Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11](I)=[CH:10][CH:9]=[C:8]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:7]=1[CH3:21])(=[O:3])[CH3:2].O1CCCC1.C(N(CC)CC)C.[C:34]([O:42][C:43]([C:45]([O:47][CH3:48])=[O:46])=[CH2:44])(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:34]([O:42]/[C:43](/[C:45]([O:47][CH3:48])=[O:46])=[CH:44]\[C:11]1[CH:10]=[CH:9][C:8]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:7]([CH3:21])[C:6]=1[CH2:5][O:4][C:1](=[O:3])[CH3:2])(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: C=C(OC(=O)c1ccccc1)C(=O)OC
Reactant: CC(=O)OCc1c(I)ccc(NC(=O)OC(C)(C)C)c1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)/C(=C/c1ccc(NC(=O)OC(C)(C)C)c(C)c1COC(C)=O)OC(=O)c1ccccc1
Yield: 95.5 %

Procedure:
3-(tert-butoxycarbonylamino)-6-iodo-2-methylbenzyl acetate (18.0 g, 44.4 mmol) in tetrahydrofuran (180.00 ml, 2197 mmol) was added triethylamine (24.76 ml, 178 mmol) followed by tetrabutylammonium chloride, hydrate (13.15 g, 44.4 mmol) and 3-methoxy-3-oxoprop-1-en-2-yl benzoate (11.91 g, 57.7 mmol). After introducing nitrogen atmosphere, palladium(II) acetate (0.898 g, 4.0 mmol) was added. The reaction mixture was refluxed for 3 h. The crude product was cooled and most of the solvent was removed. The crude product was diluted with ether (300 mL) and solids were removed by filtration. The solvent was evaporated and the crude product was purified by flash chromatography using 30% EtOAc in hexane to 50% EtOAc in hexane. The product was crystallized from a mixture of EtOAc-hexane to give a white powder of (Z)-1-(2-(acetoxymethyl)-4-(tert-butoxycarbonylamino)-3-methylphenyl)-3-methoxy-3-oxoprop-1-en-2-yl benzoate (20.5 g, 42.4 mmol, 95% yield). 1H NMR (500 MHz, CDCl3): in δ 8.08-8.06 (m, 2H), 7.75-7.74 (m, 2H), 7.60-7.58 (m, 1H), 7.49-7.44 (m, 3H), 5.25 (s, 2H), 3.85 (m, 3H), 2.24 (s, 3H), 2.07 (s, 3H), 1.52 (s, 9H); MS (ESI) 506 (M+H); Rf=2.61.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[F:16][C:17]([F:27])([F:26])[C:18]1[N:23]=[CH:22][C:21]([CH:24]=[CH2:25])=[CH:20][N:19]=1.[OH-].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:25][CH2:24][C:21]3[CH:22]=[N:23][C:18]([C:17]([F:26])([F:16])[F:27])=[N:19][CH:20]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: C=Cc1cnc(C(F)(F)F)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CN1CCc2c(c3cc(Cl)ccc3n2CCc2cnc(C(F)(F)F)nc2)C1

Procedure:
The title compound is prepared from a mixture of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole, 2-(trifluoromethyl)-5-vinylpyrimidine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([C:18]([OH:20])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1.Br[CH2:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].Cl>O1CCCC1.CCCCCC.C(OCC)C>[C:27]([O:26][C:24]([CH2:23][CH2:22][C:13]1([C:18]([OH:20])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: O=C(O)C1CCCC1
Reactant: CC(C)(C)OC(=O)CCBr
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)CCC1(C(=O)O)CCCC1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
50.4 ml of diisopropylamine were dissolved in 300 ml of absolute tetrahydrofuran under a nitrogen atmosphere, and the solution was cooled to -70° C. At this temperature, 200 ml of a 1.6 molar solution of butyllithium in n-hexane were slowly added dropwise to the solution. The reaction mixture was allowed to warm to 0° C., stirred at this temperature for 30 minutes and again cooled to -20° C. At this temperature, a solution of 16.2 ml of cyclopentanecarboxylic acid in 30 ml of absolute tetrahydrofuran was added dropwise. The reaction mixture was then stirred at room temperature for 2 hours. The mixture was subsequently cooled to -10° C. and slowly added dropwise to a solution, cooled to -10° C., of 35 g of tert-butyl 3-bromopropionate in 100 ml of tetrahydrofuran. The reaction mixture was stirred at room temperature for several hours. For working up, it was acidified with dilute aqueous hydrochloric acid solution and diluted with 375 ml of diethyl ether. The organic phase was separated, and the aqueous phase was extracted three more times with 100 ml of diethyl ether each time. The combined organic extracts were washed with aqueous sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure. The remaining residue was dissolved in 300 ml of diethyl ether. The solution was shaken six times with aqueous sodium bicarbonate solution and subsequently four times with 10% strength aqueous sodium carbonate solution. The combined sodium carbonate solutions were acidified while cooling in ice and extracted three times with 150 ml of ether each time. These ether extracts were combined with the ethereal solution, and the resulting solution was washed with aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting crude product was crystallized from ice-cold n-hexane. 7.7 g of pure 1-[2-(tert-butoxycarbonyl)ethyl]-1-cyclopentanecarboxylic acid were obtained with a melting point of 78° to 81° C.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].N1CCCCC1.C1C=CC=CC=1.[CH3:24][C:25]1[O:32][C:30](=[O:31])[CH:29]([C:33]([CH3:35])=[O:34])[C:27](=[O:28])[CH:26]=1>O>[OH:28][C:27]1[CH:26]=[C:25]([CH3:24])[O:32][C:30](=[O:31])[C:29]=1[C:33](=[O:34])[CH:35]=[CH:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: CC(=O)C1C(=O)C=C(C)OC1=O
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Solvent: C1CCNCC1
Solvent: c1ccccc1
Solvent: O
Product: Cc1cc(O)c(C(=O)C=Cc2ccc([N+](=O)[O-])cc2)c(=O)o1
Reaction time: 6 h
Yield: 81.6 %

Procedure:
4-Nitrobenzaldehyde (4.5 g, 29.7 mmol) and then a number of drops of piperidine were added to a benzene (40 ml) solution of dehydroacetic acid (5.00 g, 29.7 mmol) at room temperature, after which refluxing was performed for 6 hours while eliminating water by azeotropy. The majority of the benzene was distilled of directly, and then the distillation taken to dryness under reduced pressure. Following which, when recrystallization was performed from ethanol, 4-hydroxy-6-methyl-3-(4-nitrophenyl)acryloyl-2-pyrone (7.3 g, 82%) was obtained as orange crystals.
Reaction SMILES: [C:1]([C@@H:4]1[CH2:8][C@H:7]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH2:6][N:5]1[CH3:19])([OH:3])=O.FC(F)(F)C(O)=O.[N+:27]([C:30]1[CH:46]=[CH:45][C:33]([CH2:34][O:35][C:36]([N:38]2[CH2:44][CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)=[O:37])=[CH:32][CH:31]=1)([O-:29])=[O:28]>C(#N)C.C(N(CC)C(C)C)(C)C>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][S:9][C@@H:7]2[CH2:6][N:5]([CH3:19])[C@H:4]([C:1]([N:41]3[CH2:42][CH2:43][CH2:44][N:38]([C:36]([O:35][CH2:34][C:33]4[CH:45]=[CH:46][C:30]([N+:27]([O-:29])=[O:28])=[CH:31][CH:32]=4)=[O:37])[CH2:39][CH2:40]3)=[O:3])[CH2:8]2)=[CH:12][CH:13]=1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C)C2)cc1
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CCCNCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)CC3)N(C)C2)cc1
Temperature: 35 °C
Reaction time: 0.42 h
Yield: 72 %

Procedure:
A suspension of 1.8 g of (2S,4S)-2-carboxy-4-(4-methoxybenzylthio)-1-methylpyrrolidine [prepared as described in step (ii) above] and 1.26 g of N,N'-carbonyldiimidazole in 18 ml of dry acetonitrile was stirred at 35° C. for 25 minutes. A solution of 3.7 g of 1-(4-nitrobenzyloxycarbonyl)homopiperazine trifluoroacetate in 20 ml of dry acetonitrile and 2.0 ml of N,N-diisopropylethylamine were then simultaneously added dropwise, whilst ice-cooling, to the reaction mixture, and the resulting mixture was stirred at room temperature for 8 hours, after which it was allowed to stand overnight at room temperature. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was washed with an aqueous solution of sodium hydrogencarbonate, with a phosphate buffer solution (pH 6.86), with water and with an aqueous solution of sodium chloride, in that order. The ethyl acetate layer was then dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel (Merck Art 9385), using a 95:5 by volume mixture of acetonitrile and water, to give 2.5 g of the title compound.
Reaction SMILES: C(OC([NH:8][C@@H:9]([C:11](O)=[O:12])[CH3:10])=O)(C)(C)C.C(N(CC)CC)C.ClC(OCC)=O.[CH3:27][S:28][C:29]([CH3:36])([CH:31]([NH2:35])[CH:32]([CH3:34])[CH3:33])[CH3:30].Cl>O1CCCC1.C(OCC)(=O)C.C(O)CCC.O.C(O)(=O)C.CO>[CH3:27][S:28][C:29]([CH3:36])([CH:31]([NH:35][C:11](=[O:12])[C@@H:9]([CH3:10])[NH2:8])[CH:32]([CH3:34])[CH3:33])[CH3:30]
Reactant: CSC(C)(C)C(N)C(C)C
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCCCO
Solvent: C1CCOC1
Solvent: CO
Product: CSC(C)(C)C(NC(=O)[C@@H](C)N)C(C)C
Reaction time: 0.25 h

Procedure:
To a solution of 3.2 g (0.017 mole) N-t-butoxycarbonyl-D-alanine and 2.5 g (0.017 mole) triethylamine in 100 ml of tetrahydrofuran at -15° C. was added 1.63 ml. of ethyl chloroformate. After stirring for 15 minutes, 2.49 g (0.017 mole) 2-methylthio-2,4-dimethyl-3-aminopentane was added and the mixture stirred for one hour. The reaction mixture was diluted with ethyl acetate, washed with water, 5% aqueous citric acid (w/v), sodium bicarbonate solution and brine. The organic phase was evaporated to provide 6.0 g. of residue. This was taken up in 100 ml. methanol, 60 ml. of concentrated hydrochloric acid added and the mixture refluxed for one hour. After evaporation of methanol, the residue was taken up in water, washed with ether, the aqueous phase adjusted to pH 12 with sodium hydroxide and extracted with ethyl ether. Evaporation of the extracts gave 3.2 g. (87%) of product as a colorless oil Rf 0.56 (butanol/water/acetic acid-4:1:1 by volume.
Reaction SMILES: [N:1]([CH:4]([C:6]1[C:15]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=2)=[C:14]2[C:9]([CH:10]=[CH:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1)[CH3:5])=[N+]=[N-].CP(C)C.C(OCC)(=O)C>O1CCCC1.O>[F:22][C:20]1[CH:21]=[C:16]([C:15]2[C:6]([CH:4]([NH2:1])[CH3:5])=[CH:7][CH:8]=[C:9]3[C:14]=2[N:13]=[CH:12][CH:11]=[CH:10]3)[CH:17]=[C:18]([F:23])[CH:19]=1
Reactant: CC(N=[N+]=[N-])c1ccc2cccnc2c1-c1cc(F)cc(F)c1
Agent: CP(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(N)c1ccc2cccnc2c1-c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 7-(1-azidoethyl)-8-(3,5-difluorophenyl)quinoline (0.040 g, 0.13 mmol) in tetrahydrofuran (0.4 mL) and water (0.093 mL) was added 1.00 M of trimethylphosphine in tetrahydrofuran (0.155 mL, 0.155 mmol) at room temperature and the mixture was stirred at room temperature for 1 hour. To the mixture was added ethyl acetate and the mixture was extracted with 1 N HCl twice. The combined extracts were neutralized with solid sodium bicarbonate, and extracted with dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue showed two peaks by LCMS with same desired mass and was used directly in next step (30 mg, 81%). LCMS calculated for C17H15F2N2(M+H)+: m/z=285.120; found: 285.0.
Reaction SMILES: [C:1]([NH:8][C:9]1([C:13]([OH:15])=[O:14])[CH2:12][CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(Cl)CCl.N1C=CC=CC=1.[CH2:26](O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl.CN(C1C=CN=CC=1)C>[CH2:26]([O:14][C:13]([C:9]1([NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:12][CH2:11][CH2:10]1)=[O:15])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCC1
Reactant: OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NC1(C(=O)OCc2ccccc2)CCC1
Reaction time: 16 h

Procedure:
To a solution of 2.0 g N-Boc-1-aminocyclobutane carboxylic acid in 100 ml dichloromethane were added 2.1 g EDC, 1.4 g DMAP, 2.2 ml pyridine and 4.8 ml benzyl alcohol. After stirring for 16 h the mixture was diluted with dichloromethane and washed with 0.1 M HCl and saturated aqueous NaHCO3. The crude product obtained after evaporation of the solvent was purified by chromatography on silica using heptane/ethyl acetate 2/1 as eluent.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1.[N+:12]([O-])([OH:14])=[O:13]>C(O)(=O)C>[CH3:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc2c(c1)OCCO2
Solvent: CC(=O)O
Product: Cc1cc2c(cc1[N+](=O)[O-])OCCO2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.2 %

Procedure:
To a solution of 1 (20.0 g, 133.3 mmol) in acetic acid (135 mL) was added a solution of fuming HNO3 (10 mL) in acetic acid (50 mL) dropwise over 30 minutes. The mixture was stirred at ambient temperature for 10 minutes, then poured into a beaker containing ice to give a crystalline precipitate, which was collected by vacuum filtration and washed with water to afford the product (25.8 g, 99.2%) as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:28])[N:4]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25]Br)[C:20]=2[F:27])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[NH3:29]>CO>[NH2:29][CH2:25][C:21]1[C:20]([F:27])=[C:19]([CH:24]=[CH:23][CH:22]=1)[CH2:18][N:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])=[C:2]([Br:1])[C:3]1=[O:28]
Reactant: N
Reactant: O=c1c(Br)c(OCc2ccc(F)cc2F)ccn1Cc1cccc(CBr)c1F
Solvent: CO
Product: NCc1cccc(Cn2ccc(OCc3ccc(F)cc3F)c(Br)c2=O)c1F
Temperature: 80 °C
Yield: 60 %

Procedure:
A sealed tube containing a solution of 3-bromo-1-(3-bromomethyl-2-fluorobenzyl)-4-(2,4-difluorobenzyloxy)-1H-pyridin-2-one (0.24 g, 0.45 mmol) and NH3 (24 mL of a 7 N solution in MeOH, 168 mmol) was heated at 80° C. for 1 h. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. Purification by flash column chromatography (silica, eluent 99.5:0.5 to 96:4 methylene chloride/methanol) afforded a white solid (0.12 g, 60%): mp 160-163° C.; 1H NMR (300 MHz, CDCl3) δ 7.46-7.45 (m, 1H), 7.44-7.35 (m, 2H), 7.34-7.26 (m, 1H), 7.15-7.05 (m, 1H), 6.95-6.80 (m, 2H), 6.11 (d, J=9 Hz, 1H), 5.21 (s, 2H), 5.19 (s, 2H), 3.90 (s, 2H). ESHRMS m/z 453.0442 (M+H C20H17BrF3N2O2 requires 453.0420).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:16]=[CH:15][C:10]3[NH:11][C:12](=[O:14])[NH:13][C:9]=3[CH:8]=2)[CH2:3][CH2:2]1.[C:17]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19][CH:18]=1.CCN(CC)CC.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>CS(C)=O.C(OCC)(=O)C>[C:17]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:18]=[CH:19][C:20]([CH2:23][N:1]2[CH2:2][CH2:3][CH:4]([C:7]3[CH:16]=[CH:15][C:10]4[NH:11][C:12](=[O:14])[NH:13][C:9]=4[CH:8]=3)[CH2:5][CH2:6]2)=[CH:21][CH:22]=1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Reactant: O=c1[nH]c2ccc(C3CCNCC3)cc2[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=c1[nH]c2ccc(C3CCN(Cc4ccc(-c5ccccc5)cc4)CC3)cc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
A representative procedure for the synthesis of the piperidinyl aldehydes is the following. To a solution of compound 5 (0.15 g, 0.45 mmol) and biphenyl-4-carbaldehyde a (0.1 g, 0.55 mmol) in DMSO (2 mL) at 0° C. was added Et3N (0.13 mL, 0.97 mmol). After being stirred for 0.5 h at room temperature, NaBH(OAc)3 (0.11 g, 0.53 mmol) was added, and the mixture was stirred for 6 h. To the reaction mixture was added sat. NaHCO3 solution (10 mL), and the mixture was stirred for 15 min, followed by the addition of ethyl acetate (30 mL). The organic layer was separated and washed with sat. NaHCO3 and brine, and dried over Na2SO4 and evaporated. The light yellow solid was crystallized from diethyl ether to obtain the title compound 5a. Yield: 51%, off-white solid, mp>260° C. IR (KBr, cm−1) 3429 (CONH), 3055 (Ar—H), 2966 (Alph-H), 1703 (CO), 1620, 1518, 1422 (C—C), 1226 (C—N), 1145 (C-0); 1H NMR (500 MHz, DMSO d6) δ 1.62-1.71 (m, 4H, 2CH2), 2.04 (m, 2H, CH2), 2.48 (m, 1H, CH), 2.92 (m, 2H, CH2), 3.51 (s, 2H, NCH2), 6.77-6.81 (m, 3H, 3Ar—H), 7.32 (m, 1H, Ar—H), 7.40-7.45 (m, 4H, 4Ar—H), 7.59-7.64 (m, 4H, 4Ar—H), 10.43 (br. s, 1H, NH), 10.48 (br. s, 1H, NH), 13C NMR (125.7 MHz, DMSO d6) δ 33.64 (CH2), 41.86 (CH), 53.66 (CH2), 59.45 (NCH2), 106.91 (Ar—C), 108.42 (Ar—C), 118.99 (Ar—C), 126.56 (Ar—C), 126.66 (Ar—C), 127.42 (Ar—C), 127.98 (Ar—C), 129.03 (Ar—C), 129.06 (Ar—C), 129.63 (Ar—C), 138.92 (Ar—C), 140.11 (Ar—C), 155.59 (C═O). Anal. Calcd for C25H25N3O: C, 78.30; H, 6.57; N, 10.96%. Found: C, 78.22; H, 6.63; N, 10.86%.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8](F)[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5].[NH2:12][C@@H:13]([C:21]([NH2:23])=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN(C(C)C)C(C)C.O>CS(C)=O.CCOC(C)=O>[Br:1][C:2]1[C:3]([C:4]#[N:5])=[CH:6][C:7]([F:11])=[C:8]([NH:12][C@H:13]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]([NH2:23])=[O:22])[CH:9]=1
Reactant: NC(=O)[C@H](N)Cc1ccccc1
Reactant: N#Cc1cc(F)c(F)cc1Br
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1cc(F)c(N[C@H](Cc2ccccc2)C(N)=O)cc1Br
Yield: 99.9 %

Procedure:
A solution of 2-bromo-4,5-difluorobenzonitrile (218 mg, 1.00 mmol), D-phenylalanine amide (185 mg, 1.12 mmol) and DIEA (0.600 mL, 3.45 mmol) in DMSO (3 mL) was stirred at 120 C for 18 h. Water and EtOAc were added. The organic phase was separated, washed with water, dried over Na2SO4, concentrated in vacuo to give (R)-2-(5-bromo-4-cyano-2-fluorophenylamino)-3-phenylpropanamide (362 mg).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]([OH:10])=O)[C:5]2[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=2[N:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.[NH2:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][C:30]=1[Cl:31])[CH2:27][C:26]1([C:35](=[O:36])[NH:34][C:33](=[O:37])[N:32]1[CH3:38])[CH2:25]2.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:31][C:30]1[CH:29]=[C:28]2[C:24]([CH2:25][C:26]3([C:35](=[O:36])[NH:34][C:33](=[O:37])[N:32]3[CH3:38])[CH2:27]2)=[CH:23][C:22]=1[NH:21][C:8](=[O:10])[CH2:7][N:6]1[C:5]2[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=2[N:3]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[C:2]1=[O:1]
Reactant: O=C(O)Cn1c(=O)n(-c2ccccn2)c2ccccc21
Reactant: CN1C(=O)NC(=O)C12Cc1cc(N)c(Cl)cc1C2
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1C(=O)NC(=O)C12Cc1cc(Cl)c(NC(=O)Cn3c(=O)n(-c4ccccn4)c4ccccc43)cc1C2

Procedure:
A mixture of (2-oxo-3-pyridin-2-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetic acid (57 mg, 0.211 mmol, described in Intermediate 4), 5′-amino-6′-chloro-3-methyl-spiro[imidazolidine-4,2′-indane]-2,5-dione, enantiomer B (51 mg, 0.192 mmol, described in Intermediate 48), PyBOP (120 mg, 0.230 mmol), and N,N-diisopropylethylamine (0.033 mL, 0.192 mmol) was stirred in DMF (1 mL) at 50° C. for 18 h. The crude mixture was purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. Lyophilization provided the title compound as a white solid. MS: m/z=517 (M+1). HRMS: m/z=517.1383; calculated m/z=517.1386 for C26H22ClN6O4.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O.Cl>[CH2:22]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCCCCCCCCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCOc1ccc(C=O)cc1
Temperature: 105 °C
Reaction time: 21.5 h

Procedure:
4-Hydroxybenzaldehyde (8.00 g, 6.55×10−2 mol), 1-bromododecane (16.50 ml, 6.87×10−2 mol), K2CO3 (9.05 g, 6.55×10−2 mol) and dry DMF (100 ml) were added to a two-neck round-bottom flask. The reaction mixture was stirred at 105° C. for 21.5 h under Ar. After cooling, the solution was diluted with H2O, 2M HCl and extracted three times with CH2Cl2. The combined organic layers were washed with aqueous NaHCO3, H2O and dried over Na2SO4. The product was chromatographed on silica gel with 1:1 hexane:CH2Cl2 as the eluent. Yield=19.02 g (100% based on 8.00 g of 4-hydroxybenzaldehyde). 1H NMR (250 MHz, CDCl3): δ 9.88 (s, 1H, —CHO), 7.83 (d, 2H, J=8.8 Hz, Ph), 6.99 (d, 2H, J=8.7 Hz, Ph), 4.04 (t, 2H, J=6.5 Hz, OCH2), 1.82 (quint, 2H, J=6.9 Hz, OCH2CH2), 1.40-1.54 (m, 2H, —CH2—), 1.16-1.40 (m, 16H, —CH2—), 0.88 (t, 3H, J=6.5 Hz, —CH3). CI MS m/z: 291.232 ((M+H)+) (calcd 291.232).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[NH:9][CH:10]=[C:11]([CH3:20])[C:12]=1[CH2:13][CH2:14][C:15]([N:17]([CH3:19])[CH3:18])=O>O1CCCC1.[OH-].[Na+]>[CH3:7][C:8]1[NH:9][CH:10]=[C:11]([CH3:20])[C:12]=1[CH2:13][CH2:14][CH2:15][N:17]([CH3:19])[CH3:18]
Reactant: Cc1c[nH]c(C)c1CCC(=O)N(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c[nH]c(C)c1CCCN(C)C
Temperature: 80 °C
Reaction time: 1 h
Yield: 75.4 %

Procedure:
To the suspension of lithium aluminum hydride (2.3 g, 60 mmol) in tetrahydrofuran (50 mL) was added a solution of 3-(2,4-dimethyl-1H-pyrrol-3-yl)-N,N-dimethyl-propionamide (9.81 g, 50 mmol) in THF (50 mL) dropwise. The reaction mixture was stirred at 80° C. for 1 hour and cooled with ice bath. Ice cube was added into the reaction mixture slowly until no more gas generated. A few drops of 2 N sodium hydroxide was added and the reaction mixture was stirred at room temperature for 30 minutes, extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated to give 6.8 g (75%) of [3-(2,4-dimethyl-1H-pyrrol-3-yl)-propyl]-dimethylamine as an orange oil which was used without further purification.