Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[C:3]([OH:11])(=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH2:12]([CH:15](CCCCC)C=O)[CH2:13]C>O>[CH2:13]([CH:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[C:3]([OH:11])=[O:10])[CH2:12][CH3:15]
Reactant: CCCCCC(C=O)CCC
Reactant: CCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCC(CCC)C(=O)O

Procedure:
A reactor was charged with 0.2 g (0.005 mol) of sodium hydroxide (manufactured by Kanto Chemical Co., Inc.), 1 g of water, and 0.8 g (0.006 mol) of heptanoic acid (manufactured by Kishida Chemical Co., Ltd.), and the mixture was stirred. After the addition of 47 g of 2-propylheptanal, the mixture was bubbled with air at 40° C. for 15 hours. The mixture was stirred at 130° C. for 4 hours with nitrogen bubbling to obtain crude 2-propylheptanoic acid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH3:22])=[CH:16][CH:15]=2)[C:5]2[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=2)[N:7]=1.CCOC1C=CC(N)=CC=1.[NH2:33][C@H:34]1[CH2:39][CH2:38][C@H:37]([NH2:40])[CH2:36][CH2:35]1>O>[NH2:33][C@H:34]1[CH2:39][CH2:38][C@H:37]([NH:40][C:2]2[CH:3]=[C:4]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH3:22])=[CH:16][CH:15]=3)[C:5]3[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=3)[N:7]=2)[CH2:36][CH2:35]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: CCOc1ccc(Nc2cc(Cl)nn3c(C#N)cnc23)cc1
Agent: CCOc1ccc(N)cc1
Solvent: O
Product: CCOc1ccc(Nc2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C#N)cnc23)cc1
Reaction time: 1.5 h

Procedure:
In a 2 dram reaction vial was added 6-chloro-8-(4-ethoxyphenylamino)imidazo[1,2-b]pyridazine-3-carbonitrile (0.055 g, 0.017 mmol) from 1c and trans-1,4-diaminocyclohexane (1.0 g, 8.0 mmol). The mixture was allowed to melt at 160° C. for 1.5 hrs. The melt was then cooled, diluted with water and extracted with dichloromethane. The organic layer was concentrated and then diluted with MeOH, and then purified by preparative HPLC to give 0.039 g of the title compound as a TFA salt. 1H NMR (500 MHz, Solvent) δ ppm 7.91 (1H, s), 7.23 (2H, d, J=8.80 Hz), 6.96 (2H, d, J=8.80 Hz), 5.96 (1H, s), 4.04 (4H, q, J=6.78 Hz), 3.61-3.80 (1H, m), 2.99-3.19 (1H, m), 2.16-2.35 (2H, m, J=11.55 Hz), 2.01-2.16 (2H, m, J=12.65 Hz), 1.47-1.65 (2H, m), 1.39 (3H, t, J=7.15 Hz), 1.24-1.36 (2H, m). LC/MS, m/e 392 (M+1). HPLC Rt, 2.69 min. YMC ODSC18 column (4.6×50 mm). 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4 mL/min.
Reaction SMILES: IC1C=C(CS(NC)(=O)=O)C=[CH:4][C:3]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([Si](CC)(CC)C(O)CC#C[Si](CC)(CC)CC)C>CC([O-])=O.CC([O-])=O.[Pd+2].CN(C=O)C>[NH:14]1[C:15]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:4]=[CH:3]1
Reactant: CNS(=O)(=O)Cc1ccc(Nc2ccccc2)c(I)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC[Si](C#CCC(O)[Si](CC)(CC)CC)(CC)CC
Solvent: CN(C)C=O
Product: c1ccc2[nH]ccc2c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 149.9 %

Procedure:
A mixture of 2-iodo-4-(N-(methyl)aminosulphonylmethyl)phenyl aniline (10 g, 30.7 mmol), 1,4-bis-triethylsilyl-3-butyn-1-ol (10.97 g, 36.8 mmol) sodium carbonate (16.26 g, 153.4 mmol) and anhydrous DMF (500 ml) was degassed with N2 for 0.5 h. Pd(OAc)2 (0.7 g, 3.1 mmol) was added and the mixture heated at 100° C. for 6 h. The DMF was removed under vacuum and the residue partitioned between EtOAc (250 ml) and water (250 ml). The solutions were passed through celite to remove insolubles and the aqueous layer separated and extracted further with ethyl acetate (4×200 ml). The combined organics were dried (Na2SO4) and evaporated. The residue was dissolved in methanol (100 ml) and 5N hydrochloric acid (30 ml) was added. The mixture was stirred at room temperature for 2 h and the solvent then removed under vacuum and the residue neutralised with saturated K2CO3 solution. The aqueous was extracted with EtOAc (200 ml) and n-butanol (2×200 ml) and the combined extracts evaporated under vacuum The residue was chromatographed on silica gel eluting with CH2Cl2 /MeOH/NH3 (60:8:1) to give the title-indole (5.39 g, 66%), mp 114-116° C., δ (250 MHz, D6 -DMSO) 2.54 (3H, d, J=4.8Hz, MeNH), 2.83 (2H, t, J=7.5Hz, CH2), 3.60-3.69 (2H, m, CH2 --OH), 4.34 (2H, s, CH2), 4.65 (1H, t, J=5.4Hz, OH), 6.78 (1H, q, J=4.8Hz, MeNH), 7.06 (1H, dd, J=2.2 and 8.3Hz, Ar--H), 7.16 (1H, d, J=2.2Hz, Ar--H), 7.31 (1H, d, J=8.3Hz, Ar--H), 7.51 (1H, s, Ar--H), 10.86 (1H, s, NH).
Reaction SMILES: [Li+].[Cl-].BrCCBr.C[Si](Cl)(C)C.[CH3:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:14]=1[CH2:15]Br.[CH3:22][O:23][C:24](=[O:48])[CH2:25][C@H:26]1[C:30]2[CH:31]=[CH:32][C:33]([O:35][C@H:36]3[C:44]4[C:39](=[C:40](Br)[C:41]([C:45]#[N:46])=[CH:42][CH:43]=4)[CH2:38][CH2:37]3)=[CH:34][C:29]=2[O:28][CH2:27]1.[NH4+].[Cl-]>O1CCCC1.C(C1C=CC=C(C(C)C)C=1N1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C1=[Pd-3](Cl)(Cl)C1C(Cl)=CC=CN=1)(C)C.[Zn]>[CH3:22][O:23][C:24](=[O:48])[CH2:25][C@H:26]1[C:30]2[CH:31]=[CH:32][C:33]([O:35][C@H:36]3[C:44]4[C:39](=[C:40]([CH2:15][C:14]5[C:17]([CH3:21])=[CH:18][CH:19]=[CH:20][C:13]=5[CH3:12])[C:41]([C:45]#[N:46])=[CH:42][CH:43]=4)[CH2:38][CH2:37]3)=[CH:34][C:29]=2[O:28][CH2:27]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C#N)c4Br)ccc21
Reactant: Cc1cccc(C)c1CBr
Agent: CC(C)c1cccc(C(C)C)c1-n1ccn(-c2c(C(C)C)cccc2C(C)C)c1=[Pd-3](Cl)(Cl)c1ncccc1Cl
Agent: C[Si](C)(C)Cl
Agent: [Cl-]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C#N)c4Cc3c(C)cccc3C)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A flask charged with a stir bar and anhydrous LiCl (49 mg) is heated to 180° C. under high vacuum (ca. 1 mbar). After 30 min the flask is cooled to room temperature, filled with Ar, and Zn powder (84 mg) is added under Ar atmosphere. The flask is reevacuated (ca. 1 mbar) and heated to 180° C. After another 30 min the flask is cooled to room temperature and filled with Ar again. Tetrahydrofuran (dry, 0.5 mL) is added and the Zn is activated with 1,2-dibromoethane (2 μL) and trimethylsilyl chloride (1.5 μL) (for comparison see e.g. Synthesis 2009, 681-6). A solution of 2,6-dimethylbenzyl bromide (0.23 g) in tetrahydrofuran (dry, 2 mL) is added dropwise. The mixture is stirred for 30 min prior to addition of {(S)-6-[(R)-4-bromo-5-cyano-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (0.10 g) in tetrahydrofuran (dry, 2 mL) and [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]-(3-chloropyridyl)-palladium(II) dichloride (Pd-PEPPSI-IPr, 20 mg). The mixture is heated to 60° C. and stirred at this temperature overnight. After cooling to room temperature, aqueous NH4Cl solution is added and the resulting mixture is extracted with ethyl acetate. The combined extracts are dried (MgSO4) and concentrated. The residue is purified by HPLC on reversed phase (MeCN/water/NH4OH) to give the title compound. LC (method 4): tR=1.28 min; Mass spectrum (ESI+): m/z=468 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=[C:29]([N:36]2[CH2:40][CH2:39][C:38](F)(F)[CH2:37]2)C2N=NNC=2N=1)(C)(C)C.Br.BrCCC1C=CC=CN=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH2:15][C:40]3[CH:39]=[CH:38][CH:37]=[CH:29][N:36]=3)[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: Br
Agent: BrCCc1ccccn1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(CCc3ccccn3)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(2-bromoethyl)pyridine hydrobromide and isolated as colorless gum. MS (m/e): 388.3 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=C(C(F)(F)F)[O:10][N:9]=2)=[CH:4][CH:3]=1.Cl.NO.[C:20](=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:20][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:9][OH:10])[NH2:12])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(-c2noc(C(F)(F)F)n2)cc1
Agent: Cl
Agent: NO
Agent: [K+]
Solvent: CCO
Product: COc1ccc(C(N)=NO)cc1
Yield: 20 %

Procedure:
3-(4-hydroxyphenyl)-5-trifluoromethyl-1,2,4- oxadiazole 13.32 g (0.1 mol) 4-methoxybenzonitrile, 20.85 g (0.3 mol) of hydroxylamine hydrochloride and 41.40 g (0.3 mol) potassium carbonate was added to 400 mL absolute ethanol and refluxed 21 hours. The product was filtered and recrystallized from methanol to give 3.12 g (0.02 mol) of 4-methoxybenzamide oxime.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.F[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1.[OH-].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[N+:20]([C:17]1[CH:18]=[CH:19][C:14]([O:1][CH:2]2[CH2:3][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5]2)=[CH:15][CH:16]=1)([O-:22])=[O:21]
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(Oc2ccc([N+](=O)[O-])cc2)C1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
Tert-butyl 3-hydroxyazetidine-1-carboxylate (4.0 g, 23.3 mmol), 1-fluoro-4-nitrobenzene (6.1 g, 43.0 mmol), aqueous potassium hydroxide (35.5 ml of a 5.9 M solution, 209 mmol), and tetrabutylammonium bromide (0.975 g, 3.0 mmol) were combined and stirred at 40° C. overnight. The reaction was cooled, diluted with water and extracted three times with ethyl acetate. The combined organics were dried (sodium sulfate), filtered and concentrated. The residue was purified by regular phase flash column chromatography to give the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[NH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.[BH4-].[Na+]>CO.O>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([CH2:11][CH2:10][NH:9][CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH:13]=1
Reactant: NCCc1cccnc1
Reactant: O=Cc1ccncc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: c1cncc(CCNCc2ccncc2)c1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
4-Pyridine carbaldehyde (5.36 g) and 3-(2-aminoethyl)pyridine (6.5 ml) were added to 100 ml of methanol. The mixture was stirred at room temperature for 7 hours. The mixture was cooled to 0° C., and sodium borohydride (2.8 g) was added thereto. The mixture was further stirred at 0° C. for an hour. Water was added to the reaction mixture and methanol was distilled off under reduced pressure. The residue was subjected to extraction using dichloromethane. The organic layer was washed with saturated saline, dried with anhydrous sodium sulfate, and was condensed under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:methanol=95:5→85:5). The purified product was condensed under reduced pressure to give the title compound (10.03 g) as a colorless oily matter.
Reaction SMILES: C[O:2][P:3]([CH2:13][CH:14]([C:19](=[O:30])[NH:20][C@H:21]([C:26](=[O:29])[NH:27][CH3:28])[CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:15][CH:16]([CH3:18])[CH3:17])([CH2:5][N:6]1[C:10](=[O:11])[CH2:9][CH2:8][C:7]1=[O:12])=[O:4].Br[Si](C)(C)C>ClCCl>[CH3:17][CH:16]([CH3:18])[CH2:15][CH:14]([C:19](=[O:30])[NH:20][C@H:21]([C:26](=[O:29])[NH:27][CH3:28])[CH2:22][CH:23]([CH3:24])[CH3:25])[CH2:13][P:3]([CH2:5][N:6]1[C:10](=[O:11])[CH2:9][CH2:8][C:7]1=[O:12])(=[O:2])[OH:4]
Reactant: CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)C)CP(=O)(CN1C(=O)CCC1=O)OC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)C)CP(=O)(O)CN1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.4 %

Procedure:
60 mg of [(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl](succinimidomethyl)phosphinic acid methyl ester were dissolved in 5 ml of dichloromethane, 0.5 ml of bromotrimethylsilane was added and the mixture was stirred at room temperature for 1.5 hours. The solvent was removed by evaporation and the residue was then re-evaporated twice with 20 ml of acetone each time. The residue was dissolved in 5 ml of acetone and 0.25 ml of water. After standing at room temperature for 15 minutes, the solvent was removed by evaporation and the residue was dissolved in 20 ml of acetone/dichloromethane (1:2). The solution was then evaporated to give 56 mg of [(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl](succinimidomethyl)phosphinic acid in the form of a white foam.
Reaction SMILES: [CH2:1]([N:4]([CH2:26][CH2:27][CH3:28])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:10]([C:14](OC)=[O:15])[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].C([NH2:31])=O.C[O-].[Na+].CO.Cl>CN(C=O)C>[CH2:1]([N:4]([CH2:26][CH2:27][CH3:28])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:10]([C:14]([NH2:31])=[O:15])[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3]
Reactant: NC=O
Reactant: CCCN(CCC)C1Cc2cc(OCc3ccccc3)c(C(=O)OC)cc2C1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCCN(CCC)C1Cc2cc(OCc3ccccc3)c(C(N)=O)cc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 2-(dipropylamino)-2,3-dihydro-6-(phenylmethoxy)-1H-indene-5-carboxylate (74, 0.95 g, 2.5 mmol) and formamide (1.1 g, 25 mmol) in DMF (10 mL) at 100° C. was added 25% sodium methoxide in methanol (2.5 mmol, 0.57 mL) dropwise. The mixture stirred for 2 h. The reaction was cooled to rt and quenched with water (100 mL). The resulting precipitate was stirred for 0.5 h and the solvent was removed via filtration. This solid was crystallized from EtOAc/MeOH to give a white solid that was converted into the HCl salt and crystallized from EtOAc/MeOH to give the title compound 78 as a white solid (m.p. 247-248° C.).
Reaction SMILES: [C:1]1(=[O:20])[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=3)=[CH:7][CH:8]=2)[CH2:3][NH:2]1>CCO.[Pd]>[O:20]=[C:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)=[CH:7][CH:8]=2)[CH2:3][NH:2]1
Reactant: O=C1NCc2cc(Oc3ccc([N+](=O)[O-])cc3)ccc21
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(Oc2ccc3c(c2)CNC3=O)cc1

Procedure:
A slurry of 4-(1-isoindolinon-5-yloxy)-1-nitrobenzene (2.12 g, 7.8 mmol) and 10% Pd/C (0.20 g) in EtOH (50 mL) was stirred under an H2 atmosphere (balloon) for 4 h, then filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure to afford 4-(1-oxoisoindolin-5-yloxy)aniline as a dark yellow solid: TLC (100% EtOAc) Rf 0.15.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13](Br)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4].[C:31]([Cu])#[N:32].O.Cl>CN(C=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13]([C:31]#[N:32])[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1nc(Br)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: N#C[Cu]
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1nc(C#N)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 79.1 %

Procedure:
A mixture of 1-benzyl-8-bromo-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (200 mg, 0.43 mmol) and CuCN (77 mg, 0.86 mmol) in 5 mL of DMF was refluxed for 40 min, then cooled to r.t., and poured into a mixture of water and CH2Cl2. 4M HCl was added with vigorous stirring until no more solid was present. The aqueous layer was extracted with additional CH2Cl2 and the combined organic layer was dried over MgSO4. After evaporating the solvent in vacuo, the crude product was chromatographed (0-40% EtOAc/hexanes+2% AcOH) to give 140 mg of the title compound. MS: (+) m/z 412.12 (M+1).
Reaction SMILES: [OH:1][CH:2]([CH3:10])/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:11]1([N:17]=[C:18]=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>C1(C)C=CC=CC=1>[CH:11]1([NH:17][C:18]([O:1][CH:2]([CH3:10])/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C=NC1CCCCC1
Reactant: CCOC(=O)/C=C/C(C)O
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C/C(C)OC(=O)NC1CCCCC1

Procedure:
Reaction of 21 (rac-Ethyl (2E)-4-hydroxypent-2-enoate) (1.44 g, 10 mmol) with cyclohexyl isocyanate (2.53 ml, 20 mmol) in toluene (8 ml) according to Example 1. Purification by flash chromatography (AcOiPr:heptane fraction 15:85 to 25:75) yields 5 (rac-Ethyl (2E)-4-(cyclohexylaminocarbonyloxy)pent-2-enoate) (2.29 g, 85%) as a yellowish solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:9]=1)[C:7]#[N:8].[F:11][C:12]1[CH:17]=[C:16](B(O)O)[CH:15]=[CH:14][N:13]=1.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>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.C(O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:16]2[CH:15]=[CH:14][N:13]=[C:12]([F:11])[CH:17]=2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(Br)ccc1I
Reactant: OB(O)c1ccnc(F)c1
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: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1cc(Br)ccc1-c1ccnc(F)c1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To a sealed tube were added 5-bromo-2-iodobenzonitrile 206-1 (500 mg, 1.6 mmol), 2-fluoropyridin-4-ylboronic acid 205-4 (229 mg, 1.6 mmol), Pd(PPh3)4 (94 mg, 0.08 mmol), Na2CO3 (516 mg, 4.9 mmol), toluene (2 mL), H2O (2 mL) and ethanol (0.5 mL). The reaction mixture was stirred at 120° C. overnight. After cooling to room temperature, the solvents were evaporated and the residue was redissolved in water (5 ml) and extracted with ethyl acetate (8 mL×3). The combined organic phases were dried over Na2SO4, and concentrated. The residue was purified by silica gel flash chromatography and eluted with 15% ethyl acetate in hexane to give 5-bromo-2-(2-fluoropyridin-4-yl)benzonitrile 206-3. MS m/z 277.1 (M+1).
Reaction SMILES: C(O[CH:4]=[C:5]([C:9](=[O:11])[CH3:10])[C:6](=O)[CH3:7])C.Cl.[NH:13]([CH2:15][C:16]([O:18][CH2:19]C)=[O:17])[NH2:14].Cl>CO>[C:9]([C:5]1[CH:4]=[N:14][N:13]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:6]=1[CH3:7])(=[O:11])[CH3:10]
Reactant: CCOC(=O)CNN
Reactant: CCOC=C(C(C)=O)C(C)=O
Agent: Cl
Solvent: CO
Product: COC(=O)Cn1ncc(C(C)=O)c1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 51 %

Procedure:
To a solution of 3-(ethoxymethylene)pentane-2,4-dione (Perkin 1. 2000, 1455-1460, 1.95 g, 12.5 mmol) in MeOH (33 mL) was added a solution of ethyl hydrazinoacetate hydrochloride (2.09 g, 13.5 mmol) and conc.HCl (2.6 ml) in MeOH (10 ml) (pre-cooled to 0° C.) dropwise at −15° C. The resulting mixture was then stirred for 24 hours at room temperature. After removal of the solvent at room temperature, the residue was basified with 2N NaOH aq, and the aqueous layer was extracted several times with EtOAc. The combined organic extracts were dried over Na2SO4, and concentrated in vacuo. The aqueous layer was acidified to pH 1 with 2N HCl aq. and extracted with EtOAc 6 times. The combined organic extracts were dried over Na2SO4, and concentrated in vacuo to give the crude 2-(4-acetyl-5-methyl-1H-pyrazol-1-yl)acetic acid as a mixture of regioisomers (1.17 g, <51% yield). 1H NMR (300 MHz, DMSO-d6) δ 2.37 (3H, s), 2.43 (3H, s), 4.99 (2H, s), 7.81 (1H, s), 13.2 (1H, brs).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][C:11]([O:20][CH3:21])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[CH3:29][N:30]1[C:38]2[CH:37]=[CH:36][CH:35]=[C:34]3[CH2:39][CH2:40][CH2:41][C:32]([CH2:42][CH2:43][CH2:44]CBr)([C:33]=23)[C:31]1=[O:47].C(=O)([O-])[O-].[K+].[K+]>ClCCl.C(OCC)(=O)C.O>[CH3:21][O:20][C:11]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9][N:8]([CH2:6][CH2:44][CH2:43][CH2:42][C:32]23[CH2:41][CH2:40][CH2:39][C:34]4[C:33]2=[C:38]([CH:37]=[CH:36][CH:35]=4)[N:30]([CH3:29])[C:31]3=[O:47])[CH2:13][CH2:12]1
Reactant: CN1C(=O)C2(CCCCBr)CCCc3cccc1c32
Reactant: COC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC1(c2ccccc2)CCN(CCCCC23CCCc4cccc(c42)N(C)C3=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.1 %

Procedure:
1-t-Butoxycarbonyl-4-methoxy-4-phenyl-piperidine (510 mg, 1.7 mmol) was dissolved in dichloromethane (2 ml). Thereto was added trifluoroacetic acid (4 ml), and the resulting solution was stirred at a room temperature for 30 minutes. The reaction solution was diluted with ethyl acetate, washed with sodium hydroxide aqueous solution (1 N) and dried with anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure, and the thus obtained material was dissolved in anhydrous N,N-dimethylformamide (2 ml). Then the resulting solution was mixed with 1-methyl-2a-(4-bromobutyl)-2a,3,4,5-tetrahydrobenz[cd]indole-2(1H) -one (450 mg, 1.4 mmol) and potassium carbonate (290 mg, 2.1 mmol) and stirred at 60° C. for 3 hours. The reaction solution was mixed with ethyl acetate and water, and the reaction product was extracted with ethyl acetate, washed with saturated brine and dried with anhydrous sodium sulfate. Then the compound obtained by the evaporation of the solvent under a reduced pressure was separated and purified by a silica gel column chromatography to obtain 79 mg of the title compound (0.31 mmol, 18% in yield).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[F:9][CH:10](P(=O)(OCC)OCC)[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]2)=[C:13]([O:23][CH3:24])[CH:12]=1.[C:33]([O:38][CH3:39])(=[O:37])[C:34]([CH3:36])=O.O.C(=O)(O)[O-].[Na+]>C1COCC1.C(OCC)(=O)C>[F:9][C:10]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]2)=[C:13]([O:23][CH3:24])[CH:12]=1)=[C:34]([CH3:36])[C:33]([O:38][CH3:39])=[O:37]
Reactant: COC(=O)C(C)=O
Reactant: CCOP(=O)(OCC)C(F)c1ccc(-n2cnc(C)c2)c(OC)c1
Agent: CC(C)[N-]C(C)C
Agent: O=C([O-])O
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(C)=C(F)c1ccc(-n2cnc(C)c2)c(OC)c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 41.5 %

Procedure:
Diethyl (fluoro-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)methyl)phosphonate (1.1 g) was obtained from 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (1 g) in accordance with the method described in Tetrahedron Letters, 1996, vol. 37, no. 5, p. 629. Lithium diisopropylamide (1.5 M solution in THF, 0.25 mL) was added to a solution of the resulting diethyl (fluoro-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)methyl)phosphonate (110 mg) in THF at −78° C., and the reaction solution was stirred at −78° C. for 2 hours. Methyl pyruvate (32 mg) was added to the reaction solution at −78° C. The reaction solution was stirred at −78° C. for 15 minutes, and then further stirred at room temperature for 45 minutes. Saturated sodium bicarbonate water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane:ethyl acetate=1:1->ethyl acetate) to obtain 39 mg of methyl 3-fluoro-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-2-methylacrylate as a mixture of isomers (E) and (Z). Properties data of the compounds are as follows.