Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:6][C:7]1[N:8]=[C:9]([O:34][C:35](=[O:49])[N:36]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:10]2[N:11]=[CH:12][N:13]([C:32]=2[N:33]=1)[C@@H:14]1[O:31][C@H:21]([CH2:22][O:23][Si](C(C)(C)C)(C)C)[C@@H:16]([O:17][CH2:18]SC)[CH2:15]1)(=[O:5])[CH:2]([CH3:4])[CH3:3].C1CCCCC=1.[N-:56]=[N+:57]=[N-:58].[Na+].[NH4+].[F-]>C(Cl)Cl>[C:1]([NH:6][C:7]1[N:8]=[C:9]([O:34][C:35](=[O:49])[N:36]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:10]2[N:11]=[CH:12][N:13]([C:32]=2[N:33]=1)[C@@H:14]1[O:31][C@H:21]([CH2:22][OH:23])[C@@H:16]([O:17][CH2:18][N:56]=[N+:57]=[N-:58])[CH2:15]1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CSCO[C@H]1C[C@H](n2cnc3c(OC(=O)N(c4ccccc4)c4ccccc4)nc(NC(=O)C(C)C)nc32)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Agent: [F-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1=CCCCC1
Solvent: ClCCl
Product: CC(C)C(=O)Nc1nc(OC(=O)N(c2ccccc2)c2ccccc2)c2ncn([C@H]3C[C@H](OCN=[N+]=[N-])[C@@H](CO)O3)c2n1
Reaction time: 1.5 h
Yield: 36 %

Procedure:
To 786 mg 12 (1.1 mmol) dissolved in 8 mL dry CH2Cl2 was treated with 0.56 mL cyclohexene and 180 μL SO2Cl2 (2.2 mmol) at 0° C. and stirred for 1.5 h at the same temperature. The solvent was then removed by rotary evaporation, and further dried under high vacuum for 10 minutes. The crude product was then dissolved in 5 mL dry DMF and reacted with 600 mg NaN3 (10 mmol) at 0° C. and stirred at room temperature for 3 h. Reaction mixture was then partitioned H2O/CH2Cl2, the combined organic extract was then dried over Na2SO4, and concentrated by rotary evaporation. The crude was then dissolved in 5 mL dry MeOH, treated with 500 mg NH4F (13.5 mmol) at room temperature for more than 24 h. Then MeOH solvent was removed by rotary evaporation, and partitioned (H2O/CH2Cl2). The combined organic part was dried over Na2SO4 and concentrated by rotary evaporation and purified by silica gel column chromatography resulting pure product of 14 as white powder (230 mg, ˜36% yield in three steps; hex: EtOAc 1:1 to 1:5, (Rf=˜0.3, Hex:EtOAc/1:4). HR-MS: Obs. m/z 588.2343, calcd for C28H30O6N9 588.2319 [M+H]+. 1H-NMR (DFM-d6): δH 8.64 (brs, 1H), 7.48-7.34 (m, 10H), 6.36 (t, J=7.0 Hz), 4.93 (m, 2H), 4.76 (m, 1H), 4.04 (m, 1H), 3.57 (m, 1H), 3.34 (m, 2H), 2.97 (m, 1H), 2.81 (m, 1H), and 1.10 (m, 6H).
Reaction SMILES: O[CH2:2][N:3]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[N:4]1.S(Cl)([Cl:14])=O>ClCCl>[Cl:14][CH2:2][N:3]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[N:4]1
Reactant: COC(=O)c1cnn(CO)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1cnn(CCl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.38 g of 1-(hydroxymethyl)-4-methoxycarbonyl-1H-pyrazole was dissolved to 10 ml of dichloromethane. 1 ml of thionyl chloride was added to the solution, followed by stirring at room temperature for overnight. The reaction mixture was concentrated under reduced pressure to obtain 1.59 g of 1-(chloromethyl)-4-methoxycarbonyl-1H-pyrazole.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=O)[CH3:16])[C:10]=2[OH:18])[CH:5]=[CH:6][C:7]=1[F:8].[NH:19]([C:21]([NH:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1)=[S:22])[NH2:20].CN(C)C=O>Cl.O>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=[N:20][NH:19][C:21]([NH:23][C:24]3[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)=[S:22])[CH3:16])[C:10]=2[OH:18])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(=O)c1nn(C)c(-c2ccc(F)c(Br)c2)c1O
Reactant: NNC(=S)Nc1ccc(C(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(=NNC(=S)Nc1ccc(C(=O)O)cc1)c1nn(C)c(-c2ccc(F)c(Br)c2)c1O
Yield: 73.6 %

Procedure:
1-[5-(3-Bromo-4-fluorophenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethanone (0.139 mmol, 43.6 mg) and 4-hydrazinocarbonothioylaminobenzoic acid (0.139 mmol, 29.4 mg) were stirred with dimethylformamide (2.5 mL) and three drops of concentrated hydrochloric acid at room temperature for 24.5 hours. After addition of water, the precipitated yellow solid was recovered by filtration, washed with water and dried by means of a vacuum pump. The resulting solid was stirred with chloroform/n-hexane for a while, then recovered by filtration and dried by means of a vacuum pump to give the desired product as a yellow solid (51.8 mg, yield 74%).
Reaction SMILES: [C:1]1([CH3:29])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[O:9][C:10]1[C:11]2[N:27]([CH3:28])[CH:26]=[CH:25][C:12]=2[N:13]=[C:14]([NH:16][C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)[N:15]=1.C1C(=O)N([Cl:37])C(=O)C1>C(Cl)Cl>[Cl:37][C:25]1[C:12]2[N:13]=[C:14]([NH:16][C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=3)[N:15]=[C:10]([O:9][C:2]3[C:1]([CH3:29])=[CH:6][C:5]([CH3:7])=[CH:4][C:3]=3[CH3:8])[C:11]=2[N:27]([CH3:28])[CH:26]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cc(C)c(Oc2nc(Nc3ccc(C#N)cc3)nc3ccn(C)c23)c(C)c1
Solvent: ClCCl
Product: Cc1cc(C)c(Oc2nc(Nc3ccc(C#N)cc3)nc3c(Cl)cn(C)c23)c(C)c1
Yield: 16.3 %

Procedure:
To a solution of 4-(4-(mesityloxy)-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-2-ylamino)benzonitrile (17.3 mg, 0.05 mmol) in CH2Cl2 (5 mL) was added NCS (6.03 mg, 0.05 mmol) and the resultant mixture was refluxed for 16 h. After completion of the reaction, the solvent was concentrated and purified by preparative TLC, eluting with hexanes:ethyl acetate (3:1), to give the product as an off-white solid (3.4 mg, 6%).
Reaction SMILES: [N+:1]([CH2:4][CH:5]([C:7]1[CH:8]=[N:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=1)[OH:6])([O-])=O.C1COCC1.C([O-])=O.[NH4+]>[Pd].CO>[NH2:1][CH2:4][CH:5]([C:7]1[CH:8]=[N:9][C:10]([C:13]([F:16])([F:14])[F:15])=[CH:11][CH:12]=1)[OH:6]
Reactant: O=[N+]([O-])CC(O)c1ccc(C(F)(F)F)nc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: NCC(O)c1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.9 %

Procedure:
In a 250 mL round-bottomed flask, 2-nitro-1-(6-(trifluoromethyl)pyridin-3-yl)ethanol (2.4 g, 10.2 mmol) was combined with THF (40 ml) and methanol (40.0 ml) to give a colorless solution and placed under N2 atmosphere. 360 mg of 10% Pd/C was added. Ammonium formate (3.2 g, 50.8 mmol) was added. The reaction mixture was stirred at room temperature overnight. Complete by LCMS. The reaction mixture was purged with N2 and then filtered through Celite. The Celite filtercake was washed several times with methanol. The combined washes and filtrate was concentrated in vacuo. The residue was taken up in dichloromethane/0.01% NaOH and extracted 5 times with dichloromethane. The organic layers were dried over Na2SO4 and concentrated in vacuo. Product was still present in the aqueous phase so saturated NaCl was added to the aqueous phase and the aqueous phase was extracted 3 times with dichloromethane. The organic layers were dried over Na2SO4 and concentrated in vacuo. The combine product as a pale yellow solid was triturated with ether to get an off-white powder which was washed twice with ether/hexanes to afford 2-amino-1-(6-(trifluoromethyl)pyridin-3-yl)ethanol (1.05 g). (M+H)+=207 m/e. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.76 (dd, J=12.84, 7.93 Hz, 1H) 3.15 (dd, J=12.84, 3.78 Hz, 1H) 4.75 (dd, J=8.12, 3.97 Hz, 1H) 7.69 (d, J=8.31 Hz, 1H) 7.93 (dd, J=8.12, 1.70 Hz, 1H) 8.71 (d, J=1.51 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[S:9][C:8]([Cl:11])=[N:7][C:6]=2[C:5]([Cl:12])=[CH:4][C:3]=1[F:13].[N:14]([O-])=O.[Na+].[Sn](Cl)Cl.[OH-].[Na+]>Cl.O>[Cl:11][C:8]1[S:9][C:10]2[C:2]([NH:1][NH2:14])=[C:3]([F:13])[CH:4]=[C:5]([Cl:12])[C:6]=2[N:7]=1
Reactant: Nc1c(F)cc(Cl)c2nc(Cl)sc12
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1c(F)cc(Cl)c2nc(Cl)sc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
14.7 g 7-amino-2,4-dichloro-6-fluorobenzothiazole was dissolved in 128 ml concentrated hydrochloric acid and the mixture stirred for 30 minutes at room temperature. It was then cooled to -5° C. and, very slowly, a solution of 4.5 g sodium nitrite in 9.5 ml water was added, dropwise. The mixture was stirred for one hour and cooled to -15° C. At this temperature, a solution of 31.5 g tin (II) chloride in 19 ml concentrated hydrochloric acid was added, dropwise at a rate that the temperature did not rise above -8° C. The mixture was stirred for one hour, made alkaline using caustic soda, whilst cooling, and extracted with dichloromethane. The extract was dried over magnesium sulfate and concentrated. Yield: 7.8 g=50% of theory m.p.: 162°-180° C.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH2:12]([NH2:16])[CH2:13][CH2:14][CH3:15]>CO>[CH2:12]([NH:16][C:1](=[O:10])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCN
Reactant: COC(=O)c1ccccc1O
Solvent: CO
Product: CCCCNC(=O)c1ccccc1O
Yield: 79 %

Procedure:
10.0 g (65.7 mmol) of methyl salicylate and 33 ml of n-butylamine were dissolved in 100 ml of methanol, followed by heating at reflux for 8 hours while stirring. Methanol was distilled off under reduced pressure, and the residue was acidified by adding an aqueous 2 N hydrochloric acid, followed by extraction with dichloromethane. The organic layer was washed in turn with water and saturated sodium hydrogen carbonate, and then dried over anhydrous magnesium sulfate. The organic layer was filtered, and the filtrate was concentrated under reduced pressure, and then the resulting residue was purified by silica gel column chromatography (eluant hexane/ethyl acetate=10/1 to 5/1) to obtain 10.0 g (yield: 79%) of salicylic acid n-butylamide as an oily substance. 1H—NMR spectrum data of salicylic acid n-butylamide are as follows.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11]1=[O:19])[CH2:7][CH2:8][CH3:9])[CH3:2].[CH3:21][C:22]1[N:30]2[C:25]([C:26]([CH3:31])=[CH:27][CH:28]=[CH:29]2)=[C:24]([CH2:32][N+](C)(C)C)[CH:23]=1.[I-].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:32][C:24]2[CH:23]=[C:22]([CH3:21])[N:30]3[C:25]=2[C:26]([CH3:31])=[CH:27][CH:28]=[CH:29]3)[C:11]1=[O:19])[CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: Cc1cccn2c(C)cc(C[N+](C)(C)C)c12
Reactant: CCCC(CC(=O)OCC)n1c(=O)[nH]c2ccccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(CC(=O)OCC)n1c(=O)n(Cc2cc(C)n3cccc(C)c23)c2ccccc21
Yield: 26 %

Procedure:
To a solution of 3-(2-Oxo-2,3-dihydro-benzimidazol-1-yl)-hexanoic acid ethyl ester (50 mg, 0.18 mmol) in DMF (10 mL) were added (3,8-Dimethyl-indolizin-1-ylmethyl)-trimethyl-ammonium; iodide, CAS: (3,8-Dimethyl-indolizin-1-ylmethyl)-trimethyl-ammonium; iodide (93.4 mg, 0.27 mmol) and K2CO3 (75 mg, 0.54 mmol) at room temperature under nitrogen atmosphere. The solution was heated to 100 C for 2 hours. The solution was cooled down and water was added. The solution was extracted with EtOAc and the combined organic layer was dried with MgSO4. The solution was filtered and the filtrate was concentrated. The residue was purified by CombiFlash with 20% EtOAc in Hexane as the eluent to afford the desirable product 3-[3-(3,8-Dimethyl-indolizin-1-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoic acid ethyl ester (20 mg, 26%) as a colorless foam.
Reaction SMILES: C[CH:2]1[C:7](=[O:8])[O:6][CH2:5][C:3]1=O.[NH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1>CCO>[N:9]1([C:3]2[CH2:5][O:6][C:7](=[O:8])[CH:2]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: C1CCNC1
Reactant: CC1C(=O)COC1=O
Solvent: CCO
Product: O=C1C=C(N2CCCC2)CO1
Temperature: 25 °C

Procedure:
A mixture of methyl tetronate (2.0 g, 17.5 mmol) and pyrrolidine (4.0 mL, 48 mmol) in EtOH (20 mL) was heated at reflux for 2 hours. The mixture was cooled to room temperature, and evaporated to dryness. The resulting solid was recrystallized with benzene/hexanes to give 4-pyrrolidin-1-ylfuran-2(5H)-one as white crystals. Yield: 2.60 g, 96%.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:18][N:17]=[C:16]([CH3:19])[C:15]=2[CH:20]=O)=[CH:10][CH:9]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:18][N:17]=[C:16]([CH3:19])[C:15]=2[CH:20]=[CH2:1])=[CH:10][CH:9]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=Cc1c(C)noc1-c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Potassium tert-butoxide (1.0M in THF, 13.53 mL, 13.53 mmol) was added to a suspension of methyltriphenylphosphonium bromide (4.8 g, 13.53 mmol) in THF (40 mL) at 0° C. 5-(4-Bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde (1.8 g, 6.76 mmol) in THF (40 mL) was then added and the reaction stirred at 0° C. for 30 minutes. The reaction was then submitted to standard aqueous workup and purified on silica gel to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[S:11]([NH:14][C:15]1[C:16]([F:25])=[CH:17][C:18]2[CH2:22][O:21][B:20]([OH:23])[C:19]=2[CH:24]=1)(=[O:13])=[O:12].[H][H]>O1CCOCC1.[Pd]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([S:11]([NH:14][C:15]2[C:16]([F:25])=[CH:17][C:18]3[CH2:22][O:21][B:20]([OH:23])[C:19]=3[CH:24]=2)(=[O:12])=[O:13])=[C:2]([F:1])[CH:7]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Nc2cc3c(cc2F)COB3O)c(F)c1
Agent: [Pd]
Solvent: C1COCCO1
Product: Nc1ccc(S(=O)(=O)Nc2cc3c(cc2F)COB3O)c(F)c1
Yield: 52.1 %

Procedure:
To a solution of 2-fluoro-N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-nitrobenzenesulfonamide (1.84 g, 4.97 mmol) in 50 mL of dioxane was added Pd/C (10 wt. % on activated carbon, 500 mg). The reaction mixture was hydrogenated at room temperature under 50 psi of hydrogen for 16 hours. After Pd/C was filtered through a pad of Celite, the solution was concentrated under reduced pressure to give a yellow residue. The crude residue was purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column) to give 0.88 g of the title compound as a white solid. MS calcd for (C13H11BF2N2O4S): 340.1. MS found (ESI negative): (M−H)−=339.1. 1H NMR (DMSO-d6) δ (ppm): 9.69 (s, 1H), 9.23 (bs, 1H), 7.58 (d, 1H), 7.10-7.21 (m, 3H), 6.67 (t, 1H), 4.83 (s, 2H).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:25])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[OH:24])[N:15]=[CH:14]1>O.CO>[OH:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16]1[N:15]=[CH:14][N:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]([OH:25])=[O:4])[CH:17]=1
Reactant: COC(=O)CCCCCCCn1cnc(-c2ccccc2O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCCCCCCn1cnc(-c2ccccc2O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
Add sodium hydroxide (1.32 g, 33 mmol) in water (20 mL) to a suspension of 8-[4-(2-hydroxyphenyl)imidazol-1-yl]octanoic acid methyl ester (2.60 g, 8 mmol) in methanol (50 mL) at 0° C. under nitrogen and warm the mixture to room temperature and stir for 8 hours. Remove the solvent under reduced pressure, dilute the residue with water (200 mL), cool to 0° C., and acidify to pH 1 with 1 N HCl. Collect the precipitate to provide 8-[4-(2-hydroxyphenyl)imidazol-1-yl]octanoic acid (1.70 g, 68%). APCI mass spectrum m/z 301 [C17H22N2O3−H]−.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:17][C@@H:18]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:19](O)=[O:20])[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])=[CH:4][CH:3]=1.[NH2:26][CH2:27][C:28]#[N:29]>>[C:27]([CH2:28][NH:29][C:19](=[O:20])[C@@H:18]([NH:17][C@@H:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[F:16])[CH2:22][CH:23]([CH3:24])[CH3:25])#[N:26]
Reactant: CC(C)C[C@H](N[C@@H](c1ccc(Br)cc1)c1ccc(F)cc1F)C(=O)O
Reactant: N#CCN
Product: CC(C)C[C@H](N[C@@H](c1ccc(Br)cc1)c1ccc(F)cc1F)C(=O)NCC#N

Procedure:
Using the procedure mentioned in the Step 4 of Example 19, (2S)-2-{(S)-[(4-bromophenyl)-(2,4-difluorophenyl)-methyl]-amino}-4-methyl-pentanoic acid was coupled with amino acetonitrile to give (2S)-2-{(S)-[(4-bromophenyl)-(2,4-difluorophenyl)-methyl]-amino}-4-methylpentanoic acid cyanomethylamide as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12](Br)=[C:13]([C:15]2[CH2:19][C:18]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[O:17][N:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)(=[O:39])[CH:37]=[CH2:38].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12](/[CH:38]=[CH:37]/[C:36]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:39])=[C:13]([C:15]2[CH2:19][C:18]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[O:17][N:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CC1(C(=O)OC(C)(C)C)CC(c2cc(OCc3ccccc3)ccc2Br)=NO1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CC1(C(=O)OC(C)(C)C)CC(c2cc(OCc3ccccc3)ccc2/C=C/C(=O)OCc2ccccc2)=NO1
Reaction time: 48 h
Yield: 22.6 %

Procedure:
A mixture of tert-butyl 3-(5-(benzyloxy)-2-bromophenyl)-5-(2-tert-butoxy-2-oxoethyl)-4,5-dihydro-1,2-oxazole-5-carboxylate (1.00 g), benzyl acrylate (1.484 g), palladium acetate (0.021 g), tris(2-methylphenyl)phosphine (0.084 g), triethylamine (0.765 mL), and DMF (10 mL) was stirred at 100 C for 2 days in an argon atmosphere. To the reaction mixture, water was added, followed by extraction with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (0.260 g).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:14]=[C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]2=[C:11]2[C:7]=1[C:8]([C:27](=[O:31])[C:28]([NH2:30])=[O:29])=[C:9]([CH3:26])[N:10]2[CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.[OH-].[Li+].Cl>O1CCCC1.O>[NH2:30][C:28](=[O:29])[C:27]([C:8]1[C:7]2[C:11](=[C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]3=[CH:14][C:6]=2[O:5][CH2:4][C:3]([OH:32])=[O:2])[N:10]([CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:9]=1[CH3:26])=[O:31]
Reactant: COC(=O)COc1cc2ccccc2c2c1c(C(=O)C(N)=O)c(C)n2CC1CCCCC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C(=O)C(N)=O)c2c(OCC(=O)O)cc3ccccc3c2n1CC1CCCCC1
Temperature: 25 °C
Reaction time: 28 h
Yield: 54.2 %

Procedure:
To a solution of 2-[[3-(2-amino-1,2-dioxoethyl)-1-cyclohexylmethyl-2-methyl-1H-benz[g]indol-4-yl]oxy]acetic acid methyl ester (0.042 g, 0.096 mmol) in 60% tetrahydrofuran/40% methanol (5 mL) was added 1 M lithium hydroxide solution (3 mL). The resulting mixture was stirred at room temperature for 28 h. The mixture was warmed briefly, diluted with water, and acidified with concentrated hydrochloric acid. The resulting yellow precipitate was collected via vacuum filtration and air-dried to provide 0.022 g (54%) of the title compound. 1H NMR (DMSO-d6) δ13.00 (bs, 1H), 8.22 (d, J=8.4 Hz, 1H), 7.85 (d, J=7.3 Hz, 1H), 7.73 (bs, 1H), 7.48 (t, J=7.0 Hz, 1H), 7.45 (bs, 1H), 7.39 (t, J=7.0 Hz, 1H), 6.91 (s, 1H), 4.76 (s, 2H), 4.45 (bs, 2H), 2.55 (s, 3H), 1.90 (bs, 1H), 1.60 (m, 5H), 1.10 (m, 5H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]12[C:15]2=[CH:16][C:17]3[O:21][CH2:20][O:19][C:18]=3[CH:22]=[C:14]2[O:13][CH2:12]1.CC1(C)COC2=CC3OC[C:33]4(C=3C=C12)[C:41]1[C:36](=[CH:37]C=C[CH:40]=1)[NH:35][C:34]4=O>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:40][CH:41]1[CH2:33][CH2:34][NH:35][CH2:37][CH2:36]1)[C:8](=[O:11])[C:7]12[C:15]2=[CH:16][C:17]3[O:21][CH2:20][O:19][C:18]=3[CH:22]=[C:14]2[O:13][CH2:12]1
Reactant: O=C1Nc2c(F)cccc2C12COc1cc3c(cc12)OCO3
Reactant: CC1(C)COc2cc3c(cc21)C1(CO3)C(=O)Nc2ccccc21
Product: O=C1N(CC2CCNCC2)c2c(F)cccc2C12COc1cc3c(cc12)OCO3

Procedure:
Following the procedure as described in EXAMPLES 10.18 and 10.19, and making non-critical variations using 7′-fluorospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, 7′-fluoro-1′-(piperidin-4-ylmethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one was obtained and used in the next step.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)=[CH:5][CH:4]=1.C([Li])CCC.[CH2:21]([O:28][C:29]1[CH:44]=[CH:43][C:42](I)=[CH:41][C:30]=1[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl>O1CCCC1.[Cl-].[Zn+2].[Cl-]>[CH2:21]([O:28][C:29]1[CH:44]=[CH:43][C:42]([C:11]2[O:10][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:14])[F:15])=[CH:8][CH:7]=3)=[CH:13][CH:12]=2)=[CH:41][C:30]=1[C:31]([O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:32])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: FC(F)(F)c1ccc(-c2ccco2)cc1
Reactant: O=C(OCc1ccccc1)c1cc(I)ccc1OCc1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)c1cc(-c2ccc(-c3ccc(C(F)(F)F)cc3)o2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
To a solution (25 ml) of 2-(4-trifluoromethylphenyl)furan (3.18 g) in tetrahydrofuran was added dropwise n-butyl lithium (1.6 M solution in hexane, 10.0 ml) under an argon atmosphere at −78° C. This mixed solution was heated to room temperature, and a solution (30 ml) of zinc chloride (2.25 g) in tetrahydrofuran was added. This mixture was stirred for 1 hr., and benzyl 2-benzyloxy-5-iodobenzoate (6.66 g) and tetrakis (triphenylphosphine)palladium (0.433 g) were added. This mixture was stirred overnight under an argon atmosphere, and poured into 0.5 M hydrochloric acid. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1, volume ratio) and recrystallized from hexane-ethyl acetate to give benzyl 2-benzyloxy-5-[5-(4-trifluoromethylphenyl)-2-furyl]benzoate (3.41 g, yield 43%) as pale-yellow needle crystals. melting point: 97–98° C.
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH:11](O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH:4]1[C:5]2[CH:11]=[CH:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:1]=[CH:2][CH:3]=1
Reactant: OC1CCCCc2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: C1=Cc2ccccc2CCC1
Yield: 90.1 %

Procedure:
To a solution of 1.6 g (10 mmol) of 6,7,8,9-Tetrahydro-5H-benzocyclohepten-5-ol in 75 mL of benzene was added p-toluene sulfonic acid (19 mg, 0.1 mmol). The mixture was refluxed overnight using Dean-Stark equipment. After removal of the solvent, the residue was repartitioned between ethyl acetate and water. The organic layers was washed with saturated sodium bicarbonate solution, water and brine and dried over sodium sulfate. Removal of the solvent gave 1.3 g (88%) of 6,7-Dihydro-5H-benzocycloheptene(compound 23,scheme 11).