]=[C:15]([NH:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[C:14](Br)=[CH:13][N:12]=1.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:10][C:11]1[CH:16]=[C:15]([NH:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[C:14]([C:37]2[CH:38]=[CH:39][C:34]([O:33][CH3:32])=[CH:35][CH:36]=2)=[CH:13][N:12]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(N)ncc2Br)CC1
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: COc1ccc(-c2cnc(N)cc2NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 150 °C
Yield: 39.7 %

Procedure:
Acetonitrile (1212 μL) and 0.5M sodium carbonate solution (0.36 mL, 1.5 eq) were added to tert-butyl 4-(2-amino-5-bromopyridin-4-ylamino)piperidine-1-carboxylate (45 mg, 0.121 mmol), 4-methoxyphenylboronic acid (27.6 mg, 0.182 mmol), and tetrakis(triphenylphosphine)palladium(0) (7.00 mg, 6.06 μmol) in a microwave vial (0.5 mL). The capped vial was heated to 150° C. by microwave irradiation for 20 min. After cooling the solution was diluted with MeOH and purified by ion exchange on SCX-II acidic resin (2 g) column, eluting with MeOH then 2M ammonia in MeOH. The basic fractions were combined and concentrated. The crude product was dissolved in dichloromethane and loaded onto a Biotage SNAP silica column (10 g) which was eluted with a gradient of MeOH/NH3 (99/1) in dichloromethane to give tert-butyl 4-(2-amino-5-(4-methoxyphenyl)pyridin-4-ylamino)piperidine-1-carboxylate (19 mg, 0.048 mmol, 39%) as a colourless foam.
Reaction SMILES: [CH2:1]([C:4]1[CH2:5][CH:6]([OH:10])[CH2:7][C:8]=1[CH3:9])[CH:2]=[CH2:3].N1C=CC=CC=1.[CH3:17][C:18]1([CH3:28])[C@H:20]([CH:21]=[C:22]([CH3:24])[CH3:23])[C@H:19]1[C:25](Cl)=[O:26]>C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.C1(C)C=CC=CC=1>[CH3:17][C:18]1([CH3:28])[C@H:20]([CH:21]=[C:22]([CH3:23])[CH3:24])[C@H:19]1[C:25]([O:10][CH:6]1[CH2:7][C:8]([CH3:9])=[C:4]([CH2:1][CH:2]=[CH2:3])[CH2:5]1)=[O:26]
Reactant: C=CCC1=C(C)CC(O)C1
Reactant: CC(C)=C[C@@H]1[C@@H](C(=O)Cl)C1(C)C
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: C=CCC1=C(C)CC(OC(=O)[C@@H]2[C@@H](C=C(C)C)C2(C)C)C1
Yield: 74 %

Procedure:
To a mixture of (RS)-3-(2-propenyl)-4-methyl-3-cyclopenten-1-ol (190 mg), 2,6-di-tert-butyl-4-methylphenol (5 mg), pyridine (140 mg) and toluene (10 ml), (1R)-trans-2,2-dimethyl-3-(2-methyl-1-propenyl)-cyclopropanecarbonyl chloride was added under ice-cooling. The resulting reaction mixture was further allowed to react for 8 hours at room temperature. Then the reaction mixture was subjected to the same post-treatment as in Example 1 to afford 295 mg of (RS)-3-(2-propenyl)-4-methyl-3-cyclopenten-1-yl (1R)-trans-2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropanecarboxylate (Compound No. 40). Yield 74% nD25 1.4891
Reaction SMILES: [N+:1]([C:4]1[C:8]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=2[OH:19])=[CH:7][N:6]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[N:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[Cl:32][C:33]1[C:34](F)=[CH:35][C:36]([F:59])=[C:37]([S:39]([N:42]([CH2:48][C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][C:50]=2[O:57][CH3:58])[C:43]2[S:44][CH:45]=[N:46][N:47]=2)(=[O:41])=[O:40])[CH:38]=1>CS(C)=O.C(OCC)(=O)C>[Cl:32][C:33]1[C:34]([O:19][C:10]2[CH:11]=[CH:12][C:13]([C:15]([F:17])([F:18])[F:16])=[CH:14][C:9]=2[C:8]2[C:4]([N+:1]([O-:3])=[O:2])=[N:5][N:6]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][O:21]3)[CH:7]=2)=[CH:35][C:36]([F:59])=[C:37]([S:39]([N:42]([CH2:48][C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][C:50]=2[O:57][CH3:58])[C:43]2[S:44][CH:45]=[N:46][N:47]=2)(=[O:40])=[O:41])[CH:38]=1
Reactant: O=[N+]([O-])c1nn(C2CCCCO2)cc1-c1cc(C(F)(F)F)ccc1O
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(C(F)(F)F)cc3-c3cn(C4CCCCO4)nc3[N+](=O)[O-])cc2F)c(OC)c1
Reaction time: 0.17 h
Yield: 69.3 %

Procedure:
To a solution of 2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]-4-(trifluoromethyl)phenol (Preparation 868, 2.069 g, 5.791 mmol) in dimethyl sulfoxide (34 mL) was added potassium carbonate (1.66 g, 12.0 mmol). After stirring for 10 minutes, 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide (Preparation 247, 2.67 g, 5.78 mmol) was added. After stirring at room temperature for 16 hours, the reaction solution was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. Purification by automated flash column chromatography using a 0-100% ethyl acetate/hexanes gradient and a 40 g column gave the title compound (3.20 g, 69%) as a clear oil.
Reaction SMILES: [OH-].[Li+].O.[CH:4](=[C:6]1[CH2:15][N:14]2[C@H:8]([CH:9]=[N:10][C:11]3[CH:20]=[C:19]([O:21][CH2:22][C:23]4[CH:28]=[C:27]([O:29][CH2:30][CH2:31][N:32]([CH3:60])[CH2:33][C:34]([S:37][CH2:38][C:39]([NH:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][O:53][CH2:54][CH2:55][C:56]([O:58]C)=[O:57])=[O:40])([CH3:36])[CH3:35])[CH:26]=[C:25]([CH2:61][O:62][C:63]5[C:79]([O:80][CH3:81])=[CH:78][C:66]6[C:67](=[O:77])[N:68]7[CH2:74][C:73](=[CH:75][CH3:76])[CH2:72][C@H:69]7[CH:70]=[N:71][C:65]=6[CH:64]=5)[N:24]=4)[C:18]([O:82][CH3:83])=[CH:17][C:12]=3[C:13]2=[O:16])[CH2:7]1)[CH3:5].P([O-])([O-])([O-])=O>C1COCC1.C(Cl)Cl>[CH:75](=[C:73]1[CH2:74][N:68]2[C@H:69]([CH:70]=[N:71][C:65]3[CH:64]=[C:63]([O:62][CH2:61][C:25]4[CH:26]=[C:27]([O:29][CH2:30][CH2:31][N:32]([CH3:60])[CH2:33][C:34]([S:37][CH2:38][C:39]([NH:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][O:53][CH2:54][CH2:55][C:56]([OH:58])=[O:57])=[O:40])([CH3:35])[CH3:36])[CH:28]=[C:23]([CH2:22][O:21][C:19]5[C:18]([O:82][CH3:83])=[CH:17][C:12]6[C:13](=[O:16])[N:14]7[CH2:15][C:6](=[CH:4][CH3:5])[CH2:7][C@H:8]7[CH:9]=[N:10][C:11]=6[CH:20]=5)[N:24]=4)[C:79]([O:80][CH3:81])=[CH:78][C:66]=3[C:67]2=[O:77])[CH2:72]1)[CH3:76]
Reactant: CC=C1C[C@H]2C=Nc3cc(OCc4cc(OCCN(C)CC(C)(C)SCC(=O)NCCOCCOCCOCCOCCC(=O)OC)cc(COc5cc6c(cc5OC)C(=O)N5CC(=CC)C[C@H]5C=N6)n4)c(OC)cc3C(=O)N2C1
Agent: O=P([O-])([O-])[O-]
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC=C1C[C@H]2C=Nc3cc(OCc4cc(OCCN(C)CC(C)(C)SCC(=O)NCCOCCOCCOCCOCCC(=O)O)cc(COc5cc6c(cc5OC)C(=O)N5CC(=CC)C[C@H]5C=N6)n4)c(OC)cc3C(=O)N2C1
Reaction time: 2 h
Yield: 64.7 %

Procedure:
17.5 μl of an aqueous lithium hydroxide solution and 100 μl of water are added to 18 mg of methyl 3-{2-[2-(2-{2-[2-(2-([2-(2,6-bis[(S)-2-eth-(E)-ylidene-7-methoxy-1,2,3,11a-tetrahydropyrrolo[2,1-c][1,4]benzodiazepin-5-one-8-yloxymethyl]pyridin-4-yloxy)ethyl](methyl)amino}-1,1-dimethylethylsulphanyl)acetylamino]ethoxy}ethoxy)ethoxy]ethoxy}propanoate in solution in 270 μl of THF. After 2 h, the mixture is diluted in DCM and a phosphate buffer is added to pH=3. The resulting aqueous phase is extracted 3× with DCM, the combined organic phases are dried over MgSO4 and concentrated under RP and the residue is purified by flash chromatography on silica (Interchrom Puriflash Silica 15/35U 2G) using a gradient from 3 to 15% of methanol in DCM. 11.5 mg of 3-{2-[2-(2-{2-[2-(2-{[2-(2,6-bis[(S)-2-eth-(E)-ylidene-7-methoxy-1,2,3,11a-tetrahydropyrrolo[2,1-c][1,4]benzodiazepin-5-one-8-yloxymethyl]pyridin-4-yloxy)ethyl](methyl)amino}-1,1-dimethylethylsulphanyl)acetylamino]ethoxy}-ethoxy)ethoxy]ethoxy}propanoic acid are thus obtained. LC/MS (D): rt=0.88 min; [M+H2O+Na]+: m/z 1154; [M+H2O+H]+: m/z 1133; [M+H]+: m/z 1115.